Visible Light Photocatalyzed Redox-Neutral Organic Reactions and Synthesis of Novel Metal-Organic

Springer ThesesRecognizing Outstanding PhD Research

Visible Light PhotocatalyzedRedox-Neutral Organic Reactions andSynthesis of NovelMetal-Organic Frameworks

Basudev Sahoo

Springer Theses

Recognizing Outstanding PhD Research

Aims and Scope

The series ldquoSpringer Thesesrdquo brings together a selection of the very best PhDtheses from around the world and across the physical sciences Nominated andendorsed by two recognized specialists each published volume has been selectedfor its scientific excellence and the high impact of its contents for the pertinent fieldof research For greater accessibility to non-specialists the published versionsinclude an extended introduction as well as a foreword by the studentrsquos supervisorexplaining the special relevance of the work for the field As a whole the series willprovide a valuable resource both for newcomers to the research fields describedand for other scientists seeking detailed background information on specialquestions Finally it provides an accredited documentation of the valuablecontributions made by todayrsquos younger generation of scientists

Theses are accepted into the series by invited nomination onlyand must fulfill all of the following criteria

bull They must be written in good Englishbull The topic should fall within the confines of Chemistry Physics Earth Sciences

Engineering and related interdisciplinary fields such as Materials NanoscienceChemical Engineering Complex Systems and Biophysics

bull The work reported in the thesis must represent a significant scientific advancebull If the thesis includes previously published material permission to reproduce this

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nominationbull Each thesis should include a foreword by the supervisor outlining the signifi-

cance of its contentbull The theses should have a clearly defined structure including an introduction

accessible to scientists not expert in that particular field

More information about this series at httpwwwspringercomseries8790

Basudev Sahoo

Visible Light PhotocatalyzedRedox-Neutral OrganicReactions and Synthesisof Novel Metal-OrganicFrameworksDoctoral Thesis accepted byUniversity of Muumlnster Germany

123

AuthorDr Basudev SahooAngewandte HomogenkatalyseLIKAT RostockRostockGermany

SupervisorProf Frank GloriusOrganisch Chemisches Institut WestfaumllischeWilhelms-Universitaumlt Muumlnster

MuumlnsterGermany

ISSN 2190-5053 ISSN 2190-5061 (electronic)Springer ThesesISBN 978-3-319-48349-8 ISBN 978-3-319-48350-4 (eBook)DOI 101007978-3-319-48350-4

Library of Congress Control Number 2016955421

copy Springer International Publishing AG 2017This work is subject to copyright All rights are reserved by the Publisher whether the whole or partof the material is concerned specifically the rights of translation reprinting reuse of illustrationsrecitation broadcasting reproduction on microfilms or in any other physical way and transmissionor information storage and retrieval electronic adaptation computer software or by similar or dissimilarmethodology now known or hereafter developedThe use of general descriptive names registered names trademarks service marks etc in thispublication does not imply even in the absence of a specific statement that such names are exempt fromthe relevant protective laws and regulations and therefore free for general useThe publisher the authors and the editors are safe to assume that the advice and information in thisbook are believed to be true and accurate at the date of publication Neither the publisher nor theauthors or the editors give a warranty express or implied with respect to the material contained herein orfor any errors or omissions that may have been made

Printed on acid-free paper

This Springer imprint is published by Springer NatureThe registered company is Springer International Publishing AGThe registered company address is Gewerbestrasse 11 6330 Cham Switzerland

To my beloved parents brothers andsisters-in-law

Supervisorrsquos Foreword

In Dr Basudev Sahoorsquos thesis work conceptually novel and synthetically valuablemethods were developed using visible light photocatalysis This emerging field hasbecome an indispensable tool for organic synthesis and employs environmentallybenign and abundant visible light in the presence of a photosensitizer as anattractive alternative to harmful UV light in photo-mediated reactions During hisdoctoral studies Dr Sahoo merged the concept of gold catalysis with visible lightphotocatalysis in a dual catalytic fashion demonstrating the compatibility of thesetwo important and challenging catalytic modes for the first time This novel dualcatalytic system allowed for the development of mild protocols for the difunc-tionalization of non-activated alkenes and has since been expanded upon andemployed in further reactions by us and other groups Moreover his knowledge andexpertise in photocatalysis helped him to develop a novel trifluoromethylationmethod which combined radical addition chemistry with a polar rearrangement tosynthesize valuable fluorinated compounds The incorporation of fluorinated groupsonto organic molecules is attracting increasing attention as these compounds featureheavily in pharmaceuticals agrochemicals and material research Sincenitrogen-based heterocycles make a large class of bioactive compounds a mildmethod for the synthesis of indolizine heterocycles was also developed using aphotochemical approach which has been seldom explored for this class of com-pound During this study the product of the reaction was found to mediate its ownformation under photochemical conditions This rarely observed phenomenonobviated the need for an external photocatalyst and could inspire the futuredevelopment of autocatalytic photochemical reactions In addition to his work onphotocatalysis he has also been engaged in synthetic work focused on the prepa-ration of highly porous metal-organic framework (MOF) materials The scientific

vii

contributions made by Dr Sahoo presented in this thesis have significantlyaccelerated the development of the fields he has worked on and have inspired manynew projects in my group

Muumlnster Germany Prof Frank GloriusApril 2016

viii Supervisorrsquos Foreword

Abstract

Visible light-mediated photocatalysis has emerged as an environmental friendlyelegant approach for streamlined organic synthesis Recently many conceptuallynovel and challenging advancements have been accomplished in this growingresearch area The content of this thesis is about the developments of novelmethodologies for synthesis of valuable organic compounds using visible lightphotocatalysis as toolbox and also synthesis of novel metal-organic frameworks(MOFs) as characteristic porous materials

In initial phase of my PhD work a novel dual catalytic system combining goldwith visible light photoredox catalysis has been developed for selective intra- andintermolecular heteroarylation of non-activated alkenes under mild reactionconditions (Scheme 11) In this work the compatibility of gold catalysis withphotoredox catalysis was demonstrated for the first time Furthermore thismethodology benefits from mild reaction conditions and readily available lightsources and avoids the use of strong external oxidants in contrast to previousmethods

The second part of my PhD work was concentrated on the visible lightphotoredox-catalyzed semipinacol rearrangement for trifluoromethylation ofcycloalkanols (Scheme 12) This protocol gives access to a novel class of densely

+

regioselectivestereoretentive room temperature

no stoichiometric oxidant

N2

R2

Nu

R1

Nu

R2 R3

PhotoredoxCatalysis

GoldCatalysis

IAr

or

R3

Scheme 11 Dual gold and visible light photoredox-catalyzed heteroarylation of non-activatedalkenes

ix

functionalized trifluoromethylated cycloalkanones with all carbon quaternary cen-ters Interestingly these reactions proceed via radicalndashpolar crossover followed by12-alkyl migration To the best of our knowledge this methodology represents thefirst report of 12-alkyl migration in visible light-mediated photoredox catalysis

In third part of my PhD work we have developed a novel methodology for thesynthesis of valuable polycyclic indolizines under visible light-mediated reactionconditions (Scheme 13) To our delight these reactions do not need any externalphotosensitizing agents in contrast to conventional photocatalysis but do needvisible light irradiation Various analytical and laboratory experiments indicate thatindolizine products are responsible in some way for their own formation althoughfurther insightful investigations required for complete elucidation of mechanismFurthermore gratifyingly this indolizine product can promote other photocatalyzedreactions in lieu of standard photocatalyst

In final phase of my PhD work a triarylborane linker with three carboxylic acidanchoring groups (44prime4Prime-boranetriyltris(35-dimethylbenzoic acid) (H3TPB)) hasbeen successfully developed and incorporated into the metal-organic frameworksalong with a linear BDC co-linker to give mixed MOFs DUT-6 (Boron)(Scheme 14) This new DUT-6 (Boron) showed fluorescent activity and exhibited

O O

NR3R3

NBr

EWGN

EWG

R1R1

R2

ExternalPhotocatalyst

+ No external photocatalyst + Product can promote other photoredox reactions

Scheme 13 Visible light photocatalytic synthesis of polycyclic indolizines

( )mY

R( )m

YR

CF3

XO

HO X

( )n( )nPhotoredox

Catalysis

Semipinacol Rearrangement

S

CF3OTf

Scheme 12 Visible light photoredox-catalyzed trifluoromethylation via semipinacolrearrangement

x Abstract

higher isosteric heat of adsorption for CO2 in contrast to the DUT-6 However thismicroporous DUT-6 (Boron) represents the first example of a highly porousnon-interpenetrated MOF containing a triarylborane linker

B

OHO

O

OH

HO

O

I

Br

DUT-6 (Boron) (non-interpenetrated)

H3TPB

COOH

Zn4O6+

Scheme 14 Synthesis of triarylborane linker (H3TPB) and incorporation into DUT-6

Abstract xi

Parts of this thesis have been published in the following journal articles

6 ldquoExternal Photocatalyst-Free Visible Light-Mediated Synthesis of IndolizinesrdquoBasudev Sahoodagger Matthew N Hopkinsondagger Frank Glorius Angew Chem IntEd 2015 54 15545-15549 (daggerThese authors contributed equally to this work)

5 ldquoVisible-Light Photoredox-Catalyzed Semipinacol-Type RearrangementTrifluoro-methylationRing Expansion via a Radical-Polar MechanismrdquoBasudev Sahoo Jun-Long Li Frank Glorius Angew Chem Int Ed 2015 5411577ndash11580

4 ldquoCopolymerisation at work the first example of a highly porous MOF com-prising a triarylborane-based linkerrdquo Stella Heltendagger Basudev Sahoodagger

Volodymyr Bon Irena Senkovska Stefan Kaskel Frank GloriusCrystEngComm 2015 17 307ndash312 (daggerThese authors contributed equally)

3 ldquoDual Photoredox and Gold Catalysis Intermolecular MulticomponentOxyarylation of Alkenesrdquo Matthew N Hopkinson Basudev Sahoo FrankGlorius Adv Synth Catal 2014 356 2794ndash2800

2 ldquoDual Catalysis sees the Light Combining Photoredox with Organo- Acid andTransition Metal Catalysisrdquo Matthew N Hopkinsondagger Basudev Sahoodagger

Jun-Long Li Frank Glorius Chem Eur J 2014 20 3874ndash3886 (daggerTheseauthors contributed equally)

1 ldquoCombining Gold and Photoredox Catalysis Visible Light-Mediated Oxy- andAminoarylation of Alkenesrdquo Basudev Sahoo Matthew N Hopkinson FrankGlorius J Am Chem Soc 2013 135 5505ndash5508

xiii

Acknowledgements

Firstly I would like to express my utmost and sincere gratitude to my supervisorProf Dr Frank Glorius who provided me an opportunity to work within hisesteemed research group I am very thankful to him for his very kind guidance andvaluable suggestions or advices that contributed to the fulfillment of this work Hispositive and forgiving attitude easy availability to students constructive criticismand constant encouragement have not only led to completion of this work but alsomade a profound impression on me

I would like to extend my sincere gratitude to Prof Dr Bart Jan Ravoo and ProfDr Bernhard Wuumlnsch being my mentors and for their kind advices and assistancethroughout this work

I would like to thank Prof Dr Stefan Kaskel and his co-workers especiallyStella Helten Philipp Muumlller Dr Volodymyr Bon and Dr Irena Senkovska fromTechnical University of Dresden for their helpful contributions in MOF projects

I thank International NRW Graduate School of Chemistry Muumlnster (GSC-MS)for providing me financial support I would also like to thank Dr Hubert Koller andFrau Christel Marx for their continuous assistance

I would like to express my sincere thanks to Dr Klaus Bergander Karin Voszligand Ingo Gutowski from the NMR department Dr Matthias Letzel and JensPaweletz from the Mass Spectrometry department and Dr Constantin G Daniliucfrom crystallographic department for their kind advices and assistance I would liketo thank Linda Stegeman and Prof Dr Christian Strassert for photophysicalmeasurements I would like to thank the glass-blowing workshop the mechanicalworkshop and the electronic workshop for maintaining and developing laboratoryequipments and infrastructure I extend my thanks to the administrative office(Geshaumlftzimmer) Dr Christian Sarter Dr Michael Seppi and Guido Blanqueacute fortheir kind help throughout my PhD

I would like to thank all the members of AK Glorius and AK Garciacutea the alumni(Dr Claudia Lohre Dr Andreas Notzon Dr Thomas Droumlge Dr Slawomir UrbanDr Joanna Wencel-Delord Dr Mohan Padmanaban Dr Duo-Sheng Wang andDr Nuria Ortega Hernandez Dr Mamta Suri Dr Nathalie Wurz Dr Christoph

xv

Grohmann Dr Dennis C Koumlster Dr Nadine Kuhl Dr Corinna Nimphius Dr NilsSchroumlder Dr Zhuangzhi Shi Dr Honggen Wang Dr Dan-Tam Daniel TangDr Michael Schedler Dr Karl Collins Dr Christian Richter Dr Bernhard BeiringDr Francisco de Azambuja Jonas Boumlrgel Dr Meacutelissa Boultadakis-Arapinis DrDa-Gang Yu Dr Dongbing Zhao Dr Jun-Long Li Dr Angeacutelique Ferry Dr OlgaGarcia Manchentildeo Dr Heinrich Richter Dr Renate Rohlmann Dr StephanBeckendorf Dr Soumlren Asmus and Mercedes Zurro de la Fuente) and the presentmembers (Jędrzej Wysocki Dr Matthew Hopkinson Daniel Paul Dr Lisa CandishJohannes Ernst Mirco Fleige R Aleyda Garza Sanchez Tobias Gensh Dr AdriaacutenGoacutemez Suaacuterez Steffen Greszligies Dr Chang Guo Roman Honeker DanielJanszligen-Muumlller Dr Ju Hyun Kim Andreas Lerchen Fabian Lied Dr Wei Li DrQing-Quan Lu Theresa Olyschlaumlger Lena Martina Rakers Andreas RuumlhlingChristoph Schlepphorst Michael Teders Adrian Tlahuext Aca Suhelen VaacutesquezCeacutespedes Dr Xiaoming Wang Mario Wiesenfeldt Dr Kathryn Chepiga) for a veryhelpful and friendly behavior throughout my PhD making a great stimulatingatmosphere to work as well as the great chitchats during ldquoKaffee-Pausesrdquo I wouldlike to thank Dr Holger Frank Svenja Roumlwer Cornelia Weitkamp and KarinGottschalk for their very kind assistance

A special mention and a very big thanks to Dr Matthew Hopkinson Dr AdriaacutenGoacutemez Suaacuterez Dr Kathryn Chepiga and Adrian Tlahuext Aca for their patiencefor suffering the reading of this thesis and making valuable suggestions of itscompletion

I thank all of my Indian friends in Muumlnster Shyamal Avik Indranil RajeshTushar Sagar Aditya Sandeep Rizwan Indra da Suman da Sandip da Anup daRamananda da Soumya da Debu da Naveen A bhaiya Naveen B bhaiya Pracheedi Suresh da Sachin da Sunit da Ramesh da Rajorshi da Pritam da Chinmoy daNagma di Abhishek Sougata Narayan Soham Shuvendu Sandeep SrikrishnaProjesh Saikat Bishwarup for creating a fantastic living environment in MuumlnsterI thank Pradip da Shankar da Deo Prakash da Somnath Priyabrata Anup ArghyaAtanu Sujoy Hari Chayan Bijit Bablu Mrinmoy Sovanjit Mohakash DilipBiswajit Bani Tapas Arpita Suman Biplab Panda Barun Tarapada Milan andother friends for their constant support creating a joyful and happier environmentthroughout the ups and downs during very important years of my life

I would like to extend my sincere thanks to all of my teachers and professorsI am especially grateful to Ghorai sir Munna mam Kamal babu Soma mam Dilipbabu Samir babu Sakti babu Rabin babu Prakash babu Nanigopal babu andGokul babu

At last but not least I express the sound gratitude from my deep heart to mybeloved parents (Mr Sunadhar Sahoo and Mrs Renuka Sahoo) elder brothers(Sukdev and Joydev) my cousin sister (Malati) and my sisters-in-law (Minu andRina) for their love support and constant encouragementmdashboth mentallyand physicallymdashbeing a very essential part of my life and for their emotionaland inspirational support throughout my lifemdashhow far and how long the distancemay be

xvi Acknowledgements

Contents

1 Introduction to Photocatalysis 111 Historical Background 112 Classifications of Photocatalyst 213 Characteristics of Homogeneous Photocatalysts 314 Visible Light Photocatalysis in Organic Synthesis 5

141 Photoredox Catalyzed Organic Transformationsvia Electron Transfer 5

142 Photocatalyzed Organic Transformations via TripletEnergy Transfer 18

15 Summary 19References 20

2 Dual Gold and Visible Light Photoredox-CatalyzedHeteroarylations of Non-activated Alkenes 2521 Introduction 25

211 General Properties of Homogeneous Gold Catalysts 25212 Gold-Catalyzed Organic Transformations 27213 Aryldiazonium Salts Synthesis and Reactivity 35214 Diaryliodonium Salts Synthesis and Reactivity 36

22 Results and Discussion 37221 Inspiration 37222 Intramolecular Oxy- and Aminoarylation of Alkenes 39223 Intermolecular Oxyarylation of Alkenes 44224 Mechanistic Studies on Heteroarylations of Alkenes 49

3 Visible Light Photoredox Catalyzed Trifluoromethylation-RingExpansion via Semipinacol Rearrangement 5931 Introduction 59

311 General Features of Fluorinated Compounds 59312 Importances of Fluorinated Compounds 59

xvii

313 Radical-Polar Crossover Process 61314 Trifluoromethylation of Alkenes 61315 Semipinacol Rearrangements 67

32 Results and Discussion 69321 Inspiration 69322 Preliminary Experiments and Optimization Studies 70323 Substrate Scope and Limitations 72324 Follow up Transformations of Products 75325 Mechanistic Studies 76

4 Transition Metal Free Visible Light-Mediated Synthesisof Polycyclic Indolizines 8141 Introduction 81

411 General Properties of Indolizines 81412 Importances of Indolizines 82413 Synthesis of Indolizines 82414 Functionalization of Indolizines via Transition Metal

Catalysis 8742 Results and Discussion 89

421 Inspiration 89422 Reaction Design 90423 Preliminary Experiments and Optimization Studies 90424 Scope and Limitations 93425 Structural Manipulations of the Indolizine Product 97426 Mechanistic Investigations 98

5 Synthesis and Characterizations of Novel Metal-OrganicFrameworks (MOFs) 10951 Intoduction 109

511 Historical Background 109512 General Characteristic Features of Metal-Organic

Frameworks (MOFs) 109513 Applications of Metal-Organic Frameworks (MOFs) 112514 Synthesis of Metal-Organic Frameworks (MOFs) 113

52 Results and Discussion 116521 Inspiration 116522 Synthesis of Novel Metal-Organic

Frameworks (MOFs) 116523 Structural Analysis of Novel Metal-Organic Frameworks

(MOFs) 118

xviii Contents

524 Dye Absorption Studies of Novel Metal-OrganicFrameworks (MOFs) 122

525 Photophysical Studies of Novel Metal-OrganicFrameworks (MOFs) 123

6 Experimental Section 12761 General Considerations 12762 Synthesis of Photocatalysts 13363 Oxy- and Aminoarylations of Alkenes 138

631 Synthesis of Gold Catalysts 138632 Synthesis of Alkene Substrates 139633 Synthesis of Aryldiazonium Salts 145634 Synthesis of Diaryliodonium Salts 145635 Synthesis and Characterization

of Oxy- and Aminoarylated Products 14664 Visible Light Photoredox Catalyzed Trifluoromethylation-Ring

Expansion via Semipinacol Rearrangement 163641 Synthesis of (Oxa)Cycloalkanol Substrates 163642 Synthesis and Characterization of Trifluoromethylated

Cycloalkanone Compounds 175643 Synthetic Manipulations of Trifluoromethylated

Cycloalkanone Product 187644 Mechanistic Investigations 190

65 Transition Metal Free Visible Light Mediated Synthesisof Polycyclic Indolizines 195651 Synthesis of Substrates 195652 Photocatalytic Synthesis of Indolizines 220653 Structural Manipulations of Indolizine 235654 Mechanistic Experiments 237

66 Synthesis and Characterizations of Novel Metal-OrganicFrameworks (MOFs) 244661 Synthesis of 44prime4Prime-Boranetriyltris(35-Dimethylbenzoic

Acid) (H3TPB) 245662 Synthesis of (S)-2-(4-Benzyl-2-Oxooxazolidin-3-yl)

Terephthalic Acid 247663 Synthesis of DUT-6 (Boron) (234) 248664 Synthesis of Chiral DUT-6 (Boron) (235) 249665 Single Crystal X-Ray Analysis of DUT-6 (Boron) 249666 Determination of BET Area 250667 CO2 Physisorption Isotherms for DUT-6 250

References 251

Curriculum Vitae 255

Contents xix

Abbreviations

Ac AcetyliAm Iso-amylnBu Normal-butylnBuLi Normal-butyllithiumtBu Tertiary-butyltBuLi Tertiary-butyllithiumBn BenzylBz BenzoylCCDC Cambridge Crystallographic Data CentreCFL Compact fluorescent lampCp CyclopentadienylCy Cyclohexyld Doubletdap 29-dianisyl-110-phenanthrolineDBU 18-diazabycyclo[540]-undec-7-eneDCE 12-dichloroethaneDCM DichloromethaneDEF NN-diethylformamideDFT Density functional theoryDIPA DiisopropylamineDIPEA diisopropylethylamineDMA NN-dimethylacetamideDMAP NN-dimethylaminopyridineDMF NN-dimethylformamideDMSO DimethylsulphoxideD2O Deuterated waterdr Diastereoisomeric ratioEI Electron impact mass spectrometryESI-MS Electrospray ionization mass spectrometryEWG Electron-withdrawing group

xxi

EDG Electron-donating groupEt EthylEt2O Diethyl etherEtOAc EthylacetateEtOH Ethanolee Enantiomeric excessequiv EquivalentGC Gas chromatographyHRMS High-resolution mass spectrometryHz Hertzh Hour(s)IR Infrared spectroscopyIRMOF Isoreticular metal-organic frameworkJ NMR coupling constantLA Lewis acidLiCl Lithium chlorideLED Light-emitting diodeM Molarm MultipletMg Magnesiummg Milligrammin Minute(s)m MetamCPBA Meta-chloroperoxybenzoic acidmL MillilitermicroL MicroliterMS Molecular sievesMsOH Methanesulphonic acidMTBE Methyl-tert-butyl etherMe MethylMeOH MethanolNBS N-bromosuccinimideNMR Nuclear magnetic resonanceNTf2 Ditrifluoromethanesulfonyl amineo OrthoOTf TrifluomethanesulfonateOTs p-toluenesulfonatep ParaPG Protective groupPh PhenylPiv PivlolylP(tBu)3 tri-tert-butylphosphinePEt3 TriethylphosphinePPh3 TriphenylphosphinePMe3 Trimethylphosphine

xxii Abbreviations

iPr IsopropylnPr Normal-propylppb Parts per billionppm Parts per millionPy PyridylPC Photocatalystq QuartetQst Isosteric heat of adsorptionRF Retention factor in chromatographyRt Retention timert Room temperatures SingletSET Single electron transferSHE Standard hydrogen electrodeSCE Standard calomel electrodeSN Nucleophilic substitutionTBHP Tert-Butyl hydroperoxideTHF TetrahydrofuranTFA Trifluoroacetic acidTsOH p-toluenesulfonic acidTMS TrimethylsilylTLC Thin layer chromatographyTMEDA Tetramethylethylenediaminet TripletUV UltravioletV VoltVIS Visibleχ Electronegativity

Abbreviations xxiii

Chapter 1Introduction to Photocatalysis

11 Historical Background

On the arid lands there will spring up industrial colonies without smoke and withoutsmokestacks forests of glass tubes will extend over the plains and glass buildings will riseeverywhere inside of these will take place the photochemical processes that hitherto havebeen the guarded secret of the plants but that will have been mastered by human industrywhich will know how to make them bear even more abundant fruit than nature for nature isnot in a hurry and mankind is And if in a distinct future the supply of coal becomescompletely exhausted civilization will not be checked by that for life and civilization willcontinue as long as the sun shines [1]

mdash G Ciamician (1912)

The year 2012 was the centenary of the famous article ldquoThe photochemistry ofthe futurerdquo [1] In this inspiring article the Italian photochemist G Ciamicianpresented his great vision of the future aspects of solar energy imagining a chemicalindustry where chemicals could be manufactured in a similar way to photosynthesisas used by plants in the presence of sunlight [1] Although sunlight is considered tobe a clean safe inexpensive and abundant natural energy source the vast majorityof organic compounds do not absorb photons in the visible region of the solarspectrum but rather absorb in the UV range [1ndash5] This limitation has narrowed thescope of organic compounds able to be activated under visible light irradiationrestricting the progress of photochemical synthesis in industry until the recentdevelopment of energy-efficient UV photo-reactors Photochemical synthesis (egphoto-induced pericyclic reactions) is considered to be much cleaner and sustain-able in contrast to conventional synthetic routes According to the principles ofgreen chemistry this is assumed as a green method since direct activation of thesubstrate by light reduces or eliminates the use of additional hazardous reagents forconventional activations [4 6 7] However since UV photons possess considerablyhigh energy (in the order of the CndashC bond cleavage energy) [8] reactions con-ducted under UV light irradiation often lead to decomposition when the molecules

copy Springer International Publishing AG 2017B Sahoo Visible Light Photocatalyzed Redox-Neutral Organic Reactionsand Synthesis of Novel Metal-Organic Frameworks Springer ThesesDOI 101007978-3-319-48350-4_1

1

contain strained ring systems or relatively weak bonds Although there are inter-esting reports on multistep syntheses of some complex molecules using photo-chemical key steps interest in the photochemical synthesis of molecules hasremained confined to a small part of the scientific community [9 10]

In order to attenuate these limitations photosensitizing compounds which arecapable of absorbing photons in the visible spectrum and subsequently passing onthe energy to organic compounds have exhibited great utility in visible lightinduced organic synthesis Moreover conducting reactions in the presence of cat-alytic photosensitizers under visible light irradiation from commercially availablehousehold light sources may obviate the expense inherent to the special set up ofUV photo-reactors as well as avoiding the safety precautions needed for UV lightmediated reactions Over the last few decades attention has been focused on the useof visible light photosensitizing compounds to convert solar energy into electricityin solar cells [11ndash16] and water splitting for the production of chemical fuels [1718] However visible light active photocatalysts did not receive the wide attentionof synthetic organic chemists beyond few reports from Kellogg [19 20] Pac [21]Deronzier [22 23] Willner [24 25] and Tanaka [26] In 2008 MacMillan [27]Yoon [28] and Stephenson [29] disclosed elegant and groundbreaking reports onhighly efficient visible light photoredox catalysis reinventing this field in organicsynthesis

12 Classifications of Photocatalyst

Photocatalysts can be classified into two different major classes based on the cat-alytic nature of the materials (a) homogeneous photocatalysts and (b) heteroge-neous photocatalysts Organometallic polypyridyl metal complexes (eg [Ru(bpy)3]Cl2∙6H2O) [30 31] and organic dyes (eg eosin Y) [32ndash35] belong to the homo-geneous group of photocatalysts while inorganic semiconductors comprising ofmetal oxides [36ndash43] or sulfides [39] (eg TiO2 [36 37 39 40] ZnO [40]PbBiO2Br [39] CeO2 [38] and CdS [39]) polyoxometalates [44] and graphiticcarbon nitride (g-C3N4) polymers [45 46] and photoactive metal-organic frame-works (MOFs) [47ndash50] make up the heterogeneous group Organometallic poly-pyridyl transition metal complexes and organic dyes are the most common and mostefficient photocatalysts and are nowadays widely applied in organic synthesis [4 531 33ndash35 51ndash65] In some cases polypyridyl metal complexes or organic dyeshave been immobilized on photo-active solid supports (eg TiO2) [39] orphoto-inactive solid supports (eg silica particle) [66] or solvated in ionic liquids[67] for recyclability

2 1 Introduction to Photocatalysis

13 Characteristics of Homogeneous Photocatalysts

Due to their rich photophysical and electrochemical properties organometallicpolypyridyl transition metal complexes and organic dyes exhibit high photocat-alytic activity under visible light irradiation [11 30 38ndash74] The photo-activity ofthe photocatalysts (organometallic metal complexes or organic dyes) can be visu-alized in a Jablonski diagram (Fig 11) [75 76] Absorbing a photon the photo-catalyst PC(S0) in its singlet ground state is excited to one of the higher energyvibrational levels of the first singlet excited state PC(S1

n) which then relaxes to thelowest vibrational level of the first singlet excited state PC(S1

0) via internal con-version (vibrational relaxation) This singlet excited state PC(S1

0) can regeneratethe singlet ground state PC(S0) via a spin-allowed radiative pathway (fluorescencekf) or a non-radiative pathway (knr) Another deactivation pathway of PC(S1

0)involves its conversion to the lowest energy triplet excited state PC(T1

0) via suc-cessive fast intersystem crossing (ISC) (spin-orbital coupling) and internal con-version (vibrational relaxation) Since the transition of the triplet excited state to thesinglet ground state is spin forbidden the triplet excited state PC(T1

0) is reasonablylong lived (eg τ = 1100 ns for Ru bpyeth THORN32thorn ) This triplet excited state PC(T1

0) canundergo radiative deactivation (phosphorescence kp) or non-radiative deactivation(knr) to regenerate the singlet ground state PC(S0) completing the cycle

Photo-excited singlet states of organic dyes having heavy atoms (Br or I) andorganometallic complexes of heavy metals (eg Cu Ru Ir Au) undergo rapidintersystem crossing to the lower energy triplet excited states In the presence ofsubstrates possessing quenching ability the triplet excited state PC(T1

0) canthen be quenched to the singlet ground state PC(S0) diminishing the phosphores-cence intensity [76] In photocatalysis the photo-excited catalyst can be quenchedby the substrates via outer-sphere single electron transfer (SET) or energy transfer(ET) processes leading to productive downstream reactivity (Fig 12) [5]

x

PC(S0)

PC(S10)

kahigh ν kp

kf

kic

knrkalow ν

kic

knr

PC(T10)

PC(S1n)

kiscPC(T1

n)

Spinforbidden

Spinallowed

E00 = h(cλem)

Fig 11 Jablonski diagram PC photocatalyst ka rate of absorption kic rate of internal conver-sion kisc rate of intersystem crosssing knr rate of non-radiative deactivation kf fluorescencekp phosphorescence E00 = energy of emission from the triplet state

13 Characteristics of Homogeneous Photocatalysts 3

In an outer sphere electron transfer process the photo-excited triplet state PC(T1) can be quenched by two different mechanisms reductive quenching andoxidative quenching (Fig 12a) [5 30 31 52 60 77] In a reductive quenchingprocess the excited photocatalyst in the PC(T1) state accepts an electron from anelectron-rich substrate (RQ) affording the reduced photocatalyst (PCminus) and aradical-cation (RQbull+) The reduced photocatalyst (PCminus) then donates electron to anelectron-deficient species in a subsequent step to regenerate the ground state pho-tocatalyst (PC) The radical-cation (RQbull+) releases radical or cationic intermediatewhich can engage in a subsequent step In a similar manner in oxidative quenchingthe photocatalyst in the PC(T1) state donates an electron to an electron-deficientsubstrate (OQ) delivering the oxidized photocatalyst (PC+) and a radical-anion(OQbullminus) The oxidized photocatalyst (PC+) then accepts an electron from anelectron-rich species present in the reaction mixture to regenerate the ground statephotocatalyst (PC) and the radical-anion releases a radical upon mesolysis capableof reacting via a number of different pathways in subsequent steps This processlargely depends on the redox potentials of the species involved

In an energy transfer process the photo-excited triplet state PC(T1) interactswith the substrate which has an accessible low energy triplet state (comparable tothe photo-excited triplet state energy Fig 12b) [5] In this interaction triplet-tripletenergy transfer results in a photo-excited triplet state of the substrate and regen-erates the ground state of the photocatalyst The photo-excited substrate can thenengage in photochemical reactions Stern-Volmer luminescence quenching exper-iments are generally performed to find out the actual quencher from a set ofreagents present in the reaction mixture [31]

OQ

e-

PC+

hνvis

RQ

e-

Oxidative Quenching

Cycle

Reductive Quenching

Cycle

PC(S1)

PCminus

PC(S0)

PC(T1)

ISC

Electron Transfer (a)

PC(T1)

PC(S1)

PC(S0)

EnergyTransfer

ISC

Q(T1)

Q(S0)

Q(S1)

hνvis

Energy Transfer(b)

Fig 12 Visible light photocatalysis a photoredox catalytic cycle via single electron transfer(SET) b photocatalytic cycle via energy transfer (ET) PC photocatalyst Q quencher (egsubstrate) RQ reductive quencher OQ oxidative quencher ISC intersystem crossing S0 singletground state S1 first singlet excited state and T1 first triplet excited state

In visible light photocatalysis coordinately saturated organometallic-basedphotocatalysts are chemically and conformationally stable under the reaction con-ditions and do not generally bind to the substrates As a result no other types ofactivations are generally observed except outer sphere electron transfer or energytransfer Furthermore the long-lived excited states of the photocatalysts providesufficient time for effective interactions with the substrates in their proximity Inaddition an appropriate redox potential window of the photoredox catalyst is highlydesirable for the reaction design

In the photoredox catalyst toolbox well investigated organometallic photocat-alysts are either homoleptic (one type of ligand) or heteroleptic (two or moredifferent types of ligands) polypyridyl metal complexes The most commonhomoleptic photocatalysts are [Ru(bpy)3](PF6)2 (bpy = 22prime-bipyridine) and fac-Ir(ppy)3 (ppy = 2-phenylpyridine) [31] On the other hand the most commonheteroleptic photocatalysts are [Ir(ppy)2(dtbbpy)](PF6) (dtbbpy = 44prime-di-tert-butyl-22prime-bipyridine) and [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (dF(CF3)ppy = 2-(24-difluorophenyl)-5-trifluoromethylpyridine) [31] For organometallic photocat-alysts various sets of redox potentials can be accessed by tuning the electronicproperties of the ligands and metal ions and thus changing the HOMO-LUMOenergy gap for metal to ligand charge transfer (MLCT) [30] Electron-rich ligands(eg ppy) increases the reductive power of the ground state metal complex whileelectron-poor ligands (eg bpz bpz = 22ʹ-bipyrazine) increases the oxidativepower of the metal complex in ground state [30] The redox potential of the excitedphotoredox catalyst cannot be directly determined These values are instead cal-culated with the help of cyclic voltammetry and spectroscopic data following theRehm-Weller equation [78]

A list of organometallic photocatalysts and organic dyes is shown in Table 11The photoelectronic properties of selected photoredox catalysts are outlined inTable 12 A list of selected reductive and oxidative quenchers is given inTable 13

14 Visible Light Photocatalysis in Organic Synthesis

141 Photoredox Catalyzed Organic Transformationsvia Electron Transfer

Since photo-excited photoredox catalysts have higher oxidizing and reducingabilities compared to their ground states giving access to two different sets of redoxpotentials with reasonably long life-times (Table 12) over the last three decadesand in particular over last seven years there has been tremendous progress in the

field of photoredox catalysis in organic synthesis [4 5 31 35 51ndash59 62 64] Froma redox point of view visible light photoredox-catalyzed reactions can be classifiedinto three different categories redox-neutral net oxidative and net reductive reac-tions [31] In redox-neutral processes both the oxidation and reduction steps areinvolved in the same reaction mechanism maintaining overall redox neutrality Innet oxidative reactions the products possess higher oxidation levels than thestarting materials while in net reductive processes the products are in lower oxi-dation levels compared to the starting materials In this chapter only redox-neutralvisible light photo-redox-catalyzed processes are discussed in three sectionsalthough many interesting organic transformations have been reported based on netredox processes over the last decades [31]

Table 11 List of selected homoleptic and heteroleptic organometallic photocatalysts and organicdyes

N

NIr

fac-Ir(ppy)3

NN

N

Ru

[Ru(bpy)3](PF6)2

(PF6)2

N

NN

N

NN

N

NN

Ru

[Ru(bpz)3](PF6)2

(PF6)2

N

Ar

CuNN

Ar

Cl

[Cu(dap)2]ClAr = p-methoxyphenyl

Homoleptic Complexes

Organic Dyes

O

COOH

HO OR

R R

R

R = H FluorosceinR = Br Eosin Y

NClO4

Acridinium Dye

O

COONa

HO OI

I I

I

Rose Bengal

Cl

ClCl

Cl S

N

Cl

Methylene Blue

NMe2Me2N

N

Ir

[IrdF(CF3)ppy2(dtbbpy)]PF6

N

Ir

[Ir(ppy)2(dtbbpy)]PF6

FF

F

FF3C

CF3 (PF6)

(PF6)

Heteroleptic Complexes

Tab

le12

Photoelectronicprop

ertiesof

selected

photoredox

catalysts[31

34]

Photocatalyst

E12(M

+

M)

(V)

E12(M

Mminus)(V

)E12(M

+M

)a

(V)

E12(MM

minus)a

(V)

Absorptionλ a

bs

(nm)

Emission

λ em

(nm)

Excited-statelifetim

e(τns)

Rubp

yeth

THORN 32thorn

minus081

+077

+129

minus133

452

615

1100

Rubp

zeth

THORN 32thorn

minus026

+145

+186

minus080

443

591

740

fac-Ir(ppy

) 3minus173

+031

+077

minus219

375

494b

1900

Ir(ppy

) 2(dtbbp

y)+

minus096

+066

+121

minus151

ndash58

155

7

Ir(dF(CF 3)

ppy)

2(dtbb

py)+

minus089

+121

+169

minus137

380

470

2300

Cudap

ethTHORN 2

thornminus143

ndash+0

62

ndashndash

670c

270

Eosin

Yminus111

+083

+078

minus106

539

ndash24

000

Acridinium

perchlorate

_+2

06

_minus057

430

__

a Redox

potentialmeasuredagainstSC

Eb M

easuredin

EtOHM

eOH

(11)

c Measuredin

DCM

14 Visible Light Photocatalysis in Organic Synthesis 7

1411 Redox-Neutral Photoredox Catalysis Single Catalysis

Oxidative quenching cycle

Since photoredox catalysts are single electron transfer agents mostphotoredox-catalyzed reactions involve radical or radical-ionic intermediates duringthe process and many of these reactions proceed via a key step Radical-PolarCrossover1 In an oxidative quenching cycle the photo-excited photocatalyst behavesas a strong reductant being itself oxidized In 1984 Deronzier et al [23] disclosed anoverall redox-neutral visible light-mediated Pschorr synthesis of phenanthrenederivatives 1 in the presence of [Ru(bpy)3](BF4)2 (5 mol) This method obviatesthe formation of the undesired byproduct 2 under direct photolysis (gt360 nm) andbenefits from milder reaction conditions compared to previously reported electro-chemical processes [79] or thermal methods (Scheme 11) [23 80 81]

In a mechanistic hypothesis single electron reduction of aryldiazonium sub-strates 3 by the photo-excited [Ru(bpy)3]

2+ generates the higher-valent [Ru(bpy)3]

3+ and an aryl radical 4 which undergoes homoaromatic substitution(HAS) to deliver another cyclized radical intermediate 5 In the next step oxidationof this radical intermediate 5 to the cationic intermediate 6 by [Ru(bpy)3]

3+regenerating the photocatalyst [Ru(bpy)3]

2+ via a radical-polar crossover gives riseto the phenanthrene derivative 1 upon deprotonation (Scheme 12) [23]

After a long time in 2012 Koumlnig et al [82] reported an elegant method for thearylation of heteroarenes with aryldiazonium salts in the presence of the organic dyeeosin Y and green light (Scheme 13) This reaction proceeds via oxidativequenching of photo-excited eosin Y with aryldiazonium salts 7 delivering arylradicals 8 and oxidized eosin Y Aryl radical addition to the electron-rich

Table 13 List of selected reductive and oxidative quenchers [31 34 52 73 127 128]

Reductive Quencher (RQ)

NO O

O O

DIPEA oxalate

O

S

SR

xanthate

Oxidative Quencher (OQ)

OSO OO

O SO

OO

perdisulfate

N N

viologens

N2

phenyldiazonium

etc

etcSCF3

5-(trifluoromethyl)-dibenzothiophenium

BF3K

potassiumtrifluoroborate

1Radical-Polar Crossover process will be described in brief in Chap 3

heteroarene 9 followed by radical-polar crossover with the oxidized eosin Y leadsto cationic intermediates 10 which afford the final products 11 upon aromatizingdeprotonation (Scheme 13) [82]

This type of photoredox catalysis has been applied to generate other radicalssuch as the trifluoromethyl (bullCF3) and cyanomethyl (bullCH2CN) radical In 2011MacMillan et al [83] developed an efficient protocol for the trifluoromethylation ofa wide range of arenes and heteroarenes including some highly important drug

CO2H

CO2HHN

O

[Ru(bpy)3](BF4)2 (5 mol)

CH3CNvisible light

R1

CO2H

R1 R1

R1quantitative yields

1 2R1 = H Br OMe

R1 = H

R1 = BrR1 = OMe

20

10

8020

8080

direct photolysis

CH3CN

N2BF4

Deronzier and co-workers (1984)

3

1

Scheme 11 Pschorr synthesis of phenanthrene derivatives under photoredox catalysis and directphotolysis [23]

[Ru(bpy)3]3+[Ru(bpy)3]2+

[Ru(bpy)3]2+

PhotoredoxCatalysishνvis

SET

CO2H

N2

CO2H

HCO2H

H

CO2H

- H+

1

3

CO2H

R1N2BF4

CO2H

CO2HN

+ H2O

CO2HHN

ON

2

directphotolysis(gt360 nm)

OxidativeQuenching 4

5

6

- H+

Scheme 12 Proposed mechanism for the Pschorr synthesis of phenanthrene derivatives underphotoredox catalysis and direct photolysis [23]

molecules highlighting the practical applicability of this mild method using [Ru(phen)3]Cl2 (1ndash2 mol phen = 110-phenanthroline) and relatively inexpensiveCF3SO2Cl (1ndash4 equiv) as the bullCF3 source and K2HPO4 as base (Scheme 14)

In this line of research alkene motifs have also become successful partners withother π-congeners In late 2013 Greaney et al [84] reported a visible lightphotoredox-catalyzed three component oxy- and aminoarylation of activatedalkenes using strongly reducing fac-Ir(ppy)3 (5 mol) Zn(OAc)2 (20 mol) as anadditive and air and moisture stable diaryliodonium salts (20 equiv) as aryl

XX

Eosin Y (1 mol)

DMSO 20 degCgreen LEDs

X = O S NBoc R1 R2 = EWG EDG

N2BF4

R2

R1 R1

R21140-86

Eosin Y

Eosin Yhν

vis

SET

N2

OxidativeQuenching

Eosin Y

N2

O

H

O

H

O

N2

chain

-H+

deprotonation

Koumlnig and co-workers (2012)

75-10 equiv

91 equiv

7 8

9

10118

7

Scheme 13 Transition metal free arylation of heteroarenes by visible light photoredox catalysisand proposed reaction mechanism [82]

A B = O S N X Y Z = O N R = EWG EDG 70-94

[Ru(phen)3]Cl2 (1-2 mol)CF3SO2Cl (1-4 equiv)

K2HPO4 CH3CN 23 degC26 W CFL

B

A

Y

Z

X

R

B

A

Y

Z

X

R

CF3

MacMillan and co-workers(2011)

Scheme 14 Visible light photoredox-catalyzed trifluoromethylation of (hetero)arenes [83]

precursors under visible light irradiation from a 30 W CFL (Scheme 15a) Earlierin 2014 Koumlnig et al [85] also reported the same visible light photoredox-catalyzedaminoarylation of activated alkenes (20 equiv) using a different set of reactionconditions [Ru(bpy)3]Cl2 (05 mol) with a lower loading of the aryldiazoniumsalt (10 equiv) as aryl precursors under visible light irradiation from blue LEDs(Scheme 15a) In both cases this redox neutral Meerwein-type reaction proceedsvia oxidative quenching and radical-polar crossover similar to the mechanismdepicted in Scheme 42 in Chap 4 for oxytrifluoromethylation The same reactivitywas extended to the trifluoromethyl (bullCF3) radical by Koike et al [86] and thecyanomethyl (bullCH2CN) radical by Lei et al [87] (Scheme 44a in Chap 4 andScheme 15b respectively) In addition to these reports many impressive organictransformations based on this concept have enriched the literature [88ndash91]

Another important class of redox-neutral photoredox reactions proceeding via anoxidative quenching cycle is atom transfer radical addition (ATRA) to alkenes (seeChap 3 Sect 3143) [92]

Reductive quenching cycle

In a reductive quenching cycle the photo-excited photoredox catalyst acts as astrong oxidant being itself reduced Over the last 7 years there has been a sig-nificant amount of development of redox-neutral reactions which proceed via areductive quenching cycle In 2010 Stephenson and co-workers described thedirect functionalization of heteroarenes with activated alkyl bromides in the

NHCOR6

R4

R1

N2BF4IAr BF4

R4 R4

Ir(ppy)3 (5 mol)Zn(OAc)2 (20 mol)

R5OH or R6CN rt 30 W CFL

[Ru(bpy)3]Cl2 (05 mol)

R6CNH2O 20 degC blue LEDs

R2R3

OR3NHPh

R1R1

Ir(ppy)3 (05-15 mol)NaHCO3 (20 equiv)

R3OH or PhNH2 rt24 W CFL or blue LEDs

R2R2

Br CN

22-95

12

10 equiv 20 equiv

(05 equiv)

(a) Greaney and co-workers (2013) amp Koumlnig and co-workers (2014)

(b) Lei and co-workers (2014)

R1 R4 = EWG EDG R2 R3 = H alkyl aryl EWG R5 R6 = H alkyl

R1 = EWG EDG R2 = H aryl R3 = alkyl

CN

OR5NHCOR6

R4

R1

R2R3

R1

R2R3

10 equiv

25-83 20-92

Koumlnig and co-workersGreaney and co-workers(20 equiv)

7

Scheme 15 a Oxy- and aminoarylations of styrenes by visible light photoredox catalysis [8485] b visible light photoredox-catalyzed oxy- and aminocyanomethylation of styrenes [87]

presence of a combination of [Ru(bpy)3]Cl2 as photocatalyst a triaryl aminequencher and blue LEDs under mild conditions (Scheme 16) [93] In theirmechanistic proposal the photo-excited [Ru(bpy)3]

2+ is quenched to thereductant [Ru(bpy)3]

+ by the electron rich triaryl amine 13 The reduction ofdiethyl 2-bromomalonate (14) to the C-centered radical 15 by the reductant[Ru(bpy)3]

+ regenerates [Ru(bpy)3]2+ In the next step selective radical addition to

heteroarenes results in a stabilized benzylic radical 16 which further oxidizes togive the benzylic cation 17 via radical-polar crossover In the final step aromatizingdeprotonation of benzylic cation 17 delivers the functionalized heteroarene 18(Scheme 16) [93]

In 2012 Zheng et al [94] reported an overall redox-neutral elegant method forthe visible light photoredox-catalyzed [2+3] cycloaddition reaction betweencyclopropyl amines and activated alkenes in the presence of [Ru(bpz)3](PF6)2(2 mol) to afford cyclopentyl amines (19) (Scheme 17) Mechanistically in areductive quenching cycle photo-excited [Ru(bpz)3]

2+ is quenched by the N-arylprotected cyclopropyl amine generating the N-centered radical-cation 20 with apendant cyclopropyl ring and the reduced species [Ru(bpz)3]

+ Ring opening of thecyclopropyl ring of the N-centered radical-cation 20 leads to an intermediate 21which undergoes [2+3] cycloaddition to generate theN-centered radical-cation 22witha pendant cyclopentyl ring Single electron reduction of this radical-cation 22 results infinal product 19 and regenerates the photocatalyst [Ru(bpz)3]

2+ (Scheme 17) [94]

X XCO2EtBr

CO2Et [Ru(bpy)3]Cl2 (1 mol)

DMF rt blue LEDs

NPh

OMeMeO

20 equiv

CO2Et

R1R1

49-92

hνvis

SET

ReductiveQuenching

[Ru(bpy)3]2+ [Ru(bpy)3]+

[Ru(bpy)3]2+

PMPNPh

PMP PMPNPh

PMP

CO2EtBr

CO2Et

NBr

N CO2Et

CO2EtH

N CO2Et

CO2EtH[O]

-H+

N CO2Et

CO2Et

R1 = EWG EDG X = O NR

10 equiv

Stephenson and co-workers (2010)

13

14

15

16 17

18

Scheme 16 Visible light photoredox-catalyzed direct functionalization of heteroarenes withdiethyl 2-bromomalonate and the mechanistic hypothesis [93]

1412 Photoredox Catalysis Dual Catalysis (Transition Metal)

The concept of combining two privileged catalytic activation modes together topromote a single transformation which is not possible in the presence of eithercatalyst alone has recently captured the attention of synthetic chemists to developnovel transformations [95ndash97] Over the last few years a significant effort has beenmade to combine visible light photoredox catalysis with other catalytic modes suchas organo- transition metal and acid catalysis to develop novel dual catalyticsystems [60 61 63 65] In a dual catalytic system the photoredox catalyst interactswith either the substrate or the other catalyst or both to generate substrate-derivedreactive intermediates or active forms of the other catalyst via electron transfer

Over the last few decades the exploration of transition metal catalysis empha-sizing on understanding the reactivity modes and exploiting these in an enormousnumber of applications in organic synthesis for both academic and industrial pur-poses has been acknowledged by the award of three times Nobel Prizes (in 20012005 and 2010) to the pioneering leaders of this esteemed field of research Variousinnovative and novel concepts have been developed over the last few decades One ofthe novel concepts employed in transition metal catalysis is the cooperative effect oftwo or more catalysts together to promote unprecedented transformations [96 97]

hνvis

SET

ReductiveQuenching

[Ru(bpz)3]2+ [Ru(bpz)3]+

[Ru(bpz)3]2+

NH

Ph

NH

Ph

NH

Ph

NH

Ph

HN

Ar

HN

N ( )n

Ar

N ( )n

R2

R1R1

R2H

R1R1

[Ru(bpz)3](PF6)2 (2 mol)

degassed CH3NO2 rt

13 W CFLAr

50 equiv 71-87dr 11 to 21

28-77dr 31 to gt251

R1 = EWG EDG

R2 = Alkyl R2 = H Aryl n = 12

R3 R3

Zheng and coworkers (2012)

20 21

22

19

Scheme 17 Visible light photoredox-catalyzed [2+3] cycloaddition between N-aryl cyclopropylamines and activated alkenes and a possible mechanistic proposal [94]

In 2007 Osawa and co-workers successfully developed the firstpalladiumphotoredox dual catalytic system to promote the Sonogashira coupling ofaryl bromides and terminal alkynes (Scheme 18) [98] The combination of thephotocatalyst [Ru(bpy)3](PF6)2 and visible light enhanced the efficiency of thiscopper-free Sonogashira coupling [98] However the role of the photocatalyst wasnot clear

Later in 2011 Sanford and co-workers described another efficientpalladiumphotoredox dual catalytic system for the directed ortho-selective CndashHfunctionalization of unactivated arenes combining a palladium(IIIV) catalytic cycleand visible light photoredox catalytic cycle under mild conditions (Scheme 19)[99] Inspired by the seminal report from Deronzier et al [23] they anticipated thatthe aryl radical generated from aryldiazonium salts under photoredox conditionsmight be oxidizing enough to promote palladium-catalyzed CndashH arylation ofnon-activated arenes under mild reaction conditions [99] When they treated aryl-diazonium salts 7 with non-activated arenes 23 in the presence of palladium acetate(10 mol) and [Ru(bpy)3]Cl2∙6H2O (25 mol) under visible light irradiationfrom a 26 W CFL the desired CndashH arylation products 24 were obtained in good tomoderate yields (Scheme 19)

[Pd(MeCN)2]Cl2 (4 mol)P(tBu)3 (4 mol)

[Ru(bpy)3](PF6)2 8 mol)

NEt3 DMF rt150 W Xe lamp

+

R1 = EWG EDGR2 = Ph SiMe3 80-99

R2BrR1 R1

R2

Osawa and co-workers (2007)

Scheme 18 Dual palladiumphotoredox-catalyzed Sonogashira coupling [98]

DG

N2BF4

DG

R2

DG = Directing Group R1 = H EDG R2 = H EWG EDG

R1

Pd(OAc)2 (10 mol)[Ru(bpy)3]Cl26H2O (25 mol)

MeOH rt 26 W CFL44-87

2310 equiv

R1

R2

Sanford and co-workers (2011)

I

R2

Ar BF4

Pd(NO3)2 (10 mol)[Ir(ppy)2(dtbbpy)](PF6) (5 mol)

7 (40 equiv) 12 (20 equiv)

24

DG

2310 equiv

R1

Scheme 19 Dual palladium and visible light photoredox-catalyzed CndashH arylation ofnon-activated arenes [99 100]

In order to expand the scope of the arylating reagent Sanford and co-workerssuccessfully employed air and moisture stable diaryliodonium salts 12 in thepresence of the stronger reducing photocatalyst [Ir(ppy)2(dtbbpy)](PF6) (5 mol)and Pd(NO3)2 (10 mol) to carry out the CndashH arylation reaction of non-activatedarenes (Scheme 19) [100]

A mechanistic hypothesis for this reaction is depicted in Scheme 110 In aninitial step single electron reduction of the aryldiazonium salts 7 by thephoto-excited [Ru(bpy)3]

2+ generates highly oxidizing nucleophilic aryl radicals 8and the oxidized photocatalyst [Ru(bpy)3]

3+ In a concurrent catalytic cycle afive-membered palladacycle 25 is obtained via CndashH activation At this stage theformed aryl radical would possibly oxidize Pd(II) in the palladacycle 25 to give aPd(III) intermediate 26 which is further oxidized to a Pd(IV) intermediate 27 by[Ru(bpy)3]

3+ regenerating the photocatalyst [Ru(bpy)3]2+ In the final step

reductive elimination of both coupling fragments from the high valent palladium(IV) center results in the CndashH arylated product 24 and regenerates the palladium(II)catalyst In a high level theoretical calculation Maestro Derat and co-workersshowed that the last two steps may occur in the reverse order where reductiveelimination from a Pd(III) intermediate precedes single electron oxidation of a Pd(I)catalyst to Pd(II) [101]

As a continuation of their interest in dual catalysis in 2012 Sanford andco-workers successfully employed a copperphotoredox dual catalytic system forthe perfluoroalkylation of arylboronic acids (28) with perfluoroalkyl iodides asinexpensive perfluoroalkyl sources under mild reaction conditions (60 degC no base

PC

PalladiumCatalysis

PhotoredoxCatalysis

hνvis

C-Hactivation

reductiveelimination

SET

oxidativearylation

N2 or ArI

NPdIILn

NPdIIILn

Ar

NPdIVLn

Ar

PdIILn

NAr

24

N22H+

26

25

27

Ar

Ar N2

Ar I Ar

PC

7

12

8

H

Scheme 110 Mechanistic hypothesis for the dual palladium and visible lightphotoredox-catalyzed CndashH arylation of non-activated arenes [99 101]

or acid) to give access to perfluoroalkyl-substituted arenes 29 (Scheme 111) [102]A tentative mechanism for this trifluoromethylation of arylboronic acids is shown inScheme 112 [102] In an initial step the photo-excited [Ru(bpy)3]

2+ is quenchedby the copper(I) catalyst in a reductive quenching pathway generating a copper(II)intermediate and [Ru(bpy)3]

+ Single electron transfer from [Ru(bpy)3]+ to CF3I

produces a bullCF3 radical and regenerates [Ru(bpy)3]2+ This bullCF3 radical then oxi-

dizes the copper(II) intermediate to the copper(III) intermediate 30 bearing the CF3group Finally transmetalation of an aryl group followed by reductive eliminationfurnishes the trifluoromethylated products 29 and regenerates the copper catalyst

Very recently dual catalysis combining transition metal catalysis (Ni [103ndash108]Rh [109] Ru [110] Pd [111ndash113] and Cu [114ndash116]) and visible light photoredoxcatalysis has extensively been explored Some of them also belong to net redoxproceses

BOHHO RF

RFI

CuOAc (20 mol)[Ru(bpy)3]Cl26H2O (1 mol)

K2CO3 (10 equiv)DMF 60 degC 26 W CFL

39-93

R1R1

R1 = EWG EDG

2928

Scheme 111 Dual copper and visible light photoredox-catalyzed perfluoroalkylation ofarylboronic acids [102]

CF3I

F3C I

I CopperCatalysis CuIIIX

CF3

CuIX

CuIIX2

CF3

transmetalation

[Ru(bpy)3]2+

[Ru(bpy)3]+

PhotoredoxCatalysis

hνvis

SET

[Ru(bpy)3]2+

CF3

XB(OH)2

SET

BOH

OH

30

28

29

Scheme 112 Mechanistic proposal for dual copper and visible light photoredox-catalyzedtrifluoromethylation of arylboronic acids [102]

1413 Redox-Neutral Photoredox Catalysis EDA ComplexFormation

In visible light photoredox catalysis an external photosensitizer is generally used tocarry out the reactions [31] In contrast to reactions of this type in 2013 Melchiorreand co-workers uncovered a novel concept where two components in associationwith one another absorbs visible light leading to inner sphere charge transfer in asolvent cage and giving rise to downstream reactivity [117]

They reported the visible light-driven chiral amine-catalyzed asymmetricα-alkylation of aldehydes and cyclic ketones with high yield and selectivity(Scheme 113) [117 118] In these reactions none of the reaction componentsaldehydeketone amine catalyst and alkyl bromide in isolation absorbs light in thevisible range When these components are mixed together a colored solution isobtained which absorbs light significantly in the visible range The origin of visiblelight absorption is attributed to the electron donor-acceptor (EDA) complex formedbetween the electron donor enamine intermediate in situ generated from thealdehydeketone and the amine catalyst by condensation and the electron acceptoralkyl bromide (Scheme 114) The formed complex absorbs light and undergoeseffective electron transfer from the enamine to the alkyl bromide in the solvent cageOnce the alkyl bromide radical-anion 33 leaves the cage an alkyl radical inter-mediate 34 is generated upon mesolysis of the radical-anion This alkyl radical 34then adds to the electron rich enamine intermediate delivering another radicalintermediate 35 Subsequent electron transfer from intermediate 35 to another

R1

YR2

O

R1

YR2

O

EWG

R1

YR2

O

O R4

EWG

Br

O R4Br

NH OTMS

ArAr

Ar =

CF3

CF3 N

OMe

NH2

N31

32

31 (20 mol)26-lutidine MTBE 25 degC

23 W CFLfor aldehyde

32 (20 mol)TFA NaOAc 25 degC

300 W Xe lamp Toluenefor ketone

R1 = H aldehyde 73-95 84-94 eeR1 = H ketone 38-94 62-95 ee

R1 = H aldehydeR1 = H ketoneR1 R2 R3 = H alkyl Y = CH2 CR2 O NBocR4 = EWG EDG

R3

Melchiorre and co-workers (2013 amp 2014)

Scheme 113 Chiral amine-catalyzed asymmetric α-alkylation of aldehydes and cyclic ketonesvia visible light-driven exciplex formation [117 118]

equivalent of the alkyl bromide in a chain process leads to iminium ion 36 for-mation which delivers the final product upon hydrolysis and regenerates the aminecatalyst

Since the reaction is performed in the presence of catalytic amounts of the aminecatalyst resulting in a catalytic amount of the enamine intermediate this reaction canbe considered as a catalytic method in an analogy to standard photoredox catalysis

142 Photocatalyzed Organic Transformations via TripletEnergy Transfer

Although over the last few years visible light photoredox catalysis involvingelectron transfer has been widely exploited [31] visible light photocatalysisinvolving energy transfer still remains less explored [119ndash126] In visible lightphotoredox-catalyzed cycloaddition reactions only electron rich and electron pooralkenes can be employed as substrates These substrates are capable of donating or

Br

EWG

N

R1

R2

X

Br

EWG

N

R1

R2

X

R1

O

R2

EWG

Br

EWG

N

R1

R2

X

N

R1

R2

X

GWE

N

R1

R2

X

GWE Br

EWG

R1

O

R2

hνvis

EDA complex

tight ion-pair

Br

radicaladdition

mesolysis

SET

bareradical-anion

X = H pr imary amineX = alkyl secondary amine

hydrolysis

enamineformation

33

34

35

36

Scheme 114 Plausible reaction mechanism for the amine-catalyzed asymmetric α-alkylation ofcarbonyl compounds via visible light-driven exciplex formation [117 118]

accepting an electron to generate radical-cations or radical-anions for downstreamreactivity To overcome these limitations in substrate scope Yoon and co-workershave made significant advances in the development of cycloaddition reactionsproceeding via energy transfer Until 2012 there were only two reports ofcarbon-carbon bond-forming reactions proceeding via triplet sensitization withtransition metal complexes under visible light irradiation [119 120] Yoon et al[121] then reported an elegant method for [2+2] cross cycloadditions of styreneswith pendant substituted alkenes in an intramolecular fashion (Scheme 115)

They carried presence of [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1 mol) in DMSOand visible light from a 23 W CFL This reaction seemed to be independent ofsolvent polarity indicating the feasibility of energy transfer in contrast to thepreference of polar solvents typically required for electron transfer processes tostabilize the charged radical-ionic intermediates In general the redox potentials ofstyrenes are out of the range accessible with the photo-excited [Ir(dF(CF3)ppy)2(dtbbpy)]

+ However the calculated triplet state energy of styrenes is in thesame range or even lower than that of the photo-excited [Ir(dF(CF3)ppy)2(dtbbpy)]

+ The authors believed that these reactions proceed via tripletndashtripletenergy transfer generating a triplet excited state of the substrate which can engagein a [2+2] cycloaddition as depicted in Scheme 115

15 Summary

In summary this chapter provides an overview of emerging visible light inducedphotocatalysis encompassing a brief historical background of this field the generalfeatures of the photocatalysts and the different types of reactivity exhibited by these

X

R4 R3

( )n R2

R1

X R2

R3H R4

R1

HH

R1 = EWG EDG R2 = H alkyl aryl R3 R4 = H alkyl aryl EDG EWG X = O NTs CH2 n = 12

[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1 mol)

DMSO (001 M) 23 W CFL

64-90

X

R4 R3

( )n R2

R1

triplet state

Triplet-Triplet

Energy Transfer Radical Addition-Recombination

Yoon and co-workers (2012)

( )n

Scheme 115 Visible light photocatalyzed [2+2] cycloaddition of styrenes via tripletndashtripletenergy transfer [121]

photocatalysts Selected examples of overall redox-neutral photoredox-catalyzedorganic transformations covering different reactivity modes have been describedSome of the redox-neutral photocatalytic reactions intentionally presented in thischapter are directly or indirectly related to our own contributions described inChaps 2ndash4

References

1 G Ciamician Science 36 385ndash394 (1912)2 NS Lewis Science 315 798ndash801 (2007)3 M Oelgemoumlller C Jung J Mattay Pure Appl Chem 79 1939ndash1947 (2007)4 TP Yoon MA Ischay J Du Nat Chem 2 527ndash532 (2010)5 DM Schultz TP Yoon Science 343 1239176 (2014)6 M Fagnoni D Dondi D Ravelli A Albini Chem Rev 107 2725ndash2756 (2007)7 S Protti M Fagnoni Photochem Photobiol Sci 8 1499ndash1516 (2009)8 SJ Blanksby GB Ellison Acc Chem Res 36 255ndash263 (2003)9 N Hoffmann Chem Rev 108 1052ndash1103 (2008)

10 T Bach JP Hehn Angew Chem Int Ed 50 1000ndash1045 (2011)11 K Kalyanasundaram Coord Chem Rev 46 159ndash244 (1982)12 MK Nazeeruddin A Kay I Rodicio R Humphry-Baker E Mueller P Liska N

Vlachopoulos M Graetzel J Am Chem Soc 115 6382ndash6390 (1993)13 MK Nazeeruddin SM Zakeeruddin R Humphry-Baker M Jirousek P Liska N

Vlachopoulos V Shklover C-H Fischer M Graumltzel Inorg Chem 38 6298ndash6305 (1999)14 SH Wadman JM Kroon K Bakker RWA Havenith GPM van Klink G van Koten

Organometallics 29 1569ndash1579 (2010)15 Y Qin Q Peng Int J Photoenergy 2012 21 (2012)16 DW Ayele W-N Su J Rick H-M Chen C-J Pan NG Akalework B-J Hwang

Advances in Organometallic Chemistry and Catalysis (Wiley NY 2013) pp 501ndash51117 A Kudo Y Miseki Chem Soc Rev 38 253ndash278 (2009)18 RM Navarro Yerga MC Aacutelvarez Galvaacuten F del Valle JA Villoria de la Mano JLG

Fierro ChemSusChem 2 471ndash485 (2009)19 DM Hedstrand WH Kruizinga RM Kellogg Tetrahedron Lett 19 1255ndash1258 (1978)20 TJ Van Bergen DM Hedstrand WH Kruizinga RM Kellogg J Org Chem 44 4953ndash

4962 (1979)21 C Pac M Ihama M Yasuda Y Miyauchi H Sakurai J Am Chem Soc 103 6495ndash6497

(1981)22 H Cano-Yelo A Deronzier Tetrahedron Lett 25 5517ndash5520 (1984)23 H Cano-Yelo A Deronzier J Chem Soc Perkin Trans 2 1093ndash1098 (1984)24 Z Goren I Willner J Am Chem Soc 105 7764ndash7765 (1983)25 R Maidan Z Goren JY Becker I Willner J Am Chem Soc 106 6217ndash6222 (1984)26 K Hironaka S Fukuzumi T Tanaka J Chem Soc Perkin Trans 2 1705ndash1709 (1984)27 DA Nicewicz DWC MacMillan Science 322 77ndash80 (2008)28 MA Ischay ME Anzovino J Du TP Yoon J Am Chem Soc 130 12886ndash12887

(2008)29 JMR Narayanam JW Tucker CRJ Stephenson J Am Chem Soc 131 8756ndash8757

(2009)30 JW Tucker CRJ Stephenson J Org Chem 77 1617ndash1622 (2012)31 CK Prier DA Rankic DWC MacMillan Chem Rev 113 5322ndash5363 (2013)32 D Ravelli M Fagnoni ChemCatChem 4 169ndash171 (2012)33 D Ravelli M Fagnoni A Albini Chem Soc Rev 42 97ndash113 (2013)

34 DP Hari B Konig Chem Commun 50 6688ndash6699 (2014)35 DA Nicewicz TM Nguyen ACS Catal 4 355ndash360 (2014)36 AL Linsebigler G Lu JT Yates Chem Rev 95 735ndash758 (1995)37 N Wu J Wang DN Tafen H Wang J-G Zheng JP Lewis X Liu SS Leonard A

Manivannan J Am Chem Soc 132 6679ndash6685 (2010)38 N Zhang X Fu Y-J Xu J Mater Chem 21 8152ndash8158 (2011)39 M Cherevatskaya M Neumann S Fuumlldner C Harlander S Kuumlmmel S Dankesreiter A

Pfitzner K Zeitler B Koumlnig Angew Chem Int Ed 51 4062ndash4066 (2012)40 M Rueping J Zoller DC Fabry K Poscharny RM Koenigs TE Weirich J Mayer

Chem Eur J 18 3478ndash3481 (2012)41 P Riente A Matas Adams J Albero E Palomares MA Pericagraves Angew Chem Int Ed

53 9613ndash9616 (2014)42 C Liu W Zhao Y Huang H Wang B Zhang Tetrahedron 71 4344ndash4351 (2015)43 P Riente MA Pericagraves ChemSusChem 8 1841ndash1844 (2015)44 Y Guo C Hu J Mol Catal A Chem 262 136ndash148 (2007)45 F Su SC Mathew G Lipner X Fu M Antonietti S Blechert X Wang J Am Chem

Soc 132 16299ndash16301 (2010)46 Y Wang X Wang M Antonietti Angew Chem Int Ed 51 68ndash89 (2012)47 J Long S Wang Z Ding S Wang Y Zhou L Huang X Wang Chem Commun 48

11656ndash11658 (2012)48 P Wu C He J Wang X Peng X Li Y An C Duan J Am Chem Soc 134 14991ndash

14999 (2012)49 D Shi C He B Qi C Chen J Niu C Duan Chem Sci 6 1035ndash1042 (2015)50 X Yu SM Cohen Chem Commun 51 9880ndash9883 (2015)51 K Zeitler Angew Chem Int Ed 48 9785ndash9789 (2009)52 JMR Narayanam CRJ Stephenson Chem Soc Rev 40 102ndash113 (2011)53 F Teplyacute Collect Czech Chem Commun 76 859ndash917 (2011)54 L Shi W Xia Chem Soc Rev 41 7687ndash7697 (2012)55 J Xuan W-J Xiao Angew Chem Int Ed 51 6828ndash6838 (2012)56 DP Hari B Koumlnig Angew Chem Int Ed 52 4734ndash4743 (2013)57 M Reckenthaumller AG Griesbeck Adv Synth Catal 355 2727ndash2744 (2013)58 Y Xi H Yi A Lei Org Biomol Chem 11 2387ndash2403 (2013)59 J Xuan L-Q Lu J-R Chen W-J Xiao Eur J Org Chem 2013 6755ndash6770 (2013)60 MN Hopkinson B Sahoo J-L Li F Glorius Chem Eur J 20 3874ndash3886 (2014)61 E Jahn U Jahn Angew Chem Int Ed 53 13326ndash13328 (2014)62 T Koike M Akita Top Catal 57 967ndash974 (2014)63 N Hoffmann ChemCatChem 7 393ndash394 (2015)64 E Meggers Chem Commun 51 3290ndash3301 (2015)65 M Pentildea-Loacutepez A Rosas-Hernaacutendez M Beller Angew Chem Int Ed 54 5006ndash5008

(2015)66 GJ Barbante TD Ashton EH Doeven FM Pfeffer DJD Wilson LC Henderson P

S Francis ChemCatChem 7 1655ndash1658 (2015)67 DC Fabry MA Ronge M Rueping Chem Eur J 21 5350ndash5354 (2015)68 A Juris V Balzani F Barigelletti S Campagna P Belser A von Zelewsky Coord

Chem Rev 84 85ndash277 (1988)69 A Penzkofer A Beidoun M Daiber J Lumin 51 297ndash314 (1992)70 A Penzkofer A Beidoun Chem Phys 177 203ndash216 (1993)71 A Penzkofer A Beidoun S Speiser Chem Phys 170 139ndash148 (1993)72 MA Miranda H Garcia Chem Rev 94 1063ndash1089 (1994)73 S Fukuzumi H Kotani K Ohkubo S Ogo NV Tkachenko H Lemmetyinen J Am

Chem Soc 126 1600ndash1601 (2004)74 L Flamigni A Barbieri C Sabatini B Ventura F Barigelletti Top Curr Chem 281

143ndash203 (2007)75 A Jabłoński Nature 131 839ndash840 (1933)

References 21

76 JR Lakowicz Principles of Fluorescence Spectroscopy 3rd edn (Springer New York2006)

77 J Du KL Skubi DM Schultz TP Yoon Science 344 392ndash396 (2014)78 D Rehm A Weller Isr J Chem 8 259ndash271 (1970)79 RM Elofson FF Gadallah J Org Chem 36 1769ndash1771 (1971)80 AN Nesmeyanov LG Makarova TP Tolstaya Tetrahedron 1 145ndash157 (1957)81 B Maggio D Raffa MV Raimondi S Cascioferro S Plescia MA Sabatino G

Bombieri F Meneghetti G Daidone ARKIVOC 16 130ndash143 (2008)82 DP Hari P Schroll B Koumlnig J Am Chem Soc 134 2958ndash2961 (2012)83 DA Nagib DWC MacMillan Nature 480 224ndash228 (2011)84 G Fumagalli S Boyd MF Greaney Org Lett 15 4398ndash4401 (2013)85 D Prasad Hari T Hering B Koumlnig Angew Chem Int Ed 53 725ndash728 (2014)86 Y Yasu T Koike M Akita Angew Chem Int Ed 51 9567ndash9571 (2012)87 H Yi X Zhang C Qin Z Liao J Liu A Lei Adv Synth Catal 356 2873ndash2877 (2014)88 Y Yasu T Koike M Akita Org Lett 15 2136ndash2139 (2013)89 Y Yasu T Koike M Akita Chem Commun 49 2037ndash2039 (2013)90 R Tomita Y Yasu T Koike M Akita Beilstein J Org Chem 10 1099ndash1106 (2014)91 Y Yasu Y Arai R Tomita T Koike M Akita Org Lett 16 780ndash783 (2014)92 JD Nguyen JW Tucker MD Konieczynska CRJ Stephenson J Am Chem Soc 133

4160ndash4163 (2011)93 L Furst BS Matsuura JMR Narayanam JW Tucker CRJ Stephenson Org Lett 12

3104ndash3107 (2010)94 S Maity M Zhu RS Shinabery N Zheng Angew Chem Int Ed 51 222ndash226 (2012)95 Z Shao H Zhang Chem Soc Rev 38 2745ndash2755 (2009)96 M Rueping RM Koenigs I Atodiresei Chem Eur J 16 9350ndash9365 (2010)97 AE Allen DWC MacMillan Chem Sci 3 633ndash658 (2012)98 M Osawa H Nagai M Akita Dalton Transactions (2007) 827ndash82999 D Kalyani KB McMurtrey SR Neufeldt MS Sanford J Am Chem Soc 133 18566ndash

18569 (2011)100 SR Neufeldt MS Sanford Adv Synth Catal 354 3517ndash3522 (2012)101 G Maestri M Malacria E Derat Chem Commun 49 10424ndash10426 (2013)102 Y Ye MS Sanford J Am Chem Soc 134 9034ndash9037 (2012)103 A Noble SJ McCarver DWC MacMillan J Am Chem Soc 137 624ndash627 (2014)104 JC Tellis DN Primer GA Molander Science 345 433ndash436 (2014)105 Z Zuo DT Ahneman L Chu JA Terrett AG Doyle DWC MacMillan Science 345

437ndash440 (2014)106 O Gutierrez JC Tellis DN Primer GA Molander MC Kozlowski J Am Chem Soc

137 4896ndash4899 (2015)107 DN Primer I Karakaya JC Tellis GA Molander J Am Chem Soc 137 2195ndash2198

(2015)108 J Xuan T-T Zeng J-R Chen L-Q Lu W-J Xiao Chem Eur J nandashna (2015)109 DC Fabry J Zoller S Raja M Rueping Angew Chem Int Ed 53 10228ndash10231 (2014)110 DC Fabry MA Ronge J Zoller M Rueping Angew Chem Int Ed 54 2801ndash2805

(2015)111 SB Lang KM OrsquoNele JA Tunge J Am Chem Soc 136 13606ndash13609 (2014)112 J Zoller DC Fabry MA Ronge M Rueping Angew Chem Int Ed 53 13264ndash13268

(2014)113 J Xuan T-T Zeng Z-J Feng Q-H Deng J-R Chen L-Q Lu W-J Xiao H Alper

Angew Chem Int Ed 54 1625ndash1628 (2015)114 M Rueping RM Koenigs K Poscharny DC Fabry D Leonori C Vila Chem Eur

J 18 5170ndash5174 (2012)115 W-J Yoo T Tsukamoto S Kobayashi Angew Chem 127 6687ndash6690 (2015)116 W-J Yoo T Tsukamoto S Kobayashi Angew Chem Int Ed 54 6587ndash6590 (2015)117 E Arceo ID Jurberg A Aacutelvarez-Fernaacutendez P Melchiorre Nat Chem 5 750ndash756 (2013)

118 E Arceo A Bahamonde G Bergonzini P Melchiorre Chem Sci 5 2438ndash2442 (2014)119 H Ikezawa C Kutal K Yasufuku H Yamazaki J Am Chem Soc 108 1589ndash1594

(1986)120 RR Islangulov FN Castellano Angew Chem Int Ed 45 5957ndash5959 (2006)121 Z Lu TP Yoon Angew Chem Int Ed 51 10329ndash10332 (2012)122 Y-Q Zou S-W Duan X-G Meng X-Q Hu S Gao J-R Chen W-J Xiao Tetrahedron

68 6914ndash6919 (2012)123 E Arceo E Montroni P Melchiorre Angew Chem Int Ed 53 12064ndash12068 (2014)124 EP Farney TP Yoon Angew Chem Int Ed 53 793ndash797 (2014)125 AE Hurtley Z Lu TP Yoon Angew Chem Int Ed 53 8991ndash8994 (2014)126 X-D Xia J Xuan Q Wang L-Q Lu J-R Chen W-J Xiao Adv Synth Catal 356

2807ndash2812 (2014)127 K Ohkubo K Mizushima R Iwata K Souma N Suzuki S Fukuzumi Chem Commun

46 601ndash603 (2010)128 Y Yasu T Koike M Akita Adv Synth Catal 354 3414ndash3420 (2012)

References 23

Chapter 2Dual Gold and Visible LightPhotoredox-Catalyzed Heteroarylationsof Non-activated Alkenes

21 Introduction

211 General Properties of Homogeneous Gold Catalysts

Gold (Au) is a third row noble transition metal belonging to group 11 of theperiodic table and is situated below silver in the coinage metal series Gold withthe ground state electronic configuration [Xe]4f145d106s1 has highest first ion-ization potential (EAu(I)Au(0)

0 = +169 V vs SHE) among d-block elements due tothe relativistic contraction of 6s atomic orbital [1] As a consequence elementalgold is very stable in the presence of air and moisture and was long thought tobe inactive to perform chemical reactions Among possible oxidation states (minusI to+V) Au(I) and Au(III) species are stable existing as salts or complexes whileAu(II) is generally unstable and easily undergoes disproportionation to Au(I) andAu(III) In the presence of a strong oxidant Au(I) can be oxidized to Au(III)(EAu(III)Au(I)

0 = +141 V vs SHE) [1] Some commercially available Au(I) and Au(III) precursors are listed in Fig 21 In general for catalysis gold(I) complexesare often employed along with a co-catalyst silver(I) salt with an appropriatenon-coordinating counter-anion is added to the reaction mixture to abstract ahalide from the gold center creating a vacant coordination site accessible to thesubstrates for binding In 2005 Gagosz and co-workers developed air stablecationic (phosphine)gold(I) complexes with a loosely bound NTf2 anion whicheasily dissociates in solution [2]

The cationic gold(I) complex [LAu]+ (ie L = neutral ligand eg a phosphine orNHC) thus generated is most often employed as a highly efficient carbophilicπ-Lewis acid catalyst capable of activating carbon-carbon multiple bonds Theπ-activation of multiple bonds can be attributed to the strong in-plane σ-donation

25

from the substrate π-orbital onto the metal [π(alkyne) rarr d(Au)] with a compara-tively weak back-bonding interaction from the gold to the substrate π-orbital [π(alkyne) larr d(Au)] With alkyne substrates which have an additional out-of-planedouble bond further weak π(alkyne) rarr d(Au) bonding and π(alkyne) larr d(Au)back-bonding interactions are possible [3 4] Due to the stronger σ-acceptancecompared to π-back donation [3 4] overall charge density in the ligatedalkynealkene is reduced and electrophilicity is enhanced The predominance ofcarbophilic behavior observed with soft LAu+ species can be rationalized by thefact that it forms kinetically more labile complexes with hard basic heteroatoms(eg O and N) [5] Due to the high redox potential of the Au(I)Au(III) couple(E12[Au(III)Au(I)] = +141 V vs SHE) [1] LAu+-catalyzed reactions can beconducted under aerobic conditions and no undesired redox processes hamper thedesired reactivity As a result a wide spectrum of functional groups are tolerated inthese types of reactions [5] Alongside alkynes this activation approach can beextended to organic substrates containing π-system such as allenes and alkenes [5]

Since the last decade of the twentieth century a significant amount of interest hasbeen devoted to the development of highly emissive luminescent gold(III) com-plexes [6 7] which can absorb photons in visible range of spectrum and recentlysome polypyridyl gold(III) complexes have been shown to participate in visible lightphotoredox catalysis [8] However the vast majority of organic reactions are cat-alyzed by gold(I) complexes rather than gold(III) complexes and the absorptionabilities of mononuclear gold(I) complexes (eg Ph3PAuCl Et3PAuCl orMe3PAuCl) and coordinatively-saturated bimetallic gold(I) complexes [eg(dppm)2(AuCl)2 dppm = 11-bis(diphenylphosphino)methane] are usually confinedto the UV range of the spectrum [9ndash12] This phenomenon limits their applicationsin visible light induced gold-catalyzed organic transformations [11 13 14]

AuClN

NAu Cl P Au Cl P Au N

S

SO

CF3

O

OCF3

O

IPrAuCl Ph3PAuCl [Ph3PAu]NTf2

Gol

d(I)

Prec

urso

rs

NAuO

OCl

ClAuCl3

[PicAu]Cl2Gol

d(III

)Pre

curs

ors

AuBr3

P

Au

Au Cl

Cl

(dppm)(AuCl)2

Fig 21 Some common commercially-available Au(I) and Au(III) precursors

26 2 Dual Gold and Visible Light hellip

212 Gold-Catalyzed Organic Transformations

Over the last several years gold catalysis has played an outstanding role in variousareas of chemistry [4 5 15ndash32] AuCl3-catalyzed hydration of alkynes to ketonesreported by Thomas and co-workers in 1976 was one of the earliest reports on goldcatalysis (Scheme 21) [33] However the real breakthrough in gold(I) catalysiswas made by a group of scientists in BASF in 1998 who developed a highlyefficient (phosphine)gold(I)-catalyzed method for the addition of alcohols ontoalkynes with very high TON and TOF replacing toxic mercury(II) catalysts(Scheme 21) [34]

Since then this field has been explored enormously with highly efficient andstable gold(I) (pre)catalysts being applied [17 35 36] to access syntheticallyimportant reactivity and mechanistic insight [18 21 28 30 31] The compatibilityof gold catalysis with other reagents has also been extensively explored and studiesdevoted to extending the scope of these reactions beyond their current limitationssuch as overcoming protodeauration have been conducted [23 24 27 37] Novelmethodologies exploring many aspects of the chemistry of gold continue to bereported at a fast rate [5 25 26 38] including applications in asymmetric catalysis[20 32 39 40] and natural product synthesis [29]

2122 Difunctionalizations of CarbonndashCarbon Multiple BondsMechanistic Hypothesis

Gold(I)-catalyzed nucleophilic addition type reactions have emerged as an enablingtechnology for selective difunctionalizations of alkynes allenes and alkene sub-strates A general mechanistic scenario for these transformations exemplified foralkynes is shown in Scheme 22 [16] In an initial step commercially available orself-prepared gold(I) complexes of the form [LAuX] (37) (L = neutral ligand egphosphine NHC and X = charged ligand eg Cl Br) loses its charged ligand(X) in the presence of a scavenger (eg Ag+) to generate the catalytically-activecationic species [LAu]+ (38) This cationic species [LAu]+ (38) then enters thecatalytic cycle and coordinates to an alkyne (39) generating the alkyne-ligated gold(I) intermediate 40 and activating it towards an internal or external nucleophile The

R1

O

R2

R2R1

Ph3PAuMeMsOH

R3OH

R1 = alkyl arylR2 = alkyl aryl

Teles and co-workers (1998)

R3 = alkyl allyl

AuCl3

R1R2

OR3R3O

Thomas and co-workers (1976)Scheme 21 Early examplesof gold catalysis hydration ofalkynes and addition ofalcohols onto alkynes [33 34]

21 Introduction 27

addition of the nucleophile results in the alkenylgold intermediate 41 which is thenquenched in the presence of an electrophile releasing the product 42 and regener-ating the cationic species [LAu]+ (38) In a different scenario the alkyne bound toAu(I) in the coordination sphere of intermediates 40 and 41 could behave as vic-dicarbene synthons 43 and 44 respectively and their great potential in synthesishas been explored over the last few years [5] It is worth mentioning that allenes andalkenes can be activated in a similar manner resulting in vinylgold(I) and alkylgold(I) intermediates respectively

In the vast majority of the cases the alkenylgold intermediate 41 undergoesprotodeauration releasing hydrofunctionalized products while in a few caseshalonium ions (I+ Br+) have been used to quench the alkenylgold intermediate 41delivering halofuntionalized products [41ndash43]

Hydrofunctionalizations of alkynes allenes and to some extent alkenesundoubtedly deserve an important position among gold-catalyzed organic trans-formations and many impressive reactions based on these processes have enrichedthe library of synthetic organic chemistry [4 5 15 16 18 22 25 31] However inmany cases rapid protodeauration limits the synthetic potential of gold catalysis Inthis regard organic chemists have invested significant efforts to develop alternativeroutes for the decomplexation of organogold intermediates which can compete withthe protodeauration pathway

One inspiring approach was the use of dual metal catalytic systems whereorganogold intermediates obtained under redox-neutral gold catalysis hand overorganic fragments to other metals through transmetallation process (seeSection ldquoOrganogold Reactivity in Dual Metal Catalysisrdquo) [23]

Another approach that has captured the attention of researchers is oxidativecoupling strategy where organogold intermediates obtained under redox-neutralgold catalysis conditions take part in an oxidative coupling step delivering

AuNu

L

AuL

AuLAuL X

ENu

Nu

E

37 38

40

41

39

AuNu

L

AuL

43

44

AgX

E = H Br I

R1Nu

R2Nu

Pd catalyst

cross coupling

protodeaurationhalodeauration

oxidative coupling

Au(I)Au(III)redox cycle

π -coordination

nucleophilic addition

R2 Y

II

I

Gold Catalysis

R1 = alkyl allyl aryl R2 = aryl

R1 X

I

Y = H SiMe3 B(OH)2

42

Scheme 22 General mechanistic cycle of Au(I)-catalyzed difunctionalization of carbon-carbonmultiple bonds [5]

complex products (see Section ldquoNucleophilic AdditionRearrangement-OxidativeCouplingrdquo) [24 27 37]

Organogold Reactivity in Dual Metal Catalysis

Over the past decades dual catalysis has become a powerful tool in organic syn-thesis The concept of combining two privileged catalytic activation modes togetherto promote a single transformation which is not possible in the presence of eithercatalyst alone has recently captured the attention of synthetic chemists [44 45] Inthe field of transition metal catalysis transmetallation is a common step involved inmost cross-coupling reactions There has been a huge progress of developingefficient transmetallating reagents such as organo-magnesium tin boron zincsilicon lithium etc which have been applied in many famous metal-catalyzedcross-coupling and other reactions (Table 21)

In gold catalysis most of the reactions proceed via alkenylgold intermediates(for alkynes and allenes) or alkylgold intermediates (alkenes) being involved in oneof the steps in catalytic cycle To extend the scope of gold catalysis beyond pro-todeauration a group of scientists including Blum Hashmi and others have beeninterested in using in situ generated organogold intermediates in other transitionmetal-catalyzed processes mostly in cross-coupling type reactions as potentialtransmetallating agents in either a stoichiometric or catalytic manner [23 46ndash49]A seminal report [41] on stable alkenylgold intermediate isolation from Hammondand co-workers in 2008 has enhanced the interest of organic chemists more in thisline of research

In 2009 Blum and co-workers reported the method for the carboauration ofalkynes 45 catalyzed by palladium to generate alkenylgold intermediates 46 whichcould be subsequently used in palladium-catalyzed cross-coupling chemistry(Scheme 23a) [47] In the same year Hashmi and co-workers also developed aprotocol for cross-coupling reactions with a catalytic amount of palladium andstoichiometric amounts of stable alkenylgold intermediates (Scheme 23b) [46]One set of organogold intermediates 47 used in this study were prepared accordingto the procedure previously developed by Hammond and co-workers in 2008 [41]Moreover Blum and co-workers also reported a carboauration with palladium

Table 21 Organometallicreagents used in relatedcross-coupling reactions

Organometallic reagent Cross-coupling reaction

RndashMgX Kumada coupling

RndashSn Migita-Kosugi-Stille coupling

RndashB Suzuki-Miyaura coupling

RndashZn Negishi coupling

RndashSi Hiyama coupling

RndashCu Sonogashira-Hagihara coupling

RndashAu

21 Introduction 29

catalysis [47] In addition to palladium catalysis organogold intermediates havealso been applied in nickel-catalyzed cross-coupling reactions as transmetallatingreagents [49]

Although significant contributions have been made to the development of novelorganic transformations using dual metal systems with gold and other transitionmetals the vast majority of them reported to date are limited to the use of stoi-chiometric amount of gold [23] Another limitation is that in the cases where theother transition metal catalysts (eg Ni and Pd) can react via single electron transferthe substrate scope of the reaction is somewhat limited to compounds whichundergo fast oxidative addition as alternative competing deactivation pathwaysresulting in the reduction of organogold(I) intermediates to inactive gold(0) canotherwise occur [23] Another serious concern is the choice of an appropriateligand which is crucial to avoid the poisoning of the gold catalysts via the for-mation of coordinatively-saturated gold complexes (eg [Ph3P-Au-PPh3]

+) throughligand exchange between gold and another metal catalyst [23]

Nucleophilic AdditionRearrangement-Oxidative Coupling

Cascade difunctionalization processes constitute a new class of gold-catalyzedorganic transformations where a carbonndashcarbon or heteroatom-carbon bond for-mation generated upon nucleophilic addition onto a carbonndashcarbon multiple bondactivated by gold is accompanied by the formation of a new carbonndashcarbon orheteroatom-carbon bond under oxidative conditions [24 27 37]

An interesting observation by Hashmi and co-workers in early 2008 of a Au(III)-mediated oxidative coupling of vinyl gold intermediates derived from allenyl car-binols upon cyclization disclosed the concept of gold mediated cascade nucle-ophilic addition oxidative coupling for the first time (Scheme 24a) [50] In late

O O

PPh3Au

OOEt

Ph3PAuCl (10 equiv)AgOTf (10 equiv)

CH2Cl2

12 equiv 47 82

HO O

84-92

XPdCl2(dppf) (1 mol)

(Het)ArBr (15 equiv)CH3CN

R1

X = CH2 = H EWG EDGX = N R1

R1

= H

PPh3Au R2PdCl2(PPh3)2 (5 mol)or Pd2dba3 (5 mol)

Ph3PAuR2 (10 equiv)CH2Cl245 (10 equiv) 74-87

Pd cat

R3-X

R1 = H EWGR2 = vinyl alkynyl aryl

R1MeO2CR1MeO2C

46 35-84

Hammond and co-workers Hashmi and co-workers

(a)

(b)

Blum and co-workers (2009)

Hashmi and co-workers (2009)

R1 = H R2 = vinylR3 = methyl allyl Tolyl

R3 R2

R1MeO2C

X = Br I(one pot reaction)

Scheme 23 Palladium-catalyzed cross-coupling reactions of organogold reagents [46 47]

2008 Wegner and co-workers reported the first catalytic version of this type ofoxidative coupling reaction where cyclization-oxidative dimerization of arylpro-pionic esters 48 with HAuCl4 (5 mol) afforded dicoumarin derivatives 49 (13ndash67 ) in the presence of the oxidant tBuOOH (50 equiv) (Scheme 24b) [51]Unfortunately they could not suppress the competitive protodeauration pathwayleading to coumarin 50 formation Thereby gold-catalyzed oxidative couplingreactions remained challenging to the scientific community until 2009 when Zhangand co-workers successfully developed a catalytic cascade method for therearrangement-oxidative homocoupling of propargylic acetates 51 to (EE)-die-nones 52 in the presence of (2-biphenyl)Cy2PAuNTf2 (5 mol) and 20 equiv ofSelectfluor as an oxidant at 60 degC in a mixture of acetonitrile and water (5001Scheme 24c) [52] In all the above cases the homocoupled products are generatedupon reductive elimination from a gold(III) intermediate 53 In 2009 prior tohomocouling report Zhang and co-workers described an exciting oxidative goldcatalyzed cross coupling of propargylic acetates with arylboronic acids furnishingα-arylated enones [53]

Since then over the last six years the versatility of this novel approach has beenexploited in many impressive organic transformations particularly cascade nucle-ophilic addition-oxidative cross-coupling processes for the difunctionalization ofmultiple bonds Although alkynes and allenes have been used in most of thesetransformations alkenes have also been successfully employed [24 27 37]

Oxidative gold catalysis is an indispensable tool for the difunctionalization ofalkenes where nucleophilic addition-carboauration of C=C bond results in analkylgold intermediate forming a C(sp3)ndashAu bond which then reacts with an aryl

OH O

O

H

AuCl3 (5 mol)

CH3CN rt

47 10

Au(I)

ReductiveElimination

minor product

O O

R1

O O

OO

O O

HR1R1

48

R1

49 13-67 50 8-40

HAuCl4 (5 mol)tBuOOH (50 equiv)

(CH2Cl)2 60 degC 24 h

R1= H alkyl

(a)

(b)

c) Zhang and co-workers (2009)major product

Wegner and co-workers (2008)

Via

LAuIII

L

R2

O O

R1 NN

F

Cl

2BF4

R2

O

R2

R1

R1(2-biphenyl)Cy2PAuNTf2 (5 mol)

Selectfluor ( 20 equiv)CH3CNH2O = 5001

60 degC 25-40 min51 52 80-93R1 R2 = alkyl sole product Selectfluor

53

Scheme 24 Au-mediatedcatalyzed oxidative coupling reactions of allenes and alkynes [50ndash52]

21 Introduction 31

precursor (arylboronic acid arylsilane or simple arene) under oxidative conditionsto release an alkylated arene product via C(sp3)ndashC(sp2) bond formation It is worthmentioning that alternative well-established palladium-catalyzed reactions of thistype typically suffer from side-reactions involving competitive β-hydride elimina-tion of an alkylpalladium intermediate This elementary step is not favoured withgold catalysts

In 2010 Zhang and co-workers reported heteroarylations of non-activatedalkenes in an intramolecular fashion where 4-penten-1-ol 54 was treated withphenylboronic acid 28 (20 equiv) as an aryl precursor in the presence of a priv-ileged gold catalyst (triphenylphosphine)gold(I) chloride (Ph3PAuCl 10 mol)and an exogenous oxidant Selectfluor (20 equiv) in acetonitrile at 70 degC to deliverthe oxyarylated product 2-benzyl tetrahydrofuran 57 (Scheme 25a) [54] In orderto show the broad scope of the developed method the reactions were performedwith different alkene substrates 54ndash56 with γ-hydroxy γ-tosyl amine andβ-carboxylic acid groups as nucleophiles and also longer tethers between thenucleophile and the alkene to afford the desired 2-benzyl substituted tetrahydro-furans 57 pyrrolidines 58 lactones 59 and six membered 2-benzyl substitutedtetrahydropyrans 60 and pyrimidines 61 respectively in moderate to excellent yields(Scheme 25)

In the same year Toste and co-workers also reported similar aminoarylations ofnon-activated alkenes under slightly different reaction conditions (Scheme 25b)

In contrast to Zhangrsquos reaction conditions they employed a lower amount ofoxidant (15 equiv) lower temperature (rt-40 degC) and a slightly lower catalystloading of a bimetallic phosphinegold complex (dppm)(AuBr)2 (3 mol dppm =11-bis(diphenylphosphino-methane)) which was found to be the best catalyst forthese studies [55] The preference for bimetallic gold catalysts was thought to bebased on beneficial aurophilic stabilization of Au(III) through AuIIIndashAuI interac-tions [56]

