Exploring the Palladium-Catalysed Enantioselective Allylation of ...

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Doctoral Thesis

Exploring the palladium-catalysed enantioselective allylation ofphosphines, phosphine oxides, and arsines

Author(s): Raphaël Rochat, /

Publication Date: 2012

Permanent Link: https://doi.org/10.3929/ethz-a-007563481

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Diss. ETH No. 20634

Exploring the Palladium-Catalysed Enantioselective

Allylation of Phosphines, Phosphine Oxides, and Arsines

A dissertation submitted to

ETH ZURICH

for the degree of

DOCTOR OF SCIENCES

presented by

RAPHAËL ROCHAT

Master of Science ETH in Chemistry

born on August 6th, 1983

citizen of L’Abbaye VD

accepted on the recommendation of

Prof. Dr. Antonio Togni, examiner

Prof. Dr. Hansjörg Grützmacher, co-examiner

Prof. Dr. Paul S. Pregosin, co-examiner

Zurich 2012

"The journey is the reward."

– chinese proverb

The circle of human knowledge. The blue dot represents what we know after elementary school.

At university, knowledge specialises in a certain direction and may even reach the border of human

knowledge.

A closer look shows that a Ph.D. study starts to push the border! :)

Most importantly: never forget the big picture!

Taken from The Illustrated Guide to a Ph.D. by Matt Might

(http://matt.might.net/articles/phd-school-in-pictures/)

http://matt.might.net/articles/phd-school-in-pictures/

Ph.D.

Ph.D.

Dedicated to

my parents.

Acknowledgments Special thanks to Franz Piehler for some valuable tips and tricks concerning the use of Latex. :)

I would like to thank a number of people who helped and supported me during my Ph.D.

studies in and outside the lab:

First and foremost I would like to thank Professor Antonio Togni for giving me the op-

portunity to work in his group, for his patient supervision, his helpful advice, and the freedom

he offered to work on own ideas.

Also, I thank Professor Hansjörg Grützmacher for the co-examination of this thesis. I

am very grateful to Professor Paul S. Pregosin who thoroughly corrected this work, gave

valuable advice, and co-examinated this thesis.

I am very thankful to Dr. Jan Welch, Barbara Czarniecki and Vittorio Sacchetti for proof-reading

this thesis, giving valuable input, fruitful discussions, and improving the quality of this work.

Special thanks go to the former supervisor of my master thesis, Dr. Pietro Butti, with

whom this project was started. I thank him for his support in the starting phase of my thesis,

the interesting discussions, his ideas, tips, and tricks.

Futhermore, I thank Dr. Francesco Camponovo from whom I learned a lot during my under-

graduate education, my master thesis, and my Ph.D. studies. I am grateful for the advice and

valuable discussions.

I would like to thank more former members of the Togni Group who supported me during the

beginning of my thesis: Dr. Kyrill Stanek, Dr. Martin Althaus, and Dr. Marco Ranocchiari.

Big thanks go to Barbara Czarniecki, Dr. René Verel, Dr. Aitor Moreno, and Dr. Heinz Rüegger

for NMR assistance which is a very important and valueable task.

I thank all current and former members of the Togni Group for doing their (more or less time

consuming) group jobs which are essential for everyone in the group. Especially, I thank

the crystallographers Dr. Pietro Butti, Dr. Francesco Camponovo, Raphael Aardoom, Katrin

Niedermann, Rino Schwenk, and Elli Männel and the glovebox team Dr. Martin Althaus, Dr.

Jonas Bürgler, Barbara Czarniecki, Katrin Niedermann, Remo Senn, and Julie Charpentier.

I thank all my lab mates for the good atmosphere and the nice times we had together. Thanks

go to Raphael Aardoom and Tina Osswald from H204 and Barbara Czarniecki, Rino Schwenk,

Dr. Ján Cvengroš, Dr. Sandra Milosevic, Raul Perreira, and Peter Ludwig from H230.

I would like to thank some good labmates and friends for their support, the great times we

enjoyed together, the nice discussions (which should have been rewarded with at least 1000

i

GESS points), the lunch times, the movie nights, and all the other superb activities outside the

lab... Vittorio Sacchetti, Matthias Herrmann, Ueli Neuenschwander, Samy Boulos, Peter Ludwig,

Rino Schwenk, Barbara Czarniecki, Dr. Jan Welch, Dr. Michelle Flückiger, Katrin Niedermann,

Raphael Aardoom, Remo Senn, and Lukas Sigrist. Thank you!

Also, I would like to thank all my students from OACP II, from the first-semester Praktikum,

from the first-semester exercises, and especially Murielle Delley who worked with me during

her semester project and Partick Stücheli who synthesised some compounds for me.

I would like to thank my flat mates with whom I had a great time. It was always nice

to come home in the evening and to eat, drink, talk, laugh, have fun, watch movies, go out...

Thank you Vito, Bruna, Eva, and Angelina!

Last and mostly, I would like to thank all my friends and my family for the great sup-

port. My parents have always supported what I wanted to do and what I have done. Without

their help I would have never achieved this. Thank you very, very much!

ii

iii

iv

Contents

Abstract viii

Zusammenfassung x

1 Introduction 1

1.1 Ferrocenyl Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.1.1 Chirality of Ferrocenes . . . . . . . . . . . . . . . . . . . . . . . . . 2

1.1.2 General Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

1.1.3 Ferrocenyl Diphosphine Ligand Families . . . . . . . . . . . . . . . 4

1.1.4 The Josiphos Ligand Family . . . . . . . . . . . . . . . . . . . . . . . 5

1.2 Asymmetric Allylic Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.2.1 Catalysts and Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.2.2 Pd/Allyl Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1.2.3 Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1.2.4 Nucleophiles other than Phosphorus . . . . . . . . . . . . . . . . . 12

1.3 Previous Work on Allylic Phosphination . . . . . . . . . . . . . . . . . . . . . . . . . 17

2 Palladium/Allyl Complexes with Josiphos Ligands 23

2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

2.2 Known Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

2.3 η3-1,3-Diphenylallyl Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

2.3.1 General Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

2.3.2 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

v

2.3.3 Behaviour in Solution . . . . . . . . . . . . . . . . . . . . . . . . . . 28

2.3.4 Characterisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

2.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

3 Phosphorus Nucleophiles 33

3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

3.2 Asymmetric Allylic Phosphination with Phosphines . . . . . . . . . . . . . . . . . . 34

3.2.1 Catalytic Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

3.2.2 Mechanistic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

3.3 Asymmetric Allylic Phosphination with Secondary Phosphine Oxides . . . . . . . 54

3.3.1 Catalytic Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

3.3.2 Proposed Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . 58

3.4 Determination of the Enantioselectivity . . . . . . . . . . . . . . . . . . . . . . . . . 59

3.4.1 NMR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

3.4.2 HPLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

3.5 The Allylic Phosphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

3.5.1 General Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

3.5.2 Functionalisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

3.5.3 Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

3.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

4 Arsenic Nucleophile 75

4.1 Introductory Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

4.2 Allylic Arsination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

4.3 The Oxidation Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

4.4 Mechanistic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

4.5 Determination of the Enantioselectivity . . . . . . . . . . . . . . . . . . . . . . . . . 79

4.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

5 Conclusion and Outlook 81

vi

5.1 Allylation of Phosphorus Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 81

5.2 The Allylic Phosphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

5.3 Allylation of Diphenylarsine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

6 Experimental 83

6.1 General Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

6.1.1 Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

6.1.2 Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

6.1.3 Analytical Techniques and Instruments . . . . . . . . . . . . . . . 83

6.2 Syntheses and Mechanistic Experiments . . . . . . . . . . . . . . . . . . . . . . . . . 85

6.2.1 General Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

6.2.2 Ligands and Complexes . . . . . . . . . . . . . . . . . . . . . . . . . 93

6.2.3 Substrates and Nucleophiles . . . . . . . . . . . . . . . . . . . . . . 96

6.3 Unsuccessful Attempts to Functionalise the Allylic Phosphine . . . . . . . . . . . . 105

References 109

7 Appendix xiii

7.1 Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii

7.2 List of Numbered Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv

7.3 Selected 31P-NMR Chemical Shifts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvi

7.4 Crystallographic Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii

7.5 Curriculum Vitae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xviii

vii

Abstract

The palladium-catalysed allylation of phosphines, phosphine oxides, and arsines was investi-

gated in terms of catalytic scope and mechanism (Scheme 1).

Ph Ph

OAcHER2

5 mol-% catNEt3

additiveCH2Cl2 or C6H6

Ph Ph

ER2

E = P, P(O), As

SbF6

Fe

PPh2

Cy2P Pd

PhPh

cat

Scheme 1: General scheme for the enantioselective allylation of phosphines (E = P), phosphine oxides

(E = P(O)), and arsines (E = As) catalysed by a Pd/Josiphos complex.

The scopes of the reactions are limited. Secondary phosphines are allylated with the standard

substrate 1,3-diphenylallyl acetate, with yields up to 92% and enantioselectivities up to

94% ee. The reaction was found to be accelerated by addition of catalytic amounts of

coordinating compounds such as DBU or PMe3. In these cases, the selectivity dropped to 77 –

86% ee. Substrates and nucleophiles with aliphatic substituents work less well. The allylation

of diphenyl phosphine oxide in benzene yields the product as a precipitate in high chemical

and enantiomeric purity (> 99% ee). However, the reaction stalls at about 25% conversion

for yet unknown reasons. Diphenylarsine can be efficiently allylated using the same system as

for diphenylphosphine. Due to its sensitivity towards oxidation, no method to determine the

enantioselectivity has been found yet.

In order to investigate the mechanism of the allylation with 1,3-diphenylallyl acetate,

[Pd(η3-1,3-Ph2Allyl)(κ2-Josiphos)]SbF6 (1) was synthesised and analysed. In solution, com-

plex 1 is present as two major isomers, endo-syn-syn-1 and exo-syn-syn-1. The thermodynamic

ratio was determined to be endo/exo = 0.6:1. Complex 1 can be synthesised with different

endo/exo ratios, depending on the temperature. Additives such as DBU or PMe3 "catalyse" the

equilibration to the thermodynamic ratio.

In mechanistic studies we have classified the nucleophiles investigated as "soft", i. e. they

attack the coordinated allyl from the opposite face of palladium. For diphenylphosphine,

we have determined the favoured site of attack to be cis to the PCy2 group of Josiphos in

endo-syn-syn-1 (Scheme 2).

viii

PdFeP P Pd

FeP P

endo exo

Ph Ph

PPh2

PhPh

PPh2 PhPh

PPh2

Ph Ph

PPh2(R) (R)(S) (S)

HPPh2 HPPh2HPPh2HPPh2

Scheme 2: The preferred attack of diphenylphosphine takes place cis to the PCy2 group of Josiphos in

endo-syn-syn-1 yielding the (R) product.

Attempts to functionalise allylic phosphine 2 in order to synthesise potential P,P-ligands

were unsuccessful. The synthesis of mono- or bidentate phosphine ligands involving the

asymmetric allylic phosphination as key step could not be accomplished, partially because

the desired substrates could not be synthesised or because the allylic phosphination did not

work with these substrates. However, with simple aromatic substrates it should be possible to

access phosphine ligands via asymmetric allylic phosphination.

ix

Zusammenfassung

Die Palladium-katalysierte Allylierung von Phosphinen, Phosphinoxiden und Arsinen wurde

bezüglich ihrem katalytischen Anwendungsbereich und dem Mechanismus untersucht

(Schema 1).

Ph Ph

OAcHER2

5 mol-% catNEt3

additiveCH2Cl2 or C6H6

Ph Ph

ER2

E = P, P(O), As

SbF6

Fe

PPh2

Cy2P Pd

PhPh

cat

Schema 1: Generelles Schema für die enantioselektive Pd/Josiphos-katalysierte Allylierung von Phos-

phinen (E = P), Phosphinoxiden (E = P(O)) und Arsinen (E = As).

Die Anwendungsbreite der Reaktionen ist noch begrenzt. Sekundäre Phosphine werden

mit Ausbeuten bis zu 92% und Enantioselektivitäten bis zu 94% ee allyliert. Es wurde

entdeckt, dass die Reaktion durch Zugabe von katalytischen Mengen von koordinierenden

Verbindungen, wie DBU oder PMe3, beschleunigt wird. Allerdings fällt die Selektiviät in

diesen Fällen auf 77 – 86% ee. Substrate und Nukleophile mit aliphatischen Substituenten

sind weniger gut geeignet. Die Allylierung von Diphenylphosphinoxid in Benzol ergibt das

Produkt als kristallinen Niederschlag von hoher chemischer und Enantiomeren-Reinheit

(> 99% ee). Allerdings stoppt die Reaktion nach etwa 25% Umsatz aus noch unbekannten

Gründen. Diphenylarsin kann mit dem selben System wie für Diphenylphosphin effizient

allyliert werden. Wegen der Oxidationsempfindlichkeit konnte bisher keine Methode zur

Messung der Enantioselektivität gefunden werden.

Um den Mechanismus der Reaktion mit 1,3-Diphenylallylacetat zu untersuchen, wurde

[Pd(η3-1,3-Ph2Allyl)(κ2-Josiphos)]SbF6 (1) hergestellt und analysiert. In Lösung tritt 1 in

Form von zwei Hauptisomeren, endo-syn-syn-1 und exo-syn-syn-1, auf. Es wurde ermittelt,

dass das thermodynamische Verhältnis endo/exo = 0.6:1 ist. Abhängig von der Temperatur bei

der Synthese kann Komplex 1 mit verschiedenen endo/exo Verhältnissen hergestellt werden.

Zusätze wie DBU oder PMe3 "katalysieren" die Equilibrierung zum thermodynamischen

Verhältnis.

Mechanistische Studien haben gezeigt, dass die untersuchten Nukleophile "weich" sind, das

x

heisst sie greifen den koordinierten Allylliganden von der dem Palladium gegenüberliegenden

Seite an. Es wurde ermittelt, dass Diphenylphosphin den Allylliganden bevorzugt cis zur

PCy2-Gruppe von Josiphos in endo-syn-syn-1 angreift (siehe Schema 2).

PdFeP P Pd

FeP P

endo exo

Ph Ph

PPh2

PhPh

PPh2 PhPh

PPh2

Ph Ph

PPh2(R) (R)(S) (S)

HPPh2 HPPh2HPPh2HPPh2

Schema 2: Diphenylphosphin greift bevorzugt cis zur PCy2 Gruppe von Josiphos in endo-syn-syn-1 an

und bildet dabei das (R) Produkt.

Alle Versuche, das allylische Phosphin 2 zu funktionalisieren, um potentielle P,P-Liganden zu

synthetisieren, sind bisher gescheitert. Die Synthesen von mono- oder bidentaten Liganden

mit der allylischen Phosphinierung als Schlüsselschritt waren erfolglos, da entweder die

geplanten Modellsubstrate nicht synthetisiert werden konnten oder die allylische Phos-

phinierung mit diesen Substraten nicht funktionierte. Mit einfachen, aromatischen Substraten

sollte es aber möglich sein, Phosphinliganden mit der allylischen Phosphinierung zugänglich

zu machen.

xi

xii

1 Introduction

Asymmetric reactions are undoubtedly among the most important transformations in organic

chemistry. Therefore, the development and optimisation of such processes, including catalytic

asymmetric reactions, are major fields of research. The number of catalytic asymmetric C-C

and C-X bond forming processes, including C-P bond forming reactions, has been increasing

rapidly over the last few decades. Asymmetric C-P bond formations have become important

tools in organic synthesis and different variants of these reactions have been developed.[1–3]

Our group has recently developed a new method of C-P coupling, namely the palladium-

catalysed asymmetric allylic phosphination.[4,5] In contrast to asymmetric allylic alkylation

reactions (AAA), allylations of heteroatom nucleophiles have been less well described. This

thesis aims to further investigate the allylation of phosphorus nucleophiles with Pd/Josiphos

complexes. The introduction therefore decribes the components of this transformation, i.e.

ferrocenyl ligands and Pd/allyl chemistry involved in AAA.

1.1 Ferrocenyl Ligands

Pauson and Kealy first synthesised ferrocene by serendipity in 1951 during an attempt to

oxidatively couple cyclopentadienyl magnesium bromide to fulvalene with iron(II)chloride.[6]

The orange crystals obtained proved to be air-stable and easily sublimed. Between 1952

and 1956, several publications appeared in which the sandwich structure of ferrocene was

definitively proven by X-ray analysis.[7–9] Since then, ferrocene and its derivatives have found

many applications.[10–12]

Ferrocene-based ligands offer special features for asymmetric catalysis, and two prominent

members of this family, BPPFX and Josiphos, belong to the so-called privileged ligands

(Scheme 3). This term was originally coined by Jacobsen in 2000.[13] Privileged ligands

fulfil certain prerequisites important for industry such as scope, specifity, functional group

tolerance, catalyst performance, ligand synthesis and availability, and patent protection and

marketing.[14] In the basic design of these ligands some common features can be found. They

show rigid stuctures and multiple heteroatoms that enable strong binding to a metal. Some

of them have a twofold symmetry which reduces the number of possible transition states.[15]

Ferrocenylphosphines have several unique features differing from other privileged ligands such

as functional groups on the side chain (Y in Scheme 3) and both mono- and diphosphines

can be prepared from the same source. Another special feature of ferrocene derivatives is the

ability to possess planar chirality.[10] This will be discussed in the following subsection.

1

1 Introduction

Fe PR'2Y

X

X = PPh2, HY = NHR, PR2

XY

X = PR2Y = OH, OR

O

OR'

R'

CR''2X

CR''2X

X = PR2, OH

P P

R

R

R

R

N

X

N

X

R R

R

N N

R

OH HOR'R'

N

R

HH

OR'

N

X

SalenBOX(bisoxazolines)

DIOPTADDOL DuPhosBINAP

BINOL

Cinchona alkaloids

M

Brintzinger'sLigand

BPPF-YJosiphos

XX

X = PR2, OPR2

Spiro

PPh2

O

NR

PHOX

NH

COOH

Proline

Scheme 3: Privileged ligand families.[13–16]

1.1.1 Chirality of Ferrocenes

Ferrocenes bearing at least two different substituents in 1,2- or 1,3-position are planar-chiral.

The configuration can be assigned in analogy to the CIP system.[17,18] Most commonly, but not

necessarily according to strict IUPAC rules, the ferrocene is viewed from the top so that the

substituted cyclopentadienyl ring is in front. The substituents are then prioritised according to

CIP and the clockwise order of priorities gives R configuration, counter-clockwise order gives

S configuration (Scheme 4).

2


Fe

R1

R2

Scheme 4: A 1,2-disubstituted ferrocene displays planar chirality. Assignment of configuration: if the

priorities are R1 > R2, according to CIP, then the configuration is R.[17,18]

In addition to planar chirality, ferrocenylphosphines can also possess the more common central

chirality, including chirality at phosphorus. Some examples of P-stereogenic ferrocenyl ligands

and their applications in catalysis can be found in the literature.[11,19–28] The implementation

of these chiral elements during synthesis is discussed in the next subsection.

1.1.2 General Synthesis

As mentioned above, many ferrocenyl privileged ligands can be synthesised from a common

starting compound, Ugi’s amine (see Scheme 5).[11,12,29]

FeNMe2

FeNMe2

PPh2

FeNMe2

PPh2

PPh2

FeNMe2

X

(R,S)-PPFA

(R,S)-BPPFA

(R,S)-X-Ugi's amine

X = I, Br

(R)-Ugi's amine

1) nBuLi2) Ph2PCl

1) nBuLi, TMEDA2) Ph2PCl

1) nBuLi2) I2 or C2Br2Cl4

Scheme 5: The starting point for the synthesis of ferrocenyl ligands from Ugi’s amine.[11]

The stereogenic centre at the carbon atom on the side chain is thereby used to induce planar

chirality via diastereoselective ortho-lithiation of Ugi’s amine. Diastereoselectivity of this trans-

formation is explained by an interaction between the ortho-lithium and the amine, in which

3

1 Introduction

the methyl group on the side chain is preferentially oriented away from the ferrocene core.

FeNMe2

PPh2

(R,S)-PPFA

1 eq HPCy2

AcOH, 80 °C

0.5 eq H2PCy

AcOH, 80 °C FePCy2

PPh2

(R,S)-Josiphos

FeP

PPh2

Fe

Ph2P

Cy

(R,S)-Pigiphos

Scheme 6: PPFA as intermediate for the synthesis of Pigiphos and Josiphos.[11]

Ortho-lithiated Ugi’s amine can be quenched with different electrophiles, commonly

chlorophosphines or halogenating agents. PPFA is the intermediate in the synthesis of Josiphos

and Pigiphos which are prepared by nucleophilic substitution with a secondary or primary

phosphine, respectively (see Scheme 6).

1.1.3 Ferrocenyl Diphosphine Ligand Families

Ferrocenyl diphosphines are powerful ligands and are used in a variety of catalytic pro-

cesses.[10–12]

Fe PR'2PR2 Fe PPh2

X

PPh2

X = OH, NMe2

Josiphos BPPFOH/BPPFA

Fe PPh2X

PR'2

X = OH, NR

BoPhoz

Fe

PR2PR'2

Walphos

Fe PPh2

R PPh2R'

Taniaphos

Fe PPh2R

R'

PPh2RR'

Mandyphos

Fe

Fe H

PR2

PR2H

TRAP

Scheme 7: The most important ferrocenyl diphosphine ligand families.[11]

4


Among the most prominent members are Josiphos, BPPFOH/BPPFA, Mandyphos, Walphos,

Taniaphos, BoPhoz, and TRAP (see Scheme 7). These ligands are also popular because of

their availability as ligand kits from commercial suppliers.

1.1.4 The Josiphos Ligand Family

The Josiphos ligand familiy is a powerful and widely applied class of ligands. They are used

in many processes, such as hydrogenation, Michael additions, hydroborations, allylic substitu-

tions, alkene reductions, hydrophosphinations, cross-couplings, hydroformylations, and oth-

ers.[10–12,14] Josiphos ligands are applied in four industrial production processes, the most

important being the iridium-catalysed hydrogenation of an imine, the key step to the synthesis

of (S)-Metolachor. This is currently the largest enantioselective process operated industri-

ally.[11,14,30,31]

In the synthesis of Josiphos-type ligands, the two phosphine groups are introduced in differ-

ent steps which give access to a large set of electronically and sterically distinct ligands (see

Schemes 5 and 6). The popularity and ease of access to these ligands is impressively demon-

strated by the broad range of commercially available ligands of this type (see Scheme 8).

Fe PR22PR12

Josiphos

Ar1 = 3,5-Me2-C6H3Ar2 = 3,5-(CF3)2-C6H3

Ar3 = 3,5-Me2-4-OMe-C6H2Ar4 = 4-CF3-C6H4

Ar5 = 1-furanyl

R1 Cy tBu Cy Ph Ar Cy Cy Ar tBu tBu

R2 Ph Ph Cy Cy Ph Ar Ar Ar Cy Ar

R1 tBu Ar tBu tBu Ar Ar oTol oTol Ph oTol

R2 Ar Ar Ar 1-Np 1-Np Ar Ar Ar tBu tBu

1 1

1

2 3 2 4

2 2

3 5 5 3 5 3

Scheme 8: Currently 20 different Josiphos ligands are commerically available. The name Josiphos

refers specifically to the molecule where R1 = Cy and R2 = Ph.

Since the development of Josiphos by Togni and co-workers in 1994[30], the synthesis and ap-

plication of Josiphos, its derivatives, and other ferrocenyl ligands has had a long tradition in

our group. The classical Josiphos (R1 = Cy, R2 = Ph in Scheme 8) has also been applied in

palladium-catalysed asymmetric allylic alkylation and amination with good results. It follows,

therefore, that the development of allylic phosphination in our group started with ferrocenyl

ligands (see also section 1.3).[4,5]

5

1 Introduction

1.2 Asymmetric Allylic Substitution

The asymmetric allylic substitution reaction (also known as Tsuji-Trost reaction) has become

a widely used tool in organic synthesis since the first (non-enantioselective, non-catalytic) re-

port by Tsuji and co-workers in the 1960’s (Scheme 9).[32–34]

OAc PdII

OAcPd0

NuH Nu

LPd0 AcOH

catalytic reaction

13

13

Nu

13

R RR

R*

Scheme 9: The basic scheme of the Pd-catalysed Tsuji-Trost reaction starting from allyl acetate.

It is a versatile reaction which runs under much milder conditions than the corresponding

SN2 or SN2’ reaction and is tolerant of many functional groups. The intermediate π-allyl

complexes are obtained from a variety of different substrates and are reactive towards many

nucleophiles.[34,35] Futhermore, metal-catalysed reactions offer the possibility to tune chemo-,

regio-, and stereoselectivity. The most important metals used in allylic substitution are molyb-

denum, tungsten, ruthenium, cobalt, rhodium, iridium, nickel, palladium, platinum, and cop-

per. Nucleophiles reported so far involve carbon-, nitrogen-, oxygen-, sulfur-, silicon-, hydride-,

and fluoride-centres (see section 1.2.4, pp. 12).[33,34,36]

1.2.1 Catalysts and Ligands

A broad range of mono- and multidentate ligands have been applied in asymmetric allylic sub-

stitution. Among them are many privileged ligands (Scheme 3) and their derivatives. These

include BINAP, BPPFY/Josiphos, DIOP, DuPhos, BOX, PHOX, and Salen. A selection of addi-

tional ligands is shown in Scheme 10.[34]

The most widely used metal centre in allylic substitution is palladium, and its complexes and

chemistry are well understood. The allylic substitution chemistry of other metals is far less

well developed. A few examples of different catalyst systems, including palladium and irid-

ium, can be found in section 1.2.4. For a detailed review of catalyst systems used in allylic

substitution see the work of Ma and co-workers.[42]

6


HNNHO O

PPh2 Ph2P

N N

Ph

PhPh

Ph

N N

N PPh2

PPh

Ph Ph

PPh2Ph2P

Trost Ligand(DACH-phenyl)

Koga P,N-Ligand

Koga N,N-Ligand

Chiraphos

Fiaud Phospholane

Andersson Ligand

Scheme 10: A selection of ligands used in asymmetric allylic substitution (DACH = trans-1,2-

diaminocyclohexane).[37–41]

1.2.2 Pd/Allyl Chemistry

As palladium is the most important metal centre for allylic substitutions, its allyl complexes

have been attributed a key role in the mechanism.[33–35] These complexes have been well stud-

ied and characterised. In solution, Pd/allyl complexes undergo a number of dynamic processes

involving isomerisations and ligand exchanges. These processes influence the outcome of the

reaction to a great extent. Two important processes are discussed in the following subsections.

η3-η1-η3 isomerisation∗ This isomerisation involves a change in binding mode of the allyl

ligand, namely from an η3-π-allyl ligand to a σ-bound monodentate ligand. Depending on

the substitution pattern of the allyl ligand, this can lead to a syn/anti isomerisation, apparent

allyl rotation, or both.

The first step in both syn/anti isomerisation and apparent allyl rotation is the same, namely

the change from an η3-π-allyl to an η1-σ-allyl complex. The second step differs in the bond

around which rotation takes place, C1-C2 (for syn/anti isomerisation, Scheme 11) or Pd-C1

(for apparent allyl rotation, Scheme 12). Restoration of terhapticity completes both processes.

∗This nomenclature will be applied throughout this thesis because it is commonly accepted and widely used

in the literature. The systematic convention according to the IUPAC Red Book would be: η3-κC1-η3.[43] Another

common description is: π-σ-π.

7

1 Introduction

Pd

R

L1 L2Pd

R

L1 L2Pd

R

L1 L2Pd

L1 L2

Rsyn anti

1

2

31 1 1

22

23

3

3

Scheme 11: Illustration the syn/anti interconversion via σ-allyl complexes.

Pd

R1

L1 L2Pd

R1

L1 L2

1

2

31

23R2 R2

PdR1

L1 L2

12

3R2

PdR2

L1 L2

1

2

3R1

Scheme 12: Illustration of apparent allyl rotation via σ-allyl complexes.

It has been found that solvents or anions that coordinate to palladium accelerate the η3-

η1-η3 isomerisation. This may be attributed to stabilisation of the η1-allyl intermediate by

coordination of an external ligand.[33,35,44–46]

Pd0-catalysed Allyl Exchange In this type of isomerisation, the electrophilic π-allyl system

is attacked by a Pd0 complex, reductively displacing the PdII system on the opposing allyl face.

This leads to an inversion of configuration at all allyl atoms. Note that this is in contrast to

the apparent allyl rotation in which the configuration does not change. This interconversion

can take place during catalysis, but the concentration of both species is very low compared to

substrate and nucleophile and, therefore, it plays only a minor role or no role at all.

1.2.3 Mechanism

1.2.3.1 Catalytic Cycle A metal-π-allyl complex is needed to start the catalytic cycle (see

Scheme 13). In the case of palladium, PdII-π-allyl complexes are stable enough to be isolated

and can be used as catalyst precursors. The catalytic cycle can also be entered by oxidative

addition of an allylic substrate to a lower oxidation state metal precursor.

