STUDY AND INVESTIGATION OF CATALYTIC SYSTEMS FOR ASYMMETRIC TRANSFORMATIONS · 2018. 1. 10. ·...

STUDY AND INVESTIGATION OF CATALYTIC

SYSTEMS FOR ASYMMETRIC TRANSFORMATIONS

SIAU WOON YEW

(B.A.Sc.(Hons.), NUS)

A THESIS SUBMITTED

FOR THE DEGREE OF MASTER OF SCIENCE

DEPARTMENT OF CHEMISTRY

NATIONAL UNIVERSITY OF SINGAPORE

2013

MSc. Project by SIAU WOON YEW (A0038789H)

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Declaration

I hereby declare that this thesis is my original work and it has been written by me in its

entirety, under the supervision of Assist. Prof. Zhao Yu, Department of Chemistry,

National University of Singapore, between August 2011 and July 2013.

I have duly acknowledged all the sources of information which have been used in the

thesis.

This thesis has also not been submitted for any degree in any university previously.

SIAU WOON YEW 29 APRIL 2013

Name Signature Date


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ACKNOWLEDGEMENTS

My deepest gratitude and appreciation goes to the following people because without their

guidance, assistance, support and understanding, the successful completion of this project

would not have been possible or it would have achieved much less.

My project supervisor, Assistant Professor Zhao Yu, for his insightful advices, patient

guidance, and constant reassurances provided throughout the course of the study. He has

provided me with the necessary knowledge and resources to make this project a success.

Also, thank would like to go to Prof. Tamio Hayashi for his guidance in N-heterocyclic

carbene – olefin project.

My fellow colleagues, Dr Monissa Cuebillas Paderes and Dr Yan Hailong for the

collaborative work on both the alpha alkylation project and development of bidendate N-

heterocyclic carbene-olefin ligands for late transition metal catalysis.

My dearest family and friends, for their care, concern and kind understanding. They have

stood by me and are extremely tolerating and accommodating despite my busy schedule.

https://exchange.nus.edu.sg/owa/?ae=Item&t=IPM.Note&id=RgAAAADy1Xqh70RyQoKmmThJ4LiqBwCTDKUncnS%2fRqeav%2fD0RchHABqaAN1fAACTDKUncnS%2fRqeav%2fD0RchHAB4QTOhaAAAJ


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Lastly, I want to thank the National University of Singapore Chemistry Department (i.e.

Mass Spectrometry Laboratory, Nuclear Magnetic Resonace Laboratory, X-ray

Diffraction Laboratory etc.) to provide me with the platform to carry out the outstanding

research and train me to become a better chemist.


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Table of Contents

Summary

List of Tables

List of Figures

List of Schemes

List of Abbreviations

Chapter 1

Study of frustrated Lewis pairs (FLPs) and its application for metal-free hydrogen

activation

1.1 Introduction…………………………………………………………………………..16

1.2 Current State of the art of FLPs

1.2.1 Phosphorus/Boron Combination of Frustrated Lewis Pairs…..……………16

1.2.2 Nitrogen/Boron Combination of Frustrated Lewis Pairs………………......21

1.2.2 Chiral Frustrated Lewis Pairs……………………………………..………. 22

1.3 Experimental and Result

1.3.1 Results and Discussions……………………………………………..……. 23

1.3.2 Future work……………………………………………………………… 27

1.4 Summary………………………………………………………………………..…. 28

1.5 References………………………………………………………………………..... 29

Chapter 2

Study of N-heterocyclic carbene (NHC) and olefin bidendate ligands

2.1 Introduction…………………………..……………………………………………. 34

2.2. Bidendate Ligands

2.2.1 N-heterocyclic Carbene based Bidendate Ligands…………………….... 34

2.2.2 Olefin based Bidendate Ligands…………………………………….…... 36



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2.3.1 Results and Discussions……………………………………………..…... 37

2.3.2 On-going Research …………………………………………………..…... 44

2.4 Summary……………………………………………………………………..……. 45

2.5 References…………………………………………………………………..……... 45

Chapter 3

Bifunctional Catalysis for Alpha Alkylation of Oxindole Derivatives

3.1 Introduction…………………………………………………………………..……. 50

3.2 Asymmetric Allylic Alkylation (AAA) Reactions

3.2.1 Molybdenum Mediated Asymmetric Allylic Alkylation……………..…. 50

3.2.2 Palladium Mediated Asymmetric Benzylation……………………..……. 54

3.2.3 Anion Binding Alkylation……………………………………………..… 55


3.3.1 Results and Discussions…………………………………………..……... 57

3.3.2 On-going Research……………………………………………………… 64

3.4 Summary……………………………………………………………………..……. 65

3.5 References……………………………………………………………………..…... 66

Appendices…………………………………………………………………..…………. 69

App.1 – General Information

App.2 – General Synthetic Scheme for Chemicals

App.3 – 1H NMR, 13C NMR spectrums and HPLC spectral

App.4 – References

App.5 – Publications


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SUMMARY

This thesis covered my work in Zhao’s laboratory for the past two years. My first project

was focused on the development of frustrated Lewis pairs for H2 activation. Owing to its

operational difficulty, a simple and easily derived chiral morpholinone was tested for

frustrated Lewis pairs behavior. The result and future work on this project was also

summarized in Chapter 1.

Chapter 2 described my second project on the development of N-heterocyclic carbene

(NHC) – olefin ligands. This is the collaborative work with Prof. Tamio Hayashi. In this

chapter, the general preparation method for the ligands was described. Some of the

preliminary result and associated challenges were also reviewed. More recently, we have

successfully isolated the first Rh – NHC complex bearing olefin moiety. Its application

for late transition metal catalysis will be studied in due course.

Chapter 3 summarized recent work on alpha alkylation reactions of 3-aryloxindole and 3-

alkyloxindole derivatives using quinine derived bifunctional urea catalyst. In contrast to

previous work on urea catalysis, this work represents the first bifunctional catalysis for

alkylating protocol using simple benzyl bromide as alkylating reagent via SN1

mechanism.


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LIST OF TABLES

Table 3.1. Catalyst Screening.

Table 3.2. Effect of Solvent to the Reaction.

Table 3.3. Effect of Base to the Reaction.


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LIST OF FIGURES

Figure 1.1. Chiral Frustrated Lewis Pairs derived from (1R)-(+)-Camphor.

Figure 1.2. Possible interaction between 23a and 14.

Figure 1.3. Strategy for Modification of Current Frustrated Lewis Pairs.

Figure 2.1. N-heterocyclic carbene (NHC) based Bidendate Ligands

Figure 2.2. Olefin based Bidendate Ligands.

Figure 2.3. Design of Chiral N-heterocyclic Carbene (NHC) – Olefin

Ligands.

Figure 3.1. Representative Natural Products Bearing 3, 3-disubstituted

Oxindole Core Structure.

Figure 3.2. Various Chiral Bifunctional Organocatalysts.


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LIST OF SCHEMES

Scheme 1.1 Phosphine-Borane for Reversible Activation of Hydrogen.

Scheme 1.2. Intramolecular Frustrated Lewis Pairs System.

Scheme 1.3. Metal-free Hydrogenation of Imines and Ring Opening of

Aziridine.

Scheme 1.4. Proposed Mechanism for Metal-free Hydrogenation using

Zwitterion 2.

Scheme 1.5. Catalytic Metal-free Hydrogenation of Enamines.

Scheme 1.6. Frustrated Lewis Pairs Behavior for Amino-Borane System.

Scheme 1.7. Enantioselective Hydrogenation with Chiral Frustrated

Lewis Pairs 18 or 19.

Scheme 1.8. General Synthetic Scheme for the Preparation of Chiral

Morpholinones.

Scheme 1.9. Study of the Frustrated Lewis Pairs Behavior of Chiral

Morpholinone 23a and Control Experiment.

Scheme 1.10. Further Modifications on Chiral Morpholinone 23a.

Scheme 1.11. Removal or Protection of Hydroxyl Group of Chiral

Morpholinone 23a.

Scheme 1.12. Investigation of Frustrated Lewis Pairs Behavior of Chiral

Thio-morpholine 27.


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Scheme 2.1. General Synthetic Scheme for the Preparation of NHC-Olefin

Ligands.

Scheme 2.2. Revised Synthetic Scheme for the Preparation of Bidendate

Ligands.

Scheme 2.3. Attempt for Complexation with Rh via Transmetallation.

Scheme 2.4. Bidendate Ligands with Rigid Olefin Moiety.

Scheme 2.5. Complexation of Ligand 25a with Rhodium Salts.

Scheme 2.6. Study for the Investigation of the Compatibility between NHC

and Olefin.

Scheme 2.7. Study of Complexation via Silver Transmetallation and

Formation of Pentacoordinated Rh-complex 36.

Scheme 2.8. Study of Different Rh-complexes for Conjugate

Reaction between 38 and 39.


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Scheme 3.1. Transition Metal Mediated Allylic Alkylation Approach.

Scheme 3.2. Molybdenum-Catalyzed Asymetric Allylic Alkylation of 3-

Alkyloxindole.

Scheme 3.3. Formal Synthesis of (-)-Physostigmine.

Scheme 3.4. Palladium Catalyzed Asymmetric Benzylation of 3-

Aryloxindole Derivatives.

Scheme 3.5. Palladium Catalyzed Asymmetric Allylic Alkylation of 3-

Aryloxindole.

Scheme 3.6. Asymmetric Alkylation of Oxindoles using Organic Catalyst

with Anion-Recognition Ability.

Scheme 3.7. Formation of O-alkylation product 28a’.

Scheme 3.8. Tautomerization between Oxindole and Hydroxyindole and

Plausible Effect for Low Enantioselectivity.

Scheme 3.9. Asymmetric Alkylation of 3-Alkyloxindole Derivatives.

Scheme 3.10. Further Study on Alkylation Project.


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LIST OF ABBREVIATIONS

oC degree Celcius

Ac Acetyl

Ar Aryl

Bn Benzyl

Boc tert-Butyloxycarbonyl

n-Bu n-butyl

COD 1, 5-cyclooctadiene

DIBAL-H diisobutylaluminium hydride

DCM dichloromethane

DIPEA diispropylethylamine

DIAD diisopropyl azodicarboxylate

DMSO dimethyl sulfoxide

DMAP dimethylaminopyridine

DPPA diphenyl phosphorylazide

d doublet

EA ethyl acetate

ee enantiometric excess

Et3N triethylamine

h hour(s)

HPLC high performance liquid chromatography

LAH lithium aluminium hydride

M multiplet

Me methyl

http://en.wikipedia.org/wiki/Diisopropyl_azodicarboxylate


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Mes mesityl

m/z mass-to-charge ratio

mmol millimole

Nu nucleophile

iPr isopropyl

PDC pyridinium dichromate

Ph Phenyl

Piv pivalate

q quartet

rac racemic

r.t room temperature

s singlet

THF tetrahydrofuran

TBS tert-butyldimethylsilyl

TIPS triisopropylsilyl

TMSOTf trimethyl trifluoromethanesulfonate

TMSSPh trimethyl(phenylthio)silane

tBu tert-butyl


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Chapter 1

Study of Frustrated Lewis

Pairs and its Application

to Metal-free Hydrogen

Activation


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1.1 INTRODUCTION

In contrast to traditional Lewis acid and Lewis base combination, sterically congested

Lewis acid/base pairs would not neutralize each other to form the Lewis acid/Lewis base

adducts. This class of unquenched system demonstrated unusual reactivity for the

activation of dihydrogen and resulted in the cleavage of dihydrogen heterolytically to

form the corresponding H+/H- pairs (usually stabilized in the form of respective

phosphonium cation/hydridoboroate anion salts).1 Research groups leaded by Stephan

and Erker have successfully demonstrated the application of so-called “frustrated Lewis

pairs” for the metal-free hydrogenation. This concept has been now utilized for the

activation for other small molecules, including carbon dioxide and nitrogen monoxide.

1.2 CURRENT STATE OF THE ART OF FRUSTRATED

LEWIS PAIRS (FLPs)

1.2.1 Phosphorus/Boron Combination of Frustrated Lewis Pairs

The study of the reactivity of main group elements has directed the researchers in

Stephan’s group to investigate the impact of the systems that consists of both the

sterically encumbered Lewis acid and Lewis base within the same molecule. Such finding

served as the milestone in the frustrated Lewis pairs chemistry and have changed the state


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of the art of hydrogenation chemistry in organic chemistry.2 The researchers first

demonstrated an air and moisture stable zwitterion 2 upon the treatment of phosphino-

borane 1 in the presence of hydrogen (Scheme 1.1).3 Compound 2 underwent facile

stoichiometric loss of H2 upon heating to above 100 oC. Intramolecular phosphine-borane

Scheme 1.1. Phosphine-Borane for Reversible Activation of Hydrogen.

system was then reported by Erker and co-workers by treatment of 3 with “Piers” borane4

4 for the study of H2 activation (Scheme 1.2).5 Despite strong interaction of phosphorus

and boron in 5,6 heterolytic cleavage of hydrogen could be accomplished at ambient

Scheme 1.2. Intramolecular Frustrated Lewis Pairs System.


