Modern Amination Methods

Modern Amination Methods Edited by Alfred0 Ricci Related Titles from WILEY-VCH: E Diederich / P. J. Stand (eds.) Met...

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Modern Amination Methods Edited by Alfred0 Ricci

Related Titles from WILEY-VCH:

E Diederich / P. J. Stand (eds.) Metal-catalyzed Cross-coupling Reactions 1997, XXII. 518 pages with approx. 1000 figures and 20 tables Hardcover. ISBN 3-527-29421-X

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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.

Libary of Congress Card No: applied for British Libary Cataloguing-in-PublicationData: A catalogue record for this book is available from the British Library Die Deutsche Bibliothek - CIP Cataloguing-in-Publication-Data A catalogue record for this publication is available from DIe Deutsche Bibliothek 0 WILEY-VCH Verlag GmbH, D-69469 Weinheim (Federal Republic of Germany), 2000

ISBN 3-527-29976-9 Printed on acid-free and chlorine-free paper. All rights reserved (including those of translation in other languages). No part of this book may be reproduced in any form - nor transmitted or translated into machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Composition: Mitterweger & Partner GrnbH, D-68723 Plankstadt Printing: S t r a w Offsetdruck GrnbH, D-69509 Morlenbach Bookbinding: Osswald & Co., D-67433 Neustadt (WeinstraBe) Printed in the Federal Republic of Germany.

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 1.3 Summary 32 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

5.1 5.2

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

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 6.4.2 The Asymmetric Aziridination of Styrene with a Variety of Nitrido Complexes 183 6.4.3 Asymmetric Aziridination of Styrene Derivatives 185 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 55 2) -CAN 91Yo

&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

<

‘C02Et

<

<

)I”

PhNFi

0

82

81

0

k N MeNFi

‘C02CH2CC13

23

0

83

84

Two examples using azo compounds in allylic amination reactions will be presented in the following. Leblanc et al. have used the more reactive trichloro derivative 82 of DEAD, 81, and found that the ene reaction proceeds at various temperatures and without any Lewis acid catalyst present, for both cyclic and acyclic alkenes to give allyl amines in good yields. The reaction of the alkene 85 with 82 gave the allylic aminated compound 86 in 85 % yield (truns:cis= 85:15) (Eq. (21)) [53fl. The allyl amine 87 was formed in good yield after treatment with a suspension of zinc powder in acetic acid solution.

-

CC13CH202C, N

+

OAC

N\

C02CH2CC13

85

-

82

V

O

A

c

85 % CC13CH202CN‘NHCO~CH~CCI~ 86 trans:cis = 85:15

1 ) Zn,HOAc 2)Ac2O 89 Yo

VoA (21)

* NHAc

a7

The allylic amination reaction using aza compounds can also be promoted by Lewis acids. The reaction of between different alkenes and DEAD 81 can be catalyzed by a stoichiometic amount of SnCl,, giving yields and selectivities of the allyl-aminated products which are comparable to those of the thermal reactions [53g]. The reaction of 1-pentene 88 with DEAD 81 outlined in Eq. (22) gives the ene adduct 89 in 87 % yield (truns:cis = 11 :1). In order to preserve the alkene functionality, the nitrogen-nitrogen bond was cleavage by lithium in liquid ammonia, giving allyl amine 90 in good yield.

24

JQrgensen

88

89 trans:cis = 11:I

81

Li, liq. NHs

*

(22)

F

NHC02Et

86 % 90

Heathcook et al. have performed a diastereoselective aza-ene reaction using chiral di-(+)-menthy1 diazenedicarboxylate 91 as the nitrogen source [54]. Compound 91 was found to react with various alkenes in the presence of 2 equiv. SnCl,, and the corresponding allylic aminated product was obtained in good yield and with de up to 42 %. The problem with this approach was the removal of the chiral menthyl ester auxiliary, which was found to be rather difficult.

The most reactive electrophiles for the ene reactions are probably the nitroso compounds, as even nonactivated aliphatic nitroso compounds have been reported to undergo the ene reaction at room temperature [55]. Some nitroso compounds which have been applied in ene reactions are depicted in 92-97 [52b,56]. One of the most reactive electrophiles 97 is normally made in situ because of the extremely high reactivity, but the other nitroso compounds are reasonably stable.

1.2 Nucleophilic Amination of Functionalized Alkenes

92

93

94

95

96

25

97

The reaction of nitroso compounds with alkenes can give a variety of products, depending on the nature of the alkene. If the alkene is a diene, a Diels -Alder reaction between the nitroso compound and diene is normally observed [56,57]. A competing reaction to the Diels- Alder reaction for nitroso compounds is the ene reaction. However, the products obtained by the two routes are very different. The Diels-Alder products are quite stable, whereas many ene products tend to undergo further in situ transformations. Among them are oxidations, decompositions, disproportionations, while other reactions of the intermediate hydroxylamine can give nitroxides, nitrones, hydroxylamines, azoxy compounds, and amines. All types of products can be observed in a typical ene reaction with, e.g., nitrosobenzene. The exact mechanism for the different transformations is unknown, but many of them might involve radical reactions [56fJ .The various transformations that a hydroxylamine may undergo, might explain some of the problems encountered in this type of chemistry. It is worth noting that ene products derived from nitroso compounds with electronwithdrawing substituents on the a-carbon are relatively stable. The main reason for this is that they most likely are not oxidized as easily to nitroxides, as the ene products from nitrosobenzene [56e-g, 581. Schenk et al. have used the a-chloro nitroso compound 93 for the reaction with cyclopentene 98 in order to solve the problem with the instability of the ally1 amine product formed from the reaction with nitroso compounds [56c]. The product formed, 99, rearranges to the stable nitrone hydrochloride salt 100, which is easily hydrolyzed to the hydroxylamine 101 (Eq. (23)).

26

J#rgensen

93

98

99

100

101

The same principle was also been used by Kresse et al. for the diastereoselective ene reaction of sugar derivatives with various alkenes [56b,d]. The application of the two optically active nitroso sugar compounds 102 and 103 for the reaction with cyclopentene gave, after removal of the sugar moiety, the optically active hydoxylamines in good yield, and with high ee. The ene reactions with other alkenes were in general high-yielding, and as an alternative to the hydrolytic work-up, in situ reduction was also carried out and stable ally1 amines were isolated.

102

103

Keck et al. have used a very reactive nitroso compounds with a carbonyl groups attached to the nitrogen atom (97) such as the nitroso carbonylmethane equivalent 105 for the allylic amination alkenes [59]. The use of 105 (97)has several advantages, and the problems with regard to decomposition of the products are partly overcome. The products are quite stable, and at the same time these substituents increase the reactivity of the aminating reagent. The reaction of 1-methyl-cyclohexene 104 with 105 gives the allylic aminated product 106 in 92 % yield (Eq. (24)).

1.2 Nucleophilic Amination of Functionalized Alkenes

27

(24) anthracene 92 % 105

104

106

1.2.6 Allylic Amination with Ar-NX and a Metal Catalyst Sharpless et al. and Muccigrosso et al. were probably the first to perForm the direct allylic amination of nonfunctionalized alkenes in the presence of a metal complex [60]. The complex used for the allylic amination was the molibdooscaziridine 109 prepared by reaction of the molybdenum dioxo complex 107 and phenyl hydroxylamine 108 (Eq. (25)).

-

(25)

+ PhNHOH -H20 0

94 %

HMPA

107

108

0

HMPA 109

Sharpless et al. found that heating a solution of 109 with 2-methyl-2-hexene 110 afforded an allylic amination reaction leading to the formation of 111 in 57 % yield together with high yields of the parent molybdenum dioxo complex 107 (Eq. (26)).

109

110

111

28

J#rgensen

By the application of the molybdenum dioxo complex 107 as a catalyst (10 mol %), Nicholas et al. later developed the allylic amination reaction (Eq. (26)) into a catalytic reaction using phenyl hydroxylamine 108 as the nitrogen fragment donor [61]. Reaction of different alkenes with 108 in the presence of 107 as the catalyst leads to the formation of the corresponding allyl amines in low to moderate yield (4-52 %), together with various phenyl hydroxylamine-derived by products. Mechanistic investigations of the allylic amination reaction catalyzed by 107 using 108 as a nitrogen donor were performed using kinetics, trapping experiments, and model reactions, and these led to the proposal that the reaction is an of-metal process, which means that the metal is not involved in the amination step [62]. It was suggested that the molybdenum catalyst serves as a molybdenum(VI)/molybdenum(IV)redox shuttle, and the mechanism is outlined in Scheme 8. The first step is proposed to be an oxidation of the hydroxylamine to the corresponding nitroso compound with a concomitant reduction of the metal complex. The next step is an ene reaction leading to the hydroxylamine, which is reduced to the allyl amine giving the metal complex in an oxidized state. The function of the metal is then solely to be a redox catalyst, and the nitroso compound is liberated from the molibdooxaziridine 109 before it undergoes an ene reaction [63].

VIo ,

H //"vN-ph

IV hMo

1

ene reaction

reduction

Scheme 8

A variety of different metal complexes have been screened as catalysts for allylic amination using phenyl hydroxylamine 108 as the nitrogen fragment donor, and it was found that iron-complexeshave better redox capacity compared to molybdenum [ a ] . With the iron compounds, higher yields and a lower amount of hydroxylaminederived byproducts are obtained. These byproducts constitute one of the problems in this type of allylic amination reactions in general, as their formation is difficult to suppress. The allylic amination reaction of a-methyl styrene 112 with 108 can, e.g., be catalyzed by the molybdenum dioxo complex 107, iron phthalocyanine 114, or by the combination of the iron chlorides 115 [64,65]. It appears from the results in

1.2 Nucleophilic Amination of Functionalized Alkenes

29

Scheme 9 that both the molybdenum and iron complexes can catalyze the allylic amination of nonfunctionalized alkenes with an ene-like transposition of the double bond, but also that the yield of the allyl amine formed, 113, is moderate to high. It is generally found that higher substituted alkenes tend to give the best yields, and unsymmetrical alkenes (trisubstituted) react with virtually complete regioselectivity, as only one isomer is detected. The byproducts are primarily azoxybenzene and aniline, which arise from condensation of nitrosobenzene with phenyl hydroxylamine and reduction of phenyl hydroxylamine, respectively.

php +

PhNHOH

112

c

Cat 10 mol Yo

108

,YPh 113

0

6

FeCI2+ FeC13 (9:l)

HMPA

107 42 Yoyield

114 76 O h yield

115 41 %yield

Scheme 9

The mechanism of the iron phthalocyanine 114-catalyzed reaction is probably similar to that outlined previously in Scheme 8 [66]. Every single step of the cycle in Scheme 8 has been shown to be feasible, and in particular the oxidation and reduction of the hydroxylamines. It was proposed that the allylic amination catalyzed by 114 is an ofS-metal process, but an on-metal transfer was not excluded. Nicholas et al. have found evidence for an on-metal nitrogen fragment transfer in the iron(I1) and iron(II1) chloride-catalyzed reactions, i.e., that the nitroso moiety and/or alkene is coordinated to the metal during the ene reaction [64b-d,65]. They were able to isolate and characterize by X-ray analysis the catalytic intermediate, 116 (Scheme lo), which provides a good argument for an on-metal reaction [64c, 651. The structure of 116 is the first example of a metal complex having an azodioxide ligand, but even more importantly, 116is an amination catalyst (Scheme 10). Complex 116 can aminate 2-methyl-2-pentene 117, leading to the allyl amine 118 in 83 % yield. Furthermore, 116 can catalyze the reaction of phenyl hydroxylamine 108 with 117, giving 118. Evidence for an on-metal transfer comes from several experi-

30

J@gensen

ments, such as a competition experiment between the allylic amination of 117 and 2,3-dimethyl- 1,3-butadiene 119 and the hetero-Diels-Alder reaction of 119 using 116. In these experiments no hetero-Diels- Alder product was observed, but instead 118 and 120, in a ratio of 3:7. It should be noted that reaction of nitrosobenzene with 119 gives the hetero-Diels-Alder product. Finally, treatment of the 116 with p methyl nitrosobenzene 121 liberates nitrosobenzene 94.

PhNHOH 108

/

'18

I

117 117

/

pMeC&l4NO 121

Ph 116

x\r 119

PhNO 94

1 20

Scheme 10

118

1.2 Nucleophilic Amination of Functionalized Alkenes

31

Further evidence for the involvement of 116 in the amination reaction comes from the isolation of the related alkene complex 122 which by heating in dioxane solution gives allyl amine 117 (Eq. (28)). The latter results for the iron chlorides indicate an on-metal process with the ene reaction taking place in the sphere of the iron center, with both the nitroso and alkene compound coordinated to the sphere of the metal [64c,d].

Ph

\

-lo

00

' NPh /

-NPh

0

2 FeCI4

Ph 122

117

Postulated structure (IR, NMR and UV-vis)

Ally1 amines can also be formed in an oxidative environment. Nicholas et al. have shown that instead of phenyl hydroxylamine as the nitrogen donor, it is possible using t-BuOOH as the terminal oxidant and the molybdenum catalyst described above [65]. The procedure is analogues to the in situ hetero-Diels- Alder reaction of nitroso compounds developed earlier by others [MI. Cenini et al. have shown that the allylic amination reaction can be camed out under reductive conditions with aromatic nitro compounds 123 as nitrogen fragment donor. A ruthenium complex derived from 125 and Ru3(CO),, is used as the catalyst and carbon monoxide as the reductant (Eq. (28)) [68]. At 40 bar pressure of CO at 160 "C, the allyl amine 124, derived from the cyclohexene 58 was detected in up to 82 % yield [68]. The byproduct from the reaction is aniline. The reaction has been studied in detail from a mechanistic point of view, in an attempt to obtain insight into the mechanism and to optimize the reaction conditions [68b]. It was found that aromatic nitro compounds with electron-withdrawing substituents gave the highest yield of the allyl amine 124. The reaction can also be performed for other alkenes and up 57 % selectivity for cyclooctene was found for a nitro arene conversion of 8 1 %. On the basis of kinetic experiments, several mechanistic aspects of the reaction were discussed, and it was postulated that a coupling between a co-ordinated nitroso arene and a coordinated alkene is probably responsible for the carbon-nitrogen bond formation.

32

J@rgensen

0' 58

2 mol % R u ~ ( C O ) , ~ 6 mot YO125 ArN02

26 - 82 "/a

123

124

125 (R = H, CH3, OCH3, Cl)

The use of nitro arenes as the nitrogen fragment donor in combination with CO under catalytic, and reductive, conditions has also been presented by Nicholas et al. who have found that [CpFe(CO)2]2can be used as the catalyst [69]. A variety of different alkenes were tested, and a-methyl styrene gave the highest yield of the allyl amine 113 when nitrobenzene was used. The yield of the allyl amine depends markedly on the structure of both the alkene and the nitro compounds.

1.3 Summary The chapter has tried to cover modem aspects of allylic amination reactions. Allylic amination reactions starting from compounds having an allylic C -X (heteroatom, halide) functionality have been highly developed to also include enantioselective reactions leading to allyl amines with high enantiomeric excess. The approach for formation of allyl amines using alkenes having allylic C-H bonds as the substrate is a relatively new field, and the majority of the work done in this field has been devoted to the development of the reactions. An important future aspect for the latter type of reactions is the development of reactions for alkenes which reacts with nitrogen-fragment donors in the presence of, e.g., chiral catalyst leading to optically active allyl amines.

References

33

Acknowledgments The author wishes to thank The Danish National Research Foundation for financial support.

References [ l ] For reviews including allylic amination reactions, see e.g.: a) B. M. Trost, Angew. Chem. 1989,101, 1199; b) T. E. Miiller, M. Beller Chem. Rev. 1998,98,675; c) M. Johannsen, K. A. J~rgensen,Chem. Rev. 1998, 98, 1689. [2] R. B. Cheikh, R. Chaabouni, A. Lament, P. Mison, A. Nafti, Synthesis 1983, 685. [3] 0. Mitsunobu, Synthesis 1981, 1. [4] S. E. Sen, S. L. Roach, Synthesis 1995, 756. [5] H. Loibner, E. Zbiral, Helv. Chim. Acta 1976, 59, 2100. [6] For an example of partial rearrangement see e.g.: J. Mulzer, G. Funk, Synthesis 1995, 101. [7] a) L. E. Overman, J. Am. Chem. SOC.1976,98,2901;b) L. A. Clizbe, L. E. Overman, Org.Synth. 1978, 58, 4. [8] M. Calter, T. K. Hollis, L. E. Overman, J. Ziller, G. G. Zipp, J. Org. Chem. 1997, 62, 1449. [9] L. E. Overman, G. G. Zipp, J. Org. Chem. 1997, 62, 2288. [lo] a) Y. Donde, L. E. Overman, J. Am. Chem. SOC. 1999, 121, 2933; b) F. Cohen, L. E. Overman, Tetrahedron: Asymmetry 1998, 9, 3213. [ 111 See e.g.: a) Y.Jiand, J. M. Longmire, X. Zhang, Tetrahedron Lett. 1999.40, 1449; b) Y. Uozumi, K. Kato, T. Hayashi, Tetrahedron: Asymmetry 1998, 9, 1065. [12] P. Metz, C. Mues, A. Schoop, Tetrahedron 1992, 48, 1071. [ 131 See e. g. a) H. Imogdi, Y. Petit, M. Larchevbque, Tetrahedron Lett. 1996,37,2573; b) A. M. Doherty, B. E. Kornberg, M. D. Reily, J. Org.Chem. 1993,58,795;c) M. Mehmandoust, Y. Petit, M. Larchevbque, Tetrahedron Lett. 1992, 33, 4313; d) T. Eguchi, T. Koudate, K. Kakinuma, Tetrahedron 1993, 49, 4527; e) N. Chida, J. Takeoka, N. Tsutsumi, S. Ogawa J. Chem. SOC.,Chem. Commun. 1995, 793; f) M. Isobe, Y. Fukuda, T. Nishikawa, P. Chabert, T. Kawai, T. Goto, Tetrahedron Lett. 1990,31, 3327; g) M. M. Campbell, A. J. Floyd, T. Lewis, M. F. Mahon, R. J. Ogilvie, Tetrahedron Lett. 1989, 30, 1993; h) S. Danishefsky, J. Y. Lee, J. Am. Chem. SOC.1989, 111,4829. [14] M. S. Gibson, R. W. Bradshaw, Angew. Chem. 1968, 80,986. [ 151 a) J. 0. Osby, M. G. Martin, B. Ganem, Tetrahedron Lett. 1984.25.2093; b) T. Sasaki, K. Mnamoto, H. Itoh, J. Org. Chem. 1978,43, 2320. [ 161 a) A. Koziara, A. Zwierzak, Tetrahedron 1976.32, 1649; b) A. Zwierzak Synthesis 1982,920; c) A. Zwierzak, S. Pilichowska, Synthesis 1982, 922. [ 171 R. A. T. M. van Benthem, J. J. Michels, H. Hiemstra, W. N. Speckamp, Synlett 1994, 368. [I81 M. Morikawa, J. Takahashi, J. Tsuji, Tetrahedron Lett. 1965, 6, 4387. [19] See e.g.: a) S. A. Godleski In Comprehensive Organic Synthesis; 1 ed.; M. F. Semmelhack, Ed.; Pergarnon Press: New York, 1991; Vol. 4; p 585; b) J. P. Collman, L. S. Hegedus, J. R. Norton, R. G. Finke, Principles and Applications of Organotransition Metal Chemistry; 2 ed.; University Science Books: Mill Valley, 1987, c) T. Hayashi In Catalytic Asymmetric Synthesis; I. Ojima, Ed.; VCH Verlagsgesellschaft: Weinheim, 1993; p 325; d) B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996, 96, 395. [20] a) R. 0. Hutchins, J. Wei, S. J. Rao, J. Org. Chem. 1994.59.4007, b) R. Jumnach, J. M. J. Williams, A. C. Williams, Tetrahedroy Lett. 1993, 34, 6619. [21] R. D. Connell, T. Rein, B. Akermark, P. Helquist, J. Org. Chem. 1988, 53, 3845. [22] See e.g.: a) T. Hayashi, A. Yamamoto, Y. Ito, E. Nishioka, H. Miura, K. Yanagi, J. Am. Chem. SOC. 1989,111,6301;b) A. Togni, U. Burckhardt, V. Gramlich, P. S. Pregosin, R. Salzmann, J. Am. Chem. SOC.1996, 118, 1031; c) U. Burckhardt, M. Baumann, G. Trabesinger, V. Gramlich, A. Togni, Organometallics 1997, 16, 5252; d) P. E. Blochl, A. Togni, Organometallics 1996, 15, 4125.

34

J@rgensen

[23] (a) J. Sprinz, M. Kiefer, G. Helmchen, M. Reggelin, G. Huttner, 0. Walter, L. Zsolnai Tetrahedron Lett. 1994,35, 1523; b) H. Steinhagen, M. Reggelin, G. Helmchen, Angew. Chem, In?. Ed. Engl. 1997,36, 2108. [241 K. Selvakumar, M. Valentini, M. Worle, P. S. Pregosin, Organometdlics 1999, 18, 1207. [25] a) B. M. Trost, R. C. Bunt, J. A m Chem. SOC. 1994,116,4089; b) B. M. Trost, R. Radinov, J. Am. Chem. SOC. 1997, 119, 5962. [26] B. M. Trost, R. C. Bunt, Angew. Chem., Znt. Ed. Engl. 1996, 35, 99. [27] S.-g. Li, C. W. Lim, C. E. Song, K. M.Kim, C. H. Jun, J. Org.Chem. 1999, 64, 4445. [28] See e.g.: a) B. M. Trost, D. L. Van Vranken, J. Am. Chem. SOC. 1993, 115, 444;b) M. Mori, S. Kuroda, C.3. Zhang, S. Kato, J. Org. Chem 1997, 62, 3263. [29] A. R. Katritzky, J. Yao, B. Yang, J. Org. Chem. 1999.64, 6066. [30] J. B. Baruah, A. G. Samuelson, Tetrahedron 1991, 47, 9449. [31] a) D. Enders, M. Finkam, Synlett 1993,401; b) D. Enders, B. Jandeleit, S. von Berg, SynZett 1997, 421. [32] G. S. Silverman, S. Strickland, K. M. Nicholas, Organornetallics 1986. 5, 2117. [33] F? A. Evans, J. E. Robinson, J. D. Nielsen, J. Am. Chem SOC.1999, 121, 6761. [34] a) T. Murai, M. Yamamoto, S. Kondo, S. Kato, J. Org.Chem. 1993,58,7440, b) J. Briining, Tetrahedron Lett. 1997, 38, 3187. [35] S. Itsuno, T. Koizumi, C. Okumura, K. Ito, Synthesis 1995, 150. [36] R. M. Borzilleri, S. M. Weinreb, Synthesis 1995, 347. [37] a) D. Mansuy, Pure Appl. Chem. 1990,62,741, b) J. P. Mahy, G. Bedi, Battioni, D. Mansuy, Tetrahedron Lett. 1988, 29, 1927. [38] D. A. Evans, M. M. Fad, M. T. Bilodeau, J. A m Chem. SOC.1994, 116,2742. [39] D. A. Albome, P. S. Aujla, P. C. Taylor, S. Challenger, A. M. Derrick, J. Org.Chem. 1998.63.9569. [40] S.-M. Au, S.-B. Zhang, W.-H. Fung, W.-Y. Yu, C.-M. Che, K,-K. Cheung, Chem Commun. 1998, 2677. [41] a) P. Miiller, C. Baud, Y.Jacquier, M. Moran, I. Nageli, J. Phys. Org. Chem. 1996,9,341; b) 1. Nageli, C. Baud, G. Bernardinelli, Y.Jacquier, M. Moran, P. Miiller, Helv. Chim. Actu 1997, 80, 1087. [42] Y. Kohumura, K.4. Kawasaki, T. Katsuki, Synlen 1997, 1456. I431 a) K. B. Sharpless, T. Hori, J. Org. Chem. 1976,41,176;b) K. B. Sharpless, T. Hori, L. K. Truesdale, C. 0. Dietrich, J. Am. Chem. SOC. 1976,98, 269. [44]E. W. Harlan, R. H.Holm, J. Am. Chem. SOC. 1990, 112, 186. [45] N. Schonberger, G. Kresze, Liebigs Ann. Chem. 1975, 1725. [46] a) G. Kresze;H. Miinsterer, J. Orgy Chem. 1983,48,3561; b) T. J. Katz, S. Shi,J. Org. Chem. 1994, 59, 8297. [47] M. Bruncko, T.-A. V. Khuong, K. B. Sharpless, Angew. Chem., Znt. Ed. Engl. 1996,35, 454. [48] S. P. Singer, K. B. Sharpless, J. Org. Chem 1978, 43, 1448. [49] T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373. [50] a) S. Tsushima, Y.Yamada, T. Onami, K. Oshima, M. 0. Chaney, N. D. Jones, J. K. Swartzendruber Bull. Chem. SOC.Jpn 1989,62, 1167; b) J. K. Whitesell, H. K. Yaser, J. Am. Chem. SOC. 1991,113, 3526. [51] Y. Nishibayashi, T. Chiba, K. Ohe, S. Uemura, J. Chem. SOC., Chem. Commun. 1995, 1243. [52] a) K. Alder, F. Pascher, A. Schmitz, Chem. Ber: 1943,76,27; b) G. T. Knight, B. Pepper, Tetrahedron 1971, 27, 6201. [53] a) W. J. Kinart, J. Chem. Res. 1994,486;b) A. G. Davies, W. J. Kinart,J. Chem. SOC.,Perkin Trans.2 1993,2281; c) R. Huisgen H. Pohl, Chem. Be,: 1960.93.527; d) T. R. Hoye, K. J. Bottorff, A. J. Caruso J. F. Dellaria, J. Org. Chem. 1980,45,4287;e) W. A. Thaler, B. Franzus, J. Org.Chem. 1964, 29, 2226; f) Y. Leblanc, R. Zamboni, M. A. Bernstein, J. Org. Chem. 1991, 56, 1971; g) M. A. Brimble, C. H. Heathcock, J. Org. Chem. 1993, 58,5261. [54] M. A. Brimble, C. H. Heathcock, G. N. Nobin, Tetrahedron: Asymmetry 1996, 7, 2007. [55] W. B. Motherwell, J. S . Roberts, 1. Chem. SOC., Chem. Commun.1972, 329. [56] a) C. A. Seymour, F. D. Greene, J. Org. Chem. 1982,47,5226; b) H. Braun, Felber, G. Krek, A. Ritter, F. P. Schmidtchen, A. Schneider, Tetrahedron 1991, 47, 3313; c) C. Schenk, T. J. de Boer, Tetrahedron 1979, 35, 147; d) G. KreBe, A. Vasella, H. Felber, A. Ritter, B. Ascherl, Red. Trav. Chim. Pays-Bas 1986, 105, 295; e) M. G. Barlow, R. N. Haszeldine, K. W. Murray, J. Chem. SOC., Perkin Trans. I 1980,1960, f) P. Zuman, B. Shah Chem. Rev. 1994,94,1621; g) R. A. Abramovitch, S. R. Challand, Y. Yamada, J. Org.Chem.1975, 40, 1541.

References

35

[57] a) J. Hamer, M. Ahmad In 1,4 Cycloaddirion Reactions; J. Harner, Ed.; Academic Press: New York, 1967; pp 419; b) H. Waldrnann, Synthesis 1994,535. [58] a) G. T. Knight, J. Chem. SOC., Chem. Commun.1970,1016; b) G. E. Keck, R. R. Webb, J. B. Yates, Tetrahedron 1981, 37, 4007. [59] a) G. E. Keck, J. B. Yates, Tetrahedronk r r . 1979,20,4627; b) G. E. Keck, R. R. Webb, J. Am. Chem. SOC. 1981, 103, 3173. [60] a) S. L. Liebeskind, K. B. Sharpless, R. D. Wilson, J. A. Ibers, J. Am. Chem. SOC.1978,100,7061; b) D. A. Muccigrosso, S. E. Jacobsen, P. A. Apgar, F. Mares, J. Am. Chem. SOC. 1978, 100, 7063. [61] S . Srivastava, Y. Ma, R. Pankayatselvan, W. Dinges, K. M. Nicholas, J. Chem. Soc., Chem. Commun. 1992, 853. (621 R. S. Srivastava, K. M. Nicholas, J. Org. Chem. 1994, 59, 5365. [63] E. R. Mgller, K. A. JPrgensen, J. Am. Chem. SOC. 1993, 115, 11814. (643 a) M. Johannsen, K. A. J~rgensen,J. Org. Chem. 1994,59,214; b) R. S. Srivastava, K. M. Nicholas Tetrahedron Left 1994,35,8739; c) R. S . Srivastava, K. M. Nicholas, J. Am. Chem. SOC.1997,119, 3302; d) R. S. Srivastava, M. A. Khan, K. M. Nicholas, J. Am. Chem. SOC.1996, 118,3311; e) S.

Saaby, K. A. J~rgensen,unpublished results. R. S. Srivastava, K. M. Nicholas, J. Chem. SOC., Chem. Commun. 1996, 2335. M. Johannsen, K. A. Jsrgensen, J. 0%.Chem. 1995, 60, 5979. E. R. Moller, K. A. Jergensen, J. 0%.Chem. 1996, 61, 5770. a) S. Cenini, F. Ragaini, S . Tollari, D. Paone, J. Am. Chem. SOC.1996, 118, 11964; b) F. Ragaini, S. Cenini, S. Tollari, G. Tummolillo, R. Bertrami, Orgunometullics 1999, 18, 928. [69] R. S.Srinastava, K. Nicholas, Chem. Commun. 1998, 2705.

[65] [66] 1671 [68]

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

2 Electrophilic Amination Routes from Alkenes Elena Fernandez and John M. Brown

2.1 Introduction Considering the potential importance of amine synthesis, and the ready availability of alkene precursors, there is a surprising lack of literature on their direct or indirect amination. The probable reasons for this are threefold: firstly the ease of synthesis of amines by routes from carbonyl precursors; secondly, the synthetic difficulties associated with the direct amination of alkenes; and thirdly the lack of good general reagents and protocols for the indirect amination of organometallics derived from alkenes. This last area is moving rapidly, however. This article reviews progress and the steps being taken to circumvent or remove these limitations. It will focus mainly on hydroboration of alkenes as the initial route to amination precursors, with some discussion of relevant results derived from hydrozirconation. The discussion will be limited to the formation of a single C-N bond to the unsaturated precursor, and hence will not include the aziridination of alkenes. Cycloaddition reactions also fall outside the mandate of the Chapter. For completeness, the background in nonasymmetric reactions will be discussed as appropriate to provide an appropriate focus for asymmetric synthesis.

2.2 Indirect Stoichiometric Amination Within the past 20 years, hydroboration of alkenes coupled to transformations of the first-formed organoboranes has become one of the central methods of organic synthesis [ 1,2]. A particular reason has been the high regio- and chemoselectivity which may be imparted in the initial hydroboration step, coupled with the stereochemical integrity of the subsequent C-X bond-forming stage. An interesting example is the formation of carbon-nitrogen bonds from organoboranes as a simple and convenient route for the synthesis of amines, long of great interest due to their physiological activity and their potential as organic intermediates.

38

Fernandez and Brown

Herein is described how organoboron and additionally organozirconium compounds have proved to be valuable precursors to a variety of amines via hydroboration-amination, or less frequently hydrozirconation-amination.

2.2.1 Amination via Organoboron Compounds The addition of borane to alkenes was first reported by H. C. Brown et al. [3] in 1956. The anti-Markovnikov insertion of an unsaturated moiety into a B-H bond of the borane (R,BH, RBH, and BH,) proved to be the initial step for introduction of a very wide variety of functional groups. Within the following decade, the same author described the replacement of a boron atom by an amino group, affording a synthetic route from alkenes to amines [4](Scheme 1).

Scheme 1

Organoboranesare modest Lewis acids that react easily with a variety of neutral or negatively charged bases to form thermally stable adducts, because of the formal pvacancy on boron. Hence, the addition to alkenes may be considered to be driven by initial association of the alkene with the vacant p-orbital on boron, followed by a hydride transfer within the ensuing complex. This mechanism has been the subject of computational studies, and provides a working model for the reaction mechanism in accord with the observed selectivities [5].This cannot be the complete picture, since the employment of a borane co-ordinated to an enantiomerically pure base leads to a discernable e.e. in the product [6]. The normal synthetic pathway for hydroboration is reaction with an ambiphilic nucleophile of which the simplest example is hydroperoxide ion. This elicits a 1,2-migrationof an alkyl group from boron to oxygen with concurrent loss of hydroxide ion. The step occurs with essentially complete retention of configuration. In similar vein, ambiphilic species with the structure NH,X may be used in amination, so that the overall reaction is an addition of ammonia to the alkene with the regio- and chemoselectivity driven by the hydroboration step. A majority of reactions of organoboranes can be rationalized in terms of these ionic mechanistic pathways, or closely related protocols (Scheme 2).

2.2 Indirect Stoichiometric Amination

39

Scheme 2

An example is provided by the formation of pure trans-2-methylcyclohexylamine by a simple sequence, as illustrated in Scheme 3.

Scheme 3

The nature of the aminating reagent employed to afford the corresponding amine via an organoborane is important. Initially the nitrogen analogs of hydrogen peroxide were used as aminating reagents, i.e., hydroxylamine and hydrazine (with reference to the efficient and quantitative oxidation process of organoboranes by alkaline hydrogen peroxide), but organoboranes merely formed simple addition compounds with these bases, giving no further reaction [7] (Scheme 4).

Scheme 4

Intramolecular 1,2-migration readily took place when the base used as aminating agent was chloramine [4,8], chloramine generated in situ from sodium hypochlorite and ammonium hydroxide [9], hydroxylamine-O-sulphonicacid [7,10,11], O-mesitylenesulfonylhydroxyl-amine[ 121, azide salts [ 13,141, or other related reagents [15], all which have in common a potentially good leaving group in the borane adduct. The transfer of one of the three alkyl groups would be expected to be fol-

40

Femandez and Brown

lowed by a second similar reaction of the first-formed dialkylborinate derivative, e.g., R,B(NHR) or its hydrolysis product, by reaction with a second mole of the aminating reagent, and indeed this could be observed in practice. No further reaction could be observed after the formation of RB(NHR), due to the low electrophilicityof the organo-bis(amino)borane. These migration reactions are sensitive to both steric and electronic factors so that, at best, only two of the three alkyl groups of the borane can be utilised. This potential synthetic limitation can be overcome by using mixed organoboranes, RR’,B, in which group R derived from the original borane shows a significantly greater migratory aptitude than R’ [7]. It has been demonstrated that the methyl group of organodimethylboranesis particularly resistant to migration from boron to carbon [ 16- 181, which makes Rh4e,B (or R,BMe) a suitable organoboraneintermediate for conversion of the R-component into functional products. Furthermore, the organodimethylboranesare readily available by adding dimethylborane to alkenes [9,19-211, and any small amount of methylamine produced can be easily eliminated under the experimental conditions (Scheme 5). LiMe2BH2 R%

Tb Me3SiCi -B*~

i) H2NOSQH ii) hydrolysis

R/\/NH2

9

MeGiH LiCl

Scheme 5

Finally, to ensure a quantitative yield (> 90 %) of the amine, an excess of aminating reagent is required. Also, a systematic study of the influence of the solvent on the hydroboration - amination reaction has shown that in diethyl ether the reaction is slow, in diglyme the isolation of amines can prove rather difficult, and in tetrahydrofuran - although the aminating reagent hydroxylamine-0-sulfonic acid is insoluble - the reaction is mildly exothermic and results in a clear solution at the end of the reaction which makes the THF the solvent of choice [7].Thus, the in situ amination reaction is a straightforwardand inexpensive method for converting alkenes into the corresponding cyclic, acyclic, chiral, hindered, primary, secondary, or tertiary amines.

2.2 Indirect Stoichiometric Arnination

41

2.2.1.1 Applications to the Synthesis of Primary Amines Dimethylborane has been used to hydroborate alkenes regiospecifically. The resulting dimethylalkylborane reacted with ammonium hydroxide and sodium hypochlorite (generation of NH,C1 in situ) to yield isomerically pure alkylamines [21] (Table 2.1). Table 2.1 Stoichiomemc hydroboration - amination of alkenes Alkene

Product ~

N

Yield (%)a

Regioselectivity (%)

61 H

~ > 99

rNH2 &NH2

a

62

90

56

> 99

61

> 99

Isolated yield based on dimethylalkylborane.

Electrophilic aromatic substitution is also possible from triphenylborane [ 111 (readily accessible by reacting boron trifluoride with phenylmagnesium bromide in anhydrous ether) [22] (Scheme 6).

BF3.0Et2

+

3PhMgBr

-

i) H2NOS03H ii) hydrolysis Ph3B Ph2BOH

Scheme 6

42

Femndez and Brown

The mild reaction conditions make the amination via organoboranes a suitable method for preparing functionally substituted amines. Thus, 3-(p-tolylthio)-2methyl-1-propene is readily converted into the corresponding amine in a one-pot synthesis [9] (Scheme 7). i)BH3 ii) NH40H I NaOCl

iii) Hydrolysis

Scheme 7

Interestingly, hydroboration- amination as an isotope incorporation methodology has led to the synthesis of isomerically pure I3N- and "N-labeled primary amines from labeled ammonia [23-251 (Scheme 8). These labeled amines are valuable intermediates in pharmacology.

Scheme 8

N-trimethylsilyl protected olefinic amines and terminal diolefins have been successfully hydroborated with dimethylborane. The resulting organoborane was treated with in situ-generated chloramine or chloralkylamine to produce isomerically pure diamines or N-substituted unsymmetrical diamines in good yields [26] (Scheme 9).

2.2 Indirect Stoichiometric Amination Me2BH

#N(SiMe&

-

Me2BeN(SiMe&

I

I

i) NH3 I NaOCl ii) Hydrolysis

43

i) CH3CH2CH2NH2 I NaOCl ii) Hydrolysis

u '

i) NH3 I NaOCl ii) Hydrolysis

CHsNH2 I

Trialkylboranes also react rapidly at low temperatures with lithium r-butyl-N-tosyloxycarbamate [27] or N-chloro-N-sodiocarbamate[28] to give the corresponding N-Boc-protected primary amines and N-alkylcarbamates (Scheme 10).

RNHBoc *

LiN(0Ts)Boc

R-B,

/

NaNCICOZEt

*

RNHC02Et

up to 88 % yield

up to 83 % yield Scheme 10

Similarly, N-@-toluenesulfony1)-protected primary amines have been prepared using two different protocols, via hydroboration - amination with chloramine-T [29] (MeC6H,S0,NClNa) or with [N-@-toluenesulfonyl)imino]phenyliodinane [30], in excellent yields (Scheme 11).

RNHTs

*

up to 84 % yield

NaNClTs

R-6,

/

Phl=NTs

*

RNHTs

up to 99 % yield

Scheme 11

Hydrazoic acid, HN, can be generated either from sodium azide and an aqueous acid [ 141or from trimethylsilyl azide and MeOH [3 11, and its application leads to the formation of primary amines in good to excellent yields [32] (Scheme 12).

44

Femandez and Brown

Scheme 12

The asymmetric synthesis of enantiomerically pure primary amines has received considerable attention in recent years due to applications of the chiral amines, either as chiral auxiliaries for the synthesis of optically active molecules [33] or as a derivatizing agent for the resolution of racemic carboxylic acids [34]. Hydroborationamination is also a convenient synthetic route to epimerically clean amine derivatives in a simple one-stage reaction. Interestingly, trans-2-phenylcyclopentylamine (cypenamine), which is an antidepressant [35],can be obtained as a pure isomer in good yields by the hydroboration of 1-methylcyclopentene[7,10,36] (Scheme 13).

80 % yield

Scheme 13

Several steps are required in order to convert an alkene into the corresponding primary amine by enantioselective hydroboration, since there needs to be discrimination between the reagent and the derived B-alkyl group. This can be achieved in the manner shown in the first part of Scheme 14. Firstly, diisopinocampheylboraneis reacted with the alkene, and (especially after crystallization at low temperatures) the initial product is formed with diastereomeric homogeneity. An ingenious selective reduction of ethanal leads to regeneration of a-pinene and the desired fragment as a boronate ester. At this stage, the electrophilic reactivity is low and a further transformation is necessary in order to regenerate a reactive trialkylborane. The circuitous multistep pathway occurs in high yield, and results in a completely chemoselective alkyl transfer to the aminating agent in the desired direction [37].

2.2 Indirect Stoichiometric Amination

45

2 CHSHO 25 "C, 8h

Isolated as HCI salt 99 % ee

1 a...

92 % ee

hw

&J ii) hydrolysis yield 45 %

i ) 2H#OSO3H ii) hydrolysis ..at42

Scheme 14

This hydroboration-amination methodology shown in the second part of Scheme 14 can be extended to the synthesis of a series of enantiomerically pure terpenylamines [38,39], embracing (-)-cis-caran-truns-2-amine,(-)-cis-caran-truns-4amine, (-)-longifolamine, and (+)-cis-myrtanylamine. These are all formed in satisfactory yields by hydroboration of the corresponding alkene, if necessary purified

46

Fernandez and Brown

to enantiomeric homogeneity first, with Me,S.BH,Cl. The resulting R2BCl is then reacted with 0.33 equivalents of Me,AI to form the related R2BMecompounds, then transformed to amines in the conventional way with hydroxylamine-0-sulphonic acid. All the amines were > 99 % enantiomerically pure and were produced on a 60 millimolar scale [40](Figure 2.1). In similar vein, the initial product of a Matteson boronate ester synthesis may be converted into an enantiomerically pure amine [41]. The ability to synthesize enantiomerically pure primary amines by these diverse hydroboration methods finds useful application.