Two types of nucleophiles can be distinguished: soft nucleophiles such as stabilised carban-

ions or amines, and hard nucleophiles such as Grignard reagents or alkyl zinc reagents. The

two types of nucleophiles follow different paths in the catalytic cycle. Soft nucleophiles follow

path a in Scheme 13, directly attacking the terminal carbon atoms of the allyl ligand. Hard

nucleophiles first attack the metal centre (path b) and then migrate to the allyl ligand (c).

In terms of stereoselectivity, this means that substitution with soft nucleophiles will proceed

8


with overall retention of configuration, whereas with hard nucleophiles the configuration will

be inverted (see also sections 1.2.2 and 1.2.3.2).[35] In addition, for hard nucleophiles, enan-

tiodiscrimination could not only occur in the coupling step between the coordinated nucle-

ophile and the η3-allyl, but also in a step involving an η1-allyl intermediate before reductive

elimination of the product (see also 1.2.3.2).[35] Although in palladium chemistry η1-allyl

intermediates seem to play a minor role, they have been observed if the metal centre is coordi-

natively saturated by suitable ligands.[35,47,48] They have also been proposed to be the reactive

species in certain cases.[49,50]

R R

Nu

M

R

R

L

LX

II

M

R

RL

L

HX

0

NuH

Nu*

R R

X

*

a

c

M

R

R

L

L II

Nu

NuHHXb

Scheme 13: Generally accepted mechanism of the metal-catalysed allylic substitution with soft nucle-

ophiles (path a) and hard nucleophiles (path b/c).[33–35] For illustrative purposes a common oxidation

state pair of the metal is shown.

The attack of the nucleophile on the allyl ligand is a reductive step, leading to a complex with

the product bound as an olefin ligand. Displacement of the product by a substrate molecule

and subsequent oxidative addition closes the catalytic cycle.

Note that not all steps in the catalytic cycle must be irreversible. Formation and substitution

of the π-allyl complex may be reversible and may therefore lead to racemisation. Especially

for non-carbon nucleophiles this can cause difficulties.[35]

1.2.3.2 Stereodiscrimination and Substrates At many points in the catalytic cycle the

opportunity for stereodiscrimination occurs and several mechanisms thereof exist. Opportu-

nities for stereodiscrimination include the oxidative addition step of allylic substrates which

are prochiral or have enantiotopic leaving groups, allyl isomerisation processes that are fast

9

1 Introduction

compared to the rate of attack of the nucleophile, a stereospecific reaction with an achiral

catalyst, or enantiotopic differentiation of allyl termini.[36] If allyl isomerisation processes are

fast, stereoselectivity is induced by the regioselective attack of the nucleophile relative to the

allyl ligand. Although being on the opposite allyl face, the chiral ligand provides this regio-

control by sterical and electronic means.[51] Since the chiral ligand can only influence the

regioselectivity of the attack, the type of substrate is important for stereodiscrimination in the

reaction. Two important classes of substrates should be distinguished: symmetrical substrates

with identical substituents at C1 and C3 (RC1H=C2H-C3HXR) and unsymmetrical substrates

with different substituents at C1 and C3 (R1C1H=C2H-C3HXR2).[33,36]

Symmetrical Substrates. In the case of symmetrical substrates, chiral racemic substrates

give only one complex with a meso-η3-allyl ligand (if only the syn-syn isomer is regarded and

the ligand environment L-Pd-L is C2 symmetrical). Regiocontrol of the chiral ligand is responsi-

ble for stereoselective formation of the product (see Scheme 14). Therefore, it is unimportant

whether the chiral substrate is used enantiomerically pure or as a racemic mixture.[33,35,36]

LPd

L

R R

R R

X

RR

X[Pd0] R R

Nu

RR

NuNu-

Scheme 14: Chiral racemic symmetrical substrates lead to identical η3-allyl complexes. Regiocontrol

of the chiral ligand leads to enantiomeric products.[33,36]

Unsymmetrical Substrates. Unsymmetrically substituted allylic substrates pose a much

more complex situation. First of all, there are four possible isomers of the initial substrates

(the two regioisomers and their enantiomers) since the oxidative addition of the allylic

substrate occurs stereospecifically with inversion of configuration.[52] In Scheme 15 the

reaction pathways of these substrates are depicted. Note that the two enantiomeric forms

of these substrates do not give the same palladium complexes and these do not normally

interconvert (see section 1.2.2). Therefore, only enantiopure unsymmetrical substrates can

give enantiopure substitution products, whereas racemic unsymmetrical substrates give racemic

substitution products.[33]

10

1.2A

symm

etricA

llylicSubstitution

Pd

FeP P Pd

FeP PPd

FeP P

Pd

FeP PPd

FeP P

Pd

FeP P Pd

FeP P

Pd

FeP PPd

FeP P

Pd

FeP P Pd

FeP P

X XXX

Pd

FeP P

Nu

Nu Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu

Nu Nu

Nu

R1R1

R1

R1

R1

R1R1

R1R1

R1R1

R1

R1R1

R1R1

R1

R2

R2R2

R2

R2

R2

R2R2

R2

R2R2

R2

R2R2

R2R2

R1

R1

R1

R1R1R1R1

R1

R1

R1

R1

R1

R1

R1

R1

R1

R1

R1

R1

R1

R1

R1

R1

R2

R2

R2

R2

R2

R2

R2

R2

R2R2

R2 R2

R2

R2

R2

R2

R2

R2R2

R2

R2

R2

R2

R2

Scheme 15: Possible products of allylic substitution with unsymmetrically substituted chiral substrates catalysed by Pd/Josiphos, neglecting the

energetically unfavoured anti-anti-η3-allyl isomers. The two enantiomeric substrate pairs and their reaction routes are horizontally separated.

11

1 Introduction

1.2.4 Nucleophiles other than Phosphorus

The most common nucleophiles for allylic substitution are carbon-centred (Asymmetric Allylic

Alkylation) and nitrogen-centred (Asymmetric Allylic Amination), both summarised under the

acronym AAA. Other nucleophiles include oxygen-, sulfur-, silicon-, hydride-, and fluoride-

centres.[33,34]

In the following subsections example reactions with these heteroatom nucleophiles are given.†

1.2.4.1 Carbon Nucleophiles Carbon nucleophiles involve stabilised carbanions bearing

π-acceptors such as carbonyls, sulfones, nitriles or nitro groups.[33,34] For carbon nucleophiles,

the dimethyl malonate anion has become the standard nucleophile and 1,3-diphenylallyl ac-

etate the standard substrate for testing.

In Scheme 16 the standard benchmark AAA is shown.[53] The allylation of stabilised carbon

nucleophiles proceeds smoothly with high yields and selectivities.

Ph Ph

OAcO

O

O

O

Na+ Ph Ph

O

O

O

O

89% yield, 99% ee

N N

Ph

PhPh

Ph

L

4 mol-% [Pd(C3H5)Cl]26 mol-% L

THF, rt, 14 h

Scheme 16: Benchmark AAA with dimethyl malonate as nucleophile as reported by Norrby and co-

workers in 1995.[53]

OCOMe

MgBr

SiMe3

SiMe35 mol-% [PdCl2(L)]

THF0.5 M, 10 °C, 45 min

85% yield, 30% ee

N

Ph2PO

PPh2

(S)-L

Scheme 17: AAA with an unstabilised carbon nucleophile reported by Buono and co-workers in

1990.[54]

†Enantioselectivities will be given as enantiomeric excess defined as % ee=ma jor −minor

ma jor +minor·100. Enantiomeric

excess was historically introduced because it correlated directly to optical rotation. Nowadays it is obsolete

and enantiomeric ratios should be used. However, due to its wide acceptance and abundance in the literature,

enantiomeric excess will be used througout this thesis.

12


A rare example of a allylic alkylation with an unstabilised carbon nucleophile is shown in

Scheme 17. Buono and co-workers have used a Grignard reagent as nucleophile and obtained

the product in good yield but low selectivity.

1.2.4.2 Nitrogen Nucleophiles Carbon-centred nucleophiles aside, nitrogen nucleophiles

are the second largest group of nucleophiles for AAA. Diverse types of primary and secondary

organo-nitrogen compounds have been applied in AAA. The range starts with the benchmark

nucleophile, benzyl amine, and includes both aromatic and aliphatic compounds.[33,34]

NH2

1.5 mol-% [Pd2(dba)3]6 mol-% L

THF0.2 M, 0 °C, 90 h

NHCH2Ph

87% yield, 84% ee

Fe

PPh2

PPh2

NMe

OH

HO

(R,S)-L

OCOMe

Ph2.5 eq

Scheme 18: AAA with benzylamine as nucleophile as reported by Hayashi and co-workers in 1990.[55]

Ph NH

O 1 mol-% [Ir(COD)Cl]22 mol-% L

THF2 M, rt, 24 h Ph

N

O

92% yield, 97% ee

*

OP

ON

Ph

Ph

(Ra,Rc,Rc)-L

OCO2Me

NH2

OMe 0.5 mol-% [Ir(COD)Cl]21 mol-% L, activation

THF2 M, 50 °C, 2 h

1.2 eq

NH

MeO

*

95% yield, 95% ee

OCO2Me

Scheme 19: AAA of aliphatic and aromatic nucleophiles as reported by Hartwig and co-workers in 2002

and 2004.[56,57] For the reaction with anilines, activation of the catalyst with propyl amine for 20 min

was required.

In Scheme 18, an early reaction reported by Hayashi and co-workers is shown. The allylation of

13

1 Introduction

benzyl amine with an aliphatic, unsymmetrical substrate is catalysed by a palladium complex

with a ferrocenyl ligand.[55] Examples of the allylation of aliphatic and aromatic nitrogen

nucleophiles are shown in Scheme 19. Hartwig and co-workers have reported both reactions

with morpholine and anilines catalysed by an iridium complex containing a phosphoramidite

ligand.[56,57]

Ph Ph

OAc

Ph Ph

NH2

5 mol-% [PdCl(allyl)2]220 mol-% (R)-BINAP

1:2 aq. NH3/1,4-dioxane0.04 M, rt, 18 h 71% yield, 87% ee

Scheme 20: AAA of ammonia as reported by Kobayashi and co-workers in 2009.[58] The structure of

BINAP is depicted in Scheme 3 on page 2.

An interesting example of a special primary amine, ammonia, was provided by Kobayashi

and co-workers (Scheme 20). They have reported the monoallylation of ammonia with the

standard substrate 1,3-diphenylallyl acetate in good yields and selectivity. Monoallylation

could be achieved under optimised conditions. The reaction was catalysed by a palladium

complex containing the privileged ligand BINAP.[58]

1.2.4.3 Oxygen Nucleophiles Allylation of oxygen centred nucleophiles is far less well de-

veloped than the original allylation of C- and N-nucleophiles. A recent report by Hartwig

and co-workers shows that a phosphoamidite ligand in combination with iridium proves to be

a catalyst also capable of allylating oxygen nucleophiles.[59] The allylation of cyclohexanol

proceeds under mild conditions giving the branched product in moderate yield and good se-

lectivity (see Scheme 21).

Ph

OCOMe

OH

5 mol-% [IrL]20 mol-% 1-phenyl-1-propyne

tolueneK3PO4, rt, 40 h Ph

O OP

ON

Ph

Ph

(Ra,Rc,Rc)-L68% yield, 93% ee

Scheme 21: Asymmetric allylation of an aliphatic alcohol nucleophile as reported by Hartwig and

co-workers in 2008. The internal alkyne was used in order to avoid the vinylic side product. The

mechanism of this suppression has not been studied.[59]

14


OH

OMe

OCO2Me 1 mol-% [Pd2(dba)3]3 mol-% L

CH2Cl20.6 M, rt, 4 h

O

OMe

88% yield, 97% ee

HNNHO

PPh2 Ph2P

O

L

Scheme 22: Asymmetric allylation of a phenolic nucleophile as reported by Trost and Toste in 1998.[60]

Trost and Toste reported the O-allylation of phenols with a palladium system (see Scheme

22).[60] The reaction proceeds with good yield and high selectivity. Interestingly, the chiral

information of the new stereocentre can be transferred in a Claisen rearrangement to give the

corresponding C-allylated product.

1.2.4.4 Sulfur Nucleophiles Among the chalcogens sulfur has also been applied as a nu-

cleophile for allylations. Sulfinates are the main source of sulfur nucleophiles.[61–63]

OCOMePhSO2Na

HNNHO

PPh2 Ph2P

O

L

2.5 mol-% [Pd(C3H5)Cl]27.5 mol-% L

3 eq [N(C6H12)4]BrCH2Cl2, 0.05 M, 0 °C, 2h SO2Ph

99% yield, 98% ee3 eq

Scheme 23: Asymmetric allylation of a sulfinate nucleophile as reported by Trost and co-workers in

1995.[63]

HNNHO

PPh2 Ph2P

O

L

OCO2Me SO2tBu1.5 mol-% [Pd2(dba)3]

4.5 mol-% L

[N(C6H12)4]BrCH2Cl2/H2O, rt, 2 h

98% yield, 98% ee

LiSO2tBu

Scheme 24: Asymmetric allylation of a sulfinate nucleophile as reported by Gais and co-workers in

2003.[62]

15

1 Introduction

Trost and co-workers have used sulfinates to generate cyclic sulfones in very good yields and

selectivities (see Scheme 23), whereas Gais and co-workers have used the same ligand with

linear aliphatic substrates giving comparable results (see Scheme 24).

1.2.4.5 Silicon Nucleophiles Allylations of silyl nucleophiles have also been reported.

Hayashi and co-workers used allyl chlorides with 1,1-dichloro-1-phenyl-2,2,2-trimethyldisilane

as nucleophile in a palladium-catalysed system. Interestingly, in the first report a chiral ferro-

cenyl ligand was used (BPPFA, see Scheme 3), giving moderate selectivities (99% yield, 61%

ee), whereas in the second report the analogous ruthenocenyl ligand was used to give much

better selectivities (92% ee, see Scheme 25).[64,65]

PhCl2SiTMSSiCl2Ph

5 mol-% [Pd(C3H5)Cl]211 mol-% L

THF0.5 M, 20 °C, 15 h

Cl

83% yield, 92% ee

RuNMe2

PPh2

PPh2

(R,S)-L

Scheme 25: Asymmetric allylation of a silyl nucleophile reported by Hayashi and co-workers in

1994.[64]

1.2.4.6 Hydride as Nucleophile The reduction of allylic esters can be seen as a special case

of allylic substitution, namely with hydride acting as the nucleophile. The reaction proceeds

via a π-allylmetal complex. The key step is believed to be the reductive elimination of hydride

with the allyl from a [M(π-allyl)(H)(L)]-type complex.[66] A demonstrative example of the

reduction of an allylic, aliphatic ester with a chiral monodentate phosphine ligand as reported

by Hayashi and co-workers is shown in Scheme 26.

1.2.4.7 Fluoride as Nucleophile Only few reports of metal-catalysed allylic fluorinations

have appeared. Doyle and co-workers have published the allylic fluorination of cyclic and linear

substrates with promising results (see Scheme 27).[67–69] They propose a mechanism involving

a SN2-type attack of fluoride on a π-allylmetal complex, and not via a high-valent palladium

fluoride complex and reductive elimination.

16

1.3 Previous Work on Allylic Phosphination

Alk1

Alk2 OCO2Me

Alk1

Alk2 H

1 mol-% [Pd2(dba)3]2 mol-% L

2.2 eq HCOOH1.2 eq proton sponge

1,4-dioxane, 20 °C, 17 h 99% yield, 85% ee

PPh2

MeO

(R)-L

Scheme 26: Asymmetric reduction of allylic esters as reported by Hayashi and co-workers in 1994.[66]

As a base, proton sponge (1,8-bis(dimethylamino)naphthalene) was used.

Cl F5 mol-% [Pd(C3H5)Cl]225 mol-% L1

THF0.1 M, rt, 24 h

AgF

2 eq

Cl

AgF

3 eq

5 mol-% [Pd2(dba)3]10 mol-% L2

toluenert, 48 h

F

85% yield, 88% ee

85% yield, 90% ee

HNNHO

PPh2 Ph2P

O

L1 (Ph)L2 (Np)

Scheme 27: Asymmetric allylic fluorination of cyclic and linear substrates as reported by Doyle and

co-workers in 2010 and 2011.[67,68]

The lability of the allylic C-F bond was demonstrated by Gouverneur and co-workers in 2009

and previously by Togni and co-workers.[69,70] They have used allylic fluorides as substrates for

allylic alkylation which proceeded quite rapidly (reaction times starting from 15 min) under

mild conditions.


Until thirty years ago, allylic phosphines were synthesised by classical methods used in

organophosphorus chemistry, i.e. nucleophilic substitution of allylic leaving groups with

appropriate phosphorus nucleophiles.[71] In 1983, Fiaud published the first metal-catalysed

allylic phosphination.[72] In the first example shown in Scheme 28, lithium diphenylphosphide

was used as the nucleophile. The low yield was attributed to the coordinating properties

17

1 Introduction

of the diphenylphosphide anion which deactivates the catalyst complex. Therefore, Fiaud

changed to the corresponding, less coordinating sulfide, LiP(S)Ph2, and indeed obtained a

higher yield. The substrate (E)-but-2-enyl acetate was transformed to the branched (67%),

the linear E (25%), and the linear Z (8%) products, showing a slight scrambling of regio- and

stereochemistry.

OAc

OAc

LiPPh2

LiP(S)Ph2

5 mol-%[Pd(PPh3)4]

THF, rt

5 mol-%[Pd(PPh3)4]

THF, rt

PPh2

P(S)Ph2

< 15% yield

85% yield

OAcP(S)Ph2

P(S)Ph2LiP(S)Ph2

5 mol-%[Pd(PPh3)4]

THF, rt67% 25% E, 8% Z

OCOPh

Ph

P(S)Ph2

Ph

5 mol-%[Pd(PPh3)4]

THF, rtLiP(S)Ph2

Scheme 28: Examples of the first metal-catalysed allylic phosphinations with acyclic and cyclic sub-

strates as reported by Fiaud in 1983.[72]

With the cyclic substrate 5-phenylcyclohex-2-enyl phenyl carbonate, a stereoselective reaction

was observed. Starting with cis substituents, the phosphination gave only the cis product. This

overall retention of configuration is in line with the assumption that the nucleophile attacks

the allyl plane opposite of the palladium centre.

In 2003, Welzel and co-workers reported the allylation of phosphonites in the route of the

total synthesis of Strigol.[73] Reactions with acyclic and cyclic substrates were catalysed by an

achiral palladium complex, with which the acyclic cinnamyl acetate yielded the linear product

(Scheme 29).

18


5 mol-% [Pd(acac)2]

MeOH, 60 °C, 24 h

68% yield, rac2.5 eqrac

5 mol-% [Pd(acac)2]

MeOH, 60 °C, 22 hOAcPh P(O)Ph2Ph

OAc P(O)Ph2Ph2P(OMe)

Ph2P(OMe)

2.0 eq 68% yield

Scheme 29: Allylation of diphenyl phosphonite reported in 2003 by Welzel and co-workers.[73]

In 2005, Montchamp and co-workers investigated the allylation of H-phosphinates.[74]

In the palladium-catalysed reaction with cinnamyl chloride, 3-phenylpropyl H-phosphinate

rather than the allylic phosphinate was observed. The same reactants with a nickel catalyst

afforded the allylic product in good yield (see Scheme 30).

Ph Cl Ph P OBu

H

O

Ph P OBu

H

OPh Cl

2 mol-% [Pd(OAc)2], dppfPhNH3PO(O)H2, (BuO)4Si

CH3CN, reflux

2.5 mol-% [NiCl2(PPh3)2]PhNH3PO(O)H2, (BuO)4Si

toluene, reflux

73% yield

88% yield

Scheme 30: Palladium-catalysed reduction/hydrophosphinylation (top) and nickel-catalysed allylic

phosphination (bottom) of cinnamyl chloride reported by Montchamp and co-workers.[74]

In the case of palladium, they proposed a mechanism in which the phosphinate behaves as

a hard nucleophile, i.e. attacking the metal centre rather than the coordinated allyl. If a

subsequent proton transfer or β-hydride elimination is faster than reductive elimination, the

reduced intermediate (in this case 3-phenylpropene, R1 = Ph) is formed. Hydrophosphinyla-

tion finally yields the observed product (Scheme 31).

19

1 Introduction

ClR1 [Pd0]Pd

R1

Cl

ROP H

O

HRO

PH

HOPd

R1

PHRO

OH

Pd

PHRO

OH

R1

PR1O

HOR

Pd

PRO O

H

R1

- H+

Pd

R1

H

R1

- P(O)OR

- P(O)OR- [Pd0]

PR1O

HORR1

transferhydrogenation hydrophosphinylation

[Pd0], H2P(O)OR

observed product expected product

- [Pd0]- H+

Scheme 31: Mechanism for the coupling of H-phosphinates with allylic substrates as proposed by

Montchamp and co-workers.[74]

In 2008, our group made a contribution to this field by presenting the first asymmetric

metal-catalysed allylic phosphination.[4,5] Scheme 32 shows the reaction conditions and best

results obtained in two different solvents. The details of this reaction will be elaborated upon

in this thesis.

Ph Ph

OAc

Ph Ph

PPh2HPPh2

5.0 mol-% [Pd(dba)2]5.2 mol-% (R,S)-Josiphos

Solv, 40 °C

Solv = C6H6:Solv = CH2Cl2:

79% yield, 94% ee68% yield, 87% ee

Scheme 32: The first asymmetric metal-catalysed allylic phosphination reported by our group.[4,5]

20


After our publication, Fiaud and co-workers published the most recent work in this field

in 2011.[75] They have optimised the original reaction from 1983[72] using thiophosphides

with phosphide boranes as nucleophiles. The advantages of phosphine boranes over sec-

ondary phosphines are easier deprotonation, lower tendency to coordinate, and air-stability.

Acyclic as well as cyclic racemic substrates were tested with an achiral palladium catalyst.

More interestingly, they have reported the first allylic phosphination with a chiral nucleophile

and thereby observed a stereoselective reaction (see Scheme 33).

OAc P

Ph

Ph

LiH3B 2 mol-% [Pd(PPh3)4]

THF, rt, 43 hP

Ph

Ph

H3B

32% yield, 8:2 dr

Scheme 33: Stereoselective allylic phosphination with a chiral nucleophile reported by Fiaud and co-

workers.[75]

AcO H[Pd]

[Pd0]

- OAc-Nu H

H Nu

[Pd]

Nu

soft nucleophile

- [Pd0]

hard nucleophile

- [Pd0]

Scheme 34: Experiment devised by Fiaud and co-workers in 1987 for the classification of nucleophiles

in allylic substitution.[76]

Fiaud and co-workers had also developed an interesting classification method for nucleophiles

21

1 Introduction

in allylic substitution in 1987.[76] In order to determine whether a nucleophile is "hard" or

"soft", they used a tricyclic substrate. Upon oxidative addition, the allyl face opposite of the

metal centre is sterically blocked and only "hard" nucleophiles are expected to react because

they first coordinate to palladium and then yield the product after reductive elimination (see

Scheme 34). Soft nucleophiles should not react with this substrate.

Fiaud and co-workers applied this method to the phosphide borane nucleophiles and found

them to be soft, i.e. reacting through an outer-sphere mechanism.[75]

22

2 Palladium/Allyl Complexes with Josiphos Ligands

2.1 Introduction

The design and application of ferrocenyl ligands has a long history in our group, thus the use

of these ligands for the development of the asymmetric allylic phosphination was straightfor-

ward. Originally, tests with P,N-ligands were carried out. However, because the phosphine

nucleophile is also a good ligand for palladium, the P,N-ligand was partially replaced in the

coordination sphere of the metal during catalysis, resulting in a non-slective catalyst system.

The ligand was therefore changed to the more tightly binding P,P-chelate Josiphos.[4] Since

Josiphos was already known to perform well in AAA as reported in the first publication about

Josiphos, the choice of this ligand in our reaction was obvious.[30]

Fe

PPh2

Cy2P PdR

R

Fe

PPh2

Cy2P Pd

RR

H

H

endo exo

Scheme 35: Allyl configuration nomenclature in PdII/Josiphos/Allyl complexes. If the central allyl

C2-H vector points towards the ferrocene backbone, the allyl configuration is named endo, exo if the

opposite is true.[77]

As indicated in sections 1.2.2 and 1.2.3.2, Pd/Allyl complexes may have different isomeric

forms, such as syn/anti isomers. In addition, ferrocenyl complexes also allow for endo and exo

isomers (see Scheme 35). This fact is relevant for the following discussions.

2.2 Known Complexes

A number of PdII/Allyl complexes containing Josiphos ligands have been published (Scheme

36). They have been studied in terms of structural features (by X-ray crystallography and

NMR spectroscopy), allyl dynamics (NMR), and performance in catalysis with regard to the

aforementioned characteristics.

23


Fe

PPh2

Cy2P PdFe

PPh2

Cy2P Pd

Fe

PPh2

Cy2P Pd

PhPh

Fe

PPh2

P Pd

PhPh

Fe

PPh2

P Pd

Fe

PPh2

P Pd

Fe

PCy2

Ph2P Pd

Fe

PPh2

Ph2P Pd

Fe

Ph2P

PCy2Pd

PhPh

Fe

Ph2P

PCy2Pd

PhPh

Fe

Ph2P

PPh2Pd

PhPh

Fe

Ph2P

PPh2Pd

Fe

Ph2P

PCy2Pd

Fe

Ph2P

PCy2Pd

Scheme 36: Published PdII/Josiphos/Allyl complexes. In the top row: complexes with the

Josiphos ligand and three different allyls;[28,78–82] second row: the "Phobyl"-Josiphos ligand in al-

lyl complexes;[80,82,83] third row: complexes of "inversed" Josiphos,[80] Ph,Ph-Josiphos,[80] and Cp*-

Josiphos;[84] fourth and fifth row: complexes of annularly bridged Josiphos derivatives.[85,86]

24

2.3 η3-1,3-Diphenylallyl Complexes

Allyl dynamics is an important feature of these complexes. It depends on the Josiphos ligand

and the allyl ligand itself. In all of the complexes investigated, the allyl isomerisation was

found, by means of 2D 1H-NOESY, to be selective, i.e. the formation of a σ-bound η1-allyl

occurs by the cleavage of a specific Pd-C bond. Thereby, in the case of the small C3H5 allyl

ligand, one would expect electronic effects to be operating, and the bond trans to the donor

group with the larger trans influence to be broken. However, even for small allyl ligands, the

selective formation of the η1-allyl seems to be controlled by steric effects.[78–80,82,87]

As mentioned in section 1.2.2, the η3-η1-η3 isomerisation can lead to endo/exo interconversion

through the apparent allyl rotation mechanism. For each of the Pd/Josiphos complexes shown

in Scheme 36, different isomer compositions are observed in solution. For the allyl complexes

with the Josiphos ligand (first row in Scheme 36), isomer ratio numbers have been published.

In the case of the C3H5 allyl, the ratio is endo/exo = 2:1;[79] for the 1,3-diphenylallyl ligand it

is endo/exo = 1:2 (see also section 2.3);[5,82] and for the β-pinene allyl ligand it is endo/exo =

1:10.[81]

From a structural point of view, one interesting phenomenon in the 1,3-diphenylallyl complex

has been found: NMR studies have shown that there is π-π stacking between the allyl phenyl

ring and a phenyl ring of Josiphos.[78,82] This unique feature may, of course, also contribute to

the effects influencing the isomer ratio.


2.3.1 General Remarks

Since 1,3-diphenylprop-1-en-3-yl acetate has become the standard substrate in allylic sub-

stitution,[33] complexes with the 1,3-diphenylallyl ligand are of fundamental importance

for mechanistic investigations in this field. Therefore, the cation [PdII(κ2-Josiphos)(η3-1,3-

Ph2Allyl)]+ (1) has been studied.[5,82] For this complex there are eight possible allyl isomeric

forms in total (see Scheme 37). It is important to note that all of these isomers may participate

in an allylic substitution reaction. This complicates the system because these isomers occur

in different concentrations and possibly react at different rates. It is, therefore, important

to investigate the equilibrium concentrations of these species (thermodynamics) and their

isomerisation rates (kinetics). These points will be discussed in the following subsections.

In solution, the composition of 1 is dominated by the two syn-syn isomers (> 98%). The

syn-anti isomers make up less than 2%, and the energetically unfavoured anti-anti isomers

are unobserved and can be neglected.[82]

25


PdFeP P

PdFeP P

PdFeP P Pd

FeP P

PdFeP P Pd

FeP P

endo-syn-syn endo-anti-synendo-syn-anti

exo-syn-syn exo-anti-synexo-syn-anti

Scheme 37: Possible 1,3-diphenylallyl isomers in the Pd/Josiphos complex 1. The energetically most

unfavoured anti-anti isomers are neglected. In solution, the two syn-syn isomers account for more than

98% and all other isomers for less than 2%.[82]

2.3.2 Synthesis

The synthetic procedure for complex 1 is relevant for the following discussion and will thus

be described here. Complex 1 was synthesised under argon by mixing Josiphos and the palla-

dium precursor [PdII(µ2-Br)(1,3-Ph2Allyl)]2 in methanol at room temperature. The resulting

dark red reaction mixture was stirred at room temperature for 20 min before a slight excess

of the halogen scavenger, sodium hexafluoroantimonate, in methanol, was added. A bright

orange solid immediately precipitated. The product was filtered off under argon and washed

with little methanol and pentane. It was separated from the sodium salts by extraction of the

filter pad with dichloromethane. The product was isolated as orange crystals in 67% yield (see

Scheme 38).

