Organic Reaction Mechanisms 2006 (Organic Reaction Mechanisms Series)

ORGANIC REACTION MECHANISMS · 2006 An annual survey covering the literature dated January to December 2006 Edited by A...

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ORGANIC REACTION MECHANISMS · 2006 An annual survey covering the literature dated January to December 2006

Edited by

A. C. Knipe University of Ulster Northern Ireland

An Interscience Publication

A John Wiley and Sons, Ltd., Publication

ORGANIC REACTION MECHANISMS · 2006

ORGANIC REACTION MECHANISMS · 2006 An annual survey covering the literature dated January to December 2006

Edited by

A. C. Knipe University of Ulster Northern Ireland

An Interscience Publication

A John Wiley and Sons, Ltd., Publication

This edition first published 2010  2010 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 978-0-470-51905-9 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

Department of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK

K.K BANERJI

Indra-Kripa, A-80 Saraswati Nagar, Jodhpur 342005, INDIA

C.T. BEDFORD

Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ

M.L. BIRSA

Department of Chemistry, Al I Cuza University of Iasi, Bd. Carol I, 11, Iasi 700506, Romania

A. BRANDI

Dipartimento di Chimica Organica “U. Schiff”, Universita’ degli Studi di Firenze-Polo Scientifico, Via della Lastruccia 13 1-50019 Sesto Fiorentino (Fl), Italy

M. CHRISTLIEB

Gray Institute for Radiation Oncology and Biology – University of Oxford, Old Road Campus Research Building, Churchill Hospital, Oxford, OX3 7DQ

R.G. COOMBES

Honorary Research Fellow, Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ

M.R. CRAMPTON

Chemistry Department, The University, South Road, Durham. DH1 3LE

N. DENNIS

University of Queensland, PO Box 6382, St. Lucia, Queensland 4067, Australia

E. GRAS

CNRS, LSPCMIB Universite Paul Sabatier, 31062 Toulouse Cedex 9, France

ˇ ´ P. KOCOVSK Y

Department of Chemistry, The Joseph Black Building, The University of Glasgow, Glasgow G12 8QQ

R.A. McCLELLAND

Department of Chemistry, University of Toronto, 80 St George Street, Toronto, Ontario, M5S 1A1, Canada

B. MURRAY

Department of Science, IT Tallaght, Dublin 24, Ireland

K.C. WESTAWAY

Dept. of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario P3E 2C6, Canada

v

Preface The present volume, the forty-second in the series, surveys research on organic reaction mechanisms described in the available literature dated 2006. 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). Unfortunately the personal circumstances of an author resulted in an unexpected delay in publication of this volume, for which we apologise. The next volume is expected to be published in the same year and steps have been taken to ensure that the delay between title year and publication date will be further reduced thereafter. 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.

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 Reactions by S. K. Armstrong . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14. Molecular Rearrangements: Part 2. Other Reactions by A. Brandi and M. Gensini . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ix

1 53 91 153 175 187 203 231 277 307 317 379 419 451 513 549

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 and Ketenimines . . . . . . . . . . . . . . . Formation and Reactions of Nitrogen Derivatives . . . . . . . . . Imines: Synthesis and Tautomerism . . . . . . . . . . . . . . The Mannich Reaction . . . . . . . . . . . . . . . . . . . . . Addition of Organometallics . . . . . . . . . . . . . . . . . . Other Alkylations and Allylations of Imines . . . . . . . . . Reduction of Imines . . . . . . . . . . . . . . . . . . . . . . Iminium Species . . . . . . . . . . . . . . . . . . . . . . . . Other Reactions of Imines . . . . . . . . . . . . . . . . . . . Oximes, Hydrazones, and Related Species . . . . . . . . . . C–C Bond Formation and Fission: Aldol and Related Reactions . Stereoselective Aldol Reactions Using Proline Organocatalysts Other Stereoselective Aldol Reactions . . . . . . . . . . . . . Mukaiyama and Vinylogous Aldols . . . . . . . . . . . . . . The Aldol-Tishchenko Reaction . . . . . . . . . . . . . . . . Nitro and Nitroso Aldols . . . . . . . . . . . . . . . . . . . . Other Aldol-type Reactions . . . . . . . . . . . . . . . . . . The Aza and Morita Variants of the Baylis–Hillman Reaction Allylation and Related Reactions . . . . . . . . . . . . . . . Olefinations . . . . . . . . . . . . . . . . . . . . . . . . . . Alkynylations . . . . . . . . . . . . . . . . . . . . . . . . . Michael Additions . . . . . . . . . . . . . . . . . . . . . . . Other Addition Reactions . . . . . . . . . . . . . . . . . . . . . . General and Theoretical . . . . . . . . . . . . . . . . . . . . Addition of Organozincs . . . . . . . . . . . . . . . . . . . . Addition of Other Organometallics, Including Grignards . . . The Wittig and Aza-Wittig Reactions . . . . . . . . . . . . . Hydrocyanation, Cyanosilylation, and Related Additions . . . Hydrosilylation and Related Reactions . . . . . . . . . . . . Miscellaneous Additions . . . . . . . . . . . . . . . . . . . . Enolization and Related Reactions . . . . . . . . . . . . . . . . . α-Halogenation, α-Alkylation, and Related Reactions . . . . .

Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd

Edited by A. C. Knipe

1

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2 3 3 3 3 5 6 7 8 9 10 13 14 14 16 18 19 19 20 21 22 24 25 26 27 27 27 29 30 30 32 33 36 37

2

Organic Reaction Mechanisms 2006

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

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38 38 41 42 43 44

Formation and Reactions of Acetals and Related Species Chemoselectivities in the acetalization of p-nitro- and p-hydroxy-benzaldehyde have been studied for a range of bisnucleophiles, XCH2 CH2 Y (X, Y = OH, OH; SH, SH; SH, OH; and SH, NH).1 The relative yields of products have been analysed in terms of atomic charges, Parr’s global electrophilicity descriptor (w), and Pearson’s hard–soft acid–base concept; such a global electrophilicity descriptor has also been used to explain acetalizations and thioacetalizations of substituted benzaldehydes, although it cannot handle steric factors.2 Pd[(−)-sparteine]Cl2 catalyses the conversion of styrenes to their Markovnikov dialkyl acetals.3 Deuterium labelling studies suggest an enol ether mechanism involving a Pd–H species. The Eberlin reaction – polar acetalization and transacetalization in the gas phase – has been reviewed (249 references).4 In addition to a detailed mechanistic treatment, several analytical applications are described, as are atmospheric pressure variants, relationships with condensed-phase reactions, and other gas-phase processes closely related to acetalization. Another review covers similar ground.5 Enantiopure 1,6-dioxaspiro[4.4]nonanes [e.g. (1)] have been prepared from an α-hydroxy-ω-ene ketone, using a camphor–selenide auxiliary.6

O

O (1)

OH

OP

O

O

O

O

OP

de ee

OH

(2)

Differentiation of 1,3-anti - and -syn-diols has been achieved via the selective hydrolysis of an anti -1,3-acetonide (2) containing an adjacent syn-acetonide.7 Gallium(III) chloride catalyses two useful reactions that employ isocyanides as a C1 source: (i) an insertion into a C−O bond of an acetal and (ii) a 4 + 1-cycloaddition of α,β-unsaturated carbonyl compounds. The catalysis appears to depend on the low affinity of GaCl3 for heteroatoms.8 The reagent BH3 .NMe3 –AlCl3 has been used to bring about reductive opening of acetals.9 With mixed phenolic–benzylic acetal as reactant, the reagent acts regioselec-

de

1 Reactions of Aldehydes and Ketones and their Derivatives

3

tively (in THF at 0 ◦ C), yielding a benzylic ether and free phenol, probably because the borane first associates with the more basic benzylic oxygen. Conditions to bring about the inverse opening are being sought.

Reactions of Glucosides and Nucleosides A detailed experimental and computational study of the anomerization of glucose in water has been undertaken.10 Following measurement of kinetic isotope effects (KIE) on rate constants for approach of α-glucopyranose to its equilibrium with the β-anomer, these were converted into unidirectional KIEs using equilibrium isotope effects. Saturation transfer 13 C NMR spectroscopy then yielded the relative free energies of the transition states (TS) involved. Modelling, constrained by all the KIEs measured, then gave the anomerization TSs. Key findings include the observation that only one water molecule is required to participate, and that it must not hydrogen bridge OH(1) and O(5) simultaneously in either TS. The mechanistic role of nucleotides in directing the growth of IR-emitting semiconductor nanocrystals has been investigated for a range of nucleotides, concentrations, stoichiometries, and temperatures.11

Reactions of Ketenes and Ketenimines A short review of the first 100 years of ketene chemistry covers haloketenes, Wolff rearrangements, stereoselective nucleophilic attack, dimerization, cycloadditions, ketene-Claisen and -Cope reactions, bisketenes, and free radical processes.12 Two series of ketenimines, Ph–CH=C=N–Ph–p-R and p-R–Ph–CH=C=N–i-Pr, have been aminated with butylamine, with UV monitoring allowing rate measurement and hence construction of Hammett plots for each ring system.13 Addition to the C=N bond to give vinylidenediamine intermediate is followed by tautomerization to amidine product. A switchover in rate-determining step is observed. Calculations indicate that the N -aromatic group provides significant electronic stabilization to the first TS.14

Formation and Reactions of Nitrogen Derivatives Imines: Synthesis and Tautomerism Erbium(III) triflate is an efficient catalyst in the synthesis of aldimines, ketoimines, and enaminones.15 For aromatic imines, the problem of Michael addition found with the CeCl3 /NaI-catalysed addition to unsaturated aldehydes is avoided. An N -phosphinoylhemiaminal (3) has been used as a precursor to trifluoromethylketimines (4); in situ alkylation with a dialkylzinc in the presence of a diphosphine monoxide auxiliary gives chiral α,α,α-trifluoromethylamines (5) in high yield and ee up to 99%.16

de ee

4

Organic Reaction Mechanisms 2006 O HN

O

O Ph

P

P

N

Ph Ar

Ar CFOEt 3 (3)

Ph HN

Ph CF3

Ph

P

Ph

Ar CF R 3 (5)

(4)

The Skraup–Doebner–Von Miller synthesis of quinolines – involving condensation of an aniline with an α,β-unsaturated ketone – has been investigated using 13 Clabelled ketones in cross-over experiments: a complex fragmentation–recombination mechanism involving imine intermediates is indicated.17 In another synthesis of quinolines involving imine intermediates, o-oxazoline-substituted anilines (6) react with ketones in dry butanol reflux to give 4-amino-substituted quinolines [e.g. (7)], or 4-quinolones, using tosic acid as catalyst.18 A mechanism involving ketoimine formation with subsequent tautomerization to give an enamine which attacks the oxazoline ring is discussed. A related one-pot, three-component synthesis of β-amino carbonyl compounds has been achieved using a cascade reaction of anilines with aromatic aldehydes and carbonyl compounds, catalysed by zinc triflate.19 R2 NH2 R1

R2

R3

N

R3

O

HN

OH OH

O

de

OH

PhCHO

O N

Ph

R1 (6)

(7)

(8)

An enantioselective one-pot, three-component imino-Reformatsky reaction has been reported.20 Combining a benzaldehyde, an aniline, and an alkyl bromoacetate ester, ees of up to 92% have been achieved in the β-amino ester product, using a recyclable N -methylephedrine as auxiliary. A nickel(II) salt and dimethylzinc are employed: the latter serves as dehydrating agent, reductant, and coordinating metal. The kinetics and mechanism of the reaction of glycylglycine21 and of valine22 with ninhydrin (8) have been studied in aqueous micellar media. Cis–trans isomerization in benzylideneaniline (PhCH=NPh) has been found by computation to involve a single TS, and conformers leading to each isomer have been identified. However, kinetic selectivity of the two conformers depends on the reaction dynamics.23

ee

5


The Mannich Reaction Most reports in this category deal with asymmetric processes. For example, classic Mannich reaction of unmodified ketones, aqueous formaldehyde, and aromatic amines produces α-aminomethylation of the ketones in >99% ee, using l-proline as catalyst.24 Methyl ketones regioselectively reacted on the methylene carbon. The method is simple, using wet solvents in the presence of air. Direct Mannich reactions of cyclic 1,3-dicarbonyls with acyl imines, R1 –CH=N– CO2 R2 , gives α-quaternary-carbon-bearing products (9; X = CH2 , O; Y = Me, OMe, OEt) with yield/de/ee up to 98/90/99%, using cinchona alkaloid catalysts.25

ee

de ee

O O

OR2

HN R1

X

N

CO2H

O Y (9)

(10)

Mannich reactions between aldehydes and N -p-methoxyphenyl-protected α-imino ethyl glyoxylate (PMP−N=CH−CO2 Et) give high ees using (S)-pipecolic acid (10) as catalyst, but low des.26 (S)-Proline also gives high ee, but also predominantly syn product. Calculations indicate that the transition structures involving the s-cis- and s-trans-enamine intermediates are much closer in energy in the case of catalyst (10). A highly enantioselective direct Mannich reaction of simple N -Boc-aryl and alkylimines with malonates and β-keto esters has been reported.27 Catalysed by cinchona alkaloids with a pendant urea moiety, bifunctional catalysis is achieved, with the urea providing cooperative hydrogen bonding, and the alkaloid giving chiral induction. With yields and ees up to 99% in dichloromethane (DCM) solvent, the mild air- and moisture-tolerant method opens up a convenient route to N -Boc-amino acids. Several other asymmetric Mannich-type processes have been described. Propargyl alcohols (11) undergo an addition to imines (12), to give 2-acylallylic carbamates (13), using an oxovanadium catalyst.28 The reaction always gave the (Z)-enone, but a trial with a chiral propargyl alcohol showed virtually no enantioselectivity.

OH

O R2

+

R3

N

CO2Me

R1

HN

R1

R3 R2

(11)

(12)

CO2Me

(13)

de ee

ee

ee

6


N -Sulfonylaldimines undergo Mannich-type addition to silyl enol ethers of ketones, giving β-amino carbonyl derivatives in up to 93% ee in the presence of a chiral ferrocene bearing S- and P -substituents complexed to copper(II).29 β-Aminocarbonyl compounds have been prepared via Lewis base-catalysed Mannich reaction of TMS enol ethers and N -tosylaldimines, ArCH=N−Ts, with excellent anti selectivity in some cases.30 A zinc–bis(BINOL) complex has been employed to effect chemoselective enolate formation from an α-hydroxy ketone (in the presence of an isomerizable imine) to give a Mannich-type product in high ee.31 Chiral syn-β-amino esters have been prepared by addition of titanium ester enolates to aldimines containing an (R)-α-methylbenzylamine moiety.32 Benzaldimines bearing N -protection react diastereoselectively in a direct catalytic Mannich-type transformation with a trichloromethyl ketone donor, Me–CH2 –C(=O)– CCl3 , using a Lewis base catalyst, lithium p-methoxyphenoxide, to give syn-amino ketone (14, in protected form).33 Subsequent carbonyl reduction of (14) to give the carbinol sets up ring closure to azetidines, with the trichloromethyl moiety as the leaving group.

ee

de de ee de

de

NHPg O Ph

CCl3 Me (14)

N

O

O

Me (15)

Two redox-Mannich conversions have been described. A direct asymmmetric reductive reaction produces three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity.34 An oxidative Mannich reaction has been employed to form a γ -aminoalkylbutenolide (15).35 Starting with N ,N -dimethylaniline, C−H oxidation yields iminium ion, which is then intercepted with 2-triisopropylsilylfuran as nucleophile. Carried out in T-HYDRO reagent (70% t-BuOOH in water) in the presence of air, dirhodium caprolactamate [Rh2 (cap)4 ] catalyses the reaction, giving yields of up to 95% in a few hours, using methanol co-solvent at 60 ◦ C. Evidence for the intermediacy of the iminium ion includes rapid formation of α-methoxyamine in the absence of the furan nucleophile.

Addition of Organometallics Schiff bases, Ar1 –CH=N–Ar2 , that are unreactive with triethylaluminium alone undergo ethylation in the presence of cerium(IV); the reaction site is the methine.36 The sterically sensitive reaction is favoured by electron-donating substituents. Excess Et3 Al is required, or cleavage to aldehyde and amine results. The structure of lithiated cyclohexanone N -cyclohexylimine (16) and its reactivity towards C-alkylation has been investigated experimentally and by DFT calculations.37

de ee

7


Formed from the imine using LDA in hexane, NMR studies reveal complex solventdependent distributions of monomers, dimers, and trimers in several ethereal solvents, although a mono-solvated dimer can be selected by appropriate choice of solvent. Study of C-alkylation rates suggests that both monomer- and dimer-based mechanisms operate. The lithioimines were compared with the isostructural lithium dialkylamides, but were shown to be not simply vinylogous analogues thereof. (S)-t-Butylsulfinylferrocene has been added to a range of aryl- and alkyl-imines, via o-lithiation: some imines gave complete stereocontrol of the three stereocentres in the product, as shown by single-crystal X-ray analysis.38

LiN

R1

R2

N

N

Ph (16)

de

Ph (17)

A pseudo-C2 -symmetric tertiary diamine derived from (1S,2S)-(+)-pseudoephedrine (17, R1 = Me, R2 = Ph) has been prepared and tested in the enantioselective addition of methyllithium to aromatic imines.39 It shows comparable ee and better reactivity than a genuinely C2 -symmetric relative [17, R1 , R2 = –(CH2 )4 –]. A chiral rhodium(I)–diene complex catalyses the addition of dimethylzinc to N tosylarylimines, ArCH=NTs, with ees up to 98%.40 α-Aldiminoesters, R1 –N=CH–CO2 R2 , undergo diethylzinc addition to give the corresponding α-amino esters in high ee in the presence of a chiral titanium(IV) Lewis acid–Lewis base bifunctional catalyst.41

ee

ee

ee

Other Alkylations and Allylations of Imines Primary alkyl radicals have been generated from alkyl iodides (RCH2 I) using dimethylzinc and air as initiator; the radicals can then be used to alkylate N -tosylimines, ArCH=NTs, to give the corresponding amines, ArCH(CH2 R)NHTs.42 The latter process is promoted by BF3 etherate and catalysed by copper(II). Di(t-butyl) tartrate has been used as an auxiliary to give asymmetric addition of alkynylzincs to nitrones, yielding optically active α-substituted propargylic N hydroxylamines.43 Addition of product-like N -hydroxylamine boosted ees up to 95%. A C2 -chiral bisformamide (18) derived from diaminocyclohexane catalyses the enantioselective allylation of simple aldimines, using allyltrichlorosilane in the presence of l-proline.44 The more immediate allylating agent is, in fact, l-proline derivative (19), formed in situ, and observed by NMR and MS. Phenols have been employed as directing groups in the enantioselective allylation of aldimines and ketimines using allylchlorosilane reagents.45

ee

ee

ee

8


O

N O

NH

HN

O

Cl

Si O

NCHO OHCN (18)

(19)

Ketoimines, including aromatic, heteroaromatic, and enolizable cases, have been allylated in a catalytic enantioselective process using CuF complexed with an axially chiral DuPHOS ligand and a non-toxic allylboronic pinacol ester as nucleophile.46 Lithium isopropanoxide catalyses the reaction, and extensive 11 B NMR studies indicate that it does so by boosting formation of a copper alkoxyallylborate, H2 C=CH−CH2 – B(pinacol)− – + OR (R = i-Pr), which then reacts with copper(I) to generate allylcopper, H2 C=CH−CH2 –Cu, as immediate nucleophile. Addition of t-butanol gives even better results, through formation of a similar intermediate with R = t-Bu. Regio- and stereo-selective allylation of sulfonylimines has been carried out with trifluoro(allyl)borates and allylstannanes, using ‘palladium-pincer’ complexes as catalysts.47 Syn products predominate, in contrast to the corresponding reaction of aldehyde electrophiles; DFT calculations have been employed to probe the mechanistic differences.

ee

de

Reduction of Imines Ruthenium and iridium are commonly used in catalysts for this reaction. A selectively deuterated hydroxycyclopentadienyl ruthenium hydride catalyst has been employed to probe the mechanism.48 The relative rates of different steps determine whether the process is stereospecific (typically trans) or stereorandom. A water-soluble, recyclable ruthenium(II) complex including a chiral diamine ligand has been used for asymmetric transfer hydrogenation of cyclic imines and iminiums in water, with yields and ee up to 99%.49 Homogeneous catalytic hydrogenation of imines has been carried out using cationic iridium hydride catalysts.50 The mechanistic possibilities are compared and contrasted with C=O hydrogenations. A new class of chiral phosphine–oxazolines act as ligands in iridium-catalysed asymmetric hydrogenation of imines, and of alkenes, giving ees up to 99%.51 Acyclic aromatic N -arylimines, Ar1 –C(Me)=N–Ar2 , have been reduced to the corresponding amine with up to 99% ee, using 1 atm of hydrogen and an iridium(I) catalyst bearing a chiral diphosphinoethane chelating ligand.52 Using cheaper metals, electron-deficient imines such as sulfinylimine (20) can be reduced by diethylzinc, using a chiral nickel(II) catalyst; yields and des >90% can be achieved.53 Interestingly, ketones are unaffected by the process; many common reducing agents cannot so discriminate. 1 H NMR profiling indicates ethylene production, a

ee

ee ee

de

9


Me

O

N

S

N

PPh2

(20)

(21)

finding which supports an Et–Zn–N–C–Ni–Et intermediate, which eliminates the gas to give a nickel hydride which acts as immediate reductant of the carbon. Formamides derived from l-pipecolinic acid act as Lewis base organocatalysts for reduction of N -arylimines with trichlorosilane, giving yields and ees in the high 90s for a wide range of imine substrates.54

ee

Iminium Species A QUINAP auxiliary (21), bound to copper(I), gives excellent enantioselectivity in the addition of terminal alkynes to isolated isoquinoline iminium cations.55 DFT calculations have been used to follow the formation of iminium ions from secondary amines and acrolein.56 Energy barriers in the process can be lowered by incorporation of a heteroatom (N or O) in the α-position of the amine, or an electronwithdrawing group (carbonyl or thiocarbonyl) in the β-position. Pentafluorophenylation of iminium cations has been studied by DFT methods, and the experimental conditions have also been optimized.57 Silane reagents, (F5 C6 )4−n SiFn (n = 1, 3) have been investigated, particularly with reference to their activation by weak Lewis bases. Pentafluorophenyl significantly stabilizes pentacoordinate silicon species, but as a group it is much more reactive in an apical than an equatorial position. The synthesis and aqueous chemistry of α-acetoxy-N -nitrosomorpholine (22) has been described.58 It decomposes cleanly, with first-order kinetics, via an N -nitrosoiminium ion intermediate (23), with the pH–rate profile showing acid- and basecatalysed regions, and an extensive pH-independent region between 3 and 9, the latter being ca 100 times slower than its C-analogue, the corresponding piperidine derivative. Implications for the interaction of N -nitrosomorpholine with DNA are discussed. O N

ee

O OAc

N+

N+

NO

NO

(22)

(23)

O−

(24)

Vinylzinc reagents have been added to 3,4-dihydroisoquinoline N -oxide (24) in up to 95% ee, using a chiral 2-aminoamide as auxiliary.59

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10


Asymmetric catalysis of carbonyl transformations via iminium ion and enamine intermediates have been reviewed (35 references), including their recent merger in tandem iminium–enamine sequences.60

ee

Other Reactions of Imines Several of preparations of aziridines have been reported. The aza-Darzens reaction of an N -bromoacylcamphorsultam with N -diphenylphosphinylimines, ArCH=N−P(=O)Ph2 , gives cis-aziridine derivatives, except if the aryl is o-substituted, which gives significant trans product, and even 100% trans- with o-CF3 .61 While steric factors play a role in this inversion of selectivity, electronic effects are also important: o-methyl gives a 50:50 ratio of products. A computational study has probed the origin of the diastereoselectivity in aziridine formation from sulfur ylides, Me2 S+ –CH− –R, and imines.62 For semi-stabilized cases (R = Ph), betaine formation is non-reversible, so that selectivity is determined in the initial addition step. In contrast, for stabilized ylides (R = CO2 Me), betaine formation is endothermic, and the elimination step becomes rate and selectivity determining. Allylaziridines have been prepared in good yield by the action of allylindium reagents on azirines (e.g. 25).63 The C(3) substituent can control stereochemistry: hydroxy- (or acetoxy-) -methyl gives cis-allylation (via chelation with the indium reagent), whereas R = Me/Ph/CO2 Et gives a trans result, presumably due to steric repulsion.

Ph 3

N

R

H N

F3C

H N

de

de

de

NMe2

S

H CF3 (25)

(26)

Enantioselective nucleophilic addition to imines has been carried out with a planarchiral Lewis acid based on a 1,2-azaborolyl framework.64 Addition and cyclization reactions of imines, catalysed by Brønsted acids, have been reviewed, including examples in water solvent and enantioselective cases.65 Another review examines stereoselective nucleophilic additions to the C=N bond of aromatic azines (60 references).66 An enantioselective Strecker reaction involving Brønsted acid catalysis uses a BINOLphosphoric acid, which affords ees up to 93% in hydrocyanations of aromatic aldimines in toluene at −40 ◦ C.67 The asymmetric induction processes in the stereoselective synthesis of both optically active cis- and trans-1-amino-2-hydroxycyclohexane-1-carboxylic acids via a Strecker reaction have been investigated.68 A 2-pyridylsulfonyl group has been used as a novel stereocontroller in a Strecker-type process: ees up to 94% are suggested to arise from the ability of a chiral Lewis acid to coordinate to one of the sulfonyl oxygens.69

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11


The Strecker reaction of silyl cyanide (H3 SiCN) with benzaldehyde N -methylimine (PhCH=NMe), catalysed by an axially chiral 2,2 -bipyridine N ,N -dioxide has been explored computationally as a model for the corresponding reaction using TMSCN, PhCH=NCH2 Ph, and a biquinoline dioxide.70 The non-catalysed reaction is found to be concerted (via a five-membered ring TS), whereas the catalysis is stepwise, via a hexacoordinate hypervalent silicate. A thiourea derived from hydroquinine (a cinchona alkaloid) acts as a general organic catalyst for asymmetric addition of stabilized nucleophiles to acylimines, giving secondary amine adducts in high ee and de. Sample reactions catalysed include asymmetric nitro-aldol and aza-Henry reactions.71 Chiral thiourea (26) catalyses azaHenry reactions of N -Boc-aldimines with nitroalkanes, giving syn-β-nitroamines in high yield, de, and ee.72 A bifunctional catalysis, with the thiourea N–Hs binding the nitro group and activating C−H deprotonation via the tertiary amine substituent, is discussed. A cheap and efficient enantioselective aza-Henry reaction of nitromethane with a variety of N -protected arylaldimines has been reported.73 Using zinc triflate and (−)N -methylephedrine at −20 ◦ C, yields and ees of up to 99% have been achieved with wide tolerance of aryl substituent in terms of both electronic nature and position. The auxiliary is also easily recycled. Among addition reactions of imines, malonate esters have been added to dihydroisoquinolines (27) at C(1), to give the corresponding tetrahydro derivatives in high ee,74 and enantiopure aromatic sulfoxides (prepared by o-directed metallation) have been added enantioselectively to imines.75 R1

Cl

R2

O N

R3

Cl Ti

R1

de ee de ee

ee

ee ee

Cl O R2

1

R4 (27)

ee

H

N2 (28)

Titanium(IV) enolates derived from α-diazo-β-keto esters or ketones (28) efficiently add to TiCl4 -activated N -tosylimines to give the corresponding δ-N -tosylamino derivative.76 Subsequent diazo decomposition – catalysed by rhodium(II) or light – yields useful pyrroles or γ -lactams, respectively. Scandium triflate catalyses a highly diastereoselective addition of imines to 1,1cyclopropane diesters to give multi-substituted pyrrolidines.77 Non-activated imines have been pentafluorophenylated with (F5 C6 )3 SiF; protonation activates the imine, and chloride ions activate the silane.78 Highly substituted amides (29) have been prepared in a three-component reaction of an imine, an acid chloride, and trialkylindium.79 Proceeding under mild conditions and high metal efficiency, the ‘alkyl’ group on indium can also be aryl, heteroaryl, or vinyl.

