Organic Reaction Mechanisms, 2005 (Organic Reaction Mechanisms Series)

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ORGANIC REACTION MECHANISMS · 2005

Organic Reaction Mechanisms · 2005: An annual survey covering the literature dated January to December 2005 Edited by A. C. Knipe © 2008 John Wiley & Sons, Ltd. ISBN: 978-0-470-03403-3

ORGANIC REACTION MECHANISMS · 2005 An annual survey covering the literature dated January to December 2005

Edited by

A. C. Knipe University of Ulster Northern Ireland

An Interscience® Publication

A John Wiley and Sons, Ltd., Publication

This edition first published 2008 © 2008 John Wiley & Sons, Ltd Registered office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com. The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The Publisher and the Author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. The advice and strategies contained herein may not be suitable for every situation. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the Publisher nor the Author shall be liable for any damages arising herefrom.

Library of Congress Catalog Card Number 66-23143 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-470-03403-3 Typeset in 10/12 Times by Laserwords Private Limited, Chennai, India Printed and bound in Great Britain by TJ International, Padstow, Cornwall

Contributors S. K. ARMSTRONG K. K BANERJI C. T. BEDFORD M. L. BIRSA M. CHRISTLIEB

R. G. COOMBES

J. M. COXON M. R. CRAMPTON N. DENNIS E. GRAS ˇ ´ P. KOCOVSK Y

R. A. McCLELLAND

B. MURRAY K. C. WESTAWAY

Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK Indra-Kripa, A-80 Saraswati Nagar, Jodhpur 342005, INDIA Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ Department of Chemistry, Al I Cuza University of Iasi, Bd. Carol I, 11, Iasi 700506, Romania Gray Institute for Radiation Oncology and Biology – University of Oxford, Old Road Campus Research Building, Churchill Hospital, Oxford, OX3 7DQ Honorary Research Felllow, Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ Department of Chemistry, University of Canterbury, Canterbury, New Zealand Chemistry Department, The University, South Road, Durham, DH1 3LE University of Queensland, PO Box 6382, St Lucia, Queensland 4067, Australia CNRS, LSPCMIB Universite Paul Sabatier, 31062 Toulouse Cedex 9 Department of Chemistry, The Joseph Black Building, The University of Glasgow, Glasgow G12 8QQ Department of Chemistry, University of Toronto, 80 St George Street, Toronto, Ontario, M5S 1A1, Canada Department of Science, IT Tallaght, Dublin 24, Ireland Dept. of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada

v

Preface The present volume, the forty-first in the series, surveys research on organic reaction mechanisms described in the available literature dated 2005. In order to limit the size of the volume, it is necessary to exclude or restrict overlap with other publications which review specialist areas (e.g. photochemical reactions, biosynthesis, electrochemistry, organometallic chemistry, surface chemistry and heterogeneous catalysis). In order to minimize duplication, while ensuring a comprehensive coverage, the editor conducts a survey of all relevant literature and allocates publications to appropriate chapters. While a particular reference may be allocated to more than one chapter, it is assumed that readers will be aware of the alternative chapters to which a borderline topic of interest may have been preferentially assigned. In view of the considerable interest in application of stereoselective reactions to organic synthesis, we now provide indication, in the margin, of reactions which occur with significant diastereomeric or enantiomeric excess (de or ee). We welcome one new author to the series: Prof K. C. Westaway has reviewed ‘Nucleophilic Aliphatic Substitution’ in place of Prof I. Lee, whose cameo contribution to ORM 2004 is gratefully acknowledged. The contribution of Prof K. Banert and Dr H. Hahn to that volume is also particularly appreciated since it enabled the now returning author of ‘Molecular Rearrangements, Pt 1’ to enjoy a productive maternity leave. Thanks are also due to outgoing author Prof D. M. Hodgson who, following his expert contributions over several years, felt able to leave the ‘Carbenes and Nitrenes’ chapter in the capable hands of his co-authors. I wish to thank the production staff of John Wiley and Sons and the team of experienced contributors for their efforts to ensure that the review standards of this series are sustained.

A.C.K.

vii

CONTENTS 1. Reactions of Aldehydes and Ketones and their Derivatives by B. A. Murray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives by C. T. Bedford . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Oxidation and Reduction by K. K. Banerji . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Carbenes and Nitrenes by M. Christlieb, and E. Gras . . . . . . . . . . . . . . . . . . 5. Nucleophilic Aromatic Substitution by M. R. Crampton . . . . . . . . . . . . . . . 6. Electrophilic Aromatic Substitution by R. G. Coombes . . . . . . . . . . . . . . . . 7. Carbocations by R. A. McClelland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Nucleophilic Aliphatic Substitution by K. C. Westaway . . . . . . . . . . . . . . . . 9. Carbanions and Electrophilic Aliphatic Substitution by M. L. Birsa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Elimination Reactions by M. L. Birsa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Addition Reactions: Polar Addition by P. Koˇcovský . . . . . . . . . . . . . . . . . . 12. Addition Reactions: Cycloaddition by N. Dennis . . . . . . . . . . . . . . . . . . . . . . 13. Molecular Rearrangements: Part 1. Pericyclic Molecular Rearrangements by S. K. Armstrong . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14. Molecular Rearrangements: Part 2 by J. M. Coxon . . . . . . . . . . . . . . . . . . . Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ix

1 47 85 131 155 167 179 213 249 277 287 349 399 429 501 537

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

B. A. Murray Department of Science, Institute of Technology Tallaght (ITT Dublin), Dublin, Ireland Formation and Reactions of Acetals and Related Species . . . . . Reactions of Glucosides and Nucleosides . . . . . . . . . . . . . . Reactions of Ketenes . . . . . . . . . . . . . . . . . . . . . . . . . Formation and Reactions of Nitrogen Derivatives . . . . . . . . . Imines: Synthesis, Tautomerism, Catalysis . . . . . . . . . . The Mannich and Nitro-Mannich Reactions . . . . . . . . . . Addition of Organometallics . . . . . . . . . . . . . . . . . . Other Alkylations, Arylations, and Allylations of Imines . . . Reduction of Imines . . . . . . . . . . . . . . . . . . . . . . Iminium Species . . . . . . . . . . . . . . . . . . . . . . . . Imine Cycloadditions . . . . . . . . . . . . . . . . . . . . . Other Reactions of Imines . . . . . . . . . . . . . . . . . . . Oximes, Hydrazones, and Related Species . . . . . . . . . . C–C Bond Formation and Fission: Aldol and Related Reactions . Regio-, Enantio-, and Diastereo-selective Aldol Reactions . . Intramolecular Aldols . . . . . . . . . . . . . . . . . . . . . Mukaiyama and Vinylogous Aldols . . . . . . . . . . . . . . The Aldol–Tishchenko Reaction . . . . . . . . . . . . . . . . Nitrile/Nitro/Nitroso Aldols . . . . . . . . . . . . . . . . . . Other Aldol-type Reactions . . . . . . . . . . . . . . . . . . Pinacol-type Coupling . . . . . . . . . . . . . . . . . . . . . The Baylis–Hillman Reaction and its Aza and Morita Variants Allylation and Related Reactions . . . . . . . . . . . . . . . The Horner–Wadsworth-Emmons and Related Olefinations . . Alkynylations . . . . . . . . . . . . . . . . . . . . . . . . . Michael Additions . . . . . . . . . . . . . . . . . . . . . . . Other Addition Reactions . . . . . . . . . . . . . . . . . . . . . . General and Theoretical . . . . . . . . . . . . . . . . . . . . Addition of Organozincs . . . . . . . . . . . . . . . . . . . . Addition of Other Organometallics . . . . . . . . . . . . . . Grignard-type Reactions . . . . . . . . . . . . . . . . . . . . The Wittig Reaction . . . . . . . . . . . . . . . . . . . . . . Hydrocyanation and Cyanosilylation . . . . . . . . . . . . . . Hydrosilylation and Hydrophosphonylation . . . . . . . . . . Miscellaneous Additions . . . . . . . . . . . . . . . . . . . .

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1

2 3 4 5 5 5 6 7 8 8 9 9 11 12 12 14 16 17 17 17 19 19 21 23 23 24 25 25 26 27 28 28 29 31 31

2

Organic Reaction Mechanisms 2005

Enolization and Related Reactions . . . . . . . . . . . . . . . . . Oxidation and Reduction of Carbonyl Compounds . . . . . . . . Regio-, Enantio-, and Diastereo-selective Reduction Reactions Other Reduction Reactions . . . . . . . . . . . . . . . . . . . Oxidation Reactions . . . . . . . . . . . . . . . . . . . . . . Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

. . . . . . .

32 33 33 34 35 36 38

Formation and Reactions of Acetals and Related Species Ketones and aldehydes can be conveniently protected as their cyclic acetals (1) using ethylene glycol and 5 mol% iodine.1 HI is believed to be the actual catalyst, but it gives low yields in small-scale reactions, probably because the acidity is difficult to control. The reaction can be extended to using an α-hydroxy acid instead of an α-diol, giving ‘lactonic acetal’ protection (2). Examples include mandelic and lactic acids (i.e. R3 = Ph and Me) and, when the reactions are carried out in THF, they show some diastereoselectivity. R1 R2 O

O

R1 R2 O

O

R3 (1)

O

O (2)

OH OH

O

H

H

(3)

(4)

The rearrangement of 5-hydroxycycloctanone (3) to its hemiacetal (4) has been studied computationally.2 A concerted intramolecular nucleophilic addition process is demonstrated. gem-Diacetates, R1 CH(OAc)2 , and α-chloroalkyl esters, R1 CH(Cl)OCOR2 , have been prepared from aldehydes, R1 CHO, using Zn(OTf)2 .6H2 O as catalyst, together with acetic anhydride or an acid chloride, R2 COCl.3 Yields are high under solvent-free conditions at room temperature. Ketones also react, but in very low yields. gem-Diacylates of aromatic aldehydes have been prepared under solvent-free conditions, using anhydrides and tetrabutylammonium tribromide as catalyst.4 Deprotection can be achieved with the same catalyst on addition of methanol. The reaction proceeds via protonation of aldehyde, nucleophilic attack of the anhydride, and further nucleophilic attack on the hemiacylate intermediate, followed by regeneration of anhydride. Electron-donating groups in the aldehyde favour reaction, to the extent that such aldehydes can be chemoselectively protected in a substrate which also contains an aldehyde with an electron-withdrawing group. Such selectivity is also readily accomplished in deprotection. All the gem-diacylals studied were more stable in base than in acid, but the order of stability is the same in both types of media. This reflects the fact that stability correlates with steric crowding around the carbonyl carbon, and not with the pKa s of the corresponding acids.

de

1 Reactions of Aldehydes and Ketones and their Derivatives

3

α,α-Diacetyl ketene dibenzylthioacetal reacts, under strongly basic conditions, with arylaldehydes in a deacylation–condensation sequence.5 A transition-state analogue for an acetal hydrolysis has been used to select and amplify the production of a macrocycle from a dynamic combinatorial library of disulfides in water. The macrocycle gives a modest acceleration of the acetal hydrolysis reaction.6 Terminal isopropylidene acetals can be hydrolysed using I2 in acetonitrile; similar protection in non-terminal positions is untouched.7 Unsymmetrical cyclic benzylidene acetals (5) undergo reductive ring opening to give either a primary (path a) or secondary alcohol (path b).8 Cu(OTf)2 has been employed as a regioselective catalyst, using borane or trialkylsilanes as reductant, the former favouring path a, and the latter path b. The copper(II) triflate has dual functions: it is a Lewis acid, and its binding to the reductant brings about the regioselectivity. a

Ar

O

b O R1

R2 (5)

Reactions of Glucosides and Nucleosides SN 2 reactivity is dramatically reduced at the primary C(6) position of galactoconfigured pyranoses, relative to their gluco isomers. The low reactivity is widely attributed to dipole–dipole interactions in the transition structure, but ab initio calculations on model compounds suggest that the energy attributable to such interactions is not sufficient to explain the reactivity difference,9 whereas rotameric populations and reaction path curvature are.10 The nucleosidation mechanism of five-membered glycals promoted by N -iodosuccinimide, to give 2 -deoxy-2 -iodo-β-nucleosides, has been investigated by semiempirical methods.11 In glucosides, hemiacetal hydroxyl activation/substitution can be achieved using a sulfonic anhydride and a nucleophile, plus a base as acid scavenger.12 The reaction is catalysed by dibutyl sulfoxide (Bu2 S=O), and shows evidence of sulfur-covalent catalysis. Using benzenesulfonic anhydride [(PhSO)2 O], it is proposed to involve initial formation of a sulfonium sulfonate (6), the S(IV) centre of which then reacts with −

PhSO3 +

Bu

O

O S

O S Bu (6)

Ph

4


the sugar hydroxyl to give glycosyl sulfonate (Gluc–O–SO2 Ph). 18 O incorporation experiments and 13 C– 16/18 O isotopic NMR chemical shift perturbations have been used to probe the mechanism, which also shows evidence of a glycosyl oxosulfonium intermediate, Gluc–O–S+ –Bu2 . New DISAL (methyl 3,5-di nitrosal icylate) glycosyl donors have been prepared and used to carry out β-selective glycosylations under neutral conditions.13 Glycosylation using trichloroacetimidates [Gluc–C(=NH)–CCl3 ] has been carried out in ionic liquids based on imidazolium salts.14 Switching from non-coordinating anions in the solvent (PF6 − , BF4 − ) to triflate anion gave a reversal of stereoselectivity, indicating that triflate counterion from the solvent is sufficiently nucleophilic to interact with the oxonium ion intermediate. trans-2,3-O-Carbonate protection of glucopyranosyl donors leads to good βselectivity in glycosylations, in the absence of neighbouring group or solvent participation.15 A β-cyclodextrin bis(cyanohydrin) acts as an artificial glycosidase, giving kcat /kuncat ratios of 200–2000 in the hydrolysis of aryl glycosides. The electron-withdrawing effect of the cyano groups is proposed to acidify the geminal hydroxyls.16 A further paper shows Michaelis–Menten kinetics for the hydrolyses,17 with accelerations up to 8000. The behaviour is consistent with general acid catalysis of the bound substrate, with the cyanohydrin OH as catalytic group. An analogue with only one cyanohydrin function is also a good catalyst, and its action is compared with that of natural glycosidases, where a protonating carboxylic acid is the catalytic function. Diazeniumdiolate anions as leaving groups at the anomeric position of carbohydrates can act as prodrugs, releasing NO upon hydrolysis by a glycosidase.18

de

de

de

Reactions of Ketenes The energy surface linking ketene (7, several conformers), the corresponding oxazinium olate (8), and related imidoylketenes, oxo-ketenimines, and their cyclization products has been calculated.19 Whereas (8) ring opens easily at room temperature, (7) is not directly observable, as its energy is ca 10 kcal mol−1 above (8). Many of the reactions in this manifold are pseudopericyclic in nature. O O

O −

R

3

C

R3

N

O

O

+

R1

N R2 (7)

O R1

R2 (8)

Enantio-enriched enol esters – potential precursors of enantiopure α-arylalkanoic acids – have been prepared by asymmetric coupling of ketenes with aldehydes, using a chiral ferrocene bearing a dimethylaminopyridine function.20

ee

5


Formation and Reactions of Nitrogen Derivatives Imines: Synthesis, Tautomerism, Catalysis A large-scale, robust enantioselective synthesis of β-substituted-β-amino esters from aldehydes via imine formation with a chiral amine has been reported.21 A wide range of kinetic and thermodynamic parameters have been measured for the formation and hydrolysis of Schiff bases derived from pyridoxal 5 -phosphate and l-tryptophan over a range of pH and temperature.22 In a study of imine formation from aldehydes in aqueous solution, formation constants have been correlated with three parameters: the pKa and HOMO energy of the amine and the LUMO energy of the aldehyde.23 Sodium dodecyl sulfate micelles accelerate condensations of p-dimethylaminocinnamaldehyde with a range of substituted anilines.24 Indolizidines have been prepared by cyclization of trimethylsilylmethylenecyclopropylimines.25 A linear solvation energy relationship (LSER) study of tautomerism in aromatic Schiff bases and related azo compounds indicates that the aminoenone tautomer is always the more polar, and is specifically favoured by proton donor solvents (binding to the second lone pair of the carbonyl). Effects of aromatization and benzo fusion are also discussed.26 A BINOL-derived chiral aldehyde (9) with three hydrogen bond-donating groups has been prepared.27 It can recognize chiral 1,2-amino alcohols by reversible formation of imines. Experimental and computational results suggest that the stereoselective recognition depends on the imine bond, a resonance-assisted hydrogen bond to the imine nitrogen, and further hydrogen bonds to the oxygen of the alcohol.

ee

ee

H O O

H

HN HN

O

N H

H N O

CF3 O

O

(9)

(10)

The Mannich and Nitro-Mannich Reactions Chiral palladium complexes have been employed as enantio- and diastereo-selective catalysts of a Mannich-type addition of β-keto esters to aldimines and imino esters, in a strategy which activates both reactants.28 anti -Selective direct enantioselective Mannich reactions use a BINAP-derived axially chiral aminosulfonamide as organocatalyst.29

ee de ee

6


An enantioselective nitro-Mannich reaction of alkyl- and aryl-benzylimines gives β-nitroamines in high ee, using a chiral copper(II)–bisoxazoline catalyst, with the products affording 1,2-diamines by reduction.30 A simple pyrrolidine imide (10), derived from l-proline, brings about the direct formation of α,β-unsaturated ketones from unmodified ketones and aldehydes under mild conditions.31 Mechanistic investigation suggests a Mannich elimination process, rather than an aldol route. Diastereoselective Mannich-type reactions between ketene silyl acetals and chiral sulfinimines using simple metal-free Lewis bases such as tetraalkylammonium carboxylates have been reported. The sulfinimine can even be generated in situ (from aldehyde and a chiral sulfonamide), using cesium carbonate, followed by addition of ketene silyl acetal at −78 ◦ C, and as little as 1 mol% of catalyst.32 syn-Diastereoselective Mannich-type reaction of α-phenylseleno chlorotitanium enolates with aromatic aldimines gives α-phenylseleno-β-amino esters.33 A direct enantioselective Mannich synthesis of β-amino-α-oxyaldehydes – from unmodified β-oxyaldehydes and anilines – uses l-proline to give high des and ees.34 Fluorinated γ -amino alcohols have been prepared in moderate yield, but high de and very high ee, using a proline-catalysed cross-Mannich reaction of fluorinated aldimines with aliphatic aldehydes, followed by NaBH4 reduction.35 A chiral thiourea catalyses enantio- and diastereo-selective addition of nitroalkanes to N -protected imines.36 Enantiomerically pure β-nitroamines of enolizable aldimines and ketimines have been accessed via a diastereoselective aza-Henry reaction of N -sulfinylimines and nitromethane.37 The reaction is catalysed by sodium hydroxide, but also by tetrabutylammonium fluoride, the latter species giving an inversion of stereochemistry. An O− · · ·+ N contact ion pair is proposed in the ammonium-catalysed route.

ee

de

de de ee de ee de ee de ee

Addition of Organometallics Barbier-type C-alkylation of imines can be carried out with alkylstrontium halides generated from strontium metal and alkyl halide.38 N -Alkylation competes, and RSrI is strongly nucleophilic, as shown by α-alkylation of imines derived from enolizable aldehydes. trans-1,2-Diaminocyclohexane ligands have been used as enantioselective catalysts for the asymmetric addition of methyllithium39 and aryllithiums40 to aromatic imines. A kinetic study of the addition of n-BuLi to a chiral aliphatic aldimine has explored the roles of TMEDA (N ,N ,N ,N -tetramethylethylenediamine) and solvents (toluene, diethyl ether) on relative rates and diastereoselectivity.41 Evidence for four mechanisms was obtained, including monomeric and dimeric n-BuLi cases, and a cooperative TMEDA–Et2 O pathway. Hence the roles of chelation, aggregation, and cooperative solvation all need to be considered when solvents and additives are varied in such reactions. Copper-catalysed enantioselective addition of diorganozincs to phosphinoylimines has been reported,42 as has enantioselective addition of diethylzinc to N -acylaldimines.43

ee de

ee


7

Asymmetric addition of organometallic reagents to imines, to produce useful optically active amines, has been reviewed.44 Enantioselective exocyclic, endocyclic, and acyclic α-p-tolylsulfinyl ketimines have been reacted with Et2 AlCN.45 The cyclic substrates exhibit good yield and diastereoselectivity, but the acyclic cases are complicated by imine–enamine equilibria. Grignard addition to an enantiopure t-butylsulfinimine shows a dramatic reversal in diastereoselectivity when the solvent is changed from DCM to THF, probably due to a mechanistic switch away from chelation.46 Chiral ferrocenoylpyrrolidines catalyse the highly enantioselective addition of diethylzinc to N -sulfonylimines in the presence of copper(II) triflate.47 Whereas N -tosylimines do not coordinate diethylzinc well in polar solvents (and thus tend to give ethylated product), solvents such as toluene favour coordination, leading to reduction of the imine to secondary amines under mild conditions, via a β-hydrogen transfer mechanism.48

ee ee de de ee

Other Alkylations, Arylations, and Allylations of Imines α-Sulfinyl carbanions exhibit high stereoselectivity in reactions with achiral imines, with the magnitude and direction of the ee dependent on the electron density at nitrogen.49 Nitrile-stabilized anions, generated for example by lithiation of benzyl cyanide and propionitrile, have been added diastereoselectively to aromatic aldimines.50 Acid workup gives β-cyano amines. Alternatively, addition of RX gives β-R-substituted-βcyanoamines. The factors determining des in both reaction versions have been investigated. Recent advances in asymmetric additions of dialkyl reagents to imines have been reviewed.51 Arylboronic acids have been added diastereo- and enantio-selectively to (a) sulfinyl aldimines and (b) phosphinoyl aldimines, using rhodium(I) catalysts.52 These two methods should prove useful in preparing α-branched amines. N -Tosyl aldimines, RCH=N–Ts, add regioselectively to the C(2) of pyrroles, to give pyrrole sulfonamides (11), using copper(II) triflate as catalyst.53

ee

de

de ee

R N H

NH (11)

Ts

Anisidine imines of aldehydes, p-MeOC6 H4 –N=CHR (R = Ar, alkyl) can be allylated with anti -selectivity, using triethylborane and a Pd(II)–phosphine catalytic system, avoiding metallic or metalloid allylating agents.54 The imines can be conveniently formed in situ. A highly stereoselective benzylation has been developed: α,α-dibranched β-phenylpropylamines and -ethanolamines can be synthesized in any desired configuration

de

de

8


by reaction of o-sulfinylbenzyl carbanions with N -sulfinylketimines, followed by desulfinylation.55 Synthesis of diarylmethylamine derivatives, Ar1 –CH(Ar2 )–NHSO2 –C6 H4 -p-NO2 , has been achieved enantioselectively using rhodium-catalysed arylation of imines with arylboroxines.56

ee

Reduction of Imines Catalytic asymmetric hydrogenation of prochiral Schiff bases has been reviewed.57 A catalytic asymmetric in situ reduction of N–H imines has been achieved in a sequence in which trifluoroacetophenones, ArCOCF3 , are first converted to silylimines [using LiN(SiMe3 )2 ], and then on to give trifluoromethylated amine salts, Ar–C(CF3 )– NH2 .HCl, in good to excellent yield and ee.58 The intermediate N–H imines can be isolated via methanolysis of the N–Si bond, while the enantioselective reduction can be carried out using a chiral borane auxiliary. The mechanism of Shvo’s hydroxycyclopentadienyl ruthenium hydride (12) reduction of imines has been studied using isomerization and deuterium scrambling experiments.59 The rate-determining step is found to change from electron-deficient to electron-rich imines. A more detailed mechanistic investigation involving intramolecular trapping of a coordinatively unsaturated intermediate indicates hydrogen transfer can occur outside the metal coordination sphere.60 Ph Tol Tol OC

Ru CO (12)

Ph H

N

X

R1

+

Ph

N H

(13)

ee

O

R2

OH

ee

N

−

Ph (14)

1-Substituted-1-(pyridine-2-yl)methylamines (13, X = ∗CHNH2 ) have been prepared diastereoselectively by the reduction of enantiopure N -p-toluenesulfinyl ketimines [X = C=N– ∗ S(=O)-p-tolyl].61 See also reduction of imines with diethylzinc under Addition of Organometallics above, and ionic hydrogenation of Iminium Species below.

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Iminium Species Racemic azomethine imine (14) has been kinetically resolved using a copper(I)catalysed 3 + 2-cycloaddition, with a chiral co-catalyst.62 DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) conveniently oxidizes ketene silyl acetal (15) to give α-alkoxycarbonyl iminium salt (16).63 Subsequent reaction with nucleophiles gives amino ester derivatives, Nu–CH(NBn2 )–CO2 R. Grignards

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1 Reactions of Aldehydes and Ketones and their Derivatives +

OTMS Bu2N

DDQ

OR

X

(15)

9

NBu2

−

CO2R (16)

are typical nucleophiles, and the two reactions can be done in one pot, under mild conditions. The scope and mechanism of ionic hydrogenation of iminium cations have been investigated for a CpRuH catalyst bearing a chelating diphosphine.64 The mechanism involves three steps: hydride transfer (from the catalyst) to form an amine, coordination of H2 to the resulting ruthenium cation, followed by proton transfer from the dicoordinated H2 to the amine. The cationic intermediate [e.g. CpRu(dppm)(η2 -H2 )+ ] can be used to hydrogenate enamines provided that the latter are more basic than the product amine. The relative reactivity of C=C and C=N bonds in α,β-unsaturated iminium cations has also been investigated.

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Imine Cycloadditions Regio- and enantio-selective additions of nitrile amines (R1 –C≡N+ –N− –R2 , from the hydrazonyl bromide) to enones allows access to dihydropyrazoles close to enantiopurity, via a 3 + 2-cycloaddition.65 Sodium iodide catalyses a regioselective cycloaddition of cyclopropenes with imines, to give cis-vinylic aziridines.66 Lewis acids, especially rare earth triflates, are efficient catalysts of 1,3-dipolar cycloadditions to imines, Ar– 1 CH=N–Ar2 .67

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Other Reactions of Imines Recent advances in catalytic asymmetric addition to imines and other C=N systems have been reviewed.68 [N -(p-Tolylsulfonyl)imino]phenyliodinane, PhI=NTs, is a well-known nitrene precursor.69 It has now been used to imidate aldehydes (i.e. RCH=O → RCH=NTs) using a ruthenium(II) catalyst and triphenylphosphine. Ph3 P=NTs formation is proposed to occur, followed by aza-Wittig reaction. 2-Lithio-2-phenyl-1,3-dithiane (17) has been employed in a new umpolung asymmetric addition of N -sulfinylimines, using a Lewis acid catalyst (Et2 AlCl). The high des obtained open up a new route to enantiopure α-amino ketones.70

S

S

Li

Ph (17)

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Aldimines can be trifluoromethylated at the imine carbon using Me3 SiCF3 in dimethyl formamide at −20 ◦ C, using a lithium carboxylate as catalyst.71 It is proposed that the carbon–silicon bond of the reagent is activated via formation of a lithium silicate bearing carboxylate and DMF ligands on silicon. A similar process has been used for diastereoselective addition to sulfinyl imines.72 Strecker-type reaction of TMS cyanide with chiral sulfinimines gives diastereoselective cyanations at the imine carbon, at −78 ◦ C in DMF, using simple metal-free Lewis base catalysts such as tetraalkylammonium carboxylates.73 N -Tosylimines are alkynylated by aryl acetylenes in acetonitrile; the reaction is promoted by zinc bromide and Hunig’s base (N ,N -diisopropylethylamine).74 Vinyl aziridines have been prepared trans- and diastereo-selectively by reaction of N -t-butylsulfinylimines with telluronium ylides.75 Enantioselective synthesis of β-lactams from enolate and imine components uses a bifunctional Lewis acid/nucleophile strategy.76 A chiral nucleophile is used to form a zwitterionic enolate, and a metal ion coordinates the imine. The postulated mechanism is supported by kinetic, spectroscopic, and molecular modelling evidence. Chiral carbamoylsilanes, TMS–CO–N(Me)R*, have been added diastereoselectively to aldimines, giving α-aminoamides.77 Simple N -alkylated imines, e.g. N -methylaldimine (18, R1 = aryl, alkyl), undergo nucleophilic addition using a masked acyl cyanide reagent [19, where the masked group = −C(CN)2 –O−] with C–C bond formation to give an α-amido ester (20).78 This mild conversion does not require ‘pre-activation’ (i.e. incorporation of an activating group in the substrate) or ‘post-activation’ (i.e. Brønsted or Lewis acid, or metallic species).

Me N R1

H (18)

O

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O

O NC H NC

de

Me

(19)

R23N/–MeOH

Me

N

Me OMe

R1 O (20)

An enantioselective Strecker cyanation of ketoimines exploits Lewis acid–Lewis base bifunctional catalysts.79 Chiral ketimines derived from (R)-glyceraldehyde have been cyanated in high de.80 Catalyses of the addition of HCN to methanimine by formamidine and by formamide has been studied computationally.81 A BINOL-derived phosphoric acid derivative has been used as a catalyst in the enantioselective synthesis of α-amino phosphonates via hydrophosphonylation of imines with diisopropyl phosphite.82 A direct stereoselective addition of an activated imine to β-keto phosphonates in the presence of a chiral copper(II) catalyst has been developed.83

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Tetrakis(dimethylamino)ethylene (TDAE) combines with CF3 I to give a nucleophilic trifluoromethylation reagent which is effective with N -tosylaldimines and N -tolylsulfinimines, the latter case being diastereoselective.84 Regioselectivity control in the double nucleophilic addition of ketene silyl acetals to α,β-unsaturated imines has been reported.85 Silyl ketene imines have been acylated asymmetrically by anhydrides: evidence for a silyl-free nitrile anion intermediate is discussed.86 An aza-Baylis–Hillman reaction of N -sulfonated imines is described below.

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Oximes, Hydrazones, and Related Species 2-Alkyn-1-one O-methyl oximes (21) undergo electrophilic cyclization with a range of reagents, E–X (e.g. I2 , Br2 , ICl, PhSeBr), to give substituted isoxazoles (22).87 OMe N R1 (21)

R1

R2

R2

O

N

E (22)

O-Allylation of oximes yields O-allylated oxime ethers, whereas N -allylation gives the corresponding nitrone isomer, using an allylic carbonate or acetate as electrophile.88 With Pd(II) catalysis and carbonate leaving group, O-allylation occurs without base, whereas the acetate substrate requires K2 CO3 or Et2 Zn as base. To form nitrone product selectively, a Pd(II) Lewis acid catalyst was employed. Base-catalysed nitrosation of acetone by t-butyl nitrite to give 1-hydroxyimino-2oxopropane [H3 C–C(=O)–CH=NOH] has been studied by ab initio methods.89 Using a sodium enolate route, the cation participates to give Z-isomer, whereas a ‘naked enolate’ calculation results in the E-product being favoured. Under the relatively mild conditions of chlorosulfonic acid in toluene, ketoximes undergo Beckmann rearrangement, whereas aldoximes dehydrate to nitriles.90 Hydrolysis of cyclohexane-1,2,3-trione-1,3-dioxime (23, X = O) and its 2-imine (X = NH) has been studied in perchloric acid solution.91 The mechanism is proposed to involve a protonation pre-equilibrium, followed by slow water addition to protonated and non-protonated forms. Oxime protonation pKa s have been calculated. NOH

F5

O

O CO2Et

X N NOH (23)

(24)

NHAr

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Using a BINOL auxiliary with allylindium and indium metal, hydrazones have been allylated enantioselectively,92 to give homoallylic amines in up to 97% ee. 3-Arylhydrazono-2,4-dioxo-4-pentafluorophenyl butanoates (24) react with hydrazine (or phenylhydrazine); unexpectedly, pyridazine-5,6-dione derivatives are produced.93 The use of neutral coordinate organocatalysts such as DMF, sulfoxides, and phosphine oxides to activate allyltrichlorosilane in allylation of acylhydrazones has been reviewed.94 The kinetics of the oxidation of piperidinone thiosemicarbazones by chloramine-T have been studied in acetic/perchloric acid media.95 Nucleophilic additions to chiral α-alkoxy and α-amino nitrones have been reviewed, focusing on tuning of Lewis acid catalysts and protecting groups so as to exert stereocontrol in producing hydroxylamines and ultimately useful amino acids, amino alcohols, and nucleoside analogues.96

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C–C Bond Formation and Fission: Aldol and Related Reactions Regio-, Enantio-, and Diastereo-selective Aldol Reactions ‘Modern Aldol Reactions’ contains several pertinent reviews: (i) catalytic enantioselective aldols with chiral Lewis bases;97 (ii) the aldol–Tishchenko reaction;98 (iii) titanium–enolate aldols;99 (iv) crossed aldols mediated by boron and silicon enolates;100 (v) amine-catalysed aldols;101 and (vi) aldols catalysed by antibodies.102 Other reviews deal with aldol additions of group 1 and 2 enolates,103 direct catalytic asymmetric aldol reactions catalysed by chiral metal complexes,104 the exploitation of ‘multi-point’ recognition in catalytic asymmetric aldols,105 and recent progress in asymmetric organocatalysis of aldol, Mannich, Michael, and other reactions.106 Hartree–Fock and density functional theory (DFT) calculations have been used to probe the enantioselectivity of the direct aldol reaction of acetone and 2,2-dimethylpropanal, catalysed by (S)-proline, in DMSO solution.107 Carefully matched acid and base catalysis has been used to select the pyrrolidine–pnitrophenol combination as an efficient organocatalyst for direct aldol reactions.108 Direct intermolecular aldol reactions, catalysed by proline, between tetrahydro-4H thiopyranone (25) and racemic aldehydes exhibit enantiotopic group selectivity and dynamic kinetic resolution, with ees of >98% in some cases.109

ee

ee

ee

ee

O N

N H S (25)

N HN N (26)

The role of assistance by water in the direct asymmetric aldol catalysed by amino acids has been studied in DMSO and in DMF.110

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13

Structure–activity relationships have been probed in (S)-histidine-based dipeptides employed as organocatalysts for direct asymmetric aldol reactions, focusing on intramolecular cooperation between side-chain functions: H–Leu–His–OH proved particularly useful.111 Enantioselective aldolization using 5-pyrrolidin-2-yltetrazole (26) – in which the carboxylic acid of proline has been replaced by its well-known pharmacophore – has been modelled by DFT.112 The calculations indicate that the large charge buildup on the carbonyl oxygen during C–C bond formation is stabilized by hydrogen bonding by the tetrazole NH. 4-Substituted prolines – typically with additional chiral centre(s) in the substituent – have been found to be much more enantioselective than proline itself in aldol reactions.113 Bis-sulfonamides have been used to activate carbonyl compounds through hydrogen bonding.114 Bis-triflamides or -nonaflamides of readily available chiral diamines act as chiral Brønsted acid catalysts – through structures such as (27) – giving good to high yields and ees in representative carbonyl additions such as Mukaiyama aldol, hetero-Diels–Alder, and Friedel–Crafts reactions.

ee

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ee

ee

R∗ Tf

N H

N Tf O

H

R1 R2 (27)

Simple dipeptides bearing a primary amino N-terminus catalyse direct asymmetric intramolecular aldol reactions in up to 99% ee.115 These simple catalysts such as l-Ala-l-Ala and l-Val-l-Phe can also promote the asymmetric formation of sugars, further suggesting a possible role in prebiotic chemistry. DFT methods have been used to explore the nature of the transition states giving rise to stereoselectivity in intramolecular aldol cyclizations catalysed by amino acids.116 Proline and primary amino acids are compared, identifying the factors explaining why proline is better in some cases, but not always. Asymmetric aldol reactions promoted by chiral oxazaborolidinones can achieve high ee with critical quantities of THF, typically a 4–5-fold excess over the borane.117 Ab initio calculations on Lewis acid–aldehyde–solvent complexes have been used to rationalize such results: extended hydrogen bonding networks have been identified. β-Hydroxyaldehydes, with an intervening quaternary centre, have been synthesized enantioselectively by direct aldol reactions of α,α-dialkylaldehydes with aromatic aldehydes, using a chiral bifunctional pyrrolidine sulfonamide organocatalyst.118 A ‘DYKAT’ (dynamic kinetic asymmetric transformation) approach has been taken to de novo synthesis of triketide- and deoxy-sugars from racemic β-hydroxyaldehydes.119 Using proline as catalyst, the process involves continuous amino acidmediated racemization of the acceptor β-hydroxyaldehyde in combination with direct

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selective aldol addition, also catalysed by the proline; des >90% and ees up to 99% are reported. Dicyclohexylchloroborane mediates aldol reactions between chiral aldehydes and a chiral ketone; the reaction exhibits double diastereoselection.120 Evidence for chair-like transition states in aldol reactions of methyl ketone lithium enolates has been obtained from deuterium-labelled enolates.121 A divergent synthesis of 2-amino-1,3-diols has been reported, using a diastereoselective aldol addition to α-amino-β-silyloxyaldehydes.122 Samarium(II) iodide mediates highly stereoselective aldol reactions of acylaziridines with aldehydes, typically accompanied by ring opening, producing useful β-aminoβ -hydroxy derivatives.123 Boron-mediated ketone–ketone aldol reactions have been described, using boron enolates formed with dicyclohexylboron chloride and triethylamine.124 Following addition of the acceptor ketone to form a boron aldolate, oxidation with peroxide yields the aldol product. Several reports deal with aqueous media. Acid–base catalysis by pure water has been explored, using DFT, for the model aldol reaction of acetone and acetaldehyde.125 A Hammett correlation of nornicotine analogues (28) – a series of meta- and parasubstituted 2-arylpyrrolidines – as catalysts of an aqueous aldol reaction shows ρ = 1.14.126 Also, direct aldol reactions have been carried out in water enantioselectively, using protonated chiral prolinamide organocatalysts.127

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de de

de

ee

R

N H (28)

Intramolecular Aldols Triketone (29) undergoes an intramolecular aldol reaction – the Hajos–Parrish–Eder– Sauer–Wiechert reaction – to give (30) and subsequently enone (31), in high ee with the stereochemistries indicated being found for d-proline catalysis.128 Now a homochiral β-amino acid, (1R,2S)-cispentacin (32) has been found to give comparable ee, and indeed does so for the cyclohexyl substrate also. Me O

O

Me

CO2H NH2

Me

(29)

Me O −H2O

(32)

O

O

O

OH (30)

O (31)

The roles of proline and primary amino acids in intramolecular aldol cyclizations are compared in the previous section.

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Symmetrical bisenone (33) undergoes an intramolecular vinylogous Morita–Baylis– Hillman reaction, followed by intramolecular aldol cyclization to give dienone products (34) and (35).129 An 83% yield was obtained in 1 day at ambient temperature, with a dramatic 94:6 preference for the cross-conjugated product (34). After the first cyclization, it is proposed that the phosphonium unit of the Michael adduct (36) reacts with the adjacent carbonyl to give regioselective deprotonation (37). Evidence presented includes the observation that, although the reaction can be carried out without phosphine (i.e. just using RO− /ROH), the opposite regioselectivity results. O

O

Me

PR3

+

ROH

COMe

Me

(33) +

RO

O

(34) PR3

(35)

O

R 3P

O

−ROH

−

COMe

COMe

(36)

(37)

1,6-Dialdehydes have been converted to cyclopentene carbaldehydes via an intramolecular asymmetric aldol cyclodehydration, using hydroxyamino acids as catalysts.130 Ring-size effects have been examined in a diastereoselective intramolecular aldol cyclization.131 endo-X-Hydroxybicyclo[3.n.1]alkan-2-ones (38) can be accessed via an intramolecular aldolization of a cyclohexanone with an appropriately tethered aldehyde in the 4-position.132 Using 4-(trialkylsilyloxy)prolines as catalysts, the octanone (n = 1, X = 7) and nonanone (n = 2, X = 8) systems have been synthesized in good yield, with up to 94% ee, and >98% de.

( )n

OH (38)

de

ee de

O Ph

N O

ee

OH (39)

Five- and six-membered β-hydroxylactones have been synthesized diastereo- and enantio-selectively from α,β-unsaturated esters bearing a ketone tethered as the ester R group, in an intramolecular reductive aldol reaction catalysed by chiral bisphosphine complexes of copper(I).133

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Methyl trichlorosilyl ketene acetal reacts with aromatic and aliphatic ketones (the former enantioselectively), using chiral pyridine bis-N -oxide catalysts.134 Computations and an X-ray crystal structure of a catalyst–SiCl4 complex have helped to elucidate the mechanism. (S,S)-(+)-Pseudoephedrine proprionamide (39) has been employed as a chiral auxiliary in asymmetric acetate aldol reactions.135 A new thioester aldol reaction which uses a half-thioester (PhSOC–*CHMe–CO2 H) of methylmalonic acid and a copper–bis(oxazoline) catalyst is highly enantio- and diastereo-selective, while also being mild and tolerant of protic functional groups and enolizable aldehydes.136

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Mukaiyama and Vinylogous Aldols Catalytic, enantioselective, vinylogous aldol reactions have been reviewed, from the first report in 1994 to date.137 Many examples from natural products are given, and the remaining problems – especially the need to push beyond dienolates derived from esters – are highlighted. Ab initio calculations indicate that a model uncatalysed Mukaiyama aldol reaction – that of formaldehyde and trihydrosilylenol ether – proceeds via a concerted pathway involving a twist-boat six-membered transition state.138 A wide range of substituents on both reactants have been explored, and some combinations give rise to particularly low barriers, hopefully identifying cases that should work below room temperature. Regio-, enantio-, and diastereo-selective vinylogous aldol additions of silyl dienol ethers to aldehydes use a Lewis base (a chiral bis-BINAP-phosphoramide) to activate a Lewis acid (silicon tetrachloride).139 ˚ molecular A variety of Brønsted acid sources – benzoic acid, silica gel, 3 A sieves – catalyse vinylogous aldol reactions of O-silyl dienolates, under solvent-free conditions.140 A range of chiral pre-organized diols have been studied to assess their potential to catalyse vinylogous Mukaiyama aldol reactions enantioselectively via hydrogen bonds.141 Simple Mukaiyama aldol and Diels–Alder reactions catalysed by cationic silicon Lewis acids show significant counterion effects.142 The vinylogous Mukaiyama aldol reaction of 2-(TMS-oxy)furans with methacroleins, catalysed by boron trifluoride etherate, has been studied experimentally and computationally, to identify the factors behind observed diastereoselectivities.143 Using a chiral 4-dimethylaminopyridine–ferrocenyl catalyst, acyclic silyl ketene acetals react with anhydrides to furnish 1,3-dicarbonyl compounds containing allcarbon quaternary stereocentres in good yield and ee.144 Evidence for dual activation (anhydride → acylpyridinium, and acetal → enolate) is presented. Catalytic, enantioselective addition of silyl ketene acetals to aldehydes has been carried out using a variant of bifunctional catalysis: Lewis base activation of Lewis acids.145 The weakly acidic SiCl4 has been activated with a strongly basic phorphoramide (the latter chiral), to form a chiral Lewis acid in situ. It has also been extended to vinylogous aldol reactions of silyl dienol ethers derived from esters.

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The Aldol–Tishchenko Reaction A direct aldol–Tishchenko reaction of aromatic aldehydes with ketones proceeds with stereocontrol of up to five contiguous centres in a chain, using titanium(IV) t-butoxide and cinchona alkaloids.146 A tricyclic transition state is proposed to explain the high degree of stereoselection. A syn-2-amino alcohol, complexed with Yb(III), catalyses the aldol–Tishchenko reaction of aliphatic ketones with aromatic aldehydes to give anti -1,3-diol monoesters with three adjacent stereocentres in high yield, de, and ee.147 The aldol–Tishchenko reaction has been reviewed.98

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Nitrile/Nitro/Nitroso Aldols A direct enantioselective cross-aldol-type reaction of acetonitrile with an aldehyde (RCHO) has been reported, giving β-cyano alcohol product, R–CH*(OH)–CH2 –CN, in up to 77% ee.148 CH3 CN, acting as an acetate surrogate, is chemoselectively activated and deprotonated using a soft metal alkoxide (CuO–But ) in a strong donor solvent (HMPA), with a bulky chiral diphosphine as auxiliary. The formation of tertiary 3-nitroallylic alcohols (40) via attack of nitromethanide anion (RCHNO2 − ) on the corresponding 2-chloroisopropylbutyrophenone has been studied in DMSO and HMPA.149 Gibbs free enthalpies for various steps have been estimated, using gas-phase values and transfer enthalpies where necessary. Carbanion addition was assigned as the rate-determining step. R

ee

OH

O2N X (40)

A regio- and enantio-selective nitrosoaldol synthesis, using an achiral enamine and nitrosobenzene, employs an asymmetric TADDOL catalyst.150

Other Aldol-type Reactions A diastereoselective titanium–enolate aldol reaction of (S)-1-benzyloxy-2-methylpentan-3-one has been reported.151 The Maitland–Japp synthesis of highly substituted tetrahydropyran-4-ones152a (e.g. 41, from pentan-3-one and two benzaldehydes) has been re-explored and generalized into a one-pot diastereoselective preparation.152b Proline catalyses an aldol-type addition of acyl cyanides (RCOCN) to acetone to give β-ketocyanohydrins (42); sodium hydroxide treatment gives the corresponding 1,3-diketone (43), by elimination of HCN.153

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Organic Reaction Mechanisms 2005 O NC

OH O

R O

Ph

O

−OH

O

R

Ph

(41)

(42)

(43)

Palladium enolate chemistry has been exploited to perform a range of catalytic enantioselective reactions on carbonyl substrates, including aldol, Michael, Mannichtype, and α-fluorination.154 A rhodium bis(oxazoline) catalyst gives high ee and anti -selectivity in reductive aldols.155 2-Substituted 3-phenylsulfonyl-5-hydroxymethyl-THFs (e.g. 44) have been prepared chemo-, regio-, and diastereo-selectively via reaction of a γ ,δ-epoxycarbanion with aldehydes, RCHO.156 The initial aldol-type addition is non-diastereoselective, but reversible. The subsequent cyclization is selective, and exerts overall thermodynamic control. PhSO2 ∗

O R

∗

O (44)

Cl2 Si

O

O

Cl2 Si

O

R

Cl (45a)

R

de

+

∗

OH

ee ee de

Cl

−

(45b)

An asymmetric catalytic halo-aldol reaction of β-iodoallenoates with aldehydes has been reported, using a chiral salen-aluminium chloride catalyst.157 Crossed aldol reaction between an aromatic aldehyde and the TMS enolate of another aldehyde proceeds smoothly in wet or dry DMF using a lithium carboxylate as Lewis base catalyst.158 One-pot conversion to 1,3-diols using sodium borohydride as reductant gives up to 87% yield. A similar report, using tetrabutylammonium phenolates as Lewis bases, is diastereoselective.159 Pyridine-N -oxide is an efficient Lewis-base catalyst for aldol reactions of trimethylsilyl enolate with both aryl and alkyl aldehydes in DMF at room temperature, tolerating a wide variety of sensitive substituents in the substrate.160 Trialkylsilyl enol ethers of acetaldehyde undergo enantioselective aldol addition to aromatic aldehydes, giving the aldol product in protected form.161 Using a chiral BINAP-derived phosphoramide as Lewis base catalyst gives ees up to 96%. SiCl4 is required, a chlorohydrin intermediate (45a) is proposed, and NMR evidence suggests this exists as a 1:1 mixture of diastereomers. This masked aldol adduct presumably contributes to the high ees, by preventing side reactions. Intermediate (45a) can also be intercepted at low temperature with nucleophiles: addition of t-butyl isocyanide gave a lactone (diastereoselectively), and a hydroxyamide by-product, both representing synthetically useful processes. It is proposed that the nucleophile attacks and displaces chloride (SN 2 process), or alternatively – in an SN 1-type process – an oxocarbenium species (45b) forms first.

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Carbon kinetic isotope effects have been measured in an exploration of the mechanism of the Lewis base-catalysed enantioselective crossed-aldol reaction of aldehydes.162 The trichlorosilyl enolate of isobutyrophenone, Me2 C=CHOSiCl3 , was reacted with substituted benzaldehydes in chloroform–dichloromethane from −78 to −45 ◦ C, using a chiral BINAP-derived phosphoramide catalyst. Aldolization is rate determining, and extraction of Arrhenius activation parameters indicates large, negative S = values, with a relatively small enthalpic barrier. This is true for both electron-rich and electron-poor benzaldehydes, despite the fact that a Hammett plot of the enantiomeric ratio is V-shaped, showing a dramatic switchover at σ ≈ 0. Various scenarios for this divergent selectivity are discussed. After initial and reversible binding of the Lewis base to the silyl enolate, the two fundamental reaction steps are binding of aldehyde, followed by aldolization. On balance, the authors favour aldolization being both rate- and stereo-determining, even as selectivity changes.

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Pinacol-type Coupling The samarium–N -bromosuccinimide combination reductively dimerizes carbonyl compounds.163 This pinacol-type coupling gives diols in 60–80% yield, with some diastereoselectivity; the by-product from simple reduction (i.e. alcohol) is typically 5–10%. The conditions suggest a single electron transfer to give carbonyl radical anion, which then self-couples. Even congested ketones such as benzophenone and fluorenone worked well. Samarium metal, in the presence of various additives such as ammonium chloride or bromide, induces reductive dimerizations of aromatic ketones to give 1,2-diols, with some diastereoselectivity, and with some alcohol (i.e. reduced ketone) by-product.164 The syn-selectivity observed in many cases may be due to samarium chelation of the oxygens. Synthetically useful β, γ –δ, ε-doubly-unsaturated quaternary carbinols have been prepared enantioselectively via regioselective reductive coupling of 1,3-enynes with ketones.165 Samarium(II) iodide mediates diastereo- and enantio-selective pinacol coupling of chiral α-ketoamides.166

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The Baylis–Hillman Reaction and its Aza and Morita Variants The widely accepted mechanism of amine catalysis of the Baylis–Hillman reaction involves: 1. 2. 3.

nucleophilic addition of the amine to the enone to give enolate, followed by attack on the aldehyde to give a second zwitterionic intermediate (46), which eliminates to product.

Step 2 is considered rate limiting, and autocatalysis can also be observed. Protic solvents can accelerate the reaction, perhaps by hydrogen bonding, but the enolate should be a better acceptor. A kinetic study has re-examined these issues, and finds

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step 3 to be rate limiting in the initial phase, switching to step 2 as product (and hence autocatalysis) builds up.167 The findings should help guide the design of asymmetric catalysts, especially those bearing hydrogen bond donors tethered to the nucleophile. In particular, alkoxide intermediate (46) can exist as four diastereomers, not all of which will have the hydrogen bond donor optimally placed for selective proton transfer. −

Me O− R3

O H

+

R13N

(46)

O

H

O

R2

O

−

Me Ar

O

ArCHO

O H

O

+

N

Ar O Ar

+

N

N

N (47)

(48)

Based on reaction rate data, including primary and secondary kinetic isotope effects, a new mechanism has been proposed for the Baylis–Hillman reaction of arylaldehydes, using diazabicyclooctane as catalyst.168 Starting from methyl acrylate (H2 C=CHCO2 Me) and DABCO, addition gives a zwitterionic intermediate, and a subsequent reaction with aldehyde gives another zwitterion (47). To this point, the mechanism coincides with that which is currently widely accepted. However, based on a finding of secondorder behaviour in aldehyde and other evidence, the formation of hemiacetal-type intermediate (48) is proposed, with its breakdown to products – involving α C–H bond-breaking – being rate determining. The proposers discuss how the mechanism answers a wide range of puzzling observations about the reaction in a variety of media, and with various catalysts/additives. Baylis–Hillman reactions of benzaldehyde and its 2-nitro derivative with α,βunsaturated esters and nitriles have been carried out in water at pH 1 (T = 0 or 25 ◦ C), with tertiary amine catalysts.169 N ,N ,N ,N -Tetramethylethylenediamine (TMEDA) has been compared with DABCO in its catalysis of the reaction in aqueous medium.170 An air-stable ferrocenyl–dialkylphosphine is an effective catalyst for the Baylis– Hillman reaction; chiral analogues have also been developed to render it enantioselective.171 An enantioselective reaction of α-hydroxymethyl acrylates, using a bis-oxazoline chiral catalyst, gives the equivalent of formaldehyde aldol products in good yield and ee.172 A highly enantioselective intramolecular version, catalysed by proline, undergoes an inversion of enantioselectivity on addition of imidazole.173 The imidazole substantially increases the reaction rate: it is proposed to act as a co-catalyst, hydrogen bonding to the proline’s acid hydrogen, blocking a reactant face which is otherwise available in the proline-only route. Baylis–Hillman (and aza-BH) reactions have been reported for N -tosyl aldimines and aryl aldehydes with 3-methylpenta-3,4-dien-2-one, H2 C=C=C(Me)COMe.174

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An NMR kinetic study of a phosphine-catalysed aza-Baylis–Hillman reaction of but-3-enone with arylidene–tosylamides showed rate-limiting proton transfer in the absence of added protic species, but no autocatalysis.175 Brønsted acids accelerate the elimination step. Study of the effects of BINOL–phosphinoyl catalysts sheds light not only on the potential for enantioselection with such bifunctional catalysis, but also on their scope for catalysing racemization. Bifunctional catalysis, using a phenolic BINAP–phosphine, is proposed in the enantioselective aza-BH reaction of N -sulfonated imines with cycloalk-2-en-1-ones.176 1-Methylimidazole 3-N -oxide (49) catalyses the Morita–Baylis–Hillman reaction at room temperature under solvent-free conditions; addition to the enone reactant to give a zwitterionic enolate (50) is proposed, followed by reaction with aldehyde.177

ee

ee

O O −

+

O N

N Me

−

+

O N

O

S

R

(49)

N Me

R (50)

S

( )n (51)

A dual catalyst combination of pipecolinic acid and N -methylimidazole gives 84% ee in a Morita–BH cyclization.178 N -Sulfonated imines undergo enantioselective aza-Morita–Baylis–Hillman reactions with methyl vinyl ketone, using a BINAP-derived phosphine Lewis base.179 The α-carbon atom of α-oxoketene dithioacetals (51, n = 1, 2) reacts with aromatic aldehydes to give 1:1 and 2:1 adducts, i.e. Baylis–Hillman and ‘double-Baylis– Hillman’, using mediation by titanium tetrachloride.180 An intramolecular vinylogous Morita–Baylis–Hillman reaction, followed by intramolecular aldol cyclization,129 is described under Intramolecular Aldols above.

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Allylation and Related Reactions Lewis acid-catalysed allylboronate additions to aldehydes have been reviewed.181 An allylboronate derivative of tartaric acid developed for enantioselective allylation of aldehydes is readily recyclable without losing selectivity.182 A chiral pyridine–bisoxazoline (‘PYBOX’) ligand has been combined with indium (III) triflate to produce an enantioselective catalyst for allylation of a wide variety of aldehydes in ionic liquids;183 ees of >90% were obtained, and extraction and reuse of the catalyst–ionic liquid combination saw this figure hold up to >80% on the fourth recycle. A chiral BINOL–indium(III) complex has been used to catalyse the addition of allyltributylstannane to aldehydes in high ee.184 Aldehydes can be allylated with allyltributylstannane using cerium(III) chloride in acetonitrile, a method particularly suitable for substrates bearing acid-sensitive groups.185

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Enantioselective addition of allylstannane to straight-chain aldehydes has been achieved using a chromium–salen catalyst.186 Carboxylic acids promote the allylation of aldehydes by allyltributylstannane.187 In the case of crotylation, some regioselectivity can be achieved by an appropriate choice of acid. A proline-derived N -oxide catalyses enantioselective allylation of aldehydes, using allyltrichlorosilane at ambient temperature.188 A terpene-derived pyridine N -oxide catalyses the asymmetric allylation of aldehydes with allyl- and crotyl-trichlorosilane at −40 ◦ C, and the ees hold up well even at ambient temperature.189 Chiral BINOL–indium(III) complexes have been employed in several enantioselective allylations: (i) in the ionic liquid, hexylmethylimidazolium–PF6 , for aldehydes,190 (ii) a moisture tolerant version, for a wide variety of aldehyde types,191 and (iii) a recyclable example, useful for aromatic, aliphatic, and α,β-unsaturated ketones.192 Indium mediates a highly enantioselective Barbier-type allylation of both aromatic and aliphatic aldehydes, using a chiral ethanolamine auxiliary, readily recoverable by acid extraction.193 Barbier coupling of aldehydes can be carried out in water using tin(II) chloride, with cobalt(II) acetylacetonate as catalyst.194 In a gallium-mediated allyl transfer process, bulky gallium homoallylic alkoxides have been retro-allylated to generate (Z)- and (E)-crotylgallium reagents stereospecifically.195 Immediate reaction with aromatic aldehydes gives erythro- and threohomoallylic alcohols. Aldehydes have been allylated with allyltributyltin, using supramolecular catalysis in acidic water at 60 ◦ C.196 Using β-cyclodextrin as catalyst with all species at a 1 mmol level, high yields were obtained in a few hours. The catalyst, which can be recycled effectively, hydrogen bonds the aldehyde oxygen within the cavity. Palladium-catalysed asymmetric α-allyl alkylation of acyclic ketones has been reported: allyl enol carbonates of a wide range of ketones undergo allyl transfer in high yields and ees at room temperature.197 A regio- and enantio-selective palladium-catalysed allylic alkylation of ketones has been reported, using allyl enol carbonate chemistry in which a CO2 unit tethers the allylating agent to the nucleophile.198 Catalytic asymmetric vinylation of ketones has been achieved. Vinylzinc reagents have been generated by hydrozirconation of terminal alkynes which are then transmetallated with zinc.199 A titanium(IV) complex of a trans-cyclohexane-bis(sulfonamide) provides chiral catalysis; it also facilitates dienylation of ketones, with ees also >90% in this case. Enantioselective alkenylation and phenylation of aldehydes has been carried out using a chiral CuF complex.200 Phosphine-catalysed annulation between aldehydes (RCHO) and ethyl allenolate (H2 C=C=CHCO2 Et) gives 6-substituted 2-pyrones (52), proceeding via a zwitterionic enolate.201 The product is derived from the E-intermediate, which is favoured by the use of sterically demanding trialkylphosphines, such as tri(cyclopentyl). However, overdoing the phosphine bulk with, for example, the tri(t-butyl) derivative gives no yield.

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1 Reactions of Aldehydes and Ketones and their Derivatives R

O

O

R3

R1 X (52)

R2 Y

(53)

Quaternary stereocentres in β-keto esters have been deracemized in an enantioconvergent decarboxylative allylation process, catalysed by palladium(II).202 One catalyst is involved in both C–C bond-breaking and -making steps.

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The Horner–Wadsworth-Emmons and Related Olefinations Epimerizable aldehydes clearly undergo intermolecular Horner–Wadsworth–Emmons olefination with trimethyl phosphonoacetate, by using the weak base, lithium hexafluoroisopropoxide [LiOCH(CF3 )2 ], as catalyst.203 A Z-selective alkenylation reaction produces α-fluoro-α,β-unsaturated esters. Using the anion of an α-fluoro-α-organoselanylacetate, R1 Se–CHF–CO2 Et, to react with an aldehyde or ketone (R2 R3 C=O), it results in formation of an alcohol selenyl ether, R2 R3 C(OH)–CF(SeR1 )–CO2 Et.204 Acid treatment then eliminates a molecule of R1 SeOH to give R2 R3 C=C(F)–CO2 Et. Ketones can be olefinated with ethyl diazoacetate in the presence of triphenylphosphine, using methyltrioxorhenium as catalyst.205 Synthetically useful Lewis acid-promoted reactions of araldehydes (R2 –Ar–CHO) with styrenes have been investigated.206 Using boron halide reagents gives a variety of 1,3-diarylpropanes (53). For example, boron trihalides give the corresponding 1,3dihalo derivatives (53, X = Y = Cl, Br, I), while phenylboron dichloride gives the 3chloropropanol (53, X = Cl, Y = OH), with the anti -isomer predominating (88% de). NMR evidence suggests an oxyboronchloride intermediate [(53), X = O–B(Cl)–Ph, Y = Cl] for this reaction; presumably a similar intermediate (X = OBCl2 ) would operate in the BCl3 reaction. trans-β-Methylstyrene, in the presence of BCl3 , gave 1,3-dichloro-2-methyl product, with some diastereoselectivity. PYBOX complexes of scandium(III) triflate act as enantio- and diastereo-selective catalysts of ene reactions, including examples with trisubstituted alkenes.207 Cyclic alkenyl ethers have been prepared by intramolecular O-vinylation of β-keto esters using a pendant vinyl bromide, with copper(I) catalysis.208

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Alkynylations A short review reports high ees in the alkynylation of aromatic aldehydes, using BINAP derivatives bearing amino alcohol ligands.209 Aldehydes and ketones (R1 COR2 ) undergo an unusual tandem alkynylation and trans-hydrosilylation with alkynylsilanes (e.g. Ph–C≡C–SiHR32 ) to give oxasilacyclopentenes (54).210 A mild alkoxide initiator is required.

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Organic Reaction Mechanisms 2005 R3 R1

O Si

R3 Ph

R2 (54)

X

R2

R1

R1

X (55, X = Cl, Br)

Anhydrous iron(III) halides catalyse coupling of alkynes and aldehydes.211 Simple terminal alkynes, R1 C≡CH, react with aldehydes, R2 CHO, to give (E,Z)-1,5dihalo-1,4-dienes (55). In contrast, non-terminal arylalkynes give (E)-α,β-unsaturated ketones. The catalysts also promote standard Prins cyclization of homoallylic alcohols. Studies of intermediates and of alkyne hydration – together with calculations – all support FeX3 complex formation with alkyne as the activating step. Alkynyl nucleophiles, (R1 O)3 Si–C≡C–R2 , have been added to aldehydes, ketones, and imines, using a strong Lewis base, KOEt.212 Evidence for ethoxide attack at silicon, to give a hypervalent silicate intermediate, which then coordinates with the carbonyl (or imine), is presented. 29 Si NMR is particularly informative: when R1 = OEt, the alkyne silicon shows up at −72 ppm [similar to (EtO)4 Si at −80 ppm], but a new peak is seen very far upfield at −126 ppm, beyond a similar known silicate, (EtO)4 SiPhK at −117 ppm, and indeed close to (EtO)5 Si− , at −130 ppm. Aldehydes and ketones have been alkynylated using indium(III) and Hunig’s base (Pri2 NEt) as catalysts.213 IR and NMR evidence support a dual-activation role for indium: it is a Lewis acid for the hard electrophile (carbonyl compound), and has sufficient π -coordination ability for a soft nucleophile such as a terminal alkyne. For the latter substrate, the amine then assists proton abstraction. Dimethylzinc promotes the addition of phenylacetylene to aldehydes and ketones, to give propargyl alcohols.214 The process works at room temperature, without added ligands. The role of the carbonyl group as ‘ligand’ has been investigated: calculations suggest that acetone can coordinate, causing the linear and non-polar dimethylzinc to bend, with an associated increase in basicity of the methyl group. Using triethylaluminium and a quinine auxiliary, phenylacetylene has been added enantioselectively to unactivated acetophenones.215 An open-chain sugar has been alkynylated with 1,2-syn selectivity, using acetylides in the presence of zinc(II) chloride.216

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Michael Additions Enantioselective Michael additions of aldehydes to enones using imidazolidinones as organocatalysts show evidence of enamine intermediates.217 Several co-catalysts – mainly phenols – raise the yield and/or ee. Glycine imine esters, Ph2 C=N–CH2 –CO2 R, undergo asymmetric Michael addition to enones using an ether–water phase-transfer system.218 A chiral ammonium salt, in conjunction with cesium carbonate, gives high ees. Diphenylprolinol methyl ether catalyses the enantioselective Michael addition of simple aldehydes to simple enones.219

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Organocatalyst (56), a pyrrolidine sulfonamide derived from l-proline, catalyses the direct Michael addition of aldehydes to nitrostyrene with high ee and de, apparently exploiting its bifunctional (acid–base) nature.220

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O

N H

NHSO2CF3

R1

N NHCO2Me

N

COR3

R2 OH H

(56)

(57)

Diazenes, R1 –NHCON=N–CO2 Me, have been reacted with 1,3-dicarbonyl compounds (R2 COCH2 COR3 ) to give a convenient synthesis of highly substituted 2imidazolin-2-ones (57); the products are easily dehydrated in the presence of acid.221 Intermediate Michael adducts are isolable. An intramolecular asymmetric Michael addition of aldehydes and ketones – to give cyclopentanals – gives the otherwise disfavoured cis-products when catalysed with antibody 38C2, the first commercially available catalytic antibody.222 One case gave 99% de, 98% ee.

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Other Addition Reactions General and Theoretical CH/π hydrogen bonds in organic reactions have been reviewed, including major sections on diastereoface- and enantioface-discriminating reactions.223 The nucleophilic reactivities of silyl enol ethers (58, R1 = alkyl) and silyl ketene acetals (58, R1 = O-alkyl) have been measured for the triphenylsilyl (R2 = H5 ) substrate, and its perfluoro analogue (R2 = F5 ), using benzhydrylium cations as reference electrophiles.224 The triphenyl compound is 10 times less reactive than its trimethyl equivalent, but the perfluorination causes the C=C nucleophilicity to drop by 3–4 orders of magnitude. The new compounds have been placed on scales of nucleophilicity taken from the literature.

O

Si R2

R1

3

(58)

A computational study of hydride addition to a range of carbonyl compounds suggests that most of the negative charge resides on hydrogens, and not on the carbonyl oxygen.225 Proton affinities of a variety of simple ketones, α-diones, and α-keto esters and lactones have been calculated by a variety of methods and compared with experiment.226

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Addition of Organozincs A range of simple bis-sulfonamides (59) give mediocre ees of ca 20% in the enantioselective addition of diethylzinc to benzaldehyde at low reaction conversion, but – in a striking example of auto-induction – the catalyst evolves to give ees up to 79% at completion.227 The reactions are carried out under standard titanium(IV) isopropoxide conditions, and the mechanism of auto-induction is proposed to involve interaction of isopropoxides on the titanium with the alkoxide of the product. Replacement of isopropoxide in the titanium reagent with bulkier (but achiral) alkoxides allows the ee to be raised further. Thus in this case the enantioselectivity of the catalyst can be optimized by varying achiral ligands, considerably more convenient than having to optimize enantiopure ones. Ph

NHSO2Ar

Me

Ph

NHSO2Ar

R2N

(59)

ee

Ph SCN (60)

A study of enantioselective additions of diethylzinc to benzaldehyde, using chiral carboline and oxazolidine auxiliaries, has examined the requirements to allow the conformations of the free ligands to be related to the ees and transition states, given that several steps intervene.228 Cyclic derivatives of 1,2- and 1,3-amino alcohols have been trialled as chiral catalysts in the addition of diethylzinc to benzaldehyde.229 Enantioselective addition of diethylzinc to benzaldehyde is the subject of other reports,230,231 including the use of triazinyl-BINOLs as enantioselective catalysts of addition to araldehydes, using Ti(IV) tetraisopropoxide.232 Two optically active amino thiocyanate derivatives (60) of (−)-norephedrine act as aprotic ligands for enantioselective addition of diethylzinc to aldehydes in up to 96% ee.233 The ee drops drastically if the −SCN group is changed to −SR. Synthesis of a series of N -sulfonylated amino alcohols and their use as ligands of titanium(IV) in enantioselective addition of diethylzinc to aldehydes has been described.234 Aryl stacking effects in the transition state appear to play a role in the enantioselective addition of dimethyl zinc to benzaldehyde when an N -benzylmandelamide–Ti(IV) complex is used as catalyst.235 While β-amino alcohols have been widely studied as chiral auxiliaries, a series of (S)-amino alcohols – built into norbornane frameworks – have been examined as catalysts of enantioselective addition of dialkylzincs to benzaldehydes.236 Chiral bis-sulfonamides have been employed as catalysts of enantioselective addition of a range of organozincs to simple aryl ketones, in ees up to 99%, using Ti(IV) tetraisopropoxide methodology.237 Catalytic asymmetric addition of functionalized alkylzincs to ketones and enones has been reported.238 Functional groups include esters, silyl ethers, alkyl chlorides, and alkyl bromides, with ees >99% in some cases.

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N -Acylethylenediamine ligands, derived from Boc-protected amino acids, catalyse the enantioselective addition of vinylzinc reagents to aldehydes.239 β-Amino thiols derived from (S)-valine catalyse the enantioselective addition of alkenylzincs to aldehydes.240 Enantioselective addition of alkynylzincs to aldehydes has been described.241 Pyrrolidinylmethanols derived from (S)-proline have been employed in the zinccatalysed addition of arylboronic acids to aromatic aldehydes, giving ees up to 98%.242 An arylzinc species is generated via a boron–zinc exchange, avoiding the need for expensive diphenylzinc. BINAP-derived 1,2-amino alcohols catalyse the enantioselective phenylalkynylation and phenylation of aromatic aldehydes by zinc reagents.243 A BINOL-dicarboxamide catalyses the enantioselective phenylation of aldehydes by ethylphenylzinc.244 DFT calculations have been used to probe the mechanism of enantioselective addition of diphenylzinc to aldehydes, and in particular the enhanced selectivity which accompanies addition of diethyl zinc to the system.245 Chiral diarylmethanols have been prepared enantioselectively by phenyl transfer to benzaldehydes, using PhB(OH)2 –ZnEt2 and a new tertiary aminonaphthol auxiliary.246 A catalytic enantioselective arylation of arylaldehydes employs a chiral β-amino alcohol and a boronic acid–diethylzinc exchange reaction to generate the reactive arylzinc species.247

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Addition of Other Organometallics Potassium trifluoro(organo)borates such as ArBF3 K couple with benzaldehydes to give carbinols using the catalytic combination of Rh(H2 C=CH2 )2 Cl2 and But3 P, in toluene–water mixtures at 60 ◦ C.248 The reaction tolerates a wide range of functionality and works well for hindered benzaldehydes, and even for aliphatic aldehydes. t-Butyl-‘Amphos’ (But2 P–CH2 CH2 –NMe3 Cl) combines with RhCl3 .3H2 O to give a recyclable catalyst for cross-coupling aldehydes with aryl- and vinyl-boronic acids in aqueous solution.249 Aldehydes, R1 CHO, have been alkylated to give secondary alcohols, R1 CH(OH)R2 , using boranes, R23 B, and a nickel(II) catalyst.250 Formation of secondary alcohols, RCH(OH)Ar, from aldehydes and arylboronic acids, ArB(OH)2 , is catalysed by a range of palladium(0) complexes, but chloroform is required.251 Palladium–chloroform complexes are equally effective, and evidence for (Ph3 P)2 Pd being converted to palladium(II) intermediates, (Ph3 P)2 Pd(X)–CHCl2 , is presented (X = Cl, then OH). An enantioselective addition of trialkylaluminium to aldehydes uses chiral αhydroxy acids as ligands.252 Molecular dynamics simulations have been used to predict solvent and temperature effects in the nucleophilic addition of α-chiral carbonyl compounds.253 Prediction of diastereoselectivity ‘break’ temperatures (i.e. inversion points) has been achieved with fair accuracy by comparison with experimental data on n-BuLi addition. Dramatic differences are seen for additions to 2-phenylpropanol in pentane solvent, compared with octane.

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3-Substituted 3,4-dihydroisocoumarins (61) have been prepared enantioselectively by two diastereoselective processes: addition of aldehydes (RCHO) to laterally lithiated chiral 2-(O-tolyl)oxazolines, followed by lactonization.254

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O O ∗

R (61)

Br

O

(62)

sp 2 - and sp-hybridized organolithiums have been added to a bridgehead bromo ketone (62).255 The diastereofacial selectivity of the addition of lithioacetonitrile to 2-phenylpropanol has been studied over a wide range of temperatures, solvents, and bases.256 Eyring plots [ln(dr) vs 1/T ], activation parameters, and inversion temperatures have been characterized. In some cases, the differential entropy of activation, S = , plays an exclusive role in determining anti -selectivity.

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Grignard-type Reactions Efficient alkylation of ketones to give tertiary alcohols has been achieved using magnesium ‘ate’ complexes such as R3 MgLi or RMe2 MgLi, the latter being an ‘R’-selective reagent.257 These alkylating species can be prepared from RLi and either RMgX or R2 Mg. The R group is much more nucleophilic than that of either RLi or RMgX, and R3 MgLi is less basic. A range of substrates show higher yields and fewer by-product problems compared with Grignards. The alkyl selectivity can be dramatic: benzophenone yields >99% ethanol product on treatment with EtMe2 MgLi. The same substrate with EtMgBr gives only a 14% yield, with 68% Ph2 CHOH by-product. Organogallium reagents, R3 Ga, have been added enantioselectively to aldehydes, using TiCl4 as a Lewis acid catalyst, with a chiral salan ligand.258

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The Wittig Reaction Quantum mechanical calculations in the gas phase and DMSO solution at different temperatures can highlight the hazards of standard 0 K gas-phase calculations.259 For the Wittig reaction, a small barrier in the potential energy curve is transformed into a significant entropic barrier in the free energy profile, and the formally neutral oxaphosphetane intermediate is displaced in favour of the zwitterionic betaine in the presence of DMSO. Stabilized ylides react with aldehydes in water to give Wittig products, sometimes with remarkable acceleration.260 For example, pentafluorobenzaldehyde reacts with ester-stabilized ylide, Ph3 P=CHCO2 Me, at 20 ◦ C in 5 min in 86% yield, with 99:1 E:Z-selectivity. Water’s ability to stabilize the polar transition state of the reaction, and its participation in the reaction (as determined by deuterium exchange), are discussed.

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gem-Difluoroalkenes (63) have been prepared from aldehydes and ketones, using Wittig-type reactions.261 Difluoromethylene phosphorus ylides are prepared using Hg(CF3 )2 and NaI, together with a trialkyl-or triaryl-phosphine: reaction typically takes 2 h at 70 ◦ C. Unexpectedly, tetrafluorocyclopropanes (64) were also formed, through in situ addition of difluorocarbene. In most cases, the use of Bn3 P gives (63) almost exclusively, whereas Ph3 P favours (64), as does higher temperature. F

O R1

F

F +

R2

R

1

R

F

F

2

R1 R2

(63)

(64)

Hydrocyanation and Cyanosilylation Mono- or di-lithium salts of (R)-BINOL give high yields and good ees in cyanations of aromatic aldehydes.262 Formation of an aqua (or alcohol) complex of the catalyst gives higher and reversed ee, and non-linear effects in some cases. Asymmetric cyanohydrin synthesis from aldehydes using trimethylsilyl cyanide (TMSCN) has been carried out using a chiral Al(salen) complex–triphenylphosphine Lewis acid–base combination.263 An enantiopure cyanohydrin of 2-p-tolylsulfinylbenzaldehyde has been prepared using various metallic cyanating agents in the presence of Yb(III) or Y(III) triflate.264 Sulfoxide coordination with the metal is implicated, supported by DFT calculations. Aldehydes, RCHO, have been cyanoethoxycarbonylated with ethyl cyanoformate, to give cyanohydrin-related products, RCH*(CN)OCO2 Et, using a heterobimetallic chiral catalyst to achieve high ees.265 Kinetic studies have probed the roles of achiral additives in raising the yield and ee. Lithium chloride is a convenient catalyst for cyanosilylation of a range of ketones and aldehydes by trialkylsilyl cyanide, under solvent-free conditions: the silylated cyanohydrin product can be directly distilled out.266 As little as a microequivalent of catalyst proved effective. Evidence for nucleophilic chloride, generating a pentavalent silicon (65) as reactive species, is presented. Cl R Si NC (65)

P

−

R R

Li

+

RN

NR

NR

N (66)

Strong base (66, R = Me, pKa of conjugate acid = 32.9) catalyses the cyanosilylation of aldehydes and ketones, using TMSCN in THF at 0 ◦ C.267 Even better results are obtained with isopropyl as R group, but the isobutyl case is a much poorer catalyst, indicating a very fine balance between basicity and steric bulk in the action of these catalysts.

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A simple ionic liquid, octylmethylimidazolium (with PF6 − counterion), promotes TMSCN addition to aldehydes in yields up to quantitative, in 1 day at room temperature. Environmentally friendly and recyclable, the solvent requires no Lewis acid or other activation.268 The long-chain substituent and the nature of the counterion are important contributors to the high yield. Deprotection to give the product as cyanohydrin just requires an HCl–THF workup. A BINOL–salen ligand catalyses the enantioselective addition of TMSCN to aldehydes at room temperature, in the presence of titanium(IV) isopropoxide.269 The source of enantioselection in the trimethylsilylcyanation of benzaldehyde using chiral Schiff base–titanium(IV) complexes has been investigated by computation.270 Cyanosilylation of methyl ketones has been carried out using diphenylmethylphosphine oxide and trimethylsilyl cyanide, generating a phosphorus isonitrile-type species, Ph2 MeP(OTMS)(N=C:), as the reactive intermediate.271 A chiral oxazaborolidinium ion catalyst renders the reaction enantioselective. trans-Diaminocyclohexane-derived catalysts bearing a thiourea group are efficient enantioselective catalysts for the cyanosilylation of ketones.272 A cooperative mechanism involving nucleophilic and electrophilic activation from the amino and thiourea components is proposed. A simple amino acid salt, sodium l-phenylglycinate, catalyses the enantioselective cyanosilylation of ketones.273 Despite acetonitrile’s feeble acidity (pKa ca 29) compared with enolizable aldehydes (67, pKa s 16–17), the combination of a simple ruthenium complex, [RuCp(PPh3 )2 ]+ , and diazabicycloundecane (DBU) brings about a nitrile-selective deprotonation to give β-hydroxynitriles (68).274 A mechanism is proposed in which DBU, aldehyde, and acetonitrile can displace triphenylphosphines, with the metal centre activating acetonitrile to convert it to an NC–CH2 − ligand (proposed intermediate, 69). A nickel–diarylamidodiphosphine complex (70) also catalyses this transformation in the presence of DBU.275 O Me

R

H

H H +

(67) MeCN

Ph3P

Ru

N PPh3

(69)

P −

CH2

N Ni OTf P

OH R

CN

H H (68)

For other cyanations, see Other Reactions of Imines above.

(Pri)2

Me (70)

(Pri)2

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Hydrosilylation and Hydrophosphonylation Recent advances in the asymmetric hydrosilylation of ketones and imines have been reviewed.276 Hydrosilylation of ketones, and also of α- and β-keto esters and amides, has been achieved using polymethylhydrosiloxane in methanol, with various zinc(II) catalysts.277 The reactions are faster than in aprotic solvents, and show some enantioselectivity with chiral diaminozincs. A salalen ligand (a hybrid salicylideneimine–salicylamine) has been coordinated to aluminium to serve as an enantioselective catalyst for aldehyde hydrophosphonylation of aldehydes.278

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Miscellaneous Additions Catalytic enantioselective α-aminations and α-oxygenations of carbonyl compounds have been reviewed.279 The formaldehyde–sulfite reaction displays non-linear dynamics: it is a ‘clock’ reaction with a sudden pH excursion (from ca 7 up to 11).280 The induction period in batch processes is explained by the internal buffer systems, HSO3 − –SO3 − . However, flow reactors also exhibit pH oscillations and bistability. A 2H -2-oxo-1,4,2-oxazaphosphinane (71, X = H) can be added diastereoselectively to alkyl- or aryl-aldehydes or the corresponding aldimines to give alcohol [X = CH*(OH)R1 ] or amine [X = CH*(NHR2 )R1 ] products in high yield.281 Nucleophilic and electrophilic activation strategies have been investigated to maximize the de. Ph Ph

O N H (71)

O P

X Ph

Ar Ln

−Rh

Ar −

C CO2Me +

H

O

R

(72a)

H

C CO2Me O

+

R

(72b)

The Boyer reaction – a relative of the Schmidt process – involves 2-oxazoline formation from a 2-azidoethanol and an aldehyde (RCHO).282 Using a 2-aryl-2azidoethanol, a 2-oxazoline product and its 3-isomer are obtained using BF3 catalysis. However, on using copper(II) triflate, an acetal, RCH[OCH2 CH(Ph)N3 ]2 , resulted. A three-component reaction of aryl diazoacetates, alcohols, and araldehydes (or araldimines) has been investigated, using a rhodium(II) catalyst.283 The first two components combine in the presence of catalyst to produce a zwitterion (72a). Evidence for equilibration with an alcoholic oxonium ylide intermediate (72b) is presented. It is proposed that this species is trapped by electron-deficient araldehyde (or imine) to give new C–C bond formation. α-Silyloxy ketones have been generated regiochemically in a new cross silyl benzoin reaction catalysed by cyanide.284 Use of La(CN)3 allows extension of the reaction to alkyl and α,β-unsaturated substrates. The mechanism – and in particular the reversibility of key steps – has been investigated.

ee

de

32


Enolization and Related Reactions The effects of cationic and zwitterionic micelles on the keto–enol tautomerism of 2-phenylacetyl-furan and -thiophene (73, X = O, S) have been studied in aqueous media.285 While the micelles perturb the equilibrium only slightly, the apparent acidity of one or other tautomer is increased, as the micelles have an affinity for the enolate. The systems also show lowered ‘water’ rates at the minima of their pH–rate profiles, allowing an otherwise undetectable metal ion catalysis to be observed. O

LiO X

(73)

Li

O −

R

R

−

(74)

Solvent and concentration effects on keto–enol tautomerization have been investigated in DMSO–water mixtures and aqueous micellar solutions, for 2-acetylcyclohexanone and 2-acetyl-1-tetralone.286 Dramatic rate increases aboves 60% DMSO content have been explained in terms of solvent structure: solvent polarity alone cannot rationalize the effect. Using a transition state model for enolate formation and a database search, a thiourea with a pendant amine has been designed as a catalyst, and its ability to hydrogen bond the enolate of acetone explored.287 Both in-plane and out-of-plane hydrogen bonds, to a lone a pair and the carbonyl π -bond, respectively, were considered. Charge density analysis has been carried out for three reaction paths involving intramolecular hydrogen transfer: the keto–enol tautomerism of acetaldehyde, the pinacol rearrangement of protonated ethane-1,2-diol, and the unimolecular decomposition of methanediol, reactions involving H-transfer between C · · · O, C · · · C, and O · · · O atoms.288 A computational study of intramolecular proton transfer in acetylacetone has been carried out.289 A short review describes recent developments in the transfer of chirality within enolate alkylation reactions.290 Ketone dilithio α,β-dianion species (74) have been generated by the tin–lithium exchange reaction of the lithium enolate of β-tributyltin-substituted ketones.291 Reaction with carbon electrophiles gives substituted ketones. A range of asymmetric alkyl additions to ketones have been carried out using highly concentrated or solvent-free conditions to produce ‘greener’ conversion.292 The loading of catalyst – a bis-sulfonamide – can be significantly decreased under these conditions. Recent advances in catalytic asymmetric electrophilic α-halogenation of carbonyl compounds are described in two reviews.293,294 . Direct enantioselective catalytic α-fluorination of aldehydes has been carried out using N -fluorobenzenesulfonimide [F–N–(O2 SPh)2 ] and a chiral secondary amine (an imidazolidinone) to provide enamine organocatalysis.295

ee ee

ee

ee ee

33


Direct asymmetric α-fluorination of both branched and linear aldehydes has been carried out with a series of pyrrolidine-related catalysts.296 Chiral α-fluoro ketones (e.g. 75) bearing a gem-allyl function have been prepared by catalytic enantioselective decarboxylation of the racemic allyl ester (76), using a range of palladium(II) catalysts.297 O

O

ee

ee

O O

F

Ph

F (75)

(76)

Ph

N H (77)

Protected sulfenylation reagents (Lg–S–Pg) α-sulfenylate aldehydes, using sterically encumbered chiral pyrrolidines as enantioselective organocatalysts.298 2,5-Diphenylpyrrolidine (77) catalyses the enantioselective α-chlorination of aldehydes.299 Mechanistic and computational studies suggest that – in contrast to previously proposed mechanisms involving direct formation of the carbon-electrophile bond – N -chlorination occurs first, followed by a 1,3-sigmatropic shift of chlorine to the enamine carbon. The product iminium ion is then hydrolysed in the ratedetermining step. α-Ketol and related isomerizations – the isomerization of α-hydroxy ketones, aldehydes, and imines – have been reviewed up to 2002.300

ee

ee

Oxidation and Reduction of Carbonyl Compounds Regio-, Enantio-, and Diastereo-selective Reduction Reactions The reagent l-TarB-NO2 (78), prepared from tartaric and m-nitrophenylboronic acids, asymmetrically reduces ketones in the presence of sodium borohydride.301 Evidence for a monoacyloxyborohydride intermediate (79) is presented. O O

CO2H

B O O2N (78)

CO2H

O

NaBH4

B O O2N

−

O

BH3

ee

Na+ + H2O

CO2H

(79)

(−)-Menthol catalyses the enantioselective reduction of ketones by NaBH4 in diglyme: proton- and auto-catalytic possibilities are investigated, and trialkyl borate species generated during the reaction may also play a role in catalysis.302 The diastereoselectivities of the reduction of tricyclo[5.2.1.02,6 ]decan-10-one (80) and its 3,4-ene and 3-one derivatives have been measured, using NaBH4 in methanol

ee

de

34

Organic Reaction Mechanisms 2005 O 10

O

N

H

P Ph 3

4

(80)

N Ph (81)

as hydride reducing agent.303 The results are explained in terms of antiperiplanar and ∗ interactions, rather than hyperconjugative effects. Calculations have vicinal σ → πC=O been employed to examine the effect of sodium complexation: the conformations of the complexes are argued as being possibly more important than those of the ground-state free ketones. While chiral catalysts containing N–P=O moieties have been increasingly studied in borane-mediated asymmetric reduction of ketones, a study of a range of such species (e.g. 81) indicates that the configuration at phosphorus plays little or no role in determining enantioselectivity, and indeed the stereochemistry at the phosphorus centre may be scrambled under the reaction conditions.304 BH3 .Me2 S reduction of aryl alkyl ketones can be carried out with ees up to 98% using 3 mol% of a chiral oxazaborolidine derived from (−)-β-pinene.305 Transfer hydrogenation of aromatic ketones has been carried out in high yield and ee using propan-2-ol and a catalyst generated in situ from an iridium(I) [or rhodium(I)] hydride and a trans-1,2-diaminocyclohexane ligand.306 A hindered BINAP–phosphoric acid catalyst allows the enantioselective reduction of ketimines via transfer hydrogenation.307 Imines can be generated in situ from either aliphatic or aromatic ketones, with low catalyst loading. Substrate substituent effects on activity and enantioselectivity have been investigated in the enzymatic reduction of aryl ketones, using 24 recombinant ketoreductases.308 A recoverable fluorous prolinol catalyst has been developed for enantioselective reduction of ketones.309 A ruthenium centre, tethered to a 1-amino-2-sulfonamide auxiliary, catalyses transfer hydrogenation of ketones in high yield and ee.310

Other Reduction Reactions Catalytic reductive coupling of epoxides (82, R1 = alkyl) with aldehydes (83) yields β-hydroxy ethers (84), in a C–O bond-forming process involving yields up to 90%.311 The reaction is catalysed by (Ph3 P)3 RuCl, a species which cannot reduce the aldehyde O R1 (82)

+

OH R2 CHO (83)

R1

O (84)

R2

ee

ee

ee ee

ee

ee ee


35

in the absence of epoxides. Based on this and other evidence, ring opening precedes carbonyl reduction, a finding which opens up possibilities where the aldehyde could be replaced by other functional groups. DFT has been used to explore the mechanism of reductive etherification of aromatic aldehydes by alcohols, using BH3 as catalyst and reductant.312 The reaction is suggested to proceed by addition (rate controlling), followed by reduction, and is expected to be feasible in polar solvents such as acetonitrile. Stabilized nucleophiles have been added to allylic alcohols using ‘catalytic electronic activation’, in which a reaction has been designed where an alcohol is temporarily oxidized to a carbonyl compound.313 Aldehydes have been catalytically hydrogenated to alcohol products in a range of supercritical solvents under otherwise mild conditions.314 The redox chemistry of quinones has been reviewed in the context of hydrogen bonding, protonation, and supramolecular effects that can modify their reactivity.315 Ketonic decarboxylation, in which two molecules of acid are thermally converted to a symmetrical ketone plus carbon dioxide and water, has been reviewed.316 Radical, βketo acid, and concerted mechanisms are considered, with the reviewer favouring the last, albeit not conclusively. It is suggested that development of bifunctional catalysts may be the best way to improve the energetics of the process, and hence its synthetic utility and ‘green’ credentials. The reagent combination TiCl(Oi Pr)3 –NaBH(OAc)3 performs reductive amination of aldehydes by electron-deficient and heteroaromatic primary amines, to give secondary amine.317

Oxidation Reactions The relative rates and stereochemistry of epoxidation reactions of 5-substitutedadamantan-2-ones with two sulfur ylids (methylenedimethylsulfurane and its oxysulfurane analogue) have been studied in DMSO and in benzene.318 Oxidation of aliphatic aldehydes by quinolinium dichromate in aqueous acetic acid shows first-order kinetics in substrate and oxidant, and second-order with respect to H+ .319 Hydrated aldehyde and protonated oxidant are suggested to be the reactive species, with Zucker–Hammett plots supporting proton abstraction by water in the slow step. Oxidation of ketones by ceric perchlorate is catalysed by iridium(III) chloride, particularly in acidic media.320 Oxidation of long-chain aliphatic aldehydes by quinolinium dichromate has been studied in aqueous acetic acid–sulfuric acid mixtures.321 The kinetics of the oxidation of cyclic ketones by Caro’s acid (peroxomonosulfuric acid, H2 SO5 ) are first order in both, and the pH–rate profile has been analysed in terms of contributions from HSO5 − and SO5 2− .322 Similar results are found for aromatic aldehydes.323 Decomposition of Caro’s acid is catalysed by acetone.324 A kinetic study in aqueous alkaline medium indicates simple second-order kinetics. Nucleophilic addition of SO5 2− to the carbonyl carbon leads to oxirane by reaction with another SO5 2− to give

36


oxygen, sulfate, and regenerated ketone. Substituent effects are also described from results with other ketones. Ketones, R–CH2 COCH2 –R, undergo Z-selective oxidation to give useful acrylates (85), using KOH and molecular iodine in methanol.325 Evidence for the formation of an α,α -diiodoketone intermediate is presented, followed by a Favorskii-type rearrangement. H

R

R

CO2Me

de

(85)

A mild oxidative one-carbon homologation of aldehyde to amide has been reported.326 Ketones and aldehydes have been economically α-hydroxylated (to give α-hydroxyacetals), using iodine in basic methanol.327 Enolate formation and iodination to give α-iodocarbonyl is then followed by transformation into the hydroxyacetal, a dimethyl acetal under the MeO− /MeOH conditions employed. The tetraphenylmethane skeleton has been used to develop a series of hypervalent iodine(III) reagents, C–(C6 H4 -p-R)4 .328 Starting from the tetraiodide (R = I), a diacetate, a bis(trifluoroacetate), and a hydroxytosylate have all been prepared [i.e. R = I(OAc)2 , I(O2 C–CF3 )2 , and I(OH)OTs, respectively]. In addition to being useful for general oxidations (alcohol to ketone, hydroquinone to quinone, etc.), the recyclable reagents catalyse α-tosyloxylation of methyl alkyl ketones on the more hindered side, an ostensibly unexpected result for such a bulky reagent. The kinetics of the oxidation of d-galactose and d-xylose by an alkaline solution of sodium metaperiodate has been studied, using ruthenate ion (RuO4 2− ) as a catalyst.329 β,δ-Unsaturated alcohols undergo an oxidative esterification with aliphatic aldehydes in the presence of an iridium(I) catalyst and potassium carbonate.330 Precoordination of the ene-alkoxide with iridium is proposed, followed by reaction with aldehyde. Although the ‘ester yield’ is high, a mixture of unsaturated and saturated esters is typically obtained, except for secondary alcohols. Two new tetraphenylporphyrin (TPP) catalysts have been reviewed.331 Cr(TPP)III triflate is highly regio- and stereo-selective in rearranging epoxides into aldehydes, while the iron perchlorate analogue affords the corresponding ketones.

Other Reactions The use of carbohydrate-derived phosphorus ligands in asymmetric synthesis has been reviewed,332 as has the potential for substrate-induced asymmetric catalysis.333 In atmospheric chemistry, kinetic isotope effects have been measured for the reaction of hydroxyl radicals with acetone using the relative-rate method over a range of temperatures.334 Water vapour had relatively little effect on rates. Product studies have allowed partitioning of the reaction flux into routes that produce acetic acid directly, and secondary processes.

ee

37


In a totally selective ring opening of amino epoxides with ketones, enantiopure (2R,3S)- and (2S,3S)-3-aminoalkane-1,2-diols have been prepared in high yield, total diastereoselectivity, and without epimerization, using BF3 .Et2 O catalysis.335 NMR experiments using 2 H- and 13 C-labelled substrates indicate that acetone and dimethyloxirane are not in equilibrium.336 Thioketones such as 4,4 -dimethoxythiobenzophenone react with enantiopure (R)2-vinyloxirane to give virtually enantiopure (S)-4-vinyl-1,3-oxathiolanes (86) in high yield, using mild Lewis acid conditions (SiO2 , DCM, 0 ◦ C).337 More hindered thioketones require a stronger Lewis acid (BF3 , −78 ◦ C). The clear inversion at the oxirane C(2) indicates an efficient SN 2 mechanism.