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temperature to form the corresponding zwitterionic species 6. Owing to its unique

chemical properties for H2 activation, the researchers demonstrated the catalytic

efficiency of the frustrated Lewis pairs for the application of hydrogenation chemistry.

Hydrogenation of imines 7 and reductive ring opening of N-aryl aziridine 8 could be

accomplished in the presence of 5 mol% of 2 at 80 to 120 oC under 1-5 atm of H2

(Scheme 1.3)7. The requirement of stoichiometric catalyst for the particular reduction of

sterically less demanding imines substrates (such as benzyl protected imine) suggested

Scheme 1.3. Metal-free Hydrogenation of Imines and Ring Opening of Aziridine.


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that the Lewis basic nitrogen on the amine products could bind more strongly to the

boron center thus inhibiting the catalyst regeneration. Further studies revealed that the

reduction step was initiated by protonation of imines and followed by borohydride attack

Scheme 1.4. Proposed Mechanism for Metal-free Hydrogenation using Zwitterion 2.

of iminium species to form the amine-borane adduct 2a’. The active catalytic species 2

was regenerated and used for the next catalytic cycle in the presence of H2 (Scheme 1.4).

Later on, reduction of electron rich olefin such as enamines was demonstrated by Erker’s


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group in 2008 (Scheme 1.5).8 Practically quantitative conversion of the enamines 11 into

amines 12 were attainable at milder condition (1.5 bar of H2 and 25oC).9

Scheme 1.5. Catalytic Metal-free Hydrogenation of Enamines.


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1.1.1 Nitrogen/Boron Combination of Frustrated Lewis Pairs

Sterically bulkyl Lewis basic nitrogen, together with borane, was also shown to exhibit

“frustrated Lewis pairs” behavior upon exposure to H2. Timo and Rieger first

demonstrated with the use of 2,2,6,6-tetramethylpiperidine and B(C6F5)3, the hydrogen

could be cleavage heterolytically at one atmospheric pressure and 20oC to form the

corresponding ammonium-borate species 15 in 95% yield (Scheme 1.6).10 Subsequently,

the same group synthesized the tethered amino/borane frustrated Lewis pairs 16 for the

study of reversible H2 activation. Similar to the P/B FLPs, the amino/borane FLPs was

also tested for reduction of imines and enamines. The corresponding amine products

could be obtained in the range of 85-99% yield.

Scheme 1.6. Frustrated Lewis Pairs Behavior for Amino-Borane System.


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1.1.2 Chiral Frustrated Lewis Pairs

Enantioselective and catalytic metal-free hydrogenation was introduced in 2010 by the

group of Klankermayer with the use of chiral borane in combination with bulky

phosphine under atmospheric condition of H2 (Figure 1.1 and Scheme 1.7).11 Many works

Figure 1.1. Chiral Frustrated Lewis Pairs derived from (1R)-(+)-Camphor.

have been done thus far, researches should be more actively engaged in the direction for

the development of efficient frustrated Lewis pairs for hydrogenation reactions. In

addition, to further demonstrate its synthetic utility for more general substrate scope,

sterically less hindered imines and other imine derivatives should be addressed in the

context of frustrated Lewis pairs chemistry.12


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Scheme 1.7. Enantioselective Hydrogenation with Chiral Frustrated Lewis Pairs 18 or 19.

1.3 EXPERIMENTAL AND RESULT

1.3.1 Results and Discussions

Scheme 1.8. General Synthetic Scheme for the Preparation of Chiral Morpholinones.

We first began our study by attempting to synthesize a variety of chiral morpholinones 23

starting from commercially available chiral pools 21 (Scheme 1.8).13 Two new chiral


24

morpholinones 23a and 23b were first prepared for the study of frustrated Lewis pairs

behavior. To probe the feasibility of heterolytic cleavage of H2, the reaction was first

carried out in J-Young tube in the presence of 14 in deuterated toluene at 1 atm of H2 for

prolonged reaction time. For the ease of the investigation, a control experiment was set

Scheme 1.9. Study of the Frustrated Lewis Pairs Behavior of Chiral Morpholinone 23a

and Control Experiment.


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up. It was shown that 2,2,6,6-tetramethylpiperidine in combination with B(C6F5)3 could

cleave the hydrogen to form the corresponding ammonium-borate species 15 as

demonstrated previously in Rieger’s group. To our disappointment, the chiral

morpholinone 23a did not exhibit typical frustrated Lewis pairs behavior under similar

condition and even at elevated temperature (Scheme 1.9). Further 13C NMR indicated that

carbonyl oxygen of 23a might coordinate to Lewis acidic boron thereby showing no

frustrated Lewis pairs behavior under H2 atmosphere. The electron rich lactone carbonyl

oxygen could donate its lone pairs of electron into the empty p-orbital of the boron and

result in the formation of quenched Lewis acid/base adduct 24 (Figure 1.2). A thermal

stimulus (reaction at 70 oC) was not able to interfere such interaction and we deduced that

a thermodynamic quenched Lewis acid/base adduct was formed during the course of

reaction. Subsequently, several modifications were made on the lactone part of 23a

(Scheme 1.10). First attempt was tried to convert the ester to thionoester 25. However,

Figure 1.2. Possible interaction between 23a and 14.


26

the reaction turned out to be messy and did not lead to the desired product formation.

DIBAL-H reduction, acetylation and followed by SN2 substitution by phenylthiolate

afforded the desired thioacetal 27.14 On the other hand, following Nicolaou hydroxyl-

ketone cyclic ether formation as well as silyl protection of the hydroxyl group of the

hemiketal 26 was not successful (Scheme 1.11). We reasoned that the geminal dimethyl

group may have detrimental effect which impacted severe steric effect for the reaction to

occur. Nonetheless, we investigated the frustrated Lewis pairs behavior of the chiral

Scheme 1.10. Further Modifications on Chiral Morpholinone 23a

thiomorpholine 27 for the activation of H2 in the presence of B(C6F5)3 (Scheme 1.12). To

our disappointment, both borane 14 and 30 showed no successful result.15

1.3.2 Future Work


27

Scheme 1.11. Removal or Protection of Hydroxyl Group of Chiral Morpholinone 23a.

Scheme 1.12. Investigation of Frustrated Lewis Pairs Behavior of Chiral Thiomorpholine

27.

The strategy to circumvent current problem is illustrated in Figure 1.3. From the

standpoint of thermodynamics, the design is favored to synthesize an intramolecular

frustrated Lewis pairs structural motif (combination between morpholinone 23a and

borane 14) to avoid unwanted interaction between the boron and the carbonyl oxygen. In


28

addition, the bridging allows both the Lewis acid and Lewis basic components to stay at a

certain conformation to bring about the reactivity.

Figure 1.3. Strategy for Modification of Current Frustrated Lewis Pairs.

1.4 SUMMARY

Metal-free hydrogenation reaction is undoubtedly a great way to access a wide variety of

chiral compounds. Although biomimetic approach using Hantzsch ester for

enantioselective reduction reactions are well developed in the current technology, it is

after all not atom economical as stoichiometric amount of waste would be generated.16

Unlike transition metal catalysis for hydrogenation reaction, the main group elements are

abundant and its application for reduction serves as an environmentally benign route for

synthetic organic chemistry. It is noteworthy that the reversible activation of small


29

molecule like H2 was first demonstrated in frustrated Lewis pairs chemistry. It is

anticipated that research would be on-going and continue to expand more for frustrated

Lewis pairs for other small molecule activation in near future.17

1.5 REFERENCES

1 D. W. Stephan, G. Erker, Angew. Chem. Int. Ed. 2010, 49, 46-76.

2 a) C. P. Casey, G. A. Bikzhanova, I. A. Guzei, J. Am. Chem. Soc. 2006, 128, 2286 –

2293; b) R. Noyori, M. Kitamura, T. Ohkuma, Proc. Natl. Acad. Sci. USA 2004, 101,

5356 – 5362; c) R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97 – 102.

3 G. C. Welch, R. R. S. Juan, J. D. Masuda, D. W. Stephan. Science 2006, 314, 1124-

1126.

4 a) D. J. Parks, W. E. Piers, G. P. A. Yap, Organometallics 1998, 17, 5492 – 5503; b)

R. E. v. H. Spence, W. E. Piers, Y. Sun, M. Parvez, L. R. MacGillivray, M. J.

Zaworotko, Organometallics 1998, 17, 2459 – 2469; c) D. J. Parks, W. E. Piers,

Tetrahedron 1998, 54, 15469 – 15488; d) W. E. Piers, T. Chivers, Chem. Soc. Rev.

1997, 26, 345 – 354; e) R. E. v. H. Spence, D. J. Parks, W. E. Piers, M.-A.

McDonald, M. J. Zaworotko, S. J. Rettig, Angew. Chem. Int. Ed. 1995, 34, 1230 –

1233; f) D. J. Parks, R. E. v. H. Spence, W. E. Piers, Angew. Chem. Int. Ed. 1995, 34,

809 – 811.


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5 P. Spies, G. Erker, G. Kehr, K. Bergander, R. Frohlich, S. Grimme, D.W. Stephan,

Chem. Commun. 2007, 5072 – 5074.

6 a) U. Monkowius, S. Nogai, H. Schmidbaur, Dalton Trans. 2003, 987 – 991; b) T. J.

Malefetse, G. J. Swiegers, N. J. Coville, M. A. Fernandes, Organometallics 2002, 21,

2898 – 2904; c) N. Oohara, T. Imamoto, Bull. Chem. Soc. Jpn. 2002, 75, 1359 –

1365; d) R. B. Coapes, F. E. S. Souza, M. A. Fox, A. S. Batsanov, A. E. Goeta, D. S.

Yufit, M. A. Leech, J. A. K. Howard, A. J. Scott,W. Clegg, T. B. Marder, J. Chem.

Soc. Dalton Trans. 2001, 1201 – 1209; e) M. S. Lube, R. L.Wells, P. S.White, Inorg.

Chem. 1996, 35, 5007 – 5014.

7 P. A. Chase, G. C. Welch, T. Jurca, D. W. Stephan, Angew. Chem. Int. Ed. 2007, 46,

8050 – 8053.

8 P. Spies, S. Schwendemann, S. Lange, G. Kehr, R. Fröhlich, G. Erker, Angew. Chem.

Int. Ed. 2008, 47, 7543 – 7546.

9 K. V. Axenov, G. Kehr, R. Fráhlich, G. Erker, J. Am. Chem. Soc. 2009, 131, 3454 –

3455.

10 a) V. Sumerin, F. Schulz, M. Nieger, M. Leskelä, T. Repo, B. Rieger, Angew. Chem.

Int. Ed. 2008, 47, 6001 – 6003; b) V. Sumerin, F. Schulz, M. Atsumi, C. Wang, M.

Nieger, M. Leskelä, T. Repo, P. Pyykkö, B. Rieger, J. Am. Chem. Soc. 2008, 130,

14117–14119.


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11 D.-J. Chen, Y.-T. Wang, J. Klankermayer, Angew. Chem. Int. Ed. 2010, 49, 9475 –

9478.

12 For other examples on FLPs for hydrogenation, see: a) G. Erős, K. Nagy, H. Mehdi,

I. Pápai, P. Nagy, P. Király, G. Tárkányi, T. Soós, Chem. Eur. J. 2012, 18, 574 –

585; b) V. Sumerin, F. K. Chernichenko, M. Nieger, M. Leskelä, B. Rieger, T. Repo,

Adv. Synth. Catal. 2011, 353, 2093 – 2110.

13 See 12 b)

14 For the preparation of related compound, see: S. D. Rychnovsky, T. Beauchamp, R.

Vaidyanathan, T. Kwan, J. Org. Chem. 1998, 63, 6363 - 6374.

15 30 was prepared using known procedure, G. Erős, H. Mehdi, I. Pápai, T. A. Rokob,

P. Király, G. Tárkányi, T. Soós, Angew. Chem. Int. Ed. 2010, 49, 6559 –6563.

16 For selected reviews on asymmetric reactions using Hantzcsh ester, see: a) T. G.

Ouellet, A. M. Walji, D. W. C. Macmillan, Acc. Chem. Res. 2007, 40, 1327 – 1339;

b) M. Rueping, J. Dufour, F. R. Schoepke, Green Chem 2011, 13, 1084 – 1105. For

selected works, see: a) Z.-Y. Han, H. Xiao, X.-H. Chen, L.-Z. Gong, J. Am. Chem.

Soc. 2009, 131, 9182 – 9183; b) N. J. A. Martin, L. Ozores, B. List, J. Am. Chem.

Soc. 2007, 129, 8976 – 8977; c) J. Zhou, B. List, J. Am. Chem. Soc., 2007, 129, 7498

– 7499; d) R.-G. Xing, Y.-N. Li, Q. Liu, Y.-F. Han, X. Wei, J. Li, B.

Zhou, Synthesis 2011, 2066 – 2072; e) M. Rueping, C. Brinkmann, A. P.


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Antonchick, I. Atoresei, Org. Lett. 2010, 12, 4604 – 4607.