H2p pNH2 H2N 63 ,

- NH2

(-)-2-CarNH2

(-)-4-CarNH2

(-)-LSf"H2

(+)-MyrNHz

Figure 2.1

2.2.1.2 Applications to the Synthesis of Secondary Amines The stereoselective reaction of trialkylboranes with organic azides followed by hydrolysis leads to good yields of secondary amines. This reaction seems to be highly dependent on the steric environment of both the boron and the azide moiety [ 131. The mechanism of this reaction assumes that organoboranescan react with organic azides in a Lewis acid-base fashion to form a tetraco-ordinated boron species, which may ultimately lose nitrogen concurrent with the migration of an alkyl group from boron to nitrogen. Subsequent hydrolysis leads to secondary amines (Scheme 15).

Scheme 15

Although this reaction works well for unhindered trialkylboranes and azides, it has two major disadvantages: (i) only one of the three alkyl groups on boron is transferred; and (ii) it cannot be applied to hindered organoboranes [13] (Scheme 16).

2.2 Indirect Stoichiometric Amination

47

Scheme 16

The influence of steric factors on the organoborane also explains the unexpected insertion into 9-BBN observed in the hydroboration - amination of the dicyclopentadiene entity contained in the EPDM polymer [42] (Scheme 17).

Arninating reagent

T

V Aminating reagent

Scheme 17

To prevent the loss of alkyl groups in the 1,Zmigration step, easily available organodichloroboranes [43] proved to be the organoboranes of choice. However, when dibromoboranes were used instead, competitive migration of the alkyl group and bromide ocurred which led to the simultaneous formation of the expected secondary amine and tetraazaboroline [44](Scheme 18).

Scheme 18

48

Fernandez and Brown

Synthesis of N-alkylaziridine and N-arylaziridines is another interesting application via hydroboration- amination using organic azides as aminating reagents [ 13,451. The ready availability of 2-iodoalkylazides suggested that they might react with organodichloroboranes to give the corresponding 2-iodo-sec-amines. Subsequent treatment of these amines with base should lead via ring closure to the corresponding N-substituted aziridines, in which the relative configuration of the ring substituents may be easily defined (Scheme 19).

Scheme 19

Pyrrolidines are an important class of five-membered heterocycles with noteworthy biological properties [46]. In addition to pharmaceutical applications, the pyrrolidine moiety has also been widely used as a chiral auxiliary for asymmetric synthesis [47]. Although many elegant syntheses of chiral nonracemic pyrrolidines have been reported within the past decade or so [48-501, an alternative approach based on the intramolecular reaction of an azide and organoborane has been developed very recently [5 1-53]. This approach utilizes the hydroboration-azide alkylation tandem reaction as a key sequence, taking advantage of the efficient stereocontrolled steps. Scheme 20 shows an application of the synthesis of 3-substituted 5-(2pyrrolidiny1)isoxazolewhich has been found to have nanomolar activity, comparable to (5')-nicotine, against whole rat brain [54].

i) (IpckBAllyl ii) MeOH - M 44%

(PhO)PON3 I DBU 92 % ee

ii) MeOH i)R*H

-* Scheme 20

M

"

69 %

92 % ee

MJ

0 92%ee

"

2.2 Indirect Stoichiometric Amination

49

Successful execution of this approach requires selective migration of the w-aminoalkyl chain rather than the R substituent. This has been achieved by using halide 1551, cyclohexyl [56], ethyl or methyl nonmigrating R groups [51]. The synthesis of secondary amines from azides is efficient in terms of chemoselectivity [57] and has found valuable applications in the preparation of diamines [58,59], w-alkylaminoboronic esters [60], and in Diels- Alder-based amination reactions [61]. A convenient general route to open-chain polyamines, which play major roles in cellular differentiation and proliferation, has also been developed using the reductive alkylation of aliphatic aminoazides by (w-halogenoalky1)dichloroboranes as a key step [62] (Scheme 21). i) Br(CH2)nBC12I MeOH

R:

,N-(CH&-N3 R"

ii) NaN3 I NaOH iii) R"'BCl2 I MeOH

~

R'\ H R"/ N-W2h-N-

(CHzh-\**,

.H

Scheme 21

Enantiomerically pure secondary amines can be readily prepared from a-chiral organodichloroboranes and azides [63] (Scheme 22).

R"BH3Li

*

3HCI

t

R'BCI;!

+

3H2 3LiCI

i) R'N3 ii) NaOH

R'NHR'

up to 80% yield >99%ee

Scheme 22

Finally, the hydroboration-amination method via azides might be the key step in the synthesis of alkyl aryl ketones involving a free radical mechanism as opposed to the usual ionic pathway [64,65] (Scheme 23).

(chain propagation)

Scheme 23

50

Fernandez and Brown

The reaction of trialkylboranes with N-chloroalkylamines can be used to synthesize a wide variety of functionally substituted dialkylamines in good yields 166,671, and it complements the synthesis of secondary amines via the reaction of trialkylboranes with organic aides. The reaction is analogous to the reaction of chloramine with organoboranes, and presumably occurs via an anionotropic migration of an alkyl group from boron to nitrogen (Scheme 24).

Scheme 24

As regards the use of chloramine as aminating agent, dimethylalkylboranes have been used to prevent the loss of two alkyl residues [68,69].This reaction tolerates functionality in the organoborane, but the yields decrease dramatically for a sterically demanding N-chloralkylamine. Secondary amines can also be prepared by double-migrationreactions. In practice, however, the generation of amine reagents containing two good leaving groups is a major challenge. Nitric oxide reacts with organoboranes to give dialkylamines,but in low yield [70].A notable example involving double migration is synthesis of the secondary amine 13-azabicycl0[7.3.l]tridecan-5-olwhere the reagent is N-chloro0-2,4-dinitrophenyl hydroxylamine, generated in situ to react with the appropriate stereoisomer of perhydroboraphenalene (the hydroboration product of cis, trans, trans-cyclodeca-1,5,9-triene) [711 (Scheme 25).

Scheme 25

2.2 Indirect Stoichiornetric Amination

51

2.2.1.3 Applications to the Synthesis of Tertiary Amines The reaction of dialkylchloramines with organoboranes gives tertiary amines, if the competitive free radical reaction leading to the formation of alkylchlorides is suppressed by adding of a radical scavenger such as galvinoxyl [72,73] (Scheme 26). R3B

+

(CH&NCI

-

R(CH&N

+

RCI

Scheme 26

Azides have also been used as aminating reagent in a novel and convenient synthesis of 1-azaadamantane directly from the tetrahydrofuran complex of l-boraadamantane [74] (Scheme 27).

n

i)NaOH,Hfl2 ii)SOCI2 iii) NaOH

Scheme 27

&

2.2.2 Amination via Organozirconium Compounds In recent years, amines have also been synthesized by nitrogen insertion into a zirconium-carbon bond followed by hydrogenolysis [75] (Scheme 28).

52

F e m n d e z and Brown

Scheme 28

Organozirconium compounds prepared by hydrozirconation are useful intermediates in organic synthesis because of such applications as insertion of carbon monoxide [76,77], isocyanides [78], lithium chloroallylide [79], aldehydes [SO], halogens [77,8 I], oxygen [Sl], and single bond metathesis reactions [82]. Although metathesis with phosphines such as Ph,PC1 and PhF’Cl, occurs readily, attempts to carry out such reactions with analogous nitrogen-containing reagents such as RNHCl and RNCl,, have not been successful. There are precedents for the insertion of phenyl azide [83] or diphenyldiazomethane [84] into the Zr-C bond of dialkylzirconocenes, resulting in the formation of a new carbon-nitrogen bond (Scheme 29). PhNB

CPzZrR2

CpzZr(NRNNPh)(R) 7

1 -PhzC=N2

Cp2Zr(NRNCPhZ)(R)

Scheme 29

A further extension involves the readily synthesised zirconacyclopentanes,which react with the same reagents to give to give novel 18-electron azazirconacycles. These are very stable towards hydrolysis [75], but hydrogenolysis leads to the formation of a primary amine.

2.3 Indirect Catalytic Amination Although the B-H addition of borane etherates to simple alkenes occurs quite rapidly under ambient conditions, less electrophilic boranes are correspondingly less reactive. A classic example is given by catecholborane which reacts with alkynes only above 70°C and with alkenes under somewhat more forcing conditions [l, 851. The reason for this is not hard to find, since the electrophilic character of the borane is substantially diminished by conjugation between boron and adjacent oxygens [86,87]. At the same time, the acidity of B-H is enhanced through an

53

2.3 Indirect Catalytic Amination

onium ylid-type conjugation in the resulting anion. This makes the addition of catecholborane to transition metals correspondingly more favorable than that of secondary alkylboranes. Thus, it was shown first by Mannig and Noth that hydroboration by catecholborane could be successfully carried out at room temperature or below in the presence of catalytic amounts of one of a range of transition metal complexes [SS-901. In general, rhodium(1) complexes which are reactive in homogeneous hydrogenation provide the most effective catalysts, linking the process to both hydroformylation and more conventionally to hydrogenation. The mechanistic precedent for a process driven by the addition of catecholborane to a coordinatively unsaturated Rh center, and followed by sequential transfer of H and X,B to the alkene, lies in the mechanism of hydrogenation of alkenes by Wilkinson’s catalyst (Scheme 30). As might be expected, the chemoselectivity of catalytic hydroboration is distinct from that of the uncatalyzed reaction, and affords the possibility of selectively reacting an alkene in the presence of a carbonyl group H RhCI(PPh&

+ a o B H

0

-

RCH=CH2

5a 0 1 g d t RCH2CH2 t , P -P h 3 0

I

PPh3

0

CI

Scheme 30

Earlier work in the catalyzed addition of catecholborane to alkenes has been thoroughly reviewed [91,921. The most significant application of catalytic hydroboration has been the possibility of enantioselective hydroboration by the use of catalysts containing chiral ligands [93], in contrast to the traditional stoichiometric enantioselective hydroboration which requires one or two equivalents of a chiral auxiliary attached to boron [94]. Despite considerable efforts to find alternatives, catecholborane is the most useful borane among commonly accessible hydroborating agents; likewise rhodium complexes are the most efficient catalysts in asymmetric catalytic hydroboration (c.f. publications on catalysis with other metal complexes) [95 -971. Synthetic application of the resulting catecholborane adducts has been limited to oxidation to afford secondary alcohols, however [91,98,99]. Many of the common transformations of organoboranes do not work with boronate esters, because of the lower electrophilicity of the boron. Some success ensued when benzylic catecholboronate esters, isolated or prepared in situ, were reacted with ClMgN(Me)OSiMe3 or structurally related aminating agents. Although the enantioselectivity in the ensuing secondary amine was high, it was always accompanied by the formation of comparable amounts of the alcohol [loo]. This implies that the initial step involves either oxygen or nitrogen nucleophilic attack at boron which is irreversible, and determines whether an amine or alcohol is ultimately formed. The dual pathway was supported by I3C NMR studies with labeled reactants (Scheme 31).

54

Femandez and Brown OH

Ju

1 rnol % cat., THF, 20 then IM KOH

MeO isolated and distilled

33%. 88 % ee CF$30;

Scheme 31

In order to develop a more direct route, the necessary expedient was to activate the initial adduct towards nucleophilic attack. It had already been reported that catecholboronate esters react with Grignard reagents (2 equiv.) to form the corresponding trialkylborane [loll. This procedure could be carried out with MeMgCl (or alternatively Et,Zn) on the initial product of catalytic asymmetric hydroboration without isolation. The alkylborane thus formed is then reactive towards conventional aminating agents such as H,NOSO,H or aqueous ClNH,, leading to a one-pot asymmetric synthesis of primary benzylic amines from vinylarenes with retention of the configuration at the migrating group [102,103]. Reaction leads to the corresponding primary amine with high chemo-, regio- and enantioselectivity as indicated in Table 2.2 and Scheme 32. As in the simpler hydroboratiodoxidation reactions, there are structural constraints. The method tolerates a single substituent at the P-position, but not the a-position of the alkene, so that simple benzo-fused alkenes are suitable reactants. Step 1

A+--

1 mol % cat. THF, 20 "C [S-Quinap-Rh']

One-pot reaction

Scheme 32

1

1

Step 2

MeMgCI, THF

1

Ax.-

or ZnEtp,toluenr

diglyme

55

2.3 Indirect Catalytic Amination Table 2.2 One-pot hydrobration-amination reactions Reactant

Product

/o"

Regioselec- Isolated tivity (8) yield (%)

ee (%)

> 98

56

98

> 98

54

87

> 98

50

90

96

51

97

98

64

89

92

62

90

Me0

Me0

-

As is generally the case with Rh-catalyzed hydroborations, genuinely successful enantioselective reaction (> 90 % ee) has been recorded only for vinylarenes. Since the normal regiochemistry of these reactions places the rhodium at the benzylic position, some favorable interaction with the ring is to be expected the the reactive rhodium benzyl intermediate; this may formally be represented as an q3-complex,for which literature precedents exist [ 1041 (Scheme 33).

56

Fernandez and Brown

Scheme 33

This possibility of intimate association of rhodium with the aromatic ring suggests further experiments. A logical extension of asymmetric syntheses involving prochira1 reactants is a kinetic resolution with related chiral reactants under similar conditions. In the one case of hydroboration-amination where this has been applied, it has proved to be very effective. The reactant was prepared directly by a Heck reaction on 1,2-dihydronaphthalene,and under the standard conditions of catalytic hydroboration gave > 45 % of both enantiomerically pure recovered alkene with (after oxidative work-up) the alcohol of opposite hand, mainly as the trans-isomer. This procedure forms a simple and potentially useful route to pharmacologically active substances, demonstrated by the racemic synthesis shown [ 1051 (Scheme 34).

- Q +*; m

1) HBCat. 0.6 equiv. Rh COD (R)-QUINAP OTf Toluene 2h

2) Hfl2 I NaOH / EtOH Ph

OH

Ph

46 % yield trans :cis = 91 : 9

MeHN 1) HBCat, Toluene Rh COD (QU\NAP

I

OTL

2) E y n , Toluene 3) MeHNCI, EhO Ph

Ph

47 % yield trans :cis = 94 : 6

Scheme 34

99 % ee

2.3 Indirect Catalytic Amination

57

Following the demonstration of catalytic hydroboration- amination employing hydroxylamine-0-sulfonic acid as the electrophile, extension to the synthesis of secondary amines was considered. The method adopted involves the reaction with monochloralkylamines. These can be generated in situ by by reaction of a solution of a primary or secondary amine in an organic solvent with commercial sodium hypochlorite solution and used directly (c.f. the chloramine preparation above). A specific difference between monoalkyl and dialkylchloramines was discovered. The reaction of trialkylboranes with ClNEt,, verified by NMR as being formed cleanly, gave a range of products, and more significantly the tertiary amine was formed with complete racemisation. This is in line with the radical reaction pathway proposed by Davies, Roberts and co-workers [106]; some of the sideproducts may be formed by competing cationic routes. In contrast, the chloramines formed from primary amines reacted cleanly and with retention of configuration, providing a viable synthetic route to enantiomerically enriched benzylic secondary amines. The implication is clear; in the alkyl migration step of Scheme 35 deprotonation of the N-H either precedes or is concurrent with C-N bond formation making the pathway impossible for a secondary chloramine.

GH11NHClO "C, 5 min then 20"C, 1 h; MeO

YJ

XY" 73 I; 92 % ee

"N

PhCHflHCI 0 "C, 5

93 % ee by

FH2m

Hfl2 oxidation

75 %: 91 % ee

unmactie

Scheme 35

reactive

58

Fernandez and Brown

The successful method was demonstrated for the examples shown in Table 2.3; both the amine and the borane can be varied without detriment. The ees observed are consistently 1-5 96 lower than in the case of simple hydroboration-oxidation or the hydroboration-amination reactions discussed earlier [ 1071. Table 2.3 Alkylaminations employing in-sib-generated chloramines Entry

2

ee (%)

Yield (a)

87

71

93

73

92

82

r

91

75

/o"

90

77

91

76

78

50

87

48

Reactant

/o"

Product

MeO

3

MeO

4

MeO

5

MeO

r

2.4 Direct Alkene Amination

59

2.4 Direct Alkene Amination This field has been extensively reviewed in 1998by Muller and Beller, and the reader is referred to this article for further detail [l08]. Whilst there is yet no general method, catalytic or noncatalytic, for the conversion of a nonelectrophilic or unactivated alkene into the corresponding amine by addition of a nitrogen electrophile, progress is encouraging. The main thrust of this chapter is the development of asymmetric synthesis, but other recent relevant examples are illustrated in Scheme 36. The samarium complex-catalyzed intramolecular amination of alkenes through an exocyclic pathway forms pyrrolidines exclusively as in examples (a) and (b). Intermolecular addition is quite rare; with special activating factors it may be observed as in the allenic example (c). In the presence of Rh catalysts, styrenes react with secondary amines to form enamines with sacrificial hydrogenation of a mole of alkene, as in (d). Very reasonably, the authors suggest a pathway in which the rhodium catalyst promotes N-H insertion followed by amide addition to the alkene and p-elimination to form an RhH, intermediate and the enamide [ 1091.

catalyst

catalyst Cp*2SmCH(SiMe3)2

w

21 "C

55 turnovers/ h stereoisomers

(d)

2.5 ml%(PFh3)2pRc THF. reflux, 20 h

+

99 % of each

Scheme 36

60

Fernandez and Bmwn

Insofar as asymmetric synthesis is concerned, some pioneering work was conducted by Marks and co-workers through their demonstration of enantioselectivity in the samarium or lanthanide complex-catalyzed cyclization of aminoalkenes, an analogy of the simple reaction exemplified in Scheme 36. As before, the reaction works best for &-unsaturated amines where the product of an exocyclic ring closure pathway is a cyclopentylamine. In the most favorable cases, high turnover to the desired product is observed [110] (Scheme 37).

Scheme 37

Intermolecular asymmetric aminations are at an early stage of development, and consequently much lower turnover frequencies and catalytic yields have been observed at this stage. In the example shown, a key aspect is the activation of the indium complex catalyst by fluoride ion [lll] (Scheme 38).

75 "C, 72,h 4:l F: catalyst

95 % ee, 11 turnovers

Scheme 38

catalyst

References

61

References [ 11 H. C. Brown, Boranes in Organic Chemistry,Cornell University Press, Ithaca, New York, 1972; E-

I. Negishi, Organometallics in Organic Synthesis, Wiley Interscience, New York, 1980. [2] H. C. Brown, Organic Synthesis Via Boranes, John Wiley and Sons, New York, 1975. [3] H. C. Brown, B. C. Subba Rao, J. Am. Chem. SOC.1956, 78, 5694. [4] H. C. Brown, W. R. Heydkamp, E. Breuer, W. S. Murphy, J. Am. Chem. SOC. 1964, 86, 3565. [5] N. H o m e s , P. von R. Schleyer J. Org. Chem. 1991,56,4074; for recent computational studies of catalytic hydroboration see :D. G. Musaev, A. M. Mebel, K. Morokuma, J. Am. Chem. SOC.1994, 116, 10693; A. E. Dorigo, P. V. Schleyer, Angew. Chem., Inr. Ed. Engl. 1995, 34, 115. [6] C. Narayana, M. Periasamy, J. Chem. SOC. Chem. Commun. 1987, 1857. [7] H. C. Brown, K-W Kim,M. Srebnik, B. Singaram, Tetrahedron 1987, 43, 4071. [8] G. W. Kabalka, G. W. McCollum, S. A. Kinda, J. Org. Chem. 1984,49, 1656. [9] G. W. Kabalka, K. A. R. Sastry, G. W. McCollum, H. Yoshioka, J. Org. Chem. 1981, 46,4296. [lo] M. W. Rathke, N. Inowe, K. R. Varma, H. C. Brown, J. Am. Chem. SOC. 1966, 88,2870. [ l l ] G. W. Kabalka, J. W. Ferrell, Synth Commun. 1979, 9, 443. 1121 Y. Tamura, J. Minamikawa, S. Fuji, M. Ikeda, Synthesis 1974, 196. [ 131 H. C. Brown, M. M. Midland, A. B. Levy, A. Suzuki, S. Sono, M. Itoh, Tetrahedron 1987,43,4079. [14] G. W. Kabalka, D. A. Henderson, R. S. Varma, Organometallics 1987, 6, 1369. [I51 V. B. Jigajinni, A. Pelter, K. Smith, Tetrahedron Lett. 1978, 2, 181. [16] G. Zweifel, H. C. Brown, J. Am. Chem. SOC. 1964, 86, 393. [17] G. Zweifel, A. Horng, Synthesis 1973, 672. [I81 E. J. Corey, W. L. Seibel, Tetrahedron Lett. 1986, 27, 905. [ 191 H. C. Brown, E. Vismara, F. Fontana, G. Morini, M. Serravalle, J. Org. Chem. 1987, 52, 730. [20] H. C. Brown, T. E. Cole, M. Srebnik, K-W. Kim, J. Org. Chem. 1986, 51, 4925. [21] G. W. Kabalka, Z. Wang, N. M. Goudgaon, Synrh. Commun. 1989, 19, 2409. I221 R. Koster, P. Binger, W. Fenzl, Inorg Synth. 1974, 15, 134. [23] P. J. Kothari, R. D. Finn, G. W. Kabalka, M. M. Vora, T. E. Boothe, A. M. Emran, Appl. Radiat. hot. 1986, 37, 469. [24] G. W. Kabalka, Z. Wang, J. F. Green, M. M. Goodman, Appl. Radiat. Isor. 1992, 43, 389. [25] G. W. Kabalka, K. Sastry, G. W. Mc Collum, C. A. Lane, J. Chem. Soc., Chem. Commun. 1982,62. [26] G . W. Kabalka, Z . Wang, Synth Commun. 1990, 20, 21 13. [27] J. P. Gen&t,J. Hajicek, L. Bisschoft, C. Greck, Tetrahedron Lett. 1992, 33, 2677. [28] N. Wachter-Jursak, F. Scully, Tetrahedron Lett. 1990, 31, 5261. [29] V. B. Jigajinni, A. Pelter, K. Smith, Tetrahedron Lett. 1978, 19, 181. I301 R. Y. Yang, L. X . Dai, Synthesis 1993, 481. [31] G. W. Kabalka, N. M. Goudgaon, Y. Liang, Synrh. Commun. 1988, 18, 1363. [32] B. Carboni, M. Vaultier, Bull. SOC.Chim. Fr: 1995, 132, 1003. [33] J. M. Chang, I. S. Clarke, I. Koch, €? C. Olbach, N. J. Taylor, Tetrahedron: Asymm. 1995,6,409. 1341 C. Bussche-Hiinnefeld, C. Cescato, D. Seebach, Chem. Ber: 1992, 125, 2795. [35] W. R. McGrath, W. L. Kuhn, Arch. In?. Pharmacrodyn. Ther: 1968, 172, 405. [36] A. Burgos, J. M. Kamenka, B. Rousseau, J. Label, Compounds Radiopharm. 1991, 29, 1347. [37] H. C. Brown, K. W. Kim, T. E. Cole, B. Singaram, J. Am. Chem. SOC. 1986, 108, 6761. 1381 H. C. Brown, P. V. Ramachandran, J. Organomet. Chem. 1995,500. 1. 1391 P. V. Ramachandran, M. V. Rangaishenvi, B. Singaram, C. T. Goralski, H. C. Brown, J. Org. Chem. 1996, 61, 34 1. [401 H. C. Brown, S. V. Malhotra, P. V. Ramachandran, Tetrahedron: Asymm. 19%. 7, 3527. I411 M. V. Rangaishenvi, B. Singaram, H. C. Brown, J. Org.Chem. 1991, 56, 3286. [42] M. van Duin, L. Leemans, M. Neileu, Polymer 1999,40, 1001. [43] P. Y. Chavant, F. Lhermitte, M. Vaultier, Synletr 1993, 519. [44] B. Carboni, M. Vautier, T. Cougeon, R. Carrit, Bull. SOC. Chim. FI: 1989, 844. 1451 A. B. Levy, H. C. Brown, J. Am .Chem. SOC. 1973, 95, 4069. [46] a) G. Massiot, C. Delande, The Alkaloids, Academic Press, New York, 1986,27; b) A. Numuta, T. Ibuka, The Alkaloids, Academic Press, New York, 1987, 31.

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[47] a) J. K. Whitesell, Chem. Rev. 1989,89,1581; b) K. Tomioka, Synthesis 1990,541;c) R. Noyori, M. Kitamura, Angew. Chem Int. Ed. Engl. 1991, 30, 49. [48] A. Suzuki, S. Sono, M. Itoh, H. C. Brown, M. M. Midland, J. Am .Chem. Soc. 1971, 93, 4329. [49] H. C. Brown, M. M. Midland, J. Am .Chem. Soc. 1972, 94, 2114. [50] H. C. Brown, M. M. Midland, A. B. Levy, J. Am .Chem. SOC. 1973, 95, 2394. [51] A. Salmon, B. Carboni, J. Organomet. Chem. 1998, 567, 31. [52] J. M. Jego, B. Carboni, A. Youssofi, M. Vaultier, Synlett. 1993, 595. 1531 H. C. Brown, A. M. Salunkha, Tetrahedron Lett. 1993, 1265. [54] S. J. Wittenberger, J. Org. Chem. 1996, 61, 356. [551 J. M. Jego, B. Carboni, M. Vaultier, R. CarriC, J. Chem. Soc., Chem. Commun.1989, 142. 1561 D. A. Evans, A. E. Weber, J. Am .Chem. Soc. 1987, 109, 7151. [57] B. Carboni, M. Vaultier, R. CamC, Tetrahedron 1987, 43, 1799. [58] A. Benalil, B. Carboni, M. Vaultier, Tetrahedron 1991~.47, 8177. [59] M. Vaultier, B. Carboni, P. Martinez-Fresneda, Synth. Commun.1992, 22, 665. [60] J. M. Jego, B. Carboni, M. Vaultier, J. Organomet. Chem. 1992, 435, 1. [61] N. Noiret, A. Youssofi, B. Carboni, M. Vaultier, J. Chem. Soc., Chern. Commun. 1992, 1105. [62] B. Carboni, A. Benalil, M. Vaultier, J. Org. Chem. 1993, 58, 3736. 1631 H. C. Brown, A. M. Salunke, A. Singaram, J . 0%.Chem. 1991, 56, 1170. [64] A. Suzuki, M. Tabato, M. Ueda, Tetrahedron Len. 1975, 16, 2195. [65] A. F. Bamford, M. D. Cook, B. I? Roberts, Tetrahedron Lett. 1983, 24, 3779. [66] G. W. Kabalka, G. W. McCollum, S. A. Kunda, J. 0%.Chem. 1984,49, 1656. [67] G. W. Kabalka, 2. Wang, Organometallics 1989, 8, 1093. [68] G. W. Kabalka, 2. Wang, Synth. Commun.1990,20, 231. [69] G. W. Kabalka, 2. Wang, Synth. Commun.1990, 20, 2113. [70]S. J. Breis, A. J. Rutkowski, US. Pat. 3,147,310 (1964). [C.A., 61,1189 (1964)l [71] R. H. Mueller, Tetrahedron Lett. 1976, 17, 2925. [72] A. G. Davies, S. C. W. Hook, B. P. Roberts, J. Organomer. Chem. 1970,23, C11. [73] J. G. Shareflcin, H. D. Banks, J. 0%. Chem. 1965,30,4313. 1741 Y. N. Bubnov, M. E. Gursky, D. G. Pershin, J. Organomet. Chem. 1991, 412, 1. [75] T. Luker, R. J. Whitby, M. Webster, J. Organomet. Chem. 1995, 492, 53. 1761 D. R. Swanson, C. J. Rousset, E. Negishi, T. Takahashi, T. Seki, M. Saburi, Y. Uchida, J. Org. Chem. 1989,54, 3521. [77] C. J. Rousset , D. R. Swanson, F. Lamaty, E. Negishi, Tetrahedron Lett. 1989, 30, 5105. [78] J. M. Davis, R. J. Whitby, A. Jaxa-Chamiec, Tetrahedron Lett. 1992,33,5655,b) J. M. Davis, R. J. Whitby, A. Jaxa-Chamiec, Tetrahedron Lett. 1994,35,1445, c) J. M. Davis, R. J. Whitby, A. JaxaChamiec, Synlett. 1994, 1 11. [79] T. Luker, R. J. Whitby, Tetrahedron Lett. 1994, 35, 785. [80] C. CopCret, E. Negishi, Z. Xi, T. Takahashi, Tetrahedron Lett. 1994, 35, 695. [81] W. A. Nugent, D. F. Taber, J. Am .Chem. Soc. 1989, 112, 6435. [82] P. J. Fagan, W. A. Nugent, J. C. Calabrese, J. Am .Chern. Soc. 1994, 116, 1880. [83] K. W. Chiv, G. Wilkinson, M. Thornton-Pett, M. B. Hursthouse, Polyhedron 1984, 3, 79. [84] S. Gambarotta, C. Floriani, A. Chiesi-Villa, C. Guastini, Znorg. Chem. 1983, 22, 2029. [85] H. C. Brown, “Hydmboration” Wiley Interscience, New York, 1962. (861 G. W. Kabalka, Org. Prep. Pmceed. Znt. 1977, 9, 131. [87] A. Pelter, K. Smith, Chemistry oforganoboron Compounds, in Comprehensive Organic Chemistry, vol 111, ed. N. Jones, Pergamon Press, 1979, 194. [88] D. Mannig, H. Noth, Angew. Chem. lnt. Ed. Engl. 1985, 24, 878. [89] H. Kono, K. Ito, Y. Nagai, Chemistry Lett, 1976, 1095 [90] J. A. Long, T. B. Marder, P. E. Behnker, M. F. Hawthorne, J. Am. Chem Soc. 1984, 106, 2979. [91] K. Burgess, M. J. Ohlmeyer, Chem. Rev. 1991, 91, 1179. [92] I. Beletskaya, A. Pelter, Tetrahedron. 1997, 53,4957. [93] Z. Deloux, M. Srebnik, Chem. Rev. 1993, 93, 763. [94] H. C. Brown, P. V. Ramachandran, Current Topics in the Chemistry ofBorun, ed. G. W. Kabalka, R. S. C. London, 1994, 101. [95] S. Pereira, M. Srebnik, Organometallics 1995, 14, 3127. 1961 E. A. Bijpost, R. Duchateau, J. H. Teuben, J. Mol. Catal. 1995, 95, 121. 1971 X. M. He, J. F. Hartwig, J. Am. Chem. SOC. 1996, 118, 1696.

References

63

[98] J. M. Valk, G. A. Whitlock, T. P. Layzell, J. M. Brown, Tetrahedron: Asymmetry 1995, 6, 2593. [99] H. Doucet, E. Fernandez, T.P. Layzell, J. M. Brown, Chem. Eu,: J. 1999, 5, 1320. [IOO] F. I. Knight, J. M. Brown, D. Lazzari, A. Ricci, A. J. Blacker, Terrahedron 1997, 53, 11411. [ 1011 S. Cabiddu, A. Maccioni, M. Secci, Gau. Chim. ltal, 1972, 102, 555. [lo21 E. Fernandez, M. W. Hooper, F. I. Knight, J. M. Brown, Chem. Commun. 1997, 173. [ 1031 J. M. Brown, H. Doucet, E. Fernandez, H. E. Heeres, M. W. Hooper, D. I. Hulrnes, F. I. Knight, T. P. Layzell, G. C. Lloyd-Jones, Chemistryfor the 21st Century, ed. S-I. Murahashi and S. G. Davies, 465-483; Blackwell Science 1999. 11041 B. Windrnuller, J. Wolf, H. Werner J. Organomet. Chem. 1995,502,147; H. Werner, M. Schafer, 0. Nurnberg, J. Wolf Chem. Be,: 1994, 127, 27; M. D. Fryzuk, D. H. McConville, S. J. Rettig J. Organomet. Chem. 1993,445, 245. [I051 K. Maeda, J. M. Brown., 1999, in preparation. [lo61 A. G. Davies, S. C. W. Hook, B. P. Roberts, J. Organomet. Chem. 1970,23, C11. [I071 E. Fernandez, K. Maeda, M. W. Hooper, J. M. Brown, Chem. Eur J., submitted 1999. [108]T. E. Muller, M. Beller, Chem. Rev., 1999, 99, 675. [I091 (a) M. R. GagnC, S. P. Nolan, T. J. Marks, Organometallics,1990, 9, 1716. (b) Y.Li, T. J. Marks, J. Am. Chem. Soc., 1996,118,707. (c) L. Besson, J. Gori, B. Cazes, Tetrahedron IRtt., 1995,36,3857; see also M. Al-Mesum, M. Meguro, Y.Yamamoto, TetrahedronLett., 1997,38,6071; (d) M. Beller, M. Eichenberger, H. Trautwein, Angew. Chem. lnt. Ed. Engl, 1997, 37, 2225. [ 1101 M. R. Gagni, L. Brand, V. P. Conticello, M. R.Gardello, C. L. Stem, T. J. Marks, Organometallics, 1996, 11, 2003 [ill] R. Dorta, P. Egli, F. Zurcher, A. Togni J. Am. Chem. SOC. 1997, 119, 10857, and refs. therein.

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

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

3.1 Introduction The electrophilic amination reaction constitutes an example of the “Umpolung” methodology for the direct introduction of an amino group into organometallic compounds. This technology has created a need for versatile and efficient electrophilic aminating reagents. The chemistry of nitrogen electrophiles was excellently summarized in several reviews and books [l]. A number of electrophilic aminating reagents is now available (Scheme l), and early candidates such as haloamines 1and compounds derived from hydroxylamines 2 have been used extensively. The interesting feature of these electrophilic aminating reagents is the attachment of a leaving group to the nitrogen. Sulfonyl azides 3 allow the introduction of an “NH2+”synthon, and alkyl or aryl azides prepared with these reagents can be reduced or hydrolyzed to primary amines, [Id, 21.

H2NX

( X = CI, Br )

H2N-OL

1 N3SO2R (R = Ph, CF3)

3

!

( L = Alkyl, SOzAr, PPh2 )

2 E-NZN-E

4

( E = COgt-BU COaBn, C02Et )

RXc‘

R

N=O

5

Scheme 1

Azodicarboxylates 4 have been used in the electrophilic reaction with diethyl malonate since 1924 [3]; however only recently were these reagents recognized as particularly useful for the introduction of an amino moiety after hydrogenolysis of the hydrazide adduct [3]. More recently, chloro nitroso reagents of type 5 have been introduced by Oppolzer [4].These reagents are particularly reactive, giving

66

Genet, Greck and Lavergne

after acidic work-up the hydroxylamine, with a reductive cleavage by Zn dust of the N-0 bond providing the free amino group. The increasing application of direct metallation methods and the importance of primary amines as synthetic intermediates have created a need for new aminating reagents. In particular, reagents that could directly transfer an N-protected group rather than a free amino group. In this context several N,O-diprotected hydroxylamines have been recently reported (Scheme 2): tert-butyl and ally1 N-[(aqlsulfonyl)oxy]carbamate 6 [5] and the N, 0-bis(trimethylsily1)hydroxylamine 7 [6].

I

dOy.

N‘OSO*Ar

HN-0

0 / \ Ar-CH-N-P

7

8

Me&,

,SiMe3

0

6 Scheme 2

These species containing both a leaving group and a protecting group attached to the nitrogen are synthetic equivalents of “+NHP”(P = CO,R, SiMe,), and are very reactive to organometallic reagents. Finally, other N-protected electrophilic reagents should be mentioned such as the N-protected oxaziridines 8 [7], which so far transfer efficiently under mild conditions its N-protected fragment to N-nucleophiles but however give moderate yields with C-nucleophiles, [7c, el. In contrast to stereoselective C -C bond-forming reactions, the related electrophilic amination of chiral carbon nucleophiles is a recent conceptual advance in the repertoire of synthetic methodology. The problem is the correct choice of the nucleophile, and of the most efficient nitrogen electrophile. The chemistry of useful reagents such as sulfonyl azides 3 and chloro nitroso alkanes 5 was excellently reviewed in 1995 [ Id]. This chapter outlines a collection of the major reports that have appeared in the field of stereoselective electrophilic amination using sulfonyloxycarbamates 6 and azodicarboxylates 4.

67

3.2 Sulfonyloqrarbamates

3.2 Sulfonyloxycarbamates 3.2.1 Preparation of N-[(arylsulfonyl)oxy]carbamates Tert-butyl N-(tosy1oxy)carbamate 6a was easily obtained from commercially available tert-butyl N-hydroxycarbamate by tosylation with tosyl chloride [5a, c]. Ally1N[@-toluenesulfonyl)oxy]carbamate 6b tea-butyl and allyl N-[(mesitylsulfony1)oxylcarbamates 6c and 6d were prepared from hydroxylamine [5d, 81 (Scheme 3). The corresponding metallated N- [(arylsulfonyl)oxy]carbamates 9 were obtained by treatment with one equivalent of base (n-butyllithium, ethylmagnesium bromide or potassium hexamethyl disilazane). Tert-butyl N-lithio-N-[@-toluenesulfonyl)oxy]carbamate 9a (LiBTOC) [5a, el is less stable than tert-butyl N-lithio-N[(mesitylsulfonyl)oxy]carbamate 9c [81. THF solutions of allyl N-lithio-N-[(mesitylsulfonyl)oxy]carbamate 9d are also stable and can be stored several days at 0°C. This enhances the value of these reagents for electrophilic amination that are able to directly transfer the “+NHAlloc”or “+NHBOC”moieties to various organometallic compounds: alkyllithiums, dialkylcuprates, a-cuprophosphonates, aryl coppers, and organoboranes [5b].

H I

a

R=MU

b

R

w

R0’vNXOSO2Ar

0

t‘

Ar= *Me =

R ” K C

R=tBu

d

R

6 =

“OS02Ar

0

w

Ar= M *‘e Me

9

Scheme 3

This amination procedure involves two negative species: the metallated “nitrenoid” ArSO,N(M)CO,R 9 and the organometallic reagent that ought to repel each other. Boche and co-workers have established that tert-butyl N-lithio-N-[(mesitylsulfonyl)oxy]carbamate 9c crystallized as a dimer and the N - 0 bond in the lithiated species was longer than the related bond in its non lithiated counterpart. This structure is in accord with a nitrenoid character and the remarkable facile substitution of the sulfonate group by organometallic reagents. The amination may proceed through S,2 process [9].

68

Genet, Greck and Lavergne

3.2.2 Stereoselective Synthesis of a-Amino Carboxylic and Phosphonic Acids via Electrophilic Amination with Lithium tert-Butyl N-(tosyloxy) carbamate The importance of amino acids has stimulated the development of numerous routes for their synthesis. Among these, the electrophilic amination of chiral enolates possesses a broad degree of generality.

3.2.2.1a-Amino Carboxylic Acids The Merck group has applied the electrophilic amination using lithium tert-butyl N(tosy1oxy)carbamate9a to the chiral amide derived from ( lS,2R)-cis-amino-indanol [lo] (Scheme 4). Treatment of 10 with n-Buli in THF at -78 "C gave the lithium enolate which was reacted with CuCN. The resulting amide cuprate was allowed to react with 9a. The authors found that a single diastereomer of a-Boc-protected amino amide 11was formed. The sense of asymmetric induction observed was consistent with preferential approach of 9a from the least hindered face of the enolate. The removal of the chiral auxiliary with refluxing 6N HC1 afforded a-amino acids 12 in good yields and optical purities.

6N HCI

1) n-BuLi, -78 "C, THF 2) CUCN, -78 "C

-

*

reflux

0 'C

3)TsON(Li)Boc, -78 "C

NH2

yield = 81 - 86 % 10

11

12 ee = 89-98 %

R = En,Ph, Me, Bu, i-Pr

Scheme 4

3.2.2.2a-Amino Phosphonic Acids The phosphonic amino acids are also an important class of compounds with applications as antibiotics, antiviral agents, and enzyme inhibitors. The first example of electrophilic amination of a-cuprophosphonates 14 was reported by Genet and co-workers [5a]. This route has opened new access to N-protected a-amino phosphonic derivates 15 from the corresponding phosphonates 13 (Scheme 5).

69

3.2 Sulfonyloxycarbamates

-

0 Et0-F EtO' vR

1) RLi, THF

2)CuBr-MepS

yR -

0 EtO-p EtO'

II

0 EtO-1 EtO'

1) TsON(Li)R2

yR

2) NH&I

cu

13

yield = 50-80 O h

14

R = Me, Ph

NHR~

15 R2 = Boc. AIIoc

Scheme 5

The diastereoselective electrophilic amination of chiral a-alkyl phosphonamides derived from C, symmetric diamines with metallated tert-butyl N-[(p-toluenesulfonyl)oxy]carbamate 6a was examined. Treatment of 16 with n-BuLi followed by CuBr . Me,S at -78 "C and quenching with 9a LiBTOC provided the a-aminated Boc-protected adducts 17 in moderate to good yields and diastereoselectivities [ l I] (Scheme 6).

Yield (%)

de (%)

Me

59

30

Ph

48

35

49

52"'

Me

Me 1) n-BuLi, -78 "C, THF

he

*

2) CuBr-MepS 3) TsON(Li)Boc, -78 "C

Ph

Me

x"

'I" PhhN

Me

17

16

x"

aN

Ph

tie lnl

Major diastereomer was hydrolyzed to ( @a-amino-u-phenylmethylphosphonicacid

Scheme 6

3.2.3 Reactions of Ethyl N-[(p-nitrobenzenesulfonyl)oxy]carbamate with Chiral Enamines and Enol Ethers In contrast with the metallated N-[(arylsulfonyl)oxy]carbamates, it has been known since 1965 that ethyl N-[(p-nitrobenzenesuIfonyl)oxy]carbamate 6e is a precursor of nitrene, thus a-elimination of p-nitrobenzensulfonate ion (NsO-) from the anion of ethyl N-[(p-nitrobenzenesulfonyl)oxy]carbamate 6e leads at room temperature to the formation of (ethoxycarbony1)nitrene 18 [ 12a] (Scheme 7).