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12

Organic Reaction Mechanisms 2006 O CuCl (cat.) R3COCl

NR2 R1

R3

1/3 InR43

H

R2

N R1

R4

H (29)

Carbonyls protected as azines or other C=N derivatives can be deprotected in seconds using HOF.MeCN, a reagent easily generated from dilute fluorine in water.80 Sensitive groups such as cyclic acetals of ketones elsewhere in the substrate often survive. As the electrophilic oxygen in the reagent is derived from water, the method is easily adapted to produce isotopic oxygen labelling in carbonyls. A study of the Staudinger synthesis of β-lactams from a diazo ketone, an acid chloride, and an imine (under basic conditions) has explored the cis/trans selectivity as a function of time, temperature, solvent, and the order of addition of reagents.81 Ketone dilithio-α,β-dianions (30, formed by treatment of β-stannylketones, RCOCH2 CH2 SnBuCl2 , with 4 equiv. of BuLi) react with imines and hydrazone selectively at the β-anion portion to give dilithium enolate amides (31).82 Subsequent reaction with electrophiles gives γ -amino ketones and related heterocycles. OLi

Li

R2

R1

N

OLi

Li

R3

(imines and hydrazones)

N

R1

R3

R2

(30)

(31)

Among reports related to radicals, ab initio calculations have been used to model intramolecular additions of acyl radicals to imines.83 Imines and oxazolines bearing a pendant acyl radical at carbon have been cyclized to give 2-piperidones through a selective 6-endo-cyclization at nitrogen.84 The acyl radical is generated via CO insertion into a suitable precursor. A diastereoselective example is also reported. Nucleophilic carbon radicals can C-alkylate imines, a process which is found to be substantially facilitated by an o-phenolic substituent as in e.g. (32).85 The hydroxyl is presumed to stabilize an intermediate aminyl radical. An enantioselective version of the reaction is also reported. BEt3 H

O N

NPh O

R1 R2

Ph (32)

(33)

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ee

13


Oximes, Hydrazones, and Related Species The Beckmann rearrangement of cyclohexanone oxime has been modelled kinetically, focusing on simulation of industrial conditions, and taking into account self-catalysis and the role of polymorphs.86 Chiral 1,2-oxazines (33) have been prepared from achiral ketones, R1 –CO–CH2 –R2 , via an α-oximation step (with a tetrazolylpyrrolidine organocatalyst), followed by a Wittig reaction.87 Subsequent N−O cleavage yields enantiopure cis-allylic alcohols bearing a pendant amine. Aryl alkyl ketoxime ethers, Ar–C(R1 )=N–OR2 , have been reduced with boraneTHF at ca 0 ◦ C to give amines, Ar–*CH(R1 )–NH2 .88 A chiral BINAP with an O3 BN framework gives up to 98% ee. The kinetics of oxidative deoximation of aldo- and keto-oximes by 2,2 -bipyridinium chlorochromate (back to the parent carbonyl compounds) have been studied in DMSO, where the reaction is found to be first order in both oxime and oxidant.89 The aldoximes proved more reactive, and rates correlated well with the Pavelich–Taft dual substituent equation. Following extension of the study to hindered cases, and to 18 other solvents (analysed by Taft and Swain multi-parametrics), a cyclic intermediate is proposed for the rate-determining step. The same reaction order behaviour is found using the pyridinium version, and again electronic, steric, and solvent effects were examined.90 Electroanalytical techniques indicate the formation of two carbinolamine intermediates and one monohydrazone in the reaction of terephthalaldehyde with hydrazine at pH 7.3.91 Reaction of hydrazones with iodine under basic conditions, to give azines, shows evidence of diazo intermediates that can be trapped with an internal alkene or alkyne function.92 Unsubstituted hydrazones of aromatic ketones and aldehydes have been converted in high yield to alkyl chlorides under Swern oxidation conditions, although the substrate actually undergoes a net reduction.93 When the hydrazone is dideuterated, a deuterium ends up on the carbon, supporting the proposed intermediacy of cation (34), which tautomerizes and loses N2 , to give a carbocation which combines with the chloride. This experiment also suggests a convenient method to produce deuterium-labelled alkyl chloride from the corresponding aldehyde/ketone. A new C2 -symmetric bis-sulfoxide/N -oxide (35; R,R-) promotes allylation of N benzoylhydrazones with allyltrichlorosilane in up to 76% ee.94

O Cl−

••

N

N

N+ R

S R

O

O

Me (34)

O

H N O

N R2

S R

1

H

Me (35)

(36)

ee

ee

ee

14


Chiral N -acylhydrazones (36) – derived from an aldehyde (RCHO) and 4-benzyl-2oxazolidinone – are sufficiently conformationally restricted to impart facial selectivity to C=N bond addition.95 Using indium(III) triflate, they undergo highly diastereoselective fluoride-initiated allylsilane addition, i.e. the aza-Sakurai reaction. Mechanistic investigation suggests a dual activation process in which the hydrazone is electrophilically activated via formation of its indium complex, followed by nucleophilic attack by an allylfluorosilicate species, [(allyl)4 SiF− ], leading to homoallylic amine adducts.

de

C–C Bond Formation and Fission: Aldol and Related Reactions Stereoselective Aldol Reactions Using Proline Organocatalysts The use of l-proline, amides derived from it, and related amino acids and small peptides as asymmetric organocatalysts for aldols – and indeed many other reactions mentioned elsewhere in this chapter – expanded hugely in 2006. A review deals with the direct aldol case.96 l-Proline catalyses direct aldols of trifluoroacetaldehyde ethyl (hemi)acetals, F3 C− CH(OH)−OX (X = H, CH2 CH3 , CH2 CF3 ), with ketones at room temperature to produce β-hydroxy-β-fluoromethylated ketones with des up to 96% and ees up to 91%.97 Many reactions have also been carried out in water. The mechanisms of the reactions of acetone and 1,3-dihydroxyacetone using zinc–proline and related catalysts have been probed kinetically.98 The former exhibits an enamine route, whereas the latter involves rate-limiting deprotonation of the α-carbon and formation of an enolate. An umbelliferyl ether of dihydroxyacetone (37) has been used as a fluorogenic probe for enolization, which may prove useful in screening of aldolases in water. O HO

O O

O

de ee ee

R

O N H

ee

N H

Ph HO Ph

coumarin (37)

(38)

trans-4-Hydroxyproline is readily available in both enantiomeric forms. It catalyses direct aldols in water with high de and ee, as do several of its silyloxy analogues.99 The first asymmetric direct aldol of 1,2-diketones and ketones, to give 2-hydroxy1,4-diketones, has been reported.100 l-Proline derivatives give high regio-, diastereo-, and enantio-selectivity in the reaction of 1-arylpropane-1,2-diones with simple ketones. Several reports describe additives: for example, tertiary amine bases, weak acids, and strong acids have been examined, with limited effect, except for the strong acids, which stop the reaction completely.101 C2 -symmetric chiral diols substantially improve proline-catalysed ee, conversion efficiency, and yield in the reaction of acetone with benzaldehyde, with addition of (S)-BINOL giving further improvement.102

de ee

ee


15

PEG [poly(ethylene glycol)] – a non-toxic and widely used solvent – has been successfully used with proline; no loss of activity was found when both PEG and proline were recycled 10 times.103 Several prolinamides have been examined: (38) catalyses the reactions of acetone with both aliphatic and aromatic aldehydes with ees up to 97%.104 It is proposed that amide and alcohol groups simultaneously donate hydrogen bonds to the aldehyde, while the gem-diphenyl moiety’s bulk orients the aldehyde’s approach. An l-prolinamide gives high regio-, diastereo-, and enantio-selectivity in direct aldols of p-nitrobenzaldehyde with chloroacetone, giving anti -α-chloro-β-hydroxy ketones;105 prolinamides with groups such as tetrazole or benzimidazole attached (via a methylene) to the amide nitrogen give ees up to 96% for acetone reacting with electron-deficient aromatic aldehydes.106 A range of prolinamides, some bearing one or more additional amino groups, have been developed as catalysts in water;107 o-hydroxyaromatic substituents likewise give high selectivity in this solvent (and in neat ketone solution) for direct aldols of araldehydes with ketones.108 Sterically and electronically tuneable and bifunctional organocatalysts based on diamides derived from proline are particularly selective in reactions of heterocyclic ketones with aldehydes.109 l-Prolinethioamides (39, R = alkyl including chiral alkyl), prepared from proline and amines, are effective in acetone–benzaldehyde reactions.110 Mechanistic studies focused in particular on suppression of non-enantioselective side-reactions, and also on the role of the side-chain of the catalyst acting as hydrogen bond donor, especially as the thioamides (with their more acidic N−H protons) are more catalytic than their amide analogues.

ee

ee de ee ee ee de de ee ee

C10H23 S N H

NHR (39)

N N H

C10H23

(40)

A range of proline derivatives have been employed as enamine-based organocatalysts of direct aldols in water, without organic co-solvent.111 Using the reaction of cyclohexanone with benzaldehydes as a test bed, lipophilic diamine (40) in the presence of TFA proved to be an excellent bifunctional catalyst system, giving performance up to 99/90/99% in terms of conversion/de/ee. Alkyl chains of (40) make an organic microphase likely. A computationally derived model for catalysis of the aqueous aldol by nornicotine (41) has been tested (by the same authors) via kinetic isotope effects (KIEs) and thermodynamic measurements.112 A proton inventory indicates that the computational results are not conclusive, and a water molecule is involved in or before the ratedetermining step. New chiral α-aminophosphonates related to proline catalyse enantioselective direct aldols; syn selectivity is also achieved on addition of bases such as DBU or DBN.113

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de ee

16

Organic Reaction Mechanisms 2006 Ph

O N H N

NH (41)

N H

N O

N H

(42)

N -Benzyl-N -prolylhydrazide (42), in its protonated form, gives high ee in the acetone–benzaldehyde reaction.114 A dendrimer bearing N -prolylsulfonamide catalytic groups achieves up to 99% yield, de, and ee in direct aldols in water.115 BINAM – the diamino analogue of BINOL – has been converted to its C2 -symmetric bis(prolinamide).116 The latter acts as a recoverable catalyst of direct aldols in DMF–H2O at 0 ◦ C, giving high des and ees. Butan-2-one showed significant regioselectivity, giving predominantly the iso product. Multi-functional enantioselective catalysts for direct aldol and Mannich reactions have been prepared from (S)-proline and 2,2 -diaminoBINAP.117 Among the uses of other amino acids, l-tryptophan gives high ees and des in direct aldols of cyclic ketones and benzaldehydes in water;118 hydrophobic and aryl-stacking effects have been considered in explaining the selectivities. β-Homoamino acids have been tested as enantioselective catalysts of intra- and inter-molecular aldols.119 α- and β-amino acids, chiral primary amines, and small peptides have been investigated as organocatalysts of direct aldols in non-aqueous systems, with ees up to 99% in some cases.120 Enantioselectivities were raised in some instances by the addition of water, suggesting a significant role for hydrogen bonding. The implications for the evolution of homochirality in sugars are discussed. Small peptides – simple di- and tri-peptides with a primary amine at the N-terminus – catalyse the aqueous aldol between unmodified ketones and aldehydes with up to 86% ee.121 This is dramatically different from the corresponding amino acid-catalysed reaction, suggesting that peptide formation may have been significant in the evolution of asymmetric synthesis. Addition of α-cyclodextrin raised the ee further through the hydrophobic effect.

ee de ee de ee ee de ee

ee ee

ee

Other Stereoselective Aldol Reactions To address limitations in the use of glyceraldehyde acetonide (43) as a three-carbon chiral building block, butane-2,3-diacetal-protected glyceraldehyde (44, R1 = R2 = H) has been prepared. It undergoes diastereoselective aldol reactions with a range of carbonyl compounds: esters, thioesters, and ketones. The work has been extended to other derivatives such as the α-substituted aldehyde (44, R1 = Me, allyl) and the methyl ketone (44, R2 = Me).122a,b A highly diastereoselective aldol of an α-CF3 -substituted enolate has opened up a new route to trifluoromethyl-substituted chiral centres.123

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17

1 Reactions of Aldehydes and Ketones and their Derivatives OMe

O O

H

R1

O

R2

O

Me

O

O (43)

Ph RS BnN

OMe

(44)

SO2Mes

(45)

A new thiol auxiliary (45, R = COEt) participates in boron-mediated anti -aldol reactions with aldehydes with high yield and de.124 Reaction of the product with nucleophiles displaces it (in the form of the thiol, 45; R = H), converting the aldol product under mild conditions into esters, thiolates, phosphonates, alcohols, or acids. Hydrogen bonding and steric effects have been investigated in a theoretical study of the origin of the diastereoselectivity in the remote 1,5-stereoinduction of boron aldol reactions of β-alkoxy methyl ketones;125 high levels of 1,5-anti -stereocontrol have been achieved in such reactions of α-methyl-α-alkoxy methyl ketones, giving both Felkin and anti-Felkin products.126 (S)-2-t-Butyldimethylsilyloxypentan-3-one (46), a lactate-derived chiral ketone, undergoes titanium-mediated aldols giving all-syn products in high de.127 Low-temperature 1 H and 13 C NMR evidence suggests a likely TS to account for the selectivity.

O

de

de de

OMe

O R3

de

O R1

N Boc

R2

OMe

OBoc O

(47) Si

O

(46)

R1

R2

N R3

H (48)

A highly anti -selective catalytic aldol reaction of amides with aldehydes has been reported.128 The amide – specifically an N -Boc-anisidide (47) – gives the aldol product (48) with the Boc group transferred to oxygen. Catalysed by barium phenoxides, the reduction proceeds under mild, convenient conditions (THF, 0 ◦ C, 24–48 h), giving high yields and des. A wide variety of aldehyde types work (though aliphatics give low yields), and a trifluoromethyl ketone example is also reported, as are initial investigations of enantioselective cases. A catalytic enantio- and diastereo-selective aldol reaction of ketones with ketene silyl acetals, H2 C=C(OTMS)−OMe, gives fair to good yields and ee.129 With further substitution of the vinyl function, the reaction is diastereoselective, up to 97%. A highly developed catalyst/promoter protocol is employed: a copper(I) fluoride complex is combined with a Taniaphos auxiliary (a chiral ferrocenyldiphosphine), plus (EtO)3 SiF. Evidence for the formation of species (EtO)4−n SiFn (n ≥ 2) as active

de ee

de ee

18


trapping silyl agents is presented. These intermediates appear to form more rapidly when K+ PhBF− 3 is added, by direct reaction with (EtO)3 SiF. A systematic study of methyl ketone aldol additions with α-alkoxy and α,β-bisalkoxy aldehydes has been undertaken, under non-chelating conditions.130 With a single αalkoxy stereocentre, diastereoselectivity generally follows Cornforth/polar Felkin–Anh models. With an additional β-alkoxy stereocentre, π -facial selectivity is dramatically dependent on the relative configuration at α- and β-centres: if they are anti, high de results, but not if they are syn. A model for such acyclic stereocontrol is proposed in which the β-alkoxy substituent determines the position in space of the α-alkoxy relative to the carbonyl, thus determining the π -facial selectivity.

de

Mukaiyama and Vinylogous Aldols An aldol reaction of a trimethoxysilyl enol ether, catalysed by a lithium binaphtholate, shows anti diastereoselectivity and modest ees under dry conditions, but addition of water brings about syn adduct formation, with higher ee.131 Silyl Lewis acid-induced Mukaiyama aldol reactions have attracted considerable mechanistic attention lately.132 In a study which considers five mechanisms (including a new one), the effect of the conjugate base of the Lewis acid is examined. Considering three cases, − NTf2 , − CTf3 , and − OTf, the catalytic cycles are suggested to be significantly different between the low-nucleophilicity cases (the first two) and the relatively highly nucleophilic − OTf. Scandium(III) and lutetium(III)133 and zinc134 complexes of C2 -symmetric pyridine–bis(oxazoline) (PYBOX) ligands are highly effective enantioselective catalysts of Mukaiyama aldol reactions. A TADDOL derivative (49, Ar = 1-naphthyl) is a potent diastereo- and enantioselective catalyst; an X-ray structure of a complex of (49) with an aldehyde indicates (i) an intramolecular hydrogen bond in the catalyst and (ii) a hydrogen bond from catalyst to aldehyde.135 It is therefore proposed that the asymmetric activation of the aldehyde arises from hydrogen bonding to a pre-organized catalyst. Ar O

de ee

de

de ee

de ee

Ar OH OH

O Ar

Ar

(49)

A chiral silver-based catalyst – formed from an amino acid and AgF2 – promotes efficient enantioselective addition of enolsilanes to α-keto esters in THF at temperatures as low as −30 ◦ C, with yields and ees in the high 90s.136 Chiral sulfoximines liganded to copper(II) give highly enantioselective vinylogous Mukaiyama-type aldol reactions under mild conditions.137 A chiral sulfinyl group has been used to achieve 1,5- and 1,6-asymmetric induction in Mukaiyama aldols, using Yb(OTf)3 catalysis.138

ee

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19


The Aldol-Tishchenko Reaction A short review examines the current status and prospects for the direct asymmetric aldol-Tishchenko reaction, a process which allows for stereocontrol of three contiguous chiral centres in ‘three-aldehyde’ or ‘aldehyde–ketone–aldehyde’ reactant combinations.139 anti -1,3-Diols have been prepared in good yield and enantioselectivity, and high diastereoselectivity, by reaction of aromatic aldehydes with aliphatic or aromatic ketones.140 The chiral ytterbium catalyst employed – derived from Yb(III) triflate and an ephedrine – promotes both the aldol reaction (through enolization) and the Evans–Tishchenko reduction of the aldol intermediate.

ee

de ee

Nitro and Nitroso Aldols The catalytic asymmetric Henry reaction has been reviewed.141,142 Chiral iminopyridines catalyse nitro aldol reactions with good ees in the presence of copper(II) acetate, without the need for exclusion of air or moisture.143 A phenylalanine-derived Schiff base – also complexed to copper(II) – is also effective, with the advantage that product configuration is easily reversed (by using the enantiomeric phenylalanine).144 β,γ -Unsaturated α-keto esters such as trans-MeCH=CHCOCO2 Et undergo enantioselective reaction with nitromethane, using new catalytic auxiliaries based on cinchona alkaloids.145 Carried out at −20 ◦ C in DCM, the organocatalysts give high conversion, predominantly reaction at ketone only (typically 96%.196 Cyclobutanones can act as 1-oxobutane-1,4-diyl units: they undergo intermolecular alkyne (RC≡CR) insertion to give cyclohexanones (68), catalysed by Ni(cod)2 , apparently via a seven-membered nickelacycle.197

ee

ee

de

O R R (68)

Reductive couplings of 1,6-enynes and aldehydes, catalysed by Ni(cod)2 , show regioselectivity effects that are switchable via addition of a phosphine.198 Chelation control and steering effects due to the alkene tether have been invoked to explain this. Favorskii ethynylation of acetone with acetylene in the presence of KOH is inhibited by dibenzo-18-crown-6, but not due to deactivation of acetone, as its aldol-like

de

26


condensation is accelerated under such conditions.199 Rather, activation of acetylene by potassium cation is suggested to play an important role.

Michael Additions Direct catalytic Michael addition of aldehydes to nitrostyrenes proceeds in good yield, syn diastereoselectivity, and enantioselectivity (up to 82/90/99%, respectively) using a recyclable dendritic catalyst bearing chiral pyrrolidine moieties.200 High-yielding enantio- and diastereo-selective direct Michael addition of ketones to nitroalkenes to give aldol products employ modular acyclic primary amino acid derivatives as catalysts.201 A pyrrolidine–thiourea organocatalyst (69) facilitates Michael addition of cyclohexanone to both aryl and alkyl nitroalkenes with up to 98% de and ee.202 The bifunctional catalyst (69) can doubly hydrogen bond to the nitro group, leaving the chiral heterocycles positioned for cyclohexyl enamine formation over one face of the alkene. CF3

C10H23 NH

N H

N

CF3

N H

(69)

C10H23

(70)

HN

R1

HO

R2

O O

(72)

de ee

(71)

A direct organocatalytic Michael reaction of ketones or aldehydes with β-nitrostyrene has been reported in brine solution, using a bifunctional catalyst system: proline-derived diamine (70) and TFA.203 In some cases the conversion, yield, de, and ee all exceeded 95%. Results in water were poor, mainly due to polymerization, which is catalysed by amines. It is proposed that sodium cations stabilize the anionic intermediate formed from (70) and β-nitrostyrene, thus minimizing polymer formation. While organic co-solvent is not required, an organic-rich phase is proposed to concentrate the Michael reactants and catalysts, thus accelerating the reaction. l-Prolinamides (71) with a pendant alcohol act as recoverable bifunctional catalysts of direct nitro-Michael addition of ketones to β-nitrostyrenes, giving syn-des up to 94% and ees up to 80%.204 The pyrrolidine provides enamine catalysis, and the side-chain donors can hydrogen-bond the nitro oxygens. O

ee

O N H

S N H

de ee de

O

O

(73)

de ee

de ee

27


Diketone (72) undergoes an acid-catalysed Michael–aldol reaction to give tricyclic ketone (73).205

Other Addition Reactions General and Theoretical Recent developments in the asymmetric addition of aldehydes have been reviewed,206 as have asymmetric catalysis using metal complexes207 and nucleophile isotope effects.208 Natural bond orbital analysis of early and late TSs has been carried out to explore the factors involved in π -selectivity of nucleophilic addition to carbonyls.209 Cieplak’s σ → σ *# hyperconjugation hypothesis (where σ # is the incipient bond) is not supported by the results for early TSs, and evidence in favour of Felkin–Anh’s σ # → σ * ∗ hypothesis is weak. Late TSs are devoid of σ → πC=O interactions: here, the Cieplak model may be applicable. Alcohol (74) undergoes an unusual extrusion of its hydroxymethyl group in the presence of sodium hydride.210 That it is a reverse reaction of nucleophilic addition to formaldehyde was confirmed by trapping experiments for the latter. Relief of steric congestion is a likely cause, with the sulfinyl also helping to stabilize the incipient carbanion. The two factors combined help to reverse the equilibrium which normally favours attack on formaldehyde.

RO

Cl

S O O

OH

ee

de

OH N Bn (75)

(74)

The atmospheric chemical kinetics of linear perfluorinated aldehyde hydrates, Cx F2x+1 CH(OH)2 , have been measured for x = 1, 3, and 4, focusing on formation (from aldehyde, by hydration), dehydration, and chlorine atom- and hydroxyl radical-initiated oxidation.211 The latter reaction is implicated as a significant source of perfluorinated carboxylic acids in the environment.

Addition of Organozincs Most papers deal with diethylzinc. Chiral (3R,5R)-dihydroxypiperidines (75), derived from trans-4-hydroxy-l-proline, give up to 98% ee in its additions to benzaldehyde and heptanal.212 Cyclohexanols bearing 1-phenylethylamine attached via nitrogen in the α-position have been tested as enantioselective catalysts of diethylzinc addition to benzaldehyde.213

ee ee

28


A range of chiral bridged resorcinarene ‘bowls’ also catalyse this reaction: a mechanistic model suggests that the axial chirality of the receptor cavity, rather than a central chirality in the bridge, is responsible.214 Theoretical predictions for the reaction have been calculated for a series of catalysts, using a rapid QSSR (quantitative structure–selectivity relationship); based on quantum molecular interaction fields, the predictions have since been tested by independent experiments.215,216 Sterically congested ferrocenylaziridinoalcohol auxiliaries give up to 99.8% ee; evidence for a strong direct steric interaction with the substrate – which can even lead to inversion of configuration – is presented.217 γ -Amino alcohols derived from (+)- and (−)-α-pinene act as catalysts for enantioselective addition of diethylzinc to aromatic aldehydes.218 The ee is highly dependent on the N -substituent, and ab initio molecular modelling has been used to interpret this finding. A chiral Schiff base with pendant phenol and alcohol functions (76) catalyses addition to aldehydes in cold hexane with up to 96% ee.219 Non-linear effects on the ee suggest that zinc aggregation occurs, and NMR evidence indicates that both ethyl groups react with both hydroxyls in the catalyst.

ee

ee

ee

ee

Ph N

OH

Fe

OH O

OH (76)

Me

(78) N

O HO (77)

A chiral [2.2]paracyclophane bearing a β-hydroxyamino side-chain catalyses enantioselective reaction with aromatic and α,β-unsaturated aldehydes.220 Comparison with simpler catalysts suggests that the new one exhibits cooperative effects between planar and central chiralities. Unsymmetrical substitution of BINOL with a bulky group gives enhanced activity: 95% ee was achieved with 99% ee.227 A mandelamide diastereomer catalyses addition of both aryl- and alkyl-zincs to heteroaromatic aldehydes in high yield and ee, giving heterocyclic propargyl alcohols, under otherwise metal-free conditions.228 A chiral H8 -BINOL derivative catalyses an efficient direct enantioselective addition of diphenylzinc to both aromatic and aliphatic aldehydes, with particularly good results for straight-chain cases.229 Aggregation phenomena in solution have been studied by NMR spectroscopy. Chiral amino alcohols derived from BINAP have been employed as catalysts in a highly enantioselective addition of arylzincs (prepared in situ) to aldehydes.230 Recent progress in enantioselective addition of organozincs has been reviewed.231

ee

ee

ee

ee ee ee

Addition of Other Organometallics, Including Grignards 1,2-Additions of a range of organolithium reagents, RLi, ArLi, NC–CH2 Li, RC≡CLi, and ArC≡CLi, show ees of 65–98%, using a chiral lithium aminosulfide auxiliary, superior to similar lithium amides with an ether instead of a sulfide, or without either chelator.232 Lithium carbazolates have been added enantioselectively to aldehydes, giving heterocyclic carbinols.233 The preparation and synthetic applications of α-lithio aldehydes and ketones and related compounds have been reviewed.234 Mixed lanthanide–alkali chlorides, LnCl3 .2LiCl (Ln = La, Ce, Nd) can be readily prepared as 0.5 mol dm−3 solutions in THF.235 They act as improved promoters of addition of organomagnesium reagents to ketones, and also to aldimines, and in addition have been found to promote organolithium addition. 2,4,6-Trimethoxybenzene-1,3,5-tricarbaldehyde (79) and its keto homologue (80) involve three symmetry-equivalent carbonyl centres, each in a 1,5-relationship to their neighbours.236 Two diastereoselective reactions have been performed: (i) the trial can be trimethylated to give triol (81) with methyllithium in THF, and (ii) the triketone can be reduced (to the same product), in both cases with >95% de (anti, syn). Chelation and steric (gearing) effects about the crowded aromatic core are discussed to explain the observed diastereoselectivity. A range of di- and tri-methoxybenzaldehydes, expected to give alkyl carbinols on treatment with alkylmagnesium bromides (RMgBr), instead gave the di alkyl carbinol, (MeO)2/3 –C6 H3/2 –C(OH)R2 .237 It is proposed that the intended product is subject to an internal Cannizaro-type oxidation process to give the ketone, allowing the Grignard to re-alkylate.

ee

ee

de

30

Organic Reaction Mechanisms 2006 H

OMe O

O

Me H

MeO

HO

OMe H

O

Me

MeO

OMe

Me

OMe O

O

Me

MeO

(79)

Me

OMe OH

OMe

Me

OH (81)

O (80)

The Wittig and Aza-Wittig Reactions A detailed DFT study of the mechanism of the Wittig reaction has been carried out on a range of non-stabilized, semi-stabilized, and stabilized ylides: experimentally realistic results required explicit consideration of solvent effects, and practical large-scale systems which allow steric, electronic, and stereochemical effects to be captured.238 Significant results for the non- and semi-stabilized systems include the necessity of considering the energy of the elimination TS in order to identify E/Z selectivity. Also, puckering of the addition TS depends not on ylide stabilization, but on 1,2-, 1,3-, and C−H· · ·O interactions. For stabilized substrates, puckering depends on dipole–dipole interactions: these determine the high E selectivity seen in such cases. A QSAR (quantitative structure–activity relationship) approach has been taken to predicting stereoselectivity in the Wittig reaction.239 Pyrazolo[1,5-a]pyrimidines and imidazo[1,2-b]pyrazoles have been prepared from phosphine derivatives of 5-amino-3-phenylpyrazole in aza-Wittig reactions with selected α-chloroketones.240 An enantioselective aza-Wittig strategy has been employed in the desymmetrization of prochiral 1,3-diketoazides, to produce β-quaternary azacycles.241

ee

Hydrocyanation, Cyanosilylation, and Related Additions A range of N -heterocyclic carbenes catalyse TMSCN addition to aldehydes (RCHO) to yield cyanohydrin TMS ethers, R–*CH(OTMS)CN; acid treatment gives the cyanohydrins.242 Mechanistic possibilities are discussed, and use of a chiral carbene gives a modest ee. Several other studies used such carbenes;243 for example, a low loading of 0.01−0.5 mol% of 1,3-di-t-butylimidazol-2-ylidene (82) catalyses TMSCN addition to a wide range of aliphatic and aromatic aldehydes and ketones under mild, metalfree conditions, with a wide functional group tolerance.244 Also, (83) gives comparable results, and has also been used to convert imines to aminonitriles.245

N

N

N

N

••

••

(82)

(83)

de


31

Diastereoselectivities in the tetrabutylammonium cyanide-catalysed cyanosilylation of cyclic α,β-epoxyketones are dependent on ring size, with a switchover in selectivity between five-membered and larger rings being explained through computation of TSs.246 A range of Lewis bases catalyse the addition of TMSCN to aldehydes, with phosphines and amines the most efficient.247 Kinetic studies indicate that the orders of aldehyde, Lewis base (LB), and TMSCN are 1, 1, and 0, suggesting an Me3 Si–LB+ CN− ion pair as an intermediate. However, chiral phosphines and amines gave very low ees. A chiral aluminium-salen–Ph3 PO combination catalyses addition to ketones in up to 92% ee; the catalyst system essentially acts as a Lewis acid–Lewis base bifunctional system.248 A similar chiral manganese(III)-salen–Ph3 PO method is comparable.249 Another effective catalyst is 1,1,3,3-tetramethylguanidine, which works well at 0.1 mol% loading in solvent-free conditions at ambient temperature.250 Aliphatic aldehydes have been converted to their (R)-cyanohydrins using a biphasic system to accommodate hydroxynitrile lyase enzyme (from the Japanese apricot, Prunus mume) as the enantioselective catalyst.251 An alternative TS for asymmetric addition of cyanide to aldehydes catalysed by titanium–salen complexes has been proposed, based on a comparison with a related iron–salen complex for which a crystal structure is reported.252 High-yielding, high-ee cyanation has been achieved using a multi-component bifunctional catalyst system.253 Aldehyde (RCHO) and nitrile (NC–CO2 Et) react at −45 ◦ C in DCM to give the corresponding cyanohydrin ethyl carbonate, R–*CH(CN)– O–CO2 Et. The catalyst used has four components: a chiral BINAP, (1R,2S)-(−)-N methylephedrine, cinchonine, and titanium isopropanoxide. Evidence for all four being essential is presented. Ketones have been enantioselectively cyanocarbonated to give tetrasubstituted carbon stereocentres (84), using cinchona alkaloid catalysts and cyano esters, with ees up to 97%.254 A fall-off in ee at high conversions has been explained by a mechanism involving competing asymmetric processes, and significant retro-cyanation. O R1

NC CO2R3

R2

ee

ee ee

ee

ee

ee

ee

NC OCO2R3 R1

*

R2 (84)

Aldehydes, RCHO, have been cyanophosphorylated with diethyl cyanophosphonate [NC–P(=O)(OEt)2 ] to give cyanohydrin O-phosphonates, R–*CH(CN)–OP(=O)(OEt)2 , in up to 98% yield and 97% ee, using a YLi3 (BINAP)3 catalyst.255 DBU catalyses cyanoacylation of ketones, R1 COR2 , with aromatic acyl cyanides giving O-acyl cyanohydrin adducts, ArOCO–C(CN)R1 R2 , in fair to good yields in 2 h at ambient temperature.256 Hydroacylation of carbonyls or alkenes by aldehydes is well known. Hydroacylation of an activated ketone (85) by benzaldehyde has now been reported, giving a new asymmetric centre at the ketone carbon (86).257 In a metal-free procedure, the reaction

ee

32


is catalysed by N -heterocyclic carbenes, such as the triazole catalyst (87) shown. The reaction involves separate reduction and acylation steps, with the organocatalyst carrying out two key bond-forming processes. Whereas (86) is the major product in DCM, methanol solvent decouples reduction and acylation, giving the alcohol ‘intermediate’, Ph–*CH(OH)CO2 Me, as sole product. O PhCHO

O

N

OEt R

1

(85)

Ph

Me

N ••

N Me

O O

H * R1

O OEt

(86)

(87)

The use of homogeneous carbonylation reactions for the synthesis of biologically important compounds has been reviewed, covering many methodologies, including direct use of carbon monoxide, and also hydroformylation and alkoxy- and aminocarbonylation, both inter- and intra-molecular.258 α-Amino-β-keto esters have been prepared in high ee via catalytic electrophilic α-amination of β-keto esters, using azodicarboxylate reagents and a chiral palladium complex as catalyst.259 By immobilizing the catalyst in an ionic liquid, the system can easily be recycled. The introduction of α-heteroatom functionalization into an aldehyde or ketone is a very useful class of transformation. Performing it directly and asymmetrically, using organocatalysts, has been reviewed for reactions such as amination, oxygenation, halogenation, and sulfenylation (44 references).260 Propanal has been enantioselectively hydroxyaminated with nitrosobenzene (Ph–N= O) to give a hydroxylamino alcohol, Ph–N(OH)–*CH(Me)CH2 OH, using an axially chiral BINAP secondary amine catalyst in THF at 0 ◦ C, followed by methanolic treatment with sodium borohydride.261 Yields up to 90% and ees up to 99% were recorded, and one-pot conversions to the corresponding β-amino alcohol or β-diamine are described.

ee

de ee

ee

Hydrosilylation and Related Reactions An enantioselective metal-free hydrosilylation of aromatic ketones (and also of their imines) employs a quinolyloxazoline (88), which brings about a relatively long-range induction.262

Ph

O *

N

N (88)

ee

33


A rhodium(I)–diphosphine complex which is P -chiral catalyses enantioselective hydrosilylation of a range of simple ketones.263 After acidic workup, the corresponding alcohols are obtained in high yields and ees up to 99%. High-valent rhenium dioxo complexes, ReO2 I(PR3 )2 , catalyse the hydrosilylation of carbonyl compounds.264 DFT calculations suggest rate-determining dissociative addition of the Si–H bond (of H–Si–alkyl3 ) across the Re=O bond, with subsequent carbonyl coordination and reduction. Metal complexes of a C2 -symmetric bisproline catalyse the asymmetric hydrosilylation of ketones: 29 Si NMR spectra provide evidence of the mechanism.265 C-Silylated α-diazophosphines (89, R1 = Me2 N or i Pr–N–CH2 CH2 –N– i Pr) react with 2 mol of aldehyde under mild neutral conditions to give α-hydroxyphosphonamides (90) and alkynes.266 Chiral aldehydes can give (90) as single isomers. Isolation of some intermediates, and labelling studies which show that an aldehydic hydrogen ends up in the alkyne, indicate that the aldehyde is nucleophilically attacked by (89) to give a betaine, which rearranges to a diazomethylenephosphorane, which in turn undergoes a Wittig-type reaction with another molecule of aldehyde.

ee

ee

de

O R12P

TMS

R2CHO

N2

R12P

OH

R2

H

(89)

+ R2

(90)

Miscellaneous Additions Imidazolium salt (91) is an enantioselective catalyst for crossed aldehyde–ketone benzoin cyclization.267 Most examples involve 6-oxoaldehydes giving α-hydroxycyclohexanones, although a 5-oxo- to -cyclopentanone case is also illustrated. Considerable variation in functional group type – aromatic, aliphatic, alicyclic – is tolerated. Ph N

N+ N

Cl−

Me Me N N

Me

2

S

O

6

1

Me

(91)

S

N

N O

5

Me Ar

O

(92)

(N 1)-Acetyl-(N 6)-aroyl-2,5-dithio-3,4,7,8-tetramethylglycolurils (92) and related compounds undergo a t-butoxide-catalysed Claisen-type condensation.268 Rate constants have been measured for the template-directed process, Hammett plots have been constructed, and deuterium isotope effects measured at the acetyl group. The

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mechanism is discussed with an emphasis on the role of sulfur via comparison with the 2,5-dioxo compounds. The TEMPO moiety (2,2,6,6-tetramethylpiperidine-1-oxyl) has been incorporated into acetoacetic derivatives to achieve E-selective Knoevenagel condensations, exploiting the steric hindrance that it causes.269 In contrast, acylacetoamides (including Weinreb amides) produce Z-adducts. Downstream reductions of carbonyl groups in the products allow access to a variety of useful materials. In a revisitation of the mechanism of the Perkin condensation, a strong argument is advanced against the common belief that acetate deprotonates acetic anhydride to give its enolate, AcO–C(=CH2 )–O− .270 The pKa of acetic anhydride (estimated 20) is too high, acetate is too weak a base, and the enolate would probably decompose (to ketene and acetate) at the typical reaction temperature of 180 ◦ C. This leaves a problem: what likely two-carbon nucleophile – a formal acetic acid dianion equivalent – is available? The gem-diacetate (93) is suggested; its simple enolate might be difficult to form, but a type of neighbouring group participation could generate anion (94) as nucleophile (for reaction with the second benzaldehyde). The finding that (93) can give cinnamic acid product at room temperature (in t-BuOK–THF) supports the hypothesis, in addition to pointing the way towards milder conditions. O

O−

O Ph O

O Ph

O

O O

H

−

OAc

(93)

(94)

An isoborneol with a cis-α-amino group gives ees of up to 93% in addition of Reformatsky reagents to aldehydes.271 A wide range of benzocyclic ketones have been accessed by intramolecular arylation using aldehyde groups.272 This intramolecular Friedel–Crafts-type acylation is promoted by iodinium species, using the reagent combination IPy2 BF4 –HBF4 . Chiral benzoylformate esters, PhCOCO2 R*, react with diazomethane to give αoxiranyl esters, but de is typically negligible.273 Aryl-stabilized ammonium ylides from deprotonation of (95; X = CH, N) react with benzaldehyde to give epoxides (96).274 The diastereoselectivity is highly sensitive to the nature of the amine and the ylide substituent, e.g. it reaches 99:1 trans:cis

X N+ R

Cl− (95)

O

PhCHO t-BuOK/THF/r.t.