17 For works on activation of other molecules using FLPs, see: a) A. J. Cardenas, B. J.

Culotta, T. H. Warren, S. Grimme, A. Stute, R. Fröhlick, G. Kehr, G. Erker, Angew.

Chem. Int. Ed. 2011, 50, 7567 – 7571; b) G. Ménard, D. W. Stephan, Angew. Chem.

Int. Ed. 2011, 50, 8396 – 8399; c) M. J. Sgro, D. W. Stephan, Angew. Chem. Int. Ed.

2012, 52, 11343 – 11345.


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Chapter 2

Study of N-heterocyclic

carbene (NHC) and olefin

bidendate ligands


34

2.1 INTRODUCTION

The development of ligands remains as the central core research in transition metal

catalysis. As a matter of fact, dissociation of the ligands from metal center could be

problematic too.1 This normally will lead to diminished catalytic turnover of the catalyst

or result in the formation of racemic product (if chiral ligands were used). The search for

strong chelating ligands is therefore anticipated. Owing to its strong σ-donation effect, N-

heterocyclic carbene (NHC) has evolved as a promising class of ligand for metal

catalysis.2 Moreover, several bidendate ligands derived from N-heterocyclic carbene

(NHC) were known thus far. However, the combination of N-heterocyclic carbene (NHC)

and olefin as bidendate ligand is still not known yet. This project was targeted to design

this class of novel bidendate ligands for late transition metal catalysis.

2.2 BIDENDATE LIGANDS

2.2.1 N-heterocyclic Carbene based Bidendate Ligands

Soon after its first report as ligands for metal complexes, N-heterocyclic carbene (NHC)

based bidendate ligands has been a hot research topic in both organometallic and organic

chemistry.3 For the ease of understanding and reading, selected examples of N-

heterocyclic carbene (NHC) based bidendate ligands were summarized in Figure 2.1. N-


35

heterocyclic carbene (NHC) - alkoxy bidendate ligand 1 was developed in Alexakis’

group for copper catalyzed conjugate reaction. N-heterocyclic carbene (NHC) – sulfonate

2 was reported by Hoveyda and co-workers for various copper catalysis.4 Burgess and co-

workers reported bidendate ligand derived from N-heterocyclic carbene (NHC) and

oxazoline 3 for asymmetric hydrogenation reactions.5 Hayashi’s group reported indane-

derived N-heterocyclic carbene (NHC) – alkoxy bidendate ligand 4 for copper catalyzed

1, 4-addition and allylic substitution reactions.6

Figure 2.1. N-heterocyclic carbene (NHC) based Bidendate Ligands.


36

2.2.2 Olefin based Bidendate Ligands

On the other hand, we have witnessed the elegant chemistry using olefin based ligands.7

Independent research by Hayashi and Carreira has made significant progress in late

transition metal catalysis by introducing diene ligands 5 and 6.8 More recently, hybrid

ligands like sulfoxide – olefin 7, phosphine – olefin 8 and oxazoline – olefin 9 were

successfully synthesized and applied to rhodium and palladium catalysis.9

Figure 2.2. Olefin based Bidendate Ligands.


37


2.3.1 Result and Discussion

The research project was initiated for the development of novel bidendate ligands derived

from N-heterocyclic carbene (NHC) and olefin. Furthermore, the study of complexation

with late transition metal like rhodium and palladium was investigated. Following

previous system on N-heterocyclic carbene (NHC) – alkoxy bidendate ligands 10, we

Figure 2.3. Design of Chiral N-heterocyclic Carbene (NHC) – Olefin Ligands.

planned to introduce olefin moiety into the chiral motif 11 as shown in Figure 2.3. The

key intermediate N-Boc protected aldehydes 17 was prepared from (L)-valine 15

following a three-step procedure.10 The olefin moiety was installed by treatment with the

ylide resulted from n-BuLi and PhCH2PPh3Br and aldehydes 17. Upon removal of Boc-

group under acidic condition, the coupling between amine 19 and 20 afforded the desired

product 21 in 90% yield. Surprisingly, the reduction of 21 did not yield the desired


38

product 22. Synthetic method was revised and delightfully, Gilbertson’s one pot protocol

for the preparation of N-heterocyclic carbene ligand allowed us to access the desired

bidendate ligand 11a in shorter route (Scheme 2.2).11 With the bidendate ligands on hand,

we first examined its complexation with different rhodium salts. The silver complex 24

was obtained by the treatment of NHC – olefin precursor with Ag2O in the solvent

mixture of THF and benzene (Scheme 2.3).4b, 12 The transmetallation in the next step,

however, failed to achieve the desired rhodium complex 25. It was found that most of the

Scheme 2.1. General Synthetic Scheme for the Preparation of NHC-Olefin Ligands.


39

Scheme 2.2. Revised Synthetic Scheme for the Preparation of Bidendate Ligands

mass (>80%) for this reaction stayed at the baseline on TLC plate and remained

unidentified. Various evidence pointed to the possibility that NHC - olefin ligand may not

be stable (especially in the presence of transition metal)? Active discussion and

brainstorming was made and finally, following Prof. Tamio Hayashi’s advice, we came

Scheme 2.3. Attempt for Complexation with Rh via Transmetallation.

up with a new bidendate ligand structure 26 bearing a more rigid olefin moiety (Scheme

2.4). Delightfully, the first carbene-rhodium bond was established using NHC - olefin

ligand 26a whereas the olefin moiety was free from coordination (Scheme 2.5). In

addition, we also investigated the compatibility of carbene - olefin system using NHC


40

precursor 30 and 32.13 Successful isolation of complex 31 may imply that NHC precursor

11a and 26a were not stable in the form of free carbene upon deprotonation using KtBuO.

Although the rhodium - NHC complex was found to be air and moisture stable (in the

case of 31), the stability of rhodium – NHC containing olefin was certainly doubted since

its counterpart, iridium NHC - olefin complex 33 could be synthesized easily (Scheme

2.6). The failure example arose from di-substituted olefin ligands 11a prompted us to

investigate the use of terminal olefin as the chelating ligand. Due to the ease of

Scheme 2.4. Bidendate Ligands with Rigid Olefin Moiety.

Scheme 2.5. Complexation of Ligand 26a with Rhodium Salts.


41

introduction of allyl group onto N-mesity imidazole, we have prepared and applied this

imidazolium based NHC precursor 35 for the complexation with Rh salts (Scheme 2.7).

Despite the successful attempt to obtain the Rh-complex using silver transmellation step,

a rather unexpected bis-NHC - olefin 36 was obtained. The plane of symmetry through

Scheme 2.6. Study for the Investigation of the Compatibility between NHC and Olefin.


42

the bromide ligand on complex 36 which could not be realized from both the 1H NMR

and 13C NMR leaded us to a wrong postulation that dimeric rhodium complex 36a was

obtained in the first place. 1H NMR of the corresponding rhodium complex revealed a

Scheme 2.7. Study of Complexation via Silver Transmetallation and Formation of

Pentacoordinated Rh-complex 36.

strong coordination between olefin and rhodium as shown by the upfield shifts of the

olefinic proton from δ = 5.9, 5.3 and 5.2 ppm in the free ligand to δ = 4.5, 4.1 and 3.5

ppm in the complex respectively. Furthermore, the NHC – olefin interaction with

rhodium was unequivocally demonstrated by single-crystal X-ray analysis through slow

diffusion of pentane into a chloroform solution of the complex 36. Such pyramidal

coordinated Rh(I) center suggested a severe steric repulsion from olefin of one ligand to


43

the mesityl group of another ligand which restricted the bond rotation of N-C bond of the

mesityl group. This was again characterized by 1H NMR as three distinctive chemical

shifts were observed for each of the methyl group in the complex compared to two

chemical shifts (ortho- and para-methyl groups) in the free ligand. Phenyl-substituted

olefin – imidazolium salt 37 did not form the silver complex under standard condition

and therefore no Rh-complex was isolated. To examine the catalytic activity of the bis-

NHC – olefin Rh complex, we carried out a control experiment against the

[Rh(COD)2Cl]2 for the conjugate reaction of phenylboronic acid and cyclohexenone.

Scheme 2.8. Study of Different Rh-complexes for Conjugate Reaction between 38 and 39


44

From the preliminary study, it was demonstrated that Rh diene complex in the form of

[Rh(COD)Cl]2 is more catalytic active than the bis-NHC – olefin Rh complex and the

desired conjugate product 39 was attainable in >99% conversion within 3 hours (Scheme

2.8).15 Although it is not confirmed at this stage, we reasoned the low reactivity of the

bis-NHC – olefin complex 36 could be due to the stronger interaction between the

terminal olefin and rhodium which hindered the substrate (i.e. olefin of the

cyclohexenone) from binding to rhodium and thus halting the product formation.16

2.3.2 On-going Research

The current efforts were focused on the fine-tuning of the ligand structure in hope that

NHC – olefin complex of rhodium would adopt the desired conformation. Subsequently,

its application towards conjugate reaction between phenylboronic acid to cyclohexenone

will be studied. In addition, complexes derived from palladium and iridium will be the

subject along this research direction. Last but not least, the chiral NHC – olefin of these

metal complexes will be examined against other type of ligands in due course.

2.4 SUMMARY


45

Novel bis-NHC – olefin rhodium complex 36 was prepared via silver transmetallation

step. In spite of many failure attempts, this represents the first Rh - NHC complex with

olefin moiety as the bidendate ligand. X-ray crystallography revealed a geometry of

pyramidal structure exhibited by the Rh(I) with pentacoordination with two molecular of

NHC – olefin ligands and one bromide ligand. Such complex exhibited no catalytic

activity towards well-established conjugate reaction between phenylboronic acid and

cyclohexenone. We hoped that the study reported thus far would serve as a stepping stone

for the synthesis of desired dimeric NHC – olefin rhodium or other late transition metal

complexes.

2.5 REFERENCES

1 a) R. Cramer, J. Am. Chem. Soc. 1972, 94, 5681 – 5685.

2 For selected reviews on NHC ligands for catalysis, see: a) W. A. Herrmann, Angew.

Chem. Int. Ed. 2002, 41, 1290 – 1309; b) G. C. Fortman, S. P. Nolan, Chem. Soc.

Rev. 2011, 40, 5151 – 5169; c) F. Wang, L.-J. Liua, W. Wang, S. Lia, M. Shi,

Coordination Chemistry Reviews 2012, 256, 804 – 853. For reviews on NHC as

organocatalyst, see: a) X. Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511 – 3522;

b) M. Fèvre, J. Pinaud, Y. Gnanou, J. Vignolle, D. Taton, Chem. Soc. Rev. 2013, 42,

2142 – 2172.


46

3 H. W. Wanzlick, H. J. Schönherr, Angew. Chem. Int. Ed. 1968, 7, 141 – 142.

4 a) For selected examples, see: a) D. Martin, S. Kehrli, M. d’Augustin, H. Clavier, M.

Mauduit, A. Alexakis, J. Am. Chem. Soc. 2006, 128, 8416 – 8417; b) A. O. Larsen,

W.-H Leu, C. N. Oberhuber, J. E. Campbell, A. H. Hoveyda, J. Am. Chem. Soc. 2004,

126, 11130 – 11131; c) K.-S Lee, M. K. Brown, A. W. Hird, A. H. Hoveyda, J. Am.

Chem. Soc. 2006, 128, 7182 – 7184; d) M. K. Brown, T. L. May, C. A. Baxter, A. H.

Hoveyda, Angew. Chem. Int. Ed. 2007, 46, 1097 –1100.

5 a) M. T. Powell, D.-R. Hou, M. C. Perry, X. Cui, K. Burgess, J. Am. Chem. Soc.

2001, 123, 8878 – 8879; b) X. Cui, K. Burgess, J. Am. Chem. Soc. 2003, 125, 14212

– 14213.

6 a) R. Shintani, K. Takatsu, T. Hayashi, Chem. Commun. 2010, 46, 6822 – 6824; b) R.

Shintani, K. Takatsu, M. Takeda, T. Hayashi, Angew. Chem. Int. Ed. 2011, 50, 8656 –

8659; c) K. Takatsu, R. Shintani, T. Hayashi, Angew. Chem. Int. Ed. 2011, 50, 5548 –

5552.

7 For reviews, see: a) Comprehensive Organometallic Chemistry (Eds.: E. W. Abel, F.

G. A. Stone, G. Wilkinson), Pergamon, Oxford, 1995; b) Applied Homogeneous

Catalysis with Organometallic Compounds (Ed.: B. Cornils, W. A. Herrmann),

Wiley, New York, 2002; c) R. H. Crabtree, The Organometallic Chemistry of

Transition Metals, Wiley, New York, 001; d) L. S. Hegedus, Transition Metals in the


47

Synthesis of Complex Organic Molecules, University Science Books, Sausalito, 1999.

8 a) T. Hayashi, K. Ueyama, N. Tokunaga, K. Yoshida, J. Am. Chem. Soc. 2003, 125,

11508 – 11509; b) C. Fischer, C. Defeiber, T. Suzuki, E. M. Carreira, J. Am. Chem.

