POLITECNICO DI MILANO - opac.biblio.polimi.it

DIPARTIMENTO DI CHIMICA, MATERIALI E INGEGNERIA CHIMICA “Giulio Natta” Dottorato di Ricerca in Chimica Industriale e Ingegneria Chimica (CII) XXII ciclo 2007 - 2009

ASYMMETRIC SYNTHESIS BY ENZYME AND SOFT LEWIS ACID

CATALYSIS

Tesi di Dottorato di ASSEM MAHMOUD El SAYED BARAKAT Matricola: 710744

Coordinatore: Prof. Dr. Renato Rota Tutore: Prof. Dr. Claudio Fuganti Relatore: Prof. Dr. René Peters

POLITECNICO DI MILANO

This work is dedicated to my parents

A Gehad, mia moglie

& mio Figlio

ACKNOWLEDGEMENTS

It gives me great pleasure to express my deep sense of gratitude to Prof. Dr. Claudio Fuganti for

introducing me to the fascinating area of organic chemistry and his astute guidance. His receptive

attitude, untiring enthusiasm and positive approach will always remain a source of inspiration.

I am greatly thankful to Dr. Stefano Sera for his scientific guidance, stimulating suggestions and

encouragement related to this work. I am indebted for his kind care and concern in the lab.

My sincere thanks to Prof. Dr. Elisabetta Brenna for the valuable scientific discussions, during the

course of this work and for her excellent help in proofreading this manuscript .

I sincerely would like to thank Prof. Dr. René Peters for his support, encouragement, for his

guidance and numerous discussions during these years. I am grateful to him for giving me the

opportunity to work in his laboratory at ETH, Zurich, Switzerland and then at university of

Stuttgart, Germany as exchange student for one and half year.

I would like to thank Dr. Philip Kraft, Givaudan Schweiz AG, Fragrance Research, Dübendorf,

Switzerland, for the olfactory descriptions and for the threshold determinations.

My warmest thanks goes to my former and present colleagues from our research groups for

providing me a friendly and academically environment over the last years (Francesco G. Gatti,

Daneilla Acetti, Fabio Parmeggiani, José Cabrera-Crespo, Daniel Fischer, Simon Eitel, Haoxi

Huang, Florian Koch, Thomas Kull, Frank Maier, Helen Taylor, Paolo Tiseni, Manuel Weber,

Zhuoqun Xin). My special thanks to Dr. Daniel Fischer for helping me in various ways during the

course of this work at ETH, Zurich.

I would like to thank prof. Stefano srevi, head of department and his group for their kind

cooperation.

Moreover, I would like to thank all the people at the services of the Politecnico di Milano, ETH

Zürich and the University of Stuttgart for their help in recording the NMR spectra and the library

staff for excellent facilities.

A special thanks goes to prof. Dr. Renato Rota, coordinator of PhD students for his kind

cooperation. My special thanks to Mrs. Myriam Oggioni for her help and cooperation.

I am grateful to all the nice people with whom I shared many delightful moments and who made my

stay at Milano, Zurich, and Stuttgart pleasant.

A special thanks goes to Prof. Dr. Mohammed shaban, Prof. Dr. Adel Zaki, and Dr Mahmoud

Fawzi for helping me during master course.

A special thanks goes to Prof. Dr.Giuseppe Guanti, Prof. Dr. Luca Banfi, Prof. Dr. Renata Riva,

and Dr. Andrea Basso for their help during my stay for one year at university of genoa, Italy.

I gratefully acknowledge the financial support by the Politecnico di Milano and allowing me to go

to ETH, Zurich and University of Stuttgart for one and half year; more over for facilitating me to

attend the international conferences. My Special thanks goes to ETH and University of Stuttgart for

providing the necessary research facilities.

I am indebted to my parents and my family members who have constantly encouraged me and I am

grateful to them for all their sacrifices.

Finally, I would like to thank my wife for her patience, encouragement, and great support.

List of publications

Parts of this thesis have been published:

1. D. F. Fischer, A. Barakat, Z-q. Xin, M. E. Weiss, R. Peters., The Asymmetric Aza-Claisen

Rearrangement: Development of Widely Applicable Pentaphenylferrocenyl Palladacycle

Catalysts., Chem. Eur. J. 2009, 15, 8722. (VIP)

2. A. Barakat, E. Bernna, C. Fuganti, S. Serra, Synthesis, olfactory evaluation, and

determination the absolute configuration of the β- and γ-Iralia® isomers, Tetrahedron:

Asymmetry 2008, 18, 2316.

3. S. Serra, A. Barakat, C. Fuganti, Chemoenzymatic Resolution of Cis and Trans 3,6-

dihydroxy-α-ionone. Synthesis of the enantiomeric forms of dehydrovomifoliol and 8,9-

dehydrotheaspirone, Tetrahedron: Asymmetry 2007, 18, 2573.

Posters and presentation:

1. poster: Lipase mediated resolution of Cis and Trans-3,6-dihydroxy-α-ionone. Some

applications to the synthesis of dehydrovomifoliol and 8,9-dehydrotheaspirone. A. Barakat,

S. Serra. Organic chemistry “Target synthesis: challenges, Strategies and Methods”

Séminairehors-ville du 3éme cycle en chimie 2007 (CUSO-2007). Villars,

Switzerland, Sept, 2007.

2. attending: International symposium metal–catalyzed syntheses new ways forward for industrial processes). Accademia nationale dei lincei, fondazione “guido donegani” Roma, Italy, May, 2007.

I

Table of Contents

Abstract. 1

Chapter 1: Introduction 5

1.1 The Impact of Molecular Chirality 5

1.2 The Preparation of Enantiopure Molecules 6

1.2 Biocatalysis 8

1.2.1 Enzymes and Carbon-Carbon Bond Formation 9

1.2.3 Enzymes and Epoxidation 10

1.2.4 Enzymes and Redcution 11

1.2.5 Lipases as Biocatalysis in Organic Synthesis 11

1.2.6 Enzymes and Transamination 12

1.3 Application of Biocatalysis 12

1.3.1 Enzymes and Chiral Intermediates for Pharmaceuticals 13

1.3.2 Applications of Biocatalysis in Fragrance Chemistry 13

1.4 Chemocatalysis 14

1.4.1 Pd(II)- and Pd(0)-Catalyzed Reactions 16

1.4.2 Enantioselective Synthesis 17

1.4.2.1 Asymmetric Allylic Alkylation (AAA) 17

1.4.2.2 Asymmetric Heck Reactions 19

1.4.3 Palladacycles 19

1.4.4 Application of Palladacyles 20

1.4.4.1 Michael Additions 20

1.4.4.2 Asymmetric aza-Claisen Rearrangements 21

1.4.5 Platinacycles 25

1.5 Enzymes in Combination with Metal Catalysts for Asymmetric Catalysis 26

1.6 Conclusion 27

7.7 References and Notes 27

Chapter 2 33

Chemoenzymatic Resolution of cis- and trans -3,6-dihydroxy-α-ionone. Synthesis of the Enantiomeric

Forms of Dehydrovomifoliol and 8,9-Dehydrotheaspirone 33

2.1 Introduction 33

2.1.1 General Introduction, Motivation 33

2.2 Literature Overview. 33

2.2.1 known Ionone Isomers. 33

2.3 Results and Discussion 36

2.3.1 Preparation of Racemic Diols 36

II

2.3.2 Lipase-mediated Resolution of Diols 37

2.3.3 Determination of the Absolute Configuration of Acetates; Synthesis of

Dehydrovomifoliol.

2.3.4 Synthesis of the Enantiomeric Forms of 8,9-Dehydrotheaspirone. 40

2.3.5 Olfactory Evaluation of the Enantiomeric Forms of Dehydrotheaspirone 41

2.4 Conclusion 41

2.5 Reference 42

Chapter 3 45

Synthesis, Olfactory Evaluation and Determination of the Absolute Configuration of the β- and γ-

Iralia® Isomers 45

3.1 Introduction. 45

3.2 General Introduction, Motivation. 45

3.3 Literature Overview. 46

3.4 Results and Discussion. 47

3.4.1 Preparation of β-Isomers 47

3.4.2 Preparation of γ-Isomers 48

3.4.3 Synthesis of Enantioenriched γ-Iralia Isomers 50

3.4.4 Determination of the Absolute Configuration of γ-Iralia Isomers 51

3.4.5 Olfactory Evaluation of the Iralia Isomers 52

3.5 Conclusion 53

3.6 References 53

Chapter 4 55

The Asymmetric Aza-Claisen Rearrangement: Development of Widely Applicable

Pentaphenylferrocenyl Palladacycle Catalysts 55

4.1 Introduction 55

4.1.1 General Introduction and Motivation 55

4.1.2 Literature Overview 55

4.1.2.1 Structural Variety of Chiral Ferrocenyl Oxazoline Ligands 56

4.1.2.2 Chiral Ferrocenyl Oxazoline Ligands and Palladacycles 58

4.1.2.3 Direct Enantioselective and Diastereoselective Cyclopalladations 59

4.1.2.4 Chiral Ferrocenyl Oxazoline Derived Palladacycles and their Application 63


4.2.1 Synthesis of Oxazoline Palladacycles 74

4.2.2 Determination of the Absolute Configuration 76

4.2.3 Catalysis with Known Substrates 77

4.2.4 Catalysis 80

4.2.5 Challenging New Substrates 86

III

4.2.6 Rearrangement of Thiocarbamates 90

4.3 Modified Catalyst Design Model for the Asymmetric Aza-Claisen Rearrangement 90

4.4 Models for the Enantioselectivity Determining Step in the Aza-Claisen Rearrangement 91

4.5 Scale up of the Rearrangment of Trifluoroacetimidate and Recycling of PPFOP-Cl 93

4.6 Conclusion 94

4.7 References 95

Chapter 5 97

Intramolecular Hydroamination of Unactivated Olefins using a Highly Strained Planar Chiral

Platinacycle. 97

5.1 Introduction. 97

5.1.1 General Introduction and Motivation 97



5.2.1 Synthesis of a Bisimidazoline Platinacycle 105

5.2.2 Synthesis of Amino Olefin 105

5.2.2.1 General Procedure for the Synthesis of 4-Mono-substituted Amino Olefins 100

5.2.2.2 4,5-Di-substituted Amino Olefins 106

5.2.3 Results and Discussion 108

5.2.3.1 Catalysis 108

5.2.3.2 Investigation of the Influence of the Silver Salt 109

5.2.3.3 Investigation of the Influence of the Amino Protecting Group 110

5.2.3.4 Investigation of the Influence of Additives 111

5.3 Attempts to the Development of an Improved Catalyst 113

5.4 Development of New Catalysts 114

5.4.1 Ligand Preparation. 115

5.4.2 Screening Different Conditions for Cycloplatination 116

5.5 Conclusion 118

5.6 References 118

Chapter 6 121

Miscellaneous. 121

6.1 Synthesis of a Methoxy-substituted Pentaphenyl Ferrocenyl Imidazoline Palladacycle 121



6.2 Synthesis of a Pentaphenyl Ferrocenyl Oxazoline Palladacycle with a Pd(III) Center 125



6.3 Intramolecular Hydroalkoxylation of Unactivated Olefins 127


IV


6.3.2.1 Synthesis of Hydroxy Olefins 127

6.3.2.2 Optimization of the Reaction Conditions for Intramolecular Hydroalkoxylation of

Unactivated Olefins 128

6.4 Cyclization of Alkenyl β–diketone esters by Hydroalkylation. 131



6.4.2.1 Synthesis of Alkenyl β-keto Esters 131

6.4.2.2 Optimization of Reaction Conditions for Cyclization of Alkenyl β-keto Esters 125

6.5 Synthesis of 4,5-Didehydroionone Stereoisomers. 135

6.5.1 Literature Overview. 135

6.5.2 Results and Discussion. 137

6.5.2.1 Synthesis of 4,5-Didehydro-α-ionone 137

6.5.2.2 Synthesis of 4,5-Didehydro-β and γ-ionone 137

6.6 Conclusion 139

6.7 References 139

Chapter 7 143

Experimental 143

General 143

Synthesis of the Enantiomeric Forms of Dehydrovomifoliol and 8,9-Dehydrotheaspirone. 145

Synthesis of racemic (3RS,6SR)-3,6-dihydroxy-γ-ionone and of (3SR,6SR)-3,6-dihydroxy-γ-ionone

145

(3RS,6SR)-3,6-Dihydroxy-γ-ionone (±) 145

(3SR,6SR)-3,6-Dihydroxy-α-ionone (±) 146

General Procedure for Lipase-mediated Resolution of Racemic Substrates (±)( GP1) 147

Resolution of (3RS,6SR)-3,6-dihydroxy-γ-ionone (±) 147

(3S,6R)-3-acetoxy-6-hydroxy-α-ionone (−) 148

(3R,6S)-3-acetoxy-6-hydroxy-α-ionone (+) 148

Resolution of (3SR,6SR)-3,6-dihydroxy-α-ionone (±) 148

(3S,6S)-3-acetoxy-6-hydroxy-α-ionone (+) 149

(3R,6R)-3-acetoxy-6-hydroxy-α-ionone (−) 149

General Procedure for Conversion of 3-acetoxy-6-hydroxy-α-ionone Isomers in the

Dehydrovomifoliol Enantiomers (GP2) 149

(−)-Dehydrovomifoliol 150

(+)-Dehydrovomifoliol 150

General Procedure for Conversion of 3-acetoxy-6-hydroxy-α-ionone Isomers in the 8,9-

Dehydrotheaspirone Enantiomers (GP3) 150

V

(R)-8,9-Dehydrotheaspirone (−) 151

(5R,8S)-2,6,10,10-tetramethyl-1-oxa-spiro[4.5]deca-2,6-dien-8-yl acetate (−) 151

(R)-8,9-Dehydrotheaspirone (−) 151

(S)-8,9-Dehydrotheaspirone (+) 152

(5S,8S)-2,6,10,10-tetramethyl-1-oxa-spiro[4.5]deca-2,6-dien-8-yl acetate (−) 152

(S)-8,9-Dehydrotheaspirone (+) 152

β- and γ-Iralia® Isomers. 153

Synthesis of β -Iralia Isomers 153

8-methyl β-ionone = (E)-3-Methyl-4-(2,6,6-trimethyl-cyclohex-1-enyl)-but-3-en-2-one 153

(E)-2-methyl-3-(2,6,6-trimethyl-cyclohex-1-enyl)-acrylic acid ethyl ester (β- isomer). 153

3,5-dinitrobenzoic acid (E)-2-methyl-3-(2,6,6-trimethyl-cyclohex-1-enyl)-allyl ester 154

8-methyl β-ionone 154

10-methyl β-ionone = (E)-1-(2,6,6-trimethyl-cyclohex-1-enyl)-pent-1-en-3-one 155

(E)-3-(2,6,6-trimethyl-cyclohex-1-enyl)-prop-2-en-1-ol 155

(E)-1-(2,6,6-trimethyl-cyclohex-1-enyl)-pent-1-en-3-one 156

Synthesis of Racemic γ- Iralia Isomers 157

General procedure for Epoxidation of α -Iralia isomers (GP4) 157

(4SR,5RS,6RS)-4,5-epoxy-4,5-dihydro-8-methyl α- ionone 157

(4SR,5RS,6SR)-4,5-epoxy-4,5-dihydro-8-methyl α- ionone 158

(4SR,5RS,6RS)-4,5-epoxy-4,5-dihydro-10-methyl α- ionone 158

(4SR,5RS,6SR)-4,5-epoxy-4,5-dihydro-10-methyl α- ionone 158

General Procedure for Conversion of Epoxide into allylic alcohol (GP5) 159

(4SR,6RS)-4-hydroxy-8-methyl γ-ionone 159

(4SR,6SR)-4-hydroxy-8-methyl γ-ionone 160

(4SR,6RS)-4-hydroxy-10-methyl γ -ionone 160

(4SR,6SR)-4-hydroxy-10-methyl γ-ionone 160

General Procedure for Reduction of Allylic Alcohol to γ-Iralia Isomers (GP6). 161

8-Methyl γ-ionone = (E)-4-(2,2-Dimethyl-6-methylene-cyclohexyl)-3-methyl-but-3-en-2-one (±)

161

10-Methyl γ-ionone = (E)-1-(2,2-Dimethyl-6-methylene-cyclohexyl)-pent-1-en-3-one (±) 162

Synthesis of Enantioenriched γ-Iralia Isomers 162

Lipase-mediated Resolution of Alcohols 162

(4R,6S)-4-acetoxy-8-methyl γ-ionone (−) 163

(4R,6S)-4-acetoxy-10-methyl γ-ionone (+) 163

(4S,6R)-4-hydroxy-8-methyl γ-ionone (+) 163

(4S,6R)-4-hydroxy-10-methyl γ-ionone (−) 164

VI

Preparation of Enantioenriched γ-Iralia Isomers. 164

(S)-(−)-8-Methyl-γ-ionone (−) 164

(S)-(+)-10-Methyl-γ-ionone (+) 164

(R)-(+)-8-Methyl-γ-ionone (+) 165

(R)-(−)-10-Methyl-γ-ionone (−) 165

General Procedure for Isomerization of γ-Iralia Isomers to α and β -Iralia Isomers (GP7) 165

Pentaphenylferrocenyl Palladacycle Catalysts. 166

Synthesis of Pentaphenylferrocenyl Oxazoline Palladacyles. 166

(S)-N-(1-Hydroxy-3-methylbutan-2-yl)-pentaphenylferrocenyl amide 166

(S)-4-Isopropyl-2-pentaphenyl-ferrocenyl-4,5-dihydrooxazole 167

Di-μ-acetato-bis[(η5-(S)-(SP)-2-(2′-(4′-methylethyl)oxazolinyl) cyclopentadienyl, 1-C, 3′-N)-(η5-

pentaphenyl cyclopentadiene) ferrocene]dipalladium 167

Di-μ-chloro-bis[(η5-(S)-(SP)-2-(2′-(4′-methylethyl)oxazolinyl) cyclopentadienyl, 1-C, 3′-N)(η5-

pentaphenyl cyclopentadiene) ferrocene]dipalladium 168

(1S,2R)-N-(1-Hydroxy-1,2-diphenylethan-2-yl)pentaphenyl-ferrocenylamide 169

(4S,5S)-4,5-Diphenyl-2-pentaphenyl-ferrocenyl-4,5-dihydrooxazole 170

Di-μ-acetato-bis[(η5-(4S,5S)-(SP)-2-(2′-(4′,5'-diphenyl)-oxazolinyl) cyclopenta- 170

dienyl, 1-C, 3′-N)(η5-pentaphenylcyclopentadiene) ferrocene]dipalladium 170

Di-μ-chloro-bis[(η5-(4S,5S)-(SP)-2-(2′-(4′,5'-diphenyl)oxazolinyl) cyclopenta- 171

dienyl, 1-C, 3′-N)(η5-pentaphenyl-cyclopentadiene) ferrocene]dipalladium 171

Synthesis of an o-methoxy-substituted pentaphenyl ferrocenyl imidazoline palladacycle 172

(4R,5R)-4,5-Bis(2-methoxyphenyl)-2-pentaphenylferrocenyl-1-tosyl-4,5-dihydro-1H-imidazole

172

Di-μ-chlorobis[η5-(4`R,5`R)-(Sp)-2-(2`-4`,5`-dihydro-4`,5`-di[2-methoxy-phenyl] 173

-1`-tosyl-1`H-imidazolyl)cyclopentadienyl, 1-C, 3`-N)(η5-pentaphenylcyclo- 173

pentadienyl)-iron(II)] dipalladium(II) 173

Synthesis of an o-methoxy-substituted ferrocenyl oxazoline. 174

(4R,5R)-4,5-Bis(2-methoxyphenyl)-2-ferrocenyl-4,5-dihydro-1H-imidazole 174

(4R,5R)-4,5-Bis(2-methoxyphenyl)-2-ferrocenyl-1-tosyl-4,5-dihydro-1H-imidazole 175

General Procedure for Pre-catalyst Activation and Catalysis (GP8) 176

Catalyst Activation (GP8a) 176

Catalysis (GP8b) 176

General Procedure forTrifluoroacetamide Cleavage and ee Determination (GP9) 176

GP9a: With NaBH4 176

GP9b: With MeLi 177

General Procedure for the Preparation of Allylic N-(4-methoxyphenyl) trifluoroacetimidates (GP10)

177

VII

Modification of GP10: Use of LHMDS as base (GP11) 178

Commercially available allylic alcohols 178

Via HWE-reaction 178

Representative procedure for HWE and DIBAL-reduction – (2E, 4E)-2,4-octadienol 179

Via cuprate-addition 180

Representative procedure: Trans-methyl-(5-phenyl)-pent-2-enoate 180

Trans-methyl-(3-methyl)-but-2-enoate 181

(E)-p-Trifluoromethyl-cinnamol 181

(E)-p-Chloro-cinnamol 182

(E)-p-Methyl-cinnamol 183

(E)-p-Methoxy-cinnamol 184

3,3-Disubstituted allylic alcohols and precursors 184

Ethyl-2-butynoate 184

(E)-3-Methyl-5-phenylpent-2-enoic acid methyl ester 185

(E)-3-Methyl-5-phenylpent-2-enol 186

(E)-Methyl 3-methyl-4-phenylbut-2-enoate 186

(E)-3-Methyl-4-phenylbut-2-en-1-ol 187

(E)-3-Methylhept-2-enol 187

4-Benzyloxybut-2-ynoic acid ethyl ester 188

(Z)-4-Benzyloxy-3-methylbut-2-enoic acid ethyl ester 189

(Z)-4-Benzyloxy-3-methylbut-2-enol 190

(Z)-4-Benzyloxy-3-ethylbut-2-enoic acid ethyl ester 191

(Z)-4-Benzyloxy-3-ethylbut-2-enol 192

(Z)-3-Benzyloxymethylhept-2-enoic acid ethyl ester 192

(Z)-3-Benzyloxymethylhept-2-enol 193

(Z)-3-Benzyloxymethyl-6-triisopropylsilanyloxyhex-2-enoic acid ethyl ester 194

(Z)-3-Benzyloxymethyl-6-triisopropylsilanyloxyhex-2-enol 195

Imidates: 196

N-PMP-substituted 196

(E)-2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidic acid hex-2-enyl ester 196

(Z)-2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidic acid hex-2-enyl ester 196

(E)-2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidic acid 4-methyl-pent-2-enyl ester 197

(E)-2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidic acid 3-phenyl-allyl ester 197

(E)-2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidic acid 3-cyclo-hexyl-allyl ester 198

(E)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-(p-trifluoromethylphenyl)propenyl

ester 198

(E)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-acetimidic acid 3-(p-chlorophenyl)-propenyl ester 199

(E)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-acetimidic acid 3-(p-methylphenyl)-propenyl ester 199

VIII

(E)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-acetimidic acid 3-(p-methoxyphenyl)-propenyl ester 200

(2E,4E)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-acetimidic acid-octa-2,4-dienyl ester 201

N-Aryl/alkyl-substitutet Allylic Imidates 201

N-(Cyclohexyl)-2,2,2-trifluoroacetimidoyl chloride 201

(E)-Hex-2-enyl N-cyclohexyl-2,2,2-trifluoroacetimidate 202

(E)-Hex-2-enyl N-phenyl-acetimidate 202

Quaternary 203

(E)-2,2,2-Trifluoro-N-(4-methoxyphenyl) acetimidic acid 3-methyl-5-phenyl-pent-2-enyl ester 203

(E)-3-Methyl-4-phenylbut-2-enyl)2,2,2-trifluoro-N-(4 methoxyphenyl)Acetimidate 204

(Z)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-methyl-5-benzyloxypent-2-enyl ester

204

(Z)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-ethyl-5-benzyloxypent-2-enyl ester 205

(Z)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-butyl-5-benzyloxypent-2-enyl ester 206

(Z)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-(3-triisopropyloxy- 206

silylpropyl)-5-benzyloxypent-2-enyl ester 206

(E)-O-Hex-2-enyl dimethylcarbamothioate 207

(E)-5-Phenylpent-2-enyl 2,2,2-trichloroacetimidate 207

Allylic Amides (rearrangement products) 208

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-propylallyl)-acetamide 208

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-iso-propylallyl)-acetamide 208

(S)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-phenylallyl)-acetamide 209

(S)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-cyclohexylallyl)-acetamid 209

(S)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(1-p-trifluoromethylphenyl-allyl)-acetamide 210

(S)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(1-p-chlorophenyl-allyl)-acetamide 211

(S)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(1-p-tolylallyl)-acetamide 211

(S)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(1-p-methoxyphenyl-allyl)acetamide 212

(S)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(1-pent-2-enyl-allyl)acetamide 213

(R)-N-cyclohexyl-2,2,2-trifluoro-N-(hex-1-en-3-yl)acetamide 213

(R)-N-phenyl-N-(hex-1-en-3-yl)acetamide 214

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-phenethyl-1-methylallyl)acetamide 214

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(2-methyl-1-phenylbut-3-en-2-yl)acetamide 215

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-benzyloxymethyl-1-methylallyl)acetamide 216

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-benzyloxymethyl-1-ethylallyl)acetamide 216

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-benzyloxymethyl-1-butylallyl)acetamide 217

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-benzyloxymethyl-1-[3-triisopropyl-

silyloxypropyl]allyl)acetamide 218

Allylic Amines (de-acylated amides) 218

(R)-N-(4-Methoxyphenyl)-3-amino-1-hexene 218

IX

(R)-N-(4-Methoxyphenyl)-3-amino-4-methyl-1-pentene 219

(S)-N-(4-Methoxyphenyl)-3-amino-3-phenyl-1-propene 219

(R)-N-Ethyl-N-(hex-1-en-3-yl) aniline 220

(R)-N-(5-phenylpent-1-en-3-yl)-cyclohexylamine 220

(R)-N-(4-Methoxyphenyl)-N-(1-phenethyl-1-methylallyl)amine 221

Miscellaneous: 222

(R)-2,2,2-Trichloro- N-(1-phenylethylallyl)acetamide 222

(R)-S-Hex-1-en-3-yl dimethylcarbamothioate 222

Synthesis of a bisimidazoline platinacycle 223

Optimization of Catalytic Hydroamination. 224

Synthesis of substrates 224

(Z)-Methyl 2,2-diphenyloct-4-enoate 224

(Z)-2,2-Diphenyloct-4-en-1-ol 225

(E)-2,2-Diphenyloct-4-en-1-ol 225

(Z)-Methyl 2,2-diphenyloct-5-enoate 226

(Z)-2,2-Diphenyloct-5-en-1-ol 227

2-Methyl-4,4-diphenyltetrahydrofuran 227

2-Butyl-4,4-diphenyltetrahydrofuran 228

5,5-diphenyl-2-propyltetrahydro-2H-pyran 228

(Z)-N-Benzyl-2,2-diphenylhept-4-en-1-amine 229

1-Benzyl-4,4-diphenyl-2-propylpyrrolidine 229

N-(3-Chlorobenzyl)-2,2-diphenylpent-4-en-1-amine 230

N-Phenethyl-2,2-diphenylpent-4-en-1-amine 230

(S)-1-(3-Chlorobenzyl)-2-methyl-4,4-diphenylpyrrolidine 231

(Z)-2,2-Diphenyloct-5-enenitrile 231

(Z)-2,2-Diphenyloct-5-en-1-amine 232

(Z)-Benzyl 2,2-diphenyloct-5-enylcarbamate 232

(Z)-Benzyl 2,2-diphenylhept-4-enylcarbamate 233

N-(2,2-Diphenylpent-4-enyl)acetamide 233

N-(2,2-Diphenylpent-4-enyl)-4-methylbenzenesulfonamide 234

Hammett-Plot of C-3-Aryl substituted allylic imidates 235

References 236

X

List of Acronyms and Abbreviations

Ac Acetyl aq. Aqueous Ar Aryl Bn Benzyl Boc tert-butyloxycarbonyl Bu Butyl BuLi n-butyllithium Cat. Catalyst Cbz Benzyl formate Cp Cyclopentadienyl DBU 1,8-Diazabicycloundec-7-ene DCM Dichloromethane DCE Dichloroethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIBAL Diisobutylaluminium hydride DIPEA N,N-diisopropylethylamine DMAP Dimethylaminopyridine DMF Dimethylformamide DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone Dpa Dibenzylideneacetone Dppe 1,2-Bis(diphenylphosphino)ethane d.r. Diastereomeric ratio ee Enantiomeric excess e.g For example EI Electron impact ionisation Et Ethyl equiv. Equivalent ESI Electron spray ionisation FBI Ferrocene bisimidazoline Fc Ferrocene FIP Ferrocene imidazoline palladacycle GP General procedure H Hour(s) HB Hünig`s base HMPA Hexamethylphosphoric acid triamide HPLC High performance liquid chromatography HR-MS High resolution-mass spectroscopy I Iso IR Infrared spectroscopy L.A. Lewis acid LDA Lithium diisopropylamide LHMDS Lithium bis(trimethylsilyl)amide M Meta Me Methyl MP Melting point MS Mass spectroscopy MTBE Methyl tert-butylether NBS N-bromosuccinimide N. D. Not determined NMR Nuclear magnetic resonance

XI

NOE Nuclear overhauser effect O Ortho P Para Ph Phenyl PMP p-methoxyphenyl PPFOP Pentaphenylferrocenyl oxazoline palladacycles P.S. Proton sponge RT Room temperature SM Starting material t, tert Tertiary TBAF Tetra-n-butylammonium fluoride TBS Tert-butyldimethylsilyl TEMPO 2,2,6,6-Tetramethylpiperidine-1-oxyl Tf Trifluoromethanesulfonyl THF Tetrahydrofuran TLC Thin layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine TMS Trimethylsilyl Ts p-toluenesulfonyl

Abstract

The subject of this thesis is the use of chiral catalysts which convert prochiral substrates into

enantiomerically pure (or enriched) compounds. A principal advantage of asymmetric catalysis as

compared to stoichiometric asymmetric synthesis is that a subequimolar quantity of a chiral entity

is sufficient for the enantioselective formation of a chiral product. This results in lower cost, fewer

reaction steps and less environmental pollution. Catalysis can be performed either by biocatalysts

or chemocatalysts. Biocatalysis was applied for the synthesis of enantiopure compounds by

enzymes. We have performed two examples by enzymes. The first example describes the

straightforward synthesis of both enantiomers of cis- and trans 3-acetoxy-6-hydroxy-α-ionone. The

compounds are prepared by resolution of the diastereoisomerically pure racemic 3,6-dihydroxy-α-

ionone isomers. The later process is based on two steps. The enantio- and regioselective lipase-

mediated acetylation of diols to afford the corresponding 3-acetoxy-derivatives, and the fractional

crystallization of the latter compounds increasing their optical purity. These building blocks were

used for the synthesis of both enantiomeric forms of the natural norterpenoids dehydrovomifoliol 1

and 8,9-dehydrotheaspirone 2. 8,9-Dehydrotheaspirone 2 is a natural flavor and its odour properties

were evaluated by professional perfumers (Scheme 1).

HO

O1) chemoenzymatic

resolution2) chemical

transformation O

O

OO

OH

cis and t rans diols 3 Dehydrovomifoliol Dehydrotheaspironeenantiomers 1 enantiomers 2

OH

Scheme 1

The second example performed by biocatalysis describes the regioselective synthesis of the methyl

ionones isomers. The enantiomers of the γ isomers are prepared by enzyme-mediated resolution of

the corresponding 4-hydroxy derivatives followed by reductive elimination of the hydroxy group.

Since all the obtained isomers are components of the artificial violet odorants sold under the trade

name of Iralia®, their odour properties have been evaluated by professional perfumers (Scheme 2).

2 Abstract

O

R

R'

O

R

R'O

R

R'

β -iralia isomers γ -iralia iosmers R = H, R' = MeR = Me, R' = H

Scheme 2

In modern synthetic chemistry, soft Lewis acids such as Pd(II), Pt(II) or Au(I) have become more

and more important, since coordination of these carbophilic cations to olefins or alkynes results in a

net transfer of electron density from the ligand to the metal center thus activating the unsaturated

system for the attack of the nucleophiles. The soft Lewis acid can thus be regarded as a

chemoselective (owing to its low oxophilicity) and possibly chiral proton substitute.

The Pd(II) catalyzed aza-Claisen rearrangement of allylic trichloro- and trifluoroacetimidates

enables the transformation of achiral allylic imidates 7, readily prepared from allylic alcohols 5 in a

single high yielding step, to chiral enantioenriched allylic amides 8. Since the trihaloacetamide

protecting groups can be readily removed, the overall transformation leads to allylic amines 9, the

valuable building blocks for the synthesis of important compound classes such as unnatural amino

acids. This is the second approach of this thesis (scheme 3).

R1

O

CX3

NR3

R1

O

CX3

NR2 R3

R2

Pd(II)

R1*

NH2R2

R3 = H, PMPX = Cl, F

R1

OHR2 CX3

NR3

Cl+

5 6 7 8 9

Scheme 3

To this end, pentaphenylferrocenyl oxazoline palladacycles PPFOP-Cl 4 have been created

(Scheme 4), affording the most active enantioselective catalyst for the aza-Claisen rearrangement

of trihaloacetimidates:

Introduction: BioCatalysis and Chemocatalysis 3

ON

Fe Ph

PhPhPh

Ph

iPr Pd Cl

2

ONR3

R1

CX3

R1

NR3

CX3

OR2

R2 1°/ 2°/ 3° allylic amines

3°/ 4° stereocenter s

[PdII]

PPFOP-Cl 4

1. Pd(OAc)2, AcOH,95 °C, 93%

2. LiCl, MeOH, PhH95%

Fe

PhPh

Ph

Ph PhHO

O

1. (COCl)2, DCM,cat. DMF

2. (S)-valinol, NEt3,DCM, 0 °Cto RT

3. TsCl, NEt3, DCM,cat. DMAP

91%

Fe

PhPh

Ph

Ph Ph

NO

i-Pr

11

10

Scheme 4

Nitrogen-containing saturated heterocyclic systems are important core structures in organic

chemistry because of their presence in many bioactive natural products. One of the most appealing

approach to these heterocycles is the intramolecular hydroamination, in which the nitrogen carbon

bond is formed by the addition of an amine to an olefin. In response to the limitations associated

with the hydroamination of unactivated C=C bonds, an effective Pt-catalyzed protocol for the

intramolecular hydroamination of amino alkenes has been applied (Scheme 5).

Fe

N

Pt

N

PhPh

Cl

Ts

NN

Ph

PhTs

(5 mol%) 12(5 mol%) Ag-salt,solvent, T,t

n = 1, 2

NHPGP N

R2

R1

R2

R1R3

PGP

R3

n n

12PGP = Protective group

Scheme 5

Chapter 1

Introduction.

1.1 The Impact of Molecular Chirality.

Chirality1 is an important aspect of the most fundamental processes of the life.2 The sugars that

constitute DNA and RNA possess a uniform stereochemical configuration. The proteins encoded

by these oligonucleotides, crucial for the chemical transformations in cells, consist of chiral α-

amino acids that occur exclusively in the L-configuration. Without this chiral homogeneity, the

biomachinery that makes up all known living organisms would not be able to function. Even in the

most elementary forms of life, such as bacteria3 a myriad of different chiral molecules are involved

in complex signaling pathways. Receptor proteins on the cell membrane or within the cytoplasm or

cell nucleus can specifically bind to one enantiomer of a chiral “messenger” molecule and initiate a

corresponding cellular response.

These diastereomeric interactions are the key to modern drug development.4 The interactions

between biological systems and synthetic chiral molecules has a huge impact on contemporary

everyday life and applications ranging from flavors, fragrances, and food additives to

agrochemicals and life-saving drugs. Homochirality in drugs is as old as the first therapeutic agents

isolated from natural sources, such as quinine and morphine. However, as products of synthetic

chemistry, until recently chiral drugs were manufactured as racemates. The assumption that only

one enantiomer of a drug has biological activity and the other serves as “isomeric ballast”4 has

turned out to be a rather dangerous one. The two enantiomers of a compound most frequently bind

to different receptors, and therefore have completely different physiological effects. The presence

of the “wrong” enantiomer has, in some cases, been known to cause serious side-effects. This has

resulted in severe restrictions5 to the production of bioactive molecules and at present time “single

enantiomer drugs have a commanding presence in the global pharmaceutical landscape”.6 The

development of efficient methodologies for the synthesis of the individual enantiomers of an

asymmetric target compound is, therefore, of continuous interest to scientists in both industry and

academia.

6 Chapter 1

1.2 The Preparation of Enantiopure Molecules.

The goal of asymmetric synthesis − whether it is done in an academic or an industrial setting − is to

prepare stereochemically-enriched compounds in the most efficient and practical manner possible.

However, the choice of strategy is rarely simple, because the ways in which efficiency and

practicality are defined can depend on a large number of factors. These can include scale, reagent

costs, time allotted and required, number of steps/manipulations, potential hazards, waste

generation, specifications for product purity, volumetric productivity and/or throughput,

availability of appropriate equipment, and even the scientific background of the synthetic chemists

involved.

In selecting a method for the preparation of an enantioenriched compound, one must therefore

consider the different alternatives. There are three fundamentally different approaches,7 and these

can be defined as follows:

● Chiral pool: use of enantiopure starting materials provided by Nature.

● Resolution: separation of enantiomers by chemical or physical means.

● Enantioselective synthesis: preparation from achiral precursors using chiral reagents or catalysts.

There are numerous instances where the chiral pool approach is unbeatable, either because the

requisite starting material is produced by Nature in great abundance or because the target is itself a

complex natural product and laboratory syntheses are very expensive relative to isolation from

natural sources. Unfortunately, the range of compounds provided by Nature is limited with respect

to structure and stereochemistry, and for this reason resolution and asymmetric synthesis will

certainly always be vitally important strategies for accessing enantiopure compounds. In figure 1.1

there are selected examples for the chiral pool approach.

HO2C

HO2C H

NH2

N

SH

CO2H

HN

MeMe

O

O

NH2

O

O

O

OH

Ampicllin: antibiotic 13 Bioallethrin 14

Glutamic acid 15 (+)-Limonene 16 (−)-Menthol 17 (−)-β -Pinene 18 Fig 1.1. Selected examples for the chiral pool approach.


Resolutions fall broadly into three classes. Classical resolutions involve the use of a stoichiometric

amount of a chiral resolving agent.8 The resolving agent is associated to the substrate, either

covalently or non-covalently, to generate a pair of diastereomers. The diastereomers are separated

and, through a separate chemical transformation, the substrate is released from the resolving agent.

This approach has proven to be especially useful if salt formation is straightforward, as in the case

of amines and carboxylic acids (e. g. Scheme 1.1).9

NH2H2N

HO OH

CO2HHO2C

H2O/HOAc90 to 5 °C

(±)-19 20 21 22

+NH3H3N

OOC COO

OHHO

K2CO3 (2.equiv.)H2O/EtOH

NH2H2N

> 98%ee

40-42%

Scheme 1.1. Classical resolution of trans-1,2-Cyclohexanediamine.

Chiral chromatography generally relies on the use of a chiral stationary phase to resolve

enantiomers contained in a mobile phase, and in principle it can be carried out on analytical or

preparative scale. In reality, the large solvent volumes, long separation times, and relatively high

costs of chiral chromatography often limit the scale at which chromatographic separations can be

carried out. Kinetic resolution involves using a chiral catalyst or reagent to promote selective

reaction of one enantiomer over the other giving a mixture of enantioenriched starting material and

product, and the desired component is then isolated (Scheme 1.2).10

SS + RR + Reagent SS + PR SS or PR

(racemic (isolated)substrat)

chiral catalyst separation

Scheme 1.2. Catalytic kinetic resolution.

The “classical” resolution of racemic mixtures by diastereomeric crystallisation, to date, often

constitutes the industrial method of choice to obtain large quantities of enantiopure compounds.11

However, unless it can be recycled, half of the racemic starting material (the “unwanted”

enantiomer) is a waste-product. This intrinsic property of classical resolutions poses a major

disadvantage from an atom-economy point of view.12 The same disadvantage applies to chemical

or enzymatic kinetic resolutions, involving a reaction in which one of the two enantiomers reacts

more rapidly than the other based on a difference in transition state Gibbs energy. Although in

certain cases, (dynamic) kinetic resolution can lead to complete conversion of the starting material

by in situ racemization, generally one enantiomer reacts whereas the other remains intact.

8 Chapter 1

The remaining option for the preparation of enantiopure molecules involves the introduction of

chirality to a prochiral substrate by asymmetric induction.13 This may involve the use of

stoichiometric amounts of a chiral reagent or a chiral auxiliary followed by the subsequent

diastereoselective introduction of a stereogenic center. However, the use of equimolar amounts of

valuable chiral auxiliary materials makes these approaches rather unappealing. A far more

attractive form of stereoselective synthesis involves the application of asymmetric catalysts. A

relatively small amount of enantiopure catalyst can, in an ideal scenario, produce large quantities of

enantiopure product. Although powerful biocatalytic methods exist, employing enzymes or

antibodies as catalysts,14 their biomolecular homochirality often poses a problem when the “non-

natural” enantiomer of the product is desired. Recently, directed evolution methods have resulted in

enzymes which produce the alternative enantiomers in excess.15 Alternatively, chemical catalysts

can be adapted to provide the desired enantiomer of the product by choosing the appropriate

enantiomer of the ligand. Although asymmetric organocatalysis – based on the use of small organic

molecules as catalysts − is an emerging field,16 in the last decades considerable progress has been

made in the development of highly active metal-catalyzed asymmetric transformations based on

enantiopure ligands complexed to a (transition) metal core.17 In 2001, Noyori, Knowles and

Sharpless received the Nobel prize in chemistry18 on asymmetrically catalyzed hydrogenation and

oxidation reactions opening the field of homogeneous asymmetric catalysis. Asymmetric

reductions and oxidations have been developed to an extent that they are in some cases used for

industrial production of enantiomerically enriched compounds. However, in catalytic asymmetric

carbon-carbon bond forming reactions high catalytic activity and enantioselectivity are less well

established.

1.2 Biocatalysis.

Biocatalysis has many attractive features in the context of green chemistry: mild reaction

conditions (physiological pH and temperature), an environmentally compatible catalyst (an

enzyme) and solvent (often water) combined with high activities and chemo-, regio- and

stereoselectivities in multifunctional molecules. Furthermore, the use of enzymes generally

circumvents the need for functional group activation and avoids protection and deprotection steps

required in traditional organic syntheses. This affords processes which are shorter, generate less

waste and are, therefore, both environmentally and economically more attractive than conventional

routes.

An illustrative example of the benefits to be gained by replacing conventional chemistry by

biocatalysis is provided by the manufacture of 6-aminopenicillanic acid (6-APA) 25, a key raw

material for semi-synthetic penicillin and cephalosporin antibiotics, by hydrolysis of penicillin G


23.17 Up until the mid-1980s a chemical procedure was used for this hydrolysis (scheme 1.3). It

involved the use of environmentally unattractive reagents, a chlorinated hydrocarbon solvent

(CH2Cl2) and a reaction temperature of – 40° C.19 In contrast, enzymatic cleavage of penicillin G

23 (scheme 1.1) is performed in water at 37 °C and the only reagent used is NH3 (0.9 kg per kg of

6-APA 25), to adjust the pH.

N

SHN

OO

HH

CO2H

N

SN

ClO

HH

CO2H

N

SH2N

O

HH

CO2H

i. Me3SiClii. PCl5/CH2Cl2 − 40 °CPhNMe2

Pen acylaseH2O, 37 °C

i. BuOH, − 40 °Cii. H2O, 0 °C

Penicillin G

6 APA 25

23

24

Scheme 1.3. Enzymatic versus chemical deacylation of Penicillin G.

Biocatalysis is growing rapidly, we will discus here briefly some topics which biocatalysis were

involved.

1.2.1 Enzymes and Carbon-Carbon bond formation.

The formation of carbon–carbon bonds is central to organic chemistry, indeed to chemistry in

general. The preparation of virtually every product, be it fine chemical or bulk chemical, will

include a carbon–carbon bond formation at some stage in its synthesis. Carbon-carbon bond

formation can be catalysed by enzymes and metal transition catalyst but is not really green as

enzyme catalyst. The key to making them green is that they have to be easily separable and

reusable.

One of the pleasant example discussed here is enzymatic synthesis of cyanohydrins 26.

Cyanohydrins are versatile building blocks that are used in both the pharmaceutical and

agrochemical industries20 Consequently, their enantioselective synthesis has attracted considerable

attention (scheme 1.4).

10 Chapter 1

R CN

OH

R CN

NPhthR CN

O

R COOH

OH

R CONH2

OH

R

OH

R CN

OSO2R'

R CN

FR CN

N3

R

OH O

R

OH

O

HNH2

R

OHNH2

R' 26

Scheme 1.4. Cyanohydrins are versatile building blocks.

In 2005, Anton Glieder et al,21 were described that site directed mutagenesis has led to a Prunus

amygdalus HNL that can be employed for the preparation of (R)-2-hydroxy-4-phenylbutyronitrile

28 with excellent enantioselectivity (ee > 96%). This is a chiral building block for the

enantioselective synthesis of ACE inhibitors such as enalapril 29 (scheme 1.5).

OHCN, PaHNL

CN

OH

NH

EtO2C

O

CO2HEnalapirlconv = 98%

ee >96%

27 28 29

Scheme 1.5. Modified Prunus amygdalus HNL catalyzes the enantioselective formation of potential

precursors for ACE inhibitors.

1.2.3 Enzymes and Epoxidation.

Ramesh N. Patel et al,22 were reported the synthesis of chiral intermediate (3S,4R)-trans-3,4-

dihydro-3,4-dihydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile [(+)-trans diol 32] by the

stereoselective microbial epoxidation of 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile 30. This

compound is a potential intermediate for the total synthesis of potassium-channel openers. Several

microbial cultures were found which catalyzed the transformation of 30 to the corresponding

(3S,4S)-epoxide 31 and (+)-trans diol 32. The two best cultures, Corynebacterium sp. SC 13876

and Mortierella ramanniana SC 13840 gave reaction yields of 32 M% and 67.5 M% and optical

purities of 88 and 96 %, respectively, for (+)-trans diol 32.


O O

Omicrobialepoxidation

O

OHOH

30 31 3288%ee 96%ee

Scheme 1.6. Microbial epoxidation.

1.2.4 Enzymes and Redcution.

Baker’s yeast (Saccharomyces cerevisiae) has been used in the various transformations as an

environmentally benign reagent in organic synthesis. A. Yajima et al,23 reproted the first

biotransformations employing whole cells of baker’s yeast in fluorous media. The IBY-mediated

reductions of various ketones either with glucose or methanol as energy sources proceeded in

fluorous media without loss of stereoselectivity. The used fluorous solvent was easily and

sufficiently recovered by the filtration and methanol extraction, and was pure enough to be reused

without any purification. The combination of the biotransformation with fluorous chemistry can act

as an environmentally benign chemical process (Scheme 1.7).

O

R1 R2

immobilized bakers' yeastglucose or MeOH

in fluorous media(perfluorooctane)

OH∗

R1 R2

ee: 87-99%yield: 19-66%

Scheme 1.7. IBY mediated reduction of ketone.

1.2.5 Lipases as Biocatalysis In Organic Synthesis.

Considering their specific and limited function in metabolism, one should expect lipases to be of

limited interest for the organic chemist. However, chemists have discovered lipases to be one of the

most versatile classes of biocatalysts in organic synthesis for a few simple reasons: they can be

employed under mild reactions in common organic solvents, under atmospheric pressure, and at

room temperature. They generally safe for the environment, and can be recycled with out loss of

activity. Lipases can accommodate a wide variety of synthetic substrates, while still showing

chemo-, regio, and/or stereoselectivity.

Fuganti et al.26 applied lipases for the synthesis of enantiopure compounds in the fields of flavours

and fragrances.

12 Chapter 1

1.2.6 Enzymes and Transamination.

Optically active α-chiral primary amines are highly demanded in asymmetric synthesis owing to

the biological/pharmacological activity of many amines. Biocatalytic reductive amination or

transamination is well established for accessing α-amino acids. Wolfgang Kroutil et al,24 were

employed biocatalysis for such reductive amination of ketones. For this purpose, they combined

three enzymes: 1) an ω-transaminase transfers the amino group from alanine to the substrate to be

converted, to give the desired amine and pyruvate; 2) an amino acid dehydrogenase (for example,

alanine dehydrogenase) recycles alanine from pyruvate by consuming ammonium and NAD(P)H;

3) finally, the cofactor is recycled by using standard methods (for example, formate dehydrogenase

and formate, glucose dehydrogenase and glucose). In this concept, alanine is not consumed but

recycled.

O

R'R

ω-transaminasebuffer, pH 7.0/DMSO

NH2

R'R

NH2

CO2H

O

CO2HL-AADH

NH4 H2O

NAD(P)H NAD(P)

Formate CO2or orGlucose GluconolactoneFDH or GDH

ee: up to 99%

Scheme 1.8. Outline of the formal reductive amination concept for the preparation of optically

pure amines.

1.3 Application of Biocatalysis. There has been an increasing awareness of the enormous potential of microorganisms and enzymes

for the transformation of synthetic chemicals with high chemo-, regio- and enatioselective manner.

Chiral intermediates and fine chemicals are in high demand at pharmaceutical and agrochemical

industries for the preparation of the bulk drug substances and the agricultural products. Single

enantiomers can be produced by chemical or chemo-enzymatic synthesis. The advantages of

biocatalysis over chemical synthesis are that enzyme-catalyzed reactions are often highly

enantioselective and regioselective. They can be carried out at ambient temperature and

atmospheric pressure, thus avoiding the use of more extreme conditions which could cause

problems with isomerization, racemization, epimerization, and rearrangement. Microbial cells and

enzymes derived therefrom can be immobilized and reused for many cycles. Additionally, enzymes


can be over expressed to make biocatalytic processes economically efficient, and enzymes with

modified activity can be tailor-made. This section provides examples on the use of enzymes for the

synthesis of single enantiomers of key intermediates for drug substances.

1.3.1 Enzymes and Chiral Intermediates for Pharmaceuticals.

Biocatalytic processes have been described for the synthesis of chiral intermediates for β3- and β2-

receptor agonists, antihypertensive drugs, antiviral agents, melatonin receptor agonists,

anticholesterol, and anticancer drugs, and drugs to treat Alzheimer’s disease.

Among the antimitotic agents, paclitaxel 35 (taxol®) (Figure 1.2), a complex polycyclic diterpene,

exhibits a unique mode of action on microtubule proteins responsible for the formation of the

spindle during cell division. Paclitaxel is the only compound known to inhibit the depolymerization

process of microtubulin. Various types of cancers have been treated with paclitaxel and results in

the treatment of ovarian cancer and metastatic breast cancer are very promising. Paclitaxel was

originally isolated from the bark of the yew, Taxus brevifolia (about 0.07% yield), and has also

been found in other Taxus species in relatively low yield. Biocatalysis plays important rule for the

semisynthesis of paclitaxel 35 and the different anticancer drugs.25

NH

HO

O

OH

OAcH

OBz

OHAcO

OH

O

HOOH

OAcH

OBz

OHAcO

OH

O

O

OHO

NPh H

OPh

Baccatin III Paclitaxel sidechain Paclitaxel33 34 35

Fig 1.2. Paclitaxel an anticancer agent.

1.3.2 Applications of Biocatalysis in Fragrance Chemistry.

Fragrance chemistry is one of the fields that have witnessed the improvement in the quality and

quantity of newly prepared compounds brought about by the development of organic synthetic

methods. Odorous molecules, as well as drugs, have to interact with human beings, and, if they are

chiral, their mode of interaction will depend on their absolute configuration. It may happen that the

enantiomers of a chiral odorant show different odour properties and/or different odour thresholds.

This fact has promoted great interest in applying synthetic techniques for enantio- and diastereo-

control in the synthesis of chiral fragrances. Enzymes are important tools for the preparation of

single enantiomers: they show broad substrate tolerance, they are easy to handle and are considered

14 Chapter 1

environmentally benign. Biocatalysis employed intensively in the field of fragrances and flavour to

prepare single enantiomer. This section provides some examples were prepared by enzymatic

approach (Figure 1.3).

O

H

O

O

Ph

OH

PhOH

O

O

OO

Florhydral Florol α, β , γ −Ionone α, β , γ− Irone

Muguesia Pamplefleur Ambrox Theaspirone

O O

O

CO2Me

O

O

(−)-cis-aerangis lactone (+)-(Z)-cis-Jasmonate (−)-wine lactone (−)-menthol43 44 45 46

36 37 38 39

40 41 42 2

Fig 1.3. Selected examples were synthesised by biocatalysis.26

1.4 Chemocatalysis.

Chemocatalysis is the second approach for enantioselective synthesis of organic compounds such

as pharmaceutical products, agrochemicals, fine chemicals, flavours, fragrances, or synthetic

intermediates. In 2001 the Nobel Prize in Chemistry was awarded to William R. Knowles and

Ryoji Noyori ‘‘for their work on chirally catalyzed hydrogenation reactions’’, and to K. Barry

Sharpless ‘‘for his work on chirally catalyzed oxidation reactions’’. In 1980, Noyori, together with

Takaya, discovered an atropisomeric chiral diphosphine, BINAP. Rh(I) complexes of the

enantiomers of BINAP are remarkably effective in various kinds of asymmetric catalysis.27 This

includes enantioselective hydrogenation of α-(acylamino)acrylic acids or esters, giving amino acid

derivatives and also includes enantioselective isomerization of allylic amines to enamines. The

chiral efficiency of BINAP chemistry originates from unique dissymmetric templates created by a

transition metal atom or ions and the C2 chiral diphosphine. Noyori’s discovery of the BINAP-


Ru(II) complex catalysts was a major advance in stereoselective organic synthesis. The scope of

the application of these catalysts is far reaching. These chiral Ru complexes serve as catalyst

precursors for the highly enantioselective hydrogenation of a range of α,β- and β,γ-unsaturated

carboxylic acids (scheme 1.9).28

CO2H

MeO

(S)-BINAP-Ru(OCOCH3)2(0.5mol%)

MeOH

CO2H

MeOS-naproxen

an anti-inflammatory agent92%yield, 97%ee

+ H2

Ph2

Ph2

PP

RuOO

OO

47 48

49

Scheme 1.9. The anti-inflammatory agent (S)-Naproxen is produced in high yield and with high enantiomeric excess using Noyori’s catalyst.

Parallell to the progress in catalytic asymmetric hydrogenations Barry Sharpless has developed

chiral catalysts for very important oxidation reactions. The epoxidation reaction discovered in 1980

by Sharpless and Kazuki is a very fine example of a strategy of using a chiral ligand to achieve

stereochemical control. Using titanium(IV) tetraisopropoxide, tert-butyl hydroperoxide, and an

enantiomerically pure dialkyl tartrate, the Sharpless reaction accomplishes the epoxidation of

allylic alcohols with excellent stereoselectivity. This powerful reaction is very predictable. When

the D-(−)-tartrate ligand (D-(−)-DET) is used in epoxidation, the oxygen atom is delivered to the

top face of the olefin when the allylic alcohol is depicted as in scheme 1.10 (i.e. the OH group is

positioned in the lower right hand corner). The L-(+)-tartrate ligand (L-(+)-DET), on the other

hand, allows the bottom face of the olefin to be epoxidised.29

16 Chapter 1

R1

R2

R3

OH

HO

HO CO2Et

CO2Et

HO

HO CO2Et

CO2EtD-(−)-DET

(2S,3S)

(2R,3R)

L-(+)-DET

''O''

''O''

D-(−)-DETTi(O i-Pr)4

t-BuOOH, DCM4Å mol.sieves, −20 °C

O

R1

R2R3

OH

O R1

R3

OH

R2L-(+)-DET

(70-90% yield,≥ 90%ee)

OHL-(+)-DET, Ti(Oi-Pr)4

t -BuOOH, DCM4Å mol. sieves, −20 °C

OHO

geraniol 50 51

DET= diethyl tartrate

Scheme 1.10. The predictive stereoselectivity of the Sharpless epoxidation is shown together with

an example of its regioselectivity.

After these two examples in asymmetric catalysis, more research efforts were dedicated to this

field. Researchers are involved in this field. We will focus only on the transition metal complex

catalysts and especially on Pd and Pt metals.

1.4.1 Pd(II)- and Pd(0)-Catalyzed Reactions.

Palladium is certainly the most widely applied transition metal for catalytic processes in organic

chemistry.30 Most often it has been used as catalyst in two forms: Pd(0) and Pd(II).

In the processes catalyzed by Pd(0), e.g. Heck reactions,31 cross-couplings,32 carbonylations33 and

allylic substitutions,34 Pd(0) reacts with a substrate via oxidative addition to form a Pd(II) complex

in situ. After the requisite coupling step with the second reactant a reductive or a β-hydride

elimination step of the generated Pd(II) species regenerates Pd(0) which is used for the next

catalytic cycle. There are different sources to provide Pd(0), such as metallic palladium (e.g. Pd on

charcoal), Pd(0) complexes or Pd(0) reduced in situ from Pd(II).

When a Pd(II) salt, typically PdCl2 and Pd(OAc)2, is used as a catalyst, it often acts in different

patterns. For example, in the Wacker reaction35 Pd(II) oxidizes a substrate, and the formed Pd(0) is

reoxidized in situ by another oxidizing agent to regenerate Pd(II) for the next catalytic cycle.


However, Pd(II) compounds are also well known to behave as soft Lewis acids to catalyze

reactions without involving a redox couple of Pd(II)/Pd(0).36

1.4.2 Enantioselective Synthesis.

1.4.2.1 Asymmetric Allylic Alkylation.

Transition metal catalyzed C-C couplings have been intensively investigated since 1950s. There

are numerous reactions to form new carbon-carbon bonds using aromatic halides and olefinic

systems. In the field of asymmetric C-C bond formations the Pd-catalyzed asymmetric allylic

alkylation (AAA) achieved great popularity. The allylic alkylation was primarily used by Trost and

co-workers in 1973. Since then many improvements have been reported including enantioselective

versions. With the AAA it is possible to convert compounds from racemic mixtures into

enantiopure products through a meso-intermediate or through a dynamic asymmetric kinetic

transformation (DYKAT). In contrast to other metal-catalyzed reactions, this reaction occurs at an

sp3 instead of an sp2 carbon atom. The cycle involves olefin complexation with Pd (0) to form a π-

complex, subsequent ionization of a leaving group, and then nucleophilic addition at the meso π-

allyl intermediate. Decomplexation leads to the regenerated Pd(0)-catalyst and the chiral adduct.

Enantioselective discrimination takes place during the attack of the nucleophile at the meso

complex.

18 Chapter 1

PdL L X

R'

R

X

R'

RPd

LL

R'RPd

L L

R

R'

PdL L

∗ R'

Nu

RPd

LL

∗R

Nu

R'Pd

LL

∗ R'

Nu

R ∗R

Nu

R'or

or

Complexation

Ionization

-XNu

Nucleophilicaddition

Decomplexation

Scheme 1.11. Catalytic cycle in palladium-catalyzed asymmetric allylic alkylations by Trost and

co-workers.37

An example of a reaction that derives enantioselectivity from discrimination of prochiral

nucleophile faces is the alkylation of tetralone 52 with 1-acetoxy-2-methyl-2-propene to give

adduct 53 with a quaternary-substituted C atom in high yield (81%) and 95% ee ( scheme 1.12).

OCOCH2Ph

(0.9 mol%) ligand 55(0.4 mol%) (η3-C3H5PdCl)2TMG, toluene, 0 °C

AcO

O

COCH2Ph

R, R' = PPh2 55

81% yield, 95% ee52 53

HNNHO O

R R'

Scheme 1.12. Pd-catalyzed AAA.


1.4.2.2 Asymmetric Heck Reactions.

High enantioselectivities have been documented in both inter- and intramolecular variants of the

catalytic asymmetric Heck reaction, with Binap and Phox ligands occupying a prominent

position.38 For the intermolecular Heck reaction, the reaction of dihydrofuran 56 with aryl or

alkenyl trifates 57 has become a standard test reaction for screening new ligands. Ligand 59

afforded excellent enantioselectivities and a high yield for the reaction of 2,3-dihydrofuran with

vinyl triflates (scheme 1.13).39

PPh2 N

O

O OTf

+

O

yield: 91%ee: 98% (R)-58

(4.0 mol%) [Pd2dba3.dba],(15.0 mol%) 59,

i-Pr2NEt, benzene,5 days, 70 °C.56 57

59

Scheme 1.13. Example for asymmetric intermolecular Heck reactions.

1.4.3 Palladacycles.40

The discovery of palladacycles as extremely active catalysts for Heck and cross coupling reactions

had generated high expectations about this class of palladium catalysts. New mechanisms involving

Pd(II)/Pd(IV) intermediates were proposed in anticipation of the conservation of the coordination

sphere during the catalytic cycle which should finally allow high enantioselectivities in asymmetric

processes. The initial expectations could however not met: in the large majority of cases

palladacycles are most likely not structurally robust catalysts, but slowly release low ligated Pd(0).

Contrary to this disenchanting picture is the recent success of several palladacycles in the highly

enantioselective aza-Claisen rearrangement and in a small number of other applications which

proof that the coordination shell of the Pd(II) species is not necessarily destroyed during the

catalytic action.

Most successful asymmetric reactions catalysed by palladacycles rely on the activation of a carbon-

carbon double bond of an allylic system by Pd(II) towards the attack of an internal or external

20 Chapter 1

nucleophile. A suitable leaving group has to be attached to the allylic system to avoid a competing

β-hydride elimination, since the latter process would eventually lead to Pd(0). The overall process

is equal to an allylic substitution, however, it does not involve the formation of Pd(0) or an allylic

cation.

1.4.4 Application of Palladacyles.

1.4.4.1 Michael Additions.

Direct conjugate additions of α-carbonyl-stabilized nucleophiles to activated olefins are among the

most attractive reactions for C−C bond constructions owing to their ideal atom economy and the

versatility of the activating functional groups involved.

Peters et al.41 utilized bispalladacycle 186 as precatalyst for the enantioselective Michael addition

of α-cyanoesters 60 to vinyl ketones 61 (Scheme 1.14). The addition products 62 were obtained

with excellent yields and high enantioselectivities employing low catalyst loadings. A cooperative

bimetallic mechanism was proposed, in which coordination of the nitrile group to the Pd(II) center

would facilitate enolization and the enone would be activated by the carbophilic Pd(II). To

differentiate between the enantiotopic faces, the catalyst must control the conformation with regard

to the C-CN σ bond and also direct the enone. Control of the reactive conformation is achieved by

the use of a bulky ester moiety and an especially large sulfonate counteranion, which should point

away from each other to minimize unfavorable steric interactions.


Fe

NPd

N

PhPh

Cl

Ts2

NPd

N

PhPh

Cl

Ts2

186

t-BuO2C CN+

O

RAr

t-BuO2CR

O

Ar CN

(0.02 - 1.0 mol%) 186Ag salt, HOAc,diglyme, RT

98-99%,86-95% ee

Fe

NPd

N

PhPh

Ts

N

NPh

Ph

Ts

PdSO3Ar

O

R2

O3S

iPri -Pr

i -Pr

OHO

N

MeMe Me

X

60 61 62

Scheme 1.14. Example for a catalytic asymmetric Michael addition by Peters and co-workers.

1.4.4.2 Asymmetric aza-Claisen Rearrangements.

1.4.4.2.1 Formation of Chiral Allylic Amines.

Chiral allylic amines are widely used building blocks in synthetic processes, since the double bond

allows, for instance., the transformation of allylic amines to α- and β-amino acids (Scheme 1.15).

Additional functional groups may be introduced by the residues R1 and R2 permitting access to a

broad variety of α- and β-substituted amino acids. The synthetically versatile double bond can of

course also be converted to other types of derivatives.

R2

NH2R1

R2 CO2H

NH2R1

R2 CO2HNH2R1

R2

NH2R1

X R2

NH2R1

XY

9

63 64

65 66

Scheme 1.15.

22 Chapter 1

There are several catalytic asymmetric processes for the preparation of enantioenriched allylic

amines.42,43 The concept of the asymmetric aza-Claisen rearrangement provides a particularly

powerful platform to prepare allylic amines starting from readily available allylic alcohols, yet the

limitations of this methodology with regard to catalyst activity and scope impeded a frequent use in

synthesis.

1.4.4.2.2 The aza-Claisen Rearrangment: General Aspects.

The thermal or metal catalyzed [3,3] rearrangement of allylic imidates is long known as aza-

Claisen rearrangement which offers a valuable synthetic approach to protected allylic amines

(Scheme 1.16).

N O

R1

N O

R1

R2R3 R3

R2Δ or [M]n+

Scheme 1.16. The Aza-Claisen rearrangement.

The aza-Claisen rearrangement was first discovered by Mumm and Möller in 1937.44 N-Phenyl

benzimidate rearranged in quantitative yield by heating to 210-215 °C for 2.5-3 hours (Scheme

1.17). Since then, a number of systems have been investigated for the practical preparation of

allylic amines by this route, including urethanes, isourethanes, formimidates, isoureas and

carbonimidothioates. However, the generally required high temperature and the difficult

deprotection of the product are considerable disadvantages of this methodology.

N OPh

Ph

N OPh

Ph210 to 215 °C

quant.

68 69 Scheme 1.17. Thermal rearrangement of an N-Phenylbenzimidate.

In 1974 Overman overcame these disadvantages by introducing trichloroacetimidates for this

reaction type.45 The rearrangement of trichloroacetimidates 70 requires much lower temperatures in

refluxing m-xylene (139 oC) and provides the corresponding amides which are relatively easily

deprotected. Furthermore, it was found that 10-20 mol% Hg(II) can catalyze the rearrangement of

trichloroacetimidates at room temperature (Scheme 1.18).


HN O

CCl3

R

m-xylene, ref luxorHg(II)

HN O

CCl3

R

3 M NaOH,RT NH2

R

70 71 72 Scheme 1.18. Overman rearrangement.

Later, more efficient and less toxic palladium(II) salts became the catalysts of choice, usually in the

form of palladium(II) trifluoroacetate, Pd(MeCN)2Cl2 or Pd(PhCN)2Cl2, generally in combination

with DCM or benzene as solvent, requiring a lower catalyst loading. Other soft Lewis acids, e.g.,

Au(I)46 and Pt(II),47 were also studied as catalysts, but less effective.

The aza-Claisen rearrangement is irreversible with the transformation of the imidate to the more

stable amide. The chemical binding energy difference for the imidate-amide isomers is about 14

kcal/mol.48 The thermal aza-Claisen rearrangement is a concerted one-step reaction and usually

requires high temperatures, while the metal catalyzed aza-Claisen rearrangement is most probably

a multi-step cyclisation induced rearrangement (CIR) and proceeds typically at room temperature

or even below. The mechanism of the Lewis acid catalyzed process has been studied by Overman.49

The reaction starts with the coordination of the Lewis acid to the C=C double bond, thus activating

the olefin by reducing its electron density. After coordination of the olefin, the imidate-N attacks as

an internal nucleophile and leads to a zwitterionic six-membered ring intermediate with a new

carbon-metal σ-bond. In the last step, the ring is opened via β-elimination to regenerate the catalyst

(Scheme 1.19).

R1

ONR2

R3

L.A.

R1

ONR2

R3

R1

ONR2

R3

R1

ONR2

R3

L.A.

L.A.

Scheme 1.19. Mechanism of the Lewis acid catalysed aza-Claisen rearrangement.

24 Chapter 1

In the catalytic route, imidates with a stronger electron-withdrawing group in R3 position rearrange

slower, since the electron-withdrawing group destabilizes the positive charge in the zwitterionic

intermediate.

However, compared to the catalytic route, the charge separation is inverted in the thermal route.

The imidate moiety bears a negative partial charge and the allyl moiety bears a positive partial

charge in the non-synchronous transition state of the rearrangement process (Scheme 1.20). The

electron-withdrawing group in R3 can stabilize the negative partial charge in the transition state.

This can explain why under thermal conditions trifluoroacetimidates rearrange faster than

trichloroacetimidates, which in turn rearrange faster than benzimidates. On the other hand, if there

is an electron-donating group in the allyl moiety, it will stabilize the positive partial charge.

R1

ONR2

R3

R1

ONR2

R3

R1

ONR2

R3

R4 R4R473 74

Scheme 1.20.

A hallmark of the aza-Claisen rearrangement is the observed transfer of chirality. In the process of

a thermal rearrangement, the chirality is transferred via a six-membered chair-like transition state

(Scheme 1.21). The residue R4 connected to the chiral center can either adopt an equatorial or an

axial position in the transition state. However, the former is strongly preferred due to severe steric

hindrance in the latter. Therefore, this reaction gives a highly enantioenriched product from

enantiopure starting material.50 Under metal catalyzed conditions, the chirality can be transferred as

well at lower temperature.


R1

ONR2

R3

R1

ONR2

R3

R4 R4

NO

R3

R1

R4

ON

R4

R3R1

R2

R2

favored

unfavored Scheme 1.21. Explanation of the chirality transfer in the Aza-Claisen rearrangement.

1.4.4.2.3 Enantioselective aza-Claisen Rearrangment.

The catalyst system with the broadest scope for enantioselective aza-Claisen rearrangments was

reported by Peters et al.51 They have developed practical, highly efficient ferrocenyl–imidazoline

palladacycles (FIPs) 77 as catalysts for the aza-Claisen rearrangement of N-para-methoxyphenyl

trifluoroacetimidates 75, which are versatile substrates for the formation of protected chiral primary

allylic amines. The catalysts are not only easily prepared but also exhibit unprecedented activity,

enantioselectivity, and tolerance toward a broad spectrum of substrates (scheme 1.22).

R1

NPMP

CF3

OR2

R1

R2 O

CF3

NPMP

(0.05 - 4.0 mol%) 77,AgTFA, P.S., DCM,20 to 50 oC

R2 = H, 75-99%, 84-99.7% eeR2 ≠ H, 50-94%, 93-99.6% ee

FePh Ph

PhPhPh

N

N

Ts

Ph

PhPd Cl

2

7775 76

Scheme 1.22. aza-Claisen rearrangments of allylic imidates using FIP 77.

1.4.5 Platinacycles.

Pt(II)52 and Au(I)52a,46 catalysis have experienced a boom over the past 5 years, as these late

transition metals have the unique property to catalyze highly atom economic reactions of

26 Chapter 1

unactivated alkynes, olefins or allenes creating a significant increase of molecular complexity in a

single step using simple starting materials. The catalysts are compatible with most functional

groups due to their low oxophilicity and are usually very robust towards moisture or air. Pt(II)-

olefin complexes have been reported to be highly reactive for outer-sphere attack by nucleophiles.