For the mechanistic illustration of the developed gold-catalyzed intramolecularaminoarylation of alkene Toste and co-workers and other research groups per-formed some theoretical calculations and control experiments to identify theintermediates and also the sequence of steps involved in the catalytic cycle [55ndash57]In a study focused on elucidating the stereochemical arrangement of the amino andaryl groups in the final products 58 the deuterium labelled γ-aminoalkene substrate62 was reacted under the standard conditions This reaction delivered the expectedpyrrolidine product 63 in high diastereoselectivity with conformational analysis ofthe 1H NMR spectrum revealing that the amino and aryl groups were in an anti-orientation (Scheme 26) [54]

Based on the mechanistic studies by means of theoretical calculations andcontrol experiments a general plausible reaction mechanism is shown inScheme 27 [54ndash57] In an initial step the neutral linear gold catalyst [LAuX] getsoxidized to the square planner gold(III) intermediate A by the F+ oxidant select-fluor At this point coordination of the gold(III) metal center to the alkene isfollowed by a nucleophilic attack onto the activated alkene 55 to obtain interme-diate B In next step aryl group transfer from the arylboronic acid to the

sp3-hybridized carbon attached to Au(III) in a concerted five membered transitionstate assisted by the fluoride ion bound to Au(III) in intermediate C gives rise to theheteroarylation product 58 The anti-relationship of nucleophile and aryl groupscould be explained by syn-nucleophilic-auration of the C=C bond followed by SN2

OHOB

HO OHPh3PAuCl (10 mol)

Selectfluor (20 equiv)CH3CN 60 degC 2-8 h

54 57 n = 1 56-7360 n = 2 R1 = H 35

OHOB

56 28 (20 equiv) 59 78-79

OO

NHTs TsNB

HO OH

Ph3PAuCl (10 mol)Selectfluor (20 equiv)

CH3CN 60 degC 2-8 hZhang and co-workers

55 28 (20 equiv) 58 n = 1 44-9461 n = 2 63-82

(dppm)(AuBr)2 (3 mol)Selectfluor (15 equiv)

CH3CN rt-40 degC 12 hToste and co-workers

R1

R2R2

( )n

( )n( )n

( )n

28 (20 equiv)

R1 = H alkyl aryl R2 = EDG and EWGn = 1 2

R1 = H alkyl aryln = 1 2

(a)

(b)

(c)

Zhang and co-workers (2010)

Zhang and co-workers (2010) amp Toste and co-workers (2010)

R1 = H alkyl

Scheme 25 Oxidative gold-catalyzed intramolecular heteroarylation of non-activated alkenes[54 55]

Ph3PAuCl (10 mol)

Selectfluor (20 equiv)CH3CN 60 degC 2 h

NHTsTsNB

HO OH

62 28 (20 equiv) 63 83dr = 221

D

H DH

Scheme 26 Aminoarylation of deuterium labelled γ-aminoalkene under Zhangrsquos reactionconditions [54]

21 Introduction 33

type aryl transfer with inversion of configuration assisted by the fluoride ligandbound to the Au(III) activating the boron center of the boronic acid An alternativepossibility is anti-aminoauration of the alkene followed by transmetallation-reductive elimination or a SNi-type substitution mechanism

To show the versatility of this approach Toste and co-workers extended thisreactivity to relatively more difficult selective three component intermolecularoxyarylations of terminal alkenes using arylboronic acids as aryl precursors(Scheme 28) [58] However all these methods where arylboronic acids were usedas aryl precursors suffer from oxygen and nitrogen based functional groups toler-ance on the aryl rings To solve this problem Toste and co-workers and Russell andco-workers independently developed methods where easily synthesized arylsilaneswere successfully employed in place of arylboronic acids (Scheme 28) [59 60]The next advancement in this strategy was accomplished by Gouverneur andco-workers and Nevado and co-workers using simple arenes as potential arylprecursors in intramolecular processes [61 62]

This strategy for difunctionalizations of alkenes suffers from some seriouslimitations such as a lack of substrate scope For example electron rich alkenesubstrates (eg styrenes) and boronic acids featuring electron rich substituents (egoxygen nitrogen substituents) on the aryl ring are not well tolerated under the harshoxidative reaction conditions implicit to the use of the very strong oxidantSelectfluor Moreover these methods have been so far limited to mono-substitutedterminal alkenes

Au XL Au XL

FI III

Au FL

XIII

TsN

Au FL

XIII

TsN

PhB OH

OH

++

NN

F

Cl

2BF4

NN

Cl

BF4

H+

PhB(OH)2 (28)

NHTs

58

TsN

Ph

FB(OH)2

A

BC

oxidationreductive nucleophilic

substitution

nucleophilic attack

55

Scheme 27 Proposedmechanism for thegold-catalyzed heteroarylationof non-activated alkenes[54ndash56]

213 Aryldiazonium Salts Synthesis and Reactivity

Aryldiazonium salts are attractive reactants used in different fields of chemistrysuch as nucleophilic aromatic substitution reactions [63] transition metal catalysisas alternatives to aryl halides and aryl triflates [64] material chemistry for surfacemodification [65] and most importantly radical chemistry [66] as excellent arylradical sources The chemistry of diazonium salts benefits from (a) very easypreparation even in large scale (b) typically high chemoselectivity incross-coupling reactions due to their superior reactivity compared to aryl halides(c) ambient reaction conditions and (d) easy removal of a gaseous leaving group(nitrogen gas) without interfering reaction components [67]

Aryldiazonium salts 7 can be prepared from commercially available anilines 64in an aqueous medium with sodium nitrite and a strong acid (eg HBF4)(Scheme 29) [68] In organic solvents (Et2O DME or THF) aryldiazonium saltsare prepared using organic nitrites (tBuONO or iAmONO) and BF3-Et2O(Scheme 29) [69] The stability of the aryldiazonium salts can be tuned bychoosing an appropriate counteranion such as the o-benzenedisulphonimide anionwhich results in a high degree of stabilization and can be reused [70] In manyrecent studies aryldiazonium salts are generated in situ using organic nitrites(tBuONO or iAmONO) in organic solvents (eg CH3CN) and directly used in thenext step [71ndash74]

Depending on the reaction conditions (counteranion nucleophilic additivesolvent reducing agent and wavelength of light) aryldiazonium salts can undergohomolytic cleavage or heterolytic cleavage to obtain aryl radicals or cationsrespectively (Scheme 210) [66] Single electron reduction of aryldiazonium saltswith subsequent loss of dinitrogen delivers aryl radicals which participate inclassical name reactions (a) the Sandmayer reaction [75ndash77] (b) the Pschorr

R1( )n R1

( )n

OR3

R2

M

R2

R1 = alkyl aryl heteroarylR2 = EDG amp EWGR3 = H alkyl carbonyl

(dppm)(AuBr)2 (5 mol)Selectfluor (20 equiv) R3OH

CH3CN 50 degC 14 hToste and co-workers

Ph3PAuCl (5 mol)Selectfluor (20 equiv) R3OH

CH3CN 70 degC 15 hRussel and co-workers

M = B(OH)2

M = SiMe3

M = B(OH)2 33-91M = SiMe3 37-96

M = SiMe3

Scheme 28 Oxidative gold-catalyzed intermolecular oxyarylation of non-activated alkenes[58ndash60]

21 Introduction 35

cyclization [78] (c) the Gomberg-Bachmann reaction [79ndash81] and (d) theMeerwein arylation [82 83] and also many conceptually novel and syntheticallyimportant organic transformations [66 67 71 84] There are many single electronreductants known such as Cu(I) salts [75 76 85 86] FeSO4 [87] ferrocene [87]ascorbic acid [72 87] TiCl3 [88ndash90] Bu4NI [73 74] and TEMPONa [91] togenerate aryl radicals from aryldiazonium salts at ambient temperature [81] In thisdirection of research under visible light irradiation polypyridyl metal complexes(eg [Ru(bpy)3]Cl2) and organic dyes (eg eosin Y or fluorescein) are highlyefficient at generating aryl radicals from aryldiazonium salts allowing for milderconditions for subsequent reactions [67 92ndash94]

214 Diaryliodonium Salts Synthesis and Reactivity

Since the seminal report on diaryliodonium salts was published by Hartmann andMeyer [95] in 1894 diaryliodonium salts IUPAC nomenclature ldquodiaryl-λ3-iodi-nanesrdquo constitute a synthetically highly important class of hypervalent iodinecompounds which are widely applied in many different fields of chemistry such asin synthetic organic chemistry as arylating agents [96 97] in polymer chemistry as

NH2

NaNO2 aq HBF4

H2O 0-5 degC

tBuONO or iAmONO

BF3-Et2O Ether -15 degC

iAmONO

HCO2H or CH3CO2H0-5 degC

R1

N2X

R1

SN

S

O O

R1= H EWG EDG7

X = BF4

SHN

S

O O

64

Scheme 29 Synthesis of aryldiazonium salts [68 69]

NN

- N2

SETb) heterolytic cleavagea) homolytic cleavage

- N2

Scheme 210 Reactivity of diazonium salts (a) homolytic cleavage (b) heterolytic cleavage

cationic photoinitiators [98 99] and as precursors to 18F-labelled compounds usedin Positron Emission Tomography (PET) imaging [100]

Some important features of diaryliodonium compounds which highlight itsimportance in practical applications are listed below (a) these reagents are non-toxic mild and moisture and air stable (b) symmetrical diaryliodoniums have noissue of selectivity whereas unsymmetrical examples typically selectively transferone aryl group over another one depending on electronic factors sterics (eg theuse of a bulkier dummy aryl group generally favours transfer of the other arylmoeity) [101] and also the reaction conditions (c) diaryliodonium salts have veryhigh electrophilicity and possess a strong aryl iodide leaving group [102] (d) easycounteranion exchange has given access to a wide variety of these compoundswhich allows for judicious selections to be made to avoid potential nucleophilicattack by the counteranion under the reaction conditions or to improve solubilityTypically diaryliodonium salts with halide counteranions are sparingly soluble inorganic solvents while non-coordinating BF4 and OTf lead to improved solubility inmany widely-employed solvents [96 97]

There are many synthetic routes already developed giving access todiaryliodonium salts for practical applications in organic synthesis [96 97] Someselected routes starting from different arene precursors are shown in Scheme 211[103ndash108]

These compounds are highly electrophilic in nature at the iodine center due tothe presence of a node of a non-bonding orbital that resides on iodine Therebydiaryliodoniums react with many different nucleophiles at the iodine center Thereaction occurs through initial NundashI bond formation followed by reductive elimi-nation of one aryl group and nucleophile from the iodine center (Scheme 212a)[96] Moreover oxidative addition of these compounds to transition metals (egcopper palladium etc) results in arylndashmetal intermediates which can take part insubsequent steps of the transformation such as in cross-coupling (Scheme 212b)[96] In the presence of single electron reductants diaryliodonium salts can affordaryl radicals (Scheme 212c) [66] Very recently diaryliodonium salts have beenused by the scientific community in photoredox catalysis as aryl precursors togenerate aryl radicals for arylation of alkenes and arenes under mild conditions(Scheme 212c) [109 110]

22 Results and Discussion

221 Inspiration

In one of the earlier reports of photoredox catalysis in 1984 Deronzier andco-workers described the Pschorr reaction for the synthesis of phenanthrenederivatives 1 from aryldiazonium salts 3 in the presence of [Ru(bpy)3](BF4)2 (5 mol) in acetonitrile under visible light irradiation (gt410 nm) from a 250 W Hg lamp

21 Introduction 37

(Scheme 213 and see Sect 1411) [111] This method avoids the formation of theundesired byproduct 2 under direct photolysis (gt360 nm) and benefits from milderreaction conditions compared to previously reported electrochemical processes[112] or thermal methods (Scheme 213) [113 114]

After several intervening years in 2011 Sanford and co-workers realized thepotential of Deronzierrsquos system and successfully applied it to their well-established

I X

IO

IHO OTs R1

R2I

R1

R1R1

R1

mCPBA (1 equiv)TfOH (2-3 equiv)

CH2Cl2 rt

(4 equiv)

1 mCPBA (1 equiv)BF3OEt2 (2 equiv)

CH2Cl2 rt

2 rtB(OH)2

R2(11 equiv)

31-88

H2SO4 orAcOH Ac2O H2SO4

R2 23-98

R229-63

TMS

CH3CN heat R1 R2 = EWG EDGX = HSO4 OTs OTf BF4

(10 equiv)

I

R251-92

Scheme 211 Synthesis of diaryliodonium salts [103ndash108]

IAr1 Ar1 NuAr1 I Ar1NuX X

IAr1 Ar1 MXAr1Ar1X M

(a)

(c)

(b)

IAr1 Ar1 Ar1XIr-photocatalyst

X

follow up reactions

I

Ar1 IMetal precursors

or

Scheme 212 Reactivity of diaryliodonium salts a nucleophilic substitution b oxidative additionto metals c aryl radical formation under visible light photoredox catalysis

CO2H

CO2HHN

O

CH3CNvisible light

R1

CO2H

R1 R1

1 2R1 = H Br OMe

R1 = H

R1 = BrR1 = OMe

20

10

8020

8080

direct photolysis

CH3CN

N2BF4

3

1

Scheme 213 Pschorr reaction under photoredox catalysis and direct photolysis [111]

directed ortho-selective CndashH arylation process combining photoredox with palla-dium catalysis to access Pd(II)Pd(IV) catalytic cycles (Scheme 214 and seeSect 1412) [115]

Inspired by these two seminal reports we were interested in developing a dualcatalytic system combining photoredox catalysis and gold catalysis and anticipatedthat in analogy to Pd(II)Pd(IV) cycles photoredox-generated aryl radicals fromaryldiazonium salts may facilitate Au(I)Au(III) catalytic cycles and enable theoxyarylation of alkenes while avoiding strong external oxidants and benefiting frommilder reaction conditions

222 Intramolecular Oxy- and Aminoarylation of Alkenes

2221 Preliminary Tests and Optimization Studies

In a preliminary test 4-penten-1-ol (54) was treated with 40 equiv of phenyl-diazonium tetrafluoroborate (65) in the presence of 10 mol of the gold(I) pre-catalyst (triphenylphosphine)gold(I) chloride (Ph3PAuCl) and 5 mol of [Ru(bpy)3](PF6)2 in degassed methanol (01 M) under visible light irradiation from a23 W compact fluorescent light (CFL) bulb for 6 h To our delight we observed the5-exo-trig cyclization-arylation product 2-benzyl tetrahydrofuran (57) in 51 NMR yield as the major product (Table 22 entry 1)

As the next step we performed exhaustive optimization studies of this cascadecyclization-arylation reaction (Table 22) Our first attempt to improve the yieldinvolved the screening of different gold catalysts with various ligands and coun-teranions The reaction efficiency was highly dependent on the gold catalysts usedfor these studies Neutral (dimethylsulfide)gold(I) chloride (Me2SAuCl) deliveredthe product 57 in only 20 NMR yield while the electron-rich NHC-gold com-plex IPrAuCl (IPr = 13-bis(26-diisopropyl-phenyl)imidazol-2-ylidene) was aninefficient catalyst for this process delivering only a trace amount of product 57

DG N2BF4 DG

R2

R1

2310 equiv

R1 R2

740 equiv

24

Scheme 214 Dual palladium and visible light-mediated photoredox-catalyzed directed CndashHarylation [115]

22 Results and Discussion 39

Table 22 Optimization studiesa

OHN2BF4 O

[M] catalyst[Ru(bpy)3](PF6)223 W CFL bulb

degassed solvent rt

54 65 57

Entry [M] catalyst (mol) mol [Ru(bpy)3]

2+Equivof 65

Solvent Time(h)

Yield()b

1 Ph3PAuCl (10) 50 4 MeOH 6 51

2 (Me2S)AuCl (10) 50 4 MeOH 12 26

3 IPrAuCl (10) 50 4 MeOH 12 Trace

4 [dppm(AuCl)2] (10) 50 4 MeOH 12 22

5 AuCl (10) 50 4 MeOH 12 Trace

6 AuCl3 (10) 50 4 MeOH 12 Trace

7 [(Pic)AuCl2] (10) 50 4 MeOH 12 Trace

8 [Ph3PAu]NTf2 (10) 50 4 MeOH 4 84

9 [PhtBu2PAu(CH3CN)]SbF6 (10)

50 4 MeOH 12 ndash

10 [(Ph3P)2Au]OTf (10) 50 4 MeOH 12 50

11 [IPrAu]NTf2 (10) 50 4 MeOH 12 Trace

12 [Ph3PAu]NTf2 (10) 50 4 CH3CN 12 20

13 [Ph3PAu]NTf2 (10) 50 4 14-Dioxane 12 20

14 [Ph3PAu]NTf2 (10) 50 4 Acetone 12 14

15 [Ph3PAu]NTf2 (10) 50 4 CH2Cl2 12 3

16 [Ph3PAu]NTf2 (10) 50 4 DMA 12 17

17 [Ph3PAu]NTf2 (10) 50 4 EtOH 12 66

18 [Ph3PAu]NTf2 (10) 25 4 MeOH 4 88(79)19 [Ph3PAu]NTf2 (10) 10 4 MeOH 12 61

20 [Ph3PAu]NTf2 (5) 25 4 MeOH 12 50

21 [Ph3PAu]NTf2 (1) 25 4 MeOH 75 22

22 [Ph3PAu]NTf2 (5) 12 4 MeOH 12 70

23 [Ph3PAu]NTf2 (5) 12 3 MeOH 12 60

24 Pd(OAc)2 (10) 25 4 MeOH 6 ndash

25 Cu(OAc)2 (10) 25 4 MeOH 8 ndash

26 PtCl2 (10) 25 4 MeOH 8 ndash

27 [Ph3PAu]NTf2 (10) ndash 4 MeOH 4 4

28 ndash 25 4 MeOH 4 ndash

29c [Ph3PAu]NTf2 (10) 4 4 MeOH 4 6aAlkenol 54 (02 mmol) phenyldiazonium salt 65 [Ru(bpy)3](PF6)2 the transition metal catalystand the solvent were added to a flame-dried Schlenk flask in the absence of light The mixture wasdegassed with three freeze-pump-thaw cycles flushed with argon sealed and stirred at rt undervisible light irradiation (23 W CFL bulb) for the designated timebNMR yield using diethyl phthalate as an internal reference Isolated yields in parenthesescThe reaction was conducted in the dark dppm diphenylphosphinomethane IPr 13-bis(26-diisopropylphenyl)imidazol-2-ylidene) Pic picolinato

(Table 22 entry 2ndash3) The bimetallic gold complex (dppm)(AuCl)2(dppm = diphenylphosphinylmethane) which is known to be a good catalyst inoxidative Au(I)Au(III) catalysis [55] was less efficient in our study affordingproduct 57 in 22 NMR yield (Table 22 entry 4) Simple gold chloride (AuCl)without any ligand was unsuitable for the reaction (Table 22 entry 5) In a similarway gold(III) precatalysts AuCl3 and (Pic)AuCl2 (Pic = picolinato) were alsoinefficient catalysts for this reaction (Table 22 entry 6ndash7) Changing the coun-teranions from tightly bound chloride to loosely bound NTf2 led to a dramaticchange in the reaction efficiency The Gagosz catalyst [Ph3PAu]NTf2 which isconsidered to generate cationic [Ph3PAu]

+ upon solvation furnished product 57 in84 NMR yield (Table 22 entry 8) In a screen of cationic gold catalysts[PhtBu2PAu(CH3CN)]SbF6 showed no reactivity whereas coordinatively saturated[(Ph3P)2Au]OTf which is considered to be inactive in redox neutral gold catalysiscatalyzed this reaction in moderate efficiency delivering product 57 in 50 NMRyield (Table 22 entry 9ndash10) Again the cationic NHC-gold complex IPrAuNTf2remained ineffective to promote this reaction (Table 22 entry 11) After screeningof 11 different gold catalysts the Gagosz catalyst [Ph3PAu]NTf2 was found to bethe best for this transformation In a solvent screen methanol remained the bestsolvent for this process On moving from methanol to other non-alcoholic solventssuch as CH3CN 14-dioxane acetone CH2Cl2 and DMA the efficiency of thereaction dropped dramatically (Table 22 entry 12ndash16) In another alcoholic sol-vent ethanol a significant drop of reaction efficiency was also observed with theproduct 57 being afforded in 66 NMR yield (Table 22 entry 17) Loweringthe loading of the photocatalyst [Ru(bpy)3](PF6)2 from 5 to 25 mol furnished theproduct 57 in 88 NMR yield enhancing the reaction efficiency however furtherlowering the loading to 1 mol reduced the reaction efficiency again (Table 22entry 18ndash19) Lowering the gold catalyst loading from 10 to 5 and 1 mol had anadverse effect on the efficiency of the reaction (Table 22 entry 20ndash21) Whenloadings of gold and photocatalyst were reduced to 5 and 12 mol respectivelykeeping the ratio between the gold catalyst and photocatalyst same the efficiency ofthe reaction decreased (Table 22 entry 22) A similar effect was also observedwhen the stoichiometry of the phenyldiazonium salt 65 was reduced to 30 equiv(Table 22 entry 23) On the other hand the other transition metal catalystsPd(OAc)2 CuOAc and PtCl2 did not catalyze the reaction at all (Table 22 entry24ndash26) As a result of these studies the combination of 10 mol [Ph3PAu]NTf225 mol [Ru(bpy)3](PF6)2 and 40 equiv of the phenyldiazonium salt in methanol(01 M) as the solvent was identified as the optimized conditions for thistransformation

Control reactionss confirmed the necessities of all three components the pho-toredox catalyst [Ru(bpy)3](PF6)2 the gold catalyst [Ph3PAu]NTf2 and light(Table 22 entry 27ndash29) Without [Ru(bpy)3](PF6)2 the reaction gave only 4 yield of the product while without [Ph3PAu]NTf2 no reactivity was observed(Table 22 entry 27ndash28) In the absence of light a trace amount of product 57(6 ) was observed (Table 22 entry 29)

2222 Substrate Scope and Limitations1

With these optimal reaction conditions in hand we next investigated the scope andlimitations of the developed dual catalytic method for the oxyarylation of alkeneswhich are summarized in Tables 23 and 24

Varying the alkene substrates

At the beginning the scope and limitations of the process with respect to thealkene substrates was explored by treating 4-methylphenyldiazoniumtetrafluoroborate (86) with various substituted alkenol substrates 66ndash75 Thereaction conducted with (plusmn) 3-phenylpent-4-en-1-ol 66 a primary alcohol affordedthe cyclization-arylation product (plusmn) 2-(4-methylbenzyl)-3-phenyltetrahydro-furan76 in 70 yield and 161 dr while (plusmn) trans-2-allylcyclohexenol 67 a sec-ondary alcohol delivered (plusmn) 2-(4-methylbenzyl)octahydro-benzofuran 77 in 66 yield and 281 dr showing the tolerance of the process towards substituents on thealkyl tether (Table 23 entry 1ndash2) Under the same reaction conditions a tertiaryalcohol 3-ethylhept-6-en-3-ol 68 was reacted with 4-methylphenyldiazonium salt86 to obtain the corresponding oxyarylation product 22-diethyl-5-(4-methylbenzyl)tetrahydro-furan 78 in 56 yield (Table 23 entry 3) The reactions of11-disubstituted alkenes 69 and 70 which are unsuitable substrates for previouslyreported gold-catalyzed heteroarylations of alkenes under oxidative conditions [5455] were successful coupling partners in this study affording the desired oxyary-lation products 79 (39 ) and 80 (63 ) respectively (Table 23 entry 4ndash5) Incontrast to previously-reported oxidative gold-catalyzed heteroarylations of alkenes[54 55] internal alkenes (E)-71 and (Z)-72 were successfully employed in thisoxyarylation process under dual catalytic conditions to furnish the expectedoxyarylation products (plusmn) (RR)-81 (59 ) and (plusmn) (RS)-82 (56 ) with excellentdiastereoselectivities (in both cases dr gt 251) respectively (Table 23 entry 6ndash7)This high diastereoselectivity supports the involvement of the gold catalyst in thestereochemistry-determining steps and provides mechanistic evidence for the pro-cess (vide infra) The alkenol 75 with an extra CH2 tether was suited for this processaffording the product 85 in 34 yield (Table 23 entry 10) Alkene substrates withnitrogen nucleophiles were also successfully employed in this process Substrates73 and 74 with pendant protected amine nucleophiles delivered the correspondingpyrrolidine products 83 (84 ) and 84 (54 ) respectively (Table 23 entry 8ndash9)

Varying the aryldiazonium salts

Aryldiazonium salts 86ndash92 with diverse substitution patterns were investigatedin this study using 4-penten-1-ol as the alkene under the optimized reaction con-ditions (Table 24) Aryldiazonium salts 86 and 87 bearing electron-neutral methyland phenyl substituents respectively were well suited for this transformation givingrise to the corresponding products 93 (78 ) and 94 (64 ) (Table 24 entry 2ndash3)

1A part of the substrate scope studies was carried out by Dr Matthew N Hopkinson (WWU)

Table 23 Scope of alkene substratesa

XH

R2R3

R1

( )n( )n

X R3 R2

R1

N2BF410 mol [Ph3PAu]NTf2

25 mol [Ru(bpy)3](PF6)223 W CFL bulb

degassed MeOH rt

Entry Alkenols Product Yield(dr)[][b]

OH

170 (161)

O

OOH

66 (281)2

OH O3

56

OH

O R

O

R

59 (gt251)

3963

NHTs

RR

TsN

RR

45

6

8[d]

9[d]

10 OH O34

8454

R4 R4

PhPh

X = O Nn = 1 2

R = MeR = Ph

OH O

56 (gt251)7[c]

R = HR = Me

67

68

66

6970

7374

71

72

75

76

77

7980

78

81

82

8384

85

40 equiv

aGeneral conditions 66ndash75 (02 mmol 1 equiv) [Ph3PAu]NTf2 (002 mmol) [Ru(bpy)3](PF6)2(0005 mmol) 86 (40 equiv) degassed MeOH (01 M) rt 4ndash16 h 23 W fluorescent light bulbbIsolated yields dr determined by 1H NMRcReaction performed on a 04 mmol scaled50 equiv of 74 used

The aryldiazonium salt 88 with an electron-withdrawing ester functionality was themost efficient coupling partner among the tested aryldiazonium salts furnishing thedesired product 95 in 83 yield (Table 24 entry 4) Aryldiazonium salts 89ndash91featuring electron-withdrawing halogen functional groups such as fluoride bromideand also bromide and chloride together were successfully employed in this processto obtain the oxyarylation products 96ndash98 in which chloride and bromide func-tionalities are available for further functionalization (Table 24 entry 5ndash7)Aryldiazonium salt 92 bearing both an electron-withdrawing trifluoromethyl groupand an electron-donating methoxy group was tolerated under the reaction condi-tions giving rise to the desired product 99 in 32 yield (Table 24 entry 8) Innone of the cases was the protodeauration product detected in the reaction mixture

223 Intermolecular Oxyarylation of Alkenes

Since a multicomponent intermolecular process is more difficult than itsintramolecular version it is highly encouraging to develop methodologies for theintermolecular difunctionalization of alkenes for constructing important complexbuilding blocks One of the common methods for the arylation of alkenes in anintermolecular fashion is the palladium-catalyzed Mizoroki-Heck reaction involv-ing aryl halides and alkenes as coupling components to deliver styrene derivativesHowever there has been a significant research attention paid to the development ofmethodologies for the addition of two functional groups across the C=C doublebond instead of maintaining the alkene functionality In this regard we extendedour previously developed dual catalytic methodology to the selective three com-ponent oxyarylation of terminal alkenes under milder reaction conditions comparedto previously-reported methods [58ndash60]

In a preliminary test we employed our previously-developed standard reactionconditions where a terminal alkene 1-octene (100) was reacted with 40 equiv ofphenyldiazonium tetrafluoroborate (65) in the presence of 10 mol of [Ph3PAu]NTf2 and 25 mol of [Ru(bpy)3](PF6)2 in degassed methanol (01 M) undervisible light irradiation from a 23 W CFL bulb for 16 h We were delighted toobserve selective formation of the oxyarylation product (2-methoxyoctyl)benzene(102) in 90 NMR yield and 84 isolated yield as the major product

In order to optimize this reaction2 various gold catalysts with electron-richphosphines (tricyclohexylphosphine and tris(4-methoxyphenyl)phosphine) and anelectron-poor phosphine (tris(4-trifluoromethylphenyl)phosphine) were screened

2The optimization studies were carried out by Dr Matthew N Hopkinson (WWU Muumlnster)

Table 24 Scope of aryldiazonium salts for the AuRu-catalyzed oxyarylation of alkenesa

OH

10 mol [Ph3PAu]NTf225 mol [Ru(bpy)3](PF6)2

23 W CFL bulb

degassed MeOH rt

O

Entry [Ar-N2]BF4 Product Yield ()[b]

1

2

3

4

5

6

7

8

N2BF4

F

N2BF4

Ph

N2BF4

Cl

N2BF4

EtO2C

Br

N2BF4

OMe

N2BF4

79

78

64

83

75

60

42

F3C

Br

O

PhO

OOEtO

FO

BrO

Cl

Br

O

OMe

F3C

32

R1

N2BF4

R1

40 equiv

65

86

87

88

89

90

91

92

57

93

94

95

96

97

98

99

aAlkenol 54 (02 mmol) aryldiazonium salt 65 86-92 (08 mmol) [Ph3PAu]NTf2 (002 mmol)[Ru(bpy)3](PF6)2 (0005 mmol) and MeOH (2 mL) were added to a flame-dried Schlenk flask inthe absence of light The mixture was degassed with three freeze-pump-thaw cycles flushed withargon sealed and stirred at rt under visible light irradiation (23 W compact fluorescent light bulb)4ndash12 hbIsolated yield

because our previous intramolecular oxyarylation reactions were highly liganddependant favouring phosphine ligands In the survey of different photoredoxcatalysts such as the polypyridyl metal complexes ([Ru(bpy)3](PF6)2 and [Ir(ppy)2(dtbbpy)](PF6)) and organic dyes (eosin Y fluorescein rhodamine B androse bengal) and light sources (23 W CFL blue LEDs green LEDs) we found thata combination of 10 mol of [Ph3PAu]NTf2 and 5 mol of fluorescein indegassed methanol (01 M) under visible light irradiation from a 23 W CFL bulbcould catalyze the reaction of 1-octene (100) with 40 equiv of the phenyldiazo-nium salt with the highest efficiency delivering (2-methoxyoctyl)benzene (102) in88 NMR yield and 86 isolated yield (Scheme 215a) The use of an inex-pensive photoredox catalyst fluorescein dye (404 times cheaper than previouslyused [Ru(bpy)3](PF6)2 according to the prices offered by Sigma Aldrich in June2014) made this protocol more attractive In order to replace comparatively lessstable aryldiazonium salts air and moisture stable diaryliodonium salts were testedin the same reaction After an exhaustive screening of many different gold catalystswith a variety of ligands various photoredox catalysts light sources mixture ofsolvents and diaryliodonium salts with different counteranions we were delightedto find optimized reaction conditions for this process where treating 1-octene (100)with 40 equiv of diphenyliodonium tetrafluoroborate (101) in the presence of10 mol of [Ph3PAu]NTf2 and 5 mol of [Ir(ppy)2(dtbbpy)](PF6) in degassedmethanol (01 M) under visible light irradiation from 5 W blue LEDs furnished(2-methoxyoctyl)benzene (102) in 91 NMR yield and 82 isolated yield as themajor product (Scheme 215b) It is worth mentioning that organic dyes did notcatalyze this reaction with diaryliodonium salts and that a more strongly reducingiridium photocatalyst was required

[Ph3PAu]NTf2 (10 mol)fluorescein (5 mol)

MeOH rt 16 h23 W CFL bulb100 65

40 equiv

O

102 82100

[Ph3PAu]NTf2 (10 mol)[Ir(ppy)2(btbbpy)](PF6) (5 mol)

MeOH rt 20 h5 W blue LEDs101

40 equiv

(a)

(b)

O

102 86

N2BF4

IPh BF4

Scheme 215 Intermolecular oxyarylation of alkenes a Oxyarylation with aryldiazoniumtetrafluoroborate b oxyarylation with diaryliodonium tetrafluoroborate

Having optimized reaction conditions for both the methods in hand we exploredthe scope and limitations of both protocols for intermolecular oxyarylation in termsof alkene substrates and arylprecursors (conditions A with aryldiazonium andconditions B with diaryliodonium salts) (Table 25)

In contrast to previously reported oxyarylations of activated alkenes whichproceed via radical-addition [91 110 116 117] we could successfully employunactivated alkenes without requiring any radical stabilizing groups in these dualcatalytic methods In none of the cases were styrene-type products resulting fromMizoriki-Heck coupling or hydroetherification could be detected under the opti-mized reaction conditions Electron-withdrawing and electron-donating functionalgroups on the aryl ring in the aryldiazonium and diaryliodonium salts were welltolerated Substrates bearing a methyl substituent at the ortho- meta- or para-positions of the aryl ring were all suitable for this process under both reactionconditions employing aryldiazonium and diaryliodonium salts but a different trendof tolerance was observed in these studies The para-methyl-substituted aryldia-zonium salt reacted efficiently delivering the desired ether product 103 in 62 yield while the corresponding diaryliodonium salt afforded same product 103 in apoor yield (26 ) An opposite trend of reactivity was observed for ortho-methyl-substituted substrates with the aryldiazonium salt producing the desiredether product 104 in 28 yield (conditions A) and the diarylaiodonium salt leadingto 104 in 75 yield (conditions B) A meta-methyl substituent in both the caseswas well tolerated under both sets of reaction conditions Electron-withdrawingbromide functionality was also well tolerated under both reaction conditions fur-nishing the expected ether product 106 susceptible for further functionalization ingood yield (conditions A 69 and conditions B 65 ) Diaryliodonium saltsfeaturing electron-withdrawing fluorine and trifluoromethyl functional groups weresuccessfully applied for this process only under the reaction conditions B affordingthe ether products 107 (82 ) and 108 (36 ) respectively Ethyl ester function-ality at the para-position on the aryl ring of the aryldiazonium salt and at the meta-position on the aryl ring of the diaryliodonium salt was tolerated in theseoxyarylation processes delivering the corresponding products 109 (64 ) and 110(50 ) respectively in good to moderate yields Both compounds were isolatedwith contamination with small amounts of the corresponding methyl esters resultingfrom transesterification with the methanol solvent Diverse functional groups on thealkenes were tolerated in these dual-catalyzed oxyarylation reactions under bothsets of reaction conditions affording the ether products 111ndash114 in moderate togood yields Alkene substrates having pendant 4-methoxyphenol and a protectedamine N-phthalimide group were also successful in this process under reactionconditions B giving products 115 (26 ) and 116 (52 ) respectively in low tomoderate yields Apart from methanol other oxygen nucleophiles such as ethanol

3A part of the substrate scope was carried out by Dr Matthew N Hopkinson (WWU Muumlnster)

Table 25 Scope of intermolecular oxyarylation of alkenes with aryldiazonium salts anddiaryliodonium saltsa

OR2

102 (R2 = H) A 86 B 82 (B 20 mmol scale 91)103 (R2 = p-Me) A 62 B 26105 (R2 = m-Me) A 70 B 60104 (R2 = o-Me) A 28 B 75106 (R2 = p-Br) A 69 B 65107 (R2 = p-F) B 82 108 (R2 = p-CF3) B 36109 (R2 = p-CO2Et) A 50

[a]

110 (R2 = m-CO2Et) B 50[b]

Ph O

OPh

O

111A 75 B 78

O2N

O

OPh

Br

O

OPh

MeO2CPh

OMeO2C

Ph

MeO

O

OPh

115B 26

OR3

117 (R3 = Et) B 75118 (R3 = iPr) B 26

Y Ph

57 (Y = O) B 68120 (Y = NTs) B 79

112A 60 B 66

113A 84 B 82

114A 76 B 67

N

OPh

116B 52

O

119 B 26

O

R1

[Ph3PAu]NTf2 (10 mol)[Ir(ppy)2(dtbbpy)]PF6 (5 mol)

R3OH blue LEDs rt 20 h[Ar2I]BF4 (40 equiv)

Condition B

R1 ArO

R3[Ph3PAu]NTf2 (10 mol)

fluorescein (5 mol)

R3OH 23 W CFL rt 16 hArN2BF4 (40 equiv)

Condition A

R1

Reaction conditions A Alkene (02 mmol) aryldiazonium salt (08 mmol) [Ph3PAu]NTf2 (10 mol) and fluorescein (5 mol) in degassed MeOH (01 M) reacted in the presence of visible lightfrom a 23 W CFL for 16 h at rt Isolated yieldsaIsolated as a 928 mixture with the corresponding methyl esterReaction conditions B Alkene (02 mmol) diaryliodonium salt (08 mmol) [Ph3PAu]NTf2(10 mol) and [Ir(ppy)2(dtbbpy)]PF6 (5 mol) in degassed MeOH (01 M) reacted in thepresence of visible light from blue LEDs at rt for 20 h Isolated yieldsbIsolated as a 8119 mixture with the corresponding methyl ester

and isopropanol and even acetic acid were successfully employed in these studies togive access to ether 117ndash118 and ester 119 compounds although these nucleophileswere used as solvent We repeated the intramolecular oxy- and aminoarylation ofalkenes 54 and 73 under reaction conditions B using diaryliodonium salts Thesereactions delivered the corresponding tetrahydrofuran and pyrrolidine products 57and 120 showing that diaryliodonium salts are suitable aryl sources for ourpreviously-developed intramolecular heteroarylations of alkenes Finally werepeated the parent reaction with 1-octene diphenyliodonium tetrafluoroborate(101) and methanol on a 20 mmol scale which produced the expected product 102in 91 yield This showed that the reaction efficiency does not drop uponscaling-up the reaction

In order to investigate the selectivity of aryl transfer from diaryliodonium saltswe employed an unsymmetrical diaryliodonium salt (121) having electronicallyslightly different phenyl and para-bromophenyl groups (Scheme 216)Interestingly the electron-deficient para-bromophenyl group was transferred in aslight preference over the electron-neutral phenyl group furnishing product 106 and102 in a ratio of 131 and in 90 combined NMR yield

224 Mechanistic Studies on Heteroarylations of Alkenes4

In order to gain insight into the reaction mechanism we conducted a literaturesurvey and performed control experiments The results obtained from controlexperiments confirmed that all the components (the gold catalyst photoredox cat-alyst and visible light) are essential for this process (Table 22 entry 27ndash29) In theabsence of one of these three components either the reaction shut down or thereaction efficiency dropped dramatically

In order to investigate whether visible light irradiation is required throughout thereaction or only to initiate the process a light off-on experiment was conducted Inthis test the reaction between 4-penten-1-ol (54) and phenyldiazoniumtetrafluoroborate (65) was performed under the optimized reaction conditions on a02 mmol scale in degassed deuterated methanol (Scheme 217) The reactionmixture was subjected to stirring for sequential periods of time under visible lightirradiation from a 23 W CFL bulb followed by stirring in the dark At each timepoint an aliquot (200 microL) of the reaction mixture was taken out under argonatmosphere which was then quenched with D2O (50 microL) and diluted with a CDCl3solution (500 microL) containing the internal standard diethyl phthalate The measuredNMR yields of tetrahydrofuran 57 are displayed in Fig 22

The outcome of this experiment indicated that the reaction proceeds smoothlyunder visible light irradiation The reaction shut down when irradiation of thereaction mixture was stopped and the reactivity could be recovered upon switching

4A part of the mechanistic studies was carried by Dr Matthew N Hopkinson (WWU Muumlnster)

on the light again This experiment confirmed that continuous visible light irradi-ation is mandatory for the completion of this process

The reaction with the activated styrene substrate 70 which could potentiallyreact with aryl radicals directly in a Meerwein-type arylation process with aryl-diazonium salt 86 under the standard reaction conditions afforded the corresponding

MeOH blue LEDsrt 20 h

O

106 (R = Br) 102 (R = H)131

(90 combined NMR yield)

100 121(40 equiv)

I

Br

BF4

+

R

Scheme 216 Oxyarylation of 1-octene with an unsymmetrical diaryliodonium salt 121

OHN2BF4 O[Ph3PAu]NTf2 (10 mol)

[Ru(bpy)3](PF6)2 (25 mol)

degassed CD3OD25 h rt

54 65 (40 equiv) 57

Scheme 217 Dual gold and photoredox-catalyzed oxyarylation of 4-penten-1-ol (54) withphenyldiazonium salt 65 in deuterated methanol (MeOH-d4)

Time (min) NMR Yield ()a

0 0

20

60

90

120

150

40

41

68

81

aDiethyl phthalate used as internal standard

Fig 22 Effect of visible light irradiation on the reaction efficiency

product 80 in 63 yield whereas only 14 yield of the product 80 was obtainedomitting the gold catalyst (Table 23 entry 5) These results suggested that whilethe Meerwein-type aryl radical addition to this activated alkene is possible thisprocess is less favorable than the gold-catalyzed process As shown by a controlreaction with 4-penten-1-ol 54 and from previous-studies on aryl radical additionreactions unactivated alkenes are poor substrates for this type of process implyingthat such a radical addition pathway is unlikely to be operating in thisdual-catalyzed reaction [84 91 118] In an analogous test employing anotheractivated styrene 122 where Meerwein-type addition would preferentially give riseto a 6-membered ring product (124) resulted in the exclusive formation of the5-membered ring oxyarylation product 123 albeit in a low yield of 17 with noproducts resulting from Meerwein-type radical addition being detected In a controlreaction without the gold catalyst no reactivity was observed with this substrateFrom the above two results it seemed that the gold-catalyzed process does notinvolve a Meerwein-type radical addition and even predominates over this pathwaywith activated alkenes (Scheme 218)

Although during the substrate scope study no protodeauration products [eg2-methyltetrahydrofuran (125)] were detected in any of the reaction mixtures stillthe possibility remained that products resulting from protodeauration might beformed under these acidic conditions and become arylated in a subsequent step Inthat situation we would not be able to detect protodeauration products In order torule out this possibility we treated 2-methyltetrahydrofuran (125) with phenyl-diazonium salt 65 under the standard reaction conditions and no formation of theoxyarylated product 57 was observed (Scheme 219) The lack of2-methyltetrahydrofuran or pyrrolidine products observed throughout this studysuggests that protodeauration of the alkylgold intermediate formed in this trans-formation is not an efficient process In a relevant mechanistic study Toste andco-workers isolated various alkylgold(I) complexes and tested their stability upontreatment with p-toluenesulfonic acid and in analogy to our experminental obser-vations obtained no protodeauration product [57]

In a study focused on elucidating the stereochemical relationship between thenucleophile and the aryl group in the final products the deuterium-labelledγ-aminoalkene substrates (D)-(E)-126 and (D)-(Z)-127 were reacted under thestandard conditions delivering the expected pyrrolidine products 128 and 129 withhigh diastereoselectivities respectively with the amino and aryl group being in an

OHO

[Ph3PAu]NTf2 (10 mol)[Ru(bpy)3](PF6)2 (25 mol)

23 W CFL bulbdegassed MeOH 16 h rt

86 (40 equiv)

Ph

(E)-122

Ph

123 17

O Ph

124not detected

Scheme 218 Dual gold and photoredox-catalyzed oxyarylation of styrene-type alkenol E-122with aryldiazonium salt 86

anti-relationship in both cases (Scheme 220) [54] This fact was determined bycomparing the 1H NMR spectra for these compounds with those reported by Zhanget al [54] who in turn determined the stereochemistry by an analysis of the dif-ferences in the vicinal 3JHH coupling constants resulting from restricted rotationaround the formerly olefinic CndashC bond Similar results were also obtained wheninternal γ-hydroxyalkenes (E)-71 and (Z)-72 were employed in the intramolecularoxyarylation process under the standard conditions where the expected oxyaryla-tion products (plusmn) (RR)-81 (59 ) and (plusmn) (RS)-82 (56 ) were furnished withexcellent diastereoselectivities (dr gt 251 in the both cases) respectively(Table 23 entry 6ndash7) The above stereochemical observations imply that thenucleophile and the aryl group add in a trans-fashion across the C=C double bondof the alkenes This stereochemical event can be rationalized by an initial anti-aminoauration or oxyauration of the alkenes followed by an arylation eventoccurring with retention of stereochemistry [eg via reductive elimination fromgold(III)]

Based on previous literature reports [109 115] and our mechanistic experimentstudies we hypothesized a reaction mechanism of the type shown in Scheme 221According to the previously reported studies on alkene activation with cationic gold(I) [57] we propose that a cationic gold(I) species derived from Gagoszrsquos catalyst

N2BF4 O[Ph3PAu]NTf2 (10 mol)[Ru(bpy)3](PF6)2 (25 mol)

65 (40 equiv) 57not observed

O

125

Scheme 219 Control experiment of 2-methyltetrahydrofuran 125 with phenyldiazonium salt 65under the standard reaction conditions

H DNTs

H

TsN

H

H D

3JHH = 96 Hz

TsN

H

D H

3JHH = 34 Hz

D HNTs

H

degassed MeOH 8 h rt23 W CFL bulb

D-(E)-126 (D = 94)

D-(RS)-(129) 68 dr = 171D-(Z)-127 (D = 84)

NHTs

D

H

NHTs

H

D

D-(RR)-(128) 73 dr = 141

N2BF4

65 (40 equiv) +-( )

+-( )

Scheme 220 Dual gold and photoredox-catalyzed aminoarylation of deuterated γ-amino-alkenes(126ndash127) with phenyldiazonium salt 65

could coordinate to the alkene 130 and activate it towards anti-attack of an internalor external hydroxy or amine nucleophile leading to the formation of the alkylgoldintermediate A In a parallel photoredox catalytic cycle single electron reduction ofthe aryldiazonium salt or diaryliodonium salt with the photo-excited photoredoxcatalyst (PC) would release a nucleophilic aryl radical upon extrusion of dini-trogen or an aryl iodide molecule and generate the oxidized photoredox catalyst(PC+) At this stage the aryl radical could oxidize the alkylgold(I) intermediate A toobtain the highly reactive gold(II) intermediate B bearing both coupling fragmentsSpectroscopic and theoretical studies on the trapping of nucleophilic phenyl radicalsby gold(I) species to generate phenylgold(II) intermediates by Corma Garcia andco-workers strengthened this speculation [119] In the next step the unstable gold(II) intermediate B is expected to transfer an electron to the oxidized photoredoxcatalyst (PC+) via SET to regenerate the photoredox catalyst (PC) and deliver thegold(III) intermediate C Alternatively SET could occur with another molecule ofthe aryldiazonium or diaryliodonium salt in a radical chain process Fast reductiveelimination from gold(III) intermediate C at this point would furnish the oxy- oraminoarylation product 131 and regenerate the gold(I) catalyst

[PC]

[PC]+

SET

L [AuII]

Ar

L AuI

N2

ArN2+ (7)

or Ar2I+ (12)

R1

Nu

L AuI

R1

Nu

R1 130

R1 ArNu

131

or ArI

Ar

SET

nucleophilicaddition

PhotoredoxCatalysis

GoldCatalysis

H+

o R

R1 130

[PC] = photoredox catalyst (ie fluorescein [Ru(bpy)3]2+ or [Ir(ppy)2(dtbbpy)]+) Nu = O or NTs

or

(+ NuH forintermolecular)

7 or 12

Ar

N2 orArI

L [AuIII]

Ar

R1

Nu

A

B

C

[PC]

Scheme 221 A plausible reaction mechanism for intra- and intermolecular oxyarylation ofalkenes with aryldiazonium and diaryliodonium salts

23 Summary

In conclusion we have successfully combined two different catalytic modes goldcatalysis and photoredox catalysis in a novel dual catalytic system demonstratingtheir compatibility This novel dual catalytic system catalyzes oxyarylation andaminoarylation reactions of non-activated γ-hydroxyalkenes γ-aminoalkenes andalso a δ-hydroxyalkene with aryldiazonium salts to give access to substituted sat-urated heterocyclic compounds (tetrahydrofurans pyrrolidines and a tetrahy-dropyran) In contrast to previous reports on oxidative gold-catalyzedheteroarylations of alkenes [54 55] internal alkenes could successfully beemployed using this system This method avoids the use of strong external oxi-dizing agents such as Selectfluor hypervalent iodine reagent or tBuOOH whichlimit the substrate scope of previously-reported related processes Moreover thistransformation benefits from milder reaction conditions and the use of readilyavailable visible light sources This concept can be extended to multicomponentintermolecular oxyarylation of non-activated alkenes simple alcohols and aryl-diazonium salts using inexpensive fluorescein dye as the photocatalyst in place ofexpensive transition metal-based photocatalysts such as [Ru(bpy)3](PF6)2 Thecombination of the more oxidizing photocatalyst [Ir(ppy)2(dtbbpy)](PF6) and a goldcatalyst in the presence of visible light irradiation from blue LEDs enableddiaryliodonium salts which are readily prepared and air and moisture stable to beapplied in both intra- and intermolecular oxyarylation processes extending thescope of these reactions In this later method acetic acid could also be applied as anucleophile in addition to various alcohols

References

1 SG Bratsch J Phys Chem Ref Data 18 1ndash21 (1989)2 N Meacutezailles L Ricard F Gagosz Org Lett 7 4133ndash4136 (2005)3 MS Nechaev VM Rayoacuten G Frenking J Phys Chem A 108 3134ndash3142 (2004)4 A Fuumlrstner PW Davies Angew Chem Int Ed 46 3410ndash3449 (2007)5 A Furstner Chem Soc Rev 38 3208ndash3221 (2009)6 C-W Chan W-T Wong C-M Che Inorg Chem 33 1266ndash1272 (1994)7 W-P To GS-M Tong W Lu C Ma J Liu AL-F Chow C-M Che Angew Chem

Int Ed 51 2654ndash2657 (2012)8 Q Xue J Xie H Jin Y Cheng C Zhu Org Biomol Chem 11 1606ndash1609 (2013)9 MM Savas WR Mason Inorg Chem 26 301ndash307 (1987)

10 A Vogler H Kunkely Coord Chem Rev 219ndash221 489ndash507 (2001)11 G Revol T McCallum M Morin F Gagosz L Barriault Angew Chem Int Ed 52

13342ndash13345 (2013)12 M Tonelli S Turrell O Cristini-Robbe H El Hamzaoui B Capoen M Bouazaoui M

Gazzano MC Cassani RSC Adv 4 26038ndash26045 (2014)13 SJ Kaldas A Cannillo T McCallum L Barriault Org Lett 17 2864ndash2866 (2015)14 T McCallum E Slavko M Morin L Barriault Eur J Org Chem 2015 81ndash85 (2015)15 DJ Gorin FD Toste Nature 446 395ndash403 (2007)

16 ASK Hashmi Chem Rev 107 3180ndash3211 (2007)17 DJ Gorin BD Sherry FD Toste Chem Rev 108 3351ndash3378 (2008)18 E Jimeacutenez-Nuacutentildeez AM Echavarren Chem Rev 108 3326ndash3350 (2008)19 Z Li C Brouwer C He Chem Rev 108 3239ndash3265 (2008)20 RA Widenhoefer Chem Eur J 14 5382ndash5391 (2008)21 ASK Hashmi Angew Chem Int Ed 49 5232ndash5241 (2010)22 ND Shapiro FD Toste Synlett 2010 675ndash691 (2010)23 JJ Hirner Y Shi SA Blum Acc Chem Res 44 603ndash613 (2011)24 MN Hopkinson AD Gee V Gouverneur Chem Eur J 17 8248ndash8262 (2011)25 N Krause C Winter Chem Rev 111 1994ndash2009 (2011)26 M Rudolph ASK Hashmi Chem Commun 47 6536ndash6544 (2011)27 HA Wegner M Auzias Angew Chem Int Ed 50 8236ndash8247 (2011)28 L-P Liu GB Hammond Chem Soc Rev 41 3129ndash3139 (2012)29 M Rudolph ASK Hashmi Chem Soc Rev 41 2448ndash2462 (2012)30 I Braun AM Asiri ASK Hashmi ACS Catal 3 1902ndash1907 (2013)31 C Obradors AM Echavarren Chem Commun 50 16ndash28 (2014)32 Y-M Wang AD Lackner FD Toste Acc Chem Res 47 889ndash901 (2014)33 ROC Norman WJE Parr CB Thomas J Chem Soc Perkin Trans 1 1983ndash1987

(1976)34 JH Teles S Brode M Chabanas Angew Chem Int Ed 37 1415ndash1418 (1998)35 N Marion SP Nolan Chem Soc Rev 37 1776ndash1782 (2008)36 C-Y Wu T Horibe CB Jacobsen FD Toste Nature 517 449ndash454 (2015)37 KM Engle T-S Mei X Wang J-Q Yu Angew Chem Int Ed 50 1478ndash1491 (2011)38 M Bandini Chem Soc Rev 40 1358ndash1367 (2011)39 S Sengupta X Shi ChemCatChem 2 609ndash619 (2010)40 A Pradal PY Toullec V Michelet Synthesis 2011 1501ndash1514 (2011)41 L-P Liu B Xu MS Mashuta GB Hammond J Am Chem Soc 130 17642ndash17643

(2008)42 L Ye L Zhang Org Lett 11 3646ndash3649 (2009)43 MN Hopkinson GT Giuffredi AD Gee V Gouverneur Synlett 2010 2737ndash2742

(2010)44 AE Allen DWC MacMillan Chem Sci 3 633ndash658 (2012)45 Z Du Z Shao Chem Soc Rev 42 1337ndash1378 (2013)46 ASK Hashmi C Lothschuumltz R Doumlpp M Rudolph TD Ramamurthi F Rominger

Angew Chem Int Ed 48 8243ndash8246 (2009)47 Y Shi SD Ramgren SA Blum Organometallics 28 1275ndash1277 (2009)48 Y Shi KE Roth SD Ramgren SA Blum J Am Chem Soc 131 18022ndash18023 (2009)49 JJ Hirner SA Blum Organometallics 30 1299ndash1302 (2011)50 ASK Hashmi MC Blanco D Fischer JW Bats Eur J Org Chem 2006 1387ndash1389

(2006)51 HA Wegner S Ahles M Neuburger Chem Eur J 14 11310ndash11313 (2008)52 L Cui G Zhang L Zhang Bioorg Med Chem Lett 19 3884ndash3887 (2009)53 G Zhang Y Peng L Cui L Zhang Angew Chem Int Ed 48 3112ndash3115 (2009)54 G Zhang L Cui Y Wang L Zhang J Am Chem Soc 132 1474ndash1475 (2010)55 WE Brenzovich D Benitez AD Lackner HP Shunatona E Tkatchouk WA Goddard

FD Toste Angew Chem Int Ed 49 5519ndash5522 (2010)56 E Tkatchouk NP Mankad D Benitez WA Goddard FD Toste J Am Chem Soc 133

14293ndash14300 (2011)57 RL LaLonde JWE Brenzovich D Benitez E Tkatchouk K Kelley IIIWA Goddard

FD Toste Chem Sci 1 226ndash233 (2010)58 AD Melhado WE Brenzovich AD Lackner FD Toste J Am Chem Soc 132

8885ndash8887 (2010)59 LT Ball M Green GC Lloyd-Jones CA Russell Org Lett 12 4724ndash4727 (2010)60 WE Brenzovich J-F Brazeau FD Toste Org Lett 12 4728ndash4731 (2010)

References 55

61 MN Hopkinson A Tessier A Salisbury GT Giuffredi LE Combettes AD Gee VGouverneur Chem Eur J 16 4739ndash4743 (2010)

62 T de Haro C Nevado Angew Chem Int Ed 50 906ndash910 (2011)63 H Zollinger Acc Chem Res 6 335ndash341 (1973)64 A Roglans A Pla-Quintana M Moreno-Mantildeas Chem Rev 106 4622ndash4643 (2006)65 S Mahouche-Chergui S Gam-Derouich C Mangeney MM Chehimi Chem Soc Rev

40 4143ndash4166 (2011)66 C Galli Chem Rev 88 765ndash792 (1988)67 DP Hari B Koumlnig Angew Chem Int Ed 52 4734ndash4743 (2013)68 P Hanson JR Jones AB Taylor PH Walton AW Timms J Chem Soc Perkin Trans

2 1135ndash1150 (2002)69 MP Doyle WJ Bryker J Org Chem 44 1572ndash1574 (1979)70 M Barbero M Crisma I Degani R Fochi P Perracino Synthesis 1998 1171ndash1175

(1998)71 F Mo G Dong Y Zhang J Wang Org Biomol Chem 11 1582ndash1593 (2013)72 FP Crisoacutestomo T Martiacuten R Carrillo Angew Chem Int Ed 53 2181ndash2185 (2014)73 M Hartmann A Studer Angew Chem Int Ed 53 8180ndash8183 (2014)74 M Hartmann CG Daniliuc A Studer Chem Commun 51 3121ndash3123 (2015)75 T Sandmeyer Ber Dtsch Chem Ges 17 1633 (1884)76 T Sandmeyer Ber Dtsch Chem Ges 17 2650 (1884)77 HH Hodgson Chem Rev 40 251ndash277 (1947)78 R Pschorr Ber Dtsch Chem Ges 29 496 (1896)79 M Gomberg WE Bachmann J Am Chem Soc 46 2339ndash2343 (1924)80 OC Dermer MT Edmison Chem Rev 57 77ndash122 (1957)81 A Wetzel G Pratsch R Kolb MR Heinrich Chem Eur J 16 2547ndash2556 (2010)82 H Meerwein E Buchner K v Emsterk J Prakt Chem 152 237 (1939)83 GPratsch M Heinrich in Radicals in Synthesis III ed by M Heinrich A Gansaumluer

Vol 320 (Springer Berlin 2012) pp 33ndash5984 MR Heinrich Chem Eur J 15 820ndash833 (2009)85 H Brunner C Bluumlchel MP Doyle J Organomet Chem 541 89ndash95 (1997)86 P Mastrorilli CF Nobile N Taccardi Tetrahedron Lett 47 4759ndash4762 (2006)87 C Galli J Chem Soc Perkin Trans 2 1459ndash1461 (1981)88 ALJ Beckwith ROC Norman J Chem Soc B 403ndash412 (1969)89 A Citterio F Minisci A Albinati S Bruckner Tetrahedron Lett 21 2909ndash2910 (1980)90 R Cannella A Clerici N Pastori E Regolini O Porta Org Lett 7 645ndash648 (2005)91 M Hartmann Y Li A Studer J Am Chem Soc 134 16516ndash16519 (2012)92 J Xuan W-J Xiao Angew Chem Int Ed 51 6828ndash6838 (2012)93 CK Prier DA Rankic DWC MacMillan Chem Rev 113 5322ndash5363 (2013)94 DP Hari B Konig Chem Commun 50 6688ndash6699 (2014)95 C Hartmann V Meyer Ber Dtsch Chem Ges 27 426 (1894)96 EA Merritt B Olofsson Angew Chem Int Ed 48 9052ndash9070 (2009)97 MS Yusubov AV Maskaev VV Zhdankin ARKIVOC 1 370ndash409 (2011)98 Y Toba J Photopolym Sci Technol 16 115ndash118 (2003)99 JV Crivello J Polym Sci Part A Polym Chem 47 866ndash875 (2009)100 MS Yusubov DY Svitich MS Larkina VV Zhdankin ARKIVOC 1 364ndash395 (2013)101 KM Lancer GH Wiegand J Org Chem 41 3360ndash3364 (1976)102 T Okuyama T Takino T Sueda M Ochiai J Am Chem Soc 117 3360ndash3367 (1995)103 FM Beringer M Drexler EM Gindler CC Lumpkin J Am Chem Soc 75 2705ndash2708

(1953)104 FM Beringer RA Falk M Karniol I Lillien G Masullo M Mausner E Sommer

J Am Chem Soc 81 342ndash351 (1959)105 GF Koser RH Wettach CS Smith J Org Chem 45 1543ndash1544 (1980)106 CS Carman GF Koser J Org Chem 48 2534ndash2539 (1983)107 M Bielawski M Zhu B Olofsson Adv Synth Catal 349 2610ndash2618 (2007)

108 M Bielawski D Aili B Olofsson J Org Chem 73 4602ndash4607 (2008)109 SR Neufeldt MS Sanford Adv Synth Catal 354 3517ndash3522 (2012)110 G Fumagalli S Boyd MF Greaney Org Lett 15 4398ndash4401 (2013)111 H Cano-Yelo A Deronzier J Chem Soc Perkin Trans 2 1093ndash1098 (1984)112 RM Elofson FF Gadallah J Org Chem 36 1769ndash1771 (1971)113 AN Nesmeyanov LG Makarova TP Tolstaya Tetrahedron 1 145ndash157 (1957)114 B Maggio D Raffa MV Raimondi S Cascioferro S Plescia MA Sabatino G

Bombieri F Meneghetti G Daidone ARKIVOC 16 130ndash143 (2008)115 D Kalyani KB McMurtrey SR Neufeldt MS Sanford J Am Chem Soc 133

18566ndash18569 (2011)116 T Taniguchi H Zaimoku H Ishibashi Chem Eur J 17 4307ndash4312 (2011)117 Y Su X Sun G Wu N Jiao Angew Chem Int Ed 52 9808ndash9812 (2013)118 MR Heinrich A Wetzel M Kirschstein Org Lett 9 3833ndash3835 (2007)119 C Aprile M Boronat B Ferrer A Corma H Garciacutea J Am Chem Soc 128 8388ndash8389

(2006)

References 57

Chapter 3Visible Light Photoredox CatalyzedTrifluoromethylation-Ring Expansionvia Semipinacol Rearrangement

31 Introduction

311 General Features of Fluorinated Compounds

Fluorine with ground state electronic configuration [He]2s22p5 is the first memberof the halogen series (Group 9) in the periodic table It also has the second smallestatomic radius after hydrogen (rw = 147 and 120 Aring respectively) and it is the mostelectronegative element in the periodic table electronically fluorine is more similarto its neighbor oxygen (Pauling scale χ(F) 40 and χ(O) 35) than other halogens[1 2] The CndashF bond (d = 135 Aring) is 124 times longer than the CndashH bond(d = 109 Aring) yet the CndashF bond (CndashF bond 1054 kcalmol) is stronger than theCndashH bond (CndashH bond 988 kcalmol) [2] A trifluoromethyl (CF3) group is con-stituted when three fluorine atoms and one carbon atom are assembled formingthree C(sp3)-F bonds From structural point of view although a trifluoromethyl(CF3) group is usually compared to a methyl (CH3) group its size resembles anisopropyl group (CH(CH3)2) Due to the high electronegativity of fluorine elec-tronically the trifluoromethyl (CF3) group is highly electron-withdrawing andexerts a significant impact on pKa values thus influencing the acidity or basicity ofthe functional groups neighbor to it

312 Importances of Fluorinated Compounds

Fluorine was long thought to be an abiotic element limiting its application to militaryand some special material demands Moreover only a handful of organo-fluorinecompounds not more than a dozen exist in nature However 20 of all drugsand 30 of all agrochemicals in markets contain fluorinated compounds [3ndash8]A selection of fluorine containing drugs and agrochemicals with their respective

59

activities is shown in Fig 31 [3 5 8 9] The unique physicochemical properties offluorinated compounds have captured the attention of scientists in different fields ofresearch such as medicinal agrochemical polymer and material [3ndash5 7ndash11] Due tothe high bond energy the installment of fluorine or trifluoromethyl groups in drugmolecules reduces the susceptibility of oxidizing functionality to cytochrome P450enzyme thereby increasing metabolic stability [4] The high lipophilicity of fluori-nated drugs increases its membrane permeability The bioavailability and highlipophilicity of fluorinated agrochemicals increase their in vivo uptake and facilitatetransportation [3 5] For these reasons research in fluorine chemistry helps to designdrugs and improve the therapeutic efficacy and pharmacological properties of bio-molecules [5 8] In addition Teflon a perfluorinated polymer is used as a non-stickcoating in the production of cooking utensils due to its low friction coefficient [7]Moreover fluorinated solvents are used in catalyst recovery and purification formingan immiscible lsquofluorous phasersquo when these solvents are mixed with water or organicsolvents [12]

NN

SF3C

ON

OF

Flufenacet(Herbicide)

F3C O

CF3

O

O CN

HO

Acrinathrin(Insecticide amp Acaricide)

Triflumuron(Insecticide)

HN

O

NH

Cl

OCF3

NH

O

CF3Cl

Efavirenz(Antiviral)

OHN

F3C

Fluoxetine(Antidepressant)

N

OOH

HN

OF

HOHO

Atorvastatin(Colesterol Lowering)

N

F

Ciprofloxacin(Antibacterial)

O

OH

O

NHN

HN

NH

O

F

5-Fluorouracil(Anticancer)

HOH

SO

CF2CF3H

H

OH

Fulvestrant(Anticancer)

NH

NS

ON

OCF3

Lansoprazole(Anti-inflamatory)

Fig 31 Selected fluorine containing drugs and agrochemicals

60 3 Visible Light Photoredox Catalyzed Trifluoromethylation-Ring hellip

313 Radical-Polar Crossover Process

lsquoRadical-polar crossoverrsquo a term first introduced by John Murphy in 1993 [13] isan interesting concept applied in synthetic organic chemistry [14 15] In thisprocess a radical and a polar mechanisms are involved in the same reaction pot[14] In this type of reactions reactive intermediates involved in the radical processremain inert during the ionic process and vice versa therefore maintaining theorthogonality of radical and polar steps [14] One of the earlier reports on thisprocess is the tetrathiafulvalene (TTF) catalyzed cyclization-nucleophilic additionreaction of aryldiazonium salts (132) to obtain dihydrobenzofuran derivatives(133) reported by John Murphy and co-workers in 1993 (Scheme 31) [13] In thisprocess an electron transfer from TTF to an aryldiazonium salt (132) via SETresults in an aryl radical (134) and a radical-cation TTF+ The aryl radical (134)then adds onto the pendent alkene in a 5-exo-trig fashion leading to a secondaryalkyl radical 135 The radical 135 undergoes a radical-radical recombination withthe radical-cation TTF+∙ involving a radical-polar crossover event and affording thesulphonium intermediate 136 at the radical-polar step The nucleophilic substitutionreaction with water present in moist acetone affords the product 133

In multicomponent radical-polar crossover reactions a metal species is generallyused to selectively oxidize or reduce one of the radicals thus turning a radicalintermediate into ionic one [15]

314 Trifluoromethylation of Alkenes

Due to the high demand of fluorinated and trifluoromethyl substituted drugsagrochemicals and materials in the market the development of environmentalfriendly cost effective operationally simple and highly efficient methods for

O

N2BF4

S

SS

S

SS

SO O O

S S

SS

O

OH

S

SS

S

SS

S

N2

moisted acetone

H2O

H+BF4

-SET nucleophilic

substitution

radicaladdition

radical-radicalcombination

TTF (Cat)

TTF TTF

TTF

133 36132

134 135 136

Scheme 31 Radical-polar crossover reaction and mechanism [13]

31 Introduction 61

trifluoromethyl group incorporation in simple and complex molecular architectureshas become highly interesting to the chemists and biologists across a wide range offields in academia and industry [7 16ndash22]

3141 Trifluoromethylating Reagents

In 1984 Ruppert et al [23] reported for the first time the synthesis of a nucleophilicCF3 reagent (Me3SiCF3) which was later simplified by Prakash et al [24] In thesame year Yagupolskii et al [25] reported the synthesis of an electrophilic CF3reagent diaryl(trifluoromethyl)sulphonium salt 137 (Fig 32) Since then variousgroups of scientists around the world have devoted their attention to the develop-ment of air and moisture stable easily accessible and efficient trifluoromethylatingreagents either electrophilic [21 22 26] or nucleophilic [27ndash29] in natureAccording to the electronic nature of in situ released CF3 group in the reactiontrifluoromethylating reagents can be classified into three different categories(a) Nucleophilic ethCF3THORN (b) Electrophilic ethCF3 thorn THORN and (c) Radical ethCF3THORN [30]A list of nucleophilic radical and electrophilic CF3 sources is outlined in Fig 32Most of these reagents are commercially available Some of the nucleophilic andmost of electrophilic reagents could also be used in radical trifluoromethylationprocesses

CF3SO2Na(CF3SO2)2Zn

Me3SiCF3

K[CF3B(OMe)3]

CF3H

FSO2CF2CO2EtCF3CO2Me

Nucleophilic CF3Sources Radical CF3 Sources Electrophilic CF3 Sources

SCF3

OIF3COI

F3C

O

CF3I

SNMe2

CF3

PhO

BF4-

SCF3

BF4- (138)

OTf- (139)

OIF3C

O

CF3I

(CF3SO2)2ZnCF3SO2Na

CF3SO2Cletc etc etc

SCF3

First nucleophilic CF3 reagentRuppert and co-workers (1984)

Cl OMe

SbF6-

First electrphilic CF3 reagentYagupolskii and co-workers (1984)

Si CF3

140

137

OIF3CMe3SiCF3

141 141140

BF4- (138)

OTf- (139)

Fig 32 Selected trifluoromethylating reagents

3142 Classifications of Trifluoromethylated Compoundsand Trifluoromethylation

In most of the trifluoromethylated compounds the CF3 functionality is attached to acarbon atom either directly with a CndashCF3 bond or via hetero atom tethers (O S Seetc) eg CndashOndashCF3 CndashSndashCF3 CndashSendashCF3 etc Based on the hybridization states ofthe carbon atom attached to the CF3 group trifluoromethylated compounds can beclassified into three different categories (a) alkynyl compounds containing C(sp)ndashCF3 bonds (b) vinyl or aryl compounds possessing C(sp2)ndashCF3 bonds and(c) aliphatic compounds having C(sp3)ndashCF3 bonds For the synthesis of vinyliccompounds containing C(sp2)ndashCF3 and aliphatic compounds possessing C(sp3)ndashCF3 readily available alkene motifs could be used in a direct functionalizationprocess with trifluoromethylating reagents [18 20 31] In contrast to electrophilicand nucleophilic trifluoromethylation of alkenes transition metalcatalyzedmediated or transition metal free trifluoromethylation of alkenes viaradical or radical-polar crossover processes have been explored in large extent toenrich the library of trifluoromethylated compounds [17 18 32] For thetrifluoromethylation of alkenes copper(I) salts with or without ligand havebecome the most efficient and widely used catalysts [18] However this process canalso be efficiently catalyzed by other transition metals such as iron(II) [33 34] andsilver salts [35] Ru(PPh3)2Cl2 [36] and other metal precursors in some cases Therehas also been a significant development of transition metal free approaches for thispurpose [37ndash41]

3143 Visible Light Photoredox-Catalyzed Trifluoromethylationsvia Radical-Polar Crossover

With the rapid progress of visible light photocatalysis in organic synthesis over thelast few years many impressive trifluoromethylation processes have been devel-oped Polypyridyl transition metal complexes enabling single-electron transfer(SET) under visible light irradiation from commercially available and cheap lightsources have been used to catalyze a wide range of trifluoromethylation processesin an operationally simple and efficient manner [18 42] Electrophilictrifluoromethylating reagents are the most often used CF3 source in thetrifluoromethylation of alkenes However nucleophilic trifluoromethylating agentsare also competent for this reaction In general a photoredox catalyst acts as asingle electron transferring agent [43] In a single electron reduction process of anelectrophilic trifluoromethylating reagent (eg Umimotorsquos and Tognirsquos reagentsCF3SO2Cl and CF3I) with a photo-excited polypyridyl transition metal complex([Ru(bpy)3](PF6)2 Ir(ppy)3 etc) (oxidative quenching) an electrophilic CF3 radicalis generated in situ This CF3 radical will participate in a radical addition to analkene generating a reactive alkyl radical intermediate (Scheme 32) [44] This alkylradical species can then engage in various radical processes such as atom-transferradical addition hydrogen atom abstraction or radical-polar crossover processes

31 Introduction 63

involving ionic intermediates (carbocation) and further functionalization like intra-and intermolecular nucleophilic trapping elimination (Scheme 32)

In 2011 Stephenson and co-workers described the visible light induced pho-toredox catalyzed atom transfer radical addition (ATRA) of CF3I across C=C bondof non-activated alkenes in the presence of the photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1 mol) (Scheme 33a) [45] According to the authorsrsquoproposal this reaction is believed to proceed via a similar mechanism to pathways(a) or (b) in Scheme 32 Later Stephenson and co-workers reported the samereaction with a different set of conditions under a reductive quenching pathway[46] In 2013 Gouverneur and co-workers reported a methodology for thehydrotrifluoromethylation of non-activated alkenes in the presence of [Ru(bpy)3]Cl2sdot6H2O (5 mol) 5-(trifluoromethyl)dibenzothiophenium trifluoromethanesul-fonate (Umemotorsquos reagent 139) and methanol as hydrogen atom source(Scheme 33b) [47] The authors believed that this reaction proceeds via a mech-anistic route similar to pathway (a) in Scheme 32

In the meantime in 2012 Koike Akita and co-workers described theoxytrifluoromethylation of activated alkenes using Umemotorsquos reagent 138 andoxygen nucleophiles such as alcohols acids and even water in the presence of ahighly reducing photoredox catalyst fac-Ir(ppy)3 (1 mol) under visible lightirradiation from blue LEDs (Scheme 34a) [44 48] This reaction occurs involvinga key step a radical-polar crossover followed by nucleophilic trapping as shown inScheme 32 (pathway b) This concept of radical-polar crossover and nucleophilictrapping has been extended to nitrogen [49] carbon [50] and halogen [45 51] basednucleophiles recently by same group Masson and co-workers and Han and

CF3

Nu = O N C XNucleophilic

Addition

Elimination

R4

R3R1R2

R2

R1R3

CF3

R2

R3R5

R1R4

CF3

X

Desilylation

R5

R4

R3R1R2

R5 CF3

R2

R3R1R4

CF3Y

R4

R3R1R2

R5 CF3

R4

R3R1R2

R5 CF3

Nu

O

R3R1R2

R5 CF3

R4 = OAc

Nu = SO

Me2S

R5 = Y

R4

R5 = TMS

R-HX

SETRadical-Polar

Crossover

RadicalAddition

KornblumOxidation

HydrogenHalogenAtom Abstraction

( )n

CyclizationHydrolysis

PC

PC+

PChν

e-CF3+

PC = Photoredox Catalyst

( )n

path a

path b

path epath d

path c

path

Oxidative

f

Quenching

R3CF3R2

R5

R4

( )n

Scheme 32 Visible light photoredox catalyzed trifluoromethylation of alkenes via radical andradical-polar crossover process

co-workers respectively In 2014 Koike Akita and co-workers merged this novelreactivity with Kornblum oxidation employing DMSO as nucleophile to obtainα-trifluoromethylated aryl ketone upon dimethylsulfide elimination (Scheme 34b)[52] The same α-trifluoromethylated aryl ketone could be accessed from vinylacetates in the presence of a different CF3-source CF3SO2Cl and photoredoxcatalyst [Ir(ppy)2(dtbbpy)](PF6) following a mechanism similar to pathway (c) de-picted in Scheme 32 (Scheme 34c) [53] In continuation of this progress Cho andco-workers developed in 2013 a methodology for the preparation oftrifluoromethylated epoxides and aziridines employing allylic alcohols and aminesThe reaction conditions were [Ru(bpy)3]Cl2 (05 mol) DBU (20 equiv forepoxide) or TMEDA (20 equiv for aziridine) and CF3I (30 equiv) with visiblelight irradiation from a 14 W CFL bulb (Scheme 34d) This reactions followed amechanistic route similar to the intramolecular nucleophilic trapping illustrated inScheme 32 (path d) [54]

Later in 2014 Qing and co-workers developed an elegant method for theregioselective synthesis of β-trifluoromethylstyrenes where the regioselectivity wascontrolled by a combination of the photoredox catalyst an electrophilictrifluoromethylating reagent and the solvent (Scheme 35a) [55] The photoredoxcatalyst fac-[Ir(ppy)3] and Umemotorsquos reagent 138 in DMA delivered β-trifluoromethylstyrenes in moderate to good yields and ZE ratios while [Ru(bpy)3]Cl26H2O and Tognirsquos reagent 141 in DMF afforded (E)-β-trifluoromethylstyrenesas sole products in moderate to good yields (Scheme 35a) The latter protocoloccurs via a conventional SET-elimination pathway as depicted in Scheme 32(pathway e) whereas in the former the SET-elimination pathway is accompaniedby an additional triplet-triplet energy transfer (TTET) thus leading to the isomer-ization of the alkene double bond

R( )n

CF3

I[Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (1 mol)

DMFH2O (14) blue LEDs

(a)

(b)

R = alcohol estern = 3 4

RR CF3

H[Ru(bpy)3]Cl26H2O (5 mol)

MeOH 25 degC 24 h14 W CFL bulb

SCF3

OTf39-78

139 (12 equiv)

Gouverneur and co-workers (2013)

CF3I

(excess) 81-90

Scheme 33 Visible light photoredox catalyzed difunctionalizations of alkenesa iodotrifluoromethylation of alkenes b hydrotrifluoromethylation of alkenes [45 47]

31 Introduction 65

In 2014 Gouverneur and co-workers reported a novel methodology for theallylic trifluoromethylation of allylsilanes under two different sets of reactionconditions (Scheme 35b) [56] They were able to obtain enantioenriched productsstarting from enantiopure allylsilanes following a chiral pool strategy The authorsproposed that this reaction proceeds via desilylation of the starting material ratherthan deprotonation in a similar way to the mechanism shown in Scheme 32(pathway f)

In addition to the reports here discussed many other impressive visible lightmediated photoredox catalyzed trifluoromethylation of alkenes which are out of thescope of our discussion have been developed during the last five years [57ndash59]

(25 equiv)

CF3SO2Cl

R3R3 CF3

OR4fac-[Ir(ppy)3] (1 mol)

CH2Cl2R4OH (91)or acetoneH2O (91)

3 W blue LEDs (425 nm)

SCF3

BF4

138 (11 equiv)

R2

R1R1

R1 R2 = H alkyl arylR3 = alkyl aryl

R4 = alkyl acyl

41-96

Ar ArCF3

Ofac-[Ir(ppy)3] (2 mol)

DMSO rt 2 h3 W blue LEDs (425 nm)

140 (12 equiv)

R3

R1R1

R1 R2 = H alkyl arylR3 = H alkyl

28-87

OIF3C

OR2

R2

Koike Akita and co-workers (2014)

(a)

(b)

(c)

(d)

Ar ArCF3

O[Ir(ppy)2(dtbbpy)](PF6) (1 mol)

CH3CN rt 5-24 h13 W White LEDs

OAc

R1R1

R1 = H alkyl arylR2 = H alkyl

63-93

R2

Zhang Yu and co-workers (2013)

R1

OH

Cho and co-workers (2013)

NHR2

orN

CF3

R2

OCF3

R1

R1 = alkyl aryl 80-91

R2 = alkyl 60-65

[Ru(bpy)3]Cl2 (05 mol)DBU (20 equiv) or TMEDA (20 equiv)

CH3CN rt14 W CFL bulb

CF3I

(30 equiv)

Scheme 34 Visible light photoredox catalyzed difunctionalizations of alkenesa oxy-trifluoromethylation of activated alkene b trifluoromethylation-Kornblum oxidation ofalkene c trifluoromethylation of vinylacetate d trifluoromethylation-cyclization of allylic alcoholsand amines [44 52ndash54]

315 Semipinacol Rearrangements

The semipinacol rearrangement is a long known chemical process in organicchemistry which helps to address synthetic challenges such as the construction ofquaternary carbon centers with subsequent formation of a carbonyl functional group[60ndash62] This rearrangement benefits from a broad substrate scope as there aremany known methodologies to generate a carbocation adjacent to a carbinol carbonIn addition it is compatible with various reaction conditions (acidic basic and evenneutral) has high regioselectivity and it is also stereospecific nature in some casesIn contrast pinacol rearrangement of diols suffer from serious regio- and stereos-electivity issues [61] Organic chemists have often appreciated the potential of thesemipinacol rearrangement in organic synthesis This process has resulted in wideapplications in natural product synthesis to introduce structural complexity inmolecular architectures [61 63] This process involves the generation of a carbo-cation adjacent to a carbinol carbon and a subsequent 12-alkylaryl carbon shiftwith simultaneous formation of a CndashO π-bond (Scheme 36) Allylic alcohols couldsuccessfully be applied in this transformation as the addition of an electrophile to

Ar

ArCF3

SCF3

BF4

138 (11 equiv) 141 (12 equiv)

OIF3C

[Ru(bpy)3]Cl26H2O (2 mol)

DMF rt 20 h blue LEDs50-78 E-selective

[Ir(ppy)3] (3 mol)

DMA rt 10 h blue LED55-86 (ZE = 361 to101)

(a)

(b)

Qing and co-workers (2014)

[Ru(bpy)3]Cl26H2O (5 mol)MeOH rt 24 h 14 W CFL bulb

R1 = H alkyl R2 = H alkyl 41-83EZ 16 to gt20

R1 = alkyl R2 = aryl er(E) gt99141-59 EZ 32 to 72er(E) 8515 to 8812

Condition B

R2 R1

TMS R2 R1

SCF3

OTf

139 (18 equiv) 140 (18 equiv)

OIF3CCF3

O

[Ru(bpy)3]Cl26H2O (5 mol)EtOH rt 24 h 14 W CFL bulb

R1 = H alkyl R2 = H alkyl 22-76EZ 33 to gt20Condition A

R2 R1

TMS

Ar

Scheme 35 Visible light photoredox catalyzed difunctionalizations of alkenes a vinylictrifluoromethylation of alkenes b allylic trifluoromethylation of alkenes [55 56]

RmR1

OH

RmR1

O

E

RmR1

OE

δ+ O

ER1

Rm

+E+

-H+

-H+H

H

(b)

(a)

δ+Scheme 36 Generalmechanistic hypothesis ofelectrophile inducedsemipinacol rearrangement ofallylic alcohols

31 Introduction 67

the C=C bond could give access to an electrophilic center vicinal to the carbon atomattached to the hydroxyl group

Recently Alexakis and co-workers reported an enantioselective semipinacolrearrangement with a ring expansion of a cycloalkanol in the presence of F+ fromselectfluor as electrophile and enantiopure BINOL-phosphoric acid for chiralityinduction (Scheme 37a) [64] According to the authorsrsquo proposal the reactionproceeds via a mechanism similar to pathway (a) shown in Scheme 36 where thephosphate anion forms a tight chiral ion-pair This methodology has been extendedto bromination (Br+) [65] and iodination (I+) [66] by Alexakis and co-workers andchlorination (Cl+) by Yin and You [67]

In 2003 Tu and co-workers disclosed an elegant process of halogenation(chlorination bromination and iodination) followed by 12-alkyl or aryl migrationof a different class of allylic alcohols with stoichiometric mixture of Chloramine Tand zinc halides (Scheme 37b) [68] Later they expanded the scope to an asym-metric protonation-12-alkyl shift catalyzed by a chiral phosphoric acid [69] andalso asymmetric fluorination-semipinacol rearrangement catalyzed by chiral quinine

( )n

( )nR1

( )n

( )nR1

FO

HO

R1 = EWG EDGn = 0 1

PA (5 mol)

Na3PO4 (125 equiv)C6H5Fn-Hexane (11)

-20 degC 48-72 h 84-96dr 81 to gt201er 8713 to 973

OP

O OOH

c-C5H10

c-C5H10 c-C5H10PA

(a)

(b)

Alexakis and co-workers (2013)

NN

Cl

F(15 equiv)

Tu and co-workers (2003 amp 2013)

YOHR1R2

YR1

O

CF3

R2

YR1

O

X

R2

65-94X = Cl Br I

R1 R2 = H alkyl aryl

35-70R1 R2 = alkyl aryl

( )n

Y = CH2 On = 0 1

Chloramin T(11 equiv)ZnX2 (11 equiv)

CH3CN rt 1 min

CuBr (15 mol)CuOAc (15 mol)

CH2Cl2 28 degC

140 (15 equiv)

OIF3C

O

2BF4

Scheme 37 Electrophile induced semipinacol rearrangements of allylic alcohols a Asymmetricfluorination-ring expansion b halogenation or trifluoromethylation followed by 12-alkylarylmigration [64 68 71]

[70] Recently they have also described a copper catalyzedtrifluoromethylation-semipinacol rearrangement of the same class of allylic alco-hols used in their previous studies with Tognirsquos reagent 140 as trifluoromethyl(CF3) source where the migration step could proceed via either radical or cationicreaction pathways (Scheme 37b) [71]

321 Inspiration

We have already described earlier in this chapter the term lsquoradical-polar crossoverrsquowhich is one of the key steps involved in the visible light photoredox catalysis toaccess carbocation intermediate (Scheme 32) Although many impressive trans-formations based on this process including trifluoromethylation reactions havebeen reported these transformations are mostly limited to nucleophilic trapping orelimination reactions Therefore there is still enough scope for further developmentof new reaction pathways which are characteristic of carbocations As mentionedearlier in the chapter the key steps in the semipinacol rearrangement are the for-mation of a carbocation vicinal to a carbinol carbon and concomitant or subsequent12-alkylaryl migration with a simultaneous CndashO π-bond formation Therefore wewere interested in exploiting the carbocation formation and further develop thesemipinacol rearrangement [60ndash62] We were inspired by the recent elegant reportson halogenation driven semipinacol rearrangements from Alexakis et al and Youet al [64ndash67] However these reports were limited to halogenations involvinghighly electrophilic haloniums (F+ Cl+ Br+ and I+) from electrophilic halogensources Motivated by the previously mentioned beneficial influence of fluorine inpharmaceutical agrochemical and material chemistry we were interested intrifluoromethylation reactions with electrophilic trifluoromethylating reagents [4 57ndash9] Since the trifluoromethylation of an alkene with an electrophilictrifluoromethylating reagent requires a one-electron reducing agent [17 18 42] andfollowing our research interest in photocatalysis we considered that a photoredoxcatalyst would be a suitable candidate for this purpose We designed our reactionstarting from α-cycloalkanol-substituted styrenes as depicted in Scheme 38 Theaddition of the CF3 radical and subsequent oxidation via SET would lead to theformation of a carbocation which would undergo a 12-alkyl migration for theexpansion of the cycloalkanol group In this designed reaction scheme twoundesired side reactions need to be overcome to validate our desired process (1) theintramolecular trapping of the carbocation with a vicinal hydroxyl group deliveringan epoxide derivative and (2) deprotonation of the intermediate carbocation speciesfurnishing an alkene derivative (Scheme 38)

31 Introduction 69

322 Preliminary Experiments and Optimization Studies

In an initial experiment a mixture of 1-(1-phenylvinyl)cyclobutanol (142) and 5-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (139 14 equiv) inDMF (01 M) was irradiated with 5 W blue LEDs (λmax = 465 nm) in the presenceof the photocatalyst [Ru(bpy)3](PF6)2 (2 mol) To our delight we observed thering expanded product 2-phenyl-2-(222-trifluoroethyl)cyclopentanone (143) in60 GC yield as the major product along with the formation of the undesirednucleophilic trapping byproduct 2-phenyl-2-(222-trifluoroethyl)-1-oxaspiro[23]hexane (144) in a ratio of 143144 = 231 which was determined by 19F NMRanalysis (Table 31 entry 1)

SCF3

X139 X = OTf138 X = BF4

I O

O

F3C I OF3C

140 141

The reaction was conducted in the presence of a little excess of TMSOTf (12equiv) thus protecting the hydroxyl functional group in situ and reducing itsnucleophilicity to suppress byproduct 144 formation Delightfully the expectedproduct 143 was obtained exclusively in 98 GC yield under these reaction

Radical-Polar Crossover

RadicalAddition

ArCF3

Ar( )n

CF3

Ar( )n

CF3

( )n

Ar( )n

CF3

( )n

Ar( )n

CF3

X( )nO

HO X

O

X

NucleophilicTrapping

Elimination

SemipinacolRearrangement

Undesired

Desired

HO X( )n

( )n

HO X( )n

Undesired

ArCF3

( )n

HO X( )n

SET

RadicalAddition

ArCF3

Ar( )n

CF3

Ar( )n

CF3

( )n

Ar( )n

CF3

( )n

Ar( )n

CF3

X( )nO

HO X

O

X

Elimination

Undesired

Desired

HO X( )n

( )n

HO X( )n

Undesired

ArCF3

( )n

HO X( )n

SET

Scheme 38 Reaction design for the trifluoromethylation-semipinacol rearrangement

O

F3C142 143

Photocatalyst TMS-OTf

Solvent Light SourceCF3

+ Source

HO

CF3

O

144

Entry [PC cat] (mol) Solvent CF3 thorn THORN source (equiv) Additive (equiv) Light Yield ()b

1c [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (14) ndash BlueLEDs

60

2 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

98

3 [Ru(bpy)3](PF6)2(2)

DMF (01) 138 (14) TMSOTf(12)

BlueLEDs

81

4 [Ru(bpy)3](PF6)2(2)

DMF (01) 140 (14) TMSOTf(12)

BlueLEDs

9

5 [Ru(bpy)3](PF6)2(2)

DMF (01) 141 (14) TMSOTf(12)

BlueLEDs

ndash

6 [Ru(bpy)3](PF6)2(2)

DMSO(01)

139 (14) TMSOTf(12)

BlueLEDs

90

7 [Ru(bpy)3](PF6)2(2)

CH3CN(01)

139 (14) TMSOTf(12)

BlueLEDs

ndash

8 [Ru(bpy)3](PF6)2(2)

MeOH(01)

139 (14) TMSOTf(12)

BlueLEDs

78

9 [Ru(bpy)3](PF6)2(2)

THF (01) 139 (14) TMSOTf(12)

BlueLEDs

3

10 [Ru(bpy)3](PF6)2(2)

12-DCE(01)

139 (14) TMSOTf(12)

BlueLEDs

ndash

11 [Ir(ppy)2(dtbbpy)](PF6) (2)

DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

97

12 [Ir(ppy)3] (2) DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

96

13 Fluorescein (2) DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

ndash

14 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (14) TMSOTf(12)

23 WCFL

92

15 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (12) TMSOTf(12)

BlueLEDs

95

16 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (12) TMSOTf(05)

BlueLEDs

70

17 [Ru(bpy)3](PF6)2(1)

DMF(01)

139 (12) TMSOTf(12)

BlueLEDs

94(74)

18 ndash DMF (01) 139 (12) TMSOTf(12)

BlueLEDs

ndash

19 [Ru(bpy)3](PF6)2(1)

DMF (01) 139 (12) TMSOTf(12)

ndash ndash

a1-(1-Phenylvinyl)cyclobutanol (142 01 mmol) trimethylsilyl trifluoromethanesulfonate (TMSOTf) and the solvent were added to aSchlenk tube under argon The mixture was stirred at rt for 2 h Then frac12CF3

thorn reagent and photoredox catalyst were added to thereaction mixture and stirred at rt for 6 h under visible light irradiationbGC yield of 143 using mesitylene as an internal reference Isolated yields in parenthesescIn the absence of TMSOTf 143 was obtained along with 144 in a ratio of 143144 = 231 which was determined by 19F NMRanalysis

conditions without formation of 144 in detectable amounts (Table 31 entry 2) In asurvey of different electrophilic trifluoromethylating reagents another Umemotorsquosreagent with BF4 counteranion (138 14 equiv) afforded the product 143 in 81 GC yield reducing the reaction efficiency due to ineffective protection of thehydroxyl group whereas Tognirsquos reagent 140 (14 equiv) and 141 (14 equiv)were unsuitable (only 9 GC yield and no product respectively Table 31 entries3ndash5) The superiority of Umemotorsquos reagents compared to Tognirsquos reagents can berationalized by their redox potentials Umemotorsquos reagents (138ndash139) (minus075 V vsCp2Fe in CH3CN) Tognirsquos reagent 140 (minus134 V vs Cp2Fe in CH3CN) andTognirsquos reagent 141 (minus149 V vs Cp2Fe in CH3CN) [44] Due to its higher redoxpotential Umemotorsquos reagents were more easily reduced compared to Tognirsquosreagents Next we screened different solvents The reaction proceeded smoothly inDMSO with slightly lower efficiency while no reactivity was observed in ace-tonitrile (Table 31 entries 6ndash7) When the reaction was run in a nucleophilicsolvent such as methanol the desired product 143 was formed in 78 GC yieldalong with the methanol trapped byproduct 145 (Table 31 entry 8 andScheme 310b) In THF only trace amounts of product were obtained and noreaction occurred in 12-dichloroethane (Table 31 entries 9ndash10) After the solventscreening DMF resulted as the best solvent for this reaction In a screening ofvarious photoredox catalysts [Ir(ppy)2(dtbbpy)] (PF6) (dtbbpy = 44prime-di-tert-butyl-22prime-bipyridine) and [Ir(ppy)3] furnished the product 143 in 97 and 96 GCyields respectively (Table 31 entries 11ndash12) Unfortunately the organic fluores-cein dye remained inefficient for this transformation (Table 31 entry 13) In orderto find a more user-friendly light source a commercially available 23 W CFL bulbwas also tested This visible light source was able to promote the reaction delivering143 in 92 GC yield (Table 31 entry 14) Further optimization revealed that thestoichiometry of the Umemotorsquos reagent 139 could be reduced from 14 equiv to12 equiv without significant loss of product 143 (Table 31 entry 15) Sinceaccording to the proposed catalytic cycle TMSOTf would be regenerated at the endwe attempted to reduce the amount of TMSOTf to 05 equiv unfortunately anadverse effect on the reaction efficiency was observed (Table 31 entry 16) Finallythe loading of [Ru(bpy)3](PF6)2 could be reduced to 1 mol without hampering thereaction efficiency (Table 31 entry 17) Under these optimized conditions theproduct 143 was obtained in 94 GC yield and 74 isolated yield (Table 31entry 17) Control experiments conducting the reaction in the absence of a pho-tocatalyst and in dark confirmed that both the photocatalyst [Ru(bpy)3](PF6)2 andvisible light were essential for this process (Table 31 entries 18ndash19)

323 Substrate Scope and Limitations

With the optimized reaction conditions in hand we sought to explore the substratescope and limitations for this transformation The outcome of this evaluation hasbeen summarized in Table 32 First we studied the influence of the substituents on

Table 32 Substrate scope of trifluoromethylation-semipinacol rearrangementa

( )mYR

CF3

XO[Ru(bpy)3](PF6)2 (1 mol)

TMSOTf (12 equiv)

139 (12 equiv) DMF rt 6-8 h465 nm Blue LEDs

HO X( )n

( )n

HO

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

OHO

CF3

O

F

Cl

Me

F

Cl

Me

Me74

73

60

78

CF3O

51

149167

166148

147 165

164146

143142

HO

CF3

O

39

150168

Me Me

155 173

O

CF3O

HO

O 158 176

52 (11)

41 (101)

Substrate SubstrateProduct ProductYield(dr) Yield(dr)

(continued)

Table 32 (continued)

HO

HO O

CF3

OO

HO O

CF3

OO

27 nd[d]

29

162 180

179161

F F

CF3O

181163

CF3

O

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

O

Ph

MeO

O

Ph

MeO

O

82

90

86

80

172154

153 171

170152

151 169

CF3O

HO

156 174

Me

CF3O

HO

157 175MeO MeO

HO

159 177

HO

160 178

29 (111)

47 (gt251)

53 (151)[b]