Ph

Ar (96)

ee

de

de

35


for R = CF3 . DFT calculations suggest that – although the ylide is a high-energy species – betaine formation is reversible, as the next step of ring closure also has a high barrier. Thus groups that stabilize the ylide and/or increase the barrier to ring closure (electron-deficient aryls) favour trans selectivity. A spiro imidazolidine–oxazolidine intermediate (97) has been isolated in an aziridination of α-bromocinnamaldehyde mediated by a guanidinium ylide (98).275 Br Bn

MeN

−

N +

Br

R

BnN

O

MeN

NMe

OHC

NMe

R

Ph

Ph

Ph

Ph

R

Ph

(98)

BnN Br

Ph (97)

Ph

Biginelli synthesis of 3,4-dihydropyrimidin-2(1H )-ones (99) from an aldehyde, a β-diketone, and urea is catalysed by l-proline methyl ester hydrochloride.276 Although evidence strongly supports an enamine mechanism, the products were essentially racemic.

ee

O HN

R1

NH *

R1

R2 COR3

OH

R2

SMe (100)

(99)

Corey–Chaykovsky reaction of a ketone R1 COR2 with Me3 S+ I− –NaH in DMSO is a useful synthesis of epoxides, but a re-investigation in THF using n-BuLi as base gave significant amounts of β-hydroxymethyl thioether (100), in addition to epoxide.277 This represents formal addition of Me2 S. Di- and tri-substituted enamines of aldehydes have been generated under mild conditions (1 h, 0 ◦ C, 1.2 equiv. of amine).278 Although easily isolable, they can be conveniently employed in situ. The reaction is chemoselective (ketones present are not affected), it tolerates sensitive groups such as acetals and silyl ethers, and it works for both aliphatic and aromatic aldehydes. Chiral Schiff bases derived from salicylaldehyde, when complexed to titanium(IV), catalyse enantioselective addition of diketene (101) to aldehydes (RCHO; R = Ph, alkyl, alkenyl) to yield δ-hydroxy-β-keto esters (102), with up to 84% ee.279 2-Aryl aldehydes and ketones with an α-substituent, Ar–CHMe–COR (R = H, Me), are sulfamidated to give α,α-disubstituted product, Ar–C(NHTs)Me–COR, by

ee

36


OH

RCHO

O O

Ti(O-Pri)4/DCM/−20 °C

(101)

O

O O-Pri

R (102)

chloramine-T.280 In the case of the aldehydes, oxidation and removal of the tosyl group give access to α,α-disubstituted amino acids. The Willgerodt reaction allows amide synthesis from aromatic aldehydes or ketones, using a secondary amine and a thiating agent. The mechanism of the more convenient Kindler modification, employing sulfur and morpholine, has been reviewed.281 Tetrakis(dimethylamino)ethylene (TDAE) has been used as a reagent for the nucleophilic perfluoroalkylation of aldehydes, ketones, imines, disulfides, and diselenides.282 Analogous to triflouromethylation with CF3 I, the reagents C2 F5 I and n-C4 F9 I (‘RF -I’) give perfluoroalkylation in DMF solution. The aldehyde and ketone reactions give enhanced yields upon irradiation. TDAE is presumed to reductively cleave RF -I to give RF− and I− (and TDAE2+ ). The conjugate bases of amides, imides, and carboxylic acids have been used as Lewis acids for perfluoroalkylation of carbonyl compounds and aldimines, using TMSRF reagents (RF = CF3 , C2 F5 , and n-C3 F7 ).283 Catalytic asymmetric synthesis of enantiopure diaryl-methanols and -methylamines (important pharmaceutical intermediates) has been reviewed (76 references), focusing on (i) aryl transfers on to aryl-aldehydes and -imines and (ii) asymmetric reductions of diaryl-ketones and -ketoimines.284 Asymmetric synthesis of diarylmethanols can be achieved via rhodium-catalysed addition of arylboronic acids to benzaldehydes, using chiral mono- or bi-dentate phosphoramidites based on BINOL.285 Benzaldehyde undergoes nucleophilic arylation with phenyltrimethoxysilane, PhSi(OMe)3 , to give diphenylmethanol in good yields under moderately vigorous conditions: Bu4 N+ F− catalysis in refluxing acetonitrile.286 However, this 1,2-addition process is completely switched to give methyl benzoate, the oxidative esterification product (at 25 ◦ C), by addition of a palladium–phosphinous acid catalyst. NMR evidence suggests that the siloxane may perform three functions: generating a Lewis acidic silicate to activate the aldehyde, while acting as methoxy donor and hydride acceptor.

Enolization and Related Reactions Magnesium bis(hexamethyldisilazide), Mg(HMDS)2 , catalyses the enolization of ketones.287 On addition to propiophenone in toluene at ambient temperature, a ca 3:1 E:Z mixture of enolates (103, R=SiMe3 ) is formed. These enolates, and an initial ketone complex, have been characterized by NMR, X-ray, IR, and UV–visible spectroscopy and computational studies. Kinetics of tautomerization have been measured, with proton transfer confirmed as rate determining (kH /kD = 18.9 at 295 K). The significant temperature dependence of the primary isotope effect is indicative of tunnelling.

ee

ee

1 Reactions of Aldehydes and Ketones and their Derivatives R R

37

R R

N

N Mg Mg N O R R H

OD F F

Me

OD (104)

(103)

Enol (104), generated rapidly in acidic solution from a precursor acetal, shows remarkable stability: t1/2 > 3 h in 0.1 mol dm−3 DCl in CD3 OD at 300 K, allowing its characterization by 2D NMR spectroscopy. A DFT study of a simple model, 2,2-difluoroethenol, indicates that there are significant differences in timing of the protonation TS compared with the non-fluorinated enol.288 Keto–enol tautomerization of 3-hydropyridazine derivatives has been investigated using DFT: the 2-hydropyridazin-3-one tautomer is typically found to be the most stable.289 Triethylgallium has been used as a non-nucleophilic base to generate enolates from ketones, both cyclic and acyclic, without forming carbonyl addition products.290 The gallium enolates can then be C-benzoylated, and can participate in aldol reactions. Unsymmetrical ketones preferentially enolized at the methylene, under kinetic control. Silyl enol ethers of decalones have been synthesized which allow stereoselective protonation of the corresponding enol to be initiated and followed kinetically.291 Pendant groups have been placed so that the relative rates of intermolecular protonation and intramolecular protonation (by the proximate group) can be measured. Examples of groups which give one or other mechanism are detailed: CO2 − and CO2 H typify the latter. Commercially available amino acid derivatives have been tested as chiral proton sources for protonation of lithium enolates: catalytic N β -l-aspartyl-l-phenylalanine methyl ester gave an ee of 88%.292 A stereoselective enolate protonation has been achieved by changing the counterion of the chiral alkoxide base employed: the lithium alkoxide-generated enolate gives close to 90% of the β-epimeric ketone product, whereas the use of the potassium cation gives 99% α-epimer.293 A chiral BINAP-diphosphine complexed to silver(I), with fluoride as counterion, catalyses the enantioselective protonation of TMS-enolates, giving ketones with a tertiary asymmetric α-carbon in up to 99% ee.294

ee

ee

ee

α-Halogenation, α-Alkylation, and Related Reactions Key advances in α-fluorination which occurred in 2005, using both organo- and metallo-catalytic approaches, have been reviewed (21 references).295 A mild metal-free α-iodination of ketones uses molecular iodine in a neutral reaction medium.296 Aliphatic ketones react predominantly on the more substituted side, with

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about 1 day at room temperature being sufficient. Aryl alkyl ketones require the solvent, dimethoxyethane, to be heated to reflux for a few hours. Iodine is proposed to act as a Lewis acid promoter of initial enolization of the ketone, while HI formation should give autocatalysis; pyridine stops the reaction. A new synthesis of pyrroles generates a 1,3-diketone by reacting a lithium enolate of a ketone with an acid chloride; in situ addition of a hydrazine yields, potentially, a tetrasubstituted pyrazole.297 Tolerant of a wide range of functional groups, it is also easily adapted to rapid preparation of fused bicyclic pyrazole systems. The utility of global and local reactivity descriptors to predict chemical reactivity and C- versus O-alkylation has been investigated for the case of lithium enolates.298 The origin of the dramatically increased enantioselectivity of α-alkylation of aldehydes when 2-methylproline is substituted for proline as organocatalyst has been investigated using DFT.299 Direct catalytic intermolecular α-allylic alkylation of aldehydes and cyclic ketones has been achieved using a one-pot combination of a transition metal catalyst, Pd(PPh3 )4 , and an organocatalyst: a secondary amine which facilitates enamine catalysis.300 Pyrrolidinium tetrafluoroborate (105) serves as an organocatalyst for the reaction of benzaldehyde with N -methylpyrrole, to give the corresponding dipyrromethanes (106) under mild conditions.301 Initial formation of an iminium ion by condensation of the aldehyde with the catalyst is proposed.

ee

N+ BF − 4 H H

N

(105)

N

Me

PhCHO

Me

N Ph (106)

Me

2-, 3-, and 4-pyridinecarboxaldehyde condense with benzene in F3 C–SO3 H (triflic acid), to give the gem-diphenyl product, PyCHPh2 .302 Substituted pyridine aldehydes also gave the reaction, and deactivated arenes (e.g. o-dichlorobenzene, nitrobenzene) also work. Even hydrocarbons such as adamantine work, in the presence of highpressure CO, giving adamantanyl–CO–CH2 Py derivatives. Evidence for the formation of dicationic intermediates (diprotonated pyridinecarboxaldehydes) is seen at low temperatures in superacid (FSO3 H–SbF5 ) using 13 C NMR spectroscopy.

Oxidation and Reduction of Carbonyl Compounds Regio-, Enantio-, and Diastereo-selective Reduction Reactions An integration of readily available computational methods and visualization techniques has rendered a simple method to predict nucleophilic asymmetric induction of prochiral electrophiles.303 Taking the examples of ketone and aldehyde reductions, electrostatic potential has been mapped on to the frontier orbital involved. A distinct difference in

de

39


potential between the faces of the carbonyl has been used to predict the direction of nucleophilic attack. In a probe for the presence of stereoelectronic effects in nucleophilic addition to 12 sterically unbiased ketones, calculations have identified subtle bond length differences in the C–Nu bond of the diastereomeric alcohol products, where Nu− = H− or Me− .304 The calculated differences are weak (95% of 110b, this time with no de. Three distinct mechanistic possibilities are discussed, with the authors favouring coordination of alkyne and alkene to the metal centre during the C−C bond-forming step (favouring 110a with high de). The phosphine, however, can directly coordinate to the metal, disrupting this effect. Me X

de

i-PrCHO Ni(cod)2/Et3B

OH

OH

Et (109)

X

Me

Et

Me (110a)

Me

+ Et

Me

X Me (110b)

Me

Developments in the enantioselective formation of tertiary alcohols via asymmetric addition to ketones have been reviewed.329

ee

Other Reduction Reactions The kinetics and mechanism of hydride transfer between Michler’s hydride and 2,3,5,6tetrabromo-p-benzoquinone have been investigated spectrophotometrically, examining both solvent and pressure effects.330 A remarkable reduction protocol reduces a wide range of oxygen functionality to hydrocarbon, including carboxylic acids, aldehydes, ketones, and all alcohols: (primary, secondary and tertiary). Using a simple silane (n-butyl or diethyl) and a Lewis acid catalyst, tris(pentafluorophenyl)borane, the reaction takes a few hours in DCM under argon.331 Alkene functionality, nitro groups, and ethers are all unaffected, while phenols are merely silylated. Similar mechanisms are proposed for all reductions: hydride abstraction by boron with simultaneous oxygen attack on silicon, giving a silyloxy cation, followed by hydride return to carbon. A dynamic kinetic resolution has been employed to achieve a catalytic asymmetric reductive amination of aldehydes.332 Reductive amination of ketones and aldehydes by sodium triacetoxyborohydride has been reviewed, highlighting its advantage over other reagents.333 Reductive amination of ketones using p-anisidine and the Hantzsch ester for transfer hydrogenation is a low-yielding reaction in toluene at room temperature, but thiourea is an efficient catalyst, and yields of up to 94% are reported at 50 ◦ C.334 A mechanism involving thiourea hydrogen bonding to the intermediate imine is supported by ab initio calculations. A variety of activated carbonyls such as α-keto esters, benzils, cyclohexane-1,2dione, and α-ketophosphonates have been reduced to the corresponding α-hydroxy compounds in THF at room temperature, using alkylphosphines (PMe3 or PPhMe2 ).335

ee

42


2 H-

and 18 O-labelling experiments suggest that proton transfer from alkylphosphine occurs (via e.g. 111?), with aqueous workup releasing the product plus R2 P(=O)Me. H CH2 R O P R

HOO OOH

O OMe

R1 R2 (112)

(111)

A rhodium(I)–N -heterocyclic carbene complex has brought about a chemoselective decarbonylation, converting a cyclobutanone to the corresponding cyclopropane, while leaving an aldehydic substituent untouched.336

Oxidation Reactions Ketones, R1 COR2 , have been converted to their gem-dihydroperoxides (112) using a ‘green’ oxidant, aqueous 30% hydrogen peroxide, with iodine as catalyst.337 The iodine may enhance the electrophilic character of the carbonyl carbon and/or the nucleophilicity of the hydrogen peroxide. The reaction has also been extended to acetals and aldehydes. A new ionic liquid, 1-butyl-3-methylimidazolium tribromide can act as an oxidizing agent to convert alcohols to aldehydes and ketones.338 In the case of benzyl alcohols and diols, [Bmim][Br3 ] combines oxidizing and brominating properties in a one-pot synthesis of β-bromoethyl esters. The kinetics of the oxidation of aromatic aldehydes by N -chloronicotinamide in aqueous acetic acid are first order in both reactants and in proton.339 The effect of substituents has been studied, and data at different temperatures yield activation parameters. Several reports deal with the action of heterocycle–chromate agents such as: quinolinium dichromate on five-membered heteroaldehydes340 and quinolinium bromochromate on benzaldehydes,341,342 all in acetic acid solution. The latter studies show a secondorder dependence on proton concentration, acceleration by electron-withdrawing parasubstituents, and a substantial kinetic isotope effect for the deuterated aldehyde. Oxidative amidation of aldehydes can be achieved with primary amine hydrochlorides, CuI as catalyst, and t-BuOOH as oxidant, probably via a carbinolamine intermediate.343 An experimental and theoretical study of the Baeyer–Villiger (BV) oxidation of ketones has examined its uncatalysed and acid-catalysed forms, and fluoro- and chlorosubstituted substrates.344 In assessing migratory aptitudes, fluoroalkyl groups are only slightly less favourable than alkyl (by 0.3/0.5 kcal mol−1 , calculated/observed), whereas migration of a chlorinated substituent is significantly more difficult (ca 2.6 kcal mol−1 ).


43

Cyclohexanone and cyclopentanone monooxygenases have been used in the microbial BV oxidation of prochiral bicycloketones. A significant difference in behaviour of [3.3.0] and [4.3.0] substrates has been analysed by high-level DFT calculations.345 Al–BINOL complexes catalyse the enantioselective BV oxidation of cyclobutanones to give the corresponding γ -butyrolactones in up to 84% ee.346 Advances in the enantioselective metal-catalysed reaction have been reviewed, especially for lactone preparation.347

Other Reactions Terminal alkynals (113) of appropriate length (n = 1, 2) and substitution [X = C(CO2 Me)2 , C(CH2 OR)2 , NTs, and others] have been cyclized with decarbonylation to cycloalkenes (114), using a ruthenium(I) catalyst.348 In some cases, cycloisomerization to give conjugated aldehyde occurred. Both processes are believed to involve catalytic ruthenium vinylidenes.

X

X n

CHO

(113)

n

(114)

Alkynals and alkynones have been alkylatively cyclized in a palladium(0)-catalysed trans-addition of organoboronic acids.349 3-Silyloxy-2-aldehydes can undergo hetero-Diels–Alder reaction with aldehydes to give useful heterocycles.350 A model reaction, H2 C=C(OSiH3 )–N=CH2 with formaldehyde, has been explored theoretically. Lewis acids such as boron trifluoride catalyse the reaction by coordinating to the aldehyde oxygen, making the aldehyde more electrophilic. Concerted and stepwise mechanisms for this process are considered. Aromatic aldehydes react with triphenylphosphine and trichloroacetic acid derivatives (Cl3 C–CO2 Et, Cl3 C–CN) to give benzylidene dichlorides or α-chlorocinnamates.351 Substituent and reaction condition effects on chemo- and regio-selectivity are described. A variety of ketones and aldehydes have been condensed with sulfones, using t-BuOK catalysis in N ,N -dimethylacetamide solvent.352 Typical results – for α-methylcarbonyl compounds – include useful yields of the corresponding butadiene, whereas aromatic ketones give variations on the theme. α-Tetralone, for example, gives naphthalene and its α-methyl derivative (mainly the latter), but acetophenone interestingly gives some p-terphenyl. Rates of alkaline hydrolysis of isatin (indane-2,3-dione) and its N -methyl derivative have been measured in a range of DMSO–water mixtures from 30 to 45 ◦ C.353 Analysis of activation parameters and rate variation with dielectric constant suggest selective solvation by water.

ee ee

44


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1 Reactions of Aldehydes and Ketones and their Derivatives 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199

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Maheswaran, H., Prasanth, K. L., Krishna, G. G., Ravikumar, K., Sridhar, B., and Lakshmi Kantam, M., Chem. Commun. (Cambridge), 2006, 4066. Weeden, J. A. and Chisholm, J. D., Tetrahedron Lett., 47, 9313 (2006). Guo, H.-M., Cheng, L., Cun, L.-F., Gong, L.-Z., Mi, A.-Q., and Jiang, Y.-Z., Chem. Abs., 144, 273744 (2006). Guo, H.-M., Cheng, L., Cun, L.-F., Gong, L.-Z., Mi, A.-Q., and Jiang, Y.-Z., Chem. Commun. (Cambridge), 2006, 429. Joseph, J., Ramachary, D. B., and Jemmis, E. D., Org. Biomol. Chem., 4, 2685 (2006). Zhao, Z. Q., Peng, L. Z., and Li, Y. L., Chem. Abs., 144, 35985 (2006). Terai, H., Takaya, H., and Naota, T., Tetrahedron Lett., 47, 1705 (2006). Cee, V. J., Cramer, C. J., and Evans, D. A., J. Am. Chem. Soc., 128, 2920 (2006). Varala, R., Enugala, R., Nuvala, S., and Adapa, S. R., Tetrahedron Lett., 47, 877 (2006). Cuperly, D., Petrignet, J., Crevisy, C., and Gree, R., Chem. Eur. J., 12, 3261 (2006). Deschamp, J., Chuzel, O., Hannedouche J., and Riant, O., Angew. Chem. Int. Ed., 45, 1292 (2006). Zhao, D., Oisaki, K., Kanai, M., and Shibasaki, M., Tetrahedron Lett., 47, 1403 (2006). Zhao, D., Oisaki, K., Kanai, M., and Shibasaki, M., J. Am. Chem. Soc., 128, 14440 (2006). Shiomi, T., Ito, J., Yamamoto, Y., and Nishiyama, H., Eur. J. Org. Chem., 2006, 5594. Gausepohl, R., Buskens, P., Kleinen, J., Bruckmann, A., Lehmann, C. W., Klankermayer, J., and Leitner, W., Angew. Chem. Int. Ed., 45, 3689 (2006). Raheem, I. T. and Jacobsen, E. N., Chem. Abs., 145, 210329 (2006). Kataoka, T., Chem. Abs., 145, 356091 (2006). Teng, W.-D., Huang, R., Kwong, C. K.-W., Shi, M., and Toy, P. H., J. Org. Chem., 71, 368 (2006). Lin, Y.-S., Lin, C.-Y., Liu, C.-W., and Tsai, T. Y. R., Tetrahedron, 62, 872 (2006). Reynolds, T. E., Bharadwaj, A. R., and Scheidt, K. A., J. Am. Chem. Soc., 128, 15382 (2006). Matsui, K., Tanaka, K., Horii, A., Takizawa, S., and Sasai, H., Tetrahedron: Asymmetry, 17, 578 (2006). Kulkarni, N. A. and Chen, K., Tetrahedron Lett., 47, 611 (2006). Chen, J.-H., Venkatesham, U., Lee, L.-C., and Chen, K., Tetrahedron, 62, 887 (2006). Tang, L., Ding, L., Chang, W.-X., and Li, J., Tetrahedron Lett., 47, 303 (2006). Kwiatkowski, P., Chaladaj, W., and Jurczak, J., Tetrahedron, 62, 5116 (2006). Howell, G. P., Minnaard, A. J., and Feringa, B. L., Org. Biomol. Chem., 4, 1278 (2006). Takada, Y., Hayashi, S., Hirano, K., Yorimitsu, H., and Oshima, K., Org. Lett., 8, 2515 (2006). Rauniyar, V. and Hall, D. G., Angew. Chem. Int. Ed., 45, 2426 (2006). Tietze, L. F., Kinzel, T., and Schmatz, S., J. Am. Chem. Soc., 128, 11483 (2006). Denmark, S. E., Fu, J., Coe, D. M., Su, X., Pratt, N. E., and Griedel, B. D., J. Org. Chem., 71, 1513 (2006). Yuan, Y., Lai, A. J., Kraml, C. M., and Lee, C., Tetrahedron, 62, 11391 (2006). Motoki, R., Tomita, D., Kanai, M., and Shibasaki, M., Tetrahedron Lett., 47, 8083 (2006). Inoue, M. and Nakada, M., Angew. Chem. Int. Ed., 45, 252 (2006). Shintani, R., Inoue, M., and Hayashi, T., Angew. Chem. Int. Ed., 45, 3353 (2006). Evans, D. A. and Aye, Y., J. Am. Chem. Soc., 128, 11034 (2006). Kataoka, K., Ode, Y., Matsumoto, M., and Nokami, J., Tetrahedron, 62, 2471 (2006). Gu, Y., Ogawa, C., and Kobayashi, S., Chem. Lett., 35, 1176 (2006). Miles, R. B., Davis, C. E., and Coates, R. M., J. Org. Chem., 71, 1493 (2006). Pandey, M. K., Bisai, A., and Singh, V. K., Tetrahedron Lett., 47, 897 (2006). Sun, W., Yu, B., and Kuhn, F. E., Tetrahedron Lett., 47, 1993 (2006). Chung, M.-K., Qi, G., and Stryker, J. M., Org. Lett., 8, 1491 (2006). Ng, S.-S., Ho, C.-Y., and Jamison, T. F., J. Am. Chem. Soc., 128, 11513 (2006). Baati, R., Mioskowski, C., Barma, D., Kache, R., and Falck, J. R., Org. Lett., 8, 2949 (2006). Wolf, C. and Liu, S., J. Am. Chem. Soc., 128, 10996 (2006). Takai, K., Sakamoto, S., Isshiki, T., and Kokumai, T., Tetrahedron, 62, 7534 (2006). Trost, B. M., Weiss, A. H., and von Wangelin, A. J., J. Am. Chem. Soc., 128, 8 (2006). Kitazawa, T., Minowa, T., and Mukaiyama, T., Chem. Lett., 35, 1002 (2006). Dhondi, P. K. and Chisholm, J. D., Org. Lett., 8, 67 (2006). Cui, S.-L., Lin, X.-F., and Wang, Y.-G., Eur. J. Org. Chem., 2006, 5174. Sa-ei, K. and Montgomery, J., Org. Lett., 8, 4441 (2006). Murakami, M., Ashida, S., and Matsuda, T., Tetrahedron, 62, 7540 (2006). Moslin, R. M., Miller, K. M., and Jamison, T. F., Tetrahedron, 62, 7598 (2006). Trofimov, B. A., Nosyreva, V. V., and Mal’kina, A. G., Chem. Abs., 145, 27459 (2006).

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200

Li, Y., Liu, X.-Y., and Zhao, G., Tetrahedron: Asymmetry, 17, 2034 (2006). Xu, Y. and Cordova, A., Chem. Commun. (Cambridge), 2006, 460. Cao, C.-L., Ye, M.-C., Sun X.-L., and Tang, Y., Org. Lett., 8, 2901 (2006). Mase, N., Watanabe, K., Yoda, H., Takabe, K., Tanaka, F., and Barbas, C. F., J. Am. Chem. Soc., 128, 4966 (2006). Almasi, D., Alonso, D. A., and Najera, C., Tetrahedron: Asymmetry, 17, 2064 (2006). Reingold, I. D., Bowerman, C., John, M., Walters, R. S., Daglen, B. C., Butterfield, A. M., and Gembicky, M., Tetrahedron Lett., 47, 1653 (2006). Luo, W., Cui, J., and Liao, Z., Chem. Abs., 145, 188109 (2006). Muniz, K., Chem. Abs., 145, 27377 (2006). Anderson, V. E., Cassano, A. G., and Harris, M. E., Chem. Abs., 145, 145014 (2006). Yadav, V. K., Gupta, A., Balamurugan, R., Sriramurthy, V., and Kumar, N. ,V., J. Org. Chem., 71, 4178 (2006). Peng, L., Ma, M., Zhang, X., Zhang, S., and Wang, J., Tetrahedron Lett., 47, 8175 (2006). Salbaek Andersen, M. P., Toft, A., Nielsen, O. J., Hurley, M. D., Wallington, T. J., Chishima, H., Tonokura, K., Mabury, S. A., Martin, J. W., and Ellis, D. A., J. Phys. Chem. A, 110, 9854 (2006). Roudeau, R., Gomez Pardo, D., and Cossy, J., Tetrahedron, 62, 2388 (2006). Mastranzo, V. M., Santacruz, E., Huelgas, G., Pas, E., Sosa-Rivadeneyra, M. V., Bernes, S., Juaristi, E., Quintero, L., and de Parrodi, C. A., Tetrahedron: Asymmetry, 17, 1663 (2006). Arnott, G. and Hunter, R., Tetrahedron, 62, 992 (2006). Ianni, J. C., Annamalai, V., Phuan, P.-W., Panda, M., and Kozlowski, M. C., Angew. Chem. Int. Ed., 45, 5502 (2006). Huang, J., Ianni, J. C., Antoline, J. E., Hsung, R. P., and Kozlowski, M. C., Org. Lett., 8, 1565 (2006). Wang, M.-C., Hou, X.-H., Chi, C.-X., and Tang, M.-S., Tetrahedron: Asymmetry, 17, 2126 (2006). Szakonyi, Z., Balazs, A., Martinek, T. A., and Fulop, F., Tetrahedron: Asymmetry, 17, 199 (2006). Tanaka, T., Yasuda, Y., and Hayashi, M., J. Org. Chem., 71, 7091 (2006). Sugiyama, S., Aoki, Y., and Ishii, K., Tetrahedron: Asymmetry, 17, 2847 (2006). Harada, T. and Kanda, K., Org. Lett., 8, 3817 (2006). Chen, J., Wen, J., Li, M., and You, T., Chem. Abs., 145, 505061 (2006). Unaleroglu, C., Aydin, A. E., and Demir, A. S., Tetrahedron: Asymmetry, 17, 742 (2006). Hui, A., Zhang, J., Fan, J., and Wang, Z., Tetrahedron: Asymmetry, 17, 2101 (2006). Scarpi, D., Lo Galbo, F., and Guarna, A., Tetrahedron: Asymmetry, 17, 1409 (2006). Cozzi, P. G. and Kotrusz, P., J. Am. Chem. Soc., 128, 4940 (2006). Lutz, F., Kawasaki, T., and Soai, K., Tetrahedron: Asymmetry, 17, 486 (2006). Blay, G., Fernandez, I., Marco-Aleizandre, A., and Pedro, J. R., J. Org. Chem., 71, 6674 (2006). Qin, Y.-C. and Pu, L., Angew. Chem. Int. Ed., 45, 273 (2006). Lu, G., Kwong, F. Y., Ruan, J.-W., Li, Y.-M., and Chan, A. S. C., Chem. Eur. J., 12, 4115 (2006). Dimitrov, V. and Kostova, K., Chem. Abs., 145, 7476 (2006). Granander, J., Erikson, J., and Hilmersson, G., Tetrahedron: Asymmetry, 17, 2021 (2006). Scott, M. S., Lucas, A. C., Luckhurst, C. A., Prodger, J. C., and Dixon, D. J., Org. Biomol. Chem., 4, 1313 (2006). Caine, D., Chem. Abs., 145, 504982 (2006). Krasovskiy, A., Kopp, F., and Knochnel, P., Angew. Chem. Int. Ed., 45, 497 (2006). Lampkins, A. J., Abdul-Rahim, O., and Castellano, R. K., J. Org. Chem., 71, 5815 (2006). Sharma, A., Joshi, B. P., Singh, N. P., and Sinha, A. K., Tetrahedron, 62, 847 (2006). Robiette, R., Richardson, J., Aggarwal, V. K., and Harvey, J. N., J. Am. Chem. Soc., 128, 2394 (2006). Chen, Z.-T., Zhou, P., Li, G.-R., and Li, Z.-L., Chem. Abs., 145, 82841 (2006). Barsy, M. A. and El-Rady, E. A., J. Heterocycl. Chem., 43, 523 (2006). Lertpibulpanya, D., Marsden, S. P., Rodriguez-Garcia, I., and Kilner, C. A., Angew. Chem. Int. Ed., 45, 5000 (2006). Suzuki, Y., Abu Bakar, M. D., Muramatsu, K., and Sato, M., Tetrahedron, 62, 4227 (2006). Fukuda, Y., Maeda, Y., Ishii, S., Kondo, K., and Aoyama, T., Chem. Abs., 144, 432287 (2006). Song, J. J., Gallou, F., Reeves, J. T., Tan, Z., Yee, N. K., and Senanayake, C. H., J. Org. Chem., 71, 1273 (2006). Kano, T., Sasaki, K., Konishi, T., Mii, H., and Maruoka, K., Tetrahedron Lett., 47, 4615 (2006). Aljarilla, A., Cordoba, R., Csaky, A. G., Fernandez, I., Lopez Ortiz, F., Plumet, J., and Gomez, G. R., Eur. J. Org. Chem., 2006, 3969. Denmark, S. E. and Chung, W., J. Org. Chem., 71, 4002 (2006). Kim, S. S. and Kwak, J. M., Tetrahedron, 62, 49 (2006).

