Modern Amination Methods

Modern Amination Methods Edited by Alfred0 Ricci

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Modern Amination Methods Edited by Alfred0 Ricci

@WILEY-VCH Weinheim Chichester . New York . Toronto . Brisbane . Singapore

Prof. Dr. A. Ricci Dept. of Organic Chemistry University of Bologna Via Risorgimento 4 40136 Bologna Italy

This b k was carefully produced. Nevertheless, authors, editor and publisher do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

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Preface

The origin of this book can be traced back at least in part to the fact that the importance and practicality of amination reactions as a tool for obtaining target compounds is nowadays fully acknowledged by chemists in synthetic organic, medicinal, agricultural and natural product chemistry, as well as by the pharmaceutical and agricultural industries. This prominence is due to the explosive development during the past decade of novel and more efficient amination methods. These provide a great improvement with respect to the classical methods such as those based on the attack of a nucleophilic nitrogen atom to an electrophilic carbon, which are hampered by the difficult access to the electrophilic precursors - particularly when multifunctional derivatives are taken into consideration - and by the frequently recurring difficult reaction conditions. This book is intended to provide an overview of several areas of research in which amination plays a key role, and to introduce the reader to new concepts that have been developed quite recently for generating new C - N bonds. As the pharmaceutical and chemical industries move rapidly away from the development of racemic compounds, the access to synthetic routes that lead efficiently to enantiomerically pure materials is becoming increasingly important. For this reason, most of the contributions in this book refer to asymmetric synthesis. However, no attempt has been made to present a comprehensive work, and important areas such as asymmetric hydroxyamination [11 have not been dealt with. Furthermore, it may be worth mentioning that viable, useful and comprehensive sources of information about the methodological approaches to electrophilic amination developed since 1985 have already been reported [2], and that a chapter in Houben-Weyl reviewing several aspects of the asymmetric electrophilic amination [3] compiles important contributions up to 1995. In order to provide - whenever possible - new perspectives in the different areas treated in the book, the authors have been recruited among internationally recognized experts in their specific fields. This book is arranged in seven chapters which cover the following aspects of amination - even if the order of the contributions is somewhat arbitrary. Chapter 1 (K. A. Jdrgensen) deals with modem aspects of allylic amination reactions for preparing fundamental building blocks which have either distinct important properties or can be used for further transformations in organic synthesis. Two approaches - the

VI

Preface

nucleophilic allylic substitution and the direct allylic amination of simple alkenes are described. Considering the potential importance of electrophilic amination of alkenes, progress and steps being taken to carry out indirect amination of organometallics derived from hydroboration and hydrozirconation of alkenes are also described in Chapter 2 (E. Fernandez and J.H. Brown). In Chapter 3, J.-P. Genet, C. Greck and D. Lavergne provide an exhaustive overview of modem methods (up to 1998) based on the stereoselective electrophilic amination of chiral carbon nucleophiles for making a- and p-amino acid derivatives. Chapter 4 (H. Kunz, H. Tietgen and M. Schultz-Kukula) also addresses the synthesis of a- and p-amino acids with high enantiomeric purity, but a different approach based on the reaction of carbohydrate-derived prochiral imines with nucleophiles is used. More about the use of organometallics is to be found in the following two chapters. Thus, Chapter 5 (E. Carreira, C.S. Tomooka and H.Iikura) focuses on the various methods that have been reported for the synthesis of metal nitride complexes. These complexes have an intriguing array of reactivity and structure, and display a host of desirable properties in material sciences, medicine and chemical synthesis. The nitrogen atom transfer from a nitrido complex is reviewed in Chapter 6 by M. Komatsu and S. Minakata, with special emphasis on enantioselective transformations in aziridination reactions using nitridomanganese complexes. A fairly new approach to C - N bond formation - the transition metal-catalyzed synthesis of arylamines - is the aim of Chapter 7, in which J. F. Hartwig provides an exhaustive account of the palladiumcatalyzed amination of aryl halides and sulfonates for use in complex synthetic problems. The breakthrough required to convey efficiency and high performance is the catalyst design, and many new challenges remain for the synthetic chemist in this area. Complete reference citations have been provided since, as it is increasingly recognized, they are a requirement for manuscripts and proposals. It is my sincere hope that this book will provide synthetic chemists with new opportunities for achieving their synthetic goals. For those students who are reading the book in order to enhance their synthetic “toolkit”, I hope they will enjoy the variety of these new reactions which span from stoichiometric to catalytic, from natural product-based protocols to synthetic strategies employing organometallic complexes. I gratefully acknowledge the work done by all authors in presenting up-to-date and well-referenced contributions. Without their effort this volume would not have been possible. Furthermore, it was a pleasure to contribute with the Wiley-VCH “crew” in Weinheim, who not only did an excellent job in producing the book, but also helped me in a competent manner in all phases of its preparation. Finally, I am grateful to Dr. Golitz and to Dr. Eckerle who originally encouraged the idea of creating a book about Modern Amination Methods. Bologna, January 2000

Alfred0 Ricci

Preface

VII

References [I]

[2] [3]

(a) G. Li, H.-T. Chang, K. B. Sharpless,Angew. Chem. Int. Ed. Engl. 1996.35.451; (b) G. Li, H. H. Angert, K. B. Sharpless,Angew. Chem. Int. Ed. Engl. 1996,352813; (c) H. C. Kolb, K. B. Sharpless, Asymmetric Aminohydroxylation in Transition Metals for Organic Synthesis, Vol. 2; M. Beller, C. Bolm (Eds.);WILEY-VCH, Weinheim, 1998,243 - 260; (d) G. Schlingloff, K. B. Sharpless, Asymmetric Aminohydroxylationin Asymmetric Oxidation Reactions: A Practical Approach; T.Katsuki (Ed.); Oxford University Press, Oxford, in press. E. Erdik, M. Ay, Chem. Rev. 1989, 89, 1947. G. Boche in Houben-Weyl. Methods of Organic Chemistry, Stereoselective Synthesis, Vol. E21e; G . Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann (Eds.); Thieme, Stuttgart, 1995, 5133 5156.

Contents

Preface V List of Authors XV

Chapter 1 Modem Allylic Amination Methods 1 Karl Anker J@rgensen

Introduction 1 Nucleophilic Amination of Functionalized Alkenes 2 Amination of Allyl Alcohols 3 Amination of Allyl halides 6 Amination of Allyl Halides and Acetates Catalyzed by metal Complexes 8 Electrophilic Amination of Non-Functionalized 1.2.3 Alkenes 14 Amination with Nitrene Complexes 15 1.2.4 Amination Based on Ene-Like Processes 16 1.2.5 1.2.5.1 Type 1 Reactions: Ene Reaction Followed by [2,3]-Sigmatropic Rearrangement 19 1.2.5.2 Type 2 Ene Reactions 22 Allylic Amination with Ar-NX and a Metal Catalyst 27 1.2.6 Summary 32 1.3 Acknowledgments 33 References 33

1.1 1.2 1.2.1 1.2.2 1.2.2.1

Chapter 2 Eletrophilic Amination Routes from Alkenes 37 Elena Fernandez and John M . Brown

2.1 2.2 2.2.1 2.2.1.1 2.2.1.2 2.2.1.3 2.2.2

Introduction 37 Indirect Stoichiometric Amination 37 Amination via Organoboron Compounds 38 Applications to the Synthesis of Primary Amines 41 Applications to the Synthesis of Secondary Amines 46 Applications to the Synthesis of Tertiary Amines 5 1 Amination via Organozirconium Compounds 5 1

X

Contents

2.3 Indirect Catalytic Amination 52 2.4 Direct Alkene Amination 59 References 6 1

Chapter 3 Stereoselective Electrophilic Amination with Sulfonyloxycarbamates and Azodicarboxylates 65 Jean-Pierre Genet, Christine Greck and Damien Lavergne

Introduction 65 Sulfonyloxycarbamates 67 Preparation of N-[(arylsulfonyl)oxy]carbamates 67 Stereoselective Synthesis of a-Amino Carboxylic and Phosphonic Acids via Electrophilic Amination with Lithium rerr-Butyl N-(tosyloxy) Carbamate 68 3.2.2.1 a-Amino Carboxylic Acids 68 3.2.2.2 a-Amino Phosphonic Acids 68 Reactions of Ethyl N-((p-nitrobenzenesulfonyl)oxy(carbamate 3.2.3 with Chiral Enamines and Enol Ethers 69 Dialkylazodicarboxylates 7 1 3.3 Electrophilic Amination of Silyl Ketene Acetals 72 3.3.1 Electrophilic Amination of Chiral Amide Enolates 76 3.3.2 Electrophilic Amination of Chiral Ester Enolates 80 3.3.3 3.3.3.1 j3-Hydroxy Esters 80 3.3.3.2 P-Amino Esters 86 Electrophilic Amination of Ketone Enolates 88 3.3.4 Electrophilic Amination of Phosphorous Stabilized 3.3.5 Anions 91 3.3.5.1 Oxazaphospholanes 92 3.3.5.2 Diazaphospholidines 94 Chiral Electrophilic Aminating Reagents 96 3.4 Azodicarboxylates and Azodicarboxamides 96 3.4.1 Chiral Catalytic Approach 99 3.4.2 Conclusion 101 3.5 References 101

3.1 3.2 3.2.1 3.2.2

Chapter 4 Glycosylamines as Auxiliaries in Stereoselective Syntheses of Chiral Amino Compounds 103 Heiko

4.1 4.1.1 4.1.2 4.1.3

Tietgen, Martin Schultz-Kukula and Host Kunz

Introduction 103 Exo Anomeric Effect 104 Influence of Coordinating Centers 105 Pseudo-Enantiomeric Carbohydrates in Stereoselective Syntheses 105

Contents

4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.3 4.3.1 4.3.2

XI

Syntheses of Amino Acids 106 Syntheses of Enantiomerically Pure a-Amino Acids 106 Syntheses of Enantiomerically Pure P-Amino Acids 108 Rearrangement Reactions 111 Stereoselective Multicomponent Reactions 114 Stereoselective Syntheses of Chiral Heterocycles 118 Heterocycles Through Cycloaddition Reactions 118 Stereoselective Syntheses of Chiral Piperidines via Addition Reactions to 4-Pyridones 125 4.4 Conclusion 127 References 127

Chapter 5 Syntheses of Transition Metal Nitride Complexes 129 Craig S. Tomooka, Hitoshi likura and Erick M. Carreira

Introduction 129 Nitrogen-Atom Sources for the Reparation of Metal Nitrides 130 N3- Reagents 131 5.2.1 N2- Reagents 132 5.2.2 N1- Reagents 132 5.2.3 Reagents 133 5.2.4 Other Reagents 134 5.2.5 Ligands in Metal Nitride complexes 134 5.3 5.4 Transition Metal Nitride Complexes 140 5.4.1 Vanadium 140 5.4.2 Tantalum 142 5.4.3 Chromium 143 Molybdenum 146 5.4.4 5.4.5 Tungsten 150 5.4.6 Manganese 152 Technicium 155 5.4.7 5.4.8 Rhenium 157 5.4.9 Ruthenium 159 5.4.10 Osmium 161 5.5 Conclusion 164 References 165

5.1 5.2

Chapter 6 Asymmetric Nitrogen Transfer with Nitridomanganese Complexes 169 Satoshi Minakuta and Mitsuo Komutsu

6.1 6.2

Introduction 169 Achiral Nitrogen Atom Transfer to Olefins 170

XI1

Contents

6.2.1

Nitrogen Atom Transfer Reaction with Achiral Nitrido Complexes 170 6.2.2 Nitrogen Atom Transfer Aziridination of Olefins with Other Nitrogen Sources 174 6.3 Synthesis of Chiral Nitridomanganese Complex 177 6.4 Asymmetric Aziridination of Olefins with Chiral Nitridomanganese Complexes 179 6.4.1 Asymmetric Aziridination of Styrene with Nitrido Complex 179 The Asymmetric Aziridination of Styrene 6.4.2 with a Variety of Nitrido Complexes 183 Asymmetric Aziridination of Styrene Derivatives 185 6.4.3 6.4.4 Aziridination of Conjugated Dienes 188 6.4.5 Asymmetric Amination of Silyl Enol Ether 191 6.5 Conclusion 192 References 193

Chapter 7 Palladium-Catalyzed Amination of Aryl Halides and Sulfonates 195 John E Hartwig

7.1 7.1.1 7.1.2 7.1.3 7.1.4 7.2 7.2.1 7.2.2 7.3 7.3.1 7.3.1.1 7.3.2 7.3.2.1 7.3.2.2 7.3.2.3 7.3.2.4 7.3.2.5 7.3.3

Introduction 195 Synthetic Considerations 195 Prior C-X Bond-Forming Coupling Related to the Amination of Aryl Halides 197 Novel Organometallic Chemistry 197 Organization of the Chapter 198 Background 199 Early Palladium-Catalyzed Amination 199 Initial Synthetic Problems to be Solved 201 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates 201 Initial Intermolecular Tin-Free Aminations of Aryl Halides 201 Initial Intramolecular Amination of Aryl Halides 203 Second-Generation Catalysts: Aryl Bisphosphines 204 Amination of Aryl Halides 204 Amination of Aryl Triflates 208 Amination of Heteroaromatic Halides 209 Amination of Solid-Supported Aryl Halides 211 Amination of Polyhalogenated Aromatic Substrates 2 11 Third-Generation Catalysts with Alkylmonophosphines: High Turnover Numbers, General Amination of Bromides at Room Temperature, and General Amination of Aryl Chlorides at Low Temperatures 212

Contents

7.3.3.1

XI11

High-Temperature Aminations Involving P(t-Bu), as Ligand 212 7.3.3.2 Use of Sterically Hindered Bisphosphine Ligands 213 7.3.3.2.1 Amination of Aryl Bromides and Chlorides 213 7.3.3.2.2 Amination of Aryl Tosylates 214 7.3.3.3 P,N Ligands and Dialkylphosphinobiaryl Ligands 2 15 7.3.3.4 Phenyl Backbone-Derived P,O Ligands 216 7.3.3.5 Low-Temperature Reactions Employing P(t-Bu), as Ligand 217 Aromatic C - N Bond Formation with Non-Amine 7.4 Substrates and Ammonia Surrogates 219 7.4.1 Amides, Sulfonamides and Carbamates 221 7.4.2 Allylamine as an Ammonia Surrogate 222 7.4.3 Imines 222 7.4.4 Azoles 223 7.5 Amination of Base-Sensitive Aryl Halides 226 7.6 Applications of the Amination Chemistry 228 7.6.1 Synthesis of Biologically Active Molecules 228 7.6.1.1 Arylation of Secondary Alkylamines 228 7.6.1.2 Arylation of Primary Alkylamines 230 7.6.1.3 Arylation of Primary Arylamines 231 Applications to Materials Science 233 7.7 7.7.1 Polymer Synthesis 233 7.7.2 Synthesis of Discrete Oligomers 236 7.7.3 Synthesis of Small Molecules for Materials Applications 239 7.7.4 Palladium-Catalyzed Amination for Ligand Synthesis 240 7.8 Mechanism of Aryl Halide Amination and Etheration 241 7.8.1 Oxidative Addition of Aryl Halides to L,Pd complexes (L = P(o-Tolyl),, BINAP, DPPF) and its Mechanism 241 7.8.2 Formation of Amid0 Intermediates 244 7.8.2.1 Mechanism of Palladium Amide Formation from Amines 244 7.8.3 Reductive Eliminations of Amines from Pd(I1) Amido Complexes 247 7.8.4 Competing (P-Hydrogen Elimination from Amido Complexes 252 7.8.5 Selectivity: Reductive Elimination versus P-Hydrogen Elimination 253 7.8.6 Overall Catalytic Cycle with Specific Intermediates 255 7.8.6.1 Mechanism for Amination Catalyzed by P(o-C,H,Me), Palladium Complexes 255

XIV

Contents

Mechanism for Amination Catalyzed by Palladium Complexes with Chelating Ligands 256 7.9 Summary 257 Acknowledgments 258 References 258 7.8.6.2