70

Genet, Greck and Lavergne

18

6e Scheme 7

More recently, Tardella and co-workers disclosed the use of this reagent in the synthesis of N-(ethoxycarbony1)-a-amino ketones from enamines and nitrene 18 [12b]. Their attempts to obtain asymmetric induction started with the use of proline-derived optically active enamines of cyclohexanone. Slow addition of sulfonyloxycarbamate 6e (1 equiv.) to a stirred solution of the enamine 19 and triethylamine (1 equiv.) in dichloromethane at room temperature, followed by work-up with petroleum ether and silica gel chromatographic purification afforded the aminated product 20 in low yield and good enantiomeric excess [12c] (Scheme 8).

“’H

A

Yield

R CHpOSiMea CH20Me

(Yo)

ee (Yo)

12 18

52 77

21

The absolute configuration and enantiomeric excess of amino ketones 20 were evaluated by gas chromatography (GC) and I3C NMR studies after conversion into the diastereomeric acetals 21.The reaction proceeds via addition of the nitrene 18 to the double-bond of 19.The yield and diastereoselectivity of this reaction were significantly enhanced when using chiral enol ethers 23, generated from C , symmetric 22.The best result (36 % yield and 50 % ee) was obtained using a fivefold excess of reagent 6e and equimolar amount of triethylamine [12d] (Scheme 9).

*d

TMSOTf

22

/-(

OTMS

23 Scheme 9

NEb NSONHC02EI

X

Yield

ee

(Yo)

(Yo)

rt

Me Ph

24

36 50

36

3.3 Dialkylazodicarboxylates

71

Very recently, the same group proposed an access to a-amino P-ketoesters from chiral p-enamino esters [ 12el. The amination reaction was performed with sulfonyloxycarbamate 6e (1 to 3 equiv.) in dichloromethane without base over two days, using chiral p-enamino ester derived from C, symmetric pyrrolidines 24 or (R)1-phenylethylamine 26 (Scheme 10).

...,

/OMe

I

NsONHC02Et P

Me0P

H

CHzCI2 rt

H

H3C

CO2Et

36 % yield major (R)-25

24

-

H Me PhANH

NsONHC02Et

0

@

CH2CI2

Et

It

49 O h yield

26

27 ee = 60 YO

Scheme 10

Chemical correlation allowed the determination of the absolute configuration of the major enantiomer of compound 25 and of the enantiomeric excess of 27. The authors suggest that these reactions proceed through an intermediate aziridine. ~

3.3 Dialkylazodicarboxylates Azodicarboxylates are efficient sources of positive nitrogen used in the preparation a-hydrazino and a-amino acids starting from chiral enolates. Di-tert-butyl 4a [3b] (DTBAD) and dibenzyl4b [3c] (DBAD) azodicarboxylates are the most commonly used reagents for diastereoselective electrophilic amination (Scheme 11). Both compounds are available commercially.

72

Genet, Greck and Lavergne

0

0

V K N = N A O T >

DTBAD 4a

0

DBAD

4b

Scheme 11

3.3.1 Electrophilic Amination of Silyl Ketene Acetals The E-silylketene acetals derived from ( lR,2S)-N-methylephedne esters were shown to be very useful reagents for the TiC1,-mediated asymmetric synthesis of a-amino and a-hydrazino acids [ 131. Thus, the asymmetric electrophilic amination was achieved using TiC1,- t-BuO,CN=NCO,t-Bu (DTBAD). (lR,2S)-N-Methylephedrine was treated with acid chlorides in dichloromethane to give quantitatively the correspondingesters. LDA enolization (THF, -78 "C) and Me,SiCl trapping at 78 "C gave the silyl ketene acetals 28 (95 %, Esz 2 95/5). Slow addition of the silylketene acetal in dichloromethane to 1 equiv. of the TiC1,-DTBAD complex in dichloromethane at - 80 "C gave good overall yields of the amination products with remarkable stereoselectivity. The major diastereomer of compound 29 can be separated and isolated by flash chromatography. The crude adducts 29 were hydrolyzed to give a-hydrazino esters which were saponified to afford a-hydrazino acids (R)-30. By use of the isolated stereomer 29 or by recrystallization (EtOH, 98 %), enantiomerically pure a-hydrazino acids 30 were obtained. Finally, hydrogenolysis of the N-N bond in the presence of PtO, gave the a-amino acids (R)-31in good yields. Starting from crude a-hydrazino acids 30, the pure a-amino acids 31 were obtained with 78 to 91 % ee. The use of recrystallized 30 gave only (R)-31 (ee 2 98 %) (Scheme 12, Table 3.1).

73

3.3 Dialkylazodicarboxylates

-

R H

DTBAD,Tic14

OSiMe3

CH2C12 -80 "C

co218u

0

H

28 1) CFSCO~H, rt, 1.5 h 2) LiOH, MeOH, rt 3) Dowex 5OW

29

x."

R

*

N/NH2 H

H02C

-

y

R

1) H2 I PtOp

2) Dowex 5OW

H02C

(R)-30

NH2

(R)-31

Scheme 12 Table 3.1 R

CH3 CH,Ph CH,CH(CH3), CH,CH3 (CH2)3CH3

Yield of 29 (%)

Yield of 30 (%)

Yield of 31 (%)

ee of 31 (%)

70

78 81 81 80 78

92 89 91 93 90

90.6 91 81.5 84 78

45

70 65 45

Absolute configurations and enantiomeric excesses of the products were checked by [a], comparison, by HPLC and capillary GC using chiral columns. In summary, a-hydrazino acids and natural and unnatural a-amino acids could be obtained in both the R and S configurations by this practical method. The silylketene acetals derived from l0-(aminosulfonyl)-2-bornylesterswere also good substrates in the electrophilic amination reactions using DTBAD. Enantioselective syntheses of a-amino acids were described by Oppolzer and co-workers [ 141. The crystalline starting esters 33 were usually obtained in 82-96 % yield by reaction of acid chlorides with the chiral alcohol auxiliary 32 in the presence of AgCN (Scheme 13).

0

32 Scheme 13

33

74

Genet, Greck and Lavergne

Kinetic or thermodynamic deprotonations of 33 (R = Bu) followed by addition of DTBAD (1.25 equiv., -78 “C, 1 h) furnished diastereomeric mixtures of aminating products: 34a and 34b (Scheme 14).

34a Kinetic : 81 LDA 1.1 equiv., THF, -78 “C Thermodynamic : LDA 1.1equiv., HMPA/THF (1:4), -78 “C 27

34b 19 73

Scheme 14

Significantly higher stereoselectivities were observed in the Lewis acid-promoted 1,Cadditions. Kinetically controlled deprotonatiodsilylation of esters 33 followed by treatment of the resulting crude ketene silyl acetals 35 with TiC14/”’i(Oi-Fr)4(2: 1) and DTBAD (1.25 equiv.) at -78 “C, gave the adducts 34 in good yields and excellent diastereoselectivities (Scheme 15; Table 3.2).

LDA

33

Me3SiCI

DTBAD OSiMe3

Tic14 I Ti(0iPr)d

35

34a

34b

major Scheme 15

Table 3.2 R

Yield 34a

CH, CZH, C3H7 i-C,H7 i-C& C4H9

81 84

C6H,3

PhCH, I-AdWtylCHz

72 73 71 85 69 76 65

+ 34b (%)

Diastereomeric ratio 34a34b 96.9:3.1 98:2 98.2:l.g 9752.5 96.5:3.5 96.3:3.7 9554.5 98.2: 1.8 82:18

3.3 Dialkylazodicarboxylates

75

The diastereomeric excesses were determined by HPLC and ‘H Nh4R on the crude product. The major diastereomers Ma were then purified by flash chromatography or crystallization and obtained in virtually 100 % de. Their (2s) absolute configuration was assigned by transformation to the corresponding (259-a-amino acids. Removal of the t-butyloxycarbonyl groups was obtained by treatment of M a with a solution of trifluoroacetic acid in dichloromethane (1: 1,O “C,3 h). N-N-Hydrogenolysis was achieved under H2 (75 psi, rt, 15 h) in the presence of a catalytic amount of PtO, in ethanol to afford crystalline a-amino esters 36. Finally, the chiral auxiliary was cleaved and regenerated by nondestructive transesterification in the presence of Ti(OEt),. The a-amino acid hydrochlorides (S)-37 were obtained by heating the crude amino acid ethyl esters in 6 N aqueous HCl and after evaporation of the solution (Scheme 16).

1) TFA, CH2C12

34a

2)Ha PQ

1) Ti(OEt)4, EtOH

R

*

0

2) 6 N aq. HCI

55 - a3 %

H ~ ~ / J \ ; ~ I H ’ .Hci

65 - 95 Yo 36

+ recovered 32 (>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 BocN, THF, 3 min 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 (COD)R~(2-methylallyl)~ [32]. These complexes preformed or prepared in situ 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

<+ 0-

s

Npoc

NHBoc

anti 78

79

Scheme 37

1) LiHMDS, -78 "C, THF

0'

*

2) DTBAD, -78 "C, THF, 15 rnin 3) CH3C02H. -78 "C .

S

NBoc \

NHBoc

syn 78 Scheme 38

80

3.3 Dialkylazodicarboxylates

89

Variation of 2-alkyl substituent exerted an effect upon diastereoselectivity. The best diastereoselection was obtained when incorporating a 2-ethyl substituent for acyl dithiane oxides (Table 3.6). The diastereoselectivity and the sense of induced stereochemistry can be rationalized on the basis of a simple chelation control model.

Table 3.6 Substrate

R

R'

syn 78

CH3 CH3 H CH3 CH3 CH3 H

'ZH5

anti 78

CH3 CZH5 'ZH5 C6H5

CH3 C2HS

Yield (%)

Diastereomeric ratio (%)

42 76 89 48 37 69 72

12:l 3:1 2 99:l 2.7:1 2: 1 -

Both enantiomers of the 2-ethyl- 1,3-dithiane-1-oxide starting material may be prepared selectively in up to optical purity. The aminated products are of interest as potential synthons for chiral synthesis of both enantiomers of a-amino acids. Electrophilic amination of a-arylketone enolates was involved as a key step in the synthesis of P-aminotetralin derivatives. Dibenzylazodicarboxylate 4b was employed as electrophilic aminating reagent. In a first approach, the electrophilic amination with DBAD was followed by a highly stereoselective reduction [42]. In a second approach, a diastereoselective synthesis of the C, symmetric 2,3-diaminotetralin was performed using a highly stereocontrolled electrophilic amination as the key step of the procedure. Starting from the N,N-dibenzylprotected &amino acid 81, the synthesis of the trans-2,3-diamino-1,2,3,4-tetrahydronaphtalene84 was reported

WI. For the elaboration of the synthesis, the p-amino acid 81 was used in its racemic form and was activated with thionyl chloride in dichloromethane for the ring closure. After treatment with AlC1, at room temperature, the aminotetralone derivative 82 was obtained. For the introduction of the electrophilic nitrogen, the ketone 82 was deprotonated with n-BuLi (1.2 equiv.) in the presence of HMPA (10 equiv.) in THF at -78°C. After 2 h, a solution of DBAD (1.5 equiv.) in THF was added, the mixture was stirred at -78 "C for 2 h, after which LiEt,BH was added to the crude aminating reaction mixture at dry ice temperature. After warming to room temperature, the cis-oxazolidinone 83 was formed by intramolecular transesterification and isolated in 56 % yield. The synthesis of 84 was completed by a hydrogenolytic degradation (Scheme 39).

90

Genet, Greck and Lavergne

1) SOClp, CH2C12 rt, 3 h, 86 %

2) AIC13, CH& rt, 0.5h, 81 %

NBn2

*

&N&

81

82

1) n-BuLi, HMPA THF, 2 h, -78"C

*

82

&

1) MeOH, H29 Raney-Ni rt, 1 h

'NHCbz

2)DBAD, 2 h, -78"C 3)LiEbBH, -78"C,16 h

2) H2, Pd(OH)Z/C rt, 2 h

NBnp

56 % yield

83

84

Scheme 39

On the other hand, an effective synthesis of P-aminotetralins including an asymmetric electrophilic amination by dialkylazodicarboxylateswas reported by the same authors [MI. a-Tetralones 85 were transformed into chiral imines 86 using various enantiomericallypure amino ethers. The imines were treated with DTBAD or DBAD to afford the aminated products 87 which are the precursors of the non racemic paminotetralins 88 (Scheme 40; Table 3.7).

85

86

x

H3COCHzC

A

R,&7

1) LDA, THF, -35 "C

H3COCH2C fOzR3

fo2R3

2)d02CN=NC02R3,THF, -78 "C

*

Or

N\ NHCO~RS

B : R302CN=NC02R3,THF, rt 87a

2)H2, WIC, 12-15 bars, EtOH, 70-75 "C 3)TFNCH2C12 (1:l)

Scheme 40

..d\ NHCO&

& JR l

87b

+ R1w

1) NaBHzCN, glacial AcOH, MeOH, rt

4) HP, Raney-Ni, 50 bars, MeOH, rt

+

88a

88b

3.3 Dialkylazodicarboxylates

91

Table 3.7 Entry

1 2 3 4 5 6

R'

H H H H H OCH,

R2

Bn Bn i-Bu i-Pr t-Bu i-Pr

R3

Bn t-Bu r-Bu t-BU

t-Bu r-Bu

Aminated product Yield; de of 87 (%) A

B

66; 40 86; 72 82; 76 -; 38 85; 46 -

72; 5 0 84; 74 85; 64 85; 58 85; 14 -

P-Aminotetralin Yield; ee of 88 (%) 51; 58 57; 72 54; 73 42; 76 26; 84

Deprotonation of the imine 86 (R' = H, R2 = Bn, entry 1) with LDA (1 equiv.) at -35 "C afforded an azaenolate which was diastereoselectively attacked at -78 "C by the electrophilic reagent DBAD (1.5 equiv.). After 3 min the reaction was quenched with a 10 % aqueous NH,Cl solution. After classical work-up and flash chromatography, the aminated product 87 was obtained in 66% yield as a 7:3 mixture of diastereomers 87a:87b (method A). The major diastereomer was characterized by 'H NMR spectroscopy (DMSO-d6,100 "C). Due to an imine-enamine tautomerism, 86 could be aminated without previous deprotonation; 86 reacted with DBAD (1.4 equiv.) in THF at 0 "C for 1 h. After evaporation of the solvent and flash chromatography, 87a and 87b were isolated in 72 % yield with a diastereomeric ratio of 7525 (method B). Analogous reactions were performed with DTBAD (entries 2, 3, 4, and 5). The absolute configuration of the created stereogenic center at the 2 position turned to be

(9.

P-Aminotetralins 88 were obtained after reduction of the imine functionality, reductive removal of the chiral auxiliary and deprotection and hydrogenolysis of the hydrazino group. The ee of the fhminotetralins were determined by HPLC analysis after derivatisation of the amines with (R)-phenylethylisocyanate. 3.3.5 Electrophilic Amination of Phosphorus-Stabilized Anions Although some reactions of electrophilic amination of phosphorus-stabilized anions had already been reported in the literature [5a,d], the first example of such a stereoselective reaction opening access to optically active a-amino phosphonic acids was described in 1992 by Denmark and co-workers [45] and by Jommi and co-workers [46]. Both of these groups used chiral amino alcohols as auxiliaries for diastereoselective induction in the aminating process. Denmark and co-workers chose trisyl azide (2,4,6-triisopropylbenzenesulfonyl azide) as equivalent of "NHF', whereas Jommi and co-workers performed the reaction with DTBAD.

92

Genet, Greck and Lavergne

a-Alkyl a-aminophosphonic acids are being extensively studied because of their potential bioactivity in relation to amino acids and peptides. The methods described hereafter derive from the analogue electrophilic amination of chiral enolates, which constitutes a general approach to a-amino acids. The transfer of chirality from phosphorus to the a-carbon has been widely used in asymmetric synthesis of organophosphorus derivates [47].

3.3.5.1 Oxazaphospholanes Chiral2-alkyl-2-0x0- 1,3,2-oxazaphospholanes90and 91 were chosen by Jommi and co-workers as a substrate for theoretical and experimental studies on the prediction of the diastereoselectivity of the amination reaction leading to a new stereogenic center a to the phosphorus atom. Various molecules were considered for studying the influence of the five-membered ring conformations, and of the bulkiness of the ring substituents on the diastereomeric excess of the aminated products. Optically active (+)-ephedrine 89a and (-)-pseudo-ephedrine 89b were chosen as the chiral amino alcohols because of their relatively low cost and in view of the excellent results obtained in the similar asymmetric synthesis of a-amino carboxylic acids [ 131. The 1,3,2-oxazaphospholanes9Oa-c and 91a-c were obtained in excellent yields by cyclization of the amino alcohols 89a-c with ethyl phosphonic dichloride in toluene in the presence of triethylamine. The mixture of diastereomers at the phosphorus center were separated by silica gel chromatography. Assignation of the absolute configurations was possible through a complete analysis of the 'H N M R spectra of the diastereomers and was confirmed by X-ray analysis for one derivate (Scheme 41). Later on, Sisti and co-workers further investigated this field with the aim of designing more powerful chiral auxiliaries [48]. Varying the methyl group of (-)-pseudo-ephedrine derivatives, they increased the sterical demand by selecting phenyl or benzyl substituents. Having established by calculation the importance of the restriction of rotational freedom for the ethyl group attached to the phosphorus, they predicted that the best diastereoselectivity should be attained using the benzyl substituent. (lR, 2s)- 1,3-Dipheny1-2-(N-isopropylamino)-1-propano1 89d was prepared from R-(+)-mandelonitrile, and its subsequent cyclization with ethyl phosphonic dichloride afforded the two diastereomeric oxazaphospholanes 90d and 91d in ratios depending on the temperature of the reaction (Table 3.8).

3.3 Dialkylazodicarboxylates

91

90

89

93

Scheme 41

Table 3.8 Amino R' alcohol 89a 89b 89~ 89d

CH, CH, CH, H

RZ

R3

R4

R5

Temperature

90 H H H Bn

H Ph Ph Ph

Ph

H H H

CH, CH, i-Pr i-Pr

-20°C to rt -20°C to I? -20°C t o r t -35°C ll0"C

+

Yield

Diastereomeric ratio 90:91

90 80 90 80 58

I:1 1:l 1:2 12.6:l 1:1.3

+ 91 (a)

The 2-ethyl-2-0x0- 1,3,2-0xazaphospholanes 90a-c and 90a-c were deprotonated at -78 "Cusing LDA (1.1 equiv.) in THE The resulting carbanion was treated with di-tert-butylazodicarboxylate (DTBAD; 1.1 equiv.) at the same temperature, and the reaction mixture was quenched with glacial acetic acid after either 3 or 30 min, without any change in the yield and diasteroselectivity of the reaction. The diastereomeric ratios of hydrazino products 4 were determined by 'H and/or 31PNMR. The electrophilic amination of compounds 90d and 91d after deprotonation at -30°C with LDA (1.3 equiv.) in THF, was performed with DTBAD (1.2 equiv.) at -30°C and -65 "C without any change in the diastereomeric excess (Scheme 42; Table 3.9).

90 or 91 Scheme 42

92

94

Genet, Greck and Lavergne

Table 3.9 Substrate

Yield of 92 (%)

Diastereomeric ratio of 92 (%)

90a 91a 9Ob 91b 9oc 91c 9Od 91d

50 55 54 62 58 68 41 68

1:l 2: 1 151

3: 1 1.51

4:1 3.2: 1

11:l

The use of a molecular modeling program and the study of the geometry of the starting molecules (interatomic distances and five-membered ring conformations in compounds 90a-c and 91a-c) enabled the authors to rationalize the factors influencing the course of the reaction. The nitrogen substituent plays an important role (de increased with R = i-Pr), and the best selectivities were obtained with molecules possessing envelope-like or twist-like conformations. The prediction of the model and the experimental results proved to be in good agreement. These methods have enabled the investigation of a series of chiral oxazaphospholanes as precursors of optically active a-amino phosphonic acids. The stereoselectivity of the amination process is dependent on the substituents of the chiral auxiliary, and in some cases a good level of asymmetric induction has been achieved (up to 83 % de); unfortunately, no absolute configuration of the final products was determined.

3.3.5.2 Diazaphospholidines Another important source of chiral auxiliaries for the synthesis of optically active phosphorus derivates are the C, symmetric diamines such as 1,2-diaminocyclohexanes. In 1994, Hanessian and co-workers described the use of N,N’-dimethyl-(R,R)1,2-diaminocyclohexane93 as a chiral auxiliary in the synthesis of optically pure or enantiomerically enriched a-alkyl a-amino phosphonic acids [49]. Starting from easily accessible optically pure diamine 93, they synthesized in good yield (75 %) enantiomerically pure (R,R)-ethylphosphonamide 94 by condensation with ethyl phosphonic dichloride in benzene in the presence of triethylamine (Scheme 43).

3.3 Dialkylazodicarboxylates

-

Me

C I ,

Me

NEt3

0

11

CfP'

95

Benzene rl

Et

I

\

Me

Me

75% yield (RW-93

(RW-94

Scheme 43

With the C, symmetry of the chiral diamine, no new stereogenic center is created at the phosphorus atom, thus avoiding the need for a sometimes difficult separation of diasteroisomers, such as with amino alcohols. The phosphorus-stabilized carbanion of 94 was generated at - 100"C with LDA (1.2 equiv.) in THE Amination reactions were performed both with DTBAD and trisyl azide. Direct addition of a stoichiometric amount of DTBAD (1.1 equiv.) at - 100"C followed by acidic quench led to a mixture of hydrazino products 95 (major diastereomer indicated) in good yield and diastereoselectivity (Scheme 44).

Me

(9R)-94

Me

67 Yo yield

95

74%de

73 Oh yield

Scheme 44

The major diastereomer 95 could be obtained in optically pure form by silica gel chromatography. The absolute configuration of the amination product was dictated by the choice of the chiral diamine, and correlated with previous results in asymmetric a-alkylation. Furthermore, the major diastereomer 95 was converted to the corresponding (R)-a-aminoethyl phosphonic acid 96 by sequential treatment with: (i) TFA, CH,CI,, 0 "C; (ii) 1 N HC1; and (iii) H,, PtO,, 70 psi, followed by Dowex 50 (H+) resin chromatography in 73 % overall yield. Optical rotation of the a-amino phosphonic acid 96 allowed the confirmation of its optical purity (> 98 %) and of its absolute configuration. In the course of a study on electrophilic amination of achiral phosphonates, Maffre and co-workers described a single example starting from the same chiral phosphonamide 94, and obtained a 4:l mixture of diastereomers 95 in 33 % yield [50].

96

96

Genet, Greck and Lavergne

3.4 Chiral Electrophilic Aminating Reagents 3.4.1 Azodicarboxylates and azodicarboxamides The preparation of chiral dialkylazodicarboxylates and their use as electrophilic enolate amination reagents, were first reported in 1995 by Vederas and co-workers [51]. A series of chiral dialkyl (menthyl 97a, bornyl 97b, isobornyl 97c) azodicarboxylates were prepared by conversion of the corresponding alcohols into chloroformates, condensation with hydrazine and oxidation with N-bromosuccinimide and pyridine. Compounds 97 were obtained in 35-50 % yield (Scheme 45).

R-OH

coc12

0 II

R-O-C-CI

N2H4

NBS

ROZCC-NH-NH-CO~R

pyridine

R02C-N=N-C02R

97

Scheme 45

Ester enolates generated by treatment of the corresponding esters with 1 equiv. of LiHMDS at -78 "C, were aminated by the chiral dialkylazodicarboxylates 97 at -78 "C (Scheme 46).

1) LiHMDS 2) R02CN=NC02R

97

98 Scheme 46

*

RiYcox +

R02CN

\

R'-COX R02Cr;i

\

R02CNH

R02CNH

(9-99

(R)-99

97

3.4 Chiral Electrophilic Aminating Reagents Table 3.10 Entry

97

R2

X

1 2 3 4 5 6 7

a a b

OEt OEt OEt OEt OEt OEt NMe,

8

C

Ph CH,CO,Et Ph Ph CH,CO,Et CH,CO,Et CH3 CH(CHJ2

C

b C

C

me2

Yield (%)

(S)-99:(R)-99

59 13 57 42 49 41 12 87

2: 1 1:l 1:l 1:l 1:l 1:1

1:l 1:l

The reactions of electrophilic amination displayed little if any stereoselectivity (Table 3.10, entries 1 to 6). The chromatographic separation of the diastereomers was generally quite difficult. The menthyl and bornyl carbamate moieties in products 99a and 99b proved to be very stable and difficult to remove, even with prolonged reflux in 6 M HCl or concentrated HBr, and the corresponding a-hydrazino acids could not be obtained in reasonable yield. However, the isobornyl99c analogues were readily hydrolyzed. Anions generated from tertiary amides preferentially assumed the Z-configuration. Reaction of N,N-dimethylamides with 1 equiv. of LDA at -78°C followed by addition of 1.5 equiv. of di(-)-isobornyl azodicarboxylate 97c gave in each case a 1:l ratio of diastereomers (R)-99 and (9-99 (Table 3.10, entries 7 and 8). Double diastereoselection was tested with chiral enolates: enantiomerically pure N-acyloxazolidinone (9-100 and its enantiomer (R)-100 were aminated at -78 "C with 97c (Scheme 47).

(q-100

(S,S)-101

(S)-102

(9-100

(R,R)-101

(R)-102

Scheme 47

In both cases, only one diastereomer could be detected using high-temperature 'H NMR spectroscopy. Removal of the oxazolidinone auxiliary from compounds (S,S)-lOl and (R,R)-101 by treatment with lithium hydroperoxide followed by acidification and treatment with diazomethane generated the corresponding methyl esters (9-102and (R)-102which have opposite configuration at C2. Amination of either

98

Genet, Greck and Lavergne

compounds (S)-lOO or (R)-100 with dibenzylazodicarboxylate4b gave a 9:l ratio of diastereomers with the same relative stereochemistry. In conclusion, the geometry of the Evans enolate completely controls the diastereoselection, and the effect of the isobornyl moieties is solely to increase steric bulk and enhance the ratio. Macrocyclic azodicarboxylates containing a steroid skeleton were also synthetized using a similar synthetic route [52]. These compounds were trapped by Diels -Alder reaction with cyclopentadiene. Finally, a synthesis of a chiral azodicarboxamide containing a bridging binaphtyl moiety was described by Vederas and co-workers, and electrophilic amination reactions of achiral ester enolates were performed [53]. The chiral azocarboxamide 105 containing a binaphtyl group was prepared by an intramolecular cyclization between the bis-(N-methylamine) of 2,2-dimethyl-l,1 '-binaphtyl 103 and N,N'bis(azidocarbony1)hydrazine 104 followed by oxidation with N-bromosuccinimide (NBS)and pyridine in 15 % overall yield (Scheme 48).

1) EbN, CI~CHZCH~CI~ A, 20 h.

NHMe2 NHMe2

+

2) NBS, pyridine

N3'NH+H-"I

103

* 105

104

Scheme 48

Achiral oxazolidinones 106 were aminated at -78 "C using the standard procedure. Only one diastereomer could be detected for the products using 'HNMR spectroscopy, and X-ray crystallographic analysis of 107 (R = Me) showed that the new stereogenic center had the (S)absolute configuration (Scheme 49). Attempts to remove the binaphthyl moiety to produce the optically pure free a-hydrazino acid have been unsuccessful.

1) LDA, -78 "C

106 Scheme 49

107

Me

85

CH2Ph

92

3.4 Chiral Electrophilic Aminating Reagents

99

3.4.2 Chiral Catalytic Approach A catalytic approach to the synthesis of arylglycines was proposed by Evans and coworkers using enantioselective amination of N-acyloxazolidinones [54]. Metallobis(sulfonamide) complexes derived from chiral diamines are potential chiral catalysts. The magnesium-bis(su1fonamide) complex 109 was generated by treating (S,S)-bis(su1fonamide) 108 with dimethylmagnesium in dichloromethane (Scheme 50).

108

109

Scheme 50

The catalyzed amination of phenylacetylimide llOa employing the magnesium complex 109 (10 mol %) and N-methyl-p-toluenesulfonamide(20 mol %) in 2: 1 CH,Cl,/Et,O afforded the hydrazide l l l a with an enantiomeric ratio (2S):(2R) = 93:7 in 92 % yield (Scheme 51, Table 3.11 entry a).

DTBAD

0A & A r

U 110 Scheme 51

10 % moll09 20 O h rnol pTosNHMe

BNL

0

Boci, NHBoc

111

100

Genet, Greck and Lmergne

Table 3.11 Entry

Ar

Time (h)

Temperature ("C)

Yield (%) ~

a

Ph

b

P-F-C~H, P-CH~O-C~H,

(2s):(2R) ~

- 65

92 97 93

93:7 955 93:7

72

-75

85

91:9

e

60

- 75

84

90:10

f

48

- 95

87

91:9

48 48 48

- 75

d

C

- 65

Enantiomeric purities of compounds 111 were determined by HPLC using chiral column (Daicel-ChiralcelOD-H). This amination procedure is applicable to a variety of aryl-substituted imides (Table 3.11, entries b to f). The amination adducts 111 are all highly crystalline, and a single recrystallization of the product hydrazides led to enantiomeric enrichment (96 to 99 % ee). Finally, the potential for utilizing lower catalyst loading was demonstrated by the preparation of l l l c from llk in > 99 % ee and 81 % yield after recrystallization using 5 mol % of 109 and 10 mol % of N-methyl-p-toluenesulfonamide.The role of the latter compound in this catalytic process has not yet been completely elucidated, but a kinetic investigation revealed a first-order dependence of this addend on reaction rate. Asymmetric induction could be rationalized: the reaction proceeds via the intermediacy of a chelated tetrahedral magnesium enolate complex. The chelation of both the (2)-imide enolate and bis(su1fonamide)ligand to the tetrahedral magnesium ion enforced the conformational rigidity of the intermediate and the Si-enolate acarbon diastereoface was exposed to the incoming electrophile. Evans and co-workers described the first catalyzed enantioselective enolate-electrophile bond construction which could be extended to a general catalytic enantioselective approach to the synthesis of a-amino acids.

References

101

3.5 Conclusion Electrophilic amination is a general entry to chiral a-amino acids or functionalized pamino and P-hydroxy a-amino acids with an anti stereochemistry. The chiral enolate technology has been applied for the obtaining of C - N bond-forming reactions with stereochemical control. Only one example of catalytic approach has been reported recently. The vast arsenal of chiral catalysts that is presently available, signals that future chapters dealing with this approach will be considerably well documented.

References [ l ] a) E. Erdik, M. Ay, Chem. Rev. 1989, 89, 1947; b) J. Mulzer, Organic Synthesis Highlights, VCH, Weinheim, 1991, p. 45; c) R. M. Williams, Synthesis of optically active a-amino acids, Pergamon Press, Oxford, 1989, p. 167- 187; d) G. Boche, Stereoselective synthesis (Houben-Weyl), 1995, Vol. E21, p. 5133; e) C. Greck, J. P. Genet, Synleff 1997, 741. [2] D. A. Evans, T. C. Britton, J. A. Ellman, R. L. Dorow, J. Am. Chem. SOC. 1990, 112,4011. [3] a) 0. Diels, H. Behncke, Chem. Ber: 1924,57,653;b) Di-tert-butyl azodicarboxylate, M. Klinge, J. C. Vederas, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Chichester, 1995, p. 1586; c) Dibenzyl azodicarboxylate, Y. Leblanc, ibid., 1995, p. 1532; d) Diethyl azodicarboxylate, E. J. Stoner, ibid., 1995, p. 1790. [4] a) W. Oppolzer, 0. Tamura, Tetrahedron Lett. 1990, 31, 991; b) W. Oppolzer, E. Merifield, Helv. Chim. Acta 1993,76,957;c) W. Oppolzer, 0.Tamura, G. Sundarababu, M. Singer, J. Am. Chem. Soc. 1992,114,5900; d) W. Oppolozer, J. Deerberg, C. G. Bochet, E. Merifield, Tetrahedron Len 1994, 35, 7015. [5] a) J. P. Genet, S. Mallart, C. Greck, E. Piveteau, Tetrahedron Lett. 1991,32, 2359; b) J. P. Genet, J. Hajicek, L. Bischoff, C. Greck, Tetrahedron Left. 1992,33,2677;c) C. Greck, L. Bischoff, A. Girard, J. Hajicek, J. P. Genet, Bull. SOC.Chim. FI: 1994, 131,429; d) C. Greck, L. Bischoff, F. Ferreira, J. P. Genet, J. Org. Chem. 1995,60,7010;e) J. P. Genet, C. Greck, Encyclopedia of Reagentsfor Organic Synthesis, John Wiley and Sons, Chichester, 1995, 898. [6] a) A. Casarini, P. Dembech, D. Lazzari, E. Marini, G. Reginato, A. Ricci, G. Seconi, J. Org. Chem. 1993,58,5620;b) P. Bernardi, P. Dembech, G. Fabbri, A. Ricci, G. Seconi, J. Org. Chem. 1999,64, 641. [7] a) D. A. Niederer, J. T. Kapron, J. C. Vederas, Tetrahedron Lett. 1993,34,6859;b) J. Vidal, J. Drouin, A. Collet, J. Chem. SOC. Chem. C o w . 1991,435; c) J. Vidal, L. Guy, S. Sttrin, A. Collet, J. Org. Chem. 1993, 58, 4791; d) J. Vidal, S. Damestoy, A. Collet, Tetrahedron Left. 1995, 36, 1439; e) J. Vidal, S. Damestoy, L. Guy, J. C. Hannachi, A. Aubry, A. Collet, Chem. Eur: J. 1997, 3, 1691. [8] G. Boche, C. Boie, F. Bosold, K. Harms, M. Marsch, Angew. Chem. Int. Ed. Engl. 1994, 33, 115. [9] For recent mecanistic studies of the electrophlic amination see : P. Beak, K. Conser Basu, J. J. Li, J. Org. Chem. 1999, 64, 521 8 and references cited therein. [lo] N. Zheng, J. D. Armstrong 111, J. C. McWilliams, R. P. Volante, Tetrahedron Lett. 1997. 38, 2817. [ 111 a) F. Ferreira, PhD thesis, University P. & M. Curie (FR), 1996; b) D. Lavergne unpublished work in these laboratories. [ 121 a) W. Lwowski, J. M. Maricich, J. Am. Chem. Soc. 1965,87,3630; b) S . Fioravanti, M. A. Loreto, L. Pellacani, P. A. Tardella, J. Oq.Chem. 1985,50,5365;c) S. Fioravanti, M. A. Loreto, L. Pellacani, P. A. Tardella, J. Chem. Research (S)1987, 310; d) S. Fioravanti, M. A. Loreto, L. Pellacani, P. A. Tardella, Tetrahedron 1991,47,5877;e) E. Felice, S. Fioravanti, L. Pellacani, P. A. Tardella, Tetrahedron Lett. 1999,40,4413; the same group also studied the asymmetric amination of chiral cyclic allylsilanes, M. A. Loreto, P. A. Tardella, D. Tofani, TefrahedronLett 1995, 36, 8295.

102

Genet, Greck and Luvergne

[13] C. Gennari, L. Colombo, G. Bertolini, J. Am. Chem. Soc. 1986, 108, 6394. [14] a) W. Oppolzer, R. Moretti, Helv. Chim. Acta 1986, 69, 1923; b) W. Oppolzer, R. Moretti, Tetrahedron 1988,44, 5541. [I51 R. M. Williams, Synthesis of optically active a-amino acids, Pergamon Press, Oxford, 1989, p. 1-133. [ 161 a) D. A. Evans, T. C. Britton, R. L. Dorow, J. F. Dellaria, J. Am. Chem. Soc. 1986,108.6395;b) D. A. Evans, T. C. Britton, R. L. Dorow, J. F. Dellaria Tetrahedron 1988, 44, 5525. [17] D. A. Evans, M. D. Ennis, D. J. Mathre, J. Am. Chem. Soc. 1982, 104, 1737. [18] L. A. Trimble, J. C. Vederas, J. Am. Chem. Soc. 1986, 108, 6397. [19] R. N. Ben, A. Orellana, P. Arya, J. Org. Chem. 1998, 63, 4817. [20] G. Frater, Helv. Chim. Acta 1979, 62, 2825. [21] J. Zimmermann, D. Seebach, T. K. Ha, Helv. Chim. Acta 1988, 71, 1143. [22] J. P. Genet, S. JugC, S. Mallart, Tetrahedron Lett 1988, 29, 6765. [23] G. Guanti, L. Banfi, E. Narisano, Tetrahedron 1988,44, 5553. [24] G. Guanti, L. Banfi, E. Narisano, Tetrahedron Lett. 1989, 30, 5507. [25] G. Guanti, L. Banfi, E. Narisano, Tetrahedron Lett. 1989, 30, 5511. [26] G. Guanti, L. Banfi, E. Narisano, S. Thea, Synlett 1992, 311. [27] G. Guanti, L. Banfi, E. Narisano, R. Riva, Tetrahedron Left. 1992, 33, 2221. [28] L. Banfi, G. Cascio, G. Guanti, E. Manghisi, E. Narisano, R. Riva, Tetrahedron 1994, 50, 11967. [29] C. Greck, L. Bischoff, F. Ferreira, C. Pinel, E. Piveteau, J. P. Genet, Synlett 1993, 475. [30] M. Gautschi, D. Seebach, Angew. Chem. Int. Ed. Eng. 1992, 31, 1083. [31] R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, J. Am. Chem. Soc. 1987, 109, 5856. [32] a) J. P.Genet, C. Pinel, V. Ratovelomanana-Vidal, S. Mallart, X. Pfister, M. C. Caiio de Andrade, J. A. Lafitte, Tetrahedron:Asymmetry 1994,5,665; b) J. P. Genet, C. Pinel, V. Ratovelomanana-Vidal, S. Mallart, X. Hister, L. Bischoff, M. C. Catio de Andrade, S. Darses, C. Galopin, J. A. Lafitte, ibid. 1994, 5, 675. [33] J. P. Genet, C. Pinel, V. Ratovelomanana-Vidal, M. C. Caiio de Andrade, X. Hister, P. Guerreiro, J. Y. Lenoir, Tetrahedron Lett. 1995, 36, 4801. [34] A. Girard, C. Greck, J. P. Genet, Tetrahedron Left. 1998, 39, 4259. [35] C. Greck, L. Bischoff, J. P. Genet, Terrahedron:Asymmetty 1995, 6, 1989. [36] C. Greck, F. Ferreira, J. P. Genet, Tetrahedron Lett. 1996, 37, 2031. [37] F. Ferreira, C. Greck, J. P. Genet, Bull. Soc. Chim. F,: 1997, 234, 615. [38] 0. Poupardin, C. Greck, J. P. Genet, Synlett 1998, 1279. [39] H. Estermann, D. Seebach, Helv. Chim. Acta 1988, 71, 1824. [40] E. Fernandez-Megia, M. M. Paz, F. J. Sardina, J. Org. Chem. 1994, 59, 7643. [41] P. C. B. Page, S. M. Allin, E. W. Collington, R. A. E. Can; Tetrahedron Lett. 1994, 35, 2427. [42] a) P. Gmeiner, B. Bollinger, Tetrahedron Lett. 1991.32, 5927; b) P. Gmeiner, B. Bollinger, Liebigs Ann. Chem. 1992, 273. [43] P. Gmeiner, E. Hummel, Synthesis 1994, 1026. [44] P. Gmeiner, B. Bollinger, Tetrahedron 1994, 50, 10909. [45] S. E. Denmark, N. Chatani, S. V. Pansare, Tetruhedron 1992, 48, 2191. [46] G. Jommi, G. Miglierini, R. Pagliarin, G. Sello, M. Sisti, Tetrahedron 1992, 48, 7275. [47] a) S. E. Denmark, C. T. Chen, J. Am. Chem. Soc. 1995, 117, 11879; b) Y.L. Bennani, S. Hanessian, Tetrahedron 1996.52, 13837; c) for a recent review on the asymmetric synthesis of organophosporus coumponds see 0. I. Kolodiazhnyi, Tetrahedron: Asymmetry 1998, 9, 1279. [48] R. Pagliarin, G. Papeo, G. Sello, M. Sisti, L. Paleari, Tetruhedron 1996, 52, 13783. [49] S. Hanessian, Y. L. Bennani, Synthesis 1994, 1272. [50] D. Maffre, P. Dumy, J. P. Vidal, R. Escale, J. P. Girard, J. Chem. Res. (S) 1994, 30. [51] J. M. Harris, E. A. Bolessa, A. J. Mendonca, S. C. Feng, J. C. Vederas, J. Chem. Soc. Perkin Trans. I 1995, 1945. (521 J. M. Harris, E. A. Bolessa, J. C. Vederas, J. Chem. Soc. Perkin Trans. I 1995, 1951. [53] J. M. Harris, R. McDonald, J. C. Vederas, J. Chem. Soc. Perkin Trans. 11996, 2669. [54] D. A. Evans, S. G. Nelson, J. Am. Chem. Soc. 1997, 119, 6452.