Usually, this synthesis gave complex 1 with a ratio of about endo/exo = 1.4:1. Interestingly,

when compared to the literature,[82] we observed different values. We then found that the ob-

tained endo/exo ratio was dependent on the reaction temperature. We have prepared complex

1 at different temperatures ranging from –20 ◦C to +60 ◦C (see Figure 1).

26


Fe PPh2PCy2

SbF6

Fe

PPh2

Cy2P Pd

PhPh

PdBr

PdBr

PhPh

Ph Ph

MeOH

rt, 67%1.2 eq

NaSbF6

Scheme 38: General synthesis of [PdII(κ2-Josiphos)(η3-1,3-Ph2Allyl)]SbF6 (1).

*

Figure 1: endo/exo ratio of 1 as function of the reaction temperature after a reaction time of 20 min

(Scheme 38). The marked data point (*) was aquired after a reaction time of 14 h.

As depicted in Figure 1, there is a positive trend between the endo/exo ratio of 1 and the

reaction temperature. The lowest ratio (1.1:1) was observed after the reaction at –20 ◦C,

the highest (3.4:1) at +60 ◦C. One would expect to obtain a thermodynamic product ra-

tio at higher temperatures but, interestingly, this seems not to be the case, since we have

found the thermodynamic endo/exo ratio to be around 0.6:1 (see the following subsection).

This might be explained as follows: Upon mixing the palladium/allyl precursor with Josiphos,

a Pd/Josiphos/allyl complex is formed with a bromide anion that may be, at least to some

extent, coordinated. It can be assumed that for this complex a completely different thermo-

dynamic endo/exo ratio is favoured, with endo > exo. Elevated temperatures (or prolonged

reaction times) equilibrate the isomers to their thermodynamic ratio which is then preserved

upon precipitation with a halogen scavenger.

27


2.3.3 Behaviour in Solution

Apart from the temperature dependence of the endo/exo ratio, we also noticed that the

endo/exo ratio of solutions of 1 changed very slowly over time. Obviously, the isomeric com-

position was slowly equilibrating. As mentioned in section 1.2.2, the isomerisation rate may

be influenced by coordinating species.

Figure 2: Reaction profile for the endo/exo ratio of 1 in the presence of 1 eq of the additive specified

in the upper right corner of the plot (part I). Note that the isomerisation with PMe3 is so fast that 1 has

already reached the equilibrium ratio after 2 data points.

28


(E)-(1,3-diphenylallyl)diphenylphosphine

Figure 3: Reaction profile for the endo/exo ratio of 1 in the presence of 1 eq of the additive specified

in the upper right corner of the plot (part II).

We have tested a dozen different additives for their effect on the isomerisation rate and

the resulting endo/exo ratio (see Figures 2 and 3). Not surprisingly, the addition of non-

coordinating compounds such as the sterically demanding tri-ortho-tolylphosphine (Tolman

angle > 190◦[88]) or a phosphine oxide (trimethylphosphine oxide) did not result in a ob-

servable change of the endo/exo ratio of 1, and are therefore not shown in Figures 2 and 3.

Most of the additives we have tested are relevant for the catalytic system used for the allylic

phosphination reaction. They include the nucleophile itself, diphenylphosphine, as well as two

amine bases, the product, the acetate ion liberated by oxidative addition of the substrate to

the Pd0 complex, and others. It is clearly visible that sterically undemanding, electron-rich nu-

cleophiles lead to the highest isomerisation rates. Trimethylphosphine, DBU, and the acetate

ion are among the most efficient isomerisation "catalysts". The effect of different counterions

on isomerisation rates has not been investigated in detail (see also subsection 2.3.4.1).[5]

As seen from the reaction profiles (Figures 2 and 3), the final ratio is about endo/exo = 0.6:1.

29


After keeping a pure solution of complex 1 (initial ratio endo/exo = 1.2:1) for a prolonged

time (> 3 days) at 60 ◦C, we have also found the ratio to change to 0.6:1. This is another

clear indication that the thermodynamic ratio is endo/exo = 0.6:1.

2.3.4 Characterisation

2.3.4.1 In the Solid State Although investigations of complex 1 in solution were published

in 1995,[82] its X-ray crystal structure was unknown until 2009 (Figure 4).[5]

Figure 4: Stereoscopic ORTEP representation of endo-syn-syn-1. Hydrogen atoms are omitted for

clarity. Thermal ellipsoids are set at 50% probability. Selected bond lengths: Pd1-C43 2.231(4) Å,

Pd1-C45 2.275(3) Å, Pd1-P1 2.3092(9) Å, Pd1-P2 2.3368(9) Å. The "allyl rotation" angle (angle

between the P1-Pd1-P2 plane and the C43-C44-C45 plane) is 70.40 ◦. The "allyl" angle (torsion angle

P2-Pd1-allyl centre-C44) is 92.35 ◦.[5]

The solid state structure of 1 has been analysed before and shows no special features[5], there-

fore it will not be discussed in detail. There is, however, one remarkable observation: it can

be seen from Figure 4 that the SbF−6 counterion is located relatively close to the palladium

centre. The shortest Pd-F distance is 3.973(3) Å, still clearly larger than the sum of the van

der Waals radii, which means, a least in the solid state, there is no coordination of the SbF−6anion. But, from a spatial point of view, it seems possible that the SbF−6 counterion may par-

ticipate, at least weakly, as "isomerisation catalyst" in solution, as discussed in the previous

section (2.3.3).

As can be seen from Figure 4 and Table 1, the bulky dicyclohexyl rings on one phosphorus atom

of the Josiphos ligand lead to elogated Pd-PCy2 and Pd-C45 distances due to steric interactions.

30


A comparison of these distances with the analogous complexes bearing an unsubstituted allyl

ligand or a different aliphatic phosphine demonstrate this effect.

Complex Pd-P Distances [Å] Pd-Callyl Distances [Å]

SbF6

Fe

PPh2

Cy2P Pd

PhPh

Pd-PPh2 2.3092(9) Pd-C(cis to PPh2) 2.231(4)

Pd-PCy2 2.3368(9) Pd-C(cis to PCy2) 2.275(3)

∆ = 0.028 ∆ = 0.044

Fe

PPh2

P Pd

PhPh

OTf

Pd-PPh2 2.284 Pd-C(cis to PPh2) 2.258

Pd-P(phobyl) 2.300 Pd-C(cis to P(phobyl)) 2.275

∆ = 0.016 ∆ = 0.017

Fe

PPh2

Cy2P Pd

OTf

Pd-PPh2 2.298 Pd-C(cis to PPh2) 2.179

Pd-PCy2 2.314 Pd-C(cis to PCy2) 2.183

∆ = 0.016 ∆ = 0.004

Table 1: Comparison of crystallographic data of complex 1 and similar compounds.[5,28,83]

2.3.4.2 In Solution Pregosin and co-workers have studied the triflate salt of complex 1

in solution by means of NMR in 1995.[82] Their extensive studies (1H-NOESY, 31P,31P-EXSY)

lead to the assignment of the four major isomers (exo-syn-syn, endo-syn-syn, exo-syn-anti, and

endo-syn-anti) and their abundance. Furthermore, no direct exchange signal between the

two major isomers exo-syn-syn and endo-syn-syn was found. This is in line with the general

assumptions discussed in section 1.2.3.2 and Scheme 15 on page 11. They determined the

relative abundance of the major species to be > 98% for the syn-syn isomers and < 2% for the

syn-anti isomers (Scheme 37). In addition, Pregosin and co-workers tried to correlate the 13C

chemical shift of the allyl termini with the site of nucleophlic attack and the observed product.

However, this was unsuccessful and they concluded that "the rates of nucleophilic attack at the

various terminal allyl carbons of 1 are not equal, e.g. exo > endo, and/or the 13C criterion is

31


suspect." They further conclude that perhaps a minor isomer may react more rapidly (although

they are only present at a level < 2%), however, no evidence for this was presented.[82]

2.4 Summary

The complex [PdII(κ2-Josiphos)(η3-1,3-Ph2Allyl)]SbF6 (1) is of fundamental importance to

mechanistic investigations of palladium-catalysed allylic substitutions. It has been studied in

the solid state[5] and in solution.[82] Complex 1 has six relevant isomers (Scheme 37) which

interchange in solution via an η3-η1-η3 mechanism. Coordinating molecules can assist this

isomerisation and lead to faster equilibration. This may be important for the catalytic system.

Furthermore, depending on the reaction temperature, complex 1 can be prepared in different

endo/exo ratios. The thermodynamic endo/exo ratio was found to be 0.6:1.

32

3 Phosphorus Nucleophiles

3.1 Introduction

Metal-catalysed C-P bond formation is an important way to access organophosphorus com-

pounds. Although there are many examples of metal-catalysed C-P bond forming reactions

(see the review by Glueck[1]), it is still remarkable that metal complexes are able to catalyse

reactions involving large excesses of potential phosphorus ligands without deactivation of

the catalyst. Two types of C-P bond formations can be distinguished: hydrophosphination,

the addition of a P-H bond across a C-X (X = C, N, O) multiple bond; and phosphination,

a cross-coupling reaction involving deprotonation of the phosphorus nucleophile.[1] The

allylation of P–nucleophiles is classified as the latter type.

Most phosphorus nucleophiles include a reactive P–H bond. Additionally, in order to act as

nucleophile, the phosphorus atom must possess a free electron pair. Organophosphorus(III)

compounds fulfill this requirement and primary as well as secondary phosphines (H2PR,

HPR2) are ideal candidates. Though tertiary phosphines (PR3) may act as nucleophiles,

in our case, the allyl phosphonium cation generated would be relatively unstable. In

organophosphorus(V) compounds, no free lone pair is available for reaction. However,

primary and secondary phosphine oxides (H2P(O)R, HP(O)R2) are able to tautomerise to the

corresponding trivalent phosphinous acids (see Scheme 39).[89] Under neutral conditions, this

equilibrium lies far to the side of the secondary phosphine, whereas under basic conditions

the trivalent form is favoured.[90]

HP

R R

O

secondaryphosphine oxide phosphinous acid

P

R R

OHB-

P

R R

O

-HBP

R R

O

Scheme 39: Tautomerisation equilibrium between pentavalent secondary phosphine oxides and the

trivalent phosphinous acids.[89] Under basic conditions, the trivalent, O-centred anion is predomi-

nant.[90]

We have utilised secondary phosphines, as well as secondary phosphine oxides as nucleophiles

in allylic phosphination.

33


3.2 Asymmetric Allylic Phosphination with Phosphines

Scheme 40 shows the general reaction scheme for the allylic phosphination. The allylic sub-

strate reacts with the phosphorus nucleophile in presence of a catalyst and a base to give an

allylic phosphine. The catalyst can be generated in situ from a Pd0 source (such as [Pd(dba)2])

or a PdII source (such as [Pd(η3-C3H5)µ2-Cl]2) and the chiral ligand, or a presynthesised com-

plex such as 1 can be used.

R' R'

LGHPR2

5 mol-% catalystNEt3

solvent R' R'

PR2

Scheme 40: General reaction scheme of the allylic phosphination (LG = leaving group).

ppm 50 40 30 20 10 0 -10 -20 -30 -40

A IHGFEDCB

Figure 5: 101 MHz 31P{1H}-NMR spectrum of a typical allylic phosphination reaction mixture. Signal

assignment: A,B) complex 1, C,H) Josiphos, D) reduced allylic phosphine 4, E) vinyl phosphine 3, F)

allylic phosphine 2, G) Ph2P-PPh2 (5), I) HPPh2.

The reaction proceeds slowly (see section 3.2.1) but quite cleanly. Figure 5 shows a typical31P{1H}-NMR spectrum of a reaction mixture involving the main resonances (see also Scheme

41) of diphenylphosphine (–40 ppm) and allylic phosphine 2 (–3 ppm). The signals around

0 ppm arise from the vinylic product (3) and from the reduced allylic phosphine (4). The

signal at –15 ppm is assigned to tetraphenyldiphosphine (5), the dehydrocoupling product of

34


diphenylphosphine.[91–93] After completion, the reaction is worked up in a glovebox by filtra-

tion over a short plug of silica in order to remove the catalyst complex. The allylic phosphine

is thereby obtained in pure form.

Ph Ph

PPh2

Ph Ph

PPh2

Ph Ph

PPh2Ph2P PPh2

Scheme 41: Major products observed in allylic phosphination. From left to right: the desired allylic

phosphine (2), the vinyl phosphine (3), the reduced phosphine (4), and tetraphenyldiphosphine (5).

3.2.1 Catalytic Scope

Table 2 summarises the catalytic scope with the standard substrate, 1,3-diphenylallyl acetate,

in terms of solvents, nucleophiles, ligands, and additives (see also Scheme 42).

PH

Fe PPCy2

F3C

CF3

2

Fe PPh2P(tBu)2

Fe PCy2PPh2

Fe

PPh2

PPh Ph

PPh2

Fe PPh2PCy2

PPh2PPh2 P

H

PH

PH

PH

7 8 9

102

6

Scheme 42: Ligands and nucleophiles used in catalyses (see Table 2). From left to right: top row:

Josiphos, CF3-Josiphos (7), tBu-Josiphos (8), "inversed Josiphos" (9); middle row: Phobyl-Josiphos

(10), (R)-BINAP, 1,3-diphenylallyl(diphenylphosphine) (2), diphenylphosphine; bottom row: dicyclo-

hexylphosphine, phosphafluorene (6), bis(2-naphtyl)phosphine, bis(o-tolyl)phosphine.

35


Cat. Systema Solvent Nucleophileb Baseb Additiveb Temp. Time Yield ee

1c Complex 1 C6D6 HPPh2 5% NEt3 – 40 ◦C 120 h 67% 94%

2d Josiphos C6D6 HPPh2 NEt3 – 40 ◦C 120 h 79% 94%

3d Josiphos CD2Cl2 HPPh2 NEt3 – 40 ◦C 120 h 68% 91%

4d Josiphos d8-THF HPPh2 NEt3 – 40 ◦C 120 h 81% 51%

5c Complex 1 CD2Cl2 HPCy2 5% NEt3 – 40 ◦C 89 h 41% 30%e

6d Josiphos C6D6 HPCy2 NEt3 – 40 ◦C 74 h 44% 45%

7d Josiphos C6D6 6 NEt3 – 40 ◦C 0.3 h 84% 80%

8d Josiphos C6D6 HP(2-Np)2 NEt3 – 40 ◦C 48 h 85% 83%

9d Josiphos C6D6 HP(o-tol)2 NEt3 – 40 ◦C 48 h 82% 42%

10d Ligand 7 CD2Cl2 HPPh2 NEt3 – 40 ◦C 4 h 92% 82%




14d (R)-BINAP CD2Cl2 HPPh2 NEt3 – 40 ◦C 52 h 48% 38%


16 Complex 1 C6D6 HPPh2 NEt3 1% DBU rt 23 h 73% 77%

17 Complex 1 C6D6 HPPh2 DBU – rt 0.8 h n.d. 72%

18 Complex 1 C6D6 HPPh2 K3PO4 – rt 29 h 71% 73%

19 Complex 1 C6D6 HPPh2 3 eq NEt3 – rt 24 h 67% 73%

20 Complex 1 CD2Cl2 5 eq HPPh2 NEt3 – rt 52 h 12% 21%

21 Complex 1 CD2Cl2 HPPh2 NEt3 PMe3 rt 2 h 68% 18%

22 Complex 1 CD2Cl2 HPPh2 NEt3 5% PMe3 rt 72 h 63% 86%

23 f Complex 1 CD2Cl2 HPPh2 NEt3 – rt 44 h 67% 80%

Table 2: Representative catalytic results (see also Scheme 42). Reaction conditions: 5 mol-% catalyst

loading, 1,3-diphenylallyl acetate as substrate. acatalyst system: either 5 mol-% complex or 5 mol-%

[Pd(dba)2] and 7 mol-% of the specified ligand. bif not indicated differently, 1 eq was used. cRef.[5]

dRef.[4] edetermined by NMR (see subsection 3.4). f 5 eq of substrate were used.

Analysis of the temperature dependence of the reaction under conditions decribed in entry 16

of Table 2 revealed that, unsurprisingly, at higher temperatures a lower selectivity is obtained

and reaction times are shorter (see Figure 6). In addition to the reduction of the selectivity,

the product distribution also changes disadvantageously at higher temperatures (Figure 7).

At 10 ◦C, the desired allylic phosphine 2 is obtained in 96% yields in the crude mixture. At

80 ◦C, only 29% of the crude mixture is 2, 17% is tetraphenyldiphosphine (5), and 54% is a

mixture of the vinylic isomer (3) and the dihydro allylic phosphine (4).

36


Figure 6: Temperature dependence on reaction time and selectivity for the reaction with 5 mol-% 1,

1,3-diphenylallyl acetate as substrate, diphenylphosphine as nucleophile, triethylamine as base, and

1 mol-% DBU as additive in benzene.

Otherbyproducts

Diphosphine

Product

Figure 7: Temperature dependence of the product distribution for the reaction with 5 mol-% 1,

1,3-diphenylallyl acetate as substrate, diphenylphosphine as nucleophile, triethylamine as base, and

1 mol-% DBU as an additive in benzene. The vinylic phosphine (3) and reduced product (4) are con-

sidered to be "other byproducts" (see also section 3.2).

Substrates other than 1,3-diphenylallyl acetate have been tested, however with little success.

37


An aliphatic substrate, 1,3-dicyclohexylallyl acetate, gave only 20% yield and 40% ee.[4] Some

of the more challenging unsymmetrical substrates were equally unsuccessful.[5] Therefore, we

decided to focus our mechanistic research on the standard substrate.

3.2.2 Mechanistic Studies

3.2.2.1 General Remarks Scheme 43 shows the catalytic cycle of the palladium-catalysed

allylic substitution with soft (path a) and hard nucleophiles (path b/c) (see Scheme 43 and

also section 1.2.3).

R R

Nu

Pd

R

R

L

LX

II

Pd

R

RL

L

HX

0

NuH

Nu

*

R R

X

*

a

c

Pd

R

R

L

L II

Nu

NuHHXb

Scheme 43: Generally accepted mechanism of the palladium-catalysed allylic substitution with soft

nucleophiles (path a) and hard nucleophiles (path b/c).[33–35]

The catalytic cycle is entered by generating a PdII/π-allyl complex. We have started our inves-

tigations at this point in the cycle. In order to do so, different experiments were performed.

First of all, preliminary tests revealed that: a) there is no background reaction, i. e. there is

no conversion without catalyst; b) the oxidative addition of the substrate is reversible; this is

in line with previously reported work;[94–98] c) the dissociation of the product from the pal-

ladium complex is irreversible; d) diphenylphosphine is not deprotonated by triethylamine in

dichloromethane or benzene (no interaction detected by means of 1H- or 31P{1H}-NMR spec-

troscopy).

In the following, different mechanistic experiments will be discussed. At the end of the sub-

section, there will be a conclusion and a potential mechanistic model will be presented.

38


3.2.2.2 The Stoichiometric Reaction Under catalytic conditions, many components are

present in various concentrations in the reation mixture. In order to simplify the situation,

we have performed three different stoichiometric reactions involving [Pd(η3-1,3-Ph2Allyl)(κ2-

Josiphos)]SbF6 (1).

[Pd(η3-1,3-Ph2Allyl)(κ2-Josiphos)]SbF6 (1) + 1 eq HPPh2 + 1 eq NEt3. We have

started our investigations with an equimolar mixture of complex 1, diphenylphosphine, and

triethylamine. The corresponding 31P{1H}-NMR spectrum is shown in Figure 8.

75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0 ppm

69707172 ppm 343536 ppm 7.0 ppm

35

319319

24

35

24

3

-PPh2

-P(allyl)Ph2

-PCy2

Figure 8: 121.5 MHz 31P{1H}-NMR spectrum of the reaction mixture containing 1 eq complex 1, 1 eq

diphenylphosphine, 1 eq triethylamine. Coupling constants are given in Hz.

39


−3 −4 −5 −6 −7 −8 −9 ppm

17

182

13

192

Figure 9: 300 MHz 1H-NMR spectrum of the hydride region of the reaction mixture containing 1 eq

complex 1, 1 eq diphenylphosphine, and 1 eq triethylamine. Coupling constants are given in Hz.

ppm

12345678

−5

75

70

65

60

55

50

45

40

35

30

25

20

15

10

5

0

−5 −6 −7 ppm

free 1,3-Ph2AllylPPh2

PPh2 (Josiphos)

coordinated 1,3-Ph2AllylPPh2

PCy2 (Josiphos)

SbF6

Fe

PPh2

Cy2P Pd

HPh2P

Ph

Ph

Figure 10: 300 MHz 1H,31P-HMQC NMR spectrum of the reaction mixture containing 1 eq complex

1, 1 eq diphenylphosphine, 1 eq triethylamine. Cross-peaks of the major species are highlighted. The

proposed structure is depicted.

40


The 31P{1H}-NMR spectrum shows, in addition to the signals of 1 at 59 ppm and 17 ppm, many

different species, including the allylic phosphine (2) at –2 ppm. The main signals are assigned

as follows: δ 70.1 (dd, JPP = 319, 35 Hz, PCy2), 34.5 (dd, JPP = 319, 24 Hz, P(allyl)Ph2),

7.0 (ddd‡, JPP = 35, 24, 3 Hz, PPh2). This spin system suggests a palladium complex fea-

turing κ2-Josiphos and κP1-1,3-diphenylallyl(diphenylphosphine) trans to the PCy2 group of

Josiphos. The 1H-NMR spectrum (Figure 9) shows two hydride species, of which one couples

to the major spin system mentioned previously. A 1H,31P-HMQC NMR spectrum (Figure 10)

shows the relevant cross-peaks for this assignment. Most importantly, the phosphorus signal

at 34.5 ppm shows correlations to aromatic and allylic protons (compare the chemical shifts of

the allylic protons in the free and coordinated 1,3-Ph2AllylPPh2). Therefore, the coordination

of the allylic phosphine (2) could be proven. Since this reaction mixture is highly dynamic

and many species are involved, no complete assigment could be made. However, for the main

species we propose a Pd/κ2-Josiphos complex with ligand 2 trans to the PCy2 group of Josiphos

and a hydride ligand cis to the PCy2 group (see Scheme 44).

[Pd(η3-1,3-Ph2Allyl)(κ2-Josiphos)]SbF6 (1) + 5 eq HPPh2. A further simplification of

the system led us to the equimolar reaction of complex 1 with diphenylphosphine, since the

product is not formed in the absence base. And indeed new species could be detected by31P{1H}-NMR, however the signals were weak and broad. When the amount of diphenylphos-

phine was increased to 5 eq, a new complex dominated the 31P{1H}-NMR spectrum (Figure

11). The three major signals couple with each other and form a spin system. 1H,31P-HMQC

NMR and 31P-NMR (1JPH = 372 Hz allowed the identification of κ1-PHPh2) lead to the follow-

ing assignment: δ 81.2 (dd, JPP = 395, 8 Hz, PCy2), 26.1 (dd, JPP = 19, 8 Hz, PPh2), 2.8 (dd,

JPP = 395, 19 Hz, HPPh2). Interpretation of the spectra leads to the following conclusion:

it is a palladium-complex with a κ2-Josiphos ligand and a κ1-HPPh2 trans to the PCy2 group

of Josiphos. In addition, the allyl ligand is still present, and most probably it is binding as

η1-ligand. This was suggested by comparison of the 1H- and 13C-NMR chemical shifts of the

allyl nuclei with literature values of a similar compound (δ (1H) = 4.00 ppm for Pd-CHallyl,

lit: δ (1H) = 3.93 ppm; δ (13C) = 55.2 ppm for Pd-CHallyl, lit: δ (13C) = 46.7 ppm).[99] From

the small coupling constant of the two Josiphos phosphorus nuclei (JPP = 8 Hz compared to

JPP = 38 Hz in the free ligand), we assume a distorted square-planar coordination geometry

(see Scheme 44).

The 1H-NMR spectrum revealed a minor hydride species (Figure 12). This may arise as a con-

‡In addition to the two expected P,P couplings, this signal shows a third coupling of 3 Hz. This is due to

incomplete proton decoupling (the hydride resonance is significantly different from the carrier frequency of the

decoupling irradiation and JPH = 182 Hz is large).

41


sequence of the dehydrocoupling of diphenylphosphine (Ph2P–PPh2 is observed at –15 ppm in

the 31P{1H}-NMR spectrum, Figure 11) or the result of oxidative addition of a P-H bond before

or after the attack of diphenylphosphine on the allyl, forming allylic phosphine 2 (which is

observed at –2 ppm in the 31P{1H}-NMR spectrum).

−40−30−20−1080 70 60 50 40 30 20 10 0 ppm

81.081.582.0 ppm 26.026.5 ppm 234 ppm

8

39519 395

8 19

-PHPh2-PPh2-PCy2

SbF6

Fe

PPh2

Cy2P Pd PHPh2

Ph Ph

Figure 11: 283.4 MHz 31P{1H}-NMR spectrum of the reaction mixture containing 1 eq complex 1 and

5 eq diphenylphosphine. Coupling constants are given in Hz. The proposed structure is depicted.

−4.0 −4.5 −5.0 −5.5 −6.0 −6.5 −7.0 ppm

190

Figure 12: 700 MHz 1H-NMR spectrum of the reaction mixture containing 1 eq complex 1 and 5 eq

diphenylphosphine in the hydride region. The coupling constant is given in Hz.

42


[Pd(η3-1,3-Ph2Allyl)(κ2-Josiphos)]SbF6 (1) + 1 eq PMe3. Since we have observed that

trimethylphosphine is an efficient "isomerisation catalyst" (see section 2.3.3), we have inves-

tigated the equimolar mixture of complex 1 and PMe3. Figure 13 shows the 31P{1H}-NMR

spectrum of this mixture. The dominant signals at 59 ppm and 17 ppm are attributed to com-

plex 1. A minor species, with a similar signal pattern could be observed: δ 83.1 (dd, JPP = 45,

11 Hz, PCy2), 27.3 (dd, JPP = 19, 11 Hz, PPh2), –10.0 (dd, JPP = 415, 19 Hz, PMe3).

In this case, we assume a palladium-complex with a κ2-Josiphos ligand and a κ1-PMe3 trans

to the PCy2 group of Josiphos is present. Again, the allyl ligand is still present, and also in this

case, it is most probable that the binding mode is η1. The coupling constant of the Josiphos

phosphorus nuclei also suggests a distorted square-planar coordination geometry (see Scheme

44).

−1090 80 70 60 50 40 30 20 10 0 ppm

82838485 ppm 27.027.5 ppm −8 −10 ppm

415

11

19

19

415

11

-PCy2-PPh2

-PMe3

SbF6

Fe

PPh2

Cy2P Pd PMe3

Ph Ph

Figure 13: 121.5 MHz 31P{1H}-NMR spectrum of the reaction mixture containing 1 eq complex 1 and

1 eq trimethylphosphine. Coupling constants are given in Hz. The proposed structure is depicted.

43


Concluding Remarks. In all three cases we have observed an additional phosphorus lig-

and trans to the PCy2 group of Josiphos (Scheme 44). If we assume η1-allyl complexes are

formed, this would imply a cleavage of the Pd-η3-allyl bond trans to PCy2 of Josiphos and

subsequent coordination of the additional phosphine at that site. Interestingly, in all reported

isomerisation studies of Pd/Josiphos complexes, a selective cleavage of the Pd-allyl bond cis to

the PCy2 group was found.[78–80,82,87]

SbF6

Fe

PPh2

Cy2P Pd

HPh2P

Ph

Ph SbF6

Fe

PPh2

Cy2P Pd PHPh2

SbF6

Fe

PPh2

Cy2P Pd PMe3

Ph Ph Ph Ph

Scheme 44: Proposed structures for the three investigated stoichiometric mixtures. Left: 1 + HPPh2

+ NEt3; middle: 1 + 5 eq HPPh2; right: 1 + PMe3.

3.2.2.3 Kinetics We decided to use 31P{1H}-NMR spectroscopy for kinetic measurements.

Since the reaction is slow (ca. 7 h), this technique could be applied conveniently. Although the

signal-to-noise ratio is not as good as in 1H-NMR spectroscopy, the data quality was acceptable

because the reaction was performed at a high enough concentration (0.05 M in complex 1 and

between 0.50 M and 3.00 M in nucleophile and base). The pulse program was modified to

include proton decoupling during pulsing and aquisition. A loop with a delay was built in, in

order to record a spectrum every 2 min.

We chose pseudo first-order conditions using the isolation method. Therefore the catalyst con-

centration was kept constant while the concentration of nucleophile and base were in at least

10-fold excess and varied across a series of experiments (see section 6.2.1.2 for experimental

details).

Base Dependence. Scheme 45 shows the conditions used for the base-dependent kinet-

ics. Complex 1 was used at a constant concentration (0.05 M), diphenylphosphine was in

10-fold excess (0.50 M), and the concentration of triethylamine was varied between 10 and

60 eq (0.50 to 3.00 M). The analysis of the signal area of complex 1 at 59 ppm was used to

generate a reaction profile. Scheme 46 shows two spectra at different times.