Index

263

Abbreviations

acac Alloc BINAP BISBI Bn Boc CAN CP CP" CT dba DBAD DBU DCE de DEAD DIAD DMS DPEphos DPPBA DPPe DPPF DPPP DTBAD D'BPF dr ee EWG GPC IPC KDO LDA

Acetonylacetate Allyloxycarbonyl 2,2'-Bis(dipheny1phosphino)- 1,l' -binaphthyl 2,2'-Bis [(diphenylphosphino)methyl]-1,l '-biphenyl Benzyl tert-Butoxycarbony 1 Ceric ammonium nitrate $-C y clopentadieny 1 $-Pentamethyl cyclopentadienyl Chloramine-T 1 3 -Diphenylpenta- 1,4-dien-3-0ne Dibenzyl azodicarboxylate 1,8-Diazabicyclo[S.4.0]undec-1-ene 1,2-Dichloroethane Diastereomeric excess Azodicarboxylate Diisopropyl azodicarboxylate Dimethyl sulfide Bis(2,2'-dipheny1phosphino)diphenylether 2-(Dipheny1phosphino)benzoic acid Bis(dipheny1phosphino)ethane 1,l '-Bis(dipheny1phosphino)ferrocene Bis(dipheny1phosphino)propane Di-tert-butyl azodicarboxylate Bi s(di-tert-butylphosphino)ferrocene Diastereomeric ratio Enantiomeric excess Electron withdrawing group Gel permeation chromatography Isopinocamphenyl 3-Deoxy-D-manno-octulosonicacid Lithium diisopropylamide

XVI

Abbreviations

LiBTOC LiHMDS LUMO MAP Mes

M, MOP MTPA Mw NBS NMP NOBIN NOE NPhth Ns PHANEPHOS

PTAB PYr QUINAP RAMP rt

SAMP TBAF TBS TDCPP TeVY TFAA

THF tipt

TMP TMSCl TMSCN TMSOTf To1 TPD TPP Ts Ts,O Xantphos

tert-Butyl-N-lithio-N-[@-toluensulfonyl)oxy]carbamate Lithium hexamethyldisilazide Lowest unoccupied molecular orbital 2-Amino-2’-(diphenylphosphino)-1,l ’-binaphthyl Mesityl Number average molecular weight 2-Methoxy-2’-(diphenylphosphino)-1,l’-binaphthyl a-Methoxy-a-(trifluoromethy1)phenylacetic acid Molecular weight N-Bromosuccinimide N-Methy lpyrrolidone 2-Amino-2’-hydroxy-1,l ’-binaphthyl Nuclear Overhauser effect Phthalimide 4-Nitrobenzy lsulfonyl 4,12-Bis(diphenylphosphino)[ 2.21-paracyclophane Phenyltrimethylammonium tribromide Pyridine 1-(2-Diary lphosphino-1-naphthy1)isoquinoline (R)-(+)-1-Amino-2-(methoxymethy1)pyrrolidine Room temperature (3-( -)-1-Amino-2-(methoxymethyl)pyrrolidine Tetrabutylammonium fluoride tert-Butyldimethylsilyl meso-Tetra-2,6-dichlorophenylporphyrine Terpyridine Trifluoracetic anhydride Tetrahydrofuran Triisopropyl thiophenol 5,1Ol15,20-Tetramesitylporphyrine Chlorotrimethylsilane Cy anotrimethylsilane Trimethylsilyl trifluorometanesulfonate Tolyl 4,4’-Bis(3-methylphenylpheny1amino)biphenyl 1,5,15,20-Tetraphenylporphyrineanion Toluene-p-sulfony1 Toluene-p-sulfonyl anhydride 9,9-Dimethyl-4,6-bis(dipheny1phosphino)xanthene

List of Authors

John M. Brown Dyson Perrins Laboratory University of Oxford South Parks Rd. GB-Oxford OX1 3QY England Erick M. Carreira Laboratory of Organic Chemistry ETH-Centre Universitatstrasse 16 CH-8092 Zurich Switzerland Elena Fernandez Departament de Quimica Universitat Rovira I Virgili Placa Imperial Tarraco 1 ES-43005 Tarragona Spain Jean-Pierre Genet Laboratoire de Synthkse SClective Organique et Produits Naturels Ecole Nationale SupCrieure de Chimie de Paris 11, rue Pierre et Marie Curie F-75231 Paris Cedex 05 France

Christine Greck Laboratoire Synthkse, Interactions et Rkactivitk en Chimie Organique et Bioorganique UniversitC Versailles - Saint Quentin en Yvelines 45, avenue des Etats-Unis F-78035 Versailles Cedex France John F. Hartwig Department of Chemistry Yale University P.O. Box 208107 New Haven, CT 06520-8107 USA Hitoshi Iikura Laboratory of Organic Chemistry ETH-Centre Universitatstrasse 16 CH-8092 Zurich Switzerland Karl Anker JGrgensen Center for Metal Calalyzed Reactions Department of Chemistry Aarhus University Langelandsgade 140 DK-8000 Aarhus C Denmark

Mitsuo Komatsu Department of Applied Chemistry Osaka University Yamadaoka 2-4, Suita JP-565087 1 Osaka Japan

Martin Schultz-Kukula Institut fur Organische Chemie Universitat Mainz Duesbergweg 10- 14 D-55099 Mainz Germany

Horst Kunz Institut fur Organische Chemie Universitat Mainz Duesbergweg 10- 14 D-55099 Mainz Germany

Heiko Tietgen Institut f i r Organische Chemie Universitat Mainz Duesbergweg 10- 14 D-55099 Maim Germany

Damien Lavergne Laboratoire de Synthkse Sklective Organique et Produits Naturels Ecole Nationale Suphrieure de Chimie de Paris 11, rue Pierre et Marie Curie F-75231 Paris Cedex 05 France

Craig S. Tomooka Laboratory of Organic Chemistry ETH-Centre Universitatstrasse 16 CH-8092 Zurich Switzerland

Satoshi Minakata Department of Applied Chemistry Osaka University Yamadaoka 2-4, Suita JP-565087 1 Osaka Japan

Modern Amination Mefhods Edited by Alfredo Ricci copyright 0 WILEY-VCH Verlag GmbH, 2wO

1 Modem Allylic Amination Methods Karl Anke r J$ rg ensen

1.1 Introduction One of the challenges in organic chemistry is to prepare fundamental molecular building blocks which either have distinct important properties, or can be used for further transformations in organic synthesis. Ally1 amines 1 can be used as fundamental building blocks in organic chemistry, and their synthesis is an important industrial and synthetic goal. They can be incorporated in natural products, but often the allyl amine moiety is transfornfed to a range of products by functionalization, reduction or oxidation of the double bond.

1

The synthetic methods for the preparation of allyl amines can be divided into several types of reactions [l]. In the present chaptgr, the focus will be on the formation of allyl amines by reaction of substrates having an allylic bond which can be broken. Two approaches will be covered and these are outlined in Scheme 1: the first method (a) is the synthesis of allyl amines by nucleophilic allylic substitution of compounds having an allyl functionality; the second method (b) is the direct allylic amination of simple alkenes.

(b)

+

R’NX

-

Scheme 1

Other types of allylic amination reactions include a variety of indirect approaches such as reduction of a,p-unsaturated imines and oximes, rearrangement of aziridines, and elimination of water from vicinal amino alcohols. However, these reactions will not be considered in this chapter [2]. The present chapter on modem allylic amination methods will be restricted mainly to an overview of some of the major developments for the transformation of allylic compounds into allyl amines according to reaction types (a) and (b) in Scheme 1, and an attempt is made to cover the literature up to August 1999. The reaction type (a) in Scheme 1 for the allylic amination reaction uses substrates which have an allylic C-X (X = heteroatom, halide) bond and is mainly nucleophilic amination of functionalized alkenes, whereas reaction type (b) is a direct allylic amination of an allcene, based on electrophilic amination of nonfunctionalized alkenes and involves a cleavage of a C-H bond.

1.2 Nucleophilic Amination of Functionalized Alkenes Nucleophilic amination of alkenes functionalized by an allylic C-X (x = heteroatoms, halides) as outlined in Eq. (1) is a simple and direct procedure for the synthesis of allyl amines, since very efficient methods for the selective allylic h c tionalization of alkenes are available.

X = heteroatom. halide

1.2 Nucleophilic Amination of Functionalized Alkenes

3

1.2.1 Amination of Ally1 Alcohols The Mitsunobu reaction is an attractive procedure for the transformation of an allyl alcohol into an allyl amine [3]. The reaction can be carried out under very mild conditions with a variety of amine nucleophiles. Recently, this method has been used for the preparation of configurationally pure primary allyl amine 4 (Q. 2) by the reaction of allyl alcohols 2 with diisopropyl azodicarboxylate (DIAD)and triphenyl phosphine, followed by phthalimide (PhthNH) as the ammonia synthon giving 3 [4]. Reaction of 3 with hydrazine or methyl amine gave allyl amine 4. An advantage of this reaction sequence is the almost complete conservation of alkene geometry, both under the Mitsunobu coupling conditions and after the deprotection of the amino group. Use of iminocarbonate as the nitrogen nucleophile donor gives a mixture of trans- and cis-products.

DIADPh3P PhthNH

OH 2

HzNNHz

76-98%*

NPhth

3

R'

76-88 %4

Several examples of reactions of allyl alcohols under Mitsunobu reaction conditions using diethyl azodicarboxylate (DEAD) and triphenyl phosphine giving allyl amines are known. An example is the reaction of the steroid 5 with azide nucleophiles under Mitsunobu reaction conditions, giving the corresponding azide 6 in 63 % yield (Eq. (3)) [5]. The reaction is regioselective with inversion of the configuration and no S,21 substitution is observed.

The nucleophilic addition to allyl alcohols under Mitsunobu reaction conditions is normally regioselective with no allylic rearrangement during the reaction [6].

4

J@rgensen

The Overman rearrangement, a thermal [3,3]-sigmatropic rearrangement of allylic trichloroacetimidates, is an attractive procedure for the preparation of allyl amines from allyl alcohols (Eq. (4)) [7]. Ph

[3,3]-sigmatropic rearrangement

3

8

9

The first step in this reaction is formation of the allyl trichloroacetimide 8 formed from allyl alcohol 3 by reaction with trichloroacetonitrile. The allyl amides 9 are formed by the [3,3]-sigmatropic rearrangement of 8, followed by hydrolysis. The reaction proceeds with good yield for primary and secondary amides; however, for products where the amide nitrogen is bound to a tertiary carbon atom the yields are generally low. Overman has suggested a cyclic six-membered transition state 10 for the reaction [8]. The experimental result for the formation of substituted alkenes is similar to that observed for other [3,3]-sigmatropic rearrangements. Furthermore, the preferred formation of the trans-isomer of the di- and trisubstituted alkenes is consistent with transition state 10. The activation parameters for the [3,3]-sigmatropicrearrangements are similar to related rearrangement reactions.

10

The rearrangement reaction can be catalyzed by various metal salts, and salts such as homogeneous solutions of palladium(II) and mercury(I1) complexes have emerged as relatively good catalysts [9]. Based on the catalytic properties of soluble palladium(II) salts, attempts to perform enantioselective rearrangement reactions were performed. The used of a cationic palladium catalyst with a chiral nitrogen ligand led to the first enantioselective version of the Overman rearrangement (Eq. (5)) [9]. The [3,3]-sigmatropic rearrangement of 11 catalyzed by the chird palladium complex 13 gave 12 in 69 % yield and up to 55 % enantiomeric excess (ee).

1.2 Nucleophilic Amination of Functionalized Alkenes

5

Ar

NAr

13

5 mol Yo

12

11

55 YOee

20

The enantioselectivity of the rearrangement reaction of allylic imidates has been improved significantly by the introduction of chiral ferrocenyl oxazoline catalysts such as 14 [ 101.The use of 14 as catalyst for the reaction of a series of different Z- and E-imidates similar to 11 gave the amides in good yield and with ees higher than 90 % for several of the substrates studied and the chiral ferrocenyl oxazoline catalysts are until know the best catalysts for this rearrangement reaction. It is notable that an exchange of the bridging trifluoroacetate group with an iodine-bridging complex leads to a complex which is inactive, while the chloride-bridging complex is a poor catalyst in terms of reaction rate, but gives the same enantioselectivity as 14 [lOa]. Furthermore, it should be pointed out that the ferrocenyl trimethylsilyl substituent is also of utmost importance for the enantioselectivity as the ee of the reaction is reduced significantly by removal of this substituent [ lOa]. Overman et al. have also investigated other planar -chiral cyclopalladated ferrcenyl amines and imines as chiral catalyst for the allylic imindate rearrangement reactions [lob].

14

6

Jgrgensen

Several other chiral ligands have also been introduced for the rearrangement reaction [ 111. The use of a tridenate ligand containing an (R)-phenyloxazoline as the chiral unit gave in combination with palladium(II) up to 83 % ee for one substrate [ 1la], while Hayashi et al. have investigated the rearrangement reaction catalyzed by a series of different chiral palladium complexes including bisoxazolines and P,N chelating ligands ((S)-(+)-2-(2-diphenylphosphino)phenyl)-4-(benzyl)ox~oline) with the latter giving up to 81 % ee of the allyl amide; however, the yields were often low [1lb]. One problem with the metal-catalyzed Overman reaction is the basicity of the imidates. However, this problem has also been solved be Overman et al. by the introduction of the less basic allylic N-benzoylbenzimidates. The application of these allylic N-benzoylbenzimidates and palladium(II) chloride as the catalyst improved both the yield, selectivity and rate for the formation of the allyl amines [9]. The palladium(I1)-catalyzed rearrangement of allyl imidates for the formation of allyl amines has also been investigated for chiral imidates (Eq. (6)) [12]. The chiral imidate 15 undergoes a palladium(I1)-catalyzed rearrangement to 16, which was applied for the synthesis of (R)-N-(trichloracety1)norleucinol 17 as presented in Eq. (6).

15

16

17

Several applications of the Overman rearrangement for different type of substrates have been published and some examples can be found in [131.

1.2.2 Amination of Allyl Halides The second approach for the nucleophilic amination reactions to be considered here will be reactions of allyl halides and allyl acetates leading to allyl amines. Allyl halides are normally very reactive in S,2 reactions, but the direct coupling of allyl halides with nitrogen nucleophiles has been performed with limited success [4], as di- and trialkylated by products often predominate. The application of the Gabriel synthesis can to a certain extent eliminate the problem with polyalkylation of amines using, e.g., the stabilized phthalimide anion 19 as the nucleophile. The allyl amine 20

1.2 Nucleophilic Amination of Functionalized Alkenes

7

can thus be prepared in good yield from alkyl halides 18 by reaction with potassium phthalimide 19 (Eq. (7)) [14].

18

20

19

A problem with the use of the phthalimide anion as the nucleophile is the removal of phthaloyl group from the product [15]. Therefore, several attempts have been made to develop reagents with a more labile protecting group than the phthalimide. Compounds 21 and 22 are among some of the reagents investigated. By application of 21 and 22, better yields of some primary allyl amines were obtained, compared to the traditional method using the phthalimide [16.] The advantage of 21 and 22 as the nitrogen donor for the formation of allyl amines is that the substituents at the nitrogen atom can easily be removed with gaseous hydrogen chloride after alkylation. However, the substrate tolerance is low, and the reagents are somewhat exotic.

3

Eto.P-N-SiMe3 Em’ H 21

22

The use of the stabilized anion of di-t-butyl iminocarbonate ((Boc),NH) 24 is more promising in allylic amination reaction. It reacts under mild conditions with a variety of primary and secondary halides and mesylates 23, giving the allyl amines 25 in high yields (Eq. (8)) [17]. The use of 24 as the nitrogen donor in the amination reaction has the great advantage compared to the palladium-catalyzed amination with the same reagent, that cis-alkenes react without scrambling of the double bond, an important aspect considering the isomerization sometimes observed using palladium-catalyzed substitution.