33

65 (151)[c]

a142 146ndash163 (020 mmol) in DMF (2 mL) followed by TMSOTf (024 mmol 12 equiv) wasadded to a flame-dried Schlenk tube under argon atmosphere The reaction mixture was stirred at rtfor 2 h Then [Ru(bpy)3](PF6)2 (0002 mmol 1 mol) and the frac12CF3

thorn reagent (139 024 mmol12 equiv) were added to the reaction tube and the resulted mixture was irradiated with visiblelight from 5 W blue LEDs (λmax = 465 nm) at rt for another 6 h dr in parentheses wasdetermined by 19F NMR analysisbThe conversion of the reaction was incomplete and 22 of the starting material 159 wasrecoveredcThe reaction was conducted with 20 equiv of 139dDetected by GC-MS analysis

the aromatic ring of 1-(1-arylvinyl)cyclobutanol (142 146ndash163) on the outcome ofthe reaction Electron-withdrawing halogen substituents (146ndash147) at the paraposition of the benzene ring were well tolerated The corresponding ring expansionproducts 164 and 165 which features a chloro group susceptible for furtherfunctionalization via cross coupling could be obtained in good yields (73 and 60 respectively) The electron-rich para-methyl substituted substrate 148 delivered theexpected product 166 in 78 yield while shifting the methyl group to the metaand ortho positions decreased the reaction efficiency and yielded the desiredproducts 167 (51 ) and 168 (39 ) in 51 and 39 yield respectively Substrate151 featuring a para-phenyl substituent on the benzene ring afforded the corre-sponding product 169 in 82 yield Strongly electron-donating para-methoxy andacetal groups in substrates 152 and 153 promoted the reactions efficiently leading tothe expected products 170 (90 ) and 171 (86 ) in excellent yields The2-naphthyl substituted substrate 154 was also well suited for this transformationdelivering the product 172 in 80 yield Substrates 155ndash159 derived from1-tetralones 4-chromanone and 1-indanone were also well tolerated Substrates155 and 156 afforded the ring expansion products 173 and 174 respectively as amixture of diastereomers in moderate to low yields Surprisingly highlyelectron-rich 4-chromanone and 5-methoxy-1-tetralone derived substrates 158 and159 furnished the desired products 176 (41 ) and 175 (47 ) in very good toexcellent diastereoselectivities (dr 101 and gt251 respectively) When the1-indanone derived cycloalkanol 159 was reacted under the optimal reaction con-ditions product 177 was obtained in 53 yield and 151 dr with the recovery of159 (22 ) However increasing the amount of 139 (20 equiv) led to completeconversion affording 177 in 65 yield and 151 dr 1-(1-phenylvinyl)cyclopentanol (160) was a suitable substrate in spite of low ring strain deliveringthe expected product 178 in an acceptable yield 33 The oxa-cyclobutanolsubstrates (161ndash162) also exhibited reactivity affording the desired products 179and 180 in lower yields Substrate 163 lacking aryl ring that is in conjugation withan alkene double bond was not a suitable substrate and the formation of 181 couldonly be detected by GC-MS analysis Overall this novel methodology affords aclass of densely functionalized fluorinated cycloalkanones with quaternary carboncenter

324 Follow up Transformations of Products

Since the densely functionalized trifluoromethylated cycloalkanones possess acarbonyl functional group we further investigated the versatility of the developedmethodology We performed some follow-up reactions of the parent product 143(Scheme 39) When the product 143 was treated with sodium borohydride inmethanol the corresponding alcohol 182 was obtained in excellent yield (91 )

and diastereoselectivity (251) (Scheme 39a) In a Baeyer-Villiger oxidationproduct 143 was oxidized to the lactone 183 in 81 yield while the reaction of theproduct 143 with hydroxylamine hydrochloride in the presence of sodium acetatedelivered the oxime derivative 184 in good yield (71 ) (Scheme 39b c)

325 Mechanistic Studies

In order to have some mechanistic insights we did a literature survey [44 47ndash49]and conducted some preliminary control experiments When the reaction wasperformed in the absence of either photoredox catalyst or visible light no productwas formed (Table 31 entries 18ndash19) These experiments suggested that bothcomponents are essential for the reaction The presence of a radical trappingreagent 2266-tetramethyl-1-piperidinyloxyl (TEMPO) inhibited the reactionforming the TEMPO trapped CF3 adduct 185 which was detected by GM-MSanalysis (Scheme 310a) A methanol trapped intermediate 145 (detected by GCMSanalysis) was formed along with the desired product 143 (78 ) when methanolwas employed as solvent during the reaction optimization studies The results ofthese two reactions support that both radical and ionic intermediates are involved in

OH

F3C182 91 (dr = 251)

O

F3C143

N

F3C184 70

HO

NH2OHHCl (50 equiv)

NaOAc (40 equiv)EtOH rt 48 h

NaBH4 (15 equiv)

MeOH 0 degC 45 min

F3C183 81

O

OMMPP (33 equiv)

DMFH2O (31) 45 degC 48h

O

F3C143

O

F3C143

(a)

(b)

(c)

Scheme 39 Follow up reactions of product 143 a reduction of 183 b Baeyer-Villiger oxidationof 143 c oxime formation MMPP magnesium monoperoxyphthalate

this process According to a recent report by Koike Akita and co-workers theUmemotorsquos reagent 138 could be a quencher of the photo-excitedpolypyridyl-metal photoredox catalyst (oxidative quenching) while styrenederivative remained innocent in those Stern-Volmer quenching studies [44 48]

Following literature reports and the control experiments performed we proposethe following reaction mechanism for the visible light mediated photoredox cat-alyzed trifluoromethylation-ring expansion in scheme 311 In the presence ofvisible light from 5 W blue LEDs (λmax = 465 nm) the photoredox catalyst [Ru(bpy)3](PF6)2 gets excited to the strongly reducing photo-excited state [Ru(bpy)3](PF6)2 (E12 [Ru

3+Ru2+] = minus081 V vs SCE in CH3CN) [47 72] Single electronreduction of the Umemotorsquos reagent 139 (E12 = minus025 V vs SCE in CH3CN) [47]via SET from the photo-excited [Ru(bpy)3]

2+ species would generate an elec-trophilic radical CF3 and the higher valent [Ru(bpy)3]

3+ The addition of thiselectrophilic CF3 radical onto the C=C bond of the silyl protected intermediate Aobtained in situ by silyl protection of hydroxyl group from substrate 142 in thepresence of TMSOTf would deliver the stabilized benzylic radical intermediate BAt this stage a radical-polar crossover can occur as the key step to switch theradical pathway to an ionic one Single electron oxidation of intermediate B by thehigher valent [Ru(bpy)3]

3+ (E12 [Ru3+Ru2+] = +129 V vs SCE in CH3CN) [4772] via SET would lead to the cationic intermediate C and regenerate the pho-toredox catalyst [Ru(bpy)3]

2+ An alternative pathway might involve oxidizing theintermediate B with direct electron transfer to another equivalent of Umemotorsquosreagent 139 via SET in a chain process to obtain intermediate C The measuredquantum yield value (Φ = 38) of this photochemical process supports theinvolvement of a chain process in this transformation In the next step 12-alkyl

OH O

F3C

NO

CF3

[Ru(bpy)3](PF6)2 (1 mol)TMSOTf (12 equiv)

DMF rt Blue LEDs

143not observed

185detected by

GC-MS analysisNO (24 equiv)

142

(a)

OH O

F3C

MeOH rt Blue LEDs

14378 (GC yield)

145detected by

GC-MS analysis

142

(b)OH

CF3

OMe

SCF3

OTf

139 (12 equiv)

SCF3

OTf

139 (14 equiv)

Scheme 310 Preliminary mechanistic experiments a radical inhibition experiment withTEMPO b carbocation trapping experiment with methanol

migration with a CndashO π-bond formation would furnish the ring expanded product143 upon loosing the silyl protecting group

33 Summary

In summary we have successfully disclosed the first visible light mediated pho-toredox catalyzed semipinacol rearrangement involving an ionic 12-alkyl migra-tion The photoredox catalyzed radical-polar crossover process enabled this reactionto occur These transformations constitute a novel class of densely functionalizedtrifluoromethylated cycloalkanone derivatives possessing quaternary carbon centerMoreover these compounds could be easily converted to other important functionalmotifs This process benefits from milder reaction conditions such as room tem-perature no use of harsh and hazardous reagents and cheap readily available lightsources

CF3

O

143

[Ru(bpy)3]2+

[Ru(bpy)3]3+

[Ru(bpy)3]2+Phototedox

Catalysis

SCF3

139 OTf

S

OH

142

OTMS

TMSOTf

TfOH

radicaladditionA

OTMS

CF3B

OTMS

CF3C

139

CF3

SET

12-carbonshift

CF3

OTMS

D

TMSOTf

Radical-PolarCrossover

radicalchain

(Φ = 38)Silyl

protectionSilyl

deprotection

minus081 V vs SCE

+129 V vs SCE

minus025 V vs SCE

Scheme 311 Mechanistic proposal for the visible light photoredox catalyzedtrifluoromethyl-semipinacol rearrangement

References

1 A Bondi J Phys Chem 68 441ndash451 (1964)2 D OrsquoHagan Chem Soc Rev 37 308ndash319 (2008)3 P Jeschke ChemBioChem 5 570ndash589 (2004)4 K Muumlller C Faeh F Diederich Science 317 1881ndash1886 (2007)5 S Purser PR Moore S Swallow V Gouverneur Chem Soc Rev 37 320ndash330 (2008)6 T Yamazaki T Taguchi I Ojima in Fluorine in Medicinal Chemistry and Chemical

Biology ed by I Ojima (Wiley-Blackwell UK 2009)7 T Furuya AS Kamlet T Ritter Nature 473 470ndash477 (2011)8 J Wang M Saacutenchez-Roselloacute JL Acentildea C del Pozo AE Sorochinsky S Fustero VA

Soloshonok H Liu Chem Rev 114 2432ndash2506 (2014)9 V Gouverneur K Muumlller Fluorine in Pharmaceutical and Medicinal Chemistry

Frombiophysical Aspects to Clinical Applications (Imperial CollegePress London 2012)10 T Hiyama Organofluorine Compounds Chemistry and Applications (Springer Berlin 2000)11 WK Hagmann J Med Chem 51 4359ndash4369 (2008)12 DP Curran Angew Chem Int Ed 37 1174ndash1196 (1998)13 C Lampard JA Murphy N Lewis J Chem Soc Chem Commun 295ndash297 (1993)14 JA Murphy in Radicals in Organic Synthesis eds by P Renaud MP Sibi The Radicalndash

Polar Crossover Reaction (Wiley-VCH Weinheim 2001)15 E Godineau Y Landais Chem Eur J 15 3044ndash3055 (2009)16 OA Tomashenko VV Grushin Chem Rev 111 4475ndash4521 (2011)17 A Studer Angew Chem Int Ed 51 8950ndash8958 (2012)18 H Egami M Sodeoka Angew Chem Int Ed 53 8294ndash8308 (2014)19 E Merino C Nevado Chem Soc Rev 43 6598ndash6608 (2014)20 C Alonso E Martiacutenez de Marigorta G Rubiales F Palacios Chem Rev 115 1847ndash1935

(2015)21 J Charpentier N Fruumlh A Togni Chem Rev 115 650ndash682 (2015)22 C Ni M Hu J Hu Chem Rev 115 765ndash825 (2015)23 I Ruppert K Schlich W Volbach Tetrahedron Lett 25 2195ndash2198 (1984)24 P Ramaiah R Krishnamurti GKS Prakash Org Synth 72 232 (1995)25 LM Yagupolskii NV Kondratenko GN Timofeeva J Org Chem USSR 20 103ndash106

(1984)26 N Shibata A Matsnev D Cahard Beilstein J Org Chem 6 65 (2010)27 M Tordeux B Langlois C Wakselman J Org Chem 54 2452ndash2453 (1989)28 BR Langlois E Laurent N Roidot Tetrahedron Lett 32 7525ndash7528 (1991)29 GKS Prakash AK Yudin Chem Rev 97 757ndash786 (1997)30 G Danoun B Bayarmagnai MF Gruumlnberg LJ Gooszligen Angew Chem Int Ed 52 7972ndash

7975 (2013)31 M-Y Cao X Ren Z Lu Tetrahedron Lett 56 3732ndash3742 (2015)32 WR Dolbier Chem Rev 96 1557ndash1584 (1996)33 H Egami R Shimizu Y Usui M Sodeoka Chem Commun 49 7346ndash7348 (2013)34 T Patra A Deb S Manna U Sharma D Maiti Eur J Org Chem 2013 5247ndash5250 (2013)35 A Deb S Manna A Modak T Patra S Maity D Maiti Angew Chem Int Ed 52 9747ndash

9750 (2013)36 N Kamigata T Fukushima M Yoshida J Chem Soc Chem Commun 1989 1559ndash156037 Y Li A Studer Angew Chem Int Ed 51 8221ndash8224 (2012)38 Q Wang X Dong T Xiao L Zhou Org Lett 15 4846ndash4849 (2013)39 B Zhang C Muumlck-Lichtenfeld CG Daniliuc A Studer Angew Chem Int Ed 52 10792ndash

10795 (2013)40 B Zhang A Studer Org Lett 16 1216ndash1219 (2014)41 B Zhang A Studer Org Biomol Chem 12 9895ndash9898 (2014)42 T Koike M Akita J Fluorine Chem 167 30ndash36 (2014)

References 79

43 JW Tucker CRJ Stephenson J Org Chem 77 1617ndash1622 (2012)44 Y Yasu T Koike M Akita Angew Chem Int Ed 51 9567ndash9571 (2012)45 JD Nguyen JW Tucker MD Konieczynska CRJ Stephenson J Am Chem Soc 133

4160ndash4163 (2011)46 C-J Wallentin JD Nguyen P Finkbeiner CRJ Stephenson J Am Chem Soc 134

8875ndash8884 (2012)47 S Mizuta S Verhoog KM Engle T Khotavivattana M OrsquoDuill K Wheelhouse G

Rassias M Meacutedebielle V Gouverneur J Am Chem Soc 135 2505ndash2508 (2013)48 Y Yasu Y Arai R Tomita T Koike M Akita Org Lett 16 780ndash783 (2014)49 Y Yasu T Koike M Akita Org Lett 15 2136ndash2139 (2013)50 A Carboni G Dagousset E Magnier G Masson Chem Commun 50 14197ndash14200

(2014)51 SH Oh YR Malpani N Ha Y-S Jung SB Han Org Lett 16 1310ndash1313 (2014)52 R Tomita Y Yasu T Koike M Akita Angew Chem Int Ed 53 7144ndash7148 (2014)53 H Jiang Y Cheng Y Zhang S Yu Eur J Org Chem 2013 5485ndash5492 (2013)54 E Kim S Choi H Kim EJ Cho Chem Eur J 19 6209ndash6212 (2013)55 Q-Y Lin X-H Xu F-L Qing J Org Chem 79 10434ndash10446 (2014)56 S Mizuta KM Engle S Verhoog O Galicia-Loacutepez M OrsquoDuill M Meacutedebielle K

Wheelhouse G Rassias AL Thompson V Gouverneur Org Lett 15 1250ndash1253 (2013)57 Q-H Deng J-R Chen Q Wei Q-Q Zhao L-Q Lu W-J Xiao Chem Commun 51

3537ndash3540 (2015)58 P Xu K Hu Z Gu Y Cheng C Zhu Chem Commun 51 7222ndash7225 (2015)59 L Zheng C Yang Z Xu F Gao W Xia J Org Chem 80 5730ndash5736 (2015)60 TJ Snape Chem Soc Rev 36 1823ndash1842 (2007)61 Z-L Song C-A Fan Y-Q Tu Chem Rev 111 7523ndash7556 (2011)62 K-D Umland SF Kirsch Synlett 24 1471ndash1484 (2013)63 B Wang YQ Tu Acc Chem Res 44 1207ndash1222 (2011)64 F Romanov-Michailidis L Gueacuteneacutee A Alexakis Angew Chem Int Ed 52 9266ndash9270

(2013)65 F Romanov-Michailidis M Pupier L Guenee A Alexakis Chem Commun 50 13461ndash

13464 (2014)66 F Romanov-Michailidis L Gueacuteneacutee A Alexakis Org Lett 15 5890ndash5893 (2013)67 Q Yin S-L You Org Lett 16 1810ndash1813 (2014)68 BM Wang ZL Song CA Fan YQ Tu WM Chen Synlett 2003 1497ndash1499 (2003)69 Q-W Zhang C-A Fan H-J Zhang Y-Q Tu Y-M Zhao P Gu Z-M Chen Angew

Chem Int Ed 48 8572ndash8574 (2009)70 M Wang BM Wang L Shi YQ Tu C-A Fan SH Wang XD Hu SY Zhang Chem

Commun 5580ndash5582 (2005)71 Z-M Chen W Bai S-H Wang B-M Yang Y-Q Tu F-M Zhang Angew Chem Int

Ed 52 9781ndash9785 (2013)72 M Haga ES Dodsworth G Eryavec P Seymour ABP Lever Inorg Chem 24 1901ndash

1906 (1985)

Chapter 4Transition Metal Free VisibleLight-Mediated Synthesisof Polycyclic Indolizines

41 Introduction

411 General Properties of Indolizines

Indolizine is a heterocyclic aromatic compound bearing a bridging nitrogen atomIn this heterocyclic compound a five membered π-electron-rich pyrrole ring isfused to a six membered π-electron-deficient pyridine ring According to Huumlckelrsquos(4n + 2) rule this aromatic compound has 10π electrons with 2 π-electrons arisingfrom the bridging nitrogen atom and 8 π-electrons arising from four C=C π-bondsThe resonance energy and first ionization potential (IP1) of the parent indolizine are228 and 724 eV respectively [1] This heterocycle is isoelectronic with indole andisoindole Indolizine acts as a weak base (pKa = 394) and is more basic than indole(pKa = minus24) [2] The parent indolizine and alkyl-substituted indolizines are usu-ally air and light sensitive liquids or sometimes low-melting solids whilearyl-substituted indolizines are typically relatively stable solids [3] High level DFTcalculations have shown that an extended HOMO of the parent indolizine exclu-sively resides on the pyrrole ring while the LUMO is mostly located at the pyridinering (Fig 41) [4] Thus indolizine undergoes aromatic electrophilic substitutionreactions (SEAr) at the C-1 and C-3 positions of the π-excessive pyrrole ring whilearomatic nucleophilic substitutions (SNAr) are rare [5] However introduction of anelectron-withdrawing nitro group at the C-6 or C-8 positions makes this indolizinederivative prone to nucleophilic substitutions without loss of the pyrrole-likereactivity Thus this nitro substituted indolizine is expected to show π-amphotericbehavior [5]

81

412 Importances of Indolizines

Indolizine exists as an important core in many naturally-occurring compounds andsynthetic pharmaceuticals possessing biological activity [6ndash8] Natural and syn-thetic substituted indolizine derivatives exhibit central nervous system (CNS) de-pressant activity [9] anticancer activity [10ndash12] analgesic activity [13]anti-inflammatory activity [13] antibacterial activity [14] and antioxidant activity[15] The indolizine scaffold is present in calcium channel blockers [16]sodium-glucose linked transporter Type I (SGL T1) antagonists [17] phosphodi-esterase IV (PDE4) inhibitors [18] microtubule inhibitors [19] and 15-lipoxygenaseinhibitors [20 21] Moreover indolizidines derived from indolizines upon com-plete hydrogenation exist as an invaluable motif in many natural products andbioactive compounds [22 23]

During the combinatorial synthetic study of novel polycyclic drug-like com-pounds Park and co-workers discovered an exciting fluorescent material9-aryl-dihydropyrrolo[34-b]indolizin-3-one (Fig 42) [24] These types of com-pounds were later explored as part of a library of fluorescent materials which werenamed Seoul Fluorophores [25 26] Afterwards You Lan and co-workersdemonstrated that 3-aryl-substituted indolizines also constitute a series of fluores-cent compounds [27] Tunable substitution patterns on the indole and pyridinesubstructures and on the aryl rings of 3-aryl indolizines result in electronic per-turbation of the whole π-system As a consequence a wide range of emissionwavelengths covering from 405 to 616 nm become accessible from these colortunable fluorescent materials This class of heterocyclic compounds has been usedas photosensors for the detection of volatile organic compounds [28] and as organicsensitizers in dye-sensitized solar cells [29] Moreover indolizines serve asexcellent synthons for the synthesis of invaluable cycl[322]azines [30]

413 Synthesis of Indolizines

After the discovery of the parent indolizine by Angeli in 1890 [31 32] the firstsynthesis of this compound was performed by Scholtz in 1912 although unam-biguous identification of the product was unsuccessful at that time [33] Thereaction of 2-picoline with acetic anhydride at high temperature (200ndash220 degC) in asealed steel bomb resulting in indolizine is now called the Scholtz reaction(Scheme 41) [33]

N

8 1

2

3456

7NN

HOMO density LUMO density

Fig 41 Chemical abstractsnumbering HOMO andLUMO of indolizine [4]

82 4 Transition Metal Free Visible Light-Mediated Synthesis hellip

In 1929 Tschitschibabin and Stepanow gave a mechanistic proposal for theScholtz reaction which is depicted in Scheme 41 [34] Condensation of2-methylpyridine and acetic anhydride at 200ndash220 degC results in 2-(2-pyridyl)acetylacetone (186) which tautomerizes to an enol intermediate 187 under thereaction conditions In the next steps cyclization of intermediate 187 followed bydehydration delivers 1-acetylindolizine (189) In the presence of acetic anhydride1-acetylindolizine (189) further undergoes electrophilic acylation at the C-3 posi-tion furnishing 13-diacetylindolizine This disubstituted indolizine can be con-verted into the non-substituted parent indolizine upon hydrolysis

In common with many other nitrogen heterocycles diversely-substituted indo-lizines and their hydrogenated analogs have immense importance because of theirbiological and photophysical activities and over the last century a substantialamount of interest has grown to develop methods for the synthesis of indolizineswith diverse functionality

N

CNS depressant activity

N

SO

O

ON

OO

Calcium entry blocker

N

Antibacterial activity

NCOH

N

CN

NH

SGL T1 antagonist

O

NH2

O

Antioxidant

Seoul-fluor (SF)λem = 420-613 nm

NN

OR3

R1 R2

C3-Indo-Fluorλem = 405-616 nm

N

R1

R2

R3

N

ONC

O

N

O

HN

PDE4 inhibitor

OH

Cl

N

Cl

Fig 42 Selected natural and synthetic biologically-active compounds and fluorophorespossessing the indolizine core

41 Introduction 83

4131 Synthesis of Indolizines via Methine Formation

In 1927 Tschitschibabin developed an elegant method to synthesize indolizinesfrom quaternary pyridinium salts upon treatment with a base which has since beenpopularized as the Tschitschibabin reaction (Scheme 42 where R1 R3 = H) [35]However this reaction was unsuccessful for those indolizines featuring no sub-stituents on the pyrrole core Over the last century a significant number of methodshave been reported modifying the Tschitschibabin reaction [36] In 1960s and1970s various research groups have synthesized indolizines starting from pyridinesubstrates and α-bromocarbonyl compounds in two steps under thermal conditionsin the presence of various bases (Scheme 42) [37ndash40] The principal characteristicof these reactions is the involvement of a methine intermediate generated from aquaternary pyridinium salt upon deprotonation

4132 Synthesis of Indolizines via a 13-Dipolar Cycloaddition

Since 13-dipolar cycloaddition reactions constitute a powerful method for thesynthesis of five-membered heterocyclic compounds in 1961 Boekelheide andco-workers applied this elegant approach to the synthesis of an indolizine from1-phenacylpyridinium methylid and dimethyl acetylenedicarboxylate under dehy-drogenative conditions using PdC in toluene (Scheme 43) [41] Moreover therehave been many impressive transformations devised for the synthesis ofdiversely-substituted indolizines based on 13-dipolar cycloadditions [42 43]

N O

O O

N

O

200-220 degC

- CH3COOH- H2O

Scholtz et al (1912)

Nhydrolysis

N

O

NH

O

OH

N

cyclization

tautomerization dehydration

O200-220 degC

O

OH

186

187

189

188

Scheme 41 Scholtz reaction and its mechanistic hypothesis [33 34]

4133 Synthesis of Indolizines via a 15-Dipolar Cyclization

15-Dipolar cyclization is one of the more popular electrocyclic reactions applied inorganic chemistry Inspired by these reactions in a seminal report in 1962 Kroumlhnkeand co-workers disclosed an exciting method for synthesizing indolizines [44]Afterwards many interesting 15-dipolar cyclization-centric synthetic routes havebeen reported for indolizine synthesis [36] One of these reports developed by tworesearch groups independently was the 15-dipolar cyclization of isolated or in situgenerated N-allylpyridinium ylids upon treatment with K2CO3 (Scheme 44)[45 46]

4134 Synthesis of Indolizines via CarbeneMetal-CarbenoidFormation

Addition of a sextet carbene onto carbon-carbon multiple bonds is a classicalreactions in carbene chemistry In 1994 Liu and co-workers employed carbenechemistry for the synthesis of indolizine In this process arylchlorocarbenes derivedfrom arylchlorodiazirines upon photolysis under UVA irradiation react with2-vinylpyridine to afford 3-substituted indolizines (Scheme 45a) [47] Howeverthis method is very poor yielding (10ndash12 ) and has a highly limited substratescope (only three substrates were successfully employed) Importantly thermaltreatment or ultrasound (US) irradiation gave comparatively better yields(13ndash52 ) and a relatively larger scope (seven substrates) compared to UV light

NR1

R2

NR1

R2

R3

O

R4

Br

O

R4

R3

Br 35-100 degCN

R1

R2

R3

R4Δ

NaHCO3H2O

R1 = H alkyl R2 = aryl EWGR3 = H aryl R4 = alkyl aryl

28-85 30-94

Ames and co-workers (1959) Venturella et al (1963) Melton et al (1967) Doerge and co-workers (1972)

NR1

R2

R3

O

R4via

Scheme 42 Synthesis of indolizines via methine formation (Tschitschibabin reaction) [37ndash40]

NO

PhCOOMeMeOOC N

COOMe

OPh

PdC

toluene

18

Boekelheide and co-workers (1961)

Scheme 43 Synthesis of indolizines via a 13-dipolar cycloaddition reaction [41]

41 Introduction 85

irradiation Later in 2007 Gevorgyan and co-workers reported an exciting route forthe synthesis of indolizines from pyridotriazole and terminal alkynes proceeding viaa metal-carbenoid intermediate (Scheme 45b) [48] In this annulation reaction thedesired indolizine formation was accompanied by the formation of a cyclopropenebyproduct However careful selection of an appropriate catalyst counteranionRh2(C3F7COO)4 allowed for control over the selectivity

NR1 R2

BrN

R1

R2K2CO3

EtOH or CHCl3

4-95

R3

O OR3

NR1 R2

R3

O

Br

ether or CHCl3

rt

Barrett and co-workers (1958) Pratt Keresztesy Jr and co-workers (1967)

R1 = alkyl R2 = alkyl aryl R3 = aryl OR NR1 R2

R3

O1 5

via

Scheme 44 Synthesis of indolizines via a 15-dipolar cycloaddition reaction [45 46]

N

ClN

N

R1

N

R1

10-12

hν (λ=350 nm)Hexane

or Δ or US

50 equiv

(a) Liu and co-workers(1994)

N NN

Cl

N

R1

57-85

R1 Cl

R1 = EWG EDG

OO

(b) Gevorgyan and co-workers (2007)

via carbeneR1 = EWG EDG

Cl

R1

N

Cl

OO

RhLn

via metal carbenoid

N O

O

R1

5-10

Rh2(C3F7COO)4 (1 mol)

CH2Cl2 rt

Cl

Scheme 45 Synthesis of indolizines via carbenemetal-carbenoid formation [47 48]

4135 Synthesis of Indolizines via Oxidative Coupling-Cyclization

Transition Metal-Mediated Dehydrogenative Coupling Approach

Very recently Aggarwal and co-workers uncovered a silver-mediated method forthe synthesis of 3-arylindolizines starting from 2-pyridylacetates and terminalalkynes (Scheme 46) [49] This reaction proceeds via a stoichiometricsilver-mediated oxidative dehydrogenative C(sp3)ndashC(sp) coupling of a methylene C(sp3)ndashH bond and an acetylene C(sp)ndashH bond and a subsequent 5-endo-digcyclization This protocol benefits from a broad substrate scope of the alkyne and ahigh atom economy while the Ag2CO3 oxidant could be recovered from reactionresidue and recycled

Iodine-MediatedCatalyzed Transition Metal-Free Approach

Since the pharmaceutical industry generally prefers metal-free synthetic routes forthe synthesis of biomolecules to avoid contamination by metal impurities even atppb level a part of scientific community has devoted their attention to this line ofresearch In this context Yan and co-workers reported an iodine-mediated oxidativecyclization method for the synthesis of functionalized indolizines from enolizablealdehydes and 2-pyridylacetates (Scheme 47a) [50] Moreover very recently Leiand co-workers disclosed a route for the synthesis of substituted indolizines underoxidative conditions using a combination of I2 and tert-butyl hydrogen peroxide(TBHP Scheme 47b) [51] This reaction is believed to proceed via a radicalpathway It is worth mentioning that the same reaction can be achieved with sto-ichiometric amounts of Cu(OAc)2 instead of TBHP [52]

414 Functionalization of Indolizines via Transition MetalCatalysis

In contrast to direct synthetic methods another strategy to obtain highly-substitutedindolizines involves the direct functionalization of a pre-formed indolizine core

NEWG

R1N

EWG

R1

Ag2CO3 (20 equiv)

KOAc (20 equiv)DMF 110 degC

20 equiv

45-89R1 = EWG EDG

Aggarwal and co-workers (2014)

Scheme 46 Synthesis of indolizines via oxidative dehydrogenative coupling-cyclization [49]

41 Introduction 87

structure Over the last few decades transition metal catalysis has become apromising tool in this regard

4141 Transition Metal-Catalyzed Redox-Neutral Cross-Coupling

In 2004 Gevorgyan and co-workers and Fagnou and co-workers in 2009 inde-pendently disclosed the palladium-catalyzed selective CndashH functionalization ofindolizines at the C-3 position with aryl bromides [4 53] The selectivity for theC-3 position was attributed to the higher HOMO density at C-3 Later You Lanand co-workers reported an elegant and versatile method for the selective CndashHfunctionalization of indolizines with less reactive aryl chlorides (Scheme 48) [27]In this reaction palladium-catalyzed C-3 selective arylation of the indolizine motifgives access to a broader spectrum of fluorescent arylated indolizine derivatives

4142 Transition Metal-Catalyzed Oxidative Cross-Coupling

In addition to conventional cross-coupling methods with aryl halides a consider-able amount of research interest has been devoted to the development of syntheticmethods proceeding under oxidative conditions In 2012 Zhao et al uncovered anefficient and versatile protocol for the palladium-catalyzed selective CndashH func-tionalization of indolizines under oxidative conditions using stoichiometric amountsof silver acetate (Scheme 49a) [54] In this method aryltrifluoroborates were usedas aryl precursors In 2014 Hu Wang Ji and co-workers reported a milder methodfor the palladium-catalyzed selective CndashH functionalization of indolizines underoxidative conditions [55] In a later procedure expensive stoichiometric metaloxidants were replaced with oxygen gas as the terminal oxidant and arylboronicacids were used in place of aryltrifluoroborates (Scheme 49b)

NEWG

R1N

EWG

R1

I2 (20 mol)

TBHP (30 equiv)NaOAc (10 equiv)

DCE30 equiv

25-59R1 = EWG EDG

(b)Lei and co-workers (2015)

NEWG O N

R1

EWGI2 (60 mol)

toluene 60 degC12 equiv

40-84R1 = alkyl aryl

(a) Yan and co-workers (2014)

R1

Scheme 47 Iodine mediatedcatalyzed synthesis of indolizines [50 51]

421 Inspiration

Although over the last century many synthetic protocols have been developed forthe synthesis of indolizines with diverse substitution patterns most of these reac-tions are carried out under thermal conditions with stoichiometric reagents Withthe extensive progress of catalysis research a variety of elegant and efficientmethods have been disclosed for the synthesis of densely-substituted indolizinesHowever photochemical synthesis of this class of heterocyclic compounds hasrarely been explored Since many substituted indolizines themselves can absorblight in the UVA and UVB range with some even absorbing lower energy visiblelight intelligent design of the substitution pattern of the indolizine is important tominimize the photoactivity of the products which could have adverse effects on thereaction rates Moreover some substitution patterns of indolizines make them proneto decompose under light irradiation in the presence of air These could be thepossible reasons why chemists have somewhat neglected synthetic investigations of

N

EWGCl

R2

Pd(OAc)2 (5 mol)PCy3HBF4 (10 mol)

Cs2CO3 (30 equiv)toluene 130 degC

20 equiv

N

EWG

R255-97R1 R2 = EWG EDG

You Lan and co-workers (2012)

R1R1

Scheme 48 Palladium-catalyzed selective redox neutral CndashH arylation of indolizines [27]

N

EWG BF3K

R1

Pd(OAc)2 (10 mol)

AgOAc (10 equiv)NaOAc (10 equiv)

DMF 90 degC10 equiv

N

EWG

R140-93R1 = EWG EDG

(a)

(b)

Zhao et al (2012)

N

EWG B(OH)2

R2

Pd(OAc)2 (5 mol)picolinic acid (10 mol)

KHCO3 (30 equiv)DMSO O2 100 degC

20 equiv

N

EWG

Hu Wang Ji and co-workers (2014)

R1R1

Scheme 49 Palladium-catalyzed selective oxidative CndashH arylation of indolizines [54 55]

indolizines using photochemical reaction conditions However following ourresearch interest in visible light photocatalysis we were interested in designing asystem for the synthesis of invaluable C-3 aryl-substituted indolizines using anexternal photocatalyst which absorbs photons in the visible range

422 Reaction Design

Our reaction design starts with a bromopyridine substrate (190) and an electron-richenol carbamate (191) in the presence of a photoredox catalyst and a visible lightsource (Scheme 410)

According to our mechanistic hypothesis we envisaged that 2-bromo-2-(2-pyridyl)acetate (190) would quench the photo-excited photoredox catalyst (PC)in an oxidative quenching pathway to generate a radical-anionic intermediate A andthe oxidized photoredox catalyst (PCbull+) (Scheme 411) In a mesolysis process theradical-anionic intermediate A would then deliver an alkyl intermediate B whichwould undergo radical addition to an electron-rich enol carbamate 191 generatinganother radical intermediate C At this stage radical intermediate C would transferan electron to the oxidized photoredox catalyst (PCbull+) via SET regenerating theground state photoredox catalyst (PC) and affording a carbocationic intermediateD An alternative pathway could be possible via direct electron transfer from radicalintermediate C to another molecule of 2-bromo-2-(2-pyridyl)acetate (190) in aradical chain process through SET In a series of follow-up steps nucleophilictrapping of the carbocationic intermediate D by pyridine in intramolecular fashionwould deliver another cationic intermediate E which would then afford the indo-lizine product 192 upon successive deprotonation and elimination of an NNprime-dia-lkyl carbamic acid

To validate our hypothesis we performed a preliminary test by treating methyl2-bromo-2-(2-pyridyl)acetate (193) with 34-dihydronaphthalen-1-yl

NCO2R1

Br

O O

NR2 R2

N

OR1O

photoredox catalyst (PC)

visible light

190 191 192

Scheme 410 Visible light photoredox-catalyzed synthesis of indolizines

dimethylcarbamate (194 50 equiv) in DMF solvent in the presence of theorganometallic photoredox catalyst [Ir(ppy)2(dtbbpy)](PF6) (2 mol) and theinorganic base Na2HPO4 (20 equiv) under visible light irradiation from 5 W blueLEDs (λmax = 465 nm) for 12 h We were delighted to observe the desired indo-lizine product 195 in 62 GC yield while running the reaction in the dark did notdeliver the product 195 confirming the necessity of light (Scheme 412a b) Aninteresting observation was made when this reaction was carried out in absence ofthe photoredox catalyst [Ir(ppy)2(dtbbpy)](PF6) Rather than shutting down theexpected reactivity the indolizine product 195 was delivered in comparable yield52 GC yield under these conditions (Scheme 412c)

In order to optimize the reaction conditions we performed an exhaustivescreening of different parameters (solvent leaving group base light source stoi-chiometry) In a survey of solvents we observed that the performance of thisreaction was almost independent of solvent polarity (Table 41 entry 2ndash12) Innucleophilic solvents such as methanol and acetonitrile the reaction efficiencydropped significantly while no reactivity was observed using pyridine as solvent(Table 41 entry 3ndash4 12) Trifluorotoluene remained the best among the screenedsolvents (Table 41 entry 10) In a screening of different leaving groups a1-tetralone derived carbonate acetate trifluoromethanesulfonate and secondary

PhotoredoxCatalysis

PC

NCO2R1

Br

O

N

O

R2R2

N

O

R2R2

OR1

O

N

O

N

O

R2R2

OR1

O

N

NCO2R1

Br

NCO2R1

Br

NCO2R1

BrBr

O

N

O

R2R2

N

OR1

O

N

O

R2R2

N

OR1

O

N

OR1

O

H

-H+

-R22NCOOH

SET

Mesolysis

RadicalAddition

NucleophilicAttack

Elimination

Deprotonation

Chain192

190191

190

E

A

B

B A

C

D

F

Scheme 411 Mechanistic hypothesis for the proposed visible light photoredox-catalyzedindolizine synthesis

enamine performed very poorly while a significant drop of reactivity was observedwith a diisopropyl carbamate derivative (Table 41 entry 13ndash17) Since HBr andcarbamic acid are obtained as byproducts in this reaction we surveyed variousstrong and weak bases to neutralize in situ-generated acids (Table 41 entry 18ndash32)We found that weak bases are better for this reaction with a trend of increasingreaction efficiency upon moving from a strong base to a weak base (Table 41 entry22ndash25) The weak base HMDS (HMDS = hexamethyldisilazane pKa = 755) [56]was found to be the optimal among the screened bases (Table 41 entry 32)Changing the light source to green LEDs (λmax = 525 nm) a 23 W CFL or a 20 Wblacklight did not improve the reaction efficiency (Table 41 entry 33ndash35) Next wevaried the stoichiometry of both reacting partners Reduction of the equivalents ofthe enol carbamate (from 8 to 3) with respect to pyridine substrate had a detrimentaleffect on reaction efficiency (Table 41 entry 32 36ndash38) However employing thepyridine substrate and the carbamate in the opposite ratio did not improve thereaction efficiency (Table 41 entry 39) Degassing of the reaction mixture was verycrucial for the reaction outcome (Table 41 entry 40) In another test dilution of thereaction mixture had an adverse effect on the reaction efficiency (Table 41 entry41) Upon enhancing the equivalents of HMDS the reaction yield remained samewhile reducing the amount of HMDS to 10 equivalent increased the reaction effi-ciency slightly (Table 41 entry 42ndash43) The reaction efficiency slightly dropped inthe absence of HMDS (Table 41 entry 42) Finally control reactions using theoptimized conditions showed again that visible light is essential for the reaction(Table 41 entry 45ndash46) At the end of the optimization studies we found diethyl

NN

Br

O

N

194

+[Ir(ppy)2(dtbbpy)](PF6) (2 mol)

Na2HPO4 (20 equiv) DMF5 W blue LEDs (465 nm)

193

O

OO

195 62

NN

Br

O

N

194

+No photocatalyst

193

O

OO

NN

Br

O

N

194

Na2HPO4 (20 equiv) DMFno light

193

O

OO

195 52

195 0

(a)

(b)

(c)

Scheme 412 Visible light photoredox-catalyzed indolizine synthesis and control experiments(GC yields)

and morpholine carbamates to be suitable replacements for the 1-tetralone deriveddimethyl carbamate while pyrrolidine carbamate and pivalate analogs exhibitedmoderate efficiency (Table 41 entry 47ndash50)

O O

N

O O

N

O O

N

O O

N

O

200 201 202 203

O O

O

O O OS

N

196 197 198 199

OOF3C

O

O O

204

424 Scope and Limitations1

With the optimized reaction conditions in hand we explored the scope and limi-tations of the developed transformation The outcome of our investigations issummarized in Table 42

In the first set of investigations different ester-substituted indolizine derivativeswere obtained in moderate to good yields while a nitrile-substituted analog wasalso produced albeit in a poor yield (Table 42 195 205ndash208)

In a second set of investigations we studied the effect of substituents on the3-aryl ring of the indolizines a sub-unit derived from the enol carbamate startingmaterial Substrates with both electron-rich and electron-deficient substituents weresuitable for this transformation but electron-rich substituents such as methyl andmethoxy groups were better tolerated than electron-poor one (eg fluorine)(Table 42 209ndash212)

In a third set of investigations we set out to explore the effect of substituents onthe pyridyl ring of the indolizines In previous reports these substitution patternshave rarely been explored To our delight both electron-rich and electron-poorfunctional groups at the C-6 and C-7 positions of the indolizines were well tolerated

NN

Br

O

N

194

+base

solventlight source

193

O

OO

195

Entry Base (equiv) Solvent Substrate 193 (equiv) Substrate (equiv) Light Source Yield ()b

1c Na2HPO4 (2) DMF 1 194 (5) Blue LEDs 62

2 Na2HPO4 (2) DMF 1 194 (5) Blue LEDs 52

3 Na2HPO4 (2) CH3CN 1 194 (5) Blue LEDs 43

4 Na2HPO4 (2) MeOH 1 194 (5) Blue LEDs 31

5 Na2HPO4 (2) EtOAc 1 194 (5) Blue LEDs 50

6 Na2HPO4 (2) DCE 1 194 (5) Blue LEDs 69

7 Na2HPO4 (2) 14-dioxane 1 194 (5) Blue LEDs 69

8 Na2HPO4 (2) THF 1 194 (5) Blue LEDs 54

9 Na2HPO4 (2) toluene 1 194 (5) Blue LEDs 50

10 Na2HPO4 (2) PhCF3 1 194 (5) Blue LEDs 74

11 Na2HPO4 (2) PhCl 1 194 (5) Blue LEDs 62

12 Na2HPO4 (2) pyridine 1 194 (5) Blue LEDs ndash

15 Na2HPO4 (2) PhCF3 1 198 (5) Blue LEDs ndash

18 K2HPO4 (2) PhCF3 1 194 (5) Blue LEDs 67

19 K3PO4 (2) PhCF3 1 194 (5) Blue LEDs 15

20 KOAc (2) PhCF3 1 194 (5) Blue LEDs 28

21 NaOAc (2) PhCF3 1 194 (5) Blue LEDs 46

22 Cs2CO3 (2) PhCF3 1 194 (5) Blue LEDs 35

23 K2CO3 (2) PhCF3 1 194 (5) Blue LEDs 39

24 Na2CO3 (2) PhCF3 1 194 (5) Blue LEDs 49

25 Li2CO3 (2) PhCF3 1 194 (5) Blue LEDs 54

26 KHCO3 (2) PhCF3 1 194 (5) Blue LEDs 40

27 LiNTf2 (2) PhCF3 1 194 (5) Blue LEDs 57

28 TEA (2) PhCF3 1 194 (5) Blue LEDs 29

29 DIPEA (2) PhCF3 1 194 (5) Blue LEDs 31

30 DIPA (2) PhCF3 1 194 (5) Blue LEDs 23

31 DBU (2) PhCF3 1 194 (5) Blue LEDs ndash

(continued)

under the standard reaction conditions (Table 42 213ndash220) In products 218 and214 bromide and chloride functionalities would be potentially amenable for sub-sequent cross-coupling reactions The product 214 was unambiguously character-ized by single crystal X-ray structure analysis by Dr Constantin G Daniliuc(WWU Muumlnster Fig 43) The indolizine product 221 with an aryl substituent onthe tether and product 222 without any tether were both obtained in reasonableyields (Table 42 221ndash222) The dimethylcarbamate substrate derived from1-indanone did not show any reactivity while the diethylcarbamate derived from1-benzosuberone afforded only trace amounts of the corresponding product

32 HMDS (2) PhCF3 1 194 (5) Blue LEDs 78

33 HMDS (2) PhCF3 1 194 (5) Green LEDs ndash

34 HMDS (2) PhCF3 1 194 (5) 23 W CFL 24

35 HMDS (2) PhCF3 1 194 (5) Black CFL 22

40d HMDS (2) PhCF3 1 194 (5) Blue LEDs 52

41e HMDS (2) PhCF3 1 194 (5) Blue LEDs 73

43 HMDS (1) PhCF3 1 194 (5) Blue LEDs 77 63f

44 ndash PhCF3 1 194 (5) Blue LEDs 60

45 HMDS (1) PhCF3 1 194 (5) ndash 1

46g HMDS (1) PhCF3 1 194 (5) ndash 3

47 HMDS (1) PhCF3 1 201 (5) Blue LEDs 65h

aMethyl 2-bromo-2-(pyridin-2-yl)acetate (193 010 mmol) 34-dihydronaphthalen-1-yl dimethylcarbamate or otherprotected tetralone enol (199 or 196ndash198 and 200ndash204) the base and the solvent (1 mL) were added to a flame-driedSchlenk tube in the absence of light The mixture was degassed with three freeze-pump-thaw cycles flushed with argonsealed and stirred at rt under visible light irradiation for 12 hbGC yield using mesitylene as an internal referencecThe reaction was performed in the presence of [Ir(ppy)2(dtbbpy)](PF6) (2 mol)dThe reaction was performed without degassing the solventeSolvent (2 mL 005 M) was usedfIsolated yield on a 030 mmol scalegThe reaction mixture was heated at 80 degC in the darkhIsolated yield on a 020 mmol scale

Table 42 Substrate scope of visible light-mediated indolizine synthesisa

NN

EWG

Br

EWG

O

NR4

R4R1 R1

R2

R3

R2

50 equiv

+HMDS (1 equiv)

PhCF3 (01 M) rt 12 hBlue LEDs (465 nm)

N

OOR5

195 (R5 = Me) 63205 (R5 = Et) 61206 (R5 = tBu) 45207 (R5 = CH2Ph) 48

N

OO

N N

OO

N

OO

20816b

20967

218 (R6 = Br) 74219 (R6 = F) 55

22065

N

R6

F3C

N

OO

NN

OO

N

OO

21765

21661

21475

21368

Ph

OO

Cl

N

OO

N

OO

21542

21238b

21167b

OO

F

N

OO

22133b

Cl

N

OO

21061b

N

OO

O

OO

O

OO

N

OO

22228

O 2230 (0)c

aPyridine substrate (020 mmol) enol carbamate (100 mmol 50 equiv) and HMDS (020 mmol10 equiv) were added to ααα-trifluorotoluene (01 M) in a flame-dried Schlenk tube under argonatmosphere The reaction mixture was degassed three freeze-pump-thaw cycles Then resultedmixture was irradiated with visible light from 5 W blue LEDs (λmax = 465 nm) at rt for 12 hR4 = methyl unless otherwise statedbR4 = ethylcReaction conducted in the presence of indolizine 195 (10 mol)

However the dimethyl carbamate substrate without a stabilizing aryl group inconjugation with the C=C double bond did not show any desired reactivity even inthe presence of the pre-formed indolizine 195 (10 mol) which may aid theprogress of this reaction (vide infra) In this method unreacted excess carbamatesubstrates can be recovered

425 Structural Manipulations of the Indolizine Product

To explore further the potential of the developed methodology we carried out somestructural modifications of the parent indolizine 195 Since the indolizine 195possesses an alkyl tether (ndashCH2CH2ndash) we sought to oxidize this tether to afford thecorresponding alkene thus delivering a fully aromatic derivative When indolizine195 was reacted with 10 equiv of 23-dichloro-56-dicyano-14-benzoquinone(DDQ) in anhydrous toluene at 110 degC for 7 h the expected fully oxidizedunsaturated tetracyclic compound 224 was obtained in 71 yield (Scheme 413a)In another follow-up reaction the partially reduced tetra-substituted fused pyrrolederivative 225 was obtained in 96 when indolizine 195 was treated with Adamsrsquocatalyst (PtO2) in glacial acetic acid under a hydrogen atmosphere (20 bar) at 25 degCfor 40 h (Scheme 413b)

Fig 43 Crystal structure of indolizine 214

426 Mechanistic Investigations2

In order to shed light on the mechanism of this reaction we carried out variouscontrol experiments and spectroscopic and kinetics studies In order to identify thephotoactive species responsible for mediating the visible light-dependent processabsorption spectra were recorded for all the reaction components both in isolationand in combination While the spectra for the substrates 193 (200 microM) and 194(200 microM) and for the base HMDS (200 microM) did not reveal any notable visible lightabsorption indolizine 195 (100 microM) was found to absorb significantly at the bor-derline of the UV and visible region with a maxima in the near UV at 340 nm andshoulders at 328 and 372 nm (Fig 44a) Irradiating at either wavelength resulted ina detectable fluorescence emission at 442 nm (excited state lifetime τ = 4 nsrecorded by L Stegemann WWU Muumlnster Figs 44b and 611) In order toinvestigate whether an excited donor-acceptor complex (EDA complex or exciplex)may be being formed under the reaction conditions the absorption spectra for amixture of substrates 193 (100 mM) 201 (500 mM) and HMDS (100 mM) inPhCF3 mimicking the concentration of the actual reaction were recorded (Fig 45a)However we did not observe the appearance of any new peak or note any shift of thepeak position suggesting that no exciplex is formed between these speciesMoreover we did not observe any significant coloration upon mixing all the reactioncomponents together under degassed condition which is an indicative feature ofreactions proceeding via EDA formation (Fig 45b) [57]

At this stage we considered the possibility that the indolizine products them-selves could act as photoactive mediators for their own formation Stern-Volmerluminescence quenching experiments were performed with indolizine 195 atλemmax = 442 nm (λex = 372 nm) In these studies significant quenching of theluminescence was observed with the brominated pyridine substrate 193 while theenol carbamate substrate 194 and base HMDS remained innocent (Fig 46)According to these experiments if the indolizine product 195 serves as a photo-catalyst substrate 193 would quench the photo-excited photocatalyst to initiate thecatalytic cycle

195

N

OO

DDQ (10 equiv)

toluene 110 degC 7 h

225 96

N

OO

224 71

N

OO

PtO2 (10 mol)

H2 (20 bar)AcOH 25 degC 40 h

(b)(a)

Scheme 413 Follow-up reactions of indolizine 195 a Oxidation with DDQ and b PtO2-catalyzed partial hydrogenation

2A part of the mechanistic studies was carried out by Dr Matthew N Hopkinson (WWUMuumlnster)

Furthermore a kinetic profile of the reaction plotting of the yield of 195 as afunction of the reaction time revealed a parabolic curve consistent with the accel-eration of the reaction rate as the product concentration increases over time(Fig 47a) Furthermore spiking the mixture with increasing amounts of pre-formed195 led to a corresponding increase in the initial reaction rate (Fig 47b c) Thesesets of experiments suggest possible autocatalytic or autoinitiative behavior of theindolizine product

The involvement of an autoinitiated or autocatalytic mechanism is an intriguingpossibility Autocatalytic reactions are of fundamental importance in chemistry as

Fig 44 a Absorption spectra of 195 (100 microM in PhCF3) 193 (200 microM in PhCF3) 194 (200 microMin PhCF3) HMDS (200 microM in PhCF3) and a mixture of all three compounds (200 microM in PhCF3)b luminescence spectrum of 195 (100 microM in PhCF3) at λex = 372 nm Absorbance is measured inarbitrary units (au) Sahoo et al [65] Copyright Wiley-VCH Verlag GmbH amp Co KGaAReproduced with permission

Fig 45 a Absorption spectra of 193 (100 mM in PhCF3) 201 (500 mM in PhCF3) and amixture of all three compounds (193 (100 mM) + 201 (500 mM) + HMDS (100 mM) in PhCF3)b visualization of the reaction mixture after stirring for 10 min under ambient light (right)Absorbance is measured in arbitrary units (au)

Fig 46 Stern-Volmer luminescence quenching plots examining the 442 nm emission ofindolizine 195 in PhCF3 (1 mM) where 193 (black square) 194 (blue triangle) and HMDS(red circle) Sahoo et al [65] Copyright Wiley-VCH Verlag GmbH amp Co KGaA Reproducedwith permission

Fig 47 a Kinetic profile of the reaction showing the yield of 195 as a function of time b Effectof spiking the reaction with 10 30 or 50 mol of 195 on the initial reaction rate The left graphshows the yield expressed as the concentration of 195 minus the initial added amount as a functionof time over the first 70 min for each reaction The graph on the right is a plot of the initial rate ofeach reaction against the loading of 195 Sahoo et al [65] Copyright Wiley-VCH Verlag GmbH ampCo KGaA Reproduced with permission

they enable compounds to self-replicate and multiply [58] Accordingly auto-catalysis is widely believed to have been instrumental in the emergence of life onearth with the autocatalytic amplification of enantiomeric excess as demonstratedexperimentally by Soai and co-workers explaining the origin of biologicalhomochirality [59 60] Photochemical autocatalytic reactions are however scarcewith only a few examples having been reported notably in the context of signalamplification [61ndash63]

In order to gain insight into the redox activity of the indolizine 195 a cyclicvoltammetric measurement (CV) was conducted in 01 M TBABF4CH3CNrevealed the presence of an oxidation wave at around 09 V versus AgAgCl(Fig 48) However the irreversible nature of the wave implies that the indolizineprobably decomposes once oxidized Oxidative quenching of the indolizine by thebrominated pyridine 193 would presumably lead therefore to the concurrentdecomposition of a molecule of the indolizine However if an efficient chainmechanism is operating the amount of indolizine product generated would exceedthe amount consumed as a result of initiation

Inspired by above Stern-Volmer luminescence quenching and kinetic studies wewere curious to test the potential of the indolizine product as photocatalystphotoinitiator to promote other reactions As a proof of concept we conducted thevisible light photoredox-catalyzed alkylation of indoles originally reported byStephenson and co-workers using [Ru(bpy)3]

2+ with indolizine 195 [64] Whendiethyl 2-bromomalonate was reacted with N-methyl indole in the presence ofindolizine 195 (10 mol) under visible light irradiation from 5 W blue LEDs(λmax = 465 nm) the desired alkylated product 18 was obtained in 45 isolatedyield (Scheme 414) Control experiments confirmed the necessity of indolizine 195as well as light (Scheme 414)

Although from all these experiments it appears that indolizine 195 is itselfinvolved in this process we did not observe any significant absorption by theindolizine product at wavelengths consistent with the emission range of the 5 Wblue LEDs (λmax = 465 nm) used in these studies (for comparison see Fig 44a

Fig 48 Cyclicvoltammogram of 195 in01 M TBABF4CH3CNScan rate = 005 Vs andvoltage range = 00ndash15 VSahoo et al [65] CopyrightWiley-VCH Verlag GmbH ampCo KGaA Reproduced withpermission

and 63) In fact the luminescence of indolizine 195 (λem = 442 nm) occurs at ashorter wavelength than the emission maximum of the employed light source Assuch we speculate that an as yet unidentified photoactive species derived from theindolizine product might be responsible for catalyzing or initiating this visiblelight-mediated process

In order to verify the requirement for continuous light irradiation a light off-onexperiment was conducted (Fig 49) Switching off the light source during thelight-mediated synthesis of 195 results in a significant dropping off of the reactionefficiency which can then be readily restarted by turning the light back on As

N CO2Et

CO2Et

NCO2Et

Br

EtO2C 195 (10 mol)

Na2HPO4 (20 equiv)DMF rt 18 h

blue LEDs (465 nm)(20 equiv)(10 equiv)

18 Yield 45 (isolated)Without 195 not observedWithout light not observed

N

O

195

O

Stephensons conditions[Ru(bpy)3]Cl2 (1 mol)

DMF rtblue LEDs (435 nm)

82

NPh

OMeMeO 13 (20 equiv)

Scheme 414 Application of indolizine 195 as a photocatalyst in the visible light-mediatedalkylation of N-methylindole

Fig 49 Yield of 195 measured at different times after periods of visible light irradiation andperiods of darkness The blue shaded areas represent periods in the dark while the unshadedregions show periods under light irradiation Sahoo et al [65] Copyright Wiley-VCH VerlagGmbH amp Co KGaA Reproduced with permission

represented in Fig 49 simple regulation of the light irradiation allows for controlover the reaction progress It is important to note however that the requirement forcontinuous light irradiation does not mean that no radical chain mechanism isoperating The timescale of radical chain processes is very short and as such asimilar reaction profile would be observed during a light off-on experiment as nonew chains would be initiated in the absence of light

Since most visible light photoredox-catalyzed reactions proceed via a radicalpathway we performed our reaction in the presence of the radical scavengers2266-tetramethyl-1-piperidinyloxy (TEMPO) and 26-di-tert-butyl-α-(35-di-tert-butyl-4-oxo-25-cyclohexadien-1-ylidene)-p-tolyloxy (galvinoxyl) These additivesresulted in the complete shutdown of reactivity indicating the involvement ofradical intermediates During the reaction with TEMPO peaks consistent withadducts (226 and 227) between the radical scavenger and two different proposedradical intermediates B and C were detected by ESI mass analysis (Fig 410)(Scheme 415)

The full mechanism of this reaction remains ambiguous and further studieswould be required to gain complete insight into the nature of the photoactivespecies and its method of operation At this stage a radical chain process involvingthe key intermediates B and C seems to be the major pathway with subsequentaromatization leading to the indolizine products (Scheme 411) The key questionstill to be answered concerns the initiation of this cycle with all the data obtained todate indicating that the indolizine product is in some way involved The absorptionspectrum of the product itself however would seem to rule out the direct excitationof the indolizine and an as yet identified derivative of it may instead be acting as aphotoinitiator

43 Summary

In summary we have developed a novel methodology for the synthesis of valuablepolycyclic indolizines under visible light-mediated reaction conditions In thismethodology no additional reagents are required to activate the substrates Diversesubstitution patterns on the pyridine pyrrole and aryl rings are tolerated under thesemild reaction conditions which highlights the synthetic potential of this method Inaddition this reaction represents transition metal-free approach to access indoli-zines and thus avoids practical complications in the context of pharmaceutical orindustrial applications arising from metal contamination Furthermore structuralmanipulations of the indolizines to afford other N-heterocyclic compounds increasethe value of these products In order to shed light on the mechanism variousanalytical and laboratory experiments were carried out with the kinetic profile of thereaction a photochemical analysis of the reaction components and the apparentphotocatalytic ability of the indolizine in an unrelated visible light-mediated

reaction indicating the involvement of the indolizine products as being in some wayresponsible for their own formation Further insightful studies will be requiredhowever to fully elucidate the reaction mechanism Overall this procedure benefitsfrom mild reaction conditions such as the use of cost effective energy-efficientcommercial visible light sources without additional reagents Moreover its

O

N

226[M+Na]+ C17H26N2O3Na+

calculated mz 32918356measured mz 32918272

ON

O

ON

O O

N

227[M+Na]+ C30H41N3O5Na+

calculated mz 54629384Measured mz 54629314

Fig 410 Nanospray ESI mass spectrometry analysis of the reaction conducted in the presence ofTEMPO Two peaks consistent with adducts (226 and 227) between TEMPO and proposed radicalintermediates B and C were detected Sahoo et al [65] Copyright Wiley-VCH Verlag GmbH ampCo KGaA Reproduced with permission

intriguing mechanism with the suggestion of autocatalytic behavior could open upnew areas of photocatalysis research

References

1 MH Palmer D Leaver JD Nisbet RW Millar R Egdell J Mol Struct 42 85ndash101(1977)

2 M Shipman Sci Synth 10 745ndash787 (2000)3 WL Mosby Heterocyclic Systems with Bridgehead Nitrogen Atoms Part One (Interscience

New York 1961) p 2394 C-H Park V Ryabova IV Seregin AW Sromek V Gevorgyan Org Lett 6 1159ndash1162

(2004)5 VV Simonyan AI Zinin EV Babaev K Jug J Phys Org Chem 11 201ndash208 (1998)6 GS Singh EE Mmatli Eur J Med Chem 46 5237ndash5257 (2011)7 VR Vemula S Vurukonda CK Bairi Int J Pharm Sci Rev Res 11 159ndash163 (2011)8 V Sharma V Kumar Med Chem Res 23 3593ndash3606 (2014)9 WB Harrell RF Doerge J Pharm Sci 56 225ndash228 (1967)

10 DA James K Koya H Li G Liang Z Xia W Ying Y Wu L Sun Bioorg Med ChemLett 18 1784ndash1787 (2008)

11 Y-M Shen P-C Lv W Chen P-G Liu M-Z Zhang H-L Zhu Eur J Med Chem 453184ndash3190 (2010)

12 A Boot A Brito T van Wezel H Morreau M Costa F Proenccedila Anticancer Res 341673ndash1677 (2014)

13 JHC Nayler Chem Abstr 72 55285 (1970)14 L-L Gundersen C Charnock AH Negussie F Rise S Teklu Eur J Pharm Sci 30

26ndash35 (2007)15 OB Oslashstby B Dalhus L-L Gundersen F Rise A Bast RM Guido M Haenen Eur

J Org Chem 2000 3763ndash3770 (2000)16 J Gubin J Lucchetti J Mahaux D Nisato G Rosseels M Clinet P Polster P Chatelain

J Med Chem 35 981ndash988 (1992)17 W Mederski N Beier LT Burgdorf R Gericke M Klein C Tsaklakidis Google Patents

(2012)18 S Chen Z Xia M Nagai R Lu E Kostik T Przewloka M Song D Chimmanamada D

James S Zhang J Jiang M Ono K Koya L Sun MedChemComm 2 176ndash180 (2011)19 H Li Z Xia S Chen K Koya M Ono L Sun Org Process Res Dev 11 246ndash250 (2007)

O O

N

NBr

O

ON

OO

PhCF3 (01 M) rt 12 h

Blue LEDs (465 nm)Radical Scavenger (11 equiv)

193(10 equiv)

194(50 equiv) With TEMPO not observed

With Galvinoxyl not observed

195

Scheme 415 Radical trapping experiments reactions performed in the presence of TEMPO andgalvinoxyl

43 Summary 105

20 L-L Gundersen KE Malterud AH Negussie F Rise S Teklu OB Oslashstby Biorg MedChem 11 5409ndash5415 (2003)

21 S Teklu L-L Gundersen T Larsen KE Malterud F Rise Biorg Med Chem 13 3127ndash3139 (2005)

22 JP Michael Nat Prod Rep 24 191ndash222 (2007)23 JP Michael Nat Prod Rep 25 139ndash165 (2008)24 E Kim M Koh J Ryu SB Park J Am Chem Soc 130 12206ndash12207 (2008)25 E Kim M Koh BJ Lim SB Park J Am Chem Soc 133 6642ndash6649 (2011)26 E Kim Y Lee S Lee SB Park Acc Chem Res 48 538ndash547 (2015)27 B Liu Z Wang N Wu M Li J You J Lan Chem Eur J 18 1599ndash1603 (2012)28 M Becuwe D Landy F Delattre F Cazier S Fourmentin Sensors 8 3689 (2008)29 J Huckaba F Giordano LE McNamara KM Dreux NI Hammer GS Tschumper SM

Zakeeruddin M Graumltzel MK Nazeeruddin JH Delcamp Adv Energy Mater (2015)doi101002aenm201401629

30 Y Tominaga Y Shiroshita T Kurokawa H Gotou Y Matsuda A Hosomi J HeterocyclChem 26 477ndash487 (1989)

31 Ber Angeli Dtsch Chem Ges 23 1793ndash1797 (1890)32 Ber Angeli Dtsch Chem Ges 23 2154ndash2160 (1890)33 M Scholtz Ber Dtsch Chem Ges 45 734ndash746 (1912)34 E Tschitschibabin FN Stepanow Ber Dtsch Chem Ges 62 1068ndash1075 (1929)35 E Tschitschibabin Ber Dtsch Chem Ges 60 1607ndash1617 (1927)36 T Uchida K Matsumoto Synthesis 1976 209ndash236 (1976)37 DE Ames TF Grey WA Jones J Chem Soc 620ndash622 (1959)38 VS Venturella J Pharm Sci 52 868ndash871 (1963)39 T Melton D G Wibberley J Chem Soc C 983ndash988 (1967)40 KR Kallay RF Doerge J Pharm Sci 61 949ndash951 (1972)41 V Boekelheide K Fahrenholtz J Am Chem Soc 83 458ndash462 (1961)42 E Henrick W Ritchie Taylor Aust J Chem 20 2467ndash2477 (1967)43 Y Kobayashi I Kumadaki Y Sekine T Kutsuma Chem Pharm Bull 21 1118ndash1123

(1973)44 F Kroumlhnke W Zecher Chem Ber 95 1128ndash1137 (1962)45 W Adamson PA Barrett JW Billinghurst TSG Jones J Chem Soc 312ndash324 (1958)46 F Pratt JC Keresztesy J Org Chem 32 49ndash53 (1967)47 R Bonneau YN Romashin MTH Liu SE MacPherson J Chem Soc Chem Commun

509ndash510 (1994)48 S Chuprakov FW Hwang V Gevorgyan Angew Chem Int Ed 46 4757ndash4759 (2007)49 N Pandya JT Fletcher EM Villa DK Agrawal Tetrahedron Lett 55 6922ndash6924 (2014)50 L Xiang Y Yang X Zhou X Liu X Li X Kang R Yan G Huang J Org Chem 79

10641ndash10647 (2014)51 S Tang K Liu Y Long X Gao M Gao A Lei Org Lett 17 2404ndash2407 (2015)52 R-R Liu J-J Hong C-J Lu M Xu J-R Gao Y-X Jia Org Lett 17 3050ndash3053 (2015)53 D Lieacutegault L Lapointe A Caron KFagnou Vlassova J Org Chem 74 1826ndash1834 (2009)54 Org Zhao Org Biomol Chem 10 7108ndash7119 (2012)55 H Hu Y Liu J Xu Y Kan C Wang M Ji RSC Adv 4 24389ndash24393 (2014)56 M J OrsquoNeil (ed) The Merck IndexmdashAn Encyclopedia of Chemicals Drugs and Biologicals

13 ed (Whitehouse Station NJ Merck and Co Inc 2001) p 83757 E Arceo ID Jurberg A Aacutelvarez-Fernaacutendez P Melchiorre Nat Chem 5 750ndash756 (2013)58 J Bissette SP Fletcher Angew Chem Int Ed 52 12800ndash12826 (2013)59 K Soai T Shibata H Morioka K Choji Nature 378 767ndash768 (1995)60 G Blackmond Proc Natl Acad Sci 101 5732ndash5736 (2004)61 J-I Hong Q Feng V Rotello J Rebek Science 255 848ndash850 (1992)62 R Kottani JRR Majjigapu A Kurchan K Majjigapu TP Gustafson AG Kutateladze

J Am Chem Soc 128 14794ndash14795 (2006)

63 R Thapaliya S Swaminathan B Captain FM Raymo J Am Chem Soc 13613798ndash13804 (2014)

64 L Furst BS Matsuura JMR Narayanam JW Tucker CRJ Stephenson Org Lett 123104ndash3107 (2010)

65 B Sahoo M N Hopkinson F Glorius External-photocatalyst-free visible-light-mediatedsynthesis of indolizines Angew Chem Int Ed 54 15545ndash15549 (2015)

References 107

Chapter 5Synthesis and Characterizations of NovelMetal-Organic Frameworks (MOFs)

51 Intoduction

Metal-organic frameworks (MOFs) are an exciting class of porous crystalline mate-rials Although crystalline materials have received the attention of scientists since1960s [1] the concept of metal-organic frameworks (MOFs) began to be popularizedin 1990s [2 3] Metal-organic frameworks (MOFs) are highly crystalline porousinorganic and organic hybrid materials with a giant network structure in contrast topurely inorganic zeolites molecular sieves and purely organic activated carbonsThese hybrid materials are composed of inorganic metal ions or clusters and organicspacer molecules An inorganic metal ion or cluster is called a lsquonodersquo while anorganic spacer molecule is known as a lsquolinker or rodrsquo Although the syntheses ofMOFs were initiated in the early 1990s [2 3] it was not until 1999 that the first highlyporous and remarkably stable MOF (assigned as MOF-5) was synthesized by Yaghiet al [4] According to this report MOF-5 with the chemical composition Zn4O(BDC)3(DMF)8(C6H5Cl) (BDC = benzene-14-dicarboxylate) was prepared bytreating zinc nitrate (Zn(NO3)2) withH2BDC inDMFchlorobenzene (Fig 51) [4 5]Since then this field has grown extensively capturing the attention of many scientistsOutstanding performances of these porous materials in various applications highlightthe need to further develop this emerging field [6 7]

512 General Characteristic Features of Metal-OrganicFrameworks (MOFs)

In general metal-organic frameworks (MOFs) are highly porous (up to 90 freevolume) crystalline and thermally stable materials with a large internal surface area

109

(up to 6000 m2g) [8] Since MOFs are hybrid materials consisting of inorganicnodes and organic linkers rational design could be used to predict the possibilitiesfor their construction Reticular chemistry which involves the principles of precisedesign and successful synthesis of materials derived from secondary building unitsconnected by stronger chemical bonds is applied to the construction ofmetal-organic frameworks [9] These materials can be synthesized using variousmetal ions (eg Al Zr Cr Fe Ni Cu Zn etc) and organic linkers (ie polycar-boxylates sulfonates phosphonates imidazolates pyridines etc) by tailor madesyntheses [8] Various secondary building units (SBUs) (eg tetrahedral octahe-dral cubic rhombic dodecahedron etc) can be built up in situ by choosing theproper metal ion and reaction conditions [9 10] In addition careful selection oforganic linkers with the ideal spacer length and donor group provides a platform formodular synthesis of a wide spectrum of isoreticular MOFs with large pores foraccommodation of guest molecules and large window for their inclusion processLonger linkers sometimes result in interpenetration of one unit cell into others andresult in blocking of the cavity (Fig 52c) However the use of a mixture of linkersin a certain ratio represents useful approach to tune the cavity and window size Themixed linker strategy provides access to MOF materials with cavities of differentshapes and sizes existing in same 3D network structure which is beneficial fortuning selectivity In this context one of the interesting features of MOF materialsis that a minor change in the metal precursor organic linker or synthesis conditionscan result in a dramatic change in structural properties such as topology cavity sizeetc and sometimes prevents interpenetration In application perspective largercavities with void space are highly desirable for application in storage of gases andliquids separation and catalysis through host-guest interactions In addition ther-mal and chemical stabilities of these materials are crucial to their performance inreactions conducted inside the cavity and recyclability Apart from these featuresone of the serious concerns regarding MOF chemistry is the stability of theframeworks upon activation prior to their use it is necessary to remove solvent

Fig 51 Synthesis of MOF-5 from benzene-14-dicarboxylate (BDC) (linker) and tetra-zinc oxocluster (Zn4O) (node) generated in situ from Zn(NO3)2 Adapted from Ref [5] with the permissionof Gesellschaft Deutscher Chemiker (GDCh)

110 5 Synthesis and Characterizations of Novel

molecules or reagents under vacuum from the cavity of the MOFs as synthesizedand sometimes leads to undesired decomposition Therefore special techniquessuch as supercritical drying must be applied in MOF activation in these situationsIn some MOFs this form of activation allows for the retention of the frameworkgeometry and results in vacant coordination sites for the activation of substratestowards catalysis

HO

O OH

O

OH

OHO

O

OH

HO

O

HO

O

OH

O

NN

H3BTB H4BenzTB

NN

OHO

HOO

N N

O

OHO O

Mn

O

HO

Cl

H2BDC

H2NDC

44-Bipy

H2BPDC chiral Mn-Salen baseddicarboxylic acid linker

(a)

(b) (c)

O OH

Zn

ZnOCu

OOO O

CuOO

O O

L

Zn4O Cu2(COO)4L2Interpenetrated

structure

Fe

FeFeO OO O

OO

OO O

O

OO

OCl OH2

H2O

Fe3(micro3-O)(COO)6Cl(H2O)2

Fig 52 a Selected examples of ditopic tritopic and tetratopic organic linkers b selectedexamples of nodes with different geometries c representation of unit cells of an interpenetratedMOF

51 Intoduction 111

513 Applications of Metal-Organic Frameworks (MOFs)

MOFs have fascinated scientists from academia to industry due to their charac-teristic ultraporosity high crystallinity exceptionally large internal surface area (upto 6000 m2g) and thermal and chemical stabilities [6ndash8] Effective activation ofMOFs removes all the blockages (mostly solvents) from the cavities and channelsto obtain a large amount of void space up to 90 [8] These materials can be usedas portable storage devices for fuel gases such as hydrogen [11 12] methane[13 14] and acetylene [15] In addition MOFs can be used for gas capture(eg carbon dioxide) [16] as well as purifications and separations of chemicalmixtures in gaseous phase vapor phase or liquid phase Even structural isomerssuch as xylenes [17 18] and hexanes [19] which are very hard to separate by othermeans as well as stereoisomers (eg enantiomers and cis-trans isomers) can beseparated with the MOFs [20 21] The absorption capacity of MOFs can beimproved by tuning the physicochemical properties of the internal surface In thispurpose molecular simulations are very helpful in understanding the interactionsbetween absorbed species and MOF interiors on a molecular level which can not beobserved experimentally [22]

In addition MOF materials are being explored as chemical sensors to detectgases and volatile analytes with high sensitivity and selectivity [23] Due to thetunability of MOF structures as well as their properties the use of these materials isadvantageous compared to the known classes of chemosensors Metal-organicframeworks especially MOF films can be used as chemical sensors in chemicalthreat detection industrial process management food quality determination andmedical diagnostics [23]

Recently significant advances have been made in the field of luminescent MOFchemistry Hundreds of luminescent MOFs have been reported in the literature[24 25] Direct excitation of highly conjugated organic linkers metal-centeredemission via antenna effect (mostly lanthanide based MOFs) charge transfer viametal to ligand charge transfer (MLCT) or ligand to metal charge transfer aremostly responsible for the luminescence behavior of the metal-organic frameworksand sometimes guest induced luminescence of MOFs is also possible [24 25]These luminescent MOFs are generally used in chemical sensing as luminescencesensors electroluminescent devices nonlinear optics biomedical imaging andphotocatalysis [24 25] Recently noncentrosymmetric MOF synthesis has receivedthe attention of scientists for their second-order nonlinear optics (NLO) [26]

MOFs can be used as drug delivery systems by carrying and releasing drugmolecules the destination cells [27] For this purpose therefore MOFs and theirindividual components should be non-toxic Moreover these bioactive MOFs haveto be mechanically and chemically stable to both acidic (stomach) and basic(intestine) conditions [27] Oral administration of MOFs in the form of tablets [egtablet of ibuprofen containing MIL-53(Fe) and MIL-100(Fe) (MIL = Materials ofInstitut Lavoisier)] powders pellets or gels have been successful [27]

In another major application metal-organic frameworks have recently beenemployed in heterogeneous catalysis [28ndash31] Catalytically active MOFs serve asshape and size selective catalysts In these materials catalytic centers are immo-bilized by the organic linkers or nodes The stability of the framework andaccessibility of the large cavity define the MOF reactivity In this context to accessthe cavity window size should be wide enough and channels should be free fortransport of substrates and products With the increasing demand for enantiopurechiral compounds asymmetric catalysis has captured the interest of scientists forfew decades Since MOF catalysis reactions take place inside the cavity chiralmodification of the MOF cavity would provide a chiral environment for asymmetricinduction [29 30]

Thanks to these exciting applications in recent days MOF materials areextensively being used in industry in various purposes [6 7]

514 Synthesis of Metal-Organic Frameworks (MOFs)

Due to the great applications over the last 20 years MOF synthesis has received theattention of synthetic and material chemists [3] During the MOF synthesis manyparameters must be taken into consideration such as molar ratio of the startingmaterials (in particular for mixed MOF synthesis) solvent temperature pressurereaction time and also pH of the reaction medium Although it is said that MOFmaterials can be rationally designed practical rational designs do not always givethe expected results experimentally but rather move inspire the research Theconventional synthesis including solvothermal and nonsolvothermal procedures ofMOFs is conducted under thermal conditions without any parallelization Insolvothermal synthesis reactions are performed at high temperatures (higher thanthe boiling point of solvent) and under high pressure in closed vessels In non-solvothermal synthesis on the other hand reactions are carried out at solventrsquosboiling point or even lower temperatures at ambient pressure There has been atrend to develop synthetic protocols for the synthesis of different MOFs startingfrom same reaction ingredients Although the MOF starting materials are the samedifferent protocols provide MOFs with different yields structural morphologies andparticle sizes In addition to conventional synthesis many impressive alternativesynthetic routes have been developed with the progress of this growing fieldAlternative routes are divided into four different categories based on the energyapplied in the synthesis (a) microwave-assisted synthesis [32] (b) electrochemicalsynthesis [33] (c) mechanochemical synthesis [34] and (d) sonochemical synthesis[3 35] To accelerate the discovery of MOFs high-throughput screening methodsare used in parallel to systematic study [3] Up-scaling of the synthesis for largescale production can be achieved However obtaining phase pure crystallinematerials is difficult in MOF research Use of modulators sometimes helps inobtaining better crystals

51 Intoduction 113

In solvothermal synthesis of MOFs sensitive functional groups do not surviveunder harsh reaction conditions thus limiting the scope of functional groups thatcan be incorporated into the MOF Instead these sensitive functional groups can beincorporated into MOFs via postsynthetic modifications under relatively mildconditions through single crystal to single crystal transformations (Fig 53)[36ndash38] Postsynthetic modifications via a change in host-guest interaction havebecome an enabling technology for the fine tuning of the physicochemical prop-erties of metal-organic frameworks

Many research groups around the world including Cohen and co-workers asleading group have devoted substantial amount of time researching the postsyn-thetic modification of MOFs Although Cohen and co-workers reinitiated the studyof this field and explored extensively our group recently disclosed an elegantmethod for palladium catalyzed efficient selective and mild CndashH bond function-alization of an indole-based linker in a MOF via postsynthetic modification(Scheme 51) [39]

Since organic linkers are an essential counterpart of MOF skeletons and manyimportant outcomes arise from the modifications of these linkers the rational designand synthesis of organic linkers is one of the most important aspects of MOFresearch In this line of research it is important to consider the steric electronic andstereoelectronic properties of the organic linker in order to modify physicochemical

Fig 53 Representations of three different types of postsynthetic modifications with cartoons[38] All the linkers in each simplified MOF unit are same

properties of MOFs (interior of the MOF cavity the strength of adsorption of MOFthe thermal and chemical stability etc) Benzene-135-tribenzoic acid (BTB) is atritopic organic linker which has been incorporated into many MOFs BTB isversatile as it can be used alone or in a combination with other linkers The BTBunit in pure and substituted forms exists in 411 crystal structures [40] However inmany of these cases BTB molecule is a co-linker used in combination with otherfunctionalized linkers giving rise to mixed linker MOFs with tunable structuralproperties There have been a substantial number of reports describing the suc-cessful modifications of BTB by incorporation of various functional group [41ndash43]replacement of the middle benzene ring with other elements (eg N) [44] withother aromatic motifs (eg 135-triazene) [45ndash47]

Recently 44prime4Prime-tricarboxylatetriphenylamine (TPA) linker with a BDC co-linker as well as 44prime4Prime-s-triazene-246-triyl-tribenzoate (TATB) with no co-linkerhave been incorporated into UMCM-4 (UMCM = University of MichiganCrystalline Material) [44] and lanthanide based MOFs [45] respectively Althoughtriarylboranes possess interesting properties like fluorescence [48] co-catalyticactivity for polymerization [49] or dihydrogen activation [50] anion sensing(eg fluoride and cyanide) [51 52] and can be used in organic light-emitting diodes(OLEDs) [53] these compounds have not been extensively explored in MOFchemistry [54ndash56] Very recently Kleitz Wang and co-workers reported an eight-fold interpenetrated MOF (B-MOF) with limited porosity and accessibility using atriarylborane linker having carboxylate coordinating groups (Scheme 52) [54]

Over the last decade for asymmetric catalysis many enantiopure chiral linkershave also been developed and incorporated into MOFs [28ndash30] In 2011 our groupreported the successful synthesis and incorporation of chiral BTB linkers func-tionalized with chiral enantiopure oxazolidinone motifs into MOF (Zn3(chirBTB)2)for asymmetric catalysis [41]

O OH

OHO

N

Zn(NO3)2times4H2O

BTB DMF 85 degC16

UMCM-1-IndoleIndole-BDC

N

UMCM-1-Ph-Indole

N

Ph23

Pd(OAc)2

[Ph2I]BF4DMF rt 5 d

full conversionC2C3 gt955

H

Glorius and co-workers (2013)

23

Scheme 51 UMCM-1-indole synthesis and its postsynthetic modification via CndashH functional-ization [39] BTB benzene-135-tribenzoate UMCM University of Michigan crystalline material

51 Intoduction 115

521 Inspiration

Minor changes made to the organic linkers metal ions or reaction conditions can leadto a major change in the properties and structural topologies of MOFs As was dis-cussed earlier in this chapter H3BTB is one of thewidely used organic linkers inMOFsynthesis giving rise to highly accessible porous MOFs with large cavity sizes andhigh pore volumes We were interested in the development of novel substitutedH3BTB linkers and their application in the construction of metal-organic frameworksfor use as asymmetric catalysts in chiral separations or for screening their viability forpostsynthetic modification Since functionalized BTB linker syntheses involvelaborious multistep protocols synthetic studies on functionalized BTB linker basedMOFs are limited Fascinated by the fluorescent properties [48] cocatalytic activityfor polymerization [49] or dihydrogen activation [50] and anion sensing abilities[51 52] of triarylboranes wewere interested in non-interpenetratedB-MOF synthesisand the development of the rarely explored triarylborane based linkers as alternates toBTB featuring different steric and electronic properties as well as spacer lengths

522 Synthesis of Novel Metal-Organic Frameworks(MOFs)

Having this goal in mind the novel 44prime4Prime-boranetriyltris(35-dimethylbenzoicacid) (H3TPB) linker (228) was synthesized in a three steps (procedure shown inScheme 53) Modifying the procedure reported by Zhang Zhang and co-workerstris(4-bromo-26-dimethylphenyl)borane (230) was synthesized in improved yield

B

OH

O

OHO

HO

O

B-MOF-1Zn(NO3)2x6H2O

DMF 95 degC 3 d

(8-fold interpenetrated)

Kleitz Wang and co-workers (2013)

Scheme 52 Synthesis of interpenetrated B-MOF [54]

(42 ) in one pot starting from 5-bromo-2-iodo-13-dimethylbenzene In the nextstep tris(4-bromo-26-dimethylphenyl)borane (229) was treated with tBuLi and dryCO2 to afford 44prime4Prime-boranetriyltris(35-dimethylbenzoic acid) (H3TPB) (228) via alithium-halogen exchange followed by nucleophilic attack to CO2 This productwas formed as an inseparable mixture with the corresponding mono- and dicar-boxylic acid derivatives as byproducts We then changed our plan accordingly andin the second step a palladium catalyzed esterification of tris(4-bromo-26-dimethylphenyl)borane (230) in the presence of carbon monoxide(the carbonyl synthon) and methanol (the nucleophile) was conducted in theautoclave at 125 degC and at 40 bars of pressure was developed to furnish corre-sponding ester derivative 231 in moderate yield (47 ) Finally the hydrolysis ofthis ester derivative 231 under aqueous basic conditions followed by neutralizationwith dil mineral acid delivered the desired product 44prime4Prime-boranetriyltris(35-dimethylbenzoic acid) (H3TPB) (228) as a white solid in 95 yield

Having pure H3TPB material in hand we set out to synthesize Boron-MOFs incollaboration with Kaskel and co-workers from the Technical University Dresden1

Since triarylborane and triarylamine have similar propeller like structures the pro-cedure to synthesize UMCM-4 with benzene-14-dicarboxylic acid (H2BDC) and44prime4Prime-nitrilotribenzoic acid (H3TPA TPA = 44prime4Prime-tricarboxylatetriphenylamine)linkers in a 33 ratio was followed [44] H3TPA was replaced with H3TPB to give anew Boron-MOF However none of the attempted syntheses led to UMCM analogformation After an exhaustive screening an optimized protocol was developed tosynthesize a non-interpenetrated DUT-6 (boron) (Zn4O(TPB)43(BDC) (234)

I

Br B

Br

BrBr

B

OO

O

B

OHO

O

OH

HO

O

1) nBuLi Et2O-78 minus 0 degC

2) BF3Et2O

Pd[PPh3]4 (3x10 mol)CO (40 bar) NEt3

MeOH toluene125 degC

231 47

228 95

1) NaOHMeOHH2O (11)

2) aq H2SO4 (1M)

230 42229

Scheme 53 Synthesis of 44prime4Prime-boranetriyltris(35-dimethylbenzoic acid) (H3TPB) (228)

1The synthesis of MOFs was performed by Stella Helten (collaborator from TU Dresden)

in phase pure form (DUT = Dresden University of Technology) Zinc nitrateH2BDC (232) and H3TPB (228) were mixed in 401003 ratio in DEF and heated at80 degC for 48 h (Scheme 54) Following the developed protocol a chiral DUT-6(Boron) (Zn4O(TPB)43(chirBDC) (235) was also prepared using our previouslydeveloped chiral (S)-2-(4-benzyl-2-oxazolidin-2-yl) substituted BDC linker(233)[57] with H3TPB (228) (Scheme 54)

523 Structural Analysis of Novel Metal-OrganicFrameworks (MOFs)2

5231 PXRD Analysis

Since crystallinity is a crucial feature of MOF materials preliminary experiments todetermine the crystallinity and phase purity of the synthesized materials wereconducted using powder X-ray diffraction (PXRD) The PXRD patterns for DUT-6(Boron) (Zn4O(TPB)43(BDC)) chiral DUT-6 (Boron) (Zn4O(TPB)43(chirBDC))show their crystalline texture (Fig 54)

5232 Single Crystal X-ray Analysis

From the single crystal analysis of the B-MOF (Zn4O(TPB)43(BDC)) (234) shownin Fig 55a it is clear that Zn4O is present as SBU and both the linkers TPB andBDC are incorporated into the structure Four TPB linkers at equatorial positionsand two BDC linkers at axial positions connect to one Zn4O cluster center in an

B

OHO

O

OH

HO

OH3TPB (228)

OHO

O OH

R

H2BDC (232) R = H

chir H2BDC (233) R = NO

O

Ph

Zn(NO3)2x4H2ODEF

80 degC 48 h

DUT-6 (Boron)Zn4O(TPB)43(BDC) (234)

chirDUT-6 (Boron)Zn4O(TPB)43(chirBDC) (235)

DUT-6 (Boron) (234)

Scheme 54 Synthesis of DUT-6 (Boron) (Zn4O(TPB)43(BDC)) (234) and chiral DUT-6 (Boron)(Zn4O(TPB)43(chirBDC)) (235)

2Structural analysis of novel metal-organic frameworks (MOFs) has been done by Stella Heltenand Dr Volodymyr Bon (collaborators from TU Dresden)

Fig 54 Powder X-ray diffraction patterns of DUT-6 (Boron) (234) and chiral DUT-6 (Boron)(235) [61] Theoretical patterns were calculated from the crystal structures (black) Ref [61]reproduced by permission of The Royal Society of Chemistry

Fig 55 a Single X-ray crystal structure of DUT-6 (Boron) (Zn4O(TPB)43(BDC)) (234) withdodecahedral pores (red) and tetrahedral pores (blue) b dodecahedral pores (red) c topologicalrepresentation of SBU d tetrahedral pores (blue) Hydrogen atoms are omitted for clarityRef [61]mdashreproduced by permission of The Royal Society of Chemistry

octahedral arrangement (DUT-6 (Boron) (234) Fig 55c) There are two differenttypes of pore dodecahedral and tetrahedral present in this mixed linker DUT-6(Boron) (234) (Fig 55b d) In this microporous DUT-6 (Boron) (234) dodeca-hedral tetrahedral and window pores have diameters 15 10 and 5 Aring respectively(considering van der Waals radii) in contrast to mesoporous DUT-6 with the cor-responding pore diameters of 22 8 and 7 Aring In DUT-6 (Boron) (234) onedodecahedral pore is constructed with twelve Zn4O units interconnected by eighttrigonal and four linear linkers while a tetrahedral pore is constructed by fourtrigonal and two linear linkers interconnecting four Zn4O units (Fig 55b d) Thewindow is formed by interconnections of two trigonal and one linear linker withthree Zn4O clusters In the frozen state the angle between the planes on which arylring are lied is 884deg which is relatively higher than the angles (725deg 654deg and685deg) observed in UMCM-4 due to the steric effects of the methyl substituents onthe phenyl ring of the TPB inker

5233 TGA Analysis

Thermogravimetric analysis (TGA) of DUT-6 (Boron) (234) was performed on aSTA 409 (Netzsch) with synthetic air as a carrier gas a heating rate of 5 K min-1and a flow of 100 mL minminus1 Synthetic air was used for complete oxidation of theframework According to the DTA analysis of DUT-6 (Boron) (234) linkers start todecompose at 368degC The experimental residual mass of ZnO (3397 ) is con-sistent with the calculated residual mass of 3105 (Fig 56)

Fig 56 TGA analysis ofDUT-6 (Boron) (234) Ref[61]mdashreproduced bypermission of The RoyalSociety of Chemistry

5234 Physisorption Experiments

N2 adsorption study

Nitrogen physisorption measurements were performed on a BELSORP Max(BEL Japan) at 77 K with up to 1 bar of pressure The saturation uptake ofnitrogen by DUT-6 (Boron) (234) is 776 cm3 gminus1 which gives a pore volumeof 120 cm3 gminus1 (pp0 = 099) The Brunauer-Emmett-Teller (BET) surface area ofDUT-6 (Boron) (234) was calculated based on the adsorption branch in pressurerange of 77 10minus4 pp0 98 10minus2 The three consistency criteria pro-posed by Rouquerol et al [58] were maintained A value of 2874 m2 gminus1 wasobtained DUT-6 (Boron) (234) represents the first member of the family of highlyporous non-interpenetrated MOFs containing a triarylborane based-linker(Fig 57)

CO2 adsorption study

In order to better understand the interactions between carbon dioxide moleculeand the DUT-6 (Boron) (234) surface carbon dioxide adsorption experiments wereperformed At 1945 K saturation uptake of CO2 by the DUT-6 (Boron) (234)amounted to 63058 cm3 gminus1 This value decreased to 40327 cm3 gminus1 at 273 Kand 1 bar pressure The received data permit to calculate the isosteric heat ofadsorption (Qst) by the coverage in the range of 0036ndash18 mmol gminus1 The isostericheat of adsorption at lowest and higher coverage are 215 and 183 kJ molminus1

respectively This isosteric heat of adsorption at low coverage is relatively higherthan that for other MOFs having a Zn4O cluster at near zero or low coverage(167 kJ molminus1 for DUT-6 (see Chap 6 Sect 667) 1565 kJ molminus1 for IRMOF-1[59] 14 kJ molminus1 for MOF-177 [60] and 119 kJ molminus1 for UMCM-1) (Fig 58)[60] This higher value of DUT-6 (Boron) (234) indicates the presence of a specificinteraction arising from special sites in the frameworks This is usually observedwith MOFs having open metal sites (21ndash47 kJ molminus1) (Fig 59)

Fig 57 Nitrogenphysisorption isotherm ofDUT-6 (Boron) (234) at77 K Solid circles representadsorption and hollow circlesrepresent desorption Ref[61]mdashreproduced bypermission of The RoyalSociety of Chemistry

524 Dye Absorption Studies of Novel Metal-OrganicFrameworks (MOFs)3

The texture of MOF (Zn4O(TPB)43(BDC)) as synthesized is shown in Fig 510Since the accessibility of the MOF cavity is a crucial factor for the application of

MOFs in catalysis or separations (eg enantiomeric separation with the use of chiralMOFs) In order to further validate this concept dye absorption studies were per-formed with both DUT-6 (Boron) (234) and chiral DUT-6 (Boron) (235) Both ofthese MOFs were able to absorb organic dyes methylene blue brilliant green andrhodamine B upon dipping the crystals into the solution to furnish coloredcrystals (Fig 511) Reichardtrsquos dye could not be absorbed by these Boron-MOFs

Fig 58 Carbon dioxidephysisorption isotherm ofDUT-6 (Boron) (234) at1945 K Carbon dioxidephysisorption isotherm at273 K (inset) Ref [61]mdashreproduced by permission ofThe Royal Society ofChemistry

Fig 59 Comparison ofisosteric heats of CO2

adsorption (Qst) for DUT-6(Boron) (234) (solid bubble)and DUT-6 (solid diamonds)Ref [61]mdashreproduced bypermission of The RoyalSociety of Chemistry

3Dye absorption studies were carried out by Stella Helten (collaborator from TU Dresden)

525 Photophysical Studies of Novel Metal-OrganicFrameworks (MOFs)4

In a photophysical study H3TPB in DMF absorbs light at kmax = 324 nm and emitsat kmax = 402 nm (kex = 324 nm) while the DUT-6 (Boron) (Zn4O(TPB)43(BDC))absorbs at kmax = 364 with a broadening of spectra and emits at kmax = 443 nm(kex = 364 nm) (Fig 512a b) The observed bathochromic shift (41 nm) ofemission maximum seemingly reflects the energy change between the electronicstates of H3TPB upon incorporation into the MOF (Fig 512c)

Fig 510 Crystals of DUT-6 (Boron) (234) as synthesized Ref [61]mdashreproduced by permissionof The Royal Society of Chemistry

Fig 511 Crystals of DUT-6 (Boron) (234) (middle row) and chiral DUT-6 (Boron) (235)(bottom row) coloured by organic dyes Ref [61]mdashreproduced by permission of The RoyalSociety of Chemistry

4Photophysical studies were performed by Stella Helten (collaborator from TU Dresden)

53 Summary

In summary we have successfully developed a triarylborane linker with threecarboxylic acid anchoring groups (44prime4Prime-boranetriyltris(35-dimethylbenzoic acid)(H3TPB)) and incorporated it along with a linear co-linker benzene-14-dicarboxylic acid (H2BDC) into the metal-organic framework to give a novelmixed linker Boron-MOF DUT-6 (Boron) This DUT-6 (Boron) is highly porouswith pore volume 12 cm3 gminus1 and BET surface area of 2874 m2 gminus1 Thismicroporous DUT-6 (Boron) represents the first example of a highly porousnon-interpenetrated MOF containing a triarylborane linker In parallel followingthe same protocol a chiral DUT-6 (Boron) was also built by replacing normal BDClinker with a chiral (S)-2-(4-benzyl-2-oxazolidin-2-yl) substituted BDC linker thusgiving rise to chiral cavity Organic dye absorption studies showed pore accessi-bility in two newly synthesized Boron-MOFs In addition this new DUT-6 (Boron)showed fluorescent activity and exhibited a higher isosteric heat of adsorption forcarbon dioxide in contrast to the DUT-6 which has a similar structural topology

Fig 512 a Normalized absorption spectrum of H3TPB (228) in DMF (kmax = 324 nm) (red) andnormalized emission spectrum of H3TPB (228) in DMF (kex = 324 nm kmax = 402 nm) (blue)b normalized solid state absorption spectrum of DUT-6 (Boron) (234) (kmax = 364 nm) (red) andnormalized solid state emission spectrum of DUT-6 (Boron) (234) (kex = 364 nm kmax = 443 nm)(blue) c comparison of normalized emission spectra of H3TPB (228) (blue) and DUT-6 (Boron)(234) (red) showing bathochromic shift in emission wavelength Ref [61]mdashreproduced bypermission of The Royal Society of Chemistry

References

1 EA Tomic J Appl Polym Sci 9 3745ndash3752 (1965)2 M OrsquoKeeffe Chem Soc Rev 38 1215ndash1217 (2009)3 N Stock S Biswas Chem Rev 112 933ndash969 (2012)4 H Li M Eddaoudi M OrsquoKeeffe OM Yaghi Nature 402 276ndash279 (1999)5 S Kaskel Nachr Chem 53 394ndash399 (2005)6 U Mueller M Schubert F Teich H Puetter K Schierle-Arndt J Pastre J Mater Chem

16 626ndash636 (2006)7 AU Czaja N Trukhan U Muller Chem Soc Rev 38 1284ndash1293 (2009)8 H-C Zhou JR Long OM Yaghi Chem Rev 112 673ndash674 (2012)9 DJ Tranchemontagne Z Ni M OrsquoKeeffe OM Yaghi Angew Chem Int Ed 47 5136ndash

5147 (2008)10 DJ Tranchemontagne JL Mendoza-Cortes M OrsquoKeeffe OM Yaghi Chem Soc Rev 38