Ar

R1

OH

Ar

R1 (88)

ee

R2 OTf

(89)

R2

R1

O (86)

de

R1

O

TMS

O

de

(87)

O

Efficient ortho-difunctionalization of aromatics (87) can be achieved by insertion of arynes into the C–C σ -bonds of β-dicarbonyls (88), using a simple aryne source (89) under mild conditions.338 The β-dicarbonyl reactant can be a dione (aromatic or aliphatic), or a diester (including dilactones). A mechanism involving the formation of a benzocyclobutane is proposed. The mechanisms of asymmetric synthesis of aziridines from guanidinium ylides and arylaldehydes have been probed by varying para-substituents in the aldehyde.339 Hammett plots show a mechanistic switchover going from electron-donating to electronwithdrawing groups. In a highly selective fluoroform-type reaction, 4-hydroxy-3,3-difluoromethyl trifluoromethyl ketones [R1 R2 C(OH)–CF2 –CO–CF3 ] undergo base-promoted cleavage to give 3-hydroxy-2,2-difluoro acids [R1 R2 C(OH)–CF2 –CO2 H] and fluoroform.340 The alternative products of cleavage on the other side of the carbonyl are not observed. DFT calculations are used to rationalize this preferential cleavage of a C(=O)–CF3 over a C(=O)–CF2 R bond in both the gas phase and solution. Samarium(II) iodide has been developed as a sub-stoichiometric promoter of Reformatsky-type additions of various α-halo substrates to aldehydes, giving several advantages over Co(0)–phosphine methods.341 An examination of the reactivity of carbonyl compounds with a Mitsunobu reagent, to produce a range of products, indicates that the steric and electronic properties of the carbonyl starter can give a high degree of control over product selection.342 Particularly useful are conjugated ketones, which give 1,3-dienes containing nitrogen substituents. The classical Biginelli synthesis of heterocycles from β-diketones, urea, and aldehydes has been extended by the replacement of the dione with a cycloalkanone.343 The

de ee

38


one-pot reactions have also been carried out using thioureas, but these gave different products. 4-Pyridylpropargylic alcohols (90) are converted into (E)-propenones, with some propynone product, using pyridinium chloride in methanol at room temperature.344 Study of the progress of the reaction, and deuterium exchange results, point towards an allenol intermediate.

HO

H

R

de

NEt2 N

MgBr

R N (90)

(91)

Magnesium enamides with a tethered nitrogen coordination site (91) undergo alkylation with alkyl chlorides or fluorides to give the corresponding α-substituted ketone, with some diastereoselectivity, and tolerance of silyl groups elsewhere in the substrate.345

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277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325

1 Reactions of Aldehydes and Ketones and their Derivatives 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345

45

Bonne, D., Dekhane, M., and Zhu, J., J. Am. Chem. Soc., 127, 6926 (2005). Zacuto, M. J. and Cai, D., Tetrahedron Lett., 46, 447 (2005). Dohi, T., Maruyama, A., Yoshimura, M., Morimoto, K., Tohma, H., Shiro, M., and Kita, Y., Chem. Commun. (Cambridge), 2005, 2205. Singh, A. K., Chaurasia, N., Rahmani, S., Srivastava, J., and Singh, A. K., J. Chem. Res. (S), 2005, 304. Kiyooka, S., Ueno, M., and Ishii, E., Tetrahedron Lett., 46, 4639 (2005). Schilling, G., Chem. Abs., 142, 134015 (2005). Castillón, S., Claver, C., and D´ıaz, Y., Chem. Soc. Rev., 34, 702 (2005). Kalck, P. and Urrutigoity, M., Chem. Abs., 142, 74078 (2005). Raff, J. D., Stevens, P. S., and Hites, R. A., J. Phys. Chem. A, 109, 4728 (2005). Concellón, J. M., Suárez, J. R., Garc´ıa-Granda, S., and D´ıaz, M. R., Org. Lett., 7, 247 (2005). Zeller, K.-P., Kowallik, M., and Schuler, P., Eur. J. Org. Chem., 2005, 5151. Fedorov, A., Fu, C., Linden, A., and Heimgartner, H., Eur. J. Org. Chem., 2005, 1613. Yoshida, H., Watanabe, M., Ohshita, J., and Kunai, A., Chem. Commun. (Cambridge), 2005, 3292. Haga, T. and Ishikawa, T., Tetrahedron, 61, 2857 (2005). ´ Bosch, M. P., and Guerrero, A., J. Am. Chem. Soc., 127, 2620 Olivella, S., Solé, A., Jiménez, O., (2005). Orsini, F. and Lucci, E. M., Tetrahedron Lett., 46, 1909 (2005). Otte, R. D., Sakata, T., Guzei, I. A., and Lee, D., Org. Lett., 7, 495 (2005). Zhu, Y., Huang, S., and Pan, Y., Eur. J. Org. Chem., 2005, 2354. Erenler, R. and Biellmann, J.-F., Tetrahedron Lett., 46, 5683 (2005). Hatekeyama, T., Ito, S., Nakamura, M., and Nakamura, E., J. Am. Chem. Soc., 127, 14192 (2005).

CHAPTER 2

Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives

C. T. Bedford Department of Chemistry, University College London INTERMOLECULAR CATALYSIS AND REACTIONS . . . Carboxylic Acids and their Derivatives . . . . . . . . . . . . . (a) Acids . . . . . . . . . . . . . . . . . . . . . . . . . . (b) Esters . . . . . . . . . . . . . . . . . . . . . . . . . . (i) Transesterification . . . . . . . . . . . . . . . . (ii) Solvolysis reactions . . . . . . . . . . . . . . (iii) Aminolysis reactions . . . . . . . . . . . . . . (c) Acyl Halides and Acid Anhydrides . . . . . . . . . . (d) Amides . . . . . . . . . . . . . . . . . . . . . . . . . (e) Imides and Imidates . . . . . . . . . . . . . . . . . . (f) Carbonates, Carbamates, Ureas, and Hydroxamic Acids (g) Other Heterocyclic Nitrogen Centres . . . . . . . . . (h) Thioesters and Thiocarbonates . . . . . . . . . . . . . (i) Thiocarbamates . . . . . . . . . . . . . . . . . . . . . Phosphoric Acids and their Derivatives . . . . . . . . . . . . (a) Phosphates and Phosphonates . . . . . . . . . . . . . Sulfonic Acids and their Derivatives . . . . . . . . . . . . . . (a) Sulfonates and Sulfonyl Halides . . . . . . . . . . . . (b) Sultams . . . . . . . . . . . . . . . . . . . . . . . . . ASSOCIATION-PREFACED CATALYSIS . . . . . . . . . . . BIOLOGICALLY SIGNIFICANT REACTIONS . . . . . . . Enzymic Catalysis . . . . . . . . . . . . . . . . . . . . . . . . (a) Peptidases . . . . . . . . . . . . . . . . . . . . . . . (b) β-Lactamases . . . . . . . . . . . . . . . . . . . . . . Intermolecular, Biomimetic, and Model Reactions . . . . . . . (a) Carboxylic Acids and their Derivatives . . . . . . . . (i) Esters . . . . . . . . . . . . . . . . . . . . . . (ii) Amides and polypeptides . . . . . . . . . . . . (iii) β-Lactams . . . . . . . . . . . . . . . . . . . (b) Phosphoric Acids and their Derivatives . . . . . . . . (i) Phosphate and phosphonate monoesters . . . . (ii) Phosphate diesters . . . . . . . . . . . . . . . (iii) Phosphate and phosphonate triesters . . . . . . (iv) Phosphoryl and phosphonyl halides . . . . . . (v) Thiophosphates . . . . . . . . . . . . . . . . .

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47

48 48 48 50 50 50 53 54 56 56 57 60 63 64 64 64 65 65 66 66 68 68 68 68 69 69 69 72 73 74 74 75 77 78 79

48


(c) Sulfonic Acids and their Derivatives (i) Sulfates . . . . . . . . . . . (ii) Sulfonamides . . . . . . . . References . . . . . . . . . . . . . . . . . . .

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. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

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80 80 80 81

. . . .

INTERMOLECULAR CATALYSIS AND REACTIONS

Carboxylic Acids and their Derivatives (a) Acids Esterification of carboxylic acids with alcohols, including bulky secondary ones, by equimolar di-2-thienyl carbonate (2-DTC) in the presence of a catalytic amount of 4(dimethylamino)pyridine in toluene solvent at room temperature followed by addition of a catalytic amount of hafnium(IV) trifluoromethanesulfonate, Hf(OTf)4 , afforded the corresponding esters in good to high yields. In step 1 (Scheme 1), interaction of the acid and 2-DTC (1) produces the thienyl ester (2) with evolution of CO2 and formation of 2(5H)-thiophenone (3). In step 2, the added Hf(OTf)4 forms with (2) an activated complex (4), alcoholysis of which yields the ester (5) and a further molecule of 2(5H)thiophenone.1 The procedure was also effective for converting ω-hydroxyacids into 10- or 12-membered lactones.2 The rate constants for the reaction of different cycloalkenylcarboxylic acids, cycloalkenylacetic acids, and phenylacetic acid with diazodiphenylmethane were determined Step 1: O R OH (1.0 equiv.) +

O DMAP (0.02 equiv.)

O

R

O

+ CO2

S

+

O

O

S (3)

(2) S

O

S

(1) Step 2:

(OTf)4 (2)

O

Hf (OTf)4

R

Hf

S

O R′OH

R

O

O (5)

(4) Scheme 1

R′ +

O

S

2 Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives

49

in 10 alcohols3 and in 12 aprotic solvents at 30 ◦ C.4 In order to explain the kinetic results through solvent effects, the second-order rate constant of the examined acids was correlated using the Kamlet–Taft solvatochromic equation. Tetrakis(pyridin-2-yloxy)silane, Si(OPy)4 (6), is a very mild dehydrating agent that can be employed to form amides from acids and amines at 20 ◦ C in THF (Scheme 2), without the need to use any basic promoter such as tertiary amines or 4-(dimethylamino)pyridine. The proposed mechanism (Scheme 3) implicates an intermediate (A) formed from Si(OPy)4 and the acid (7) which reacts with the amine (8) to give the amide (9), with 2-pyridone and silica, (SiO2 )n , as by products.5

Si

N

O

4

[Si(OPy)4] (6)

O R1

+

HNR

2R3

OH

(1.2 equiv.)

Si(OPy)4 (0.6 equiv.) THF, r.t., 24 h

O R1

NR2R3

(1.0 equiv.)

Scheme 2 O R1

O OH

(7) + HNR2R3 (8)

R1 O

Si(OPy)4 –2-PyOH

R1

X O A

Si

X X

X = OPy, OSi, OCOR1, NR2R3

(8)

NR2R3 (9) + (SiO2)n + 2-PyOH

Scheme 3

Since the addition of dimethylpyrazole to an isocyanate is reversible by heating at 60 ◦ C, the product (10) is known as a ‘blocked isocyanate’. Now, it has been shown that magnesium triflate, Mg(OTf)2 , is highly active as a catalyst in the reaction at 60 ◦ C between an acid and a ‘blocked isocyanate’ to give an amide. Thus blocked hexyl isocyanate (10) and heptanoic acid (11) when heated in equimolar quantities in CHCl3 at reflux for 1 h in the presence of 1 mol% Mg(OTf)2 gave a quantitative yield of N -heptyloctamide (12) with evolution of CO2 .6

50

Organic Reaction Mechanisms 2005 O N H

O N

+

HO

N

(10)

(11)

HN

O

N

−CO2 [Mg]

N H (12)

(b) Esters (i) Transesterification Oxotitanium acetylacetonate, TiO(acac)2 , was found to be a very efficient catalyst for the transesterification of methyl (and ethyl) esters. The mechanism probably involves initial formation from reactant, ROH, of TiO(OR)2 (acac)2 , which upon complexation with the methyl ester, R CO2 Me, progresses from (13) to a tetrahedral intermediate containing a TiO bond (14), which rearranges to yield the product, R CO2 R, and TiO(OR)OMe)(acac)2 (Scheme 4).7 OR

O

Ti

O O R′

O O OR O

O O

OR Ti

O O

R′CO2R

O R′

(13)

O OR (14)

Scheme 4

(ii) Solvolysis reactions The results of a multiple isotope effect study of the acid-catalysed hydrolysis of HCO2 Me (Scheme 5) have provided a detailed picture of the transition-state structure for the reaction, which involves one hydronium ion and two water molecules (15).8 DFT calculations on the water-assisted neutral hydrolysis of MeCO2 Et indicated that a stepwise process involving four molecules of H2 O is energetically favoured.9 In an ab initio study of the substituent effects on the relative stability of the E and Z conformers of 4-X-substituted phenyl acetates (16; R = Me) and trifluoroacetates (16; R = CF3 ) (Scheme 6), it was shown that increasing electron-withdrawing ability


51

18k = 0.9945

O

Dk = 0.81

18k = 1.0009

O

H+

H C OMe

H C OH

13k = 1.028

+ H2O

+ MeOH

18k = 0.995

Scheme 5 δ+

O R

OH2

H

Me

C O H

H O

H O H δ+

(15) O R

R O

O

O

X E

X (16)

Z

Scheme 6

of X increases the preference for the Z conformer; the results were discussed in terms of molecular orbital interactions.10 Theoretical studies on 12 4-substituted phenyl acetates concluded that, in contrast to the proposed interpretation based on 13 C NMR chemical shifts and ground-state destabilization calculations, the electrophilicity of the C=O group increases due to the effect promoted by the electron-withdrawing groups in these systems.11 A DFT investigation of the alkaline hydrolysis of 4-nitrophenyl acetate has shown that a model including seven water molecules proceeds via a concerted transition state.12 Kinetic studies of the reaction at pH 7.7 of 4-nitrophenyl acetate with three hydroxamates, RCONHO− (R = Me, Ph, 2-HOC6 H4 ) in various water–solvent (DMSO, DMF, MeCN, and 1,4-dioxane) mixtures have shown that these α-effect nucleophiles react faster with increasing percentages of DMF and DMSO, but not with MeCN and 1,4dioxane. The likely explanation is desolvation of the hydroxamate ions by the highly polar solvents, DMF and DMSO.13

52


The kinetics of the neutral hydrolysis of 4-methoxyphenyl 2,2-dichloroacetate in aqueous solution have been studied in the presence of varying amounts of MeCN, THF and polyethylene glycol (PEG 400) in order to assess the role of solvent activity and solute–solute interactions.14 Generally, the rate of alkaline hydrolysis of a series of substituted phenyl benzoates was decreased in the presence of 0.5 m Bu4 NBr, the retardation being larger for esters with electron-donating substituents. The data from 22 esters were fitted to a multiparameter equation, the results showing that solvent electrophilicity was the main factor responsible for changes in the ortho, para and meta polar substituent effects with medium.15 o-Iodosobenzoate is a potent α-effect nucleophile, its reaction with aryl benzoates (17) proceeding via an intermediate (18) that breaks down to benzoate (19) with regeneration of o-iodosobenzoate (20) (Scheme 7). Now a series of these intermediates (18; X = Me, H, Cl, CN, NO2 ) has been prepared and their rates of hydrolysis determined in 13% (v/v) MeCN–H2 O at 18–45 ◦ C at pH 8. The results, supported by theoretical calculations of the partial charges on iodine and on the carbon of the C=O group, indicate that water and HO− attack the iodine atom of (18), the latter involving a transition state (21) in which the departure of benzoate is well advanced.16 O

O X

C O

I

Y

O O−

O X

C O

I

O O

(17)

(18) O

I

O + X O−

CO2−

(20)

(19) Scheme 7

O O δ−

I

HO

O O C δ−

(21)

X


53

(iii) Aminolysis reactions The kinetics and mechanism of the aminolysis of a series of 3- and 4-substituted phenyl acetates by imidazole in aqueous solution at 20 ◦ C have been compared with corresponding data for thiophenyl acetates.17 A computational study of the ammonolysis of methyl benzoate has concluded that the most favourable pathway is through a general base-catalysed neutral stepwise mechanism.18 The aminolysis of a series of o-methyl benzoates by cyclic secondary amines in which either the non-leaving group (22) or the leaving group (23) is variously substituted have been determined in 1:4 DMSO–H2 O solution at 25 ◦ C. For (22), the Yukawa–Tsuno plots were linear with large r values (1.06–1.70), suggesting that stabilization of the ground state through resonance interaction between the electron-donating substituent X and the C=O group is significant. Reactions of (23) with piperidine gave a curved Brønsted-type plot, consistent with a stepwise mechanism in which the rate-determining step changes from the formation to the breakdown of the tetrahedral intermediate.19 Me

Me O

O

C O

NO2

X

C O Y

(22)

(23) CN

CN (CH2)n

R

N

O

N

H (24)

H (25)

(26)

+

O

NO2

O NH2

O

[catalyst]

N

CDCl3

O

(28)

(27)

H

+ NO2 HO

The influence of a series of alkyl-substituted 3-cyano-2-pyridones (24; R = Me, Et, Pri , But ) and (25; n = 1, 2, 3) on the kinetics of the aminolysis in CHCl3 of p-nitrophenyl acetate (27) by butylamine (26) was studied. It was proposed that the pyridone catalysts (present as 1:1 pyridone–amine complexes) form a weakly bound

54


complex with p-nitrophenyl acetate (27), which in a rate-determining step breaks down to yield the products, N -butylacetamide (28) and p-nitrophenol.20

(c) Acyl Halides and Acid Anhydrides Application of the extended Grunwald–Winstein equation to solvolyses of propyl chloroformate, PrOCOCl, in a variety of pure and binary solvents indicated an addition–elimination pathway in the majority of the solvents but an ionization pathway in the solvents of highest ionizing power and lowest nucleophilicity. For methanolysis, a solvent deuterium isotope effect of 2.17 was compatible with the incorporation of general-base catalysis into the substitution process.21 Ethanolysis of methyl and ethyl chloroglyoxylates, ROCOCOCl, proceeded about 106 times faster than for the corresponding chloroformates, necessitating rate measurements at and below −60 ◦ C. The correlation parameters obtained from application of the extended Grunwald–Winstein equation were consistent with an addition–elimination mechanism over the full range of alcohols investigated (which included fluorinated alcohols), with the addition step being rate determining.22 Rates and product selectivities {S = ([ester product]/[acid product]) × ([water]/ [alcohol solvent]} were reported for solvolyses of chloroacetyl chloride at −10 ◦ C and phenylacetyl chloride at 0 ◦ C in EtOH– and MeOH–water mixtures. Additional kinetic data were reported for solvolyses in acetone–water, 2,2,2-trifluoroethanol (TFE)– water, and TFE–EtOH mixtures. Selectivities and solvent effects for chloroacetyl chloride, including the kinetic solvent isotope effect (KSIE) of 2.18 for MeOH, were similar to those for solvolyses of p-nitrobenzoyl chloride; rate constants in acetone–water were consistent with a third-order mechanism, and rates and products in EtOH–and MeOH–water mixtures could be explained quantitatively by competing third-order mechanisms in which one molecule of solvent (alcohol or water) acts as a nucleophile and another acts as a general base (an addition–elimination reaction channel) (29; R = Et, Me, H).23 R

R

H O

H O Cl

O Cl

(29)

Product selectivities were also reported for solvolyses of p-methoxybenzoyl chloride in aqueous MeOH, EtOH, 2,2,2-trifluoroethanol, PrOH, Pri OH, and But OH at 25, 35, and 45 ◦ C. The S values were small and depended significantly on the alcohol cosolvent, varying from 1.3 in MeOH to 0.1 in But OH, but depended only slightly on the solvent composition and temperature. As S adjusts the product ratios for changes in bulk solvent compositions, it was concluded that preferential solvation by either alcohol or water at the reaction site was not a major factor influencing rates or products. Logarithms of rate of solvolyses of p-methoxybenzoyl chloride correlated well with Kosower Z values (based on solvatochromism).24


55

Kinetic studies at high pressure at various temperatures of the aminolysis by substituted pyridines of benzoyl chloride have shown that the reactions proceed in typical SN 2 fashion.25 A theoretical study of the acetylation of But OH by acetic anhydride catalysed by 4-(dimethylamino)pyridine has confirmed the generally accepted pathway in which an initially formed acetylpyridinium/acetate ion pair suffers attack by the alcohol in a rate-determining step to form the ester together with deactivitated (protonated) catalyst. Regeneration of the latter requires an auxiliary base such as triethylamine. Deprotonation of the alcohol in the rate-determining step is effected by the acetate counterion.26 The kinetics of the reactions of phthalic and maleic anhydrides with Z-substituted phenols (Z = H, m-Me, p-Me, m-Cl, p-Cl, and m-CN) (Scheme 8) were studied in aqueous solution at pH 8.5. Two kinetic processes well separated in time were observed. The fast process was attributed to the formation of the aryl ester in equilibrium with the anhydride and allowed the determination of the rate of nucleophilic attack of the phenol on the anhydride. From the slow kinetic process, the equilibrium constant for this reaction was determined. The Brønsted-type plots for the nucleophilic attack of substituted phenols on the anhydrides were linear with slopes βNuc of 0.45 and 0.56 for phthalic and maleic anhydride, respectively. The results are consistent with a mechanism involving rate-determining nucleophilic attack and also with a concerted mechanism.27 O−

O

Z

O O

O

+ O−

Z

O

O Scheme 8

Among six different Group VIb oxometallic species examined, dioxomolybdenum dichloride, MoO2 Cl2 , and oxomolybdenum tetrachloride, MoOCl4 , were found to be the most efficient catalysts for the nucleophilic acyl substitution (NAS) of anhydrides with a myriad array of alcohols, amines and thiols in high yields and high chemoselectivity (Scheme 9). The mechanism of the alcoholysis reaction involves the initial formation of a diacyloxyoxomolybdenum dichloride (30), which suffers attack by the alcohol, ROH, to yield the product ester with regeneration of the catalyst (Scheme 10).28 O R XH + R′

O O

1 mol% MoO2Cl2

R′

CH2Cl2 X = O, NH, S

Scheme 9

O R

X R′ 91–100%

56


O R′ Cl Cl

O O

O

R′

O−

R Cl

Mo+

Cl

O

O

R′

Mo O

O H

O

O −MoO2Cl2

R′

−R′CO2H

O

R

O R′ (30)

Scheme 10

(d) Amides Theoretical studies have been reported for the neutral29 and alkaline30,31 hydrolysis of formamide. A theoretical study of the acid hydrolysis of N -formylaziridine concluded that both N - and O-protonated pathways compete.32 In an historical overview of tetrahedral intermediates in the reactions of carboxylic acid derivatives with nucleophiles, several citations of amide reactions are included.33 A kinetic study on the cleavage of N -methylphthalamic acid (31) in mixed acidic aqueous MeCN solvent revealed the formation of both phthalic anhydride (32) (through O-cyclization) and N -methylphthalimide (33) (through N -cyclization). The formation of (33) decreased from ∼20% to ∼3% with increase in the content of MeCN from 2 to 70% (v/v).34 O O CO2H

O (32)

NHMe O

O

(31)

NMe O (33)

(e) Imides and Imidates A review has compared the mechanisms of acid hydrolysis of amides and benzimidates.35 Hydrazinolysis of N -phenylphthalimide (34; R = Ph) yielded N -aminophthalimide (36) via loss of aniline from the initial product of ring scission (35).36

2 Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives O

O

O NHR

NR + NH2NH2

NHNH2

O

NNH2

−RNH2

O

O (35)

(34)

57

(36)

(f) Carbonates, Carbamates, Ureas, and Hydroxamic Acids The properties of dimethyl carbonate, (MeO)2 CO, as an ambident electrophile have been investigated by analysis of the products of its reaction with various nucleophiles having different hard–soft character. Results were in good agreement with the Hard–Soft Acid–Base theory, hard nucleophiles attacking the hard C=O group and soft nucleophiles the soft Me group (Scheme 11).37 Soft Soft Nu−

MeO

O C

OMe

MeO Hard C O MeO

Hard Nu−

BAl2 mechanism BAC2 mechanism

NuMe + CO2 + MeO−

NuCOOMe + MeO−

Scheme 11

A kinetic study of the aminolysis of p-cresyl p-nitrophenyl carbonate by BuNH2 in C6 H6 at 27 ◦ C in the presence of pyridine, Et3 N, or imidazole has shown that each of the three bases are very effective catalysts.38 A concerted mechanism of aminolysis of di(4-nitrophenyl) carbonate (37; X = NO2 ) by anilines at 25 ◦ C in 44% EtOH–water was indicated by a linear Brønsted-type plot showing β = 0.65. However, the aminolysis of two related compounds, 4-methylphenyl (37; X = Me) and 4-chlorophenyl 4-nitrophenyl carbonate (37; X = Cl), with β = 0.85 and 0.78, respectively, proceeded by a stepwise mechanism.39 O X

O C O

NO2

(37)

The aminolyses of the carbonates derived from cyclopentane-1,2-diol (38) and cyclohexane-1,2-diol (39) by hexylamine at 70 ◦ C were much slower than that of ethylene carbonate, the latter (39) being about twice as reactive as the former (38). Computational calculations confirmed that ring strain was the main determining factor.40

58


O

O

O O

O O

(38)

(39)

Treatment of alcohols with t-butyl dicarbonate (Boc2 O) in the presence of anhydrous Mg(ClO4 )2 at 40 ◦ C in CH2 Cl2 produces the corresponding t-butyl ethers. The proposed mechanism involves initial formation from the alcohol, ROH, of a mixed dicarbonate (40), which, complexes with the catalyst to form (41). This decomposes to the t-butyl ether (42) and CO2 via a concerted mechanism (Scheme 12).41

R OH

O

Boc2O

RO

O OBut

O (40)

Mg(ClO4)2

O R OBut

−CO2

R O

Mg(ClO4)2 O

O (42)

O (41)

Scheme 12

In the synthesis of carbamates, R NH.CO2 R, from N ,N -dialkylureas, (R NH)2 CO, and dialkyl carbonates, (RO)2 CO, dibutyltin oxide, Bu2 SnO, acted as an efficient catalyst. The proposed mechanism (Scheme 13) involves addition of the dialkyl carbonate to Bu2 SnO to give an adduct (43), which is attacked by the urea to yield a new tin complex (44) and one molecule of carbamate. Attack by dialkyl carbonate upon this complex (44) yields a further molecule of carbamate and regenerates the original tin complex (43), which can continue the catalytic cycle.42 The rates of O-acetylation by Ac2 O in MeCN or dioxane of a series of 4-Xsubstituted benzohydroxamic acids, 4-X-C6 H4 CONHOH, alone or in the presence of Et3 N or pyridine were, as to be expected, little affected by the nature of the remote aryl substituent.43 Formamidine–urea compounds (45) exchange imine fragments with primary amines (R4 NH2 ) in non-protic solvents via the breakdown of the tetrahedral intermediate


59

Bu2SnO (RO)2CO OCOOR Sn

R′NHCOOR

OR (43)

R′NHCONHR′

OCONHR′ Sn OR

ROCOOR

R′NHCOOR

(44) Scheme 13

H R4

N

H R1

N

O N R2 (45)

R4NH2

NHR3

R1

N H

N a

H b

NHR3

N R2 +

a

R4

O

R1NH2

O

N R2 (46)

H

NHR3

R4

N

b

N H

R1

(47) + O HN

NHR3

R2 Scheme 14

(TI) (46) by pathway a. However, when protons are made available intra- or intermolecularly, loss of urea from the TI (46) via pathway b also occurs to give a formamidine (47) (Scheme 14). The proposed mechanism for the intramolecular pathway b is illustrated by the reaction between the t-butyl compound (48) and an ω-hydroxyamine (such as 5-aminopentanol) in Scheme 15.44

60

Organic Reaction Mechanisms 2005 O H N

O N

H2N

NH

OH

NHMe

N H

Me (48)

H O

N

NHMe

Me path b

OH

H N

N H

Scheme 15

Lawesson’s reagent (LR) is a very effective thionating agent of carbonyl compounds. However, attempted thionation with LR of N -alkylhydroxamic acids gave maximum yields of 55–60%. Previous work had established that the thionation products, the thiohydroxamic acids (THA), were accompanied by the corresponding amides (A) formed by reduction and the thioamides (TA), the products of thionation of the amides (A) (Scheme 16). Now the reaction of N -isopropylhydroxamic acid (HA; R = Pri ) with LR has been followed by 31 P NMR spectroscopy and several Pcontaining intermediates have been identified. This has permitted the delineation of a rational, but complex, pathway to each of the products of the reaction.45

(g) Other Heterocyclic Nitrogen Centres In the acid-catalysed hydrolysis of 4-alkyl-4-methyl-2-aryl-4,5-dihydro-1,3-oxazol-5ones (49) to the corresponding 2-alkyl-2-benzoylaminopropanoic acids (50), the steric bulkiness of the alkyl group at the 4-position gradually more and more favours the attack at C(2) by a water molecule. Based on data from Taft and Hammett correlations, the proportions of hydrolysis taking place at C(5) and C(2) were estimated to be about 70 and 30%, respectively, in the case of the 4-t-butyl derivative. In the same paper, the aminolysis of 4-isopropyl-4-methyl-2-phenyl-1,3-oxazol-5(4H )-one (49; R = Pri , Y = H) and 4-isopropyl-2-(4-methoxyphenyl)-4-methyl-1,3-oxazol-5(4H )one (49; R = Pri , Y = 4-MeO) by propylamine to give the respective amides (51) takes place in such a way that the rate-limiting step is the decomposition of the zwitterionic intermediate (52). However, for the 4-nitro derivative (49; R = Pri Y = 4-NO2 ), the rate-limiting step is the formation of the zwitterionic intermediate (52).46 The 1,4-benzodiazepinones, exemplified by diazepam (53), undergo hydrolysis in acid and base to yield the corresponding o-aminobenzophenones (54). However, unusual byproducts were observed when diazepam (53) or 2-(N -methyl)amino-5chlorobenzophenone (54) was hydrolysed in aqueous methanolic hydrochloric acid, and now a mechanism involving a nitrene has been proposed to account for the


61

S Ar

N

OH

R THA

S

O Ar

N

OH

+

Ar

LR

N

H

R TA

R HA O Ar

N

H

R A S S P P S S

LR = MeO

OMe

Scheme 16

O C Y

H2O

Y (49)

N

Me R

O

O

Me

NH C COOH R (50)

R1 NH2

O C Y

Me

NH C CONHR1 R (51)

observed products, some of which were doubly chlorinated. The elimination of molecular hydrogen from (55) (Scheme 17) would give an unstable nitrene (56) that could react with Cl− to give the 3,5-dichloro intermediate (57). This unstable intermediate (57) could be stabilized to a 3,5-dichloroaminobenzophenone (58; R = Me or H) or react with the o-hydrogen of the second phenyl ring affording 3,5-dichloroacridones (59; R = Me or H).47

62

Organic Reaction Mechanisms 2005 Me N Y

O

Me CH Me +

O−

NH2 R1

(52) Me

Me O

N

N H

N

Cl

C O

Cl

(53)

(54)

R N Cl

R H H+

C O

N

−H2

Cl

R +

+

C O

Ph

Cl

C O

Ph

(55)

Ph

(56) Cl−

Cl

H

R N

Cl

C O Ph (57)

Scheme 17

Cl

R

Cl

NMe

R N

(57) Cl

C O Ph (58)

N

Cl

C O (59)


63

(h) Thioesters and Thiocarbonates Quantitative relationships have been reported between the global electrophilicity index and the experimental rate coefficients for the reactions of thiolcarbonates and dithiocarbonates with piperidine. The validated scale of electrophilicity was then used to rationalize the reaction mechanisms of these systems. This scale also makes it possible to predict both rate coefficients and Hammett substituent constants for a series of systems that have not been experimentally evaluated to date.48 The aminolysis of a series of S-2,4-dinitrophenyl 4-Y-benzoates (60; Y = Me, H, Cl, NO2 ) with a series of substituted pyridines at 25 ◦ C in 44% ethanol–water proceeded stepwise through a zwitterionic tetrahedral intermediate, the rate-determining step changing from its breakdown to its formation as the basicity of the amine increased.49 However, the aminolysis of the same series of benzoates (60) with secondary alicyclic amines in the same solvent was judged to be concerted, and the reasons for the proposed change in mechanism were discussed.50 NO2

O Y

C

S

NO2

(60)

Kinetic data indicate that the hydrolysis of S-2,4-dinitrophenyl 4 -hydroxythiobenzoate (61) in mild alkaline solutions (pH 8–11) most likely follows a dissociative, E1cB pathway, through a p-oxoketene intermediate, whereas at higher pH values an associative mechanism carries the reaction flux (Scheme 18). LFER relationships obtained from a kinetic study on the alkaline hydrolyses of substituted S-aryl 4 hydroxythiobenzoates seem to suggest that the associative pathway is a concerted, one-step process, rather than the classical mechanism via a tetrahedral intermediate.51

O

OH

O−

C

C

SAr (61)

O

E1cB

Associative

SAr

O

C O

Products

Concerted

Scheme 18

The aminolysis of the aryl S-methyl thiocarbonates (62–64) by secondary alicyclic amines in aqueous solution at 25 ◦ C proceeded by a stepwise mechanism in the case of the 4-nitro compound (62), but by a concerted mechanism for the other two substrates (63, 64).52

64

Organic Reaction Mechanisms 2005 X

O Me

S

C O

(62) X = 4-NO2 (63) X = 2,4-(NO2)2 (64) X = 2,3,4,5,6-F5

(i) Thiocarbamates Kinetic studies at 100 ◦ C revealed that ethyl N -ethylthionocarbamate, EtOC(S)NHEt, was hydrolysed in acid by an A1 mechanism and in base by a BAc 2 mechanism.53 The concerted mechanism proposed for the aminolysis at 30 ◦ C in MeCN of aryl N -ethyl thionocarbamates, (XC6 H4 O)C(S)NHEt, by benzylamine was supported by a negative cross-interaction constant, ρXZ = −0.87 and failure of the reactivity–selectivity principle.54 Similar conclusions, for the same reasons, were made for the aminolysis of the corresponding thiolocarbamates, (XC6 H4 S)C(O)NHEt, by benzylamine in MeCN at 10 ◦ C.55 The basic hydrolysis of a series of aryl N -(4-X-benzenesulfonyl)-N -methyldithiocarbamates (65; X = MeO, Me, H, Cl, NO2 , CF3 ) in 30% aqueous dioxane at 25 ◦ C proceeded via a BAc 2 mechanism to give thiophenol, COS, and the corresponding N -methylsulfonamide, 4-X-C6 H4 SO2 NHMe.56

O

X

S

O N

S S

Me (65)

Phosphoric Acids and their Derivatives (a) Phosphates and Phosphonates DFT analysis of the hydrolysis of dimethyl phosphate by hydroxide ion and water in the gas phase and in water was reported.57 The kinetics of the acid hydrolysis at 97 ◦ C of 4-bromo-2,6-dimethylphenyl phosphate were reported.58 Kinetic data at 35–55 ◦ C of the neutral hydrolysis (pH 6.9–7.5) of a series of substituted benzoyl phosphates (66; X = 4-Me, H, 4-Cl, 4-CN, 4-NO2 , 3,5-dinitro) revealed that sizeable substituent effects on both H = and S = were apparent. This, it was claimed, showed the contribution of solvation of the leaving benzoate and a substituent-induced shift of the structure of the transition state.16 In a kinetic study of the reactions of a series of hydroxamates, RCONHO− , with ethyl p-nitrophenyl ethylphosphonate (67; R = Et) and diethyl 4-nitrophenyl phosphate (67; R = OEt), their known typical α-nucleophile reactivities were in evidence, but anomalously high nucleophilicity was observed for anions possessing substituents

2 Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives X

O

O

C O

P

65

O−

O− (66)

capable of providing intramolecular general base catalysis. For example, o-hydroxybenzohydroxamic acid (68) was 50-fold more reactive than o-methoxybenzohydroxamic acid towards diethyl p-nitrophenyl phosphate (67; R = OEt), and this was attributed to the formation from (68) of intramolecular hydrogen-bonded complexes, A and B (Scheme 19).59

EtO R

O OC6H4NO2−p

P

(67) O C O (68)

O NHOH H

−H+

C

H+

O A

O NHO− H

−H+

C

H+

−

O

N

O−

H

B

Scheme 19

Sulfonic Acids and their Derivatives (a) Sulfonates and Sulfonyl Halides Rates of the alkaline hydrolysis of 12 ortho-, meta- and para-X-substituted phenyl tosylates, 4-MeC6 H4 SO2 C6 H4 X, in aqueous 0.5 m Bu4 NBr over a wide temperature range have been analysed using the modified Fujita–Nishioka multi-parameter equation. It was concluded from both these and previously reported data by the same group that solvent electrophilicity was the main factor responsible for changes in the ortho, meta and para polar substituent effects with medium.60 In a kinetic study of the reactions of a series of hydroxamates, RCONHO− , with 4-nitrophenyl tosylate, their well-known α-nucleophile reactivities were confirmed, but anomalously high nucleophilicity was observed for anions possessing amino substituents capable of providing intramolecular general base catalysis.59 Aminolysis of pentafluorophenyl (PFP) arenesulfonates was shown to be efficiently catalysed by Bu4 N+ Cl− , but not by any other halide ion. The hard sulfonyl centre suffers nucleophilic attack by Cl− to yield the corresponding sulfonyl chloride, which reacts very rapidly with the amine to give the sulfonamide (Scheme 20).61 Studies of the aminolysis of benzenesulfonyl chloride by primary and secondary amines in aqueous solution at 25 ◦ C at high pH has led to the identification of a

66

Organic Reaction Mechanisms 2005 O Ar

O S

OPFP Cl−

O

O S

Ar

Cl

O Ar

O S

NHR

R NH2

Scheme 20 Cl S

Ph

O O

B R1 N H R

Scheme 21

third-order reaction (Scheme 21; B = R2 NH, RNH2 , HO− ).62 4-Nitrobenzenesulfonyl chloride undergoes hydrolysis in water and binary aqueous solvents along two pathways of SA N mechanism involving cyclic intermediates with a pentacoordinate sulfur atom, (H2 O)SO2 (Cl)Ar.nH2 O and (HO− ) SO2 (Cl)Ar.nH2 O.63 Studies of the hydrolysis of 2-methylbenzenesulfonyl chloride, 1,5-naphthalenedisulfonyl chloride, and 4acetamidobenzenesulfonyl chloride in water–Pri OH mixtures identified two pathways: one of them involves a water dimer as a bifunctional catalyst along with a water molecule as a nucleophile, and the other involves an alcohol hydrate.64 Solvolysis of SOCl2 by polyfluorinated alcohols, H(CF2 )n CH2 OH; n = 2, 4, catalysed by Et3 N proceeded by an SN 2 mechanism; evidence for ion-pair, RO− Et3 NH+ , attack on S=O was obtained.65

(b) Sultams Computational studies were reported of the ammonolysis of N -methyl β-sultam (69; X = CH2 , R = Me)66 and the alcoholysis of N -benzyl 3-oxo-β-sultam (69; X = CO, R = CH2 Ph).67 X RN

S

O

O (69)

ASSOCIATION-PREFACED CATALYSIS Kinetic studies of the hydrolysis of Z-phenyl hydrogenmaleates (70; Z = H, p-Me, m-Me, p-Cl, m-Cl) were carried out in the presence and absence of hydroxypropyl-β-

2 Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives O

67

Z O OH

O (70)

cyclodextrin (HPCD) at variable pH from 1 to 3. The reaction involves the formation of maleic anhydride as an intermediate and, since the neighbouring carboxylate group is a better catalyst than the carboxylic group, the rate of its formation is strongly dependent on the pH. The rate constant for the formation of maleic anhydride decreases as the HPCD concentration increases in a nonlinear fashion. The results were interpreted in terms of the formation of a 1:1 inclusion complex of the esters with HPCD. The results suggest that the reactive complexes have the maleic moiety inside the cavity, rather than the phenyl ring.68 The hydrolysis at 25 ◦ C of p-nitrophenyl picolinate (71) catalysed by the Cu(II) complex of 4-chloro-2,6-di(N -hydroxyethylaminomethyl)phenol (72; R = CH2 NH CH2 CH2 OH) was studied kinetically at different pH in the presence of three surfactants: hexadecyltrimethylammonium bromide, sodium lauroylsarcosinate, and polyoxyethylene (23) lauryl ether.69 The Cu(II) complexes of two N -alkyl-3,5-di(hydroxymethyl)-1,2,4-triazoles (73; R = C10 H21 , C12 H25 ) were better than the Ni(II) complexes as catalysts for the hydrolysis of p-nitrophenyl picolinate (71) in CTAB micelles.70 OH R

R

CH2OH N HOCH2

N

CO2Ar (71)

Cl (72)

N R (73)

N

Kinetic studies of the aminolysis of p-nitrophenyl decanoate and acetate by BuNH2 in chlorobenzene in the presence of a glyme with four oxygen atoms, MeO(CH2 CH2 O)3 Me, have revealed a new pathway that shows a first-order dependence on the concentration of the phase transfer catalyst and a second-order dependence on BuNH2 .71 Studies of the spontaneous hydrolysis of a series of substituted benzoyl chlorides and of 4-X-benzenesulfonyl chlorides at 25 ◦ C in cationic, anionic, and sulfobetaine micelles have allowed an assessment to be made of micellar charge effects on hydrolysis mechanisms.72

68

Organic Reaction Mechanisms 2005 BIOLOGICALLY SIGNIFICANT REACTIONS

Enzymic Catalysis In a review of the proficiencies of enzymes and how they achieve them, it was claimed that ground-state conformations and transition state stabilization cannot explain the very large efficiencies of enzymes; instead, they must proceed, it was concluded, by covalent enzyme–substrate intermediates.73 A riposte to this contentious hypothesis has appeared, claiming that account was not taken of the fact that high enzyme efficiency is determined by the value for the water reaction k0 rather than by the enzymatic rate constant kcat /kM .74 In the ‘spatiotemporal model’ of enzyme catalysis, fast intramolecular and enzymatic rates are ascribed to short distances that are imposed rigidly upon the reacting entities. In a review of this model, an equation relating rate and distance was set forth, as were experimental and computational data supporting this relationship. Finally, enzyme systems themselves were analysed in terms of the distance parameter and the so-called ‘split-site’ model in which ground-state geometrics play a crucial role. Among the many surprising conclusions is a transition-state stabilization by noncovalent forces (e.g. hydrogen bonding) that are positioned far away from the actual transition-state chemistry. The model also confronts and dismisses the claim in classical enzymology that the ubiquitous enzyme–substrate complex is either inconsequential or inhibitory to the overall reaction rate.75

(a) Peptidases The results of a computational study revealed that the sedolisins, a family of serinecarboxyl peptidases, may evoke different catalytic machineries than do classical serine proteases in achieving transition-state stabilization. The family is characterized by a unique catalytic triad, Ser–Glu–Asp, that operates primarily through a general acid–base mechanism.76

(b) β-Lactamases β-Lactamases are a major cause of resistance to β-lactam antibiotics. Co-administration of a β-lactamase inhibitor is an important therapeutic strategy and the methylene penems are strong inhibitors that have shown promise. Now, the crystal structure of a βlactamase in complex with 6-(N 1 -methyl-1,2,3-triazolylmethylene)penem (74) has confirmed that (74) becomes covalently linked with Ser64. Moreover, it has confirmed the occurrence of the proposed rearrangement mechanism involving the opening of the thiazole ring system of (74) leading via (75) and (76) to a cyclic β-aminoacrylate– enzyme complex (77) (Scheme 22).77

2 Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives Me N N

Me N N

Me N N

N

N

N3′ S Enz

OH +

N O

S−

S O OH

CO2−

O

N

(74)

OH

CO2−

Ser

S

1

3

6 5

Ser

CO2−

2

7

O

+

(76)

Me N N3′

N

Ser

(75)

N

69

O

CO2−

N4 H

(77) Scheme 22

Intermolecular, Biomimetic, and Model Reactions (a) Carboxylic Acids and their Derivatives (i) Esters A 1,10-phenanthroline-containing polyamine macrocycle (78) was designed to complex with Zn2+ ion and, because of the rigidity of the phenanthroline moiety, leave some ‘free’ binding sites at the metal for ligands such as water, which easily deprotonate to give stable hydroxo species. The hydrolysis of methyl acetate in the gas phase by such a monohydroxy–Zn(II) complex [Zn(78)(OH)]+ has been investigated by quantum mechanical procedures and some pathways delineated.78

N HN

H N

N N H (78)

M

N

N NH

H

2+

H (79)

OMe

70


The mechanism of methanolysis at 25 ◦ C of p-nitrophenyl acetate (PNA) by a Zn2+ (MeO− ) complex of 1,5,9-triazacyclododecane (79; M = Zn) involves pre-equilibrium binding of PNA to (79; M = Zn) followed by rate-limiting intramolecular attack of the coordinated methoxide to form a tetrahedral intermediate stabilized via coordination to the Zn2+ .79 Metal-catalysed hydrolysis of p-nitrophenyl picolinate at pH 7.5 was in the order Cu(II) > Ni(II) > Zn(II) > Co(II) > La(III). The probable mechanism is via attack by external HO− on the metal–ion complex (80).80 High catalytic activity in the hydrolysis at pH 7 of p-nitrophenyl picolinate, but not p-nitrophenyl acetate, was displayed by the metal complexes M(2-aminopyridine)2 (OAc)2 (M = Zn, Ni), showing that they were good models for hydrolytic metalloenzymes.81

C

N M

O

OH− O

H H N

O

‡

O

H

n+

Me

O NO2 (80)

(81)

The possible catalytic effect of the vicinal hydroxyl group during the ammonolysis of acetylcatechol was studied by first principle calculations. A very efficient intramolecular catalysis was found to occur, via transition state (81), when the catechol ester o-OH group is deprotonated: the activation energy of the ammonolysis decreases by 24 kcal mol−1 compared with that of acetylphenol ammonolysis. The analogy with the aminolysis of peptidyl-tRNA that occurs during protein biosynthesis implies several orders of magnitude acceleration due to complete or partial deprotonation of its 3 -terminal adenosine 2 -OH, providing a mechanistic possibility for general acid-base catalysis by the ribosome.82 A trifluoroacetic anhydride (TFAA)-catalysed opening of the oxirane system of glycidyl esters (82) with a simultaneous migration of the acyl group provides a new, efficient entry to either 2-monoacylglycerols (84) or 1,3-symmetrical triglycerides (85) as potential prodrug frameworks (Scheme 23). The products of attack of the glycidyl esters (82) by 4 equiv. of TFAA at 20 ◦ C for 2 h (step A) are the 1,3-bis(trifluoroacetyl)-2-acylglycerols (83), which can be transesterified quantitatively with MeOH–pyridine (step B) to the 2-acylglycerols (84); acylation with R1 COCl–pyridine (step C) then effects efficient conversion, without isomerization, to the triglycerides (85). The proposed mechanism for step A (Scheme 24) involves initial coordination of the epoxide oxygen by a strongly electrophilic TFAA, followed by the opening of the activated oxirane ring via an intramolecular attack of the adjacent carbonyl group to form cyclic acyliumglycerol cation A. This is

2 Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives OCOCF3

71

OH

OCOR

OCOR

OCOCF3

Step B

OH

(83)

(84)

Step A

Step C OCOR1

O

OCOR OCOR1

OCOR (82)

(85) Scheme 23

O F3C O

O O

R O

CF3

O

F3C

O O

R

+

O

A −

O

O

CF3 O

R = alkyl or aryl

O O F3C

O

R O

O

CF3 O

(83) Scheme 24

apparently the rate-determining step of the reaction as opening of the oxirane ring does not occur under these conditions without assistance of the neighbouring carbonyl group. The acylium ion A then collapses in a fast reaction to the corresponding 1,3bis(trifluoroacetyl)-2-acylglycerol (83) by a regioselective attack of a trifluoroacetate ion on the primary carbon atom of the dioxolane ring.83

72


(ii) Amides and polypeptides A novel synthetic receptor (86) capable of binding with acids or amines has been shown by NOESY and T-ROESY 1 H NMR experiments to form a 1:1:1 complex with benzoic acid and benzylamine (BnNH2 ), thus explaining the modest, but encouraging, catalytic competence (×5.5) of (86) in the formation of N -benzylbenzamide, PhCONHBn.84 O 12 20

22

O

18

N

N H

HN

H3′

5

11

4

H3

N 14

9

H7′ H7

(86)

The water-promoted hydrolyses of a bicyclic amide, 1-azabicyclo[2.2.2]octan-2-one (87), and a planar analogue, 1,4-dimethylpiperidin-2-one (88), were studied using density functional theory in conjunction with a continuum dielectric method to introduce bulk solvent effects. The aim of these studies was to reveal how the twisting of the C–N bond affects the neutral hydrolysis of amides. The results predict important rate accelerations of the neutral hydrolysis of amides when the C–N bond is highly twisted, the corresponding barrier relaxation depending on the specific reaction pathway and transition state involved.85 Me

N (87)

O

O N Me (88)

Hydrolysis and carbonyl hydration of adamantane-based twisted amide (89; R1 , R2 , = Me) were studied computationally. The importance of the bridgehead methyl substituents on these reactions was determined by computational analysis of two dimethyl, (89; R1 = H, R2 = R3 = Me) and (89; R1 = R2 = Me, R3 = H), and two monomethyl analogues, (89; R1 = Me, R2 = R3 = H) and (89; R1 = R2 = Me, R3 = H), and the parent compound, (89; R1 , R2 , R3 = H). The carbonyl hydration of the fully methylated amide (89; R1 , R2 , R3 = Me) to the gem-diol (91) (Scheme 25) is structurally and energetically much like the hydration of a transition state for amide C–N bond rotation. However,hydrolysis of (89; R1 , R2 , R3 = Me) to the amino acid R3

2 Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives N Me O

N R

3

+

NH2

R1 R2

Me

Me OH

N

O−

OH Me

Me Me

(89)

O

Me

O

73

Me Me

(90)

(91) Scheme 25

(90) is dependent on the bridgehead methyl substituents and less like hydrolysis of an amide transition state.86 The first evidence for a general-buffer catalytic mechanism for a carbinolamide cleavage has been demonstrated in model studies with N -(hydroxymethyl)benzamide (92). The results obtained were consistent with a process involving specific acid followed by general base catalysis (Scheme 26) or a general-acid catalysed mechanism, and support the proposal that the lyase portion of peptidylglycine α-amidating monooxygenase utilises a general acid–base catalytic method to cleave the carbinolamide intermediates.87 O

H

OH N H

+ H+

O+

H

OH N H

(92)

O NH

+ A− O

+ H

H

+ HA Scheme 26

(iii) β-Lactams Theoretical studies were reported of the thiolysis by 2-mercaptoethanol and 2-mercaptoethylamine of simple models of the bicyclic ring systems of penicillin and cephalosporin88 and of the alkaline hydrolysis of sanfetrinem (93).89 The major determinant in allergies induced by penicillins is the penicilloyl group bound to the amino group of the Lys residues present in the carrier protein. Now a study is reported of the polyelectrolyte polyethylenimine (94) as a model of the carrier protein and its catalysis of the aminolysis of benzylpenicillin.90

74

Organic Reaction Mechanisms 2005 OH

H H

H N

N O

H N

N

n

OMe COO−

NH2

(93)

(94)

(b) Phosphoric Acids and their Derivatives (i) Phosphate and phosphonate monoesters An ab initio study in the gas phase of the alcoholysis and thiolysis of methyl and phenyl phosphate, as models for phosphatase action, showed that they could react through either an associative or dissociative mechanism.91 Following a brief communication in 2004, a full paper92 has appeared reporting the remarkable reactivity towards nucleophiles of the phosphate ester of 8-(dimethylamino)-1-naphthol. Phosphate transfer from the 8-dimethylammoniumnaphthyl-1phosphate monoanion (95) to water and to a range of nucleophiles shows general acid catalysis by the neighbouring NH+ group, through the strong intramolecular hydrogen bond (Scheme 27). A strong intramolecular hydrogen bond is present in the product, 8-(dimethylamino)-1-naphthol (96), but also in the reactant, as evidenced by major perturbations in the pKa s of the phosphate and dimethylamino groups, to 3.94 and 9.31, respectively, and by ab initio calculations.92 Nuc −

O

−O

O P

O

H

+

NMe2 Nuc

O P O− O−

(95)

O

H

NMe2

+

(96)

Scheme 27

A comparative study of the effects of Li+ and K+ on the ethanolysis of a series of X-phenyl methyl phenyl phosphinates (97) has revealed that kEtO− is < kMOEt , contrary to the generally observed reactivity order in nucleophilic substitution processes.93 Ph O P O Me (97)

X


75

(ii) Phosphate diesters Potentiometry was used to investigate the speciation of La(III) in methanolic methoxide solutions, with and without diphenyl phosphate or methyl 4-nitrophenyl phosphate (98), substrates which are very efficiently methanolysed by such solutions.2 La(III)catalysed methanolysis is thus regarded as a good model for the metal-containing RNAses and DNases which cleave phosphate diester linkages. In the high [La(III)] domain, the data fitted, as one possibility among several, a spontaneous decomposition of (La3+ )2 :(98):(MeO− )5 .94 O MeO

P

NO2

O

O− (98)

A new crowned Schiff base ligand and its cobalt(II) and manganese(III) complexes have been synthesized and characterized. These complexes were used to catalyse the hydrolysis of di(4-nitrophenyl) phosphate (DNPP) in order to mimic the action of hydrolytic metalloenzymes. The proposed mechanism involves the formation of a complex between two molecules of the ligand, one molecule of DNPP and water, the latter being activated by the metal ion to yield a metal hydroxide. Within the complex, attack of the bonded hydroxide ion at phosphorus of DNPP occurs, as shown in Scheme 28. Subsequently, a similar process converts the monoester to 4-nitrophenol and inorganic phosphate. The function of the crown ether ring and the effects of the reaction conditions on the catalytic hydrolysis of DNPP were discussed.95 Novel complexing agents for Ce(IV) in neutral solutions based on Tris [tris(hydroxymethylamino)methane] were synthesized and investigated as catalysts for the hydrolysis of di(4-nitrophenyl) phosphate.96

O O

O

O

N

O

CH

O

O

O M O CH

O O

N

P O H O O

M = Co(II), Mn(III)Cl

Scheme 28

+

O R R O

O

O O

H+

76


HN N N H

N

HN NH

N H

HN

N

R

N

9: R = H 10: R = COOMe

(99)

The kinetics of the hydrolysis of di(2,4-dinitrophenyl) phosphate (DDNPP) were studied in basic solutions buffered with Bis-Tris propane (BTP) in the presence of La3+ , Sm3+ , Tb3+ , and Er3+ . Two equivalents of the 2,4-dinitrophenolate ion were liberated for each equivalent of DDNPP and the reaction showed first-order kinetics. Potentiometric titrations showed the formation of dinuclear complexes such as [Ln2 (BTP)2 (OH)n ](6−n) , with values of n varying as a function of pH for all studied metals. Hence the catalytic effect depends on the formation of dinuclear lanthanide ion complexes with several hydroxo ligands.97 Metal-free catalysts for the hydrolysis of RNA derived from 2-aminobenzimidazoles were reported. The most active catalysts, tris derivatives (99; R = H, CO2 Me) built upon a framework of tris(2-aminoethyl)amine, were shown by fluorescence correlation spectroscopy to aggregate with oligonucleotides. However, at very low concentrations the compounds were still active in the non-aggregated state. Conjugates of the ester (99; CO2 Me) with antisense oligonucleotides or RNA binding peptides will, it was claimed, be promising candidates as site specific artificial ribonucleases.98 2-Methylbenzimidazole ribonucleosid-2 -yl aryl phosphates (100; R = Ph) and alkyl phosphates (100; R = CH2 CH2 OMe) were synthesized as RNA model compounds containing a minimized number of exchangeable protons. Intramolecular transesterification of these substrates was studied in H2 O and D2 O solutions over a wide pL range and apparent kinetic solvent deuterium isotope effects on the alkaline cleavage of both substrates and of the cleavage and isomerization of the alkyl phosphate N Me N

MeO O

O

O

OH

P

O−

OR (100)


77

(100; R = CH2 CH2 OMe) under neutral and acidic conditions were determined. The observed kH2 O /kD2 O of 4.9 obtained for the alkaline cleavage of the 3 -isomer of the aryl phosphate (100; R = Ph) could be primarily attributed to the pK of the attacking nucleophile. The alkyl leaving group in (100; R = CH2 CH2 OMe) brings about an additional 1.5-fold isotope effect (kH2 O /kD2 O = 7.1), which, considering the pL dependence of the reaction, could not be explained by a process involving a proton transfer. In contrast to alkaline cleavage, under neutral and acidic conditions the cleavage and isomerization of the alkyl compound (100; R = CH2 CH2 OMe) showed no apparent solvent isotope effect, a result for which several precedents were cited and discussed.99

(iii) Phosphate and phosphonate triesters An ab initio study in the gas phase of the alcoholysis and thiolysis of trimethyl phosphate and dimethyl phenyl phosphate, as models for phosphatase action, showed that they reacted through an associative mechanism.91 The methanolyses of a series of O,O-diethyl O-aryl phosphates (101; X = O) and O,O-diethyl S-aryl phosphorothioates (101; X = S) promoted by methoxide and two metal ion systems, (La3+ )2 (MeO− )2 and a complex of Zn2+ (MeO− ) with 1,5,9triazacyclododecane (79; M = Zn), has been studied in methanol at 25 ◦ C. The kinetic data for the metal-catalysed reactions were analysed in terms of a common mechanism where there is extensive cleavage of the P–XAr bond in the transition state. The relevance of these findings to the mechanism of action of a phosphotriesterase enzyme present in a soil bacterium that hydrolyses paraoxon was discussed.100 The methanolyses of several phosphate/phosphonate esters and their thio analogues [e.g. O,O-diethyl O-(4-nitrophenyl) phosphate, paraoxon (101; X = O, Z = 4-NO2 ), O,O-diethyl S-(3,5-dichlorophenyl) phosphorothioate, (102; R = OEt), and O-ethyl S-(3,5-dichlorophenyl) methylphosphonothioate (102; R = Me)] catalysed by methoxide and the complex of Zn2+ (MeO− ) with 1,5,9-triazacyclododecane (79; M = Zn) were studied in methanol at 25 ◦ C. The reaction of methoxide and (79; M = Zn) with the entire series of esters appears to adhere to a common mechanism that involves pre-equilibrium binding of the substrate, followed by intramolecular attack of the coordinated methoxide concerted with OAr or SAr leaving group departure.79 In a study of the kinetics of methanolysis at 25 ◦ C catalysed by methoxide, La3+ and the same zinc-containing catalyst (79; M = Zn) of six O-ethyl O-aryl methylphosphonates (103; X = 4-MeO, 4-Cl, H, 3-NO2 , 4-NO2 , 4-Cl-2-NO2 ) as simulants for chemical warfare agents, Brønsted plots gave βlg = −0.76, −1.26, and −1.06, respectively, Cl O O EtO

P

Z X

OEt (101)

EtO

P

O

S

EtO P

R Cl (102)

X O

Me (103)

78


pointing to significant weakening of the P–OAr bond in the transition state. The catalysis afforded by the metal ions is remarkable, being about 106 -fold and 108 -fold for poor and good leaving groups, respectively. A unified mechanism for the metal-catalysed reactions was presented which involves pre-equilibrium coordination of the substrate to the metal ion followed by intramolecular delivery of a coordinated methoxide.101 Hydrolytic reactions of 2 ,3 -O-methyleneadenosin-5 -yl di(5 -O-methyluridin-3 yl) phosphate (104) have been followed over a wide pH range to elucidate the role of the 2 -OH group as an intramolecular hydrogen bond donor facilitating the cleavage of (104). Under alkaline conditions, the 2 -OH group facilitates the cleavage of (104) by a factor of 27 compared with the 2 -OMe counterpart, the influence on the P–O3 and P–O5 bond cleavage being equal. Accordingly, the 2 -hydroxy group stabilizes the phosphorane intermediate, not the departing 3 -oxyanion, by hydrogen bonding.102 MeO

Ura O O

O

P

OH O

Ade O

OH O

Ura

O

O

O

OMe (104)

(iv) Phosphoryl and phosphonyl halides Catalysis of the phosphorylation of cyclohexanol by diphenyl phosphoryl chloride, (PhO)2 P(O)Cl, was achieved by an imidazole moiety linked to a polyether chain of varying length (105; n = 2, 3) in the presence of divalent triflates, X(OTfl)2 ; X = Cu, Mg. Compelling evidence for a coordinated intermediate (106) for the largest molecule (105; n = 3) was obtained by 31 P NMR spectroscopic studies.103 Results of theoretical studies on the alkaline hydrolysis of sarin, MeP(O)F(OPri ), gave excellent agreement with the experimental enthalpy of activation.104 O O

O

O n

Me

N

N

O Me

(105)

N

O Mg

2+

O

+

N

P Cl−

OPh OPh

(106)

O O


79

(v) Thiophosphates Enthalpies and entropies of activation for the hydrolysis reactions of representative mono- (107; X = S), di- (108; X = S), and tri-esters of thionophosphoric acid (109; X = S) and the corresponding oxygen analogues, (107; X = O), (108; X = O) and (109; X = O), respectively, have been determined and compared in an investigation of the ‘thio effect’. The ‘thio effect’ is reported as ko /ks , the ratio of the rate of phosphoryl transfer to that for thiophosphoryl transfer. For triesters and diesters, the ‘thio effect’ is large (50–150) and modest (5–10), respectively, but for monoesters an inverse ‘thio effect’ of 0.1–0.3 is seen; an explanation is offered.105 X O2N

O

P

X O−

O2N

O

O−

OEt

(107)

(108) X

O2N

O

P OEt

(109)

O−

P

S OEt

Me

P

X O

Me (110)

Two publications79,100 on thiophosphate and thiophosphonate triesters, which also dealt with their oxygen analogues, were referred to earlier. Earlier work on the hydrolysis of aryl phosphinothioate esters had led to contradictory mechanistic conclusions. To resolve this mechanistic ambiguity, LFERs (βnuc and βlg ) and KIEs for the reactions of oxyanions with aryl dimethylphosphinothioates (110) were measured. For the attack of nucleophiles on 4-nitrophenyl dimethylphosphinothioate (110; X = 4-NO2 ), βnuc = 0.47 ± 0.05 for phenoxide nucleophiles (pKa < 11) and βnuc = 0.08 ± 0.01 for hydroxide and alkoxide nucleophiles (pKa ≥ 11). Linearity of the plot in the range that straddles the pKa of the leaving group (4-nitrophenoxide, pKa 7.14) is indicative of a concerted mechanism. The much lower value of βnuc for the more basic nucleophiles reveals the importance of a desolvation step prior to rate-limiting nucleophilic attack. The reactions of the same series of substituted aryl dimethylphosphinothioate esters (110) gave the same value for βlg with the nucleophiles HO− (β = −0.54 ± 0.03) and PhO− (β = −0.52 ± 0.09). These and other data are consistent with a concerted reaction and disfavour a stepwise mechanism.106 In a theoretical study of the alkaline hydrolysis of O,S-dimethyl methylphosphonothiolate, it was found that the P–O and P–S bond cleavage processes were kinetically competitive but that the products of P–S bond cleavage were thermodynamically favoured.104

80


(c) Sulfonic Acids and their Derivatives (i) Sulfates The mechanism of hydrolysis of 8-N ,N -dimethylaminonaphthyl sulfate (111) closely resembles that of the corresponding phosphate monoester (95) (cf. ref. 92). Nucleophilic attack by water on the sulfate group of the zwitterion (111z) is catalysed by the neighbouring dimethylammonium group, acting as a particularly efficient general acid through the intramolecular hydrogen bond (Scheme 29). At pH < 2, attack by H2 O occurs on the cation (111+ ). At alkaline pH, deprotonation of (111z) to the anion (111− ) yields an inert species. The estimated rate acceleration for the hydrolysis of the zwitterion (111z) is 6 × 105 at 60 ◦ C.107 H2O:

O O S H + HO O NMe2

(111+) ±H+ −

O

Nu: O

O S

O

H

+

O

NMe2

H

NMe2 O + Nu

S

O

O

−

(111z) ±H+ −

O

O

O S

O

NMe2

(111−) Scheme 29

(ii) Sulfonamides Attaching a dipeptide (112) to a sulfanilamide (113) gives a prodrug that may break down in vivo by protease action. In principle, either N 4 -acyl- (114) or N 1 -acyl-


81

sulfanilamides (115) may be formed by acylation (Scheme 30), but pilot laboratory experiments led only to N 4 -acyl compounds (114). With the aim of determining the factors that affect the nucleophilicity of the sulfonamide group, a DFT study on bioactive and model sulfonamides was carried out and the implication of the results for the design of prodrugs discussed.108

R1

H N

O

O

OH

+

H2

R2 (112)

O R1

H N

HN R2

4

(113)

O

S HN1 R3

O

O S HN1 R3

N4

O H2N4

S

R1

(114)

O

N1 R3

H N

O R2

(115) Scheme 30

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

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25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69

2 Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108

83

Qui, L.-G., Xie, A.-J., and Shen, Y.-H., Chem. Abs., 143, 439774 (2005). Basilio, N., Garcia-Rio, L., Leis, J. R., Mejuto, J. C., and Perez-Lorenzo, M., Chem. Commun. (Cambridge), 2005, 3817. Bunton, C. A., J. Phys. Org. Chem., 18, 115 (2005). Zhang, X. and Houk, K. N., Acc. Chem. Res., 38, 379 (2005). Bruice, T. C. and Bruice, P. Y., J. Am. Chem. Soc., 127, 12478 (2005). Menger, F. M., Pure Appl. Chem., 77, 1873 (2005). Guo, H., Wlodawer, A., and Guo, H., J. Am. Chem. Soc., 127, 15662 (2005). Michaux, C., Charlier, P., Frere, J.-M., and Wouters, J., J. Am. Chem. Soc., 127, 3262 (2005). Bazzicalupi, C., Bencini, A., Berni, E., and Di Vaira, M., Chem. Abs., 142, 197446 (2005). Maxwell, C., Neverov, A. A., and Brown, R. S., Org. Biomol. Chem., 3, 4329 (2005). Cheng, S.-Q., Chem. Abs., 143, 211535 (2005). Tian, Y., Huang, Z., Hu, Y., Kou, X., Hu, C., and Zeng, X., Chem. Abs., 143, 459647 (2005). Rangelov, M. A., Vayssilov, G. N., Yomtova, V. M., and Petkov, D. D., Org. Biomol. Chem., 3, 737 (2005). Stamatov, S. D. and Stawinski, J., Tetrahedron, 61, 3659 (2005). Condamine, E., Moore, G., Marsais, F., Dupas, G., Papamicael, C., and Levacher, V., Chem. Lett., 34, 912 (2005). Morgan, K. M., Rawlins, M. L., and Montgomery, M. N., J. Phys. Org. Chem., 18, 310 (2005). Mujika, J. I., Mercero, J. M., and Lopez, X., J. Am. Chem. Soc., 127, 4445 (2005). Mennenga, A. G., Johnson, A. L., and Nagorski, R. W., Tetrahedron Lett., 46, 3079 (2005). Garcias, R. C., Coll, M., Donoso, J., Vilanova, B., and Munoz, F., Int. J. Chem. Kinet., 37, 434 (2005). Fasoli, H. J. and Frau, J., Helv. Chim. Acta, 88, 774 (2005). Arcelli, A., Cecchi, R., Prozi, G., and Sandri, M., J. Phys. Org. Chem., 18, 255 (2005). Arantes, G. M. and Chaimovich, H., J. Phys. Chem. A, 109, 5625 (2005). Kirby, A. J., Dutta-Roy, N., da Silva, D., Goodman, J. M., Lima, M. F., Roussev, C. D., and Nome, F., J. Am. Chem. Soc., 127, 7033 (2005). Onyido, I., Albright, K., and Buncel, E., Org. Biomol. Chem., 3, 1468 (2005). Gibson, G. T. T., Neverov, A. A., Teng, A. C.-T., and Brown, R. S., Can. J. Chem., 83, 1268 (2005). Zhang, J., Xie, J.-Q., Tang, Y., Li, J., Li, J.-Z., Zeng, W., and Hu, C.-W., J. Chem. Res. (S), 2005, 130. Maldonado, A. L. and Yatsimirsky, A. K., Org. Biomol. Chem., 3, 2859 (2005). Longhinotti, E., Domingos, J. B., de Silva, P. L. F., Szpoganicz, B., and Nome, F., J. Phys. Org. Chem., 18, 167 (2005). Schefer, U., Strick, A., Ludwig, V., Peter, S., Kalden, E., and Goebel, M. W., J. Am. Chem. Soc., 127, 2211 (2005). Virtanen, N., Polari, L., Vaelilae, M., and Mikkola, S., J. Phys. Org. Chem., 18, 385 (2005). Liu, T., Neverov, A. A., Tsang, J. S. W., and Brown, R. S., Org. Biomol. Chem., 3, 1525 (2005). Lewis, R. E., Neverov, A. A., and Brown, R. S., Org. Biomol. Chem., 3, 4082 (2005). Loennberg, T. and Korhonen, J., J. Am. Chem. Soc., 127, 7752 (2005). Jones, S., Northen, J., and Rolfe, A., Chem. Commun. (Cambridge), 2005, 3832. Seckute, J., Menke J. L., Emnett, R. J., Patterson, E. V., and Cramer, C. J., J. Org. Chem., 70, 8649 (2005). Purcell, J. and Hengge, A. C., J. Org. Chem., 70, 8437 (2005). Onyido, I., Swierczek, K., Purcell, J., and Hengge A. C., J. Am. Chem. Soc., 127, 7703 (2005). Kirby, A. J., Gesser, J. C., Hollfelder, F., Priebe, J. P., and Nome, F., Can. J. Chem., 83, 1629 (2005). Gomes, J. R. B. and Gomes, P., Tetrahedron, 61, 2705 (2005).

CHAPTER 3

Oxidation and Reduction

K. K. Banerji Faculty of Science, National Law University, Mandore, Jodhpur, India Oxidation by Metal Ions and Related Species . . . . Chromium, Manganese, and Nickel . . . . . . . Copper, Silver, and Gold . . . . . . . . . . . . Cerium and Vanadium . . . . . . . . . . . . . . Lead and Palladium . . . . . . . . . . . . . . . Lanthanides . . . . . . . . . . . . . . . . . . . Group VIII Metals . . . . . . . . . . . . . . . . Oxidation by Compounds of Non-metallic Elements . Nitrogen and Sulfur . . . . . . . . . . . . . . . Halogens . . . . . . . . . . . . . . . . . . . . . Ozonolysis and Ozonation . . . . . . . . . . . . . . . Peracids and Peroxides . . . . . . . . . . . . . . . . Photo-oxygenation and Singlet Oxygen . . . . . . . . Triplet Oxygen and Autoxidation . . . . . . . . . . . Other Oxidations . . . . . . . . . . . . . . . . . . . . Reduction by Complex Metal Hydrides . . . . . . . Other Reductions . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

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85 85 87 88 88 89 89 93 93 96 101 101 109 109 113 115 118 123

Oxidation by Metal Ions and Related Species Chromium, Manganese, and Nickel Oxidation of several primary aliphatic alcohols with potassium dichromate, pyridinium dichromate, quinolinium dichromate (QDC), imidazolium dichromate, nicotinium dichromate, isonicotinium dichromate, pyridinium fluorochromate (PFC), quinolinium fluorochromate, imidazolium fluorochromate, pyridinium chlorochromate (PCC), quinolinium chlorochromate (QCC), and pyridinium bromochromate (PBC), in aqueous acetic acid and in the presence of perchloric acid, showed similar kinetics. The values of the reaction constants did not differ significantly, indicating operation of a common mechanism.1 In the 2,2 -bipyridine(bipy)-catalysed Cr(VI) oxidation of DMSO to the sulfone, a Cr(VI)–bipy complex is formed in a pre-equilibrium step, which undergoes nucleophilic attack by DMSO to form a positively charged reactive intermediate. The Organic Reaction Mechanisms · 2005: An annual survey covering the literature dated January to December 2005 Edited by A. C. Knipe © 2008 John Wiley & Sons, Ltd. ISBN: 978-0-470-03403-3

85

86


anionic surfactant (SDS) accelerates the process whereas the cationic surfactant (CPC) retards the reaction.2 The catalytic activities of bipy and oxalic acid in the chromic acid oxidation of some substituted trans-cinnamic acids have been investigated in acidic solutions. The Cr(VI)–bipy and Cr(VI)–oxalic acid complexes are believed to be the probable reactive electrophiles in this redox process. Electron-releasing groups enhance the reactivity to a significant extent whereas the electron-withdrawing groups reduce the rate marginally. It appears that the oxidation of unsaturated systems involves an electrophilic attack of the reactive complex at the C–C double bond.3 The effect of metal ions such as Mn(II) and Fe(II) and complexing ligands such as EDTA, salicylic acid, phthalic acid, and oxalic acid on the chromic acid oxidation of pentan-1-ol and pentan-2-ol has been studied.4 The oxidation of substituted β-benzoylpropionic acids by PFC follows the Hammett relation with a negative reaction constant. A possible mechanism for the oxidation has been discussed.5 The oxidation of maleic, fumaric, crotonic, and cinnamic acids by PCC is of first order with respect to PCC and the acid. The oxidation rate in 19 organic solvents has been analysed by Kamlet’s and Swain’s multiparametric equations. A mechanism involving a three-centre transition state has been postulated.6 The relative reactivity of bishomoallylic tertiary alcohols toward PCC, to yield substituted THF products via the tethered chromate ester, is dependent only on the number of alkyl groups. This observation suggests a symmetrical transition state in this intramolecular Cr(VI)–alkene reaction.7 Mechanisms have been proposed for the oxidation of 2-nitrobenzaldehyde with PBC8 and of crotonaldehyde with tetraethylammonium chlorochromate.9 Zucker–Hammett treatment showed that water acts as a proton-abstracting agent in the slow step of oxidation of aliphatic aldehydes by QDC. Hydrated aldehydes and protonated QDC are suggested as reactive species.10 A rate-determining decomposition of the chromate ester of aldehyde hydrate has been suggested in the oxidation of aliphatic hydrates by QDC.11 The oxidation of alkan-2-ones,12 benzoic acid,13 and substituted benzoic acids14 by QDC is proposed to involve formation of a cyclic chromate ester, which undergoes decomposition to yield the corresponding hydroxy acids. Mechanisms have been proposed for the oxidation of maleic and acrylic acids15 and of methionine with QCC.16 The oxidation of four vicinal and four non-vicinal diols and two of their monoethers by quinolinium bromochromate is of second order. The oxidation of [1,1,2,2-2 H4 ]ethanediol exhibited a primary kinetic isotope effect, kH /kD = 5.83 at 298 K. The temperature dependence of the kinetic isotope effect indicated a symmetrical transition state in the rate-determining step.17 The recent developments in homogenous Mn(salen)- and Cr(salen)-mediated asymmetric epoxidation, with a variety of co-oxidants, have been reviewed. The possible mechanistic pathways (including concerted reaction and metallooxetane intermediate formation) and trajectory of alkene approach are discussed on the basis of experimental results and theoretical calculations.18 Jacobsen epoxidation of cyclohexa-1,4-dienes allowed a direct comparison of Mn (III)salen-catalysed epoxidation and C–H oxidation within the same molecule

87

3 Oxidation and Reduction

and showed evidence for radical pathways during the epoxidation.19 A dynamic supramolecular system involving hydrogen bonding between an Mn(III)salen catalyst and a Zn(II) porphyrin receptor exhibited chemoselectivity for pyridine appended cis-β-substituted styrene derivatives over phenyl appended derivatives in a catalytic epoxidation reaction.20 A mechanism involving the formation of a complex between the oxidant and substrate has been proposed for ruthenium(III)-catalysed oxidation of atenolol by alkaline permanganate21 and for the oxidation of l-proline by alkaline permanganate.22 A positive Hammett rho value has been determined for the oxidation of acetophenone by acid permanganate, which is first order with respect to both the substrate and oxidant, and a suitable mechanism has been proposed.23 The oxidation of toluene with acidic permanganate, in the presence of Mn(II), takes place by two pathways, direct oxidation by permanganate and oxidation by Mn(III), generated by the reaction of permanganate and Mn(II). Several possible reaction mechanisms are discussed.24 Ruthenium(III)-catalysed oxidation of atenolol25 and of 4-hydroxycoumarin26 with diperiodatonickelate(IV) (DPN) in alkaline medium showed a first-order dependence on DPN and ruthenium(III) and apparent less than unit order dependence on both the reductant and alkali. Mechanisms involving the formation of a complex between the reductant and ruthenium(III) species, which reacts with DPN in a rate-determining step, resulting in the formation of a free radical, have been postulated.

Copper, Silver, and Gold The oxidation of isonicotinate ion by diperiodatocuprate(III) in aqueous alkali is proposed to involve the formation of an intermediate complex in a pre-equilibrium. The intermediate subsequently disproportionates in the rate-determining step.27 The oxidation of glutamic acid by dihydroxydiperiodatoargentate(III) (DPA) in alkaline medium was found to be first order with respect to DPA and glutamic acid. No free radical was detected. A mechanism has been discussed.28 Gold has emerged as an effective catalyst for the selective oxidation of methane to methanol. Various possible pathways for the oxidation are discussed.29 Suitably substituted furans are transformed into phenols by the use of gold catalyst (1). It has been suggested, on the basis of kinetic isotope effect and trapping studies, that the key intermediate is an arene oxide. The postulation is also supported by DFT calculations.30

N Cl

Au Cl (1)

O

88


Cerium and Vanadium The Ru(III)-catalysed oxidation of phenethyl alcohol by Ce(IV) showed a firstorder dependence on Ce(IV) and fractional order with Ru(III). A linear Hammett plot is obtained with a negative reaction constant. A plausible mechanism has been proposed.31 Mechanisms involving the formation of an adduct in a pre-equilibrium have been proposed for the chromium(III)-catalysed oxidation of isobutyl alcohol32 and formic acid33 by cerium(IV) in dilute sulfuric acid. Ce(SO4 )2 has been found as the kinetically active species in both cases. Ce(NO3 )4 (H2 O)2 is assumed to be the reactive species in the Mn(II)-catalysed oxidation of amino alcohols by Ce(IV). A mechanism involving the formation of an Mn(III)–amino alcohol complex has been suggested.34 The oxidation of aliphatic ketones by ceric perchlorate, catalysed by iridium(III), is first order in catalyst, and first order with respect to oxidant and ketones at lower concentrations, tending to become zero order at higher concentrations.35 The cerium(IV) ammonium nitrate and N -bromosuccinimide combination converts oxiranes and aziridines to α-hydroxy ketones and α-amino ketones respectively, in excellent yields.36 Kinetic resolution of secondary alcohols has been efficiently achieved using a vanadium(V) complex and oxygen as a stoichiometric oxidant. The ligand architecture allows access to both enantiomers of a secondary alcohol by choice of ligand stereoisomer. The mild reaction conditions and chemoselectivity of the catalyst system provide access to a range of α-hydroxy esters in high yields and excellent enantioselectivities. It has been shown that molecular oxygen functions solely to reoxidize a vanadium(IV) intermediate to the catalytically active vanadium(V) species, and its presence is not necessary for initial alcohol oxidation.37 A vanadium complex with C2 -symmetric bishydroxamic acids catalyses the epoxidation of allylic alcohols with ees up to 97% and excellent yields. The catalysts have been used for kinetic resolution of secondary allylic alcohols with high ee. The structure of a possible intermediate has been suggested.38 A computational study with the IMOMM (Becke3LYP:MM3) method has been carried out on the mechanism of the enantioselective reaction of complex V(O)(L)(OOH) (L = bulky tridentate Schiff base) and bis(t-butyl) disulfide. The experimental trends in selectivity for catalysts are reproduced by the calculations. The reaction model, generated by the computational analysis, explained one of the most remarkable aspects of this reaction, namely the large effect on enantioselectivity of ligands seemingly far from each other in the catalyst.39

Lead and Palladium B3LYP modelling of the reaction of lead tetraacetate with tricyclododec-10-enes indicated that the addition to the double bond is concerted.40 A chemo- and highly regio-selective Pd-catalysed allylic oxidation reaction that proceeds via a novel mechanism where two different ligands interact serially with palladium to promote different steps of the catalytic cycle has been reported. Initial formation of a dimeric π -allylpalladium acetate complex has been proposed.41

ee

ee


89

A Pd-catalysed method for C–H activation/C–C bond formation, with iodine(III) reagent, [Ph2 I]BF4 , has been reported. The reaction showed a high functional group tolerance, regioselectivity, and scope under relatively mild conditions. Preliminary mechanistic experiments have provided evidence in support of a Pd(II)/(IV) catalytic cycle for this transformation.42

Lanthanides A catalytic asymmetric epoxidation reaction of α,β-unsaturated esters via conjugate addition of an oxidant using chiral yttrium–biphenyldiol–Ph3 As=O complexes has been developed. Yields up to 90% and ees up to 99% have been achieved.43

ee

Group VIII Metals Osmium-catalysed dihydroxylation has been reviewed with emphasis on the use of new reoxidants and recycling of the catalysts.44 Various aspects of asymmetric dihydroxylation of alkenes by osmium complexes, including the mechanism, acceleration by chiral ligands,45 and development of novel asymmetric dihydroxylation processes,46 has been reviewed. Two reviews on the recent developments in osmium-catalysed asymmetric aminohydroxylation of alkenes have appeared. Factors responsible for chemo-, enantio- and regio-selectivities have been discussed.47,48 Osmium tetraoxide oxidizes unactivated alkanes in aqueous base. Isobutane is oxidized to t-butyl alcohol, cyclohexane to a mixture of adipate and succinate, toluene to benzoate, and both ethane and propane to acetate in low yields. The data are consistent with a concerted 3 + 2 mechanism, analogous to that proposed for alkane oxidation by RuO4 , and for alkene oxidations by OsO4 .49 Sharpless asymmetric dihydroxylation in ionic liquids followed by use of supercritical carbon dioxide in the separation process allowed the isolation of the diol, in high yield and ee.50 Os(VIII)-catalysed asymmetric aminohydroxylations of chiral, nonracemic acrylamides, with chloramine-T as the stoichiometric oxidant, are proposed to proceed via osma(VI)azaglyolate and osma(VIII)azaglycolate intermediates.51 An enantioselective synthesis of several β-adrenergic blocking agents has been achieved. The key steps are Os(VIII)-catalysed Sharpless asymmetric dihydoxylation of aryl allyl ethers and conversion of cyclic sulfates into corresponding epoxides.52 Excellent regioselectivities were obtained in Sharpless asymmetric dihydroxylation of straight-chain dienoates, all trienoates, ketones, and amides. Lower regiocontrol was observed in remotely branched isopropyl and t-butyl dienoates. This has been attributed to steric interaction between the branched methyl group of isopropyl or tbutyl groups and the ethyl group on the (DHQD)2 PHAL ligand.53 Introduction of an aryl ketamine group in allylic amines improved the stereoselectivity in their osmiumcatalysed dihydroxylation reaction. With (E)-compounds, anti selectivity up to 19:1 and with (Z)-compounds syn selectivity of >100:1 are obtained. Probable transition states for the oxidation have been suggested.54 Oxidative cyclization of diols derived from 1,5-dienes to yield enantiopure cis-tetrahydrofurans has been achieved with catalytic amounts of osmium tetroxide in acidic solutions.55

ee

ee

ee

de

90


Pincer-ligated iridium complexes have been used as homogeneous catalysts for the dehydrogenation of aliphatic polyalkenes to give partially unsaturated polymers. The catalyst appears to be selective for dehydrogenation in branches as compared with the backbone of the polymer.56 The mechanism shown in Scheme 1 has been suggested for an [IrCl(cod)]2 -catalysed oxidative esterification reaction of aliphatic aldehydes and olefinic alcohols.57 O Ph

CHO

+ Ph

OH

Ph

O

Ph

Ph Ir O Ph

Ph

Ir O

O

H

Ph

H O

Scheme 1

DFT calculations have shown that in C–H hydroxylation of cyclohexane, the nonhaem oxidant (N4 Py)FeIV =O2+ is more reactive than P450 Cpd I and is predicted to involve multi-state reactivity with a strong solvent effect and a temperature-dependent stereoselectivity reflecting spin crossover effects.58 The oxidation of cyclobutanol with haem and non-haem oxoiron(IV) species yielded exclusively cyclobutanone, demonstrating that the oxidation is a two-electron process. The oxidation of deuteriated benzyl alcohol (C6 D5 CD2 OH) exhibited a very large kinetic isotope effect, confirming cleavage of the α-C–H bond in the rate-determining step. The oxidation of para-substituted benzyl alcohols yielded a Hammett reaction constant, ρ ≈ −0.4. Oxidation with [(N4 Py)Fe(IV)=18 O]2+ indicated a hydride-ion transfer during the formation of benzaldehyde.59 The oxidation of ascorbic acid with Fe(CN)5 L2− (L = pyridine, isonicotinamide, or 4,4 -bipyridine) complexes is postulated to proceed as a rate-determining reaction between Fe(III) complexes and the ascorbic acid in the form of H2 A, HA− , and A2− , depending on the pH of the solution, followed by rapid scavenging of the ascorbic acid radicals by Fe(III) complex. The kinetic results are compatible with the Marcus prediction.60 The oxidation of substituted 4-oxo-4-arylbutanoic acids by hexacyanoferrate(III) [HCF(III)] in aqueous alkaline medium is first order in the oxo acid, hydroxide ion, and the HCF(III) ion. A mechanism involving the formation of enolate anion from the oxo compound and subsequent rate-determining electron transfer is proposed.