8

J#rgensen

5 mol % Lil

23

24

25

1.2.2.1 Amination of Ally1 Halides, Acetates, etc. Catalyzed by Metal Complexes In 1965, Tsuji et al. observed that palladium could catalyze the allylic alkylation reaction [18]. This discovery, which is a very attractive way to expand the scope of the allylic amination reactions mentioned above, has stimulated an intense research in this field, and even though complexes of nickel, platinum, rhodium, iron, ruthenium, molybdenum, cobalt, and tungsten have been found also to catalyze the alkylation, palladium complexes have received by far the greatest attention [19]. As a spin off,the allylic alkylation reaction, allylic amination reactions can now be carried out in high yield and selectivity and the palladium-catalyzed allylic amination reaction is now a cornerstone reaction in organic chemistry [la,19]. The palladium-catalyzed allylic amination is generally accepted to proceed via a palladium Rallyl complex 27 (Scheme 2). The E-ally1 complex intermediate 27 is formed by a nucleophilic attack on 26 by palladium and in a second step the amine attacks directly the allylic ligand leading to retention of configuration in the product 28 [19c,d]. It has been observed that the unsymmetrical allyl systems are attacked by the amine nucleophile at the less substituted carbon atom, although there have been observations of reactions on nonsymmetrical substrates with low regioselectivity.

1.2 Nucleophilic Amination of Functionalized Alkenes

9

I

Pd 26

27 \

*

/

N

R’J+A2

Pd(O), 28

Scheme 2

In the palladium-catalyzed allylic amination reaction, primary and secondary amines can be used as nucleophiles, whereas ammonia does not react. Therefore, many ammonia synthons have been developed, and a variety of protected primary ally1 amines can now be prepared using azide, sulphonamide, phthalimide, di-t-butyl iminocarbonate ((Boc),NLi), and dialkyl N-(tert-butoxycarbony1)phosphoramide anions as the nucleophile [20]. An example of the use of ((Boc),NLi) 30 as the amine nucleophile in the palladium-catalyzed allylic amination reaction is shown in Eq. (9). This reaction also illustrates the problem with the regioselectivity in the reaction as a mixture of the products 31-33 are obtained [21]. 4 mol % Pd(dba)2

-oAc 29

5.5 mol Yo diphos +

(BOC)#

Li’

*

30

(9)

31 40 %

32

33

47 %

7 Yo

10

&%ensen

One of the fascinating modem aspect of allylic amination reactions using allyl halides and allyl acetates as the substrate is to achieve the catalytic amination step in a regio-, diastereo-, and enantioselective fashion, and thus much attention has been devoted to the development of efficient chiral catalysts. Due to the wealth of the literature available on allylic amination catalyzed by chiral palladium complexes, only some representative results will be presented in the following [ 191. An example is the reaction of 1,3-diphenyl-2-propenyl acetate 34 with benzylamine 35 catalyzed by palladium(0) in the presence of the four classes chiral ligands 37-40 outlined in Scheme 3 [22-241. The mechanism for the catalytic enantioselective allylic amination reaction involving the allyl palladium complexes has been thoroughly investigated, as the complexes are often relatively easy to crystallize and, as palladium(II) is diamagnetic, the complexes may also be analyzed by standard NMR techniques [22-241. OAc Phd \ p

Pdo/L'

h

+

BnNH2

*

35

34

37 93 % yield 97 % ee

36

38

90 - 95 % yield 99 % ee

R-

Ph2P

N

Ph 39 98 % yield 94 Yoee

Scheme 3

Ph

40 99 % yield 92 % ee

1.2 Nucleophilic Amination of Functionalized Alkenes

11

The enantioselective palladium-catalyzed allylic amination reaction is highly dependent on the class of substrates, such as cyclic and acyclic substrates. It is notable that many of the ligands developed for acyclic substrates are largely inefficient on cyclic substrates. Trost et al. have succeeded in developing a ligand type based upon 2-(dipheny1phosphino)benzoicacid (DPPBA) and a chiral C,-symmetric diamine or diol which is very efficient for both acyclic and cyclic substrate types [25]. An example is the use of ligand 44 in Eq. (lo), which in combination with palladium catalyzes the reaction of racemic five- to seven-membered rings 41 with the anion of the phthalimide 42 as nucleophile to give the corresponding allyl amines 43 in good yield and high ee. The use of a bulky ammonium cation in combination with CH,Cl, as solvent is essential to obtain a high enantioselectivity. The authors suggest that a tight ion pair might be involved, and the effect of the bulky ammonium ion to be more pronounced in the less polar CH,Cl, solvents compared to THF where lower selectivity is observed and a less tight ion pair is probably present. 2.5 mol % (C3H5PdC1)2 7.5 mol % 44 * 41

42

NPhth

43

yield 84-95 % 94-90 % ee

(10)

Vinyl epoxides can also be used as substrates for formation of optically active allyl amines catalyzed by the same type of chiral palladium complexes as in Eq. (1 0). By reaction of simple vinyl epoxides with phthalimide as the nitrogen source in the presence of the chiral palladium complexes as the catalyst, very high ee (> 98 %) and regioselectivity (> 97 %) were obtained [26]. A variety of different applications of the use of the palladium-catalyzed approach for the formation of allyl amines and the use of this in total synthesis has been pursued by several research groups, and further details can be obtained in a review by Trost et al. [19d]. Ally1 amines can also be formed by desymmetrization of allyl diols with tosyl isocyanate in the presence of chiral palladium complexes [19d,27]. Trost et al., as well as others, have recently used this approach for the synthesis of natural products [28]. An approach recently developed by Katritzky et al. which also should be mentioned here, is the palladium-catalyzed reaction of N-alkylbenzotriazoles with amines, leading to an intramolecular allylic amination route to 2-vinylpyrrolidines and 2-vinylpiperidines in good yield under mild conditions [29].

12

Jergensen

The majority of the allylic amination reactions using the approach outlined in Scheme 2 are performed using palladium as the metal, and only very few reports have appeared on allylic amination promoted by metals other than palladium. A mixture of copper(II) perchlorate and metallic copper has been shown to catalyze the allylic amination of, e.g., 3-bromocyclohexene 45 by N-methyl aniline 46,giving the allylic aminated product 47 in high yield (Eq.(11)) [30]. The yields of the ally1 amines using secondary amines as nucleophiles are generally high, and a somewhat different regioselectivity compared to the palladium-catalyzed substitutions has been observed as the nucleophile has a tendency to attack at the highest substituted carbon atom of the alkene moiety.

6 45

1 eq. CU(CIO~)~ 1.2 eq. Cu(0)

+ PhNHMe 46

94 Yo

NMePh

-8 47

Iron complexes can also catalyze allylic amination [31,32]. Enders et al. have demonstrated the nucleophilic addition of various acyclic and cyclic amines to the optically active 1-methoxycarbonyl-3-methyI-(~3-allyl)-tetracarbonyliron cation 49 formed in high yield from reaction of 48 with iron carbonyls. Oxidative removal of the tetracarbonyliron group by reaction with CAN gives 50 with high optical purity and retention of the stereochemistry (Eq. (12)) [31]. The reaction proceeds well for the different amines, and has been used for the synthesis of a compound showing cytotoxic activity against diverse cell lines [3lb].

1.2 Nucleophilic Amination of Functionalized Alkenes

13

49 >95 Yo ee

48

1) RzNH 2) -CAN 91Yo 55

&OM. NRZ

50 >95 - 98 Yo ee

Evans et al. have recently demonstrated a highly enantioselective synthesis of allyl amines 52 from enantiomerically pure carbonates 51 catalyzed by rhodium complexes (Eq. (13)) [33]. The reaction proceeds with excellent regioselectivities, and the allyl amines are isolated in high yields and with a high degree of conservation of the optical purity. The scope of this reaction is demonstrated by the synthesis of, e.g., optically active nitrogen-containing heterocycles.

51

52

Allylic amination of allyl halides can also be achieved using lithium and potassium bis(trimethylsily1)amides [34] and potassium 1,1,3,3-tetramethyldisilazide[35] as the nucleophiles. It has been found that for the reaction of alkyl-substituted allyl chlorides using lithium bis(trimethylsily1)amidesas the nucleophile the allylic amination proceeds smoothly in a SN2fashion to give N,N-disilylamines in high yields when silver(1) iodide was used as an additive. Other metal complexes such as copper(1) iodide and other silver(1) salts can also be used as additives for the reaction.

14

J#rgensen

1.2.3 Electrophilic Amination of Non-Functionalized Alkenes An attractive procedure for allylic amination is the direct electrophilic amination of

alkenes. The single-step procedure allows a convenient allylic functionalization, which is an important part of this amination chemistry. However, compared to the nucleophilic amination of functionalized alkenes, the electrophilic amination of nonfunctionalized alkenes is much more complex, both from a synthetic and mechanistic point of view. The majority of direct electrophilic aminating reagents for alkenes can be divided into two subgroups (path (i) and (ii), Scheme 4). The first group consists of the nitrene precursors containing electron-withdrawing groups (EWG), which by treatment with a metal catalyst, such as copper and manganese complexes, transfers the nitrene fragment to the alkene 53. The addition is either direct to the alkene, forming an aziridine 54, or by insertion in the allylic C-H bond, forming the allyl amine 55. The aziridine 54 can undergo a thermal or metal-catalyzed rearrangement to 55 (path (i), Scheme 4). The second group of electrophilic amination reagents are aza compounds which undergo the ene reaction forming the allyl amine 57 directly via an ene-reaction transition state 56 (path (ii)) [36].

.

LH

Mn-salts

-

EWG-N LNH-EWG 55

53

J

TH - LN-EWG path (ir)

ene reaction

56

Scheme 4

57

1.2 Nucleophilic Amination of Functionalized Alkenes

15

1.2.4 Amination with Nitrene Complexes Several reagents can be used as nitrogen sources for electrophilic amination. As outlined in Scheme 4, a nitrene fragment provides the possibility of adding to an alkene leading to an aziridine, or inserting into the allylic C-H bond, forming an allyl amine. Mansuy et al. [37] have stated that by correct choice of the metal catalyst, such as the rneso-tetra-2,6-dichlorophenylporphyrinmanganese perchlorate (Mn(TDCPP)ClO,) complex, the chemoselective addition of PhI = NTs 59 to either the alkene or the allylic C-H bond of cyclohexene 58 can be controlled to give the allyl amine 60 in 70 % yield (Eq. (14)). However, the analogous reactions with other cyclic systems did not exceed 44 % yield, while the reaction with a cisalkene gave a range of isomeric products [37]. It should also be noted that Evans et al. obtained related results [38]. Generally, the manganese catalysts tend to give the allylic amination product, whereas the copper catalysts give the aziridine as the main product. The reason for this change in reaction course using different metal complexes is not yet understood. Other reagents, such as chloroamine-T trihydrate can also be used as the nitrogen fragment donor, but only moderate yield of the allyl amine was obtained [39]. Mn(TDCPP)C104

+ 58

Phl=NTs 59

5 70 rnolYo%

-

QNHTS

(14)

60

A bis(tosyl)amidoruthenium(III) complex has been prepared and characterized by X-ray analysis [40]. This complex was found to react with, e.g., cyclohexene (58) to give the allyl toluene-p-sulfonoamide, 60, in 63 % yield. Furthermore, the reaction was found to be catalytic when PhI = NTs was used as the terminal nitrogen source. Attempts to achieve asymmetric nitrene insertion reactions catalyzed by chiral transition metal complexes have also been performed [41,42]. The reaction of the nosyl-imine derivative as the nitrene donor with indane 61 catalyzed by the chiral rhodium complex 63 gave the optically active allyl amine 62 in good yield and moderate ee (Eq. (15)) [41].

16

J@rgensen

63 Phl=NNs 71 %

63

Attempts have also been made to use a combination of copper salts and bisoxazolines, and other chiral ligands, for the amination reaction using N-(p-toluenesulfony1)peroxycarbamate as the nitrogen source, but the yield and ee of the allyl amines obtained were generally low [42].

1.2.5 Amination Based on Ene-Reaction-Like Processes The properties of the nitrogen sources which determine the reaction course can sometimes be very subtle, and several compounds can transfer a nitrogen fragment. In Eq. (16) (Scheme 5), it is shown how N-tosyliminophenyliodinane59, in the presence of a manganese porphyrin as the catalyst, reacts with cyclohexene to give the allyl amine 60 by a nitrene addition reaction. The analogous sulfur reagent, 64,also facilities nitrogen transfer to alkenes; however, in this case the reaction takes place through an ene reaction-sigmatropic rearrangement process giving allyl amine 60 (Eq. (17), Scheme 5 ) [43], while the dialkyl sulfimine 65 transfers the tosyl nitrogen fragment to a molybdenum complex, forming a molybdenum nitrene complex 66, which reacts with phosphines, giving aminated phosphines 67 (Eq. (1 8), Scheme 5) [MI.

1.2 Nucleophilic Amination of Functionalized Alkenes

N.Ts

17

Mn(TDCPP)C104 nitrene addition

59

64

Me

Me

' S '

A'Ts

- DMS

*

Scheme 5

The ene reactions are in general all normal-electron demand reactions, i.e., the enophile reacts as the electrophilic partner. The highest reactivity should thus be expected to be found for enophiles with low LUMO energy, i.e., the lower in energy the LUMO is located, the more reactive is the enophile. Since the frontier molecular orbitals of the more electronegative heteroatoms such as oxygen and nitrogen are lower in energy compared to carbon, the LUMO energy of the enophile is also lower in energy compared to the LUMO energy of an alkene, which makes them more reactive in normal-electron demand ene reactions. For the same reason, substitution at either end of the enophile with an electron-withdrawing group enhances the reactivity even further.

18

J@rgensen

The regioselectivity can vary depending on the properties of the enophile (type 1 and 2, Scheme 6). It is generally observed that the nucleophilic attack by the allylic system takes place at the end of the enophile where the least electronegative atom is positioned. Thus, only nitroso and azo compounds should be attacked at the nitrogen atom (type 2), which directly gives rise to the allyl amine through the ene reaction. When selenium- or sulfur imido compounds are applied in the ene synthesis, the regioselectivity is reversed, and an intermediate “hetero” homo allyl amine is formed (type 1). This designation is used to emphasize that a homo allyl amine is formed, but that this also contains the selenium or sulfur heteroatom. The initially formed homo allyl amine undergoes a second in situ pericyclic [2,3]-sigmatropic rearrangement to give the allyl amine.

!

-

type 1 X: S=NR or S e = N c

R”

YHR e S + N R

“Hetero”homo allyl amine

J type2

X:O

or NR

X: S=NR

I

[2,3]-sigmatropic rearrangement

FNHR

@.Y Allyl amine Scheme 6

Allyl amine

1.2 Nucleophilic Amination of Functionalized Alkenes

19

1.2.5.1 Type 1 Reactions: Ene Reaction followed by [2,3]-Sigmatropic Rearrangement

As presented for the type 1 reactions in Scheme 6, selenium- and sulfur diimido compounds, 68-71, can undergo a two-step reaction sequence when treated with an allyl alkene to form the allyl amine.