The resulting Pt(II)-alkyl intermediates undergo rapid protonolysis53 with Brønsted acids rather

than β-hydride elimination known to be the usually preferred pathway for Pd(II)-alkyl complexes.

In contrast, ligand exchange is relatively slow for Pt(II) complexes.52 Catalysts allowing for a more

rapid ligand exchange could thus lead to enhanced activity of this expensive metal and might

expand the scope to additional valuable applications. In addition to the reactivity issue and despite

considerable progress, asymmetric activation of π-ligands by Au or Pt complexes is still an area of

high development potential.52

Peters et al.54 synthesised platinacycle 12, which was employed in the intramolecular

enantioselective Friedel-Crafts alkylation of indoles 78 as a first example for a highly

enantioselective reaction catalysed by a platinacycle (Scheme 1.23).

Fe

N

Pt

N

PhPh

Cl

Ts

NN

Ph

PhTs

NY

RR

X

Z

NY

R

R

X

Z

(5.0 mol%) 12(5.0 mol%) AgO2CC3F7,CF3CH2OH, 50 °C, 60 h

7915 examples45-95% yield78-92% ee

78

12

Scheme1.23. Friedel-Crafts alkylation of indoles.

1.5 Enzymes in Combination with Metal Catalysts for Asymmetric Catalysis.

Enzyme catalysis (for the resolution of a racemate) and metal catalysis (for the racemization of the

slower reacting enantiomer) are a powerful combination for obtaining successful DKR processes.

The high efficiency of these processes makes them attractive alternatives to existing methods in

asymmetric catalysis for obtaining highly functionalized chiral alcohols and amines in

enantiomerically pure form.55


Reetz and co-workers demonstrated the first example of chemoenzymatic DKR for the preparation

of enantiopure amines.56 Thus, the combination of immobilized CALB as biocatalysts and

palladium on carbon as racemization catalysts was used for the synthesis of (R)-N-(1-

phenylethyl)acetamide 81 from 1-phenylethylamine 80 in moderate yield (64%) and

enantiomerically pure form (Scheme 1.24).

NH2Pd/C-CALBNEt3/AcOEt

NHAc

64% yield, 99% ee80 81

Scheme 1.24. Example of chemoenzymatic DKR for the preparation of enantiopure amines.

1.6 Conclusion.

In a summary, short overview about biocatalysis and chemocatalysis have been presented.

1.7 References and Notes.

1 Chirality (Greek, handedness, derived from the word stem χειρ~, ch[e]ir~, hand~) is a

“dissymmetry” property important in several branches of science. An object or a system is

called chiral if it differs from its mirror image. The term chirality was coined by Lord

Kelvin: (a) W. T. Kelvin, Baltimore Lectures on Molecular Dynamics and the Wave

Theory of Light, C. J. Clay and Sons: London, 1904. For further stereochemical definitions,

see (b) E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds, Wiley: New

York, 1994.

2 (a) F. Krick, Life Itself, McDonald & Co.: London, 1981; (b) M. Gardner, The

Ambidextrous Universe, 2nd Ed., C. Scribner: New York, Harmondsworth: UK, 1982.

3 For a review on chemical signaling among bacteria, see: G. J. Lyon, T. W. Muir, Chem.

Biol. 2003, 10, 1007.

4 E. J. Ariens, W. Soudijin, P. B. M. W. M. Timmermans (Eds.), Stereochemistry and

Biological Activity of Drugs, Blackwell Scientific Publications: Oxford, 1983.

5 Food and Drug Administration, Fed. Reg. 1992, 22, 249.

6 A. M. Rouhi, Chem. Eng. News 2003, 81, 45.

7 E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic Compounds, Wiley,

New York, 1994.

28 Chapter 1

8 J. Jacques, A. Collet, S. H. Wilen, Enantiomers, Racemates, and Resolutions, Krieger,

Malabar, FL, 1991.

9 J. F. Larrow, E. N. Jacobsen, Org. Synth. 1998, 75, 1. Reviews: (a) H. B. Kagan, J. C.

Fiaud In Topics in Stereochemistry (Eds.: E. L. Eliel, J. C. Fiaud), Wiley, New York, 1988;

Vol. 18, pp 249; (b) A. H. Hoveyda, M. T. Didiuk, Curr. Org. Chem. 1998, 2, 537.

10 (a) J. Jacques, A. Collet, S. H. Wilen, Enantiomers, racemates, and resolutions, Wiley:

New York, 1981; (b) A. N. Collins, G. N. Sheldrake, J. Crosby (Eds.), Chirality in Industry

II, Wiley: Chichester, 1997; (c) T. Vries, H. Wynberg, E. van Echten, J. Koek, W. ten

Hoeve, R. M. Kellogg, Q. B. Boxterman, A. J. Minnaard, B. Kaptein, S. van der Sluis, L.

Hulshof, J. Kooistra, Angew. Chem. Int. Ed. 1998, 37, 2349.

11 B. M. Trost, Angew. Chem. Int. Ed. Engl. 1995, 34, 259.

12 J. Seyden-Penne, Chiral Auxiliaries and Ligands in Asymmetric Catalysis, Wiley: New

York, 1995.

13 (a) J. Wagner, R. A. Lerner, C. F. Barbaras III, Science 1995, 270, 1797; (b) A. M.

Klibanov, Nature 2001, 409, 241.

14 For reviews on the directed evolution of enantioselective enzymes, see: (a) M. T. Reetz,

Tetrahedron 2002, 58, 6595; (b) M. T. Reetz, Proc. Natl. Acad. Sci. USA 2004, 101, 5716;

(b) M. T. Reetz In Methods in Enzymology, Vol. 388, D. E. Robertson, J. P. Noel (Eds.),

Elsevier: San Diego, 2004, 238. See also: (d) N. J. Turner, Trends Biotechnol. 2003, 21,

474.

15 A. Berkessel, H. Gröger (Eds.), D. MacMillan, Asymmetric Organocatalysis: From

Biomimetic Synthesis to Applications in Asymmetric Synthesis, Wiley-VCH: Weinheim,

2005.

16 E. N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis, Vol.

1-3, Springer: Berlin, 1999.

17 (a) W. S. Knowles, Angew. Chem. Int. Ed. 2002, 41, 1998; (b) R. Noyori, Angew. Chem.

Int. Ed. 2002, 41, 2008;(c) K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41, 2024.

18 R. A. Sheldon, Chemtech, 1994, 38.

19 R. A. Sheldon, J. Chem. Technol. Biotechnol.1997, 68, 381.

20 a) G. Seoane, Curr. Org. Chem. 2000, 4, 283; b) K. Faber, Biotransformations in Organic

Chemistry, 5th edn., Springer, Berlin, Heidelberg, New York, 2004; c) J. Sukumaran, U.

Hanefeld, Chem. Soc. Rev. 2005, 34, 530; d) R. J. H. Gregory, Chem. Rev. 1999, 99, 3649;

e) J. Brussee, A. van der Gen, in Stereoselective Biocatalysis, P. N. Ramesh (Ed.), Marcel

Dekker, New York, 2000, pp. 289; f) M. North, Tetrahedron: Asymmetry 2003, 14, 147; j)

J.-M. Brunel, I. P. Holmes, Angew. Chem. Int. Ed. 2004, 43, 2752; h) M. Breuer, K.


Ditrich, T. Habicher, B. Hauer, M. Kesseler, R. Sturmer, T. Zelinski, Angew. Chem. Int.

Ed. 2004, 43, 788.

21 R. Weis, R. Gaisberger, W. Skranc, K. Gruber, A. Glieder, Angew. Chem. Int. Ed. 2005,

44, 4700.

22 R.N. Patel, A. Banerjee, B. Davis, J. Howell, C. McNamee, D. Brzozowaski, J. North, D.

Kronenthal, L. Szarka, Bioorg. Med. Chem. 1994, 2, 535.

23 A. Yajima, K. Naka, G. Yabuta, Tetrahedron Lett. 2004, 45, 4577.

24 D. Koszelewski, I. Lavandera, D. Clay, G. M. Guebitz, D. Rozzell, W. Kroutil, Angew.

Chem. Int. Ed. 2008, 47, 9337.

25 a) M . Suffness, M. E. Wall: Discovery and development of taxol. In Taxol: Science and

Application. Edited by Suffness M. New York: CRC press; 1995; b) R. Patel, Annu. Rev.

Microbiol. 1998, 52, 361; c) R. N. Patel, A. Banerjee, R. Y. Ko, J. M. Howell, W. S. Li, F.

T. Comezoglu, R. A. Partyka, L. J. Szarka: Biotechnol. Appl. Biochem. 1994, 20, 23.

26 a) M . Suffness, M. E. Wall: Discovery and development of taxol. In Taxol: Science and

Application. Edited by Suffness M. New York: CRC press; 1995. b) R. Patel, Annu. Rev.

Microbiol. 1998, 52, 361; c) R. N. Patel, A. Banerjee, R. Y. Ko, J. M. Howell, W. S. Li, F.

T. Comezoglu, R. A. Partyka, L. J. Szarka: Biotechnol. Appl. Biochem. 1994, 20, 23.

27 see review: (a) E. Brenna, C. Fuganti, S. Serra, Chem. Soc. Rev. 2008, 37, 2443; (b) E.

Brenna, C. Fuganti, S. Serra, P. Kraft, Eur. J.org. Chem. 2002, 967;(c) S. Serra, C. Fuganti,

E. Brenna. Trends in Biotechnology, 2005, 23, 193; (d) A. Abate, E. Brenna, C. Fuganti, F.

G. Gatti, T. Giovenzana, L. Malpezzi, S. Serra. J. Org. Chem. 2005, 70, 1281.

28 A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T. Souchi, R. Noyori, J.Am.Chem.

Soc. 1980, 102, 7932.

29 T. Ohta, H. Takaya, R. Noyori, Inorg. Chem. 1988, 27, 566.

30 (a) T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974; (b) E. N. Jacobsen, I.

Marko, W. S. Mungall, G. Schröder, K.B. Sharpless, J. Am. Chem. Soc. 1988, 110, 1968.

31 Selected books for review: a) Handbook of Organopalladium Chemistry for Organic

Synthesis, Ed. E-i. Negishi, John Wiley & Sons, 2002; b) Palladium Reagents and

Catalysts-New Perspectives for the 21st Century, J. Tsuji, John Wiley & Sons, 2004.

32 Selected reviews: a) W. Cabri, I. Candiani, Acc. Chem. Res. 1995, 28, 2; b) G. T. Crisp,

Chem. Soc. Rev.1998, 27, 427. c) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000,

100, 3009.

33 See, for review: a) Cross-Coupling Reaction-A Practical Guide, Ed. N. Miyaura, (Series:

Topics in Current Chemistry), Springer, Berlin, 2002; b) A. F. Littke, G. C. Fu, Angew.

Chem. Int. Ed. 2002, 41, 4176; c) R. R. Tykwinski, Angew. Chem. Int. Ed. 2003, 42, 1566;

30 Chapter 1

d) Metal-Catalyzed Cross-coupling Reactions, 2nd Edition, Ed. A. de Meijere, F.

Diederich, Wiley-VCH, Weinheim, 2004.

34 See, for review: a) M. Gauss, A. Seidel, P. Torrence, P. Heymanns, in Applied

Homogeneous Catalysis with Organometallic Compounds, Ed. B. Cornils, W. A.

Herrmann, VCH, Weinheim, 1996, pp. 104; b) J. Muzart, Tetrahedron 2005, 61, 9423.

35 See, for review: a) B. M. Trost, C. Lee, in Catalytic Asymmetric Synthesis, Ed. I. Ojima,

Wiley-VCH, New York, 2000, pp. 593; b) B. M. Trost, M. L. Crawley, Chem. Rev. 2003,

103, 2921.

36 See, for review: a) S. S. Stahl, Angew. Chem. Int. Ed. 2004, 43, 3400; b) M. S. Sigman, D.

R. Jensen, Acc. Chem. Res. 2006, 39, 221.

37 Selected examples: a) K. Mikami, K. Takahashi, T. Nakai, T. Uchimaru, J. Am. Chem. Soc.

1994, 116, 10948; b) E. Hagiwara, A. Fujii, M. Sodeoka, J. Am. Chem. Soc. 1998, 120,

2474; c) Y. Hamashima, D. Hotta, M. Sodeoka, J. Am. Chem. Soc. 2002, 124, 11240.

38 see, for review: B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921.

39 M. Sawamura, R. Kuwano Y. Ito, Angew. Chem. Int. Ed. Engl. 1994, 33, 111.

40 Y. Hashimoto, Y. Horie, M. Hayashi, K. Saigo, Tetrahedron: Asymmetry 2000, 11, 2205.

41 J. Dupont, C. S. Consorti, J. Spencer, Chem. Rev. 2005, 105, 2527.

42 S. Jautze, R. Peters, Angew. Chem. Int. Ed. 2008, 47, 9284.

43 Some recent examples: a) R. Takeuchi, S. Kezuka, Synthesis 2007, 3349; b) O. V. Singh,

H. Han, J. Am.Chem. Soc. 2007, 129, 774; c) C. Defieber, A. Ariger, P. Moriel, E. M.

Carreira, Angew. Chem. Int. Ed. 2007, 46, 3139; d) Y. Yamashita, A. Gopalarathnam, J. F.

Hartwig, J. Am. Chem. Soc. 2007, 5, 7508; e) S. Spiess, C. Berthold, R. Weihofen, G.

Helmchen, Org. Biomol. Chem. 2007, 5, 2357; f) G. Helmchen, A. Dahnz, P. Dübon, M.

Schelwies, R. Weihofen, Chem. Commun. 2007, 675; g) I. Dubovyk, I. D. G. Watson, A.

K. Yudin, J. Am. Chem. Soc. 2007, 129, 14172; h) M. J. Pouy, A. Leitner, D. J. Weix, S.

Ueno, J. F. Hartwig, Org. Lett. 2007, 9, 3949; i) C. Liang, F. Collet, F. Robert-Peillard, P.

Muller, R. H. Dodd, P. Dauban, J. Am. Chem. Soc. 2008, 130, 343; f) C. Welter, R. M.

Moreno, S. Streiff, G. Helmchen, Org. Biomol. Chem. 2005, 3, 3266.

44 a) J. R. Porter, G. Wirschun, K. W. Kuntz, M. L. Snapper, A. H. Hoveyda, J. Am. Chem.

Soc. 2000, 122, 2657;b) M.-Y. Ngai, A. Barchuk, M. J. Krische, J. Am. Chem. Soc. 2007,

129, 12644; c) N. Abermil, G. Masson, J. Zhu, J. Am. Chem. Soc. 2008, 130, 12596.

45 O. Mumm, F. Möller, Chem. Ber. 1937, 70, 2214.

46 a) L. E. Overman, J. Am. Chem. Soc. 1974, 96, 597; b) L. E. Overman, J. Am. Chem. Soc.

1976, 98, 2901.

47 A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180.

48 A. R. Chianese, S. J. Lee, M. R. Gagné, Angew. Chem. Int. Ed. 2007, 46, 4042.


49 P. Beak, J. Bonham, J. T. Lee, J. Am. Chem. Soc. 1968, 90, 1569.

50 a) L. E. Overman, Angew. Chem. Int. Ed. 1984, 23, 579; b) P. Watson, L. E. Overman, R.

G. Bergman, J. Am. Chem. Soc. 2007, 129, 5031.

51 See, for example: Y. Yamamoto, H. Shimoda, J. Oda, Y. Inouye, Bull. Chem. Soc. Jpn.

1976, 49, 3247.

52 M. E. Weiss, D. F. Fischer, Z.-q. Xin, S. Jautze, W. B. Schweizer, R. Peters, Angew.

Chem. Int. Ed. 2006, 45, 5694.

53 a) A. Fürstner, P. W. Davies, Angew. Chem. Int. Ed. 2007, 46, 3410; b) A. R. Chianese, S.

J. Lee, M. R. Gagné, Angew. Chem. Int. Ed. 2007, 46, 4042; c) selected very recent

asymmetric application: C. A. Mullen, A. N. Campbell, M. R. Gagné, Angew. Chem. Int.

Ed. 2008, 47, 6011.

54 F. P. Fanizzi, F. P. Intini, L. Maresca, G. Natile, J. Chem. Soc.,Dalton Trans. 1992, 309.

55 H. Huang, R. Peters, Angew. Chem. Int. Ed. 2009, 48, 604.

56 see, e.g.: a) O. Pàmies, J-E. Bäckvall, Chem. Rev. 2003, 103, 3247. b) T. R. Ward, Chem.

Eur. J. 2005, 11, 3798.

57 M. T. Reetz, K. Schimossek, Chimia 1996, 50, 668.

Chapter 2

Chemoenzymatic Resolution of Cis and Trans -3,6-dihydroxy-α-ionone. Synthesis of the Enantiomeric Forms of Dehydrovomifoliol and 8,9-Dehydrotheaspirone.1

2.1 Introduction. This chapter describes the synthesis of both enantiomers of cis- and trans-3-acetoxy-6-

hydroxy-α-ionone. The title compounds are prepared by resolution of the

diastereoisomerically pure racemic 3,6-dihydroxy-α-ionone isomers. These building blocks

were used for the synthesis of both enantiomeric forms of the natural norterpenoids

dehydrovomifoliol 1 and 8,9-dehydrotheaspirone 2.

2.1.1 General Introduction and Motivation. Numerous methods are available for the syntheses of 3,6-dihydroxy-α-ionone isomers. In the

preceding chapter a straightforward synthesis of all isomeric forms of the 3-acetoxy-6-hydroxy-α-

ionone were developed.

2.2 Literature Overview.

2.2.1 Known Ionone Isomers.

Ionone isomers and their hydroxylated derivatives are important starting materials for the synthesis

of several natural products. Since many of the latter compounds show biological activity, which is

strictly related to their absolute configuration, their synthesis requires optically active starting

materials.2 Therefore the enantioselective preparation of these chiral building blocks has become an

important research topic. Ionone isomers and their hydroxylated derivatives are potential building

bloks for the stereospecific synthesis of compounds of the general structure 82 (Figure 2.1).

34 Chapter 2

R'OH

O

R

O

12

3 4 5

6

7

89

10

OO

OH

O

OH

OCOOH

R= OH, H or OR'= carotenoids or

apocarotenoid chain

O

( carotenoidnumbering )

82

83 1

284

Fig 2.1.

Carotenoids and apocarotenoids of type 82 have been isolated3 from different natural sources and

the most known is (+)-abscisic acid 83 that is well established as an important growth regulator in

most plants.4 Also (+)-dehydrovomifoliol 98 occurs in nature5, but its relevance is due to its use as

penultimate precursor in the well established synthesis of 83.6 Moreover, spiroderivatives 84 and 2

are important flavors. Theaspirone 84 is a component of thea scent7 whereas the less known

dehydrotheaspirone 2 has received increasing attention after its isolation from tobacco,8 Riesling

wine,9 nectarines,10 honey,5c and Reseda odorata flowers.11 All the above mentioned compounds

share the same difficult accessibility by chemical synthesis, particularly in their enantiomerically

pure forms. On this topic the known procedures are based essentially on three approaches: the

resolution of the enantiomers, the asymmetric synthesis and the use of two easily available C-9

chiral building blocks. The first method10,12 proved to be unsuitable for preparative purposes and

was applied in few analytical studies dedicated to the evaluation of the physical12a-b or

organoleptic10,12c properties of compounds 84 and 2, respectively. Concerning the second

pathway,13 some leading methods exploited Sharpless epoxidation13a and chiral bicyclic lactams13b

or ketals13c alkylation procedure as a key step in the formation of the quaternary asymmetric centre.

The obtained chiral intermediates were then manipulated in order to obtain derivatives 1 and 2. On

the other hand, the third pathway is based on the use of (4R,6R) and (4R,6S) isomers of 4-hydroxy-

2,2,6-trimethylcyclohexanone2,14 that are in turn obtained in high optical purity by microbial

reduction of oxoisophorone and by fractional crystallization of its diastereoisomeric esters,

respectively. The latter two compounds were used as starting materials in a number of

carotenoids syntheses involving the preparation of compounds of type 1, 82, 83.

Synthesis of the enantiomeric forms of dehydrovomifoliol and 8,9-dehydrotheaspirone 35

Fuganti et al. have been working on the enantioselective synthesis of different norterpenoid

compounds such as ionone,15 irone,16 damascone17 and 7,11-epoxymegastigma-5(6)-en-9-

one18 isomers.

In 1998, Fuganti et al.19 reported a successful combination of simple chemical and enzymic

methods allowed to prepare extremely valuable (R)- and (S)- α-ionone using inexpensive racemic

α-ionone 85 as a starting material (scheme 2.1). Two different approaches have been devised by

interchanging the application of traditional techniques of fractional crystallisation and enzyme-

mediated reactions. Fractional crystallisations, from hexane, of 4-nitrobenzoate derivatives of α-

ionol were successfully used in both synthetic paths to achieve diastereoisomeric purity, while

optical activation was assured by enantioselective enzyme-mediated acetylation of α-ionol and

hydrolysis of α-ionol acetate.

O O O

(±)-85 (S)-86, 97%ee (R)-86, 97%ee

+

Scheme 2.1. Chemoenzymatic approach for synthesis enantiopure of (R)- and (S)- α-ionone.

In 2005, the same group also reported the synthesis of the isomers of the natural C-13

norterpenoids derivatives 7,11-epoxymegastigma-5(6)-en- 9-one and 7,11-epoxymegastigma-5(6)-

en-9-ols. The racemic compounds were resolved for the first time by mean of lipase-mediated

acetylation. All isomers were obtained in very good yield and high enantiomeric purity (scheme

2.2).18

O

(±)-85 (±)- 87 (−)-88 (+)-88

O

O

O

OH

O

OH

Scheme 2.2. Chemo-enzymatic approach for the synthesis of 7,11-epoxymegastigma-5(6)-en-9-one and 7,11-epoxymegastigma-5(6)-en-9-ol.

Recently, fuganti et al.17 reported a new chemio-enzymatic approach to all the isomeric forms of

the norterpenoid flavor damascone (scheme 2.3). The synthetic pathway is divergent, compact, and

operationally simple and does not require demanding reaction conditions or reagents. The starting

material is a racemic α-ionone that is inexpensive and commercially available. The procedure

described gives access to the title compounds in high regio- and enantiomeric purity and compares

favorably to the previously reported syntheses.

36 Chapter 2

O

(±)-85 (S)-(−)-α-Damascone, 99%ee (R)-(+)-α-Damascone, 98%ee(S)-(+)-γ -Damascone, 98%ee (R)-(−)-γ -Damascone, 99%ee

OO

89 90

Scheme 2.3. Chemo-enzymatic approach for the synthesis of damascone isomers.

From these different chemoenzymatic approaches, it is found that different hydroxylated

ionone derivatives are good substarte in this resolution protocol.

2.3 Results and Discussion.

2.3.1 Preparation of Racemic Diols 93 and 95. Accordingly, we extended this flexible enzymic methodology to the resolution of 3,6-dihydroxy- α

-ionone derivatives. Our study first needed a valuable amount of racemic starting materials.

Preliminary experiments demonstrated that different lipases catalyze the irreversible kinetic

acetylation of the 3-hydroxy group of the abovementioned isomers with complete regioselectivity

and with very low diastereoselectivity. Therefore, we selected two diastereoselective preparations

of racemic cis- and trans- 3,6-dihydroxy-α-ionone 93 and 95, respectively (Scheme 2.4). In

accordance with previously reported methods, both diols were prepared by starting from the easily

available 3,4-dehydroxy-β-ionone 91. Treatment of the latter compound with oxygen and visible

light in the presence of rose bengal as a photosensitizer12a provided the stable peroxyderivative 92,

which was reduced with thiourea20 to give the cis-3,6-dihydroxy-α-ionone 93. Conversely, the

oxidation of 91 with MCPBA afforded the epoxy-derivative 94, which is not stable in the reaction

environment and rearranged to give a 5:1 mixture of diols 95 and 93, respectively.21 Due to the

different crystal properties of the latter compounds, the crystallization of the crude reaction mixture

afforded pure diol 95.

O

O

OO

OOH

HO

OH

HO

O

iii, iv

O

O

i ii

91

92 (±)-93

94 (±)-95


Scheme 2.4. Preparation of racemic diols 93 and 95. Reagents and conditions: (i) Rose Bengal, O2, MeOH; (ii) thiourea, MeOH, RT, 56% (two steps); (iii) MCPBA, Et2O, 0 °C; (iv) NaHCO3, H2O, RT, then crystallization from hexane/AcOEt, 59% (two steps).

2.3.2 Lipase-Mediated Resolution of Diols 93 and 95.

Each of the two diastereoisomerically pure diols 93 and 95 was treated with vinyl acetate in t-

BuOMe solution in the presence of lipases (lipase PS, CRL, and PPL). The reactivity of each

substrate toward the irreversible acetylation was tested by monitoring at regular time intervals the

product distribution by GC analysis. After interruption of the reaction, the products were isolated

and their ee and absolute configuration were determine by optical rotation values measurements

and chemical correlation with the known dehydrovomifoliol 1, respectively (see 2.3.3). The results

of this study are collected in the Table 2.1 and allow some interesting considerations.

Table 2.1. Results of the enzyme-mediated acetylation of diols (±)-93 and (±)-95.

Diol Enzyme Conversion (%) ee and absolute

configuration a E b

PPL 3% 9% (3S,6R) 1.2

CRL 42% 3% (3S,6R) 1.1 (±)-93

Lipase PS 50% 60% (3S,6R) 7.2

PPL 15% 3% (3S,6S) 1.1

CRL 30% 8% (3R,6R) 1.2 (±)-95

Lipase PS 13% 36% (3S,6S) 2.3 a The ee and absolute configuration were determined on the isolated 3-acetoxy derivative 96 and 97

according with 2.3.3. b E=ln[1−c×(1+eep)]/ln[1−c×(1−eep)].

All the lipases tested catalysed regioselectively the acetylation of the secondary alcohol function.

Transformation of cis diol 93 afforded (3S,6R)-3-acetoxy-derivative with an enantioselectivity that

ranged from very low for PPL and CRL to moderate for lipase PS. Similarly, PPL and lipase PS

mediated the conversion of trans diol 95 in the (3S,6S)-3-acetoxy-derivative with very low and

modest enantioselectivity, respectively. In a different way, CRL catalysed the acetylation of the

same diol with opposite enantioselectivity showing preference for the 3R configuration and thus

affording the (3R,6R)-3-acetoxy-derivative. Also in the latter case the enantioselectivity was very

low. Overall, the enantiomer ratio does not exceed the value of 1.2 for PPL and CRL whereas

showed the value of 7.2 and 2.3 when lipase PS catalysed the acetylation of 93 and 95,

38 Chapter 2

respectively. Even though by the employment of the latter enzyme, an efficient resolution process

of 93 and 95 was not easily achieved. Providentially, we observed that both cis and trans 3-

acetoxy-derivatives were nice crystalline compounds and for ee inferior to 60-70%, racemic

crystals were much less soluble than enantiomeric enriched ones. The combined application of the

enzyme-mediated acetylation and of the fractional crystallisation was a successful path to

enantiopure 3-acetoxy-derivatives.

Taking advantage of the results described above, we devised a large-scale method for the resolution

of the title compounds. According to the Scheme 2.5, diols 93 and 95 were submitted to lipase PS-

mediated acetylation to afford acetates (−)-96 and (+)-97, respectively, and unreacted diols (+)-93

and (−)-95, respectively. After chromatographic separation, the later diols were converted in the

corresponding acetates (+)-96 and (−)-97, respectively, by treatment with pyridine and acetic

anhydride. The optical purity of the obtained four acetates was increased by crystallization from

hexane/ethyl acetate. The obtained crystals showed very low ee value. Thus, the liquid phases were

submitted again to the crystallisation process which was repeated using the mother liquors till the

crystals showed optical rotation value superior of that measured for the liquid. At this point a

further crystallisation of the solid afforded enantiomeric pure acetate whose optical rotation value

did not increase by recrystallisation. All the crystal crops showing low ee were collected and then

converted again in the starting diols 93 and 95 by mean of treatment with methanolic KOH.

Although a number of simple chemical manipulation are necessary, the recycling of compounds

with low ee increase the significance of the method and overall the process give access to the

enantiomeric forms of acetate 96 and 97 in high ee.


OH

AcO

O

OOH

AcO

(+)-96(low ee)

(+)-93 +

OH

AcO

O

OOH

AcO

(±)-93

(±)-95

i

(+)-96(96% ee)

(−)-96(97% ee)

+

(−)-96(low ee)

(−)-96

(+)-96

(−)-97(low ee)

(−)-95 +

i

(−)-97(97% ee)

(+)-97(98% ee)

+

(+)-97(low ee)

(+)-97

(−)-97

ii

iiiii

ii

iiiii

iv

iv

iv

iv (±)-95

(±)-95

(±)-93

(±)-93

Scheme 2.5. Preparation of the enantiomeric forms of acetates 96 and 97 by a chemoenzymatic

resolution procedure. Reagents and conditions: (i) lipase PS, t-BuOMe, vinyl acetate, column chromatography; (ii) fractional crystallization procedure; (iii) Ac2O, Py; (iv) KOH, MeOH.

2.3.3 Determination of the Absolute Configuration of Acetates (−)-96 and (+)-97; Synthesis of Dehydrovomifoliol.

The absolute configuration of the enantiomeric forms of 96 and 97 was not known. Therefore, we

decided to assign these data by chemical correlation. Since we were not able to determine

accurately the ee of the above mentioned compounds by GC or HPLC analysis, we converted these

acetates in (−) and (+) enantiomers of dehydrovomifoliol 98 of known absolute configuration,

which display high and well measurable optical rotation value.13a-b,14

According with Scheme 2.6, enantiomerically pure (−)-96 and (+)-97, were treated with methanolic

KOH and the obtained diols were oxidized with MnO2 in CH2Cl2 to afford (−)-(R) and (+)-(S)

dehydrovomifoliol 98, respectively. Judging from the comparison of the measured optical rotation

value, [α]20D = −219.5 (c = 0.5 g/dL, CH2Cl2) and [α]20

D = +222 (c = 0.5 g/dL, CH2Cl2), with that

reported in the Lit.13b [α]20D = −219 (c = 0.4 g/dL, CH2Cl2) for (−)-98 of ee > 95%, we assigned the

absolute configurations of (−)-96 and (+)-97, as (3S,6R) and (3S,6S), respectively. Concerning the

40 Chapter 2

enantiomeric purity of the latter two compounds we assert that both show ee > 95%. This

assumption has been confirmed by chiral GC analysis of dehydrotheaspirones (−)-103 and (+)-103

(see 2.3.4.).

OOH

O

OOH

O(S)-dehydrovomif oliol

(R)-dehydrovomifoliol(−)-96i, ii

(+)-97i, ii

(−)-98

(+)-98

69%

72% Scheme 2.6. Chemical correlation of acetates 96 and 97 with dehydrovomifoliol 98. Reagents and

conditions: (i) KOH, MeOH; (ii) MnO2, CH2Cl2, RT.

2.3.4 Synthesis of the Enantiomeric Forms of 8,9-Dehydrotheaspirone 103.

As mentioned in the introduction, enantioenriched 3,6-dihydroxy-α-ionone derivatives are

important synthetic intermediates. Since we are involved in a research program devoted to the

preparation of enantiopure odorants, we decided to exploit the use of compounds 96 and 97 for the

synthesis of flavours of type 82 and 103. Herein, we describe the transformation of the

enantioenriched acetates (−)-96 and (+)-97 in the 8,9-dehydrotheaspirone enantiomers (−)-103 and

(+)-103, respectively.

According with Scheme 2.7, regioselective hydrogenation of (−)-96 and (+)-97 using Ni Raney as

catalyst afforded hemiacetals 99 and 100, respectively each of them as a inseparable mixture of

diastereoisomers. The latter compounds were not characterized and were used in the next step.

Thus, dehydratation of 99 and 100 with POCl3 and Et3N afforded compound (−)-101 and (−)-102,

respectively. The removal of the acetyl protecting group by reaction with methanolic KOH and the

following oxidation of the obtained allyl alcohols by MnO2 treatment, afforded dehydrotheaspirone

isomers (−)-103 and (+)-103, respectively. The enantiomeric excesses of the latter compounds were

easily measured by chiral GC analysis as 97% and 98%, respectively. These values indicate also

the ee of the starting materials (−)-96 and (+)-97 and the ee of the synthesized (−)-(R) and (+)-(S)

dehydrovomifoliol 98. All these data (absolute configuration and optical purity) are in good

agreement with those described above (see 2.3.3) and reported by other authors.12c, 13b


AcOO

OO

AcOO OH

AcOO OH

OO

(R)-8,9-dehydrotheaspirone (S)-8,9-dehydrotheaspirone

AcOO

(+)-97(-)-96

(-)-101 (-)-102

(-)-103 (+)-103

i i

ii ii

iii, iv iii, iv

57% 55%

87% 87%

99 100

Scheme 2.7. Preparation of the enantiomeric forms of 8,9-dehydrotheaspirone 103 starting from

acetates 96 and 97. Reagents and conditions: (i) H2, AcOEt, Ni Raney cat.; (ii) POCl3, Et3N, 0 °C; (iii) KOH, MeOH; (iv) MnO2, CH2Cl2, RT.

2.3.5 Olfactory Evaluation of the Enantiomeric Forms of Dehydro- theaspirone 103.

The enantiomerically enriched forms of 8,9-dehydrotheaspirone were evaluated by qualified

perfumers (Givaudan Schweiz AG, Fragrance Research). The following results were obtained:

(−)-(R)-103: woody, dry, cedarwood odor with a green, earthy, tobacco and olibanum inflection

and floral-fruity nuances. Odor threshold (5 panellists): 13.7 ng/L air.

(+)-(S)-103: floral, woody-ambery, powdery, reminiscent of Cetonal with natural fruity, orris-like

facets. Odor threshold (5 panellists): 9.8 ng/L air.

2.4 Conclusion. A number of results have been achieved. We reported a new chemo-enzymatic approach to all

isomeric forms of the 3-acetoxy-6-hydroxy-α-ionone. Our synthetic pathway consist in the

preparation of the diastereoisomerically pure racemic 3,6-dihydroxy-α-ionone isomers and then in

42 Chapter 2

their resolution by mean of the combination of the lipase-mediated enantioselective acetylation and

of the fractional crystallization of the obtained acetates. The proposed process is operationally

simple, does not require demanding reaction conditions or reagents and the starting material is the

inexpensive 3,4-dehydro-β-ionone. The obtained chiral building blocks were used for the synthesis

of the enantiomeric forms of the natural norterpenoid dehydrovomifoliol 98 and 8,9-

dehydrotheaspirone 103. Finally, the odour properties of the latter compound were evaluated by

professional perfumers.

2.5 References.

1 S. Serra, A. Barakat, C. Fuganti, Tetrahedron: Asymmetry 2007, 18, 2573.

2 (a) H. Mayer, Pure & Appl. Chem. 1979, 51, 535; (b) H. Pfander, Pure & Appl. Chem.

1991, 63, 23.

3 (a) B. Diallo, M. Vanhaelen, Phytochemistry 1987, 26, 1491; (b) H. Achenbach, E.

Blümm, R. Waibel, Tetrahedron Lett. 1989, 30, 3059; (c) M. Tsushima, E. Mune, T.

Maoka, T. Matsuno, J. Nat. Prod. 2000, 63, 960; (d) T. Matsuno, M. Tsushima, T. Maoka,

J. Nat. Prod. 2001, 64, 507; (e) M. DellaGreca, C. Di Marino, A. Zarrelli, B. D’Abrosca, J.

Nat. Prod. 2004, 67, 1492.

4 F.T. Addicott,. Abscisic Acid; Praeger: New York, 1983.

5 (a) M. Takasugi, M. Anetai, N. Katsui, T. Masamune, Chem. Lett. 1973, 245; (b) H.

Achenbach, M. Lottes, R. Waibel, G. A. Karikas, M. D. Correa, M. P. Gupta,

Phytochemistry 1995, 38, 1537; (c) B. R. D’Arcy, G. B. Rintoul, C. Y. Rowland, A. J.

Blackman, J. Agric. Food Chem. 1997, 45, 1834; (d) H. Kai, M. Baba, T. Okuyama, Chem.

Pharm. Bull. 2007, 55, 133.

6 D. L. Roberts, R. A. Heckman, B. P. Hege, S. A. Bellin, J. Org. Chem. 1968, 33, 3566.

7 G. Ohloff, Scent and Fragrances: The Fascination of Fragrances and their Chemical

Perspectives; Springer-Verlag: Berlin, 1994.

8 T. Fujimori, Y. Takagi, K. Kato, Agric. Biol. Chem. 1981, 45, 2925.

9 P. Winterhalter, M. A. Sefton, P. J. Williams, J. Agric. Food Chem. 1990, 38, 1041.

10 H. Knapp, C. Weigand, J. Gloser, P. Winterhalter, J. Agric. Food Chem. 1997, 45, 1309.

11 H. Surburg, M. Güntert, H. Harder, In Bioactive Volatile Compounds from Plants;

Teranishi, R.; Buttery, R. G.; Sugisawa, H., Eds. ACS Symposium Series 525.American

Chemical Society: Washington, DC, 1993; pp.168.

12 (a) M. Koreeda, G. Weiss, K. Nakanishi, J. Am. Chem. Soc. 1973, 95, 239; (b) B. T. Kim,

Y. K. Min, T. Asami, N. K. Park, O. Y. Kwon, K. Y. Cho, S. Yoshida, Tetrahedron Lett.


1997, 38, 1797; (c) K. Hitomi, N. Hideki, K. Taro, I. Masakazu, Japanese Patent, 2002, JP

2002069479 A.

13 (a) M. Acemoglu, P. Uebelhart, M. Rey, C. H. Eugster, Helv. Chim. Acta. 1988, 71, 931;

(b) A. I. Meyers, M. A. Sturgess, Tetrahedron Lett. 1989, 30, 1741; (c) T. R. Smith, A. J.

Clark, G. J. Clarkson, P. C. Taylor, A. Marsh, Org. Biomol. Chem. 2006, 4, 4186.

14 K. Mori, Tetrahedron 1974, 30, 1065.

15 (a) E. Brenna, C. Fuganti, S. Serra, P. Kraft, Eur. J. Org. Chem. 2002, 967; (b) S. Serra, C.

Fuganti, E. Brenna, Helv. Chim. Acta. 2006, 89, 1110.

16 E. Brenna, C. Fuganti, S. Serra, C. R. Chimie 2003, 6, 529.

17 S. Serra, C. Fuganti, Tetrahedron: Asymmetry 2006, 17, 1573.

18 E. Brenna, C. Fuganti, S. Serra, Tetrahedron: Asymmetry 2005, 16, 1699.

19 E. Brenna, C. Fuganti, P. Grasselli, M. Redaelli, S. Serra, J. Chem. Soc., Perkin Trans. 1,

1998, 4129.

20 (a) T. Kato, H. Kondo, Y. Kitano, G. Hata, Y . Takagi, Chem. Lett. 1980,757; (b) Kato, T.;

Kondo, H. Bull. Chem. Soc. Jpn. 1981, 54, 1573.

21 C. R. Strauss, E. Dimitriadis, B. Wilson, P. J. Williams, J. Agric. Food Chem. 1986, 34,

145.

Chapter 3

Synthesis, Olfactory Evaluation and Determination of the Absolute Configuration of the β- and γ-Iralia® Isomers.1

3.1 Introduction. This chapter describes the regioselective synthesis of the methyl ionones isomers. The enantiomers

of the γ isomers 106 and 109 are prepared by enzyme-mediated resolution of the corresponding 4-

hydroxy derivatives followed by reductive elimination of the hydroxy group. The absolute

configuration of the latter compound is determined by chemical correlation with the known α

isomers. Since all the obtained isomers are component of the artificial violet odorants sold under

the trade name of Iralia®, their odour properties are evaluated by professional perfumers.

3.2 General Introduction and Motivation. The industrial creation of new perfumes2 needs of two essential lines of researches: the discovery

of new odorous molecules and reinvestigation or chemical modification of older commercial

products. Due to the unpredictable relationship between chemical structure and odour,3 the latter

approach is particularly interesting from a chemical point of view. Indeed, many fragrances are

sold as a mixture of isomers whose specific contribution to the perceived odor may be very

different. Moreover, enantiomer composition of a single chemical compound greatly affected the

fragrance properties either in terms of features or as odor thresholds.4

As a part of a program of synthesis of enantioenriched odorant, Fuganti et al. have previously

prepared a large number of enantiomerically pure isomers of commercial fragrances and natural

flavours by enzyme mediated methods.4,5 In this context, our attention have focused on the

odorants with ionone framework6 that are of pivotal relevance in industrial perfumery.

46 Chapter 3

3.3 Literature Overview. Methyl ionones isomers 104-109 are relevant artificial violet odorants sold as a mixture of isomers

under the trade name of Iralia®(Figure 3.1).2a

O

(±)-107

O O

O

12

3 4 5

67

89 10(carotenoid

numbering )

OD4,5 α -ionone 85D5,6 β -ionone 119D5,13 γ -ionone 120

13

O

O

(±)-106

(±)-109

105

108

(±)-104

Fig 2.1.

Methyl ionone isomers are not found in the nature. They were first prepared by Tiemann in 18937,

by condensation of citral with ethyl methyl ketone followed by acid-catalyzed cyclisation. The first

step proceeds without selectivity whereas the second one shows a regioselectivity that depend on

the kind of the acid used. Concentrated phosphoric acid affords α isomers with high selectivity

whereas sulfuric acid or Lewis acids afforded β or γ isomers, respectively with low selectivity

(scheme 3.1).

O O

O

Conc H2SO4

OO

Conc H3PO4

Mixture

Regioselective α Mixture of β &γ

Scheme 3.1. Methyl ionone isomers synthesis catalyzed by acid.

Synthesis of the enantiomeric forms of the Iralia® isomers 47

As a consequence of this fact, the overall quality of the product is affected by the synthetic method

used. Moreover, α and γ isomers are a mixture of enantiomers and the specific preparation of β

and γ .

Recently, Fuganti et al.6f have described the preparation and odour evaluation of the enantiomeric

forms of α isomers 104 and 107 that are the main component of commercial Iralia® (Scheme 3.2).

O

O

O

O

EnzymaticApproaches

Scheme 3.2. Enzymatic approach for α-methyl ionone isomers by Fuganti and co-workers.

Otherwise, the impact of the minor components on the final odour could be relevant and their

specific evaluation is highly desired. This aspect is particularly evident for γ-isomers of ionone8

and methyl-ionone9 that have showed isomers fragrance performances superior to those described

for the corresponding α isomers.

In the proceeding chapter report on the stereoselective preparation of β and γ isomers 106, 108 and

106, 109, respectively. In addition, the four enantiomeric forms of the latter γ isomers were

prepared and determined their absolute configuration by chemical correlation. All the obtained

isomers were evaluated by professional perfumers to achieve a complete description of each

component of iralia®.


3.4.1 Preparation of β -Isomers 105 and 108. As mentioned above, only compounds with high isomeric purity are suitable for a correct olfactory

evaluation. This aspect is relevant especially for methyl-ionone isomers that are inseparable by the

usual methodologies. It was found that cyclization of methyl-pseudoionone isomers (3,6,10-

trimethylundeca-3,5,9-trien-2-one and 7,11-dimethyldodeca-4,6,10-trien-3-one) affords β isomers

105 or 108 contaminated with a substantial amount of the corresponding α-isomers. Therefore, two

different regiospecific pathways were studied to these compounds (Scheme 3.3). 8-Methyl β-

ionone 105 was prepared starting from citral. The Horner-Emmons reaction of the latter aldehyde

48 Chapter 3

with triethyl 2-phosphonopropionate afforded ester 114 that was cyclized using H2SO4 as acid

catalyst. The obtained ester 115 was reduced with LiAlH4 to give the corresponding alcohol that

was converted into ester 116 by treatment with 3,5-dinitrobenzoyl chloride and pyridine.

The later compound was then purified by crystallization from methanol in order to remove all the

unwanted isomers. The pure ester was saponified and the alcohol was oxidized by mean of MnO2.

The lacking carbon atom was then introduced by treatment of the obtained aldehyde with methyl

magnesium iodide and the resulting ionol was converted into pure 105 by MnO2 oxidation.

A different pathway was used for the preparation of isomer 108. β-ionone 119 is commercially

available in good isomeric purity (up to 96%) and was used as starting material. The haloform

reaction (Br2/NaOH) afforded acid 11710 that was converted into alcohol 118 by mean of

esterification to the corresponding methyl ester followed by reduction with LiAlH4. The latter

allylic alcohol was oxidized and the obtained aldehyde was treated with ethyl magnesium bromide.

The resulting ionol was then converted into pure 108 by MnO2 oxidation.

OEt

O O

OEt

O

ONO2

NO2

OH

i

iii, iv, v

61%

Citralii

78%

vi, vii, viii, vii

63%

ix vii, xi, vii

90%

CO2H x, iii

69%

β / α 4:1

19117 118

105

108

115

116

114

Scheme 3.3. Regioselective preparation of β-iralia isomers 105 and 108. Reagents and conditions: (i) NaH, triethyl 2-phosphonopropionate, THF, reflux; (ii) H2SO4/AcOOH, −5 °C; (iii) LiAlH4, Et2O, 0 °C; (iv) 3,5-dinitrobenzoyl chloride, Py/CH2Cl2; (v) two crystallization from MeOH; (vi) NaOH, MeOH; (vii) MnO2, CHCl3, reflux; (viii) MeMgI, Et2O; (ix) Br2, NaOH/H2O, dioxane; (x) MeOH/ H2SO4; (xi) EtMgBr, Et2O.

3.4.2 Preparation of γ -Isomers 106 and 109. As mentioned in the introduction, the specific preparation of γ isomers 106 and 109 has not

previous reported although some studies on their isolation and characterization from the


commercial product was described many year ago.12 Indeed, the synthesis of γ-ionone derivatives

by cyclization afforded invariably an inseparable mixture of regioisomers. Otherwise, α isomers

104 and 107 are preparable on a large scale and in good isomeric purity by cyclization of 3,6,10-

trimethyl-undeca-3,5,9-trien-2-one and from α-ionone 85, respectively (Section 7.2 ). Fuganti et al.

have previously developed a stereoselective procedure that allows the conversion of α-ionone

derivatives into γ-ionone derivatives.5c,12 The regioselective base-mediated isomerization of 4,5-

epoxy-4,5-dihydro-α-ionone followed by reductive elimination of the obtained allylic alcohols

were the key steps of our syntheses. Therefore, by applying the latter synthetic pathway for the

conversion of compounds 104 and 107 into 106 and 109, respectively (Scheme 3.4).

Accordingly, methyl ionones 104 and 107 were submitted to epoxidation procedure with m-

chloroperbenzoic acid to afford the cis/trans mixtures of epoxides 121a/121b and 122a/122b,

respectively. The latter compounds were added to an excess (2.5-3 equiv., −78 °C) of LDA in THF

and then warmed at reflux. After quenching, the cis/trans mixtures of alcohol were obtained

123a/123b and 124a/124b, respectively showing the same diastereoisomeric ratio of the starting

epoxides (cis/trans 4:1). The obtained allylic alcohols were acetylated and then the acetate group

was reductively removed by treatment with triethylammonium formate and palladium catalyst to

give 8-methyl γ-ionone 106 and 10-methyl γ-ionone 109, respectively. As previously reported in

the synthesis of γ-ionone, the later reduction proceeds with good regioselectivity although with

some slight differences among the isomers. The above mentioned γ-ionones were obtained with the

following isomeric purity: 120 (97%), 105 (96-97%), 109 (94%). (±)-107(±)-104

(±)-106 (±)-109

O

O

O

O

O

OH

O

OH

ii 83%

O

O

O

O

O

OH

O

OH

i 85%

121a 121b

123a 123b

122a 122b

124a 124b

121a/121b 4:1

i 88%

122a/122b 4:1ii 78%

iii, iv

+ +

++

80%iii, iv 86%

50 Chapter 3

Scheme 3.4. Regioselective preparation of racemic γ-iralia isomers 106 and 109. Reagents and conditions: (i) MCPBA, CH2Cl2, O °C; (ii) LDA, THF, −78 °C then reflux; (iii) Ac2O/Py; (iv) HCOOH, Et3N, PPh3, PdCl2(PPh3)2 cat., THF, reflux.

3.4.3 Synthesis of Enantioenriched γ -Iralia Isomers (+) and (−)-106 and (+) and (−)-109.

The above mentioned allylic alcohols 123 and 124 are suitable starting materials for the preparation

of enantioenriched isomers 106 and 109, respectively. Indeed, we have established6c that lipase-

mediated acetylation of 4-hydroxy γ-ionone yield enantiopure (4R,6S)-4-acetoxy-γ-ionone. The

reaction proceeds with high enantioselectivity and with complete diastereoselectivity allowing the

exclusive transformation of the cis isomers. Preliminary acetylation experiments confirmed that

alcohols 123 and 124 showed the same behavior.

Therefore, the enzyme mediated resolution of the above mentioned alcohols were performed

(Scheme 3.5). The described reductive elimination of the acetate group (Section 3.3.2) proceeds

without racemization allowing the preparation of enantioenriched methyl-γ-ionone isomers. It is

noteworthy that, since the diastereoisomeric allylic alcohols 123a/123b and 124a/124b are not

separable by chromatography, the resolution procedure gives the corresponding acetylated

compounds with high ee and de leaving unreacted alcohols with low de. Fortunately, epoxide 121a

is separable from its diastereoisomer 121b and the following base mediated isomerization afforded

123a as exclusive isomers. Accordingly, racemic alcohol 123a was acetylated with vinyl acetate in

the presence of lipase PS as catalyst. The reaction was interrupted at 50% of conversion to give

unreacted alcohol (+)-123a (99% de, 87% ee) and acetate (−)-125 (99% de, 99% ee). The reductive

removal of the acetoxy group converted the latter compounds into (+)-8-methyl γ-ionone (87% ee)

and (−)-8-methyl γ-ionone (99% ee), respectively. Otherwise, epoxides 122a and 122b are not

separable and the 4:1 mixture of alcohols 124a and 124b was used in the resolution step. The latter

racemic compounds were treated with vinyl acetate in the presence of lipase PS as catalyst. The

reaction was interrupted at 40% of conversion to give acetate (+)-126 (99% de, 99% ee) and an

inseparable mixture of unreacted alcohols (4S,6R)- 124a and racemic 124b (50% de, 85% ee). As

described above, the reductive removal of the acetoxy group converted the latter compounds into

(+)-10-methyl γ-ionone (99% ee) and (−)-10-methyl γ-ionone (65% ee), respectively.


O

OAc

O

OH

ii, iii

O

OH

O

OAc

iii

+

OO

OO

(R)-(+)-106

(S)-(+)-109(R)-(−)-106

(S )-(−)-106

+

(−)-125(45%)

(+)-126(35%)

(+)-123a(49%)

(±)-123a

(±)124a/124b (4S ,6R)-124a + (±)-124b

(60%)

i

i

ii, iii iii

Scheme 3.5. Preparation of enantioenriched γ-iralia isomers 106 and 109. Reagents and

conditions: (i) Vinyl acetate, t-BuOMe, lipase PS; (ii) Ac2O/Py; (iii) HCOOH, Et3N, PPh3, PdCl2(PPh3)2 cat., THF, reflux.

3.4.4 Determination of the Absolute Configuration of γ-Iralia Isomers. The absolute configuration of the enantiomeric forms of 106 and 109 was unknown. In order to

associate odour descriptions with the configuration of γ-ionone isomers, it was necessary to assign

these data. Since the absolute configuration of the enantiomers of α isomers 104 and 107 was

determined unambiguously,6f we decided to correlate the enantiomeric forms of 106 and 109 with

the above mentioned α isomers. Indeed, it is known6c that treatment of γ-ionone isomers with

concentrated phosphoric acid give isomerization of the exocyclic double bond without any

racemization. Therefore, a sample of compound (−)-106 and of compound (−)-109 were treated

with H3PO4 (Scheme 3.6). By this mean a complete isomerization of the starting γ-isomers to α and

β isomers were achieved. 8-methyl γ-ionone (−)-106 afforded a mixture of (S)-(−) 8-methyl α-

ionone 104 and 8-methyl β-ionone 105 whereas 10-methyl γ-ionone (−)-108 afforded a mixture of

(R)-(+) 10-methyl α-ionone 107 and 10-methyl β-ionone 108. In conclusion, the absolute

configuration of (−)-106 and (−)-109 were assign unambiguously as (S) and (R), respectively.

52 Chapter 3

O

(−)-109

O

(−)-106

i

71%

O

(S)-(−)-104

i

O

(R)-(+)-10765%

+ 105

+ 108

α/ β 83:17

α/ β 78:22

Scheme 3.6. Chemical correlation of enantioenriched γ-iralia isomers 106 and 109 with enantioenriched α-iralia isomers 104 and 107. Reagents and conditions: (i) 85% H3PO4.

3.4.5 Olfactory Evaluation of the Iralia Isomers. The regioisomers of β-iralia and the enantiomerically enriched forms of γ-iralia were evaluated by

qualified perfumers (Givaudan Schweiz AG, Fragrance Research). The following results were

obtained:

8-Methyl β-ionone 105 - Floral-woody and powdery violet note with a more pronounced woody,

powdery cedarwood character and fatty-buttery aspects. Weaker than 108 and beta-ionone on the

blotter, less dry than beta-ionone. Dry down weak powdery-woody, and less substantive than 108.

10-Methyl β-ionone 108 - Strong and typical floral-woody beta-ionone note with a more

pronounced floral violet side, less woody-powdery and stronger than 105 on blotter. Dry down

floral-woody, typical beta-ionone like, more substantive than 105.

(S)-(−) 8-Methyl γ-ionone 106 - Woody-ambery mix odor between methyl ionone and Iso E Super

of dry character.

(R)-(+) 8-Methyl γ-ionone 106 - Rich and interesting woody-ambery leather odor with fruity-floral

facets in the direction or irone and methyl ionone and additional green accents.

(S)-(+) 10-Methyl γ-ionone 109 - Woody-floral odor in the direction of methyl ionone, with a

fruity-floral violet inclination and facets of orris, but also an oily background

(R)-(−) 10-Methyl γ-ionone 109 - Woody odor in the direction of methyl ionone with

additional dry, leathery aspects.


3.5 Conclusion. A number of results have been achieved. New regioselective syntheses of the methyl ionones

isomers 104-109 were reported. The enantiomers of the γ isomers 106 and 109 are prepared by a

chemo-enzymatic approach and their absolute configuration is determined by chemical correlation

with the known α isomers. Finally, the odor properties of all the above mentioned compounds were

evaluated by professional perfumers. In a previous works, Fuganti et al. reported the odour

descriptions of the enantiomers of α isomers 104 and 107. Therefore, a complete description of

each component of the commercial odorants Iralia® were achieved. The following considerations

are noteworthy:

a) All the isomeric forms show distinct olfactory features.

b) For the methyl ionone isomers, the difference between α isomers and γ isomers, although

evident, are less pronounced than those reported for ionone series.6a

c) The difference between enantiomers of γ-methyl ionone isomers are much less pronounced than

those reported for ionone series.

d) Overall, these data show that any structural modification to the ionone framework (methyl group

introduction and position, double bond position absolute configuration) gives a definite and

unpredictable modification of the odour.

3.6 References.

1 A. Barakat, E. Brenna, C. Fuganti, S. Serra, Tetrahedron: Asymmetry 2008, 19, 2316.

2 (a) G. Ohloff, Scent and Fragrances: The Fascination of Fragrances and their Chemical

Perspectives; Springer-Verlag: Berlin, 1994; (b) P. Kraft, J.A. Bajgrowicz, C. Denis, G.

Fráter, Angew. Chem. Int. Ed. 2000, 39, 2980.

3 C.S. Sell, Angew. Chem. Int. Ed. 2006, 45, 6254.

4 E. Brenna, C. Fuganti, S. Serra, Tetrahedron: Asymmetry 2003, 14, 1.

5 (a) A. Abate, E. Brenna, C. Fuganti, F.G. Gatti, S. Serra, Chem. Biodiv. 2004, 1, 1888; (b)

A. Abate, E. Brenna, C. Fuganti, F.G. Gatti, S. Serra, J. Mol. Cat. B: Enzym. 2004, 32, 33;

(c) E. Brenna, C. Fuganti, S. Serra, Tetrahedron: Asymmetry 2005, 16, 1699; (d) E.

Brenna, C. Fuganti, F.G. Gatti, L. Malpezzi, S. Serra, Tetrahedron: Asymmetry 2008, 19,

800.

6 (a) E. Brenna, C. Fuganti, S. Serra, P. Kraft, Eur. J. Org. Chem. 2002, 967; (b) E. Brenna,

C. Fuganti, S. Serra, C. R. Chimie 2003, 6, 529; (c) S. Serra, C. Fuganti, E. Brenna, Helv.

54 Chapter 3

Chim. Acta. 2006, 89, 1110; (d) S. Serra, C. Fuganti, Tetrahedron: Asymmetry 2006, 17,

1573; (e) S. Serra, A. Barakat, C. Fuganti, Tetrahedron: Asymmetry 2007, 18, 2573; (f) A.

Abate, E. Brenna, C. Fuganti, L. Malpezzi, S. Serra, Tetrahedron: Asymmetry 2007, 18,

1145.

7 F. Tiemann, to haarmann & Reimer, Ger. Patent 75, 120, 1893.

8 C. Fuganti, S. Serra, A. Zenoni, Helv. Chim. Acta 2000, 83, 2761.

9 M. Matsui, T. Kawanobe, T. Kurihara, 1991, Japanese Patent N° JP03188062.

10 J.-F. He, Y.-L. Wu, Tetrahedron 1988, 44, 1933.

11 (a) E.T. Theimer, W.T. Somerville, B. Mitzner, S. Lemberg, J. Org. Chem. 1962, 27, 635;

(b) E.T. Theimer, W.T. Somerville, B. Mitzner, S. Lemberg, J. Org. Chem. 1962, 27, 2934.

12 S. Serra, C. Fuganti, E. Brenna, Flavour Fragr. J. 2007, 22, 505.

Chapter 4

The Asymmetric Aza-Claisen Rearrangement: Develop- ment of Widely Applicable Pentaphenylferrocenyl Palla- dacycle Catalysts.1

4.1 Introduction.

This chapter describes the synthesis of pentaphenyl ferrocenyl oxazolines and their

diastereoselective ortho-metallation with Pd(II) to the corresponding pentaphenylferrocenyl

oxazoline palladacycles (PPFOP).

The synthesis of pentaphenylferrocenyl oxazoline 11, based on valinol, and a route to its

palladacycle 4 (preliminary study, improvement of catalyst preparation, characterisation and

application) were conducted in the Peters group (ETH Zurich, Switzerland) by the author. New

aza-Claisen substrates (not known in the literature) used in this chapter were prepared and

characterised by Daniel F. Fischer (former Ph.D. student, ETHZ) except for 211 (N-cyclohexyl),

while literature known substrates were prepared by the author.

4.1.1 General Introduction and Motivation. The preparation of pentaphenyl ferrocenyl oxazoline palladacycles was investigated to study if the

high catalytic activity and selectivity of pentaphenyl ferrocenyl imidazoline palladacycle 77 (FIP-

X) is mainly due to the N-sulfonylated imidazoline- or due to the pentaphenylferrocenyl moiety.

4.1.2 Literature Overview. Despite the impressive progress achieved in asymmetric catalysis during the last decade, an

increasing number of new catalysts, ligands, and applications are reported every year to satisfy the

need to embrace a wider range of reactions and to improve the efficiency of existing processes.

Because of their availability, unique stereochemical aspects, and a wide variety of coordination

modes and possibilities for the fine-tuning of steric and electronic properties, ferrocene-based

56 Chapter 4

ligands constitute one of the most versatile ligand architectures in the current scenario of

asymmetric catalysis. Over the last few years ferrocene catalysts have been successfully applied in

an amazing variety of enantioselective processes. This short survey documents these recent

advances, with special emphasis on the most innovative asymmetric processes and the development

of novel and efficient types of ferrocene ligands.

4.1.2.1 Structural Variety of Chiral Ferrocenyl Oxazoline Ligands. In recent years an amazing number and variety of chiral ferrocenyl oxazoline ligands have been

used in asymmetric catalysis. The asymmetric hydrogenation of heteroaromatic compounds is a

challenging field that is receiving increasing attention. In a recent study, Zhou and co-workers2

have shown the usefulness of ferrocenyloxazolinylphosphines (Fc-Phox, 131) as P,N ligands in the

Ir-catalyzed asymmetric hydrogenation of 2-substituted and 2,6-disubstituted quinolines. The

hydrogenation of 2-methylquinoline was chosen as a model reaction to assess the optimization of

the ligand structure revealing that the tert-butyl-substituted ligand 131 was the most efficient (90%

ee, >95% conversion; scheme 4.1).

N

O

Fe t-BuPPh2N

[{Ir(COD)Cl}2]/131/I2

toluene, H2(600psi), RT NH

S/C: 100; conv [%]: >95; ee [%]: 90 Fc-Phox-131129 130

Scheme 4.1. Fc-Phox/Ir-catalyzed asymmetric hydrogenation of 2-methylquinoline.

Regarding the hydrogenation of the challenging class of simple ketones, in a very recent study at

Solvias it was demonstrated that complexes prepared in situ from [RuCl2(PPh3)3] and the readily

available ferrocenyl phosphine oxazoline ligands (Fc-Phox, 134) are extremely effective and

reactive catalysts for the hydrogenation of aryl alkyl ketones with remarkable enantioselectivities

(up to 99% ee) and excellent S/C ratios (up to 10000–50000)3 (scheme 4.2).

N

O

Fe i -PrPPh2

R = H, 98.5% ee Fc-Phox- 134R = Cl, 96% eeR = F, 96% eeS/C 10000 to 50000

R

O

R

OHRuCl2(PPh3)3/134H2 (20−80 bar)

toluene, 1M NaOH, RT132 133

Scheme 4.2. Fc-Phox/Ru-catalyzed hydrogenation of aryl ketones.

Asymmetric Aza-Claisen Rearrangement & PPFOPCl 57

Moyano and co-workers4 found that the Phox ligand 139, analogous to 138 but with a geminal

dimethyl group at the C5 position of the oxazoline ring, led to a significant enantioselectivity in the

asymmetric allylic alkylation reaction of dimethyl malonate 136 with 2-cyclohexenyl acetate 135

(58% ee; Table 4.1, entry 2), while ligand 138 provided the product in only 11% ee. The authors

hypothesized that the geminal dimethyl group in ligand 139 restricts the conformational mobility of

the ligand, the ferrocene moiety becoming oriented towards the π-allylpalladium moiety. A

sterically highly demanding class of planar chiral Phox ligands, possessing a pentamethylferrocene

backbone, have been recently developed by Helmchen and co-workers.5 In particular, ligand 140

with matched central and planar chirality has provided excellent yields and enantioselectivities

(94% ee) in the Pd-catalyzed asymmetric allylic alkylation6 of cycloalkenyl acetates with dimethyl

sodiomalonate (Table 4.1, entries 3) using 1 mol% of catalyst.

Table 4.1: Ferrocene ligands in the asymmetric allylic alkylation of cyclic substrates.

OAc

R

MeO2C CO2Me[{Pd(η3-C3H5)Cl}2] (0.5-2 mol%),L∗ (1.1-5mol%),

BSA(0.3 equiv.), LiOAc (cat)n

MeO2C CO2MeR

n136 (3.0 equiv.)

+

FeO

N

H

Ph2P

FeO

N

H

Ph2P

FeN

O

t-BuR

135 137

138 139 140- R = PPh2

# n R Solvent T[°C] L* Yield[%] ee[%]/[config.]

1 2 H THF RT 138 - 11% (S)

2 2 H THF RT 139 60 58% (S)

3 3 H THF RT 140 93 94% (R)

Chiral ferrocenyl oxazoline ligands have widely emerged for the catalytic asymmetric Heck

reaction,7,8 asymmetric Diels–Alder reactions,9,10 addition of diethylzinc to aldehydes,11,12,13 and

[3+2] cycloadditions.14 More recently the catalytic asymmetric intramolecular version of the

Kinugasa reaction has been developed.15 The new family of phosphaferrocene–oxazoline ligands

143 provided excellent results in terms of reactivity and stereoselectivity (Scheme 4.3). A range of

tricyclic β-lactams 142 containing a 6,4 or a 7,4 ring system were obtained with very good

58 Chapter 4

enantiocontrol under catalysis with the combination CuBr/143 (5 mol%). The i-Pr-substituted

ligand 143a was typically found to be the ligand of choice for the generation of a β-lactam fused to

a six-membered ring (86–90% ee), whereas for seven-membered rings the t-Bu-substituted

analogue 143 gave superior results (85–91% ee).

PFe

N

O

RPhX

NArO

n

X

NH H

O Ar

nCuBr/143 (5.0 mol%),Cy2NMe (0.5 equiv.),CH3CN, 0 °C

R = i-Pr, 143aR = t-Bu,143b

141 142

X n L* yield[%] ee[%]

CH2 1 143a 74 88

O 2 143b 68 91

Scheme 4.3. Catalytic enantioselective synthesis of polycyclic β-lactams through intramolecular Kinugasa reaction.

4.1.2.2 Chiral Ferrocenyl Oxazoline Ligands and Palladacycles. Over the past decade or so, there has been a great deal of interest in the application of palladacycles

as catalysts for organic synthesis.

Based on the synthesis of enantiopure 2-ferrocenyl oxazolines 144 and their diastereoselective

ortho-lithiation which was independently reported by Uemura, Sammakia and Richards in 1995,17

some years later, Overman published the first synthesis of 2-ferrocenyl oxazoline palladacycles

(FOP 146, see Scheme 4.4 a).18 Since the desired relative configuration with respect to planar

chirality was opposite to the outcome of a simple one-step lithiation protocol, a multi-step

procedure had to be used with first blocking the undesired ortho-position and subsequent

introduction of an iodo-substituent, followed by oxidative addition with Pd(0). The indirection via

iodination and oxidative addition of Pd(0) had to be used since Overman reported the oxidative

decomposition of the ligand by Pd(II).18b Very recently, however, the direct cyclopalladation of

such ferrocenyl oxazolines 147 with Pd(II) acetate to 148 was reported (Scheme 4.4 b).19


N

O

Fe

1. s-BuLi, then TMS-Cl2. t-BuLi, then ICH2CH2I

Fe

ON

TMS

I

Fe

NO

TMS

PdI2

Pd2(dba)3

a)

b)

N

O

Fe

Pd(OAc)2, DCMΔ

N

O

Fe Pd

AcO2

144 145 146

147 148

Scheme 4.4. Two routes to 2-ferrocenyl oxazoline palladacycles.

Concerning the field of pentamethyl/pentaphenyl ferrocenes, only very few oxazolines are known.

Richards et al. prepared a 2-pentaphenylferrocenyl oxazoline derived from (L)-serine and modified

the ester functionality to obtain bidentate ligands 149 (Scheme 4.5). A palladacycle with a C-Pd σ-

bond has not been reported, though. In 2006, Helmchen et al.5 reported the synthesis and ortho-

lithiation of 2-pentamethylferrocenyl oxazolines 151 to prepare planar chiral

pentamethylferrocenyl oxazolines 151, but again, those complexes were only used to prepare

palladacycles.

In addition, there is Richards’ COP-X 150 which was published in 1999 and since 2003 used for

the aza-Claisen rearrangement.20

O

Ni -PrPdX

2

Co PhPh

Ph Ph

Fe

PPh2O

Nt-BuPhFe

PhPhPh

PhN

O

R

R = OH, OMe, OPPh2, PPh2R' = H, Me, Ph

R'R'

149151 150

Scheme 4.5. Metal sandwich complex oxazolines with a spectator ligand other than Cp.

4.1.2.3 Direct Enantioselective and Diastereoselective Cyclopalladations The first direct diastereoselective cyclopalladation via C-H activation was reported by Sokolov in

1977 (Scheme 4.6).21 Treatment of Ugi’s amine with Na2PdCl4 in MeOH in the presence of NaOAc

generated palladacycle 153 in 84% yield with a dr of 85:15. Later, Lόpez repeated this reaction and

was able to improve the diastereoselectivity.22

60 Chapter 4

FeNMe2

Pd Cl2

FeNMe2

Na2PdCl4,NaOAc, MeOH

84%,dr = 85:15

Fe

PdNMe2

Cl2

disfavored

+

152 153 Scheme 4.6. First diastereoselective cyclopalladation. Richards and co-workers studied the cyclopalladation of the cobalt sandwich complex derived

imidazoles 154 (Scheme 4.7).23 The rotamer 154 is more favored than 154b due to the fact that

former one minimizes interactions of either the cyclohexyl or tert-butyl substituent with the

tetraphenylcyclobutadienyl floor. The bottom face of the imidazole is blocked by the bulky floor.

The palladation occurred exclusively via the preferred rotamer 154a. The imidazole can thus be

regarded as being in an environment of virtual planar chirality. The palladacycles 155 were

afforded in good yields with high diastereoselectivities, i.e., only the major diastereomer was found

by NMR spectroscopy.

Pd(OAc)2,AcOH

Co

Pd NN

AcO

2

Ph Ph

PhPh

Co

NN

Ph Ph

PhPh

R = t-Bu, 75%R = Cy, 76%

RMeH R

MeH

155154a

Co

N

NPh Ph

PhPh

Me

H R

154b Scheme 4.7. Cyclopalladation of the cobalt sandwich complex derived imidazoles.

Richards also reported the highly diastereoselective cyclopalladation of a cobalt sandwich complex

derived oxazoline 156 (Scheme 4.8).20a Only a single cyclopalladated diastereoisomer 150 (X =

OAc) was formed in 72% yield (R = i-Pr). A severe repulsion between the phenyl rings of the

cyclobutadiene ligand and the oxazoline connected i-Pr group results in a preferred conformation

displaying effective planar chirality. Therefore, the cyclopalladation proceeds with high

diastereoselectivity. In contrast and surprisingly, if R is a t-Bu group, the opposite


diastereoselectivity was observed in palladacycle 159. This effect was explained with the steric

repulsion between the attacking Pd and t-Bu group, which is predominant over the repulsion

between the cyclobutadiene substituent and the t-Bu group.24

Pd(OAc)2,AcOH

Co

Pd NO

i-PrX

2

Ph Ph

PhPh

Co

N

O

R

Ph Ph

PhPh

Co

PdN

O

t-BuOAc

2

PhPh

Ph Ph

R = i-Pr

Pd(OAc)2,AcOH

R = t-Bu

150 (X = OAc)

Co

NO

Ph Ph

PhPh

HMe

[Pd]

Co

N

O

Ph Ph

PhPh

MeMe

[Pd] Me

Me

vs. vs.