Soc. 2004, 126, 1628 – 1629.

9 For selected examples of sulfoxide – olefin, see: a) G. Chen, J. Gui, L. Li, J. Liao,

Angew. Chem. Int. Ed. 2011, 123, 7823 –7827; b) W.-Y. Qi, T.-S. Zhu, M.-H. Xu,

Org. Lett. 2011, 13, 3410 – 3413; c) F. Xue, X. Li, B. Wan, J. Org. Chem. 2011, 76,

7256 – 7262. For selected examples of phosphine – olefin, see: a) W.-L. Duan, H.

Iwamura, R. Shintani, T. Hayashi, J. Am. Chem. Soc. 2007, 129, 2130 – 2138; b) R.

Narui, S. Hayashi, H. Otomo, R. Shintani, T. Hayashi, Tetrahedron: Asymmetry

2012, 284 – 293; c) Z. Cao, Y. Lin, Z. Liu, X. Feng, M. Zhuang, H. Du, Org. Lett.

2011, 13, 2164 – 2167; d) Z. Liu, H. Du, Org. Lett. 2010, 12, 3054 – 3057; For

oxazoline – olefin, see: a) B. T. Hahn, F. Tewes, R. Fröhlich, F. Glorius, Angew.

Chem. Int. Ed. 2010, 49, 1143 –1146.

10 J. R. Luly, J. F. Dellaria, J. J. Plattner, J. L. Soderquist, N. Yi, J. Org. Chem. 1987,

52, 1487 – 1492.

11 B. A. B. Prasad, S. R. Gilbertson, Org. Lett. 2009, 11, 3710 – 3713.

12 See Appendix for spectrum.

13 a) A. Zanardi, E. Peris, J. A. Mata, New J. Chem., 2008, 32, 120 – 126; b) S. Wolf,

http://pubs.acs.org/action/doSearch?action=search&author=Prasad%2C+B.+A.+Bhanu&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Gilbertson%2C+Scott+R.&qsSearchArea=author


48

H. Plenio, J. Organomet. Chem. 2009, 694, 1487 – 1492.

14 B. T. Hahn, F. Tewes, R. Fröhlich, F. Glorius, Angew. Chem. Int. Ed. 2010, 49, 1143

– 1146.

15 For more details, see Appendix for the comparison between diene ligand and NHC –

olefin ligand.


49

Chapter 3

Bifunctional Catalysis for

Alpha Alkylation of

Oxindole Derivatives


50

3.1 INTRODUCTION

Asymmetric synthesis of all carbon quaternary centers-containing organic compounds

has been a challenging issue for organic chemists.1 Numerous organocatalytic approaches

have been devised for the construction of molecular entity containing a quaternary

stereogenic carbon center.2 3,3-disubstituted oxindoles belong to a class of naturally

occurring molecule with interesting biologically activity in medicinal chemistry.3 Its core

structure could be easily found in therapeutic agents and could serve as the target in drug

discovery (Figure 3.1). Owing to the therapeutic significance of these compounds, several

asymmetric transformations have been introduced. Both the transition metal catalysis and

organocatalysis were documented for the direct alkylation of the C3 position of the

oxindole framework and these include: (1) transition metal assisted asymmetric allylic

substitution reactions; (2) anion binding alkylation

3.2 ASYMMETRIC ALLYLIC ALKYLATION (AAA)

REACTIONS

3.2.1 Molybdenum Mediated Asymmetric Allylic Alkylation

Asymmetric allylic alkylation (AAA) is a powerful tool for direct alkylation in

asymmetric catalysis.4 The proceeding η3-allyl-metal complex lowers the HOMO for the

electrophile and hence, the approaching nucleophile attacks in the fashion to avoid the


51

Figure 3.1. Representative Natural Products Bearing 3, 3-disubstituted Oxindole Core

Structure.

steric repulsion exerted by the chiral ligands on the metal to furnish the desired alkylation

products (Scheme 3.1). In 2006, Trost and co-workers reported a chiral molybdenum

system for allylic alkylation of 3-alkyloxindoles.5 The synthesis features highly

enantioselective allylic alkylation reaction using prochiral 3-alkyloxindoles with allyl

carbonate to generate quaternary stereocenters (Scheme 3.2). In this report, the

researchers postulated that chiral molybdenum catalyst was able to interact with the

nucleophiles and as a result, the nucleophile could attack the symmetrical allyl carbonate

in a more stereocontrolled manner. The enantioselectivity attainable was better than the

case in palladium catalysis.6 They also demonstrated the synthetic utility of this protocol


52

Scheme 3.1. Transition Metal Mediated Allylic Alkylation Approach.

Scheme 3.2. Molybdenum-Catalyzed Asymetric Allylic Alkylation of 3-Alkyloxindole.


53

for the formal synthesis of (-)-physostigmine 2 and its analogues (Scheme 3.3). Oxidation

of the allylated oxindole 7a followed by two recrystallization from isopropyl alcohol-

cyclohexane afforded the aldehydes 8 in 66% overall yield and 99% ee. Following

optimized condition disclosed by Overman, they furnished the reductive cyclization

intermediate 9 in 90% yield. Subsequent demethylation using BBr3 and coupling with

isocyanate accomplished the total synthesis of the natural products, (-)-physostigmine

and (-)-phenserine.7

Scheme 3.3. Formal Synthesis of (-)-Physostigmine.


54

3.1.2 Palladium Mediated Asymmetric Benzylation

Following their initial report on asymmetric allylic alkylation reaction, the Trost group

further demonstrated asymmetric benzylation of 3-aryloxindoles derivatives using chiral

palladium catalyst (Scheme 3.4).8 The desired benzylated products could be obtained in

44-98% yield with 77-96% ee. It is noteworthy that the N-benzylated by-product was not

observed in this transformation. More recently, the same group disclosed

Scheme 3.4. Palladium Catalyzed Asymmetric Benzylation of 3-Aryloxindole

Derivatives.

a new Pd-AAA reaction employing 3-aryloxindole and germinal dicarboxylate 16 as the

electrophiles for the synthesis of 3, 3-disubstituted oxindole structural motifs bearing a

quaternary stereocenter (Scheme 3.5).9


55

Scheme 3.5. Palladium Catalyzed Asymmetric Allylic Alkylation of 3-Aryloxindole.

3.2 ANION BINDING ALKYLATION

Despite successful examples of alkylation have been demonstrated using palladium and

molybdenum chemistry in the context of allylic alkylation reactions, organocatalytic

approach is scarcely reported in this arena. In recent years, we have witnessed the

successful emergence of organocatalysis and its application in organic chemistry.10

Unlike enamine or iminium catalysis that involves covalent bond formation between

catalyst and reactant, anion binding catalysis evolved as an eminent approach for

asymmetric transformation.11 Since then, such conceptually interesting chemistry has

been widely utilized in practical synthetic issues especially for alkylation reactions.12 In

2011, Ooi and co-workers documented an anion binding approach for the asymmetric


56

alkylation of oxindoles using chiral 1, 2, 3-triazolium salts as a new cationic organic

catalysts.13 In the corresponding communication, they applied the triazolium salt 19 to the

reaction between oxindole 18 and benzyl bromide to afford the alkylation product 20 in

excellent enantioselectivity (Scheme 3.6).

Scheme 3.6. Asymmetric Alkylation of Oxindoles using Organic Catalyst with Anion-

Recognition Ability.


3.3.1 Results and Discussions


57

In spite of the existing methods for the construction of chiral oxindole derivatives bearing

a stereogenic carbon center, the lack of the synthesis for both C3-aryl and C3-alkyl

oxindole using one catalytic system has driven us for the search in this area. Hence, our

approach is to employ bifunctional catalysis for the construction of both C3-aryl and C3-

alkyl oxindole derivatives using simple and easily derived organic catalyst. We initiated

Table 3.1. Catalyst Screeninga.

Entry Cat. Time (hr) Yieldb (%) Eec (%)

1 22a 36 42 16

2 22b 36 71 51

3 22c 48 93 24

4 22d 48 89 3

5 22e 48 90 3

6 23 48 >99 -15

7 24 43 65 7

8 25 >72 Trace amount N.D.

9 26 42 90 32

10 27 42 92 4

11 28 120 80 0

a Reactions conditions (unless otherwise specified): chloroform (1.0 ml), tert-butyl-2-

oxo-3-phenylindoline-1-carboxylate 21a (0.05 mmol, 1.0 equiv.), benzyl bromide (0.1

mmol, 2.0 equiv.), K2CO3 (0.1 mmol, 2.0 equiv.), catalyst (0.01 mmol, 0.20 equiv) at -


58

20oC. b Isolated yield after column chromatography. c Determined by chiral HPLC. d N.D.

= Not Determined

this project by examining the reaction between oxindole 21a and benzyl bromide in the

presence of cinchona alkaloid derived thiourea/ urea catalysts 22-27. The preliminary

results were shown in Table 3.1 in which different bifunctional organocatalysts were

screened for the model reaction. It was found that the quinine derived urea catalyst could


59

Figure 3.2. Chiral Bifunctional Organocatalysts.

promote this reaction more effectively than the thiourea counterpart (Table 3.1, entries 1

and 2). Followed by this was the investigation of electronic properties on the phenyl ring

of the urea catalyst (Table 3.1., entries 3-5). It turned out that 3, 5-CF3 substituent on the

phenyl ring played a crucial role for the observed enantioselectivity and may be

Table 3.2. Effect of Solvent to the Reaction.

Entrya Solvent Yieldb (%) Eec (%)

1 CHCl3 92 51

2 CH2Cl2 85 36

3 PhMe 96 32


60

4 PhCF3 94 32

5 EtOAc 98 5

6 CCl4 94 23

7 TBME 89 16

8e CHCl3 N.D.d N.D.d

9f CHCl3 80 0

10e, g CHCl3 75 9

a Reactions conditions (unless otherwise specified): solvent (1.0 ml), tert-butyl-2-oxo-3-

phenylindoline-1-carboxylate 21a (0.05 mmol, 1.0 equiv.), benzyl bromide (0.1 mmol,

2.0 equiv.), K2CO3 (0.1 mmol, 2.0 equiv.), catalyst (0.01 mmol, 0.20 equiv) at -20oC. b

Isolated yield after column chromatography. c Determined by chiral HPLC. d N.D. = Not

Determined. e Reaction conducted at -30oC. f Benzyl iodide as alkylating reagent. g TBAI,

tetrabutyl ammonium iodide (1.2 equiv.) was used as additive.

indicative that the hydrogen bonding character is important for the transformation. The

bifunctional urea catalyst bearing binapthyl backbond gave almost racemic product

(Table 3.1., entry 7). The indanol-derived urea catalyst developed by Ricci was not

suitable for this reaction either.14 Despite quinine and quinidine are diastereomer, their

stereochemical influence for this reaction was distinctly different (Table 3.1., entries 9

and 10). The incorporation of additional chiral motif into the quinine-derived urea

catalyst proved to be futile for this transformation (Table 3.1., entry 11). We therefore

postulated that the dihedral angle between the tertiary amino group and hydrogen

bonding site (hydroxyl group) was important for the reaction to take place in a

stereocontrolled manner. Subsequent solvent screening revealed that chlorinated solvent

(chloroform) was the best solvent of choice among other solvents (Table 3.2., entry 1). In


61

addition, racemic product was obtained when benzyl iodide was used as the alkylating

reagent and to our surprise, no drastically improvement was observed in the

enantioselectivity when tert-butylammonium iodide (TBAI) was used as the additive at

the temperature where both the background reactivity and catalyzed reactivity were

diminished (Table 3.2., entries 9 and 10). The preliminary of this result would suggest

Table 3.3. Effect of Base to the Reaction.

Entrya Base Yieldb (%) Eec (%)

1 K2CO3 92 51

2 DIPEA 90 38

3 Et3N 75 6

4 3, 4-lutidine N.D.d N.D.d

5 2, 6-lutidine N.D.d N.D.d

6 KF 82 33

7 Proton sponge N.D.d N.D.d

8 - N.D N.D

a Reactions conditions (unless otherwise specified): chloroform (1.0 ml), tert-butyl-2-

oxo-3-phenylindoline-1-carboxylate 21a (0.05 mmol, 1.0 equiv.), benzyl bromide (0.1

mmol, 2.0 equiv.), base (0.1 mmol, 2.0 equiv.), catalyst (0.01 mmol, 0.20 equiv) at -20oC. b Isolated yield after column chromatography. c Determined by chiral HPLC. d N.D. = Not

Determined.


62

that urea moiety in the catalyst would recognize the anion and in this case bromide

recognition is better than that of iodide. Different bases were also tested for this reaction.

Organic bases like N, N-diisopropylethylamine (DIPEA) and triethylamine (Et3N) were

less effective for this transformation. The rationale for this effect is because these are

more soluble bases in the reaction mixture and hence, increasing the background

reactivity between the substrates. On the other hand, nucleophilic bases like 3, 4-lutidine,

2, 6-lutidine and proton sponge (1, 8-bis(dimethylamino)naphthalene) were totally

ineffective for the reaction to take place (Table 3.3, entry 4, 5 and 7). Inorganic base and

Scheme 3.7. Formation of O-alkylating product 28a’.