68

69

70

71

This amination reaction, which is similar to the selenium dioxide-promoted allylic oxidation, was independently discovered by Kresze et al. in 1975 (sulfur imido amination) [45] and by Sharpless et al. in 1976 (sulfur and selenium imido amination) [43]. The compounds 68 and 69 were introduced first [43,45], followed by 70 [46] and 71 [47] more recently. The use of compounds 68-71 for the allylic amination reactions is attractive. These synthetic procedures proceed under mild reaction conditions and are quite selective, the biggest problem being the final deprotection. The cleavage of the nitrogen-selenium or sulfur bond can be carried out. This either occurs in situ (in the case of selenium), or by alkaline hydrolysis at room temperature (in the case of sulfur). Removal of the N-tosylate group can cause some difficulties for the first generation of amination reagents, but the recent developed alternatives for the original reagents can be deprotected easily [46,47]. Several procedures, such as Ndnaphthalene, are available for the detosylation of the amines. A milder version has been developed but requires three to four additional steps [48]. The substitution of the tosylate with the o-nitro benzenesulfonyl (nosyl, NS) is a major improvement as this group can be removed under almost neutral conditions [49]. The carbamate group can, in contrast to the tosylate group, be removed by simple alkaline hydrolysis [46a]. The use of 68-71 as amination reagents has been investigated for different types of alkenes, and the yield of allyl amines are moderate to good, depending on the substrate and the aminating agent used. The aminations normally give truns-alkenes, regardless of the configuration of the starting alkene and when disubstituted dienes are employed, the allylic amination normally proceeds with rates in the order CH, > CH, > CH. The results for the allylic amination of cyclahexene 58 with the reagents 68,68 and 71 are shown in Eq. (19). The sulfur compound 68 is generally found to give the most clean and high yielding reactions of the four reagents with the

20

J@rgensen

simple alkenes. The selenium reagents 69 and 71 are attractive, mainly because of the very simple one-pot procedure for amination and the mild and easy deprotection strategy for the nosy1derivatives, and this recent development increases the synthetic value for the latter reagent even further. The amination with the alkoxycarbonyl sulfur diimido compound 70 also proceeds well, though this reagent is not quite as reactive as the sulfonate compounds, and prolonged reaction times are often required [46a].

6

I;JHR

*-NR

68, 69,71

In situ KOH or

6

*

ene reaction [2,3]-sigmatropic rearrangement 58

72 68: yield 70 % 69: yield 51 Ye 71:yield 45 %

A few attempts have been made to perform the reaction diastereoselectively [50]. Asymmetric allylic amination of different alkenes such as methylene cyclohexane, cyclohexene, 1-heptene and cyclooctene with N,N'-bis-[N-@-tolylsulfonyl)benzenesulfonimidoyl]selenium diimide gave the allylic amides with 42 %, 34 %, 32 % and 20 % de, respectively [5Oa]. Whitesell et al. have used trans-2-phenylcyclohexanol as the chiral auxiliary which gives a very good chiral induction (Scheme 7) [50b]. The reaction proceeds well for a series of cyclic and acyclic alkenes, such as 73 which reacts with the N-sulfinylcarbamate 76 of trans-Zphenylcyclohexanol in the presence of SnC14as the Lewis acid giving the allylic product 74 in reasonable yields, and with absolute stereocontrol at both the carbon and sulfur stereocenter. The following [2,3]-sigmatropic rearrangement is promoted by silylation of the intermediary ene product giving the ally1 amine 75 in 75 % yield and with a de > 90%.

21

1.2 Nucleophilic Amination of Functionalized Alkenes

74

73

(Me&i)*NH

1

H pRBu [2,3] *RBu ~0~N.~,0SiMe3 XOKN5s\osiMe3 .. 0

0

Scheme 7

Enantioselective catalysis has also been used for the synthesis of optically active sulfimines [51]. By application of 5 mol % of the bisoxazoline-copper(1)catalyst 80, the sulfide 77 is oxidized catalytically to 78 which undergoes a [2,3]-sigmatropic rearrangement to give ally1 amine 79 in 80 % yield and with 58 % ee (Eq. (20)). Other dkenes were found to give lower ee.

22

J#rgensen

77

78

80 [2,3]-sigmatropic rearrangement 80 Yo

-

?=

NP,~, NJ

Ph

/

79 58 O h ee

1.2.5.2 Type 2 Ene Reactions The type 2 ene reactions in Scheme 6 uses the very reactive dienophiles, the azo and nitroso compounds, as the nitrogen donor fragment. The ability for these compounds to undergo the ene reaction have been known for some time [52]. Although these compounds have been known for a long time, their ene reaction chemistry has been exploited only to a very limited extent. This might be incidental, but it can also be related to problems and complexity with their chemistry (vide infra). Some of the most frequently used azo compounds for the ene reactions are 81-84, listed according to their reactivity. Compounds 83 and 84 are found to be very reactive, probably caused by extra ring tension in these compounds [53].

1.2 Nucleophilic Amination of Functionalized Alkenes Et02C,

0

CI&H2C02C,

YN

7N


95%)

(s)-37

Scheme 16

The ( 2 8 absolute configuration and enantiomeric purities (up to 99 % ee) of the crude amino acids 37 were readily determined by GC comparison (using a chiral capillary column) of their (N-trifluoroacety1)-n-propylesters with those of racemic and enantiomerically pure authentic samples and were further supported by chiroptic comparison. The observed n-face differentiation of the electrophilic amination process was rationalized by the authors [ 14bl. NMR Nuclear Overhauser experiments agree with the (E)-configuration of the 0-silyl ketene acetals 35 and with a syn-periplanar disposition of the C’-OSi and C2-Ha bonds. Electrophiles “E”’, such as Lewis acidsco-ordinated DTBAD, attack 35 preferentially from the less hindered C(a)-Si (back) face (Scheme 17).

76

Genet, Greck and Lavergne

Scheme 17

In summary, this methodology is a predictable enantioselective entry to (29-aamino acids. (2R)-a-Amino acids could be obtained in the same manner, starting from the commercially available antipode of the alcohol 32. These methods have the following advantages : (i) stereomeric excesses in the range 78-91 %; (ii) good chemical yields; (iii) both enantiomers of the chiral auxiliaries are commercially available materials; (iv) the chiral auxiliaries can be recycled; and (v) the absolute configuration of the reaction products is easily predictable.

3.3.2 Electrophilic Amination of Chiral Imide Enolates Chiral glycine enolate synthons have been employed in diastereoselective alkylation reactions [IS]. A complementary approach to the synthesis of a-amino acids is the electrophilic amination of chiral enolates developed by Evans [ 161. Lithium enolates derived from N-acyloxazolidinones38, reacted readily with DTBAD to produce the hydrazide adducts 39 in exceIlent yields and diastereoselectivities (Scheme 18). Carboximides 38 were obtained by N-acylation of (S)-4-(phenylmethyl)-2-oxazolidinone and the lithium-2-enolates of 38 were generated at -78 "C in THF under inert atmosphere using a freshly prepared solution of lithium diisopropylamide (LDA, 1.05 equiv.) [17].

77

3.3 Dialkylazodicarboxylates

1) LDA

2) DTBAD

Yield = 91 - 96 O h de = 94 - 99 Yo

f-Bu02CNH

CHpPh

39

In all experiments the lithium enolates (0.12M in THF) reacted instantaneously with DTBAD (1.2equiv., 0.19M in CH,Cl,). After a reaction time of 1 to 3 min, the reactions were quenched with acetic acid. After chromatography, the diastereomerically pure hydrazides 39 (> 300/1)were isolated in yields exceeding 90%. The authors favored a pericyclic transition state for the reaction of DTBAD with the lithium imide enolates. Several transition structures for this reaction are possible; the high degree of organization can be achieved through co-ordination of the lithium atom with either the carbonyl or the nitrogen of DTBAD. The first type of coordination involves an 8-centered pericyclic transition state, while the second type gives 6-centered pericyclic structures which are now commonly accepted. The following transition state structure might be favored on the base of steric hindrance (Scheme 19).

Scheme 19

Three types of reactions were possible for the non-destructive removal of the oxazolidinone auxiliary (Scheme 20) : 0 0 0

hydrolysis (2.3equiv. of LiOH; THF/H,O (2:l);3 h; 0°C) methanolysis (2 equiv. of MeOMgBr, 0.08 M in MeOH; 0.5 h; 0°C) benzylalcohol transesterification (2 equiv. of PhCH,OLi, 0.14 M in THF; 2 h; -50 "C).

78

Genet, Greck and hvergne

39

40 a, b, c R = H, Me, Bn

Scheme 20

These cleavages proceeded generally in good yields with no perceptible racemization for the following substrates: R = CH,Ph, CHMe, and CMe,. Hydrolysis of the hydrazide 39 R = Ph afforded the derived acid 40 with no more than 2 % racemization. In contrast, the more highly basic conditions required for the transesterification caused considerable racemization, and the benzyl ester 40 was obtained in 22 % ee. Enantiomerically pure a-hydrazino and a-amino acids were generated from hydrazides 40 by deprotection of the carbamates and hydrogenolysis of the hydrazine bond (Scheme 21).

Yield of 41 (%)

*

'$OR'

FBoc

BocNH

1) TFA, CH2C12 2) HP,Raney-Ni, 500 psi, rt 3) (+)-MTPA-Cl, Et3N

R$OR' NH (+)-MTPA

Diastereomeric ratio (2s):(2R)

CH2Ph

94

>200:1

Ph

99

99 : 1

Scheme 21

The unpurified a-amino esters obtained after the two first steps were acylated with (+)-MTPA chloride (MTPA = a-methoxy-a-(trifluoromethy1)phenylaceticacid) to afford the (+)-MTPA amides 41. In the case of R = CH,Ph, the final compound 41 was found to be identical to the (+)-MTPA amide derived from L-phenylalanine.The (2s) configuration was correlated for 41 and capillary GC analysis proved that the diastereomeric ratio (2S):(2R) was > 200:l.

3.3 Dialkylazodicarboxylates

79

Using a similar approach, Vederas and co-workers reported the electrophilic amination of lithium enolates of chiral carboximides with various dialkylazodicarboxylates [18] (Scheme 22).

43

42 Scheme 22

Table 3.3

R

R'

Yield of 43 (%)

Diastereomeric ratio (2R):(2S)

91 92 83 88 90 88 85

90:10 69:31 75:25 94:6 93:7 97:3

By treatment with 1.1equiv. of LDA in THF at -78 "C, the chiral carboximides 42 were converted to their Z-enolates which were treated with a solution of alkylazodicarboxylates 4 (1.1 equiv., 0.8 M in THF) at -78 "C. The reaction mixtures were immediately quenched with aqueous NH,Cl to give the hydrazides 43. The diastereomeric ratios were determined by HPLC: these indicated that the natures of the substituents of both the substrate and the dialkylazodicarboxylate influence the stereoselectivity. The diastereoselectivity increases with the size of the R and R' groups: R = Me < CH2Ph < i-Pr and R' = Me < Et < CH,Ph r-Bu (Table 3.3). Classical methods for removal of the chiral oxazolidinone moiety such as benzyl alcohol transesterification, caused some epimerization at the newly aminated center. The use of anhydrous LiSH (1 equiv., THF, 20 "C, 10 min) was successful and the cleavage occurred without sensible epimerisation. Treatment of the resulting reaction mixture with THF/CH,CO,H (1 :1 mixture, 40 % in H20) gave the carboxylic acids 44 in 76- 85 % yields. Compounds 44 were hydrogenolyzed under classical conditions (H2, PdC)to the free a-hydrazino acids which were converted to the a-amino acids 45 by subsequent cleavage of the N-N bond in the presence of Raney-Ni (500 psi, 10 % aqueous AcOH) with 80-95 % yield (Scheme 23).

-

80

Genet, Greck and Lavergne

1) LiSH

R'O2CN . / $ R'O2CNH Pr

2) THF I CH3CO3H

43

'$OH R'02CN / R'02CNH

1) H2, Pd/C

+

2) Hz, Raney-Ni

'$OH NH2

44

Scheme 23

Recently, a stereoselective synthesis of carbon-linked analogues of a- and P-galactoserine glycoconjugates has been reported using asymmetric enolate methodology [19]. The key step involved the electrophilic amination of a chiral oxazolidinone enolate with DTBAD. In conclusion, the amination of enolates of N-acyloxazolidinoneswith dibenzyl or di-t-butylazodicarboxylatespresented the following properties: (i) diastereomeric excesses in the range 80-98 %; (ii) good chemical yields; (iii) efficient route to both chiral a-hydrazino and a-amino acid derivatives; and (iv) non-destructive removal of the chiral oxazolidinone auxiliaries.

3.3.3 Electrophilic Amination of Chiral Ester Enolates 3.3.3.1 P-Hydroxy Esters Chiral P-hydroxy esters and 1,3-dioxan-4-ones are well-known substratesfor diasteroselective a-alkylation reactions developed by Frater [20] and Seebach [21]. These c h i d compounds are available in both enantiomeric forms, and have been also aminated at the a-carbon with high stereoselectivity. Two reports appeared simultaneously in 1988 describing the electrophilic amination with DTBAD of P-hydroxybutyrate and its 1,3-dioxan-4-0ne protected form [22] and of various 0-hydroxy esters [23]. The authors obtained similar results. P-Hydroxy esters 46 or 48 were deprotonated at the a-carbon with LDA (2 equiv.) in THF at low temperature and the resulting enolates reacted rapidly with DTBAD at -78°C to give an easily separable mixture of syn and anti adducts 47 or 49 in which the anti diastereomer was the major compound. The adducts are very useful intermediates since compounds with anti stereochemistry are not easily accessible by other established methods for a-amino P-hydroxy acids synthesis (Schemes 24 and 25).

45

81

3.3 Dialkylazodicarboxylates 1) LDA P 2) DTBAD, -78 "C, H3C =OR

H3C=OR

THF, 3 min

BoCE,

Yield (Yo)

46

+

H3C?OR BocN,

NHBoc

NHBoc

syn 47

anti 47

R = CH3

58

82

18

R = C2H5

57

77

23

Scheme 24

XOR

1) LDA P 2) DTBAD, -78 "C, H 3 C y O R THF, 3 min BocN, NHBoc

H3C

Yield (%)

48

+

H3C

.

, NHBoc

Boci

syn 49

anti 49

R = CH3

75

84

16

CF3

62

87

13

C6H13

74

90

10

C5H11

81

85

15

Scheme 25

'

Subsequently, as an application of this method, D-ribo-C ,-phytosphingosine has been prepared stereoselectively from (S)-malic acid dimethyl ester 50. The electrophilic aminating reaction with DTBAD proceeded with 62 % yield and the anti ahydrazino P-hydroxy ester 51 was obtained as the major diastereomer (anti:syn = 67:33). After separation of the two isomers, the synthesis of the enan52 has been achieved [24] (Scheme 26). tiopure tetra-acetyl-D-ribo-C1,-sphingosine

OH &C02Me MeO&

--

OH

0

TBDPSOJJLOMe BocN, NHBoc

50 Scheme 26

51

--

OAc ~-CI~HZS G

NHAc

O 6Ac

52

A

C

82

Genet, Greck and Lavergne

Starting from (3-ethyl-P-hydroxybutanoate53, different synthetic applications have been developed such as the preparation of synthetic equivalents of 2,4deoxy-2-amino-L-threose 54 and L-erythrose 55 [25], and the obtaining of 4-acetylamino-2,4,6-trideoxy-L-ribo-hexose 56 [26], of N-acetyl-L-tolyposamine 57 [27] and of cis-monobactams 58 [28] (Scheme 27).

1

CHO

CHO

55

54

53

56

58

Scheme 27

The moderate diastereose..xtivities observe in the electrophilic amination of phydroxy esters with DTBAD were due to the acyclic nature of the substrates. When the P-hydroxybutanoic acid was protected as 1,3-dioxan-4-0nes, deprotonation and amination afforded the a-hydrazinodioxanones 60 in good yields and high diastereomeric excesses [22,29] (Scheme 28).

-

R

R

Yield

(“N

(“/4

CH2CHZPh

95

>95

H

90

>95

1) LDA

2) DTBAD, -78 “C, THF, 3 min

H3C

: EbCi,

59

NHBoc

de

60 Scheme 28

An additional bulky group on the dioxanone moiety was not required for stereoinduction, and an excellent diastereomeric excess was obtained starting from 59 when R = H. Enantioselective synthesis of D-allothreonine 61 has been achieved from 60 (R = CH,CH,Ph) with 42 % yield [22]. (3-Trifluorothreonine methyl ester 63 has also been synthesized in 57 % yield from the 2-t-butyl-l,3-dioxan-4-ones 62 using a related approach [30] (Scheme 29).