1257ndash1283 (2009)11 LJ Murray M Dinca JR Long Chem Soc Rev 38 1294ndash1314 (2009)12 MP Suh HJ Park TK Prasad D-W Lim Chem Rev 112 782ndash835 (2012)13 W Zhou Chem Rec 10 200ndash204 (2010)14 Y Peng V Krungleviciute I Eryazici JT Hupp OK Farha T Yildirim J Am Chem

Soc 135 11887ndash11894 (2013)15 Y Hu S Xiang W Zhang Z Zhang L Wang J Bai B Chen Chem Commun 7551ndash

7553 (2009)16 K Sumida DL Rogow JA Mason TM McDonald ED Bloch ZR Herm T-H Bae J

R Long Chem Rev 112 724ndash781 (2012)17 R El Osta A Carlin-Sinclair N Guillou RI Walton F Vermoortele M Maes D de Vos

F Millange Chem Mater 24 2781ndash2791 (2012)18 D Peralta K Barthelet J Peacuterez-Pellitero C Chizallet G Chaplais A Simon-Masseron G

D Pirngruber J Phys Chem C 116 21844ndash21855 (2012)19 ZR Herm BM Wiers JA Mason JM van Baten MR Hudson P Zajdel CM Brown

N Masciocchi R Krishna JR Long Science 340 960ndash964 (2013)20 J-R Li RJ Kuppler H-C Zhou Chem Soc Rev 38 1477ndash1504 (2009)21 J-R Li J Sculley H-C Zhou Chem Rev 112 869ndash932 (2012)22 RB Getman Y-S Bae CE Wilmer RQ Snurr Chem Rev 112 703ndash723 (2012)23 LE Kreno K Leong OK Farha M Allendorf RP Van Duyne JT Hupp Chem Rev

112 1105ndash1125 (2012)24 MD Allendorf CA Bauer RK Bhakta RJT Houk Chem Soc Rev 38 1330ndash1352

(2009)25 Y Cui Y Yue G Qian B Chen Chem Rev 112 1126ndash1162 (2012)26 C Wang T Zhang W Lin Chem Rev 112 1084ndash1104 (2012)27 P Horcajada R Gref T Baati PK Allan G Maurin P Couvreur G Feacuterey RE Morris C

Serre Chem Rev 112 1232ndash1268 (2012)28 J Lee OK Farha J Roberts KA Scheidt ST Nguyen JT Hupp Chem Soc Rev 38

1450ndash1459 (2009)29 L Ma C Abney W Lin Chem Soc Rev 38 1248ndash1256 (2009)30 M Yoon R Srirambalaji K Kim Chem Rev 112 1196ndash1231 (2012)31 A Dhakshinamoorthy AM Asiri H Garcia Chem Commun 50 12800ndash12814 (2014)32 J Klinowski FA Almeida Paz P Silva J Rocha Dalton Trans 40 321ndash330 (2011)33 U Mueller H Puetter M Hesse H Wessel in US patent Vol WO2005049892 200534 A Pichon A Lazuen-Garay SL James CrystEngComm 8 211ndash214 (2006)35 JH Bang KS Suslick Adv Mater 22 1039ndash1059 (2010)36 Z Wang SM Cohen Chem Soc Rev 38 1315ndash1329 (2009)37 KK Tanabe SM Cohen Chem Soc Rev 40 498ndash519 (2011)38 SM Cohen Chem Rev 112 970ndash1000 (2012)

References 125

39 T Droumlge A Notzon R Froumlhlich F Glorius Chem Eur J 17 11974ndash11977 (2011)40 F Allen Acta Crystallogr Sect B Struct Sci 58 380ndash388 (2002)41 K Gedrich M Heitbaum A Notzon I Senkovska R Froumlhlich J Getzschmann U Mueller

F Glorius S Kaskel Chem Eur J 17 2099ndash2106 (2011)42 PV Dau KK Tanabe SM Cohen Chem Commun 48 9370ndash9372 (2012)43 H-R Fu F Wang J Zhang Dalton Trans 43 4668ndash4673 (2014)44 A Dutta AG Wong-Foy AJ Matzger Chem Sci 5 3729ndash3734 (2014)45 S Ma X-S Wang D Yuan H-C Zhou Angew Chem Int Ed 47 4130ndash4133 (2008)46 S Ma D Yuan X-S Wang H-C Zhou Inorg Chem 48 2072ndash2077 (2009)47 J Park D Feng H-C Zhou J Am Chem Soc 137 1663ndash1672 (2015)48 PCA Swamy P Thilagar Inorg Chem 53 2776ndash2786 (2014)49 EY-X Chen TJ Marks Chem Rev 100 1391ndash1434 (2000)50 GC Welch RRS Juan JD Masuda DW Stephan Science 314 1124ndash1126 (2006)51 E Galbraith TD James Chem Soc Rev 39 3831ndash3842 (2010)52 CR Wade AEJ Broomsgrove S Aldridge FP Gabbaiuml Chem Rev 110 3958ndash3984

(2010)53 M-S Lin L-C Chi H-W Chang Y-H Huang K-C Tien C-C Chen C-H Chang C-

C Wu A Chaskar S-H Chou H-C Ting K-T Wong Y-H Liu Y Chi J Mater Chem22 870ndash876 (2012)

54 BA Blight R Guillet-Nicolas F Kleitz R-Y Wang S Wang Inorg Chem 52 1673ndash1675 (2013)

55 Y Liu K Mo Y Cui Inorg Chem 52 10286ndash10291 (2013)56 X Wang J Yang L Zhang F Liu F Dai D Sun Inorg Chem 53 11206ndash11212 (2014)57 M Padmanaban P Muller C Lieder K Gedrich R Grunker V Bon I Senkovska S

Baumgartner S Opelt S Paasch E Brunner F Glorius E Klemm S Kaskel ChemCommun 47 12089ndash12091 (2011)

58 J Rouquerol P Llewellyn F Rouquerol in Characterization of Porous Solids VIIProceedings of the 7th International Symposium on the Characterization of Porous Solids(COPS-VII) Aix-en-Provence France 26ndash28 May 2005 vol 160 eds by JRPLLlewellyn F Rodriquez-Reinoso N Seaton (Elsevier 2007) pp 49ndash56

59 B Mu PM Schoenecker KS Walton J Phys Chem C 114 6464ndash6471 (2010)60 JA Mason K Sumida ZR Herm R Krishna JR Long Energy Environ Sci 4 3030ndash

3040 (2011)61 S Helten B Sahoo V Bon I Senkovska S Kaskel F Glorius CrystEngComm 17 307ndash

312 (2015)

Chapter 6Experimental Section

61 General Considerations

Procedures

Complete characterisation (Rf NMR IR MS) was carried out for compoundswithout literature precedence Unless otherwise noted all reactions were carried outin flame-dried glassware under argon atmosphere Air and moisture sensitivecompounds were stored and weighed into reaction vessels under argon in a glovebox (M Braun) The oxygen level within the glove box was typically below 1 ppmLight sensitive compounds were stored in freezer at minus20 degC in dark Reactiontemperatures are reported as the temperature of the oil bath surrounding the vesselor the temperature inside the custom-made light box No attempts were made tooptimize the yield for the synthesis of starting substrates

Solvents and chemicals

The following solvents were purified by distillation over the drying agentsindicated in parentheses THF (Nabenzophenone) Et2O (Nabenzophenone)toluene (CaH2) CH2Cl2 (CaH2) nhexane (CaH2) tAmylOH (CaH2) Et3N (CaH2)Additional anhydrous solvents (lt50 ppm H2O) were purchased from AcrosOrganics Sigma-Aldrich or Carl Roth and stored over molecular sieves under argonatmosphere Commercially available chemicals were obtained from ABCR AcrosOrganics Alfa Aesar Combi-Blocks Fisher Scientific Fluorochem HeraeusJohnson-Matthey Maybridge Merck Sigma-Aldrich Strem Chemicals TCIEurope or VWR and used as received unless otherwise stated

Thin layer chromatography (TLC)

Analytical TLC was performed on either silica gel 60 F254 aluminum plates(Merck) or Polygram SIL GUV254 Alox B plates They were visualized byexposure to short wave UV light (254 or 366 nm) or using a KMnO4 stainingsolution followed by heating

127

Flash column chromatography (FCC)

FCC was performed on Merck silica gel (minus40 to 63 microm) or alox B(EcoChromtrade MP alumina N Act I) Solvents (CH2Cl2 EtOAc

npentane diethylether toluene) were distilled prior to use MeOH was used in pa grade

Nuclear magnetic resonance spectroscopy (NMR)

NMR spectra were recorded at room temperature on a Bruker DPX300 AV300AV400 or an Agilent DD2 600 or VNMRS 500 Chemical shifts (δ) are given inppm For 1H- and 13C-NMR spectra the residual solvent signals were used asreferences and the chemical shifts converted to the TMS scale (CDCl3δH = 726 ppm δC = 7716 ppm CD2Cl2 δH = 532 ppm δC = 5384 ppm C6D6δH = 716 ppm δC = 12806 ppm DMSO-d6 δH = 250 ppm δC = 3952 ppmCD3OD δH = 331 ppm δC = 4900 ppm) [1] 19F- and 19F-NMR [2] spectra arenot calibrated and δ (ppm) is given relative to CCl3F

31P-NMR spectra are notcalibrated and δ (ppm) is given relative to H3PO4 NMR data was analysed withMNova software from Mestrelab Research S L Multiplicities of signals areabbreviated as s (singlet) d (doublet) t (triplet) q (quartet) quint (quintet) sext(sextet) sept (septet) m (multiplet) bs (broad singlet) or a combination of theseCoupling constants (J) are quoted in Hz

Fourier transform infrared spectroscopy (FT-IR)

FT-IR spectra were recorded on a Varian Associated FT-IR 3100 ExcaliburSeries with a Specac Golden Gate Single Reflection ATR unit and analysed with aresolution program from Varian Associated The wave numbers (ν) of recordedsignals are quoted in cmminus1

Gas chromatography-mass spectrometry (GC-MS)

GC-MS spectra were recorded on an Agilent Technologies 7890A GC systemwith an Agilent 5975 inert mass selective detector or a triple-axis detector (EI) and aHP-5MS column (025 mm times 30 m film 025 microm) from JampW ScientificA constant flow of helium (99999 ) as the carrier gas was used The methodsused start with the initial temperature T0 After holding this temperature for 3 minthe column is heated to temperature T1 with a linear temperature gradient and thistemperature is held for an additional time t (e g method 50_40 T0 = 50 degCT1 = 290 degC gradient = 40 degCmin t = 3 min) The total ion count was recordedand evaluated with an Agilent ChemStation Enhanced Data Analysis programmeThe major signals are quoted in mz with the relative intensity in given inparentheses Exact EI mass spectra were recorded on a Waters-Micromass GC-Tof

Electrospray ionisation-mass spectrometry (ESI-MS)

Exact mass spectra were recorded on a Bruker Daltonics MicroTof High res-olution mass spectra were recorded on a Thermo-Fisher Scientific Orbitrap LTQXL Major signals are quoted in mz

128 6 Experimental Section

CHN elemental analyses were performed on a CHNS 932 analyser (LECO)

Polarimetry

The specific optical rotation frac12a24D of chiral compounds was measured using aPerkin Elmer Polarimeter 341 (T = 24 degC λ = 589 nm) using a quartz cuvette(10 cm path length)

Single Crystal X-ray crystalography

Data sets were collected with a Nonius KappaCCD diffractometer Programs useddata collection COLLECT data reduction Denzo-SMN [3] absorption correctionDenzo [4] structure solution SHELXS-97 [5] structure refinement SHELXL-97 [6]and graphics XP (BrukerAXS 2000) R-values are given for observed reflectionsand wR2 values are given for all reflections A pale yellow plate-like specimen ofC19H16ClNO3 approximate dimensions 0040 mm times 0140 mm times 0200 mm wasused for the X-ray crystallographic analysis The X-ray intensity data were measuredA total of 3257 frames were collected The total exposure time was 1739 h Theframes were integrated with the Bruker SAINT Software package using a wide-framealgorithm The integration of the data using a monoclinic unit cell yielded a total of32320 reflections to a maximum θ angle of 6832deg (083 Aring resolution) of which2801 were independent (average redundancy 11539 completeness = 998 Rint = 532 Rsig = 221 ) and 2480 (8854 ) were greater than 2σ(F2) Thefinal cell constants of a = 92567(2) Aring b = 76968(2) Aring c = 216732(5) Aringβ = 981490(10)deg volume = 152856(6) Aring3 are based upon the refinement of theXYZ-centroids of 9934 reflections above 20 σ(I) with 8242deg lt 2θ lt 1365deg Datawere corrected for absorption effects using the multi-scan method (SADABS) Theratio of minimum to maximum apparent transmission was 0732 The calculatedminimum and maximum transmission coefficients (based on crystal size) are 06490and 09110 The final anisotropic full-matrix least-squares refinement on F2 with 219variables converged at R1 = 317 for the observed data and wR2 = 861 for alldata The CCDC-1038989 contains the supplementary crystallographic data for thecompound 214 This data can be obtained free of charge from the CambridgeCrystallographic Data Centre via wwwccdccamacukdata_requestcif

The dataset from the single crystal of DUT-6 (boron) Zn4O(TPB)43(BDC)(234) prepared in a glass capillary was collected at beamline BL142 JointBerlin-MX Laboratory of Helmholtz Zentrum Berlin equipped with a MX-225CCD detector (Rayonics Illinois) and 1-circle goniometer [7] The data collectionwas performed at room temperature using monochromatic radiation withλ = 088561 Aring A plethora of single crystals from different batches with variouslinear dimensions (up to 05 mm in all dimensions) were used for single crystaldiffraction experiments at room temperature and at 100 K In spite of sufficient sizeof single crystals and highly intensive synchrotron radiation the sufficient inten-sities could be observed up until a resolution of 10ndash11 Aring The indexing of theimage frames suggests a primitive cubic lattice for the crystal structure The image

61 General Considerations 129

frames were integrated and scaled using XDSAPP 10 [8] graphic shell for the XDSprogram [9] The obtained set of intensities was carefully analyzed on extinctionAs a result systematic absences were found for the glide plane perpendicular to theface diagonal suggesting the Pm-3n space group for the crystal structure solutionand refinement The structure was solved by direct methods and refined byfull-matrix least square on F2 using SHELXS and SHELXL [10] programsrespectively All non-hydrogen atoms were refined in the anisotropic approxima-tion Hydrogen atoms were generated geometrically regarding the hybridization ofthe parent atom and refined using the ldquoriding modelrdquo with Uiso(H) = 15 Uiso(C) forCH3 and Uiso(H) = 12 Uiso(C) for CH groups The anisotropic refinementdecreased the data to parameter ratio for the observed reflections that had a stronginfluence on the refinement stability from the dataset with mean Iσ(I) = 236 Thisprompted us to use 11 distance restraints to fix the geometry of the organic ligandsBesides that lattice solvent molecules could not be located from the differenceFourier map due to disorder in the highly symmetrical space group Thus theSQUEEZE procedure in PLATON was performed to correct the intensities cor-responding to the disordered part of the structure [11] This results in 5202 electronssqueezed from 13642 Aring3 that corresponds to 155 molecules of DEF per formulaunit CCDC-1009603 contains the supplementary crystallographic data for thecompound 234 This data can be obtained free of charge from the CambridgeCrystallographic Data Centre via wwwccdccamacukdata_requestcif

Powder X-ray diffraction measurement

Powder X-Ray Diffraction data were collected on a STADI P diffractometer withCu-Kα1 radiation (λ = 15405 Aring) at room temperature

Photospectrometry

Liquid UV-Vis measurements were carried out on a JASCO V-650 spec-trophotometer and UV-1650PC spectrophotometer (Shimadzu) Solid state UV-Vismeasurements were performed on a Cary 4000 UV-Vis Spectrophotometer withpraying mantis geometry using PTFE as white standard Liquid state fluorescencemeasurements were conducted on a Cary Eclipse fluorescence spectrophotometerand a JASCO FP6500 spectrofluorometer Solid state fluorescence measurementswere conducted on a Cary Eclipse fluorescence spectrophoto-meter

The luminescence lifetime of indolizine 195 was recorded on a FluoTime300spectrometer from PicoQuant equipped with a 300 W ozone-free Xe lamp (250ndash900 nm) a 10 W Xe flash-lamp (250ndash900 nm pulse width lt 10 micros) with repeti-tion rates of 01ndash300 Hz an excitation monochromator (Czerny-Turner 27 nmmmdispersion 1200 groovesmm blazed at 300 nm) diode lasers (pulse width lt 80ps) operated by a computer-controlled laser driver PDL-820 (repetition rate up to80 MHz burst mode for slow and weak decays) two emission monochromators(Czerny-Turner selectable gratings blazed at 500 nm with 27 nmmm dispersionand 1200 groovesmm or blazed at 1250 nm with 54 nmmm dispersion and 600groovesmm) Glan-Thompson polarizers for excitation (Xe-lamps) and emission

a Peltier-thermostatized sample holder from Quantum Northwest (minus40 to 105 degC)and two detectors namely a PMA Hybrid 40 (transit time spread FWHM lt 120 ps300ndash720 nm) and a R5509-42 NIR-photomultiplier tube (transit time spreadFWHM 15 ns 300ndash1400 nm) with external cooling (minus80 degC) from HamamatsuSteady-state and fluorescence lifetime was recorded in TCSPC mode by a PicoHarp300 (minimum base resolution 4 ps) Lifetime analysis was performed using thecommercial FluoFit software The quality of the fit was assessed by minimizing thereduced chi squared function (χ2) and visual inspection of the weighted residualsand their autocorrelation (see the Fig 611)

TGA analysis

Thermogravimetric Analysis was carried out on a STA 409 (Netzsch) with aheating rate of 5 K minminus1 and synthetic air as carrier gas with a flow rate of100 mL minminus1

Physisorption measurement

Nitrogen physisorption experiments were performed on a BELSORP-max (BelJapan) at 77 K up to 1 bar CO2 physisorption measurements were performed on aBELSORP-max (Bel Japan) at 195 and 273 K up to 1 bar

Visible light sources

Visible light from compact fluorescent light bulbs (CFL) was provided by astandard household desk lamp purchased from Massive fitted with the appropriatelight bulb (14 23 or 32 W) (see Fig 61) Blue LEDs (5 W λ = 465 nm) and greenLEDs (5 W λ = 525 nm) were used for blue and green light irradiation respectivelyIn each case the light source was placed 5 cm from the reaction vessel In the caseof the blue and green LED irradiation a custom made ldquolight boxrdquo was used with 6blue and green LEDs arranged around the reaction vessels (see Fig 62 and 64)A fan attached to the apparatus was used to maintain the temperature inside the ldquoboxrdquoat no more than 9 degC above room temperature

Fig 61 Photograph forreactions conducted under23 W CFL bulb irradiation

Fig 62 Photographs of the custom-made ldquolight boxrdquo used for reactions conducted under blueLED irradiation

Fig 63 Emission spectrumof commercial blue LED(5 W λmax = 465 nm)Recorded by L StegemannWWU Muumlnster

62 Synthesis of Photocatalysts

All the organic dyes (Eosin Y Fluorescein dye Rhodamine B and Rose Bengal)were commercially available

Fig 64 Photographs of the custom-made ldquolight boxrdquo used for reactions conducted under greenLED irradiation

Fig 65 Emission spectrumof commercial green LED(5 W λmax = 525 nm)Recorded by L StegemannWWU Muumlnster

62 Synthesis of Photocatalysts 133

Synthesis of Tris(22prime-bipyridyl)ruthenium(II) bis(hexafluorophosphate)[Ru(bpy)3](PF6)2

NN

N

Ru (PF6)2

Following a modified procedure reported by Yoon et al [12] in a round bottomedflask equipped with a magnetic stir bar and connected with a reflux condenser underargon ruthenium(III) chloride (RuCl3xH2O 207 mg 100 mmol 100 equiv) and22prime-bipyridine (960 mg 615 mmol 615 equiv) were dissolved in dry ethanol(38 mL) The reaction mixture was refluxed at 80 degC for 12 h under argon Aftercooling to rt potassium hexafluorophosphate (KPF6 709 mg 385 mmol 385equiv) was added to the reaction mixture and stirred for another 1 h The solidprecipitate was collected by vacuum filtration and purified by column chromatog-raphy through silica (eluent acetonesatd aq KPF6 191) to furnish pure [Ru(bpy)3](PF6)2 (330 mg 0384 mmol 38 )

1H NMR (300 MHz acetone-d6) δ (ppm) 882 (dt J = 82 11 Hz 6H) 821(td J = 79 15 Hz 6H) 806 (ddd J = 56 15 07 Hz 6H) 758 (ddd J = 7756 13 Hz 6H) 13C NMR (755 MHz acetone-d6) δ (ppm) 1581 1527 13891288 1253 19F NMR (100 MHz acetone-d6) δ (ppm) minus7252 (dJ = 7079 Hz) 31P NMR (100 MHz acetone-d6) δ (ppm) minus13910 (septJ = 7075 Hz) HR-MS (ESI) mz calculated for [C30H24N6F6PIr]

+ ([M-PF6]+)

7150748 measured 7150773

Synthesis of Tris(22prime-bipyrazyl)ruthenium(II) bis(hexafluorophosphate)[Ru(bpz)3](PF6)2

22prime-Bipyrazine (bpz)N

N

NN

Following a modified procedure reported by Rillema et al [13] 2-(tributylstannyl)pyrazine (630 microL 2 mmol 100 equiv) was added to a solution of2-chloropyrazine (182 microL 204 mmol 102 equiv) in m-xylene (8 mL) Thereaction mixture was degassed by sparging argon for 30 min Then Pd(PPh3)4(116 mg 01 mmol 005 equiv) was added to the reaction mixture and degassedagain sparging argon for 15 min The resulting reaction mixture was refluxed for

3 d After cooling to rt solvent was removed under reduced pressure and purifiedby flash column chromatography through silica (eluent ethyl acetate) to afford pure22prime-bipyrazine (225 mg 142 mmol 71 ) as a white solid

1H NMR (300 MHz acetonitrile-d3) δ (ppm) 961 (d J = 12 Hz 1H) 867(s 2H) HR-MS (ESI) mz calculated for [C8H7N4]

+ ([M + H]+) 1590665measured 1590672

Tris22prime-bipyrazyl)ruthenium(II) bis(hexafluorophosphate) [Ru(bpz)3](PF6)2

N

NN

N

NN

N

NN

Ru (PF6)2

Following a modified procedure reported by Rillema et al [14] in a round bot-tomed flask equipped with a magnetic stir bar and connected with a reflux con-denser under argon ruthenium(III) chloride (RuCl3xH2O 21 mg 010 mmol 100equiv) and 22prime-bipyrazine (50 mg 032 mmol 32 equiv) were dissolved inethylene glycol (2 mL) The reaction flask was evacuated and flushed with argon(three times) The reaction mixture was refluxed at 200 degC for 1 h under argonAfter cooling to rt potassium hexafluorophosphate (KPF6 74 mg 040 mmol 400equiv) was added to the reaction mixture and stirred for another 15 min The solidprecipitate was filtered off and washed with water Then the product was dissolvedin acetonitrile to remove solid residue Solvent was removed under reduced pres-sure to furnish pure [Ru(bpz)3](PF6)2 (38 mg 0044 mmol 44 )

1H NMR (300 MHz acetonitrile-d3) δ (ppm) 978 (d J = 09 Hz 6H) 865(d J = 32 Hz 6H) 783 (dd J = 30 09 Hz 6H) 13C NMR (755 MHzacetonitrile-d3) δ (ppm) 1513 1498 1481 1465 19F NMR (100 MHzacetonitrile-d3) δ (ppm) minus7284 (d J = 7068 Hz) 31P NMR (100 MHzacetonitrile-d3) δ (ppm) minus14465 (sept J = 7067 Hz) HR-MS (ESI) mz cal-culated for [C24H18N6F6PIr]

+ ([M-PF6]+) 7210457 measured 7210461

Synthesis of fac-Tris(2-phenylpyridinato-C2N)iridium(III) [Ir(ppy)3]Tetrakis(2-phenylpyridinato-C2Nprime)(μ-dichloro)diiridium(III) [Ir(ppy)2Cl]2

N

Ir

N

Ir

Cl

Following a modified procedure from Watts et al [15] in a two necked roundbottomed flask equipped with a magnetic stir bar and connected with a refluxcondenser iridium(III) chloride (IrCl33H2O 429 mg 122 mmol 100 equiv) and2-phenyl pyridine (783 mg 770 μL 505 mmol 615 equiv) were dissolved in2-methoxyethanol (33 mL) and water (11 mL) The reaction mixture was refluxedat 110 degC for 24 h After cooling the reaction mixture to rt yellow precipitate wascollected on a Buumlchner funnel under vacuum filtration and washed with ethanol andacetone Finally the complex was dissolved in dichloromethane to separate fromthe iridium residue Removal of the solvent afforded [Ir(ppy)2Cl]2 (531 mg0493 mmol 81 ) as yellow solid which was used directly in next step

1H NMR (300 MHz DMSO-d6) δ (ppm) 966 (dd J = 800 56 Hz 4H)821 (dd J = 243 82 Hz 4H) 805 (dtd J = 251 78 16 Hz 4H) 775 (ddJ = 162 78 Hz 4H) 751 (dt J = 362 64 Hz 4H) 680ndash694 (m 4H) 673 (dtJ = 217 75 Hz 4H) 596 (dd J = 1765 76 Hz 4H) HR-MS (ESI) mz cal-culated for [C22H16N2Ir]

+ ([12M-Cl]+) 5010937 measured 5010947

fac-Tris(2-phenylpyridinato-C2N)iridium(III) [Ir(ppy)3]

N

NIr

Following a modified procedure reported by Thompson et al [16] in a heat gundried round bottomed flask equipped with a magnetic stir bar and connected with areflux condenser under argon [Ir(ppy)2Cl]2 (200 mg 0187 mmol) 2-phenyl pyr-idine (726 mg 67 microL 0468 mmol 250 equiv) and dry K2CO3 (258 mg187 mmol 100 equiv) were dissolved in ethylene glycol (10 mL) The reactionmixture was degassed using three freeze-pump-thaw cycles The flask was then

flushed with argon The reaction mixture was refluxed at 200 degC for 40 h Aftercooling to rt the reaction mixture was diluted with water The brownish gelatinoussolid precipitate was filtered off on a Buumlchner funnel under vacuum filtration andwashed with two portions of methanol and diethyl ether followed by hexane until apowdered yellow solid obtained Finally the crude mixture was purified by flashcolumn chromatography through silica (eluent dichloromethane) to deliver fac-[Ir(ppy)3] (120 mg 0183 mmol 49 ) as pure yellow solid

1H NMR (300 MHz CD2Cl2) δ (ppm) 792 (dt J = 83 11 Hz 3H) 760ndash771 (m 6H) 757 (ddd J = 56 17 09 Hz 3H) 684ndash697 (m 6H) 769ndash782(m 6H) 13C NMR (755 MHz CD2Cl2) δ (ppm) 1668 (Cq) 1614 (Cq) 1475(CH) 1442 (Cq) 1371 (CH) 1366 (CH) 1300 (CH) 1244 (CH) 1225 (CH)1202 (CH) 1192 (CH) HR-MS (ESI) mz calculated for [C33H24N3IrNa]

+

([M + Na]+) 6781493 measured 6781481

Synthesis of Bis(2-phenylpyridinato-C2N)(44prime-Di-tert-butyl-44prime-bipyridyl)iri-dium(III) hexafluorophosphate [Ir(ppy)2(dtbbpy)]PF6

N

Ir (PF6)

Following a modified procedure reported by Bernhard and Malliaras andco-workers [17] in a heat gun dried round bottomed flask equipped with a magneticstir bar and connected with a reflux condenser under argon previously synthesized[Ir(ppy)2Cl]2 (400 mg 0370 mmol 100 equiv) and 44prime-di-tert-butyl-22prime-bipyr-idine (dtbbpy 217 mg 0810 mmol 220 equiv) were dissolved in ethylene glycol(19 mL) The reaction mixture was refluxed at 150 degC for 15 h After cooling to rtthe reaction mixture was diluted with water (280 mL) Excess of 44prime-di-tert-butyl-22prime-bipyridine was removed through three times extractions with diethylether (3 times 150 mL) The aqueous phase was heated at 70 degC After 10 min heatingNH4PF6 (187 g 115 mmol 31 equiv) in water (19 mL) was added to the aqueousphase and a yellow solid started to precipitate out immediately This aqueous phasewas cooled to 0 degC to complete the precipitation The yellow solid was filtered offon a Buumlchner funnel under vacuum filtration and washed with water After dryingunder vacuum overnight pure [Ir(ppy)2(dtbbpy)]PF6 (649 mg 071 mmol 96 )was obtained as a yellow powder

1H NMR (300 MHz acetone-d6) δ (ppm) 888 (d J = 20 Hz 2H) 823 (dJ = 81 Hz 2H) 785ndash803 (m 6H) 779 (ddd J = 58 16 08 Hz 2H) 771 (ddJ = 59 20 Hz 2H) 713 (ddd J = 74 58 14 Hz 2H) 703 (td J = 75 13 Hz2H) 691 (td J = 74 14 Hz 2H) 634 (dd J = 76 12 Hz 2H) 141 (s 18H)

13C NMR (100 MHz acetone-d6) δ (ppm) 1688 1699 1568 1519 15111499 1450 1395 1325 1312 1264 1258 1244 1233 1208 364 304 19FNMR (300 MHz acetone-d6) δ (ppm) minus7265 (d J = 7075 Hz) 31P NMR(300 MHz acetone-d6) δ (ppm) minus14429 (sept J = 7075 Hz) HR-MS (ESI)mz calculated for [C40H40N4Ir]

+ ([M-PF6]+) 7692879 measured 7692900

Synthesis of Bis(2-(24-difluorophenyl)-5-(trifluoromethyl)pyridinato-C2Nprime)(44prime-di-tert-butyl-44prime-bipyridyl)iridium(III) hexafluorophosphate [Ir(dF(CF3)ppy)2(dtbbpy)](PF6)

This iridium photocatalyst was synthesized by Dr Matthew N Hopkinson(WWU Muumlnster) [18]

63 Oxy- and Aminoarylations of Alkenes

631 Synthesis of Gold Catalysts

The gold complexes (tht)AuCl (tht = tetrahydrothiophene) Me2SAuCl Ph3PAuCl[PhtBu2PAu(CH3CN)]SbF6 [dppm(AuCl)2] (dppm = diphenylphosphinomethane)AuCl [(pic)AuCl2] (pic = picolinato) and AuCl3 were commercially availableIPrAuCl (IPr = 13-bis(26-diisopropylphenyl)imidazol-2-ylidene) was preparedfollowing a literature procedure reported by Nolan and co-workers [19] The gold(I)chloride complexes ((4-OMe)C6H4)3PAuCl ((2-Me)C6H4)3PAuCl ((4-CF3)C6H4)3PAuCl and Cy3PAuCl were prepared by reacting an equimolar ratio of theappropriate phosphine with (tht)AuCl (tht = tetrahydrothiophene) or Me2SAuCl indichloromethane in a method analogous to that of Hashmi et al [20] [IPrAu]NTf2[((4-OMe)C6H4)3PAu]NTf2 [((4-CF3)C6H4)3PAu]NTf2 and [Cy3PAu]NTf2 wereprepared by reacting the corresponding gold(I) chloride complex with an equimolaramount of AgNTf2 in dichloromethane in a procedure analogous to that of Gagoszet al [21] [(Ph3P)2Au]OTf [22] was prepared by reacting Ph3PAuCl with AgOTfand PPh3 in a method analogous to that of Williams et al [23] All above mentionedgold catalysts were synthesized by Dr Matthew N Hopkinson (WWU Muumlnster)The following gold complex was synthesized by self according to the proceduresgiven in the cited reference

[111-Trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamidato-κN](triphenylphos phine)gold(I) [Ph3PAu]NTf2

Following a literature report from Gagosz et al [21] Ph3PAuCl (198 mg040 mmol) and AgNTf2 (172 mg 040 mmol) were weighed in a round bottomedflask and then dichloromethane (28 mL) was added to the mixture After stirring atrt for 15 min the crude suspension was filtered through Celite Volume of thefiltrate was reduced to 13 and the complex [Ph3PAu]NTf2 (250 mg 034 mmol85 ) was recrystallized as a white crystalline solid by adding pentane slowly

1H NMR (300 MHz CDCl3) δ (ppm) 745ndash759 (m 15H) 19F NMR(300 MHz CDCl3) δ (ppm) minus7516 31P NMR (300 MHz CDCl3) δ (ppm)minus3045 (sept J = 7075 Hz)

632 Synthesis of Alkene Substrates

Some substrates were commercially available A part of the substrate synthesis andscope were carried out by Dr Matthew N Hopkinson (WWU Muumlnster) A part ofsubstrates was also synthesized by Kristina Oldiges and M Wuumlnsche (all WWUMuumlnster) The following substrates were synthesized by self according to theprocedures given in the cited references No attempts were made to optimize yieldsfor the synthesis of substrates

(ndash)-(RS)-2-Allylcyclohexan-1-ol (67) [24]

OH

Following a literature report from Waser et al [24] in a heat gun dried two neckedround bottomed flask equipped with a magnetic stir bar and connected with a refluxcondenser under argon cyclohexene oxide (294 mg 304 microL 300 mmol 100equiv) was added dropewise to a solution of allyl magnesium bromide (91 mL91 mmol 1 M in Et2O 30 equiv) diluted with Et2O (73 mL) The reactionmixture was refluxed for 4 h at 40 degC After cooling to rt the reaction was quen-ched with satd aq NH4Cl and extracted with diethyl ether The combined organiclayers were washed with brine and dried over MgSO4 The crude reaction mixturewas purified by flash column chromatography through silica (eluentdichloromethanemathanol 991 to 964) to afford pure (plusmn)-(RS)-2-allylcyclohexan-1-ol (67 353 mg 252 mmol 84 ) as a colourless oil

1H NMR (300 MHz CDCl3) δ (ppm) 586 (ddt J = 173 101 73 Hz 1H)493ndash515 (m 2H) 314ndash337 (m 1H) 233ndash255 (m 1H) 188ndash208 (m 2H)157ndash183 (m 4H) 107ndash142 (m 4H) 086ndash104 (m 1H) HR-MS (ESI) mzcalculated for [C9H16ONa]

+ ([M + Na]+) 1631093 measured 1631090

(ndash)-3-Phenylpent-4-en-1-ol (66) [25]

OH

Following a procedure reported by Zhang et al [25] in a Schlenk tube a solution oftriethyl orthoacetate (138 mL 75 mmol 100 equiv) (E) cinnamyl alcohol

63 Oxy- and Aminoarylations of Alkenes 139

(129 mL 10 mmol 133 equiv) and butyric acid (100 microL 100 mmol013 equiv) in toluene (40 mL) was refluxed at 150 degC for 12 h The reactionmixture was concentrated and purified by flash column chromatography (eluentpentaneethyl acetate 173) to produce ethyl 3-phenylpent-4-enoate (119 g583 mmol 78 ) as colourless oil This ester was directly used in next step

Ethyl 3-phenylpent-4-enoate (118 g 578 mmol 100 equiv) was dissolved inTHF (22 mL) and LiAlH4 (526 mg 139 mmol 24 equiv) was added at 0 degC Theresulting reaction mixture was allowed to warm and stirred at rt for 6 h Thereaction mixture was poured into aq 1 M NaOH solution (55 mL) and ice withvigorous stiring A suspension of aluminium hydroxide was formed The suspen-sion was filtered through Celite and then aqueous phase was extracted with diethylether (3 times 50 mL) The combined organic layers were washed with aq 1 N HClsolution (45 mL) brine (45 mL) dried over MgSO4 and concentrated underreduced pressure The crude product was purified by flash column chromatographythrough silica (eluentpentaneethyl acetate 51) to deliver pure (plusmn)-3-phenylpent-4-en-1-ol (66 600 mg 370 mmol 64 ) as a colourless oil

1H NMR (300 MHz CDCl3) δ (ppm) 711ndash741 (m 5H) 598 (ddd J = 176102 76 Hz 1H) 499ndash520 (m 2H) 354ndash373 (m 2H) 347 (q J = 76 Hz 1H)182ndash210 (m 2H) 121ndash139 (m 1H) HR-MS (ESI) mz calculated for[C11H14ONa]

+ ([M + Na]+) 1850937 measured 1850935

3-Ethylhept-6-en-3-ol (68) [26]

OH

Following a similar procedure reported by Zhang et al [25] in a heat gun dried twonecked round bottomed flask equipped with a magnetic stir bar and connected witha reflux condenser under argon homoallyl bromide (116 mL 114 mmol 114equiv) in THF (24 mL) was added to a heterogeneous mixture of Mg turnings(288 mg 120 mmol 120 equiv) in THF (24 mL) The reaction mixture wasrefluxed for 2 h After cooling to rt the Grignard solution was diluted with THF(5 mL) and then added to a solution of 3-pentanone (106 mL 10 mmol 100equiv) in THF (10 mL) at minus78 degC The resulting reaction mixture was allowed tostir for another 1 h The reaction was quenched with satd aq NH4Cl and extractedwith diethyl ether The combined organic layers were washed with brine dried overMgSO4 and concentrated under reduced pressure The crude product was purifiedby flash column chromatography through silica (eluentpentaneethyl acetate 91) todeliver pure 3-ethylhept-6-en-3-ol (68 611 mg 430 mmol 43 ) as a colourlessoil

1H NMR (300 MHz CDCl3) δ (ppm) 585 (ddt J = 168 102 66 Hz 1H)455ndash515 (m 2H) 208 (dtt J = 95 64 15 Hz 2H) 140ndash156 (m 6H) 114 (s1H) 086 (t J = 75 Hz 6H) HR-MS (ESI) mz calculated for [C9H18ONa]

+

([M + Na]+) 1651250 measured 1651244

4-Methylpent-4-en-1-ol (69) [27]

OH

Following a procedure reported by Harmata et al [28] The solution of methallylalcohol (420 microL 5 mmol 100 equiv) and propionic acid (210 microL 0560 equiv)in triethyl orthoacetate (105 mL 573 mmol 115 equiv) was refluxed at 120 degCfor 8 h After cooling to rt the reaction mixture was diluted with diethyl etherextracted with 10 HCl satd aq NaHCO3 The combined organic layers werewashed with brine dried over MgSO4 and concentrated under reduced pressureThe crude ester (668 mg 47 mmol) was obtained as an oil and directly used innext step

The crude ester (650 mg 457 mmol 100 equiv) in THF (26 mL) was added toa suspension of LiAlH4 (520 mg 137 mmol 300 equiv) in THF (10 mL) at 0 degCThe reaction mixture was stirred for 30 min and then quenched with water (4 mL)The suspension was filtered through Celite extracted with diethyl ether(3 times 20 mL) washed with brine dried over MgSO4 and concentrated under reducedpressure The crude reaction mixture was purified by flash column chromatographythrough silica (eluentpentaneethyl acetate 91) to affoed pure 4-methylpent-4-en-1-ol (69 256 mg 256 mmol 56 ) as a colourless oil

1H NMR (300 MHz CDCl3) δ (ppm) 469ndash472 (m 2H) 364 (t J = 65 Hz2H) 208 (t J = 76 Hz 2H) 171 (s 3H) 163ndash175 (m 2H)

4-Methyl-N-(pent-4-en-1-yl)benzenesulfonamide (73) [29]

NHS

O

Following a procedure reported by Marcotullio et al [29] in heat gun dried roundbottomed flask triethylamine (70 mL 50 mmol 50 equiv) was added slowly to asolution of pent-4-en-1-ol (11 mL 100 mmol 100 equiv) and methanesulphonylchloride (543 microL 120 mmol 120 equiv) in dichloromethane (50 mL) at 0 degCThe reaction mixture was sirred at 0 degC for 1 h The reaction was quenched withwater extracted with dichloromethane washed with brine and concentrated underreduced pressure to give pent-4-en-1-yl 4-methylbenzenesulfonate (175 g730 mmol) This reaction was repeated The mesyl protected alcohol was directlyused in the next step without further purification

KOH (18 g 32 mmol 15 equiv) was dissolved in DMF (30 mL) at 120 degCand p-tolylsulphonyl amide (547 g 320 mmol 150 equiv) was then added to thereaction mixture After 30 min stirring a solution of pent-4-en-1-yl4-methylbenzenesulfonate (350 g 146 mmol) in DMF (12 mL) was added tothe reaction mixture The resulting reaction mixture was stirred for another 15 h at

120 degC After cooling to rt the reaction was quenched with water extracted withdiethyl ether washed with brine dried over MgSO4 and then concentrated underreduced pressure The crude reaction mixture was purified by flash column chro-matography through silica (eluentpentaneethyl acetate 91) to affoed pure4-methyl-N-(pent-4-en-1-yl)benzenesulfonamide (73 318 g 133 mmol 66 ) asa colourless oil

1H NMR (300 MHz CDCl3) δ (ppm) 774 (dt J = 84 17 Hz 2H) 731(d J = 84 Hz 2H) 570 (ddt J = 170 103 67 Hz 1H) 481ndash520 (m 2H)431ndash454 (m 1H) 294 (q J = 68 Hz 2H) 243 (s 3H) 204 (dtt J = 79 6615 Hz 2H) 151ndash165 (m 2H) HR-MS (ESI) mz calculated for[C12H17NO2SNa]

+ ([M + Na]+) 2620872 measured 2620869N-(22-Dimethylpent-4-en-1-yl)-4-methylbenzenesulfonamide (74) [25]

NHS

O

Following a procedure reported by Zhang et al [25] in heat gun dried roundbottomed flask n-butyllithium (150 mL 24 mmol 16 M in hexane 12 equiv)was added slowly to a solution of diisopropylamine (336 mL 240 mmol 120equiv) in THF (50 mL) at 0 degC and stirred for 20 min at same temperatureIsobutyronitrile (18 mL 20 mmol 10 equiv) was then added to the generatedLDA solution at 0 degC and stirred for 2 h Allyl bromide (208 mL 24 mmol 120equiv) was then added to the reaction mixture After 3 h stirring the reaction wasquenched with water (10 mL) and extracted with diethyl ether (3 times 30 mL) Thecombined organic layers were washed with brine dried over MgSO4 and con-centrated under reduced pressure to give 22-dimethylpent-4-enenitrile (790 mg723 mmol) which was directly used for next step

22-dimethylpent-4-enenitrile (790 mg 723 mmol 10 equiv) in diethyl ether(16 mL) was then treated with LiAlH4 (110 g 289 mmol 40 equiv) at rt Thereaction mixture was refluxed for 2 h After cooling to 0 degC in ice bath the reactionwas quenched with water and aq 15 NaOH solution The suspension was filteredthrough Celite and extracted with diethyl ether The filtrate was extracted withdiethyl ether washed with brine dried over MgSO4 and then concentrated underreduced pressure to give 22-dimethylpent-4-en-1-amine (278 mg 246 mmol12 over two steps)

Triethyl amine (670 microL 480 mmol 207 equiv) was added to a mixture of22-dimethylpent-4-en-1-amine (278 mg 246 mmol 106 equiv) and p-tolylsul-phonyl chloride (442 mg 232 mmol 100 equiv) in dichloromathae (77 mL) at0 degC The mixture was stirred at rt for 12 h

The reaction mixture was washed with aq 10 NaHCO3 solution and brinedried over MgSO4 and concentrated under reduced pressure The crude reaction

mixture was purified by flash column chromatography through silica (eluentpen-taneethyl acetate 173) to afford pure N-(22-dimethylpent-4-en-1-yl)-4-methylbenzenesulfonamide (74 502 mg 188 mmol 81 ) as a light greenishsolid

1H NMR (300 MHz CDCl3) δ (ppm) 773 (d J = 83 Hz 2H) 731 (dJ = 80 Hz 2H) 573 (ddt J = 178 103 74 Hz 1H) 493ndash510 (m 2H) 440(bs 1H) 268 (d J = 69 Hz 2H) 243 (s 3H) 196 (d J = 74 Hz 2H) 086 (s6H) HR-MS (ESI) mz calculated for [C14H21NO2SNa]

+ ([M + Na]+) 2901185measured 2901189

(Z)-4-Methyl-N-(pent-4-en-1-yl-5-d)benzenesulfonamide (127) [25]

NHS

O

D

Following a procedure reported by Zhang et al [25] DIAD (118 mL 600 mmol120 equiv) was added to a solution of pent-4-yn-1-ol (465 microL 500 mmol 100equiv) N-(tert-butoxycarbonyl)-p-toluenesulfonamide (149 g 550 mmol 110equiv) and triphenylphosphine (157 g 600 mmol 120 equiv) in THF (10 mL)at 0 degC The reaction mixture was stirred at rt for 12 h After concentrating thereaction mixture crude product was purified by flash column chromatographythrough silica (eluentpentaneethyl acetate 51) to afford pure tert-butylpent-4-yn-1-yl(tosyl)carbamate (161 g 477 mmol 95 ) as a white solid

In a heat gun dried round bottomed flask n-butyllithium (244 mL 391 mmol16 M 120 equiv) was added slowly to a solution of tert-butyl pent-4-yn-1-yl(tosyl)carbamate (110 g 326 mmol 100 equiv) in THF (33 mL) at minus78 degCAfter stirring at minus78 degC for 20 min the reaction mixture was quenched with D2O(600 microL 326 mmol 10 equiv) and stirred at 0 degC for 2 h The reaction mixturewas extracted with dichloromethane and purified by flash column chromatographythrough silica (eluentpentaneethyl acetate 61) to afford tert-butyl(pent-4-yn-1-yl-5-d)(tosyl)carbamate (730 mg 216 mmol 67 ) as a white waxysolid

A solution of DIBAL-H (323 mL 388 mmol 12 M in toluene 200 equiv)was added slowly to a solution of ZrCp2Cl2 (113 g 387 mmol 200 equiv) inTHF (26 mL) at 0 degC The suspension was stirred at rt for 1 h tert-Butyl(pent-4-yn-1-yl-5-d)(tosyl)carbamate (655 mg 194 mmol 100 equiv) in THF(26 mL) was added to the reaction mixture After stirring for 1 h the reactionmixture was quenched with water (25 mL) and continued stirring for another 1 hThe reaction mixture was poured into a solution of saturated aqueous NaHCO3

solution (150 mL) extracted with diethyl ether (3 times 60 mL) The combinedorganic layers were washed with brine dried over MgSO4 filtered through Celiteand then concentrated under reduced pressure Purification by flash column

chromatography through silica (eluentpentaneethyl acetate 91) afforded pure tert-butyl (Z)-(pent-4-en-1-yl-5-d)(tosyl)carbamate (270 mg 079 mmol 41 )

A solution of tert-Butyl (Z)-(pent-4-en-1-yl-5-d)(tosyl)carbamate (250 mg073 mmol 100 equiv) and K2CO3 (660 mg 477 mmol 650 equiv) in methanol(158 mL) was refluxed for 2 h The reaction mixture was diluted with water(15 mL) and extracted with diethyl ether (3 times 40 mL) The combined organiclayers were washed with brine dried over MgSO4 and then concentrated underreduced pressure Purification by flash column chromatography through silica(eluentpentaneethyl acetate 51) afforded pure (Z)-4-methyl-N-(pent-4-en-1-yl-5-d)benzenesulfonamide (126 118 mg 049 mmol 67 ) as a viscous oil

1H NMR (300 MHz CDCl3) δ (ppm) 774 (d J = 83 Hz 2H) 731 (dJ = 80 Hz 2H) 555ndash581 (m 1H) 494 (dt J = 102 12 Hz 1H) 439 (bs 1H)296 (q J = 69 Hz 2H) 243 (s 3H) 204 (q J = 72 66 Hz 2H) 157 (quintJ = 70 Hz 2H) HR-MS (ESI) mz calculated for [C12H16DNO2SNa]

+

([M + Na]+) 2630935 measured 2630932

Dimethyl 2-allyl-2-benzylmalonate [30]

O

Following a procedure reported by Fuumlrstner et al [30] dimethyl malonate(287 mL 250 mmol 125 equiv) was added dropwise to a suspension NaH(800 mg 200 mmol 100 equiv) in THF (100 mL) at 0 degC and stirred for 30 minAllyl bromide (169 mL 200 mmol 100 equiv) was then added to the reactionmixture and allowed to stir at rt for 14 h The reaction mixture was quenched withsaturated aq NH4Cl extracted with methyl tert-butyl ether washed with brinedried over MgSO4 and concentrated under reduced pressure The crude reactionmixture was purified by flash column chromatography through silica (eluentpen-taneethyl acetate 91) to affoed pure dimethyl 2-allylmalonate (231 g 134 mmol67 ) as a colourless oil

According to the literature procedure by Curran et al [31] dimethyl2-allylmalonate (500 mg 290 mmol 100 equiv) in THF (2 mL) was added to asuspension of NaH (130 mg 325 mmol 60 in mineral oil 112 equiv) in THF(8 mL) After stirring for 30 min benzyl bromide (386 microL 325 mmol 112equiv) was added dropwise to the reaction mixture The resulting reaction mixturewas stirred for 12 h and then quenched with water (5 mL) The aqueous layer wasextracted with diethyl ether The combined organic layers were washed with brinedried over MgSO4 and concentrated under reduced pressure The crude reactionmixture was purified by flash column chromatography through silica (eluent

pentanediethyl ether 91) to affoed pure dimethyl 2-allyl-2-benzylmalonate(310 mg 118 mmol 41 ) as a colourless oil

1H NMR (400 MHz CD2Cl2) δ (ppm) 719ndash731 (m 3H) 704ndash712 (m 2H)576 (ddt J = 159 113 73 Hz 1H) 496ndash524 (m 2H) 371 (s 6H) 324(s 2H) 256 (dt J = 72 13 Hz 2H) GC-MS tR (50_40) 84 min EI-MS mz() 221 (55) 202 (15) 199 (13) 190 (11) 189 (100) 171 (19) 143 (51) 142 (18)141 (16) 139 (30) 129 (16) 128 (33) 121 (26) 115 (32) 91 (79) 65 (17) 59 (11)41 (10)

633 Synthesis of Aryldiazonium Salts

General Procedure 1

Following a modified procedure reported by Hanson et al [32] aniline (1 equiv)was added to a mixture of 50 aq HBF4 (340 microLmmol) and water(400 microLmmol) After cooling to 0 degC NaNO2 (1 equiv) in water (150 microLmmol)was added portionwise to the reaction mixture After stirring at 0 degC for 30 min theprecipitate was filtered and washed with a little amount of chilled water The solidprecipitate was dissolved in acetone and precipitated by adding diethyl ether Thesolid product was collected by filtration and dried overnight

All the aryldiazonium salts (65 86ndash92) were synthesized following the GP1 andused directly for the reaction

634 Synthesis of Diaryliodonium Salts

General Procedure 2

Following a modified procedure reported by Olofsson et al [33] in a roundbottomed flask m-CPBA (11 equiv 77 ) was dried under vacuum for 1 hDichloromethane (34 mLmmol) was then added to the flask to dissolve m-CPBAunder argon Aryl iodide (10 equiv) followed by BF3OEt2 (25 equiv) was addedto the solution at rt The resulting reaction mixture was stirred at rt for 1 h Aftercooling to 0 degC arylboronic acid (11 equiv) was added to the reaction mixtureAfter stirring at rt for another 15ndash30 min the crude mixture was poured on silicaplug (3 gmmol) in column chromatogram and eluted with dichloromethane toremove aryl iodide and m-CPBA followed by eluting with an eluent (dichlor-omethanemethanol = 201) to deliver pure diaryliodonium tetrafluoroborate

All the diaryliodonium salts were synthesized following the GP2 and useddirectly for the reaction

635 Synthesis and Characterizationof Oxy- and Aminoarylated Products

General Procedure 3

XH

R3

R4

R2

( )n( )n

X R4 R3

R2

R1

N2BF4

R1

23 W lightbulb

degassed MeOH rt

X = O Nn = 1 2

R5 R5

[Ru(bpy)3](PF6)2 (43 mg 50 micromol 25 mol) [Ph3PAu]NTf2 (148 mg200 micromol 10 mol) the diazonium salt (08 mmol 4 equiv) and the alkenesubstrate (02 mmol 10 equiv) were added to a flame-dried Schlenk flask con-taining a stirring bar In the absence of light anhydrous methanol (20 mL 01 M)was added and the mixture was degassed using three freeze-pump-thaw cyclesunder argon The flask was then flushed with argon sealed and the mixture wasstirred under irradiation from a desk lamp fitted with a 23 W fluorescent light bulbAfter evolution of nitrogen ceased (4ndash16 h) the mixture was stirred for a further30 min before being quenched with water (2 mL) and saturated aqueous K2CO3

solution (1 mL) The crude reaction mixture was then extracted with diethyl ether(4 times 5 mL) and the combined organic fractions were dried over anhydrous sodiumsulfate filtered and concentrated in vacuo The crude products were purified bycolumn chromatography over silica gel (eluent = pentanesdichloromethane 11 orpentanediethyl ether 41 to 91)

General Procedure 4

R1 + ArN2+ BF4

-

MeOH 23 W CFL rt 16 h R1 Ar

O

Fluorescein (33 mg 10 micromol 5 mol) [Ph3PAu]NTf2 (148 mg 200 micromol10 mol) the aryldiazonium salt (080 mmol 40 equiv) and the alkene substrate(020 mmol 10 equiv) were added to a flame-dried Schlenk flask containing astirring bar In the absence of light anhydrous methanol (20 mL 010 M) wasadded and the mixture was degassed using three freeze-pump-thaw cycles Theflask was then flushed with argon sealed and the mixture was stirred under irra-diation from a desk lamp fitted with a 23 W fluorescent light bulb (situated 5 cmaway from the reaction vessel) After evolution of nitrogen ceased (16 h) themixture was stirred for a further 30 min before being filtered through a short pad of

silica gel (eluent = EtOAc) and the solvent was removed in vacuo The crudeproducts were purified by column chromatography over silica gel (eluentpentanedichloromethane or pentaneethyl acetate)

General Procedure 5

R1 + [Ar2I]+ BF4-

R3OH blue LEDs rt 20 h R1 Ar

OR3

[Ir(ppy)2(dtbbpy)](PF6) (91 mg 10 micromol 5 mol) [Ph3PAu]NTf2 (148 mg200 micromol 10 mol) the diaryliodonium salt (080 mmol 40 equiv) and thealkene substrate (020 mmol 10 equiv) were added to a flame-dried Schlenk flaskcontaining a stirring bar In the absence of light anhydrous methanol (or otheralcohol or acid 20 mL 010 M) was added and the mixture was degassed usingthree freeze-pump-thaw cycles The flask was then flushed with argon sealed andthe mixture was stirred under irradiation from blue LEDs (situated 5 cm awayfrom the reaction vessel in a custom-made ldquolight boxrdquo see Fig 62) After 20 h ofirradiation the mixture was filtered through a short pad of silica gel(eluent = EtOAc) and the solvent was removed in vacuo The crude products werepurified by column chromatography over silica gel (eluentpentanedichloromethane or pentaneethyl acetate)

2-Benzyltetrahydrofuran (57)

O

GP3 Prepared from 4-penten-1-ol (54) and benzenediazonium tetrafluoroborate(65) Colorless oil (26 mg 016 mmol 79 )

GP5 Prepared from 4-penten-1-ol (54) and diphenyliodonium tetrafluoroborate(101) Colorless oil (22 mg 014 mmol 68 )

Rf (pentanediethyl ether 91) 026 1H NMR (300 MHz CDCl3) δ (ppm)717ndash731 (m 5H) 406 (m 1H) 390 (m 1H) 374 (m 1H) 292 (dd J = 13664 Hz 1H) 274 (dd J = 136 65 Hz 1H) 180ndash197 (m 3H) 156 (m 1H) 13CNMR (755 MHz CDCl3) δ (ppm) 1389 (Cq) 1291 (CH) 1282 (CH) 1261(CH) 80 (CH) 678 (CH2) 419 (CH2) 309 (CH2) 255 (CH2) GC-MS tR(50_40) 72 min EI-MS mz () 91 (42) 71 (100) 65 (13) 43 (31) 41 (12)HR-MS (ESI) mz calculated for [C11H14ONa]

+ ([M + Na]+) 1850937 mea-sured 1850944 IR (ATR) ν (cmminus1) 3027 2968 2926 2859 1604 1497 14541372 1067 1011 919 874 745 700 625

2-(4-Methylbenzyl)tetrahydrofuran (93)

O

GP3 Prepared from 4-penten-1-ol (54) and 4-methylbenzenediazoniumtetrafluoroborate (86) Colorless oil (28 mg 016 mmol 78 )

Rf (pentanedichloromethane 11) 017 1H NMR (300 MHz CDCl3) δ(ppm) 709ndash715 (m 4H) 405 (apparent dq J = 81 64 Hz 1H) 390 (m 1H)374 (m 1H) 290 (dd J = 136 64 Hz 1H) 271 (dd J = 136 66 Hz 1H) 233(s 3H) 177ndash198 (m 3H) 155 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm)1359 (Cq) 1356 (Cq) 1291 (CH) 1290 (CH) 802 (CH) 679 (CH2) 415(CH2) 301 (CH2) 256 (CH2) 211 (CH3) GC-MS tR (50_40) 76 min EI-MSmz () 105 (27) 77 (12) 71 (100) 70 (11) 43 (28) HR-MS (ESI) mz calcu-lated for [C12H16ONa]

+ ([M + Na]+) 1991093 measured 1991093 IR (ATR) ν(cmminus1) 2971 2922 2861 1516 1458 1446 1370 1183 1061 799 656

(ndash)-(3aR7aS)-2-(4-Methylbenzyl)octahydrobenzofuran ((ndash)-(RS)-77)

O

(plusmn)

GP3 Prepared from (ndash)-(1S2R)-2-allylcyclohexanol ((ndash)-(SR)- 67) and4-methylbenzenediazonium tetrafluoroborate (86) GCMS analysis indicated acrude dr of 291 Pale yellow oil (30 mg 013 mmol 66 partially separablemixture of diastereoisomers dr = 281) [Characterization data for majordiastereoisomer]

Rf (pentanedichloromethane 11) 039 1H NMR (300 MHz CDCl3) δ(ppm) 707ndash714 (m 4H) 423 (m 1H) 303 (apparent td J = 102 34 Hz 1H)291 (dd J = 135 55 Hz 1H) 264 (dd J = 135 78 Hz 1H) 231 (s 3H) 211(m 1H) 163ndash194 (m 4H) 153 (td J = 120 90 Hz 1H) 114ndash140 (m 4H)096ndash114 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm) 1356 (Cq) 1356(Cq) 1293 (CH) 1289 (CH) 838 (CH) 784 (CH) 440 (CH) 426 (CH2) 352(CH2) 341 (CH2) 291 (CH2) 259 (CH2) 243 (CH2) 210 (CH3) GC-MS tR(50_40) 88 min EI-MS mz () 230 (5) 125 (89) 107 (52) 106 (10) 105 (48)91 (17) 81 (100) 79 (36) 77 (15) 55 (12) HR-MS (ESI) mz calculated for[C16H22ONa]

+ ([M + Na]+) 2531563 measured 2531567 IR (ATR) ν (cmminus1)2931 2857 1516 1456 1447 1351 1142 1073 799 633

2-(4-Methylbenzyl)-3-phenyltetrahydrofuran (76)

O

(plusmn)

GP3 Prepared from 3-phenyl-4-penten-1-ol (66) and 4-methylbenzenediazoniumtetrafluoroborate (86) Colorless oil (35 mg 014 mmol 70 inseparable mixtureof diastereoisomers dr = 161) Major diastereoisomer assigned as (ndash)-(RR)-76 bycomparison of literature data for this isomer [34]

Rf (pentanedichloromethane 11) 039 1H NMR (300 MHz CDCl3) δ(ppm) Major Diastereoisomer 731ndash736 (m 2H) 720ndash729 (m 3H) 711 (dJ = 84 Hz 2H) 708 (d J = 84 Hz 2H) 396ndash410 (m 3H) 297 (apparent qJ = 86 Hz 1H) 289 (dd J = 142 36 Hz 1H) 271 (dd J = 142 78 Hz 1H)228ndash250 (m 2H) 231 (s 3H) 212 (m 1H) Minor Diastereoisomer 731ndash736(m 2H) 720ndash729 (m 3H) 705 (d J = 80 Hz 2H) 695 (d J = 80 Hz 2H)416ndash425 (m 2H) 388 (td J = 88 69 Hz 1H) 336 (m 1H) 228ndash250 (m 4H)230 (s 3H) 212 (m 1H) Note Several peaks for the diastereoisomers overlap13C NMR (755 MHz CDCl3) δ (ppm) Major and Minor Diastereoisomers1422 (Cq) 1419 (Cq) 1362 (Cq) 1357 (Cq) 1355 (Cq) 1354 (Cq) 1292 (CH)1289 (CH) 1288 (CH) 1288 (CH) 1286 (CH) 1286 (CH) 1282 (CH) 1277(CH) 1266 (CH) 1264 (CH) 866 (CH) 837 (CH) 676 (CH2) 669 (CH2) 503(CH) 478 (CH) 392 (CH2) 372 (CH2) 355 (CH2) 335 (CH2) 210 (CH3) 210(CH3) GC-MS tR (50_40) Major Diastereoisomer 92 min EI-MS mz ()148 (11) 147 (100) 146 (16) 117 (26) 115 (11) 105 (21) 91 (52) MinorDiastereoisomer 92 min EI-MS mz () 148 (12) 147 (100) 146 (14) 118(14) 117 (37) 115 (13) 105 (21) 91 (43) 73 (15) HR-MS (ESI) mz calculatedfor [C18H20ONa]

22-Diethyl-5-(4-Methylbenzyl)tetrahydrofuran (78)

O

GP3 Prepared from 3-ethyl-6-hepten-3-ol (68) and 4-methylbenzenediazoniumtetrafluoroborate (86) Pale yellow oil (26 mg 011 mmol 56 )

Rf (pentanedichloromethane 11) 05 1H NMR (300 MHz CDCl3) δ(ppm) 707ndash713 (m 4H) 410 (tt J = 77 53 Hz 1H) 300 (dd J = 13351 Hz 1H) 262 (dd J = 133 80 Hz 1H) 298 (s 3H) 183 (m 1H) 141ndash171

(m 7H) 087 (td J = 74 48 Hz 6H) 13C NMR (755 MHz CDCl3) δ (ppm)1358 (Cq) 1355 (Cq) 1292 (CH) 1289 (CH) 858 (Cq) 797 (CH) 421 (CH2)340 (CH2) 315 (CH2) 313 (CH2) 310 (CH2) 210 (CH3) 87 (CH3) 86 (CH3)GC-MS tR (50_40) 83 min EI-MS mz () 203 (11) 131 (59) 128 (12) 127(80) 118 (10) 115 (11) 110 (9) 109 (100) 106 (10) 105 (62) 91 (16) 83 (21) 77(13) 67 (12) 57 (29) 55 (19) 41 (11) HR-MS (ESI) mz calculated for[C16H24ONa]

2-Methyl-2-(4-methylbenzyl)tetrahydrofuran (79)

O

GP3 Prepared from 4-methyl-4-penten-1-ol (69) and 4-methylbenzenediazoniumtetrafluoroborate (86) Pale yellow oil (15 mg 78 μmol 39 )

Rf (pentanedichloromethane 11) 019 1H NMR (300 MHz CDCl3) δ(ppm) 706ndash714 (m 4H) 373ndash389 (m 2H) 276 (s 2H) 233 (s 3H) 169ndash194(m 3H) 160 (m 1H) 117 (s 3H) 13C NMR (755 MHz CDCl3) δ (ppm)1355 (Cq) 1354 (Cq) 1303 (CH) 1286 (CH) 829 (Cq) 674 (CH2) 464 (CH2)361 (CH2) 263 (CH3) 260 (CH2) 210 (CH3) GC-MS tR (50_40) 76 minEI-MS mz () 105 (27) 85 (100) 43 (49) HR-MS (ESI) mz calculated for[C13H18ONa]

+ ([M + Na]+) 2131250 measured 2131251 IR (ATR) ν (cmminus1)2966 2924 2866 1514 1452 1373 1112 1086 1045 813 751 625

(ndash)-(R)-2-((R)-1-(p-Tolyl)ethyl)tetrahydrofuran ((ndash)-(RR)-81)

(plusmn)

O

GP3 Prepared from (E)-4-hexen-1-ol ((E)-71) and 4-methylbenzenediazoniumtetrafluoroborate (86) 1H NMR of the crude reaction mixture showed crudediastereoselectivity of gt201 Pale yellow oil (22 mg 012 mmol 59 dr gt 251)

Rf (pentanedichloromethane 11) 020 1H NMR (300 MHz CDCl3) δ(ppm) 710 (s 4H) 373ndash393 (m 3H) 269 (dq J = 83 69 Hz 1H) 232 (s3H) 174ndash184 (m 2H) 167 (m 1H) 145 (m 1H) 134 (d J = 69 Hz 3H) 13CNMR (755 MHz CDCl3) δ (ppm) 1416 (Cq) 1357 (Cq) 1290 (CH) 1276(CH) 842 (CH) 681 (CH2) 449 (CH) 300 (CH2) 257 (CH2) 210 (CH3) 189(CH3) GC-MS tR (50_40) 75 min EI-MS mz () 190 (6) 120 (10) 119 (25)117 (11) 91 (13) 71 (100) 43 (19) HR-MS (ESI) mz calculated for

[C13H18ONa]+ ([M + Na]+) 2131250 measured 2131252 IR (ATR) ν (cmminus1)

2963 2926 2870 1515 1457 1376 1068 815 631The stereochemistry is assigned based on mechanistic rationale (see assignment

for the aminoarylation of deuterated substrates D-(E)-126 and D-(Z)-127) [25]These assignments are also consistent with literature 1H and 13C NMR data forclosely related compounds [35 36]

(ndash)-(R)-2-((S)-1-(p-Tolyl)ethyl)tetrahydrofuran ((ndash)-(RS)-82)

(plusmn)

O

GP3 Prepared from (Z)-4-hexen-1-ol ((Z)-72) and 4-methylbenzenediazoniumtetrafluoroborate (86) on a 04 mmol scale 1H NMR of the crude reaction mixtureshowed crude diastereoselectivity of gt201 Pale yellow oil (43 mg 022 mmol56 dr gt 251)

Rf (pentanedichloromethane 11) 027 1H NMR (300 MHz CDCl3) δ(ppm) 710ndash719 (m 4H) 395 (dt J = 72 69 Hz 1H) 381 (dt J = 83 68 Hz1H) 370 (m 1H) 278 (apparent quin J = 72 Hz 1H) 233 (s 3H) 192ndash203(m 1H) 177ndash188 (m 2H) 158 (m 1H) 126 (d J = 71 Hz 3H) 13C NMR(755 MHz CDCl3) δ (ppm) 1416 (Cq) 1356 (Cq) 1289 (CH) 1275 (CH)838 (CH) 681 (CH2) 444 (CH) 295 (CH2) 258 (CH2) 210 (CH3) 182 (CH3)GC-MS tR (50_40) 77 min EI-MS mz () 190 (5) 119 (23) 117 (10) 91(12) 71 (100) 43 (21) HR-MS (ESI) mz calculated for [C13H18ONa]

+

([M + Na]+) 2131250 measured 2131259 IR (ATR) ν (cmminus1) 296828721515 1417 1378 1365 1184 1108 1066 1038 922 818 732 720 658623

The stereochemistry is assigned based on mechanistic rationale (see assignmentfor the aminoarylation of deuterated substrates D-(E)-126 and D-(Z)-127) [25]These assignments are also consistent with literature 1H and 13C NMR data forclosely related compounds [35 36]

2-(4-Methylbenzyl)tetrahydro-2H-pyran (85)

O

GP3 Prepared from 5-hexen-1-ol (75) and 4-methylbenzenediazoniumtetrafluoroborate (86) Colorless oil (13 mg 68 μmol 34 )

Rf (pentanedichloromethane 11) 042 1HNMR(600 MHzCDCl3) δ (ppm)709ndash712 (s 4H) 396 (m 1H) 347 (dtd J = 108 66 20 Hz 1H) 342 (tdJ = 118 24 Hz 1H) 285 (dd J = 137 66 Hz 1H) 262 (dd J = 137 66 Hz1H) 233 (s 3H) 181 (m 1H) 155ndash163 (m 2H) 149 (m 1H) 143 (m 1H)

128 (m 1H) 13C NMR (151 MHz CDCl3) δ (ppm) 1357 (Cq) 1355 (Cq) 1292(CH) 1289 (CH) 789 (CH) 686 (CH2) 428 (CH2) 314 (CH2) 261 (CH2) 235(CH2) 210 (CH3)GC-MS tR (50_40) 78 minEI-MSmz () 190 (5) 105 (24)85 (100) 84 (17) 77 (10) 67 (16) 57 (14) 43 (12) 41 (12) HR-MS (ESI) mzcalculated for [C13H18ONa]

+ ([M + Na]+) 2131250 measured 2131251 IR(ATR) ν (cmminus1) 2933 2842 1515 1462 1439 1377 1351 1261 1195 1173 10901042 903 816 667 623 1142 1073 799 633

2-(4-Methylbenzyl)-1-tosylpyrrolidine (83)

NSO O

GP3 Prepared from 4-methyl-N-(pent-4-en-1-yl)benzenesulfonamide (73) and4-methylbenzenediazonium tetrafluoroborate (86) Viscous oil that solidified uponstanding (55 mg 017 mmol 84 )

Rf (pentanediethyl ether 41) 018 1H NMR (300 MHz CDCl3) δ (ppm)777 (d J = 83 Hz 2H) 732 (d J = 80 Hz 2H) 714 (m 4H) 381 (m 1H)341 (m 1H) 309ndash325 (m 2H) 272 (dd J = 133 97 Hz 1H) 243 (s 3H)234 (s 3H) 159ndash174 (m 2H) 135ndash153 (m 2H) 13C NMR (755 MHzCDCl3) δ (ppm) 1433 (Cq) 1359 (Cq) 1354 (Cq) 1346 (Cq) 1296 (CH) 1295(CH) 1291 (CH) 1275 (CH) 617 (CH) 492 (CH2) 422 (CH2) 298 (CH2)237 (CH2) 215 (CH3) 210 (CH3) GC-MS tR (50_40) 119 min EI-MS mz() 226 (6) 225 (14) 124 (100) 155 (34) 105 (16) 91 (47) HR-MS (ESI) mzcalculated for [C19H23NO2SNa]

+ ([M + Na]+) 3521342 measured 3521339 IR(ATR) ν (cmminus1) 2974 2951 2925 2872 1598 1515 1494 1449 1342 11971158 1110 1093 1034 987 816 734 666 589

(ndash)-D-(RR)-(2-(4-Methylbenzyl)-1-tosylpyrrolidine (ndash)-D-(RR)-(128) [25]

NSO O D

GP3 Prepared from D-(E)-4-methyl-N-(pent-4-en-1-yl)benzenesulfon-amide(D-(E)-126 D = 94 ) and benzenediazonium tetrafluoroborate (65) Pale yellowviscous oil that solidified upon standing (46 mg 015 mmol 73 dr = 141D = 96 )

Rf (pentanedichloromethane 11) 018 1H NMR (400 MHz CDCl3) δ(ppm) 776 (d J = 83 Hz 2H) 728ndash734 (m 4H) 720ndash726 (m 3H) 381 (dddJ = 96 77 32 Hz 1H) 340 (m 1H) 313 (dt J = 102 71 Hz 1H) 274 (dJ = 96 Hz 1H) 242 (s 3H) 234 (s 3H) 159ndash171 (m 2H) 136ndash151 (m 2H)13C NMR (755 MHz CDCl3) δ (ppm) 1433 (Cq) 1384 (Cq) 1346 (Cq) 1296(CH) 1296 (CH) 1284 (CH) 1275 (CH) 1264 (CH) 615 (CH) 492 (CH2)424 (t J = 20 Hz CDH) 298 (CH2) 238 (CH2) 215 (CH3) GC-MS tR(50_40) 114 min EI-MS mz () 225 (17) 224 (100) 124 (100) 155 (40) 92(22) 91 (58) 65 (12) HR-MS (ESI) mz calculated for [C18H20DNO2SNa]

+

([M + Na]+) 3391248 measured 3391250 IR (ATR) ν (cmminus1) 3027 29752924 1598 1494 1450 1334 1195 1153 1108 1091 1030 988 820 731 700661 607

(ndash)-D-(RS)-(2-(4-Methylbenzyl)-1-tosylpyrrolidine (ndash)-D-(RS)-(129) [25]

NSO O D

GP3 Prepared from D-(Z)-4-methyl-N-(pent-4-en-1-yl)benzenesulfon-amide(D-(Z)-127 D = 99 ) and benzenediazonium tetrafluoroborate (65) Pale yellowviscous oil that solidified upon standing (43 mg 014 mmol 68 dr = 171D = 99 )

Rf (pentanediethyl ether 41) 015 1H NMR (300 MHz CDCl3) δ (ppm)776 (d J = 82 Hz 2H) 722ndash733 (m 7H) 379ndash384 (m 1H) 336ndash343 (m1H) 323 (d J = 34 Hz 1H) 309ndash317 (m 1H) 242 (s 3H) 157ndash172 (m 2H)135ndash151 (m 2H) 13C NMR (755 MHz CDCl3) δ (ppm) 1433 (Cq) 1384(Cq) 1348 (Cq) 1296 (CH) 1296 (CH) 1284 (CH) 1275 (CH) 1264 (CH)615 (CH) 492 (CH2) 423 (t J = 196 Hz CDH) 298 (CH2) 238 (CH2) 215(CH3) GC-MS tR (50_40) 115 min EI-MS mz () 225 (14) 224 (100) 155(36) 92 (16) 91 (41) HR-MS (ESI) mz calculated for [C18H20DNO2SNa]

+

([M + Na]+) 3391248 measured 3391253 IR (ATR) ν (cmminus1) 3026 29742874 1598 1495 1450 1343 1196 1155 1091 1036 989 816 733 702 662600

44-Dimethyl-2-(4-methylbenzyl)-1-tosylpyrrolidine (84)

NSO O

GP3 Prepared from N-(22-dimethylpent-4-en-1-yl)-4-methylbenzene sulfonamide(74) and 4-methylbenzenediazonium tetrafluoroborate (86) Pale yellow oil (39 mg011 mmol 54 )

Rf (pentanedichloromethane 11) 024 GC-MS tR (50_40) 12 min 1HNMR (300 MHz CDCl3) δ (ppm) 778 (d J = 83 Hz 2H) 732 (d J = 80 Hz2H) 711 (s 3H) 376 (m 1H) 354 (dd J = 131 35 Hz 1H) 312 (s 2H) 272(dd J = 131 99 Hz 1H) 243 (s 3H) 232 (s 3H) 139ndash155 (m 2H) 099 (s3H) 044 (s 3H) 13C NMR (755 MHz CDCl3) δ (ppm) 1433 (Cq) 1358 (Cq)1354 (Cq) 1352 (Cq) 1296 (CH) 1294 (CH) 1291 (CH) 1275 (CH) 616(CH) 616 (CH2) 457 (CH2) 424 (CH2) 372 (Cq) 264 (CH3) 258 (CH3) 215(CH3) 210 (CH3) EI-MS mz () 253 (16) 252 (100) 155 (25) 105 (13) 91(45) HR-MS (ESI) mz calculated for [C21H27NO2SNa]

+ ([M + Na]+) 3801655measured 3801653 IR (ATR) ν (cmminus1) 2959 2926 2873 1598 1515 14521344 1156 1092 1048 815 709 661

2-([11prime-Biphenyl]-4-ylmethyl)tetrahydrofuran (94)

O

GP3 Prepared from 4-penten-1-ol (54) and 4-phenylbenzenediazoniumtetrafluoroborate (87) Pale yellow oil (31 mg 013 mmol 64 )

Rf (pentanedichloromethane 11) 017 1H NMR (300 MHz CDCl3) δ(ppm) 750ndash761 (m 4H) 740ndash747 (m 2H) 729ndash736 (m 3H) 411 (m 1H)393 (m 1H) 376 (td J = 78 63 Hz 1H) 295 (dd J = 136 67 Hz 1H) 281(dd J = 136 62 Hz 1H) 180ndash203 (m 3H) 158 (m 1H) 13C NMR(755 MHz CDCl3) δ (ppm) 1411 (Cq) 1391 (Cq) 1381 (Cq) 1296 (CH)1287 (CH) 1271 (CH) 1270 (CH) 1270 (CH) 800 (CH) 680 (CH2) 416(CH2) 311 (CH2) 256 (CH2) GC-MS tR (50_40) 96 min EI-MS mz ()

238 (13) 168 (13) 167 (24) 165 (26) 152 (12) 71 (100) 43 (21) HR-MS (ESI)mz calculated for [C17H18ONa]

+ ([M + Na]+) 2611250 measured 2611256 IR(ATR) ν (cmminus1) 3028 2970 2861 1602 1520 1487 1448 1409 1370 10601008 843 761 697 632

2-(4-Fluorobenzyl)tetrahydrofuran (96)

O

F

GP3 Prepared from 4-penten-1-ol (54) and 4-fluorobenzenediazoniumtetra-fluoroborate (89) Pale yellow oil (27 mg 015 mmol 75 )

Rf (pentanedichloromethane 11) 031 1H NMR (300 MHz CDCl3) δ(ppm) 719 (dd J = 84 56 Hz 2H) 698 (apparent t J = 87 Hz 1H) 404 (m1H) 388 (m 1H) 374 (dd J = 143 77 Hz 1H) 287 (dd J = 138 67 Hz1H) 274 (dd J = 138 60 Hz 1H) 181ndash199 (m 3H) 159 (m 1H) 13C NMR(755 MHz CDCl3) δ (ppm) 1615 (d J = 244 Hz CF) 1346 (d J = 3 Hz Cq)1316 (d J = 8 Hz CH) 1150 (d J = 21 Hz CH) 799 (d J = 1 Hz CH) 679(CH2) 410 (CH2) 309 (CH2) 256 (CH2)

19F NMR (282 MHz CDCl3) δ(ppm) minus1174 GC-MS tR (50_40) 72 min EI-MS mz () 109 (48) 83 (14)71 (100) 43 (35) 41 (13) HR-MS (ESI) mz calculated for [C17H18ONa]

+

Ethyl 4-((tetrahydrofuran-2-yl)methyl)benzoate (95)

O

OO

GP3 Prepared from 4-penten-1-ol (54) and 4-(ethoxycarbonyl)-benzene diazoniumtetrafluoroborate (88) Pale yellow oil (39 mg 017 mmol 83 )

Rf (pentanedichloromethane 11) 017 1H NMR (300 MHz CDCl3) δ(ppm) 797 (d J = 82 Hz 2H) 730 (d J = 82 Hz 1H) 436 (q J = 71 Hz2H) 408 (m 1H) 388 (dt J = 133 68 Hz 1H) 373 (dd J = 138 74 Hz 1H)294 (dd J = 136 67 Hz 1H) 282 (dd J = 136 60 Hz 1H) 180ndash199 (m3H) 154 (m 1H) 138 (t J = 71 Hz 3H) 13C NMR (755 MHz CDCl3) δ(ppm) 1661 (C = O) 1444 (Cq) 1296 (CH) 1292 (CH) 1285 (Cq) 795 (CH)680 (CH2) 608 (CH2) 419 (CH2) 310 (CH2) 256 (CH2) 143 (CH3) GC-MStR (50_40) 89 min EI-MS mz () 164 (29) 71 (100) 43 (21) HR-MS (ESI)

mz calculated for [C14H18O3Na]+ ([M + Na]+) 2571148 measured 2571152 IR

(ATR) ν (cmminus1) 2976 2941 2868 1714 1611 1416 1367 1273 1178 11041062 1022 857 759 708 631

2-(3-Methoxy-5-(trifluoromethyl)benzyl)tetrahydrofuran (99)

O

F3C

GP3 Prepared from 4-penten-1-ol (54) and 3-methoxy-5-(trifluoro-methyl)ben-zenediazonium tetrafluoroborate (92) Pale yellow oil (17 mg 64 μmol 32 )

Rf (pentanedichloromethane 11) 028 1H NMR (300 MHz CDCl3)δ (ppm) 708 (s 1H) 697 (s 2H) 408 (m 1H) 388 (m 1H) 383 (s 3H) 374(m 1H) 289 (dd J = 138 68 Hz 1H) 279 (dd J = 138 58 Hz 1H) 181ndash202 (m 3H) 155 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm) 1597 (Cq)1416 (Cq) 1316 (q J = 32 Hz Cq) 1240 (q J = 272 Hz CF3) 1186 (qJ = 1 Hz CH) 1183 (q J = 4 Hz CH) 1083 (q J = 4 Hz CH) 794 (CH) 680(CH2) 554 (CH3) 417 (CH2) 310 (CH2) 256 (CH2)

19F NMR (282 MHzCDCl3) δ (ppm) minus1626 GC-MS tR (50_40) 79 min EI-MS mz () 189(13) 71 (100) 43 (27) HR-MS (ESI) mz calculated for [C13H15F3O2Na]

+

([M + Na]+) 2830916 measured 2830926 IR (ATR) ν (cmminus1) 2947 28691605 1466 1441 1352 1319 1247 1167 1057 872 704 630

2-(4-Bromobenzyl)tetrahydrofuran (97)

O

Br

GP3 Prepared from 4-penten-1-ol (54) and 4-bromobenzenediazoniumtetra-fluoroborate (90) Pale yellow oil (29 mg 012 mmol 60 )

Rf (pentanedichloromethane 11) 028 1H NMR (300 MHz CDCl3)δ (ppm) 740 (d J = 83 Hz 2H) 711 (d J = 83 Hz 2H) 398ndash407 (m 1H)384ndash391 (m 1H) 369ndash378 (m 1H) 283 (dd J = 137 67 Hz 1H) 272 (ddJ = 137 60 Hz 1H) 179ndash198 (m 3H) 153 (m 1H) 13C NMR (755 MHzCDCl3) δ (ppm) 138 (Cq) 1313 (CH) 1310 (CH) 1200 (Cq) 796 (CH) 680(CH2) 413 (CH2) 310 (CH2) 256 (CH2) GC-MS tR (50_40) 82 min EI-MS

mz () 171 (11) 169 (12) 90 (13) 89 (11) 71 (100) 43 (26) HR-MS (ESI) mzcalculated for [C11H13BrONa]

+ ([M + Na]+) 2630042 measured 2630050 IR(ATR) ν (cmminus1) 2969 2930 2862 1488 1404 1071 1062 1012 833 633

2-(2-Bromo-4-chlorobenzyl)tetrahydrofuran (98)

OBr

Cl

GP3 Prepared from 4-penten-1-ol (54) and 2-bromo-4-chlorobenzene diazoniumtetrafluoroborate (91) Pale yellow oil (23 mg 84 μmol 42 )

Rf (pentanedichloromethane 11) 044 1H NMR (300 MHz CDCl3)δ (ppm) 755 (d J = 17 Hz 1H) 719ndash727 (m 2H) 412 (m 1H) 390 (m 1H)374 (m 1H) 293 (d J = 64 Hz 2H) 179ndash203 (m 3H) 159 (m 1H) 13CNMR (755 MHz CDCl3) δ (ppm) 1371 (Cq) 1327 (Cq) 1322 (CH) 1321(CH) 1275 (CH) 1249 (Cq) 781 (CH) 679 (CH2) 410 (CH2) 310 (CH2) 256(CH2) GC-MS tR (50_40) 85 min EI-MS mz ()89 (10) 71 (100) 43 (20)HR-MS (ESI) mz calculated for [C11H12BrClONa]

+ ([M + Na]+) 2989631measured 2989635 IR (ATR) ν (cmminus1) 2970 2867 1586 1556 1469 13801061 1037 838 631

(2-Methoxyoctyl)benzene (102)

O

GP4 Prepared from 1-octene benzenediazonium tetrafluoro-borate and methanolColorless oil (38 mg 017 mmol 86 )

GP5 Prepared from 1-octene diphenyliodonium tetrafluoroborate and metha-nol Colorless oil (36 mg 016 mmol 82 ) The reaction was also conducted on a200 mmol scale (402 mg 182 mmol 91 )

Rf (pentanedichloromethane 31) 020 1H NMR (300 MHz CDCl3)δ (ppm) 725ndash733 (m 2H) 717ndash724 (m 3H) 336 (m 1H) 332 (s 3H) 285(dd J = 137 62 Hz 1H) 270 (dd J = 137 62 Hz 1H) 137ndash149 (m 3H)119ndash136 (m 7H) 088 (t J = 68 Hz 3H) 13C NMR (755 MHz CDCl3)δ (ppm) 1394 (Cq) 1295 (CH) 1283 (CH) 1261 (CH) 825 (CH) 571 (CH3)403 (CH2) 337 (CH2) 320 (CH2) 296 (CH2) 254 (CH2) 228 (CH2) 142(CH3) GC-MS tR (50_40) 81 min EI-MS mz () 135 (11) 130 (10) 129(100) 117 (12) 104 (10) 103 (12) 97 (79) 91 (46) 69 (11) 65 (10) 55 (54) 45(20) 43 (11) 41 (11) HR-MS (ESI) mz calculated for [C15H24ONa]

+

([M + Na]+) 2431719 measured 2431731 IR (ATR) ν (cmminus1) 2927 28571495 1455 1377 1360 1181 1097 1031 909 733 699

1-(3-Methoxy-4-phenylbutoxy)-4-nitrobenzene (112)

O

O2N

GP5 Prepared from 1-(but-3-en-1-yloxy)-4-nitrobenzene diphenyliodoniumtetrafluoroborate and methanol Pale yellow oil (40 mg 013 mmol 66 )

Rf (pentaneethyl acetate 91) 026 1H NMR (400 MHz CDCl3) δ (ppm)818 (dm J = 93 Hz 2H) 728ndash734 (m 2H) 720ndash728 (m 3H) 692 (dmJ = 93 Hz 2H) 408ndash418 (m 2H) 364 (dddd J = 90 67 56 36 Hz 1H)336 (s 3H) 297 (dd J = 137 56 Hz 1H) 278 (dd J = 137 68 Hz 1H) 201(dddd J = 145 79 68 36 Hz 1H) 187 (m 1H) 13C NMR (101 MHzCDCl3) δ (ppm) 1641 (Cq) 1415 (Cq) 1382 (Cq) 1296 (CH) 1285 (CH)1265 (CH) 1260 (CH) 1145 (CH) 788 (CH) 656 (CH2) 575 (CH3) 401(CH2) 334 (CH2) GC-MS tR (50_40) 107 min EI-MS mz () 210 (34) 209(18) 178 (100) 164 (10) 152 (53) 91 (48) 71 (14) 65 (10) HR-MS (ESI) mzcalculated for [C17H19NO4Na]

+ ([M + Na]+) 3241206 measured 3241209 IR(ATR) ν (cmminus1) 2931 2826 1607 1592 1510 1497 1468 1454 1338 13321298 1260 1173 1110 1032 992 862 845 752 728 701 658 630

Dimethyl 2-benzyl-2-(2-methoxy-3-phenylpropyl)malonate (114)

OO

O

GP5 Prepared from dimethyl 2-allyl-2-benzylmalonate diphenyl-iodoniumtetrafluoroborate and methanol Colorless oil (50 mg 014 mmol 67 )

Rf (pentaneethyl acetate 91) 017 1H NMR (300 MHz CDCl3) δ (ppm)723ndash734 (m 3H) 713ndash720 (m 2H) 698ndash712 (m 3H) 661ndash666 (m 2H) 366(s 3H) 3 60 (s 3H) 352 (tdd J = 101 42 18 Hz 1H) 328 (s 3H) 328 (dJ = 139 Hz 1H) 305 (d J = 139 Hz 1H) 299 (dd J = 133 41 Hz 1H) 257(dd J = 133 83 Hz 1H) 204 (dd J = 150 103 Hz 1H) 191 (dd J = 15018 Hz 1H) 13C NMR (755 MHz CDCl3) δ (ppm) 1720 (Cq) 1716 (Cq)1380 (Cq) 1359 (Cq) 1299 (CH) 1298 (CH) 1287 (CH) 1283 (CH) 1268(CH) 1265 (CH) 794 (CH) 572 (CH3) 570 (Cq) 522 (CH3) 522 (CH3) 404(CH2) 383 (CH2) 368 (CH2) GC-MS tR (50_40) 104 min EI-MS mz ()279 (30) 247 (26) 219 (13) 188 (17) 187 (100) 155 (10) 143 (19) 128 (14)

117 (11) 115 (14) 91 (56) HR-MS (ESI) mz calculated for [C22H26O5Na]+

([M + Na]+) 3931672 measured 3931668 IR (ATR) ν (cmminus1) 2950 28281731 1496 1454 1435 1294 1265 1254 1221 1197 1176 1090 1060 10311012 951 927 918 891 819 736 701 630

1-(3-Methoxy-4-phenylbutoxy)-4-methoxybenzene (115)

O

MeO

GP3 Prepared from 1-(but-3-en-1-yloxy)-4-methoxybenzene diphenyliodoniumtetrafluoroborate and methanol Colorless oil (15 mg 52 μmol 26 )

Rf (pentaneethyl acetate 91) 031 1H NMR (300 MHz CDCl3) δ (ppm)718ndash733 (m 5H) 692 (s 4H) 396ndash403 (m 2H) 376 (s 3H) 365 (dtdJ = 83 62 39 Hz 1H) 333 (s 3H) 291 (dd J = 137 60 Hz 1H) 279 (ddJ = 137 63 Hz 1H) 176ndash203 (m 2H) 13C NMR (755 MHz CDCl3) δ(ppm) 1538 (Cq) 1533 (Cq) 1387 (Cq) 1297 (CH) 1285 (CH) 1263 (CH)1156 (CH) 1147 (CH) 792 (CH) 653 (CH2) 576 (CH3) 559 (CH3) 404(CH2) 339 (CH2) GC-MS tR (50_40) 98 min EI-MS mz () 286 (54) 164(10) 163 (100) 137 (35) 135 (11) 131 (28) 124 (65) 123 (15) 109 (30) 107(13) 103 (14) 92 (13) 91 (71) 77 (17) 65 (14) HR-MS (ESI) mz calculated for[C18H22O3Na]

+ ([M + Na]+) 3091461 measured 3091465 IR (ATR) ν (cmminus1)2930 2832 1507 1466 1454 1389 1361 1289 1266 1229 1181 1156 10981039 824 795 735 700 637 624

2-(3-Methoxy-4-phenylbutyl)isoindoline-13-dione (116)

O

N

O

GP5 Prepared from 2-(but-3-en-1-yl)isoindoline-13-dione diphenyliodoniumtetrafluoroborate and methanol Colorless oil which solidified upon standing(32 mg 010 mmol 52 )

Rf (pentaneethyl acetate 91) 014 1H NMR (300 MHz CDCl3) δ (ppm)785ndash791 (m 2H) 772ndash779 (m 2H) 728ndash736 (m 2H) 719ndash728 (m 3H) 384(t J = 71 Hz 2H) 352 (dddd J = 75 66 56 41 Hz 1H) 340 (s 3H) 296(dd J = 137 56 Hz 1H) 281 (dd J = 137 67 Hz 1H) 175ndash196 (m 2H) 13CNMR (755 MHz CDCl3) δ (ppm) 1685 (Cq) 1383 (Cq) 1340 (CH) 1323(Cq) 1296 (CH) 1284 (CH) 1263 (CH) 1233 (CH) 802 (CH) 571 (CH3)398 (CH2) 350 (CH2) 323 (CH2) GC-MS tR (50_40) 107 min EI-MS mz() 219 (15) 218 (100) 187 (12) 186 (89) 160 (91) 133 (13) 130 (11) 104 (12)91 (42) 77 (17) 76 (12) 71 (16) 65 (10) HR-MS (ESI) mz calculated for[C19H19NO3Na]

+ ([M + Na]+) 3321257 measured 3321254 IR (ATR)

ν (cmminus1) 2930 2827 1771 1707 1495 1467 1439 1396 1373 1267 11881100 1026 923 866 793 735 719 700 630 604

1-Methyl-4-(2-Methoxyoctyl)benzene (103)

O

GP4 Prepared from 1-octene p-toluenediazonium tetrafluoroborate and methanolColorless oil (29 mg 012 mmol 62 )

Rf (pentanedichloromethane 31) 039 1H NMR (300 MHz CDCl3) δ(ppm) 708ndash715 (m 4H) 696ndash707 (m 3H) 327ndash346 (m 4H) 282 (ddJ = 137 61 Hz 1H) 267 (dd J = 137 62 Hz 1H) 233 (s 3H) 138ndash152 (m3H) 121ndash138 (m 7H) 085ndash095 (m 3H) 13C NMR (755 MHz CDCl3) δ(ppm) 1363 (Cq) 1355 (Cq) 1294 (CH) 1290 (CH) 826 (CH) 571 (CH3)399 (CH2) 337 (CH2) 320 (CH2) 296 (CH2) 255 (CH2) 228 (CH2) 212(CH3) 142 (CH3) GC-MS tR (50_40) 82 min EI-MS mz () 149 (10) 130(11) 129 (93) 128 (28) 117 (25) 115 (24) 106 (11) 105 (81) 103 (21) 98 (10)97 (100) 92 (21) 79 (20) 78 (12) 77 (26) 69 (11) 55 (43) 43 (12) 41 (30) 39(12) HR-MS (EI) mz calculated for [C16H26ONa]

+ ([M + Na]+) 2571876measured 2571878 IR (ATR) ν (cmminus1) 2954 2926 2857 2822 1515 14581377 1359 1206 1184 1097 1039 1023 909 841 803 734 648 629

O

GP4 Prepared from 1-octene o-toluenediazonium tetrafluoroborate and methanolColorless oil (13 mg 5546 μmol 28 )

GP5 Prepared from 1-octene di(o-tolyl)iodonium tetrafluoroborate andmethanol Colorless oil (35 mg 015 mmol 75 )

Rf (pentanedichloromethane 31) 031 1H NMR (300 MHz CDCl3) δ(ppm) 709ndash719 (m 4H) 336 (m 1H) 330 (s 3H) 291 (dd J = 138 66 Hz1H) 267 (dd J = 138 64 Hz 1H) 235 (s 3H) 139ndash154 (m 3H) 120ndash139(m 7H) 084ndash093 (m 3H) 13C NMR (755 MHz CDCl3) δ (ppm) 1377 (Cq)1364 (Cq) 1304 (CH) 1303 (CH) 1263 (CH) 1259 (CH) 819 (CH) 573(CH3) 380 (CH2) 342 (CH2) 320 (CH2) 296 (CH2) 256 (CH2) 228 (CH2)199 (CH3) 142 (CH3) GC-MS tR (50_40) 82 min EI-MS mz () 130 (13)129 (100) 128 (25) 119 (13) 117 (15) 115 (32) 106 (10) 105 (79) 104 (11) 103(23) 97 (97) 91 (22) 79 (23) 78 (12) 77 (15) 71 (10) 69 (13) 58 (11) 55 (46)45 (16) 43 (22) 41 (24) 39 (11) HR-MS (EI) mz calculated for [C16H26ONa]

+

([M + Na]+) 2571876 measured 2571885 IR (ATR) ν (cmminus1) 2954 29272857 2822 1493 1459 1378 1360 1186 1129 1096 1013 909 867 843 824735 629 615

1-Bromo-4-(2-methoxyoctyl)benzene (106)

OBr

GP4 Prepared from 1-octene p-bromobenzenedia-zonium tetrafluoroborate andmethanol Colorless oil (41 mg 014 mmol 69 )