63

in particular, potassium carbonate (K2CO3) remained as the best choice under this

reaction condition. In view of the usefulness of nucleophilic base in anion binding

catalysis 15, we employed 29 as the alkylating reagent in the model reaction and it turned

out that the O-alkylated product 28a’ is favored (Scheme 3.7). We attributed such finding

to the change of softer benzylic carbon to harder benzylic carbon which favoured the

oxyanion (oxygen is comparatively harder than carbon) to attack the alkylating agent in

the form of 29. Considering the reaction mechanism, we inferred that the rate of the

tautomerization between the oxindole and hydroxyindole may affect the observed

enantioselectivity as the more nucleophilic hydroxyindole may undergo alkylation via a

non-stereoselective manner (Scheme 3.8). To probe this hypothesis, we began our

Scheme 3.8. Tautomerization between Oxindole and Hydroxyindole and Plausible Effect

for Low Enantioselectivity.

investigation on the reaction between a C3-alkylated oxindole derivatives 21h with


64

benzyl bromide using the reaction condition established before (Scheme 3.9). To our

delight, the reaction proceeded at 0 oC and the alkylation product could be obtained in

87% yield with improved enantioselectivity (80% ee).

Scheme 3.9. Asymmetric Alkylation of 3-Alkyloxindole Derivatives.

3.3.2 On-going research

This research project is still actively ongoing in the laboratory. The current focus of this

project was to elaborate the substrate scope for 3-alkyloxindole derivatives and in the

meantime, optimizing the reaction for 3-aryloxindole in term of the amount of base used

in the reaction and reaction concentration. Further optimization of catalyst structure is

also being actively pursued. Although the mechanistic action of the catalysis is still not

known thus far, we are pleased to see the dramatic effect demonstrated by different

alkylating reagent as it serves as a hint for us to establish a stronger interaction between

the urea moiety and the bromide in the alkylation source. Current efforts were also


65

extended to other alkylating reagent like methyl iodide (which could not be achieved by

transition metal catalyzed asymmetric allylic alkylation reaction).

Scheme 3.10. Further Study on Alkylation Project.

3.4. SUMMARY

The current catalytic system can tolerate both the C3-aryl or C3-alkyl oxindole

derivatives. In addition, the preparation of the catalyst is easy and could be available in

large quantity. The reaction demonstrated above was carried out without stringent

reaction condition to exclude air and moisture. More importantly, we hope to demonstrate

that this catalytic system could be expanded for other alkylation transformations.

3.5. REFERENCES


66

1 For reviews, see: a) Quaternary Stereocenters (Eds.: J. Christoffers, A. Baro), Wiley-

VCH, Weinheim, 2005; b) E. J. Corey, A. Guzman-Perez, Angew. Chem. Int. Ed.

1998, 37, 388 – 401; c) J. Christoffers, A. Mann, Angew. Chem. Int. Ed. 2001, 40,

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e) J. P. Das, I. Marek, Chem. Commun. 2011, 47, 4593 – 4623.

2 For selected examples, see: a) N. Shibata, E. Suzuki, T. Asahi, M. Shiro, J. Am.

Chem. Soc. 2001, 123, 7001 – 7009; b) Y. Hamashima, T. Suzuki, H. Takano, Y.

Shimura, M. Sedeoka, J. Am. Chem. Soc. 2005, 127, 10164 – 10165; c) T. Ishimaru,

N. Shibata, T. Horikawa, N. Yasuda, S. Nakamura, T. Toru, M. Shiro, Angew. Chem.

Int. Ed. 2008, 47, 4157 – 4161; d) T. Bui, N. R. Candeias, C. F. Barbas III, J. Am.

Chem. Soc. 2010, 132, 5574 – 5575; e) S. Nakamura, N. Hara, H. Nakashima, K.

Kubo, N. Shibata, T. Toru, Chem. Eur. J. 2008, 14, 8079 – 8081; f) T. Bui, S. Syed,

C. F. Barbas III, J. Am. Chem. Soc. 2009, 131, 8758 – 8759; g) R. He, S. Shirakawa,

K. Maruoka, J. Am. Chem. Soc. 2009, 131, 16620 – 16621; h) W.-Y. Siau, W. Li, F.

Xue, Q. Ren, M. Wu, S. Sun, H. Guo, X. Jiang, J. Wang, Chem. Eur. J. 2012, 18,

9491 – 9495.

3 For selected reviews, see: a) C. Marti, E. M. Carreira, Eur. J. Org. Chem. 2003, 2209

– 2210; b) A. B. Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945 – 2963; c) C.

V. Galliford, K. A. Scheidt, Angew. Chem. Int. Ed. 2007, 46, 8748 – 8758.


67

4 For reviews, see: a) B. M. Trost, D. L. van Vranken, Chem. Rev. 1996, 96, 395 - 422;

b) B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921 – 2943; c) B. M. Trost,

M. R. Machacek, A. Aponick, Acc. Chem. Res. 2006, 39, 747 – 760; d) Z. Lu, S. Ma,

Angew. Chem. Int. Ed. 2008, 47, 258 – 297.

5 B. M. Trost, Y. Zhang, J. Am. Chem. Soc. 2006, 128, 4590 – 4591.

6 Previous work on Pd-AAA, see: B. M. Trost, M. U. Frederiksen, Angew. Chem. Int.

Ed. 2005, 44, 308 – 310.

7 a) T. Matsuura, L. E. Overman, D. J. Yoon, J. Am. Chem. Soc. 1998, 120, 6500 –

6503; b) A. Huang, J. J. Kodanko, L. E. Overman, J. Am. Chem. Soc. 2004, 126,

14043 – 14053.

8 B. M. Trost, L. C. Czabaniuk, J. Am. Chem. Soc. 2010, 132, 15534 – 15536.

9 B. M. Trost, J. T. Masters, A. C. Burns, Angew. Chem. Int. Ed. 2013, 52, 2260 –

2264.

10 For selected books on organocatalysis, see: a) Berkessel, A.; Groger, H. Asymmetric

Organocatalysis; Wiley: Weinheim, 2005; b) Dalko, P. I. Enantioselective

Organocatalysis; Wiley: Weinheim, 2007; c) Reetz, M. T.; List, B.; Jaroch, S.;

Weinmann, H. Organocatalysis; Springer, 2007; (d) List, B. Asymmetric

Organocatalysis; Springer, 2009.


68

11 For review, see: a) R. J. Phipps, G. L. Hamilton, F. D. Toste, Nature Chemistry 2012,

4, 603 – 614.

12 Selected Jacobsen’s works on anion binding alkylation, see: a) M. S. Taylor, E. N.

Jacobsen, J. Am. Chem. Soc. 2004, 126, 10558 – 10559; b) I. T. Raheem, P. S.

Thiara, E. A. Peterson, E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129, 13404 – 13405;

c) A. R. Brown, W.-H. Kuo, E. N. Jacobsen, J. Am. Chem. Soc. 2010, 132, 9286 –

9288.

13 K. Ohmatsu, M. Kiyokawa, T. Ooi, J. Am. Chem. Soc. 2011, 133, 1307 – 1309.

14 R. P. Herrera, V. Sgarzani, L. Bernadi, A. Ricci, Angew. Chem. Int. Ed. 2005, 44,

6576 – 6579.

15 a) J. A. Birrell, J.-N. Desrosiers, E. N. Jacobsen, J. Am. Chem. Soc. 2011, 133, 13872

– 13875; b) E. G. Klauber, C. K. De, T. K. Shah, D. Seidel, J. Am. Chem. Soc. 2010,

132, 13624 – 13626, and references cited therein.

16 For relevant work, see: Q. Zhu, Y. Lu, Angew. Chem. Int. Ed. 2010, 49, 7753 – 7756.


69

APPENDICES

APP.1 GENERAL INFORMATION

Chemicals and solvents were purchased from commercial suppliers and used as received.

1H and 13C NMR spectra were recorded on a Bruker ACF300 (300 MHz) or AMX500

(500 MHz) spectrometer. Chemical shifts were reported in parts per million (ppm), and

the residual solvent peak was used as an internal reference: proton (chloroform δ 7.26),

carbon (chloroform δ 77.0) or tetramethylsilane (TMS δ 0.00) was used as a reference.

Multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m

(multiplet), dd (doublet of doublet), bs (broad singlet). Coupling constants were reported

in Hertz (Hz). Low resolution mass spectra were obtained on a Finnigan/MAT LCQ

spectrometer in ESI mode, and a Finnigan/MAT 95XL-T mass spectrometer in EI mode.

All high resolution mass spectra were obtained on a Finnigan/MAT 95XL-T mass

spectrometer. For thin layer chromatography (TLC), Merck pre-coated TLC plates

(Merck 60 F254) were used, and compounds were visualized with a UV light at 254 nm.

Further visualization was achieved by staining with KMnO4 solution, or ninhydrin

followed by heating using a heat gun. Flash chromatography separations were performed

on Merck 60 (0.040-0.063 mm) mesh silica gel. The enantiomeric excesses of products


70

were determined by chiral phase HPLC analysis. Optical rotations were recorded on

Jasco DIP-1000 polarimeter.


71

APP.2 GENERAL SYNTHETIC SCHEME FOR CHEMICALS

Chapter 1:

Bargellini reaction for the preparation of chiral morpholinone:1

Chiral amino alcohol 22a (3.00 g, 20.0 mmol, 1.0 equiv), benzyltriethylammonium

chloride (46.0 mg, 0.20 mmol, 0.01 equiv), 2.4 mL of CHCl3 (30.0 mmol, 1.50 equiv.)

and 15 mL of acetone (200.0 mmol, 10.0 equiv) were dissolved in 25 mL of CH2Cl2 and

cooled to 0 °C. Powdered NaOH (1.00 g, 7.50 mmol, 5 equiv) was added portionly, and

the reaction was maintained at a temperature between 0 and 6 °C for 6 h. After 6 h, the

reaction was allowed to slowly warm to room temperature over a 12 h period. The

resulting white suspension was filtered and the resulting filter cake was rinsed with

CH2Cl2. The white powder was dissolved in 50 mL of MeOH and filtered, and the

solvent was removed under reduced pressure to give the carboxylate salt. The crude

carboxylate salt was suspended in 100 mL of toluene and sparged with argon for 15 min.

(+)-Camphorsulfonic acid (20.0 g, 90.0 mmol, 4.50 equiv) was added to the suspension,

and the reaction mixture was refluxed for 10 h. The suspension was then poured into

saturated NaHCO3, extracted (3 x EtOAc), washed (brine), dried (MgSO4), filtered, and


72

concentrated under reduced pressure to give a yellow-orange oil. Colum chromatography

yielded the product 23a in 46% as white solid. 1H NMR (300 MHz, CDCl3) δ 7.39 – 7.31

(m, 1H), 7.22 (qd, J = 4.2, 1.8 Hz, 3H), 5.17 (ddd, J = 7.3, 6.3, 4.5 Hz, 1H), 4.60 (d, J =

6.3 Hz, 1H), 3.39 (dd, J = 17.2, 7.3 Hz, 1H), 3.22 (dd, J = 17.2, 4.4 Hz, 1H), 1.71 (s, 1H),

1.51 (s, 3H), 1.35 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 174.6, 140.8, 139.1, 128.8,

127.4, 124.9, 124.7, 80.1, 55.5, 54.2, 38.7, 27.3, 23.6.

Compound 23b was synthesized using above procedure. The yield is extremely low (2%,

~20mg of product was isolated). 1H NMR (500 MHz, CDCl3) δ 4.40 (dd, J = 10.7, 3.5

Hz, 1H), 4.16 (t, J = 10.9 Hz, 1H), 2.84 (dd, J = 11.2, 3.5 Hz, 1H), 1.41 (s, 3H), 1.39 (s,

3H), 0.92 (s, 9H).

Study of H2 activation:2

The reaction was performed on double-manifold H2(Ar)/vacuum lines. General procedure:

Inside the glovebox, B(C6F5)3 (0.10 mmol, 51.0 mg, 1.00 equiv.), dry deuterated toluene


73

(0.50 mL), and an amine (0.1 mmol) were placed in a J-Young tube. The tube was sealed

properly with teflon stopcock before connecting to manifold. The reaction mixture was

degassed by freezing, evacuation, and thawing 3 times and the tube was refilled with H2

(1 atm). The reaction mixture was stand for 12 hr at 25oC and analysed on next day. 1H

NMR (500 MHz, Tol) δ 3.96 (s, 1H), 3.41 (d, J = 169.3 Hz, 2H), 1.50 – 1.30 (m, 2H),

1.27 – 1.13 (m, 4H), 1.07 – 0.91 (m, 12H). 13C NMR (126 MHz, Tol) δ 149.7, 147.7,

138.5, 136.5, 36.2, 29.1, 16.8. 11B NMR (160 MHz, Tol) δ -23.9.

Similar procedure was done for 23a.