91

Application of the Olson–Simonson rule substantiated the participation of negatively charged ions in the rate-determining step. The reaction constant, ρ, is positive.61 The retarding effect of 18-crown-6 and benzo-15-crown-5 on the oxidation of triethylamine and N -methylpyrrolidine by alkaline HCF(III) is found to be dependent on the concentration of crown ether.62 Ruthenium(VI)-catalysed oxidation of propane-1,2-diol, cyclohexane-1,2-diol, and propanetriol by alkaline HCF(III) exhibits a zero-order dependence on HCF(III) and first-order dependence on Ru(VI) and the rate increased with a decrease in alkali concentration. The reaction showed a Michaelis–Menten type of behaviour with respect to the reductant. A tentative mechanism has been proposed.63 In the ruthenium(III)catalysed oxidation of sulfanilic acid by HCF(III) in alkaline medium, the proposed ruthenium(III) active species is [Ru(H2 O)5 OH]2+ .64 Iridium(III) chloride-catalysed oxidation of diethylene glycol by alkaline HCF(III) is proposed to proceed through complex formation.65 Oxidation of benzoin to benzil with Fe(III), in the presence of 2,2 -bipyridine or ferrozine is of first order in Fe(III) and benzoin. An inverse second-order dependence was observed with respect to hydrogen ions. For oxidation of substituted benzoins the reaction constant is ρ ≈ 1.2, indicating an electron-rich transition state and an inner sphere mechanism has been proposed.66 The order with respect to iodide, in the reaction of iodide ions with a diiron(III)–1,10-phenanthroline complex, is 2. The hydrolytic derivatives of the complex are not kinetically active. Both inner and outer sphere pathways are operative.67 The oxidation of 1-phenyl-2-(4-methylphenyl)diazenes, 4 -substituted with a dimethylamino or methoxy group, with ferric chloride resulted in the generation of radical cation by a single electron transfer. It has been proposed that an electron, in the first step of oxidation, is extracted from the azo and/or from the amino nitrogen atom.68 The oxidation of 2 -deoxyguanosine 3 -monophosphate (3 -dGMP) with [Pt(IV)Cl4 (dach)] (dach = diaminocyclohexane) has been reported. The final oxidation product is cyclic [5 -O-C(8)]-3 -dGMP. The proposed mechanism (Scheme 2) involves Pt(IV) binding to N(7) of 3 -dGMP followed by nucleophilic attack of a 5 -hydroxyl oxygen to C(8) of G and an inner-sphere, two-electron transfer to produce cyclic [5 -O-C(8)]3 -dGMP and [Pt(II)Cl2 (dach)].69 Oxidation of organic compounds by ruthenium tetraoxide has been reviewed. The oxidation of various types of organic compounds such as alkanes, alkenes, allenes, aromatic rings, alcohols, amines, and sulfides has been discussed The cyclic oxoruthenium(VI) diesters that are formed in the initial step of the oxidation of alkenes are considered to be intermediates in the formation of 1,2-diols.70 The development of new and selective oxidative transformations under ruthenium tetroxide catalysis during the past 10 years has been reviewed. The state of research in this field is summarized and a systematic overview of the reactivity and the reaction mode of ruthenium tetroxide is given.71 It has been shown that toxic carbon tetrachloride can be replaced by ethyl acetate in the ruthenium-catalysed oxidation of alkenes and monoenic fatty acids. Oxidative

92


Pt (dach) Cl4 + 3′-d GMP

H2 N Cl Cl Pt Cl N H2 O

−Cl−

N

NH

H N

HO

N

NH2

O

O O

P

O−

OR −Cl− −2H+

H2 N

Cl Pt

N H2

O N

+

N

O

Cl

N O

N

NH2

O O

P

O−

OR Scheme 2

cleavage of the C=C bond was accomplished in good yields with H2 O–MeCN–AcOEt solvent system.72 For the ruthenium tetraoxide-catalysed oxidation of propan-1-ol by diperiodatocuprate(III), hexacyanoferrate(III), periodate, and chloramine-T, a mechanism of direct reaction between Ru(VIII) and propan-1-ol in a slow step to give propanal and Ru(VI) followed by a fast oxidation of Ru(VI) to Ru(VIII) by the co-oxidant has been proposed.73 Complex (2) is an effective catalyst for the asymmetric hydroxylation of aromatic hydrocarbons with 2,6-dichloropyridine N -oxide as terminal oxidant. Up to 76% ee was achieved for the catalytic hydroxylation of 4-ethyltoluene, 1,1-diethylindane, and benzylcyclopropane. Both electron-donating and -withdrawing substituents were found to accelerate the catalytic oxidation reaction. A large primary kinetic isotope effect (kH /kD = 11 at 298 K) was observed for the catalytic ethylbenzene-d10 oxidation. A

ee

93


N

X

N

Ru N

Y

N

(2) a; X = CO, Y = MeOH, Ru(II) b; X = Y = O2−, Ru(IV)

mechanism involving rate-limiting hydrogen atom abstraction by reactive oxoruthenium species is postulated.74

Oxidation by Compounds of Non-metallic Elements Nitrogen and Sulfur The 2,6-dichloropyridine N -oxide–Ru(IV)(TMP)Cl2 (TMP = tetramesitylporphyrinato) system converts N -acyl cyclic amines to N -acylamino acids via oxidative C–N bond cleavage. The kinetic isotope effect was measured using N -benzoyl[2,2d2 ]pyrrolidine. The intramolecular kinetic isotope effect in the oxidation of was found to be 9.8 ± 0.2, strongly suggesting that the rate-determining step is hydrogen abstraction and not one-electron oxidation.75 A catalytic system, based on TEMPO and Cu(II), has been developed for the selective oxidation of primary alcohols to aldehydes under very mild conditions. Cu(II) is generated in situ by oxidation of elemental copper and chelated by means of 2,2 -bipyridine. The reaction is dependent on pH. New insights into the currently accepted mechanism have been discussed.76 Allylic and benzylic alcohols are selectively oxidized with trimethylamine N -oxide in the presence of cyclohexa-1,3dieneiron carbonyl.77 Three newly synthesized C2 -symmetric bicyclic nitroxides with α-hydrogens showed high efficiency and good turnover as catalysts for the oxidation of alcohols but only one showed modest enantioselectivity. The rationale for poor selectivity is attributed to the alkyl methyl substituents around the nitroxide not providing enough steric interaction to induce selectivity.78 Iminium salt-catalysed epoxidation reactions have been carried out in organic solvents, including dichloromethane and acetonitrile, with tetraphenylphosphonium

ee

94


monoperoxybisulfate as the stoichiometric oxidant. The iminium is initially oxidized to oxaziridinium salt (3), which is the reactive species of epoxidation. The reaction is moderately diastereoselective.79

+

de

Ph

N

O

O O (3)

Benzene has been observed as a product of both the OH- and NO2 -initiated oxidation of cyclohexa-1,3-diene, indicating a hydrogen atom abstraction in both reactions. In the presence of NO and molecular oxygen, the NO2 -initiated reaction leads to removal of cyclohexa-1,3-diene by reaction with both NO2 and OH. Formic acid was detected as a product in this system, providing evidence for significant formation of stabilized C6 α-hydroxyperoxy radicals from the OH-initiated chemistry, and their subsequent reaction with NO. Mechanisms consistent with the observations have been proposed.80 Reaction pathways are calculated by the DFT method in the B2LYP/6–31G∗ approximation for direct oxidation of cyclohexene and butene with nitrous oxide. Two possible reaction channels differing in their intermediates are analysed. Two-step mechanisms are predicted for the reactions.81 Proline-derived sulfonylcarboxamides are excellent catalysts for the direct enantioselective α-oxidation of ketones and aldehydes with nitrosobenzene. The alkyland arylsulfonylcarboxamides furnished the corresponding α-aminoxylated products in good yields with up to >99% ee.82 Oxidation of indole-3-acetic acid with peroxodisulfate (PDS) showed a first-order dependence on PDS and the reductant. Added hydrogen ions had no effect on the reaction. The non-radical mechanism shown in Scheme 3 has been proposed.83 First-order dependence is observed with respect to both the oxidant and reductant in the oxidation of substituted anilines with peroxomonosulfate anion. Addition of acid causes retardation of the reaction. Yukawa–Tsuno correlation of the rates gave a negative reaction constant (ρ ≈ −1.7) and analysis of the effect of solvent in terms of Grunwald–Winstein equation (m ≈ 0.4) indicated an SN 2-type reaction. A mechanism involving a nucleophilic attack of the amine on the persulfate oxygen has been proposed.84 Possible mechanisms have been discussed for the oxidation of sulfanilic acid,85 benzaldehyde, p-nitrobenzaldehyde,86 and cyclic ketones87 with peroxomonosulfuric acid. The role of the acid catalyst during the oxidation of epoxides with DMSO has been explored by DFT studies of three acids, namely H3 O+ , Li+ , and Mg2+ . Stationary points have been obtained at the B3LYP/6–31++G(d,p) level of theory and the reaction barriers have been evaluated through free-energy calculations. The mechanism proceeds in two steps, namely ring opening followed by an intramolecular proton transfer that leads to an α-hydroxy carbonyl compound.88 The epoxidation

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3 Oxidation and Reduction CH2COOH +

−

O

O2S

O O

Slow

SO2 O−

−SO42−

H

N H

CH2COOH

CH2COOH O +

SO2 O−

O

H

N

N H

H

H

−H+

SO2

O

CH2COOH −HSO4−

O

N H

H

O

SO2 O− H O

HOOCH2C −O

N

O2S

O

O

SO2O− +

−SO42−

OH

N H

H CH2

−HSO4− −CO2

+

N

N H

H

CH2 OH

C

O

H

O

CH2

−H+

OH

SO2 O−

O

Scheme 3

of β-methylstyrene with Oxone (potassium peroxymonosulfate) catalysed by the Shi fructose-derived ketone has been studied using experimental kinetic isotope effects and DFT calculations. The observation of a large β-olefinic 13 C isotope effect and a small α-carbon isotope effect indicated an asynchronous transition state with more advanced formation of the C–O bond to the β-olefinic carbon.89 Arabinose-derived ketones, containing a butane-2,3-diol moiety as the steric blocker, displays ee up to 90% in the catalytic asymmetric epoxidation of trans-disubstituted and trisubstituted alkenes with Oxone. The stereochemical outcome has been attributed to steric effects with no contribution from electronic effects.90 Cyclooctene and other alkenes are epoxidized in almost quantitative yields with Oxone in an aqueous micellar solution of an amphiphilic ketone, which was derived from hepta(ethylene glycol)monodecyl ether.91 Chiral cyclic secondary amines bearing a fluorine atom at the β-position relative to the amino centre catalyse the asymmetric epoxidation of alkenes using Oxone. A dual role, as a phase-transfer catalyst and an Oxone activator, has been suggested for the amine in these epoxidation reactions.92

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Trisubstituted cyclic alkenes have been kinetically resolved via a chiral dioxirane (4), generated in situ from the ketone and Oxone. A sequential desymmetrization and kinetic resolution of cyclohexa-1,4-dienes has also been achieved. The observed stereochemical results have been rationalized on the basis of a spiro-planar transition state model.93

O

O

ee

O O

O

O O (4)

A range of cis-substituted alkenes have been epoxidized with a new dihydroisoquinolinium salt catalyst, using tetraphenylphosphonium monoperoxysulfate as the stoichiometric oxidant, giving ees of up to 97%.94

Halogens The oxidation of sulfides to sulfoxides with halogens has been reviewed.95 The kinetics of the oxidation of 1-phenyl-2-thiourea by chlorite, in aqueous acidic media, are strongly influenced by the pH and show a complex acid dependence. The proposed mechanism involves HOCl as a major intermediate whose autocatalytic production determines the observed kinetics of the reaction. The oxidation involved the formation of two stable intermediates, the sulfinic acid and the sulfonic acid, on the pathway towards total desulfurization to form phenylurea. A comprehensive 29reaction scheme has been proposed to describe the observed complex kinetics.96 The oxidation of trimethylthiourea (TMTU) by chlorite in slightly acidic media is very fast. The oxidation of TMTU proceeds through the formation of sulfinic acid then to the sulfoxylate anion. The direct reaction of chlorine dioxide and TMTU is autocatalytic and is also inhibited by acid. A series of 28 reactions have been proposed to describe the mechanism.97 Oxidation of piperidinone thiosemicarbazones with chloramine-T (CAT) is first order in CAT and fractional order in the substrate. The reaction showed an inverse fractional order dependence on acidity. A plausible mechanism has been indicated.98 Kinetics of oxidation of n-propylamine and n-butylamine by CAT and chloramine-B (CAB) have been determined and mechanisms have been proposed.99 Mechanisms have been proposed and rate laws derived for the oxidation of dimethylglyoxime100 and p-cresol101 with CAT. The oxidation of pantothenic acid (PA) by CAT in acid solution is first order in CAT and exhibits a frational order with respect to PA. The reaction is retarded by an increase

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in the acidity of the solution. The rate decreases in deuterium oxide. A mechanism involving an attack by TsNHCl on the amide-carbonyl group to form a hypochlorite derivative has been suggested. The oxidation in alkaline medium, catalysed by Os(VIII), is first order in PA and fractional order in alkali and Os(VIII). A mechanism in which a TsNHCl–Os(VIII) complex attacks the amide-carbonyl group, in the ratedetermining step, has been suggested.102 The kinetics of Pd(II)- and Os(VIII)-catalysed oxidation of crotonic acid by CAT in perchloric acid have been interpreted.103 Mechanisms for the Os(VIII)-catalysed oxidation of maleic and fumaric acids with CAT in alkaline medium have been postulated. The mode of oxidation of the acids differed and is attributed to their geometric forms.104 The kinetics of the Os(VIII)-catalysed oxidation of alanine,105 valine, and leucine106 with CAT were obtained and mechanisms have been suggested. Alkenes are oxidized to 2-amino ketones in an osmium-catalysed oxidation with CAT. The reaction can also be carried out as a sequential process consisting of asymmetric aminohydroxylation and subsequent oxidation to enantiopure 2-amino ketones.107 The kinetics of oxidation of d-fructose and d-glucose in aqueous alkaline medium with nine sodium salts of mono- and di-substituted N -chloroarylsulfonamides have been determined. The Hammett reaction constants, ρ, for the oxidation of glucose and fructose are 0.28 and 0.54, respectively. The results have been explained by a plausible mechanism, and the related rate laws have been deduced.108 It has been suggested that the oxidation of benzaldehyde and o-chlorobenzaldehyde with N -chlorosaccharin involves a reaction of the hydrated form of the aldehydes and (H2 OCl)+ .109 N -t-Butyl-N -chlorocyanamide, a source of positive chlorine, oxidizes sulfides to sulfoxides, in aqueous acetonitrile, in a highly chemoselective way. The yields are almost quantitative.110 Kinetics of oxidation of propan2-ol111 and 2,4-dichlorophenoxyacetic acid112 with trichloroisocyanuric acid have been determined and mechanisms have been proposed. Kinetics have been determined and mechanisms have been proposed for the oxidation of substituted acetanilides by trichloromelamine113 and for the oxidation of chloramphenicol by 1-chlorobenzotriazole in acid solution.114 A facile, substrate-selective and transition metal-free oxidation of alcohols catalysed by β-cyclodextrin with sodium hypochlorite as an oxidant, using water as the only solvent, has been developed.115 Oxidation of metronidazole with bromamine-T (BAT), in both acidic and alkaline solutions, has been reported. In acidic solutions, (TsNH2 Br)+ has been proposed as the oxidizing species, whereas in alkaline solutions, the postulated reactive oxidizing species is either HOBr or OBr− .116 Electron-withdrawing groups enhance the rate whereas electron-releasing groups inhibit the rate of Os(VIII)-catalysed bromamine-B (BAB) oxidation of diaryl sulfoxides. The anion RNBr− is postulated as the reactive oxidizing species and a probable reaction mechanism has been discussed.117 Ru(III)-catalysed oxidation of p-hydroxyazobenzene (PHAB) by four sodium N haloarenesulfonamidates show first-order dependences on the oxidant, PHAB and Ru(III), and less than first-order dependence on hydrogen ions. The rates follow the sequence BAB > BAT > CAB > CAT. This effect is attributed to electronic factors.118 Ru(III)-catalysed oxidation of cyclopentanol and cyclohexanol with

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N -bromoacetamide (NBA) is of zero order in the alcohol and first order with respect to both NBA and Ru(III). An increase in the concentration of acid and chloride ion increases the rate, whereas addition of acetamide reduces the rate. (H2 OBr)+ and (RuCl6 )3− have been postulated as the reactive species. A hydride-ion transfer from the alcohol has been suggested.119 Mechanisms have been suggested for the N -bromosuccinimide (NBS) oxidation of cyclopentanol and cyclohexanol, catalysed by iridium(III) chloride,120 of ethanolamine, diethanolamine, and triethanolamine in alkaline medium,121 and for ruthenium(III)catalysed and uncatalysed oxidation of ethylamine and benzylamine.122 A suitable mechanism has been suggested to explain the break in the Hammett plot observed in the oxidation of substituted acetophenone oximes by NBS in acidic solution.123 Oxidation of substituted benhydrols with NBS showed a C–H/C–D primary kinetic isotope effect and a linear correlation with σ + values with ρ = −0.69. A cyclic transition state in the absence of mineral acid and a non-cyclic transition state in the presence of the acid are proposed.124 Sulfides are selectively oxidized to sulfoxides with NBS, catalysed by β-cyclodextrin, in water. This reaction proceeds without over-oxidation to sulfones under mild conditions.125 The observed substituent effect on the reaction rate in the oxidation of substituted aliphatic ketoximes by N -bromosaccharin has been rationalized in terms of a mechanism.126 The oxidation of acetophenones with N -bromophthalimide exhibited a linear correlation with Brown’s σ + with reaction constant ρ = −0.52. An Exner plot gave an isokinetic temperature β = 263 K. A mechanism consistent with the kinetic data has been proposed.127 The oxidation of α-hydroxy acids by hexamethylenetetramine–bromine (HABR) is first order with respect to each of the hydroxy acids and HABR. The oxidation of α-deuteriomandelic acid exhibited a kinetic isotope effect of kH /kD = 5.91 at 298 K. The rates of oxidation of the substituted mandelic acids show excellent correlation with Brown’s σ + values with negative reaction constants. A mechanism involving transfer of a hydride ion from the acid to the oxidant has been postulated.128 Oxidation of thio acids by tetrabutylammonium tribromide showed Michaelis– Menten-type kinetics with respect to the thio acid. The effect of solvent composition was analysed using the Grunwald–Winstein equation. A mechanism involving the formation of an intermediate complex in the pre-equilibrium and its subsequent decomposition in a slow step is proposed.129 A new recyclable ditribromide reagent, 1,2-dipyridiniumtribromide–ethane, has been synthesized and used for the bromination of several aromatic compounds.130 Belousov–Zhabotinskii (B–Z) oscillations have been observed with a Ce4+ and acid bromate system having oxalic acid and glucose as a mixed organic substrate, neither of which alone acts as a bromine scavenger. Both single and double frequency oscillations have been observed. ESR and polymerization studies indicated the important role of free radicals in influencing the reaction mechanism. A tentative dual control mechanism has been suggested involving autocatalysis of HBrO2 and BrO2 .131 The effect of oxygen on the time-dependent bifurcations of transient oscillations in the B–Z oscillating chemical reaction of mandelic acid–bromate in a closed system has been studied. Experiments show that the oscillations disappear through


99

different bifurcations depending on the oxygen concentration in the gas phase above the reaction solution. A kinetic scheme consistent with the effects observed in has been described.132 Mechanisms have been proposed for ruthenium(III)-catalysed oxidation of leucine by acid bromate133 and for the chemoselective oxidation of vicinal diols to α-hydroxy ketones with NaBrO3 /NaHSO3 reagent.134 The oxidation of substituted benzylamines by pyridinium hydrobromide perbromide is of first order with respect to both the oxidant and the amine. The oxidation of deuterated benzylamine exhibited a kinetic isotope effect (kH /kD = 3.20 at 303 K.). The rates showed excellent correlations in terms of Taft’s and Charton’s multiparametric equations. A mechanism has been proposed.135 A catalytic amount of hydrobromic acid with an excess of hydrogen peroxide is found to be an effective reagent for the facile regeneration of carbonyl compounds from their 1,3-dithiane and 1,3-dithiolane derivatives.136 Bromide-assisted oxidation of substituted phenols with hydrogen peroxide, catalysed by heterogenous WO4 2− ions, resulted in the formation of p-quinols and their ethers in almost quantitative yields.137 The ruthenate ion-catalysed oxidation of d-galactose and d-xylose by alkaline periodate in an alkaline solution showed a zero-order dependence on reducing sugar and a first-order dependence on ruthenate ion. The first-order dependence of the reaction on periodate and alkali at their low concentrations tends to zero order at higher concentrations. A mechanism consistent with the kinetics has been proposed.138 The kinetics of the periodate oxidation of p-bromoaniline139 and 4-chloro-2-methylaniline140 have been determined and interpreted. It has been shown by density functional quantum mechanical calculations that the presence of a suitable ortho-substituent increases the alcohol oxidizing power of 2-iodoxybenzoic acid by lowering the barrier for hypervalent twisting of a 2iodoxybenzoic acid–alcohol intermediate; this coordinated motion of ligands is driven by the need to generate a stable, planar form of the by-product 2-iodobenzoic acid.141 Selective oxidation of N -alkyl-N -arylthioureas by using 1-(4-diacetoxyiodobenzyl)3-methylimidazolium tetrafluoroborate ([dibmim]+ [BF4 ]− ) in ionic liquids resulted in the formation of 2,4-dialkyl-3,5-bis(arylimino)-1,2,4-thiadiazolidines in good yields.142 In an ionic liquid, [dibmim]+ [BF4 ]− oxidizes primary and secondary alcohols to the carbonyl compounds in high yield. No over-oxidation of aldehydes to carboxylic acids was observed.143 Palladium-catalysed directed C–H oxidation with (diacetoxy)iodobenzene of a series of meta-substituted aryl pyridine and aryl amide derivatives resulted in the formation of the corresponding acetoxy compounds. The reactions generally proceed with high levels of regioselectivity for functionalization of the less sterically hindered ortho-C–H bond.144 The mechanism shown in Scheme 4 has been proposed for the oxidation of 2,6-dimethylphenol with (diacetoxyiodo)benzene for the formation of 3,5,3 ,5 tetramethyl-biphenyl-4,4 -diol, via C–C coupling.145 Symmetrical and unsymmetrical aldazines are converted to 2,5-disubstituted 1,3,4oxadiazoles by oxidation with bis(trifluoroacetoxy)iodobenzene in yields ranging from 49 to 80%.146 Lithium bromide catalyses efficiently the dihydroxylation of alkenes

100


OH + Phl (OAc)2

O

O

2,6-dmp

+ 2,6-dmp

HO

OH

Scheme 4

R3SiO

H

O

R1

R1

n

R3SiOH

R3SiO

H

OH

R1

n

OSiR3 R1

(salen) MnIII

PhlO

Phl R3SiO R

1

H

OSiR3 n

R

1

(salen) MnIV OH (salen) MnV = O

R3SiO R1

H

H n

OSiR3 R1

Scheme 5

to afford syn- and anti -diols with excellent diastereoselectivity depending on the use of sodium periodate or (diacetoxyiodo)benzene, respectively, as the oxidant.147 Direct oxidation of symmetrical alkanes with iodosylbenzene to give optically active ketones, in the presence of chiral Mn(salen) complex catalysts, has been achieved. The catalytic system can be applied to the enantioselective oxidative transformation of 1,3-


101

and 1,4-disilyl ethers to the corresponding optically active β- and γ -siloxy ketones, respectively, with high enantioselectivity (up to 93% ee). The observed kinetic isotope effect (kH /kD = 7.1) indicated the cleavage of a C–H bond in the rate-determining step; Scheme 5 has been proposed to account for the results.148 Addition of 2,4,6-tri-t-butylphenolate in the Mn(salen)-catalysed epoxidation of cis-alkenes with iodosobenzene yielded essentially pure trans-epoxides.149 Alcohols are selectively oxidized to carbonyl products under anaerobic conditions with aqueous I2 –KI–K2 CO3 . The yields are excellent. A mechanism involving formation of a hypoiodide ester as an intermediate has been proposed.150 Oxidation of two major metabolites formed after S-oxygenation of dimethylthiourea, viz. dimethylaminoiminomethanesulfinic acid and dimethylaminoiminomethanesulfonic acid, with iodine and acidic iodate has been studied to explain the observed genotoxicity.151 Simple acyclic ketones are oxidized to (Z)-2,3-trisubstituted α,β-unsaturated esters in the presence of iodine. Mechanistic studies suggest that an electrocyclic reaction governs the Favorskii-related rearrangement.152

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Ozonolysis and Ozonation A theoretical investigation showed that the most favourable unimolecular decomposition path of primary fluorozonide is a concerted cleavage to carbonyl oxide and formyl fluoride. The secondary fluorozonide decomposition takes place most readily in a stepwise manner initiated by the O–O bond rupture.153 DFT calculations have shown that ozone–difluoroethylene reactions are initiated by the formation of van der Waals complexes and then yield primary ozonides, which rapidly open to carbonyl oxide compounds. The formation of primary ozonide has been predicted to be the rate-controlling step of the oxidation process.154 The rate constants for oxidation of a series of cycloalkenes with ozone have been determined using a relative rate method. The effect of methyl substitution on the oxidation of cycloalkenes and formation of secondary organic aerosols has been analysed.155 Butadiene, styrene, cyclohexene, allyl acetate, methyl methacrylate, and allyl alcohol were epoxidized in a gas-phase reaction with ozone in the absence of a catalyst. With the exception of allyl alcohol, the yield of the corresponding epoxide ranged from 88 to 97%.156 Kinetic control of distereoselection in ozonolytic lactonization has been reported in the reaction of prochiral alkenes.157 Ozone, in acetic acid, reacts with nitrotoluenes in two competitive directions. The influence of structure and temperature upon oxidation selectivity on a methyl group was investigated. A mechanism has been proposed.158 7,7-Dimethyl-2methylenenorbornan-1-ol undergoes an anomalous ozonolysis to yield a mixture of a rearranged β-hydroxy ketone and a fragmented carboxylic acid.159

Peracids and Peroxides Asymmetric epoxidations of alkenes catalysed by chiral monomeric organorhenium (VII) and organomolybdenum(VI) compounds,160 ketones,161 and salen–metal complexes162 have been reviewed. The advances in the catalysed Baeyer–Villiger oxidation

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in the last 10 years are reviewed.163 Development of metal catalysts for asymmetric Baeyer–Villiger oxidations of racemic or prochiral ketones for the synthesis of optically active products has been reviewed. The scope of these new variants of the Baeyer–Villiger reaction yielding enantioselectivities exceeding 95% ee has been discussed.164 Chiral Katsuki-type salen catalyst has been recycled several times following its use in a model epoxidation reaction of 1,2-dihydronaphthalene in an ionic liquid. The enantioselectivity was comparable to that in dichloromethane, but recovery of the catalyst was easier and the activity was higher.165 The kinetic parameters of the oxidation of DMSO with benzoyl peroxide in some dipolar aprotic solvents and superbasic media were correlated with the main physicochemical characteristics of solvents. A two-step scheme of the oxidation involving preliminary cleavage of the peroxide to perbenzoate with the base has been suggested.166 A systematic study of the stoichiometric and kinetic efficiencies of six different Fe-based catalysts in the oxidation of 2,4,6-trichlorophenol by hydrogen peroxide has been carried out. Illumination with visible light significantly enhanced the rate of oxidation.167 [Fe(II)(BPMEN)(CH3 CN)2 ](ClO4 )2 [BPMEN = N ,N -dimethyl-N ,N bis(2-pyridylmethyl)ethane-1,2-diamine] catalyses the hydroxylation of benzoic acid to salicylic acid by hydrogen peroxide in good yield under mild conditions.168 Alkanes are oxidized mainly to alkyl hyperoxides by an H2 O2 –FeCl3 –2,2 -bipyridine system in acetonitrile. It has been suggested that bipyridine facilitates proton abstraction from a hydrogen peroxide molecule coordinated to the iron ion to generate hydroxyl radicals from the hydrogen peroxide. Hydroxyl radicals then attack alkane molecules, finally yielding the alkyl hydroperoxide.169 The kinetics of the oxidation of substituted phenyl methyl sulfides by hydrogen peroxide in borate–boric acid buffers has been investigated. The Hammett ρ values for the reactions of a range of substituted phenyl methyl sulfides with hydrogen peroxide, monoperoxoborate, and diperoxoborate are −1.50, −0.65 and −0.48, respectively. The negative ρ values indicate positive charge development on the sulfur atom in the transition state consistent with nucleophilic attack by the organic sulfides. The kinetic parameters are discussed in terms of the differences in the transition state of reactions involving peroxoboron species with respect to those of other peroxides.170 A sulfide with an imidazole moiety was treated with di-p-toluoyl-d-tartaric acid and the precipitated salt was oxidized with hydrogen peroxide–triethylamine to yield the enantiomerically pure sulfoxide.171 The carboxylic acid-promoted cis-dihydroxylation and epoxidation of alkenes catalysed by [Mn2 O(tmtacn)2 ] employing hydrogen peroxide as oxidant has been reported. The use of carboxylic acids at co-catalytic levels not only is effective in suppressing the inherent catalase activity of the catalyst but also permits the tuning of the catalyst’s selectivity toward cis-dihydroxylation and epoxidation.172 Selenomethionine is oxidized with aqueous hydrogen peroxide to selenomethionine oxide and an Se–N selenurane. The 77 Se chemical shifts were in good agreement theoretical estimates.173

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Dimethoxybenzene derivatives are smoothly converted to monohydroxy compounds with hydrogen peroxide, acetic acid and p-toluenesulfonic acid. Peracetic acid, generated in situ, is reported as the hydroxylating reagent. The reaction is visualized as an aromatic electrophilic substitution (Scheme 6).174 R d− C O O d+ O H

H −

−RCO2

MeO Me

OMe

OH

H +

−H+

MeO Me

OMe

HO

H

Me

OMe

MeO

Scheme 6

Epoxidation of cyclooctene with hydrogen peroxide, catalysed by the methoxideligated form of iron(III) tetrakispentafluorophenyl [F20TPPFe(III)] porphyrin, is proposed to involve a reaction of F20TPPFe(III) with hydrogen peroxide to form an iron(III) hydroperoxide species, which then undergoes both heterolytic and homolytic cleavage to form iron(IV) π -radical cations and iron(IV) oxo species, respectively. The iron(IV) π -radical cations are responsible for the epoxidation of cyclooctene, whereas the iron(IV) oxo species are responsible for the decomposition of hydrogen peroxide (Scheme 7).175 Good yields of corresponding phenols are obtained in the oxidation of hydroxylated and methoxylated benzaldehydes and acetophenones with hydrogen peroxide and methyltrioxorhenium (MTO) in ionic liquids, [bmim]BF4 and [bmim]PF6 .176 Various hydrocarbons are oxidized to the corresponding ketones or alcohols by MTO and heterogeneous MTO catalyst systems in ionic liquids using hydrogen peroxide as the oxidant.177 In the presence of bicarbonate as co-catalyst, hexathiocyanatorhenate(IV) functions as an extremely effective catalyst in the epoxidation of alkenes using aqueous hydrogen peroxide as the terminal oxidant.178 Polyoxovanadometalate ion, which has a [VO–(μ-OH)2 –VO] core, catalyses the epoxidation of alkenes with hydrogen peroxide. This system showed very high stereospecificity, distereoselectivity and regioselectivity.179 Excellent yields and moderate to good enantioselectivities were achieved in the epoxidation of aromatic olefins using Ru complexes of N ,N ,N -pyridinebisimidazoline ligands with hydrogen peroxide as the oxidant.180 Copper(II) complex (5) catalyses the oxidation of sulfides to sulfoxides with hydrogen peroxide in high yields. Addition of a catalytic amount of TEMPO to the reaction mixture enhances the conversion and selectivity.181 Chiral 2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilanyloxymethyl]pyrrolidine was found to be an efficient catalyst for the asymmetric epoxidation of α,β-unsaturated

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Organic Reaction Mechanisms 2005 O Fe(IV) −•OH

+ MeOH + H2O2 − •OOH − H2O

Fe(III)

+ H2O2 − MeOH − •OOH

OOH O Fe(III) + H2O2

MeOH +

Fe(III)

Fe(IV) + •

OMe

H2O OMe MeOH

Fe(III)

+

O

OMe

Scheme 7

N

N Cu

O

O (5)

aldehydes to α,β-epoxyaldehydes with hydrogen peroxide. Good yields and excellent enantioselectivities were obtained. It has been postulated that the first step is the formation of the iminium intermediate by reaction of the α,β-unsaturated aldehyde with the chiral amine. In the next step, the peroxide adds as a nucleophile to the electrophilic α,β-carbon atom, leading to an enamine intermediate.182 The epoxidation of α,β-unsaturated acids with hydrogen peroxide, catalysed by Na2 WO4 or Na2 MoO4 , involves the rapid formation of a diperoxo complex. In the oxidation of cis-prop-1-enylphosphonic acid, the P=O corrdinates with the metal centre and the oxidation is a unimolecular process. The C=C bond in α,β-unsaturated

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carboxylic acids cannot corrdinate with the metal centre. The oxygen transfer is, therefore, a bimolecular process. A spiro-transition structure is envisaged for the nucleophilic attack of the olefinic bond on the peroxo bond.183 Complex salts [MoO(O2 )2 (QO)][PPh4 ] (2•PPh4 ) and [WO(O2 )2 (QO)][PPh4 ] (4·PPh4 ) (QOH = quinolin-8-ol) showed catalytic properties in the oxidation of alcohols using hydrogen peroxide as the terminal oxidant. A probable mechanism for the oxidation has been suggested.184 Monosubstituted Keggin–polyoxymetalate complex Na6 [SiW11 ZnH2 O40 ]. 12H2 O is an effective catalyst for the selective oxidation of alcohols with hydrogen peroxide as oxidant in an aqueous–oil biphasic system.185 It has been postulated that the catalytic active centre in Sn-Beta and Sn-MCM-41 zeolites for Baeyer–Villiger oxidations of ketones with hydrogen peroxide involves not only the framework Sn sites but also an associated ‘basic’ oxygen that stabilizes the reaction transition state through hydrogen bonding.186 Ketones are oxidized by hydrogen peroxide in a reaction catalysed by palygorskite-supported tin complexes, affording corresponding lactones or esters in 90–100% selectivity. A mechanism has been suggested.187 Asymmetric epoxidation of α,β-unsaturated aldehydes, catalysed by 2-[bis-(3,5bistrifluoromethylphenyl)trimethylsilanyloxymethyl]pyrrolidine (6), with hydrogen peroxide, in aqueous alcohol solutions, proceeds with moderate to high yields and up to 96% ee.188

F

F F

Si

F

F

O

F N

F

F

F

F

F

F (6)

Cyclodextrin ketones have been used as powerful catalysts of amine oxidation in the presence of hydrogen peroxide as the stoichiometric oxidant. This oxidation follows Michaelis–Menten kinetics and depending on the substrate the oxidation rate is increased up to 1100-fold. It has been proposed that hydrogen peroxide reacts with the ketone to form a hydroperoxide adduct and this adduct is responsible for oxidizing the amine, bound in the cavity, to the hydroxylamine.189 The oxidation of methyl phenyl sulfide with hydrogen peroxide, in the presence of ammonium hydrogencarbonate, takes place by a mechanism involving HCO4−

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as a more active oxidant than hydrogen peroxide.190 The kinetics of indigocarmine oxidation by hydrogen peroxide, under catalytic action of the Co(II)–citric acid complex, has been determined.191 Oxidation of cyclohexane, to the corresponding alcohol and ketone, with hydrogen peroxide is catalysed by oligo- and poly-nuclear copper triethanolamine complexes.192 Benzylic alcohols are oxidized to aldehydes by using the TEMPO–HBr–H2 O2 system in ionic liquid [bmim]PF6 . The electron-deficient and electron-neutral benzylic alcohols were oxidized in good to excellent yields, whereas the electron-rich benzylic alcohols failed to afford the desired product due to side-reactions.193 It has been suggested that poly-l-leucine (PLL)-catalysed epoxidation of substituted chalcones proceeds via a reversible addition of chalcone to a PLL-bound hydroperoxide, forming a fleeting hydroperoxy enolate species. The origin of enantioselectivity in this system has been rationalized.194 RB3LYP calculations indicate that the s-cis conformer of peroxy acids is more stable than the s-trans conformer. Calculations on the reaction of prop-2-enol with some peroxy acids showed that trans-transition states collapse to the epoxide via a 1,2-shift, whereas a 1,4-shift is operable for cis-transition states.195 Quantum mechanical calculations have been performed on the migration step of the Baeyer–Villiger rearrangements of some substituted acetophenones with m-chloroperbenzoic acid (mCPBA). The energy barriers, charge distributions and frontier molecular orbitals, determined for the aryl migration step, have been used to explain the effects of substituents on the reactivity of the ketones.196 Trapping of the free radical intermediates, by 2,4,6-tri-t-butylphenol, in the oxidation of meso-tetrakis(pentafluorophenyl)porphynatoiron(III) chloride with m-CPBA, revealed that more than one reactive intermediate is formed in dichloromethane. In acetonitrile, formation of a single intermediate is indicated.197 In the presence of bases such as potassium hydroxide or carbonate, m-CPBA allowed the selective formation of oxiranes only from alkenes gem-disusbstituted with strongly electron-withdrawing groups.198 Atropisomeric aromatic amides bearing 2-sulfanyl groups are oxidized with m-CPBA to the corresponding sulfoxides with high diastereoselectivity. The selectivity has been attributed to thermodynamical stability. The thermodynamic selectivity is reported to arise mainly from electronic repulsion between the C=O and S−O dipoles.199 2,2-Dimethyloxazolidines have been utilized as chiral auxiliaries for the diastereoselective functionalization of the optically active tiglic acid derivatives by means of epoxidation with dimethyldioxirane (DMD) or m-CPBA and ene reactions with 1 O2 or 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). In the DMD and m-CPBA epoxidations, high diastereoselectivities but opposite senses of diastereomer selection was observed. In contrast, the stereochemistry of the 1 O2 and PTAD ene reactions depended on the size of the attacking enophile; whereas essentially perfect diastereoselectivity was obtained with PTAD, much lower stereoselection was observed with 1 O2 . The stereochemical results for the DMD and m-CPBA epoxidations and the PTAD ene reaction are explained in terms of the energy differences for the corresponding diastereomeric transition states, dictated by steric and electronic effects.200

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Oxygenation of 2-substituted adamantanes with methyl(trifluoromethyl)dioxirane showed a reaction constant, ρ = −2.31, consistent with a strongly electron-demanding transition state. Analysis of the effect of solvents on the rate yielded a positive regression coefficient with Dimroth–Reichardt ETN solvent polarity parameter. A mechanism involving an electrophilic O atom insertion has been postulated for the formation of alcohols and carbonyl compounds.201 Enantioselective epoxidation of α,β-unsaturated ketones has been achieved using commercially available α,α-diphenyl-l-prolinol as a bifunctional organocatalyst and t-butyl hydroperoxide (TBHP) as an oxidant. The epoxides have been obtained in good yields and with up to 80% ee.202 Enantioselectivity of epoxidation of allylic alcohols with TBHP, assisted by poly(ethylene glycol) monomethyl ether (MPEG) tartrate ester, depends on the molecular weight of the appended PEG. Enantioreversal was observed when MPEGs of different molecular weights were used.203 Dirhodium caprolactamate is an effective catalyst for benzylic oxidation with TBHP under mild conditions. The benzylic methylene is converted to a carbonyl group. Sodium hydrogen carbonate is the optimal base additive for substrate conversion. Mechanistic experiments have indicated an advanced role for base in the reaction.204 Pd-catalysed ligand-modulated Wacker oxidation of styrene derivatives with TBHP leads to the formation of terminal methyl ketones in high yield. The reaction is first order in the Pd complex but zero order with respect to TBHP and styrene. Isotopic labelling experiments support a dominant pathway wherein TBHP acts as the oxygen source in the addition to the alkene followed by a hydride shift process wherein the protons on styrene are incorporated into product.205 Vanadium-catalysed epoxidation of allylic alcohols with TBHP is decelerated by the ligand (7), in non-aqueous solutions. However, in water it turns into a ligand-accelerated process.206 Ph

ee

ee

O

Ts-NH Ph

N OH Ph (7)

Asymmetric epoxidation of allylic alcohols, in good yields with up to 67% ee and complete control of the diastereoselectivity, has been achieved by employing VO(acac)2 as catalyst, N -hydroxy-N -phenylbenzamide, and optically pure (+)norcamphor-derived hydroperoxide as oxygen atom donor and chiral source. Variation of the reaction parameters has a significant effect on the level of asymmetric induction.207 Oxaziridines are sufficiently activated by Lewis acids such as zinc chloride to transfer oxygen to sulfides. Asymmetric sulfoxidation with new chiral oxaziridines afforded enantioselectivities from 22 to 63%.208 It has been found that hydrophobic oxaziridinium salts, containing an aromatic ring, cause a very high rate enhancement in epoxidation of hydrophobic alkenes, whereas DMD oxidizes crotonic acid and cinnamic acid at almost the same rate.209

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An asymmetric synthesis of benzenesulfinates bearing a phosphonate group at the ortho-position has been achieved by a diastereoselective oxidation of the corresponding sulfenates with chiral oxaziridines.210 DMD-mediated oxidation of phenylethyne leads to the formation of phenylacetic acid, mandelic acid, and oligomeric mandelic acid, depending on the reaction conditions. The results have been explained by the initial formation of phenyloxirene, which equilibrates with phenylformylcarbene and benzoylcarbene (Scheme 8).211 O

Ph

Ph

O

H

O

Ph

H Ph

H O

O

Ph

O H2O

C O

Ph

OH

H O O

H Ph

O O

RO O

+ROH (CCl4) Ph

Ph

O

OH

O +

H PH

H O−

H O

H2O

Ph H HO

O OH

n

O O

Ph H

O O O

H

Ph −CO2

O

OH

Ph O

Scheme 8

Pulse radiolysis reaction of iodide ions with a series of halogenated alkylperoxyl resulted in the oxidation of a total of three iodide ions. The rate constants were determined as a function of pH, polarity of solvent mixtures, and electronegativity of

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the substituents at the α-C atom of the peroxyl radicals. A good linear relationship is obtained between log k and the dielectric constant of the solvent mixture. The rate constants depend strongly on the substituents at the alkylperoxyl moiety and correlate with Taft’s inductive substituent constants σ ∗ . The overall multi-electron oxidation mechanism of alkylperoxyl radicals has been discussed.212

Photo-oxygenation and Singlet Oxygen Recent advances in the chemistry of singlet oxygen have been reviewed.213 The reactivity of five acenes, viz. benzene, naphthalene, anthracene, tetracene, and pentacene, toward the 1,4-addition of singlet oxygen has been studied using the highlevel ab initio model of G3(MP2). The results showed that there are nine concerted and exothermic pathways and the most reactive sites on the acenes are the centre ring’s meso-carbons. Reactivity increases along the series benzene < naphthalene < anthracene < tetracene < pentacene. The reactivity has been rationalized in terms of natural bond orbital and frontier molecular orbital analysis.214 N -Substituted pyridones easily undergo oxidation with singlet oxygen to give exclusively the corresponding endoperoxides, which decompose to give pyridones again while liberating singlet oxygen in high yield. The reaction thus serves as a chemical source of singlet oxygen.215 The reaction mechanism and electronic effect of substituents on the cycloaddition reaction of 7-substituted 5H -benzocycloheptenes with singlet oxygen and the chemistry of the endoperoxides obtained has been explored.216 Photochemically generated singlet oxygen adds chemoselectively to pseudodiosgenin diacetate to give diosone, an important intermediate for the preparation of many steroidal drugs, and an ene product.217 The major products of the photolysis of glycolaldehyde are HCHO and CO, methanol and OH production was also observed. Photolysis of glycolaldehyde was used as the OH source to measure the reaction rate constants of OH with a series of dienes by the relative method and to identify and quantify the oxidation products of the OH-initiated oxidation of propan-2-ol. HCHO is observed to be the major product of the OH-initiated oxidation of glycolaldehyde. The results indicate that the OH reaction and photolysis can compete as tropospheric sinks for glycolaldehyde.218 The kinetics of the oxidation of adenosine and caffeic acid by t-butoxyl radicals has been studied by the photolysis of t-BuOOH in the presence of t-BuOH. The rates and the quantum yields of oxidation of caffeic acid by t-BuO• radicals have been determined in the absence and presence of various concentrations of adenosine. An increase in the concentration of adenosine has been found to decrease the rate of oxidation of caffeic acid, suggesting that adenosine and caffeic acid compete for t-BuO• radicals. It has been suggested that caffeic acid not only protects adenosine from t-BuO• radicals but also repairs adenosine radicals formed by the reaction of t-BuO• radicals.219

Triplet Oxygen and Autoxidation Wacker oxidation, a catalytic conversion of alkanes with aerial oxygen to carbonyl compounds, and its potential for large-scale applications has been reviewed.220 Aerobic

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Baeyer–Villiger oxidation of ketones, in the presence of flavin catalyst, resulted in an excellent yield of the ester. A new flavin-type catalyst, 5-ethyl-3-methyl-2 ,4 :3 ,5 di-O-methyleneriboflavinium perchlorate, have been synthesized and used in these reactions.221 The times of the complete oxidation of alkanes with oxygen or air under the action of nanosecond pulsed discharges have been determined.222 The kinetics of liquid-phase oxidation of isomeric methoxy(1-methylethyl)benzenes with oxygen to the corresponding hydroperoxides has been studied. The overall activation energies of the oxidation and initiating properties of some of the hydroperoxides were determined.223 Oxidation and pyrolysis of ethane at reflected shock pressures from 5 to 1000 bar have been reported. The experimental data have been used to develop a model for the oxidation and pyrolysis. The previously intractable problem concerning the simulation of concentration of acetylene has been solved. A new product channel involving addition of hydroxyl radical to ethane has been suggested.224 An experimental and modelling study of the oxidation of toluene has been presented. The ignition delays of toluene–oxygen–argon mixtures were measured behind reflected shock waves for low temperatures. The low-temperature oxidation has been studied in a continuous flow stirred tank reactor. The main reaction paths have been determined by sensitivity and flux analyses.225 Ignition delay times of pent-1-ene–oxygen–argon mixtures have been measured behind shock waves. A detailed mechanism of the combustion of pent-1-tene has been generated. Comparisons with but-1-ene and hex-1-ene under the same conditions show that pent-1-ene has a higher reactivity, which is attributed to its decomposition to give ethyl radicals, which rapidly yield very reactive hydrogen atoms, whereas the decomposition of but-1-ene and hex-1-ene leads to less reactive methyl radicals.226 The mechanism and kinetics of the atmospheric oxidation of alkynes, initiated by OH radicals, have been studied particularly to determine the role of alkyne oxidation in tropospheric ozone formation. A general mechanism for OH-initiated oxidation of alkynes has been developed with the aid of thermodynamic calculations. In general, the significance of atmospheric alkynes to the formation of tropospheric ozone was found to be smaller than for alkanes and alkenes, due to the absence of the hydroxy peroxyforming product channel in the OH-initiated atmospheric oxidation of alkynes.227 The mechanism of the hydroxyl radical-initiated oxidation of β-pinene in the presence of NO has been investigated using a discharge-flow system. Propagation of hydroxyl radicals was observed after the addition of O2 and NO, and the measured concentration profiles were compared with simulations based on both the master chemical mechanism and the regional atmospheric chemistry mechanism for β-pinene oxidation.228 Chiral (nitrosyl)ruthenium(salen) complexes have been found to be efficient catalysts for aerobic oxidative desymmetrization of meso-diols under photoirradiation to give optically active lactols. With the suitable catalysts, high enantioselectivities up to 93% has been achieved. The kinetics of the oxidation depend on the nature of the ligand. On the basis of kinetic parameters and the kinetic isotope effect, it has been suggested that when a ligand with an apical hydroxy group is used, the hydrogen atom

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abstraction step mainly contributes to the rate-determining step. With an apical chloro group, SET and ligand exchange steps become rate determining.229 Oxidation of 2,6-di-t-butylphenol with dioxygen, catalysed by Mn(II) complexes with tetradentate Schiff bases as ligands, is of pseudo-first order in dioxygen.230 The cyclopropyl derivative of 2,6-di-t-butylphenol has been used as a probe to investigate the mechanism of base-catalysed autoxidation of phenol derivatives. A one-electron reduction of molecular oxygen by phenolate ion gives phenoxyl radical. The coupling of phenoxyl radical and superoxide radical gives peroxylate anion and produces the final epoxy alcohol adduct (Scheme 9).231 O•

O

But

But

O

But

But

But

But

O2 •O

• •

2

Ph Ph

Ph O Bu

t

But O2 OOH Ph

Scheme 9

EPR in conjuction with the spin trapping technique has provided evidence for the intermediacy of free radicals in the formation of an endoperoxide by spontaneous addition of oxygen on a dienol; it has been suggested that a long-lived triplet biradical intermediate is formed by addition of 3 O2 to dienol.232 A probable mechanism (Scheme 10) has been postulated for the formation of 1,2-dioxane and acetophenone in the reaction of an alkene with Co(II)–O2 –Et3 SiH.233 The kinetics of the aerobic oxidation of alcohols catalysed by Pd(OAc)2 – triethylamine have been studied experimentally and computationally. Measurement of various kinetic isotope effects and the activation parameters and also rate law derivation support a rate-limiting deprotonation of the palladium-coordinated alcohol, contrary to the previously proposed rate-limiting β-hydride elimination.234 The catalytic efficiency of Pd(OAc)2 –triethylamine and palladium alkoxides in the aerobic oxidation of alcohols has been evaluated. A new catalyst, Pd(IiPr)(OPiv)2 , is found to operate efficiently at room temperature.235 The aerobic oxidation of nitrobenzene to 2-nitrophenol, catalysed by H5 PV2 Mo10 O40 polyoxometalate, under pseudo-zero-order conditions is first order in the catalyst and

112

Organic Reaction Mechanisms 2005 OO

HCo(III)/O2

Ph

•

Ph Ph

Ph Co(II)/Et3SiH

OOSiEt3 Ph Ph Ph

Ph

Ph

•

O2/Co(II)/Et2SiH

Ph

OOSiEt

O O

O O

O• Ph

O

Ph

O Ph

+

O2/Co(II)/Et3SiH

•

Ph

O

Et3SiOO Ph

O

Scheme 10

molecular oxygen. The oxidation of C6 D5 NO2 yielded a kinetic isotope effect, kH /kD = 2.5. Use of 18 O2 resulted in 86% incorporation of labelled oxygen. Formation of a polyoxometallate–nitrobenzene intermediate and its reaction with molecular oxygen in the rate-determining step has been suggested.236 The liquid-phase autoxidation of onitrotoluene takes place in two steps. The first step, oxidation to o-nitrobenzaldehyde, is a first-order reaction. The second step, formation of o-nitrobenzoic acid, is a half-order reaction. The experimental results have been compared with theoretical calculations.237 Aerobic oxidation of primary alcohols to aldehydes is catalysed by a three-component system, acetamido-TEMPO–Cu(ClO4 )2 –DMAP, in the ionic liquid [bmpy]PF6 .238 Oxidation of crotonaldehyde with molecular oxygen and the role of accumulated percrotonic acid in the process have been studied.239 A copper(I)-mediated regio- and stereoselective hydroxylation of steroids with oxygen provides a short synthetic route to 12β-hydroxy-17-oxo steroids, which are otherwise difficult to prepare.240 Methoxymethyl radicals, formed initially on reaction of dimethyl ether with oxygen at elevated temperatures, react further with oxygen by two product pathways. The first


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produces methoxymethylperoxy radicals and the second produces OH radicals and formaldehyde molecules. The experimental and kinetic modelling results indicated a strong preference for the thermal decomposition of alkoxy radicals as compared with their reaction with oxygen.241 A kinetic study of the aerobic oxidation of 4nitrotoluene-2-sulfonic acid (PNTS), with Mn(II) sulfate as catalyst, showed that it comprised two consecutive steps, i.e. first PNTS was converted into 4,4 -dinitro2,2 -dibenzyldisulfonic acid (NDS), which was then oxidized to 4,4 -dinitro-2,2 stilbenedisulfonic acid.242 The reactivity of the hydrocarbons increases in the order ortho < meta < para in the liquid-phase catalytic oxidation of methyl derivatives of biphenyl into acids by air. The mechanism of the oxidation of hydroxymethylbiphenyls and hydroxymethylbenzenes involves the formation of an unstable cation radical, which is then stabilized by emitting a proton, giving hydroxybenzyl radical.243

Other Oxidations Recent advances in the catalytic asymmetric α-hydroxylation of ketones and ketohydroxylation of alkanes,244 synthesis of sulfones by oxidation of sulfides or sulfoxides,245 and catalytic asymmetric sulfide oxidations for the syntheses of biologically active sulfoxides have been reviewed.246 Recent progress in organic reactions, including oxidation and reduction, catalysed by transition metals in supercritical carbon dioxide, has been reviewed.247 A review tracing the developments in the homogeneous and heterogeneous catalytic systems in asymmetric epoxidation has appeared. Chiral metal catalysts including titanium, vanadium, porphyrin systems, chiral carbonyl compounds, iminium salts, salen systems, and supported systems have been discussed.248 Asymmetric sulfoxidation catalysed by chiral organometallic species to give very high enantioselectivities has been reviewed.249 Two types of catalytic oxidation of amines, viz. oxidation controlled by enzymes, oxidases and oxygenases, and transition metal-catalysed reactions of amines with various oxidizing agents, are reviewed.250 A review focusing on three catalytic systems for the oxidative cleavage of carbon–carbon double bonds, viz. two-step syntheses of carboxylic acid via carbonyl compounds or diols, application of ruthenium catalysts using peroxo compounds as oxidant, and syntheses of aldehydes/carboxylic acid using organorhenium(VII) catalyst systems, has appeared.251 The development of aluminium-based catalysts for the asymmetric Meerwein– Schmidt–Ponndorf–Verley–Oppenauer (MSPVO) reduction/oxidation systems is reviewed with emphasis on the mechanistic understanding of the origin for activity and selectivity in monometallic catalysts.252 Electrochemical oxidation of some catecholamines such as dopamine, l-dopa, and methyldopa has been studied using cyclic voltammetry. The catecholamines undergo intramolecular cyclization to form the corresponding o-quinone derivatives. The significant differences in the electrochemical behaviour of the catecholamines have been attributed to the effects of the side-chain carboxyl group.253 Electron-transfer reactions of 2 -deoxyguanosine-5 -monophosphate (dGMP) in phosphate buffers by cyclic

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voltammetry are reported. At pH 2.9 and 7.1, formation of a UV-absorbing intermediate, which decayed in a pseudo-first-order reaction, has been indicated. A tentative redox mechanism has been suggested for the electro-oxidation of dGMP.254 The reaction between C2 H5 O2 and NO has been studied using the turbulent flow CIMS technique. The reaction has a negative temperature dependence and is invariant with pressure. The intermediacy of an energized intermediate (C2 H5 O2 NO∗ ) has been postulated. It has been suggested that the intermediate is too short-lived to be affected by collisions and decomposes via simple bond fission to yield C2 H5 O and NO2 .255 Products of oxidation of sulfides by chemical electron transfer (CET) with cerium (IV) ammonium nitrate and photoinduced electron transfer (PET) with C(NO2 )4 depend on the nature of the sulfide. CET led to fragmentation and α-deprotonation products, whereas PET gave mainly sulfoxides, although in some cases fragmentation was also observed.256 Oxidatively generated oxocarbenium ions have been used for intramolecular epoxide activation. Cascade reactions to form oligotetrahydrofuran products that demonstrated a strong preference for the exo-cyclization pathway were achieved in good yields when disubstituted epoxides were used as substrates. High stereoselectivity was observed in these reactions, with complementary diastereomers being formed from diastereomeric epoxides.257 Ar1 Ar2

NO2 +

Ar1

MeCN

BNAH

− •

Ar2

NO2

‡

NO2 BNAH NO2

Transition State O2

Ar1

−

NO2

Ar2 O NO2 O•

Ar1

−

NO2

Ar2 H NO2

−e

Ar1

Ar1 O Ar2

NO2

Ar2 O O

NO2 Scheme 11

Ar1 H NO2 Ar2 H NO2

+•

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A mixed oxide of ruthenium, copper, iron and alumnium has been developed as a catalyst for the synthesis of aldehydes and ketones from alcohols.258 Oxidation of chiral secondary 1,2-diols with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone under ultrasound wave promotion leads to the selective oxidation of benzylic or allylic hydroxyl group. The configuration of the adjacent chiral centre is retained.259 The kinetics of oxidation of ethylbenzene in the presence of acetic anhydride have been studied.260 The reaction of 1-benzyl-1,4-dihydronicotinamide (BNAH) with a series of 1,1di-para-substituted-phenyl-2,2-dinitroethylenes in oxygen-saturated acetonitrile produced various amounts of the corresponding ethanes and diaryl ketones depending on the electronic structure of the substituent groups, thereby indicating a spectrum of behaviour intermediate between polar and SET mechanisms (Scheme 11).261

Reduction by Complex Metal Hydrides A new chiral acyloxyborohydride has been prepared by combining sodium borohydride with a tartaric acid-based reagent. This reagent effects the reduction of aromatic ketones to provide the product alcohols in ees of 93–98%. Several aliphatic ketones were also reduced with moderate to excellent enantioselectivity. A mechanism has been provided with supporting calculations for the proposed active species and transition state.262 Reduction of imines with hydroxycyclopentadienylruthenium hydride demonstrated a change in the rate-limiting step as a function of imine basicity. Reduction of electrondeficient N -benzylidenepentafluoroaniline resulted in free amine and kinetic isotope effects kOH /kOD = 1.61, kRuH /kRuD = 2.05, and kRuHOH /kRuDOD = 3.32, indicative of rate-limiting concerted hydrogen transfer. Reduction of electron-rich N -isopropyl-(4methyl)benzilidenamine was accompanied by facile imine isomerization and scrambling of deuterium labels from reduction with 5-RuDOH into the N -alkyl substituent of both the amine complex and into the recovered imine. Inverse equilibrium isotope effects were observed in the reduction of N -benzilidene-t-butylamine (kOH /kOD = 0.89, kRuH /kRuD = 0.64, and kRuHOH /kRuDOD = 0.56. It has been proposed that the reaction begins by a trans-addition of proton and hydride to the imine and formation of a coordinatively unsaturated intermediate. In the case of the electron-deficient imines, this step is rate limiting. For electron-rich alkyl-substituted imines, the intermediate undergoes back hydrogen transfer to ruthenium at a rate competitive with or faster than that for coordination of nitrogen. For these electron-rich imines, the rate-limiting step is the coordination of nitrogen to ruthenium, and reversible hydrogen transfer leads to imine isomerization, deuterium scrambling, and inverse isotope effects.263 Catalytic systems generated in situ from the chiral PNNP ligands (8) with iridium or rhodium hydride complexes exhibited excellent catalytic activity and good enantioselectivity in the asymmetric transfer hydrogenation of aromatic ketones without added base. The best result was obtained in the IrH(CO)(PPh3 )3 –PNNP–ligand catalytic system with up to 99% yield and 97% ee.264

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N H

N H

P Ar

P ArAr

Ar

(8)

The ionic hydrogenation of an iminium cation, catalysed by CpRu(P–P)H (where P–P is a chelating diphosphine), involves (1) rate determining hydride transfer to form an amine, (2) the coordination of hydrogen to the resulting ruthenium cation, and (3) the transfer of a hydrogen ion from the coordinated dihydrogen to the amine formed in (1). A methyl substituent on the Cp ring decreases the hydride-transfer rate and the turnover frequency slightly whereas electron-donating substituents on the phosphine cause corresponding increases. Ionic hydrogenation shows the expected preference for the hydrogenation of C=N over the hydrogenation of C=C, although a terminal C=C can block the coordination of another hydrogen after hydride transfer. With an α,β-unsaturated iminium cation, the initial 1,4 hydride transfer gives an enamine that is then protonated and hydrogenated to an ammonium cation.265 Reduction of imines by [2,5-Ph2 -3,4-Tol2 (η5 -C4 COH)]Ru(CO)2 H (A) produces kinetically stable ruthenium amine complexes. Reduction of an imine by A in the presence of an external amine trap gives only the complex of the newly generated amine. Reaction of A with H2 N-p-C6 H4 N=CHPh, which contains an intramolecular amine trap, gave a 1:1 mixture of a product formed by coordination of the newly generated amine to the ruthenium centre and another product formed by coordination of the amine already present in the substrate. These results require transfer of hydrogen to the imine outside the coordination sphere of the metal to give a coordinatively unsaturated intermediate that can be trapped inside the initial solvent cage. Amine diffusion from the solvent cage must be much slower than coordination to the metal centre.266 Addition of lithium bis(trimethylsilyl)amide to perfluorinated ketones and solvolysis of the N–Si bond in methanol resulted the formation of stable, isolable N–H imine Z–E isomer mixtures along with a methanol adduct. Enantioselective reduction of these three-component mixtures with oxazaborolidine catalysts and catecholborane provided trifluoromethylated amines in 72–95% yields and 75–98% ee.267 Several lithium hydride derivatives, viz. lithium aluminium hydride (LAH), LiAlH (OBut )3 , LiBHEt3 , and LiBH4 , can be used to reduce an ester group to the corresponding alcohol without affecting a nearby peroxy group. LiBH4 appeared to be the best reagent for this purpose.268 With LAH, gem-difluorinated vinyloxiranes reacted at the allylic epoxide carbon to produce homoallylic alcohols exclusively. Reactions with DIBAL-H and BH3 –THF afforded (E)- and (Z)-allylic alcohols respectively with excellent selectivity.269 New chiral Schiff bases, prepared from carbonyl compounds and two 2-amino alcohols, catalyse the reduction of acetophenone with LAH

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in high chemical yield (up to 93%) with moderate enantiomeric excess.270 Perbenzylated 6A ,6D -dideoxy-α-cyclodextrin undergoes two sequential regioselective clockwise de-O-debenzylations with DIBAL-H to yield a novel C2 -symmetric cyclodextrin.271 A diphenylprolinol derivative, having hydrophobic perfluoroalkyl phase tags, has been synthesized and used as a pre-catalyst to generate in situ a fluorous oxazaborolidine catalyst for the reduction of prochiral ketones with borohydride. The system afforded high enantioselectivities and the pre-catalyst is easily separated and recycled.272 Reduction of enantiopure N -p-toluenesulfinyl ketimines derived from 2-pyridyl ketones with sodium borohydride affords N -p-toluenesulfinylamines with good yields and diastereoselectivities.273 It has been demonstrated that the phosphorus stereochemistry, in diastereomeric pairs of chiral catalysts, containing the (5S)-1,3-diaza-2-phospha-2-oxo-3-phenylbicyclo[3.3.0]octane moiety, has no significant role in directing the stereochemical pathway in the borane-mediated asymmetric reduction of prochiral ketones.274 Alkyl aryl ketones are reduced with borane–dimethyl sulfide complex, in the presence of a βmethoxyoxazaborolidine catalyst, in high yields and with ees in the range 93–98%.275 A new calcium hydride–zinc chloride (or bromide) combined reagent reduced a variety of ketones and imines to the corresponding alcohols and amines, respectively, in very good yields, in the presence of a catalytic amount of a Lewis acid such as metal isopropoxides and zinc fluoride.276 Imines are reduced with silane–MoO2 Cl2 in excellent to moderate yields and chemoselectivity.277 Trialkyl borates, generated in situ from sodium borohydride and an alcohol, catalyse reduction of ketones with borohydride. With (-)-menthol as the initiating alcohol, the NaBH4 + 4ROH

NaBH4-n(OR)n B(OR)3 + RONa

B(OR)3 + RONa + 4H2 B(OR−)4 Na +

B(OR)3 O R H

−

R

•

+

R BH3−

H

R H

Na+ R′

BH3

−

B(OR)3

+

R

+

H

R′

BH3 + NaB(H) (OR)3

−B(OR)

ONa R

BH3

O

R′

B(OR)3 + NaBH4

O

−

B(OR)3

O

R′ H B(OR)3 Scheme 12

3

Na+ R

H

R′

B(OR)3

ee

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enantioselective reductions of a range of prochiral ketones in quantitative yields and moderate ees (generally 58–87%) were obtained. The mechanism (Scheme 12) is proposed to involve either an electrophilic activation of the substrate or of the hydride reagent nucleophilically.278

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Other Reductions A review which covered the different known methods for the preparation of chiral amines and analysis of the different chiral catalysts used, correlating them according to their efficiency, selectivity, and flexibility, has been presented.279 Reduction reactions of alkenes, arenes, alkynes and allenes resulting in the formation of two or more C–H bonds280 and reduction and addition reactions of alkynes to alkenes to form one or more C=C bonds281 have been reviewed. Triorganyl-sulfonium, -selenonium and -telluronium salts are reduced by carbon dioxide radical anions/solvated electrons produced in aqueous solution by radiolysis. The radical expulsion accompanying reduction occurred with the expected leaving group propensities, i.e. benzyl > secondary alkyl > primary alkyl > methyl > phenyl. Much higher product yields in the reduction of selenonium and telluronium compounds have been accounted for in terms of a chain reaction with carbon-centred radicals, with formate serving as the chain transfer agent.282 The mechanism of the reduction of N -alkylhydroxamic acids with Lawesson’s reagent has been established by investigating the products of the reaction. The primary intermediate is an adduct, O-dithiophosphonylated hydroxamic acid (DHA), which decomposes to yield metathiophosphonate (AnsPOS), a sulfur atom, and an amide. At the same time, owing to the coexistence of DHA and metadithiophosphonate (AnsPSS) in equilibrium, the carbonyl group is thionated. AnsPOS takes part in a controlled transformation to form a dimer, the corresponding pyrothiophosphonate, together with the intermediate O-thiophosphonylated hydroxamic acid. A hydrolysed product of AnsPOS, namely (4-methoxyphenyl)thiophosphonic acid, participates in the last reaction.283 Reduction of trichloroethylene by a series of well-characterized outer-sphere electron-transfer reagents, viz. the radical anions of naphthalene, pyrene, perylene, decamethylcobaltocene, and cobaltocene, resulted in the formation of cis- and transdichloroethylene in ratio varying from 0.87 to 4.5, whereas in the reduction by vitamin B12 , the ratio was 30:1. This indicated that reduction with vitamin B12 occurs with a non-outer-sphere electron-transfer mechanism. A mechanism involving initial formation of a radical ion followed by an ejection of a chloride to give cis-dichlorovinyl radical and trans-dichlorovinyl radical has been proposed.284 A rhodium-based catalytic system, comprising a chiral monodentate phosphoramide and achiral monodentate phosphine ligands, gives asymmetric hydrogenation with up to 99% ee.285 Highly enantioselective catalytic asymmetric hydrogenation of substituted N -benzoyliminopyridinium ylides has been achieved with [Ir(COD)Cl]2 and iodine as catalyst and phosphinooxazolines as the chiral ligands. Yields in excess of 98% and ee up to 97% are obtained.286

ee

de

ee

ee

119


Monodentate phosphoramidites, in particular (9) and its octahydro analogue, are found to be excellent ligands for the rhodium-catalysed asymmetric hydrogenation of aromatic enol acetates, enol carbamates, and 2-dienol carbamates with up to 98% ee.287

O

P

O

ee

N

(9)

Hydrogenation of dienes with up to 20:1.0 diastereoselectivity and 99% ee is mediated by carbene complexes. The scope and limitations of these reactions were investigated.288 Asymmetric transfer hydrogenation to prochiral ketones, catalysed by a Ru(II) complex (10) or its dimer, with formic acid–triethylamine has been reported. The protocol leads to high yields and enantioselectivity up to 96%. It has been suggested that 16-electron Ru(II) and the Ru–H intermediates are involved in this reaction.289

ee

ee

Ts Ru Cl

N Ph

N H Ph (10)

A novel hydrogenation methodology for asymmetric synthesis of N -sulfonyl-αamino acids using chiral ruthenium catalysts and phosphine ligands has been developed. This reaction is fairly general with respect to the substitution at nitrogen.290 Ruthenium phosphine complexes, with (1S,2S)-DPENDS [(1S,2S)-1,2-diphenyl-1,2ethylenediamine sulfonate disodium] as a chiral modifier, catalysed the asymmetric hydrogenation of aromatic ketones in hydrophilic ionic liquids. The synergistic effect between (1S,2S)-DPENDS and KOH significantly accelerated the reaction and enhanced the enantioselectivity up to 84%.291 Significant correlation of relative rates of homogeneous hydrogenation of alkenes using Wilkinson’s catalyst separately in terms of ionization potentials and LUMOs indicated that the rate-determining step is a nucleophilic addition to the double bond. The addition is subject to both electronic and steric effects.292 Chiral phosphine–phosphates (11) are found to be effective ligands for the

ee

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120

Organic Reaction Mechanisms 2005 But R

R P

O

O

P

O But

(11)

iridium-catalysed enantioselective hydrogenation of imines. Enantioselectivities up to 84% in the reduction of N -arylimines have been obtained.293 Cinnamic acid and its derivatives were reduced in high yields under mild conditions using ammonium formate as hydrogen donor, in the presence of palladium(II) as catalyst in ionic liquids.294 The SmI2 –H2 O–amine-mediated reduction of 1-chlorodecane is first order in amine and 1-chlorodecane, second order in SmI2 , and zero order in water. Initial rate studies of more than 20 amines show a correlation between the base strength (pKBH+ ) of the amine and the logarithm of the observed initial rate, in agreement with the Brønsted equation. The reduction of 1-iododecane and 1-bromodecane exhibited 13 C kinetic isotope effects of 1.037 and 1.062, respectively. This shows that cleavage of the carbon–halide bond occurs in the rate-determining step. A suitable mechanism for the reduction of alkyl halides has been proposed.295 Addition of proton donors results in an initial increase in the amount of the benzhydrol formed in the reduction of benzophenone by SmI2 to benzopinacol. However, the benzhydrol:benzopinacol ratio reached a maximum, decreased, and then levelled off as the proton donor concentration was further increased. The momentary concentration of the intermediate radicals governs the product distribution.296 Dissymmetric ferrocenyldiphosphines have been synthesized from (R)-(+)-N ,N dimethylaminoethylferrocene. The diphosphines have been used as ligands in asymmetric transfer hydrogenation of acetophenone in the presence of ruthenium catalysts.297 Asymmetric transfer hydrogenation of α,β-unsaturated aldehydes with Hantzsch dihydropyridines and a catalytic amount of MacMillan imidazolidinone salt (12) leads to the saturated carbonyl compounds in high yields and excellent chemoand enantio-selectivities.298

O

N +

N H2

Cl3CO2−

(12)

Thiocarbonyl derivatives are deoxygenated on treatment with (Bu4 N)2 S2 O8 and sodium formate in DMF in excellent yields. The deoxygenation is proposed to be

ee

ee

121


initiated by the transfer of a single electron to thiocarbonyl derivatives from CO2 • rather than from SO4 • .299 Regioselectivity of the Birch reductive alkylation of polysubstituted biaryls is affected by the electronic nature of substituents on both aromatic rings. The electronrich 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, whereas phenols and aniline are not dearomatized under these conditions. Biaryls possessing a phenol moiety are alkylated on the second ring, provided that the acidic proton has been removed prior to the Li–NH3 reduction.300 The redox reaction between diphenylbenzidine and thiosulfate is of first order with respect to thiosulfate, diphenylbenzidine, and hydrogen ions.301 Zinc–diaminecatalysed reduction of various ketones with polymethylhydrosiloxane in protic conditions show moderate enantioselectivities. Probable mechanisms are proposed.302 Reduction of non-activated aryl and alkyl halides by a neutral ground-state organic molecule (13) afforded the corresponding indolines in excellent yields. A tentative mechanism has been suggested (Scheme 13).303

I

N

N

N

N

N

Ms

Me

Me

+

(13) I

− •

+

N

N

+

•

N

N

N

Ms

Me

Me

−I− • •

N

N

N

Ms

Ms

Ms

Scheme 13

Trialkyl ferrates(II) or the related manganese(II) and cobalt(II) compounds are excellent catalyst for reduction of organic compounds by dissolved metals such as magnesium. The protocol provides for tuning of catalytic activity by way of metal and ligand.304

122


Phosphoric acid catalysts, bearing bulky groups, have been devised for the asymmetric transfer hydrogenation of imines with Hantsch ester. With the catalyst (14), enantioselectivity up to 93% has been achieved in the reduction of aromatic imines. For an aliphatic imine a lower ee is obtained.305 R

ee

R

O O

R P R

R

O OH

R

R = isopropyl (14)

Enantioselective reduction of prochiral ketones by transfer hydrogenation is catalysed by amino acid derivatives. A mechanistic suggestion for the origin of enantioselective induction has been proposed.306 α,β-Unsaturated nitriles are efficiently reduced by a Cu(I)–H species in the presence of bisphosphine ligands. The active Cu(I)–H species was generated by the reaction of copper(II) acetate and polymethylhydrosilane.307 A ruthenium complex containing a novel imidazolium salt moiety catalyses the asymmetric transfer hydrogenation of acetophenone derivatives, with a formic acid– triethylamine azeotropic mixture in an ionic liquid, [bmim][PF6 ]. The yields and ee are excellent.308 Epoxides are deoxygenated with indium metal in the presence of indium(I) chloride or ammonium chloride. It is proposed that the reaction occurs through an SET process with indium as an electron donor.309 The spontaneous decomposition of N 1 -nitrosomelatonin (NOMel) is accelerated by acidification, presence of oxygen, and TEMPO. In the reduction of NOMel with ascorbic acid, the reactive species is melatonin radical. Based on kinetic data and DFT calculations, a mechanism for the denitrosation of NOMel has been suggested.310 Tetracyanoethylene oxide (TCNEO) not only oxidizes sulfides to sulfoxides but also reduces sulfoxides to sulfides with generation of two molecules of carbonyl cyanide (17). The reduction mechanism involves a zwitterion intermediate (15) that produces sulfide and two molecules of (17) by simultaneous cleavage of the C−C and O−S bonds. A mechanism (Scheme 14) that involves a zwitterion (16) as a common intermediate is proposed for the formation of ylide and sulfoxide.311 The deoxygenation of styrene oxide with dichlorocarbene exhibits a normal 13 C isotope effect of 1.016 for the α-carbon of the styrene oxide and an inverse isotope

ee

ee

123

3 Oxidation and Reduction NC

R S

+

O

TCNEO

R

CN

R +

S

O

−

CN

O

R

R CN

CN S

+ 2 O C

R

CN

(15)

R S

(17)

+ TCNEO

R

NC R R

CN

+

S

−O

NC CN

R

CN

R

CN

S O

NC CN

R

CN

R

+S

−

CN CN

O

CN

(16)

R

CN S

R

R + (17)

S

CN

O + TCNE

R Scheme 14

effect of 0.995 at the β-carbon. This is indicative of a highly asynchronous process in which the Cα −O bond is broken without any progress in the breakage of the Cβ −O bond. Theoretical calculations support this interpretation.312 In the presence of titanocene(II), anilides undergo reductive alkylation with thioacetals to yield anilines with a secondary alkyl group.313 The dithioacetals are reduced with gallium(II) chloride followed by acid treatment to afford sulfides in good yields.314 Aromatic N -oxides, such as N -arylnitrones, azoxybenzenes, and N -heteroarene N -oxides, selectively undergo deoxygenation with ruthenium(III) chloride.315 Epoxides are chemoselectively deoxygenated with ZrCl4 –NaI in excellent yields. The reaction proceeded with absolute stereospecificity.316 Disulfides are reduced to thiols by hydrogen in the presence of RhH(PPh3 )4 . RhH(PPh3 )4 and 1,4-bis(diphenylphosphino)butane catalyse the oxidation of thiols to disulfides by oxygen.317 Synthesis of N −protected (R)-3-alkylisoindolin-1-ones via diastereoselective reductive alkylation with Grignard reagent and triethylsilane has been reported. The emphasis is on the stereochemical outcome of the key diastereoselective reactions.318

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3 Oxidation and Reduction 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195

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3 Oxidation and Reduction 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290

129

Koshel, G. N., Koshel, S. G., Postnova, M. V., Lebedeva, N. V., Kuznetsova, E. A., Belysheva, M. S., and Yun’kova, T. A., Chem. Abs., 142, 239958 (2005). Plietker, B., Tetrahedron: Asymmetry, 16, 3453 (2005). Tan, X.-J., Wang, D.-S., and Li, J.-H., Chem. Abs., 142, 55623 (2005). Dehli, J. R. and Bolm, C., Chem. Abs., 143, 193531 (2005). Jiang, H.-F., Chem. Abs., 143, 193532 (2005). Xia, Q.-H., Ge, H.-Q., Ye, C.-P., Liu, Z.-M., and Su, K.-X., Chem. Rev., 105, 1603 (2005). Kagan, H. B. and Luukas, T. O., Chem. Abs., 143, 115072 (2005). Murahashi, S.-I. and Imada, Y., Chem. Abs., 143, 115073 (2005). Kuehn, F. E., Fischer, R. W., Herrmann, W. A., and Weskamp, T., Chem. Abs., 143, 115070 (2005). Graves, C. R., Campbell, E. J., and Nguyen, S. T., Tetrahedron: Asymmetry, 16, 3460 (2005). Afkhami, A., Nematollahi, D., Khalafi, L., and Rafiee, M., Int. J. Chem. Kinet., 37, 17 (2005). Goyal, R. N., Sondhi, S. M., and Lahoti, A. M., New J. Chem., 29, 587 (2005). Bardwell, M. W., Bacak, A., Raventos, M. T., Percival, C. J., Sanchez-Reyna, G., and Shallcross, D. E., Int. J. Chem. Kinet., 37, 253 (2005). Penenory, A. B., Arguello, J. E., and Puiatti, M., Eur. J. Org. Chem., 2005, 114. Kumar, V. S., Wan, S., Aubele, D. L., and Floreancig, P. E., Tetrahedron: Asymmetry, 16, 3570 (2005). Wakui, K., Okamoto, K., and Yamane, H., Chem. Abs., 142, 335856 (2005). Peng, K., Chen, F., She, X., Yang, C., Cui, Y., and Pan, X., Tetrahedron Lett., 46, 1217 (2005). Nosacheva, I. M., Revkov, O. A., and Perkel, A. L., Chem. Abs., 143, 211565 (2005). Xu, H.-J., Dai, D.-M., Liu, Y.-C., Li, J., Luo, S.-W., and Wu, Y.-D., Tetrahedron Lett., 46, 5739 (2005). Cordes, D. B., Nguyen, T. M., Kwong, T. J., Suri, J. T., Luibrand, R. T., and Singaram, B., Eur. J. Org. Chem., 2005, 5289. Casey, C. P. and Johnson, J. B., J. Am. Chem. Soc., 127, 1883 (2005). Dong, Z.-R., Li, Y.-Y., Chen, J.-C., Li, B.-Z., Xing, Y., and Gao, J.-X., Org. Lett., 7, 1043 (2005). Guan, H., Iimura, M., Magee, M. P., Norton, J. R., and Zhu, G., J. Am. Chem. Soc., 127, 7805 (2005). Casey, C. P., Bikzhanova, G. A., Cui, Q., and Guzei, I. A., J. Am. Chem. Soc., 127, 14062 (2005). Gosselin, F., O’Shea, P. D., Roy, S., Reamer, R. A., Chen, C.-Y., and Volante, R. P., Org. Lett., 7, 355 (2005). Jin, H.-X., Liu, H.-H., and Zhang, Q., and Wu, Y., J. Org. Chem., 70, 4240 (2005). Ueki, H., Chiba, T., and Kitazume, T., Org. Lett., 7, 1367 (2005). Tumerdem R., Topal, G., and Turgut, Y., Tetrahedron: Asymmetry, 16, 865 (2005). Bistri, O., Sinay, P., and Sollogoub, M., Tetrahedron Lett., 46, 7757 (2005). Dalicsek, Z., Pollreisz, F., Gomory, A., and Soós, T., Org. Lett., 7, 3243 (2005). Chelucci, G., Baldino, S., Solinas, R., and Baratta, W., Tetrahedron Lett., 46, 5555 (2005). Basavaiah, D., Chandrashekar, V., Das, U., and Reddy, G. J., Tetrahedron: Asymmetry, 16, 3955 (2005). Krzemiński, M. P. and Wojtczak, A., Tetrahedron Lett., 46, 8299 (2005). Aida, T., Kuboki, N., Kato, K., Uchikawa, W., Matsuno, C., and Okamoto, S., Tetrahedron Lett., 46, 1667 (2005). Fernandes, A. C. and Romao, C. C., Tetrahedron Lett., 46, 8881 (2005). Chandrasekhar, S. and Hota, R. Tetrahedron: Asymmetry, 16, 751 (2005). Brunel, J. M., Chem. Abs., 142, 155302 (2005). Micouin, L., Chem. Abs., 142, 297604 (2005). Regan, A. C., Chem. Abs., 142, 297610 (2005). Eriksson, P., Engman, L., Lind, J., and Merenyi, G., Eur. J. Org. Chem., 2005, 701. Przychodzen, W., Eur. J. Org. Chem., 2005, 2002. Follett, A. D. and McNeill, K., J. Am. Chem. Soc., 127, 844 (2005). Hoen, R., Boogers, J. A., Bernsmann, H., Minnard, A. J., Meetsma, A., Tiemersma-Wegman, T. D., de Vries, A. H. M., de Vries, J. G., and Feringa, B. L., Angew. Chem. Int. Ed., 44, 4209 (2005). Legault, C. Y. and Charette, A. B., J. Am. Chem. Soc., 127, 8966 (2005). Panella, L., Feringa, B. L., de Vries, J. G., and Minnaard, A. J., Org. Lett., 7, 4177 (2005). Cui, X, Ogle, J. W., and Burgess, K., Chem. Commun. (Cambridge), 2005, 672. Hayes, A. M., Morris, D. J., Clarkson, G. J., and Wills, M., J. Am. Chem. Soc., 127, 7318 (2005). Shultz, C. S., Dreher, S. D., Ikemoto, N., Williams, J. M., Grabowski, E. J. J., Krska, S. W., Sun, Y., Dormer, P. G., and DiMichele, L., Org. Lett., 7, 3405 (2005).

130 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318

Organic Reaction Mechanisms 2005 Xiong, W., Lin, Q., Ma, H., Zheng, H., Chen, H., and Li, X., Tetrahedron: Asymmetry, 16, 1959 (2005). Nelson, D. J., Li, R., and Brammer, C., J. Org. Chem., 70, 761 (2005). Vargas, S., Rubio, M., Suarez, A., and Pizzano, A., Tetrahedron Lett., 46, 2049 (2005). Baan, Z., Finta, Z., Keglevich, G., and Hermecz, I., Tetrahedron Lett., 46, 6203 (2005). Dahlen, A. and Hilmersson, G., J. Am. Chem. Soc., 127, 8340 (2005). Kleiner, G., Tarnopolsky, A., and Hoz, S., Org. Lett., 7, 4197 (2005). Cabou, J., Brocard, J., and Pelinski, L., Tetrahedron Lett., 46, 1185 (2005). Yang, J. W., Fonseca, M. T. H., Vignola, N., and List, B., Angew. Chem. Int. Ed., 44, 108 (2005). Park, H. S., Lee, H. Y., and Kim, Y. H., Org. Lett., 7, 3187 (2005). Lebeuf, R., Robert, F., and Landais, Y., Org. Lett., 7, 4557 (2005). Perveen, A., Farrukh, M. A., and Naqvi, I. I., Chem. Abs., 143, 193623 (2005). Bette, V., Mortreux, A., Savoia, D., and Carpentier, J.-F., Chem. Abs., 143, 211524 (2005). Murphy, J. A., Khan, T. A., Zhou, S.-Z., Thomson, D. W., and Mahesh, M., Angew. Chem. Int. Ed., 44, 1356 (2005). Hoffmann, R. W., Angew. Chem. Int. Ed., 44, 6277 (2005). Hoffmann, S., Seayad, A. M., and List, B., Angew. Chem. Int. Ed., 44, 7424 (2005). Yim, A. S. Y. and Wills, M., Tetrahedron, 61, 7994 (2005). Kim, D., Park, B.-M., and Yun, J., Chem. Commun. (Cambridge), 2005, 1755. Kawasaki, I., Tsunoda, K., Tsuji, T., Yamaguchi, T., Shibuta, H., Uchida, N., Yamashita, M., and Ohta, S., Chem. Commun. (Cambridge), 2005, 2134. Mahesh, M., Murphy, J. A., and Wessel, H. P., J. Org. Chem., 70, 4118 (2005). De Biase, P. M., Turjanski, A. G., Estrin, D. A., and Doctorovich, F., J. Org. Chem., 70, 5790 (2005). Nakayama, J., Tai, A., Iwasa, S., Furuya, T., and Sugihara, Y., Tetrahedron Lett., 46, 1395 (2005). Singleton, D. A. and Wang, Z., Tetrahedron Lett.,46, 2033 (2005). Takeda, T., Yatsumonji, Y., and Tsubouchi, A., Tetrahedron Lett., 46, 3157 (2005). Ikeshita, K.-I., Kihara, N., and Ogawa, A., Tetrahedron Lett., 46, 8773 (2005). Kumar, S., Saini, A., and Sandhu, J. S., Tetrahedron Lett., 46, 8737 (2005). Firouzabadi, H., Iranpoor, N., and Jafarpour, M., Tetrahedron Lett., 46, 4107 (2005). Arisawa, M., Sugata, C., and Yamaguchi, M., Tetrahedron Lett., 46, 6097 (2005). Chen, M.-D., He, M.-Z., Zhou, X., Huang, L.-Q., Ruan, Y.-P., and Huang, P.-Q., Tetrahedron, 61, 1335 (2005).

CHAPTER 4

Carbenes and Nitrenes

M. Christlieb,1 and E. Gras2 1 Gray

Institute for Radiation Oncology and Biology, University of Oxford Laboratoire de Synthèse et Physico-Chimie des Molécules d’Intérêt Biologique, Université Paul Sabatier, Toulouse, France

2

Reviews . . . . . . . . . . . . . . . . . Generation, Structure, and Reactivity Metal-bound Carbenes . . . . . . . . . Carbenes as Ligands . . . . . . . Carbenes as Reagents . . . . . . Addition and Fragmentation . . . . . Insertion and Abstraction . . . . . . . Rearrangement . . . . . . . . . . . . . Nitrenes . . . . . . . . . . . . . . . . . Phosphinidenes . . . . . . . . . . . . . Nucleophilic and Basic Carbenes . . . Electrophilic and Acidic Carbenes . . Oxidation and Reduction . . . . . . . Silylenes and Germylenes . . . . . . . Stannylenes . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . .

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131 132 135 135 136 139 140 141 143 147 147 149 149 150 151 151

Reviews A short review by Christmann discussed recent developments in the asymmetric Stetter reaction; nucleophilic carbenes based on imidazoles, triazoles, and thiaazoles were discussed.1 In keeping with the theme of applications, the use of stable N heterocyclic carbenes (NHCs) as ligands for catalysis metals in organic chemistry has been reviewed.2 Specific examples include the use of metal–carbene complexes in hydrosilylation, Ru-catalysed furan synthesis and alkene metathesis. A general review of the 1,2-group migration reactions of carbenes has been presented by authors who have a particular interest in Rh(II) carbenes.3 A review of the synthesis and reactions of iminium ylides discusses the synthesis of such ylides from carbenes and metallo-carbenes.4 The use of carbenes in setting up asymmetric quaternary centres


131

132


was reviewed.5 The synthesis, structure, and applications of silver-bound NHCs have been treated in a major review in Chemical Reviews.6 The review is focused on the inorganic chemistry of silver and silver clusters. A short section refers to pharmaceutical aspects and catalysis. Enantioselective insertion of carbenes into allylic CH bonds was reviewed by Davies and Nikolai.7 The key intermediates are rhodium-bound carbenes with one donor and one acceptor group attached. The acceptor group is an ester, but the donor can be an electron-rich aromatic, a heteroaromatic, or a vinylic group. Yields are variable, generally above 50%, and greater than 90% has been achieved. Diastereoselectivity is generally excellent (>98%). Although ees are usually high (over 90%), they can be as low as the mid-60% range. A review covering the use of titanium carbene complexes in organic synthesis has appeared.8 Special emphasis is placed on titanium carbene generated from titanocene bis(triethylphosphate) by action on thioacetals or gem-dichlorides. Generation of triplet carbenes from photolysis of iodonium ylides has been discussed in a short review.9 Although electrophilic carbenes react with the sulfur atom of CS double bonds, dimethoxycarbene reacts at the carbon atom.10 A review commentary covers the limited range of literature available covering 2,2,4,4-tetramethyl-1,3-cyclobutanedithione, diarylthiones, o-methyl thiobenzoate, methyl dithiobenzoate, and dimethyl xanthate. The synthetic reactions of nucleophilic carbenes have been reviewed.11 Isonitriles, dimethoxycarbene, and NHCs are covered. The review focuses on the 1,3-dipolar cycloaddition reactions made possible when the nucleophilic carbene reacts with electrophiles such as dimethylacetylene dicarboxylate. Such reactions were also the subject of research papers during 2005 (see the section on nucleophilic and basic carbenes). The synthetic applications of 1,3-dipolar cycloaddition of carbonyl ylids generated from diazo ketones have been reviewed with particular focus on pseudolaric acids.12

Generation, Structure, and Reactivity Methylhydroxycarbene, MeC(OH), has been generated in one of the three reaction pathways of the collision-induced dissociation of protonated butane-2,3-dione.13 Its enthalpy of formation was found to be 16 ± 4 kcal mol−1 . Fluorophenoxycarbene (PhOCF) has been generated inside a hydrophobic hemicarcerand (1) by irradiation of the corresponding confined diazirine.14 Its reactivity (especially dimerization and reaction with water) was significantly lowered by the incarceration, allowing its persistence for days at room temperature. New (amino)(silyl)carbenes (2) have been generated and their structure–activity relationship studied. They showed behaviour similar to those of previously reported (amino)(alkyl)carbene.15 Analogues of imidazolylidene bearing two adjacent boron atoms in the heterocycle (3) have been synthesized and their coordination chemistry has been studied.16 They were shown to be better σ -donors than their classical counterparts. The imidazo[1,5a]pyridine has been shown to be a modular base for new stable NHCs (4).17 The same platform also allowed the isolation of ‘abnormal’ NHCs (5) with a mesoionic structure and a strong σ -donor character.

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4 Carbenes and Nitrenes R

R

R

R

O

O

O O

O

O

O

O

O

O

O

O (H2C)4

(H2C)4

(CH2)4

GUEST

O

O

O

O

O

O O

O

O

O

R

(CH2)4

O O

R

R

R

R = n-pentyl (1) Me2N R2N

NMe2 B B

SiPh2But Ar

N

(2)

N

R′′ R′

N (3)

−

N R

N

R′′

+

N R Ph

R′ (4)

Ar

(5)

Post-Hartree–Fock calculations have been carried out to study the structure of stable triplet carbenes.18 The structural parameters obtained for substituted bisarylcarbene are in better agreement with X-ray data than the parameters obtained from DFT studies. Dibromocarbenes have been shown to react with t-butylisonitrile with near diffusion-limited rate constants to give ketenimines (6) that can be readily detected by

134

Organic Reaction Mechanisms 2005 R But

Br

R N

C N Br

Cl (6)

N

Cl

(7)

(8)

time-resolved infrared spectroscopy.19 Kinetic studies of the photochemical decomposition of vinylchlorodiazirines (7) to chlorocyclopropene (8) in solution have been carried out.20 Evidence was given that both the free carbene and an excited diazirine are possible pathways to the cyclopropene. The effect of halogen substitution on the geometries and relative energies of o-phenylenebiscarbenes has been explored by computation.21 No significant effect was found on symmetrical systems whereas a pronounced stabilization was determined (especially with fluorine) for the A states. Photochemically excited bis(heteroaryl)alkynes such as (9) have been reported to behave as a 1,2-biscarbene in their cycloadddition with cyclohexa-1,4-diene leading to polycycles (10).22 F F

F

F

N

N N

F F

F

N

F

(9)

(10)

PhCBr + Br− (11)

CN

−

CN

Ph

−

PhCBr2

Br

(14)

Br

slow

Br Ph

Br Ph

CN (13)

(12)

135

4 Carbenes and Nitrenes

Insight into the nature of the intermediate in the cyclopropanation of electron-rich and electron-poor alkenes was given by laser flash photolysis (LFP) studies of phenylbromodiazirine in the presence of various amounts of tetrabutylammonium bromide.23 Electron-rich alkenes react exclusively with the carbene (11) leading to (12). Electronpoor alkenes yield cyclopropanes (13) only slowly with the carbene (11) and more rapidly with the carbanion (14) arising from the addition of the bromide to the carbene. The persistent (amino)(hydrazino)carbene (15) was shown to fragment rapidly homolytically at the N–N bond at temperatures above −20 ◦ C, yielding (16) and (17).24 Rapid H-abstraction then afforded the amidine (18) and the imine (19). H Pri Me2N

Pri

N

N

H2C Pri

(15)

N +

Pri

Pri

N

N

Me (16)

iPr

Pri

Pri

N N H

Me +

Pri H2C

(18)

(17)

N

(19)

Metal-bound Carbenes Carbenes as Ligands A highly original approach to unsymmetrical NHCs was reported.25 The NHC was synthesized in the coordination sphere of the metal. Nucleophilic attack of propargylamine on the isocyanide moiety of manganese complexes (20) is followed by intramolecular hydroamination to give (21). A 1,3-H shift moves the double bond to give the coordinated NHC (22). Interestingly, attack by propargyl alcohol under basic catalysis yielded the N ,O-heterocyclic carbene (23), a previously unreported structure. Ph NH2

[Mn]

C

N Ph

N [Mn] N H

(20)

(21)

Ph 1,3-H shift

N [Mn] N H (22)

The metal–carbene bond of NHCs with late transition metals has been studied theoretically and crystallographically.26 Discrepancies between theory and experiment are put down to an increased p-character of the carbenoid carbon rather than a multiple bond between carbon and metal. Chiral silver complexes bearing bidentate NHC ligands (24) have been synthesized. They are used in alkene metathesis and allylic alkylation reactions; high diastereoselectivity is observed induced by the chiral backbone on the prochiral biphenyl.27 Ruthenium-based complexes obtained from transmetalation with a Grubbs–Hoveyda complex exhibited high activities and enantioselectivities in ring-opening metathesis/

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Organic Reaction Mechanisms 2005 Ph

Ph N N

N

MesN

O Mn

Ph N

CO CO OH

CO (23)

(24)

cHex cHex

N

N

cHex cHex

(25)

cross-metathesis processes. Copper-catalysed asymmetric allylic alkylation was also conducted with good yields and enantioselectivities. Aromatic aldehydes were arylated at position 2 and/or 6 via a C–H activation in the presence of Pd(OAc)2 and NHC precursors provided an efficient route to biphenyl carbaldehyde.28 Highly bulky NHCs such as (25) proved to be efficient partners in Suzuki–Miyaura cross-coupling of aryl and vinyl chlorides at temperatures varying from ambient to 50 ◦ C.29 2 H NMR studies gave insights into the stabilization of nanoclusters of iridium in imidazolium-type ionic liquids.30 It has been clearly established by H/D scrambling under a D2 atmosphere that NHCs are involved in this stabilization. Cyclotrimerization of triynes has been reported using cobalt or iron complexes of NHCs without CO and Cp ligands.31 Benzannulated compounds have been isolated with up to quantitative yields.

ee

Carbenes as Reagents The 2005 Nobel Prize in Chemistry has highlighted the importance of alkene metathesis. A comprehensive survey is beyond the scope of this chapter; highlights include tandem ring-opening metathesis/cross-metathesis32 and enyne metathesis. The latter has been exploited in ring-closing macrocyclization, although the yields reported for dimers such as (26) remained modest. A tandem enyne cross-metathesis/Diels–Alder strategy has been applied to the synthesis of fused carbocycles (29) from readily accessible starting materials (27) and (28).33 β-lactams (30) were obtained diastereoselectively by ruthenium-catalysed decomposition of α-diazoacetamide (31) followed by 1,3-CH insertion.34 Similarly,

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4 Carbenes and Nitrenes O

O

O

O (26)

OTBS CN

CN OTBS

(27) +

H

MeO

MeO (29)

(28) EtO2C

O

O N

R1

R1

O

N

OEt

R2

R2

(30)

N2 (31)

Ts

Ts

O

R

R′ N2 (32)

R

COR′ (33)

cyclopropanes (33) have been obtained by rhodium-catalysed decomposition of βtosyl-α-diazo compounds (32).35 Treatment of 1-chloroalkyl phenyl sulfoxides with isopropylmagnesium chloride has been reported to yield magnesium carbenoids that also undergo 1,3-CH insertion to cyclopropanes (35) when a geminal methyl or benzyl group is present as in (34).36 Larger rings such as (36) were made by insertion of a rhodium carbenoid into phenolic OH bonds.37 Triarylamines have been isolated from a rhodium-catalysed reaction of diarylamines with 2-diazocyclohexane-1,3-dione.38 Enantiopure alkynyl(alkoxy)carbene (37) complexes were produced by formal alkyne insertion into Fisher carbene complexes.39 Reaction of (37) with 1-azadiene gave functionalized 1,4-dihydropyridine (38) with high enantiomeric excess.

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R1 O

R1 R1

R

R1 = H, Ph

S

R1

O O

Ph

R1

R

Cl (34)

O

(35)

Ac

(36)

W(CO)5

OHC NPr

OR*

Ph

Ph

N Pr

(37)

(38) CO2Et MeO

O

R O

(39)

(40)

Chloromethylenetitanium complexes have been generated by oxidative addition of chloroform to a mixture of TiCl4 and Mg in THF.40 These carbene complexes were efficiently added to enolizable and bulky carbonyl compounds to yield the corresponding vinyl chlorides. Formal addition of ethyl diazoacetate to benzyl bromides was catalysed by palladium, yielding aryl acrylates (39).41 A carbene insertion into the Pd–C bond is thought to be involved in the catalytic cycle. Rhodium- and copper-catalysed cyclopropanation of 8-oxabicyclo[3.2.1]octane by diazocarbonyl compounds was achieved in poor to moderate yields. Ring opening of the cyclopropane (40) upon treatment with SmI2 offered a desymmetrization of the original bicycle. Silver scorpionate (41) catalysed the Büchner reaction, yielding the cycloheptatrienes (43) from the corresponding aromatics (42).42 Rearrangement of β-thio-α-diazo carbonyl compounds (44) occurred upon decomposition of the diazo function by metals, especially Rh(II).43 1,2-Thio migration adducts (45) were obtained with moderate to high diastereoselectivities. The outcome of the decomposition of (46) by Rh(II) was shown to be highly dependent on the nature of the X substituent.44 When X = OH, (47) has been exclusively observed, whereas (48) was the only product isolated when X = NHC(O)CCl3 .

139

4 Carbenes and Nitrenes CO2Et SR1

CO2Et N2

O

R2 (41)

R

R3

F3C

N2 (44)

(45)

F3C

H B CF3 N N N N N N Ag

CF3

R3

R2 SR1

R (43)

(42)

O

CF3

CF3

THF (41) X

X

CO2Et

CO2Et R

N2 (46)

CO2Et R

H (47)

H

+ X

R (48)

Addition and Fragmentation Pathways of the cycloaddition reactions of triplet methylene were studied using DFT at the B3LYP/6–31(d) level of theory.45 Methylene addition was driven by spin polarization and the subsequent ring closure shown to be a pericyclic process. The critical stationary points of the addition of singlet methylene to acetylene in the gas phase have been refined using an extrapolated complete basis set theory.46 The resulting cyclopropene can rearrange to propyne or allene with equal probability, the outcome depending on the collision energy. The mechanism of the cycloaddition of singlet dibromocarbene to formaldehyde was studied using DFT at the B3LYP/6–31G* level of theory.47 The energy barrier is estimated as 13.7 kJ mol−1 . Reaction paths for the addition of dichlorocarbene to 1,2disubstituted cyclopropenes were studied using the same level of theory as above.48 The addition gives 1,3-dienes or bicyclobutanes and was predicted to be concerted following an asymmetric approach. Addition of aryloxychlorocarbene to acetylenedicarboxylate led to 1,3-dienes (49) together with 8-oxatricyclo[3.2.1.02.4 ]oct-6-enes (50) or aryloxycarbonylmaleates (51), depending on the reaction temperature.49

140

Organic Reaction Mechanisms 2005 OAr O CO2R OAr Cl

Cl OAr CO2R (49)

OR

Cl RO2C OAr

Cl

CO2R

RO2C

CO2R O

CO2R OAr

(50)

H (51)

Fluorocarbenes reacted with imines yielding the corresponding azomethine ylides. The latter cyclized to fluoroaziridines. In the presence of alkene or alkyne dipolarophiles, azomethine ylides gave dihydropyrroles or pyrroles, respectively, after HF elimination.50 Chiral and achiral 1,2,4-triazolium salts were synthesized and found to be bench stable precursors of NHCs that efficiently catalyse both Stetter reactions and additions to α-bromoaldehydes in an enantioselective fashion.51

O O

Cl

O

Cl

Cl

(52)

(53)

(54)

Related oxychlorocarbenes have been studied in detail. The alkyl groups were endonorbonenyl-2-oxychlorocarbene (52),52 exo-norbonenyl-2-oxychlorocarbene (53),53 and 3-nortricyclyloxychlorocarbene (54).54 MeO

MeO

O

MeO

O CO2Me

O (55)

O

OMe (56)

The chemistry of allyloxy(methoxy)carbene (55) depends on the temperature at which it is generated.55 At 110 ◦ C, the carbene homolytically dissociated yielding mainly allylic ester. At 50 ◦ C, the carbene dimerized and underwent a Claisen rearrangement to (56).

Insertion and Abstraction The stationary points of H-atom abstraction reactions of triplet CF2 with XHn (n = 1–4: X = H, F, Cl, Br, O, S, N, P, C, and Si) were computed using UCCSD(T) methods with 6–311++G(3df,2p) and aug-cc-pVTZ basis sets.56 Covalent surface

ee

141


crossing heights were found to correlate well with the computed classical barrier heights. In general, H-abstractions were calculated to be energy-demanding processes for second-row atoms (X), but become more facile for their third-row counterparts. The mechanisms for the insertion reactions of alkylidenecarbenes with methanol were investigated at the B3LYP/6–311G(d,p) level of the theory.57 The products are predicted to be vinyl ethers with a mixture of cis- and trans-isomers. The reactivity of the carbenes decreases in the order HFC=C > HClC=C > HBrC=C > H(Me)C= C > H2 C=C.