3.3 Dialkylazodicarboxylates

83

61

I ) fBuLi, DTBAD 2) HCI, MeOH

ho

3) H2. PtO2

F3C

62

*

F3C=OMe fiH2

63

Scheme 29

This method gives the aminated products with complete control of stereochemistry, and the subsequent deprotection and hydrogenolysis of the hydrazine functionality yield the desired a-amino P-hydroxy acid derivatives. Another alternative to obtain high anti diastereoselectivity for the electrophilic amination of P-hydroxy ester enolates has been designed using the chelation of the dianion by higher organometallic species [29]. If the enolate was generated with 2 equiv. of LDA-t-BuOK or with LDA in the presence of Ti(0i-Pr), or EbZn, the aminating reaction with DTBAD afforded only the anti a-hydrazino P-hydroxy ester in low yield. In contrast, the use of LDA as base in the presence of MeZnBr gave the anti product 65 in chemical yields up to 70 %. The best experimental conditions were defined as follows (Scheme 30, Table 3.4): 1. Dropwise addition of a P-hydroxy ester THF solution to a THF solution of MeZnBr (1 equiv.) at 0 "C. 2. Cooling at -78 "C and dropwise addition of a solution of LDA (2 equiv.) in THF. 3. Dropwise addition of a THF solution of DTBAD (2 equiv.) at -78 "C. Stirring for 10 min. 4. Hydrolysis at -78 "C with a saturated aqueous solution of NH4Cl.

64

Scheme 30

65 de >98 %

84

Genet, Greck and Lavergne

Table 3.4

Entry

R'

Yield (%)

C

63 58 66

d

69

a

b

e

70

BnO

CI

f

E t w

Me

h

(MeO),CHCH2

CH3

53

CH,

55

CH3

66

Functionalized P-hydroxy esters 64 e,f,g,h were obtained quantitatively with excellent enantiomeric excesses (> 98 %) by hydrogenation of P-ketoesters in the presence of chiral ruthenium catalysts. This convenient methodology gives both optical antipodes with equal ease using (R) or (9atropoisomer ligand for the metal complex. The first transition metal catalysis using BINAP-ruthenium complex in homogeneous phase for enantioselective hydrogenation of P-ketoesters was developed by Noyori and co-workers [31]. Genet and co-workers described a general synthesis of chiral diphosphine ruthenium(II) catalysts from commercially available [32]. These complexes preformed or prepared in situ (COD)R~(2-methylallyl)~ have been found to be very efficient homogeneous catalysts for asymmetric hydrogenation of various substrates such as P-ketoesters at atmospheric pressure and at room temperature [33]. By coupling the two sequential reactions: catalytic hydrogenation and electrophilic amination, a general and practical method for the preparation of both enantiomers of anti-a-hydrazino-P-hydroxy esters (R,R)-65 and (S,9-65 from the corresponding P-ketoesters 66 has been proposed, and different synthetic applications have been developed [le] (Scheme 31).

85

3.3 Dialkylazodicarboxylates

cat : (R)-L2*RuBr2

/ 1) hydrogenation R' H

O

66

R

Z

\

2) electrophilic amination

cat : (S)-L2*RuBr2

R' m

*

O

R

2

R302Cfi-NHC02R3

-

(RW-65

(S9-65 Scheme 31

Starting from (R,R)-65e, the synthesis of the non-natural amino acid (2R,3R)-2hydroxy-rn-chloro-p-hydroxyphenylalanine,component of vancomycin, has been described [34]. a-Hydrazino- p-hydroxy esters 65 are also chiral building blocks for the synthesis of functionalized nitrogen heterocycles. (3S,4S)-4-Hydroxy-2,3,4,5-tetrahydropyridazine-3-carboxylic acid 67, component of luzopeptine A [35], (2R,3R)-3-hydroxypipecolic acid 68 [36] or (-)-swainsonine 69 [37], and trans-3-hydroxy-D-proline70 [38] were synthesized (Scheme 32).

67

68

69

70

U

a

(S,S)-65f

(S,S)-65h

Scheme 32

In conclusion, the electrophilic amination of chiral P-hydroxy ester enolates with DTBAD presents the following advantages : (i) diastereomeric excesses > 98 96 by using MeZnBr as chelating complex; (ii) the obtainment of both antipodes of anti ahydrazino-P-hydroxy esters is possible starting from a j3-ketoester by coupling catalytic hydrogenation and electrophilic amination; and (iii) anti a-hydrazino-p-hydroxy esters are the synthetic precursors of various natural and unnatural products of biological interest.

86

Genet, Greck and Lavergne

3.3.3.2

P- Aminoesters

In 1988, Seebach and co-workers described the diastereoselective alkylation and amination of 3-aminobutanoic acid [39]. The enantiomerically pure 3-aminobutanoic acids (R)- and (9-71 were obtained by preparative HF'LC separation of two diastereomers resulting from the addition of (9-phenylethylamine to methyl crotonate and subsequent hydrogenolysis. After classical benzoylation and esterification, (R)- and (9-72 were available (Scheme 33). 1) BzCl NaOHIH20

OH

BzNH

2)MeqSiCI(2.2equiv.1

0

&OMe

Scheme 33

(S)-Methyl-3-(benzoylamino)butanoate(9-72 is also available by enzymatic resolution with pig liver esterase. Alkylation and amination were run on the racemic compounds. One example of electrophilic amination is reported starting from rac-72 which is doubly deprotonated with LDA at low temperature (-60 "C to -45 "C).The enolate intermediate adopts an ( E ) configuration. After treatment at -70 "C with DTBAD (1.2 equiv.) in THF,the product 73 is obtained with 96 96 yield and an excellent diastereoselectivity: de > 99 % in favor of the anti-diastereomer (Scheme 34). The absolute configuration of the created stereogenic center was assigned by chemical correlation with the known anti-2,3-diaminobutanoicacid.

BzNH

U

0

O

M

LDA (2.2 equiv.)

e

rac-72

0 1) DTBAD (1.2 equiv.) -70 "C

-60 "Cto - 45 "C THF

BocN-NHBoc

73 Scheme 34

More recently a stereoselective synthesis of (3S)-N-Pf-3-aminoaspartate(Pf= 9phenylfluoren-9-yl) by reaction of N-Pf-aspartate enolates with electrophilic aminating reagents was reported by Sardina and co-workers [40].Electrophilic aminations were run using trisylazide or dialkylazodicarboxylates:DTBAD and DBAD. N-Pf-

87

3.3 Dialkylazodicarboxylates

aspartates 74 were treated with different bases (1.2equiv.) to generate the enolates in THF at -78 "C. The enolates were allowed to form for 1 h at -55 "C, and after cooling the reaction mixture at -78 "C, a precooled (-78 "C) solution of azodicarboxylate (1.3 equiv.) in dichloromethane was added via cannula. After 4.5 min, the reaction was quenched with AcOH. Classical work-up and flash chromatography afforded the aminated products with the anti diastereomers as the major stereomers (Scheme 35; Table 3.5). RO~CN-NHCOZR

1) base, THF -78 "C to -55 "C

*

2) R02CN=NC02R

Me02C/YC NHPf oZMe

?f

Me02C' V 2 M e

Me02C

NHPf

-78 "C 3) AcOH

74

R02CN-NHC02R

NHPf

anti 75

syn 75

Scheme 35 Table 3.5 R = t-Bu

Base

LHMDS BuLilLHMDS (113) KHMDS LHMDS (HMPA)

R=Bn

antihyn

Yield (%)

anti/syn

Yield (%)

2.511

83 85 82 80

211 111 111 1811

79

2.311 21 1 301 1

85 80

75

The stereochemistry of the 3-hydrazinoaspartates 75 (R = t-Bu) was established by chemical correlation with dimethyl-N,N'-bis(benzyloxycarbonyl)-3-aminoaspartate and with 1,3-bis(benzyloxycarbonyl)-4,5-bis(methoxycarbonyl)imidazolidin-2one. The authors proposed that the reacting enolate be an equilibrium mixture of an open form 76 and a chelated form 77,both of which have the bulky N-Pf group in the equatorial position (Scheme 36).

H\

L

-

L

Scheme 36

Pf @Re

N'

0 kJl:C Me0

H

O2Me

k'

L'

76

C02Me

'L

77

88

Genet, Greck and Lavergne

The open form would be favored by strongly coordinating ligands (HMPA) or by the use of K+, as the enolate counterion and the electrophilic amination would occur on the Si-face of the enolate leading to the anti-aminated product.

3.3.4 Electrophilic Amination of Ketone Enolates Enolate anions derived from 2-substituted2-acyl-l,3-dithiane- 1-oxideswere diastereoselectively aminated using DTBAD as the nitrogen electrophile [41]. The lithium enolate of anti 2-ethyl-2-propanoyl-1,3-dithiane-1 -oxide 78 was generated using LiHMDS (1.1 equiv.) in dry THF at -78°C and transferred by cannula to a precooled solution of DTBAD (1.1 equiv.) in dry THF at -78°C. After allowing 10- 15 rnin for reaction with DTBAD at -78 "C, the reaction mixture was quenched at -78 "C using acetic acid. The desired aminated product 79 was isolated in 52 % yield and characterized as a single diastereomer: only one product isomer being detectable by 400 MHz 'H N M R spectroscopy. If the reaction mixture was allowed to reach room temperature over 12 h before quenching with aqueous NH,C1 and normal work-up, the aminated product was obtained with a similar yield but as a 2:l mixture of inseparable diastereomers. The major diastereomer proved to have the same stereochemistry for both 78°C and room temperature quench (Scheme 37). Under the same conditions, the syn compounds 78 gave predominantly 80 as the major stereomer (Scheme 38).

0-

1) LIHMDS, -78 "C, THF

*

2) DTBAD, -78 "C, THF, 15 min

3)CHBCO~H,-78 "C

90% yields under mild conditions using tri(o-toly1)phosphineligated palladium as catalyst. These materials were characterized by conventional spectroscopic means, including microanalysis. Each carbon could be observed by 13C NMR spectrometry, and a molecular ion was observed by mass spectroscopy. The electrochemical behavior of the three-fold symmetric dendrimer at the top of the scheme was complex and showed a large number of reversible electrochemical waves. The radical cation was generated in solution, was stable, and was observed by ESR spectroscopy. This material also shows a high glass-transition temperature. Multiple arylations of polybromobenzenes were also conducted to generate electron-rich arylamines. Tribromotriphenylamine and 1,3,5-tribromobenzeneall react cleanly with N-aryl piperazines using either P(~-tolyl)~ or BINAP-ligated catalysts to form hexamine products [ 1071. Reactions of other polyhalogenated arenes have also been reported [ 1081.

7.7 Applications to Materials Science

239

7.7.3 Synthesis of Small Molecules for Materials Applications Palladium-catalyzed amination has also been used to prepare small arylamines that can function as sensors, nonlinear optical materials, magnetic materials, electrode modifiers, hole-transport materials, and dyestuffs. N-arylpolyamines that can have multiple applications have also been prepared. Azacrown ethers with chromophores bound to the nitrogen for metal-cation selective detection systems have been prepared. Aza- 18-crown-6 reacts in modest yields with 9-bromoanthracene using palladium catalysts to form the N-aryl azacrown (Eq. (37) [177]. Of the reactions using the four ligands P(o-tolyl),, BINAP, DPPP (DPPP = 1,3-diphenylphosphinopropane), and DPPF, the one containing DPPF as ligand occurred in the highest yield, 29%. Barlow and Marder showed that N,N-diarylaminoferrocenescan be prepared by the palladium chemistry. Readily available aminoferrocene [ 1781 reacts with 4bromotoluene under rigorously anaerobic palladium-catalyzed conditions using DPPF as ligand to produce N,N-di-p-tolylferrocene in 58% yield [ 1791. This material is readily oxidized to the radical cation. The radical resides predominantly on the ferrocene, but the metal -1igand charge transfer band is red-shifted. These researchers have also shown that unsymmetrical triarylamines can be prepared, as shown in Eqs. (40) and (41), by sequentially reacting aniline with two different aryl halides, or by reacting 4,4’-dibromobiphenyl with an arylamine and then a second aryl halide using DPPF-ligated palladium as catalyst [ 1801. Buchwald has subsequently published similar results on the formation of mixed alkyl diarylamines starting from a primary alkylamine [18 11.

NH2

NaO-t-Bu, 1) Pdp(dba)@PPF BrCsH4-pR

RQNaB

R=-(CH&-O-CH&H=CH2 1) Pd2(dba)&PPF NaO-t-Bu, BrCsH4-pBu

Br*Br

/ \

+ Ar1-NH2

1) Pd2(dba)3/DPPF NaO-t-Bu

2) ASBr

Ar2

(411

240

Hartwig

Ipaktschi and Sharifi reported the palladium-catalyzed synthesis of 2,7-diamino fluorenones by two indirect routes due to the base sensitivity of fluorenones [182]. First, 2,7-dibromofluorene was reacted with secondary amines, and subsequent oxidation of the product formed the diamhofluorenone. Alternatively, reaction of aminostannanes derived from secondary amines with 2,7-dibromofluorenone gave yields of the fluorenone ranging from 42 to 58%. Beletskaya has used the DPPFligated palladium system to conduct selective monoarylation of ethylene diamine, diethylene triamine, triethylene tetra-amines, and 2,2-dimethyl butane- l ,3diamine [ 1831.

7.7.4 Palladium-catalyzed Amination for Ligand Synthesis Amido compounds are increasingly important in early transition metal chemistry as supporting ligands, and materials with both phosphorus and nitrogen donor atoms are increasingly used as non-C,-symmetric ligands for asymmetric catalysis. Thus, the amination chemistry can provide a useful method for ligand synthesis, and several reports of such methods for ligand preparation have appeared. Schrock reported a palladium-catalyzed synthesis of triamido ligands that are useful for conducting a-olefin polymerization chemistry using Group IV metals (Eq. (42) [184]. A similar approach was followed to prepare a small library of C,-symmetric N, N'-diaryldiamine ligands. Using BINAP-ligated palladium as catalyst, (S,S)- 1,Zdiphenyl- 1,2-diaminoethane was reacted with a variety of aryl bromides to give the N,N'-diaryldiamines in modest to excellent yields [ 185,1861. Kocovsky has reacted his NOBIN aminoalcohol (Eq. (43)) with phenyl bromide to modify this basic ligand structure [128, 187-1891. Use of the P,N ligand MAP led to significant rate accelerations. Buchwald and Singer have also conducted palladium-catalyzed amination on binaphthyl ligand substructures. They reacted benzophenone imine with the triflates formed from homochiral binaphthol to prepare similar N,O ligands without need for resolution [ 1901.

N(CH2CH2NH2)3+ 3 ArBr

Pdp(dba)s, BlNAP N(CHZCHZNHAr13 NaO-f-Bu, toluene 80-100 "C

(42)

7.8 Mechanism of Aryl Halide Amination and Etheration

L=BINAP or MAP

OH

24 1

(43)

7.8 Mechanism of Aryl Halide Amination and Etheration The previous sections described synthetic methods involving palladium- and nickelcatalyzed additions of alcohols and amines to aryl halides and triflates. The development of procedures and catalysts used in these processes has occurred hand-inhand with mechanistic analysis of the amination chemistry. The following sections describe the current understanding of why these procedures and catalysts are effective, and how this understanding led to some of the breakthroughs described above.

7.8.1 Oxidative Addition of Aryl Halides to L,Pd complexes (L = P(o-tolyl),, BINAP, DPPF) and its Mechanism L,Pd(O) complexes containing the three ligands P(o-tolyl),, BINAP, and DPPF are the resting states of the catalyst when the isolated Pd(0) complex is used as catalyst in mechanistic studies and when Pd(OAc), is used as catalyst precursor in more synthetically convenient procedures 179,1911. Pd(0) ligated by dba and BINAP [192] in combination with the L,Pd(O) complex is the resting state of reactions catalyzed by BINAP and Pd,(dba), complexes [ 1931. Thus, oxidative addition is the turnoverlimiting step with these catalyst systems, and the mechanism and rate of these reactions determines the production of arylamine products.