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

4 Glycosylamines as Auxiliaries in Stereoselective Syntheses of Chiral Amino Compounds Heiko Tietgen, Martin Schultz-Kukula and Horst Kunz

4.1 Introduction During the past few years carbohydrates have received increasing interest as stereodifferentiating auxiliaries in stereoselective syntheses. Since the first review in 1993 [ 11 which covered the synthetic possibilities of carbohydrate-derived auxiliaries in asymmetric synthesis, several hundred articles have been published describing carbohydrates as exhibiting efficient stereoselecting effects in asymmetric syntheses. This chapter will focus on the use of glycosylamines in the synthesis of biologically interesting compounds. Developments in asymmetric conversions using carbohydrates have recently been published in other reviews [2]. Although carbohydrates are cheap and readily available chiral compounds, their application in stereoselective synthesis was for a long time limited to ex-chiral-pool syntheses [3]. They have been considered too complex compared to other chiral auxiliaries, for example a-pinene in borane-chemistry [4] or BINAP-derivatives in reduction chemistry [5]. However, it has been shown during the past few years that carbohydrates can be successfully applied as stereodifferentiating tools in many different reaction types such as aldol- [6], hydrogenation- [7], carbonyl addition- [8], Michael- [9], Diels- Alder- [ lo], hetero-Diels- Alder [ 113, and rearrangement reactions [12]. In many cases, the substrate to be subjected to asymmetric conversion is coupled to the carbohydrate via the anomeric position. For the synthesis of amino compounds, the substrate is linked to the carbohydrate as a derivative of a glycosylamine. After completion of the asymmetric synthesis the product can be detached from the carbohydrate auxiliary by acidic hydrolysis. In most cases auxiliary and product can be separated by extraction or recrystallization techniques, and the carbohydrate auxiliary readily regenerated from its recovered detachment derivative. The class of carbohydrates offers many possibilities tuning the electronic and steric environments around the auxiliary-bound substrate. The steric shielding of the substrate can be varied by the choice of carbohydrate itself, and by the steric demand of groups attached to the neighbouring hydroxyl groups- these are often alkoxy-or ester groups (see Scheme 1).

104

Tietgen, Schultz-Kukulu and Kunz

OPiv

PivOk

N I0 H

2

2

Scheme 1

The higher steric demand of carbohydrate templates containing the pivaloyl ester usually results in a higher stereoselectivityin their reactions compared to those of the acetyl-protected analogues [ 131.

4.1.1 Exo Anomeric Effect The stereoelectronic situation of anomerically bound substrates is decisively influenced by the exo anomeric effect. Lemieux et al. [14] have found that the rotation around the exocyclic C-0-bond of glycosides is strongly hindered. This observation is interpreted as a delocalization of the lone pair of the oxygen into the CY*of the ring-C1-06bond of the carbohydrate. Analogous no* delocalization sterically adjusts glycosylamine derivatives in a preferred conformation (Scheme 2).

C'-N-projection

Scheme 2

The Newman projections illustrate that the lone pair electrons of the nitrogen should be preferentially antiperiplanar to the C'-06 bond. For a-anomers, the exo anomeric effect opposes the anomeric effect, thereby making the exo anomeric effect a more important conformational factor in equatorially orientated glycosides than in its a-anomeric analogues [15].

4.I Introduction

105

4.1.2 Influence of Coordinating Centers Carbohydrates easily complex oxygenophilic electrophiles, e.g., lithium cations and zinc(I1) chloride. The coordination between the carbohydrate moiety and the Lewis acids is an important factor which orients the auxiliary-bound substrate. The complexation of lithium cations through the carbohydrate moiety influences the reactivity and stereodifferentiation in carbohydrate-derived esters and their enolates [ 161. Coordination of the Lewis acid zinc(I1) chloride to glycosyl imines has strong influence on the stereodifferentiation in nucleophilic addition reactions to these imines (see Scheme 3).

Pivo

ppiv

complex A

Scheme 3

The zinc complex A is probably the reactive [ 171species in these conversions, as it activates the imine and tethers the carbonyl group of the ester group in 2-position with the anomeric imine. The Reside is shielded efficiently and the attack of nucleophiles at the Si-side of the imine is strongly favored.

4.1.3 Pseudo-Enantiomeric Carbohydrates in Stereoselective Syntheses A number of commonly used auxiliaries are available in both enantiomeric forms, for example the proline-derived auxiliaries RAMP and SAh4P [ 181 giving rise to the complementary stereoselecting reactions. However, many natural carbohydrates are available in only one configuration. The other enantiomer (usually the Lform) is very expensive in most cases and difficult to prepare. To overcome this limitation, readily available and cheap pseudo-enantiomeric carbohydrates can be used. Scheme 4 shows the pseudo-enantiomeric pairs D-galactose 3/D-arabinose 4 [ 191 and D-2-deoxyglucose 5L-2-deoxyrhamnose 6 [20].

106

Eetgen, Schultz-Kukula and Kunz

HO QH

PH

QH

D-arabinose

D-galactose 3

!

D-2-dso&umse

4

'

LQd~~rnnose 6

5

Scheme 4

D-Arabinose can be considered as an equivalent to L-galactose, as has been demonstrated in asymmetric Strecker syntheses [ 19bl.

4.2 Syntheses of Amino Acids 4.2.1 Syntheses of Enantiomerically Pure a-Amino Acids The stereoselective synthesis of a-amino acids is still an important goal in organic synthesis due to the growing importance of biomimetics. Schollkopf's asymmetric synthesis of a-amino acids is one of the most popular methods for the construction of enantiomerically pure a-amino acids [21]. Asymmetric variations of the Strecker synthesis of amino acids are of interest because only inexpensive and readily available substrates are required [22]. Stereoselective Strecker syntheses are achieved using glycosylamines, e.g., the tetra-0-pivaloyl-P-D-galactosylamine2 [23] as the chiral auxiliary. During this reaction galactosyl imines 7 of aldehydes with predominant E-configuration are formed [ 17,241. In the presence of zinc(II) chloride in isopropanol or tin tetrachloride in THF, these galactosyl imines 7 react with trimethylsilylcyanide (TMSCN) to give almost quantitatively the corresponding N-galactosyl-a-amino-nitriles 8 in high diastereomeric excesses (R:S 7- 13:1). The pure diastereomers are readily obtained by recrystallization from hexane. pivoOPiv

pivoOPiv

R-CHO

PivOk

N

OPiv

2

Scheme 5

b

Me3SiN PivO

A ZnCI,. ',-PIOH

b N y " BSnCI,,THF 7

H

PivO

a

R

4.2 Syntheses of Amino Acids

107

The hydrolysis of the pure R-aminonitriles 8a with HC1 and formic acid or HBr in acetic acid leads to the free D-amino acids 9 without racemization in high yields.

C P HCI, HCOOH or HBr t

CH3COOH

PivO

g,

H3N@

COOH

\

8a

CI

CI

Scheme 6

L-Amino acids 11are available by the same methodology using tri-0-pivaloyl-aD-arabinosylamine 10 as the chiral auxiliary [19b]. The stereoselectivity L:D 710:1 is slightly lower compared to that observed for the syntheses of R-aminonitriles 8 with galactosyl imines 7.The free a-amino acid is released from the auxiliary by hydrolysis with HCl in formic acid.

C P

a) R-CHO

PivO OPiv

b) Me3SiCN,SnCI,, THF c) HCI, HCOOH

10

m

H,&?COOH 50-1

R

11

Scheme 7

An alternative access to L-amino acids was found by using chloroform as solvent in the asymmetric Strecker synthesis with galactosyl imines [24]. This interesting reverse of asymmetric induction compared to the reactions shown in Scheme 5 can be explained by considering the zinc complex A as the crucial reactive species. Due to the exo anomeric effect, which is a delocalization of the n-electrons into the cr* of the ring C-0-bond, the imines adopt the conformation represented in Scheme 8.

108

Tietgen, Schultz-Kukula and Kunz

chloroform as solvent

THF as solvent Scheme 8

The conformation is proved by a significant NOE between the aldimine proton and the anomeric proton [ 17,241. In polar solvents, free cyanide attacks the complex A, preferably from the unshielded Si-side. In unpolar solvents like chloroform, cyanide is not set free from the silyl derivative. The activation of the cyanide proceeds by an interaction between the e m chloride of the zinc complex and the silyl group. Thus, the cyanide is directed to the Re-side of the glycosyl imine (see Scheme 8). This nucleophilic attack produces L-aminonitriles with moderate or good stereoselectivity (S:R 3-9:l) and high yields. The Ugi reaction provides another access to a-amino acid derivatives [25]. This important multicomponent reaction will be discussed in Section 4.2.4.

4.2.2 Syntheses of Enantiomerically Pure P-Amino Acids Glycosylamineswere shown efficient stereodifferentiatingtemplates in the synthesis of enantiomerically pure P-amino acids. They react with silylketene acetals and zinc(I1) chloride as the promoting Lewis acid via a Mannich-type pathway to give p-amino acid esters 12 in high yields and high diastereoselectivity [26], (Scheme 9).

OPiv

OSiMe,

PivO

p i v o & G y7

ZnCI,, >=(,Me THF, -30 "C

H

PivO 12

DV 20-200:1

Scheme 9

109

4.2 Syntheses of Amino Acids

The original assignment of the absolute configuration (3s) for products 12 based on a comparison of the optical rotation value with a reported one for the phenyl derivative [27] must be considered uncertain. It would contradict the preferred attack of the nucleophile from the unshielded back side and the stereoselectivity observed in the reaction of N-galactosyl imines 7 with prochiral bis-silyl ketene acetals [28]. N-Galactosyl p-amino acids 13 are produced from bis-silylketene acetals in high yields and excellent diastereoselectivity (Scheme 10). The configuration at the P-position is R.

H PivO

OSiMea PivO

ZnC12, THF, -30 "C

k

erythro

&# / Q i P

OPiv

7

y

H

y

OH

OPiv 13

R

O

DV 20:1:O:O

Scheme 10

During this reaction, two new chiral centres are formed. The formation of one diasteromer with high selectivity shows the potential of the chirality transfer from carbohydrate templates. Conversion of the 2,3-diphenyl alanine into the corresponding 3-amino propanol proved the erythro configuration of the major diastereomer. Carbohydrate-derived homoallylamines have been demonstrated as being useful chiral synthons for the stereoselective synthesis of p-amino acids. With allyltributylstannane or allyltrimethylsilane as the nucleophiles, glycosyl imines form homoallylamines with high efficiency [29-3 13. Promoted by SnCl,, the nucleophile allyltributylstannane attacks from the sterically less hindered side.

SnC14,THF b

PivO

PivO 7a

Scheme 11

110

lletgen, Schultz-Kukula and Kunz

The product 14a is obtained in excellent diastereoselectivity(> 251) (Scheme 11). Zinc (11) chloride is not able to promote the nucleophilic addition. If the reaction temperature can be held below 10°C, no anomerization is observed. The Si-side attack is rationalized by a complex B between SnCl, and the glycosyl imine 7a (Scheme 12).

complex B

Scheme 12

The nucleophile attack of the allylstannane again proceeds at the unshielded Siside of the imine and finally leads to the desired homoallylamines with (S)-configuration. These homoallylamines (16) are detached from the carbohydrate auxiliary by acid-catalyzed hydrolysis, and can be converted into the enantiomerically pure pamino acids (17) in a two-step procedure via oxidative degradation of the terminal double bond.

Scheme 13

The corresponding (R)-homoallylamines are correspondingly synthesized from arabinosyl imines 18b or fucosyl imines 18a with high diastereoselectivity (> 251) [30,32], (Scheme 14).

4.2 Syntheses of Amino Acids

111

PivO

SnC14,THF c

R R=CH 19a R=H \9b

R=CH3 18a R=H 18b

Scheme 14

Reactions of glycosyl imines derived from aliphatic aldehydes must be carried out at low temperature due to their higher sensibility towards anomerization. Yields and diastereoselectivity rank in the same region as those achieved for galactosyl homoallylamines. The results of different stereoselective allylations, are summarized in Table 4.1.

Table 4.1 Diastereoselective formation of homoallylamines ~

~

~

GIycosylimine

Nucleophile

Yield (%)

Diastereomeric acid (S:R)

14a 14a 18a 18b

Bu,Sn-ally1 Bu,Si-all yl Bu,Sn-ally1 Bu,Sn-ally1

85 80 19

> 251 > 20:l

15

1:15 1:18

Recently, p-amino acids have been reported attractive for the construction of ppeptides [33] which adopt interesting secondary structures [34]. A number of alternative stereoselective syntheses of p-amino acids have been reviewed recently [35].

4.2.3 Rearrangement Reactions Stereoselective rearrangement reactions can involve sugar-linked functionalities. An example of this type is the Overman rearrangement of allylic trichloracetimidates formed from a D-glucofuranose derivative 20 [36]. This methods affords (L)-a-amino acids 25 from (Z)-allylic imidate 23 and (R)-a-amino acids 25 from (a-imidates 23 with a diastereoselectivity of about 16:1. The oxidative cleavage of compound 24 with RuO, yields the a-amino acid 25, (Scheme 15).

112

Tietgen, Schultz-Kukula and Kunz

H2/Pd/CaCOi

I -

KH, CCgCN

A, Xylene

R'=C&; $=H (D) R'=H; R2=C& (L) 25

24

Scheme 15

Rearrangement reactions which result in ring opening of the carbohydrate ring give access to interesting classes of compounds. Thus, glycosyl homoallylamines can be used for stereoselective chain extension reactions on carbohydrates [ 121. After treatment with boron trifluoride etherate or titanium tetrachloride, galactosyl homoallylamine 14a undergoes cationic aza- Cope-rearrangements with high diastereoselectivity.The reaction was carried out at room temperature, and gave almost quantitative yield of 26 within 10 min (Scheme 16).

pivo OPiv

pivo OPiv

PivOk ! - P h PivO

Qi 14a

BF3-etherate

Mene

c

PivOk

N

*

P

h

PivO $3)

-= 26

Scheme 16

The reaction mechanism was rationalized as an Lewis acid-induced ring opening of the carbohydrate. This iminium cation is subjected to an aza-cope-rearrangement.

4.2 Syntheses of Amino Acids

Piv?

113

pPiv BF,-etherate

PivOk%!*Ph

PivO

C

$-$-..

-

pivo OPiv

PivO

PivO 4

PivO

-e

Scheme 17

The process yields an interesting synthon for the synthesis of higher sugars with complete stereocontrol. Higher sugars play important roles in many biological processes. Prominent examples are KDO (3-deoxy-D-manno-octulosonic acid), a component of bacterial liposaccharides [37], and N-acetylneuraminic acid, which is a crucial component of human and animal glycoconjugates [38,39]. In addition, derivatives of N-acetylneuraminic acid show remarkable antiviral properties [40]. This aza-Cope-rearrangement is a common reaction type for glycosyl homoallylamines with high stereoselectivity and proceeds in excellent yields. D-Arabinosyl homoallylamines 19 and D-glucosyl homoallylamines 27 rearrange accordingly in the described way [41], (Scheme 18).

OPiv OPiv OPiv PivO PivO k

c

! PivOA

P

h

2-

28

27

PivO

OPiv OPiv

*

19

Scheme 18

29

114

i’ietgen, Schultz-Kukula and Kunz

Table 4.2 Chain extension of carbohydrates via aza-Cope-rearrangements Glycosylhomoallylamine Lewis acid 14a 14a

27 27 19

BFOEt, TiCl, BF,*OEt, TiCl, BFtOEt,

Yield (%)

Diastereomeric acid (R:S)

Quant. 85 92 Quant 88

> 25:l 20:1 15:l 20:1 1:18

4.2.4 Stereoselective Multicomponent Reactions The newly available biological high-throughput screening (HTS) systems have induced many initiatives in the field of combinatorial chemistry [42]. Besides oligopeptide syntheses [43], multicomponent reactions offer attractive methods for the production of high-diversity libraries. Passerini and Ugi reactions (Scheme 19) are frequently used for synthesis of libraries containing thousands of compounds 1441.

Passerini reaction

Ugi reaction

Scheme 19

The Ugi reaction produces a-amino acid amides from four components (isonitrile, carboxylic acid, aldehyde, and amine) in a one-pot reaction. With glycosylamines and ZnC1, as promoting Lewis acid, a-amino acid amides are obtained [ 13,451 with excellent stereoselectivity in these reactions. For example, the galactosylamine 2 gave Ugi product 30 with formic acid as carboxylic component and various aldehydes and isonitriles in high yields and a diastereoselectivity of 19:l in favor of the D-amino acid amides 30 (Scheme 20).

4.2 Syntheses of Amino Acids pivo OPiv

115

OPiv

HCOOH, R-CHO,ZnCl tBu-NC ,, THF t PivOk

NOPiv

ST$&

pivo

b

OPiv 30

2

R

Scheme 20

Glycosyl imines from aliphatic aldehydes are sensitive to anomerization. However, the anomerization can be avoided by conducting the reactions at lower temperatures (-78 "C). Recrystallization of the crude products (methanoVwater for aliphatic, heptane for aromatic compounds) gave the diastereomerically pure D-amino acid amides (Table 4.3). Table 4.3 Diastereoselective Ugi synthesis of D-amino acid amides with galactosylamine 2

R' n-propyl isopropyl rert-butyl phenyl StYVl

Temperature ("C)ltime D:L-ratio

Yield (%)"I

-7812 days

80 86 80 80

94:6 955 96:4 955 955

-7812 days

-2513 days -2511 days -2511 days

15

Yield is given for pure D-amino acid amides.

The high stereoselectivity can be explained again by means of the zinc complex A (see Scheme 3). The nucleophilic isonitrile attacks the glycosyl imine from the sterically less shielded Re-side. The bulky pivaloyl group at the 2-position and the formed zinc complex block the Si-side efficiently. The exchange of the pivaloyl for the acetyl group decreases the selectivity of the reaction (1O:l instead of 30:l) [13]. L-Amino acids amides 31 can be synthesized easily according to this procedure in high yields and high diastereoselectivity using the pivaloylated D-arabinosylamine 10 as the auxiliary [19].

PivO

PivO OPiv

R-CHO, tBu-NC t

HCOOH, ZnCI,, THF

10

Scheme 21

31

116

Tietgen, Schultz-Kukula and Kunz

The pure diastereomers of compounds 31 are obtained by recrystallization or flash chromatography (Scheme 2 1). The stereoselective synthesis of aliphatic, aromatic, branched-chain, and heteroaromatic amino acid amides has been demonstrated by using this methodology. Table 4.4 illustrates the wide scope of the reaction. 'lhble 4.4 Diastereoselective Ugi synthesis of L-amino acid amides with D-arabinosylamine 10

R'

Temperature ["C]Itime L:D

Yield (%)a)

tert-Butyl Benzyl 4-Chlorphenyl 2-F~ryl 2-Thienyl

-2513 -7811 -2511 -2511 -2511

85 87

a)

days days days days days

973 97:3 98:2 96:4 4:96

91

85 85

Yield of pure L-amino acid amides.

D-Arabinosylamine10is more reactive and shows even higher asymmetric induction than D-galactosylamine 2 in this case [19b]. A variation of this method was reported by Ugi et al., who used 2-acetamidoglucosyl imine derivatives for the synthesis of @)-amino acid derivatives [46]. Linderman and his group applied so-called "convertible" isonitriles [47]for this type of glycosylamine-based Ugi reaction. The 0-silylprotected isonitrile 32 was reacted with tri-0-pivaloylarabinosyl imines or tetra-0-pivaloylgalactosyl imines (Scheme 22). The diastereoselectivity ranked in the same range as that given in Table 4.3.

-

32

33

kNb

34

OPiv

SUg'=

Pi*

pi&piv

NH2

OPiv 2

Scheme 22

10

a)MeOH, sat. HCI 0 % 1 h,rt,3h b) HsO, rt, 12 h

117

4.2 Syntheses of Amino Acids

Ziegler et al. used anomeric glycosyl isonitriles for stereodifferentiation in Passerini and Ugi reactions [48](Scheme 23). Peracetylated and perbenzylated glycosyl isonitriles were chosen in these reactions. Passerini reactions are performed with acetic acid 38 as carboxylic acid component and N-Boc-protected glycinal 37a or phenylalaninal 37b. In the Ugi reactions, the glycosyl isonitriles were reacted with iso-butanal40b, N-Boc-glycine 41, and n-propyl amine (Scheme 24). No significant diastereoselectivity has been observed in these processes, and the results are summarized in Table 4.5.These results illustrate that the stereodifferentiating influence of the carbohydrate depends decisively on its relative position to the reaction center.

Passerini reaction

R2-COOH

R3-NH,

Scheme 23

OAc OAc NC

A -c AcO

H~

N

H

B

~

" O0Y

0 R=H 37a R=CHPPh Wb

36

38

OBn

/

HO' f " ~ ~ o c

QBn

BnoN -C BnO

0

0 39

R=H 4Oa R&H,

Scheme 24

40b

W T N H ,

0 41

42

118

Tietgen, Schultz-Kukula and Kunz

Table 4.5 Ugi and Passerini reactions with glycosyl isonitriles ~

R-NC R-CHO R-COOH

36 36 36 36 36 39 39 39

37a 37b 40a 40b 40b 37a 3713

4Ob

38 38 38 41 42 38 38 41

R-NH,

Solventkime

CH,C12/3 days CH,CI2/3 days CH,C12/l days CH2CI2/37days MeOW8 days CH,C12/6 days CH2C12/8days CH,C1,/25 days

Yield (%)

(Diaste- Product reomeric ratio (R:S)

23 41 80 22 15 31 35 35

55:45 58:42 5050 55:45 63:37 57:43 52:48 6040

Passerini-product Passerini-product Passerini-product Ugi-product Ugi-product Passerini-product Passerini-product Ugi-product

4.3 Stereoselective Syntheses of Chiral Heterocycles Heterocycles are very important in pharmaceutical research [49,50] and the stereocontrolled synthesis of chiral heterocyclic compounds is therefore a major task in modem organic chemistry. Besides catalytic methods, auxiliaries are valuable for asymmetric syntheses of chiral heterocycles. Carbohydrates have been used as auxiliaries in the stereoselective formation of heterocycles, as well as in the stereoselective introduction of functionalities into the heterocyclic framework.

4.3.1 Heterocycles Through Cycloaddition Reactions

+

Glycosyl imines are not very reactive dienophiles in [4 21 cycloaddition reactions. However, they can be subjected to cycloaddition reactions after activation with Lewis acids [511. N-Galactosyl imines 7 were shown to react with isoprene in the presence of zinc(II) chloride to give the corresponding 4-methyl piperidine derivatives 43 (Scheme 25).

PivO

PivO H 7

DV 4-10:l

Scheme 25

.. El

43

4.3 Stereoselective Syntheses of Chiral Heterocycles

119

The diastereoselectivity achieved in these conversations is moderate (4- 10: 1). However, all products 43 can be obtained in diastereomerically pure form either through recrystallization or flash chromatography. The absolute configuration of the products has not yet been confirmed, but it can be assumed that the major diastereomers have (S) configuration according to a controlled approach of the diene to zinc complex A from the less shielded side. Some examples of these Aza-DielsAlder reactions. are shown in Table 4.6.

Table 4.6 Diastereoselective Aza-Diels- Alder reactions with N-galactosyl imines and isoprene R

Temperature T ("C)

Yield (%)

Diastereome- Isolated pure diastereomer ric ratio (%)

p-ClC6Hd p-FC,H, 2-F~ryl 2-Thienyl

$4 +4

95 90 98 95

87:13 91:9

12h

12h 4 days 4 days

+ 20

+ 20

80:20 84:16

60 % 52 % 65 % 56 %

The reactions can also be promoted by SnCl,, the diastereomers with the opposite enantiomeric configuration being obtained by using imines 18 derived from D-arabinosylamine 10 [32] (see Scheme 26).

PivO

PivO

18

H'

Scheme 26

The isolation of an intermediate revealed that the reaction proceeds via a tandem Mannich- Michael addition pathway. The zinc (11) chloride-promoted cascade reaction starts with a Mannich reaction. For a number of reactions, the Mannich-type intermediate can be isolated if the reaction is stopped by addition of diluted ammonium chloride solution [52,53].

120

fietgen, Schultz-Kukula and Kunz O-SiMe3

a) aq. HCI

Me0

L

PivO

PiVO

H

7

46

OPiv

aq. HCI

PivO 45

Scheme 27

The Mannich reaction is followed by an intramolecular Michael addition and a subsequent condensation reaction. The so-formed 2-substituted didehydropiperidines 46 are obtained in high yields and excellent diastereoselectivity (Scheme 27). The reaction can be carried out with glycosyl imines derived from a broad range of aliphatic, aromatic, and heteroaromatic aldehydes. Piperidinones of opposite enantiomeric configuration are available by applying the corresponding D-arabinosyl imines 18 [32]. The major diastereomers are isolated by flash chromatography or recrystallization in high yields. The 2-propyl dehydropiperidine 46a can be readily converted into enantiomerically pure (R)-coniine hydrochloride 47 (Scheme 28).

Pivo

a) L-Selectride

YPiv

b)

PivO

Piv46a

-

"'WSH IBF,

c) HP, Raney-Ni d) HCVMeOH

/ \

H H

(R)-coniine hydrochloride 47

Scheme 28

The confusion about the configuration of natural coniine in the literature [54] was clarified by a X-ray analysis of crystals of 46a, which proved the R-configuration of the synthesized compound, and also of the naturally occuring coniine [53]. The formation of (S)-anabasine hydrochloride 48 [5 1,521 (Scheme 29) confirms a backside attack of the diene system at the zinc complex A during the initial Mannich reaction of the 3-pyridyl aldimine 7b (see Scheme 3)

121

4.3 Stereoselective Syntheses of Chiral Heterocycles ,0-SiMe3 P

i

v

k

a) Me0

~

P

ZnCI,, THF, -20 "C PivO

\ N

N\

PivO

*

i

v

PivO

46a

H H

~

PivO

b ) aq HCI 7b

kN

IS\

yh'

C) H2, Raney-Ni d) HCVMeOH

"'

(9-anabasine hydrochloride 48

Scheme 29

The chiral piperidinones 46 formed by the reaction between Danishefsky's diene and the glycosyl imines are valuable synthons for the synthesis of higher substituted piperidine derivatives. 2,6-Disubstituted piperidinones 49 are obtained by addition of organocuprates complexes with boron trifluoride [53]. The reaction pathway is illustrated in Scheme 30. pivo OPiv

R2MgCI, Cul, BF3'Et20 PivO

*

THF, -78°C

kNVo PivO R' 46

49

Scheme 30

The cis 2,6 disubstituted piperidinones 49 are formed preferentially in this Michael-type addition reaction (Table 4.7). Table 4.7 Synthesis of 2,6-disubstituted piperidinones 49 ~~

R

R'

Yield (%)

Diastereorneric ratio &:trans

i-propyl 3-fury1 4-cyanophenyl 5-hexenyl 3-fu~l

allyl i-propyl allyl n-propyl i-amyl

66 61 16 81 61

3: 1 > 12:l > 8:l > 12:l > 8.1

o

122

Tietgen, Schultz-Kukula and Kunz

The reaction can be alternatively carried out with TMSCl as a Lewis acid and organocuprates [53].(-)-Dihydro-pinidine, the enantiomer of an alkaloid from Pinus jeflei, has been synthesized in excellent overall yield following this method. Piperidinone 46a was treated with Gilman's cuprate and trimethylsilylchloride in THF at -78 "C,such that the 2'6-disubstituted piperidinone 49a was obtained in high yield and diastereoselectivity. Its carbonyl group was reduced in a two-step procedure via formation of the dithiolane and subsequent desulfurization with Raney nickel. The (-)-dihydro-pinidine hydrochloride 51 was released quantitatively from the carbohydrate auxiliary by treatment with 0.1 N HC1 and methanol. The auxiliary can be recovered during the work-up procedure (see Scheme 31).

~~o

Pi"&

pivO

a) THF. Me2CuLi. -78 TMSCl "C b) TBAF, THF

Pivo

pi*

pvo

DV z 1O:l 4911

46a

b) **SH

c) H2, Raney-Ni 1

PivO

PivO 15

OH OH

tHi/N\ N \ HH

Q

-

%I (-)-dihydm-pinidinehydrochloride 51

0.1 M HCVMeOH ( 1 5 ) PivO 50

Scheme 31

The chiral piperidinone derivative 46a also opens up an efficient way to synthesize indolizidine alkaloids [53],e.g., gephyrotoxin 167B 54 [55], a minor alkaloid from glandular secretions of Dendrobutes pumilio, a South American frog of the tropical forest [56]. The 3-(1-ethoxy-ethoxy)-propylgroup was introduced into 46a via a 1,4 addition, with moderate diastereoselectivity. The decreased diastereoselectivity in this reaction has been rationalized by an interfering coordination effect exhibited by the functionalized side-chain of the organocuprate. The formed 2,6-disubstituted piperidinones (cidtruns, 3: 1) were cleaved from the carbohydrate auxiliary by acidic hydrolysis, the ethoxyethyl group being removed under these conditions. The free piperidinone 52 was converted into the corresponding chloride by an Appel reaction [57]. This then cyclized to give the pure cis indozilidinone 53 [53].The trans isomer

mF3

123

4.3 Stereoselective Syntheses of Chiral Heterocycles

obviously does not cyclize under these reaction conditions. The cis indozilidinone 53 was reduced in the two-step procedure via desulfurization of the dithiolane with Raney nickel (Scheme 32). Gephyrotoxin 167B 54 was obtained without further purification in the enantiomerically pure form.

3:l

Me3SiCI,THF, -78 "C c

PivO

HO

b) 0.1 N HCI, MeOH

H 52

1

I a)

HSMSH /eF3 CH2Cb

c) H,, Raney-Ni, i-PmH, 70 "C gephymtoxin 1678 54

PPh3 CCI, Et3N,'MeCN

cy-

pure cis

53

Scheme 32

Decahydroquinolines are another important class of alkaloids isolated from the skin of tropical frogs. Frogs of the family Dendrobates pumilio produce highly toxic alkaloids, the pumiliotoxins [%I. hmiliotoxin C, one of the prominent members of this class of compounds, has a cis-annulated decahydroquinoline structure, whereas toxins of the related family of Dendrobates histrionicus have trans-annulated decahydroquinoline structures [49]. These decahydroquinoline systems can be synthesized from the galactosylamine auxiliary 2 in a 12-step pathway(see Scheme 33)

WI.

124

Tietgen, Schultz-Kukula and Kunz

/

-a) 0

N & 3iP

Pentane, MS 4A OSiMe3 ~~

PivO

&-t

2

/

Pivo

b' Me ZnCI2'0Et2, THF, -20 C '

46b DV > 4O:l

I PivO P i

v

o

h

b a) Na104, K20s04cat. aq. Dioxan b) NaOH, dibenzo-l8cr.-6 benzene

55

v

h

k

,

PivO 491,

a) Me2Culi, MgSiCl THF. -78 "C b) TBAF

DV > 1O:l

a) HCI aq. MeOH b) Z-CI, NaHC03

\

c) HS-SH PivO

PivO P i

4

PivO

1

n-PrMgCI, Cul ~ ~ ~ 9THF. 0 ~ -704o c.

PivO

DV > 15:l:O:O

56

U

BF3*OEt, d) H2, Raney-Ni 9) HCI

I' -\

H H 4a-epi-pumiliotoxinC hydrochloride 57

Scheme 33

Galactosylamine 2 gave the corresponding galactosyl imine 7 with 5-hexenal. The galactosyl imine reacted with Danishefsky's diene to give the piperidinone system 46b with excellent diastereoselectivity. The 2,6-disubstituted piperidinone 49b was obtained by Michael addition of the cuprate in high yield and diastereoselectivity. The terminal double bond was converted into the aldehyde by oxidative cleavage. A base-induced intramolecular aldol condensation furnished the pumiliotoxin skeleton 55. The conjugate addition of Gilman's cuprate in the presence of trimethylsilyl chloride resulted in the formation silyl enolether of the 1,Cmethyl adduct. Treatment of the silyl enolether with aqueous tetrabutylammonium fluoride surprisingly gave the trans-annulated decahydroquinoline system 56. Comins and Dehghani [60] have reported the protonation of this type of silyl enolethers carrying a phenoxycarbonyl group as the amino-protecting group by an analogous fluoride-induced cleavage. However, these protonations proceeded with preferred formation of cis-annulated decahydroquinolinones. It is interesting to note, that the carbohydrate moiety is obviously able to steer the protonation of the intermediate enolate stereoselectively to the thermodynamically disfavored direction. This first example of a carbohydrate-

4.3 Stereoselective Syntheses of Chiral Heterocycles

125

induced selective protonation was confirmed by X-ray analysis of the rrans decahydroquinoline derivative 56 [59]. The decahydroquinoline has been released from the carbohydrate auxiliary by acid-catalyzed hydrolysis. After introduction of the N-benzyloxycarbonyl (Z) group, the above-mentioned two-step reduction of the carbonyl group and the subsequent hydrogenolytic removal of the Z-group furnished enantiomerically pure 4aepi pumiliotoxin C hydrochloride 57.

4.3.2 Stereoselective Syntheses of Chiral Piperidines via Addition Reactions to 4-Pyridones An alternative stereoselective synthesis of chiral heterocycles based on carbohydrate-induced stereodifferentiation includes nucleophilic addition reactions on heterocyclic systems already bound to the carbohydrate auxiliary. An example of this strategy has been shown by stereoselective addition of Grignard reagents to carbohydrate-linked 4-pyridones [61]. For this purpose, trimethylsiloxypyridine was glycosylated regioselectively using pivaloyl-protected glycosyl fluorides.

QSiMe3 PivO

PivO

%

PivO

PivO

PivO Lewis Acid I DCE, 70°C

F

59

58

R=CH,OPiv R=H PivO PivO

Scheme 34

I

a) i-Pr,SiOTf 2,6 Lutidin. CH,CI, b) R' MgX, THF or OEt,

PivO

126

Tietgen, Schultz-Kukula and Kunz

The reaction, which was reminiscent of the Vorbriiggen methodology [62], must be catalyzed by titanium tetrachloride and gave the N-glycosylpyridones 59 in high yields and with excellent regioselectivity. These N-glycosyl pyridones 59 can be activated via 0-silylation using triisopropylsilyltrifluoro-methanesulfonatein the presence of 2,6-lutidine. The so-formed 4-siloxypyridinium salts have been treated with a variety of Grignard reagents to form the corresponding 1,4 addition products 60 with excellent regio- and stereodifferentiation. The results of this synthesis are summarized in Scheme 35 and Table 4.8. Table 4.8 Stereoselective addition of Grignard reagents at N-glycosylpyridones ~~

R

R'

Reaction time (h)

CH,OPiv CH,OPiv CH,OPiv H

Me

2.5 1 2

H H H

n-Pr Ph n-Pr Ph

n-Bu Me

Yield (%)

9.55 90:lO 0:loo 88:12 0: 100 88: 12 1oo:o

14

1

84 83 100

1 1 4

96 91 31

Diastereomeric ratio (S:R)

This methodology opens up an efficient stereoselective access to chiral piperidinone derivatives 60 which have opposite configuration compared to compounds 46 obtained by the tandem Mannich -Michael reaction sequence described in Section 4.3.2. The high diasteroselectivity and regioselectivity in these reactions once again illustrate the stereodifferentiatingpotential of carbohydrates in the synthesis of chiral heterocyclic systems.

P

i

v

O

k ~~o

a) 2,6-lutidine, i-Pr3SiOTf CH& h

PivO

P i d h N v 0 PivO PivO

b) RMgX, THF or OEt2

PivO

X=

59

60

R

,O--SiMe3

A

a) Me0

ZnC12, THF, -20 "C

p i v o & H U c b) & aq HCI y R PivO 7

Scheme 35

..

P

*

i

v

o

kN

~

PivO PivO

46

R "

n

References

127

4.4 Conclusions Carbohydrate-derived auxiliaries exhibit an efficient stereoselective potential in a number of nucleophilic addition reactions on prochiral imines. a-Amino acids, pamino acids and their derivatives can be synthesized in few synthetic steps, and with high enantiomeric purity. A variety of chiral heterocycles can readily be obtained from glycosyl imines by stereoselective transformations, providing evidence that carbohydrates have now been established as useful auxiliaries in stereoselective syntheses of various interesting classes of chiral compounds.

References [ I ] H. Kunz, K. Ruck, Angew. Chem. Int. Ed. Engl., 32, 1993, 336. [2] a) P. G. Hultin, M. A. Earl, M. Sudarshan, Tetrahedron, 53,1997, 14823; b) H. Kunz, M. Weymann, M. Follmann, K. Oertel, M. Schultz-Kukula, A. Hofmeister, Polish J. Cbem., 73, 1999, 15; c) H. Kunz, Pure Appl. Cbem., 67, 1995, 1627. [3] a) S. Hanessian in Total Syntheses of Natural Products, The Chiron Approch, Pergamon Press: Oxford UK. 1983; b) G. Bringmann, R. Gotz, S. Marmsen, J. Holenz, R. Walter, Liebigs Ann., 1996, 2045; c) S. Laschat, Liebigs AndRecueil 1. 1997; d) D. Tramer, S. Porth, T. Opatz, J. W. Bats, G. Giester, J. Mulzer, Synthesis, 1998, 653. [4] H. C. Brown, U. S. Racherla, J. Org. Cbem., 56, 1991, 401. I51 R. Noyon, T.Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H. Kurnobayashi, S. Akutagawa, J. Am. Chem. Suc., 109, 1987, 5856. [6] a) T. P. Loh, U. L. Chua, J. J. Vittal, M. G., Wong Chem. Cornmun., 1998,8,861;b) S. Pinheiro, S. F. Pedraza, M. A. Peralta, J. Carbohydr: Cbem., 17, 1998, 6, 901. [7] a) K. Yonohare, T. Hashizume, K. Ohe, S. Hernura, Bull. Chem. Soc. Jpn., 71, 1998, 8 , 1967.;b) L. Shamia, Indian J. Cbem. Sect. B. Org. Chem. bid. Med. Cbem., 36,1997,796;c) H. C. Brown, W. S. Park, B. T. Cho, P. V. Ramachandran, J. Org. Chem., 52, 1987, 5402. [8] a) D. Felix, I. Szymoniah, C. Moise, Tetrahedron, 53, 1997, 16097; b) J. Chika, H. Takei, Tetra bedron Lett., 39, 1998, 605; c) B. T. Cho, Y. S. Chun, Tetrahedron Asymm., 9, 1998, 1489. [9] a) P. Areces, M. V. Gil, F. J. Higes, E. Roman, J. A. Serrano, Tetrahedron Lett., 39, 1998, 8557; b) P. Bako, K. Vizvardi, Z. Bajor, L. Toke, Cbem. Cornmun., 1998, 1193. [ 101 a) M. L. G. Ferreira, S. Pinheiro, C. C. Perrone, P. R. R. Costa, V. F. Ferreira, Tetrahedron Asynim., 9, 1998,267 1 ;b) S. Jarosz, J. Chem. Soc. Perkin Trans. I , 1997,2579.;c ) M. R. Banks, J. 1. G. Cadogan, I. Gosney, S. Gaur, P. K. G. Hodgson, Tetrahedron Asymm., 5 , 1994, 2447, 2458. [ 1 I ] a) L. F. Tietze, G. Kettschau, Hetero Diels-Alder reactions in Organic Chemistry, Top. Curr: Chem., 189, 1997,l; b) A. Defoin, H. Sarazin, J. Streith, Tetrahedron, 53, 1997, 40, 13769. 1121 S. Deloisy, H. Kunz, Tetrahedron Lett., 39, 1998, 791. 1131 H. Kunz, W. Pfrengle, Tetrahedron, 44, 1988, 5487. [ 141 a) R. U. Lernieux, A. A. Pavia, J. C. Martin, K. A. Watanabe, Can. J. Chem., 47,1969,4427;b) R. U. Lemieux, J. P. Praly, Can. J. Chem., 65, 1987, 213. 151 M. J. Collins, R. J. Femer Monosaccharides, John Wiley & Suns. New York, 1995. [16] a) H. Kunz, J. Mohr, J. Chem. Soc., Cbem. Cornmun., 1988, 1315; b) H. Kunz, R. Kullmann, Terrahedmn Lett., 33, 1992, 6115. [I71 H. Kunz, W. Sager, Angew. Cbem. Int. Ed. Engl., 26, 1987, 557. [I81 D. Enders Asymmetric Syntheses, Vol. 3, Ed.: Morrison J.D., Academic Press, Orlando, 1984,275. 1191 a) H. Kunz, W. Pfrengle, W. Sager, Tetrahedron Lett., 30, 1989,4109; b) H. Kunz, W. Pfrengle, K. Ruck, W. Sager, Synthesis, 1991, 1039. 1201 H. Kunz, W. Stahle, Synletr, 1991, 260.