Rearrangement The rearrangement of cyclopropylcarbene to cyclobutene was studied theoretically using B3LYP at the 6–311G(d) level.58 The results show that the rearrangement of cyclopropylcarbene to cyclobutene is an electrophilic rearrangement, very different from the traditional mechanism of nucleophilic rearrangement for carbocations. The reaction of vinylic phenyliodium salts (57) with cyanide anions could be mistaken for a simple substitution reaction.59 However, the presence of both allylic (58) and vinylic (59) nitrile products suggests a more complex picture. Deuterium labelling experiments show that the allylic product is formed via the Michael addition of cyanide to the vinylic iodonium salt, followed by elimination of iodobenzene and a 1,2hydrogen shift in the 2-cyanocycloalkylidene intermediate (60). H-shift occurs from the methylene carbon in preference to the methine carbon. The effects of substitution and different nucleophiles were examined. +

IPh CN

−CN

(57)

(60)

CN

(58)

CN

(59)

Thermolysis of 2-acetoxy-2-methoxy-5,5-dimethyl-3 -1,3,4-oxadiazoline affords acetoxy(methoxy) carbene.60 The thermal rearrangement of acetoxy(methoxy) carbene to methyl pyruvate was studied by DFT at the B3PW91/6–31G(d,p) level. The conformation of the carbene was considered, as were competing fragmentations to radical pairs. The authors concluded that the reaction is a concerted 1,2-migration rather than a fragmentation–recombination process. The silyl migration and decarbonylation of methoxysiloxycarbenes (MeOC: OSiH2 X) has been examined using quantum chemical calculations and natural bond order analysis.61 Inductively electron-withdrawing groups lower the barriers to silyl migration (oxygen to carbon) and decarbonylation (to give MeOSiH2 X). This is taken to be consistent with a symmetry-forbidden concerted rearrangement involving either intramolecular nucleophilic attack by the carbene lone pair at silicon in the case of silyl migration or attack of the methoxy oxygen at silicon in the case of decarbonylation.

142


Hammett correlations and hyperconjugation effects were assessed. That migration is favoured over decarbonylation is explained by hyperconjugation effects, in this case a competition between oxygen and carbene lone pairs for interaction with the SiO antibonding orbital. The oxidation of phenylacetylene with dimethyldioxirane yields mandelic acid and/or phenylacetic acid.62 The initially formed oxirene rearranges via two αoxocarbenes to phenylketene from which both products are derived. The vinylidene–acetylene rearrangement has been used in the synthesis of arenediynes.63 Treatment of a vinyl dibromide with an organolithium causes lithium–halogen exchange, which is followed by a 1,2-hydrogen shift to give the alkyne. Two transformations per molecule were demonstrated with yields of 34–96%. Heterocyclic aromatics performed noticeably less well than carbocyclics. In a brief paper, a 1,2-aryl shift in 2-aminophenylphenylvinylidenes was observed that competed with the formation of indoles by NH insertion.64 It was shown that the ratio of indole to acetylene was strongly dependent on the polarity of the ethereal solvent.

Cl Cl (61)

(62)

Cl

Cl

(63)

Ph

(64)

Ph

Ph hn

Ph

Ph Ph

(65)

(66)

(67)

Ph Ph

Ph

Ph Ph Ph (69)

(68)


143

The rearrangement of cyclopropylchlorocarbenes (61) and (62) into the corresponding cyclobutenes (63) and (64) was studied.65 The activation energies were 3–4 kcal mol−1 and the activation entropies −20 eu. The authors remarked that these values are close to those observed for the parent cyclopropylchlorocarbene. These observations were taken to suggest that the published differences between observed and calculated activation parameters for the parent system are real and that they may represent an important aspect to the reaction. Photolysis of (65) provided (67) via the assumed intermediate (66).66 The observation of (68) and (69) supported (66) as an intermediate, as did experiments designed to generate (66) independently.

Nitrenes The reaction of aryl azides with manganese porphyrin complexes gave metal-bound nitrenes.67 Halogen- and alkyl-substituted aryl rings were explored, but the authors noted that the aryl ring must be substituted. The formation of nitrenes requires either thermal or photochemical activation. Formation of a singlet nitrene is followed by two competing pathways: ring expansion to the corresponding azepine, which can then polymerize in concentrated solutions, or, in more dilute solutions, the azepine can revert to the singlet nitrene, which may then relax to the triplet state. It is the triplet state which is claimed as the key intermediate in formation of the manganese nitrido complexes. Triazines have been formed from the reaction of imidazol-2-ylidenes with azides.68 The reaction could be thought of as the reaction of a carbene with a nitrene. The reaction gives 54–94% yields and one of the products was induced to lose nitrogen when heated to above 120 ◦ C. A picosecond Raman spectroscopic examination of the reactions of 2-fluorenylnitrene and 4-methoxyphenylnitrene with water revealed singlet nitrenium ions.69 Evidence was presented to suggest that the nitrenes were produced during the photolysis of the corresponding azides. The 4-methoxyphenylnitrene decayed much faster than the 2-fluorenylnitrene. Inue et al. claimed the first report of the infrared detection of an aryl nitroso oxide, made from the reaction of 4-nitrophenylnitrene with molecular oxygen.70 The singlet nitroso diradical is formed from the triplet nitrene and oxygen at a temperature of 50 K in argon or xenon matrices. The reaction does not occur at 40 K. Hemicarcerands have been used as a convenient way of isolating nitrenes from the environment and studying their reactions.71 Singlet phenylnitrene rearranges to cyclic ketenimine inside a suitable capsule; low-temperature NMR spectroscopy allowed the determination of the observed rate constant kobs = 3.2 × 10−4 s−1 , which agreed with that obtained by FT-IR spectroscopy. The ring-expansion rate constant k1 and intersystem-crossing rate constant kISC of the cyclic ketenimine in the hemicarcerand were identical with those measured in pentane, supporting the assumptions that neither the ketenimine nor the singlet nitrene react with the hemicarcerand. The initial product of photolysis of aryl azides, such as (70), is a singlet nitrene that relaxes into the triplet form below 160 K.72 The reactivity below 160 K is

N

N

N3

(70) (R = H) (71) (R = Me)

R

R

254 nm

EtOH Et2NH

N

N

N

N

N N

NEt2 15%

N N

N

N

N

N N 2

N

N+ N

−

N

NEt2

+ 35% : 20% : 10% : 0%

293 K 39% : 18% : 24% : 0% 90 K 10% : 69% : tr : 0% 90 K + 450 nm 20% : 0% : 2% : 55%

NH2

N

N NH

144 Organic Reaction Mechanisms 2005


145

dominated by dimerization and intramoleclar CH insertion reactions. Above 160 K, singlet chemistry dominates, including trapping by nucleophiles. At room temperature, isomerization to the dehydroazepine and trapping of this species by nucleophiles occur. The intermediates and products were characterized spectroscopically and the reaction sequence studied by calculation (B3LYP/6–31G*). The reactions of (70) were compared with those of a bis(methyl)-substituted derivative and the authors concluded that cyclization to the heteropentalenes requires that the pyrazole nitrogen lone pair faces the nitrene nitrogen atom. The percentage of this conformation may differ in (70) and (71); the nucleophilicity of the pyrazole nitrogen lone pair is increased by the methyl groups and intersystem crossing may be faster in (70) than in (71), thus siphoning away singlet nitrene more rapidly than it can cyclize. A DFT approach to o-phenylene halocarbenonitrenes and o-phenylene chlorocarbenocarbenes has been reported.73 The calculations suggest that the nitrenes (72) (Y = N) have a quinoidal singlet ground state. Ring opening to the unsaturated nitriles was shown to be more favourable for X = halogen than for X = H, but the presence of halogens had a less marked effect for the ring closing reaction to cyclobutenes. Attempts to observe (72) (X = halogen) were unsuccessful. The ultimate products of the reactions were (73) and (74), the major product being the thermodynamically more stable in each case studied. The carbene (75) was observed for X = Br only. For Y = CH, a quinoidal ground state is again predicted. Attempts to isolate this dicarbene in matrix gave cyclobutene (76), nitrile (77), and cyclic alkyne (78) products; the last was thought to arise from an all-carbon equivalent to (75). Flash vacuum thermolysis (FVT) of 9-azidophenanthrene, 6-(5-tetrazolyl)phenanthridine, and [1,2,3]triazolo[1,5-f ]phenanthridine give 9-cyanofluorene as the principal product and 4-cyanofluorene as a minor product.74 A nitrene intermediate was detected by ESR in the case of 9-azidophenanthrene; a carbene intermediate was detected from the other two starting materials. DFT calculations were applied to examine other potential reaction products and it was concluded that although the observed products are not the kinetically favoured products, they are the thermodynamic sink and cannot be avoided under FVT conditions. Decomposition of 2,6-difluorophenyl azide by LFP (266 nm) generated a singlet nitrene which was detected by time-resolved IR spectroscopy (1404 cm−1 ).75 The nitrene could only be detected between 243 and 283 K. At 298 K, the nitrene decay products, a ketenimine (1576 cm−1 ) and a triplet nitrene (1444 cm−1 ), were observed. The IR assignments were consistent with DFT calculations and previous UV–visible detection results. The rates of reaction of triplet nitrenes and carbenes were compared by DFT and MO calculations.76 Triplet nitrenes are more stable than the analogous carbene and CO bonds stronger than NO bonds; the two effects are nearly additive in the reaction of nitrenes and carbenes with molecular oxygen. The formation of aziridines using bromamine-T was catalysed by cobalt porphyrins.77 Yields range from the mid-50% level to >90% with aliphatic and aromatic alkenes. Sulfonimidamide also yielded aziridines when treated with iodosylbenzene diacetate in the presence of dirhodium tetraacetate.78

YN2

CXN2

Ar, 13 K

hn

(72)

Y

X

Y = CH

Y=N

(76)

(73)

CH

N

(77)

(74)

CHCl

N

CX

(78)

(75)

CHCl

NBr


147


The reaction of benzoylnitrene with lithium bromide was studied to determine whether a nitreneoid [PhCON(Li)Br] or a Hoffman intermediate (PhCON− Br) would be formed.79 Time-resolved IR spectroscopy combined with DFT modelling indicated that the Hoffman intermediate is formed. The mechanism of insertion of 2-alkylphenylnitrenes into a 1,5-related CH bond was studied by three methods:80 determination of isotope effects, stereochemistry, and radical clock. During the formation of indolines, a kH /kD of 12.6–14.7 was observed coupled with complete loss of stereochemical integrity at the CH carbon. When the CH insertion carbon bore a cyclopropane group, ring-opening products were observed. These observations suggest a mainly radical H-atom abstraction mechanism. The sensitivity of the isotope effects to solvent was taken to imply a small concerted nitrene insertion contribution.

Phosphinidenes Just as six-electron nitrogen atoms can be found in either nitrene or nitrenium variants, so in principle could six-electron phosphorus atoms. Most papers reporting on phosphinidenes cite indirect evidence for the presence of the six-electron uncharged phosphorus atom. Calculations which investigate the mechanism by which phenylphosphirane fragments to phenylphosphinidene (PhP) and ethylene have been published.81 Theory suggests that the fragmentation to form triplet phosphinidene is both kinetically (12.2 kcal mol−1 ) and thermodynamically (21.2 kcal mol−1 ) favoured over formation of the singlet state. Further work on the stepwise fragmentation of anti -cis-2,3dimethyl-P -mesitylphosphirane suggests that although the stereochemistry of the reaction is consistent with results published by previous authors, the activation barriers mean that free phosphinidene is unlikely to have been formed (uncatalysed) at the reaction temperatures cited.82

Nucleophilic and Basic Carbenes The affinity of 1-ethyl-3-methylimidazol-2-ylidene for protons in the gas phase was measured at 251.3 kcal mol−1 by an extended version of the kinetic method.83 DFT calculations were performed and gave a result which differed by only 9.5 kcal mol−1 , which confirms this compound as one of the strongest bases reported. The reactivity of phosphino(trimethylsilyl)carbenes (79) with various organic acids has confirmed the basic character of these carbenes.84 1,3-Dimesitylimidazolium chloride, phenylacetylene, acetonitrile, and acetyltrimethylsilane were used as acids and the pKa s in DMSO were estimated as being between 18 and 31. However, the

SiMe3

Ph2P

A-H

Ph2P

+

SiMe3

A A−

H (79)

(80)

(81)

Ph2P

SiMe3

148


authors observed that DFT calculations suggest that the experimental results cannot be taken at face value and that the proton transfer should be rather endothermic (ca. 100 kcal mol−1 ). They suggested that the reaction is driven forwards by the interaction of (80), the conjugate acid of the phosphino(trimethylsilyl)carbene, with (81) the conjugate base of the acids used. Dimethoxycarbene (DMC) is well known as a nucleophilic carbene, usually generated from 2,5-dihydro-2,2-dimethoxy-5,5-dimethyl-1,3,4-oxadiazole at 110 ◦ C. 2,5-Dihydro-2,2-dimethoxy-5-methyl-5-(p-methoxy)phenyl-1,3,4-oxadiazole has been shown to decompose to DMC at 40–50 ◦ C, making much milder reaction conditions possible.85 A 1:1 adduct (82) was not detected and the stereochemistry of (83) and (84) was unaffected by the stereochemistry of the starting material, leading the authors to propose a nucelophilic addition resulting in a zwitterionic intermediate. A similar reaction was used synthetically.86 Dimethoxycarbene acted as a nucleophile in the presence of dimethyl acetylenedicarboxlate to give a zwitterionic intermediate which reacted with 1-aryl-2,2-dicyanoethane to give cyclopentenone dimethylacetal derivatives. Yields did not exceed 60%.

NC MeO

CO2Me

MeO2C

OMe MeO2C

CN

NC

CN

NC OMe MeO2C

OMe OMe

OMe MeO2C OMe CO2Me NC OMe (82) (83) MeO2C NC

O

OMe

OMe CO 2Me NC (84)

NHCs have long been used as nucleophilic carbenes. α,β-Unsaturated aldehydes were converted to saturated esters in the presence of an alcohol, a base (DBU), and a catalytic quantity of, for example, imidazolium salts.87 The reaction proceeds along the same lines as the Stetter and benzoin reactions, but this time homoenolate chemistry is being invoked in place of the acyl anion chemistry of the two named reactions. Yields range from poor (56%) to usable (90%); a kinetic resolution was attempted, giving an ‘s-factor’ of 4.8 at 40% conversion. Another use for homoenolate chemistry was demonstrated in the one-step formation of γ -butyrolactones from benzoins or benzaldehydes.88 Depending on the presence of substituents on the aromatic rings, yields varied from 32% (p-fluoro) to 76% (no substitution). The trifluoromethylation of enolizable and non-enolizable aldehydes was catalysed by N ,N -diadamantyl NHC.89 Yields in the range 54–90% were achieved with catalyst loadings of 0.5–1%. Aldehydes were selected over ketones. Similarly, NHCs were used to transform unactivated esters into amides.90 Primary amines were used and the yields were higher than

149

4 Carbenes and Nitrenes O R1

H

C

R

R2

R = But

(86)

NaH, Tol, 90 °C

R′

N

R′

(85)

R2

N+ Cl−

+

+

R1 = Ph R1 = CO2Me R2 = CO2Me R2 = CO Me 2

NaH, THF, r.t.

R1

O

R2

R′

R1

NR

RN NHR

NR

O

R2 R1

80% for all except the least electrophilic esters. The closely related transesterification reaction has been studied by DFT.91 This study concluded that the primary role of the NHC catalyst was to assist proton transfer from alcohol to carbonyl oxygen. When used with activated acetylenes (85) and aromatic aldehydes (86), NHCs are incorporated into the reaction products in a way that depends strongly on the conditions and substituents.92

Electrophilic and Acidic Carbenes A study of the photochemistry of the diazo derivatives of Meldrum’s acids was conducted.93 At 210 nm, in the presence of water or methanol, the reaction produced mainly the Wolff rearrangement product with some rearrangement (98%) by combining the racemate with the carbanion of (R)-methyl-p-tolylsulfoxide, separating the neutral diastereomeric adducts, and then removing the chiral auxiliary in a novel Pummerer-like reaction in which the cation and not a proton was the electrofuge.56 Reaction of aldehydes (21) with guaiazulene (22) in methanol in the presence of hexafluorophosphoric acid gives salts (23) in excellent yields;57 a later paper from the same group showed the same reaction occurs with aldehydes of furan, thiophene, and pyrrole.58 Crystal structures of the perchlorate salts of six viologen analogues were reported.59 The cations serve as models of the acceptor component of novel charge-transfer complexes where stilbene is the donor. A series of triarylmethyl cations combining ferrocenyl and 4-(2-ferrocenylethenyl)phenyl groups with phenyl, 1-naphthyl, and

ee

186

Organic Reaction Mechanisms 2005 R2

R2

R1 +

PF6− H

+

R1 CHO (21)

(22)

(23)

4-dimethylamino-4 -stilbenyl groups were prepared.60 These cations show significant electronic absorption in the near-infrared region and appear to possess substantial first hyperpolarizabilities. The 1,8-bis(diphenylmethylium)naphthalenediyl dication undergoes reduction with an especially high oxidation potential, a property that has been exploited in developing a diaryl ether synthesis via the oxidative arylation of phenols with 4-phenylthioanilines.61 The visible spectra of Crystal Violet in the presence of β-cyclodextrin can be broken down into three Gaussians.62 The Gaussian at longest wavelength is suggested to be due to a pyramidal structure where the carbocations is solvated through the OH groups of the cyclodextrin. Using several different homodesmotic reaction systems, aromatic stabilization energy calculations show substantial destabilization of the fluorenyl cation, supporting its categorization as an antiaromatic species.63 Highly stabilized carbocations were analysed theoretically on the basis of different intrinsic characteristics; calculated pKR+ values showed good qualitative agreement with experimental data.64 Diaryl carbinols Ar1 CH(OH)Ar2 , where Ar1 is a π -deficient aromatic heterocycle, were reduced to the diarylmethane by sodium borohydride–trifluoroacetic acid.65 A diaryl carbocation was proposed as the intermediate.

Carbocation Reactivity–Quantitative Studies Picosecond absorption spectroscopy was employed to study the dynamics of contact ion pairs produced upon the photolysis of substituted diphenylmethyl acetates in the solvents acetonitrile, dimethyl sulfoxide, and 2,2,2-trifluoroethanol.66 A review appeared of the equation developed by Mayr and co-workers: log k = s(N + E), where k is the rate constant at 20 ◦ C, s and N are nucleophile-dependent parameters, and E is an electrophilicity parameter.67 This equation, originally developed for benzhydrylium ions and π -nucleophiles, has now been employed for a large number of different types of electrophiles and nucleophiles. The E, N , and s parameters now available can be used to predict the rates of a large number of polar organic reactions. Rate constants for the reactions of benzhydrylium ions with halide ions were obtained

7 Carbocations

187

by flash photolysis in various solvents, including neat and aqueous acetonitrile and alcohols.68 Nucleophilicity parameters N were thus obtained for halide ions in different solvents. Reactions of carbocations with free CN− occur preferentially at carbon, and not nitrogen as predicted by the principle of hard and soft acids and bases.69 Isocyano compounds (N-attack) are only formed with highly reactive carbocations where the reaction with cyanide occurs without an activation barrier because the diffusion limit has been reached. A study with the nitrite nucleophile led to a similar observation.70 This led to a conclusion that the ambident reactivity of nitrite in terms of charge control versus orbital control needs revision. In particular, it is proposed that SN 1-type reactions of carbocations with nitrite only give kinetically controlled products when these reactions proceed without activation energy (i.e. are diffusion controlled). Activation controlled combinations are reversible and result in the thermodynamically more stable product. The kinetics of the reactions of benzhydrylium ions with alkoxides dissolved in the corresponding alcohols were determined.71 The order of nucleophilicities (OH− MeO− < EtO− < n-PrO− < i-PrO− ) shows that alkoxides differ in reactivity only moderately, but are considerably more nucleophilic than hydroxide. Nucleophilicity parameters were determined for eight tertiary phosphines and two phosphites,72 and for tris(pentafluorophenyl)silyl- and triphenylsilyl enol ethers and ketene acetals.73 The latter study demonstrated that the cation-stabilizing ability of the tris(pentafluorophenyl)silyloxy group is similar to that of methyl. Electrophilicity parameters were determined for a series of highly electron-deficient aromatic and heteroaromatic compounds; these neutral electrophiles proved to be of a similar reactivity to stabilized carbocations such as the tropylium ion.74 The local electrophilicity of a series of carbenium ions has been ranked within a theoretical absolute scale.75 The model is used to predict rate coefficients in terms of the experimental electrophilicity parameters determined by Mayr et al. for these cations. Kinetics of decay of the bis(4-methoxyphenyl)methyl cation were determined in a 1:1 mixture of 2,2,2trifluoroethanol (TFE) and various ionic liquids.76 The ionic liquids accelerate the decay compared with that in 1:1 TFE:acetonitrile. The absolute rate constant of propagation of ion pairs in the carbocationic polymerization of 2,4,6-trimethylstyrene was determined, along with the rate and equilibrium constants for ionization of the chloride initiator.77 In a similar study, the absolute rate constant of propagation of ion pairs in the cationic polymerization of p-methylstyrene was determined.78

Acylium Ions Acylium–SbCl6 − salts, obtained by reaction of the acid chloride with SbCl5 in dichloromethane, were characterized by a combination of IR and X-ray spectroscopy.79 The subsequent Friedel–Crafts acylation of these salts with aromatic compounds was investigated. The cation Et3 Si+ , generated in CD2 Cl2 at −70 ◦ C from Et3 SiH and − Ph3 C+ B(C6 F5 )4 , reacted with the ketene Ph2 C=C=O to give the acylium ion (24), which was characterized by NMR spectroscopy.80 Detailed kinetic and product studies of the solvolysis of p-methoxybenzoyl chloride in water–alcohol mixtures were

188

Organic Reaction Mechanisms 2005 Ph Ph

+

C C O SiEt3 (24)

+

+

EtO

O

Me EtO

O

OCH2Ph (26)

(25)

reported.81 The p-methoxybenzoyl cation is proposed as the key intermediate in this system. The acylium ion (CH3 )2 CHC+ =O was subjected to detailed theoretical examination, with the objective to explore the reason why experiments have shown that the C=O moiety behaves nonclassically.82 The calculations show that upon complexation of CO with (CH3 )2 CH+ , the s character of the C−O bond increases, resulting in a stronger, not a weaker, bond.

Carbocations Containing Oxygen and Sulfur A combination of crystal structure, NMR spectroscopy, and computation shows that the dioxocarbenium ion (25) prefers the conformation with the methyl substituent at C(4) pseudoequatorial, but (26) with an alkoxy substituent at C(4) places the substituent pseudoaxial.83 In a related paper, the factors controlling C-glycosylation of ribose derivatives were examined experimentally, with conclusions being made regarding the lowest energy conformers of the oxocarbenium ion that is intermediate in the reaction.84 In a further related paper, these conformational preferences were employed in a study that demonstrates that solvent-equilibrated ions and not tight ion pairs are involved in the stereoselective nucleophilic addition reactions of cyclic oxocarbenium ions.85 X-ray crystal structures have been obtained for salts of protonated carboxylic acids (i.e. [R–C(OH)2 ]+ SbF6 − or AsF6 − ).86 Based on bond-order analysis, the cations are suggested to consist of two equivalent resonance structures with the positive charge shared by the two oxygen atoms, and little, if any, positive charge on the central carbon. Density functional theory calculations on tetra-O-methyl-d-mannopyranosyl and -glucopyranosyl oxocarbocations reveal two families of conformations.87 Modelling nucleophilic attack by methanol on these cations provided a rationale for facial selectivity. An ab initio molecular dynamics study of the specific-acid catalysed formation of the glycosidic bond concluded that the reaction proceeds via a DN AN mechanism.88 The DN step consists of concerted protonation of the O1 hydroxyl group with breaking of the C1 –O1 bond and formation of an oxocarbenium ion. A highly stereoselective vinylogous Pummerer rearrangement [(27) → (29)] occurs when o-sulfinylbenzyl Tol S

1. LiNiPr2

R

Tol

Tol

O

2. Me3SiCl

S +

S

−

OSiMe3 H

R R

(27)

(28)

(29)

OH

189

7 Carbocations

carbanions are treated with trimethylsilyl chloride.89 Ion pair (28), that collapses before loss of stereochemistry, is implicated.

Carbocations Containing Silicon The cation (30) was prepared as a tetraarylborate salt and characterized by NMR and X-ray analysis.90 The cation is considered aromatic, the all-silicon analogue of the cyclopropenylium cation. The secondary cation (31) has been obtained as its Hf2 Cl9 − salt.91 The X-ray structure reveals strong hyperconjugative interaction with the two Sn atoms. The novel cation (32), the silicon analogue of the imidazolium ion, was prepared as a persistent species, and characterized by a combination of NMR parameters.92 Cation (33) was prepared as its − B(C6 F5 )4 salt by hydride abstraction from (Me3 Si)3 CSiMePhH with Ph3 C+ .93 X-ray crystallography and NMR spectroscopy suggest that the phenonium ion resonance form (33b) is a minor contributor, with the major contributor (33a) where a phenyl group bridges two silicons. Ringopening protonolysis of sila[1]ferrocenophenes produces species FcR2 SiX in which the degree of coordination of X to silicon varies from polar covalent to largely ionic, examples of the latter being seen with X = [3,5-(CF3 )2 C6 H3 ]4 B.94 The [C5 Me5 Si]+ cation (36) was prepared as its [B(C6 F5 )4 ]− salt by protonation of (34), resulting in cleavage of an Me5 C5 H ring.95 The protonating agent of choice was the protonated Me5 C5 H2 cation (35), supplied as its [B(C6 F5 )4 ]− salt. Oxidation potentials of triphenyl- and tributyl-Si-, -Ge-, and -Sn-centred radicals forming the corresponding cations have been measured in three solvents.96 The experimental trends have been substantiated through quantum chemical calculations, which included a contribution from solvation. Hydrosilanes R3 Si–H react with hydroxylic reagents R OH in the presence of Zn(II) and Cd(II) halides to give R3 Si–OR .97 A discussion of the mechanism of this reaction raised the possibility of the formation of silicon cations R3 Si+ . Disilanes R3 Si–SiR3 are fragmented to two silyl radicals R3 Si upon photoinduced electron transfer with tetrachlorophthalic anhydride TCPA.98 One possible mechanism involves fragmentation of a TCPA radical anion/disilane radical cation pair to TCPA radical anion–R3 Si+ –SiR3 . Reverse electron transfer from the radical anion to the silyl cation generates the second silyl radical. Density functional calculations were reported on the electronic structure and chemical behaviour of carbenium and silylium ions Men H3−n X+ cations (n = 0–3, X = C, Si).99,100 Two papers appeared examining the migration of the cationic center in SiC6 H7 + ions through computations and a radiochemical method.101,102 But

SiMeBut3

But

3Si

Si

Si +

Me3Si Si

H SiBut

3

(30)

H C +

SnMe3 (31)

SnMe3 H SiMe3

N + Si CH(SiMe3)2 N But (32)

190

Organic Reaction Mechanisms 2005 Me2 Si

Me2 Si

(Me3Si)2C +

+

(Me3Si)2C

Si Me2

Si Me2

(33a)

(33b) +

Si Si

(34)

+ [C5Me5H2]+

(35)

(36)

Halogenated Carbocations Dissociative photoionization studies of dihalomethanes provided heats of formation of the cations CH2 Cl+ , CH2 Br+ , and CH2 I+ .103 A study of bromine addition to unsymmetrical alkenes (e.g. styrene, methyl cinnamate) in the presence of cyclodextrins led to the conclusion that the cyclodextrin stabilizes the open carbocationic intermediate.104 Common ion rate depression studies show that the solvolysis reactions of α-methylbenzyl-gem-dichlorides in water proceed by a stepwise mechanism through α-chloro-α-methylbenzyl carbocation intermediates.105 The carbocation Br– + CH–COOH was proposed as an intermediate in the oxidation of bromomalonic acid with hypobromous acid in dilute sulfuric acid.106 A high-level theoretical paper appeared investigating the halogenated cations of mono-, di-, tri-, and tetra-methylethylenes.107 Density functional calculations were reported for a series of 1-aryl-2-haloethyl cations, with the objective of quantifying the interactions of chlorine and bromine with the neighbouring cationic centre.108 Electron-donating groups on the aromatic ring diminish bridging, whereas bridging is stronger with electronwithdrawing groups. A computational investigation of the cis-bromination of alkynes suggests that the reaction proceeds without cationic intermediates, in contrast to the standard textbook mechanism for such a bromination.109 The calculations in particular show that a bromonium–tribromide ion pair collapses to a covalent adduct without an energy barrier. Cationic intermediates (bromonium ions, carbenium ions, and nonclassical carbonium ions) of the electrophilic addition reaction of bromine to various bicyclic alkenes were subjected to quantum chemical studies.110–113

Carbocations Containing Other Heteroatoms Structural parameters of the cation (37) in vacuum and in acetonitrile have been calculated by high-level theoretical methods.114 The bis(phosphanyl)carbenium ion (38),

191

7 Carbocations SiMe3 +

PCl3 N

R

+

P

P

R

+

H

C N Cl3P

N (37)

PCl3

H H (38)

(CO)3Cr

Ph (39)

obtained as its CF3 SO3 − salt, was characterized by NMR spectroscopy and by a crystal structure determination.115 The reactions of cation (39) with carbon nucleophiles were studied, with the objective of determining the facial stereoselectivity with respect to the nucleophile.116 Silyl enol ethers and enamines showed poor and good stereoselectivity, respectively, results that were explained through a combination of steric and electronic factors. Ferrocenylaminophosphine ligands with potential application in asymmetric catalysis were prepared taking advantage of the property of the αferrocenyl carbonium ion that allows replacement of a leaving group with retention of configuration.117

Carbocations in Zeolites and Other Materials Durene (1,2,4,5-tetramethylbenzene) was observed to form a long-lived, mechanistically relevant arenium ion within the micropores of zeolite H-beta.118 A laser flash photolysis study of the zeolite-mediated conversion of diarylmethanes to diarylmethyl cations was reported.119 This oxidation is a multistep process involving initial formation of a radical cation, deprotonation to a diarylmethyl radical which is oxidized to the cation. All three reactive intermediates were observed. A detailed kinetic study of C=C shift, hydrogen exchange, and carbon scrambling of but-1-ene on zeolite ferrierite pointed to the involvement of an s-butyl cation.120 Two studies of the hydrogen exchange reactions of propanes isotopically labelled at various atoms concluded that that the exchange occurs via a pentacoordinated carbonium ion.121,122 A 13 C NMR study of the early stages of propane activation over Zn-modified HMFI catalyst confirmed a monofunctional carbonium mechanism for the unmodified catalyst, and pointed to a bifunctional carbonium–carbenium mechanism over the modified catalyst.123 A detailed kinetic study of the skeletal isomerization of n-butane and isobutane on sulfated zirconia was reported, with the conclusion that carbenium ion isomerization was the rate-limiting step, and not hydride transfer between carbenium ion and alkane.124 Isomerization reactions of various saturated hydrocarbons on H-mordenite, H-beta, and sulfated zirconia were proposed to proceed by way of carbocation intermediates.125 The isomerisation of α-pinene over beta-zeolites was shown to proceed via a carbenium ion, which rearranges before capture by nucleophiles to form hydrocarbons such as camphene, terpinenes, and terpinolenes.126 Zeolites with low concentrations of acid sites were found to be the most active and selective catalysts for the cracking of C5 alkenes to C2 –C4 alkenes, with the reaction

192


proposed to involve the formation of oligomeric carbenium ion intermediates.127 Propylene, introduced over MCM-22 zeolite catalyst, forms polymeric species through intermediate isopropyl cations.128 The conversion of 13 C-labeled n-butane on zeolite H-ZSM-5 has been demonstrated to proceed through two pathways, both initiated by intermolecular hydride transfer between an initially formed carbenium ion and n-butane.129 The reactions of n-octane following co-condensation with aluminium chloride were proposed to occur via two pathways, depending on the nature of the promoter.130 With t-butyl chloride, products consistent with the formation of the t-butyl cation are observed, but with CoCl2 , the mechanism involves hydride transfer and the disproportionation of a nonclassical carbonium ion. Carbonaceous deposits formed during the alkylation of isobutane with but-1-ene over La-Y zeolite were explained by a mechanism involving isododecyl or higher carbocations.131 Through a combination of solid-state NMR spectroscopy and theoretical calculations, the initial cations formed in the Beckmann rearrangement of acetophenone oxime over two zeolites were identified.132 The cracking of n-heptane over HBEA zeolite yields C3 and C4 alkenes as the main products, which suggests a successive isomerization–cracking process with the participation of a carbocation chain mechanism.133 Kinetic simulation of the cationic polymerization of isobutene provides a rate constant for the propagation that is in agreement with values estimated by diffusion clock and competition methods, but disagrees with previous values obtained kinetically.134 The β-scission of pentenium ions catalysed by AlH2 (OH)2 − and AlHCl3 − ions was investigated by density functional computations and explicit-contact modelling.135 Due to the different basicities of the two catalysts, different mechanisms with different intermediates were suggested for them. The same group reported a theoretical study comparing Lewis acid and Brønsted acid catalysis in the cleavage of n-hexane to propane and propene.136 A carbenium ion is suggested to be the key intermediate with Lewis acid catalysis, whereas Brønsted acid catalysis is proposed to proceed via carbonium ions. Density functional calculations were performed for the reaction of isobutene with H-ferrierite, with application of periodic boundary conditions corresponding to a large cell.137 The calculations show that a π complex is the minimum, but the t-butyl cation is of lower energy than covalent alkoxides. Density functional theory was employed to calculate the adsorption energies of various molecules to H3 PW12 O40 and H3 PMo12 O40 acids.138 One result of these computations is that these heteropolyacids are predicted to have higher activation energies than zeolites for carbenium ion formation. A computational study of the interaction of cyclohexene with HZSM-5 zeolite examined the presence of carbenium ion species as opposed to covalent complexes, with the conclusion that the latter were favoured.139 Molecular simulation and group contribution methods were employed to estimate enthalpies of formation of compounds involved in catalytic hydrocracking processes, including the free radicals and carbocations proposed as intermediates in such processes.140 A single-event microkinetic model was developed for coke formation in the catalytic cracking of hydrocarbons based on elementary steps involving a number of carbenium ion intermediates.141

193

7 Carbocations

Allylic Systems Recent applications of the Nazarov reaction, the cyclization of a 3-hydroxyphenylpenta-1,4-dienyl cation, were reviewed.142 Tandem processes and asymmetric cyclizations were a particular focus of attention. Irradiation of (40) in aqueous base results in regioselective and stereoselective formation of (42).143 The allylic cation (41) is proposed as the key intermediate. A computational investigation was performed into the cofacial intermolecular π –π orbital interaction between π -conjugated main chains (Cn Hn+2 ) and allylic cations C3 H5 + .144

N

+

H

H

N

hn

N

H2O

+

OH (40)

(41)

(42)

Vinyl Cations Twelve cations of structure (43) with various aryl substituents were prepared as tetraaryl borate salts.145 NMR analysis shows that there is substantial stabilization through π -resonance with the aromatic ring and its substituents and through σ delocalization via the β-silyl groups. Laser flash irradiation of a vinyl bromide precursor resulted in a transient identified as cation (44).146 This cation is proposed as a model of the transition state for an in-plane vinylic SN 2 reaction. Vinyl cations PhCH=C+ R and PhCR=C+ H (R = Me and CF3 ) were generated photochemically in methanol solvent from halide precursors.147 The experimentally derived order of stability is α-CF3 < β-CF3 < β-Me < α-Me, as verified by quantum chemical calculations. Cyclopropylethynes (45, R = H, Me) were proposed as probes to distinguish radical and ionic intermediates.148 The vinyl cation (46) opens the cyclopropyl ring toward the methoxy substituent to give the cation (47), whereas the corresponding vinyl radical opens toward the phenyl. The lifetime of the cation (46) was estimated as 1–100 ps. Cationic intermediates formed in the addition of halogens to alkynes were studied computationally, with the objective of comparing the stabilities of bridged halonium ions, β-halovinyl cations, and α-halovinyl cations obtained by rearrangement.149 A related computational study probed the gas-phase addition reaction of molecular bromine Ar Me2Si

SiMe2

MeO

+

C

C+ Ar

S

(43)

(44)

OMe

194


+

R

•

R Ph

Ph

OMe (45)

Ph

R

OMe (46)

(47)

+OMe

and alkynes.150 One conclusion from the study is that reactions starting from a 2:1 Br2 –alkyne complex can produce both trans- and cis-dibromides without the formation of ionic intermediates.

Aryl Cations The photosensitized cleavage of benzenediazonium salts and related compounds, whereby aryl cations are formed in the triplet state, has been reviewed.151 These highly reactive intermediates add to alkenes, alkynes, and arenes, giving arylation products in good yields. Four examples from this group were also reported. (i) Triplet aryl cations Ar+ obtained by irradiation of aryl halides and esters (ArX) with electrondonating substituents were shown to react with H–C≡C–R and Me3 Si–C≡C–R to give arylacetylenes, Ar–C≡C–R, in good to excellent yields.152 (ii) Photolysis of 4XC6 H4 N2 +. BF4 − salts in acetonitrile was shown to produce singlet aryl cations with X = H, t-Bu, and NMe2 , which react with the solvent to give acetanilides.153 With X = Br, CN, COMe, and NO2 , inter-system crossing competes with or overcomes C–N fragmentation and triplet aryl cations are generated. Sensitization with xanthone produces triplet cations across the entire series. As noted above, the triplet cations react with π nucleophiles such as benzene and allyltrimethylsilane. (iii) Allylphenol and allylanisole derivatives present in plants (e.g. safrole) were prepared via the reaction of allyltrimethylsilane with aryl cation intermediates obtained by irradiation of the corresponding chorophenols or chloroanisoles.154 (iv) Photolysis of 2,6-dimethyl4-chlorophenol in alcohol solvents was shown to proceed via the triplet hydroxyphenyl cation, which could be trapped by allylsilane nucleophiles.155 The mechanism of the solvolysis of the p-tolyldiazonium ion in water was studied by a combination of isotope effects, computation, and dynamics.156 The process is concluded to lie at the boundary between SN 2Ar and SN 1 mechanisms, with an accurate picture requiring consideration of dynamic effects. Equilibrium structures and transition states were computed for the rearrangements of C7 H7 + ions, o-, m-, and p-tolyl, benzyl, and tropylium.157 The o-tolyl cation rearranges to the m-tolyl cation and the benzyl cation through barriers of 40.0 and 25.1 kcal mol−1 , respectively.

Arenium Ions Acylium ion salts, characterized by crystal structures, react with electron-rich aromatics to give Friedel–Crafts products by way of benzenium ions; these Wheland

195

7 Carbocations NO2 N R2N

NR2

N +

O

O N

NR2 (48)

NO2

O (49)

−

O

NO2

N H

H

R2N

NO2 NR2

+

(50)

NR2

intermediates were observed with transient UV–visible spectroscopy.79 Supernucleophilic neutral carbon reagents (48) react with superelectrophilic neutral carbon reagent (49) to form zwitterionic adducts (50) in which one portion is the Wheland intermediate of electrophilic aromatic substitution and the other portion is the Meisenheimer intermediate of bimolecular nucleophilic aromatic substitution.158 IR photodissociation was employed to characterize gas-phase protonated aromatic compounds, in particular protonated p-fluoro- and p-chlorophenol.159 A crystal structure of H3 O+ ·[CHB11 C11 ]− deposited from benzene shows a solvate structure where the H3 O+ is π -complexed to three benzene molecules, whereas interactions between the cation and the anion are absent.160 Electrochemical oxidation of 1,4-dimethoxybenzene in methanol in the presence of various azoles gives a mixture of products including 1,1,4,4-tetramethoxycyclohexa-2,5-diene and 1,1,4-trimethoxy-4-(azol-1-yl)cyclohexa-2,5-diene.161 The proposed mechanism involves the formation of the 1,1,4-trimethoxybenzenium ion as the key intermediate. In order to model reactions proposed to occur in zeolite H-Beta, a quantum chemical study of the heptamethylbenzenium ion was performed, with a particular focus on intramolecular isomerization reactions and eliminations of small alkenes.162 The latter were found to occur by two pathways, one initiated by ring contraction and the other by ring expansion. The conversion of benzene to phenol by reaction with FeO+ was examined by computational methods.163 One mechanism considered to be favourable involves oxygen insertion to form an arenium intermediate. Density functional calculations were performed for the addition of CH3 + and SiH3 + to benzene.164 With the silyl cation, the initial adduct is the most stable isomer, but with the carbenium ion, migration of a proton occurs through computed barriers to the more stable ptoluenearenium ion. Reaction profiles for the nitration of benzene and toluene with NO2 + were examined by density functional methods.165 Computational study of the Beckmann rearrangement of acetophenone oxime suggests the involvement of two cationic intermediates, one of which is the π complex (51).166 The singlet state of m-benzoquinone (52) is calculated to 0.93 eV higher in energy than a triplet ground state.167 Spin crossing to the singlet, however, provides a low-energy pathway for the decarbonylation reaction that is observed when triplet m-benzoquinone is generated in the gas phase.

196


O−

O +

Me

C

+

N

(51)

(52)

Nitrenium Ions A review appeared summarizing and analysing published data on direct electrophilic amination of aromatic compounds by nitrenium ions.168 The nitrenium ion (53) was observed by flash photolysis following irradiation of the corresponding N -pyridinium ion.169 Kinetic trapping data indicate that this cation is much more reactive to simple nucleophiles, including water, than similar 4-substituted phenylnitrenium ions such as the 4-biphenylylnitrenium ion. Reactions of the diphenylnitrenium ion were studied by flash photolysis in combination with product analysis and computations.170 In the absence of trapping agents, the ion cyclizes to form carbazole in a concerted cyclization–proton transfer process. With electron-rich aromatics, the ion reacts through an initial one-electron transfer. Time-resolved resonance Raman spectroscopy was employed to observe directly the 2-fluorenylnitrenium ion reacting with guanosine in aqueous acetonitrile.171 The two react to form a second transient intermediate, assigned on the basis of a comparison of experimental and calculated Raman bands to the adduct of the nitrenium ion at the C(8) position of guanine. The 7-bromo2-fluorenylnitrenium ion was observed by flash photolysis with resonance Raman detection.172 The structure of this cation, in particular its structure in comparison with the parent 2-fluorenylnitrenium ion, was studied by density functional calculations. The azepinium ion (54), the first nitrogen analogue of the tropylium ion, was reported in 2004.173 A 2005 paper considered the reaction with aromatic nucleophiles. Unlike the tropylium ion, the reactivity of which is low, (54) readily reacts to give Friedel–Crafts adducts, a 2-aryl-2H -azepine being the major product.

+N

Me

+

N

But

R

+ N (53)

(54)

OMe O (55), R = H, Ac

3-Nitrobenzanthorne, a chemical found in diesel exhaust and urban air pollution, is metabolized to intermediates that form purine DNA adducts.174 The structure of these adducts implicates nitrenium ions (55) as the electrophilic intermediates that react

197

7 Carbocations O OMe

O N

+

O O

+

N

OMe

MeO (56)

(57)

with the DNA. Aristolochic acid I, a naturally occurring nephrotoxin and carcinogen, is activated by human cytochrome P450 to a reactive intermediate that forms a DNA adduct.175 The structure of this adduct is consistent with the cyclic nitrenium ion (56) as the DNA-reacting electrophile. The nitrenium ions derived from metabolism of anti-tumour 2-(4-aminophenyl)benzothiazoles have been investigated by density functional methods.176 The N -4-nitrobenzoate ester derived from 1-hydroxy-2,2,6,6tetramethylpiperidine undergoes solvolysis in various solvents to a five-membered cyclic iminium ion which yields 2,2-dimethylpyrrolidne on hydrolysis.177 A mechanism was proposed for this reaction involving SN 1 ionization with rearrangement through an incipient dialkylnitrenium ion. Nitrenium ions [e.g. (57)], obtained by oxidation of NH precursors with PhI(OOCCF3 )2 , add to the adjacent aromatic ring to give spirocyclic compounds of interest as natural products.178 A related synthetic approach involves a nitrenium ion obtained with PhI(OOCCF3 )2 reacting intramolecularly with a carbon–carbon triple bond to form 5-aroyl-2-pyrrolidones.179 Computational studies were performed for the phenyloxenium ion, the phenylnitrenium ion, and their 4-methyl and 4-phenyl derivatives.180 The calculations show that the oxenium ions are best described as 4-oxocyclohexa-2,5-dienyl carbocations [i.e. (58a) rather than (58b)]. The 4-phenyl group stabilizes the phenyloxenium ion to a greater extent than it stabilizes the phenylnitrenium ion. Using the azide-clock method, the lifetime of cation (58) in water was estimated as 12 ns.181 The cation was formed by C–O bond heterolysis of an acetate precursor. α-Tocopherol, and two chroman analogues, are oxidized with 2 mol of NO+ SbF6 − to form remarkably persistent cations (59), R = [CH2 CH2 CH2 CH(Me)]3 Me, Me, and COOH.182 These cations were characterized by IR, 1 H and 13 C NMR spectroscopy. Density functional calculations O+ O

O+

+

O

Ph

Ph

R

(58a)

(58b)

(59)

198


on diprotonated Methyl Red show a highly delocalized structure with carbocationic canonical structures reminiscent of those suggested for arylnitrenium ions.183

Aromatic Systems Cations (60) and related isomers were prepared as BF4 − salts.184 The cations were characterized by NMR and X-ray analyses, and various aspects of their chemistry were studied. Weakly fluorescing alkenes (61) are converted by acid into strongly fluorescing cations (62).185 This system is suggested as an acid-sensing fluorophore with utility as indicators of weakly acidic environments. Reactions of the 2,3-diferrocenyl1-methylthiocyclopropenylium ion with organometallic reagents were described.186 Principal products are ring-opened 1,3-dienes and 1,3,5-trienes. Density functional calculations were employed to assess the aromaticity/antiaromaticity of X-substituted cyclopentadienyl cations and 5-X-substituted indenyl cations.187 Computational studies have shown that conjugate bases of tris(substituted-amino)cyclopropenyl cations possess superbasic properties in the gas phase and in acetonitrile.188 Density functional calculations on anthocyanidins suggest that these cations should be regarded as naturally occurring, stable carbocations.189 Ph N

Me O

N

X +

N Me

Me N

O

N O

O

Me

(60), X = NPh, O

Ar

Ar

Ar

Ar H

H+

+ (61)

(62)

Dications Optically pure (R)-binaphthylic dienes (63) are electrochemically oxidized to 1,4dications (64) with the R,R-configuration.190 Since the dications can be electrochemically reduced back to (R)-(3), these systems can be used as electrochiroptical responses, by which the electrochemical input is transduced into spectral outputs. Dication (65) has been obtained as its bis-BF4 − salt and characterized by X-ray stucture analysis.191 The proximity of the methylium centres leads to strong electrostatic

199

7 Carbocations Ar Ar Ar

Ar

Ar

+

Ar Ar

+

H

Ar H

−2e− +2e−

[(R,R)-64]

[(R)-63]

Ar = 4-MeOC6H4, 9-xanthenylidene

Ar

Ar Ar

Ar

C

+

+

+C

Y

(65), Ar = 4-ClC6H4

H

(66)

+OH

H

+

+

H H

(67)

R

H N

+

Y

+

N+ H (68)

repulsions that are exacerbated by the electron-withdrawing chloro substituents on the aryl rings. Dications (66) were obtained by two-electron electrochemical oxidation of diarylmethylidenefluorenes.192 Electron delocalization and antiaromaticity in the fluorene system were probed by computational methods. In superacids HSO3 F and CF3 SO3 H, 3-arylindenones are doubly protonated to give persistent dications [e.g. (67)] that can be characterized by NMR spectroscopy.193 These dications undergo 2 + 2-photodimerization under daylight. Pyrazine alkenes react with benzene–CF3 SO3 H to give anti-Markovnikov products, i.e. products of alkylation at the terminal end of the alkene C=C.194 Trication (68) obtained by triple protonation is proposed as the alkylating electrophile. Resonance energies of the trimethylenemethane dication, CH2 =C(CH2 + )2 , and the butadienyl dication, + CH2 CH=CHCH2 + , were evaluated by two independent computation methods, with the conclusion that the resonance energy in the former is substantially greater.195 A computational study explored the dissociation of benzene dication, in particular the three major dissociation channels: C6 H6 2+ → 2C3 H3 + , C4 H3 + + C2 H3 + , and C5 H3 + + CH3 + .196 Methyl glycidate

200


reacts with electron-rich arenes in trifluoromethanesulfonic acid to give products Ar–CH2 CHOHCO2 Me; the superelectrophilic dication + CH2 CHOHC+ (OH)(OMe) is proposed as the intermediate.197

Polycyclic Systems Treatment of C70 in chloroform with an excess of AlCl3 gave rise to the solvent adduct (69a).198 This was converted to the alcohol (69b), which on dissolving in CF3 SO3 H gave the cation (C70 -CHCl2 )+ (70) as a long-lived species that could be characterized by NMR spectroscopy. The annulenium ions formed by two-electron oxidation [e.g. (72)] and protonation [e.g. (73) and (74)] of nonalternant isomers of pyrene were studied by density functional theory.199 Computational studies directed at the understanding of structure–reactivity relationships and substituent effects on carbocation stability in aza-polycyclic aromatic hydrocarbons were reported.200,201 Cyclopenta-fused polycyclic aromatic hydrocarbons, compounds identified in combustion exhausts, show positive mutagenic responses.202 With support from quantum chemical calculations, a mechanism is proposed involving epoxidation at the five-membered ring [for example, to form (75)], followed by ring opening to monohydroxy-carbocations [e.g. (76) and (77)].

R

R

(69) R = CHCl2 (a) X = Cl; (b) X = OH

n

H

+

X

H

(71), n = 0 (72), n = 2+

(70)

H

H

H +

H

H

(73)

H

H

(74)

H +

201

7 Carbocations O +

(75)

OH

(76)

OH

+

(77)

Carbonium (Bridged) Ions A high-level theoretical investigation of CH5 + including zero point energies has led to the conclusion that all five protons are equivalent in the ground state, precluding the assignment of a unique structure to the cation.203 The ethane dication and its silicon analogues were compared through high-level computations.204 For C2 H6 2+ , the most stable structure is the two-electron, three-centre-bonded carbonium–carbenium dication (78). With Si2 H6 2+ however, the doubly hydrogen bridged structure (79) proves to be the most stable. A detailed theoretical study examining correlation effects in C-n-butonium cations appeared.205 The potential energy surface relating to the C7 H11 + bicyclobutonium cation and its isomers was investigated computationally.206 An unsymmetrical bicyclobutonium ion is the global minimum, being slightly more stable than the boat conformer of the bicyclo[3.1.0]heptyl-1-carbinyl cation. Theoretical calculations show that geometrically constrained dienes can form a sandwich complex with a proton.207 The resulting cation has five-centre, four-electron bonding, with a central tetracoordinate hydrogen [see (80)]. Such cations may play a role in some biosynthetic terpenoid cyclizations. The existence of CH4 Li+ and its clusters with H2 were examined by computational methods.208 The molecular structures so determined were significantly different from the parent carbonium clusters. Computations show that replacing one or more of the CH groups in carbonium ions with BCO (boron carbonyl) gives cationic species with geometries and electronic structures similar to those of the carbonium counterparts.209 For example, the hypercoordinated CH5 + becomes [H4 BCO]+ , the hydrogen-bridged vinyl cation C2 H3 + becomes [(BCO)2 H]+ , and the carbon-bridged norbornyl cation becomes [(BCO)2 C5 H9 ]+ . Theoretical analysis of the transition structures for [1, n] hydrogen shifts in carbocations shows that these have three-centre indices that are similar to those of other three-centre carbocations.210 A high-level computational study of the protonation of cubane showed that an edge attack of H+ is favoured, leading to a C–C bond protonated minimum (81).211 Under experimental conditions, however, (81) can only survive very briefly since there are rearrangement pathways with very low barriers ultimately resulting in protonated 1,8-dihydropentalene (82). A computational study incorporating solvent effects was reported for the cationic cyclization of (83).212 A protonated cyclopropane (84) was found to be the key intermediate on the potential energy surface. Fragmentation of (S)-endo-5-norbornenyl-2-oxychlorocarbene was studied in nonpolar and polar solvents.213 In the latter, fragmentation occurs via carbocation–chloride ion pairs that provide access to the norbornenyl–nortricyclyl cation system.

202

Organic Reaction Mechanisms 2005 H H

+

H

+

H

C C+ H H

H

+ Si

H

(78)

H Si+ H H H

H

(79)

(80) +

+

H

+

H Lg (81)

(82)

(83)

H (84)

Carbocations in Biosynthesis Histidine and phenylalanine ammonia lyases catalyse the elimination of ammonia by triggering the abstraction of weakly acidic β-protons.214 A review of these reactions presents evidence that the catalytically active group in these enzymes is a highly electrophilic 5-methylene-3,5-dihydroimidazol-4-one (MIO). A mechanism is proposed whereby this group adds to the aromatic (heteroaromatic) ring of the amino acid forming a Wheland intermediate, the positive charge of which activates the β-proton for stereospecific abstraction, followed by elimination of ammonia, and eventual regeneration of the MIO. Recent advances in understanding the mechanism of the cyclizations of 2,3-oxidosqualene and squalene to give polycyclic triterpenes were discussed.215 The dienol–benzene rearrangement forming steroids with aromatic A rings was reviewed.216 This reaction occurs with a wide range of substrates containing two double bond equivalents and a carbocation source on rings A or B. Diene analogues of isopentenyl diphosphate and dimethylallyl diphosphate were found to be potent active site-directed irreversible inhibitors of isopentenyl diphosphate isomerase.217 A mechanism was proposed whereby an allylic carbocation formed by protonation of the diene in the enzyme active site is positioned to react with a cysteine SH group forming the enzyme-bound adduct. Carbocation intermediates formed during squalene cyclization were trapped at intermediate stages when squalene analogues with diols at the 6,7- and 10,11-positions were incubated with squalene cyclase.218 These trapping experiments established that six-membered monocyclic, 6/6-fused bicyclic, and 6/6/5-fused tricyclic cations, all of which are tertiary, are involved in the cyclization. Labelling studies established a unique biosynthetic pathway to anisotomenes, a class of bicyclic irregular diterpenes.219 The proposed pathway involves multiple carbocation intermediates, with the initial step being a head-to-head coupling of two geranyl diphosphate units. Crystal structure determinations of trichodiene synthases were reported, including structures of ternary complexes incorporating inorganic pyrophosphate and an aza analogue of the bisabolyl carbocation intermediate.220,221 The conformation and orientation of the carbocation analogue lead to the conclusion that carbocation intermediates

203

7 Carbocations

form in terpene cyclization reactions under kinetic rather than thermodynamic control. A detailed study was reported into several aspects of the structure and reactivity of the dammarenyl cation, the last common intermediate in the cyclization of oxidosqualene to a diverse array of secondary triterpene metabolites in plants.222 Previous studies have suggested that sesquiterpene cyclases stabilize an allylic carbocation intermediate by the carbonyl oxygens of a triad of three consecutive threonines; site-directed mutagenesis studies have now revealed that the hydroxyl group of the threonine at the first position is essential for catalytic activity.223 The cyclization of geranylgeranyl diphosphate catalysed by taxadiene synthase, the first committed step of taxol biosynthesis, was studied with various deuterated224 and fluorosubstituted substrates.225 The proposed mechanism involves several carbocation intermediates, with exquisite stereocontrol exerted in their interconversions. A related study probing the cyclization using a set of geranylgeranyl diphosphate analogs with perturbed or absent C=C nucleophilicity concluded that the reaction proceeds via carbocationic intermediates.226 The reaction of verticillol with various acids was investigated, leading to a proposal of a mechanism involving a number of carbocation intermediates in the biosynthesis of the diterpenes taxadiene and phomactatriene.227 The observation that isomerization of all-trans retinal to 11-cis-retinal is inhibited by positively charged retinoid analogues provides support for a mechanism that involves a retinyl carbocation intermediate.228 A high-level computational study addressed the key step in Johnson’s 1975 total synthesis of longifolene, a step proposed at that time to involve a cationic cyclization.229 The theoretical study concluded that the three cationic intermediates (85), (86), and (87) proposed by Johnson were viable intermediates, with the norbornenyl cation (87) being nonclassical.

+ +

(85)

+

(86)

(87)

The lipase-catalysed hydrolysis of methyl 2-fluoro-2-arylpropionates was proposed to proceed via a mechanism whereby, after ester hydrolysis, the enzyme facilitates the elimination of fluoride ion with the formation of a carbocation stabilized by the adjacent CO2 − group.230 Determination of the crystal structure of human sialidase Neu2, an enzyme that catalyses the hydrolysis of sialic acids, reveals a tyrosine residue that is positioned in the active site to stabilize the carbocation proposed as an intermediate in the hydrolysis.231 11-Fluoro-all-trans-retinol is found to undergo isomerization to its 11-cis form in the presence of visual cycle enzymes, in contrast to a previous study where no isomerization was reported.232 The result of the prior study was taken as evidence for a carbonium ion pathway in the isomerization. Although the authors of the present study do not rule out such a mechanism, they suggest that the isomerization mechanism remains unknown. Data obtained in a study of the oxidation of

204


capsaicinoids by cytochrome P450 enzymes were consistent with the hypothesis that metabolism was governed, in part, by the stability and propensity to form an intermediate carbocation.233 The role of carbocations in the alkylation of guanine residues of DNA by nitrogen mustards (aziridinium ions) was investigated at the theoretical level.234

Carbocations in Synthesis Organic syntheses that proceed via the electrochemical generation of reactive intermediates, including carbocations, were reviewed.235–237 A review of the use of GaCl3 in organic synthesis presented several examples of high-yielding reactions involving carbocation intermediates stabilized by the presence of GaCl3 .238 Hydrogen iodide reduces a variety of substituted carbinols to the corresponding substituted methanes under mild conditions. Several lines of evidence reveal that the first step in the reduction process is conversion of the alcohol to a carbocation.239 β-Lactams [e.g. (88)] undergo ionization in polar medium to carbocations [e.g. (89)], which undergo ring expansion to N -acyliminium ions [e.g. (90)], which are trapped by nucleophiles with good diastereoselectivity to give 2-pyrrolidinones.240 A tertiary carbocation formed with a chirality centre at the α-carbon was converted to Ritter products with conversion of the chirality.241 Pt(II) complexes are excellent catalysts for the cyclization of 1,6- and 1,7-dienes into monoterpene-like compounds.242 In analogy with the biosynthetic route to such compounds, carbocation intermediates are proposed and supported by trapping experiments. Br

+

MeO

MeO

N+

N

N

But

O

But

O

MeO

(88)

But

O

(89)

(90)

A key step in the total synthesis of the indole terpene alkaloid α-cyclopiazonic acid was a carbocationic cascade (91) → (92), terminated by a 4-nitrosulfonamide and initiated by a benzylic carbocation formed from an O-silyl precursor.243 An alkylation–cyclization sequence for the preparation of 1-aryltetralins and 1-arylbenzopyrans NH-4-Ns H2C+

N-4-Ns

H

COOEt

H

N Ts

N Ts

(91)

(92)

COOEt

7 Carbocations

205

was developed; the cyclization step involved a benzylic carbocation.244 Under acidic conditions, the N(1)–C(4) bond of 4-(4 -hydroxyphenyl)azetidin-2-ones are cleaved with the formation of a stabilized benzylic carbocation, which can be reduced by silanes or employed in Friedel–Crafts reactions to produce tyrosine mimetics.245 1Arylhept-6-en-1-ynes form bicyclic structures containing a cyclobutene on treatment with PtCl2 . A benzylic cation is proposed as an intermediate.246 A variety of substituted polycyclic aromatics were prepared by the reaction of 2-(1-alkynyl)biphenyls with electrophilic reagents.247 Vinyl cations ArC+ =CHX, generated by protonation of an alkyne precursor in fluorosulfonic acid, reacted with various benzene derivatives in a synthetically useful manner.248 Methoxybenzene derivatives are efficiently hydroxylated by ethaneperoxoic acid generated in situ via the formal addition of OH+ to the aromatic ring.249 A mild and efficient process was developed for the Friedel–Crafts adamantylation of aromatic substrates in a room temperature ionic liquid.250 Substituted polycyclic aromatic compounds are prepared in good yields by the reaction of 2-(1-alkynyl)biphenyls with ICl, I2 , N -bromosuccinimide, and pO2 NC6 H4 SCl.251 The proposed mechanism involves an initial bridged cation which adds to the adjacent phenyl ring in a Friedel–Crafts reaction. The alkylation of benzene with carbocations derived from dodec-1-ene was investigated in ionic imidazoliumbased ionic liquids, with the objective of identifying the that liquid which exhibited the maximum catalytic performance.252 Arylvinylidenecyclopropanes undergo a Lewis acid-catalysed rearrangement to 6aH -benzo[c]fluorene derivatives via a double intramolecular Friedel–Crafts reaction.253 A stereochemical study of the synthesis of unsaturated 1,4-aminoalcohols via the reaction of unsaturated 1,4-alkoxyalcohols with chorosulfonyl isocyanate revealed a competition between an SN i retentive mechanism and an SN 1 racemization mechanism, with the latter having a greater proportion with systems where the carbocation intermediate is more stable.254 An ‘interrupted’ Nazarov reaction was observed, in which a nonconjugated alkene held near the dienone nucleus undergoes intramolecular trapping of the Nazarov cyclopentenyl cation intermediate.255 Cholesterol couples to 6-chloropurine under the conditions of the Mitsunobu reaction; the stereochemistry and structural diversity of the products indicate that a homoallylic carbocation derived from cholesterol is the key intermediate.256 1-Siloxy-1,5-diynes undergo a Brønsted acid-promoted 5-endo-dig cyclization with a ketenium ion and a vinyl cation proposed as intermediates.257 Electrochemical oxidation of [PhCH(OMe)]2 in CH2 Cl2 in the presence of allyltrimethylsilane results in a near quantitative yield of PhCH(OMe)CH2 CH=CH2 .258 A mechanism is proposed whereby one-electron oxidation results in a cation radical that dissociates the central C–C bond producing PhCH+ (OMe) cation and the corresponding radical. A further one-electron oxidation of the radical produces a second cation. A regio- and stereo-selective synthesis of cyclic ethers from 1,2,n-triols was reported.259 This involved the in situ generation of a 1,3-dioxolan-2-ylium ion from the 1,2-diol portion of the starting material, followed by reaction of this cation with the remote OH group opening the dioxolan-2-ylium ion to give the cyclic ether. Chiral oxocarbenium ions were employed to carry out highly diastereoselective and enantioselective acetate aldol addition reactions.260 Alkoxycarbenium ions, H2 C+ –O(CH2 )n OR, were obtained

206


electrochemically via the ‘cation pool’ method followed by reaction with nucleophiles such as allylsilanes.261 The cations have no substituent on the cationic carbon, but are stabilized by interaction with a remote ether group. Trimethylsilyl-protected peroxycarbenium ions obtained from silyl peroxy ketals reacted with alkenes to form cyclic peroxides.262

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Organic Reaction Mechanisms 2005 Stiborova, M., Sopko, B., Hodek, P., Frie, E., Schmeiser, H. H., and Hudecek, J., Cancer Lett., 229, 193 (2005). Hilal, R., Khalek, A. A. A., and Elroby, S. A. K., THEOCHEM , 731, 115 (2005). Henry-Riyad, H., Kobayashi, S., and Tidwell, T. T., ARKIVOC , 2005, (vi), 266; Chem. Abs., 144, 6634 (2006). Wardrop, D. J. and Burge, M. S., J. Org. Chem., 70, 10271 (2005). Serna, S., Tellitu, I., Dominguez, E., Moreno, I., and San Martin, R., Org. Lett., 7, 3073 (2005). Glover, S. A. and Novak, M., Can. J. Chem., 83, 1372 (2005). Novak, M. and Glover, S. A., J. Am. Chem. Soc., 127, 8090 (2005). Lee, S. B., Lin, C. Y., Gill, P. M. W., and Webster, R. D., J. Org. Chem., 70, 10466. Park, S.-K., Lee, C., Min, K.-Y., and Lee, N.-S., Bull. Korean Chem. Soc., 26, 1170 (2005). Naya, S., Nishimura, J., and Nitta, M., J. Org. Chem., 70, 9780 (2005). Wang, Z., Xing, Y., Shao, H., Lu, P., and Weber, W. P., Org. Lett., 7, 87 (2005). Berestneva, T. K., Klimovav, E. I., Stivalet, J. M. M., Hernandez-Ortega, S., and Garcia, M. M., Eur. J. Org. Chem., 2005, 4406. Pincock, J. A. and Speed, A. W. H., Can. J. Chem., 83, 1287 (2005). Gattin, Z., Kovacevic, B., and Maksic, Z. B., Eur. J. Org. Chem., 2005, 3206. Woodford, J. N., Chem. Phys. Lett., 410, 182 (2005). Ohta, E., Higuchi, H., Kawai, H., Fujiwara, K., and Suzuki, T., Org. Biomol. Chem., 3, 3024 (2005). Wang, H. and Gabbai, F. P., Org. Lett., 7, 283 (2005). Mills, N. S., Tirla, C., Benish, M. A., Rakowitz, A. J., Bebell, L. M., Hurd, C. M. M., and Bria, A. L. M., J. Org. Chem., 70, 10709 (2005). Walspurger, S., Vasilyev, A. V., Sommer, J., and Pale, P., Tetrahedron, 61, 3559 (2005). Zhang, Y., Briski, J., Zhang, Y., Rendy, R., and Klumpp, D. A., Org. Lett., 7, 2505 (2005). Dworkin, A., Naumann, R., Seigfred, C., and Karty, J. M., J. Org. Chem., 70, 7605 (2005). Anand, S. and Schlegel, H. B., J. Phys. Chem. A, 109, 11551 (2005). Linares-Palomino, P. J., Prakash, G. K. S., and Olah, G. A., Helv. Chim. Acta, 88, 1221 (2005). Kitagawa, T., Lee, Y., Masaoka, N., and Komatsu, K., Angew. Chem. Int. Ed., 44, 1398 (2005). Okazaki, T. and Laali, K. K., Org. Biomol. Chem., 3, 286 (2005). Borosky, G. L. and Laali, K. K., Chem. Res. Toxicol., 18, 1876 (2005). Borosky, G. L. and Laali, K. K., Org. Biomol. Chem., 3, 1180 (2005). Otero-Lobato, M. J., Kaats-Richters, V. E. M., Loper, C., Vliestra, E. J., Havenith, R. W. A., Jenneskens, L. W., and Seinen, W., Mutat. Res., 581, 115 (2005). Thompson, K. C., Crittenden, D. L., and Jordan, M. J. T., J. Am. Chem. Soc., 127, 4954 (2005). Rasul, G., Prakash, G. K. S., and Olah, G. A., J. Phys. Chem. A, 109, 798 (2005). Lobayan, R. M., Sosa, G. L., Jubert, A. H., and Peruchena, N. M., J. Phys. Chem. A, 109, 181 (2005). Fuchs, J.-F. and Mareda, J., THEOCHEM , 718, 93 (2005). Gutta, P. and Tantillo, D. J., Angew. Chem. Int. Ed., 44, 2719 (2005). Szymczak, J. J., Roszak, S., Skowronski, P., and Leszczynski, J., Mol. Phys., 103, 2215 (2005). Wang, Z.-X., Chen, Z., Jiao, H., and Schleyer, P. v. R., J. Theor. Comput. Chem., 2005, 669; Chem. Abs., 144, 232561 (2006). Ponec, R., Bultinck, P., Van Damme, S., Carbo-Dorca, R., and Tantillo, D. J., Theor. Chem. Acc., 113, 205 (2005). Fokin, A. A., Tkachenko, B. A., Gunchenko, P. A., and Schreiner, P. R., Angew. Chem. Int. Ed., 44, 146 (2005). Bollot, G., Fouillet, C. C. J., and Mareda, J., Chimia, 59, 97 (2005). Moss, R. A., Fu, X., Sauers, R. R., and Wipf, P., J. Org. Chem., 70, 8454 (2005). Poppe, L. and Retey, J., Angew. Chem. Int. Ed., 44, 3668 (2005). Wendt, K. U., Angew. Chem. Int. Ed., 44, 3966 (2005). Hanson, J. R., J. Chem. Res., 2005, 141. Wu, Z., Wouters, J., and Poulter, C. D., J. Am. Chem. Soc., 127, 17433 (2005). Abe, T. and Hoshino, T., Org. Biomol. Chem., 3, 3127 (2005). van Klink, J. W., Becker, H., and Perry, N. B., Org. Biomol. Chem., 3, 542 (2005). Vedula, L. S., Rynkiewicz, M. J., Pyun, H.-J., Coates, R. M., Cane, D. E., and Christianson, D. W., Biochemistry, 44, 6153 (2005). Vedula, L. S., Cane, D. E., and Christianson, D. W., Biochemistry, 44, 12719 (2005). Xiong, Q., Rocco, F., Wilson, W. K., Xu, R., Ceruti, M., and Matsuda, S. P. T., J. Org. Chem., 70, 5362 (2005). Chang, Y.-J., Jin, J., Nam, H.-Y., and Kim, S.-U., Biotechnol. Lett., 27, 285 (2005).

7 Carbocations 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262

211

Jin, Q., Williams, D. C., Hezari, M., Croteau, R., and Coates, R. M., J. Org. Chem., 70, 4667 (2005). Jin, Q., Williams, D. C., Croteau, R., and Coates, R. M., J. Am. Chem. Soc., 127, 7834 (2005). Chow, S. Y., Williams, H. J., Huang, Q., Nanda, S., and Scott, A. I., J. Org. Chem., 70, 9997 (2005). Tokiwano, T., Endo, T., Tsukagoshi, T., Goto, H., Fukishi, E., and Oikwawa, H., Org. Biomol. Chem., 3 2713 (2005). Golczak, M., Kuksa, V., Maeda, T., Moise, A. R., and Palczewski, K., Proc. Natl. Acad. Sci. USA, 102, 8162 (2005). Ho, G. A., Nouri, D. H., and Tantillo, D. J., J. Org. Chem., 70, 5139 (2005). Bellezza, F., Cipiciani, A., Ricci, G., and Ruzziconi, R., Tetrahedron, 61, 8005 (2005). Chavas, L. M. G., Tringali, C., Fusi, P., Venerando, B., Tettamanti, G., Kato, R., Monti, E., and Wakatsuki, S., J. Biol. Chem., 280, 469 (2005). Fishkin, N., Yefidoff, R., Gollipalli, R., and Rando, R. R., Bioorg. Med. Chem., 13, 5189 (2005). Reilly, C. A. and Yost, G. S., Drug Metab. Dispos., 33, 530 (2005). Bhattacharyya, P. K. and Medhi, C., Indian J. Chem., Sect. B , 44, 1319 (2005). Moinet, C., Hurvois, J.-P., and Jutand, A., Adv. Org. Synth., 1, 403 (2005). Yoshida, J., Chem. Commun. (Cambridge), 2005, 4509. Suga, S., Okajima, M., Fujiwara, K., and Yoshida, J., QSAR Comb. Sci., 24, 728 (2005). Amemiya, R. and Yamaguchi, M., Eur. J. Org. Chem., 2005, 5145. Gordon, P. E., Fry, A. J., and Hicks, L. D., ARKIVOC , 2005, vi, 393; Chem. Abs., 144, 6536 (2006). Van Brabandt, W. and De Kimpe, N., J. Org. Chem., 70, 3369 (2005). Shklyaev, Y. V., Glushkov, V. A., El’tzov, M. A., Gatilov, Y. V., Bagryanskaya, I. Y., and Tolstikov, A. G., Mendeleev Commun., 2005, 125; Chem. Abs., 144, 51431 (2006). Kerber, W. D. and Gagne, M. R., Org. Lett., 7, 3379 (2005). Haskins, C. M. and Knight, D. W., Chem. Commun. (Cambridge), 2005, 3162. Volonterio, A. and Zanda, M., Tetrahedron Lett., 46, 8723 (2005). Mandal, P. K., Cabell, L. A., and McMurray, J. S., Tetrahedron Lett., 46, 3715 (2005). Furstner, A., Davies, P. W., and Gress, T., J. Am. Chem. Soc., 127, 8244 (2005). Yao, T., Campo, M. A., and Larock, R. C., J. Org. Chem., 70, 3511 (2005). Savechenkov, P. Y., Rudenko, A. P., Vasil’ev, A. V., and Fukin, G. K., Russ. J. Org. Chem., 41, 1316 (2005). Bjorsvik, H.-R., Occhipinti, G., Gambarotti, C., Cerasino, L., and Jensen, V. R., J. Org. Chem., 70, 7290 (2005). Laali, K. K., Sarca, V. D., Okazaki, T., Brock, A., and Der, P., Org. Biomol. Chem., 3, 1034 (2005). Yao, T. Y., Campo, M. A., and Larock, R. C., J. Org. Chem., 70, 3511 (2005). Xin, H., Wu, Q., Han, M., Wang, D., and Jin, Y., Appl. Catal. A, 292, 354 (2005). Xu, G.-C., Liu, L.-P., Lu, J.-M., and Shi, M., J. Am. Chem. Soc., 127, 14552 (2005). Jung, Y. H. and Kim, J. D., Arch. Pharmacol. Res., 28, 382 (2005); Chem. Abs., 144, 212432 (2006). Giese, S., Mazzola, R. D., Amann, C. M., Arif, A. M., and West, F. G., Angew. Chem. Int. Ed., 44, 6546 (2005). Cadenas, R. A., Gelpi, M. E., and Mosettig, J., J. Heterocycl. Chem., 42, 1 (2005). Sun, J. and Kozmin, S. A., J. Am. Chem. Soc., 127, 13512 (2005). Okajima, M., Suga, S., Itami, K., and Yoshida, J., J. Am. Chem. Soc., 127, 6930 (2005). Zheng, T., Narayan, R. S., Schomaker, J. M., and Borhan, B., J. Am. Chem. Soc., 127, 6946 (2005). Kanwar, S. and Trehan, S., Tetrahedron Lett., 46, 1329 (2005). Suga, S., Suzuki, S., and Yoshida, J., Org. Lett., 7, 4717 (2005). Ramirez, A. and Woerpel, K. A., Org. Lett., 7, 4617 (2005).

CHAPTER 8

Nucleophilic Aliphatic Substitution

K. C. Westaway Department of Chemistry and Biochemistry, Laurentian University SN Reactions Forming C–C bonds . . . . . . . . . . . . . Allylic and Vinylic Substitutions . . . . . . . . . . . . . . Polycyclic Systems . . . . . . . . . . . . . . . . . . . . . . Epoxide Reactions . . . . . . . . . . . . . . . . . . . . . . Aziridines and Other Small Ring Substitutions . . . . . . Nucleophilic Substitution on Elements Other than Carbon Intramolecular Substitutions . . . . . . . . . . . . . . . . Studies Using Kinetic Isotope Effects . . . . . . . . . . . . Gas-phase Substitution Reactions . . . . . . . . . . . . . . Radical Processes . . . . . . . . . . . . . . . . . . . . . . . Medium Effects/Solvent Effects . . . . . . . . . . . . . . . Structural Effects . . . . . . . . . . . . . . . . . . . . . . . Theoretical Studies . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Kinetic Studies . . . . . . . . . . . . . . . . SN Reactions Producing Polymers . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

213 213 218 218 223 224 225 225 227 227 227 230 233 237 243 244 244

SN Reactions Forming C–C bonds The photodecomposition of aryl diazonium ions (Scheme 1) or aryl halides (Scheme 2) or sulfonate esters with electron-donating substituents gives aryl cations that can react in polar media with alkenes, forming C–C bonds in SN 1 reactions.1 An extensive review of the SN reactions forming C–C bonds has been published.2

Allylic and Vinylic Substitutions Several papers on allylic and vinylic substitution have been published. The effect of seven different phosphoramidite ligands (1) on the [IrCODCl]2 catalyst used in the SN reaction between allylic esters and either benzylamine or sodium dimethylmalonate was studied.3 The best ligand, which gave a 99% yield of the SN 2 product that was 99% ee in both reactions, had an o-methyl group on each aromatic ring.


213

ee

214


N2BF4

hn

SiMe3

+

+

+SiMe

3

xanthone

triplet

Scheme 1

Me2N

Cl

hn

Me2N

+

Me2N singlet

+ H+

Scheme 2

O O P N

Z

Z Me

Me (1)

In another study,4 the substituents on the phosphoramidite ligand on the [IrCODCl]2 catalyst were altered from aryl groups to 1-naphthyl groups. This led to higher yields (≥94%), and greater regio- and enantio-selectivities in the SN 2 reaction between several substituted allylic carbonates and amines or phenoxides. The SN 2 /SN 2 product ratios were ≥91:9 with the new catalyst. The iridium- and palladium-catalysed reactions of allyl carbonates with hydroxylamine derivatives with electron-withdrawing substituents on the nitrogen have been investigated.5 Regiospecific substitution by oxygen at Cα was observed with the iridium catalyst [Ir(CODCl]2 , whereas regiospecific substitution by oxygen was found at Cγ when a Pd(PPh)3 )4 catalyst was used. Oxygen was the nucleophile in these reactions because the electron-withdrawing substituent on the nitrogen of the hydroxylamine reduced the nucleophilicity of the nitrogen. Experimental KIEs and theory were used to investigate the mechanism of the palladium-catalysed alkylation of 1,1-dimethylallylacetate (2) by dimethyl malonate.6 A significant 12 C/13 C KIE of 1.037 at C(1) and small KIEs (1.00) at C(2) and C(3)

215

8 Nucleophilic Aliphatic Substitution

O

‡

O

O Me

+

CH2(CO2Me)2

Me Me

O

Pd2(dba)3 Ph3P, THF BSA, 25 °C

2.11

2.24

Pd

(2)

2.05

Me

Me Me

3.07

(PPh3)2 CH(CO2Me)2 Me Me

CH(CO2Me)2 +

(3) Me

Me

(4)

(5)

were found using Singleton’s NMR method.7 These KIEs suggested there was C–O bond rupture at C(1) and π -complexation at C(1), C(2) and C(3) in transition state (3) of the rate-determining step of the reaction. The 76:24 ratio of products (4) and (5) arises as a consequence of preferential attack at the more highly substituted C(1) in a subsequent step. Several transition structures were calculated at the B3LYP/BS2 level of theory. Onsager’s model for the reaction in THF and explicit solvent molecules to stabilize the charges were used in some calculations. The calculated KIEs were in good agreement with the experimental values for C(1)–C(3) but larger (by 99% ee. Catalysis by trifluoroacetate ions and trifluoroacetic anhydride30 converts 1-acyl- or -alkyl-glycidols into the 1-acyl- or alkyl-sn-glycerols. The reaction is an SN 2 process with nucleophilic attack of the trifluoroacetate ion on the primary carbon of the epoxide ring and trifluoroacetic anhydride reacting with the incipient alkoxide ion on C(2) simultaneously (Scheme 6). Transesterification of the bis(trifluoroacetyl) product with methanol gives the 1-acyl- or -alkyl-sn-glycerols stereospecifically with retention of configuration at C(2). Overall yields range from 92 to 95%. The ring opening of epoxides bearing an oxygen atom in an allylic or homoallylic relationship, by methanol in (i) 0.2 n H2 SO4 , (ii) with 0.2 n H2 SO4 and chelating LiClO4 and (iii) under chelating conditions with D3 + in the gas phase have been compared.31 In 0.2 n H2 SO4 , the attack by methanol was not regiospecific. Under chelating conditions in solution and in the gas phase, the chelating agent forms a bridge between the oxirane oxygen and the oxygen in the allylic or homoallylic position in

de

ee

ee

de

ee

220

Organic Reaction Mechanisms 2005 −O(O)CCF

RO

O

3

O

F3C

O O

F3C F3C

CF3

O

O OR

O

O R = C17H33CO; C16H33 Scheme 6

the side-chain; nucleophilic attack then occurs preferentially at the carbon furthest from the allylic or homoallylic oxygen. The reagent formed by reacting allylmagnesium halides with chlorotitanium triphenoxide32 was found to add an allyl group, via the anti pathway, to the most highly substituted carbon of di- and tri-substituted epoxides in a regiospecific reaction. Acyclic trisubstituted epoxides give a mixture of stereoisomers because the reaction occurs by an SN 1 mechanism. 2,3-Disubstituted epoxides with an ether linkage in the side-chain also gave non-steroeospecific products via an SN 1 mechanism. A stereospecific ring opening was achieved with trisubstituted epoxides with an ether linkage in the group on the quaternary carbon. These reactions proceeded by an SN 2 mechanism via the anti pathway. The amount of catalyst (scandium trisdodecyl sulfate) and ligand, (14), in the ring opening of cis-1,2-disubstituted oxiranes with primary and secondary aromatic amines in water were varied to maximize the yields.33 In all but two cases, the reaction, under ideal conditions, yielded the β-amino alcohols in ≥81% yield with enantioselectivity ≥86%.

N

N

But

But OH

HO (14)

Thiophenoxide ion was found to react with α,β-epoxycarboxylic acids regiospecifically at Cβ stereospecifically with inversion of configuration when an InCl3 catalyst was used in water at pH 4.0.34 Other Lewis acid catalysts gave poorer yields. At pH 9.0, the reaction was not regiospecific, with attack at the Cα predominating. The pH 4.0 reaction was thought to proceed via a borderline SN 2 transition state with a partial positive charge on Cβ whereas the pH 9.0 reaction occurred at Cα via a normal SN 2 transition state. Homochiral nucleophiles such as (15) give a pure stereoisomer in high yield when reacted with ethylene oxide in the presence of BF3 .Et2 O.35

ee

221


But

N

s-BuLi

N

O

(−)-sparteine

O

C O

But

O

Li/sparteine

OH

N

BF3•Et2O

C O

O But

(15)

C O

Reaction between a series of enantiopure 2-(1-dibenzylaminoethyl) epoxides and several carboxylic acids in the presence of BF3 .Et2 O and chlorotrimethylsilane gave the monoester whereas the diester was formed in the absence of chlorotrimethylsilane36 (Scheme 7). Both reactions were regio- and stereo-specific.

R

BF3

+

O

O

R

BF3

Bn2N

NBn2

R2

HO

O

O

O R

− F3B

R2

NBn2 O

R

O

O

H O

R2

R2

+

NBn2

R2

O

O

C

OH

ClSiMe3

OH

OSiMe3 R

R2

O NBn2

O

BF3

R

R2

O

H2O

NBn2

O

Scheme 7

In another study using BF3 .Et2 O, the regiospecific character of the SN 2 ring opening of 2-substituted-1-vinyl epoxides with R–C≡C–Li was enhanced by electron-donating substituents on the acetylide ion but not by the groups on C(2) of the epoxide.37 However, when the nucleophile was EtO–C≡C–AlEt2 and no BF3 .Et2 O was present, the reaction was also regiospecific but gave the SN 2 product with a mixture of the

222


E- and Z-isomers except when the SN 2 reaction encountered severe steric hindrance. The Al atom is thought to coordinate with the oxygen of the epoxide in the first step of these reactions. The alkyne anion then reacts intramolecularly giving the product. Different catalysts and reaction conditions that added a bromine or chlorine atom regiospecifically giving the SN 2 product with (i) retention or (ii) inversion of configuration or (iii) the SN 2 product from gem-difluorinated vinyloxiranes were discovered.38 The catalysts investigated were MgBr2 .Et2 O, Li2 CuCl4 , LiBr/AcOH, LiCl/AcOH, BCl3 , and Brønstead acids with a pKa < 4.0. Another study investigated the effect of using different cuprates and either methyl lithium or a Grignard reagent for these reactions.39 CuI and MeLi only gave the SN 2 product with an E configuration whereas the SN 2 product with an anti -stereochemistry was the major product when CuCl and RMgBr was used in a 1:3 ratio. A mechanism was suggested for the SN 2 and SN 2 reactions. An SN 2 reaction with retention of configuration occurred when AlR3 was the catalyst. Both regio- and stereo-selective SN 2 bromination at the CF2 carbon of gem-difluorovinyloxiranes was achieved by reacting the oxirane with LiBr/AcOH in acetonitrile.40 The major product (≥97%) was the E-isomer. Conditions giving either the inverted or retained stereoisomer from an SN 2 reaction were also reported. Aryl- and vinyl-substituted epoxides were shown to give reasonable yields of the syn addition product when they were treated with a phenol in the presence of aryl borates.41 The boron atom was thought to bond to the oxygen in the ring weakening the C–O bond and generating a partial positive charge on the substituted carbon of the ring. The reaction is completed when the phenoxide anion tethered to the boron reacts with the most substituted carbon of the substrate intramolecularly. In the presence of β-cyclodextrin, that binds to the R group of substituted epoxides, benzeneselenol reacts regio- and stereo-specifically to give an 80% yield of the βhydroxy selenide.42 Because the selenol only attacks the least substituted carbon with inversion of configuration, the reaction must occur by an SN 2 mechanism. Ring opening of cis-2,3-dimethyloxirane by triphenylphosphine has been modeled using the B3LYP functional with the 6–31G(d) basis set.43 The calculations suggest that the first step of the reaction is an SN 2 process with simultaneous C–C bond rotation giving an oxaphosphetane intermediate that decomposes to the trans-alkene; no betaine intermediate is formed. The presence of hydroxyl groups, both adjacent and remote from the epoxide group, have been found to control the regio- and stereo-specificity of the tetracyanoethylenecatalysed methanolysis of cyclohexane epoxides.44 Because the nucleophilic attack occurs at the carbon remote from the hydroxyl group with inversion of configuration, it was suggested the hydroxyl group participates in the reaction. Negative ρ values of −1.51 and −0.96 versus σ + were found for the syn/anti ratio in the reaction between 1-aryl-1,2-epoxycyclohexanes and MeOH in 0.2 n H2 SO4 / MeOH and in the gas phase catalysed by D3 + respectively.45 This led the authors to suggest that these reactions occur via a mechanism where the methanol attacks an ion–dipole pair rather than a full carbenium ion intermediate, except when the para-substituent is MeO or NO2 . The p-MeO reaction was thought to be an SN 1 process whereas the p-NO2 -substituted compound reacts via an SN 2 mechanism.

de


223

Aziridines and Other Small Ring Substitutions The ring opening of N -tosylaziridines has also been investigated extensively. Examples include the regiospecific ring opening of substituted N -tosylaziridines with trimethylsilyl cyanide, azide, bromide or iodide catalysed by N ,N ,N ,N -tetramethylethylenediamine.46 The nucleophile only attacks the least substituted carbon of the aziridine ring. In another study, the reaction of trimethylsilyl azide, chloride, or iodide with N -tosylaziridines in DMF opened the aziridine ring by attack at the least substituted carbon giving the trans product in high yield.47 However, when a phenyl group was on the aziridine ring, both possible products were obtained and attack at the benzyl carbon predominated. Thiocyanate ion was found to open N -tosylaziridines in the presence of catalytic amounts of LiClO4 in acetonitrile.48 When a benzyl substituent was present, the SN reaction occurred at the benzyl carbon of the aziridine ring but at the less-substituted carbon when the substituent on the aziridine ring was alkyl. Every substitution product had a trans stereochemistry. The reaction of 2-aryl-N -tosylaziridines was studied in water containing β-cyclodextrin, which formed an inclusion complex with the aziridine.49 The products were formed from attack at the benzyl carbon with inversion of configuration. The yields were high. When N -tosylaziridines were reacted with amines or thiols in acetonitrile in the presence of 5 mol% DABCO,50 the nucleophile attacked regiospecifically at the least substituted carbon of the aziridine ring. When a benzyl carbon was present in the aziridine ring, both possible products were obtained although the major product was from attack at the benzyl carbon. The catalytic role of DABCO (which may form an ammonium zwitterion which can deprotonate the nucleophile) is under investigation. Zinc(II) chloride, bromide and iodide were found to ring open N -tosyl-2-phenylaziridines forming the trans-β-haloamine in a regiospecific reaction at the benzylic carbon of the aziridine ring.51 In the absence of a benzylic carbon, the halide ion attack was mainly at the least substituted carbon of the ring. The effect of several different organometallic nucleophiles and LiOMe on the ring opening of vinyl and cyclic alk-2-enyl-N -tosylaziridines was investigated.52 High regio-(SN 2 ) and stereo-selectivity (the E-isomer) were found with most of the organometallic nucleophiles when the substrate was the vinylaziridine. The reactions of the cyclic alk-2-enylaziridines were not regiospecific, giving mixtures of the SN 2 and SN 2 products that varied with the catalyst used in the reaction. NO in air, probably reacting as NO2 , opens N -tosylaziridines at the most substituted carbon with a high regio- and stereo-selectivity with the bulky N -tosyl and nitrate groups trans.53 No reason for the observed regiospecificity was given. The ring opening of N -tosylaziridines with benzyltriethylammonium tetrathiomolybdate has been investigated.54 The reactions produce sulfides and disulfides and sulfur heterocycles, most with high regio- and stereo-specificity. The initial attack is primarily at the least substituted carbon. The reaction between 2-(1-aminoalkyl)aziridines (16) and thiols in the presence of BF3 .Et2 O has been investigated.55 The proposed mechanism suggests that the reaction

224

Organic Reaction Mechanisms 2005 HSR′

−

R

N

1

F 3B

R BF3

NBn2

N+

R1

R

R R1

N N+ Bn2

Bn2N

−

BF3

(16)

+

SR′ R1

HSR′ NHR

H2O

NBn2

R1

SR′

R N

−

R1

BF3

NBn2 R1

R N

+

−

BF3

NBn2 H

= Me, BnOCH2

occurs via two sequential SN reactions. The reaction begins when the aziridine ring nitrogen coordinates with BF3 , then, in the first SN reaction, the nitrogen in the sidechain opens the aziridine ring giving an aziridinium ion that reacts with the thiol in the subsequent SN 2 reaction. The transition states for the ring opening reaction of an aziridinium ion by chloride ion were calculated using the IRC and QRC methods.56 Whereas the IRC method found only one transition state for the reaction, the QRC method suggested that there were two transition states that occurred sequentially along the reaction coordinate without an intervening intermediate. Aryl borates such as catechol butylborate and triphenyl borate undergo a synstereoselective reaction with arylazirines.41 The syn-stereoselectivity was attributed to a transition state where the phenoxide tethered to the boron is transferred intramolecularly to the most substituted carbon. The reaction is completed when the phenoxide anion tethered to the boron reacts with the most substituted carbon of the substrate in an intramolecular reaction. KHF2 and Bu4 N[Ph3 SnF2 ] were used in the ionic liquid solvent, N -methylpyridinium tosylate, to open the aziridine ring of various nosylepimine derivatives of 1,6-anhydro-β-d-hexopyranoses.57 The product was the trans-diaxial amino fluoride.

Nucleophilic Substitution on Elements Other than Carbon The apparent SN reactions of chlorosulfines with sodium arylsulfinates to give sulfonylsulfines with inversion of configuration in high yield was suggested to proceed via an addition-elimination mechanism rather than an SN 2 mechanism.58 Hydroxide ion has been found to react with 3-methoxy-2,2,6-trimethyl-3-phenyl1,3-oxaphosphorinanium salts (17) by displacing the methoxy group on phosphorus with complete retention of configuration.59 The oxygen in the ring was deemed responsible for changing the stereochemistry of these phosphorinanium salt reactions, which usually occur with 100% inversion of configuration at phosphorus.

225

8 Nucleophilic Aliphatic Substitution Me O +

P

Me

Me OMe

Ph

BF4−

(17)

Product and relative rate studies suggest that the reaction between diisopropylamine and PSCl3 to give (i-Pr2 N)2 P(S)Cl proceeds via an intermediate formed by initial attack of the sterically hindered amine at sulfur rather than at the expected phosphorus.60

Intramolecular Substitutions New strategies for preparing either 1,2-cis- or 1,2-trans-glycosides stereoselectively have been reported.61 A chiral auxiliary containing a nucleophile is used to control the anomeric selectivity of the glycosylation. A sample reaction is shown in Scheme 8. +

O RO

X

O Ph

O

RO −X−

R′OH

O

A+

O

RO

O

Ph

Nu

Nu

Nu+ Ph

A+ = activating group

O RO

OR′

O Ph

Nu

Scheme 8

Studies Using Kinetic Isotope Effects Experimental KIEs and theory were used to investigate the mechanism of the palladium-catalysed alkylation of 1,1-dimethylallyl acetate (2) by dimethyl malonate.6 The transition structure in THF is believed to have long Pd–C bonds and significant SN 1 character, as described earlier. The secondary α-deuterium KIEs of 0.97 and 0.95 found for the acid-catalysed hydrolysis of trans-3-deutero- and 3,3-dideutero-2-(4-methoxyphenyl)oxiranes, respectively, were taken as evidence of the SN 1 mechanism for the formation of the

226


1,2-diols.62 At pH ≥ 8.7, larger KIEs of 1.17 and 1.43, respectively, were observed for the hydrolysis of these substrates. These larger KIEs are the result of a competing reaction where a hydride (deuteride) is transferred from C(3) to C(2) of the ionic intermediate in the transition state of the partially rate-determining step forming the aldehyde (Scheme 9). 1

O

H 2

3

H

L

H

+

+ H+

OH H

MeO

L

MeO

L = H,D δ+

H

δ+ +

OH

L H MeO

O

H L

H

MeO

Scheme 9

The effect of stereochemistry on the SN 2 reaction between methyl fluoride and free fluoride ion63 has been calculated for the normal inversion transition state and for a transition state where the fluoride attacks from the same side as the departing fluoride ion leaving group. The same comparison has been made for reaction with a LiF2 − ion pair via cyclic transition states. For the free-ion reaction, the inversion transition state is much lower in free energy than the retention transition state. The opposite is true for the ion-pair reaction. The secondary α-deuterium KIE was calculated for all four reactions. In the free-ion reaction, the KIE for the retention mechanism with the bent F–Cα –F bond was much larger (1.68 versus 0.98) than the KIE for the inversion transition state with a linear F–Cα –F. In the ion-pair reactions where both transition states have bent F–Cα –F bonds, the KIEs are large for both the retention and the inversion mechanism with the smaller KIE (1.49 versus 1.86) for the retention reaction. It was suggested that the KIE becomes larger as the F–Cα –F transition state bond angle decreases, i.e. when the transition state is more bent. An analysis of the contributions to these KIEs showed that they were due to a delicate balance between small entropy and enthalpy terms. The α-carbon k 12 /k 13 KIEs calculated for the SN 2 reactions between methyl chloride and 22 different nucleophiles at the B1LYP/aug-cc-pVDZ level of theory64 showed that all the KIEs were near the theoretical maximum and did not change significantly with transition state structure. A review showed that the α-carbon KIEs found experimentally for SN 2 reactions were also all near the theoretical maximum KIE. This suggests that the Melander–Westheimer curve,65,66 relating the magnitude of these


227

KIEs to transition state structure, has a very broad maximum. Unfortunately, this means that these KIEs will not be useful in determining transition state structure in SN 2 reactions. The temperature-independent factor (imaginary frequency ratio) and the tunnelling contribution to the KIE ranged from 57.5 to 69.0% of the total KIE.