Synthesis of compound 27:3


74

Morpholinone 23a (1.00 g, 4.60 mmol, 1.0 equiv) was dissolved into 50 mL of Et2O and

cooled to 0 °C. A solution of DIBAL-H (8.51 mL, 8.51 mmol, 1.85 equiv) was added

dropwise by syringe at -78oC. After 10 min, the reaction was quenched by sequential

addition of MeOH (5.0 mL) and 30% NaK tartrate solution. The mixture was warmed to

room temperature, extracted (3 x EtOAc), washed (brine), dried (MgSO4), and

concentrated under reduced pressure to give a wax-like compound. The crude product

was directly used for next step, in which 4-dimethylaminopyridine (DMAP) (15.0 mg,

0.12 mmol, 0.026 equiv.) and Et3N (3.21 mL, 23.0 mmol, 5.00 equiv.) was added into a

solution of the containing 26. This was followed by addition of Ac2O (0.87 mL, 9.20

mmol, 2.0 equiv.) After being stirred for 12 h, the reaction was quenched with saturated

aqueous NaHCO3, extracted (3 x CH2Cl2), washed (brine), dried (Na2SO4) and

concentrated under reduced pressure. Chromatography (EtOAc/hexanes = 1: 20 to 1: 10

to 1: 5) gave 0.74 g (62%) of the product as a diastereomeric pair. Confirmed by 1H

NMR, the acetoxy acetal intermediate was re-dissolved in 50 mL of CH2Cl2 and followed

by addition of TMSOTf (2.52 mL, 14.0 mmol, 5.00 equiv.) and TMSSPh (5.30 mL, 28.0

mmol, 10.0 equiv.). The reaction mixture was brought to reflux for 3 days before


75

quenched with saturated NaHCO3, extracted (3 x CH2Cl2), washed (15% NaOH, brine),

dried (Na2SO4) and concentrated under reduced pressure. The pure product was obtained

by column chromatography (EtOAc/hexanes = 1: 10 to 1: 2) in 43% yield. 1H NMR (500

MHz, Tol) δ 7.81 – 7.52 (m, 2H), 7.39 – 7.02 (m, 6H), 5.14 (s, 1H), 4.89 (dd, J = 7.3, 3.1

Hz, 1H), 4.13 (d, J = 4.7 Hz, 1H), 3.08 (d, J = 16.6 Hz, 1H), 2.94 (dd, J = 16.4, 5.6 Hz,

1H), 1.63 (s, 0H), 1.35 (s, 1H), 1.09 (s, 3H). 13C NMR (126 MHz, Tol) δ 144.8, 140.4,

130.9, 129.0, 127.6, 126.8, 126.5, 125.1, 125.0, 91.6, 69.9, 58.5, 52.5, 37.2, 29.0, 27.0.

Study of H2 activation:

Similar procedure was followed as above.

Compound 30 was synthesized based on known method.4

Chapter 2:


76

Compound 18, 23 were prepared based on reported procedure.5

Synthesis of NHC-olefin ligand 11a:

To a solution containing 18 was slowly added 4 M solution of HCl in dioxane. The

reaction mixture was allowed to stir at 25oC until no starting material was detected on

TLC. The reaction mixture was quenched (saturated NaHCO3 solution), extracted (3 x

EtOAc), dried (MgSO4), and concentrated under reduced pressure to amine, which was

used directly for the next step. The amine, 23, CH(OEt)3 (2.00 equiv.) and 10 mol%

formic acid was mixed together in a seal-tube under Ar atmosphere. After being heated at

120oC for 12-18 hr, the resulting dark sticky mixture was concentrated in vacuo and

triturated with Et2O (with vigorous stirring for overnight). Pure product of 11a was

obtained in 50% yield as yellow solid by column chromatography using EtOAc/ hexanes

= 1: 1 to MeOH/EtOAc = 1: 1). 1H NMR (300 MHz, CDCl3) δ 9.31 (s, 1H), 7.46 (d, J =

6.7 Hz, 2H), 7.39 – 7.17 (m, 4H), 7.04 (d, J = 15.6 Hz, 1H), 6.90 (s, 2H), 6.27 (dd, J =

15.7, 9.0 Hz, 1H), 4.96 (t, J = 8.5 Hz, 1H), 4.39 – 4.10 (m, 4H), 2.28 (d, J = 10.5 Hz,

9H), 1.12 (d, J = 6.5 Hz, 3H), 1.08 (s, 1H), 1.04 (d, J = 6.5 Hz, 3H). 13C NMR (75 MHz,


77

CDCl3) δ 157.6, 140.4, 138.0, 135.4, 135.0, 130.3, 130.0, 128.7, 126.9, 121.9, 66.2, 50.8,

46.7, 29.8, 21.0, 20.0, 19.0, 18.3.

Two other NHC-olefin ligands were synthesized based on the procedure mentioned

above. However, similar phenomenon and result was obtained for their complexation

with [Rh(COD)Cl]2.

Synthesis of silver complex 24:

To an oven-dried 25 mL Schlenk tube was added 11a, Ag2O (2.0 equiv.) and 4Å

molecular sieves were added under Ar atmosphere. The flask was covered with a layer of


78

aluminium foil and THF and benzene were added via syringe. The mixture was allowed

to stir for overnight (~ 12 hr). The mixture was quickly filtered through a pad of Celite,

washed with CH2Cl2 and concentrated in vacuo to afford white solid 24.

Synthesis of bidendate ligand 26a:

26a’ was prepared using known procedure.6

To a solution of 26a’, PPh3 (1.20 equiv.), DIAD (1.20 equiv.) in THF was slowly added

DPPA (1.20 equiv.) at 0oC. After being stirred for 12 h, the solution was heated to 50 oC

for 2 h. Then triphenylphosphine (1.30 equiv.) was added and heating was maintained

until the gas evolution has ceased (2 h). The solution was cooled to room temperature,

and 1 mL of water was added and the solution was stirred for 3 h. Solvents were removed

in vacuo and directly purified on column (EtOAc/hexanes = 1: 1, MeOH/EtOAc = 1: 5 to

1: 0) to afford the amine intermediate. To an oven-dried seal-tube was charged with the

amine 23 in a mixture of CH(OEt)3 (2.00 equiv.), formic acid (0.10 equiv.) and toluene

(0.50 mL). After being stirred at 1200C for 12 h, the mixture was concentrated in vacuo

and triturated with Et2O (with vigorous stirring for overnight). Pure product of 26a was


79

obtained in 64% yield as light yellow solid after decanting the ethereal solution. 1H NMR

(500 MHz, CDCl3) δ 9.10 (s, 1H), 7.24 – 7.09 (m, 10H), 6.85 (s, 2H), 5.55 – 5.26 (m,

1H), 4.43 – 4.28 (m, 2H), 4.23 (dd, J = 11.9, 8.8 Hz, 2H), 3.45 (dd, J = 16.2, 7.5 Hz, 2H),

3.23 – 3.05 (m, 2H), 2.32 (s, 6H), 2.23 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 157.1,

140.2, 136.0, 135.2, 134.6, 130.4, 129.9, 128.3, 128.2, 127.5, 56.0, 50.9, 46.4, 42.9, 20.9,

18.7.

Complexation with Rh:

[Rh(COD)Cl]2 (10.0 mg, 0.02 mmol, 1.00 equiv.) was dissolved in 10 mL of THF inside

the glovebox. KtBuO (4.90 mg, 0.04 mmol, 2.20 equiv.) was slowly added into the

solution and the reaction mixture was allowed to stir for another 1 h before addition of a

solution of NHC precursor 26a in THF (5.00 mL). The reaction mixture was allowed to

stir for another 4 h before subjecting it to vacuum to remove the solvents. The pure

product of 29 was obtained as a yellow solid (75%) upon column chromatography (2-3


80

cm in length) using EtOAc/ hexanes = 1: 10. 1H NMR (500 MHz, CDCl3) δ 7.26 – 7.15

(m, 10H), 7.00 (s, 1H), 6.89 (s, 1H), 6.69 – 6.59 (m, 1H), 5.13 – 4.90 (m, 2H), 3.79 (m,

1H), 3.77 (m, 1H), 3.72 – 3.69 (m, 1H), 3.69 – 3.65 (m, 2H), 3.59 (dd, J = 17.9, 8.1 Hz,

1H), 3.45 (dd, J = 16.8, 8.3 Hz, 1H), 3.24 (d, J = 7.2 Hz, 1H), 3.11 (d, J = 17.7 Hz, 1H),

2.91 (d, J = 16.8 Hz, 1H), 2.61 (s, 3H), 2.48 – 2.35 (m, 1H), 2.33 (s, 3H), 2.08 (s, 3H),

2.03 (dt, J = 14.5, 6.5 Hz, 1H), 1.90 – 1.85 (m, 2H), 1.62 (dd, J = 14.5, 8.3 Hz, 1H), 1.39

– 1.34 (m, 1H), 1.32 – 1.29 (m, 1H). 13C NMR (126 MHz, CDCl3) δ 211.2 (d, JC-Rh = 100

Hz)138.0, 137.8, 137.6, 136.3, 136.2, 135.0, 134.5, 130.0, 128.4, 128.3, 128.2, 128.1,

128.0, 127.1, 127.0, 96.2 (d, JC-Rh = 6.3 Hz), 95.6 (d, JC-Rh = 6.3 Hz), 71.2 (d, JC-Rh = 14.0

Hz), 70.0 (d, JC-Rh = 14.0 Hz), 57.3, 53.4, 51.7, 43.2, 42.8, 34.8, 30.9, 29.6, 27.4, 22.0,

21.0, 18.2.

Complexes 31 and 33 were obtained using known procedure.7


81

To an oven-dried round bottom flask was charged with 1-mesityl-1H-imidazole and

followed by allyl bromide (3.0 equiv.). A minimal amount of toluene was necessary to

make the reaction mixture homogenous and the reaction mixture was allowed to stir for

16 h before it was concentrated to remove the residual solvent. The brown-yellow solid

was triturated with Et2O several times to afford the beigh-colored 3-allyl-1-mesityl-1H-

imidazol-3-ium bromide salt 35 in 90% yield. 1H NMR (500 MHz, CDCl3) δ 10.02 (s,

1H), 7.91 (s, 1H), 7.15 (s, 1H), 6.78 (s, 2H), 6.01 – 5.88 (m, 1H), 5.33 (d, J = 17.0 Hz,

1H), 5.21 (dd, J = 10.1, 3.7 Hz, 1H), 5.15 (d, J = 4.6 Hz, 2H), 2.12 (d, J = 3.2 Hz, 3H),

1.85 (d, J = 3.3 Hz, 6H).13C NMR (126 MHz, CDCl3) δ 140.5, 136.8, 133.6, 130.1,

130.0, 129.2, 123.1, 123.0, 121.6, 51.5, 20.5, 17.1.

To an oven-dried round bottom flask containing activated 3Å MS was added 3-allyl-1-

mesityl-1H-imidazol-3-ium bromide salt 35, Ag2O and dichloromethane. The reaction


82

flask was properly sealed and wrapped with aluminium foil to avoid exposure to light.

This was then allowed to stir for overnight (~16 h) before it was filtered through a

0.45μm PTFE (with 3 times of washing) to afford the NHC-silver intermediate 35a

（90% yield）. 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), 7.04 – 6.74 (m, 3H), 5.93

(ddd, J = 16.0, 10.8, 5.6 Hz, 1H), 5.24 (d, J = 10.2 Hz, 1H), 5.10 (d, J = 17.0 Hz, 1H),

4.71 (d, J = 5.4 Hz, 2H), 2.29 (s, 3H), 1.86 (s, 6H). Due to solubility issue, the 13C NMR

was difficult to perform under this standard condition.

The NHC-silver intermediate was re-dissolved in dichloromethane and [Rh(C2H4)2Cl]2

was added into the reaction mixture as solid form. The reaction mixture was continued to

stir for 1 h before it was filtered through a 0.45μm PTFE (washed with DCM, 3 x 20

mL). The solvent was removed in vacuo to afford yellow solid, which was washed with

hexane/Et2O to afford the desired Rh-complex in 86 % yield. 1H NMR (500 MHz,

CDCl3) δ 7.00 (s, 1H), 6.96 (d, J = 1.8 Hz, 1H), 6.89 (s, 1H), 6.39 (d, J = 1.8 Hz, 1H),


83

4.55 (dd, J = 11.8, 4.6 Hz, 1H), 4.14 (d, J = 11.9 Hz, 1H), 3.50 (d, J = 11.1 Hz, 1H), 2.77

(d, J = 5.3 Hz, 1H), 2.38 (s, 3H), 2.32 (s, 3H), 2.26 (dd, J = 10.9, 2.5 Hz, 1H), 1.83 (s,

3H). 13C NMR (126 MHz, CDCl3) δ 180.7 (Jc-Rh = 38 Hz), 138.7, 137.6, 135.4, 135.2,

129.0, 128.1, 121.9, 118.9, 59.4 (Jc-Rh = 13 Hz), 51.6, 40.1 (Jc-Rh = 13 Hz), 21.2, 19.3,

17.5.