201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248

1 Reactions of Aldehydes and Ketones and their Derivatives 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298

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300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347

1 Reactions of Aldehydes and Ketones and their Derivatives 348 349 350 351 352 353

51

Varela, J. A., González-Rodriguez, C., Rub´ın, S. G., Castedo, L., and Saa, C., J. Am. Chem. Soc., 128, 9576 (2006). Tsukamoto, H., Ueno, T., and Kondo, Y., J. Am. Chem. Soc., 128, 1406 (2006). Bongini, A. and Panunzio, M., Eur. J. Org. Chem., 2006, 972. Matveeva, E. D., Erin, A. S., Osetrov, A. G., Leshcheva, I. F., and Kurts, A. L., Chem. Abs., 145, 314440 (2006). Garst, M. E., Dolby, L. J., Esfandiara, S., Okrent, R. A., and Avey, A. A., J. Org. Chem., 71, 553 (2006). Fathalia, M. F. and Ismail, A. M., Chem. Abs., 145, 438188 (2006).

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 and Lactams . . . . . . . . . . . . . . . . . . . (e) Imides . . . . . . . . . . . . . . . . . . . . . . . . . . (f) Carbonates and Carbamates . . . . . . . . . . . . . . . (g) Other Heterocyclic Nitrogen Centres . . . . . . . . . . (h) Thioacids, Thioesters, Thiolactones, and Thiocarbonates (i) Thiocarbamates and Thioacyl Halides . . . . . . . . . . Phosphoric Acids and their Derivatives . . . . . . . . . . . . . (a) Phosphates and Phosphinates . . . . . . . . . . . . . . . (b) Phosphoramidates and Phosphonamidates . . . . . . . . Sulfonic Acids and their Derivatives . . . . . . . . . . . . . . . (a) Sulfonates and Sulfonyl Halides . . . . . . . . . . . . . (b) Sultams, Sulfinamides, and Amidosulfites . . . . . . . . ASSOCIATION-PREFACED CATALYSIS . . . . . . . . . . . . BIOLOGICALLY SIGNIFICANT REACTIONS . . . . . . . . Enzymic Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . (a) Peptidases . . . . . . . . . . . . . . . . . . . . . . . . (b) Phosphatases and Phosphotransferases . . . . . . . . . . Intermolecular, Biomimetic, and Model Reactions . . . . . . . . (a) Carboxylic Acids and their Derivatives . . . . . . . . . (i) Esters, lactones and carbonates . . . . . . . . . . (ii) Amides and polypeptides . . . . . . . . . . . . . (iii) Lactams . . . . . . . . . . . . . . . . . . . . . (b) Phosphoric Acids and their Derivatives . . . . . . . . . (i) Phosphate and phosphonate monoesters . . . . . (ii) Phosphate diesters . . . . . . . . . . . . . . . . (iii) Phosphate and phosphonate triesters . . . . . . . (iv) Thiophosphates . . . . . . . . . . . . . . . . . .



53

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

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

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

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

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

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

54 54 54 55 55 55 58 58 59 60 61 61 62 64 66 66 67 67 67 68 68 70 70 70 70 71 71 71 74 77 79 79 81 84 84

54


(c) Sulfonic Acids and Their Derivatives . . . . . . . . . . . . . . . . . (i) Sulfates, Sulfamates, and β-Sultams . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85 85 86

INTERMOLECULAR CATALYSIS AND REACTIONS

Carboxylic Acids and their Derivatives (a) Acids Reactions between a representative range of alkyl- and aryl-amines and of aliphatic and aromatic acids showed that the direct formation of amides from primary amines and carboxylic acids without catalyst occurs under relatively low-temperature conditions (Scheme 1). The best result obtained was a 60% yield of N -benzyl-4-phenylbutanamide from benzylamine and 4-phenylbutanoic acid. For all these reactions, an anhydride intermediate was proposed. Boric and boronic acid-based catalysts improved the reaction, especially for the less reactive aromatic acids, and initial results indicated that bifunctional catalysts showed even greater potential. Again, anhydride intermediates were proposed, in these cases mixed anhydrides of carboxylic acids and arylboronic acids, e.g. (1).1 O R1

+

H2N R2

OH

0.1 or 10 mol% catalyst reflux (toluene or fluorobenzene) Soxhlet (3 Å mol. sieves)

O R1

N

R2

H

Scheme 1

O R

H O (1)

O B

Ar

The text-book Walden-style cycle which interconverts the stereochemical configurations of chlorosuccinate (3) and malate (5) involves a β-lactone intermediate (2) in preference to an α-lactone intermediate (4) (Scheme 2) because the Onuc –C–Cl angle in the transition structure for the former (174◦ ) is more favourable than that for the latter (139◦ ), as determined by PCM(ε = 78.4)/B3LYP/6–31+G* calculations; the smaller ring-strain energy of the β-lactone contributes little to the reactivity difference.2 N ,N -Dimethylethanolamine esterified hexanoic acid about 10-fold faster than did hexanol as a consequence of intermolecular hydrogen bonding; a sevenmembered transition state (6) was proposed.3

2 Reactions of Carboxylic, Phosphoric and Sulfonic Acids and their Derivatives CO2− −Cl−

O O

Cl −O

H

2C

(2)

−Cl−

−O

H

O

2C

−

CO2

55

O

(3)

(4)

HO− H3O+ or HO−

H OH −O

2C

CO2− (5)

Scheme 2

O

H NMe2

‡

R HO

O H (6)

(b) Esters (i) Transesterification The rates and mechanisms of hydrolysis and transesterification of phenyl benzoate in aqueous ethanolic KOH solution were determined by non-linear least-squares regression.4 Kinetic studies of the transesterification of a series of 4-nitrophenyl 3- and 4-substituted benzoates by 4-chlorophenol in DMF in the presence of potassium carbonate at various temperatures were reported.5 (ii) Solvolysis reactions Solvolysis of esters was discussed in a review of secondary isotope effects.6 Statistical analysis of various combinations of eight descriptors (e.g. bond lengths, atomic charges, LUMO, HOMO) that might allow the prediction of alkaline hydrolysis rates of esters showed that two of them, charge distribution of the C=O group and LUMO energy, are the best indicators.7 An introduction to the concept of ‘instantaneous rate constants’ was made together with a description of its application to the alkaline hydrolysis of p-nitrophenyl acetate in water and in aqueous MeCN.8 Hydroxidecatalysed ester hydrolysis for molecules of coexisting species has been quantitated in terms of microscopic rate constants, a new species-specific physicochemical parameter. Such rate constants take account of the various protonation states of the basic site(s) adjacent to the ester group, and they have been determined for the hydroxidecatalysed ester hydrolysis of phenylalanine methyl ester (7) and histidine methyl ester (8), which possess one and two adjoining basic groups, respectively, and yield two and four, respectively, microscopic rate constants.9

56

Organic Reaction Mechanisms 2006 O

O H2N

H 2N CH

OMe

N

CH2

CH

OMe

CH2 N H

(7)

(8)

In a review of nucleophile isotope effects in chemistry, the hydrolysis of formates was discussed.10 The effect of dioxane on the acid-catalysed hydrolysis of ethyl formate was studied by carrying out the reaction in 0–80% (v/v) dioxane at different temperatures ranging from 20 to 40 ◦ C. It was proposed that up to 1.5 mol of water are associated with the activated complex.11 Kinetic studies of the alkaline hydrolysis of ethyl decanoate12 in DMF–H2 O solutions and of ethyl isovalerate13 in aqueous acetone were reported. Hydrolysis of p-tolyl trichloroacetate in MeCN–H2 O mixtures was studied as a function of water concentration in the range 5.5–55.5 m. The proton inventory technique, in H2 O–D2 O mixtures, showed, for a value of D atom fraction in the solvent n = 0.5, deviations from the expected value (for a reaction with one proton being transferred) of 7.5 and 12.3%, for experiments in the presence of 16.6 and 33.3 m L2 O (L = H or D), respectively. Theoretical treatment of the data obtained at [L2 O] = 16.6 and 33.3 m using the Gross–Butler equation were consistent with, respectively, a cyclic transition-state structure with three protons involved and a transition state in which multiple water molecules are involved.14 The pH-independent hydrolysis of 4-nitrophenyl heptafluorobutyrate in MeCN–H2 O proceeded via a cyclic transition state containing the ester and three water molecules.15 Kinetic studies of the alkaline hydrolysis of a wide range of alkyl benzoates, PhCO2 R (R = Me, CH2 Cl, CH2 CN, CH2 C≡CH, CH2 Ph, CH2 CH2 Cl, CH2 CH2 OMe, Et) in various solvents concluded that the solvent electrophilicity, E, was the main factor responsible for changes in alkyl substituent effects with medium.16 Kinetic and theoretical studies of the hydrolysis reaction of Z-phenyl hydrogenmaleates (9; Z = H, m-CH3 , p-CH3 , m-Cl, p-Cl and m-CN) in aqueous solution showed that the Brønsted-type plot was linear with slope βlg = −1, the results being consistent with a mechanism that involves significant bond breaking in the rate-limiting transition state (αlg = 0.64). Theoretical results for the reaction in the gas phase showed an excellent Brønsted-type dependence with a βlg of −1.03, but a tetrahedral intermediate could not be found through DFT gas-phase studies (B3LYP/6–311+G*). It was suggested that an enforced concerted mechanism best describes these reactions.17 O H

O O−

H O

(9)

Z

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

57

In a study of the influence of DMSO on the α-effect, second-order rate constants (kNu− ) were determined for reactions of a series of substituted phenyl acetates with butane-2,3-dione monooximate (Ox− , α-nucleophile) and p-chlorophenoxide (pClPhO− , reference nucleophile) in DMSO–H2 O mixtures of varying compositions at 25 ◦ C. The magnitude of the α-effect, kOx −/kp-ClPhO− , increased as the DMSO content in the medium increased up to 40–50 mol%, resulting in a bell-shaped α-effect profile regardless of the nature of the substrates. The bell-shaped α-effect profile was attributed to the differential change in the sensitivity of the medium effect on the Ox− and p-ClPhO− systems but not due to a change in the reaction mechanism or to a drastic change in the basicity of the two nucleophiles upon addition of DMSO to the medium. Through application of calorimetric measurements of ground-state solvation combined with the diagnostic βnuc values, it was shown that the transition-state effect is more dominant than the ground-state effect as the origin of the α-effect in this system.18 The same group reported results of similar studies with 4-nitrophenyl benzoate, and made comparisons with their previous results obtained in a study of 4-nitrophenyl acetate. Both esters showed a bell-shaped profile for their reactions of butane-2,3-dione monooximate in DMSO–H2 O mixtures, and this modulation of the α-effect by the solvent medium was attributed to a ground-state effect in the H2 O-rich region and a transition-state effect in the DMSO-rich region.19 The ortho substituent effect in the alkaline hydrolysis of aryl esters of substituted benzoic acids in water was evaluated.20 A kinetic study was reported for the reactions of 4-nitrophenyl X-benzoates and Y-phenyl benzoates with two anionic nucleophiles (OH− and CN− ) and three amines (piperidine, hydrazine, and glycylglycine) in H2 O–DMSO (4:1) at 25 ◦ C. Each Hammett plot exhibited two intersecting straight lines for the reactions of the 4-nitrophenyl benzoates with the anionic nucleophiles and piperidine, whereas the Yukawa–Tsuno plots for the same reactions were linear. The Hammett plot for the reactions of the phenyl benzoates with hydrazine and glycylglycine demonstrated much better linear correlations with σ − constants than with σ 0 or σ constants, indicating that the leaving group departure occurs at the rate determining step (RDS). By contrast, σ − constants resulted in poorer Hammett correlation than σ 0 constants for the corresponding reactions with OH− and CN− , indicating that the leaving group departure occurs after the RDS for the reactions with the anionic nucleophiles. The large ρx value (1.7 ± 0.1) obtained for the reactions of the 4-nitrophenyl benzoates with the anionic nucleophiles supported the proposal that the reactions proceed through an addition intermediate with its formation being the RDS.21 When acyloxymethyl iodides (10) were treated with PhO− in acetone, the major products were the phenoxymethyl esters (11) resulting from attack at sp 3 carbon (b), with lesser amounts of the phenyl esters (12), the products of PhO− attack at the C=O group (a) (Scheme 3). However, when the corresponding acyloxymethyl chlorides (10; Cl instead of I) were treated similarly, attack at only C=O was observed.22 Rate and equilibrium constants were reported for reactions between a series of N benzoyloxypyridinium salts and pyridine N -oxides and DMAP in MeCN.23

58

Organic Reaction Mechanisms 2006 O R

O

CH2I

O

PhO−

R b

a

O

C O (11)

(10)

CH2OPh

+ R

OPh (12)

Scheme 3

(iii) Aminolysis reactions DFT was employed to study the mechanism of ammonolysis of phenyl formate in the gas phase, and the effect of various solvents on the title reaction was assessed by the polarizable continuum model (PCM). The calculated results show that the neutral concerted pathway is the most favourable one in the gas phase and in solution.24 The structure and stability of putative zwitterionic complexes in the ammonolysis of phenyl acetate were examined using DFT and ab initio methods by applying the explicit, up to 7H2 O, and implicit PCM solvation models. The stability of the zwitterionic tetrahedral intermediate required an explicit solvation by at least five water molecules with stabilization energy of approximately 35 kcal mol−1 .25 The rates of the reactions of 2,4-dinitrophenyl X-benzoates and Y-phenyl benzoates with a series of alicyclic secondary amines in MeCN at 25 ◦ C were only slightly larger than those in H2 O, although the amines studied were approximately 8 pKa units more basic in the aprotic solvent than in H2 O. The electronic nature of the substituent X in the non-leaving group did not affect the rate-determining step for the aminolysis of the 2,4-dinitrophenyl X-benzoates, for which a concerted mechanism was proposed. The medium change from H2 O to MeCN appears to force the reaction to proceed concertedly by decreasing the stability of the zwitterionic tetrahedral intermediate in the aprotic solvent.26 The aminolysis of Y-phenyl X-benzoates by piperidine in 20 mol% DMSO–H2 O at 25 ◦ C proceeded, on the basis of a curved Brønsted-type plot, via a zwitterionic tetrahedral intermediate with a change in the RDS; the curvature centre of the plots was at pKa = 6.4 regardless of the electronic nature of the substituent X in the benzoyl moiety.27 The rates of aminolysis of a series of Y-phenyl benzoates by acylic secondary amines were compared with new results for similar reactions with Y-phenyl diphenylphosphinates (discussed further in the section Phosphates and Phosphinates). The results showed that the C=O compounds were more reactive than the P=O compounds.28 (c) Acyl Halides and Acid Anhydrides Solvolysis rates of isopropenyl chloroformate, CH2 =C(Me)OC(O)Cl, were shown to be very similar to those for 4-nitrobenzoyl chloride in mechanism and reactivity.29 Stepwise mechanisms were observed in the aminolysis of aryl chloroformates by a series of substituted quinuclidines – which were more reactive than isobasic secondary alicyclic amines.30 The pH-independent hydrolysis of 4-nitrophenyl chloroformate in MeCN–H2 O mixtures proceeded via a cyclic transition state containing the ester and two water molecules.15 Solvolyses of 2-furancarbonyl chloride in most


59

solvents proceeded via an elimination–addition pathway, in contrast to those of 2thiophenecarbonyl chloride, which progressed via initial ionization.31 Steric effects were evaluated by a study of the DMAP-catalysed acylation of 1γ , 2γ and 3γ alcohols by acetic, propionic, isobutyric, isovaleric, and pivalic anhydrides in CH2 Cl2 at 20 ◦ C. In all cases the reaction kinetics could be described by rate laws containing a DMAP-catalysed term and an uncatalysed (background) term. Steric effects were evident in both reactions, but were generally greater for the DMAP-catalysed reaction. For example, the uncatalysed reactions between cyclohexanol and acetic and pivalic anhydrides differed about 500-fold, but for the corresponding DMAP-catalysed reactions the factor was 8000-fold. The implications of these findings for the kinetic resolution of alcohols were discussed.32

(d) Amides and Lactams Hydrolysis of amides was discussed in a review of secondary isotope effects.6 Results of a multiple KIE study of the acid-catalysed hydrolysis of formamide (Scheme 4) were consistent with a stepwise mechanism, involving at least one tetrahedral intermediate (TI). In this mechanism, rapid protonation of the amide (pKa = −2) is followed by the rate-determining attack of water, as evidenced by a levelling of the rate at high acid concentration and the lack of a sizable leaving-N KIE (15 k = 1.0050). The carbonyl-O was shown to exchange very little 18 O with the solvent, which was further evidence for the rate-determining formation of the TI, followed by the rapid breakdown to products. The formyl-H KIE was large and inverse (D kobs = 0.79), indicating that the transition state (13) resembled the structure of the TI.33 The free-energy profile for the first step of formamide hydrolysis in aqueous alkaline solution was computed using Car–Parrinello molecular dynamics simulation combined with umbrella 18k Dk

= 0.996

= 0.79

15k

O

= 1.0050 H+

H C NH2 13k

H2O

= 1.031 Scheme 4 +δ

H

O

H C

H

δ+

NH2 H

O H

O H

(13)

O H C OH NH4+

60


sampling. Activation and reaction free energies were estimated from the potential of mean force and were in unprecedentedly good agreement with the corresponding free enthalpies obtained from experiment.34 The same group also conducted ab initio metadynamics calculations on this reaction, leading to two possible mechanisms.35 For N -methylacetamide, N ,N -dimethylformamide, and N ,N -dimethylacetamide, in which some or all of the H atoms of formamide are replaced by Me groups, theoretical studies showed that the total number of water molecules H-bonding with the attacking HO− in the transition state decreases from three (in formamide) to two.36 Studies of the acid hydrolysis of N -(2-hydroxyphenyl)phthalamic acid in MeCN– H2 O revealed that the expected intramolecular general-acid catalysis, as in (14), was not observed.37 An equimolar mixture of ε-caprolactam (15) and 3-nitrobenzoic acid (16; R = 3-O2 NC6 H4 ) when heated at 180 ◦ C with p-toluenesulfonic acid yielded N (3-nitrobenzoyl)-ε-aminocaproic acid (17; R = 3-O2 NC6 H4 ), the reaction involving ring opening to an acyclic anhydride in which an N–O acyl migration occurs, as shown in Scheme 5; pentanoic acid (16; R = C4 H9 ) reacted similarly.38 H O O N H OH O (14)

+

H O C O + RCOOH NH (16) (15)

O

C C R O (CH2)5 N H H

RC(O)NH(CH2)5COOH (17)

Scheme 5

(e) Imides Studies of the alkaline hydrolysis of N -benzylphthalimide in MeCN–H2 O and DMF–H2 O solutions concluded that the reaction mechanism is similar to that of other N -alkyl congeners.39


61

(f) Carbonates and Carbamates Aminolysis of a series of aryl 2,4-dinitrophenyl carbonates by a series of quinuclidines gave linear Brønsted-type plots, the magnitudes of their slopes confirming their mechanisms as concerted.40 A comparison41 of the aminolysis, by primary amines, of 4-nitrophenyl phenyl carbonate (31; X = O) with its thiono analogue (31; X = S) is discussed in the section Thioacids, Thioesters, Thiolactones, and Thiocarbonates below. A full paper on the conversion of alcohols into t-butyl ethers by treatment with tbutyl dicarbonate (Boc2 O) and Mg(ClO6 )2 [or, less effectively, Al(ClO4 )3 ] in CH2 Cl2 has elaborated upon the proposal made in a 2005 communication (see ORM 2005, p. 58). The process is now seen to involve initial formation of a mixed anhydride (18), which, catalysed by the metal, progresses to the product via a synchronous mechanism in a six-membered ring transition state (Scheme 6).42 Mn+ O O

O

Mn+ O

O CMe3 O R (18)

O

O

ROCMe3 + 2CO2 + Mn+

O CMe3 O R

Scheme 6

Rates of reactivity of HO− and HO2− towards p-nitrophenyl N ,N -dimethylcarbamate in ROH–H2 O mixtures increased with increasing concentrations of Pri OH and But OH, but the reverse was true for (CH2 OH)2 .43 Kinetic studies of the alkaline hydrolysis of a series of secondary N -thiazolylcarbamates (19; R = H) and tertiary N -methyl-N -thiazolylcarbamates (19; R = Me) have shown that they proceed by an ElcB and a BAc 2 mechanism, respectively.44 N X

S

Y

O N

O

R (19)

(g) Other Heterocyclic Nitrogen Centres The acid and base hydrolysis of N -propionyl-imidazole and -benzimidazole derivatives proceeded via tetrahedral intermediates in both acidic and basic regions.45

62


(h) Thioacids, Thioesters, Thiolactones, and Thiocarbonates A combined experimental and computational mechanistic study of amide formation from thioacids and azides has shown that there are two distinct mechanistic pathways depending on the electronic character of the azide component (21) (Scheme 7). Highly electron-poor azides couple (Path 1 ) via bimolecular union of the terminal nitrogen of the azide with sulfur of the thiocarboxylate (20a) to give linear adducts (22) (Step I ). Cyclization of these intermediates (Step II ) gives thiatriazolines (23). Relatively electron-rich azides undergo bimolecular coupling with thiocarboxylates (Path 2 ) via an anion-accelerated 3 + 2-cycloaddition to give directly the same thiatriazolines (23). Decomposition to amide (24) (Step III ) proceeds via retro-3 + 2-cycloaddition of the neutral thiatriazoline intermediates (23). Computational analysis [DFT, 6–31+G(d)] identified pathways by which both classes of azide undergo cycloaddition with thioacid to give thiatriazoline intermediates, although these paths are higher in energy than the thiocarboxylate amidations.46 Path 1:

O O

R1

S

−

R2

−

+

+ N

R1

Step I

N N

(20a)

S

N N −

(21)

N

R2

(22) H+ Step II

Path 2: S R1

−

O

(20b)

+

N

+

−

R2

H

+

HO

N N

R1

S

N N N

R2 (23)

(21)

O

Step III −N2S

R1

N H

R2

(24)

Scheme 7

In studies of the reactions of S-(4-nitrophenyl) 4-methylthiobenzoate with a series of six secondary alicyclic amines and a series of eight pyridines in 44 wt% ethanol–water at 25 ◦ C, the Brønsted-type plots were non-linear with the curvature centre defined as pKa0 located at pKa 9.7 and 9.4 for the reactions of secondary alicyclic amines and pyridines, respectively. The plots are consistent with a zwitterionic tetrahedral intermediate on the reaction path and, as the basicity of the amine increases, a change in rate-determining step from its breakdown to its formation.47 The reactions of 4-nitrophenyl benzoate and O-4-nitrophenyl X-thionobenzoates (25) with a series of pyridines in 20 mol% DMSO were studied at 25 ◦ C (Scheme 8). O-4-Nitrophenyl thionobenzoate (25; X = H) was more reactive than its oxygen

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

S

C O

NO2

+N

X

63

+

C N X

Z

Z +

(25) −O

NO2

Scheme 8

analogue towards all the pyridines studied. The Brønsted-type plot was linear with βnuc = 1.06 for reactions of the benzoate but curved for the corresponding reactions of the thionobenzoate, with βnuc decreasing from 1.38 to 0.38 as the pyridine basicity increases, indicating that the reaction mechanism is also influenced on changing the electrophilic centre from C=O to C=S. The curvature centre (pKa 0 ) of the curved Brønsted-type plots occurred at pKa = 9.3 regardless of the electronic nature of the substituent X in the non-leaving group.48 Boron trifluoride and indium(III) triflate were found to catalyse efficiently the isomerization of thionolactones (26) to thiolactones (27) in good yields. When applied to an optically active γ -thionolactone [(R)-28], the isomerization reaction proceeded with complete inversion of configuration to [(S)-29] by using BF3 .OEt2 (Scheme 9). The proposed mechanism (Scheme 10) implicates a double SN 2-type process involving two molecules of thionolactone, each complexed with BF3 , that progresses to the product via the dimer (30).49 Lewis acid

S

O (26)

R

toluene reflux

O

S (27)

R

BF3.OEt2 (10 mol%)

S

toluene, reflux

O (R)–(28) 98% ee

O

S (S)–(29), 97% ee 70% isolated yield

Scheme 9

In a study of the aminolysis of 4-nitrophenyl phenyl carbonate (31; X = O) and thionocarbonate (31; X = S) with a series of primary amines, the thiono compound was found to be less reactive than its oxygen analogue toward strongly basic amines but was more reactive towards weakly basic CF3 CH2 NH2 . As the Brønsted-type plots obtained from the aminolyses of both compounds were curved downwards, it was proposed that the reactions proceeded via a stepwise mechanism with a change in the rate-determining step.41

ee

64

Organic Reaction Mechanisms 2006 −

BF3 S BF3

S

O

R

−

+

O

F 3B R

+

O

+

R

R S

O

S −

S O+ − BF3

R

BF3 (30)

S

S

R

Scheme 10

X PhO C O

NO2 (31)

The reliability and usefulness of a new empirical nucleofugality index, which is defined as the group electrophilicity of the leaving group embedded in the substrate that undergoes the nucleophilic attack, were tested against experimental kinetic data recorded for aminolysis reactions of variously substituted phenoxy- and thiophenoxycarbonyl and the corresponding thiocarbonyl derivatives.50

(i) Thiocarbamates and Thioacyl Halides Two classical tools, the intermolecular stretching force constants of H-bonded complexes and the molecular electrostatic potential, were used to develop a nucleophilicity index, which was validated against kinetic data recorded for the aminolysis of S-methyl 2,4-dinitrophenylthiocarbamate.51 Aminolysis of N -phenylthionocarbamates by benzylamines in MeCN proceeded by a stepwise mechanism in which the rate-determining step was the breakdown of the zwitterionic tetrahedral intermediate.52 Methoxide converted a series of X-phenyl N -(4-thiocarboxamidophenyl)carbamates (32; X = 4-MeO, 3-MeO, 4-Cl, 3-Cl, H) into methyl N -(4-thiocarboxamidophenyl) carbamate (33) and the corresponding phenate via an ElcB mechanism (Scheme 11). However, when a series of the corresponding aryl N -(2-thiocarboxamidophenyl)carbamates (34; R1 = H, R2 = 4-MeO, 3-MeO, 4-Me, 3-Cl, 4-Cl, 3-NO2 , H) were treated similarly, a rapid intramolecular cyclization occurred to give 4-thioxo-1H ,3H quinazolin-2-one (35; R1 = H) and the corresponding phenate (Scheme 12). All the


65

S H2N N C O H

X

O

(32) MeO−

S

O−

S

MeO−

+

H2N

H2N N C OMe

N C O

X

H

O

(33) Scheme 11

S C

S NH2

NH

N C O R1

O (34)

O−

R

2

MeONa

N R1 (35)

O

+ R2

Scheme 12

experimental evidence, in this case, pointed to a BAc 2 mechanism (Scheme 13), involving initial formation of anion (36), which either progressed stepwise to a tetrahedral intermediate (37) and thence, with expulsion of phenate, to the product (35) or formed product concertedly via transition state (38).53 The pyridinolysis of S-methyl chlorothioformate, MeSC(O)Cl, showed a biphasic Brønsted-type plot, in agreement with a stepwise mechanism and a change in the rate-limiting step, from formation of a zwitterionic tetrahedral intermediate (T± ) at high pKa to its breakdown at low pKa . The reaction of the same substrate with secondary alicyclic amines showed a linear Brønsted-type plot of slope 0.23, which is in accordance with a stepwise mechanism where formation of T± is the ratedetermining step for the whole pKa range examined.54

66

Organic Reaction Mechanisms 2006 S C

S −

NH

NH O

N C O R1

N R2

O (36)

S C

‡

S δ− NH δ− O δ− N O R1 (38)

NH2

O −

R1

(37) −R2C6H4O−

−R2C6H4O−

S

R2

NH

N C O R

1

R2

N R2

O

R

O

1

(35)

(34)

Scheme 13

Phosphoric Acids and their Derivatives (a) Phosphates and Phosphinates The hydrolysis of phosphates is discussed in reviews of nucleophile10 and secondary6 isotope effects. The kinetics and mechanism of the acid hydrolysis of 3-aminophenyl phosphate were studied in 0.1–0.6 m HCl at 90 ◦ C.55 The rates of aminolysis of Y-phenyl diphenylphosphinates (39) (Scheme 14) by a series of alicyclic secondary amines were determined in 20 mol% DMSO–H2 O at 25 ◦ C. The phosphinates were less reactive than the corresponding Y-phenyl benzoates (the rates of which had been reported earlier). The reactions of 2,4-dinitrophenyl diphenylphosphinate [39; Y = 2,4-(NO2 )2 ] with alicyclic secondary amines resulted in a linear Brønsted-type plot, whereas the corresponding reactions of 2,4-dinitrophenyl O P

O + HN

O

P

Y

+

NH

+

−

O Y

(39) Scheme 14


67

benzoate had yielded a curved Brønsted-type plot, indicating, respectively, a concerted mechanism and a change in the rate-determining step of a stepwise mechanism.28

(b) Phosphoramidates and Phosphonamidates When the mixed anhydride, R2 CHP(O)(NEt2 )OS18 O2 Ar (R2 CH = 9-fluorenyl, Ar = p-tolyl) underwent nucleophilic substitution (elimination–addition) with Et2 NH (0.4 m in CHCl3 ), the phosphene intermediate, R2 C=P(O)NEt2 , recombined with the sulfonate leaving group (internal return), causing scrambling of the 18 O label, more quickly than it diffused away; efficient conversion into R2 CHP(O)(NEt2 )2 therefore depends on preassociation between the substrate and the nucleophile.56 Kinetic studies were reported of the acid hydrolysis in 0.1–7.0 m HCl at 80 ◦ C of N -(2,5dichlorophenyl)phosphoramidic acid.57

Sulfonic Acids and their Derivatives (a) Sulfonates and Sulfonyl Halides Studies of the reaction between 2,4-dinitrophenyl benzenesulfonate and OH− , CN− , and N3− in 20 mol% DMSO–H2 O at 25 ◦ C have shown that OH− attacks exclusively at the sulfonyl group, but the softer nucleophiles react – as shown in (40) – to give mixtures of products of S–O and C–O bond fission, the fraction of the latter being 0.10 for CN− and 0.66 for N3− . 58 The rate of reaction of hydroperoxide ion with 4-nitrophenyl 4-toluenesulfonate was reported.43 NO2 O

Nu−

NO2

S

O

O

Nu− (40)

Contrary to earlier suggestions of an SN 1 pathway for solvolyses of N ,N -dimethylsulfamoyl chloride (41), the results of an extended Grunwald–Winstein equation treatment of the specific rates of solvolysis of (41) in 32 solvents pointed to an SN 2 pathway. Results of a similar treatment of its rates of solvolysis in a range of solvents supported an SN 2 pathway for 2-propanesulfonyl chloride (42).59 O

Me N Me

S

O (41)

Me Cl

O CH S

Me

O (42)

Cl

68


(b) Sultams, Sulfinamides, and Amidosulfites The ring opening of β-sultam via an H2 O-assisted ammonolysis process was studied by using a DFT method at the B3LYP/6–31G* level as a further step in the theoretical investigation of the ammonolysis reaction of β-sultams. The calculated pathways were analogous to those previously described for the non-assisted ammonolysis reaction.60 Acid hydrolysis of N -(Z-aryl)-Y-benzenesulfinamides (43) to Y-benzenesulfonic acids and Z-arylamines (Scheme 15) proceeded via a hypervalent intermediate (44).61 Studies of the acid hydrolysis of three N -(X-phenyl)amidosulfites (45; X = H, Me, Cl) showed that the ring-opened products (46) were formed via water attack at the S=O group of an N -protonated intermediate.62 O O YPh

S

NHArZ

H3O+

YPh

S

−H+

OH HNHArZ +

(43)

YPhSO2H + ZArNH2

(44) Scheme 15

Me

O S

O

Me

N

OH

H3O+ N

X

H X (45)

(46)

ASSOCIATION-PREFACED CATALYSIS Alkaline hydrolysis rates of a series of thiophenyl 4-X-benzoates (47; X = H, Me, NO2 ) was significantly enhanced in the presence of cyclodextrins (CDs), and this was attributed to strong binding of the benzoyl moiety within the CD cavity and covalent catalysis by secondary hydroxy groups of the CDs (48).63 The effect of MeCN and MeOH on the alkaline hydrolysis of acetylsalicylic acid in aqueous micellar solutions was reported.64 Butylaminolysis of p-nitrophenyl acetate in chlorobenzene in the presence of different kinds of phase-transfer catalysts (crown ethers and glymes) supported the existence of a novel reaction pathway exhibiting a first-order dependence on the concentration of the phase-transfer catalyst and a second-order