Gas-phase Substitution Reactions MP2/6–311++G∗∗ //B3LYP/6–311+G∗∗ -level calculations reproduced the experimental rate constants and thermodynamic parameters obtained from negative ion pulsed ionization high-pressure mass spectrometry for the formation of the encounter complex of the gas-phase SN 2 reactions between halide ions and α-halo-α-cyanoalkanes extremely well.67 The results indicated that the binding energy between the halide ion nucleophile and the substrate in the encounter complex was due to a combination of a dipole–ion interaction and hydrogen bonding to C–H hydrogens in the substrate.

Radical Processes Three reviews discussing the SN reactions proceeding via electron transfer (ET) mechanisms have been published. The first of these68 provides a general discussion of ET mechanisms. The second69 deals specifically with the formation of organofluorides and the third70 discusses all the ways C–C and C–heteroatom products can be synthesized using an ET process. These ET reactions are found where reaction by the normal SN mechanisms fail due to steric hindrance and/or steric strain.

Medium Effects/Solvent Effects A normal, a special, and a negative special salt effect have been detected in the SN 1 reaction between benzhydryl chloride and LiClO4 in γ -butyrolactone.71 t-Butyl chloride reacts slowly in a pseudo-first-order reaction in 60 vol.% aqueous acetone.72 The second-order rate constant for the reaction between benzyl bromide and diphenylamine was measured in 13 solvents including alcohols, ketones, nitriles, and dipolar aprotic solvents.73 The rate constants correlated well (correlation coefficient = 0.934) with a three-parameter equation based on the polarity, the nucleophilicity, and the hydrogen bonding ability of the solvent. Polarity is the most important property of the solvent in solvating the transition state whereas hydrogen bonding ability and nucleophilicity play the largest roles in solvating the reactants. The large negative S = found for these reactions is consistent with the formation of ions in the transition state. Several reports on the effect of ionic liquids on SN reactions have been published. The rate constants of the SN 2 reactions of several anions with n-hexyl and n-octyl mesylates in two ionic liquids, [hexmim]ClO4 and [hexmim]PF6 containing 2000 ppm of water, were compared with the reactivity in chlorobenzene, DMSO, and MeOH.74 The results indicated that the relative nucleophilicities in the ionic liquids were similar to those in the other solvents. The rates in the ionic liquids were generally faster than those in MeOH but slower than those in DMSO or chlorobenzene.

228


The rate and stereochemistry of the SN 1 reaction between (R)-3-chloro-3,7-dimethyloctane and triethylamine in the ionic liquid [Bmim][N(CF3 SO2 )2 ]–methanol has been studied using 35 Cl NMR spectroscopy.75 The amount of inversion decreases from 90% in methanol to 25% when the mole fraction of the ionic liquid is 0.72. This decrease occurred because the ionic liquid reduced the ion pairing between the carbenium ion and the chloride ion, allowing the nucleophile to attack from either side of the carbenium ion. Some possible reasons for the rate increase and subsequent decrease as the amount of ionic liquid in the solvent increased were suggested. SN 2 reactions between methyl p-nitrobenzenesulfonate and halide ions and amines in several different ionic liquids have been investigated.76 The rates of reaction can be understood using the Hughes–Ingold rules77 if one considers the ion–ion interactions and ion–dipole interactions that occur with the ionic liquid solvent. Changing the ionic liquid solvent can reverse the relative reactivity of Cl− , Br− , and I− nucleophiles. A review on ionic liquid solvents, part of which discusses their use in carrying out SN reactions, has also been published.78 Ab initio calculations were used to study the SN 2 reactions between CH3 OCH2 I and CH3 O− and with one to four molecules of CH3 OH.79 The results showed that adding CH3 OH to the methoxide ion reaction reduced the rate of reaction by solvating the nucleophile. However, adding extra CH3 OH molecules to the reaction with methanol increased the reaction rate. In fact, the reaction when the nucleophile is a methanol tetramer occurs 1015 times faster than when the nucleophile is a single MeOH molecule. This is because the extra MeOH molecules in the transition state act as both an acid and base catalyst, i.e. they remove the hydrogen from the CH3 OH nucleophile and hydrogen bond to the I− leaving group. A very interesting paper80 reported studies of the reactions of several substituted benzhydryl carbenium ions, generated by laser flash photolysis, with halide ions in several solvents. This work provided the nucleophilicity ‘N’of chloride and bromide ions in several solvents. These data, along with the ionization rate constants and the solvolysis rate constants for the reactions of substituted benzyhdryl halides, was used to construct quantitative energy surfaces for the SN 1 reactions of substituted benzhydryl halides in several solvents. The SN 2 displacements of sulfonium or oxonium salt leaving groups by solvated fluoride ion in water have been investigated using B3LYP/6–31++G∗∗ calculations.81 The polar interaction between F− and the positive charge on the sulfur/oxygen in the reactant complex and transition structure and a large positive entropy of activation enable F− to be a reactive nucleophile in spite of its very high solvation energy in water. In spite of this attraction between the positive charge on the sulfur/oxygen and the negative charge on the F− , the normal SN 2 stereochemistry is preferred. The oxonium ion salt reaction is faster and has an earlier transition structure due to its better leaving group. The transition structures for the hydrolysis reactions of methyl, t-butyl, and adamantyl chlorides in the gas phase and in water were calculated using the B3LYP/6–31G(d) level of theory and the PCM solvation model.82 In the gas phase, backside attack is strongly favoured for the methyl chloride reaction and slightly favoured for the t-butyl chloride reaction. Frontside attack is favoured for the adamantyl chloride

229


reaction. The transition states found in water for the hydrolysis of methyl and t-butyl chloride indicate that these reactions occur by an SN 2 mechanism with inversion of configuration whereas adamantyl chloride reacts by frontside attack. A comparison of the gas-phase and solution reactions sheds light on the role of the solvent in these reactions. Picosecond absorption spectroscopy studies of the contact ion pairs formed in the photo-initiated SN 1 reaction of three substituted benzhydryl acetates (18) provided the rate constants for the k1 and k2 steps of the reaction (Scheme 10), in acetonitrile and DMSO.83 The activation parameters for the k1 and k2 steps were obtained from the temperature dependence of these steps and the transition state energies were calculated from the rate constants. This allowed the energy surfaces for three substituted substrates to be calculated in each solvent. The effect of solvent reorganization on the reactions of the unsubstituted and methyl-substituted benzhydryl contact ion pairs (CIP) was significant, causing a breakdown of transition state theory for these reactions. The results indicated that it will be very difficult to develop a simple theory of nucleophilicity in SN 1 reactions and that Marcus theory cannot be applied to SN 1 processes. The B3LYP/6–31+G(d,p) level of theory has been used to calculate the rotamer populations, the energy barriers, and the reaction path curvature for the SN 2 identity O O C Me O

S1

+ −O

Z hn

O

k1

O C CH3

Z

C Me

CIP

Z

k2

(18) Z = H, Me, OMe

O +

Z Scheme 10

−

O C Me

SSIP

230


reactions of three differently substituted C(6) chlorotetrahydropyrans in the gas phase and in DMF.84,85 The Onsager model and the IPCM models were used for the DMF calculations. The results showed that the local dipole–dipole interactions in the transition state86 cannot account for the much faster reactions of glucopyranose substrates relative to their galactopyranose isomers. Rather, the difference in the rate of reaction was due to differences in rotamer populations, the reaction barriers and reaction path curvature. The free energies of activation for the SN 2 reactions between acetate ion and ethyl chloride, bromide, and iodide in DMSO and in water have been calculated at the MP4/CEP-31+G(d)/MP2 level of theory.87 The solvent was accounted for using the PCM method. There was good agreement (≤2.6 kcal mol−1 ) between the calculated and experimental values for the reactions in DMSO and water and the relative reactivities of the halides were predicted correctly in both solvents. However, the rate increases found experimentally when the solvent was changed from water to DMSO were underestimated by up to 4.5 kcal mol−1 .

Structural Effects Methylene chloride has been found to react rapidly in an SN 2 reaction in a macrocyclic amine via transition state (19).88 The rapid reaction is due to the stabilization of the leaving chloride ion by hydrogen bonding to the NH nitrogens and the interaction between the slightly positive C–H hydrogens and the macrocyclic ether oxygens. A secondary (kH /kD )α = 0.75 confirmed the SN 2 mechanism for the reaction.89 ‡

But

O

O NH

HN

δ−

Cl

Me O

CH2Cl +

Nδ

O

(19)

The rates of solvolysis of o- and p-carbomethoxybenzyl bromides in several solvents have been compared.90 Analysis using both the simple and extended Grunwald–Winstein equation91 suggests that the solvolysis of the para-isomer proceeds via a simple SN 2 mechanism with a late transition state. The ortho-isomer, on the other hand, is thought to react with nucleophilic assistance from both the solvent and the carbomethoxy group.

231

8 Nucleophilic Aliphatic Substitution (CH2)n OMe

O

− SiMe2

O

(CH2)n

−

(CH2)n

OMe

O

Nu

O+

SiMe2

Nu

Me n = 2−5

Nu =

SiMe3

Scheme 11

Ether groups in the side-chain were found to stabilize primary alkoxycarbenium ions via neighbouring group participation (Scheme 11).92 This allowed these intermediates to react with carbon nucleophiles in SN reactions, giving alkylated products in moderate to good yields. The second step of these reactions was rate determining. Since the five- and six-membered ring intermediates were the most stable, they reacted slowest with the carbon nucleophile. The effect of using a leaving group that can coordinate with the nucleophile in an SN reaction was found to increase the rate of reaction by 4–200 times.93 The leaving groups used were arylsulfonates with either oligomeric ether or crown ether units in an ortho side-chain. When the nucleophile for the reaction was added as a metal salt, the cation coordinated with the ether groups on the ortho side-chain of the leaving group (Scheme 12). O

O S

O O

O

Ph

O O

O

O

O

+ M+Nu−

O S

O

Nu−

O

Ph O O

O

n

O

M+

O O n

O S

O− O

O

O

O M+ O O

+

Nu

Ph

n

Scheme 12

The rate enhancement was caused by reducing the entropic factor for the reaction and by having the coordinated cation provide electrophilic catalysis for removal of the leaving group. The increase in rate using this strategy increased with the number of ether linkages in the side-chain. Adding a crown ether to the side-chain had the largest effect. All the reactions using this type of leaving group gave high yields of product. The smaller secondary β-deuterium KIE of 1.07 and 1.0594 for [(20)], the smaller Hammett ρ + value95 of −1.29 [for (21)], the smaller H = , and more negative S =

232


D3C D3C

Cl

Y

Cl

R

(20)

R

(21)

values found when R = CH2 OCH3 rather than H in the SN 1 reactions of (20) and (21) in 80% aqueous ethanol and 97% aqueous TFE96 indicated that both the π -bond (from previous work) and the lone pair electrons on the oxygen of the CH2 OCH3 group provide neighbouring group participation in the transition states of the rate-determining step of these solvolyses. The effect of several chiral ligands on the SN reaction of 1-(2-naphthyl)ethyl acetate and its 6-methoxy-substituted analogue with diethylmalonate anion were investigated.97 The best results (90% ee) were obtained using a Pd–bis(dibenzylidene)acetone/(R,R)-i-Pr-DUPHOS (22) catalyst in DMSO at 70 ◦ C. However, the substitution: elimination ratio was only 15:85. Pri P P Pr

Pri Pri

i

(22)

When a deuterium-labelled bicyclic dienyl acetate reacted with a palladium catalyst using a PPh3 ligand, the major product formed by an SN 2 reaction. However, when the reaction was carried out using a DPPP or DPPB ligand, the major product was formed by an SN 2 reaction.98 Both reactions gave predominantly the cis-isomer (Scheme 13). SN2 Pd Cat.

SN2 Nu:−

AcO

Nu SN2′

SN2′

SN2′

OAc

SN2′

Pd+L−

Pd Cat.

Nu:−

SN2

SN2

Pd+L−

Scheme 13

Nu

ee


233

Theoretical Studies Most of the theoretical studies have been carried out on methyl halide SN 2 reactions99–109 . These include the following. Calculations on the methyl chloride identity SN 2 reaction using a 4D CCSD(T) potential energy surface and time-independent quantum scattering theory in hyperspherical coordinates99 showed that (1) exciting the C–Cl stretch and C–H umbrella bending and methyl C–H stretching vibrations simultaneously plays a much more important role for cross-sections than for reaction probabilities, and (2) transition state theory, dimensionality-reduced quantum and J shifting quantum methods give better agreement with the experimental rate constant than the reduced-dimensionality quantum theory. Reasons for this are given. The structures and energies of the solvated and unsolvated ground states, encounter complexes, transition states, and potential energy surfaces for the identity SN 2 reactions of methyl chloride in several solvents were calculated using several levels of theory in the gas phase and the isodensity-polarized continuum model in solution.100 The enthalpy and entropy of formation for the mono-solvated nucleophiles and encounter complexes were measured experimentally in several protic and aprotic solvents using negative ion pulsed-ionization high-pressure mass spectrometry. The experimental and theoretical results are in good agreement except when the solvent is SO2 . The results suggest that there is significant solvent reorganization on going from the encounter complex to the transition state. The results show that the rate of reaction slows significantly as the ε of the solvent increases up to ε = 20 but not significantly as ε increases further. Also, there is an excellent inverse correlation between the energy of formation of the encounter complex and the free energy of activation in the different solvents. The SN 2 reactions between Cl− and methyl bromide and Br− and methyl chloride were also investigated. Calculations of the methyl chloride identity reaction in a (6,6) carbon nanotube101 at the B3LYP/6–31+G∗ level for the reactants and at the B3LYP/3–21G and B3LYP/ 6–31+G∗ levels for the nanotube skeleton have shown that the reaction is much slower in the nanotube. The classical barrier height is 6.6 kcal mol−1 higher using the B3LYP/3–21G level of theory and 9.1 kcal mol−1 higher using the B3LYP/6–31+G∗ level of theory. PCM calculations using a calculated ε = 1.6 for the nanotube also indicated that the energy barrier was larger for the nanotube reaction. Calculations have been carried out on the SN 2 reactions between chloride ion and methyl chloride or chlorosilane at several DFT levels of theory up to the OLYP/TZ2P level.102 The OLYP/TZ2P method gave much better (excellent compared with the CCDD(T)/aug-cc-pVQZ level) values than the other density functionals for both the geometry and the energies of the reactant complex and transition state for the methyl chloride reaction and the stable transition complex that forms in the chlorosilane reaction. The potential energy surfaces and the transition states suggested by B3LYP/aug-ccpVDZ, MP2/aug-cc-pVTZ, and CCSD(T) calculations for the SN 2 reaction between chloride ion and methyl bromide in the presence of between one and four molecules of water have been compared.103 The water molecules were treated with the B3LYP-, MP2-, or DFT-based EFP1 potential. The DFT method gives much lower free energies than the MP2 or CCSD(T) methods. Adding one water molecule to the reaction

234


increased the energy barrier significantly as it stabilized the ionic initial state more than the dipolar transition state. In agreement with experiment, adding additional water molecules increased the free energy of activation even more, but the effect is smaller with each additional water molecule. The lowest energy transition state for the twowater system is when two water molecules form a bridge between the two halide ions in the transition state. For three and four water molecules, the water forms a cyclic structure and does not stabilize the transition state further. The results suggest that using the MP2/aug-cc-pVDZ for the solute and the EFP1 method for the solvent successfully models the effect of solvent on SN 2 reactions. The energies of the ion–molecule complexes and the transition structures for seven different identity SN 2 reactions of methyl substrates have been calculated using RHF, MP2, B3LYP, BLYP, BP86, CCSD, and CCSD(T) and three different basis sets, DZP+dif, TZ2P+dif, and TZ2Pf+dif.104 Core correlation and scalar relativistic effects were also used. Although the encounter complexes differed markedly, all the transition states were effectively linear even though the nucleophile was changed markedly. All methods performed well for the encounter complexes but there were significant differences in the transition state energies with the different methods. The changes in energy caused by each new method relative to each simpler method are given as a percentage. The results show that correlation levels up to CCSD(T) are critical if one wishes to calculate the energies of the transition states to within 1 kcal mol−1 and that even core correlation and relativistic effects contribute significantly. Finally, the results also indicated that conventional Marcus theory did not give reliable values for the activation energies for SN 2 reactions but that augmented Marcus theory was capable of predicting the activation energies for these reactions. Two studies of the SN 2 reaction between Cl− and CH3 Br have been published. In the first, a 4D potential energy surface has been constructed using CCSD(T) electronic energies.105 The 4D model illustrates the effect of adding the symmetric C–H stretching and umbrella bending vibrations of the methyl group to the calculations. Adding the two new degrees of freedom to the calculation did not push the system towards the RRKM behaviour. The second study investigated the reaction using time-independent quantum scattering calculations on a coupled-cluster energy surface.106 The model for these calculations considers the C–Cl, the C–Br, and the C–H stretching and umbrella bending vibrations. The results indicate there is a strong synergy between excitation of the C–H umbrella bending mode and the C–Br stretching vibration. Exciting the C–H stretching vibration also affects the reaction probability but its effect does not correlate with the effect of C–Br excitation. The results also suggest the products form with a high degree of excitation in the new Cα –Cl bond. For the SN reaction between methyl fluoride and a lithium isocyanate ion pair, calculations for eight possible reaction paths at the MP2(full)/6–31+G∗∗ //HF/6–31+G∗∗ level suggest that the reaction occurs with the oxygen atom of the nucleophile via a six-membered ring transition structure with inversion of configuration in the gas phase.107 PCM calculations at the HF/6–31+G∗∗ level in acetone and CCl4 indicate that (1) the transition structures are looser in solution, (2) the reaction is faster in the gas phase than in solution, (3) the reaction is faster in the less polar solvent, (4) the major product is formed from attack by the nitrogen, rather than the oxygen, of the

235


ion pair, and (5) the inversion mechanism via a six-membered transition structure is still the lowest energy pathway. In a related study, MP2(full)/6–31+G∗∗ //HF/6–31+G∗∗ calculations of the SN reaction between methyl fluoride and the free isothiocyanate ion or the lithium isothiocyanate ion pair108 indicate that the free-ion reaction occurs at the sulfur atom via a normal SN 2 mechanism with inversion of configuration. In the ion-pair reaction, sulfur is again the nucleophilic atom and the reaction occurs with an inversion of configuration but via a six-membered ring transition structure (23). As one might expect, the ion-pair reaction in the gas phase is faster than the free ion gas-phase reaction. N C δ−

2.038

136.8

Li

H

S 2.545

δ+

1.714

F δ−

C 2.053

HH (23)

Experimentally, the SN 2 reaction between alkyl iodides and pyrazolide anions (24) is regiospecific when X = N and gives a slight excess of this isomer when X = CH.109 Calculations of this SN 2 reaction using the mPW1K density functional method and the 6–31+G(d) basis set suggested that the SN 2 reaction is regiospecific when X = N because a sodium ion is complexed with two of the nitrogens and the developing chloride ion in the transition state (25) where the substrate was methyl chloride. The calculations also indicated the activation energy increased and the regiospecificity decreased from the gas phase to toluene to THF. ‡ Ph R X

N N−

(24)

N 2.52

N N

δ− 2.06

+ Na 2.31

Me

2.80

2.30

Cl

δ−

(25)

The transition states (27) calculated at the B3LYP/6–31++G∗∗ and B3LYP/6–31G∗ levels of theory for the alkylation of 1-methylimidazole (26) by alkyl bromides and chlorides, forming imidazolium halide ionic liquids (28),110 had a hydrogen bond between the incipient halide ion and the hydrogen on C(2) of the substrate. The conversion of 1,2-dihaloethanes (X = Br, Br and Cl or Cl) into the monosulfide and disulfide by reaction with the K+ − SCH2 CH3 ion pair in the absence and presence of hydrazine was investigated at the B3LYP/LANL2DZ level of theory.111 The calculations showed the reaction with hydrazine to be faster and to give more substitution when a bromide leaving group was available. The calculations suggest that

236


δ+

N N Me (26)

R

+

N

+

R X

N

H

Me

X

N

δ−

N

R X−

Me (27)

(28)

the reactions proceed via four-centre transition states involving the K+ − SCH2 CH3 ion pair. In the hydrazine-catalysed reaction, the hydrazine stabilizes the KX leaving group in both the encounter complex and the transition state. Calculations on ethyl halide reactions include that on the SN 2 reaction between ethyl chloride and cyanide ion in DMSO.112 The calculated free energy of activation at the CCSD(T)/6–31+G(2df,2p) level on the B3LYP/6–31G(d)-optimized structure was within 1.5 kcal mol−1 of the experimental value. The energy surface for the E2/SN 2 reaction between ethyl fluoride and fluoride ion was calculated using the hills method within a Car–Parrinello molecular dynamics simulation.113 The SN 2 reaction was found to occur faster than the E2 reaction. The results demonstrated that this theoretical method can determine the potential energy surfaces where competing concerted reactions occur via different transition states. QM/MM calculations were used to compare the SN 2 reaction between a carboxylate anion and dichloromethane in water and catalysed by the haloalkane dehalogenase enzyme DhlA.114 The detailed trajectories for these reactions indicated that catalysis by the enzyme was primarily due to three factors; (i) the transmission coefficient was 1.4 times larger in the enzyme reaction, (ii) the electrostatic reaction field hinders the transfer of the positively charged α-carbon in solution whereas it stabilizes the transfer in the transition state in the enzyme reaction, and (iii) differences in the solvation of the oxygens of the carboxylate group on going to the transition states, i.e. in solution, both the carboxylate oxygens become desolvated whereas in the enzyme only the reacting oxygen is desolvated and the other oxygen becomes more strongly hydrogen bonded to groups in the enzyme. In fact, the different solvation on the non-reacting oxygen in the two reactions, accounts for approximately two-thirds of the catalytic effect. The solution and enzyme transition states are not significantly different. Reactions discussed earlier include mention of theoretical studies of hydrolysis reactions of methyl, t-butyl, and adamantyl chlorides in the gas phase and in water,82 SN 2 identity reactions of tetrahydropyrans in the gas phase and in DMF,84,85 SN 2 reactions of solvated fluoride ion with sulfonium or oxonium salt leaving groups in water,81 SN 2 reactions of acetate ion with ethyl halides (X = Cl, Br, I) in DMSO and in water,87 SN 2 reactions between CH3 OCH2 I and CH3 O− and one to four molecules of CH3 OH,79 ring-opening reactions of an aziridinium ion by chloride ion,56 and ring opening of cis-2,3-dimethyloxirane by Ph3 P.43 The effect of different heteroatoms on the ring opening of substituted threemembered rings was investigated at the B3LYP/TZV+P level of theory.115 Two specific water molecules were included in the calculations and the COSMO method was used to include the bulk solvent. With the methyl thiolate nucleophile, thiirane was


237

the most reactive and aziridine was the least reactive. Whereas the ester substituent had only a small effect on the rates, adding a carboxylic acid group to the reacting carbon made the oxirane reaction slower than the aziridine reaction. The calculations correctly determined the effect of ester and carboxylic acid groups on the reactivity and regioselectivity of these reactions.

Miscellaneous Kinetic Studies Reactions of nitrite ion with a series of benzhydryl carbenium ions116 at rates below the diffusion controlled limit occur at the nitrogen atom giving nitromethanes, whereas the reactions of less stable benzhydrilium ions at the diffusion control rate limit occur preferentially (kO /kN = 3.4) at the oxygen atom giving nitrites. The O/N selectivity in the SN 2 reactions between nitrite ion and methyl substrates varies markedly with the solvent (the O:N ratio is three times larger when the solvent is THF instead of EtOH) and slightly with the leaving group (the O:N ratio is 2.4 times higher when a hard methylating agent is used); the results are not predicted by frontier orbital theory. Plotting the activation parameters versus the σ constants for different substituents on a benzene ring in a reaction has allowed the substituent effect on the bond changes (δ Hint + ) and on the change in solvation on going to the transition state (δ Sext = ) of an SN reaction to be determined.117 Several examples are discussed. The effects of aryl substituents at the silyl atom on the solvolysis of 2-(arylmethylsilyl)ethyl chlorides in 60% aqueous ethanol at 50 ◦ C118 correlated with non-resonant (polar) σ values in the Yukawa–Taft equation119 with a large ρ of −1.75 and an r of 0.1 with σ + . Total scrambling of deuterium atoms at C(1) and a Winstein–Grunwald m value91 = 0.73 indicated that the reaction occurred via a cyclic, anchimerically assisted SN 1/E1 mechanism (Scheme 14). Corresponding ρ values, in the range −1.75 to −0.95, were determined for other leaving groups. An investigation of the reactions of various silver acetylides with adamantyl bromide or iodide in several solvents showed that SN products could be formed in low to satisfactory yields.120 Because adamantane is one of the products, the reaction may occur by an SRN 1 rather than an SN 1 mechanism. The reaction of benzyl methyl carbonate with sodium benzenesulfinate and different palladium catalysts has shown that the best yields were obtained when a Pd(η3 C3 H5 )Cl2 – (DPEphos) catalyst was used in DMSO at 80 ◦ C.121 Most of the reactions gave ≥90% yields of the benzyl aryl sulfone. In the suggested mechanism, the methyl carbonate leaving group is displaced by the catalyst, forming an (η3 -benzyl)palladium intermediate that reacts with the sodium salt of the arenesulfinate. A detailed and elegant study of the SN 1 solvolysis reactions of several substituted 1-phenylethyl tosylates in 50% aqueous TFE has enabled the rates of (1) separation of the carbocation–ion pair to the free carbocation, (2) internal return with the scrambling of oxygen isotopes in the leaving group, (3) racemization of the chiral substrate that formed the carbocation–ion pair, and (4) attack by solvent to be determined.122 A tracer study using Cl2 AlD opened the ring of syn- and anti -2-substituted-cis-4methyl-5-trifluoromethyl-1,3-dioxolane in a regiospecific SN 2-type cleavage.123 DFT calculations using the B3LYP functional and the 6–31G∗∗ basis set suggest that the

238


X

MeSiMe D H D H Y

MeSiMe +

H H

D D

HOS HOS

X

H H

X

MeSiMe D D SO

MeSiMe D H D H OS

Scheme 14

CF3 CF3

O O

CF3

Ph + AlCl2D

AlCl2 ‡ D Ph

O

CF3

O (30)

CF3 CF3

OAlCl2 D Ph O H

HX

CF3 CF3

OH H

D Ph

+

AlCl2X

deuteride ion is transferred to C(2) via the four-membered ring SN 2-like transition state (30). The reaction of cyanide ion with substituted benzhydryl carbenium ions to form nitriles and isocyanides is controlled by the rates of reaction at carbon and nitrogen.124 In slow reactions, far from the diffusion limit, the attack is completely at the cyanide carbon. Very fast reactions, with little or no reaction barrier reacting at the diffusioncontrolled limit, occur at both the N and the C of the cyanide ion. SN 2 reactions occur almost exclusively at carbon regardless of the substrate or source of the cyanide ion. The HSAB principle cannot predict the products of these reactions. Criteria for determining whether an intermediate is formed in simple reactions previously thought to occur in one step have been suggested.125 A mechanism that requires the formation of an intermediate ion–dipole complex in a rapid pre-equilibrium step before the rate-determining substitution is proposed for the SN 2 reaction between 4-nitrophenoxide ion and methyl iodide.

239


The normal U-shaped Hammett plots were found for both the catalysed [by a copper(II)salen complex (31)] and uncatalysed asymmetric alkylation of enolates by substituted benzyl bromides,126 indicating that both reactions occur via an SN 2 mechanism (Scheme 15). Because both reactions were faster when electron-withdrawing substituents were on the benzyl bromide, it was concluded that there was more bond formation than bond rupture in the SN 2 transition states. Because the curvature of the Hammett plot was greater for the catalysed reaction, it was concluded that the catalysed reaction has a later transition state with a greater negative charge on Cα . The role of the catalyst was to increase the nucleophilic character of the enolate anion. R H Ar

N

CO2R′

HO−

−

Ar

N

R

CH2Br Z

CH2 R Z

CO2R′ N

Ar

N

CO2R′

N Cu

O

O

(31)

Scheme 15

The effect of adding a benzoyl group to methyl bromide and tosylate was investigated.127 The large l and small m values in the extended Grunwald–Winstein equation91 and small kOTs /kBr ratios found in several solvents indicate that these reactions are SN 2 processes. The benzoyl group only decreased the rate by between 1.1 and 11.3 times depending on the solvent. The transition state was slightly tighter in the reaction with the benzoyl group. The alpha effect in the SN 2 reactions of methyl substrates with three different nucleophiles was shown to correlate with Koopman’s theorem ionization potentials for the leaving group.128 This was taken as evidence that (1) the size of the alpha effect in SN 2 reactions depends on the ability of the nucleophile and the leaving group to donate an electron to the methyl group and (2) these transition states have some SET character. The results support the Hoz model129 for the alpha effect. Neighbouring group participation by a nitro group was suggested130 for the reaction in Scheme 16 because the reaction stopped at the tosylate (32) when the nitro group was in the para position on the benzene ring attached to the nitrogen of the substrate. The SN 2 reactions of azetidinium triflates with nitrogen or oxygen nucleophiles, e.g. azide ion or acetate ion, occur with a high regiospecificity that depends on the

240

Organic Reaction Mechanisms 2005 CH2OH NO2

CH2OTs NO2

TsCl, pyridine, CH2Cl2, reflux

N

N

(32) δ−

‡

OTs Oδ−

O

+

N

+

N O

N O

N

Cl−

CH2Cl NO2 N

Scheme 16

Ph −

N3

+

N+ Bn

Ph N3

CO2Et

CO2Et Me

Me

N

Bn

Scheme 17

substituents on the azetidinium ion.131 α-Substituted azetidinium triflates react at the least substituted carbon (Scheme 17), whereas α,α -disubstituted azetidinium triflates react at the carbon with an electron-withdrawing group. A new method of methylating aniline at the nitrogen in supercritical methanol has been reported;132 alternative cyclic transition states involving one and two methanol molecules have been proposed for the base-catalysed reaction, which gives N -methylaniline in ≥98% yields. The effects of different solvents and palladium catalyst ligands on the allylic alkylation of aryl α-cyano esters have been investigated;133 up to 55% ee has been obtained in the presence of (−)-sparteine in THF at room temperature.

ee

241


N -Substituted imidazoles have been synthesized quickly in high yields and with high stereoselectivity from the adducts formed from Baylis–Hillman acetates134 and DABCO in 20% aqueous THF at room temperature.135 The substitution reaction with imidazole appears to proceed via an SN 2 –SN 2 mechanism (Scheme 18). H

OAc R

CO2Me N

N

R

+

AcO−

N

N

N

CO2Me

N

N

N

CO2Me

R

Scheme 18

A wide variety of organocopper reagents in the presence of LiCl in THF at −78 ◦ C reacted with γ -phosphoryloxy-α,β-unsaturated lactams (33) giving the anti -SN 2 product with high regio- and stereo-selectivity (Scheme 19).136 The best results were obtained using equimolar amounts of MeMgCl and CuI with LiCl. Although LiCl was required for the reaction, its role is not understood. OP(O)(OPh)2 Bn Me

Bn MeCuI, MgCl 2LiCl

N

Me

N

Me O

O (33) Scheme 19

The regiospecific alkylation, sulfonation, or acylation of the C(4) or the C(4) and C(6) OH groups of myo-inositol orthoesters (34) has been achieved by using the lithium rather than the sodium salts of the bases that form the appropriate alkoxide ion(s).137 Chelation between the alkoxide ions and the lithium cation is the factor that determines the regiospecificity of the reactions (Scheme 20). When either the C(4) or the C(6) oxygen was sterically hindered to attack, alkylation occurred at the C(2)-OH group. The C(4)-OH group reacts fastest because it is the most acidic hydroxyl group and the alkoxide ion can be stabilized by hydrogen bonding to the C(6)-OH group. Sulfonation gives the best yields of product. The perbenzylated α-glycosyl iodides are thought to react with oxetane via the mechanisms shown in Schemes 21 and 22 (where R=PhCH2 ).138 The amount of the β-product increases as the reaction temperature decreases. In fact, at −60 ◦ C, the β:α ratio in the product from the perbenzylated derivatives of galactosyl, mannosyl, and glucosyl iodides ranges from 10:1 to 50:1, indicating that the reaction in Scheme 21 is faster than that in Scheme 22.

242

Organic Reaction Mechanisms 2005 H O

H O

O

O LiH

HO

O

O

O RX

HO

RX

HO

H O

O

HO −O

OH

OR Li+

(34)

R = alkyl, acyl or sulfonyl

R O

OR

Scheme 20

RO n(RO)

O

I−

RO

O

O

n(RO)

RO

O

n(RO)

+

O

I

O 3

I Scheme 21

RO n(RO)

I−

O

RO n(RO)

RO O

I

O

n(RO)

O +

I RO n(RO)

O

I−

O O

I

Scheme 22

Two different mechanisms, both involving two SN 2 reactions (Scheme 23), have been suggested for the preparation of fluorodiaziridines.139 N -Substituted imines react with mesitylmagnesium bromide to form very reactive magnesium enamides that undergo SN 2 reactions with several different alkyl halides (Scheme 24).140 Even normally unreactive alkyl chlorides and fluorides give high yields of product. The best yields were obtained when the group on the nitrogen of the imine was (CH2 )2 NEt2 . Other metallic catalysts do not give good yields of the desired product. Enantiomerically pure α-bromacyl-imidazolidinones can be reacted with nitrogen nucleophiles to give pure stereoisomers with either retention or inversion of configuration141 (Schemes 25 and 26, respectively). The products can be readily converted to pure amino acids stereoselectively.

243

8 Nucleophilic Aliphatic Substitution N

Cl ArO Cl

a

N

F−

Cl

N

F

N

ArO

N

F

N

N

−ArO−

N

b

F−

a

F

b −Cl−

N

ArO F−

F

N

Scheme 23

NEt2

NEt2 mesityl MgBr

N

THF

N

MgBr

O

H+

RX

R

H2O

Scheme 24

O Me

N

n

N

Ph

Br Me

Ph

DKR epimerizing conditions PhCH2NH2

O Me

N

N

n

Ph

NHCH2Ph Me

Ph

Scheme 25

The suggested chiral episelenonium ion intermediate (35) underwent a regio- and stereo-specific ring opening when treated with aromatic hydrocarbon nucleophiles, e.g. anisole, when the aryl group on se was 2-pyridyl or 2,4,6-tri-t-butylbenzene but not when the aryl group was phenyl.142 Adding electron-withdrawing groups to the aryl group on selenium effectively stopped the racemization of the chiral carbon. (Chloromethylene)dimethylammonium chloride has been used to convert selected alcohols into sulfides in moderate to high yields with inversion of configuration.143

SN Reactions Producing Polymers The use of the anions of sulfonamides to prepare linear polymers from several different 1-substituted N -tosyl- and -mesyl-aziridines has been reported.144 Kinetics, spectroscopic evidence, and thermodynamic parameters have been used to elucidate the mechanism of both the triethylamine-catalysed and the uncatalysed reactions that form polyetherols from the tetrahydroxymethyl derivative of uric acid and ethylene oxide or propylene oxide.145,146

244

Organic Reaction Mechanisms 2005 O

Me

N

O n

N

non-epimerizing

Ph

conditions − N3

Br Me

Ph

Me

N

n

N

Ph

N3 Me

Ph

Scheme 26

MeO HO

Lewis acid

H Ph

Ph

H

MeO +

Se

SeAr

Ar (35)

H Ph

SeAr

But Ar =

But

, N But

Acknowledgements The considerable assistance of Yao-ren Fang and helpful discussions with G. A. Arteca are gratefully acknowledged.

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Fagnoni, M. and Albini, A., Acc. Chem. Res., 38, 713 (2005). Aitken, D. J. and Faure, S., in Comprehensive Organic Functional Group Transformations, II , (Eds Katritzky, A. R. and Taylor, R. J. K.), Elsevier, Oxford, 2005, pp. 463–531. Polet, D. and Alexakis, A., Org. Lett., 7, 1621 (2005). Leitner, A., Shu, C., and Hartwig, J. F., Org. Lett., 7, 1093 (2005). Miyabe, H., Yoshida, K., Yamauchi, M., and Takemoto, Y., J. Org. Chem., 70, 2148 (2005). Singleton, D. A. and Christian C. F., Tetrahedron Lett., 46, 1631 (2005). Matsson, O. and Westaway, K. C., Adv. Phys. Org. Chem., 31, 238 (1998). Yadav, J. S., Subba Reddy, B. V., Basak, A. K., Narsaiah, A. V., Prabhakar, A., and Jagadeesh, B., Tetrahedron Lett., 46, 639 (2005). Krawczyk, E., Owsianik, K., and Skowrońska, A., Tetrahedron, 61, 1449 (2005). Streitwieser, A., Jayasree, E. G., Leung, S. S.-H., and Choy, G. S.-C., J. Org. Chem., 70, 8486 (2005). Cardillo, G., Fabbroni, S., Gentilucci, L., Perciaccante, R., Piccinelli F., and Tolomeelli, A., Org. Lett., 7, 533 (2005). Lalic, G., Blum, S. A., and Bergman, R. G., J. Am. Chem. Soc., 127, 16790 (2005). Yorimitsu, H. and Oshima, K., Angew. Chem. Int. Ed., 44, 4435 (2005). Trushkov, I. V. and Brel, V. K., Tetrahedron Lett., 46, 4777 (2005). Saloˇn J., Milata, V., Gatial, A., Prónayová, N., Leˇsko, J., Cernuchová, P., Rappoport, Z., Vo-Thanh, G., and Loupy, A., Eur. J. Org. Chem., 2005, 4870. Reddy, C. R. V., Urgaonkar, S., and Verkade, J. G., Org. Lett., 7, 4427 (2005). Fang, Y. and Li C., Chem. Commun., 2005, 3574.

8 Nucleophilic Aliphatic Substitution 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

245

Yamaguchi, T., Yamamoto, Y., Fujiwara, Y., and Tanimoto, Y., Org. Lett., 7, 2739 (2005). Kulkarni, S. S., Liu, Y.-H., and Hung, S.-C., J. Org. Chem., 70, 2808 (2005). Azizi, N. and Saidi, M. R., Org. Lett., 7, 3649 (2005). Placzek, A. T., Donelson, J. L., Trivedi, R., Gibbs, R. A., and De, S. K., Tetrahedron Lett., 46, 9029 (2005). Kamal, A., Ramu, R., Azhar, M. A., and Khanna, G. B. R., Tetrahedron Lett., 46, 2675 (2005). Carrée, F., Gil, R., and Collin, J., Org. Lett., 7, 1023 (2005). Pastor, I. M. and Yus, M., Curr. Org. Chem., 9, 1 (2005). Kim, B. H., Piao, F., Lee, E. J., Kim, J. S., Jun, Y. M. and Lee, B. M., Bull. Korean Chem. Soc., 25, 881 (2004). McCluskey, A., Leitch, S. K., Garner, J., Caden, C. E., Hill, T. A., Odell, L. R., and Stewart, S. G., Tetrahedron Lett., 46, 8229 (2005). Kamal, A., Ahmed, S. K., Sandbhor, M., Naseer, M., Khan, A., and Arifuddin, M., Chem. Lett., 34, 1142 (2005). Bradley, D., Williams, D. B. G., and Lawton, M., Org. Biomol. Chem., 3, 3269 (2005). Thakur, S. S., Li, W., Kim, S.-J., and Kim G.-J., Tetrahedron Lett., 46, 2263 (2005). Stamatov, S. D. and Stawinski, J., Tetrahedron Lett., 46, 1601 (2005) Crotti, P., Renzi, G., Roselli, G., Bussolo, V. D., Lucarelli, L., and Romano, M. R., Tetrahedron, 61, 7814 (2005). Tanaka, T., Hiramatsu, K., Kobayashi, Y., and Ohno, H., Tetrahedron, 61, 6726 (2005). Azoulay, S., Manabe, K., and Kobayashi, S., Org. Lett., 7, 4593 (2005). Fringuelli, F., Pizzo, F., Tortoioli, S., and Vaccaro, L., Org. Lett., 7, 4411 (2005). Deng, X. and Mani, N. S., Tetrahedron: Asymmetry, 16, 661 (2005). Concellón, J. M., Suárez, J. R., Solar, V. D., and Llavona, R., J. Org. Chem., 70, 10348 (2005). Restorp, P. and Somfai, P., Eur. J. Org. Chem., 2005, 3946. Ueki, H. and Kitazume, T., J. Org. Chem., 70, 9354 (2005). Ueki, H., Chiba, T., Yamazaki, T., and Kitazume, T., Tetrahedron, 61, 11141 (2005). Ueki, H. and Kitazume, T., Tetrahedron Lett., 46, 5439 (2005). Pineschi, M., Bertolini, F., Haak, R. M., Crotti, P., and Macchia, F., Chem. Commun., 2005, 1426. Sridhar, R., Srinivas, B., Surendra, K., Krishnaveni, N. S., and Rao, K. R., Tetrahedron Lett., 46, 8837 (2005). Kalaiselvan, A. and Venuvanalingam, P., Tetrahedron Lett., 46, 4087 (2005). Uyanik, C., Hanson, J. R., Hitchcock, P. B., and Lazar, M. A., Tetrahedron, 61, 4323 (2005). Crotti, P., Bussolo, V. D., Macchia, F., Favero, L., Pineschi, M., Lucarelli, L., Roselli, G., and Renzi, G., J. Phys. Org. Chem., 18, 321 (2005). Minakata, S., Okada, Y., Oderaotoshi, Y., and Komatsu, M., Org. Lett., 7, 3509 (2005). Wu, J., Sun, X., and Xia, H.-G., Eur. J. Org. Chem., 2005, 4769. Yadav, J. S., Subba Reddy, B. V., Jyothirmai, B., and Murty, M. S. R., Tetrahedron Lett., 46, 6385 (2005). Somi Reddy, M., Narender, M., Nageswar, Y. V. D., and Rao, K. R., Tetrahedron Lett., 46, 6437 (2005). Wu. J., Sun, X., and Li, Y., Eur. J. Org. Chem., 2005, 4271. Ghorai, M. K., Das, K., Kumar, A., and Ghosh, K., Tetrahedron Lett., 46, 4103 (2005). Cunha, R. L. O. R., Diego, D. G., Simonelli, F., and Comasseto, J. V., Tetrahedron Lett., 46, 2539 (2005). Liu, Z.-Q., Fan, Y., Li, R., Zhou, B., and Wu, L.-M., Tetrahedron Lett., 46, 1023 (2005). Sureshkumar, D., Koutha, S. M., and Chandrasekaran, S., J. Am. Chem. Soc., 127, 12760 (2005). Concellón, J. M., Bernad, P. L., and Suárez, J. R., J. Org. Chem., 70, 9411 (2005). Silva, M. A. and Goodman, J. M., Tetrahedron Lett., 46, 2067 (2005). Kroutil, J. and Jenistova, K., Collect. Czech. Chem. Commun., 70, 2075 (2005). EI-Sayed, I., Monatsh. Chem., 136, 543 (2005). López-Cortina, S., Basiulis, D. I., Marsi, K. L., Muñoz-Hernández, M. A., Ordoñez M., and Fernández-Zertuche, M., J. Org. Chem., 70, 7473 (2005). Harger M. J. P., Chem. Commun., 2005, 2863. Kim, J.-H., Yang, H., and Boons, G.-J., Angew. Chem. Int. Ed., 44, 947 (2005). Ukachukwu, V. C., Mohan, R. S., and Whalen, D. L., Arkivoc, 2006, 48. Hasanayn, F., Streitwieser, A., and Al-Rifai, R., J. Am. Chem. Soc., 127, 2249 (2005). Matsson, O., Dybala-Defratyka, A., Rostkowski, M., Paneth, P., and Westaway, K. C., J. Org. Chem., 70, 4022 (2005).

246 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111

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8 Nucleophilic Aliphatic Substitution 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146

247

Almerindo, G. I. and Pliego, J. R., Org. Lett., 7, 1821 (2005). Ensing, B. and Klein, M. L., Proc. Nat. Acad. Sci. USA, 102, 6755 (2005). Soriano, A., Silla, E., Tuño´ n, I., and Ruiz-López, M. F., J. Am. Chem. Soc., 127, 1946 (2005). Helten, H., Schirmeister, T., and Engels, B., J. Org. Chem., 70, 233 (2005). Tishkov, A. A., Schmidhammer, U., Roth, S., Riedle, E., and Mayr, H., Angew. Chem. Int. Ed., 44, 4623 (2005). Ruff, F., Internet J. Mol. Des., 3, 474 (2005). Fujio, M., Uchida, M., Okada, A., Alam, M. A., Fujiyama, R., Siehl, H.-U., and Tsuno, Y., Bull. Chem. Soc. Jpn, 78, 1834 (2005). Tsuno, Y. and Fujiio, M., Adv. Phys. Org. Chem., 32, 267 (1999). Pouwer, R. H., Williams, C. M., Raine, A. L., and Harper J. B., Org. Lett., 7, 1323 (2005). Kuwano, R., Kondo, Y., and Shirahama T., Org. Lett., 7, 2973 (2005). Tsuji, Y. and Richard, J. P., Chem. Rec., 5, 94 (2005). Morelli, C. F., Fornili, A., Sironi, M., Dur`ı, L., Speranze, G., and Manitto, P., Tetrahedron Lett., 46, 1837 (2005). Tishkov, A. A. and Mayr, H., Angew. Chem. Int. Ed., 44, 142 (2005). Parker, V. D., Pure Appl. Chem., 77, 1823 (2005). Banti, D., Belokon, Y. N., Fu, W.-L., Groaz, E., and North, M., Chem. Commun., 2005, 2707. Kevill, D. N. and Kim, C.-B., J. Org. Chem., 70, 1490 (2005). Fountain, K. R., J. Phys. Org. Chem., 18, 481 (2005). Hoz, S., J. Org. Chem., 47, 3534 (1982). Donaghy, M. J. and Stanforth, S. P., J. Heterocycl. Chem., 42, 1215 (2005). Couty, F., Durrat, F., and Evano, G., Synlett, 11, 1666 (2005). Takebayashi, Y., Morita, Y., Sakai, H., Abe, M., Yoda, S., Furuya, T., Sugeta, T., and Otake, K., Chem. Commun., 2005, 3965. Nowicki, A., Mortreux, A., and Agbossou-Niedercorn, F., Tetrahedron Lett., 46, 1617 (2005). David, H. O. and Kenneth, M. N., J. Org. Chem., 68, 6427 (2003). Li, J., Wang, X., and Zhang, Y., Tetrahedron Lett., 46, 5233 (2005). Niida, A., Oishi, S., Sasaki, Y., Mizumoto, M., Tamamura, H., Fujii, N., and Otaka, A., Tetrahedron Lett., 46, 4183 (2005). Devaraj, S., Shashidhar, M. S., and Dixit, S. S., Tetrahedron, 61, 529 (2005). EI-Badry, M. H. and Gervay-Hague, J., Tetrahedron Lett., 46, 6727 (2005). Moss, R. A., Chu, G., and Sauers, R. R., J. Am. Chem. Soc., 127, 2408 (2005). Hatakeyama, T., Ito, S., Nakamura, M., and Nakamura, E., J. Am. Chem. Soc., 127, 14192 (2005). Treweeke, N. R., Hitchcock, P. B., Pardoe, D. A., and Caddick, S., Chem. Commun., 2005, 1868. Toshimitsu, A., Phosphorus Sulfur Silicon Relat. Eleme., 180, 935 (2005). Kawano, Y., Kaneko, N., and Mukaiyama, T., Chem. Lett. 34, 1612 (2005). Stewart, I. C., Lee, C. C., Bergman, R. G., and Toste, F. D., J. Am. Chem. Soc., 127, 17616 (2005). Cisek-Cicirko, I. and Lubczak, J., Int. J. Chem. Kinet., 37, 464 (2005). Cisek-Cicirko, I. and Lubczak, J., Int. J. Chem. Kinet., 37, 472 (2005).

CHAPTER 9

Carbanions and Electrophilic Aliphatic Substitution

M. L. Birsa Faculty of Chemistry, ‘Al. I. Cuza’ University of Iasi, Iasi, Romania Carbanion Structure and Stability . . . . . . . . . Carbanion Reactions . . . . . . . . . . . . . . . . . Enolates and Related Species . . . . . . . . . Heteroatom-stabilized Species . . . . . . . . . Organometallic Species . . . . . . . . . . . . (a) Organolithium species . . . . . . . (i) Directed lithiation . . . . . . (ii) Addition and other reactions (b) Organomagnesium species . . . . . (c) Organozinc species . . . . . . . . . (d) Other organometallic species . . . . Proton-transfer Reactions . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . Electrophilic Aliphatic Substitution . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

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249 252 252 256 260 260 260 261 264 265 268 270 271 272 273

Carbanion Structure and Stability It has been reported that 1H -benz[f ]indene (1), 1H -benz[e]indene (2), 1H -benz[fg] acenaphthylene (3), and 1H -cyclopenta[l]-phenanthrene (4), possessing planar carbon frameworks with a single secondary C(sp 3 )H2 centre, exhibit modest acidity in the gas-phase and in DMSO.1 The origin of their amplified acidity compared with cyclopentane, cyclopentene, and cyclopentadiene is the more pronounced anionic resonance, which distributes the negative charge over the whole planar carbon skeleton via mobile π -electrons. An ab initio study of the effect of α-substituents on the acidity of cyclopropabenzene has shown that α-substituents stabilize the cyclopropabenzenyl anion (5) less efficiently than the cyclopropenyl anion (6).2 The attachment of inductively/field acting substituents attached to the carbanionic site predominantly stabilize the cyclopropenyl anion by increasing the s character of the lone pair, diminishing the antiaromatic character of the three-membered ring at the same time.


249

250

Organic Reaction Mechanisms 2005 H

H

H

H

H

H

(1)

H

H

(2)

(3) _ ..

(4) _ .. X

X (5)

(6)

X = H, Me, NH2, OH, F, CH=CH2, SiH3, CF3, NC, CN, CHO, NO2, SO2H

An overview on cycloproparenyl anions has also been reported.3 According to theoretical calculation, cyclopropabenzenyl anion is by ca 145 kJ mol−1 more stable than the parent cyclopropenyl anion. It has been shown that the stability of the cyclopropabenzenyl anion could be considerably enhanced by substitution of the aromatic ring with fluorine and cyano groups, and also by a linear extension of the aromatic backbone. Gas-phase observation of C60 1− , C60 3− , and C60 4− anions has been reported.4 Detection of both C60 3− and C60 4− in these experiments demonstrated that these metastable polyanions may be observed in the gas phase by first generating them in solution and spraying into the gas phase. DFT calculations have been performed to examine the possible formation of mixed aggregates between chloromethyllithium carbenoids and lithium dimethylamide (LiDMA).5 In the gas phase, the major species are mixed trimers and mixed tetramers. In THF, the coordinating ethereal ligands change the aggregation state, disfavouring the mixed tetramers in favour of the mixed dimer and trimers. The aggregation states are predicted to be more temperature sensitive compared with the gas phase, primarily due to the entropy effects from the dissociation of coordinated THF ligands. Computational methods have been used to determine the structure, bonding, and aggregation states of oxiranyllithium in the gas phase and in THF solution, at 200 and 298 K.6 Oxiranyllithium was found to exist predominantly as the tetramer in the gas phase, whereas the dimer was the dominant species in THF solution. Quantum chemical DFT calculations at the B3LYP/6–31G(d) level have been used to study the enantioselective lithiation/deprotonation of O-alkyl and O-alk-2-enyl carbamates in the presence of (−)-sparteine and (−)-(R)-isosparteine.7 Complete geometry optimization of the precomplexes consisting of the carbamate, the chiral ligand, and the base (i-PrLi), for the transition states of the proton-transfer reaction, and for the resulting lithio carbamates have been performed in order to quantify activation barriers and reaction energies. Ab initio and DFT methods have been used to describe electrical and thermochemical properties of all fluoropyrroles and their anions and cations.8 The study of

ee

251

9 Carbanions and Electrophilic Aliphatic Substitution

electrical properties has been based on the values of orbital energy spacing including the HUMO–LUMO gap (HLG) and electronic spatial extent (ESE) calculated at the DFT-B3LYP/6–31G level of theory. Results of this computational study are compatible with the assumptions that electron transport occurs through the LUMO, and that the conduction barrier is determined by the molecular electrochemical potential. A No-D 1 H NMR study has indicated the long-term stability of (7a)/(7b) (in the absence of additional n-BuLi) and suggested a mechanistic sequence, in which (7a)/(7b) is deprotonated a second time prior to LiH ejection (Scheme 1).9 Li n-BuLi

Li2COT2− Li (7a)

(7b) Scheme 1

Structural studies on the mechanism of the THF-catalyzed vinylic lithiation of allylamine derivatives have been performed using 2D and diffusion-ordered NMR spectroscopy.10 NMR evidence has suggested that in THF the mixed aggregate has close contact between the alkene and the β-CH2 of n-BuLi, whereas in the absence of THF, the allyl chain appears to be pointed away from the nearest n-BuLi residues. A structural (multinuclear magnetic resonance), thermodynamic (pKa ), and kinetic (Marcus intrinsic reactivity) study of the ionization of benzylic carbon acids activated by an exocyclic (α) SO2 CF3 group and SO2 CF3 or S(O)(=NSO2 CF3 )CF3 in the para position of the phenyl ring has been reported.11 The latter has been found to exert an enormous acidifying effect of ca 8 pK units as compared with H(4) benzyltriflone in Me2 SO solution. 1 H, 13 C, and 19 F NMR data support the view that in the case of the triflones the carbanion negative charge resides for the most part at the exocyclic Cα carbon, implying a major role of a polarizability effect. Kinetic experiments have been used to establish the free energy, enthalpy, and entropy of activation for the enantiomerization of three structural classes of 2-lithiopyrrolidines.12 These studies on unstabilized (alkyl group on nitrogen), unstabilized and chelated (methoxyethyl group on nitrogen), and dipole-stabilized and chelated (Boc group on nitrogen) lithiopyrrolidines have revealed free energies for enantiomerization in the range 19–22 kcal mol−1 at 0 ◦ C. Despite the similarity of these numbers, the enthalpic and entropic contributions to the free energies vary widely and exhibit a marked dependence on solvent. Kinetic acidities have been reported for methane, ethane, propane, cyclopropane, isobutane, neopentane, tetramethylbutane, norbornane, nortricyclene, and adamantane by tritiodeprotonation or deuteriodeprotonation in cyclohexylamine catalyzed by caesium cyclohexylamide.13 The synthesis and structural characterization of azaacepentalenide (8) and its perchloro derivative (9) has been reported.14 Although the air-sensitive anion (8) appears

ee

252

Organic Reaction Mechanisms 2005 Cl .. N

Cl

L

.. N

Cl

Cl

..

L

L L

Cl

Cl (8)

(9)

L

4 OTf

L = DMAP

_

(10)

to be indefinitely stable in THF solution at room temperature, attempts to isolate pure lithium salts have failed. Anion (9) is stable in the absence of acids but it is not sufficiently nucleophilic to be alkylated like (8). The SASAPOS protocol has been applied to a small variety of pentafluoro benzene derivatives C6 F5 –E [E = −C(O)H, −C(N−Ph) H, −PCl2 /−P(L+ )2 , −H] yielding the ion clusters C6 (L+ )5 −E (F3 CSO3 − )5 .15 The reaction conditions required to observe a heteropolar C−C or C−P disconnection, with a highly stabilized pentakisoniosubstituted phenyl anion (10) as the key intermediate have been specified. The nature of the N -substituent of the aziridine moiety has been found to play an important role in the deprotonation reaction of oxazolinylaziridines.16 An electrondonating group appeared to be the N -substituent of choice when the oxazoline moiety has a cis relationship with respect to the proton to be removed. The high stability of the resulting aziridinyllithium may be due to the coordinative effect of the oxazoline ring.

Carbanion Reactions Enolates and Related Species Recent developments in the transfer of chirality within enolate alkylation reactions have been highlighted.17 A book Modern Aldol Reaction has featured recent developments of titanium,18 boron, and silicon19 enolates in the aldol reaction. The aldol and Michael addition of enolates generated by decarboxylation20 and vinylogous aldol reactions21 have been reviewed. Recent developments in asymmetric α-halogenation via catalytic generation of enolates have been featured.22,23 Gas-phase activation energies have been calculated for three lithium enolate reactions by using several different ab initio and DFT methods to determine which levels of theory generate acceptable results.24 It has been found that transition state geometry optimization with B3LYP followed by single-point MP2 calculations generally provided acceptable results compared with higher level ab initio methods. A new catalytic cycle for the enantioselective protonation of cyclic ketone enolates with sulfinyl alcohols has been developed (Scheme 2).25 In this method, the achiral alcohol plays two roles: it is involved in the turnover of the chiral proton source and also in the generation of a transient enolate through the reaction of its corresponding alkoxide with the enol trifluoroacetate precursor. Stereoselectivity was found highly dependent on the structure of the achiral alcohol.

ee

ee

253

9 Carbanions and Electrophilic Aliphatic Substitution .. _ O .. :

R1 R2

R1 HX*

+

R2

Y

R1

•

O

O *

+ Y

X*

_

Y

_

HY

R2 Scheme 2

Ph

X

Ph

MeI

MeO

R

MeO O

LDA, THF, −78 °C

(11)

O X = O, CH2;

X R re*

+

Ph

X R

MeO O

si*

R = H, Me, OMe Scheme 3

The stereoselectivity of the C-methylation of oxolanyl and cyclopentyl acetate enolates (11, X = O, CH2 ) has been investigated (Scheme 3).26 The methylation has proceeded re ∗ -selectively, although with very different degrees of selectivity (re ∗ :si ∗ from 62:38 to 96:4). The most important stereodirecting effect was a steric one exerted by the 5-phenethyl substituent, and this steric effect was strongly increased by the stereodirecting effect of a 3-OMe group. The extended cyclic enolate derived from a simple pyrrol-3-en-2-one (butenolactam) has been deuterated at the 5-position with very high diastereoselectivity if the nitrogen atom carries a α-methyl-p-methoxybenzyl group (de > 99:1).27 A similar diastereoselective protonation has been observed in a pyrrol-3-en-2-one formed by dearomatizing cyclization of a pyrrole. A new and efficient method for the synthesis of optically active esters and lactones having a tertiary or a quaternary stereogenic centre at the γ -position has been developed.28 Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides having two different substituents at the 2-position with the lithium enolate of t-butyl acetate gave optically active adducts in 99% chiral induction from the sulfur stereogenic centre. Experimental evidence for chair-like transition states in aldol reactions of methyl ketone lithium enolates has been provided.29 The results are consistent with predictions based on ab initio calculations. Ketone dilithio α,β- and α,β -dianions have been generated by a tin–lithium exchange reaction of the lithium enolate of β-tributyltin-substituted ketones.30 A chelation-aided approach, which employs β-dichlorobutyltin-substituted ketones and n-BuLi, has been used for the generation of ketone α,β-dianions having the Z-geometry at the alkene. The generated dianions have been transformed into ketones

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Organic Reaction Mechanisms 2005 OTMS TMSCl

LiO

O

Li

..

R1

R1

..

R1

OLi

R2X

R1

R2

R3X

R2

O

R1

R2 R3

Scheme 4

by sequential reaction at the β and α positions with a variety of carbon electrophiles (Scheme 4). Phenoxide anions have been proved to be good Lewis base catalysts to promote syn-selective aldol reaction between TMS enolates and aldehydes.31 Mechanistic studies on the asymmetric alkylation of amino ester enolates have been performed using a copper(II)salen catalyst (12) (Scheme 5).32 Hammett data have indicated that the asymmetric alkylation proceeded by an asynchronous SN 2 reaction and that the role of the catalyst is to enhance the nucleophilicity of the enolate. R1 H Ar

N

COOR2

R3 R1

(12), NaOH, R3Br

Ar

N

COOR2

H3O+

ee

R3 R1 H2N

COOH

Scheme 5

An efficient and highly selective access to enantioenriched α-carbonyl all-carbonsubstituted quaternary stereocentres has been provided by enantioselective alkylations of tributyltin enolates catalyzed by Cr(salen)Cl (13, M = Cr).33

N N Cu O O

N N M O O

But

But But

But (12)

ee

(13)

A new class of asymmetric bifunctional organic catalysts (14)–(16) originating from the privileged Cinchona alkaloid scaffold has been developed.34 The compound (16b) has provided the necessary positioning of Lewis basic and Brønsted acidic functional groups to allow desirable activation and organization of malonate nucleophiles and nitroalkene Michael acceptors leading to the adducts in good yield and enantioselectivity (ee >89%).

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N

N

N

H N

N O

H N R

H N

N H

SO2

Ph

N

Ph

N

N

OR

H S

R (14)

(15a): R = Me (15b): R = 4-MeC6H4

(16a): R = Ph (16b): 3, 5-(CF3)2C6H3

(17a): R = TMS (17b): R = TES (17c): R = TBS

Diphenylprolinol silyl ethers (17) have been found to be efficient organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes. A rhenium complex, [ReBr(CO)3 (thf)]2 , has been found able to catalyse the intermolecular reactions of 1,3-dicarbonyl compounds with terminal alkynes to give the corresponding alkenyl derivatives in excellent yields (Scheme 6).35 These reactions could apply to an intramolecular version and gave the corresponding cyclic compounds quantitatively. Tributylphosphine has been found to be a superior catalyst for the α-C-addition of 1,3-dicarbonyl compounds to electron-deficient alkynes.36 O

OH

O +

Ph

H

O

[ReBr(CO)3(thf)]2 neat, 50 °C, 24 h, 100%

Ph Scheme 6

Sn-chelated glycine ester enolates have been proved efficient nucleophiles for highly stereoselective 1,4-additions toward nitroalkenes.37 In the presence of acyl halides the tin also acts as a reducing agent of the nitronate intermediates, giving direct access to nitriles in a one-pot protocol. The arylation of ethyl acetoacetate, ethyl benzoylacetate, and diethyl malonate under the catalysis of CuI/l-proline in DMSO has been performed at 40–50 ◦ C in the presence of Cs2 CO3 to provide the 2-aryl-1,3-dicarbonyl compounds in good yields.38 Both aryl iodides and aryl bromides are compatible with these reaction conditions. The mechanism of the Baylis–Hillman reaction has been re-evaluated in terms of implications in asymmetric catalysis.39 These studies have shown that in the absence of added protic species, the initial stage of the Baylis–Hillman involves rate-limiting proton transfer. The Baylis–Hillman reaction of aromatic aldehydes with various activated alkenes catalysed by TMEDA in aqueous medium has been reported.40 It was demonstrated

ee

256


that this amine is not only a very efficient catalyst for the Baylis–Hillman reaction, but also outperforms the most widely used catalyst DABCO. Studies on catalytic asymmetric aza-Baylis–Hillman reaction has shown that the reaction involves rate-limiting proton transfer in the absence of added protic species, but exhibits no autocatalysis.41 Brønsted acidic additives lead to substantial rate enhancements through acceleration of the elimination step. Furthermore, it has been found that phosphine catalysts, either alone or in combination with protic additives, can cause racemization of the aza-Baylis–Hillman product by proton exchange at the stereogenic centre. Diastereofacial selectivity in the addition of lithioacetonitrile to 2-phenylpropanal has been found to be temperature and solvent dependent.42 Each solvent studied (benzene, toluene, n-hexane, cyclohexane, methylcyclohexane, THF, and diethyl ether) showed a different Eyring plot of ln(anti /syn) versus 1/T with specific differential activation parameters H # and S # , and disclosed the presence of inversion temperatures (Tinv s). The cooperative catalysis of CpRu(PPh3 )2 (CH3 CN)PF6 (18) and DBU has permitted chemoselective nucleophilic activation of acetonitrile in the presence of base-sensitive aldehydes to afford corresponding β-hydroxynitriles (19) in good yield (Scheme 7).43

MeCN

+

R

CHO

(18), DBU

OH R

+

CN

R = Me(CH2)4 (19)

Ph3P

Ru

PPh3

de

PF6− NCMe

(18)

Scheme 7

The stereochemical course in addition of lithiated benzyl cyanide and propionitrile to aromatic Schiff bases has been investigated and the origin of the stereochemical results has been discussed.44 A carbanionic intermediate with an adjacent stereogenic centre, formed as a result of fast isomerization of the initially formed azanions, has been proved to be involved in the formation of the stereochemical ratios.

de

Heteroatom-stabilized Species A review on the Ramberg–Backlund reaction has updated the Paquette review of 1977.45 Benzyl benzyl sulfone systems have been found to give unexpectedly high Zstereoselectivity (up to E:Z = 1:16) in the Meyers variant of the Ramberg–Bäcklund reaction.46 The nucleophilic addition of lithiated allyl phenyl sulfone to nitrones has proceeded exclusively α to the phenylsulfonyl group affording anti adducts in high yield.47 At 0 ◦ C isoxazolidines have been obtained with complete all-trans selectivity.

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Hydroxymethyl-substituted tetrahydrofurans have been prepared with high diastereoselectivity by reaction of the carbanion derived from 3,4-epoxybutyl phenyl sulfone with aldehydes in the presence of a mixture of lithium and potassium t-butoxides (Scheme 8).48 Initial formation of aldol-type adducts is a non-diastereoselective but reversible process; thus, subsequent formation of one main diastereoisomer is controlled by the relative rates of cyclization. The configuration of the carbon stereocentre at the oxirane ring is inverted in the course of the SN 2 process, and two new centres are created diastereoselectively (up to 87:13:0:0).

O PhSO2

R

RCHO ButOK ButOLi

.. O .. :

PhSO2 O

PhSO2

de

R

OH

O

R = aryl, alkyl Scheme 8

A novel synthesis of allyl sulfoxides has been developed by the reaction of primary α-lithiosulfinyl carbanions with group 6 Fischer carbene complexes (Scheme 9).49 The Fischer carbene complex experiments involve a 1,2-addition of two molecules of sulfinyl carbanion to give an intermediate that, after a β-elimination, furnishes the mentioned product. OMe (OC)5W

R1

O +

Li R1

S

1. THF, −78 °C

R2

R1

2. SiO2

= aryl, alkenyl, alkynyl;

R2 O

R2

= alkyl, aryl

Scheme 9

A general and highly stereoselective method for the synthesis of α,α-dibranched β-phenylpropylamines and ethanolamines has been developed through the reaction of the o-sulfinylbenzyl carbanions with the N -sulfinylketimines.50 The configuration at each of the newly formed chiral centres was controlled by the configuration of the sulfinyl groups at the reagents. Lithium 2-p-tolylsulfinylbenzyl carbanions have been reacted with different N -substituted imines affording 1,2-diarylamines with high stereoselectivity control at both benzylic (only dependent on the sulfur configuration) and iminic carbons.51 The anti:syn ratio was found to be dependent on the electronic density at the nitrogen atom. The reaction of optically active (1-diethoxyphosphoryl)vinyl p-tolyl sulfoxide (20) with sulfur ylides has provided the corresponding cyclopropanes (21) in high yields (Scheme 10).52,53 With fully deuterated dimethyl(oxo)sulfonium methylide, (CD3 )2 S(O)CD2 , the cyclopropanation reaction occurred in a highly diastereoselective

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de

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258

EtO EtO


O

O

P

S

C6H4Me-p

+

.. (CH3)2S(O)CH2

DMSO 90%

O

O

EtO P EtO

S

(S)-(20)

C6H4Me-p

(S)-(21) Scheme 10

manner, producing the cyclopropane-d2 as a major diastereomer in which the newly formed quaternary α-carbon atom is chiral due to isotopic substitution (CH2 vs CD2 ). The stereochemistry and reactivity of sulfur ylides with 5-substituted adamantan2-ones has been reported in different solvents.54 The electronic perturbative effect of substituents was found to depend on the solvent and reactant. A novel application of dimethylsulfonium methylide for the general preparation of non-readily accessible and synthetically valuable 1-substituted vinylsilanes and styrene derivatives has been developed.55 It has been found that by varying conditions, the reactions can be tuned in either direction to give an alkene or cyclopropane exclusively. An account on telluronium and sulfonium ylides has briefly described the development of ylide olefination, cyclopropanation, epoxidation, and aziridination.56 Optically active cis-2-substituted vinylaziridines (22) have been synthesized by the reaction of N -t-butylsulfinylimines with telluronium ylides with excellent diastereoselectivity (de > 98%) in good to excellent yields (56–98%) (Scheme 11).57 But 1. LiHMDS

L2Te X

_

R1

But

R1 = H, Ph, TMS;

S

N

O

N

O

2.

S

de

R2

R2

R2 = alkyl, aryl;

R1 (22)

Scheme 11

The reaction of 2-chloroisobutyrophenones and nitromethanide anion has stereoselectively provided (E)-3-nitro allylic alcohols.58 The Gibbs free enthalpies of reaction in DMSO for carbanion addition, epoxide formation, and rearrangement to 3-nitro allylic alcohol, as elementary steps for the reaction, have been estimated from corresponding neutral gas reactions and using a thermodynamic approach to the transfer of gaseous compounds to DMSO. It has been proved that stable and easily available N -sulfinylimines react with nitromethane anion in a highly diastereselective manner under mild conditions providing enantiomerically pure versatile β-nitroamines derived from aromatic or aliphatic aldehydes and ketones.59 These reactions are strongly catalysed by ammonium ions,

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9 Carbanions and Electrophilic Aliphatic Substitution O R2 R1

NHSOC6H4Me-p NO2

MeNO2 TBAF

p-MeC6H4

S

MeNO2 NaOH, 4 Å MS

R2

48% de

R1 p-MeC6H4OSHN

R1 = Ar, alkyl, vinyl; R2 = H, Ar, alkyl

R1

R2 NO2

94% de Scheme 12

which favours formation of the opposite diastereomer with moderate selectivity (Scheme 12). The Michael addition of nitroalkanes to α,β-unsaturated enones catalyzed by a novel chiral imidazolidine-2-yltetrazole organocatalyst has been investigated.60 The new more soluble organocatalyst (23) has decreased reaction times and improved enantioselectivities compared with other catalysts (up to 92% ee).

Bn

N N H

Ph

Ph

N

HN

(23)

N N

ee

Ph P O MeO

C6H4NO2-p O (24)

1,2-Oxaphosphetane (24) has been successfully isolated for the first time as stable crystals in the typical Wittig reaction of cyclopropylidenetriphenylphosphorane with activated carbonyl compounds.61 X-ray analysis of (24) showed that the phosphorus atom is at the centre of a slightly distorted trigonal bipyramidal structure. The effects of the solvent and finite temperature (entropy) on the Wittig reaction have been studied by using DFT in combination with molecular dynamics and a continuum solvation model.62 The free energy profile has been found to have a significant entropic barrier to the addition step of the reaction where only a small barrier was present in the potential energy curve. Water has been illustrated as an efficient medium for the Wittig reaction employing stabilized ylides and aldehydes.63 It has been demonstrated that the solubility of the reagents and substrates is relatively unimportant, even though pronounced hydrophobic entities are present. Benzonitriles have been synthesized by the reaction of nitric oxide (NO) with parasubstituted benzyltriphenylphosphonium chlorides or bromides.64 Asymmetric alkylation of dimethoxyphosphoryl-N -[1-(S)-α-methylbenzyl]acetamide enolates has been reported.65 The synthesis of both stereoisomers from the same source of chirality has been achieved by changing the equivalents of LDA.

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260


Organometallic Species (a) Organolithium species (i) Directed lithiation 4-Fluoro- and 4-chloro-benzoic acids have been metallated preferentially in the position adjacent to the carboxylate upon treatment with s-BuLi, s-BuLi–TMEDA, or t-BuLi at −78 ◦ C.66 A complete reversal in regioselectivity has been observed for 4-fluorobenzoic acid when treated with LTMP. Tuning of selectivity in the metallation of m-anisic acid has been realized by an appropriate choice of base.67 The results obtained with LTMP have indicated that the regiochemistry of the lithiation of m-anisic acid is thermodynamically controlled. Resonance and inductive effects favour removal of the H(2) proton. In contrast, superbases such as n-BuLi–t-BuOK are not significantly influenced by ortho-directing groups and preferentially attack H(4), the inductively activated aromatic position next to the most electronegative heteroatom and/or the most acidic position available. A similar behaviour has been recorded for unprotected naphthalene-1-carboxylic acid and biphenyl-2-, 3-, and -4-carboxylic acids.68,69 The metallation of alkoxy-substituted dibromobenzenes C6 H3 (OR)Br2 with LDA has been investigated.70 For 1-alkoxy-3,5-dibromobenzenes, different selectivities have been observed depending on the reaction conditions and the size of the alkoxy group. The methoxy group was an effective ortho director whereas this was not the case for the bulky trimethylsilyloxy group. The metallation of related 2,5-dibromoanisole has also been examined showing a significant meta-directing effect by the methoxy group. Sterically controlled regioselective para-substitution of aniline has been achieved by introduction of sterically demanding 1-isopropyl-2-methylpropyl or triisopropylsilyl groups at the nitrogen of aniline using a lithiation–substitution sequence.71 Lithiation of a series of cyclic aralkyl tertiary amines (25)–(28) with s-BuLi in various solvents has been studied.72 ortho-Lithiation has been observed only in the case of the eight-membered cyclic amine (28, R = H) and the ease of benzylic lithiation with respect to nitrogen was in the surprising order γ > β α, δ. R

R

R

N

N

N

N

R = H, Li, C(OH)Ph2, SiMe3 (25)

(26)

(27)

R (28)

The lithiation of a series of aryl benzyl ethers containing fluorine and methoxy groups has been studied.73 It has been found that the presence of one or two fluorine atoms in the meta-position relative to the oxygen atom prevents the lithiation at the benzyl carbon atom. An unusual regioselectivity pattern for the ortho lithiation of 3-aryl-and 3-styrylfurans has been uncovered wherein lithiation occurs preferentially at the sterically

261


encumbered 2-position.74 The results have been attributed to stabilization of the intermediate furyl anion by through-space donation of π -electron density from the substituent appended at the 3-position to the lithium cation. Regioselective substitution reactions of a series of 2- and 3-hydroxybiaryls including BINOL have been performed via a new directed ortho-metallation procedure.75 O-Aryl N -isopropylcarbamates, conveniently prepared from phenols and isopropyl isocyanate, have been temporarily and in situ N -protected by means of silyl triflates to form stable intermediates for low-temperature lithiation reactions using nBuLi–TMEDA in diethyl ether. The N ,N -dialkyl aryl O-sulfamate has been reported as a new directed metallation group.76 The sulfoximine group has proved to be an excellent ortho-directing group in lithiation reactions.77 The use of prochiral electrophiles has afforded ortho-functionalized arylsulfoximines in good yields and modest to good diastereoselectivities up to 95%. The ortho lithiation–trapping sequence of phenylaziridines has been reported.78 The methodology provided easy access to functionalized arylaziridines and also to phthalans and phthalides (Scheme 13).

R

N

R BusLi, THF

N E+

Li CO2

R

N E

R1R2CO

NHR

NHR

O O

O R 1 R2 R = Me, Et, Pr, Bu

Scheme 13

The cyano group has been used as an ortho-directing group for lithiation in the pyridine series.79 Lithiation of 4-cyanopyridine using LiTMP and trapping the lithio intermediate with electrophiles have provided an efficient and straightforward access to ortho-substituted-4-cyanopyridines. The lithiation of anisylpyridines has been studied.80 Whereas usual reagents did not react or gave addition products on the pyridine ring, the BuLi–LiDMAE superbase has induced exclusive pyridino-directed metallation. The latter selectivity has been attributed to an internal cooperating lithium complexation by both the pyridine nitrogen and methoxy group.

(ii) Addition and other reactions The implications of organolithium compounds in organic synthesis have been reviewed.81,82 A review on rearrangements of

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organolithium compounds has featured carbon–carbon and carbon–heteroatom bond formation.83 The importance of hetero-aggregate structures in understanding the structure and reactivity patterns of organolithium reagents has been reviewed.84 The kinetically controlled deprotonation of allylic carbamate esters (29) by nBuLi–(−)-sparteine has preferentially removed the pro-S proton, leading to the lithium intermediate (S)-(30) (Scheme 14).85 Trapping experiments with chlorotrimethylsilane has afforded the α-substitution products, with R-configuration.

ee

HR HS OCb

(29) sparteine BuLi

Li

Li

slow

OCb

OCb

(30) TMSCl

TMSCl

SiMe3

SiMe3

OCb

OCb Scheme 14

Boron trifluoride has been used in combination with organolithium–Lewis base complexes for the enantioselective nucleophilic ring opening of various oxiranes with excellent yields and high ee values.86,87 The reaction of both cis- and trans-2,3-diphenyloxirane, (31) and (32), respectively, with an excess of lithium and a catalytic amount of 4,4 -di-t-butylbiphenyl (DTBB, 2.5 mol%) in the presence of different carbonyl compounds as electrophiles has provided the same organolithium intermediate (33) and, consequently, the same 1,3-diols (34) (Scheme 15).88 In the case of cis-epoxide, an inversion of the configuration at the benzylic carbanionic centre explained the results. An effective and general method for the synthesis of 2,3-dihydrobenzofuran derivatives has been developed via an intramolecular carbolithiation reaction of o-lithioaryl ethers (Scheme 16).89 This process was the first example in which the carbolithiation reaction has been stopped at the 2,3-dihydrobenzofuran stage by appropriate selection of the ether moiety. A broad survey of asymmetric lithiation–substitution reactions has been carried out with 2- and 3-substituted N -Boc-allylamines.90 Determination of absolute configurations has suggested that reactions with inversion of configuration are favoured for reaction of these organolithium nucleophiles with most electrophiles.

ee

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263


O

LiO

Li, DTBB

Ph

Li

Ph

Ph

HO

HO R1 R2

Ph

Ph

Ph

(31)

(33)

(34)

LiO

O Li, DTBB

Ph

R1R2CO

(32)

Li

Ph

Ph

Ph Scheme 15

E R2

Br

1. ButLi (2 equiv.) 2. TMEDA (2.2 equiv.)

R2 O

3. E+, H2O

O R1

R1 Li R

2

R2 O R

R1

1

OH R1

= Me, But, TMS; R2 = H, Me Scheme 16

Enantioselective addition of various aryllithium reagents to aromatic imines has been catalysed by readily accessible 1,2-diamines to afford a wide range of protected diarylmethylamines in up to 94% ee.91 Regio- and stereo-selective deprotonation of N -t-butylsulfonyl-protected terminal aziridines with LiTMP has generated a non-stabilized aziridinyl anion that undergoes in situ or external electrophile trapping under experimentally straightforward conditions to give trans-disubstituted aziridines in good to excellent yields.92 Lithiation of 1-bromo-4-trisubstituted silylbuta-1,3-diene derivatives with t-BuLi has afforded substituted siloles (35) in high yields (e.g. Scheme 17).93 A pentaorganosilicate has been proposed to be the intermediate for this reaction. Selective cleavage was observed when the silyl group possessed different substituents. Results have shown that vinyl and phenyl substituents on the silicon atom were substituted much

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Organic Reaction Mechanisms 2005 Et Et Et

Et SiMe3

1. ButLi

Br

2. NaHCO3

Et SiMe2 Et

Et

Et (35)

Scheme 17

more easily than methyl groups, whereas a methyl group was exclusively deleted from an i-Pr–SiMe2 moiety.

(b) Organomagnesium species A highly efficient alkyl-selective addition to ketones with magnesium ate complexes derived from Grignard reagents and alkyllithiums has been described.94 The nucleophilicity of R in R3 MgLi is remarkably increased compared with that of the original RLi or RMgX, while the basicity of R3 MgLi is decreased. Inexpensive and readily available Grignard reagents and stable dinuclear Cu complexes have been used for the first time in catalytic enantioselective conjugate addition reactions to simple acyclic α,β-unsaturated methyl esters.95 These reactions have provided access to highly valuable β-substituted chiral esters in good yields and with excellent enantioselectivities (up to 99% ee). Iron-catalysed homo-coupling of aryl Grignard reagents has been successfully developed.96 A variety of aryl Grignard reagents have been efficiently converted into the corresponding symmetrical biaryls in the presence of FeCl3 and a stoichiometric amount of 1,2-dichloroethane as oxidant (Scheme 18). MgBr

Cl

Cl

FeCl3 (1–5 mol%)

R

Et2O, reflux

R = alkyl, OMe, Cl

R

R

Scheme 18

A new role of iron catalyst in the Grignard conjugate addition has been disclosed.97 It catalysed 1,6-addition of aryl Grignard reagents to 2,4-dienoates or -dienamines in a highly regio- and stereo-selective manner. A direct transformation of functionalized aromatic/heteroaromatic halides into sulfones has been performed via reactions of organomagnesium intermediates with sulfur dioxide (Scheme 19).98 The ratio of sulfones has been considerably increased by the use of polar aprotic solvents such as DMF or DMSO and of allylic and primary halides.

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9 Carbanions and Electrophilic Aliphatic Substitution 1. c-PentylMgBr

ArX

2. SO2 3. RX′

ArSO2R + ArSO(O)R

Ar = functionalized aromatic or heteroaromatic groups X = I, Br RX′ = primary bromide or iodide, Michael acceptors

Scheme 19

The direct alkenylation of arylamines at the ortho-position with magnesium alkylidene carbenoids has been investigated using both theoretical and experimental approaches.99 In some cases, the reaction has proceeded in a highly stereospecific manner at the carbon bearing the chlorine and the sulfinyl group. The anti -stereocontrolled alkylative ring-opening reaction of azabicyclic alkenes has been reported.100 N -(2-Pyridyl)sulfonylazabenzonorbornadiene (36) has reacted with Grignard reagents in the presence of catalytic amounts of CuCN to afford, in good yields and excellent anti selectivity, the corresponding dihydronaphthalene-1-amines (37) (Scheme 20). O2 S

N

N

O2 S

N

R

RMgX CuCN (10 mol%)

(36)

R = alkyl, aryl

(37)

Scheme 20

(c) Organozinc species Radical reactions initiated by dimethylzinc have been reviewed.101 Commercially available 2m Me2 Zn in toluene has been found able to promote the addition of phenylacetylene to aldehydes and ketones.102 This reactivity was determined by a new, unprecedented mechanism, which involves activation of the zinc reagent via coordination with carbonyl substrates that behave ‘ligand like’. The addition of Ph2 Zn to aldehydes has been investigated by DFT calculations.103 The experimentally observed increase in enantioselectivity upon addition of Et2 Zn to the reaction mixture was rationalized from calculations of all isomeric transition states. New substituted BINOL ligands have been obtained by directed ortho-lithiation or Suzuki cross-coupling.104 The ligand (R)-(38) has shown improved catalytic properties for the asymmetric diethylzinc addition to aromatic aldehydes. A series of N -acylethylenediamine-based ligands have been synthesized from Bocprotected amino acids.105 The ligands have been screened for their ability to catalyse the asymmetric addition of vinylzinc reagents to aldehydes. The optimized ligand (39)

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Organic Reaction Mechanisms 2005 N N

N N

OH OH

Et2N

(38)

NHBoc

(39)

catalysed the formation of 15 different (E)-allylic alcohols with enantioselectivities that ranged from 52 to 91% ee. This ligand was especially effective for the reaction of aromatic aldehydes with vinylzinc reagents derived from bulky terminal alkynes. The use of bis(sulfonamide) ligands derived from stilbenediamine in the asymmetric addition of diethylzinc to benzaldehyde has resulted in large changes in product ee over the course of the reaction.106 This effect has been attributed to autoinduction. During the reaction the catalyst evolves by incorporation of the product of the asymmetric addition reaction. The first catalytic asymmetric addition of functionalized organozinc reagents to ketones has been reported.107 These investigations indicated that catalyst (40) is tolerant to a variety of functionalized zinc reagents and enantioselectivities generally exceed 90%.

Me

O2S

NH

HN

Me

SO2

HO Me

Me OH (40)

O2S OH

NH

HN

SO2 HO

(41 ortho, meta, para)

ee

ee

ee

267


An easy and simple synthesis of different chiral trans-1-arenesulfonylamino-2isoborneolsulfonylaminocyclohexane derivatives (41) has been reported.108 These ligands have proved to be excellent promoters for the catalytic enantioselective alkylation and arylation of ketones (up to 99% ee), very good for the alkenylation process, and modest for the allylation and alkynylation reactions. The enantioselectivity of the addition reactions of diethylzinc to benzaldehyde has been studied in the presence of cyclic derivatives of 1,2- and 1,3-amino alcohols as catalysts.109,110 The asymmetric arylation of aldehydes in the presence of a catalytic amount of chiral amino alcohol111 or of chiral tertiary aminonaphthol112 has been described. The reactive arylzinc species have been generated in situ from a boron–zinc exchange instead of employing the more expensive diphenylzinc. The chiral diaryl carbinols have been obtained in high yields and ees. The enantioselective addition of diethylzinc to aromatic aldehydes has been performed in the presence of an N -sulfonylated amino alcohol–Ti(O-i-Pr)4 catalytic system.113 In the presence of (42), excellent enantioselectivities (up to 94% ee) have been obtained. The study revealed that the steric bulk of the camphor group does not affect the stereocontrol.

R O2S HO Ph

Et

O N

SH

NH

Et

ee

ee

ee

Me

N S

Ph

CN

R = C4H9, (CH2)5

CH2Ph (42)

R Zn

ee

(43)

(44)

A new class of efficient aminothiol ligands has been used in asymmetric alkenyl addition to aldehydes with very low catalytic loading of 1 mol%.114 Efficient formation of chiral (E)-allylic alcohols with ees of up to 99% has been achieved in the presence of (43). Optically active amino thiocyanate derivatives of (−)-norephedrine [e.g. (44)] have been found to act as effective aprotic ligands for enantioselective addition of diethylzinc to aldehydes.115 This reaction has provided optically active secondary alcohols with ee up to 96%. A nickel catalyst, Ni(acac)2 , has been utilized for the four-component connection reaction of Me2 Zn, alkynes, buta-1,3-diene, and carbonyl compounds in this order in a 1:1:1:1 ratio to furnish (3E, 6Z)-nonadien-1-ol (45) with high stereoselectivity and in excellent yield (Scheme 21).116 Highly enantioselective conjugate addition of Et2 Zn to acyclic and cyclic enones has been performed in the presence of copper/phosphorus containing catalysts.117–119

ee

ee

de

ee

268

Organic Reaction Mechanisms 2005 HO Et

Me2Zn +

+

+ PhCHO

Et

Ni(acac)2 rt, 30 min

Ph Et Me Et (45)

Scheme 21

Catalytic asymmetric 1,6-additions to 2,4-dien-1-ones have been realized with up to 98% ee using a chiral bisphosphine–rhodium catalyst, arylzinc reagents, and a chlorosilane.120 The scope and application of asymmetric addition of diorganozinc reagents to imines has also been reviewed.121 It has been found that strong coordination with diethylzinc enables N -tosylimines to be directly reduced through a β-H transfer mechanism in nonpolar solvents to afford the corresponding secondary amines.122 The coordination is hindered in polar solvents or in the presence of TMEDA. Various phosphorus catalysts have been employed in enantioselective addition of dialkylzinc reagents to sulfonylimines.123–125 A library of chiral zinc complexes formed in situ by the combination of achiral and racemic diimines with 3,30-di(3,5-ditrifluoromethylphenyl)-BINOL and diethylzinc have been evaluated in the asymmetric addition of diethylzinc to N -acylimines.126 High enantioselectivities of up to 97% ee and yields of up to 96% have been achieved for a wide range of aromatic imines in dichloromethane at −30 ◦ C. A stereospecific and stereoselective synthesis of 2-(1-hydroxyalkyl)-1-alkylcyclopropanols (46) has been realized from α,β-epoxy ketones and bis(iodozincio)methane (Scheme 22).127 The diastereoselective reaction has been explained by chelation effects.

O Ph

Me O

OH

CH2(ZnI)2

Me

THF, 25 °C

Ph

ee ee

ee

ee

de

OH

Me H (46)

Me

Scheme 22

(d) Other organometallic species Organic transformations using main group metals, rubidium and caesium,128 calcium,129 barium,130 gallium,131 germanium,132 and lead133 have been reviewed. The first examples of the enantioselective titanium-mediated trialkylaluminium additions to aromatic and aliphatic aldehydes catalysed by optically active α-hydroxy

ee

269

9 Carbanions and Electrophilic Aliphatic Substitution R1

R1

Ar O O

P

Ar O

N

O

Ar R1 (Ra, S, S)-(47) Ar = Ph (Ra, S, S)-(48) Ar = 2-C10H8

R1

R2 P

N R2 Ar

(S, S)-(49) Ar = Ph, R1 = Me, R2 = Me (S, S)-(50) Ar = 2-C10H8, R1 = Me, R2 = Me (S, S)-(51) Ar = Ph, R1 = H, R2 = Et

acids have been reported.134 The reactions proceeded with very good yields and good asymmetric induction (up to 92% ee). Simple phosphoramidite ligands (47)–(51) have afforded good to excellent levels of enantioselectivity in 1,4-additions of AlR3 species to enones (ee >90%).135 The enantioselective addition of allyltributylstannanes to aldehydes and ketones has been performed in the presence of various chiral indium(III) complexes derived from (R)-BINOL,136 (S)-BINOL,137,138 and PYBOX.139,140 A facile and highly selective indium(0)-mediated allylation of hydrazones utilizing BINOL ligands has been described.141 Chiral (R)-3,3 -bistrifluoromethyl-BINOL has afforded homoallylic amines in up to 97% ee. It has been demonstrated by 1 H, 13 C, and 109 Ag NMR that a π -alkyne–Ag complex and then an alkynyl silver are formed in situ from alkyne and silver salt under conditions related to those used for Ag-catalysed alkynylation or for Ag/Pd-catalysed sp –sp 2 cross-coupling reactions.142 These observations have prompted a rationale of the mechanisms of these reactions. Alkynylation of adamantyl iodide has been performed in one-step procedure with silver(I) acetylides.143 The procedure is not applicable to substrates such as t-butyl iodide that can easily eliminate HI. The stereo- and regio-selective conjugate addition of organocopper reagents to various enones has been reported.144–146 Models accounting for the stereochemical outcome have been presented. Experimental and theoretical studies with 13 C kinetic isotope effects have revealed that the C–C bond formation is the rate-determining step of the 1,6-cuprate additions to 2-en-4-ynoates.147 The reaction intermediates have been determined and the calculated activation barrier for the transition state was found to be in good agreement with the experimental value. Addition of organocuprates to N -sulfinyl α,β-unsaturated imines has proceeded with good yields with good diastereoselectivities.148 α,β-Unsaturated sulfinyl ketimines and aldimines have both been shown to be suitable substrates for this reaction. It has been shown for the first time that aryl fluorides bearing an o-carboxylate group can undergo Pd-catalysed couplings (Scheme 23).149 On the basis of the computational study and subsequent experimental verifications of its predictions, it has been found

ee ee

ee

de

de

270


F O2N

Pd(PPh3)4, base

+

COOH

DMF, 80 °C

O2N

M

COOH

M = Bu3Sn or B(OH)2 Scheme 23

that such a reaction was facilitated by stabilization of the transition state by proximal oxyanions. A substoichiometric protocol for Reformatsky-type addition of α-halo esters, α-halo ketones, α-halonitriles, and α-halophosphonates to carbonyl compounds has been developed via samarium-mediated reaction.150 β-Hydroxy esters and βhydroxynitriles have been obtained in good to excellent yields.

Proton-transfer Reactions The gas-phase acidities of meta- and para-substituted phenylacetylenes and benzyl alcohols have been determined by measuring equilibrium constants of proton-transfer reactions using an FT-ICR spectrometer.151 The gas-phase acidities have been related linearly to those of benzoic acids with a slope of unity. Prototropic isomerization of the propene molecule in the presence of hydroxide ion has been studied using ab initio and DFT methods in the gas phase and in DMSO solution;152 the mechanism involves formation of an intermediate complex of the allyl anion with a water molecule. The mechanism of a proton transfer in an allyl system involving the hydroxide ion has been investigated by the RHF/6–31+G∗ and MP2/6–31+G∗ methods with one, two, and four water molecules.153 A possible mechanism of intramolecular proton transfer involving easy exchange of water molecules between the first and second coordination spheres of the propenide ion was considered. A range of variously substituted piperidines, piperazines and dialkylamines have been conveniently deuterated in a single step by isotopic exchange with deuterium oxide in the presence of an appropriate ruthenium complex catalyst.154 The isotopic exchange has been carried out efficiently in dimethylsulfoxide at positions both α and β to the NH group. An iridium catalyst (52) has been found to catalyse H–D exchange in a variety of unsaturated carboxylic acids, ketones and amines.155 The mechanism presumably involves displacement of cyclooctadiene by a solvent molecule, which later on is replaced by the α,β-unsaturated compound. The dynamics of proton transfer within a variety of substituted benzophenone–N methylacridan contact radical ion pairs [e.g. (53)] in benzene have been examined.156 Correlation of the rate constants for proton transfer with the thermodynamic driving force has revealed both normal and inverted regions for proton transfer in benzene.