X-ray crytal structure of 36:


84

To an oven-dried round bottom flask was charged with 1-mesityl-1H-imidazole and

followed by cinnamyl bromide. A minimal amount of toluene was necessary to make the

reaction mixture homogenous and the reaction mixture was allowed to stir for 16 h before

it was concentrated to remove the residual solvent. The brown-yellow solid was triturated

with Et2O several times to afford the beigh-colored 3-cinnamyl-1-mesityl-1H-imidazol-3-

ium bromide salt 37 in . 1H NMR (500 MHz, CDCl3) δ 10.15 (s, 1H), 8.00 (s, 1H), 7.30

(d, J = 7.0 Hz, 2H), 7.22 – 7.09 (m, 4H), 6.88 (d, J = 15.7 Hz, 1H), 6.83 (s, 2H), 6.51 –

6.32 (m, 1H), 5.40 (d, J = 6.8 Hz, 2H), 2.18 (s, 3H), 1.94 (s, 6H). 13C NMR (126 MHz,

CDCl3) δ 140.7, 137.3, 137.0, 134.9, 133.8, 130.4, 129.4, 128.3, 128.2, 126.6, 123.1,

123.0, 120.6, 51.5, 20.7, 17.3.

[Rh(COD)Cl]2 and PhB(OH)2 was first added into an oven-dried Schlenk tube as solid

form. The tube was attached to Schlenk line and was subjected to vacuum and re-filled

with Ar (3 times) before dioxane was added and followed by cyclohexenone. The


85

reaction mixture was allowed to stir at 40oC oil bath for 3 h before it was diluted with

Et2O and filtered through a pad of short silica gel (subsequently washed several times

with Et2O). The crude reaction mixture was concentrated and was analyzed using 1H

NMR in CDCl3. 1H NMR (300 MHz, CDCl3) phenylboroxine: δ 8.33 – 8.15 (m, 2H),

7.68 – 7.45 (m, 4H);

3-phenylcyclohexanone (40): 7.40 – 7.29 (m, 2H), 7.29 – 7.16 (m, 3H), 3.02 (ttt, J =

11.4, 3.9 Hz, 1H, Ha), 2.69 – 2.32 (m, 4H), 2.15 (ddd, J = 24.1, 12.1, 8.8 Hz, 2H), 1.91 –

1.73 (m, 2H).

[Rh(NHC-olefin)]2 and PhB(OH)2 was first added into an oven-dried Schlenk tube as

solid form. The tube was attached to Schlenk line and was subjected to vacuum and re-

filled with Ar (3 times) before dioxane was added and followed by cyclohexenone. The

reaction mixture was allowed to stir at 40oC oil bath for 3 h before it was diluted with

Et2O and filtered through a pad of short silica gel (subsequently washed several times

with Et2O). The crude reaction mixture was concentrated and was analyzed using 1H


86

NMR in CDCl3. 1H NMR (300 MHz, CDCl3) phenylboroxine: δ 8.26 (d, J = 7.0 Hz, 5H),

7.72 – 7.31 (m, 13H);

Cyclohexenone (38): 7.16 – 6.94 (m, 1H), 6.99 – 6.66 (m, 1H), 6.06 (d, J = 10.1 Hz, 1H),

2.73 – 2.23 (m, 5H), 2.15 – 1.69 (m, 4H).

Chapter 3

Compounds 21a to 21k were synthesized using known procedure.8

Catalysts 22a-22e, 23, 24, 25 and 28 were prepared using known procedure.9

Representative procedure for the alkylation protocol:

To an oven-dried test-tube was charged with 21a (15.5 mg, 0.05 mmol, 1.00 equiv.),

K2CO3 (13.8 mg, 0.10 mmol, 2.00 equiv.) and cat. 22b (5.80 mg, 0.01 mmol, 0.20

equiv.). The test-tube was seal properly and subject to vacuum and back-filled with Ar (3

times). 1.0 mL of CHCl3 to dissolve the solids and was cooled to -20oC for 15 minutes

before addition of BnBr (12.0 µL, 0.10 mmol, 2.00 equiv.). The reaction mixture was

allowed to stir for 48 h until no starting materials was detected on TLC plate. The crude


87

product was directly loaded on silica gel for purification using EtOAc/hexanes = 1: 30 to

afford the white solid product of 28a (92% yield). 1H NMR (500 MHz, CDCl3) δ 7.62 (d,

J = 8.2 Hz, 1H), 7.52 – 7.40 (m, 2H), 7.33 (dd, J = 9.9, 4.9 Hz, 2H), 7.28 (d, J = 7.1 Hz,

1H), 7.25 – 7.20 (m, 1H), 7.15 (dd, J = 3.7, 1.8 Hz, 2H), 7.03 (dt, J = 14.7, 7.1 Hz, 3H),

6.81 (d, J = 7.5 Hz, 2H), 3.78 (d, J = 12.9 Hz, 1H), 3.43 (d, J = 12.8 Hz, 1H), 1.53 (s,

9H). 13C NMR (125 MHz, CDCl3) δ 176.4, 148.8, 139.9, 139.5, 135.0, 130.0, 128.6,

128.4, 127.7, 127.5, 126.7, 125.4, 124.0, 114.9, 83.9, 58.5, 44.7, 28.0; HPLC analysis:

Chiral IC (Hex/IPA = 90:10, 1.0 mL/min, 254 nm, 25oC), 5.49 min (major), 11.04 min

(minor).

1H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 7.9 Hz, 1H), 7.44 – 7.33 (m, 2H), 7.31 – 7.22

(m, 1H), 7.20 – 7.13 (m, 2H), 7.05 (td, J = 8.6, 4.5 Hz, 3H), 6.94 – 6.79 (m, 4H), 3.81 (s,

3H), 3.76 (d, J = 12.9 Hz, 1H), 3.42 (d, J = 12.8 Hz, 1H), 1.56 (s, 9H). 13C NMR (126

MHz, CDCl3) δ 176.7, 159.0, 148.9, 139.9, 135.2, 131.5, 130.1, 130.0, 128.6, 128.3,

127.6, 126.7, 125.4, 124.0, 114.9, 113.9, 83.9, 57.8, 55.3, 44.8, 28.0.


88

1H NMR (500 MHz, CDCl3) δ 7.64 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.29 –

7.21 (m, 1H), 7.17 (dd, J = 6.9, 4.3 Hz, 4H), 7.10 – 6.99 (m, 3H), 6.84 (d, J = 7.1 Hz,

2H), 3.78 (d, J = 12.9 Hz, 1H), 3.43 (d, J = 12.9 Hz, 1H), 2.34 (s, 3H), 1.55 (s, 10H). 13C

NMR (126 MHz, CDCl3) δ 176.6, 148.9, 139.9, 137.4, 136.5, 135.2, 130.2, 130.0, 129.3,

128.3, 127.6, 127.3, 126.7, 125.4, 124.0, 114.9, 83.9, 58.2, 44.7, 28.0, 21.0.


(m, 8H), 6.81 (d, J = 6.6 Hz, 2H), 3.74 (d, J = 12.8 Hz, 1H), 3.41 (d, J = 12.8 Hz, 1H),

1.55 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 176.4, 163.9, 160.6, 148.8, 139.9, 135.1,


89

134.8, 129.9, 129.7, 129.3, 129.2, 128.6, 127.7, 126.9, 125.4, 124.1, 115.6, 115.3, 115.0,

84.1, 57.9, 45.0, 28.0. 19F NMR (282 MHz, CDCl3) δ -38.79 (tt, J = 8.4, 5.2 Hz, 1F).

1H NMR (500 MHz, CDCl3) δ 7.83 (ddd, J = 14.3, 10.6, 9.3 Hz, 4H), 7.69 (d, J = 8.2 Hz,

1H), 7.58 (dd, J = 8.7, 1.9 Hz, 1H), 7.54 – 7.41 (m, 2H), 7.36 – 7.27 (m, 1H), 7.24 – 7.17

(m, 2H), 7.14 – 7.00 (m, 3H), 6.88 (d, J = 7.3 Hz, 2H), 3.91 (d, J = 12.8 Hz, 1H), 3.58 (d,

J = 12.8 Hz, 1H), 1.56 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 176.4, 148.9, 140.0, 136.9,

135.0, 133.1, 132.7, 130.1, 130.0, 128.5, 128.4, 128.2, 127.7, 127.5, 126.8, 126.4, 126.3,

126.2, 125.5, 124.1, 115.0, 84.0, 58.7, 44.5, 28.0.


90


(m, 2H), 7.10 (ddd, J = 6.1, 3.6, 1.3 Hz, 2H), 7.08 – 7.01 (m, 4H), 6.97 (s, 1H), 6.89 –

6.82 (m, 2H), 3.83 (d, J = 12.8 Hz, 1H), 3.44 (d, J = 12.8 Hz, 1H), 2.32 (s, 6H), 1.58 (s,

9H). 13C NMR (126 MHz, CDCl3) δ 176.4, 148.9, 139.9, 139.5, 138.1, 135.2, 130.1,

130.0, 129.4, 128.2, 127.6, 126.7, 125.3, 125.2, 124.0, 114.8, 83.9, 58.5, 44.5, 28.0, 21.5.

1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 8.1 Hz, 1H), 7.21 (td, J = 7.8, 1.7 Hz, 1H),

7.17 – 7.03 (m, 5H), 6.88 – 6.78 (m, 2H), 3.15 (d, J = 13.0 Hz, 1H), 3.00 (d, J = 13.0 Hz,

1H), 1.57 (s, 9H), 1.52 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 178.8, 148.9, 139.0,

135.5, 131.8, 129.9, 128.0, 127.7, 126.7, 124.0, 123.2, 114.8, 83.9, 50.2, 45.7, 28.0, 23.3;

HPLC analysis: Chiral ODH (Hex/IPA = 95:5, 0.5 mL/min, 254 nm, 25oC), 8.46 min

(major), 9.10 min (minor).


91

1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8.3 Hz, 1H), 7.17 – 7.05 (m, 3H), 7.01 (d, J =

8.3 Hz, 1H), 6.91 (s, 1H), 6.87 – 6.80 (m, 2H), 3.13 (d, J = 13.0 Hz, 1H), 2.99 (d, J =

13.0 Hz, 1H), 2.35 (s, 3H), 1.56 (s, 11H), 1.50 (s, 3H). 13C NMR (126 MHz, CDCl3)

δ178.9, 148.9, 136.6, 135.5, 133.5, 131.7, 129.8, 128.4, 127.6, 126.6, 123.8, 114.5, 83.7,

50.1, 45.7, 28.0, 23.3, 21.0; HPLC analysis: Chiral ODH (Hex/IPA = 95:5, 0.5 mL/min,

254 nm, 25oC), 6.98 min, 9.34 min.

1H NMR (500 MHz, CDCl3) δ 7.56 (d, J = 8.7 Hz, 1H), 7.18 (dd, J = 8.7, 2.2 Hz, 2H),

7.16 – 7.04 (m, 3H), 6.96 – 6.79 (m, 2H), 3.15 (d, J = 13.1 Hz, 1H), 2.98 (d, J = 13.1 Hz,

1H), 1.56 (s, 9H), 1.51 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 177.9, 148.7, 137.5,

134.9, 133.6, 129.7, 129.5, 128.0, 127.8, 126.9, 123.4, 116.0, 84.2, 50.3, 45.7, 28.0, 23.1;

HPLC analysis: Chiral ODH (Hex/IPA = 95:5, 0.5 mL/min, 254 nm, 25oC), 7.02 min,

9.44 min.


92

1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 8.9 Hz, 1H), 7.19 – 7.03 (m, 3H), 6.87 (dd, J

= 7.5, 1.6 Hz, 2H), 6.73 (dd, J = 8.9, 2.7 Hz, 1H), 6.63 (d, J = 2.7 Hz, 1H), 3.78 (s, 3H),

3.12 (d, J = 13.1 Hz, 1H), 2.99 (d, J = 13.1 Hz, 1H), 1.57 (s, 9H), 1.50 (s, 3H). 13C NMR

(126 MHz, CDCl3) δ 178.8, 156.5, 149.0, 135.4, 133.1, 132.4, 129.9, 127.7, 126.7, 115.6,

112.6, 109.6, 83.7, 55.6, 50.4, 45.6, 28.0, 23.3; HPLC analysis: Chiral ODH (Hex/IPA =

95:5, 0.5 mL/min, 254 nm, 25oC), 7.06 min, 9.51 min.