Rf (pentanedichloromethane 31) 033 1H NMR (300 MHz CDCl3) δ(ppm) 737ndash744 (m 2H) 705ndash713 (m 2H) 326ndash337 (m 4H) 276 (ddJ = 138 64 Hz 1H) 268 (dd J = 138 58 Hz 1H) 137ndash151 (m 3H) 117ndash137 (m 7H) 082ndash095 (m 3H) 13C NMR (755 MHz CDCl3) δ (ppm) 1383(Cq) 1314 (CH) 1313 (CH) 1200 (Cq) 822 (CH) 572 (CH3) 397 (CH2) 336(CH2) 320 (CH2) 295 (CH2) 254 (CH2) 228 (CH2) 142 (CH3) GC-MS tR(50_40) 88 min EI-MS mz () 171 (39) 169 (35) 134 (29) 130 (12) 129(100) 115 (10) 98 (10) 97 (66) 91 (17) 90 (29) 89 (23) 58 (12) 55 (42) 45 (13)43 (11) 41 (10) 41 (12) HR-MS (EI) mz calculated for [C15H23BrONa]

+

Ethyl and Methyl 4-(2-methoxyoctyl)benzoate (109)

O O

O

R

GP4 Prepared from 1-octene p-(ethoxycarbonyl)benzenediazonium tetrafluorob-orate and methanol Colorless oil (37 mg 64 ) The ethyl ester product wasobtained as an inseparable 928 mixture with the corresponding methyl ester whichpresumably results from partial transesterification with the methanol solvent Theyield reported is the calculated oxyarylation yield based on this ratio of the twocompounds The NMR data below refer to the major ethyl ester product

Rf (pentanedichloromethane 11) 034 1H NMR (300 MHz CDCl3) δ(ppm) 796 (dm J = 83 Hz 2H) 727 (dm J = 83 Hz 2H) 436 (q J = 71 Hz2H) 336 (m 1H) 329 (s 3H) 285 (dd J = 137 65 Hz 1H) 276 (dd J = 13758 Hz 1H) 133ndash149 (m 6H) 118ndash133 (m 7H) 082ndash092 (m 3H) 13C NMR(755 MHz CDCl3) δ (ppm) 1668 (Cq) 1448 (Cq) 1296 (CH) 1295 (CH)1285 (Cq) 822 (CH) 609 (CH2) 572 (CH3) 404 (CH2) 338 (CH2) 319(CH2) 295 (CH2) 254 (CH2) 227 (CH2) 145 (CH3) 142 (CH3) GC-MS tR(50_40) 93 min EI-MS mz () 247 (20) 207 (15) 164 (37) 163 (12) 147(10) 135 (20) 131 (10) 129 (100) 118 (18) 115 (12) 107 (19) 103 (10) 97 (88)91 (25) 90 (23) 89 (12) 77 (10) 55 (45) 45 (19) 43 (16) 41 (19) HR-MS (EI)mz calculated for [C18H28O3Na]

1447 1416 1391 1367 1311 1273 1178 1101 1022 910 860 822 761 732706 648 629

1-(2-Methoxyoctyl)-4-(trifluoromethyl)benzene (108)

OCF3

GP5 Prepared from 1-octene di(p-trifluoromethyl)-phenyliodonium tetrafluorob-orate and methanol Colorless oil (21 mg 73 μmol 36 )

Rf (pentanedichloromethane 31) 041 1H NMR (300 MHz CDCl3) δ(ppm) 754 (dm J = 81 Hz 2H) 732 (dm J = 81 Hz 2H) 337 (m 1H) 330(s 3H) 285 (dd J = 138 64 Hz 1H) 278 (dd J = 138 58 Hz 1H) 137ndash151(m 3H) 118ndash137 (m 7H) 083ndash092 (m 3H) 13C NMR (151 MHz CDCl3) δ(ppm) 1436 (q J = 1 Hz Cq) 1299 (CH) 1285 (q J = 32 Hz Cq) 1252 (qJ = 4 Hz CH) 1245 (q J = 272 Hz Cq) 821 (CH) 572 (CH3) 402 (CH2) 337(CH2) 320 (CH2) 295 (CH2) 254 (CH2) 228 (CH2) 142 (CH3)

19F NMR(564 MHz CDCl3) δ (ppm) minus624 GC-MS tR (50_40) 79 min EI-MS mz() 203 (25) 183 (11) 172 (11) 171 (11) 159 (93) 151 (16) 140 (12) 129 (100)119 (12) 109 (32) 97 (84) 91 (10) 71 (12) 69 (15) 58 (11) 55 (53) 45 (21) 43(20) 41 (27) 39 (10) HR-MS (EI) mz calculated for [C16H23F3ONa]

+

([M + Na]+) 3111593 measured 3111601 IR (ATR) ν (cmminus1) 2930 28722859 2827 1619 1459 1440 1418 1323 1163 1120 1109 1067 1020 909849 823 734 659 640

O

O R

GP5 Prepared from 1-octene di(m-(ethoxycarbonyl)phenyl)iodoniumtetrafluoroborate and methanol Colorless oil (29 mg 50 ) The ethyl ester pro-duct was obtained as an inseparable 8119 mixture with the corresponding methylester which presumably results from partial transesterification with the methanolsolvent The yield reported is the calculated oxyarylation yield based on this ratio ofthe two compounds The NMR data below refer to the major ethyl ester product

Rf (pentanedichloromethane 11) 034 1H NMR (300 MHz CDCl3) δ(ppm) 786ndash791 (m 2H) 731ndash744 (m 2H) 437 (q J = 71 Hz 2H) 336 (m1H) 330 (s 3H) 286 (dd J = 138 65 Hz 1H) 276 (dd J = 138 58 Hz 1H)135ndash151 (m 6H) 118ndash135 (m 7H) 082ndash092 (m 3H) 13C NMR (755 MHzCDCl3) δ (ppm) 1706 (Cq) 1669 (Cq) 1397 (Cq) 1342 (CH) 1305 (CH)1283 (CH) 1274 (CH) 823 (CH) 610 (CH2) 572 (CH3) 402 (CH2) 337(CH2) 320 (CH2) 295 (CH2) 254 (CH2) 227 (CH2) 145 (CH3) 142 (CH3)GC-MS tR (50_40) 92 min EI-MS mz () 247 (38) 163 (15) 135 (15)

129 (95) 119 (18) 118 (15) 115 (12) 97 (100) 91 (11) 90 (20) 89 (15) 55 (18)55 (11) 45 (13) 43 (12) 41 (16) HR-MS (EI) mz calculated for [C18H28O3Na]

+

NSO O

Prepared from 4-methyl-N-(pent-4-en-1-yl)benzenesulfonamide (73) anddiphenyliodonium tetrafluoroborate (101) Viscous oil that solidified upon standing(50 mg 016 mmol 79 )

Rf (pentaneethyl acetate 91) 020 1H NMR (400 MHz CDCl3) δ (ppm)776 (d J = 83 Hz 2H) 719ndash734 (m 7H) 383 (m 1H) 340 (m 1H) 325 (ddJ = 133 46 Hz 1H) 313 (dt J = 101 71 Hz 1H) 276 (dd J = 133 96 Hz1H) 242 (s 3H) 158ndash171 (m 2H) 136ndash151 (m 2H) 13C NMR (101 MHzCDCl3) δ (ppm) 1434 (Cq) 1386 (Cq) 1347 (Cq) 1298 (CH) 1297 (CH)1285 (CH) 1276 (CH) 1265 (CH) 617 (CH) 493 (CH2) 428 (CH2) 299(CH2) 239 (CH2) 216 (CH3) GC-MS tR (50_40) 112 min EI-MS mz ()225 (14) 224 (100) 155 (37) 91 (60) 65 (17) HR-MS (ESI) mz calculated for[C18H21NO2SNa]

+ ([M + Na]+) 3381185 measured 3381199 IR (ATR) ν(cmminus1) 2974 2927 2873 1598 1595 1453 1339 1305 1289 1267 1196 11561092 1033 1017 987 847 816 802 734 702 663 631607

64 Visible Light Photoredox CatalyzedTrifluoromethylation-Ring Expansionvia Semipinacol Rearrangement

641 Synthesis of (Oxa)Cycloalkanol Substrates

Substrate 156 157 and 158 were synthesized by Dr Jun-Long Li (WWUMuumlnster)The following substrates were synthesized by self according to the procedures

given in the cited references No attempts were made to optimize yields for thesynthesis of substrates

General Procedure 6

Y

O

Y = CH2 On = 0 1

( )nY

Br

( )n

Br2 (12 equiv) P(OPh)3 (11 equiv)

NEt3 (13 equiv) DCM -78 degC - rt 24 - 36 hR R

Y = CH2 O n = 0 1

Following a modified report from Prati et al [37] bromine (12 equiv) wasadded dropwise to a solution of triphenyl phosphite (11 equiv) in anhydrousdichloromethane (8 mLmmol) at minus78 degC under argon Anhydrous triethylamine(13 equiv) ollowed by acetophenone (10 equiv) was added to the faint orangereaction mixture at minus78 degC (if acetophenone is solid then a solution in anhydrousdichloromethane was prepared and used) The reaction mixture was stirred at rt for24ndash36 h The crude reaction mixture was directly loaded on silica plug for purifi-cation by flash column chromatography (eluentpentane ethyl acetate 501 to 201)to afford pure vinylic bromide vinylic bromides were directly used in next step

General Procedure 7

Br

R R

OH1 Mg (3 eq) I2 (005 equiv) EtBr (04 equiv) THF 65 degC 3 h

2 (14 equiv) 65 degC 9 h

X

X = CH2 O

X O

Following a modified procedure from Toste et al [38] in a heat gun dried twonecked round bottomed flask equipped with a magnetic stir bar and a reflux con-denser under argon atmosphere addition of dry THF (5 mLmmol) to a mixture ofmagnesium turnings (30 equiv) and iodine crystals (005 equiv) resulted in anintense brown reaction mixture Brown colour disappeared when bromoethane (04equiv) was added to the heterogeneous reaction mixture at rt A solution of(1-bromovinyl)arene (10 equiv) in THF (15 mLmmol) was added dropwise tothe reaction mixture The reaction mixture was allowed to stir at 65 degC for 3 hA solution of cyclic ketone (14 equiv) in THF (15 mLmmol) was added

dropwise at 65 degC and the resulted reaction mixture was allowed to stir at 65 degC foranother 9 h The reaction mixture was quenched with satd NH4Cl solution (aq)The organic phase was extracted with ethyl acetate and dried over MgSO4 Solventswere removed under reduced pressure and the crude reaction mixture was purifiedby flash column chromatography through silica gel (eluent = pentaneethyl acetate191 to 91) to afford pure product

General Procedure 8

Y

Br

Y = CH2 O

Y

Y = CH2 O

OH1 tBuLi (20 equiv) THF - 78 degC 30 min

2O

(10 equiv)- 78 degC - rt 2 h

R R

Following a modified procedure from Alexakis et al [39] in a heat gun driedSchlenk flask equipped with a magnetic stir bar under argon atmosphere tBuLi inheptane (17 M 20 equiv) was added dropwise to a solution of vinylic bromide(10 equiv) in THF (25 mLmmol) at minus78 degC over 10 min The resulted reactionmixture was stirred at minus78 degC another 30 min Cyclic ketone (10 equiv) wasadded dropwise to the reaction mixture and stirred at minus78 degC for 1 h Then thereaction mixture was allowed to warm up at rt and stirred for another 1 h Thereaction was quenched with water and aqueous layer was extracted with dichlor-omethane The combined organic layers was dried over MgSO4 removed underreduced pressure and the crude reaction mixture was purified by flash columnchromatography through silica gel (eluent = pentaneethyl acetate 91) to affordpure product

1-(1-Phenylvinyl)cyclobutan-1-ol (142)

GP7 1-(1-Phenylvinyl)cyclobutan-1-ol was prepared from (1-bromovinyl)ben-zene (11 g 60 mmol) Colourless oil (860 mg 494 mmol 82 )

OH

Rf (pentaneethyl acetate 91) 020 1H NMR (300 MHz CDCl3) δ (ppm)744ndash752 (m 2H) 727ndash738 (m 3H) 537 (d J = 47 2H) 237ndash265 (m 2H)214ndash233 (m 2H) 187ndash208 (m 2H) 141ndash171 (m 1H) 13C NMR (755 MHzCDCl3) δ (ppm) 1525 1392 1283 1277 1277 1130 782 358 135GC-MS tR (50_40) 74 min EI-MS mz () 174 (17) 146 (47) 145 (70)

64 Visible Light Photoredox Catalyzed Trifluoromethylation hellip 165

132 (20) 131 (55) 129 (21) 128 (27) 127 (21) 119 (10) 118 (97) 117 (100) 116(22) 115 (43) 104 (16) 103 (82) 102 (21) 96 (12) 91 (35) 78 (25) 77 (55)63 (10) 51 (22) 43(10) HR-MS (ESI) mz calculated for [C12H14ONa]

+

([M + Na]+) 1970937 measured 1970933

1-(1-(4-Fluorophenyl)vinyl)cyclobutan-1-ol (146)

OH

F

GP6 1-(1-Bromovinyl)-4-fluorobenzene was prepared from 4prime-fluoroacetophenone(829 mg 600 mmol) Light yellow oil (680 mg 338 mmol 56 )

1H NMR (300 MHz CDCl3) δ (ppm) 753ndash761 (m 2H) 696ndash709 (m 2H)605 (d J = 21 Hz 1H) 576 (d J = 21 1H) GC-MS tR (50_40) 64 minEI-MS mz () 202 (10) 122 (10) 121 (100) 120 (36) 101 (52) 95 (10) 94(13) 81 (22) 79 (14) 75 (22) 74 (19) 63 (16) 51 (11) 50 (20) 38 (10)

GP7 1-(1-(4-Fluorophenyl)vinyl)cyclobutan-1-ol was prepared from 1-(1-bromovinyl)-4-fluorobenzene (503 mg 250 mmol) Colourless oil (230 mg120 mmol 48 )

Rf (pentaneethyl acetate 91) 019 1H NMR (300 MHz CDCl3) δ (ppm)737ndash756 (m 2H) 693ndash706 (m 2H) 534 (dd J = 94 08 Hz 2H) 235ndash256(m 2H) 214ndash231 (m 2H) 179ndash206 (m 2H) 154ndash169 (m 1H) 13C NMR(755 MHz CDCl3) δ (ppm) 1625 (d J = 2464 Hz) 1515 1351 (dJ = 33 Hz) 1294 (d J = 79 Hz) 1151 (d J = 212 Hz) 1130 (d J = 12 Hz)782 357 135 19F NMR (300 MHz CDCl3) minus11508 GC-MS tR (50_40)75 min EI-MS mz () 192 (13) 174 (11) 164 (43) 163 (76) 150 (12) 149(54) 147 (26) 146 (47) 145 (39) 144 (17) 136 (46) 135 (88) 134 (25) 133(63) 123 (12) 122 (14) 121 (99) 120 (47) 117 (15) 115 (39) 109 (75) 107 (23)102 (11) 101 (100) 96 (37) 95 (47) 94 (26) 83 (18) 81 (11) 77 (14) 75 (60) 74(28) 71 (13) 70 (15) 69 (12) 68 (12) 62 (18) 57 (12) 53 (15) 51 (27) 50 (24) 44(11) 43 (59) 42 (33) 41 (36) 39 (67)

HR-MS (ESI) mz calculated for [C12H13FONa]+ ([M + Na]+) 2150843

measured 2150840

1-(1-(4-Chlorophenyl)vinyl)cyclobutan-1-ol (147)

OH

Cl

GP6 1-(1-Bromovinyl)-4-chlorobenzene was prepared from 4prime-chlor-oacetophenone (124 g 800 mmol) Pale yellow solid (406 mg 187 mmol23 )

GC-MS tR (50_40) 72 min EI-MS mz () 218 (19) 216 (14) 139 (34)138 (16) 137 (100) 136 (16) 102 (43) 101 (48) 76 (10) 75 (32) 74 (22) 63 (16)62 (12) 51 (21) 50 (25)

GP7 1-(1-(4-Chlorophenyl)vinyl)cyclobutan-1-ol was prepared from 1-(1-bromovinyl)-4-chlorobenzene (395 mg 182 mmol) Light yellow oil (130 mg0623 mmol 34 )

Rf (pentaneethyl acetate 91) 019 1H NMR (300 MHz CDCl3) δ (ppm)740ndash747 (m 2H) 723ndash732 (m 2H) 537 (dd J = 62 07 Hz 2H) 235ndash253(m 2H) 211ndash229 (m 2H) 180ndash210 (m 2H) 153ndash169 (m 1H) 13C NMR(755 MHz CDCl3) δ (ppm) 1514 1376 1335 1291 1284 1135 781 357135 GC-MS tR (50_40) 81 min EI-MS mz () 208 (10) 146 (11) 145(100) 139 (10) 137 (19) 128 (10) 127 (20) 125 (14) 117 (58) 116 (20) 115 (46)102 (27) 101 (29) 91 (10) 77 (14) 75 (26) 74 (11) 63 (10) 51 (14) 43 (12) 39(15) HR-MS (ESI) mz calculated for [C12H13ClONa]

+ ([M + Na]+) 2310547measured 2310541

1-(1-(p-Tolyl)vinyl)cyclobutan-1-ol (148)

OH

GP6 1-(1-Bromovinyl)-4-methylbenzene was prepared from 4prime-methylacetophe-none (107 g 800 mmol) Light yellow oil (740 mg 375 mmol 47 )

1H NMR (300 MHz CDCl3) δ (ppm) 750 (d J = 83 Hz 2H) 716 (dJ = 83 Hz 2H) 608 (d J = 20 Hz 1H) 573 (d J = 20 1H) 237 (s 3H)GC-MS tR (50_40) 69 min EI-MS mz () 198 (14) 196 (13) 118 (10) 117(100) 116 (20) 115 (87) 91 (39) 89 (23) 65 (14) 63 (32) 62 (16) 51 (19) 50(16) 39 (19)

GP7 1-(1-(p-Tolyl)vinyl)cyclobutan-1-ol was prepared from 1-(1-bromovinyl)-4-methylbenzene (591 mg 300 mmol) Light yellow oil (345 mg 183 mmol61 )

Rf (pentaneethyl acetate 91) 022 1H NMR (300 MHz CDCl3) δ (ppm)738 (d J = 82 Hz 2H) 714 (d J = 82 2H) 533 (s 2H) 240ndash259 (m 2H)235 (s 2H) 218ndash230 (m 2H) 188ndash204 (m 2H) 153ndash179 (m 1H) 13C NMR(755 MHz CDCl3) δ (ppm) 1524 1374 1363 1290 1276 1122 783 359212 135 GC-MS tR (50_40) 78 min EI-MS mz () 188 (19) 160 (14) 159(14) 146 (21) 145 (100) 141 (11) 132 (32) 131 (23) 129 (18) 128 (19) 127(14) 118 (14) 117 (96) 116 (26) 115 (95) 105 (28) 103 (10) 102 (12) 92 (14)91 (52) 89 (17) 77 (19) 65 (17) 63 (17) 51 (13) 43 (14) 41 (10) 39 (22)

HR-MS (ESI) mz calculated for [C13H16ONa]+ ([M + Na]+) 2111093 mea-

sured 2111094

1-(1-([11prime-Biphenyl]-4-yl)vinyl)cyclobutan-1-ol (151)

OH

GP6 4-(1-Bromovinyl)-11prime-biphenyl was prepared from 4prime-phenylacetophenone(118 g 600 mmol) White solid (820 mg 316 mmol 53 )

1H NMR (300 MHz CDCl3) δ (ppm) 755ndash775 (m 6H) 733ndash751 (m 3H)618 (d J = 21 Hz 1H) 581 (d J = 20 Hz 1H) GC-MS tR (50_40) 89 minEI-MS mz () 260 (200) 258 (210) 180 (150) 179 (1000) 178 (640) 177(100) 176 (150) 152 (160) 151 (100) 89 (140) 76 (120)

GP7 1-(1-([11prime-Biphenyl]-4-yl)vinyl)cyclobutan-1-ol was prepared from 4-(1-bromovinyl)-11prime-biphenyl (518 mg 200 mmol) White solid (346 mg138 mmol 69 )

Rf (pentaneethyl acetate 91) 015 1H NMR (400 MHz CDCl3) δ (ppm)764ndash754 (m 6H) 747ndash743 (m 2H) 733ndash738 (m 1H) 543 (dd J = 13008 Hz 2H) 248ndash257 (m 2H) 225ndash233 (m 2H) 196ndash207 (m 2H) 160ndash178(m 1H) 13C NMR (100 MHz CDCl3) δ (ppm) 1520 1409 1405 13811289 1281 1274 1271 1270 1129 783 359 136 GC-MS tR (50_40)96 min EI-MS mz () 251 (16) 250 (75) 222 (24) 221 (27) 208 (11) 207(17) 205 (14) 204 (15) 203 (24) 202 (14) 194 (56) 193 (24) 191 (17) 189 (10)180 (23) 179 (100) 178 (99) 177 (16) 176 (19) 167 (45) 165 (35) 154 (17) 153(12) 152 (35) 151 (15) 115 (17) 77 (15) 76 (11) 43 (11) HR-MS (ESI) mzcalculated for [C18H18ONa]

+ ([M + Na]+) 2731250 measured 2731256

1-(1-(4-Methoxyphenyl)vinyl)cyclobutan-1-ol (152)

OH

O

GP6 1-(1-Bromovinyl)-4-methoxybenzene was prepared from 4prime-methox-yacetophenone (120 g 800 mmol) Light sensitive purple solid (758 mg356 mmol 45 )

1H NMR (300 MHz CDCl3) δ (ppm) 753 (d J = 88 Hz 2H) 687 (dJ = 88 Hz 2H) 601 (d J = 19 Hz 1H) 567 (d J = 20 1H) 382 (s 3H)GC-MS tR (50_40) 82 min EI-MS mz () 204 (62) 186 (13) 176 (37) 175

(40) 162 (15) 161 (41) 160 (14) 159 (34) 155 (11) 148 (40) 147 (36) 146 (12)145 (77) 144 (14) 134 (20) 133 (100) 132 (11) 131 (10) 128 (15) 127 (10) 121(50) 119 (10) 118 (19) 117 (29) 116 (10) 115 (36) 108 (13) 105 (21) 103 (18)102 (11) 91 (28) 90 (20) 89 (29) 79 (14) 78 (11) 77 (33) 65 (17) 64 (10) 63(21) 51 (13) 43 (11) 39 (16)

GP7 1-(1-(4-Methoxyphenyl)vinyl)cyclobutan-1-ol was prepared from 1-(1-bromovinyl)-4-methoxybenzene (639 mg 300 mmol) Light yellow oil(366 mg 179 mmol 60 )

Rf (pentaneethyl acetate 91) 019 1H NMR (300 MHz CDCl3) δ (ppm)743 (d J = 89 Hz 2H) 687 (d J = 89 Hz 2H) 530 (dd J = 39 09 Hz 2H)381 (s 3H) 238ndash255 (m 2H) 215ndash232 (m 2H) 189ndash207 (m 2H) 153ndash170(m 2H) 13C NMR (755 MHz CDCl3) δ (ppm) 1592 1517 1314 12881137 1116 783 554 358 135 GC-MS tR (50_40) 82 min EI-MS mz() 204 (62) 186 (13) 176 (37) 175 (40) 162 (15) 161 (41) 160 (14) 159 (34)155 (11) 148 (40) 147 (36) 146 (12) 145 (77) 144 (14) 134 (20) 133 (100) 132(11) 131 (10) 128 (15) 127 (10) 121 (50) 119 (10) 118 (19) 117 (29) 116 (10)115 (36) 108 (13) 105 (21) 103 (18) 102 (11) 91 (28) 90 (20) 89 (29) 79 (14)78 (11) 77 (33) 65 (16) 64 (14) 63 (20) 51 (13) 43 (11) 39 (16) HR-MS (ESI)mz calculated for [C13H16O2Na]

+ ([M + Na]+) 2271043 measured 2271050

1-(1-(Benzo[d][1 3]dioxol-5-yl)vinyl)cyclobutan-1-ol (153)

OH

O

GP6 5-(1-bromovinyl)benzo[d][13]dioxole was prepared from 1-(benzo[d][13]dioxol-5-yl)ethan-1-one (985 mg 600 mmol) Light sensitive greenish oil(640 mg 282 mmol 47 )

GC-MS tR (50_40) 78 min EI-MS mz () 228 (17) 226 (18) 148 (11)147 (100) 145 (10) 117 (16) 89 (52) 73 (15) 63 (33) 62 (18)

GP7 1-(1-(benzo[d][13]dioxol-5-yl)vinyl)cyclobutan-1-ol was prepared from5-(1-bromovinyl)benzo[d][13]dioxole (668 mg 250 mmol) Light yellow oil(445 mg 204 mmol 82 )

Rf (pentaneethyl acetate 91) 015 1H NMR (300 MHz CDCl3) δ (ppm)695ndash702 (m 2H) 677 (d J = 80 Hz 1H) 595 (s 2H) 515ndash537 (m 2H)235ndash261 (m 2H) 214ndash230 (m 2H) 191ndash204 (m 2H) 155ndash169 (m 1H) 13CNMR (100 MHz CDCl3) δ (ppm) 1520 1476 1472 1332 1212 11231083 1081 1011 783 358 135 GC-MS tR (50_40) 85 min EI-MS mz() 219 (10) 218 (80) 190 (26) 189 (12) 162 (57) 161 (41) 160 (100) 159 (13)148 (18) 147 (100) 145 (12) 135 (49) 133 (10) 132 (77) 131 (49) 122 (13)

117 (20) 115 (25) 104 (28) 103 (38) 91 (14) 90 (11) 89 (75) 78 (17) 77 (31)73 (15) 65 (13) 64 (10) 63 (54) 62 (15) 53 (13) 51 (29) 43 (17) 41 (11) 39(29) HR-MS (ESI) mz calculated for [C13H14O3Na]

+ ([M + Na]+) 2410835measured 2410834

1-(1-(Naphthalen-2-yl)vinyl)cyclobutan-1-ol (154)

OH

GP6 2-(1-Bromovinyl)naphthalene was prepared from 2-acetonaphthone (119 g700 mmol) Pale yellow solid (900 mg 386 mmol 55 )

1H NMR (300 MHz CDCl3) δ (ppm) 809 (d J = 19 Hz 1H) 776ndash793 (m3H) 765ndash773 (m 1H) 747ndash756 (m 2H) 626 (dd J = 21 08 Hz 1H) 588(dd J = 21 08 Hz 1H) GC-MS tR (50_40) 84 min EI-MS mz () 234(17) 232 (20) 154 (11) 153 (100) 152 (75) 151 (24) 150 (11) 127 (10) 126(13) 76 (10) 75 (10) 74 (10) 63 (13) 50 (11)

GP7 1-(1-(Naphthalen-2-yl)vinyl)cyclobutan-1-ol was prepared from 2-(1-bromovinyl)naphthalene (700 mg 300 mmol) Light yellow oil (445 mg198 mmol 66 )

Rf (pentaneethyl acetate 91) 017 1H NMR (300 MHz CDCl3) δ (ppm)781ndash791 (m 1H) 771ndash778 (m 3H) 754 (dd J = 85 18 Hz 1H) 734ndash743(m 2H) 541 (dd J = 62 08 Hz 2H) 240ndash251 (m 2H) 211ndash229 (m 2H)181ndash204 (m 2H) 251ndash265 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm)1527 1367 1334 1329 1284 1278 1277 1266 1262 1261 1261 1135784 360 136 GC-MS tR (50_40) 71 min EI-MS mz () 224 (32) 196(12) 195 (23) 181 (23) 179 (15) 178 (20) 168 (54) 167 (39) 166 (12) 165(32) 154 (12) 153 (75) 152 (100) 151 (40) 150 (15) 141 (25) 139 (12) 128 (22)127 (17) 126 (15) 115 (15) 43 (20) 39 (16) HR-MS (ESI) mz calculated for[C16H16ONa]

+ ([M + Na]+) 2471093 measured 2471097

1-(1-(m-Tolyl)vinyl)cyclobutan-1-ol (149)

OH

1H NMR (300 MHz CDCl3) δ (ppm) 731ndash746 (m 1H) 720ndash729 (m 1H)715 (ddq J = 75 20 09 Hz 1H) 611 (d J = 19 Hz 1H) 577 (d J = 19 Hz1H) 238 (s 3H) GC-MS tR (50_40) 66 min EI-MS mz () 198 (19) 196(19) 117 (95) 116 (21) 115 (100) 91 (40) 89 (22) 74 (13) 65 (16) 63 (30) 62(14) 51 (20) 50 (19) 39 (23)

GP7 1-(1-(m-Tolyl)vinyl)cyclobutan-1-ol was prepared from 1-(1-bromovinyl)-3-methylbenzene (296 mg 150 mmol) Light yellow oil (85 mg 045 mmol30 )

Rf (pentaneethyl acetate 91) 022 1H NMR (300 MHz CDCl3) δ (ppm)718ndash736 (m 3H) 711 (dtd J = 72 17 08 Hz 1H) 535 (dd J = 70 10 Hz2H) 241ndash254 (m 2H) 236 (s 3H) 217ndash231 (m 2H) 189ndash207 (m 2H) 156ndash173 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm) 1526 1392 1379 12841284 1282 1248 1128 782 358 217 135 GC-MS tR (50_40) 77 minEI-MS mz () 207 (14) 145 (47) 132 (57) 131 (14) 129 (15) 128 (10) 117(84) 116 (21) 115 (100) 105 (11) 102 (13) 91 (46) 89 (15) 77 (19) 65 (18) 63(20) 43 (21) 42 (20) 39 (29) HR-MS (ESI) mz calculated for [C13H16ONa]

+

([M + Na]+) 2111093 measured 2111093

1-(1-(o-Tolyl)vinyl)cyclobutan-1-ol (150)

OH

GP6 1-(1-Bromovinyl)-2-methylbenzene was prepared from 2prime-methylacetophe-none (107 g 800 mmol) Colourless oil (703 mg 357 mmol 45 )

1H NMR (300 MHz CDCl3) δ (ppm) 701ndash727 (m 4H) 580 (d J = 16 Hz1H) 565 (d J = 15 1H) 232 (s 3H) GC-MS tR (50_40) 66 min EI-MS mz() 198 (13) 196 (13) 117 (85) 116 (29) 115 (100) 91 (32) 89 (17) 65 (10) 63(23) 62 (13) 51 (14) 50 (14) 39 (17)

GP7 1-(1-(o-Tolyl)vinyl)cyclobutan-1-ol was prepared from 1-(1-bromovinyl)-2-methylbenzene (591 mg 300 mmol) Light yellow oil (302 mg 160 mmol53 )

Rf (pentaneethyl acetate 41) 022 1H NMR (400 MHz CDCl3) δ (ppm)710ndash724 (m 4H) 554 (d J = 14 Hz 1H) 499 (d J = 14 Hz 1H) 236ndash249(m 2H) 229 (s 3H) 204ndash215 (m 2H) 190ndash202 (m 1H) 184 (s 1H) 154ndash164 (m 1H) 13C NMR (100 MHz CDCl3) δ (ppm) 1527 1400 1364 13031291 1274 1253 1137 786 358 206 137 GC-MS tR (50_40) 76 minEI-MS mz () 146 (15) 145 (40) 141 (13) 131 (12) 129 (10) 128 (14) 117(68) 116 (34) 115 (100) 92 (10) 91 (40) 89 (14) 77 (10) 73 (21) 65 (10) 63(10) 43 (17) 41 (10) 39 (23) HR-MS (ESI) mz calculated for [C13H16ONa]

+

([M + Na]+) 2111093 measured 2111105

1-(34-Dihydronaphthalen-1-yl)cyclobutan-1-ol (155)

OH

GP6 4-Bromo-12-dihydronaphthalene was prepared from 34-dihydronaphthalen-1(2H)-one (910 mg 640 mmol) Pale yellow oil (924 mg 442 mmol 69 )

1H NMR (300 MHz CDCl3) δ (ppm) 747 (dd J = 74 16 Hz 1H) 706ndash721 (m 2H) 696ndash705 (m 1H) 637 (t J = 48 Hz 1H) 277 (t J = 81 Hz 2H)226ndash233 (m 2H) GC-MS tR (50_40) 77 min EI-MS mz () 210 (16) 208(18) 130 (11) 129 (100) 128 (71) 127 (30) 64 (14) 63 (11) 51 (12)

GP8 1-(34-Dihydronaphthalen-1-yl)cyclobutan-1-ol was prepared from4-bromo-12-dihydronaphthalene (585 mg 280 mmol) White solid (421 mg210 mmol 75 )

1H NMR (300 MHz CDCl3) δ (ppm) 752 (dt J = 65 16 Hz 1H) 711ndash723 (m 3H) 620 (t J = 47 Hz 1H) 275 (t J = 79 Hz 2H) 250ndash260 (m 2H)229ndash240 (m 4H) 191ndash205 (m 2H) 153ndash168 (m 1H) 13C NMR (755 MHzCDCl3) δ (ppm) 1396 1375 1323 1280 1269 1262 1255 1254 875359 283 233 140 GC-MS tR (50_40) 85 min EI-MS mz () 200 (34)182 (27) 172 (40) 171 (21) 167 (22) 165 (11) 157 (40) 155 (11) 154 (22) 153(33) 152 (24) 144 (24) 143 (13) 141 (20) 130 (26) 129 (100) 128 (82) 127(29) 117 (12) 116 (21) 115 (30) 77 (10) HR-MS (ESI) mz calculated for[C14H16ONa]

+ ([M + Na]+) 2231093 measured 2231096

1-(Cyclohex-1-en-1-yl)cyclobutan-1-ol (163)

OH

GP6 1-Bromocyclohex-1-ene was prepared from cyclohexanone (785 mg800 mmol) Pale yellow oil (850 mg 528 mmol 66 )

1H NMR (300 MHz CDCl3) δ (ppm) 603 (tt J = 40 17 Hz 1H) 238ndash246(m 2H) 203ndash210 (m 2H) 167ndash181 (m 2H) 155ndash165 (m 2H) GC-MS tR(50_40) 54 min EI-MS mz () 160 (10) 81 (100) 79 (30) 77 (12) 53 (33) 51(12) 41 (12) 39 (15)

GP7 1-(Cyclohex-1-en-1-yl)cyclobutan-1-ol was prepared from1-bromocyclohex-1-ene (483 mg 300 mmol) Colourless oil (200 mg 131 mmol44 )

1H NMR (300 MHz CDCl3) δ (ppm) 570ndash575 (m 1H) 222ndash238 (m 2H)193ndash212 (m 6H) 179ndash193 (m 1H) 145ndash170 (m 6H) 13C NMR (755 MHzCDCl3) δ (ppm) 1404 1207 783 342 252 230 230 224 133 GC-MS tR(50_40) 68 min EI-MS mz () 134 (19) 124 (31) 123 (21) 119 (11) 110(25) 109 (69) 106 (12) 105 (21) 96 (19) 95 (44) 93 (11) 92 (13) 91 (57) 82(18) 81 (100) 80 (35) 79 (50) 78 (20) 77 (31) 67 (35) 66 (13) 65 (15) 55 (20)53 (27) 51 (17) 43 (51) 41 (30) 39 (33) HR-MS (ESI) mz calculated for[C10H16ONa]

+ ([M + Na]+) 1751093 measured 1751096

3-(1-Phenylvinyl)oxetan-3-ol (161)

OHO

GP7 3-(1-Phenylvinyl)oxetan-3-ol was prepared from (1-bromo-vinyl)benzene(11 g 60 mmol) White solid (860 mg 494 mmol 82 )

1H NMR (300 MHz CDCl3) δ (ppm) 744ndash752 (m 2H) 727ndash738 (m 3H)537 (d J = 47 2H) 237ndash265 (m 2H) 214ndash233 (m 2H) 187ndash208 (m 2H)141ndash171 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm) 1525 1392 12831277 1277 1130 782 358 135 GC-MS tR (50_40) 74 min EI-MS mz() 174 (17) 146 (47) 145 (70) 132 (20) 131 (55) 129 (21) 128 (27) 127 (21)119 (10) 118 (97) 117 (100) 116 (22) 115 (43) 104 (16) 103 (82) 102 (21) 96(12) 91 (35) 78 (25) 77 (55) 63 (10) 51 (22) 43(10) HR-MS (ESI) mzcalculated for [C12H14ONa]

+ ([M + Na]+) 1970937 measured 1970933

3-(1-(4-Fluorophenyl)vinyl)oxetan-3-ol (162) [40]

OHO

F

GP7 3-(1-(4-Fluorophenyl)vinyl)oxetan-3-ol was prepared from 1-(1-bromovinyl)-4-fluorobenzene (302 mg 150 mmol) White solid (117 mg120 mmol 48 )

1H NMR (300 MHz CDCl3) δ (ppm) 730ndash746 (m 2H) 682ndash710 (m 2H)555 (s 1H) 539 (s 1H) 489 (dd J = 69 10 Hz 2H) 477 (dd J = 69 09 Hz2H) 249 (s 1H) 13C NMR (755 MHz CDCl3) δ (ppm) 1628 (dJ = 2479 Hz) 1482 1287 (d J = 80 Hz) 1158 1155 1149 (d J = 11 Hz)832 767 19F NMR (300 MHz CDCl3) minus11372 GC-MS tR (50_40) 77 minEI-MS mz () 165 (11) 164 (100) 163 (69) 149 (39) 147 (23) 146 (22) 145(20) 136 (34) 135 (69) 134 (21) 133 (36) 121 (46) 120 (21) 117 (14) 115 (24)109 (32) 107 (10) 101 (51) 96 (20) 95 (17) 75 (30) 74 (10) 63 (10) 57 (10) 1(15) 50 (11) 43 (20) 39 (11) HR-MS (ESI) mz calculated for [C11H10FO2Na]

+

([M + Na]+) 2170635 measured 2170647

1-(1-Phenylvinyl)cyclopentan-1-ol (160)

OH

GP7 1-(1-Phenylvinyl)cyclopentan-1-ol was prepared from (1-bromovinyl)ben-zene (732 mg 400 mmol) Colourless oil (300 mg 159 mmol 40 )

Rf (pentaneethyl acetate 91) 025 1H NMR (300 MHz CDCl3) δ (ppm)739ndash745 (m 2H) 727ndash738 (m 3H) 547 (d J = 14 Hz 1H) 511 (dJ = 15 Hz 1H) 177ndash199 (m 6H) 164ndash175 (m 2H) 148 (s 1H) 13C NMR(755 MHz CDCl3) δ (ppm) 1551 1419 1286 1280 1272 1133 842 394234 GC-MS tR (50_40) 77 min EI-MS mz () 189 (10) 188 (63) 170 (28)160 (10) 159 (36) 155 (17) 146 (12) 145 (28) 142 (33) 141 (43) 131 (37) 129(36) 128 (29) 127 (15) 118 (20) 117 (40) 116 (16) 115 (45) 105 (24) 104 (94)103 (100) 102 (23) 97(34) 92 (14) 91 (75) 85 (30) 79 (12) 78 (33) 77 (79) 76(13) 67 (34) 65 (14) 63 (16) 57 (17) 55 (20) 53 (11) 52 (11) 51 (36) 50 (12)43 (17) 41 (28) 39 (27) HR-MS (ESI) mz calculated for [C13H16ONa]

+

([M + Na]+) 2111093 measured 2111093

1-(1H-inden-3-yl)cyclobutan-1-ol (159) [39]

OH

Following a procedure from Alexakis et al [39] n-BuLi (336 mL 537 mmol16 M in hexane 15 equiv) was added to a solution of indene (631 microL537 mmol 15 equiv) in diethylether (10 mL) at minus78 degC The reaction mixturewas stirred at rt for 3 h After cooling to minus78 degC cyclobutanone

(270 microL 358 mmol 100 equiv) was added dropwise to the reaction mixture Theresulting reaction mixture was warmed up slowly and continued the stirring for 4 hAfter cooling to 0 degC the reaction mixture was quenched with glacial acetic acid(360 microL) The quenched reaction mixture was then diluted with water and extractedwith diethyl ether The organic layer was washed with brine dried over MgSO4 andconcentrated under reduced pressure The crude mixture was purified by flashcolumn chromatography through silica (eluentpentaneethyl acetate 91 to 41) todeliver pure product (614 mg 329 mmol 92 ) as white solid

1H NMR (400 MHz CDCl3) δ (ppm) 759 (dt J = 77 10 Hz 1H) 749 (dtJ = 74 10 Hz 1H) 730 (td J = 76 12 Hz 1H) 723 (td J = 74 12 Hz 1H)646 (t J = 21 Hz 1H) 341 (d J = 20 Hz 2H) 251ndash263 (m 2H) 230ndash246(m 2H) 186ndash197 (m 1H) 157ndash169 (m 2H) 13C NMR (755 MHz CDCl3) δ(ppm) 1474 1452 1428 1283 1261 1250 1242 1217 741 377 357134 GC-MS tR (50_40) 82 min EI-MS mz () 186 (41) 168 (22) 167 (20)159 (13) 158 (97) 157 (33) 153 (13) 142 (18) 141 (19) 140 (28) 139 (30) 130(22) 129 (42) 128 (27) 127 (12) 116 (63) 115 (100) 114 (10) 89 (14) 71 (17)65 (11) 64 (12) 63 (17) 51 (10) 43 (28) 39 (10) HR-MS (ESI) mz calculatedfor [C13H14ONa]

+ ([M + Na]+) 2090937 measured 2090948

642 Synthesis and Characterization of TrifluoromethylatedCycloalkanone Compounds

General Procedure 9

( )mYR

CF3

XO

[Ru(bpy)3](PF6)2 (1 mol)TMSOTf (12 eq)

139 (12 eq) DMF rt 8 h465 nm Blue LEDs

HO X( )n

( )n

In a heat gun dried Schlenk tube equipped with a magnetic stirring bar substrate(142 146ndash163 02 mmol 10 equiv) followed by trimethylsilyltrifluoromethanesulfonate (43 microL 024 mmol 12 equiv) was dissolved in anhy-drous DMF (2 mL) The reaction mixture was stirred for 2 h [Ru(bpy)3](PF6)2(170 mg 0002 mmol 0010 equiv) and 5-(trifluoromethyl)dibenzothio-pheniumtrifluoromethanesulfonate (139 97 mg 024 mmol 12 equiv) were then added tothe reaction mixture and the mixture was allowed to stir for 6 h under irradiation ofvisible light from 5 W blue LEDs (λmax = 465 nm situated 5 cm away from thereaction vessel in a custom-made ldquolight boxrdquo see Fig 62) The reaction mixturewas quenched with aq saturated Na2SO3 solution (5 mL) and extracted with ethyl

acetate (3 times 10 mL) The combined organic layers were washed with water(15 mL) brine solution (15 mL) dried over MgSO4 and concentrated underreduced pressure The crude reaction mixture was purified by flash column chro-matography through silica gel (pentanedichloromethane 91 to 32 for 143 164ndash172 178ndash180 and pentaneethyl acetate 991 to 191 for 173ndash177) to afford pureproduct (143 164ndash180)

2-Phenyl-2-(222-trifluoroethyl)cyclopentan-1-one (143)

O

F3C

GP9 Prepared from 1-(1-phenylvinyl)cyclobutan-1-ol (142 35 mg 020 mmol)Colourless oil (36 mg 015 mmol 74 )

Rf (pentanedichloromethane 32) 031 1H NMR (300 MHz CDCl3) δ(ppm) 725ndash736 (m 4H) 718ndash724 (m 1H) 286 (dd J = 132 63 Hz 1H)274 (dq J = 155 112 Hz 1H) 242 (dq J = 155 110 Hz 1H) 186ndash232 (m4H) 162ndash183 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm) 2163 (Cq)1361 (Cq) 1291 (CH) 1278 (CH) 1269 (CH) 1263 (q J = 2777 Hz CF3)534 (q J = 19 Hz Cq) 421 (q J = 274 Hz CH2) 356 (CH2) 325 (qJ = 13 Hz CH2) 184 (CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6040 (tJ = 111 Hz) GC-MS tR (50_40) 74 min EI-MS mz () 242 (44) 187 (11)186 (100) 153 (13) 131 (38) 129 (14) 128 (11) 117 (37) 115 (35) 104 (22) 103(48) 102 (10) 91 (24) 78 (18) 77 (28) 65 (10) 51 (16) 39 (11) HR-MS (ESI)mz calculated for [C13H13F3ONa]

+ ([M + Na]+) 2650811 measured 2650817IR (ATR) ν (cmminus1) 2976 1739 1497 1447 1432 1372 1301 1258 1213 11551116 1083 1036 981 842 753 699 636

2-Phenyl-2-(222-trifluoroethyl)-1-oxaspiro[23]hexane (144)

CF3

O

Obtained as colourless oilRf (pentanedichloromethane 32) 060 1H NMR (600 MHz CDCl3) δ

(ppm) 734ndash736 (m 2H) 727ndash730 (m 3H) 301 (dq J = 153 101 Hz 1H)252ndash257 (m 1H) 241ndash247 (m 1H) 229 (dq J = 150 102 Hz 1H) 220ndash225(m 1H) 187ndash194 (m 1H) 176ndash181 (m 1H) 167ndash174 (m 1H) 13C NMR(150 MHz CDCl3) δ (ppm) 1367 (Cq) 1283 (CH) 1278 (CH) 1263 (CH)1260 (q J = 2787 Hz CF3) 693 (Cq) 617 (q J = 26 Hz Cq) 388 (qJ = 282 Hz CH2) 293 (CH2) 288 (CH2) 125 (CH2)

19F NMR (600 MHzCDCl3) δ (ppm) minus6098 (t J = 102 Hz) GC-MS tR (50_40) 71 min EI-MSmz () 242 (21) 214 (50) 213 (57) 186 (46) 173 (12) 172 (62) 171 (64)

159 (11) 153 (12) 152 (19) 151 (33) 145 (13) 143 (32) 133 (13) 131 (52) 129(20) 128 (31) 127 (13)) 122 (36) 117 (27) 115 (41) 105 (40) 104 (13) 103(100) 102 (19) 91 (29) 78 (27) 77 (93) 71 (12) 63 (13) 54 (15) 53 (20) 51 (42)43 (17) 42 (26) 39 (48) HR-MS (ESI) mz calculated for [C13H13F3ONa]

+

([M + Na]+) 2650811 measured 2650815 IR (ATR) ν (cmminus1) 2933 14261364 1306 1358 1139 1123 1112 1063 832 730 701 663 632 610

2-(4-Fluorophenyl)-2-(222-trifluoroethyl)cyclopentan-1-one (164)

O

F3C

F

GP9 Prepared from 1-(1-(4-fluorophenyl)vinyl)cyclobutan-1-ol (146 38 mg020 mmol) Colourless oil (38 mg 015 mmol 73 )

Rf (pentanedichloromethane 32) 057 1H NMR (300 MHz CDCl3)δ (ppm) 732ndash742 (m 2H) 697ndash709 (m 2H) 290 (dd J = 132 63 Hz 1H)279 (dq J = 155 112 Hz 1H) 243 (dq J = 155 112 Hz 1H) 217ndash235(m 2H) 192ndash216 (m 2H) 167ndash189 (m 1H) 13C NMR (755 MHz CDCl3)δ (ppm) 2161 (Cq) 1623 (d J = 2475 Hz Cq) 1316 (d J = 33 Hz Cq) 1288(d J = 81 Hz CH) 1263 (q J = 2783 Hz CF3) 1160 (d J = 214 Hz CH)528 (q J = 19 Hz Cq) 422 (q J = 275 Hz CH2) 356 (CH2) 329(q J = 14 Hz CH2) 184 (CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6042(t J = 110 Hz)ndash11466 (s) GC-MS tR (50_40) 74 min EI-MS mz () 260(37) 205 (11) 204 (100) 171 (11) 149 (23) 135 (15) 133 (16) 121 (41) 109(12) 101 (18) HR-MS (ESI) mz calculated for [C13H12F4OAg]

+ ([M + Ag]+)3669870 measured 3669876 IR (ATR) ν (cmminus1) 2975 2893 1740 16041510 1472 1461 1434 1408 1373 1302 1258 1236 1215 1166 1156 11191075 1014 982 850 837 821 721 662 628

2-(4-Chlorophenyl)-2-(222-trifluoroethyl)cyclopentan-1-one (165)

O

F3C

Cl

GP9 Prepared from 1-(1-(4-chlorophenyl)vinyl)cyclobutan-1-ol (147 42 mg020 mmol) Colourless oil solidified upon cooling (33 mg 012 mmol 60 )

Rf (pentanedichloromethane 32) 051 1H NMR (300 MHz CDCl3)δ (ppm) 729ndash736 (m 4H) 285ndash292 (m 1H) 271ndash283 (m 1H) 236ndash253(m 1H) 196ndash234 (m 4H) 167ndash188 (m 1H) 13C NMR (755 MHz CDCl3)δ (ppm) 2159 (Cq) 1345 (Cq) 1340 (Cq) 1292 (CH) 1285 (CH) 1263(q J = 2782 Hz CF3) 530 (q J = 18 Hz Cq) 421 (q J = 275 Hz CH2) 356(CH2) 327 (q J = 15 Hz CH2) 185 (CH2)

19F NMR (300 MHz CDCl3)

δ (ppm) minus6039 (t J = 110 Hz) GC-MS tR (50_40) 80 min EI-MS mz ()278 (12) 276 (37) 222 (32) 221 (12) 220 (100) 213 (26) 185 (10) 165 (16) 151(12) 139 (11) 137 (32) 129 (11) 128 (11) 116 (10) 115 (24) 102 (18) 101 (20)75 (14) 51 (11) HR-MS (ESI) mz calculated for [C13H12ClF3ONa]

+

([M + Na]+) 2990421 measured 2990391 IR (ATR) ν (cmminus1) 2977 28901741 1493 1473 1433 1372 1301 1258 1213 1199 1172 1154 1117 10751013 982 848 809 742 703 662 631

2-(p-Tolyl)-2-(222-trifluoroethyl)cyclopentan-1-one (166)

O

F3C

GP9 Prepared from 1-(1-(p-tolyl)vinyl)cyclobutan-1-ol (148 38 mg 020 mmol)Colourless oil upon cooling solidified (40 mg 016 mmol 78 )

Rf (pentanedichloromethane 32) 034 1H NMR (300 MHz CDCl3) δ(ppm) 728 (d J = 83 Hz 2H) 717 (d J = 83 Hz 2H) 291 (dd J = 13263 Hz 1H) 280 (dq J = 155 113 Hz 1H) 248 (dq J = 154 111 Hz 1H)192ndash239 (m 4H) 234 (s 3H) 172ndash189 (m 1H) 13C NMR (755 MHzCDCl3) δ (ppm) 2164 (Cq) 1376 (Cq) 1330 (Cq) 1298 (CH) 1268 (CH)1264 (q J = 2784 Hz CF3) 531 (q J = 17 Hz Cq) 421 (q J = 272 Hz CH2)356 (CH2) 326 (q J = 14 Hz CH2) 211 (CH3) 184 (CH2)

19F NMR(300 MHz CDCl3) δ (ppm) minus6038 (t J = 112 Hz) GC-MS tR (50_40)77 min EI-MS mz () 256 (38) 201 (12) 200 (100) 145 (33) 131 (11) 129(12) 128 (12) 118 (11) 117 (34) 116 (11) 115 (35) 91 (27) HR-MS (ESI) mzcalculated for [C14H15F3ONa]

+ ([M + Na]+) 2790967 measured 2790980 IR(ATR) ν (cmminus1) 2975 1739 1513 1459 1432 1407 1371 1301 1258 12111197 1156 1116 1075 1032 1022 981 876 846 807 738 721 658 653 625

2-([11prime-Biphenyl]-4-yl)-2-(222-trifluoroethyl)cyclopentan-1-one (169)

O

F3C

GP9 Prepared from 1-(1-([11prime-biphenyl]-4-yl)vinyl)cyclobutan-1-ol (151 50 mg020 mmol) Colourless oil (52 mg 016 mmol 82 )

Rf (pentanedichloromethane 32) 040 1H NMR (300 MHz CDCl3)δ (ppm) 754ndash764 (m 4H) 741ndash748 (m 4H) 732ndash738 (m 1H) 296(dd J = 134 63 Hz 1H) 285 (dq J = 154 112 Hz 1H) 253 (dq J = 155110 Hz 1H) 198ndash243 (m 4H) 176ndash195 (m 1H) 13C NMR (755 MHzCDCl3) δ (ppm) 2163 (Cq) 1406 (Cq) 1403 (Cq) 1351 (Cq) 1290 (CH)1277 (CH) 1277 (CH) 1274 (CH) 1272 (CH) 1264 (q J = 2784 Hz CF3)

533 (q J = 14 Hz Cq) 421 (q J = 274 Hz CH2) 357 (CH2) 326(q J = 16 Hz CH2) 185 (CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6030(t J = 111 Hz) GC-MS tR (50_40) 95 min EI-MS mz () 319 (12) 318(50) 263 (18) 262 (100) 207 (19) 179 (26) 178 (35) 165 (10) 152 (11) HR-MS(ESI) mz calculated for [C19H17F3ONa]

+ ([M + Na]+) 3411124 measured3411145 IR (ATR) ν (cmminus1) 2974 1739 1488 1474 1432 1406 1371 13151301 1258 1214 1198 1155 1116 1074 1034 1007 982 919 875 851 817761 731 698 661 632

2-(4-Methoxyphenyl)-2-(222-trifluoroethyl)cyclopentan-1-one (170)

O

F3C

O

GP9 Prepared from 1-(1-(4-methoxyphenyl)vinyl)cyclobutan-1-ol (152 41 mg020 mmol) Colourless oil (49 mg 018 mmol 90 )

Rf (pentanedichloromethane 32) 054 1H NMR (300 MHz CDCl3) δ(ppm) 727ndash732 (m 2H) 685ndash690 (m 2H) 379 (s 3H) 287 (dd J = 13262 Hz 1H) 269ndash286 (m 1H) 239ndash251 (m 1H) 193ndash236 (m 4H) 170ndash188(m 1H) 13C NMR (100 MHz CDCl3) δ (ppm) 2163 (Cq) 1592 (Cq) 1282(CH) 1276 (Cq) 1264 (q J = 2783 Hz CF3) 1144 (CH) 553 (CH3) 527 (qJ = 19 Hz Cq) 421 (q J = 271 Hz CH2) 355 (CH2) 327 (q J = 16 HzCH2) 184 (CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6040 (tJ = 111 Hz) GC-MS tR (50_40) 81 min EI-MS mz () 272 (31) 217 (12)216 (100) 161 (30) 133 (32) HR-MS (ESI) mz calculated for [C14H15F3O2Na]

+

([M + Na]+) 2950916 measured 2950921 IR (ATR) ν (cmminus1) 2962 28411738 1609 1581 1512 1463 1442 1407 1372 1294 1254 1214 1187 11561116 1074 1034 981 875 847 811 661 641 625

2-(Benzo[d][13]dioxol-5-yl)-2-(222-trifluoroethyl)cyclopentan-1-one (171)

O

F3C O

O

GP9 Prepared from 1-(1-(benzo[d][13]dioxol-5-yl)vinyl)cyclobutan-1-ol (15344 mg 020 mmol) Colourless oil (49 mg 017 mmol 86 )

Rf (pentanedichloromethane 32) 041 1H NMR (300 MHz CDCl3) δ(ppm) 688 (d J = 19 Hz 1H) 683 (dd J = 82 20 Hz 1H) 677 (dJ = 82 Hz 1H) 595ndash596 (m 2H) 279ndash286 (m 1H) 275 (dq J = 155112 Hz 1H) 211ndash251 (m 3H) 193ndash211 (m 2H) 171ndash188 (m 1H) 13CNMR (755 MHz CDCl3) δ (ppm) 2160 (Cq) 1485 (Cq) 1472 (Cq) 1295(Cq) 1264 (q J = 2783 Hz CF3) 1205 (CH) 1086 (CH) 1075 (CH) 1014

(CH2) 530 (q J = 17 Hz Cq) 422 (q J = 272 Hz CH2) 355 (CH2) 330 (qJ = 16 Hz CH2) 184 (CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6044 (tJ = 111 Hz) GC-MS tR (50_40) 85 min EI-MS mz () 286 (37) 231 (11)230 (100) 229 (26) 175 (19) 147 (14) 89 (11) 63 (10) HR-MS (ESI) mzcalculated for [C14H13F3O3Na]

+ ([M + Na]+) 3090709 measured 3090717 IR(ATR) ν (cmminus1) 2974 2894 1737 1504 1489 1437 1373 1301 1238 11991171 1149 1116 1074 1038 984 898 879 841 807 729 700 651 631

2-(Naphthalen-2-yl)-2-(222-trifluoroethyl)cyclopentan-1-one (172)

O

F3C

GP9 Prepared from 1-(1-(naphthalen-2-yl)vinyl)cyclobutan-1-ol (154 45 mg020 mmol) Colourless oil (47 mg 016 mmol 80 )

Rf (pentaneethyl acetate 91) 049 1H NMR (300 MHz CDCl3) δ (ppm)770ndash798 (m 4H) 739ndash767 (m 3H) 306 (dd J = 138 58 Hz 1H) 292 (dqJ = 155 112 Hz 1H) 258 (dq J = 155 111 Hz 1H) 211ndash243 (m 3H) 199ndash209 (m 1H) 176ndash193 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm) 2162(Cq) 1335 (Cq) 1334 (Cq) 1327 (Cq) 1290 (CH) 1283 (CH) 1276 (CH)1266 (CH) 1266 (CH) 1264 (q J = 2782 Hz CF3) 1263 (CH) 1244 (CH)537 (q J = 17 Hz Cq) 420 (q J = 275 Hz CH2) 357 (CH2) 327 (qJ = 14 Hz CH2) 185 (CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6029 (tJ = 111 Hz) GC-MS tR (50_40) 90 min EI-MS mz () 293 (10) 292 (56)237 (16) 236 (100) 181 (33) 167 (13) 166 (11) 165 (25) 154 (15) 153 (33) 151(39) 128 (20) HR-MS (ESI) mz calculated for [C17H15F3ONa]

+ ([M + Na]+)3150967 measured 3150960 IR (ATR) ν (cmminus1) 2976 1738 1598 15061459 1432 1371 1300 1257 1197 1152 1120 1074 986 864 812 747 648615

2-(m-Tolyl)-2-(222-trifluoroethyl)cyclopentan-1-one (167)

O

F3C

GP9 Prepared from 1-(1-(m-tolyl)vinyl)cyclobutan-1-ol (149 38 mg 02 mmol)Colourless oil (26 mg 010 mmol 51 )

Rf (pentanedichloromethane 32) 034 1H NMR (300 MHz CDCl3) δ(ppm) 716ndash731 (m 3H) 707ndash714 (m 1H) 286 (dd J = 133 64 Hz 1H)279 (dq J = 155 113 Hz 1H) 251 (dq J = 155 111 Hz 1H) 191ndash222 (m4H) 236 (s 3H) 169ndash191 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm)2164 (Cq) 1387 (Cq) 1361 (Cq) 1289 (CH) 1286 (CH) 1276 (CH) 1264 (q

J = 2784 Hz CF3) 1237 (CH) 534 (q J = 17 Hz Cq) 421 (q J = 273 HzCH2) 356 (CH2) 325 (q J = 14 Hz CH2) 217 (CH3) 184 (CH2)

19F NMR(300 MHz CDCl3) δ (ppm) minus6037 (t J = 113 Hz) GC-MS tR (50_40)76 min EI-MS mz () 256 (46) 213 (12) 201 (12) 200 (100) 145 (40) 131(18) 129 (18) 128 (17) 118 (29) 117 (36) 116 (15) 115 (45) 105 (10) 92 (15)91 (34) 65 (12) 39 (11) HR-MS (ESI) mz calculated for [C14H15F3ONa]

+

2-(o-Tolyl)-2-(222-trifluoroethyl)cyclopentan-1-one (168)

O

F3C

GP9 Prepared from 1-(1-(o-tolyl)vinyl)cyclobutan-1-ol (150 38 mg 020 mmol)Colourless oil (20 mg 008 mmol 39 )

Rf (pentanedichloromethane 32) 046 1H NMR (300 MHz CDCl3) δ(ppm) 715ndash725 (m 2H) 708ndash713 (m 1H) 700ndash703 (m 1H) 273ndash300 (m3H) 237ndash249 (m 1H) 246 (s 3H) 215ndash233 (m 2H) 186ndash198 (m 1H) 157ndash173 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm) 2174 (Cq) 1368 (Cq)1364 (Cq) 1337 (CH) 1279 (CH) 1273 (CH) 1263 (q J = 2784 Hz CF3)1262 (CH) 547 (q J = 15 Hz Cq) 387 (q J = 273 Hz CH2) 363 (CH2) 334(q J = 15 Hz CH2) 214 (CH3) 183 (CH2)

19F NMR (300 MHz CDCl3) δ(ppm) minus6044 (t J = 115 Hz) GC-MS tR (50_40) 77 min EI-MS mz ()257 (11) 256 (73) 225 (10) 214 (12) 213 (22) 201 (10) 200 (79) 199 (11) 185(19) 173 (15) 165 (15) 155 (18) 146 (14) 145 (81) 143 (13) 131 (42) 130 (13)129 (49) 128 (36) 127 (12) 118 (37) 117 (86) 116 (32) 115 (100) 105 (19) 92(19) 91 (68) 89 (14) 77 (20) 71 (13) 69 (10) 65 (23) 63 (16) 55 (14) 51 (18)39 (25) HR-MS (ESI) mz calculated for [C14H15F3ONa]

+ ([M + Na]+)2790967 measured 2790972 IR (ATR) ν (cmminus1) 2962 1745 1490 14561433 1370 1298 1259 1138 1118 1074 982 633

2prime-(Trifluoromethyl)-3prime4prime-dihydro-2primeH-spiro[cyclopentane-11prime-naphthalen]-2-one (173)

CF3O

GP9 Prepared from 1-(34-dihydronaphthalen-1-yl)cyclobutan-1-ol (155 40 mg020 mmol) White solids (28 mg 010 mmol 52 11 dr)

Diastereomer A

Rf (pentaneethyl acetate 191) 0211H NMR (600 MHz CDCl3) δ (ppm)

711ndash717 (m 2H) 707ndash710 (m 1H) 676ndash679 (m 1H) 292ndash301 (m 3H)253ndash268 (m 3H) 204ndash219 (m 4H) 184ndash195 (m 1H) 13C NMR (150 MHzCDCl3) δ (ppm) 2223 (Cq) 1413 (Cq) 1349 (Cq) 1293 (CH) 1275 (qJ = 2806 Hz CF3) 1272 (CH) 1270 (CH) 1269 (CH) 538 (q J = 14 Hz Cq)459 (q J = 254 Hz CH) 400 (q J = 11 Hz CH2) 358 (q J = 15 Hz CH2)287 (CH2) 203 (q J = 28 Hz CH2) 189 (q J = 11 Hz CH2)

19F NMR(600 MHz CDCl3) δ (ppm) minus6538 (d J = 96 Hz) GC-MS tR (50_40)84 min EI-MS mz () 268 (38) 213 (13) 212 (100) 144 (10) 143 (28) 141(14) 129 (16) 128 (30) 115 (21) HR-MS (ESI) mz calculated for [C15H16F3O]

+

([M + H]+) 2691148 measured 2691146 IR (ATR) ν (cmminus1) 2962 29041742 1493 1451 1407 1385 1342 1317 1269 1229 1151 1124 1101 10741012 976 945 888 822 755 725 687 629

Diastereomer B

713ndash718 (m 2H) 708ndash712 (m 1H) 695ndash698 (m 1H) 297ndash302 (m 1H)277ndash284 (m 1H) 264ndash273 (m 2H) 254ndash260 (m 1H) 247ndash254 (m 1H)236ndash245 (m 2H) 213ndash219 (m 2H) 204ndash209 (m 1H) 13C NMR (150 MHzCDCl3) δ (ppm) 2186 (Cq) 1389 (Cq) 1363 (Cq) 1291 (CH) 1280 (CH)1272 (q J = 2823 Hz CF3) 1268 (CH) 1268 (CH) 530 (Cq) 466 (qJ = 251 Hz CH) 415 (q J = 12 Hz CH2) 383 (q J = 12 Hz CH2) 272(CH2) 201 (q J = 30 Hz CH2) 187 (CH2)

19F NMR (600 MHz CDCl3) δ(ppm) minus6342 (d J = 98 Hz) GC-MS tR (50_40) 85 min EI-MS mz () 268(37) 213 (13) 212 (100) 144 (11) 143 (28) 141 (15) 129 (17) 128 (31) 116(10) 115 (23) HR-MS (ESI) mz calculated for [C15H16F3O]

+ ([M + H]+)2691148 measured 2691146 IR (ATR) ν (cmminus1) 3025 2968 2927 29082851 1740 1493 1450 1446 1407 1384 1350 1302 1272 1229 1188 11401117 1081 1048 1020 984 921 873 846 820 784 760 683

3-(Trifluoromethyl)spiro[chromane-41prime-cyclopentan]-2prime-one (176)

O

CF3O

GP9 Prepared from 1-(2H-chromen-4-yl)cyclobutan-1-ol (158 46 mg022 mmol) White solid (24 mg 009 mmol 41 101 dr)

Major diastereomer

708ndash721 (m 1H) 692ndash697 (m 2H) 687ndash691 (m 1H) 470 (dd J = 11761 Hz 1H) 424 (ddq J = 117 28 14 Hz 1H) 271ndash283 (m 1H) 263ndash271

(m 1H) 239ndash257 (m 3H) 209ndash224 (m 2H) 13C NMR (100 MHz CDCl3) δ(ppm) 2168 (Cq) 1544 (Cq) 1286 (CH) 1281 (CH) 1258 (q J = 2819 HzCF3) 1242 (Cq) 1218 (CH) 1174 (CH) 614 (q J = 39 Hz CH2) 498 (Cq)450 (q J = 260 Hz CH) 407 (CH2) 381 (CH2) 182 (CH2)

19F NMR(300 MHz CDCl3) δ (ppm) minus6314 (d J = 93 Hz) GC-MS tR (50_40)83 min EI-MS mz () 270 (30) 215 (12) 214 (100) 145 (26) 131 (10) 115(16) 77 (10) HR-MS (ESI) mz calculated for [C14H13F3O2Na]

+ ([M + Na]+)2930760 measured 2930762 IR (ATR) ν (cmminus1) 2998 2971 2916 17371609 1585 1492 1466 1453 1397 1369 1313 1282 1247 1223 1136 11081075 1055 1008 946 918 862 829 796 761 736 703 689 637 606

5prime7prime-Dimethyl-2prime-(trifluoromethyl)-3prime4prime-dihydro-2primeH-spiro[cyclopentane-11prime-naphthalen]-2-one (174)

OCF3

GP9 Prepared from 1-(57-dimethyl-34-dihydronaphthalen-1-yl)cyclobutan-1-ol(156 46 mg 020 mmol) White solids (17 mg 006 mmol 29 111 dr)

Major diastereomer

686 (s 1H) 641 (s 1H) 278ndash297 (m 2H) 259ndash271 (m 4H) 196ndash226 (m4H) 223 (s 3H) 217 (s 3H) 178ndash193 (m 1H) 13C NMR (755 MHz CDCl3)δ (ppm) 2230 (Cq) 1414 (Cq) 1365 (Cq) 1360 (Cq) 1303 (Cq) 1296 (CH)1275 (q J = 2807 Hz CF3) 1255 (CH) 539 (Cq) 457 (q J = 255 Hz CH)403 (CH2) 359 (CH2) 260 (CH2) 212 (CH3) 202 (q J = 26 Hz CH2) 199(CH3) 189 (CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6043 (dJ = 95 Hz) GC-MS tR (50_40) 89 min EI-MS mz 297 (12) 296 (60) 254(14) 253 (76) 241 (15) 240 (96) 226 (15) 225 (100) 157 (10) 156 (13) 155(14) 142 (12) 141 (20) 128 (16) 115 (11) HR-MS (ESI) mz calculated for[C17H19F3ONa]

+ ([M + Na]+) 3191280 measured 3191286 IR (ATR) ν(cmminus1) 2951 1743 1613 1480 1457 1407 1384 1345 1317 1297 1268 12281150 1120 1074 1036 1036 1015 981 942 902 853 713 656 631

Minor diastereomer

687 (s 1H) 659 (s 1H) 232ndash285 (m 8H) 225 (s 3H) 220 (s 3H) 220ndash228(m 3H) 13C NMR (755 MHz CDCl3) δ (ppm) 2192 (Cq) 1385 (Cq) 1361(Cq) 1356 (Cq) 1320 (Cq) 1295 (CH) 1272 (q J = 2822 Hz CF3) 1264(CH) 534 (Cq) 457 (q J = 253 Hz CH) 419 (CH2) 384 (CH2) 239 (CH2)213 (CH3) 200 (q J = 29 Hz CH2) 198 (CH3) 186 (CH2)

19F NMR(300 MHz CDCl3) δ (ppm) minus6335 (d J = 99 Hz) GC-MS tR (50_40)

90 min EI-MS mz () 297 (11) 296 (57) 268 (11) 254 (14) 253 (77) 241(17) 240 (92) 226 (17) 225 (100) 157 (11) 156 (14) 155 (12) 153 (10) 142(12) 141 (21) 129 (12) 128 (16) 115 (13) HR-MS (ESI) mz calculated for[C17H19F3ONa]

+ ([M + Na]+) 3191280 measured 3191283 IR (ATR) ν(cmminus1) 2966 2916 1741 1482 1459 1381 1272 1199 1181 1142 1128 11131087 1043 1015 854 792 656 644 609

6prime-Methoxy-2prime-(trifluoromethyl)-3prime4prime-dihydro-2primeH-spiro[cyclopentane-11prime-naphthalen]-2-one (175)

CF3O

O

GP9 Prepared from 1-(6-methoxy-34-dihydronaphthalen-1-yl)cyclobutan-1-ol(157 46 mg 020 mmol) White solid upon cooling (28 mg 009 mmol47 gt 251 dr)

Major diastereomer

687 (d J = 87 Hz 1H) 674 (dd J = 88 28 Hz 1H) 662 (d J = 27 Hz 1H)377 (s 3H) 292ndash302 (m 1H) 226ndash283 (m 7H) 199ndash220 (m 3H) 13C NMR(755 MHz CDCl3) δ (ppm) 2190 (Cq) 1580 (Cq) 1377 (Cq) 1309 (Cq) 1291(CH) 1272 (q J = 2823 Hz CF3) 1134 (CH) 1132 (CH) 553 (CH3) 525((Cq) 464 (q J = 252 Hz CH) 413 (CH2) 381 (CH2) 273 (CH2) 201 (qJ = 31 Hz CH2) 185 (CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6335 (dJ = 99 Hz) GC-MS tR (50_40) 92 min EI-MS mz () 298 (18) 270 (11)243 (15) 242 (100) 174 (11) 115 (13) HR-MS (ESI) mz calculated for[C16H17F3O2Na]

+ ([M + Na]+) 3211073 measured 3211078 IR (ATR) ν(cmminus1) 2964 1740 1612 1578 1503 1462 1381 1347 1320 1302 1264 12441229 1189 1142 1123 1083 1066 1047 945 896 869 851 819 735 703 627

2prime-(Trifluoromethyl)-2prime3prime-dihydrospiro[cyclopentane-11prime-inden]-2-one (177)

O

CF3

Prepared from 1-(1H-inden-3-yl)cyclobutan-1-ol (159 37 mg 020 mmol) Whitesolids (27 mg 011 mmol 53 151 dr) The starting material 1-(1H-inden-3-yl)cyclobutan-1-ol (159 80 g 004 mmol 22 ) was recovered

The reaction was repeated with 139 (20 equiv) under similar conditions Whitesolids (33 mg 013 mmol 65 151 dr)

Major diastereomer

719ndash732 (m 3H) 703ndash710 (m 1H) 335ndash354 (m 1H) 304ndash324 (m 2H)235ndash267 (m 4H) 205ndash229 (m 2H) 13C NMR (100 MHz CDCl3) δ (ppm)2164 (Cq) 1452 (Cq) 1411 (Cq) 1281 (CH) 1276 (CH) 1268 (qJ = 2794 Hz CF3) 1250 (CH) 1225 (CH) 607 (q J = 15 Hz Cq) 544 (qJ = 271 Hz CH) 384 (CH2) 373 (CH2) 321 (q J = 13 Hz CH2) 200 (CH2)19F NMR (300 MHz CDCl3) δ (ppm) minus6468 (d J = 90 Hz) GC-MS tR(50_40) 80 min EI-MS mz () 254 (31) 199 (12) 198 (100) 129 (41) 128(25) 115 (10) HR-MS (ESI) mz calculated for [C14H13F3ONa]

Minor diastereomer

713ndash731 (m 3H) 696 (dd J = 67 16 Hz 1H) 343ndash367 (m 1H) 311ndash329 (m2H) 257ndash268 (m 1H) 238ndash252 (m 2H) 204ndash226 (m 3H) 13C NMR(100 MHz CDCl3) δ (ppm) 2185 (Cq) 1456 (Cq) 1397 (Cq) 1281 (CH) 1276(CH) 1270 (q J = 2781 Hz CF3) 1250 (CH) 1227 (CH) 615 (q J = 15 HzCq) 489 (q J = 272 Hz CH) 374 (CH2) 323 (q J = 17 Hz CH2) 318 (qJ = 27 Hz CH2) 188 (CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6558 (dJ = 99 Hz)GC-MS tR (50_40) 79 min EI-MSmz () 254 (30) 199 (12) 198(100) 129 (41) 128 (24) 115 (11) HR-MS (ESI) mz calculated for[C14H13F3ONa]

+ ([M + Na]+) 2770811 measured 2770817 IR (ATR) ν (cmminus1)2975 2922 2902 1737 1477 1443 1396 1327 1276 1253 1196 1164 11461117 1077 1045 1008 965 933 875 837 816 765 733 707 690 648 632

4-Phenyl-4-(222-trifluoroethyl)dihydrofuran-3(2H)-one (179)

O

F3C

GP9 Prepared from 3-(1-phenylvinyl)oxetan-3-ol (161 35 mg 020 mmol)Colourless oil (130 mg 005 mmol 27 )

Rf (pentanedichloromethane 32) 046 1H NMR (400 MHz CDCl3) δ(ppm) 749 (t J = 76 Hz 2H) 739 (t J = 76 Hz 2H) 732 (t J = 76 Hz 1H)505 (d J = 107 Hz 1H) 422 (d J = 107 Hz 1H) 411 (d J = 175 Hz 1H)392 (d J = 175 Hz 1H) 303 (dq J = 155 110 Hz 1H) 253 (dq J = 155105 Hz 1H) 13C NMR (100 MHz CDCl3) δ (ppm) 2117 (Cq) 1342 (Cq)1292 (CH) 1284 (CH) 1267 (CH) 1260 (q J = 2781 Hz CF3) 741 (qJ = 24 Hz CH2) 696 (CH2) 521 (Cq) 389 (q J = 288 Hz CH2)

19F NMR(300 MHz CDCl3) δ (ppm) minus6086 (t J = 108 Hz) GC-MS tR (50_40)

72 min EI-MS mz () 187 (11) 186 (100) 153 (11) 117 (21) 115 (17) 103(45) 78 (16) 77 (18) 51 (11) HR-MS (ESI) mz calculated for [C12H11F3O2Na]

+

4-(4-Fluorophenyl)-4-(222-trifluoroethyl)dihydrofuran-3(2H)-one (180)

O

F3C

F

GP9 Prepared from 3-(1-(4-fluorophenyl)vinyl)oxetan-3-ol (162 39 mg020 mmol) Colourless oil (15 mg 006 mmol 29 )

Rf (pentanedichloromethane 32) 043 1H NMR (300 MHz CDCl3) δ(ppm) 739ndash757 (m 2H) 700ndash715 (m 2H) 501 (d J = 109 Hz 1H) 421 (dJ = 109 Hz 1H) 411 (d J = 176 Hz 1H) 392 (d J = 176 Hz 1H) 301 (dqJ = 156 110 Hz 1H) 248 (dq J = 157 105 Hz 1H) 13C NMR (100 MHzCDCl3) δ (ppm) 2114 (Cq) 1626 (d J = 2484 Hz Cq) 1297 (d J = 33 HzCq) 1287 (d J = 83 Hz CH) 1259 (q J = 2781 Hz CF3) 1162 (dJ = 216 Hz CH) 743 (q J = 23 Hz CH2) 695 (CH2) 516 (q J = 15 Hz Cq)389 (q J = 288 Hz CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6083ndash11370 GC-MS tR (50_40) 72 min EI-MS mz () 205 (11) 204 (100) 171(12) 133 (13) 121 (68) 101 (24) 96 (10) HR-MS (ESI) mz calculated for[C12H10F4O2Na]

+ ([M + Na]+) 2850509 measured 2850516 IR (ATR) ν(cmminus1) 2920 1728 1605 1513 1435 1415 1374 1310 1259 1238 1163 11341110 1056 931 835 639

2-Phenyl-2-(222-trifluoroethyl)cyclohexan-1-one (178)

O

F3C

GP9 Prepared from 1-(1-phenylvinyl)cyclopentan-1-ol (160 38 mg 020 mmol)Colourless oil (17 mg 007 mmol 33 )

Rf (pentanedichloromethane 32) 054 1H NMR (300 MHz CDCl3) δ(ppm) 730ndash739 (m 2H) 724ndash730 (m 1H) 716ndash722 (m 2H) 299ndash304 (m1H) 245ndash279 (m 2H) 218ndash239 (m 2H) 189ndash203 (m 1H) 160ndash189 (m 4H)13C NMR (755 MHz CDCl3) δ (ppm) 2106 (Cq) 1384 (Cq) 1293 (CH) 1276(CH) 1271 (CH) 1267 (q J = 2782 Hz CF3) 546 (q J = 18 Hz Cq) 431 (qJ = 267 Hz CH2) 393 (CH2) 343 (q J = 18 Hz CH2) 282 (CH2) 215 (CH2)19F NMR (300 MHz CDCl3) δ (ppm) minus5875 (t J = 115 Hz) GC-MS tR(50_40) 77 min EI-MS mz () 256 (18) 213 (12) 212 (77) 186 (18) 145(14) 130 (11) 129 (100) 128 (12) 117 (30) 116 (11) 115 (39) 109 (14)

103 (26) 91 (41) 78 (12) 77 (22) 51 (12) 42 (11) 39 (10) HR-MS (ESI) mzcalculated for [C14H15F3ONa]

+ ([M + Na]+) 2790967 measured 1650971 IR(ATR) ν (cmminus1) 2949 1709 1497 1451 1427 1373 1305 1264 1233 11641125 1099 1038 906 843 727 651 628

643 Synthetic Manipulations of TrifluoromethylatedCycloalkanone Product

Synthesis of (E)-2-Phenyl-2-(222-trifluoroethyl)cyclopentan-1-one oxime(184)

N

F3C184 70

HOO

F3C143

NH2OHHCl (5 eq) NaOAc (4 eq)

EtOH rt 48 h

Hydroxylamine hydrochloride (63 mg 091 mmol 50 equiv) and sodiumacetate (60 mg 073 mmol 40 equiv) were added to a solution of 2-phenyl-2-(222-trifluoroethyl)cyclopentan-1-one (143 44 mg 018 mmol 10 equiv) inethanol (18 mL) and the resulting reaction mixture was stirred at rt for 48 h Water(2 mL) was then added to quench the reaction The organic layer was extracted withethyl acetate (3times10 mL) washed with brine dried over MgSO4 and concentratedunder reduced pressure The crude reaction mixture was purified by flash columnchromatography through silica gel (pentane ethyl acetate 191) to afford pure (E)-2-phenyl-2-(222-trifluoroethyl)cyclopentan-1-one oxime (184 33 mg 013 mmol70 ) as a white solid

(E)-2-Phenyl-2-(222-trifluoroethyl)cyclopentan-1-one oxime (184)

N

F3Cxx

HO

Rf (pentaneethyl acetate 191) 018 1H NMR (300 MHz CDCl3) δ (ppm)742ndash750 (m 2H) 729ndash738 (m 2H) 722ndash728 (m 1H) 275ndash303 (m 2H)247ndash268 (m 2H) 239 (ddt J = 192 94 20 Hz 1H) 177ndash201 (m 2H) 148ndash172 (m 1H) 13C NMR (755 MHz CDCl3) δ (ppm) 1686 (Cq) 1393 (Cq)1287 (CH) 1274 (CH) 1272 (CH) 1264 (q J = 2785 Hz CF3) 503 (qJ = 17 Hz Cq) 436 (q J = 268 Hz CH2) 353 (q J = 15 Hz CH2) 257(CH2) 206 (q J = 07 Hz CH2)

19F NMR (300 MHz CDCl3) δ (ppm) minus6010

(t J = 112 Hz) GC-MS tR (50_40) 81 min EI-MS mz () 258 (14) 257(93) 241 (22) 240 (94) 225 (10) 215 (10) 212 (47) 200 (46) 199 (28) 188 (15)186 (23) 179 (12) 175 (12) 174 (95) 173 (35) 170 (10) 164 (13) 160 (14) 159(87) 158 (16) 157 (11) 156 (18) 151 (17) 147 (11) 146 (26) 143 (14) 141 (10)135 (18) 134 (10) 133 (21) 131 (10) 130 (25) 129 (41) 128 (47) 127 (22) 117(32) 116 (30) 115 (100) 109 (61) 104 (23) 103 (54) 102 (22) 101 (11) 91 (73)89 (15) 78 (27) 77 (63) 76 (12) 75 (11) 73 (12) 69 (12) 65 (17) 64 (11) 63(16) 54 (19) 52 (12) 51 (39) 50 (13) 41 (20) 39 (23) HR-MS (ESI) mzcalculated for [C13H14F3NONa]

+ ([M + Na]+) 2800920 measured 2800911 IR(ATR) ν (cmminus1) 3299 2995 1497 1457 1448 1426 1370 1295 1260 12401209 1160 1120 1083 1042 998 958 917 830 733 700 649

Synthesis of 2-Phenyl-2-(222-trifluoroethyl)cyclopentan-1-ol (182)

OH

F3C182 91 dr = 251

O

F3C143

NaBH4 (15 equiv)

MeOH 0 degC 45 min

Sodium borohydride (17 mg 045 mmol 15 equiv) was added to a solution of2-phenyl-2-(222-trifluoroethyl)cyclopentan-1-one (143 70 mg 029 mmol 10equiv) in methanol (2 mL) at 0 degC and the resulting reaction mixture was stirred atsame temperature for 45 min Water (2 mL) was then added to quench the reactionThe organic layer was extracted with ethyl acetate (3times15 mL) washed with brinedried over MgSO4 and concentrated under reduced pressure The crude reactionmixture was purified by flash column chromatography through silica gel (pentaneethyl acetate 191 to 173) to afford pure 2-phenyl-2-(222-trifluoroethyl)cyclopentan-1-ol (182 64 mg 026 mmol 91 dr = 251) as a colourless oil

2-Phenyl-2-(222-trifluoroethyl)cyclopentan-1-ol (182)

OH

F3C

Major diastereomer Rf (pentaneethyl acetate 41) 054 1H NMR(300 MHz CDCl3) δ (ppm) 743ndash756 (m 4H) 736ndash742 (m 1H) 424ndash430(m 1H) 268 (dqd J = 153 112 10 Hz 1H) 224ndash253 (m 3H) 206ndash222 (m2H) 189ndash203 (m 1H) 171ndash187 (m 1H) 152 (s 1H) 13C NMR (755 MHzCDCl3) δ (ppm) 1408 (Cq) 1320 (Cq) 1289 (CH) 1280 (CH) 1272 (CH)1265 (q J = 2788 Hz CF3) 798 (q J = 13 Hz CH) 528 (q J = 14 Hz Cq)413 (q J = 236 Hz CH2) 306 (CH2) 303 (q J = 16 Hz CH2) 200 (CH2)

19FNMR (300 MHz CDCl3) δ (ppm) minus5961 (t J = 109 Hz) GC-MS tR (50_40)76 min EI-MS mz () 245 (10) 244 (75) 226 (30) 211 (22) 200 (23) 198(10) 187 (11) 186 (26) 174 (35) 173 (63) 161 (10) 153 (12) 147 (15) 144 (10)143 (78) 133 (41) 129 (26) 128 (28) 127 (16) 118 (12) 117 (100) 116 (17) 115(65) 109 (58) 105 (17) 104 (11) 103 (52) 102 (12) 92 (11) 91 (78) 79 (12) 78

(27) 77 (44) 71 (33) 65 (11) 57 (32) 51 (21) 43 (17) 39 (15) HR-MS (ESI)mz calculated for [C13H15F3ONa]

Synthesis of 6-Phenyl-6-(222-trifluoroethyl)tetrahydro-2H-pyran-2-one (183)

O

F3CF3C

O

MMPP (33 equiv)

143183 81

Magnesium monoperoxyphthalate hexahydrate (MMPP 243 mg 0492 mmol330 equiv) was added to a solution of 2-phenyl-2-(222-trifluoroethyl)cyclopentan-1-one (143 36 mg 015 mmol 10 equiv) in DMFH2O(375 microL125 microL) and the resulting reaction mixture was stirred at 45 degC for 48 hAfter cooling to rt the reaction mixture was treated with saturated aqueousNa2S2O3 solution (2 mL) followed by saturated aqueous NaHCO3 (2 mL) Theorganic layer was extracted with ethyl acetate (3 times 10 mL) washed with brinedried over MgSO4 and concentrated under reduced pressure The crude reactionmixture was purified by flash column chromatography through silica gel (pentaneethyl acetate 91 to 41) to afford pure product (183 31 mg 012 mmol 81 ) as awhite solid

6-Phenyl-6-(222-trifluoroethyl)tetrahydro-2H-pyran-2-one (183)

O

F3C7

Rf (pentaneethyl acetate 41) 0151H NMR (300 MHz CDCl3) δ (ppm) 730ndash

744 (m 5H) 264ndash287 (m 2H) 232ndash257 (m 3H) 222 (td J = 138 13443 Hz 1H) 174ndash185 (m 1H) 147ndash163 (m 1H) 13C NMR (755 MHzCDCl3) δ (ppm) 1703 (Cq) 1414 (Cq) 1291 (CH) 1284 (CH) 1251 (CH)1268 (q J = 2787 Hz CF3) 836 (q J = 20 Hz Cq) 469 (q J = 274 Hz CH2)312 (q J = 15 Hz CH2) 290 (CH2) 161 (CH2)

19F NMR (300 MHz CDCl3) δ(ppm) minus5980 (t J = 105 Hz)GC-MS tR (50_40) 81 min EI-MSmz () 186(33) 176 (13) 175 (100) 147 (47) 117 (12) 115 (17) 111 (21) 105 (90) 103 (26)91 (16) 78 (13) 77 (52) 70 (44) 55 (24) 51 (23) 42 (65) 41 (10) 39 (14)HR-MS(ESI) mz calculated for [C13H13F3O2Na]

+ ([M + Na]+) 2810760 measured2810768 IR (ATR) ν (cmminus1) 2945 1733 1496 1448 1383 1354 1321 11221083 1047 1000 971 937 916 862 833 766 736 703 683 658 610

644 Mechanistic Investigations

6441 Intermediate Trapping Experiments

Radical Trapping Experiment

OH

S

CF3OTf

O

F3C

N

O CF3

TMSOTf (12 equiv)

DMF rt

Blue LEDs

139 (12 equiv) 143(not observed)

185(detected by GC-MS analysis)

N

O (24 equiv)

142 (10 equiv)

In a flame dried Schlenk tube equipped with a magnetic stirring bar 1-(1-phenylvinyl)cyclobutan-1-ol (142 174 mg 010 mmol 100 equiv) followedby trimethylsilyl trifluoromethanesulfonate (22 microL 012 mmol 12 equiv) wasdissolved in anhydrous DMF (1 mL) The reaction mixture was stirred for 2 h [Ru(bpy)3](PF6)2 (090 mg 0001 mmol 0010 equiv) 5-(trifluoromethyl)dibenzoth-iophenium trifluoromethanesulfonate (139 49 mg 012 mmol 12 equiv) and2266-tetramethyl-1-piperidinyloxyl (TEMPO 38 mg 024 mmol 24 equiv)were then added to the reaction tube and the mixture was allowed to stir for 10 hunder irradiation of visible light from 5 W blue LEDs (λmax = 465 nm situ-ated 5 cm away from the reaction vessel in a custom-made ldquolight boxrdquo seeFig 62) The product 2-phenyl-2-(222-trifluoroethyl)cyclopentan-1-one (143)was not observed by GC-MS analysis (applied method has been mentioned ingeneral information) but an adduct 185 between radical scavenger TEMPO radicaland trifluoromethyl radical was observed (see Fig 66)

Carbocation Trapping Experiment

OH

SCF3

OTf

O

F3C

MeOH rtBlue LEDs

139 (14 equiv) 143 78 145(detected by GC-MS analysis)

142 (10 equiv)

OH

CF3

OMe

In a heat gun dried Schlenk tube equipped with a magnetic stirring bar 1-(1-phenylvinyl)cyclobutan-1-ol (142 174 mg 010 mmol 100 equiv) followedby trimethylsilyl trifluoromethanesulfonate (22 microL 012 mmol 12 equiv) wasdissolved in anhydrous MeOH (1 mL) The reaction mixture was stirred for 2 h

[Ru(bpy)3](PF6)2 (18 mg 0002 mmol 0020 equiv) and 5-(trifluoromethyl)dibenzothiophenium trifluoromethane-sulfonate (139 57 mg 014 mmol 14equiv) were then added to the reaction tube The mixture was allowed to stir for 6 hunder irradiation of visible light from 5 W blue LEDs (λmax = 465 nm situ-ated 5 cm away from the reaction vessel in a custom-made ldquolight boxrdquo seeFig 62) The product 2-phenyl-2-(222-trifluoroethyl)cyclopentan-1-one (3aa)was obtained in 78 GC yield as major product along with the formation ofmethanol trapped adduct 145 (detected by GC-MS analysis applied method hasbeen mentioned in general information) (see Fig 67)

6442 Quantum Yield Measurement

Following a modified procedure reported by Melchiorre et al [41] an aq fer-rioxalate actinometer solution was prepared and stored in dark The actinometersolution measures the photodecomposition of ferric oxalate anions to ferrous

Fig 66 Radical inhibition experiment in presence of radical scavenger TEMPO an adduct (185tR = 573 min) between radical scavenger TEMPO radical and trifluoromethyl radical wasdetected in GC-MS analysis (above) and fragmentation pattern of the adduct (185 tR = 573 min)in mass spectrum was shown (below) Sahoo et al [56] Copyright Wiley-VCH Verlag GmbH ampCo KGaA Reproduced with permission

oxalate anions which are reacted with 110-phenanthroline to form FeethPhenTHORN32thornand estimated by monitoring UVVis absorbance at wavelength 510 nm Thenumbers of FeethPhenTHORN32thorn complex formed are related to the numbers of photonsabsorbed by the actinometer solution

Preparation of the solutions used for the studies

1 Potassium ferrioxalate solution Potassium ferrioxalte trihydrate (295 mg) and95ndash98 H2SO4 (140 microL) were added to a 50 mL volumetric flask and filled tothe mark with distilled water

2 Buffer solution Sodium acetate (494 g) and 95ndash98 H2SO4 (10 mL) wereadded to a 100 mL volumetric flask and filled to the mark with distilled water

3 The reaction solution 1-(1-phenylvinyl)cyclobutanol (142 87 mg 050 mmol10 equiv) Umemotorsquos reagent (139 241 mg 060 mmol 12 equiv) and [Ru(bpy)3](PF6)2 (43 mg 0005 mmol 001 equiv) were dissolved in 2 mL ofDMF in a 5 mL volumetric flask followed by addition of TMSOTf (108 microL060 mmol 12 equiv) Finally the flask was filled to the mark with DMF

Fig 67 Carbocation Trapping experiment an adduct (145 tR = 791 min) between methanoland intermediate C was detected in GC-MS analysis (above) and fragmentation pattern of theadduct (145 tR = 791 min) in mass spectrum was shown (below) Sahoo et al [56] CopyrightWiley-VCH Verlag GmbH amp Co KGaA Reproduced with permission

The actinometry measurements

(a) 1 mL of the actinometer solution was taken in a quartz cuvette (l = 1 cm)1 mL of the reaction solution was also taken in a quartz cuvette (l = 1 cm)Both the cuvettes of actinometer solution and reaction solution were placednext to each other at a distance of 5 cm away from a 5 W blue LED(λmax = 465 nm) and irradiated for 6 min The same process was repeated fordifferent time intervals 75 min 9 min and 105 min

(b) After irradiation the actinometer solution was transferred to a 10 mL volu-metric flask containing 10 mg of 110-phenanthroline in 2 ml of buffersolution The flask was filled to the mark with distilled water In a similarmanner a blank solution (10 mL) was also prepared using the actinometersolution stored in dark

(c) Absorbance of the actinometer solution after complexation with110-phenanthroline at λ = 510 nm was measured by UVVis spectropho-tometer (Fig 68)

(d) According to the Beerrsquos law the number of moles of Fe2+ formed (x) for eachsample was determined

Fe2thorn frac14 v1v3DA 510 nmeth THORN103v2le 510 nmeth THORN

v1 Irradiated volume (1 mL)v2 The aliquot of the irradiated solution taken for the estimation of

Fe+ ions (1 mL)v3 Final volume of the solution after complexation with

110-phenanthroline (10 mL)ε(510 nm) Molar extinction coefficient of FeethPhenTHORN32thorn complex

(11100 L molminus1 cmminus1)

Fig 68 Absorption spectraof actinometer solutions andblank solution

l Optical path-length of the cuvette (1 cm)ΔA(510 nm) Difference in absorbance between the irradiated solution and

the solution stored in dark (blank)

(e) The number of moles of Fe2+ formed (x) was plotted as a function of time(t) (Fig 69) The slope (dxdt) of the line is equal to the number of moles ofFe2+ formed per unit time

(f) This slope (dxdt) was correlated to the number of moles of incident photonsper unit time (F = photon flux) by using following equation

U keth THORN frac14dxdt

F 1 10A keth THORNeth THORN

Ф(λ) The quantum yield for Fe2+ formation which is 09 at 450 nm [41]A(λ) Absorbance of the ferrioxalate actinometer solution at a wavelength of

450 nm which was measured placing 1 mL of the solution in a cuvetteof pathlength 1 cm by UVVis spectrophotometer We obtained anabsorbance value of 0289

The determined incident photon per unit time (F) is 9145 times10minus9 einstein secminus1

(g) The number of moles of the product 143 formed was determined by GC(FID) analysis using mesitylene as internal standard reference The measuredabsorbance of the reaction solution at 450 nm by UVVis spectrophotometer isgreater than 3 Thus the number of moles of photons absorbed by reactionsample per unit time F times (1ndash10minusA(λ)) is roughly equal to the number ofmoles of incident photon per unit time (F) The number of moles of product143 formed was plotted against the number of moles of photon absorbed bythe reaction (Table 61 and Fig 610) The slope of the line is equal to thequantum yield of the reaction The calculated apparent quantum yield (Ф) ofthe reaction is 38

y = 4E -09

Rsup2 = 09816

0

00000005

0000001

00000015

0000002

00000025

0000003

-100 100 300 500 700

Mol

es o

f Fe(

II) f

orm

ed

Time (s)

x

Fig 69 Formation of Fe2+

upon photodecomposition offerrioxalate in different timeintervals Sahoo et al [56]Copyright Wiley-VCH VerlagGmbH amp Co KGaAReproduced with permission