271


O Ir

N

O

H3C C O (53)

(52)

Acidity constants and rates of reversible deprotonation of triphenylphosphonium ion (54), (55) and pyridinium ions (56), (57) by amines in water, 50:50 v/v DMSO–water, and 90:10 v/v DMSO–water have been determined.157 The intrinsic rate constants for proton transfer were relatively high for all four carbon acids and showed little solvent dependence. This is in contrast with nitroalkanes, which have much lower intrinsic rate constants and show a strong solvent dependence.158 O

O PPh3

Me (54)

PPh3

Ph

N

O Ph

(55)

Me O Ph

(56)

N

O

Me

S (57)

Miscellaneous Experimental results of an unprecedented haloform-type reaction in which 4-alkyl-4hydroxy-3,3-difluoromethyl trifluoromethyl ketones undergo base-promoted selective cleavage of the CO–CF3 bond, yielding 3-hydroxy-2,2-difluoro acids and fluoroform, have been rationalized using DFT (B3LYP) calculations.159 The solvent-induced effects on the two pathways, introduced within the SCRF formalism through PCM calculations, do not reverse the predicted preference of the CO−CF3 over the CO–CF2 bond cleavage in the gas phase. The gas-phase proton affinity of the N -heterocyclic carbene 1-ethyl-3-methylimidazol-2-ylidene has been determined as 251.3 ± 4 kcal mol−1 using the kinetic method, a value which makes the carbene one of the strongest bases reported thus far.160 Density functional theory calculations have been carried out at the B3LYP/ 6–31+G(d) level to compare the high experimental value with that estimated theoretically. The Lewis base-catalysed additions of alkynyl nucleophiles to aldehydes, ketones, and imines have been described.161 Mechanistic studies strongly indicated that the use of new triethoxysilylalkynes facilitate access of a reactive hypervalent silicate intermediate (Scheme 24). The non-electrophilic pyridine N -alkylation reactions of 2,6-bis(imino)pyridines have been attributed to the special electronic and steric characteristics of these compounds.162 These facilitated strong binding of the bis(imino)pyridine to the main group metal centres while disfavouring attack at the imino nitrogen or carbon centres due to

272


KOEt 10 mol%

R1

(RO)3Si

RO RO R1,

OH

O

OR R2

R1

Si

R3

OEt

R2,

R3

R2

R1

R3 = alkyl, aryl

Scheme 24

the presence of bulky iminoaryl substituents. Another important factor was the capacity of pyridine and imino functionalities to engage in metal-to-ligand charge transfer and, under certain circumstances, even to accept formally one or more electrons. Concurrent cyclopropanation by carbenes and carbanions has been investigated.163 It has been demonstrated that the deliberate addition of halide ions afforded concurrent cyclopropanation of electron-poor alkenes by an equilibrating mixture of phenylhalocarbenes and phenyldihalomethide carbanions, permitting smooth modulation of selectivity between electron-rich and electron-poor alkenes. Enantioselective organocatalytic cyclopropanations have been performed using directed electrostatic activation conditions.164 Using a new class of iminium catalysts, cyclopropanation has been conducted with enals but not electron deficient alkenes, such as unsaturated nitrile, nitro, or alkylidene malonate systems. Dianion (58) has been used as a reagent for p-cyanophenylation of aromatic nitriles.165 Based on experimental data and the results of quantum chemical calculations, a mechanism that includes a charge-transfer complex between (58) and the aromatic nitrile as the key intermediate has been suggested. CN P 2−

*

Pd P

CN (58)

2+

OH2

2 TfO−

OH2

(59)

P *

+

Pd P

H O

+

Pd O H

P P

− * 2 TfO

(60)

Electrophilic Aliphatic Substitution Catalytic enantioselective fluorination using chiral Pd complexes (59) and (60) has been reported.166,167 This method has provided various fluorinated compounds, including β-keto phosphonates, oxindoles, and phenylacetate derivatives, in a highly enantioselective manner (75–96% ee). Direct chiral Lewis acidic enantioselective chlorination and fluorination of βketophos-phonates has been presented.168 The chlorination proceeds in high yields and with up to 94% ee using NCS as the chloro source, whereas fluorination with (PhSO2 )2 NF (NFSI) gives the optically active α-fluoro-β-ketophosphonates in moderate to good yields and with up to 91% ee.

ee

ee


273

Substituent effects on the rate of electrophilic amination of phenylmagnesium bromides, magnesium diphenylcuprates, and catalytic phenylzinc cyanocuprates with O-methylhydroxylamine in THF have been investigated in a competitive kinetic study.169 The mechanistic differences between these three reactions were discussed on the basis of the experimental results. The reaction of 2,2-dialkoxycyclopropane-1-carboxylates and 2-ethoxycyclopropane-1-carboxylate with NOCl has provided isoxazoline- and/or isoxazole-3carboxylates by regioselective ring opening at the C(1)–C(2) bond.170 A mechanistic interpretation has suggested well-stabilized dipolar species as intermediates.

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9 Carbanions and Electrophilic Aliphatic Substitution 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139

275

Barluenga, J., Fañanás, F. J., Sanz, R., and Marcos, C., Chem. Eur. J., 11, 5397 (2005). Kim, D. D., Lee, S. J., and Beak, P., J. Org. Chem., 70, 5376 (2005). Cabello, N., Kizirian, J.-C., Gille, S., Alexakis, A., Bernardinelli, G., Pinchard, L., and Caille, J.-C., Eur. J. Org. Chem., 2005, 4835. Hodgson, D. M., Humphreys, P. G., and Ward, J. G., Org. Lett., 7, 1153 (2005). Wang, Z., Fang, H., and Xi, Z., Tetrahedron Lett., 46, 499 (2005). Hatano, M., Matsumura, T., and Ishihara, K., Org. Lett., 7, 573 (2005). López, F., Harutyunyan, S. R., Meetsma, A., Minnaard, A. J., and Feringa, B. L., Angew. Chem. Int. Ed., 44, 2752 (2005). Nagano, T. and Hayashi, T., Org. Lett., 7, 491 (2005). Fukuhara, K. and Urabe, H., Tetrahedron Lett., 46, 603 (2005). Wu, J.-P., Emeigh, J., and Su, X.-P., Org. Lett., 7, 1223 (2005). Satoh, T., Ogino, Y., and Ando, K., Tetrahedron, 61, 10262 (2005). Arrayas, R. G., Cabrera, S., and Carretero, J. C., Org. Lett., 7, 219 (2005). Yamada, K.-i., Yamamoto, Y., and Tomioko, K., Chem. Abs., 142, 176245 (2005). Cozzi, P. G., Rudolph, J., Bolm, C., Norrby, P.-O., and Tomasini, C., J. Org. Chem., 70, 5733 (2005). Rudolph, J., Bolm, C., and Norrby, P.-O., J. Am. Chem. Soc., 127, 1548 (2005). Guo, Q.-S., Liu, B., Lu, Y.-N., Jiang, F.-Y., Song, H.-B., and Li, J.-S., Tetrahedron: Asymmetry, 16, 3667 (2005). Richmond, M. L., Sprout, C. M., and Seto, C. T., J. Org. Chem., 70, 8835 (2005). Costa, A. M., Garcia, C., Carroll, P. J., and Walsh, P. J., Tetrahedron, 61, 6442 (2005). Jeon, S.-J., Li, H., Garcia, C., LaRochelle, L. K., and Walsh, P. J., J. Org. Chem., 70, 448 (2005). Forrat, V. J., Ramón, D. J., and Yus, M., Tetrahedron: Asymmetry, 16, 3341 (2005). Hajji, C., Testa, M. L., Zaballos-Garcia, E., and Sepúlveda-Arques, J., J. Chem. Res. (S), 2005, 420. Zhu, H. J., Jiang, J. X., Saebo, S., and Pittman, C. U., J. Org. Chem., 70, 261 (2005). Braga, A. L. Lüdtke, D. S., Vargas, F., and Paixão, M. W., Chem. Commun. (Cambridge), 2005, 2512. Ji, J.-X., Wu, J., Au-Yeung, T. T.-L., Yip, C.-W., Haynes, R. K., and Chan, A. S. C., J. Org. Chem., 70, 1093 (2005). Hui, X.-P., Chen, C.-A., and Gau, H.-M., Chem. Abs., 143, 325768 (2005). Tseng, S.-L. and Yang, T.-K., Tetrahedron: Asymmetry, 16, 773 (2005). Jin, M.-J., Kim, Y.-M., and Lee, K.-S., Tetrahedron Lett., 46, 2695 (2005). Kimura, M., Ezoe, A., Mori, M., and Tamaru, Y., J. Am. Chem. Soc., 127, 201 (2005). Ito, K., Eno, S., Saito, B., and Katsuki, T., Tetrahedron Lett., 46, 3981 (2005). Zhang, W., Wang, C.-J., Gao, W., and Zhang, X., Tetrahedron Lett., 46, 6087 (2005). ˇ Sebesta, R., Pizzuti, M. G., Boersma, A. J., Minnaard, A. J., and Feringa, B. L., Chem. Commun. (Cambridge), 2005, 1711. Hayashi, T., Yamamoto, S., and Tokunaga, N., Angew. Chem. Int. Ed., 44, 4224 (2005). Charette, A. B., Boezio, A. A., Côté, A., Moreau, E., Pytkowicz, J., Desrosiers, J.-N., and Legault, C., Chem. Abs., 143, 266996 (2005). Gao, F., Deng, M., and Qian, C., Tetrahedron, 61, 12238 (2005). Esquivias, J., Arrayas, R. G., and Carretero, J. C., J. Org. Chem., 70, 7451 (2005). Soeta, T., Kuriyama, M., and Tomioka, K., J. Org. Chem., 70, 297 (2005). Wang, M.-C., Xu, C.-L., Zou, Y.-X., Liu, H.-M., and Wang, D.-K., Tetrahedron Lett., 46, 5413 (2005). Liu, H., Zhang, H.-L., Wang, S.-J., Mi, A.-Q., Jiang, Y.-Z., and Gong, L.-Z., Tetrahedron: Asymmetry, 16, 2901 (2005). Nomura, K., Oshima, K., and Matsubara, S., Angew. Chem. Int. Ed., 44, 5860 (2005). Seijiro, M., Chem. Abs., 142, 155278 (2005). Hwu, J. R. and King, K.-Y., Chem. Abs., 142, 155279 (2005). Yanagisawa, A., Chem. Abs., 142, 155280 (2005). Yamaguchi, M., Chem. Abs., 142, 155281 (2005). Akiyama, T., Chem. Abs., 142, 155283 (2005). Kano, T. and Saito, S., Chem. Abs., 142, 155284 (2005). Bauer, T. and Gajewiak, J., Tetrahedron: Asymmetry, 16, 851 (2005). Alexakis, A., Albrow, V., Biswas, K., d’Augustin, M., Prieto, O., and Woodward, S., Chem. Commun. (Cambridge), 2005, 2843. Teo, Y.-C., Goh, J.-D., and Loh, T.-P, Org. Lett., 7, 2743 (2005). Teo, Y.-C., Tan, K.-T., and Loh, T.-P, Chem. Commun. (Cambridge), 2005, 1318. Teo, Y.-C., Goh, J.-D., and Loh, T.-P, Tetrahedron Lett., 46, 4573 (2005). Lu, J., Ji, S.-J., and Loh, T.-P., Chem. Commun. (Cambridge), 2005, 2345.

276 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170

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CHAPTER 10

Elimination Reactions

M. L. Birsa Faculty of Chemistry, ‘Al. I. Cuza’ University of Iasi, Iasi, Romania E 1cB Mechanisms . . . . . . . . . E 2 Mechanisms . . . . . . . . . . . Pyrolytic Reactions . . . . . . . . . Cycloreversions . . . . . . . Acid Derivatives . . . . . . . Other Pyrolytic Reactions . . Elimination Reactions in Synthesis Other Reactions . . . . . . . . . . References . . . . . . . . . . . . . .

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277 277 279 279 279 280 281 283 284

E 1cB Mechanisms The mechanism of base-induced β-elimination reactions in systems activated by a pyridine ring, with halogen leaving groups (F, Cl, and Br), has been investigated.1 These systems represent borderline cases between E1cB and E2 elimination reaction mechanisms. The combined experimental and theoretical results indicated an E1cB irreversible mechanism with F. Since no stable anionic intermediate was found when the leaving group is Cl or Br, the concerted elimination mechanism is strongly supported. A similar borderline system, trans-bis[2-(2-chloroethyl)pyridine]palladium chloride (1), has been prepared and structurally characterized by X-ray spectroscopy and computational study.2 A study on the elimination reaction of (1) induced by quinuclidine in acetonitrile has been performed (Scheme 1). The results suggest that the initial product of elimination is a palladium complex of vinylpyridine and that displacement from this complex is partially rate determining in the formation of the uncoordinated product. Despite experimental efforts, it was not possible to distinguish between two possible mechanisms, E2 concerted or E1cB.

E 2 Mechanisms The concerted bimolecular β-elimination reaction of substituted alkanes (X–Cα H2 – Cβ H2 – . . .) has been studied using the semilocalized quantum chemical approach.3 Organic Reaction Mechanisms · 2005: An annual survey covering the literature dated January to December 2005 Edited by A. C. Knipe © 2008 John Wiley & Sons, Ltd. ISBN: 978-0-470-03403-3

277

278

Organic Reaction Mechanisms 2005 Cl N Cl

Cl

Cl Pd N

Quinuclidine

+

CH3CN

N

N

Cl

(1) Scheme 1

The indirect influence of the base on the characteristics of the heteroatom-containing (X–Cα ) bond has been proved to consist of two components: (i) the additional indirect electron-donating effect of the initially occupied (bonding) orbital of the H–Cβ bond upon the X–Cα bond, wherein the orbital of the base participates as a mediator, and (ii) the indirect electron-donating effect of the base itself upon the same bond by orbitals of the H–Cβ bond. Elimination reactions of N -alkyl-N -chlorothenylamines (2) with MeONa–MeOH and Et2 NH–MeCN have been studied kinetically.4 The elimination reactions are regiospecific, producing only the conjugated imines (3) (Scheme 2). The reactions proceed by the E2 mechanism via an E2-central transition state. The structure of the transition state changes towards more product-like with concomitant decrease in the substrate steric effect as the base–solvent is changed from MeONa–MeOH to Et2 NH–MeCN. X

S

CL2NR

base

X

S

CL

NR

Cl (2)

R = Me, Et, Pri, But X = H, Me, Br, NO2 L = H, D

(3)

Scheme 2

An ab initio study of the SN 2 and E2 mechanisms has been performed for the reaction between the cyanide ion and ethyl chloride in dimethyl sulfoxide solution.5 Theoretical calculations have predicted a free energy barrier for nitrile formation of 24.1 kcal mol−1 , close to the experimental value of 22.6 kcal mol−1 (Scheme 3). It has also been predicted that the isonitrile formation is less favorable by 4.7 kcal mol−1 , while the elimination mechanism is less favorable by more than 10 kcal mol−1 . These results indicated that isonitrile formation and bimolecular elimination are not significant side-reactions for primary alkyl chloride reactions. Theoretical calculations of the reactions of CH3 SSR (R = H or CH3 ) with fluoride, hydroxide or allyl anion in the gas phase have been performed to determine the mechanism for both elimination and substitution reactions.6 The elimination reactions have

279

10 Elimination Reactions H2C CH2 + HNC + Cl− ΔG‡ = 36.4 kcal mol−1 ‡

EtCl + CN−

−1

ΔG = 38.9 kcal mol H2C CH2 + HCN + Cl−

S N2

E2

E2

S N2

EtCN + Cl− ΔG‡ = 24.1 kcal mol −1 ΔG‡ = 28.8 kcal mol −1 EtNC + Cl−

Scheme 3

been shown to follow the E2 mechanism. The elimination reactions with F− and HO− are preferred to the substitution reactions, whereas allyl anion prefers the substitution route. Elimination has been found favored both kinetically and thermodynamically.

Pyrolytic Reactions Cycloreversions The mechanism and kinetic aspects of the retro-ene reaction of the allyl n-propyl sulfide and its deuterated derivatives have been studied using four different types of DFT methods with eight different levels of the basis sets.7 The mechanistic studies revealed that the reaction proceeds through an asynchronous concerted mechanism. Theoretical calculations have indicated that the reaction displays a kinetic isotope effect of 2.86 at 550.65 K. Three 3 + 2-cycloreversions of 2-acetoxy-2-methoxy-5,5-dimethyl-3 -1,3,4oxadiazolines have been examined by DFT methods.8 The lowest activation energies have been found for cycloreversion to 2-diazopropane and acetic methylcarbonic anhydride and for cycloreversion to nitrogen and a carbonyl ylide. Those are the reactions that have also been observed experimentally.

Acid Derivatives The kinetics and mechanisms of gas-phase elimination of ethyl 1-piperidinecarboxylate, ethyl pipecolinate, and ethyl 1-methylpipecolinate has been determined in a static reaction system.9 The reactions proved to be homogeneous, unimolecular, and obey a first-order rate law. The first step of decomposition of these esters is the formation of the corresponding carboxylic acids and ethylene. The acid intermediate undergoes a very fast decarboxylation process. The mechanism of these elimination reactions has been suggested on the basis of the kinetic and thermodynamic parameters. 3-Phenoxypropanoic acid, 3-(phenylthio)propanoic acid, 4-phenylbutanoic acid and the corresponding ethyl and methyl esters have been pyrolysed between 520 and 682 K.10 Analysis of the pyrolysates showed the elimination products to be acrylic acid and the corresponding arene. The thermal gas-phase elimination kinetics and product analysis have been found compatible with a thermal retro-Michael reaction pathway involving a four-membered cyclic transition state. A theoretical study on the thermolysis of two carbonate esters, ethyl methyl and diethyl carbonate, has been carried out at the MP2/6–31G(d) and MP2/6–311++

280


G(2d,p) levels of theory.11 The results indicated that the mechanism is a two-step process. The first step, which is rate determining, occurs via a six-membered cyclic transition state in which the carbonyl oxygen participates, followed by a rapid decomposition via a four-membered cyclic transition state of the alkoxy acid so formed. The gas-phase elimination kinetics of ethyl oxamate, ethyl N ,N -dimethyloxamate and ethyl oxanilate have been determined in a static reactor system, seasoned with allyl bromide and in the presence of a free radical inhibitor.12 These reactions are homogeneous, unimolecular and appear to proceed through moderately polar cyclic transition states. The kinetics of the gas-phase elimination of ethyl and t-butyl carbazates have been studied in a static reactor system over the temperature range 220.3–341.7 ◦ C and pressure range 21.1–70.0 torr.13 Theoretical calculations on the thermal decomposition of ethyl carbazate (4) suggest that the reaction proceeds by a concerted non-synchronous mechanism, through a quasi-three-membered ring transition state (Scheme 4). In contrast, the transition state structure for the thermal decomposition of t-butyl carbazate is an almost planar six-membered ring. O

O H

N

O

NH2

Et

+ EtNH2 H

N

O

(4) HNO + CO Scheme 4

Other Pyrolytic Reactions The kinetics of the gas-phase elimination of 3-hydroxy-3-methylbutan-2-one have been investigated in a static system, seasoned with allyl bromide, and in the presence of the free chain radical inhibitor toluene.14 The reaction was found to be homogeneous, unimolecular and to follow a first-order rate law. The products of elimination are acetone and acetaldehyde. Theoretical estimations suggest a molecular mechanism involving a concerted non-synchronous four-membered cyclic transition state process. The behaviour of 16 substituted benzoyl/arylcarbamoyl and benzoyl/arylthiocarbamoyl stabilized ylides under conditions of flash vacuum pyrolysis has been investigated.15 Kinetic studies show the thiocarbamoyl ylides to react consistently faster than their carbamoyl analogues and substituent effects suggest a polar cyclic transition state, which involves attack by the benzoyl oxygen on the carbamoyl/thiocarbamoyl NH (Scheme 5). The kinetics of dehydrochlonination of poly(vinyl chloride) powder have been studied.16

281

10 Elimination Reactions Ph Ph3P X

N

O

FVP

H

500 °C

Ph Ph

NCX

+

Ph3P

Ph3P C OH

O

H Ph

X = O, S

Ph

PhC CH + Ph3PO Scheme 5

Elimination Reactions in Synthesis The formation of ‘one or more C=C bond(s) by elimination of S, Se, Te, N, P, As, Sb, Bi, Si, Ge, B, or metal functions’ and ‘the Ramberg–Bäcklund reaction’ have been reviewed.17,18 Benzyl benzyl sulfone systems have been found to give unexpectedly high Z-stereoselectivity (up to E:Z = 1 : 16) in the Meyers variant of the Ramberg–Bäcklund reaction.19 A range of sulfones, bearing various aryl substituents, have been explored to rationalize this unprecedented selectivity for (Z)-stilbene systems. Methyltrioxorhenium has been found to catalyse the olefination of ketones with ethyl diazoacetate in the presence of triphenylphosphane.20 The optimized system allows the olefination of aromatic, aliphatic, unsaturated, cyclic, and trifluoromethyl ketones. The effects of the solvent and finite temperature (entropy) on the Wittig reaction are studied by using density functional theory in combination with molecular dynamics and a continuum solvation model.21 The introduction of the solvent dimethyl sulfoxide causes a change in the structure of the intermediate from the oxaphosphetane structure to the dipolar betaine structure. Water has been illustrated as an efficient medium for the Wittig reaction employing stabilized ylides and aldehydes.22 It has been demonstrated that solubility of the reagents and substrates is not of a paramount nature, even though pronounced hydrophobic entities are present. The synthesis of α,β-unsaturated halides has been realized via new dephosphorylation reactions of α,β-ethylenic and acetylenic phosphonic acid monoesters with (biscollidine)iodine(I) or (biscollidine)bromine(I) hexafluorophosphate (Scheme 6).23 The Z-selective formation of α-fluoro-α,β-unsaturated esters has been achieved using the deselenenic acid of the syn- and/or anti -3-aryl-2-fluoro-3-hydroxy-2organoselanylacetates with trifluoromethanesulfonic acid. R1 OEt P OH

R2 O

(coll)2X+PF6− CH2Cl2

R1 + R2

R1, R2 = alkyl, aryl; X = Br, I Scheme 6

X

O

P

O

OEt

de

de

282


A valuable preparative method for the generation of cyclobutenyl anion has been developed by reductive removal of the selenyl group with lithium naphthalenide.24 Various alkyl and aryl azides have been transformed into the corresponding nitriles using bromine trifluoride in moderate to good yields (30–60%).25 The reaction is general and gives positive results with aliphatic, aromatic, cyclic, functionalized, and optically active azides. Two alternative mechanisms have been proposed. Sodium bis(trimethylsily)amide has been developed as a deoxygenating agent for the coupling of nitroarenes to azoxyarenes (Scheme 7).26 The entire process is presumed to involved three deoxygenating steps, during which the silyl groups removed oxygen atoms from the intermediates through intramolecular 1,2-eliminations. Y X

NaN(SiMe3)2 THF, 150 °C

NO2

sealed tube 20–51%

Y

X

N

+

N

O− X Y

X = H, OMe, OEt, SMe Y = H, OMe, NMe2 X + Y = –OCH2CH2O–, –O(CH2CH2O)4– Scheme 7

A novel synthesis of chroman-2,3-dicarboxylic acid derivatives has been performed by thermal extrusion of sulfur dioxide from benzosultones via o-quinone methides.27 A new protocol for the generation of o-quinodimethanes via 1,4-elimination of o-(silylmethyl)benzylic acetates has been developed using potassium fluoride.28 An unusual cyclopropanation of 9-bromocamphor derivatives (5) to a 7-spirocyclopropyl camphor derivative (6) has been realized by the action of potassium t-butoxide (or sodium hydride) in warm DMSO (Scheme 8).29 The exo-hydroxy group and a nonhydrogen endo-substituent at C(2) were proven to be essential structural elements, and the solvent DMSO the sole effective reaction medium. Br

7

ButO−K+ or NaH OH

1

R (5)

OH

DMSO R = Alkyl, Aryl

R (6)

Scheme 8

The stereochemical outcome in the elimination reaction of acyclic (E)-allylic acetates (7) to the corresponding dienes by the use of [Pd(dppe)2 ] as a catalyst in the presence of DBU has been elucidated by E2 -elimination.30 The unprecedented Z-preference has been rationalized by the ‘syn-effect’ in the transition state of deprotonation, which arose from a σ → π ∗ interaction.

283

10 Elimination Reactions OAc

O

Ph (7)

(8)

Stereochemistry of the 1,4-eliminative ring opening of [3-substituted (E)-prop-1enyl]oxiranes, e.g. (8), to the corresponding 2,4-dienyl alcohols by LDA has been investigated.31 The results have been rationalized by the ‘syn-effect’ in the transition state of deprotonation, which mainly arose from a σ → π ∗ interaction.

Other Reactions Both X-ray crystallography and electronic structure calculations using the cc-pVDZ basis set at the DFT B3LYP level have been employed to study the explosive properties of triacetone triperoxide (TATP) and diacetone diperoxide (DADP).32 The thermal decomposition pathway of TATP has been investigated by a series of calculations that identified transition states, intermediates, and the final products. Calculations predict that the explosion of TATP is not a thermochemically highly favoured event. It rather involves entropy burst, which is the result of formation of one ozone and three acetone molecules from every molecule of TATP in the solid state. A systematic ab initio investigation of the water-assisted decomposition of chloromethanol, dichloromethanol, and formyl chloride as a function of the number of water molecules (up to six) building up the solvation shell has been reported.33 The decomposition reactions of the chlorinated methanols and formyl chloride are accelerated substantially as the reaction system involves additional explicit coordination of water molecules. All species involved in the decomposition of CH2 FSH and CH3 FS have been studied using density functional theory (DFT).34 Vibrational mode analysis was used to elucidate the relations of the intermediates, transition states, and products. Transition state structures for HX and DX elimination (X = F, Cl) from chemically activated CF3 CH2 CH2 Cl, C2 H5 CH2 Cl, and C2 D5 CH2 Cl calculated by DFT has been found to give pre-exponential factors that agree with experimental pre-exponential factors for C2 H5 Cl, C2 H5 F, and CF3 CH3 to within the experimental uncertainty.35 The unimolecular 1,2-HF and 2,3-HF elimination reactions of CF3 CHFCH3 have been characterized using the chemical activation technique for an average vibrational energy of 97 kcal mol−1 .36 The transition state for 1,2-HF elimination has a two-fold larger pre-exponential factor than that for 2,3-HF elimination, because three F atoms attached to carbon atoms of the four-membered ring have lower frequencies than those in a CF3 group. Non-catalytic reaction pathways and rates of reaction of diethyl ether in supercritical water have been determined in a quartz capillary by observing the liquid- and gasphase 1 H and 13 C NMR spectra.37 At 400 ◦ C, diethyl ether undergoes, competitively, proton-transferred fragmentation and hydrolysis as primary steps. The former path generates acetaldehyde and ethane and is dominant over the wide water density range up to

284


0.5 g cm−3 . The acetaldehyde is further subjected to such reactions as decarbonylation and non-catalytic self- and cross-disproportionations, which generate ethanol. The kinetic resolution of a variety of racemic epoxides has been performed using a chiral bicyclic diamine ligand (9).38 Using 5 mol % of catalyst, both epoxide and allylic alcohol can be obtained in up to 99% ee when the reaction is stopped shortly before or after 50% conversion is reached. N Ph N N

NH N (9)

O

Me Me

Me (10)

The fragmentation of epoxy imino-1,3,4-oxadiazoline (10) has been studied by a combination of isotope effects and theoretical calculations.39 Significant primary 13 C isotope effects have been observed at the two oxadiazoline carbons but isotope effects at the remaining carbons are negligible. This was consistent with a rate-limiting fragmentation of the oxadiazoline without fragmentation of the adjacent epoxide ring. Investigation of site selectivity of the stereoselective deprotonation of cyclohexene oxide has been performed using kinetic resolution of isotopic enantiomers in natural abundance.40

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Alunni, S., De Angelis, F., Ottavi, L., Papavasileiou, M., and Tarantelli, F., J. Am. Chem. Soc., 127, 15151 (2005). Alunni, S., Bellachioma, G., Clot, E., Del Giacco, T., Ottavi, L., and Zuccaccia, D., J. Org. Chem., 70, 10688 (2005). Gineityte, V., Chem. Abs., 143, 366775 (2005). Pyun, S. Y., Lee, D. C., Seung, Y. J., and Cho, B. R., J. Org. Chem., 70, 5327 (2005). Almerindo, G. I. and Pliego, J. R., Org. Lett., 7, 1821 (2005). Bachrach, S. M. and Pereverzev, A., Org. Biomol. Chem., 3, 2095 (2005). Izadyar, M., Gholami, M. R., and Haghgu, M., Chem. Abs., 142, 155446 (2005). Czardybon, W., Warkentin, J., and Werstiuk, N. H., J. Org. Chem., 70, 8431 (2005). Rosas, F., Monsalve, A., Tosta, M., Herize, A., Dominguez, R. M., Brusco, D., and Chuchani, G., Chem. Abs., 143, 477512 (2005). Al-Awadi, S. A., Agdallah, M. R., Dib, H. H., Ibrahim, M. R., Al-Awadi, N. A., and ElDusouqui, O. M. E., Tetrahedron, 61, 5769 (2005). Notario, R., Quijano, J., Sanchez, C., and Velez, E., J. Phys. Org. Chem., 18, 134 (2005). Chacin, E. V., Tosta, M., Herize, A., Dominguez, R. M., Alvarado, Y., and Chuchani, G., J. Phys. Org. Chem., 18, 539 (2005). Rotinov, A., Dominguez, R. M., Cordova, T., and Chuchani, G., J. Phys. Org. Chem., 18, 616 (2005). Graterol, M., Rotinov, A., Cordova, T., and Chuchani, G., J. Phys. Org. Chem., 18, 595 (2005). Aitken, R. A., Al-Awadi, N. A., Dawson, G., El-Dusouqi, O. M. E., Farrell, D. M. M., Kaul, K., and Kumar, A., Tetrahedron, 61, 129 (2005). Yoshioka, T., Saitoh, N., and Okuwaki, A., Chem. Lett., 34, 70 (2005). Eustache, J., Bisseret, P., and Van de Weghe, P., Chem. Abs., 142, 297611 (2005).

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10 Elimination Reactions 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

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Taylor, R. J. K. and Casy, G., Chem. Abs., 142, 55657 (2005). Foot, J. S., Giblin, G. M. P., Whitwood, A. C., and Taylor, R. J. K., Org. Biomol. Chem., 3, 756 (2005). Pedro, F. M., Hirner, S., and Kuhn, F. E., Tetrahedron Lett., 46, 7777 (2005). Seth, M., Senn, H. M., and Ziegler, T., J. Phys. Chem. A, 109, 5136 (2005). Dambacher, J., Zhao, W., El-Batta, A., Anness, R., Jiang, C., and Bergdahl, M., Tetrahedron Lett., 46, 4473 (2005). Lahrache, H., Robin, S., and Rousseau, G., Tetrahedron Lett., 46, 1635 (2005). Murakami, M., Usui, I., Hasegawa, M., and Matsuda, T., J. Am. Chem. Soc., 127, 1366 (2005). Sasson, R. and Rozen, S., Org. Lett., 7, 2177 (2005). Hwu, J. R., Das, A. R., Yang, C. W., Huang, J.-J, and Hsu, M.-H., Org. Lett., 7, 3211 (2005). Wojciechowski, K. and Dolatowska, K., Tetrahedron, 61, 8419 (2005). Kuwano, R. and Shige, T., Chem. Lett., 34, 728 (2005). Li, W.-D. Z. and Yang, Y.-R., Org. Lett., 7, 3107 (2005). Takenaka, H., Ukaji, Y., and Inomata, K., Chem. Lett., 34, 256 (2005). Takeda, N., Chayama, T., Takenaka, H., Ukaji, Y., and Inomata, K., Chem. Lett., 34, 1140 (2005). Dubnikova, F., Kosloff, R., Almog, J., Zeiri, Y., Boese, R., Itzhaky, H., Alt, A., and Keinan, E., J. Am. Chem. Soc., 127, 1146 (2005). Phillips, D. L., Zhao, C., and Wang, D., J. Phys. Chem. A, 109, 9653 (2005). Zhou, X., Han, Z., Shi, Y., and Zhou, Z., Chem. Abs., 143, 266488 (2005). Ferguson, J. D., Johnson, N. L., Kekenes-Huskey, P. M., Everett, W. C., Heard, G. L., Setser, D. W., and Holmes, B. E., J. Phys. Chem. A, 109, 4540 (2005). Holmes, D. A. and Holmes, B. E., J. Phys. Chem. A, 109, 10726 (2005). Nagai, Y., Matubayasi, N., and Nakahara, M., J. Phys. Chem. A, 109, 3550 (2005). Gayet, A. and Andersson, P. G., Tetrahedron Lett., 46, 4805 (2005). Singleton, D. A. and Wang, Z., Tetrahedron Lett., 46, 819 (2005). Diner, P., Pettersen, D., Nilsson Lill, S. O., and Ahlberg, P., Tetrahedron: Asymmetry, 16, 2665 (2005).

CHAPTER 11

Addition Reactions: Polar Addition P. Koˇcovsky´ Department of Chemistry, University of Glasgow Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophilic Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Halogenation and Related Reactions . . . . . . . . . . . . . . . . . . . Additions of ArSX, ArSeX, and Related Reagents with Electrophilic Sulfur . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additions of Hydrogen Halides and Other Acids . . . . . . . . . . . . Additions of Electrophilic Oxygen . . . . . . . . . . . . . . . . . . . . Additions of Electrophilic Nitrogen . . . . . . . . . . . . . . . . . . . Additions of Electrophilic Carbon . . . . . . . . . . . . . . . . . . . . Additions Initiated by Metals and Metal Ions as Electrophiles . . . . . Miscellaneous Electrophilic Additions . . . . . . . . . . . . . . . . . . Nucleophilic Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additions to Multiple Bonds Conjugated with C=O . . . . . . . . . . Additions to Multiple Bonds Activated by Other Electron-withdrawing Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additions of Organometallics to Activated Double Bonds . . . . . . . Miscellaneous Nucleophilic Additions . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . .

287 288 288

. . . . . . . . .

294 294 295 296 297 298 312 313 313

. . . .

327 331 341 341

Reviews During the coverage period of this chapter, reviews have appeared on the following topics: kinetics of electrophile–nucleophile combinations as a general approach to polar organic reactivity;1 ionic liquids: solvent properties and organic reactivity;2 preparation of alkenes by addition reactions;3 preparation of alkenes by reduction of C–X bonds (X = C, Hal, O, S, Se, Te, N, P, As, Sb, Bi, B, Si, Ge) and by addition of H to alkynes and allenes;4 transition metal-catalysed addition reactions of X–H or X–X to double and triple bonds;5 neighbouring group effects in Heck reactions;6 catalytic hydroamination reactions catalysed by transition metals;7 catalytic asymmetric hydroamination of non-activated alkenes;8 the conjugate addition reaction;9 progress in the aza-Michael reaction;10 recent developments in the Michael addition of sulfur and selenium nucleophiles;11 catalytic enantioselective aza-Michael reaction as a novel protocol for asymmetric synthesis of β-amino acids and other β-amino carbonyl compounds;12 chiral phosphine Lewis bases in catalytic, asymmetric aza-Morita–Baylis–Hillman reaction;13 chalcogenide–Lewis acid-mediated tandem Organic Reaction Mechanisms · 2005: An annual survey covering the literature dated January to December 2005 Edited by A. C. Knipe © 2008 John Wiley & Sons, Ltd. ISBN: 978-0-470-03403-3

287

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288


Michael–aldol reaction as an alternative to the Morita–Baylis–Hillman reaction;14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes;15 asymmetric cyclopropanation of chiral (1-phosphoryl)vinyl sulfoxides;16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates;17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds;18 Michael additions catalysed by transition metals and lanthanide species;19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis;20 and nucleophilic phosphine organocatalysis.21

Electrophilic Additions Halogenation and Related Reactions Full geometric optimization of exo-tricyclo[3.2.1.02.4 ]oct-6-ene (exo-TCO) has been carried out using semiempirical methods.22 The double bond of the molecule has been found to be endo-pyramidalized and its two faces non-equivalent The exo-face has regions having high electron density and larger negative potential. The exo-TCO·Br2 system was studied by the AM1 method and the exo-TCO·Br2 (exo) molecular complex was found to be relatively more stable than the exo-TCO·Br2 (endo) complex. The cationic intermediates of the reaction were also studied by semiempirical methods and the exo-bromonium cation proved to be more stable than its endo counterpart. exoFacial selectivity was observed in the addition of bromine to exo-TCO as a result of the combination of electronic and steric effects. The exo-classical bromocarbonium cation is more stable than the corresponding rearranged cation, formed via Wagner–Meerwein rearrangement, and has been shown to be actually the most stable ion among the cationic intermediates; therefore, the addition is believed to occur via this cation.22 In a related study, the electronic and geometric structures of homobenzonorbornadiene (HBNB) have been investigated by using ab initio HF/3–21G*, HF/3–21G**, HF/6–31G* and HF/6–311G* methods.23 As in the previous case, the double bond was found to be endo-pyramidalized. The HF/3–21G* calculations have been performed for the 1:1 molecular system of chlorine with HBNB and their stable configurations have been determined. The stable configurations of the HBNB·Cl2 system correspond to HBNB·Cl2 (exo) and HBNB·Cl2 (endo) molecular complexes, formed by the exo and endo orientation of Cl2 molecules to the double bond of HBNB in axial position, respectively. The exo-molecular complex has been found to be relatively more stable than its endo counterpart. The subsequently formed cationic intermediates have been studied by ab initio SCF method at the 3–21G*, 3–21G**, 6–31G* and 6–311G* level. The exo-chloronium cation was found to be more stable than the endo-chloronium cation, so that the exo-facial selectivity of chlorination should predominate. Again, the non-classical delocalized cation has been found to be more stable than the classical rearranged cation and can be regarded as the intermediate in the chlorination.23 Full geometric optimization of bicyclo[3.2.2]nona-6,8-diene (BND) based on semiempirical and ab initio methods has revealed that the double bond situated in the

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11 Addition Reactions: Polar Addition

289

opposite direction of the methylene group is more exo pyramidalized than the other double bond.24 The electron density of the former double bond in the HOMO orbital is higher than that of the latter double bond. The exo and endo faces of the exopyramidalized double bonds of the molecule are not equal and the electron density is higher in the endo faces. The molecular complexes of BND with bromine were studied by the AM1 method and their stable configurations determined. The endo molecular complexes were found to be more stable than their exo counterparts, apparently owing to both electronic and steric factors. Due to electronic factors, the BND·Br2 (endo1) complex is more stable than BND·Br2 (endo2). The endo-facial stereoselectivity and regioselectivity has been predicted.24 The final contribution of this series25 concerned norbornadiene (NB), the full geometry optimization of which has been carried out by ab initio HF/3–21G*, HF/3–21G**, HF/6–31G*, HF/6–311G* and HF/6-311G* methods. Again, the double bonds have been shown to be endo pyramidalized. As a result, the electron densities (HOMO) on the exo and endo faces of the double bonds are not equal and have been found to be higher on the exo face. The NB·Cl2 system was investigated by the HF/3–21G* method and the stable configurations were determined. These stable configurations correspond to NB·Cl2 (exo) and NB·Cl2 (endo) molecular complexes that are formed by the exo and endo orientation of the Cl2 molecule to the double bond of NB, respectively. The exo molecular complex has been found to be relatively more stable than the endo complex. The cationic intermediates of the reaction have been studied by ab initio methods. The exo-chloronium cation was found to be more stable than its endo-diastereoisomer, leading to the predominant exo-facial selectivity in the chlorination. The results indicate that a multicentred non-classical chlorocarbonium cation formed by the rearrangement of the exo-chloronium cation is the most stable species among the cationic intermediates. Therefore, it is likely that the ionic addition reaction proceeds via the non-classical chlorocarbonium ion, resulting in the formation of the rearranged products.25 Iodine is commonly used to accelerate the equilibration of Wittig cis/trans-alkene products. Computational chemistry has been employed to study the mechanism in detail for seven different examples of 1,2-disubstituted alkenes.26 The iodo intermediates of the conventional three-step reaction path have been found to be weakly stable, bound by less than 7 kJ mol−1 in five cases and non-existent in the other two. These variations in relative stability have been interpreted as being closely related to the degree of conjugation interruption in the alkene upon attachment of iodine. The rate-determining reaction barrier always occurs in the middle step, namely the internal rotation of the iodo intermediate, and the variations in the barrier heights are dictated by varying levels of the steric hindrance in all seven cases. The regioselectivity of the iodine atom addition and noticeable hyperconjugative effects have been discussed. Comparisons between various theoretical approximations were performed to demonstrate the great difficulty in obtaining accurate results for the iodine atom bond-forming and bond-breaking energies.26 The effect of cyclodextrin complexation on the bromination of styrene, methyl cinnamate, phenylacetylene, and allylbenzene has been studied.27 The corresponding bromohydrin was obtained as a major product along with dibromide in the bromination

de

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of styrene and methyl cinnamate (PhC=CHX; X = H or CO2 Me). The percentage of bromohydrin decreases as the cavity size increases. With phenylacetylene (PhC≡CH), bromophenylacetylene and phenacyl bromide were obtained in addition to the dibromides. In the bromination of cyclodextrin complexes of allylbenzene, the product distribution was identical with that found for solution bromination. The results demonstrate the efficiency of cyclodextrin in stabilizing the open carbocationic intermediate and thus provide chemical evidence for the participation of cyclodextrin hydroxyl groups.27 LiBr has been reported to catalyse the dihydroxylation of alkenes (1) to afford synand anti -diols (2/3) with excellent diastereoselectivity, depending on the use of NaIO4 (30 mol%) or PhI(OAc)2 (1 equiv.), respectively, as the oxidant.28 The authors claim that ‘oxidation of non-benzylic halides was achieved for the first time to afford the corresponding diols in excellent yields’28 is not really justified as the development of the ‘silver-free Prévost–Woodward dihydroxylation’ for non-benzylic substrates had been reported much earlier.29,30 HO R2

R1

1. NaIO4 (30 mol%) LiBr (20 mol%) AcOH, 95 °C, 18 h 2. K2CO3, MeOH 25 °C, 24 h

OH (2)

1. PhI(OAc)2 (1 equiv.) LiBr (20 mol%) R2 AcOH, 95 °C, 18 h

R1

HO R2

R1

2. K2CO3, MeOH 25 °C, 24 h

OH

(1)

(3)

The diastereoselective halohydrin formation, resulting from the reaction of chiral N -enoyl-2-oxazolidinones with Br2 /I2 and water, promoted in the presence of silver(I), in aqueous organic solvents, has been found to occur with high regioselectivity and moderate to good diastereoselectivities. The alkenoyl, cinnamoyl, and electrondeficient cinnamoyl substrates readily produced the bromohydrin in aqueous acetone, but no iodohydrin formation was observed under these conditions. On the other hand, electron-rich cinnamoyl substrates preferred to afford iodohydrins in aqueous acetone with moderate diastereoselectivity; enhanced diastereoselectivity was observed for aqueous THF.31 Diastereoselective iodocyclizations of α-hydroxy acids (4) provides 3-hydroxy-3,4dihydrofuran-2(5H )-ones (5/6) as a result of an exclusive participation of the carboxyl group; the stereochemical outcome depends on the nature and position of the substituents in the substrate and the choice of solvent and base.32 Lewis acid-catalysed intramolecular haloarylation of tethered alkenes (7) has been performed using N -halosuccinimide (NXS) as the halogen source. Among the Lewis HO R1

I2, NaHCO3

R1

R1

R2

HO

HO2C

I R2 (4)

O

de

O (5)

+

R2

HO

I O

O (6)

de

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11 Addition Reactions: Polar Addition Y

Z

Y NXC, MLn (cat.)

R1

Z

R1

+

Y

X

X R2

R2

R2

Z

(7)

(8)

acids investigated, (TfO)3 Sm proved to be the best catalyst. This process represents a general approach to the regio- and stereo-selective synthesis of annulated arene heterocycles and carbocycles (8), such as 2-chromanones, chromans, 2-quinolones, tetrahydroquinolines, and tetralins possessing a halo functionality.33 Intermediates formed in halogen addition (X = Br, Cl, F) to alkynes (9) (ethyne, propyne, but-2-yne, trifluoromethylethyne, trimethylsilylethyne, and 1-trimethylsilylpropyne) have been studied computationally by MP2 at the MP2/6–311++G(3df,3pd) level and/or by DFT at the B3LYP/6–31+G(d) level (Scheme 1).34 Structure optimization and frequency calculations were performed to identify the minima and their relative energies. The PCM calculations (with H2 O, CH2 Cl2 , and CCl4 as model solvents) were employed to examine solvation effects on the relative stabilities in the resulting bridged halonium, β-halovinyl, or α-halovinyl cations. GIAO-MP2 and GIAO-DFT calculations were employed to compute the NMR chemical shifts (13 C, 19 F, and 29 Si as appropriate). In selected cases, PCM-GIAO calculations were also performed to investigate the extent of solvent effects on the computed NMR shifts. The NPA-derived charges and the GIAO shifts were examined in comparative cases to shed light on structural features. In several cases, structure optimization starting with the β-halovinyl cations (10) resulted in α-halovinyl cations (11) (via formal hydride shift or trimethylsilyl shift). With the CF3 derivative (when X = F), a formal F shift resulted in polyfluoroallyl cation generation from fluorovinyl cation as starting geometry.34 H

+

H C C H

H

X

H

+

X (9a)

H (10a)

Me3Si Me3Si

C C CH3

(11a)

+

CH3

Br

+

Br (9b)

SiMe3 CH3

( 10b)

(11b)

(X = Br, Cl, I)

Scheme 1

A DFT calculation study of the addition reaction between molecular bromine and a number of symmetrical or unsymmetrical substituted alkynes, R–C≡C–R (R = R =

de

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H, Me, t-Bu, or Ph; or R = H and R = Me, t-Bu, or Ph), was performed. Two possible reactions were investigated: (a) the reactions suitable for the gas-phase interactions, which start from a 1:1 Br2 –alkyne π -complex and do not enter into a 2:1 Br2 –alkyne π -complex; and (b) the processes passing through a 2:1 Br2 –alkyne π -complex, which appear more realistic for the reactions in solutions. The structures of the reactants and the final products and also the possible stable intermediates have been optimized and the transition states for the predicted process have been found. Both trans- and cis-dibromoalkenes may ensue without the formation of ionic intermediates from a π complex of two bromine molecules with the alkyne (solution reactions). The geometry around the double bond formed in dibromoalkenes strongly depends on the nature of the substituents at the triple bond. The ‘cluster model’ was used for the prediction of the solvent influence on the value of the activation barrier for the bromination of the but-2-yne.35 The cis-bromination of acetylenes (Scheme 2) has also been studied by a combination of extensive DFT calculations at the B3LYP/6–31G*+ZPE and B3LYP/6–31G (2df)+ZPE levels with an experimental elucidation of the bromination of 3,3,6,6tetramethylthiacycloheptyne-1,1-dioxide (a strained acetylene) at low temperature, using 13 C NMR spectroscopy. A new mechanism has been proposed to account for the predominant cis-bromination: thus, acetylene (12) first forms the expected π -complex (13), which then rearranges to the cis-bromotribromide species (15) via the transition state (14). The latter intermediate then collapses to cis-dibromide (16). Note that this mechanism excludes the participation of cationic intermediates. A similar mechanism, including a species analogous to (15), may also operate in certain alkenes, such as acenaphthylene, that are known to produce predominantly the corresponding syn-adducts.36 A variety of substituted isoindolin-1-ones (18) have been prepared in good to excellent yields under very mild conditions by the reaction of o-(alk-1-ynyl)benzamides (17) with ICl, I2 , and NBS,37 as a result of 5(N )-exo-dig cyclization.38 In a few Br Br H

H

H

Br Br

Br

H

H

Br

(13)

(14)

‡

Br Br

H

Br

H

(12)

Br

H

‡

Br

Br H

Br

Br

H

(16)

Br

Br

Br H

H (15)

Scheme 2

Br

de

de

293

11 Addition Reactions: Polar Addition O

O

O NHR1

I2NICl

N R1

N

+

R1 R2

R

2

I

(17)

I

R2

(18) O

(19) O

I+

I Br

Br (20)

(21)

cases, substituted isoquinolin-1-ones (19), originating from 6(N )-endo-dig ring closure, were obtained as the major products instead. This methodology accommodates various alkynylamides and functional groups and has been successfully extended to heterocyclic starting materials. An application to the synthesis of cepharanone B has been presented.37 An interesting intramolecular iodoarylation reaction of the heteroatom-tethered ωarylalkynes, such as (20), has been reported as an efficient route to benzofused heterocycles (21).39 Iodine, NIS, PhSeCl, and AuCl3 have been shown to trigger the electrophilic 6(O)π,n -endo-dig cyclization of 2-(alk-1-ynyl)alk-2-en-1-ones (22) to produce highly substituted furans (23) (Scheme 3). Various nucleophiles, including functionally substituted alcohols, H2 O, carboxylic acids, 1,3-diketones, and electron-rich arenes, and a range of cyclic and acyclic 2-(alk-1-ynyl)alk-2-en-1-ones readily participate in these cyclizations.40 R3

O R

E+

1

O

R1

R3

NuH

Nu

R2

E R

(22)

2

(23)

E = I+; Nu = ROH, RCO2H, H2O E = PhSe+; Nu = ROH E = H+ (AuCl3 cat.); NuH = ROH, enol, ArH

Scheme 3

294


+ ArBrI2

R (24)

BF3•Et2O

(25)

R

B

F•BF 3 Ar

(26)

Stereoselective Markovnikov addition of difluoro(aryl)-λ3 -bromane (25) to terminal acetylenes (24) has been reported, which gives rise to (E)-β-fluoroalkenyl-λ3 bromanes (26).41 An unprecedented halodephosphorylation of α,β-acetylenic and α,β-ethylenic phosphonic acid monoesters (27) and (29) with (biscollidine)bromine(I) or (biscollidine) iodine(I) hexafluorophosphate, leading to alkynyl (28) and vinyl halides (30), respectively, has been reported.42 O R1

P

OH OEt

(Coll)2Br+PF6− CH2Cl2

R1

(27) R1 R2

O P OH

Br (28)

(Coll)2X+PF6−

OEt (29)

R1 R2

X (30)

Iodoalkylation of 1,2-allenyl sulfides or selenides, ArXCH=C=CH2 (X = S or Se), with I2 in MeCN–ROH (20:1) has been shown to afford (Z)-3-alkoxy-2-iodopropenyl sulfides or selenides, ArXCH=C(I)–CH2 OR, in high stereoselectivity and moderate to good yields.43

Additions of ArSX, ArSeX, and Related Reagents with Electrophilic Sulfur Stereochemistry of the addition of a cyclic disulfonium dication generated from 1,4dithiane to alkenes has been shown to be non-stereospecific, presumably as a result of a stepwise mechanism.44 The PhSeCl-initiated electrophilic 6(O)π,n -endo-dig cyclization of 2-(alk-1-ynyl) alk-2-en-1-ones (22) to furans (23)40 has been mentioned earlier (Scheme 3).

Additions of Hydrogen Halides and Other Acids Hydrogen chloride, generated by mixing AcCl with EtOH, brings about Markovnikov hydrochlorination of alkenes in excellent yields. The products can be isolated in high purity by removal of the volatile components under reduced pressure.45 The Brønsted acidic anilinium salt [PhNH3 + ][− B(C6 F5 )4 ] has been developed as a catalyst for the hydroamination and hydroarylation of alkenes, such as styrenes, norbornene, cyclic alkenes, and cyclohexadiene, with anilines. The weakly coordinating

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counterion plays a key role in this transformation. The reaction can be tuned towards predominantly hydroamination or hydroarylation products by varying the reaction time, temperature, and substrate substitution.46 Hydration of o-thioquinone methide (32), generated by flash photolysis of (31) in aqueous solution, has been investigated.47 The reaction rates were measured in perchloric acid solutions, using H2 O and D2 O as the solvent, and also in acetic acid and aqueous tris(hydroxymethyl)methylammonium ion buffers. The rate profiles constructed from these data show hydronium ion-catalysed and uncatalysed hydration reaction regions, similar to those found for the oxygen analogue, i.e. o-quinone methide. However, the solvent isotope effects on hydronium ion catalysis of hydration of the two substrates were dramatically different: kH /kD = 1.66 for (32) and 0.42 for the oxygen quinone methide. The inverse nature (kH /kD < 1) of the isotope effect in the oxygen system indicates that this reaction occurs by a pre-equilibrium protontransfer mechanism, with protonation of the substrate on its oxygen atom being fast and reversible, whereas the capture of the benzyl cationic intermediate [an oxygen analogue of (33)] thus formed is rate determining. On the other hand, the normal direction (kH /kD > 1) of the isotope effect in the sulfur system (32) suggests that the protonation of the substrate at the sulfur atom is rate determining, while the carbocation capture is fast. A semiquantitative argument supporting this hypothesis has been presented.47 S

S

(31)

(32) H3O+ rds

SH

SH

fast

OH (34)

+

−H+

H2O

+

CH2 (33)

Additions of Electrophilic Oxygen N -Alkoxycarbonyl- and N -carboxamido-oxaziridines (35) have been developed as reagents capable of converting aromatic alkenes into epoxide, aziridine, or hydrooxidation products, in ratios depending on the oxaziridine structure. Chiral oxaziridines can effect epoxidation and hydrooxidation with promising levels of asymmetric induction.48 Stereo- and regio-selective epoxidation of tricyclic trienes, such as (36), followed by Lewis acid-catalysed opening of the resulting monoepoxide with alcohols, has been reported to occur exclusively at the vinyl terminus of unsaturated system through a typical SN 2 process, affording 1,6-dioxygenated derivatives (e.g. 37).49

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296


O N

Y

O Z (35)

CO2Me

CO2Me

HO

OR′

1. MCPBA 2. R′OH Lewis acid

R

R

(36)

(37)

Using a relative rate method, rate constants for the gas-phase reactions of O3 with 1- and 3-methylcyclopentene, 1-, 3- and 4-methylcyclohexene, 1-methylcycloheptene, cis-cyclooctene, 1- and 3-methylcyclooctene, cycloocta-1,3- and 1,5-diene, and cycloocta-1,3,5,7-tetraene have been measured at 296 ± 2 K and atmospheric pressure. The rate constants obtained (in units of 10−18 cm3 molecule−1 s−1 ) are as follows: 1-methylcyclopentene, 832 ± 24; 3-methylcyclopentene, 334 ± 12; 1-methylcyclohexene, 146 ± 10; 3-methylcyclohexene, 55.3 ± 2.6; 4-methylcyclohexene, 73.1 ± 3.6; 1methylcycloheptene, 930 ± 24; cis-cyclooctene, 386 ± 23; 1-methylcyclooctene, 1420 ± 100; 3-methylcyclooctene, 139 ± 9; cis,cis-cycloocta-1,3-diene, 20.0 ± 1.4; cycloocta-1,5-diene, 152 ± 10; and cycloocta-1,3,5,7-tetraene, 2.60 ± 0.19; the indicated errors are two least-squares standard deviations and do not include the uncertainties in the rate constants for the reference alkenes (propene, but-1-ene, cis-but-2-ene, trans-but-2-ene, 2-methylbut-2-ene, and terpinolene). These rate data were compared with the few available literature data, and the effects of methyl substitution have been discussed.50

Additions of Electrophilic Nitrogen A highly diastereoselective aziridination of 8-phenylmenthol-derived α,β-unsaturated esters (38) with 3-acetoxyamino-2-ethylquinazolinone (39) has been reported. The yields of the resulting aziridines (40) were greatly improved in the presence of hexamethyldisilazane.51

R3

CO2Menth

R2

R1

Q +

HMDS

N O

N

CH2Cl2 −18 °C

R3

N

R2

R1

H NOAc (38)

(39)

CO2Menth

(40)

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Additions of Electrophilic Carbon The reactions of aryl aldehydes Ar1 CH=O with styrene derivatives Ar2 CH=CH2 , mediated by various boron Lewis acids, have been investigated. 1,3-Dihalo-1,3-diarylpropanes, Ar1 CH(X)CH2 CH(X)Ar2 (X = Cl, Br, I), were obtained in high yields with boron trihalides (BX3 ), whereas 3-chloro-1,3-diarylpropanols, Ar1 CH(OH)CH2 CH(X) Ar2 , were obtained in good to excellent yields with phenylboron dichloride (PhBCl2 ).52 Triethysilyl-protected peroxycarbenium ions (42), generated from acetals (41) on treatment with SnCl4 , have been developed as the optimal reagents to effect addition to alkenes, which gives rise to a variety of 1,2-dioxolanes (43) in 28–92% yields. This novel method allowed the synthesis of plakinic acid analogues in three steps from the corresponding ketone and alkene.53

Et3SiO

OSiEt3

O

O

R1

R2

SnCl4

Et3SiO

R3 +

O

R1

(41)

R4

R1

(28–92 °C)

R2

O O

R2

(42)

R3 R4

(43)

Vinyl pyrazines (44) have been shown to react with benzene in the presence of CF3 SO3 H to afford anti-Markovnikov-type addition products (45). This unusual outcome suggests that acid-catalysed addition reactions can give anti-Markovnikov-type products when a multiply charged (i.e. superelectrophilic) group is adjacent to the alkene.54 N

C6H6 CF3SO3H 80 °C

N

N Ph

N

(44)

(45)

Ene cyclization of a variety of 4-aza-1,7-dienes (46) (R1 = H, R2 = CO2 Me; R1 = R = CO2 Me) affords 3,4-disubstituted piperidines (47) with up to >200:1 diastereoisomeric ratios for the reactions catalysed by MeAlCl2 .55 This high preference for the 2

Ts N

R1

Ts N

Lewis acid

R2 (46)

R1

R2 (47)

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trans-product contrasts with the behaviour of extremely bulky Lewis acids that are known to favour the formation of the cis-isomers.56

Additions Initiated by Metals and Metal Ions as Electrophiles Treatment of pyridine borane (Py·BH3 ) with iodine, bromine, or strong acids affords activated Py·BH2 X complexes that are capable of hydroborating alkenes at room temperature. Evidence has been presented for an unusual hydroboration mechanism, involving a leaving group displacement. In contrast to THF·BH3 , hydroboration with Py·BH2 I selectively affords the monoadducts. The crude hydroboration products can be converted into potassium alkyltrifluoroborate salts (R–BF3 − K+ ) upon treatment with methanolic KHF2 .57 The hydroboration of stilbenes and related disubstituted alkenes catalysed by QUINAP complexes may proceed with high enantio- and regio-selectivity [(48) → (49)]; rhodium and iridium catalysts give the same regioisomer but opposite enantiomers.58 O O

O

O

CF2 CF2

O

O O

(48)

R1

R2 (50)

CF2 CF2

OH (49)

O

R3

O

ee

+

O B B

O

O (51)

1. [Rh], QUINAP 2. H2O2

R3 R2 HO

R1 OH

(52)

The rhodium-catalysed reaction between simple alkenes (50) and bis(catecholato) diboron (51) has been reported to result in the syn addition of the diboron across the alkene. The 1,2-bis(boronate) thus obtained was subsequently oxidized to provide the corresponding 1,2-diol (52). In the presence of QUINAP ligand, high enantioselection in the diboration was attained. The reaction was found to be highly selective for trans- and trisubstituted alkenes and can also be selective for some monosubstituted alkenes.59 The Pd-catalysed three-component coupling of readily available aryl iodides (53), internal alkynes (54), and arylboronic acids (55) has been developed as a one-step, regio- and stereo-selective route to tetrasubstituted alkenes (56) in good to excellent yields, although electron-poor aryl iodides and dialkylalkynes normally afford only low yields under standard reaction conditions. The right combination of substrates and reaction conditions has been shown to be important for attaining high yields. The presence of water substantially increased the yields of the desired tetrasubstituted

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R2 +

ArI + R1

R3B(OH)2

R1

[Pd]

R2 R3

Ar (53)

(54)

(55)

(56)

alkenes. The reaction is believed to involve syn addition of the aryl group from the aryl iodide to the less hindered or more electron-rich end of the alkyne, while the aryl group from the arylboronic acid adds to the other end.60 Reaction of (diisopropylamino)chloroboryl ethers of alkynols (57) with alkynylstannanes (58) in the presence of nickel catalysts has been reported to afford formal trans-alkynylboration products (60), which could undergo the Suzuki–Miyaura coupling with organic halides. The 2-borylalkenylnickel(II) complex (59) was isolated as an intermediate in a reaction of the chloroboryl ether (57) with 1 equiv. of a nickel(0)–phosphine complex and characterized by X-ray crystallography.61 Pr 2i N O R1

B

SnBu3 Cl

R2

+

( )n

O R1

R3

(57)

Pr 2i N

L2NiCl2 (2 mol%)

(58)

B

Pr 2i N

R2

O

L Ni L Ce ( 59)

B

R2

R1 (60

R3

The reactions of terminal alkynes RC≡CH with allylgallium reagents, generated in situ from gallium and allyl bromides, CH2 =C(R )CH2 Br, give the corresponding 1,4dienes CH2 =C(R)CH2 C(R )=CH2 in good yield via Markovnikov addition in THF at 70 ◦ C.62 The mercury(II) trilate-catalysed cyclization of (61) has been developed as the first example of Hg(II)-catalysed biomimetic cascade cyclization, which gave rise to the tricyclic product (62) in 98% yield with up to 100 catalytic turnovers.63 Ab initio simulation of Lewis acid-catalysed hydrosilylation of alkynes has been reported.64 Hydrosilylation of terminal alkynes, such as diethynylarenes, with MeO MeO

OMe

OMe (TfO)2Hg (1 mol%) MeNO2, 0 °C, 6 min

H

(61)

(62)

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HSiMe2 Ph, catalysed by the complex of ruthenium with a diphosphinidenecyclobutene ligand, has been shown to proceed with high Z-selectivity.65 Hydrosilylation of terminal alkynes RC≡CH with a variety of silanes R3 SiH, catalysed by the Grubbs metallocarbene Cl2 (Cy3 P)2 Ru=CHPh, afforded mainly the Z-adducts (Z)-RCH=CHSiR3 via anti addition in excellent yields. Intramolecular hydrosilylation of a homopropargylic silyl ether was shown to give the syn addition product.66 A highly regioselective hydroselenation of terminal alkynes RC≡CH with benzeneselenol (PhSeH) can be achieved in the presence of palladium acetate as catalyst in pyridine, giving rise to the corresponding terminal alkenes R(PhSe)CH=CH2 as the sole products. Here, the pyridine is believed to serve as a ligand for active palladium intermediates.67 Bu2 Sn(OTf)H, readily prepared from Bu2 SnH2 and TfOH, has been found to be a valuable reagent for highly regio- and stereo-selective hydrostannylation of various propargyl alcohols R1 R2 C(OH)–C≡CR3 , affording (Z)-γ -stannylated allyl alcohols R1 R2 C(OH)–CH=C(R3 )SnBu3 . The latter stannylation is applicable to the synthesis of hydroxy-substituted (Z)-vinylstannanes from terminal alkynes bearing a hydroxy group at the homoallylic or bishomoallylic position. The coordination of the hydroxy group to the Lewis acidic tin centre is believed to play the key role in determining the regio- and stereo-chemistry of this reaction.68 The hydrostannation of activated alkynes RC≡CCOX with Bu3 SnH, catalysed by [(Ph3 P)CuH]6 , proceeds with exclusive regioselectivity, planting the tin group into the α-position [RCH=C(SnBu3 )COX]. Interestingly, syn hydrostannation was observed for alkynoates RC≡CCO2 R , whereas anti or syn adducts were obtained from alkynones RC≡CCOR . Coordination of the Cu to both the triple bond and Bu3 SnH has been suggested.69 A highly efficient inter- and intra-molecular addition of 1,3-diketones/β-keto esters to styrenes (ArCH=CH2 ) has been developed. Silver triflate was identified as the most efficient catalyst (10 mol%). The reaction, affording formally the Markovnikov products, is reversible through the cleavage of a carbon–carbon bond by silver at an elevated temperature.70 Intramolecular hydroamination of aminoalkenes CH2 =CH(CH2 )n CH2 NH2 and the corresponding alkynes can be catalysed by the calcium β-diketiminato complex [{HC (C(Me)2 N-2,6-Pri2 C6 H3 )2 }Ca{N(SiMe3 )2 }(THF)] to produce the corresponding pyrrolidines and piperidines.71 A detailed study of the regioselective hydroamination of terminal alkynes in the presence of (Et2 N)4 Ti and various aryloxo and alkoxo ligands has demonstrated that depending on the ligand, the regioselectivity towards the Markovnikov and the antiMarkovnikov addition product can be controlled. The experimentally observed isomer distribution has been rationalized by theoretical investigation; apparently, the regioselectivity is determined by the relative stability of the corresponding alkynetitanium π -complexes.72 The synthesis of the pyrazino[1,2-a]indole nucleus (64)/(65) was attained by intramolecular cyclization of several 2-carbonyl-1-propargylindoles (63) in the presence of ammonia. The reaction conditions were optimized using microwave heating and a

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11 Addition Reactions: Polar Addition R N

R

NH3

N

O

R

R +

N

N R1

1

(63)

N R1

(64)

(65)

library of catalysts. Cyclization of 1-alkynylindole-2-carbaldehydes was easily accomplished under standard heating conditions; microwave heating further accelerated the reaction and improved overall yields. Moreover, fine tuning of the microwave irradiation time allowed the selective synthesis of both pyrazino[1,2-a]indole isomers. TiCl4 proved to be the catalyst of choice to obtain pyrazinoindoles in good yields, starting from 1-alkynyl-2-acetylindoles and 1-alkynyl-2-benzoylindole derivatives. The uncatalysed versus catalysed reaction mechanism was discussed.73 Titanium alkoxide-mediated coupling of functionalized allenes and acetylenes afforded various types of products; the first propargyltitanation of acetylenes was achieved by the appropriate choice of allenes.74 (Z)-Phenol-substituted alkenes (67) can be produced by the palladium(0)-catalysed reaction of propargylic oxiranes (66) with phenols. This regio- and stereo-selective addition is believed to occur via the formation of π -propargyl- and π -allylpalladium complexes. The phenoxy-substituted enones were obtained as by-products and their proportion depended on the reaction conditions.75 O

O R

R

ArOH

OAr

Pd (0)

(66)

de

(67)

The intermolecular hydroamination of alkynes, catalysed by the aquapalladium complex [(dppe)Pd(H2 O)2 ](OTf)2 , has been reported. The reaction is believed to proceed through the equilibrium between the hydroxopalladium and the amidopalladium complexes, followed by aminopalladation of alkynes.76 Regioselective 1,2-diamination of 1,3-dienes by dialkylureas, catalysed by (MeCN)2 PdCl2 in the presence of 1 equiv. of p-benzoquinone, has been developed as a highly efficient method.77 The first examples of direct palladium-catalysed arylation and heteroarylation of cyclopropenes with ArI, catalysed by (AcO)2 Pd, have been reported. Mechanistic studies strongly suggest an electrophilic mechanism for this Heck-type transformation.78 A stereoselective synthesis of substituted tetrahydrofurans (69) via Pd-catalysed reactions of aryl and vinyl bromides with γ -hydroxy terminal alkenes (68) has been described. This transformation affords trans-2,5- and trans-2,3-disubstituted tetrahydrofurans with up to >20:1 dr. This methodology also provides access to bicyclic and spirocyclic tetrahydrofuran derivatives in good yield with 10–20:1 dr. The effect of

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Organic Reaction Mechanisms 2005 OH R

ArBr, Pd (0)

R

ButONa

(68)

Ar O (69)

substrate sterics and electronics on yield and stereoselectivity has been investigated and discussed and a plausible mechanism has been proposed.79 Palladium-catalysed hydrosilylation of reactive alkenes, such as norbornene, with silanes R3 SiH, chiral at the silicon atom, has been reported to occur with asymmetric amplification.80 Palladium-catalysed addition of cyanoboranes Y2 B–CN, [Y2 = (i-Pr)2 NCH2 CH2 N (i-Pr)2 ], to alkynes, such as Ar-C≡CR, produces the Z-configured α,β-unsaturated β-boryl nitriles ArC(CN)=C(BY2 )R with good regio- and stereo-selectivity.81 The new metallocarbene complex 1,3-bis(2,6-diisopropylphenyl)-4,5-dimethyl-3H imidazolidenylpalladium(0) has been reported to catalyse the dimerization of butadiene in the presence of propan-2-ol to afford octa-1,3,7-triene, rather than the usual telomerization products, typical for other palladium catalysts. The new catalyst is characterized by an unprecedented efficiency (TON > 80 000 and TOF > 5000 h−1 ).82 The PdCl2 -catalysed cyclocarbonylation of propargylic amines (70) with CuCl2 and p-benzoquinone afforded (E)-α-chloroalkylidene-β-lactams (71) in moderate to good yields. The formation of the corresponding Z-isomers or five-membered ring products was not observed. The stereoselectivity in this reaction is different from that observed with propargylic alcohols; a mechanistic rationale has been proposed.83

ee

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Cl NHR3

PdCl2 (5 mol%) CuCl2 (2 equiv.)

R2

R–BQ (1 equiv.) CO (300 psi), THF, 40 °C

R1 (70)

R2

R1 N O

R3

(71)

Four cationic palladium intermediates in the Pd(0)-catalysed three-component cascade double addition–cyclization of organic halides, 2-(2,3-allenyl)malonates, and imines have been characterized by the high-resolution ESI-FTMS technology.84 Pyrroles and thiophenes have been found to react with alkynes in the presence of dinuclear palladium complexes with high cis stereoselectivity in almost all cases. Whereas regioselectivity in the reaction with pyrroles depends on the substituents on the nitrogen atom and alkynes, all reactions of thiophenes afforded 2-alkenylthiophenes.85 A palladium(0)-catalysed cascade cyclization–Suzuki coupling reaction of various 1,6-enynes (72) with ArB(OH)2 has been developed as a new approach to the synthesis of stereodefined α-arylmethylene-γ -butyrolactones, lactams, multifunctional tetrahydrofurans, pyrrolidines, and cyclopentanes (73) (X = O, H2 , Y = O, CH2 , NR3 ). A π -allylpalladium intermediate and a chair-like transition state were suggested to account for the stereochemistry of this reaction.86

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11 Addition Reactions: Polar Addition R1

Cl

Ar ArB (OH)2

X

Y

Pd (0)

R2

R1 X

R2

Y

(72)

(73)

The N ,N ,N ,N -tetramethylthiourea–Pd complex has been established as a novel type of catalyst for the Pauson–Khand reaction of allylpropargylamines.87 With 1-alkoxyallenes as proelectrophiles, the palladium-catalysed asymmetric allylic alkylation proceeds with 1,3-dicarbonyl compounds as pronucleophiles with excellent regioselectivity; good enantioselectivity (82–99% ee) was obtained with the Trost ligand. The pH of the medium proved crucial for the reactivity and selectivity. By using the more acidic Meldrum’s acids, the reactions required a co-catalytic amount of a Brønsted acid, such as CF3 CO2 H. On the other hand, the less acidic 1,3-diketones failed to react under these conditions but the reaction proved to occur in the presence of the weaker benzoic acid, suggesting the need for general base catalysis. Indeed, a mixture of Et3 N and PhCO2 H proved to be optimal (93–99% ee). A mechanistic model to rationalize these results has been developed.88 The Pd-catalysed inter- and intra-molecular additions of cyclic amides (75) (nitrogen pronucleophiles) to methylenecyclopropanes (74) has been developed. This reaction proceeded smoothly in the presence of catalytic amounts of (Ph3 P)4 Pd to afford the corresponding hydroamination products (76) in good to high yields with high regioselectivities. The ring opening of methylenecyclopropanes occurs at the distal position of the cyclopropane ring.89 R1 + HN R2

O O

(74)

(75)

(Ph3P)4 Pd 120 °C

R1

N R2

O O

(76)

Electron-rich, electron-poor, and hindered styrenes (ArCH=CH2 ) undergo hydroamination with carboxamides (e.g. PhCONH2 ) in the presence of a 1:2 mixture of [PtCl2 (H2 C=CH2 )]2 and (4-CF3 C6 H4 )3 P (5 mol%) in mesitylene at 140 ◦ C for 24 h, to produce (PhCONH)CH(Me)Ar in moderate to good yields with excellent Markovnikov selectivity.90 Electrophilic Pt(II) complexes have been shown to catalyse efficient hydroaminations of alkenes by sulfonamides and weakly basic anilines. Catalysts include the structurally characterized complex (COD)Pt(OTf)2 and the known dimer [(C2 H4 )PtCl2 ]2 , activated by AgBF4 . Experiments with substituted anilines established an empirical pKa cut-off (conjugate acid pKa < 1) for the participation of nitrogen substrates in this

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catalysis. Arylsulfonamides (conjugate acid pKa ≈ −6) with various para-substituents hydroaminate alkenes, such as cyclohexene, in ≥95% yields at 90 ◦ C. Hydroamination of propylene by p-toluenesulfonamide proceeds with Markovnikov selectivity, suggesting a mechanism that involves alkene activation at Pt. With norbornene and p-toluenesulfonamide as the substrates and (COD)Pt(OTf)2 as the catalyst, intermediate [(COD)Pt(norbornene)2 ][OTf]2 was identified and characterized by 19 F and 195 Pt NMR spectroscopy and mass spectrometry. Kinetic studies provide the empirical rate law, rate = kobs [Pt][sulfonamide], consistent with a mechanism in which attack of a sulfonamide on the Pt-coordinated alkene is the rate-determining step.91 Platinum-catalysed intramolecular hydroamination of unactivated alkenes with secondary alkylamines has been reported. Thus, a number of γ - and δ-aminoalkenes reacted in the presence of a catalytic 1:2 mixture of [PtCl2 (H2 C=CH2 )]2 (2.5 mol%) and PPh3 in dioxane at 120 ◦ C for 16 h to form the corresponding pyrrolidine derivatives in moderate to good yields. The reaction displayed excellent functional group compatibility and low moisture sensitivity.92 A new class of benzimidazolylidene carbene–Pt(0) complexes has been developed and used to catalyse efficiently the hydrosilylation of alkenes.93 Three-component cross-coupling reactions between 3-iodopyridines, terminal alkynes (RC≡CH), and ArSK took place in the presence of (Ph3 P)4 Pt as catalyst to give the Z-configured pyridine derivatives (3-C5 H4 N)CH=C(R)SAr with conjugated vinyl groups in moderate yields.94 Internal aryl alkynes ArC≡CR with ortho- or para-substituents (NO2 , CN, CHO, CO2 Et, CH2 OAc, i-Pr) undergo a hydrosilylation reaction with Et3 SiH, catalysed by PtO2 and H2 PtCl6 to produce ArC(SiEt3 )=CHR. The regioselectivity of the H–Si bond addition was found to be controlled by the ortho substituent rather than the nature of the platinum catalyst. Arylalkynes with an ortho substituent, regardless of its electronic nature, direct the silyl substituent mainly to the α-position. PtO2 proved to be a versatile and powerful catalyst compared with H2 PtCl6 , since it prevents the alkyne reduction.95 Addition of ethoxalyl chloride (ClCOCO2 Et) to terminal alkynes at 60 ◦ C in the presence of a rhodium(I)–phosphine complex catalyst affords 4-chloro-2-oxoalk-3enoates regio- and stereo-selectively; functional groups (Cl, CN, OR, OSiR3 , and OH) are tolerated. The oxidative addition of ethoxalyl chloride to [(R3 P)2 RhCl(CO)] proceeds readily at 60 ◦ C or room temperature and gives [RhCl2 (COCO2 Et)(CO)(PR3 )2 ] (R3 P = Ph2 MeP, PhMe2 P, Me3 P) complexes in high yields; the structure of [(Ph2 Me)2 PRhCl2 (COCO2 Et)(CO)] was confirmed by X-ray crystallography. Thermolysis of these ethoxalyl complexes has revealed that those ligated by more electron-donating phosphines are fairly stable against decarbonylation and reductive elimination; [(Ph2 MeP)2 RhCl2 (COCO2 Et)(CO)] reacts with oct-1-yne at 60 ◦ C to form ethyl 4-chloro2-oxodec-3-enoate. Therefore, the reaction is likely to proceed via oxidative addition of ethoxalyl chloride, followed by insertion of an alkyne into the Rh–Cl bond of the resulting intermediate, and reductive elimination of alkenyl–COCO2 Et.96 Rhodium perfluorobutyramide, (pfm)4 Rh2 , has been shown to catalyse the conversion of alkenes to trichloroethoxysulfonyl, nosyl, and tosyl aziridines on reaction with the corresponding sulfonamide and PhI(OAc)2 .97

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A mild, efficient, and selective aziridination of alkenes catalysed by dirhodium(II) caprolactamate [(cap)4 Rh2 ·2CH3 CN] has been reported. The use of p-toluenesulfonamide (TsNH2 ), N -bromosuccinimide (NBS), and potassium carbonate leads to aziridines in ≤95% yields under mild conditions with as little as 0.01 mol% (cap)4 Rh2 . Aziridine formation occurs through an Rh2 5+ -catalysed aminobromination, followed by a base-induced ring closure. An X-ray crystal structure of an Rh2 5+ –halide complex, resulting from the reaction between (cap)4 Rh2 and N -chlorosuccinimide, has been presented to support the mechanism.98 The mechanism of cyclopropenations of alkynes with ethyl diazoacetate, catalysed by (AcO)4 Rh2 and (DPTI)3 Rh2 (OAc), has been studied by a combination of kinetic isotope effects and theoretical calculations. With each catalyst, a significant normal 13 C KIE was observed for the terminal acetylenic carbon, while a very small 13 C KIE was detected at the internal acetylenic carbon. These isotope effects are consistent with the canonical variational transition structures for cyclopropenations with intact tetrabridged rhodium carbenoids but not with a 2 + 2-cycloaddition on a tribridged rhodium carbenoid structure.99 1,6-Enynes (77) can react with arylboronic acids in the presence of a catalytic amount of a rhodium(I) complex under mild conditions to give (Z)-1-(1-arylethylidene)-2-vinylcyclopentanes (78).100 In analogy, the rhodium-catalysed cyclization of the cyano-substituted alkynes (79) with arylboronic acids has been reported to produce the cyclic ketone (80) as the first example of a nucleophilic addition of an Rh(I) species to a cyano group.101

de

Me Me X

ArB(OH)2 Rh (I) Ln

Ar X

OMe (77)

(78) R

MeO2C MeO2C

R C N (79)

ArB(OH)2 Rh (I) Ln

MeO2C

Ar

MeO2C

O (80)

An enantioselective rhodium(II)-catalysed intramolecular cyclopropanation, followed by a regioselective allylic alkylation and a diastereoselective rhodium(I)-catalysed 5 + 2-cycloaddition has been reported.102 A detailed mechanistic investigation revealed the steps of the anti-Markovnikov hydroamination of vinylarenes (81) with alkylamines catalysed by (COD)Ru(2-methylallyl)2 , bis(diphenylphosphino)pentane, and TfOH. Treatment of the catalyst components with an excess of styrene under the catalytic conditions afforded a new

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ruthenium η6 -styrene complex with an ancillary tridentate PCP ligand. This ruthenium complex proved to be an active catalyst for the hydroamination of styrene with morpholine to give the anti-Markovnikov adduct (82) as a single regioisomer in high yield. Investigation of the reactivity of the η6 -styrene complex revealed two reactions that comprise a catalytic cycle for the anti-Markovnikov hydroamination: nucleophilic addition of morpholine to the ruthenium η6 -styrene complex (81) to afford a ruthenium η6 -(2-aminoethyl)benzene complex (82) and arene exchange of the ruthenium η6 -(2aminoethyl)benzene complex (82) with styrene to regenerate the ruthenium η6 -styrene complex (81). The addition of morpholine and the exchange of arene occurred with comparable rates. These results have been interpreted as strongly suggesting that the ruthenium-catalysed anti-Markovnikov addition of alkylamines to vinylarenes occurs by a new mechanism, involving nucleophilic attack on the η6 -vinylarene complex and exchange of the aminoalkylarene complex product with free vinylarene. This mechanism is a rare example of catalytic chemistry through π -arene complexes and the mechanistic data accumulated were used to select derivatives of the DPPP ligand that improve the rates of the catalytic process.103 NR2 R2NH

Ph2P

+

Ru

PPh2

Ph2P

H +Ph

(81)

−Ph

arene exchange

NR2

+

Ru

PPh2

H (82)

The kinetics of enyne metathesis, catalysed by the Grubbs’ second-generation Ru catalyst, i.e. (dihydrolMes)(Cy3 P)Cl2 Ru=CHPh, were studied by IR spectroscopy for a variety of alkyne–alkene combinations (R–C≡CH and R –CH=CH2 ). The rate law was determined for alkyne–ethylene and alkyne–hex-1-ene cross metathesis. In the cases examined, greater substitution on the alkyne accelerates the rate of metathesis, and chelation by propargylic esters was ruled out through rate comparison with hydrocarbon alkynes. These findings were discussed in terms of an alkylidenefirst reaction mechanism, phosphine-bound ruthenium carbene resting states, and the rate-determining turnover of vinylcarbene intermediates (for alkyne–hex-1-ene metatheses).104 A Hammett plot for the overall reaction, catalyst initiation, and vinylcarbene turnover has also been determined.105 An Ru-catalysed anti-Markovnikov addition of secondary amides, anilides, lactams, ureas, bislactams, and carbamates to terminal alkynes has been investigated. Two complementary protocols have been developed that provide stereoselective entries to either the E- or the Z-isomers of the resulting enamides.106 Good enantioselectivities and excellent regioselectivities have been attained in the Rh-catalysed asymmetric hydroformylation of 2,5- and 2,3-dihydrofuran using diphosphite ligands, resulting in the formation of the 3-formyltetrahydrofuran in both

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11 Addition Reactions: Polar Addition Ph

Ph P

P Ph

P

H

H

P

Ph

(83)

(84)

instances. The backbone of the diphosphite ligands employed proved to be crucial to suppressing isomerization and obtaining high enantioselectivities.107 A highly regio- and enantio-selective hydroformylation of alkenes, such as PhCH= CH2 , CH2 =CHCH2 CN, and CH2 =CHOAc, catalysed by ruthenium complexes with 2,5-disubstituted phospholane ligands has been reported. With (83) as the ligand, the turnover rates over 4000 h−1 at 80 ◦ C, have been attained.108 (Acac)Rh(CO)2 – TangPhos [Tangphos = (84)] has been developed as a new enantioselective catalyst for asymmetric hydroformylation of norbornene and other [2.2.1]-bicyclic alkenes (55–92% ee).109 A theoretical investigation of solvent effects on hydroformylation has been carried out at the B3LYP/6–31G (d,p) level (LANL2DZ + Polar for Rh, P) via the Onsager model. All stagnation points in the reaction potential profile were optimized completely for cyclohexane (ε = 2.02), benzene (ε = 2.25), THF (ε = 7.58), CH2 Cl2 (ε = 8.93), MeOH (ε = 32.63), and H2 O (ε = 78.39) as solvents. The free energies and activating free energies were also calculated at the same level and the data obtained for different solvents were compared at all points. This study demonstrated that the activating free energies decrease with increasing of the ε value of the solvent. Therefore, water with ε = 78.39 as solvent for hydroformylation of alkenes is regarded as being better than the others. These theoretical results are consistent with experimental observations.110 An intermolecular hydroacylation of alkynes or electron-poor alkenes (e.g. CH2 = CHCO2 Me) with β-thioacetal-substituted aldehydes, catalysed by [(dppe)Rh]ClO4 , has been reported to occur in acetone at 50 ◦ C. The reaction is believed to proceed via a chelated rhodium acyl intermediate.111 TpRu(PPh3 )(CH3 CN)2 PF6 (10 mol%) catalyst has been shown to effect the nucleophilic addition of water, alcohols, aniline, acetylacetone, pyrroles, and dimethyl malonate to unfunctionalized enediynes (85) under suitable conditions (100 ◦ C, 12–24 h), resulting in the formation of the functionalized benzene products (86) in good yields (Scheme 4). In this novel cyclization, nucleophiles very regioselectively attack the internal C(1 ) alkyne carbon of enediynes to give benzene derivatives as a single regioisomer. Experiments with methoxy substituents excluded the possible involvement of naphthyl cations as reaction intermediates in the cyclization of (o-ethynylphenyl) alkynes. Deuterium labelling experiments indicate that ruthenium–π -alkyne rather than ruthenium–vinylidene is the catalytically active species. Aromatization of o-(2 iodoethynyl)phenylalkynes with alcohols lends further credence to this hypothesis. A nucleophilic addition–insertion is believed to be the mechanism for this nucleophilic aromatization.112 The cationic ruthenium complex [(Cy3 )2 P(CO)(Cl)Ru=CHCH=C(CH3 )2 ]+ BF4 − has been identified as an effective catalyst for the coupling reaction of aniline and

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Nu NuH [Ru+]

R1 (85)

R4

2

R3

R1

R4

R

(86)

R3 = H, Me, Et R4 = H, I NuH = H2O, ROH, PhNH2 Pyrrole, MeCOCH2CO2Et, CH2 (CO2Me)2 Scheme 4

ethylene to form a ∼1:1 ratio of N -ethylaniline and 2-methylquinoline. The analogous reaction with 1,3-dienes resulted in the preferential formation of Markovnikov addition products. The normal isotope effect of kNH /kND = 2.2 (aniline and aniline-d7 at 80 ◦ C) and the Hammett ρ = −0.43 (correlation of para-substituted p-X-C6 H4 NH2 ) suggest an N–H bond activation as the rate-limiting step.113 Facile, regioselective ring opening–cross-metathesis reactions between unsymmetrical norbornene derivatives and electron-rich alkenes in the presence of the secondgeneration Grubbs catalyst have been reported to generate highly substituted furans and pyrroles.114 A ruthenium-catalysed hydrative cyclization of enynes has been developed. The reaction converts a range of 1,5-enynes bearing terminal alkyne and Michael acceptor moieties (87) into cyclopentanone derivatives (90). From extensive catalyst screening experiments, a trinuclear ruthenium complex, [(dppm)3 Cl5 Ru3 ]PF6 , has been identified as an effective catalyst in mediating the 1,1-difunctionalization of alkynes. The authors proposed that this novel umpolung reaction proceeds through the formation of a ruthenium vinylidene (88), anti-Markovnikov hydration, and intramolecular Michael addition of the acyl ruthenium (89) to the activated double bond.115 Allylic and propargylic hydrazines were obtained via the new cobalt-catalysed hydrohydrazination reaction of dienes and enynes; the reaction occurs with good chemo- and regio-selectivity.116 The [HCo(CO)3 ]-catalysed hydroformylation of allene and propyne has been investigated at the B3LYP level of density functional theory. The calculations suggest that hydroformylation of allene favours the linear anti-Markovnikov product in high regioselectivity both kinetically and thermodynamically. The origin of this regioselectivity stems from the enhanced stability of the η3 -allylic intermediate [(η3 -CH2 CHCH2 )Co (CO)3 ]. By contrast, propyne did not exhibit any regioselectivity. The possible interconversion between allene and propyne, mediated by the catalyst, has also been explored.117

309

11 Addition Reactions: Polar Addition EWG

EWG

H2O [(dppm)3Ru3Cl2]PF6 dioxane, 120 °C, 12 h

(87)

•

[Ru]

(88) H2O

EWG

EWG [Ru]–H

O

O (89)

(90)

Novel chiral Robson-type tetraimine macrocyclic complexes with Co(II), Co(III), Mn(II), and Mn(III) have been synthesized by metal template condensation of 2,6diformyl-4-methylphenol with (1R,2R)-diaminocyclohexane or (1R,2R)-diphenylethylenediamine. The dinuclear Co(II) and Co(III) complexes were shown to catalyse asymmetric cyclopropanation of styrene with diazoacetate cooperatively and with high enantioselectivity.118 A wide range of substituted isoquinolines (93) have been synthesized via a highly efficient nickel-catalysed annulation of the t-butylimines of 2-iodobenzaldehydes (91) and various alkynes (92); examination of the regiochemistry of the reaction revealed the operation of two different alkyne insertion pathways.119 R1

N

R2

But + R3

R4

I

(dppe) NiBr2 Zn, MeCN 80 °C, 0.2–3 h

R1

N

R2

R4 R3

(91)

(92)

(93)

The mechanism of the unprecedented chromium-catalysed selective tetramerization of ethylene to oct-1-ene has been investigated. The unusually high oct-1-ene selectivity of this reaction apparently results from the unique extended metallacyclic mechanism in operation. Both oct-1-ene and higher alk-1-enes were formed by further ethylene insertion into a metallacycloheptane intermediate, whereas hex-1-ene was formed by elimination from this species as in other trimerization reactions. Further mechanistic support was obtained by deuterium labelling studies, analysis of the molar distribution of alk-1-ene products, and identification of secondary co-oligomerization reaction products. A bimetallic disproportionation mechanism was proposed to account for the available data.120

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The Pauson–Khand reaction, promoted by (CO)3 Mo(DMF)3 , has been found to take place under very mild conditions in the absence of any promoter. High yields of the adducts were obtained in the cyclization of a wide variety of functionalized 1,6- and 1,7-enynes. Enynes bearing electron-withdrawing groups at the alkene terminus proved to be particularly good substrates.121 The exclusive formation of cyclopentenones was observed in the molybdenum hexacarbonyl (10 mol%)-catalysed Pauson–Khand reactions of 1,6-allenynes under 1 atm of CO (balloon) in excellent yields.122 The tungsten(II) carbonyl complex (CO)4 W(μ-Cl)3 W(SnCl3 )(CO)3 has been identified as a very effective catalyst for the hydroarylation of norbornene conducted in arene solution at room temperature. Norbornene adducts with benzene, toluene, p-xylene, and mesitylene have been isolated. On the basis of 1 H NMR monitoring of several catalytic reactions, a possible mechanism, involving coordination of norbornene to the W(II) atom and its activation, has been proposed.123 According to a detailed study of the relationship between the stereochemical elements of a phosphoramidite ligand and the stereoselectivity of iridium-catalysed amination of allylic carbonates, catalyst activation proceeds as follows: a complex of a phosphoramidite ligand possessing one axial chiral binaphtholate group and two homochiral phenethyl substituents (94) is converted into a more reactive cyclometallated complex containing one distal chiral substituent at nitrogen, one substituent that becomes part of the metallacycle, and one unperturbed binaphtholate group. Systematic changes were made to the different stereochemical elements. Replacement of the distal chiral phenethyl substituent with a large achiral cycloalkyl group led to a catalyst that reacts with rates and enantioselectivities similar to those of the original catalyst with the phenethyl group. Studies of the reactions of diastereoisomeric ligands containing (R)- or (S)-binaphtholate groups on phosphorus, along with one (R)-phenethyl and one achiral cyclododecyl group on nitrogen, showed that the complexes of the two diastereoisomeric ligands underwent cyclometallation at much different rates. To access both diastereoisomeric catalysts and to determine if the reaction can occur selectively with an even simpler ligand containing a phenethyl substituent at nitrogen as the only scalemic stereochemical element, the catalyst derived from a phosphoramidite containing a biphenolate group (95) was studied. Catalysts generated from this ligand were shown to react in all cases with nearly the same rates, regioselectivities, and enantioselectivities as catalysts derived from the original more elaborate ligand. The absolute configuration of the product implies that the major enantiomer is formed from the (Ra ,Rc )-atropoisomer of the catalyst containing the biphenolate group.124 Iridium(III) hydrides, such as (98), proved to be air-stable active catalysts for intramolecular hydroalkoxylation and hydroamination of internal alkynes with proximate nucleophiles (e.g. 96). The cyclization follows the 6-endo-dig pathway with high preference (when regioselectivity is an issue).125 A variation within the osmium-catalysed asymmetric dihydroxylation (AD) of alkenes has been described that yields cyclic boronic esters from alkenes in a straightforward manner. A protocol based on the Sharpless AD conditions (for enantioselective oxidation of prochiral olefins) has been developed that gives cyclic boronic esters, rather than free diols, with excellent enantiomeric excesses. Some of the

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Ir

L

O P

Ir

O

L

O P

O

N

N Ph

Ph

R

Ph (95)

(94)

NHPh

Ph N

[Ir] (0.5 mol%)

O Prn

r.t., 2 h (96 °C)

PPh3 + O Ir H PPh3

Prn (96)

(97)

(98)

enantioselectivities were actually higher than those reported for conventional AD. A detailed investigation showed that PhB(OH)2 does not interfere with the chiral ligand, leaving the enantioselective step of alkene oxidation intact. Its main role–apart from protecting the diol products against potential over-oxidation – is to remove the diol via an electrophilic cleavage, which is in contrast to the conventional hydrolytic cleavage of the AD protocols.126 Asymmetric, osmium-catalysed dihydroxylation of 1,1-disubstituted and 1,3disubstituted allenes has been employed to synthesize chiral α-hydroxy ketones. α,α Dihydroxy ketones were obtained from 1,3-disubstituted allenes with high enantioselectivity.127 The first examples of the diastereoselective aminohydroxylation of chiral acryl amides, R3 CH=C(R2 )CONHCH*(Me)R1 , have been reported. The reaction is believed to proceed within the so-called ‘second catalytic cycle’ with diastereoisomeric excesses reaching >99:1. The reaction relies solely on the stereochemical information provided by the enantiomerically pure starting materials. A stereochemical model for the observed asymmetric induction has been proposed.128 A first example of an enantioselective catalytic diamination of alkenes has been developed, which employs enantiopure titanium complexes as catalysts and bis(tbutylimido)dioxoosmium(VIII) as the nitrogen source.129 Neutral scandium amido complexes have been developed as viable catalysts for intramolecular hydroamination of alkenes, such as MeC*H(NH2 )CH2 CH2 CH=CH2 . The catalytic activity proved to be strongly dependent on the electronic character of the Sc(III) ligand environment; chelating, sterically congested diamines, such as ArNHCH2 CH2 NHAr, exhibited substantially improved activity and superb diastereoselectivity in the synthesis of trans-2,5-disubstituted pyrrolidines.130