O S

C

O X

S O

C

69

−

(47) X (48)

dependence on the concentration of butylamine.65 Three double-headed hydroxamates, − ONHC(O)(CH2 )n C(O)NHO− (n = 1, 2, 3) exhibited α-nucleophile reactivities towards p-nitrophenyl acetate at pH 7.9 that were enhanced by cetyltrimethylammonium bromide (CTAB); the order of reactivity was (n) 1 > 2 > 3.66 In a wider study, the effect of cationic, anionic, and non-ionic surfactants on the reactivity towards pnitrophenyl acetate of the α-nucleophile N -phenylbenzohydroxamate, PhC(O)N(Ph) O− , at pH 7.7 was reported.67 p-Nitrophenyl picolinate (49) has been studied in three reports. In the first, complexes of Ni(II) with dioxocyclam (50) increased the rate of hydrolysis of (49) some 3000-fold in the presence of a variety of surfactants, n-lauroylsarcosine sodium proving the most potent.68 In the second, studies of the hydrolysis of (49) mediated by the micellar catalytic systems of two gemini cationic surfactants with different hydrophobic tail groups [ethanediyl-1,2-bis(dodecyldimethylammonium bromide) (12-2-12, 2Br− ), and dimethylene-1,2-bis(cetyltrimethylammonium bromide) (16-216, 2Br− )] in the pH range 7.0–9.0 and at 25 ◦ C showed that (16-2-16, 2Br− ) enhanced the hydrolytic reaction notably more than gemini surfactant (12-2-12, 2Br− ) under the same reaction conditions, which may be ascribed to the micelle effect.69 In the third, the effect of Brij 35 surfactant on the hydrolysis of (49) catalysed by Ni2+ , Zn2+ , and Co2+ complexes of N -methyldiethanolamine, MeN(CH2 CH2 OH)2 , was studied kinetically at pH 7.00 and 30 ◦ C.70 R O

O C O

NO2

H

O N

N

N

N

H

N H (49)

(50)

H

70


R2

NOH

Br− N

+

R1

51a 51b 51c 51d 52a 52b 52c 52d

R1 Me Me Me Me n-C8H17 n-C10H21 n-C12H25 n-C16H33

R2 n-C8H17 n-C10H21 n-C12H25 n-C16H33 Me Me Me Me

The amphiphilic pyridinium ketoximes 4-[1-(hydroxyimino)alkyl]-1-methylpyridinium bromides (51a–d) and 1-alkyl-4-[1-(hydroxyimino)ethyl]pyridinium bromides (52a–d) are isomeric cationic surfactants bearing the nucleophilic hydroxyimino group but differing in the position of the nucleophilic function relative to the polar head group and the hydrophobic alkyl chain. 4-Nitrophenyl diphenyl phosphate cleavage by the oximate anions generated from (51a–d) and (52a–d) was used as a model reaction for the investigation of the influence of the structure and lipophilicity of functional surfactants on their reactivity in micelles and microemulsions. Investigation of the model reaction in cationic micelles of CTAB, in non-ionic micelles (Triton X-11 and Brij 35) and in oil–water microemulsion (isooctane–phosphate buffer–CTAB and butanol) revealed that lipophilicity is the most important factor influencing the localization and reactivity of functional surfactants in nanoaggregates.71 The rate of alkaline hydrolysis of 2,4-dichloro- and 2,4-dibromo-phenyl phosphate increased in the presence of CTAB, an observation attributed to bromide ions in the micellar pseudophase.72 BIOLOGICALLY SIGNIFICANT REACTIONS

Enzymic Catalysis (a) Peptidases In a review of nucleophile isotope effects, results of studies of the hydrolysis of esters and amides by carboxypeptidase were discussed.10

(b) Phosphatases and Phosphotransferases Although alkaline phosphatase evolved to hydrolyse phosphate monoesters, it also has significant diesterase activity. Now studies using a series of substituted methyl phenyl phosphate diesters have shown that phosphodiester hydrolysis within the enzyme proceeds by a similar transition state to that found in solution, validating the rational design of synthetic enzymes that operate in solution. Furthermore, those studies suggest that stabilizing the solution-phase transition state affords enzymes a degree of promiscuity that allows them to evolve alternative catalytic specificities.73 Results of studies of secondary isotope effects of enzymes that effect phosphoryl transfer were reviewed.6


71

Intermolecular, Biomimetic, and Model Reactions (a) Carboxylic Acids and their Derivatives (i) Esters, lactones and carbonates Acetylcholine, Me3 N+ CH2 CH2 OCOMe, is a neurotransmitter generated from choline, Me3 N+ CH2 CH2 OH, and acetyl coenzyme A. As a model of this process, a cavitand derived from resorcinarenes that specifically guests a trimethylammonium group has been derivatized at its periphery with a Zn-salen known to catalyse the acetylation of alcohols with acetic anhydride (Ac2 O). The salen-catalysed rate of acetylation of choline with Ac2 O was thereby enhanced 23-fold.74 The rate of alkaline hydrolysis of the local anaesthetic novocaine (diethylaminomethyl 4-aminobenzoate) was reported.75 Kinetic studies of the reactions of polyalkylamines with aryl acetates and aryl methyl carbonates at pH 7–11.5 showed that concerted mechanisms operate.76 The hydrolysis of glycine methyl ester, CH2 (NH2 )CO2 Me, and methionine methyl ester, MeSCH2 CH2 CH(NH2 )CO2 Me, was catalysed with high effectiveness by the Cu(II) complex of N ,N ,N ,N -tetramethylethylenediamine, the observed catalytic enhancement being 104 -fold.77 Binuclear Mn(II) and Zn(II) complexes of a polyether-bridged dihydroxamic acid, [CH2 OCH2 CH2 OC6 H4 C(O)NHOH]2 , as models of metallohydrolases exhibited high catalytic activity in the hydrolysis of p-nitropicolinate (49).78 In a further development by the same group, bis complexes of two hydroxamic acids (53; n = 4, 6) containing benzo-crown-5 with Cu(II), Co(II), Zn(II), or Mn(II) were also highly effective catalysts for the hydrolysis of (49), the rate enhancements observed being more than 1000-fold.79 O

O

CO(CH2)nC N

O

O OH O

O (53)

Studies of the ability of the lipase B from Candida antarctica (CAL-B) to catalyse the enantioselective aminolysis of esters by cis- and trans-2-phenylcycloalkanamines (54; n = 1, 3, 4) have been followed up by molecular modelling approaches in order to probe the lipase-catalysed aminolysis mechanism. CAL-B possesses a typical serinedependent triad, so it was possible, with access to an X-ray crystal structure of CALB, to model a series of phosphonamidates (55; n = 1, 3, 4) as analogues of the tetrahedral intermediate (TI) resulting from attack of the amine on the carbonyl of the acyl-enzyme. The results suggested as the most plausible intermediate for the CALB-catalysed aminolysis a zwitterionic TI resulting from the direct His-assisted attack of the amine on to a C=O group of the acyl-enzyme.80 Native chemical ligation of unprotected peptide segments involves reaction between a peptide-α-thioester and an N-terminal cysteine-peptide to yield a product with a

72

Organic Reaction Mechanisms 2006 Ser 105 O

Ph (CH2)n

P

NH NH2

Me O

Ph

(54)

(CH2)n (55)

native amide bond at the ligation site. Peptide-α-thioalkyl esters, used because of their ease of preparation, are rather unreactive so the ligation reaction is catalysed by in situ transthioesterification with thiol additives. Although full details of the mechanism of native chemical ligation have not yet been elucidated, reaction is envisioned to occur in the following way (Scheme 16).81 A peptide-α-thioalkyl ester (56) is activated in situ by a thiol additive RSH to (57), which is reacted at pH 7 with a peptide containing an N-terminal cysteine (Cys) residue (58). Transthioesterification of (57) via the side-chain thiol of the N-terminal Cys results in a thioester-linked intermediate (59), which spontaneously rearranges through a favourable five-membered ring intramolecular nucleophilic attack by the Cys α-amino group to form a peptide (60) with a native amide bond. The most common thiol catalyst, RSH, used to date has been a mixture of thiophenol and benzenethiol, when ligation reactions typically take 24–48 h. In order to find a better catalyst, 14 thiol compounds were evaluated. A highly effective and practical catalyst was found to be (4-carboxylmethyl)thiophenol (MPAA), a non-malodorous, water-soluble thiol. Use of MPAA gave an order of

O

H N

RSH

SR′ R′′ (56)

HS

O

H N

+

SR

H 2N

R′′ (57)

O (58)

R′′ O

H N R′′

HS N H

N H C

S O NH2

O

O

(60)

(59) Scheme 16


73

magnitude faster reaction in model studies of native chemical ligation and in the synthesis of a small protein.81 The Staudinger ligation is another method for the chemoselective ligation of peptide fragments. A highly efficient variant of it couples a peptide with a C-terminal phosphinothioester with a second peptide having an N-terminal azido acid. Now, detailed 13 C NMR studies of a model reaction in DMF–H2 O between two glycine derivatives, (61) and the [13 C]azide (62), have delineated the mechanism.82 Fugitive amounts of two 13 C-labelled intermediates, (63) and (64), were detected in addition to the 13 C-labelled product of the reaction, the desired coupled ‘peptide’ (65) and (unlabelled) (diphenylphosphono)methanethiol (66) (Scheme 17). The proposed mechanism (Scheme 18) involves initial formation of an iminophosphorane (67) with evolution of N2 , which undergoes rapid cyclization to a tetrahedral intermediate (68), collapse of which generates an amidophosphonium salt (69) that rapidly hydrolyses to an amide (70) and the phosphine oxide (71). An experiment with H218 O confirmed the final step, the label being found only in the phosphine oxide (71).82 Homocysteine, HSCH2 CH2 CH(NH2 )CO2 H, is a toxic amino acid that is thought to acylate lysine residues on proteins via its corresponding thiolactone (72) (Scheme 19). Now, for the first time, the kinetics have been studied of the aminolysis of (72) and of two model compounds, γ -thiobutyrolactone (72; H instead of NH2 ) and N trimethylamino homocysteine thiolactone (72; Me3 N+ instead of NH2 ). A Brønsted plot for homocysteine thiolactone (72) gave β = 0.66. This and other data supported O

H N

S

PPh2

O (61) (1 equiv.)

DMF–H2O (6:1)

+ H H 13 C

N3

O

H N

+

S

PPh2 −

O

N

NHBn

H 13C

O

H NHBn

(63) O (62) (1 equiv.)

O HS

PPh2

H N

+ O

O

H H 13 C NHBn N H O

H N

O

H H 13 C

N +

O

PPh2 O

−S

(66)

(65)

(64) Scheme 17

NHBn

74


O S

H2O

PPh2

−N2 (g)

+ N3

R

+

S

PPh2 −N

R′

+

S

−

PPh2

O

N R

R′

R′ (68)

(67)

A

O O

O HS

+

PPh2

R

N H

R′

R

N +

R′

PPh2

−S

(71)

(70)

(69)

Scheme 18

O

+

NH2 + S + H

NH2

NH2

H N

SH O

(72) Scheme 19

the formation of a zwitterionic tetrahedral intermediate as the rate-determining step in the aminolysis of all three thiolactones.83 Intramolecular O–N alkoxycarbonyl (carbonate → carbamate) migration is potentially a useful reaction in peptide synthesis. Now, in model studies carbonates of 2-amino alcohols (73) have been shown to undergo facile intramolecular rearrangement under mildly basic conditions to yield N -(2-hydroxyethyl)carbamates (74) (Scheme 20).84

(ii) Amides and polypeptides α,α-Dimethylglycines are among the simplest and most widely used structural units in the construction of peptides with a predetermined secondary structure. However, steric crowding prevents their easy incorporation into a peptide chain. A promising way round this difficulty is to synthesize the α,α-dimethylglycine unit already incorporated into the peptide chain. The four-component Ugi–Passerini reaction can yield compounds of the desired type, e.g. N ,N -disubstituted α,α-dimethylglycine cyclohexylamides (75; R = aryl). Now, results of a study of the acidolysis of a series of seven of these compounds (75; R = 4-X-phenyl) in 5% TFA in MeCN have been


75

R1 R2

H2N

R1 O

PBS

O O

R2

N H

pH 7.4

R O

OH

O R (73)

(74) PBS = phosphate-buffered saline Scheme 20

used to assess the influence of the substituents on the lability of the terminal amide (which needs to be removed to generate a free carboxyl group at the C-terminus). The N -phenylacetyl group plays a key role in the acidolysis by facilitating the ready formation of an intermediate oxazolone (76; R = 4-X-phenyl) (Scheme 21) which ring opens to an N -acyl-N -4-X-phenyl-α,α-dimethylglycine (77; R = 4-X-phenyl).85 O Me PhCH2

N

Me

Me H N

R

R TFA

Me

+

O

N O

O

H2O

PhCH2

(75)

(76) O Me PhCH2

Me OH

N R

O

(77) Scheme 21

Indomethacin (78) and acemethacin (79) are both anti-inflammatory drugs, the latter being the glycollic acid ester of the former. As N -benzoylindoles, the amide linkage is CH2COOH

CH2COOCH2COOH

MeO

MeO Me

Me

N

N C

O (78)

Cl

C O (79)

Cl

76


fairly labile; indeed, it was found to be only about 100-fold less reactive than the ester grouping in acemethacin (79) in 2–10 m HClO4 . At 8 m HClO4 , the mechanism of acid hydrolysis of (78) and (79) changes over from A-2 to A-1.86 N -Carbamoylalanine (80; R = Me) was formed by the action of cyanate – as cyanic acid (HNCO) – upon alanine (Ala) in bicarbonate buffer at pH 7.1, and upon heating at 80 ◦ C for several days a small amount of Ala–Ala was formed. The proposed mechanism (Scheme 22) involves elimination of ammonia from N -carbamoylalanine (80; R = Me) to form an isocyanate (81; R = Me), which cyclizes to an N -carboxylanhydride (82; R = Me), attack of which by Ala yields Ala–Ala.87 NCO− CO2−

Ala

R

HNCO

O

CO2− R

HN C NH2

O

R

N C O

N H

O (80)

(81)

O

(82)

amino acid + peptides Scheme 22

When N -(2-hydroxyacetyl)-2-pyrrolidone (83) (Scheme 23) was dissolved in water at pH > 8, irreversible cleavage of the exocyclic and endocyclic amide C–N bond occurs. The former led to γ -butyrolactam (87) and glycollic acid (88). The latter, a O

HO O

O

N

O

O

−

HO N

O

O

O

N

O NH

(84−)

(84)

(83)

O

(85)

HO−

HO−

O

O O

NH + −

O

(87)

NH

HO

OH

O

(88)

(86) Scheme 23

O−


77

lactam scission, and a minor reaction (which, however, occurred to a greater extent at high pH) yielded N -(4-hydroxyacetyl)butanoic acid (NBA) (86). It was proposed that NBA (86) was produced by ester hydrolysis of the ester–amide macrocycle (85) that is in equilibrium with the cyclol form (84) of (83). NMR evidence was obtained for the intermediacy of (84) and (85), and a rationale was proposed for their formation vis-àvis the alternative direct attack of HO− upon the C=O group of the 2-pyrrolidone (83). Compound (83) may be regarded as a candidate drug, since it is a substituted derivative of the lactam form of γ -aminobutyric acid (GABA), an inhibiting neurotransmitter in the brain.88 A new class of chiral 4-N ,N -dialkylaminopyridine acyl-transfer catalysts has been developed that are capable of exploiting both van der Waals (π ) and H-bonding interactions to allow remote chiral information to control stereochemically the kinetic resolutions of secondary alcohols with moderate to excellent selectivity (S = 6–30). Catalysts derived from (S)-α,α-diarylprolinol (89; Ar = Ph, 2-naphthyl) in combination with isobutyric anhydride were found to possess high activity and selectivity across a broad range of substrates.89

N

O N

N HO Ar

Ar

(89)

(iii) Lactams Reviews have appeared of theoretical studies on ring-opening of β-lactams in both solution and in enzymatic media90 and of a comparison of the mechanisms of reactions of β-lactams and β-sultams, including their reactions with some serine enzymes.91 An ab initio study of the acid hydrolysis of the lactam 1-azabicyclo[2.2.2]octan-2one (described as a ‘highly twisted amide’) and of the model compound 3-methyl-δvalerolactam showed that both proceed via a stepwise mechanism, but N -protonation is preferred to O-protonation by the ‘twisted amide’, whereas the reverse is the case for the model compound.92 [18]Crown-6 binds alkylammonium ions specifically and this property has been exploited in the development of a model cyclotransferase that converts γ -, δ-, or ε-amino acids into the corresponding lactam. A short side-arm on [18]crown-6 of a –CH2 OCOCH2 NMe2 group provides scope for displacement of the chloro group of activating agent 2-chloro-4,6-dimethoxy-s-triazine by the Me2 N group to yield a quaternary ammonium compound that can form a complex with the δ-amino acid (90). This complex (90) juxtaposes the carboxylate and the triazine ring leading to

78

Organic Reaction Mechanisms 2006 OMe N MeO

+

OMe

N N

N

MeO

NMe2

N O−

N

O

O O

O

O O

NMe2 O O

O

+

O

O

NH3

O

O H

H N+ H

O O

O

(90)

O

O

O

OMe (91) O

N O

N N

OMe

NH2 O

OMe N NH + HO

N N OMe

(92)

Scheme 24

the formation of a bound triazinyl ester (91). Upon release by the polyether, the ester cyclizes with expulsion of 2-hydroxy-4,6-dimethoxy-s-triazine to form the lactam (92) (Scheme 24).93 N -(4-Methoxyphenyl)-3-(4-X-phenyl)-4-(methylsulfonoxymethyl)azetidinones (93; X = MeO, Cl, F) were attacked by secondary amines in DMF or MeCN at the sp 3 carbon, but by MeO− or NH3 in MeOH by ring-opening attack at the sp 2 carbon (Scheme 25). The former attack led to 4-dialkylaminomethyl derivatives (94), but the attack by the harder nucleophiles at the C=O group led to the rearranged aziridin-2ylacetamides (96; Nu = NH2 ) by reaction with NH3 –MeOH at room temperature (r.t.) or to the analogous esters (96; Nu = OMe) by reaction with MeO− –MeOH at reflux. The open-chain intermediate (95) could be isolated by reaction with MeO− –MeOH at r.t., which upon heating in Et3 N–EtOH at reflux yielded (96; Nu = OMe) by intramolecular displacement of mesylate by the arylamino group. Compounds (96; Nu = NH2 ) and (96; Nu = OMe) are of interest as possible carboxypeptidase A inhibitors.94

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

X

HNu2 RR′NH

OSO2Me

NRR′

N

HNu1 O

79

N PMP

O

(93)

PMP (94)

NaOMe–MeOH r.t.

X

OSO2Me N H O

X

PMP

N

Et3N–EtOH reflux

OMe (95)

O

PMP

Nu (96)

PMP = 4-MeOC6H4 Scheme 25

(b) Phosphoric Acids and their Derivatives (i) Phosphate and phosphonate monoesters Systematic calculations of the potential surfaces of the reactions of a series of phosphate monoesters with different leaving groups involving ab initio calculations with implicit solvent models to ab initio QM/MM free energy calculations showed that the character of the transition state changes from associative to dissociative with decrease in the pKa of the leaving group.95 Using the B3LYP method of DFT, theoretical studies of the hydrolysis mechanism of 5 -adenosine monophosphate and methyl phosphate (as a model compound) concluded that each reaction is single channel with a two-step process and a pentacoordinated intermediate is formed first.96

Me R OH +

2−

O3P

O

COO−

R

O

O

(97)

COO− PO32−

R

O COO− enoylpyruvyl product + HPO42−

Scheme 26

80


The carboxyvinyltransferases catalyse the addition of hydroxy compounds, ROH, to phosphoenoylpyruvate (97) to form, via a tetrahedral intermediate, an enoylpyruvyl product and inorganic phosphate (Scheme 26). The enzyme-catalysed formation of phosphate was found to proceed exclusively via C–O cleavage and, surprisingly, neither protonation of the non-bridging oxygens nor interactions with cationic side-chains had measurable effects on the C–O bond cleavage. This prompted a computational investigation of a series of simple alkyl and aryl phosphate monoesters, ROP(O)(OH)2 , in order to elucidate the structural features, especially the extent of protonation or not, that influence whether C–O or P–O bond cleavage occurs. The results showed that protonating the bridging oxygen when the non-bridging oxygens were already protonated favoured C–O cleavage, whereas protonating the bridging oxygen of the dianion form, (RO)PO2− 3 , favoured O–P cleavage. Alkyl R groups capable of forming stable cations were more prone to C–O bond cleavage with But > Pri > Me.97 β-Ketophosphonic acids (98) were found to undergo facile dephosphonylation under fairly mild conditions (Scheme 27). The rate of dephosphonylation was dependent on the electronic nature of the substituent at the carbon atom α to phosphorus, with electron-withdrawing groups accelerating the process. 31 P NMR studies supported a mechanism at low pH that either (Scheme 28) involved water attack in a bimolecular process (path a) or transient formation of metaphosphate (path b), a process analogous to the decarboxylation of β-keto acids.98 O O

P

ONa

O 1:1 H2O–CH3CN

OH

reflux

R1

R2 (98)

+ R1

R2

O

ONa P OH

HO

Scheme 27

H+

O

O P

R1 R2 H+

O

H O H

O a

OH OH

R1 R2 O

O

R1 R2

P O H OH

O +

b

+

R1 R2

Scheme 28

OH P OH OH

O

O P OH


81

(ii) Phosphate diesters DFT methods have been used to study the in-line reactivity of H2 O, MeOH, HO− , and MeO− towards dianionic, monoanionic, and neutral forms of ethylene phosphate and cyclic-2 ,3 -ribose phosphate, the analysis generally supporting an associative mechanism.99 The hydrolysis of methyl 8-dimethylamino-1-naphthyl phosphate (99) and its reactions with a representative range of nucleophiles are catalysed by the dimethylammonium group at acidic pH with rate accelerations of the order of 106 . The reaction persists up to pH 7 because the strong intramolecular hydrogen bond, which is the key to efficient general acid catalysis, is present also in the reactant. The sensitivity to the basicity of the nucleophile (Brønsted βnuc = 0.29) lies between values measured previously for mono- and tri-esters. The comparisons suggest that general acid catalysed reactions of phosphate mono- or di-esters with strongly basic oxyanion nucleophiles (such as those derived from a serine oxygen or a bound water molecule in an enzyme active site) will be fastest when their negative charges are neutralized by protonation. It was suggested that the reaction of (99) involving NH2 OH as an α-effect nucleophile proceeds through the pre-equilibrium formation of the tautomer H3 N+ –O− as the active nucleophile; ab initio calculations supported that idea.100

R=

HO OH HO

−

O O Nu H + P NMe2 MeO O

OH N R

N H

H N

N H

HO N R

HN O

(99)

(100)

The kinetics of the alkaline hydrolysis of di(p-nitrophenyl) phosphate (DNPP) in aqueous DMSO, dioxane, and MeCN were studied. In all solvent mixtures, the reaction rate steadily decreased to half of its value in pure water in the range 0–70 vol.% of organic cosolvent and sharply increased in mixtures with lower water content. Alkali metal ions catalysed the DNPP hydrolysis, the catalytic activity decreasing in the order Li+ > Na+ > K+ > Rb+ > Cs+ .101 Sapphyrins, which are pentapyrrolic porphyrinlike macrocycles, are known to bind phosphate diesters selectively at neutral pH. Now, a doubly substituted sapphyrin (100) has been assessed as a metal-free catalyst for phosphodiester hydrolysis using the reactive DNPP as test substrate. The attached side-arms were pentahydroxylated and it was proposed that the two distal HO groups of each side-arm were involved in the modest catalysis observed.102

82


Intramolecular transesterification rates of the RNA model compound 2-hydroxypropyl p-nitrophenyl phosphate (HPNPP) (101) have been used to compare the reactivity of a mononuclear complex with peripheral hydrogen bonding aminopyridyl groups (102) with a dinuclear zinc complex (103) that cannot hydrogen bond to the transition state. It was found that hydrogen bonding is more important than having two metal centres in determining the rate of hydrolysis of HPNPP (101) to propylene phosphate and p-nitrophenate (Scheme 29).103 When hydrogen-bonding aminopyridyl groups were appended to the periphery of the dizinc complex, the resulting complex (104) accelerated the transesterification of (101) with a 106 -fold rate acceleration at pH 7.4 and 25 ◦ C; this is claimed to be the most active artificial zinc complex for catalysing this transesterification. It also displayed turnover, although it was found that the phosphodiester product bound as tightly to the dizinc core as the phosphodiester substrate did to the artificial enzyme, so product inhibition was occurring. HPNPP (101) has a better leaving group and a poorer intramolecular nucleophile than RNA, so the observation that complex (104) also catalysed the transesterification of the dinucleotide uridyl-3 ,5 -uridine (UpU) with a 106 -fold rate acceleration confirms that the high reactivity of this catalyst is not confined to the activated substrate. The addition of the peripheral aminopyridyl groups accelerated UpU transesterification by two orders of magnitude.104

O−

HO O

P

+

O

−

O O

O

O P

O 2N

−

O O

O2N (101) Scheme 29

NH2 NH2 N

OH2 Zn

N

N

(102)

N

O(H)

Zn N

H2O

OH2 O

N

N

Zn N

N

(103)

HPNPP (101) was also used to probe the catalytic ability of zinc- and coppercontaining calix[4]arenes that carried two or three [12]ane-N3 macrocycles on their upper rim. Cooperativity was found between the catalytically active metal complexes during phosphodiester transesterification provided that they were adjacent to each other, i.e. on proximal positions of the calixarene rim, whereas those on opposite

2 Reactions of Carboxylic, Phosphoric and Sulfonic Acids and their Derivatives NH2

H 2N H2O

OH2

NH2 N

H 2N

N Zn

O

Zn

N

N

83

N

N

(104)

sides did not cooperate during catalysis. The copper complexes cleaved the diribonucleotide monophosphates UpU and UpG with an ability comparable to the best existing synthetic di/tricopper and di/trizinc complexes.105 A di(zinc[12]ane-N3) complex (105) catalysed the transesterification of the RNA model compound HPNPP (101) and of the DNA model compound methyl p-nitrophenylphosphate with methoxide in methanol. This dinuclear complex exhibited an enormous 1012 -fold rate enhancement for each ester, and a mechanism involving coordination of both Zn(II) ions to the phosphate was suggested.106 The hydrolysis of HPNPP (101) was also used to assess the catalytic ability of cyclen-based lanthanide complexes. Appending amine arms to the cyclen was shown to increase the catalytic ability greatly and shifted maximum activity into the physiological pH range, an effect that was attributed to hydrogen bonding and/or general acid catalysis to the bound phosphate ester. The possibility that the pendant amines deprotonated second-sphere water molecules to make them more nucleophilic was also proposed.107 The cleavage rates of UpU and the p-nitrophenyl analogue UpPNP (106) were used to study the catalytic mechanism of a previously studied di(zinc[9]ane-N3) complex (107). Greater transition state stabilization during the cleavage of UpU compared with UpPNP was found, which was attributed to stabilizing interactions between the catalyst and the alkoxy leaving group attached to C(5 ) of the departing ribonucleoside.108 O

U

HO H

N

2+

Zn

N

N

2+

Zn

N

N

H

H (105)

N

H O

O OH P

−O

O Ar

Ar = p-nitrophenyl (106)

N NH Zn NH

OH

N Zn NH NH

(107)

A series of heptameric single-stranded (ss) DNAs and RNAs having a central 9guanylate ion have been investigated by 31 P NMR spectroscopy in order to determine its effect on each of the flanking phosphate moieties. The results showed that the ssRNAs, but not the ssDNAs, were affected, the electronic properties and chemical reactivities of the internucleotidic phosphates being dissimilar in a sequence-specific manner

84


because of their non-identical microenvironments. To complement these results, preferential cleavages at various phosphates were observed when the heptameric ssRNAs were subjected to alkaline hydrolysis at pH 12.5.109

(iii) Phosphate and phosphonate triesters Homo- and hetero-bimetallic Cu(II), Zn(II), and Co(II) complexes based on the binucleating ligand N ,N ,N ,N -tetrakis[(2-benzimidazoyl)methyl]-2-hydroxy-1,3-diaminopropane (108; X = OH) and its new p-toluoyl ester derivative [108; X = OC(O)-pTol] catalyse the hydrolysis of p-nitrophenyl diphenyl phosphate at ambient temperature with activities rivalling the fastest known systems. These catalysts are useful in the decontamination of organophosphorus pesticides and nerve agents.110 Two other papers address the issue of contamination protocols for organophosphorus pesticides and nerve agents. In one, the effects of aqueous mixtures of Pri OH, But OH, and (CH2 OH)2 upon the reactivity of HO− and HO2− towards ethyl p-nitrophenyl ethylphosphonate and diethyl p-nitrophenyl phosphate were reported. Rates increased as the alcohol content increased for both anions, but the reverse was true for (CH2 OH)2 .43 In the other, kinetic studies of the reaction between a large set of oximate anions and sarin, soman, and di(4-nitrophenyl) methyl- (DNPMP) and phenylphosphonate (DNPPP) were reported. The Brønsted-type plots of these α-nucleophiles revealed a clear tendency for the reactivity of the oximates to suffer a saturation effect with increasing basicity in aqueous solution. In the case of sarin, soman, and DNPMP, this behaviour was reflected in a levelling off at pKa ≈ 9, but for DNPPP a decrease in rate at higher pKa values was seen. However, plots in 70:30 DMSO–H2 O were linear for all four compounds. The result in the latter, less saturating medium supports the view that desolvation of oximates must occur prior to nucleophilic attack.111 H N

H N

N N

NH

N

N

X N

N

NH

(108)

(iv) Thiophosphates The hydrolysis rates of the dianions of phosphate and phosphorothioate monoesters are substantially accelerated by the addition of polar aprotic solvents such as DMSO and MeCN because the activation barrier G = becomes smaller due to a lowering of the enthalpy of activation. The enthalpy transfer of the transition states in the


85

two solvents was calculated from the enthalpy of transfer of p-nitrophenyl phosphate and p-nitrophenyl phosphorothioate from water to 0.6 m aqueous DMSO which were determined calorimetrically. The results show that the reduced enthalpies of activation in both hydrolysis reactions arise not from a destabilization of the reactants in the mixed solvent, but from the fact that the enthalpy of transfer of the transition states to the mixed solvent is significantly more negative than the enthalpy of transfer of the reactants.112

(c) Sulfonic Acids and Their Derivatives (i) Sulfates, Sulfamates, and β-Sultams Structure–reactivity and structure–structure correlations of five sulfate monoesters and 11 sulfamate esters determined by low-temperature X-ray crystallography revealed similar ground-state deformations that suggest similar reaction coordinates for sulfuryl and sulfamyl group transfer. The results support a mechanism that proceeds through significant bond lengthening of the scissile S–Ob bond and a dissociative, sulfur trioxide-like transition state. This work suggests a close mechanistic relationship of sulfamyl and sulfuryl group transfer that is similar to but distinct from phosphoryl group transfer.113

H2N

SO2

O

NO2

(109)

−

HN

SO2

O

2−

NO2

N

SO2

O

(110)

(111)

−

O

[H N

NO2

−

NO2

SO2]

O

[N

(112)

SO2]−

(113) H2N SO2 NR′R′′ + HO-Np (114) Scheme 30

NO2

86


Anti-cancer drugs that are sulfamate esters, ROSO2 NH2 , appear to act by inhibition of sulfatases. Now, kinetic studies of the aminolysis of p-nitrophenyl sulfamate (109) by secondary alicyclic amines in MeCN at 310 K are reported that model the enzyme reaction. The Brønsted-type plot was biphasic, the break point at pKa ≈ 18.2 more or less corresponding to the pKa of the ester (109) (17.8). The proposed mechanism (Scheme 30) involves a sequential double deprotonation of (109) leading first, via (110), to the sulfenamine (112) and at higher basic strength to (111) and thence to a novel anionic sulfenamine (113), the products in each case being an N ,N -dialkylsulfamide (114) and p-nitrophenol.114 Theoretical studies of the hydrolysis of N -benzyl-3-oxo-β-sultam (115) showed that the activation energies for the pathways leading to the products of C–N and S–N cleavage for the uncatalysed hydrolysis were very similar. However, when a second water molecule was involved, cleavage of the C–N bond was preferred.115 In a review, the mechanisms of reactions of β-sultams have been compared with those of β-lactams, including their reactions with some serine enzymes.91 O PhCH2N

S

O

O (115)

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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