65 Transition Metal Free Visible Light MediatedSynthesis of Polycyclic Indolizines

651 Synthesis of Substrates

6511 Synthesis of Bromopyridine Substrates

Synthesis of 2-bromo-5-phenylpyridine

N Br

I

N Br

BHO OH

Pd(PPh3)4 (1 mol) K2CO3 (29 equiv)

tolueneH2O (11) 120 degC 4 d

881 equiv1 equiv

Following a modified procedure from von Zelewsky et al [42] a mixture of2-bromo-5-iodopyridine (511 g 18 mmol) phenylboronic acid (219 g 18 mmol)Pd(PPh3)4 (208 mg 002 mmol) in toluene (72 mL) and K2CO3 (72 g 522 mmol)in water (72 mL) in a round bottomed flask equipped with a condenser was allowed

y = 38439xRsup2 = 09966

0

0000005

000001

0000015

000002

0000025

-1E-06 5E-21 0000001 2E-06 3E-06 4E-06 5E-06 6E-06

Mol

s of

pro

duct

Mols of absorbed photons

Fig 610 The plot of molesof product 143 formed againstmoles of photon absorbedSahoo et al [56] CopyrightWiley-VCH Verlag GmbH ampCo KGaA Reproduced withpermission

Table 61 The formation of the product 143 in different time intervals upon absorbing photons

Time interval (s) The amount of 143 formed (mol) The photon absorbed (mol)

0 0 0

360 118 times 10minus5 3292 times 10minus6

Sahoo et al [56] Copyright Wiley-VCH Verlag GmbH amp Co KGaA Reproduced withpermission

65 Transition Metal Free Visible Light Mediated Synthesis hellip 195

to heat at 120 degC for 4 d After cooling to rt the layers were separated and aqueouslayer was extracted with dichloromethane (3 times 15 mL) The combined organiclayers were washed with water until the pH was brought to 7 dried with MgSO4

and concentrated under reduced pressure The crude mixture was purified by flashcolumn chromatography through silica using pentaneethyl acetatetriethylamine(6501) to afford (372 g 158 mmol 88 ) as a white solid

Rf (pentaneethyl acetateNEt3 6501) 0691H NMR (400 MHz CDCl3) δ

(ppm) 859 (d J = 23 1H) 773 (dd J = 83 26 Hz 1H) 753ndash760 (m 3H)740ndash751 (m 3H) 13C NMR (101 MHz CDCl3) δ (ppm) 1486 1410 13711366 1362 1294 1287 1281 1271 GC-MS tR (50_40) 86 min EI-MSmz () 236 (12) 235 (93) 234 (12) 233 (93) 155 (14) 154 (100) 153 (21) 128(28) 127 (68) 126 (23) 77 (19) 63 (15) 51 (12) HR-MS (ESI) mz calculated for[C11H8BrNNa]

+ ([M + Na]+) 2559732 measured 2559719 IR (ATR) ν (cmminus1)3090 3057 3020 1575 1546 1439 1390 1364 1353 1318 1278 1228 11391082 1041 1027 994 946 914 831 756 653 635 615

Synthesis of tert-butyl 2-(pyridin-2-yl)acetate and benzyl 2-(pyridin-2-yl)acetate

NH

OH

O

Cl

N OtBu

O

N OBn

O

DMAP (5 mol) DCC (1 equiv)

NEt3 (2 equiv) tBuOH (15 equiv)CH2Cl2 45 degC 12 h

DMAP (10 mol) EDCHCl (15 equiv)

DIPEA (1 equiv) BnOH (4 equiv)CH2Cl2 rt 16 h

35

66

tert-Butyl 2-(pyridin-2-yl)acetate

N O

O

Following a modified procedure from Fuchs et al [43] triethyl amine (224 mL161 mmol) and 13-dicyclohexylcarbodiimide (DCC) (166 g 803 mmol) 4-(dimethylamino)pyridine (DMAP) (49 mg 040 mmol) were added to a suspensionof 2-pyridylacetic acid hydrochloride (139 g 803 mmol) and tert butanol(115 mL 121 mmol) in dichloromethane (40 mL) at rt The reaction mixture wasstirred overnight at 45 degC The reaction mixture was filtered to remove13-dicyclohexylurea The filtrate was washed with water (3 times 10 mL) dried withMgSO4 and concentrated under reduced pressure The crude product was purified

by flash column chromatography through silica gel (eluent = pentaneethyl acetate51 to 21) to afford (102 g 528 mmol 66 ) as a light yellow oil

Rf (pentaneethyl acetate 32) 048 1H NMR (300 MHz CDCl3) δ (ppm)854 (ddd J = 49 18 09 Hz 1H) 764 (td J = 76 18 Hz 1H) 722ndash733 (m1H) 716 (dt J = 75 49 12 Hz 1H) 375 (s 2H) 144 (s 9H) 13C NMR(755 MHz CDCl3) δ (ppm) 1701 1551 1494 1366 1240 1220 813 452282 GC-MS tR (50_40) 72 min EI-MS mz () 120 (31) 93 (26) 92 (38) 65(19) 57 (100) 41 (31) 39 (17) HR-MS (ESI) mz calculated for [C11H15NO2Na]

+

([M + Na]+) 2160995 measured 2161014 IR (ATR) ν (cmminus1) 2979 29331728 1592 1572 1475 1436 1393 1368 1339 1254 1141 1092 1050 996952 873 834 752 666 621

Benzyl 2-(pyridin-2-yl)acetate

N O

O

NN-diisopropyl ethyl amine (DIPEA) (087 mL 501 mmol)N-(3-dimethylaminopropyl)-Nrsquo-ethylcarbodiimide hydrochloride (EDCHCl)(142 g 752 mmol) and 4-(dimethylamino)pyridine (DMAP) (61 mg 05 mmol)were added to a suspension of 2-pyridylacetic acid hydrochloride (087 g501 mmol) and benzyl alcohol (207 mL 200 mmol) in dichloromethane(163 mL) The reaction mixture was allowed to stir at rt for 16 h The reactionmixture was diluted with ethyl acetate (10 mL) and extracted with 2 M HCl(3 times 10 mL) The combined aqueous layers were neutralized with solid NaHCO3

(63 g) and extracted with ethyl acetate (3 times 15 mL) The organic layers were driedover MgSO4 and concentrated under reduced pressure The crude mixture waspurified by flash column chromatography through silica gel (eluent = pentaneethylacetate 21) to afford (393 mg 173 mmol 35 ) as a light yellow oil

Rf (pentaneethyl acetate 32) 036 1H NMR (300 MHz CDCl3) δ (ppm)857 (d J = 44 Hz 1H) 767 (td J = 77 18 Hz 1H) 727ndash739 (m 6H) 721(ddd J = 75 49 11 Hz 1H) 517 (s 2H) 392 (s 2H) 13C NMR (755 MHzCDCl3) δ (ppm) 1706 1543 1494 1370 1358 1287 1284 1283 12421224 669 439 GC-MS tR (50_40) 88 min EI-MS mz () 93 (100) 92(21) 91 (68) 65 (23) HR-MS (ESI) mz calculated for [C14H13NO2Na]

+

([M + Na]+) 2500849 measured 2500837 IR (ATR) ν (cmminus1) 3065 30352955 1734 1592 1572 1498 1475 1456 1436 1378 1337 1258 1237 12131148 1091 1050 996 911 831 748 699 645 619 598

Synthesis of methyl esters of pyridyl-2-yl acetic acid

N Br

R

N

R

CO2Me

CO2MeN

R

CO2Me

CuI (5 minus 20 mol)2-picoIinic acid (20 minus 80 mol)

Cs2CO3 (3 equiv) 14-dioxane70 degC 24 minus 36 h

MeO2C CO2Me(2 equiv)

LiCl (1 equiv)

DMSO H2O (1 equiv)120 degC 5 h

General Procedure 10

Following a modified procedure from Kwong et al [44] a flame dried Schlenkflask equipped with a magnetic stir bar was charged with CuI (0050ndash020 equiv)2-picolinic acid (020ndash080 equiv) Cs2CO3 (30 equiv) and if solid the pyridyliodide (10 equiv) under argon Dry 14-dioxane followed dimethyl malonate (20equiv) and if liquid the pyridyl iodide (10 equiv) was added to the reactionvessel The Schlenk flask was sealed tightly and placed in a preheated oil bath at70 degC for 36 h After cooling to rt the reaction mixture was quenched with satd aqNH4Cl solution and extracted with ethyl acetate The combined organic layers weredried over MgSO4 filtered and concentrated under reduced pressure The crudereaction mixture was purified by flash column chromatography through silica gel(eluent = pentaneethyl acetate) to afford the pure dimethyl 2-(pyridin-2-yl)malonates

Dimethyl 2-(pyridin-2-yl)malonate (10 equiv) in DMSO was treated withlithium chloride (20ndash25 equiv) and water (10 equiv) The resulting mixture washeated at 120 degC for 5 h After cooling to rt the reaction mixture was quenchedwith brine and extracted with ethyl acetate The organic layers were dried overMgSO4 filtered and concentrated under reduced pressure The crude reactionmixture was purified by flash column chromatography through silica gel (elu-ent = pentaneethyl acetate) to afford the pure methyl 2-(pyridin-2-yl)acetates

Dimethyl 2-(5-fluoropyridin-2-yl)malonate

N O

O

OO

F

Prepared following GP10 on a 57 mmol scale from 2-bromo-5-fluoropyridine(10 g 57 mmol 10 equiv) CuI (163 mg 0856 mmol 15 mol) 2-picolinicacid (420 mg 341 mmol 0600 equiv) Cs2CO3 (551 g 169 mmol 300 equiv)and dimethyl malonate (130 mL 114 mmol 200 equiv) in 14-dioxane

(115 mL) Purification via flash column chromatography through silica gel (elu-ent = pentaneethyl acetate 91) afforded methyl 2-(5-fluoropyridin-2-yl)malonate(253 mg 111 mmol 20 ) as a greenish yellow oil

Rf (pentaneethyl acetate 41) 032 1H NMR (300 MHz CDCl3) δ (ppm)842 (dt J = 29 06 Hz 1H) 753 (ddd J = 87 44 07 Hz 1H) 744 (dddJ = 87 79 29 Hz 1H) 498 (s 1H) 379 (s 6H) 13C NMR (75 MHz CDCl3) δ(ppm) 1679 1593 (d J = 2571 Hz) 1488 (d J = 41 Hz) 1378 (dJ = 241 Hz) 1251 (d J = 46 Hz) 1239 (d J = 186 Hz) 595 (d J = 13 Hz)533 19F NMR (282 MHz CDCl3) minus12746 GC-MS tR (50_40) 75 minEI-MSmz () 281 (18) 227 (27) 196 (25) 195 (10) 169 (12) 168 (45) 152 (38)151 (11) 147 (12) 140 (100) 138 (10) 137 (47) 125 (58) 124 (27) 112 (18) 111(25) 110 (27) 109 (36) 97 (12) 96 (25) 82 (24) 81 (15) 73 (22) 59 (34) HR-MS(ESI) mz calculated for [C10H10FNO4Na]

Methyl 2-(5-fluoropyridin-2-yl)acetate

N O

OF

Prepared following GP11 on a 236 mmol scale from dimethyl 2-(5-fluoropyridin-2-yl)malonate (470 mg 236 mmol 100 equiv) lithium chloride(250 mg 590 mmol 250 equiv) and water (32 microL 24 mmol 10 equiv) inDMSO (42 mL) Purification via flash column chromatography through silica gel(eluent = pentaneethyl acetate 32) afforded methyl 2-(5-fluoropyridin-2-yl)ac-etate (162 mg 0958 mmol 41 ) as a pale yellow oil

Rf (pentaneethyl acetate 32) 048 1H NMR (300 MHz CDCl3) δ (ppm)841 (d J = 28 Hz 1H) 739 (td J = 83 28 Hz 1H) 731 (d J = 86 44 Hz1H) 385 (s 2H) 372 (s 3H) 333 (s 3H) 13C NMR (75 MHz CDCl3) δ(ppm) 1710 1588 (d J = 2555 Hz) 1503 1377 (d J = 239 Hz) 1250 (dJ = 43 Hz) 1238 (d J = 186 Hz) 524 429 19F NMR (282 MHz CDCl3)minus12916 GC-MS tR (50_40) 66 min EI-MS mz () 169 (27) 154 (20) 138(14) 137 (13) 124 (11) 111 (43) 110 (100) 84 (10) 83 (34) 59 (19) 57 (16)HR-MS (ESI) mz calculated for [C8H8FNO2Na]

+ ([M + Na]+) 1920431 mea-sured 1920432 IR (ATR) ν (cmminus1) 2956 1736 1587 1485 1437 1391 13421254 1226 1195 1160 1018 914 834 667 617 610

Methyl 2-(5-(trifluoromethyl)pyridin-2-yl)acetate

N O

OF3C

Prepared following GP10 on a 140 mmol scale from 2-bromo-5-(trifluoromethyl)pyridine (316 g 140 mmol 100 equiv) CuI (400 mg 210 mmol 15 mol)

2-picolinic acid (103 g 840 mmol 0600 equiv) Cs2CO3 (137 g 421 mmol300 equiv) and dimethyl malonate (32 mL 28 mmol 20 equiv) in 14-dioxane(14 mL) Purification via flash column chromatography through silica gel (elu-ent = pentaneethyl acetate 91) afforded an inseparable yellow mixture (38 g) ofdimethyl 2-(5-(trifluoromethyl)pyridin-2-yl)malonate (22 g 79 mmol 57 (NMR)) and dimethyl malonate (16 g 12 mmol) in the ratio of 115 Thismixture was used directly in the next step

Prepared following GP11 on a 705 mmol scale from dimethyl 2-(5-(tri-fluoromethyl)pyridin-2-yl)malonate (195 g 705 mmol 100 equiv) lithiumchloride (747 mg 176 mmol 250 equiv) and water (96 microL 71 mmol 10equiv) in DMSO (126 mL) Purification via flash column chromatography throughsilica gel (eluent = pentaneethyl acetate 31) afforded methyl 2-(5-(tri-fluoromethyl)pyridin-2-yl)acetate (473 mg 216 mmol 15 over two steps) as ayellow oil

Rf (pentaneethyl acetate 32) 055 1H NMR (400 MHz CDCl3) δ (ppm)883 (dt J = 20 10 Hz 1H) 788 ndash793 (m 1H) 746 (d J = 82 Hz 1H) 374(s 2H) 374 (s 3H) 13C NMR (101 MHz CDCl3) δ (ppm) 1702 1581 1463(q J = 39 Hz) 1339 (q J = 34 Hz) 1253 (q J = 332 Hz) 1238 1235 (qJ = 2725 Hz) 524 435 19F NMR (300 MHz CDCl3) minus6244 GC-MS tR(50_40) 65 min EI-MS mz () 219 (21) 204 (26) 200 (10) 188 (24) 187(12) 174 (11) 161 (53) 160 (100) 140 (20) 133 (15) 113 (15) 63 (11) 59 (35)HR-MS (ESI) mz calculated for [C9H8F3NO2Na]

+ ([M + Na]+) 2420399measured 2420407 IR (ATR) ν (cmminus1) 2958 2861 2341 1738 1610 15771438 1395 1327 1260 1246 1162 1126 1080 1048 1018 943 838 751 695661 629

Dimethyl 2-(5-methylpyridin-2-yl)malonate

N O

O

OO

Prepared following GP10 on a 500 mmol scale from 2-bromo-5-methylpyridine(860 mg 500 mmol 100 equiv) CuI (48 mg 025 mmol 5 mol) 2-picolinicacid (123 mg 100 mmol 20 mol) Cs2CO3 (489 g 150 mmol 300 equiv)and dimethyl malonate (114 mL 100 bmmol 200 equiv) in 14-dioxane(10 mL) Purification via flash column chromatography through silica gel (elu-ent = pentaneethyl acetate 21 to 11) afforded dimethyl 2-(5-methylpyridin-2-yl)malonate (225 mg 123 mmol 25 ) as a light yellow oil

Rf (pentaneethyl acetate 41) 013 1H NMR (400 MHz CDCl3) δ (ppm)839 (dt J = 24 09 Hz 1H) 752 (ddd J = 81 23 09 Hz 1H) 737 (ddJ = 80 09 Hz 1H) 494 (s 1H) 377 (s 6H) 233 (d J = 08 Hz 3H) 13CNMR (101 MHz CDCl3) δ (ppm) 1682 1500 1499 1376 1330 12335b99 531 183 GC-MS tR (50_40) 81 min EI-MS mz () 223 (38) 192

(27)191 (25) 165 (37) 164 (25) 148 (30) 137 (10) 136 (100) 134 (12) 133 (57)132 (10) 122 (34) 121 (33) 120 (22) 108 (14) 107 (30) 106 (21) 105 (10) 104(24) 93 (13) 92 (18) 79 (12) 78 (15) 77 (22) 65 (14) 59 (15) 51 (12) HR-MS(ESI) mz calculated for [C11H13NO4Na]

Methyl 2-(5-methylpyridin-2-yl)acetate

N O

O

Prepared following GP11 on a 2464 mmol scale from dimethyl 2-(5-methylpyridin-2-yl)malonate (550 mg 2464 mmol 100 equiv) lithium chlo-ride (261 mg 616 mmol 250 equiv) and water (33 microL 25 mmol 10 equiv) inDMSO (44 mL) Purification via flash column chromatography through silica gel(eluent = pentaneethyl acetate 21) afforded methyl 2-(5-methylpyridin-2-yl)ac-etate (126 mg 0763 mmol 31 ) as a light yellow oil

Rf (pentaneethyl acetate 21) 019 1H NMR (400 MHz CDCl3) δ (ppm)839 (d J = 22 Hz 1H) 751 (dd J = 79 18 Hz 1H) 722 (d J = 79 Hz 1H)386 (s 2H) 372 (s 3H) 333 (s 3H) 13C NMR (101 MHz CDCl3) δ (ppm)1712 1511 1493 1380 1321 1238 524 430 183 GC-MS tR (50_40)71 min EI-MS mz () 165 (39) 134 (12) 133 (17) 120 (10) 107 (83) 106(100) 79 (28) 78 (12) 77 (31) HR-MS (ESI) mz calculated for [C9H11NO2Na]

+

Dimethyl 2-(5-phenylpyridin-2-yl)malonate

N O

O

OO

Prepared following GP10 on a 64 mmol scale from 2-bromo-5-phenylpyridine(15 g 64 mmol 10b equiv) CuI (183 mg 0961 mmol 015 equiv) 2-picolinicacid (473 mg 385 mmol 0600 equiv) Cs2CO3 (630 g 192 mmol 300 equiv)and dimethyl malonate (147 mL 128 mmol 200 equiv) in 14-dioxane(65 mL) Purification via flash column chromatography through silica gel (elu-ent = pentaneethyl acetate 41) afforded dimethyl 2-(5-phenylpyridin-2-yl)malonate (104 g 365 mmol 57 ) as a pale yellow oil

Rf (pentaneethyl acetate 41) 019 1H NMR (400 MHz CDCl3) δ (ppm)879 (dd J = 24 08 Hz 1H) 781 (dd J = 82 24 Hz 1H) 757 (dt J = 8010 Hz 3H) 744ndash752 (m 2H) 737ndash744 (m 2H) 505 (s 1H) 381 (s 6H) 13CNMR (101 MHz CDCl3) δ (ppm) 1680 1515 1478 1373 1364 13561293 1284 1273 1238 599 532 GC-MS tR (50_40) 98 min EI-MS mz() 285 (100) 281 (31)254 (15) 253 (30) 253 (11) 209 (25) 207 (18) 198 (33)198 (56) 195 (68) 191 (12) 184 (12) 183 (13) 169 (13) 168 (15) 139 (16) 115(15) HR-MS (ESI) mz calculated for [C16H15NO4Na]

+ ([M + Na]+) 3080893measured 3080892 IR (AbTR) ν (cmminus1) 3060 2955 1736 1596 1581 15641475 1436 1374 1307 1267 1246 1200 1150 1029 1008 939 913 846 756735 699 622 599

Methyl 2-(5-phenylpyridin-2-yl)acetate

N O

O

Prepared following GP11 on a 592 mmol scale from dimethyl 2-(5-phenylpyridin-2-yl)malonate (169 g 592 mmol 100 equiv) lithium chloride(774 mg 183 mmol 300 equiv) and water (99 microL 73 mmol 12 equiv) inDMSO (13 mL) Purification via flash column chromatography through silica gel(eluent = pentaneethyl acetate 32) afforded methyl 2-(5-phenylpyridin-2-yl)ac-etate (607 mg 267 mmol 45 ) as a yellowish brown solid

Rf (pentaneethyl acetate 32) 039 1H NMR (300 MHz CDCl3) δ (ppm)879 (dd J = 24 09 Hz 1H) 786 (dd J = 80 2b4 Hz 1H) 754ndash760 (m 2H)743ndash752 (m 2H) 734ndash743 (m 2H) 391 (s 2H) 375 (s 3H) 13C NMR(755 MHz CDCl3) δ (ppm) 1712 1532 1480 1377 1354 1353 12921282 1272 1239 523 435 GC-MS tR (50_40) 90 min EI-MS mz () 227(59) 195 (20) 170 (14) 169 (100) 168 (76) 167 (26) 141 (32) 139 (14) 115(26) HR-MS (ESI) mz calculated for [C14H13NO2Na]

+ ([M + Na]+) 2500838measured 2500850 IR (ATR) ν (cmminus1) 3028 3012 2956 2928 1737 15961583 1563 1481 1450 1434 1404 1376 1345 1260 1221 1189 1147 10351003 898 839 775 755 721 695 647 610 576

Dimethyl 2-(4-chloropyridin-2-yl)malonate

N

Cl

O

OO

Prepared following GP10 on a 500 mmol scale from 2-bromo-4-chloropyridine(962 mg 500 mmol 100 equiv) CuI (48 mg 025 mmol 5 mol) 2-picolinic

acid (123 mg 100 mmol20 mol) Cs2CO3 (489 g 150 mmol 300 equiv) anddimethyl malonate (086 mL 75 mmol 15 equiv) in 14-dioxane (10 mL)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 173 to 32) afforded dimethyl 2-(4-chloropyridin-2-yl)malonate(430 mg 177 mmol 24 ) as a light yellow oil

Rf (pentaneethyl acetate 41) 023 1H NMR (600 MHz CDCl3) δ (ppm)847 (d J = 54 Hz 1H) 754 (d J = 18 Hz 1H) 729 (dd J = 54 20 Hz 1H)497 (s 1H) 380 (s 6H) 13C NMR (150 MHz CDCl3) δ (ppm) 1674 15431502 1452 1245 1239 599 533 GC-MS tR (50_40) 81 min EI-MS mz() 244 (11) 243 (31) 214 (19) 213 (12) 212 (60) 211 (19) 187 (13) 186 (13)185 (39) 184 (32) 180 (11) 170 (19) 168 (50) 158 (31) 156 (100) 155 (24) 154(23) 153 (67) 143 (25) 142 (30) 141 (58) 140 (33) 129 (10) 128 (31) 127 (35)126 (29) 125 (28) 114 (14) 113 (15) 112 (31) 99 (11) 93 (10) 91 (11) 90 (45)89 (11) 78 (18) 77 (12) 76 (15) 73 (11) 65 (15) 64 (13) 63 (60) 62 (27) 61(10) 59 (92) 51 (21) 50 (13) 39 (13) HR-MbS (ESI) mz calculated for[C10H10ClNO4Na]

+ ([M + Na]+) 2660191 measured 2660193 IR (ATR)ν (cmminus1) 3008 2956 2361 2341 1736 1621 1575 1558 1464 1435 13931312 1272 1234 1200 1151 1103 1026 992 939 913 835 702 629

Methyl 2-(4-chloropyridin-2-yl)acetate

N

Cl

O

Prepared following GP11 on a 171 mmol scale from dimethyl 2-(4-chloropyridin-2-yl)malonate (417 mg 171 mmol 100 equiv) lithium chloride(145 mg 342 mmol 200 equiv) and water (23 microLb 17 mmol 10 equiv) inDMSO (3 mL) Purification via flash column chromatography through silica gel(eluent = pentaneethyl acetate 31) afforded methyl 2-(4-chloropyridin-2-yl)ac-etate (122 mg 0657 mmol 38 ) as a yellow oil

Rf (pentaneethyl acetate 32) 039 1H NMR (400 MHz CDCl3) δ (ppm)845 (d J = 54 Hz 1H) 734 (d J = 19 Hz 1H) 723 (dd J = 54 19 Hz 1H)385 (s 2H) 373 (s 3H) 13C NMR (101 MHz CDCl3) δ (ppm) 1705 15581503 1450 1245 1229 525 434 GC-MS tR (50_40) 72 min EI-MS mz() 185 (23) 170 (12) 156 (11) 154 (34) 153 (16) 140 (11) 129 (26) 128 (38)127 (81) 126 (100) 99 (25) 91 (12) 90 (27) 73 (12) 64 (16) 63 (25) 59 (28) 51(10) HR-MS (ESI) mz calculated for [C10H8ClNO2Na]

+ ([M + Na]+) 2080136measured 2080137 IR (ATR) ν (cmminus1) 3055 3007 2954 1736 1576 15561468 1436 1395 1337 1293 1257 1239 1196 1159 1103 1010 936 905 882829 763 752 709 648 626

N O

O

OO

Prepared following GP10 on a 18 mmol scale from 2-bromo-4-methylpyridine(020 mL 18 mmol 10 equiv) CuI (17 mg 89 μmol 5 mol) 2-picolinic acid(44 mg 036 mmol 020 equiv) Cs2CO3 (176 g 540 mmol 300 equiv) anddimethyl malonate (041 mL 36 mmol 20 bequiv) in 14-dioxane (72 mL)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 73) afforded dimethyl 2-(4-methylpyridin-2-yl)malonate (191 mg0856 mmol 48 ) as a pale yellow oil

Rf (pentaneethyl acetate 41) 016 1H NMR (300 MHz CDCl3) δ (ppm)837 (dd J = 51 08 Hz 1H) 722ndash740 (m 1H) 703 (ddd J = 51 16 08 Hz1H) 490 (s 1H) 373 (s 6H) 232 (s 3H) 13C NMR (755 MHz CDCl3) δ(ppm) 1679 1525 1491 1482 1245 1242 600 530 211 GC-MS tR(50_40) 80 min EI-MS mz () 223 (39) 192 (45) 191 (29) 165 (62) 164(18) 148 (43) 137 (10) 136 (100) 134 (18) 133 (76) 122 (42) 121 (37) 120(24) 108 (18) 107 (40) 106 (23) 105 (10) 104 (24) 93 (15) 92 (26) 79 (13) 78(18) 77 (21) 65 (18) 59 (18) 52 (10) 51 (11) 39 (11) HR-MS (ESI) mzcalculated for [C11H13NO4Na]

N O

O

Prepared following GP11 on a 273 mmol scale from dimethyl 2-(4-methylpyridin-2-yl)malonate (610 mg 273 mmol 100 equiv) lithium chloride(290 mg 685 mmol 250 equiv) and water (37 microL 27 mmol 10 equiv) inDMSO (49 mL) Purification via flash column chromatography through silica gel(eluent = pentaneethyl acetate 21 to 11) afforded methyl 2-(4-methylpyridin-2-yl)acetate (200 mg 121 mmol 44 ) as a pale yellow oil

Rf (pentaneethyl acetate 32) 043 1H NMR (300 MHz CDCl3) δ (ppm)841 (d J = 82 08 Hz 1H) 710ndash716 (m 1H) 705 (dt J = 52 11 Hz 1H)385 (s 2H) 373 (s 3H) 236 (s 3H) 13C NMR (755 MHz CDCl3) δ (ppm)1712 1539 1488 1487 1251 1235 524 434 212 GC-MS tR (50_40)71 min EI-MS mz () 165 (26) 134 (19) 133 (16) 120 (11) 107 (100) 106(92) 79 (30) 78 (10) 77 (30) 39 (10) HR-MS (ESI) mz calculated for

[C9H11NO2Na]+ ([M + Na]+) 1880682 measured 1880687 IR (ATR) ν

(cmminus1) 2953 1735 1605 1562 1435 1337 1265 1247 1200 1154 1016 998918 829 652 620 601

Synthesis of methyl 2-(isoquinolin-1-yl)acetate

N NO

N

O

mCPBA (10 equiv)

CH2Cl2 rt 4 h

Ac2ODMF

0 degC - rt 15 h

O

25

59

(12 equiv)

Isoquinoline 2-oxide

NO

Following a modified procedure from Lakshman et al [45] meta-chloroperbenzoicacid (mCPBA 477 g 194 mmol 70 wt) was added portion wise to a stirredsolution of isoquinoline (228 mL 194 mmol) in chloroform (7 mL) at 0 degC Theresulting mixture was allowed to stir at rt for 4 h The reaction mixture was dilutedwith chloroform (8 mL) solid K2CO3 (101 g 774 mmol) was added and theresulting mixture was stirred for another 10 min After filtration to remove solidby-products the filtrate was dried over MgSO4 and concentrated under reducedpressure Purification by flash column chromatography through neutral alumina(eluent = dichloromethanemethanol 1000 to 501) afforded isoquinoline 2-oxide(166 g 114 mmol 59 ) as a white solid

Rf (on neutral alumina dichloromethanemethanol 501) 014 1H NMR(300 MHz CDCl3) δ (ppm) 874 (s 1H) 810 (dd J = 71 16 Hz 1H) 773ndash781(m 1H) 751ndash781 (m 5H) 13C NMR (755 MHz CDCl3) δ (ppm) 1368 13631296 1295 1292 1289 1267 1251 1244 GC-MS tR (50_40) 69 minEI-MSmz () 130 (11) 129 (100) 128 (19) 102 (29) 51 (10)HR-MS (ESI)mzcalculated for [C9H7NONa]

Methyl 2-(isoquinolin-1-yl)acetate

N

O

Following a modified procedure from Funakoshi et al [46] methyl acetoacetate(129 mL 120 mmol) was added to a solution of isoquinoline 2-oxide (145 g100 mmol) in acetic anhydride (227 mL)DMF (10 mL) in a NaClice (13) bathThe resulting mixture was stirred at the same temperature for 3 h and then at rt for12 h The reaction mixture was diluted with ethyl acetate (80 mL) and washed with10 aq Na2CO3 solution (2 times 50 mL) and brine (5 times 80 mL) The organic layerswere extracted with 10 HCl (5 times 30 mL) and the HCl layer was made alkalinewith 1 M NaOH solution (200 mL) The alkaline aqueous layers were finallyextracted with dichloromethane dried over MgSO4 and concentrated under reducedpressure Purification via flash column chromatography through silica gel (elu-ent = pentaneethyl acetate 41) followed by recrystallization (2times) from hexaneafforded Methyl 2-(isoquinolin-1-yl)acetate (510 mg 253 mmol 25 ) as a paleyellow semi-solid compound

Rf (pentaneethyl acetate 32) 030 1H NMR (400 MHz CDCl3) δ (ppm)848 (d J = 58 Hz 1H) 809 (dt J = 85 10 Hz 1H) 787 (dt J = 82 10 Hz1H) 771 (ddd J = 82 69 12 Hz 1H) 760ndash767 (m 2H) 439 (s 2H) 372 (s2H) 13C NMR (101 MHz CDCl3) δ (ppm) 1709 1545 1417 1366 13061279 1276 1275 1253 1208 525 419GC-MS tR (50_40) 84 min EI-MSmz () 201 (52) 170 (13) 169 (24) 158 (12) 144 (11) 143 (100) 142 (58) 140(14) 116 (15) 115 (91) 114 (10) 89 (11) HR-MS (ESI) mz calculated for[C12H11NO2Na]

+ ([M + Na]+) 2240682 measured 2240682 IR (ATR) ν (cmminus1)3066 3006 2955 2362 2339 1740 1706 1624 1588 1563 1501 1452 14351386 1330 1291 1260 1227 1210 1171 1088 1012 978 831 800 753 673

Synthesis of methyl 2-bromo-(5-bromopyridin-2-yl)acetate

N Cl

O2N

N

O2N

CO2Me

N

O2N

CO2Me

N

Br

CO2MeN

H2N

CO2Me

NaH (22 equiv) DMF

0 degC minus 70 degC 18 h

NaCl (2 equiv)

DMSOH2O120 degC 3 h

PdC (5) EtOH

HCOONH4 (5 equiv)80 degC 15 h

CuBr (2 equiv) aq HBr (48)

NaNO2 (13 equiv)0 degC minus RT 15 h

70 28

Br

Dimethyl 2-(5-nitropyridin-2-yl)malonate

N

O2N

O

OO

Dimethyl malonate (721 ml 631 mmol) was added dropwise to a suspension ofsodium hydride (267 g 667 mmol 60 wt in mineral oil) in dry DMF (26 ml)with vigorous stirring at 0 degC for 15 min The stirring was continued at 0 degC foranother 45 min To the stirred reaction mixture a solution of 2-chloro-5-nitropyridine (500 g 315 mmol) in dry DMF (52 ml) was added dropwise andthen the stirring was continued at 70 degC for 18 h After cooling to rt the reactionmixture was quenched with saturated aq NH4Cl solution Filtration followed bydrying under vacuum afforded dimethyl 2-(5-nitropyridin-2-yl)malonate (56 g22 mmol 70 ) as an orange solid

Rf (pentaneethyl acetate 32) 051 1H NMR (300 MHz CDCl3) δ (ppm)938 (dd J = 27 07 Hz 1H) 851 (dd J = 87 27 Hz 1H) 776 (dd J = 8607 Hz 1H) 510 (s 1H) 381 (s 6H) 13C NMR (755 MHz CDCl3) δ (ppm)1669 1587 1448 1439 1320 1245 601 536 GC-MS tR (50_40) 86 minEI-MS mz () 254 (28) 223 (70) 222 (15) 196 (18) 195 (100) 179 (50) 178(12) 168 (10) 167 (52) 165 (16) 164 (38) 153 (10) 152 (91) 151 (19) 149(15) 148 (24) 147 (12) 137 (12) 134 (14) 133 (21) 122 (10) 121 (74) 106 (16)105 (16) 104 (13) 93 (19) 92 (39) 91 (25) 90 (13) 79 (17) 78 (17) 77 (16) 64(12) 63 (46) 62 (17) 59 (94) 51 (15) 50 (12) 39 (11) HR-MS (ESI) mzcalculated for [C10H10N2O6Na]

+ ([M + Na]+) 2770431 measured 2770434 IR(ATR) ν (cmminus1) 3077 2958 2923 2854 2361 2341 1729 1663 1638 15991579 1522 1438 1378 1352 1329 1308 1278 1239 1201 1161 1119 10891038 1018 991 947 936 913 843 795 744 729 705 688 655 641 605

Methyl 2-(5-nitropyridin-2-yl)acetate

N

O2N

O

A solution of NaCl (253 g 433 mmol) in water (15 mL) was added to dimethyl 2-(5-nitropyridin-2-yl)malonate (550 g 216 mmol) in DMSO (15 mL) in around-bottomed flask equipped with a condenser The reaction mixture was heated at120 degC for 3 h After cooling to rt the mixture was diluted with water extracted withethyl acetate dried with MgSO4 and concentrated under reduced pressure The crudereaction mixture was purified by flash column chromatography through silica gelusing (eluent = pentaneethyl acetate 41) to afford methyl 2-(5-nitropyridin-2-yl)acetate (238 g 121 mmol 28 ) as a yellow oil

Rf (pentaneethyl acetate 32) 042 1H NMR (400 MHz CDCl3) δ (ppm)938 (d J = 26 1H) 846 (dd J = 85 26 Hz 1H) 754 (d J = 85 1H) 400 (s2H) 375 (s 3H) 13C NMR (101 MHz CDCl3) δ (ppm) 1699 1607 14501434 1318 1244 527 437 GC-MS tR (50_40) 79 min EI-MS mz () 196(56) 181 (71) 165 (63) 164 (23) 150 (13) 138 (84) 137 (62) 122 (37) 107 (10)106 (23) 94 (12) 93 (10) 92 (34) 91 (21) 90 (16) 80 (41) 79 (16) 78 (16) 77 (21)66 (30) 65 (27) 64 (75) 63 (67) 62 (14) 59 (100) 53 (12) 52 (30) 51 (24) 50(20) 39 (21) 38 (14) HR-MS (ESI) mz calculated for [C8H8N2O4Na]

+

([M + Na]+) 2190376 measured 2190378 IR (ATR) ν (cmminus1) 3102 3078

2962 2361 2340 1730 1600 1580 1508 1476 1434 1411 1362 1261 12371187 1169 1118 1022 991 944 903 865 848 827 725 684 630

Methyl 2-(5-aminopyridin-2-yl)acetate

N

H2N

O

A suspension of methyl 2-(5-nitropyridin-2-yl)acetate (117 g 596 mmol) inethanol (55 ml) was added to 5 PdC (235 mg) in ethanol (37 mL) Ammoniumformate (188 g 298 mmol) was added to the heterogeneous reaction mixture andrefluxed under argon for 15 h The reaction mixture was filtered through Celite andthe solvents were removed under reduced pressure The residue was purified byflash column chromatography through silica gel (eluent = dichloromethanemethanol 241) to afford methyl 2-(5-aminopyridin-2-yl)acetate (798 mg476 mmol 80 ) as a pale yellow oil

Rf (dichloromethanemethanol 191) 019 1H NMR (300 MHz CDCl3) δ(ppm) 805 (dd J = 28 08 Hz 1H) 714ndash703 (m 1H) 698 (dd J = 8328 Hz 1H) 375 (s 2H) 370 (s 3H) 324 (s 2H broad) 13C NMR (755 MHzCDCl3) δ (ppm) 1717 1437 1416 1366 1242 1229 523 426 GC-MS tR(50_40) 80 min EI-MS mz () 166 (38) 108 (14) 107 (100) 80 (21) HR-MS(ESI) mz calculated for [C8H10N2O2Na]

+ ([M + Na]+) 1890634 measured1890635 IR (ATR) ν (cmminus1) 3436 3341 3213 2954 2361 2340 1728 16291602 1575 1493 1436 1340 1297 1267 1247 1197 1161 1016 902 838 735697 647 609

Methyl 2-bromo-(5-bromopyridin-2-yl)acetate

N

Br

O

Br

Following a modified procedure reported from Morgentin et al [47] NaNO2

(117 mg 170 mmol) was added portionwise to a solution of methyl 2-(5-aminopyridin-2-yl)acetate (218 mg 131 mmol) and CuBr (375 mg 261 mmol)in 48 aq HBr (6 mL) at 0 degC and the mixture was stirred at rt for 15 h AqNaOH solution (1 N) was added to adjust the pH to 5 The reaction mixture wasextracted with ethyl acetate (3 times 10 mL) The combined organic phases were driedover MgSO4 filtered and concentrated under reduced pressure The crude mixturewas purified by flash column chromatography through silica gel (eluent = pentaneethyl acetate 191) to afford methyl 2-bromo-(5-bromopyridin-2-yl)acetate (47 mg015 mmol 12 ) as a white solid upon cooling

Rf (pentaneethyl acetate 41) 053 1H NMR (300 MHz CDCl3) δ (ppm)860 (dd J = 24 08 Hz 1H) 788 (dd J = 84 23 Hz 1H) 762 (dd J = 8407 Hz 1H) 548 (s 1H) 382 (s 3H) 13C NMR (755 MHz CDCl3) δ (ppm)

1680 1539 1504 1401 1252 1211 538 464 GC-MS tR (50_40) 83 minEI-MS mz () 311 (13)309 (25) 307 (14) 252 (29) 250 (59) 248 (31) 231(14) 230 (100) 229 (14) 228 (99) 202 (67) 200 (75) 199 (10) 197 (11) 186(16) 184 (16) 173 (17) 172 (19) 171 (29) 170 (18) 169 (14) 145 (13) 143 (17)93 (22) 91 (11) 90 (54) 64 (13) 63 (51) 62 (20) 59 (26) 50 (12) 39 (10)HR-MS (ESI) mz calculated for [C8H7Br2NO2Na] + ([M + Na] +) 3298736measured 3298722 IR (ATR) ν (cmminus1) 3009 2980 2955 1747 1575 15581459 1438 1371 1324 1278 1249 1220 1172 1149 1135 1092 1001 973920 903 865 844 775 704 628

Bromination of 2-pyridine acetic acid esters to form brominated pyridines

N

R1

CO2R2CNN

R1

CO2R2CN

AIBN (5 mol) NBS (11 equiv)

PhCF3 rt 6 h23 W CFL

Br (10 equiv)

In an oven dried round bottomed flask equipped with a magnetic stir bar N-bromosuccinimide (NBS 11 equiv) and azobisisobutyronitrile (AIBN 5 mol)were added to a solution of the pyridine substrate (10 equiv) inααα-trifluorotoluene The reaction mixture was allowed to stir at rt for 6 h underirradiation of visible light from a household 23 W CFL The solvent was removedunder reduced pressure and the crude reaction mixture was purified by flash columnchromatography through silica gel (eluent = pentaneethyl acetate 91) to afford thepure brominated pyridines

Methyl 2-bromo-2-(pyridin-2-yl)acetate

N

Br

O

Prepared following GP12 on a 106 mmol scale from methyl 2-(pyridin-2-yl)ac-etate (160 g 106 mmol 100 equiv) N-bromosuccinimide (NBS 208 g116 mmol 110 equiv) and azobisisobutyronitrile (AIBN 80 mg 049 mmol5 mol) in ααα-trifluorotoluene (16 mL 066 M) Purification via flash columnchromatography through silica gel (eluent = pentaneethyl acetate 91) affordedMethyl 2-bromo-2-(pyridin-2-yl)acetate (169 g 735 mmol 70 ) as a yellow oil

Rf (pentaneethyl acetate 41) 029 1H NMR (400 MHz CDCl3) δ (ppm)855 (ddd J = 49 18 10 Hz 1H) 775 (td J = 77 18 Hz 1H)

769 (dt J = 80 12 Hz 1H) 721ndash732 (m 1H) 553 (s 1H) 381 (s 3H)13C NMR (101 MHz CDCl3) δ (ppm) 1683 1554 1494 1375 1238 1238537 474 GC-MS tR (50_40) 75 min EI-MS mz () 231 (13) 229 (14) 172(42) 170 (43) 151 (10) 150 (100) 122 (46) 120 (11) 119 (23) 106 (17) 122 (46)94 (15) 93 (19) 92 (14) 91 (47) 79 (10) 78 (17) 65 (21) 64 (26) 63 (34) 62 (12)51 (11) HR-MS (ESI) mz calculated for [C8H8BrNO2Na]

+ ([M + Na]+)2519631 measured 2519623 IR (ATR) ν (cmminus1) 3056 3009 2955 17421589 1573 1469 1435 1332 1281 1253 1228 1191 1146 1093 1051 999903 862 748 706 616

Ethyl 2-bromo-2-(pyridin-2-yl)acetate

N

Br

O

Prepared following GP12 on a 302 mmol scale from ethyl 2-(pyridin-2-yl)acetate(500 mg 302 mmol 100 equiv) N-bromosuccinimide (NBS 592 g 333 mmol110 equiv) and azobisisobutyronitrile (AIBN 30 mg 018 mmol 5 mol) inααα-trifluorotoluene (60 mL 050 M) Purification via flash column chromatog-raphy through silica gel (eluent = pentaneethyl acetate 91) afforded ethyl2-bromo-2-(pyridin-2-yl)acetate (615 mg 252 mmol 83 ) as a yellow oil

Rf (pentaneethyl acetate 31) 048 1H NMR (300 MHz CDCl3) δ (ppm)849 (ddd J = 49 18 10 Hz 1H) 762ndash772 (m 2H) 719 (ddd J = 71 4916 Hz 1H) 547 (s 1H) 415ndash 426 (m 2H) 122(t J = 71 Hz 3H) 13C NMR(755 MHz CDCl3) δ (ppm) 1676 1553 1492 1372 1236 1236 627 477131 GC-MS tR (50_40) 77 min EI-MS mz () 243 (14) 200 (12) 198 (11)191 (53) 173 (59) 172 (100) 171 (65) 170 (100) 164 (40) 120 (55) 119 (35)108 (31) 93 (15) 92 (53) 91 (57) 90 (10) 80 (10) 78 (13) 65 (36) 64 (37) 63(40) 62 (13) 51 (11) HR-MS (ESI) mz calculated for [C9H10BrNO2Na]

+

tert-Butyl 2-bromo-2-(pyridin-2-yl)acetate

N

Br

O

Prepared following GP12 on a 31 mmol scale from tert-butyl 2-(pyridin-2-yl)acetate (060 g 31 mmol 10 equiv) N-bromosuccinimide (608 mg 342 mmol110 equiv) and azobisisobutyronitrile (AIBN 26 mg 016 mmol 5 mol) inααα-trifluorotoluene (5 mL 06 M) Purification via flash column chromatographythrough silica gel (eluent = pentaneethyl acetate 91) afforded tert-butyl

2-bromo-2-(pyridin-2-yl)acetate (071 g 26 mmol 94 ) as a light greenish yel-low solid

Rf (pentaneethyl acetate 41) 043 1H NMR (300 MHz CDCl3) δ (ppm)853 (ddd J = 49 18 10 Hz 1H) 778ndash763 (m 2H) 761ndash779 (m 2H) 723(ddd J = 71 49 15 Hz 1H) 541 (s 1H) 146 (s 9H) 13C NMR (755 MHzCDCl3) δ (ppm) 1666 1559 1492 1372 1237 1235 835 491 279GC-MS tR (50_40) 79 min EI-MS mz () 173 (12) 171 (12) 91 (10) 57(100) 41 (22) HR-MS (ESI) mz calculated for [C11H14BrNO2Na]

+ ([M + Na]+)2940100 measured 2940099 IR (ATR) ν (cmminus1) 3003 2978 2936 28801741 1586 1574 1472 1459 1438 1394 1370 1331 1283 1283 1258 11571133 1093 1049 995 954 871 843 761 748 670 614

Benzyl 2-bromo-2-(pyridin-2-yl)acetate

N

Br

O

Prepared following GP12 on a 083 mmol scale from benzyl 2-(pyridin-2-yl)acetate(230 mg 0830 mmol 100 equiv) N-bromosuccinimide (NBS 163 mg0916 mmol 110 equiv) and azobisisobutyronitrile (AIBN 68 mg 004 mmol005 equiv) in ααα-trifluorotoluene (16 mL 052 M) Purification via flash col-umn chromatography through silica gel (eluent = pentaneethyl acetate 91)afforded benzyl 2-bromo-2-(pyridin-2-yl)acetate (250 mg 0817 mmol 98 ) as alight yellow oil

Rf (pentaneethyl acetate 41) 033 1H NMR (300 MHz CDCl3) δ (ppm)855 (ddd J = 49 18 10 Hz 1H) 774 (td J = 76 18 Hz 1H) 719 (dtJ = 80 12 Hz 1H) 731ndash738 (m 5H) 727 (td J = 49 14 Hz 1H) 559 (s1H) 525 (d J = 38 Hz 2H) 13C NMR (75 MHz CDCl3) δ (ppm) 16761553 1492 1376 1351 1287 1286 1283 1239 1238 684 474 GC-MStR (50_40) 94 min EI-MS mz () 120 (93) 93 (13) 92 (20) 91 (100) 65 (20)HR-MS (ESI) mz calculated for [C14H12BrNO2Na]

+ ([M + Na]+) 3279944measured 3279940 IR (ATR) ν (cmminus1) 3063 3034 3010 2959 1743 15891574 1498 1468 1457 1436 1377 1329 1258 1225 1141 1093 1050 996972 972 908 746 699 631

2-Bromo-2-(pyridin-2-yl)acetonitrile

N

Br

N

Prepared following GP12 on a 423 mmol scale from 2-(pyridin-2-yl)acetonitrile(500 mg 423 mmol 100 equiv) N-bromosuccinimide (NBS 829 mg466 mmol 110 equiv) and azobisisobutyronitrile (AIBN 35 mg 021 mmol5 mol) in ααα-trifluorotoluene (60 mL 070 M) Purification via flash column

chromatography through silica gel (eluent = pentaneethyl acetate 91) afforded2-bromo-2-(pyridin-2-yl)acetonitrile (811 mg 412 mmol 97 ) as a pink solid

Rf (pentaneethyl acetate 31) 035 1H NMR (300 MHz CDCl3) δ (ppm)863ndash865 (m 1H) 782 (td J = 77 18 1H) 767 (dt J = 79 10 1H) 735(ddd J = 76 49 11 Hz 1H) 558 (s 1H) 13C NMR (755 MHz CDCl3) δ(ppm) 1525 (Cq) 1503 (CH) 1381 (CH) 1247 (CH) 1224 (CH) 1158 (Cq)289(CH) GC-MS tR (50_40) 72 min EI-MS mz () 118 (21) 117 (100) 90(28) 78 (11) 63 (12) HR-MS (ESI) mz calculated for [C7H5BrN2Na]

+

Methyl 2-bromo-2-(5-fluoropyridin-2-yl)acetate

N

Br

O

OF

Prepared followingGP12 on a 076 mmol scale frommethyl 2-(5-fluoropyridin-2-yl)acetate (162 mg 0958 mmol 100 equiv) N-bromosuccinimide (NBS 174 mg0975 mmol 110 equiv) and azobisisobutyronitrile (AIBN 73 mg 004 mmol5 mol) in ααα-trifluorotoluene (18 mL 042 M) Purification via flash columnchromatography through silica gel (eluent = pentaneethyl acetate 91) affordedmethyl 2-bromo-2-(5-fluoropyridin-2-yl)acetate (206 mg 0830 mmol 87 ) as alight yellow oil

Rf (pentaneethyl acetate 41) 045 1H NMR (300 MHz CDCl3) δ (ppm)833 (d J = 29 Hz 1H) 770 (ddd J = 88 43 06 Hz 1H) 741 (ddd J = 8779 29 Hz 1H) 550 (s 1H) 376 (s 3H) 13C NMR (755 MHz CDCl3) δ(ppm) 1680 (d J = 08 Hz) 1590 (d J = 2586 Hz) 1512 (d J = 40 Hz) 1374(d J = 243 Hz) 1251 (d J = 49 Hz) 1241 (d J = 189 Hz) 536 462 (dJ = 17 Hz) 19F NMR (282 MHz CDCl3) minus12596 GC-MS tR (50_40)73 min EI-MS mz () 190 (33) 188 (33) 169 (11) 168 (100) 140 (52) 137(20) 124 (16) 111 (12) 110 (14) 109 (38) 96 (10) 83 (14) 82 (22) 81 (17) 59(14) HR-MS (ESI) mz calculated for [C8H7BrFNO2Na]

Methyl 2-bromo-2-(5-(trifluoromethyl)pyridin-2-yl)acetate

N

Br

O

OF3C

Prepared following GP12 on a 080 mmol scale from methyl 2-(5-(trifluoromethyl)pyridin-2-yl)acetate (176 mg 0803 mmol 100 equiv) N-bromosuccinimide(NBS 157 mg 0882 mmol 110 equiv) and azobisisobutyronitrile (AIBN66 mg 40 μmol 5 mol) in ααα-trifluorotoluene (16 mL 050 M) Purificationvia flash column chromatography through silica gel (eluent = pentaneethyl acetate91) afforded methyl 2-bromo-2-(5-(trifluoromethyl)pyridin-2-yl)acetate (151 mg0507 mmol 63 ) as a pale yellow oil

Rf (pentaneethyl acetate 41) 0611H NMR (300 MHz CDCl3) δ (ppm)866ndash890 (m 1H) 794ndash805 (m 1H) 786 (dt J = 83 08 Hz 1H) 556 (s 1H)383 (s 3H) 13C NMR (755 MHz CDCl3) δ (ppm) 1678 1591 1462 (qJ = 40 Hz) 1347 (q J = 34 Hz) 1267 (q J = 333 Hz) 1238 1232 (qJ = 2726 Hz) 539 462 19F NMR (282 MHz CDCl3) minus6256 GC-MS tR(50_40) 72 min EI-MS mz () 240 (28) 238 (29) 219 (14) 218 (100) 190(16) 187 (19) 174 (36) 161 (12) 160 (17) 159 (22) 139 (10) 132 (10) 63(15)59 (28) HR-MS (ESI) mz calculated for [C9H7BrF3NO2Na]

+ ([M + Na]+)3199504 measured 3199499 IR (ATR) ν (cmminus1) 2959 1747 1606 15791438 1396 1329 1296 1257 1131 1080 1017 1027 631

Methyl 2-bromo-2-(5-methylpyridin-2-yl)acetate

N

Br

O

Prepared following GP12 on a 076 mmol scale from methyl 2-(5-methylpyridin-2-yl)acetate (125 mg 0757 mmol 100 equiv) N-bromosucci-nimide (NBS 148 mg 0830 mmol 110 equiv) and azobisisobutyronitrile (AIBN62 mg 38 μmol 5 mol) in ααα-trifluorotoluene (15 mL 05 M) Purificationvia flash column chromatography through silica gel (eluent = pentaneethyl acetate91) afforded methyl 2-bromo-2-(5-methylpyridin-2-yl)acetate (149 mg0610 mmol 80 ) as a yellow oil

Rf (pentaneethyl acetate 41) 033 1H NMR (400 MHz CDCl3) δ (ppm)838 (dt J = 19 08 Hz 1H) 737ndash777 (m 2H) 555 (s 1H) 381 (s 3H) 235(s 1H) 13C NMR (101 MHz CDCl3) δ (ppm) 1684 1524 1494 1383 1234537 470 184 GC-MS tR (50_40) 109 min EI-MS mz () 245 (11) 243(11) 186 (31) 184 (32) 165 (14) 164 (100) 136 (96) 134 (10) 133 (16) 120(11) 108 (10) 107 (29) 106 (23) 105 (13) 104 (31) 92 (13) 79 (26) 78 (32) 77(43) 65 (14) 59 (13) 52 (17) 51 (25) 50 (13) 39 (19) HR-MS (ESI) mzcalculated for [C9H11BrNO2Na]

Methyl 2-bromo-2-(5-phenylpyridin-2-yl)acetate

N

Br

O

Prepared following GP12 on a 0801 mmol scale from methyl 2-(5-phenylpyridin-2-yl)acetate (182 mg 0801 mmol 100 equiv) N-bromosucci-nimide (NBS 157 mg 0882 mmol 110 equiv) and azobisisobutyronitrile (AIBN66 mg 40 μmol 5 mol) in ααα-trifluorotoluene (16 mL 050 M) Purificationvia column chromatography through silica gel (eluent = pentaneethyl acetate 91)afforded methyl 2-bromo-2-(5-phenylpyridin-2-yl)acetate (209 mg 0701 mmol88 ) as a pale yellow solid

Rf (pentaneethyl acetate 41) 042 1H NMR (300 MHz CDCl3) δ (ppm)877 (dd J = 24 08 Hz 1H) 793 (dd J = 81 24 Hz 1H) 776 (dd J = 8208 Hz 1H) 754ndash761 (m 2H) 737ndash752 (m 3H) 560 (s 1H) 384 (s 3H) 13CNMR (755 MHz CDCl3) δ (ppm) 1683 1539 1477 1370 1368 13581293 1286 1273 1237 537 472 GC-MS tR (50_40) 97 min EI-MS mz() 307 (10) 305 (10) 248 (10) 246 (11) 227 (21) 226 (70) 199 (15) 198 (100)169 (29) 168 (19) 167 (21) 166 (20) 141 (15) 140 (14) 139 (27) 115 (13)HR-MS (ESI) mz calculated for [C14H12BrNO2Na]

+ ([M + Na]+) 3279944measured 3279934 IR (ATR) ν (cmminus1) 3009 2978 2956 2361 2340 17471588 1564 1473 1450 1435 1375 1349 1327 1306 1279 1249 1220 11851170 1141 997 897 871 851 749 727 701 691 661 626 613

Methyl 2-bromo-2-(4-chloropyridin-2-yl)acetate

N

Cl

Br

O

Prepared following GP12 on a 0620 mmol scale from methyl 2-(4-chloropyridin-2-yl)acetate (115 mg 0620 mmol 100 equiv) N-bromosucci-nimide (NBS 121 mg 0680 mmol 110 equiv) and azobisisobutyronitrile (AIBN51 mg 31 μmol 5 mol) in ααα-trifluorotoluene (12 mL 05 M) Purificationvia column chromatography through silica gel (eluent = pentaneethyl acetate 91)afforded methyl 2-bromo-2-(4-chloropyridin-2-yl)acetate (108 mg 0408 mmol66 ) as a white solid

Rf (pentaneethyl acetate 41) 045 1H NMR (300 MHz CDCl3) δ (ppm)844 (dd J = 53 06 Hz 1H) 772 (dd J = 19 06 Hz 1H) 727 (dd J = 5319 Hz 1H) 548 (s 1H) 382 (s 3H) 13C NMR (755 MHz CDCl3) δ (ppm)1679 1568 1501 1464 1243 1242 538 464 GC-MS tR (50_40) 79 minEI-MS mz () 206 (36) 204 (26) 186 (33) 185 (12) 184 (100) 156 (24) 153

(16) 140 (25) 128 (11) 127 (20) 126 (14) 125 (20) 112 (10) 99 (12) 90 (21) 63(30) 62 (15) 59 (23) HR-MS (ESI) mz calculated for [C8H7BrClNO2Na]

+

N

Br

O

Prepared following GP12 on a 100 mmol scale from methyl 2-(4-methylpyridin-2-yl)acetate (165 mg 100 mmol 100 equiv) N-bromosuccini-mide (NBS 196 mg 110 mmol 110 equiv) and azobisisobutyronitrile (AIBN82 mg 50 μmol 5 mol) in ααα-trifluorotoluene (20 mL 050 M) Purificationvia flash column chromatography through silica gel (eluent = pentaneethyl acetate91) afforded methyl 2-bromo-2-(4-methylpyridin-2-yl)acetate (185 mg0758 mmol 76 ) as a light yellow solid

Rf (pentaneethyl acetate 41) 0421H NMR (300 MHz CDCl3) δ (ppm)840 (d J = 51 08 Hz 1H) 750 (dt J = 16 08 Hz 1H) 707 (ddd J = 5116 08 Hz 1H) 551 (s 1H) 381 (s 3H) 238 (s 3H) 13C NMR (75 MHzCDCl3) δ (ppm) 1684 1550 1490 1490 1248 1245 537 475 213GC-MS tR (50_40) 78 min EI-MS mz () 245 (10) 243 (10) 186 (33) 184(33) 165 (13) 164 (100) 149 (14) 136 (65) 134 (24) 133 (14) 120 (16) 108 (10)107 (23) 106 (16) 105 (12) 104 (25) 92 (13) 79 (19) 78 (23) 77 (26) 65 (10) 52(10) 51 (12) 39 (10) HR-MS (ESI) mz calculated for [C9H10BrNO2Na]

+

Methyl 2-bromo-2-(isoquinolin-1-yl)acetate

N

Br

O

Prepared following GP12 on a 112 mmol scale from methyl 2-(isoquinolin-1-yl)acetate (223 mg 112 mmol 100 equiv) N-bromosuccinimide (NBS 213 mg122 mmol 110 equiv) and azobisisobutyronitrile (92 mg 56 μmol 5 mol) inααα-trifluorotoluene (20 mL 056 M) Purification via column chromatographythrough silica gel (eluent = pentaneethyl acetate 91) afforded methyl 2-bromo-2-(isoquinolin-1-yl)acetate (177 mg 063 mmol 56 ) as a light yellow solid

Rf (pentaneethyl acetate 41) 030 1H NMR (400 MHz CDCl3) δ (ppm)848 (d J = 56 Hz 1H) 821 (dq J = 80 09 Hz 1H) 780ndash796 (m 1H) 752ndash776 (m 3H) 631 (s 1H) 385 (s 3H) 13C NMR (101 MHz CDCl3) δ (ppm)1677 1548 1420 1370 1307 1280 1278 1259 1247 1221 539 471GC-MS tR (50_40) 91 min EI-MS mz () 281 (24) 279 (26) 222 (13) 220(13) 201 (14) 200 (57) 173 (12) 172 (100) 170 (13) 169 (17) 144 (17) 143 (35)142 (15) 141 (29) 140 (42) 129 (10) 128 (12) 115 (29) 114 (27) 113 (17)HR-MS (ESI) mz calculated for [C12H10BrNO2Na]

+ ([M + Na]+) 3019787measured 3019784 IR (ATR) ν (cmminus1) 3056 3014 2996 2963 2950 17411624 1585 1562 1500 1438 1386 1353 1297 1272 1213 1192 1166 11371083 1044 1023 995 966 907 882 830 798 752 723 667 643 579

6512 Synthesis of Enol Carbamate Substrates

O

R1

R2

O

R1

R2

O

NR3

R3

i) NaH (60 wt 11 equiv) DMSO rt 1 h

ii) rt 16 h

Cl NR32

O

(11 equiv)

Following a modified procedure from Feringa et al [48] sodium hydride (60 wtin mineral oil 11 equiv) was added to anhydrous DMSO (05 M) and the sus-pension was stirred at 50 degC for 2 h under an argon atmosphere The mixture wascooled to rt a solution of the ketone (10 equiv) in anhydrous DMSO (20 M) wasadded dropwise over 15 min and stirring was continued at rt for an additional 1 hThe dialkyl carbamyl chloride (11 equiv) was then added dropwise over 15 minand the mixture was stirred for 16 h at rt Water was added to quench the reactionand the mixture was then extracted with ethyl acetate (2 times 15 mL) The combinedorganic fractions were washed with brine dried over anhydrous Na2SO4 filteredand concentrated under reduced pressure The crude products were purified bycolumn chromatography through silica gel to afford the pure enol carbamates

34-Dihydronaphthalen-1-yl dimethylcarbamate [49]

O

N

Prepared following GP13 on a 250 mmol scale from 1-tetralone (366 g250 mmol 100 equiv) NaH (60 wt in mineral oil 120 g 300 mmol 120equiv) and dimethylcarbamoyl chloride (277 mL 300 mmol 120 equiv)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 41) afforded 34-dihydronaphthalen-1-yl dimethylcarbamate (281 g129 mmol 52 ) as a pink solid

Rf (pentaneethyl acetate 21) 038 1H NMR (300 MHz CDCl3) δ (ppm)709ndash720 (m 4H) 571 (t J = 47 Hz 1H) 313 (s 3H) 300 (s 3H) 286 (tJ = 81 Hz 2H) 244 (ddd J = 90 74 47 Hz 2H) 13C NMR (755 MHzCDCl3) δ (ppm) 1549 1461 1366 1313 1278 1276 1265 1208 1152368 365 277 222 GC-MS tR (50_40) 88 min EI-MS mz () 217 (21)115 (11) 72 (100) HR-MS (ESI) mz calculated for [C13H15NO2Na]

+

34-Dihydronaphthalen-1-yl diethylcarbamate

O

N

Prepared following GP13 on a 500 mmol scale from 1-tetralone (731 mg500 mmol 100 equiv) NaH (60 wt in mineral oil 220 mg 550 mmol 110equiv) and diethylcarbamoyl chloride (697 μL 550 mmol 110 equiv)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 91) afforded 34-dihydronaphthalen-1-yl diethylcarbamate (992 mg404 mmol 81 ) as a colorless oil

Rf (pentaneethyl acetate 91) 022 1H NMR (400 MHz CDCl3) δ (ppm)707ndash721 (m 4H) 573 (t J = 47 Hz 1H) 347 (q J = 71 Hz 2H) 338 (qJ = 71 Hz 2H) 287 (t J = 81 Hz 2H) 244 (ddd J = 91 75 47 Hz 2H)129 (t J = 71 Hz 3H) 120 (t J = 72 Hz 3H) 13C NMR (101 MHz CDCl3) δ(ppm) 1541 1461 1365 1314 1277 1275 1264 1207 1150 422 419276 222 144 134 GC-MS tR (50_40) 91 min EI-MS mz () 245 (16)128 (7) 127 (5) 117 (5) 115 (16) 101 (6) 100 (100) 91 (6) 72 (47) 44 (8)HR-MS (ESI) mz calculated for [C15H19NO2Na]

+ ([M + Na]+) 2681308 mea-sured 2681308 IR (ATR) ν (cmminus1) 2936 2832 1714 1658 1488 1473 14581419 1379 1361 1337 1316 1270 1230 1223 1184 1154 1131 1078 1019957 936 917 856 782 758 735 631

34-Dihydronaphthalen-1-yl pyrrolidine-1-carboxylate

O

N

Prepared following GP13 on a 500 mmol scale from 1-tetralone (731 mg500 mmol 100 equiv) NaH (60 wt in mineral oil 220 mg 550 mmol 110equiv) and 1-pyrrolidine carbamyl chloride (608 μL 550 mmol 110 equiv)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 41) afforded 34-dihydronaphthalen-1-yl pyrrolidine-1-carboxylate(104 g 427 mmol 85 ) as a white solid

Rf (pentaneethyl acetate 41) 020 1H NMR (300 MHz CDCl3) δ (ppm)709ndash722 (m 4H) 575 (t J = 47 Hz 1H) 359 (d J = 66 Hz 2H) 346 (tJ = 66 Hz 2H) 286 (t J = 81 Hz 2H) 208 (ddd J = 90 74 47 Hz 2H)182ndash204 (m 4H) 13C NMR (755 MHz CDCl3) δ (ppm) 1531 1458 13651314 1277 1274 1264 1208 1150 465 464 276 259 250 222GC-MS tR (50_40) 98 min EI-MS mz () 243 (12) 128 (6) 115 (14) 99 (6)98 (100) 91 (5) 56 (18) 55 (48) HR-MS (ESI) mz calculated for[C15H17NO2Na]

+ ([M + Na]+) 2661151 measured 2661151 IR (ATR) ν(cmminus1) 2939 2879 1710 1676 1659 1487 1464 1442 1427 1401 1357 13321323 1277 1230 1220 1181 1126 1094 1050 1033 1021 1012 966 913 873848 769 752 747 704 658 608

34-Dihydronaphthalen-1-yl morpholine-4-carboxylate

O

N

O

Prepared following GP13 on a 500 mmol scale from 1-tetralone (731 mg500 mmol 100 equiv) NaH (60 wt in mineral oil 220 mg 550 mmol 110equiv) and 4-morpholine carbonyl chloride (643 μL 550 mmol 110 equiv)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 21) afforded 34-dihydronaphthalen-1-yl morpholine-4-carboxylate(119 g 459 mmol 92 ) as a white solid

Rf (pentaneethyl acetate 21) 033 1H NMR (300 MHz CDCl3) δ (ppm)712ndash722 (m 3H) 709 (m 1H) 573 (t J = 47 Hz 1H) 363 minus 381 (m 6H)356 (br s 2H) 287 (t J = 81 Hz 2H) 245 (ddd J = 90 75 47 Hz 2H) 13CNMR (101 MHz CDCl3) δ (ppm) 1537 1459 1366 1311 1280 12771265 1206 1155 668 668 450 443 276 222 GC-MS tR (50_40)98 min EI-MS mz () 193 (9) 115 (32) 114 (100) 91 (14) 70 (77) 45 (10)42 (21) 40 (7) HR-MS (ESI) mz calculated for [C15H17NO3Na]

+ ([M + Na]+)

2821101 measured 2821107 IR (ATR) ν (cmminus1) 3024 2979 2965 29132890 2848 2926 1708 1657 1485 1452 1422 1370 1358 1333 1296 12771241 1220 1178 1159 1133 1114 1086 1067 1049 1033 982 942 914 887865 840 789 761 756 738 723 677 641

Cyclohex-1-en-1-yl dimethylcarbamate [49]

O O

N

Prepared following GP13 on a 250 mmol scale from cyclohexanone (245 g250 mmol 100 equiv) NaH (60 wt in mineral oil 120 g 300 mmol 120equiv) and dimethylcarbamyl chloride (277 mL 300 mmol 120 equiv)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 61) afforded cyclohex-1-en-1-yl dimethylcarbamate (121 g715 mmol 29 ) as a colorless oil

Rf (pentaneethyl acetate 21) 045 1H NMR (300 MHz CDCl3) δ (ppm)532ndash535 (m 1H) 292 (s 3H) 291 (s 3H) 205ndash216 (m 4H) 167ndash175 (m2H) 152ndash160 (m 2H) 13C NMR (755 MHz CDCl3) δ (ppm) 1551 14881136 365 364 273 238 228 219 GC-MS tR (50_40) 72 min EI-MS mz() 169 (13) 72 (100) HR-MS (ESI) mz calculated for [C9H15NO2Na]

+

34-Dihydronaphthalen-1-yl methyl carbonate

O O

O

Prepared following a modified procedure from Stoltz et al [50] 1-Tetralone(439 mg 300 mmol 100 equiv) was added dropwise over 15 min to a solution oflithium hexamethyldisilazide (LiHMDS 552 mg 330 mmol 110 equiv) in THF(70 mL) at 0 degC The mixture was stirred for an additional 15 h at 0 degC beforebeing added dropwise to a solution of methyl chloroformate (278 μL 360 mmol12 equiv) in THF (170 mL) at minus78 degC over 15 min The mixture was allowed towarm to rt and stirred for 16 h before being quenched by pouring into a mixture ofdichloromethane (20 mL) water (10 mL) and sat aq NH4Cl solution (10 mL) Thecrude product was extracted into dichloromethane (2 times 20 mL) washed with brine

(40 mL) dried over anhydrous MgSO4 filtered and concentrated under reducedpressure Purification via flash column chromatography (eluent = pentaneethylacetate 982 to 973) afforded 34-Dihydronaphthalen-1-yl methyl carbonate(310 mg 152 mmol 51 ) as a colorless viscous oil

713ndash721 (m 4H) 581 (t J = 47 Hz 1H) 388 (s 3H) 287 (t J = 81 Hz 2H)245 (ddd J = 89 75 47 Hz 2H) 13C NMR (755 MHz CDCl3) δ (ppm)1543 1463 1365 1303 1282 1277 1266 1208 1152 555 275 221GC-MS tR (50_40) 81 min EI-MS mz () 205 (11) 204 (86) 159 (38) 146(11) 145 (94) 144 (29) 129 (148) 128 (72) 127 (18) 117 (54) 116 (24) 115(100) 105 (11) 91 (31) 90 (12) 89 (17) 63 (10) 59 (14) HR-MS (ESI) mzcalculated for [C12H12O3Na]

652 Photocatalytic Synthesis of Indolizines

O O

NR4R4

N

Br

CO2R2CNN

CO2R2CN

Blue LEDs (465 nm)

(10 equiv) (50 equiv)

R1

R3

In a flame dried screw capped Schlenk tube equipped with a magnetic stir barthe enol carbamate (50 equiv) was dissolved in ααα-trifluorotoluene (010 M)and then the 2-bromopyridine substrate (10 equiv) and hexamethyldisilazane (10equiv) were added via syringe The resulting mixture was degassed using threefreeze-pump-thaw cycles and the tube was finally backfilled with argon Thereaction mixture was allowed to stir at rt for 12 h under irradiation of visible lightfrom 5 W blue LEDs (λmax = 465 nm) The solvent was removed under reducedpressure and the crude reaction mixture was purified by flash column chromatog-raphy through silica gel to afford the pure indolizine products 195 205ndash222

Methyl 56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (195)

N

OO

Prepared following GP14 on a 030 mmol scale from methyl 2-bromo-2-(pyridin-2-yl)acetate (69 mg 030 mmol 10 equiv) 34-dihydronaphthalen-1-yldimethylcarbamate (324 mg 150 mmol 500 equiv) and hexamethyldisilazane(63 μL 030 mmol 10 equiv) in ααα-trifluorotoluene (30 mL 010 M)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 201) afforded 195 (52 mg 019 mmol 63 ) as a white solidUnreacted enol carbamate (262 mg 121 mmol 402 equiv) was also recovered

Rf (pentaneethyl acetate 91) 027 1H NMR (600 MHz CDCl3) δ (ppm)869 (dt J = 70 11 Hz 1H) 832 (dt J = 90 12 Hz 1H) 774 (d J = 77 Hz1H) 735 (dd J = 73 08 Hz 1H) 732 (d J = 77 15 Hz 1H) 717 (td J = 7412 Hz 1H) 708 (ddd J = 90 67 11 Hz 1H) 683 (td J = 68 14 Hz 1H)393 (s 3H) 320ndash324 (m 2H) 292 (t J = 73 Hz 2H) 13C NMR (150 MHzCDCl3) δ (ppm) 1660 (Cq) 1375 (Cq) 1367 (Cq) 1311 (Cq) 1288 (CH) 1287(Cq) 1267 (CH) 1258 (CH) 1240 (CH) 1226 (Cq) 1221 (CH) 1204 (CH)1193 (CH) 1132 (CH) 1015 (Cq) 509 (CH3) 302 (CH2) 224 (CH2) GC-MStR (50_40) 120 min EI-MS mz () 278 (19) 277 (100) 276 (13) 246 (13)244 (30) 218 (24) 217 (54) 216 (23) 215 (12) 189 (10) 109 (20) 108 (10)HR-MS (ESI) mz calculated for [C18H15NO2]

+ ([M]+) 2771103 measured2771093 calculated for [C18H15NO2Na]

+ ([M + Na]+) 3000995 measured3000994 IR (ATR) ν (cmminus1) 3055 3012 2945 2902 2843 1681 1632 16001507 1488 1457 1434 1395 1357 1321 1283 1234 1203 1146 1124 11081069 1026 914 822 778 750 740 710 688 660 646 621

Ethyl 56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (205)

N

OO

Prepared following GP14 on a 030 mmol scale from ethyl 2-bromo-2-(pyridin-2-yl)acetate (73 mg 030 mmol 10 equiv) 34-dihydronaphthalen-1-yldimethylcarbamate (324 mg 150 mmol 500 equiv) and hexamethyldisilazane(63 μL 030 mmol 10 equiv) in ααα-trifluorotoluene (30 mL 010 M)Purification via flask column chromatography through silica gel (eluent = pentane

ethyl acetate 201) afforded 205 (53 mg 018 mmol 61 ) as a pale yellow oilwhich solidified upon cooling Unreacted enol carbamate (260 mg 120 mmol399 equiv) was also recovered

Rf (pentaneethyl acetate 91) 045 1H NMR (300 MHz CDCl3) δ (ppm)867 (d J = 69 Hz 1H) 833 (dt J = 90 12 Hz 1H) 773 (d J = 79 Hz 1H)732 (td J = 74 14 Hz 2H) 717 (td J = 74 11 Hz 1H) 707 (ddd J = 9067 10 Hz 1H) 681 (td J = 69 14 Hz 1H) 441 (q J = 71 Hz 2H) 324 (ddJ = 82 64 Hz 2H) 292 (t J = 73 Hz 2H) 145 (t J = 71 Hz 3H) 13C NMR(755 MHz CDCl3) δ (ppm) 1655 (Cq) 1374 (Cq) 1366 (Cq) 1311 (Cq) 1288(CH) 1287 (Cq) 1267 (CH) 1257 (CH) 1239 (CH)1225 (Cq) 1219 (CH)1204 (CH) 1193 (CH) 1130 (CH) 1017 (CH2) 595 (CH2) 302 (CH2) 223(CH2) 148 (CH3) GC-MS tR (50_40)113 min EI-MS mz () 292 (21) 291(100) 263 (25) 262 (21) 246 (12) 244 (25) 219 (10) 218 (36) 217 (58) 216(21) 215 (11) 92109 (18) HR-MS (ESI) mz calculated for [C19H17NO2Na]

+

([M + Na]+) 3141151 measured 3141152 IR (ATR) ν (cmminus1) 3056 29802927 2905 1677 1631 1599 1509 1479 1453 1408 1384 1357 1322 12831232 1201 1147 1124 1108 1071 1031 985 949 837 823 778 751 742 722717 687 656 650 624

tert-Butyl 56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (206)

N

OO

Prepared following GP14 on a 030 mmol scale from tert-Butyl 2-bromo-2-(pyridin-2-yl)acetate (82 mg 030 mmol 10 equiv) 34-dihydronaphthalen-1-yldimethylcarbamate (324 mg 150 mmol 500 equiv) and hexamethyldisilazane(63 μL 030 mmol 10 equiv) in ααα-trifluorotoluene (30 mL 010 M)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 201) afforded 206 (43 mg 013 mmol 45 ) as a yellow oilUnreacted enol carbamate (274 mg 126 mmol 420 equiv) was also recovered

Rf (pentaneethyl acetate 91) 047 1H NMR (300 MHz CDCl3) δ (ppm)867 (dt J = 71 11 Hz 1H) 831 (dt J = 90 13 Hz 1H) 772ndash775 (m 1H)728ndash736 (m 2H) 716 (td J = 75 12 Hz 1H) 705 (ddd J = 91 67 11 Hz1H) 679 (td J = 69 15 Hz 1H) 323 (dd J = 82 64 Hz 2H) 292 (tJ = 73 Hz 1H) 167 (s 9H) 13C NMR (755 MHz CDCl3) δ (ppm) 1650 (Cq)1372 (Cq) 1366 (Cq) 1311 (Cq) 1288 (CH) 1267 (CH) 1256 (CH) 1238(CH) 1223 (Cq) 1216 (CH) 1203 (CH) 1192 (CH) 1129 (CH) 1031 (Cq)799 (Cq) 303 (CH2) 289 (CH3) 223 (CH2) GC-MS tR (50_40) 98 min

EI-MS mz () 220 (12) 219 (100) 218 (70) 217 (41) 207 (11) HR-MS (ESI)mz calculated for [C21H21NO2Na]

+ ([M + Na]+) 3421465 measured 3421464IR (ATR) ν (cmminus1) 3059 2974 2932 2893 2838 2360 2340 1678 1631 16021530 1505 1488 1453 1440 1399 1365 1322 1281 1243 1223 1203 11681155 1122 1107 1069 1016 988 947 880 837 784 755 732 702 687 659638 622

Benzyl 56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (207)

N

OO

Prepared following GP14 on a 020 mmol scale from benzyl 2-bromo-2-(pyridin-2-yl)acetate (61 mg 020 mmol 10 equiv) 34-dihydronaphthalen-1-yldimethylcarbamate (217 mg 100 mmol 500 equiv) and hexamethyldisilazane(42 μL 020 mmol 10 equiv) in ααα-trifluorotoluene (20 mL 010 M)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 201) afforded 207 (34 mg 96 micromol 48 ) as a light yellow oilUnreacted enol carbamate (180 mg 829 micromol 414 equiv) was also recovered

Rf (pentaneethyl acetate 91) 054 1H NMR (300 MHz C6D6) δ (ppm)868 (dt J = 90 13 Hz 1H) 818 (dd J = 71 12 Hz 1H) 734ndash749 (m 3H)718ndash727 (m 5H) 706ndash715 (m 1H) 669 (ddd J = 90 67 10 Hz 1H) 626(td J = 69 14 Hz 1H) 547 (s 2H) 337 (dd J = 81 66 Hz 2H) 273 (tJ = 73 Hz 2H) 13C NMR (75 MHz C6D6) δ (ppm) 1648 (Cq) 1379 (Cq)1378 (Cq) 1377 (Cq) 1313 (Cq) 1289 (Cq) 1289 (CH) 1287 (CH) 1284(CH) 1267 (CH) 1258 (CH) 1238 (CH) 1227 (Cq) 1218 (CH) 1206 (CH)1195 (CH) 1129 (CH) 1021 (Cq) 654 (CH2) 303 (CH2) 228 (CH2) [Note onepeak at δ (ppm) = 1280 (CH) overlaps with the benzene carbon peak but isobserved in the DEPT spectrum] GC-MS tR (50_40) 150 min EI-MS mz ()354 (27) 353 (100) 263 (10) 262 (43) 246 (13) 244 (29) 219 (28) 218 (72) 217(100) 216 (29) 215 (12) 203 (10) 190 (10) 189 (11) 116 (15) 91 (47) 73 (10)65 (15) HR-MS (ESI) mz calculated for [C24H19NO2]

+ ([M]+) 3531410 mea-sured 3531439 mz calculated for [C24H19NO2Na]

+ ([M + Na]+) 3761308measured 3761302 IR (ATR) ν (cmminus1) 3032 2941 2890 2834 1736 16831631 1602 1504 1454 1439 1403 1368 1322 1280 1228 1202 1184 11591123 1107 1066 1019 780 755 739 697 631

56-Dihydrobenzo[g]pyrido[12-a]indole-7-carbonitrile (208)

N

Prepared following GP14 on a 030 mmol scale from 2-bromo-2-(pyridin-2-yl)acetonitrile (59 mg 030 mmol 10 equiv) 34-dihydronaphthalen-1-yl diethyl-carbamate (368 mg 150 mmol 500 equiv) and hexamethyldisilazane (63 μL030 mmol 10 equiv) in ααα-trifluorotoluene (30 mL 010 M) Purification viaflash column chromatography through silica gel (eluent = pentaneethyl acetate201) afforded 208 (12 mg 49 micromol 16 ) as a white solid Unreacted enol car-bamate (280 mg 114 mmol 380 equiv) was also recovered

Rf (pentaneethyl acetate 91) 024 1H NMR (400 MHz CDCl3) δ (ppm)867 (dt J = 71 11 Hz 1H) 760ndash778 (m 2H) 730ndash740 (m 2H) 720 (tdJ = 75 12 Hz 1H) 709 (ddd J = 89 67 10 Hz 1H) 687 (td J = 6914 Hz 1H) 290ndash303 (m 4H) 13C NMR (101 MHz CDCl3) δ (ppm) 1386(Cq) 1363 (Cq) 1310 (Cq) 1292 (CH) 1281 (Cq) 1270 (CH) 1265 (CH)1245 (CH) 1223 (Cq) 1220 (CH) 1196 (CH) 1182 (CH) 1164 (Cq) 1137(CH) 818 (Cq) 299 (CH2) 217 (CH2) GC-MS tR (50_40) 116 min EI-MSmz () 245 (17) 244 (100) 243 (50) 242 (39) HR-MS (EI) mz calculated for[C17H12N2Na]

+ ([M + Na]+) 2670893 measured 2670891 IR (ATR) ν (cmminus1)2209 1511 1487 1438 1396 1207 1144 1023 744 721 687

Methyl 3-methoxy-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (209)

N

OO

O

Prepared following GP14 on a 030 mmol scale from methyl 2-bromo-2-(pyridin-2-yl)acetate (69 mg 030 mmol 10 equiv) 6-methoxy-34-dihydronaphthalen-1-yl dimethylcarbamate (371 mg 150 mmol 500 equiv) andhexamethyldisilazane (63 μL 030 mmol 10 equiv) in ααα-trifluorotoluene(30 mL 010 M) Purification via flash column chromatography through silica gel(eluent = pentaneethyl acetate 201 to 51) afforded 209 (62 mg 020 mmol67 ) as a pale yellow solid Unreacted enol carbamate (298 mg 121 mmol 402equiv) was also recovered

861 (dt J = 71 Hz 1H) 829 (dd J = 91 12 Hz 1H) 766 (d J = 85 Hz 1H)704 (ddd J = 90 67 10 Hz 1H) 694 (d J = 26 Hz 1H) 676ndash688 (m 2H)392 (s 3H) 385 (s 3H) 321 (dd J = 82 64 Hz 2H) 290 (dd J = 83 62 Hz2H) 13C NMR (755 MHz CDCl3) δ (ppm) 1660 (Cq) 1576 (Cq) 1388 (Cq)1369 (Cq) 1294 (Cq) 1236 (CH) 1225 (Cq) 1218 (Cq) 1215 (CH) 1205(CH) 1203 (CH) 1152 (CH) 1130 (CH) 1112 (CH) 1012 (Cq) 554 (CH3)508 (CH3) 307 (CH2) 223 (CH2) GC-MS tR (50_40) 144 min EI-MS mz() 308 (20) 307 (100) 293 (10) 292 (55) 276 (7) 274 (5) 253 (5) 249 (6) 232(12) 205 (8) 204 (29) 203 (11) 177 (8) 137 (5) 135 (6) 102 (8) 75 (5) 73 (12)59 (6) HR-MS (ESI) mz calculated for [C19H17NO3]

+ ([M + Na]+) 3301101measured 3301098 IR (ATR) ν (cmminus1) 3079 3056 3013 2977 2945 29022840 1680 1632 1600 1506 1490 1457 1434 1395 1355 1321 1282 12321201 1192 1100 1145 1123 1108 1068 1025 1006 968 821 778 748 740722 710 687 660 644 622

Methyl 10-bromo-3-methoxy-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (218)

N

OO

O

Br

Prepared following GP14 on a 020 mmol scale from methyl 2-bromo-2-(5-bromopyridin-2-yl)acetate (62 mg 020 mmol 10 equiv)6-methoxy-34-dihydronaphthalen-1-yl dimethylcarbamate (247 mg 100 mmol500 equiv) and hexamethyldisilazane (42 μL 020 mmol 10 equiv) inααα-trifluorotoluene (20 mL 010 M) Purification via flash column chromatog-raphy through silica gel (eluent = pentaneethyl acetate 201) afforded 218 (57 mg015 mmol 74 ) as a yellow solid Unreacted enol carbamate (203 mg821 micromol 410 equiv) was also recovered

Rf (pentaneethyl acetate 91) 036 1H NMR (400 MHz C6D6) δ (ppm)831ndash834 (m 1H) 830 (dd J = 95 08 Hz 1H) 814 (d J = 85 Hz 1H) 679(d J = 27 Hz 1H) 672 (dd J = 95 16 Hz 1H) 650 (dd J = 85 27 Hz 1H)365 (s 3H) 338 (s 3H) 310ndash331 (m 2H) 264 (t J = 73 Hz 2H) 13C NMR(101 MHz C6D6) δ (ppm) 1652 (Cq) 1584 (Cq) 1390 (Cq) 1350 (Cq) 1298(Cq) 1237 (CH) 1235 (CH) 1232 (Cq) 1214 (Cq) 1211 (CH) 1210 (CH)1155 (CH) 1115 (CH) 1081 (Cq) 1032 (Cq) 549 (CH3) 505 (CH3) 306(CH2) 227 (CH2) GC-MS tR (50_40) 134 min EI-MS mz () 388 (21) 387(95) 386 (22) 385 (100) 373 (10) 372 (45) 371 (11) 370 (44) 354 (11) 312

(11) 310 (10) 284 (13) 204 (17) 203 (21) 202 (19) 177 (10) 176 (12) 102 (13)101 (12) HR-MS (ESI) mz calculated for [C19H16Br

79NO3]+ ([M]+) 3850308

measured 3850309 mz calculated for [C19H16Br79NO3Na]

+ ([M + Na]+)4080206 measured 4080209 IR (ATR) ν (cmminus1) 3009 2944 2906 28341694 1616 1577 1520 1437 14141391 1332 1312 1298 1281 1265 12531235 1167 1125 1076 1057 1045 984 966 917 896 874 813 792 765 730717 702 685 648 590

Methyl 10-fluoro-3-methoxy-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (219)

N

OO

O

F

Prepared following GP14 on a 020 mmol scale from methyl 2-bromo-2-(5-fluoropyridin-2-yl)acetate (50 mg 020 mmol 10 equiv)6-methoxy-34-dihydronaphthalen-1-yl dimethylcarbamate (247 mg 100 mmol500 equiv) and hexamethyldisilazane (42 μL 020 mmol 10 equiv) inααα-trifluorotoluene (20 mL 010 M) Purification via flash column chromatog-raphy through silica gel (eluent = pentaneethyl acetate 201) afforded 219 (36 mg011 mmol 55 ) as a yellowish brown solid Unreacted enol carbamate (198 mg801 micromol 401 equiv) was also recovered

Rf (pentaneethyl acetate 91) 025 1H NMR (300 MHz C6D6) δ (ppm)838 (ddd J = 98 61 07 Hz 1H) 807 (ddd J = 58 24 07 Hz 1H) 712 (dJ = 85 Hz 1H) 679 (d J = 26 Hz 1H) 662 (dd J = 85 27 Hz 1H) 651(ddd J = 99 77 21 Hz 1H) 366 (s 3H) 339 (s 3H) 323ndash328 (m 2H) 264(t J = 73 Hz 2H) 13C NMR (755 MHz C6D6) δ (ppm) 1652 (Cq) 1583 (Cq)1543 (d J = 2350 Hz Cq) 1389 (Cq) 1344 (Cq) 1302 (d J = 2350 Hz Cq)1237 (d J = 18 Hz Cq) 1215 (Cq) 1211 (d J = 2350 Hz CH) 1208 (CH)1153 (CH) 1122 (d J = 246 Hz CH) 1117 (CH) 1102 (d J = 4130 Hz CH)1030 (Cq) 549 (CH3) 505 (CH3) 307 (CH2) 228 (CH2)

19F NMR (282 MHzCDCl3) minus13974 GC-MS tR (50_40) 134 min EI-MS mz () 326 (21) 325(100) 311 (10) 310 (51) 250 (13) 222 (26) HR-MS (ESI) mz calculated for[C19H16FNO3]

+ ([M]+) 3251114 measured 3251110 mz calculated for[C19H16FNO3Na]

+ ([M + Na]+) 3481006 measured 3481006 IR (ATR) ν(cmminus1) 3090 2990 2954 2939 2909 2835 1697 1646 1601 1580 1534 149814701437 1425 1397 1351 1334 1306 1287 1248 1202 1186 1153 11081071 1036 996 947 942 898 862 847 791 742 719 696 650 614

Methyl 3-methoxy-10-(trifluoromethyl)-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (220)

N

OO

O

F3C

Prepared following GP14 on a 020 mmol scale from methyl 2-bromo-2-(5-(tri-fluoromethyl)pyridin-2-yl)acetate (60 mg 020 mmol 10 equiv)6-methoxy-34-dihydronaphthalen-1-yl dimethylcarbamate (247 mg 100 mmol500 equiv) and hexamethyldisilazane (42 μL 020 mmol 10 equiv) inααα-trifluorotoluene (20 mL 010 M) Purification via flash column chromatog-raphy through silica gel (eluent = pentaneethyl acetate 201) afforded 220 (49 mg013 mmol 65 ) as a yellow solid Unreacted enol carbamate (198 mg801 micromol 401 equiv) was also recovered

Rf (pentaneethyl acetate 91) 029 1H NMR (400 MHz C6D6) δ (ppm)849 (q J = 14 Hz 1H) 841 (dt J = 94 09 Hz 1H) 682 (d J = 26 Hz 1H)675 (dd J = 94 16 Hz 1H) 650 (dd J = 85 27 Hz 1H) 365 (s 3H) 337 (s3H) 325 (dd J = 81 65 Hz 2H) 264 (t J = 73 Hz 2H) [one proton peakpartially overlaps with benzene proton peak at δ (ppm) = 716] 13C NMR(101 MHz C6D6) δ (ppm) 1651 (Cq) 1586 (Cq) 1391 (Cq) 1363 (Cq) 1307(Cq) 1246 (q J = 2712 Hz Cq) 1242 (Cq) 1220 (q J = 62 Hz CH) 1212(CH) 1211 (CH) 1210 (Cq) 1167 (q J = 335 Hz Cq) 1160 (q J = 25 HzCH) 1158 (CH) 1115 (CH) 1039 (Cq) 549 (CH3) 507 (CH3) 305 (CH2) 226(CH2)

19F NMR (282 MHz CDCl3) minus6205 GC-MS tR (50_40) 123 minEI-MS mz () 376 (22) 375 (100) 360 (44) 300 (11) 272 (16) HR-MS (ESI)mz calculated for [C20H16F3NO3Na]

+ ([M + Na]+) 3980974 measured3980984 IR (ATR) ν (cmminus1) 2944 2837 2358 1690 1645 1617 1579 15161498 14321406 1363 1341 1325 1307 1250 1214 1162 1120 1077 10531037 983 955 888 865 831 817 805 773 716 702 682 651 637 599

Methyl 3-methoxy-10-methyl-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (217)

N

OO

O

Prepared following GP14 on a 020 mmol scale from methyl 2-bromo-2-(5-methylpyridin-2-yl)acetate (49 mg 020 mmol 10 equiv) 6-methoxy-34-dihydronaphthalen-1-yl dimethylcarbamate (247 mg 100 mmol 500 equiv)and hexamethyldisilazane (42 μL 020 mmol 10 equiv) in ααα-trifluorotoluene(20 mL 010 M) Purification via flash column chromatography through silica gel(eluent = pentaneethyl acetate 201) afforded 217 (42 mg 013 mmol 65 ) as apale yellow solid Unreacted enol carbamate (198 mg 801 micromol 401 equiv) wasalso recovered

Rf (pentaneethyl acetate 91) 029 1H NMR (600 MHz C6D6) δ (ppm)857 (d J = 91 Hz 1H) 806 (d J = 12 Hz 1H) 746 (d J = 85 Hz 1H) 685(d J = 27 Hz 1H) 674 (dd J = 84 27 Hz 1H) 654 (dd J = 91 14 Hz 1H)371 (s 3H) 341 (s 3H) 334ndash338 (m 2H) 272 (t J = 73 Hz 2H) 182 (s 3H)13C NMR (150 MHz C6D6) δ (ppm) 1656 (Cq) 1581 (Cq) 1391 (Cq) 1362(Cq) 1294 (Cq) 1284 (CH) 1242 (CH) 1224 (Cq) 1222 (Cq) 1215 (CH)1210 (CH) 1202 (Cq) 1154 (CH) 1117 (CH) 1020 (Cq) 549 (CH3) 504(CH3) 310 (CH2) 230 (CH2) 183 (CH3) GC-MS tR (50_40) 154 minEI-MS mz () 322 (21) 321 (100) 307 (11) 306 (59) 246 (10) 218 (21)HR-MS (ESI) mz calculated for [C20H19NO3]

+ ([M]+) 3211359 measured3211359 mz calculated for [C20H19NO3Na]

+ ([M + Na]+) 3441257 measured3441254 IR (ATR) ν (cmminus1) 3023 2978 2948 2899 2830 1682 1609 15811540 1512 1495 1465 1436 1399 1342 1308 1301 1274 1246 1219 11851172 1129 1101 1069 1031 981 958 920 903 847 797 779 695 655 621597

Methyl 3-methoxy-10-phenyl-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (216)

N

OO

O

Prepared following GP14 on a 020 mmol scale from methyl 2-bromo-2-(5-phenylpyridin-2-yl)acetate (61 mg 020 mmol 10 equiv)6-methoxy-34-dihydronaphthalen-1-yl dimethylcarbamate (247 mg 100 mmol500 equiv) and hexamethyldisilazane (42 μL 020 mmol 10 equiv) inααα-trifluorotoluene (20 mL 010 M) Purification via flash column chromatog-raphy through silica gel (eluent = pentaneethyl acetate 201) afforded 216 (47 mg012 mmol 61 ) as a yellow solid Unreacted enol carbamate (203 mg821 micromol 410 equiv) was also recovered

Rf (pentaneethyl acetate 91) 0261H NMR (300 MHz CD2Cl2) δ (ppm)

874 (t J = 15 Hz 1H) 824 (dd J = 93 09 Hz 1H) 747 (d J = 85 Hz 1H)

751ndash759 (m 2H) 736ndash747 (m 2H) 729ndash736 (m 1H) 725 (dd J = 9316 Hz 1H) 687 (d J = 26 Hz 1H) 678 (dd J = 85 28 Hz 1H) 381 (s 3H)375 (s 3H) 306ndash315 (m 2H) 282 (t J = 73 Hz 2H) 13C NMR (755 MHzCD2Cl2) δ (ppm) 1660 (Cq) 1583 (Cq) 1394 (Cq) 1385 (Cq) 1362 (Cq) 1302(Cq) 1296 (CH) 1283 (CH) 1276 (Cq) 1275 (CH) 1234 (Cq) 1222 (CH)1221 (Cq) 1217 (CH) 1211 (CH) 1203 (CH) 1156 (CH) 1117 (CH) 1018(Cq) 558 (CH3) 511 (CH3) 311 (CH2) 278 (CH2) GC-MS tR (50_40)146 min EI-MS mz () 384 (30) 383 (100) 368 (36) 323 (18) 308 (10) 281(19) 280 (16) 265 (11) 165 (13) 145 (10) 139 (11) 73 (16) HR-MS (ESI) mzcalculated for [C25H21NO3]