44


SbF6

Fe

PPh2

Cy2P Pd

PhPh

NEt3 HPPh2

internalstandard

CH2Cl2 Ph Ph

PPh2

1 eqconstant0.05 M

0.025 mmol

10 eqconstant0.50 M

0.250 mmol

10 - 60 eqin steps of 10 eq

0.50 - 3.00 M0.250 - 1.500 mmol

Scheme 45: Reaction conditions for the base dependent kinetic runs.

−40−30−20−1060 50 40 30 20 10 0 ppm

A B C DE F G H I J K

t = 418 min

t = 2 min

Scheme 46: 202.5 MHz 31P{1H}-NMR spectra of a kinetic run. Bottom: spectrum no. 2 (t = 2 min);

top: spectrum no. 210 (t = 418 min). The signals are assigned as follows: A,D) complex 1, B,F)

[Pd(Josiphos)(HPPh2)n], C) HP(O)Ph2, E,J) free Josiphos, G) internal standard (P(O)(OMe)3), H)

allylic phosphine 2, I) Ph2P-PPh2, K) HPPh2.

It is interesting to see that under these conditions a new complex (signals B and F) is formed.

45


NMR analysis suggested it to be [Pd0(κ2-Josiphos)(κ1-PHPh2)n] (n = 1 or 2). In the presence

of an excess of HPPh2 it is not surprising that this complex is formed after the allyl ligand is

attacked and released as product 2. The signal of complex 1 at 59 ppm (signal A in Scheme

46) is well separated and therefore ideal for analysis. This signal was used to calculate the

raction rates at different concentrations. A plot of reaction rate vs. triethylamine concentra-

tion (Figure 14) shows no real base dependence. The values are scattered in a range between

0.7·10−4 and 2.3·10−4 s−1. The reaction was quite sensitive to small perturbations of the sys-

tem, therefore the reproducibility was not optimal. However, the amplitude of the scattering

is not so large when compared to the data of the phosphine dependent runs (Figure 15).

0 0.5 1 1.5 2 2.5 3 3.50

1

2

Triethylamine conc. [M]

reac

tion

rate

[10-

4 /s]

Figure 14: Kinetic plot of the base-dependent runs. An NEt3 concentration of 0.5 M corresponds to

10 eq, 3.0 M corresponds to 60 eq.

Nucleophile Dependence. In this case, analogous conditions to those used to study base

dependence were applied (Scheme 47). Complex 1 and triethylamine were kept at constant

concentrations, whereas the phosphine concentration was varied from 10 to 60 eq. Analysis

of the complex 1 resonance at 59 ppm yielded the kinetic plot shown in Figure 15.

46


SbF6

Fe

PPh2

Cy2P Pd

PhPh

NEt3 HPPh2

internalstandard

CH2Cl2 Ph Ph

PPh2

1 eqconstant0.05 M

0.025 mmol

10 eqconstant0.50 M

0.250 mmol

10 - 60 eqin steps of 10 eq

0.50 - 3.00 M0.250 - 1.500 mmol

Scheme 47: Reaction conditions for the phosphine dependent kinetic runs.

0 0.5 1 1.5 2 2.5 3 3.50

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Diphenyl phosphine conc. [M]

reac

tion

rate

[10-

4 /s]

Figure 15: Kinetic plot of the nucleophile-dependent runs. A HPPh2 concentration of 0.5 M corre-

sponds to 10 eq, 3.0 M corresponds to 60 eq. The change of the slope of the curve is at 1.5 M or 30 eq

diphenylphosphine.

This plot shows two different rate dependences. At first a change in mechanism was assumed,

but it is important to keep in mind the reaction conditions and the origin of the data. This

47


plot represents the reaction rates obtained from the degradation of the signal of complex 1 in

the presence of a high phosphine concentration. Consequently, this is not a kinetic plot of the

allylic phosphination reaction, but rather of the "decomposition" of complex 1 in the presence

of excess of phosphine. In the presence of large amounts of diphenylphosphine, complex

1 reacts to [Pd0(κ1-PHPh2)4]. Under catalytic conditions (5 mol-% catalyst, meaning 20-fold

excess of HPPh2), the complex is stable, however at 60-fold excess of HPPh2, [Pd0(κ1-PHPh2)4]

is formed rapidly. This is also supported by the fact that the crystals found in the NMR tube

after the reaction with 60 eq HPPh2 proved to be [Pd0(κ1-PHPh2)4] by X-ray analysis (Figure

16). From Figure 15 we conclude that the maximal excess of phosphine, under which complex

1 is stable enough, is 30-fold, i.e. the minimal catalyst loading is 3.3 mol-%.

Figure 16: Stereoscopic ORTEP representation of [Pd0(κ1-PHPh2)4]. Hydrogen atoms on the phenyl

rings are omitted for clarity. Thermal ellipsoids are set at 50% probability. The structure has not been

completely refined as it has already been published. Selected bond distance: Pd–P 2.3213(6) Å.[100]

In chemistry, varying colours are always important indicators of change. In the palladium-

catalysed allylic phosphination with catalyst 1, the inital solution is coloured orange from

the catalyst complex. Over the course of the reaction, it changes to violet (see also Figure

17). The colour change might be partially explained by the formation of small amounts of

[Pd0(κ1-PHPh2)4] (this is supported by the fact that in the course of the reaction Josiphos is

liberated). As soon as the phosphine concentrations is lowered (by conversion to the product),

this PdL4 complex seems to dissociate in a equlibrium reaction to PdL3 and PdL2 complexes

more efficiently than back to a Pd/Josiphos complex (Scheme 48). The PdL4 complex, which

is stable in the presence of excess of L, is yellow. However, PdL3, PdL2 subsequently form

48


polynuclear L-bridged complexes that are intensively coloured. A yellow [Pd0(κ1-PHPh2)4]

crystal gives a dark violet solution when redissolved in absence of phosphine.[100,101]

Figure 17: NMR tubes with internal standard capillaries after phosphine-dependent kinetic runs. From

left to right: 10 eq, 20 eq, 30 eq, 40 eq, 50 eq, 60 eq HPPh2. In the case of 60 eq, crystals of [Pd0(κ1-

PHPh2)4] are visible at the bottom of the tube.

PdL4 PdL3 PdL2+L

-L

+L

-L

PPd Pd

PPPPh

HPh

Ph

HPh

PhPh

PhPh

Scheme 48: PdL4 complexes tend to dissociate ligands in solution. The equilibrium between PdL4,

PdL3, and PdL2 depends on the ligand and conditions. PdL3 and PdL2 complexes may additionally

form various intensively coloured polynuclear L-bridged complexes, as depicted for the case where L =

PHPh2.[100,101]

49


Concluding Remarks. The kinetic runs did not lead to a successful determination of

the rate law of the allylic phosphination because phosphines are good ligands for palladium,

thereby poisoning the complex under the conditions used for kinetic investigations (formation

of [Pd0(κ2-Josiphos)(κ1-PHPh2)n] (n = 1 or 2) in the base-dependent runs and formation of

[Pd0(κ1-PHPh2)4] in the nucleophile-dependent runs). In order to correctly determine rates,

it would be necessary to use complex 1 in excess. However, since this would be very material-

and cost-intensive, we did not perform such investigations. At least in NMR, concentration

(sensitivity) problems would arise if the complex concentration would be lowered to an ac-

ceptable level. Therefore, other spectroscopic methods would have to be applied.

3.2.2.4 Classification of Diphenylphosphine The Fiaud experiment was designed to clas-

sify nucleophiles (see also subsection 1.3). "Soft" nucleophiles attack the allyl ligand directly

at the face opposite to the metal, whereas "hard" nucleophiles first coordinate to the metal

centre and then intramolecularly attack the allyl. In order to determine whether a nucleophile

is soft or hard, a sterically hindered allyl ligand was designed.[76] Soft nucleophiles will there-

fore not react, but hard nucleophiles are expected to attack the allyl from the metal side (see

Scheme 49).

AcO H[Pd]

[Pd0]

- OAc-Ph2P H

H PPh2

[Pd]

PHPh2

HPPh2external attack

- [Pd0]- H+

internal attack

- [Pd0]- H+

HPPh2

Scheme 49: Concept for the classification of diphenylphosphine with the Fiaud acetate (11).[76]

Diphenylphosphine was classified according to this idea. Experimentally, this was carried out

as a competition experiment between the unhindered cyclopentenyl acetate and the sterically

hindered Fiaud acetate (11) under standard catalytic conditions (Scheme 50).

50


AcO HAcO

5 mol-%[Pd(Josiphos)(1,3-Ph2Allyl)]SbF6

NEt3, CD2Cl2, rt Ph2P H PPh2

0.5 eq 0.5 eq 1 eq

HPPh2

48% 0%

Scheme 50: Competition experiment for the classification of diphenylphosphine.[76]

The reaction mixture was kept at room temperature for 2 days before it was worked-up and

analysed. Cyclopentenyldiphenylphosphine was isolated in 48% yield, and 70% of the unre-

acted Fiaud acetate could be recovered. No Fiaud phosphine could be detected (for experi-

mental details see subsection 6.2.1.2). Therefore, diphenylphosphine was classified as soft

nucleophile, i. e. it attacks the allyl ligand in an outersphere mechanism.

3.2.2.5 Site of Attack A series of experiments was designed to determine at which

allyl terminus (cis or trans to the PCy2 group of Josiphos) of which isomer of [Pd(η3-1,3-

Ph2Allyl)(κ2-Josiphos)]SbF6 (1) the nucleophile attacks preferentially (see Scheme 51).

PdFeP P Pd

FeP P

endo-syn-syn exo-syn-syn

Kiso

Ph Ph

PPh2

PhPh

PPh2 PhPh

PPh2

Ph Ph

PPh2(R) (R)(S) (S)

kendo,ciskendo,trans kexo,trans kexo,cis

Scheme 51: Scheme for the determination of the site of attack. The two isomers endo-syn-syn-1 and

exo-syn-syn-1 are in equilibrium (Kiso). The descriptors cis and trans are relative to the PCy2 group of

Josiphos.

51


In a simplified model, we consider only the major isomers of complex 1, namely endo-syn-syn-

1 and exo-syn-syn-1. These two isomers make up 98% of the species obseved in solution of

1 (see also subsection 2.3.1). If we assume a negligeable equilibration rate between the two

isomers under these conditions, it is possible to calculate the relative rates of attack from the

ratio of these two isomers and the enantiomeric ratio of the products obtained (Scheme 51

and Equation (2)).

Kiso =[exo-syn-syn-1][endo-syn-syn-1]

(1)

[(R)-2][(S)-2]

=[endo-syn-syn-1]kendo,cis + [exo-syn-syn-1]kexo,t rans

[endo-syn-syn-1]kendo,t rans + [exo-syn-syn-1]kexo,cis

=[endo-syn-syn-1]kendo,cis + Kiso[endo-syn-syn-1]kexo,t rans

[endo-syn-syn-1]kendo,t rans + Kiso[endo-syn-syn-1]kexo,cis

=kendo,cis + Kisokexo,t rans

kendo,t rans + Kisokexo,cis

(2)

exo/endo (= Kiso)

enan

tiom

eric

ratio

R/S

°

°° °

°

°

°°

0.8 1.0 1.2 1.4 1.6

4

6

8

10

12

14

16

Figure 18: Plot of the data points obtained and the curve fitting. The dashed lines mark the error

estimates. The data point at (1.23, 14.97) was considered to be an outliner and was not accounted for

in the fit. Due to measuring uncertainties in both dimensions, the data quality is poor and the results

of the fit have to be taken only as a hint for the order of magnitude and not as absolute values.

52


We have performed a series of experiments starting with different endo/exo ratios of [Pd(η3-

1,3-Ph2Allyl)(κ2-Josiphos)]SbF6 (1). The results of these experiments have to be analysed

with care. A number of assumptions and simplifications were made and some of them may

lead to (more or less) large errors: a) there are eight possible isomers of 1 in solution. It is

therefore questionable if the minor isomers (< 2% composition) can be neglected although

this has already been proposed in the literature.[82] b) under experimental conditions, the

isomerisation between endo-syn-syn-1 and exo-syn-syn-1 cannot be completely ignored, as

diphenylphosphine itself acts as "isomerisation catalyst". c) endo-syn-syn-1 seems to be in

exchange with a minor isomer (indicated by broad signals in 31P-NMR[82]).

A manual, non-linear fitting of the parameters to Equation (2) (see Figure 18) gave the

following relative rates:§

kendo,cis = 100± 5

kendo,t rans = 2.5± 0.5

kexo,cis = 9± 2

kexo,t rans = 12± 1

From the fitted data it can be said that the attack of the nucleophile takes place preferentially

cis to the PCy2 group of endo-syn-syn-1. The attack on both allyl termini of exo-syn-syn-1 is

much slower, therefore, mainly (R)-2 is formed. This is not in agreement with the 13C chemical

shift criterion mentioned by Pregosin and co-workers in 1995.[82] They have correlated the 13C

chemical shift of the allyl termini with the site of attack. It was assumed that the carbon with

a shift of 96.4 ppm (trans to PCy2 in exo-syn-syn-1) would be attacked preferentially, whereas

the two carbons with almost identical shifts, 89.6 ppm and 90.2 ppm (both allyl termini in

endo-syn-syn-1), would be attacked at about the same rate. However, Pregosin and co-workers

have investigated carbon nucleophiles and not phosphines. Moreover, NMR chemical shifts

are thermodynamic properties and must not relate to kinetic data.

In the presence of "isomerisation catalysts", such as PMe3 (see subsection 2.3.3), equilibriation

to the thermodynamic ratio, endo/exo = 0.6:1, is accelerated. In agreement with the data

shown in Figure 18, this leads to a lowered enantioselectivity.

3.2.2.6 Proposed Mechanism From the mechanistic experiments described above, we pro-

pose the catalytic cycle depicted in Scheme 52. Diphenylphosphine is not deprotonated by tri-

ethylamine under reaction conditions. The nucleophile attacks the coordinated allyl opposite

§The quality of the data is poor due to measuring uncertainties in both dimensions. The data fit was performed

manually and the obtained values should only be a hint for the order of magnitude of the rates.

53


to the metal, preferentially cis to the PCy2 of endo-1, thereby reducing the metal centre. Most

probably, the resulting phosphonium cation is then deprotonated before the product is released

and a new substrate molecule can be oxidatively added to close the cycle. Coordinating addi-

tives, such as PMe3, accelerate the reaction but lower the selectivity (see subsection 3.2.1). If

we assume the dissociation of the product to be rate-limiting (which is likely, since the prod-

uct is a ligand), then the addition of small, weakly coordinating additives may accelerate the

dissociation of the product and therefore increase the overall reaction rate. The decrease in

selectivity may be explained by the fact that a thermodynamic mixture of 1 (endo/exo = 0.6:1)

leads to a lower enantiomeric excess (see Figure 18).

Ph Ph

PPh2

Pd

Ph

Ph

Ph2P

Cy2P II

Pd

Ph

Ph

Ph2P

Cy2P

+HNEt3

0

Ph2P

Ph Ph

OAc

*

*

Pd

Ph

Ph

Ph2P

Cy2P 0Ph2P

*

H

NEt3

HPPh2

Scheme 52: Proposed catalytic cycle for the palladium-catalysed allylic phosphination with

diphenylphosphine as nucleophile.

3.3 Asymmetric Allylic Phosphination with Secondary Phosphine Oxides

As mentioned in the introduction to this section (3.1) and in Scheme 39, secondary phos-

phine oxides are able to tautomerise to the corresponding trivalent phosphinous acid.[89]

Diphenylphosphine oxide is slightly more acidic than diphenylphosphine (pKa(HP(O)Ph2) =

20.6, pKa(HPPh2) = 22.9, values in DMSO solutions[102]). The phosphinous acid posesses a

lone pair and is therefore a potential nucleophile. As a preliminary experiment, we allylated

54


diphenylphosphine oxide in benzene (see Scheme 53).

Ph Ph

OAcHP(O)Ph2

5 mol-% catalystNEt3

C6D6 or CD2Cl2additive, 0.32 M

Ph Ph

PPh2O

Scheme 53: Reaction scheme for the allylation of diphenylphosphine oxide with catalyst 1 yielding 12.

ppm 56 52 48 44 40 36 32 28 24 20 16 12 8 4 0 -4 -8

A EDCB

Figure 19: 121.5 MHz 31P{1H}-NMR spectrum of a typical reaction mixture of the allylic phosphination

with diphenylphosphine oxide in benzene. Assignment of the signals: A,D) catalyst 1, B) product 12,

C) diphenylphosphine oxide, E) internal standard trimethylphosphate.

Interestingly, diphenylphosphine oxide is soluble in benzene, whereas the allylation product

(12) is poorly soluble. Therefore, product 12 precipitates from the benzenic reaction solution

(Figure 19). After filtering and washing with benzene and pentane, an analytically pure com-

pound is obtained. Furthermore, the enantiomeric excess of 12 was determined to be > 99%.

Figure 20 shows a 1H-NMR spectrum of the allylic phosphine oxide (12).

55


ppm 8.2 8.0 7.8 7.6 7.4 7.2 7.0 6.8 6.6 6.4 6.2 6.0 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0

ab c

Figure 20: 300 MHz 1H-NMR spectrum of the allylic phosphine oxide 12 in CD2Cl2. Assignment:

Ph–CHa(P(O)Ph2)–CHb=CHc–Ph.

3.3.1 Catalytic Scope

Since the reaction works with air-stable phosphine oxides, we also tried to run the reaction

under atmospheric conditions. And indeed, even in wet solvents, no reduced reactivity or

selectivity were observed.

Although the product is easily isolated in pure form, the reaction has a drawback. The isolated

yield never exceeded 25%. After a few hours of reaction time, the benzenic solution started

to get cloudy. After 24 h a massive white precipitate (which alomst completely solidifies

the reaction mixture) could be isolated. However, it was far from an acceptable yield. The

reaction seems to stall at a certain point. Even if a first portion of product was filtered off, only

very little product was formed and precipitated after that. The reaction was also carried out

in dichloromethane. The reaction failed to proceed to full conversion in this solvent as well.

Additionally, a soluble product cannot be isolated by filtration and the isolation method used

in the reaction with diphenylphosphine as nucleophile could not be applied. That method

relied on the low polarity of the product compared to the catalyst complex. In the case of

the allylic phosphine oxide, both the product and the catalyst are very polar and can not be

separated in a satisfactory manner. Therefore, the reaction solution in dichloromethane had

to be concentrated and the product isolated by crystallisation from benzene.

56


In order to exclude solubility issues, we have performed the reaction in different mixtures of

benzene and dichloromethane, therefore regulating the solubility properties of the reaction

medium. Figure 21 summarises the results. The solubility of product 12 drops from 26 mg/mL

in pure CH2Cl2 to 6 mg/mL in pure C6H6. However, no correlation between the solubility and

the conversion of the reaction after 24 h could be found.

Figure 21: Solubility of 12 in mixtures of C6H6 / CH2Cl2 and the corresponding conversions of the

allylic phosphination with diphenylphosphine oxide after 24 h.

Table 3 shows the results of catalyses with different solvent and base systems. As mentioned

above, no yield greater than 25% was observed. However, the observed enantiomeric excess

was > 99% in all cases. One has to analyse these results carefully. In every case, the product

had to be isolated by crystallisation (for the reasons mentioned above). Recrystallisation of

compounds with high enantiopurity may result in an increase thereof. We have observed

this effect directly. A sample of allylic phosphine oxide 12 with 88% ee can be recrystallised

to increase its enantiopurity to 99% ee. Therefore, the enantiomeric excess observed in the

catalyses with diphenylphosphine oxide may not be a true measure of selectivity.

57


Solvent Basea Additivea Yield ee

1 C6D6 NEt3 – 25% > 99%

2 C6D6 NEt3 1 mol-% DBU 24% > 99%

3 CD2Cl2 NEt3 1 mol-% DBU 22%b > 99%

Table 3: Representative catalytic results (see also Scheme 53). Reaction conditions: 5 mol-% cata-

lyst 1, 1,3-diphenylallyl acetate as substrate, diphenylphosphine oxide as nucleophile, agitated at rt.

Isolated yields after 24 h. aif not indicated differently, 1 eq was used. bafter 24 days.

3.3.2 Proposed Mechanism

We have classified diphenylphoshpine oxide according to the method of Fiaud and co-workers

(see also see subsection 3.2.2.4 and Scheme 49).[76] The reaction conditions are given in

Scheme 54 (experimental details in subsection 6.2.1.2).

AcO HAcO


NEt3, CD2Cl2, rt Ph2P H PPh2

0.5 eq 0.5 eq 1 eq

HP(O)Ph2

OO

77% 0%

Scheme 54: Competition experiment for the classification of diphenylphosphine oxide.[76]

The Fiaud acetate (11) was not converted at all and 91% thereof could be recovered.

Cyclopentenyl acetate reacted with diphenlphosphine oxide and yielded 77% cyclopen-

tenyldiphenylphosphine oxide. Therefore, diphenylphosphine oxide was classified as soft

nucleophile.

From the results presented, and in analogy to the allylic phosphination with diphenylphos-

phine, a catalytic cycle according to Scheme 55 is proposed. As for diphenylphosphine, there

is no detectable interaction between the nucleophile and the base. Attack of the phosphi-

nous acid tautomer on the coordinated allyl opposite to the metal generates a protonated η2-

coordinated allylic phosphine oxide which is deprotonated and dissociated. A new substrate

molecule is oxidatively added to regenerate the catalyst complex.

58

3.4 Determination of the Enantioselectivity

Ph Ph

PPh2

Pd

Ph

Ph

Ph2P

Cy2P II

Pd

Ph

Ph

Ph2P

Cy2P

+HNEt3

0Ph2P

Ph Ph

OAc

*

*

Pd

Ph

Ph

Ph2P

Cy2P 0Ph2P

*

OH

NEt3

HP

PhPh

OP

PhPh

OH

O

O

Scheme 55: Proposed catalytic cycle for the allylation of diphenylphosphine oxide.


We have established two methods to determine the enantiopurity of the allylic phosphine and

the allylic phosphine oxide. In the beginning we used NMR spectroscopy to measure the

enantiomeric excess of the allylic phosphine itself. Later on, HPLC conditions were found

for oxidised allylic phosphines. Both methods give the same numbers and are constistent[4,5]

In order to calibrate these methods, a racemic sample of the phosphine was needed. This

was prepared from 1,3-diphenylallyl acetate and diphenylphosphine in methanol catalysed by

[Pd(dba)2] (see subsection 6.2.1.1 for experimental details).

3.4.1 NMR

Fe PdNMe2

PPh2

Ph

Ph

Fe PdNMe2

Cl FePdMe2N

Cl

Ph Ph

PPh2 CD2Cl2

0.5 eq

Cl

Scheme 56: Coordination of allylic phosphine 2 to the enantiopure ferrocenyl-based derivatisation

agent 13.[4,5]

59


ppm 49.4 49.2 49.0 48.8

0.977

19.24

Figure 22: 121.5 MHz 31P{1H}-NMR Specturm of allylic phosphine 2 coordinated to the enantiopure

derivatisation agent 13. The two diastereoisomers resonate at 49.3 ppm (R,S,S) and 49.1 ppm (R,S,R).

The enantiomeric excess in this sample was determined to be 90%.

Figure 23: Stereoscopic ORTEP representation of allylic phosphine 2 coordinated to the enantiopure

derivatisation agent 13.[4,5] Hydrogen atoms are omitted for clarity. Thermal ellipsoids are set at 50%

probability. This X-ray structure was used to determine the absolute configuration of the phosphine.

In order to determine the enantioselectivity by means of NMR spectroscopy, an enantiopure

palladium complex (13) was used as derivatisation agent. The allylic phosphine coordinates to

palladium and forms two diastereomeric complexes which give rise to two sets of NMR signals.

In our case, 31P{1H}-NMR was very useful since the spectra are simple and uncrowded. We

60

3.5 The Allylic Phosphine

have used a ferrocene-based palladacycle (13) as precursor (see Scheme 56).[4,5] A 31P{1H}-

NMR spectrum of the diastereomeric complex obtained is shown in Figure 22. The two di-

astereoisomers resonate at 49.3 ppm (R,S,S) and 49.1 ppm (R,S,R). From the integrals of the

signals, the enantiomeric excess of 2 was calculated. Additionally, the complex was obtained

in form of single crystals that were subjected to an X-ray diffraction study (see Figure 23).

By this means, the absolute configuration of allylic phosphine 2 could be assigned to the 31P

chemical shifts of the diastereomeric complexes.[4,5]

3.4.2 HPLC

Because allylic phosphine 2 is an air-sensitive compound, the oxide (12) was subjected to

HPLC. Samples of 2 were originally oxidised by elemental sulfur,[4,5] and more recently by aq.

solutions of hydrogen peroxide after workup (for experimental details see subsection 6.2.1.1).

These compounds could easily be analysed by HPLC. Retention times for the phosphine sul-

fides: tR 125 min (S), 140 min (R); OJ, hexane / iPrOH = 75:25, 0.1 mL/min flow rate, 2 µL

injection volume.[4,5] Retention times for the phosphine oxides: tR 17.6 min (S), 20.3 min (R);

OD-H, hexane / iPrOH = 90:10, 0.5 mL/min flow rate, 5 µL injection volume.


3.5.1 General Properties

1,3-Diphenylallyl(diphenylphosphine) 2 is an air-sensitive, white solid. It can be easily crys-

tallised. Figure 24 shows a X-ray crystal structure thereof. A 1H-NMR spectrum of 2 is depicted

in Figure 26 on page 77.

Figure 24: Stereoscopic ORTEP represenation of allylic phosphine 2.[5] Hydrogen atoms are omitted

for clarity. Thermal ellipsoids are set at 50% probability.

61


3.5.1.1 Oxidation The allylic phosphine (2) can be oxidised to the corresponding sulfide

by reaction with elemental sulfur in THF.[5] Oxidation to the phosphine oxide (12) is accom-

plished by simply adding an aq. solution of hydrogen peroxide to a solution of phosphine 2

in THF (see also experimental section 6.2.1.1). The oxidised allylic phosphines were used to

determine the enantioselectivity of the reactions by HPLC (see subsection 3.4.2).

3.5.1.2 Reduction of the Phosphine Oxide The allylic phosphine oxide 12 was success-

fully reduced according to a procedure by Lemaire and co-workers.[103] The phosphine oxide is

thereby suspended with tetramethyldisiloxane and 10 mol-% [Ti(OiPr)4] in methylcyclohex-

ane (see Scheme 57 and experimental section 6.2.1.1 for details). The reaction is proposed

to involve a reduction by a titanium hydride complex generated from the silane via σ-bond

metathesis.

Ph Ph

PPh2O

H Si O Si H

10 mol-% [Ti(OiPr)4]

CyMe, 100 °C, 20 h Ph Ph

PPh21.3 eq

66%

Scheme 57: Ti-catalysed reduction of allylic phosphine oxide 12 with TMDS.[103]

3.5.1.3 Recrystallisation of the Phosphine Oxide As mentioned in subsection 3.3.1, the

allylic phosphine oxide obtained from the allylation of diphenylphosphine oxide in benzene,

showed a enantiopurity of> 99% ee. However, this may be due to the fact that recrystallisation

of enantioenriched compounds may lead to an improved enantiomeric excess. A sample of

allylic phosphine oxide 12 (88% ee) was recrystallised from benzene and the enantiomeric

excess of the crystalline fraction was found to be improved to > 99% ee.

3.5.1.4 Reactivity Towards Strong Bases In two experiments, we have reacted lithium

diphenylphosphide with allylic phosphine 2 and allylic phosphine oxide 12 (Scheme 58). In

the first case, 1,3-diphenylprop-1-ene and tetraphenyldiphosphine were obtained. This can be

rationalised by a nucleophilic attack of the phosphide on the diphenylphosphine group of 2

and subsequent cleavage of the P-Callyl bond.

62


Ph Ph

PPh2

1. LiPPh2 2. H2O

THF, 18 h, rtPh Ph

Ph Ph

PPh2O

Ph Ph

PR2O

rac

Ph2P PPh2

HPPh2

1. LiPPh2 2. H2O

THF, 18 h, rt

Scheme 58: Reactivity of allylic phosphine 2 and allylic phosphine oxide 12 towards lithium

diphenylphosphide.

Ph Ph

PPh2

1. tBuLi2. D2O

Et2O1.5 h, 0 °C to rt

Ph Ph

PPh2

Ph Ph

PPh2O

1. tBuLi2. D2O

Et2O1.5 h, 0 °C to rt Ph Ph

PPh2

OD

rac

no deuterationno racemisation

deuterationracemisation

Scheme 59: The allylic phosphine oxide (12) was deprotonated by tBuLi. After quenching with D2O,

qunatitative α-deuteration was found, and the compound had racemised.

In the second case, the phosphine oxide was not attacked, but the relatively acidic allyl pro-

ton was abstracted to form diphenylphosphine, and, after reprotonation during workup, the

racemised allylic phosphine oxide 12 was isolated.