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Ph3 PAuOTf has been shown to catalyse the intermolecular addition of phenols and carboxylic acids to terminal alkenes, RCH2 CH=CH2 , at 85 ◦ C in toluene with Markovnikov selectivity to produce RCH2 CH(OR)Me.131 AuCl3 triggers the electrophilic 6(O)π,n -endo-dig cyclization of 2-(alk-1-ynyl)alk-2-en-1-ones to produce highly substituted furans in analogy with other electrophiles (see above; Scheme 3).40 An yttrium(III) complex derived from ligand (100) has been shown to be a superior catalyst for enantioselective intramolecular hydroaminations of alkenes that provide cyclic amines with enantioselectivities ranging from 69 to 89% ee.132

ee

Me SiMe2Ph

N SH SH N

SiMe2Ph

Me (100)

Ytterbium trifluoromethanesulfonate promoted a radical atom-transfer addition of chiral 3-bromoacetyl-2-oxazolidinones to norbornadiene, which afforded the corresponding 5-exo-3-bromo-5-nortricycleneacetic acid derivatives in good yields and with high diastereoselectivity (90–96% de, when using the chiral 4-isopropyl- and 4-benzyl-substituted 2-oxazolidinone auxiliaries).133

Miscellaneous Electrophilic Additions Two different carbon functional groups can be introduced simultaneously into 1,2positions of aromatic skeletons based on a novel insertion reaction of arynes (101) into a carbonyl–cyanomethyl σ -bond of α-cyanocarbonyl compounds (102) to produce 1,2-disubstituted aromatics (103).134 CN +

R

R1 (101)

(102)

r.t. THF

CN

R

O

O R1 (103)

A simple and highly regioselective method has been developed for the allylation of unactivated terminal alkynes, such as PhC≡CH, with allyl bromide using Zn–[bmim]PF6 , to produce dienes, e.g. CH2 =CHCH2 C(Ph)=CH2 .135

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Nucleophilic Additions To separate the effect of substituents into two parts, referring to the interaction of the reacting molecules and the solvation, the δ H = and δ S = reaction constants have been defined and determined from the dependence of activation parameters on the substituent constants, by analogy with the Hammett equation. The new reaction constants illustrate the effect of the substituents on the reaction in energy units; δ G= , δ H * and δ S = can be divided into internal (δ Xint , X = G, H , S) and external (δ Xext ) parts, which refer to the bond formation and the solvation, respectively. The contribution of the substituents to the internal part of the entropy of activation = (δ Sint ) and the external part of the free energy of activation (δ Gext ), originating from solvent reorganization, have been suggested to be zero. Accordingly, δ G= and = = δ S = are likely to present a good approximation to δ Hint and δ Sext , describing the effect of substituents on the energy barrier of the reaction and on the solvation, respectively. The δ G= reaction constant has been interpreted in the same way as the ρ constant in the Hammett equation. The δ S = reaction constant reflects the change in solvation with the substituents in the reaction. A tentative interpretation of δ S = , based on the solvation of charged species in organic solvents and the rearrangement of the solvent structure in water-containing mixtures, has been discussed for some nucleophilic additions, nucleophilic substitution, and acid-catalysed reactions. A break of the δ H = vs σ and δ S = vs ρ plots at σ ≈ 0 has been identified as diagnostic for the change in solvation with the electronic effect of the substituents. The δ S = reaction constants can be used to describe the change in solvation with the substituents for a reaction in a solvent.136

Additions to Multiple Bonds Conjugated with C=O The nature of the cation (K+ or Na+ ) in hydroxides has been found to affect the temperature plot of the equilibrium constants of the reaction of KOH and NaOH with 2,6-di-t-butylphenol (ArOH). The nature of the cation in the resulting phenoxides ArOK or ArONa is a factor determining the kinetics of the addition of ArOH to CH2 =CHCO2 Me. Two different kinetic schemes have been proposed to describe the transformation of ArOH in the presence of ArONa or ArOK.137 Nucleophilic vinylic substitutions of 4H -pyran-4-one and 2,6-dimethyl-4H -pyran4-one with a hydroxide ion in aqueous solution were calculated by the density functional theory (B3LYP) and ab initio (MP2) methods using the 6–31+G(d) and 6–31G (d) basis sets. The aqueous solution was modelled by a supermolecular approach, where 11 water molecules were involved in the reaction system. The calculations confirmed a different addition–elimination mechanism of the reaction compared with that in the gas phase or non-polar solution. Addition of OH− at the C(2) vinylic carbon of the pyranone ring with an activation barrier of 10–11 kcal mol−1 (B3LYP) has been identified as the rate-determining step, in good quantitative and qualitative agreement with experimental kinetics. Solvent effects increase the activation barrier of the addition step and, conversely, decrease the barrier of the elimination step.138 The conjugate addition of CH3 COSH to methacrylamides with chiral C2 -symmetric trans-2,5-disubstituted pyrrolidines afforded the Michael addition products in excellent

314


diastereoselectivities (>99% de) and good yields (80–90%). The high selectivity was attributed mainly to the steric effect of the chiral auxiliaries. The cyclic nature of the chiral auxiliaries also seemed important for both the stereoselectivity and the reaction rate.139 The addition reaction of benzylamines XC6 H4 CH2 NH2 to benzylidenehepta-3,5dione [BHD; YC6 H4 CH=C(COEt)2 ] in acetonitrile has been investigated. The reaction was found to be slower than the addition of benzylidene diethylmalonate [YC6 H4 CH= C(CO2 Et)2 ] as the result of a greater steric hindrance in the planar dicarbonyl transition state. The kinetic isotope effects (kH /kD ) involving deuterated amine nucleophiles XC6 H4 CH2 ND2 proved to be greater than 1 (1.37–2.04), indicating the N–H bond stretching with concurrent N–Cα and H–Cβ bond formation in the transition state. The trend of change in kH /kD with variation of substituent X in the nucleophile conforms to the Bell–Evans–Polanyi principle. It has been stressed that the dicarbonyl group activated alkenes exhibit insignificant charge imbalance in the transition state for the benzylamine additions in acetonitrile as a result of the two strong nc → π *C=O vicinal charge-transfer interactions.140 Boric acid (10 mol%) efficiently catalyses the conjugate addition of aliphatic amines RNH2 and R2 NH to α,β-unsaturated compounds R1 CH=C(R2 )X (R1 and R2 = alkyl, H; X = COMe, CO2 Me, CONH2 ) in water at room temperature to produce β-amino derivatives. Aromatic amines do not participate effectively in the reaction.141 Highly enantioselective catalytic conjugate addition of N -heterocycles, namely purines, benztriazole, benzimidazole, and 5-phenyltetrazole, to α,β-unsaturated ketones and imides has been attained with chiral, salen-type (Jacobsen) aluminium complexes as catalysts.142 A straightforward synthesis of aziridines from electron-rich azide R–N3 (R = alkyl or aryl), electron-deficient alkene, and triflic acid in cold acetonitrile has been reported. The only byproduct was dinitrogen (N2 ).143 The mechanism of the Morita–Baylis–Hillman reaction has been re-evaluated (Scheme 5). In accord with the commonly accepted mechanism, acrylate (104) reacts with the nucleophilic catalyst (e.g. DABCO) to generate enolate (105), which then reacts with aldehyde to form the zwitterionic intermediate (106). Previously, it was assumed that protic solvents (known to have an accelerating effect) facilitate the reaction by hydrogen bonding the aldehyde carbonyl to render it more prone to react with the enolate (105). In this new study, the authors argue that this is actually less likely than the hydrogen bonding of the protic solvent to the more basic enolate (105). According to this new insight, the role of the protic acid should actually be in facilitating the deprotonation of the zwitterion (106) via (108). This new kinetic study has shown that in the absence of added protic species, step 3 (i.e. the proton transfer) is rate limiting in the initial stages of the reaction. Once the concentration of the product (107) has built up, proton transfer becomes more efficient [note the OH group in the product (107)] and step 2 becomes rate limiting, which is consistent with the previously observed autocatalysis. These findings appear to have significant implications for asymmetric catalysis: since most of the successful catalysts have hydrogen bond donors (e.g. OH) appended to the nucleophile, it is likely that the latter group facilitates the deprotonation, which now becomes an intramolecular process (109),

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315

11 Addition Reactions: Polar Addition O−

O

R3N

OEt

OEt

step1

R3N

(104)

(105) step2

PhCHO

H

O

O− O

Ph

Ph step3

OEt

OEt +

R3N

(107)

−O

H

(106)

O H

Ph

O

R

−O

CO2Et

H

R

+

R 3N

O H

CO2Et

Nu

(108)

(109) Scheme 5

with one of the possible diastereoisomers reacting faster than the other competing species.144 In a different study, based on the reaction rate data collected in aprotic solvents, the Morita–Baylis–Hillman reaction has been found to be second order in aldehyde and first order in DABCO and acrylate. On the basis of these data, a new mechanism has been proposed, involving a hemiacetal intermediate (110). The proposed mechanism is further supported by two different kinetic isotope effect experiments.145 Ar O

O

H

OMe

Ar +

N

O

N (110)

316


N ,N ,N ,N -Tetramethylethylenediamine (TMEDA) as catalyst of the Morita– Baylis–Hillman reaction has been found to be more efficient than DABCO in aqueous media.146 1-Methylimidazole 3-N -oxide promotes the Morita–Baylis–Hillman reaction of various activated aldehydes with α,β-unsaturated ketones and esters CH2 = CHCOR (R = Me, OMe) in solvent-free systems.147 In another study, the Morita– Baylis–Hillman reaction has been successfully performed under aqueous acidic conditions at pH 1, using a range of substrates and tertiary amines as catalysts.148 A highly enantioselective proline-catalysed intramolecular Morita–Baylis–Hillman reaction of hept-2-enedial (111) has been reported. Addition of imidazole to the mixture resulted in an unusual inversion of enantioselectivity.149 The first example of a TiCl4 -mediated Morita–Baylis–Hillman-type reaction of α-acetyl cyclic ketene dithioacetals with arylaldehydes has been described.150 HO

O

HO O

L-proline

MeCN 0 °C (15% ee)

L-proline

O

O

imidazole

ee

O H

MeCN 0 °C (93% ee)

(111)

Chiral nitrogen Lewis bases, namely the tricyclic cinchona alkaloid derivatives, have been identified as effective catalysts for the asymmetric aza-Morita–Baylis–Hillman reaction of N -sulfonated imines, ArCH=NR (R = Ts, Ms, Ns, SES), with various activated olefins, such as CH2 =CHCOR [R = Me, Et, H, OMe, OPh, O(α-Napth), CN], to produce the corresponding adducts in moderate to good yields with good to high enantioselectivities (≤99% ee) at −30 or 45 ◦ C in various solvents, including DMF–MeCN (1:1, v/v). The adducts derived from CH2 =CHCOR (R = Me, Et) had the opposite absolute configuration to those from CH2 =CHCOR (R = H, OMe, OAr). A plausible mechanism has been proposed on the basis of previous reports and the authors’ investigations, which relies on the bifunctional character of the Lewis base–Brønsted acid system.151 Another class of bifunctional organocatalysts for the enantioselective aza-Morita– Baylis–Hillman reaction of imines (112) with enones (113) (Scheme 6) is based on BINOL (115). The efficiency of the catalysts proved to be mainly influenced by the position of the Lewis basic moiety attached to the BINOL scaffold. The activation of the substrate by acid–base functionalities and the fixing of conformation of the catalyst (115) are apparently harmonized to maximize the enantiocontrol (≤95% ee).152 Kinetics of the addition of Ph3 P to p-naphthoquinone in 1,2-dichloromethane, using the initial rate method, revealed the order of reaction with respect to the reactants; the rate constant was obtained from pseudo-first-order kinetic studies. A variable time method using UV–visible spectrophotometry (at 400 nm) was employed to monitor this addition, for which the following Arrhenius equation was obtained: log k = 9.14 − (13.63/2.303RT). The resulting activation parameters Ea , H = , G= , and

S = at 300 K were 13.63, 14.42 and 18.75 kcal mol−1 and −14.54 cal mol−1 K−1 ,

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317


+

R (112)

H NTs

O

NTs

O

115 (10 mol%)

R

R

−15 °C

(113)

R (114)

N OH

N

OH

(115) Scheme 6

respectively. The results suggest that the reaction is first order with respect to both Ph3 P and p-naphthoquinone.153 (R)-2 -Diphenylphosphanyl-[1,1 ]binaphthalenyl-2-ol (10 mol%), a Lewis basic chi˚ has been developed as ral phosphine, in combination with molecular sieve (4 A), a new organocatalyst for the aza-Morita–Baylis–Hillman reaction of N -sulfonated imines (N -arylmethylidene-4-methylbenzenesulfonamides and others) with methyl vinyl ketone, ethyl vinyl ketone, and acrolein. The latter reactions result in the formation of the corresponding products in good yields and with good to high enantioselectivities (70–95% ee) at low temperature (ca −30 to −20 ◦ C) or at room temperature in THF, respectively. With phenyl acrylate or naphthyl acrylate (in CH2 Cl2 at 40 ◦ C), the reaction exhibited moderate enantioselectivities (52–77% ee). The key enolate intermediate, stabilized by intramolecular hydrogen bonding, was observed by 31 P and 1 H NMR spectroscopy.154 According to another NMR study, the mechanism of bifunctional activation in the asymmetric aza-Morita–Baylis–Hillman reaction (Scheme 7) involves rate-limiting proton transfer (116) in the absence of added protic species155 (in consonance with the report summarized in Scheme 5144 ), but exhibits no autocatalysis. Addition of Brønsted acids led to substantial rate enhancements through acceleration of the elimination step. Furthermore, it was found that phosphine catalysts, either alone or in combination with protic additives, can cause racemization of the reaction product by proton exchange at the stereogenic centre. This behaviour indicates that the spatial arrangement of a bifunctional chiral catalyst for the asymmetric aza-Morita–Baylis–Hillman reaction is crucial not only for the stereodifferentiation within the catalytic cycle but also for the prevention of subsequent racemization.155 Triphenylphosphine and tributylphosphine proved to be excellent catalysts for the Michael addition of β-dicarbonyl compounds to electron-poor alkenes, including sterically demanding partners.156

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318


O

NTs +

Ar

H

Ph3P

R

R

O

Ts N

Ph3P (113)

TsNH O

H +

(112)

Ar

Ar

O R

R

(116)

(114)

Scheme 7

In the presence of DABCO (30 mol%), the addition of various selenosulfonates, PhSO2 SeAr, to α,β-unsaturated ketones proceeds smoothly at room temperature to give the corresponding Michael adducts in good yields under mild conditions.157 Highly diastereoselective conjugate additions (97:3 to 99:1 dr) were observed between α,β-unsaturated ketones and metalloenamines derived from N -sulfinyl ketimines chiral at the sulfur atom.158 Over the years, there have been a number of reports on the kinetic conjugate addition of metallated arylacetonitriles to enones. Several proposals have been made to explain the mechanism and outcome of this reaction based on the nucleophile structure or aggregation state or on the HSAB properties of the reactants. A reexamination of these studies has now revealed that in each case the 1,4-adducts resulted from equilibration of the kinetically formed 1,2-adducts to the more stable 1,4-adducts. The 1,2-addition, retro-1,2-addition, 1,4-addition, and retro-1,4- addition of PhC=C=NLi to PhCH=CHCOMe were examined, and a free energy level diagram was constructed.159 Nitrogen heterocycles with contiguous quaternary and tertiary stereocentres (118) have been prepared in high enantiomeric purity (≤95% ee) by intramolecular conjugate addition of enolates generated from α-amino acid derivatives (117) via memory of chirality.160 Me * CO2Et BOC

(117)

ee

CO2But CO2

N

de

But

KHMDS

MeO2C Me * N BOC (118)

Titanium enolates, derived from methyl phenylselenoacetate and other acetates bearing a selenium-containing chiral auxiliary, have been employed to bring about 1,4-addition reactions to enones, affording δ-oxo-α-seleno esters in good yields and with excellent regio- and diastereo-selectivities. These results clearly indicate that the Lewis acids employed to activate the starting enones towards addition greatly influence

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both the reactivity and the stereochemical outcome. TiCl4 complexation resulted in particularly efficient promotion of the 1,4-addition.161 A task-specific ionic liquid, [bmIm]OH, has been introduced as a catalyst and as a reaction medium for Michael addition. The addition of open-chain 1,3-dicarbonyls to α,β-unsaturated ketones gave the mono-addition products, whereas α,β-unsaturated esters and nitriles afforded mainly bis-addition products.162 A series of quinone monoacetals (119) bearing electron-withdrawing groups (CO2 Me or CONHPh) were treated with diethyl malonate, ethyl 3-nitropropionate, and other bifunctional nucleophiles in the presence of But OK in THF. Reactions of ethyl 3-nitropropionate or diethyl malonate resulted in single conjugate addition adducts. On the other hand, when ethyl acetoacetate was used as a nucleophile, bridged bicyclic products (120) were obtained in good yields. The regiochemistry of the conjugate addition turned out to be dependent on the quinone monoacetal substitution.163 O

O

EWG

EtO

OEt

CO2Et

O

CO 2 Et ButOK (0.15 equiv.) THF

OH

EtO EtO

EWG (120)

(119)

Addition of dimethylsulfonium methylide (122) to various Michael acceptors (121), followed by alkylation, has been reported to produce functionalized 1-substituted alkenes (124), arising via the unprecedented elimination (123), rather than the usual cyclopropanation products. In silyl substituted substrates, where a facile Peterson-type olefination is possible from the adduct, elimination took place instead. Aryl-substituted Michael acceptors (121 R1 = Ar) underwent a similar olefination to give 1-substituted styrene derivatives with moderate yields along with a side product, which arose by nucleophilic demethylation from the adduct of dimethylsulfonium methylide and arylidene malonates. Hammett studies revealed that selectivity for olefination versus demethylation increases as the aryl substituent becomes more electron deficient.164 R1

CO2Me CO2Me (121) base

+ Me CH2

R1 H

S

CH2

−

CO2Me R2X

CO2Me

S

R1

CO2Me CO2Me R2

Me Me

(122)

(123)

(124)

320


Enantioenriched Michael adducts (S)-(126) with up to 72% ee were obtained from the achiral phosphoglycine synthon (125) and suitable activated alkenes in the presence of (R,R)-TADDOL-type catalysts. The scope and limitation of the process, the role of the base (solid alkali metal t-butoxides), and the nature of the transition complex were examined.165 Ph2C N

P(O)(OR)2

1. Base, TADDOL

2.

W −78 °C, tolueue

ee

Ph2C N * P(O)(OR)3

W (125)

(126)

The enantioselective addition (≤97% ee) of β-keto esters (127) to unsaturated N −acylthiazolidinethiones (128), catalysed by Ni(II) Tol–BINAP Lewis acid complexes (130), has been reported; no external base was required.166

CO2But + 2 R

R1 (127)

S

O

O

N

O S

130 (10 mol%)

R2

S

O N

R1

ee

S

CO2But (129)

(128)

(Tol)2 X P Ni P X (Tol)2 (130) (X = TfO or BF4)

Addition of the chiral Ni(II) complex of the Schiff base of glycine (131) to (S)or (R)-3-[(E)-enoyl]-4-phenyl-1,3-oxazolidin-2-ones (132) in the presence of a nonchelating base (e.g. DBU) has been systematically studied as a general approach to β-substituted pyroglutamic acids (133) and related compounds. These reactions occur at room temperature with high diastereoselectivity (>98% de) at both newly formed stereogenic centres. The stereochemical outcome of the reactions was found to be overwhelmingly controlled by the stereochemical preferences of the Michael acceptors (132), whereas the chirality of the glycine complex (131) influenced only the reaction rate. Thus, in the reactions of both the S-configured Ni(II) complex (131)

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and the Michael acceptors (132), the reaction rates were exceptionally high, allowing the preparation of the corresponding products (133) with virtually quantitative (>98%) chemical and stereochemical yields. By contrast, reactions of the S-configured Ni(II) complex (131) and R-configured Michael acceptors (132) proceeded at noticeably lower rates, but the addition products (133) were obtained in high diastereoand enantio-meric purity. To rationalize the observed stereoselectivity, an enzyme– substrate-like mode of interaction involving a topographical match or mismatch of two geometric figures has been proposed.167 This approach parallels an earlier study where NOBIN was employed as a chiral phase-transfer catalyst, eliminating the need for a stoichiometric chiral auxiliary.168 Asymmetric Michael addition of glycine imine esters to simple α,β-unsaturated ketones via phase-transfer catalysis with the chiral quaternary ammonium salt derived from α-methylnaphthylamine in conjunction with Cs2 CO3 has also been reported to proceed with high enantioselectivities.169

1. R

O N

Ni N

O

ee

ee

Ph

O

Ph

de

N Ph

N

O

O O (132) DBU (15 °C), DMF, r.t. 2. H3O+

* O

R

N * H (133)

oxazolidinone + ligand CO2H + + NiCl2

(131)

Ruthenium amido complexes (137) effected asymmetric Michael addition of β-keto esters (134) to cyclopent-2-en-1-one (135) to give quantitatively the corresponding Michael adducts (136) with excellent enantioselectivity (≤97% ee), although with a 1:1 diastereoisomer ratio (Scheme 8). The stereochemical outcome of the reaction was significantly influenced by the structure of the catalysts (137) and β-keto esters.170 A hydroxyapatite-bound La complex (LaHAP), prepared by using a cation-exchange method, has been reported to function as an efficient heterogeneous catalyst for the Michael addition of 1,3-dicarbonyls to enones under aqueous or solvent-free conditions. Further application to an asymmetric version by a fluoroapatite-bound La complex catalyst modified with (R,R)-tartaric acid has also been described.171 An enantioselective intermolecular Michael addition of aldehydes (138) to enones (139), catalysed by imidazolidinones (140), has been reported. Chemoselectivity (Michael addition versus aldol) can be controlled through judicious choice of hydrogen bond-donating co-catalysts. The optimal imidazolidinone–hydrogen bond donor pair affords Michael addition products in ≤90% ee. Furthermore, the enamine intermediate was isolated and characterized and its efficacy as a nucleophile in the observed Michael addition reactions was demonstrated.172

ee

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Organic Reaction Mechanisms 2005 O O

O

O

*

O

OMe +

R

R

MeO2C (134)

(136)

(135) R1SO2

Ph

N

Ph

N H

Ru

(137) R = Me, Et, Pri, But, Ph R1 = p-tolyl, Me Scheme 8 O

O +

H

R2

R1 (138)

Bu

O

(139)

Me N N H

O

O

(140) (20 mol%)

4 (EtO2C)-Catechol (20 mol%)

R2

H R1 (141)

Michael addition of nitromethane to chalcones can be catalysed by cinchona alkaloid-derived chiral bifunctional thiourea (142) (0.5–10 mol%) to give the corresponding products at 25–100 ◦ C in high chemical yields and high enantioselectivity (≤97% ee).173 A highly enantioselective synthesis of (2S)-α-(hydroxymethyl)glutamic acid, a potent metabotropic receptor ligand, has been accomplished via the catalytic Michael addition of t-butyl 2-naphthalen-1-yl-2-oxazoline-4-carboxylate to CH2 =CHCO2 Et, using the phosphazene base (143) and the (S)-binaphthyl quaternary ammonium salt (144) as the chiral phase-transfer reagent in CH2 Cl2 at −60 ◦ C (≤97% ee).174 Diphenylprolinol methyl ether (145) catalyses intermolecular Michael addition of simple aldehydes to enones in the absence of solvents with high enantioselectivities (95–99% ee) and significantly lower catalyst loadings (5 mol%) than have been typical in this arena.175 The first asymmetric direct Michael addition of enolizable aldehydes RCH2 CH=O to vinyl sulfones CH2 =C(SO2 Ph)2 catalysed by N -Pri -2,2 -bipyrrolidine (146) has been reported. The 1,4-adducts were obtained in good yields and enantioselectivities

ee

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323


N

H N

H

H N

CF3 But N

S

MeO

CF3

N

MeN

(142)

NEt2

P

NMe

(143)

Ar Ph Ph

+

N

N H

Ar (144) Ar = 3′,4′,5′-trifluorophenyl

N

SO2Ph

N

N H

OMe

(145)

Pri (146)

R

N PhSO2 Pri (147)

and their absolute configuration is consistent with the postulated Si,Si transition state model (147), as shown previously for nitroalkenes.176 A novel antibody-catalysed intramolecular Michael addition of aldehydes and ketones to enones [(148) → (149)] has been accomplished. The reaction is enantioand diastereo-selective with a high ee and cis/trans ratio. Antibody 38C2 is the only catalyst to date capable of generating this selectivity in Michael addition products.177 O

O Ar

R O

Antibody 38C2

de ee

R

Ar O

(148)

(149)

A highly enantioselective Mukaiyama–Michael addition of silyl ethers, CH2 = C(OSiMe3 )R1 , to α,β-unsaturated aldehydes, R2 CH=CHCHO, catalysed by MacMillan’s chiral imidazolidinone (150), in the presence of 2,4-(NO2 )2 C6 H3 CO2 H as an acid

ee

324

Organic Reaction Mechanisms 2005 Me N

Me N

N

N H

N H

N

But Ph

Ph

N H (150)

N

(151)

additive, carried out in t-BuOH–i-PrOH, afforded the corresponding δ-keto aldehydes in high yields (56–87%) and high enantioselectivities (85–97% ee).178 The Michael addition of nitroalkanes to α,β-unsaturated enones, catalysed by the novel chiral imidazolidine-2-yltetrazole (151), has been investigated. The new, more soluble organocatalyst decreases reaction times and improves enantioselectivities compared with other catalysts. The Michael addition adducts were obtained with up to 92% ee.179 A novel method for enantioselective organocatalytic cyclopropanation has been developed, using a new class of iminium intermediates and based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide (153) and enal (152) substrates through the formation of the iminium intermediate (155) and electrostatic activation (156). The resulting trisubstituted cyclopropanes (157) were obtained with high levels of enantio- and diastereo-control.180 R

O (152) N H

O +

Me2S

CO2H

CO− 2

(154)

Ph

−

CHCl3, 23 °C, (78%)

(153)

+

N H R (155) Me O Me S+ O O−

O R

−

Ph

R N

CHO (157)

H (156)

H

Ph

ee

ee

de

325


The conjugate addition of carbonyl anions catalysed by thiazolium salts (via umpolung) that is fully operative under neutral aqueous conditions has been accomplished. The combination of α-keto carboxylates (157) and thiazolium-derived zwitterions (e.g. 160) in a buffered protic environment (pH 7.2) generates reactive carbonyl anions that readily undergo conjugate additions to substituted α,β-unsaturated 2-acylimidazoles (158) to produce (159). The scope of the reaction has been examined and found to accommodate various α-keto carboxylates and β-aryl-substituted unsaturated 2acylimidazoles. The optimum precatalyst for this process is the commercially available thiazolium salt (160), a simple analogue of thiamine diphosphate. In this process, no benzoin products from carbonyl anion dimerization were observed. The resulting 1,4dicarbonyl compounds (159) can be efficiently converted into esters and amides by way of activation of the N -methylimidazole ring via alkylation.181 O

O O−Na+

R1

+

R2

O

R1

Me N

(160) pH 7.2 (−CO2)

N

(157)

(158)

Ph

N

O

Me N

R2 OH

S

O

(159)

N

+

Me (160)

Dimethylphenylsilyllithium adds to (Z)-γ -alkoxy-α,β-unsaturated esters (161) to produce almost exclusively (i) the syn-adduct when the reaction is carried out in THF and (ii) the anti -adduct when carried out in the presence of HMPA. By contrast, poor stereocontrol was observed with the stereoisomeric (E)-γ -alkoxy-α,βunsaturated esters.182 O

CO2Me

O (161)

A new iodine-catalysed, remarkably simple Michael reaction of indoles with enones, e.g. PhCH=CHCOR, has been developed.183 The SmI3 -catalysed reaction of indoles with electron-deficient alkenes (e.g. enones) afforded the corresponding Michael adducts in high yields. As in the previous case, the substitution on the indole nucleus occurred exclusively at the 3-position and N -alkylation products have not been observed.184

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The fluoride ion-induced intramolecular conjugate addition of propargylsilanes to the dihydropyridone moiety (162 → 163) has been shown to occur in the presence of tetrabutylammonium triphenyldifluorosilicate (TBAT) as an air-stable, non-hygroscopic fluoride ion source. This catalytic cyclocondensation provides the corresponding 1-vinylideneindolizidines (163) in high yields as single isomers, whereas Lewis acid catalysts were ineffective. The scope of this method was further investigated in reactions leading to compounds with a larger ring size. In these cases, dihydropyridones with the propargylsilane located in the side-chain underwent cyclization to give 9-vinylidenequinolizidines with significantly lower yields.185 SiMe3 O ( )n

•

R (162) (n = 1,2)

O

TBAT (2.0 equiv.) THF, 30 °C, 1.5 h

N

H

( )n N R (163)

Second-order rate constants (kN ) have been measured for the Michael-type reaction of propynones X–C6 H4 –CO–C≡CH (X = 4-MeO, 4-Me, H, 4-Cl, 4-CN, 3-NO2 ) with a series of primary amines in H2 O at 25.0 ± 0.1 ◦ C. A linear Brønsted-type plot with a small βnuc value (βnuc = 0.30) has been obtained for the reactions of 1phenylprop-2-yn-1-one with non-α-nucleophile amines. Hydrazine turned out to be more reactive than other primary amines of similar basicity (e.g., glycylglycine and glycine ethyl ester), which resulted in a positive deviation from the linear Brønstedtype plot. The reactions of propynones with hydrazine exhibited a linear Hammett plot, whereas additions of non-α-nucleophile amines gave linear Yukawa–Tsuno plots, indicating that the electronic nature of the substituent X does not affect the reaction mechanism. The α-effect increases as the substituent X in the phenyl ring of the propynones becomes a stronger electron-donating group. However, the magnitude of hydrazine glycylglycine the α-effect for the reactions of propynones is small (e.g. kN /kN = 4.6–13) regardless of the electronic nature of the substituent X. The small βnuc has been suggested to be responsible for the small α-effect. A solvent kinetic isotope effect H O D O (e.g. kN 2 /kN 2 = 1.86) was observed for the reaction with hydrazine but absent for the reactions with non-α-nucleophile amines. The reactions with hydrazine has been suggested to proceed through a five-membered intramolecular H-bonding structure, whereas primary amines are believed to react via a six-membered intermolecular Hbonding structure. The transition state modelled on the former mechanism can account for the substituent dependent α-effect and the difference in the solvent kinetic isotope effect exhibited by the reactions with hydrazine and other primary amines. It has been proposed that the magnitude of the α-effect is influenced more by the βnuc value than by the hybridization type of the reaction site.186

327


The first examples of a Michael–Stork enamine addition to allenyl esters and ketones R1 CH=C=C(R2 )COX (X = alkyl, alkoxyl) has been reported. Mechanistic investigation revealed that 2 equiv. of enamine are required for optimum yields. In the case of an allenyl methyl ketone, cyclopentyl enamine addition afforded 8oxobicyclo[3.2.1]octane, providing evidence for the in situ formation of an enamine intermediate following the initial Michael–Stork reaction.187 A novel approach to the consecutive α- and β-activation of conjugated alkynes has been developed. This concept is based on the 1,4-addition of a tertiary amine to a conjugated alkyne, followed by an aldol-type addition to an aldehyde and subsequent intramolecular silyl migration. This sequential process is generally applicable for 3-trimethylsilylpropiolates. The combination of methyl 3-trimethylsilylpropiolate, 1,4diazobicyclo[2.2.2]octane (DABCO), and aromatic aldehydes brought about dominotype C–C bond formation to afford highly functionalized alkenes as the major products. On the other hand, aliphatic aldehydes, including the sterically demanding aromatic aldehydes, such as 2,6-dimethylbenzaldehyde, afforded alkyne derivatives as the sole products, presumably by the reaction pathway common to the first cases. The intramolecular version of the reaction was successfully applied to the cyclization of trimethylsilylpropiolic esters derived from salicylaldehydes, leading to a new formylcoumarin synthesis. Reaction mechanisms to account for these transformations have been studied.188 An improved one-pot access to α-substituted cinnamate esters (165) exploiting the addition of 1,3-diketones, β-keto esters, and malonates to alkynoates (164) catalysed by phosphines has been reported. Among the catalysts, n-Bu3 P was found to be most effective, allowing the reaction to proceed under milder conditions and in a more general manner than with other phosphines.189 −O

Ar

CO2Me

Bu3P

+

Bu3P Ar

(164)

O

O R

R

O

R CO2Me

Ar

R CO2Me (165)

Additions to Multiple Bonds Activated by Other Electron-withdrawing Groups The conjugate addition of protected pyranose alkoxides to 1-nitro- and 1-nitrosoalkenes gave 2-nitroalkyl and 2-oximinoalkyl glycosides. In several cases, the reaction proceeded with preferential formation of the α-glycoside (α:β ≤ 4:1).190 The use of heteroaryl vinyl sulfides and vinyl dithiocarbamates (166) as heteroMichael addition acceptors has been described. Combined chelating and electronwithdrawing effects were postulated to stabilize the transient anionic species and allow smooth Michael-induced ring closure to produce C-glycosides (167).191 Nucleophilic addition of benzylamines XC6 H4 CH2 NH2 to α-cyano-β-phenylacrylamides YC6 H4 CH=C(CN)CONH2 have been investigated in acetonitrile at 25.0 ◦ C.

de

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OH

N S

N base

O

S X

X (166)

(167)

The reaction was found to be first order with respect to amines and acrylamides and no base catalysis was observed. The reaction is believed to occur in a single step in which the addition of amine to Cβ of acrylamide and proton transfer from amine to Cα of acrylamide take place concurrently with a four-membered cyclic transition-state structure. The Hammett (ρX ) and Brønsted (βX ) coefficients are rather small, suggesting an early transition state (TS). The sign and magnitude of the cross-interaction constant, ρXY (= −0.26), is comparable to those found in the bond formation processes in the SN 2 and addition reactions. The normal kinetic isotope effect (kH /kD > 1.0) and relatively low H = and large negative S = values are also consistent with the mechanism proposed.192 A highly enantioselective intermolecular hydrophosphination reaction has been developed, relying on the new (Pigiphos)nickel(II) complex as catalyst; (R)(S)-Pigiphos = bis{(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl}cyclohexylphosphine. The addition of secondary phosphines R2 PH to methacrylonitrile CH2 = C(Me)CN gives chiral 2-cyanopropylphosphines in good yield and high enantiomeric excess (≤94% ee). A mechanism has been proposed, which involves coordination of CH2 =C(Me)CN to the dicationic nickel catalyst, followed by 1,4-addition of the phosphine, and then rate-determining proton transfer. This mechanism is supported by (a) the experimentally determined rate law (rate = k [Ni][methacrylonitrile][t-Bu2 PH]); (b) a large primary deuterium isotope effect kH /kD = 4.6(1) for the addition of t-Bu2 PH(D) at 28.3 ◦ C in toluene-d8 ; (c) the isolation and characterization of the species [Ni(κ 3 -Pigiphos)(κN -methacrylonitrile)]2+ ; and (d) DFT calculations of model compounds.193 The kinetics of nucleophilic addition of thiophenol (PhSH) to β-nitrostyrene (PhCH=CHNO2 ) in 80% (v/v) MeCN–H2 O at 25 ◦ C has been investigated. The reaction is second order, being first order in each reactant, and a decrease in polarity of the medium decreases the reaction rate. A mechanism involving the formation of a zwitterionic complex in a fast equilibration step, followed by its conversion into the product by a slow step, has been proposed. Evaluation of the equilibrium constant for the formation of zwitterion indicates that the rate law is kobs = K1 kc [PhSH] rather than being of Michaelis–Menten type. The kinetics of the same reaction catalysed by Et3 N have also been studied in the same solvent system and its rate was found to be considerably increased in the presence of added base. The latter reaction is first order in [β-nitrostyrene] and [thiophenol] but fractional order (0.769) in [Et3 N]. The rate of the reaction was found to increase with decrease in polarity of the medium. The plot of kobs /[PhSH] vs [Et3 N] gave a straight line with a definite intercept, which indicates that catalytic and non-catalytic pathways operate concurrently. On the basis of the kinetic results, a stepwise mechanism involving the formation of a zwitterion with PhSH and

ee

329


PhCH=CHNO2 and a complex with the zwitterion and Et3 N in equilibration steps, followed by their conversion into the product, has been invoked. Both catalytic (kb ) and non-catalytic (k) rate constants were derived from the rate law.194 Tin(II)- and zinc(II)-chelated glycine ester enolates have been found to act as efficient nucleophiles for highly diastereoselective 1,4-additions toward nitroalkenes, such as PhC*H(Me)=CHNO2 (≤99% ds) or RCH=CHNO2 .195,196 An easy and efficient method to generate indolylnitroalkane (169) and the analogous pyrrolylnitroalkane in high yields using β-nitrostyrene derivative (168) and indole/pyrrole at room temperature in the presence of iodine (50 mol%) has been reported as an alternative to the known Lewis acid or rare earth metal catalysts.197

NO2 O

Ar

indole I2 (50 mol%)

HN

Et2O, r.t., 2.5 d

NO2 O

(168) Ar = p-Cl-C6H4

de

Ar

(169a), b-NO2 (169b), a-NO2

A highly enantioselective addition (≤99% ee) of aldehydes RCH2 CH=O and R1 R2 CHCH=O to nitrostyrene derivatives ArCH=CHNO2 , catalysed by the proline-derived sulfonamide (170), has been reported. The reaction is assumed to proceed via the corresponding enamine and the transition state (171).198 Highly enantioselective Michael addition of aldehydes to nitrostyrene can also be catalysed by diphenylprolinol silyl ethers (172) (≤99% ee)199 and that of ketones (e.g. cyclohexanone) to β-nitrostyrenes with (S)-homoproline hydrochloride (173) (77–96% ee).200 Similarly, enantioselective addition of β-dicarbonyls to nitrostyrene (85–99% ee) was attained with cinchona alkaloid-based organocatalysts.201 A highly enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported that employs a newly developed Ni(II)–(bis)diamine-based catalyst (174). The reaction scope includes substituted and unsubstituted malonates, β-keto esters, and nitroalkenes bearing aromatic and aliphatic residues.202 A family of derivatives of 9-amino(9-deoxy) epicinchonine, possessing a range of mono- and bi-dentate hydrogen bond donor groups at the 9-position, were synthesized and evaluated for asymmetric organocatalytic Michael addition of CH2 (CO2 Me)2 to β-nitrostyrene; the thiourea derivative [related to (142)] was identified as the most effective bifunctional organic catalyst (≤97% ee at 10 mol% loading).203 Another thiourea derivative with a binaphthyl scaffold (175) has been developed as an efficient organocatalyst for the Michael addition reactions (using as low as 1 mol% loading) of diketones to nitroalkenes (≤97% ee).204 Bifunctional organocatalysts bearing both a thiourea moiety and an imidazole group on a chiral scaffold were synthesized and

ee

ee

ee

ee

ee

330


N H

N H NSO2CF3

H

N

Ph Ph

SO2CF3

N H

NO2 R Ar

(170)

(171)

(172) Br N

Br

Br N

Ni N N Br Br Br

+

N Cl− H 2

OSiR3

CO2H

(173)

(174)

applied to the Strecker synthesis and nitro-Michael reaction. The addition of acetone in the presence of these organocatalysts gave enantioselectivities (up to 87% ee) that are superior to those generated by the proline and/or homo-proline tetrazole catalysts described in the literature.205 S N N H H NMe2

(175)

ee

CF3 O

O S

CF3 (176)

The first organocatalytic and asymmetric vinylogous Michael reaction that employs the electron-deficient vinyl malononitriles as the nucleophilic species has been reported. This new transformation, catalysed by (DHQD)PYR (a ligand originally developed for the Sharpless dihydroxylation), exhibits exclusive γ -selectivity and high diastereoand enantio-selectivity (≤94% ee) in the addition to nitroalkenes.206 Also developed was the first conjugate addition of α-cyanoacetates RCH(CN)CO2 Et (R = aryl or alkyl) to vinyl sulfones CH2 =CHSO2 Ar. The reaction proceeded in high yields and with excellent enantioselectivity in the presence of organocatalysts derived from C(6 )OH cinchona alkaloids.207 A supramolecular aqueous system for the Michael addition of thiols ArSH from the secondary side of β-cyclodextrin to α,β-unsaturated compounds residing at the primary side has been developed and shown to proceed in quantitative yields; products of side-reactions, resulting from polymerization, were not observed. The use of cyclodextrin precludes the use of either acid or base and the catalyst can be recovered and reused.208

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331

The regioselectivity of the double nucleophilic addition of ketene silyl acetals to α,β-unsaturated imines has been found to be highly dependent on the subtle difference in the reactivities of the ketene silyl acetals; the factors are mainly derived from the ability of the ketene silyl acetals to undergo the silicon–aluminium exchange reaction, where the aluminium enolate preferentially undergoes 1,4-addition.209 The cyclopropanation of 2-[(S)-(4-methylphenyl)sulfinyl]cyclopent-2-en-1-one (176) with various sulfur ylides has been examined. The reaction with methylenesulfonium ylides gave the corresponding cyclopropanes with low diastereoselectivity; formation of the second product, arising from the subsequent methylenation of the C=O group, was also observed. A clean cyclopropanation of (176) took place with ethyl (dimethylsulfanylidene)acetate affording the corresponding cyclopropanes with high π -facial selectivity, but low endo/exo ratio. A high endo/exo selectivity, but low π -facial selectivity, was observed for the reaction with (2-ethoxy-2oxoethyl)(diphenyl)sulfonium tetrafluoroborate. The use of α-bromoacetate carbanion as the cyclopropanation reagent exhibited very high facial and endo/exo selectivity. In a proposed explanation of the stereochemical outcome of the cyclopropanations, the ground-state conformation of the sulfoxide (176) and the transition-state structure of the initial addition step were taken into account.210 Alkyl and aryl sulfides RSH react with equimolecular amounts of p-toluenesulfonylacetylene, HC≡C–SO2 Tol, in CH3 CN at 0 ◦ C or room temperature in the absence of any catalytic reagent to give Z-adducts RS–CH=CH–SO2 Tol with total diastereoselectivity. On the other hand, in the presence of 1.1 equiv. of NaH in THF, the same reaction affords the corresponding E-diastereoisomers also with total diastereoselectivity.211

de

de

Additions of Organometallics to Activated Double Bonds Under the conditions of a rapid injection experiment, the conjugate addition reactions of Gilman reagents (177) (X = CN or I) with cyclohex-2-enone has been studied in detail. Formation of various species (178–181) and the oscillation of their concentrations have been monitored by 1 H NMR spectroscopy (Scheme 9).212 The mechanism of remote conjugate addition of lithium organocuprates to a polyconjugated carbonyl compound, namely HC≡CCH=CHCH=CHCH=O, has been investigated by computational methods and the energy of various competing transition states and intermediates established.213 Further insight was gained by investigation of the 13 C kinetic isotope effect in the 1,6-addition to (t-Bu)C≡CCH=CHCO2 Et by experimental and theoretical methods.214 Conjugate additions of various organocopper reagents to the enones derived from glycals, e.g. 2-(diethoxyphosphoryl)hex-1-en-3-uloses, has been described. The reactions proved to be rapid, clean, and diastereoselective, giving rise to the formation of 3-oxo-2-phosphono-α-C-glycosides or the corresponding enol acetates.215 Conjugate addition of vinyl cuprate and dimethyl malonate to 4,4-dimethylcyclohexa-2,5-dienones has allowed facile access to mono- and bis-adducts in good yields. Whereas the high diastereoselectivity to afford trans-bis-adducts was predictable,

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Organic Reaction Mechanisms 2005 Li

O

Me Cu Me k2

O Me Cu Me Li

Li

k−2

LiX

O

Li

X Li Me

k1

+

X (177)

+

Cu

k−1

Me

(178) k4

k−4

k3

k−3

−

OLi

OLi Me

k5

I

+ Cu + 2 LiX •

Me

cage

Me

LiX +

k−5

III

Cu

Li

Me Cu X

− +

k7 k−7

X Me k8

−

k−8

OLi +

Li + LiX Me

Me Cu

LiX +

Me

O CuMe

X

k−6

Li

O Li + LiX

+

Li

Me k6

O

LiX

k9 k−9

Mecu(X)Li +

(181)

Me (180)

Scheme 9

(179)

− +

Li

333


an unprecedented regioselectivity was observed with 2,4,4-trimethylcyclohexa-2,5dienone, with the first addition occurring exclusively at the C(5) carbon atom (distal from the methyl group) and with the second addition of a bulky nucleophile such as dimethyl malonate even prevented.216 Various substituted arylcuprates, e.g. Ar2 CuMgBr, undergo addition to γ -alkoxyα,β-enoates, such as R2 OCH2 CH(OR1 )CH=CHCO2 Et, with exclusive diastereoselectivity in favour of the anti -configured product. A model accounting for this stereochemical outcome has been presented.217 Stereoselective copper-promoted conjugated additions of Grignard reagents in the presence of Zn(II) salts to chiral cinnamoyl- and crotonyl-amides RCH=CHCO(N*) derived from (4S,5S)- and (4R,5R)-trans-hexahydrobenzoxazolidin-2-ones has been employed for the preparation of the corresponding 1,4-addition products.218 Conjugate additions of the simple monosilylcuprate reagent Li[PhMe2 SiCuI] to α,β-unsaturated carbonyl compounds has been investigated in detail. The presence of dimethyl sulfide, either as a component originating from the (CuI)4 (SMe2 )3 complex or as a solvent added, has been shown to have a dramatic effect on both chemical yield and the level of diastereoisomeric ratio (dr) of the products. Gilman-type silylcyanocuprates {Li(Ph2 MeSi)2 Cu/LiCN} have previously been used to guarantee good results in conjugate addition reactions and required external additives, such as HMPA, Bu3 P, or R2 Zn. With the simple Li[PhMe2 SiCuI], the latter additives are not necessary. The authors have further demonstrated that the monosilylcuprate reagent with Me2 S as the solvent is particularly useful with sterically hindered (β,β-disubstituted) enones. Furthermore, the simple monosilylcuprate are not hampered with the problem of oligomerization, typical for other cuprates. High diastereoslectivities (≤99:1) were attained with amides derived from enantiopure amines, such as (182).219 Ph

(182)

de

de

Ph O

N O

de

O

Li [PhMe2SiCuI] −78 °C to −20 °C, 7 h THF or Me2S

O

N PhMe2Si

O

O

(183)

Stereochemical control of the addition of silyl- and stannyl-metals to chiral γ alkoxyalkylidene malonates proved to be dependent on the nature of the counter ion and of the solvent but in a rather unpredictable way.220 A systematic study of the conjugate additions of dimethyl cuprate to diastereoisomeric ethyl γ -hydroxy(or t-butyldimethylsilyloxy)-δ-p-tolylsulfinylpent-2-enoates (184) (R = H or TBDMS; X =:) and the analogous sulfones (X = O) showed mainly 3,4-anti -diastereoselectivity when the reaction occurred in the presence of Me3 SiCl. The π -facial diastereoselection is mainly governed by the γ -hydroxy or silyloxy group, whereas the role of the sulfur functionality is to increase the reactivity of the pentenoate system, presumably by assisting the transfer of the alkyl group from the cuprate. This was evidenced by the reactions on similar systems that lack the sulfur functions. The

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Organic Reaction Mechanisms 2005 O OR

O S

EtO2C

X p-Tol

1. Me2CuLi

O O

O

+

2. Me3SiCl TMEDA

SOn (p-Tol) (184)

SOn (p-Tol)

40:60 to 17:83

appropriate choice of NH4 OH or HCl hydrolysis in the workup allowed direct access to the open-chain products or the lactones.221 Addition of organocuprates to N -sulfinyl imines R2 CH=CH–C(R1 )=NS(O)–(t-Bu) proceeds in good yields and with good diastereoselectivities (≤96:4).222 Copper-catalysed conjugate addition of Me3 Al to 3-methylcyclohexenones, carried out in the presence of ligand (185) and its congeners, has been shown to afford the products of 1,4-addition in ≤96% ee.223,224 Less efficient (≤93% and ≤86% ee) were the phoshoramidite (186)225 and the P,O-bidentate phosphine ligand BINPO (187).226 Enantioselective conjugate addition of Grignard reagents to α,β-unsaturated esters RCH=CHCO2 Me, catalysed by Me2 S·CuBr (5 mol%) in the presence of ligands (188) or (189), gives the products with ≤99% ee.227 Dialkylzinc addition to N -substituted 2,3-dehydro-4-piperidones, carried out in toluene and catalysed by (TfO)2 Cu (5 mol%) in the presence of the phosphoramidite ligand (190) (10 mol%), occurred with ≤97% ee.228

de ee

ee

Ph O P O

N

* *

(2-Naphthyl)

O P

(2-Naphthyl)

N

O Ph

(185)

(186)

Phosphite–pyridine ligands (191) derived from racemic biphenyl units and homochiral BINOL have been developed for enantioselective (≤96% ee) Cu(I)-catalysed conjugate additions of Et2 Zn to a variety of acyclic enones, such as ArCH=CHCOR.229 Ligand (192) was equally successful (90–99% ee).230 Addition of dialkylzinc reagents to β-aryl- and β-alkyl-nitroalkenes, RCH=CHNO2 , catalysed by a complex of (TfO)2 Cu with the proline-derived amidophosphine (193), afforded the corresponding nitroalkanes with moderate to good enantioselectivities (54–80% ee). The performance was highly dependent on the reaction procedure: thus,

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11 Addition Reactions: Polar Addition Me PPh2 Fe

Me

Pcy2 PPh2

Fe

PPh2 Pcy3

P(O)Ph2 (187)

(188)

(189) O

Ph O P

N

O Ph

(190)

N

O P

O

R

O

(191)

OH PBu2n

(192)

N H

N PPh2 O

(193)

the addition of nitroalkene to the mixture of copper–amidophosphane and dialkylzinc gave higher ee than the addition of dialkylzinc to a mixture of copper–amidophosphane and nitroalkene.231 Scalemic N -silylamidocuprates (194), prepared from O-methylnorephedrine, are exceedingly reactive and give excellent enantiomeric excesses with chalcone. Thus, the butyl N -diphenylmethylsilylamidocuprate adds to chalcone to afford (S)-PhC*H(Bu) CH2 COPh in 99.2% ee (99% yield). The remarkably high yields with this and other silyl ligands have been attributed to the extraordinary activating effect of a β-silicon atom on organocuprate reactions. The high ee is believed to be a consequence of the larger size of the silyl ligands compared with that of the unsubstituted or methylsubstituted analogues.232 Asymmetric conjugate addition of dialkylzinc to α,β-unsaturated N -2,4,6-triisopropylphenylsulfonylaldimines ArCH=CHCH=NS(O2 )Ar can be catalysed by 5 mol%

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336


Ph2MeSi

NCu−BuLi+

N

Ph OMe (194)

PPh2 O

BOCNH (195)

of N -Boc-l-valine-connected amidophosphane (195)–Cu(MeCN)4 BF4 in the presence ˚ molecular sieve in toluene to afford, after hydrolysis of an imine to an aldeof 4 A hyde through a short alumina column and reduction with sodium borohydride, the corresponding β-alkylated alkanols (R)-ArC*H(Me)CH2 CH2 OH with 67–91% ee in good yields.233 The copper-catalysed addition of dialkylzinc reagents to the chalcone-derived (2pyridylsulfonyl)imines, Ar CH=CH−C(Ar)=NSO2 (α-pyridyl), has been reported. The reaction proceeds rapidly in the presence of chiral phosphoramidite ligand (Sa )-(190) to afford exclusively the 1,4-addition product. With Me2 Zn, enantioselectivities in the range of 70–80% ee were attained. The presence of the metal-coordinating 2pyridylsulfonyl group proved to be essential for this reaction to proceed.234 A copper-catalysed, enantioselective, conjugate addition of a terminal alkyne, which undergoes an in situ metallation, has been reported. The addition of phenylacetylene to Meldrum’s acid-derived acceptors (196) takes place in aqueous medium, without recourse to an inert atmosphere. The success of the enantioselective reaction was made possible by the use of PINAP (198), a new class of P,N -ligands (cf. QUINAP), which have the advantage of easier resolution. Furthermore, these modular ligands are responsive to numerous electronic and steric modifications that permit optimization of the reaction. The products (197) were obtained in good yields and with 82–97% ee.235 The cyclization of 2-(alk-1-ynyl)alk-2-en-1-ones (199) to afford highly substituted furans (200) can be readily induced in the presence of alcohols with a catalytic amount of Cu(I)Br in DMF at 80 ◦ C. This catalyst is easy to handle, compared with the previously known system that employed the moisture-sensitive AuCl3 .236 Copper(II) tetrafluoroborate Cu(BF4 )2 ·xH2 O has been identified as a new and highly efficient catalyst for Michael addition of thiols to α,β-unsaturated carbonyl compounds under solvent-free conditions and in H2 O at room temperature. The reactions are very fast and are completed within 2 min to 1 h. The rate of thiol addition is dependent on the steric hindrance at the β-carbon of the α,β-unsaturated carbonyl substrate. In the case of chalcones, the reactions are best carried out in MeOH as solvent.237 The α-hydrostannation of activated alkynes RC≡CCOR with Bu3 SnH, catalysed by (Ph3 PCuH)6 , has been mentioned earlier.69 1,6-Addition of aryl Grignard reagents ArMgX to 2,4-dienoates and 2,4-dienamides can be catalysed by iron salts, such as FeCl2 , to produce 5-aryl-3-enoates and the corresponding amides, respectively, in a highly regio- and stereo-selective manner.238 Chiral phosphine–alkene (201) has been designed as a novel bidentate ligand for the rhodium-catalysed asymmetric 1,4-addition of aryl boronic acids to maleimides,

ee

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337


O

O

O

O

PhC CH (AcO)2Cu (5–20 mol%)

O

O

O

198 (5–20 mol%) H2O, 0 °C

O

R

R

(196)

Ph

(197)

Ph Et Et

HN N

OH

N MeO

PPh2

(198) R O

O

R +

R′OH

CuBr (10 mol%) DMF, 80 °C

OR′ (199)

(200)

cycloalkenones, and related activated cyclic alkenes with up to 98% ee.239 The structurally related diene ligand (202) exhibited high enantioselectivity in the Rh-catalysed 1,4-addition of arylboronic acids to α,β-unsaturated Weinreb amides RCH=CHCON (OMe)Me (≤92% ee),240 vinylsilanes R3 SiCH=CHCOR (93–99% ee),241 and substituted acroleins RCH=CHCH=O (≤94% ee).242 The modified diene ligand (203) was employed for the addition of ArB(OH)2 to a series of cinnamates Ar CH=CHCO2 (tBu) (89–93% ee).243 Phosphoramidite (204) was also employed as a chiral ligand in this area, namely to the Rh-catalysed 1,4-addition of ArB(OH)2 to cyclohexenone and its congeners at room temperature (≤99% ee).244 Potassium trifluoroborates RBF3 K (the more stable substitutes for boronic acids) have been added to α,β-unsaturated esters in a reaction catalysed by chiral rhodium(I) complexes with BINAP (205) (≤96%).245 The latter ligand has also been employed in the Rh-catalysed 1,6-addition dienones, in particular alk-3-enylcyclohex-2-enones (≤96% ee).246 The first Pd-catalysed addition of ArB(OH)2 to linear substrates R1 CH=CCHCOR2 (R1 = aryl, alkyl, H; R2 = alkyl, OEt) with DuPHOS (206) as chiral ligand required 50 ◦ C (≤99% ee).247 Its non-enantioselective version, carried out with bipyridine as ligand, has also been reported.248

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Organic Reaction Mechanisms 2005 MeO

PPh2

Ph

Ph

Me

Ph

Ph (201)

(202)

(203)

O P

PPh2

P

PPh2

P

NEt2

O

(204)

(205)

(206)

A diastereoselective Rh(I)-catalysed conjugate addition reaction of aryl- and alkenylboronic acids to unprotected 2-phenyl-4-hydroxycyclopentenone (207) has been investigated. The free OH group on the substrate was found to be responsible for the stereochemistry, which is cis for arylboronic derivatives (208). In the case of the alkenylboronic compounds, the stereochemistry can be tuned to either a cis (with a base as additive) or trans addition (209) (with CsF as additive), without the need for protecting groups.249 O

O Ph R

HO (208)

O Ph

ArB(OH)2 or RCH=CH–B(OH)2

de

Ph RCH=CH–B(OH)2

base

CsF

HO (207)

R

HO (209)

Chiraphos (210) has been found to induce high enantioselectivity in the construction of all-carbon quaternary stereogenic centres via the Rh-catalysed conjugate addition of alkenylboronic acids to β,β-disubstituted α,β-unsaturated 2-pyridylsulfones RC(Me)=CHS(O)2 (α-pyridyl).250 The first examples of catalytic asymmetric conjugate addition of alkylzinc reagents to trisubstituted nitroalkenes, such as PhC(Me)=CHNO2 , leading to the formation of nitroalkanes bearing a quaternary carbon stereogenic centre, have been reported. Reactions are promoted by the readily available amino acid-based phosphine (211) (4 mol%) and (TfOCu)·C6 H6 (2 mol%), exhibit up to 98% ee, and can be carried out with a variety of dialkylzinc reagents and trisubstituted nitroalkenes.251 Diarylindium(III) hydroxides, Ar2 InOH, have been shown to react with α,βunsaturated carbonyl compounds R1 CH=CHCOR2 in the presence of a rhodium catalyst to afford the 1,4-addition products R1 CH(Ar)CH2 R2 in high yield.252

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11 Addition Reactions: Polar Addition I

But Me

PPh2

Me

H N

N

OH O

PPh2

PPh2

CONEt2 OH OBu

I

(211)

(210)

(212)

Asymmetric conjugate alkynylation of alkynylboronates R1 C≡C–B(OPri )2 to enones R2 CH=CHCOR3 can be catalysed by binaphthols, such as (212), in the absence of other metals. The high enantioselectivities observed (≤95% ee) are comparable to those obtained using stoichiometric amounts of binaphthol-modified boronate reagents, suggesting that this is a ligand-accelerated process. This report represents the first demonstration that catalytic amounts of chiral diols can be used with boronates to effect high levels of stereochemical control.253 The ruthenium complex Cp*Ru(bipyridyl)Cl has been developed as a catalyst for the first regioselective tandem Michael addition–allylic alkylation of activated Michael acceptors. The net outcome is the decarboxylative insertion of Michael acceptors into allyl β-keto esters to produce (215). The reaction combines the generation of Ru–π allyl and enolate from (213); the enolate is first added to the Michael acceptor (214) and the resulting species is captured by the Ru–π -allyl.254 O

O

R1

Z +

O R2 (213)

Z

R3 (214)

Cp*Ru (bpy) Cl (10 mol%)

O

ee

R3 Z

R1

Z

CH2Cl2, 2 h

R2 (215)

1-Alkynyl(aryl)(tetrafluoroborato)-λ3 -bromanes (217) have been developed as highly efficient Michael acceptors in the uncatalysed conjugate addition of 1-alkynyl(trialkyl)stannanes (216) to afford the corresponding buta-1,3-diynes (218).255 Chiral (salen)Al complex (219) catalyses the highly enantioselective conjugate addition of carbon- and nitrogen-based nucleophiles [NuH = NH3 , RCH2 NO2 , and RCH(CN)EWG] to acyclic α,β-unsaturated ketones.256 Samarium iodobinaphtholate (222) has been reported to act as an efficient enantioselective catalyst for the Michael addition of aromatic amines to fumaryl oxazolidinone (220), affording the aspartic acid derivatives (221) in good yields. Elucidation of the influence of temperature on the addition of p-anisidine revealed an isoinversion effect with a maximum ee of 88% at −40 ◦ C.257 A non-enantioselective version of this reaction has also been reported.258

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Organic Reaction Mechanisms 2005 R

SnMe3 R′

R′

(216)

−

+ R

′

Br

Ar

−ArBr

Br

F·BF3

F·BF3 R

R

CF3

R′

R (218)

(217)

N

N Al But

But

O

O

But

But (219)

O EtO2C

O N

ArNH

ArNH2,

O

(222) (10 mol%)

O

EtO2C

CH2Cl2, 4 Å MS

(220)

O N

O

(221)

O SmI·(THF)2 O

(222)

The asymmetric conjugate addition of arylalkynes ArC≡CH to nitroalkenes can be mediated by dimethylzinc (or diethylzinc) and (1R,2R)-2-(dimethylamino)-1,2diphenylethanol as chiral ligand in toluene; the resulting products were obtained in high ee (≤99%) and good yields. The presence of 0.03 equiv. of galvinoxyl improved the reaction yield.259 PtCl2 /AgOTf-catalysed hydroarylation of ethyl propiolate, HC≡CCO2 Et, with ArH in CF3 CO2 H has been developed as a method for the preparation of ethyl (Z)cinnamates, (Z)-ArCH=CHCO2 Et, in good to high yields, without the formation of

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diethyl (1E,3Z)-4-arylbuta-1,3-diene-1,3-dicarboxylates, which was observed in the (AcO)2 Pd-catalysed reaction. This interesting reaction involves a C–H activation of the arene.260 A catalytic enantioselective conjugate addition of cyanide to α,β-unsaturated N acylpyrroles, R1 CH=C(R2 )CO(NC4 H4 ), has been found to proceed in the presence the chiral gadolinium catalyst generated from (Pri O)3 Gd and the d-glucose-derived ligand (223). Generally, high enantioselectivities were attained (83–98% ee) with a wide range of substrates, including those possessing β-aryl and β-vinyl substituents and the α,β-disubstituted substrates.261 O

Ph2P O

ee

HO O

F

HO

F

(223)

Miscellaneous Nucleophilic Additions The first examples of chiral Lewis acid catalysis in the opening of diactivated cyclopropane derivatives (224) with nitrones (225) has been demonstrated, giving rise to the tetrahydro-1,2-oxazines (226). High enantioselectivities (71–96% ee) were attained with Ni(ClO4 )2 and Ph–DBFOX ligand (227).262

RO2C

CO2R

−O

+

+

N

R1

Ni (ClO4)2 (10 mol%) Ph–DBFOX CH2Cl2, r.t., 4 Å MS

R2 (224)

RO2C

O

(225)

O N

N

Ph

Ph (227)

References 2

N

(226)

O

1

CO2R R2

Mayr, H. and Ofial, A. R., Pure Appl. Chem., 77, 1807 (2005). Chiappe, C. and Pieraccini, D., J. Phys. Org. Chem., 18, 275 (2005).

O

R1

ee

342 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

39 40 41 42 43 44 45 46

Organic Reaction Mechanisms 2005 Regan, A. C., in Comprehensive Organic Functional Group Transformations II (Eds Katritzky, A. R. and Taylor, R. J. K.), Vol. 1, 2005, p. 533; Chem. Abs., 142, 297610 (2005). Rousseau, G., in Comprehensive Organic Functional Group Transformations II (Eds Katritzky, A. R. and Taylor, R. J. K.), Vol. 1, 2005, p. 427; Chem. Abs., 142, 297608 (2005). Beletskaya, I. P., Pure Appl. Chem., 77, 2021 (2005). Oestreich, M., Eur. J. Org. Chem., 2005, 783. Kawatsura, M., Farumashia, 41, 675 (2005); Chem. Abs., 143, 193530 (2005). Hultzsch, K. C., Org. Biomol. Chem., 3, 1819 (2005). Alexakis, A., in Transition Metals for Organic Synthesis (Eds Beller, M. and Bolm, C.), Wiley-VCH Verlag GmbH, Weinheim, 2nd edn, Vol. 1, 2004, p. 553; Chem. Abs., 143, 115090 (2005). Xu, L.-W., Xia, C.-G., Wu, H., Yang, L., Zhou, W., Zhang, Y., Youji Huaxue, 25, 167 (2005); Chem. Abs., 143, 59281 (2005). Kamimura, A., Yuki Gosei Kagaku Kyokaishi , 62, 705 (2004); Chem. Abs., 142, 316179 (2005). Xu, L.-W. and Xia, C.-G., Eur. J. Org. Chem., 2005, 633. Shi, M. and Chen, L.-H., Pure Appl. Chem., 77, 2105 (2005). Kataoka, T. and Kinoshita, H., Eur. J. Org. Chem., 2005, 45. Ballini, R., Bosica, G., Fiorini, D., Palmieri, A., and Petrini, M., Chem. Rev., 105, 933 (2005). Mikolajczyk, M., Pure Appl. Chem., 77, 2091 (2005). Lu, X., Du, Y., and Lu, C., Pure Appl. Chem., 77, 1985 (2005). Riant, O., Mostefai, N., and Courmarcel, J., Synthesis 2004, 2943; Chem. Abs., 142, 74061 (2005). Comelles, J., Moreno-Mañas, M., Vallribera, A., ARKIVOC , 2005, 207; Chem. Abs., 143, 26072 (2005). Hayashi, Y., Yuki Gosei Kagaku Kyokaishi , 63, 464 (2005); Chem. Abs., 142, 429710 (2005). Methot, J. L. and Roush, W. R., Adv. Synth. Catal. 2004, 346; Chem. Abs., 142, 155289 (2005). Abbasoglu, R. and Yilmaz, S. S., Indian J. Chem., Sect. A, 43, 2497 (2004); Chem. Abs., 142, 113473 (2005). Abbasoglu, R., THEOCHEM , 686, 1 (2004); Chem. Abs., 142, 155400 (2005). Abbasoglu, R., Yilmaz, S. S., and Goek, Y., Indian J. Chem., Sect. A, 44, 221 (2005); Chem. Abs., 143, 172411 (2005). Abbasoglu, R., Indian J. Chem., Sect. B , 44, 1708 (2005); Chem. Abs., 143, 439730 (2005). Hepperle, S. S., Li, Q., and East, A. L. L., J. Phys. Chem. A, 109, 10975 (2005). Manickam, M. C. D., Annalakshmi, S., Pitchumani K., and Srinivasan, C., Org. Biomol. Chem., 3, 1008 (2005). Emmanuvel, L., Ali Shaikh, T. M., and Sudalai, A., Org. Lett., 7, 5071 (2005). ˇ y, V., Collect. Czech. Chem. Commun., 54, 2211 (1989). Cern´ ˇ y, V. and Budˇesˇ´ınský, M. Collect. Czech. Chem. Commun., 55, 2738 (1990). Cern´ Hajra, S., Karmakar, A., and Bhowmick, M., Tetrahedron, 61, 2279 (2005). Kaur, P., Singh, P., and Kumar, S., Tetrahedron, 61, 8231 (2005). Hajra, S., Maji, B., and Karmakar, A., Tetrahedron Lett., 46, 8599 (2005). Okazaki T. and Laali, K. K., J. Org. Chem., 70, 9139 (2005). Zabalov, M. V., Karlov, S. S., Lemenovskii, D. A., and Zaitseva, G. S., J. Org. Chem., 70, 9175 (2005). Herges, R., Papafilippopoulos, A., Hess, K., Chiappe, C., Lenoir, D., and Detert, H., Angew. Chem. Int. Ed., 44, 1412 (2005). Yao, T. and Larock, R. C., J. Org. Chem., 70, 1432 (2005). ˇ y, V., and Synácˇ ková, M., Collect. Czech. Chem. ComFor the notation, see (a) Koˇcovský, P., Cern´ mun., 44, 1483 (1979); (b) Koˇcovský, P. and Stieborová, I., J. Chem. Soc., Perkin Trans. 1 , 1987, 1969; (c) Koˇcovský, P. and Pour, M., J. Org. Chem., 50, 5580 (1990). Barluenga, J., Trincado, M., Marco-Arias, M., Ballesteros, A., Rubio, E., and González, J. M., Chem. Commun., 2005, 2008. Yao, T., Zhang, X., and Larock, R. C., J. Org. Chem., 70, 7679 (2005). Ochiai, M., Nishi, Y., Mori, T., Tada, N., Suefuji, T., and Frohn, H. J., J. Am. Chem. Soc., 127, 10460 (2005). Lahrache, H., Robin, S., and Rousseau, G., Tetrahedron Lett., 46, 1635 (2005). Fu, C., Chen, G., Liu, X., and Ma, S., Tetrahedron, 61, 7768 (2005). Shevchenko, N. E., Nenajdenko, V. G., Muzalevskii, V. M., and Balenkova, E. S., Russ. Chem. Bull. (Transl. of Izv. Akad. Nauk, Ser. Khim.), 53, 1726 (2004); Chem. Abs., 142, 261084 (2005). Yadav, V. K. and Ganesh Babu, K., Eur. J. Org. Chem., 2005, 452. Anderson, L. A., Arnold, J., and Bergman, R. G., J. Am. Chem. Soc., 127, 14542 (2005).

11 Addition Reactions: Polar Addition 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103

343

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11 Addition Reactions: Polar Addition 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262

347

Martina, S. L. X., Minnaard, A. J., Hessen, B., and Feringa, B. L., Tetrahedron Lett., 46, 7159 (2005). Navarre, L., Pucheault, M., Darses, S., and Genet, J.-P., Tetrahedron Lett., 46, 4247 (2005). Hayashi, T., Yamamoto, S., and Tokunaga, N., Angew. Chem. Int. Ed., 44, 4224 (2005). Gini, F., Hessen, B., and Minnaard, A. J., Org. Lett., 7, 5309 (2005). Lu, X. and Lin, S., J. Org. Chem., 70, 9651 (2005). de la Herrán, G., Mba, M., Murcia, M. C., Plumet, J., and Csákÿ, A. G., Org. Lett., 7, 1669 (2005). Mauleón, P. and Carretero, J. C., Chem. Commun., 2005, 4961. Wu, J., Mampreian, D. M., and Hoveyda, A. H., J. Am. Chem. Soc., 127, 4584 (2005). Miura, T. and Murakami, M., Chem. Commun., 2005, 5676. Wu, T. J. and Chong J. M., J. Am. Chem. Soc., 127, 3244 (2005). Wang, C. and Tunge, J. A., Org. Lett., 7, 2137 (2005). Ochiai, M., Nishi, Y., Goto, S., and Frohn, H. J., Angew. Chem. Int. Ed., 44, 406 (2005). Taylor, M. S., Zalatan, D. N., Lerchner, A. M., and Jacobsen, E. N., J. Am. Chem. Soc., 127, 1313 (2005). Reboule, I., Gil, R., and Collin, J., Tetrahedron: Asymmetry, 16, 3881 (2005). Reboule, I., Gil, R., and Collin, J., Tetrahedron Lett., 46, 7761 (2005). Yamashita, M., Yamada, K., and Tomioka, K., Org. Lett., 7, 2369 (2005). Oyamada, J. and Kitamura, T., Tetrahedron Lett., 46, 3823 (2005). Mita, T., Sasaki, K., Kanai, M., and Shibasaki, M., J. Am. Chem. Soc., 127, 514 (2005). P. Sibi, M. P., Ma, Z., and Jasperse, C. P., J. Am. Chem. Soc., 127, 5764 (2005).

CHAPTER 12

Addition Reactions: Cycloaddition

N. Dennis University of Queensland, PO BOX 6382, St. Lucia, Queensland, Australia 2 + 2-Cycloaddition . . . . . 2 + 3-Cycloaddition . . . . . 2 + 4-Cycloaddition . . . . . Miscellaneous Cycloadditions References . . . . . . . . . . .

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349 353 362 384 393

A DFT study of the 2 + 2/4 + 2-cycloaddition of benzyne with thiophene to produce 1-naphthyl- and 2-naphthyl phenyl sulfides led to a modification of the originally proposed reaction pathway.1 The reaction of an E–Z mixture of 7-benzylidenecycloocta1,3,5-triene (1) with TCNE yields a mixture of 2 + 2- [(2) and (3)], 4 + 2- [(4) and (5)], and 8 + 2- (6) cycloadducts. The presence of pentadienyl and homotropylium zwitterions accounts for the products isolated (Scheme 1).2 Rhodium (II)-catalysed 3 + 2- and 3 + 4-cycloaddition of diazocarbonyl compounds (7) with conjugated dienes (e.g. 2,3-dimethylbuta-1,3-diene) provides a simple and rapid route to dihydrofurans (8) and dihydrooxepins (9) in high yields. A stepwise mechanism involving delocalized zwitterions has been proposed for the formation of the cycloadducts (Scheme 2).3 The nature of the iminic nitrogen substituent influences the cycloaddition pathway (4 + 2 versus 3 + 2) followed in the reactions of α-nitrosoalkenes with alkyl/arylsubstituted acyclic imines.4 The problem of rotamer control in Lewis acid-catalysed 3 + 2- and 4 + 2-cycloaddition reactions of α,β-disubstituted acryloylimides was solved by the use of N–H imide templates.5

2 + 2-Cycloaddition By using the hypersensitive molecular mechanistic probe 2-(2-methoxy-3-phenylcyclopropyl)-5-methylhexa-2,4-diene in the 2 + 2-photocycloaddition of [60]fullerene, it was shown that the reaction proceeds via a biradical and not a dipolar intermediate.6 Zirconium-induced cyclodimerization of heteroaryl-substituted alkynes produces tetrasubstituted cyclobutenes with high regio- and stereo-selectivity.7 The rutheniumOrganic Reaction Mechanisms · 2005: An annual survey covering the literature dated January to December 2005 Edited by A. C. Knipe © 2008 John Wiley & Sons, Ltd. ISBN: 978-0-470-03403-3

349

350

Organic Reaction Mechanisms 2005 H

Ph

H

TCNE

Ph

NC

AcOEt, reflux

CN NC NC CN

(1)

CN

(2)

CN CN

+ H Ph CN

CN CN

CN

NC

CN +

NC NC

CN Ph H CN

(4)

CN CN

(3)

+ NC NC

CN CN

H Ph CN

+ H

H

NC

CN CN

Ph (5)

(6) Scheme 1

O

O N2 O (7)

O

Me

Rh2(OAc) (1 mol%) 2,3-dimethyl buta-1,3-diene

CH2

r.t. 6 h

O (8) 44%

Me

Me

+

Me O (9) 46%

Scheme 2

catalysed 2 + 2-cycloadditions between norbornene and cyclic and acyclic ynamides produce the corresponding cyclobutene cycloadducts in moderate to good yields.8 Electron-rich bifunctional vinyl ethers (e.g. ethylene glycol divinyl ether) react with electron-poor alkenes (e.g. TCNE) to produce cyclobutanes in good yields via tetramethylene zwitterion intermediates. In some cases, cyclobutanes reacted with the solvent (MeCN) to yield tetrahydropyridines.9 Trifluoromethanesulfonimide is an

351

12 Addition Reactions: Cycloaddition

efficient catalyst for the 2 + 2-cycloaddition reactions of silyl enol ethers with acrylates and propiolates to yield highly substituted cyclobutanes in high yield and high stereoselectivity. This method provides a facile route to the core structure of protoilludanes (e.g. altanticone D).10 The diastereoselective 2 + 2-cycloaddition of aldehydeand ketone-derived silyl enol ethers with acrylates produces hydroxycyclobutanecarboxylic acid esters with high yields and high diastereoselectivity. The bulky bis(2,6diphenylphenoxide) aluminium triflimide catalyst and the tris(trimethylsilyl)silyl group must be used for high diastereoselectivity, reactivity, and yield.11 A one-pot thermal 2 + 2-cycloaddition of aldehyde-derived enamines with fumarates to produce 4substituted 3-dialkylaminocyclobutane-1,2-dicarboxylates has been achieved by combining the aldehyde, secondary amine, and dialkyl fumarate with potassium carbonate in MeCN.12 The intramolecular 2 + 2-photocycloaddition of the dimeric vinyl pyridine 2,2[1,2-ethanediylbis(oxy)]bis(5-ethenylpyridine) (10) formed the corresponding syn- and anti -pyridinophanes [(11)–(13)] via a singlet-excited species (Scheme 3).13 CH2 H2C

hn (Pyrex) MeCN

N

N O

O (10)

+ N

N O

+ N

O

N O

N

N O

O

O

cis, exo, syn

cis, endo, syn

cis, anti

(11)

(12)

(13)

Scheme 3

The 2 + 2-cycloaddition of chlorosulfonyl isocyanate with chiral alkoxyallenes, derived from ethylidene and benzylidene l-erythritol and d-threitol, produces azetidinones that are readily converted into the corresponding tricyclic cephams. NMR and CD spectroscopy were used to assign the absolute configurations of the azetidinones

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and cephams.14 The thermal intramolecular 2 + 2-cycloaddition of allenenes (14) and allenynes (16) yields 3-azabicyclo[4.2.0]oct-5-ene derivatives (15) and 3-azabicyclo [4.2.0]octa-1(8),5-diene derivatives (17) in high yields. This experimental process has the potential for producing fused bicyclic cyclobutane derivatives useful in synthetic and medicinal chemistry (Scheme 4).15 H Me

H Me

•

DMF 150 °C

Me N

Me N

Ph

Mts

Ph

Mts

(14)

(15) H

Me

H Me

•

dioxane

Me

reflux

Me

N

N Ph

Mts

Ph

Mts

(16)

(17) Scheme 4

In a kinetic study of the intramolecular ketene–alkene 2 + 2-cycloadditions, it was shown that the reaction for forming five-membered rings is much faster than that for six-membered rings.16 The Staudinger 2 + 2-cycloaddition of unsymmetrical cyclic ketenes with N -substituted imines produces 1,3-thiazolidine-derived spiro-βlactams, which can be converted into α-keto-β-lactams.17 The Lewis acid-catalysed Staudinger 2 + 2-cycloaddition of trimethylsilylketenes with an α-imino ester, trans(methoxycarbonyl)-N -methylformaldimine, produced silylated cis-β-lactams stereoselectively.18 The intramolecular 2 + 2-cycloaddition of iminoketenimines produces 1aryl-2-methyl-2-phenyl-1,2,4,5-tetrahydroazeto[1,2-a]imidazoles. Acid-catalysed hydrolysis of azeto[1,2-a]imidazoles yields 6,6,7-trisubstituted hexahydro-1,4-diazepin5-ones.19 The 2 + 2-cycloaddition of the ketene imine 1,1,5,5-tetramethyl-9,10-bis (trifluoromethyl)-7-thia-12-azaspiro[5,6]dodeca-10,11-diene-9-carbonitrile (18) with ethyl vinyl ether produced the diastereomeric cycloadducts (19) and (20) via addition at the C=N double bond. The exact mechanism of this reaction is unknown (Scheme 5).20 Regioselectivity of the Paternò –Büchi reaction of 1,3-dimethylthymine with benzophenone and its 4,4 -disubstituted derivatives has been shown to be temperature dependent in the range −40 to 70 ◦ C.21

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12 Addition Reactions: Cycloaddition CF3 Me O

Me S

Me

CF3 CN CF3

Me

C2H5OCH=CH2

O

N

Me S

Me

CN CF3 N

Me

Me H OC2H5

(18)

(19) + CF3 Me O

Me S

Me

CN CF3 N

Me C2H5O H

(20)

Scheme 5

2 + 3-Cycloaddition The Lewis acid-catalysed 3 + 2-cycloaddition of cyclopropanes with aldehydes yields tetrahydrofurans with high diastereoselectivity.22 The enantiospecific Sn(II)and Sn(IV)-catalysed formal 3 + 2-cycloadditions of aldehydes with donor–acceptor cyclopropanes produce optically active tetrahydrofurans.23 The bulky phosphites and phosphoramidites are excellent ligands which promote the Pd-catalysed 3 + 2intramolecular cycloaddition between alkylidenecyclopropanes and alkynes.24 The 3 + 2-cycloaddition of cyclopropylmethylsilanes and α-ketoaldehydes produces 2silylmethyltetrahydrofurans in good yields.25 The catalyst, [Cu(MeCN)4 ]BF4 –(R)DM-SEGPHOS, promotes the enantioselective 3 + 2-cycloaddition of 1-alkylsubstituted allenylsilanes with α-imino esters to produce silyl-substituted dehydroproline derivatives in high yields and enantioselectivities.26 The total synthesis of the antitumour annonaceous acetogenin (+)-bullatacin has been achieved by the diastereoselective 3 + 2-cycloaddition of the highly enantiomerically enriched allylsilane (21) with the racemic aldehyde (22) producing the key bis-tetrahydrofuran intermediate (23) with >20:1 ds (Scheme 6).27 The phosphine-catalysed 3 + 2-cycloaddition of 5-methylenehydantoins (24) with the ylide (25) produces spiroheterocyclic product (26), which can be converted to carbocyclic hydantocidin and 6,7-diepi-carbocyclic hydantocidin (Scheme 7).28

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Organic Reaction Mechanisms 2005 OTBOPS CHO

OTBS

Me

TBSO

+

9

O PhMe2Si

SiMe2Ph

TBSO

CH2 (21)

Me

8

(22) SnCl4

OTBDPS OTBS

Me

TBSO 9

PhMe2Si O

O PhMe2Si TBSO

8

Me

(23)

Scheme 6

+

O

BnN

CO2Et

PBu3 O

CH2 +

H2C

−

OEt

NBn O

BnN O

(24)

(25)

O NBn

(26)

Scheme 7

Semiempirical AM1 and DFT (B3LYP/6–31G∗ ) calculations were used to investigate the highly diastereoselective 1,3-dipolar cycloaddition of 1,4-dihydropyridinecontaining azomethine ylides to [60]fullerene (Prato’s reaction). The activation energy for the four calculated transition state structures favours the formation of SSaS and

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RSaS stereoisomers.29 The 1,3-dipolar cycloaddition of [60]fullerene with diazomethane, nitrile oxide, and nitrone afforded fullereno-pyrazolines and -isoxazolines. These reactions were modelled at the B3LYP/6–31G(d,p)//AM1 level and the reaction mechanisms, regiochemistry, and nature of addition were investigated.30 The Lewis acid-mediated domino reaction between cyclohex-2-enone and methyl azide has been investigated at the B3LYP/6–31G∗ and B3LYP/6–31-G∗∗ //B3LYP/ 6–31G∗ levels of theory. A domino process comprising three consecutive reactions yields a cyclopentanone derivative as the product.31 The Cp∗ RuCl(PPh3 )2 -catalysed 1,3-dipolar cycloaddition of organic azides with terminal alkynes produces 1,5-disubstituted 1,2,3-triazoles.32 The Lewis acid-catalysed 3 + 2-cycloaddition of aziridine-2-carboxylates with isocyanates proceeds regio- and stereo-specifically to produce enantiomerically pure 4-substituted imidazolin-2-ones in high yields.33 The reaction of ethyl 7iodo-2-heptynoate (27), 2-arylaziridines (28), and K2 CO3 produces polysubstituted indolizidines (30) via an SN 2/formal 3 + 2-cycloaddition (29) process (Scheme 8).34 H N

X I

R1

(28)

X R2

I

−

+N

K2CO3 dry MeCN

(27)

R1

X

R1

(29)

R2

two SN2

N

R2

(30)

X = CO2Et, P(O)(OEt)2, COPh, Ts Scheme 8

The 1,3-dipolar cycloaddition of the carbonyl ylide (31) to the aldimine (32) produces the adduct (33), which has been used to synthesize the taxol C(13) side-chain (34), which is known to be required for the antitumour activity of taxol (Scheme 9).35 The dirhodium tetraacetate-catalysed decomposition of 1-diazo-5-phenylpentane-2,5dione (35) yields the carbonyl ylide (36), which cycloadds to methylenecyclopropanes (37) to produce spirocyclopropanated 8-oxabicyclo[3.2.1]octan-2-ones [(38)–(40)] in 6–75% yields (Scheme 10).36 The 1,3-dipolar cycloadditions of aliphatic or alicyclic thiocarbonyl ylides with thiobenzophenone produce both regioisomeric 1,3-dithiolanes as expected. However, in the case of highly sterically hindered thiocarbonyl ylides, ‘methylene transfer’ leads to the formation of 4,4,5,5-tetraphenyl-1,3-dithiolane.37,38 The 1,3-dipolar cycloaddition of phosphonodithioformate S-methanides (41) with aromatic thio ketones (42) yields 1,3-dithiolanes (43) and (44). These S-methanides are also trapped by TCNE, maleic anhydride, N -phenylmaleimide, and dimethyl diazenedicarboxylate (Scheme 11).39 The key step in the stereoselective total synthesis of erythronolide A is the Mg(II)mediated 1,3-dipolar cycloaddition of the functionalized nitrile oxide (45) with the allylic alcohol (46) to produce the isoxazoline (47) as a single diastereomer in high

356


+

Ph

O

−

CO2Et

Me

+ Ph

Rh(OAc)4

N

(31)

CH2Cl2

Ph

(32) Ph

NHCOPh HO2C

Ph

Me Ph

N

O

OH Ph

EtO2C (34)

(33) Scheme 9

Ph

[Rh(OAc)2]2 0.3 – 0.7 mol%

O

Ph +

CH2Cl2, 20 °C

N2

O −

(35)

O

(36) R1

(37) 2 – 5 equiv. 1h

Ph R1 O

Ph R2

R2

Ph R1

O

+

(38)

R1 R2

O

+

O

O

R2

O (39)

R1 = Ph, n-C7H15, Br, CO2Me R2 = H, Cl Scheme 10

(40)

357


S RO RO

S

O P

S

O

OR P OR SMe

SMe

− +

S (41)

CH2

THF

+

(43)

(42)

+ O

OR P OR S MeS S

(44) Scheme 11

yield (Scheme 12).40 The kinetic solvent effects on the 1,3-dipolar cycloadditions of benzonitrile oxide with N -substituted maleimides and with cyclopentene were investigated in water, organic solvents, and binary mixtures. Solvent polarity and specific hydrogen bond interactions were shown to be important in the rates of reaction.41 The magnesium-mediated, hydroxyl-directed diastereoselective nitrile oxide cycloadditions with homoallylic alcohols produce 2 -isoxazolines diastereoselectively.42 The substrate specificity and mechanistic parameters of the murine monoclonal antibody (29G12)-catalysed 1,3-dipolar cycloaddition of 4-acetamidobenzonitrile N -oxide with N ,N -dimethylacrylamide have been investigated. Isoxazoline cycloadducts were produced with excellent regio- and stereo-chemical control (78–98% ee).43 The DFT study of the 3 + 2-cycloaddition between ketene and N -silyl-, N -germyl-, and N -stannyl-imines shows that the N -germylimine reaction is a two-step process; the N -stannylimine reaction is a competition between two- and three-step processes whereas the N -silyl process follows a three-step process.44 A new and convenient synthesis of functionalized furans and benzofurans based on 3 + 2-cycloaddition/oxidation has been reported. The cyclization of cyclic 1,3-bissilyl enol ethers (48) with 1-chloro-2,2-dimethoxyethane (49), via a dianion, produced 5,6-bicyclic 2-alkylidenetetrahydrofurans (50), which are readily oxidized with DDQ to 2,3-unsubstituted benzofurans (51) (Scheme 13).45 The Evans bis(oxazoline)–Cu(II) complex catalyses the asymmetric 1,3-dipolar cycloaddition of α -hydroxyenones with nitrones to produce isoxazolidines.46 The 1,3-dipolar cycloaddition of chiral sugar-derived nitrones with 3-(prop-2-enoyl)1,3-oxazolidin-2-one generates the sterically favoured isoxazolidin-5-yl-substituted

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Organic Reaction Mechanisms 2005 Ph OSBT O

O

N

OH +

Me

Me RO Me Me

Me Me

(45)

OH (46) Ph

1. t-BuOCl, CH2Cl2, −78 °C

OSBT O

O

N

O

Me

2. i-PrOH, EtMgBr, CH2Cl2, 0 °C to r.t

OH Me

Me RO Me Me

Me

(47) Scheme 12

adducts, whereas the electronically favoured regioisomers with isoxazolidin-4-yl substituents are obtained in the presence of Lewis acid, [Ti(OPri )2 Cl2 ].47 The key step in the total synthesis of functionalized azaoxobicyclo[x.3.0]alkane amino acids involves the intramolecular 1,3-dipolar cycloaddition of a nitrone on 5-allyl- or 5-homoallylproline.48 The 1,3-dipolar cycloaddition of 3-p-tolylsulfinylfuran-2(5H )-ones to cyclic and acyclic nitrones produces furoisoxazolidines in high yields under mild conditions. The sulfinyl group greatly enhances the reactivity of the dipolarophile.49 The enantioselective 1,3-dipolar cycloadditions of nitrones to methacrolein are effectively catalysed by rhodium and iridium Lewis acid cations [(η-C5 Me5 )M{(R)Prophos}(H2 O)]2+ [(R)-Prophos = 1,2-bis(diphenylphosphino)propane].50 The Zn(II) triflate-catalysed 1,3-dipolar cycloaddition reaction between C-(2-thiazolyl)nitrones and allyl alcohol showed enhanced rate of reaction under microwave irradiation.51 A chiral binaphthyldiimine–Ni(II) complex, prepared from N ,N -bis(3,5-dichloro2-hydroxybenzylidene)-1,1 -binaphthyl-2,2-diamine and Ni(ClO4 )2 .6H2 O, has been used to catalyse the 1,3-dipolar cycloaddition of nitrones with 3-(alk-2-enoyl)2-thiazolidinethiones with excellent exo selectivity (exo:endo => 99:1 to 86:14) and enantioselectivity (95–82% ee).52 A key synthetic step in the preparation of optically pure fused or bridged tricyclic β-lactams involves the use of the intramolecular nitrone–alkene cycloaddition of monocyclic 2-azetidinone-tethered alkenylaldehydes.53 The intramolecular 1,3-dipolar cycloaddition of nitrones derived from homochiral β-amino acids yields homochiral bicyclic isoxazolidinylpyridin4(1H )-ones, which can be further manipulated to produce functionalized piperidones.54 The 1,3-dipolar cycloaddition of acryloyloxazolidinone with diphenylnitrone has been catalysed by chiral catalysts involving the chiral ligands TADDOL, bis(oxazolines) (box), and bis(oxazolinyl)pyridine (pybox). The endo/exo selectivity can be controlled by the nature of the divalent cation used. Exo-catalysts are formed with Mg(II), Co(II), and Ni(II).55 The intramolecular 1,3-dipolar cycloaddition

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12 Addition Reactions: Cycloaddition OSiMe3 OSiMe3 R1

O

MeO

Cl

MeO

COR1

MeO

(49)

R2

R4

DBU, THF, 20 °C

R4

R2

R3

R3

(48)

(50) DDQ, 1,4-dioxane, 24 h

O MeO

COR1

R4

R2 R3 (51)

Scheme 13

of N -boranonitrones, derived from O-t-butyldimethylsilyloximes and BF3 .OEt2 , with alkenes yields N -non-substituted tetrahydroisoxazoles with high diastereoselectivity.56 A review of the intramolecular 1,3-dipolar cycloaddition of azomethine ylides featuring reactivity, stereochemistry, and synthesis has been presented.57 The 1,3-dipolar cycloaddition of azomethine ylide with ethene and but-2-ene to produce pyrrolidines proceeds via a synchronous concerted π 4 s + π 2 s mechanism.58 The use of asymmetric catalysis in the enantioselective 1,3-dipolar cycloaddition of azomethine ylides with alkenes to produce highly substituted proline derivatives has been investigated. The results show that N ,P -ligands–Ag(I), P ,P -ligands–Cu(II), and N ,N -ligands–Zn(II) are suitable combinations for this class of asymmetric cycloaddition.59 Silver fluoride and hydrocinchonine catalyse the diastereo- and enantio-selective 1,3-dipolar cycloaddition between azomethine ylides and acrylates to yield endo-pyrrolidines.60 The bifunctional AgOAc-catalysed asymmetric 3 + 2-cycloaddition of azomethine ylides with electron-deficient alkenes, using ferrocenyloxazoline-derived N ,P -ligands (52), produces optically active pyrrolidine derivatives.61,62 Silver acetate-catalysed asymmetric 1,3-dipolar cycloadditions of N -metallated azomethine ylides with chiral acrylamides show excellent diastereoselectivity.63 Chiral copper-catalysed 3 + 2cycloadditions have been used for kinetic resolutions of azomethine imines.64 The azomethines (53) produce the 2-azaallyl anions 4-alkylidene-4H -pyridin-1-ides (54), which react with CS2 to produce lithium 2,3-dihydro-1,3-thiazole-5-thiolates (55), which can be converted to the corresponding 1,3-thiazole-5(2H )-thiones (56) (Scheme 14).65 Thiocarbonyl S-methylides have been shown to undergo 1,3-dipolar cycloaddition only with trithiocarbonates and dithioesters. However, the present work has shown

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360


Fe

Bn N P(4-CF3C6H4)2 (52)

R2 N N

R1 R1 = Me, Ph R2 = Ph, t-Bu, a-naphthyl, C6H4-4-Ph, C6H4-4-OMe

(53)

R2

R2 N LiN

(54)

R1

CS2

R

LiN N

S S (55)

R2

1

N N

R1

S S (56)

Scheme 14

that thiocarbonyl ylides do react with a thionolactone.66 The 3 + 2-cycloaddition of 2,2,6,6-tetramethylcyclohexanethione S-methylide with 2,3-bis(trifluoromethyl)fumaronitrile is a two-step process involving an intermediate zwitterion.67 Lewis acids such as Yb(OTf)3 are essential for the success of the 1,3-dipolar cycloaddition of 1methoxy-2-benzopyrylium-4-olate with a variety of imines.68 Chiral 2,6-bis(oxazolinyl)pyridine–rare earth metal complexes catalyse the enantioselective 1,3-dipolar cycloaddition reactions of 2-benzopyrylium-4-olates with several benzyloxyacetaldehyde derivatives.69 The silver acetate-promoted 1,3-dipolar cycloaddition of nitrilimines with 3(R ∗ )phenyl-4(R ∗ )-cinnamoyl-2-azetidinone produced the major adduct, 4-(4,5-dihydropyrazol-5-yl)carbonyl-2-azetidinones, with high stereoselectivity.70 The 1,3-dipolar cycloadditions of substituted 2,7-dimethyl-3-thioxo-3,4,5,6-tetrahydro-2H -[1,2,4] triazepin-5-one with N -aryl-C-ethoxycarbonylnitrilimines are highly chemoselective, where the sulfur atom of the dipolarophile interacts with the carbon atom of the dipole.71 The enantioselective 1,3-dipolar cycloaddition of nitrile imines with electron deficient acceptors produces dihydropyrazoles in the presence of 10 mol% of chiral Lewis acid catalyst.72 A simple chiral silane Lewis acid has been used in the highly diastereo- and enantio-selective 3 + 2-cycloaddition of acylhydrazones with enol ethers.73 The 1,3dipolar cycloaddition of isocyanides (CNCH2 EWG) with electron-deficient alkynes

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361


(RC≡CEWG) yields 2,4-di-EWG-substituted pyrroles in the presence of copper catalyst but 2,3-di-EWG-substituted pyrroles in the presence of a phosphine catalyst.74 The 3 + 2-cycloaddition of diazoalkanes to (S)-3-p-tolylsulfinylfuran-2(5H )-one produces diastereoisomeric pyrazolines in almost quantitative yield and with des >98%. The sulfinyl group is responsible for the complete control of the π -facial selectivity in all these reactions.75 The Rh(II)-catalysed intramolecular 1,3-dipolar cycloaddition reaction of diazoamides (57) with alkenyl and heteroaromatic π -bonds yields pentacyclic compounds (59), via the ylide (58), in good to excellent yields and in a stereocontrolled manner (Scheme 15).76 O N

[Rh2OAc]4

Me O

N

N2 CH2

Me

25 °C

O CO2Et

(57)

O

O N +

O

N Me

CH2

−

N

25 °C

Me

N

92%

O

Me

O

Me

O

CO2Et CO2Et

(58)

(59) Scheme 15

A one-step quantitative 3 + 2-cycloadditon of SnSAsF6 with 1,4-benzoquinone (60) yields benzo-fused-1,3,2-dithiazolylium [AsF6 − ] salt (61), which readily reduces to the corresponding 7π radical (62) with SO2 (Scheme 16).77 O

O

H

SNSMF6

S +

SO2 0.5 h

O (60)

OH

O

H

N

S

(61) Scheme 16

SO2 24 h

S +

S OH (62)

N

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2 + 4-Cycloaddition A review cataloging intramolecular Diels–Alder reactions as key steps in the total synthesis of natural products has been published.78 A key step in the total synthesis of (+)-dihydrocompactin (66) is the intramolecular ionic Diels–Alder reaction of the trienone (63) to yield the (+)-compactin core compound (65) via the intermediate cyclic vinyloxocarbenium ion (64) (Scheme 17).79 The intramolecular Diels–Alder reaction of the Asp–Thr tethered compound (67) produced the cycloadduct (68) with high regio- and stereo-selectivity (Scheme 18).80 Mixed quantum and molecular mechanics (QM/MM) combined with Monte Carlo simulations and free-energy perturbation (FEP) calculations have been used to show that macrophomate synthase

TMSO

OTMS TMSO

Al(OTf)3 3 equiv/ TfOH 0.1 equiv

O Me

+

O Me

CH2Cl2, −20 °C

(64) (63) HO HO TMSO O

+

O

H

H

Me H

H (65) O O

O O

Me

OH

Me

H Me

H (66) (+)-dihydrocompactin Scheme 17

Me

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12 Addition Reactions: Cycloaddition CH2

Me

Me H CH2

CH2

O O

BocHN O

O

O

H N

H

O PhMe, 150 °C

H

O

75%

H Me CO2Me

BocHN

H

O

(67)

O H Me CO2Me

O

H N

H

(68) Scheme 18

derived from the phytopathogenic fungus Macrophoma commelinae is not a natural Diels–Alderase as previously claimed.81 The intramolecular Diels–Alder cycloaddition of fulvenes provides a rapid entry to the polycyclic ring skeletons of natural products, kigelinol, isokigelinol, neoamphilectane, and kempene-2. For example, the thermal intramolecular cycloaddition of the fulvene (69) in toluene produced the key tricyclic ester (70) that was transformed into the tricyclic core (71) of kempene-2 (Scheme 19).82 The use of a chiral template in the intramolecular Diels–Alder reactions of the perhydro-1,3-benzoxazine (72) provides the cycloadducts (73) as single

CO2Et

Me Me

Me

H

reflux

H

H

PhMe

Me CO2Me

H (69)

CO2Et (70)

Me

H Me H HH H EtO2C

H OH

H Cl (71) Scheme 19

CO2Me

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Organic Reaction Mechanisms 2005 Me

Bn O N

Me Me

50–60 °C

H ArN

R1

O R2

O R1, R2 = H, H; Me, H; H, Me; H, Ph

(72) Me

Bn

R2 1. H2/10% Pd/C, EtOH, r.t. 2. 2% HCl, EtOH, reflux

O

N

Me Me

H ArN

R1 O NH H

O

O O

HO

R1 R2

(73)

(74) Scheme 20

diastereoisomers. On hydrolysis of the chiral template, the resulting perhydroepoxyisoindolones (74) are enantiopure with up to five stereocentres (Scheme 20).83 The intramolecular Diels–Alder cycloaddition of the (E)-nitrolactone (75) produces a mixture of epimeric nitronates (76) and (77) that represent the correct relationship for the quaternary stereogenic centres in the core structure of daphnilactone B (78) (Scheme 21).84 DFT calculations on the intramolecular Diels–Alder reaction of penta-1,3-dienyl acrylates predict stereoselectivities that are in good agreement with the experimental results.85 Another DFT study at the B3LYP/6–31G(d) level of the intramolecular Diels–Alder cycloaddition of 5-vinylcyclohexa-1,3-dienes has been reported. Reaction rates are influenced by dienophile twisting and substituent effects.86 The intramolecular dehydro-Diels–Alder reactions of ynamides (79) provides a new synthesis of benzo[b]-, tetrahydrobenzo[b]-, naphtho[1,2-b]-, and dibenzo[a,c]carbazoles (80) (Scheme 22).87 The intramolecular 4 + 2-cycloaddition of ynamides with conjugated enynes produces substituted indolines that can be oxidized to indoles with o-chloranil.88 The double Diels–Alder cycloaddition of the linear conjugated tetraene (81) yields the single diastereoisomeric product (82) in quantitative yield (Scheme 23).89 The Diels–Alder cycloaddition of 1,2-dimethylene[2.n]metacyclophanes (83) with DMAD followed by aromatization (84) and photoinduced transannular cyclization produced phenanthrene-anellated polycyclic aromatic hydrocarbons (85) (Scheme 24).90 The non-selective thermal Diels–Alder reaction of hexa-2,4-dienol with methyl acrylate is made enantioselective by using the Lewis acid template (86) to assemble the reagents for cycloaddition.91 The Me2 AlCl-catalysed intramolecular Diels–Alder

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12 Addition Reactions: Cycloaddition Me

O −

O

+

N

Me

SnCl4, CH2Cl2 −60 to 0 °C

OMe

O

68%

O (75) Me −

O

+

N

Me

Me

O

OMe

−

O

+

N

Me

O

O

O

OMe Me N

O

O

O (76) major

H

H

O (77) minor

(78) daphnilactone B

Scheme 21

EWG

EWG

N

R

N R

heat

(79)

(80) Scheme 22

H H

OH MA 2 equiv. PhMe, heat, then CH2N2

Me

HH

H Me H O

(81) Scheme 23

O

O

H CO2Me O

O (82)

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Organic Reaction Mechanisms 2005 MeO

MeO CH2

1. DMAD 2. DDQ

CO2Me

CH2

CO2Me

MeO

MeO (84)

(83)

1. hn/I2 or FeCl3 in CH2Cl2

MeO

CO2Me CO2Me MeO (85)

Scheme 24

H2C

CH2 OMe O

Zn

O

O O

MgBr

(86)

reaction of the optically active allenic ketone (87) produced a single cycloadduct (88); an oxatricyclic system needed for the synthesis of the arisugacin class of natural product acetylcholinesterase inhibitors (Scheme 25).92 The Diels–Alder reactions of the cross-conjugated tetraene [4]dendralene (89) with N -methylmaleimide yields mono(90), di- [(91) and (92)], and tri- [(93) and (94)] adducts with up to eight stereocentres, three new rings, and six C–C bonds (Scheme 26).93

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12 Addition Reactions: Cycloaddition C7H15 O

C7H15 H

O

Me2AlCl

•

Me O Me

−78 to −20 °C 88%

Me

H Me

O Me

Me

Me

(87)

(88)

Scheme 25

H2C CH2

NMM

CH2

H2C

CH2

THF, r.t.