+ ([M]+) 3831516 measured 3831510 mz calculatedfor [C25H21NO3Na]

+ ([M + Na]+) 4061414 measured 4061406 IR (ATR) ν(cmminus1) 3074 3032 2958 2934 2906 2836 2362 1676 1607 1582 1540 15081489 14331397 1350 1339 1315 1289 1248 1214 1200 1177 1143 11071072 1033 996 982 955 899 879 806 779 753 699 655 637 606 591

Methyl 9-chloro-3-methoxy-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (214)

N

OO

O

Cl

Prepared following GP14 on a 020 mmol scale from methyl 2-bromo-2-(4-chloropyridin-2-yl)acetate (53 mg 020 mmol 10 equiv)6-methoxy-34-dihydronaphthalen-1-yl dimethylcarbamate (247 mg 100 mmol500 equiv) and hexamethyldisilazane (42 μL 020 mmol 10 equiv) inααα-trifluorotoluene (20 mL 010 M) Purification via flash column chromatog-raphy through silica gel (eluent = pentaneethyl acetate 201) afforded 214 (51 mg015 mmol 75 ) as a yellow solid Unreacted enol carbamate (197 mg797 micromol 398 equiv) was also recovered

Rf (pentaneethyl acetate 91) 025 1H NMR (400 MHz C6D6) δ (ppm)863 (dd J = 24 08 Hz 1H) 776 (d J = 72 Hz 1H) 713 (d J = 85 Hz 1H)679 (d J = 27 Hz 1H) 673 (dd J = 85 27 Hz 1H) 623 (dd J = 74 24 Hz1H) 360 (s 3H) 340 (s 3H) 327 (dd J = 81 66 Hz 2H) 264 (t J = 73 Hz2H) 13C NMR (101 MHz C6D6) δ (ppm) 1651 (Cq) 1584 (Cq) 1390 (Cq)1367 (Cq) 1302 (Cq) 1240 (CH) 1230 (Cq) 1216 (Cq) 1209 (CH) 1195(CH) 1153 (CH) 1138 (CH) 1118 (CH) 1024 (Cq) 549 (CH3) 505 (CH3)307 (CH2) 226 (CH2) [Note one Cq peak overlaps with the benzene carbon

peak] GC-MS tR (50_40) 166 min EI-MS mz () 343 (35) 342 (22) 341(100) 328 (19) 327 (11) 326 (51) 266 (10) 238 (15) HR-MS (ESI) mz cal-culated for [C19H16ClNO3Na]

+ ([M + Na]+) 3640711 measured 3640710 IR(ATR) ν (cmminus1) 3076 2990 2953 2932 2895 2832 1687 1607 1582 15271503 1498 1462 1439 1424 1381 1364 1332 1310 1246 1203 1180 11191091 1051 1029 994 965 894 881 863 806 761 739 711 679 660 624 594

N

OO

O

Prepared following GP14 on a 020 mmol scale from methyl 2-bromo-2-(4-methylpyridin-2-yl)acetate (49 mg 020 mmol 10 equiv)6-methoxy-34-dihydronaphthalen-1-yl dimethylcarbamate (247 mg 100 mmol500 equiv) and hexamethyldisilazane (42 μL 020 mmol 10 equiv) inααα-trifluorotoluene (20 mL 010 M) Purification via flash column chromatog-raphy through silica gel (eluent = pentaneethyl acetate 201) afforded 213 (44 mg014 mmol 68 ) as a greenish yellow solid Unreacted enol carbamate (192 mg776 micromol 388 equiv) was also recovered

Rf (pentaneethyl acetate 91) 017 1H NMR (400 MHz C6D6) δ (ppm)847 (dt J = 22 11 Hz 1H) 808 (d J = 71 Hz 1H) 733 (d J = 85 Hz 1H)683 (d J = 25 Hz 1H) 675 (dd J = 84 28 Hz 1H) 611 (dd J = 72 20 Hz1H) 372 (s 3H) 342 (s 3H) 331ndash337 (m 2H) 271 (t J = 73 Hz 2H) 201 (s3H) 13C NMR (101 MHz C6D6) δ (ppm) 1657 (Cq) 1580 (Cq) 1388 (Cq)1379 (Cq) 1320 (Cq) 1293 (Cq) 1231 (CH) 1224 (Cq) 1222 (Cq) 1207 (CH)1195 (CH) 1153 (CH) 1152 (CH) 1117 (CH) 1009 (Cq) 549 (CH3) 504(CH3) 310 (CH2) 229 (CH2) 210 (CH3) GC-MS tR (50_40) 156 minEI-MS mz () 322 (24) 321 (100) 307 (13) 306 (63) 246 (11) 218 (17) 217(10) HR-MS (ESI) mz calculated for [C20H19NO3]

Methyl 10-methoxy-1213-dihydrobenzo[67]indolo[21-a]isoquinoline-14-carboxylate (215)

N

OO

O

Prepared following GP14 on a 020 mmol scale from methyl 2-bromo-2-(isoquinolin-1-yl)acetate (56 mg 020 mmol 10 equiv) 6-methoxy-34-dihydronaphthalen-1-yl dimethylcarbamate (247 mg 100 mmol 500 equiv)and hexamethyldisilazane (42 μL 020 mmol 10 equiv) in ααα-trifluorotoluene(20 mL 010 M) Purification via flash column chromatography through silica gel(eluent = pentaneethyl acetate 201) afforded 213 (300 mg 0084 mmol 42 )as a pale yellow solid Unreacted enol carbamate (208 mg 841 micromol 421 equiv)was also recovered

Rf (pentaneethyl acetate 91) 018 1H NMR (300 MHz CDCl3) δ (ppm)922 (ddt J = 85 14 07 Hz 1H) 841 (d J = 74 Hz 1H) 758ndash770 (m 2H)754 (ddd J = 85 71 16 Hz 1H) 745 (ddd J = 77 71 13 Hz 1H) 691ndash702 (m 2H) 685 (dd J = 85 27 Hz 1H) 399 (s 3H) 385 (s 3H) 300ndash314(m 2H) 290 (dd J = 84 59 Hz 2H) 13C NMR (755 MHz CDCl3) δ (ppm)1672 (Cq) 1579 (Cq) 1392 (Cq) 1318 (Cq) 1285 (Cq) 1275 (CH) 1270 (Cq)1270 (CH) 1268 (CH) 1261 (CH) 1259 (Cq) 1241 (Cq) 1222 (CH) 1213(CH) 1151 (CH) 1133 (CH) 1113 (CH) 1070 (Cq) 555 (CH3) 515 (Cq) 310(CH2) 228 (CH2) GC-MS tR (50_40) 162 min EI-MS mz () 358 (26) 357(100) 342 (35) 254 (18) 253 (10) HR-MS (ESI) mz calculated for[C23H19NO3]

+ ([M]+) 3571359 measured 3571359 mz calculated for[C23H19NO3Na]

+ ([M + Na]+) 3801257 measured 3801253 IR (ATR) ν(cmminus1) 2995 2947 2929 2899 2837 2359 1695 1608 1579 1536 1497 14571434 1353 1335 1300 1265 1247 1195 1160 1143 1100 1066 1046 1036996 971 872 856 817 789 761 716 676 644 601

Methyl 2-fluoro-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (212)

N

OO

F

Prepared following GP14 on a 030 mmol scale from methyl 2-bromo-2-(pyridin-2-yl)acetate (69 mg 030 mmol 10 equiv) 7-fluoro-34-dihydronaphthalen-1-yl diethylcarbamate (395 mg 150 mmol 500 equiv) andhexamethyldisilazane (63 μL 030 mmol 10 equiv) in ααα-trifluorotoluene(30 mL 010 M) Purification via flash column chromatography through silica gel(eluent = pentaneethyl acetate 201) afforded 212 (34 mg 012 mmol 38 ) as acolorless solid Unreacted enol carbamate (331 mg 126 mmol 419 equiv) wasalso recovered

1H NMR (300 MHz CDCl3) δ (ppm) 859 (d J = 71 Hz 1H) 831 (dtJ = 91 13 Hz 1H) 741 (dd J = 103 25 1H) 727 (dd J = 82 61 Hz 1H)711 (ddd J = 91 67 11 Hz 1H) 680 minus 689 (m 2H) 392 (s 3H) 320 (ddJ = 82 65 Hz 2H) 287 (t J = 73 Hz 2H) 13C NMR (101 MHz CDCl3) δ(ppm) 1658 (Cq) 1619 (d J = 243 Hz Cq) 1378 (Cq) 1318 (Cq) 1318 (dJ = 3 Hz Cq) 1299 (d J = 8 Hz Cq) 1298 (d J = 9 Hz CH) 1238 (CH) 1225(CH) 1218 (d J = 2 Hz Cq) 1204 (CH) 1135 (CH) 1118 (d J = 21 Hz CH)1066 (d J = 24 Hz CH) 1017 (Cq) 509 (CH3) 294 (CH2) 225 (CH2)

19FNMR (282 MHz CDCl3) minus1154 Rf (pentaneethyl acetate 201) 022GC-MS tR (50_40) 118 min EI-MS mz () 296 (20) 295 (100) 294 (13) 279(8) 265 (7) 264 (15) 263 (5) 262 (34) 236 (23) 235 (39) 234 (21) 233 (8) 208(5) 134 (11) 131 (11) 117 (21) HR-MS (ESI) mz calculated for[C18H14FNO2Na]

Methyl 24-dimethyl-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate(211)

N

OO

Prepared following GP14 on a 030 mmol scale from methyl 2-bromo-2-(pyridin-2-yl)acetate (69 mg 030 mmol 10 equiv)57-dimethyl-34-dihydronaphthalen-1-yl diethylcarbamate (410 mg 150 mmol500 equiv) and hexamethyldisilazane (63 μL 030 mmol 10 equiv) inααα-trifluorotoluene (30 mL 010 M) Purification via flash column chromatog-raphy through silica gel (eluent = pentaneethyl acetate 201) afforded 211 (61 mg020 mmol 67 ) as a pale yellow solid Unreacted enol carbamate (296 mg108 mmol 361 equiv) was also recovered

Rf (pentaneethyl acetate 201) 025 1H NMR (400 MHz C6D6) δ (ppm)859 (dt J = 90 13 Hz 1H) 831 (dt J = 70 12 Hz 1H) 723 (s 1H)

675 (s 1H) 663 (ddd J = 90 67 11 Hz 1H) 617 (td J = 69 15 Hz 1H)369 (s 3H) 329ndash335 (m 2H) 267 (t J = 74 Hz 2H) 220 (s 3H) 212 (s 3H)13C NMR (101 MHz C6D6) δ (ppm) 1655 (Cq) 1377 (Cq) 1359 (Cq) 1350(Cq) 1321 (Cq) 1309 (Cq) 1291 (CH) 1288 (Cq) 1239 (CH) 1233 (Cq) 1215(CH) 1207 (CH) 1186 (CH) 1128 (CH) 1021 (Cq) 504 (CH3) 254 (CH2)227 (CH2) 215 (CH3) 203 (CH3) GC-MS tR (50_40_320) 118 min EI-MSmz () 306 (23) 305 (100) 304 (9) 274 (8) 273 (5) 272 (21) 246 (10) 245(19) 244 (6) 231 (6) 230 (7) 228 (6) 129 (5) HR-MS (ESI) mz calculated for[C20H19NO2]

Methyl 23-dimethoxy-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate(210)

N

OO

O O

Prepared following GP14 on a 030 mmol scale from methyl 2-bromo-2-(pyridin-2-yl)acetate (69 mg 030 mmol 10 equiv)67-dimethoxy-34-dihydronaphthalen-1-yl diethylcarbamate (458 mg 150 mmol500 equiv) and hexamethyldisilazane (63 μL 030 mmol 10 equiv) inααα-trifluorotoluene (30 mL 010 M) Purification via flash column chromatog-raphy through silica gel (eluent = tolueneethyl acetate 21) afforded 210 (62 mg018 mmol 61 ) as a yellow solid Unreacted enol carbamate (293 mg959 μmol 320 equiv) was also recovered

Rf (tolueneethyl acetate 21) 0481H NMR (400 MHz C6D6) δ (ppm) 862

(dt J = 90 13 Hz 1H) 819 (d J = 71 Hz 1H) 711 (s 1H) 666 (s 1H) 664(ddd J = 90 67 10 Hz 1H) 622 (td J = 68 15 Hz 1H) 371 (s 3H) 353 (s3H) 347 (s 3H) 338ndash343 (m 2H) 272 (t J = 75 Hz 2H) 13C NMR(101 MHz C6D6) δ (ppm) 1656 (Cq) 1485 (Cq) 1484 (Cq) 1372 (Cq) 1303(Cq) 1298 (Cq) 1232 (CH) 1231 (Cq) 1218 (Cq) 1211 (CH) 1208 (CH)1140 (CH) 1129 (CH) 1070 (CH) 1023 (Cq) 567 (CH3) 558 (CH3) 505(CH3) 301 (CH2) 232 (CH2) GC-MS tR (50_40) 160 min EI-MS mz ()338 (19) 337 (100) 323 (6) 322 (41) 293 (10) 208 (8) 191 (10) 44 (5) 40 (6)HR-MS (ESI) mz calculated for [C20H19NO4]

+ ([M + Na]+) 3601206 measured3601208 IR (ATR) ν (cmminus1) 3016 2933 2832 1681 1631 1608 1581 1505

1466 1452 1433 1405 1389 1363 1335 1321 1310 1277 1256 1239 12141189 1183 1150 1127 1109 1065 1038 1027 1010 982 935 919 880 853813 791 779 740 725 718 691 676 664 615 605

Methyl 5-(34-dichlorophenyl)-56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (221)

N

OO

Cl

Prepared following GP14 on a 030 mmol scale from methyl 2-bromo-2-(pyridin-2-yl)acetate (69 mg 030 mmol 10 equiv) 4-(34-dichlorophenyl)-34-dihydronaphthalen-1-yl diethylcarba-mate (584 mg 150 mmol 500 equiv)and hexamethyldisilazane (63 μL 030 mmol 10 equiv) in ααα-trifluorotoluene(30 mL 010 M) Purification via flash column chromatography through silica gel(eluent = pentanetoluene 11 to pentaneethyl acetate 41) afforded 221 (42 mg010 mmol 33 ) as a yellow solid Unreacted enol carbamate (494 mg127 mmol 423 equiv) was also recovered

Rf (pentanetoluene 11) 0351H NMR (400 MHz C6D6) δ (ppm) 855 (dt

J = 90 13 Hz 1H) 811 (dm J = 71 Hz 1H) 739 (dd J = 79 12 Hz 1H)716 (s 1H) 710 (tm J = 77 Hz 1H) 694 (td J = 75 12 Hz 1H) 690 (dJ = 83 Hz 1H) 675 (dt J = 76 11 Hz 1H) 659ndash666 (m 2H) 619 (tdJ = 69 15 Hz 1H) 375 (dd J = 102 58 Hz 1H) 361 (s 3H) 361 (ddJ = 164 58 Hz 1H) 341 (dd J = 164 102 Hz 1H) 13C NMR (101 MHzC6D6) δ (ppm) 1653 (Cq) 1440 (Cq) 1381 (Cq) 1380 (Cq) 1329 (Cq) 1310(CH) 1309 (Cq) 1307 (CH) 1291 (Cq) 1291 (CH) 1287 (Cq) 1281 (CH)1272 (CH) 1262 (CH) 1238 (CH) 1220 (CH) 1208 (CH) 1199 (CH) 1132(CH) 1025 (Cq) 505 (CH3) 452 (CH) 301 (CH2) [Note One quaternarycarbon peak was not detected due to overlapping with the signal for C6D6]GC-MS tR (50_40_320) 163 min EI-MS mz () 424 (15) 423 (80) 422 (29)421 (100) 415 (13) 405 (9) 355 (5) 343 (5) 342 (9) 332 (16) 329 (10) 328 (10)327 (12) 325 (7) 282 (16) 276 (21) 269 (9) 268 (12) 265 (5) 261 (22) 254 (7)251 (12) 244 (28) 221 (12) 217 (27) 216 (17) 195 (8) 194 (16) 159 (19) 149(14) 147 (16) 145 (19) 135 (22) 119 (7) 73 (8) HR-MS (ESI) mz calculatedfor [C24H17NO2Cl2]

+ ([M]+) 4210631 measured 4210634 mz calculated for[C24H17NO2Cl2Na]

+ ([M + Na]+) 4440529 measured 4440530 IR (ATR) ν(cmminus1) 3101 3081 3057 2975 2949 2910 2851 1682 1634 1597 1561 15311518 1508 1473 1455 1436 1396 1357 1327 1319 1303 1295 1236 12281197 1167 1146 1128 1103 1072 1054 1030 998 971 947 921 911 895870 834 820 778 761 752 737 723 710 704 690 681 666 650 617

Methyl 3-(4-methoxyphenyl)indolizine-1-carboxylate (222) [51]

N

OO

O

Prepared following GP14 on a 020 mmol scale from methyl 2-bromo-2-(pyridin-2-yl)acetate (46 mg 020 mmol 10 equiv) 1-(4-methoxyphenyl)vinyldimethylcarbamate (221 mg 100 mmol 500 equiv) and hexamethyldisilazane(42 μL 020 mmol 10 equiv) in ααα-trifluorotoluene (20 mL 010 M)Purification via flash column chromatography through silica gel (eluent = pentaneethyl acetate 201) afforded 222 (16 mg 55 micromol 28 ) as a white solidUnreacted enol carbamate (170 mg 768 micromol 384 equiv) was also recovered

Rf (pentaneethyl acetate 91) 021 1H NMR (400 MHz C6D6) δ (ppm)871 (dt J = 91 13 Hz 1H) 787 (dt J = 71 11 Hz 1H) 760 (s 1H) 714ndash723 (m 2H) 676ndash690 (m 2H) 671 (ddd J = 91 66 11 Hz 1H) 616 (tdJ = 69 14 Hz 1H) 381 (s 3H) 340 (s 3H) 13C NMR (101 MHz C6D6) δ(ppm) 1651 (Cq) 1599 (Cq) 1366 (Cq) 1304 (CH) 1265 (Cq) 1240 (Cq)1233 (CH) 1218 (CH) 1206 (CH) 1162 (CH) 1148 (CH) 1124 (CH) 1048(Cq) 549 (CH3) 506 (CH3) GC-MS tR (50_40) 113 min EI-MS mz () 282(19) 281 (100) 267 (11) 266 (61) 250 (27) 179 (13) 178 (17) 89 (11) HR-MS(ESI) mz calculated for [C17H15NO3Na]

+ ([M + Na]+) 3040944 measured3040943 IR (ATR) ν (cmminus1) 3003 2964 2839 2361 2340 1686 1635 16131573 1551 1528 1510 1492 1440 1409 1370 1331 1305 1287 1260 12431214 1173 1147 1106 1046 1030 1009 949 919 861 834 807 776 746 660624 608 593 576

653 Structural Manipulations of Indolizine

195

N

OO

DDQ (1 equiv)

22471

N

OO

22596

N

OO

PtO2 (10 mol)

Oxidation of Methyl 56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate(195)Methyl benzo[g]pyrido[12-a]indole-7-carboxylate (224)

N

OO

In a screw capped Schlenk tube 23-dichloro-56-dicyano-14-benzoquinone(DDQ 57 mg 025 mmol 10 equiv) was added to a solution of 195 (70 mg025 mmol 10 equiv) in dry toluene (25 mL) The reaction vessel was sealedtightly and heated at 110 degC for 7 h After cooling to rt the reaction mixture wasconcentrated under reduced pressure The crude reaction mixture was purified viaflash column chromatography through silica gel (eluent = pentaneethyl acetate191 to 173) to afford methyl benzo[g]pyrido[12-a]indole-7-carboxylate (22449 mg 018 mmol 71 ) as a yellow solid

Rf (pentaneethyl acetate 91) 012 1H NMR (300 MHz CDCl3) δ (ppm)928 (dt J = 73 11 Hz 1H) 846ndash873 (m 3H) 808 (dd J = 80 14 Hz 1H)787 (d J = 89 Hz 1H) 772 (ddd J = 85 70 14 Hz 1H) 755 (ddd J = 8070 10 Hz 1H) 736 (ddd J = 92 66 10 Hz 1H) 701 (ddd J = 73 6615 Hz 1H) 405 (s 3H) 13C NMR (755 MHz CDCl3) δ (ppm) 1663 (Cq)1401 (Cq) 1310 (Cq) 1301 (CH) 1277 (Cq) 1272 (CH) 1271 (CH) 1271(CH) 1249 (CH) 1239 (CH) 1232 (Cq) 1232 (Cq) 1212 (CH) 1208 (CH)1197 (CH) 1126 (CH) 971 (Cq) 510 (CH3) GC-MS tR (50_40) 130 minEI-MS mz () 276 (20) 275 (100) 245 (11) 244 (60) 217 (33) 216 (30) 215(22) 214 (13) HR-MS (ESI) mz calculated for [C18H13NO2Na]

+ ([M + Na]+)2980838 measured 29800841 IR (ATR) ν (cmminus1) 3177 2946 2846 16801618 1598 1529 1503 1474 1439 1415 1380 1351 1288 1257 1199 11611127 1113 1081 1016 965 848 812 728 678 616

Reduction of Methyl 56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate(195)Methyl 56891011-hexahydrobenzo[g]pyrido[12-a]indole-7-carboxylate(225)

N

OO

In a glass vial equipped with a magnetic stiring bar Platinum (IV) oxide (PtO244 mg 0020 mmol 10 mol) was added to a solution of 195 (55 mg020 mmol 10 equiv) in glacial acetic acid (1 mL) The reaction vessel was placedin a stainless-steel reactor The autoclave was purged three times with hydrogen gasbefore setting up the reaction pressure at 20 bar The reaction mixture was allowedto stir at 25 degC for 40 h The reaction mixture was diluted with water neutralizedwith NaHCO3 and extracted with ethyl acetate The organic phase was washed withbrine solution dried over MgSO4 and concentrated under reduced pressure Thecrude reaction mixture was purified via flash column chromatography throughneutral alumina (eluent = pentaneethyl acetate 191 to 91) to afford Methyl56891011-hexahydrobenzo[g]pyrido[12-a]indole-7-carboxylate (225 54 mg019 mmol 96 ) as a white solid upon cooling

Rf (on neutral alumina pentaneethyl acetate 91) 033 1H NMR(300 MHz CDCl3) δ (ppm) 740 (dd J = 77 13 Hz 1H) 717ndash726 (m 2H)707 (td J = 74 12 Hz 1H) 426 (t J = 58 Hz 2H) 381 (s 3H) 318 (tJ = 64 Hz 2H) 296 (ddd J = 83 65 17 Hz 2H) 284 (dd J = 86 55 Hz2H) 185ndash205 (m 4H) 13C NMR (755 MHz CDCl3) δ (ppm) 1664 (Cq)1384 (Cq) 1366 (Cq) 1295 (Cq) 1286 (CH) 1280 (Cq) 1265 (CH) 1250(CH) 1235 (Cq) 1209 (CH) 1082 (Cq) 505 (CH3) 468 (CH2) 309 (CH2) 249(CH2) 237 (CH2) 217 (CH2) 198 (CH2) GC-MS tR (50_40) 118 minEI-MS mz () 282 (20) 281 (100) 280 (12) 266 (43) 250 (13) 248 (12) 222(31) 221 (26) 220 (20) 180 (18) HR-MS (ESI) mz calculated for[C18H19NO2Na]

654 Mechanistic Experiments

6541 Radical Trapping Experiments

O O

N

Br

O

N

OO

193(10 equiv)

195

In a flame dried screw capped Schlenk tube equipped with a magnetic stir bar34-dihydronaphthalen-1-yl dimethylcarbamate (194 109 mg 0500 mmol 500equiv) was dissolved in ααα-trifluorotoluene (10 mL) and then 2-bromo-2-(pyridin-2-yl)acetate (193 23 mg 010 mmol 10 equiv) hexamethyldisilazane(21 microL 010 mmol 10 equiv) and 2266-tetramethyl-1-piperidinyloxyl(TEMPO 17 mg 011 mmol 11 equiv) or 26-di-tert-butyl-α-(35-di-tert-butyl-4-oxo-25-cyclohexadien-1-ylidene)-p-tolyloxyl (galvinoxyl 46 mg011 mmol 11 equiv) were added The resulting mixture was degassed using threefreeze-pump-thaw cycles and the tube was finally backfilled with argon Thereaction mixture was allowed to stir at rt for 12 h under irradiation of visible lightfrom 5 W blue LEDs (λmax = 465 nm) The reaction mixture was analyzed bynanospray ESI mass spectrometry In both cases methyl 56-dihydrobenzo[g]pyr-ido[12-a]indole-7-carboxylate (195) was not observed For the reaction withTEMPO peaks consistent with adducts (226 and 227) between the radical scav-enger and two different proposed radical intermediates B and C (see Scheme 411)were detected (Fig 410)

6542 Cyclic Voltammetry Measurements of Indolizine Compound

The cell used for cyclic voltametry measurement consisted of an AgAgCl referenceelectrode a Pt counter electrode and a Pt working electrode The measurement wasconducted on a degassed solution of 195 (005 mM) prepared in 01 M tetrabuty-lammonium tetrafluoroborate (TBABF4) solution in CH3CN The data wasrecorded using an Autolab potentiostat (Eco chemie Netherlands) running GPESsoftware and was plotted with Origin software (see Fig 48 in Chap 4)

6543 Determination of the Luminescence Lifetime of IndolizineCompound

The luminescence lifetime of indolizine 195 was recorded on a FluoTime300spectrometer from PicoQuant equipped with a 300 W ozone-free Xe lamp (250ndash900 nm) a 10 W Xe flash-lamp (250ndash900 nm pulse width lt 10 micros) with repeti-tion rates of 01ndash300 Hz an excitation monochromator (Czerny-Turner 27 nmmmdispersion 1200 groovesmm blazed at 300 nm) diode lasers (pulse width lt 80ps) operated by a computer-controlled laser driver PDL-820 (repetition rate up to80 MHz burst mode for slow and weak decays) two emission monochromators(Czerny-Turner selectable gratings blazed at 500 nm with 27 nmmm dispersionand 1200 groovesmm or blazed at 1250 nm with 54 nmmm dispersion and600 groovesmm) Glan-Thompson polarizers for excitation (Xe-lamps) andemission a Peltier-thermostatized sample holder from Quantum Northwest (minus40 to105 degC) and two detectors namely a PMA Hybrid 40 (transit time spreadFWHM lt 120 ps 300ndash720 nm) and a R5509-42 NIR-photomultiplier tube (transittime spread FWHM 15 ns 300ndash1400 nm) with external cooling (minus80 degC) from

Hamamatsu Steady-state and fluorescence lifetime was recorded in TCSPC modeby a PicoHarp 300 (minimum base resolution 4 ps) Lifetime analysis was per-formed using the commercial FluoFit software The quality of the fit was assessedby minimizing the reduced chi squared function (χ2) and visual inspection of theweighted residuals and their autocorrelation (see Fig 611) The luminescencelifetime of indolizine 195 thus measure was 4 ns (Fig 611)

6544 Stern-Volmer Luminescence Quenching Experiments

In a quartz cuvette an appropriate amount of quencher X (193 194 or HMDS) wasadded to a solution of 195 in PhCF3 (10 mM) The intensity of the emission peakat 442 nm (λex = 372 nm) expressed as the ratio I0I where I0 is the emissionintensity of 195 at 442 nm in the absence of a quencher and I is the observedintensity as a function of the quencher concentration was measured Stern-Volmerplots for each component are given in Fig 46 in Chap 4

6545 Effect of Suspending Visible Light Irradiation

In a flame dried screw capped Schlenk tube equipped with a magnetic stir bar34-dihydronaphthalen-1-yl dimethylcarbamate (194 109 mg 0500 mmol 500equiv) was dissolved in ααα-trifluorotoluene (10 mL) and then 2-bromo-2-(pyridin-2-yl)acetate (193 23 mg 010 mmol 10 equiv) and hexamethyldisi-lazane (21 microL 010 mmol 10 equiv) were added The resulting mixture wasdegassed using three freeze-pump-thaw cycles and the tube was finally backfilledwith argon The reaction mixture was allowed to stir at rt with alternating periods ofvisible light irradiation (5 W blue LEDs λmax = 465 nm) followed by periods indarkness Aliquots were taken under a flow of argon and the yield of indolizine 195was monitored by GC analysis using mesitylene as an internal standard

Fig 611 Determination of the luminescence lifetime of indolizine 195 A graph showing theexcited state decay and the mathematical fitting is given on the left and a table displaying theobtained data is given on the right Sahoo et al [56] Copyright Wiley-VCH Verlag GmbH amp CoKGaA Reproduced with permission

The measured yields of 195 at different time points are shown in the table and graphin Fig 612 A significant dropping off of the reaction efficiency was observedduring periods of darkness which could be restarted upon applying light irradiation

6546 Visible Light-Mediated Indolizine-Catalyzed Alkylation of N-Methylindole

N CO2Et

CO2Et

N

CO2Et

Br

EtO2C Catalyst (195 10 mol)

Na2HPO4 (20 eq)DMF rt 18 h

blue LEDs (465 nm)

(20 equiv)(10 equiv) 18 45

N

O

195

O

Diethyl 2-(1-methyl-1H-indol-2-yl)malonate (18)

In a flame dried screw capped Schlenk tube equipped with a magnetic stir bardiethyl 2-bromomalonate (68 μL 040 mmol 20 equiv) was added to a solution ofN-methylindole (25 μL 020 mmol 10 equiv) methyl 56-dihydrobenzo[g]pyrido[12-a]indole-7-carboxylate (195 56 mg 20 μmol 10 mol) Na2HPO4 (57 mg040 mmol 20 equiv) in anhydrous DMF (20 mL) under argon The resultingmixture was degassed using three freeze-pump-thaw cycles and the tube wasbackfilled with argon The degassed reaction mixture was allowed to stir at rt for18 h under irradiation of visible light from 5 W blue LEDs (λmax = 465 nm)

[b] GC yield using mesitylene as internal standard

Time (h) Phase Yield ()b0 Dark 01 Light 112 Dark 163 Light 574 Dark 615 Light 1496 Dark 1537 Light 2668 Dark 2819 Light 41310 Dark 43311 Light 555

Fig 612 Yield of 195 measured at different times after periods of visible light irradiation andperiods of darkness On the graph on the right the blue shaded areas represent periods in the darkwhile the unshaded regions show periods under light irradiation Sahoo et al [56] CopyrightWiley-VCH Verlag GmbH amp Co KGaA Reproduced with permission

The reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate(3 times 5 mL) The combined organic layers were dried over MgSO4 and concen-trated under reduced pressure The crude reaction mixture was purified via flashcolumn chromatography through silica gel (eluent = pentaneethyl acetate 191 to91) to afford diethyl 2-(1-methyl-1H-indol-2-yl)malonate (18 26 mg 90 μmol45 ) as a yellowish orange oil

N

OO

Rf (pentaneethyl acetate 41) 0411H NMR (400 MHz CDCl3) δ (ppm) 778

(d J = 79 Hz 1H) 747ndash755 (m 2H) 742 (ddd J = 83 70 13 Hz 1H) 730(ddd J = 80 70 11 Hz 1H) 678 (s 1H) 512 (s 1H) 441ndash452 (m 4H) 391(s 3H) 149 (t J = 71 Hz 6H) 13C NMR (101 MHz CDCl3) δ (ppm) 16711584 1380 1310 1274 1221 1209 1198 1094 1031 623 514 304142 GC-MS tR (50_40) 95 min EI-MS mz () 290 (10) 289 (55) 217 (15)216 (100) 188 (15) 171 (13) 146 (32) 144 (41) 143 (18) 115 (19) HR-MS(ESI) mz calculated for [C16H19NO4Na]

+ ([M + Na]+) 3121206 measured3121202 IR (ATR) ν (cmminus1) 3057 2982 2937 2361 2340 1732 1541 14681401 1368 1342 1303 1265 1236 1207 1150 1097 1030 743 632

6547 Single Crystal X-ray Analysis of Indolizine Compound (214)

Tables 62 63 64 and 65

Parameters Compound 214

Empirical formula C19H16ClNO3

Molecular weight 34178 gmolminus1

Crystal system space group Monoclinic P 2 lc (14)

Unit cell dimensions a = 92567(2) Aring α = 90000degb = 76968(2) Aring β = 981490(10)degc = 216732(5) Aring γ = 90000deg

Volume 152856(6) Aring3

Z calculated density 4 1485 g cmminus3

Absorption coefficient 2367 mmminus1

F(000) 7120

θ Range 41212ndash682644deg

Limiting indices minus11 le h le 11minus9 le k le 9minus26 le l le 26

Reflections collectedunique 323202801 [R(int) = 00532]

Datarestraintsparameters 28010219(continued)

(continued)

Goodness-of-fit on F2 1054

Final R indices [I gt 2σ(I)] R1 = 00317 wR2 = 00828

R indices (all data) R1 = 00362 wR2 = 00861

Largest diff peak and hole 0264 and minus0298 eAringminus3

Table 62 Bond lengths (Aring) for compound 214

Cl1ndashC6 17392(15) O1ndashC17 12128(18)

O2ndashC17 13534(18) O2ndashC18 14434(18)

O3ndashC15 13731(18) O3ndashC19 14285(18)

N1ndashC8 13804(19) N1ndashC4 13922(19)

N1ndashC1 14052(19) C1ndashC2 1405(2)

C1ndashC5 1412(2) C2ndashC3 1414(2)

C2ndashC17 1456(2) C3ndashC4 1378(2)

C3ndashC9 14997(19) C4ndashC12 1460(2)

C5ndashC6 1360(2) C5ndashH5 095

C7ndashH7 095 C8ndashH8 095

C9ndashC10 1533(2) C9ndashH9A 099

C9ndashH9B 099 C10ndashC11 1513(2)

C10ndashH10A 099 C10ndashH10B 099

C11ndashC16 1391(2) C11ndashC12 1412(2)

C12ndashC13 1399(2) C13ndashC14 1385(2)

C13ndashH13 095 C14ndashC15 1393(2)

C16ndashH16 095 C18ndashH18A 098

C18ndashH18B 098 C18ndashH18C 098

C19ndashH19C 098

Table 63 Bond angles (deg) for compound 214

C17ndashO2ndashC18 11489(11) C15ndashO3ndashC19 11676(12)

C8ndashN1ndashC4 12983(13) C8ndashN1ndashC1 12090(12)

C4ndashN1ndashC1 10893(12) C2ndashC1ndashN1 10731(12)

C2ndashC1ndashC5 13421(14) N1ndashC1ndashC5 11842(13)

C1ndashC2ndashC3 10698(13) C1ndashC2ndashC17 12757(13)

C3ndashC4ndashN1 10760(13) C3ndashC4ndashC12 12346(13)

N1ndashC4ndashC12 12885(13) C6ndashC5ndashC1 11918(14)

C6ndashC5ndashH5 1204 C1ndashC5ndashH5 1204(continued)

C5ndashC6ndashC7 12167(14) C5ndashC6ndashCl1 11974(12)

C7ndashC6ndashCl1 11858(11) C8ndashC7ndashC6 11918(14)

C8ndashC7ndashH7 1204 C6ndashC7ndashH7 1204

C7ndashC8ndashN1 12052(14) C7ndashC8ndashH8 1197

N1ndashC8ndashH8 1197 C3ndashC9ndashC10 10891(12)

C3ndashC9ndashH9A 1099 C10ndashC9ndashH9A 1099

C3ndashC9ndashH9B 1099 C10ndashC9ndashH9B 1099

H9AndashC9ndashH9B 1083 C11ndashC10ndashC9 11281(12)

C13ndashC14ndashC15 11993(14) C13ndashC14ndashH14 1200

C15ndashC14ndashH14 1200 O3ndashC15ndashC16 12441(13)

O3ndashC15ndashC14 11569(13) C16ndashC15ndashC14 11990(13)

C11ndashC16ndashH16 1199 O1ndashC17ndashO2 12220(13)

O1ndashC17ndashC2 12518(14) O2ndashC17ndashC2 11262(12)

O2ndashC18ndashH18A 1095 O2ndashC18ndashH18B 1095

H18AndashC18ndashH18B 1095 O2ndashC18ndashH18C 1095

H18AndashC18ndashH18C 1095 H18BndashC18ndashH18C 1095

Table 64 Torsion angles (deg) for compound 214

C8ndashN1ndashC1ndashC2 minus17320(12) C4ndashN1ndashC1ndashC2 074(15)

C8ndashN1ndashC1ndashC5 44(2) C4ndashN1ndashC1ndashC5 17837(12)

N1ndashC1ndashC2ndashC3 096(16) C5ndashC1ndashC2ndashC3 minus17613(16)

N1ndashC1ndashC2ndashC17 minus17937(14) C5ndashC1ndashC2ndashC17 35(3)

C1ndashC2ndashC3ndashC4 minus235(16) C17ndashC2ndashC3ndashC4 17797(14)

C1ndashC2ndashC3ndashC9 17774(14) C17ndashC2ndashC3ndashC9 minus19(2)

C2ndashC3ndashC4ndashN1 280(16) C9ndashC3ndashC4ndashN1 minus17727(12)

C8ndashN1ndashC4ndashC3 17103(14) C1ndashN1ndashC4ndashC3 minus219(15)

C2ndashC1ndashC5ndashC6 17423(15) N1ndashC1ndashC5ndashC6 minus26(2)(continued)

66 Synthesis and Characterizations of NovelMetal-Organic Frameworks (MOFs)

The following compounds were synthesized by self according to the proceduresgiven in the cited references DUT-6 (Boron) 234 and chiral DUT-6 (Boron) 235were synthesized and characterized by Stella Helten Dr Volodymyr Bon (allTechnical University of Dresden Dresden)

C1ndashC5ndashC6ndashC7 minus02(2) C1ndashC5ndashC6ndashCl1 minus17920(11)

C5ndashC6ndashC7ndashC8 13(2) Cl1ndashC6ndashC7ndashC8 minus17967(11)

C6ndashC7ndashC8ndashN1 05(2) C4ndashN1ndashC8ndashC7 minus17592(14)

C1ndashN1ndashC8ndashC7 minus34(2) C4ndashC3ndashC9ndashC10 2899(18)

C2ndashC3ndashC9ndashC10 minus15111(15) C3ndashC9ndashC10ndashC11 minus4994(16)

C16ndashC11ndashC12ndashC13 18(2) C10ndashC11ndashC12ndashC13 17839(13)

C3ndashC4ndashC12ndashC13 15700(15) N1ndashC4ndashC12ndashC13 minus192(2)

C3ndashC4ndashC12ndashC11 minus195(2) N1ndashC4ndashC12ndashC11 16431(14)

C12ndashC13ndashC14ndashC15 11(2) C19ndashO3ndashC15ndashC16 91(2)

C19ndashO3ndashC15ndashC14 minus17105(13) C13ndashC14ndashC15ndashO3 minus17886(13)

C13ndashC14ndashC15ndashC16 10(2) O3ndashC15ndashC16ndashC11 17822(13)

C10ndashC11ndashC16ndashC15 minus17635(13) C18ndashO2ndashC17ndashO1 35(2)

C3ndashC2ndashC17ndashO1 63(2) C1ndashC2ndashC17ndashO2 72(2)

C3ndashC2ndashC17ndashO2 minus17317(13)

Table 65 Hydrogen bond distances (Aring) and angles (deg) for compound 214

Donor-H Acceptor-H Donor-acceptor Angle

C5ndashH5O2 095 240 29315(18) 1147

C16ndashH16O1 095 247 33219(18) 1496

661 Synthesis of 44prime4Prime-Boranetriyltris(35-Dimethylbenzoic Acid) (H3TPB)

Tris(4-bromo-26-dimethylphenyl)borane(230)

B

Br

BrBr

Following a modified procedure by Zhang et al [52] a flame dried Schlenk tubewas charged with 5-bromo-2-iodo-13-dimethyl benzene (229 10 g 3216 mmol)in a glovebox Dry diethyl ether (20 ml) was added to the flask and the mixture wascooled to minus78 degC To the reaction mixture at minus78 degC a solution of n-BuLi (16 M2 ml 3216 mmol) in hexane was added dropwise The reaction mixture wasallowed to warm up to 0 degC and stirred for 30 min The reaction mixture was againcooled down to minus78 degC and BF3Et2O (01 ml 08 mmol) was added dropwiseThe whole reaction mixture was slowly allowed to warm up to rt and stirredovernight Water was added to quench the reaction and the mixture was extractedwith diethyl ether The organic layers were washed with brine dried over anhy-drous MgSO4 and the solvents were removed under reduced pressure The crudereaction mixture was purified by column chromatography (eluentpentane) to givetris(4-bromo-26-dimethylphenyl)borane (230) as a white solid (1892 mg 42 )

Rf (pentane) 0361H NMR (300 MHz CDCl3) δ (ppm) 711 (s 6H) 197

(s 18H) 13C NMR (755 MHz CDCl3) δ (ppm) 1447 1426 1309 1245229 HR-MS (ESI) mz calculated for [C24H24B1Br3HCOO]

minus ([M + HCOO]minus)6049504 measured 6049491 IR (ATR) ν (cmminus1) 2966 2923 1565 14371240 1201 1118 1030 938 881 850 712 662

Trimethyl 44prime4Prime-boranetriyltris(35-dimethylbenzoate)(231)

B

OO

O

Tris(4-bromo-26-dimethylphenyl)borane (230 100 mg 0178 mmol) and tetrakis(triphenylphosphine)palladium(0) (624 mg 0054 mmol) were added to an

66 Synthesis and Characterizations hellip 245

oven-dried screw-capped 3 ml glass vial equipped with a magnetic stirring barunder argon Dry toluene (06 ml) distilled triethylamine (03 ml) and drymethanol (06 ml) were added to the vial The vial was placed in a 150 mlstainless-steel reactor (Note four vials were placed in a reactor at a time) Theautoclave was carefully purged with carbon monoxide gas three times before thepressure was adjusted 40 bar The reaction mixture was stirred at 125 degC for 36 hThen the mixture was allowed to cool down to rt and the autoclave was carefullydepressurized The crude mixture was filtered through a plug of Celite using ethylacetate as eluent and the solvents were removed under reduced pressure Theresidue was purified by column chromatography (eluentpentaneethyl acetate =101) to give trimethyl 44prime4Primeboranetriyltris(35-dimethylbenzoate)(231) as a lightbrown foamy solid (419 mg 47 )

761 (s 6H) 390 (s 9H) 205 (s 18H) 13C NMR (755 MHz CDCl3) δ (ppm)1673 1506 1408 1314 1289 522 230 HR-MS (ESI) mz calculated for[C30H33B1O6Na]

+ ([M + Na]+) 5232262 measured 5232263 IR (ATR) ν(cmminus1) 2953 2360 1719 1553 1435 1410 1301 1208 1142 1115 1016 984898 837 768 746 711 66644prime4Prime-Boranetriyltris(35-dimethylbenzoic acid)(228)

B

OHO

O

OH

HO

O

In a 250 ml round bottom flask trimethyl 44prime4Prime-boranetriyltris(35-dimethylbenzoate) (231 694 mg 1387 mmol) was dissolved in 28 mlmethanol To this methanol solution sodium hydroxide (2774 mg 6935 mmol) in28 ml water was added and the reaction mixture was refluxed at 70 degC for 15 h(turbid reaction mixture turned to clear solution) After cooling the reaction mixturedown to rt it was diluted with water and filtered through Buumlchner funnel equippedwith a sinter disc The filtrate was acidified with aq H2SO4 solution (1 M) at pH 5ndash6 to precipitate out the product The precipitate was filtered and dried under vacuumto give 44prime4Prime-boranetriyltris(35-dimethylbenzoic acid) (228) as a white solid(604 mg 95 )

1H NMR (300 MHz DMSO-d6) δ (ppm) 1296 (broad signal 3H) 755 (s6H) 202 (s 18H) 13C NMR (755 MHz DMSO-d6) δ (ppm) 1672 14971402 1319 1284 222 HR-MS (ESI) mz calculated for [C27H26B1O6]

minus ([Mndash

H]minus) 4571828 measured 4571812 IR (ATR) ν (cmminus1) 2963 2925 16861549 1418 1295 1228 1199 1119 1031 899 834 771 719 665

662 Synthesis of (S)-2-(4-Benzyl-2-Oxooxazolidin-3-yl)Terephthalic Acid

(S)-4-benzyloxazolidin-2-one was synthesized in practical courses and used asreceived

Dimethyl 2-bromoterephthalate

O O

OO

Br

Following our previous procedure [53] in a two necked round bottomed flaskeqquiped with a magnetic stir bar and connected with a reflux condenser2-bromoterephthalic acid (365 g 149 mmol 1 equiv) was suspended in MeOH(125 mL) and heated at 70 degC for 15 min SOCl2 (224 mL 298 mmol 20 equiv)was then added to the solution and refluxed for another 12 h After cooling thereaction mixture to rt MeOH was removed under reduced pressure The residuewas extracted with diethyl ether and the organic phase was washed with aq 10 KOH followed by brine The organic layer was dried over MgSO4 and concentratedunder reduced pressure The crude reaction mixture was purified by flash columnchromatography (eluentpentaneethyl acetate 91) to afford pure dimethyl2-bromoterephthalate (321 g 118 mmol 79 ) as a white solid

1H NMR (300 MHz CDCl3) δ (ppm) 831 (d J = 16 Hz 1H) 800 (ddJ = 81 16 Hz 1H) 781 (d J = 81 Hz 1H) 396 (s 3H) 394 (s 3H)

Dimethyl (S)-2-(4-benzyl-2-oxooxazolidin-3-yl)terephthalate

N

O O

OO

Following our previous procedure [53] in a Schlenk tube under argon NNprime-dimethylethylenediamine (310 microL 288 mmol 031 equiv) was added to a mixtureof dimethyl 2-bromoterephthalate (256 g 937 mmol 100 equiv) (S)-4-benzyloxazolidin-2-one (183 g 101 mmol 110 equiv) CuI (268 mg141 mmol 015 equiv) and K2CO3 (260 g 188 mmol 201 equiv) in drytoluene (154 mL) and heated at 110 degC for 48 h After cooling to rt the reactionmixture was filtered through a short silica plug (eluent ethyl acetate) The solventwas removed under reduced pressure and purified by flash column chromatography

(eluentpentaneethyl acetate 11) to deliver pure dimethyl (S)-2-(4-benzyl-2-oxooxazolidin-3-yl)terephthalate (170 g 460 mmol 49 ) as yel-lowish foamy solid

1H NMR (300 MHz CDCl3) δ (ppm) 802 (d J = 10 Hz 2H) 793 (s 1H)706ndash730 (m 5H) 458ndash477 (m 1H) 446 (t J = 85 Hz 1H) 425 (dd J = 8766 Hz 1H) 396 (s 3H) 394 (s 3H) 311 (dd J = 136 47 Hz 1H) 291 (ddJ = 136 98 Hz 1H) HR-MS (ESI) mz calculated for [C20H19NO6Na]

+

([M + Na]+) 3921105 measured 3921106

(S)-2-(4-Benzyl-2-oxooxazolidin-3-yl)terephthalic acid

N

HO O

OHO

OO

Following our previous procedure [53] in a two necked round bottomed flaskeqquiped with a magnetic stir bar and connected with a reflux condenser dimethyl(S)-2-(4-benzyl-2-oxooxazolidin-3-yl)terephthalate (169 g 459 mmol 100equiv) was dissolved in a mixture of MeOH (179 mL) and THF (179 mL) Afteradding aq 1 N NaOH (152 mL) the resulting reaction mixture was allowed to stirfor 16 h The reaction mixture was acidified with conc HCl to pH 5ndash6 and theorganic solvents were removed under reduced pressure The aqueous phase wasextracted with CHCl3

iPrOH (51) mixture The combined organic layers were driedover MgSO4 and concentrated under reduced pressure The crude residue wasdissolved in acetone and precipitated out by adding pentane The solid was filteredoff and dried to give pure (S)-2-(4-Benzyl-2-oxooxazolidin-3-yl)terephthalic acid(233 150 g 441 mmol 96 ) as a white solid

1H NMR (300 MHz CDCl3) δ (ppm) 1338 (s 2H) 783ndash795 (m 3H) 709ndash723 (m 5H) 468ndash485 (m 1H) 444 (t J = 85 Hz 1H) 420 (dd J = 8567 Hz 1H) 293 (s 1H) 291 (d J = 28 Hz 1H) HR-MS (ESI) mz calculatedfor [C18H14NO6]

minus ([MndashH]minus) 3400816 measured 3400839

663 Synthesis of DUT-6 (Boron) (234)

Zn(NO3)24H2O (56 mg 020 mmol 111 equiv) terephthalic acid (900 mg0054 mmol 300 equiv) and 44prime4Prime-boranetriyltris(35-dimethylbenzoic acid)(810 mg 0018 mmol 100 equiv) were dissolved in NN-diethylformamide(10 mL) by ultrasonication The solution was placed in a glass Pyrex tube with asize of 100 times 16 mm The vial was sealed tightly with a screw cap and heated at80 degC in an oven for 48 h After cooling down to room temperature the motherliquor was pipetted off and the colourless crystals were washed with fresh DEF five

times The solvent was then exchanged with ethanol five times 24 h were leftbetween consecutive washing and solvent exchange steps

For physisorption measurements the ethanol was removed from the pores bydrying in supercritical CO2

Elemental Analysis calculated values for Zn4O(C8H4O4)(C27H24BO6)43 C5039 H 346 measured C 4992 H 373

664 Synthesis of Chiral DUT-6 (Boron) (235)

Zn(NO3)24H2O (60 mg 020 mmol 714 equiv) (S)-2-(4-Benzyl-2-oxazilidin-3-yl)terephthalic acid (0028 mg 0048 mmol 171 equiv) and 44prime4Prime-borane-triyltris(35-dimethylbenzoic acid) (130 mg 0028 mmol 100 equiv) were dis-solved in NN-diethylformamide (10 mL) by ultrasonication The vial was sealedtightly with a screw cap and heated at 80 degC in an oven for 48 h After coolingdown to room temperature the mother liquor was pipetted off and replaced by freshDEF five times The solvent was then exchanged with ethanol five times 24 h wereleft between consecutive washing and exchange steps

665 Single Crystal X-Ray Analysis of DUT-6 (Boron)

Parameters DUT-6 (boron) Zn4O(C27H24BO6)43(C8H4O4) (234)

Empirical formula C1215H2065B133N155O285Zn4Molecular weight 26164 gmolminus1

Crystal system space group Cubic Pm3n (223)

Unit cell dimensions a = 26510(3) Aring

F(000) 83920

Datarestraintsparameters 15061182

CCDC-1009603 contains the supplementary crystallographic data for this compound This datacan be obtained free of charge from the Cambridge Crystallographic Data Centre via wwwccdccamacukdata_requestcif

666 Determination of BET Area

Rouquerol and Llewellyn [54] suggested three consistency criteria when using theBET method to determine the surface area of metal-organic frameworks We chosethe area of the adsorption branch for BET area determination accordingly

The first criterion states that the analysis should be limited to the range in which

the term n 1 pp0

increases continuously as a function of the relative pressure

which can be well seen in Fig 613 depicting this function with the chosen pressurerange of 77 times 10minus4 le pp0 le 98 times 10minus2

The second criterion states that the BET constant resulting from the linear fitshould be positive and have a minimum value of C = 10 which is also met as theresulting BET constant is C = 34312

According to the third consistency criterion the relative pressure that corre-

sponds to the calculated BET monolayer capacity applying equation pp0

nmfrac14 1ffiffiffi

Cp thorn 1

should be located in the chosen pressure range Inserting the determined BET

constant into this equation gives pp0

nmfrac14 005122 which is located in the

above mentioned chosen pressure range and therefore all three consistency criteriaare met

667 CO2 Physisorption Isotherms for DUT-6

Figures 614 and 615

Fig 613 BET plot of thepp0 range chosen for thedetermination of the BETsurface area Ref [55]mdashreproduced by permission ofThe Royal Society ofChemistry

References

1 GR Fulmer AJM Miller NH Sherden HE Gottlieb A Nudelman BM Stoltz JEBercaw KI Goldberg Organometallics 29 2176ndash2179 (2010)

2 M Bandini Chem Soc Rev 40 1358ndash1367 (2011)3 Z Otwinowski W Minor Methods Enzymol 276 307ndash326 (1997)4 Z Otwinowski D Borek W Majewski W Minor Acta Crystallogr A59 228ndash234 (2003)5 GM Sheldrick Acta Crystallogr A46 467ndash473 (1990)6 GM Sheldrick Acta Crystallogr A64 112ndash122 (2008)7 U Mueller N Darowski MR Fuchs R Foumlrster M Hellmig KS Paithankar S Puumlhringer

M Steffien G Zocher MS Weiss J Synchrotron Radiat 19 442ndash449 (2012)8 M Krug MS Weiss U Heinemann U Mueller J Appl Crystallogr 45 568ndash572 (2012)9 W Kabsch Acta Crystallogr D Biol Crystallogr 66 125ndash132 (2010)

10 GM Sheldrick Acta Crystallogr A 64 112ndash122 (2008)11 AL Spek Acta Crystallogr D Biol Crystallogr 65 148ndash155 (2009)12 MA Ischay Z Lu TP Yoon J Am Chem Soc 132 8572ndash8574 (2010)13 C Bronner OS Wenger Phys Chem Chem Phys 16 3617ndash3622 (2014)14 DP Rillema G Allen TJ Meyer D Conrad Inorg Chem 22 1617ndash1622 (1983)15 S Sprouse KA King PJ Spellane RJ Watts J Am Chem Soc 106 6647ndash6653 (1984)16 AB Tamayo BD Alleyne PI Djurovich S Lamansky I Tsyba NN Ho R Bau ME

Thompson J Am Chem Soc 125 7377ndash7387 (2003)

Fig 614 CO2 physisorptionisotherm at 194 K of DUT-6solid symbols representadsorption empty symbolsrepresent desorption Ref[55]mdashreproduced bypermission of The RoyalSociety of Chemistry

Fig 615 CO2 physisorptionisotherm at 273 K of DUT-6(solid symbols representadsorption empty symbolsrepresent desorption Ref[55]mdashreproduced bypermission of The RoyalSociety of Chemistry

References 251

17 JD Slinker AA Gorodetsky MS Lowry J Wang S Parker R Rohl S Bernhard GGMalliaras J Am Chem Soc 126 2763ndash2767 (2004)

18 D Hanss JC Freys G Bernardinelli OS Wenger Eur J Inorg Chem 2009 4850ndash4859(2009)

19 P de Freacutemont NM Scott ED Stevens SP Nolan Organometallics 24 2411ndash2418 (2005)20 ASK Hashmi I Braun M Rudolph F Rominger Organometallics 31 644ndash661 (2012)21 N Meacutezailles L Ricard F Gagosz Org Lett 7 4133ndash4136 (2005)22 WF Gabrielli SD Nogai JM McKenzie S Cronje HG Raubenheimer New J Chem

33 2208ndash2218 (2009)23 PG Jones AG Maddock MJ Mays MM Muir AF Williams J Chem Soc Dalton

Trans 1434ndash1439 (1977)24 S Nicolai J Waser Org Lett 13 6324ndash6327 (2011)25 G Zhang L Cui Y Wang L Zhang J Am Chem Soc 132 1474ndash1475 (2010)26 IM Pastor I Pentildeafiel M Yus Tetrahedron Lett 49 6870ndash6872 (2008)27 A Fernaacutendez-Mateos P Herrero Teijoacuten L Mateos Buroacuten R Rabanedo Clemente R Rubio

Gonzaacutelez J Org Chem 72 9973ndash9982 (2007)28 Z Cai N Yongpruksa M Harmata Org Lett 14 1661ndash1663 (2012)29 MC Marcotullio V Campagna S Sternativo F Costantino M Curini Synthesis 2006

2760ndash2766 (2006)30 H Teller M Corbet L Mantilli G Gopakumar R Goddard W Thiel A Fuumlrstner J Am

Chem Soc 134 15331ndash15342 (2012)31 DP Curran N Fairweather J Org Chem 68 2972ndash2974 (2003)32 P Hanson JR Jones AB Taylor PH Walton AW Timms J Chem Soc Perkin Trans

2 1135ndash1150 (2002)33 M Bielawski D Aili B Olofsson J Org Chem 73 4602ndash4607 (2008)34 Y Senda H Kanto H Itoh J Chem Soc Perkin Trans 2 1143ndash1146 (1997)35 S Nagumo Y Ishii Y-I Kakimoto N Kawahara Tetrahedron Lett 43 5333ndash5337 (2002)36 JP Wolfe MA Rossi J Am Chem Soc 126 1620ndash1621 (2004)37 A Spaggiari D Vaccari P Davoli G Torre F Prati J Org Chem 72 2216ndash2219 (2007)38 X-Z Shu M Zhang Y He H Frei FD Toste J Am Chem Soc 136 5844ndash5847 (2014)39 F Romanov-Michailidis L Gueacuteneacutee A Alexakis Angew Chem Int Ed 52 9266ndash9270

(2013)40 Q Yin S-L You Org Lett 16 1810ndash1813 (2014)41 SR Kandukuri A Bahamonde I Chatterjee ID Jurberg EC Escudero-Adaacuten

P Melchiorre Angew Chem Int Ed 54 1485ndash1489 (2015)42 M Duggeli C Goujon-Ginglinger SR Ducotterd D Mauron C Bonte Av Zelewsky H

Stoeckli-Evans A Neels Org Biomol Chem 1 1894ndash1899 (2003)43 HY Kim DA Lantrip PL Fuchs Org Lett 3 2137ndash2140 (2001)44 SF Yip HY Cheung Z Zhou FY Kwong Org Lett 9 3469ndash3472 (2007)45 HP Kokatla PF Thomson S Bae VR Doddi MK Lakshman J Org Chem 76 7842ndash

7848 (2011)46 K Funakoshi H Inada M Hamana Chem Pharm Bull 32 4731ndash4739 (1984)47 R Morgentin F Jung M Lamorlette M Maudet M Meacutenard P Pleacute G Pasquet F Renaud

Tetrahedron 65 757ndash764 (2009)48 L Panella BL Feringa JG de Vries AJ Minnaard Org Lett 7 4177ndash4180 (2005)49 M Boultadakis-Arapinis MN Hopkinson F Glorius Org Lett 16 1630ndash1633 (2014)50 DC Behenna JT Mohr NH Sherden SC Marinescu AM Harned K Tani M Seto S

Ma Z Novaacutek MR Krout RM McFadden JL Roizen JA Enquist DE White SRLevine KV Petrova A Iwashita SC Virgil BM Stoltz Chem Eur J 17 14199ndash14223(2011)

51 L Xiang Y Yang X Zhou X Liu X Li X Kang R Yan G Huang J Org Chem 7910641ndash10647 (2014)

52 J Li G Zhang D Zhang R Zheng Q Shi D Zhu J Org Chem 75 5330ndash5333 (2010)

53 M Padmanaban P Muller C Lieder K Gedrich R Grunker V Bon I Senkovska SBaumgartner S Opelt S Paasch E Brunner F Glorius E Klemm S Kaskel ChemCommun 47 12089ndash12091 (2011)

54 J Rouquerol P Llewellyn F Rouquerol in Characterization of Porous Solids VIIProceedings of the 7th International Symposium on the Characterization of Porous Solids(COPS-VII) Aix-en-Provence France 26ndash28 May 2005 Vol 160 ed by JRPL LlewellynF Rodriquez-Reinoso N Seaton (Elsevier 2007) pp 49ndash56

55 S Helten B Sahoo V Bon I Senkovska S Kaskel F Glorius CrystEngComm 17 307ndash312 (2015)

56 B Sahoo J-L Li F Glorius visible-light photoredox-catlyzed semipinacol-type rearrange-ment trifluoromethylationring expansion via a radical-polar mechanism Angew Chem IntEd 54 11577ndash11580 (2015)

References 253

Curriculum Vitae

Dr Basudev SahooPersonal Informations

Date of Birth 04041987Nationality Indian

Professional Experience

102015ndashPresent Postdoctoral Fellow at Leibniz-Institut fuumlr Katalyse eV ander Universitaumlt Rostock (LIKAT Rostock) RostockGermany (Advisor Prof Dr Matthias Beller)

Education

102011ndash082015 PhD Thesis under the supervision of Prof Dr Frank Gloriusat the Westfaumllische Wilhelms-Universitaumlt MuumlnsterGermany Grade Summa Cum Laude (highest distinction)Thesis Visible Light Photocatalyzed Redox Neutral OrganicReactions and Synthesis of Novel Metal-Organic Frameworks(MOFs)

052010ndash062010 Summer Research Internship under the supervision of ProfDr Munna Sarkar at the Saha Institute of Nuclear Physics(SINP) Kolkata IndiaProject The Binding Ability of Copper Complexes ofNon-Steroidal Anti-Inflammatory Drugs (NSAIDs) with DNAto Investigate Anticancer Activity through DNA BackboneDistortion

082009ndash052011 MSc in Chemistry from the Indian Institute of Technology(IIT) Kanpur India (Master Thesis under the supervision ofProf Dr Manas K Ghorai) CGPA 92 out of 10

copy Springer International Publishing AG 2017B Sahoo Visible Light Photocatalyzed Redox-Neutral Organic Reactionsand Synthesis of Novel Metal-Organic Frameworks Springer ThesesDOI 101007978-3-319-48350-4

255

Thesis Lewis Acid Catalyzed Regioselective Ring Opening ofSmall Azacyclic Compounds with Active MethyleneCompounds to Construct γ-Amino Butyric Acid Analogues

072006ndash072009 BSc in Chemistry (Honours) Mathematics and Physics fromthe Ramakrishna Mission Residential College(Narendrapur) University of Calcutta Kolkata IndiaCumulative percentage (Honours) 719 (1st class)

072004ndash062006 Higher Secondary (10+2) from the Satmile High School underthe West Bengal Council of Higher Secondary Education(WBCHSE) India Marks obtained 854 (1st division)

051994ndash052004 Secondary (10) from the North Junbani Brajamal PrimarySchool and Chandanpur Birendra Siksha Sadan under theWest Bengal Board of Secondary Education (WBBSE)India Marks obtained 859 (1st division)

Publications

11 ldquoAccelerated Discovery in Photocatalysis using a Mechanism-BasedScreening Methodrdquo Matthew N Hopkinson Adriaacuten Gόmez-SuaacuterezMichael Teders Basudev Sahoo Frank Glorius Angew Chem 2016128 4434-4439 Angew Chem Int Ed 2016 55 4361ndash4366

10 ldquoDual GoldPhotoredox-Catalyzed C(sp)ndashH Arylation of Terminal Alkyneswith Diazonium Saltsrdquo Adrian Tlahuext Acadagger Matthew N Hopkinsondagger

Basudev Sahoo Frank Glorius Chem Sci 2016 7 89ndash93 (daggerTheseauthors contributed equally to this work)

9 ldquoExternal Photocatalyst-Free Visible Light-Mediated Synthesis ofIndolizinesrdquo Basudev Sahoodagger Matthew N Hopkinsondagger Frank GloriusAngew Chem 2015 127 15766ndash15770 Angew Chem Int Ed 2015 5415545ndash15549 (daggerThese authors contributed equally to this work)

8 ldquoVisible Light Photoredox-Catalyzed Semipinacol-Type RearrangementTrifluoromethylationRing Expansion via a Radical-Polar MechanismrdquoBasudev Sahoo Jun-Long Li Frank Glorius Angew Chem 2015 12711740minus11744 Angew Chem Int Ed 2015 54 11577ndash11580

7 ldquoFunctional group tolerance in BTB-based Metal-Organic Frameworks(BTBmdashbenzene-135-tribenzoate)rdquo Stella Helten Basudev Sahoo PhilippMuumlller Daniel Janszligen-Muumlller Nicole Klein Ronny Gruumlnker VolodymyrBon Frank Glorius Stefan Kaskel Irena Senkovska MicroporousMesoporous Mater 2015 216 42ndash50

6 ldquoCopolymerisation at work the first example of a highly porous MOFcomprising a triarylborane-based linkerrdquo Stella Heltendagger Basudev Sahoodagger

Volodymyr Bon Irena Senkovska Stefan Kaskel Frank GloriusCrystEngComm 2015 17 307ndash312 (daggerThese authors contributed equally tothis work)

256 Curriculum Vitae

5 ldquoN-Heterocyclic Carbene Catalyzed Switchable Reactions of Enals withAzoalkenes Formal [4+3] and [4+1] Annulations for the Synthesis of12-Diazepines and Pyrazolesrdquo Chang Guo Basudev Sahoo Constantin GDaniliuc Frank Glorius J Am Chem Soc 2014 136 17402minus17405

3 ldquoConjugate Umpolung of ββ-Disubstituted Enals by Dual Catalysis with anN-Heterocyclic Carbene and a Broslashnsted Acid Facile Construction ofContiguous Quaternary Stereocentersrdquo Jun-Long Li Basudev SahooConstantin G Daniliuc Frank Glorius Angew Chem 2014 126 10683minus10687 Angew Chem Int Ed 2014 53 10515ndash10519

2 ldquoDual Catalysis sees the Light Combining Photoredox with Organo- Acidand Transition Metal Catalysisrdquo Matthew N Hopkinsondagger BasudevSahoodagger Jun-Long Li Frank Glorius Chem Eur J 2014 20 3874ndash3886(daggerThese authors contributed equally to this work)

1 ldquoCombining Gold and Photoredox Catalysis Visible Light-Mediated Oxy-and Amino-arylation of Alkenesrdquo Basudev Sahoo Matthew N HopkinsonFrank Glorius J Am Chem Soc 2013 135 5505ndash5508

Conferences and Presentations

4 ldquoPhotoredox Catalysis Meets Gold Catalysis Visible Light MediatedDifunctionalization of Alkenesrdquo 8th AsianndashEuropean Symposium on MetalMediated Efficient Organic Synthesis (AES-MMEOS) Izmir TurkeySeptember 7ndash10 2014 (poster presentation)

3 ldquoPd Catalyzed C-H Functionalization of a Metal-Organic Framework(MOF) Mild Selective and Efficientrdquo International MOF Symposium 2013Dresden Germany September 16ndash17 2013 (poster presentation)

2 ldquoDifunctionalization of Alkenes Using a Dual Gold and PhotoredoxCatalytic Systemrdquo 14th Tetrahedron Symposium Challenges in Organic andBioorganic Chemistry Vienna Austria June 25ndash28 2013 (posterpresentation)

1 ldquoSynthesis of a Novel Organic Linker and its Metal-Organic FrameworksTowards Heterogeneous Catalysisrdquo 13th Belgian Organic SynthesisSymposium (BOSS XIII) Leuven Belgium July 15-20 2012 (posterpresentation)

Academic AchievementsAwards

bull Recipient of Springer Thesis Prize from the Springer Germany (2016) forrecognizing outstanding PhD research

bull Awarded with a special certificate by the Rector of WestfaumllischeWilhelms-Universitaumlt Muumlnster Germany (December 2015) for obtainingSumma Cum Laude (highest distinction) in PhD

bull Recipient of a competitive Doctoral Research Fellowship from the NRWInternational Graduate School of Chemistry Muumlnster Germany to pur-sue doctoral research (2011ndash2014)

bull Recipient of a competitive Summer Research Internship Fellowship with acertificate from the Saha Institute of Nuclear Physics (SINP) Kolkata(52010ndash62010)

bull Recipient of a Merit Scholarship from the Department of ChemistryIndian Institute of Technology (IIT) Kanpur (2009ndash2011)

bull Selected for an interview for prestigious ldquoShyama Prasad Mukherjee(SPM) Fellowshiprdquo (a fellowship by CSIR India) 2011 for doctoralstudies in India

bull Qualified for a doctoral research fellowship upon passing the GraduateAptitude Test (GATE) conducted by IITs in February 2011 (All India Rank1 among 10608 chemical science candidates)

bull Qualified for a Junior Research Fellowship (JRF) upon passing theNational Eligibility Test (NET) conducted by the Joint CSIR (Council ofScientific amp Industrial Research)mdashUGC (University GrantCommission) India in December 2010 (All India Rank 14 among 1067chemical science candidates)

bull Secured All India Rank 22 among 2585 chemistry candidates appeared in theJoint Admission Test for MSc (IIT-JAM) conducted by IITs (2009)

Teaching Experience

bull Supervision of two Master and one Bachelor students for their projects at theWestfaumllische Wilhelms-Universitaumlt Muumlnster Germany

Abstract
Acknowledgements
Contents
Abbreviations
1 Introduction to Photocatalysis
- 11 Historical Background
- 12 Classifications of Photocatalyst
- 13 Characteristics of Homogeneous Photocatalysts
- 14 Visible Light Photocatalysis in Organic Synthesis
- - 141 Photoredox Catalyzed Organic Transformations via Electron Transfer
  - - 1411 Redox-Neutral Photoredox Catalysis Single Catalysis
    - 1412 Photoredox Catalysis Dual Catalysis (Transition Metal)
    - 1413 Redox-Neutral Photoredox Catalysis EDA Complex Formation
    - - 142 Photocatalyzed Organic Transformations via Triplet Energy Transfer
      - 15 Summary
        
        References
        
        2 Dual Gold and Visible Light Photoredox-Catalyzed Heteroarylations of Non-activated Alkenes
        
        21 Introduction
        
        
        
        
        2122 Difunctionalizations of CarbonndashCarbon Multiple Bonds Mechanistic Hypothesis
        
        
        
        
        
        
        221 Inspiration
        
        
        
        
        
        
        
        224 Mechanistic Studies on Heteroarylations of Alkenes
        
        23 Summary
        
        References
        
        3 Visible Light Photoredox Catalyzed Trifluoromethylation-Ring Expansion via Semipinacol Rearrangement
        
        31 Introduction
        
        
        
        
        
        
        3142 Classifications of Trifluoromethylated Compounds and Trifluoromethylation
        
        3143 Visible Light Photoredox-Catalyzed Trifluoromethylations via Radical-Polar Crossover
        
        
        
        321 Inspiration
        
        
        
        
        
        33 Summary
        
        References
        
        4 Transition Metal Free Visible Light-Mediated Synthesis of Polycyclic Indolizines
        
        41 Introduction
        
        
        
        
        
        
        
        4134 Synthesis of Indolizines via CarbeneMetal-Carbenoid Formation
        
        
        
        
        414 Functionalization of Indolizines via Transition Metal Catalysis
        
        
        
        
        421 Inspiration
        
        422 Reaction Design
        
        
        424 Scope and Limitations
        
        
        
        43 Summary
        
        References
        
        5 Synthesis and Characterizations of Novel Metal-Organic Frameworks (MOFs)
        
        51 Intoduction
        
        
        512 General Characteristic Features of Metal-Organic Frameworks (MOFs)
        
        
        
        
        521 Inspiration
        
        522 Synthesis of Novel Metal-Organic Frameworks (MOFs)
        
        523 Structural Analysis of Novel Metal-Organic Frameworks (MOFs)
        
        5231 PXRD Analysis
        
        
        5233 TGA Analysis
        
        
        524 Dye Absorption Studies of Novel Metal-Organic Frameworks (MOFs)
        
        525 Photophysical Studies of Novel Metal-Organic Frameworks (MOFs)
        
        53 Summary
        
        References
        
        6 Experimental Section
        
        
        
        
        
        
        
        
        635 Synthesis and Characterization of Oxy- and Aminoarylated Products
        
        
        
        642 Synthesis and Characterization of Trifluoromethylated Cycloalkanone Compounds
        
        643 Synthetic Manipulations of Trifluoromethylated Cycloalkanone Product
        
        
        
        
        
        
        65 Transition Metal Free Visible Light Mediated Synthesis of Polycyclic Indolizines
        
        
        
        
        
        
        
        
        
        6543 Determination of the Luminescence Lifetime of Indolizine Compound
        
        
        
        
        
        
        
        
        
        
        
        
        
        References
        
        Curriculum Vitae

Page 2: Visible Light Photocatalyzed Redox-Neutral Organic Reactions and Synthesis of Novel Metal-Organic

Springer Theses

Recognizing Outstanding PhD Research

Aims and Scope

Basudev Sahoo

123

MuumlnsterGermany

vii

Abstract

+

N2

R2

Nu

R1

Nu

R2 R3

PhotoredoxCatalysis

GoldCatalysis

IAr

or

R3

ix

O O

NR3R3

NBr

EWGN

EWG

R1R1

R2

( )mY

R( )m

YR

CF3

XO

HO X

( )n( )nPhotoredox

Catalysis

S

CF3OTf

x Abstract

B

OHO

O

OH

HO

O

I

Br

H3TPB

COOH

Zn4O6+

Abstract xi

xiii

Acknowledgements

xv

Contents

xvii

(MOFs) 118

xviii Contents

References 251

Contents xix

Abbreviations

xxi

xxii Abbreviations

Abbreviations xxiii

1

x

PC(S0)

PC(S10)

kahigh ν kp

kf

kic

knrkalow ν

kic

knr

PC(T10)

PC(S1n)

kiscPC(T1

n)

Spinforbidden

Spinallowed

E00 = h(cλem)

OQ

e-

PC+

hνvis

RQ

e-

Oxidative Quenching

Cycle

Reductive Quenching

Cycle

PC(S1)

PCminus

PC(S0)

PC(T1)

ISC

PC(T1)

PC(S1)

PC(S0)

EnergyTransfer

ISC

Q(T1)

Q(S0)

Q(S1)

hνvis

Energy Transfer(b)

N

NIr

fac-Ir(ppy)3

NN

N

Ru

[Ru(bpy)3](PF6)2

(PF6)2

N

NN

N

NN

N

NN

Ru

[Ru(bpz)3](PF6)2

(PF6)2

N

Ar

CuNN

Ar

Cl

Organic Dyes

O

COOH

HO OR

R R

R

NClO4

Acridinium Dye

O

COONa

HO OI

I I

I

Rose Bengal

Cl

ClCl

Cl S

N

Cl

Methylene Blue

NMe2Me2N

N

Ir

N

Ir

FF

F

FF3C

CF3 (PF6)

(PF6)

Tab

le12

Photoelectronicprop

ertiesof

selected

photoredox

catalysts[31

34]

Photocatalyst

E12(M

+

M)

(V)

E12(M

Mminus)(V

)E12(M

+M

)a

(V)

E12(MM

minus)a

(V)

Absorptionλ a

bs

(nm)

Emission

λ em

(nm)

e(τns)

Rubp

yeth

THORN 32thorn

minus081

+077

+129

minus133

452

615

1100

Rubp

zeth

THORN 32thorn

minus026

+145

+186

minus080

443

591

740

fac-Ir(ppy

) 3minus173

+031

+077

minus219

375

494b

1900

Ir(ppy

) 2(dtbbp

y)+

minus096

+066

+121

minus151

ndash58

155

7

Ir(dF(CF 3)

ppy)

2(dtbb

py)+

minus089

+121

+169

minus137

380

470

2300

Cudap

ethTHORN 2

thornminus143

ndash+0

62

ndashndash

670c

270

Eosin

Yminus111

+083

+078

minus106

539

ndash24

000

Acridinium

perchlorate

_+2

06

_minus057

430

__

a Redox

Eb M

easuredin

EtOHM

eOH

(11)

c Measuredin

DCM

NO O

O O

DIPEA oxalate

O

S

SR

xanthate

OSO OO

O SO

OO

perdisulfate

N N

viologens

N2

phenyldiazonium

etc

etcSCF3

BF3K

CO2H

CO2HHN

O

CH3CNvisible light

R1

CO2H

R1 R1

1 2R1 = H Br OMe

R1 = H

R1 = BrR1 = OMe

20

10

8020

8080

direct photolysis

CH3CN

N2BF4

3

1

[Ru(bpy)3]2+

SET

CO2H

N2

CO2H

HCO2H

H

CO2H

- H+

1

3

CO2H

R1N2BF4

CO2H

CO2HN

+ H2O

CO2HHN

ON

2

5

6

- H+

XX

Eosin Y (1 mol)

N2BF4

R2

R1 R1

R21140-86

Eosin Y

Eosin Yhν

vis

SET

N2

OxidativeQuenching

Eosin Y

N2

O

H

O

H

O

N2

chain

-H+

deprotonation

75-10 equiv

91 equiv

7 8

9

10118

7

B

A

Y

Z

X

R

B

A

Y

Z

X

R

CF3

NHCOR6

R4

R1

N2BF4IAr BF4

R4 R4

R2R3

OR3NHPh

R1R1

R2R2

Br CN

22-95

12

10 equiv 20 equiv

(05 equiv)

CN

OR5NHCOR6

R4

R1

R2R3

R1

R2R3

10 equiv

25-83 20-92

7

2+ (Scheme 17) [94]

X XCO2EtBr

DMF rt blue LEDs

NPh

OMeMeO

20 equiv

CO2Et

R1R1

49-92

hνvis

SET

ReductiveQuenching

[Ru(bpy)3]2+

PMPNPh

PMP PMPNPh

PMP

CO2EtBr

CO2Et

NBr

N CO2Et

CO2EtH

N CO2Et

CO2EtH[O]

-H+

N CO2Et

CO2Et

10 equiv

13

14

15

16 17

18

hνvis

SET

ReductiveQuenching

[Ru(bpz)3]2+

NH

Ph

NH

Ph

NH

Ph

NH

Ph

HN

Ar

HN

N ( )n

Ar

N ( )n

R2

R1R1

R2H

R1R1

degassed CH3NO2 rt

13 W CFLAr

50 equiv 71-87dr 11 to 21

28-77dr 31 to gt251

R1 = EWG EDG

R3 R3

20 21

22

19

+

R2BrR1 R1

R2

DG

N2BF4

DG

R2

R1

2310 equiv

R1

R2

I

R2

Ar BF4

7 (40 equiv) 12 (20 equiv)

24

DG

2310 equiv

R1

PC

PalladiumCatalysis

PhotoredoxCatalysis

hνvis

C-Hactivation

SET

oxidativearylation

N2 or ArI

NPdIILn

NPdIIILn

Ar

NPdIVLn

Ar

PdIILn

NAr

24

N22H+

26

25

27

Ar

Ar N2

Ar I Ar

PC

7

12

8

H

BOHHO RF

RFI

39-93

R1R1

R1 = EWG EDG

2928

CF3I

F3C I

CF3

CuIX

CuIIX2

CF3

transmetalation

[Ru(bpy)3]2+

[Ru(bpy)3]+

PhotoredoxCatalysis

hνvis

SET

[Ru(bpy)3]2+

CF3

XB(OH)2

SET

BOH

OH

30

28

29

R1

YR2

O

R1

YR2

O

EWG

R1

YR2

O

O R4

EWG

Br

O R4Br

NH OTMS

ArAr

Ar =

CF3

CF3 N

OMe

NH2

N31

32

R3

Br

EWG

N

R1

R2

X

Br

EWG

N

R1

R2

X

R1

O

R2

EWG

Br

EWG

N

R1

R2

X

N

R1

R2

X

GWE

N

R1

R2

X

GWE Br

EWG

R1

O

R2

hνvis

EDA complex

tight ion-pair

Br

radicaladdition

mesolysis

SET

bareradical-anion

hydrolysis

enamineformation

33

34

35

36

15 Summary

X

R4 R3

( )n R2

R1

X R2

R3H R4

R1

HH

64-90

X

R4 R3

( )n R2

R1

triplet state

Triplet-Triplet

( )n

References

References 21

References 23

21 Introduction

25

AuClN

S

SO

CF3

O

OCF3

O

Gol

d(I)

Prec

urso

rs

NAuO

OCl

ClAuCl3

[PicAu]Cl2Gol

d(III

)Pre

curs

ors

AuBr3

P

Au

Au Cl

Cl

(dppm)(AuCl)2

R1

O

R2

R2R1

Ph3PAuMeMsOH

R3OH

R3 = alkyl allyl

AuCl3

R1R2

OR3R3O

21 Introduction 27

AuNu

L

AuL

AuLAuL X

ENu

Nu

E

37 38

40

41

39

AuNu

L

AuL

43

44

AgX

E = H Br I

R1Nu

R2Nu

Pd catalyst

cross coupling

oxidative coupling

π -coordination

R2 Y

II

I

Gold Catalysis

R1 X

I

Y = H SiMe3 B(OH)2

42

RndashAu

21 Introduction 29

O O

PPh3Au

OOEt

CH2Cl2

12 equiv 47 82

HO O

84-92

R1

= H

Pd cat

R3-X

R1MeO2CR1MeO2C

46 35-84

(a)

(b)

R3 R2

R1MeO2C

OH O

O

H

AuCl3 (5 mol)

CH3CN rt

47 10

Au(I)

minor product

O O

R1

O O

OO

O O

HR1R1

48

R1

49 13-67 50 8-40

R1= H alkyl

(a)

(b)

Via

LAuIII

L

R2

O O

R1 NN

F

Cl

2BF4

R2

O

R2

R1

53

21 Introduction 31

OHOB

54 57 n = 1 56-7360 n = 2 R1 = H 35

OHOB

56 28 (20 equiv) 59 78-79

OO

NHTs TsNB

HO OH

55 28 (20 equiv) 58 n = 1 44-9461 n = 2 63-82

R1

R2R2

( )n

( )n( )n

( )n

28 (20 equiv)

(a)

(b)

(c)

R1 = H alkyl

Ph3PAuCl (10 mol)

NHTsTsNB

HO OH

62 28 (20 equiv) 63 83dr = 221

D

H DH

21 Introduction 33

Au XL Au XL

FI III

Au FL

XIII

TsN

Au FL

XIII

TsN

PhB OH

OH

++

NN

F

Cl

2BF4

NN

Cl

BF4

H+

PhB(OH)2 (28)

NHTs

58

TsN

Ph

FB(OH)2

A

BC

substitution

nucleophilic attack

55

R1( )n R1

( )n

OR3

R2

M

R2

M = B(OH)2

M = SiMe3

M = B(OH)2 33-91M = SiMe3 37-96

M = SiMe3

21 Introduction 35

NH2

NaNO2 aq HBF4

H2O 0-5 degC

tBuONO or iAmONO

iAmONO

R1

N2X

R1

SN

S

O O

R1= H EWG EDG7

X = BF4

SHN

S

O O

64

NN

- N2

221 Inspiration

21 Introduction 37

I X

IO

IHO OTs R1

R2I

R1

R1R1

R1

CH2Cl2 rt

(4 equiv)

CH2Cl2 rt

2 rtB(OH)2

R2(11 equiv)

31-88

R2 23-98

R229-63

TMS

(10 equiv)

I

R251-92

(a)

(c)

(b)

X

follow up reactions

I

or

CO2H

CO2HHN

O

CH3CNvisible light

R1

CO2H

R1 R1

1 2R1 = H Br OMe

R1 = H

R1 = BrR1 = OMe

20

10

8020

8080

direct photolysis

CH3CN

N2BF4

3

1

DG N2BF4 DG

R2

R1

2310 equiv

R1 R2

740 equiv

24

OHN2BF4 O

degassed solvent rt

54 65 57

2+Equivof 65

Solvent Time(h)

Yield()b

1 Ph3PAuCl (10) 50 4 MeOH 6 51

2 (Me2S)AuCl (10) 50 4 MeOH 12 26

4 [dppm(AuCl)2] (10) 50 4 MeOH 12 22

8 [Ph3PAu]NTf2 (10) 50 4 MeOH 4 84

50 4 MeOH 12 ndash

10 [(Ph3P)2Au]OTf (10) 50 4 MeOH 12 50

12 [Ph3PAu]NTf2 (10) 50 4 CH3CN 12 20

15 [Ph3PAu]NTf2 (10) 50 4 CH2Cl2 12 3

16 [Ph3PAu]NTf2 (10) 50 4 DMA 12 17

17 [Ph3PAu]NTf2 (10) 50 4 EtOH 12 66

20 [Ph3PAu]NTf2 (5) 25 4 MeOH 12 50

21 [Ph3PAu]NTf2 (1) 25 4 MeOH 75 22

22 [Ph3PAu]NTf2 (5) 12 4 MeOH 12 70

23 [Ph3PAu]NTf2 (5) 12 3 MeOH 12 60

XH

R2R3

R1

( )n( )n

X R3 R2

R1

degassed MeOH rt

OH

170 (161)

O

OOH

66 (281)2

OH O3

56

OH

O R

O

R

59 (gt251)

3963

NHTs

RR

TsN

RR

45

6

8[d]

9[d]

10 OH O34

8454

R4 R4

PhPh

X = O Nn = 1 2

R = MeR = Ph

OH O

56 (gt251)7[c]

R = HR = Me

67

68

66

6970

7374

71

72

75

76

77

7980

78

81

82

8384

85

40 equiv

OH

23 W CFL bulb

degassed MeOH rt

O

1

2

3

4

5

6

7

8

N2BF4

F

N2BF4

Ph

N2BF4

Cl

N2BF4

EtO2C

Br

N2BF4

OMe

N2BF4

79

78

64

83

75

60

42

F3C

Br

O

PhO

OOEtO

FO

BrO

Cl

Br

O

OMe

F3C

32

R1

N2BF4

R1

40 equiv

65

86

87

88

89

90

91

92

57

93

94

95

96

97

98

99

40 equiv

O

102 82100

40 equiv

(a)

(b)

O

102 86

N2BF4

IPh BF4

OR2

[a]

110 (R2 = m-CO2Et) B 50[b]

Ph O

OPh

O

111A 75 B 78

O2N

O

OPh

Br

O

OPh

MeO2CPh

OMeO2C

Ph

MeO

O

OPh

115B 26

OR3

117 (R3 = Et) B 75118 (R3 = iPr) B 26

Y Ph

57 (Y = O) B 68120 (Y = NTs) B 79

112A 60 B 66

113A 84 B 82

114A 76 B 67

N

OPh

116B 52

O

119 B 26

O

R1

Condition B

R1 ArO

fluorescein (5 mol)

Condition A

R1

O

106 (R = Br) 102 (R = H)131

100 121(40 equiv)

I

Br

BF4

+

R

54 65 (40 equiv) 57

0 0

20

60

90

120

150

40

41

68

81

OHO

86 (40 equiv)

Ph

(E)-122

Ph

123 17

O Ph

124not detected

O

125

H DNTs

H

TsN

H

H D

3JHH = 96 Hz

TsN

H

D H

3JHH = 34 Hz

D HNTs

H

D-(E)-126 (D = 94)

D-(RS)-(129) 68 dr = 171D-(Z)-127 (D = 84)

NHTs

D

H

NHTs

H

D

D-(RR)-(128) 73 dr = 141

N2BF4

65 (40 equiv) +-( )

+-( )

[PC]

[PC]+

SET

L [AuII]

Ar

L AuI

N2

ArN2+ (7)

or Ar2I+ (12)

R1

Nu

L AuI

R1

Nu

R1 130

R1 ArNu

131

or ArI

Ar

SET

PhotoredoxCatalysis

GoldCatalysis

H+

o R

R1 130

or

7 or 12

Ar

N2 orArI

L [AuIII]

Ar

R1

Nu

A

B

C

[PC]

23 Summary

References

References 55

(2006)

References 57

31 Introduction

59

NN

SF3C

ON

OF

F3C O

CF3

O

O CN

HO

HN

O

NH

Cl

OCF3

NH

O

CF3Cl

OHN

F3C

N

OOH

HN

OF

HOHO

N

F

O

OH

O

NHN

HN

NH

O

F

HOH

SO

CF2CF3H

H

OH

NH

NS

ON

OCF3

O

N2BF4

S

SS

S

SS

SO O O

S S

SS

O

OH

S

SS

S

SS

S

N2

moisted acetone

H2O

H+BF4

-SET nucleophilic

substitution

radicaladdition

TTF (Cat)

TTF TTF

TTF

133 36132

134 135 136

31 Introduction 61

CF3SO2Na(CF3SO2)2Zn

Me3SiCF3

K[CF3B(OMe)3]

CF3H

SCF3

OIF3COI

F3C

O

CF3I

SNMe2

CF3

PhO

BF4-

SCF3

BF4- (138)

OTf- (139)

OIF3C

O

CF3I

(CF3SO2)2ZnCF3SO2Na

CF3SO2Cletc etc etc

SCF3

Cl OMe

SbF6-

Si CF3

140

137

OIF3CMe3SiCF3

141 141140

BF4- (138)

OTf- (139)

31 Introduction 63

CF3

Addition

Elimination

R4

R3R1R2

R2

R1R3

CF3

R2

R3R5

R1R4

CF3

X

Desilylation

R5

R4

R3R1R2

R5 CF3

R2

R3R1R4

CF3Y

R4

R3R1R2

R5 CF3

R4

R3R1R2

R5 CF3

Nu

O

R3R1R2

R5 CF3

R4 = OAc

Nu = SO

Me2S

R5 = Y

R4

R5 = TMS

R-HX

SETRadical-Polar

Crossover

RadicalAddition

KornblumOxidation

( )n

PC

PC+

PChν

e-CF3+

( )n

path a

path b

path epath d

path c

path

Oxidative

f

Quenching

R3CF3R2

R5

R4

( )n

R( )n

CF3

(a)

(b)

RR CF3

SCF3

OTf39-78

139 (12 equiv)

CF3I

(excess) 81-90

31 Introduction 65

(25 equiv)

CF3SO2Cl

R3R3 CF3

SCF3

BF4

138 (11 equiv)

R2

R1R1

R4 = alkyl acyl

41-96

Ar ArCF3

140 (12 equiv)

R3

R1R1

28-87

OIF3C

OR2

R2

(a)

(b)

(c)

(d)

Ar ArCF3

OAc

R1R1

63-93

R2

R1

OH

NHR2

orN

CF3

R2

OCF3

R1

R2 = alkyl 60-65

CF3I

(30 equiv)

Ar

ArCF3

SCF3

BF4

138 (11 equiv) 141 (12 equiv)

OIF3C

[Ir(ppy)3] (3 mol)

(a)

(b)

Condition B

R2 R1

TMS R2 R1

SCF3

OTf

139 (18 equiv) 140 (18 equiv)

OIF3CCF3

O

R2 R1

TMS

Ar

RmR1

OH

RmR1

O

E

RmR1

OE

δ+ O

ER1

Rm

+E+

-H+

-H+H

H

(b)

(a)

31 Introduction 67

( )n

( )nR1

( )n

( )nR1

FO

HO

R1 = EWG EDGn = 0 1

PA (5 mol)

OP

O OOH

c-C5H10

c-C5H10 c-C5H10PA

(a)

(b)

NN

Cl

F(15 equiv)

YOHR1R2

YR1

O

CF3

R2

YR1

O

X

R2

65-94X = Cl Br I

( )n

Y = CH2 On = 0 1

CH3CN rt 1 min

CH2Cl2 28 degC

140 (15 equiv)

OIF3C

O

2BF4

321 Inspiration

31 Introduction 69

SCF3

X139 X = OTf138 X = BF4

I O

O

F3C I OF3C

140 141

RadicalAddition

ArCF3

Ar( )n

CF3

Ar( )n

CF3

( )n

Ar( )n

CF3

( )n

Ar( )n

CF3

X( )nO

HO X

O

X

Elimination

Undesired

Desired

HO X( )n

( )n

HO X( )n

Undesired

ArCF3

( )n

HO X( )n

SET

RadicalAddition

ArCF3

Ar( )n

CF3

Ar( )n

CF3

( )n

Ar( )n

CF3

( )n

Ar( )n

CF3

X( )nO

HO X

O

X

Elimination

Undesired

Desired

HO X( )n

( )n

HO X( )n

Undesired

ArCF3

( )n

HO X( )n

SET

O

F3C142 143

+ Source

HO

CF3

O

144

1c [Ru(bpy)3](PF6)2(2)

60

2 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

98

3 [Ru(bpy)3](PF6)2(2)

DMF (01) 138 (14) TMSOTf(12)

BlueLEDs

81

4 [Ru(bpy)3](PF6)2(2)

DMF (01) 140 (14) TMSOTf(12)

BlueLEDs

9

5 [Ru(bpy)3](PF6)2(2)

DMF (01) 141 (14) TMSOTf(12)

BlueLEDs

ndash

6 [Ru(bpy)3](PF6)2(2)

DMSO(01)

139 (14) TMSOTf(12)

BlueLEDs

90

7 [Ru(bpy)3](PF6)2(2)

CH3CN(01)

139 (14) TMSOTf(12)

BlueLEDs

ndash

8 [Ru(bpy)3](PF6)2(2)

MeOH(01)

139 (14) TMSOTf(12)

BlueLEDs

78

9 [Ru(bpy)3](PF6)2(2)

THF (01) 139 (14) TMSOTf(12)

BlueLEDs

3

10 [Ru(bpy)3](PF6)2(2)

12-DCE(01)

139 (14) TMSOTf(12)

BlueLEDs

ndash

DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

97

12 [Ir(ppy)3] (2) DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

96

BlueLEDs

ndash

14 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (14) TMSOTf(12)

23 WCFL

92

15 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (12) TMSOTf(12)

BlueLEDs

95

16 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (12) TMSOTf(05)

BlueLEDs

70

17 [Ru(bpy)3](PF6)2(1)

DMF(01)

139 (12) TMSOTf(12)

BlueLEDs

94(74)

18 ndash DMF (01) 139 (12) TMSOTf(12)

BlueLEDs

ndash

19 [Ru(bpy)3](PF6)2(1)

DMF (01) 139 (12) TMSOTf(12)

ndash ndash

( )mYR

CF3

TMSOTf (12 equiv)

HO X( )n

( )n

HO

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

OHO

CF3

O

F

Cl

Me

F

Cl

Me

Me74

73

60

78

CF3O

51

149167

166148

147 165

164146

143142

HO

CF3

O

39

150168

Me Me

155 173

O

CF3O

HO

O 158 176

52 (11)

41 (101)

(continued)

HO

HO O

CF3

OO

HO O

CF3

OO

27 nd[d]

29

162 180

179161

F F

CF3O

181163

CF3

O

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

O

Ph

MeO

O

Ph

MeO

O

82

90

86

80

172154

153 171

170152

151 169

CF3O

HO

156 174

Me

CF3O

HO

157 175MeO MeO

HO

159 177

HO

160 178

29 (111)

47 (gt251)

53 (151)[b]

33

65 (151)[c]

OH

F3C182 91 (dr = 251)

O

F3C143

N

F3C184 70

HO

NH2OHHCl (50 equiv)

NaBH4 (15 equiv)

MeOH 0 degC 45 min

F3C183 81

O

OMMPP (33 equiv)

O

F3C143

O

F3C143

(a)

(b)

(c)

OH O

F3C

NO

CF3

DMF rt Blue LEDs

143not observed

185detected by

142

(a)

OH O

F3C

MeOH rt Blue LEDs

14378 (GC yield)

145detected by

GC-MS analysis

142

(b)OH

CF3

OMe

SCF3

OTf

139 (12 equiv)

SCF3

OTf

139 (14 equiv)

33 Summary

CF3

O

143

[Ru(bpy)3]2+

[Ru(bpy)3]3+

Catalysis

SCF3

139 OTf

S

OH

142

OTMS

TMSOTf

TfOH

radicaladditionA

OTMS

CF3B

OTMS

CF3C

139

CF3

SET

12-carbonshift

CF3

OTMS

D

TMSOTf

radicalchain

(Φ = 38)Silyl

protectionSilyl

deprotection

minus081 V vs SCE

+129 V vs SCE

minus025 V vs SCE

References

References 79

1906 (1985)