H

H

Co

ON

Ph Ph

Ph

MeMe

[Pd]

H

Co

ON

Ph Ph

Ph

MeMe

[Pd]

H

Me

159

156

Scheme 4.8. Diastereoselective cyclopalladation of a cobalt sandwich complex derived oxazoline.

The first diastereoselective syntheses of planar chiral metallocene bispalladacycles was reported by

Kang et al. in 2002. A variety of optically active bispalladacycles were prepared via

diastereoselective bis-ortho-lithiation followed by iodination and cyclopalladation by oxidative

addition (Scheme 4.9).25

62 Chapter 4

NMe2

NMe2

Fe

Et

Et

NMe2

NMe2

Fe

Et

Et

II

NPd

Et N

I

NPd

Et

IFe

N

NO

NO

FeN

O

NO

Fe II

NPd

O YR

I

NPd

O

IFe

YR

YR = SMe, OMe or Oi-Pr

1. n-BuLi, RT2. I2, −78 oC to RT

1. MeI, acetone, 0 oC2. MeNH(CH2)2NMe2,

CH3CN, 50 oC3. Pd2(dba)3, PhH, RT

1. sec-BuLi, −78 oC2. I(CH2)2I, −78 oC to RT

160 161162

163 164

165

Scheme 4.9. Diastereoselective syntheses of planar chiral metallocene bispalladacycles.

Richards and co-workers26 recently reported the formation of planar chiral phosphapalladacycles

167 via a highly enantioselective transcyclopalladation in high yields (Scheme 4.10). The complex

150 (X = OAc) (see Scheme 4.8) was used as the palladium source. The driving force of this

reaction is the formation of a more stable palladacycle with a more favorable P-Pd bond instead of

a N-Pd bond.

167 156R = Ph or Cy

Co

Pd N

O

i -PrAcO

2

Ph Ph

PhPh

toluene,80 oC

Co

N

O

i-Pr

Ph Ph

PhPhFe

P

RR

Fe

PdP

RR

OAc

2

+ +

166 150

Scheme 4.10. Enantioselective transcyclopalladation.

In 2009, the same group has demonstrated an extension of the Sokolov procedure for the

enantioselective synthesis of planar chiral ferrocene palladacycles. The use of N-

acetylphenylalanine as a chiral carboxylic acid resulted in superior enantioselectivities as compared

to N-acetylleucine. Palladacycles 168 were formed by a concerted metalation–deprotonation


mechanism in which the coordinated chiral carboxylate acts as a base in the enantioselective

carbon-metal bond forming step (scheme 4.11). 41

Fe

P

RR

Fe

PdP

RR

Cl

2O

NH

Me CO2H

Ph

1.0 equiv. Na2PdCl4pH 8.0

Up to 59% ee166 168

Scheme 4.11. N-protected amino acid mediated enantioselective palladation.

4.1.2.4 Chiral Ferrocenyl Oxazoline Derived Palladacycles and their Application.

In 1999, Donde and Overman reported the formation of ferrocenyl oxazoline palladacycle 146, and

its application to the aza-Claisen rearrangement of allylic benzimidates.18b This is the first example

for the asymmetric aza-Claisen rearrangement which proceeded with > 90% ee, obtained with a

(Z)-configured imidate. In contrast, the rearrangement of (E)-configured substrates provided the

product in moderate to high yields but with lower enantioselectivities. Substantial evidence points

to a cyclization-induced rearrangement mechanism for this reaction in which a pivotal step is the

attack of the imidate nitrogen onto a palladium-complexed alkene 169. Subsequent

deoxypalladation of 170 yields the rearranged amide 67 and regenerates the Pd(II) catalyst (scheme

4.12).

N O

R3

R1

Pd(II) N O

R3

R1

[Pd]

N O

R3

R1

[pd]

R2N O

R3

R1

R2R2 R2-Pd(II)

66 169 170 67 Scheme 4.12. Pd-catalyzed aza-Claisen rearrangement.

64 Chapter 4

Table 4.2. Enantioselective aza-Claisen rearrangement of allylic benzimidates by Overman et al in

1999:

Fe

Pd N

O

t-BuI

TMS

2

ON

R2

R1

R

ON

R2

R1

R*

66 67 146

(5.0 mol%) 146,(10.0 mol%) AgTFA,DCM, RT

# E/Z R R1 R2 Time

[h]

Yield

[%]

ee [%]

[config.]

1 Z n-Pr 4-CF3-Ph Ph 72 67 91 (R)

2 E n-Pr 4-CF3-Ph Ph 48 57 79 (S)

3 E n-Pr PMP Ph 18 93 83 (S)

4 Z n-Pr PMP Ph 21 83 91 (R)

5 Z Me PMP Ph 15 96 75 (R)

6 Z Bn PMP Ph 23 85 88 (R)

7 E i-Bu PMP Ph 25 97 84 (S)

8 Z i-Bu PMP Ph 25 89 96 (R)

9 Z i-Bu PMP o-Tol 38 97 96 (R)

10 Z CH2C6H11 PMP Ph 26 87 90 (R)

11 Z neopentyl PMP Ph 89 35 92 (R)

12a Z neopentyl PMP Ph 47 77 87 (R)

13a Z i-Pr PMP Ph 72 59 86 (R)

14 E Ph PMP Ph 26 59 63 (R)

15 Z Ph PMP Ph 20 11 77 (S) a This reaction was run in toluene at 75 oC.

In 2002, Kang and co-workers27 synthesized a variety of planar chiral bispalladacyles derived from

ferrocene and studied the application of these complexes in the rearrangement of allylic

benzimidates. Catalyst 173 proved to be more reactive than Overman’s precatalyst 150. For

example, the rearrangement of imidate 171 proceeded with higher ee values (92% vs. 83%) but

much shorter reaction time, i.e. 0.5 h (Table 4.3, Entry 1) vs. 18 h (Table 4.2, Entry 3).


Table 4.3. Enantioselective aza-Claisen rearrangement of allylic benzimidates by Kang et al in

2002:

NPd

O O-i-Pr

OTFA

NPd

O

OTFAFe

O-i -Pr

ON

PhPMP

R

ON

PhPMP

R*

(5.0 mol%) 173,DCM, RT

171 172

173

# E/Z R Time

[h]

Yield

[%]

ee [%]

[config. ]

1 E n-Pr 0.5 91 92 (R)

2 Z n-Pr 12 85 90 (S)

3 E i-Bu 10 74 95 (R)

4 Z i-Bu 10 70 86 (S)

5 E Ph 1 90 87 (S)

6 E Me 12 68 90 (R)

Kang et al. also applied the known cobalt oxazoline palladacycle 150 (X = Cl)20a as precatalyst in

the rearrangement of benzimidates.27 The rearrangement of especially (Z)-configured substrates

was carried out with good yields and enantioselectivities (Table 4.4).

66 Chapter 4

Table 4.4. Enantioselective aza-Claisen rearrangement of allylic benzimidates by Kang et al in

2003:

ON

i-PrPdX

2

Co PhPh

Ph Ph150 (X = Cl)

ON

PhPMP

R

ON

PhPMP

R*

(5.0 mol%) 150(X = Cl),(10.0 mol%) AgTFA,DCM, RT

171 172

# E/Z R Time

[h]

Yield

[%]

ee [%]

[config.]

1 Z n-Pr 3 92 94 (R)

2 Z i-Bu 7 72 95 (R)

3 E n-Pr 13 82 45 (S)

4 E i-Bu 12 82 50 (S)

5 E Ph 13 70 68 (R)

Almost at the same time, Overman and Richards described the application of the same catalyst 150

with X = OCOCF3 for the rearrangement of trifluoroacetimidates 174 to provide

trifluoroacetamides which were readily deprotected (Table 4.5, Entries 1-7).20b Additionally, cobalt

oxazoline palladacycle 150 (X = Cl) proved to be active for the rearrangement without being

activated by silver or thallium salts (Entries 8-16). However, relatively high catalyst loading (5

mol% of the dimer, i.e. 10 mol% Pd(II)) was applied for good yields and selectivities. Generally,

the rearrangements of (Z)-configured substrates provided better enantioselectivities but lower

yields compared to the cases of (E)-configured substrates. When R is a bulkier group, higher ee

values were obtained. If R = Me, then both catalysts were not able to achieve an enantionselectivity

of 90% (Entries 3, 10 and 11).


Table 4.5. Enantioselective aza-Claisen rearrangement of allylic trifluoroacetimidates by Overman

et al in 2003:

ON

i -PrPdX

2

Co PhPh

Ph Ph150 (X = Cl)

ON

CF3PMP

R

ON

CF3PMP

R*

(5.0 mol%) 150 (X = OTFA),or(5.0 mol%) 150 (X = Cl),DCM, RT

174 175

# E/Z R Yield

[%]

ee

[%]

# E/Z R Yield

[%]

ee

[%]

1a E n-Pr 79 89 9b Z n-Pr 78 89

2a Z n-Pr 70 95 10b E Me 85 82

3a E Me 90 73 11b Z Me 87 86

4a E (CH2)2Ph 80 88 12b E (CH2)2Ph 86 93

5a Z (CH2)2Ph 76 96 13b Z (CH2)2Ph 77 97

6a E i-Bu 80 92 14c Z (CH2)2Ph 99 96

7a Z i-Bu 67 97 15b E i-Bu 88 94

8b E n-Pr 92 92 16b Z i-Bu 58 90 a 150(X = OTFA), 20 mol% H.B., 30 h. b 150(X = Cl), 60 h.

In 2007, Richards and Nomura observed that the enantioselectivity of the rearrangement catalyzed

by 150 (X = Cl) was still useful over a temperature range of 50 to 80 oC with acetonitrile as the

solvent, at least for certain substrates.28 The optimum yield was obtained at 70 oC with a catalyst

loading of only 0.25 mol% with and a reaction time of 48 h. These conditions were successfully

applied to few (E)-configured trichloroacetimidates to give the product amides in moderate to good

yields and good to high enantioselectivities (84-94% ee) (Table 4.6, Entries 1-5). However, the

barrier of low yields and low enantioselectivities for (Z)-configured (Entry 7) or 3-aryl (Entry 6)

substituted imidates still remained.

68 Chapter 4

Table 4.6. Enantioselective aza-Claisen rearrangement of allylic trichloroacetimidates by Richards

et al in 2007:

ON

i -PrPdX

2

Co PhPh

Ph Ph150 (X = Cl)

OHN

CCl3

R

OHN

CCl3

R*

150 (X = Cl),MeCN, 70 oC

70 71

# R E/Z 150 (X = Cl)

[mol%]

Time

[h]

Yield

[%]

ee

[%]

1 Me E 0.25 48 82 89

2 CH2Ph E 0.25 48 68 90

3 n-Pr E 0.25 48 79 92

4a CH2CH=CH2 E 0.75 72 68 84

5 CH2OTBDMS E 0.25 48 72 94

6b Ph E 1.0 96 31 0

7 n-Pr Z 0.25 72 21 67 a Additional 150 (X = Cl) (0.5 mol%) added after 48 h and the reaction maintained for a further 24 h. b 0.5 mol% 150 (X = Cl), plus additional 0.5 mol% after 48 h and the reaction maintained for a

further 48 h.

Peters and coworkers reported the synthesis of the first ferrocenyl imidazoline palladacycles

(Scheme 4.13).29 N-Alkyl substituted pentamethylferrocene imidazolines 176 could not be

diastereoselectively cyclopalladated directly because of either low diastereoselectivities (with

Na2PdCl4, MeOH) or oxidative decomposition (Pd(OAc)2, AcOH). Therefore the palladacycles 177

were obtained via ortho-lithiation, iodination and oxidative addition of Pd2(dba)3. In contrast, the

N-alkyl substituted pentaphenylferrocene imidazoline palladacycles 179 could not be obtained via a

lithiation approach but via direct cyclopalladation with high diastereoselectivity (16:1). Later these

results were extended to N-sulfonyl ferrocene imidazolines 178 enabling also the direct

cyclopalladation of pentamethylferrocenes.30


FeN

NPh

I

FeN

NPh

Pd I

2

Pd2(dba)3benzene

FePh PhPhPh

Ph

N

N

R2

R1

R1Na2PdCl4, NaOAcMeOH, Benzene

FePh PhPhPh

Ph

N

N

R2

R1

R1Pd Cl

2

176 177

178 179 Scheme 4.13. Diastereoselective synthesis of ferrocene imidazoline palladacycles. In an effort to overcome the previous limitations for the synthetically useful trifluoroacetimidate

substrates 174 (i.e. catalyst loadings ≥ 10 mol%, difficult access to catalysts and limited structural

variation of the catalyst), Peters et al.29,30 designed a new palladacycle system FIP based on

ferrocene imidazoline as C,N-ligand for Pd(II) (Figure 4.1). The design of the catalyst allows the

independent variation of five different modules (Figure 4.1). The Cp-spectator ligand (the Cp ring

at the bottom, dark red can, e.g., be Cp (R4 = H), Cp* (R4 = Me) or CpФ (R4 = Ph) allowing for a

steric and electronic tuning. With the electron withdrawing effect of 5 Ph groups in CpФ the

electron density on the Pd(II)-centre decreases and the catalyst becomes more active due to an

enhanced Lewis acidity. Additionally, the enhanced bulk led to an improvement of the

enantioselectivity. The iron atom of the ferrocene core (red) can either be Fe(II) or the less electron

rich Fe(III). A ferrocenium Fe(III) species formed during the catalyst activation via oxidation with

a silver salt, is probably one major reason for the enhanced catalytic activity as compared to the

COP catalyst. The influence of the residues R1 in the imidazoline backbone (green) is not as

significant as the product yields obtained using different imidazoline derivatives for the

rearrangement vary only slightly, while the enantioselectivity remains almost unchanged for

different imidazoline substituents R1. Owing to its better accessibility the imidazoline backbone

carrying two phenyl substituents was chosen.

FeR4 R4

R4R4

R4

N

N

R2

R1

R1Pd X

2

Fig 4.1. Ferrocene imidazoline palladacycle (FIP).

70 Chapter 4

The nitrogen substituent R2 (pink) directly influences the electron density of the Pd(II)-centre.

Peters et al. have investigated both alkyl and sulfonyl residues. Although the conditions used with

these two different catalyst types are slightly different, sulfonyl groups apparently resulted in better

activity because of their electron withdrawing effect. The sulfonyl group offers the additional

advantages that Pd can be incorporated by a direct diastereoselective cyclopalladation employing a

simple Pd(II) salt due to enhanced stability of the ferrocene core against oxidative decomposition

(decreased electron density) and owing to a chirality transfer from R1 to the neighbouring N atom

effecting a preferred conformation in which the sulfonyl moiety point away from the ferrocene

moiety. Out of the different sulfonyl groups tested, tosyl proved to be the most attractive. Different

counteranions X (blue) coordinating to the Pd centre were employed by breaking the chloro bridge

in the dimeric precursor by different silver salts. AgO2CCF3 provided the best results (X =

O2CCF3).

The results obtained with the pentaphenylferrocene imidazoline palladacycle (FIPФ) are presented

in Table 4.7. Enantioselectivities were good to excellent and the yields were in general high. The

catalyst loadings could be decreased by a factor of hundred as compared to the previous results

obtained by others (see above), without effecting enantioselectivities and yields to a large degree.

The catalysis can be performed under almost solvent free conditions giving an economical and

environmental advantage. Furthermore, the high stability of the activated catalyst allows

performing of the catalysis at elevated temperature.


Table 4.7. Enantioselective aza-Claisen rearrangement of allylic trifluoroacetimidates 174 with

FIPΦ-Cl 77 by Peters in 2006:

FePh Ph

PhPh

Ph

N

N

Ts

Ph

PhPd Cl

2

NO N∗

OPMP

CF3 CF3

PMPFIPΦ-Cl 77, AgTFA,PS, DCM, 40 °C

R

174 174

R

FIPΦ-Cl 77

# E/Z R FIPΦ

[mol%]T

[°C] t

[h] Yield [%]

Ee [%]

1a Z n-Pr 5 40 24 72 93 (S)

2a Z (CH2)2Ph 5 40 24 95 95 (S)

3a Z i-Bu 5 40 24 82 96 (S)

4 E n-Pr 0.5 20 24 95 98 (R)

5 E n-Pr 0.1 40 24 89 97 (R)

6 E n-Pr 0.05 40 48 95 95 (R)

7 E Me 0.1 20 48 91 95 (R)

8 E Me 0.05 40 48 98 92 (R)

9 E (CH2)2Ph 1.0 20 24 94 99(R)

10 E (CH2)2Ph 0.05 40 48 99 98 (R)

11 E i-Bu 0.2 40 24 96 98 (R)

12 E i-Bu 0.1 40 24 95 98 (R)

13 E i-Pr 0.5 40 24 75 96 (R)

14 E i-Pr 0.1 40 48 81 93 (R)

15 E Ph 1.0 40 24 99 88 (R)

16 E Ph 0.5 40 24 97 84 (R) a The pentamethylferrocene imidazoline palladacycle analogue was utilized.

The high catalytic activity enabled the utilisation in the previously unprecedented aza-Claisen

rearrangement to form N-substituted quaternary stereocentres.42 Entry 15 shows that the catalyst

does not need to distinguish between different sized substituents on the double bond (R1 = CD3, R2

= CH3, ee = 96%; for a discussion of the stereoselective step see chapter 4.4). The allylic amides

can be transferred to almost enantiopure quaternary α- and β-amino acids. The overall value of the

method is thus increased since quaternary centres are not accessible via hydrogenation.

72 Chapter 4

Table 4.8. Enantioselective aza-Claisen rearrangement to form quaternary stereocentres with

FIPΦ-Cl 77 by Peters in 2007:

NO N OR3

R2

CF3 CF3

R3

R2

FIPΦ-Cl 77, AgTFA,PS, DCM, 50 °C

R1R1

180 181

# R1 R2 FIPΦ

[mol%]Yield[%]

ee [%]

1 (CH2)2Ph Me 2 94 99.6 (R)

2a (CH2)2Ph Me 0.5 79 97 (R)

3 n-Bu Me 2 63 93 (R)

4 (CH2)2CH=CMe2 Me 2 74 98 (R)

5 (CH2)3OSi(i-Pr)3 Me 2 73 96 (R)

6 (CH2)3O(CO)OBn Me 2 84 97 (R)

7 (CH2)3NBnBoc Me 2 64 93 (R)

8 (CH2)2CO2Et Me 2 50 96 (R)

9 Me (CH2)3OSi(i-Pr)3 2 74 98 (S)

10 Me CH2OBn 2 84 99 (R)

11b Et CH2OBn 4 68 91 (R)

12c n-Pr CH2OBn 4 63 >99.5 (R)

13c n-Bu CH2OBn 4 61 98 (R)

14c (CH2)3OSi(i-Pr)3 CH2OBn 4 51 97 (R)

15 CD3 Me 1 95 96 (R)

60 h. a 240 h. b E/Z ratio SM = 4:96. c 84 h.

The same catalyst 77 was also examined for the enantioselective rearrangement of imidates 180

carrying different N-substituents to give rise to secondary allylic amines 182 after hydrolytic or

reductive amide cleavage (Table 4.9).43 Enantioselectivities obtained were, in general, very good

while yields were moderate to very good.


Table 4.9. Enantioselective aza-Claisen rearrangement to form secondary amines 182 by Peters in

2008:

NO N OR3

R2

CF3 CF3

R3

R2

FIPΦ-Cl 77, AgTFA,PS, DCM, 50 °C

R1R1

NaBH4, EtOH,0 °C to RT

75-90%NH

R3

R2

R1

180 181 182

# R1 R2 FIPΦ

[mol%]Yield [%]

ee [%]

1 (CH2)2Ph Me 2 94 99.6 (R)

2 (CH2)2Ph Me 0.5 79 97 (R)

3 n-Bu Me 2 63 93 (R)

4 (CH2)2CH=CMe2 Me 2 74 98 (R)

5 (CH2)3OSi(i-Pr)3 Me 2 73 96 (R)

6 (CH2)3O(CO)OBn Me 2 84 97 (R)

7 (CH2)3NBnBoc Me 2 64 93 (R)

8 (CH2)2CO2Et Me 2 50 96 (R)

9 Me (CH2)3OSi(i-Pr)3 2 74 98 (S)

10 Me CH2OBn 2 84 99 (R)

11 Et CH2OBn 4 68 91 (R)

12 n-Pr CH2OBn 4 63 >99.5 (R)

13 n-Bu CH2OBn 4 61 98 (R)

14 (CH2)3OSi(i-Pr)3 CH2OBn 4 51 97 (R)

15 CD3 Me 1 95 96 (R)

Peters et al.40 also developed a short synthesis of enantiomerically pure ferrocenyl–bisimidazolines

185 which have been utilized for diastereoselective biscyclopalladation reactions, thereby giving

access to structurally fascinating dimeric macrocyclic Pd(II) complexes 186. These are the first

highly active enantioselective catalysts for the aza-Claisen rearrangement of Z-configured

trifluoroacetimidates, requiring as little as 0.1 mol% of catalyst precursor for most of the substrates,

whereas the best catalyst systems so far required 5 mol%.

74 Chapter 4

n-BuLi, TMEDA,Et2O, RT,thenClC(=S)NMe2−78 °C to RT N

NPh

PhTs

2. TsCl, NEt3, DMAP,0 °C to RT(54-62%, 2 steps)

1. Et3O+ BF4-, DCM, RT,

then , RT

NN

Ph

PhTs

H2N

Ph

NH2

Ph

54%Fe

NMe2

S

NMe2

S

Fe Fe

NPd

N

PhPh

Cl

Ts2

NPd

N

PhPh

Cl

Ts

2

Na2PdCl4,NaOAc, MeOH

56% yielddr > 100:1

FeO N

PMPCF3

R'

NPMP

CF3

O

(0.01-1.0 mol%) 186,(0.6-6 mol%) AgOTs,CHCl3, 22-55 °CR'

64-99% yield93-99% ee

(Z)-187 188

185

186

R' = Me, Pr, (CH2)2Ph, i-Bu, i-Pr(CH2)2CO2Me, (CH2)3OBn,CH2OTHP,CH2OBn, CH2OTBS

183 184

Scheme 4.14. Synthesis of bispalladacycle 186, the best catalyst for the rearrangement of (Z)-

configured imidates 187.


4.2.1 Synthesis of Oxazoline Palladacycles.

2-Pentaphenylferrocenyl oxazolines 11 (R1 = i-Pr, R2 = H) and 191 (R1 = R2 = Ph) were prepared

in 86% and 66% yield, respectively, in a simple and scalable two-step procedure via formation of

the secondary amide 189, 190 (Scheme 4.15) from pentaphenyl ferrocene carboxylic acid 10 and

(S)-valinol 192 or (1R,2S)-1,2-diphenylethanolamine 193, followed by tosylation of the free OH-

group to induce ring formation (Scheme 4.15).

Fe

PhPh

Ph

Ph Ph Fe

PhPh

Ph

Ph PhNH Fe

PhPh

Ph

Ph Ph

NOHO

O O

HO

R1

R2

a, b c

10 189/190 11/191

H2N OH

H2N OH

192

193

R1

R2


Scheme 4.15. Oxazoline formation. a) (COCl)2, DCM, cat. DMF, b) (S)-valinol, NEt3, DCM, 0 °C to RT, 91% (189) / (1R,2S)-2-amino-1,2-diphenylethanol, DCE, pyridine, 80 °C, 83% (190); c) TsCl, NEt3, cat. DMAP, DCM, 91% (11) / 79% (191).

While formation of the amide of valinol (192, R1 = i-Pr, R2 = H) proceeded between 0 °C and RT,

preparation of the corresponding amide of 1,2-diphenyl-ethanolamine (193, R1 = R2 = Ph) required

heating to 80 °C. Treatment of those amides with p-tosylchloride then led to smooth ring closure to

the diastereomerically pure oxazolines, even though in the case of 191, a benzylic tosylate is

formed as intermediate which, however, fortunately does not epimerise.

Upon heating oxazolines 11 and 191 with palladium(II) acetate in acetic acid, palladacycles 194

and 195 precipitated in diastereomerically pure form and could be isolated by filtration, while by-

products and possibly the other diastereomer stayed in solution (see Scheme 4.16). Further

purification was carried out by preparative crystallisation allowing pentane to diffuse into a

solution of the crude complex in DCE, a method which was found to be superior to recrystallisation

from AcOH or cyclohexane as well as column chromatography and which still allows a preparation

on a multi-gram scale, delivering 194 and 195 in 93% and 72% yield, respectively.

Fe

PhPh

Ph

Ph PhO

NR1

R2

Fe

PhPh

Ph

Ph Ph

Pd OAcO

NR1

R2

2Pd(OAc)2,HOAc,95 °C

93/72%

11/191 194/195 Scheme 4.16. Cyclopalladation with palladium(II) acetate in acetic acid. 194: 93%, 195: 72%.

Other conditions for cyclopalladation than Pd(OAc)2 in acetic acid, notably Na2PdCl4 in

combination with NaOAc in methanol/benzene or DCM, as well as Pd(OAc)2 in DCM or benzene

failed to give any cyclopalladated product, though a change in the 1H-NMR-spectrum was observed

within minutes after mixing, being evidence for a coordination of Pd(II) to the oxazoline. Instead of

cyclopalladation, a complete decomposition was found to take place within less than 30 min. This

decomposition also occurred when the mixture of palladium(II) acetate in acetic acid with

oxazoline 11, leading to a dark red solution, was diluted with water and extracted with DCM

without prior heating. These results suggest that while Pd(II) in principle destroys the ligand, acetic

acid prevents this decomposition and allows at elevated temperature to form a carbon-Pd-σ-bond in

the initially formed Pd-oxazoline complex.

Conversion of the acetate bridged palladacycles 194 and 195 to the chloride bridged complexes 4

and 196 took place in 95% and 93% yield, respectively, by simply stirring a suspension of 194 or

76 Chapter 4

195 and LiCl in methanol/benzene. While the acetate bridged dimers exist as a single diastereomer

relative to the Pd-acetate square plane (see Figure 6.2), the chloride bridged complexes were found

as a ca. 2:1 mixture of diastereomers (geometrical isomers around the Pd-Cl-square plane).

Fe

PhPh

Ph

Ph Ph

Pd OAcO

NR1

R2

2

Fe

PhPh

Ph

Ph Ph

Pd ClO

NR1

R2

2

LiCl, PhH,MeOH, RT

95/93%

4/196194/195 Scheme 4.17. Exchange of the bridging ligand acetate with chloride. 4: 95%, 196: 93%.

4.2.2 Determination of the Absolute Configuration.

The absolute configuration of palladacycle 194 was determined by X-ray crystal structure analysis

(see Figure 4.2). In contrast to 194 (X = OAc), the iso-propyl group is pointing towards the

sandwich core.

Fig 4.2. Crystal structure of 194. The unit cell consists of 4 asymmetric units, with each asymmetric

unit consisting of two molecules which differ in the sense of orientation of the CpΦ phenyl groups (only one rotamer is shown for clarity); one molecule of solvent (DCE) is also incorporated per asymmetric unit. Concerning the distance between the two Pd-atoms, a metal-metal bond seems likely. CCDC-number: 703503.

The chloride bridged complexes, 4 and 196, were readily distained by treatment of the acetate

bridged palladacycles with LiCl in methanol/benzene. While the acetate bridged dimers exists as

single geometrical isomer around the Pd-acetate square plane (Figure 4.3, left side), the chloride


bridged complexes were found to be a ca. 2:1 mixture of geometrical isomers (Figure 4.3, right

side).

PdN Cl

ClPd

N

PdN Cl

ClPd

Cl bridged cis-isomer

Cl bridged tr ans-isomer

N

PdN O

O

PdO

ON

acetate bridged dimer Fig 4.3.

The absolute configuration of palladacycle 195 was indirectly assigned through the known absolute

configuration of the catalysis outcome of the aza-Claisen rearrangement of imidate and confirmed

by 1H-NOESY experiments.

Fe

PhPh

Ph Ph

Pd

2

NO

OAcPhH

HPh

Fig 4.4. 1H-NOESY for Palladacycle 195.

4.2.3 Catalysis with Known Substrates.

4.2.3.1 Substrate Synthesis. All imidates bearing no base-sensitive functional groups were prepared in THF in high yields by

reaction of imidochloride 6 with the corresponding allylic alcohol 5 which was deprotonated with

either NaH or LHMDS (see Scheme 4.21b). The latter base, available as 1 M solution in THF, gave

identical results. Its advantage compared to solid NaH is the generally more convenient handling of

a solution under inert atmosphere. In addition, it reacts almost immediately with the allylic alcohol,

while NaH reacts significantly slower due to poor solubility.

78 Chapter 4

The formation of imidoyl chlorides 6 was achieved by using a primary amine, triphenylphosphine

and carbon tetrachloride in the presence of trifluoroacetic acid and triethylamine. This is a multiple

step reaction carried out in one-pot.31 All of the reagents are mixed and heated to reflux to furnish

the required imidoyl chloride 6 in good yield. During the reaction an amide is formed and reacts in

situ with excess triphenylphosphine and carbon tetrachloride to generate the corresponding imidoyl

chloride.

R NH2

PPh3, CCl4, NEt3,TFA, Δ

N Cl

CF3

R

6 Scheme 4.18. Methods for the formation of imidoyl chlorides 6.

PPh3

CCl4Ph3P Cl CCl3

CF3CO2H

OPh3P

O

CF3Cl

−CHCl3

R NH2

NH

O

CF3R

Ph3P Cl CCl3

NR

O

CF3PPh3 Cl

N Cl

CF3R

−Ph3PO

−Ph3PO−CHCl36

Scheme 4.20. Mechanism of the formation of imidoyl chlorides.

Allylic alcohols 5 without functional groups in the residue R are either commercially available

(trans- or cis-2-hexenol (E/Z)-197, trans-cinnamol (E)-199) or were prepared from the

corresponding α,β-unsaturated esters 198 by reduction with DIBAL (see Scheme 4.21, a). The

standard method to obtain these esters is the trans-selective Horner-Wadsworth-Emmons32 (HWE)

reaction (for (E)-configuration) or the Still-Gennari33 modification of this method (for (Z)-

configuration). Compounds bearing Ph(CH2)2, i-Pr, c-hex, or t-Bu as residue were prepared

according to this way following literature procedures (see experimental part in Chapter 7).


R O

PO

OMe

O

OMeOMe

BuLi, THFR O

OMe

2.7 equiv. DIBALTHF, −78 °C to RT

R OH

PO

OMe

O

OCH2CF3

OCH2CF3

KHMDS,18-C-6 (5 equiv.)

R OMeO

2.7 equiv. DIBALTHF, −78 °C to RT

R

OH

R OH

R O CF3

N

OMe

NaH or LHMDS, then 6

a)

b)

~60-99%

(Z)-198 (E )-198

(Z)-199 (E)-199

5 7

Scheme 4.21. a) Synthetic routes to (E)- and (Z)-configured allylic alcohols 199 via Horner-Emmons (right) and Still-Gennari (left) reaction; b) formation of N-PMP-trifluoroacetimidates 7. 18-C-6: 1,4,7,10,13,16-Hexaoxacyclooctadecane.

Selectivity of the HWE reaction is usually fair to poor (in some cases, a 1:1 mixture was obtained)

requiring a separation of isomers by preparative column chromatography; highest (E)-selectivities

are generally obtained when working in 1,2-dimethoxyethane at RT, while in THF at –78 °C

mainly the (Z)-isomer is formed. Also the Still-Gennari modification only provides good

selectivities if the aldehyde moiety is α,β-unsaturated or aromatic. It is, however, of highest

importance to use diastereomerically pure allylic alcohols since the minor diastereomer is almost

exclusively converted to the minor enantiomer. Only 0.5% of the minor diastereomer will thus

lower the highest possible ee by 1.0% in the case of full conversion.

An alternative method to prepare α,β-unsaturated esters 198 is the Cu(I)-mediated 1,4-addition of

alkyl-lithium or Grignard reagents to methyl- or ethylpropiolate 200 (Scheme 4.22). In this

reaction, it is often possible to obtain almost absolute diastereoselectivity (minor isomer below

detection limit in NMR) or at least to produce only few percent of the undesired isomer hence

facilitating purification.34 The reaction is also possible, though limited in utility, in the introduction

of an iso-propyl group which proceeded with complete diastereoselectivity, but with a

comparatively low yield of only 26%, since a competitive reduction of Cu(I) by iso-propyl

magnesium halide takes place.

80 Chapter 4

R O

OMe 2.7 equiv. DIBALTHF, −78 °C to RT

R OHH CO2Me

CuI, RLi, THF, −40 °C to −78 °CorCuI, RMgHal, TMEDA, THF,−40 °C to −78 °C

26-73%E:Z 95:5 to >99:1

200 198 199

Scheme 4.22. Copper(I)-mediated conjugate addition onto propiolic acid esters.

4.2.4 Catalysis.

4.2.4.1 Primary Investigation of the Aza-Claisen Rearrangement Using a Model Substrate.

Utilizing the optimized conditions for activating imidazoline catalyst FIP-Cl 77, that is 3.75 equiv

of AgTFA per precatalyst dimer,30 oxazoline PPFOP-Cl 4 (0.5 mol%) rearranged the 3-

monosubstituted model substrate 201 with only 44% yield and 90% ee (Table 4.10, entry 1) at 40

°C for 24 h (83% conversion after 72 h), whereas FIP-Cl 77 gave practically full conversion and

95% ee with 1/10 of the catalyst amount. As the nature of the Ag salt has a large impact on the

reaction rate and selectivity, further Ag salts were examined. It was found that AgNO3 generates a

highly active and selective catalyst (Table 4.10, entry 2), whereas AgOTs allows high activity

(Table 4.10, entry 3) but considerably lower enantioselectivity. Further studies were thus carried

out with AgNO3.

By using 2 equiv of AgNO3 per Cl-bridged dimer PPFOP-Cl 4, full conversion and 96% ee were

obtained with 0.5 mol% precatalyst, whereas 0.2 mol% led to only 45% conversion (Table 4.10,

entries 4, 5). Part of this catalytic activity might be explained by oxidation of 4 to the

corresponding active ferrocenium system on the surface of precipitated AgCl.

However, nonactivated 194 also has some, yet low, catalytic activity (6% conversion with 1 mol%

catalyst at 40 °C for 24 h; Table 4.10, entry 6). Complete oxidation to the corresponding

ferrocenium species is accomplished with 4 equiv of AgNO3 per Cl-bridged dimer resulting in the

best reactivity.

In addition to i-Pr-substituted complex 4, the 4,5-diphenyl-substituted oxazoline palladacycle 196

was examined. While there is practically no difference in enantioselectivity, the catalytic activity

slightly decreases (Table 4.10, entries 7–10). Whereas 0.1 mol% 4 completely converted the test

substrate within 24 h at RT (Table 4.10, entry 10), the same amount of 196 at 40 °C resulted in

only 70% yield due to incomplete conversion (Table 4.10, entry 9). Since complex 196 was

prepared in lower yields and from a more expensive amino alcohol than 4, all further investigations

were carried out with 4.


A screening of the catalyst amount was performed for both the E- and the Z-configured test

substrates (E)-/(Z)-201. As for the imidazoline palladacycle FIP-Cl 77, the E-configured substrate

not only reacts considerably faster than its Z-configured counterpart, but it also provides

significantly higher ee values. Although (E)-201 reacts completely within 1 d at 40 °C using only

0.05 mol% precatalyst (Table 4.10, entry 11), full conversion for (Z)-201 requires 2 mol% (Table

4.10, entry 12). Ferrocenyl bisimidazoline bispalladacycle complexes thus remain the catalysts of

choice for Z-configured substrates.40

The enantioselectivity obtained for (E)-201 did not significantly change within the investigated

temperature range. Catalyst loadings below 0.05 mol% were studied as well, but the results were

not reliable, which is most probably explained by a partial catalyst deactivation by trace impurities

of the substrate. A certain threshold of catalyst is thus necessary on laboratory scale. The same was

found with FIP-Cl 77, in which catalyst loadings below 0.05 mol% had resulted in low

conversions even at prolonged reaction times.

82 Chapter 4

Table 4.10. Optimization of the rearrangement of model substrates E-/Z-201 catalyzed by 4, 196:

Pr

NPMP

CF3

O

Pr

NPMP

CF3

O

(Y mol%) Cat*, AgX,(4Y mol%) P.S., DCM

*

201 202

Fe

PhPh

Ph

Ph Ph

Pd ClO

Ni-Pr 2

Fe

PhPh

Ph

Ph Ph

Pd ClO

NPh

Ph

2

4196

# E/Z

201

Cat* Cat*

loading

[mol%]

AgX

/ Y

Temp. /

Time

[°C]/ [h]

Yield

[%]a

ee

[%]b

[config.]

1 E 4 0.5 AgTFA / 3.75 40 / 24 44 90 (R)

2 E 4 0.5 AgNO3 / 3.75 40 / 24 >99 97 (R)

3 E 4 0.5 AgOTs / 3.75 40 / 24 98 77 (R)

4 E 4 0.5 AgNO3 / 1.0 40 / 24 99 96 (R)

5 E 4 0.2 AgNO3 / 0.4 40 / 24 45 N.D.

6c E 4 1.0 --- 40 / 24 6 N.D.

7 E 4 0.2 AgNO3 / 3.75 RT / 24 >99 97 (R)

8 E 196 0.2 AgNO3 / 3.75 RT / 24 >99 97 (R)

9 E 196 0.1 AgNO3 / 3.75 40 / 24 70 N.D.

10 E 4 0.1 AgNO3 / 3.75 RT / 24 99 97 (R)

11 E 4 0.05 AgNO3 / 3.75 40 / 24 99 97 (R)

12 Z 4 2.0 AgNO3 / 3.75 40 / 24 97 88 (S)

13 Z 4 1.0 AgNO3 / 3.75 40 / 24 87 88 (S) a determined by 19F-NMR spectroscopy. b determined by HPLC after hydrolysis to the amine.


4.2.4.2 Aza-Claisen Rearrangement of Previous Substrates Catalyzed by 4. Oxazoline 4 activated by AgNO3 is in general more reactive than imidazoline FIP-Cl 77 (Table

4.11, entries 2–15). For instance, with the (E)-3-Ph-substituted substrate 26h, a temperature of 40

°C was necessary using FIP-Cl 77, whereas 4 is effective already at RT (Table 4.9, entry 2). Also,

the 3,3-disubstituted substrate 210 (R’= (CH2)3OTIPS, R=CH2OBn), which required 4 mol% FIP-

Cl 77 and a reaction time of 3.5 d to give a yield of 51%, reacted within 2 d in a nearly quantitative

yield (or within 3 d with 2 mol% catalyst; Table 4.11, entries 12, 13).

Like with FIP-Cl 77, N-substituted quaternary stereocenters can be generated with almost perfect

stereocontrol (Table 4.11, entries 8–13).

Due to the enhanced catalytic activity, the substrates that could not be processed with FIP-Cl 77 or

any other reported chiral catalyst were investigated: whereas allylic trifluoroacetimdates bearing a

tBu or a Bn moiety as R1 still did not react at useful rates (Table 4.11, entries 6, 7) although mono-

α-branched aliphatic residues R1 such as i-Pr or c-Hex are well tolerated (Table 4.11, entries 4, 5),

this catalyst is for the first time able to rearrange substrates bearing branched aliphatic N-

substituent R3 (Table 4.11, entries 14, 15): the N-cyclohexyl-substituted imidate 211 rearranged

with reasonable catalyst loadings (1.0 or 4.0 mol%) and excellent enantioselectivities, thus yielding

the protected secondary allylic amine 223.

The formation of a tertiary allylic amine bearing three different N-substituents would require a

couple of steps with the traditional protecting group/alkylation strategy (vide supra). In contrast,

rearrangement of an allylic imidate already containing the complete carbon skeleton would only

entail a reduction of the amide functionality, for example, with LiAlH4, to provide the tertiary

amine. To establish the proof of the principle, allylic imidate 229 (Scheme 4.23) was prepared in a

one-pot reaction from acetanilide 226 to study if enolizable imidates bearing α-acidic hydrogen

atoms can be employed. Imidate 229 was found to be in equilibrium with its tautomer, the ketene

N,O-acetal 228 (ratio 228/229 = ca. 3:1). With 0.2 mol% 4 activated by AgNO3 the rearrangement

product was formed in high yield and with excellent enantioselectivity (Table 4.11, entry 16). A

Claisen rearrangement product was not detected.

FIP-Cl 77 is not able to rearrange allylic trichloroacetimidates with a free NH, the substrates of the

original Overman rearrangement, presumably since it is deactivated by coordination with the free

NH group. In contrast, 4 was found to be a highly active catalyst for these compounds (Table 4.11,

entries 17, 18), producing trichloroacetamide 225 in 24 h at 60 °C with a quantitative yield and

95% ee using 0.25 mol% of precatalyst.

84 Chapter 4

N OPh

nPr

PhNH

O

(COCl)2,lutidine,DCM,0 °C to RT Ph

N Cl

E-2-hexenol,LHMDS, THF,−78 °C to RT

NH

OPh

nPr

30% (2 steps)

N OPh

nPr

(0.2 mol%) 4,(0.75 mol%) AgNO3,(1.5 mol%) PS, DCM

96%ee = 94%

NEtPh

nPr

LAH, (10 mol%)NEt3, Et2O, RT

78%

226 227

228

229

230 231

Scheme 4.23. Synthesis of the enolizable acetimidate 229 and its use for the catalytic asymmetric formation of tertiary amine 231.


Table 4.11. Investigation of the substrate scope of the rearrangement of trifluoroacetimidates with

4:

(x mol%) 4,(3.7x mol%) AgNO3,4x mol% PS,DCM, T, t

*

ONR3

R1

CX3

R1

NR3

CX3

OR2R2

# Imidate R1 R2 R3 CX3 Product x

mol%

4

t /

[h]

T /

[°C]

yield[a]

/ [%]

ee /

[%]

1 201 n-Pr H PMP CF3 214 0.05 24 40 99 97[b]

2 202 Ph H PMP CF3 215 0.5 24 20 98 98 [b]

3 202 Ph H PMP CF3 215 0.2 24 40 96 90 [b]

4 203 i-Pr H PMP CF3 216 0.5 24 20 76 99 [b]

5 204 c-Hex H PMP CF3 217 0.5 24 40 99 99 [b]

6 205 tBu H PMP CF3 218 2.0 24 50 2 n.d.

7 206 CH2Ph Me PMP CF3 219 2.0 24 50 12 n.d.

8 207 (CH2)2Ph CH3 PMP CF3 220 2.0 24 50 71 98[c]

9 207 (CH2)2Ph CH3 PMP CF3 220 2.0 72 50 90 99[c]

10 208 CH3 CH2OBn PMP CF3 221 1.0 24 50 98 97[c]

11 208 CH3 CH2OBn PMP CF3 221 0.5 24 70 74 96[c]

12 209 (CH2)3OTIPS CH2OBn PMP CF3 222 4.0 48 50 95 97[d]

13 209 (CH2)3OTIPS CH2OBn PMP CF3 222 2.0 72 50 95 97[d]

14 211 (CH2)2Ph H c-Hex CF3 223 4.0 48 50 90 99[b]

15 211 (CH2)2Ph H c-Hex CF3 223 1.0 72 70 91 98[b]

16 212 n-Pr H Ph CH3 224 0.2 48 50 96 94[c]

17 213 (CH2)2Ph H H CCl3 225 0.25 24 60 99 95[c]

18 213 (CH2)2Ph H H CCl3 225 0.5 24 50 85 97[c] a ee determined by chiral stationary phase HPLC after hydrolysis to the amine. b ee determined by chiral stationary phase HPLC. c ee determined by chiral stationary phase HPLC after cleavage of

TIPS with TBAF.

86 Chapter 4

4.2.5 Challenging New Substrates.

4.2.5.1 Synthesis of Substrates. Trifluoroacetimidates 234 with 3-aryl prop-2-enyl residues were prepared starting from the

corresponding cinnamic acid/aldehyde derivatives 232, which are commercially available in

diastereomerically pure form. 4-Trifluoromethyl (232a), 4-methyl (232c) and 4-chloro- (232b)

cinnamic acid were converted to the corresponding methyl ester with MeI/K2CO3 in DMF and then

reduced with DIBAL. 4-Methoxy cinnamic aldehyde (236) was reduced with NaBH4 in ethanol.

Cinnamoyl alcohol 232d itself is commercially available.

Synthesis and purification of the corresponding imidates 234 proceeded smoothly except for

imidate 234d bearing the electron rich 4-methoxy-phenyl substituent: this compound rearranged

partially during synthesis and could not be isolated in absolutely pure form via column

chromatography, even if solvents were removed at RT. However, trituration with pentane gave

sufficiently pure material, which was then stored at –18 °C.

NPMP

CF3

O

R

CO2H1. MeI, K2CO3, DMF2. DIBAL, DCM

R

OH

CF3N

ClPMP

LHMDSR

R = CF3 aR = Cl bR = Me c

O

MeO

NaBH4, EtOH OH

MeO

NPMP

CF3

OCF3N

ClPMP

LHMDSMeO

232a-c 233a-c 234a-c

235

236 233d 234d

235

Scheme 4.24. Synthesis of 3-aryl-imidates 234. Overall yield: 234a: 86%, 234b: 84%, 234c: 84%, 234d: 37%.

2,4-Octadienyl substituted imidate 240 was prepared from hex-2-enal 238 via Wittig-Horner-

Emmons reaction and reduction with DIBAL. While the synthesis is unproblematic, the imidate

can not be stored for more than a few days even at –18 °C since also in this case, a relatively fast

thermal rearrangement occurs.

O

1. HWE2. DIBAL OH

NPMP

CF3

OCF3N

ClPMP

LHMDS, THF, −78 °C75%

60%238 239 240

235

Scheme 4.25. Synthesis of an imidate containing two conjugated double bonds.


Imidate 211 was prepared from N-cyclohexyl trifluoroacetimidoyl chloride 241,35 and imidate 205

from 4,4-dimethyl-pent-2-enol.36 206 (Me/Bn) was prepared via CuI-mediated 1,4-addition of

benzyl magnesium bromide to ethyl butynoate, followed by reduction with DIBAL and

condensation with imidochloride 235.

N

CF3

O

Ph

N PMP

CF3ON

PMPCF3

O

211 205 206 Fig 4.5. Sterically demanding imidates.

Trichloroacetimidates 243 and 213 were prepared via NaH-catalysed addition of the corresponding

alcohols onto trichloroacetonitrile,37 O-Hex-2-enyl thiocarbamate 245 was obtained via

condensation of hex-2-enol with N,N-dimethyl thiocarbamoyl chloride.38

HN

CCl3

O

Ph

HN

CCl3

O S

NMe2

O

243 213 245 Fig 4.6. Other substrates.

4.2.5.2 Catalysis with New Substrates.

Substrates were investigated which could previously not be rearranged in an asymmetric fashion

because they already react in the absence of a transition metal simply via a thermal rearrangement

to a considerable degree:

Allylic trifluoroacetimidates tend to undergo a thermal rearrangement at ambient temperature if the

bond O-C(1) is weak, i.e. if a carbocation 246 would be comparatively stabilised.

NPMP

CF3

ONPMP

CF3

O NPMP

CF3

OC1

202 215246

Scheme 4.26. If the bond C1-O is weakened and the transition state structure has some carbocation type character, a fast thermal rearrangement results.

88 Chapter 4

Though allylic imidates can always result in an allylic carbocation, the resonance stabilisation

through a further aromatic substituent considerably favours the stabilisation of this carbocation. As

a consequence, imidate 234 reacted with COP-X 150 in 72% yield and only 81% ee (5 mol%) due

to a competing thermal rearrangement at 40 °C (and decomposition via the carbocation),24 while

FIP-X 77 was able to rise these values to 99% yield and 88% ee, which is however still far below

the ee-values obtained for substrates bearing aliphatic residues. Better results would not be

achieved without heavily raised catalyst loadings since a temperature of 40 °C had been necessary

to obtain reasonable conversions.

PPFOP-Cl 4, on the other hand, could convert 215 at RT and was thus able to produce an ee-value

of 98% (see Table 4.12.a), entry 5). To extend the use of aza-Claisen rearrangements, we prepared

a series of aryl-substituted imidates 234 with different substituents, ranging from the rather electron

poor 4-trifluoromethyl-phenyl to the electron rich 4-methoxy-phenyl as well as a diene substrate

bearing two conjugated double bonds.

Substrates bearing a weakly electron donating or even withdrawing substituent have an intrinsic

thermal rearrangement rate constant, low enough to allow for a successful asymmetrically

catalysed reaction at RT, while 234d, bearing a 4-methoxy-phenyl group, reacts simply too “fast”,

even in the fridge (Table 4.12, entry 8).

The same problem occurs with 240, bearing two conjugated double bonds, though this compound

reacts faster in the metal-catalysed rearrangement due to its α-unbranched residue, allowing to

obtain 86% ee.

NPMP

CF3

ONPMP

CF3

O(1.0 mol%) 4, (3.7 mol%) AgNO3,(4.0 mol%) PS, DCM, RT, 72 h

y: 99%, ee: 86%

240 247

Scheme 4.26. Rearrangement of a substrate bearing two conjugated double bonds.


Table 4.12. Rearrangement of aryl-substituted imidates with PPFOP-Cl 4:

NPMP

CF3

ONPMP

CF3

O(x mol%) 4,(3.7x mol%) AgNO3,4x mol% PS, DCM

R R243a-d 248a-d

# Imidate R t/[h] T/[°C] mol% cat. yield[/%] ee/[%]a

1 243a CF3 48 RT 1.0 99 92

2 243b Cl 24 RT 1.0 95 98

3 243b Cl 24 40 0.2 80 87

4 243c Me 48 RT 1.0 99 98

5 202 H 24 RT 0.5 98 98

6 202 H 24 40 0.2 96 90

7 243d OMe 24 RT 1.0 93 28

8 243d OMe 48 + 4 1.0 52 34 a Determined by chiral stationary phase HPLC.

A kinetic study of the thermal rearrangement at 40 °C of three of these imidates allowed to

determine rate constants for the 1st order kinetics which fit well with the Hammet σ+-values for the

three substituents (for details see Chapter 7, page 235).

p-chlorophenyl

phenyl

p-methylphenyl

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40 45time/hours

perc

ent r

emai

ning

Sta

rtin

g-M

ater

ial

Fig 4.6. Thermal rearrangement of three aryl-substituted imidates at 40 °C in CDCl3. Conversion was determined by 19F-NMR.

90 Chapter 4

4.2.6 Rearrangement of Thiocarbamates.

Recently, Overman published the COP-Cl 150 catalysed rearrangement of O-allylic

thiocarbamates 249 to S-allylic thiocarbamates 250 as surrogates of allylic thiols with up to 87%

ee.38

R

S

NR'2

O

R

S

NR'2

O(1-5 mol% )COP-Cl 150,DCM, 40 °C

249 250

Scheme 4.27. [3,3] sigmatropic rearrangement of thiocarbamates 249 catalysed by COP-Cl 150. R = n-Pr, i-Bu, CH2OTBS, CH2OTIPS, CH2OH, CH2NPhBoc, (CH2)2COMe; R’2 = Me2 or 1-azetinyl.

We were curious to establish whether PPFOP-Cl 4 could also convert this substrate class which,

due to its sulphur atom is potentially a potent catalyst poison, and thus prepared 245 as a test

substrate.

S

NMe2

OS

NMe2

O (2.0 mol%) PPFOP-Cl 4,(7.4 mol%) AgNO3, DCM, 50 °C, 24 h

yield 60%, ee: 90%245 251

Scheme 4.28. Reaction of a test substrate 245 with PPFOP-Cl 4.

While the yield is not as good as the one reported by Overman and the rate is slightly lower, a

clearly better enantiomeric excess was obtained for this test substrate (literature: 72% yield, 82%

ee).

4.3 Modified Catalyst Design Model for the Asymmetric Aza-Claisen Rearrangement.

According to the previously accepted hypothesis from Overman, the ideal catalyst design is

represented by 4 (Figure 4.7, left side). The residue (1) next to the N-binding site should point away

from the sandwich complex core (2), and all the previously highly enantioselective sandwich

complexes used for the aza-Claisen rearrangement fulfilled this model. However, by comparison of

the ideal model and the structure of the most efficient catalyst 4, which is carrying an isopropyl


residue pointing towards the sandwich core, it can be concluded that the position of the block (1) is

not necessarily related to high enantioselectivity. Therefore, the original ideal catalyst model 252

has to be revised to the modified representation 253, where the much more important factor is the

choice of (2) and (3) to completely shield the bottom face of the catalyst in order to achieve a face-

selective olefin coordination.

FePh PhPh

Ph

Ph

O N i-Pr

PdX

2

(1)

(2)

PdX

Y

(2)(3)

PdX

Y

4 253252 Fig 4.7

4.4 Models for the Enantioselectivity Determining Step in the Aza-Claisen Rearrangement.

There are various models for the enantioselectivity determining step of the Pd(II)-catalyzed aza-

Claisen rearrangement.

Kang et al.27 suggested that the enantioselectivity determining step is a face selective coordination

of the catalyst to the olefin (scheme 4.29). However, in their model the olefin is coplanar with the

palladacycle contradicting the usual coordination mode of olefins in square planar complexes.

PdN

X

O

i-Pr

ON

R

ArPh

PdN

X

O

i-Pr

O

N

RAr

Ph

favored disfavored

Scheme 4.29. Top view of the suggested transition states by Kang for the rearrangement of Z-imidates.

Overman, Bergman et al. reported kinetic data and binding constants in a recent publication.35

Additionally, calculations were performed. Based on these findings and on the mechanistic model

which was earlier published by our group, they suggested that the olefin binds to the palladium in

trans-position with respect to the N donor (scheme 4.30). The olefin moiety is then

intramolecularly attacked by the imidate N leading to an aminopalladation of the double bond and

92 Chapter 4

the formation of the six membered zwitterionic ring intermediate (scheme 4.30). Overman and

coworkers assumed that this is the rate and stereo determining step. However, the different energies

for olefin complexes resulting from coordination to the enantiotopic olefin faces were not included

in these calculations.

N O

N O

R3

R3

R2

R2

R1

R1

N O

R3

R2

R1

L.A

N OR1

R3

L.AR2

N O

R3

R2

R1

L.A

Co PhPh

Ph Ph

ON

Pd

i-Pr

H

ClHN

O H

R

Cl3C

Co PhPh

Ph Ph

ON

Pd

i-Pr

Cl

H

N

O

Cl3C R

Si face attack Re face attack

Scheme 4.26. Model for the enantioinduction according to Overman/Bergman, left transition state

leading to the major enantiomer, right transition state leading to the minor enantiomer.

The Overman/Bergman39 model is able to explain the enantioselectivities observed in their

experiments, but it has some drawbacks. For purpose of the calculations the catalyst was simplified

and it is still unclear if the formation of the 6 membered ring from the olefin complex is a stepwise

process as suggested by Overman et al. The influence of the enantioface selective coordination of

the olefin was not discussed based on the assumption that the coordination is reversible. However,

even in this case, one has to consider that a face selective coordination will lead to an excess of one

species and therefore a potentially higher reaction rate via this pathway will result.

In contrast, the model of Peters et al. is based on simple chemical principles and on the observed

enantioselectivity data. Opposite absolute configurations were obtained for the major enantiomers

of rearrangement products 202 starting from either E or Z-201. This is accounted for by the

working model depicted in Figure 4.8 Assuming that the olefin as a π-acidic ligand will

preferentially coordinate trans to the imidazoline N atom, due to a trans effect,42 and that the cis-

position is blocked by the negatively charged counterion, the imidate N atom, which is not


coordinated to the Pd center, will approach the olefin via an outer sphere attack (remote to the Pd

center). Increased steric interactions of the coordinated olefin with bulky substituted CpФ spectator

ligands presumably result in a better face selectivity of the olefin coordination explaining the

higher enantioselectivity as compared to derivatives bearing the unsubstituted Cp.

Pd XO

R NAr

CF3

FeIIIPh Ph

Ph

PhPh

NPd

N

PhPh

TsX

O

R NAr

CF3

Pd XO

NAr

CF3R

FeIIIPh Ph

Ph

Ph

Ph

NPd

N

PhPh

TsX

O

NAr

CF3R

FeIII FeIII

Fig 4.8. Explanation of the stereospecific outcome of the aza Claisen rearrangement; transition

state with FIPΦ.

The enantioselectivity of the rearrangement is apparently largely independent upon the steric

discrimination of the two residues R1 and R2 at the 3-position of the imidate. This suggests that the

enantioselectivity determining step is the enantioface selective coordination of the olefin part to the

Pd(II) center (Figure 4.8) thus avoiding a differentiation of the steric demand of R1 and R2. If this

hypothesis is correct, even substrates in which R1 and R2 have an identical size should consequently

provide high enantioselectivities.

Pd X

Ph

Ph

N

O

Fe

iPr

PdX

Ph

Ph

Ph

O

R1 NPMP

CF3R2 O

R1 NPMP

CF3R2

III

FeIII

Fig 4.8. Explanation of the enantioselectivity by enantioface selective olefin coordination.

4.5 Scale up of the Rearrangment of Trifluoroacetimidate and Recycling of PPFOP-Cl 4.

94 Chapter 4

The rearrangement could be scaled up without any problem. Using 10.0 mmol of substrate (E)-201

(3.01 g) in combination with 0.1 mol% 4 (0.4 mol% AgNO3, 40 °C) resulted in complete

conversion and an isolated yield of 98% with 97.5% ee.

In an initial attempt to develop a recycling procedure, pentane was added after completion of the

aza-Claisen rearrangement to precipitate the catalyst 4, and left overnight at −20 °C. The

precipitate was a fine powder, which was separated from the suspension via centrifuge (~2000

rpm) and subsequently dried. A stem solution in DCM was prepared and used for aza-Claisen

rearrangement. Only 3% conversion was detected after 48h at 40 °C (entry 3). The investigation of

the recycling procedure of the catalyst is thus still in the progress.

Table 4.13. scale up of the rearrangement of model substrate E-201 and recycling of 4:

nPr

NPMP

CF3

O

nPr

NPMP

CF3

O

(0.1 mol%) 4,(4.0 mol%) AgNO3,(4 mol%) P.S., DCM

*

201 202

Fe

PhPh

Ph

Ph Ph

Pd ClO

Ni-Pr 2

4

# 201

[mmol]

Time

[h]

Tem.

[oC]

Yield

[%]

eea

[%]

1 1.0 48 40 91 97

2 10.0 48 40 98 97.4

3 0.06 48 40 3 ND a Determined by chiral stationary phase HPLC.

4.6 Conclusion. As described above, PPFOP-X 4 is more reactive than the previously most active catalyst

FIP-X 77. With this improvement, the catalytic asymmetric aza-Claisen rearrangement

now offers a very broad scope. Now, the methodology not only allows the formation of

highly enantioenriched primary allylic amines, but also secondary and tertiary amines, as

well as allylic amines with quaternary N-substituted stereocenters, can be generated with

high enantiocontrol. The reaction conditions tolerate many important functional groups,

thus providing stereoselective access to valuable functionalized building blocks, e.g., for

the synthesis of unnatural amino acids. Our studies suggest that face-selective olefin


coordination is the enantioselectivity determining step which is almost exclusively

controlled by the element of planar chirality.

4.7 References.

1 D. F. Fischer, A. Barakat, Z.-q. Xin, M. E. Weiss, R. Peters, Chem. Eur. J. 2009, 15, 8722.

2 S.-M. Lu, X.-W. Han, Y.-G. Zhou, Adv. Synth. Catal. 2004, 346, 909.

3 F. Naud, C. Malan, F. Spindler, C. Rüggeberg, A. T. Schmidt, H.-U. Blaser, Adv. Synth.

Catal. 2006, 348, 47.

4 A. Bueno, R. M. Moreno, A. Moyano, Tetrahedron: Asymmetry, 2005, 16, 1763.

5 F. M. Geisler, G. Helmchen, J. Org. Chem. 2006, 71, 2486.

6 For recent reviews on asymmetric allylic alkylation, see: a) B. M. Trost, M. L. Crawley,

Chem. Rev. 2003, 103, 2921; b) T. Graening, H.-G. Schmalz, Angew. Chem. Int. Ed. 2003,

42, 2580; c) B. M. Trost, J. Org. Chem. 2004, 69, 5813.

7 For a recent review, see: M. Shibasaki, E. M. Vogl, T. Ohshima, Adv. Synth. Catal. 2004,

346, 1533.

8 W.-P. Deng, X.-L. Hou, L.-X. Dai, X.-W. Dong, Chem. Commun. 2000, 1483.

9 For a review, see: D. Carmona, M. P. Lamata, L. A. Oro, Coord. Chem. Rev. 2000, 200–

202, 717 – 772.

10 S.-i. Fukuzawa, Y. Yahara, A. Kamiyama, M. Hara, S. Kikuchi, Org. Lett. 2005, 7, 5809.

11 M. Li, X.-Z. Zhu, K. Yuan, B.-X. Cao, X.-L. Hou, Tetrahedron: Asymmetry 2004, 15, 219.

12 J. Rudolph, F. Schmidt, C. Bolm, Adv. Synth. Catal. 2004, 346, 867.

13 S. Özçubukçu, F. Schmidt, C. Bolm, Org. Lett. 2005, 7, 1407.

14 M. M.-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 4572.

15 R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082.

16 J. Dupont, C. S. Consorti, J. Spencer, Chem. Rev. 2005, 105, 2527.

17 a) T. Sammakia, H. A. Latham, D. R. Schaad, J. Org. Chem. 1995, 60, 10; b) C. J.

Richards, T. Damalidis, D. E. Hibbs, M. B. Hursthouse, Synlett 1995, 74; c) Y.

Nishibayashi, S. Uemura, Synlett 1995, 79.

18 a) C. E. Anderson, Y. Donde, C. J. Douglas, L. E. Overman, J. Org. Chem. 2005, 70, 648;

b) Y. Donde, L. E. Overman, J. Am. Chem. Soc. 1999, 121, 2933.

19 J.-B. Xia, S.-L. You, Organometallics 2007, 26, 4869.

20 20a) A. M. Stevens, C. J. Richards, Organometallics 1999, 18, 1346. b) L. E. Overman, C.

E. Oven, M. M. Pavan, C. J. Richards, Org. Lett. 2003, 5, 1809.

21 V. I. Sokolov, L. L. Troitskaya, O. A. Reutov, J. Organomet. Chem. 1977, 133, C28.

22 C. Lόpez, R. Bosque, X. Solans, M. Font-Bardia, Tetrahedron: Asymmetry 1996, 7, 2527.

96 Chapter 4

23 G. Jones, C. J. Richards, Organometallics 2001, 20, 1251.

24 R. S. Prasad, C. E. Anderson, C. J. Richards, L. E. Overman, Organometallics 2005, 24,

77.

25 J. Kang, K. H. Yew, T. H. Kim, D. H. Choi, Tetrahedron Lett. 2002, 43, 9509.

26 F. X. Roca, M. Motevalli, C. J. Richards, J. Am. Chem. Soc. 2005, 127, 2388.

27 J. Kang, T. H. Kim, K. H. Yew, W. K. Lee, Tetrahedron: Asymmetry 2003, 14, 415.

28 H. Nomura, C. J. Richards, Chem. Eur. J. 2007, 13, 10216.

29 R. Peters, Z.-q. Xin, D. F. Fischer, W. B. Schweizer, Organometallics 2006, 25, 2917.

30 M. E. Weiss, D. F. Fischer, Z.-q. Xin, S. Jautze, W. B. Schweizer, R. Peters, Angew. Chem.

Int. Ed. 2006, 45, 5694.

31 K. Tamura, H. Mizukami, K. Maeda, H. Watanabe, K. Uneyama, J. Org. Chem. 1993, 58,

32.

32 S. K. Thompson, C. H. Heathcock, J. Org. Chem. 1990, 55, 3386.

33 W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405.

34 This reaction is in principal known, see for an early example a) D. Michelot, G.

Linstrumelle, Tetrahedron Lett. 1976, 17, 275. For an investigation about the scope of

carbon-nucleophiles (methylbutynoate-addition), see also b) R. J. Anderson, V. L. Corbin,

G. Cotterrell, G. R. Cox, C. A. Henrick, F. Schaub, J. B. Siddall, J. Am. Chem. Soc. 1975,

97, 1197.

35 Prepared in analogy to: K. Tamura, H. Mizukami, K. Maeda, H. Watanabe, K. Uneyama, J.

Org. Chem. 1993, 58, 32.

36 Prepared from pivaloyl aldehyde via HWE and reduction with DIBAL, see: S. K.

Thompson, C. H. Heathcock, J. Org. Chem. 1990, 55, 3386.

37 L. E. Overman, J. Am. Chem. Soc. 1974, 96, 597.

38 L. E. Overman, S. W. Roberts, H. F. Sneddon, Org. Lett. 2008, 10, 1485.

39 P. Watson, L. E. Overman, R. G. Bergman, J. Am. Chem. Soc. 2007, 129, 5031.

40 S. Jautze, P. Seiler, R. Peters, Angew. Chem. Int. Ed. 2007, 46, 1260.

41 M. E. Güunay, C. J. Richards, Organometallics 2009, 28, 5833.

42 D. F. Fischer, Z.-q. Xin, R. Peters, Angew. Chem. Int. Ed. 2007, 46, 7704.

43 Z.-q. Xin, D. F. Fischer, R. Peters, Synlett 2008, 1495.

Chapter 5

Intramolecular Hydroamination of Unactivated Olefins using a Highly Strained Planar Chiral Platinacycle.

5.1 Introduction. This chapter describes Pt(II) complexes 12 which catalyze the intramolecular oxidative amination

of unactivated olefins1 with alkyl amines, amides, and sulphonamides.

Pt(II) complexes 12 were prepared in two steps starting from a ferrocene bisimidazoline 185 by

diastereoselective cycloplatination.2

This research project was carried out by the author in the Peters group (University of Stuttgart,

Stuttgart, Germany).

5.1.1 General Introduction and Motivation. Functionalized nitrogen heterocycles are the components of a wide range of naturally occurring and

biologically active molecules. This, coupled with the limitations associated with traditional

methods for C-N bond formation, has stimulated considerable interest in the development of new

and more efficient methods for the synthesis of nitrogen heterocycles. The intramolecular addition

of the N-H bond of an amine across an unactivated C=C bond (hydroamination) represents an atom

economical and potentially expedient approach to the synthesis of nitrogen heterocycles. However,

despite considerable effort in this area, the intramolecular hydroamination of unactivated C=C

bonds with alkylamines remains problematic. For example, rare earth,3 alkali,4 alkaline earth,5 and

group 46 metal complexes catalyze the intramolecular hydroamination of unactivated C=C bonds

with alkyl amines, but the synthetic utility of these protocols is compromised by the poor functional

group compatibility and extreme moisture-sensitivity of the catalysts. Alkyl 4-pentenyl amines

undergo intramolecular hydroamination in the presence of Brønsted acids, but forcing conditions

are required.7 Conversely, late transition metal-catalyzed systems for the intramolecular

hydroamination of unactivated C=C bonds with alkylamines have typically been restricted to vinyl

arenes and conjugated dienes.

98 Chapter 5

In response to the limitations associated with the hydroamination of unactivated C=C bonds, an

effective Pt-catalyzed protocol for the intramolecular hydroamination of amino alkenes has been

applied.

5.1.2 Literature Overview. Nitrogen-containing saturated heterocyclic systems are important core structures in organic

chemistry because of their presence in many natural products. For this reason, simple procedures

for the formation of pyrrolidines and piperidines are highly desirable. One of the most appealing

approaches to these heterocycles is hydroamination, in which the nitrogen carbon bond is formed

by the addition of an amine to an olefin.

The development of efficient methodologies for the synthesis of nitrogen heterocycles is of high

importance in the context of an economical and environmentally benign preparation of

sophisticated targets with biological activities. An intermolecular catalytic asymmetric

hydroamination might face this challenge by efficient cyclisation of functionalised substrates. Until

now, various amino–alkene, amino–diene and amino–allene derivatives were successfully

enantioselectively transformed into the corresponding heterocycles.

Different researchers have worked in this field and the most important recent examples will be

discussed here.

R. A. Widenhoefer and coworker8 have reported effective Pt(II)-catalyzed protocols for the

addition of carbon,9 nitrogen,10 and oxygen11 nucleophiles to unactivated olefins.12 The platinum-

catalyzed hydroamination of γ-amino olefins tolerated substitution at the allylic and internal

olefinic carbon atoms and tolerated both primary and secondary N-bound alkyl groups. Heating a

concentrated dioxane solution of γ-amino olefin 287 (0.5 M) with a catalytic mixture of

[PtCl2(H2C=CH2)]2 (2.5 mol %) and PPh3 (5 mol %) at 120 °C for 16 h led to the isolation of

pyrrolidine 288 in 75% yield (scheme 5.1).

NHBnBnN

PhPh

Ph

Ph

[PtCl2(H2C=CH2)]2 (2.5 mol%)PPh3 (5 mol%)

dioxane, 120 °C, 16h75%287 288

Scheme 5.1. Hydroamination of amino olefins catalyzed by a mixture of Pt(II) and Ph3P.

It was reported that gem-dialkyl substitution at the β-position of the γ-amino olefin facilitated

hydroamination, but was not essential. Platinum-catalyzed hydroamination tolerated a range of

functionality including bromo, nitro, and cyano groups, carboxylic esters, acetals, and benzyl and

silyl ethers.

Intramolecular Hydroamination of Unactivated Olefins 99

The reaction mechanism proceeds via formation of a platinum amine complex and subsequent C-N

bond formation and presumably occurs via intramolecular ligand exchange followed by outer-

sphere attack.

In 2008, R. A. Widenhoefer and coworker13 have reported that mixtures of PtCl2 and sterically

hindered o-biphenyl phosphines catalyze the intramolecular hydroamination of amino alkenes at

60°–80 °C displaying improved scope and generality relative to the catalyst generated from Zeise’s

dimer and PPh3 protocols,8 as a supporting ligand for platinum-catalyzed hydroamination (scheme

5.2).

NHBn BnN(5 mol%)PtCl2,

(5 mol%) 291,

diglyme, 60 °C, 10h86%

P

Me2N

t -But-Bu

289 290 291

Scheme 5.2. Hydroamination of amino olefins catalyzed by a mixture of PtCl2 and ligand 291.