H O

CH2

H N

O

Me (89)

(90) +

O

O H

H

MeN

MeN

CH2

CH2

+

H O H

H O H

H O

H N

H O

O

N

Me

Me

(91)

(92)

H

NMe

MeN H

H

O H

H H

O

H

H

MeN

H

H H O

O

H N

Me

Me

(93)

(94)

Scheme 26

NMe

H

O H

H N

O

O

O H

O

+

+ O

O

H

O

O

368


The Diels–Alder reaction of cyclopentadiene with the acrylate containing an achiral auxiliary produced from levoglucosenone proceeded with satisfactory diastereomeric excess.94 The Lewis acid-catalysed Diels–Alder reactions between cyclopentadiene and methacrolein can be modified by the use of stilbene diols. Thus, the enantiomeric excess reported for the exo-adduct can be increased by 21% by modifying the electron density on the aromatic ring.95 Chiral ammonium salts catalyse the enantioselective Diels–Alder reaction of 5-(benzyloxymethyl)cyclopentadiene, cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, and isoprene with α-(p-methoxybenzoyloxy) acrolein.96 The toluene-coordinated silyl borate {[Et3 Si(C6 H5 Me)]B(C6 H5 )4 } catalyses the Diels–Alder reaction of methyl acrylate with cyclohexa-1,3-diene.97 The reaction of N -substituted indolazepines (95) with α,β-unsaturated aldehydes (96) produces the tetracyclic compounds (98) via an intramolecular Diels–Alder cyclization between the indolacrylate–dienamine intermediates (97) produced in situ (Scheme 27).98 The Lewis acid-catalysed Diels–Alder reaction of S-indoline chiral acrylamides with cyclopentadiene proceeds with high diastereoselectivity, producing either endo-R or endo-S adducts.99 A chiral indium(III) complex was used to catalyse the enantioselective Diels–Alder reaction of cyclic and acyclic dienes with 2-methacrolein and 2-bromoacrolein.100 The thermal and Lewis acid-mediated Diels–Alder reaction of the enethiol equivalents (Z)- and (E)-ethyl-2-carbomethoxyethenesulfinates with dienes produces cycloadducts in 34–94% yield. Further reduction of cycloadducts produced β-mercaptol (or sulfanyl) carbinols in 32–97% yield.101

de

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de ee

CHO Me

N H

NHCH2Ph CH2

(96)

NR

PhMe reflux

CO2Me

N H

CO2Me

(95) R = Bn, allyl, Et, n-Bu

N

CH2Ph N

H

N H MeO2C

N H

(98)

CH2Ph CH2

CH2 CO2Me (97)

Scheme 27

Steric factors have been shown to be important in controlling the face sensitivities in 4 + 2-cycloadditions of diastereotopically non-equivalent π -facial 1,6-annulatedcyclohexa-1,3-dienes.102 The diastereoselectivity of the Diels–Alder reactions of 1-(tbutyldimethylsiloxy)buta-1,3-diene with C(2) symmetric tartrate-derived dienophiles

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depends on the 1,2-diol protecting group in the dienophiles.103 Theoretical studies of the asymmetric Diels–Alder reaction of dichlorovinylborane and vinyl-9-BBN with chiral dienes predict high reactivity and regio- and stereo-selectivity.104 The Diels–Alder reactions of Baylis–Hillman adducts with dienes were highly diastereoselective.105 The rhodium(I)-catalysed intramolecular 4 + 2-cycloaddition of diene-tethered alkynyl halides (99) yields a variety of halogenated bicyclic adducts (100) in good yields (70–87%). These halogenated cycloadducts can be used for the synthesis of more complex polycyclic natural products (101) (Scheme 28).106 DFT (B3LYP/6–31G∗ ) studies on the Diels–Alder reaction of 3-, 4-, and 5-halo-substituted (2H )-pyran-2-ones with alkenes can predict the regioand stereo-selectivity of these additions.107 The enantioselective Diels–Alder reaction of 1-phenoxy-1,2-dihydropyridine with 1-substituted 2-acryloylpyrazolidin-3ones in the presence of chiral cationic palladium–phosphinooxazolidine catalyst produced chiral isoquinuclidines with 97% ee.108 The π -facially selective Lewis acid-catalysed intermolecular Diels–Alder cycloaddition of 3-butadienylazetidin2-ones with dienophiles (maleic anhydride, NPM, N -p-tolylmaleimide, benzoquinone, and naphthoquinone) generate diastereomerically pure 1,3,4-trisubstituted 2azetidinones.109 Diels–Alder reactions of cyclohexylsulfinyl-3-methylbuta-1,3-dienes and 1-[1-(cyclohexylsufinyl)ethenyl]cyclohexane with NPM demonstrate that the sulfur atom of the 2-sulfinyldienes is the only controller of diastereofacial selectivity in these Diels–Alder reactions.110 The use of β-acyloxysulfonyl tethers in the thermally mediated intramolecular Diels–Alder cycloaddition of the sulfone (102) resulted in

X X

n

[RhCl(COD)]2, AgSbF6,

Y

acetone, 25 °C

R

n

Y H (100)

(99) X = Cl, Br, I Y = O, NTs, C(CO2E)2 R = H, Me CO2Me

Me O H (101) Scheme 28

R

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Organic Reaction Mechanisms 2005 R1 R2 S O2

H2C

O R1

O2S CH2

heat, PhMe, 0.01 – 0.04 M

R2

O O

O (103)

(102) 1

R = H, Me, Ph, t-Bu R2 = H, Me, Br Scheme 29

the formation of the endo-cycloadduct (103) with complete regioselectivity and high (10:1) to complete endo/exo selectivity (Scheme 29).111 The highly regioselective Diels–Alder reactions of N -(tosylvinyl)diene (105) with lactam dienophile (104) produced the single regioisomer (106), which was converted to the spirocyclopentane (107), an intermediate in the total synthesis of oroidin alkaloids, axinellamine and palau’amine. The electron-withdrawing Tsv group could easily be converted to the more electron-rich tosylethyl group by hydrogenation (Scheme 30).112 1,4-Difluoro-2,5-dimethoxybenzene was used as a precursor for iterative double benzyne–furan Diels–Alder reactions leading ultimately to highly substituted anthracenols.113 The intramolecular Diels–Alder reactions of conjugated enynes, arenynes, and dienes with benzynes (109), derived from the TBAT-promoted 1,2elimination of o-(trimethylsilyl)aryl triflates (108), produce condensed polycyclic aromatic compounds (110) (Scheme 31).114 The transient aryne, 7,8-quinolyne, has been trapped by the Diels–Alder reaction with furan derivatives.115 DFT theory at the B3LYP/6–31G(d,p) level was used to investigate the Diels–Alder reactions of o-quinone methides with various ethenes. Calculations show that solvent decreases the activation energy and increase the asynchronicity.116 The Diels–Alder reaction of ortho-quinone methides derived from 3H -1,2-benzoxathiole 2,3-dioxides with maleimides produces chroman 2,3-dicarboxylic acid derivatives.117 The intermolecular Diels–Alder reaction between the dibromoenone (111) and dienes (112) provides access to bicyclo[5.4.0]undecane systems (113) that are common core structures of many natural products (Scheme 32).118 The allo-threoninederived O-(p-biphenylcarbonyloxy)-B-phenyloxazaborolidinone catalyses the enantioselective Diels–Alder reaction of acyclic enones with dienes.119 The reversal of facial selectivity in the Diels–Alder cycloaddition of a semicyclic diene with a bromoenone was induced by the presence of the bromo substituent in the dienophile.120 Mixed Lewis acid catalyst (AlBr3 /AlMe3 ) catalyses the Diels–Alder reaction of hindered silyloxydienes with substituted enones to produce highly substituted cyclohexenes.121 Chiral N -enoyl sultams have been used as chiral auxiliaries in the asymmetric Diels–Alder reactions with cyclopentadiene.122

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12 Addition Reactions: Cycloaddition HOCH2

Ts

O +

TsN

N

TIPSO

2,4-lut, PhH, 95 °C, 2-4 d

Ts

O H

N

O

OSPIT (104)

N DMB

N H

O

OTBDPS N

BMD

Ts (105)

(106)

Ts TIPSO Ts

N H

O

H

N O

O

OTBDPS Cl DMB (107)

Scheme 30

R1 TfN

OTf

R1 R2

2 equiv. TBAT 1.5 equiv. BHT

R2

TfN

SiMe3

(108)

(109)

R1

TfN

R2

(110)

Scheme 31

372


R

O

Br

R

CH2 130 °C, 30 h

+

O

CH2

Br (111)

O

H

H (113)

(112)

Br Br

Scheme 32

The 4 + 2-cycloaddition of 2-substituted 1,2-dihydropyridines with nitrosobenzene produces [2.2.2]bicycloadducts, which are readily reduced by alane to trans-2substituted 3-amino-1,2,3,6-tetrahydropyridines stereospecifically.123 The intramolecular nitroso-Diels–Alder reaction of α-acetoxynitroso derivatives in aqueous medium produces 3,6-dihydro-1,2-oxazines in high yield.124 The nitroso-Diels–Alder reaction of acyclic OTIPS-dienes (115) and 6-methyl-2-nitrosopyridine (114) in the presence of [Cu(MeCN)4 (difluorosegphos)]PF6 yielded the dihydro 1,2-oxazine cycloadduct (116) with high yield and enantioselectivity (Scheme 33).125

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TIPSO Me N N

O

OSPIT +

CH2Cl2, −85 to −20 °C (S)-difluorophos (10.5 mol%)

Me

Me

Me [Cu(MeCN)4]PF6 (10 mol%)

Me

N

N O

Me (114)

(116) 95%

(115 ) Scheme 33

The Diels–Alder reaction of 5-acetyl-3-methylthio-1,2,4-triazine with cyclic enamines produces 3-acetyl-1-methylthiocycloalka[c]pyridines, which are synthons for the preparation of sempervirine and its analogues.126 Cycloadditions of aryl-substituted 1,2,4-triazines (117) with 2-cyclopropylidene-1,3-dimethylimidazolidine (118) yield Diels–Alder adducts (120) that eliminate N2 to form dispiropyridines (121), which rearrange to pyrrolo[3,2-c]pyridines (122). At low temperatures, zwitterions (119) formed by nucleophilic attack of (118) on the triazines could be detected spectroscopically and, in some reactions, isolated (Scheme 34).127 Molecular electrostatic potentials have been used to explain the regioselectivity exhibited in the Diels–Alder cycloaddition reactions between 1-trimethylsilyloxybutadiene and the quinones 5-formyl-8-methyl-1,4-naphthoquinone, 5-methoxy7-methyl-1,4-phenanthrenequinone, and 5,6,7-trimethyl-1,4-phenanthrenequinone.128 The intramolecular Diels–Alder reaction of masked o-benzoquinones (123) with a variety of dienes provides adducts (124) which rearrange to functionalized cis-decalins (125) with complete stereocontrol of up to five stereocentres. This methodology

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12 Addition Reactions: Cycloaddition Ar

Ar Ar

Ar N

N

+

N

MeN

NMe

−40 °C

−

N

N

N MeN

R

+

N Me

R (117)

(118)

Ar

(119)

Ar MeN

Me

Ar

−N2

Ar

N

N Me

N

N

Ar N MeN Ar N N Me R

R

R (122)

(121)

(120)

Scheme 34

R4 R5 R1

O

R2

O R3 (123)

R5

R5

R4 O

THF

R1 R2

R1

R2

Cope

OMe R3

O

(124)

R4

O

R3 O OMe

(125)

Scheme 35

allows for the synthesis of biologically active marine metabolites, (±)-xestoquinone and its 9,10-methoxy derivatives (Scheme 35).129 The Diels–Alder reaction of 5trimethylsilylthebane with benzoquinone proceeds from the same face as the silyl group, indicating that the trimethylsilyl group cannot hinder reaction from this face.130 A pivotal step in the synthesis of terpenoids, (−)-colombbiasin A and (−)-elisapterosin B, is the quinone Diels–Alder reaction between the quinone (126) and diene (127) to produce the unstable adduct (128). A new, monomeric [(Schiff base)Cr(III)] complex (129) catalysed this reaction (Scheme 36).131 The Diels–Alder reactions of (1Z,3E)and (1E,3E)-4-aryl-1-phthalimido-2-trialkylsiloxybuta-1,3-dienes with maleimide and quinones display exo stereospecificity, resulting from the presence of phthalimido and aryl groups.132 The uranyl salophen complex (130) catalyses the Diels–Alder addition

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Organic Reaction Mechanisms 2005 O MeO + Me

catalyst (129) 5 mol%

OTES Me

PhMe 5Å MS, 0 °C

Me

O (126)

(127) Me

O

O

H

H

Me

N

OTES

OH2

Cr O OH2Cl

Me

(128)

(129) Scheme 36

C12H25O

OC12H25

N

N O

U O2

O

(130)

of benzoquinone with cyclohexa-1,3-diene.133 The 4 + 2-cycloadditions of cyclic and acyclic dienes with tricarbonyl(1,4-naphthoquinone) complexes yield the corresponding tricarbonyl(tetrahydro-9,10-antraquinone) complexes with perfect endo selectivity and in high yields.134 In a new benzannulation procedure, the 4 + 2-cycloaddition of lithium ynolates (131) with (trialkylsilyl)vinylketenes (132) yields, via an intermediate 3-(oxido)dienylketene (133), the highly substituted phenols (134), which can be converted to benzofurans and benzopyrans (Scheme 37).135 The reaction of buta-2,3-dienoate with vinylketenimine yields the expected Diels–Alder adduct together with an unexpected aniline formed by a competing 2 + 2-cycloaddition.136 The first example of a

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12 Addition Reactions: Cycloaddition R1

O

OLi C

SiR3

R1

+ OLi (131)

C

SiR3

C

R2

O

R3 (132)

R2 R3 (133)

1

R = i-Pr, n-Bu, CH2CH=CH, R2 = R3 = Me cyclohexyl R2, R3 = –(CH2)4– R2 = Me, R3 = Et

OSiR3 R

1

R2

HO R3 (134) Scheme 37

4 + 2-cycloaddition of keteniminium triflates, [MeN(Ts)CH=C=NR1 (R2 )]+ TfO− , with cyclopenta-1,3-diene to yield trinorbornenone derivatives has been reported.137 Microwave-assisted Diels–Alder reactions of 9-substituted anthracenes with 2acetamidoacrylate in DMF generate conformationally constrained bicyclic bisaryl α-amino acid derivatives with high regioselectivity.138 The Sc(OTf)3 -catalysed Diels–Alder reaction of anthracenes with methyl vinyl ketone does not proceed via an electron-transfer process from anthracenes to the MVK–Sc(OTf)3 complex.139 (−)-(R)-9-(1,2-Dimethoxyethyl)anthracene has been used as a chiral template in the Diels–Alder/retro-Diels–Alder sequence for the synthesis of α,β-unsaturated lactams.140 G3(MP2) studies on the Diels–Alder reaction between singlet oxygen and acenes, benzene, naphthalene, anthracene, tetracene, and pentacene, indicate that all the pathways investigated are concerted and exothermic.141 The 4 + 2-cycloaddition of N substituted 2-pyridones with singlet oxygen yields 1,4-endoperoxides in high yield.142 The Diel–Alder reactions of 2-substituted N -acyl-5-vinyl-2,3-dihydro-4-pyridones with various dipolarophiles produce octahydroquinolines. This technique was used to synthesize the core decahydroquinoline skeleton of the alkaloid gephyrotoxin.143 The relative rates of oxazaborolidinium ion-catalysed Diels–Alder reaction of a series of dienophiles have been calculated by a set of pairwise competition experiments. Trifluoroethyl acrylate is more reactive with cyclopentadiene than with methyl acrylate, even though the methyl ester binds more strongly to the catalyst.144 A DFT study on the oxa-Diels–Alder reaction of buta-1,3-diene with formaldehyde, catalysed by Co(II) and Co(III) complexes, has shown that axial coordination of an

376


aldehyde plays a crucial role in the spin transition that enhances the Lewis acidity of the cobalt complex and improves enantioselectivity.145 Another DFT study with the 6–31 + G∗ basic set of the 4 + 2-cycloaddition reactions of ethene and formaldehyde with buta-1,3-dien-1-one and derivatives shows that all the reactions are either pericyclic or pseudopericyclic.146 The oxa-Diels–Alder reaction of chiral dienes (135) with α,β-unsaturated aldehydes (136) provides a route to all-cis-2,3,6-trisubstituted tetrahydro-γ -pyrones (137). These compounds are possible building blocks in the synthesis of complex polyketide macrocycles (Scheme 38).147 The oxa-Diel–Alder reactions of aminosiloxydiene with unactivated aldehydes are catalysed by the axially chiral 1,1 -biaryl-2,2 -dimethanol through hydrogen bonding.148 Titanium(IV) tridentate Schiff base complexes catalyse the asymmetric oxa-Diels–Alder reactions of the Brassard diene with aldehydes under mild conditions.149 The (R)-BINOL–Ti(IV) complex catalyses the highly enantioselective oxa-Diels–Alder reaction between trans1-methoxy-2-methyl-3-trimethylsiloxybuta-1,3-diene and aldehydes.150 The chemoselectivity in the Diels–Alder reaction of α,β-unsaturated aldehydes and ketones with cyclopentadiene can be reversed when catalysed with bulky Lewis acids or Brønsted acids.151 Reversible Diels–Alder chemistry between various dienes and dienophiles has been investigated.152

ee

ee

OTBS R1 +

R2CH=CHCHO (136)

O Me

1. BF3.Et2O, Et2O 2. AcOH, TBAF, THF

O Me

(135)

R1 R2

O O

O

Me

Me

(137)

Scheme 38

The hetero-Diels-Alder cycloaddition of N -sulfinylper(poly)fluoroalkanesulfinamides with dienes at −78 ◦ C produces the corresponding cycloadducts with complete regioselectivities and good diastereoselectivities.153 The intermolecular hetero-Diels– Alder reaction of 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester with N -arylidine-N -methylformamidines and N -arylidine guanidine gives rise to pyrimido[4,5-d]pyrimidines possessing antitumour drug activity.154 The intramolecular hetero-Diels–Alder reaction of erythronolide, ABT-773, (138) in aqueous alcoholic solution produces the cycloadduct (139) in 20–50% yield (Scheme 39).155 Diarylazines react with dibenzoylacetylene in refluxing toluene to produce the Diels–Alder adducts, 3,6-diaryl-4,5-dibenzoylpyridazines.156 The hetero4 + 2-cycloaddition of optically active 2 -thiazolines with acyl Meldrum’s acid derivatives generates the optically active isomers 3R,9R-1,3-oxazinones and not the previously reported 6-acylpenams.157 The hetero-Diels–Alder reactions of 5-chloro2(H )-1,4-oxazin-2-one as a 2-azadiene with electron-rich, electron-deficient, and

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N

ROH, H2O

Me

O Me

O

70 – 80 °C 5–7 d

Me

H N

O

OH

Me Me

O

O O

O Me O

O

NMe2

Me

Me (138) Me O H N O

Me O

H

Me

H

Me Me O

O Me O

O

N

Me (139) Scheme 39

electron-neutral dipolarophiles have been investigated using DFT at the B3LYP/6– 31G∗ level.158 The sequential oxidation and asymmetric Diels–Alder cycloaddition of hydroxamic acids and N -hydroxyformate esters are catalysed by the chiral ruthenium salen complex (140) to produce bridged oxazinolactams.159 The sulfur- or seleniumcatalysed Diels–Alder reaction of [1,4,2]diazaphospholo[4,5-a]pyridines with 1,3dimethylbutadiene and isoprene proceeds diastereo- and regio-selectively.160 A novel formal inverse-electron-demand hetero-Diels–Alder reaction between 2aryl-α,β-unsaturated aldehydes and ketones produces dihydropyran derivatives stereospecifically.161 The inverse-electron-demand Diels–Alder reaction of 3,4-t-butylthiophene 1-oxide with electron-rich dienophiles shows syn-π -face and endo selectivity.162 The inverse-electron-demand Diels–Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6dicarboxylate with a variety of dienophiles produces phthalazine-type dihydrodiol and diol epoxides which were synthesized as possible carcinogens.163

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NLN Ru OLO

O2N

NO2

NO2

O2N

L = PPh3 (140)

A DFT study, at the B3LYP/6–31G(d) level, of the aza-Diels–Alder reaction between cyclopentadiene and the protonated N -benzylimine of methyl glyoxylate indicates a highly asynchronous concerted mechanism leading to exo stereoselectivity.164 The titanium tetrachloride-mediated aza-Diels–Alder cycloaddition of PTAD and the chiral diene (141) produces the dehydropiperazic acid derivative (142) diastereospecifically and in high yield. Further manipulation of (142) leads to the synthesis of (S)piperazic acid (143) (Scheme 40).165 The MgI2 -catalysed aza-Diels–Alder reactions of 4-iodo-2-trimethylsilyloxybutadiene with N -aryl- and N -benzyl-imines produce 2,3dihydropyridin-4-ones.166 The Yb(OTf)3 -catalysed intermolecular aza-Diels–Alder CH2 PTAD TiCl4 (3 equiv.), CH2Cl2 −78 to r.t. 17 h

N

O

O O (141) O Ph

N

N N ∗

HN HN ∗

O N

O O

CO2H (S)-piperazic acid

O

(142)

(143)

95% Scheme 40

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reaction of N -benzhydrylimines with trans-1-methoxy-2-methyl-3-trimethylsiloxybuta-1,3-diene generated 2,5-disubstituted 2,3-dihydro-4-pyridones in high yields.167 The zirconium complex-catalysed asymmetric aza-Diels–Alder reaction of benzoylhydazones with Danishefsky’s dienes is the key step in the asymmetric formal synthesis of (S)-(+)-coniine.168 (S)-Proline catalyses the one-pot three-component enantioselective aza-Diels–Alder reaction between aqueous formaldehyde, aromatic amines, and α,β-unsaturated cyclic ketones to produce azabicyclic ketones with >99% ee.169 The aza-Diels–Alder cycloadditions of 4-phosphinyl- and 4-phosphonyl-1,2-diazabuta-1,3dienes with dienophiles, styrene, cyclopentadiene, dihydrofuran, and norbornadiene yield tetrahydropyridazines with a phosphane oxide or a phosphonate substituent.170 High yields of chromenes have been obtained by the DABCO-catalysed 4 + 2-cycloaddition of salicyl-N -tosylimines with ethyl buta-2,3-dienoate and penta-3,4-dien2-one.171 Imidazolinium salts behave as catalysts for the Diels–Alder reaction of imines with Danishefsky’s diene.172 The Diels–Alder cycloaddition of EWG-bearing thiophene-1,1-dioxide with 1,3-dienes yields cycloadducts with high chemo-, regio-, and stereo-selectivity.173 The key step in the total synthesis of the indolizidine alkaloid (−)-2091 (148) is the one-pot formal 4 + 2-cycloaddition of secondary cyclic γ -chloropropylamines (144) with conjugated alkynoates (145) to afford substituted indolizidines (146, 147) (Scheme 41).174 H R

H

ee

de

CO2Et

CO2Et (145)

R = n-C5H11, (CH2)3OBn

Cl

N

ee

HO

Na2CO3/NaI, i-PrOH, reflux

C5H11-n

H (144)

(146) + H

CO2Et

HO Me (148)

N

C5H11-n (147)

indolizine (−)-2091 Scheme 41

Nitrosonium terafluoroborate initiates the cation radical-mediated imino-Diels– Alder reaction of N -arylimines with N -vinylpyrrolidinones to give cis-4-(2-oxopyrrolidin-1-yl)tetrahydroquinolines.175 Also, 2,4,6-triphenylpyrylium tetrafluoroborate catalyses the Diels–Alder addition of N -arylimines with N -vinylpyrrolidinone and N -vinylcarbazole to yield the corresponding 2-oxopyrrolidin-1-yl- and carbazole-9yl-tetrahydroquinolines.176 The tricyclic core (151) of the batzelladine alkaloids has been prepared by a diastereoselective 4 + 2-annelation of the vinylcarbodiimide (150)

de

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Organic Reaction Mechanisms 2005 BnO2C H

H

+

OTBDPS

Me

N

N

(149)

C

N

PMB

(150)

(ClCH2)2, 23 °C, 86%

H BnO2C H Me H

H

+

BnO2C

N N OH PMB

N H

H

H

OR

N

Me

N H

N

PMB

(151)

H N

H2N +

NH2

(CH2)4 O

O H

H

+

N

Me

N H H

H N H

(CH2)8Me

(152) Scheme 42

with the chiral N -alkylimine (149). Further elaboration of (151) has led to the total synthesis of (−)-batzelladine D (152) (Scheme 42).177 A DFT study of the polar Diels–Alder reaction of 4-aza-6-nitrobenzofuroxan with cyclopentadiene found only one highly asynchronous transition state structure associated with the formation of the 4 + 2-adduct.178 4-Nitrobenzodifuroxan has been shown to be a highly reactive nitroalkene in Diels–Alder reactions with common dienes (cyclopentadiene) to produce stable NED adducts and with ethyl vinyl ether to produce IED adducts.179 Unlike α-acylfuran, 2-nitrofurans have been shown to be active dienophiles in thermal NED Diels–Alder reactions with a variety of buta-1,3-dienes, including Danishefsky’s diene.180 The Diels–Alder reaction of a difluorinated dienophile with furans produced cycloadducts which could be converted to difluorinated cyclohexane or cyclohexane polyols.181 Heptaleno[1,2-c]furans undergo Diels–Alder cycloaddition with electron-deficient dienophiles (DMAD, DCE) to produce the corresponding

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1,4-epoxybenzo[d]heptalenes, which can be transformed into 2- and 3-substituted benzo[a]heptalenes.182 3-(Alkoxyvinyl)benzo-furans, -furopyridines, and -indoles behave as good dienes in the 4 + 2-cycloaddition reactions with acrylates and MVK. The endo/exo selectivity depends on the activation conditions used in the reactions.183 The highly pyramidalized tricyclo[3.3.0.03,7 ]octene derivatives [e.g. (153)] have been successfully trapped with dienes [11,12-dimethylene-9,10-dihydro9,10-ethanoanthracene (154), 1,3-diphenylisobenzofuran, 2,5-dimethylfuran and furan] as cycloadducts [e.g. (155)] in Diels–Alder reactions (Scheme 43).184 The stereoselectivity of furan–maleic anhydride and furan–maleimide Diels–Alder reactions has been investigated theoretically and experimentally. Neither of these reactions proved to be prototypical examples of Diels–Alder 4 + 2-cycloadditions.185 The intermolecular Diels–Alder reactions of the annulated furan (156) with maleic anhydride, N phenylmaleimide, and DMAD to yield cycloadducts [e.g. (157)] have been investigated as a potential key step in the total synthesis of Eunicellin diterpenoids, eleutherobin and sarcodictyin A (Scheme 44).186 A key step in the total synthesis of the marine metabolite (−)-solanopyrone D (161) is the enantioselective organocatalytic intramolecular Diels–Alder reaction of the trienal (158) to the decalin aldehyde (160) in the presence of the imidazolidinone catalyst (159) (Scheme 45).187 Protonated 1,2-diamino-1,2-diphenylethane has been

H2C H2C +

(153)

1,4-dioxane, r.t.

(154)

(155) 44% Scheme 43

OSBT O H

O OSBT H

MA PhMe, 85 °C

H Me

O H

O H

H

Me Me (156)

Me (157)

Scheme 44

O

de

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382


O

Ph

CHO

N N H

Me Me Me

Me CHO

(159) 20 mol%

Me

H

5 °C, MeCN

H

(158)

(160)

O Me

O H

CHO

Me

OMe

OH

O

H

H

H

MeO

O

(−)-solanopyrone (161) Scheme 45

Me

Me

NH N CH2Ph

O (162)

used as an organocatalyst in the asymmetric Diels–Alder addition of cyclopentadiene with crotonaldehyde. High endo/exo selectivity and endo enantioselectivity have been displayed.188 Cyclic hydrazides [e.g. (162)] display asymmetric organocatalysis in aqueous Diels–Alder reactions between cyclopenta-1,3-diene and cinnamaldehyde.189 Bis-triflamides of chiral diamines catalyse the Diels–Alder reaction with carbonyl compounds through hydrogen bonding.190 The intermolecular Diels–Alder reactions of 1,3-dithioles (163) with DMAD and DEAD produced the first 7H -thieno[2,3-c]thiopyran-7-thiones (164) and 4H -thieno [3.2-c]thiopyran-4-thiones (165), the structures of which were confirmed by X-ray diffraction. Further work on the mechanism of the cycloaddition and subsequent rearrangement is in progress (Scheme 46).191

de ee

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12 Addition Reactions: Cycloaddition CO2Me

S S

CO2Me

DMAD or DEAD heat, xylene

S

Cl (163) RO2C

MeO2C S MeO2C

S (164)

S

CO2R

MeO2C

S

+ MeO2C

S R = Me, Et

CO2R S

CO2R

(165)

Scheme 46

The kinetics of the Diels–Alder reaction between cyclopentadiene and N -n-butylmaleimide in mixtures of water with MeOH, MeCN, and poly(ethylene glycol) have been investigated. The results were analysed using the Abraham–Kamlett–Taft model. The solvent effects in aqueous mixtures were not satisfactorily explained by this model.192 The intramolecular Diels–Alder reaction of the α,β-unsaturated iminium dipolarophile (166) in water has furnished the macrocyclic core (167) of the marine phytotoxin gymnodimine as a single exo-adduct (Scheme 47).193 The effect of salt, concentration, and temperature on the asparagine-based aqueous Diels–Alder cycloadditions has been investigated. Temperature and concentration have a modest impact on the cycloaddition stereochemistry and Lewis acid salts reduce the diastereoselectivity for endo-adducts.194 The effect of Lewis acid catalysts on the Diels–Alder reaction between cyclopentadiene and dienophiles in ionic liquids has been investigated in depth. The combination of 1-hexyl-3-methylimidazolium tetrafluoroborate with cerium triflate proved to be an efficient catalyst in increasing reaction rates and enhancing stereoselection.195 The origin of the high reaction rates of the Diels–Alder reactions between 9-hydroxymethylanthracene and N -ethylmaleimide in fluorous solvents and supercritical CO2 is attributed to the presence of a hydrogen bond between the two reactants in the TS.196 A new Lewis acid-assisted Lewis acid has been developed as a moisture-tolerant catalyst (168) for the enantioselective Diels–Alder reaction of cyclopentadiene with α,β-unsaturated ketones and aldehydes.197 Diels–Alder reactions of (Z)-N -substituted-4-methylene-5-propylidene-2-oxazolidinone dienes with methyl vinyl ketone, methyl propiolate, and captodative alkenes yield the highest regio- and stereo-selectivities in mixtures of H2 O and MeOH or under BF3 .Et2 O catalysis.198 The asymmetric Diels–Alder reaction of cyclopentadiene and 3-acryloyl-2-oxazolidinone is catalysed by a new Cu(II) catalyst containing a chiral sterically congested ‘roofed’ (2-diphenylphosphino)phenylthiazoline ligand (169).199

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384 OH


CH2

OH CH2

OH

Me

OH

H

O

Me

O

Me

Me N

N

Me

Me

(166)

(167) Scheme 47

Me Me

Me R N

B

O

N

Me

PPh2

S

(168)

(169)

R = n-octyl, CH2(1-naphthyl)

The hetero-Diels–Alder reaction of N -sulfonylindoloquinone (170) with heterodienes (171) under a pressure of hydrogen (10 bar) and in the presence of palladium produced piperidinoindoloquinones [(172) and (173)] in a one-pot reaction. The piperidinoindoloquinone core is present in marine alkaloids such as discorhabdin (Scheme 48).200 A moderate asymmetric induction was observed when (salen) chromium(III) complexes were used to catalyse the high-pressure Diels–Alder reaction of buta-1,3-diene with glyoxylic acid derivatives.201 1-Triflylpyrroles are efficient dienophiles in the 4 + 2-cycloaddition with substituted dienes under high pressure and Lewis acids.202 The thermal and high-pressure Diels–Alder reaction of electron-rich 2H -pyran-2-ones with alkynes generate aniline derivatives.203 Lewis acid catalysts and high pressure activate the 4 + 2-cycloadditions of substituted pyrroles with electronrich dienes provided that the aromatic rings possess at least two electron-withdrawing groups.204

Miscellaneous Cycloadditions NaI catalyses the regioselective 1 + 2-cycloaddition of cyclopropenes with imines to yield cis-vinylic aziridines.205 The synthesis of a new series of mixed Rh(II)2

385

12 Addition Reactions: Cycloaddition NMe2

O

EtOH H2/Pd/C

N + N

R2

SO2Ph

O

R1

(170)

(171) R1, R2 = H, H; H, Me; Me, H; H, Et; Et, H; Ph, H

H N

R1

O +

N

R2 R1

O

R2

O

SO2Ph

(172)

N H

N O (173)

SO2Ph

Scheme 48

complexes containing bridged acetate and R,R-diphenyl-N -triflylimidazolidinone (DPTI) ligands has been described. These complexes catalyse the enantiselective 2 + 1-cycloaddition of ethyl diazoacetate with terminal alkynes to yield chiral cyclopropanes.206 A review has been published describing the recent advances in the transition metalcatalysed 2 + 2 + 2-cycloadditions leading to complex polycycles and heterocycles, biologically active molecules, and unusual amino acids.207 The chemo-, regio-, and enantio-selective 2 + 2 + 2-cycloaddition of unsymmetrical α,ω-diynes with alkyl isocyanates, in the presence of 5% [Rh(COD)]BF4 –(R)-DTBM (Segphos), produces a range of axially chiral 2-pyridones with up to 92% ee.208 Rhodium catalysts, e.g. [Rh(COD)2 ]BF4 , have been used in the intermolecular 2 + 2 + 2-cycloaddition of 1,6enynes with symmetrical and unsymmetrical alkynes to produce bicyclic cyclohexa1,3-dienes.209,210 The cobalt-catalysed regioselective 2 + 2 + 2-cocyclotrimerization of alkynyl alcohols and amines affords benzolactones and benzolactams in a one-pot process.211 N -Heterocyclic carbene (176)–CoCl2 /Zn or – FeCl3 /Zn compounds catalyse the intramolecular cyclotrimerization of triynes (174) to annulated benzenes (175) in high yields (Scheme 49).212 A rhodium(I)–H8-BINAP complex-catalysed intermolecular cross-cyclotrimerization of internal alkynes with DMAD produces axially chiral biaryls with high enantioselectivity (96% ee).213 Ni–imidazolylidene complexes (179) catalyse the 2 + 2 + 2-cycloaddition of diynes (177) with aldehydes and

ee

ee

ee

386

Organic Reaction Mechanisms 2005 Y

R1

R2

Z

[2 (176) + CoCl2] or [(176) + FeCl3] (1 − 5 mol%) Zn powder (10%), THF r.t. to 50 °C

(174)

Y R1 R2 Z (175)

R1, R2 = H, SiMe3, Ar, alkyl, CH2OH, CH2OBn Y, Z = O, C(CO2Et)2 Pri

Pri N

N Pri

Pri (176)

Scheme 49

ketones (178) to produce pyrans (180) and dienones (181) in good to high yields (Scheme 50).214 The Cp∗ RuCl(cod) (Cp∗ = η5 -C5 Me5 , cod = cycloocta-1,5-diene)catalysed 2 + 2 + 2-cycloaddition of α,ω-diynes with nitriles, isocyanates, and isothiocyanates affords a variety of heterocyclic compounds.215 The regio- and enantioselective rhodium-catalysed 2 + 2 + 2-carbocyclization of carbon- and heteroatomtethered 1,6-enynes (182) with unsymmetrical 1,2-disubstituted alkynes (183) to produce the corresponding bicyclohexadienes (184, 185) in excellent yields has been reported. This methodology will be developed for the total synthesis of natural products (Scheme 51).216 The photocycloaddition of diarylalkynes, in which one of the aryl groups is either a pyridine or a pyrazine, with cyclohexa-1,4-diene, produces 1,5diaryl-substituted tetracyclo[3.3.0.02,8 .04,6 ]octanes. However, in the case of pyrazinylacetylenes, the primary homoquadricyclane rearranges photochemically to diaryl substituted tricyclo[3.2.1.04,6 ]oct-2-enes.217 The domino Suzuki coupling–Heck reaction sequence involving dihydroaromatic alkenyl-substituted boronic esters (186) with diiodobenzene, bromoiodobenzene, or iodoaniline derivatives yields substituted phenanthrene (187) and phenanthridene derivatives regiospecifically (Scheme 52).218 The Rh metal-catalysed [(2 + 2) + 2]- and [(2 + 2) + (2 + 2)]-reactions of 1,8dialkynylnaphthalenes (188) with norbornadiene produced fluoranthenes (189) and the heptacycles (190), respectively (Scheme 53).219 A review describing 3 + 3-cycloadditions and their application in the synthesis of naturally occurring alkaloids has been reported.220 An extensive review of the formal

387

12 Addition Reactions: Cycloaddition Me

Me

Me

Me N

N

(10 mol%)

Me Me Me

R1 O + (177 ) R1

PhMe, r.t.

R2 R3 (178)

R1

Me

(179 ) Ni(COD)2 (5 mol%)

R1

R2

R2

R3 O

O R1

R1

(180)

(181)

R3

Scheme 50

COMe Ts Ph

H Ts

N

CH2

N

COMe

R (184)

(183) [RhCl(COD)]2 (S)-Xyl-P-PHOS

Ph

+

AgBF4, THF, 60 °C

R

Ph

(182)

Ts

N

R = H, Me R (185)

COMe

Scheme 51

3 + 3-cycloaddition approach for preparing complex natural-product heterocycles has been published. The formal cycloaddition requires condensation of α,β-unsaturated iminium salts with 1,3-dicarbonyl equivalents via a Knoevenagel-type condensation followed by a reversible 6π -electron electrocyclic ring closure.221 DFT studies have been reported for the formal hetero 3 + 3-cycloaddition reaction between vinylogous

388


R

Me

CH2

Me

B

O

O Me

Me Me Me

R

1. 1,2-diiodobenzene PdCl2 (dppf) THF, aq. NaOH, 12 h, r.t. to 60 °C

Me

2. DDQ, PhMe, r.t. 0.5 h

(187)

(186) R = H, Me Scheme 52

R1

R2 R1

(188) =

R2

R2

+

p-xylene

R1

R1

R2

5 mol% Rh catalyst norbornadiene

(189)

(190)

= Ph, 4-t-Bu-C6H4, 2-Br-C6H4, 4-MeCO2-C6H4 Scheme 53

amides and α,β-unsaturated imine cations. The reaction proceeds by several steps in which the final 6π -electron electrocyclic ring closure is not reversible.222 Chiral secondary amine salts promote the enantioselective intramolecular formal aza-3 + 3cycloaddition of vinylogous amide to quinolizidines. The enantioselectivity of the reaction depends on the structure of the chiral amines.223 A DFT study on the GaCl3 -catalysed 4 + 1-cycloaddition of α,β-unsaturated ketones with 2,6-dimethylphenyl isocyanide to produce unsaturated lactones shows the reaction is stepwise and exothermic.224,225 The rhodium N -heterocyclic carbine complex [Rh(IMes)(COD)] [IMes = N ,N bis(2,4,6-trimethylphenyl)imidazol-2-ylidine; COD = cycloocta-1,5-diene] catalyses the 4 + 2 + 2-carbocyclization of 1,6-enynes (191) to carbocycles [(192) and (193)] (Scheme 54).226 Computational and experimental evidence of a new reaction pathway for the diastereospecific intermolecular rhodium-catalysed 4 + 2 + 2-carbocyclization reactions of 1,6-enynes with π -components has been reported.227 A DFT analysis of the Lewis acid-induced 4 + 3-cycloaddition of 2-silyloxyacroleins with furan indicates a three-step process.228 The 4 + 3-cycloaddition of

ee

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12 Addition Reactions: Cycloaddition Ph

Ph

Ph TsN

RhCl(IMes)(COD) buta-1,3-diene

TsN

Me

AgOTf PhMe, heat 70%

Me

OTBS

TsN

+ H

H

Me

H

H

OTBS

(191)

OTBS

(192)

(193)

Scheme 54 −

O Br

O Br

cyclopentadiene, TEA

+

Br

TFE–Et2O (1:1) −78 °C to r.t.

(194)

cyclopentadiene

O Br

AcO

O H (196)

(195)

OAc

O

CO2Me

AcO Me (197)

Scheme 55

2,5-dibromocyclopentanone (194) with cyclopentadiene yields cycloadduct (195) in 70% yield. This cycloadduct can be converted to the carbocyclic core (196) of tricycloclavulone (197), a marine prostanoid from the Okinowan soft coral (Scheme 55).229 The chiral Lewis acid-catalysed enantioselective 4 + 3-cycloaddition of nitrogen stabilized oxyallyl cations, derived from allenamides, produces cycloadducts with high enantioselectivity when bisoxazoline ligand and CuOTf2 are used in the reaction.230

ee

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Organic Reaction Mechanisms 2005 Me Me Fe(CO)3 Me3NO

H

−CO2

NPh

O

O

N Ph

(198)

(199) Scheme 56

−

O

O R1

R1 Et3N, PhMe

O

O

reflux

R2 O

+

O

(200) R1

= H, SiMe3 O

O

O

O

R1

HO O

O (202)

(201) O OH HO O (203) cordytropolone Scheme 57

391


The dimerization of thioformylketene was investigated by B3LYP and G3MP2B3 methods. The 4 + 4-pathway has the lowest energy barrier and calculations suggest that the reaction is pseudopericyclic.231 The stereospecific intramolecular 4 + 4cycloaddition reaction between cyclohexadiene iron tricarbonyl complex and appended dienes (198) generates cyclooctadiene tricyclic adducts (199) (Scheme 56).232 The first example of an asymmetric intermolecular 4 + 4-photocycloaddition reaction in solution between 9-cyanoanthracene and chiral 2-methoxy-1-naphthamides has been reported. The ‘frozen’ chirality is effectively transferred to the optically active product.233 A DFT study at the B3LYP/6–31G∗ level on the intramolecular 5 + 2-cycloaddition reactions of 3-OR (R = SiMe3 , H, CHO, Me)-substituted β-hydroxy-γ -pyrones tethered to alkenes and alkynes has been reported. Calculations indicate an initial transfer MeO hn cyclohexane

CH2 OH (204) MeO H

H +

HO

OMe

H

HO

(205)

H

(

206)

OH OH

OH Me O HO H

H CH2OH

(207) stemodinone

(208) aphidicolin Scheme 58

ee

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Organic Reaction Mechanisms 2005 [Rh(CO)2Cl]2 5 mol%

O

CO (1 atm)

+

OH (209)

toluene, 60 °C, 48 h

CH2

H

H

(210) O

O

OH HO (211) 56%

Scheme 59

O AcO

CH2Cl2 (dry)

R1

O

OH−

Et3N (dry)

R1 = H, Me

+

O

(212) R2

R3

(213)

R2 R

3

R2 R

O

3

O O

(215)

O (214)

R2 = R3 = Me, Ar, R2–R3 = –(CH2)5–, –(CH2)6–

Scheme 60

of the R group with formation of an oxidopyrylium ylide intermediate, which undergoes an intramolecular 5 + 2-cycloaddition.234 The first base-assisted intramolecular 5 + 2-cycloaddition of 6-acetoxypyranonealkynes (200) produces 3,11-dioxatricyclo [5.3.1.01,5 ]undeca-5,9-dien-8-ones (201), which can be converted to the β-diketone (202), a possible key intermediate in the total synthesis of cordytropolone (203) (Scheme 57).235 The first examples of the intramolecular [Rh(CO)2 Cl]2 -catalysed


393

5 + 2-cycloaddition of vinylcyclopropanes with substituted allenes to produce cycloheptanones has been reported.236 A key step in the synthesis of the polycyclic ring systems of stemodinone (207) and aphidicolin (208) is the alkene–arene metaphotocycloaddition of compound (204) to the photocycloadducts (205) and (206) in 90% yield (Scheme 58).237 A rhodium-catalysed four-component [5 + 1 + 2 + 1]cycloaddition of vinylcyclopropanes (209), alkynes (210), and CO produces hydroxyindanone derivatives (211) in good to excellent yields (Scheme 59).238 The catalyst CoI2 (dppe)–Zn/ZnI2 catalyses the 6 + 2-cycloaddition of cycloheptatriene with terminal alkynes to afford 7-alkylbicyclo[4.2.1]nona-2,4,7-trienes in good yields.239 The intermolecular 6 + 3-cycloaddition of fulvenes (213) with 3-oxidopyrylium betaines (212) yields (214), which, after a 1,5-hydrogen shift, yields the 5,8-fused oxabridged cyclooctanoids (215). This methodology can be used for the preparation of fused cyclooctanoid natural products such as dactylol and precapnelladiene (Scheme 60).240

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12 Addition Reactions: Cycloaddition 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126

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396 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174

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12 Addition Reactions: Cycloaddition 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221

397

Zhou, Y., Jia, X., Zhengang, R. L., Liu, Z., and Wu, L., Tetrahedron Lett., 46, 8937 (2005). Zhang, W., Guo, Y., Liu, Z., Jin, X., Yang, L., and Liu, Z.-L., Tetrahedron, 61, 1325 (2005). Arnold, M. A., Duron, S. G., and Gin, D. Y., J. Am. Chem. Soc., 127, 6924 (2005). Arroyo, P., Picher, M. T., Domingo, L. R., and Terrier, F., Tetrahedron, 61, 7359 (2005). Kurbatov, S., Goumont, R., Lakhdar, S., Marrot, J., and Terrier, F., Tetrahedron, 61, 8167 (2005). Rosa, C. D., Kneeteman, M. N., and Mancini, M. E., Tetrahedron Lett., 46, 8711 (2005). Crowley, P. J., Fawcett, J., Griffith, G. A., Moralee, A. C., Percy, J. M., and Salafia, V., Org. Biomol. Chem., 3, 3297 (2005). Uebelhart, P., Weymuth, C., and Hansen, H.-J., Helv. Chim. Acta, 88, 1250 (2005). Le Strat, F., Vallette, H., Toupet, L., and Maddaluno, J., Eur. J. Org. Chem., 2005, 5296. Camps, P., Fernandez, J. A., Font-Bardia, M., Solans, X., and Vazquez, S., Tetrahedron, 61, 3593 (2005). ˇ Ruliˇsek, L., Sebek, P., Halvas, Z., Hrabal, R., Capek, P., and Svatoˇs, A., J. Org. Chem., 70, 6295 (2005). Sperry, J. B., Constanzo, J. R., and Janisski, J., Butcher, R. J., and Wright, D. L., Tetrahedron Lett., 46, 2789 (2005). Wilson, R. M., Jen, W. S., and MacMillan, D. W. C., J. Am. Chem. Soc., 127, 11616 (2005). Kim, K. H., Lee, S., Lee, D.-W., Ko, D.-H., and Ha, D.-C., Tetrahedron Lett., 46, 5991 (2005). Lemay, M. and Ogilvie, W. W., Org. Lett., 7, 4141 (2005). Whuang, W., Poulsen, T. B., and Jorgensen, K. A., Org. Biomol. Chem., 3, 3284 (2005). Ogurtsov, V. A., Rakitin, O. A., Rees, C. W., Smolentsev, A. A., Belyakov, P. A., Golovanov, D. G., and Lyssenko, K. A., Org. Lett., 7, 791 (2005). Rispens, T. and Engberts, J. B. F. N., J. Phys. Org. Chem., 18, 725 (2005). Johannes, J. W., Wenglowsky, S., and Kishi, Y., Org. Lett., 7, 3997 (2005). Mahindaratne, M. P. D., Quinones, B. A., Recio, A., Rodriguez, E. A., Lakner, F. J., and Negrete, G. R., Tetrahedron, 61, 9495 (2005). Silvero, G., Arevalo, M. J., Bravo, J. L., Jimenez, J. L., and Lopez, I., Tetrahedron, 61, 7105 (2005). Garcia, J. I., Mayoral, J. A., and Slvatella, L., J. Org. Chem., 70, 1456 (2005). Futatsugi, K. and Yamamoto, H., Angew. Chem. Int. Ed., 44, 1484 (2005). Fuentes, A., Martinez-Palou, R., Jimenez-Vazquez, H. A., Delgardo, F., Reyes, A., and Tamariz, J., Monatsh. Chem., 136, 177 (2005). Yamakuchi, M., Matsunaga, H., Tokuda, R., Ishizuka, T., Nakajima, M., and Kunieda, T., Tetrahedron Lett., 46, 4019 (2005). Gentili, J. and Barret, R., Tetrahedron Lett., 46, 1639 (2005). Kosior, M., Kwiatkowski, P., Asztemborska, M., and Jurczak, J., Tetrahedron: Asymmetry, 16, 2897 (2005). Chretien, A., Chataigner, I., and Piettre, S. R., Chem. Commun. (Cambridge), 2005, 1351. Kranjc, K. and Koˇcevar, M., New J. Chem., 29, 1027 (2005). Chretien, A., Chataigner, I., and Piettre, S. R., Tetrahedron, 61, 7907 (2005). Ma, S., Zhang, J., Lu, L., Jin, X., Cai, Y., and Hou, H., Chem. Commun. (Cambridge), 2005, 909. Lou, Y., Remarchuk, T. P., and Corey, E. J., J. Am. Chem. Soc., 127, 14223 (2005). Kotha, S., Brahmachary, E., and Lahiri, K., Eur. J. Org. Chem., 2005, 4741. Tanaka, K., Wada, A., and Noguchi, K., Org. Lett., 7, 4737 (2005). Shibata, T., Arai, Y., and Tahara, Y.-k., Org. Lett., 7, 4955 (2005). Evans, P. A., Sawyer, J. R., Lai, K. W., and Huffman, J. C., Chem. Commun. (Cambridge), 2005, 3971. Chang, H.-T., Jeganmohan, M., and Cheng, C.-H., Chem. Commun. (Cambridge), 2005, 4955. Saino, N., Kogure, D., and Okamoto, S., Org. Lett., 7, 3065 (2005). Tanaka, K., Nishida, G., Ogino, M., Hirano, M., and Noguchi, K., Org. Lett., 7, 3119 (2005). Tekevac, T. N. and Louie, J., Org. Lett., 7, 4037 (2005). Yamamoto, Y., Kinpara, K., Saigoku, T., Takagishi, H., Okuda, S., Nishiyama, H., and Itoh, K., J. Am. Chem. Soc., 127, 605 (2005). Evans, P. A., Lai, K. W., and Sawyer, J. R., J. Am. Chem. Soc., 127, 12466 (2005). Zeidan, T. A., Kovalenko, S. V., Manoharan, M., Clark, R. J., Ghiviriga, I., and Alabugin, I. V., J. Am. Chem. Soc., 127, 4270 (2005). Hilt, G., Hess, W., and Schmidt, F., Eur. J. Org. Chem., 2005, 2526. Wu, Y.-T., Linden, A., and Siegel, J. S., Org. Lett., 7, 4353 (2005). Harrity, J. P. A. and Provoost, O., Org. Biomol. Chem., 3, 1349 (2005). Hsung, R. P., Kurdyumov, A. V., and Sydorenko, N., Eur. J. Org. Chem., 2005, 23.

398 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240

Organic Reaction Mechanisms 2005 Wang, Y., Fang, D.-C., and Liu, R.-Z., Tetrahedron, 61, 5663 (2005). Gerasyuto, A. I., Hsung, R. P., Sydorenko, N., and Slafer, B., J. Org. Chem., 70, 4248 (2005). Wu, Y., Xu, K., and Xie, D., Tetrahedron, 61, 507 (2005). Oshita, M., Yamashita, K., Tobisu, M., and Chatani, N., J. Am. Chem. Soc., 127, 761 (2005). Evans, P. A., Baum, E. W., Fazal, A. N., and Pink, M., Chem. Commun. (Cambridge), 2005, 63 Baik, M.-H., Baum, E. W., Burland, M. C., and Evans, P. A., J. Am. Chem. Soc., 127, 1602 (2005). Saez, J. A., Arno, M., and Domingo, L. R., Tetrahedron, 61, 7538 (2005). Harmata, M. and Wacharasindhu, S., Org. Lett., 7, 2563 (2005). Huang, J. and Hsung, R. P., J. Am. Chem. Soc., 127, 50 (2005). Sadasivam, D. V. and Birney, D. M., Org. Lett., 7, 5817 (2005). Pearson, A. J. and Wang, X., Tetrahedron Lett., 46, 4809 (2005). Sakamoto, M., Unosawa, A., Kobaru, S., Saito, A., Mino, T., and Fujita, T., Angew. Chem. Int. Ed., 44, 5523 (2005). Zaragozá, R. J., Aurell, M. J., and Domingo, L. R., J. Phys. Org. Chem., 18, 610 (2005). Celanire, S., Marlin, F., Baldwin, J. E., and Adlington, R. M., Tetrahedron, 61, 3025 (2005). Wegner, H. A., de Meijere, A., and Wender, P. A., J. Am. Chem. Soc., 127, 6530 (2005). Boyd, J. W., Graeves, N., Kettle, J., Russell, A. T., and Steed, J. W., Angew. Chem. Int. Ed., 44, 944 (2005). Wender, P. A., Gamber, G. G., Hubbard, R. D., Pham, S. M., and Zhang, L., J. Am. Chem. Soc., 127, 2836 (2005). Achard, M., Tenaglia, A., and Buono, G., Org. Lett., 7, 2353 (2005). Radhakrishnan, K. V., Krishnan, K. S., Bhadbhade, M. M., and Bhosekar, G. V., Tetrahedron Lett., 46, 4785 (2005).

CHAPTER 13

Molecular Rearrangements: Part 1. Pericyclic Molecular Rearrangements S. K. Armstrong Department of Chemistry, University of Glasgow [3,3]-Sigmatropic Rearrangements . . . . . All-carbon Pericyclic Systems . . . . . One Heteroatom . . . . . . . . . . . . Two or More Heteroatoms . . . . . . . [2,3]-Sigmatropic Rearrangements . . . . . [1,n]-Sigmatropic Rearrangements . . . . . Vinylcyclopropane–Cyclopentene, Bergman, Diradical Rearrangements . . . . . . . . . . Electrocyclic Rearrangements . . . . . . . . Ene Reactions . . . . . . . . . . . . . . . . . Tandem Pericyclic Rearrangements . . . . . References . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Di-π -methane, and . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Related . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . .

. . . . . .

399 399 400 409 415 416

. . . . .

. . . . .

417 419 424 424 427

Experimental and computational approaches to elucidating mechanistic details in pericyclic rearrangements have been reviewed,1 as have preparations of alkenes by rearrangement reactions.2 The formation of saturated carbon atoms with no attached heteroatoms by sigmatropic or electrocyclic rearrangement reactions has been reviewed.3

[3,3]-Sigmatropic Rearrangements All-carbon Pericyclic Systems Single-reference coupled-cluster calculations employing the completely renormalized CCSD(T) [CR-CCSD(T)] approach have been found to favour the concerted mechanism of the Cope rearrangement of hexa-1,5-diene, involving an aromatic transition state.4 The Cope rearrangements of hexa-1,5-diene and three polycyano derivatives have been investigated using topological analysis of the electron localization function and Thom’s catastrophe theory. The calculations supported suggestions of a half-allyl, half-biradical transition state for Cope rearrangement of 1,3,5-tricyanohexa-1,5-diene.5 Bicyclo[2.2.2]octenones (1) bearing an endo vinyl substituent have been shown to give cis-decalin enones (2) on heating via a Cope rearrangement.6 DFT calculations on the allenyl Cope rearrangement of syn-7-allenylnorbornene have given results which were not consistent either with experiment or with earlier Organic Reaction Mechanisms · 2005: An annual survey covering the literature dated January to December 2005 Edited by A. C. Knipe © 2008 John Wiley & Sons, Ltd. ISBN: 978-0-470-03403-3

399

de

400

Organic Reaction Mechanisms 2005 R2 O R1

R3

H

R2 R3

Δ

O

R1 (1)

(2)

CASSCF calculations.7 Treatment of substituted 5-triethylsilyloxyhexa-1,2,5-triene derivatives with catalytic amounts of W(CO)6 was found to give the products of formal Cope rearrangement: 2-triethylsilyloxyhex-1-en-5-ynes. The mechanism is believed to involve 6-endo attack by the silyl enol ether on the tungsten-activated allene, followed by ring opening with simultaneous loss of W(CO)5 .8 The degenerate Cope rearrangements of semibullvalene, barbaralane, bullvalene, and dihydrobullvalene have been investigated by DFT methods. The height of the activation barrier was found to be influenced by relief of ring strain and conjugation between cyclopropane and ethene moieties, in addition to interallylic (‘bishomoaromatic’) stabilization.9 A DFT study on the Cope rearrangements of cis-divinylcyclopropane, cis-divinyloxirane, and their NH, S and PH analogues has found that all five rearrangements proceed via a boat-like aromatic transition state. The predicted activation barriers were found to increase in the order CH2 < NH < O < PH < S. Since the ring strain in the unsubstituted three-membered rings is known to decrease in the order CH2 > NH > O > PH > S, it was concluded that release of ring strain appears to have an important effect on development of the transition state.10 Ring expansions of sterically congested alk-1-enyl-3-alkylidenecyclobutanol derivatives such as (3), or the equivalent lithium alkoxides, to 2-methylenecyclohex-4-enecarboxylates (6) have been studied, and non-pericyclic revised mechanisms proposed (Scheme 1). At high temperatures, the silyl ethers were found to give preferentially the exo products, such as (6), by breaking of bond a to give diradical (4), preferred over (5) for a combination of steric and electronic reasons. By contrast, the lithium alkoxides were shown to react at low temperatures to give preferentially endo products such as (10), by breaking of bond b, which is known to give the greatly preferred anion (8), and spontaneous conjugation of the enone.11

de

de

One Heteroatom Recent advances in charge-accelerated 3-aza-Cope rearrangements have been reviewed.12 3-Aza-Cope rearrangements have been used to enlarge tetrahydropyrrole and hexahydropyridine derivatives (11) into 9- and 10-membered ring products (13) containing (E)-alkenes. PM3 modelling has suggested that the (Z)-enolates (12) generated before rearrangement can readily adopt a conformation favourable to rearrangement.13 Iminium ions (16) and (17) were shown to be interconverted by a 2-azonia-Cope rearrangement. The position of equilibrium was found to favour (16) strongly, but the

de

O

Me

Me

EtO

EtO

O

(8)

(i)

(3)

Ph

O

Ph

OSiMe3

Δ

Me

O

Ph EtO2C

(4)

Me

Li O

EtO2C

Me3SiO

EtO

(i) 1. TsOH, 2. LiHMDS, −78 °C

Li

a

b

Me

EtO

Ph

(5)

Me

CO2Et

(9) + diastereomer

H

(6)

H

O

Ph

Me

Me3SiO

LiO

not

Scheme 1

Ph

Ph

OSiMe3

CO2Et

Me

Ph

HF

OSiMe3

O

H

(7)

Ph

Ph

Me

Me

CO2Et

Me

CO2Et

Me

(10) (7) : (10) ratio 1 : 5

(7) +

O

H

13 Molecular Rearrangements: Part 1. Pericyclic Molecular Rearrangements

401

402


n

n

N ButMe

2SiO

N

(i)

Ph

O Ph

n

O

ButMe2SiO

(11; n = 1 or 2)

NH O Ph

Li

(12)

OSiMe2But

(13; n = 1 or 2)

(i) 1. LiHMDS, 2. H2O, PhMe H N

O

m

O

(i)

m

n

N H

n

O

O

+ O O

(14)

(15) (ii)

+ n

(iii)

m

+

N

m

N

n

(17)

(16) n = 1, 2 or 3; m = 1 or 2 (i) dimedone, H+ (ii) H2C=O (iii) dimedone

Scheme 2

further equilibrium between (17) and (15) was found to be controllable by addition of either formaldehyde or dimedone (as a formaldehyde scavenger). Thus the conversion of 4-butenylamine-substituted acetals (14) into 1-azabicyclic systems (15) having angular allyl substitution is believed to proceed by the sequence shown in Scheme 2, which has been supported by deuterium labelling studies.14 Reaction of crotylboronates (18) with aldehydes in the presence of In(OTf)3 has been found to be temperature dependent. At low temperatures, the expected 2substituted homoallylic alcohols (19) were formed. At room temperature, by contrast,


O

O

OH

R

(i)

R

2

B

(ii)

O

O

R1

R1 R2 (19)

403

B

O

R R1 R2

(18)

(iii)

R1 R

R1 R

+

O

R2

R2

R

O

(TfO)3In O

+

O

H

R

R

H

B

O

O R R1 R2

R1 R O

B O

OH

O

R2 O

R H

R2

R R1 (20)

(i) excess RCHO, 10% In(OTf)3, −78 °C (ii) excess RCHO, 10% In(OTf)3, room temperature (iii) RCHO•••In(OTf)3

Scheme 3

4-substituted homoallylic alcohols (20) were formed with clean retention of alkene geometry. A mechanism requiring a slight excess of aldehyde has been proposed (Scheme 3). The observation of (19) as the major product at room temperature with substoichiometric aldehyde supports this mechanism.15 Elegant intramolecular competition reactions have been used to show that oxonia-Cope rearrangements are generally faster than the competing Prins cyclizations (Scheme 4). It was found that substituents could affect the relative rates, presumably by stabilizing or destabilizing cationic intermediates. The stereochemical outcome of the Prins cyclization was found to be affected by a balance between ion pair effects and nucleophile reactivity. Detailed mechanistic interpretations have been proposed.16

404


+

OAc R

(ii)

(i)

O

R

O

R

+

scalemic

O Nu−

Nu (iii)

R

O scalemic +

(ii) R

O +

R

achiral

O Nu−

Nu

R

O racemic (i) Lewis acid (ii) Prins cyclization (iii) oxonia-Cope rearrangement Scheme 4

Competitive experiments with 2 H-, 13 C- and 18 O-labelled chorismate derivatives and three different chorismate mutase enzymes have shown that in all catalysed and noncatalysed Claisen rearrangements a non-synchronous, concerted, pericyclic transition state is involved, with C−O bond cleavage considerably in advance of C−C bond formation. Some evidence has suggested that the ionic active site of the enzymes may polarize the transition state more than occurs in solution. Similar findings apply to the retro-ene fragmentation of chorismate to 4-hydroxybenzoate.17 An aromatic Claisen rearrangement has been used as a key step in a total synthesis of racemic heliannuols C and E.18 A formal synthesis of (−)-perhydrohistrionicotoxin has used Claisen rearrangement of an amino acid ester enolate as the key step, in which almost total chirality transfer was observed from (S,E)-oct-3-en-2-ol in the sense predicted by a chair-shaped transition state with chelation control of enolate geometry.19 Treatment of 1-(cyclohex-1-enyl)-6-methoxy-2-propargylindanol derivatives with base


405

under microwave irradiation has been found to trigger a 5-endo-dig cyclization which sets up a 2,3-disubstituted cyclohex-2-enyl-5-methylenetetrahydrofuran. This was found to undergo spontaneous Claisen rearrangement to deliver the fused tetracyclic system characteristic of the natural product frondosin C.20 Suitably protected mono- and di-saccharide derivatives containing an allyl vinyl ether in the form of a 1methylene-6-vinyltetrahydropyranyl unit have been shown to yield cyclooct-4-enones on heating, via a Claisen rearrangement.21 DFT studies on the facial selectivities of six Johnson–Claisen rearrangements (Scheme 5) analogous to those used in the synthesis of gelsemine have reproduced experimental results in five out of the six cases, but have predicted formation of the same product (21) in all six reactions. The selectivity in these cases has been attributed to a combination of steric repulsions between vinylic proton H(1) and allylic proton H(7) or H(14), and electrostatic attractions between C(1) and the oxetane hydrogens C(5)–H and C(16)–H. Both of these factors, however, apparently predicted the non-observed product in the conversion of (22) into (23).22 Rapid Claisen rearrangement of allyl phenyl ether and meta-substituted derivatives has been reported to occur with poor regioselectivity at 250 ◦ C in dicationic ionic liquids, especially (24).23 Claisen rearrangement of resorcinol allyl ethers (25) was found to have poor regioselectivity under thermal or microwave conditions, but it was further found that selectivity for the 6-substituted product (26) over (27) could be improved to 13:1 using boron trichloride and an appropriately protected ether (25; R = SiPh2 But ).24 The reactions of allyloxy(methoxy)carbene in solution have been studied at 110 and 50 ◦ C, using deuterium labelling and carbene- and radical-trapping agents. At the higher temperature, significant fragmentation of the carbene to radicals was found to occur, and sigmatropic migration was not the major pathway. At the lower temperature, by contrast, carbene fragmentation was found to be negligible. In addition to [1,2]migration, dimerization of the carbene to 1,2-diallyloxy-1,2-dimethoxyethene followed by Claisen rearrangement to methyl 2-allyoxy-2-methoxypent-4-enoate was proposed to be a major pathway, consistent with observations from trapping experiments.25 Excellent stereocontrol in the Claisen rearrangements of cyclic bis-allylic esters to give tri- and tetra-substituted alkenes has been achieved, and attributed to remote steric (and to a lesser extent electronic) effects involving substituents outside the pericyclic ring.26 Stereoselective synthesis of cis- and trans-2,3-disubstituted eightmembered ring ethers has been achieved by stereospecific synthesis of (E)- or (Z)3-alkoxyprop-2-enyl glycolate esters, their Ireland–Claisen rearrangements, and ring closing metathesis. The selectivity of the rearrangements was found to be consistent with a chair-shaped transition state.27 It has been shown that allylic α-tosylacetates undergo Claisen rearrangement followed by decarboxylation when treated with N ,O-bis(trimethylsilyl)acetamide and potassium acetate, in either quantitative or catalytic amounts. Extensive experimental replacement of one or other reagent has led to the proposal of a catalytic cycle for the mechanism (Scheme 6). With suitable starting materials, stereoselective rearrangements have been observed.28 Similarly, allylic tosylmalonate esters have been shown to rearrange on treatment with base and a silylating agent to derivatives of methyl

de

406


O2N

O2N O

HO

EtO

7

1 5

14

16

allylic alcohol E or Z o-nitrobenzene allylic or vinylic C(5)–C(16) alkene or oxetane O2N

EtO2C

(21)

O2N

O2N

EtO

H

H O

HO

O

O (22)

O2N EtO2C

O (23) Scheme 5

13 Molecular Rearrangements: Part 1. Pericyclic Molecular Rearrangements +

N

407

+

N

N

N

.2 NTf2− (24)

RO

RO

O

OH

H

H

O

O

(25)

(26) + OH H OR O (27)

2-tosylpent-4-enoate, alkylated at positions 3, 4, and/or 5. Since it was found that the base need not be nucleophilic, and at least one equivalent of silylating agent was found to be required, it has been proposed that the mechanism involves an Ireland–Claisen rearrangement followed by decarboxylative silatropic fragmentation of the resulting diester and eventual hydrolysis of the silyl ketene acetal thus formed.29 Asymmetric decarboxylative Claisen rearrangements of allylic acetates (28) bearing a range of N -arylsulfonyl sulfoximines on the acetate group have been shown to proceed with moderate to good asymmetric induction. A chair-shaped transition state model (29) has been proposed, in which the S=N bond is antiperiplanar to the ketene acetal C=C bond, and the allylic group approaches syn to the sulfoximine oxygen as shown.30 The first catalytic Z-selective Claisen rearrangement of simple allyl vinyl ethers to 3,5- or 4,5-disubstituted pent-4-enal derivatives has been achieved using a chromium (III) tetraphenylporphyrin chloride catalyst at 5 mol% catalyst loading. For allyl vinyl ethers lacking vinylic substituents, (E)-aldehydes were found to be the predominant products. A transition state model has been proposed involving chromium coordination to the ether oxygen and steric hindrance between the α-substituent and the porphyrin.31 It has been shown that arylalkynes (30) bearing an ortho 1,5-dihydro3H -2,4-dioxepine group give bridged bicyclic ketoethers (32) on treatment with PtCl2 and β-pinene. The proposed mechanism, which is consistent with a deuterium labelling

ee

408

Organic Reaction Mechanisms 2005 OSiMe3 +

Me3SiN

KOAc

O Ts

Ts

O K+

R

−

O

R

+ Me3SiOAc

Me3SiN

+ CO2

O + KOAc

Me3SiN H

OSiMe3 Ts

O

OSiMe3 (i)

R

Ts

O

R (i) [3,3]-sigmatropic rearrangement Scheme 6

study, involves platinum-catalysed intramolecular carboalkoxylation of the alkyne, followed by a non-concerted Claisen rearrangement which may not involve the platinum catalyst, as shown (Scheme 7). An ionic, stepwise [3,3]-sigmatropic rearrangement has been proposed because of geometrical constraints in the proposed tricyclic intermediate (31).32 Aryl allyl ethers have been found to undergo Claisen rearrangement followed by ring closure of the phenol on to the alkene on treatment with IrCl3 –AgOTf, giving 2substituted dihydrobenzofurans.33 Treatment of quinones (33) bearing a leaving group in the 4-position with an allylindium reagent has been shown to give o-allylphenols (35) by a formal Claisen rearrangement. A mechanism has been suggested as shown (Scheme 8), but the proposed intermediate (34) could not be isolated.34 A biomimetic total synthesis of gambogin and some analogues has been performed, involving two Claisen rearrangements. Both were observed to be accelerated considerably by protic and particularly by aqueous solvents. This has been attributed

409


O Ar

O S

N

O S Ph

O O

(i)

R (28)

O

Ph R S

ArO2SN

OSiMe3 O

O Ar

O S

N

O

R

S Ph

(29) (i) MeC(OSiMe3)=NSiMe3, KOAc, PhMe, reflux

to hydrogen bonding in both starting material and transition state, in accordance with previous theoretical studies. Thus, as the Claisen rearrangement moves towards the transition state, decreased conjugation of an oxygen lone pair allows an extra hydrogen bond to form, thereby allowing extra stabilization of the transition state by protic solvents.35 When a range of 1-substituted 3-trimethylsilylpropargyl alcohols was treated with triethyl orthopropionate in the presence of catalytic propionic acid, only the cyclohexyl derivative was found to give the stereodefined silylallene expected from an orthoester Claisen rearrangement.36 2-Substituted butyne-1,4-diols have been shown to undergo double orthoester Claisen rearrangement on heating to give, stereoselectively, E-substituted derivatives of diethyl 3,4-dimethylenehexanedioic acid. The 2-furyl derivative was found to undergo only a single rearrangement and the observed product supports the suggestion that the unsubstituted rearrangement occurs first. The formation of E-products is consistent with a chair-shaped transition state for the second, substituted, rearrangement.37 Strong heating of 2-substituted 5-propargylsulfanyl-3-aryl-3H -pyrimidin-4-ones, and their 5-allylsulfanyl derivatives, has been shown to lead to 2-substituted 3-aryl6-methyl-3H -thieno[3,2-d]pyrimidin-4-ones and their 6,7-dihydro derivatives. The proposed mechanism in both cases is a [3,3]-sigmatropic thia-Claisen rearrangement followed by tautomerization and a 5-exo-dig or 5-exo-trig cyclization.38

Two or More Heteroatoms Crystallographic and activation parameter sudies on diaza-Cope rearrangements of meso and chiral diimines (36) and (37) have shown that the chiral isomer (37) is highly preorganized by internal hydrogen bonding into a chair conformation with all aromatic substituents equatorial, whereas the meso isomer (36) is much less preorganized for the required boat conformation. The very high stereoselectivity which has been observed in the rearrangements of the chiral isomer (37) was consistent with this finding.39 Iso(thio)cyanates (39) and (40) have been found to react with azanorbornenes (38) via a zwitterionic diaza-Cope rearrangement to give fused bicyclic (thio)urea derivatives (42). Competition experiments have shown that the reaction proceeds faster with isothiocyanates, even though isocyanates reacted faster with the simple nucleophile pyrrolidine. This is consistent with rapid, reversible formation of zwitterions (41), followed by a rate-limiting rearrangement step. Electron-deficient iso(thio)cyanates were found to react faster than electron-rich reagents, and at room temperature gave a mixture of (thio)ureas and iso(thio)ureas, presumably due to competing diaza and azaoxa

de

R2

R2

(30)

O

O

R1

O

(31)

R1

O

PtCl2

R2

R2

R

2

Cl2 Pt

O

R1

Scheme 7

O

R1

O

O

+

O−

O

PtCl2

R1

R2

R2

R2

(32)

R1

O

+

R1

O

+

O O

R1

O

−

PtCl2

O

−

PtCl2



O

O (i)

R2

R2

MeO R1

O

InL2

(33)

OH

R2

MeO R1

411

R2 R1

R1

(34)

(35) (i) In, allyl bromide Scheme 8

O

Me O

H

O

N

O

H

Me O

N

N

N

H

H

O Me

O

O Me

(36) O

O

Me O

H

O

H

N

N

N

N

H

O Me

O

H

Me O

O Me

(37)

rearrangements. This has been attributed to the greater localization of the negative charge in the zwitterionic intermediates in these cases.40 Treatment of vinyl or aryl sulfilimines (43) with dichloroketene was found to give γ -thio-γ -lactams (44), presumably by the sequence shown. For phenyl substituted sulfilimines, yields were found to be very low, presumably because of the stability of the phenyl ring, but N -tosylamides (45) were isolated as byproducts, which supports the proposed mechanism.41 It has been shown that allylic azides can be trapped, using either phenylacetylene cycloaddition to the azide, or alkene epoxidation, and that [3,3]-sigmatropic equilibration of the possible allylic azides is generally faster than the trapping reactions.42 Nucleoside-derived azide (46) has been shown to undergo reversible [3,3]-sigmatropic

412


+ R2N C X

N R1

(39; X = O) (40; X = S)

(38)

1 + N R

+ 1 N R

X−

N

X−

N

R2

R2 (41)

R2

H

X

N N

H

R1

(42) Cl R1 +

S

(i) −

N

R1 Cl +

Ts

S

R2

R1

−

O N

Cl Cl O −

N

+

Ts

S

R2

R

Ts

2

(43)

R2S Cl

Cl

O (45)

R1 H N

Ts

Cl

Cl

(i) Cl2C C O

O R2S

N Ts

(44)

rearrangement giving (47). The reaction rate has been shown to be unaffected by addition of sodium azide or by absence of light, but was found to be greater in DMSO than in methanol, consistent with a pericyclic mechanism. By contrast, rearrangement of the corresponding nucleoside-derived phenyl or tosyl sulfides was found to follow an intermolecular radical pathway.43 It has been found that the thermodynamic ratio of isomeric allylic azides, interchangeable by stereoselective [3,3]-sigmatropic rearrangement, can be affected by steric and electronic factors in the presence of a bulky (chiral) auxiliary. Under Mitsunobu conditions, treatment of allylic alcohols (48; R = Ph) was shown to give a

413

13 Molecular Rearrangements: Part 1. Pericyclic Molecular Rearrangements H N

O O

H N

O O

O

N

O

N

N3 OH

N3

OH

(46)

(47)

mixture of allylic azides (49) and (50). The latter has been attributed to SN 2 displacement; the former, in addition, to the expected SN 2 displacement followed by spontaneous [3,3]-sigmatropic rearrangement as shown, with the SN 2 displacement product (51) sterically disfavoured. This steric bias was found to be overcome by conjugation when R = Ph, giving (51) as the observed major product. However, the competing SN 2 displacement (now followed by [3,3]-sigmatropic rearrangement) was more favourable, giving larger amounts of minor diastereomer (52). Support for this analysis was provided by the observation that treatment of diastereomer (53; R = Ph) gave (51) and (52) in opposite proportions, again presumably by a mixture of nonselective SN 2 displacement followed by [3,3]-sigmatropic rearrangement, competing with stereospecific SN 2 displacement.44

N3

OH (i)

R

N3 R

+

R

(49; β-N3) (50; α-N3)

(48)

(51; β-N3) (52; α-N3) OH

(51) (iv)

(49)

(iii)

(48)

(ii)

(49) + (50)

R

(iv) (53)

(51) + (52) (52)

(iii)

(53)

(i) HN3, DEAD, PPh3, PhH (ii) SN2′ displacement (iii) SN2 displacement (iv) [3,3]-sigmatropic rearrangement

(ii)

(iv)

(51) + (52)

de

414


The [3,3]-sigmatropic rearrangements of allylic phosphorimidates, readily prepared in situ from an allylic alcohol, an organic azide, and a chlorophosphite, into phosphoramidates have been extensively investigated, and found to require high temperatures and a non-polar solvent, in addition to bulky spectator substituents on the phosphorus atom. A crossover experiment has shown the rearrangement to be intramolecular, and both chirality transfer and the selective formation of (E)-alkenes were consistent with a conventional chair-like transition state. A range of alkene substitution patterns was found to be well tolerated when benzyl azide was the starting material, but the use of electron-deficient azides such as tosyl or benzyloxycarbonyl azides necessitated activation of the alkene component using either an electron-withdrawing group or a Pd(II) catalyst. Interestingly, the catalyst proved ineffective with the more electron-rich azide derivatives.45 Independent investigations of the closely related [3,3]-sigmatropic rearrangements of allyloxyiminodiazaphospholidines, similarly prepared from allylic alcohols, organic azides, and aminophospholidines, into N -allylphosphoramides used only electrondeficient azides, and always required Pd(II) catalysis to avoid competing [1,3]sigmatropic rearrangement. Again, a range of alkene substituents was tolerated, and good stereochemical transfer was achieved, consistent with a chair-like transition state. A mechanism for the Pd-catalysed reaction has been proposed, involving attack of the nitrogen lone pair on the Pd-coordinated alkene to give an intermediate σ -Pdcoordinated phosphonium ion. Moderate diastereomeric induction was shown to be achievable using a chiral auxiliary on the phosphorus, and was found to be independent of the alkene geometry in the starting material. Transition state models have been proposed to account for this, based on chair-like transition states for the trans starting materials and boat-like transition states for the cis starting materials. After considerable experimentation, it was found that enantioselective [3,3]-sigmatropic rearrangements could be carried out using a chiral cobalt oxazoline palladacycle catalyst in the presence of silver trifluoroacetate, but although good enantioselectivity could be obtained with either cis- or trans-alkene starting materials, good yields were obtained only from cis-alkenes.46 Treatment of α-allenyl alcohols with methanesulfonyl chloride and triethylamine was found to give cis-1,2-disubstituted 3-mesyloxybutadiene derivatives in moderate yields and total selectivity, presumably by [3,3]-sigmatropic rearrangement of the initially formed α-allenyl mesylate. The total cis selectivity has been attributed to a chairshaped transition state.47 Treatment of tertiary cyclopropylmethanol derivatives with molybdenum or rhenium oxo complexes in the presence of 2,6-di-t-butyl-p-cresol as a polymerization inhibitor has been found to give 2,2-disubstituted tetrahydrofurans. The suggested mechanism involves the formation of an oxometal cyclopropanemethanolate intermediate, which is then proposed to undergo a homo-[3,3]-sigmatropic rearrangement. The cyclization of the resulting homoallylic alcohol was found to be partially suppressed by addition of potassium carbonate, and is thought to be independent of the oxometal catalyst.48

ee

de

de

ee

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415

[2,3]-Sigmatropic Rearrangements Ylids (54) containing a spirocyclic tetrahydropyridinium unit have been shown to undergo competing [1,2]- and [2,3]-sigmatropic rearrangement reactions. In spiro[6.6] ylids (54; n = 1) the [1,2]- and [2,3]- products are formed in 1:1 ratio, whereas in spiro[6.7]ylids (54; n = 2) the latter predominate, presumably because the greater conformational flexibility allows interconversion of the exo and endo anions before rearrangement.49

EtO2C O

+

−

N X

(54) n = 1 or 2 X = O or CH2

N

EtO2C O n

X

+ n

EtO2C O

N X

n

mixture of diastereomers

Several strategies have been evaluated, with little success, for achieving asymmetric aza-[2,3]-Wittig reactions, and a range of chiral auxiliaries assessed. Several gave total selectivity for anti products, but the best selectivity achieved for one anti product over the other was 85:15.50 By contrast, Oppolzer’s chiral sultam has been shown to be a highly effective chiral auxiliary for [2,3]-sigmatropic rearrangement of glycine-derived N -allylammonium ylids, conferring extremely high diastereoselectivity in addition to excellent chirality transfer. A transition state model has been proposed for one such rearrangement.51 It has also been shown that chiral diazaborolidines can be used to mediate asymmetric [2,3]-sigmatropic rearrangements of allylic ammonium ylids with very good enantiomeric induction. Suitable transition states and intermediates have been proposed to rationalize the stereoselectivity, and some evidence found to favour kinetic over thermodynamic control. It has been proposed that the reaction occurs with the diazaborolidine boron atom also forming part of an oxazaborolidine ring incorporating the oxygen of a pendant amide and the ylid nitrogen atom, thus allowing the auxiliary to exert asymmetric control.52 [2,3]-Sigmatropic rearrangements of allylic nitro compounds have been achieved in good yields by heating with an excess of DABCO; hydrolytic workup was used to isolate allylic alcohols. In several cases involving cyclohexene-based substrates, the rearrangement has been demonstrated to occur suprafacially.53 The [2,3]-sigmatropic rearrangement of ylids derived from allyl or propargyl aryl sulfides and α-diazoamides bearing Oppolzer’s chiral sultam, in the presence of Cu(I), has been found to be highly stereoselective when a diimine ligand is used (Scheme 9). Although the selectivity of the reaction was slightly influenced by the chirality of the diimine ligand, it was found to depend very largely on the sultam auxiliary.54

de

ee

ee

416


N2 S N O2

R

+

R2

(i)

2

ArS S N O2

SAr

R1 O

R1 O

2

vinyl sulfide: R = H propargyl sulfide: R2 = H or Me

Cl

(i) Cu(I), ligand R

R

N

N

Cl

Cl

Cl

Ligand; R2 = H2 or (CH2)4

Scheme 9

[1,n]-Sigmatropic Rearrangements Formation of alkenes by ‘retro sigmatropic shift’ processes has been reviewed.55 Applications of [1,3]-hydrogen shifts to the removal of allyl and propargyl protecting groups from amines and amides have been reviewed.56 The mechanism of enantioselective α-chlorination of simple aldehydes catalysed by 2,5-diphenylpyrrolidine has been thoroughly investigated both theoretically and experimentally. The proposed mechanism involves N -chlorination of intermediate enamine (55), followed by rapid, enantioselective [1,3]-chlorine shift giving iminium ion (56), hydrolysis of which is proposed to be the rate-determining step. This mechanism has been supported by DFT calculations, which accurately model both the extent and the sense of enantioselection, and also by deuterium labelling and kinetic studies, and the linearity of enantioselectivity.57 A [1,5]-sigmatropic shift of hydrogen from an N -methyl group to the carbonyl carbon atom in protonated 3-(N ,N -dialkylhydrazono)-1,1,1-trifluoroalkan-2-ones has been found to be a key step for the acid-catalysed cyclization of these ketones to 6-trifluoromethyl-3,6-dihydro-2H -[1,3,4]oxadiazines.58 Gas-phase kinetic studies on interconversions of monodeuterocyclohexadienes have given activation parameters in reasonable agreement with previous experimental and theoretical data.59 The mechanism of photoisomerization of 2-vinylbiphenyl derivatives (57) into 9,10dihydrophenanthrene derivatives (59) has been investigated by deuterium labelling and by DFT calculations, which have given conflicting results. Labelling studies have shown that aromatization of the initial photocycloadducts (58) occurs by two [1,2]-H(D) migrations in preference to the [1,5]-shift previously supposed, although the latter process has been found to become more important at low temperature for (58; R1 = Ph, R2 = H). DFT studies, by contrast, have given a lower energy barrier

ee

417


Ph

Ph

N H

Ph

Ph

N

NCS

Cl

+ R

O

+

Ph

Ph

N

R

R

(55)

Ph

Ph

N H

Ph

+

Ph

N

+

Cl Cl

O

R1

R R1

R2

(57)

R (56) R1

R2

hν

(58)

R2

(59)

R1 = H, R2 = Me or R1 = Ph, R2 = H

for the [1,5]-shift. Three possible explanations have been proposed: adiabatic photocyclization followed by double [1,2]-H(D) shift from an excited state of intermediates (58); migration by tunnelling to bypass the activation barrier; or an overestimate of the activation barriers by DFT calculations owing to insufficient experimental kinetic data for related reactions.60 Transition states in the acetotropic rearrangement of 2-acetoxytropone derivatives, a [1,9]-sigmatropic rearrangement, have been calculated using MOPAC.61

Vinylcyclopropane–Cyclopentene, Bergman, Di-π-methane, and Related Diradical Rearrangements The study of Bergman, Myers–Saito and related biradical cyclizations using an unrestricted broken spin symmetry approach refined by single-point energy coupled-cluster calculations has been reviewed, and a simple rule outlined for predicting biradical involvement in such ‘Cope-type’ rearrangements: radicals were found to be probable

418


intermediates if stabilized by either allyl resonance or aromaticity.62 The isomerization of quadricyclane to norbornadiene via a Woodward–Hoffmann forbidden pathway has been studied by CASSCF calculations, which found the transition state to have high biradical character, and the reaction to be highly asynchronous, with one bond cleaving entirely before the transition state and the second cleaving after it.63 DFT and ab initio calculations have shown that α,β-unsaturated acyl radicals and α-ketenyl radicals are not resonance forms but are rapidly interconverting isomers separated by a low but not negligible energy barrier of

Organic Reaction Mechanisms, 2005 (Organic Reaction Mechanisms Series)

Organic Reaction Mechanisms , Organic Reaction Mechanisms, 1997

Organic Reaction Mechanisms 2006 (Organic Reaction Mechanisms Series)