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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 and Silver . . . . . . . . . . . . . . . . . . . . . . . . . Cerium, Titanium, Vanadium, Cobalt, Tungsten, and Molybdenum Lead, Bismuth, and Palladium . . . . . . . . . . . . . . . . . . . Group VIII Metals . . . . . . . . . . . . . . . . . . . . . . . . . Oxidation by Compounds of Non-metallic Elements . . . . . . . . . . Nitrogen, Sulfur, and Boron . . . . . . . . . . . . . . . . . . . . Halogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ozonolysis and Ozonation . . . . . . . . . . . . . . . . . . . . . . . . Peracids and Peroxides . . . . . . . . . . . . . . . . . . . . . . . . . Photo-oxygenation and Singlet Oxygen . . . . . . . . . . . . . . . . . Triplet Oxygen and Autoxidation . . . . . . . . . . . . . . . . . . . . Other Oxidations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduction by Complex Metal Hydrides . . . . . . . . . . . . . . . . Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transfer Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . Other Reductions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

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

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

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

91 91 97 98 100 100 103 103 107 112 113 120 120 123 126 133 137 141 144

Oxidation by Metal Ions and Related Species Chromium, Manganese and Nickel The experimental data for oxidation of benzyl alcohol,1 aliphatic primary and secondary alcohols,2 and cholesterol3 with cetyltrimethylammonium (CTA) dichromate indicated that the reactions occur in a reverse micelle system produced by the oxidant. Michaelis–Menten-type kinetics were observed with respect to the reductants. The product of the oxidation of cholesterol depends on the solvent. In dichloromethane, the product is 7-dehydrocholesterol, whereas with dichloromethane containing acetic acid the product is 5-cholesten-3-one. A low kinetic isotope effect, kH /kD = 2.81, was observed in the oxidation of methanol-d4 ; this, combined with the rate data and the reverse solvent isotope effect [k(H2 O)/k(D2 O) = 0.76], suggests that these reactions



91

92

Organic Reaction Mechanisms 2006 O O

Cr

OCrO2O−CTA+ O−CTA+

PhCH2OH + H PhCH

O O

Cr

O

Cr

OCrO2O−CTA+ OH

+ CTA+

OCrO2O−CTA+ OH

O− CTA+ OCrO2O−CTA+ Cr OH O

O

O

+ H+

HO

slow

Cr

CTA+O−

OCrO2O−CTA+ OH

+ PhCHO

Scheme 1

proceed through formation of a chromate ester (e.g. Scheme 1), which decomposes in the rate-determining step. A second-order dependence on both the reductant and acidity was observed in the oxidation of alcohols with butyltriphenylphosphonium dichromate; study of MeCD2 OH and Me2 CDOH indicated the presence of a substantial kinetic isotope effect. The reaction was studied in 19 organic solvents and the rates were correlated with multiparametric equations. The reaction is susceptible to both electronic and steric effects of the substituents. A mechanism involving the formation of a dichromate ester and an α-C–H cleavage has been proposed.4 Oxidation of aryl alkyl ketones with quinolinium dichromate (QDC) in acidic medium is proposed to involve a reaction between the enol form of the ketone and protonated QDC in the rate-determining step to form a chromate ester. Subsequently, the ester undergoes a C−C bond cleavage.5 Although no evidence for the intermediacy of free radicals by ESR spectroscopy was obtained in the oxidation of thio acids with QDC to the corresponding disulfides,6 the formation of Cr(V) was indicated by ESR spectroscopy in the oxidation of fluorene to fluorenone with QDC.7 Formation and disproportionation of a chromate ester have been suggested in the oxidation of salicylic acids8 and pyridinecarboxylic acids9 with QDC. The kinetic isotope effect (kH /kD = 5.8) for oxidation of acetaldehyde-d1 with QDC indicated aldehydic C–H bond cleavage in the rate-determining step. A rate-determining decomposition of a chromate ester of the aldehyde hydrate involving a cyclic transition state has been suggested.10 Similar mechanisms have also been suggested for the oxidation of unsaturated aldehydes,11 α-keto acids,12 salicylaldehydes,13 and heteroaldehydes.14 Formation of an acyclic chromate ester has been proposed in the oxidation of dihydric phenols to the corresponding quinines with QDC.15 Kinetics and activation parameters for the oxidation of phenol with tetrakis(pyridine) cobalt(II) chromate have been determined.16 The oxidation of oximes of cyclopentanone, cyclohexanone, and cycloheptanone with pyridinium fluorochromate is first order each in the oxidant and oxime. The observed reactivity sequence has been rationalized on the basis of I-strain.17

3 Oxidation and Reduction

93

The oxidation of meta- and para-substituted anilines with imidazolium fluorochromate (IFC)18 and nicotinium dichromate (NDC),19 in several organic solvents, in the presence of p-toluenesulfonic acid (TsOH) is first order in the oxidant and TsOH and is zero order with respect to substrate. A correlation of rate data in different solvents with Kamlet–Taft solvatochromic parameters suggests that the specific solute–solvent interactions play a major role in governing the reactivity, and the observed solvent effects have been explained on the basis of solute–solvent complexation. The oxidation rates with NDC exhibited negative reaction constants, while the oxidation with IFC did not correlate well with any linear free energy relationships. Michaelis–Menten-type kinetics were found for oxidation of alcohols with tetramethylammonium fluorochromate indicating the formation of an intermediate. The formation constant and the rate of disproportionation of the intermediate have been determined. A two-electron reaction scheme has been proposed.20,21 Michaelis–Menten-type kinetics were observed for alcohols in their oxidation by piperidine chlorochromate. The reaction is first order with respect to Cr(VI) and acidity. The mechanistic aspects have been discussed.22 The solvent effect on the oxidation of some unsaturated acids,23 thio acids,24 methionine,25 aliphatic aldehydes,26 and aliphatic alcohols27 with benzyltriemthylammonium chlorochromate has been analysed in terms of Kamlet’s and Swain’s multiparametric equations. The hydrogen ion dependence has the form kobs = a + b[H+ ]. Michaelis–Menten-type kinetics were observed with respect to methionine,25 whereas a first-order dependence was obtained with other reductants. The oxidation of MeCD2 OH displayed a kinetic isotope effect, thereby confirming the cleavage of a C−H bond in the rate-determining step.27 A mechanism involving a three-centre transition state has been proposed for the oxidation of unsaturated acids, whereas the oxidation of thio acids, aldehydes, and alcohols is proposed to proceed via a chromate ester. The rates of oxidation of ortho-, meta-, and para-substituted phenyl methyl sulfides with quinolinium bromochromate (QBC) showed excellent correlation with Charton’s LDR/LDRS equations. Oxidation of alkyl phenyl sulfides is sensitive to both polar and steric effects of the alkyl group. The polar reaction constants are negative, indicating an electron-deficient sulfur centre in the slow step. An analysis of the solvent effect with Swain’s equation showed that both cation- and anion-solvating powers of the solvent played important roles in the oxidation process. A mechanism involving the formation of a sulfurane intermediate has been suggested.28 The oxidation of PhCDO with QBC exhibited a substantial primary kinetic isotope effect, confirming the cleavage of the aldehydic C−H bond in the rate-determining step. The results of correlation analysis of the rates of para-substituted benzaldehydes indicated an electron-deficient reaction centre in the transition state. Rapid formation of a chromate ester of the hydrated benzaldehyde and its subsequent slow decomposition has been suggested.29 Chromic acid oxidation of d-sorbitol and d-mannitol has been studied in the presence and absence of 2,2 -bipyridyl (bipy). A monomeric species of Cr(VI) has been found to be kinetically active in absence of bipy, whereas in the catalysed path the Cr(VI)–bipy complex has been found to be the active oxidant. Sodium dodecyl sulfate

94


N

Ka

+ H+

N

4 NH+ (Ka = 28 × 10 for bipy)

N

LH+

L HCrO4−

2H+

+

+

Kb

LH+

C1

+

+

N

N

O Cr O

H 2O

OH2

(C1) Kc

+

C1

R

C2 +

CH2OH

H+

‡ +

‡

+

N

+

N

H 2O

Cr

O

O

or

H 2O

−O

R CH

+

N

O

H

R CH

N Cr

O O− H

(C2) C2

k2

RCHO + CrIV

L

(where L = bipy) Scheme 2

has been found to accelerate the oxidation whereas N -cetylpyridinium chloride retards it. A mechanism (Scheme 2) has been proposed for the bipy-catalysed reaction.30 A Cr(VI)–catalyst complex has been proposed as the reactive oxidizing species in the oxidation of trans-stibene with chromic acid, catalysed separately by 1,10phenanthroline (PHEN), oxalic acid, and picolinic acid (PA). The oxidation process is believed to involve a nucleophilic attack of the olefinic bond on the Cr(VI)–catalyst complex to generate a ternary complex.31 PA- and PHEN-catalysed chromic acid oxidation of primary alcohols also is proposed to proceed through a similar ternary complex. Methanol-d4 reacted nearly six times slower than methanol, supporting a hydride transfer mechanism in this oxidation.32 Kinetics of chromic acid oxidation of dimethyl and diethyl malonates, in the presence and absence of oxalic acid, have been obtained and the activation parameters have been calculated.33 Reactivity in the chromic acid oxidation of three alicyclic ketoximes has been rationalized on the basis of I-strain. Kinetic and activation parameters have been determined and a mechanism

95


has been suggested.34 Hammett’s acidity function and the role of water have been examined in the chromic acid oxidation of amoxicillin and 6-aminopenicillanic acid.35 It is known that substituent effects on the oxidation of alkenes with permanganate are relatively small. However, a B3LYP/6–311++G∗∗ study predicted much larger substituent effects. This was shown to be due to the formation of an initial charge–dipole complex that leads to products via the rate-determining step. PCM calculations indicated that the complex should disappear in aqueous solution and, under these conditions, most of the alkenes were predicted to have about the same activation energy. CCSD/6–311++G∗∗ calculations indicated a very early transition state. Kinetic data indicated that the initial reaction between permanganate ion and crotonic acid has a first-order dependence on both reactants and is independent of hydroxide ion concentration. The kinetic and spectroscopic data suggested the process shown in Scheme 3.36 R O

O Mn

O

O−

R

R

H

H

+

R OH−

O

O Mn O

O−

R

R

OH

O Mn

−

MnO4−

R

R

MnO4−

OH Mn

Mn O

R

R O

O

O

O−

O

O

O

O−

Scheme 3

The oxidation of acetylacetone with permanganate ion in acidic and alkaline solutions has been investigated. The rate constants for the oxidation of keto, enol, and enolate ion forms have been determined. The slow oxidation of the enol has been attributed to π -electron delocalization by conjugation. In acid-catalysed oxidation of the keto form, a nucleophilic attack of permanganate ion occurs on the carbonyl-C atom. The enolate ion suffers a base-catalysed electron abstraction.37 A mechanism involving the formation of bicyclic intermediates has been suggested for the oxidation of acetylenic compounds with alkaline permanganate. A nucleophilic attack by a permanganateoxygen on the bridgehead carbon of the triple bond has been contemplated.38 In the acid permanganate oxidation of propan-1- and -2-ol, permanganic acid is postulated as the reactive species. In the presence of the surfactant Tween-20, the reactants are distributed between the aqueous phase and micellar pseudo-phase before reacting. Compensation between water destruction and substrate–micelle interaction is proposed to play an important role in the oxidation in the presence of the surfactant.39

96


Boron trifluoride forms an adduct, [BF3 –MnO4 ]− , with permanganate ion that oxidizes hydrocarbons at rates over seven orders of magnitude faster than that by permanganate alone. The kinetic isotope effects for the oxidation of perdeuterated cyclohexane, toluene, and ethylbenzene, at 298 K, are 5.3, 6.8, and 7.1, respectively. The rate-limiting step for all of these reactions is most likely hydrogen atom transfer from the substrate to an oxo group of the adduct. A good linear correlation between log(rate constant) and C–H bond energies of the hydrocarbons was found. The accelerating effect of boron trifluoride on the oxidation of methane has been studied computationally by the DFT method. A significant decrease in the reaction barrier results from BF3 coordination to permanganate. The BF3 coordination increases the ability of the metal centre to achieve a d 1 Mn(VI) electron configuration in the transition state.40 Potassium permanganate oxidizes terminal alkenes to the corresponding α-hydroxy ketones in good yields. The reaction is highly chemoselective in the presence of differently protected hydroxy groups and can be utilized for the preparation of polyfunctional compounds.41 The oxidation of hexamine with alkaline permanganate is proposed to proceed through an intermediate complex, which decomposes in the slow step to generate a free radical. The activation parameters for the slow step have been evaluated.42 The oxidation of l-norleucine, l-leucine, l-isoleucine, and l-t-leucine with permanganate in strong acid medium showed an autocatalysis by Mn(II), except in the case of l-leucine. For the autocatalytic activity to initiate, a certain concentration of Mn(II) is required. Moreover, the autocatalytic phenomenon vanishes in concentrations of sulfuric acid that are greater than 4.3 mol dm−3 . The oxidation showed a good correlation in a biparametric equation, with ρ = −4.57 and δ c = 2.23 at 318 K.43 Oxidation of sulfoxides with oxo(salen)Mn(V) complexes follows second-order kinetics. Sodium hypochlorite is used as a terminal oxidant. The oxidation of substituted sulfoxides yielded a reaction constant ρ = −2.57. The reduction of substituted Mn(V) complexes showed a reaction constant of 0.50. A valid reactivity–selectivity principle is operative in this system. An SN 2- type mechanism has been proposed.44 In aqueous media (pH 2.5–6.0), the Mn(IV) tetramer [Mn4 (µ-O)6 (bipy)6 ]4+ oxidizes both glyoxylic and pyruvic acid to formic and acetic acid, respectively. Kinetic studies suggest that the tetramer, its oxo-bridge protonated form, i.e. [Mn4 (µ-O)5 (µOH)(bipy)6 ]5+ , the reducing acids (RH), and their conjugate bases (R− ) all take part in the reaction. The oxo-bridge protonated form is a stronger oxidant. The gem-diol forms of the α-oxo acids are the possible reductants. A one-electron/one-proton electroprotic mechanism operates in the rate-determining step.45 Oxidation of some tetrapeptides with manganese(III) acetate showed a first-order dependence on Mn(III), acetate ion, and the peptide. An inverse-order dependence was observed on hydrogen ion. There is no effect of Mn(II). A mechanism involving [Mn(OAc)4 ]− as the active oxidizing species has been proposed. The oxidation by Mn(III) in sulfuric acid medium is found to be faster than that by manganese(III) acetate.46 Michaelis–Menten-type kinetics and formation of free radicals have been observed in the oxidation of some α-keto esters47 and 1,3-diketones48 with Mn(III) pyrophosphate. Manganese(III) porphyrins bearing nitro substituents at β-postions


97

catalyse the oxidation of activated aromatic compounds with hydrogen peroxide. Yields improved considerably on using imidazole as a co-catalyst.49 A convenient enantioselective catalytic oxidation of a variety of differently substituted, cyclic (E) and acyclic (Z)-enol phosphates with (salen)manganese(III) complex has been reported. The influence of electronic and steric effects of the enol phosphate substituents on the stereoselectivity of oxidation has been studied.50 The oxidation of butane-1,2-diol with dihydroxydiperiodatonickelate(IV) showed a first-order dependence on Ni(IV) and an order between one and two in the reductant. The rate constant increased with increasing concentration of alkali and decreasing concentration of periodate ion. A plausible mechanism involving a two-electron transfer has been proposed.51

Copper and Silver (µ-η2 :η2 -Peroxo)Cu(II)2 complex, [Cu2 (O2 )(H–L)]2+ , is capable of not only intramolecular hydroxylation of the m-xylyl linker of the dinucleating ligand H–L but also intermolecular epoxidation of styrene and hydroxylation of THF. Epoxidation of substituted styrenes yielded a Hammett ρ = −1.9, indicating a rate-limiting electrophilic attack of the peroxo ligand on the sp2 carbon of the substrate. Hydroxylation of THF-d8 showed a very large kinetic isotope effect, confirming that the reaction involves a rate-limiting H-atom abstraction process from THF. Although bis(µ-oxo)dicopper(III) was not detected in the reaction system, a small amount of bis(µ-oxo)dicopper(III) species present in a rapid pre-equilibrium may not be excluded as a reactive intermediate.52 Pyridylarenes undergo Cu(II)-catalysed diverse oxidative C–H functionalization reactions. The tolerance of alkene, alkoxy, and aldehyde functionality is a synthetically useful feature of this reaction. A radical-cation pathway (Scheme 4) has been postulated to explain the data from mechanistic studies. A single electron transfer (SET) from the aryl ring to the coordinated Cu(II) leading to the cation-radical intermediate is the rate-limiting step. The lack of reactivity of biphenyl led to the suggestion that the coordination of Cu(II) to the pyridine is necessary for the SET process. The observed ortho selectivity is explained by an intramolecular anion transfer from a nitrogen-bound Cu(I) complex.53 A mechanism involving the formation of an intermediate complex between the oxidant and reductant has been proposed for the oxidation of isonicotinate ion with diperiodatocuperate(III) in alkaline solution. The activation parameters for the slow step have been evaluated.54 The catalytic activity of Os(VIII) is more than that of Ru(III) in the catalysed oxidation of paracetamol with diperiodatoargentate(III) (DPA). The active species of catalysts and oxidant have been identified and a mechanism has been proposed.55 The oxidation of aspirin, both uncatalysed56 and catalysed by Os(VIII) and Ru(III)57 with DPA in alkaline solution is of first order in DPA and has less than unit order in both aspirin and alkali. The order with respect to the catalyst is one. A decrease in the dielectric constant of the medium increases the rate of the reaction. A mechanism has been proposed.

ee

98


SET

N AcO

Cu

N

+•

Py +

H+

Cu AcO

OAc

SET

OAc

OAc

N

•

OAc H

Scheme 4

The oxidation of butane-1,4-diol,58 ethanediol, and butane-1,3-diol59 by dihydroxydiperiodatoargentate(III) (DDPA) in alkaline solution is first order in Ag(III), ethanediol, and butane-1,3-diol. The order with respect to butane-1,4-diol is between one and two. A plausible mechanism involving the formation of an adduct in a pre-equilibrium between the DDPA and reductant is proposed. The activation parameters along with rate constants of the rate-determining step have been calculated. The rate of oxidation of butane-1,2-diol with dihydroxyditelluratoargentate(III), in alkaline solutions, decreases with increase in the concentration of TeO4 2− ions. The dihydroxymonotelluratoargentite(III) species is assumed as the reactive form. A two-electron mechanism has been proposed.60

Cerium, Titanium, Vanadium, Cobalt, Tungsten, and Molybdenum The oxidation of d-fructose with cerium(IV) in sulfuric acid medium is inhibited by an increase in the acidity. A cationic surfactant, CTAB, catalyses the reaction, whereas SDS has no effect. The catalytic role of CTAB has been explained using the pseudophase model of Menger and Portnoy. A mechanism involving the formation of an intermediate complex between β-d-fructopyranose and Ce(SO4 )3 2− has been proposed.61 The oxidation of cycloalkanones with cerium(IV) in sulfuric acid medium showed a negligible effect of acidity. Formation of an intermediate complex, which decomposes in the rate-determining step, has been suggested.62 Ce(SO4 )2 is found to be the reactive species in the iridium(III)-catalysed oxidation of t-butyl alcohol,63 cyclohexanol,64 and methanol65 with cerium(IV) in sulfuric acid. The reaction is first order in cerium(IV) but of fractional order in the reductants. Induced polymerization of acrylonitrile indicated the generation of free radicals. Mechanisms have been suggested on the basis of experimental results.

99


The oxidation of benzoin with cerium(IV) in perchloric acid solution is proposed to involve an interaction between Ce4+ (aq.) ions and the keto alcohol, resulting in the formation of free radicals. The final product is benzoic acid.66 The rate of oxidation of crotyl alcohol with cerium(IV) is independent of the concentration of Ce(IV). The reaction induced polymerization of acrylonitrile indicating the formation of free radicals. The kinetics and activation parameters for the reaction have been determined.67 For the Ir(III)-catalysed oxidation of methyl ketones68 and cyclic ketones69 with Ce(IV) perchlorate, successive formation of complex between the reductant and Ce(IV) and then with the catalyst has been proposed. Results showed that in acidic solutions, iridium(III) is a more efficient catalyst than osmium and ruthenium compounds. The rhodium(III)-catalysed oxidation of maleic acid70 and fumaric acid71 with Ce(IV) in acidic medium shows a first-order dependence on Ce(IV), the reductant, and Rh(III). There is no significant effect of ionic strength. Suitable mechanisms have been postulated. Oxidation of 3,4-dihydropyrimidin-2(1H )-ones (DHPMs) with ceric ammonium nitrate (CAN) in acetic acid resulted in ethyl 2,4-dioxo-6-phenyltetrahydropyrimidin-5carboxylates as the major product. However, DHPMs undergo a regioselective oxidation with CAN in the presence of sodium hydrogencarbonate in neutral aqueous acetone solution to yield ethyl 6-methyl-4-aryl(alkyl)pyrimidin-2(1H )-one-5-carboxylates. A mechanism involving a nitrolic acid intermediate has been suggested.72 A titanium complex (1) with a salen ligand is an efficient catalyst for the enantioselective epoxidation of alkenes with hydrogen peroxide as the terminal oxidant. The participation of a titanium–peroxo species, activated by hydrogen bonding, in the reaction, has been postulated.73 R1

R1

H

H N

N Ti

R3

O R2

R3

O

O

R2 2 (1)

Kinetics of oxidation of iron(II) by the surfactant complex ions cis-chloro/bromo (dodecylamine)bis(ethylenediamine)cobalt(III) have been reported. The second-order rate constant remains constant below the critical micelle concentration (cmc), but increases with cobalt(III) concentration above the cmc. The rate of reaction was not affected by the added hydrogen ions. It is suggested that the reaction proceeds by an inner-sphere mechanism.74

ee

100


Oxidation of promazine and chlorpromazine with hexaimidazolecobalt(III) in acidic solution results in the formation of Co(II) and a cationic radical. The kinetic and activation parameters have been determined and mechanistic aspects have been discussed.75 The catalytic action of CDTA complexes of Fe(III), Ni(II), Cu(II), Cr(III), and Mn(II) on the oxidation of l-ascorbic acid with tris(oxalato)cobaltate has been investigated. The rate is proportional to the concentration of the complex. Fe(III)–CDTA is the best catalyst for the reaction.76 An oxo–diperoxo tungstate(VI) complex, PPh4 [WO(O2 )2 (QO)], is generated from H2 WO4 , hydrogen peroxide, quinolin-8-ol (QOH), and PPh4 Cl. This complex is highly efficient as a catalyst for epoxidation of alkenes in tandem with sodium hydrogencarbonate as co-catalyst and hydrogen peroxide as as a terminal oxidant. The initial rate of oxidation followed first-order kinetics.77 A catalytic asymmetric oxidation of mono-, di-, and tri-substituted alkenes using a chiral bishydroxamic acid (BHA) complex of molybdenum catalyst in air at room temperature leads to good to excellent selectivity. It has been suggested that the Mo–BHA complex combines with the achiral oxidant to oxidize the alkene in a concerted fashion by transfer of oxygen from the metal peroxide to the alkene.78 The chiral BHA–molybdenum complex has been used for the catalytic asymmetric oxidation of sulfides and disulfides, utilizing 1 equiv. of alkyl peroxide, with yields up to 83% and ees up to 86%. An extension of the methodology combines the asymmetric oxidation with kinetic resolution providing excellent enantioselectivity (ee = 92–99%).79

Lead, Bismuth, and Palladium Mn(II)-catalyzed oxidation of cyclic ketones with lead tetraacetate is zero order in the oxidant. The order of reactivity is cyclohexanone>cyclooctanone>cycloheptanone ≈ cyclopentanone. The reactivity has been analysed in terms of the conformation.80 The rate of oxidation of acetophenoximes with bismuth(V) fluoride in a mixture of hydrogen fluoride and perchloric acid follows first-order kinetics in both the oxime and Bi(V). The reaction is acid catalysed. A bridged outer-sphere mechanism, involving formation of an iminoxy radical, has been suggested.81 Oxidation of methane to acetic acid, catalysed by Pd(II) in concentrated sulfuric acid, has been investigated by DFT calculations. The results show that Pd2+ cations in such solutions are ligated by two bisulfate anions and by one or two molecules of sulfuric acid. Methane activation occurs primarily via addition of methane across one of the Pd–O bonds of a bisulfate ligand. A likely route to products involves the oxidation of Pd(HSO4 )(CH3 )(H2 SO4 )2 and Pd(HSO4 )(CH3 -CO)(H2 SO4 )2 to form Pd(η2 HSO4 )(HSO4 )2 (CH3 )(H2 SO4 ) and Pd(η2 -HSO4 )(HSO4 )2 (CH3 CO)(H2 SO4 ), respectively, which then can readily eliminate CH3 HSO4 or CH3 COHSO4 , respectively. Pd(0) formed as a result of the reaction is reoxidized to Pd(II) by either sulfuric acid or oxygen.82

Group VIII Metals Pentadentate dispidine-based Fe(II) complexes catalyse the oxidation of cyclooctene with hydrogen peroxide to afford the expected epoxide product, with the reaction

ee


101

rate dependent on the ligand structure. Under anaerobic conditions in acetonitrile cisand trans-1,2-diols are also obtained. The data support a mechanism which involves formation of a low-spin Fe(III)–hydroperoxo intermediate that produces (FeIV =O). Epoxide is formed both by direct transfer of the ferryl oxygen atom and by a radical based process with molecular oxygen. Diols are formed by the reaction of an adduct of the alkene and Fe(IV) with HO• within the solvent cage of the iron complex.83 Ferrate(VI) oxidation of ibuprofen is slowed with an increase in the pH of the solution and the rates are related to protonation of ferrate(VI). The use of Fe(VI) in removing ibuprofen from water has been discussed.84 Bleomycin (BLM), a glycopeptide antibiotic chemotherapy agent, damages singleand double-stranded DNA. The experimental and computational studies on the reaction coordinate of activated bleomycin (ABLM) strongly showed the low-spin (ABLM) FeIII –OOH complex as the active oxidizing species. Kinetic experiments yielded a deuterium isotope effect, kH /kD = 3, for ABLM decay, indicating the involvement of a hydrogen atom in the rate-determining step. H-atom donors with relatively weak X–H bonds accelerate the reaction rate, establishing that ABLM is capable of hydrogen atom abstraction. Direct H-atom abstraction by ABLM generates a reactive FeIV = O species, which is capable of cleaving a second DNA strand, as is observed in vivo. It has been shown that BLM does not follow the haem paradigm, which involves heterolytic O–O bond cleavage to generate a reactive FeV = O intermediate.85 It has been demonstrated that the oxidation of alcohols with hexacyanoferrate(III) (HCF) shows a hyperbolic variation with HCF concentration, and the reaction order varies from one to zero on increasing the HCF concentration. This rate law is obeyed during the initial moments of the reaction and at any subsequent time. These results rule out the possibility that any substance produced during the course of the reaction acts as an activator or inhibitor of the reaction rate. The mixed order has been attributed to the comparable rates of complex decomposition and catalyst regeneration steps.86 HCF acts as a selective oxidizing agent for the oxidation of catechols even in the presence of 2-mercaptobenzoxazole, as an easily oxidizable thiol, to produce related catechol thio ethers.87 Hexacyanoferrate(II) has a retarding effect on the oxidation of vanillin with HCF in alkaline solutions. A mechanism based on the observed kinetics has been proposed.88 The reactions of butane-2,3-diol by HCF in alkaline medium using Ru(III) and Ru(VI) compounds as catalysts leads to similar experimental rate equations for both the reactions. The mechanism involves the formation of a catalyst–substrate complex that yields a carbocation for Ru(VI) or a radical for Ru(III) oxidation. The role of HCF is in catalyst regeneration. The rate constants of complex decomposition and catalyst regeneration have been determined.89 A probable mechanism invoving formation of an intermediate complex has been proposed for the iridium(III)-catalysed oxidation of propane-1,2-diol and of pentane-1,5-diol, butane-2,3-diol, and 2-methylpentane-2,4diol with HCF.90–92 The Ru(VIII)-catalyzed oxidation some α-hydroxy acids with HCF proceeds with the formation of an intermediate complex between the hydroxy acid and Ru(VIII), which then decomposes in the rate-determining step. HCF regenerates the spent catalyst.93

102


A zero-order dependence on methionine concentration was observed in the Os(VIII)catalyzed oxidation by HCF. A slow step consisting of reaction between a hydroxoosmium derivative and HCF to form an intermediate has been suggested. The reaction of this intermediate with methionine in a fast step is postulated to yield a sulfur radical cation.94 Novel chiral tridentate ligands, N ,N ,N -pyridine-2,6-bisoxazolines (pybox) and N ,N ,N -pyridine-2,6-bisoxazines (pyboxazine) have been synthesized.95 Asymmetric epoxidation of alkenes with 30% hydrogen peroxide in the presence of ruthenium complexes of these ligands has been studied. Mono-, 1,1-di-, cis- and trans-1,2di-, tri-, and tetra-substituted aromatic alkenes with versatile functional groups are epoxidized with this type of catalyst in good to excellent yields (up to 100%) with moderate to good enantioselectivies (up to 84% ee). It is shown that the presence of weak organic acids or an electron-withdrawing group on the catalyst increases the reactivity. New insights into the reaction intermediates and reaction pathway of the ruthenium-catalysed epoxidation are proposed on the basis of density functional theory calculation and experiments.96 α-Acetoxysulfones were formed in palladium-catalysed asymmetric allylic alkylations of allylic geminal dicarboxylates with sodium benzenesulfinate. The directing ability of this novel functional group has been demonstrated in a series of dihydroxylations, carried out with Os(VIII) and NMO, affording syn-diols exclusively anti to the acetoxysulfone as single diastereomers in excellent yields.97 Application of computaional methods to the enantioselective dihydroxylations of alkenes by osmium complexes have been reviewed with a special focus on methods used to study the origin of high enantioselectivity. The use of a vast number of computational techniques such as QM, MM, Q2MM, QM/MM, molecular dynamics, and genetic algorithms has been enumerated.98 1,2-Dioxane-4,5-diols (peroxydiols) are conveniently synthesized in yields up to 98% and with de >90% by dihydroxylation of 3,6-substituted 3,6-dihydro-1,2dioxines with osmium tetroxide.99 Sharpless asymmetric aminohydroxylation has been modified using N -sulfonyloxycarbamates as reoxidants for the tethered aminohydroxylation reaction for allylic substrates. The yields are high and the reaction proceeds through an osmium azaglycolate intermediate. The use of N -sulfonyloxy carbamates resulted in higher yields than the use of an N -halocarbamate salt.100 In OsO4 -mediated oxidative cleavage of alkenes, OsO4 can be replaced with alternative, easier to handle, less volatile, and more innocuous osmium sources such as osmium trichloride, potassium osmate, or polymer-bound osmium tetroxide.101 Oxidation of α,β-unsaturated nitriles, amide, and acids with pentachlorohydroxoplatinate(IV) in alkaline solution is first order in the oxidant, reductant and alkali. The oxidation takes place with an inner-sphere mechanism. A tentative mechanism involving a two-electron oxidation has been suggested and the activation parameters have been calculated.102 Platinum complexes, [PtCl2 {(R,R)-XantBino}] (2) and its S,S analogue, were treated with tin(II) chloride to form the pre-catalyst for chemo-, regio-, and enantio-selective hydroformylation of styrene, vinyl acetate and allyl acetate. Although the reaction showed good chemo- and regio-selectivities, only moderate ee was obtained.103

ee

ee

de

ee

103


O O

P

P O

Pt Cl

Cl

O

O

(2)