128

Tietgen, Schultz-Kukula and Kunz

[21] V. Schollkopf in Enantioselective Syntheses of Nonproteinogenic Amino Acids, Top. Curr Chem., 109, 1983, 65. [22] R. M. Williams in Syntheses of Optically Active a-Amino Acids, Pergamon, Elmsford, New York, 1989,208. [23] H. Kunz, W. Sager, D. Schanzenbach, Liebigs Ann. Chem., 1991, 649. [24] H. Kunz, W. Sager, W. Pfrengle, D. Schanzenbach, Tetrahedron Lett.,29, 1988, 4397. 1251 I. Ugi, K. Offermann, H. Herlinger, D. Marquading, Liebigs Ann. Chem., 1, 1967, 1. [26] H. Kunz, D. Schanzenbach, Angew. Chem. Int. Ed. Engl., 28, 1989, 1068. [27] Y.Furukawa, M. Okabe, T. Yoshioka, T. Ishiura, Spec. Publ. R. SOC.Chem., 52, 1984, 163. [28] H. Kunz, A. Burgard, D. Schanzenbach, Angew. Chem. Int. Ed. Engl., 36, 1997, 386. [29] S. Laschat, H. Kunz, Synlen, 1990, 51. [30] S. Laschat, H. Kunz, Synlett, 1990, 629. [31] S. Laschat, H. Kunz, J. Org. Chem., 56, 1991, 5883. 1321 D. Hebrault, H. Kunz, u ~ p u ~ l i s h eresults. d [33] D. Seehach, M. Overhand, F. N. M. Kuehnle, B. Martinoni, Helv. Chem. Acta, 79, 1996, 931. 1341 D. Seebach, J. Podlech, Angew. Chem. Int. Ed. Engl., 34, 1995, 471. [35] E. Juaristi (Ed.), Enantioselective Synthesis of P-Amino Acids, Wiley-VCH, New York, Chichester, Weinheim, Brishane, Singapore, Toronto, 1997. [36] K. Kahinuma, T. Koudate, H. Y. Li, T. Eguchi, Tetrahedron Lett., 32, 1991, 5801. [37] F. M. Unger, Adv. Curbohyds Chem. Biochem., 38, 1981, 323. 1381 A. Rosenberg in Biology of Sialic Acids, Plenum, New York, 1995. [39] M. Mammen, S. K. Choi, G. Whitesides, Angew. Chem. Int. Ed. Engl., 37, 1998, 2754. [40] M. von Itzstein, W. Y. Wu, G. B. Kok, M. S. Pegg, J. C. Dyason, B. Jin, T. Van Phan, M. L. Smythe, H. F. White, S. W. Oliver, P. M. Colman, J. N. Varghese, D. M. Ryan, J. M. Woods, R. C. Bethell, V. J. Hotham, J. M. Cameron, C. R. Penn, Nature, 363, 1993,418. [41] H. Kunz, H. Tietgen, unpublished results. [42] F. Balkenhohl, C. von dem Bussche-Hiinnefeld, A. Lansky, C. Zechel, Angew. Chem. Int. Ed. Engl, 35, 1996, 2288. [43] F. J. Friichtel, G. Jung, Angew. Chem. Int. Ed. Engl., 35, 1996, 17. [44] I. Ugi, H. Bock, J. Prakt. Chem., 1997, 499. [45] H. Kunz, W. Pfrengle J. Am. Chem. Soc., 110, 1988, 651. [46] I. Ugi, S. Lehnhoff, M. Gobel, R. M. Karl, R. Klosel, Angew. Chem. Int. Engl. Ed., 34,1995, 1104. [47] R. J. Lindermann, S. Binet, S. R. Petrich, J. Org. Chem., 64, 1999, 336. [48] T. Ziegler, R. Schlomer. C. Koch, Tetrahedron Lett., 39, 1998, 5957. [49] J. W. Daly, H. M. Garrato, T. F. Spande in Alkaloids (Ed. Cordell G.A.) Academic Press, San Diego, 1993, Vol. 43. 185. [SO] a) S. W. PeIletier (Ed) in Alkaloids: Chemicals and Biological Perspectives, J.Wiley, New York, 1985; b) Silvermann R.B. in The Organic Chemistry of Drug Design and Drug Action, Academic Press, San Diego, 1992. [51] W. Pfrengle, H. Kunz, J. Org. Chem., 54, 1989, 4261. [52] H. Kunz, W. Pfrengle, Angew. Chem. Int. Ed. Engl., 28, 1989, 1067. [53] M. Weymann, W. Pfrengle, D. Schollmeyer, H. Kunz,Synthesis, 1997, 1151. [54] H. W. Tallent, E. C. Horning, J. Am. Chem. SOC., 78, 1956, 4467; Beilstein E IMV, Vol. 20, 1611. [55] R. P. Polniaszek, S. E. Belmont, J. Org. Chem., 55, 1990, 4688. 1561 T. Tokujama, T. Tsujita, A. Shimade, H. M. Garrafo, T. F. Spande, J. W. Daly, Tetrahedron,47,1991, 5401, and literature cited therein. [57] R. Appel, Angew. Chem. Int. Ed. Engl., 14, 1975, 801. [58] a) J. W. Daly, T. Tokuyama, G. Habermehl, I. L. Karle, B. Witkop, Liebigs Ann. Chem., 729,1969, 198; h) T. Tokuyama. N. Nishimori, I. L. Karle, M. W. Edwards, J. W. Daly, Tetrahedron, 43, 1987, 643., c) for biological activity of pumiliotoxin: C: J. W. Daly, Y. Nishizawa, W. L. Padgett, T. Tokuyama, P. J. McCloskey, L. Waycole, G. A. Schultz, R. S. Aronstam, Neurochem. Res., 16,1991, 1207. [59] M. Weymann, M. Schultz-Kukula, H. Kunz, Tetrahedron Letters, 39, 1998, 7835. [60] D. L. Comins, A. Dehghani, J. Chem. SOC. Chem Commun.,1993, 1838. [61] M. Follmann, H. Kunz, Synlett, 1998, 989. [62] H. Vorbriiggen, K. Krolikiewicz, B. Bennua, Chem. Bes, 114, 1981, 1234.

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

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

5.1 Introduction A large collection of data and extensive studies of transition metal complexes possessing metal -nitrogen multiple bonds has been documented [ 13. Not only does this class of inorganic coordination complexes display an array of interesting bonding and structural features, but it also has important applications. In particular, transition-metal complexes with terminal nitrido ligand have recently become of great interest for a number of important reasons: (i) they are considered as intermediates in the fixation of nitrogen [2];(ii) they have been shown to participate in nitrogenatom transfer reactions to both inorganic [3]and organic [4] acceptors; (iii) they have found applications in new materials because of their thermal and chemical stability; (iv) they have medical applications as imaging agents [5]; and (v) nitrido ligands can serve as a versatile bridging ligand between metal centers. It is the aim of this chapter to provide an overview of the various transition metal nitrides that have been reported. The term “nitride” is used to designate complexes possessing an N-atom ligand which is bonded only to the transition metal and in which the ratio of metal to nitride is 1:l. For example, the complexes (TPP)Mn(N) 1 (TPP = 1,5,15,20-tetraphenylporphynatodianion) or (i-Pr,N),Cr(p-N),Cr(Ni-Pr,), 2 fall within this definition (Figure 5.1); however, because of space limitations the chapter does not include complexes such as Cl,V(NCl) or (TPP)Fe(pN)Fe(TPP). The reader is referred to a number of excellent comprehensive reviews which have previously appeared [ 11. This chapter will attempt to review the general methodologies available for the synthesis of metal nitride complexes. Additionally, discussion is presented of the structurally diverse ligands that have been incorporated in metal-nitride complexes.

130

Tomooka, Zikura, and Carreira N Mn(TPP)

1 terminal

i-PrZN. N ,.

c'\. Cr, i-Pr2N N

,Ni-Pr2

.

N+Pr2

2 M2W-Nz)

Figure 5.1. Typical structures of transition-metal nitrides discussed in this review.

Three distinct approaches can be envisioned for the preparation of metal nitrides incorporating varied organic ligands (Figure 5.2). In the fxst approach, the nitride is generated by the reaction of the metal complex with a reagent molecule serving as a nitrogen-atom source. In the second, the desired transition metal -nitride complex is prepared from a starting coordination complex which already incorporates a metal nitrogen bond, requiring only an oxidation state adjustment. The third approach the synthesis commences with a simple X,M fN complex and new ligands are introduced without modification of the formal oxidation state at the metal.

Nitride-introducing reaction Metal modification reaction Ligand modification reaction

Figure 5.2. Three approaches to the synthesis of metal nitrides.

5.2 Nitrogen-Atom Sources for the Preparation of Metal Nitrides There are well over 30 different reagents that have been reported as N-atom sources for the preparation of nitrido metal complexes. The evaluation of the relative importance of these reagents currently is difficult because no single method has emerged as general and, as a result, the existing reagents and methods are complementary to each other. A useful means of categorizing these N-atom transfer reagents is on the basis of the number of electrons they contribute in the reaction with the metal center to form the nitride complex. An N3--equivalent reagent contributes six valence-electrons to the metal center; thus with these reagents, no electrons are formally supplied or demanded from a metal center to form the corresponding

5.2 Nitrogen-Atom Sources for the Preparation of Metal Nitrides

131

metal nitride. An N2--equivalent reagent can be considered a five valence-electron donor; thus, in forming a metal nitride the metal center supplies one-electron. An N' --equivalent reagent includes four valence-electrons, and equivalent includes three valence-electrons. Below, we discuss specific examples of the various reagents that have been used preparatively.

5.2.1 N3- Reagents These reagents formally utilize an N3- anion-equivalent with concomitant formation of cationic co-products. It is important to note that in these reactions, the formal oxidation state of the metal center does not undergo any net change during the course of the reaction. Examples of these reagents and the reactions that have been described with various metal complexes are summarized in Table 5.1. Ammonia as well as bis(trimethylsily1)-, tris(trimethylsily1)-, and tris(trimethylstanny1)amines have been utilized with a variety of transition metals. The reagent [Hg2N]Br (Table 5.1, Entry 2)-known as Millon's base-has proven quite versatile in the ready synthesis of tungsten nitrides. Lithium t-butyl amide (Entry 6) has been employed in the preparation of manganese nitrides, leading to the formation of isobutylene as co-product. The N,N',N'-tris(trimethylsily1)derivative of benzamidine likely functions in an analogous manner to (Me,Si),N with the added advantage that it is considerably less volatile.

Table 5.1 N3- reagents in the synthesis of metal nitrides Entry Reagent 1 2 3

4 5 6 7 8

NH, [HgzNlBr N(SnMe,), HN(SiMe,), N(SiMe,), Li(NHt-Bu) PhC(NSiMe,)(N(SiMe,),) t-BuNCO

Metal Osvlll

Rev"

WV' Tav Crv', MoV' W"' MnV" Wv' Osv", RuV*

Nitride

Co-products

Os-N,Re-N W=N Ta = N Cr = N, Mo = N W=N Mn=N W r N 0 s = N, Ru = N

H+ 2Hg+, Br+ Me3Sn+ Me&+ Me$+ Li+, 2H+, Me& = CH, Me&+, PhCN CO,, H+, Me& = CH,

The preparation of metal nitrides with N3- reagents typically employs do metal complexes as starting materials. However, the reactions of t-butyl isocyanate with metal-oxo complexes of 0s'' and Ru"' represent rare examples of the use N3- reagents with d'-metals. It has been postulated that reaction of the isocyanate with metal-oxo 3 affords a four-membered ring intermediate 4, followed by the extrusion of carbon dioxide to yield t-butyl metal imide 5 (Scheme 1). Elimination of isobutylene from this complex then produces the metal nitride and the isobutylene.

132

Tomooka, Iikura, and Carreira

4

3

5

7

6

Scheme 1

5.2.2 N2- Reagents Urea is the sole N2- reagent reported for the synthesis of a metal nitride. The generation of metal nitride from urea requires a one-electron oxidation at the metal center, and for the cases reported in can be speculated that these involve a bimetallic intermediate (Scheme 2).

8

9

10

11

Scheme 2

5.2.3 N'- Reagents The use of these reagents for the preparation of metal nitrides formally requires that the metal reagent supply two electrons to the N-atom donor. A listing of these reagents is provided in Table 5.2. Table 5.2. "--reagents Entry

for nitride synthesis

Reagent

Metal nitride formed Product Cr", MnV, Mow, Mo", Osvl, ReV, Re"', ReV1', Vv, WIV, WV'

2 3 4

NH,/NaOCI; NH&; NH,/PhIO; NHJNBS NSCl

Cr = N, Mn = N, Mo = N, Mo = N, 0 s = N, Re 5 N, Re = N, Re = N, V=N, WEN, WEN

Co-product N2

Crv, MnV

H+

MoVI, R e v Crv'

SCI+ Phenanthrene

5.2 Nitrogen-Atom Sources for the Preparation of Metal Nitrides

133

Of these reagents, N3- is one of the most widely-used with do, d', and d2 metals, including Group V (V), Group VI (Cr, Mo, W), Group VII (Mn, Tc, Re), Group VIII (0s). Coordination of N3- generates an intermediate metal azide that thermally or photochemically decomposes to afford N, and the corresponding metal nitride. The sodium amide derived from 2,3,5,6-dibenzo-7-aza bicyclo[2,2,1]hapta-2,5-diene (Table 5.2, Entry 4) works in a way similar analogous to N3-, and was reported for the synthesis of a Cr,, nitride. The use of this reagent has distinct advantages over the use of N3- salts which can be explosion hazards and display poor solubility in organic solvents. The combination of ammonia with oxidizing reagents (NaOC1, Cl,, PhIO, NBS, tBuOC1) leads to formation of electrophilic nitrogen that participates in nitride formation. This procedure has been used as a general, powerful method for the preparation of CrVand MnV nitrides. It has been reported that the use of ammonia in combination with NBS or sodium hypochlorite constitutes mild reaction conditions that allow the synthesis of a wide range of manganese nitrides, considerably expanding the class of ligands that can be employed with manganese. Another mild method for the preparation of metal nitrides involves transfer of a preformed metal nitride from one metal center to a second. A number of CrVand MnVnitrides have been synthesized with this method.

5.2.4 No Reagents These reagents are formally at an oxidation-state level equivalent to elemental nitrogen. The reacting metal partner in these reactions is formally required to undergo a three-electron oxidation. As shown in Table 5.3, NO, N, and RCN have all been utilized as nitrogen sources for nitride synthesis. These processes have attracted much attention since they involve activation and atom transfer methodologies commencing with small, normally inert molecules. The release of strain energy associated with the starting diaziridine as the thermodynamic driving force that leads to efficient nitride formation.

Table 5.3. No reagents for nitride syntheses. Entry

Reagent

Metal

1 2 3 4

NO N2 RCN MnV = N

Cr"', Ru"' MoV' WV'

Mn"

134

Tomooka, likura, and Carreira

5.2.5 Other Reagents Additional nitrogen sources have been reported in the synthesis of metal nitrides. These include trichloramine, hydrazine, and N,N-diphenylhydrazine (Table 5.4). Based on the details provided it is not clear how these may be categorized within the organizational classification discussed above

Table 5.4. Other nitrogen transfer reagents. Entry

Reagent

Metal

1 2 3

NCI, WNHZ Ph,NNH,

MeV*, ReV" ReV, Tc" Tcw

5.3 Ligands in Metal Nitride Complexes The ligands that have been used in the preparation of metal nitride complexes are quite varied. They include halides, carbogenic groups (alkyl moiety and Cp*), pnictogens (amine, amide, imide, phosphine, and arsine), and chalcogens (ether, alkoxide, 0x0, thioalkoxide, and selenides). Chart 1 provides a listing of the various ligands and the associated nitrido metal complexes.

0

L

3

c,

N donor

CN-

Carbanionic

Halides

OS(VI) Ru(VI)

CH3-

F-

dbabh

CI-

Mn(VII)

he Mes

Mo(VI)

Mo(lV), Mn(V), Mo(VI), W(W. W(IV). Re(V)

Br-

Cr(Vl)

Tc(V), Re(V), Re(VI)

I-

Cr(V1)

Cr(Vl)

136

Tornooka, likura, and Carreira

z?

xz 0

Chart l b

$

137

5.3 Ligands in Metal Nitride Complexes

f

6 *0 f

z 5

\ / O

\'

1 b /

Q

c*:]

0

0

WZ

f zs

rQ

0

fI

f

zd

2

i

i:

a I

1 b 5

E

qY

iQ. &f a

a

\'

L i

1

I

b

/

r

a

#

G \ &

z-

'z

5'

r n \ i / / r n

m

Chart l c

iij

E U

z i

a

x 1

t5

E

'15

@

z

c

co b

138

Tonzooka, Iikura, and Carmira

0 I

t f

0

2 %f

3

lo0 <

fI

c I

s

a' I

0 I

Chart Id

5.3 Ligands in Metal Nitride Complexes

g U

2 a

Chart l e

139

140

Tomooka, Iikura, and Carreira

5.4 Transition Metal Nitride Complexes In this section a collection of the various metal nitrides that have been reported are arranged by metal. The abbreviations employed for the various ligands can be found in Chart 1.

5.4.1 Vanadium The large majority of reportec. vanadium nitrides have a Vv center with halide, amine, and C* ligands. Only one example of a VN complex has been isolated, and it is part of a mix-valent VV(p-N),VV' unit. A variety of different methods have been employed, with the use of azide being most common. Reaction of V' complexes of 1,4,7-triazacyclononane (13) or 1,2,3,4,5-pentamethyIcyclopentadiene (Cp*) with an equivalent of Me3SiN, followed by heating or UV-irradiation provided the corresponding nitride as shown in Eqs (1-2) [6]. Whereas the complex incorporating triazacyclononane ligand 12 affords 14 bearing a terminal nitride as ligand, the complex bearing a Cp* ligand was isolated as a rare dinuclear complex 17 with two bridging p-N ligands. In this complex, all four VV-N bonds are equivalent with bond lengths of 1.77 A, longer than the typical terminal Vv-nitride (1.57 A).

[LV(acac)(N3)]CIOd

hv

N [LV(acac)]CI04

(1)

14

12

L = 1,4,7-triaza-cycIononane (13)

[cpvc12l3 15

-

Me3SiN3 (16) benzene reflux

N [Cp'VCl]p 17

Reaction of VCI, with Me3SiN, affords the corresponding N-silylated Vv nitride 19 (Eq. (3)) which following treatment with Ph,PCl provides the corresponding salt [7,8] Nitride 20 has been prepared through a different route by treatment of (Me3SiO),VN with Cl,V=O (Eq. (4)). When 19 was exposed to aromatic amines such as 4-tert-butylpyridine and quinoline, the corresponding adducts 21 and 22 were isolated (Eq. (5)).

5.4 Transition Metal Nitride Complexes

Me3SiN3

VCI,, 18

SiMe3 NI Ph4PCI

SiMe31+ N I 111

~ p

141

vc13

vc14

19

20

(3)

4-terBu-py

CI3VNSiMe3

23 TMEDA

VC12(quinoline)2 24

Equations 3-5

When the V'" alkyl diamide complex 25 is treated at 60 atm of H, followed by N,, the cationic dinuclear Vv'-Vv nitride 26 was isolated (Eq. (6)) [9, 101. Although there is evidence for N, functioning as a nitride source has been described in the literature, the mechanistic details of this particular reaction has not been established. Complex 24 constitutes a rare example of a V" nitride; it is interesting to note that all of V-N bonds are of approximately the same length, namely 1.77 A.

142

Tomooka, Iikura, and Carreira Me. ME Me3Si-N,

= I - -

,si.' /"\

(Me3Si)2N

--

2. N2 (48 h)

,CHp

,

(Me3Si) (Me3Si)pN

PMe3

25

26

Equation 6

5.4.2 Tantalum There are only a few of these metal nitrides that have been reported and extensively characterized. Reaction of Cp*TaV(Me), 27 with excess ammonia provided Ta" nitride 28 (Eq. (7)). In this transformation, three of the methyl groups function as proton acceptors to yield methane gas [ l l , 121. Treatment of [Cp*TaV(Me)N],29 with Na/K afforded the reduced Cp*Ta"(Me)N- complex 30. This product could be readily reoxidized to the starting Tav trimer upon treating with Cp,Fe+ (Eq. (8)) 11%

Cp'Ta(Me)4

excess NH3

20 "C,2 d

N [Cp'Ta(Me)13 + CH4

(7)

28

27

Equation 7

! Cp'Ta( Me) 29

NalK

N

7 [Cp'fa(Me)]Cp2Fe+

30

Equations 8

Alkilidine tantalum complexes have also been utilized for the preparation of nitrido Tav. Reaction of ammonia with 31 or 32 afforded nitride 33 in moderate yields [14]. The structure of 33 has been determined by single-crystal X-ray crystallography and shown to consist of a pentameric complex, as depicted in Eq. (9). All of the Ta-N bond lengths are equivalent (2.00 A), suggesting a structure with extensive delocalization of the multiple bonds.

5.4 Transition Metal Nitride Complexes

-

(~-BuCH~)~T~(NM~&

31 (t-BuCH&Ta=CH'Bu

NH3

t-Bu f-BU t - B u ~ ] I-f-Bu ,Ta. ,Ta, N [ ( ~ - B u C H ~ ) ~ T ~t-Bu ]~ I N,I I NI I t-Bu \Ta' Ta' 'Ta&

I /'I

33

t-Bu t-Bu t-~,,

32

143

(9)

f-BU

Equation 9

5.4.3 Chromium The most common preparation of chromium nitrides involves the reaction of Cr"' with N-' reagents. The processes are remarkably facile and provide access to a wide range of complexes. In the typical reaction process, heating or irradiation of solutions of azides and CP' affords the corresponding nitrides in good yields for chromium coordinated with polydentate ligands such as porphyrins, phthalocyanine, salen, along with 1,4,7-triazacyclonane and diamide (see Chart 1) [Is, 16,6a, 171. The nitrides derived from tetradentate ligands such as salen, and porphyrin are typically 5-coordinate and square-pyramidal as determined by X-ray crystallography. In contrast, chromium nitrides derived from other ligands such as acac, tacac, pic, phen furnish 6-coordinate octahedral complexes. In addition to thermal and irradiation methods employing azides as the N-atom source, the combination of ammonia and a variety of oxidants has been known to be useful for the preparation of chromium nitrides containing porphyrin or phthalocyanine ligands (Eq. (10)) [ 181. N

oxidant

Equation 10

Another useful method that has been investigated is the transfer of nitride from one metal center to a another. Thus, porphyrin manganese nitrides have been documented to participate in nitrogen transfer reactions to Cp-porphyrin and CP'-salen to furnish the corresponding Cr-nitrides (Eq. (11)) [19].

144

Tomooka, Iikura, and Carreira N Crll'(L)+ Mn(Por)

36

-

37

N CrL + Mn"'(Por)

38

39

L = porphyrin or salen

Equation 11

The stability of the chromium nitride triple bond makes it possible to subject preformed Crv* nitrides to reductive conditions that produce the corresponding Crv nitride. A recent example of this process was reported in which treatment of 40 with N a g afforded nitride 41. X-ray crystallographic analysis revealed a dimeric complex with M,(p-N), core (Eq. (12)) [20].

40

41

Equation 12

As discussed above, the ligands that have been typically utilized for the preparation of chromium nitrides are multidentate. Consequently, ligand exchange reactions of such complexes are difficult and rare. Wieghardt and co-workers have reported such a process, however, for the synthesis of a nitrido chromium cyanide complex 43 (Eq. (13)) [18]. Thus, treatment of CrN(salen) 42 with excess sodium cyanide and tetramethyl ammonium chloride results in the formation of a six-coordinate pentacyano chromium nitride [21].

N Cr(salen) 42

Equation 13

NaCN

(NMe4)CI

[NMe4]2Na[CrN(CN)5]

43

5.4 Transition Metal Nitride Complexes

145

There has been remarkable progress recently in the chemistry of CrV' nitrido complexes, most notably by Cummins and co-workers. Thus, a variety of nitrides have been reported with ligands possessing N, 0, S, and C donor groups. Most of these have been prepared by ligand exchange processes and commence with CrN(NRR'), or CrN(OR),. Three different general nitride sources have been utilized in the preparation of these complexes, namely N3-, N1-, and No. The Cr"' nitrides incorporating alkoxide, amide, or halide ligands have been synthesized in this manner. The reaction of Crvr oxide 44 with the N3- reagent bis-(trimethylsily1)aminegave Crw nitride 45, as shown in Eq. (14) 1221. The formation of strong Si-0 bonds in the product likely provides a strong driving force for this process.

(NH4)2Cr207

Me3SiCl

N Cr(0t-B~)~

HN(Me3Si)z tert-BuOH

45

44

Equation 14

Cummins has reported that treatment of CrV' complex 47 with 48 at elevated temperature affords the corresponding nitride 49 (Eq. (15)) [23]. This method offers auseful alternativeto the other existing methodologiesfor the preparationof chromium nitrides. The thermodynamic stability of anthracene contributes significantly to the driving force for this process. Cummins has also reported the preparation of chromium nitride 51 from NO and a C p triamide 50, and (THF),V(Mes), (Eq. (16)) [24].

RIRN-Cr< N R R ~ NRR' 50

Equations 15- 16

1. NO

N NRR1

2. (THF)V(M~S)~* R'RN-Cr;

51

NRR'

146

Tomooku, Iikura, and Carreira

Ligand exchange reactions of monodentate amides, iodides, or alkoxide complexes with other amides, alkoxides as well as sulfides, and carbon ligands has been documented 123,251. A rather unique reaction of a trimethylsilylmethyl ligand bound to a chromium nitride has been reported; thus, reaction of tert-butyl isocyanide with 52 is reported to furnish 53 (17)).

(m.

52

53

Equation 17

5.4.4 Molybdenum

Nitrido molybdenum complexes have been reported for Mo"', Mov, and Mom. Among these, Mow nitrides have been the most extensively studied. For the other two classes of nitrido molybdenum complexes, phosphine and thioalkoxide ligands are common, as they are suggested to stabilize the lower oxidation states through Aback bonding. h i d e s are the sole reagent that has been utilized for the synthesis of Mow nitrides. For example, reaction of 54 with Me,SiN, gave 55; it has been proposed that an intermediate Mo" bis-azide complex is generated that subsequently undergoes further two-electron oxidation to give the observed Mow complex. It is interesting to note that in the presence of excess Me,SiN, further oxidation of the metal center was observed, leading to the formation of a trinuclear complex [26].

54

55

Equation 18

Ligand exchange reactions with nitrido molybdenum complex 56 has been documented (Eq. (19)).Treatment of 56 with 2 equiv. of HX (X = C1 or Br) leads to the formation of 57 which, following treatment with triethylamine, afforded 58, wherein a halide has been substituted for the wide ligand found in 56 [27]. The introduction of a nitride onto a Mo" complex has been carried out by treatment of Mom or Mow

5.4 Transition Metal Nitride Complexes

147

halide complexes with Me,SiN, in the presence of phosphine or thioalkoxide ligands [28,29]. Thus, treatment of 59 or 61 with Me,SiN, delivers the corresponding nitrides in good yields (Eqs. (20,21)).

MoC13(THF)2

Me3SiN3

N [MoC I~ (S ~ P (OR )~ ]~

-S2P10R)2

59

61

60

62

Equations 19 -21

The reduction of MoV'nitrides with iodide has also been reported. As shown in Eq. (22),reaction of nitrido MoV' nitrides with MePh,PI afforded the corresponding MoV nitride complex 65 [30]. In a related process, treatment of a nitrido MoV' complex with sodium naphthalide leads not only to the MoVnitride but also to the formation of a M O " ~ M O( P~-~N ) tetramer ~ [3 11. The structure of the latter product has been firmly established via single crystal X-ray crystallography.

148

Tomoka, Iikura, and Carreira N [MePPh3][MoC14] 63

MePhSPI

or N ..

N [MePPh&.[MoC14]

Ill

65

[MePPh3][MoC13] 64

Equation 22

The most commonly studied class of nitrido molybdenum complexes are Mov'derived. This family of complexes enjoy the widest versatility with regard to the wide range of preparative methods, as well as the large scope of ligand exchange processes in which they are observed to participate. A number of reagents have been employed for the generation of nitrido MoV' complexes, including N3-, N2-, N'- , and reagents and Moo, Mon, Mo"', Mow or Mov. The molybdenum-bound ligands can be quite varied with the complexes incorporating monodentate (alkoxide, amide, halide), as well as polydentate ligands (bipyridine, terpyridine). The use of (Me,Si),NH and urea as nitrogen sources for Mo"' and Mo" complexes, respectively has been documented (Eqs. (23,24)) [32]. By far the most common class of agents that serve as nitrogen sources in the synthesis of molybdenum nitrides are azides. The list of such reagents include TMSN,, NaN,,AgN,, (Et4N)N3, ClN,, and IN, [33]. Azides have also been utilized with Moo, Mon, and Mom complexes as starting materials, as shown in Eqs. (25-28).

MoCISGPCI~+

68

OC(NH&

69

-

N [MoCI~.OPCI& 70

5.4 Transition Metal Nitride Complexes Me3SiN3

MoX4

N MoL

P

(Ligand) 71

149

(25 1

72

Equations 23 -28

There are selected examples of the use of additional nitrogen sources such as NSCl, N,, and NCl, (Eqs. (29,30)). The molybdenum nitride halide complexes were isolated from the reaction of a Mo"' complex and NSCl in the presence of C1- or F- [34]. Cummins reported the remarkable reaction of low-valent Mo'" triamide with N, (1 atm) to afford the corresponding nitride 80 (Eq. (29)). The presence of bulky amide ligands is critical to the success of the reaction, for it prevents the formation of the stable dimer [(ArRN),Mo],.

Mo(NArR)3

N2

79

~

0 81

Equations 29,30

1

Mo(NArR)3 80

~

~

NC13 0 )

~

N MOCI~ 82

150

Tomooka, likura, and Carreira

Ligand exchange reactions of Mow nitrides are well documented. Thus, the formation of MoVINCl,, or [MoNCIJ, or MoN(OR), from N-, C-, S-, 0-,P-, and halide- donors have been studied 1351.

5.4.5 Tungsten

Only one nitrido Wrv complex has been documented. This was prepared by the action of Me,SiN, followed by oxidation on dinitrogen @ complex 83 (Eq. (31)) [36]. It has been proposed that the reaction of 83 with trimethylsilylazide affords a Wn complex bearing two N,-ligands; a subsequent two-electron oxidation of the metal center then affords nitrido tungsten complex 84.

83

84

Equation 31

A number of preparative methods are available for the synthesis of Ww nitrides. The reaction of Millon's base [Hg,N]Br with WBr, provides nitride 86 (Eq. (32)) [37]. The same reagent has been utilized in the synthesis of an interesting Wv complex 87 (Eq. (33)). This W,(p-N) complex can, in turn,be utilized to prepare a WN nitride 88. Thus, treatment of 87 with Ph,PBr leads to a disproportionation reaction affording 88 and 89.

WBr6 85

-

PPh4Br

[PPh4](W2NBr8] 87

Equations 32,33

[Hg2N]Br

N WBr3

86

!

[PPh4lWBr4l + [PPh41~"%Brl01 88

89

(33)

5.4 Transition Metal Nitride Complexes

151

Two organic reagents that function as a nitride sources have been reported for this class of componds, namely, N(SiMe,), and tris(trimethylsily1)benzamidine [38,39]. In an example involving the use of the former reagent, the reaction of N(SiMe,), with WC1, afforded WNCl, (Eq. (34)). Reaction of tris(trimethylsily1)benzamidine with tungsten hexachloride provided the corresponding Wv' nitride complex (Eq. (35)). Using a similar strategy, the nitrido Wv' chloride could be prepared. 1. PhC(NSiMe3)[N(SiMe3)z]

WC16

2. PhCN

90

WClS 92

*

WNC13.NCPh

(34)

91

PhC(NMe3Si)(NMe&.) 93

-

N WBr3(PhCN) + 3 Me3SiCl

(35)

94

Equations 34,35

As has been discussed in the preparation of Mo nitrides, by far the most commonly employed agents for the preparation of Wv' nitride are azides, such as Me,SiN,, IN,, ClN,, (Ph,P)N, [40-441. Both Wv and Wv' have been utilized as starting materials (Eq. (36)). In this regard, a single-crystal X-ray structure of the Wv' N-chloronitrido complex [ [C1,W(NC1),],C1}3- with bridging chlorine atoms has been reported [45]. The nitride is subsequently generated following heterolytic dissociation of the N- C1 bond.

Equation 36

An unusual reaction of W"' with nitriles has been reported by Schrock et al. to provide metal a nitrido tungsten complex 1461. Treatment of 98 with acetonitrile or benzonitrile provides the tungsten carbyne 99, along with the nitrido complex 100 (Eq. (37)). Additional studies resulted in the identification of reaction conditions that

152

Tornooka, Iikura, and Carreira

lead to the formation of the nitrido tungsten complex along with the symmetrical alkyne (Eq. (38)) [47].

RCN __F

R=MeorPh

FR

W(OmBu)3 99

!i

+

W(OmBu)3

(37)

100

(RO)3W=W(OR)3 101

Equations 37,38

In addition to the reagents described, NCI, has been reported to generate trichlorotungsten nitride 105 from the corresponding tungsten hexacarbonyl 104 (Eq. (39)).

104

105

Equation 39

5.4.6Manganese A number of nitrido manganese complexes have been reported. Most of these complexes are MnV,with only one example reported for MnVI1.These complexes typically incorporate polydentate ligands; thus, no examples could be found of simple halide or alkoxide nitrido manganese complexes. Since the original disclosure by Groves and co-workers that these could be utilized as nitrogen transfer reagents, they have received considerable attention 148,491 . Irradiation of manganese azides derived from Mn(III) porphyrin, cyclam, and polyamide complexes represents one of the earliest methods reported for the preparation of nitrido manganese complexes (Eq. (40)) [50]. Additional methods have become available for the synthesis of manganese nitrides that utilize ammonia in combination with oxidants such as Cl,, PhIO, NaClO, and NBS (Eq. (41)) [51-531. Employing these methods, the manganese nitrides incorporating porphyrin, phathlocyanine, cyclam, salen, and bidentate Schiff base complexes have been documen-

5.4 Transition Metal Nitride Complexes

153

ted [54]. Such methods represent some of the more versatile means for the preparation of nitrido manganese complexes. Carreira has reported that in cases involving more labile bidentate ligands, the use of NH,/NBS is preferred as a consequence of the mildness of the reaction conditions.

Mn"l(N3)L

hv

N MnVL

---+

107

106

MnlI'L

-

N MnVL

NH3, oxidant

109

108

Equations 40,41

The transfer of a nitrogen atom from a metal nitride to another metal complex is a process that works quite well with MnVnitrides. Thus manganese nitrides derived from porphyrin or salen ligands participate in nitride transfer reaction to salen and porphyrin Mnm complexes to give new nitrido manganese products (Eq. (42);Chart 2) [55,56].

!

Mn"'(L)+ Mn(L') 110

Equation 42

N

A Mn(L) 111

+

Mn"'(L') 112

(42)

154

a

Tomooka, likura, and Carreira

Ph

NH

N

-Ph

\

salen

Ph

Et

OEP

(=J2b

TPP

Chart 2

Ligand exchangeprocesses for Mnv nitrides are rather rare. This is probably due to the fact that such nitrides are typically prepared from kinetically and thermodynamically stable multidentate ligands such as porphyrins and salen. However, ligand exchangeprocesses have been noted for a selection of MnVnitrides possessing threecoordinate and four-coordinate ligands wherein treatment with CN- affords the corresponding cyan0 manganese nitrides [57,58]. The oxidation of bound porphyrin or phathalocyanine ligands complexed to manganese nitride has also been reported. However, in these cases the structure of the adduct has not been fully elucidated. Reduction of 115 followed by treatment with Me1 leads to bisrnethylation of the porphyrin core 116 (Scheme 3) [59]. Such a strategy provides new avenues for the preparation of novel porphyrin nitrido manganese complexes.

N Mn(salen) 113

Equation 43

NaCN, CsCl

----+

N CspNa[Mn(CN)s] 114

(43)

155

5.4 Transition Metal Nitride Complexes

-N

E

tN N

a

'M!V Et

\

'N \N

,I /

Et

Et

Et

2. 1. NaNp Me1

E

hiv

-N tN N

BMe

\N ,

Et

Me Et

\

N'

Et

115

Et

116

Scheme 3

A single example of a MnV" nitride has been documented [60]. Treatment of Mn(Nt-Bu),Cl with Li(NHt-Bu) leads to the formation of the corresponding nitride (Eq. (44)). The mechanistic postulate that accounts for the formation of the nitride is intriguing. It has been suggested that following coordination of the amide base, elimination of isobutylene leads to the formation of the observed product.

Li(NH t-Bu)

Mn(Nt-Bu)&I

M~(N~-BIJ)~

-

N

Mn(Nt-Bu)3 120

117

118

119

(44) Equation 44

5.4.7 Technicium Nitrido complexes of Tcv and Tcv' have been prepared and studied. The 99Tcvnitride complexes are stable and play an important role in nuclear medicine. Consequently, a large family of ligands have been investigated in the preparation of these complexes. The Tc"' nitrides are considerably less stable, and have a tendency to undergo reduction to the corresponding Tcv nitride complex. The introduction of a nitride ligand onto Tc-complexes is somewhat limited. However, 126 is easily prepared and, importantly, readily participates in ligand exchange reactions. This has permitted the

156

Tomooka, likura, and Camira

preparation of a number of complexes incorporating N, 0, S donors. The reaction of N,N-disubstituted hydrazines with [Bu4N]TcOC14in the presence of triphenylphosphine affords entry to the corresponding nitrido complex (Scheme 4) [61]. A number of different hydrazines have also been employed. The use of NaN, with a Tcvu starting material 124 has been shown to deliver the corresponding Tcv*-nitride (Eq. (45)) WI.

RR"NH2

or

N TcCI2(PPh&

PPh3

TcC14(PPh&

122

m N + N RR"NH2 = Ph2NNH2 or HN,

123

NH2oHCI

25 - 60 Yo

Scheme 4

[NH4]Tc04 124

NaN3 HX

( X = CI or Br)

NaTcNX4

(45)

125

Equation 45

The available methods for the synthesis of Tc-nitrides by introduction of the nitride ligand directly onto a pre-existing Tc complex are limited. However, the availability of TcNC1, and its ready participation in ligand exchange reactions allows for ready access to numerous complexes (Scheme 5). In this regard, a variety of ligands have been incorporated [63- 671. Ligand exchange reactions are also reported for a Tcv species, namely, TcNC1,(PPh3), [68].

Scheme 5

5.4 Transition Metal Nitride Complexes

157

5.4.8 Rhenium Rhenium nitrides have been reported for a wide range of Re-complexes including Re", ReV', and Rev". Azides, hydrazines, and NSCl have all been utilized in the reaction wih Re"', Re", and ReV" to give the corresponding ReV nitrides (Eqs. (46-49); Scheme 6) [69-711. ReX3(PPh3),

+

NaN3

-

!i

ReX2(PPh3),

128

129

ReCI4(NSCI)POC13

+

PPh3

130

PPh3 + EtOH + NaRe04 + HCI 132

HCI

ReC13(Por) 135 or

N ReC12(PPh& 131

NH2NH2

[ReO(Por)120 136

133

! ReC12(PPh3),

ReCt4(NSCt)(OPCl3) + PPh3 -----+

(48)

134

N Re(Por) 137

Equations 46-49

Scheme 6

(47)

ReO(OEt)C12(PPh3)2

NHzNH2

138

(46)

ReNC12(PPh3)2 139

(491

158

Tomooka, Iikura, and Carreira

A single example of a nitride introduction was reported for the synthesis of a Rew nitride. Treatment of ReC1, with ClN, afforded the corresponding Rew nitride (Eq. (50)) [72]. Reduction or oxidation processes on Re nitrides can provide entry into new nitrides (Eqs. (51, 52)) [73,74]. For example, when ReNCI, was treated with POC1, a tetrameric Re nitride was isolated. Similarly, as shown below treatment of Re" nitride in the presence of oxygen produced the Re"' nitride.

ReNCI4 + POCI~ 142

02

Na2(ReN(tipt)d 144

PPh4CI

N (ReCI3 POC13)4 143

(51)

N [PPh41[Re(tipt)41 145

A tip!

Equations 50-52

An alternative to the above methods are the ligand exchange reactions of ReNC1,[75 - 771. The preparation of ReV1'nitrides has been well studied, but although several different methodologies are available the ligands utilized are limited. Thus, ReV" nitrides can be prepared by treating a variety of starting complexes with KNH,, NaN,, or NCl, (Eqs. (53-55)) [78-801. As an example of a ligand exchange process for a nitrido Re"" (Eq. (56)) [81], treatment of chloro rhenium nitride with fluorine gas provided a Re"" nitrido fluoride complex.

5.4 Transition Metal Nitride Complexes

Rep07+ 3 KNHP

-

1

K2Re03+ KRe04+ 2 NH3

146

159

(53)

1 47

ReFG+NaN3 148

ReC15+ NCl3

-

N Ill ReF4

(54)

149

-

N ReC4

1 50

(55)

151

Equations 53-55

N ReC14 + F2

-

N 111 ReF4*ReF5(NCI)

152

153

Equations 56

5.4.9 Ruthenium All of the reported ruthenium nitrides possess Ru". Once again, azides can be employed to prepare the corresponding nitrides. The reaction of ruthenium oxides with NaN, provides the corresponding nitrido ruthenium halides (Eq. (57)) [82]. The reaction of Ruvr' 0x0 complex 1577 with t-BUNCOprovides an interesting and novel synthesis of a nitrido ruthenium complex 158 (Eq. (58)) [83]. Reduction and oxidation sequences have also been utilized for the preparation of Ru-nitrides. Thus, treatment of 159 with NaBH, readily affords nitride 160 in high yields (Eq. (59)) [84].The structure determination of this product was determined firmly by single-crystal X-ray crystallography [85].

-

NaN3 trar~s-[Ru(O)~X~]

154

II;'

WX)i

155

or N Ru(X)<

(57) I56

160

Tomooka, likura, and Carreira

Equation 57

157

158

Ligand exchange reactions can provide a facile method for the preparation of novel nitrides [86]. Treatment of 161 with ethyl bromide afforded the corresponding tetrabromide rhenium nitride 162 (Eq. (60)). In turn, this complex can participate in exchange reactions with alkoxides to give the correspondingruthenium nitride tetralkoxides (Eq.(61)) [87]. These alkoxide complexes represent useful starting materials for the subsequent preparation of alkyl Ru nitrides. Reaction of 165 with organomagnesium or organoaluminum reagents provides alkyl ruthenium nitride 166 (Eq. (62)) [87]. Control over the number of alkyl groups that may be introduced can be exercised by appropriate selection of the reaction stoichiometry. Treatment of 167 with hydrochloric acid or AuCl leads to substitution of the alkyl ligands yielding the corresponding mixed complexes 168 (Eq. (63)) [88].