In order to gain more insight into these unexpected reactions, we reacted both the allylic phos-

phine 2 and the allylic phosphine oxide 12 with tBuLi (Scheme 59). For the allylic phosphine

oxide the same reactivity as in the case with lithium diphenylphosphide was found. Interest-

ingly, allylic phosphine 2 did not react with tBuLi. Obviously, tBuLi is not nucleophilic enough

to attack the diphenylphosphine group.

3.5.2 Functionalisation

The olefin of allylic phosphine (2) can be transformed into a wide range of other groups. At-

taching a second phosphine to the backbone (e. g. by hydrophosphination) would give rise to

bidentate P,P-ligands with stereogenic carbon centres next to the phosphorus atoms (Scheme

63


60). Further, P,N-ligands could be accessible in this way. To the best of our knowledge, up to

now no such P,N-ligands with a chiral backbone have been reported except for two comparable

examples.[104,105]

Ph Ph

PPh2

Ph Ph

PPh2Ph2P

Scheme 60: Functionalisation of allylic phosphine 2 to a potential P,P-ligand.

Bidentate P,P-ligands of this type have already been described in the literature.[106–119]

Bis(diarylphosphino)pentanes (BDPP) were first reported in the early eighties. However, the

multistep synthesis of these ligands has not been improved significantly during the past three

decades. All reported procedures follow the same scheme: starting from 2,4-pentadione, ei-

ther hydrogenation or reduction with sodium borohydride yields the diol. This step is carried

out enantioselectively or the racemate produced is separated as diastereomeric sulfonic esters.

Subsequent substitution with secondary phosphide anions leads to the P,P-ligand. This syn-

thetic route in general leads to C2-symmetric ligands (two reported exceptions[106,114]). The

allylic phosphination could provide diverse carbon backbones which then could be completed

with different phosphines to give C1- or C2-symmetric ligands.

We have therefore tried to functionalise the olefin of the allylic phosphine 2 and the allylic

phosphine oxide 12. At first, we attempted to hydrophosphinate the double-bond with dicy-

clohexylphosphine (Scheme 61). However, no conversion at all was observed.

Ph Ph

EPh2

Ph Ph

EPh2Cy2PHPCy2 tBuOK

DMSO

16 h, rt

Scheme 61: Hydrophosphination attempt with E = P or P(O).[120]

Ph Ph

PPh2O

Ph Ph

PPh2OI1.3 M HI in AcOH

27 h, 120 °C

Scheme 62: First hydroiodination attempt. HI in AcOH was prepared from aqueous HI.[121]

64


Ph Ph

PPh2O 7.4 M aq. HI

22 h, 120 °C Ph Ph

PPh2OI

Scheme 63: Second hydroiodination attempt. 36% of the potential product was isolated but also the

alcohol and the reduced product were obtained.

We then tried to add hydrogen halides across the olefinic double bond. 1.3 M hydroiodic acid

in acetic acid did not yield the desired product, even after heating to 120 ◦C for 27 h (Scheme

62). Harsher conditions, 7.4 M aq. hydroiodic acid at 120 ◦C for 22 h, yielded 36% of a new

compound which might have been the desired product (Scheme 63). The compound slowly

decomposed and could not be completely analysed. However, as side products, the alcohol

and the reduced starting material were also obtained.

Ph Ph

PPh2O

Ph Ph

PPh2OIPMHS, I2

CHCl3, 30 h, rt

Scheme 64: Third hydroiodination attempt with a different HI source.[122]

Ph Ph

PPh2O

Ph Ph

PPh2OBr5.7 M HBr in AcOH

1 h, rt

Scheme 65: Attempted hydrobromination.

Another attempt to hydroiodinate 12 was performed with a different source of HI (Scheme

64). A combination of polymethylhydrosiloxane and elemental iodine, generating HI in situ,

was published as a mild method to prepare alkyl and alkenyl iodides.[122] However, this proce-

dure also failed to yield the desired product.. We then changed to hydrobromination (Scheme

65) which was unsuccessful as well.

We went further to explore epoxidation reactions. Scheme 66 shows the attempted Jacobsen

epoxidation with a manganese/Salen complex as catalyst precursor.[123] This experiment as

well as the attempted Shi epoxidation (Scheme 67) did not show any conversion.

65


Ph Ph

PPh2O

2 mol-% cat1.5 eq aq. NaOCl

CH2Cl2, 115 h, rt Ph Ph

PPh2OO

N N

O O

tBu

tBu

tBu

tBuMnCl

cat

Scheme 66: Attempted Jacobsen epoxidation.[123]

Ph Ph

PPh2O

1.4 eq oxone0.3 eq epoxone

0.04 eq [NBu4][HSO4]

Na2B4O7, Na2H2EDTAaq. K2CO3, THF, 1.5 h, rt Ph Ph

PPh2OO

Scheme 67: Attempted Shi epoxidation.[124]

Finally, we tried to hydrosilylate the olefin by palladium catalysis (Scheme 68), however, un-

successfully. And also a metathesis with a first-generation Grubbs catalyst was unsuccessfully

attempted. In this case, the formation of stilbene fails to drive the reaction toward desired

product. Usually, ethylene or other low-boiling olefins are formed which can be removed from

the solution easily, and therefore shift the equilibrium toward the desired product.

Ph Ph

PPh2O

1 mol-% [Pd(dba)2]1 mol-% PPh3

CH2Cl2, 24 h, rt Ph Ph

PPh2OCl3SiHSiCl3

Scheme 68: Attempted hydrosilylation.[125]

Ph Ph

PPh2O 5 mol-% cat

CH2Cl2, 24 h, 45 °C Ph

PPh2O

Ph

Ph2P O

PCy3

RuPCy3

PhClCl

cat

Scheme 69: Metathesis with a first-generation Grubbs catalyst.[126]

In conclusion, we have found no practical way to functionalise to allylic phosphines. Surpris-

66


ingly, it seems that the diphenylphosphine (oxide) group in allylic position strongly deactivates

the system.

3.5.3 Applications

3.5.3.1 As Ligand Since the functionalisation of the allylic phosphine (oxide) was unsuc-

cessful, its use as a mixed-donor ligand was considered.

PR2

Ph

OPPh2PdN CO2Me

CO2Me

Ar

Ph

Ph2P

Pd PhPh

PF6

Ph

Ph2P

RhCl

2

Fe PPh2

R

Scheme 70: Examples of P-olefin ligands and complexes used in catalysis. From left to right: top

row: used in Pd-catalysed Negishi coupling;[127] applied in Suzuki coupling, the olefin is essential;[128]

bottom: used in AAA;[129] used for 1,4-additions of boronic acids to maleimides;[130] applied in Pd-

catalysed AAA.[131]

Hemilabile ligands stabilise low-coordinate metal species without poisoning them. π-

accepting olefin moieties stabilise electron-rich and low oxidation state metals in catalytic

cycles. They are known to accelerate reductive elimination.[127,129–143] Scheme 70 shows

examples of γ,δ-unsaturated phosphines with applications in catalysis. As mentioned in sub-

section 3.2.1, the allylic phosphine 2 was also applied as ligand in the allylic phosphination

reaction, however, with low performance (see Scheme 71).[4]

HPPh2

10 mol-% [Pd(dba)2]10 mol-% Ph2AllylPPh2, NEt3

CH2Cl2, 40 °C, 52 h50% yield, 18% ee

Ph Ph

PPh2

Ph Ph

OAc

Scheme 71: Allylic phosphination with allylic phosphine 2 as ligand.[4]

67


This led us to the design of substrates for allylic phosphination that could give potential phos-

phine ligands. Two projects are presented in the following.

P,P,olefin Ligand. In order to improve the binding of the allylic phosphine to a metal

centre while still preserving the advantages of a hemilabile system, we decided to prepare a

P,P,olefin ligand via allylic phosphination as key step (Scheme 72).

PP

PhPh

PhH

PP

PhPh

H

O

PhO

PP

PhPh

Ph Ph

Ph**

PP

PhPh

PhH

O

Scheme 72: Targeted P,P,olefin ligand (14) to be prepared via allylic phosphination as key step from

three possible starting molecules (from left to right: diphosphine 15, diphosphine monooxide 16,

diphosphine dioxide 17).

Diphosphine dioxide 17 could be prepared by ortho-lithiation of triphenylphosphine oxide,

quenching with N,N-diethyl-P-phenyl-phosphonamidous chloride (18), and subsequent oxi-

dation in 35% overall yield (Scheme 73). It could be reduced to the diphosphine (15) with

trichlorosilane in 91% yield. However, the secondary phosphine oxide group in 17 could not

be selectively reduced to afford the monooxide (16) (Scheme 74).

PPh2P

OPh

N

Ph2P O 1. PhLi2. ClPPh(NEt2)

Et2O -25 °C

Ph2PPHPh

OOaq. HCl

Scheme 73: Synthetic route to diphosphine dioxide 17 starting from triphenylphosphine oxide (35%

overall yield).[144]

68


Ph2PPHPh

OO

HSiCl3pyr

PhMe

selectivereduction PPh2

PHPh

OPPh2PHPh

Scheme 74: Reduction of diphosphine dioxide 17 to diphosphine 15 with trichlorosilane in 91%

yield.[145] A successful method for the selective reduction of the secondary phosphine was not found.

Diphosphine dioxide 17 did not react with 1,3-diphenylallyl acetate under standard allylic

phosphination conditions. Diphosphine 15 did react under these conditions, however, in 1H-

NMR spectra, no allylic protons were detected. The reaction was not followed up any further

and the project was stopped at that point.

Phosphacyclopentenes. Phosphacyclopentenes are similar to a class of privileged lig-

ands, namely DuPhos (see Scheme 3), which has proven to be successful in palladium-

catalysed asymmetric allylic alkylation, rhodium-catalysed asymmetric hydrogenation, and

other prominent reactions.[146]

We planned to synthesise phosphacyclopentenes via an intramolecular allylic phosphination.

This would create stereogenic centres at phosphorus and the adjacent carbon atom. Depend-

ing on the substituent (R1 in Scheme 75), a mono- or bidentate ligand would be generated.

OAcR2HP R1 P

R2R1

** PR2 R1

**

ML

Lcat. Pd/Josiphos "ML2"

R1 = PHR2, OBnR2 = Ar

PPh PHPh

**PPh PPh2

**PPh OBn

**

Scheme 75: Proposed intramolecular allylic phosphination to give phosphacyclopentenes, a potentially

promising class of ligands.

For the synthesis of the substrates needed, alcohol 19 was prepared in two steps from pro-

tected D-mannitol (Scheme 76). The first target substrate we attempted to synthesise was the

symmetric diphosphine 20 (Scheme 77). We preferred a symmetrical substrate in order to

69


prevent regioselectivity issues during allylic phosphination (see also subsection 1.2.3.2).

OO

OO

OH

HO

OO O

OEt OO OH

1. NaIO4, aq. NaHCO32. (EtO)2P(O)CH2COOEt

6 M aq. K2CO3

DIBALH

CH2Cl2

Scheme 76: Synthesis of the starting alcohol 19 from protected D-mannitol.[147]

OO OH

OO Br

P

HO P PhH3B H

HPhBH3 P

AcO P PhH3B H

HPhBH3

PPh3, CBr4

Ac2O, DMAPpyridine

HOHO Br

BrHO Br

HCl, MeOH

PPh3, CBr4

PhP(BH3)H210% Bu4NBr

aq. KOH / PhMe

HOHO OH

PPh3, CBr4

HCl, MeOH

Scheme 77: Synthetic route to the symmetrical diphosphine substrate 20.[147–149]

70


OO OBn

HOHO OBn

BrHO OBn

P

HO OBn

HPhBH3

P

AcO OBn

HPhBH3

HCl, MeOH

PPh3, CBr4


aq. KOH / PhMe

Ac2O, DMAPpyridine

nBuLi, HMPABnBr

THF, -78°COO OH

TsOHO OBn

TsOTBDMSO OBn

TBDMSO OBn

PHPhBH3

TsCl

pyr, 0°C

TBDMSClDMF, K2CO3


aq. KOH / PhMe

TBAF

THF

Scheme 78: Synthetic route to the unsymmetrical benzylate substrate 21.[147–149]

O

OBr

O

OP N

HO

HOP H

O1. BuLi2. PhPCl(NEt2)

THF

aq. HCl

BnO

HOP H

O

BnO

AcOP H

O

pyridine, BnCl

Ac2Opyridine

Scheme 79: Attempted preparation of a unsymmetrical benzylate substrate 22 by electrophilic phos-

phination.

71


Alcohol 19 could be successfully deprotected yielding the corresponding triol. However, sub-

stitution of the primary alcohols with bromide could not be performed selectively. Also,

bromination of alcohol 19, deprotection, and repeated bromination failed reduce the num-

ber and amounts of undesired products. We therefore attempted to prepare the benzylic ether

monophosphine substrate 21 according to Scheme 78.

Alcohol 19 was first benzylated and the acetal group was cleaved to give the diol. The pri-

mary alcohol could not be selectively substituted by bromide, however, it could be selectively

tosylated. The remaining, secondary alcohol group was then protected with TBDMSCl. The

next step, nucleophilic substitution of the tosylate with a primary phosphine borane, was un-

successful. Thus, we tried to incorporate the phosphine group by electrophilic phosphination

(Scheme 79). The allylic bromide, prepared from alcohol 19, was lithiated and quenched with

a phosphine chloride. Workup with aqueous hydrochloric acid directly yielded the phosphine

oxide diol. However, the phosphination was low-yielding and not regioselective.

O

OOH

Ac2ODMAP

pyr O

OOAc

cat. Pd/JosiphosH2PPh, NEt3

CH2Cl2 O

OPHPh

Scheme 80: Attempted preparation of a unsymmetrical benzylate substrate 22 by allylic phosphination

with phenylphosphine.

As second electrophilic phosphination method, we tried to apply palladium-catalysed allylic

phosphination with phenylphosphine (Scheme 80). The reaction proceeded sluggishly and

unselectively, yielding linear and branched products.

Since no satisfying method to prepare the required substrates for intramolecular allylic phos-

phination was found, the project was stopped at that point.

3.5.3.2 Organocatalysis Recently, tertiary phosphines have also found applications in di-

verse processes as organocatalysts.[150–157] At first appearance, it seems interesting to use the

chiral allylic phosphine (2) as such a catalyst. However, it might not be suitable for this pur-

pose. Mechanistically, all of the above mentioned organocatalytic reactions have the common

feature that the substrate is covalently bonded to phosphorus, creating a tetravalent phospho-

nium group. This would most probably lead the the cleavage of the P-Callyl bond, generating a

neutral, tertiary phosphine and the 1,3-diphenylallyl cation. Allylic phosphine 2 was tested as

organocatalyst in a Michael addition according to Scheme 81.

72

3.6 Summary

O

O

O

OP

O

OO O

O

O

O

POEtOOEt

10 mol-% Ph2AllylPPh2

CH3CN, rt, 6.5 h

Scheme 81: Michael addition for the test of Ph2AllylPPh2 (2) as organocatalyst.[151]

After 6.5 h and even after more than 2 days at the given reaction conditions, no conversion

was observed. Therefore, we conclude that the allylic substituent on phosphorus of compound

2 makes it inapplicable as an organocatalyst.

3.6 Summary

Both phosphines and phosphine oxides are successfully allylated by the Pd/Josiphos system.

The catalytic scope is still limited, however, valuable insight into the mechanism was gained.

Both nucleophile types are classified as soft, meaning they attack the coordinated allyl oppo-

site to the metal. For diphenylphosphine as nucleophile, the attack takes place preferentially

cis to the PCy2 group of endo-1. Most probably, the dissociation of the product from the metal

is the rate-limiting step. Weakly coordinating additives may accelerate this step. However,

such additives also accelerate the allyl isomerisation of catalyst complex 1, and its thermo-

dynamic composition leads to a lower enantioselectivity in the allylic phosphination. In the

reaction with diphenylphosphine oxide as nucleophile, the product precipitates from the reac-

tion mixture in high enantiopurity. Since the enantiopurity of the allylic phosphine oxide can

be increased by recrystallisation, the effective enantioselectivity of the reaction could not be

determined.

The allylic phosphine is an air-sensitive compound which could not be functionalised at the

double-bond. Neither the application as ligand nor as organocatalyst has proven successful to

date.

73


74

4 Arsenic Nucleophile

4.1 Introductory Remarks

From Group 15 of the periodic table, the pnictogens, we have established phosphorus in addi-

tion to nitrogen centres as nucleophiles in allylic substitution reactions. For the next member

in the group, arsenic, preliminary tests were carried out. Organoarsenic chemistry has signif-

icant relevance in synthesis,[158] whereas the chemistries of organoantimony and organobis-

muth compounds play a minor role.[159–162]

4.2 Allylic Arsination

For preliminary tests, the standard substrate, 1,3-diphenylallyl acetate, and diphenylarsine

as nucleophile (see Scheme 82) were used in order to be able to directly compare the allylic

arsination with the allylic phosphination.

Ph Ph

OAc5 mol-%

[Pd(Josiphos)(1,3-Ph2Allyl)]SbF6

NEt3, C6D6, rtHAsPh2

Ph Ph

AsPh2

Scheme 82: Allylic arsination with diphenylarsine as nucleophile.

Diphenylarsine was prepared in analogy to the synthesis of diphenylphosphine. Triphenylar-

sine was reduced with potassium in 1,4-dioxane and then carefully quenched with water to

give a very air-sensitive liquid (see section 6.2.3 for details).[163]

In contrast to the phosphination reaction which could be conveniently followed by 31P{1H}-

NMR, 75As-NMR spectroscopy is not suitable to monitor the allylic arsination because the

relatively large quadrupolar moment (I = 3/2, Q = 31.4 fm2)[164] which allows reasonable

liquid state spectroscopy for highly symmetric compounds only.[165,166] However, the reaction

can be easily followed by 1H-NMR spectroscopy (see Figure 25). The allylic region of the

spectrum (6.80 ppm to 4.50 ppm) is very informative. The resonance of the HAsPh2 proton

appears at 4.99 ppm and can be followed without overlapping any other signals. In addition,

the three allylic signals of the substrate and product (23) are also well separated. This allows

for detailed tracking of the compounds involved. Figure 25 shows the disappearence of the

HAsPh2 proton and the substrate signals, and the appearance of the product signals over time.

75


4.64.85.05.25.45.65.86.06.26.46.6 ppm

t = 0.25 h

t = 1 h

t = 2 h

t = 14 h

acb

Figure 25: 300 MHz 1H-NMR spectra of the allylic region of an allylic arsination reaction mixture in

C6D6 at different times. The signal at 4.99 ppm corresponds to the HAsPh2 proton. The allylic signals

are assigned as follows: Ph–CHa(AsPh2)–CHb=CHc–Ph.

Figure 26 shows a comparison of the 1H-NMR spectra of the allylic phosphine (2) and the

allylic arsine (23). The allylic proton signals of the allylic phosphine show a coupling to

phosphorus in addition to the proton-proton couplings (2JPH = 5.4 Hz for the α-proton, 3JPH

= 6.5 Hz for the β-proton, and 4JPH = 2.5 Hz for the γ-proton). In the case of the allylic

arsine (23), no coupling to arsenic is visible (see also the singlet of the HAsPh2 proton in

Figure 25) due to the quadrupolar moment. Not surprisingly, the chemical shifts for both

substances are very similar.

76

4.2 Allylic Arsination

4.55.05.56.06.57.07.5 ppm

ab c

Figure 26: Comparison of the 300 MHz 1H-NMR spectra of the allylic phosphine (2, top) and the

allylic arsine (23, bottom). For the allylic phosphine, couplings of the allylic protons with phosphorus

are visible. Assignment: Ph–CHa(EPh2)–CHb=CHc–Ph.

Figure 27: Stereoscopic ORTEP representation of allylic arsine 23. Hydrogen atoms are omitted for

clarity. Thermal ellipsoids are set at 50% probability. Selected bond length: As1-C1 1.961(3) Å, for

comparison in allylic phosphine 2: P1-C1 1.873(2) Å (see Scheme 24).

As implied by the time scale in Figure 25 and Table 2, the allylic arsination is much faster than

the allylic phosphination. After 2 h at room temperature, the reaction has almost reached full

77


conversion, whereas the allylic phosphination requires about 120 h at 40 ◦C under otherwise

identical conditions. One explanation for this might be the fact that phosphorus is a much

better ligand donor for palladium than arsenic. This means that the allylic arsination is not

an exception with respect to reaction rate, but the allylic phosphination is exceptionally slow

(the allylic amination is also much faster than the allylic phosphination).

4.3 The Oxidation Problem

Organoarsenic(III) compounds are quite air-sensitive. Diphenylarsine readily oxidises upon

exposure to air giving diphenylarsinic acid, a white solid. The allylic phosphine (2) is also air-

sensitive but can be oxidised with sulfur or aqueous hydrogen peroxide to give the correspond-

ing phosphine sulfides or phosphine oxides, respectively, which are then used to determine the

enantioselectivity of the reaction (see sections 3.4.2 and 3.5.1). However, in the case of the

allylic arsines, such harsh conditions are not applicable. The arsenic atom is so oxophilic that

the rather labile As-Callyl bond is broken and diphenylarsinic acid is formed.¶ The cleavage of

the As-Callyl bond is additionally favoured by the formation of an allylic anion which is rather

stable. Even borane-protected arsines oxidise easily because the As-Callyl bond is so weak.[167]

4.4 Mechanistic Considerations

We have classified diphenylarsine according to the method of Fiaud and co-workers (see also

subsection 3.2.2.4 and scheme 49).[76] The reaction conditions are shown in Scheme 83

(experimental details are given in subsection 6.2.1.2). 57% of the unreacted Fiaud acetate

(11) could be recovered. Cyclopentenyl acetate was fully converted to cyclopentenyldipheny-

larsine and 83% thereof could be isolated. Therefore, we have classified diphenylarsine as

soft nucleophile.

AcO HAcO


NEt3, CD2Cl2, rt Ph2As H AsPh2

0.5 eq 0.5 eq 1 eq

HAsPh2

83% 0%

Scheme 83: Competition experiment for the classification of diphenylarsine.[76]

¶Single bond dissociation energies: C-N: 305 kJ/mol (72 kcal/mol), C-P: 264 kJ/mol (63 kcal/mol), C-As:

200 kJ/mol (48 kcal/mol).[162]

78


Ph Ph

AsPh2

Pd

Ph

Ph

P

P II

Pd

Ph

PhP

P

H+

0

Ph2As

*

Ph Ph

OAc

*

*

*

HAsPh2

Scheme 84: Proposed catalytic cycle for the Pd/Josiphos catalysed allylic arsination with diphenylar-

sine as nucleophile.

Based on the fact that the reaction does not proceed without a catalyst, the result of the Fiaud

experiment,[76] and the general aspects established for allylic substitution,[33–35] we propose

the catalytic cycle depicted in Scheme 84.


Because of the air-sensitivity of organoarsenic compounds, analytical studies of the al-

lylic arsine have to be carried out in the absence of air. Therefore, determination of the

enantiomeric excess of the allylic arsination by HPLC is not applicable. However, using

an enantiopure derivatisation agent in NMR spectroscopy is a valuable method and might

be applied in analogy to the allylic phosphine (see also subsection 3.4.1).[4,5] The use of

enantiopure palladium and platinum complexes as derivatisation agents were unsuccessful

because the corresponding products were dynamic in solution and showed exchange signals

in 1H-NOESY spectra (Scheme 85).[168] We therefore attempted to coordinate the arsine to an

enantiopure borane or borate which would have given diastereomeric complexes suitable for

NMR analysis. However, these experiments were unsuccessful. Until now, no method for the

determination of the enantiopurity of allylic arsines was found.

79


PtNMe2

PtMe2N

ClCl Pt

NMe2

Cl

PhPh

Ph2AsPh Ph

AsPh2 CD2Cl2

0.5 eq

Scheme 85: Allylic arsine 23 was coordinated to an enantiopure platinum complex for the purpose

of determining the enantiomeric excess by NMR spectroscopy. Due to dynamics this could not be

accomplished.

4.6 Summary

Diphenylarsine can be efficiently allylated with 1,3-diphenylallyl acetate under standard con-

ditions. The reaction proceeds to full conversion within 3 hours. It can be followed conve-

niently by 1H-NMR spectroscopy. The allylic arsine is very air-sensitive and oxidises readily

to diphenylarsenic acid upon exposure to air. Unfortunately, no method to determine the

enantioselectivity of the reaction has been found to date.

80

5 Conclusion and Outlook

5.1 Allylation of Phosphorus Nucleophiles

We have successfully allylated phosphines and phosphine oxides using either [Pd(η3-1,3-

Ph2Allyl)(κ2-Josiphos)]SbF6 (1) or a mixture of [Pd(dba)2] and Josiphos as catalyst system.

The scope of both reactions is still limited; so far only aromatic substrates and phosphines

have performed satisfyingly.

In terms of mechanism, new insights were gained. We have found that both nucleophile types

can be classified as soft, i. e. they attack the coordinated allyl opposite to the metal. In the

case of diphenylphosphine as nucleophile, the attack takes place preferentially cis to the PCy2

group of Josiphos in endo-syn-syn-1.

Kinetic experiments were unsuccessful in determining the rate of the reaction because un-

der the conditions used (nucleophile and base in excess), complex 1 decomposed either to

[Pd0(κ1-PHPh2)4] (nucelophile dependent runs) or [Pd0(κ2-Josiphos)(κ1-PHPh2)n] (base de-

pendent runs). However, in order to avoid catalyst decomposition, the minimal loading was

determined to be 3.3 mol-%. Reasonable kinetic experiments should be performed with an ex-

cess of complex 1. Due to sensitivity issues in NMR spectroscopy, this would be very material-

and cost-intensive. Therefore, other, more sensitive spectroscopic methods such as UV/VIS,

should be applied.

The determination of the site of attack was based on data of relatively poor quality and should

be possibly repeated under more stable conditions in order to reduce large uncertainties in

both dimensions. The obtained values have nevertheless a high qualitative validity.

By addition of sterically undemanding coordinating compounds, the equilibration of the dif-

ferent isomers of complex 1 is accelerated. This leads to faster but less selective allylation

reactions. A possibility to circumvent this issue could be to tune a ligand such that the per-

ferred attack takes place on the thermodynamically favoured isomer, thus leading to a faster

and more selective reaction.


So far, the application of allylic phosphine (oxide) 2 (12) as a starting material for further lig-

and syntheses was unsuccessful. The phosphine group seems to deactivate the olefin strongly,

consequently inhibiting a way to prepare useful derivatives. The use of 2 as ligand is limited

since its coordinating properties seem to be weak.

As organocatalyst, allylic phosphine 2 is unsuitable. The generation of a covalent P-C bond as

81

5 Conclusion and Outlook

part of the catalytic cycle creates a phosphonium group. Since the allylic substituent of the

phosphonium ion is a good leaving group (allyl cation), the P-Callyl bond is easily cleaved and

the catalyst decomposed.

The biggest potential for application lies in the use as hemilabile ligand. However, two projects

preparing substrates for the allylation to potential ligands failed during synthesis. These sub-

strates should be chosen to be as simple as possible, i. e. symmetrically substituted. Moreover,

they should be aromatically substituted in order to avoid sluggish reactivity (as seen with

aliphatic substrates).

5.3 Allylation of Diphenylarsine

In analogy to the allylic phosphination reaction, diphenylarsine can be allylated using the same

catalyst system. The reaction proceeds smoothly within 3 h using 5 mol-% catalyst and can be

monitored conveniently by 1H-NMR spectroscopy. The allylic arsine is very air-sensitive and

oxidises readily upon exposure to air to diphenylarsenic acid. Therefore, chromatographic

methods for the determination of the enantiomeric excess cannot be used. Coordination to

chiral derivatisation agents was possible, however, these complexes were dynamic. So far, all

attempts to determine the enantiopurity were unsuccessful.

Thank you for reading this thesis thorougly. :)May the Force be with you...

82

6 Experimental

6.1 General Remarks

6.1.1 Techniques

All reactions with air- or moisture-sensitive materials were carried out under argon using

standard Schlenk techniques or in a glove box (MBraun MB 150B-G and Lab Master 130)

under an atmosphere of nitrogen. Glassware were preheated at 140 ◦C in an oven or dried

under HV with a heat gun and put then under argon. The solvents used for synthetic and

recrystallization purposes were of "puriss p.a." quality (Sigma-Aldrich, Riedel-de-Haen, J.T.

Baker or Merck) and were degassed by saturating with argon or by 3 freeze-pump-taw cycles.

Anhydrous solvents, when needed, were freshly distilled under argon from Na/benzophenone

(toluene, THF, Et2O), Na/benzophenone/diglyme (n-pentane), Na/benzophenone/tetraglyme

(n-hexane), Na/diethyl phthalate (EtOH) or CaH2 (MeOH, CH2Cl2, MeCN). For flash chro-

matography and TLC, technical grade solvents were generally used. Deuterated solvents were

purchased from Cambridge Isotope Laboratories or Armar Chemicals (CDCl3). For sensitive

compounds they were purified by bulb-to-bulb distillation from Na (C6D6, d8-THF) or CaH2

(CD2Cl2), degassed by 3 freeze-pump-taw cycles and stored under argon in a Young Schlenk

flask. Alternatively, the deuterated solvent (C6D6, d8-toluene) coming from new, sealed bottles

was dried and stored over activated 3 Å molecular sieves and degassed by 3 freeze-pump-taw

cycles.