Oxidation by Compounds of Non-metallic Elements Nitrogen, Sulfur, and Boron The initial pathways of oxidation of dimethyl sulfide, dimethyl disulfide, and methanethiol with the nitrate radical have been examined using DFT and ab initio methods. It is seen that sulfur compounds exhibit a general trend of hydrogen abstraction following the formation of an initial sulfur–nitrate complex. The results are in agreement with experimental work on dimethyl sulfide and methanethiol. Oxygen addition does not seem to be the dominant oxidation pathway in the case of dimethyl disulfide. The rate constants obtained from kinetics calculations are consistent with experimental findings and exhibit a negative temperature dependence. The importance of nitrate radical in the oxidation of reduced sulfur compounds in the atmosphere is confirmed.104 The importance of the nitrate radical in the troposphere oxidation of dimethyl sulfide has been examined by DFT and ab initio methods.105 A kinetic model of the oxidation of dimethyl sulfide with nitrogen dioxide has been constructed and the parameters thereof were verified by experimental data.106 An unexpected aromatization that takes place during the N -alkylation reaction performed on several 3-(2-nitrobenzoyl)-4,5-dihydro-1H -pyrazole-5-carboxylic acid methyl esters, giving rise to a mixture of 1-alkyl-3-(2-nitrobenzoyl)-4,5-dihydro-1H pyrazole-5-carboxylic acid methyl esters and 1-alkyl-3-(2-nitrobenzoyl)-1H -pyrazole5-carboxylic acid methyl esters is reported. It is suggested that reaction involves both inter- and intra-molecular oxidation by the nitro group.107 Palladium-catalysed chemo- and enantio-selective oxidation of allylic esters and carbonates has been achieved using nitronates as nucleophilic oxidants. The products, α,β-unsaturated carbonyl compounds, were obtained in excellent yields and ees. The mechanism in Scheme 5 has been suggested for the reaction.108 N -Phenyltriazolinedione is an efficient and chemoselective reagent for the oxidation of thiols to their corresponding symmetrical disulfides. The method is applicable to aromatic, aliphatic, and bifunctional thiols and excellent yields are obtained. A twostep mechanism (Scheme 6) has been proposed.109

ee

104


R1

R1

K+

−O

Ph

+N −O

Pd(0)

X

Pri

THF

Pd(0) R2

R2

R1

R1

O−

H O

N

+

O

Ph

OH Pri

Ph

R2

Pri

R2

N

+

Scheme 5

Ph

Ph O

O

O

O

N N R

R

S H d− d+

R

Ph

HN NH

N NH

S H d− d +

Ph O

O

S

O

HO

+ R

S

S

R

N NH

Scheme 6

Odourless and non-volatile organosulfur compounds grafted to an imidazolium ionic liquid scaffold has been synthesized. The sulfoxides have been used for an efficient oxidation of primary allylic and benzylic alcohols into aldehydes and secondary alcohols to ketones under Swern oxidation conditions and the corresponding sulfides can be recovered and recycled.110 The unsubstituted hydrazones derived from aromatic ketones and aldehydes are converted to the corresponding alkyl chlorides, in high yield, under Swern oxidation conditions. In this unusual oxidation/reduction sequence, the substrate undergoes a net reduction. Unsubstituted hydrazones derived from cyclohexyl ketones yielded elimination products. The mechanism in Scheme 7 has been postulated.111 A series of dihydoisoquinolium salts (3) based on a dioxane-containing structure have been synthesized and used in the asymmetric epoxidation of alkenes with Oxone

ee

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N R

+

Cl−

NH2

+

S

S Cl

N

Et3N

R

R

N

+

N

R

Cl−

R

+ Et3N.HCl R

Cl−

H

Cl−

NH

NH + Me2S

+

N

R

R

− N2

Cl

+

R

H

R

+ Cl−

R

H

R

Scheme 7

Ph4B− N

+

O O

R (3)

as the terminal oxidation. Almost quantitative yields and ees up to 71% have been realized.112 Homologous biphenyl and binaphthyl tertiary azepines (4) and quaternary iminium salts, prepared from (+)-(S,S)-l-acetonamine, behave as effective catalysts for the enantioselective epoxidation of unfunctionalized alkenes with Oxone (ee up to 83%).113

O N O Ph (4)

ee

106


Oxidative dearomatization of p-alkylphenols into 4-alkyl-4-hydroperoxycyclohexa2,5-dienones (p-peroxyquinols) and 4-alkyl-4-hydroxycyclohexa-2,5-dienones (pquinols) using Oxone as a source of singlet oxygen in excellent yields have been achieved in aqueous solutions.114 Highly enantioselective epoxidation of benzylidenecyclobutanes115 and tetrasubstituted benzylidenecyclobutanes116 has been achieved using a readily available glucose-derived ketone (5) as catalyst and Oxone as an oxidant. The epoxidation is likely to proceed mainly via a spiro transition state.

ee

O O

O

N O

O O

(5)

A variety of conjugated dienes are epoxidized with high enantioselectivity using glucose-derived oxazolidinone catalysts and Oxone as an oxidant. The epoxidations are stereospecific and no isomerization is observed, thus cis-epoxides are formed exclusively from cis-alkenes. The regio- and enantio-selectivity of the reaction are dependent on the substitution pattern of the diene system.117 Up to 93% ee was achieved in asymmetric epoxidation of a series of 6- and 8-substituted chromenes using chiral dioxiranes, generated in situ from oxazolidinone and Oxone. Higher ees are obtained when substrates are substituted at the 6-position. The enhanced enantioselectivity is likely due to the van der Waals forces and/or hydrophobic interactions between the 6-substituent of the substrate and the N -aryl or alkyl group of the ketone catalyst.118 A convenient asymmetric epoxidation of substituted styrenes using chiral dioxiranes generated in situ from N -aryl-substituted oxazolidinone-containing ketones and Oxone has been reported. High enantioselectivity has been achieved for both electron-rich and electron-poor styrenes.119 A new class of enantiomerically pure tetrahydropyran4-ones with an axial α-substituent has been developed as catalysts for asymmetric epoxidation of alkenes using Oxone as the oxidant affording epoxides with up to 83% ee. In these monocyclic pyranone derivatives, there is some loss of enantioselectivity compared with bicyclic systems, but good results are still obtained, indicating that an axial heteroatom can be an effective controller.120 A series of 2-fluoro-8-oxabicyclo[3.2.1]octan-3-ones were prepared and tested as catalysts for alkene epoxidation with Oxone. These catalysts provide trans-stilbene oxide with up to 83% ee. These are effective catalysts for alkene epoxidation using Oxone, but afford lower enantioselectivities than their monosubstituted counterparts.121 The ee values in the asymmetric epoxidation of cis-ethyl cinnamate with arabinose-derived ketones as catalyst and Oxone as the terminal oxidant were found to increase inversely with the size of the catalyst acetal blocking group. The catalyst with the least bulky methoxy acetal group displayed the best enantioselectivity and afforded ethyl (2R,3R)3-phenylglycidate in 68% ee.122 Homologous biphenyl and binaphthyl tertiary azepines

ee

ee

ee

ee


107

and quaternary iminium compounds have been synthesized and used as effective catalysts for the enantioselective (ee up to 87%) epoxidation of unfunctionalized alkenes with Oxone as the terminal oxidant.123 A V-shaped pH profile (pH = 0–4.73), obtained in the oxidation of furfural with peroxomonosulfuric acid, has been rationalized by considering oxidation of neutral and protonated forms of furfural with HSO5 − and SO5 2− ions. A suitable rate law has been deduced.124 A half-order dependence on hydrogen ion concentration has been observed in the Ag(I)-catalysed oxidation of some alkyl mandalates with peroxydisulfate. A free radical mechanism has been suggested.125 The reaction of thiourea126 with Methylene Blue (MB) is enhanced by an addition of mercaptosuccinic acid. The oxidation of phenylthiourea with MB127 is unaffected by the addition of the corresponding disulfide. The reactions exhibited a zero-order dependence on MB and a first-order dependence on the thiourea. The kinetic features have been explained in terms of reaction between half-reduced MB radical and the thiourea molecule. Molybdenum(VI)-catalysed perborate oxidation of sulfides is first order with respect to the sulfide and Mo(VI) but zero order in perborate. The uncatalysed reaction is first order in each the reductant and oxidant. Trichloroacetic acid enhances the oxidation rate. Oxidation of para-substituted S-phenylmercaptoacetic acids yielded a Hammett ρ of −0.54 at 293 K, indicating an electron-deficient sulfur atom in the transition state. A mechanism involving a diperoxomolybdenum(VI) species as the reactive oxidizing species has been proposed.128

Halogens Oxidation of oxalic acid with dimethyl-N ,N -dichlorohydantoin and dichloroisocyanuric acid is of first order with respect to the oxidant. The order with respect to the reductant is fractional. The reactions are catalysed by Mn(II). Suitable mechanisms are proposed.129 A mechanism involving synchronous oxidative decarboxylation has been suggested for the oxidation of α-amino acids with 1,3-dichloro-5,5dimethylhydantoin.130 Kinetic parameters have been determined and a mechanism has been proposed for the oxidation of thiadiazole and oxadiazole with trichloroisocyanuric acid.131 Oxidation of two phenoxazine dyes, Nile Blue and Meldola Blue, with acidic chlorite and hypochlorous acid is of first order with respect to each of the reductant and chlorite anion. The rate constants and activation parameters for the oxidation have been determined.132 In the oxidation of alkanethiols to disulfides with chloramine-T (CAT), in alkaline solution, the proposed reactive species are hypochlorous acid and TsNCl− anion. A correlation of reaction rate with Taft’s dual substituent parameter equation yielded ρ ∗ = −5.28 and δ = −2.0, indicating the rate-enhancing effect of electron-donating substituents.133 Michaelis–Menten-type kinetics have been observed in the oxidation of atenolol with CAT in alkaline solutions. TsNHCl is assumed to be reactive species. A mechanism has been suggested and the activation parameters for the rate-determining step were calculated.134 The Ru(III)-catalysed oxidation of diphenyl

ee

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sulfoxide (DPSO) with CAT and chloramine-B (CAB) in acidic solution is first order with respect to the oxidant, hydrogen ions, and Ru(III). The reaction rate is independent of DPSO concentration and increases with added chloride ions. The activation parameters have been determined and mechanisms have been suggested.135 The kinetics of the oxidation of cyclopentanol and cyclohexanol with CAT, catalysed by ruthenium(III), have been reported.136–138 Michaelis–Menten-type kinetics have been observed in the oxidation of thiamine with CAT. An inverse fractional order in acidity has been observed. Activation parameters have been determined and a mechanism has been proposed.139 A second-order dependence on crotonic acid has been observed in its Os(VIII)catalysed oxidation with CAT in alkaline solution. The reaction rate varied linearly with the concentration of Os(VIII). A mechanism has been proposed.140 The kinetics of the ruthenium(III)-catalysed oxidation of the secondary amines with CAT in acidic medium have been obtained and mechanisms have been postulated.141 Uncatalysed and Ru(III)-catalysed oxidation of ethylenediamine, diethylenetriamine, triethylenetetramine, aminoethylpiperazine, and isophoronediamine with CAT in HCl solution showed a fractional dependence on the amine, hydrogen ions, and Ru(III), and it is independent of CAT concentration. TsNH2 Cl has been postulated as the reactive species and a mechanism has been suggested.142 The oxidation of glutamic acid to cyanopropionic acid with CAB in acid solution showed an inverse fractional dependence on acidity. Similarly in alkaline medium, the order in alkali is fractional inverse.143 Kinetics of ruthenium(III)-catalysed oxidation of diols with CAB have been obtained. The products arise due to a fission of the glycol bond.144 The oxidation of isatins with CAB, in alkaline solutions, showed a first-order dependence on CAB and isatin and fractional order in alkali. The rates correlate with the Hammett relationship, the reaction constant ρ being −0.31. The observed results have been explained by a plausible mechanism and the related rate law has been deduced.145 The oxidation of cysteine with CAB in sulfuric acid medium is first order in CAB and cysteine and the rate is decreased with an increase in the hydrogen ion concentration.146 The kinetics and mechanism of the oxidation of aromatic aldehydes by N -chlorosuccinimide (NCS) have been reported.147 A zero-order dependence has been observed with respect to maleic and crotonic acids in their Pd(II)-catalysed oxidation with NCS in acid solution. There is no effect of hydrogen ions on the rate.148 The oxidation of phenylalanine and leucine with NCS, in acidic solution, is retarded by addition of succinimide.149 A zero-order dependence on the aldehydes was observed in the oxidation of aromatic aldehydes with N -chloronicotinamide (NCN).150 With alcohols,151 however, the reaction showed a fractional order dependence. A retarding influence of added nicotinamide was observed in both reactions. Suitable mechanisms have been postulated.150,151 Oxidation of S-phenylmercaptoacetic acid with NCN showed a firstorder dependence on the reductant, NCN and hydrogen ions.152 Electron-donating groups accelerate the rate of oxidation of aromatic aldehydes with NCN, whereas electron-withdrawing groups have the opposite effect. Activation parameters were determined and a mechanism has been suggested.153

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The oxidation of N -amino-3-azabicyclo[3.3.0]octane with chloramine follows a second-order rate law and exhibits specific acid catalysis. The nature of the product is pH dependent; in strongly alkaline solutions, the product is 3,4-diazabicyclo[4.3.0]non2-ene. A mechanism involving a nitrene insertion (Scheme 8) has been suggested.154 N NH2

NH2Cl

N NHCl

H N N

alkali

OH−

insertion

N NH H

N NH

OH

+ H 2O

Scheme 8

Oxidation of phenothiazines with 1-chlorobenzotriazole followed a first-order dependence on the oxidant and a zero-order dependence on the reductant concentration. Hypochlorous acid has been suggested as the rective oxidizing species. A mechanism consistent with the observed results has been proposed.155 The Ru(III)-catalysed oxidation of o-, m-, and p- hydroxybenzoic acids156–158 with bromamine-B (BAB) in acidic solution showed a first-order dependence on the reductant, BAB, and Ru(III). An inverse first-order dependence with respect to acidity has been observed. Mechanistic aspects have been discussed. A substantial kinetic isotope effect (kH /kD = 5.88) has been observed in the oxidation of α-deuteriomandelic acid with N -bromobenzamide (NBB) in acidic solution, confirming the cleavage of the C–H bond in the rate-determining step. The oxidation of substituted mandelic acids correlated with Brown’s σ + with negative reaction constants. A mechanism involving transfer of a hydride ion to the oxidant is postulated.159 The oxidation of glycolic acid with NBB in the presence of CTAB showed Michaelis–Menten kinetics with respect to the reductant. The oxidation is inhibited by CTAB. The results have been explained by Piszkiewicz model.160 Iridium (III)-catalysed oxidation of methyl glycol with NBB exhibited a fractional order dependence on the catalyst and a zero-order dependence on the glycol. A mechanism has been suggested.161 The rates of oxidative cleavage of para-substituted benzanilides with N -bromoacetamide, in acidic solution, correlate with Swain’s F and R parameters. The rates for ortho-substituted compounds correlate well with a

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triparametric equation involving steric effects. In this reaction, the field effects are more pronounced than the resonance effects.162 The oxidation of some dipeptides and the corresponding amino acids with N -bromosuccinimide (NBS) is independent of the hydrogen ion concentration. The cationic form of the amino acid or dipeptide is assumed to be the reactive species. The relative reactivity has been correlated in terms of hydrophobicity.163 The Ru(III)- and Ir(III)-catalysed oxidation of malic acid with NBS show identical kinetics. A suitable mechanism in conformity with the observed kinetics has been proposed.164 The reaction between selenium(IV) and tetrabutylammonium tribromide is postulated to involve a direct two-electron transfer as the test for the formation of free radical was negative. The proposed active reacting species are tribromide ion and HSeO3 − ion.165 The uncatalysed Belousov–Zhabotinsky (B–Z) reaction between malonic acid and acid bromate proceeds by two parallel mechanisms. In one reaction channel the first molecular products are glyoxalic acid and carbon dioxide, whereas in the other channel mesoxalic acid is the first molecular intermediate. The initial reaction for both pathways, for which mechanisms have been suggested, showed first-order dependence on malonic acid and bromate ion.166 The dependence of the maximal rate of the oxidation of hemin with acid bromate has the form v = k[hemin]0.8 [BrO3 − ] [H+ ]1.2 . Bromate radical, BrO2 • , rather than elemental bromine, is said to play the crucial role. A mechanism has been suggested taking into account the bromate chemistry in B–Z reactions and appropriate steps for hemin. Based on the proposed mechanism, model calculations have been carried out. The results of computation agree with the main experimental features of the reaction.167 The Os(VIII)-catalysed oxidation of crotonic acid with bromate ion in alkaline solution showed a zero-order dependence in bromate and the order with respect to crotonic acid is one at low concentration, tending to be zero at higher concentration. A mechanism has been postulated and the rate law has been deduced.168 Oxidation of diethanolamine and triethanolamine by acid bromate in the presence of ruthenium(III) chloride as catalyst exhibited a first-order dependence on bromate and Ru(III). A first-order dependence on the reductant was observed at lower concentration, which became fractional at higher concentration. An inverse fractional order with respect to hydrogen ion concentration was observed. A mechanism involving the formation of a ternary complex between Ru(III), amino alcohol, and bromate ion prior to the rate-determining step is proposed.169 Additon of chloride ions increased the rate of Ir(III)-catalysed oxidation of some cyclic alcohols170 and cyclic ketones171 with acid bromate. The rate is independent of the acidity of the solution. A change of solvent from H2 O to D2 O had no significant effect on the rate. Suitable mechanisms have been suggested. A convenient method for the selective oxidation of oximes to carbonyl compounds using N -bromo-N -benzoyl-4-toluenesulfonamide is reported.172 A convenient method for the preparation of 2-phenylthio-3-bromopropene by bromination of allyl phenyl sulfide is shown to proceed via the formation of a 1,3-dibromo-2-(phenylthio)propane intermediate.173


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The reactivity of sulfanilic acid towards haloamines, in alkaline solutions, follows the order BAB > bromamine-T > CAB > CAT. This has been attributed to the difference in the electrophilicities of Cl+ and Br+ ions and the van der Waal’s radii of chlorine and bromine. A probable mechanism has been suggested.174 The reactive species in the oxidation of secondary alcohols with benzyltrimethylammonium dichloroiodate, in the presence of zinc chloride, is proposed to be [PhCH2 Me3 N]+ [IZn2 Cl6 ]− . The reactions exhibit a first-order dependence on the oxidant, reductant, and zinc chloride. The oxidation of benzhydrol-α-d showed the presence of a kinetic isotope effect, indicating a C−H bond cleavage in the rate-determining step. A mechanism involving transfer of a hydride ion from the alcohol to the oxidant has been proposed.175 The same reactive oxidizing species has been proposed for the oxidation of methionine also. A mechanism involving formation of halosulfonium cation was proposed.176 Kinetic and activation parameters for the oxidation of hydroxylamine by iodine have been determined.177 Rh2 (OAc)4 -catalysed oxidative amination of the sulfamate ester of 2-piperidinylmethanol with (diacetoxy)iodobenzene (DAIB) gives rise to seven-membered ring structures. The unusual regioselectivity observed in nitrogencontaining systems has been rationalized on the basis of conformational factors.178 An unusual enamide–phenol coupling of a 1-methylene-1,2,3,4-tetrahydroisoquinoline derivative with DIAB has been reported. It was found that the formation of the phenoxide is an essential step for the reaction of the phenolic hydroxyl group with DAIB, leading to the formation of the desired product. Better yields are obtained in solvents of low nucleophilicity such as hexafluoropropan-2-ol.179 Alkoxysulfonyl aziridine heterocycles were prepared through selective intra- and inter-molecular alkene oxidation reactions with DAIB and a rhodium catalyst. For intermolecular processes, trichloroethyl sulfamate was identified as a novel and markedly effective N -atom source.180 Oxidation of styrene with iodosobenzene is efficiently catalysed by manganese– porphyrin cages confining palladium and gold clusters. Absorption spectroscopic studies indicated that the accumulation of inactive species is efficiently suppressed when the cage catalysts are employed.181 Asymmetric epoxidation of α,β-unsaturated aldehydes is achieved with iodosobenzene using an imidazolidinone as catalyst. The slow release of monomeric iodosobenzene from an iminoiodinane source provides high levels of reaction efficiency and enantiomeric control in the asymmetric epoxidation of electron-deficient alkenes (Scheme 9, LG = leaving group).182 Reactions of commercially available fluorous alkyl iodides with 80% hydrogen peroxide and trifluoroacetic anhydride gave CF3 (CF2 )n−1 I(OCOCF3 )2 . These iodides efficiently oxidize aliphatic and benzylic secondary alcohols to the corresponding ketones in the presence of aqueous potassium bromide. Bromide ion activates the reagents and/or generates a relay oxidant such as a functional equivalent of Br+ .183 A high-yielding method for sulfation of alcohols has been developed, proceeding via sulfite and sulfate diester intermediates. The procedure involves oxidation of sulfite ester with periodate, catalysed by ruthenium(III).184 A mechanism involving a ratedetermining attack by the oxidant on the amine-nitrogen has been suggested in the

ee

112


Me R

O

O

Me

R

O

HX

H2O

Me Me

H2O

•

N N H

Ph

catalyst 1 Me N

Me

Me

O X

−

Me

+

Me Me

O

Me Me

N Ph O

X−

N +

N Ph

iminium

R

R Me

LG

O − O

N

Me

LG

••

Me Me

N Ph

enamine

LG O R

Scheme 9

acid iodate oxidation of N -methyl- and N -ethyl-anilines. The faster rate of oxidation of the methyl compound has been attributed to the steric effect.185

Ozonolysis and Ozonation Mechanistic aspects of ozonolysis of saturated organic compounds such as hydrocarbons, alcohols, ethers, cyclic acetals, and organometallic hydrides have been reviewed. The role of alkyl hydrotrioxides and dihydrogen trioxide as key intermediates is discussed.186 A review has appeared on the kinetic and mechanistic aspects of the ozonization of ketones.187 Use of ozone as a clean and efficient reagent in chemical reactions has been reviewed. Examples highlighting the successful use of ozone in both academic synthesis and industrial chemical processes have been presented. Generation of interesting new pharmaceutical and fine chemicals using ozone as a reactant has been highlighted.188 Ozonolysis of alkenes in the presence of amine N -oxides resulted in reductive ozonolysis, i.e, the direct formation of aldehydes in high yields, avoiding the generation and isolation of ozonides or other peroxide products. Use of DMSO and tertiary amines improved the yield of aldehydes but some amount of ozonides remained. This

113


O+

O− +

−

O

N+R3 O

H

O− R

R

R

O N +R 3

O + O2

NR3

O3

Scheme 10

reaction appears to involve an unprecedented trapping (Scheme 10) of the short-lived carbonyl oxide intermediates to generate a zwitterionic adduct, which fragmented to produce the carbonyl group, an amine and 1 O2 .189,190 The rate constants of the reaction of 2,6-dimethyloct-7-en-2-ol separately with ozone and hydroxyl radical, in the gas phase, have been determined. The OH radical can either abstract hydrogen or add to the double bond. Ozone adds to the double bond. The formation of acetone, 2-methylpropanal, 2-methylbutanal, ethanedial, and 2-oxopropanal was discussed.191 The rate laws and activation parameters for the ozone oxidation of alcohols in aqueous solution have been determined and explained on the basis of formation of an ozone–alcohol complex.192 The reactivity of alkenes towards ozone, in aqueous solution, correlates well with Taft’s equation.193 Oxidation with ozone, under physiological conditions, follows the rate order uric acid ≈ ascorbic acid > glutathione. The amounts of ozone absorbed and antioxidant consumed have been simulated with a mathematical model and reaction rate constants of the oxidations have been evaluated.194 Various facets of transition metal-catalysed oxidation of benzylic compounds with ozone have been reported. The correlation of the effect of substituents with Hammett constants and steric factors has been discussed. The reaction seemed to proceed via a radical mechanism.195 Ozonation of various silanes and germanes produced the corresponding hydrotrioxides, R3 SiOOOH and R3 GeOOOH. Ozone reacts with the H–Si/Ge bond via a concerted 1,3-dipolar insertion mechanism. The hydrotrioxides decompose in various solvents into the corresponding silanols/germanols, disiloxanes/digermoxanes, singlet oxygen, and dihydrogen trioxide (HOOOH), where quantum chemical calculations indicated the importance of catalytic amounts of water. The formation of HOOOH as a decomposition product of organometallic hydrotrioxides in acetone-d6 is a new and convenient method for the preparation of this simple, biochemically important polyoxide.196

Peracids and Peroxides A new approach to the oxyfunctionalization of alkanes with isolated dioxiranes has been reviewed. Dioxiranes achieve oxidation of alkanes with high selectivity for both

114


simple and structurally complex targets.197 The syntheses and synthetic uses of peroxides in the oxidation of sulfides, alcohols, C–H bonds, and organonitrogen compounds and in epoxidation, vicinal dihydroxylation, Baeyer–Villiger oxidation, and oxidative halogenation of hydrocarbons have been reviewed.198 Recent advances in enantioselective metal-catalysed Baeyer–Villiger oxidation, especially the preparation of chiral lactones, have been reviewed with an emphasis on the role of different ligands.199 The metal-catalysed asymmetric epoxidation of unactivated terminal alkenes with hydrogen peroxide has been reviewed with an emphasis on recent developments. It has been concluded that the state-of-the-art catalysts for asymmetric epoxidation catalysts using aqueous hydrogen peroxide as the oxidant are [Ti(salalen)] and [Ti(salan)] complexes.200 Calculations based on DFT predicted that substitution on the cyclic enol ether influences the level of diastereoselectivity in the epoxidation reaction of dihydropyrans and oxepenes with dimethyldioxirane (DMDO). This is in agreement with the reported experimental results. In all cases, the oxidations are asynchronous and proceed through the spiro-transition state. It is apparent from the calculations that the degree of synchronicity in the transition state is important in the diastereoselectivity.201 The stereoselectivity of the key epoxidation step, with DMDO, in the synthesis of guanacastepene is shown, by computational study, to be controlled by torsional steering. In this particular epoxidation reaction, the transition structure energetic difference is enhanced by the great asynchronicity of the forming C−O bonds that intensifies the torsional interactions.202 The oxidation of a series of aliphatic ethers with DMDO is first order in both the ether and DMDO. The competition between oxygen insertion and radical mechanisms has been discussed. DFT calculations of the oxidation of methyl ethers indicated a possible increase in the probability of oxidation via the radical route for substrates containing electron-withdrawing substituents.203 Chiral pyrrolidine derivatives, proline, and amino acid-derived imidazolidinones mediate the asymmetric epoxidation of α,β-unsaturated aldehydes. Protected α,αdiphenyl-2-prolinol catalyses the asymmetric formation of 2-epoxyaldehydes, with hydrogen peroxide or sodium percarbonate as the oxygen sources, with 81–95% conversion with up to 96:4 dr and 98% ee.204 Sulfides are oxidized to sulfoxides and sulfones with hydrogen peroxide in the presence of zirconium tetrachloride in methanol at room temperature. Under these conditions, the sulfide function is highly reactive, and various other functional groups such as alkene and ketone remain unaffected.205 The mechanism of the oxidation of cysteine with hydrogen peroxide has been reformulated based on mathematical models. It has been pointed out that experimental results are not sufficient to make a choice between the two models.206 A mechanism has been proposed for the oxidation of styrene with hydrogen peroxide in the presence of sodium tungstate and oxalic acid on the basis of the kinetics of the reaction.207 The oxidation of phenols, cinnamic acids, and methyl aryl sulfides with hydrogen peroxide is efficiently catalysed by manganese 1,4,7-trimethyl-1,4,7-triazacyclononane complexes. The results of spectroscopic and kinetic studies coupled with Hammett correlations and labeling experiments suggested that the active oxidizing species is an electrophilic, mononuclear oxo–Mn(V) species.208

ee

ee

de

de

de ee


115

The oxidation of benzyl alcohols with hydrogen peroxide showed marked rate acceleration when catalysed by two bridged ketocyclodextrins. These catalysts function as artificial enzymes and show Michaelis–Menten kinetics. The oxidation of parasubstituted benzyl alcohols exhibited a Hammett ρ = 1.9. This value suggests that the transition state is ionic and has some negative charge at the reaction centre. A comparison of 1-phenylethanol with its 1-deuterated analogue reveals a small isotope effect (kH /kD = 1.4). A suitable mechanism has been proposed.209 Activation parameters have been determined for the oxidation of α-ethylacrolein and crotonic aldehyde with hydrogen peroxide.210 A probable mechanism, involving hydroxyl radicals, has been postulated for the gas-phase free radical chain oxidation of pyridine derivatives with hydrogen peroxide.211 The oxidation of diethyl sulfide with hydrogen peroxide is catalysed by nitrite ions. The observed kinetics indicated the formation of peroxynitrous acid as an intermediate.212 Alkylated phenol and methoxytoluene derivatives are selectively oxidized to the corresponding 1,4-benzoquinones in good yields with hydrogen peroxide and methyltrioxorhenium in 1-butyl-3-methylimidazolium tetrafluoroborate, a neutral ionic liquid.213 Certain dinuclear iron complexes are found to be efficient catalysts for the oxidation of primary and secondary alcohols with hydrogen peroxide.214 Metalloporphyrins are used as peroxidase mimics in the oxidation of phenol with hydrogen peroxide. A kinetic model has been constructed.215 New diphosphine–pentafluorophenyl-Pt(II) chiral catalysts epoxidize terminal alkenes with hydrogen peroxide as oxidant, resulting in the production of the corresponding terminal epoxides in moderate to good yields, with ee up to 98%, and complete regioselectivity in the case of dienes. The choice of Pt(II) as the metal centre and –C6 F5 as the ligand imparted the proper electronic properties to the metal, while at the same time increasing the rigidity and steric hindrance of the complexes, thereby accounting for the strong steric effect observed with different substrates.216 The epoxidation of alkenes by hydrogen peroxide is highly accelerated in 1,1,1,3,3,3hexafluoropropan-2-ol (HFIP). Kinetic studies indicated that higher order solvent aggregates are responsible for the rate acceleration. A large negative entropy of activation supported a highly ordered transition state. DFT simulations revealed a pronounced decrease in the activation barrier for oxygen transfer from hydrogen peroxide to ethene with increasing number of coordinated HFIP molecules. The oxygen transfer was unambiguously identified as a polar concerted process. Combined DFT and MP2 simulations of the epoxidation of (Z)-but-2-ene are in excellent agreement with the experimental data.217 Iodine-catalysed hydroperoxidation of cyclic and acyclic ketones with aqueous hydrogen peroxide in acetonitrile is an efficient and eco-friendly method for the synthesis of gem-dihydroperoxides and the reaction is conducted in a neutral medium with a readily available low-cost oxidant and catalyst.218 Aryl benzyl selenoxides, particularly benzyl 3,5-bis(trifluoromethyl)phenyl selenoxide, are excellent catalysts for the epoxidation of alkenes and Baeyer–Villiger oxidation of aldehydes and ketones with hydrogen peroxide.219 Efficient, eco-friendly, and selective oxidation of secondary alcohols is achieved with hydrogen peroxide using aqueous hydrogen bromide as a catalyst. Other peroxides such as t-butyl hydroperoxide (TBHP), sodium

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perborate, and sodium percarbonate are also effective. The following mechanism has been proposed:220 H2 O2 + Br2 −−−→ 2HOBr R2 CHOH + HOBr −−−→ R2 CHOBr + H2 O R2 CHOBr −−−→ R2 CO + HBr The oxidation of different sulfur compounds (sulfides, dibenzothiophenes, and thiophenes) with TBHP occurs on crystalline molecular sieves CoAPO-5 and Co/H-Y, and on MoOx /Al2 O3 catalysts. CoAPO-5 produced the highest organosulfur oxidation rates, reflecting the role of tetrahedral Co2+ framework cations that undergo facile redox cycles The relative reactivity of these organosulfur compounds increased with increasing electron density at their sulfur atom (phenyl sulfide > diphenyl sulfide > 4-methyldibenzothiophene > 2,5-dimethylthiophene) on all catalysts.221 Moderate ees are obtained in the epoxidation of alkenes with TBHP catalysed by a ruthenium(III) complex with a sugar-based ligand and 2,2 -bipyridine. A mechanism in which an Ru(V)–oxo species transfers an oxygen to the alkene through a metalloxetane has been proposed.222 Catalytic enantioselective epoxidation of enones using a series of chiral pyrrolidinylmethanol-based dendritic catalysts and TBHP as an oxidant has been reported. The epoxides were obtained in good yields and ee up to 78%.223 Catalytic enantioselective epoxidation of α,β-unsaturated ketones promoted by TBHP and diaryl-2-pyrrolidinemethanols has been reported. Investigation on structural modifications of the diaryl-2-pyrrolidinemethanols showed that fine tuning of the stereoelectronics of the substituents on the aryl moiety is important to achieve high efficiency. By employing a structurally optimized organocatalyst, high yields and up to 90% ees have been achieved.224 The Sharpless asymmetric epoxidation of (+)-zerumbol with TBHP, in the presence of l-diethyl tartrate, gave only an allerythro-bisepoxide which has five stereogenic centres. It is proposed that the reaction proceeds with a diastereoselective but non-enantioselective monoepoxidation at the 2,3-position followed by a second highly enantioselective epoxidation at the 10,11position giving efficient kinetic resolution.225 The enantioselective oxidation of β-keto sulfides with TBHP in the presence of a titanium complex with (S,S)-hydrobenzoin is a convenient route to the corresponding β-ketosulfoxides in terms of reaction conditions, yields and enantioselectivities (ee > 98%). Aryl ketosulfoxides on reduction with DIBAL–ZnCl2 yielded the corresponding β-sulfinyl alcohols with a retention of configuration.226 Dialkylzinc reagents combine with BINOL to generate, in situ, a catalyst for homogeneous epoxidation of (E)-α,β-enones to the corresponding trans-epoxy ketones. TBHP and cumene hydroperoxide (CHP) are effective terminal oxidants for this process; ees of up to 96% have been achieved. Mechanistic investigations point towards an electrophilic activation (Scheme 11) of the substrates by the chiral BINOL–zinc catalyst and a subsequent nucleophilic attack of the oxidant.227 Incorporation of substituted BINOL ligands improved the enantioselectivity of asymmetric Baeyer–Villiger oxidations of prochiral cyclobutanones with CHP and

ee

ee

ee

ee de

ee

ee

ee

(R)