5.4 Transition Metal Nitride Complexes N [Bu~N]RuCI~

EtBr

*

161

N [Bu~NIRuCI~

(60)

162

NaOSiMe3

N [Bu~N]Ru(OS~M~~)~ 164

*

163

Me2Mgor AIMe3 N * [Bu~N]Ru(OS~M~~)~ 165

N HCI or Au(PPh,)CI [Bu~NIRuR~ * 167

N [Bu4N]RuBr4

161

(61)

N [ B u ~ N ] R u M ~ ~ ( O S ~ M ~ & , (62) 166

N [Bu~N]RuR~.,CI, 168

R = CH2SiMe3,x = 1-2 R=Me,x=1-3

Equations 60-63

5.4.10 Osmium There are examples of direct introduction of a terminal nitride ligand onto an osmium complex incorporating organic ligands, albeit only a few. Treatment of 169 with Me,SiN, or MeN, generates the corresponding nitrido complex 170 (Eq. (64)) [S9]. In analogy with the chemistry of ruthenium 0x0 complexes, reaction of 171 with t-BUNCOgenerates the corresponding Osw nitride complex 172 (Eq.(65)) [90].

162

Tomooka, likura, and Carreira

d

171

172

Equation 64,65

The most widely utilized approach for the synthesis of nitrido osmium complexes proceeds by ligand exchange reactions of simple nitrido osmates. These are readily prepared from KOsO,N, itself synthesized by treatment of OsO, with KOH and ammonia (Eq.(66)) [91]. Subsequent treatment of KOs0,N with KCVHCl then affords K,OsCl,N (Eq. (67)); this and related salts are a commonly used precursors for the synthesis of osmium nitrides.

KOSO~N+ KCI + 6HCI

__t

K ~ O S C I ~+N CIz

+

3H20

(67)

Equations 66,67

A number of ligand exchange processes for the synthesis of novel nitrido osmates are illustrated in Eqs. (68,69). A variety of nitrido osmium complexes possessing mono- or polypyridyl ligands has been reported by Ware and Taube [92]. Treatment of [Bu,N][OsNCl,] with picolinate cleanly substitutes one or two of the chlorides, depending on the stoichiometry used. Among the several interesting ligand exchange processes, treatment of [Bu,N] [OsNCI,] with terpyridine furnished the corresponding nitrido complex.

5.4 Transition Metal Nitride Complexes

163

(68) [/?-B~~N][OSNC~~]

+ OsNC4(pic)

or

O~NCla(pic)~

Equations 68,69

A related process has been reported for the synthesis of osmium nitrido complexes with 1,2-benzenedithiolateligands. Thus, the synthesis of 173 was effected by treatment of (Bu,N)[OsNCl,] with deprotonated 1,2-benzenedithiol (Eq. (70)). Interestingly, when 173 is treated with Me,OBF, alkylation is observed to occur on the sulfur; this contrasts the reaction of 173 with Ph,CPF,, for which reaction at the terminal nitride is observed [93].

173

Equation 70

Ligand substitution reactions of [Bu,N][OsNCl,] with oxyananions and carbanions have been documented. Thus, treatment of [Bu,N][OsNCI,] with NaOSiMe,, CH2CMe,, CH,Ph, or CH,SiMe, affords the corresponding organometallic complexes (Eqs. (71,72)) [94]. The adduct with CH2SiMe, has been utilized in the synthesis of the first cyclopentadienyl-nitrido complex 180 (Eq. (73)) [95].

164

Tomooka,Iikura,and Carreira

- CH2CMe-

.vu-

91-L C M e 3

CHiPh

180

equation^ 71-73

5.5 Conclusion This review has focused on the various methods that have been reported for the synthesis of metal nitride complexes, as well as even larger number of metal nitrides that have been isolated for a wide range of transition metals throughout the periodic table. It is clear that these complexes have an intriguing array of reactivity and structure. There is a burgeoning field of study that has demonstrated that these complexes already display a host of desirable properties in materials science, medicine, and chemical synthesis. Further investigations of the structure and reactivity of metal nitrides complexes will undoubtedly yield important contributions in the evolution of this exciting field.

References

165

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1581 K. Meyer, J. Bendix, N. M. Nolte, T. Weyhermuller, K. Wieghardt, J. Am. Chem. SOC. 1998, 120, 7260. [59] J. W. Buchler, C. Dreher, K. L. Lay, Y. J. A. Lee, W. R. Scheidt, Inorg. Chem. 1983, 22, 888. [60] A. A. Danopoulos, G. Wilkinson, T. K. N. Sweet, M. B. Hursthouse, J. Chem. SOC.Dalton Trans. 1995, 205. 1611 M. J. Abrams, S. K. Larsen, S. N. Shaikh, J. Zubieta, Inorg. Chim. Acta. 1991, 185, 7. 1621 a) J. Baldas, J. F. Boas, J. Bonnyman, G. A. Williams, J. Chem. SOC.Dalton Trans. 1984,2395. b) J. Baldas, J. Bonnyman, G. A. Williams, Inorg. Chem. 1986, 25, 150. [63] J. Baldas, J. F. Boas, S. F. Colmanet, M. F. Mackay, Inorg. Chim. Acta. 1990, 170, 233. [64] A. Marchi, R. Rossi, L. Magon, A. Duatti, U. Casellato, R. Graziani, M. Vidal, F. Riche, 1. Chem. SOC. Dalton Trans. 1990, 1935. 1651 U. Abram, S. Abrarn, J. Stach, W. Dietzsch, W. Hiller, Z. Naturforsch. 1991, 468, 1183. 1661 A. Marchi, A. Duatti, R. Rossi, L. Magon, R. Pasqualini, U. Bartolasi, V. Ferretti, G. Gilli, J. Chem. SOC.Dalton Trans. 1988, 1743. [67] J. Baldas, J. Bonnymann, G. A. Williams, Inorg. Chem. 1986, 25, 150. [68] U. Abram, S. Abram, R. Munze, E. G. Jager, J. Stach, R. Kirmse, G. Admiraal, R. T. Beurskens, Inorg. Chim. Acta. 1991, 182, 233. [69] H. G. Hauck, P. Klingelhofer, U. Miiller, K. Dehnicke, 2. Anorg. Allg. Chem. 1984, 510, 180. 1701 a) J. Chatt, C. D. Falk, G. J. Leigh, R. J. Paske, J. Chem. SOC. A 1969, 2288. b) E. Forsellini, U. Casellato, R. Graziani, L. Magon, Acta Cryst. 1982, 838, 3081. [71] J. W. Buchler, A. D. Cian, J. Fischer, S. B. Kruppa, R. Weiss, Chem. Ber. 1990, 123, 2247. [72] K. Dehnicke, W. Liese, P. Kohler, Z. Naturforsch. 1977, 328, 1487. [73] P. J. Blower, J. R. Dilworth, J. Chem. SOC.Dalton Trans. 1985, 2305. 1741 a) W. Liese, K. Dehnicke, I. Walker, J. Striihle, Z. Naturforsch. 1980, 358, 776. b) W. Liese, K. Dehnicke, J. Chem. SOC.Dalton Trans. 1981, 1061. [75] D. Niisshtir, F. Weller, K. Dehnicke, Z. Anorg. Allg. Chem. 1993, 610, 1121. 1761 M. A. A. F. de C. T. Carrondo, R: Shakir, A. C. Skapski, J. Chem. SOC. Dalton Trans. 1978, 844. [77] W. Kafitz, F. Weller, K. Dehnicke, Z. Anorg. Allg. Chem. 1982, 490, 175. 1781 A. F. Clifford, R. R. Olsen, Inorg. Synth. 1960, 6, 167. [79] J. Fawcett, R. D. Peacock, Russell, D. R., J. Chem. SOC.Dalton Trans. 1987, 567. 1801 W. Liese, K. Dehnicke, I. Walker, J. Striihle, Z. Nuturforsch. 1979, 348, 693. 1811 W. Kaftitz, K. Dehnicke, E. Schweda, J. Striihle, Z. Naturforsch. 1984, 398, 1114. 1821 a) W. P. Griffith, D. Pawson, J. Chem. SOC.Dalton Trans. 1973,1315. b) D. Collison, C. D. Gamer, F. E. Mabbs, T. J. King, J. Chem. SOC. Dalton Trans. 1981, 1820. 1831 W. H. Leung, G. Wilkinson, B. H. Bates, M. B. Hursthouse, J. Chem. SOC.Dalton Trans. 1991,2791. [84] D. Sellmann, G. Binker, Z. Naturforsch. 1987, 428, 341. 1851 D. Sellmann, M. W. Wemple, W. Donaubauer, F. W. Heinemann, Inorg. Chem. 1997,36, 1397. 1861 C. Collison, C. D. Garner, F. N. Mabbs, T. J. King, J. Chem. SOC.Dalton Trans. 1981, 1820. [87] P. A. Sharpley, J. P. Wepsiec, Organometallics 1986, 5, 1515. [88] P. A. Sharpley, H. S. Kim, S. R. Wilson, Organometallics 1988, 7, 928. 1891 C. Barner, T. J. Collins, B. E. Mapes, B. E. B. D. Santarsiero, Inorg. Chem. 1986, 25, 4323. [90] W. H. Leung, G. Wilkinson, B. Hussain-Bates, M. B. Hursthouse, J. Chem. SOC.Dalton Trans 1991, 2791. [91] A. F. Clifford, C. S. Kobayashi, Inorg. Synth. 1960, 6, 204. [92] D. C. Ware, H. Taube, Inorg. Chem. 1991, 30,4598. [93] D. Sellrnan, Wemple, Donaubauer, F. W. Heinemann, Inorg. Chem. 1997.36, 1397. [94] P. A. Belmonte, Z. Y. Own, J. Am. Chem. SOC. 1984, 106, 7493. [951 R. W. Marshman, J. M. Shusta, S. R. Wilson, P. A. Shapley, Organometallics 1991, 10, 1671.

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

6 Asymmetric Nitrogen Transfer with Nitridomanganese Complexes Satoshi Minakata and Mitsuo Kornatsu

6.1 Introduction Heteroatom transfer reactions to carbon- carbon double bonds using catalytic or stoichiometric amounts of transition-metal complexes have recently attracted considerable interest in the convenient synthesis of three-membered heterocycles (Eq. (1)).The latter are versatile building blocks for the construction of complex organic compounds, such as natural products and biologically active compounds (Eq. (1))

ill.

Q: heteroatom Equation (1)

Among these, a variety of oxygen atom transfer reactions have been described [la,b] and highly stereoselective reactions have been reported [2]. Although the formation of aziridines by the reaction of nitrenes with olefins is well known, the efficiency is moderate, because of the competition between hydrogen abstraction and insertion processes [3]. A typical example is shown (Eq. 2) [3d].

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Minakata and Komatsu

PhSOzN3

+

0cu A

DNSOzPh

+

+

+

PhS02NH2

Equation (2)

Aziridinations of carbon -carbon double bonds constitute an important transformation in organic synthesis, because the two carbon-nitrogen bonds can be simultaneously formed. Thus, efficient nitrogen atom-transfer reactions are currently advanced to obtain achiral aziridines by employing a few reagents as nitrogen sources, which are [N-(p-toluenesulfonyl)imino]phenyliodinane (PhI = NTs) [4], 3-acetoxyaminoquinazolines [5], dimethoxyamine [6], chloramine-T [7], and others [8]. Some of these methodologies have been applied to asymmetric aziridination [9]. On the other hand, it is noteworthy that an alternativeapproach for direct aziridination using nitrido(5,10,15,20-tetramesitylporphyrinato)manganese (TMPMnN) has been reported by Groves and co-workers [lo], whose study was one of the earliest examples of a nitrogen atom-transfer reaction with a nitride reagent. Recently, this type of reaction was extended by Carreira and co-workers to the amination of enol silyl ethers and glycals with new types of nitridomanganese complexes [ 111. This chapter mainly reviews aziridination using nitridomanganese complexes, but with special emphasis on enatioselective transformations.

6.2 Achiral Nitrogen Atom Transfer to Olefins 6.2.1 Nitrogen Atom Transfer Reaction with Achiral Nitrido Complexes

In this section, a brief introduction to the development of nitrogen transfer reactions using achiral nitrido complexes is presented. In 1983, Groves and co-workers reported an example of the transfer of nitrogen from a nitridomanganese(V)porphyrin complex to an olefin [lo]. The nitridomanganese complex 2 was isolated in 80 % yield by irradiation of azide complex 1.Treatment of 2 with trifluoroacetic anhydride (TFAA) in the presence of cyclooctene provided the corresponding aziridine 3 in 82-94% yield (Scheme 1). Although this study is one of the earliest examples of a nitrogen atom transfer reaction utilizing nitrido complex, it is restricted to the use of cis-cyclooctene as an olefinic substrate.

6.I Introduction

171

N Ar

- hu N2

Ar*r Ar

80 % 1

2 Ar = 2,4,6-trimethylphenyI

Scheme 1. Achiral aziridination of cyclooctene with (TMP)Mn(N).

Alternatively, an electrochemical procedure was employed in the synthesis of amino acids from nitridomolybdenum complex 4 via nitrogen-carbon and carbon-carbon bond formations involving imide 5 and nitrogen ylides 6. trans[MoCl(N)(Ph2PCH2CH2PPh,)]4 reacted with methyl iodoacetate to give the cationic complex 5. Complex 6 was obtained by the deprotonation of 5 at the a-carbon followed by treatment with Me1 to afford the cationic methyl derivative 7. Electrochemical cleavage of the Mo-N bond of the complex 5 or 7 proceeded in the presence of acetic acid to release amino acid esters in 70-80 96 yield (Scheme 2) [12].

172

Minakata and Komatsu

0

N 111

ICH2C02Me 65 o/‘

CI

-

4

CJ

H.$XOMe N I

+N

=

111

Et3N ___)

CI

CI

5

6

Ph2pbpPh2 +N O x oMe Me

Met 74 Yo

111

e CI

7 electroreductive cleavage 5 or 7

H+ 70-80 Yo

-

OQc,OMe H2N-k,-H R

..

R = H or Me

Scheme 2. Electrochemical cleavage of the Mo-N bond.

The methodology found by Groves has, since 1996, been elegantly extended to practical organic synthesis by Cmeira’s group [ 111. They prepared a new type of nitridomanganese complex, (saltmen)Mn(N) 8 [ 1la], derived from 2,3-diamho2,3-dimethylbutane, and applied this complex as a nitrogen transfer reagent to the amination of electron-rich olefins, such as silyl enol ethers [lla] and glycals [l lb]. The 2:l complexes 9a-e were also synthesized by the reaction of the ligands with Mn(OAc), 4H,O, liquid ammonia and N-bromosuccinimide (NBS) under mild conditions (see Section 6.3). The complex 9c was applied to the aminohydroxylation of styrene [llc]. In particular, the one-step reaction of glycals with complex 8 represents a practical method for the formation of the corresponding 2-amino sugars [llb,e] (Schemes 3 and 4).

6.1 Introduction

Me

Me L M e

173

9a: R = Ph, R' = Me 9b:R=Ph,R'=Pr 9c: R = Ph, R'= Ph 9d: R = MeO, R' = Me 9e: R = MeO,R' = Ph

8

Scheme 3.

93

OSi Me3

OMe

+/

TBDPSO~O)

Me+O Me

&

8, (CF3CO)20, pyridine b

CH2C12

1.8, (CF3CO)*O, . - CHCle - 2. silica gel

TBDPSO L

"NHCOCF~

62 %

Me

1 . 9 ~(CF&O)20, , CH2C12

Ph-

HC0CF3

OMe

78 %

L

PhK N H C O C F 3

2. aq. NaHCOflHF 64 %

Scheme 4. Nitrogen atom transfer to olefins with nitridomanganese complexes 8 and 9c.

As shown above, nitrogen atom transfer using nitridomanganese complexes is suitable for electron-rich olefins. In other words, the methodology has the potential for application to a variety of unsaturated substrates.

174

Minakata and Komatsu

6.2.2 Nitrogen Atom Transfer Aziridination of Olefins with Other Nitrogen Sources As mentioned in the introduction of this chapter, there are many types of methodologies for the preparation of aziridines because they are useful intermediates in organic synthesis [lc-g]. In 1994, Evans reported an excellent study of the coppercatalyzed aziridination of olefins using PhI = NTs and described the alternative methods in the introductory part in great detail [4g]. The studies dealing with aziridination have been continued by a large number of research groups, and novel methods have been discovered in the field of basic transformation of organic synthesis. In this Section, representative recent approaches to the construction of an aziridine ring from olefins are described. Pellacani and co-workers reported the aziridination of olefins by using carboethoxynitrene generated from ethyl N-[(4-nitrophenyl)sulfonyl]oxycarbamate (also known as 4-nitrobenzenesulfonoxyurethane or the Lwowski reagent) and bases, such as triethylamine, K,CO, or CaO [13] (Scheme 5). In some cases, allylic amination products were obtained in low yields.

CaO

H

78 %

7%

Scheme 5. Aziridination of cyclohexene with Lwowski reagent.

More recently, chloramine-T (CT) was found to be an efficient nitrogen source for the aziridination of olefins by our group [7a]. Among the transition metals, copper(1) chloride was the most suitable catalyst for the aziridination of olefins with CT. For example, trans-P-methylstyrene was successfully aziridinated with CT at 25 "C in acetonitrile in the presence of a catalytic amount of CuCl (Scheme 6). Other olefins have also been aziridinated by the reaction, whose products are shown in Scheme 7.

175

6.1 Introduction

Ts ph/\\/Me

N-TS +

CI’ chloramine-T (CT)

I

*P

CuCl (5 mol YO),MS-5A MeCN

Ph 64 O h (trans only)

Scheme 6. Copper-catalyzed aziridination of trans-P-methylstyrene with CT.

Scheme 7.

Following the publication of our method, similar procedures were reported by two other groups. One involves the use of bromamine-T as a nitrogen source instead of CT for the aziridination of olefins [141; the other is the copper(1) triflate-catalyzed aziridination and allylic amination with CT trihydrate [7d] (Schemes 8 and 9). Ts

Ph

+

N?

N-TS

:B

I

CuCl(5 mol Yo),MSdA MeCN

bromamine-T

Ph

81 %

Scheme 8. Copper-catalyzed aziridination of a-methylstyrene with bromamine-T.

74 %

Scheme 9. Copper-catalyzed aziridination of styrene with CT 3H20.

176

Minakata and Komatsu

The most impressive methodology utilizing CT, which has been developed by the group of Sharpless, is the vicinal aminohydroxylation of olefins catalyzed by osmium tetroxide [15]. The method has been elegantly extended to a practical asymmetric synthesis [16]. The reaction system was employed to the achiral aminohydroxylation of a,f.3-unsaturated amides to afford two hydroxysulfonamide regioisomers. The crude mixtures were cyclized to the aziridines in a one-pot procedure, without the need for purification of the intermediates [17] (Scheme 10).

P

CTBH20, Os04 (0.5 mot%)

"Me2

MeCN / H20 (1 I 1)

99 Yo

TsHr 0 'f OH

-'"

10

1

Ts

I

1) MSCI, EhN, CH2C12,O "C

*

2) Et3Nor DBU, rt

\NMe2

0

81 Yo

Scheme 10. 'ho-step aziridination of a,fSunsaturated amide via aminohydroxylation.

Although the reaction in Scheme 10 is a highly efficient procedure, a two-step process was required to prepare aziridines from olefins. Two more convenient methods for the one-step aziridination using CT were discovered by the authors in 1998, one of which involves the iodine-catalyzed aziridination of unfunctionalyzed olefins with CT trihydrate [7b] (Scheme 11). The bromine-catalyzed aziridination of unfunctionalyzed olefins and allylic alcohols with anhydrous CT was reported at the same time [7c], though in this case phenyltrimethylammonium tribromide (PTAB), and not Br,, was used as a catalyst (Scheme 12). These two reactions are applicable to a wide range of olefins, and are considered to proceed by almost the same pathway.

I2 (1 0 mol %) R1/\\/R2

+

CT 3H20

MeCN I neutral buffer (1 I 1) or M~CN 38-91

Scheme 11. Iodine-catalyzed aziridination of olefins with CT.

*/o

R'

6.3 Synthesis of Chiral Nitridomanganese Complex

+

CT (anhydrous)

PTAB (10 mol %)

177

I

MeCN

93 %

Scheme 12. PTAB-catalyzed azindination of 3-hexene with CT.

6.3 Synthesis of Chiral Nitridomanganese Complex Although numerous reports exist on the preparation of various types of nitrido complexes from the standpoint of their physico-chemical properties [ 18,191, the application of the complexes to organic synthesis has not been studied, except for a few instances (see Section 6.2.1). Thus far, only three types of chiral nitrido complexes have been synthesized, and only one could be successfully utilized for organic synthesis. One of the most common and practical synthetic procedures for the preparation of a nitrido complex is the transformation of low-valency metals with ammonia and aqueous sodium hypochlorite [ 19a-c]. Carreira and co-workers reported an alternative method for preparing the new nitridomanganese complex by employing NBS and liquid ammonia. With the discovery of this new, mild method for Mn-N multiple bond formation in hand, they applied this procedure to the preparation of chiral nitridomanganese complexes l l a and l l b from the readily available, optically active bidentate oxazoline ligand 10 (Scheme 13). Some of the features of l l a have been revealed by the X-ray crystal structure of the compound [llc]. R 1. f~in(OAc)~. 4H20

OH 10a: R = P r lob: R = P h

*

2. NHs I NBS, -45 "C

R = Pr llb: R=Ph lla:

Scheme 13. Synthesis of c h i d nitridomanganese complex using liquid NH,/NBS system.

At almost the same time, the two chiral nitridomanganese complexes having different types of salen ligands were prepared by J@rgensen'sgroup, and by the authors' group. The manganese@) salen complex 12, derived from (lR, 2R)- 1,2-diphenylethylenediamine was converted to chiral nitridomanganese complex 13by employ-

178

Minakata and Komatsu

ing Carreira's method (Scheme 14), and the structure of 13 was characterized by Xray diffraction [20].

12 X=CI,OAc

13

Scheme 14. Synthesis of chiral nitridomanganese complex using liquid NH,/NBS system.

An alternative procedure to afford the chiral nitridomanganese complex 15 was developed by our group. This procedure consists of a reaction of the chiral Mnm complex 14 [21] with gaseous NH, and chloramine-T as the oxidant in MeOH [22] (Scheme 15). Other derivatives 16-21 which have (lR,Z)-diaminocyclohexme as a backbone were synthesized by the usual method using aqueous NH, and NaOC1. Complex 22 was also synthesized from diphenylethylenediamineas a chiral source (Scheme 16).

NH3 (gas), chloramine-T 3H20 MeOH, rt, 40 h 84 Ye 14

15

scheme 15. Synthesis of chiral nitridomanganese complex using gaseous NH,/CT system.

6.4 Asymmetric Aziridination of Olefins with Chiral Nitridomanganese Complexes

179

6.4 Asymmetric Aziridination of Olefins with Chiral Nitridomanganese Complexes Since a chiral nitride complex is considered to be a good candidate for an asymmetric nitrogen transfer reagent, the intention of the authors' group was to apply some complexes to asymmetric organic synthesis [22]. Optically active aziridines are highly versatile building blocks in organic synthesis, and can be converted into a variety of useful nitrogen-containing compounds by cleavage of the strained three-membered ring [ lc-g]. Therefore, great efforts have been made to develop efficient methods for the stereoselective synthesis of chiral aziridines [23]. Among the various routes, the reagent-controlled asymmetric aziridinations of carbon-carbon double bonds are remarkable in terms of their simplicity and convenience as a synthetic procedure [9]. During the past decade, a number of organic chemists have paid great attention to this mode of chemistry, and have established metal-catalyzed asymmetric aziridinations with PhI = NTs as a nitrogen source [9a-j]. Although Groves and Takahashi revealed the first example of aziridination of cis-cyclooctene using nitrido complex 2, only one substrate was adapted to this method [ lOa]. In order to'extend this methodology, asymmetric aziridinations of styrene derivatives have been achieved as follows.

6.4.1 Asymmetric Aziridination of Styrene with Nitrido Complex Although TFAA was used by both Groves and Carreira for the activation of nitrido complexes [lo, 111, when it was employed in the aziridination of styrene with the chiral nitridomanganese complex 15 the anticipated aziridine was not obtained, and, rather, the ring-opening product 23 was isolated in 43 % (13 % ee). When the reaction was carried out with trichloroacetic anhydride, compounds 24 and 25 were produced (Scheme 17). While (CF,SO,),O, (t-BuOCO),O, TsCl and Me,SiCl were not effective for the reaction, p-toluenesulfonic anhydride (Ts,O) was found to be an efficient activator of complex 15 for the aziridination of olefins [22].

180

Minakuta and Komatsu

n

15 OH

2

0

L+,

Ph

PhL

O

i,cx3

0 23 X-F

CI

43 YO(13 YOee) 0%

R"

0

0

N

tJ

Ph

24

25

0 Yo

0 Yo

20 Yo

24 %

Scheme 17. The reactions of complex 15 with styrene using (CX,CO),O as activators.

The reaction of nitrido complex 15 with styrene (10 equiv) in methylene chloride at room temperature for 3 h in the presence of Ts,O (1.2 equiv) and pyridine (0.5 equiv) gave the corresponding N-tosylaziridine in 63 % yield based on 15 with 31 % ee. The reaction path is assumed to be as follows. Initially, the N-tosylpyridiniumsalt was generated in situ, the salt reacted with complex 15 to afford imido complex 26. The reactive intermediate 26 transferred the N-Ts unit to styrene to give the desired product (Scheme 18). Since the Mnm complex was formed during the course of the reaction, the complex was recovered and regenerated to the nitrido complex by treatment with NH, and aqueous NaOCl in 79% yield. The regenerated complex was reusable for the present reaction to give the same result (61 %, 32% ee) [22].

6.4 Asymmetric Aziridination of Olefins with Chiral Nitridomanganese Complexes

181

n

+

ph%

TS

I

pyridine (0.5 equiv) TszO (1.2 equiv) CHzCIz, rt, 3 h

Ph

63 % (31

ee)

t

15

26

Mn"'complex

1

1. NH3 aq. 2. NaOCl aq

complex 15 (79 %)

reusable for the reaction

Scheme 18. Aziridination of styrene with complex 15 and Ts,O: the reaction pathway and regenerationof complex 15 from recovered Mn"' complex.

In order to increase the yield and/or the enantioselectivity of the reaction, the reaction temperature and additives were examined. Although aziridination was found to proceed smoothly at 0 "C, the product was not obtained at lower temperatures. Katsuki and co-workers have reported that pyridine N-oxide is an effective additive for the asymmetric epoxidation catalyzed by salen-manganese(II1) complexes [24], and applied these findings to the asymmetric aziridination of olefins with PhI = NTs [9fl. Thus, the addition of pyridine N-oxide at 0 "C improved the enantioselectivity and allowed the reaction to proceed even at -20 "C (Table 6.1). Other additives, such as 4-phenylpyridine N-oxide, 4-methylmorphorine Noxide and 1-methylimidazole were used in the place of pyridine N-oxide, but positive effects were not observed.

182

Minakata and Komatsu Ts

complex15

+

I

additive (1.2 equiv) Ph10 equiv

pyridine (0.5 equiv), TszO (1.2 equiv) CHzClp, rt, 3 h

Ph

Table 6.1 Effect of pyridine N-oxide for the aziridination of stvrene with comDlex 15. additive

Temperature ("C)

Yield (%)

ee (%)

None None None F'yridine N-oxide Fyridine N-oxide F'yridine N-oxide

rt

63 73

31 30 33 41

~

0 - 20

rt 0 - 20

0

64 78 48

~~

~

40

The use of pyridine N-oxide improved not only the yield of the product but also the enantioselectivity [22]. The reason for this is presently unclear, but the N-oxide might act as an axial ligand (complex 27), thus increasing the reactivity of complex 15 with Ts,O. In addition, the conformation of the generated imido complex 28 coordinated by pyridine N-oxide might be different from that of the complex 26 coordinated by tosylate (Scheme 19). As a result, the conformation of the complex 28 might be more preferable to permit the higher enantioselectivity.

27

Scheme 19.

28

183

6.4 Asymmetric Aziridination of Olefins with Chiral Nitridomanganese Complexes

6.4.2 The Asymmetric Aziridination of Styrene with a Variety of Nitrido Complexes The nitrido complexes 16-21, as shown in Section 6.3, which bear various substituents on the para (R')and/or ortho (R2) positions of a benzene ring of complex 15 were employed in the asymmetric aziridination of styrene (Table 6.2). The reaction of styrene with complex 16 or 17 gave lower product yields and enantioselectivities compared to the reaction with the complex 15. Complex 18 decreased the yield of the aziridination, but the enantioselectivity was not affected; however, when complex 19 was employed, the yield and the selectivity were low. In the case of 20, the enantioselectivity was moderate but the yield was very low; complex 21, which bears Jacobsen's ligand, showed a similar result with complex 20. Thus far, complex 15 is the best nitrogen source for the asymmetric aziridination of styrene.

complex 16-21

+

phA 10 equiv

pyridine (0.5 equiv) TspO( 1.2 equiv) pyridine Noxide (1,2 equiv) CH2C12,O

"C,3 h

Ts I Ph

Table 6.2 Effect of the substituents of the ligand CornplexR'

R2

Yield (%) ee (%)

16 17

H

H

54 68

OMe

H

57

'Bu

H 'Bu 'Bu

24

18 19

20 21

NO,

c1 H

'Bu

2 9

7

29 39 19 45 50

Although the mechanism of asymmetric induction is unclear at present, a plausible mechanism can be presumed from the absolute configuration of the product. As mentioned above, imido complex 28 might be generated in situ by the reaction of nitridomanganese complex 15 with Ts,O in the presence of pyridine N-oxide, and this complex would be an active species for aziridination of olefins. The transition state of the reaction may be involved in the reaction of 28 with olefins. It would be reasonable to assume that the imido complex 28 is folded under the aziridination conditions, since Katsuki and his co-workers reported that the structure of the ligand of the 0x0 salen species is not planar but folded in the asymmetric epoxidation using chiral manganese complexes [25].As shown in Figure 6.1, intermediate 28 is considered to be bent by the conformation of the diaminocyclohexane moiety. In the aziridination of styrene, the substrate approaches the tosyl group-substituted nitrogen of complex 28 from the open space (route a), while route b is blocked by the

184

Minakata and Komatsu

ligand. In route a, four types of approach (a,-a4) of styrene are possible. Among them, route a, would be most unfavorable approach because of steric repulsion between the benzene ring of styrene and the cyclohexane ring of complex 28. As a result, the moderate ee was obtained with R configuration excess.

Ts

b

_-

.

-k)

28

Figure 6.1. Plausible mechanism for the reaction of complex 28 with styrene.

In the case with the nitrido complex 21 which bears rert-butyl groups on the benzene ring, the imido complex 29 was generated (Figure 6.2). Because of the steric repulsion between the benzene ring and terf-butyl group of complex 29, the approach of styrene via routes a3and a4 would be disfavored, and route a, represents the only favorable route for aziridination. The decrease in the yield and the increase in enantioselectivity, compared to those using complex 28 can be explained by the above rationale. Complex 22 derived from (lS, 2s)-1,2-diphenylethylenediamine[26] gave a moderate yield and selectivity (Scheme 20). In this reaction, the opposite absolute configuration of the product was observed compared to the cases with complexes 15-21.

185

6.4 Asymmetric Aziridination of Olefins with Chiral Nitridomanganese Complexes

29

Figure 6.2. Plausible mechanism for the reaction of complex 29 with styrene.

complex22

+

Ph10 equiv

pyridine (0.5 equiv) Ts20 (1.2 equiv) pyridine N-oxide (1,2 equiv)

Ts I

D

CHzC12,O "C,3 h

,A ph"; ( s) 44 % (37 o/o ee)

Scheme 20. Aziridination of styrene with complex 22.

6.4.3 Asymmetric Aziridination of Styrene Derivatives Some P-substituted styrene derivatives were employed in the reaction to establish the generality of the present asymmetric synthesis. The pronounced effect of pyridine Noxide was also observed in the aziridination of trans-P-methylstyrene. While this compound was not aziridinated below room temperature in the absence of pyridine N-oxide, the addition of the N-oxide to the reaction system resulted in both high yield and enantioselectivity of the aziridinated product, even at 0 "C (Table 6.3).

186

Minakata and Komatsu

complex15

+

Ph*Me

additive (1.2 equiv) pyridine (0.5 equiv) Ts2O (1.2 equiv)

Ts I P

CHzC12,3 h

10 equiv

Table 6.3 Aziridination of trans-fGmethylstyrenewith 15. Additive

Temperature ("C)

Yield (%)

ee (%)

None None Pyridine N-oxide

rt

60 0

13

12

85

0 0

-

In contrast, the aziridination of cis-f3-methylstyrene was not observed at 0 "C in spite of the presence of pyridine N-oxide. At room temperature, in the absence of the N-oxide, the cis-aziridine was obtained in a poor yield and with a low ee value (Table 6.4). The addition of the N-oxide improved the yield of the product, but did not cause a dramatic change in the ee value.

complex 15

Ph?

+

additive (1.2 equiv) pyridine (0.5 equiv) TszO (1.2 equiv)

Me 10 equiv

Ts I *

CH2C12,3 h

Ph

Me

Table 6.4 Aziridination of cis-P-methylstyrene with 15. ~~~

Additive

Temperature ("C)

Yield (%)

ee (%)

None F'yridine N-oxide None Pyridine N-oxide

0 0

0 0 14 34

30 25

rt ri

-

It is noteworthy that high stereospecificity was observed in all the aziridinations of trans- and cis-1,2-disubstituted olefins, although such reactions in the presence of metal catalysts and PhI=NTs did not always show high stereospecificity [4,sa-j]. Other trans-substituted styrene derivatives were examined, and gave excellent enantioselectivities, as shown in Table 6.5.

6.4 Asymmetric Aziridination of Olefins with Chiral Nitridomanganese Complexes

complex 15 1 equiv

+

187

pyridine (1.2 equiv) TszO (1.2 equiv) pyridine Noxide (1.2 equiv) Olefin

CH2CIz

10 equiv

-

Aziridine

Table 6.5 Asymmetric aziridination of trans-substituted styrene derivatives with complex 15 Olefin

Conditions

Aziridine

Yield (%)

ee (%)

66

90

53

94

12

86

Ts I

7

Ph

0°C. 3 h Ph Ts

4

Ph

0°C5h Ph

Ts

&

Ph

rt, 24 h Ph’

Ak

The enantioselectivity became higher with an increase in the bulkiness of the substituent at the P-position of styrene. Although the reason for this phenomenon is unclear, the absolute configuration of the aziridine derived from trans-P-methylstyrene is consistent with a reaction pathway as follows. The steric repulsion between the methyl or phenyl group of an olefin and the cyclohexane ring of complex 28 disturbs the formation of (S,S)-aziridineby route al. On the other hand, the approach of trans-P-methylstyrene to complex 28 by route a2is more favorable to providing the (R,R)-aziridine in good yield and enantiomeric excess (Figure 6.3).

188

Minakata and Komatsu Me,.

Figure 6.3. Plausible mechanism for the reaction of complex 28 with trans-P-methylstyrene.

6.4.4Aziridination of Conjugated Dienes When l-phenyl-l,5hexadiene was treated with complex 15, the chemoselective aziridination proceeded at the olefin portion attached to the phenyl group to give good enantioselectivity (Scheme 2 1). In other words, unconjugated olefins such as alkyl-substituted olefins were not aziridinated under these conditions. pyridine (0.5 equiv) Ts20 (1.2 equiv) pyridine Noxide (1,2 equiv) complex15 1 equiv

+

ph

\ 10 equiv

CH~CIP, 0 "C, 4h

-+ Ts

Ph

25 % (87 % W)

Scheme 21. Chemoselective aziridination of 1-phenyl- i,5-hexadiene with complex 15.

Thus, conjugated dienes were employed in the reaction utilizing the nitridomanganese complex to expand the generality of the methodology. The synthesis of alkenyl aziridines is usually accomplished by carbon -carbon double bond formation after the construction of the aziridine ring [27]. Although there are many examples of the direct nitrene addition to 1,3-dienes, their yields range from low to good, with the inherent problems of photolysis and thermolysis of azides resulting in a variety of byproducts [28]. Recently, the copper-catalyzed nitrogen transfer reaction to 1,3dienes using PhI = NTs have been reported and sometimes gave the mixtures of alkenyl aziridines and pyrroline derivatives [28]. However, the use of the racemic nitrido complex 15 selectively led to the alkenyl aziridine in good yield (Scheme 22).

189

6.4 Asymmetric Aziridination of Olefns with Chiral Nitridomanganese Complexes

rac-complex 15 1 equiv

PhkNTs

+

pyridine (0.5 equiv) Ts20 (1.2 equiv) pyridine N-oxide (1,2 equiv)*

+

H N T s

CH2C12,O "C, 2 h 10 equiv

67 o/'

Cu(acac)p (0.1 equiv), MeCN Ts

60 o/'

1

3

Scheme 22. Comparison of aziridination of 1.3-diene with nitrido complex versus PhI=NTs.

The achiral aziridination with the racemic nitrido complex 15 was successfully applied to a wide range of 1,3-dienes (Table 6.6). Cyclic conjugated dienes were smoothly aziridinated under mild conditions with no [4 11 adducts. Among these, cyclohexadiene and cycloheptadiene reacted with the complex in good yields. When the unsymmetrical dienes were employed in the reaction, the azindinations of isoprene and trans- 1,3-hexadiene proceeded, giving two regioisomers in 70:30 and 945,respectively. The major isomers in both reactions were formed by the aziridination of the less substituted olefins of the 1.3-dienes.

+

190

Minakata and Komatsu

Table 6.6 Aziridination of 1.3-dienes with rac-complex 15 Diene

Conditions -

Product

Yield (%)

78 "C+

- 20"C, 5

53 h

82

O"C,0.5 h 85

O T , 0.6 h

O T , 7h

55

0°C 3 h

52

O T ,3 h (70

:

30)

NTs

.-+-+NTs

0°C. 1.5 h

(94

:

61

56

4)

Since the nitridomanganese complex was found to be a good reagent for the aziridination of 1,3-dienes, chiral nitridomanganese complexes were applied to the reaction. When I-vinylcyclohex-1-ene was treated with complex 15 in methylene chloride at 0 "C for 2 h in the presence of Ts,O, pyridine and pyridine N-oxide, two regioisomers of alkenyl aziridines were obtained in a 91:9 ratio and the enantioselectivities of these compounds were not good (Scheme 23). To increase the enantioselectivity of the reaction, complex 19 was employed in the reaction to give moderate enantioselectivities.

6.4 Asymmetric Aziridination of Olejins with Chiral Nitridomnganese Complexes

complex 15 1 equiv

191

pyridine (0.5 equiv) Ts20 (1.2 equiv) pyridine Noxide (1,2 equiv)

+

L

CH2C12,O "C, 2 h 10 equiv

41 Yo

91

:

9

(28 % ee)

(1 0 % ee)

(30 % ee)

(28 % ee)

Scheme 23. Asymmetric miridination of I-vinylcyclohex- 1-ene with chiral nitridomanganese complexes.

Alkenyl aziridines are useful synthetic building blocks and can be converted to allylamines by conjugate addition of organocuprates [29], to pyrroline derivatives by rearrangement [30] and to p-lactams by Pd-catalyzed carbonylation [3 11.

6.4.5 Asymmetric Amination of Silyl Enol Ether The nitrido complex was applied to the direct asymmetric amination with a silyl enol ether as a substrate. Although several examples for achiral aminations of silyl enol ethers have been reported [32], an asymmetric version of reagent-controlled reaction has not appeared except for the one recent example [33] and the diastereoselective reactions with silyl enol ethers having a chiral auxiliary [34]. The amination, which is presumed to take place via an aziridine intermediate [5g, 1 Id, 321, proceeded smoothly to give the N-tosylated a-aminoketone in 76 % yield with 48 % ee. When the same silyl enol ether was treated with complex 15 under Carreira's condition, the N-trifluoroacetylated a-aminoketone was obtained in 58 % yield with 79% ee (Scheme 24).

192

Minakata and Komatsu

& TMSo

complex

+

pyridine (0.5 equiv) T+O (1.2 equiv) pyridine Koxide (1$2equiv) CHpCl2,O "C, 3 h

1 eauiv 10 equiv

76 ?Ao (48 % ee)

1 equiv

58 % (79 YOee)

Scheme 24. Asymmetric amination of silyl enol ether with complex 15.

Very recently, Jorgensen's group reported the preparation of some chiral nitridomanganese complexes, which closely resemble those synthesized by the authors' group, and the application to asymmetric amination of silyl enol ethers with the chiral complexes using Carreira's method [35]. These results were very similar to those of the authors [22].

6.5 Conclusion The development of novel methodologies which utilize nitridomanganese complexes for organic synthesis, mainly asymmetric aziridination, has been outlined. The methods for asymmetric aziridinations of olefins, including the present reactions, are very important in the simultaneous building of two carbon-nitrogen bonds, because the two neighboring chiral centers can be induced by a one-step reaction. The chiral nitridomanganese complexes were found to be good reagents for asymmetric Nl unit transfer reaction to olefins, such as styrene derivatives, conjugated dienes, and electron-rich olefins. In particular, highly enantioselective reactions proceeded in the asymmetric aziridinations of trans-substituted styrene derivatives. The results described here represent just a beginning in the use of nitrido complexes. The basic information may lead to the development of a nitrido complex that might be a practical nitrogen source for organic synthesis. Although, in general, the nitrido complexes are highly stable and easy to synthesize and handle, the reaction system has, at present, a disadvantage in that stoichiometric amounts of the complexes are required for the reaction to proceed. In the near future, a great deal of effort should be expended in the area of catalytic systems via nitrido complexes in order to realize more practical and efficient processes.