6.1.2 Chemicals

(R)-Ugi’s amine was kindly provided by Solvias AG (Basel) as a tartrate salt and was obtained

as enantiomerically pure free amine following a modified procedure by Ugi.[29] Commer-

cially available chemicals were purchased from ABCR, Acros AG, Sigma-Aldrich, or Pressure

Chemical Co. and metal precursors from Johnson Matthey (Na2PdCl4, IrCl3 ·3 H2O) and used

without further purification. Cyclopentenyl acetate[169] was prepared by Patrick Stücheli.

6.1.3 Analytical Techniques and Instruments

Thin layer chromatography (TLC): Merck Silica gel 60 F254 visualized by fluorescence

quenching at 254 nm. In addition, TLC plates were stained using permanganate (1 g KMnO4,

2 g NaCO3, 100 mL EtOH) or vanillin (12 g vanillin, 2 mL H2SO4 conc., 200 mL EtOH). R f is

the retention factor for the ratio of given solvents.

83

6 Experimental

Flash Chromatography (FC): chromatographic purification of products was performed on

Fluka Silica Gel 60 (230-400 mesh) or MP Alumina N, Akt. I or II (MP Biomedicals GmbH)

using the given solvent ratios and a forced flow of eluent at 0.1 – 0.2 bar pressure.

NMR spectra were recorded on Bruker 700 Avance, 500 DPX Avance, 400 DPX Avance, 300

DPX Avance, 300 Avance III HD Nanobay, 250 DPX Avance or 200 DPX Avance spectrome-

ters operating at the given spectrometer frequency. The samples were measured as solutions

in the given solvent at room temperature (if not indicated differently) and in non-spinning

mode. The chemical shifts (δ) are expressed in part per millions (ppm) relative to TMS as an

external standard for 1H- and 13C-NMR spectra and are calibrated against the solvent residual

peak. For CD2Cl2 as solvent δ = 5.32 ppm and δ = 53.8 ppm were used for the calibration

of 1H- and 13C-NMR spectra respectively. For 19F-NMR spectra, CFCl3 and for 31P-NMR spectra

H3PO4 (85%), respectively, were used as external standards. Coupling constants J are given

in Hertz (Hz) as absolute values. The multiplicity of the signals are abbreviated as follows: s

= singlet, d = doublet, t = triplet, q = quartet, quint. = quintet, sept. = septet, br = broad,

m = multiplet.

High-resolution mass spectra (HiRes-MS) were measured by the MS-Service of the "Labora-

torium für organische Chemie der ETHZ". The signals are given as mass per charge number

(m/z).

Elemental Analysis (EA) were carried out by the microelemental analysis service of the "Lab-

oratorium für organische Chemie der ETHZ" on a LECO CHN-900 analyzer. The content of the

specified element is expressed in mass percent (%).

High Pressure Liquid Chromatography (HPLC) was run on either a Hewlett-Packard 1050

Series or an Agilent 1100 Series with detection at three different wave lengths (210, 230,

254 nm) using the specified column (Diacel Chiralcel OJ, OD-H or OB-H), flow rate of the

solvents (mL/min), ratio of n-hexane/i-PrOH and sample injection volume (µL; sample con-

centration approximately 1 mg/mL). Retention times tR are given in minutes (min).

Crystallography: Intensity data of single crystals glued to a glass capillary were collected at

the given temperature (usually 100 K) on a Bruker SMART APEX platform with CCD detec-

tor and graphite monochromated Mo Kα radiation (λ = 0.71073 Å). The program SMART

served for data collection; integration was performed with the software SAINT.[170] The struc-

tures were solved by direct methods or Patterson methods, respectively, using the program

SHELXS 97.[171] The refinement and all further calculations were carried out using SHELXL

97.[172] All non-hydrogen atoms were refined anisotropically using weighted full-matrix least

squares on F2. The hydrogen atoms were included in calculated positions and treated as rid-

ing atoms using SHELXL default parameters. In the end absorption correction was applied

(SADABS)[173] and weights were optimized in the final refinement cycles. The absolute con-

84

6.2 Syntheses and Mechanistic Experiments

figuration of chiral compounds was determined on the basis of the Flack parameter.[174,175]

The standard uncertainties (s.u.) are rounded according to the "Notes for Authors" of Acta

Crystallographica.[176]


6.2.1 General Procedures

6.2.1.1 Catalyses

Preparation of (rac)-(E)-(1,3-Diphenylallyl)diphenylphosphine Oxide (12) as Refer-

ence Sample for HPLC. [Pd(dba)2] (0.080 g, 0.14 mmol, 0.025 eq) was dissolved in

methanol (50 mL) under argon. 1,3-Diphenylallyl acetate (1.22 mL, 5.41 mmol, 1.000 eq)

and diphenylphosphine (0.94 mL, 5.41 mmol, 1.000 eq) were added. The mixture was stirred

at 45 ◦C for 24 h. The precipitated allylic phosphine was filtered off, washed with methanol,

and dried in vacuo. 1.6 g (80%) of a white solid was obtained.

Oxidation procedure (for ee determination by HPLC): The allylic phosphine (60 mg) was dis-

solved in THF (ca. 2 mL), and 30% aq. hydrogen peroxide (3 drops) was added. The mixture

was stirred for 30 min before it was dried with magnesium sulfate, filtered, and concentrated

to give the allylic phosphine oxide.

Determination of the enantiomeric excess: To a sample (ca. 2 mg) was added hexane / iPrOH

(60:40, ca. 1.5 mL) until it was completely dissolved. This was injected into the HPLC (OD-H,

hexane / iPrOH = 90:10, 0.5 mL/min flow rate, 5 µL injection volume).

Analytical data for (E)-(1,3-diphenylallyl)diphenylphosphine oxide (12) (C27H23OP,

394.44 g/mol): 1H-NMR (300 MHz, CD2Cl2): δ 7.90 (m, 2 H, CHarom), 7.68 – 7.20 (m, 18 H,

CHarom), 6.59 (m, 1 H, PhCH=CH), 6.36 (m, 1 H, PhCH=CH), 4.46 (m, 1 H, CH(P(O)Ph2)).13C{1H}-NMR (125.8 MHz, CD2Cl2): δ 137.1 (s, 2 C, Cq), 136.7 (s, 1 C, Cq), 136.6 (s, 1 C, Cq),

134.4 (d, J = 11 Hz, 1 C, CHallyl), 133.2 (d, J = 11 Hz, 1 C, CHarom), 131.9 (m, 3 C, CHarom),

131.9 (s, 1 C, CHarom), 131.8 (s, 2 C, CHarom), 131.6 (s, 1 C, CHarom), 131.5 (s, 1 C, CHarom),

129.9 (s, 1 C, CHarom), 129.8 (s, 1 C, CHarom), 128.9 (s, 1 C, CHarom), 128.8 (s, 1 C, CHarom),

128.7 (s, 1 C, CHarom), 128.5 (s, 1 C, CHarom), 128.0 (s, 1 C, CHarom), 127.3 (d, J = 3 Hz, 2 C,

CHarom), 126.6 (s, 1 C, CHarom), 126.6 (s, 1 C, CHarom), 125.2 (d, J = 7 Hz, 1 C, CHallyl), 52.3

(d, J = 64 Hz, CHallyl).31P{1H}-NMR (121.5 MHz, CD2Cl2): δ 30.2 (s, 1 P, P(O)Ph2). MS

(HiRES MALDI): m/z 395.1559 [M+]. EA: Anal. Calcd. for C27H23OP (394.45): C, 82.21; H,

5.88. Found: C, 81.96; H, 6.02. HPLC: tR 17.6 min (S), 20.3 min (R).

85

6 Experimental

Allylation of Phosphines. The catalyst complex [Pd(η3-1,3-Ph2Allyl)(κ2-Josiphos)]SbF6

(1) (9.0 mg, 8 µmol, 0.05 eq) was dissolved in dry and degassed dichloromethane or ben-

zene (0.5 mL) in a NMR tube in a glove box. Then the substrate (159 µmol, 1.00 eq), the

nucleophile (159 µmol, 1.00 eq), the base (159 µmol, 1.00 eq), and, optionally, an additive

(2 µmol, 0.01 eq) were added and the NMR tube was sealed with Teflon® tape and Parafilm®.

The tube was agitated at rt or warmed in an oil bath for the specified time. The reaction

progress was followed by 31P{1H}- and 31P-NMR spectroscopy. The reaction was worked-up in

a glove box. The dichloromethane was removed and the residue taken up in benzene. The

benzenic reaction solution was filtered over a short plug of silica (0.5 x 3 cm) with benzene

(ca. 4 mL) as eluent. The volatiles were removed in vacuo to give pure allylic phosphine.

Analytical data for (E)-(1,3-diphenylallyl)diphenylphosphine (2) (C27H23P, 378.47 g/mol,

CAS 1049296-93-6): 1H-NMR (300 MHz, CD2Cl2): δ 7.65 – 7.20 (m, 20 H, CHarom), 6.45

(m, 1 H, PhCH=CH), 6.27 (m, 1 H, PhCH=CH), 4.44 (m, 1 H, CH(PPh2)). 13C{1H}-NMR

(125.8 MHz, CD2Cl2): δ 141.2 (d, J = 10 Hz, 1 C, Cq), 137.7 (s, 1 C, Cq), 137.29 (d, J =

13 Hz, 1 C, Cq), 137.1 (d, J = 14 Hz, 1 C, Cq), 134.6 (d, J = 20 Hz, 2 C, CHarom), 133.9 (d, J

= 19 Hz, 2 C, CHarom), 131.8 (d, J = 10 Hz, 1 C, CHallyl), 130.4 (d, J = 13 Hz, 1 C, CHallyl),

129.5 (s, 2 C, CHarom), 129.4 (d, J = 21 Hz, 2 C, CHarom), 129.0 (s, 2 C, CHarom), 128.8 (d, J

= 10 Hz, 2 C, CHarom), 128.6 (d, J = 8 Hz, 2 C, CHarom), 128.4 (d, J = 8 Hz, 2 C, CHarom),

127.6 (s, 1 C, CHarom), 126.8 (m, 1 C, CHarom), 126.4 (s, 2 C, CHarom), 50.5 (d, J = 14 Hz,

1 C, CHallyl). 31P{1H}-NMR (202.5 MHz, CD2Cl2): δ -0.7 (s, 1 P, PPh2). MS (EI): m/z 378.15

[M+], 192.10 [PhCH=CH-C+HPh]. EA: Anal. Calcd. for C27H23P (378.47): C, 85.69; H, 6.13.

Found: C, 84.10; H, 6.09. HPLC: tR 17.6 min ((S)-oxide), 20.3 min ((R)-oxide).

Allylation of Phosphine Oxides. The catalyst complex [Pd(η3-1,3-Ph2Allyl)(κ2-

Josiphos)]SbF6 (1) (9.0 mg, 8 µmol, 0.05 eq) was dissolved in benzene (0.5 mL) in a NMR

tube under atmospheric conditions. Then the substrate (159 µmol, 1.00 eq), the nucleophile

(159 µmol, 1.00 eq), the base (159 µmol, 1.00 eq), and, optionally, an additive (2 µmol,

0.01 eq) were added and the NMR tube was sealed with Teflon® tape and Parafilm®. The tube

was agitated at rt or warmed in an oil bath for the specified time. The reaction progress was

followed by 31P{1H}- and 31P-NMR spectroscopy. The product precipitated from the reaction

solution and was filtered off and washed with cold benzene.

Analytical data for (E)-(1,3-diphenylallyl)diphenylphosphine oxide (12) is given above.

Preparation of (rac)-(E)-(1,3-diphenylallyl)diphenylarsine (23) as Reference Sam-

ple. Di-µ2-bromo-bis[η3-1,3-diphenylallyl]-dipalladium(II) (38 mg, 0.05 mmol, 0.05 eq)

and 1,2-bis(diphenylphosphino)ethane (24 mg, 0.06 mmol, 0.06 eq) were dissolved in

86


dichloromethane (3.5 mL) and stirred for 20 min under argon. 1,3-Diphenylallyl acetate

(0.23 mL, 1.00 mmol, 1.00 eq), diphenylarsine (0.18 mL, 1.00 mmol, 1.00 eq), and triethyl-

amine (0.14 mL, 1.00 mmol, 1.00 eq) were added. The reaction mixture was stirred for 24 h

at rt. Volatiles were removed in vacuo. The residue was dissolved in benzene and filtered over

silica. Concentration and drying in vacuo gave 0.42 g (99%) of a white solid.

Analytical data for (E)-(1,3-diphenylallyl)diphenylarsine (23) (C27H23As, 422.39 g/mol):1H-NMR (300 MHz, CD2Cl2): δ 7.65 – 7.20 (m, 20 H, CHarom), 6.45 (m, 1 H, PhCH=CH),

6.27 (m, 1 H, PhCH=CH), 4.44 (m, 1 H, CH(PPh2)). 13C{1H}-NMR (125.8 MHz, CD2Cl2):

δ 139.9 (s, 1 C, Cq), 138.3 (s, 1 C, Cq), 138.2 (s, 1 C, Cq), 136.4 (s, 1 C, Cq), 133.3 (s,

2 C, CHarom), 132.4 (s, 2 C, CHarom), 129.4 (s, 1 C, CHallyl), 129.3 (s, 1 C, CHallyl), 129.0 (s,

1 C, CHarom), 127.7 (s, 1 C, CHarom), 127.5 (s, 2 C, CHarom), 127.4 (s, 2 C, CHarom), 127.4 (s,

2 C, CHarom), 127.3 (s, 2 C, CHarom), 127.2 (s, 2 C, CHarom), 126.0 (s, 1 C, CHarom), 125.1 (s,

1 C, CHarom), 125.0 (s, 2 C, CHarom), 50.2 (s, 1 C, CHallyl). Arsenic compounds could not be

subjected to EA or MS.

Allylation of Diphenyl Arsine. The catalyst complex [Pd(η3-1,3-Ph2Allyl)(κ2-

Josiphos)]SbF6 (1) (9.0 mg, 8 µmol, 0.05 eq) was dissolved in dry and degassed d2-

dichloromethane (0.5 mL) in a NMR tube in a glove box. Then the substrate (159 µmol,

1.00 eq), diphenyl arsine (28.2 µL, 159 µmol, 1.00 eq), the base (159 µmol, 1.00 eq), and,

optionally, an additive (2 µmol, 0.01 eq) were added and the NMR tube was sealed with

Teflon® tape and Parafilm®. The tube was agitated at rt. The reaction progress was followed

by 1H-NMR spectroscopy. The reaction was worked-up in a glove box. The dichloromethane

was removed and the residue taken up in benzene. The benzenic reaction solution was filtered

over a short plug of silica (0.5 x 3 cm) with benzene (ca. 4 mL) as eluent. The volatiles were

removed in vacuo to give pure allylic arsine.

Analytical data for (E)-(1,3-diphenylallyl)diphenylarsine (23) is given above.

6.2.1.2 Mechanistic Experiments

Fiaud Classification of Nucleophiles with Complex 1. Diphenylphosphine,

diphenylphosphine oxide, and diphenylarsine were classified with [Pd(η3-1,3-Ph2Allyl)(κ2-

Josiphos)]SbF6 (1) according to Fiaud and co-workers (see Scheme 34 in section 1.3).[76] The

results are presented in Table 4.

87

6 Experimental

AcO HAcO

HNu


NEt3, CD2Cl2, rt Nu H Nu

0.5 eq 0.5 eq 1 eqA B C D

a

Nucleophile Aa [%] Ba [%] C [%] D [%] Classification

HPPh2

0 70 48 0soft

–c 90b – 0

HP(O)Ph2

0 91 77b 0soft

–c 76 – 0

HAsPh2

0b 57b 83b 0b

soft–c 65b – 0b

morpholined 0 97 41 0 soft

Na[C9H7]d,e –c 0 – 66 hard

Table 4: Results of the Fiaud experiments for the classification of diphenylphosphine, diphenylphos-

phine oxide, and diphenylarsine.[76] Amounts of products and recovered substrates are given as iso-

lated yields. arecovered starting material. bNMR yield. csubstrate B was used alone. dreference

reaction, no base was used. ecarried out in THF.

Procedure: The catalyst complex [Pd(η3-1,3-Ph2Allyl)(κ2-Josiphos)]SbF6 (1) (9.0 mg,

8 µmol, 0.05 eq) was dissolved in dry and degassed d2-dichloromethane or d8-THF (0.5 mL)

in a NMR tube in a glove box. Then the substrates (80 µmol, 0.50 eq), the nucleophile

(159 µmol, 1.00 eq), and, if required, triethylamine (22 µL, 159 µmol, 1.00 eq) were added

and the NMR tube was sealed with Teflon® tape and Parafilm®. The tube was agitated at rt.

The reaction progress was followed by 31P{1H}- and/or 1H-NMR spectroscopy.

For HPPh2: The reaction was worked-up in a glove box. The dichloromethane was removed in

vacuo and the residue taken up in benzene. The benzenic reaction solution was filtered over a

short plug of silica (0.5 x 3 cm) with benzene (ca. 4 mL) as eluent. The volatiles were removed

in vacuo. Outside the glovebox two drops of aq. hydrogenperoxide (30%) were added and

the suspension mixed for 20 min. The solvents were removed under reduced pressure and the

residue subjected to flash chromatography (hexane / ethyl acetate = 95:5→ dichloromethane

/ methanol = 95:5) to afford the unreacted substrate B and then the phosphine oxide C.

88


For HP(O)Ph2: The reaction mixture was concentrated and filtered over a short plug of sil-

ica (0.5 x 3 cm) with hexane / ethyl acetate = 95:5 (ca. 4 mL) as eluent. Evaporation of

this first fraction gave unreacted substrate B. The residue was washed down the silica with

dichloromethane / methanol = 95:5 (ca. 4 mL). To the solution containing product C, re-

maining diphenylphosphine oxide, and catalyst was added 10.3 mg triphenylphosphine and

the yield of product C was determined by 31P{1H}-NMR (30◦ pulse, 0.9 s aquisition time, 2 s

relaxation delay).

For HAsPh2: The reaction was worked-up in a glove box. The dichloromethane was removed

in vacuo and the residue taken up in benzene. The benzenic reaction solution was filtered

over a short plug of silica (0.5 x 3 cm) with benzene (ca. 4 mL) as eluent. The volatiles

were removed in vacuo. The residue was dissolved in CDCl3 and transferred to a NMR tube.

5.0 mg ferrocene were added as internal standard. The NMR tube was sealed with Teflon®

tape and Parafilm®. Product and substrate amounts were determined by 1H-NMR (30◦ pulse,

2.6 s aquisition time, 15 s relaxation delay).

For morpholine: The reaction mixture was diluted with dichloromethane (2 mL) and 2 M

hydrochlorid acid (1.5 mL) was added. The organic phase was concentrated and the residue

filtered over a short plug of silica (0.5 x 3 cm) with hexane / ethyl acetate = 95:5 (ca. 4 mL)

as eluent. Evaporation of the solvent gave substrate B. The aqueous phase was neutralised

with 2 M sodium hydroxide solution (2 mL) and extracted with diethyl ether. Evaporation of

the solvent gave the substitution product C.

For Na[C9H7]: The reaction mixture was diluted with diethyl ether (2 mL) and washed with

water (2 x 2 mL). Flash chromatography (hexane→ hexane / ethyl acetate = 95:5) afforded

the substitution product D which was detected by GC-MS (calc. 248; found 248 [M]+). By

TLC no unreacted substrate B was found.

Kinetics. Procedures for the kinetic experiments described in section 3.2.2.3.

For the base dependent runs: Three stock solutions were prepared. Solution A: complex 1

in CH2Cl2 (565 mg in 2.000 mL, 0.250 M, by measuring flask); solution B: HPPh2 in CH2Cl2(0.870 mL in 2.000 mL, 2.500 M, by means of Gilson® pipette and measuring flask); solution

C: NEt3 in CH2Cl2 (1.390 mL in 2.000 mL, 5.000 M, by means of Gilson® pipette and measur-

ing flask). Procedure: Solution A, solution C, and, if necessary, CH2Cl2 were mixed in an NMR

tube in a glovebox (see Table 5). The tube was sealed with a NMR septum and Parafilm®. The

NMR spectrometer was prepared and preshimmed before 100 µL of solution B were added to

the tube, mixed, and the measurement started immediately.

89

6 Experimental

NEt3 (eq) Complex Solution (A) HPPh2 Solution (B) NEt3 Solution (C) CH2Cl210 100 µL 100 µL 50 µL 250 µL

20 100 µL 100 µL 100 µL 200 µL

30 100 µL 100 µL 150 µL 150 µL

40 100 µL 100 µL 200 µL 100 µL

50 100 µL 100 µL 250 µL 50 µL

60 100 µL 100 µL 300 µL 0 µL

Table 5: Solutions needed for base dependent kinetic runs. Conditions: 1 eq complex 1, 10 eq HPPh2,

10 to 60 eq NEt3

For the nucleophile dependent runs: Three stock solutions were prepared. Solution A:

complex 1 in CH2Cl2 (565 mg in 2.000 mL, 0.250 M, by measuring flask); solution B: HPPh2

in CH2Cl2 (1.740 mL in 2.000 mL, 5.000 M, by means of Gilson® pipette and measuring flask);

solution C: NEt3 in CH2Cl2 (0.697 mL in 2.000 mL, 2.500 M, by means of Gilson® pipette and

measuring flask). Procedure: Solution A, solution B, and, if necessary, CH2Cl2 were mixed

in an NMR tube in a glovebox (see Table 6). The tube was sealed with a NMR septum and

Parafilm®. The NMR spectrometer was prepared and preshimmed before 100 µL of solution

C were added to the tube, mixed, and the measurement started immediately.

HPPh2 (eq) Complex Solution (A) HPPh2 Solution (B) NEt3 Solution (C) CH2Cl210 100 µL 50 µL 100 µL 250 µL

20 100 µL 100 µL 100 µL 200 µL

30 100 µL 150 µL 100 µL 150 µL

40 100 µL 200 µL 100 µL 100 µL

50 100 µL 250 µL 100 µL 50 µL

60 100 µL 300 µL 100 µL 0 µL

Table 6: Solutions needed for nucleophile dependent kinetic runs. Conditions: 1 eq complex 1, 10 to

60 eq HPPh2, 10 eq NEt3

The reaction was followed by 31P{1H}-NMR spectroscopy. To the pulse program a loop with

delay was added in order to record a spectrum (32 scans, 54 s per spectrum) every two

minutes.

90


Determination of the Site of Attack. Several runs of the reaction as shown in Scheme

86 were performed. As base, proton sponge, 1,8-bis(dimethylamino)naphthalene, was chosen

because it is sterically hindered and therefore is a weak "isomerisation catalyst" compared to

triethylamine (see section 2.3.3). For these runs, multiple batches of complex 1 with differ-

ent endo/exo ratios were used. These originated from different syntheses or from "high endo"

batches which were kept for a short period of time at elevated temperatures in order to equi-

librate the isomers.

SbF6

Fe

PPh2

Cy2P Pd

PhPh

N NHPPh2

Ph Ph

PPh2CH2Cl2

3 eq 1 eq 1 eq

Scheme 86: Reaction scheme for the reactions determining the site of attack.

A stock solution was prepared: proton sponge (214.3 mg, 1.0 mmol) and HPPh2 (174 µL,

1.0 mmol, Gilson® pipette) in 10 mL CH2Cl2 (measuring flask). Procedure: Complex 1

(33.9 mg, 0.03 mmol, 3 eq) was dissolved in CH2Cl2 (0.4 mL) in a NMR tube under ar-

gon. The tube was sealed with a NMR septum and Parafilm®. A 31P{1H}-NMR spectrum was

recorded in order to determine the initial endo/exo ratio of 1. Immediately thereafter, 100 µL

of the stock solution (0.1 M) were added, and the mixture agitated. After 3 h, the reaction was

worked up in a glovebox. The solution was concentrated in vacuo and the residue taken up in

benzene. The benzenic reaction solution was filtered over a short plug of silica (0.5 x 3 cm)

with benzene (ca. 4 mL) as eluent. The volatiles were removed in vacuo to give pure allylic

phosphine. Outside the glovebox two drops of aq. hydrogenperoxide (30%) were added and

the suspension was mixed for 20 min. The solvents were removed under reduced pressure.

The enantioselectivity was determined by HPLC (see above).

6.2.1.3 Temperature Dependent Synthesis of [Pd(η3-1,3-Ph2Allyl)(κ2-Josiphos)]SbF6

(1) To a solution of Josiphos (17.8 mg, 30 µmol, 1.0 eq) in methanol (0.5 mL) under argon

was added di-µ2-bromo-bis[η3-1,3-diphenylallyl]-dipalladium(II) (11.4 mg, 15 µmol, 0.5 eq)

at the desired temperature. The reaction mixture was stirred at that temperature for 20 min.

91

6 Experimental

Then, a solution of sodium hexafluoroantimonate (0.275 mL, 0.131 M, 36 µmol, 1.2 eq) in

methanol was added. The product immediately precipitated in form of an orange solid. The

suspension was stirred for another 15 min, before it was filtered under argon and washed with

little methanol and pentane. The solid was taken up in dichloromethane, filtered, and trans-

ferred to a NMR tube. The endo/exo ratio was determined by integration of the PPh2 signals

at 16.0 ppm (exo) and 15.9 ppm (endo) in 31P{1H}-NMR spectroscopy. Standard parameters

(relaxation delay 1 s, aquisition time 1.5 s) were used. The legitimation to use standard pa-

rameters was verified by control measurements with more carefully chosen settings (relaxation

delay 60 s, aquisition time 1.5 s, inverse gated decoupling).

6.2.1.4 Reduction of Allylic Phosphine Oxide 12[103] Allylic phosphine oxide 12 (50 mg,

0.127 mmol, 1.0 eq) was suspended in dry and degassed methylcyclohexane (0.5 mL).

Tetramethyldisiloxane (29 µL, 0.165 mmol, 1.3 eq) and titanium(IV)isopropoxide (4 µL,

0.013 mmol, 0.1 eq) were added. The reaction mixture was heated to 100 ◦C. After 20 h,

66% of allylic phosphine 2 was obtained. Analytical data are given above.

6.2.1.5 Solubility of Allylic Phosphine Oxide 2 A saturated solution of the allylic phos-

phine oxide was prepared by adding it to the solvent (CH2Cl2 or C6H6) until no more was

dissolved. The suspension was stirred for several minutes before an aliquot was filtered and

transferred to a tared measuring flask (2 mL). The solvent was removed under reduced pres-

sure and the mass of the residue was determined.

6.2.1.6 NMR Experiments Samples for NMR experiments were all prepared under protec-

tive atmosphere, either in a glove box under nitrogen or at the Schlenk line under argon. The

amount of material was appropriately chosen and measured by means of a balance, synringes,

or micropipettes. For experiments involving complex 1, a concentration of 0.06 M was chosen

in order to obtain satisfactory signal-to-noise ratios. For very sensitive compounds or long-

time NMR experiments, Young NMR tubes or flame sealed standard NMR tubes were used. In

all other cases, standard NMR tubes sealed with Teflon® tape and Parafilm® were used.

92


6.2.2 Ligands and Complexes

PhO

Ph

PhO

Ph

Pd

Bis(dibenzylideneacetone)palladium(0)[177]

C34H28O2Pd, 575.04 g/mol, CAS 32005-36-0

Palladium(II) chloride (0.70 g, 3.95 mmol, 1.0 eq) and sodium

chloride (0.23 g, 3.95 mmol, 1.0 eq) were dissolved in dry methanol

(20 mL) under argon. The mixture was stirred for 22 h at rt. The

solution was filtered over Celite® to remove any solids and was diluted to ca. 150 mL. It was

warmed to 60 ◦C and dibenzylideneacetone (3.05 g, 13.03 mmol, 3.3 eq) was added. After

15 min, sodium acetate (5.99 g, 73.00 mmol, 18.5 eq) was added and the solution was slowly

cooled to rt. The precipitated product was filtered off, washed with cold methanol, water, and

acetone, and dried in vacuo to yield 1.8 g (80%) of a brown-violet powder.

EA: Anal. Calcd. for C34H28O2Pd (575.04): C, 71.02; H, 4.91. Found: C, 71.70; H, 4.93.

PdBr

PdBr

Ph

Ph Ph

PhDi-µ2-bromo-bis[η3-1,3-diphenylallyl]-dipalladium(II)[178]

C30H26Br2Pd2, 759.18 g/mol, CAS 918545-55-8

3-Bromo-1,3-diphenylprop-1-ene (0.852 g, 3.12 mmol, 2.4 g)

was dissolved in degassed THF (580 mL) under argon.