Subsequently, J. Uenishi and coworkers14 illustrated the Pd(II)-catalyzed intramolecular cyclization

of N-protected δ-amino allylic alcohols 292 and the stereospecific synthesis of 2-substituted and

2,6- disubstituted piperidines 294 (scheme 5.3). The reaction gives a syn SN2′ product majorly

through syn-coordination of the Pd(II)-catalyst to the allylic alcohol followed by syn-azapalladation

and syn-elimination of PdCl(OH), leading to the product. Although the syn-azapalladation is found

to be more favored, the formation of a minor isomer suggests that the anti-azapalladation is also

possible and the reaction pathway depends upon the substrate and solvent. The advantages of this

method are: (i) No oxidant such as CuCl2 is required, because the Pd(II)-catalyst is regenerated

during the reaction. This is how it differs from other oxidative cyclizations to an alkene15 by

Wacker-type reactions. (ii) The reaction proceeds smoothly at 0 °C with excellent selectivities.

NHPG

OHPdCl2(CH3CN)2

(20 mo%)CH2Cl2 or THF

NPG

NH HCli. Pd(OH)2/C, MeOH

H2, 24hii. HCl gas, Et2O

PG = Cbz, Boc292 293 294

Scheme 5.3. Pd(II)-catalyzed cyclizations of nitrogen nucleophile to chiral allylic alcohols. The development of chiral catalysts for the asymmetric hydroamination of alkenes (AHA) has

remained challenging.

100 Chapter 5

The first chiral rare earth metal based hydroamination catalysts were reported by Marks and co-

workers in 1992.16a-b Although enantioselectivities of up to 74% ee were achieved, the application

of these C1-symmetric chiral ansa-lanthanocenes was limited due to a facile epimerization process

via reversible protolytic cleavage of the metal cyclopentadienyl bond under the reaction conditions

of catalytic hydroamination.16b-c

K. C. Hultzsch et al.17 had developed rare earth metal complexes with sterically demanding tris-

(aryl)silyl-substituted binaphtholate ligands which are efficient catalysts for the asymmetric

hydroamination/cyclization of aminoalkenes and the kinetic resolution of R-substituted

aminopentenes (scheme 5.4). Catalytic activities are comparable to those of lanthanocene catalyst

systems, while enantioselectivities of up to 95% ee were attained in the cyclization of achiral

aminopentenes. The hydroamination mechanism for the binaphtholate catalyst system is similar to

that proposed for lanthanocene catalysts, based on the rate dependencies on substrate and catalyst

concentrations and the observed activation parameters.

R4 NH2

R3

R2R1

n

SiAr3

OO

SiAr3

Ln = Sc, Y, La, Lu

∗HN

R1

R2

R3

R4

n

R1, R2, R3 = H, alkyl,arylR4 = H, Aryln = 1, 2

ee = up to 95%

Ln X

297

295 296

Scheme 5.4. Catalytic hydroamination/cyclization of aminoalkenes by using a binaphtholate

catalyst.

A new chiral tetradentate ligand has been prepared by Xiang et al.18 These organolanthanide

amides have displayed moderate to good catalytic activity for the asymmetric

hydroamination/cyclization of representative aminoalkenes, although enantioselectivities have

remained low (up to 24% ee) ( scheme 5.5).


NH2Ln = Sm, Y, Yb

∗HN

ee = up to 24%

N

N

N

N

Lnthf

N(SiMe3)2

300

298 299

Scheme 5.5. Catalytic hydroamination/cyclization of aminoalkenes using organlanthanide amides. S. R. Chemler and coworkers19 reported that copper(II) promoted the diastereoselective synthesis

of disubstituted pyrrolidines via an intramolecular aminooxygenation of alkenes. He investigated

the aminooxygenation reaction of 4-pentenyl sulfonamide 305 using catalytic amounts of

copper(II) salts. The use of a bisoxazoline ligand [(R,R)-Ph-box 308] gave better conversion than

the 2,2′-dipyridyl ligand 307 under catalytic conditions using O2 (1 atm) (scheme 5.6).

R1

NHR2

NR1O N

R2

Cu(EH)2 (1.5 equiv)Cs2CO3, TEMPO (3 equiv.)xylenes, 130 °C, 24h

76-97%

R1 = i -Pr, CH2OTBDPS, Bu, 3-Butenyl dr = > 20: 1R2 = Ts, PMBS, NsEH = 2-ethylhexanoate

301 302

NO N

Cu(EH)2 (1.5 equiv)Cs2CO3, TEMPO (1.5 equiv.)xylenes, 130 °C, 24h

59%NH

SO2SO2

dr = > 20: 1303 304

102 Chapter 5

NHPMBS

NO N

PMBS

Cu(OTf)2 (0.2 equiv),ligand (0.2 equiv.),Cs2CO3 (1.0 equiv.),TEMPO (3 equiv.),xylenes, 130 °C, 24h

N N

OO

PhPhN N

2, 2'-dipyridyl 307 (R, R)- Ph-box 30820% yield 60% yield

305 306

Scheme 5.6. Copper(II) promoted diastereoselective formation of 2,5-cis-Pyrrolidines.

L. L. Schafer et al.20 have established that commercially available Ti(NMe2)4 may be used in a

facile protocol for the catalytic preparation of pyrrolidine and piperidine heterocyclic products from

aminoalkene substrates in good yields (scheme 5.7).

R NH2

PhPh

n

HN

PhPh

Rn

(5 mol%) Ti(NMe2)4,toluene, 110 °C

R = H, Phn = 1, 2

yield up to 92%309 310

Scheme 5.7. Catalytic hydroamination/cyclization of aminoalkenes by Ti(NMe2)4.

In 2006, L. L. Schafer et al.21 presented the first amidate-supported Zr imido complex 311 that

exhibits a unique pentagonal-pyramidal geometry in the solid state. This is also the first neutral

group 4 imido complex that is a precatalyst for intramolecular alkene hydroamination.

NH2

HN(5 mol%) cat 311,

toluene, 110 °C, 96hHN

syn: ant i , 1: 11.372% yield Ph

O

N

O PPh3

ZrN

2

312 314

311

Scheme 5.8. Catalytic cyclohydroamination.

Later in 2007, the same group22 has illustrated the first chiral neutral amidate zirconium complexes

that can be used for enantioselective cyclohydroamination of primary aminoalkenes with up to 93%


ee, which is, to the best of our knowledge, the highest reported enantioselectivity for this typical

test substrate (scheme 5.9).

NH2

HN(10 mol%) precat 317a,

toluene, 110 °C, 3h> 98%conversion N

NZr

NMe2

NMe2

O

O

R

R

a: R = b : R = c: R =

93%ee

315 316

317

Scheme 5.9. Catalytic enantioselective cyclohydroamination of primary aminoalkenes.

More recently, Hollis and coworkers23 reported the use of Rh and Ir complexes supported by

pincer-type N-heterocyclic carbene ligands (5 mol % M) for the hydroamination of terminal

alkenes by tethered secondary alkyl- and phenylamines, while Liu and Hartwig24 disclosed the use

of a rhodium complex that catalyzes cyclizations of aminoalkenes under mild conditions with

substrates containing primary or secondary alkylamines and terminal or internal alkenes (scheme

5.10).

NHR RN

R'R''

R'

R'' n n O

(2.5mol%) Rh(COD)2BF4,(3.0mol%) ligand,

dioxane , 70 °C, 7h

R = Alkyl, Benzyl, HR', R'' = H, Alkyl, PhN = 1, 2

P(NEt2)2 P(NEt2)2

PCy2 orMe2N

Ligand

318 319

320 321

Scheme 5.10. Rhodium catalyzed intramolecular hydroamination of aminoalkenes. In 2009, M. Stradiotto et al.25 reported that [Ir(COD)Cl]2 is an effective precatalyst for the

hydroamination of unactivated alkenes with pendant secondary alkyl- or arylamines, at relatively

low loadings (typically 0.25-5 mol % Ir) and without the need for added ligands or cocatalysts

(scheme 5.11).

104 Chapter 5

NHRRN

R'R'

R'

R'

cat. [Ir(COD)Cl]2

1,4-dioxane

R = Bn, R' = Ph, yield up to 89%318 319

Scheme 5. 11. Intramolecular hydroamination of unactivated alkenes by secondary alkylamines

employing [Ir(COD)Cl]2 as a pre-catalyst.

Specifically, the development of hydroamination protocols using an inexpensive and

environmentally benign metal catalyst is greatly anticipated. To date, most of the investigations on

the intramolecular hydroamination of alkenes catalyzed by late transition metals have focused on

the use of amides or carbamates bearing electron-withdrawing N-substituents such as Ts, Cbz, Boc,

or Ac groups instead of free amines.26 M. Sawamura and coworkers27 introduced a Cu-Xantphos

system [Cu(O-t-Bu)-Xantphos, 10-15 mol %] that catalyzes the intramolecular hydroamination of

unactivated terminal alkenes bearing an unprotected aminoalkyl substituent in alcoholic solvents,

giving pyrrolidine and piperidine derivatives in excellent yields (scheme 5.12).

NHR1 N

R2

R2

R2

R2

cat. Cu(O-t-Bu)-Xantphos

alcoholic solventhigh yield

R1 = H, alkyl, COR R2 = alkyl, Ph,n = 1,2

n n

FGH2C

FG = OMe, F, CN, CO2Me

O

Me Me

PPh2 PPh2

Xantphos 324

R1

322 323

Scheme 5.12. Cu(I)-catalyzed hydroamination of unactivated alkenes bearing secondary amino or

amido groups. The intramolecular addition of the N-H bond of an amine across an unactivated C=C bond

(hydroamination) represents an atom economical and potentially expedient approach to the

synthesis of nitrogen heterocycles. However, despite considerable efforts in this area, the

intramolecular hydroamination of unactivated C=C bonds with alkylamines remains problematic. A

Pt(II)-catalyzed protocol for the intramolecular hydroamination of amino alkenes has been applied.



5.2.1 Synthesis of a Bisimidazoline Platinacycle 12.

A bisimidazoline platinacycle 12 was prepared according to R. Peters et al.2 with an overall 40%

yield in two steps. Bisimidazoline 185 was treated with Zeise’s salt giving a mixture of a monomer

and a Cl-bridged dimer. Treatment of the reaction mixture with Na(acac) completely converts both

the monomer and dimer to the same monomeric acac-complex, which provides the

diastereomerically pure monomer 325 after treatment with LiCl and HCl (scheme 5.13).

Fe

N

Pt

N

PhPh

O

Ts

N

N Ph

Ts Ph

Fe

N

N Ph

Ts Ph

K[(H2C=CH2)PtCl3],NaOAc, MeOH, benzene,RT, then Na(acac), RT

185 Pt-Bis-Imi-acac 325

N

N Ph

Ts Ph

O LiCl, HCl,MeOH, benzene

Fe

N

Pt

N

PhPh

Cl

Ts

N

N Ph

Ts Ph12

90%dr > 50 :1

Scheme 5.13. Formation of the strained complex 12 by diastereoselective cycloplatination.

5.2.2 Synthesis of Amino Olefin.

5.2.2.1 General Procedure for the Synthesis of 4-Mono-substituted Amino Olefins.

Mono-substituted amino olefins were prepared by applying a methodology which has been reported

by R. A. Widenhoefer et al,8 starting from commercially available diphenylacetonitrile in three

steps with moderate to very good yields as shown in (scheme 5.14).

106 Chapter 5

NH2

Ph

Ph

Ph

Ph NH

R

CNPh

Ph

i. RCHO, MeOHii. NaBH4

i. LAH, Et2Oii. NaOH, H2OCNPh

Ph

i. NaH, DMFii. allyl bromide

89% 78%

R = Ph (84%) 287R = m-ClPh (53%) 327R = CH2Ph (28%) 328

326

Scheme 5.14. General scheme for the synthesis of monosubstituted amino olefins.

N-Benzyl-2,2-diphenylpent-4-en-1-amine 287, which is a model substrate for catalysis

experiments, was prepared with an overall yield of 58%. N-(3-Chlorobenzyl)-2,2-diphenylpent-4-

en-1-amine 327 and N-phenethyl-2,2-diphenylpent-4-en-1-amine 328 were prepared by Markus

Bischoff (research student) in overall yields of 37% and 19%, respectively.

N-(2,2-Diphenylpent-4-enyl)-4-methylbenzenesulfonamide 330 was prepared starting from 2,2-

diphenylpent-4-en-1-amine 326 with TsCl in the presence of Et3N in 71% yield. N-(2,2-

Diphenylpent-4-enyl)acetamide 329 was prepared starting from 2,2-diphenylpent-4-en-1-amine

326 with AcCl in the presence of pyridine in 98% yield (scheme 5.15).

NH2

Ph

Ph

Ph

Ph NH

TsTsCl, Et3N,DCM, RT

71%98%

Ph

Ph NH

CH3COCl, Py,DCM, 0 °C, RT

O

329 326 330 Scheme 5.15. Protection of amino olefin 326 with TsCl or AcCl.

5.2.2.2 4,5-Di-substituted Amino Olefins.

(Z)-N-Benzyl-2,2-diphenylhept-4-en-1-amine 333 was prepared according to the same method used

for the preparation of mono-substituted olefins8 with an overall 49% yield as shown below

(scheme 5.16).


NH2

Ph

Ph

Ph

Ph NH

Ph

CNPh

Ph

i. PhCHO, MeOHii. NaBH4

i. LAH, Et2Oii. NaOH, H2OCNPh

Ph

i. NaH, DMFii. allyl bromide

84% 94%

Et

EtEt 331 332

62%

333

Scheme 5.16. Synthesis of di-substituted Amino olefin.

(Z)-Benzyl 2,2-diphenylhept-4-enylcarbamate 334 was prepared starting from (Z)-2,2-

diphenylhept-4-en-1-amine 332 with benzyl chloroformate in the presence of NaHCO3 in 90%

yield (scheme 5.17).

NH2

Et Et

CbzCl, NaHCO3EtOH/H2O (3:2)

90%

Ph

Ph

Ph

Ph NH

Cbz

332 334

Scheme 5.17. Protection of di-substituted amino olefin with Cbz.

The same methodology was applied in order to prepare (Z)-benzyl 2,2-diphenyloct-5-

enylcarbamate, but without success. Introducing a modification in the first step by using

homoallylic iodide and LHMDS instead of homoallylic bromide and NaH provided the target

product with an overall yield of 68% as shwon in (scheme 5.18).

108 Chapter 5

Ph

Ph CN I LHMDS, THF-78 °C, RT

CNPhPh

Et

PhPh

Et

PhPh

Et

i. LAH, Et2Oii. NaOH, H2O


95% 79%NH2

NHCbz

335 336

91%

337

Scheme 5.18. Synthesis of 5,6-di-substituted amino olefin protected with Cbz group.

5.2.3 Results and Discussion

5.2.3.1 Catalysis.

Initial screening experiments were performed by using 1 equiv. of Ag-salt per precatalyst (5 mol%)

12 in three different solvents (benzene, dioxane, and toluene) thus exchanging Cl− by a more labile

binding counterion. Heating for 20 h at 110 °C led to >99% conversion in case of the entry 1,2 with

12% and 22% ee, respectively (Table 5.1), while in the case of the entry 3, 73% conversion with 14

% ee (Table 5.1) was observed.

Table 5.1. Pt (II)-Catalyzed intramolecular hydroamination of aminoalkene:

NHBnBnN

PhPh

Ph

Ph

(5 mol%)12,(5 mol%) AgOOCC3F7,Y, 110 °C, 20h

287 288 # Y yielda/[%] eeb/[%]

1 Benzene >99 12

2 Dioxane >99 22

3 Toluene 73 14 a determined by H-NMR by comparing the integrals of product and starting material, followed by

multiplication with the mass balance.b determined by HPLC.


From these initial results, it can be seen that there is catalytic activity of Pt(II) towards

hydroamination of the unactivated olefins. The solvent was found to have no great influence on the

reaction outcome, and the reaction rate shows a slight decrease in the case of toluene being used as

a solvent.

5.2.3.2 Investigation of the Influence of the Silver Salt.

Utilizing 1 equiv. of different Ag-salts per precatalyst (5 mol%) 12 in dioxane and heating up for

48h at 70 °C gave >99% conversion in case of the entry 1, 3 and 5 with 15%, 16%, and 15% ee

respectively (Table 5.2), while in case of the entry 2 and 4 conversion values of 79 and 56% with

9% and 7% ee, respectively (Table 5.2) were observed. In the entry 6 no silver salt was involved,

and the reaction did not occur.

Table 5.2. Screening of silver salts with model substrate:

NHBnBnN

PhPh

Ph

Ph

(5 mol%) 12,(5 mol%) Y,dioxane, 70 °C, 48h

287 288

# Y yielda/[%] eeb/[%]

1 A >99 15.5 2 B 79 9.4 3 C >99 16.4 4 D 56 7 5 E >99 15.5

6 - -c - a determined by H-NMR by comparing the integrals of product, and starting material followed by

multiplication with the mass balance.b determined by HPLC.c No reaction.

OSO

AgO

OSO

AgOO

SO

AgO

OSO

AgO

O

O OO

SO

AgO

A B C D E

Very good catalytic activity was obtained with different Ag-salt as an activating agent, and the

reaction rate was still quite high when the temperature was decreased. The counter ion was found

to have no significant influence on the reaction outcome. The enantioselectivities still show no

great variations.

110 Chapter 5

5.2.3.3 Investigation of the Influence of the Amino Protecting Group. The effect of different amino protecting groups was tested for the intramolecular hydroamination of

unactivated olefins. Different amino protecting groups such as aryl units, amides, carbonate esters,

and sulphonamides were examined, in order to see the influence of the protecting group on the

reaction outcome. The amide, and sulphonamide substrates were studied under the following

reaction conditions utilizing (5 mol%) 12 precatalyst in dioxane and heating at 70 °C for 48h

(Table 5.3 entry 1,2). m-Chlorobenzyl amine was tested using 1.0 equiv. of AgOOCC3F7 per

precatalyst (5 mol%) in dioxane and heating at 110 °C for 20h (Table 5.3, entry 3). A carbamate of

a disubstituted olefin was also examined under the following reaction conditions: (i) (5 mol %) 12

precatalyst in dioxane and heating at 90 °C for 48h; (ii) 1 equiv. of AgOSO2CF3 precatalyst (5

mol%) 12 in dioxane and heating at 100 °C for 48h. In addition aryl substituted and free amines

were also examined using 1 equiv. of AgOOCC3F7 per precatalyst (5 mol%) 12 in dioxane and

heating at 110 °C for 20h (Table 5.3, entry 8, 9).

Table 5.3. Screening of different protecting groups.

NHRRN

PhPh

Ph

Ph

(5.0 mol%) 12,Y-(5.0 mol%),

dioxane, T (°C), t (h)R1

R1

n n397 a-e

# R R1 N Amino

olefin

Y-Ag-salt T[°C]

/t[h]

yielda/

Product 397

eeb/[%]

1 Ac H 1 329 - 70 /48 NR 2 Ts H 1 330 - 70 /48 NR 3 mClPhCH2 H 1 327 AgOOCC3F7 110 /20 >99 12

4 Cbz Et 1 334 - 90/48 25% isomerization

5 Cbz Et 1 334 AgOSO2CF3 100/48 Isomerization 6 Cbz Et 2 337 - 90/48 Decomposed 7 Cbz Et 2 337 AgOSO2CF3 100/48 Isomerization 8 Bn Et 1 233 AgOOCC3F7 110/20 33 c

9 H H 1 326 AgOOCC3F7 110/20 Decomposed a determined by 1H-NMR by comparing the integrals of product, and starting material, followed by

multiplication with the mass balance. b determined by HPLC. c No success for determination ee.

From the results reported in Table 5.3 we observed no influence on the reaction outcome changing

from an aryl protecting group to an amide, sulfone amide or carbonate ester. In case of the entry 1

and 2, there was no reaction at all. In case of the entry 3, the product was formed with > 99%

conversion and with 12% ee. In case of the entry 4, 5, and 7, an isomerized olefin was obtained


while in case of the entry 7 the aminoalkene decomposed. In the case of the disbstituted amino

olefin (entry 8), the product was formed in 33 % conversion. For ee determination different HPLC

methods, chiral GC, and the formation of the corresponding Mosher amide were examined but all

attempts were not successful. The primary amines (entry 9) were found to be decomposing.

5.2.3.4 Investigation of the Influence of Additives. Utilizing 1 equiv. of Ag-salt per precatalyst (5 mol%) in dioxane in the presence of of pyridine or

acetonitrile and heating for 48h at 70 °C gave no conversion in case of (entry 1), and 73%

conversion in case of the entry 2 (Table 5.4).

Table 5.4: screening of additives with model substrate 287.

NHBnBnN

PhPh

Ph

Ph

(5 mol%) 12,(5 mol%) AgOOCC3F7,Y, 70 °C, 48h

287 288

# Y [20.0 mol%] yielda/[%] eeb/[%]

1 Pyridine NR - 2 CH3CN 73 19

a determined by 1H-NMR by comparing the integrals of product, and SM, followed by multiplication with the mass balance. b determined by HPLC.

It was observed from these two runs that pyridine inactivated the catalyst while the less Lewis basic

acetonitrile had no influence on the reaction outcome, but still enantioselectivity was low with 19%

ee.

After investigation of the effects of solvent, silver salts, protecting groups and additives on the

reaction outcome it is likely that the reaction pathway has two potential mechanisms which have to

be considered (Scheme 5.19) and which have been discussed for alternative Pt-catalyzed additions

to alkenes. 1b Coordination of a C=C bond to an electrophilic Pt center activates the alkene toward

outer sphere attack by a protic nucleophile NuH. The newly formed Pt-C bond is then cleaved by

protonolysis (see below) to regenerate the catalyst.

Scheme 5.20 shows an alternate inner-sphere mechanism, in which the nucleophile first coordinates

to Pt by deprotonation of NH and ligand exchange. The key step is a 1,2-migratory insertion of a

bound olefin into the Pt-N bond. Again, the newly formed Pt-C bond is cleaved by protonolysis.

112 Chapter 5

Fe PtN

NTs

Ph

Ph

N

N

Ts

Ph

Ph

A

Fe PtN

NTs

Ph

Ph

N

N

Ts

Ph

Ph

ANHBn

Fe PtN

NTs

Ph

Ph

N

N

Ts

Ph

Ph

A

BnNPh

Ph

NHBnPh

Ph

outer-spherenucleophilic attack

Protonolysis

A = O2CC3F7

Ph

Ph

BnHN

Ph Ph

Scheme 5.19. Possible route to the product distribution observed when N-Benzyl-2,2-diphenylpent-4-en-1-amine 287 is Reacted with Pt(II) -12.


Fe PtN

NTs

Ph

Ph

N

N

Ts

Ph

Ph

Fe PtN

NTs

Ph

Ph

N

N

Ts

Ph

Ph

A

BnNPh

Ph

NHBnPh

Ph

1,2-migratoryinseration

Protonolysis

A = O2CC3F7

A HNBn Ph

Ph

Fe PtN

NTs

Ph

Ph

N

N

Ts

Ph

Ph HNBn Ph

Ph

A .

A

Fe PtN

NTs

Ph

Ph

N

N

Ts

Ph

PhHN

Bn Ph

Ph

Scheme 5.20. Possible route to the product distribution observed when N-Benzyl-2,2-diphenylpent-

4-en-1-amine 287 is reacted with Pt(II)-12.

5.3 Attempts to the Development of an Improved Catalyst. Platinacycle 12 catalyzed the intramolecular hydroamination with high reactivity yet with low

enantioselectivity as a result of a competing inner- and outer-sphere attack. By introducing strongly

binding anionic ligands like for instance Ph or C6F5 the inner-sphere attack should be largely

impeded, leaving only one site for coordination free. Several attempts were tested.

Fe

N

Pt

N

PhPh

Ts

N

N Ph

Ts Ph

ClFe

N

Pt

N

PhPh

Ts

N

N Ph

Ts Ph

R

R = Ph, Me, C6F5

12 338

Scheme 5.21. General approach for the development of a suitable catalyst.

114 Chapter 5

Reaction conditions have been applied which are described in literature for other Pt-complexes.

Several attempts were made by testing for instance MeMgBr, Et2O: PhH / RT);28 PhMgBr, THF/

RT; PhLi, PhH/RT; Ph−≡, CuI, Et3N, DCM, RT; 29, 30,31 C6F6/THF, − 35 °C; Na/I2, THF;32 Na/MeI,

THF. The crude 1H NMR spectra show that none of these experiments give the target product.

5.4 Development of New Catalysts.

Palladium(II) and platinum(II) complexes containing chiral ligands attract great interest because of

their potential applications in different fields. It is well known that compounds of this kind are

useful in homogeneous catalysis and as chiral derivatising agents, as reagents to determine enantio-

or diastereomeric excesses of organic substrates, or even due to their antitumoral activity. The

utility of chiral pallada- and platinacycles in asymmetric catalytic processes including asymmetric

aza-Claisen rearrangements is well documented. Notably, Peters et al.2 have recently described the

first highly diastereoselective cycloplatination of an enantiopure ferrocene that promotes the first

highly enantioselective asymmetric intramolecular Friedel-Crafts alkylation of indoles with

disubstituted internal olefins.

On the other hand, palladium(II) complexes containing (N), (N,E), (C,N)– or (C,N,E)– (E = N , S

or P) ferrocenyl ligands have attracted great interest in recent years, mainly because of their

applications in homogeneous catalysis or in organometallic synthesis. Platinum(II) analogues are

less common. Some of these also exhibit antitumoral activity against cis-platinum-resistant cells.

Despite a) the wide variety of chiral ferrocene derivatives reported so far, b) the prochiral nature of

the ferrocenyl unit in the metallation process and c) the interest in chiral platinum(II) complexes

containing ferrocenyl units, only a few enantio- or diastereomerically pure platinum(II) derivatives

are known. After the improvement of the catalyst failed (chapter 5.3), several attempts were made to develop a

new catalyst and apply it in synthetic organic reactions. A number of ligands were prepared and

tested for cycloplatination (scheme 5.22).


Fe

PhPh

Ph

Ph Ph

NO

Fe

PhPh

Ph

Ph Ph

NO

OR

Fe

NO

OR

Fe

NO

S

Fe

PhPh

Ph

Ph Ph

NN

Ph

Ts

Fe

NN

Ph

Fe

NN

Ts

OMe

OMe

Fe

PhPh

Ph

Ph Ph

NO

S

11 149 348

341 344 345

346 347

R = H, PPh2

R = H, PPh2

Scheme 5.22. Ligands for testing cycloplatinations.

5.4.1 Ligand Preparation. The synthesis of Ligand 11 is described in chapter 4. Ligand 149 and 347 were prepared according

to Richards et al.33 Ligand 348 and 346 were prepared utilizing the methods of C. J. Richards33 as

described. Ligand 34435 and 345 were prepared by R. Peters et al.34

The preparation of imidazoline ligand 341 consists of two steps starting from iminoether 339 and

diamine 342, a condensation reaction followed by tosylation in 68% overall yield.

116 Chapter 5

Fe

NN

Ts

OMe

OMe

TsCl, DMAP,NEt3, DCM

91%Fe

NNH

OMe

OMeFe

F4BH .HN

EtO75%

NH2H2N

DCM, 0 °C to RT

OMeMeO

339 340 341

342

Scheme 5.23. (4R,5R)-4,5-Bis(2-methoxyphenyl)-2-ferrocenyl-1-tosyl-4,5-dihydro-1H-imidazole.

5.4.2 Screening Different Conditions for Cycloplatination. In a first attempt to evaluate the potential metallation abilities of the ferrocenyl ligands with a

platinum(II) source, their reactivity with the platinum(II) complexes [PtCl2(L)2] (L = dmso, CH3CN

or Cl,) or Zeise salt was studied under different experimental conditions.

Ligand 11 was examined under different reaction conditions (Table 5.5, Entry 1, 2, 3): (i) 1 equiv.

of cis-[PtCl2(dmso)2], 2 equiv. of AcONa in (MeOH: PhH 4:1), and heating at 70 °C for 2 h; (ii) 2

equiv. of K[(H2C=CH2)PtCl3], 4 equiv. of NaOAc , and stirring overnight at RT, then heating at 60

°C for 30 min; (iii) 2 equiv. K2PtCl4 in AcOH, 110 °C, 24h. The 1H NMR spectra of the crude

reaction mixtures showed that in case of conditions (i) and (ii) Pt(II) binds to N. After addition of

Ph3P, ligand 11 is released again demonstrating that C-Pt bond formation did not take place, while

in case of using reaction conditions (iii) ring opening of the oxazoline moity is noticed.

Ligand 149 was examined under the following reaction conditions (Table 5.5, Entry 4-9): (i) 2

equiv. K2PtCl4, in AcOH, 110°C, 12h. (ii) 2 equiv. K2PtCl4, AcONa in (MeOH: PhH 4:1), 110 °C,

15h. (iii) 1 equiv. of cis-[PtCl2(dmso)2] in (MeOH: PhH 4:1), 110 °C, 15h. (iv) 1 equiv. of

PtCl2(CH3CN)2 in PhMe, 110 °C, 1h. (v) K[(H2C=CH2)PtCl3](1.equiv.),NaOAc (2.equiv.), (MeOH:

PhMe 4:1), 110 °C, 15h. The 1H NMR spectra of the crude reaction mixtures showed that in case of

(i) ring opening of the oxazoline moity occurs. In case of (ii) no product formation has occurred. In

contrast, in case of (iii) and (v) the starting material decomposed, while in case of (iv) the 1H-NMR

spectrum is too complex.

Ligand 348 was treated with 1 equiv. K[(H2C=CH2)PtCl3], 2 equiv. NaOAc in (MeOH: PhMe 4:1),

and stirred at RT for 15h (Table 5.5, entry 10). The 1H NMR spectrum of the crude reaction

mixture showed that the starting material decomposed.

Ligand 341 was treated with 2 equiv. K[(H2C=CH2)PtCl3], 4 equiv. NaOAc in (MeOH: PhMe 4:1),

and stirred at RT for 48h (Table 5.5, entry 11). The 1H NMR spectrum of the crude reaction

mixture showed that Pt(II) binds to N, but addition of Ph3P regenerates ligand 341.


Ligand 344 was treated with 2 equiv. K[(H2C=CH2)PtCl3], 4 equiv. NaOAc in (DCE: tBuOH 4:1),

and stirred at RT−80 °C. The 1H NMR spectrum of the crude reaction mixture showed that the Me-

N bond was cleaved.

Ligand 345 was treated with 2 equiv. K[(H2C=CH2)PtCl3], 4 equiv. NaOAc in MeOH: PhH 4:1 and

stirred at RT for 70h. No product formation occurred. In case of ligand 346 the same conditions

were applied (Table 5.5, entry 14) giving a Pt(II) coordination to N, yet a C-Pt bond is not formed.

Ligand 347 was examined under the following reaction conditions (Table 5.5, Entry 15,16): (i) 1

equiv. of cis-[PtCl2(dmso)2] in (MeOH: PhH 4:1), RT, 15h; (ii) K[(H2C=CH2)PtCl3] (2.equiv.),

NaOAc (4.equiv.), (MeOH: PhMe 4:1), RT, 48h. A complex mixture was formed with (i), while in

case of (ii) decomposition was found. Table 5.5. Investigation of the cycloplatination of different ligands.

# Ligand Conditions Comment

1 11 PtCl2(DMSO)2 (1.equiv.), NaOAc (2.equiv.), (MeOH: PhH 4:1) , 70 °C, 2h

Coordination to N and after addition of Ph3P give SM

2 11 K[(H2C=CH2)PtCl3](2.equiv.),NaOAc (4.equiv.), (MeOH: PhH 4:1), RT over night -30 min at 60 °C


3 11 K2PtCl4 (2.equiv.), AcOH, 110 °C, 24h Ring opening of oxazoline

4 149, R = H K2PtCl4 (2.equiv.), AcOH, 110 °C, 12h Ring opening of oxazoline

5 149, R = H K2PtCl4 (2.equiv.), AcONa, (MeOH: PhMe 4:1), 110 °C, 15h

No reaction

6 149,R=Ph2P PtCl2(DMSO)2 (1.equiv.), (MeOH: PhMe 4:1) , 110 °C, 15h

Decomposed

7 149,R=Ph2P K2PtCl4 (2.equiv.), AcONa, (MeOH: PhMe 4:1), 110 °C, 15h

Just give ligand A

8 149,R=Ph2P K[(H2C=CH2)PtCl3](1.equiv.), NaOAc (2.equiv.), (MeOH: PhMe 4:1), 110 °C, 15h

Decomposed

9 149,R=Ph2P PtCl2(CH3CN)2 (1.equiv.), PhMe, 110 °C, 1h Too complex spectra

10 348 K[(H2C=CH2)PtCl3](1.equiv.), NaOAc (2.equiv.), (MeOH: PhH 4:1), RT, 15h

Decomposed



12 344 K[(H2C=CH2)PtCl3](2.equiv.), NaOAc (4.equiv.), (DCE: t-BuOH 1:1), RT−> 80 °C

N-Me bond was cleaved


SM



15 347, R = H PtCl2(DMSO)2 (1.equiv.), (MeOH: PhMe 4:1) , RT, 15h

Too complex spectra

16 347,R=Ph2P K[(H2C=CH2)PtCl3](2.equiv.), NaOAc (4.equiv.), (MeOH: PhH 4:1), RT, 48h

Decomposed

After screening different conditions for cycloplatination in order to get platinacycles, we have

noticed that some ligands are not stable for C-Pt formation, others give coordination to N, while in

118 Chapter 5

case of Ligand 11, and 149 entry 3, 4, Table 5.5, ring opening of the oxazoline36 was observed as

shown in the (scheme 5.24).

Fe

PhPh

Ph

Ph PhNHFe

PhPh

Ph

Ph Ph

NO

OH3CO2K2PtCl4, AcOH

reflux, 24h

11 343

Scheme 5.24. Ring opening of oxazoline.

5.5 Conclusion. In conclusion, a Pt(II)-catalyzed intramolecular hydroamination of unactivated olefins has been

developed giving pyrrolidine and piperidine derivatives. Enantioselectivity was low as a result of a

competing inner-sphere and outer-sphere mechanism. Further extensions of this chemistry towards

improved selectivity by developing other platinacycles can be envisioned, and are currently

explored in the Peters group.

5.6 References.

1 a) A. Fürstner, P. W. Davies, Angew. Chem. Int. Ed. 2007, 46, 3410; b) A. R. Chianese, S. J.

Lee, M. R. Gagné, Angew. Chem. Int. Ed. 2007, 46, 4042; c) selected very recent asymmetric

application: C. A. Mullen, A. N. Campbell, M. R. Gagné, Angew. Chem. Int. Ed. 2008, 47,

6011.


3 (a) S. Hong, T. J. Marks, Acc. Chem. Res. 2004, 37, 673; (b) D. Riegert, J. Collin, A. Meddour,

E. Schulz, A. Trifonov, J. Org. Chem. 2006, 71, 2514; (c) J. Y. Kim, T. Livinghouse, Org.

Lett. 2005, 7, 4391; (d) J. Y. Kim, T. Livinghouse, Org. Lett. 2005, 7, 1737; (e) D. V. Gribkov,

K. C. Hultzsch, F. Hampel, J. Am. Chem. Soc. 2006, 128, 3748; (f) G. A. Molander, E.

Dowdy, D. J. Org. Chem. 1999, 64, 6515; (g) Y. K. Kim, T. Livinghouse, Y. Horino, J. Am.

Chem. Soc. 2003, 125, 9560.

4 P. H. Martínez, K. C. Hultzsch, F. Hampel, Chem. Commun. 2006, 2221.

5 M. R. Crimmin, I. J. Casely, M. S. Hill, J. Am. Chem. Soc. 2005, 127, 2042.

6 S. Majumder, A. L. Odom, Organometallics 2008, 27, 1174.

7 L. Ackermann, L. T. Kaspar, A. Althammer, Org. Biomol. Chem. 2007, 5, 1975.

8 C. F. Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2005, 127, 1070.


9 (a) C. Liu, X. Han, X. Wang, R. A. Widenhoefer, J. Am. Chem. Soc. 2004, 126, 3700; (b) X.

Wang, R. A. Widenhoefer, Chem. Commun. 2004, 660.

10 X. Wang, R. A. Widenhoefer, Organometallics 2004, 23, 1649.

11 H. Qian, X. Han, R. A. Widenhoefer, J. Am. Chem. Soc. 2004, 126, 9536.

12 For recent examples of Pt-catalyzed olefin coupling see: (a) C. Hahn, M. E. Cucciolito, A.

Vitagliano, J. Am. Chem. Soc. 2002, 124, 9038; (b) W. D. Kerber, J. H. Koh, M. R. Gagné,

Org. Lett. 2004, 6, 3013.

13 C. F. Bender, W. B. Hudson, R. A. Widenhoefer, Organometallics 2008, 27, 2356.

14 S.M. Hande, N. Kawai, J. Uenishi, J. Org. Chem. 2009, 74, 244.

15 (a) Z. Zhang, C. Pan, Z. Wang, Chem. Commun. 2007, 4686; (b) R. M. Trend, Y. K. Ramtohul,

B. M. Stoltz, J. Am. Chem. Soc. 2005, 127, 17778.

16 (a) M. R. Gagné, L. Brard, V. P. Conticello, M. A. Giardello, T. J. Marks, C. L. Stern,

Organometallics 1992, 11, 2003; (b) M. A. Giardello, V. P. Conticello, L. Brard, M. R. Gagné,

T. J. Marks, J. Am. Chem. Soc. 1994, 116, 10241; (c) J.-S. Ryu, T. J. Marks, F. E. McDonald,

J. Org. Chem. 2004, 69, 1038.

17 D. V. Gribkov, K. C. Hultzsch, F. Hampel, J. Am. Chem. Soc. 2006, 128, 3748.

18 L. Xiang, Q. Wang, H. Song, G. Zi, Organometallics 2007, 26, 5323.

19 M. C. Paderes, S. R. Chemler, Org. Lett. 2009, 11, 1915.

20 J. A. Bexrud, J. D. Beard, D. C. Leitch, L. L. Schafer, Org. Lett. 2005, 7, 1959.

21 R.K. Thomson, J. A. Bexrud, L. L. Schafer, Organometallics 2006, 25, 4069.

22 M. C. Wood, D. C. Leitch, C. S. Yeung, J. A. Kozak, L. L. Schafer, Angew. Chem. Int. Ed.

2007, 46, 354.

23 E. B. Bauer, G. T. S. Andavan, T. K. Hollis, R. J. Rubio, J. Cho, G. R. Kuchenbeiser, T. R.

Helgert, C. S. Letko, F. S. Tham, Org. Lett. 2008, 10, 1175.

24 Z. Liu, J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 1570.

25 K. D. Hesp, M. Stradiotto, Org. Lett. 2009, 11, 1449.

26 (a) F. E. Michael, B. M. Cochran, J. Am. Chem. Soc. 2006, 128, 4246; For Au, see: (b) J.

Zhang, C.-G. Yang, C. Chuan, J. Am. Chem. Soc. 2006, 128, 1798.

27 H. Ohmiya, T. Moriya, M. Sawamura, Org. Lett. 2009, 11, 2145.

28 B. L. Madison, S. B. Thyme, S. Keene, B. S. Williams, J. Am. Chem. Soc. 2007, 129, 9538.

29 J. B. Seneclauze, P. Retailleau, R. Ziessel, New J. Chem. 2007, 31, 1412.

30 S. Diring, P. Retailleau, R. Ziessel, J. Org. Chem. 2007, 72, 10181.

31 S. Diring, P. Retailleau, R. Ziessel, Synlett 2007, 3027.

32 L. Schwartsburd, R. Cohen, L. Konstantinovski, D. Milstein, Angew. Chem. Int. Ed. 2008, 47,

3603.

33 G. Jones, C. J. Richards, Tetrahedron: Asymmetry 2004, 15, 653.

120 Chapter 5

34 R. Peters, Z.-q. Xin, D. F. Fischer, W. B. Schweizer, Organometallics, 2006, 25, 2917.

35 R. Peters, D. F. Fischer, Org. Lett. 2005, 7, 4137.

36 J. S. Fossey, C. J. Richards, Organometallics 2004, 23, 367.

37 R. W. Wason, K. McGrouther, P. R. R. Ranatunge-Bandarage, B. H. Robinson, J. Simpson,

Appl. Organomet. Chem. 1999, 13, 163.

Chapter 6

Miscellaneous.

This chapter describes projects which were not completed due to one of these reasons: results were

not useful, they were of moderate attractiveness or were completely different from those originally

targeted.

6.1 Synthesis of a Methoxy-Substituted Pentaphenyl Ferrocen- yl Imidazoline Palladacycle.

6.1.1 Literature Overview.

In 2002, Kang et al. published a study with several ferrocen-1,1’-diyl bispalladacycles 165 as

catalysts for the rearrangement of N-aryl benzimidates 171 (see Chapter 4.1.2.4).1 Complex 165,

bearing an isopropyl ether as third donor tooth is a remarkably active and still selective catalyst for

the rearrangement of benzimidate 171. (5 mol%) of 165 converted 172 in only 30 min at RT in

DCM in 91% yield and with 92% ee.

Fe

O

N

Pd

PdOI

N

O

OI

O

n-Pr

Ph

NPMP

O

n-Pr

Ph

NPMP

(5 mol%) 165,(10 mol%) AgOTFADCM, RT, 30 min

y: 91%, ee: 92%

171 172 165

Scheme 6.1. Tridentate bispalladacycles as catalysts for the aza-Claisen rearrangement.

One reason for the high activity seems to be the ether donor acting as a highly labile ligand for

Pd(II), which readily liberates a free coordination site. This enhances the rate of substrate

coordination.

We were thus interested to see if a similar rate enhancement could be achieved for pentaphenyl

ferrocenyl imidazoline palladacycles FIP-Cl by installation of a hemilabile ether donor.

122 Chapter 6

6.1.2 Results and Discussion.

Enantiopure 1,2-diphenyl ethylenediamines bearing substituents on the phenyl groups have become

commercially available only very recently. A short route to diamine 342 was published only after

most of this work had been done; compound 342 was thus prepared via a rather lengthy synthesis

starting from ortho-anisaldehyde 349 (see Scheme 6.2, a):2 Aluminium in basic methanol leads to

formation of a benzoin derivative which is oxidised by a “Swern” like reaction to the benzil

derivative 350. All further steps are in analogy to the synthesis of unsubstituted diamine 342.

O

OMe

1. Al, KOH, MeOH2. HBr, DMSO, Δ

OOMe

OMeO N

OMeN

MeO

NH4OAc,cyclohexanone,AcOH, Δ

1. Li, liquid NH3, THF−78 °C, then EtOH2. HCl aq.

NH2OMe

H2NMeO tartaric acid,

EtOH

NH2OMe

H2NMeO

a)

b)

NH2OH

H2NHO

O

OMe

DMSO, 70 °C

NOH

NHO

OMeMeON

OHN

HO

OMeMeO

352

349 350

342

349

353 354

351

Scheme 6.2. Synthesis of diamine 342. a) Route used in this project: b) Alternative route. For a) and b), literature yields are given which could not be reproduced in a single run.

The alternative route starts with commercially available (though rather expensive) ortho-OH

diamine 352, which forms a diimine 353 with various substituted benzaldehyde derivatives. This

diimine undergoes in situ a [3,3] sigmatropic rearrangement. The equilibrium lies stongly on the

product side due to more favourable hydrogen bonds (Scheme 6.2, b). The reaction has been found

to proceed with practically full transfer of chirality.

Miscellaneous 123

The compound prepared by the original route a) was found to be rather sensitive and was thus

stored as a frozen solution in benzene. Attempts to acylate the two amino functionalities (for ee-

determination by chiral column HPLC) with Ac2O and triethylamine in DCM at 0 °C failed since

the compound mainly decomposed, probably via an elimination pathway.

Gratifyingly, such an elimination was not observed neither in the formation of ferrocenyl

imidazoline 355 nor in the subsequent tosylation, allowing the preparation of imidazoline ligand

356 in 62% overall yield (Scheme 6.3).

Fe

PhPh

Ph

Ph Ph

NN

MeO-Ph

MeO-Ph

TsFe

PhPh

Ph

Ph Ph

NNH

Fe

PhPh

Ph

Ph PhHBF4

.HN

EtOdiamine 342,DCE, 80 °C, 7 h

OMe

OMe


Na2PdCl4, NaOAc, MeOH, PhH Palladacycle 357a-c356

356yield: 62%over 2 steps

87%

355

Scheme 6.3. Formation of ortho-OMe imidazoline, tosylation and cyclopalladation.

Cyclopalladation took place under the identical conditions as used before, but as in the case of

unsubstituted FIP-Cl, only moderate conversion was obtained by overnight reaction, while

allowing the reaction mixture to stand for several weeks led to nearly complete conversion to 357.

The constitution of palladacycle 357 could be assigned only via X-ray crystal structure analysis. A

standard 1H-NMR had given reason to believe that Pd(II) was not bound to any carbon atom of the

upper Cp-ring (357a); on the other hand, a MALDI-MS measurement as well as NMR-experiments

with the addition of dppe had given unambiguous prove that there was a Pd-C σ-bond present, so

that initially, a structure where Pd was bound to a phenyl group of the pentaphenyl-Cp ligand was

assumed (357a).

124 Chapter 6

Fe

PhPh

Ph

Ph Ph

Pd

2

NNMeO-Ph

Ts

Cl

OMe

Fe

PhPh

Ph

Ph Ph

PdN

NMeO-Ph

Ts

OCl

PhFe

PhPh

PhN

NPh-OMe

OPdCl

Ts

357a 357b 357c

Figure 6.1. Possible structures of palladacycle. Left: Constitution assumed after 1H-NMR analysis. Middle: Originally anticipated and targeted constitution. Right: constitution determined by X-ray crystallography.

The crystal structure analysis could be solved only partially: The CpΦ-part seems to have an

inherent disorder, while the upper Cp-ring, including the palladium–chloride square plane and the

imidazoline, could be solved, showing unambiguously that structure 357c is correct. Contrary to

the expectations, this complex is also found as a chloride bridged dimer and not as a monomer with

OMe acting as a ligand as depicted in 357b (Figure 6.1). Though structure 357c is thus correct, in

solution, there still is probably a certain amount of monomeric structure 357b present, since some

minor signals in 1H-NMR disappear when at least 1 equiv. of a dppe is added.

The position of a monodentate phosphine coordinating to Pd is not as clear as with other

palladycycles described in previous chapters, where usually shortly after mixing only one isomer

was detected with P always found trans to the coordinating N. Even after 2 d in solution, there are

still two signals in 31P-NMR with relative intensities of ca. 6:1 at 17 ppm and −2 ppm respectively,

while the ratio after one hour is ca. 1:2. By correlating chemical shifts, the signal at 17 ppm (minor

signal after 1 h, major after 2 d) is assigned to a phosphine coordinated trans to N.

As a result of the lower preference for one coordination site, lower enantioselectivity is expected

for the aza-Claisen rearrangement which is based upon the premise that the olefin moiety is

coordinating trans to N.

Miscellaneous 125

6.2 Synthesis of a Pentaphenyl Ferrocenyl Oxazoline Pallada-

cycle with a Pd(III) Center.

6.2.1 Literature Overview. Palladium is a common transition metal for catalysis, and the fundamental organometallic

reactivity of palladium in its 0, I, II and IV oxidation states is well established. The potential role of

Pd(III) in catalysis has not been investigated because organometallic reactions that involve Pd(III)

have not been reported previously.

Recently in 2009, Ritter et al.4 have identified a previously unappreciated pathway for carbon–

heteroatom bond formation from Pd(III) and have evaluated its relevance to catalysis. Carbon–

chlorine (Scheme 6.4), carbon–bromine and carbon–oxygen reductive eliminations from discrete

bimetallic Pd(III) complexes were presented. This report discloses the first recognized

organometallic reactions from Pd(III) and implicates bimetallic Pd(III) catalysis as a mechanistic

alternative to monometallic Pd(II)–Pd(IV) redox cycles.

N N

(5.0 mol%) 360NCS, MeCN,100 °C, 50h

N

N

Pd

Pd

OO

OO

Cl

Cl

Cl

360

90% yield

358 361

N

Pd(OAc)2

−AcOHN

Pd

AcO

2

PhICl2CH2Cl2, –30 °C

358 359

Scheme 6.4. Chlorination of 358 with NCS is catalysed by 360. We were interested to see if a similar reaction could be achieved for pentaphenyl ferrocenyl

oxazoline palladacycles PPFOP-X 4, as both Pd(II) centers are already in close contact for a metal-

metal interaction as X-ray crystal structure analysis has revealed (se chapter 4.2.2).

6.2.2 Results and Discussion. Initial attempts investigated the addition of one equivalent of PhICl2 to PPFOP-Cl 4 in CH2Cl2 at

−50 °C resulting in an immediate colour change from red to dark brown. After the reaction mixture

126 Chapter 6

was stirred at −50 °C for 10 min the organic byproduct was removed from the crude reaction

mixture by trituration with diethyl ether. The crude solid was analyzed by 1H-NMR but the targeted

product could not be detected and only decomposition was observed (scheme 6.5).

Fe

PhPh

Ph

Ph Ph

Pd

2

NO

Cl

PhICl2DCM, −50 °C Fe

PhPh

Ph

Ph Ph

Pd

2

NO

ClCl

4 362

Scheme 6.5. Oxidation of PPFOP-Cl with PhICl2. After these first attempts were unsuccessful, palladium acetate dimer 195 was examined utilizing 1

equiv. of PhICl2 in CH2Cl2 at −70 °C. The reaction mixture was stirred at −70 °C for 10 min and

then solvent was removed by flushing N2 at the same temperature. The crude solid was triturated

with diethyl ether and was subsequently checked by 1H-NMR. The spectra were found to be more

promising than in the first attempt. The product could be purified by cholumn chromatography

using DCM:Et2O (2:1) as eluent.

PhICl2, DCM, −70 °C

Fe

PhPh

Ph

Ph Ph

NO

Pd OAc2

Fe

PhPh

Ph

Ph Ph

NO

Pd OAc2Cl

57%PhPh

Ph Ph

195 363

Scheme 6.6. Oxidation of PPFOP-Ac with PhICl2.

The product which might be the Pd(III) species 363 was obtained in 57% yield after purification.

The preliminary 1H-NMR spectra are completely different from starting material as the H3CCO

singlet of the CpΦ signals are shifted. Subsequently, for structure confirmation the mass spectra for

PPFOP-Cl 4, PPFOP-OAc 195, and the new product were obtained. By comparison the three

spectra were completely different from each other but the structure of 363 could not be

unambiguously confirmed so far. A possibility to determine the structure would be X-ray crystal

structure analysis. Several attempts were made to obtain suitable crystal for X-Ray measurements

but were not successful.

Miscellaneous 127

6.3 Intramolecular Hydroalkoxylation of Unactivated Olefins.

6.3.1 Literature Overview. The prevalence of saturated oxygen heterocycles in both naturally occurring and biologically active

molecules5 including the acetogenins and polyether antibiotics has fueled interest in the

development of new and efficient methods for the synthesis of cyclic ethers. Inter- or

intramolecular hydroalkoxylation, the formal addition of alcohols to carbon–carbon multiple bonds,

is a direct and efficient procedure for the synthesis of various ethers and oxygen-containing

heterocycles.6 The nucleophilic addition of alcohols under basic conditions has been studied

widely7 but the use of transition metal catalysts is more favorable for the hydroalkoxylation than

the use of bases, primarily due to their effectiveness and the milder conditions.8 In general, the

intermolecular addition of alcohols is more difficult than the intramolecular process.9 It has been

considered that the use of soft Lewis acidic transition metal catalysts is needed for intramolecular

hydroalkoxylation.

In 2004, Widenhoefer et al.8a have developed a mild and efficient platinum-catalyzed protocol for

the intramolecular hydroalkoxylation of unactivated γ- and δ-hydroxy olefins to form cyclic ether

(scheme 6.7).

OH O

PhPh

Ph

Ph

(1.0 mol%) [PtCl2(H2C=CH2)]2(2.0 mol%) P(4-C6H4CF3)3

Cl2CHCHCl2, 70 °C78%364 365

Scheme 6.7. Intramolecular hydroalkoxylation olefins catalyzed by a mixture of Pt(II) and P(4-CF3-C6H4)3.

We were thus interested to see if a similar reaction could be achieved enantioselectively by using a

soft Lewis acidic chiral platinacycle 12 to produce enantiopure cyclic ethers.


6.3.2.1 Synthesis of Hydroxy Olefins. All hydroxy olefins were prepared in THF in high yields in two steps by reaction of the

corresponding allylic or homoallylic halide 366 with methyl 2,2-diphenylacetate which was

deprotonated with either LDA or LHMDS ( Scheme 6.8). The latter base, available as 1 M solution

in THF, gave identical results as LDA. Its advantage compared to LDA is the generally more

convenient handling of a solution under inert atmosphere. In addition, it reacts almost immediately.

128 Chapter 6

Esters 367 were obtained from the alkylation step and were subsequently reduced by LAH to

generate the hydroxy olefins 368 in almost quantitative yield.

OHPh

PhR

O

OPh

PhR

O

OPh

Ph LHMDS, THF−78 °C −>RT

LAH, Et2O−0 °C −>RT

n nR = Et, Prn = 1, 2X = Br, I

366 367 368

X Rn

Scheme 6.8. General procedure for the preparation of hydroxy olefins.

6.3.2.2 Optimization of the Reaction Conditions for Intramolecular Hydro-

alkoxylation of Unactivated Olefins. Chiral platinacycle 12, which is readily prepared by diastereoselective cycloplatination of ferrocene

bisimidazoline 185, was studied as catalyst for the intramolecular hydroalkoxylation of unactivated

olefins. The influence of the solvent (e.g., dichloroethane, tetrachloroethane, chloroform, dioxane,

acetone, trifluorobenzene, methanol, and trifluoroethanol), and of the silver salt (e.g., AgOTs,

AgOTf, AgBF4, AgTFA, AgPF6, AgClO4, AgOOCC3F7) on the cyclization of one model substarte

364 was first examined in the presence of 12 (3 mol%, Table 6.1). Whereas unsaturated alcohol

364 led to tetrahydropyran 365 in all solvents tested, no reaction occurred in entry 8 in

tetrachloroethane where the reaction was done at RT. The yield reached up to 95% providing only

poor enantioselectivity (19%, ee entry 10). The 369 was formed in the reaction mixture as

byproduct.

Miscellaneous 129

Table 6.1. Optimization of the reaction conditions for the intramolecular hydroalkoxylation of γ,δ-

unsaturated alcohols catalyzed by Pt(II)-12:

OH O

PhPh

Ph

Ph

(3 mol%) Pt(II)-12Ag-salt, Solvent, T, t

OHPh

Ph

+

Fe

N

Pt

N

PhPh

Cl

Ts

NN

Ph

PhTs12

X364 365 369

# [Ag-salt] Solvent T[°C]/t[h] Yield [%]a

of 365

ee/[%]b

1 10mol%AgOTs DCE 70/48 20 -

2 6mol% AgOTf Cl2CHCHCl2 70/48 34 -

3 6mol% AgBH4 Cl2CHCHCl2 70/48 15 -

4 6mol% AgTFA Cl2CHCHCl2 70/48 58 10

5 6mol%AgOOCC3F7 Cl2CHCHCl2 70/96 92 11

6 6mol%AgOOCC3F7 Cl2CHCHCl2 70/60 65 12

7 6mol%AgOOCC3F7 Cl2CHCHCl2 50/60 17 -

8 6mol%AgOOCC3F7 Cl2CHCHCl2 RT/96 0 -

9 6mol%AgOOCC3F7 Dioxane 70/96 33 -

10 6mol%AgOOCC3F7 CF3Ph 70/96 80 19

11 6mol%AgOOCC3F7 Acetone 70/96 95 4

12 6mol% AgPF6 MeOH 70/96 39 -

13 6mol% AgClO4 MeOH 70/96 55 -

14 - MeOH 70/96 39 - a determined by 1H-NMR by comparing the integrals of product, and SM, followed by

multiplication with the mass balance. b determined by HPLC.

The highest reactivity was obtained in acetone, tetrachloroethane and trifluorobenzene. Catalyst

activation by a silver salt slightly increased the activity but had nearly no impact on the

enantioselectivity. The highest reactivity was obtained by activating 12 in situ with AgO2CC3F7

delivering at 70 °C and after 96 h the targeted product in 95% yield yet with only 4% ee (entry 11).

130 Chapter 6

The cyclization of unsaturated alcohols possessing an internal disubstituted olefin moiety with

either Z or E configuration was examined by using a catalytic amount of 12 (5.0 mol%) activated

by AgOOCC3F7 (Table 6.2). Formation of either five or six membered cyclic ethers was not

observed.

Table. 6.2. Attempts toward the intramolecular hydroalkoxylation of disubstituted olefins

catalyzed by 12.

OH O

PhPh

Ph

Ph

(5 mol%) Pt (II)-12(5 mol%) AgO2CC3F7Solvent, T, t

Fe

N

Pt

N

PhPh

Cl

Ts

NN

Ph

PhTs12368 370

R

Rn

n

# R E/Z n Solvent T[°C]/t[h] Yield[%] ee/[%]

1 n-Pr Z 1 DCE 70/50 -

2 n-Pr Z 1 2-Butanone 90/70 -

3 n-Pr Z 1 CF3Ph 90/70 -

4 n-Pr Z 1 1,3,5-trifluorobenzene 90/70 -

5 n-Pr Z 1 Cl2CHCHCl2 90/70 -

6 n-Pr Z 1 Neat 90/70 -

7 n-Pr E 1 DCE 70/50 -

8 Et Z 2 DCE 70/50 -

9 Me Z 1 Cl2CHCHCl2 70/48 -

No catalytic activity was also observed at elevated temperature nor by addition of a base (e.g.,

NaH) to increase nucleophilicity of the hydroxyl group.

Miscellaneous 131

6.4 Cyclization of Alkenyl β–diketone esters by Hydro-

alkylation.

6.4.1 Literature Overview. Six- to eight-membered-ring carbocycles are common structural units of biologically important

natural products.10 Although many methods have been developed for the synthesis of these

carbocyclic compounds,11 transition metal catalyzed cyclization is considered to be one of the most

effective strategies.12 Recently, Widenhoefer and co-workers reported that alkenyl 1,3-diketones

were cyclized to form six-membered ring compounds in the presence of a catalytic amount of

PdCl2(MeCN)2.13 For unsaturated β-keto esters, the palladium(II)-catalyzed cyclization was

efficient in the presence of Me3SiCl (2 equiv.) or Me3SiCl (2 equiv)/CuCl2 (1 equiv.).14 According

to the proposed mechanism for the cyclization reaction,13,14 the key is to increase the enol

population. Me3SiCl (2 equiv.) was believed to form the alkenyl silyl enol ether in situ, thereby

increasing the reaction rate and yields (scheme 6.9).

O

R2

OR1

O PdCl2(CH3CN)2Me3SiCl, CuCl2Dioxane, 55 °C

O

R2

OR1

O

371 372 Scheme 6.9 Palladium catalyzed cyclization of alkenyl β-keto esters.

We were thus interested to see if a similar reaction could be achieved by using the chiral

platinacycle 12 to produce enantiopure carbocycles.


6.4.2.1 Synthesis of Alkenyl β-Keto Esters. The synthesis of alkenyl β-keto esters which is literature known21 could not be reproduced in a

single run. They were prepared in THF in moderate yields in one step by reaction of the

corresponding allylic or homoallylic halide 366 with acetoacetate 373 which was double

deprotonated with either LDA or NaH/n-BuLi (Scheme 6.10.).

132 Chapter 6

O

OR

O

Et

O

OR

O LDA, DMPU,THF, 0 °C

EtI

O

OR

O

Et

NaH, BuLi,THF, 0 °C

Et

Br

374a R = Et, 57% yield. 374b R = Me, 53% yield

R = Me, Et373

Scheme 6.10. Synthesis of alkenyl β-keto esters.

6.4.2.2 Optimization of Reaction Conditions for Cyclization of Alkenyl β-Keto Esters.

Cyclization of alkenyl β-keto esters was examined by using a catalytic amount of Pt(II) precatalyst

12 (5 mol%) and (5 mol%)AgOOCC3F7. According to the proposed mechanism for the cyclization

reaction, the key is to increase the enol population or alternatively, the formation of an enamine

intermediate. Consequently, catalytic additives were also added (e.g., acids, bases, or nucleophilic

amines). The results are summarized in (Table 6.3). The reactions were carried out in different type

of solvents (e.g., trifluoroethanol, dioxane, benzene).

Miscellaneous 133

Table 6.3. Optimization of the reaction conditions for the cyclization of alkenyl β-keto esters

catalyzed by Pt(II)-12.

(5 mol%) Pt (II)- 12(5 mol%)AgOOCC3F7Y (1 equiv.)Solvent, T, t

O

OR

O

Et

O

OR

O

Et

OH

OR

O

Etn nn 374 375 376

# R Y n Solvent T[°C]/t[h] Yield[%]a

375

dr/[%]c ee/[%]d

1 Et - 0 Ph-H 70/40 - - -

2 Et BnNH2 0 Ph-H 70/40 - - -

3 Et Pyrrolidine 0 Ph-H 70/40 - - -

4 Et AcOH 0 Ph-H 70/40 - - -

5 Et Sc(OTf)3 0 CH3CH2OH 60/48 99 4:1 N.D

6b Et Sc(OTf)3 0 CH3CH2OH 60/48 99 4:1 N.D

7 Et Sm(OTf)3 0 CH3CH2OH 60/48 - - -

8 Et Di-tert-

butylpyridine

0 CH3CH2OH 60/48 - - -

9 Et K2CO3 0 CH3CH2OH 60/48 - - -

10 Et EuCl3/HCl 0 Dioxane 90/24 99 4:1 N.D

11 Et ScCl3/HCl 0 Dioxane 90/24 99 4:1 N.D

12 Et Me3SiCl 0 Ph-H 90/48 - - -

13 Me Sc(OTf)3 1 Dioxane 60/24 - - -

14 Me Sc(OTf)3 1 CH3CH2OH 60/24 99 4:1 N.D

15b Me Sc(OTf)3 1 CH3CH2OH 60/24 99 4:1 N.D

16 Me Yb(OTf)3 1 Dioxane 60/48 - - -

17 Me Mg(OTf)3 1 CH3CH2OH 60/48 - - -

18 Me Zn(OTf)3 1 CH3CH2OH 60/48 - - -

19 Me Cu(OTf)3 1 CH3CH2OH 60/48 - - -

20 Me Er(OTf)3 1 CH3CH2OH 60/48 - - - a determined by 1H-NMR by comparing the integrals of product, and SM, followed by

multiplication with the mass balance. b without Pt(II)- 12 per catalyst loading. c determined by 1H-NMR. d yet not determined.

134 Chapter 6

As shown in (Table 6.3), cyclization of alkenyl β-keto esters provided five or six membered rings.

Bases and acids failed to promote the cyclization, whereas certain hard Lewis acids (e.g., Sc and

Eu) gave quantitatively the carbocycles. Background reactions were tested using identical

conditions in the absence of the platinacycle also giving the targeted product (entry 6, 15). 1H-

NMR shows that the product appears in keto-enol form as shown in the above scheme with 4:1.

At the end Pt(II) thus seems to display no catalytic activity on the reaction outcome. In addition,

these results could open a possibility for enantioselective cyclization using lanthanide with chiral

ligands.

Miscellaneous 135

6.5 Synthesis of 4,5-Didehydroionone Stereoisomers.

6.5.1 Literature Overview. Ionones and damascones (Figure 6.1) are recognized among the most highly valued fragrance

constituents as a result of their distinctive fine violet and rose scents.15 Besides their use in the

perfumery industry, ionones and damascones are also appreciated synthetic building blocks.16 Both

of these C13 norterpenoids exist in nature as three distinct regioisomers, which differ in the

position of the double bond, and are called the α-, β-, and γ-isomers. Olfactory evaluation shows

that the regioisomeric purity and the absolute stereochemistry of these isomers dramatically

determine the fragrance properties, sometimes with amazingly pronounced differences between the

notes and the odor thresholds even of the two enantiomers. Furthermore, the endocyclic double

bond confers particularly characteristic nuances to the fragrance that can favorably complement the

use of other widely used compounds from the same family.

O O

O

Ionones Damascones

O

4,5-Didehydro- 3,4-Didehydro-ionones ionones

Fig 6.1

In 2004, G. Vidari et al.,17 were descirbed an efficient highly enantioselective (ee ≥ 99%) synthesis

of α-ionone and α-damascone (scheme 6.11). Both enantiomers of title compounds were

synthesized through two straightforward pathways diverging from enantiopure (R)- or (S)-α-

cyclogeraniol. These versatile building blocks were obtained by regioselective ZrCl4-promoted

biomimetic cyclization of (6S)- or (6R)-(Z)-6,7-epoxygeraniol, respectively, followed by

deoxygenation of the so formed secondary alcohol. The chiral information was encoded by a highly

regioselecive Sharpless asymmetric dihydroxylation of inexpensive geranyl acetate.

136 Chapter 6

OAc

i. Admixβii. Biomimeticcyclization OH

HOOH

O

O

α-ionone

α-damascone

377 378

Scheme 6.11. Enenatioselective synthesis of α-ionones and α-damascones.

Highly enantioselective enzyme-based synthesis of useful precursors of damascones and ionones

have been published recently. They are exemplified by the preparation of (S)-α-damascone (ee ca.

100%) by Mori,17 as well as of (R) -α-ionone (85% ee) by Pfander18 and of (R) -α-ionone (98% ee)

and (S)-α-ionone (97% ee) by Fuganti et al.19

Recently In 2006, Fuganti et al.20 were described new stereospecific approach to the isomeric

forms of 3,4 didehydroionone isomers. The 3,4-didehydroionone isomers were prepared starting

from commercially available a-ionone in a few regioselective steps. Enantiomer-enriched

compounds were prepared by means of diastereoselective and enantioselective lipase-mediated

acetylation of the racemic intermediate hydroxyionone followed by a number of chemoselective

and regioselective reactions (Scheme 6.12).

O

O

O

O

Stereospecificapproach

O

O

3,4-Diheydro- 3,4-Diheydro-γ -ionone isomers β -ionone

Scheme 6.12. Chemoselective and regioselective synthesis of 3,4-didehydroionone isomers.

We were thus interested to see if a possibility to synthesize of 4,5-didehydroionone isomers and see

if the double bond in the position of 4,5 has impact factor on the fragrances properties.

Miscellaneous 137


6.5.2.1 Synthesis of 4,5-Didehydro-α-Ionone 379. While aldol condensation of readily aldehyde with acetone in the presence of base and Wittig

reaction with phosphonate were not successful to reach the target compound because isomeric

products that are inseparable by the usual methodologies. It was found that the readily alcohol 380

is good starting material for the synthesis. Tosylation of the free OH-group, followed by addition of

phenyl thiol whereas deprotonated by NaH afforded the sulphide 381 in 95% yield. Oxidation of

the later compound with a mixture of (NH4)6.Mo7O24 and H2O2 gives the sulphone 382 in moderate

yield where the disulfide was occurred as byproduct. Deprotonation of sulphone 382 using n-BuLi

at −78 °C and epoxide in DMP were added then BF3.OEt2 added to the reaction mixture. The

reaction mixuter stirred for further 5h at −78 °C and leave overnight to warm at RT to give 383 in

38% yield that was oxidized by Dess Martin to give the corresponding ketone in quantitative yield.

Removal of PhSO2 group by DBU regenerates the target compound 379 in good yield (scheme

6.13).

OH

OH

i. TsCl, DCMii. PhSH, NaH,DMF, 50 °C

95%

SPh (NH4)6.Mo7O24,H2O2, MeOH, RT

40%

SO2Ph

i. nBuLi, THF, −78 °C

iii. BF3.OEt2

Oii. ,DMP

SO2Ph

i. Dess Marten, DCMii. DBU, DCM, RT

O

380 381 382

379 383 Scheme 6.13. Synthesis of 4,5-didehydro-α-ionone 379.

6.5.2.2 Synthesis of 4,5-Didehydro β and γ-Ionone 384 and 385. Several attempts were done to prepare 4,5-didehydro-β and γ-ionone but were not successful due to

isomeric products that are inseparable by the usual methodologies. The most routes were promising

but it comes at certen point and stops. For istance, synthesis of 4,5-didehydro-β-ionone starts form

3-oxo-β-ionone readily available by synthetic way. The later compound was reduced specifically

by NaBH4 and subsequently protected by Ac group using Ac2O/Py. Unsaturated double bond at the

position 4,5 388 was done by DDQ in refluxing benzene for 10h. Thioketal 389 formation and

reductive elimination by rany nickel was failed, also stereo specific reduction and then reductive

138 Chapter 6

elimination using Pd couldnot help (Scheme 6.14a). Pathway b which starts from readily alcohols

380 where oxidized using Dess Marten regenerates aldehyde where the double bond at 2,3 can

isomerized easly by DBU into 1,2 position. The later aldehyde reacts with bromoacetate ester in the

presence of Zn in THF to regenerate mixture of α and β isomers where not separated (Scheme

6.14b).

OH

O

O

i. NaBH4, MeOH,0 °C −>10 °C, 10 minii. Ac2O/Py, RT, 1.5h

OAc

O

OAc

O

DDQ, Benzene,reflux, 10h

SH

SHBF3.(Et2O)2,CHCl3, 0 °C

OAc

S S

Raney Nickel,EtOH, RT

OAcO

Oi. Dess Martin, DCMii. DBU, DCM

OEt

OOH

OEtBr

O

Zn, THF, 1h

a)

b)

386 387 388

389384 391

380 391 384/385

Scheme 6.14. Different approaches for synthesis of 4,5-didehydero- β-ionone.

In case of 4,5-didehydero- γ-ionone 393 it starts the synthesis from 5-hydroxy- γ-ionone 392.

Different condition was examined for dehydration such as protection of OH group by (e.g., Ms, Ts,

Ac) and base catalyzed reductive elimination (e.g., t-BuOK, DBU). Wolf kischner also was tested

but no one of these conditions afford the product (scheme 6.15).

OHO

O

392 393 Scheme 6.15. Approache for the synthesis of 4,5-didehydero- γ-ionone.

Miscellaneous 139

6.6 Conclusion. In a summary, these projects were carried out by the author either in the Fuganti or Peters research

laboratory. Further extensions of this chemistry are still in the progress.

6.7 References.

1 J. Kang, K. H. Yew, T. H. Kim, D. H. Choi, Tetrahedron Lett. 2002, 43, 9509.

2 Y. Liu, C. A. Sandoval, Y. Yamaguchi, X. Zhang, Z. Wang, K. Kato, K. Ding, J. Am.

Chem. Soc. 2006, 128, 14213.