93

APP.3 1H NMR, 13C NMR and HPLC SPECTRAL

Spectrum of chiral morpholinone 23a

0.9

998

2.0

388

0.9

967

0.9

999

1.0

569

2.1

497

3.1

277

3.3

724

0.8

826

Inte

gra

l

7.1

506

7.1

367

7.0

548

7.0

409

7.0

308

7.0

270

7.0

157

7.0

018

6.9

098

6.8

959

4.5

182

4.5

131

4.5

043

4.4

993

4.4

955

4.4

904

4.4

854

4.4

816

4.4

766

4.0

643

4.0

517

2.9

574

2.9

486

2.9

233

2.9

145

2.9

070

2.8

918

2.8

729

2.8

578

1.1

873

1.1

659

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.610.0

173.3

685

142.0

327

139.8

611

128.7

916

127.5

017

125.2

135

79.7

184

56.2

312

54.4

094

39.3

318

27.6

210

23.4

234

(ppm)

0102030405060708090100110120130140150160170180190


94

Spectrum of control experiment

0.5

68

4

1.9

99

0

2.0

43

1

4.0

49

2

12

.00

0

Inte

gra

l

3.7

47

9

3.3

64

6

3.0

26

7

1.2

13

8

1.2

03

7

1.1

91

1

1.0

18

4

1.0

05

8

0.9

94

4

0.8

36

8

0.8

11

6

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0

1H AMX500

control_H(After)

14

9.6

918

14

7.6

805

36

.20

55

29

.13

67

20

.81

46

19

.89

63

16

.82

11

(ppm)

0102030405060708090100110120130140150160170180190

13C AMX500

contro_C(after)


95

Spectrum of chiral morpholinone 23a in 1 atm of H2

1.4

26

0

2.0

49

5

1.0

07

8

1.0

25

6

1.0

52

4

2.0

81

5

2.9

54

6

3.0

72

6

Inte

gra

l

7.0

15

7

7.0

08

1

7.0

00

5

6.9

93

0

6.9

84

1

6.9

71

5

6.9

22

4

6.9

13

5

6.7

40

8

6.7

25

7

4.0

79

4

4.0

69

3

3.5

67

6

3.5

57

5

2.3

42

1

2.3

33

3

1.0

83

9

0.9

37

7

(ppm)

0.01.02.03.04.05.06.07.08.09.010.0

*** Current Data Parameters ***

NAME : afterb~1

EXPNO : 2

PROCNO : 1

*** Acquisition Parameters ***

LOCNUC : 2H

NS : 10

NUCLEUS : off

O1 : 3088.51 Hz

PULPROG : zg30

SFO1 : 500.1330885 MHz

SOLVENT : Tol

SW : 20.6557 ppm

TD : 32768

TE : 298.1 K

*** Processing Parameters ***

LB : 0.30 Hz

SF : 500.1300200 MHz

*** 1D NMR Plot Parameters ***

NUCLEUS : off

1H AMX500

H(After)

18

7.7

392

14

9.2

327

14

7.3

088

12

5.3

738

12

5.1

260

88

.40

50

55

.60

45

54

.16

89

36

.14

72

27

.67

20

24

.87

36

(ppm)

0102030405060708090100110120130140150160170180190

13C AMX500

WY_C(after)

High field chemical

shift of the carbonyl

carbon to 187 ppm


96

Spectrum of chiral thiomorpholine 27

3.0

00

9

6.1

17

0

1.0

08

0

0.9

99

8

1.0

00

3

1.0

43

6

1.0

47

7

1.0

22

8

3.2

49

4

3.1

94

2

Inte

gra

l

7.5

40

1

7.5

25

0

7.4

46

8

7.4

33

0

7.1

20

3

7.1

05

2

7.0

96

4

7.0

92

6

7.0

81

2

7.0

66

1

7.0

52

2

7.0

11

9

6.9

95

5

6.9

79

1

6.9

67

8

6.9

65

2

4.9

27

9

4.6

93

4

4.6

83

3

4.6

72

0

3.9

23

1

3.9

13

0

2.8

86

8

2.8

54

0

2.7

50

6

2.7

39

3

2.7

17

8

2.7

06

5

1.4

15

5

1.1

43

2

0.8

78

4

(ppm)

0.01.02.03.04.05.06.07.08.09.010.0


NAME : before

EXPNO : 4

PROCNO : 1


LOCNUC : 2H

NS : 30

NUCLEUS : off

O1 : 3088.51 Hz

PULPROG : zg30

SFO1 : 500.1330885 MHz

SOLVENT : Tol

SW : 20.6557 ppm

TD : 32768

TE : 297.6 K


LB : 0.30 Hz

SF : 500.1300200 MHz


NUCLEUS : off

1H AMX500

WY_SPh

14

4.8

530

14

0.4

455

13

0.9

615

12

8.5

759

12

7.6

086

12

6.7

940

12

6.5

104

12

5.1

867

12

5.1

140

91

.64

34

69

.91

88

58

.58

74

52

.51

44

37

.28

47

29

.00

07

27

.04

42

(ppm)

0102030405060708090100110120130140150160170180190

13C Standard AC300

WY_SPh_C_before


97

1H NMR spectrum of chiral thiomorpholine with boranes 14 and 30 after H2

(ppm)

0.01.02.03.04.05.06.07.08.09.010.0


NAME : borane~1

EXPNO : 1

PROCNO : 1


LOCNUC : 2H

NS : 18

NUCLEUS : off

O1 : 3088.51 Hz

PULPROG : zg30

SFO1 : 500.1330885 MHz

SOLVENT : Tol

SW : 20.6557 ppm

TD : 32768

TE : 303.4 K


LB : 0.30 Hz

SF : 500.1300200 MHz


NUCLEUS : off

1H AMX500

WY_SPh+B

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0

1H AMX500

SPh+B(Mes)

No split of H2

was observed


98

Spectrum of NHC – olefin precursor 11a

0.9

26

0

1.8

87

0

3.5

70

1

0.9

55

3

1.9

94

0

1.0

92

5

1.0

01

8

4.0

84

6

9.1

34

1

3.0

15

4

0.9

61

9

3.1

39

8

Inte

gra

l

9.3

12

0

7.4

71

7

7.4

49

3

7.3

47

9

7.3

27

7

7.3

02

4

7.2

74

5

7.2

60

3

7.0

66

3

7.0

14

3

6.9

00

3

6.3

07

0

6.2

77

4

6.2

55

0

6.2

25

4

4.9

91

1

4.9

62

6

4.9

34

6

4.3

73

1

4.3

38

0

4.3

01

3

4.2

83

2

4.2

54

2

4.2

20

2

4.1

85

7

2.2

94

0

2.2

59

5

1.1

33

6

1.1

11

7

1.0

75

6

1.0

49

3

1.0

27

4

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0

1H normal range AC300

WY_NHC_Olefin_01

15

7.5

983

14

0.4

001

13

8.0

536

13

5.3

791

13

5.0

439

13

0.3

363

13

0.0

448

12

8.6

893

12

6.9

404

12

1.9

412

66

.17

83

50

.82

38

46

.69

18

29

.85

07

20

.96

74

19

.56

82

18

.55

53

18

.32

21

(ppm)

0102030405060708090100110120130140150160170180190

13C AMX500

IPr_C


99

Spectrum of silver complex 24

1.9

83

0

1.9

68

1

0.9

91

8

2.0

52

4

1.0

56

0

1.0

08

0

1.0

37

0

4.1

43

5

2.9

80

8

2.9

69

9

3.0

48

3

1.2

53

7

3.1

47

5

3.0

63

8

Inte

gra

l

7.4

03

7

7.3

88

6

7.3

38

2

7.3

23

0

7.3

06

6

7.2

42

3

7.2

28

5

6.8

86

8

6.8

78

0

6.6

63

7

6.6

30

9

6.2

77

9

6.2

61

5

6.2

45

1

6.2

30

0

4.1

83

8

4.1

67

4

4.1

47

3

3.5

96

3

3.5

83

7

3.5

68

6

3.5

64

8

3.5

58

5

3.5

44

6

3.5

35

8

3.5

30

8

3.5

24

5

3.5

09

3

3.5

04

3

3.4

96

7

3.4

90

4

3.4

77

8

2.2

58

7

2.2

05

7

2.1

73

0

2.0

57

0

2.0

43

1

2.0

29

2

2.0

21

7

2.0

16

6

2.0

09

1

1.9

95

2

1.9

82

6

1.0

62

3

1.0

49

6

1.0

14

3

1.0

00

5

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0

1H AMX500

WY_Ag_second spot


100

Spectrum of NHC – olefin precursor 26a


101

COSY for NHC – olefin Rh complex 29


102

HMBC for NHC – olefin Rh complex 29


103

Spectrum of NHC – olefin ligand 35


104

Spectrum of silver complex 35a


105

Spectrum of NHC – olefin Rh complex 36


106

Spectrum of NHC – olefin ligand 37


107

Crude 1H NMR spectrum between the reaction of 38 and 39 catalyzed by

[Rh(COD)Cl]2

Characteristic proton of 40: Ha


108

Crude 1H NMR spectrum between the reaction of 38 and 39 catalyzed by Rh(NHC-

olefin)2Br

Olefinic proton Hb and Hc of 38


109

1H NMR of PdCl2(COD)


110

Spectrum of compound 28a


111

Spectrum of compound 28b


112

Spectrum for compound 28c


113

Spectrum for compound 28d


114


115

Spetrum for compound 28e


116

Spectrum for compound 28f


117

Spectrum for compound 28h


118

Spectrum for compound 28i


119

Spectrum for compound 28j


120

Spectrum of compound 28k


121

HPLC spectral for compound 28a and 28h


122


123

APP.4 REFERENCES

1 J. T. Lai, Synthesis 1984, 122 – 123.

2 V. Sumerin, F. Schulz, M. Nieger, M. Leskelä, T. Repo, B. Rieger, Angew. Chem. Int.

Ed. 2008, 47, 6001 –6003.

3 For related compound, see: S. D. Rychnovsky, T. Beauchamp, R. Vaidyanathan, T.

Kwan, J. Org. Chem. 1998, 63, 6363 - 6374.

4 G. Erős, H. Mehdi, I. Pápai, T. A. Rokob, P. Király, G. Tárkányi, T. Soós, Angew.

Chem. Int. Ed. 2010, 49, 6559 –6563.

5 J. R. Luly, J. F. Dellaria, J. J. Plattner, J. L. Soderquist, N. Yi, J. Org. Chem. 1987,

52, 1487 – 1492; b) B. A. B. Prasad, S. R. Gilbertson, Org. Lett. 2009, 11, 3710 –

3713.

6 S. Mueller, M. J. Webber, B. List, J. Am. Chem. Soc. 2011, 133, 18534 – 18537.

7 a) A. Zanardi, E. Peris, J. A. Mata, New J. Chem., 2008, 32, 120 – 126; b) S. Wolf,

H. Plenio, J. Organomet. Chem. 2009, 694, 1487 – 1492.

8 a) For C3-alkyl and C3-aryl oxindoles, see: S.-W. Duan, J. An, J.-R. Chen, W.-J.

Xiao, Org. Lett. 2011, 13, 2290 – 2293 and Y. Hamashima, T. Suzuki, H. Takano, Y.

Shimura, M. Sodeoka, J. Am. Chem. Soc. 2005, 127, 10164 – 10165; b) For C3-allyl

http://pubs.acs.org/action/doSearch?action=search&author=Prasad%2C+B.+A.+Bhanu&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Gilbertson%2C+Scott+R.&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Duan%2C+S&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=An%2C+J&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Chen%2C+J&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Xiao%2C+W&qsSearchArea=author

http://pubs.acs.org/action/doSearch?action=search&author=Xiao%2C+W&qsSearchArea=author


124

oxindoles, see: M. G. Kulkarni, A. P. Dhondge, S. W. Chavhan, Y. B. Shaikh, D. R.

Birhade, M. P. Desai, N. R. Dhatrak, Beilstein J. Org. Chem. 2010, 6, 876 – 879.

9 a) B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett, 2005, 7, 1967 – 1969; b) K.

Greenaway, K. P. Dambruoso, A. Ferrali, A. J. Hazelwood, F. Sladojevich, D. J.

Dixon, Synthesis 2011, 1880‐1886; c) J. Wang, H. Li, X. Yu, L. Zu, W. Wang, Org.

Lett. 2005, 7, 4293 – 4296; d) R. P. Herrera, V. Sgarzani, L. Bernadi, A. Ricci,

Angew. Chem. Int. Ed. 2005, 44, 6576 – 6579; e) A. Nakano, S. Kawahara, S.

Akamatsu, K. Morokuma, M. Nakatani, Y. Iwabuchi, K. Takahashi, J. Ishihara, S.

Hatakeyama, Tetrahedron, 2006, 62, 381 – 389; f) Q. Zhu, Y. Lu, Angew. Chem. Int.

Ed. 2010, 49, 7753 – 7756.


125

APP.5 LIST OF PUBLICATIONS

1. Woon-Yew Siau, Yao Zhang, Yu Zhao. Stereoselective Synthesis of Z-Alkenes.

Topics in Current Chemistry, 2012, 327, 33–58

2. Shenci Lu, Sibei Poh, Woon-Yew Siau, Yu Zhao. Kinetic Resolution of Tertiary

Alcohols: Highly Enantioselective Access to 3- Hydroxy-3- Substituted Oxindoles.

(This work has been highlighted in Synfacts, issue 03/13). Angewandte Chemie

International Edition, 2013, 52(6), 1731-1734.

3. Shenci, Lu, Sibei Poh, Woon-Yew Siau, Yu Zhao. Kinetic Resolution of 3-Hydroxy-

3-substituted oxindoles through NHC-Catalyzed Oxidative Esterification (Review).

Synlett (accepted).

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