References

193

References [I] a) E. N. Jacobsen in Comprehensive Organometallic Chemistry 11, Vol. I 2 (Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson), Pergamon, Oxford, 1995, p. 1097; b) S.4. Murahashi, T. Naota in Comprehensive Organometallic Chemistry ll, Vol. 12 (Eds.: E. W.Abel, F. G. A. Stone, G. Wilkinson), Pergamon, Oxford, 1995, p. 1177; c) J. A. Deyrup in The Chemistry of Heterocyclic Compounds, Vol. 42 (Ed.: A. Hassner), Wiley, New York, 1993; d) A. Padwa, A. D. Woolhouse in Comprehensive Heterocyclic Chemistry, Vol. 7 (Ed.; W. Lwowski), Pergamon, Oxford, 1984, p. 47; e) W. H. Pearson, B. W. Lian, S. C. Bergmeier in Comprehensive Heterocyclic Chemistry II.Vol. IA (Ed.: A. Padwa), Pergamon, Oxford, 19%; f) K. M. L. Rai, A. Hassner in Comprehensive Heterocyclic Chemistry 11, Vol. I A (Ed.: A. Padwa), Pergarnon, Oxford, 1996, p. 61; g) J. E. G. Kemp in Comprehensive Organic Synthesis, Vol. 7 (Ed.: S . V. Ley), Pergamon, Oxford, 1991, p. 469. [2] a) K. A. J~gensen,Chem. Rev. 1998,89,43 I ; b) H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483; c) E. J. Corey, M. C. Noe, J. Am. Chem. SOC. 1996, 118, 11038, and referenses therein. [3] a) W. Lwowski in Nitrenes (Ed.: W. Lwowski), Interscience, New York, 1970, p. 185; b) 0.E. Edwards in Nitrenes (Ed.: W. Lwowski), Interscience, New York, 1970, p. 225; c) W. Lwowski in Azides and Nitrenes, Reactivity and Utility (Ed.: E. F. V. Scriven), Academic, New York, 1984, p. 205; d) H. Kward, A. A. Kahn, J. Am. Chem. SOC.1967,89, 1951. [41 a) Y. Yamada, T. Yarnamoto, M. Okawara, Chem. Lett. 1975, 361; b) D. Mansuy, J.-P. Mahy, A. Dureault, B. Bedi, P. Battioni, J. Chem. SOC. Chem. Commun. 1984, 1161; c) J.-P. Mahy, G. Bedi, P. Battioni, D. Mansuy, Tetrahedron Lett. 1988, 29, 1927; d) J.-P. Mahy, G. Bedi, P.Battioni, D. Mansuy, J. Chem. SOC.,Perkin Trans. 2 1988, 1517; e) D. A. Evans, M. M. Fad, M. T. Bilodeau, J. Org. Chem. 1991,56,6744; f) P. J. Pirez, M. Brookhart, J. L. Templeton, Organometallics 1993, 12, 261; g) D. A. Evans, M. M. Fad, M. T. Bilodeau, J. Am. Chem. SOC.1994, 116, 2742; h) P. Muller, C. Baud, Y. Jacquier, Tetrahedron 1996, 52, 1543; i) P. Dauban, R. H. Dodd, Tetrahedron Left. 1998, 39, 5739, [ 5 ] a) R. S. Atkinson in Azides and Nitrenes (Ed.: E. F. V. Scriven), Academic, New York, 1984, p. 247; b) R. S. Atkinson, G. Tughan, J. Chem. SOC., Perkin Trans. 1 1987, 2787; c) R. S. Atkinson, G. Tughan, ibid. 1987, 2803; d) R. S. Atkinson, B. J. Kelly, J. Chem. SOC.,Chem. Commun. 1988, 624; e) R. S. Atkinson, M. J. Grimshire, B. J. Kelly, Tetrahedron 1989, 45, 2875; f ) Z. Chilmonczyk, M. Egli, C. Behringer, A. S. Dreiding, Helv. Chim. Acta 1989, 72, 1095; g) J. T. Kapron, B. D. Santarsiero, J. C. Vederas, J. Chem. SOC., Chem, Commun. 1993, 1074; h) R. S. Atkinson, M. P. Coogan, C. L. Cornell, ibid. 1993, 1215; i) R. S. Atkinson, E. Barker, C. K. Heades, H. A. Alber, ibid. 1998, 29. [6] a) V. F. Rudchenko, S. M. Ignatov, R. G. Kostyanovsky, J. Chem. SOC., Chem. Commun.1990,261; b) E. Vedejs, H. Sano, Tetrahedron Lett. 1992, 33, 3261. 171 a) T. Ando, S. Minakata, I. Ryu, M. Komatsu, Tetrahedron Lett. 1998,39,7669; b) T. Ando, D. Kano, S. Minakata, I. Ryu, M. Komatsu, Tetrahedron 1998,54,13485;c) J. U. Jeong, B. Tao, I. Sagasser, H. Henniges, K. B. Sharpless, J. Am. Chem. Soc. 1998,120,6844; d) D. P. Albone, P. S. Aujla, P. C. Taylor, S. Challenger, A. M. Derrick, J. Org. Chem. 1998,63, 9569. 181 a) For example, see: M. M. Pereira, P. P. 0. Santos, L. V. Reis, A. M. Lobo, S. Prabhakar. J. Chern. SOC.,Chem. Commun.1993, 38. 191 a) D. A. Evans, K. A. Woerpel, M. M. Hinrnan, M. M. Fad, J. Am. Chem. SOC. 1991,113,726;b) R. E. Lowenthal, S. Masamune, Tetrahedron Lett. 1991,32,7373; c) K. J. O’Connor, S.-J. Wey, C. J. Burrows, ibid. 1992,33, 1001; d) Z. Li, K. R. Conser, E. N. Jacobsen, J. Am. Chem. SOC.1993,115, 5326; e) D. A. Evans, M. M. Fad, M. T. Bilodeau, B. A. Anderson, D. M. Barnes, ibid. 1993, 115, 5328; f) K. Noda, N. Hosoya, R. hie, Y. lto, T. Katsuki, Synleft 1993,467;g) W. Zhang, N. H. Lee, E. N. Jacobsen, J. Am. Chem. SOC. 1994,116,425;h) Z . Li, R. W. Quan, E. N. Jacobsen, ibid. 1995,117, 5889; i) A. M. Harm, J. G. Knight, G. Stemp, Synlett 1996, 677; j) H. Nishikori, T. Katsuki, Tetrahedron Lett. 1996,37,9245; k) R. S. Atkinson, W. T. Gattrell, A. P. Ayscough, T. H. Raynham, J. Chem. SOC., Chem. Commun. 1996, 1935; 1) R. S. Atkinson, T.A. Claxton, I. S. T. Lochrie, S. Ulukanli, Tetrahedron Lett. 1998, 39, 5113. [ 101 a) J. T. Groves, T. Takahashi, J. Am. Chem. SOC.1983,105,2073;b) J. T. Groves, T. Takahashi, W. M. Butlar, Inorg. Chem. 1983, 22, 884.

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[ l l ] a) J. D. Bois, J. Hong, E. M. Carreira,M. W. Day,J.Am. Chem.SOC. 1996,118,915;b) J. D. Bois, C. S. Tomooka, J. Hong, E. M. Carreira, ibid. 1997,119,3179; c) J. D. Bois, C. S. Tomooka, J. Hong, E. M. Carreira, M. W. Day, Angew. Chem 1997, 109, 1722; Angew. Chem. Inr. Ed. Engl. 1997.36, 1645; d) J. D. Bois, C. S. Tomooka, J. Hong, E. M . Carreira, Acc. Chem. Res. 1997,30,364; e) E. M. Carreira, J. Hong, J. D. Bois, C. S. Tomooka, Pure & Appl. Chem. 1998, 70, 1097. [12] a) D. L. Hughes, S. K. Ibrahim, C. J. Macdonald, H. M. Ali, C. J. Pickett, J. Chem Soc., Chem. Commun. 1992,1762; b) S. A. Fairhurst, D. L. Hughes, S.K. Ibrahim, M.-L. Abasq, J. Talarmin, M. A. Queiros, A. Fonseca, C. J. Pickett, J. Chem. SOC., Dalton Trans. 1995, 1973, and references therein. [13] M. Barani, S. Fioravanti, M. A. Loreto, L. Pellacani, P. A. Tardella, Tetrahedron 1994,50,3829, and references therein. [14] R. Vyas, B. M. Chanda, A. V. Bedekar, Tetrahedron Lett. 1998, 39, 4715. [15] a) K. B. Sharpless, A. 0. Chong, K. Oshima, J. Org. Chem. 1976, 41, 177; b) E. Herranz, K. B. Sharpless, ibid. 1978.43, 2544; c) E. Herranz, K.B. Sharpless, Org. Synrh. 1981, 61, 85. [16] G. Li, H.-T. Chang, K. B. Sharpless, Angew. Chem. 1996, 108,449; Angew. Chem. Inr. Ed. Engl. 1996,35,451. [17] A. E. Rubin, K. B. Sharpless, Angew. Chem. 1997,109,2751;Angew. Chem. lnt. Ed. Engl. 1997,36, 2637. [18] Reviews, see: a) K. Dehnicke, J. Strme, Angew. Chem. 1992,104,978;Angew. Chem. Int. Ed. Engl. 1992,31, 955; b) J. Baldas, Topics in Current Chemistry 1996, 176, 37. [19] For example, see: a) C. L. Hill, F. J. Hollander, J. Am. Chem.SOC.1982,104,7318; b) J. W. Buchler, C. Dreher, K.-L. Lay, Z. Naturforsch. B: Anorg. Chem., Org. Chem. 1982, 37B, 1155; c) J. W. Buchler, C. Dreher, K.-L. Lay, Y. J. A. Lee, W. R. Scheidt, Inorg. Chem. 1983, 22, 888; d) C. E. Laplaza, C. C. Cummins, Science 1995, 268, 861. [20] A. S. Jepsen, M. Roberson, R. G. Hazell, K. A. Jergensen, Chem. Commun. 1998, 1599. The same chiral nitridomanganese complexes including JBrgensen’s complex were prepared and characterized by Gray’s group. See; C. J. Chang, W. B. Connick, D. W. Low, M. W. Day, H. B. Gray, Inorg. Chem 1998, 37, 3107. [21] J. F. Larrow, E. N. Jacobsen, Y. Gao. Y. Hong, X. Nie, C. M. Zepp, J. Org. Chem 1994,59, 1939. [22] S. Minakata, T. Ando, M. Nishimura, I. Ryu, M. Komatsu, Angew. Chem. 1998, 110, 3596; Angew. Chem. lnt. Ed. Engl. 1998,37, 3392. [23] a) D. Tanner, Angew. Chem. 1994,106,625; Angew. Chem. Int. Ed. Engl. 1994,33,599; b) H. M. I. Osbom, J. Sweeney, Tetrahedron: Asymmetry 1997.8, 1693; c) A.-H. Li, L.-X. Dai, V. K. Aggawal, Chem. Rev. 1997, 97, 2341. [24] R. Irie, Y.Ito, T. Katsuki, Synlen 1991, 265. [25] a) T. Hamada, T. Fukuda, H. Imanishi, T. Katsuki, Tetrahedron 1996,52,515; b) Y. Noguchi, R. hie, T. Fukuda, T. Katsuki, Tetrahedron Lett. 1996, 37, 4533. [26] E. J. Corey, F. N. M. Kiihnle, Tetrahedron Lett. 1997, 38, 8631. [27] a) D. Borel, Y. Gelas-Mialhe, R. Vessiere, Can. J. Chem. 1976,54, 1582; b) J. Ahman, F? Somfai, Tetrahedron Lett. 1995, 36, 303. [28] J. G. Knight, M. P. Muldowne, Synlett 1995, 949, and references therein. [29] P. Wipf, P. C. Fritch, J. Org. Chem. 1994, 59,4875, and references therein. [30] a) A. G. Schultz, R. R. Staib, K. K. Eng, J. Org. Chem. 1987,52,2968; b) K. Miura, K. Fugami, K. Ohshima, K. Utimoto, Tetrahedron Lett. 1988, 29, 1543; c) W. H. Pearson, S. C. Bergmeier, S . Degan, C.-L. KO, Y.-F. Poon, J. M. Schkeryantz, J. P. Williams, J. 0%.Chem. 1990, 55, 5719. [31] For example, see: D. Tanner, Pure Appl. Chem. 1993. 65, 1319. [32] a) S. Lociuro, L. Pellacani, P. A. Tardella, Tetrahedron Lett. 1983,24,593; b) A. Cipollone, M. A. Loreto, L. Pellacani, P. A. Tardella, J. Org. Chem. 1987, 52, 2584. [33] P. Phukan, A. Sudalai, Tetrahedron: Asymmetry 1998, 9, 1001. [34] a) L. A. Trimble, J. C. Vederas, J. Am. Chem. SOC.1986,108,6397; b) D. A. Evans, Th. C. Britton, R. L. Dorow, J. F. Dellaria, Jr., Tetrahedron 1988, 44, 5525. [35] N. Svenstrup, A. Bogevig, R. G. Hazell, K. A. Jqrgensen J. Chem. Soc., Perkin Trans. I , 1999, 1559.

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

7 Palladium-Catalyzed Amination of Ary 1 Halides and Sulfonates John F: Hartwig

7.1 Introduction The transition metal-catalyzed synthesis of arylamines by the reaction of aryl halides or triflates with primary or secondary amines has rapidly become a valuable synthetic tool for a variety of applications. This process can form monoalkyl or dialkyl anilines, mixed diarylamines or mixed triarylamines, as well as N-arylimines, carbonates, and hydrazones. The aromatic carbon-nitrogen bond in an N-aryl amide or tosylamide can be formed intramolecularly.The mechanism of this reaction involves several new organometallic reactions. For example, the C-N bond is formed by reductive elimination of amine, and the metal amido complexes that undergo reductive elimination may be formed in the catalytic cycle by N-H activation. Side products are formed by p-hydrogen elimination from amides, examples of which have recently been observed directly. An overview that covers the development of synthetic methods to form arylamines by this palladium-catalyzed chemistry is presented. In addition to the synthetic information, a description of the pertinent mechanistic data on the overall catalytic cycle, on each elementary reaction that comprises the catalytic cycle, and on competing side reactions is presented. The review covers manuscripts that appeared in press before September 1, 1999. This chapter is based on a review covering the literature through May 1, 1997. However, roughly 100 papers on this topic have appeared since that time, requiring an updated review. Other reviews have been published in the interim [l-31.

7.1.1 Synthetic Considerations

Arylamines are commonplace, as components of molecules with medicinally or electronically important, catalytic active, or structurally interesting properties. An aryl-nitrogen linkage is included in nitrogen heterocycles such as indoles [4,5] and benzopyrazoles, conjugated polymers such as polyanilines [6- 121, and readily oxidized triarylamines used in electronic applications such as 4,4’-bis(3-methylphe-

196

Hartwig

nylpheny1amino)biphenyl (TPD) [13-161. The use of aryl halides and triflates in these coupling reactions to form arylamines allows a single group to be used as a synthetic intermediate in aromatic carbon -carbon cross-coupling and amination reactions as part of structure activity studies or library synthesis in drug development. Despite the simplicity of the arylamine moiety, syntheses of these materials are often difficult. Procedures involving nitration, reduction, and substitution are incompatible with many functional groups and often involve protection and deprotection steps. Reductive amination provides a convenient route to some alkyl arylamines, but this procedure requires a pre-existing aromatic C -N bond [ 17- 201. Addition of amines or alcohols to benzyne intermediates gives varying regiochemistry [21], and direct nucleophilic substitution of aryl halides typically requires a large excess of reagent, a highly polar solvent, and either high reaction temperatures or highly activated aryl halides [22,23]. Alternatively, transition metal arene complexes have been used to accelerate substitution of the aryl halide, but stoichiometric amounts of transition metal complex are required in this case [24,25]. Thus, the new, mild, general catalytic methods for replacement of aryl halogen or sulfonate with amine provide an invaluable route to arylamines. The procedure that is most competitive with the palladium chemistry is the traditional copper-mediated (Ullmann) substitution. However, these reactions typically occur at high temperatures [26 -291, precluding chemistry with sensitive functionality. Further, these reactions often give products from diarylation of primary arylamines substrates. The Ullmann couplings are also substrate-specific. Primary alkylamines and even dialkylamines give modest or poor yields. Related coppermediated reactions involving aromatic carbon-nitrogen bond formation with weakly nucleophilic nitrogen substrates, such as imidazole and amides have been accomplishedrecently by a different copper-mediated process: coupling of arylboronic acids with the nitrogen nucleophile [30]. This chemistry is mild, but requires two steps from an aryl halide because of the intermediacy of the boronic acid. Prior to the development of palladium-catalyzed amination chemistry, palladiumcatalyzed coupling had been a powerful method to form a new C-C bond at an aryl halide or triflate by replacement of the aryl halogen or pseudohalogen with a carbon nucleophile [31-381. A variety of main group and transition metal reagents are used as the source of the carbon nucleophile. Tin and boron are most commonly used, but aluminum, zinc, magnesium and silicon reagents are also effective in this “crosscoupling” chemistry. Nickel and palladium complexes are now the most common catalysts. The cross-coupling chemistry has been reviewed on several occasions, many of which are cited in the reference list.

7. I Introduction

197

7.1.2 Prior C-X Bond-Forming Coupling Chemistry Related to the Amination of Aryl Halides There is a substantial body of literature on the palladium- and nickel-catalyzed formation of aryl sulfides, selenides and phosphines from aromatic and heteroaromatic halides. A recent review covers the types of transformations that can be conducted and the types of catalysts that are used [39]. In general, either a stannyl sulfide, boryl sulfide, or alkali metal thiolate will react under mild conditions with a variety of aromatic and heteroaromatic halides to form mixed sulfides. Aryl or heteroaryl halides or triflates react with silyl phosphides or secondary phosphines in the presence of a base to form arylphosphines when catalyzed by palladium and nickel complexes. Particularly useful examples are the conversions of binaphthol to binaphthylphosphines via the triflate intermediate using palladium and nickel catalysts [40]. The soft thiolate and phosphide make formation of the palladium thiolate or phosphide complexes a favorable step; ironically, their high nucleophilicity also makes their elimination to form phosphine and sulfide facile, in accordance with results concerning electronic effects on reductive elimination in Section 7.8.3 [41]. C-S bond cleavage can create problems in the synthesis of sulfides, however. A mixture of sulfides can result from reaction of an aryl halide with an arene thiol containing a different aromatic group [42-441.

7.1.3 Novel Organometallic Chemistry The reductive elimination to form C-C and C-H bonds [45] is a crucial step in the cross-coupling processes, as well as many other transition metal-catalyzed reactions. Reductive elimination reactions comprise an early chapter in any organometallic text. Many examples of these reactions have been studied, and a great deal is known about the mechanisms of these processes. Similarly, the cleavage of C-H bonds by oxidative addition, including the C-H bond in methane, is now known [46]. Again, questions remain about how these reactions occur, but a variety of mechanistic studies have revealed key features of these reactions. Even some remarkably mild C-C cleavage reactions have now been observed with soluble transition metal complexes [47,48]. In contrast, few examples of reductive elimination reactions that form the C-N bond in amines are known. Only in the past several years have complexes been isolated that undergo these reactions [49- 541. These reductive eliminations are the crucial C-N bond-forming step of the aryl halide and triflate amination chemistry discussed in this review. Information on how these reactions occur, and what types of complexes favor this process, has been crucial to the understanding and development of new amination catalysts [50].

198

Hartwig

The cleavage of alkylamine N-H bonds by late transition metals is also rare [55,56]. N-H cleavage reactions, either oxidative additions or sigma-bonded ligand exchanges, produce a transition metal amido complex. For the case of late transition metal systems, the resulting amido complexes are highly reactive [57,58]. It appears that the amination of aryl halides can involve an unusual NH activation process by a palladium alkoxide to form a highly reactive palladium amide [51]. As a result, the discovery of N-H activation processes is crucial to catalysis with amines as substrates, including the amination of aryl halides. In general, catalytic organometallic chemistry that forms carbon -heteroatom bonds is less developed and less understood than that which forms C-C bonds. One organometallic oxidation process is conducted on a large industrial scale: the oxidation of ethylene to acetaldehyde, or the Wacker process [59,60]. However, the detailed mechanism of this process and most other oxidation chemistry remains an unsolved problem. Likewise, hydrocarbon oxidation also remains an area of active research today, despite many years of study [61,62]. Other processes that form carbon- heteroatom bonds by homogeneous catalysis include oxidative carbonylations of amines and alcohols [60]. These carbonylations can supplant the use of phosgene as an intermediate in urethane and carbonate syntheses. Nonoxidative carbonylation includes the reaction between aryl halide, CO, and an alcohol or amine to form esters or amides [60]. These reactions presumably involve attack of alcohol (or amine) at a metal phenacyl complex. An additional catalytic process, the amination and aquation of olefins, could form the C-X bonds in alcohols or amines. An efficient, intermolecular aquation or hydroamination of aryl halides is a highly sought-after process that is currently unknown, despite some interesting intramolecular examples [63- 651 and some slow intermolecular examples [66,67]. Other nonoxidative organometallic reactions that form C-N or C - 0 bonds are rare. Thus, the selectivities, deactivation mechanisms, and potential transformations of alkoxo and amido intermediates in such reactions are not well understood. It is even rare for transition metal amido and alkoxo complexes to be clearly identified as intermediates in catalytic chemistry. The hydrogenation of imines and ketones presumably involves such intermediates [68], but they have not been clearly detected in these reactions [69]. The catalytic reduction of CO on surfaces may involve alkoxides, but well-characterized homogeneous analogs are unusual [58].

7.1.4 Organization of the Chapter This chapter will cover the recent developments in palladium-catalyzed amination of aryl halides and sulfonates. The nickel-catalyzed process requires much higher catalyst loads and has a more narrow substrate scope, and will not be reviewed [70,71]. The first sections will cover the development of different palladium catalysts for the

7.2 Background

199

synthesis of arylamines and related structures. This work rests upon Kosugi’s initial finding [72,73] that palladium complexes catalyze the formation of arylamines from tin amides and aryl halides. The second section will cover the various arenas in which the palladium chemistry has been applied. The final section will present current mechanistic data concerning these processes with different catalysts.

7.2 Background 7.2.1 Early Palladium-Catalyzed Amination During the 1980s a few results suggested that a general metal-catalyzed method to form arylamines from aryl halides would be possible. In 1983, Kosugi, Kameyama, and Migita published a short paper on the reaction of tributyltin amides with aryl bromides catalyzed by [P(o-C,H,Me),],PdCl, (1) shown in Eq. (1) [72,73]. The scope of this reaction appeared to be limited to dialkylamides and electron-neutral aryl halides. For example, nitro-, acyl-, methoxy- and dimethylamino-substituted aryl halides gave poor yields upon palladium-catalyzed reaction with tributyltin diethylamide. Further, aryl bromides were the only aryl halides that gave any reaction product. Vinyl bromides gave modest yields of enamines in some cases. Only unhindered dialkyl tin amides gave substantial amounts of amination product. The mechanism did not appear to involve radicals or benzyne intermediates.

ygc02Me

Me02cFe

Me

Me02C

H2N Br

+ \

[Pd(PPh&] (2)

-

Me

HN \

200

Hartwig

Boger reported studies on palladium-mediated cyclization to form the CDE ring system of lavendamycin, as shown in Eq. (2) [74-761. These reactions were conducted with stoichiometric amounts of [Pd(PPh3)4](2). When used in a 1 mol% quantity, 2 failed to catalyze these reactions, presumably because of the absence of a base. Until almost 10 years later, no palladium-catalyzed amination chemistry was reported, and few citations of the early amination chemistry existed. Paul, Patt, and Hartwig revealed the reactions involved in the amination chemistry using tin reagents [77]. Although these studies focused on what is now an outdated synthetic method, the classes of stoichiometric reactions that comprise the catalytic cycle are general to many current amination procedures. They showed that the active catalyst was a (Pd [P(o-C,H4Me),],) (3), which oxidatively added aryl halides to give dimeric aryl halide complexes (4). These aryl halide complexes reacted directly with tin amides to form arylamine products (Eq. (3)). Thus, this chemistry could accurately be viewed as a rough parallel to Stille coupling.

-

ArBr L-Pd-L(3) L=P(@C6H4Me)3

-

L\ /B'. /Ar R3SnNR2 Pd Pd ArNR2+Pdo \ / \ Br L (4)

(3)

Guram and Buchwald showed that the chemistry could be extended beyond just electron-neutral aryl halides [78]. Using in situ-derived tin amides, this chemistry encompassed aryl halides bearing esters, amino, and alkoxo groups (Eq. (4)). However, reactions that gave 80% yield or greater were still limited to tin amides derived from secondary amines.

BuzSn-N,

-

FtHNRR' Bu3SnNRR' Et

[L~P~C~ZI

L=P(G C ~ H ~ M ~ ) ~

base (4) X=alkyl, ester, amino, alkoxo

7.3 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates

20 1

7.2.2 Initial Synthetic Problems to be Solved The initial results concerning aryl halide amination and related results in chemistry forming aryl sulfides and phosphines strongly suggested that a mild, convenient route to arylamines from aryl halides could be developed. However, a source of the amido group must be less toxic, more thermally stable, and less air-sensitive than tin amides. The type of aryl halide that can undergo this reaction must extend beyond electron-neutral aryl halides. Aryl chlorides and iodides, along with aryl triflates and less reactive, but more convenient, sulfonates should be included in the substrates able to undergo amination. Of course, heteroaromatic amines and halides are also important substrates and should be included. Perhaps most important, reactions of primary amines needed to be developed since the aryl halide amination with primary amines would give secondary alkyl arylarnines. These substrates are tedious to prepare by classical methods. Finally, the rates and turnover numbers provided by the catalysts must be much higher than those in Kosugi’s chemistry and in Boger’s stoichiometric cyclization reaction, allowing for the use of weaker bases and lower reaction temperatures.

7.3 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates 7.3.1 Initial Intermolecular Tin-Free Aminations of Aryl Halides In 1995, Hartwig and Buchwald published concurrently their two groups’ results on tin-free amination of aryl halides [79, SO], Instead of isolating or generating a tin amide in situ, the amination reactions were conducted by reacting an aryl halide with the combination of an amine and either an alkoxide or silylamide base (Eq. (5)). These reactions were typically conducted between 80 and 100°C in toluene solvent. The catalysts used initially were 1, 3, or a combination of [Pd,(dba),] (5a) (dba = trans, trans-dibenzylidene acetone) and P(o-C,H,Me),. Catalysts used subsequently will be described below. As shown in Table 7.1, secondary amines were viable substrates, but primary amines gave substantial yields with

base X=o, m, or p-alkyl, phenacyl, amino, alkoxy base = NaO-f-Bu,or LiN(SiMe&

202

Hartwig

Table 7.1 Initial tin-free aminations of aryl halides catalyzed by L,PdCI, L = P(o-C,H,Me), Base

Amine

P

h

e

r

Product

NaO-r-Bu

Yield (%)

86 89

MeO--@r

-

LiN(TMS),

Me0

a9 Me0

NaO-t-Bu

81

mBr

NaO-t-Bu

78 0

B rO Ph

BU*B1

-

NaO-t-Bu LiN(TMS),

~ N H h e x y l Ph

-

72 <2

only electron-poor aryl halides. Little product was observed from reaction of primary amines with electron-neutral aryl halides, and arenes were the major product instead. Reaction conditions were initially optimized for amination of aryl iodides with the P(o-C,H,Me),-based catalysts [8 I], but improved methods using chelating ligands are presented below. Primary amines, including aniline, gave poor yields with unhindered aryl iodides.

7.3 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates

203

7.3.2 Initial Intramolecular Amination of Aryl Halides Intramolecular aryl halide aminations to form nitrogen heterocycles were included in the initial reports on tin-free aryl halide aminations [80]. For example, the reactions in Eq. (6) occurred in greater than 80% yield. In this case, the halide could be iodide or bromide, and [Pd(PPh,),] was a more effective catalyst than was {Pd[P(oC,H,Me),l,C1,1.

100 "C NaO-t-Bul

X=Br. I

K2C03

PhCH3

Bn

83-96 % n = 1-3

Subsequent to the initial report, Buchwald has provided an extensive account of the intramolecular amination reactions [82]. K2C03 was an effective base, but a combination of NaO-t-Bu and K2C03 was most effective. Aryl iodides proved to be the preferred substrate under optimized conditions with Pd(PPh,), as catalyst. Iodide substrates also allowed for the use of triethylamine as base. Screening of a variety of combinations of phosphine ligands and palladium precursors showed that chelating ligands such as Ph,P(CH,)"PPh, (n = 2-4) or 1,l '-bis-(diphenylphosphin0)ferrocene (DPPF) gave good yields of cyclized product, as did a combination of Pd,(dba), and P(2-furyl),, but none were better than using [Pd(PPh,),]. Presumably, the catalysts discussed in Section 7.4, which were developed after this work was published, would provide milder conditions for these reactions.

204

Hartwig

7.3.2 Second-Generation Catalysts: Aryl Bisphosphines 7.3.2.1 Amination of Aryl Halides With the exception of intramolecular amination reactions, all of the chemistry described above involved reactions catalyzed by palladium complexes containing the sterically hindered P(o-C,H,Me),. Mechanistic studies, which will be described below, showed that the catalytic cycle involved exclusively mono-phosphine intermediates. However, stoichiometric studies on reductive elimination from PPh,-ligated palladium amides [49,83] and on P-hydrogen elimination from related d8 square planar iridium amides [84] suggested that palladium complexes with chelating ligands would be particularly effective catalysts for the amination chemistry. In fact, many of the reasons why such complexes should be effective for this amination process parallel the reasons why they are effective for cross-coupling chemistry involving nucleophilic main group alkyl substrates [85]. In papers published back-to-back in 1996, Hartwig and Buchwald reported amination chemistry with palladium complexes of DPPF and BINAI? as catalysts [50,86]. These palladium complexes provided aminations of aryl bromides and iodides with primary alkyl amines, with cyclic secondary amines, and with anilines. It is ironic that the amination chemistry was first discovered by using a particularly labile phosphine, but was dramatically improved by the use of chelating ligands.

"m'

H2NQ

X= Br, I R=o, m, pOMe, Me, Ph R'=pCI, Ph, H

L,d"

650rlOO"C dioxane * R

-q3 R'

(7)

80-94 %

DPPF-ligated palladium provided nearly quantitative yields for amination of aryl halides with anilines (Eq.(7)). Electron-rich, electron-poor, hindered or unhindered aryl bromides or iodides all participated in the amination chemistry, with only a few exceptions. Nitro haloarenes gave no amination product with aniline substrates,

7.3 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates

205

while aryl halides with carbonyl groups bearing enolizable hydrogens gave poor yields, and esters were converted to the t-butyl ester by the r-butoxide base. These groups have now been shown to be amenable to amination processes that use Cs,C03 as base [87]. DPPF-ligated palladium also gave good yields of mixed alkyl arylamines with a variety of substrates (Eq. (8)). With electron-poor aryl halides, excellent yields of N-alkyl anilines were obtained. With electron-neutral aryl halides, 6092 % yields were obtained, depending on the location of alkyl substituents [50,88]. In the cases of unhindered and electron-neutral aryl halides coupled with unhindered primary amines, diarylation can occur. In these cases, running reactions with excess amine prohibits the formation of diarylation products [88]. For most of these reactions, 5 mol % catalyst was employed, although 1 mol % can be used in most cases. Table 7.2. Selected aryl bromide aminations catalyzed by BINAPIPd,(dba), Halide

Amine

Catalyst (%) Time (h)

Product

MeT

R = hexyl 0.5

-2

1

Isolated Yield (%)

Me

Me

R=Bn 0.5

2

88

4 7

79

2

81

79

0.05

( E d BnHN

Br

H,NBn

BnHN

4

&Br

5

+Br Me

Me

0.5

206

Hartwig

BLNAP-ligated palladium provided higher yields than complexes of DPPF in the case of electron-neutral aryl halides and alkyl amines as shown in Table 7.2. The increased yields resulted in large part from the lack of diarylation products. Slightly less reduction product was also observed, although the amount of arene formed when using BINAP or DPPF is low in both cases. Further, in favorable cases, it was shown that 0.05 mol % catalyst could be used. Racemic and resolved BINAF' gave identical results and again, aryl iodides are suitable substrates. A subtle, but sometimes important, advantage of the chelating ligands is its ability to prevent racemization of amines that possess a stereogenic center a- to nitrogen. Reactions of optically active amines have been evaluated, and the racemization that occurs in some cases with the original P(o-tolyl)3catalyst system does not occur when using ruc-BINAP as ligand ~391. In general, BINAP-ligated palladium is exquisitely selective for monoarylation of primary amines, and is the preferred catalyst for reactions of primarily alkylamine substrates. This result is mutually exclusive with mild, high-yield reactions of secondary amines with aryl halides to form tertiary amines. Thus, reactions of secondary amines with aryl halides using BINAP-ligated palladium as the catalyst are less reliable. For example, reactions of morpholine gave good yields, but reactions of piperidine and reactions of acyclic secondary amines give low to modest yields.

@h2/

popepph2 4

\

-

Ph2P

M

e

PPh2

Ph2P

PHANEPHOS

O

DPEphos

6

7a,b Figure 7.1. Chelating and hemilabile ligands used in palladium-catalyzed amination of aryl halides.

7.3 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates

207

Related bisphosphine ligands and some additional aryl bisphosphines or hemilabile arylphosphines have been used in the amination chemistry and may be valuable for certain aryl halide aminations (Figure 7.1). For example, PHANEPHOS has been shown to give good yields in a specific case of resolution of 2,2’-dibromo[2,2]paracyclophane [90]. More extensive studies have not been reported. However, Buchwald has reported that reactions employing DPEphos (bis-(2,2’-diphenylphosphin0)diphenylether) gave higher yields for the formation of certain diarylamines than reactions using BINAP or DPPF [91]. As described in more detail below, solutions to the problem of coupling acyclic dialkylamines and to conditions employing milder bases began with the use of Kumada’s phosphinoether ligand 6 [87,92]. In addition, Uemura has reported the amination of aryl bromides using arene -chromium complexes 7a,b as phosphinoether and phosphinoamine analogues of Kumada’s ferrocene-based ligands; good yields were observed for reactions of cyclic and acyclic secondary amines [93]. Finally, Boche has used a sulfonated BISBI ligand 8 to conduct aminations in a two-phase aqueous solution containing watedmethanol, water/methanol/toluene, or wated2-butanol. Electron-poor aryl halides reacted under these aqueous palladium-catalyzed conditions with aniline to give diarylamines [94]. c-r”\tOTf

+H

DPPF/[Pd(dba)d (5b)

z N C

-\

NaO-t-Bu toluene *

- ’R R‘ 85°C R = MeO, Ph, Me, or ArOTf = 2-naphthyl triflate

80-94Yo

L24pd(dw 2 1

D

Y/-

O

T

f + H2N-R R=alkyl

NaO-f-Bu

85 oc

Y = 0,rn, or palkyl, CN, C(O)Ph, OMe, Ph Lz=DPPF or BINAP

( 10) 48-90 %

Y = ealkyl, pCN, pC(O)Ph, p, eC(O)Me, p-OMe HNRR’=primary amine, cyclic secondary amine, HNMeBn, HNMePh

208

Hartwig

7.3.2.2 Amination of Aryl Triflates PalIadium(0) complexes containing P(o-C,H,Me), as ligand show low reactivity toward aryl triflates [95,96]. Thus, the original catalyst is not effective for the amination of aryl triflates. However, palladium complexes with the chelating phosphines DPPF and BINAP are effective [97,98]. Selected aminations of aryl triflates by aniline are shown in Eq. (9), and selected aminations of aryl triflates by alkylamines in Eq. (10). As was the case for the amination of aryl halides, DPPF was an effective ligand for amination reactions involving anilines or aminations involving electron-poor aryl triflates. The yields for formation of mixed diarylamines exceeded 90% in all examples explored [97]. Reactions of electron-neutral aryl halides with alkylamines gave yields in the range of 42-75% using DPPF as ligand. This combination of substrate gave yields in the range of 54-77% using BINAP or Tol-BINAP as ligand; several examples, particularly the triflate derived from the p-OMe-substituted phenol, showed higher yields in reactions employing BINAP as ligand rather than DPPF. The reactions of electron-poor aryl triflates were plagued by triflate cleavage to form phenol, presumably due to the stable phenolate that initially results from cleavage. Low concentrations of triflate should minimize the relative rate of cleavage versus amination. Slow addition of the triflate in the case of electron-poor triflates allows amination to occur in high yields with these substrates in some cases [97]. Alternatively, the problem of triflate cleavage can be reduced in a more general fashion by using Cs,C03 as base, as shown in Eq. (11) [99]. Under these conditions, primary and secondary amines react in high yields with electron-poor or electron-rich aryl triflates using BINAP-ligated palladium as catalyst. However, no reactions of unhindered, unactivated aryl triflates with primary amines were reported using Cs2C0, as base, and this combination gave modest 47 - 65% yields when using NaO-t-Bu as base. Reactions in toluene solvent gave higher yields than those in THF, although good yields were obtained in THF solvent in some cases. The use of [PdJdba),] (5a,b) or Pd(OAc), (9) as precursor, rather than L,PdCl,, was important for this chemistry; [(DPPF),PdCl,] gave much lower yields than did a combination of 5b and DPPF. The amination of aryl triflates allows one to use a phenol derivative for directed metalation [lo01 and ultimatively to convert the oxygen directing group into a leaving group. Further, it is possible to conduct amination reactions with amino phenols, with reaction occuring selectively at the amino group [loll. Thus, the phenol, which can be converted to a triflate or nonaflate in the presence of an amino group, can act as a convenient source of a leaving group for several applications. In principle, sulfonates are recyclable, and one could regenerate the sulfonating reagent from the sodium triflate byproduct. Sulfonate salts are also less corrosive than alkali halides.

7.3 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates

209

7.3.2.3 Amination of Heteroaromatic Halides Many nitrogen heterocycles are strong-binding ligands to late transition metals. As a result, heteroaromatic halides with basic nitrogens can displace weakly binding ligands such as P ( O - C ~ H ~ MThe ~ ) original ~. catalyst system containing P(o-C6H4Me), as ligand was ineffective for aminations with heteroaromatic substrates that could bind to palladium. It has been shown in stoichiometric studies that pyridine displaces P(o - C~ H , M ~to) ~form pyridine-ligated palladium complexes [1021. Chelating phosphines are not displaced by pyridines; thus, the advent of amination reactions using chelating ligands allowed for the amination of pyridyl halides [103]. However, studies discussed below on third-generation catalysts show that chelating ligands are not required for amination of pyridines. Results with two phosphine ligands and two different precursors have been published (Table 7.3). The most general palladium precursor is palladium acetate. Again, BINAP was generally effective for amination with either primary or secondary amines. However, unbranched primary amines gave lower yields than branched amines such as cyclohexylamine. DPPP [bis-(diphenylphosphine)propane], which is less expensive than BINAP, in combination with either 5a or 9, acted as an effective catalyst system for amination of pyridyl bromides by secondary amines or amines Iacking hydrogens a to the nitrogen. As was the case for aminations of aryl halides using DPPF and BINAP, acyclic secondary amines gave only low yields of the amino pyridines.

210

Hartwig

Table 7.3 Palladium-catalyzedamination of pyridyl halides Halopyridine

Amine

Product

Catalyst

Yield(%)

P&(dba),/DPPP

86

Q

Pdz(dba),/DPPP

87

BnYMe ti

Pd,(dba),/(f)BINAP

77

ti2No

Pd,(dba),/(i)BINAP

82

1(

Pd,( 0Ac)@PPP

91

HzNhexyl

Pd,(OAc)d(f)BINAP

67

H,Nhexyl

Pd,(OAc),/(f)BINAP

71

Bn.N.Me

k

NH2

7.3 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates

211

7.3.2.4 Aminations of Solid-Supported Aryl Halides Two groups [ l a , 1051 have reported results on the solid-phase amination of aryl halides using both P(O-C6H4Me), and chelating ligands. Since the arylamhe group is found in many biologically active materials, the ability to use the amination chemistry in combinatorial chemistry may be important for this approach to drug discovery. It has been shown that Stille and Suzuki reactions are reliable, high-yielding processes for substrates loaded on solid supports [106]. Thus, aryl halides are now extremely versatile in solid-phase combinatorial chemistry and can be used to form new C-C, C-N, and also presumably C-S, C-P, and C - 0 bonds. Both Farina and Ward [ 1051 at Boehringer Ingelheim and Willoughby and Chapman [lo41 at Merck have reported successful amination reactions for aryl halides supported on polystyrene Rink and Rapp TentaGel S RAM resin. The results closely parallel those obtained in the solution phase. Secondary amines are successfully coupled with solid-supported aryl halides in high yields using P(0-C6H4Me), as the ligand on palladium. Primary amines required either BINAP or DPPF for successful coupling with the aryl halides, and similar results were obtained using either ligand. N-H groups for which no arylation chemistry had been reported in the solution phase were unsuccessful for chemistry on the solid supports. For example, nitroanilines, aminotriazine, 5-aminouracil, 6-diaminoanthraquinone, histidine, 2aminobenzimidazole, imidazole and pyrazole gave no products of C-N bond formation in the solid phase using P(o-C,H,Me),, DPPF, or BINAP-ligated palladium.