3 a) H. Kim, Y. Nguyen, C. P.-H. Yen, L. Chagal, A. J. Lough, B. M. Kim, J. Chin, J. Am.

Chem. Soc. 2008, 130, 12184. In an older report, the high diastereoselectivity of this

reaction has been described already: b) F. Vögtle, E. Goldschmitt, Chem. Ber. 1976, 109,

1.

4 D. C. Powers, T. Ritter, Nature Chem. 2009, 1, 302.

5 (a) M. C. Elliot, J. Chem. Soc., Perkins Trans 1 2000, 1291; (b) M. C. Elliot, E. Williams,

J. Chem. Soc., Perkins Trans 1 2001, 2303; (c) F. Q. Alali, X. X. Liu, J. L. McLaughlin, J.

Nat. Prod. 1999, 62, 504.

6 For recent reviews of catalytic hydroalkoxylation, see: (a) K. Tani, Y. Kataoka, In

Catalytic Heterofunctionalization; A. Togni, H. Grützmacher, Eds.; Wiley-VCH:

Weinheim, 2001; pp 171–216; (b) F. Alonso, I. P. Beletskaya, M. Yus, Chem. Rev. 2004,

104, 3079.

7 D. Tzalis, C. Koradin, P. Knochel, Tetrahedron Lett. 1999, 40, 6193.

8 For recent examples of Lewis acidic transition metal catalyzed hydroalkoxylation, see: (a)

H. Qian, X. Han, R. A. Widenhoefer, J. Am. Chem. Soc. 2004, 126, 9536; (b) N. T. Patil,

N. K. Pahadi, Y. Yamamoto, Can. J. Chem. 2005, 83, 569; (c) Y. Oe, T. Ohta, Y. Ito,

Synlett 2005, 179; (d) Y. Matsukawa, J. Mizukado, H. Quan, M. Tamura, A. Sekiya,

Angew. Chem. Int. Ed. 2005, 44, 1128; (e) L. Coulombel, I. Favier, E. Duñach, Chem.

Commun. 2005, 2286; (f) T. Hirabayashi, Y. Okimoto, A. Saito, M. Morita, S. Sakaguchi,

Y. Ishii, Tetrahedron 2006, 62, 2231; (g) K. M. Gligorich, M. J. Schultz, M. S. Sigman, J.

Am. Chem. Soc. 2006, 128, 2794; (h) L. Coulombel, M. Rajzmann, J.-M. Pons, S. Olivero,

E. Duñach, Chem. Eur. J. 2006, 12, 6356; (i) X. Yu, S. Y. Seo, T. J. Marks, J. Am. Chem.

Soc. 2007, 129, 7244; (j) P. Lemechko, F. Grau, S. Antoniotti, E. Duñach, Tetrahedron

Lett. 2007, 48, 5731.

9 For recent examples of gold-catalyzed intramolecular hydroalkoxylation, see: (a) A.

Hoffmann-Röder, N. Krause, Org. Lett. 2001, 3, 2537; (b) Y. Liu, F. Song, Z. Song, M.

Liu, B. Yan, Org. Lett. 2005, 7, 5409; (c) A. S. K. Hashmi, M. C. Blanco, D. Fischer, J. W.

140 Chapter 6

Bats, Eur. J. Org. Chem. 2006, 1387; (d) V. Belting, N. Krause, Org. Lett. 2006, 8, 4489;

(e) B.; Liu, J. K. De Brabander, Org. Lett. 2006, 8, 4907; (f) Z. Zhang, C. Liu, R. E.

Kinder, X. Han, H. Qian, R. A. Widenhoefer, J. Am. Chem. Soc. 2006, 128, 9066; (g) Z.

Zhang, R. A. Widenhoefer, Angew. Chem. Int. Ed. 2007, 46, 283; (h) B. Alcaide, P.

Almendros, T. M. del Campo, Angew. Chem. Int. Ed. 2007, 46, 6684; (i) C. Deutsch, B.

Gockel, A. Hoffmann-Röder, N. Krause, Synlett 2007, 1790; (j) F. Volz, N. Krause, Org.

Biomol. Chem. 2007, 5, 1519; (k) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste,

Science 2007, 317, 496; (l) J. Erdsack, N. Krause, Synthesis 2007, 3741.

10 (a) C. H. Heathcock, S. L. Graham, M. C. Pirrung, W. Plavac, C. T. White, In The Total

Synthesis of Natural Products; Apsimon, J. W., Ed.; Wiley: New York, 1983; Vol. 5, p

333; (b) J. H. Rigby, In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;

Elsevier Science Publishers B. V.: Amsterdam, 1988; Vol. 12, p 233; (c) B. M. Fraga, Nat.

Prod. Rep. 1996, 13, 307; (d) G. Dyker, Angew. Chem. Int. Ed. Engl. 1995, 34, 2223.

11 (a) Comprehensive Organic Synthesis; B. M. Trost, I. Fleming, M. F. Semmelhack, Eds.;

Pergamon: Oxford, 1991; Vol. 5; (b) W. Carruthers, Cycloaddition Reactions in Organic

Synthesis; Pergamon: Oxford, 1990; (c) M. Hesse, Ring Enlargement in Organic

Chemistry; VCH: Weinheim, 1991; (d) P. Renaud, M. P. Sibi, Eds. Radicals in Organic

Synthesis; Wiley-VCH: Weinheim, 2001.

12 (a) E. Negishi, C. Cope´ret, S. Ma, S.-Y. Liou, F. Liu, Chem. Rev. 1996, 96, 365; (b) I.

Ojima, M. Tzamarioudaki, Z. Li, R. J. Donovan, Chem. Rev. 1996, 96, 635; (c) R. W.

Bates, V. Satcharoen, Chem. Soc. Rev. 2002, 35, 12.

13 T. Pei, R. A. Widenhoefer, J. Am. Chem. Soc. 2001, 123, 11290; (b) T. Pei, X. Wang, R. A.

Widenhoefer, J. Am. Chem. Soc. 2003, 125, 648; (c) H. Qian, R. A. Widenhoefer, J. Am.

Chem. Soc. 2003, 125, 2056.

14 T. Pei, R. A. Widenhoefer, Chem. Commun. 2002, 650.

15 (a) G. Ohloff, Scent and Fragrances: The Fascination of Fragrances and their Chemical

Perspectives; Springer-Verlag: Berlin, 1994; (b) D. H. Pybus, C. S. Sell, The Chemistry of

Fragrances; The Royal Society of Chemistry: London, 1999.

16 (a) G. Fra´ter, J. A. Bajgrowicz, P. Kraft, Tetrahedron 1998, 54, 7633; (b) R. Buchecker,

R. Egli, H. Regel-Wild, C. Tscharner, C. H. Eugster, G. Uhde, G. Ohloff, Helv. Chim. Acta

1973, 56, 2548; (c) P. G. Baraldi, A. Barco, S. Benetti, G. P. Pollini, E. Polo, D. Simoni, J.

Chem. Soc., Chem. Commun. 1986, 757; (d) P. Übelhart, A. Baumeler, A. Haag, R. Prewo,

J. H. Bieri, C. H. Eugster, Helv. Chim. Acta 1986, 69, 816; (e) M. I. Colombo, J. Zinczuk,

E. A. Ruveda, Tetrahedron 1992, 48, 963.

17 (a) H. Mayer, A. Ruttimann, Helv. Chim. Acta 1980, 63, 1451; (b) K. Mori, M. Amalke, M.

Itou, Tetrahedron 1993, 49, 1871.

Miscellaneous 141

18 H. Pfander, P. A. Semadeni, Aust. J. Chem. 1995, 48, 145.

19 (a) E. Brenna, C. Fuganti, P. Grasselli, M. Redaelli, S. Serra, J. Chem. Soc., Perkin Trans.

1 1998, 4129; (b) J. Aleu, E. Brenna, C. Fuganti, S. Serra, J. Chem. Soc., Perkin Trans. 1

1999, 271.

20 S. Serra, C. Fuganti, E. Brenna, Helv. Chim. Acta 2006, 89, 1110.

21 (a) Q. Zhang, R.M. Mohan, L. Cook, S. Kazanis, D. Peisach, B. M. Foxman, B. B. Snider,

J. Org. Chem. 1993, 58, 7640; (b) Y. Morizawa, T. Hiyama, K. Oshima, H. Nozaki, Bull.

Chem. Soc. Jpn, 1984, 57, 1123.

Chapter 7

Experimental.

General.

MP.

Melting points were measured using a Büchi 535 melting point apparatus or a Reichert apparatus,

equipped with a Reichert microscope, in open glass capillaries and are uncorrected.

Optical Rotation.

Optical rotations were measured on a Jasco-DIP-181 digital polarimeter or a Jasco DIP-100

digital Polarimeter or a Perkin Elmer 241 Polarimeter operating at the sodium D line with a 100

mm path length cell.

NMR.

NMR-spectra were recorded on a Varian Gemini 300 and a Varian Mercury 300 spectrometer

operating at 300 MHz (1H), 75 MHz (13C) and 282 MHz (19F), a Bruker AC-400 spectrometer

operating at 400 MHz (1H) and 100 MHz (13C), a Bruker AV-400 operating at 400 MHz (1H) and a

Bruker AV-600 operating at 600 MHz (1H). Chemical shifts are referred in terms of ppm with

tetramethylsilane or the solvent residue peak as internal standard. Coupling constants (J) are given

in Hz. Abbreviations for multiplicities are as follows: s (singulet), d (doublet), t (triplet), q

(quartet), quin (quintet), m (multiplet), b (broad signal). 13C NMR spectra are proton broad band

decoupled. 2-D spectra were measured by the NMR service at the Politecneco di Milano/ETH

Zürich/Universität Stuttgart. Deuterated solvents were used as obtained from the commercial

suppliers.

IR.

IR-spectra were recorded on a Perkin–Elmer 2000 FT-IR spectrometer or a Perkin Elmer Spectrum

RX I FT-IR and the signals are given in wave numbers (cm−1). Samples were prepared by thin film

technique.

144 Chapter 7

MS.

Mass spectra (MS) were obtained from the Politecnico di Milano MS Service, ETH Zürich MS

Service and the MS service of the Universität Stuttgart. GC–MS analyses: HP-6890 gas

chromatograph equipped with a 5973 mass detector, using a HP- 5MS column (30 m × 0.25 mm,

0.25 µm film thickness; Hewlett Packard) with the following temperature program 60 °C (1 min)–6

°C/min–150 °C (1 min)–12 °C/min–280 °C (5 min); carrier gas, He; constant flow 1 mL/min. High

resolution (HI-RES) MALDI spectra were recorded using an Ion Spec 4.7T Ultima HiRres FT-ICR

MS MALDI-FT-ICR MS employing 3HPA (3-hydroxy-picolinic acid) and two layer technique in

positive or negative mode. HI-RES EI mass spectra were performed on a Micromass AutoSpec

Ultima and were calibrated with perfluorotributylamine (PFTBA) and Ultramark 1621 as internal

standard. High resolution ESI was performed on an IonSpec HiRes FT-ICR MS at 4.7 Tesla

employing a waters 2spray source or a Bruker MikroTOFQ at the Universität Stuttgart.

Combustion Analysis.

Combustion analysis was performed by the Politecnico di Milano on an analyzer 1106 from Carlo

Erba, Mikroelementaranalytisches Laboratorium at the ETH Zürich and the

Elementaranalyseabteilung of the Institute for Organic Chemistry at the Universität Stuttgart.

Techniques.

Unless otherwise indicated, all reactions were carried out in oven dried glassware under a positive

pressure of nitrogen. Unless otherwise indicated, all liquids were added via syringe. Reactions were

magnetically stirred and monitored by high performance liquid chromatography (HPLC, reversed

phase column, H2O/MeCN gradient) or GC–MS or by thin layer chromatography (TLC) using

silica gel plates from Merck (silica gel 60 F254). Visualisation occurred by fluorescence quenching

under UV light and by staining with KMnO4 / NaOH. Purification by flash chromatography was

performed on silica gel 60Å, 32-62, provided by Fluka, using a forced flow of eluent at 0.2-0.4 bar

pressure. For work-up procedures and flash chromatography, distilled technical grade solvents

were used. Solvents were removed using a heating bath temperature of 40 °C under reduced

pressure. Non-volatile compounds were dried at about 0.1 mbar. Yields refer to purified

compounds, unless stated otherwise, and are calculated in mol% of the starting material.

Solvents and Reagents.

Dichloromethane, toluene, diethyl ether and THF were purified by distillation and dried over

activated alumina under an atmosphere of nitrogen. Chloroform (Aldrich, >99%, <0.005% H2O), n-

hexane (Fluka, UV quality), methanol (Fluka, HPLC grade), pentane (J.T. Baker, UV quality), and

triethylamine (Fluka, >99.5%) were used as purchased. Cyclohexane (Thommen & Furler, purum)

Experimental 145

and ethyl acetate (Thommen & Furler, purum) were destilled prior to use. Lipase from Porcine

pancreas (PPL) type II, Sigma, 147 units/mg; lipase from Candida rugosa (CRL) type VII, Sigma,

1150 units/mg and Lipase from Pseudomonas cepacia (PS), Amano Pharmaceuticals Co., Japan, 30

units/mg. Silver nitrate (ABCR, >99.99%) was ground to powder and stored in a glovebox.

Pd(OAc)2 (Fluka, purum, 47% Pd) was used without further purification. Triethyloxonium

tetrafluoroborate (Meerwein`s salt) was purified by washing with diethylether (3x). 2,2,2-Trifluoro-

N-(4-methoxyphenyl)acetimidoyl chloride 235 was prepared from p-methoxyaniline and

trifluoroacetic acid following a literature procedure.1 The known trifluoroacetimidates were

prepared according to literature procedures.2 All other laboratory chemicals were purchased from

ABCR, Aldrich, Fluka, Merck, TCI or J.T. Baker and were used without purification.

7.1 Synthesis of the Enantiomeric forms of Dehydrovomifoliol and 8,9-Dehydrotheaspirone.

Synthesis of racemic (3RS,6SR)-3,6-dihydroxy-γ-ionone and of (3SR,6SR)-

3,6-dihydroxy-γ-ionone.

(3RS,6SR)-3,6-Dihydroxy-γ-ionone (±)-93.

Oi. Rose Bengal, O2, MeOHii. Thiourea, MeOH, rt

56% (two steps)

OHO

HO91 93

A solutionof 3,4-dehydro-β-ionone 91 (25 g, 132 mmol) and Rose Bengal (0.3 g, 0.3 mmol) in

methanol (600 mL) was irradiated with 12 8-W visible light lamps with continuous purging of dry

oxygen until starting compound 91 was less than 5% of the mixture (2 days, GC analysis). The

reaction was then flushed with nitrogen and a sample of the solution (10 mL) was concentrated in

vacuo and purified by CC (hexane/Et2O from 95:5 to 7:3) to allow the isolation of the stable

peroxy-derivative 92.

O

OO 92

C13H20O3, MW: 224.14 g/mol. 1H NMR (400 MHz, CDCl3, 21 °C): δ = 6.97 (d, J = 16.1 Hz,

1H), 6.42 (d, J = 16.1 Hz, 1H), 6.32 (dq, J = 6.2, 1.7 Hz, 1H), 4.61 – 4.55 (m, 1H), 2.27 (s, 3H),

2.01 (dd, J = 13.0, 3.8 Hz, 1H), 1.87 (d, J = 1.7 Hz, 3H), 1.36 (dd, J = 13.0, 2.0 Hz, 1H), 1.13 (s,

146 Chapter 7

3H), 0.98 (s, 3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ = 196.6, 142.3, 138.8, 130.6, 124.7,

84.2, 72.4, 40.1, 35.1, 28.9, 27.9, 25.0, 19.4. IR (film, cm–1): ν = 1701, 1679, 1629, 1441, 1363,

1256, 986. GC–MS m/z (rel intensity): 222 (M+, 10), 179 (54), 166 (9), 151 (4), 137 (11), 125

(50), 107 (22), 95 (100), 83 (24), 67 (15), 55 (20).

The remaining solution was treated with thiourea (12 g, 158 mmol) stirring at room temperature

for 12 h and then concentrated at reduced pressure. The residue obtained was chromatographed

(hexane/Et2O from 9:1 to 1:1) to afford starting 91 (1.1 g, 5.7 mmol) and cis-3,6-dihydroxy-γ-

ionone 93 (15.3 g, 68.3 mmol, 56% yield based on reacted 91, as a colorless oil that crystallized on

standing.

C13H20O3, MW: 224.14 g/mol. Mp: 71 – 73 °C. GC: 96% (chemical purity). 1H NMR (400 MHz,

CDCl3, 21 °C): δ = 6.74 (d, J = 16.4 Hz, 1H), 6.47 (d, J = 16.4 Hz, 1H), 5.65 (s, 1H), 4.26 (br s,

1H), 2.63 (br s, 1H), 2.55 (s, 1H), 2.28 (s, 3H), 1.79 (dd, J = 13.4, 6.0 Hz, 1H), 1.71 (dd, J = 13.4,

8.0 Hz, 1H), 1.65 (s, 3H), 0.98 (s, 3H), 0.96 (s, 3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ =

198.2, 148.0, 136.8, 130.3, 128.3, 77.2, 64.9, 41.9, 38.4, 27.9, 24.4, 24.2, 19.1. IR (film, cm–1): ν =

3364, 3317, 1683, 1459, 1250, 1022, 988. GC–MS m/z (rel intensity): 191 (<1), 164 (1), 155 (5),

137 (1), 121 (1), 111 (1), 105 (43), 104 (100), 91 (6), 85 (2), 79 (5), 77 (5), 71 (4). Anal.Calcd for

C13H20O3: C, 69.61; H, 8.99. Found: C, 69.75; H, 9.00.

(3SR,6SR)-3,6-Dihydroxy-α-ionone (±)-95.

Oi. MCPBA, Et2O, 0 °Cii. NaHCO3, H2O, rt

59% (two steps)

OHO

HO91 95

A solution of 3,4-dehydro-β-ionone 91 (30 g, 158 mmol) in diethyl ether (250 mL) was treated with

MCPBA (29.4 g, 170 mmol) stirring at 0 °C until no more starting compound 91 was detected by

TLC analysis (3 h). The reaction was then treated with a 5% solution of Na2S2O5 aq (100 mL) and

stirred at rt for 2 h. Powdered NaHCO3 (20 g, 238 mmol) was then added portionwise and the

mixture was diluted with water (80 mL). The aqueous phase was separated and extracted with ether

(2 ×100 mL). The organic layer was washed in turn with saturated NaHCO3 solution (100 mL) and

brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was

purified by chromatography (hexane/Et2O from 7:3 to 1:2) and the obtained oil was crystallized

from hexane/ethyl acetate (1:1) to give pure trans-3,6-dihydroxy-γ-ionone 95 (20.9 g, 59% yield)

as colorless crystals.

Experimental 147

C13H20O3, MW: 224.14 g/mol. Mp: 114 – 115 °C (lit.3 mp 116 – 117 °C). GC: 98% (chemical

purity). 1H NMR (400 MHz, CDCl3, 21 °C): δ = 6.83 (d, J = 15.8 Hz, 1H), 6.34 (d, J = 15.8 Hz,

1H), 5.64 – 5.60 (m, 1H), 4.30 (br s, 1H), 2.28 (s, 3H), 1.91 (br s, 1H), 1.87 (ddd, J = 13.4, 6.5, 1.4

Hz, 1H), 1.79 (s, 1H), 1.67 – 1.57 (m, 1H), 1.63 (t, J = 1.7 Hz, 3H), 1.04 (s, 3H), 0.92 (s, 3H). 13C

NMR (100 MHz, CDCl3, 21 °C): δ = 198.3, 148.6, 136.8, 129.4, 128.8, 78.9, 65.4, 44.0, 39.8,

27.8, 25.0, 22.4, 17.3. IR (film, cm–1): ν = 3360, 3315, 1684, 1619, 1454, 1109, 990. GC–MS m/z

(rel intensity): 224 (M+, 1), 206 (M+−H2O, 17), 191 (8), 164 (30), 150 (31), 135 (31), 125 (49), 111

(32), 108 (100), 97 (23), 91 (11), 77 (15), 71 (15), 55 (15). Anal.Calcd for C13H20O3: C, 69.61; H,

8.99. Found: C, 69.55; H, 9.03.

General Procedure for Lipase-Mediated Resolution of Racemic Substrates

(±)-93 and (±)-95 ( GP1). A mixture of the racemic diol (15 g, 67 mmol), lipase PS (15 g), vinyl acetate (50 mL), and t-

BuOMe (180 mL) was stirred at rt and the formation of the acetate was monitored by TLC analysis.

The reaction was stopped at about 50% of conversion by filtration of the enzyme and evaporation

of the solvent at reduced pressure. The residue was purified by chromatography using hexane-

diethyl ether as eluent to give the enantiomeric enriched (3S)-acetate and (3R)-diol. The latter

compound was converted into the corresponding (3R)-acetate by treatment with pyridine (20 mL)

and acetic anhydride (30 mL) and left at rt until no more starting diol was detected by TLC analysis

(4 h) after which the solvents were removed at reduced pressure. The enantiomeric purity of both

acetates was increased by crystallization from hexane/ ethyl acetate (3:1). The recrystallization

procedure was identical for all the acetates and the number of the steps depend upon the ee of the

starting compounds.

A general protocol is the following. The crystals were filtered and washed with a minimum amount

of cold solvent. The liquid was concentrated in vacuo and the specific rotation values were

measured for both phases. Usually, for ee of the starting acetates inferior to 60 –70%, racemic

crystals were less soluble than the enantiomeric enriched ones. The corresponding solid crop

showed specific rotation values inferior to those measured for the liquid. Thus the latter phase was

submitted again to the crystallization process, which was repeated using the mother liquors until

the crystals showed an optical rotation value superior to that measured for the liquid. At this point,

a further crystallization of the solid afforded enantiomerically pure acetate whose specific rotation

value does not increase by recrystallization.

Resolution of (3RS,6SR)-3,6-dihydroxy-γ-ionone (±)-93.

148 Chapter 7

According to the general procedure GP1, (±)-93 was converted into acetate (−)-96 and diol (+)-93.

The latter compound was acetylated to give (+)-96 and both esters were submitted to the fractional

crystallization procedure to afford enantiopure (−)-96 (3.6 g, 20% yield after 3 crystallizations) and

(+)-96 (2.8 g, 16% yield after 4 crystallizations) showing the following spectral data:.

(3S,6R)-3-acetoxy-6-hydroxy-α-ionone (−)-96.

OHO

AcO 96 C15H22O4, MW: 266.15 g/mol. Mp: 69 – 72 °C GC: 98% (chemical purity). [α]20

D = −198.8 (c = 1

g/dL, CHCl3). 1H NMR (400 MHz, CDCl3, 21 °C): δ 6.71 (d, J = 15.8 Hz, 1H), 6.43 (d, J = 15.8

Hz, 1H), 5.61 (s, 1H), 5.34 – 5.26 (m, 1H), 2.28 (s, 3H), 2.05 (s, 3H), 1.88 (dd, J = 14.2, 6.4 Hz,

1H), 1.78 (s, 1H), 1.75 (dd, J = 14.2, 6.1 Hz, 1H), 1.67 (t, J = 1.5 Hz, 3H), 1.02 (s, 3H), 0.98 (s,

3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ 197.6, 170.5, 147.0, 139.5, 130.2, 123.9, 77.6, 67.5,

38.4, 37.7, 28.1, 24.3, 23.8, 21.2, 18.7. IR (film, cm–1): ν = 3492, 1734, 1675, 1624, 1361, 1245,

1120, 1021, 991, 948. GC-MS m/z (rel intensity) 248 (M+−H2O, <1), 233 (2), 224 (5), 206 (33),

191 (32), 163 (82), 150 (74), 135 (42), 123 (95), 108 (100), 93 (22), 91 (22), 77 (21), 69 (14), 55

(20). Anal. Calcd for C15H22O4: C, 67.64; H, 8.33. Found: C, 67.80; H, 8.35.

(3R,6S)-3-acetoxy-6-hydroxy-α-ionone (+)-96.

OHO

AcO96

C15H22O4, MW: 266.15 g/mol. Mp: 70 –73 °C GC: 98% (chemical purity). [α]20

D= −194.3 (c = 1

g/dL, CHCl3). IR, 1H-NMR, MS: in accordance with that of (−)-96.

Resolution of (3SR,6SR)-3,6-dihydroxy-α-ionone ((±)-95). According to general procedure GP1 (±)-95 was converted in the acetate (+)-97 and diol (−)-95.

The latter compound was acetylated to give (−)-95 and both esters were submitted to the fractional

crystallisation procedure to afford enantiopure (+)-97 (2.1 g, 12% yield after 3 crystallizations) and

(−)-97 (1.75 g, 10% yield after 4 cristallizations) showing the following spectral data:

Experimental 149

(3S,6S)-3-acetoxy-6-hydroxy-α-ionone (+)-97.

OHO

AcO97

C15H22O4, MW: 266.15 g/mol. Mp: 132 – 133 °C GC: 98% (chemical purity). [α]20

D = +164 (c =

1 g/dL, CHCl3). 1H NMR (400 MHz, CDCl3, 21 °C): δ 6.82 (d, J = 15.8 Hz, 1H), 6.36 (d, J = 15.8

Hz, 1H), 5.57 – 5.52 (m, 1H), 5.41 – 5.32 (m, 1H), 2.29 (s, 3H), 2.06 (s, 3H), 1.90 (ddd, J = 13.4,

6.5, 1.4 Hz, 1H), 1.77 (s, 1H), 1.78 – 1.68 (m, 1H), 1.64 (t, J = 1.5 Hz, 3H), 1.08 (s, 3H), 0.94 (s,

3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ 198.0, 170.7, 148.0, 139.0, 129.6, 124.3, 78.6, 68.5,

39.7, 39.6, 27.9, 24.8, 22.3, 21.2, 17.5. IR (film, cm–1): ν = 3502, 1732, 1675, 1651, 1362, 1251,

1113, 1021, 973. GC-MS m/z (rel intensity) 248 (M+−H2O, <1), 233 (1), 224 (7), 206 (53), 191

(33), 163 (100), 150 (56), 135 (33), 121 (40), 108 (85), 93 (21), 91 (20), 77 (17), 69 (15), 55 (20).

Anal. Calcd for C15H22O4: C, 67.64; H, 8.33. Found: C, 67.70; H, 8.35.

(3R,6R)-3-acetoxy-6-hydroxy-α-ionone (−)-97.

OHO

AcO97

C15H22O4, MW: 266.15 g/mol. Mp: 129 – 130 °C GC: 98% (chemical purity). [α]20

D = −162.6 (c =

1 g/dL, CHCl3). IR, 1H-NMR, MS: in accordance with that of (+)-97.

General Procedure for Conversion of 3-acetoxy-6-hydroxy-α-ionone Isomers in the Dehydrovomifoliol enantiomers (GP2).

A sample of acetate 96 or 97 (400 mg, 1.5 mmol) was treated with a solution of KOH (1 g, 17.8

mmol) in methanol (10 mL) stirring at rt until no more starting acetate was detected by TLC

analysis. The mixture was diluted with water (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The

combined organic phases were washed with brine, dried (Na2SO4) and concentrated. The residue

was dissolved in CH2Cl2 (20 mL) and treated with MnO2 (1.5 g, 17.2 mmol) stirring at rt for 4 h.

The mixture was then filtered; the organic phase concentrated under reduced pressure and the

residue was purified by chromatography (hexane/Et2O from 9:1 to 2:1) to afford pure

dehydrovomifoliol 98.

150 Chapter 7

(−)-Dehydrovomifoliol (−)-98.

OHO

O98

According to general procedure GP2, (−)-96 was converted into (6R)-3-oxy-6-hydroxy-α-ionone

(−)-98 (230 mg, 69%) as a colorless oil that crystallized on standing.

C13H18O3, MW: 222.13 g/mol. Mp: 68 – 70 °C GC: 97% (chemical purity). [α]20D = −219.5 (c =

0.5 g/dL, CH2Cl2). 1H NMR (400 MHz, CDCl3, 21 °C): δ 6.84 (d, J = 15.7 Hz, 1H), 6.47 (d, J =

15.7 Hz, 1H), 5.97 – 5.94 (m, 1H), 2.49 (d, J = 17.1 Hz, 1H), 2.37 (s, 1H), 2.34 (dd, J = 17.1, 1.1

Hz, 1H), 2.30 (s, 3H), 1.89 (d, J = 1.5 Hz, 3H), 1.11 (s, 3H), 1.03 (s, 3H); 13C NMR (100 MHz,

CDCl3, 21 °C): δ 197.4, 197.0, 160.5, 145.1, 130.4, 127.7, 79.2, 49.6, 41.4, 28.2, 24.3, 22.9, 18.6.

IR (film, cm–1): ν = 3438, 1698, 1651, 1629, 1266, 1076, 987. GC-MS m/z (rel intensity) 222 (M+,

1), 204 (M+−H2O, 1), 189 (1), 180 (3), 166 (16), 149 (7), 124 (100), 109 (3), 95 (8), 77 (4), 69 (6),

55 (5). Anal. Calcd for C13H18O3: C, 70.24; H, 8.16. Found: C, 70.35; H, 8.15.

(+)-Dehydrovomifoliol (+)-98.

O

O

OH

98

According to general procedure GP2, (+)-96 was converted in (6S)-3-oxy-6-hydroxy-α-ionone

(+)-98 (240 mg, 72%) as a colorless oil that crystallized on standing.

C13H18O3, MW: 222.13 g/mol. Mp: 68 – 69°C; Lit.4 69 − 70°C, GC: 96% (chemical purity). [α]20D

= +222 (c = 0.5 g/dL, CH2Cl2). IR, 1H-NMR, MS: in accordance with that of (−)-98.

General Procedure for Conversion of 3-acetoxy-6-hydroxy-α-ionone Isomers in the 8,9-dehydrotheaspirone Enantiomers (GP3).

A solution of acetates 96 or 97 (1 g, 3.8 mmol) in AcOEt (50 mL) were hydrogenated at

atmospheric pressure using Ni Raney as catalyst. After complete consumption of the starting

materials (TLC monitoring, 1 h) the organic phases were filtered and concentrated in vacuo. The

residues were dissolved in triethylamine (10 mL) and cooled to 0°C. POCl3 (1 mL, 10.7 mmol) was

added dropwise to the resulting solutions and the reactions were vigorously stirred for 30 min. The

mixtures were then poured in an ice cooled sat. solution of NaHCO3 (100 mL) and then extracted

with diethyl ether (2 x 50 mL). The combined organic phases were washed with brine, dried

Experimental 151

(Na2SO4) and concentrated in vacuo. The residues were purified by chromatography (eluting with

hexane/ether/triethylamine 94:5:1) to afford pure compounds 101 and 102, respectively as a

colorless oil. The latter spiro derivatives were treated with a solution of KOH (1 g, 17.8 mmol) in

methanol (10 mL) stirring at rt until no more starting acetates were detected by TLC analysis. The

mixtures were diluted with water (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined

organic phases were washed with brine, dried (Na2SO4) and concentrated. The residues were

dissolved in CH2Cl2 (20 mL) and treated with MnO2 (2 g, 23 mmol) stirring at rt for 2 h. The

mixtures were then filtered, the organic phases concentrated under reduced pressure and the

residues were purified by chromatography (hexane/Et2O from 95:5 to 9:1) to afford pure

dehydrotheaspirone 103 as colorless oil that crystallized on standing.

(R)-8,9-Dehydrotheaspirone (−)-103. According to general procedure GP3, (−)-96 afforded acetate (−)-101 (0.54 g, 57% yield), that was

transformed into (R)-dehydrotheaspirone (−)-103 (0.39 g, 87% yield). The latter compounds

showed the following analytical data:

(5R,8S)-2,6,10,10-tetramethyl-1-oxa-spiro[4.5]deca-2,6-dien-8-yl acetate (−)-101.

OAcO 101

C15H22O3, MW: 250.16 g/mol. GC: 99% (chemical purity). [α]20D = −17.4 (c = 1 g/dL, CHCl3). 1H

NMR (400 MHz, CDCl3, 21 °C): δ 5.37 (s, 1H), 5.27 – 5.20 (m, 1H), 4.44 – 4.40 (m, 1H), 2.69

(dm, J = 15.7 Hz, 1H), 2.40 (dm, J = 15.7 Hz, 1H), 2.03 (s, 3H), 1.79 – 1.74 (m, 8H), 1.02 (s, 3H),

0.93 (s, 3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ 170.8, 154.7, 141.6, 121.1, 94.2, 90.1, 68.1,

38.4, 37.1, 35.0, 23.5, 22.5, 21.3, 17.9, 13.3. IR (film, cm–1): ν = 1737, 1683, 1380, 1246, 1189,

1016, 973, 951. GC-MS m/z (rel intensity) 251 (M++ 1, 3), 250 (M+, 23), 208 (2), 194 (37), 190

(36), 175 (100), 152 (48), 147 (37), 131 (29), 120 (64), 109 (36), 105 (51), 91 (23), 79 (12), 77

(13), 55 (7). Anal. Calcd for C13H18O3: C, 71.97; H, 8.86. Found: C, 71.80; H, 8.90.

(R)-8,9-Dehydrotheaspirone (−)-103.

OO 103

152 Chapter 7

C13H18O2, MW: 206.13 g/mol. Mp: 80 – 82°C [α]20D = −34.2 (c = 1 g/dL, CHCl3).1H NMR (400

MHz, CDCl3, 21 °C): δ 5.69 (bs, 1H), 4.52 – 4.48 (m, 1H), 3.02 (dm, J = 15.7 Hz, 1H), 2.46 (dm,

J = 15.7 Hz, 1H), 2.41 (d, J = 16.8 Hz, 1H), 2.23 (d, J = 16.8 Hz, 1H), 1.97 (d, J = 1.5 Hz, 3H),

1.82 – 1.79 (m, 3H), 1.09 (s, 3H), 1.01 (s, 3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ 198.0,

164.7, 155.2, 123.9, 93.7, 90.7, 48.8, 40.6, 37.1, 22.8, 22.7, 18.2, 13.1 IR (film, cm–1): ν = 1675,

1628, 1382, 1262, 1188, 935. GC-MS m/z (rel intensity) 206 (M+, 68), 191 (16), 173 (6), 163 (7),

150 (53), 136 (35), 121 (28), 108 (100), 93 (50), 91 (21), 79 (15), 77 (22), 53 (9). Anal. Calcd for

C13H18O2: C, 75.69; H, 8.80. Found: C, 75.55; H, 8.82.

(S)-8,9-Dehydrotheaspirone (+)-103.

According to general procedure GP3, (+)-97 afforded acetate (−)-102 (0.52 g, 55% yield), that was

transformed into (S)-dehydrotheaspirone (+)-103 (0.37 g, 87% yield). The latter compounds

showed the following analytical data:

(5S,8S)-2,6,10,10-tetramethyl-1-oxa-spiro[4.5]deca-2,6-dien-8-yl acetate (−)-102.

OAcO

102

C15H22O3, MW: 250.16 g/mol. [α]20D = − 48.7 (c = 1 g/dL, CHCl3). 1H NMR (400 MHz, CDCl3,

21 °C): δ 5.38 – 5.30 (m, 1H), 5.27 – 5.23 (m, 1H), 4.45 – 4.40 (m, 1H), 2.78 (dm, J = 15.7 Hz,

1H), 2.44 (dm, J = 15.7 Hz, 1H), 2.03 (s, 3H), 1.83 (ddd, J = 13.2, 6.5, 1.4 Hz, 1H), 1.75 – 1.78 (m,

3H), 1.73 (t, J = 1.5 Hz, 3H), 1.57 (dd, J = 13.2, 9.1 Hz, 1H), 1.06 (s, 3H), 0.94 (s, 3H). 13C NMR

(100 MHz, CDCl3, 21 °C): δ 170.6, 155.1, 143.8, 119.4, 94.0, 90.8, 69.1, 39.3, 39.0, 38.7, 23.6,

22.2, 21.3, 17.1, 13.2. IR (film, cm–1): ν = 1735, 1713, 1376, 1256, 1101, 1053, 1011, 972, 936.

GC-MS m/z (rel intensity) 251 (M++ 1, 2), 250 (M+, 17), 208 (2), 194 (31), 190 (32), 175 (100),

152 (42), 147 (38), 131 (36), 120 (73), 109 (35), 105 (58), 91 (24), 79 (13), 77 (14), 55 (8). Anal.

Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.85; H, 8.90.

(S)-8,9-Dehydrotheaspirone (+)-103.

OO 103

C13H18O2, MW: 206.13 g/mol. Mp: 79 – 81°C [α]20D = + 35 (c = 1 g/dL, CHCl3). IR, 1H-NMR,

MS: in accordance with that of (−)-103.

Experimental 153

7.2 β- and γ-Iralia® Isomers.

Synthesis of β -Iralia Isomers 105 and 108.

8-methyl β-ionone = (E)-3-Methyl-4-(2,6,6-trimethyl-cyclohex-1-enyl)-but-3-en-2-one 105.

(E)-2-methyl-3-(2,6,6-trimethyl-cyclohex-1-enyl)-acrylic acid ethyl ester 115 (β- isomer).

O OEt

O O

OEtNaH, triethyl 2-phosphono-propionate, THF, reflux

H2SO4,AcOH, −5 °C

78%110 114 115

Triethyl 2-phosphonopropionate (38.1 g, 160 mmol) was added dropwise under nitrogen over a

period of 1 h to a stirred suspension of NaH (7 g, 60% in mineral oil, 175 mmol) in dry THF (200

mL) at RT. To the resulting mixture citral (23 g, 151 mmol) in dry THF (100 mL) was added

slowly and the reaction was heated at reflux for 2 h. After cooling, the mixture was poured onto

ice-water and extracted with diethyl ether (3x200 mL). The organic phase was washed with brine

(2x100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was diluted

with hexane (30 mL) and, while stirring at − 5 °C, a mixture of 120 g of concentrated sulfuric acid

and 35 g of glacial acetic acid was added dropwise. After 1 h the reaction was quenched by

addition of ice and extracted with hexane (2x200 mL). The combined organic phases were washed

in turn with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried (Na2SO4) and

concentrated under reduced pressure. The residue was purified by distillation to give colorless oil

pure ester 115 (27.9 g, 78% yield) as a 4:1 mixture of β/α isomers.

C15H24O2, MW: 236.18 g/mol. 1H NMR (400 MHz, CDCl3, 21 °C): δ 7.22 (bs, 1H), 4.22

(q, J = 7.2 Hz, 2H), 1.99 (bt, J = 6.0 Hz, 2H), 1.71 (d, J = 1.3 Hz, 3H), 1.68 − 1.60 (m,

2H), 1.55 − 1.45 (m, 2H), 1.47 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H), 0.98 (s, 6H). IR (film, cm–

1): ν = 1711, 1635, 1366, 1245, 1112, 1033, 975, 743. GC-MS m/z (rel intensity) 236 (M+,

68), 221 (100), 193 (35), 175 (51), 163 (29), 147 (91), 133 (18), 119 (24), 107 (59), 91

(31), 77 (17), 69 (10), 55 (9).

154 Chapter 7

3,5-dinitrobenzoic acid (E)-2-methyl-3-(2,6,6-trimethyl-cyclohex-1-enyl)-allyl ester 116.

O

ONO2

NO2

O

OEti. LAH, Et2O, 0 °Cii. 3,5-dinitrobenzoyl chloride, Py/CH2Cl2iii. two crystallizations f rom MeOH

61%115 116

The above mentioned ester 115 was added dropwise to a stirred and cooled (0 °C) suspension of

LiAlH4 (4.5 g, 119 mmol) in dry ether (200 mL). After work-up procedure the crude alcohol was

dissolved in pyridine (30 mL) and treated with a solution of 3,5-dinitrobenzoyl chloride (29 g, 126

mmol) in dry CH2Cl2 (100 mL). After complete conversion of the starting alcohol the mixture was

diluted with water (200 mL) and extracted with CH2Cl2 (2x250 mL). The combined organic phases

were washed with saturated NaHCO3 solution, brine and then dried (Na2SO4). Concentration at

reduced pressure gave an oil that was purified by CC (hexane/Et2O 9:1) and crystallized twice from

methanol to afford pure 116 (28.2 g, 61% yield), as colorless crystals.

C20H24N2O6, MW: 388.16 g/mol. Mp: 69 – 70°C. 1H NMR (400 MHz, CDCl3, 21 °C): δ 9.22

(m, 1H), 9.16 (m, 2H), 6.13 (s, 1H), 4.94 (s, 2H), 1.99 (bt, J = 6.0 Hz, 2H), 1.69 − 1.59 (m, 2H),

1.65 (d, J = 1.1 Hz, 3H), 1.52 (s, 3H), 1.51 − 1.45 (m, 2H), 0.97 (s, 6H). 13C NMR (100 MHz,

CDCl3, 21 °C): δ 162.3, 148.8, 134.6, 134.2, 131.5, 129.5, 129.3, 129.1, 122.2, 72.2, 39.1, 34.6,

31.9, 28.2, 20.9, 19.3, 15.5. IR (nujol, cm–1): ν = 1716, 1630, 1551, 1294, 1167, 952, 727. GC-MS

m/z (rel intensity) 388 (M+, 9), 373 (23), 207 (7), 195 (25), 176 (16), 161 (100), 149 (17), 133 (30),

119 (52), 105 (59), 91 (29), 75 (14), 55 (13).

8-methyl β-ionone 105.

O

O

ONO2

NO2

i. NaOH, MeOHii. MnO2, CHCl3, reflux (6h)iii. MeMgBr, Et2O, 5 °Civ. MnO2, CHCl3, reflux (12h)

63%116 105

A sample of 116 (25 g, 64.4 mmol) was treated with a solution of NaOH (5 g, 125 mmol) in

methanol (150 mL) stirring at rt until no more starting acetate was detected by TLC analysis. The

mixture was diluted with water (300 mL) and extracted with diethyl ether (2x150 mL). The

combined organic phases were washed with brine, dried (Na2SO4) and concentrated. The residue

was dissolved in CHCl3 (200 mL) and treated with MnO2 (30 g, 345 mmol) stirring at reflux for 6

Experimental 155

h. The mixture was then cooled, filtered and the organic phase concentrated under reduced pressure

to afford an oil (13 g) The latter was dissolved in dry diethyl ether (150 mL) and treated under

stirring with an excess of methylmagnesiun iodide (100 mL of a 1 M solution in ether) keeping the

reaction temperature under 5 °C by external cooling (ice bath). The usual work-up afforded crude

carbinol that was dissolved in CHCl3 (200 mL) and treated with MnO2 (30 g, 345 mmol) stirring at

reflux for 12 h. After filtration and concentration, the crude ketone was purified by chromatography

(hexane/Et2O 95:5) and bulb to bulb distillation (oven temperature 105 °C, 0.4 mmHg) to afford

pure 105 (8.4 g, 63% yield), as colorless oil.

C14H22O, MW: 206.17 g/mol. 1H NMR (400 MHz, CDCl3, 21 °C): δ 7.09 (s, 1H), 2.36 (s, 3H),

2.01 (t, J = 6.2 Hz, 2H), 1.70 − 1.61 (m, 2H), 1.66 (d, J = 1.2 Hz, 3H), 1.53 − 1.48 (m, 2H), 1.46 (s,

3H), 0.99 (s, 6H). 13C NMR (100 MHz, CDCl3, 21 °C): δ 199.9, 140.6, 139.5, 134.8, 129.7, 39.0,

34.7, 31.8, 28.3, 25.6, 21.1, 19.1, 12.9. IR (film, cm–1): ν = 1670, 1625, 1431, 1384, 1363, 1251,

1101, 1034, 997, 897. GC-MS m/z (rel intensity) 206 (M+, 2), 191 (100), 176 (5), 163 (4), 149

(12), 136 (7), 123 (8), 105 (5), 91 (9), 77 (5), 69 (2), 55 (3).

10-methyl β-ionone = (E)-1-(2,6,6-trimethyl-cyclohex-1-enyl)-pent-1-en-3-one 108.

(E)-3-(2,6,6-trimethyl-cyclohex-1-enyl)-prop-2-en-1-ol 118.

OHCO2H i. MeOH/H2SO4, 1h

ii. LAH, Et2O, 0 °C

90%117 118

A solution of (E)-3-(2,6,6-trimethyl-cyclohex-1-enyl)-acrylic acid 117 (20 g, 103 mmol) in

methanol (100 mL) was treated with concentrated sulfuric acid (25 mL) and then heated under

reflux for 1 h. The reaction was then cooled, poured in ice and extracted with ether (2 x 150 mL).

The organic phase was washed in turn with saturated NaHCO3 solution (100 mL) and brine (100

mL) then dried (Na2SO4) and concentrated under reduced pressure. The obtained ester was added

dropwise to a stirred and cooled (0 °C) suspension of LiAlH4 (2.95 g, 78 mmol) in dry ether (150

mL). After work-up procedure the crude alcohol was purified by chromatography (hexane/AcOEt

95:5) to afford pure 118 (16.8 g, 90% yield), as a colorless oil.

C12H20O, MW: 180.15 g/mol. 1H NMR (400 MHz, CDCl3, 21 °C): δ 6.11 (d, J = 16.0 Hz, 1H),

5.61 (dt, J = 16.0, 6.0 Hz, 1H), 4.19 (bs, 2H), 1.98 (bt, J = 6.2 Hz, 2H), 1.67 (s, 3H), 1.65 − 1.53

(m, 2H), 1.49 − 1.41 (m, 2H), 1.31 (bs, 1H), 1.00 (s, 6H). 13C NMR (100 MHz, CDCl3, 21 °C): δ

136.8, 132.4, 129.8, 129.1, 64.2, 39.7, 34.0, 32.8, 28.7, 21.3, 19.3. IR (film, cm–1): ν = 3351, 1360,

156 Chapter 7

1094, 1011, 972. GC-MS m/z (rel intensity) 180 (M+, 79), 165 (86), 147 (100), 137 (14), 121 (65),

105 (81), 91 (75), 81 (50) 67 (25), 55 (39), 41 (42).

(E)-1-(2,6,6-trimethyl-cyclohex-1-enyl)-pent-1-en-3-one 108.

OH

i. MnO2, CHCl3, reflux (5h)ii. EtMgBr, Et2O, 5 °Ciii. MnO2, CHCl3, reflux (12h)

O

69%118 108

A solution of alcohol 118 (12.5 g, 69.3 mmol) in CHCl3 (200 mL) was treated with MnO2 (25 g,

287 mmol) stirring at reflux for 5 h. The mixture was then cooled, filtered and the organic phase

concentrated under reduced pressure to afford oil (12 g). The latter was dissolved in dry diethyl

ether (150 mL) and treated under stirring with an excess of ethylmagnesiun bromide (100 mL of a

0.9 M solution in ether) keeping the reaction temperature under 5 °C by external cooling (ice bath).

After the usual work-up, the obtained crude carbinol was dissolved in CHCl3 (200 mL) and was

treated with MnO2 (30 g, 345 mmol) stirring at reflux for 12 h. Filtration and concentration

afforded the crude ketone that was purified by chromatography (hexane/Et2O 95:5) and bulb to

bulb distillation (oven temperature 115 °C, 0.9 mmHg) to give pure 108 (9.9 g, 69% yield), as a

colorless oil

C14H22O, MW: 206.17 g/mol. 1H NMR (400 MHz, CDCl3, 21 °C): δ 7.29 (dd, J = 0.7, 16.4 Hz,

1H), 6.12 (d, J = 16.4 Hz, 1H), 2.57 (q, J = 7.4 Hz, 2H), 2.06 (t, J = 6.2 Hz, 2H), 1.75 (d, J = 0.7

Hz, 3H), 1.67 − 1.58 (m, 2H), 1.52 − 1.46 (m, 2H), 1.13 (t, J = 7.4 Hz, 3H), 1.07 (s, 6H). 13C NMR

(100 MHz, CDCl3, 21 °C): δ 200.8, 141.8, 136.3, 135.2, 130.5, 39.9, 34.1, 33.7, 33.5, 28.8, 21.6,

19.0, 8.3. IR (film, cm–1): ν = 1694, 1673, 1607, 1459, 1376, 1361, 1195, 1114, 1037, 980. GC-

MS m/z (rel intensity) 206 (M+, 7), 191 (100), 177 (7), 163 (4), 149 (15), 135 (6), 121 (10), 107

(9), 91 (11), 77 (7), 57 (13).

Experimental 157

Synthesis of Racemic γ- Iralia Isomers 106 and 109.

General Procedure for Epoxidation of α -Iralia Isomers (GP4).

R1

R2

O

R2

O

O

R2

O

OR1 R1

(±)-104, R1 = Me, R2 =Me(±)-107, R1 = H, R2 = Et

+

121a/121b 4:1, 85%yield, R1 = Me, R2 = Me122a/122b 4:1, 88%yield,, R1 = H, R2 = Et

121a/122a 121b/122b

MCPBA,CH2Cl2, 0 °C

m-Chloroperbenzoic acid (12 g, of 75% wet acid, 52.1 mmol) was added to a solution of racemic

α-iralia isomer 4 or 5 (10 g, 48.5 mmol) in methylene chloride (100 mL) at 0 °C. The reaction

mixture was stirred at 0 °C for 2 h and then filtered in order to remove the m-clorobenzoic acid

precipitate. The organic phase was washed in turn with saturated Na2SO3 solution and saturated

NaHCO3 solution, dried (Na2SO4) and concentrated under reduced pressure. The residue was

chromatographed on a silica gel column (hexane/Et2O 9:1) to give the corresponding α-epoxy-

derivatives.

Epoxide 121 (85% yield) 121a: 121b = 4:1 separable by chromatography. Both colorless oil.

Epoxide 122 (88% yield) 122a: 122b = 4:1; inseparable mixture. Colorless oil.

(4SR,5RS,6RS)-4,5-epoxy-4,5-dihydro-8-methyl α- ionone 121a. O

O 121a C14H22O2, MW: 222.16 g/mol. 1H NMR (400 MHz, CDCl3, 21 °C): δ 6.65 (dd, J = 10.8, 1.3 Hz,

1H), 3.08 (s, 1H), 2.50 (d, J = 10.8 Hz, 1H), 2.36 (s, 3H), 2.05 − 1.88 (m, 2H), 1.85 (d, J = 1.3 Hz,

3H), 1.45 (ddd, J = 13.7, 9.8, 5.7 Hz, 1H), 1.23 (s, 3H), 1.02 (dt, J = 13.7, 5.1 Hz, 1H), 0.96 (s,

3H), 0.76 (s, 3H). 13C NMR (100MHz, CDCl3, 21 °C): δ 199.8, 141.6, 138.8, 59.6, 59.2, 47.6,

31.8, 29.0, 28.3, 26.4, 25.5, 24.1, 21.7, 11.8. IR (film, cm–1): ν = 1670, 1368, 1253, 1177, 1095,

910. GC-MS m/z (rel intensity) 222 (M+, 2), 207 (5), 193 (10), 179 (16), 165 (9), 153 (12), 137

(30), 123 (100), 109 (53), 95 (17), 81 (16), 69 (15), 55 (16).

158 Chapter 7

(4SR,5RS,6SR)-4,5-epoxy-4,5-dihydro-8-methyl α- ionone 121b. O

O121b

C14H22O2, MW: 222.16 g/mol. 1H NMR (400 MHz, CDCl3, 21 °C): δ 6.54 (dd, J = 11.6, 1.4 Hz,

1H), 3.00 (s, 1H), 2.69 (d, J = 11.6 Hz, 1H), 2.35 (s, 3H), 2.05 (dm, J = 15.5 Hz, 1H), 1.97 − 1.87

(m, 1H), 1.86 (d, J = 1.4 Hz, 3H), 1.50 − 1.36 (m, 1H), 1.20 − 1.12 (m, 1H), 1.17 (s, 3H), 0.89 (s,

3H), 0.79 (s, 3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ 199.4, 140.8, 139.7, 59.7, 58.1, 49.5,

32.8, 32.5, 29.4, 25.7, 23.3, 21.5, 21.4, 11.8. IR (film, cm–1): ν = 1672, 1368, 1250, 1154, 1067,

908. GC-MS m/z (rel intensity) 222 (M+, 2), 207 (5), 189 (3), 179 (14), 165 (15), 153 (10), 137

(15), 123 (100), 109 (55), 95 (14), 79 (13), 69 (14), 55 (16).

(4SR,5RS,6RS)-4,5-epoxy-4,5-dihydro-10-methyl α- ionone 122a. O

O122a


1H), 6.04 (d, J = 16.1 Hz, 1H), 3.01 (s, 1H), 2.68 − 2.48 (m, 2H), 2.01 (d, J = 10.3 Hz, 1H), 1.98 −

1.78 (m, 2H), 1.43 − 1.26 (m, 1H), 1.18 (s, 3H), 1.05 (t, J = 7.3 Hz, 3H), 0.94 (dt, J = 13.6, 4.9 Hz,

1H), 0.86 (s, 3H), 0.69 (s, 3H). GC-MS m/z (rel intensity) 222 (M+, 3), 207 (4), 193 (72), 179 (8),

165 (54), 147 (19), 137 (20), 123 (100), 109 (72), 95 (60), 81 (28), 69 (35), 57 (69).

(4SR,5RS,6SR)-4,5-epoxy-4,5-dihydro-10-methyl α- ionone 122b. O

O122b


1H), 6.10 (d, J = 15.7 Hz, 1H), 2.93 (s, 1H), 2.68 − 2.48 (m, 2), 2.25 (d, J = 11.2 Hz, 1H), 1.98 −

1.78 (m, 2H), 1.43 − 1.26 (m, 1H), 1.14 − 1.00 (m, 1H), 1.12 (s, 3H), 1.06 (t, J = 7.3 Hz, 3H), 0.79

(s, 3H), 0.74 (s, 3H). GC-MS m/z (rel intensity) 222 (M+, 8), 207 (9), 193 (19), 179 (13), 165 (60),

147 (21), 137 (22), 123 (100), 109 (77), 95 (49), 81 (23), 69 (32), 57 (85).

IR (for 122a/122b mixture, film, cm−1): ν = 1699, 1675, 1627, 1379, 1367, 1204, 991.

Experimental 159

General Procedure for Conversion of Epoxide 121 and 122 into Allylic Alcohol 123 and 124, Respectively (GP5).

R2

O

O

R2

O

OR1 R1+

121a/121b, R1 = Me, R2 = Me122a/122b, R1 = H, R2 = Et

121a/122a 121b/122b

R2

O

R2

O

R1 R1+

123a/123b 4:1, 83%yield, R1 = Me, R2 = Me124a/124b 4:1, 78%yield,, R1 = H, R2 = Et

123a/124a 123b/124b

LDA,THF, −78 °C,then reflux

OH OH

BuLi (5.5 mL of a 10 M solution in hexane) was added dropwise to a cooled (−78 °C) solution of i-

Pr2NH (5.8 g, 57.3 mmol) in dry THF (90 mL) under nitrogen. The mixture was stirred at this

temperature for 30 min. then a solution of the epoxide 15 or 17 (4.5 g, 20.2 mmol) in dry THF (20

mL) was added dropwise. The reaction was gradually warmed to RT (1 h) and then was heated at

reflux until no more starting epoxide was detected by TLC analysis (3 h). After cooling to r.t., the

mixture was poured into a mixture of crushed ice and 5% HCl soln. (80 mL) and extracted with

Et2O (3 x 200 mL). The organic phase was successively washed with satd. aq. NH4Cl soln. (100

mL), brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified

by chromatography (eluting from hexane/AcOEt 9:1 to hexane/AcOEt 1:1) to give allylic alcohol

123 (123a:123b = 4:1, 83% yield) or allylic alcohol 124(124a: 124b = 4:1, 78% yield).

(4SR,6RS)-4-hydroxy-8-methyl γ-ionone 123a. O

OH123a


1H), 5.15 (s, 1H), 4.65 (s, 1H), 4.10 (m, 1H), 2.86 (d, J = 9.9 Hz, 1H), 2.37 (s, 3H), 2.04 − 1.93 (m,

1H), 1.74 (d, J = 1.3 Hz, 3H), 1.66 − 1.45 (m, 3H), 0.90 (s, 3H), 0.89 (s, 3H). 13C NMR (100 MHz,

CDCl3, 21 °C): δ 199.7, 149.5, 141.4, 139.0, 106.6, 72.6, 51.3, 38.0, 36.0, 32.2, 29.4, 25.6, 21.2,

11.4. GC-MS m/z (rel intensity) 222 (M+, 2), 204 (11), 189 (13), 179 (100), 161 (53), 148 (13),

135 (18), 123 (33), 109 (30), 91 (24), 79 (19), 69 (15), 55 (16).

160 Chapter 7

(4SR,6SR)-4-hydroxy-8-methyl γ-ionone 123b. O

OH123b


1H), 5.03 (s, 1H), 4.67 (s, 1H), 4.31 (bt, J = 4.6 Hz, 1H), 3.33 (d, J = 10.0 Hz, 1H), 2.34 (s, 3H),

2.08 − 1.80 (m, 3H), 1.80 − 1.67 (m, 1H), 1.78 (d, J = 1.3 Hz, 3H), 0.95 (s, 3H), 0.85 (s, 3H). 13C

NMR (100 MHz, CDCl3, 21 °C): δ 199.6, 149.4, 141.4, 139.2, 110.1, 71.6, 49.6, 35.7, 34.5, 30.5,

29.0, 25.7, 22.4, 11.4. GC-MS m/z (rel intensity) 222 (M+, 2), 204 (8), 189 (13), 179 (100), 161

(55), 148 (14), 135 (19), 123 (32), 109 (28), 96 (26), 81 (18), 69 (15), 55 (17).

IR (for 123a/123b mixture, film, cm−1): ν = 3424, 1666, 1387, 1368, 1250, 1071, 1049, 993, 900.

(4SR,6RS)-4-hydroxy-10-methyl γ -ionone 124a. O

OH124a


1H), 6.09 (d, J = 15.8 Hz, 1H), 5.16 (s, 1H), 4.69 (s, 1H), 4.05 (m, 1H), 2.58 (q, J = 7.4 Hz, 2H),

2.55 (d, J = 10.3 Hz, 1H), 2.00 − 1.91 (m, 1H), 1.75 − 1.35 (m, 4H), 1.12 (t, J = 7.4 Hz, 3H), 0.89

(s, 3H), 0.87 (s, 3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ 200.8, 150.4, 144.8, 132.0, 107.0,

72.4, 55.7, 37.9, 35.6, 33.5, 32.1, 29.6, 21.5, 8.1. GC-MS m/z (rel intensity) 222 (M+, 6), 207 (8),

189 (7), 175 (13), 165 (99), 147 (71), 135 (29), 122 (36), 107 (55), 91 (43), 81 (30), 69 (31), 57

(100).

(4SR,6SR)-4-hydroxy-10-methyl γ-ionone 124b. O

OH124b


1H), 6.15 (d, J = 15.9 Hz, 1H), 5.06 (s, 1H), 4.72 (s, 1H), 4.28 (bs, 1H), 2.96 (d, J = 9.9 Hz, 1H),

2.58 (q, J = 7.4 Hz, 2H), 1.90 − 1.80 (m, 1H), 1.75 − 1.35 (m, 4H), 1.11 (t, J = 7.4 Hz, 3H), 0.94 (s,

3H), 0.87 (s, 3H). GC-MS m/z (rel intensity) 222 (M+, 5), 207 (6), 189 (7), 175 (12), 165 (99), 147

(100), 135 (23), 123 (27), 105 (36), 91 (41), 81 (28), 69 (30), 57 (87).

Experimental 161

IR (for 124a/124b mixture, film, cm−1): ν = 3408, 1715, 1675, 1627, 1206, 1049, 989, 902.

General Procedure for Reduction of Allylic Alcohol 123 and 124 to γ-Iralia Isomers 106 and 109, Respectively (GP6).

R2

O

R2

O

R1 R1+

123a/123b, R1 = Me, R2 = Me124a/124b, R1 = H, R2 = Et

123a/124a 123b/124bOH OH

R2

O

R2

O

R1 R1+

(±)-106, 80%yield, R1 = Me, R2 = Me(±)-109, 80%yield, R1 = H, R2 = Et

(±)-106 (±)-109

i. Ac2O/Pyii. HCOOH, Et3N,PPh3, PdCl2(PPh3)2,THF, reflux.

A sample of compound 123 or 124 (3 g, 13.5 mmol) was converted in the corresponding acetate by

treatment with pyridine (20 mL) and Ac2O (20 mL) at RT. for 24 h. The crude product was added

to a solution of formic acid (1.2 g, 26 mmol), Et3N (2.7 g, 26.7 mmol), (PPh3)2PdCl2 (280 mg, 0.4

mmol) and triphenylphosphine (0.5 g, 1.9 mmol) in dry THF (60 mL). The mixture was refluxed

under a static nitrogen atmosphere until reduction was complete (2 h, TLC analysis). The reaction

was then diluted with ether (150 mL) and washed with water (50 mL), 5% HCl soln. (50 mL), satd.

aq. NaHCO3 soln. (50 mL), and brine. The organic phase was dried (Na2SO4) and concentrated

under reduced pressure. The residue was purified by chromatography (hexane/Et2O 95:5) and bulb-

to-bulb distillation to give γ-iralia isomers 106 (86% yield, 97% isomeric purity (GC)) or 109 (80

% yield, 94% isomeric purity (GC)), respectively.

8-Methyl γ-ionone = (E)-4-(2,2-Dimethyl-6-methylene-cyclohexyl)-3-methyl-but-3-en-2-one (±)-106.

O

106 C14H22O, MW: 206.17 g/mol. 1H NMR (400 MHz, CDCl3, 21 °C): δ 6.76 (dd, J = 10.1, 1.3 Hz,

1H), 4.77 (s, 1H), 4.51 (s, 1H), 2.88 (d, J = 10.1 Hz, 1H), 2.36 − 2.25 (m, 1H), 2.35 (s, 3H), 2.12 −

2.02 (m, 1H), 1.77 (d, J = 1.3 Hz, 3H), 1.68 − 1.52 (m, 3H), 1.45 − 1.35 (m, 1H), 0.92 (s, 3H), 0.87

(s, 3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ 199.6, 147.6, 142.2, 138.7, 109.0, 53.1, 39.1,

35.9, 34.5, 29.2, 25.5, 23.2, 22.9, 11.4. IR (film, cm−1): ν = 1670, 1645, 1439, 1386, 1367, 1262,

1233, 889. GC-MS m/z (rel intensity) 206 (M+, 17), 191 (25), 178 (15), 163 (100), 149 (16), 135

(93), 123 (70), 107 (22), 95 (36), 77 (17), 69 (26), 55 (9).

162 Chapter 7

10-Methyl γ-ionone = (E)-1-(2,2-Dimethyl-6-methylene-cyclohexyl)-pent-1-en-3-one (±)-109.

O

109

C14H22O, MW: 206.17 g/mol. 1H NMR (400 MHz, CDCl3, 21 °C): δ 6.97 (dd, J = 9.9,

15.7 Hz, 1H), 6.11 (dd, J = 15.7, 0.6 Hz, 1H), 4.78 (s, 1H), 4.55 (s, 1H), 2.62 − 2.53 (m,

1H), 2.58 (q, J = 7.4 Hz, 2H), 2.27 (dt, J = 13.5, 5.8 Hz, 1H), 2.06 (dt, J = 13.5, 6.7 Hz,

1H), 1.65 − 1.55 (m, 2H), 1.55 − 1.47 (m, 1H), 1.40 − 1.30 (m, 1H), 1.11 (t, J = 7.4 Hz,

3H), 0.91 (s, 3H), 0.86 (s, 3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ 200.6, 148.5,

145.7, 131.5, 109.5, 57.6, 38.6, 35.5, 34.1, 33.6, 29.1, 23.9, 23.1, 8.1. IR (film, cm−1): ν =

1695, 1677, 1626, 1460, 1366, 1207, 1187, 990, 891. GC-MS m/z (rel intensity) 206 (M+,

25), 191 (26), 178 (38), 163 (99), 149 (92), 135 (100), 123 (47), 109 (57), 93 (41), 81 (59),

69 (63), 57 (47).

Synthesis of Enantioenriched γ-Iralia Isomers (+) and (−)-106 and (+) and (−)-109.

Lipase-Mediated Resolution of Alcohols 123 and 124.

Diastereoisomerically pure alcohol 123a (obtained from epoxide 121a) and the cis/trans 4:1

mixture of 124a/124b were employed in the resolution procedure. A sample of the above

mentioned racemic material (5 g, 22.5 mmol), lipase PS (5 g), vinyl acetate (25 mL) and t-BuOMe

(100 mL) was stirred at RT. and the formation of the acetate was monitored by TLC analysis. The

reaction was stopped at about 50% of conversion when the substrate was 123a and at 40% of

conversion when the substrate was the 124a/124b mixture. The enzyme was then filtered, the

solvent was evaporated at reduced pressure and the residue was purified by chromatography

(eluting from hexane/AcOEt 9:1 to hexane/AcOEt 1:1). The first-eluted fractions afforded

derivatives (−)-125 (45% yield) and (+)-126 (35% yield), respectively. The last eluted fractions

afforded derivatives (+)-123a (49% yield) and a mixture of (4S,6R)- 124a and racemic 124b (60%

yield), respectively.

Experimental 163

(4R,6S)-4-acetoxy-8-methyl γ-ionone (−)-125. O

OAc125

C16H24O3, MW: 264.17 g/mol. GC: 98% (chemical purity), 99% de (GC); 99% ee (chiral GC).

[α]20D = −17.1 (c = 1.5 g/dL, CHCl3). 1H NMR (400 MHz, CDCl3, 21 °C): δ 6.72 (dd, J = 10.0,

1.4 Hz, 1H), 5.28 − 5.19 (m, 1H), 5.01 (s, 1H), 4.67 (s, 1H), 2.93 (d, J = 10.0 Hz, 1H), 2.36 (s, 3H),

2.10 (s, 3H), 2.00 − 1.90 (m, 1H), 1.76 (d, J = 1.4 Hz, 3H), 1.73− 1.61 (m, 2H), 1.59 − 1.47 (m,

1H), 0.92 (s, 3H), 0.91 (s, 3H). 13C NMR (100 MHz, CDCl3, 21 °C): δ 199.3, 169.7, 144.4, 140.5,

139.1, 108.3, 73.6, 51.4, 37.3, 35.7, 29.1, 28.8, 25.6, 21.6, 21.1, 11.5. IR (film, cm−1): ν = 1743,

1674, 1652, 1369, 1240, 1041, 998, 900. GC-MS m/z (rel intensity) 264 (M+, 1), 249 (9), 222 (19),

204 (55), 189 (34), 179 (59), 161 (100), 148 (50), 135 (35), 123 (36), 105 (34), 91 (29), 77 (17), 69

(12), 55 (13).

(4R,6S)-4-acetoxy-10-methyl γ-ionone (+)-126. O

OAc126


[α]20D = +27.1 (c = 1.7 g/dL, CHCl3). 1H NMR (400 MHz, CDCl3, 21 °C): δ 6.94 (dd, J = 15.7,

10.3 Hz, 1H), 6.12 (d, J = 15.7 Hz, 1H), 5.22 − 5.16 (m, 1), 5.02 (s, 1H), 4.71 (s, 1H), 2.61 (d, J =

10.3 Hz, 1H), 2.57 (q, J = 7.4 Hz, 2H), 2.10 (s, 3H), 1.96 − 1.85 (m, 1H), 1.78 − 1.58 (m, 2H), 1.52

− 1.38 (m, 1H), 1.12 (t, J = 7.4 Hz, 3H), 0.90 (s, 3H), 0.89 (s, 3H). 13C NMR (100 MHz, CDCl3,

21 °C): δ 200.3, 169.8, 145.3, 144.0, 131.7, 109.1, 73.5, 55.9, 36.8, 35.3, 34.0, 29.2, 28.7, 22.2,

21.1, 8.0. IR (film, cm−1): ν = 1743, 1677, 1630, 1369, 1264, 1125, 1040, 996, 898. GC-MS m/z

(rel intensity) 264 (M+, 1), 249 (6), 222 (24), 204 (36), 189 (14), 175 (30), 163 (63), 147 (100), 135

(29), 119 (25), 105 (35), 91 (37), 79 (15), 69 (16), 57 (52).

(4S,6R)-4-hydroxy-8-methyl γ-ionone (+)-127a. O

OH127a

164 Chapter 7


[α]20D = +32.6 (c = 2 g/dL, CHCl3). IR, 1H-NMR, MS: in accordance with that of (±)-123a.

(4S,6R)-4-hydroxy-10-methyl γ-ionone (4S,6R)-128a. O

OH128a

C14H22O2, MW: 222.16 g/mol. GC: 96% chemical purity, 50% de (GC); 85% ee (chiral GC). IR,

1H-NMR, MS: in accordance with that of (±)-124a. Optical rotation power of this compound is

near to 0. Therefore we describe the optical rotation value of the corresponding acetylated

(Ac2O/Py) derivative: [α]20D = −12.6 (c = 1.5 g/dL, CHCl3).

Preparation of enantioenriched γ-iralia isomers.

The above obtained compounds (−)-125, (+)-127, (+)-126 and (4S,6R)-128a were submitted to the

reductive deoxygenation procedure described in GP6 to afford γ-iralia isomers (−)-106, (+)-106,

(+)-109, and (−)-109, respectively. The latter compounds showed the following analytical data:

(S)-(−)-8-Methyl-γ-ionone (−)-106. O

106

C14H22O, MW: 206.17 g/mol. GC: 99% (chemical purity), 96% (regioisomeric purity). [α]20D =

−19.8 (c = 1 g/dL, CHCl3). IR, 1H-NMR, MS: in accordance with that of (±)-106.

(S)-(+)-10-Methyl-γ-ionone (+)-109. O

109


+18.7 (c = 1 g/dL, CHCl3). IR, 1H-NMR, MS: in accordance with that of (±)-109.

Experimental 165

(R)-(+)-8-Methyl-γ-ionone (+)-106. O

106


+16.4 (c = 2 g/dL, CHCl3). IR, 1H-NMR, MS: in accordance with that of (±)-106.

(R)-(−)-10-Methyl-γ-ionone (−)-109. O

109


−13.8 (c = 1 g/dL, CHCl3). IR, 1H-NMR, MS: in accordance with that of (±)-109.

General Procedure for Isomerization of γ-Iralia Isomers to α and β -Iralia Isomers (GP7).