Bis(dibenzylideneacetone)palladium(0) (1.495 g, 2.60 mmol, 2.0 eq) was added and

the mixture stirred at rt for ca. 1 h. The yellow precipitate was filtered off, washed with

benzene and pentane, and dried in vacuo to give 0.98 g (99%) of a pale yellow, light-sensitive

powder.1H-NMR (300 MHz, CDCl3): δ 7.82 – 7.80 (m, 8 H, CHarom), 7.47 – 7.39 (m, 12 H, CHarom),

7.02 (t, JHH = 11.9 Hz, 2 H, CHallyl), 5.34 (d, JHH = 11.9 Hz, 4 H, CHallyl). EA: Anal. Calcd.

for C30H26Br2Pd2 (759.18): C, 47.46; H, 3.45. Found: C, 45.90; H, 3.52.

Fe PPh2NMe2

(S)-2-Diphenylphosphino-1-[(1R)-1-(dimethylamino)-

ethyl]ferrocene ((R,S)-PPFA)[179]

C26H28FeNP, 441.33 g/mol, CAS 74311-54-9

Ugi’s amine (5.22 g, 20.30 mmol, 1.0 eq) was dissolved in diethyl ether

(20 mL) under argon and cooled to –78 ◦C. sec-butyllithium (1.3 M, 18.7 mL, 24.36 mmol,

1.2 eq) was added over 10 min and the mixture was stirred for 30 min at –78 ◦C before

it was let warm to rt and kept at that temperature for 1.3 h. After recooling to –78 ◦C,

chlorodiphenylphosphine (4.74 mL, 26.39 mmol, 1.3 eq) was added to the red solution.

The reaction mixture was let warm to rt overnight, yielding an orange suspension. It was

quenched with a sat. aq. NaHCO3 solution, which was then extracted three times with

93

6 Experimental

CH2Cl2. The organic phase was washed with brine, dried with MgSO4, and concentrated

under reduced pressure. Flash chromatography (hexane / ethyl acetate / triethyl amine =

49:49:2) afforded 6.35 g (71%) of an orange solid.1H-NMR (250 MHz, CDCl3): δ 7.63 (m, 2 H, CHarom), 7.38 (m, 3 H, CHarom), 7.20 (m, 5 H,

CHarom), 4.40 (m, 1 H, CHCp), 4.27 (m, 1 H, CHCp), 4.20 (m, 1 H, CHMe), 3.96 (s, 5 H, CHCp′),

3.88 (m, 1 H, CHCp), 1.80 (s, 6 H, NMe2), 1.26 (d, JHH = 6.7 Hz, 3 H, CHMe). 31P{1H}-NMR

(101.3 MHz, CDCl3): δ –22.8 (s, 1 P, PPh2).

Fe PPh2PCy2

(R,S)-Josiphos[30]

C36H44FeP2, 594.59 g/mol, CAS 158923-09-2

Acetic acid was degassed by three cyclces of freeze-pump-thaw. (R,S)-PPFA

(6.35 g, 14.39 mmol, 1.0 eq) and dicyclohexylphosphine (3.78 mL,

18.70 mmol, 1.3 eq) were dissolved in acetic acid (40 mL) under argon. The reaction mixture

was stirred at 80 ◦C for 3 h. After cooling to rt, the volatiles were removed in vacuo. After

filtration over silica (hexane / ethyl acetate = 1:1), and recrystallisation from degassed

ethanol, 7.77 g (91%) of an orange solid was obtained.1H-NMR (300 MHz, C6D6): δ 7.87 (m, 2 H, CHarom), 7.58 (m, 2 H, CHarom), 7.27 – 7.10

(m, 6 H, CHarom), 4.39 (m, 1 H, CHCp), 4.35 (m, 1 H, CHCp), 4.25 (m, 1 H, CHCp), 3.95 (s,

5 H, CHCp′), 3.69 (m, 1 H, CHMe), 1.95 – 1.28 (m, 25 H, CHCy and CHMe). 31P{1H}-NMR

(121.5 MHz, C6D6): δ 15.2 (d, JPP = 38 Hz, 1 P, PCy2), –25.6 (d, JPP = 38 Hz, 1 P, PPh2).

SbF6

Fe

PPh2

Cy2P Pd

PhPh[Pd(η3-1,3-Ph2Allyl)(κ2-Josiphos)]SbF6 (1)[4,5]

C51H57F6FeP2PdSb, 1129.96 g/mol, CAS 1049746-17-9

(R,S)-Josiphos (1.253 g, 2.01 mmol, 1.0 eq) and [Palladium(µ2-

bromo)(η3-1,3-Ph2Allyl)]2 (0.800 g, 1.05 mmol, 0.5 eq) were

dissolved in degassed methanol (8 mL) under argon. The

obtained dark red solution was stirred at rt for 20 min before a solution of sodium hexafluo-

roantimonate (0.654 g, 2.53 mmol, 1.2 eq) in methanol (16 mL) was added. An immediate

precipitation of an orange solid was observed. It was filtered off over Celite® under argon

and washed with little methanol and pentane. The product was extracted from the filter cake

with dichloromethane. After concentration and drying in vacuo, 1.4 g (60%) of an orange

solid was obtained.1H-NMR (500 MHz, CD2Cl2): δ 7.97 (dd, JHH = 7.6, 12.5 Hz, 2 H, CHarom), 7.79 (s, 4 H,

CHarom), 7.57 (m, 10 H, CHarom), 7.42 (s, 6 H, CHarom), 7.36 (m, 1 H, CHarom), 7.21 (d, JHH

= 7.3 Hz, 1 H, CHarom), 7.08 (m, 4 H, CHarom), 6.99 (s, 4 H, CHarom), 6.89 (m, 2 H, CHarom),

94


6.70 (s, 2 H, CHarom), 6.60 (d, JHH = 7.3 Hz, 2 H, CHarom), 6.55 (m, 2 H, CHarom), 6.54 (s,

1 H, CHallyl), 6.06 (t, JHH = 12.7 Hz, 1 H, CHallyl), 5.28 (ddd, JHH = 2.1, 8.5, 11.2 Hz, 1 H,

CHallyl), 4.97 (s, 1 H, CHallyl), 4.80 (t, JHH = 11.5 Hz, 1 H, CHallyl), 4.66 (s, 1 H, CHCp, endo),

4.63 (s, 1 H, CHCp, exo), 4.43 (s, 1 H, CHCp, endo), 4.38 (s, 1 H, CHCp, exo), 4.13 (s, 1 H,

CHCp, endo), 4.06 (s, 1 H, CHCp, exo), 3.87 (t, JHH = 19.21 Hz, 1 H, CHallyl), 3.78 (s, 5 H,

CHCp′ endo), 3.73 (s, 5 H, CHCp′ exo), 3.22 (m, 1 H, CHMe exo), 3.01 (m, 1 H, CHMe endo),

2.51 (dd, JHH = 10.6, 21.1 Hz, 1 H, CHCy), 2.09 (d, JHH = 11.0 Hz, 1 H, CHCy), 1.98 (m,

2 H, CHCy), 1.90 (dd, JHH = 8.0, 18.3 Hz, 3 H, CHMe exo), 1.85 (dd, JHH = 7.7, 17.7 Hz,

3 H, CHMe endo), 1.81 (m, 4 H, CHCy), 1.65 (m, 11 H, CHCy), 1.54 (d, JHH = 11.3 Hz, 6 H,

CHCy), 1.42 (m, 5 H, CHCy), 1.32 (s, 1 H, CHCy), 1.31 (s, 2 H, CHCy), 1.20 (m, 6 H, CHCy),

0.97 (dd, JHH = 12.1, 21.8 Hz, 2 H, CHCy), 0.83 (dd, JHH = 11.8, 23.5 Hz, 1 H, CHCy),

0.71 (s, 1 H, CHCy), 0.5 (dd, JHH = 10.1, 22.2 Hz, 1 H, CHCy). 13C{1H}-NMR (125.8 MHz,

CD2Cl2): δ 138.5 (Carom), 136.9 (Carom), 136.3 (CHarom), 136.0 (CHarom), 135.6 (Carom), 134.1

(Carom), 132.9 (CHarom), 132.7 (CHarom), 132.5 (CHarom), 131.8 (Carom), 131.5 (Carom), 131.1

(CHarom), 130.7 (CHarom), 130.3 (CHarom), 129.9 (CHarom), 129.6 (CHarom), 129.5 (CHarom),

129.4 (CHarom), 129.2 (CHarom), 128.9 (CHarom), 128.7 (CHarom), 128.6 (CHarom), 128.5

(CHarom), 128.4 (CHarom), 128.3 (CHarom), 110.9 (1 C, CHallyl exo), 96.5 (1 C, CHallyl exo),

96.4 (CHarom), 92.3 (CHarom), 92.1 (CHarom), 81.2 (1 C, CHallyl exo), 81.0 (CHarom), 75.8 (1 C,

CHCp exo), 75.7 (1 C, CHCp endo), 70.9 (10 C, CHCp), 70.2 (1 C, CHCp exo), 69.9 (1 C, CHCp

exo), 69.3 (1 C, CHCp endo), 69.2 (1 C, CHCp exo), 36.9 (CHCy), 35.7 (CHCy), 35.6 (CHCy),

34.4 (CHCy), 32.3 (CHCy), 32.1 (1 C, CHMe endo), 32.0 (CHCy), 31.6 (CHCy), 31.3 (CHCy),

31.2 (CHCy), 31.1 (1 C, CHMe exo), 31.0 (CHCy), 30.2 (CHCy), 30.1 (CHCy), 29.7 (CHCy), 29.2

(CHCy), 28.1 (CHCy), 28.0 (CHCy), 27.9 (CHCy), 27.8 (CHCy), 27.7 (CHCy), 27.5 (CHCy), 27.4

(CHCy), 27.1 (CHCy), 26.7 (CHCy), 26.6 (CHCy), 26.5 (CHCy), 26.2 (CHCy), 26.1 (CHCy), 25.9

(CHCy), 17.0 (1 C, CHMe endo), 16.7 (1 C, CHMe exo). 31P{1H}-NMR (121.5 MHz, CD2Cl2):

δ 59.5 (d, JPP = 68 Hz, 1 P, PCy2 exo), 58.7 (d, JPP = 68 Hz, 1 P, PCy2 endo), 17.4 (d, JPP =

68 Hz, 1 P, PPh2 exo), 16.0 (d, JPP = 68 Hz, 1 P, PPh2 endo). MS (HiResMALDI): m/z 447,

(10%, [Pd(1,3-Ph2Allyl)(Josiphos)]2+), 893 (100%, [Pd(1,3-Ph2Allyl)(Josiphos)]+). EA: Anal.

Calcd. for C51H57F6FeP2PdSb (1129.96): C, 54.21; H, 5.08; P, 5.48. Found: C, 54.25; H, 5.33;

P, 5.44.

95

6 Experimental

6.2.3 Substrates and Nucleophiles

Ph Ph

OAcrac-(E)-1,3-Diphenylallyl acetate[180]

C17H16O2, 252.33 g/mol, CAS 87751-69-7

Acetic anhydride (2.92 mL, 31 mmol, 1.3 eq) was added to a solution of 3-hydroxy-1,3-

diphenylprop-1-ene (5.00 g, 24 mmol, 1.0 eq), triethylamine (8.3 mL, 60 mmol, 2.5 eq), and

DMAP (0.145 g, 1.19 mmol, 0.05 eq) in dichloromethane (50 mL) in a Schlenk flask at 0 ◦C

under argon. The reaction mixture was stirred at that temperature for 1 h and then let warm

to rt overnight. The volatiles were removed under reduced pressure. The oily residue was

dissolved in ethyl acetate (50 mL) and washed with diluted aq. potassium carbonate solution,

1 M hydrochloric acid, and water. The organic phase was dried with magnesium sulfate,

filtered, and concentrated. Flash chromatography (hexane / ethyl acetate = 85:15) afforded

4.2 g (70%) of a colourless oil.1H-NMR (300 MHz, CDCl3): δ 7.47 – 7.29 (m, 10 H, CHarom), 6.71 – 6.66 (m, 1 H, CHallyl),

6.45 – 6.36 (m, 2 H, CHallyl), 2.16 (s, 3 H, CH3). EA: Anal. Calcd. for C17H16O2 (252.33): C,

80.93; H, 6.39. Found: C, 80.66; H, 6.52.

H OH

rac-3a,4,5,6,7,7a-Hexahydro-(1α,3aα,4aα,7α,7aα)-4-7-methano-1H-inden-1-

ol (24)[76,181,182]

C10H14O, 150.22 g/mol, CAS 58616-86-7

Dicyclopentadiene (20.4 mL, 151 mmol, 1.00 eq) was dissolved in ethanol

(300 mL). Palladium on activated charcoal (10%, 1.0 g, 1 mmol, 0.01 eq) was added and the

solution was saturated with hydrogen by bubbling for 10 min. A hydrogen-filled balloon was

connected and the black suspension stirred for ca. 2 h until full conversion of the substrate

(checked by GC-MS). The mixture was filtered over Celite® and concentrated under reduced

pressure. The residue was dissolved in chloroform (100 mL) and sodium acetate (4.0 g,

48 mmol, 0.32 eq) was added. Peracetic acid (35%, 33 mL, 174 mmol, 1.15 eq) was carefully

added without allowing the temperature of the reaction mixture to rise above 25 ◦C. The

solution was stirred at rt for 3 h. The reaction mixture was neutralised by adding 1 M aq.

sodium hydroxide (80 mL). After phase separation, the aqueous phase was extracted twice

with dichloromethane. The combined organic phases were washed with water, dried over

magnesium sulfate, filtered, and concentrated under reduced pressure. The crude epoxide

was used without further purification in the next step. A mixture of the epoxide (6.6 g,

44 mmol, 1.0 eq) and HMPA (39 mL, 220 mmol, 5.0 eq) in diethyl ether (50 mL) was

slowly added to a freshly prepared solution of lithium diisopropylamine (110 mmol, 2.5 eq)

in diethyl ether (50 mL) at rt. The reaction mixture turned dark brown and was stirred

96


overnight. The diluted reaction mixture (+100 mL Et2O) was quenched with 150 mL 1 M

hydrochloric acid. The aqueous phase was extracted twice with diethyl ether. The combined

organic phases were washed three times with water, dried over magnesium sulfate, filtered,

and concentrated. The dark brown residue was distilled (90 ◦C, 0.1 mbar) to yield ca. 1.8 g

(27%) of a colourless liquid.1H-NMR (300 MHz, CDCl3): δ 5.90 (m, 1 H), 5.79 (m, 1 H), 4.67 (br s, 1 H), 3.12 (m, 1 H),

2.41 – 2.20 (m, 3 H), 1.53 – 1.03 (m, 6 H). 13C{1H}-NMR (75 MHz, CDCl3): δ 139.3 (s, 1 C,

CHolefin), 133.1 (s, 1 C, CHolefin), 77.7 (s, 1 C, HCOH), 54.4 (s, 1 C), 52.0 (s, 1 C), 41.5 (s,

1 C), 39.6 (s, 1 C), 39.1 (s, 1 C), 24.8 (s, 1 C), 23.3 (s, 1 C).

O

rac-3a,4,5,6,7,7a-Hexahydro-(1α,3aα,4aα,7α,7aα)-4-7-methano-1H-inden-1-

one (25)[76]

C10H12O, 148.20 g/mol, CAS 5019-96-5

Alcohol 24 (1.80 g, 12.0 mmol, 1.0 eq) was dissolved in acetone (13 mL). To this

solution, a solution of chromium(VI) oxide (2.04 g, 20.4 mmol, 1.7 eq) and conc. sulfuric

acid (1.0 mL, 18.8 mmol, 1.6 eq) in water (4 mL) was added dropwise at 0 ◦C. The dark

red-brown reaction mixture was stirred at rt for 10 min before it was diluted with ca. 200 mL

water and extracted three times with diethyl ether. The combined organic phases were

washed twice with water, dried over magnesium sulfate, filtered and concentrated under

reduced pressure to yield 1.44 g (81%) of a low-melting solid which was used without further

purification.1H-NMR (300 MHz, CDCl3): δ 7.57 (m, 1 H), 6.08 (m, 1 H), 3.21 (m, 1 H), 2.59 (m, 2 H),

2.49 (br s, 1 H), 1.63 (m, 2 H), 1.40 (m, 2 H), 1.14 (m, 2 H). Further analytical data can be

found in the literature.

HO H

rac-3a,4,5,6,7,7a-Hexahydro-(1β ,3aα,4aα,7α,7aα)-4-7-methano-1H-inden-1-

ol (26)[76]

C10H14O, 150.22 g/mol, CAS 19926-79-5

A DIBALH solution (14.6 mL, 1 M in hexane, 14.6 mmol, 1.5 eq) was added to an

ice-cooled solution of enone 25 (1.44 g, 9.7 mmol, 1.0 eq) in hexane (50 mL) under argon.

The reaction mixture was stirred for 2 h at this temperature. Methanol (50 mL) and tartaric

acid were added until the aluminium salts were dissolved. Diethyl ether (100 mL) and water

(50 mL) were added. The phases were separated and the aqueous phase extracted twice with

diethyl ether. The combined organic phases were washed with water, dried over magnesium

sulfate, filtered over Celite®, and concentrated under reduced pressure. 1.39 g (95%) of a

97

6 Experimental

yellowish oil was obtained. It was used without further purification in the next step.1H-NMR (300 MHz, CDCl3): δ 5.65 (m, 2 H), 4.78 (m, 1 H), 2.72 (m, 1 H), 2.51 (m, 1 H),

2.23 (br s, 2 H), 1.70 – 1.10 (m, 6 H). Further analytical data can be found in the literature.

AcO H

rac-3a,4,5,6,7,7a-Hexahydro-(1β ,3aα,4aα,7α,7aα)-4-7-methano-1H-inden-

1-yl acetate (11)[76]

C12H16O2, 192.25 g/mol, CAS 107407-81-8

Alcohol 26 (1.39 g, 9.25 mmol, 1.0 eq), DMAP (0.11 g, 0.93 mmol 0.1 eq),

and triethylamine (1.55 mL, 11.1 mmol, 1.2 eq) were dissolved in diethyl ether (20 mL)

under argon and cooled to 0 ◦C. Acetic anhydride (0.96 mL, 10.2 mmol, 1.1 eq) was added

dropwise. The reaction mixture was stirred at 0 ◦C for 2 h. The reaction was quenched by

addition of 2 M hydrochloric acid (50 mL). The phases were separated and the aqueous phase

was extracted twice with diethyl ether. The combined organic phases were washed with a

sat. aq. NaHCO3 solution, dried over magnesium sulfate, filtered, and concentrated under

reduced pressure. Flash chromatography (hexane / ethyl acetate = 9:1) yielded 0.55 g (31%)

of a colourless oil.1H-NMR (300 MHz, CDCl3): δ 5.89 (m, 1 H, CHolefin), 5.69 (m, 1 H, CHolefin), 5.56 (m, 1 H),

2.83 (m, 2 H), 2.34 (br s, 1 H), 2.13 (br s, 1 H), 2.05 (s, 3 H, C(O)CH3), 1.61 – 1.18 (m,

6 H). 13C{1H}-NMR (101 MHz, CDCl3): δ 171.0 (s, 1 C, C=O), 137.1 (s, 1 C, CHolefin), 129.7

(s, 1 C, CHolefin), 78.7 (s, 1 C), 51.1 (s, 1 C), 46.4 (s, 1 C), 41.3 (s, 1 C), 40.6 (s, 1 C), 39.5

(s, 1 C), 24.7 (s, 1 C), 23.7 (s, 1 C), 21.1 (s, 1 C, C(O)CH3). EA: Anal. Calcd. for C12H16O2

(192.25): C, 74.97; H, 8.39. Found: C, 74.90; H, 8.43.

PCl

N

N,N-diethyl-P-phenyl-phosphonamidous chloride (18)[183]

C10H15ClNP, 215.66 g/mol, CAS 4073-31-8

Diethylamine was distilled over potassium hydroxide under argon.

Dichlorophenylphosphine (14.9 mL, 110 mmol, 1.00 eq) was dissolved in hexane (100 mL)

under argon. Then, pyridine (17.8 mL, 220 mmol, 2.00 eq) was added slowly via an addition

funnel. After diethylamine (22.8 mL, 220 mmol, 2.00 eq) was added to the suspension, it was

refluxed (85 ◦C) for 3 h. The reaction mixture was filtered and concentrated under argon

and distilled under reduced pressure (95 ◦C, 2.5·10−2 mbar). Ca. 21 g (90%) of a colourless

liquid was obtained.1H-NMR (200 MHz, CDCl3): δ 7.82 –7.74 (m, 2 H, CHarom), 7.50 – 7.46 (m, 3 H, CHarom),

3.19 (m, 4 H, NCH2CH3), 1.15 (t, JHH = 7.2 Hz, 6 H, NCH2CH3). 31P{1H}-NMR (80 MHz,

98


CDCl3): δ 142 (s, 1 P).

Ph2PO

P HPh

ODiphenyl(2-(phenylhydrophosphoryl)phenyl)phosphine oxide (17)[144]

C24H20O2P2, 402.36 g/mol

A phenyl lithium solution (1.57 M in Bu2O, 20.4 mL, 32.0 mmol, 1.0 eq) was

diluted with diethyl ether (20 mL) under argon and cooled to –25 ◦C using a

cryostate. Triphenylphosphine oxide (8.90 g, 32.0 mmol, 1.0 eq) was added in one portion.

The mixture was stirred at –25 ◦C for 72 h. N,N-diethyl-P-phenyl-phosphonamidous chloride

(18) (6.6 mL, 38.4 mmol, 1.2 eq) was added slowly to the reaction mixture, then it was let

warm to rt overnight. The reaction was quenched by carefully adding 50% aq. hydrochloric

acid (150 mL). It was diluted with dichloromethane and the phases were separated. The

aqueous phase was extracted twice with dichloromethane. The combined organic phases

were washed with a sat. aq. NaHCO3 solution, dired over magnesium sulfate, filtered, and

concentrated under reduced pressure. Flash chromatography (CH2Cl2 → CH2Cl2/MeOH =

95:5, r f = 0.3) yielded 4.5 g (35%) of an offwhite solid.1H-NMR (200 MHz, CDCl3): δ 9.0 (d, JPH = 540 Hz, 1 H, P(O)H), 8.51 (m, 1 H, CHarom),

7.84 – 7.18 (m, 18 H, CHarom). 31P{1H}-NMR (80 MHz, CDCl3): δ 32.4 (d, JPP = 8 Hz, 1 P,

Ph2P(O)R), 15.4 (d, JPP = 8 Hz, 1 P, RPhP(O)H).

Ph2PP HPh

Diphenyl(2-(phenylphosphino)phenyl)phosphine (15)[145]

C24H20P2, 370.36 g/mol

Diphosphine dioxide 17 (200 mg, 0.50 mmol, 1.0 eq) and pyridine (0.482 mL,

5.96 mmol, 12.0 eq) were dissolved in toluene under argon. Trichlorosilane (0.221 mL,

2.19 mmol, 4.4 eq) was added. The suspension was refluxed (130 ◦C) for 7 h. The reaction

mixture was filtered in air, washed with diethyl ether, and concentrated under reduced

pressure. Flash chromatography (hexane/ethyl actetate = 99:1) yielded ca. 170 mg (91%) of

an air-stable white solid.1H-NMR (300 MHz, C6D6): δ 7.55 - 7.00 (m, 19 H, CHarom), 5.63 (dd, JPH = 219, 10 Hz, 1 H,

RPHPh). 13C{1H}-NMR (101 MHz, CDCl3): δ 142.0 8(1 C, Cq), 141.6 (1 C, Cq), 136.9 (1 C,

Cq), 136.6 (1 C, Cq), 135.1 (1 C, CHarom), 134.6 (2 C, CHarom), 134.5 (1 C, Cq), 133.9 (1 C,

CHarom), 133.8 (2 C, CHarom), 133.7 (2 C, CHarom), 129.1 (1 C, CHarom), 128.8 (1 C, CHarom),

128.7 (1 C, CHarom), 128.7 (1 C, CHarom), 128.6 (2 C, CHarom), 128.5 (2 C, CHarom), 128.5

(1 C, CHarom), 128.4 (2 C, CHarom). 31P{1H}-NMR (80 MHz, C6D6): δ –11.8 (d, JPP = 34 Hz,

1 P, Ph2PR), –47.2 (d, JPP = 34 Hz, 1 P, RPhPH). MS (HiResMALDI): m/z 371.1110, [M+]

(Calcd. for C24H20P+2 : 371.1113). EA: Anal. Calcd. for C24H20P2 (370.36): C, 77.83; H, 5.44;

99

6 Experimental

P, 16.73. Found: C, 77.70; H, 5.68; P, 16.67.

OO O

OEt

(2E)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-propenoic acid ethyl

ester (27)[147]

C10H16O4, 200.23 g/mol, CAS 64520-58-7

1,2:5,6-Di-O-isopropylidene-D-mannitol (2.62 g, 10 mmol, 1.0 eq) was suspended in an

aqueous sodium bicarbonate solution (5%, 20 mL) at 0 ◦C. Sodium periodate (2.78 g,

13 mmol, 1.3 eq) in water (20 mL) was slowly added. The mixture was let warm to rt and

stirred for 1 h before it was recooled to 0 ◦C. Triethyl phosphonoacetate (8.13 mL, 41 mmol,

4.1 eq) and an aqueous potassium carbonate solution (6 M, 65 mL) were added. After 10 min

the mixture was warmed to rt and stirred for 24 h. The reaction mixture was extracted 4

times with CH2Cl2, dried over magnesium sulfate, filtered and concentrated under reduced

pressure. The crude product was purified by flash chromatography (hexane / ethyl acetate

= 9:1). TLC: R f = 0.5 (hexane / ethyl acetate = 8:2, KMnO4 stain). 3.00 g (75%) of a

colourless liquid was obtained.1H-NMR (300 MHz, CDCl3): δ 6.91 (dd, JHH = 15.7, 5.7 Hz, 1 H, CHvinyl), 6.13 (dd, JHH =

15.7, 1.5 Hz, 1 H, CHvinyl), 4.7 (m, 1 H, CH2CHOR), 4.24 (q, JHH = 7.3 Hz, 2 H, OCH2CH3),

4.20 (dd, JHH = 6.6, 1.1 Hz, 1 H, ROCH2CH), 3.71 (dd, JHH = 8.1, 7.1 Hz, ROCH2CH), 1.48

(s, 3 H, C(CH3)2), 1.44 (s, 3 H, C(CH3)2), 1.33 (t, JHH = 7.1 Hz, 3 H, CH2CH3). Further

analytical data can be found in the literature.

OO OH(2E)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-propen-1-ol

(19)[147,148]

C8H14O3, 158.19 g/mol, CAS 79060-23-4

Ester 27 (2.88 g, 14.4 mmol, 1.0 eq) was dissolved in CH2Cl2 (75 mL) and cooled to –78 ◦C

under argon. A DIBALH solution (1 M in hexane, 35.9 mL, 35.9 mmol, 2.5 eq) was added

during 15 min. The reaction mixture was stirred for 2 h at –78 ◦C before water (2 mL) and an

aqueous solution of sodium potassium tartrate (80 mL) was added. The mixture was warmed

to rt and extracted 3 times with CH2Cl2. The organic phases were dried over magnesium

sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by

flash chromatography (hexane / ethyl acetate = 1:1), R f = 0.4 (KMnO4 stain). 2.25 g (99%)

of alcohol 19 was obatined.1H-NMR (300 MHz, CDCl3): δ 5.99 (m, 1 H, CHvinyl), 5.74 (m, 1 H, CHvinyl), 4.56 (q, JHH =

7.2 Hz, 1 H, CH2CHOR), 4.19 (m, 2 H, CH2OH), 4.12 (dd, JHH = 8.1, 6.0 Hz, 1 H, ROCH2CH),

3.63 (t, JHH = 7.9 Hz, 1 H, ROCH2CH), 1.45 (s, 3 H, C(CH3)2), 1.41 (s, 3 H, C(CH3)2).

100


Further analytical data can be found in the literature.

OO OAc(2E)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-propen-1-yl ac-

etate[180]

C10H16O4, 200.23 g/mol, CAS 130931-40-7

To a solution of alcohol 19 (5.01 g, 31.7 mmol, 1.0 eq), triethylamine (7.6 mL, 57.2 mmol,

1.8 eq), and DMAP (20 mg, 0.2 mmol, 6 mol-%) in THF (22 mL) was added acetic anhydride

(3.6 mL, 38.1 mmol, 1.2 eq) at 0 ◦C under argon. The reaction was stirred over night at

that temperature before it was concentrated under reduced pressure. The crude mixture was

taken up in CH2Cl2, washed three times with water and twice with brine. The aqueous phase

was extracted twice with CH2Cl2, dried over magnesium sulfate, filtered, and concentrated

under reduced pressure. The product was purified by flash chromatography (hexane / ethyl

acetate = 8:2) to yield 6.08 g (96%) of the acetate.1H-NMR (300 MHz, CDCl3): δ 5.91 (dt, JHH = 15.6, 5.3 Hz, 1 H, CHCH2), 5.76 (dd, JHH =

15.5, 6.7 Hz, 1 H, CH(O)CH=CH), 4.58 (d, JHH = 5.4 Hz, 2 H, CH2OC(O)CH3), 4.11 (dd, JHH

= 11.0, 4.6 Hz, 1 H, CH2OC(CH3)2), 3.61 (t, JHH = 5.2 Hz, 1 H, CH2OC(CH3)2), 2.09 (s, 3 H,

OC(O)CH3), 1.44 (s, 3 H, C(CH3)2), 1.40 /s, 3 H, C(CH3)2). Further analytical data can be

found in the literature.