7.3.2.5 Amination of Polyhalogenated Aromatic Substrates Multiple arylations of polybromobenzenes have been conducted to generate electron-rich arylamines. Tribromotriphenylamine and 1,3,5-tribrornobenzeneall react cleanly with N-aryl piperazines using either P(a-tolyl), or BINAP-ligated catalysts to form hexamine products [ 1071. Reactions of other polyhalogenated arenes have also been reported [ 1081. Competition between aryl bromides and iodides or aryl bromides and chlorides has been investigated for the formation of aryl ethers [109], and presumably similar selectivity is observed for the amination. In this case bromo, chloroarenes reacted preferentially at the aryl bromide position. This selectivity results from the faster oxidative addition of aryl bromides and is a common selectivity observed in cross-coupling. Sowa showed complete selectivity for amination of the aryl chloro, bromo, or iodo over aryl-fluoro linkages [110]. This chemistry produces fluoroanilines, whereas the uncatalyzed chemistry typically leads to substitution for fluoride.

212

Hartwig

7.3.3 Third-Generation Catalysts with Alkylmonophosphines: High Turnover Numbers, General Amination of Bromides at Room Temperature, and General Amination of Aryl Chlorides at Low Temperatures In general, alkylphosphines have been used less often than arylphosphines in crosscoupling chemistry. However, several studies pointed to the potential of such ligands in palladium-catalyzed amination of aryl halides. Most remarkable is the milder temperatures for amination of aryl bromides, improved yields with acyclic secondary amines, high turnover numbers for these reactions, and the ability to conduct mild aminations of inexpensive aryl chlorides and tosylates. As discussed in more detail in Section 7.8 on reaction mechanisms, the major product that competes with arylamine is arene resulting from hydrodehalogenation of the aryl halide. Hartwig showed that steric hindrance was crucial for minimization of this side product when using monophosphines [1111. A second side product when using primary amines is diary1 alkyl tertiary amine, resulting from arylation of the secondary amine product. Buchwald showed that chelating ligands such as BINAP minimize the formation of this product, presumably because of the increased steric demands at the metal center created by the four-coordinate amido intermediate when using bis-phosphines [86].

7.3.3.1 High-Temperature Aminations Involving P(t-Bu), as Ligand Subsequent to these mechanistic and synthetic findings, a group at Tosoh Corporation reported high yield formation of arylpiperazines when using P(t-Bu), as ligand for palladium at high temperatures [ 1121. Yamamoto, Nishiyama and Koie found that unprotected piperazine reacted with aryl bromides at 120 "C to form good yields of the monoarylated piperazines with turnover numbers as high as 7000. Arylpiperazines are useful pharmaceutical intermediates, and the high turnover numbers demonstrate that the amination chemistry may be industrially feasible on a large scale to produce less expensive specialty chemicals. In a subsequent report, these authors showed that triarylamines, which are useful as components of light-emitting diodes, can be prepared from aryl halides and diamines using the same catalyst system with 4000 turnovers [1131. These studies suggested that sterically hindered alkylphosphines can generate highly active catalysts for cross-coupling reactions.

7.3 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates

213

7.3.3.2 Use of Sterically Hindered Bisphosphine Ligands 7.3.3.2.1 Amination of Aryl Bromides and Chlorides Hartwig first reported the high-yield amination of unactivated aryl chlorides under mild conditions by using D'BPF bis(di-t-buty1phosphino)ferrocene [ 114,1151 and similar sterically hindered bisphosphines ligands developed by Spindler, Togni, and Blaser for asymmetric hydrogenations [ 116- 1181. Activated aryl chlorides react much like unactivated aryl bromides, and reactions of these substrates with the original catalyst were reported [119]. Nickel complexes are also known to react readily with aryl chlorides in cross-coupling chemistry [120-1251, and they have also been used for the amination of aryl chlorides [70,71]. In general, the nickel-catalyzed chemistry occurs with lower turnover numbers and with a more narrow substrate scope than the palladium-catalyzed reactions with third-generation ligands. For example, primary alkylamines are not suitable substrates for unhindered aryl halides when using the nickel catalysts, although cyclic secondary amines and anilines can give good yields. Thus, the palladium, rather than nickel, chemistry will be described in detail.

cat. Pd(dba)2or Pd(0Ac)pR NaO-f-Bu, toluene rt-110°C

10

11

12

L=10 X=Br: R=4-Me, HN(R)R'=H2NPh,rt 94 YO X=l: R=~-Bu, HN(R)R'=H2NPh,rt 95 % R-2,5-Me2, HN(R)R1=H2NBu,rt 49 OO/ L = l l X=CI: R=4-Me, HN(R)R'=H2NPh,85 "C 92 % R=4-Me, HN(R)R0=H2NBu, 85 "C 89 % L=12 X=CI: R=2-Me, HN(R)R'=H2NBu,85 "C 94 % L=10 x=cI:R=3-OMe, HN(R)R'=rnorpholine, 100 "C81 YO

N(R)R'

2 14

Hartwig

Motivated by the synthetic studies with hindered monophosphines described in the previous section, and by the benefits of chelating ligands in controlling the selectivity in reactions with primary amines, Hartwig and Hamann employed the three sterically hindered alkyl bisphosphine ligands in Eq. (12) for the amination chemistry. Reactions employing D'BPF (10) as ligand gave high yields of amination products under mild conditions (80- 100 "C),using unactivated aryl halides and either anilines or cyclic secondary amines. Reactions of aryl bromides were remarkably fast and occurred at room temperature for the first time. However, this ligand did not give high yields for reactions of primary amines as planned. This result, and additional results on the use of this ligand in ketone arylation and in the formation of diary1 ethers from aryl halides, suggest that D'BPF acts as a monodentate ligand during the catalytic cycle. Thus, commercially available sterically hindered bisphosphines were tested for their selectivity with primary amines. The ligands 11and 12 in Eq. (12), first prepared by Spindler, Togni, and Blaser, are more constrained to a geometry that ensures chelation and may improve selectivity. Indeed, reactions of primary amines with unactivated aryl chlorides gave high yields of coupled product with high selectivity for C-N coupling over hydrodehalogenation and for monoarylation of the primary amine. These ligands generate catalysts that provide the most favorable combination of monoarylation over diarylation, amination over hydrodehalogenation, and mild activation of aryl chlorides. 2 O h PdfOA~)2lll NaO-t-Bu

fi

7.3.3.2.2 Amination of Aryl Tosylates Aryl tosylates are, of course, more convenient to prepare and are more stable reagents than aryl triflates, and they are generated from phenols using a cheaper sulfonating agent. However, the palladium-catalyzed coupling of aryl tosylates has not been reported. Only one report exists of any palladium-catalyzed coupling with arene sulfonates, and this involves an electron-deficient aryl fluoroarene sulfonate [ 1261. One report of carbonylation of an activated aryl tosylate has been published [ 1273. Thus, it is remarkable that the complexes derived from ligand 11are active catalysts for the amination of aryl tosylates as shown in Eq. (13). These reactions require 110°C for unactivated aryl tosylates, but the yields are high. Because of the tight chelation of these ligands, high selectivity is observed for reactions of primary arylamines with the unhindered and unactivated p-tolyltosylate.

7.3 Palladium-Catalyzed Amination of Alyl Halides Using Amine Substrates

215

7.3.3.3 P,N Ligands and Dialkylphosphinobiaryl Ligands Buchwald's group showed that phosphinoether ligands developed by Kumada and Hayashi for asymmetric cross-coupling gave high yields for formation of tertiary amines from aryl bromides and acyclic secondary amines [92]. Kocovsky showed that MAP, an amino analogue of MOP that is based on a binaphthyl structure, gives fast rates for arylation of anilines [ 1281. To convert palladium complexes of these ligands into catalysts suitable for amination of aryl chlorides, Buchwald's group prepared cyclohexyl analogues of MAP and of BINAP, one of which (ligand 13) is shown in Eq. (14) [129]. These ligands generate catalysts for high-yield aminations of unhindered aryl bromides with secondary amines at room temperature, and of ortho-substituted aryl bromides with primary amines. The catalysts bearing these ligands also allowed for amination of activated aryl chlorides at room temperature and unactivated aryl chlorides at 80- 100 "C. The cyclohexyl MAP analog 13 is generally more suitable for reactions of secondary amines than primary amines, but it does provide mild coupling chemistry when using primary amines with ortho-substituted aryl halides.

cat. Pd2(dba)3/L

N(R)R'

PCY2

NaO-t-Bu. toluene rt-1 00 "C

Me2N

X=Br: R=4-Me, HN(R)R'=HNBu2, rt 96 Yo R=4-Me, HN(R)R'=HNMePh, rt 95 o/o R-2,5-Me2,HN(R)R'=rnorpholine, rt 97 YO R-2,6-Me2,HN(R)R'=H2Nhexyl, rt 88 o/o

L=

13

(14)

X=CI: R=4-Me, HN(R)R'=HNBu2, 100 "C 95 Yo R=4-Me, HN(R)R'=HNMePh, 80 "C 98 Yo R=4-OMe, HN(R)R'=rnorpholine, 80 "C 91 YO R=2,5-Me2, HN(R)R'=H2Nhexyl, 80 "C 99 O/O

These ligands are cumbersome to prepare, and the Kumada ligands are prohibitively expensive for large-scale synthesis. Although the P,O and P,N structures and their potential hemilability were part of the design and selection of these ligands [2], the nitrogen substituent proved to detract rather than enhance the catalytic performance of palladium complexes of these ligands. Thus, their desamino analogues, dialkylphosphino-2-biphenylligands 14 and 15 in Eq. (15), generated more active catalysts and are simpler to prepare. For example, the dicyclohexylphosphino-2-biphenyl and di-t-butylphosphino-2-biphenylligands allow for room-temperature amination of aryl chlorides in selected cases. The examples, the cases that gave mild amination using the cyclohexylphosphino P,N ligand gave room-temperature reactions using the 2-di-t-butylphosphinobiphenylligand.

216

Hartwig

gX+

R'+

L=

HN(R)R'

&& R=Cy 14 Fkt-6~ 15

cat. Pda(dba)JL

NaO-t-Bu, toluene. rt

R,-g N( R)R'

R=t-Bu X=CI: R'=4-Me, HN(R)R'=HNBu2,81 % R'=4-Me, HN(R)R'=HNMePh,98 YO R1=4-OMe,HN(R)R'=morpholine,90 YO R'=2,5-Me2,HN(R)R'=H2NBn, 99 YO

7.3.3.4 Phenyl Backbone-Derived P,O Ligands

A related set of ligands was discovered from a screening study conducted at Symyx Technologies by Guram et al. They found that phenyl backbone-derived P,O and P,N ligands were effective for amination chemistry and that a cyclohexylphosphino version of these ligands, 16, gave high yields for the amination of aryl chlorides using secondary amines at 105 "C [130,131]. The ligand 16 in Eq. (16) provided good yields of tertiary amines from aryl bromides and acyclic secondary amines, similar to the results with Kumada's ligand 6 [92]. However, the Symyx ligands are more straightforward to prepare than 6. Simply replacing the diphenylphosphino group with a dicyclohexylphosphino group, as in ligand 17, generated catalysts that are similar in activity to those bearing the cyclohexylphosphino biphenyl amine ligand 14. Unactivated aryl chlorides reacted with secondary cyclic or acyclic amines with good yields, and unactivated ortho-substituted aryl chlorides reacted with primary aryl- or alkylamines with good yields when using this ligand in combination with Pd(dba),. Reactions of primary amines with unhindered aryl halides were not reported, and these ligands presumably generate side products from diarylation and hydrodehalogenation as observed with other catalysts generated from monophosphines.

7.3 Palladium-Catalyzed Amination of Aryl Halides Using Amine Substrates X

+ HN(R)R'

217

N(R)R' cat. Pd(dba)aR NaO-f-Bu, toluene, 105 "C

R=Cy X=CI: R'=3,5-Me~, HN(R)R'=HN(Me)octyl,95 % R'=3,5-Me2,HN(R)R'=morpholine,92 Yo R1=4-OMe,HN(R)R'=H2Noctyl,83 Yo R'=2,4-Me2,HN(R)R'=HpNoctyl,92 %

L=

(16)

R=Ph 16 R=Cy 17

7.3.3.5 Low-temperature Reactions Employing P(t-Bu), as Ligand As discussed above, the group at Tosoh company reported high turnover numbers for the arylation of piperazine at high temperatures using excess of the ligand P(t-Bu),. During preliminary kinetic studies on this process, Hartwig's group discovered that the reactions occurred under much milder conditions when using the isolated Pd(0) complex as catalyst, and even milder conditions when using a 1:I ratio of ligand to Pd(dba), [ 1321. Moreover, this catalyst system gave essentially quantitative yields with all secondary amines tested, including acyclic dialkylamines. Aryl chlorides were also suitable substrates, and in all cases this catalyst system provided high yields at 70 "C for reactions of secondary amines or anilines. Primary amines react in good yields at 100-110°C [133]. In some cases, including an example of an unactivated aryl halide, room-temperature reactions were observed with aryl chlorides. The 1:l ratio of ligand:palladium, low molecular weight of the ligand, and simple structure (and therefore cost) make this catalyst system an economical one for large-scale synthesis. This ligand is more air-sensitive than the biphenylyl ligands 14 and 15, but is available as a 10% solution in hexanes in a Sure/Seal bottle from Strem. Several examples of the coupling using this ligand are shown in Table 7.4.

218

Hartwig

Table 7.4. Reactions of aryl bromides and chlorides with mines catalyzed by Pd(O)/P(t-Bu),

Entry Aryl Bromide Amine

Product

1

2

3

(0):" (0):"

4

Conditionsa

Yieldb (%)

RTI%PdIh

91

RT16Pd4h

97

RT 1 % Pd 1 h

97

RTI%Pdlh

94

5

(0);

RT I % P d l h

85

6

ONHE

RTI%PdIh

87

7

m u 2

RTI%Pd4b

90

RT2%PdC6h

81

RT1%PdC6h

96

RTl%Pd6h

99

8

9

10

HNnO

W

219

7.4 Aromatic C-N Bond Formation with Non-Amine Substrates Table 7.4. continued ~~

Entry Aryl Bromide

Amine

Product

I1

12

ON""'

D ' P h

Conditionsa

Yieldb (%)

nl%Pd5h

95

l%Pdrt12h

90

1% Pd 70°C 12 h

88

NC

13

oNPh2

14

Wh2

NC

1 % Pd rt 5.5 h

89

15

H,NPh

HNPh,

5 % Pd rt 25 h

75

16

Wh2

Me0

a

DNPhZ 4 % Pd 70°C 16 h

80

Reactions run with 1 mmol of aryl halide in 1-2 mL of toluene solvent at room temperature. Pd(dba), used in combination with 0.8 equiv of ligand/Pd. Isolated yields are an average of at least two runs. Pd(OAc), used in place of Pd(dba),

7.4 Aromatic C-N Bond Formation with Non-Amine Substrates and Ammonia Surrogates The scope aromatic C-N bond formation extends beyond simple amine substrates. For example, selected imines, sulfoximines, hydrazines, lactams, moles, and carbamates give useful products from intermolecular aromatic C-N bond formation. Intramolecular formation of aryl amides has been reported. In addition, allylamine undergoes arylation, providing a readily cleaved amine alternative to the ammonia surrogates benzylamine, t-butylcarbamate, or benzophenone imine. Although it is an amine substrate, the reaction of this reagent is included here because of its special purpose.

220

Hartwig

[Pd(OAc)&MOP * 100 "C

m

Bn

o

n=l , 8 2 % n=2,94 % n=3,88 %

@

[Pd(OAc)d~, 100 "C cs2co3 R=Ac. Cbz, BOC PhCH3 L=MOP, DPEphos, Xantphos

Xantphos=

qq I

Ph2P

PPh2

R n=l ,82-92 % n=2181-95 % n=3,79-90 %

(19)

7.4 Aromatic C-N Bond Formation with Non-Amine Substrates

22 1

7.4.1 Amides, Sulfonamides, and Carbarnates Amides and sulfonamides undergo intramolecular chemistry to form aryl amides and aryl sulfonamides (Eqs. (17- 19)). These reactions were reported several years ago using palladium catalysts ligated by monophosphines [82], and a recent report has appeared that details improved yields with MOP, DPEphos and Xantphos [134]. In general, Cs,CO, was used for the cyclization of acetamides and carbamates, but K2C03 was the best base for cyclization of benzamides. In the initial report, P(furyl),, P(o-C,H,M~)~were the ligands that gave the most effective catalysts, and five- and six-membered rings, but not seven-membered rings, could be formed with acceptable yields. The more recent report improves on the procedures for amide arylation and extends the chemistry to carbamates. However, the reaction times are still longer than the amination of aryl halides, and the reactions require 100"C temperatures. Nevertheless, five-, six-, and seven-membered rings can be formed with benzamides, acetamide, N-carbobenzyloxy and t-butylcarbamate substituents tethered to aryl halides as shown in Eqs. (18) and (19). The optimal ligand depended on the particular substrate.

n: ,,N$ln

0 5 % Pd(OAc)Z/DPPF

~

NaO-t-Bu, toluene, 120 "C R 16-48 h n=l, 20-52 o/o R=H, CF3, COPh, CN, OMe n=2,70-90 Yo n=3,21-89 % n=4, 43-94 o/o

(20)

Although no intermolecular coupling of acyclic amides has been reported, the coupling of lactams with aryl halides has been successful in certain cases. Shakespeare showed that a combination of Pd(OAc), and DPPF formed N-aryl lactams in good yields when using five-membered lactams (Eq. (20)) [135]. Reaction times were long for reactions involving electron-neutral aryl halides, but did proceed in good yields. Four-, six-, and seven-membered lactams gave poor yields with unactivated aryl halides, but good yields with electron-poor aryl halides. No reaction was, of course, observed in the absence of catalyst.

222

Hartwig

X

O

A0,t-Bu H2N R=o, p M e , pCN, pOMe X=CI, Br

2.5-4 Oh Pd(OAc)2/P(t-Bu)3R-

R - g +

NaOPh,16-48 toluene, h 100 "C *

a , , , l oH, t - B u X=Br 62-86 Yo X=CI, R=Me 59 Yo

(21)

An intermolecular version of the arylation of carbamates has been recently published by Hartwig et al. (Eq. (21)) [132]. His group showed that reactions catalyzed by a combination of Pd(OAc), and P(t-Bu), formed N-aryl carbamates from aryl bromides or chlorides and t-butylcarbamate as substrate. Again, the reaction conditions were not as mild as those for amination, but were similar to those of the intramolecular reactions. For the intermolecular reactions, the use of sodium phenoxide as base was crucial. Reactions using Cs,CO, showed low conversions. Those involving NaO-t-Bu as base rapidly formed a gel, presumably from the deprotonated carbamate, and also showed little or no conversion. The products of these reactions serve as conveniently protected anilines, and t-butylcarbamate can be considered one type of ammonia surrogate. In addition, the products of these reactions are suitable for subsequent directed metalation procedures [1001.

7.4.2 Allylamine as an Ammonia Surrogate Allylamine serves as an additional ammonia surrogate [ 1361. Using palladium catalysts ligated by P(o-tolyl)3, diallylamine reacted with aryl bromides in modest yields. Reactions of allylamine catalyzed by (DPPF)PdCl, with aryl and heteroaryl bromides gave higher yields. Presumably, these reactions can be conducted in a more general fashion with the improved catalysts described above. Cleavage of the ally1 group to the parent arylamine was achieved using methansulfonic acid and PdC.

7.4.3 Imines Benzophenone imine is commercially available and serves as an ammonia surrogate that reacts with aryl halides in high yields under standard palladium-catalyzed conditions. Catalysts based on both DPPF- and BINAP-ligated palladium gave essentially quantitative yields for reactions of aryl bromides. These reactions can be conducted with either Cs,CO, or NaO-t-Bu as base [ 137,1381. The products are readily isolated by chromatographic techniques or by crystallization. They can be cleaved to the parent aniline by using hydroxylamine, acid, or Pd/C [ 1381.

7.4 Aromatic C-N Bond Formation with Non-Amine Substrates

0

NH

x

223

Pd(dba)z or Pd(0Ac)p L

phKph

R=o, m, p-alkyl, alkoxo, CN

NaO-t-Bu * 65-80°C

L=DPPF, BINAP X=Br, OTf

R L=DPPF 86-93 %o L=BINAP 84-98 Yo

(22)

Sulfoximines have also proven to be suitable substrates for palladium-catalyzed C-N bond formation, although the chemistry is less general than using benzophenone imine, as shown in Eq. (23) [139]. Instead of serving as protected anilines, the products may be used as ligands for asymmetric catalysis. S-Methyl-S-phenyl sulfoximine was reacted with aryl bromides using P(o-tolyl)3, BINAP-, and DPPF-ligated palladium catalysts and using alkoxide and carbonate base. Reaction times were long, but good yields were obtained from reactions with electron-deficient aryl halides and either BINAP or DPPF as ligand. Reactions using unactivated aryl halides gave good yields when an excess of the aryl halide was used or when the sufoximine was added slowly.

..

R=H, 2-CN, 4-C02Me, 4-t-Bu L=DPPF, BINAP

48 h

L=DPPF 87 Yo L=BINAP 67-94 Oo/

7.4.4 Azoles Azoles can be produced from products of palladium-catalyzed hydrazone arylation and can serve as substrates for arylation reactions to produce N-aryl azoles. The Fischer indole synthesis uses N-aryl hydrazones, and these hydrazones can be generated by palladium-catalyzed chemistry. Benzophenone hydrazone was found by both the Yale and MIT groups to be a particularly effective substrate for palladium-catalyzed reactions, as summarized in Eq. (24) [140,141]. Reactions of benzophenone hydrazone with either aryl bromides or iodides occur in high yields using either DPPF- or BINAP-ligated palladium. These reactions are general and occur with electron-rich, electron-poor, hindered or unhindered aryl halides. The products of these reactions can be converted to hydrazones that bear enolizable hydrogens and are suitable for indole synthesis in the presence of acid and ketone [140].

224

Hartwig

R=O, palkyl, palkoxo, pCF3, C(O)Me, or ArBr=l-naphthyl L=DPPF, BINAP X=Br, I

H

R'

k3

R'

Indoles, pyrroles and carbazoles themselves are suitable substrates for palladiumcatalyzed amination. An initial study of this reaction using DPPF-ligated palladium as catalyst showed that these reactions occurred readily with electron-poor aryl halides. With unactivated aryl bromides, the reaction with pyrrole or indole resulted in good yield, but reaction times were long and the temperature was 120"C. Thus, an improved catalyst system was necessary for reactions to occur in a more general fashion and with temperature- or base-sensitive substrates. The sterically hindered alkylmonophosphines provide an improved catalyst system (Table 7.5) [132]. In this case, reactions occur at 100 "Cover 8 h for activated or deactivated aryl bromides and with electron-poor or electron-neutral aryl chlorides. Reactions of ortho-substituted aryl halides were surprising, providing a mixture of 1and 3-substituted indoles. However these aryl halides were suitable substrates when the 3-position of the indole was substituted. The origin of this C- versus N-arylation is unknown.

225

7.4 Aromatic C-N Bond Formation with Non-Amine Substrates Table 7.5. Reactions of aryl halides with azoles catalyzed by Pd(O)/P(r-Bu), Entry Aryl halide

Azole

Product

Conditionsa Yieldb (%)

MeofP ' Meom NQ

4 % P d 12h

H

a$

3 % Pd 12h

H

H

12

F

88

@a

3%Pd6h 83 OMe

Q

3%Pd6h

71

H

5 % P d 12h

64

H

a

Reactions were run with 1 mmol of azole in 1-2 mL of toluene solvent at 100 "C.Pd(dba), used in combination with 0.8- 1.0 equiv of 1igandiPd. Isolated yields are an average of at least two runs.

Beletskaya has shown that the reaction of benzotriazoles with aryl halides catalyzed by a mixture of dppe (bis-(dipheny1phosphino)ethane) and copper(1) iodide or copper(I1) carboxylates proceeds in good yield in DMF solvent and with a phasetransfer catalyst [ 1421. The mechanism of these reactions is unknown, and copper is known to catalyze such reactions. However, it was shown that both copper and palladium are required for these reactions to occur at the N-l position in high yields. Similar results were observed in aqueous solvent using aryliodonium salts as electrophile [143].

(DPPE)PdCI2(2 rnol %) Cu(ll),(2 rnol %)

DMF, 150 "C, 4-8 h

-

a

N N N 75-98%

R1=H, pF, pCI, pBr, pBI, pMe, pOMe, o-Br, mBr, 01, pCN, pMeCO, pEtOOC no copper: 55-60 % N1-aviation product, 25-30 YON2-arylation product no palladium: no reaction

(25)

226

Hariwig

A remarkable process was recently reported by Mori that uses dinitrogen as the origin of the nucleophile to form anilines, as shown in Eq.(26) [ 1441. In this chemistry, dinitrogen is used to generate “titanium nitrogen fixation complexes” by reactions of titanium tetrachloride or tetraisopropoxide,lithium metal, TMS chloride and nitrogen. These complexes are then reacted with aryl halide and palladium catalyst to generate a mixture of aryl and diarylamine. In general, palladium ligated by DPPF gave higher yields of arylamine product, which was as high as 77% when using 4biphenylbromide and 80 % when using 1-naphthyl triflate. N2+ Ti&

+ Li + TMSCl

11-80 ?”

7.5 Amination of Base-Sensitive Aryl Halides A significant drawback of the standard conditions for palladium-catalyzedamination of aryl halides is the use of strong base. This procedure precludes the use of substrates with aromatic nitro groups, many substrates with enolizable hydrogens, substrates with esters other than t-butylesters, and substrates with base-sensitive stereochemistry, such as some protected amino acids. Thus, conditions that employ milder bases are required. A solution that involves reaction temperatures as low as those for reactions employing sodium t-butoxide has not been developed. However, carbonate and phosphate bases can be used with certain catalysts at reaction temperatures comparable to those of reactions involving the first- and second-generation catalysts.

R R-@

-

+

HN R

1-4 mol % Pd,(dba), k 7 or 13

C S Z C O~ or K3P04 R 80-100 “C R=pBd, pOMe, C(O)Me, C(0)OMe , base = Cs2C03 for L=7 R=C(O)OMe, C(O)Me, base = K3P04 for L=13

(27)

7.5 Amination of Base-SensitiveAryl Halides

227

As discussed above, the reactions of amines with aryl triflates instead of aryl halides allows for the use of Cs,CO, as base. Further, reactions of activated aryl halides can be conducted using Cs,C03 as base instead of t-butoxide, without requiring a change of catalyst [87]. However, reactions of unactivated aryl halides with this weaker base require a different catalyst. A solution to the problem of using unactivated aryl halides in the presence of base-sensitive functionality began with the use of one of Kumada's phosphinoether ligands (Eq. (27)) [87,92]. Catalysts containing Kumada's P,O ligand allowed for aminations of unactivated aryl halides using Cs,C03 as base. More recently, Buchwald has used the biaryl P,N ligand 4 for the amination of aryl halides using Cs,C03 and the less expensive and less toxic K,P04 [129]. However, hemilabile ligands are not necessary, and simple, hindered monophosphines are suitable for this procedure, presumably because the amine can coordinate to the three-coordinate, 16electron, monophosphine intermediate formed after oxidative addition of aryl halides to complexes with hindered monophosphines [ 102,1451. Indeed, the catalyst containing commercially available P(t-Bu), allows for the reaction of unactivated aryl halides with secondary amines using Cs,C03 or as base [ 1321. Thus, simple t-butylmonophosphinesappear to generate active catalysts for reactions involving weaker bases, albeit at temperatures in the range of 85- 100"C. Presumably ligands 14 and 15 can also provide active catalysts for reactions using these bases.

228

Hartwig

7.6 Applications of the Amination Chemistry Studies on the applications of the amination chemistry have begun to emerge. These results demonstrate the utility of the amination in the construction of complex, biologically active molecules, in the synthesis of electronically important structures, and in the synthesis of ligands for other catalytic chemistry.

7.6.1 Synthesis of Biologically Active Molecules Stoichiometricpalladium-mediated cyclization was used in natural product synthesis by Boger a number of years ago, as was noted in the introduction. More recently, an intramolecular palladium-catalyzed amination of a heteroaromatic halide has been used as a step in the synthesis of an a-carboline natural product analog [146]. As discussed above, the diphenylhydrazone arylation can also be used for nitrogen heterocycle synthesis [ 1401.

7.6.1.1 Arylation of Secondary Alkylamines N-Arylpiperazines are common substructures of molecules that have activity in the central nervous system; therefore, the arylation of monoprotected piperazines and the single arylation of unprotected piperazines have been studied. As discussed above, the monoarylation of piperazines was the reaction for which Nishiyama, Koie, et al. initially applied catalysts bearing P(t-Bu), as ligand to obtain high turnover numbers at high temperatures [112]. Two other reports of piperazine arylation have appeared, one involving a Boc-protected piperazine [147], and one using an unprotected piperazine (the original P(o-tolyl),lPd(O) catalyst system) [1481. Morita has used the arylation of piperazines as a crucial step in the synthesis of a metabolite of Aripiprazole, as shown in Eq. (29) [149]. This reaction involved the use of a tetrasubstituted dichloro bromo arene as substrate to give a product that is readily converted to the final target. Researchers at Sepracor have conducted the amination of an N-aryl aryl triazolone using a piperazine to generate the two enantiomeric versions of hydroxyitraconazole (Figure 7.2) [ 1SO]. Finally, Schmid reported the use of a piperidine or morpholine group installed by palladium chemistry as a directing and then leaving group in a concise synthesis of raloxifene. Reaction of the cyclic secondary amines with 2-bromobenzo[b]thiophene generated a structure that could be acylated and then reacted at the amino position to deliver an aryl Grignard for synthesis of a 2-aryl benzothiophene [ 1511.

7.5 Amination of Base-Sensitive Aryl Halides

Cl&Bn

229

HNZNH 2 YOPd2(dba)3

Br

6YoBlNAP NaO-t-Bu, PhMe reflux, 18 h NH

f"

HN,)

MCI steps

Figure 7.2. The disconnection used to form hydroxyitraconazole.

Buchwald has used the intramolecular reaction of acyclic secondary amines with an aryl halide in the total synthesis or the formal total synthesis of a series of tetrahydropyrroloquinolines using palladium-catalyzed amination [ 1521. A brief description of the methods employed is shown in Eqs. (30) and (31). The approach in Eq. (30) involves formation of the six-membered ring system by using the palladiumcatalyzed intramolecular amination. The reaction conditions employed K,CO, as base for the cyclization and involved high temperatures. However, the use of NaO-t-Bu, which presumably would have allowed for reaction at lower temperatures, led to cleavage of the carbamate. The cleavage products apparently inhibited catalyst activity.

230

Hartwig

A second approach involved formation of the indole five-membered ring by amination chemistry and the six-membered ring by Zr-benzyne chemistry (Eq. (3 1)). In this case, the optimal cyclization conditions could be employed, and the reaction temperature was milder. The product of the cyclization is an intermediate in the previous total syntheses of makaluvamine C and of damirones A and B.

1. 2.5 % Pd2dba3

Me0 OMe

2. 12, CHzClp Me0 3. BnNH2,THF

OMe

P( etolyl)3 NaO-t-bu, to1 80 "C, 72 % @H 2. 10 % PdIC Me0 HC02NH4 OMe MeOH, reflux 80 Yo

(31)

7.6.1.2 Arylation of Primary Alkylamines Several reports on the application of the intermolecular arylation of primary alkylamines have appeared. For example, the reaction of primary amines with chloro 1,3 azoles has been used to produce the H-1-antihistaminic norastemizole [ 1531. As shown in Eq. (32), the palladium chemistry is dictated by the steric properties of the amines. This property creates selectivity that complements the thermal chemistry, which is dictated by amine nucleophilicity. These researchers have also shown that this high selectivity for arylation of primary over secondary amines with catalysts containing BINAP as ligand allows for the rapid assembly of other multiamino-based structures [154].

7.5 Amination of Base-Sensitive Aryl Halides 1.25 YO Pdp(dba)3 3.75Y o BINAP

23 1

FHZC6H4'PF

(32)

major product

Chida has reacted glycosylamines with 6-chloropurines to prepare models of spicamycin and septacidin, two Streptomyces metabolites that have antitumor activity [ 1551. As shown in Eq. (33), 5 mol% catalyst was used, and the reaction temperature was high (140 "C). Nevertheless, good yields of the desired N-aryl glycosylamine were obtained when using BINAP as ligand, NaO-t-Bu as base, and either MPM or SEM as the N9 protective group. The gluco isomer was also amenable to the palladium-catalyzed arylation, although two anomers were obtained as products.

7.6.1.3 Arylation of Primary Arylamines The palladium-catalyzed formation of diarylamines has been used in several contexts to form molecules with biological relevance. The ability to prepare haloarenes selectively by an ortho-metallation halogenation sequence allows for the selective delivery of an amino group to a substituted aromatic structure. Snieckus has used directed metallation to form aryl halides that were subsequently reacted with anilines to prepare diarylamines (Eq. 34)) [156]. Frost and Mendonqa have reported an iterative strategy to prepare (by palladium-catalyzed chemistry) amides and sulfonamides that may act as peptidomimetics. Diarylamine units are constructed using the DPPF-ligated palladium catalysts, and the products are then acylated or sulfonated with 4-bromo benzoyl or arylsulfonyl chlorides [ 1571.

232

Hartwig

Pd(DPPF)CI2or NaO- t-Bu aniline

R

W o recent reports have detailed the palladium-catalyzed formation of diarylamines to prepare nucleosides of damaged DNA. Sigurdsson et al. reported the formation of a precursor to an interstrand cross-link by the reaction in Eq. (35) [158]. Lakshman reported the reaction of bromonucleosides with amines shown in Eiq. (36) as a route to the DNA adducts of carcinogenic aminobiphenyls [ 1591. In this case, a number of reaction conditions were attempted and those using potassium phosphate and the P,N ligand 13were effective for the transformation, albeit with high catalyst loads.

TBDMSO,

w

NH2

I

OTBDMS

YBn

+

TBDMSO

PWbah BllNAP NaO-t-Bu toluene 40 Yo OBn

OTBDMS

(35)

< OTBDMS

TBDMsok2 OTBDMS

20 % L RO hPO4, DME, ArNH2

RO

R=TBDMS

RO

7.7 Applications to Materials Science

233

7.7 Applications to Materials Science Arylamines display electronic properties that are favorable for materials science. In particular, arylamines are readily oxidized to the aminium form, and this leads to conductivity in polyanilines, hole-transport properties in triarylamines, stable polyradicals with low energy or ground-state, high-spin structures, and the potential to conduct electrochemical sensing. The high yields of the palladium-catalyzed formation of di- and triarylamines has allowed for ready access to these materials as both small molecules and discrete oligomeric or polymeric macromolecules.

B

r

e

B

r

+

HN>(CH2),,CNH

[L~P~C~ZI L=P(c46H4Me)3 * toluene NaO-t-Bu or LiN(SiMe&

7.7.1 Polymer Synthesis Several reports on the synthesis of polymeric arylamines by palladium-catalyzed chemistry have appeared. One group used the initial amination of aryl halides with dialkylamines to prepare arylamine polymers (Eq. (37)) [160]. A bifunctional diamine and dihalo arene were used to generate the polymers as shown in Eq. (15). The highest molecular weights achieved were in the range of 5000-6000, indicating an average of 20 monomers each in a chain. Subsequent to this paper, this group published work on using BINAP and P(t-Bu), instead of P(o-tolyl), as ligand. Several surprising results were obtained, including higher molecular weights formed when using P(o-tolyl), than when using P(t-Bu),, despite the higher yields for the formation of triarylamines in small molecule studies on triarylamine synthesis using P(t-Bu), [113,132,161]. Characterization of the molecular composition of these materials is not detailed. Branching and end-capping as a result of phosphine incorporation [ 1621, molecular weight-limiting cyclization [ 161,1631, and precipitation of polymer may account for these results.

234

Hartwig

M,=9000

0

Polymers containing chromophores such as acridine and azobenzene have also been prepared by palladium-catalyzed amination following two approaches [ 164- 1661. The first approach involved polymerization of monomers containing the chromophore. For example, 4-aminoazobenzene was condensed with 1,3-dibromobenzene (Eq. (38)) or 4,4’-dibromobiphenyletherto form polymeric material with M, values of 9.0 and 19 x lo3 respectively. Alternatively, polymers prepared by polymerization of 4-bromostyrene or copolymerization of styrene and 4-bromostyrene were reacted with N-phenyl-4-amino azobenzene. The degree of substitution of the aryl bromides by the amino azobenzene unit was essentially quantitative when using P(t-Bu), as ligand. A related approach to the formation of triarylamine-containing polymers involves synthesis of a monomer containing the triarylamine unit and a second functional group that is amenable to polymerization. Grubbs et al. reported the synthesis of norborene monomers containing a tethered triarylamine using DPPF-ligated palladium as a catalyst to form the triarylamine unit. Ruthenium-catalyzed ring opening metathesis polymerization then formed the triarylamine-containing polymer [167-1691. Pd(0Ac)p

Br

GPC in NMP GPC in THF Mw=39,000 Mw=8800 PDk3.6 Mn=l.6

(39)

Poly(rn-aniline) has also been prepared by palladium-catalyzed condensation of 1,3-dibromobenzene and 1,3-phenylene diamine by two different research groups (Eq. (39)) [170,171]. In this case, reactions using BINAP as ligand gave the highest molecular weights. Kanbara has reported M, and M, values in formamide solvent of 42 400 and 20 100. Meyer et al. have carefully analyzed the products of these reactions, and their results cast doubt on the molecular weight data obtained by Kanbara,

7.7 Applications to Materials Science

235

as shown in Eq. (39). First, studies on the reaction yields using small molecules suggest that a M, value near 7000 should be obtained. Second, M, values in NMP and THF solvent are dramatically different: 24000-39000 in NMP and 6300-8200 in THF; thus, the values in THF appear more realistic. Some incorporation of BINAP ligand was also observed in the polymer product. A small degree of cross-linking may be present, though small molecule studies showed only 0.05 % yield of triarylamine. In addition to the linear poly(rn-aniline), a hyperbranched version of this polymer was prepared [170].

I

R Scheme 1

A

M, =48 000 M, = 7 300 R=t-Bu

n

236

Hartwig

Detailed chemical studies on the formation of triarylamine polymers based on an early communication [ 1721 have now appeared [ 1611. Goodson, Hauck and Hartwig reported the use of improved catalysts and synthetic strategies to prepare pure, soluble, linear triarylamine polymers with high molecular weights (Scheme 1). A large number of ligands were prepared and tested for their ability to catalyze the formation of triarylamines in quantitative yields. A phosphinoether ligand and P(t-Bu), were chosen as the most effective. True, polymeric N-aryl versions of poly(p-anilines), poly(rn-anilines), alternating poly(rn-and p-ani1ine)s and alternating donor- acceptor copolymers were prepared. In the cases of polymerizations using substrates with rn-linkages, cyclization to form tetra-azacyclophanes occurred in competition with polymerization. The polymerization of oligomeric fragments and/or the separation of the macrocycles from polymer by size-exclusion chromatography provided purely linear material. Incorporation of phosphine into the polymer by P-C bond cleavage or ligand metallation processes is common in the formation of polymers by palladium-catalyzed cross-coupling [ 173,1741. The materials formed with P(t-Bu), as catalyst contained no phosphorus as determined by long 31PNMR spectroscopic acquisitions and by ‘H NMR spectroscopy. Thus, the use of P(t-Bu), as ligand is important to observe coupling in yields that are high enough to generate polymer, to employ low catalyst loads, and to prevent metallation or P-C cleavage reactions of the phosphine ligand.

7.7.2 Synthesis of Discrete Oligomers Buchwald’s group and Hartwig’s group have both used exponential growth strategies to prepare discrete arylamine materials. Buchwald, Sadighi, and Singer prepared oligomers based on diarylamine structures [175,176], while Hartwig and Louie prepared discrete triarylamine oligomers [ 1011. The exponential growth strategy relies on orthogonal protection of two functional groups at the termini of the oligomers. Buchwald’s group used N-aryl benzophenone imines as protected anilines and trimethylsilylarenesas masked aryl halides. In addition, Boc groups were used to protect internal diarylamine nitrogens in the monomer units. This protection served to make the materials soluble and to make them less susceptible to air or chemical oxidation. BINAP-ligated palladium complexes were used to conduct the couplings to form the diarylamine linkages. Deprotection of the Boc group and the end-functionalized termini produced materials suitable for studies on the electronic properties of polyanilines with variable chain lengths.

237

7.7 Applications to Materials Science

Ar

Ar

TBSO NfO

A;

- -tetrarner

Y#qrBn Nf = FgC4SO2-

Ar

Ar

Ha, PdIC* l P d ( 0 )

TBSO

Ar

Ar

base C~H4-3,5-Bf2

Scheme 2

The synthesis of triarylamine materials of variable chain length [I011 was conducted by using palladium chemistry to couple diarylamines with aryl nonaflates, as shown in Scheme 2. The diarylamines were protected with an N-benzyl group, and the aryl nonaflate was masked as a TBS-protected phenol. The TBS-protected phenol was directly converted to the nonaflate using CsF and F,C,SO,F, and the benzyl group was, of course, removed by hydrogenolysis. The building blocks were prepared prior to the use of P(t-Bu), for this chemistry. The C-N bonds of the chain were, therefore, constructed using a catalyst containing DPPF as ligand; bromide additive appeared to increase reaction yields, but it is unclear how large an effect this additive had on this amination process. The product materials were soluble in organic solvents by virtue of methoxy substitution on the pendant N-aryl groups.

238

Hartwig

Hyperbranched triarylamine materials were also prepared using the amination chemistry, as shown in Scheme 3. The material contains exclusively p-phenylene diamine linkages and triarylamines.The triarylamines were constructed using a combination of benzyl-protected 4,4'-dibromodiarylamines and lithium diarylamides. The formation of the triarylamine linkage using aryl bromides and lithium diarylamides occurred in > 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]

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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

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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