O

O

O

O

(S)-(−)-104

(R)-(+)-107

+ 105 α /β 83:17

+ 108 α /β 78:22

(−)-106

(−)-109

85% H3PO4

85% H3PO4

γ-Iralia isomers (0.25 g, 1.2 mmol) were stirred in 85% H3PO4 (2 ml) at r.t until no more starting γ

isomer was detected by GC analysis (2 h). The reaction was poured onto crushed ice and the

products were extracted with ether (2x40 ml). The organic phase was washed with satd. aq.

NaHCO3 soln. (60 mL), and brine. The organic phase was dried (Na2SO4), concentrated under

reduced pressure and the residue was purified by CC (hexane/Et2O 9:1) and bulb-to-bulb

distillation to give a α/β-iralia isomers mixture. According to the above described procedure

compound (−)-106 ([α]20D = −19.8 (c = 1 g/dL, CHCl3)) afforded a mixture of (−)-104 and 105

(71% yield, 98% chemical purity, α/β 83:17, [α]20D = −401.8 (c = 1 g/dL, CHCl3)) whereas

compound (−)-109 ([α]20D = −8.2 (c = 1 g/dL, CHCl3)) afforded a mixture of (+)-107 and 108 (65%

yield, 98% chemical purity, α/β 78:22, [α]20D = +97.2 (c = 1 g/dL, CHCl3).

166 Chapter 7

7.3 Pentaphenylferrocenyl Palladacycle Catalysts.

Synthesis of Pentaphenylferrocenyl Oxazoline Palladacyles.

(S)-N-(1-Hydroxy-3-methylbutan-2-yl)-pentaphenylferrocenyl amide 189.

Fe

PhPh

Ph

Ph PhFe

PhPh

Ph

Ph PhNH

O

OHOH

O1. (COCl)2, DCM.cat. DMF, RT2. (S)-valinol, NEt3,DCM, 0 °C -> RT

95%

10 189

To a suspension of pentaphenylferrocenyl carboxylic acid (10, 306 mg, 0.5 mmol, 1 equiv.) in

DCM (10 mL) and DMF (ca. 5 µL, ca. 0.1 equiv.) at RT was added oxalylchloride in two portions

within 5 min. Warning: significant amounts of CO and corrosive HCl are released, pressure

exchange via balloon. When all solid had dissolved, stirring was continued for 30 min, then all

volatiles were removed under reduced pressure. The resulting dark red solid residue was dissolved

in DCM (8 mL) and triethylamine (101 mg, 130 µL, 1 mmol, 2 equiv.), cooled to 0 °C, and a

solution of (S)-valinol (192, 52 mg, 0.5 mmol, 1 equiv.) in DCM (2 mL) was added in one portion.

Stirring was continued at RT overnight, then all volatiles were removed under reduced pressure and

the red orange residue was purified by column chromatography (pentane:EtOAc 3:1 -> pure

EtOAc) to yield the title product 189 as orange solid or foam (330 mg, 0.47 mmol, 95%).

C46H41FeNO2, MW: 695.62 g/mol. Mp: 237.5 – 238.5 °C. [α]24.4D (c = 0.26 g/dL, CHCl3) = –74.8.

1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.25 – 7.04 (m, 25H, arom. H), 5.72 (d, J = 6.9, 1H, NH),

4.72 (d, J = 1.5 Hz, 1H, m-C5H4R), 4.58 (d, J = 1.5 Hz, 1H, m-C5H4R), 4.40 (d, J = 1.8 Hz, 1H, o-

C5H4R), 3.52 – 3.44 (m, 3H, NHCH2OH), 2.34 (t, J = 5.4 Hz, 1H, OH), 1.89 – 1.83 (m, 1H,

CH(CH3)2), 0.93 – 0.86 (m, 6H, CH(CH3)2). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 168.7, 134.9,

132.3, 127.2, 126.5, 88.1, 81.4, 77.9, 77.8, 74.5, 72.9, 63.4, 58.3, 29.1, 19.3, 14.2. IR (film, cm−1):

ν = 3442, 3058, 2960, 1636, 1601, 1503, 1444, 1312, 1075, 1028, 911, 711, 700. MS (MALDI)

m/z: 696.2 [100%, (MH)+]. HRMS (MALDI) m/z: Calcd for (MH+) C46H42FeNO2: 696.2560.

Found: 696.2568. A sufficient microanalysis could not be obtained due to solvent inclusion.

Experimental 167

(S)-4-Isopropyl-2-pentaphenyl-ferrocenyl-4,5-dihydrooxazole 11.

Fe

PhPh

Ph

Ph PhNH

O

OHTsCl, NEt3,DMAP, DCM, RT Fe

PhPh

Ph

Ph Ph

NO

91%

189 11 Amide 189 (330 mg, 0.47 mmol, 1 equiv.) was dissolved in DCM (3 mL) and triethylamine (151

mg, 200 µl, 1.5 mmol, ~ 3 equiv.). DMAP (ca. 6 mg, 0.05 mmol, 0.1 equiv.) and p-tosylchloride

(114 mg, 0.6 mmol, 1.25 equiv.) were added and the mixture was stirred at RT overnight. All

volatiles were subsequently removed under reduced pressure and the residue was purified by

column chromatography (pentane:EtOAc 4:1) to yield the title product 11 as bright orange solid

(295 mg, 0.43 mmol, 91% yield).

C46H39FeNO, MW: 677.61 g/mol. Mp: 222.5 – 233.8 °C. [α]24D (c = 0.28 g/dL, CHCl3) = –129.6.

1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.26 – 7.02 (m, 25H, arom. H), 4.77 (t, J = 1.8 Hz, 1H,

m-C5H4R), 4.33 (m, 1H, o-C5H4R), 3.89 – 3.77 (m, 2H, OCH2), 3.57 – 3.54 (m, 1H, NCH), 1.45 –

1.33 (m, 1H, CH(CH3)2), 0.96 (d, J = 6.6 Hz, CH3CH), 0.73 (d, J = 6.6 Hz, CH3CH). 13C NMR (75

MHz, CDCl3, 21 °C): δ = 162.3, 135.2, 132.4, 132.3, 128.3, 127.2, 126.3, 88.1, 77.7, 77.6, 77.5,

76.3, 75.2, 74.7, 74.1, 73.1, 69.3, 32.5, 19.7, 18.3. IR (film, cm−1): ν = 3058, 2959, 1652, 1601,

1503, 1444, 1380, 1304, 1114, 1028, 909, 735, 700. MS (MALDI) m/z: 678.1 [100%, (MH)+].

HRMS (MALDI) m/z: Calcd for (MH+) C46H40FeNO: 678.2454. Found: 678.2451. Anal. Calcd

for C46H39FeNO: C, 81.41; H, 5.94; N, 2.06. Found: C, 81.61; H, 6.03; N, 1.80.

Di-μ-acetato-bis[(η5-(S)-(SP)-2-(2′-(4′-methylethyl)oxazolinyl) cyclopentadienyl, 1-C, 3′-N)-(η5-pentaphenyl cyclopentadiene) ferrocene]dipalladium 194.

Fe

PhPh

Ph

Ph PhO

Ni-Pr

Fe

PhPh

Ph

Ph Ph

Pd OAcO

Ni-Pr 2

Pd(OAc)2,HOAc,95 °C

93%

11 194 A solution of oxazoline 11 (400 mg, 0.59 mmol) and Pd(OAc)2 (132 mg, 0.59 mmol, 1 equiv.) in

glacial acetic acid (2 mL) was heated in a preheated oil bath to 95 °C for 30 min, furnishing a red

precipitate. The mixture was cooled to room temperature and the solid product was separated by

filtration and washed with further glacial acetic acid (2 mL), showing only one diastereomer in 1H-

168 Chapter 7

NMR. For further purification 195 was dissolved in a minimum of DCE (ca. 2 mL for 0.5 g of

crude complex) and transferred into a crystallisation beaker (ca. 3 mm height of the solution, 5 cm

diameter) which was placed into a desiccator containing n-pentane (height ca. 2 cm, ca. 25 cm

diameter). After generally 1 day, dark red crystals of chemically and diastereomerically pure 194

had formed. The supernatant was decanted and the crystals were dried in vacuo (460 mg, 0.27

mmol, 93%).

C96H82Fe2N2O6Pd2, MW: 1684.14 g/mol. Mp: 230.0 – 231.3 °C (decomp). [α]23.4D (c = 0.274

g/dL, CHCl3) = –1018.5. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.25 – 7.01 (m, 25H, arom. H),

4.25 (d, J = 2.1 Hz, 1H, m-C5H3R3), 4.24 (d, J = 2.1 Hz, 1H, o-C5H3R3), 3.95 (d, J = 1.5 Hz, 1H, o-

C5H3R3), 3.84 – 3.69 (m, 2H, OCH2), 2.90 – 2.83 (m, 1H, NCH), 2.06 (s, 3H, CH3COO), 2.00 –

1.95 (m, 1H, CH(CH3)2), 0.61 (d, J = 7.2 Hz, CH3CHCH3), 0.03 (d, J = 6.9 Hz, CH3CHCH3). 13C

NMR (75 MHz, CDCl3, 21 °C): δ = 181.1, 177.1, 135.4, 132.7, 132.4, 126.9, 126.2, 90.8, 88.5,

77.8, 77.7, 75.8, 71.2, 70.8, 66.8, 28.2, 24.2, 20.7, 14.5. IR (film, cm−1): ν = 3057, 2961, 1576,

1503, 1413, 909, 738, 699. MS (MALDI) m/z: 782 [100%, (MH)+]. HRMS (MALDI) m/z: Calcd

for C46H39FeNOPd (loss of bridging OAc-ligand): 782.1350 Found: 782.1365. Anal. Calcd for

C96H84Fe2N2O6Pd2: C, 67.45; H, 5.17; N, 1.71. Found: C, 67.73; H, 5.14; N, 1.67.

Di-μ-chloro-bis[(η5-(S)-(SP)-2-(2′-(4′-methylethyl)oxazolinyl) cyclopentadienyl, 1-C, 3′-N)(η5-pentaphenyl cyclopentadiene) ferrocene]dipalladium 4.

Fe

PhPh

Ph

Ph Ph

Pd OAcO

Ni-Pr 2

Fe

PhPh

Ph

Ph Ph

Pd ClO

Ni-Pr 2

LiCl, PhH,MeOH, RT

95%

4194 To a suspension of acetate bridged complex 194 (145 mg, 0.086 mmol) in MeOH (20 mL),

benzene (5 mL) and LiCl (250 mg) was added. The reaction mixture was stirred at RT for 1 h, then

diluted with water and the phases were separated. The organic phase was washed with brine and

dried over MgSO4. All volatiles were removed under reduced pressure to yield the title product 4 as

dark red solid (138 mg, 0.082 mmol, 95%), which did not require further purification.

C92H76Fe2N2O2Cl2Pd2, MW: 1636.36 g/mol. Mp: 204.5 – 205.5 °C (decomp). [α]22.7D (c = 0.275

g/dL, CHCl3) = –1129.4. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.36 – 7.24 & 7.09 – 6.99 (m,

25H, arom. H), 4.46 – 4.10 (m, 5H, o-C5H3R3, m-C5H3R3, OCH2), 3.87 – 3.84 (m, 1H, NCH), 2.41

(m, 1H, CH(CH3)2), 0.81 – 0.75 (m, 3H, CH3CHCH3), 0.08 – 0.05 (m, 3H, CH3CHCH3). 13C NMR

(75 MHz, CDCl3, 21 °C): δ = 178.0, 135.0, 134.8, 132.6, 126.7, 126.2, 125.9, 94.8, 88.8, 88.7,

76.5, 75.8, 71.4, 71.1, 67.9, 28.8, 20.7, 14.1. IR (film, cm−1): ν = 3057, 2960, 2365, 1602, 1505,

Experimental 169

1444, 1372, 1185, 1028, 909, 737, 700. MS (MALDI) m/z: 1636.3 [100%, (MH)+]. HRMS

(MALDI) m/z: Calcd for C92H76Fe2N2O2Cl2Pd2: 1636.3646 Found: 1636.2240. Anal. Calcd for

C92H76Fe2N2O2Cl2Pd2: C, 67.42; H, 4.80; N, 1.71. Found: C, 67.23; H, 5.04; N, 1.79.

(1S,2R)-N-(1-Hydroxy-1,2-diphenylethan-2-yl)pentaphenyl-ferrocenylamide 190.

Fe

PhPh

Ph

Ph PhFe

PhPh

Ph

Ph PhNH

O

OH

Ph

OH

O 1. (COCl)2, DCMcat. DMF, RT2. (1S,2R)-2-amino-1,2-diphenylethanol,DCE, py, 80 °C, 3 h Ph

83%

10 190 To a suspension of pentaphenylferrocenyl carboxylic acid (10, 784 mg, 1.28 mmol, 1 equiv.) in

DCM (20 mL) and DMF (ca. 13 µL, ca. 0.1 equiv.) at RT was added oxalylchloride in two portions

within 5 min. Warning: significant amounts of CO and corrosive HCl are released, pressure

exchange via balloon. When all solid had dissolved, stirring was continued for 30 min, and then all

volatiles were removed under reduced pressure. The resulting dark red solid residue was dissolved

in DCE (20 mL) and pyridine (303 mg, 3.84 mmol, 3 equiv.), then (1R, 2S)-2-amino-1,2-

diphenylethanol, (193, 327 mg, 1.5 mmol, 1.2 equiv.) was added. Stirring was continued at 80 °C

for 3 h, then all volatiles were removed under reduced pressure and the red orange residue was

purified by column chromatography (pentane:EtOAc 3:1 -> pure EtOAc) to yield the title product

190 as orange solid or foam (858 mg, 1.06 mmol, 83%).

C55H43FeNO2, MW: 805.74 g/mol. Mp: 165.0 – 170.0 °C. [α]24.8D (c = 0.260 g/dL, CHCl3) = –

10.4. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.25 – 6.89 (m, 35H, arom. H), 6.33 (d, J = 6.9 Hz,

NH), 5.05 – 5.01 (dd, J = 7.2 Hz, J = 6.9 Hz, 1H, CH(Ph)OH), 4.92 (bs, 1H, NHCHPH), 4.67 (bs,

2H, m-C5H4R), 4.39 (d, J = 1.8 Hz, 2H, o-C5H4R), 2.78 (bs, 1H, OH). 13C NMR (75 MHz, CDCl3,

21 °C): δ = 167.7, 140.1, 136.2, 134.6, 132.1, 127.9, 127.8, 127.5, 127.4, 127.1, 126.9, 88.0, 81.0,

78.2, 78.0, 77.4, 76.1, 74.4, 73.3, 60.5. IR (film, cm−1): ν = 3432, 3059, 2361, 1646, 1601, 1504,

1444, 1378, 1312, 1178, 1028. MS (MALDI) m/z: 788.2 [100%, (M-H2O)+]. HRMS (MALDI)

m/z: Calcd for (MH)+) C55H44FeNO2: 806.2721. Found: 806.2685. A sufficient microanalysis

could not be obtained due to solvent inclusion.

170 Chapter 7

(4S,5S)-4,5-Diphenyl-2-pentaphenyl-ferrocenyl-4,5-dihydrooxazole 191.

Fe

PhPh

Ph

Ph PhNH

O

OH

PhTsCl, NEt3,DMAP, DCM, RT Fe

PhPh

Ph

Ph Ph

NO

Ph

Ph

Ph

79%

190 191 To a solution of amide 190 (630 mg, 0.77 mmol, 1 equiv.) in DCM (5 mL) and triethylamine (233

mg, 320 µL, 2.3 mmol, 3 equiv.), DMAP (ca. 10 mg, 0.077 mmol, 0.1 equiv.) and p-tosylchloride

(177 mg, 0.93 mmol, 1.2 equiv.) were added and the mixture was stirred at RT overnight. After

that, all volatiles were removed under reduced pressure and the residue was purified by column

chromatography (pentane:EtOAc 4:1) to yield the title product 191 as bright orange solid (480 mg,

0.6 mmol, 79%).

C55H41FeNO, MW: 787.72 g/mol. Mp: 188.0 – 192.0 °C. [α]25.1D (c = 0.28 g/dL, CHCl3) = –164.4.

1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.28 – 6.76 (m, 35H, arom. H), 5.05 (d, J = 10.2 Hz, 1H,

OCHPh), 4.97 (t, J = 2.4 Hz, 1H, m-C5H4R), 4.87 (t, J = 2.1 Hz, 1H, m-C5H4R), 4.85 (d, J = 10.2

Hz, 1H, NCHPh), 4.46 (m, 1H, o-C5H4R), 4.41 (m, 1H, o-C5H4R). 13C NMR (75 MHz, CDCl3, 21

°C): δ = 164.2, 141.0, 138.8, 135.0, 132.9, 132.5, 132.3, 128.8, 128.6, 128.3, 127.4, 127.2, 127.0,

126.4, 125.8, 89.7, 88.3, 79.1, 78.3, 75.3, 75.1, 74.2. IR (film, cm−1): ν = 3059, 1647, 1601, 1502,

1444, 1280, 1178, 1115, 1075, 1028, 910, 739, 669. MS (MALDI) m/z: 788.2 [100%, (MH)+].

HRMS (MALDI) m/z: Calcd for (MH+) C55H42FeNO: 788.2611. Found: 788.2616. A sufficient

microanalysis could not be obtained due to solvent inclusion.

Di-μ-acetato-bis[(η5-(4S,5S)-(SP)-2-(2′-(4′,5'-diphenyl)-oxazolinyl) cyclopentadienyl, 1-C, 3′-N)(η5-pentaphenylcyclopentadiene) ferrocene]dipalladium 195.

Fe

PhPh

Ph

Ph PhO

NPh

Ph

Fe

PhPh

Ph

Ph Ph

Pd OAcO

NPh

Ph

2Pd(OAc)2,HOAc,95 °C

72%

191 195 A solution of oxazoline 191 (423 mg, 0.53 mmol, 1 equiv.) and Pd(OAc)2 (120 mg, 0.53 mmol, 1

equiv.) in glacial acetic acid (2 mL) was stirred in a preheated oil bath at 95 °C for 30 min,

furnishing a red precipitate. The mixture was cooled to room temperature and the solid product was

separated by filtration and washed with further glacial acetic acid (2 mL), showing only one

Experimental 171

diastereomer in 1H-NMR. For further purification, 195 was dissolved in a minimum of DCE (ca. 2

mL for 0.5 g of crude complex) and transferred into a crystallization beaker (ca. 3 mm height of the

solution, 5 cm diameter) which was placed into a desiccator containing n-pentane (height ca. 2 cm,

ca. 25 cm diameter). After generally 1 day, dark red crystals of chemically and diastereomerically

pure 195 had formed. The supernatant was decanted and the crystals were dried in vacuo (370 mg,

0.38 mmol, 72%).

C114H88Fe2N2O6Pd2, MW: 1906.37 g/mol. Mp: 201.5 – 202.5 °C (decomp). [α]25.3D (c = 0.28 g/dL,

CHCl3) = –794.5. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.33 – 6.85 (m, 33H, arom. H), 6.37 (d,

J = 7.2 Hz, 2H, arom.H), 5.27 (d, J = 10.2 Hz, 1H, OCHPh), 4.05 (d, J = 1.5 Hz, 1H, o-C5H3R3),

3.92 (d, J = 2.1 Hz, 1H, o-C5H3R3), 3.79 (t, J = 2.1 Hz, 1H, m-C5H3R3), 3.76 (d, J = 6.9 Hz, 1H,

NCHPh), 1.66 (s, 1H, CH3CO2). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 179.7, 176.8, 138.4,

136.9, 135.3, 134.6, 132.6, 131.9, 128.6, 128.3, 128.1, 127.4, 127.0, 126.8, 125.9, 125.1, 92.3,

91.4, 88.3, 76.2, 76.1, 73.8, 72.1, 23.9. IR (film, cm−1): ν = 3059, 2925, 1582, 1502, 1414, 1361,

1181, 1028, 910, 739, 669. MS (MALDI) m/z: 892.1 [100%, (MH)+]. HRMS (MALDI) m/z:

Calcd for (MH+) C55H40FeNOPd: 892.1509. Found: 892.1493. A sufficient microanalysis could

not be obtained due to solvent inclusion.

Di-μ-chloro-bis[(η5-(4S,5S)-(SP)-2-(2′-(4′,5'-diphenyl)oxazolinyl) cyclopentadienyl, 1-C, 3′-N)(η5-pentaphenyl-cyclopentadiene) ferrocene]dipalladium 196.

Fe

PhPh

Ph

Ph Ph

Pd OAcO

NPh

Ph

2

Fe

PhPh

Ph

Ph Ph

Pd ClO

NPh

Ph

2

LiCl, PhH,MeOH, RT

93%

196195 To a suspension of 195 (210 mg, 0.11 mmol) in MeOH (25 mL) and benzene(5 mL), LiCl (450

mg) was added. The reaction mixture was stirred at RT for 1h, then diluted with water, the phases

were separated, the organic phase was washed with brine and dried over MgSO4, After that, all

volatiles were removed under reduced pressure to yield the title product 196 as dark red solid (190

mg, 0.1 mmol, 93%) that did not require further purification.

C110H82Fe2N2O2Cl2Pd2, MW: 1859.19 g/mol. Mp: 240.0 – 241.0 °C (decomp). [α]25.5D (c

= 0.264 g/dL, CHCl3) = –1342.3. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.41 – 6.83 (m,

33H, arom. H), 6.5 (d, J = 7.5 Hz, 2H, arom. H), 5.38 (d, J = 7.2 Hz, 1H, OCHPh), 4.70 (d,

J = 7.5 Hz, 1H, o-C5H3R3), 4.48 (m, 1H, o-C5H3R3), 4.27 (m, 1H, m-C5H3R3), 4.22 (d, J =

1.8 Hz, 1H, NCHPh). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 178.0, 138.7, 138.5, 137.7,

172 Chapter 7

135.0, 134.8, 134.4, 132.7, 128.8, 126.8, 126.0, 95.2, 93.7, 88.8, 88.6, 88.3, 75.9, 71.1,

53.5. IR (film, cm−1): ν = 3057, 2924, 2360, 2341, 1600, 1503, 1456, 1361, 1180, 1028,

910, 739, 698. MS (MALDI) m/z: 1856 [100, (MH)+]. HRMS (MALDI) m/z: Calcd for

(MH+) C110H82Fe2N2O2Cl2Pd2: 1858.2556. Found: 1858.2528. A sufficient microanalysis

could not be obtained due to solvent inclusion.

Synthesis of an o-Methoxy-Substituted Pentaphenyl ferrocenyl Imidazoline Palladacycle.

(4R,5R)-4,5-Bis(2-methoxyphenyl)-2-pentaphenylferrocenyl-1-tosyl-4,5-dihydro-1H-imidazole 356.

Fe

PhPh

Ph

Ph Ph

NN

MeO-Ph

MeO-Ph

TsFe

PhPh

Ph

Ph Ph

NNH

Fe

PhPh

Ph

Ph PhHBF4

.HN

EtO diamine 342,DCE,80 °C, 7 h

OMe

OMe


356yield: 62%over 2 steps355

To neat pentaphenylferrocene carbamide5 ( 427 mg, 0.70 mmol, 1 equiv.) was added a solution of

triethyloxonium tetrafluoroborate (133 mg, 0.70 mmol, 1 equiv.) in DCE (4 mL), leading to

complete dissolution within few minutes and a colour change to dark red, followed by precipitation

of the iminium ester tetrafluoroborate after ca. 30 min. Complete conversion was monitored by 1H-

NMR.

The suspension was cooled to 0 °C, then a solution of diamine 342 (190 mg, 0.7 mmol, 1 equiv.) in

DCE (4 mL) was added in one portion, leading to an orange colour. The mixture was heated to 50

°C overnight, then cooled to RT, diluted with DCM and washed twice with aqueous 1 N NaOH

solution. The solvent was removed and the resulting orange residue was filtrated over silica

(pentane:EtOAc 4:1 -> pentane:EtOAc 2:1 + 3% NEt3). [1H NMR (300 MHz, CDCl3, 21 °C): δ =

7.14 – 6.97 & 6.95 – 6.65 (m, 33H, aromatic H), 5.3 (m, 1H), 4.99 – 4.80 (m, 3H), 4.64 (bs, 1H),

4.41 – 4.31 (m, 2H), 3.52 (s, 6H, OCH3). MS (MALDI): m/z 847.3 [100, MH+].]. The product 355

was used in the next step without further purification.

A solution of imidazoline 355 (1 equiv.), p-tosylchloride (174 mg, 0.91 mmol, ca. 1.3 equiv.),

DMAP (8 mg, 0.07 mmol, ca. 0.1 equiv.) and triethylamine (133 µl, 1 mmol, ca. 1.4 equiv.) in

DCM (7 mL) was stirred at RT overnight. Conversion was monitored by TLC (pentane:EtOAc

3:1). Subsequently, sat. aqueous NaHCO3 was added and the mixture was stirred for 20 min, then

Experimental 173

the phases were separated. The solvent was removed and the orange residue was purified by

column chromatography (pentane:EtOAc 3:1 -> 1:1) to yield the title 356 product as bright orange-

red solid (460 mg, 0.46 mmol, 65% over 2 steps).

C64H52FeN2O4S, MW: 1001.01 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.23 – 6.94 (m,

31H, aromatic H), 6.83 (d, J = 8.1 Hz, 1H, aromatic H), 6.72 (d, J = 8.1 Hz, 1H, aromatic H), 6.53

(t, J = 7.5 Hz, 2H, aromatic H), 6.39 (d, J = 7.5 Hz, 1H, aromatic H), 6.05 (d, J = 7.5 Hz, 1H,

aromatic H), 5.33 & 5.31 (bs, 1H each), 4.96 (s, 1H), 4.84 (d, J = 5.4 Hz, 1H), 4.41 & 4.39 (bs, 1H

each), 3.68 (s, 3H, OCH3), 3.50 (s, 3H, OCH3), 2.34 (s, SO2Ph-CH3).

Di-μ-chlorobis[η5-(4`R,5`R)-(Sp)-2-(2`-4`,5`-dihydro-4`,5`-di[2-methoxy-phenyl] -1`-tosyl-1`H-imidazolyl)cyclopentadienyl, 1-C, 3`-N)(η5-pentaphenylcyclo- pentadienyl)-iron(II)] dipalladium(II) 357.

Fe

PhPh

Ph

Ph Ph

Pd

2

NNMeO-Ph

Ts

Cl

OMe

Fe

PhPh

Ph

Ph Ph

NN

MeO-Ph

MeO-Ph

Ts

Na2PdCl4, NaOAc,MeOH, PhH, RT

87%

356 357 To a solution or suspension (depending on the purity of the starting material) of 356 (100 mg, 0.10

mmol, 1 equiv.) and sodium acetate (8 mg, 0.10 mmol, 1 equiv.) in methanol (2 mL) and benzene

(1 mL), sodium tetrachloropalladinate (26 mg, 0.10 mmol, 1 equiv.) was added in one portion,

leading to a colour change to dark red after some minutes. The mixture was stirred for 4 weeks (not

optimised) and then diluted with DCM and filtrated over a plug of silica, followed by a purification

by column chromatography (pentane:EtOAc 3:1) to yield 357 as black-purple powder (100 mg, 87

µmol, 87%). The dr could not be determined yet, but is probably high.

C128H102Fe2N4O8S2Pd2Cl2, MW: 2283.76 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.55 (d,

J = 8.4 Hz, 2 H, aromatic H), 7.37 – 6.70 (m, 66 H, aromatic H), 6.62 (d, J = 8.4 Hz, 2 H, aromatic

H), 6.37 (d, J = 4.5 Hz, 2 H, aromatic H), 5.68 (d, J = 2.1 Hz, 2 H, N-CH), 5.22 – 5.19 (m, 2 H,

C5H3), 5.11 – 4.99 (m, 4 H, C5H3), 4.36 (m, 2 H, NCH), 4.16 (m, 1 H), 3.20 (s, 3 H, OCH3), 2.70 (s,

3 H, OCH3), 2.52 (s, 3 H, PhCH3).

174 Chapter 7

Synthesis of an o-Methoxy-Substituted Ferrocenyl Oxazoline.

(4R,5R)-4,5-Bis(2-methoxyphenyl)-2-ferrocenyl-4,5-dihydro-1H-imidazole 340.

Fe

OEt

NH.HBF4

75%Fe

N

HN

NH2H2N

DCM, 0 °C to RT

OMeMeO MeO

MeO

339 340

342

To a stirred solution of diamine 3426 (205.34 mg, 1.08 equiv.) in abs. DCM (3 mL/mmol) was

slowly added at 0 °C within 30 min a solution of the iminiumether salt 339 (241 mg, 0.69 mmol) in

the same solvent (4.5 mL/mmol) while vigorously stirring the resulting yellow-orange solution.

After 30 min, the mixture was allowed to warm to room temperature and stirring was continued for

16 h. The reaction mixture was further diluted with DCM, washed twice with 1 N NaOH and then

evaporated to dryness. The residue was subsequently purified by column chromatography

(pentane:EtOAc 4:1 -> pentane:EtOAc 2:1 + 3% NEt3) affording the title product 340 (240 mg,

75%) as orange solid.

C27H26FeN2O2, MW: 466.35 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.49 (d, J =

7.2 Hz, 2H, arom. H), 7.27 – 7.21 (td, J = 7.8 Hz, J = 1.6 Hz, 2H, arom. H), 6.98 (td, J =

5.3 Hz, J = 0.6 Hz, 2H, arom. H), 6.87 (d, J = 8.1 Hz, 2H, arom. H), 5.25 (bs, 2H,

MeOPhCH & NH), 4.79 (m, 1H, o-C5H4R), 4.76(m, 1H, o-C5H4R), 4.35(m, 2H, o-C5H4R),

4.30 (d, J = 12.9 Hz, 1H, MeOPhCH), 4.18 (s, 5H, Cp), 3.69 (s, 6H, OCH3). 13C NMR (75

MHz, CDCl3, 21 °C): δ = 164.3, 156.8, 132.3, 128.1, 127.2, 120.2, 110.7, 69.9, 69.8, 69.5,

69.4, 68.3, 68.1, 55.2. IR (film, cm−1): ν = 2934, 15098, 1284, 1488, 1458, 1239, 1106,

1026, 1000, 816, 749. MS (ESI): m/z 467.1 [100%, MH+]. HRMS (MALDI) m/z: Calcd

for (MH+) C21H23FeN2: 467.1420. Found: 467.1417. Anal. Calcd for C27H26FeN2O2: C,

69.53; H, 5.97; N, 6.08. Found: C, 69.53; H, 5.89; N, 6.07.

Experimental 175

(4R,5R)-4,5-Bis(2-methoxyphenyl)-2-ferrocenyl-1-tosyl-4,5-dihydro-1H-imidazole 341.

FeN

HN

MeO

MeOFe

N

N

MeO

MeO


Ts

91%

340 341 A solution of imidazoline 340 (150 mg, 0.32 mmol, 1 equiv.), p-tosylchloride (80 mg, 0.41

mmol, ca. 1.3 equiv.), DMAP (8 mg, 0.07 mmol, ca. 0.1 equiv.) and triethylamine (66.5

μL, 0.5 mmol, ca. 1.4 equiv.) in DCM (7 mL) was stirred at RT overnight. Conversion was

monitored by TLC (pentane:EtOAc 3:1). Subsequently, sat. aqueous NaHCO3 was added

and the mixture was stirred for 20 min, then the phases were separated. The solvent was

removed and the orange residue was purified by column chromatography (DCM, 5%

MeOH) to yield the title product 341 as yellow orange foam (172 mg, 0.29 mmol, 91%

yield).

C34H32FeN2O4S, MW: 620.54 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.46 (dd, J = 7.5

Hz, J = 1.6 Hz, 1H, arom. H), 7.36 – 7.30 (td, J = 8.2 Hz, J = 1.7 Hz, 1H, arom. H), 7.25 – 6.93 (m,

8H, arom. H), 6.78 (d, J = 7.5 Hz, 1H, arom. H), 6.59 (td, J = 7.5 Hz, J = 0.9, 1H, arom. H), 6.34

(dd, J = 7.5 Hz, J = 1.6 Hz, 1H, arom. H), 5.37 (d, J = 4.1 Hz, 1H, MeOPhCH), 5.30 (d, J = 4.1 Hz,

1H, MeOPhCH), 4.98 (m, 2H, o-C5H4R), 4.41(m, 1H, o-C5H4R), 4.32(m, 1H, o-C5H4R), 4.25 (s,

5H, Cp), 3.81 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 2.36 (s, 3H, SO2Ph-CH3). 13C NMR (75 MHz,

CDCl3, 21 °C): δ = 159.0, 156.3, 143.7, 135.7, 131.3, 130.5, 129.2, 128.8, 127.9, 127.7, 126.9,

120.7, 120.1, 110.9, 109.7, 74.7, 73.1, 70.9, 70.6, 70.4, 69.2, 68.7, 66.8, 55.5, 54.9, 21.5. IR (film,

cm−1): ν = 1631, 1598, 1587, 1490, 1456, 1363, 1290, 1244, 1170, 1088, 1020, 810, 749. MS

(ESI): m/z 621.1 [100%, MH+]. HRMS (MALDI) m/z: Calcd for (MH+) C34H32FeN2O4S:

621.1506 Found: 621.1506. Anal. Calcd for C34H32FeN2O4S: C, 65.22; H, 5.24; N, 4.51. Found:

C, 65.32; H, 5.25; N, 4.44.

176 Chapter 7

General Procedure for Pre-catalyst Activation and Catalysis (GP8).

Catalyst Activation (GP8a).

A solution of the dimeric pre-catalyst (1 equiv.) in dry DCM (1 mL/3 µmol) is added to AgX (3.75

equiv. if nothing else is specified, see below) in a dry pear shaped flask under N2, sealed, shielded

from light and stirred for 3 h or overnight at RT. The resulting suspension is filtrated under N2

atmosphere through celite/CaH2 (~1:1, ca. 5 mm thickness) and the filter cake is washed with dry

DCM (1 mL/3 µmol). Proton sponge (as 0.1 M solution in DCM, 2 to 4 equiv.) is added. 1 mol%

catalyst relative to 60 µmol substrate are equivalent to 400 µL of this solution.

Filtration setup: A sintered glass frit (D4, ca. 1 cm diameter) was fixed to a 1 mL syringe by

cutting off the upper part of this syringe, melting the cutting site with a heat-gun and then plugging

the outlet of the glass frit into the molten plastic, leading to a vacuum-proof connection. By use of a

standard needle, this allows to connect the filtration equipment directly to any flask with a rubber

septum.

Catalysis (GP8b).

The calculated amount of activated catalyst as solution in DCM is transferred to a flask containing

the imidate (1 equiv., for most experiments 60 µmol). A stream of N2 is passed through the flask

until the solvent volume reaches 0.2 mL or less. The flask is sealed with a plastic cap and stirred

for the indicated time at the indicated temperature. After the reaction, remaining solvent is removed

in vacuo at room temperature and the residue is purified by column chromatography (CyH:EtOAc

9:1 or pentane:EtOAc 9:1). For screening experiments, purification by column chromatography

was replaced by a simple filtration over a plug of silica (ca. 1 cm in a Pasteur pipette,

pentane:EtOAc 9:1; the product was first dissolved with ca. 100 µL DCM before adding 1 mL of

the above mentioned solvent mixture).

General Procedure for Trifluoroacetamide Cleavage and ee Determination (GP9).

GP9a: With NaBH4 To the corresponding allylic trifluoroacetamide 284, 285 (60 µmol or less) in i-PrOH:H2O 10:1

(0.75 mL) at 0 °C is added NaBH4 (9 mg, 0.24 mmol, 4 equiv.). The solution is allowed to warm to

RT and stirred for 4 h. (Warning: allow for pressure exchange). Water is subsequently added and

the mixture is extracted with DCM or MTBE three times. The combined organic phases are dried

over MgSO4 and the solvent is removed in vacuo.

Experimental 177

GP9b: With MeLi

To the corresponding allylic trifluoroacetamide 286, 287 (60 µmol or less) in THF (0.5 mL) at –78

°C is added MeLi (1.6 M solution in Et2O, 100 µl, 160 µmol, ~2.5 equiv.). The solution is allowed

to warm to RT and stirred for 2 h. An aqueous solution of saturated ammonium chloride (1 mL) is

added and the mixture is extracted with MTBE three times. The combined organic phases are dried

over MgSO4 and the solvent is removed in vacuo.

General procedure for the preparation of allylic N-(4-methoxyphenyl) trifluoroacetimidates (GP10).

OMe

NH2

2 equiv. PPh3, NEt3, TFA, CCl4, Δ

91%

OMe

N

CF3

Cl

235

2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidoyl chloride 235 was prepared from p-

methoxyaniline (anisidine) and trifluoroacetic acid following a literature procedure.1

[C9H7F3NOCl, MW: 237.61 g /mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.32 (d, J = 9.0 Hz,

2 H, arom-H), 6.96 (d, J = 9.0 Hz, 2 H, arom-H), 3.85 (s, 3 H, OCH3), 19F NMR (282 MHz,

CDCl3, 21 °C): δ = −71.1]

N

F3C Cl

HO RNaH, THF

0 °C -> RT

OMe

+F3C

N

O

OMe

R

235 5a 7a To a solution of the allylic alcohol 5a in THF (2 mL/mmol) at 0 °C was added sodium

hydride (60% in mineral oil, 1.1 equiv.). After stirring at room temperature for 2 h, a

solution of 2,2,2-trifluoro-N-(4-methoxy-phenyl)-acetimidoyl chloride 235 (1.0 equiv.) in

THF (0.5 mL/mmol) was added. Stirring was continued for 2 h, then water (10 mL/mmol)

and MTBE (10 mL/mmol) were added. Phases were separated and the aqueous phase was

extracted with MTBE (10 mL/mmol). The combined organic phases were dried over

MgSO4 and concentrated in vacuo. The residue was purified by column chromatography.

178 Chapter 7

Modification of GP10: Use of LHMDS as base (GP11).

N

F3C Cl

HO RLHMDS, THF, −78 °C

OMe

+

F3C

N

O

OMe

R

R'

R'

235 5b 7b

Alternatively, LHMDS (or NaHMDS), commercially available as 1 M solutions in THF, were

used: To a solution of the allylic alcohol 5b in THF (2 mL/mmol) at –78 °C is added LHMDS (1 M

in THF, 1 equiv.). After stirring at this temperature for 5 min, a solution of 2,2,2-trifluoro-N-(4-

methoxy-phenyl)-acetimidoyl chloride (235) (1.0 equiv.) is added neat. The solution is allowed to

warm to RT and stirred for 2 h. Instead of an aqueous work-up, the reaction is then quenched by

addition of silica gel and MTBE, followed by filtration and solvent removal. The crude residue is

purified by column chromatography.

Results were identical if at the end of the reaction time, the solvent was directly removed, though

column chromatography may become difficult due to large amounts of lithium chloride which can

block the column. These modifications were used for the synthesis of 3,3-disubstituted imidates 7b.

To avoid side-reactions in allylic alcohols bearing an alcoholate-sensitive functional group, the

following modification of GP9 was used:

LHMDS and imidochloride 235 are added simultaneously to a solution of the allylic alcohol in

THF (ca. 2 mL/mmol) at –78 °C. All further manipulations are identical to GP10.

Commercially Available Allylic Alcohols.

The following allylic alcohols used in these investigations are commercially available in

sufficiently high isomerical purity:

Trans-2-hexenol (E)-197, cis-2-hexenol (Z)-197, trans-cinnamol (E)-199.

OH OH OH

(E )-197 (Z)-197 (E )-199

Via HWE-reaction:

The following allylic alcohols were prepared according to literature procedures utilising the

Horner-Wadsworth-Emmons reaction, followed by chromatographic separation of isomers and

subsequent reduction with DIBAL:

Experimental 179

Trans-5-phenyl-pent-2-enol (254),7 trans-3-methyl-pent-2-enol (255),8 trans-3-cyclohexyl-prop-2-

enol (256),9 and trans-4,4-dimethyl-pentenol (242)10

OH OH

OH OH

254 255

256 242

Representative procedure for HWE and DIBAL-reduction – (2E, 4E)-2,4-octadienol 239.

O

EtOOHO (EtO)2P(O)CH2CO2Et,

BuLi, DME, thentrans-hex-2-enal

DIBAL, DCM−78 °C -> RT

65% 93%257 239238

To a solution of triethylphosphonacetate (2.24 g, 1.99 mL, 10 mmol, 1 equiv.) in dry DME (20 mL)

at 0 °C was added nBuLi (1.6 M in hexane, 6.25 mL, 10 mmol, 1 equiv.). The solution was allowed

to warm to RT and placed in a water bath at this temperature, then trans-2-hexenal (238, 1.08 g, 11

mmol, 1.1 equiv.) was added in one portion. The resulting turbid mixture was stirred for 2h, then

water and sat. ammonium chloride solution were added. The mixture was extracted twice with

MTBE, the combined organic phases were washed with brine and dried over MgSO4. Removal of

the solvent under reduced pressure gave a yellowish oil (crude E:Z-ratio ca. 10:1, determined by

NMR) that was purified by column chromatography (pentane/6% Et2O) to give 257 as colourless

oil (1.09 g, 6.49 mmol, 65%, not optimised). [1H-NMR (300 MHz, CDCl3, 21 °C): δ = 7.26 (dd, J

= 15.6 Hz, J = 10.2 Hz, 1 H, Pr-CH=CH-CH=CHCO2Et), 6.21 – 6.08 (m, 2 H, Pr-CH=CH-

CH=CHCO2Et), 5.77 (d, J = 15.3 Hz, 1 H, Pr-CH=CH-CH=CH-CO2Et), 4.20 (q, J = 7.2 Hz, 2 H,

OCH2CH3), 2.15 (q, J = 6.0 Hz, 2 H, CH2CH2CH3), 1.55 – 1.31 (m, 2 H, CH2CH2CH3), 1.29 – 1.21

(t, J = 7.2 Hz, 3 H, OCH2CH3), 0.90 (t, J = 7.5 Hz, 3 H, CH2CH2CH3)].

To a solution of the ester (257, 1.09 g, 6.49 mmol, 1 equiv.) in DCM (15 mL) at –78 °C was added

DIBAL (1 M in DCM, 17 mL, 17 mmol, 2.6 equiv.) in one portion. The solution was allowed

warm to RT, then cooled again to –78 °C after 1h, and carefully aqueous hydrochloric acid (1 M)

was added until all solid had dissolved. The mixture was extracted with DCM twice, the combined

organic phases were dried over MgSO4 and the solvent was removed under reduced pressure to

180 Chapter 7

give alcohol 239 (0.77 g, 6.11 mmol, 93%) as colourless oil that did not require further

purification.

C8H14O, MW: 126.20 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 6.21 (dd, J = 14.1 Hz, J =

10.8 Hz, 1 H, Pr-CH=CH-CH=CH2OH), 6.05 (dd, J = 15.0 Hz, J = 10.5 Hz, 1 H, Pr-CH=CH-

CH=CH2OH), 5.77 – 5.66 (m, 2 H, Pr-CH=CH-CH=CHCH2OH), 4.16 (app t, J = 5.4 Hz, 2 H,

CH2OH), 2.07 (q, J = 6.9 Hz, 2 H, CH2CH2CH3), 1.55 – 1.31 (m, 2 H, CH2CH2CH3), 1.29 (t, J =

6.0 Hz, 1 H, OH), 0.91 (t, J = 6.6 Hz, 3 H, CH2CH2CH3)]. All other analytical data were in

accordance with the literature.11

Via cuprate-addition: The following α,β-unsaturated ester could also be prepared by CuI-mediated 1,4-addition of

alkylmagnesium halides to methylpropiolate and were subsequently reduced with DIBAL:

Representative procedure: Trans-methyl-(5-phenyl)-pent-2-enoate 258.

O

OMe

H CO2Me

CuI, Ph(CH2)2MgBr,TMEDA, THF, −40 °C to −78 °C

Ph200 258

Magnesium turnings were activated by grinding inside a glovebox in a mortar, the metal (0.960 g,

40 mmol, ca. 1.3 equiv.) was suspended in THF (30 mL) and a few drops of a solution of iodine in

MTBE were added. Then 2-phenylethylbromide (5.500 g, 30 mmol, 1 equiv.) was added

portionwise at RT. After addition of the first portion, the flask was placed in an ultrasonic bath for

five minutes or until the reaction had started, visible by the disappearance of the yellow color of

iodine. The temperature was kept below 45 °C by cooling in a water bath.

A suspension of CuI (6.650 g, 35 mmol, ~1.2 equiv.) in THF (50 mL) was cooled to ca – 40 °C.

TMEDA (N,N,N’,N’-tetramethylethylenediamine) (12.20 g, 15.80 mL, 105 mmol, 3 equiv.) was

subsequently added followed by the solution of 2-phenylethylmagnesiumbromide (30 mL, 30

mmol, 1 equiv.). The grey suspension, which may turn to yellow-brown, was stirred at – 40 °C for

30 min and then cooled to – 78 °C. Methyl propiolate (200, 2.52 g, 2.70 mL, 30 mmol, 1 equiv.)

was added in one portion and the resulting grey to orange suspension was stirred for 2 h at –78 °C.

The reaction was quenched by addition of methanol (technical grade, ca. 10 mL) and the cooling

bath was subsequently removed. Saturated aqueous ammonium sulfate (ca. 10 mL) was added and

the suspension was warmed to RT. Aqueous ammonia (ca. 20%) was added until complete

dissolution of all solids, followed by extraction with MTBE (2 x) and washing of the combined

organic phases with additional aqueous ammonia. The solution was dried over MgSO4 and the

Experimental 181

volatiles were removed in vacuo. The (E)/(Z)-ratio of 95:5 was determined by 1H-NMR (significant

signals: olefinic protons). The isomers were separated by column chromatography

(pentane/diethylether 16:1) to give the desired (E)-isomer as a colorless oil (4.156 g, 21.8 mmol,

73%).

C12H14O2, MW: 190.23 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.31 − 7.16 (m, 5 H,

C6H5), 7.00 (dt, J = 15.9 Hz, J = 9.3 Hz, 1 H, CH2CH=CH), 5.84 (d, J = 15.9 Hz, CH2CH=CH),

3.72 (s, 3 H, OCH3), 2.76 (t, J = 7.2 Hz, 2 H, PhCH2CH2), 2.45 (dt, J = 9.3 Hz, J = 7.2 Hz,

PhCH2CH2). All other analytical data were in accordance with the literature.7

Trans-methyl-(3-methyl)-but-2-enoate 259.

O

OMe

259 Following the procedure used for 258 with iso-propyl magnesium chloride, ester 259 was obtained

in 26% yield. The undesired isomer was below the detection limit (1H NMR).

C7H12O2, MW: 128.16 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 6.94 (dd, J = 15.9 Hz, J =

6.9 Hz, 1 H, CHCH=CH), 5.76 (d, J = 15.9 Hz, 1 H, CHCH=CH), 3.73 (s, 3 H, OCH3), 2.52-2.40

(m, 1 H, CH(CH3)2), 1.05 & 1.00 (d, J = 6.9 Hz, 3 H each, CH(CH3)2). All other analytical data

were in accordance with the literature.

Derivatives of trans-cinnamol were prepared from commercially available cinnamic acid

derivatives:

(E)-p-Trifluoromethyl-cinnamol 234a.

CF3

HO2CCF3

MeO2CK2CO3,MeI, DMF

CF3

HODIBAL, DCM−78 °C -> RT

95% over 2 steps

232a

233a

4-Trifluoromethyl-cinnamic acid (232a, 1.00 g, 4.6 mmol, 1 equiv.) and potassium carbonate (0.69

g, 5 mmol, ca. 1.1 equiv.) were suspended in DMF (10 mL). Methyl iodide (0.71 g, 0.31 mL, 5

mmol, ca. 1.1 equiv.) was added in one portion and the mixture was stirred over night. After

addition of saturated aqueous ammonium chloride (ca. 10 mL), the mixture was stirred for 30 min,

182 Chapter 7

then it was extracted with MTBE twice. The combined organic phases were washed twice with

brine, then dried over MgSO4. After removing the solvent under reduced pressure, the ester was

obtained as off-white solid which was used in the next step without further purification. [1H-NMR

(300 MHz, CDCl3, 21 °C): δ = 7.73 – 7.63 (m, 5 H, CHCHCO2Me and aromatic H), 6.50 (d, J =

16.2 Hz, 1 H, CHCHCO2Me), 3.82 (s, 3 H, CO2CH3)].

To a solution of the ester in DCM (20 mL) at –78 °C was added DIBAL (1.1 M in CyH, 11.3 mL,

12.5 mmol, ca. 2.7 equiv.) in one portion. After 30 min stirring at –78 °C, the solution was slowly

warmed to 0 °C and stirred for 1 h, then cooled again to –78 °C. The reaction was quenched by

dropwise addition of 1 N aqueous HCl. After warming to RT, additional 6 N HCl and DCM were

carefully added until complete dissolution of the precipitate. The aqueous phase was extracted

twice with DCM and the combined organic phases were dried over MgSO4. Subsequent solvent

removal under reduced pressure gave alcohol 233a (0.884 g, 4.37 mmol, 95% over two steps) as

off-white solid which did not require further purification.

C10H9F3O, MW: 202.17 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.58 (d, J = 8.4 Hz, 2 H,

aromatic H), 7.47 (d, J = 8.4 Hz, 2 H, aromatic H), 6.67 (d, J = 15.9 Hz, 1 H, CH=CHCH2OH),

6.48 (dt, J = 10.5 Hz, J = 5.4 Hz, 1 H, CH=CHCH2OH), 4.36 (app t, J = 5.7 Hz, 2 H, CH2OH),

1.56 (t, J = 6.0 Hz, 1 H, OH). All other analytical data were in accordance with the literature.12

(E)-p-Chloro-cinnamol 233b.

ClHO2C

i. K2CO3, MeI, DMFii. DIBAL, DCM−78 °C -> RT Cl

HO

91% over 2 steps232b 233b

4-Chloro-cinnamic acid (232b, 1.82 g, 10 mmol, 1 equiv.) and potassium carbonate (1.38 g, 10

mmol, 1 equiv.) were suspended in DMF (10 mL). Methyl iodide (2.13 g, 0.93 mL, 15 mmol, 1.5

equiv.) was added in one portion and the mixture was stirred for 2 d or until complete conversion

was observed by HPLC. After addition of aqueous saturated ammonium chloride (ca. 10 mL), the

mixture was stirred for 30 min, then it was extracted with MTBE twice. The combined organic

phases were washed two times with brine, then dried over MgSO4. After removing the solvent

under reduced pressure, the ester was obtained as off-white solid which was used in the next step

without further purification. [1H-NMR (300 MHz, CDCl3, 21 °C): δ = 7.63 (d, J = 15.9 Hz, 2 H,

CHCHCO2Me), 7.43 (d, J = 8.7 Hz, 2 H, aromatic H), 7.35 (d, J = 8.7, 2 H, aromatic H), 6.40 (d, J

= 15.9 Hz, 1 H, CHCHCO2Me), 3.81 (s, 3 H, CO2CH3)].

To a solution of the ester in DCM (20 mL) at –78 °C was added DIBAL (1 M in DCM, 25 mL, 25

mmol, ca. 2.7 equiv.) in one portion. After 30 min stirring at –78 °C, the solution was slowly

Experimental 183



added carefully until complete dissolution of the precipitate. The aqueous phase was extracted


removal under reduced pressure gave alcohol 233b (1.520 g, 9.01 mmol, 91% over two steps) as


C9H9ClO, MW: 168.62 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.32 – 7.25 (m, 4 H,

C6H4Cl), 6.60 (d, J = 18.9 Hz, 1 H, CH=CHCH2OH), 6.33 (dt, J = 18.9 Hz, J = 5.7 Hz, 1 H,

CH=CHCH2OH), 4.32 (app. t, J = 4.5 Hz, 2 H, CH2OH), 1.63 (t, J = 5.4 Hz, 1 H, OH).

All other analytical data were in accordance with the literature.13

(E)-p-Methyl-cinnamol 233c. HO2C MeO2CK2CO3,

MeI, DMF

HODIBAL, DCM−78 °C -> RT

89% over 2 steps233c

232c

4-Methyl-cinnamic acid (232a, 1.62 g, 10 mmol, 1 equiv.) and potassium carbonate (1.38 g, 10

mmol, 1 equiv.) were suspended in DMF (10 mL). Methyl iodide (2.13 g, 0.93 mL, 15 mmol, 1

equiv.) was added in one portion and the mixture was stirred over night or until complete

conversion was observed by HPLC. After addition of aqueous saturated ammonium chloride (ca.

10 mL), the mixture was stirred for 30 min, then it was extracted with MTBE twice. The combined

organic phases were washed twice with brine, then dried over MgSO4. After removing the solvent

under reduced pressure, the ester was obtained as off-white solid which was used in the next step

without further purification. [1H-NMR (300 MHz, CDCl3, 21 °C): δ = 7.69 (d, J = 15.9 Hz, 2 H,

CHCHCO2Me), 7.42 (d, J = 7.8 Hz, 2 H, aromatic H), 7.19 (d, J = 7.8 Hz, 2 H, aromatic H), 6.40

(d, J = 15.9 Hz, 1 H, CHCHCO2Me), 3.80 (s, 3 H, CO2CH3), 2.37 (s, 3 H, C6H4CH3)].

To a solution of the ester in DCM (20 mL) at –78 °C was added DIBAL (1 M in DCM, 25 mL, 25

mmol, ca. 2.7 equiv.) in one portion. After 30 min stirring at –78 °C, the solution was slowly



added carefully until complete dissolution of the precipitate. The aqueous phase was extracted


removal under reduced pressure gave alcohol 233c (1.316 g, 8.89 mmol, 89% over two steps) as


184 Chapter 7

C10H12O, MW: 148.20 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.29 (d, J = 8.4 Hz, 2 H,


6.33 (dt, J = 11.7 Hz, J = 5.7 Hz, 1 H, CH=CHCH2OH), 4.32 (d, J = 5.7 Hz, 2 H, CH2OH), 2.34 (s,

3 H, CH3), 1.50 (bs, 1 H, OH). All other analytical data were in accordance with the literature.

(E)-p-Methoxy-cinnamol 233d.

OMeNaBH4, EtOH0 °C to RT OMe

HOO

quant.236 233d

To a solution of 4-methoxy-cinnamaldehyde (236, 1.62 g, 10 mmol, 1 equiv.) in EtOH (20 mL) at 0

°C was added sodium borohydride (0.39 g, 10 mmol, 1 equiv.) in one portion. The resulting turbid

mixture was stirred at RT for 30 min, then it was cooled again to 0 °C and acetone (ca. 5 mL) was

added. After stirring for 10 min, sat. aqueous ammonium chloride and water were added and the

mixture was extracted 2x with MTBE. The combined organic phases were dried over MgSO4 and

the solvent was removed under reduced pressure to give alcohol 233d (1.64 g, 10 mmol, quant.

yield) as yellow solid which could be used in the next step without further purification.

C10H10O2, MW: 164.20 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.31 (d, J = 9.0 Hz, 2 H,


6.33 (dt, J = 15.9 Hz, J = 5.7 Hz, 1 H, CH=CHCH2OH), 4.30 (d, J = 5.7 Hz, 2 H, CH2OH), 3.81 (s,

3 H, CH3), 1.50 (bs, 1 H, OH). All other analytical data were in accordance with the literature.13

3,3-Disubstituted Allylic Alcohols and Precursors.

Ethyl-2-butynoate 260. BuLi, THF, −78 °C,then chloroethylformate,−78 °C to RT

Me H Me CO2Et81%

260 Propyne (6.0 g, 0.150 mol, 1 equiv.) was condensed at –78 °C into a flask containing THF (100

mL). n-Butyllithium (1.6 M in hexane, 93 mL, 0.150 mol, 1 equiv.) was added via cannula within

10 min and the resulting turbid mixture was stirred at –78 °C for 30 min. Ethylchloroformate (17.4

g, 15.4 mL, 0.160 mol, 1.07 equiv.) was added in one portion. After 10 min, the mixture was

allowed to warm to RT, then saturated aqueous ammonium chloride (ca. 10 mL) was added

resulting in the formation of a white precipitate. The suspension was washed with water (50 mL),

the organic phase was dried over MgSO4 and most of the solvent was removed in vacuo.

Experimental 185

Distillation (60 mbar, 80 °C bath temperature) afforded 260 as colorless oil (13.76 g, 0.122 mol,

81%).

C6H8O2, MW: 112.13 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 4.20 (q, J = 7.2 Hz, 2 H,

CO2CH2CH3), 1.97 (s, 3 H, CCCH3), 1.29 (t, J = 7.2 Hz, 3 H, CO2CH2CH3). All other analytical

data were in accordance with the purchased material.

(E)-3-Methyl-5-phenylpent-2-enoic acid methyl ester 261.

Me

O

OMe1. Mg, THF, RT2. CuI, TMEDA, −40 °C

3. methyl-2-butynoate (262),−78 °C (88%)

PhBr

Ph261

Magnesium turnings were activated by grinding inside a glovebox in a mortar, the metal (0.840 g,

35 mmol, ca. 1.4 equiv.) was suspended in THF (50 mL) and a few drops of a solution of iodine in

MTBE were added. Then 2-phenylethylbromide (4.625 g, 25 mmol, 1 equiv.) was added

portionwise at RT. After addition of the first portion, the flask was placed in an ultrasonic bath for

five minutes or until the reaction had started, visible by the disappearance of the yellow color of

iodine. The temperature was kept below 45 °C by cooling in a water bath.

A suspension of CuI (1.840 g, 9.6 mmol, 1.2 equiv.) in THF (25 mL) was cooled to ca−40 °C.

TMEDA (N,N,N’,N’-tetramethylethylenediamine) (2.78 g, 3.61 mL, 24.0 mmol, 3 equiv.) was

subsequently added followed by the solution of 2-phenylethylmagnesiumbromide (16.0 mL, 8.0

mmol, 1 equiv.). The grey suspension, which may turn to yellow-brown, was stirred at – 40 °C for

30 min and then cooled to – 78 °C. Methyl-2-butynoate (262, 0.784 g, 784 µL, 8.0 mmol, 1.0

equiv.) was added in one portion and the resulting grey to orange suspension was stirred for 2 h at –

78 °C. The reaction was quenched by addition of methanol (technical grade, ca. 10 mL) and the

cooling bath was subsequently removed. Saturated aqueous ammonium sulfate (ca. 10 mL) was

added and the suspension was warmed to RT. Aqueous ammonia (ca. 20%) was added until

complete dissolution of all solids, followed by extraction with MTBE (2 x) and washing of the

combined organic phases with additional aqueous ammonia. The solution was dried over MgSO4

and the volatiles were removed in vacuo. The (E)/(Z)-ratio of 98:2 was determined by 1H-NMR

(allylic CH3-group: (E): 2.21 ppm, (Z): 1.89 ppm). The isomers were separated by column

chromatography (pentane/diethylether 16:1) to give the desired (E)-isomer as a colorless oil (1.440

g, 7.06 mmol, 88%). Similar results were obtained with ethyl ester 261.

C13H16O2, MW: 204.26 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.29 − 7.16 (m, 5 H, Ar-

H), 5.69 (app d, J = 1.2 Hz, 1H, C=CH), 3.68 (s, 3 H, OCH3), 2.78 (dd, J = 10.5 Hz, J = 7.8 Hz, 2

H, Ar-CH2-CH2), 2.45 (dd, J = 10.5 Hz, J = 7.8 Hz, 2 H, Ar-CH2-CH2), 2.21 (app d, J = 1.2 Hz,

186 Chapter 7

3H, C=C-CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 166.9, 159.1, 140.8, 128.3, 126.0, 115.5,

50.8, 42.7, 33.9, 19.0. IR (film, cm−1): ν = 3027, 2948, 1721, 1650, 1603, 1495, 1435, 1385, 1359,

1280, 1225, 1147, 1080, 1048. MS (EI) m/z: 91.0 [100%], 204.1 [2.2%, MH+]. HRMS (EI) m/z:

Calc. for [MH+]: 204.1145. Found: 204.1147. Anal. Calcd. for C13H16O2: C, 76.44; H, 7.89.

Found: C, 76.16, H, 7.91.

(E)-3-Methyl-5-phenylpent-2-enol 263.

Me

O

OMe

Ph

2.7 equiv. DIBAL,DCM, −78 °C to 0 °C Me OH

Ph97%261 263

(E)-3-Methyl-5-phenylpent-2-enoic acid methyl ester (1.440 g, 7.06 mmol, 1.0 equiv) was

dissolved in DCM (20 mL) and cooled to –78 °C. DIBAL (1 M in DCM or hexanes, 20 mL, 20

mmol, 2.8 equiv.) was added in portions within 1 min. After 30 min stirring at –78 °C, the solution

was slowly warmed to 0 °C and stirred for 1 h, then cooled again to –78 °C. The reaction was

quenched by dropwise addition of 1 N aqueous HCl. After warming to RT, additional 1 N HCl and

DCM were added until complete dissolution of the precipitate. The aqueous phase was extracted


removal under reduced pressure gave 263 (1.205 g, 6.84 mmol, 97%) as colorless oil which did not

require further purification.

C12H16O, MW: 176.25 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.30 − 7.28 (m, 2 H, Ar-

H), 7.20 − 7.16 (m, 2 H, Ar-H), 5.41 (t, J = 6.9, Hz 1 H, C=CH), 4.14 (t, J = 5.4 Hz, 2 H, CH2OH),

2.27 & 2.32 (t, J = 7.5 Hz, 2 H each, CH2CH2), 1.73 (s, 3 H, C=C-CH3), 1.03 (t, J = 5.4 Hz, 1 H,

CH2OH). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 141.8, 138.8, 128.25, 128.20, 125.7, 123.8,

59.2, 41.4, 34.4, 16.5. IR (film, cm−1): ν = 3334, 2927, 2858, 1669, 1602, 1495, 1453, 1382, 1001.

MS (EI) m/z: 91.0 [100%], 176.1 [3.3%, M+]. HRMS (EI) m/z: Calc. for [M+]: 176.1196. Found:

176.1198. Anal. Calcd. for C12H16O: C, 81.77; H, 9.15. Found: C, 81.66, H, 9.23.

(E)-Methyl 3-methyl-4-phenylbut-2-enoate 264.

CO2MeCuI, TMEDA, −40 °CBnMgCl, THF, −78 °C Ph

O

OMe

76% 264 A suspension of CuI (1.840 g, 9.6 mmol, 1.2 equiv.) in THF (25 mL) was cooled to ca. −40 °C.

TMEDA (N,N,N’,N’-tetramethylethylenediamine) (2.78 g, 3.61 mL, 24.0 mmol, 3 equiv.) was

subsequently added followed by the solution of benzylmagnesiumchloride (8.0 mL, 8.0 mmol, 1

equiv.). The grey suspension, which may turn to yellow-brown, was stirred at −40 °C for 30 min

Experimental 187

and then cooled to −78 °C. Methyl-2-butynoate (0.784 g, 784 μL, 8.0 mmol, 1.0 equiv.) was added

in one portion and the resulting grey to orange suspension was stirred for 2 h at −78 °C. The

reaction was quenched by addition of methanol (technical grade, ca. 10 mL) and the cooling bath

was subsequently removed. Saturated aqueous ammonium sulfate (ca. 10 mL) was added and the

suspension was warmed to RT. Aqueous ammonia (ca. 20%) was added until complete dissolution

of all solids, followed by extraction with MTBE (2 x) and washing of the combined organic phases

with additional aqueous ammonia. The solution was dried over MgSO4 and the volatiles were

removed in vacuo. The isomers were separated by column chromatography (pentane/diethylether

16:1) to give the desired (E)-isomer as a colorless oil (1.15 g, 6.04 mmol, 76%).

C12H14O2, MW: 190.24 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.25 − 7.14 (m, 5 H,

C6H5), 5.69(m, 1H, C=CH), 3.75 (s, 3H, OCH3), 3.43 (s, 3H, CH3). All other analytical data were in

accordance with the literature.15

(E)-3-Methyl-4-phenylbut-2-en-1-ol 265.

2.7 equiv. DIBAL,DCM, −78 °C to 0 °CPh

O

OMe

Ph87%264 265

OH

(E)-3-Methyl-4-phenylbut-2-enoic acid methyl ester (1.150 g, 6.04 mmol, 1.0 equiv) was dissolved

in DCM (20 mL) and cooled to −78 °C. DIBAL (1 M in DCM, 16.9 mL, 16.9 mmol, 2.8 equiv.)

was added in portions within 1 min. After 30 min stirring at −78 °C, the solution was slowly

warmed to 0 °C and stirred for 1 h, then cooled again to −78 °C. The reaction was quenched by


added until complete dissolution of the precipitate. The aqueous phase was extracted twice with

DCM and the combined organic phases were dried over MgSO4. Subsequent solvent removal under

reduced pressure gave (855 g, 5.27 mmol, 87%) as colorless oil which did not require further

purification.

C11H14O, MW: 162.23 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.25 − 7.16 (m, 5 H,

C6H5), 5.52 − 5.46 (m, 1H, C=CH), 4.19 (d, J = 6.9 Hz, 2H, OCH2), 3.32 (s, 3H, CH3), 1.33 (bs,

1H, CH2OH). All other analytical data were in accordance with the literature.15

(E)-3-Methylhept-2-enol 268. 2.7 equiv. DIBAL,DCM, −78 °C to 0 °C

CO2Et

BuLi, CuI,THF, −78 °C

Bu

Me

O

OEt

Bu

Me OH

90%266 267 268

188 Chapter 7

3-Methylhept-2-enoic acid ethyl 267 ester was prepared by CuI-mediated addition of BuLi to

ethylbutynoate 266, following a literature procedure. To a solution of this ester (0.520 g, 1.88

mmol, 1.0 equiv.) in DCM (10 mL) at −78 °C was added DIBAL (1 M in DCM, 5 mL, 5 mmol, 2.7

equiv.) in portions within 1 min. After 30 min stirring at −78 °C, the solution was slowly warmed

to 0 °C and stirred for 1 h, then cooled again to −78 °C. The reaction was quenched by dropwise

addition of 1 N aqueous HCl. After warming to RT, additional 1 N aqueous HCl and DCM were



reduced pressure gave 268 (0.400 g, 1.7 mmol, 90%) as colorless oil which did not require further

purification.

C8H16O, MW: 128.21 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 5.36 (t, J = 0.9 Hz, 1 H,

C=CH), 4.10 (d, J = 5.4 Hz, 2 H, CH2OH), 1.98 (t, J = 7.2 Hz, 2 H, CH2CH2CH2CH3), 1.89 (bs, 1

H, OH), 1.63 (s, 3 H, C=CCH3), 1.39 −1.27 (m, 4 H, CH2CH2CH2CH3), 0.89 (t, J = 6.9 Hz, 3 H,

CH2CH2CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 139.7, 124.0, 59.1, 39.1, 29.7, 22.2,

15.9, 13.8. IR (film, cm−1): ν = 3330, 2958, 2873, 1670, 1467, 1380, 1238, 1181, 1075, 999, 789,

730. MS (EI) m/z: 128.1 [4.5%, M+]. HRMS (EI) m/z: Calc. for [M+]: 128.1196. Found:

128.1195. Anal. Calcd. for C8H16O: C, 74.94; H, 12.58. Found: C, 74.65; H, 12.44.

4-Benzyloxybut-2-ynoic acid ethyl ester 271.

HO BnO BnO OEt

O

1. NaH, DMF2. BnBr

1. BuLi, THF, −78 °C2. Cl-COOEt

75% 72%269 270 271

Propargylic alcohol (269, 3.360 g, 3.48 mL, 60 mmol, 1 equiv.) was added in portions to a

suspension of NaH (60% in mineral oil, 2.40 g, 60 mmol, 1 equiv.) in DMF (100 mL) at 0 °C.

After 30 min at RT, the now homogeneous solution was cooled again to 0 °C and benzyl bromide

(10.26 g, 7.20 mL, 60 mmol, 1 equiv.) was added. The solution was stirred for 30 min at RT, then

ammonia (in water or methanol, 20 mL of a saturated solution) was added and the mixture was

stirred at RT overnight. Water was added and the mixture was extracted three times with MTBE.

The combined organic phases were washed three times with water and once with 1 N aqueous HCl

and were then dried over MgSO4. The solvent was removed in vacuo to give benzyl propargylether

270 as slightly yellowish oil (6.570 g, 45 mmol, 75%) after filtration over silica with pentane/Et2O

1:1. [1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.37 − 7.26 (m, 5 H, Ar-H), 4.62 (s, 2 H, PhCH2O),

4.18 (s, 2 H, BnOCH2), 2.47 (s, 1 H, CH).]

Experimental 189

Benzyl propargylether (3.30 g, 22.6 mmol, 1.0 equiv.) was dissolved in THF (30 mL) and cooled to

−78 °C. nBuLi (1.6 M in hexanes, 15.0 mL, 24.0 mmol, 1.06 equiv.) was added and the solution

was stirred for 30 min followed by addition of ethylchloroformate (2.72 g, 2.40 mL, 25 mmol, 1.1

equiv.). After five minutes, the reaction mixture was allowed to warm to RT and then quenched by

addition of saturated aqueous ammonium chloride. After addition of water the aqueous phase was

extracted twice with MTBE, the combined organic phases were dried over MgSO4 and the solvent

was removed under reduced pressure. Column chromatography (pentane/diethylether 16:1 →

pentane/diethylether 1:1) gave 271 as colorless to slightly yellow oil (3.560 g, 16.3 mmol, 72%)

which contained an unidentified impurity. Alternatively, 271 can be purified by distillation

(Kugelrohr distillation, 0.1 mbar, 170 °C).

C13H14O3, MW: 218.25 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.36 −7.26 (m, 5 H, Ar-

H), 4.62 (s, 2 H, C6H5CH2O), 4.29 (s, 2 H, OCH2CCCOOEt), 4.24 (q, J = 7.2 Hz, 2 H, OCH2CH3),

1.32 (t, J = 7.2 Hz, 3 H, OCH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 152.9, 136.7, 128.6,

128.4, 128.2, 128.0, 128.0, 68.1, 78.3, 72.0, 62.1, 56.8, 14.1. IR (film, cm−1): ν = 2983, 2859,

2235, 1715, 1455, 1366, 1251, 1090, 1056, 749, 698. MS (EI): no unambiguously assignable peak

was found. Anal. Calcd. for C13H14O3: C, 71.54; H, 6.47; Found: C, 71.52; H, 6.70.

(Z)-4-Benzyloxy-3-methylbut-2-enoic acid ethyl ester 272.