242

Hartwig

{ Pd[P(o-tolyl),],} underwent oxidative addition of aryl halides to provide the unusual dimeric aryl halide complexes { Pd[P(o-tolyl),](Ar)(Br)}, (Eq. (44)) [77,102]. It is unusual for phosphine-ligated aryl halide complexes formed by oxidative addition to be dimeric. These oxidative addition products were isolated and structurally characterized. They remain dimeric in solution, as determined by solution molecular weight measurements, but react as the monomers, as described below. These oxidative addition products have been used as precursors to aryl halide complexes containing several P,O and P,N ligands, as discussed in Section 7.3.3. In these cases, monomeric complexes with or without 0- or N-coordination are observed. With these systems, it is difficult to determine if the heteroatom coordination exists in the complex that lies on the reaction pathway or if the observed complexes are simply the most stable structures; coordination and dissociation of the heteroatom is generally kinetically undetectable. The three structures obtained are shown schematically in Figure 7.3. Both Kumada’s [92] and Guram’s [130] ligand systems derived from o-acetyl phosphines generate monomeric, monophosphine structures. Guram’s ligand derived from the o-formyl phosphine forms standard monomeric, bisphosphine aryl halide complexes. Kocovsky has shown that MAP adopts an unusual conformation involving Pd-C coordination [1941, which is observed in some binaphthol complexes [195], as part of a complex equilibrium between the expected P,N ligation mode and a third binding mode without C or N coordination.

Figure 73. Structuresof various aryl halide complexes containing P.0 and P,N ligands used in the amination of aryl halides.

The mechanism of the oxidative addition of aryl bromides to the bis-P(o-tolyl), Pd(0) complex 3 was surprising [196]. It has been well established that aryl halides undergo oxidative addition to L,Pd fragments [197-2001; thus, one would expect oxidative addition of the aryl halide to occur directly to 3 and ligand dissociation and dimerization to occur subsequently. Instead, the addition of aryl halide to (Pd[P(otolyl),],} occurs after phosphine dissociation, as shown by an inverse frrst-order dependence of the reaction rate on phosphine concentration and the absence of any tris -phosphine complex in solution [1961.

7.8 Mechanism of Aryl Halide Amination and Etheration

243

Three mechanisms consistent with phosphine dissociation before oxidative addition are shown in Scheme 4. In one case, a one-coordinate 12-electron intermediate adds the aryl halide. A second mechanism involves formation of a solvated one-coordinate 12-electron intermediate formed by ligand dissociation and addition of aryl halide to this solvated species. A third pathway involves reversible displacement of a phosphine ligand by aryl halide to generate an aryl halide complex with the carbonhalogen bond intact. Reaction rates in benzene, toluene, and p-xylene solvent were all essentially identical, despite their different abilities to coordinate a transition metal. Thus, it is unlikely that a complex with solvent directly bound to the metal is an intermediate. In the published work it was not possible to distinguish between the other two intermediates, but in subsequent studies involving the measurement of phosphine dependence at two very different aryl bromide concentrations, it has been shown that an associative pathway involving displacement of phosphine by aryl bromide does not occur and that the reactive intermediate is the monoligated {Pd [P(o-tolyl),] } [201]. A similar mechanism presumably operates for the oxidative addition of aryl halides to Pd(0) complexes coordinated by two P(t-Bu), ligands.

ArBr

r"f

3' L-Pd-L Br I

/B! / P ( ~ t o l y l ) ~ Pd Pd (&tolyl)3P / \Br/ \Ar Ar,

4

- I - L-Pd-S

+ArBr -L

-

- ArBr +L

Pd' / \ (etolyl)3P s

Ar, /Br L-Pd-(ArBr) Pd / (etolyl)3P

4

4

Scheme 4. Potential mechanisms for oxidative addition of aryl halides to L,Pd(O) L = P(o-tolyl),.

Oxidative addition to a monophosphine palladium complex is unusual, but is a reasonable pathway if one bears in mind that reductive eliminations often occur from monophosphine palladium complexes [202,203]. These reductive eliminations from monophosphine Pd" species would form a monophosphine Pdo complex as the initial metal product, and these Pdo products are similar to the intermediate in the oxidative addition of aryl halide deduced from kinetic studies.

244

Hartwig

Although unpublished at the time of preparation of this manuscript, Alcazar-Roman and Hartwig have presented the results of kinetic studies on the oxidative addition of aryl halides to L,Pd(O) complexes ligated by BINAP and DPPF [201]. It was shown that full dissociation of the chelating ligand occurs to give rise to the LPd(0) species prior to oxidative addition of the aryl halide. Again, detailed kinetic analysis showed that the naked LPd(0) species is the reactive intermediate that cleaves the carbon-halogen bond. The relative rates for reassociation of ligand and addition of aryl halide varied depending on ligand and altered the kinetic behavior of the systems. When the BINAP complexes were studied, it was found that the addition of aryl halide to the LPd(0) fragment was much faster than reassociation of BINAP at high aryl bromide concentrations. Thus, the reactions are zero order in aryl bromide under these conditions. This result indicates that the catalytic cycle will be zero order in all reagents because aryl bromide concentration is much higher than free ligand concentration in synthetic reactions. Under these conditions, ligand dissociation from (BINAP),Pd is the turnover-limiting step. For complexes of DPPF, ligand reassociation to LPd(0) was faster than aryl bromide addition, making the stoichiometric oxidative addition reactions and, therefore, the catalytic cycle first order in aryl bromide and inverse first order in free ligand.

7.8.2 Formation of Amid0 Intermediates 7.8.2.1 Mechanism of Palladium Amide Formation from Amines

In the original process using tin amides, transmetallation formed the amido intermediate. However, this synthetic method is outdated and the transfer of amides from tin to palladium will not be discussed. In the tin-free processes, reaction of palladium aryl halide complexes with amine and base generates palladium amide intermediates. One pathway for generation of the amido complex from amine and base would be reaction of the metal complex with the small concentration of amide that is present in the reaction mixtures. This pathway seems unlikely considering the two directly observed alternative pathways discussed below and the absence of benzyne and radical nucleophilic aromatic substitution products that would be generated from the reaction of alkali amide with aryl halides.

7.8 Mechanism of Aryl Halide Amination and Etheration

-

/Br, /P(o-tolyl)3 R'RHN\ /Ar Pd Pd Pd / \ / \Ar 2 HNRR' Br' \ P ( ~ t o l y l ) ~ (o-tolyl)3P Br 4 18 Ar,

245

(45 1

Paul, Patt, and Hartwig showed that the dimeric aryl halide complexes { Pd[P(oC6H4Me),](Ar)(Br)J2react with a variety of amines to form monometallic, amineligated aryl halide complexes { Pd[P(o-C,H,Me),](amine)(Ar)(Br)) (18) (Eq. (45)) [ 1021. Buchwald and Widenhoeffer published similar results subsequently and showed that primary amines can even displace the phosphine ligand [ 145,204,2051.These amine complexes are important in the catalytic cycle because the acidity of the N-H bond is enhanced when coordinated to the metal. Amineligated aryl halide complexes can be formed in a similar fashion from [Pd(PPh,),] in cases where the amine can coordinate intramolecularly [49,83], and it is likely that similar amine-ligated monophosphine complexes are formed when other hindered phosphines are employed, such as the t-butyl- and cyclohexylphosphine ligands discussed in Section 7.3.3.

The amine-ligated aryl halide complexes react with alkoxide or silylamide bases to form arylamine products (Eq. (46)) [206]. The reaction of {Pd[P(oC,H,Me),](HNEt,)@-Bu")(Br)} and LiN(SiMe,), occurred immediately at room temperature to form arylamine in greater than 90% yield. Low-temperature reactions conducted in the NMR spectrometer probe allowed direct observation of the anionic halo amido complex { Pd[P(o-C,H,Me),](NEtJ(Ar)(Br)}- [206]. The neutral metallacycle {Pd(PPh3)(q2-NHC,H,C,H,)J, was formed after deprotonation of the azametallacycle { Pd(PPh,)(q2-NH,C,H4C6H4)(Br)}[49,83]. Thus, one experimentally supported mechanism for generation of the amido aryl intermediate is coordination of amine to form a square planar 16-electron complex that reacts with base. Presumably, it is this type of complex that reacts with the relatively insoluble and weaker bases Cs2C0, and K,P04. An alternative pathway when soluble alkoxide or silylamido bases are used, involves reaction of a palladium amido aryl complex with the alkoxide or silylamide to form an intermediate alkoxide or amide. These complexes can react with amines to form the required amido aryl intermediate. This pathway seems to occur for aryl halide aminations catalyzed by complexes with chelating ligands. The inorganic

246

Hartwig

chemistry involved in this transformation is unusual, since the reaction between an alkoxide complex and an alkylamine to form an amido complex had not been observed prior to work described below.

The reaction of (Pd(PPh,)(Ph)(pOH)}, with primary alkylamines to generate palladium amido complexes and water (Eq. (47)) [56,207] was an initial indication that the conversion of an alkoxide to an amide could be occurring during the catalytic cycle. These reactions are reversible, but the equilibrium favors the amido complex. The formation of alkoxo intermediates may be occumng when monophosphines are used, but the stability of the amine complexes favors the deprotonation of coordinated amine. Instead, the alkoxo complexes may be important in catalytic systems involving chelating ligands [5 11. Indeed, the DPPF complex { Pd(DPPF)@Bu'C,H,)(O-t-Bu) ) reacted with diphenyl amine, aniline, or piperidine, as shown in Eq. (48), to give the product of amine arylation in high yields in each case [51]. Since, no alkali metal is present in this stoichiometric reaction, the palladium amide is formed by a mechanism that cannot involve external deprotonationby alkali metal base.

p""" (DPPF)Pd,

0-t-B"

HNRR' t-BuoH

-

~R R NJ=(+ NRR' 25-75°C R=R'=ptol 92 -1 00 % R=H, R'=Ph NRR'= N 3 (DPPF)Pd

\

+ Pd(0)

7.8 Mechanism of Aryl Halide Amination and Etheration

247

In the actual catalytic process, it is possible that coordination of amine and deprotonation are faster than formation of alkoxide and subsequent N-H bond cleavage. However, stoichiometric reactions of [ Pd(DPPF)(p-Bu'C,H,)(Br) } with amine and alkoxide base rapidly gave rise to [ Pd(DPPF)(p-Bu%,H,)(O-t-Bu) }, indicating that substitution is faster than coordination and deprotonation. This alkoxide was shown to form the arylamine product by reaction with amine 1511. The intimate mechanism for N- H bond cleavages by palladium complexes containing chelating ligands is not clear at this time, but palladium amido complexes are certainly thermodynamically accessible by reaction of a palladium alkoxide with free amine. Of course, reactions involving the carbonate and phosphate bases that are insoluble and that would act as poor ligands are more likely to occur by a coordination and deprotonation mechanism, even when chelating ligands are used.

7.8.3 Reductive Eliminations of Amines from Pd(I1) Amido Complexes Reductive elimination of amines is the key bond-forming step in the catalytic amination processes. These reactions were unknown a couple of years ago, but several examples of this reaction now exist, and the factors that control the rates of this process are beginning to be understood. The identity of the intermediates in some of these reductive elimination reactions has recently been uncovered. The best-understood examples of reductive eliminations that form the C -N bond in amines involve palladium complexes. Both Boncella et al. [52] and Hartwig et al. [49,50,83] have observed these reactions from palladium amido aryl complexes. Hartwig's group has studied the mechanism of this process in detail 149,831. Although monomeric and dimeric amido complexes have been isolated, the monomeric species undergoes reductive elimination. For complexes with monodentate ligands, kinetic studies indicated that the actual C-N bond formation occurs simultaneously from both three- and four-coordinate intermediates. With chelating phosphines, the chemistry is, therefore, likely to occur from the four-coordinate complexes observed in solution. The reductive elimination of arylamines is favored by increasing nucleophilicity of the amido group and increasing electrophilicity of the aryl group.

248

Hartwig

90% rate = k&s[l9]

19

1131-

. n

87% rate = k&s[20]’”

Ph3P 21

90% rate = k&s[21]

Scheme 5. Reductive elimination of arylamines from PPh,-ligated Pdn amido complexes.

The mechanisms of the reductive eliminations in Scheme 5 were studied [49,83], and potential pathways for these reactions are shown in Scheme 6. The reductive eliminations from the monomeric diarylamido aryl complex 20 illustrate two important points in the elimination reactions. First, these reactions were first order, demonstrating that the actual C-N bond formation occurred from a monomeric complex. Second, the observed rate constant for the elimination reaction contained two terms (Eq. (49)). One of these terms was inverse first order in PPh, concentration, and the other was zero order in PPh,. These results were consistent with two competing mechanisms, Path B and Path C in Scheme 6, occurring simultaneously. One of these mechanisms involves initial, reversible phosphine dissociation followed by C -N bond formation in the resulting 14-electron, three-coordinate intermediate. The second mechanism involves reductive elimination from a 16-electron four-coordinate intermediate, presumably after trans-to-cis isomerization.

7.8 Mechanism of Aryl Halide Amination and Etheration

Path A K

-

IAr kl

Ar-NAr'2

+

249

Pd(0)

Z L3Pd\NAr'2

Scheme 6. Potential mechanisms for reductive elimination of arylamines from PPh,-ligated Pd" amido complexes.

-d[19]/ dt = kobs[l9]

The dimeric amido complexes underwent reductive elimination after cleavage to form two monomeric, 3-coordinate, 1Celectron amido complexes. In the case of the anilido dimer 20, a half-order rate dependence in the palladium complex showed that the reductive elimination occurred after reversible cleavage of the dimer to form two monomers. In the case of the t-but ylamido complex 21,rapid reductive elimination occurred after irreversible dimer cleavage. This conclusion was supported by reaction rates that were first order in palladium dimer and by the lack of crossover during the reductive elimination reactions containing two doubly-labeled dimers. The observation that the reductive elimination process involved a pathway through four-coordinate, presumably cis, monomeric amido aryl complexes led to the preparation of palladium amido complexes with chelating ligands [50].Results with these complexes confirmed that elimination can occur from these species and led to the development in our laboratory of second-generation catalysts based on palladium complexes with chelating ligands [208]. DPPF-ligated palladium amido aryl complexes in Scheme 7 underwent reductive elimination of arylamines in high yields [50,83].The rates for these reactions were first order in palladium, and zero order in trapping ligand. Thus, the data on the reductive elimination reactions are consistent with a direct, concerted formation of the C-N bond from the cis, fourcoordinate DPPF complex.

250

Hartwig

-

PhNH(sw6u)

%heme 7. Reductive elimination of arylamines from DPPF-ligated palladium amido complexes.

Because the reductive elimination from DPPF-ligated palladium did not involve geometric rearrangements or changes in coordination number before the rate-determining step, the DPPF complexes allowed for an assessment of the electronic properties of the transition state in this reaction. The relative rates for elimination from amido groups was alkylamido > arylamido > diarylamido. This trend implies that the more nucleophilic the amido group, the faster the elimination process. Variation of the aryl group showed similar results to those of an extensive study on the electronic aspects of C-S bond-forming eliminations of sulfides [41]. The data for electronic effects on sulfide and amine eliminations shown in Figure 7.4 were similar. They showed that electron-withdrawing groups accelerated the reductive elimination process, and that substituents with large crR values affected the reaction rates more than substituents with large crI values. Resonance effects were stronger than inductive effects, perhaps due to arene coordination during the reaction. In a more rough sense, the amido group acts as a nucleophile, and the aryl group as the electrophile.

7.8 Mechanism of Aryl Halide Amination and Etheration

0 -

25 1

0.2 0 -0.2

-1 -1.2 -0.25 -0.2 -0.15 -0.1 -0.05 0 0.05

sigmabar

pR-1 PI = 2; PR-

= 3.9,

1.9

Figure 7.4. Electronic analysis using a combination of of,and okO for the reductive elimination of aryl arylamines.