41 Introduction

81

N

8 1

2

3456

7NN

N

SO

O

ON

OO

N

NCOH

N

CN

NH

SGL T1 antagonist

O

NH2

O

Antioxidant

NN

OR3

R1 R2

N

R1

R2

R3

N

ONC

O

N

O

HN

PDE4 inhibitor

OH

Cl

N

Cl

41 Introduction 83

N O

O O

N

O

200-220 degC

- CH3COOH- H2O

Nhydrolysis

N

O

NH

O

OH

N

cyclization

O200-220 degC

O

OH

186

187

189

188

NR1

R2

NR1

R2

R3

O

R4

Br

O

R4

R3

Br 35-100 degCN

R1

R2

R3

R4Δ

NaHCO3H2O

28-85 30-94

NR1

R2

R3

O

R4via

NO

PhCOOMeMeOOC N

COOMe

OPh

PdC

toluene

18

41 Introduction 85

NR1 R2

BrN

R1

R2K2CO3

EtOH or CHCl3

4-95

R3

O OR3

NR1 R2

R3

O

Br

ether or CHCl3

rt

R3

O1 5

via

N

ClN

N

R1

N

R1

10-12

or Δ or US

50 equiv

N NN

Cl

N

R1

57-85

R1 Cl

R1 = EWG EDG

OO

Cl

R1

N

Cl

OO

RhLn

via metal carbenoid

N O

O

R1

5-10

CH2Cl2 rt

Cl

NEWG

R1N

EWG

R1

Ag2CO3 (20 equiv)

20 equiv

45-89R1 = EWG EDG

41 Introduction 87

NEWG

R1N

EWG

R1

I2 (20 mol)

DCE30 equiv

25-59R1 = EWG EDG

NEWG O N

R1

EWGI2 (60 mol)

R1

421 Inspiration

N

EWGCl

R2

20 equiv

N

EWG

R1R1

N

EWG BF3K

R1

Pd(OAc)2 (10 mol)

DMF 90 degC10 equiv

N

EWG

R140-93R1 = EWG EDG

(a)

(b)

Zhao et al (2012)

N

EWG B(OH)2

R2

20 equiv

N

EWG

R1R1

422 Reaction Design

NCO2R1

Br

O O

NR2 R2

N

OR1O

visible light

190 191 192

PhotoredoxCatalysis

PC

NCO2R1

Br

O

N

O

R2R2

N

O

R2R2

OR1

O

N

O

N

O

R2R2

OR1

O

N

NCO2R1

Br

NCO2R1

Br

NCO2R1

BrBr

O

N

O

R2R2

N

OR1

O

N

O

R2R2

N

OR1

O

N

OR1

O

H

-H+

-R22NCOOH

SET

Mesolysis

RadicalAddition

NucleophilicAttack

Elimination

Deprotonation

Chain192

190191

190

E

A

B

B A

C

D

F

NN

Br

O

N

194

193

O

OO

195 62

NN

Br

O

N

194

+No photocatalyst

193

O

OO

NN

Br

O

N

194

193

O

OO

195 52

195 0

(a)

(b)

(c)

O O

N

O O

N

O O

N

O O

N

O

200 201 202 203

O O

O

O O OS

N

196 197 198 199

OOF3C

O

O O

204

NN

Br

O

N

194

+base

solventlight source

193

O

OO

195

(continued)

34 HMDS (2) PhCF3 1 194 (5) 23 W CFL 24

45 HMDS (1) PhCF3 1 194 (5) ndash 1

46g HMDS (1) PhCF3 1 194 (5) ndash 3

NN

EWG

Br

EWG

O

NR4

R4R1 R1

R2

R3

R2

50 equiv

+HMDS (1 equiv)

N

OOR5

N

OO

N N

OO

N

OO

20816b

20967

218 (R6 = Br) 74219 (R6 = F) 55

22065

N

R6

F3C

N

OO

NN

OO

N

OO

21765

21661

21475

21368

Ph

OO

Cl

N

OO

N

OO

21542

21238b

21167b

OO

F

N

OO

22133b

Cl

N

OO

21061b

N

OO

O

OO

O

OO

N

OO

22228

O 2230 (0)c

195

N

OO

DDQ (10 equiv)

225 96

N

OO

224 71

N

OO

PtO2 (10 mol)

(b)(a)

N CO2Et

CO2Et

NCO2Et

Br

EtO2C 195 (10 mol)

N

O

195

O

82

NPh

43 Summary

O

N

226[M+Na]+ C17H26N2O3Na+

ON

O

ON

O O

N

227[M+Na]+ C30H41N3O5Na+

References

O O

N

NBr

O

ON

OO

193(10 equiv)

195

43 Summary 105

References 107

51 Intoduction

109

HO

O OH

O

OH

OHO

O

OH

HO

O

HO

O

OH

O

NN

H3BTB H4BenzTB

NN

OHO

HOO

N N

O

OHO O

Mn

O

HO

Cl

H2BDC

H2NDC

44-Bipy

(a)

(b) (c)

O OH

Zn

ZnOCu

OOO O

CuOO

O O

L

structure

Fe

FeFeO OO O

OO

OO O

O

OO

OCl OH2

H2O

51 Intoduction 111

51 Intoduction 113

O OH

OHO

N

Zn(NO3)2times4H2O

BTB DMF 85 degC16

N

UMCM-1-Ph-Indole

N

Ph23

Pd(OAc)2

[Ph2I]BF4DMF rt 5 d

H

23

51 Intoduction 115

521 Inspiration

B

OH

O

OHO

HO

O

DMF 95 degC 3 d

I

Br B

Br

BrBr

B

OO

O

B

OHO

O

OH

HO

O

2) BF3Et2O

231 47

228 95

1) NaOHMeOHH2O (11)

2) aq H2SO4 (1M)

230 42229

5231 PXRD Analysis

B

OHO

O

OH

HO

OH3TPB (228)

OHO

O OH

R

H2BDC (232) R = H

O

Ph

Zn(NO3)2x4H2ODEF

80 degC 48 h

DUT-6 (Boron) (234)

5233 TGA Analysis

N2 adsorption study

53 Summary

References

References 125

312 (2015)

Procedures

127

Polarimetry

Photospectrometry

TGA analysis

NN

N

Ru (PF6)2

+ ([M-PF6]+)

7150748 measured 7150773

N

NN

+ ([M + H]+) 1590665measured 1590672

N

NN

N

NN

N

NN

Ru (PF6)2

+ ([M-PF6]+) 7210457 measured 7210461

N

Ir

N

Ir

Cl

+ ([12M-Cl]+) 5010937 measured 5010947

N

NIr

+

([M + Na]+) 6781493 measured 6781481

N

Ir (PF6)

+ ([M-PF6]+) 7692879 measured 7692900

OH

+ ([M + Na]+) 1631093 measured 1631090

OH

+ ([M + Na]+) 1850937 measured 1850935

OH

+

([M + Na]+) 1651250 measured 1651244

OH

NHS

O

NHS

O

+ ([M + Na]+) 2901185measured 2901189

NHS

O

D

+

([M + Na]+) 2630935 measured 2630932

O

General Procedure 1

General Procedure 2

General Procedure 3

XH

R3

R4

R2

( )n( )n

X R4 R3

R2

R1

N2BF4

R1

23 W lightbulb

degassed MeOH rt

X = O Nn = 1 2

R5 R5

General Procedure 4

R1 + ArN2+ BF4

-

O

General Procedure 5

R1 + [Ar2I]+ BF4-

OR3

O

(plusmn)

O

(plusmn)

O

(plusmn)

O

(plusmn)

O

+

O

NSO O

NSO O D

+

NSO O D

+

NSO O

O

F

+

O

OO

(ATR) ν (cmminus1) 2976 2941 2868 1714 1611 1416 1367 1273 1178 11041062 1022 857 759 708 631

O

F3C

+

O

Br

OBr

Cl

O

+

O

O2N

OO

O

MeO

O

N

O

ν (cmminus1) 2930 2827 1771 1707 1495 1467 1439 1396 1373 1267 11881100 1026 923 866 793 735 719 700 630 604

O

+

OBr

+

O O

O

R

1447 1416 1391 1367 1311 1273 1178 1101 1022 910 860 822 761 732706 648 629

OCF3

+

O

O R

+

NSO O

General Procedure 6

Y

O

Y = CH2 On = 0 1

( )nY

Br

( )n

Y = CH2 O n = 0 1

General Procedure 7

Br

R R

X

X = CH2 O

X O

General Procedure 8

Y

Br

Y = CH2 O

Y

Y = CH2 O

2O

R R

OH

+

([M + Na]+) 1970937 measured 1970933

OH

F

measured 2150840

OH

Cl

+ ([M + Na]+) 2310547measured 2310541

OH

sured 2111094

OH

+ ([M + Na]+) 2731250 measured 2731256

OH

O

(40) 162 (15) 161 (41) 160 (14) 159 (34) 155 (11) 148 (40) 147 (36) 146 (12)145 (77) 144 (14) 134 (20) 133 (100) 132 (11) 131 (10) 128 (15) 127 (10) 121(50) 119 (10) 118 (19) 117 (29) 116 (10) 115 (36) 108 (13) 105 (21) 103 (18)102 (11) 91 (28) 90 (20) 89 (29) 79 (14) 78 (11) 77 (33) 65 (17) 64 (10) 63(21) 51 (13) 43 (11) 39 (16)

+ ([M + Na]+) 2271043 measured 2271050

OH

O

+ ([M + Na]+) 2410835measured 2410834

OH

+ ([M + Na]+) 2471093 measured 2471097

OH

+

([M + Na]+) 2111093 measured 2111093

OH

+

([M + Na]+) 2111093 measured 2111105

OH

+ ([M + Na]+) 2231093 measured 2231096

OH

+ ([M + Na]+) 1751093 measured 1751096

OHO

+ ([M + Na]+) 1970937 measured 1970933

OHO

F

+

([M + Na]+) 2170635 measured 2170647

OH

+

([M + Na]+) 2111093 measured 2111093

OH

+ ([M + Na]+) 2090937 measured 2090948

General Procedure 9

( )mYR

CF3

XO

HO X( )n

( )n

O

F3C

CF3

O

+

O

F3C

F

O

F3C

Cl

+

O

F3C

O

F3C

O

F3C

O

+

O

F3C O

O

F3C

O

F3C

+

O

F3C

CF3O

Diastereomer A

+

Diastereomer B

O

CF3O

Major diastereomer

OCF3

Major diastereomer

Minor diastereomer

CF3O

O

Major diastereomer

O

CF3

Major diastereomer

Minor diastereomer

O

F3C

+

O

F3C

F

O

F3C

N

F3C184 70

HOO

F3C143

EtOH rt 48 h

N

F3Cxx

HO

OH

F3C182 91 dr = 251

O

F3C143

NaBH4 (15 equiv)

MeOH 0 degC 45 min

OH

F3C

O

F3CF3C

O

MMPP (33 equiv)

143183 81

O

F3C7

OH

S

CF3OTf

O

F3C

N

O CF3

TMSOTf (12 equiv)

DMF rt

Blue LEDs

N

O (24 equiv)

142 (10 equiv)

OH

SCF3

OTf

O

F3C

MeOH rtBlue LEDs

142 (10 equiv)

OH

CF3

OMe

y = 4E -09

Rsup2 = 09816

0

00000005

0000001

00000015

0000002

00000025

0000003

-100 100 300 500 700

Mol

es o

f Fe(

II) f

orm

ed

Time (s)

x

N Br

I

N Br

BHO OH

881 equiv1 equiv

y = 38439xRsup2 = 09966

0

0000005

000001

0000015

000002

0000025

-1E-06 5E-21 0000001 2E-06 3E-06 4E-06 5E-06 6E-06

Mol

s of

pro

duct

0 0 0

NH

OH

O

Cl

N OtBu

O

N OBn

O

35

66

N O

O

+

N O

O

+

N Br

R

N

R

CO2Me

CO2MeN

R

CO2Me

LiCl (1 equiv)

N O

O

OO

F

N O

OF

N O

OF3C

N O

O

OO

N O

O

+

N O

O

OO

N O

O

N

Cl

O

OO

N

Cl

O

N O

O

OO

N O

O

(cmminus1) 2953 1735 1605 1562 1435 1337 1265 1247 1200 1154 1016 998918 829 652 620 601

N NO

N

O

mCPBA (10 equiv)

CH2Cl2 rt 4 h

Ac2ODMF

0 degC - rt 15 h

O

25

59

(12 equiv)

NO

N

O

N Cl

O2N

N

O2N

CO2Me

N

O2N

CO2Me

N

Br

CO2MeN

H2N

CO2Me

NaH (22 equiv) DMF

NaCl (2 equiv)

DMSOH2O120 degC 3 h

PdC (5) EtOH

70 28

Br

N

O2N

O

OO

N

O2N

O

+

2962 2361 2340 1730 1600 1580 1508 1476 1434 1411 1362 1261 12371187 1169 1118 1022 991 944 903 865 848 827 725 684 630

N

H2N

O

N

Br

O

Br

N

R1

CO2R2CNN

R1

CO2R2CN

Br (10 equiv)

N

Br

O

N

Br

O

+

N

Br

O

N

Br

O

N

Br

N

+

N

Br

O

OF

N

Br

O

OF3C

N

Br

O

N

Br

O

N

Cl

Br

O

+

N

Br

O

+

N

Br

O

R1

R2

O

R1

R2

O

NR3

R3

ii) rt 16 h

Cl NR32

O

(11 equiv)

O

N

+

O

N

O

N

O

N

O

+ ([M + Na]+)

O O

N

+

O O

O

O O

NR4R4

N

Br

CO2R2CNN

CO2R2CN

Blue LEDs (465 nm)

R1

R3

N

OO

N

OO

+

N

OO

N

OO

N

OO

O

N

OO

O

Br

79NO3]+ ([M]+) 3850308

N

OO

O

F

N

OO

O

F3C

N

OO

O

N

OO

O

N

OO

O

Cl

N

OO

O

N

OO

O

N

OO

F

N

OO

N

OO

O O

1466 1452 1433 1405 1389 1363 1335 1321 1310 1277 1256 1239 12141189 1183 1150 1127 1109 1065 1038 1027 1010 982 935 919 880 853813 791 779 740 725 718 691 676 664 615 605

N

OO

Cl

N

OO

O

195

N

OO

DDQ (1 equiv)

22471

N

OO

22596

N

OO

PtO2 (10 mol)

N

OO

N

OO

O O

N

Br

O

N

OO

193(10 equiv)

195

N CO2Et

CO2Et

N

CO2Et

Br

blue LEDs (465 nm)

(20 equiv)(10 equiv) 18 45

N

O

195

O

N

OO

F(000) 7120

(continued)

O2ndashC17 13534(18) O2ndashC18 14434(18)

O3ndashC15 13731(18) O3ndashC19 14285(18)

N1ndashC8 13804(19) N1ndashC4 13922(19)

N1ndashC1 14052(19) C1ndashC2 1405(2)

C2ndashC17 1456(2) C3ndashC4 1378(2)

C3ndashC9 14997(19) C4ndashC12 1460(2)

C11ndashC16 1391(2) C11ndashC12 1412(2)

C12ndashC13 1399(2) C13ndashC14 1385(2)

C19ndashH19C 098

C5ndashH5O2 095 240 29315(18) 1147

C16ndashH16O1 095 247 33219(18) 1496

B

Br

BrBr

B

OO

O

B

OHO

O

OH

HO

O

minus ([Mndash

O O

OO

Br

N

O O

OO

+

([M + Na]+) 3921105 measured 3921106

N

HO O

OHO

OO

F(000) 83920

the term n 1 pp0

nmfrac14 1ffiffiffi

Cp thorn 1

Figures 614 and 615

References

References 251

References 253

Curriculum Vitae

Education

255

Publications

Teaching Experience

Abstract
Acknowledgements
Contents
Abbreviations
      - 15 Summary
        
        References
        
        
        21 Introduction
        
        
        
        
        
        
        
        
        
        
        221 Inspiration
        
        
        
        
        
        
        
        
        23 Summary
        
        References
        
        
        31 Introduction
        
        
        
        
        
        
        
        
        
        
        321 Inspiration
        
        
        
        
        
        33 Summary
        
        References
        
        
        41 Introduction
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        421 Inspiration
        
        422 Reaction Design
        
        
        
        
        
        43 Summary
        
        References
        
        
        51 Intoduction
        
        
        
        
        
        
        521 Inspiration
        
        
        
        5231 PXRD Analysis
        
        
        5233 TGA Analysis
        
        
        
        
        53 Summary
        
        References
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        References
        
        Curriculum Vitae

Page 3: Visible Light Photocatalyzed Redox-Neutral Organic Reactions and Synthesis of Novel Metal-Organic

Aims and Scope

Basudev Sahoo

123

MuumlnsterGermany

vii

Abstract

+

N2

R2

Nu

R1

Nu

R2 R3

PhotoredoxCatalysis

GoldCatalysis

IAr

or

R3

ix

O O

NR3R3

NBr

EWGN

EWG

R1R1

R2

( )mY

R( )m

YR

CF3

XO

HO X

( )n( )nPhotoredox

Catalysis

S

CF3OTf

x Abstract

B

OHO

O

OH

HO

O

I

Br

H3TPB

COOH

Zn4O6+

Abstract xi

xiii

Acknowledgements

xv

Contents

xvii

(MOFs) 118

xviii Contents

References 251

Contents xix

Abbreviations

xxi

xxii Abbreviations

Abbreviations xxiii

1

x

PC(S0)

PC(S10)

kahigh ν kp

kf

kic

knrkalow ν

kic

knr

PC(T10)

PC(S1n)

kiscPC(T1

n)

Spinforbidden

Spinallowed

E00 = h(cλem)

OQ

e-

PC+

hνvis

RQ

e-

Oxidative Quenching

Cycle

Reductive Quenching

Cycle

PC(S1)

PCminus

PC(S0)

PC(T1)

ISC

PC(T1)

PC(S1)

PC(S0)

EnergyTransfer

ISC

Q(T1)

Q(S0)

Q(S1)

hνvis

Energy Transfer(b)

N

NIr

fac-Ir(ppy)3

NN

N

Ru

[Ru(bpy)3](PF6)2

(PF6)2

N

NN

N

NN

N

NN

Ru

[Ru(bpz)3](PF6)2

(PF6)2

N

Ar

CuNN

Ar

Cl

Organic Dyes

O

COOH

HO OR

R R

R

NClO4

Acridinium Dye

O

COONa

HO OI

I I

I

Rose Bengal

Cl

ClCl

Cl S

N

Cl

Methylene Blue

NMe2Me2N

N

Ir

N

Ir

FF

F

FF3C

CF3 (PF6)

(PF6)

Tab

le12

Photoelectronicprop

ertiesof

selected

photoredox

catalysts[31

34]

Photocatalyst

E12(M

+

M)

(V)

E12(M

Mminus)(V

)E12(M

+M

)a

(V)

E12(MM

minus)a

(V)

Absorptionλ a

bs

(nm)

Emission

λ em

(nm)

e(τns)

Rubp

yeth

THORN 32thorn

minus081

+077

+129

minus133

452

615

1100

Rubp

zeth

THORN 32thorn

minus026

+145

+186

minus080

443

591

740

fac-Ir(ppy

) 3minus173

+031

+077

minus219

375

494b

1900

Ir(ppy

) 2(dtbbp

y)+

minus096

+066

+121

minus151

ndash58

155

7

Ir(dF(CF 3)

ppy)

2(dtbb

py)+

minus089

+121

+169

minus137

380

470

2300

Cudap

ethTHORN 2

thornminus143

ndash+0

62

ndashndash

670c

270

Eosin

Yminus111

+083

+078

minus106

539

ndash24

000

Acridinium

perchlorate

_+2

06

_minus057

430

__

a Redox

Eb M

easuredin

EtOHM

eOH

(11)

c Measuredin

DCM

NO O

O O

DIPEA oxalate

O

S

SR

xanthate

OSO OO

O SO

OO

perdisulfate

N N

viologens

N2

phenyldiazonium

etc

etcSCF3

BF3K

CO2H

CO2HHN

O

CH3CNvisible light

R1

CO2H

R1 R1

1 2R1 = H Br OMe

R1 = H

R1 = BrR1 = OMe

20

10

8020

8080

direct photolysis

CH3CN

N2BF4

3

1

[Ru(bpy)3]2+

SET

CO2H

N2

CO2H

HCO2H

H

CO2H

- H+

1

3

CO2H

R1N2BF4

CO2H

CO2HN

+ H2O

CO2HHN

ON

2

5

6

- H+

XX

Eosin Y (1 mol)

N2BF4

R2

R1 R1

R21140-86

Eosin Y

Eosin Yhν

vis

SET

N2

OxidativeQuenching

Eosin Y

N2

O

H

O

H

O

N2

chain

-H+

deprotonation

75-10 equiv

91 equiv

7 8

9

10118

7

B

A

Y

Z

X

R

B

A

Y

Z

X

R

CF3

NHCOR6

R4

R1

N2BF4IAr BF4

R4 R4

R2R3

OR3NHPh

R1R1

R2R2

Br CN

22-95

12

10 equiv 20 equiv

(05 equiv)

CN

OR5NHCOR6

R4

R1

R2R3

R1

R2R3

10 equiv

25-83 20-92

7

2+ (Scheme 17) [94]

X XCO2EtBr

DMF rt blue LEDs

NPh

OMeMeO

20 equiv

CO2Et

R1R1

49-92

hνvis

SET

ReductiveQuenching

[Ru(bpy)3]2+

PMPNPh

PMP PMPNPh

PMP

CO2EtBr

CO2Et

NBr

N CO2Et

CO2EtH

N CO2Et

CO2EtH[O]

-H+

N CO2Et

CO2Et

10 equiv

13

14

15

16 17

18

hνvis

SET

ReductiveQuenching

[Ru(bpz)3]2+

NH

Ph

NH

Ph

NH

Ph

NH

Ph

HN

Ar

HN

N ( )n

Ar

N ( )n

R2

R1R1

R2H

R1R1

degassed CH3NO2 rt

13 W CFLAr

50 equiv 71-87dr 11 to 21

28-77dr 31 to gt251

R1 = EWG EDG

R3 R3

20 21

22

19

+

R2BrR1 R1

R2

DG

N2BF4

DG

R2

R1

2310 equiv

R1

R2

I

R2

Ar BF4

7 (40 equiv) 12 (20 equiv)

24

DG

2310 equiv

R1

PC

PalladiumCatalysis

PhotoredoxCatalysis

hνvis

C-Hactivation

SET

oxidativearylation

N2 or ArI

NPdIILn

NPdIIILn

Ar

NPdIVLn

Ar

PdIILn

NAr

24

N22H+

26

25

27

Ar

Ar N2

Ar I Ar

PC

7

12

8

H

BOHHO RF

RFI

39-93

R1R1

R1 = EWG EDG

2928

CF3I

F3C I

CF3

CuIX

CuIIX2

CF3

transmetalation

[Ru(bpy)3]2+

[Ru(bpy)3]+

PhotoredoxCatalysis

hνvis

SET

[Ru(bpy)3]2+

CF3

XB(OH)2

SET

BOH

OH

30

28

29

R1

YR2

O

R1

YR2

O

EWG

R1

YR2

O

O R4

EWG

Br

O R4Br

NH OTMS

ArAr

Ar =

CF3

CF3 N

OMe

NH2

N31

32

R3

Br

EWG

N

R1

R2

X

Br

EWG

N

R1

R2

X

R1

O

R2

EWG

Br

EWG

N

R1

R2

X

N

R1

R2

X

GWE

N

R1

R2

X

GWE Br

EWG

R1

O

R2

hνvis

EDA complex

tight ion-pair

Br

radicaladdition

mesolysis

SET

bareradical-anion

hydrolysis

enamineformation

33

34

35

36

15 Summary

X

R4 R3

( )n R2

R1

X R2

R3H R4

R1

HH

64-90

X

R4 R3

( )n R2

R1

triplet state

Triplet-Triplet

( )n

References

References 21

References 23

21 Introduction

25

AuClN

S

SO

CF3

O

OCF3

O

Gol

d(I)

Prec

urso

rs

NAuO

OCl

ClAuCl3

[PicAu]Cl2Gol

d(III

)Pre

curs

ors

AuBr3

P

Au

Au Cl

Cl

(dppm)(AuCl)2

R1

O

R2

R2R1

Ph3PAuMeMsOH

R3OH

R3 = alkyl allyl

AuCl3

R1R2

OR3R3O

21 Introduction 27

AuNu

L

AuL

AuLAuL X

ENu

Nu

E

37 38

40

41

39

AuNu

L

AuL

43

44

AgX

E = H Br I

R1Nu

R2Nu

Pd catalyst

cross coupling

oxidative coupling

π -coordination

R2 Y

II

I

Gold Catalysis

R1 X

I

Y = H SiMe3 B(OH)2

42

RndashAu

21 Introduction 29

O O

PPh3Au

OOEt

CH2Cl2

12 equiv 47 82

HO O

84-92

R1

= H

Pd cat

R3-X

R1MeO2CR1MeO2C

46 35-84

(a)

(b)

R3 R2

R1MeO2C

OH O

O

H

AuCl3 (5 mol)

CH3CN rt

47 10

Au(I)

minor product

O O

R1

O O

OO

O O

HR1R1

48

R1

49 13-67 50 8-40

R1= H alkyl

(a)

(b)

Via

LAuIII

L

R2

O O

R1 NN

F

Cl

2BF4

R2

O

R2

R1

53

21 Introduction 31

OHOB

54 57 n = 1 56-7360 n = 2 R1 = H 35

OHOB

56 28 (20 equiv) 59 78-79

OO

NHTs TsNB

HO OH

55 28 (20 equiv) 58 n = 1 44-9461 n = 2 63-82

R1

R2R2

( )n

( )n( )n

( )n

28 (20 equiv)

(a)

(b)

(c)

R1 = H alkyl

Ph3PAuCl (10 mol)

NHTsTsNB

HO OH

62 28 (20 equiv) 63 83dr = 221

D

H DH

21 Introduction 33

Au XL Au XL

FI III

Au FL

XIII

TsN

Au FL

XIII

TsN

PhB OH

OH

++

NN

F

Cl

2BF4

NN

Cl

BF4

H+

PhB(OH)2 (28)

NHTs

58

TsN

Ph

FB(OH)2

A

BC

substitution

nucleophilic attack

55

R1( )n R1

( )n

OR3

R2

M

R2

M = B(OH)2

M = SiMe3

M = B(OH)2 33-91M = SiMe3 37-96

M = SiMe3

21 Introduction 35

NH2

NaNO2 aq HBF4

H2O 0-5 degC

tBuONO or iAmONO

iAmONO

R1

N2X

R1

SN

S

O O

R1= H EWG EDG7

X = BF4

SHN

S

O O

64

NN

- N2

221 Inspiration

21 Introduction 37

I X

IO

IHO OTs R1

R2I

R1

R1R1

R1

CH2Cl2 rt

(4 equiv)

CH2Cl2 rt

2 rtB(OH)2

R2(11 equiv)

31-88

R2 23-98

R229-63

TMS

(10 equiv)

I

R251-92

(a)

(c)

(b)

X

follow up reactions

I

or

CO2H

CO2HHN

O

CH3CNvisible light

R1

CO2H

R1 R1

1 2R1 = H Br OMe

R1 = H

R1 = BrR1 = OMe

20

10

8020

8080

direct photolysis

CH3CN

N2BF4

3

1

DG N2BF4 DG

R2

R1

2310 equiv

R1 R2

740 equiv

24

OHN2BF4 O

degassed solvent rt

54 65 57

2+Equivof 65

Solvent Time(h)

Yield()b

1 Ph3PAuCl (10) 50 4 MeOH 6 51

2 (Me2S)AuCl (10) 50 4 MeOH 12 26

4 [dppm(AuCl)2] (10) 50 4 MeOH 12 22

8 [Ph3PAu]NTf2 (10) 50 4 MeOH 4 84

50 4 MeOH 12 ndash

10 [(Ph3P)2Au]OTf (10) 50 4 MeOH 12 50

12 [Ph3PAu]NTf2 (10) 50 4 CH3CN 12 20

15 [Ph3PAu]NTf2 (10) 50 4 CH2Cl2 12 3

16 [Ph3PAu]NTf2 (10) 50 4 DMA 12 17

17 [Ph3PAu]NTf2 (10) 50 4 EtOH 12 66

20 [Ph3PAu]NTf2 (5) 25 4 MeOH 12 50

21 [Ph3PAu]NTf2 (1) 25 4 MeOH 75 22

22 [Ph3PAu]NTf2 (5) 12 4 MeOH 12 70

23 [Ph3PAu]NTf2 (5) 12 3 MeOH 12 60

XH

R2R3

R1

( )n( )n

X R3 R2

R1

degassed MeOH rt

OH

170 (161)

O

OOH

66 (281)2

OH O3

56

OH

O R

O

R

59 (gt251)

3963

NHTs

RR

TsN

RR

45

6

8[d]

9[d]

10 OH O34

8454

R4 R4

PhPh

X = O Nn = 1 2

R = MeR = Ph

OH O

56 (gt251)7[c]

R = HR = Me

67

68

66

6970

7374

71

72

75

76

77

7980

78

81

82

8384

85

40 equiv

OH

23 W CFL bulb

degassed MeOH rt

O

1

2

3

4

5

6

7

8

N2BF4

F

N2BF4

Ph

N2BF4

Cl

N2BF4

EtO2C

Br

N2BF4

OMe

N2BF4

79

78

64

83

75

60

42

F3C

Br

O

PhO

OOEtO

FO

BrO

Cl

Br

O

OMe

F3C

32

R1

N2BF4

R1

40 equiv

65

86

87

88

89

90

91

92

57

93

94

95

96

97

98

99

40 equiv

O

102 82100

40 equiv

(a)

(b)

O

102 86

N2BF4

IPh BF4

OR2

[a]

110 (R2 = m-CO2Et) B 50[b]

Ph O

OPh

O

111A 75 B 78

O2N

O

OPh

Br

O

OPh

MeO2CPh

OMeO2C

Ph

MeO

O

OPh

115B 26

OR3

117 (R3 = Et) B 75118 (R3 = iPr) B 26

Y Ph

57 (Y = O) B 68120 (Y = NTs) B 79

112A 60 B 66

113A 84 B 82

114A 76 B 67

N

OPh

116B 52

O

119 B 26

O

R1

Condition B

R1 ArO

fluorescein (5 mol)

Condition A

R1

O

106 (R = Br) 102 (R = H)131

100 121(40 equiv)

I

Br

BF4

+

R

54 65 (40 equiv) 57

0 0

20

60

90

120

150

40

41

68

81

OHO

86 (40 equiv)

Ph

(E)-122

Ph

123 17

O Ph

124not detected

O

125

H DNTs

H

TsN

H

H D

3JHH = 96 Hz

TsN

H

D H

3JHH = 34 Hz

D HNTs

H

D-(E)-126 (D = 94)

D-(RS)-(129) 68 dr = 171D-(Z)-127 (D = 84)

NHTs

D

H

NHTs

H

D

D-(RR)-(128) 73 dr = 141

N2BF4

65 (40 equiv) +-( )

+-( )

[PC]

[PC]+

SET

L [AuII]

Ar

L AuI

N2

ArN2+ (7)

or Ar2I+ (12)

R1

Nu

L AuI

R1

Nu

R1 130

R1 ArNu

131

or ArI

Ar

SET

PhotoredoxCatalysis

GoldCatalysis

H+

o R

R1 130

or

7 or 12

Ar

N2 orArI

L [AuIII]

Ar

R1

Nu

A

B

C

[PC]

23 Summary

References

References 55

(2006)

References 57

31 Introduction

59

NN

SF3C

ON

OF

F3C O

CF3

O

O CN

HO

HN

O

NH

Cl

OCF3

NH

O

CF3Cl

OHN

F3C

N

OOH

HN

OF

HOHO

N

F

O

OH

O

NHN

HN

NH

O

F

HOH

SO

CF2CF3H

H

OH

NH

NS

ON

OCF3

O

N2BF4

S

SS

S

SS

SO O O

S S

SS

O

OH

S

SS

S

SS

S

N2

moisted acetone

H2O

H+BF4

-SET nucleophilic

substitution

radicaladdition

TTF (Cat)

TTF TTF

TTF

133 36132

134 135 136

31 Introduction 61

CF3SO2Na(CF3SO2)2Zn

Me3SiCF3

K[CF3B(OMe)3]

CF3H

SCF3

OIF3COI

F3C

O

CF3I

SNMe2

CF3

PhO

BF4-

SCF3

BF4- (138)

OTf- (139)

OIF3C

O

CF3I

(CF3SO2)2ZnCF3SO2Na

CF3SO2Cletc etc etc

SCF3

Cl OMe

SbF6-

Si CF3

140

137

OIF3CMe3SiCF3

141 141140

BF4- (138)

OTf- (139)

31 Introduction 63

CF3

Addition

Elimination

R4

R3R1R2

R2

R1R3

CF3

R2

R3R5

R1R4

CF3

X

Desilylation

R5

R4

R3R1R2

R5 CF3

R2

R3R1R4

CF3Y

R4

R3R1R2

R5 CF3

R4

R3R1R2

R5 CF3

Nu

O

R3R1R2

R5 CF3

R4 = OAc

Nu = SO

Me2S

R5 = Y

R4

R5 = TMS

R-HX

SETRadical-Polar

Crossover

RadicalAddition

KornblumOxidation

( )n

PC

PC+

PChν

e-CF3+

( )n

path a

path b

path epath d

path c

path

Oxidative

f

Quenching

R3CF3R2

R5

R4

( )n

R( )n

CF3

(a)

(b)

RR CF3

SCF3

OTf39-78

139 (12 equiv)

CF3I

(excess) 81-90

31 Introduction 65

(25 equiv)

CF3SO2Cl

R3R3 CF3

SCF3

BF4

138 (11 equiv)

R2

R1R1

R4 = alkyl acyl

41-96

Ar ArCF3

140 (12 equiv)

R3

R1R1

28-87

OIF3C

OR2

R2

(a)

(b)

(c)

(d)

Ar ArCF3

OAc

R1R1

63-93

R2

R1

OH

NHR2

orN

CF3

R2

OCF3

R1

R2 = alkyl 60-65

CF3I

(30 equiv)

Ar

ArCF3

SCF3

BF4

138 (11 equiv) 141 (12 equiv)

OIF3C

[Ir(ppy)3] (3 mol)

(a)

(b)

Condition B

R2 R1

TMS R2 R1

SCF3

OTf

139 (18 equiv) 140 (18 equiv)

OIF3CCF3

O

R2 R1

TMS

Ar

RmR1

OH

RmR1

O

E

RmR1

OE

δ+ O

ER1

Rm

+E+

-H+

-H+H

H

(b)

(a)

31 Introduction 67

( )n

( )nR1

( )n

( )nR1

FO

HO

R1 = EWG EDGn = 0 1

PA (5 mol)

OP

O OOH

c-C5H10

c-C5H10 c-C5H10PA

(a)

(b)

NN

Cl

F(15 equiv)

YOHR1R2

YR1

O

CF3

R2

YR1

O

X

R2

65-94X = Cl Br I

( )n

Y = CH2 On = 0 1

CH3CN rt 1 min

CH2Cl2 28 degC

140 (15 equiv)

OIF3C

O

2BF4

321 Inspiration

31 Introduction 69

SCF3

X139 X = OTf138 X = BF4

I O

O

F3C I OF3C

140 141

RadicalAddition

ArCF3

Ar( )n

CF3

Ar( )n

CF3

( )n

Ar( )n

CF3

( )n

Ar( )n

CF3

X( )nO

HO X

O

X

Elimination

Undesired

Desired

HO X( )n

( )n

HO X( )n

Undesired

ArCF3

( )n

HO X( )n

SET

RadicalAddition

ArCF3

Ar( )n

CF3

Ar( )n

CF3

( )n

Ar( )n

CF3

( )n

Ar( )n

CF3

X( )nO

HO X

O

X

Elimination

Undesired

Desired

HO X( )n

( )n

HO X( )n

Undesired

ArCF3

( )n

HO X( )n

SET

O

F3C142 143

+ Source

HO

CF3

O

144

1c [Ru(bpy)3](PF6)2(2)

60

2 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

98

3 [Ru(bpy)3](PF6)2(2)

DMF (01) 138 (14) TMSOTf(12)

BlueLEDs

81

4 [Ru(bpy)3](PF6)2(2)

DMF (01) 140 (14) TMSOTf(12)

BlueLEDs

9

5 [Ru(bpy)3](PF6)2(2)

DMF (01) 141 (14) TMSOTf(12)

BlueLEDs

ndash

6 [Ru(bpy)3](PF6)2(2)

DMSO(01)

139 (14) TMSOTf(12)

BlueLEDs

90

7 [Ru(bpy)3](PF6)2(2)

CH3CN(01)

139 (14) TMSOTf(12)

BlueLEDs

ndash

8 [Ru(bpy)3](PF6)2(2)

MeOH(01)

139 (14) TMSOTf(12)

BlueLEDs

78

9 [Ru(bpy)3](PF6)2(2)

THF (01) 139 (14) TMSOTf(12)

BlueLEDs

3

10 [Ru(bpy)3](PF6)2(2)

12-DCE(01)

139 (14) TMSOTf(12)

BlueLEDs

ndash

DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

97

12 [Ir(ppy)3] (2) DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

96

BlueLEDs

ndash

14 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (14) TMSOTf(12)

23 WCFL

92

15 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (12) TMSOTf(12)

BlueLEDs

95

16 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (12) TMSOTf(05)

BlueLEDs

70

17 [Ru(bpy)3](PF6)2(1)

DMF(01)

139 (12) TMSOTf(12)

BlueLEDs

94(74)

18 ndash DMF (01) 139 (12) TMSOTf(12)

BlueLEDs

ndash

19 [Ru(bpy)3](PF6)2(1)

DMF (01) 139 (12) TMSOTf(12)

ndash ndash

( )mYR

CF3

TMSOTf (12 equiv)

HO X( )n

( )n

HO

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

OHO

CF3

O

F

Cl

Me

F

Cl

Me

Me74

73

60

78

CF3O

51

149167

166148

147 165

164146

143142

HO

CF3

O

39

150168

Me Me

155 173

O

CF3O

HO

O 158 176

52 (11)

41 (101)

(continued)

HO

HO O

CF3

OO

HO O

CF3

OO

27 nd[d]

29

162 180

179161

F F

CF3O

181163

CF3

O

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

O

Ph

MeO

O

Ph

MeO

O

82

90

86

80

172154

153 171

170152

151 169

CF3O

HO

156 174

Me

CF3O

HO

157 175MeO MeO

HO

159 177

HO

160 178

29 (111)

47 (gt251)

53 (151)[b]

33

65 (151)[c]

OH

F3C182 91 (dr = 251)

O

F3C143

N

F3C184 70

HO

NH2OHHCl (50 equiv)

NaBH4 (15 equiv)

MeOH 0 degC 45 min

F3C183 81

O

OMMPP (33 equiv)

O

F3C143

O

F3C143

(a)

(b)

(c)

OH O

F3C

NO

CF3

DMF rt Blue LEDs

143not observed

185detected by

142

(a)

OH O

F3C

MeOH rt Blue LEDs

14378 (GC yield)

145detected by

GC-MS analysis

142

(b)OH

CF3

OMe

SCF3

OTf

139 (12 equiv)

SCF3

OTf

139 (14 equiv)

33 Summary

CF3

O

143

[Ru(bpy)3]2+

[Ru(bpy)3]3+

Catalysis

SCF3

139 OTf

S

OH

142

OTMS

TMSOTf

TfOH

radicaladditionA

OTMS

CF3B

OTMS

CF3C

139

CF3

SET

12-carbonshift

CF3

OTMS

D

TMSOTf

radicalchain

(Φ = 38)Silyl

protectionSilyl

deprotection

minus081 V vs SCE

+129 V vs SCE

minus025 V vs SCE

References

References 79

1906 (1985)

41 Introduction

81

N

8 1

2

3456

7NN

N

SO

O

ON

OO

N

NCOH

N

CN

NH

SGL T1 antagonist

O

NH2

O

Antioxidant

NN

OR3

R1 R2

N

R1

R2

R3

N

ONC

O

N

O

HN

PDE4 inhibitor

OH

Cl

N

Cl

41 Introduction 83

N O

O O

N

O

200-220 degC

- CH3COOH- H2O

Nhydrolysis

N

O

NH

O

OH

N

cyclization

O200-220 degC

O

OH

186

187

189

188

NR1

R2

NR1

R2

R3

O

R4

Br

O

R4

R3

Br 35-100 degCN

R1

R2

R3

R4Δ

NaHCO3H2O

28-85 30-94

NR1

R2

R3

O

R4via

NO

PhCOOMeMeOOC N

COOMe

OPh

PdC

toluene

18

41 Introduction 85

NR1 R2

BrN

R1

R2K2CO3

EtOH or CHCl3

4-95

R3

O OR3

NR1 R2

R3

O

Br

ether or CHCl3

rt

R3

O1 5

via

N

ClN

N

R1

N

R1

10-12

or Δ or US

50 equiv

N NN

Cl

N

R1

57-85

R1 Cl

R1 = EWG EDG

OO

Cl

R1

N

Cl

OO

RhLn

via metal carbenoid

N O

O

R1

5-10

CH2Cl2 rt

Cl

NEWG

R1N

EWG

R1

Ag2CO3 (20 equiv)

20 equiv

45-89R1 = EWG EDG

41 Introduction 87

NEWG

R1N

EWG

R1

I2 (20 mol)

DCE30 equiv

25-59R1 = EWG EDG

NEWG O N

R1

EWGI2 (60 mol)

R1

421 Inspiration

N

EWGCl

R2

20 equiv

N

EWG

R1R1

N

EWG BF3K

R1

Pd(OAc)2 (10 mol)

DMF 90 degC10 equiv

N

EWG

R140-93R1 = EWG EDG

(a)

(b)

Zhao et al (2012)

N

EWG B(OH)2

R2

20 equiv

N

EWG

R1R1

422 Reaction Design

NCO2R1

Br

O O

NR2 R2

N

OR1O

visible light

190 191 192

PhotoredoxCatalysis

PC

NCO2R1

Br

O

N

O

R2R2

N

O

R2R2

OR1

O

N

O

N

O

R2R2

OR1

O

N

NCO2R1

Br

NCO2R1

Br

NCO2R1

BrBr

O

N

O

R2R2

N

OR1

O

N

O

R2R2

N

OR1

O

N

OR1

O

H

-H+

-R22NCOOH

SET

Mesolysis

RadicalAddition

NucleophilicAttack

Elimination

Deprotonation

Chain192

190191

190

E

A

B

B A

C

D

F

NN

Br

O

N

194

193

O

OO

195 62

NN

Br

O

N

194

+No photocatalyst

193

O

OO

NN

Br

O

N

194

193

O

OO

195 52

195 0

(a)

(b)

(c)

O O

N

O O

N

O O

N

O O

N

O

200 201 202 203

O O

O

O O OS

N

196 197 198 199

OOF3C

O

O O

204

NN

Br

O

N

194

+base

solventlight source

193

O

OO

195

(continued)

34 HMDS (2) PhCF3 1 194 (5) 23 W CFL 24

45 HMDS (1) PhCF3 1 194 (5) ndash 1

46g HMDS (1) PhCF3 1 194 (5) ndash 3

NN

EWG

Br

EWG

O

NR4

R4R1 R1

R2

R3

R2

50 equiv

+HMDS (1 equiv)

N

OOR5

N

OO

N N

OO

N

OO

20816b

20967

218 (R6 = Br) 74219 (R6 = F) 55

22065

N

R6

F3C

N

OO

NN

OO

N

OO

21765

21661

21475

21368

Ph

OO

Cl

N

OO

N

OO

21542

21238b

21167b

OO

F

N

OO

22133b

Cl

N

OO

21061b

N

OO

O

OO

O

OO

N

OO

22228

O 2230 (0)c

195

N

OO

DDQ (10 equiv)

225 96

N

OO

224 71

N

OO

PtO2 (10 mol)

(b)(a)

N CO2Et

CO2Et

NCO2Et

Br

EtO2C 195 (10 mol)

N

O

195

O

82

NPh

43 Summary

O

N

226[M+Na]+ C17H26N2O3Na+

ON

O

ON

O O

N

227[M+Na]+ C30H41N3O5Na+

References

O O

N

NBr

O

ON

OO

193(10 equiv)

195

43 Summary 105

References 107

51 Intoduction

109

HO

O OH

O

OH

OHO

O

OH

HO

O

HO

O

OH

O

NN

H3BTB H4BenzTB

NN

OHO

HOO

N N

O

OHO O

Mn

O

HO

Cl

H2BDC

H2NDC

44-Bipy

(a)

(b) (c)

O OH

Zn

ZnOCu

OOO O

CuOO

O O

L

structure

Fe

FeFeO OO O

OO

OO O

O

OO

OCl OH2

H2O

51 Intoduction 111

51 Intoduction 113

O OH

OHO

N

Zn(NO3)2times4H2O

BTB DMF 85 degC16

N

UMCM-1-Ph-Indole

N

Ph23

Pd(OAc)2

[Ph2I]BF4DMF rt 5 d

H

23

51 Intoduction 115

521 Inspiration

B

OH

O

OHO

HO

O

DMF 95 degC 3 d

I

Br B

Br

BrBr

B

OO

O

B

OHO

O

OH

HO

O

2) BF3Et2O

231 47

228 95

1) NaOHMeOHH2O (11)

2) aq H2SO4 (1M)

230 42229

5231 PXRD Analysis

B

OHO

O

OH

HO

OH3TPB (228)

OHO

O OH

R

H2BDC (232) R = H

O

Ph

Zn(NO3)2x4H2ODEF

80 degC 48 h

DUT-6 (Boron) (234)

5233 TGA Analysis

N2 adsorption study

53 Summary

References

References 125

312 (2015)

Procedures

127

Polarimetry

Photospectrometry

TGA analysis

NN

N

Ru (PF6)2

+ ([M-PF6]+)

7150748 measured 7150773

N

NN

+ ([M + H]+) 1590665measured 1590672

N

NN

N

NN

N

NN

Ru (PF6)2

+ ([M-PF6]+) 7210457 measured 7210461

N

Ir

N

Ir

Cl

+ ([12M-Cl]+) 5010937 measured 5010947

N

NIr

+

([M + Na]+) 6781493 measured 6781481

N

Ir (PF6)

+ ([M-PF6]+) 7692879 measured 7692900

OH

+ ([M + Na]+) 1631093 measured 1631090

OH

+ ([M + Na]+) 1850937 measured 1850935

OH

+

([M + Na]+) 1651250 measured 1651244

OH

NHS

O

NHS

O

+ ([M + Na]+) 2901185measured 2901189

NHS

O

D

+

([M + Na]+) 2630935 measured 2630932

O

General Procedure 1

General Procedure 2

General Procedure 3

XH

R3

R4

R2

( )n( )n

X R4 R3

R2

R1

N2BF4

R1

23 W lightbulb

degassed MeOH rt

X = O Nn = 1 2

R5 R5

General Procedure 4

R1 + ArN2+ BF4

-

O

General Procedure 5

R1 + [Ar2I]+ BF4-

OR3

O

(plusmn)

O

(plusmn)

O

(plusmn)

O

(plusmn)

O

+

O

NSO O

NSO O D

+

NSO O D

+

NSO O

O

F

+

O

OO

(ATR) ν (cmminus1) 2976 2941 2868 1714 1611 1416 1367 1273 1178 11041062 1022 857 759 708 631

O

F3C

+

O

Br

OBr

Cl

O

+

O

O2N

OO

O

MeO

O

N

O

ν (cmminus1) 2930 2827 1771 1707 1495 1467 1439 1396 1373 1267 11881100 1026 923 866 793 735 719 700 630 604

O

+

OBr

+

O O

O

R

1447 1416 1391 1367 1311 1273 1178 1101 1022 910 860 822 761 732706 648 629

OCF3

+

O

O R

+

NSO O

General Procedure 6

Y

O

Y = CH2 On = 0 1

( )nY

Br

( )n

Y = CH2 O n = 0 1

General Procedure 7

Br

R R

X

X = CH2 O

X O

General Procedure 8

Y

Br

Y = CH2 O

Y

Y = CH2 O

2O

R R

OH

+

([M + Na]+) 1970937 measured 1970933

OH

F

measured 2150840

OH

Cl

+ ([M + Na]+) 2310547measured 2310541

OH

sured 2111094

OH

+ ([M + Na]+) 2731250 measured 2731256

OH

O

(40) 162 (15) 161 (41) 160 (14) 159 (34) 155 (11) 148 (40) 147 (36) 146 (12)145 (77) 144 (14) 134 (20) 133 (100) 132 (11) 131 (10) 128 (15) 127 (10) 121(50) 119 (10) 118 (19) 117 (29) 116 (10) 115 (36) 108 (13) 105 (21) 103 (18)102 (11) 91 (28) 90 (20) 89 (29) 79 (14) 78 (11) 77 (33) 65 (17) 64 (10) 63(21) 51 (13) 43 (11) 39 (16)

+ ([M + Na]+) 2271043 measured 2271050

OH

O

+ ([M + Na]+) 2410835measured 2410834

OH

+ ([M + Na]+) 2471093 measured 2471097

OH

+

([M + Na]+) 2111093 measured 2111093

OH

+

([M + Na]+) 2111093 measured 2111105

OH

+ ([M + Na]+) 2231093 measured 2231096

OH

+ ([M + Na]+) 1751093 measured 1751096

OHO

+ ([M + Na]+) 1970937 measured 1970933

OHO

F

+

([M + Na]+) 2170635 measured 2170647

OH

+

([M + Na]+) 2111093 measured 2111093

OH

+ ([M + Na]+) 2090937 measured 2090948

General Procedure 9

( )mYR

CF3

XO

HO X( )n

( )n

O

F3C

CF3

O

+

O

F3C

F

O

F3C

Cl

+

O

F3C

O

F3C

O

F3C

O

+

O

F3C O

O

F3C

O

F3C

+

O

F3C

CF3O

Diastereomer A

+

Diastereomer B

O

CF3O

Major diastereomer

OCF3

Major diastereomer

Minor diastereomer

CF3O

O

Major diastereomer

O

CF3

Major diastereomer

Minor diastereomer

O

F3C

+

O

F3C

F

O

F3C

N

F3C184 70

HOO

F3C143

EtOH rt 48 h

N

F3Cxx

HO

OH

F3C182 91 dr = 251

O

F3C143

NaBH4 (15 equiv)

MeOH 0 degC 45 min

OH

F3C

O

F3CF3C

O

MMPP (33 equiv)

143183 81

O

F3C7

OH

S

CF3OTf

O

F3C

N

O CF3

TMSOTf (12 equiv)

DMF rt

Blue LEDs

N

O (24 equiv)

142 (10 equiv)

OH

SCF3

OTf

O

F3C

MeOH rtBlue LEDs

142 (10 equiv)

OH

CF3

OMe

y = 4E -09

Rsup2 = 09816

0

00000005

0000001

00000015

0000002

00000025

0000003

-100 100 300 500 700

Mol

es o

f Fe(

II) f

orm

ed

Time (s)

x

N Br

I

N Br

BHO OH

881 equiv1 equiv

y = 38439xRsup2 = 09966

0

0000005

000001

0000015

000002

0000025

-1E-06 5E-21 0000001 2E-06 3E-06 4E-06 5E-06 6E-06

Mol

s of

pro

duct

0 0 0

NH

OH

O

Cl

N OtBu

O

N OBn

O

35

66

N O

O

+

N O

O

+

N Br

R

N

R

CO2Me

CO2MeN

R

CO2Me

LiCl (1 equiv)

N O

O

OO

F

N O

OF

N O

OF3C

N O

O

OO

N O

O

+

N O

O

OO

N O

O

N

Cl

O

OO

N

Cl

O

N O

O

OO

N O

O

(cmminus1) 2953 1735 1605 1562 1435 1337 1265 1247 1200 1154 1016 998918 829 652 620 601

N NO

N

O

mCPBA (10 equiv)

CH2Cl2 rt 4 h

Ac2ODMF

0 degC - rt 15 h

O

25

59

(12 equiv)

NO

N

O

N Cl

O2N

N

O2N

CO2Me

N

O2N

CO2Me

N

Br

CO2MeN

H2N

CO2Me

NaH (22 equiv) DMF

NaCl (2 equiv)

DMSOH2O120 degC 3 h

PdC (5) EtOH

70 28

Br

N

O2N

O

OO

N

O2N

O

+

2962 2361 2340 1730 1600 1580 1508 1476 1434 1411 1362 1261 12371187 1169 1118 1022 991 944 903 865 848 827 725 684 630

N

H2N

O

N

Br

O

Br

N

R1

CO2R2CNN

R1

CO2R2CN

Br (10 equiv)

N

Br

O

N

Br

O

+

N

Br

O

N

Br

O

N

Br

N

+

N

Br

O

OF

N

Br

O

OF3C

N

Br

O

N

Br

O

N

Cl

Br

O

+

N

Br

O

+

N

Br

O

R1

R2

O

R1

R2

O

NR3

R3

ii) rt 16 h

Cl NR32

O

(11 equiv)

O

N

+

O

N

O

N

O

N

O

+ ([M + Na]+)

O O

N

+

O O

O

O O

NR4R4

N

Br

CO2R2CNN

CO2R2CN

Blue LEDs (465 nm)

R1

R3

N

OO

N

OO

+

N

OO

N

OO

N

OO

O

N

OO

O

Br

79NO3]+ ([M]+) 3850308

N

OO

O

F

N

OO

O

F3C

N

OO

O

N

OO

O

N

OO

O

Cl

N

OO

O

N

OO

O

N

OO

F

N

OO

N

OO

O O

1466 1452 1433 1405 1389 1363 1335 1321 1310 1277 1256 1239 12141189 1183 1150 1127 1109 1065 1038 1027 1010 982 935 919 880 853813 791 779 740 725 718 691 676 664 615 605

N

OO

Cl

N

OO

O

195

N

OO

DDQ (1 equiv)

22471

N

OO

22596

N

OO

PtO2 (10 mol)

N

OO

N

OO

O O

N

Br

O

N

OO

193(10 equiv)

195

N CO2Et

CO2Et

N

CO2Et

Br

blue LEDs (465 nm)

(20 equiv)(10 equiv) 18 45

N

O

195

O

N

OO

F(000) 7120

(continued)

O2ndashC17 13534(18) O2ndashC18 14434(18)

O3ndashC15 13731(18) O3ndashC19 14285(18)

N1ndashC8 13804(19) N1ndashC4 13922(19)

N1ndashC1 14052(19) C1ndashC2 1405(2)

C2ndashC17 1456(2) C3ndashC4 1378(2)

C3ndashC9 14997(19) C4ndashC12 1460(2)

C11ndashC16 1391(2) C11ndashC12 1412(2)

C12ndashC13 1399(2) C13ndashC14 1385(2)

C19ndashH19C 098

C5ndashH5O2 095 240 29315(18) 1147

C16ndashH16O1 095 247 33219(18) 1496

B

Br

BrBr

B

OO

O

B

OHO

O

OH

HO

O

minus ([Mndash

O O

OO

Br

N

O O

OO

+

([M + Na]+) 3921105 measured 3921106

N

HO O

OHO

OO

F(000) 83920

the term n 1 pp0

nmfrac14 1ffiffiffi

Cp thorn 1

Figures 614 and 615

References

References 251

References 253

Curriculum Vitae

Education

255

Publications

Teaching Experience

Abstract
Acknowledgements
Contents
Abbreviations
      - 15 Summary
        
        References
        
        
        21 Introduction
        
        
        
        
        
        
        
        
        
        
        221 Inspiration
        
        
        
        
        
        
        
        
        23 Summary
        
        References
        
        
        31 Introduction
        
        
        
        
        
        
        
        
        
        
        321 Inspiration
        
        
        
        
        
        33 Summary
        
        References
        
        
        41 Introduction
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        421 Inspiration
        
        422 Reaction Design
        
        
        
        
        
        43 Summary
        
        References
        
        
        51 Intoduction
        
        
        
        
        
        
        521 Inspiration
        
        
        
        5231 PXRD Analysis
        
        
        5233 TGA Analysis
        
        
        
        
        53 Summary
        
        References
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        References
        
        Curriculum Vitae

Page 4: Visible Light Photocatalyzed Redox-Neutral Organic Reactions and Synthesis of Novel Metal-Organic

Basudev Sahoo

123

MuumlnsterGermany

vii

Abstract

+

N2

R2

Nu

R1

Nu

R2 R3

PhotoredoxCatalysis

GoldCatalysis

IAr

or

R3

ix

O O

NR3R3

NBr

EWGN

EWG

R1R1

R2

( )mY

R( )m

YR

CF3

XO

HO X

( )n( )nPhotoredox

Catalysis

S

CF3OTf

x Abstract

B

OHO

O

OH

HO

O

I

Br

H3TPB

COOH

Zn4O6+

Abstract xi

xiii

Acknowledgements

xv

Contents

xvii

(MOFs) 118

xviii Contents

References 251

Contents xix

Abbreviations

xxi

xxii Abbreviations

Abbreviations xxiii

1

x

PC(S0)

PC(S10)

kahigh ν kp

kf

kic

knrkalow ν

kic

knr

PC(T10)

PC(S1n)

kiscPC(T1

n)

Spinforbidden

Spinallowed

E00 = h(cλem)

OQ

e-

PC+

hνvis

RQ

e-

Oxidative Quenching

Cycle

Reductive Quenching

Cycle

PC(S1)

PCminus

PC(S0)

PC(T1)

ISC

PC(T1)

PC(S1)

PC(S0)

EnergyTransfer

ISC

Q(T1)

Q(S0)

Q(S1)

hνvis

Energy Transfer(b)

N

NIr

fac-Ir(ppy)3

NN

N

Ru

[Ru(bpy)3](PF6)2

(PF6)2

N

NN

N

NN

N

NN

Ru

[Ru(bpz)3](PF6)2

(PF6)2

N

Ar

CuNN

Ar

Cl

Organic Dyes

O

COOH

HO OR

R R

R

NClO4

Acridinium Dye

O

COONa

HO OI

I I

I

Rose Bengal

Cl

ClCl

Cl S

N

Cl

Methylene Blue

NMe2Me2N

N

Ir

N

Ir

FF

F

FF3C

CF3 (PF6)

(PF6)

Tab

le12

Photoelectronicprop

ertiesof

selected

photoredox

catalysts[31

34]

Photocatalyst

E12(M

+

M)

(V)

E12(M

Mminus)(V

)E12(M

+M

)a

(V)

E12(MM

minus)a

(V)

Absorptionλ a

bs

(nm)

Emission

λ em

(nm)

e(τns)

Rubp

yeth

THORN 32thorn

minus081

+077

+129

minus133

452

615

1100

Rubp

zeth

THORN 32thorn

minus026

+145

+186

minus080

443

591

740

fac-Ir(ppy

) 3minus173

+031

+077

minus219

375

494b

1900

Ir(ppy

) 2(dtbbp

y)+

minus096

+066

+121

minus151

ndash58

155

7

Ir(dF(CF 3)

ppy)

2(dtbb

py)+

minus089

+121

+169

minus137

380

470

2300

Cudap

ethTHORN 2

thornminus143

ndash+0

62

ndashndash

670c

270

Eosin

Yminus111

+083

+078

minus106

539

ndash24

000

Acridinium

perchlorate

_+2

06

_minus057

430

__

a Redox

Eb M

easuredin

EtOHM

eOH

(11)

c Measuredin

DCM

NO O

O O

DIPEA oxalate

O

S

SR

xanthate

OSO OO

O SO

OO

perdisulfate

N N

viologens

N2

phenyldiazonium

etc

etcSCF3

BF3K

CO2H

CO2HHN

O

CH3CNvisible light

R1

CO2H

R1 R1

1 2R1 = H Br OMe

R1 = H

R1 = BrR1 = OMe

20

10

8020

8080

direct photolysis

CH3CN

N2BF4

3

1

[Ru(bpy)3]2+

SET

CO2H

N2

CO2H

HCO2H

H

CO2H

- H+

1

3

CO2H

R1N2BF4

CO2H

CO2HN

+ H2O

CO2HHN

ON

2

5

6

- H+

XX

Eosin Y (1 mol)

N2BF4

R2

R1 R1

R21140-86

Eosin Y

Eosin Yhν

vis

SET

N2

OxidativeQuenching

Eosin Y

N2

O

H

O

H

O

N2

chain

-H+

deprotonation

75-10 equiv

91 equiv

7 8

9

10118

7

B

A

Y

Z

X

R

B

A

Y

Z

X

R

CF3

NHCOR6

R4

R1

N2BF4IAr BF4

R4 R4

R2R3

OR3NHPh

R1R1

R2R2

Br CN

22-95

12

10 equiv 20 equiv

(05 equiv)

CN

OR5NHCOR6

R4

R1

R2R3

R1

R2R3

10 equiv

25-83 20-92

7

2+ (Scheme 17) [94]

X XCO2EtBr

DMF rt blue LEDs

NPh

OMeMeO

20 equiv

CO2Et

R1R1

49-92

hνvis

SET

ReductiveQuenching

[Ru(bpy)3]2+

PMPNPh

PMP PMPNPh

PMP

CO2EtBr

CO2Et

NBr

N CO2Et

CO2EtH

N CO2Et

CO2EtH[O]

-H+

N CO2Et

CO2Et

10 equiv

13

14

15

16 17

18

hνvis

SET

ReductiveQuenching

[Ru(bpz)3]2+

NH

Ph

NH

Ph

NH

Ph

NH

Ph

HN

Ar

HN

N ( )n

Ar

N ( )n

R2

R1R1

R2H

R1R1

degassed CH3NO2 rt

13 W CFLAr

50 equiv 71-87dr 11 to 21

28-77dr 31 to gt251

R1 = EWG EDG

R3 R3

20 21

22

19

+

R2BrR1 R1

R2

DG

N2BF4

DG

R2

R1

2310 equiv

R1

R2

I

R2

Ar BF4

7 (40 equiv) 12 (20 equiv)

24

DG

2310 equiv

R1

PC

PalladiumCatalysis

PhotoredoxCatalysis

hνvis

C-Hactivation

SET

oxidativearylation

N2 or ArI

NPdIILn

NPdIIILn

Ar

NPdIVLn

Ar

PdIILn

NAr

24

N22H+

26

25

27

Ar

Ar N2

Ar I Ar

PC

7

12

8

H

BOHHO RF

RFI

39-93

R1R1

R1 = EWG EDG

2928

CF3I

F3C I

CF3

CuIX

CuIIX2

CF3

transmetalation

[Ru(bpy)3]2+

[Ru(bpy)3]+

PhotoredoxCatalysis

hνvis

SET

[Ru(bpy)3]2+

CF3

XB(OH)2

SET

BOH

OH

30

28

29

R1

YR2

O

R1

YR2

O

EWG

R1

YR2

O

O R4

EWG

Br

O R4Br

NH OTMS

ArAr

Ar =

CF3

CF3 N

OMe

NH2

N31

32

R3

Br

EWG

N

R1

R2

X

Br

EWG

N

R1

R2

X

R1

O

R2

EWG

Br

EWG

N

R1

R2

X

N

R1

R2

X

GWE

N

R1

R2

X

GWE Br

EWG

R1

O

R2

hνvis

EDA complex

tight ion-pair

Br

radicaladdition

mesolysis

SET

bareradical-anion

hydrolysis

enamineformation

33

34

35

36

15 Summary

X

R4 R3

( )n R2

R1

X R2

R3H R4

R1

HH

64-90

X

R4 R3

( )n R2

R1

triplet state

Triplet-Triplet

( )n

References

References 21

References 23

21 Introduction

25

AuClN

S

SO

CF3

O

OCF3

O

Gol

d(I)

Prec

urso

rs

NAuO

OCl

ClAuCl3

[PicAu]Cl2Gol

d(III

)Pre

curs

ors

AuBr3

P

Au

Au Cl

Cl

(dppm)(AuCl)2

R1

O

R2

R2R1

Ph3PAuMeMsOH

R3OH

R3 = alkyl allyl

AuCl3

R1R2

OR3R3O

21 Introduction 27

AuNu

L

AuL

AuLAuL X

ENu

Nu

E

37 38

40

41

39

AuNu

L

AuL

43

44

AgX

E = H Br I

R1Nu

R2Nu

Pd catalyst

cross coupling

oxidative coupling

π -coordination

R2 Y

II

I

Gold Catalysis

R1 X

I

Y = H SiMe3 B(OH)2

42

RndashAu

21 Introduction 29

O O

PPh3Au

OOEt

CH2Cl2

12 equiv 47 82

HO O

84-92

R1

= H

Pd cat

R3-X

R1MeO2CR1MeO2C

46 35-84

(a)

(b)

R3 R2

R1MeO2C

OH O

O

H

AuCl3 (5 mol)

CH3CN rt

47 10

Au(I)

minor product

O O

R1

O O

OO

O O

HR1R1

48

R1

49 13-67 50 8-40

R1= H alkyl

(a)

(b)

Via

LAuIII

L

R2

O O

R1 NN

F

Cl

2BF4

R2

O

R2

R1

53

21 Introduction 31

OHOB

54 57 n = 1 56-7360 n = 2 R1 = H 35

OHOB

56 28 (20 equiv) 59 78-79

OO

NHTs TsNB

HO OH

55 28 (20 equiv) 58 n = 1 44-9461 n = 2 63-82

R1

R2R2

( )n

( )n( )n

( )n

28 (20 equiv)

(a)

(b)

(c)

R1 = H alkyl

Ph3PAuCl (10 mol)

NHTsTsNB

HO OH

62 28 (20 equiv) 63 83dr = 221

D

H DH

21 Introduction 33

Au XL Au XL

FI III

Au FL

XIII

TsN

Au FL

XIII

TsN

PhB OH

OH

++

NN

F

Cl

2BF4

NN

Cl

BF4

H+

PhB(OH)2 (28)

NHTs

58

TsN

Ph

FB(OH)2

A

BC

substitution

nucleophilic attack

55

R1( )n R1

( )n

OR3

R2

M

R2

M = B(OH)2

M = SiMe3

M = B(OH)2 33-91M = SiMe3 37-96

M = SiMe3

21 Introduction 35

NH2

NaNO2 aq HBF4

H2O 0-5 degC

tBuONO or iAmONO

iAmONO

R1

N2X

R1

SN

S

O O

R1= H EWG EDG7

X = BF4

SHN

S

O O

64

NN

- N2

221 Inspiration

21 Introduction 37

I X

IO

IHO OTs R1

R2I

R1

R1R1

R1

CH2Cl2 rt

(4 equiv)

CH2Cl2 rt

2 rtB(OH)2

R2(11 equiv)

31-88

R2 23-98

R229-63

TMS

(10 equiv)

I

R251-92

(a)

(c)

(b)

X

follow up reactions

I

or

CO2H

CO2HHN

O

CH3CNvisible light

R1

CO2H

R1 R1

1 2R1 = H Br OMe

R1 = H

R1 = BrR1 = OMe

20

10

8020

8080

direct photolysis

CH3CN

N2BF4

3

1

DG N2BF4 DG

R2

R1

2310 equiv

R1 R2

740 equiv

24

OHN2BF4 O

degassed solvent rt

54 65 57

2+Equivof 65

Solvent Time(h)

Yield()b

1 Ph3PAuCl (10) 50 4 MeOH 6 51

2 (Me2S)AuCl (10) 50 4 MeOH 12 26

4 [dppm(AuCl)2] (10) 50 4 MeOH 12 22

8 [Ph3PAu]NTf2 (10) 50 4 MeOH 4 84

50 4 MeOH 12 ndash

10 [(Ph3P)2Au]OTf (10) 50 4 MeOH 12 50

12 [Ph3PAu]NTf2 (10) 50 4 CH3CN 12 20

15 [Ph3PAu]NTf2 (10) 50 4 CH2Cl2 12 3

16 [Ph3PAu]NTf2 (10) 50 4 DMA 12 17

17 [Ph3PAu]NTf2 (10) 50 4 EtOH 12 66

20 [Ph3PAu]NTf2 (5) 25 4 MeOH 12 50

21 [Ph3PAu]NTf2 (1) 25 4 MeOH 75 22

22 [Ph3PAu]NTf2 (5) 12 4 MeOH 12 70

23 [Ph3PAu]NTf2 (5) 12 3 MeOH 12 60

XH

R2R3

R1

( )n( )n

X R3 R2

R1

degassed MeOH rt

OH

170 (161)

O

OOH

66 (281)2

OH O3

56

OH

O R

O

R

59 (gt251)

3963

NHTs

RR

TsN

RR

45

6

8[d]

9[d]

10 OH O34

8454

R4 R4

PhPh

X = O Nn = 1 2

R = MeR = Ph

OH O

56 (gt251)7[c]

R = HR = Me

67

68

66

6970

7374

71

72

75

76

77

7980

78

81

82

8384

85

40 equiv

OH

23 W CFL bulb

degassed MeOH rt

O

1

2

3

4

5

6

7

8

N2BF4

F

N2BF4

Ph

N2BF4

Cl

N2BF4

EtO2C

Br

N2BF4

OMe

N2BF4

79

78

64

83

75

60

42

F3C

Br

O

PhO

OOEtO

FO

BrO

Cl

Br

O

OMe

F3C

32

R1

N2BF4

R1

40 equiv

65

86

87

88

89

90

91

92

57

93

94

95

96

97

98

99

40 equiv

O

102 82100

40 equiv

(a)

(b)

O

102 86

N2BF4

IPh BF4

OR2

[a]

110 (R2 = m-CO2Et) B 50[b]

Ph O

OPh

O

111A 75 B 78

O2N

O

OPh

Br

O

OPh

MeO2CPh

OMeO2C

Ph

MeO

O

OPh

115B 26

OR3

117 (R3 = Et) B 75118 (R3 = iPr) B 26

Y Ph

57 (Y = O) B 68120 (Y = NTs) B 79

112A 60 B 66

113A 84 B 82

114A 76 B 67

N

OPh

116B 52

O

119 B 26

O

R1

Condition B

R1 ArO

fluorescein (5 mol)

Condition A

R1

O

106 (R = Br) 102 (R = H)131

100 121(40 equiv)

I

Br

BF4

+

R

54 65 (40 equiv) 57

0 0

20

60

90

120

150

40

41

68

81

OHO

86 (40 equiv)

Ph

(E)-122

Ph

123 17

O Ph

124not detected

O

125

H DNTs

H

TsN

H

H D

3JHH = 96 Hz

TsN

H

D H

3JHH = 34 Hz

D HNTs

H

D-(E)-126 (D = 94)

D-(RS)-(129) 68 dr = 171D-(Z)-127 (D = 84)

NHTs

D

H

NHTs

H

D

D-(RR)-(128) 73 dr = 141

N2BF4

65 (40 equiv) +-( )

+-( )

[PC]

[PC]+

SET

L [AuII]

Ar

L AuI

N2

ArN2+ (7)

or Ar2I+ (12)

R1

Nu

L AuI

R1

Nu

R1 130

R1 ArNu

131

or ArI

Ar

SET

PhotoredoxCatalysis

GoldCatalysis

H+

o R

R1 130

or

7 or 12

Ar

N2 orArI

L [AuIII]

Ar

R1

Nu

A

B

C

[PC]

23 Summary

References

References 55

(2006)

References 57

31 Introduction

59

NN

SF3C

ON

OF

F3C O

CF3

O

O CN

HO

HN

O

NH

Cl

OCF3

NH

O

CF3Cl

OHN

F3C

N

OOH

HN

OF

HOHO

N

F

O

OH

O

NHN

HN

NH

O

F

HOH

SO

CF2CF3H

H

OH

NH

NS

ON

OCF3

O

N2BF4

S

SS

S

SS

SO O O

S S

SS

O

OH

S

SS

S

SS

S

N2

moisted acetone

H2O

H+BF4

-SET nucleophilic

substitution

radicaladdition

TTF (Cat)

TTF TTF

TTF

133 36132

134 135 136

31 Introduction 61

CF3SO2Na(CF3SO2)2Zn

Me3SiCF3

K[CF3B(OMe)3]

CF3H

SCF3

OIF3COI

F3C

O

CF3I

SNMe2

CF3

PhO

BF4-

SCF3

BF4- (138)

OTf- (139)

OIF3C

O

CF3I

(CF3SO2)2ZnCF3SO2Na

CF3SO2Cletc etc etc

SCF3

Cl OMe

SbF6-

Si CF3

140

137

OIF3CMe3SiCF3

141 141140

BF4- (138)

OTf- (139)

31 Introduction 63

CF3

Addition

Elimination

R4

R3R1R2

R2

R1R3

CF3

R2

R3R5

R1R4

CF3

X

Desilylation

R5

R4

R3R1R2

R5 CF3

R2

R3R1R4

CF3Y

R4

R3R1R2

R5 CF3

R4

R3R1R2

R5 CF3

Nu

O

R3R1R2

R5 CF3

R4 = OAc

Nu = SO

Me2S

R5 = Y

R4

R5 = TMS

R-HX

SETRadical-Polar

Crossover

RadicalAddition

KornblumOxidation

( )n

PC

PC+

PChν

e-CF3+

( )n

path a

path b

path epath d

path c

path

Oxidative

f

Quenching

R3CF3R2

R5

R4

( )n

R( )n

CF3

(a)

(b)

RR CF3

SCF3

OTf39-78

139 (12 equiv)

CF3I

(excess) 81-90

31 Introduction 65

(25 equiv)

CF3SO2Cl

R3R3 CF3

SCF3

BF4

138 (11 equiv)

R2

R1R1

R4 = alkyl acyl

41-96

Ar ArCF3

140 (12 equiv)

R3

R1R1

28-87

OIF3C

OR2

R2

(a)

(b)

(c)

(d)

Ar ArCF3

OAc

R1R1

63-93

R2

R1

OH

NHR2

orN

CF3

R2

OCF3

R1

R2 = alkyl 60-65

CF3I

(30 equiv)

Ar

ArCF3

SCF3

BF4

138 (11 equiv) 141 (12 equiv)

OIF3C

[Ir(ppy)3] (3 mol)

(a)

(b)

Condition B

R2 R1

TMS R2 R1

SCF3

OTf

139 (18 equiv) 140 (18 equiv)

OIF3CCF3

O

R2 R1

TMS

Ar

RmR1

OH

RmR1

O

E

RmR1

OE

δ+ O

ER1

Rm

+E+

-H+

-H+H

H

(b)

(a)

31 Introduction 67

( )n

( )nR1

( )n

( )nR1

FO

HO

R1 = EWG EDGn = 0 1

PA (5 mol)

OP

O OOH

c-C5H10

c-C5H10 c-C5H10PA

(a)

(b)

NN

Cl

F(15 equiv)

YOHR1R2

YR1

O

CF3

R2

YR1

O

X

R2

65-94X = Cl Br I

( )n

Y = CH2 On = 0 1

CH3CN rt 1 min

CH2Cl2 28 degC

140 (15 equiv)

OIF3C

O

2BF4

321 Inspiration

31 Introduction 69

SCF3

X139 X = OTf138 X = BF4

I O

O

F3C I OF3C

140 141

RadicalAddition

ArCF3

Ar( )n

CF3

Ar( )n

CF3

( )n

Ar( )n

CF3

( )n

Ar( )n

CF3

X( )nO

HO X

O

X

Elimination

Undesired

Desired

HO X( )n

( )n

HO X( )n

Undesired

ArCF3

( )n

HO X( )n

SET

RadicalAddition

ArCF3

Ar( )n

CF3

Ar( )n

CF3

( )n

Ar( )n

CF3

( )n

Ar( )n

CF3

X( )nO

HO X

O

X

Elimination

Undesired

Desired

HO X( )n

( )n

HO X( )n

Undesired

ArCF3

( )n

HO X( )n

SET

O

F3C142 143

+ Source

HO

CF3

O

144

1c [Ru(bpy)3](PF6)2(2)

60

2 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

98

3 [Ru(bpy)3](PF6)2(2)

DMF (01) 138 (14) TMSOTf(12)

BlueLEDs

81

4 [Ru(bpy)3](PF6)2(2)

DMF (01) 140 (14) TMSOTf(12)

BlueLEDs

9

5 [Ru(bpy)3](PF6)2(2)

DMF (01) 141 (14) TMSOTf(12)

BlueLEDs

ndash

6 [Ru(bpy)3](PF6)2(2)

DMSO(01)

139 (14) TMSOTf(12)

BlueLEDs

90

7 [Ru(bpy)3](PF6)2(2)

CH3CN(01)

139 (14) TMSOTf(12)

BlueLEDs

ndash

8 [Ru(bpy)3](PF6)2(2)

MeOH(01)

139 (14) TMSOTf(12)

BlueLEDs

78

9 [Ru(bpy)3](PF6)2(2)

THF (01) 139 (14) TMSOTf(12)

BlueLEDs

3

10 [Ru(bpy)3](PF6)2(2)

12-DCE(01)

139 (14) TMSOTf(12)

BlueLEDs

ndash

DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

97

12 [Ir(ppy)3] (2) DMF (01) 139 (14) TMSOTf(12)

BlueLEDs

96

BlueLEDs

ndash

14 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (14) TMSOTf(12)

23 WCFL

92

15 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (12) TMSOTf(12)

BlueLEDs

95

16 [Ru(bpy)3](PF6)2(2)

DMF (01) 139 (12) TMSOTf(05)

BlueLEDs

70

17 [Ru(bpy)3](PF6)2(1)

DMF(01)

139 (12) TMSOTf(12)

BlueLEDs

94(74)

18 ndash DMF (01) 139 (12) TMSOTf(12)

BlueLEDs

ndash

19 [Ru(bpy)3](PF6)2(1)

DMF (01) 139 (12) TMSOTf(12)

ndash ndash

( )mYR

CF3

TMSOTf (12 equiv)

HO X( )n

( )n

HO

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

OHO

CF3

O

F

Cl

Me

F

Cl

Me

Me74

73

60

78

CF3O

51

149167

166148

147 165

164146

143142

HO

CF3

O

39

150168

Me Me

155 173

O

CF3O

HO

O 158 176

52 (11)

41 (101)

(continued)

HO

HO O

CF3

OO

HO O

CF3

OO

27 nd[d]

29

162 180

179161

F F

CF3O

181163

CF3

O

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

O

HO

CF3

O

Ph

MeO

O

Ph

MeO

O

82

90

86

80

172154

153 171

170152

151 169

CF3O

HO

156 174

Me

CF3O

HO

157 175MeO MeO

HO

159 177

HO

160 178

29 (111)

47 (gt251)

53 (151)[b]

33

65 (151)[c]

OH

F3C182 91 (dr = 251)

O

F3C143

N

F3C184 70

HO

NH2OHHCl (50 equiv)

NaBH4 (15 equiv)

MeOH 0 degC 45 min

F3C183 81

O

OMMPP (33 equiv)

O

F3C143

O

F3C143

(a)

(b)

(c)

OH O

F3C

NO

CF3

DMF rt Blue LEDs

143not observed

185detected by

142

(a)

OH O

F3C

MeOH rt Blue LEDs

14378 (GC yield)

145detected by

GC-MS analysis

142

(b)OH

CF3

OMe

SCF3

OTf

139 (12 equiv)

SCF3

OTf

139 (14 equiv)

33 Summary

CF3

O

143

[Ru(bpy)3]2+

[Ru(bpy)3]3+

Catalysis

SCF3

139 OTf

S

OH

142

OTMS

TMSOTf

TfOH

radicaladditionA

OTMS

CF3B

OTMS

CF3C

139

CF3

SET

12-carbonshift

CF3

OTMS

D

TMSOTf

radicalchain

(Φ = 38)Silyl

protectionSilyl

deprotection

minus081 V vs SCE

+129 V vs SCE

minus025 V vs SCE

References

References 79

1906 (1985)

41 Introduction

81

N

8 1

2

3456

7NN

N

SO

O

ON

OO

N

NCOH

N

CN

NH

SGL T1 antagonist

O

NH2

O

Antioxidant

NN

OR3

R1 R2

N

R1

R2

R3

N

ONC

O

N

O

HN

PDE4 inhibitor

OH

Cl

N

Cl

41 Introduction 83

N O

O O

N

O

200-220 degC

- CH3COOH- H2O

Nhydrolysis

N

O

NH

O

OH

N

cyclization

O200-220 degC

O

OH

186

187

189

188

NR1

R2

NR1

R2

R3

O

R4

Br

O

R4

R3

Br 35-100 degCN

R1

R2

R3

R4Δ

NaHCO3H2O

28-85 30-94

NR1

R2

R3

O

R4via

NO

PhCOOMeMeOOC N

COOMe

OPh

PdC

toluene

18

41 Introduction 85

NR1 R2

BrN

R1

R2K2CO3

EtOH or CHCl3

4-95

R3

O OR3

NR1 R2

R3

O

Br

ether or CHCl3

rt

R3

O1 5

via

N

ClN

N

R1

N

R1

10-12

or Δ or US

50 equiv

N NN

Cl

N

R1

57-85

R1 Cl

R1 = EWG EDG

OO

Cl

R1

N

Cl

OO

RhLn

via metal carbenoid

N O

O

R1

5-10

CH2Cl2 rt

Cl

NEWG

R1N

EWG

R1

Ag2CO3 (20 equiv)

20 equiv

45-89R1 = EWG EDG

41 Introduction 87

NEWG

R1N

EWG

R1

I2 (20 mol)

DCE30 equiv

25-59R1 = EWG EDG

NEWG O N

R1

EWGI2 (60 mol)

R1

421 Inspiration

N

EWGCl

R2

20 equiv

N

EWG

R1R1

N

EWG BF3K

R1

Pd(OAc)2 (10 mol)

DMF 90 degC10 equiv

N

EWG

R140-93R1 = EWG EDG

(a)

(b)

Zhao et al (2012)

N

EWG B(OH)2

R2

20 equiv

N

EWG

R1R1

422 Reaction Design

NCO2R1

Br

O O

NR2 R2

N

OR1O

visible light

190 191 192

PhotoredoxCatalysis

PC

NCO2R1

Br

O

N

O

R2R2

N

O

R2R2

OR1

O

N

O

N

O

R2R2

OR1

O

N

NCO2R1

Br

NCO2R1

Br

NCO2R1

BrBr

O

N

O

R2R2

N

OR1

O

N

O

R2R2

N

OR1

O

N

OR1

O

H

-H+

-R22NCOOH

SET

Mesolysis

RadicalAddition

NucleophilicAttack

Elimination

Deprotonation

Chain192

190191

190

E

A

B

B A

C

D

F

NN

Br

O

N

194

193

O

OO

195 62

NN

Br

O

N

194

+No photocatalyst

193

O

OO

NN

Br

O

N

194

193

O

OO

195 52

195 0

(a)

(b)

(c)

O O

N

O O

N

O O

N

O O

N

O

200 201 202 203

O O

O

O O OS

N

196 197 198 199

OOF3C

O

O O

204

NN

Br

O

N

194

+base

solventlight source

193

O

OO

195

(continued)

34 HMDS (2) PhCF3 1 194 (5) 23 W CFL 24

45 HMDS (1) PhCF3 1 194 (5) ndash 1

46g HMDS (1) PhCF3 1 194 (5) ndash 3

NN

EWG

Br

EWG

O

NR4

R4R1 R1

R2

R3

R2

50 equiv

+HMDS (1 equiv)

N

OOR5

N

OO

N N

OO

N

OO

20816b

20967

218 (R6 = Br) 74219 (R6 = F) 55

22065

N

R6

F3C

N

OO

NN

OO

N

OO

21765

21661

21475

21368

Ph

OO

Cl

N

OO

N

OO

21542

21238b

21167b

OO

F

N

OO

22133b

Cl

N

OO

21061b

N

OO

O

OO

O

OO

N

OO

22228

O 2230 (0)c

195

N

OO

DDQ (10 equiv)

225 96

N

OO

224 71

N

OO

PtO2 (10 mol)

(b)(a)

N CO2Et

CO2Et

NCO2Et

Br

EtO2C 195 (10 mol)

N

O

195

O

82

NPh

43 Summary

O

N

226[M+Na]+ C17H26N2O3Na+

ON

O

ON

O O

N

227[M+Na]+ C30H41N3O5Na+

References

O O

N

NBr

O

ON

OO

193(10 equiv)

195

43 Summary 105

References 107

51 Intoduction

109

HO

O OH

O

OH

OHO

O

OH

HO

O

HO

O

OH

O

NN

H3BTB H4BenzTB

NN

OHO

HOO

N N

O

OHO O

Mn

O

HO

Cl

H2BDC

H2NDC

44-Bipy

(a)

(b) (c)

O OH

Zn

ZnOCu

OOO O

CuOO

O O

L

structure

Fe

FeFeO OO O

OO

OO O

O

OO

OCl OH2

H2O

51 Intoduction 111

51 Intoduction 113

O OH

OHO

N

Zn(NO3)2times4H2O

BTB DMF 85 degC16

N

UMCM-1-Ph-Indole

N

Ph23

Pd(OAc)2

[Ph2I]BF4DMF rt 5 d

H

23

51 Intoduction 115

521 Inspiration

B

OH

O

OHO

HO

O

DMF 95 degC 3 d

I

Br B

Br

BrBr

B

OO

O

B

OHO

O

OH

HO

O

2) BF3Et2O

231 47

228 95

1) NaOHMeOHH2O (11)

2) aq H2SO4 (1M)

230 42229

5231 PXRD Analysis

B

OHO

O

OH

HO

OH3TPB (228)

OHO

O OH

R

H2BDC (232) R = H

O

Ph

Zn(NO3)2x4H2ODEF

80 degC 48 h

DUT-6 (Boron) (234)

5233 TGA Analysis

N2 adsorption study

53 Summary

References

References 125

312 (2015)

Procedures

127

Polarimetry

Photospectrometry

TGA analysis

NN

N

Ru (PF6)2

+ ([M-PF6]+)

7150748 measured 7150773

N

NN

+ ([M + H]+) 1590665measured 1590672

N

NN

N

NN

N

NN

Ru (PF6)2

+ ([M-PF6]+) 7210457 measured 7210461

N

Ir

N

Ir

Cl

+ ([12M-Cl]+) 5010937 measured 5010947

N

NIr

+

([M + Na]+) 6781493 measured 6781481

N

Ir (PF6)

+ ([M-PF6]+) 7692879 measured 7692900

OH

+ ([M + Na]+) 1631093 measured 1631090

OH

+ ([M + Na]+) 1850937 measured 1850935

OH

+

([M + Na]+) 1651250 measured 1651244

OH

NHS

O

NHS

O

+ ([M + Na]+) 2901185measured 2901189

NHS

O

D

+

([M + Na]+) 2630935 measured 2630932

O

General Procedure 1

General Procedure 2

General Procedure 3

XH

R3

R4

R2

( )n( )n

X R4 R3

R2

R1

N2BF4

R1

23 W lightbulb

degassed MeOH rt

X = O Nn = 1 2

R5 R5

General Procedure 4

R1 + ArN2+ BF4

-

O

General Procedure 5

R1 + [Ar2I]+ BF4-

OR3

O

(plusmn)

O

(plusmn)

O

(plusmn)

O

(plusmn)

O

+

O

NSO O

NSO O D

+

NSO O D

+

NSO O

O

F

+

O

OO

(ATR) ν (cmminus1) 2976 2941 2868 1714 1611 1416 1367 1273 1178 11041062 1022 857 759 708 631

O

F3C

+

O

Br

OBr

Cl

O

+

O

O2N

OO

O

MeO

O

N

O

ν (cmminus1) 2930 2827 1771 1707 1495 1467 1439 1396 1373 1267 11881100 1026 923 866 793 735 719 700 630 604

O

+

OBr

+

O O

O

R

1447 1416 1391 1367 1311 1273 1178 1101 1022 910 860 822 761 732706 648 629

OCF3

+

O

O R

+

NSO O

General Procedure 6

Y

O

Y = CH2 On = 0 1

( )nY

Br

( )n

Y = CH2 O n = 0 1

General Procedure 7

Br

R R

X

X = CH2 O

X O

General Procedure 8

Y

Br

Y = CH2 O

Y

Y = CH2 O

2O

R R

OH

+

([M + Na]+) 1970937 measured 1970933

OH

F

measured 2150840

OH

Cl

+ ([M + Na]+) 2310547measured 2310541

OH

sured 2111094

OH

+ ([M + Na]+) 2731250 measured 2731256

OH

O

(40) 162 (15) 161 (41) 160 (14) 159 (34) 155 (11) 148 (40) 147 (36) 146 (12)145 (77) 144 (14) 134 (20) 133 (100) 132 (11) 131 (10) 128 (15) 127 (10) 121(50) 119 (10) 118 (19) 117 (29) 116 (10) 115 (36) 108 (13) 105 (21) 103 (18)102 (11) 91 (28) 90 (20) 89 (29) 79 (14) 78 (11) 77 (33) 65 (17) 64 (10) 63(21) 51 (13) 43 (11) 39 (16)

+ ([M + Na]+) 2271043 measured 2271050

OH

O

+ ([M + Na]+) 2410835measured 2410834

OH

+ ([M + Na]+) 2471093 measured 2471097

OH

+

([M + Na]+) 2111093 measured 2111093

OH

+

([M + Na]+) 2111093 measured 2111105

OH

+ ([M + Na]+) 2231093 measured 2231096

OH

+ ([M + Na]+) 1751093 measured 1751096

OHO

+ ([M + Na]+) 1970937 measured 1970933

OHO

F

+

([M + Na]+) 2170635 measured 2170647

OH

+

([M + Na]+) 2111093 measured 2111093

OH

+ ([M + Na]+) 2090937 measured 2090948

General Procedure 9

( )mYR

CF3

XO

HO X( )n

( )n

O

F3C

CF3

O

+

O

F3C

F

O

F3C

Cl

+

O

F3C

O

F3C

O

F3C

O

+

O

F3C O

O

F3C

O

F3C

+

O

F3C

CF3O

Diastereomer A

+

Diastereomer B

O

CF3O

Major diastereomer

OCF3

Major diastereomer

Minor diastereomer

CF3O

O

Major diastereomer

O

CF3

Major diastereomer

Minor diastereomer

O

F3C

+

O

F3C

F

O

F3C

N

F3C184 70

HOO

F3C143

EtOH rt 48 h

N

F3Cxx

HO

OH

F3C182 91 dr = 251

O

F3C143

NaBH4 (15 equiv)

MeOH 0 degC 45 min

OH

F3C

O

F3CF3C

O

MMPP (33 equiv)

143183 81

O

F3C7

OH

S

CF3OTf

O

F3C

N

O CF3

TMSOTf (12 equiv)

DMF rt

Blue LEDs

N

O (24 equiv)

142 (10 equiv)

OH

SCF3

OTf

O

F3C

MeOH rtBlue LEDs

142 (10 equiv)

OH

CF3

OMe

y = 4E -09

Rsup2 = 09816

0

00000005

0000001

00000015

0000002

00000025

0000003

-100 100 300 500 700

Mol

es o

f Fe(

II) f

orm

ed

Time (s)

x

N Br

I

N Br

BHO OH

881 equiv1 equiv

y = 38439xRsup2 = 09966

0

0000005

000001

0000015

000002

0000025

-1E-06 5E-21 0000001 2E-06 3E-06 4E-06 5E-06 6E-06

Mol

s of

pro

duct

0 0 0

NH

OH

O

Cl

N OtBu

O

N OBn

O

35

66

N O

O

+

N O

O

+

N Br

R

N

R

CO2Me

CO2MeN

R

CO2Me

LiCl (1 equiv)

N O

O

OO

F

N O

OF

N O

OF3C

N O

O

OO

N O

O

+

N O

O

OO

N O

O

N

Cl

O

OO

N

Cl

O

N O

O

OO

N O

O

(cmminus1) 2953 1735 1605 1562 1435 1337 1265 1247 1200 1154 1016 998918 829 652 620 601

N NO

N

O

mCPBA (10 equiv)

CH2Cl2 rt 4 h

Ac2ODMF

0 degC - rt 15 h

O

25

59

(12 equiv)

NO

N

O

N Cl

O2N

N

O2N

CO2Me

N

O2N

CO2Me

N

Br

CO2MeN

H2N

CO2Me

NaH (22 equiv) DMF

NaCl (2 equiv)

DMSOH2O120 degC 3 h

PdC (5) EtOH

70 28

Br

N

O2N

O

OO

N

O2N

O

+

2962 2361 2340 1730 1600 1580 1508 1476 1434 1411 1362 1261 12371187 1169 1118 1022 991 944 903 865 848 827 725 684 630

N

H2N

O

N

Br

O

Br

N

R1

CO2R2CNN

R1

CO2R2CN

Br (10 equiv)

N

Br

O

N

Br

O

+

N

Br

O

N

Br

O

N

Br

N

+

N

Br

O

OF

N

Br

O

OF3C

N

Br

O

N

Br

O

N

Cl

Br

O

+

N

Br

O

+

N

Br

O

R1

R2

O

R1

R2

O

NR3

R3

ii) rt 16 h

Cl NR32

O

(11 equiv)

O

N

+

O

N

O

N

O

N

O

+ ([M + Na]+)

O O

N

+

O O

O

O O

NR4R4

N

Br

CO2R2CNN

CO2R2CN

Blue LEDs (465 nm)

R1

R3

N

OO

N

OO

+

N

OO

N

OO

N

OO

O

N

OO

O

Br

79NO3]+ ([M]+) 3850308

N

OO

O

F

N

OO

O

F3C

N

OO

O

N

OO

O

N

OO

O

Cl

N

OO

O

N

OO

O

N

OO

F

N

OO

N

OO

O O

1466 1452 1433 1405 1389 1363 1335 1321 1310 1277 1256 1239 12141189 1183 1150 1127 1109 1065 1038 1027 1010 982 935 919 880 853813 791 779 740 725 718 691 676 664 615 605

N

OO

Cl

N

OO

O

195

N

OO

DDQ (1 equiv)

22471

N

OO

22596

N

OO

PtO2 (10 mol)

N

OO

N

OO

O O

N

Br

O

N

OO

193(10 equiv)

195

N CO2Et

CO2Et

N

CO2Et

Br

blue LEDs (465 nm)

(20 equiv)(10 equiv) 18 45

N

O

195

O

N

OO

F(000) 7120

(continued)

O2ndashC17 13534(18) O2ndashC18 14434(18)

O3ndashC15 13731(18) O3ndashC19 14285(18)

N1ndashC8 13804(19) N1ndashC4 13922(19)

N1ndashC1 14052(19) C1ndashC2 1405(2)

C2ndashC17 1456(2) C3ndashC4 1378(2)

C3ndashC9 14997(19) C4ndashC12 1460(2)

C11ndashC16 1391(2) C11ndashC12 1412(2)

C12ndashC13 1399(2) C13ndashC14 1385(2)

C19ndashH19C 098

C5ndashH5O2 095 240 29315(18) 1147

C16ndashH16O1 095 247 33219(18) 1496

B

Br

BrBr

B

OO

O

B

OHO

O

OH

HO

O

minus ([Mndash

O O

OO

Br

N

O O

OO

+

([M + Na]+) 3921105 measured 3921106

N

HO O

OHO

OO

F(000) 83920

the term n 1 pp0

nmfrac14 1ffiffiffi

Cp thorn 1

Figures 614 and 615

References

References 251

References 253

Curriculum Vitae

Education

255

Publications

Teaching Experience

Abstract
Acknowledgements
Contents
Abbreviations
      - 15 Summary
        
        References
        
        
        21 Introduction
        
        
        
        
        
        
        
        
        
        
        221 Inspiration
        
        
        
        
        
        
        
        
        23 Summary
        
        References
        
        
        31 Introduction
        
        
        
        
        
        
        
        
        
        
        321 Inspiration
        
        
        
        
        
        33 Summary
        
        References
        
        
        41 Introduction
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        421 Inspiration
        
        422 Reaction Design
        
        
        
        
        
        43 Summary
        
        References
        
        
        51 Intoduction
        
        
        
        
        
        
        521 Inspiration
        
        
        
        5231 PXRD Analysis
        
        
        5233 TGA Analysis
        
        
        
        
        53 Summary
        
        References
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        
        References
        
        Curriculum Vitae

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Visible Light Photocatalyzed Redox-Neutral Organic Reactions and Synthesis of Novel Metal-Organic

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