BnO OEt

O O

OEtBnOCuI, MeLi,

THF, −78 °C

95%271 272

CuI (1.140 g, 6.0 mmol, 1.1 equiv.) was suspended in THF (16 mL) and cooled to ca −40 °C. To

the suspension was added MeLi (1.6 M in diethylether, 3.50 mL, 5.5 mmol, 1 equiv.). The mixture

was stirred at −40 °C for 30 min and was then cooled to −78 °C. A solution of 4-benzyloxybut-2-

ynoic acid ethyl ester (271, 1.200 g, 5.5 mmol, 1 equiv.) in THF (4 mL) was added in one portion

and the resulting suspension was stirred for 4 h at −78 °C. The reaction was quenched by addition

of methanol (technical grade, ca. 2 mL), and the cooling bath was subsequently removed. Saturated

aqueous ammonium chloride (ca. 10 mL) was added. The mixture was extracted three times with

MTBE, and the combined organic phases were dried over MgSO4. The solvent was removed under

reduced pressure and the residue was purified by column chromatography (pentane/Et2O 16:1) to

give (Z)-4-benzyloxy-3-methylbut-2-enoic acid ethyl ester 272 as colorless oil (1.222 g, 5.22

mmol, 95%). The (E)-isomer could not be detected by 1H-NMR.


H), 5.77 (t, J = 1.5 Hz, 1H, C=CH), 4.68 (s, 2 H, CH2Ph), 4.52 (s, 2 H, CH2OBn), 4.14 (q, J = 7.2

190 Chapter 7

Hz, 2 H, OCH2CH3), 2.02 (s, 3 H, C=C-CH3), 1.27 (t, J = 6.9 Hz, 3 H, OCH2CH3). 13C NMR (75

MHz, CDCl3, 21 °C): δ = 165.7, 156.8, 138.1, 128.2, 127.5, 117.2, 72.7, 69.3, 59.8, 21.8, 14.4. IR

(film, cm−1): ν = 3032, 2981, 2860, 1713, 1649, 1497, 1445, 1375, 1336, 1223, 1150, 1096, 1065,

1029, 852. MS (EI) m/z: 91.0 [100%], 235.1 [0.1%, MH+]. HRMS (EI) m/z: Calc. for [MH+]:

235.1329. Found: 235.1329. Anal. Calcd. for C14H18O3: C, 71.77; H, 7.75. Found: C, 71.81, H,

7.90.

(Z)-4-Benzyloxy-3-methylbut-2-enol 273.

O

OEtBnO 2.7 equiv. DIBAL

DCM, −78 °C to 0 °C OHBnO

80%

272 273 (Z)-4-Benzyloxy-3-methylbut-2-enoic acid ethyl ester (272, 1.220 g, 5.2 mmol, 1 equiv.) was

dissolved in DCM (10 mL) and cooled to −78 °C. DIBAL (1 M in DCM or hexanes, 14.0 mL, 14.0

mmol, 2.7 equiv.) was added in portions within 1 min. After 30 min stirring at −78 °C, the solution

was slowly warmed to 0 °C and stirred for 1 h, then cooled again to −78 °C and quenched by

dropwise addition of 1 N HCl. After warming to RT, additional 1 N aqueous HCl and DCM were



reduced pressure gave 273 (0.800 g, 4.16 mmol, 80%) as colorless oil which did not require further

purification.


H), 5.63 (t, J = 6.9 Hz, 1H, C=CH), 4.48 (s, 2 H, CH2Ph), 4.09 (t, J = 6.0 Hz, CH2OH), 4.02 (s, 2

H, CH2OBn), 2.36 (app d, J = 4.5 Hz, 1H, CH2OH), 1.83 (d, J = 1.2 Hz, 3 H, C=C-CH3). 13C NMR

(75 MHz, CDCl3, 21 °C): δ = 137.9, 135.8, 128.4, 128.3, 127.7, 72.2, 68.6, 58.5, 22.1. IR (film,

cm−1): ν = 3390, 2064, 3031, 2971, 2917, 2862, 1671, 1606, 1496, 1453, 1366, 1311, 1248, 1205,

1073, 1027, 1000, 738, 698. MS (EI) m/z: 91.0 [100%], 174.1 [1.5%, (M-H2O)+]. HRMS (EI)

m/z: Calc. for [(M-H2O)+]: 174.1039. Found: 174.1040. Anal. Calcd. for C12H16O2: C, 74.97; H,

8.39. Found: C, 74.70; H, 8.22.

Experimental 191

(Z)-4-Benzyloxy-3-ethylbut-2-enoic acid ethyl ester 274.

BnO OEt

O Et O

OEtBnOCuI, EtMgBr,

TMEDA, THF, −78 °C

49%271 274

To a suspension of CuI (0.950 g, 5.0 mmol, 1.25 equiv.) in THF (30 mL) at −40 °C

ethylmagnesiumbromide (3 M in diethylether, 1.34 mL, 4 mmol, 1 equiv.) and TMEDA (1.74 g,

2.26 mL, 15.0 mmol, 3.75 equiv.) were added successively. The grey suspension which may turn to

purple was stirred at −40 °C for 30 min and then cooled to −78 °C. 4-Benzyloxybut-2-ynoic acid

ethyl ester (271, 0.872 g, 4.0 mmol, 1.0 equiv.) was added in one portion and the resulting

suspension was stirred for 2 h at −78 °C. The reaction was quenched by dropwise addition of

methanol (technical grade, ca. 5 mL) and the cooling bath was subsequently removed. Saturated

aqueous ammonium sulfate (ca. 5 mL) was added and the suspension was allowed to warm to RT.

Then aqueous ammonia (ca. 20%) was added until complete dissolution of all solids, followed by

extraction with MTBE (2 x) and washing of the combined organic phases with additional aqueous

ammonia and brine. The solution was dried over MgSO4 and the volatiles were removed in vacuo.

Purification by column chromatography (pentane/Et2O 16:1) afforded (Z)-4-benzyloxy-3-ethylbut-

2-enoic acid ethyl ester 274 (492 mg, 1.98 mmol, 49%) as a colorless oil. The (E)/(Z)-ratio of 4:96

was determined by 1H-NMR (characteristic signals: E: 5.95 ppm, Z: 5.74 ppm, C=CH).

BnO OEt

O Et O

OEtBnO

CuI, EtLi, THF, −78 °C

68%271 274

Utilising a procedure analogous to 274, but with EtLi (1.7 M in Bu2O), 271 (3.600 g, 16.5 mmol, 1

equiv.) was converted to 274 (2.790 g, 11.2 mmol, 68% yield). The other isomer could not be

detected (1H-NMR).


H), 5.75 (t, J = 1.5 Hz, 1 H, C=CH), 4.69 (s, 2 H, CH2Ph), 4.52 (s, 2 H, CH2OBn), 4.14 (q, J = 7.2

Hz, 2 H, OCH2CH3), 2.38 (q, J = 7.5 Hz, 2 H, C=C-CH2CH3), 1.25 (t, J = 6.9 Hz, 3 H, OCH2CH3),

1.10 (t, J = 7.5 Hz, 3 H, C=C-CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 166.1, 161.5,

128.2, 128.2, 127.5, 127.4, 115.6, 72.6, 68.2, 59.7, 27.5, 14.1, 12.0. IR (film, cm−1): ν = 2975,

2934, 2878, 2363, 1713, 1647, 1497, 1454, 1377, 1309, 1212, 1150, 1074, 1036, 868, 736. MS

(EI) m/z: 91.0 [100%], 157.0 [25%, (M-C7H7)+]. HRMS (EI) m/z: Calc. for [M-C7H7)+]: 157.0860.

Found: 157.0860. Anal. Calcd. for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.47, H, 8.10.

192 Chapter 7

(Z)-4-Benzyloxy-3-ethylbut-2-enol 275.

Et O

OEtBnO 2.7 equiv. DIBAL,

DCM, −78 °C to 0 °C

Et

OHBnO

83%

274 275 (Z)-4-Benzyloxy-3-ethylbut-2-enoic acid ethyl ester (274, 0.434 g, 1.75 mmol, 1.0 equiv) was

dissolved in DCM (10 mL) and cooled to −78 °C. DIBAL (1.1 M in cyclohexane, 4.3 mL, 4.7

mmol, 2.7 equiv.) was added in portions within 1 min. After 30 min stirring at −78 °C, the solution

was slowly warmed to 0 °C and stirred for an additional hour, then cooled again to −78 °C and

quenched by dropwise addition of 1 N aqueous HCl. After warming to RT, additional 1 N HCl and

DCM were added until complete dissolution of the precipitate. The aqueous phase was extracted


removal under reduced pressure gave 275 (0.299 g, 1.45 mmol, 83%) as colorless oil which did not

require further purification.


H), 5.65 (t, J = 6.6 Hz, 1H, C=CH), 4.48 (s, 2 H, CH2Ph), 4.13 (d, J = 6.9 Hz, CH2OH), 4.02 (s, 2

H, CH2OBn), 2.40 (bs, 1H, CH2OH), 2.17 (q, J = 7.5 Hz, 2 H, C=C-CH2CH3), 1.04 (t, J = 7.5 Hz, 3

H, C=C-CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 141.1, 137.8, 128.3, 127.7, 127.6,

126.9, 72.3, 67.6, 58.5, 28.3, 12.2. IR (film, cm−1): ν = 3391, 3064, 3031, 2965, 2932, 2874, 1953,

1870, 1811, 1668, 1607, 1586, 1496, 1454, 1366, 1310, 1246, 1205, 1174, 1071, 1012. MS (EI)

m/z: 91.0 [100%], 188.1 [1.5%, (M-H2O)+]. HRMS (EI) m/z: Calc. for [(M-H2O)+]: 188.1196.

Found: 188.1196. Anal. Calcd. for C13H18O2: C, 75.69; H, 8.79. Found: C, 75.41; H, 8.69.

(Z)-3-Benzyloxymethylhept-2-enoic acid ethyl ester 276.

BnO OEt

O

CuI, BuLi,THF, −78 °C

Bu O

OEtBnO

73%271 276

To a suspension of CuI (0.760 g, 4 mmol, 1.33 equiv.) in THF (10 mL) at −40 °C nBuLi (1.6 M in

hexane, 2.06 mL, 3.3 mmol, 1.1 equiv.) was added. The grey suspension that may turn to purple

was stirred at −40 °C for 30 min and then cooled to −78 °C. 4-Benzyloxy-but-2-ynoic acid ethyl

ester (271, 0.654 g, 3.0 mmol, 1.0 equiv.) was added in one portion and the resulting suspension

stirred for 2 h at −78 °C. The reaction was quenched by dropwise addition of methanol (technical

grade, ca. 5 mL) and the cooling bath was subsequently removed. Saturated aqueous ammonium

sulfate (ca. 5 mL) was added and the suspension was allowed to warm to RT. Then aqueous

ammonia (ca. 20%) was added until complete dissolution of all solids, followed by extraction with

Experimental 193

MTBE (2 x) and washing of the combined organic phases with additional aqueous ammonia and

brine. The solution was dried over MgSO4 and the volatiles were removed in vacuo. Purification by

column chromatography (pentane/Et2O 16:1) afforded (Z)-3-benzyloxymethylhept-2-enoic acid

ethyl ester 276 (608 mg, 2.20 mmol, 73%) as a colorless oil. An unidentified impurity could only

be removed after the subsequent reduction step. The (Z)/(E)-ratio of > 100:1 was determined by 1H-

NMR (characteristic signals: E: 5.99 ppm, Z: 5.76 ppm, C=CH).


H), 5.76 (t, J = 1.5 Hz, 1H, C=CH), 4.68 (s, 2H, OCH2Ph), 4.52 (s, 2H, CH2OBn), 4.15 (q, J = 7.2

Hz, 2 H, OCH2H3), 2.35 (t, J = 8.1 Hz, 2 H, C=CH-CH2CH2CH2CH3), 1.60 − 1.29 (m, 4 H, C=CH-

CH2CH2CH2CH3), 1.29 (t, J = 7.2 Hz, 3H, OCH2CH3), 0.92 (t, J = 7.2 Hz, 3H, C=CH-

CH2CH2CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 166.0, 160.3, 138.2, 128.2, 127.5,

127.4, 116.5, 72.6, 68.0, 59.7, 34.4, 29.8, 22.3, 14.1, 13.8. IR (film, cm−1): ν = 2958, 2932, 2862,

1713, 1642, 1497, 1454, 1377, 1261, 1206, 1151, 1096, 1038, 735, 697. MS (EI) m/z: 91.0

[100%], 185.1 [25%, (M-C7H7)+]. HRMS (EI) m/z: Calc. for [(M-C7H7)+]: 185.1173. Found:

185.1173.

(Z)-3-Benzyloxymethylhept-2-enol 277.

Bu O

OEtBnO 2.7 equiv. DIBAL,

DCM, −78 °C to 0 °C

Bu

OHBnO

95%

276 277 (Z)-3-Benzyloxymethylhept-2-enoic acid ethyl ester (276, 0.278 g, 1.0 mmol, 1.0 equiv) was

dissolved in DCM (5 mL) and cooled to −78 °C. DIBAL (1.1 M cyclohexane, 2.5 mL, 2.75 mmol,

2.75 equiv.) was added in portions within 1 min. After 30 min stirring at −78 °C, the solution was

slowly warmed to 0 °C and stirred for an additional hour then cooled again to −78 °C and quenched

by dropwise addition of 1 N aqueous HCl. After warming to RT, additional 1 N HCl and DCM

were added until complete dissolution of the precipitate. The aqueous phase was extracted twice

with DCM and the combined organic phases were dried over MgSO4. After solvent removal under

reduced pressure the crude product was purified by column chromatography (pentane/Et2O 1:1)

furnishing 277 (0.224 g, 0.95 mmol, 95%) as a colorless oil.


H), 5.65 (t, J = 6.9 Hz, 1H, C=CH), 4.49 (s, 2 H, CH2Ph), 4.11 (t, J = 6.3 Hz, CH2OH), 4.01 (s, 2

H, CH2OBn), 2.25 (bs, 1H, CH2OH), 2.12 (t, J = 6.9 Hz, 2 H, C=C-CH2CH2CH2CH3), 1.44 − 1.28

(m, 4 H, C=C-CH2CH2CH2CH3), 0.91 (t, J = 7.2 Hz, 3 H, C=C-CH2CH2CH2CH3). 13C NMR (75

MHz, CDCl3, 21 °C): δ = 139.9, 137.8, 128.3, 127.9, 127.7, 127.6, 72.4, 67.6, 58.6, 35.5, 30.1,

22.5, 14.0. IR (film, cm−1): ν = 3368, 3031, 2956, 2929, 2860, 2363, 1664, 1496, 1454, 1363,

194 Chapter 7

1245, 1205, 1071, 1010. MS (EI) m/z: 91.0 [100%], 216.1 [1.2%, (M-H2O)+]. HRMS (EI) m/z:

Calc. for [(M-H2O)+]: 216.1509. Found: 216.1507. Anal. Calcd. for C15H22O2: C, 76.88; H, 9.46.

Found: C, 76.65; H, 9.49.

(Z)-3-Benzyloxymethyl-6-triisopropylsilanyloxyhex-2-enoic acid ethyl ester 278.

BnO OEt

O

CuI, TIPSO(CH2)3MgBrTMEDA, −78 °C, THF

O

OEtBnO

TIPSO67%

271 278 3-(Triisopropylsilyloxy)propylbromide was prepared following a literature procedure from 3-

bromopropanol and TIPSCl with imidazol as base in DCM at RT. Magnesium turnings were

activated by grinding in a mortar inside a glovebox, the metal (0.210 g, 5 mmol, ca. 1.2 equiv.) was

suspended in THF (5 mL), followed by addition of a few drops of a solution of iodine in MTBE.

Then 3-(triisopropylsilyloxy)propylbromide (1.220 g, 4.1 mmol, 1 equiv.) was added at RT in one

portion. The flask was placed in an ultrasonic bath until the reaction had started, visible by the

disappearance of the yellow color of iodine. The temperature was kept below ca. 45 °C by cooling

in a water bath. This Grignard solution (1 equiv., 5 mL, 4.1 mmol) was added to a suspension of

CuI (0.760 g, 4 mmol, 1.33 equiv.) in THF (10 mL) at −40 °C. The grey suspension that may turn

to purple was stirred at −40 °C for 30 min and then cooled to −78 °C. 4-Benzyloxy-but-2-ynoic

acid ethyl ester (271, 0.736 g, 3.5 mmol, 1.0 equiv.) was added in one portion and the resulting

suspension stirred for 2 h at −78 °C. The reaction was quenched by dropwise addition of methanol

(technical grade, ca. 5 mL) and the cooling bath was subsequently removed. After 0 °C was

reached, saturated aqueous ammonium sulfate (ca. 5 mL) was added and the suspension was

allowed to warm to RT. Then aqueous ammonia (ca. 20%) was added until complete dissolution of

all solids, followed by extraction with MTBE (2 x) and washing of the combined organic phases

with additional aqueous ammonia and brine. The solution was dried over MgSO4 and the volatiles

were removed in vacuo. Purification by column chromatography (pentane/Et2O 16:1) afforded (Z)-

3-benzyloxymethyl-6-triisopropylsilanyloxyhex-2-enoic acid ethyl ester 278 (1026 mg, 2.36 mmol,

67%) as a colorless oil. The (Z)/(E)-ratio of >100:1 was determined by 1H-NMR (characteristic

signals: E: expected ca. 6.00 ppm, Z: 5.77 ppm, C=CH).

C25H42O4Si, MW: 434.68 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.35 − 7.26 (m, 5 H, Ar-

H), 5.79 (t, J = 1.2 Hz, 1H, C=CH), 4.68 (s, 2H, OCH2Ph), 4.52 (s, 2H, CH2OBn), 4.15 (q, J = 7.2

Hz, 2 H, OCH2H3), 3.72 (t, J = 6.3 Hz, 2 H, CH2CH2CH2OTIPS), 2.46 (t, J = 6.6 Hz, 2 H,

CH2CH2CH2OTIPS), 1.78 − 1.72 (m, 2 H, CH2CH2CH2OTIPS), 1.29 (t, J = 7.2 Hz, 3H,

OCH2CH3), 1.11 − 1.02 (m, 21 H, Si(CH(CH3)2)3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 166.0,

Experimental 195

160.0, 138.2, 128.2, 127.5, 127.4, 116.6, 72.6, 68.1, 62.6, 59.7, 31.2, 31.0, 17.9, 14.1, 11.8. IR

(film, cm−1): ν = 2943, 2892, 2866, 2727, 1746, 1714, 1643, 1497, 1463, 1378, 1257, 1212, 1148,

1107, 1037, 882. MS (EI) m/z: 91.0 [100%], 391.2 [17.6%, (M-C3H7)+]. HRMS (EI) m/z: Calc.

for [(M-C3H7)+]. 391.2300. Found: 391.2302. Anal. Calcd. for C25H42O4Si: C, 69.08; H, 9.74.

Found: C, 68.94; H, 9.63.

(Z)-3-Benzyloxymethyl-6-triisopropylsilanyloxyhex-2-enol 279.

2.7 equiv. DIBAL,DCM, �78 °C to 0 °C

O

OEtBnO

TIPSO

BnO

TIPSOOH

92%

278 279 (Z)-3-Benzyloxymethyl-6-triisopropylsilanyloxyhex-2-enoic acid ethyl ester (278, 0.635 g, 1.46

mmol, 1.0 equiv) was dissolved in DCM (5 mL) and cooled to –78 °C. DIBAL (1.1 M in

cyclohexane, 3.6 mL, 3.9 mmol, 2.7 equiv.) was added in portions within 1 min. After 30 min

stirring at –78 °C, the solution was slowly warmed to 0 °C and stirred for an additional hour then

cooled again to –78 °C and quenched by dropwise addition of 1 N aqueous HCl. After warming to

RT, additional 1 N HCl and DCM were added until complete dissolution of the precipitate. The

aqueous phase was extracted twice with DCM and the combined organic phases were dried over

MgSO4. Subsequent solvent removal under reduced pressure gave 279 (0.530 g, 1.35 mmol, 92%)

as colorless oil which did not require further purification.

C23H40O3Si, MW: 392.65 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.40 – 7.26 (m, 5 H, Ar-

H), 5.68 (t, J = 6.9 Hz, 1 H, C=CH), 4.49 (s, 2 H, OCH2Ph), 4.12 (d, J = 7.2 Hz, 2 H, CH2OH),

4.03 (s, 2 H, CH2OBn), 3.68 (t, J = 12.9 Hz, 2 H, CH2CH2CH2OTIPS), 2.22 (t, J = 8.4 Hz, 2 H,

CH2CH2CH2OTIPS), 2.10 (bs, 1 H, CH2OH), 1.73 – 1.63 (m, 2 H, CH2CH2CH2OTIPS), 1.13 – 1.02

(m, 21 H, Si(CH(CH3)2)3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 139.7, 137.8, 128.3, 128.1,

127.7, 127.6, 71.5, 67.8, 62.9, 58.7, 32.2, 31.4, 18.1, 12.1. IR (film, cm−1): ν = 3380, 2943, 2866,

2376, 1462, 1382, 1249, 1108, 013, 882. MS (EI) m/z: 91.0 [100%, (C7H7)+], 241.1 [9%]. Anal.

Calcd. for C23H40O3Si: C, 70.36; H, 10.27. Found: C, 70.46, H, 10.39.

196 Chapter 7

Imidates:

N-PMP-substituted:

(E)-2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidic acid hex-2-enyl ester ([E]-201).

N

F3C Cl

HO

NaH, THF,0 °C -> RT

OMe

+F3C

N

O

OMe

90%

235 (E )-197 (E )-201 (E)-201 was prepared from commercially available trans-2-hexenol (E)-197 following GP10 as

slightly yellowish oil after purification by column chromatography over silica with pentane + 3 %

NEt3 (15 mmol-scale, 90% yield).

C15H18F3NO2, MW: 301.30 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 6.85 (td, J = 8.8 Hz,

J = 2.2 Hz, 2 H, aromatics), 6.84 – 6.71 (m, 2 H, aromatics), 5.92 – 5.79 (m, 1H, C=CH), 5.75 –

5.62 (m, 1 H, HC=C), 4.70 (bs, 2 H, OCH2), 3.79 (s, 3 H, OCH3), 2.08 (app. q, J = 7.1 Hz, 2 H,

CH2CH2CH3), 1.48 – 1.39 (m, 2H, CH2CH2CH3), 0.94 (t, J = 7.4 Hz, 3 H, CH2CH2CH3).


(Z)-2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidic acid hex-2-enyl ester ([Z]-201).

N

F3C Cl HO


OMe

+F3C

N

O

OMe

78%

235 (Z)-197 (Z)-201 (Z)-201 was prepared from commercially available cis-2-hexenol (Z)-197 following GP10 as

slightly yellowish oil after purification by column chromatography over silica with pentane + 3 %

NEt3 (2 mmol-scale, 78% yield).

C15H18F3NO2, MW: 301.30 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 6.84 (td, J = 8.8 Hz,

J = 2.2 Hz, 2 H, aromatics), 6.76 (m, 2 H, aromatics), 5.76 – 5.63 (m, 2 H, HC=CH), 4.80 (bs, 2 H,

OCH2), 3.79 (s, 3 H, OCH3), 2.16 – 2.06 (m, 2 H, CH2CH2CH3), 1.43 – 1.39 (m, 2H, CH2CH2CH3),

0.90 (t, J = 7.4, 3 H, CH2CH2CH3).


Experimental 197

(E)-2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidic acid 4-methyl-pent-2-enyl ester 203.

N

F3C Cl

HO


OMe

+F3C

N

O

OMe

71%

235 255 203 203 was prepared from trans-4-methyl-pent-2-enol 255 following GP10 as slightly yellowish oil

after purification by column chromatography over silica with pentane + 4 % NEt3 (5 mmol-scale,

71% yield).

C15H18F3NO2, MW: 301.30 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 6.86 – 6.75 (m, J =

1.5 Hz, 4H, aromatics), 5.86 – 5.79 (m, 1H, HC=CH), 5.67 – 5.58 (m, 1H, HC=CH), 4.69 (d, J =

5.4 Hz, 2H, OCH2), 3.79 (s, 3H, OCH3), 2.36 (m, 1H, (CH3)2-CH-CH), 1.04 (d, J = 6.9 Hz, 6H,

CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 156.1, 145.2 (q, JCF = 34.0), 144.0, 137.5, 120.7,

120.0, 116.0 (q, JCF = 284.2), 113.9, 68.8, 55.4, 31.0, 22.1. 19F-NMR (282 MHz, CDCl3, 21 °C): δ

= −65.1. IR (film, cm−1): ν= 1703, 1508, 1467, 1321, 1290, 1244, 1206, 1142, 1106, 1037. MS

(EI) m/z: 301.1, [4.6 %, M+]. HRMS (EI) m/z: Calc. for [M+]: 301.1290. Found: [M+]: 301.1285.

Anal. Calcd. for C15H18F3NO2: C, 59.79; H, 6.02; N, 4.65. Found: C: 59.69, H: 6.05, N: 4.77.

(E)-2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidic acid 3-phenyl-allyl ester 202.

N

F3C Cl

HO


OMe

+F3C

N

O

OMe

96%

235 (E )-199 202 202 was prepared from commercially available trans-cinnamol (E)-199 following GP10 as faintly

yellowish solid after purification by column chromatography over silica with pentane + 2 % NEt3

(1 mmol-scale, 96% yield).

C18H16F3NO2, MW: 335.32 g/mol. Mp: 53.9 – 54.0 °C. 1H NMR (300 MHz, CDCl3, 21 °C): δ =

7.46 – 7.25 (m, 5H, C6H5), 6.89 – 6.73 (m, 5H, C6H4OMe & HC=CH), 6.41 (m, 1H, HC=CH), 4.93

(d, J = 6.0 Hz, 2H, OCH2), 3.81 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 156.2,

145.0 (q, JCF = 37.6), 137.3, 135.9, 134.8, 128.5, 128.1, 126.6, 122.1, 120.6, 114.2 (coupling with F

not resolved), 113.9, 68.4, 55.5. 19F-NMR (282 MHz, CDCl3, 21 °C): δ = − 65.1. IR (film, cm−1):

ν = 3029, 2953, 2837, 1699, 1610, 1581, 1506, 1450, 1383, 1322, 1290, 1243, 1206, 1140, 1106,

198 Chapter 7

1035, 967. MS (EI) m/z: 335.1, [5.8 %, M+]. HRMS (EI) m/z: Calc. for [M+]: 335.1133. Found:

[M+]: 335.1134. Anal. Calcd. for C18H16F3NO2: C, 64.47; H, 4.81; N, 4.18. Found: C, 64.58; H,

4.88; N, 4.21.

(E)-2,2,2-Trifluoro-N-(4-methoxy-phenyl)-acetimidic acid 3-cyclo-hexyl-allyl ester 204.

N

F3C Cl

HO

LHMDS, THF,−78 °C

OMe

+F3C

N

O

OMe

86%

235 (E)-256 204 204 was prepared from 3-cyclo-hexyl prop-2-enol (E)-256 following GP10 as slightly yellowish oil

after purification by column chromatography over silica with pentane + 2 % NEt3 (2 mmol-scale,

86% yield).

C18H22F3NO2, MW: 341.37 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 6.86 – 6.74 (m, 4H,

C6H4OMe), 5.83 – 5.59 (m, 2H, HC=CH), 4.70 (d, J = 5.4 Hz, 2H, OCH2CH), 3.79 (s, 3H, OCH3),

2.02 – 1.05 (m, 11H, C6H11). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 156.1, 145.2 (q, JCF = 34.0),

142.9, 137.5, 116.0 (q, JCF = 284.2), 120.6, 120.3, 113.8, 68.8, 55.3, 40.3, 32.3, 25.9, 25.8. 19F-

NMR (282 MHz, CDCl3, 21 °C): δ = − 65.1. IR (film, cm−1): ν = 2928, 2853, 2362, 1670, 1612,

1508, 1450, 1386, 1324, 1291, 1244, 1205, 1142. MS (EI) m/z: 341.2, [2.9%, M+]. HRMS (EI)

m/z: Calc. for [M+]: 341.1597. Found: [M+]: 341.1597. Anal. Calcd. for C18H22F3NO2: C, 63.33,

H, 6.50; N, 4.10. Found: C: 63.37, H: 6.62, N: 4.09.

(E)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-(p-trifluoromethylphenyl)-propenyl ester 234a.

LHMDS, THF,−78 °C to RT

O

CF3

91%F3C

N

Cl

OMe

+ HO

CF3 F3C

N

OMe

235 233a 234a

According to GP10, imidate 234a was obtained from allylic alcohol 233a (485 mg, 2.4 mmol, 1.2

equiv.) as a colorless solid (738 mg, 1.83 mmol, 91 %).

C19H15F6NO2, MW: 403.32 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.60 (d, J = 8.4 Hz, 2

H, C6H4CF3), 7.50 (d, J = 8.1 Hz, 2 H, C6H4CF3), 6.87 – 6.74 (m, 5 H, C6H4OMe & CH=CH-

CH2O), 6.51 – 6.42 (m, 1 H, CH=CH-CH2O), 4.95 (d, J = 5.7 Hz, 2 H, CH2O), 3.80 (s, 3 H, OCH3),

Experimental 199

2.35 (s, 3 H, C6H4CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 156.1, 145.5 (q, JC-C-F = 32.7),

139.3, 136.9, 132.7, 129.7 (q, JC-F = 335.7), 126.6, 125.4, 125.3, 124.8, 120.5, 116.0 (q, JC-F =

285.4), 113.9, 67.8, 55.4. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 62.3, – 65.2. IR (film, cm−1):

ν = 2960, 1711, 1616, 1507, 1390, 1326, 1241, 1206, 1149, 1126, 1066, 1030. MS (EI) m/z: 185.0

[100%, (CF3C6H4CH=CHCH2)+], 403.1 [10.8%, M+]. HRMS (EI) m/z: Calc. for [M+]: 403.1002.

Found: 403.1000. Anal. Calcd. for C19H15F6NO2: C, 56.58; H, 3.75; N, 3.47. Found: C, 56.65, H,

3.95, N, 3.35.

(E)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-(p-chlorophenyl)-propenyl ester 234b.


O

Cl

92%Cl

N

CF3

OMe

+ HO

Cl F3C

N

OMe

235 233b 234b According to GP10, imidate 234b was obtained from allylic alcohol 233b (406 mg, 2.4 mmol, 1.2

equiv.) as a colorless solid (685 mg, 1.85 mmol, 92%).

C18H15ClF3NO2, MW: 369.77 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.34 – 7.27 & 6.86

– 6.63 (m, 9 H, aromatic H & CH=CH-CH2O), 6.43 – 6.31 (m, 1 H, CH=CH-CH2O), 4.91 (d, J =

6.9 Hz, 2 H, CH2O), 3.80 (s, 3 H, OCH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 156.0, 145.5 (q,

JC-C-F = 32.7), 137.0, 134.3, 133.6, 133.3, 128.6, 127.6, 122.5, 120.5, 116.0 (q, JC-F = 285.4), 113.8,

68.1, 55.4. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 65.1. IR (film, cm−1): ν = 2841, 1707,

1610, 1508, 1493, 1449, 1386, 1326, 1301, 1244, 1204, 1164, 1106, 1091, 1031, 1013, 969. MS

(EI) m/z: 151.0 [100%, (Cl-C6H4CH=CH-CH2)+], 369.0 [4%, M+]. HRMS (EI) m/z: Calc. for

[M+]: 369.0738. Found: 359.0740. Anal. Calcd. for C18H15ClF3NO2: C, 58.47; H, 4.09; N, 3.79.

Found: C, 58.50; H, 4.17; N, 3.65.

(E)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-(p-methylphenyl)-propenyl ester 234c.


O94%Cl

N

CF3

OMe

+ HO

F3C

N

OMe

235 233c 234c According to GP10, imidate 234c was obtained from allylic alcohol 233c (354 mg, 2.4 mmol, 1.2

equiv.) as a colorless solid (662 mg, 1.89 mmol, 94%).

200 Chapter 7


H, C6H4CH3), 7.15 (d, J = 8.1 Hz, 2 H, C6H4CH3), 6.86 – 6.62 (m, 5 H, C6H4OMe & CH=CH-

CH2O), 6.38 – 6.29 (m, 1 H, CH=CH-CH2O), 4.90 (d, J = 6.3 Hz, 2 H, CH2O), 3.80 (s, 3 H, OCH3),

2.35 (s, 3 H, C6H4CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 156.1, 145.5 (q, JC-C-F = 32.7),

138.0, 137.3, 134.9, 133.6, 133.1, 129.2, 128.9, 126.5, 120.9, 120.6, 116.0 (q, JC-F = 285.4), 113.9,

68.5, 55.4, 21.3. 19F NMR (282 MHz, CDCl3, 21 °C): δ = –65.2. IR (film, cm−1): ν = 2941, 2838,

1703, 1610, 1506, 1455, 1383, 1320, 1290, 1242, 1206, 1145, 1109, 1030. MS (EI) m/z: 131.0

[100%, (CH3C6H4CH=CHCH2)+], 349.1 [0.8%, M+]. HRMS (EI) m/z: Calc. for [M+]: 349.1285.

Found: 349.1285. Anal. Calcd. for C19H18F3NO2: C, 65.32; H, 5.19; N, 4.01. Found: C, 65.42, H,

5.30, N, 3.89.

(E)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-(p-methoxyphenyl)-propenyl ester 234d.


O

OMe

37%Cl

N

CF3

OMe

+ HO

OMe F3C

N

OMe

235 233d 234d According to GP10, imidate 234d was obtained from allylic alcohol 233d (146 mg, 0.89 mmol) as

a colorless solid (120 mg, 0.33 mmol, 37%). Column chromatography was performed with

pentane:Et2O 4:1 + 3% NEt3 as eluent; solvents were removed at a temperature below 40 °C. The

solid product was purified further by trituration with pentane.

Note: The 13C-NMR-spectrum was recorded in deuterated benzene rather than chloroform since in

unstabilised chloroform, significant quantities (ca. 40%) of rearranged product are formed within

less then 2 h.


H, aromatic H), 6.89 – 6.61 (m, 7 H, aromatic H & CH=CH-CH2O), 6.30 – 6.20 (m, 1 H, CH=CH-

CH2O), 4.89 (d, J = 5.7 Hz, 2 H, CH2O), 3.82 & 3.80 (s, 3 H each, OCH3). 13C NMR (75 MHz,

C6D6, 21 °C): δ = 160.0, 145.2 (q, JC-C-F = 32.7), 137.7, 135.0, 128.1, 127.8, 127.5, 120.9, 119.8,

116.5 (q, JC-F = 285.4), 114.3, 69.0, 54.8, 54.7. 19F NMR (282 MHz, CDCl3, 21 °C): δ = –65.0. IR

(film, cm−1): ν = 2938, 2840, 1694, 1608, 1583, 1512, 1493, 1465, 1444, 1408, 1342, 1299, 1254,

1207, 1186, 1153, 1092, 1035, 1015, 997, 939. MS (EI) m/z: 147.0 [100%,

(CH3OC6H4CH=CHCH2)+], 365.1 [0.4%, M+]. HRMS (EI) m/z: Calc. for [M+]: 365.1234. Found:

365.1237. Anal. Calcd. for C19H18F3NO3: C, 62.46; H, 4.97; N, 3.83. Found: C, 62.49; H, 5.01; N,

3.78.

Experimental 201

(2E,4E)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid-octa-2,4-dienyl ester 240.


O91%Cl

N

CF3

OMe

+ HO

F3C

N

OMe

235 239 240

According to GP10, imidate 240 was obtained from allylic alcohol 239 (252 mg, 2 mmol) as a

colorless oil (490 mg, 1.50 mmol, 75%). Column chromatography was performed with pentane/3%

NEt3 as eluent; solvents were removed at a temperature below 40 °C.

C17H20F3NO3, MW: 327.34 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 6.86 – 6.83 & 6.82 –

6.77 (m, 4 H, aromatic H), 6.38 – 6.29 (m, 1 H, olefinic H), 6.12 – 6.04 (m, 1 H, olefinic H), 5.83 –

5.69 (m, 2 H, olefinic H), 4.45 (d, J = 6.3 Hz, 2 H, CH2O), 3.79 (s, 3 H, OCH3), 2.08 (q, J = 7.2 Hz,

2 H, CH2CH2CH3), 1.57 – 1.37 (m, 2 H, CH2CH2CH3), 0.93 (t, J = 7.5 Hz, 3 H, CH2CH2CH3). 13C

NMR (75 MHz, CDCl3, 21 °C): δ = 156.1, 145.5 (q, JC-C-F = 32.7), 137.0, 135.7, 129.0, 122.7,

120.6, 116.0 (q, JC-F = 285.4), 113.8, 68.3, 55.2, 34.6, 22.1, 13.5. 19F NMR (282 MHz, CDCl3, 21

°C): δ = – 65.0. IR (film, cm−1): ν = 3021, 2959, 2931, 2873, 1673, 1597, 1489, 1458, 1380, 1365,

1275, 1244, 1169, 1037. MS (EI) m/z: 109.0 [52.6%, (C3H7CH=CHCH=CHCH2)+], 327.1 [4.2%,

M+]. HRMS (EI) m/z: Calc. for [M+]: 327.1441. Found: 327.1439. Anal. Calcd. for

C17H20F3NO3: C, 62.38; H, 6.16; N, 4.28. Found: C, 62.37; H, 6.22; N, 4.33.

N-Aryl/alkyl-substitutet Allylic Imidates.

N-(Cyclohexyl)-2,2,2-trifluoroacetimidoyl chloride 244.

TFA, PPh3, NEt3, CCl40°C -> 80 °C, 2h

NH2 N

CF3

Cl74%

244

A mixture of triphenylphosphine (6.6 g, 25 mmol), triethylamine (1.4 mL, 10 mmol), CCl4 (8.1

mL), and TFA (0.62 mL, 8.35 mmol) was stirred for about 10 min at 0 °C, then cyclohexylamine

(1.15 ml, 10.08 mmol) was added. The mixture was refluxed for 2 hours, then solvents were

removed under reduced pressure, and the residue was diluted with hexane and filtered. The filter

cake was washed with hexane 3 times. The filtrate was concentrated under reduced pressure, and

the residue was distilled (20 mbar, 120 °C) to afford 244 (1.6 g) in 74% yield as yellow oil.

202 Chapter 7

C8H11ClF3N, MW: 213.63 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 3.74 − 3.69 (m, 1H,

CHN), 1.82 − 1.26 (m, 10H, cHex-H). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 129.6, 129.0,

128.3, 121.9, 118.3, 114.6, 62.2, 31.6, 25.2, 23.9. 19F NMR (282 MHz, CDCl3, 21 °C): δ = − 71.4.

(E)-Hex-2-enyl N-cyclohexyl-2,2,2-trifluoroacetimidate 211.


O Ph82%Cl

N

CF3

+ HO

F3C

NPh

244 254 211 According to GP10, imidate 211 was obtained from (E)-5-phenylpent-2-en-1-ol (254, 500 mg, 3.00

mmol, 1 equiv.) and imidochloride 244 (658 mg, 3.00 mmol, 1 equiv.) as a yellowish oil (844 mg,

2.48 mmol, 82%) after purification by column chromatography (pentane:EtOAc 4:1 + 3% NEt3).

C19H24F3NO, MW: 339.18 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.32 – 7.17 (m, 5 H,

aromatic H), 5.87 – 5.63 (m, 2H, HC=CH), 4.52 (d, J = 6.0 Hz, 2 H, CH2O), 3.63 (bs, 1 H, NCH),

2.72 (t, J = 7.2 Hz, 2 H, PhCH2), 2.43 (q, J = 7.2 Hz, 2 H, CH2CH2CH), 1.77 – 1.28 (m, 10 H,

cHex-H). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 144.2 (q, JC-F = 33.9), 143.8, 141.4 135.1,

128.3, 128.1, 125.8, 124.3, 118.0, 114.2 q, JC-F = 285.4), 66.9, 55.6, 35.2, 34.5, 34.0, 25.5, 24.0. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 66.1 (major isomer), – 68.4 (minor isomer). IR (film,

cm−1): ν = 3028, 2934, 2858, 1699, 1604, 1497, 1453, 1315, 1198, 1147, 1080, 969. MS (EI) m/z:

91.0 [100%], 339.1 [1.0%, M+]. HRMS (EI) m/z: Calc. for [M+]: 339.1805. Found: 339.1798.

Anal. Calcd. for C19H24F3NO: C, 67.24; H, 7.13; N, 4.13. Found: C, 67.30; H, 7.09; N, 4.3.

(E)-Hex-2-enyl N-phenyl-acetimidate 229.

HN N

Cl

(COCl)2, 2,4,6-trimethylpyridine,DCM, 0 °C -> RT

O


O30%over 2 steps

N

Cl

+ HO N

226 227

227 (E )-197 229 Following a literature procedure,19 to a solution acetamide (1.35 g, 10 mmol, 1 equiv.) and 2,4,6-

trimethylpyridine (2.00 g, 16.6 mmol, 1.66 equiv.) in DCM (40 mL) at 0 °C was added a solution

of oxalylchloride (1.27 g, 10 mmol, 1 equiv.) in DCM (10 mL) in portions within 30 min. The

Experimental 203

resulting clear solution was stirred at RT for 30 min, then most of the solvent was removed under

reduced pressure (ca. 80%). The resulting grey suspension was suspended in pentane (40 mL) and

filtrated to yield a yellowish solution. Removal of all volatiles led to a dark yellow oil which turned

black after some hours and was used without further purification

To a solution of trans-2-hexenol (197, 1.00 g, 10 mmol, 1 equiv.) in THF (10 mL) at –78 °C,

LHMDS (1 M in THF, 10 mmol, 1 equiv.) was added. After five minutes, the crude imidochloride

227 was dissolved in pentane (5 ml) and added in one portion. All further manipulations were

carried out according to GP10, giving imidate 229 as colourless oil (668 mg 3.0 mmol, 30% over

two steps).

C14H19NO, MW: 217.31 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.28 (t, J = 8.1, 2 H,

aromatic H), 7.03 (t, J = 7.5 Hz, 1 H, aromatic H), 6.74 (d, J = 8.1 Hz, 2 H, aromatic H), 5.84 –

5.67 (m, 2 H, CH=CH-CH2O), 4.64 (d, J = 6.0 Hz, CH2O), 2.08 (q, J = 6.6 Hz, 2 H, CH2CH2CH3),

1.84 (s, 3 H, N=C-CH3), 1.44 (tq, J = 7.2 Hz, J = 6.6 Hz , 2 H, CH2CH2CH3), 0.93 (t, J = 7.2, 2 H,

CH2CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 160.6, 148.9, 135.4, 128.9, 124.7, 122.6,

121.0, 66.6, 34.5, 22.2, 16.3, 13.8. IR (film, cm−1): ν = 3038, 2006, 2957, 2911, 2838, 2456, 2360,

2343, 2058, 1881, 1694, 1658, 1608, 1578, 1513, 464, 1384, 1322, 1288, 1248, 1206, 1140, 1105,

1034, 969, 906. MS (EI) m/z: 93.0 [100%], 217.1 [3%, M+]. HRMS (EI) m/z: Calc. for [M+]:

217.1461. Found: 217.1462. Anal. Calcd. for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C,

77.12; H, 8.94; N, 6.25.

Quaternary

(E)-2,2,2-Trifluoro-N-(4-methoxyphenyl) acetimidic acid 3-methyl-5-phenyl-pent-2-enyl ester 207.


O Ph98%F3C

N

Cl

OMe

+ HO

F3C

N

OMe

Ph

235 263 207 According to GP10, imidate 207 was obtained from allylic alcohol 263 (430 mg, 2.48 mmol) as a

colorless solid (917 mg, 2.43 mmol, 98%).

C21H22F3NO2, MW: 377.40 g/mol. Mp.: 28.5 – 29.5 °C. 1H NMR (300 MHz, CDCl3, 21 °C): δ =

7.32 – 7.25 & 7.21 – 7.18 (m, 5 H, C6H5), 6.87 – 6.83 & 6.82 – 6.74 (m, 4 H, C6H4OMe), 5.47 (t, J

= 6.9 Hz, 1 H, C=CH), 4.76 (d, J = 6.9 Hz, 2 H, CH2O), 3.79 (s, 3 H, OCH3), 2.78 & 2.38 (t, J =

8.7, 2 H each, CH2CH2), 1.79 (s, 3 H, C=C-CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 156.0,

145.5 (q, JC-C-F = 32.7), 142.5, 141.5, 137.5, 128.3, 128.2, 125.9, 120.6, 117.9, 116.0 (q, JC-F =

285.4), 113.8, 64.7, 55.4, 41.4, 34.2, 16.8. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 65.5. IR

204 Chapter 7

(film, cm−1): ν = 3389, 2958, 2912, 2823, 2359, 1698, 1507, 1314, 1243, 1205, 1140. MS (EI) m/z:

91.0 [100%], 377.1 [0.8%, M+]. HRMS (EI) m/z: Calc. for [M+]: 377.1597. Found: 377.1599.

Anal. Calcd. for C21H22F3NO2: C, 66.83; H, 5.88; N, 3.71. Found: C, 66.95, H, 6.04, N, 3.67.

(E)-3-Methyl-4-phenylbut-2-enyl)2,2,2-trifluoro-N-(4 methoxyphenyl) Acetimidate 206.


OPh

F3C

N

Cl

OMe

+ HOPh

F3C

N

OMe

70%

25 265 206

According to GP10, imidate 206 was obtained from (E)-3-methyl-4-phenylbut-2-en-1-ol (265, 850

mg, 5.23 mmol, 1 equiv.) and imidochloride 235 (1.11 g, 4.67 mmol, 0.9 equiv.) as a yellowish oil

(1.2 gm, 3.3 mmol, 70%) after purification by column chromatography (pentane:EtOAc 4:1 + 3%

NEt3).

C20H20F3NO2, MW: 363.37 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.17 – 7.04

(m, 5 H, C6H5), 6.72 – 6.58 (m, 4 H, C6H4), 5.42(t, J = 6.3 Hz, 1H, C=CH), 4.67 (d, J = 6.3

Hz, 2 H, CH2O), 3.65 (s, 3H, OCH3), 3.24 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3, 21

°C): δ = 156.2, 142.3 145.5 (q, JC-C-F = 32.7), 139.0, 137.6, 128.9, 128.4, 126.3, 120.7,

119.5, 119.5 (q, JC-F = 285.4), 113.9, 55.4, 46.0, 16.4. 19F NMR (282 MHz, CDCl3, 21

°C): δ = – 65.2. IR (film, cm−1): ν = 1697, 1505, 1313, 1240, 1200, 1133, 1033, 832, 698.

MS (EI) m/z: 386.1 [100%, {( C20H20F3NO2, M Na }+] HRMS (EI) m/z: Calc. for {(

C20H20F3NO2, M –Na }+] 386.1344 Found: 386.1338. Anal. Calcd. for C20H20F3NO2: C,

64.97; H, 5.54; N, 4.01. Found: C, 64.81; H, 5.52; N, 3.98.

(Z)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-methyl-5-benzyloxy pent-2-enyl ester 208.


O93%F3C

N

Cl

OMe

+ HO

F3C

N

OMeOBn

OBn

235 268 208 According to GP10, imidate 208 was obtained from allylic alcohol 268 (380 mg, 2 mmol) as a

colorless oil (730 mg, 1.86 mmol, 93%).

Experimental 205

C21H22F3NO3, MW: 393.40 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.36 – 7.25 & 7.21

– 7.18 (m, 5 H, C6H5), 6.87 – 6.83 & 6.82 – 6.74 (m, 4 H, C6H4OMe), 5.69 (t, J = 6.3 Hz, 1 H,

C=CH), 4.81 (d, J = 6.6 Hz, 2 H, CH2O), 4.49 (s, 2 H, OCH2Ph), 4.11 (s, 2 H, CH2OBn), 3.80 (s, 3

H, OCH3), 1.92 (s, 3 H, C=C-CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 156.1, 145.5 (q, JC-C-F

= 32.7), 139.4, 138.0, 137.4, 128.3, 127.6, 121.8, 120.6, 116.0 (q, JC-F = 285.4), 113.9, 72.1, 68.4,

63.9, 55.4, 21.8. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 65.0. IR (film, cm−1): ν = 2950, 2837,

1699, 1610, 1587, 1454, 1380, 1338, 1314, 1290, 1243, 1205, 1141, 1106, 1036, 949, 834, 737.

MS (MALDI) m/z: 416.1 [20%, (MNa)+]. HRMS (MALDI) m/z: Calc. for [MNa]+: 416.1444.

Found: 416.1440. Anal. Calcd. for C21H22F3NO3: C, 64.11; H, 5.64; N, 3.56. Found: C, 64.15; H,

5.66; N, 3.78.

(Z)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-ethyl-5-benzyloxy pent-2-enyl ester 280.


EtO60%F3C

N

Cl

OMe

+ EtHO

F3C

N

OMeOBn

OBn

235 275 280

According to GP10, imidate 280 was obtained from allylic alcohol 275 (250 mg, 1.21 mmol) as a

colorless oil (298 mg, 0.73 mmol).

C22H24F3NO3, MW: 407.43 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.36 – 7.25 (m, 5 H,

C6H5), 6.85 – 6.81 & 6.80 – 6.72 (m, 4 H, C6H4OCH3), 5.64 (t, J = 6.3 Hz, 1 H, C=CH), 4.82 (d, J

= 7.2 Hz, 2 H, C=CHCH2O), 4.47 (s, 2 H, OCH2Ph), 4.08 (s, 2 H, CH2OBn), 3.79 (s, 3 H, OCH3),

2.22 (q, J = 6.0 Hz, 2 H, CH2CH3), 1.05 (t, J = 7.2 Hz, 3 H, CH2CH3). 13C NMR (75 MHz, CDCl3,

21 °C): δ = 156.1, 145.5 (q, JC-C-F = 32.7), 144.3, 138.0, 137.4, 128.3, 127.64, 127.60, 120.6,

120.4, 116.0 (q, JC-F = 285.4), 113.9, 72.2, 67.5, 64.1, 55.4, 28.1, 12.4. 19F NMR (282 MHz,

CDCl3, 21 °C): δ = – 65.0. IR (film, cm−1): ν = 3033, 2966, 2877, 1700, 1610, 1582, 1507, 1455,

1321, 1290, 1243, 1204, 1141, 1105, 1036, 947, 834. MS (EI) m/z: 91.0 [100%], 407.1 [0.3%,

M+]. HRMS (EI) m/z: Calc. for [M+]: 407.1705. Found: 407.1705. Anal. Calcd. for

C22H24F3NO3: C, 64.86; H, 5.94; N, 3.44. Found: C, 64.91; H, 5.97; N, 3.61.

206 Chapter 7

(Z)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-butyl-5-benzyloxy pent-2-enyl ester 281.


BuO78%F3C

N

Cl

OMe

+ BuHO

F3C

N

OMeOBn

OBn

235 277 281


colorless oil (177 mg, 0.4 mmol, 78%).

C24H28F3NO3, MW: 435.48 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.34 – 7.26 (m, 5 H,

C6H5), 6.85 – 6.81 & 6.80 – 6.72 (m, 4 H, C6H4OCH3), 5.65 (t, J = 6.6 Hz, 1 H, C=CH), 4.83 (d, J

= 7.2 Hz, 2 H, C=CHCH2O), 4.47 (s, 2 H, OCH2Ph), 4.07 (s, 2 H, CH2OBn), 3.79 (s, 3 H, OCH3),

2.19 (t, J = 7.2 Hz, 2 H, CH2CH2CH2CH3), 1.48 – 1.30 (m, 4 H, CH2CH2CH2CH3), 0.92 (t, J = 7.2,

3 H, CH2CH2CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 156.0, 145.5 (q, JC-C-F = 32.7),

142.5, 137.9, 137.4, 128.2, 128.0, 127.6, 127.5, 121.4, 120.6, 116.0 (q, JC-F = 285.4), 113.8, 72.1,

67.3, 64.1, 55.4, 35.0, 30.0, 22.5, 14.0. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 65.0. IR (film,

cm−1): ν = 2932, 2860, 1702, 1611, 1507, 1458, 1315, 1290, 1243, 1204, 1141, 1105. MS (EI) m/z:

91.0 [100], 435.2 [0.1%, M+]. HRMS (EI) m/z: Calc. for [M]+: 435.2016. Found: 435.2006. Anal.

Calcd. for C24H28F3NO3: C, 66.19; H, 6.48; N, 3.22. Found: C, 66.15; H, 6.54; N, 3.35.

(Z)-2,2,2-Trifluoro-N-(4-methoxyphenyl)acetimidic acid 3-(3-triisopropyloxy- silylpropyl)-5-benzyloxypent-2-enyl ester 210.


O81%F3C

N

Cl

OMe

+ HO

F3C

N

OMeOBn

OBn

OTIPS

OTIPS235 279 210


colorless oil (597 mg, 1 mmol, 81%).

C32H46F3NO4Si, MW: 593.79 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.39 – 7.26 (m, 5

H, C6H5), 6.83 – 6.81 & 6.80 – 6.72 (m, 4 H, C6H4OCH3), 5.68 (t, J = 6.6, 1 H, C=CH), 4.83 (d, J =

6.9 Hz, 2 H, C=CHCH2O), 4.48 (s, 2 H, OCH2Ph), 4.09 (s, 2 H, CH2OBn), 3.79 (s, 3 H, OCH3),

3.72 (t, J = 6.2 Hz, 2 H, CH2CH2CH2OTIPS), 2.30 (t, J = 7.5, 2 H, CH2CH2CH2OTIPS), 1.77 –

1.68 (m, 2 H, CH2CH2CH2OTIPS), 1.09 – 1.01 (m, 3 + 18 H, Si(CH(CH3))3). 13C NMR (75 MHz,

Experimental 207

CDCl3, 21 °C): δ = 156.1, 145.5 (q, JC-C-F = 32.7), 142.6, 137.9, 137.4, 128.3, 127.6, 127.5, 121.6,

120.6, 116.0 (q, JC-F = 285.4), 113.9, 72.2, 67.5, 64.1, 62.8, 55.4, 31.7, 31.2, 18.1, 12.1. 19F NMR

(282 MHz, CDCl3, 21 °C): δ = –65.5. IR (film, cm−1): ν = 2944, 2866, 1699, 1611, 1582, 1507,

1464, 1384, 1365, 1339, 1315, 1290, 1243, 1205, 1141, 1105, 1037, 883, 833. MS (EI): 91.0

[100%, (C7H7)+]. Anal. Calcd. for C32H46F3NO4Si: C, 64.73; H, 7.81; N, 2.36. Found: C, 64.45;

H, 7.66; N, 2.57.

(E)-O-Hex-2-enyl dimethylcarbamothioate 245.

OH

Cl N

S

NaH, NaI, THF

then O NMe

S

Me(E)-197 245

A solution of trans-2-hexen-1-ol (197, 1.2 mL, 1.0 mmol) in THF (20 mL) was added to a solution

of NaH (1.2 g of 60% NaH in mineral oil, 3.0 mmol, 3 equiv) in THF (40 mL) at 0 °C. The solution

was maintained at 0 °C for 30 min, then NaI (150 mg, 0.998 mmol, 0.1 equiv) and N,N-

dimethylthiocarbamoyl chloride (1.48 g, 12.0 mmol, 1.2 equiv) were added successively. The

solution was allowed to warm to RT and was maintained at RT for 1 h. Saturated aqueous NH4Cl

was added, and the mixture was extracted with Et2O (3 x 20 mL). The combined organic layers

were washed with H2O, brine, dried (MgSO4), and concentrated under reduced pressure.

Purification by silica chromatography (6% Et2O:pentane) afforded (245, 1.64 g, 88% yield) as a

pale yellow oil.

C9H17NOS, MW: 187.10 g /mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 5.80 (ddd, J = 15.4, 6.7

Hz, 6.7 Hz, 1H), 5.65 (ddd, J = 15.3, 6.4, 6.4 Hz, 1H), 4.91 (d, J = 6.3 Hz, 2H), 3.37 (s, 3H), 3.12

(s, 3H),2.05 (q, J = 7.1 Hz, 2H), 1.48 (qn, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H)

The other analytical data are in accordance with the literature.16

(E)-5-Phenylpent-2-enyl 2,2,2-trichloroacetimidate.

Ph OH Cl3C NNaH, Et2O,0 °C −> RT

78%HN O

CCl3

Ph254 225

Sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol, 0.1 equiv.) was suspended in Et2O (10 mL)

at 0 °C, then allylic alcohol 254 (1.62 g, 1.38 ml, 10 mmol) was added slowly. After complete

dissolution of NaH, 2,2,2-trichloroacetonitrile ( 1.44 gm, 1 ml, 10 mmol) was added. The reaction

mixture was stirred at RT for 1 h, then water (10 mL / mmol) and Et2O (20 mL / mmol) were

added. Phases were separated and the combined organic phases were dried over MgSO4 and

208 Chapter 7

concentrated in vacuo. The residue was purified by column chromatography (pentane: 3 % Et3N) to

give XX as a yellow oil (3.8g, 78%).

C13H14Cl3NO, MW: 429.19 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 8.57 (bs, 1H, NH),

7.29 – 7.17 (m, 5 H, C6H5), 5.94 – 5.88 (m, 1 H, CH2CH2CH=CH), 5.26 (m, 2 H, CH2CH=CH2O),

4.54 (d, J = 4.0 Hz, 2H, CH2O), 2.78 – 2.71 (m, 2H, PhCH2), 2.43 – 2.39 (q, J = 4.15 Hz, 2 H ,

PhCH2CH2).


Allylic Amides (rearrangement products):

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-propylallyl)acetamide ([R]-214).

N

MeOO

CF3

Pr214

According to GP8, allylic amide 214 was obtained from imidate 201. The ee values were

determined after hydrolysis with NaBH4 in i-PrOH/H2O following GP9a.

C15H18F3NO2, MW: 301.30 g /mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.06 (app dd, J =

18.9 Hz, J = 9.3 Hz, 2H, C6H4OMe), 6.88 (app t, J = 9.0 Hz, 2H, C6H4OMe), 5.55 (ddd, J = 18.0

Hz, J = 10.2 Hz, J = 0.9 Hz, 1H, H2C=CH), 5.26 (m, 1H, HHC=CH), 5.19 (m, 1H, HHC=CH), 5.02

(q, J = 7.8 Hz, 1H, CHN), 3.83 (s, 3H, OCH3), 1.64 – 1.52 (m, 1H, CH2CH2CH3), 1.50 – 1.28 (m,

3H, CH2CH2CH3), 0.93 (t, J = 7.2 Hz, 3H, CH2CH3). The other analytical data are in accordance

with the literature.

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-iso-propylallyl)acetamide 216.

N

MeOO

CF3

216 According to GP8, allylic amide 216 was obtained from imidate 203. The ee values were

determined after hydrolysis with NaBH4 in i-PrOH/H2O following GP9a.

C15H18F3NO2, MW: 301.30 g /mol. [α]23D (c = 0.735 g/dL, CHCl3) = – 28.9. 1H NMR (300 MHz,

CDCl3, 21 °C): δ = 7.15 (app d, J = 7.8 Hz, 1H, C6H4OMe), 7.05 (app d, J = 7.8 Hz, 1H,

C6H4OMe), 6.86 (m, 2H, C6H4OMe), 5.53 (m, 1H, CH2=CH), 5.23 (m, 2H, CH2=CH), 4.49 (app t,

Experimental 209

J = 9.9 Hz, 1H, CHN), 3.81 (s, 3H, OCH3), 1.92 (m, 1H, CH(CH3)2), 1.10 (d, J = 6.6 Hz, 3H,

CH(CH3)2), 0.82 (d, J = 6.6 Hz, 3H, CH(CH3)2). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 159.6,

156.9 (q, JCF = 33.9), 134.9, 131.9, 130.3, 120.0, 116.5 (q, JCF = 286.7), 113.7, 69.2, 55.4, 29.1,

20.0, 19.8. 19F-NMR (282 MHz, CHCl3, 21 °C): δ = – 67.0. IR (film, cm−1): ν = 3082, 2968,

2877, 2642, 1694, 1642, 1608, 1445, 1417, 1389, 1370, 1339, 1298, 1253, 1205, 1152, 1109, 1036,

1101. MS (EI) m/z: 301.1 [7.5%, M+]. HRMS (EI) m/z: Calc. for [M+]: 301.1290. Found: [M+]:

301.1280. Anal. Calcd. for C15H18F3NO2: C, 59.79; H, 6.02; N, 4.65. Found: C: 59.63, H: 6.30, N:

4.81.

(S)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-phenylallyl)acetamide 215.

N

MeOO

CF3

215 According to GP8, allylic amide 215 was obtained from imidate 202. The ee values were

determined after hydrolysis with NaBH4 in i-PrOH/H2O following GP9b.

C18H16F3NO2, MW: 335.32 g/mol. [α]23D (c = 0.900 g/dL, CHCl3) = + 7.8. 1H NMR (300 MHz,

CDCl3, 21 °C): δ = 7.29 – 7.26 (m, 3H, C6H5), 7.20 – 7.15 (m, 3H, C6H5 + NC6H4OCH3), 6.87 (d, J

= 6.9 Hz, 1H, NC6H4OCH3), 6.63 (d, J = 6.9 Hz, 1H, NC6H4OCH3), 6.43 (d, J = 6.9 Hz, 1H,

NC6H4OCH3), 6.35 (d, J = 8.4 Hz, CHN), 6.01 (ddd, J = 16.8 Hz, J = 8.1, J = 1.8 Hz, 1H,

CH2=CH), 5.43 (ddd, J = 27.3 Hz, J = 16.8 Hz, J = 2.1 Hz, 2H, CH2=CH), 3.78 (s, 3H, OCH3). 13C

NMR (75 MHz, CDCl3, 21 °C): δ = 160.0, 157.0 (q, JCF = 34.5), 137.8, 133.4, 131.9, 128.8, 128.6,

128.3, 128.1, 120.5, 116.7 (q, JCF = 286.9), 113.6, 63.9, 55.5. 19F-NMR (282 MHz, CDCl3, 21

°C): δ = – 67.4. IR (film, cm−1): ν = 3065, 3035, 2960, 2937, 2840, 2552, 1890, 1694, 1607, 1584,

1515, 1455, 1444, 1416, 1343, 1299, 1254, 1206, 1186, 1152, 1109, 1076, 1035, 999. MS (EI)

m/z: 335.1 [5.6 %, M+]. HRMS (EI) m/z: Calc. for [M+]: 335.1133. Found: [M+]: 335.1127. Anal.

Calcd. for C18H16F3NO2: C, 64.47; H, 4.81; N, 4.18. Found: C: 64.51, H: 4.89, N: 4.14.

(S)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-cyclohexylallyl)-acetamid 217.

N

MeOO

CF3

217

210 Chapter 7

According to GP8, allylic amide 217 was obtained from imidate 204. The ee values were

determined after hydrolysis with NaBH4 in i-PrOH/H2O following GP9a (chiral stationary phase

HPLC [Chiralcel OD-H, 99.8:0.2 n-hexane/i-PrOH, 0.8 mL/min, detection at 250 nm]).

C18H22NO2F3. MW: 341.37 g/mol. [α]20D (c = 0.225 g/dL, CHCl3) = – 3.4. 1H NMR (300 MHz,

CDCl3, 21 °C): δ = 7.13 – 6.87 (m, 4H, C6H4OMe), 5.54 (dt, J = 18.5 Hz, J = 9.6 Hz, 1H, CHCH2),

5.28 – 5.20 (m, 2H, CHCH2), 4.54 (t, J = 9.9 Hz, 1H, NCH), 3.84 (s, 3H, OCH3), 2.01 – 1.05 (m,

11H, C6H11). 13C NMR (75.5 MHz, CDCl3, 21 °C): δ = 159.6, 156.9 (q, JC,F = 34.6), 134.7, 131.9,

130.3, 129.0, 120.0, 116.4 (q, JC,F = 288.9), 113.6, 68.2, 55.3, 46.1, 37.9, 30.0, 30.0, 26.1, 25.6,

11.5. 19F NMR (282 MHz, CDCl3, 21 °C): δ = − 67.39 (CF3); IR (film, cm−1): ν = 2934, 2854,

1694, 1609, 1513, 1449, 1417, 1350, 1298, 1252, 1206, 1152. MS (EI) m/z: 341.2 [4.4%, M+];

HRMS (EI) m/z: Calc. for [M+]: 341.1597; found [M+]: 341.1595. Anal. Calcd. for

C18H22NO2F3: C, 63.33; H, 6.50; N, 4.10. Found: C, 63.29; H, 6.53; N, 4.20.

(S)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(1-p-trifluoromethylphenyl-allyl)acetamide 248a.

N

MeOO

CF3

F3C 248a

According to GP8, allylic amide 248a was obtained from imidate 234a. The ee value was

determined by chiral column HPLC: Chiralcel AD-H, n-hexane/i-PrOH 99:1, 1.5mL/min, detection

at 210 nm.

C19H15F6NO2, MW: 403.32 g/mol. [α]23.9D (c = 0.69 g/dL, CHCl3) = + 24.3 @ 92% ee. 1H NMR

(300 MHz, CDCl3, 21 °C): δ = 7.55 & 7.32 (d, J = 8.1, 2 H each, C6H4CF3), 7.14 & 6.89 & 6.68 &

6.53 (d, J = 6.9 Hz, 1 H each, C6H4OMe), 6.31 (d, J = 8.4 Hz, 1 H, CHN), 6.00 (ddd, J = 18.3 Hz, J

= 10.2 Hz, J = 1.5 Hz, 1 H, CH=CH2), 5.40 (dd, J = 16.8 Hz, J = 8.4 Hz, 2 H, CH=CH2), 3.79 (s, 3

H, OCH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 159.7, 156.8 (q, JC-C-F = 35.1), 141.5, 132.3,

131.5, 131.1, 129.9 (q, JC-C-F = 32.1), 128.5, 127.6, 123.7 (q, JC-F = 269.5), 121.1, 116.0 (q, JC-F =

285.4), 113.7, 113.4, 63.8, 55.4. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 62.4, – 66.8. IR (film,

cm−1): ν = 1697, 1618, 1513, 1421, 1328, 1300, 1255, 1208, 1185, 1128, 1069. MS (EI) m/z: 185.0

[100%, (CF3C6H4C3H4)+], 403.1 [14.8%, M+]. HRMS (EI) m/z: Calc. for [M+]: 403.1002. Found:


3.45.

Experimental 211

(S)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(1-p-chlorophenyl-allyl)acetamide 248b.

N

MeOO

CF3

Cl 248b

According to GP8, allylic amide 248b was obtained from imidate 234b. The ee value was

determined by chiral column HPLC: Chiralcel OD-H, n-hexane/i-PrOH 99.5:0.5, 1.5mL/min,

detection at 210 nm.

C18H15ClF3NO2, MW: 369.77 g/mol. [α]24.6D (c = 0.4155 g/dL, CHCl3) = + 54.8 @ 99% ee. 1H

NMR (300 MHz, CDCl3, 21 °C): δ = 7.25 & 7.10 (d, J = 8.4 Hz, 2 H each, C6H5Cl), 7.12 & 6.87

& 6.66 & 6.46 (d, J = 7.5 Hz, 1 H each, C6H4OMe), 6.29 (d, J = 8.4 Hz, 1 H, CHN), 6.01 (ddd, J =

17.1 Hz, J = 8.1 Hz, J = 2.1 Hz, 1 H, CH=CH2), 5.40 (dd, J = 17.1 Hz, J = 9.3 Hz, 2 H, CH=CH2),

3.79 (s, 3 H, OCH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 159.6, 156.8 (q, JC-C-F = 34.5), 136.0,

133.8, 132.6, 131.4, 129.7, 128.4, 127.5, 120.5, 116.0 (q, JC-F = 285.4), 113.6, 63.2, 55.4. 19F

NMR (282 MHz, CDCl3, 21 °C): δ = – 66.8. IR (film, cm−1): ν = 3085, 2960, 2938, 2840, 1897,

1693, 1641, 1608, 1584, 1513, 1493, 1465, 1444, 1410, 1344, 1299, 1254, 1207, 1186, 1153, 1109,

1093, 1035, 1101, 997. MS (EI) m/z: 151.0 [100%, (ClC6H4CHCH=CH2)+], 369.0 [5%, M+].

HRMS (EI) m/z: Calc. for [M+]: 369.0738. Found: 369.0737. Anal. Calcd. for C18H15ClF3NO2:

C, 58.47; H, 4.09; N, 3.79. Found: C, 58.44; H, 4.16; N, 3.78.

(S)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(1-p-tolylallyl)acetamide 248c.

N

MeOO

CF3

248c According to GP8, allylic amide 248c was obtained from imidate 234c. The ee value was

determined by chiral column HPLC: Chiralcel OD-H, 99.5:0.5 n-hexane/i-PrOH, 1.5 mL/min,


C19H18F3NO2, MW: 349.35 g/mol. [α]25.6D (c = 0.5625 g/dL, CHCl3) = + 50.6 @ 98% ee. 1H NMR

(300 MHz, CDCl3, 21 °C): δ = 7.19 – 7.02 (m, 5 H, C6H4CH3 & C6H4OMe), 6.86 & 6.65 & 6.46

(d, J = 8.4, 1 H each, C6H4OMe), 6.31 (d, J = 8.1 Hz, 1 H, CHN), 6.00 (ddd, J = 17.1 Hz, J = 8.1

Hz, J = 2.1 Hz, 1 H, CH=CH2), 5.38 (dd, J = 17.1 Hz, J = 9.3 Hz, 2 H, CH=CH2), 3.79 (s, 3 H,

212 Chapter 7

OCH3), 2.32 (s, 3 H, C6H4CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 159.8, 156.8 (q, JC-C-F =

34.5), 137.9, 134.7, 133.6, 131.7, 129.1, 128.5, 128.0, 120.0, 116.0 (q, JC-F = 285.4), 113.5, 113.6,


2937, 1892, 1693, 1682, 1642, 1608, 1583, 1513, 1463, 1444, 1415, 1345, 1299, 1253, 1205, 1152,

1109, 1035, 997. MS (EI) m/z: 131.0 [100%, (CH3C6H4CHCH=CH2)+], 349.1 [1.6%, M+]. HRMS

(EI) m/z: Calc. for [M+]: 349.1285. Found: 349.1283. Anal. Calcd. for C19H18F3NO2: C, 65.32; H,

5.19; N, 4.01. Found: C, 65.04; H, 5.28;N, 4.02.

(S)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(1-p-methoxyphenyl-allyl) acetamide 248d.