Although it involved the reductive elimination of ethers and not amines, a recent study revealed the importance of steric hindrance in accelerating the reductive elimination process. Until recently, reductive elimination of acyclic aryl ethers occurred only from palladium complexes containing highly electron-poor palladium-bound aryl groups [51]. The lower nucleophilicity of alkoxides and aryloxides relative to amides makes the elimination process slow enough that reactions occur only with palladium complexes containing strongly electrophilic aryl groups. However, the use of ligands with demanding steric properties accelerated this reaction to the point that reductive elimination was observed from complexes containing electron-neutral aryl groups bound to palladium [209]. The dimeric phenoxide corngave diarylether at 70 "Cin roughly plex { Pd[F~P(t-Bu)~](o-tolyl)(OCsH,-~-4-OMe)}~ 20 % yield. Addition of P(t-Bu), to this complex led to some phosphine exchange that ultimately provided the diarylether in close to quantitative yield. Thus, the strong electron-donating property of alkylphosphines is dominated by the steric demands, and this steric demand appears to have a large accelerating affect on the rate of reductive elimination.

252

Hartwig

7.8.4 Competing P-Hydrogen Elimination from Amido Complexes The amination chemistry depends on the absence of irreversible P-hydrogen elimination from the amido complexes before reductive elimination of amine. At the early stages of the development of the amination chemistry, it was remarkable that the unknown reductive elimination of arylamines could be faster than the presumed rapid [57,58] P-hydrogen elimination from late metal amides. In fact, directly-observed p-hydrogen elimination from late metal amido complexes was rare, and no examples were observed to occur irreversibly from a simple monomeric amid0 species [69]. At this point, it is clear that C-N bond-forming reductive elimination of amines and ethers can be rapid, and that P-hydrogen elimination can be slow. P-Hydrogen elimination from amido complexes is a process that people assumed was rapid, but that had not been observed directly with monomeric amido complexes until recently. Fryzuk and Piers have studied the related insertion of imines into a dimeric, bridging hydride of Rh' [69]. Their results showed that imine insertion was reversible when the imine was isoquinoline, suggesting that insertion and elimination processes are nearly thermoneutral.

+ (PPh3)3(CO)lrH 23 95 Yo

Recently, Hartwig prepared 16-electron, square planar amido complexes that undergo irreversible p-hydrogen elimination [84]. This observation allowed the beginning of a mechanistic understanding of this process, but also highlighted the unfounded assumption that this P-hydrogen elimination process is typically rapid. Three different monomeric amido complexes with P-hydrogens were prepared from Vaska's complex. One complex contained a primary alkylamide and two contained N-alkylanilines, including the N-benzylanilide shown in Eq. (50). All three complexes underwent high-yielding P-hydrogen elimination processes. The alkylamide and N-methylanilide gave products from imine disproportionation, but the Nbenzylanilide 22 in Eq. (50) produced the stable imine and iridium hydride 23 in nearly quantitative yields. P-hydrogen elimination from 22 required temperatures of 100 "C or above, and elimination from an alkylamide required 70 "C. In contrast, Schwartz and co-workers showed that the analogous alkyl complexes underwent P-hydrogen elimination below room temperature [210,211].

7.8 Mechanism of Aryl Halide Amination and Etheration

253

The mechanism for P-hydrogen elimination from 22, which forms a stable imine product, involved monomeric amido complexes. The intermediate that underwent C-H bond cleavage was a 14-electron, three-coordinate complex that formed by reversible phosphine dissociation (Eq. (5 1)). Importantly, there was no detectable competing P-hydrogen elimination from a 16-electron, four-coordinate complex. The mechanism for P-hydrogen elimination from a 14-electron intermediate parallels those for P-hydrogen elimination from square planar alkyl complexes [212,213]. P-hydrogen elimination from the alkylamido complex and from the N-methylanilide were less well defined, and firm conclusions on the coordination number of the complex that cleaves the P-hydrogen requires further study.

7.8.5 Selectivity: Reductive Elimination versus P-Hydrogen Elimination Two studies have been conducted that outline the effects of ligand steric and electronic properties on the relative rates for reductive elimination of amine and P-hydrogen elimination from amides. One study focused on the amination chemistry catalyzed by P(o-C,H,Me), palladium complexes [ 11I], while the second focused on the chemistry catalyzed by complexes containing chelating ligands [88]. Studies of aryl halide amination using secondary aminostannanes and palladium catalysts bearing P(o-C6H,Me), ligands are summarized in Scheme 8 and revealed four factors that control the amount of aryl halide hydrodehalogenation versus amination that forms. First, complexes with electron-withdrawing groups on the aryl ring gave more amination and less hydrodehalogenation product than those with donating groups. This result is consistent with the faster reductive elimination of amines with electron-poor aromatic groups discussed above. Second, N-alkyl arylamides gave more hydrodehalogenation product, consistent with arylamides undergoing reductive elimination of amines more slowly than the dialkylamides. Third, deuterium labeling experiments showed that the majority of the dehalogenation product after catalyst initiation came from P-hydrogen elimination from the amido group.

254

Hartwig

Reductive elimination

BuaSnNRp

LPd,

rn “R2

Accelerated by: 1. Electron-withdrawing X 2. Larger, more donating R 3. Larger L

\

\

p-Hydrogen elimination

H

a (+irnine)

Scheme 8. Factors controlling selectivity for amination versus hydrodehalogenation of aryl halides.

The final point concerned the steric effects of the phosphine aryl groups on the relative amounts of arene and arylamine products. Careful monitoring of the products formed from both stoichiometric and catalytic reactions employing palladium complexes containing P(o-C,H,Me),, P(o-C6H,Me),Ph, P(o-C,H,Me)Ph,, and PPh, showed steadily decreasing ratios of amine:arene as the size of the ligand was decreased. Since arene formation by hydrodehalogenation occurred predominantly by p-hydrogen elimination, it is clear that larger phosphine ligands enhance the reductive elimination of amines at the expense of P-hydrogen elimination processes. Reductive elimination of amine decreases the metal’s coordination number, while phydrogen elimination from an amide either increases the metal’s coordination number because of formation of a coordinated imine along with the hydride, or maintains the same coordination number if imine is extruded without coordination. Large groups on the phosphine ligand will enhance the rate of the reaction that decreases coordination number, and will, therefore, increase the rate for reductive elimination [214] of amines relative to the rate for 0-hydrogen elimination. This study foreshadowed the ability of even larger t-butylphosphine ligands to drive the amid0 intermediate toward reductive elimination to form the arylamine instead of 0-hydrogen elimination, even when sterically undemanding primary amines are used as substrate [ 133,2 151. Results obtained with chelating ligands that display varied steric properties contrasted those obtained with monodentate ligands [88]. Large, chelating phosphine ligands such as bis- 1,l ’-(di-o-toly1phosphino)ferrocenegave more hydrodehalogenation product than did DPPF. Reactions employing electron-poor DPPF derivatives, which should generate a more electron-poor metal that favors reductive elimination of amine, gave more arene than did those employing electron-rich DPPF derivatives. Further, ligands with large bite angles gave more arene than those with small bite angles, in contrast to previous studies that showed an increase in rate of C -C bond-forming reductive elimination with increasing bite angle [216]. Although the origin of the unusual results with chelating phosphines in

7.8 Mechanism of Aryl Halide Amination and Etheration

255

the amination chemistry are not fully understood at this time, it is clear that chemistry other than reductive elimination of amine and P-hydrogen elimination from an amide is occurring. The arene produced from reactions of amines that are deuterated in the position a to the nitrogen or in the N-H position was primarily protiated when the catalysts contained any of several chelating phosphine ligands. The source of hydrogen is unclear at this time, but much of the arene generated in reactions employing DPPF or BINAP does not form by a simple P-hydrogen elimination and C - H bondforming reductive elimination sequence.

7.8.6 Overall Catalytic Cycle with Specific Intermediates At this time, one can put together the results on reductive elimination and oxidative additions to make a justified prediction about the mechanism for the amination chemistry catalyzed by palladium complexes containing both monodentate and chelating ligands. These catalytic cycles differ in the coordination number of the palladium complexes that lie on the catalytic cycle and the factors that control amination or etheration versus aryl halide reduction. We have shown that the catalytic cycle for the amination of aryl halides catalyzed by P(o-C,H,Me), and related sterically hindered monophosphine-ligated palladium complexes exclusively contains intermediates with a single phosphine ligand. In contrast, the chemistry catalyzed by DPPF- or BINAP-palladium complexes involves bis-phosphine complexes as a result of ligand chelation and reductive elimination without ligand dissociation.

7.8.6.1 Mechanism for Amination Catalyzed by P(o-C,H,Me)3 Palladium complexes Scheme 9 shows an experimentally supported mechanism for amination catalyzed by P(o-C,H,Me), phosphine complexes; a similar mechanism is likely to occur with catalysts containing the sterically hindered monophosphines discussed in Section 7.3.3. The Pdo complex is a 14-electron two-coordinate species that loses one of the phosphine ligands before aryl halide oxidative addition. The aryl halide complexes react with amine to generate amine-ligated aryl halide complexes 18 by either reaction with monomer or associative reaction with dimeric 4. Reactions of these amine complexes with base generate a three-coordinate amido species that undergoes rapid reductive elimination. In the case of reactions catalyzed by complexes containing monodentate ligands, the use of large phosphines accelerates the overall rate by favoring monophosphine complexes, and creates amine product by accelerating reductive elimination relative to P-hydrogen elimination.

256

Hartwig

L2Pd

Reductive R2NAr elimination of amine

3

--

Reduction L2PdBrpor Pd(OAc)2

+:!: ~

Oxidative addition

Scheme 9. Overall mechanism for aryl halide amination catalyzed by P(o-C,H,Me),-ligated palladium complexes.

7.8.6.2 Mechanism for Amination Catalyzed by Palladium Complexes with Chelating Ligands Scheme 10 shows a mechanism for the amination of aryl halides catalyzed by DPPFor BINAP-ligated palladium complexes, and this mechanism is presumably similar for reactions catalyzed by other bisphosphine complexes. As discussed in the section on oxidative addition of aryl halides, the monochelate Pd(0) complex is formed by dissociation of BINAP or DPPF, and these 14-electron intermediates add aryl halide. The monochelate complex containing DPPF as ligand undergoes recoordination of phosphine faster than oxidative addition of aryl halide, while the monochelate complex containing BINAP adds aryl bromide faster than it recoordinates ligand when an excess of aryl bromide is present. The amido complex is generated by either deprotonation of coordinated amine, or by reaction of amine with an intermediate alkoxide complex [51]. When aryl sulfonates are used as substrates a third pathway for amide generation is possible. Although not verified in mechanistic studies, amine could displace the triflate or tosylate ligand to generate a cationic amine complex. The coordinated amine in this species would be readily deprotonated by even weak carbonate base.

7.9 Summary

+P

p-Hydrogen R~ elimination p Blocked M+ by chelation

(

base -MX

R2

-

(phd

'*%

H2NR

11 - P P

I

hd' p/ \NHR

HO-t-Bu

P

257

NHRR" //Ar

\x

==

R2 p\ ,Ar

(

Pd p/ \x

R2

R2

(

jR2 dpdt-BU

A O - t - B u -NaX

Scheme 10. Overall mechanism for aryl halide amination catalyzed by bisphosphine-ligated palladium complexes.

The amido aryl complexes that result undergo reductive elimination directly from the 16-electron four-coordinate complex, rather than from the three-coordinate, 14electron, monophosphine complex generated when catalysts bear sterically hindered monophosphines. For reactions involving chelating phosphines, the selectivity for reductive elimination rather than P-hydrogen elimination results from chelation, which blocks phosphine dissociation and accompanying pathways for P-hydrogen elimination from 14-electron, three-coordinate species. Many mechanistic questions remain poorly understood at this point, but these results provide a general, experimentally supported pathway for reactions catalyzed by complexes with monodentate and chelating phosphines.

7.9 Summary The amination of aryl halides and triflates catalyzed by palladium complexes is suitable for use in complex synthetic problems. Many substrates will produce high yields of mixed arylamines with one of the existing catalyst systems. Nevertheless, there are many combinations of substrates for which the amination chemistry may be substantially improved. For the most part, these reactions involve nitrogen centers, such as those in pyrroles, indoles, amides, imidazoles and other heterocyclic groups that are less basic than those in standard alkylamines. Although mild reaction conditions have been developed for many substrates, the harsh conditions used in many of the applications indicate that continued studies on developing mild condi-

258

Hartwig

tions are warranted. Further, turnover numbers must be improved for the use of this reaction in many industrial applications. Finally, mechanistic information is emerging with some of the second-generation catalysts, but data on the most recent catalysts are sparse. Data on reactions of substrates more complicated than simple amines and aryl halides are not available.

Acknowledgments Parts of my group’s contributions to this work have been supported by NIH (R29GM55382-01-03), and DOE. We also gratefully acknowledge support from a DuPont Young Professor Award, a Union Carbide Innovative Recognition Award, a National Science Foundation Young Investigator Award, a Dreyfus Foundation New Faculty Award and Camille Dreyfus Teacher-Scholar Award for support for this work. The author is a fellow of the Alfred P. Sloan Foundation. We also thank Johnson-Matthey AlphdAesar for donations of palladium chloride. I am deeply indebted to the graduate students, postdoctoral associates, and undergraduates in my laboratory whose names appear in the references and whose experimental and intellectual contributions to this project have been invaluable.

References [I1 [2] [3] [4] [5] [6]

[7] [S] [9] [lo] [Ill [12] [13] [14] [IS] [16] [17] [I81 [19] [20]

C. G. Frost, P. Mendonca, Chem SOC,- -r&in, Trans 1998, 5 5. J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. L. Buchwald, Acc. Chem. Res. 1998, 31, 805. B. H. Yang, S. L. Buchwald, J. Orgnnomet. Chem. 1999, 576, 125. R. A. Glennon, J. Med. Chem. 1987, 30, 1. H. Hugel, D. J. Kennaway, Org. Prep. Pmc. Int. 1995, 27, 1. A. Kitani, M. Kaya, J. Yano, K. Yoshikawa, K. Sasaki, Synthetic Metals 1987, 18, 341. F.-L. Lu, F. Wudl, M. Nowak, A. J. Heeger, J. Am. Chem.SOC. 1986, 108, 8311. A. G. MacDiarmid, J. C. Chiang, A. F. Richter, A. J. Epstein, Synthetic Metals 1987, 18, 285. A. G. MacDiarmid, A. J. Epstein, Faraday Discuss. Chem. SOC.1989, 88, 317. A. G. MacDiarmid, A. J. Epstein, In Science and Applications of Conducting Polymers; W. R. Salaneck, D. T. Clark and E. J. Samuelsen, Ed.; Adam Hilget: New York, 1991. A. Ray, A. F. Richter, D. L. Kershner, A. J. Epstein, Synthetic Metals 1989, 29, E141. D. Vachon, R. 0.Angus, F. L. Lu, M. Nowak, Z. X. Liu, H. Schaffer, F. Wudl, A. J. Heeger, Synthetic Metals 1987, 18, 297. M. Stolka, J. F. Yanus, D. M. Pai, J. Phys. Chem. 1984, 88,4707. E. Ueta, H. Nakano, Y. Shirota, Chem. Lett. 1994, 2397. Y. Kuwabara, H. Ogawa, H. Inada, N. Noma, Y. Shirota, Adv. Mate,: 1994, 6, 677. M. Strukelj, R. H. Jordan, A. Dodabalapur, J. Am. Chem. SOC.1996, 118, 1213. J. March, Advanced Organic Chemistry; 3rd ed.; John Wiley and Sons: New York, 1985. G. W. Gribble, P. D. Lord, J. Skotnicki, S. E. Dietz, J. T. Eaton, J. L. Johnson,,J. Am. Chem. SOC. 1974, 96, 7812. P. Marchini, G. Liso, A. Reho, J. Org. Chem. 1975,40, 3453. C. F. Lane, Synthesis 1975, 135.