OO Br(2E)-1-Bromide-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-propen

(28)[148]

C8H13BrO2, 221.09 g/mol, CAS 198402-59-4

To a solution of alcohol 19 (0.76 g, 4.9 mmol, 1.0 eq) and triphenylphosphine (1.54 g,

5.9 mmol, 1.2 eq) in CH3CN (40 mL) was added carbon tetrabromide (1.95 g, 5.9 mmol,

1.2 eq) at 0 ◦C under argon. After 5 min the mixture was warmed to rt. The reaction was

stirred at rt for 30 min before it was concentrated under reduced pressure. The crude product

was purified by flash chromatography (hexane / ethyl acetate = 9:1) to yield 0.54 g (50%) of

the allylic bromide.1H-NMR (300 MHz, CDCl3): δ 6.04 (m, 1 H, CHvinyl), 5.79 (m, 1 H, CHvinyl), 4.56 (q, JHH =

6.8 Hz, 1 H, CHOR), 4.15 (m, 1 H, CH2OC(CH3)2), 3.98 (d, JHH = 7.1 Hz, 2 H, CH2Br), 3.64

(m, 1 H, CH2OC(CH3)2), 1.46 (s, 3 H, C(CH3)2), 1.42 (s, 3 H, C(CH3)2). Further analytical

data can be found in the literature.

101

6 Experimental

OO OBn(2E)-1-Phenylmethoxy-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-

propen (29)[147]

C15H20O3, 248.32 g/mol, CAS 128373-64-8

To a solution of alcohol 19 (1.50 g, 9.5 mmol, 1.0 eq) in THF (14 mL) was added 1,10-

phenanthroline (2 crystals) under argon at –78 ◦C. A n-butyllithium solution (1.6 M in

hexane, 7 mL, 11.2 mmol, 1.2 eq) was added slowly and the reaction mixture turned red.

After 15 min HMPA (2.4 mL, 13.8 mmol, 1.5 eq) was added. During 10 min benzyl bromide

(1.9 mL, 16.0 mmol, 1.7 eq) was added and the mixture stirred for 1 h before it was let

warm to rt over night. The reaction mixture was washed three times with water, dried over

magnesium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography

(hexane / ethyl acetate = 9:1) afforded 1.57 g (67%) product.1H-NMR (300 MHz, CDCl3): δ 7.40–7.30 (m, 5 H, CHarom), 5.94 (dt, JHH = 15.2, 7.2 Hz,

1 H, CHvinyl), 5.77 (dd, JHH = 15.5, 7.6 Hz, 1 H, CHvinyl), 4.56 (dd, JHH = 17.9, 6.0 Hz, 1 H,

ROCHCH=CH), 4.55 (s, 2 H, OCH2Ph), 4.12 (q, JHH = 7.1 Hz, C(CH3)2OCH2), 4.07 (d, JHH

= 4.4 Hz, 2 H, CH2OBn), 3.63 (t, JHH = 7.8 Hz, 1 H, C(CH3)2OCH2), 1.46 (s, 3 H, C(CH3)2),

1.42 (s, 3 H, C(CH3)2). Further analytical data can be found in the literature.

HOHO OH(S,E)-Pent-3-ene-1,2,5-triol[147]

C5H10O3, 118.13 g/mol, CAS 1244773-11-2

Alcohol 19 (1.03 g, 6.5 mmol, 1.0 eq) was dissolved in methanol (10 mL). Aqueous hy-

drochloric acid (1.2 M, 19 mL) was added and the mixture stirred for 3 h. It was washed

three times with CH2Cl2. The aqueous phase was concentrated under reduced pressure. The

crude mixture was purified by flash chromatography (ethyl acetate / methanol = 9:1) to give

0.42 g (56%) of the desired product.1H-NMR (300 MHz, CDCl3): δ 5.90 (dt, JHH = 14.4, 4.3 Hz, 1 H, CHvinyl), 5.72 (dd,

JHH = 14.4, 5.8 Hz, 1 H, CHvinyl), 4.12 (m, 3 H, CH(OH) and CHCH2OH), 3.52 (m, 2 H,

CH2(OH)CH(OH)). Further analytical data can be found in the literature.

HOHO Br(S,E)-5-Bromopent-3-ene-1,2-diol[147]

C5H9BrO2, 181.03 g/mol

Allylic bromide 28 (0.78 g, 3.6 mmol, 1.0 eq) was dissolved in methanol (5 mL). Aqueous

hydrochloric acid (1.2 M, 11 mL) was added and the mixture stirred for 5 h. It was washed


crude mixture was purified by flash chromatography (hexane /ethyl acetate = 4:6) to give

0.12 g (17%) of the desired product.

102


1H-NMR (300 MHz, CDCl3): δ 6.05 (dt, JHH = 19.4, 5.6 Hz, 1 H, CHvinyl), 5.83 (dd, JHH

= 13.9, 5.6 Hz, 1 H, CHvinyl), 4.35 (m, 1 H, CH(OH)), 4.06 (dd, JHH = 22.8, 6.8 Hz, 2 H,

CH2Br), 3.74 (dd, JHH = 10.7, 4.8 Hz, 1 H, CH2(OH)), 3.60 (dd, JHH = 10.7, 6.9 Hz, 1 H,

CH2(OH)), 1.59 (br s, 2 H, OH).

HOHO OBn(2S,3E)-5-phenylmethoxy-3-Pentene-1,2-diol (30)[147]

C12H16O3, 208.25 g/mol, CAS 128373-66-0

Benzylate 29 (1.57 g, 6.3 mmol, 1.0 eq) was dissolved in methanol (10 mL). Aqueous

hydrochloric acid (1 M, 19 mL) was added and the mixture stirred for 5 h. It was washed


crude mixture was purified by flash chromatography (hexane /ethyl acetate = 4:6) to give

0.82 g (62%) of the desired product.1H-NMR (300 MHz, CDCl3): δ 7.40–7.30 (m, 5 H, CHarom), 5.96 (dt, JHH = 21.0, 5.4 Hz, 1 H,

CHvinyl), 5.77 (dd, JHH = 16.3, 5.6 Hz, 1 H, CHvinyl), 4.56 (s, 2 H, OCH2Ph), 4.28 (dd, JHH

= 8.2, 6.0 Hz, 1 H, CH(OH)), 4.09 (d, JHH = 5.6 Hz, 2 H, CH2OBn), 3.67 (dd, JHH = 11.3,

3.5 Hz, 1 H, CH2(OH)), 3.51 (dd, JHH = 11.2, 7.2 Hz, 1 H, CH2(OH)), 2.76 (br s, 2 H, OH).

Further analytical data can be found in the literature.

TsOHO OBn(S)-(E)-1-(4-Methylbenzenesulfonate)-5-(phenylmethoxy)-3-

pentene-1,2-diol (31)[147]

C19H22O5S, 362.44 g/mol, CAS 128373-68-2

A solution of 30 (0.81 g, 3.9 mmol, 1.0 eq) in pyridine (6 mL) under argon was cooled to 0◦C using a cryostate. Tosyl chloride (0.81 g, 4.3 mmol, 1.1 eq) was added and the reaction

mixture was stirred for 17 h at 0 ◦C. The reaction mixture was diluted with ethyl acetate

and washed twice with water and four times with an aqueous solution of copper sulfate. The

organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced

pressure. Flash chromatography (hexane / ethyl acetate = 7:3) afforded 1.06 g (75%) of the

product.1H-NMR (300 MHz, CDCl3): δ 7.82 (d, JHH = 6.5 Hz, 4 H, CHarom), 7.40–7.30 (m, 5 H,

CHarom), 5.95 (dt, JHH = 12.9, 5.2 Hz, 1 H, CHvinyl), 5.70 (dd, JHH = 12.9, 5.2 Hz, 1 H,

CHvinyl), 4.53 (s, 2 H, OCH2Ph), 4.44 (m, 1 H, CH(OH)), 4.10 (m, 4 H, CH2OTs and CH2OBn),

2.48 (s, 3 H, PhCH3). Further analytical data can be found in the literature.

103

6 Experimental

TsOTBDMSO OBn(S,E)-5-(Benzyloxy)-2-((tert-butyldimethylsilyl)oxy)pent-3-en-1-

yl 4-methylbenzenesulfonate[184]

C25H36O5SSi, 476.70 g/mol

Alcohol 31 (1.06 g, 2.9 mmol, 1.0 eq) was dissolved in DMF (0.3 mL) under argon. Oven-

dried potassium carbonate (0.41 g, 2.9 mmol, 1.0 eq) was added to the solution and this

was stirred at rt for 5 min before TBDMSCl (0.50 g, 3.3 mmol, 1.1 eq) was added. The

reaction was stirred over night and then filtered. The filter cake was washed with CH2Cl2.

The combined filtrates were concentrated under reduced pressure and subjected to flash

chromatography (hexane / ethyl acetate = 9:1) to yield 0.17 g (12%) of product.1H-NMR (300 MHz, CDCl3): δ 7.82 (d, JHH = 8.6 Hz, 4 H, CHarom), 7.40-7.30 (m, 5 H,

CHarom), 5.89 (dt, JHH = 14.3, 5.7 Hz, 1 H, CHvinyl), 5.65 (dd, JHH = 17.1, 5.7 Hz, 1 H,

CHarom), 4.52 (s, 2 H, OCH2Ph), 4.42 (q, JHH = 4.0 Hz, 1 H, CH(OSiR)), 4.03 (d, JHH =

5.4 Hz, 2 H, CH2OBn), 3.90 (dd, JHH = 27.6, 5.8 Hz, 1 H, CH2OTs), 3.89 (dd, JHH = 8.0,

5.8 Hz, 1 H, CH2OTs), 2.47 (s, 3 H, PhCH3), 0.88 (s, 9 H, C(CH3)3), 0.09 (s, 3 H, SiCH3),

0.08 (s, 3 H, SiCH3).

AsH

Diphenylarsine[163]

C12H11As, 230.14 g/mol, CAS 829-83-4

Prior to use, 1,4-dioxane was distilled over sodium and degassed by three

cycles of freeze-pump-thaw. Triphenylarsine (3.06 g, 10 mmol, 1.0 eq) was dissolved in

1,4-dioxane (13 mL). Then potassium (1.02 g, 26 mmol, 2.6 eq) was added and the mixture

was refluxed (110 ◦C) for 3.5 h to obtain a red mixture. It was then cooled in an ice

bath, and degassed water was added slowly. The whole workup procedure was done under

an argon atmosphere. The aqueous phase was extracted twice with diethyl ether. The

combined organic phases were washed with water, dried over magnesium sufate, filtered,

and concentrated. Distillation in vacuo (Tvap = 71 ◦C, 10−3 mbar) gave ca. 1.2 g (52%) of a

colourless, airsensitive liquid.1H-NMR (250 MHz, C6D6): δ 7.55 – 7.48 (m, 4 H, CHarom), 7.18 – 7.11 (m, 6 H, CHarom),

5.02 (s, 1 H, AsH). Arsenic compounds could not be subjected to EA or MS.

Na+

THF

Sodium indenide THF adduct[185]

C13H15NaO, 210.25 g/mol, CAS 23181-84-2

A solution of indene (90%, 3.24 mL, 25 mmol, 1.0 eq) in THF (20 mL) was

added to a suspension of sodium hydride (0.96 g, 40 mmol, 1.6 eq) in THF

(10 mL) during 1 h at rt under argon. The reaction mixture was stirred overnight before it

104

6.3 Unsuccessful Attempts to Functionalise the Allylic Phosphine

was filtered by cannula. The filtering process was stopped after ca. 35%. The filtrate was

concentrated in vacuo and washed 5 times with pentane. Drying in vacuo yielded 1.36 g

(corrected ca. 70%) of a light violet powder.1H-NMR (300 MHz, d8-THF): δ 7.35 (m, 2 H, CHarom), 6.64 (m, 1 H, CHarom), 6.44 (m, 2 H,

CHarom), 5.98 (m, 2 H, CHarom), 3.65 (m, 4 H, OCH2CH2), 1.81 (m, 4 H, OCH2CH2).


Ph Ph

PPh2O

OJacobsen Epoxidation of Allylic Phosphine Oxide 12[123]

To a solution of phosphine oxide 12 (0.1 g, 0.25 mmol, 1.0 eq) and

Jacobsen’s catalyst (CAS 149656-63-3, 3.2 mg, 2 mol-%) in CH2Cl2 at 0 ◦C

was added an aqueous solution of sodium hypochlorite (0.6 M, 0.7 mL, 0.38 mmol, 1.5 eq).

The mixture was stirred vigorously at 0 ◦C for 30 min before it was let warm to rt and stirred

for 5 days. The mixture was diluted with water and extracted twice with ethyl acetate. The

organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced

pressure. The substrate was recovered by flash chromatography (hexan / ethyl acetate = 1:1).

Ph Ph

PPh2O

OShi Epoxidation of Allylic Phosphine Oxide 12[124]

Allylic phosphine oxide 12 (100.0 mg, 254 µmol, 1.0 eq) was dissolved

in THF (8 mL). To this solution, D-Epoxone® (CAS 18422-53-2, 19.6 mg,

76 µmol, 0.3 eq), [NBu4][HSO4] (3.4 mg, 4 mol-%), and an aqueous disodium tetraborate

/ disodium EDTA buffer solution (0.05 M in borate, 0.4 mM in EDTA, 2.54 mL) were added.

The mixture was cooled in an ice bath. By means of a syringe pump, a solution of Oxone®

(CAS 104548-30-3, 0.21 M, 1.65 mL, 355 µmol, 1.4 eq) in 0.4 M aqueous disodium EDTA

and an aqueous solution of potassium carbonate (0.89 M, 1.65 mL, 1.47 mmol, 5.8 eq) were

added during 1.5 h. The reaction mixture was the let warm to rt and stirred for 63 h. The

volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate

and washed with water. The aqueous phase was extracted twice with ethyl acetate, dried over

magnesium sulfate, filtered, and concentrated under reduced pressure. The starting material

was recovered.

Ph Ph

PPh2O

IHydroiodination of Allylic Phosphine Oxide 12 with HI in AcOH[121]

Preparation of HI in AcOH: aqueous HI (57%, ca. 3 mL) was washed with

triethylphosphate (ca. 5 mL) in CH2Cl2 (20 mL) to get a colourless solution.

105

6 Experimental

The aqueous acid (2 mL) was placed in a Schlenk flask under Ar. Acetic anhydride (3.8 mL,

1 eq to water) was added carefully at 15 ◦C.

To this acid solution, allylic phosphine oxide 12 (50 mg, 0.127 mmol) was added. The

mixture was stirred at 120 ◦C for 24 h before the mixture was concentrated in vacuo as far

as possible. The mixture was filtered over silica (CH2Cl2 / ethyl acetate = 4:6). The filtrate

was diluted with ethyl acetate and washed with water and an aqueous sodium thiosulfate

solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated

under reduced pressure. The reduced phosphine oxide, 1,3-diphenyl-1-(diphenylphosphine

oxide)propane, was detected by 1H-NMR.

Ph Ph

PPh2O

IHydroiodination of Allylic Phosphine Oxide 12 with I2 and PMHS[122]

To a mixture of phosphine oxide 12 (45 mg, 0.114 mmol, 1.0 eq) and PMHS

(388 mg, 0.171 mmol, 1.5 eq) in chloroform (2 mL) was added iodine

(29 mg, 0.114 mmol, 1.0 eq). The reaction was stirred at rt for 30 h before the volatiles were

removed in vacuo. The residue was filtered over silica (heptane / ethyl acetate = 1:1→ 1:2).

In addition to PMHS, only starting material was detected.

Ph Ph

PPh2O

IHydroiodination of Allylic Phosphine Oxide 12 with Aqueous HI

Allylic phosphine oxide 12 (50 mg, 0.127 mmol) was suspended in aqueous

HI (7.4 M, 2 mL). The mixture was warmed to 120 ◦C and stirred for 24 h

before it was cooled to rt and diluted with water. The reaction mixture was neutralised

with a saturated aqueous sodium carbonate solution and extracted three times with ethyl

acetate. The brownish organic phase was washed with a sodium thiosulfate solution and

brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Flash

chromatography (CH2Cl2 / ethyl acetate = 4:6) yielded 20 mg (36%) of a brownish solid.

Additionally, 24 mg of the reduced phosphine oxide, 1,3-diphenyl-1-(diphenylphosphine

oxide)propane was isolated. The brownish solid decomposed and could not be characterised.

Ph Ph

PPh2O

BrHydrobromination of Allylic Phosphine Oxide 12 with HBr in AcOH

Phosphine oxide 12 (32 mg, 81.1 µmol) was dissolved in a solution of HBr

in acetic acid (5.7 M, 2 mL). The mixture was stirred for 1 h at rt before it

was diluted with water. The solution was neutralised with a saturated aqueous solution of

sodium carbonate and extracted three times with ethyl acetate. The combined organic phases

were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Only

106


starting material was detected.

Ph Ph

PPh2O

PCy2Hydrophosphination of Allylic Phosphine (Oxide) 2 (12) with HPCy2

[120]

Allylic phosphine 2 (50 mg, 0.132 mmol, 1.0 eq) or allylic phosphine

oxide 12 (50 mg, 0.127 mmol, 1.0 eq) and potassium tert-butoxide (3 mg,

0.026 mmol, 0.2 eq) were dissolved in DMSO. To this solution dicyclohexylphosphine (29 µL,

0.145 mmol, 1.1 eq) was added. The reaction was stirred for 17 h at rt. TLC showed no

conversion and the reaction was stirred for another 24 h at 40 ◦C without any progress.

Ph Ph

PPh2O

SiCl3Hydrosilylation of Allylic Phosphine Oxide 12 with HSiCl3

[125]

Allylic phosphine oxide 12 (50 mg, 0.127 mol, 1.0 eq), [Pd(dba)2] (0.7 mg,

1 mol-%), and triphenylphosphine (0.3 mg, 1 mol-%) were dissolved in

CH2Cl2 under argon. The solution was cooled to 0 ◦C and trichlorosilane (16 µL, 1.58 mmol,

1.3 eq) was added. The reaction was slowly let warm to rt and stirred over night. No

conversion was detected.

Ph

Ph2PPh

PPh2O

OMetathesis of Allylic Phosphine Oxide 12[126]

Allylic phosphine oxide 12 (20.0 mg, 51 µmol, 1.0 eq) and Grubbs catalyst

I (CAS 172222-30-9, 2.1 mg, 5 mol-%) were dissolved in CH2Cl2 (1.5 mL)

under argon. The reaction was kept at 43 ◦C for 24 h. No conversion was

detected.

107

6 Experimental

108

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7 Appendix

7.1 Abbreviations

Ac acetyl

aq. aqueous

arom aromatic

Bn benzyl

Bu butyl

dba dibenzylideneacetone

CIP Cahn-Ingold-Prelog system for the assignment of stereoconfiguration

Cp cyclopentadienyl

Cp* pentamethylcyclopentadienyl

DIBALH diisobutylaluminium hydride

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

DMSO dimethylsulfoxide

dr diastereomeric ratio

EA elemental analysis

EDTA ethylenediaminetetraacetic acid

ee enantiomeric excess

Et ethyl

eq equivalent

h hour

HMPA hexamethylphosphoramide

HPLC high performance liquid chromatography

Hz Hertz

IR infrared

J coupling constant

Me methyl

MeOH methanol

min minute

NMR nuclear magnetic resonance

Np naphthyl

ORTEP Oak Ridge thermal ellipsoid plot

xiii

Appendix

OTf trifluoromethanesulfonate (triflate)

oTol ortho-tolyl

Ph phenyl

PMHS polymethylhydrosiloxane

ppm parts per million

rt room temperature

sat. saturated

SPO secondary phosphine oxide

TBAA tetrabutylammonium acetate

TBAF tetrabutylammonium fluoride

TBAT tetrabutylammonium difluorotriphenylsilicate

TBDMS tert-butyldimethylsilyl

tBu tert-butyl

THF tetrahydrofuran

TMDS tetramethyldisiloxane

TMEDA tetramethylethylendiamine

Ts tosyl

xiv

Appendix

7.2 List of Numbered Compounds

1 [Pd(η3-1,3-Ph2Allyl)(κ2-Josiphos)]SbF6

2 (E)-(1,3-Diphenylallyl)diphenylphosphine

3 (Z)-(1,3-Diphenylprop-1-en-1-yl)diphenylphosphine

4 (1,3-Diphenylpropyl)diphenylphosphine

5 Tetraphenyldiphosphine

6 Phosphafluorene

7(R)-1-{(S)-2-[Bis[3,5-bis(trifluoromethyl)phenyl]phosphino]ferrocenyl}-

ethyldicyclohexylphosphine ("CF3-Josiphos")

8(R)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine

("tBu-Josiphos")

9(S)-1-[(R)-2-(Dicyclohexylphosphino)ferrocenylethyl]diphenylphosphine

("Inverse Josiphos")

10(R)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyl-phoblyphosphine

("Phobyl-Josiphos")

11 rac-3a,4,5,6,7,7a-Hexahydro-(1β ,3aα,4aα,7α,7aα)-4-7-methano-1H-inden-1-yl acetate

12 (E)-(1,3-Diphenylallyl)diphenylphosphine oxide

13 Di-µ2-chlorobis[2-[1-(dimethylamino-κN)ethyl]-κC-ferrocenyl]-dipalladium

14 (E)-(1,3-diphenylallyl)(2-(diphenylphosphino)phenyl)(phenyl)phosphine

15 Diphenyl(2-(phenylphosphino)phenyl)phosphine

16 Diphenyl(2-(phenylphosphino)phenyl)phosphine oxide

17 Diphenyl(2-(phenylhydrophosphoryl)phenyl)phosphine oxide

18 N,N-diethyl-P-phenyl-phosphonamidous chloride

19 (2E)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-propen-1-ol

20 (E)-P,P-Diborano-1,5-bis(phenylphosphino)pent-3-en-2-yl acetate

21 (E)-P-Borano-5-(benzyloxy)-1-(phenylphosphino)pent-3-en-2-yl acetate

22 (E)-1-(benzyloxy)-5-(phenylhydrophosphoryl)pent-3-en-2-yl acetate

23 (E)-(1,3-Diphenylallyl)diphenylarsine

24 rac-3a,4,5,6,7,7a-Hexahydro-(1α,3aα,4aα,7α,7aα)-4-7-methano-1H-inden-1-ol

25 rac-3a,4,5,6,7,7a-Hexahydro-(1α,3aα,4aα,7α,7aα)-4-7-methano-1H-inden-1-one

26 rac-3a,4,5,6,7,7a-Hexahydro-(1β ,3aα,4aα,7α,7aα)-4-7-methano-1H-inden-1-ol

27 (2E)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-propenoic acid ethyl ester

28 (2E)-1-Bromide-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-propen

29 (2E)-1-Phenylmethoxy-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-propen

30 (2S,3E)-5-Phenylmethoxy-3-pentene-1,2-diol

31 (S,E)-1-(4-Methylbenzenesulfonate)-5-(phenylmethoxy)-3-pentene-1,2-diol

xv

Appendix

7.3 Selected 31P-NMR Chemical Shifts

Compound C6D6 CD2Cl2 CDCl3

Ph Ph

PPh2s –1.5 –1.9 –0.1

Ph Ph

PPh2O

s 29.0a 31.4 32.1

Ph Ph

PCy2s 13.8 15.2

Ph Ph

PCy2O

s 48.6

HPPh2 d, JPH = 217 Hz –40.5 –39.9 –40.3

HP(O)Ph2 d, JPH = 482 Hz 17.6 20.4 21.7

HPCy2 d, JPH = 194 Hz –27.9 –27.8 –27.9

HP(O)Cy2 d, JPH = 431 Hz 45.4 48.3 50.0

PPh3 s –5.3 –5.5 –5.3

Ph2P–PPh2 s –14.7 –15.8 –14.6

PO O

O

O10, JPH = 11 Hz 3.2 0.0 0.0

JosiphosPCy2, d, JPP = 38 Hz 15.2 15.7 15.8b

PPh2, d, JPP = 38 Hz –25.6 –25.8 –25.7b

SbF6

Fe

PPh2

Cy2P Pd

PhPh PCy2 exo, d, JPP = 68 Hz 57.0 59.5 57.5

PCy2 endo, d, JPP = 68 Hz 56.5 58.7 57.6

PPh2 exo, d, JPP = 68 Hz 16.0 17.4 16.2

PPh2 endo, d, JPP = 68 Hz 15.9 16.0 15.6

Fe PdNMe2

ClPPh2

Ph

Ph

(R)-(S)-(S), s 49.3 50.3

(R)-(S)-(R), s 49.1 50.1

Table 9: Selected 31P-NMR chemical shifts relative to H3PO4 (85%), calibrated with external standard.apoorly soluble. bslow decomposition.

xvi

Appendix

7.4 Crystallographic Data

(1,3-Diphenylallyl)diphenylarsine (23)

identification code RR210 CCDC number

cryst. method. C6H6 empirical formula C27H23P

shape needle moiety formula C27H23P

color colourless Mr 422.37

cryst size (mm) 0.27 × 0.07 × 0.05 T (K) 100(2)

exp. time/frame (s) 6 solution method direct

crystal system orthorhombic space group Fdd2

a (Å) 35.848(7) α (◦) 90

b (Å) 40.949(8) β (◦) 90

c (Å) 5.6190(12) γ (◦) 90

V (Å3) 8248(3) Z 16

ρcalc (g cm−3) 1.360 µ (mm−1) 1.658

θmin, θmax (◦) 1.51, 28.37 F000 3488

limiting indices −47≤ h≤ 47 data 5165

−54≤ k ≤ 54 restraints 1

−7≤ l ≤ 7 parameters 253

collected/unique reflexions 21143 / 5165 Rint 0.0949

Tmax, Tmin ∆ρmax, ∆ρmin (e Å−3) 0.741, –0.473

final R [I > 2σ(I)] 0.0494 S 1.020

final R [all data] 0.0629 Flack parameter 0.006(12)

xvii

Appendix

7.5 Curriculum Vitae

Name Rochat

First Name Raphaël

Date of Birth 6th of August 1983

Citizenship Swiss

Education

06.2008 - 08.2012 Ph.D. in Chemistry, Laboratory of Inorganic Chemistry, ETH Zurich

Title of the thesis: ”Exploring the Palladium-Catalysed Enantioselective

Allylation of Phosphines, Phosphine Oxides, and Arsines”

Supervisor: Prof. Dr. Antonio Togni

Co-examiners: Prof. Dr. Hansjörg Grützmacher, Prof. Dr. Paul S. Pregosin

10.2006 - 10.2007 M.Sc. in Chemistry, ETH Zurich

Title of the thesis: ”Catalytic Asymmetric Allylic Phosphination”

Supervisor: Prof. Dr. Antonio Togni

10.2003 - 10.2006 B.Sc. in Chemistry, ETH Zurich

09.1999 - 08.2002 Matura (Mathematics and Natural Sciences), Gymnasium Minerva, Zurich

Working Experience

09.2011 - 01.2012 Lecture Assistant in the first-year ”Inorganic Chemistry” course

09.2011 - 01.2012 Teaching Assistant in the ”Basic Inorganic Chemistry Lab Course”

02.2011 - 05.2011 Supervising a semester student during her research project

09.2008 - 01.2011 Teaching Assistant in the ”Advanced Inorganic Chemistry Lab Course”

10.2007 - 04.2008 Internship in Medicinal Chemistry at F. Hoffmann-La Roche AG in Basel

List of Publications

• Rochat, R.; Butti, P.; Togni, A. "Enantioselective Allylation of Phosphines and Phosphine

Oxides", Poster Presentation, 24th ICOMC 2010, Taipeh, Taiwan.

xviii

Appendix

• Rochat, R.; Butti, P.; Togni, A. "Enantioselective Allylation of Phosphines and Phosphine

Oxides", Poster Presentation, Swiss Chemical Society Fall Meeting 2010, Zurich, Switzer-

land.

• Rochat, R.; Butti, P.; Togni, A. "Recent Developments in Palladium-catalysed Enantio-

selective Allylic Phosphination", Poster Presentation, EuCOMC XVIII 2009, Gothenburg,

Sweden.

• Rochat, R.; Butti, P.; Togni, A. "Recent Developments in Palladium-catalysed Enantio-

selective Allylic Phosphination", Poster Presentation, Swiss Chemical Society Fall

Meeting 2009, Lausanne, Switzerland.

• Rochat, R.; Butti, P.; Togni, A. "Palladium-Catalyzed Enantioselective Allylic Phosphin-

ation", Poster Presentation, Swiss Chemical Society Fall Meeting 2008, Zurich, Switzer-

land

• Butti, P.; Rochat, R.; Sadow, A. D.; Togni, A. "Palladium-Catalyzed Enantioselective

Allylic Phosphination", Angewandte Chemie International Edition 2008, 47, 4878–4881.

xix



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