N

MeOO

CF3

MeO 248d

According to GP8, allylic amide 248d was obtained from imidate 234d. The ee value was

determined by chiral column HPLC: Chiralcel OD-H, n-hexane/i-PrOH 99.5:0.5, 1.5mL/min,


C19H18F3NO3, MW: 365.35 g/mol. [α]24.3D (c = 0.536 g/dL, CHCl3) = +15.3 @ 34% ee. 1H NMR

(300 MHz, CDCl3, 21 °C): δ = 7.13 & 6.80 & 6.63 & 6.42 (d, J = 8.1 Hz,1 H each, C6H4OMe),

7.04 & 6.82 (d, J = 8.4 Hz, 2 H each, NCH-C6H4OMe), 6.33 (d, J = 8.1 Hz, 1 H, CHN), 6.00 (ddd,

J = 17.7 Hz, J = 8.1 Hz, J = 2.1 Hz, 1 H, CH=CH2), 5.40 (dd, J = 19.2 Hz, J = 9.9, 2 H, CH=CH2),

3.78 (s, 6 H, OCH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 159.4, 159.0, 156.4 (q, JC-C-F = 35.1),

133.4, 131.6, 129.8, 129.4, 127.6, 119.8, 116.0 (q, JC-F = 285.4), 114.4, 113.5, 63.2, 55.4. 19F


1513, 1465, 1444, 1414, 1299, 1252, 1205, 1177, 1152, 1109, 1034. MS (EI) m/z: 147.0 [100%,

(CH3OC6H4C3H4)+], 365.1 [0.4%, M+]. HRMS (EI) m/z: Calc. for [M+]: 365.1234. Found:


3.79.

Experimental 213

(S)-2,2,2-trifluoro-N-(4-methoxyphenyl)-N-(1-pent-2-enyl-allyl)acetamide 247.

N

MeOO

CF3

247 According to GP8, allylic amide 247 was obtained from imidate 240. The ee-values were

determined after hydrolysis to the aminde with MeLi in THF following GP7c.

C17H20F3NO2, MW: 327.34 g/mol. [α]24.8D (c = 0.0485 g/dL, CHCl3) = – 48.5 @ 86% ee. 1H

NMR (300 MHz, CDCl3, 21 °C): δ = 7.05 & 6.85 (d, J = 9.0, 2 H each, C6H4OMe), 5.83 – 5.66

(m, 2 H, olefinic H), 5.53 (t, J =7.5 Hz, 1 H, CHN), 5.35 – 5.18 (m, 2 H, olefinic H), 3.81 (s, 3 H,

OCH3), 2.00 (app. q, J = 6.9 Hz, 2 H, CH2CH2CH3), 1.37 (td, J = 7.5 Hz, J = 6.9 Hz, CH2CH2CH3),

0.85 (t, J = 7.5 Hz, CH2CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 159.7, 156.8 (q, JC-C-F =

35.1), 136.3, 134.5, 131.2, 128.2, 125.2, 118.6, 116.0 (q, JC-F = 285.4), 113.4, 62.6, 55.6, 34.5,

22.2, 13.8. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 67.1. IR (film, cm−1): ν = 2961, 2934,

2874, 2841, 1694, 1608, 1584, 1560, 1506, 1465, 1444, 1419, 1298, 1252, 1205, 1187, 1152, 1108,

1036, 975. MS (EI) m/z: 67.0 [100%], 327.1 [2.7%, M+]. HRMS (EI) m/z: Calc. for [M+]:

327.1441. Found: 327.1440. Anal. Calcd. for C17H20F3NO2: C, 62.38; H, 6.16; N, 4.28. Found: C,

62.32; H, 6.29; N, 4.36.

(R)-N-cyclohexyl-2,2,2-trifluoro-N-(hex-1-en-3-yl)acetamide 223.

N O

CF3

Ph223

According to GP8, allylic amide 223 was obtained from imidate 211. The ee was determined after

hydrolysis to the amine following GP9b. C19H24F3NO, MW: 339.18 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.33 – 7.17 (m, 5 H,

aromatic H, both enantiomer), 6.40 – 6.28 (m, 1 H, CH=CH2, major enantiomer), 5.87 (m, 1 H,

CH=CH2, minor enantiomer), 5.39 (m, 2 H, CH=CH2, minor enantiomer) 5.24 (t, J = 10.2 Hz, 2 H,

CH=CH2, Major enantiomer), 4.37 (q, J = 6.6 Hz, 1 H, CHCH=CH2), 3.69 (m, 1H, NCH (cHex)),

3.01 (m, 4 H, CH2CH2Ph, minor enantiomer), 2.75 – 2.39 (m, 4 H, CH2CH2Ph, major enantiomer),

1.95 – 0.91 (m, 10 H, c-Hex-H). 13C NMR (100 MHz, CDCl3, 21 °C): δ = 156.2 (q, JC-F = 34),

141.09, 135.7, 128.58, 128.38, 126.2, 117.9, 116.0 (q, JC-F = 275), 58.2, 58.1, 33.9, 32.9, 31.7,

214 Chapter 7

31.1, 28.6, 26.1, 25.6, 25.5, 24.9. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 67.9, – 69.0. IR

(film, cm−1): ν = 3086, 3028, 2936, 2859, 1688, 1497, 1454, 1332, 1255, 1209, 1137, 995, 928. MS

(EI) m/z: 91.0 [100%], 270.1 [27%] 339.1 [2.9%, M+]. HRMS (EI) m/z: Calc. for [M+]: 339.1805.

Found: 339.1807. Anal. Calcd. for C19H24F3NO: C, 67.24; H, 7.13; N, 4.13. Found: C, 67.04; H,

7.01; N, 4.11.

Note: the compound exists in two isomeric forms (rotamers).

(R)-N-phenyl-N-(hex-1-en-3-yl)acetamide 230.

N O

230 According to GP8, allylic amide 230 was obtained from imidate 229 as slightly yellowish oil. The

ee value was determined by chiral column HPLC: Chiralcel AD-H, n-hexane/i-PrOH 99:1, 0.8

mL/min, detection at 250 nm.

C14H19NO, MW: 217.31 g/mol. [α]25.3D (c = 0.628 g/dL, CHCl3) = + 7.2 @ 92% ee. 1H NMR (300

MHz, CDCl3, 21 °C): δ = 7.41 – 7.35 (m, 3 H, aromatic H), 7.12 – 7.09 (m, 2 H, aromatic H), 5.60

(ddd, J = 17.4 Hz, J = 10.2 Hz, J = 7.8 Hz, 1 H, CH=CH2), 5.21 – 5.08 (m, 2+1 H, CH=CH2 &

NCH), 1.75 (s, 3 H, C(O)CH3), 1.60 – 1.25 (m, 4 H, CH2CH2CH3), 0.91 (t, J = 7.2 Hz, 3 H,

CH2CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 170.0, 140.1, 137.3, 130.0, 129.1, 128.1,

117.4, 57.5, 34.3, 3.4, 19.6, 13.9. IR (film, cm−1): ν = 2959, 2933, 2873, 1660, 1595, 1494, 1384,

1314, 1118, 1074, 997, 914. MS (EI) m/z: 132.0 [100%], 217.1 [3%, M+]. HRMS (EI) m/z: Calc.

for [M+]: 217.1461. Found: 227.1464.

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-phenethyl-1-methylallyl) acetamide 220.

N

CF3

OMe

220

MeO

Ph According to GP8, allylic amide 220 was obtained from imidate 207 as a colorless oil. The ee

values were determined by chiral column HPLC: Chiralcel OD-H, n-hexane/i-PrOH 99:1, 0.8

mL/min, detection at 210 nm.

Experimental 215

C21H22F3NO2, MW: 377.40 g /mol. [α]22.5D (c = 2.18 g/dL, CHCl3) = – 22.3 (@ 99.6% ee). 1H

NMR (300 MHz, CDCl3, 21 °C): δ = 7.29 –7.17 (m, 5 H, C6H5), 7.16 & 6.89 (d, J = 9.0 Hz, 2 + 2

H, C6H4OMe), 6.20 (dd, J = 17.4 Hz, J = 10.8 Hz, 1 H, CH=CH2), 5.16 (dd, J = 17.4 Hz, J = 10.8

Hz, 2 H, CH=CH2), 3.84 (s, 3 H, OCH3), 2.65 – 2.55 & 2.23 –2.10 (m, 3 + 1 H, CH2CH2), 1.31 (s, 3

H, NCCH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 159.6, 156.3 (q, JC-C-F = 33.3), 141.4, 140.8,

131.8, 131.7, 129.3, 128.3, 128.2, 125.8, 116.0 (q, JC-F = 288.1), 113.8, 113.5, 113.3, 66.5, 55.5,


2990, 2937, 1697, 1606, 1583, 1510, 1456, 1444, 1397, 1299, 1525, 1202, 1183, 1151, 1108, 1072.

MS (EI) m/z: 91.0 [100%], 377.1 [1.1%, M+]. HRMS (EI) m/z: Calc. for [M+]: 377.1597. Found:

377.1597. Anal. Calcd. for C21H22F3NO2: C, 66.83; H, 5.88; N, 3.71. Found: C, 67.09, H, 6.00, N,

3.73.

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(2-methyl-1-phenylbut-3-en-2-yl)acetamide 219.

N

CF3

OMe

219

MeO

Ph

According to GP8, allylic amide 219 was obtained from imidate 206 as a colorless oil. The ee

values were determined by chiral column HPLC: Chiralcel OD-H, n-hexane/i-PrOH 99:1, 0.8

mL/min, detection at 210 nm. C20H20F3NO2, MW: 363.37 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.32 – 7.30 (m, 3 H,

C6H5), 7.22 – 7.18 (dd, J = 10.8 Hz, J = 5.8 Hz, 2 H, C6H5), 6.83 (dd, J = 8.7 Hz, J = 1.8 Hz, 1

H, C6H4OMe),6.72 (dd, J = 8.7 Hz, J = 3.0 Hz, 1H, C6H4OMe), 6.56(dd, J = 9.3 Hz, J = 3.0 Hz,

1 H, C6H4OMe), 6.34(dd, J = 17.4 Hz, J = 10.8 Hz, 1 H, C6H4OMe), 5.85 (q, J = 8.7 Hz, 1H,

HC=CH2), 5.17(t, J = 17.1 Hz, 2H, HC=CH2), 3.89 (d, J = 13.2 Hz, 1H, CH2C6H5), 374 (s, 3H,

OCH3), 3.07 (d, J = 13.2 Hz, 1H, CH2C6H5),1.0 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3, 21 °C):

δ = 159.3, 157.1 (q, JC-C-F = 37.5), 142.0, 137.0, 131.7, 131.6, 130.9, 128.2, 126.9, 113.3 (q, JC-F =

288.1), 66.6, 55.3, 42.1, 24.9. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 67.6. IR (film, cm−1): ν

= 1691, 1508, 1251, 1199, 1180, 1032, 908, 731, 704. MS (EI) m/z: 386.1 [100%, {(C20H20F3NO2,

M-Na }+] HRMS (EI) m/z: Calc. for {( C20H20F3NO2, M-Na }+] 386.1345 Found: 386.1338. Anal.

Calcd. for C20H20F3NO2: C, 64.97; H, 5.54; N, 4.01. Found: C, 64.81; H, 5.52; N, 3.98.

216 Chapter 7

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-benzyloxymethyl-1-methylallyl) acetamide 221.

Me

N

CF3

O

221

MeO

BnO

According to GP8, allylic amide 221 was obtained from imidate 208 as a colorless oil. The ee value

was determined by chiral column HPLC: Chiralcel OD-H, n-hexane/i-PrOH 99.8:0:2, 0.8 mL/min,


C21H22F3NO3, MW: 393.40 g /mol. [α]28.9D (c = 0.870 g/dL, CHCl3) = +3.6 (@ 99% ee). 1H NMR

(300 MHz, CDCl3, 21 °C): δ = 7.36 – 7.12 (m, 5 + 2 H, C6H5 & C6H4OMe), 6.84 – 6.79 (m, 2 H,

C6H4OMe), 6.17 (dd, J = 17.4 Hz, J = 10.8 Hz, 1 H, CH=CH2), 5.17 (dd, J = 17.4 Hz, J = 10.8 Hz,

2 H, CH=CH2), 3.84 (s, 3 H, OCH3), 4.53 (app dd, J =17.1 Hz, J = 12.3 Hz, 2 H, OCH2Ph), 4.17 &

3.64 (d, J = 9.0 Hz, 1 H each, CH2OBn), 3.82 (s, 2 H, CH2OBn), 1.22 (s, 3 H, NCCH3). 13C NMR

(75 MHz, CDCl3, 21 °C): δ = 159.8, 156.5 (q, JC-C-F = 33.9), 139.6, 138.4, 132.9, 132.3, 129.7,

128.5, 127.8, 127.7, 116.0 (q, JC-F = 287.5), 114.2, 113.4, 113.2, 73.5, 73.0, 66.4, 55.5, 23.0. 19F


1607, 1582, 1510, 1455, 1404, 1271, 1300, 1251, 1202, 1184, 1151, 1105, 1033, 931, 841, 803,

761, 737. MS (MALDI) m/z: 416.2 [56%, (MNa)+]. HRMS (MALDI) m/z: Calc. for [M-Na]+:

416.1444. Found: 416.1447. Anal. Calcd. for C21H22F3NO3: C, 64.11; H, 5.64; N, 356. Found: C,

64.23, H, 5.59, N, 3.57.

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-benzyloxymethyl-1-ethylallyl) acetamide 282.

Et

N

CF3

O

282

MeO

BnO


was determined by chiral column HPLC: Chiralcel OD-H, n-hexane/i-PrOH 99.8:0.2, 0.8 mL/min,


C22H24F3NO3, MW: 407.43 g/mol. [α]28.9D (c = 0.740 g/dL, CHCl3) = – 23.5). 1H NMR (300

MHz, CDCl3, 21 °C): δ = 7.35 – 7.19 (m, 5+2 H, C6H5 & C6H4OMe), 6.78 (d, J = 6.9 Hz, 2 H,


2 H, CH=CH2), 4.50 (s, 2 H, OCH2Ph), 4.00 & 3.88 (d, J = 9.6 Hz, 1 H each, CH2OBn), 3.84 (s, 3

Experimental 217

H, OCH3), 3.81 (s, 2 H, CH2OBn), 1.82 – 1.69 (m, 2 H, CH2CH3), 0.83 (t, J = 7.5 Hz, 2 H,

CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 159.4, 156.5 (q, JC-C-F = 33.3), 138.0, 137.8,

132.7, 132.5, 129.2, 128.5, 127.6, 127.5, 116.0 (q, JC-F = 288.5), 114.4, 112.9, 112.8, 73.2, 69.3,

69.0, 55.2, 26.9, 8.3. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 67.1. IR (film, cm−1): ν = 3089,

3032, 2970, 2939, 2884, 1694, 1607, 1584, 1511, 1455, 1404, 1364, 1299, 1251, 1202, 1183, 1151,

1106, 1034, 929, 841. MS (EI) m/z: 91.0 [100%], 407.1 [0.28%, M+]. HRMS (EI) m/z: Calc. for

[M+]: 407.1703. Found: 407.1706. Anal. Calcd. for C22H24F3NO3: C, 64.86; H, 5.94; N, 3.44.

Found: C, 64.99; H, 6.01; N, 3.43.

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-benzyloxymethyl-1-butylallyl) acetamide 283.

Bu

N

CF3

O

283

MeO

BnO


was determined after removal of the trifluoroacetyl-group according to GP7b [1H NMR of the

secondary amine (300 MHz, CDCl3, 21 °C): δ = 7.33 – 7.29 (m, 5 H, C6H5), 6.77 – 6.69 (m, 4 H,


2 H, CH=CH2), 4.47 (s, 2 H, OCH2Ph), 3.74 (s, 3 H, OCH3), 3.45 (s, 2 H, CH2OBn), 1.78 – 1.57 &

1.31 – 1.19 (m, 6 H, CH2CH2CH2CH3), 0.88 (t, J = 6.9 Hz, CH2CH2CH2CH3)] by chiral column

HPLC: Chiralcel OD-H, n-hexane/i-PrOH 95:5, 0.8 mL/min, detection at 210 nm.

C24H28F3NO3, MW: 435.48 g/mol. [α]28.9D (c = 0.567 g/dL, CHCl3) = – 25.2 (@98% ee). 1H NMR

(300 MHz, CDCl3, 21 °C): δ = 7.37 – 7.20 (m, 5 +2 H, C6H5 & C6H4OMe), 6.81 – 6.77 (m, 2 H,


2 H, CH=CH2), 4.49 (s, 2 H, OCH2Ph), 3.81 (s, 3 H, OCH3), 3.39 (s, 2 H, CH2OBn), 1.78 – 1.57 &

1.23 – 1.17 (m, 6 H, CH2CH2CH2CH3), 0.84 (t, J = 6.6 Hz, CH2CH2CH2CH3). 13C NMR (75 MHz,

CDCl3, 21 °C): δ = 159.3, 156.3 (q, JC-C-F = 33.3), 138.1, 132.7, 132.4, 129.3, 128.2, 127.5, 116.0

(q, JC-F = 288.1), 114.3, 113.8, 112.8, 73.3, 69.7, 69.1, 55.3, 33.9, 26.2, 23.1, 14.0. 19F NMR (282

MHz, CDCl3, 21 °C): δ = – 67.1. IR (film, cm−1): ν = 2968, 2939, 2872, 1698, 1608, 1510, 1456,

1400, 1299, 1251, 1202, 1182, 1151, 1107, 1034, 927, 841, 803, 737. MS (EI) m/z: 91.0 [100%],

435.2 [0.59%, M+]. HRMS (EI) m/z: Calc. for [M+]: 435.2016. Found: 435.2020. Anal. Calcd. for

C24H28F3NO3: C, 66.19; H, 6.48; N, 3.22. Found: C, 66.34, H, 6.62, N, 3.30.

218 Chapter 7

(R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-benzyloxymethyl-1-[3-triisopropyl-silyloxypropyl]allyl)acetamide 222.

N

CF3

O

222

MeO

BnO

TIPSO According to GP8, allylic amide 222 was obtained from imidate 210 as a colorless oil. The ee value

was determined by chiral column HPLC: Chiralcel OD-H, n-hexane/EtOH 99.97:0.03 (i.e. 300

ppm EtOH), 0.8 mL/min, detection at 210 nm. Alternative method for ee-determination: Cleavage

of the TIPS-group with TBAF (6 equiv. in THF) for 3 h at RT. Chiralcel OD-H, n-hexane/i-PrOH

95:5, 0.8 ml/min, detection at 210 nm.

C32H46F3NO4Si, MW: 593.79 g/mol. [α]29D (c = 0.805g/dL, CHCl3) = – 15.8 (@97% ee). 1H NMR

(300 MHz, CDCl3, 21 °C): δ = 7.37 – 7.18 (m, 5+2 H, C6H5 & C6H4OMe), 6.77 (d, J = 7.5 Hz, 2

H, C6H4OMe), 5.80 (dd, J = 17.7 Hz, J = 11.1 Hz, 1 H, CH=CH2), 5.15 (dd, J = 17.7 Hz, J = 11.1

Hz, 2 H, CH=CH2), 4.51 (app q, J = 3.9 Hz, 2 H, OCH2Ph), 4.07 & 3.87 (d, J = 9.9 Hz, 1 H each,

CH2OBn), 3.81 (s, 3 H, OCH3), 3.58 (t, J = 5.7 Hz, 2 H, CH2CH2CH2O), 1.95 – 1.80 & 1.70 – 1.50

& 1.49 – 1.44 (m, 2 H each, CH2CH2CH2O), 1.07 – 0.95 (m, 18 + 3 H, Si(CH(CH3)2)3). 13C NMR

(75 MHz, CDCl3, 21 °C): δ = 159.4, 156.3 (q, JC-C-F = 33.3), 138.07, 138.04, 132.6, 129.1, 128.2,

127.5, 116.0 (q, JC-F = 288.1), 114.5, 113.0, 112.9, 73.3, 69.6, 68.8, 63.2, 55.3, 30.9, 27.6, 18.1,

12.0. 19F NMR (282 MHz, CDCl3, 21 °C): δ = – 67.2. IR (film, cm−1): ν = 2944, 2866, 1698,

1608, 1510, 1463, 1390, 1366, 1300, 1251, 1202, 1182, 1152, 1106, 1035, 882. MS (MALDI) m/z:

616.3 [100%, (MNa)+]. HRMS (MALDI) m/z: Calc. for [MNa]+: 616.3040. Found: 616.3029.

Anal. Calcd. for C32H46F3NO4Si: C, 64.73; H, 7.81; N, 2.36. Found: C, 65.01; H, 7.77; N, 2.28.

Allylic Amines (de-acylated amides):

(R)-N-(4-Methoxyphenyl)-3-amino-1-hexene 284.

NH

MeO

Pr284 Application of the hydrolysis procedure GP9a gave the deacylated product; the ee was determined

by chiral stationary phase HPLC (Chiralcel OD-H, 99.8:0.2 n-hexane/i-PrOH, 0.8 mL/min,

detection at 250 nm).

Experimental 219

C13H19NO, MW: 205.30 g/mol. [α]22.5D (c = 0.39g/dL, CHCl3) = – 8.1. The other analytical data

are in accordance with the literature.2

(R)-N-(4-Methoxyphenyl)-3-amino-4-methyl-1-pentene 285.

NH

MeO

285

Application of the hydrolysis procedure GP9a gave the deacylated product; the ee was determined

by chiral stationary phase HPLC (Chiralcel OD-H, 99.8:0.2 n-hexane/i-PrOH, 0.8 mL/min,

detection at 250 nm).

C13H19NO, MW: 205.30 g/mol. [α]22.5D (c = 0.200 g/dL, CHCl3) = – 7.1. 1H NMR (300 MHz,

CDCl3, 21 °C): δ = 6.77 – 6.73 (m, 2H, arom-H), 6.59 – 6.55 (m, 2H, arom-H), 5.71 (ddd, J = 17.1

Hz, J = 10.2 Hz, J = 6.6 Hz, 1H, CH2=CH), 5.14 (m, 2H, CH2=CH), 3.73 (s, 3H, OCH3), 3.56 (dd,

J = 6.3 Hz, J = 5.1, NCH), 1.86 (m, CH(CH3)2), 0.99 (d, J = 6.9 Hz, CH(CH3)2), 0.95 (d, J = 6.9

Hz, CH(CH3)2). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 151.6, 141.9, 138.0, 115.9, 114.6, 114.5,

62.4, 55.8, 32.4, 19.0, 15.5. IR (film, cm−1): ν = 2960, 1691, 1586, 1512, 1467, 1232, 1039, 914,

817. MS (EI) m/z: 205.1 [15.5 %, M+]. HRMS (EI) m/z: Calc. for [M+]: 205.1467. Found: [M+]:

205.1469. Anal. Calcd. for C13H19NO: C, 76.06; H, 9.33; N, 6.82. Found: C, 75.46; H, 9.07; N,

6.84. No satisfactory microanalysis was obtained due to a rapid product oxidation/decomposition.

(S)-N-(4-Methoxyphenyl)-3-amino-3-phenyl-1-propene 286.

NH

MeO

286 Application of the hydrolysis procedure GP9b gave the deacylated product in 88% yield as yellow

semi-solid; the ee was determined by chiral stationary phase HPLC (Chiralcel OD-H, 98.2:1.8 n-

hexane/i-PrOH, 0.8 mL/min, detection at 250 nm).

C16H17NO, MW: 239.31 g/mol. [α]22.5D (c = 0.350 g/dL, CHCl3) = – 28.3. 1H NMR (300 MHz,

CDCl3, 21 °C): δ = 7.41 – 7.25 (m, 5H, C6H5), 6.76 – 6.72 (m, 2H, arom-H), 6.59 – 6.55 (m, 2H,

arom-H), 5.04 (ddd, J = 16.2 Hz, J = 10.2 Hz, J = 6.0 Hz, 1H, CH2=CH), 5.24 (m, 2H, CH2=CH),

4.87 (d, J = 6.0 Hz, 1H, NCH), 3.73 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ =

142.2, 142.1, 141.5, 129.5, 127.4, 127.1, 127.0, 115.9, 114.9, 114.7, 61.8, 55.7. IR (film, cm−1): ν

220 Chapter 7

= 3394, 3060, 3028, 2927, 2854, 2892, 1512, 1463, 1452, 1406, 1242, 1179, 1115, 1037. Anal.

Calcd. for C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C: 79.70, H: 7.42, N: 5.85. No

satisfactory microanalysis was obtained due to rapid product oxidation/decomposition.

(R)-N-Ethyl-N-(hex-1-en-3-yl) aniline 231.

NN

O

LAH, NEt3Et2O, RT, 1.5h

78%230 231 A solution of amide 230 (21.7 mg, 0.1 mmol) in Et2O (0.5 ml), NEt3 (1.0 equiv.) was added and

the mixture stirred for 5 min [Without addition of triethylamine, a competing reduction of the

olefin moiety is observed, probably catalysed by traces of Pd(0)], then LAH (7.4 mg, 2 equiv.

0.2mmol) was added. The mixture was stirred at RT for 1.5 h, and then treated with 0.5 ml of water

and 1 ml of 15% sodium hydroxide. The solid was filtered off and washed with Et2O. The filtrate

was dried over MgSO4. The crude product was purified by flash chromatography on silica gel

(Et2O/cyclohexane = 1:20) to give the tertiary allylic amine as a colourless oil (231,16 mg, 0.078

mmol, 78% yield). The product is relatively volatile.

C14H21N, MW: 203.32 g/mol. [α]22.5D (c = 1.0 g/dL, CH2Cl2) = + 97.5 @ 92% ee. 1H NMR (300

MHz, CDCl3, 21 °C): δ = 7.24 − 7.17 (dd, J = 12.3 Hz, J = 15.9 Hz, 2H, m-arom-H), 6.78 (d, J =

8.1 Hz, 2H, o-arom-H), 6.68 (t, J = 7.2 Hz, 1H, p-arom-H), 5.83 (m, 1H, CH=CH2), 5.14 (dd, J =

9.3 Hz, J = 8.9 Hz, 2H, CH=CH2), 4.22 (q, J = 6.0 Hz, 1H, CHCH=CH2), 3.29 − 3.21 (m, 2H,

NCH2CH3), 1.69 − 1.55 (m, 2H, CH2CHCH=CH2), 1.41 − 1.33 (m, 2H, CH3CH2CH2), 1.17 (t, J =

6.9, 3H, NCH2CH3), 0.94 (t, J = 7.2 Hz, 3H, CH3CH2CH2) . 13C NMR (75 MHz, CDCl3, 21 °C): δ

= 148.7, 138.2, 129.0, 116.1, 115.5, 113.4, 60.2, 39.7, 34.3, 20.0, 14.3, 14.1. IR (film, cm−1): ν =

2958, 2929, 2870, 1595, 1500, 1374, 1261, 1184, 991, 916, 743, 690. MS (EI) m/z: 203.2 [20%,

(C14H21N), M+], 160.1 [100%, (C11H15N), M+]. HRMS (EI) m/z: Calc. for [M+]: 204.1747. Found:

204.1746.

(R)-N-(5-phenylpent-1-en-3-yl)-cyclohexylamine .

NH

Ph

Experimental 221

Application of the hydrolysis procedure GP9c gave the deacylated product in 90% yield as yellow

oil; the ee was determined by chiral stationary phase HPLC (Chiralcel OD-H, 99.8:0.2 n-hexane/i-

PrOH, 0.8 mL/min, detection at 250 nm). C17H25N, MW: 243.38 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.29 – 7.17 (m, 5 H,

aromatic H), 5.61 – 5.55 (m, 1 H, CH=CH2), 5.15 (t, J = 8.7 Hz, 2 H, CH=CH2), 3.21 (q, J = 5.4

Hz, 1 H, CHCH=CH2), 2.66 – 2.48 (m, 3H, NCH (cHex) and PhCH2), 1.86 – 1.09 (m, 13 H, NH,

CH2CH2Ph, cHex-H). 13C NMR (100 MHz, CDCl3, 21 °C): δ = 142.2, 141.7, 128.3, 128.2, 126.9,

125.6, 115.6, 57.9, 53.3, 37.5, 34.6, 33.1, 32.2, 29.6, 26.1, 25.2, 24.9. IR (film, cm−1): ν = 3064,

3026, 2926, 2853, 1603, 1496, 1452, 1123, 994, 915, 747, 698. MS (EI) m/z: 138.1 [100%], 243.1

[1.9%, M+]. HRMS (EI) m/z: Calc. for [M+]: 243.1982. Found: 243.1984. Anal. Calcd. for

C17H25N, MW: 243.38: C, 67.24; H, 7.13; N, 4.13. Found: C, 67.04; H, 7.01; N, 4.11.

(R)-N-(4-Methoxyphenyl)-N-(1-phenethyl-1-methylallyl)amine 287.

NHMe

MeO

Ph287

Following GP9b (R)-2,2,2-Trifluoro-N-(4-methoxyphenyl)-N-(1-phenethyl-1-methylallyl)

acetamide (220, 1.720 g, 4.55 mmol) was converted to (R)-N-(4-methoxyphenyl)-N-(1-phenethyl-

1-methyl-allyl)amine (287) which was obtained as colorless oil (0.997 g, 3.55 mmol, 78%) after

purification by column chromatography (pentane/EtOAc 9:1).

C19H23NO, MW: 281.18 g/mol. [α]26.3D (c = 0.760 g/dL, CHCl3) = –19.1. 1H NMR (300 MHz,

CDCl3, 21 °C): δ = 7.32 –7.15 (m, 5 H, C6H5), 6.76 (s, 4 H, C6H4OMe), 6.03 (dd, J = 18.0 Hz, J =

10.8 Hz, 1 H, CH=CH2), 5.25 (dd, J = 17.4 Hz, J = 10.8 Hz, 2 H, CH=CH2), 3.77 (s, 3 H, OCH3),

3.41 (bs, 1 H, NH), 2.74 – 2.62 & 2.09 – 1.85 (m, 2 H each, CH2CH2), 1.41 (s, 3 H, NCCH3). 13C

NMR (75 MHz, CDCl3, 21 °C): δ = 152.5, 145.4, 142.3, 140.0, 128.4, 128.3, 125.7, 118.6, 114.2,

113.6, 57.8, 55.7, 42.9, 30.3, 25.1. IR (film, cm−1): ν = 3400, 3061, 3026, 2948, 2832, 1603, 1511,

1454, 1411, 1371, 1297, 1236, 1179, 1039. MS (MALDI) m/z: 281.1 [56%, M+], 282.1 [80%,

(MH)+]. HRMS (MALDI) m/z: Calc. for [M]+: 281.1774. Found: 281.1772. Anal. Calcd. for

C19H23NO: C, 81.10; H, 8.24; N, 4.98. Found: C, 81.05, H, 8.25, N, 5.05.

222 Chapter 7

Miscellaneous:

(R)-2,2,2-Trichloro- N-(1-phenylethylallyl)acetamide 225.

HN

CCl3

O

(0.5 - 0.1 mol%) 4,AgNO3, PS, DCM

O NH

CCl3

Ph

Ph213 225

According to GP8, allylic amide 225 was obtained from trichloroacetimidate 213 as yellowish oil.

The ee value was determined by chiral column HPLC: Chiralcel AD-H, n-hexane/i-PrOH 95:5,

0.8mL/min, detection at 210 nm.

C13H14Cl3NO, MW: 429.19 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.32 – 7.18 (m, 5 H,

C6H5), 6.54 (d, J = 7.2 Hz, 1H, NH), 5.93 – 5.79 (m, 1 H, CH=CH2), 5.26 (d, J = 9.0 Hz, 2 H,

CH=CH2), 4.50 (m, 1H, CH), 2.71(t, J = 7.8 Hz, 2H, PhCH2), 2.08 – 1.97 (m, 2 H , PhCH2CH2).

The other analytical data are in accordance with the literature.

(R)-S-Hex-1-en-3-yl dimethylcarbamothioate 251.

S

N

O(2.0 mol%) PPFOP-4,AgNO3, PS, DCMOS

N

40°C245 251

251 was obtained from 245 as yellowish oil. The ee value was determined by chiral column HPLC:

Chiralcel AD-H, n-hexane/i-PrOH 99.9:0.1, 1.5mL/min, detection at 210 nm.

C9H17NOS, MW: 187.30 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 5.83 (ddd, J = 18.3,

10.2, 8.3 Hz, 1H), 5.25 (d, J = 17.0 Hz, 1H), 5.08 (d, J = 10.2 Hz, 1H), 4.05 (app q, J = 15.1, 7.5

Hz, 1H), 3.00 (s, 6H), 1.74 – 1.66 (m, 2H), 1.47 – 1.40 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).

Experimental 223

7.4 Hydroamination and Hydroalkoxylation of Unactivated Olefins.

Synthesis of a bisimidazoline platinacycle 12.18

Fe

N

Pt

N

PhPh

O

Ts

N

N Ph

Ts Ph

Fe

N

N Ph

Ts Ph

K[(H2C=CH2)PtCl3],NaOAc, MeOH, benzene,RT, then Na(acac), RT

185 Pt-Bis-Imi-acac 325

N

N Ph

Ts Ph

O LiCl, HCl,MeOH, benzene

Fe

N

Pt

N

PhPh

Cl

Ts

N

N Ph

Ts Ph12

90%dr > 50 :1

To a suspension of bisimidazoline 185 (360.0 mg, 0.385 mmol) in benzene (4 mL) was added a

solution of KPtCl3(C2H4) (283.8 mg, 0.77 mmol) and NaOAc (126.3 mg, 1.54 mmol) in MeOH (4

mL). A clear solution was obtained while stirring was continued for 24 h at RT. The solution was

then filtrated over a pad of Al2O3 (5 cm, 90 act. basic, Merck) and the filter cake was washed with

EtOAc. The filtrate was evaporated to dryness and the residue was treated with sodium

acetylacetonate (144.4 mg, 1.16 mmol) in benzene/MeOH (1:1, 10 mL) for 2 h at RT. The solution

was then diluted with benzene (30 mL), washed with H2O (3 × 10 mL) and dried over MgSO4. The

crude product was purified by flash chromatography on silica gel (EtOAc/cyclohexane = 1:4, 3%

TEA) to give Pt-Bis-Imi-acac 325 as a dark red solid (212.7 mg, 0.173 mmol, 45% yield).

C59H52N4O6S2FePt: MW: 1228.12 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.26 − 7.50

(m, 12H, arom. H), 7.01 − 7.17 (m, 12H, arom. H), 6.65 (d, J = 6.9 Hz, 2H, Ts-H), 6.59 (d, J = 6.9

Hz, 2H, Ts-H), 5.56 (d, J = 2.4 Hz, 1H, Ph-H), 5.29 (t, J = 1.2 Hz, 1H, Cp-H), 5.10 (s, 1H, acac-H),

5.09 (m, 2H, Ph+Cp-H), 4.95 (m, 3H, Ph+Cp-H), 4.86 (d, J = 4.8 Hz, 1H, Cp-H), 4.75 (m, 1H, Cp-

H), 4.57 (m, 2H, Cp-H), 2.40 (s, 3H, Ts-CH3), 2.39 (s, 3H, Ts-CH3), 1.78 (s, 3H, acac-CH3), 1.32

(s, 3H, acac-CH3).

The above Pt-Bis-Imi-acac (325, 212.7 mg, 0.173 mmol) was dissolved in benzene (3 mL). A

solution of conc. aqueous HCl (0.4 mL) and lithium chloride (1.10 g, 25.9 mmol) in methanol (2

mL) was added. The mixture was stirred for 20 min at RT and was diluted with dichloromethane

(10 mL), then it was washed with water (2 × 5 mL) and saturated aqueous NaHCO3 (5 mL). The

solvent was

removed and the residue was purified by column chromatography (DCM) to give

diastereomerically pure Pt-Bis-Imi-Cl 12 as a dark red solid (183.7 mg, 0.156 mmol, 90% yield).

C54H45N4O4S2ClFePt: MW: 1180.51 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): = 7.32 − 7.60

(m, 16H, arom. H), 7.17 (m, 3H, arom. H), 7.01 (m, 5H, arom. H), 6.89 (m, 2H, arom. H), 6.68 (d, J

224 Chapter 7

= 7.5 Hz, 2H, arom. H), 6.45 (d, J = 7.5 Hz, 2H, arom. H), 5.58 (m, 1H, Cp-H), 5.55 (d, J = 2.7 Hz,

1H, Cp-H), 5.51 (d, J = 2.7 Hz, 1H, Ph- H), 5.35 (d, J = 2.7 Hz, 1H, Ph-H), 5.22 (d, J = 3.3 Hz, 1H,

Ph-H), 5.10 (d, J = 2.7 Hz, 2H, Ph+Cp-H), 4.94 (m, 1H, Cp-H), 4.68 (m, 1H, Cp-H), 4.62 (dd, J =

2.7 Hz, J = 2.4 Hz, 1H, Cp-H), 4.34 (m, 1H, Cp-H), 2.45 (s, 3H, CH3), 2.33 (s, 3H, CH3).


Optimization of Catalytic Hydroamination. The calculated amount of precatalyst 12 (5mol%) and AgOOCC3F7 (1.equiv.) was weighed

in an analytical vial. The substrate (0.05 mmol) and solvent (70 µL) were added

successively. The resulting reaction mixture was stirred for the indicated time at the

indicated temperature. After the reaction, remaining solvent was removed in vacuo at room

temperature and the residue was purified by column chromatography (CyH:EtOAc 9:1 or

pentane:EtOAc 9:1). For screening experiments, purification by column chromatography

was replaced by a simple filtration over a plug of silica (ca. 1 cm in a Pasteur pipette,

pentane:EtOAc 9:1; the product was first dissolved with ca. 100 µL DCM before adding 1

mL of the above mentioned solvent mixture).

Synthesis of Substrates.

(Z)-Methyl 2,2-diphenyloct-4-enoate 394.

O

O

Ph

PhLDA, THF,− 78 °C, RT+

O

O

70%

Ph

Ph

394

Br

A solution of methyl diphenylacetate (1.38 g, 6.13 mmol) in THF (3 mL) was added slowly to a

solution of LDA [generated from diisopropylamine (1.02 g, 7.23 mmol) and n-BuLi [(3.9 mL, 1.6

M in hexanes, 6.24 mmol) in THF (5 mL) at –78 °C] over 30 min and the resulting solution was

stirred for additional 15 min. Allyl bromide (1.20 g, 7.36 mmol) was added over 10 min and the

resulting mixture was warmed to room temperature, stirred overnight, quenched with HCl (3 N, 10

mL), and extracted with ether (4 × 25 mL). The combined ether extracts were washed with water

(25 mL), dried (MgSO4), and concentrated under vacuum. Column chromatography of the residue

(SiO2; EtOAc - pentane = 9:1) gave 394 as a viscous colorless oil (1.35 g, 70%).

C21H24O2, MW: 308.41 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.54 (d, J = 7.2 Hz, 1 H,

aromatic H), 7.30 (d, J = 7.2 Hz, 1 H, aromatic H), 7.24 – 7.16 (m, 8 H, aromatic H), 5.30 – 5.21

Experimental 225

(m, 2H, HC=CH), 3.67 (s, 3 H, CH3O), 3.15 (d, J = 6.6 Hz, 2 H, CCH2CH=CH), 1.78 (q, J = 13.8

Hz, 2 H, CH2CH2CH3), 1.23 – 1.14 (m, 2 H, CH2CH2CH3), 0.78 (t, J = 7.2 Hz, 3H, CH2CH3). 13C

NMR (75 MHz, CDCl3, 21 °C): δ = 174.7, 142.5, 134.6, 132.6, 129.0, 128.9, 127.7, 126.7, 125.3,

124.7, 60.6, 60.3, 52.3, 41.6, 36.1, 34.7, 29.3, 22.4, 13.7.

(Z)-2,2-Diphenyloct-4-en-1-ol 368a.

O

O

OHLAH, THF,− 0 °C, RT

61%

Ph

Ph

Ph

Ph

394 368a

A solution of ester 394 (1.25 g, 4.05 mmol) in THF (5 mL) was added slowly to a suspension of

LiAlH4 (0.21 g, 5.63 mmol) in THF (5 mL) at 0 °C. The resulting mixture was stirred at room

temperature overnight, quenched by sequential addition of water (5 mL) and aqueous NaOH (15%,

5 mL) at 0 °C. The resulting suspension was filtered through celite eluting with ether. The ethereal

solution was dried (MgSO4) and concentrated under vacuum. Chromatography of the residue (SiO2;

EtOAc: petrol ether = 1:9 −> 2:8) gave (Z)-2,2-diphenyl-4-octen-1-ol 368a (0.7 g, 61%) as

colourless viscous oil.

C20H24O, MW: 280.40 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.33 – 7.17 (m, 10 H,

aromatic H), 5.41 – 5.37 (m, 1H, HC=CH), 5.09 – 5.05 (m, 1H, HC=CH), 4.15 (d, J = 6.6 Hz, 2 H,

CH2OH), 2.96 (d, J = 7.2 Hz, 2 H, CCH2CH=CH), 1.97 (q, J = 14.4 Hz, 2 H, CH2CH2CH3), 1.34 –

1.26 (m, 2 H, CH2CH2CH3), 0.88 (t, J = 3.9 Hz, 3H, CH2CH3). 13C NMR (75 MHz, CDCl3, 21

°C): δ = 145.4, 134.3, 132.8, 128.2, 128.1, 126.3, 126.2, 125.6, 124.9, 68.2, 68.0, 52.0, 51.8, 39.8

34.6, 34.1, 29.4, 22.6, 22.5, 13.8, 13.6. MS (EI) m/z: 197.1 [100%, {(M – CH-CHPh2)H}+]; 280.2

[5%, M+].

(E)-2,2-Diphenyloct-4-en-1-ol 368b.

O

O


78%

Ph

Ph

Ph

Ph

395 368b

A solution of ester 395 (0.7 g, 2.27 mmol) in THF (3 mL) was added slowly to a suspension of


temperature overnight, quenched by sequential addition of water (5 mL) and aqueous NaOH (15%,

5 mL) at 0 °C. The resulting suspension was filtered through Celite and eluted with ether. The ether

226 Chapter 7

eluant was dried (MgSO4) and concentrated under vacuum. Chromatography of the residue (SiO2;

EtOAc – Petrol ether = 0.5:9.5 to 1:9) gave (E)-2,2-diphenyl-4-octen-1-ol 368b (0.5 g, 78%) as a

viscous colorless oil.

C20H24O, MW: 280.40 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ =7.33 – 7.16 (m, 10 H,

aromatic H), 5.49 – 5.42 (m, 1H, HC=CH), 5.09 – 5.01 (m, 1H, HC=CH), 4.15 (d, J = 6.8 Hz, 2 H,

CH2OH), 2.91 (d, J = 7.2 Hz, 2 H, CCH2CH=CH), 1.88 (q, J = 14.4 Hz, 2 H, CH2CH2CH3), 1.53 –

1.21 (m, 2 H, CH2CH2CH3), 0.83 (t, J = 3.9 Hz, 3H, CH2CH3). 13C NMR (75 MHz, CDCl3, 21

°C): δ = 145.4, 134.3, 132.8, 128.2, 128.1, 126.3, 126.2, 125.6, 124.9, 68.2, 68.0, 52.0, 51.8, 39.8

34.6, 34.1, 29.4, 22.6, 22.5, 13.8, 13.6. MS (EI) m/z: 197.1 [100%, {(M –CH-CHPh2)H}+]; 280.2

[5%, M+].

(Z)-Methyl 2,2-diphenyloct-5-enoate 396.

O

O

Ph

Ph I LHMDS, THF,− 78 °C, RT

O

O

+96%

Ph

Ph

396

To a solution of methyl diphenylacetate (424.88 mg, 1.85 mmol) in THF (2 mL) at –78 °C under

N2 was added LHMDS (1.06M in THF, 1.85 mmol, 1.74 ml) over 5 min at –78 °C, and the

resulting solution was stirred for additional 15 min. Allyl iodide (440 mg, 2.06 mmol) was added

over 10 min and stirred for 1 hour at –78 °C, then stirring was continued overnight at RT. The

solvent was removed in a rotary evaporator, the residue purified using silica gel chromatography

and hexane:Et2O (30:1 to 30:5) as eluent to give as colourless oil (545 mg, 1.76 mmol, 96%

yield).

C21H24O2, MW: 308.41 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.32 – 7.21 (m, 10H,

aromatic H), 5.37 – 5.24 (m, 2H, HC=CH), 3.68 (s, 3 H, CH3O), 2.41 – 2.35 (m, 2 H,

CH2CH2CH=CH), 1.89 – 1.74 (m, 4H, CH2CH2CH=CHCH2CH3), 0.87 (t, J = 7.5 Hz, 3H,

CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 174.7, 142.9, 132.1, 128.8, 128.3, 127.8, 126.7,

60.2, 52.2, 38.4, 26.9, 23.2, 20.3, 14.29.

Experimental 227

(Z)-2,2-Diphenyloct-5-en-1-ol 368c.

O

O


89%

Ph

Ph

Ph

Ph

396 368c A solution of ester 396 (545 mg, 1.76 mmol) in THF (2 mL) was added slowly to a suspension of


temperature for 3 h, quenched by sequential addition of water (5 mL) and aqueous NaOH (15%, 5

mL) at 0 °C. The resulting suspension was filtered through celite and eluted with ether. The ether

eluant was dried (MgSO4) and concentrated under vacuum. Chromatography of the residue (SiO2;

EtOAc – petrol ether = 1:9 to 2:8) gave (Z)2,2-diphenyl-5-octen-1-ol 368c (0.44 g, 89%) as a

viscous colorless oil.

C20H24O, MW: 280.40 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.33 – 7.19 (m, 10H,

aromatic H), 5.29 – 5.18 (m, 2H, HC=CH), 4.10 (d, J = 6.3 Hz, 2 H, CH2OH), 2.14 – 2.08 (m, 2 H,



36.4, 22.1, 20.3, 14.3.

2-Methyl-4,4-diphenyltetrahydrofuran 365.21

OH(10 mol%) FeCl3,(30 mol%) AgOTf,DCE, 83 °C

88%

Ph

PhO

PhPh364 365

A cationic iron complex was prepared in situ from iron(III) chloride (1.62mg, 0.01 mmol) and

AgOTf (7.7 mg, 0.03 mmol) in DCE (0.25 mL) for 2 h at room temperature. To this solution was

added the solution of hydroxyolefin 364 (23.83 mg, 0.1 mmol) in DCE (0.25 mL) under N2

atmosphere. After heating for 1 h, the reaction mixture was cooled, filtered through a short silica-

gel column using hexane/ethyl acetate as an eluent. Separation by column chromatography (silica-

gel, Petrol ether/Et2O (3%)) afforded product 365 as a yellowish oil (21 mg, 0.088 mmol, 88%)


aromatic H), 4.52 (d, J = 8.7 Hz, 1 H, Ph2CCH2O), 4.15 – 4.03 (m, 2 H, Ph2CCH2O & CHCH3),

2.58 – 2.52 (dd, J = 12.0 Hz, J = 5.6 Hz, 1 H, Ph2CCH2CH), 2.22 – 2.15 (dd, J = 12.0 Hz, J = 9.5

228 Chapter 7

Hz, 1 H, Ph2CCH2CH), 1.23 (d, J = 6.2 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ =

146.5, 146.2, 128.5, 128.3, 128.2, 127.1, 126.9, 126.4, 126.2, 74.7, 56.4, 48.1, 47.4, 46.5, 21.3.

2-Butyl-4,4-diphenyltetrahydrofuran 370a.

OH (10 mol%) FeCl3,(30 mol%) AgOTf,DCE, 83 °C

OBu

85%

Ph

PhPh

Ph368a 370a

To cationic iron complex, which was prepared in situ from iron chloride (0.81mg, 0.005 mmol) and

AgOTf (3.85 mg, 0.015 mmol) in DCE (0.25 mL) for 2 h at room temperature, was added the

solution of hydroxyolefin 368a (15mg, 0.05 mmol) in DCE (0.25 mL) under N2 atmosphere. After

heating for 4h, the reaction mixture was cooled, filtered through a short silica-gel column using

hexane/ethyl acetate as an eluent. Separation by column chromatography (silica-gel) using Petrol

ether/Et2O (3%) solvent afforded product 370a (12 mg, 0.042 mmol, 85.5%).


aromatic H), 4.60 (d, J = 8.7 Hz, 1 H, CH2O), 4.12 (d, J = 8.7 Hz, 1 H, CH2O), 4.01 – 3.97 ( m, 1H,

CHBu), 2.63 – 2.57 (d d, J = 5.7 Hz, 1 H, C(Ph2)CH2CH), 2.30 – 2.23 (d d, J = 9.6 Hz, 1 H,

C(Ph2)CH2CH), 1.66 – 1.62 (m, 2 H, CH2CH2CH2CH3), 1.55 – 1.50(m, 2 H, CH2CH2CH2CH3),

1.42 – 1.27(m, 2 H, CH2CH2CH2CH3), 0.85 (t, J = 13.8 Hz, 3H, CH2CH2CH2CH3). 13C NMR (75

MHz, CDCl3, 21 °C): δ = 146.4, 146.2, 128.3, 128.2, 127.1, 127.1, 126.3, 126.1, 56.0, 44.9, 35.8,

28.3, 22.7, 14.0.

5,5-diphenyl-2-propyltetrahydro-2H-pyran 370c.

OH (10 mol%) FeCl3,(30 mol%) AgOTf,DCE, 83 °C O

Ph

PhnPr67%

Ph

Ph

368c 370c

To cationic iron complex, which was prepared in situ from iron chloride (1.35mg, 0.008 mmol) and

AgOTf (6.41 mg, 0.025 mmol) in DCE (0.25 mL) for 2 h at room temperature, was added the

solution of hydroxyolefin 368c (25 mg, 0.08 mmol) in DCE (0.25 mL) under N2 atmosphere. After

heating for 2h, the reaction mixture was cooled, filtered through a short silica-gel column using

hexane/ethyl acetate as an eluent. Separation by column chromatography (silica-gel) using Petrol

ether/Et2O (3%) solvent afforded product 370c (15 mg, 0.053 mmol, 67%).

Experimental 229


aromatic H), 4.58 – 4.53 (dd, J = 12.0 Hz, J = 2.6 Hz, 1 H, CH2O), 3.49 (d, J = 12 Hz, 1 H, CH2O),

3.33 ( m, 1H, CHPr), 2.39 – 2.31 (m, J = 5.7, 2 H, C(Ph2)CH2CH2), 1.49 – 1.11 (m, 6 H,

CH2CHCH2CH2CH3), 0.82 (t, J = 7.2 Hz, 3H, CH2CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C):

δ = 146.8, 145.9, 128.9, 128.2, 127.9, 127.0, 126.2, 125.5, 46.0, 38.1, 34.8, 27.7, 18.6, 14.1.

(Z)-N-Benzyl-2,2-diphenylhept-4-en-1-amine 333.20

NH2 NHBni. PhCHO, MeOH,RT, 3.5hii. NaBH4, RT.

62%

Ph

Ph

Ph

Ph

332 333 A solution of 2,2-diphenyl-4-pentenylamine (332, 0.40 g, 1.59 mmol) and benzaldehyde (0.180 g,

1.74 mmol) in MeOH (5 mL) was stirred at room temperature for 3.5 h, treated with NaBH4 (94

mg, 2.46 mmol) and stirred overnight. The resulting mixture was treated with water (20 mL) and 1

M NaOH (10 mL) and then extracted with CH2Cl2 (3×50mL). The combined organic extracts were

dried (MgSO4) and concentrated. The resulting oily residue was chromatographed (hexanes-EtOAc

= 8:1) to give 333 (350 mg, 62%) as a viscous oil.

C26H29O, MW: 355.52 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.28 – 7.16 (m, 15 H,

aromatic H), 5.34 – 5.30 (m, 1H, HC=CH), 4.98 – 4.94 (m, 1H, HC=CH), 3.72 (s, 2 H, CH2Ph),

3.20 (s, 2 H, CH2NH), 3.00 (d, J = 7.2 Hz, 2 H, CCH2CH=CH), 2.00 – 1.97 (q, 2 H, =CHCH2CH3),

0.85 (t, J = 7.5 Hz, 3H, CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ = 147.0, 140.7, 134.1,

128.2, 128.1, 127.9, 127.8, 126.6, 125.9, 124.6, 55.6, 54.4, 50.4, 34.7, 20.7, 14.1.

1-Benzyl-4,4-diphenyl-2-propylpyrrolidine 397e20

NHBn

(2.5 mol%) PtCl2(5 mol%) PPh3Dioxane, 120°C,16h, 50%

NnPr

Ph

Et

Ph

PhPh

Ph50%

333 397e A solution of amine 333 (35 mg, 0.10 mmol), PtCl2 (0.63 mg, 0.002 mmol) and PPh3 (1.31 mg,

0.005 mmol) in dioxane (50 μL) was stirred at 120 °C for 16 h, then filtered through a short plug of

silica gel using EtOAc:Petrol ether 1:9 and concentrated under vacuo. The crude was purified by

column chromatography (silica gel) using EtOAc:Petrol ether 0.5:9.5 afforded a 397e (17 mg, 0.05

mmol, 50% yield).

230 Chapter 7


aromatic H), 4.14 (d, J = 12.6 Hz, 1 H, C(Ph2)CH2N), 3.65 (d, J = 9.9 Hz, 1 H, C(Ph2)CH2N), 3.23

(d, J = 13.2 Hz, 1 H, PhCH2N), 2.94 – 2.87 (dd, J = 12.3 Hz, J = 7.6 Hz, 1 H, C(Ph2)CH2CH), 2.78

– 2.67 (m, 2H, PhCH2N, C(Ph2)CH2CH), 2.26 – 2.19 (d d, J = 13.2 Hz, J = 8.2 Hz, 1 H,

C(Ph2)CH2CH), 1.66 – 1.62 (m, 2 H, CH2CH2CH2CH3), 1.67(m, 2 H, CH2CH2CH3), 1.31(m, 2 H,

CH2CH2CH3), 0.90 (t, J = 6.9, 3H, CH2CH2CH3).

N-(3-Chlorobenzyl)-2,2-diphenylpent-4-en-1-amine 327.

NH2 NH

i. m-ClPhCHO, MeOH,RT, 3.5hii. NaBH4, RT.

53%

Ph

Ph

Ph

PhCl

326 327 A solution of 2,2-diphenyl-4-pentenylamine 326 (0.50 g, 2.1 mmol) and 3-chlorobenzaldehyde

(309 mg, 2.2 mmol) in MeOH (10 mL) was stirred at RT for 3.5h and after that the solution was

treated with NaBH4 (119 mg, 3.1 mmol) and stirred overnight. The resulting yellow mixture was

treated with water (50 mL) and 1M NaOH (10 mL) and then extracted with CH2Cl2 (3 x 50 mL).

The combined organic phases were dried with MgSO4 and concentrated. The resulting slight green

oily residue was chromatographed (Petrol ether/EtOAc 9:1) to give N-(3-chlorobenzyl)-2,2-

diphenylpent-4-en-1-amine 327 (400 mg, 1.1 mmol, 53%) as a green oil.

C24H24ClN, MW: 361.91 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.29 – 6.99 (m, 14H,

aromatic H), 5.31 – 5.17 (m, 1 H, CH=CH2), 4.95 – 4.89 (dt, J = 17.0 Hz, J = 1.2 Hz, 1 H,

CH=CH2), 4.85 – 4.80 (dt, J = 10.1 Hz, J = 1.0 Hz, 1 H, CH=CH2), 3.60 (s, 2 H, mClPhCH2N),

3.09 (s, 2 H, Ph2CCH2N), 2.96 (d, J = 7.0 Hz, 2 H, Ph2CCH2CH=CH2). 13C NMR (75 MHz,

CDCl3, 21 °C): δ = 146.6, 142.8, 134.7, 134.1, 129.4, 129.2, 128.2, 128.0, 127.9, 127.7, 126.9,

126.0, 117.7, 55.1, 53.5, 50.1, 41.5.

N-Phenethyl-2,2-diphenylpent-4-en-1-amine 328.

NH2 NH

i. PhCH2CHO, MeOH,RT, 3.5hii. NaBH4, RT.

28%

Ph

Ph

Ph

PhPh

326 328

A solution of 2,2-diphenyl-4-pentenylamine 326 (0.50 g, 2.1 mmol) and 3-phenylacetaldehyde

(264 mg, 2.2 mmol) in MeOH (10 ml) was stirred at RT for 3.5 h and after that the solution was

treated with NaBH4 (119 mg, 3.1 mmol) and stirred overnight. The resulting yellow mixture was

treated with water (50ml) and 1M NaOH (10ml) and then extracted with CH2Cl2 (3 x 50ml). The

Experimental 231

combined organic phases were dried with MgSO4 and concentrated. The resulting oily residue was

chromatographed (Petrol ether/EtOAc 9:1) to give N-phenethyl-2,2-diphenylpent-4-en-1-amine 328

(200 mg, 0.59 mmol, 28%) as a yellow oil.

C25H27N, MW: 341.49 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.28 – 6.97 (m, 15H,

aromatic H), 5.35 – 5.21 (m, 1 H, CH=CH2), 4.92 – 4.82 (dt, J = 18.5 Hz, J = 1.1 Hz, 2 H,

CH=CH2), 3.14 (s, 2 H, Ph2CCH2N), 2.91 (d, J = 7.2 Hz, 2 H, Ph2CCH2CH=CH2), 2.72(dt, J = 6.7

Hz, J = 1.4 Hz, 2 H,CH2CH2Ph), 2.59 (t, J = 6.6 Hz, 2 H,CH2CH2Ph). 13C NMR (75 MHz, CDCl3,

21 °C): δ = 146.6, 140.1, 134.8, 130.0, 129.7, 129.3, 129.2, 129.2, 128.7, 128.6, 128.5, 128.3,

128.2, 128.0, 127.9,127.7, 127.5, 126.5, 126.0, 125.9, 117.6, 55.7, 51.6, 50.0, 41.6, 36.0.

(S)-1-(3-Chlorobenzyl)-2-methyl-4,4-diphenylpyrrolidine 397c.

NH

Ph

PhPt-cat, Ag salt,Solvent, T N

Cl

Ph

Ph

Cl

327 397c

C24H24ClN, MW: 361.16 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.37 – 7.10 (m, 14H,

aromatic H), 4.05 (d, J = 13.5 Hz, 1 H, C(Ph2)CH2N), 3.63 (d, J = 9.6 Hz, 1 H, C(Ph2)CH2N), 3.25

(d, J = 13.5 Hz, 1 H, mClPhCH2N), 3.04 – 2.75 (m, 3 H, mClPhCH2N C(Ph2)CH2CH), 2.25 – 2.19

(m, 1H,C(Ph2)CH2CH), 1.16 (d, J = 5.4 Hz, 3H, CH3).

(Z)-2,2-Diphenyloct-5-enenitrile 335.

CN

Ph

Ph I LHMDS, THF,− 78 °C, RT

CN

Et

95%

PhPh

335

To a solution of diphenylacetonitrile (919 mg, 4.76 mmol) in THF (2 mL) at –78 °C was added

LHMDS (1.06 M in THF, 4.76 mmol, 4.49 ml) over 5 min at –78 °C, and the resulting solution was

stirred for additional 15 min. Allyl Iodide (1.0 g, 4.76 mmol) was added over 10 min and stirring

was continued for 1 hour at –78 °C, then at RT overnight. The solvent was removed in a rotary

evaporator, the residue was purified using silica gel and Petrol ether:Et2O (30:1 to 30:5) as eluent

to give 335 as a colourless oil (1.25 g, 4.5 mmol, 95% yield).


aromatic H), 5.42 – 5.30 (m, 2H, HC=CH), 2.42 – 2.36 (m, 2 H, CH2CH2CH=CH), 2.18 – 2.10(m,

2H, CH2CH2CH=CH), 1.99 – 1.89 (q, 2H, CH2CH3), 0.91 (t, J = 7.5 Hz, 3H, CH2CH3). 13C NMR

232 Chapter 7

(75 MHz, CDCl3, 21 °C): δ = 140.0, 133.3, 128.8, 127.8, 126.8, 126.5, 122.2, 51.5, 39.6, 23.5,

20.4, 14.2.

(Z)-2,2-Diphenyloct-5-en-1-amine 336.

Et

PhPhCN

Et

PhPh

LAH, Et2O− 0 °C

79%

NH2

335 336 A suspension of LiAlH4 (0.68 g, 18.02 mmol) in ether (25 mL) was treated with (Z)-2,2-

diphenyloct-5-enenitrile 335 (1.25 g, 4.5 mmol) at 0 °C and was then warmed slowly to room

temperature and stirred for additional 4 h. The resulting suspension was cooled to 0 °C and

quenched by slow addition of 6 M NaOH (20 mL). The resulting mixture was extracted with ether

(4 X 50 mL) and the combined ether extracts were dried (MgSO4) and concentrated to give (Z)-2,2-

diphenyloct-5-en-1-amine 336 (1.00 g, 79%) as a pale yellow, viscous oil.


aromatic H), 5.32 – 5.28 (m, 2H, HC=CH), 3.34 (s, 2 H, CH2NH2), 2.16 – 2.10 (m, 2 H,



48.9, 36.6, 22.0, 20.3, 14.3.

(Z)-Benzyl 2,2-diphenyloct-5-enylcarbamate 337.

Et

PhPh

NH2

Et

PhPh

HN Cbz


91%336 337

Benzyl chloroformate (0.25 mL, 1.78 mmol) was added slowly to a mixture of (Z)-2,2-diphenyloct-

5-enyl-1-amine 336 (0.500 g, 1.78 mmol) and NaHCO3 (0.23 g, 2.63 mmol) in ethanol/water (3:2,

10 mL) at room temperature. The resulting suspension was stirred for 1 h and treated with water

(40 mL). The resulting mixture was extracted with ether (2 X 50 mL) and the combined ether

extracts were dried (MgSO4) and concentrated. The resulting oily residue was chromatographed

(hexanes-EtOAc = 20:1) to give 337 as a colourless oil (670 mg, 1.62 mmol, 91%).

C28H31NO2, MW: 413.24 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.39 – 7.15 (m, 15H,

aromatic H), 5.31 – 5.23 (m, 2H, HC=CH), 5.15 (s, 2 H, OCH2Ph), 4.29 (t, J = 4.2 Hz, 1H, NH),

3.98 (d, J = 6.0 Hz, 2 H, CH2NH), 2.10 – 2.06 (m, 2 H, CH2CH2CH=CH), 1.86 –1.68 (m, 4H,

Experimental 233

CH2CH2CH=CHCH2CH3), 0.85 (t, J = 7.8 Hz, 3H, CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C):

δ = 156.3, 145.6, 136.4, 132.0, 128.5, 128.3, 128.1, 127.9, 126.4, 66.7, 50.3, 47.6, 37.0, 22.0, 14.3.

(Z)-Benzyl 2,2-diphenylhept-4-enylcarbamate 334.

NH2

Et Et


90%

Ph

Ph

Ph

Ph NH

Cbz

332 334 Benzyl chloroformate (0.18 mL, 1.31 mmol) was added slowly to a mixture of (Z)-2,2-

diphenylhept-5-enyl-1-amine 332 (0.35 g, 1.31 mmol) and NaHCO3 (0.17 g, 1.94 mmol) in

ethanol/water (3:2, 10 mL) at room temperature. The resulting suspension was stirred for 1 h and

treated with water (40 mL). The resulting mixture was extracted with ether (2 X 50 mL) and the

combined ether extracts were dried (MgSO4) and concentrated. The resulting oily residue was

chromatographed (hexanes-EtOAc = 20:1) to give 334 as a colourless oil (470 mg, 1.17 mmol,

90%).

C28H31NO2, MW: 413.24 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.28 – 7.16 (m, 15H,

aromatic H), 5.39 – 5.30 (m, 1H, HC=CH), 5.13 – 5.03 (m+s, 3 H, HC=CH and OCH2Ph), 4.34 (t,

J = 5.1 Hz, 1H, NH), 3.94 (d, J = 6.0 Hz, 2 H, CH2NH), 2.86 (d, J = 7.2 Hz, 2 H, CH2CH=CH),

1.83 (q, 2H, CH2CH3), 0.78 (t, J = 7.5 Hz, 3H, CH2CH3). 13C NMR (75 MHz, CDCl3, 21 °C): δ =

156.2, 145.2, 136.4, 134.8, 128.5, 128.2, 128.1, 128.0, 126.4, 123.3, 66.7, 50.3, 47.9, 34.6, 26.9,

20.6, 13.9.

N-(2,2-Diphenylpent-4-enyl)acetamide 329.

NH2

98%

Ph

Ph

Ph

Ph NH

CH3COCl, Py,DCM, 0 °C, RT

O

326 329 Acetyl chloride (0.15 mL, 2.2 mmol) was added slowly to a solution of amine 326 (0.500 g, 2.1

mmol) and pyridine (0.25 mL, 3.2 mmol) in CH2Cl2 (10 mL) at 0 °C, warmed, and stirred

overnight at room temperature. The resulting solution was diluted with CH2Cl2 (30 mL), washed

with 1 M HCl (3 × 10 mL), 1 M NaOH (10 mL), and brine (10 mL), dried (MgSO4), and

concentrated. The resulting oily residue was chromatographed (EtOAc–CH2Cl2 = 1:2) to give 329

as a white solid (580 mg, 2.07 mmol, 98%).

234 Chapter 7

C19H21NO, MW: 279.16 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.35 7.18 (m, 10H,

aromatic H), 5.68 – 5.55 (m, 1H, HC=CH2), 4.85 – 4.79 (m, 1H, HC=CH2) 4.57 (s, 3 H, CH2NH),

2.81 (dt, J = 6.8 Hz, J = 1.0 Hz, 2 H, CH2CH=CH2), 1.91 (s, 3 H, NHCOCH3).

N-(2,2-Diphenylpent-4-enyl)-4-methylbenzenesulfonamide 330.

NH2

Ph

Ph

Ph

Ph NH

TsTsCl, Et3N,DCM, RT

71%326 330

To a solution of amine 326 (0.5 g, 2.1 mmol) and TsCl (1 equiv. 400 mg, 2.1 mmol) in CH2Cl2 (10

ml) was added Et3N (2 equiv. 0.58 ml, 4.2 mmol). The reaction mixture was stirred overnight.

Water was added and the aqueous layer was extracted with CH2Cl2. The combined organic phases

were dried over MgSO4. After filtration and evaporation, the residue was purified by column

chromatography on silica gel using EtOAc:Petrol ether 2:8- 4:6 to afford p-toluenesulfonamide

330 (590 mg, 1.40 mmol, 71%).

C24H25NO2S, MW: 391.16 g/mol. 1H NMR (300 MHz, CDCl3, 21 °C): δ = 7.60 (d, J = 8.3 Hz, 2

H, C6H4), 7.37 – 7.17 (m, 10H, aromatic H), 7.05 (d, J = 6.2 Hz, 2 H, C6H4), 4.95 – 4.90 (m, 1H,

HC=CH2), 3.80 (t, , J = 6.3 Hz, 1H, NH), 3.52(d, J = 6.4 Hz, 2H, CH2NH), 2.90 (d, J = 7.1 Hz, 2

H, CH2CH=CH2), 2.40 (s, 3 H, C6H4CH3).

Experimental 235

Hammett-Plot of C-3-Aryl Substituted Allylic Imidates.

Thermal Rearrangement Ph-substituted imidates40 °C in CDCl3

y = 100e-0,0056x

R2 = 0,9973

y = 100e-0,0106x

R2 = 0,9879

y = 100e-0,0468x

R2 = 0,9989

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40 45

time/hours

perc

ent r

emai

ning

Sta

rtin

g-M

ater

ial

p-Chlorophenylp-H-phenylp-Methylphenyl

Hammett-Plot

y = -0,4675xR2 = 0,9952

-0,35

-0,3

-0,25

-0,2

-0,15

-0,1

-0,05

0

0,05

0,1

0,15

0,2

-0,4 -0,2 0 0,2 0,4 0,6 0,8

sigma

log(

krel

)

236 Chapter 7

7.5 References. 1 K. Tamura, H. Mizukami, K. Maeda, H. Watanabe, K. Uneyama, J. Org. Chem. 1993, 58, 32.

2 Most imidates are literature known, see L. E. Overman, C. E. Owen, M. M. Payan, C. J.

Richards, Org. Lett. 2003, 5, 1809.

3 T. Kato, H. Kondo, Y. Kitano, G. Hata, Y. Takagi, Chem. Lett. 1980, 757.

4 M. Acemoglu, P. Uebelhart, M. Rey, C. H. Eugster, Helv. Chim. Acta 1988, 71, 931.

5 R. Peters, Z.-q. Xin, D. F. Fischer, W. B. Schweizer, Organometallics 2006, 25, 2917.

6 Diamine 342 was perpared by D. F. Fischer, former PhD student ETH Zurich.

7 M. T. Nunez, V. S. Martin, J. Org. Chem. 1990, 55, 1928.

8 E. Piers, G. L. Jung, E. H. Ruediger, Can. J. Chem. 1987, 65, 670.

9 R. Takeuchi, N. Ue, K. Tanabe, K. Yamashita, N. Shiga, J. Am. Chem. Soc. 2001, 123, 9534.

10 J. Mulzer, O. Lammer, Chem. Ber. 1986, 119, 2178.

11 O. P. Vig, M. L. Sharma, R. Gupta, J. Ind. Chem. Soc. 1990, 67, 37.

12 Z. Wu, G. S. Minhas, D. Wen, H. Jiang, K. Chen, P. Ziminak, J. Zheng, J. Med. Chem. 2004,

47, 3282.

13 J. Penjisevic, V. Sukalovi, D. Andric, S. Kostic-Rajacic, V. Soskic, G. Roglic, Arch. Pharm.

2007, 340, 456.

14 Y. H. Jung, J. D. Kim, Arch. Pharm. Res. 2003, 26, 667.

15 C. L. Richard, S. Ding, J. Org. Chem. 1993, 58, 804.

16 L. E. Overman, S. W. Roberts, H. F. Sneddon, Org. Lett. 2008, 10, 1485.

17 S. F. Kirsch, L. E. Overman, M. P. Watson, J. Org. Chem. 2004, 69, 8101.


19 R. F. Cunico, R. K. Pandey, J. Org. Chem. 2005, 70, 5344.

20 C. F. Bender, R. A. Widenhoefer, J. Am. Chem. Soc. 2005, 127, 1070.

21 K.Komeyama, T. Morimoto, Y. Nakayama, K. Takaki, Tetrahedron Lett. 2007, 48, 3259.

Documents

POLITECNICO DI MILANO - opac.biblio.polimi.it