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[I221 [I231 [I241 [I251 [I261 [I271 [ 1281 (1291 [ 1301

262 [172] [I731 [174] [1751 [1761 [177] [1781 [179] [I801 [181] [I821 [I831 [184] [185] [186] [I871 [I881 [I891 [190] [I911 [192] [193] [I941 [I951 [I961 [197] [I981 [I991 [200] [201] (2021 [203] [204] 12051 [206] (2071 [208] [209] [210] [211] [212] [213] [214] [215] I2161

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Modern Amination Mefhods Edited by Alfredo Ricci copyright 0 WILEY-VCH Verlag GmbH, 2wO

Index

A Acridine 234 Acylation - with (+)-a-methoxy-a-(trifluoromethyl) phenylacetic acid 78 Acyl dithiane oxide Alkoxide 247 N-Alkylbenzotriazoles 11 Allyl alcohol 3 Allyl toluene-p-sulfonamide 15 Allylamines 1, 222 Allylic alkylation 8 Allylic amination 2 - palladium-catalyzed 9 - of a-methyl styrene 29 - of non functionalized alkenes 29 - under reductive conditions 31 Allylic compounds 2 - allyl halides 6 - allyl acetates 6 Allylic functionalization 2 Amides 221 Amido complexes - of iridium 252 - of Pd(I1) 247 - of rhodium 252 Amination - asymmetric of enol silyl ethers 191, 192 - intermolecular-asymmetric 61 - of enol silyl ethers and glycals 170 - via organoboron compounds 38 Amines - acyclic 12 - cyclic 12 - synthesis of primary amines 41 - synthesis of secondary amines 46 a-Amino acids 72, 100, 106, 114 - from DTBAD 74 - from lithium rert-butyl N -[@-toluensulfonyl)oxy] carbamate 68 - from nitridomolybdenum complexes 171 - unnatural 73

(2R,3R)-2-hydroxy-m-chloro-p-hydroxyphenylalanine 85 P-Amino acids 108 - N-galactosyl 109 Aminobiphenyls 232 Aminoferrocene 239 a-Amino /3-hydroxy acids 80 0-Aminoesters 86 Aminohy droxylation - of styrene 172 - using chlorarnine-T 176 a-Amino ketoesters 71 a-Aminoketones 70 R-Aminonitriles 107 a-Amino phosphonic acid - from diazaphospholidines 94 - from di-rert-butylazodicarboxylate 91 - from lithium terf-butyl N -[(p-toluensulfonyl)oxy]carbamate 68 - from oxazaphospholanes 93 - from trisyl azide 91 Amino pyridines 209 Aminotetralins - 8-aminotetralin 90, 91 - C, symmetric 2,3-diamminotetralin 89 Arninotetralone 89 D-Arabinosylamine 115, 116, 119 - tri-0-pivaloyl-a-protected 107 Aryl chlorides 213, 215, 216, 217 Arylglycines 99 N-Arylpiperazines 228 Aryl tosylates 214 Aryl triflates 208 1-Azaadamantane 51 Azacrown ethers 239 Azides 9, 133 Aziridination - asymmetric 192 - asymmetric aziridination of olefins with [N-(p-toluenesulfonyl)imino]phenyliodinane 179, 181 - asymmetric aziridination of styrene 183 -

264

Index

- chemoselective of 1-phenyl-1,5-hexadiene 188

-

copper-catalyzed 174 bromine-catalyzed 176 iodine-catalyzed 176 of carbon-carbon double bond 170 - of cis-~-methylstyrene 186 - of cyclic conjugated dienes 189 - of isoprene and truns-1,3-hexadiene 189 - of styrene 179 - of trans-p-methylstyrene 185 - stereospecificity in 186 - using bromamine-T 175 - using carboethoxynitrene 174 - using chloramine-T 174 Aziridines 14, 169 - synthesis of alkenyl aziridine 188, 190 - synthesis of N-alkyl aziridines 48 - synthesis of N-aryl aziridines 48 Azo compounds 23 Azobenzene 234 Azodicarboxylates 65, 66, 79 - bomyl azodicarboxylate 96 - dibenzyl azodicarboxylate 71, 89, 90, 91 - di-tert-butyl azodicarboxylate 71, 72, 76, 80, 81, 82, 83, 85, 86, 88, 90, 91, 93, 95

- diisopropyl azodicarboxylate 3 - (+)-dimenthy1 diazenedicarboxylate 24 - isobomyl azodicarboxylate 96, 97 - menthyl azodicarboxylate 96 Azoles 219.223

B Benzophenone imine 219,222, 236, 240 Benzotriazoles 225 N-Benzoylbenzimidates 5 Benzyne 196 Bis-1,l '-(di-o-toly1phosphino)ferrocene 254 Bis-silyl ketene acetals 109 Bis(trimethylsily1)amides 13 Bond, metal-nitrogen multiple 129 I-Boraadamantane 51 Boranes 67 - a-chiral organodichloro 49 - organodichloro 47 - (w-halogenoalky1)dichloro 49 N-Bromosuccinimide 96 tea-Butyloxycarbonyl group 236 - removal of 75

C CAN 12 Carbamates 222 - tert-butylcarbamate 219 - deprotection of 78 Carbazoles 224 Carbonates 13

Cesium carbonate 205, 208, 222, 227, 245 Catalysis - enantioselective 21 Catecholborane 52 - catalyzed addition to alkenes 53 Chelation 83, 89, 100 Chiral auxiliaries - amino alcohols 92 - carbohydrate-derived 103, 110, 127 - C,-symmetric diamines 94 Chiral catalysts 99 Chiral heterocycles 118 Chiral enamines - reaction with ethyl N-[p-nitrobenzenesulfonyl)oxy] carbamate 69 Chiral nitrido complexes - preparation with ammonia and aqueous sodium hypochlorite 177 - preparation with gaseous ammonia and chloramine-T 178 - preparation with NBS and liquid ammonia 177 Chloramine-T trihydrate 15 N-Chloroalkylamines 50

N-Chloro-N-sodiocarbamate43 Cobalt 8 Copper 225 - bisoxazoline-copper (I) catalysts 21 - complexes 14 - cyanide 68 Cuprates - arylcopper 67 - a-cuprophosphonates 67 - dialkylcuprates 67 Cycloaddition reactions 118

D Decahydroquinolines 123, 124, 125 Deprotonation - double with LDA 86 - kinetically controlled 74 - thermodynamic 74 DialkyI-N-(tert-butoxycarbony1)phosphoramide 9

Diallylamine 222 Diazaphospholidines 94 Dieis-Alder reactions - aza-Diels-Alder reactions 119 - hetero-Diels-Alder reactions 30 Diethylzinc 83 Diphenyldiazomethane 52 DNA 232 [(DPPF),PdCl,, 208

E Electrophilic amination 2, 65 - a-face differentiation of 75 - of a-alkyl phosphonamides 69

index - of aza enolates 86, 91 - of chiral ester enolates 80, 82, 83 - of chiral imide enolates 76, 79, 80 - of ester enolates 96 - of P-hydroxy ester enolates 80 - of ketone enolates 88 - of oxazaphospholanes 92 - of oxazolidinones 98, 99 - of phosphorus-stabilized anions 91 - of silyl ketene acetals 72, 73 - with azodicarboxylates 66, 71, 72, 74, 76, 80, 81, 82, 87 - with chiral azodicarboxylates 96, 97 - with chiral azodicarboxamides 98 - with chloro nitroso alkanes 66 - with sulphonyloxycarbamates 66 - with trisylazide 87, 91 Enantioselective hydroboration - with diisocamphenylborane 44 Ene reactions 17, 20 - aza-ene reaction 24 - with nitrosobenzene 25 Enol ethers - reaction with ethyl N-[p-nitrobenzenesulfonyl)oxy] carbamate 69 Enzymatic resolution 86 Epimerisation 79 Epoxidation - asymmetric epoxidation 181 (8-Ethyl-P-hydroxybutanoate 82 Exo anomeric effect 104 Exponential growth 236

F Ferrocenyl oxazoline chiral catalyst 5 Fluoroanilines 211 Fluorenones 240 G Gabriel synthesis 6 a- and 8-Galactoserine 80 /I-D-Galactosylamine 115, 116, 123, 124 -tetra-0-pivaloyl- protected 106 N-Galactosyl imines 118 Glycosylamines 231, 103, 114 Glycosyl imines 105, 109, 115 Glycosyl isonitriles 117, 118 N-Glycosylpyridones 126 H Heteroatomic halides 209 Hole transport 233 Homoallylamines 109, 111 - D-arabinosyl 113 - D-glucosyl 113 - “hetero” homoallylamines 18 - (R)-homoallylamines 110

265

Hy drazides diastereochemically pure 77 Hydrazines 134, 219 a-Hydrazino acids 72, 73 Hydrazoic acid 43 Hydroboration - rhodium-catalyzed 55 Hydroboration-amination 38 - with chloramine-T 43 - with mono chloroalkylamines 57 - with [N-@-toluenesulfonyl)imino] phenyliodinane 43 Hydrodehalogenation 253, 254 Hydrogenation 198 - of P-ketoesters 84 P-Hydrogen elimination 252, 253 Hydrogenolysis - of the N-N bond 75, 78, 79 P-Hydroxy esters 80 Hydroxylamines 25, 65 - N,O-bis(trimethylsilyl) 66 - N-chloro-O-2,4-dinitrophenyl 50 - N.0-diprotected 66 - 0-sulphonic acid 45 Hydrozirconation-amination 38 Hyperbranched materials 238 -

I Imides - N,N-bis-[N-@-tolylsulfonyl) benzenesulfonimidoyl] selenium diimide 20 Imines 219 Iminocarbonate 3, 7, 9 Indoles 224 Indolizidine alkaloids 122 Intramolecular amination 203 Iridium 252 Isoxazole - 3-substituted 5-(-pyrrolidinyl) 48

L Lactams 219, 221 Lanthanide complex - for the catalyzed cyclization of aminoalkenes 60 Ligands - BINAP 84, 204, 206, 208, 211,222, 223, 230, 231, 235, 236, 238, 239, 241, 244, 255, 256 - BISBI 207 - D‘BPF 213, 214 - DPEphos 207,221 - D p p 225 - DPPF 203, 204, 206, 208, 211, 222, 223, 234, 237,239,241, 244, 246,247,249, 250,255, 256 - DPPP 209, 239 - in metal nitride complexes 134 - 139 - Kumada ligand

266

Index

MAP, 215,240 MOP 215, 221 NOBIN 240 P(t-Bu), 212,217,222,227,228,234,236,237, 243,251 - P(o-C,H,Me), 202, 204, 208, 209, 211, 221, 245,253, 255 - P(furyl), 221 - P(2-f~ryl), 203 - P(o-tOlyl), 222, 223, 228, 234, 238, 241, 243 - PHANEPHOS 207 - PPh, 245, 248 - Tol-BINAP 208 - Xantphos 221 Lithium tea-butyl-N-tosyloxycarbamate43 -

M Manganese - complexes 14 - meso-tetra-2,6-dichlorophenylporphyrin manganese perchlorate 15 Mannich reaction 108, 120 Mannich-Michael tandem addition 119, 126 Metal nitride - general preparation 130 N-Methyl aniline 12 (S)-Methyl-3-@enzoylamino)butanoate 86 Methylzinc bromide 85 Michael addition 120, 124 Millons base 131, 150 Mitsonobu reaction 3 Molecular modeling 94 Molibdenum 8 - molybdooxaziridine 27 Multicomponent reactions 114

N Natural products 169 - D-allothreonine 82 - (9-anabasine hydrochloride 120 - a-carboline 228 - (R)-coniine hydrochloride 120 - damirones A andB 230 - (-)-dihydro-pinidine 122 - gephyrotoxin 167B 122, 123 - hydroxyitraconazole 228 - frans-3 -hydroxy-D-proline - lavendamycin 200 - makaluvamine C 230 - norastemizole 230 - pumiliotoxin 123, 125 - raloxifene 228 - D-ribo-CIS-phytosphingosine81 - septacidin 231 - spicamych 231 - (-)-swainsonine 85 - (R)-N-(trkhloroacetyI)norleucinol 6

-

vancomycin 85 N-H activation 198 Nickel 8 Nitrene 14, 15, 67 - (ethoxycarbony1)nitrene 69 Nitrides 129, 130 - from reagents 133 - from N" reagents 132 - from N2-reagents 132 - from N3-reagents 131 Nitridomanganese complexes 152, 153 - chiral 190 Nitriles 133 Nitrogen heterocycles 85 Nitrogen fixation 133, 226 Nitrogen monoxide 133 Nitrogen transfer 153 - using achiral nitrido complexes 170 Nitrones 25 Nitroso compounds 24 Nitroxides 25 Nonaflate 208, 237 Normal-electron demand reactions 17 Nosyloxy group 19

0 08-metal process 28 On-metal process 29 a-Olefin polymerization 240 Oligomers 233, 236 Oxaziridines 66 Oxazolidines - N-acyloxazolidinones 76 - removal of 78, 79 Oxidative addition 241 Oxygen atom transfer reactions - stereoselective 169

P Palladium (BINAP),Pd 244 - palladium (II) chloride 6 - n-ally1 complex 8 Passerini reaction 118 Peptidomimetics 23 1 (3.9-N-9 -(Phenylfluoren-9-yl)-3-aminoaspartate 86 Phenyl azide 52 Phosphate 226 Phosphines - aminated 16 Phosphinoamine 207 Phosphinoether 207 Phosphonates - a-cupro 68 Phthalimide 3 , 9 Piperidine derivatives 118

-

Index - chiral 125 Piperidinones - chiral 121, 122 - 2.6-disubstituted 121, 122, 124 4-Pyridones 125 - N-glycosyl 125 Polyanilines 195,233 Poly(m-aniline) 235, 236 Poly@-aniline) 236 Potassium phosphate 227, 245 Pseudo-enantiomeric pairs 105 Pyrroles 224

R Rearrangements - aza-Cope 112, 113 - metal-catalyzed 14 - Overman 4 - [3,3]-sigmatropic 4, 20 - enantioselective 4 - stereoselective 11 1 Reductive amination 196 Reductive elimination 197,247, 253 Rhodium 252, 8 Ruthenium catalysts 8, 84,234 - BINAPcomplex 84 - bis(tosyl)amidoruthenium(III) 15

S Salen 153 Samarium complex - for the catalyzed amination of alkenes 59 Sodium phenoxide 222 Solid-phase amination 211 Stereoselective synthesis 103 Strecker synthesis - stereoselective 106 Sulfides 250 Sulfimines 16 Sulfonamides 221, 231, 9 Sulfonyl azides 65 Sulfonyloxycarbamates - allyl N-[(mesitylsulfonyl)oxy] carbamate 67 - allyl N-[@-toluensulfonyl)oxy] carbamate 67

267

- ethyl N-[p-nitrobenzenesulfonyl)oxy] carbamate 69 - tert-butyl N-[(mesitylsulfonyl)oxy] carbamate 67 - tert-butyl N-[@-toluensulfonyl)oxy] carbamate 67 Sulfoximines 219, 223

T Tetrahydropyrroloquinolines 229 1,1,3,3-Tetramethyldisilazide 13 Three-membered heterocycles 169 Tin amides 199 [N-@-Toluenesulfonyl)imino] phenyliodinane 16 TPD 196 Transition metal nitride complexes - chromium nitrides 143, 144, 145 - Iigand exchange reactions 146, I54 - manganese nitrides 152 - molibdenum nitrides 146, 149 - osmium nitrides 161, 162 - rhenium nitrides 157 - ruthenium nitrides 159 - tantalum nitrides 142 - technicium nitrides 155 - tungsten nitrides 150, 151 - vanadium nitrides 140 Trichloramine 134 Triflates 240 Trimethylsilyl azide 43 Tungsten 8

U Ugi reaction 114, 116, 118 Ullmann substitution 196 Urea 132

V Vinyl epoxides 11 Vinylpiperidines 11 Vinylpyrrolidines 11 W Wacker process 198