BINOL + ZnEt2 −EtH

O

O

ZnLn

R

O Ph

O

R S

Scheme 11

R

R

δ+

R

O

O O Ph

Ph

δ− O

R′OOH

O Ph

ZnLn

R

R

R′

O

O

O

O

H

O

O Ph

O

O Ph

O

ZnLn

ZnLn

R′OH


117

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catalysed by aluminium-based Lewis acids. NMR studies indicated the formation of non-monomeric reactive species and their relevance in determing the stereochemistry. The involvement of a pentacoordinated aluminium complex has been suggested.228 The efficiency of a new chiral non-racemic and C2 -symmetric 2,2-bipyridyl ligand (6) in copper(I)-catalysed asymmetric allylic oxidation reactions of the cyclic alkenes with t-butyl peroxybenzoate has been evaluated. On performing the reaction of cyclopentene, cyclohexene, and cycloheptene in acetonitrile the corresponding product, (1S)-cycloalk-2-enyl benzoate, was isolated in up to 69% yield and in 91% ee.229 Me

Me

N

N

O

O O

Et

O

Et

Et Et

(6)

Hydroxylation of alkenes with m-chloroperbenzoic acid is efficiently catalysed by an Ni(II)–tris(2-pyridylmethyl)amine complex. The participation of an NiO+ (nickel– oxo) active species has been suggested.230 A new transition state (7) of the addition step in the Baeyer–Villiger reaction was found by B3LYP calculations. The role of proton acceptor is played by the carbonyloxygen atom, and the free energy barrier is lower than that previously estimated. This finding changes the mechanism for the acid catalysis.231 Me

O H O

O H O

Me Me

O

Me

O (7)

A combined theoretical and experimental study of the Baeyer–Villiger reaction of acetone and pentan-3-one, including their fluorinated and chlorinated derivatives, with performic acid revealed that the first step is rate determining for all substrates examined, even in the presence of acid. Acid catalysts generally decrease the G = of the first transition state (TS1), but increase the G = of the second (TS2). The optimal

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reaction path for acetone proceeds over the uncatalysed step for both TS1 and TS2, whereas the reaction with pentanone proceeds best via TS1-cat and TS2. Migration of the ethyl group in pentanone is energetically most favourable. The introduction of a fluorine substituent decreases the migratory aptitude by a moderate amount, both experimentally and theoretically. Both theory and experiment show the migration of a chlorinated substituent to be significantly more difficult than that of the alkyl group.232 DFT-based quantum chemical calculation has shown that the epoxidation of alkenes with peracids is a proton-catalysed reaction. The protonation site is the carbonyloxygen. The transition state and activation barriers to the attack of several peracids and their protonated forms on ethylene have been evaluated. Some important and puzzling kinetic data for epoxidation by peracids have been elucidated.233 Allylic oxidation of a variety of cyclic alkenes with copper complexes of different pybox ligands (8) and with various peresters shows high enantioselectivity (80–96% ee). Use of phenylhydrazine as an additive and acetone as solvent accelerates the reaction. It has been suggested that the phenylhydrazone is responsible for the observed acceleration. Using EPR spectra, it has been shown that the Cu(II) species is reduced to Cu(I) by phenylhydrazine and phenylhydrazone. It has been found that the presence of a gem-diphenyl group at C(5) and a secondary or tertiary alkyl substituent at the chiral centre at C(4) of the oxazoline rings is crucial for high enantioselectivity. A stereochemical outcome of the reaction is explained on the basis of a proposed transition state.234,235

Ph O Ph

O

N N

N

Ph Ph

(8)

The rate constants for oxidation of alkanes and alkenes with peroxynitrous acid in aqueous–gas phase are bell-shaped functions of the volume ratio between the liquid and gas phases. The kinetics of the generation of OH radicals and its importance in understanding the mechanism of lipid membrane oxidation has been stressed.236 Computational studies showed that the nature of the reactive species in the oxidation of trimethylamine, iodide ion, and dimethyl sulfide with lumiflavin is a C4 α-hydroperoxide complexed with water. The other two species, C4 α-hydroperoxide and C4 α-peroxide, yielded higher activation energies.237 Kinetic and spectroscopic studies on the effect of basic solvents, ethers, esters, and amides, on the oxidation of thianthrene-5-oxide with substituted peroxybenzoic acids indicated the involvement of the basic solvent in the transition state of the reactions. A solvent parameter, Xtc , based on the ratio of the trans to the cis form of thianthrene-5,10-dioxide, has been introduced.238

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Photo-oxygenation and Singlet Oxygen Recent developments in the stereoselective singlet oxygen allylic photo-oxygenations of alkenes have been reviewed. A number of factors, such as solvent, electronic effects, and non-bonded interactions that dictate the ene product selectivity, and also the various mechanisms of this reaction, have been highlighted.239 The oxidation of diethyl and diphenyl sulfides photo-sensitized by dicyanoanthracene (DCA), N -methylquinolinium tetrafluoroborate, and triphenylpyrylium tetrafluoroborate has been explored by steady-state and laser flash photolysis studies. In the Et2 S–DCA system, sulfide-enhanced intersystem crossing leads to the generation of 1 O2 , which eventually gives the sulfoxide via a persulfoxide. In all other cases an electron-transfer mechanism is involved. Electron-transfer sulfoxidation occurs with efficiency essentially independent of the sulfide structure, is subject to quenching by benzoquinone, and does not lead to Ph2 SO co-oxidation. Formation of the radical cations R2 S+• has been assessed by flash photolysis and confirmed by quenching with 1,4-dimethoxybenzene. Although it is possible that different mechanisms operate with different sensitizers, a plausible unitary mechanism has been proposed.240 Singlet oxygen reacts with binaphthylphosphine derivatives such as 1,1 -binaphthyldit-butylphosphine to form the corresponding binaphthyl-2-oxide phosphine oxides. This intramolecular arene epoxidation reaction proceeds with complete retention of stereochemistry. The binaphthyl-2-oxide di-t-butylphosphine oxide undergoes a slow ‘NIH rearrangement’ to form the corresponding hydroxylated product. A transient phosphadioxirane intermediate has been directly observed by low-temperature NMR.241 A simple route to 1,2-diols by organocatalytic enantioselective α-oxidation of aldehydes with singlet molecular oxygen, catalysed by protected diarylprolinols, has been reported. The oxidation produced α-hydroxy ketones, which are reduced with borohydride to the diols. The 1,2-diols were isolated in high yields with up to 98% ee. The oxidant was photo or chemically generated 1 O2 .242 Rates of oxidation of para-substituted arylphosphines with singlet oxygen show good correlation with the Hammett σ parameter (ρ = −1.53) and with the Tolman electronic parameter. The only products are the corresponding phosphine oxides. However, for ortho-substituted phosphines with electron-donating substituents, there are two products, namely a phosphinate formed by intramolecular insertion and phosphine oxide. Kinetic analyses demonstrated that both products are formed from the same intermediate, a phosphadioxirane. VT NMR experiments showed that peroxidic intermediates can only be detected for highly hindered and very electron-rich arylphosphines.243

Triplet Oxygen and Autoxidation The atmospheric oxidation of dimethyl sulfide (DMS) and DMSO has been reviewed. Kinetics of oxidation of DMS and DMSO with OH and NO3 radicals and with halogen and halogen oxides have been described and the mechanistic aspects have been discussed.244 A review of recent studies of the mechanism and kinetics of the gasphase oxidation of dimethyl ether has mentioned the pressure dependence of the

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products.245 Synthetic and mechanistic aspects of catalytic autoxidation using nitroxyls radicals, either alone or in combination with transition metals, have been reviewed. The role of persistent dialkylnitroxyl such as TEMPO and reactive diacylnitroxyls derived from N -hydroxyphthalimide or N -hydroxysaccharin in the autoxidation of hydrocarbons and alcohols has been discussed.246 Aerobic oxidation mediated by phosphovanadomolybdates has been reviewed. These aerobic oxidations are selective and synthetically useful in various transformations, notably diene aromatization, phenol dimerization, and alcohol oxidation. The usefulness of newer catalysts including binary complexes of the polyoxometalate and an organometallic compound useful, for example, for methane oxidation, and nanoparticles stabilized by polyoxometalates effective for aerobic alkene epoxidation are described.247 Various simulation schemes were examined and a new model is proposed to explain ignition delays found for reaction of n-decane and oxygen diluted in argon over a range of temperature (1239–1616 K) and pressure (1.82–10.0 atm).248 The radical-chain initiation in the main stage of cyclohexane autoxidation is largely caused by a concerted bimolecular reaction of the primary cyclohexyl hydroperoxide intermediate with cyclohexanone, a major oxygenated product. During this reaction, the breaking of the hydroperoxide O–O bond is assisted by simultaneous abstraction of a weakly bound α-H atom from the ketone by the nascent OH radical as it breaks away from the hydroperoxide. Complementary theoretical and experimental evidence has been produced to suggest that CyOOH initiation proceeds through a similar bimolecular process, involving concerted hydrogen abstraction from a CyH substrate molecule by the nascent OH radical.249 Incorporation of bismuth greatly enhances the catalytic performance of vanadium–phosphorus oxide catalyst in the liquid-phase oxidation of cyclohexane. It has been suggested that the oxidation of cyclohexane to cycloheanone does not proceed through cyclohexanol.250 The use of platinum, heteropoly compounds, and metal-containing heteropoly compounds in the aerobic oxidation of cyclohexane, cyclohexene, and α-pinene in the liquid phase has been reviewed. The catalysts serve to control free radical processes. The role of peroxide intermediate in determining the final products is discussed.251 Uncatalysed oxidation of cycloalkanes and alkylarenes by molecular oxygen with acetaldehyde as sacrificial co-reductant occurs efficiently in supercritical carbon dioxide under mild multiphase conditions.252 The oxidation of o-, m-, and p-xylenes with oxygen–argon mixtures were measured behind reflected shock waves. The main reaction paths have been determined by sensitivity and flux analyses and have been used to explain the slight differences in the reactivity.253 The lowest-lying potential energy surfaces for the O(3 P) + CH2 =C=CH2 reaction were theoretically characterized using CBS-QB3, RRKM statistical rate theory, and weak-collision master equation analysis using the exact stochastic simulation method. The results predicted that the electrophilic O-addition pathways on the central and terminal carbon atom are dominant up to combustion temperatures. Major predicted end-products are in agreement with experimental evidence. New H-abstraction pathways, resulting in OH and propargyl radicals, have been identified.254

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The kinetics of the gas-phase reactions of O(3 P) atoms with (Z)-CHCl=CHCl, CCl2 =CH2 , CCl2 =CCl2 , and (E/Z)-CFCl=CHCl were studied using a discharge flow tube system under pseudo-first-order conditions with [O(3 P)]0 [chloroethene]. Halogen substitution in the alkenes has been discussed in terms of reactivity with O(3 P) and its relation to the ionization potential and the reactivity with OH radicals.255 Mechanistic aspects of the oxidation of alkenes with molecular oxygen using a Schiff base–Mn(III) complex as catalyst, in the presence of sodium borohydride, have been reported.256 Mechanisms for the formation of multiple products observed for liquidphase autoxidation of nonan-5-one have been proposed.257 Benzaldehyde is formed in the liquid-phase oxidation of t-butyl phenylacetate via a hydroperoxide and also by a non-radical pathway, probably via a dioxetane intermediate; both reactions are catalysed by benzoic acid. The kinetic parameters have been calculated by solving an inverse kinetic equation.258 High-yield conversions of thiols into disulfides,259 alcohols into ketones, benzylic carbons to their ketones, and arenes to their quinones260 have been achieved in subcritical water with oxygen without any catalyst or supporting materials. A thiol–alkene–co-oxygenation radical chain reaction involving molecular oxygen converts 2 -isopropenylacetophenones directly into cyclic peroxy hemiketal products with three new bonds.261 Chiral N -salicylidene vanadyl carboxylates are efficient catalysts for asymmetric aerobic oxidation of α-hydoxy esters and amides with divergent substituents. These catalysts have been explored for the kinetic resolution of secondary alcohols also. The stereochemical origin of the almost total asymmetric control has been probed.262 An efficient and convenient methodology for the aerobic oxidation of alcohols catalysed by sol–gel trapped perruthenate and promoted by an encapsulated ionic liquid in supercritical carbon dioxide solution has been reported. The reaction is highly selective and useful for substrates otherwise difficult to oxidize.263 A fourcomponent system consisting of acetamido-TEMPO–Cu(ClO4 )2 –TMDP–DABCO has been developed for aerobic alcohol oxidation at room temperature. The catalytic system shows excellent selectivity towards the oxidation of benzylic and allylic alcohols and is not deactivated by heteroatom-containing (S, N) compounds. The use of DMSO as the reaction medium allows the catalysts to be recycled and reused for three runs with no significant loss of catalytic activity.264 A new catalytic system consisting of a persistent macrocyclic aminoxyl radical and the couple Mn(NO3 )2 –Co(NO3 )2 for the aerobic oxidation of alcohols to carbonyl compounds has been developed. The rate-determining step has been identified by studying the effect of substituents on the oxidation of benzyl alcohol. The chemistry of aminoxyl, amidoxyl, and imidoxyl radicals has been discussed.265 The geometries, vibrational frequencies and energies of all the stationary points for the ketene–oxygen reaction have been calculated. Relationships of the reactants, transition states, intermediates, and products are confirmed by intrinsic reaction coordinate calculations and important aspects of the mechanism have been highlighted.266 A theoretical study of the aerobic oxidation of alcohol using a Pd(OAc)2 –DMSO catalyst system has brought out the essential role of DMSO in the oxidation process. The transition state of the β-hydride elimination was identified computationally.267

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Various mechanisms for the aerobic oxidation of alcohols catalysed by (NHC)Pd (carboxylate)2 (H2 O) complexes [NHC = 1,3-bis(2,6-diisopropylphenyl)imidazol-2ylidene] were investigated using DFT combined with a solvent model. Of these, reductive β-hydride elimination, in which the β-hydrogen of a palladium-bound alkoxide is transferred directly to the free oxygen of the bound carboxylate, provided the lowestenergy route and explained the published kinetic isotope effect, activation enthalpy, reaction orders, and dependence of rate on carboxylate pKa .268 An eco-friendly oxidation of alcohols under an oxygen atmosphere using catalytic amounts of [bis(acetoxy)iodo]benzene–TEMPO–KNO2 has been reported. The use of a catalytic amount of poly[4-(bis(acetoxy)iodo)]styrene allowed the successful recycling of this catalytic component. The protocol can be used to promote the oxidation of different kinds of alcohols in the presence of other functional groups and also in the oxidation of primary benzylic alcohols in the presence of secondary and aliphatic ones. Primary alcohols can be oxidized to the corresponding aldehydes without any noticeable overoxidation to the carboxylic acids.269 The pathways for autoxidation of linalool, leading to hydroperoxides via a linalool– O2 biradical intermediate state, have been investigated using quantum mechanical and DFT calculations. The major hydroperoxide found both experimentally and by calculations is 7-hydroperoxy-3,7-dimethylocta-1,5-dien-3-ol.270 Both anionic and cationic cobalt(II)–porphyrin complexes were found to be efficient catalysts for the oxidation of 2-mercaptoethanol with oxygen.271 The mechanism of base-catalysed oxygenation of phenol derivatives is proposed to involve a one-electron reduction of oxygen to form phenoxy radical. The phenoxy radicals couple with superoxide radical anion to yield peroxy anions and then finally lead to the epoxy alcohol adduct.272 The temperature dependence of the degradation of dimethyl ether in the presence of oxygen and chlorine has been studied. The main products of the reaction are formaldehyde, methyl formate and formic acid. Formation of formaldehyde shows pressure dependence but that of methyl formate is independent of pressure.273

Other Oxidations Sustainable oxidation of organic compounds, particularly pollutants, has been reviewed. The emphasis is on the catalysed oxidation by molecular oxygen without the use of transition metal ions. A number of less toxic options have been examined.274 Basics of oxidation involving transition metal ions have been reviewed.275 Platinum(II)catalysed rearrangements of carbocations involved in diene cyloisomerizations have been reviewed.276 Factors influencing the stability of catalysts, enantiomeric excess, and turnover numbers of three classes of chiral metalloporphyrins catalysing asymmetric oxidations have been reviewed. The role of porphyrins in various oxidation reactions such as hydroxylation, alkene epoxidation, N -oxidation, S-oxidation, and dealkylations has been stressed.277 The development of mild, general, and selective transition metal-catalysed methods for the oxidative functionalization of carbon–hydrogen bonds has been reviewed. The likelihood of these reactions serving as powerful tools for the rapid and direct synthesis of diverse functionalized products for structure–activity relationship studies in medicinal and materials chemistry has been discussed.278

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Special properties of water as solvent, with the hydrophobic effect promoting rapid and selective reactions have been reviewed. The use of addition of prohydrophobic and antihydrophobic materials to the water solution to understand the geometry of transition states for a number of classical reactions has been discussed.279 Guanine bases in DNA are the most sensitive to oxidation. The oxidation of guanine bases by various one- and two-electron processes has been reviewed. Some key intermediates and the description of the oxidation products that can be generated from these intermediates depending on the reaction conditions are described.280 The reactions of arene dihydroxylating dioxygenase enzymes, their structure and mechanism, and recent examples of the application of arene cis-dihydrodiol bioproducts as chiral precursors in the synthesis of natural and unnatural products and chiral ligands have been reviewed. Alternative mechanisms of arene cis-dihydroxylations are discussed. The construction of new designer dioxygenases capable of producing cis-diols having unnatural configurations and regioisomers, and in improved yields, is mentioned. The expected applications are in the areas of new and improved synthetic routes to increasingly complex biologically active natural products, e.g. morphine and vinblastine, using a wider range of monocyclic arene cis-dihydrodiol precursors.281 A comparative study involving singlet oxygen, ozone, and 4-phenyl-1,2,4-triazoline3,5-dione oxidation of chiral oxazolidinone substituted enecarbamates has shed light on the mechanistic intricacies of the oxidative cleavage of alkenyl double bonds.282 Quantitative information on the antioxidant actions of allicin (by radical scavenging through one-step allylic hydrogen transfer) against the oxidation of cumene and methyl linoleate (ML) initiated with 2,2 -azobis(isobutyronitrile) in chlorobenzene has been obtained.283 13 C kinetic isotope effects (KIEs) of four cinnamyl alcohol oxidations have been determined by 13 C NMR spectroscopy using competition reactions with reactants at natural 13 C abundance. Primary 13 C KIEs of the Pd(II)-catalysed oxidation and of the MnO2 oxidation are similar (∼1.02) and indicate the C−H bond cleavages to be the irreversible and rate-limiting steps in the respective reactions. Low primary 13 C KIEs in Swern and Dess–Martin oxidations, however, indicate that the initial C−H bond breakings and proton transfers are not the irreversible steps in these mechanisms, which control the rate.284 The increase in the rate of oxidation of methanol with supercritical water concentration at 500 ◦ C has been attributed to the increase in the concentration of OH radicals in a quasi-stationary-state.285 The outermost surface compositions and chemical nature of active surface sites present on orthorhombic Mo–V–O and Mo–V–Te–Nb–O phases have been determined using methanol and allyl alcohol as probes. It is suggested that the vastly different catalytic behaviours shown by Mo–V–O and Mo–V–Te–Nb–O phases are due to different surface locations of V5+ ions.286 A theoretical analysis of methanethiol +• OH reaction at the QCISD(T)/6–311+G (2df,2pd)//UMP2/6.311+G(d,p) level indicated that the oxidation proceeds mainly by a direct hydrogen atom transfer. The cysteine +• OH system presented slight variations in major parameters from those of methanethiol. The calculated rate constants, in aqueous solution, are found to be in good agreement with the experimental rate


125

constants. The calculations indicated that the thiol oxidation is not very sensitive to hydrogen bonding and local electrical polarity.287 Oxidation of guanine and 8-oxo-7,8-dihydroguanine with a Mn(IV)=O species, a two-electron oxidant and riboflavin, a known photosensitizer and a one-electron oxidant, was studied. A quantification of the ratio between one- and two-electron oxidation mechanisms of guanine oxidation by electron transfer led to the conclusion that one-electron oxidation predominates and the two-electron oxidation process is a minor pathway.288 The major characteristics of excitable media, such as oscillating chemical reactions, and some important concepts necessary for understanding their behaviour have been discussed. The capacity of Belousov–Zhabotinsky (BZ) reactions for spontaneous spatiotemporal auto-organization is described.289 The complete metabolic fate of N -benzyl-N -cyclopropylamine (BCP) and N benzyl-N -(1 -methylcyclopropyl)amine with P450 in vitro has been determined. 3-Hydroxypropionaldehyde (3HP) was obtained in 57% yield, along with cyclopropanone hydrate (34%), cyclopropylamine (9%), benzaldehyde (6%), benzyl alcohol (12%), and benzaldoxime (19%). N -Benzyl-N -cyclopropyl-N -methylamine was found not to inactivate P450 and not to give rise to 3HP as a metabolite without first undergoing oxidative N -demethylation to BCP. These observations argue against a role for single electron transfer mechanisms in the P450 oxidation of cyclopropylamines. It has been suggested that a conventional hydrogen abstraction–hydroxyl recombination mechanism at C–H bonds leads to non-rearranged carbinolamine intermediates and thereby to N -dealkylation products including cyclopropanone hydrate.290 A plausible mechanism for Baeyer–Villiger biotransformations of prochiral bicycloketones promoted by cycloalkanone monooxygenase has been established by means of high-level DFT/B3LYP calculations.291 Kinetic isotope effects for C–H hydroxylation of N ,N -dimethylaniline by cytochrome P450 enzymes indicate that a low-spin mechanism applies.292 The oxidation of Michler’s hydride with 2,3,5,6-tetrabromo-p-benzoquinone follows a second-order rate law. It involves a stepwise electron–proton–electron transfer through a charge-transfer complex. The formation of the charge-transfer complex was observed experimentally at low temperature.293 A stereoselective approach to the precursor of (+)-myriocin, 3-deoxy-1,2:5,6-di-O-isopropylidene-3-methoxycarbonylamino-α-d-glucofuranose 3-C-carboxylic acid, via the [3,3]-sigmatropic rearrangement of allylic thiocyanates prepared from d-glucose, has been reported.294 It has been found that whether hydrogen transfer from NADH analogues to triplet excited states of 3,6-disubstituted tetrazines (R2 Tz∗ ) proceeds via a one-step process or sequential electron and proton transfer processes depends on a subtle difference in the electron donor ability and the deprotonation reactivity of the radical cations of NADH analogues and also the electron-acceptor ability of R2 Tz∗ .295 Two tandem alkene metathesis–oxidation procedures using Grubb’s secondgeneration ruthenium catalyst resulted in unique functional group transformations. Use of sodium periodate and cerium(III) chloride, in acetonitrile–water, furnished cisdiols. Oxidation with Oxone, in the presence of sodium hydrogencarbonate, yielded α-hydroxy ketones.296 Secondary alcohols are oxidized to ketones by a hydrogen

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transfer process with dodec-1-ene acting as a hydrogen acceptor and a ruthenium complex as a catalyst.297

Reduction by Complex Metal Hydrides A review describing the major advances in the field of asymmetric reduction of achiral ketones using borohydrides, exemplified by oxazaborolidines and β-chlorodiisopinocamphenylborane, has appeared. Use of sodium borohydride in combination with chiral Lewis acids has been discussed.298 The usefulness of sodium triacetoxyborohydride in the reductive amination of aldehydes and ketones has been reviewed. The wide scope of the reagent, its diverse and numerous applications, and high tolerance for many functional groups have been discussed.299 The preparation, properties, and synthetic application of lithium aminoborohydrides (LABs) have been reviewed. The role of LABs, a new class of solid, selective, and air-stable reducing reagents, in the reduction of various organic functional groups is mentioned. Tandem amination–reduction reactions of LAB reagents, which are believed to occur via an SN Ar mechanism, are discussed.300 Hyperforin is not reduced by sodium borohydride. Reduction with hydride-transfer reagents such as lithium aluminium hydride (LAH), RED-AL, and DIBAL-H, gave varied products in good yields. Its two dicarbonyl systems are amenable to reduction or deoxygenation upon treatment with alane reducing agents and pave the way to new and interesting modifications of the natural product.301 A series of new chiral lithium aluminum hydrides (BIFAl-Hs) based on biphenyl2,2 -bisfenchol and various alkyl alcohols has been synthesized and used to reduce aryl alkyl ketones with up to 62% ee. The observed enantioselectivities are explained on the basis of computational transition structure analyses. In addition to their application as hydride transfer reagents, the BIFAl-H species are promising chiral Lewis acids.302 SN 2 reduction of the allylic phosphonium salts of cyclic compounds with LAH resulted in the creation of a stereogenic tertiary carbon centre with high selectivity. This protocol has been applied to the formation of trans-isomer at the C(3)–C(8) position of the taxol C-ring.303 The reduction of 2,2,4,4-tetrachloro-8-oxabicyclo[3.2.1]oct6-en-3-one with LAH yielded the exo-alcohol as the dominant product. This is in contrast to most halo-substituted oxabicyclic ketones, which give predominantly the corresponding endo-alcohols.304 Chiral diol (9) and an α-amino alcohol mediated reduction of prochiral ketones with LAH gives alcohols in almost quantitative yields and up to 98% ee.305

OH H H OH (9)

ee

ee

de

ee

127


Enantiopure N -p-toluenesulfinyl ketimines derived from 2-pyridyl ketones bearing an additional substituent on the 6-position of the pyridine ring are reduced, with DIBAL, to N -p-toluenesulfinylamines with high yields and diastereoselectivities. The reduction of optically active 1-substituted N -toluenesulfinyl-1-(6-bromopyridin2-yl)methylamine in a number of more complex pyridine derivatives with maintenance of the toluenesulfinyl group N -protecting group is also reported.306 Deuterium-labeled experiments indicated that the reduction of secondary alkyl bromides with diisobutylaluminium hydride and ethylmagnesium chloride, catalysed by palladium complexes of chelating diphosphine, does not take place via halogen–metal exchange.307 The coupling reaction of diphenylphosphine sulfide with N ,N -disubstituted formamides in the presence of an excess of sodium hydride resulted in the corresponding aminomethyldiphenylphosphine sulfides in good yields. It is suggested that the carbon–oxygen bond is cleaved by sodium hydride (Scheme 12).308 H − Ph2 P (S)

de

NMe2 O

Ph2(S)P

Ph2(S)P

NMe2 O−

H

+ Me2N−

O NaH reduction

Ph2(S)P

NMe2

Ph2(S)P

OH

Scheme 12

Regioselective reductive openings of mixed phenolic–benzylic cyclic acetals, using BH3 –NMe3 –AlCl3 , under mild conditions to yield a benzylic ether and free the phenol group have been attributed to association of boron with the more basic oxygen (benzylic) followed by reaction with aluminium chloride.309 Enantioselective reduction of oxime ethers promoted by chiral spiroborate esters (10) with an O3 BN framework is reported. In the presence of (R,S)-10, aralkyloxime ethers are reduced by borane–THF at give (S)-1-aralkylamine in high yield and excellent enatiomeric excess (up to 98% ee). A possible mechanism (Scheme 13) of the catalytic reduction is suggested.310 The hydroboration of acetophenone in the chiral solvent (S)-methyl lactate exhibits moderate enantioselectivities. A six-membered transition state (11) involving the ketone, the borane, and the lactate as the only chiral source is proposed. Molecular modeling explains the experimentally observed enantioselectivities.311 A guanidine derivative (12)312 and (2S)-2-anilinomethylpyrrolidine (13)313 have been synthesized and successfully employed as chiral catalytic sources for the

ee

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O

O

O

O

H3B–THF

B

B

NH

O

HN

O THF BF3

(10) NOR'

THF

BH2

R′O

Ar

N RA

R

R

O O

−

B

O H

B N+

O N AR

O

OR′

O Ar

BH2

R Scheme 13

‡ Me H BH2 O H

O

O H

O O O (11) H N N (12)

O

NOR′ HN H R

BH2

129

3 Oxidation and Reduction H N H

HN (13)

borane-mediated asymmetric reduction of prochiral ketones to provide the corresponding secondary alcohols in high enantiomeric purity. Reaction of achiral and chiral bis(oxazolines) (BOX) with catecholborane (CATBH) provides boron–BOXate complexes that can be used as catalysts in the enantioselective reduction of ketones. It has been shown that asymmetric transfer of the hydride ion from the boron atom of CATBH to the prochiral carbonyl is the rate-determining step of the catalytic reaction.314 A highly enantioselective reduction of α,β-unsaturated nitriles has been conducted by using a Cu(OAc)2 –josiphos complex as the catalyst under hydrosilylation conditions. This reaction provides access to valuable β-aryl-substituted chiral nitriles in good yields and with excellent enantioselectivities by employing a stable catalytic precursor and a readily available commercial bisphosphine ligand. The active reducing species is believed to be copper(I) hydride.315 Various benzophenones and aryl alkyl ketones substituted with a fluorine atom on the ortho position were effectively converted into the corresponding alcohols with high to excellent enantioselectivities in the presence of the optically active ketoiminatocobalt(II) complexes (14). The combination of o-F substituent and a modified lithium borohydride reagent contributed to the high yield and high enantioselectivity (88–96% ee).316

N

N Co

O

O

O

O

(14)

Mechanisms of sodium borohydride reactions with primary, secondary, and tertiary amides have been investigated both at the B3LYP/6–31++G(d,p)//B3LYP/6–31G(d,p) and B3LYP/6–31++G(d,p)//HF/6–31G(d,p) levels of theory. The predicted structures of the key intermediates were then confirmed by experiment.317 For chemoselective reductions of α-substituted and aromatic esters with sodium borohydride, agreement between experimental results and theoretical computations at the B3LYP/6–31++ G(d,p)//HF/6–31G(d,p) levels of theory have been reported.318

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130


High enantioselectivities (up to 94%) are obtained in the sodium borohydride reduction of aliphatic ketones using a tartaric acid-derived boronic ester (TarB–NO2 ) as a chiral catalyst. A mechanism (Scheme 14) involving an acyloxyborohydride intermediate has been postulated.319 R

R

+ R′

TarB-NO2

NaBH4

B

THF

H

H B− + Na O

H

R′ O

O

ee

C O O CO2H

NO2

OH ∗

R

R′

Scheme 14

An efficient reduction of alkenes with sodium borohydrde as the reducing agent using 0.5–1.0 mol% Ru(PPh3 )4 H2 as catalyst, in the presence of water, has been reported. The ruthenium complex probably catalyses both the formation of hydrogen from borohydride–water and the subsequent reduction process.320 Reduction of chiral β-enamino ketones with sodium borohydride in acetic acid is convenient, stereoselective, and high yielding and allowed the preparation of enantiopure γ -amino alcohols with syn diastereoselectivity. A mechanistic hypothesis (Scheme 15) has been presented.321 Substituted 2-azetidinones are reduced with sodium borohydride in aqueous isopropanol giving 3-aminopropan-1,2-diols. The degree of conversion depends on the substitution pattern in the 3- and 4-positions of the 2-azetidinone ring and shows good correlation with carbonyl LUMO energies of starting material.322 A variety of N -t-butanesulfinylimines are reduced with sodium borohydride in THF containing 2% water to the corresponding secondary sulfinamides in high yield and diastereoselectivity. By changing the reductant to L-Selectride, the stereoselectivity is reversed to afford the opposite product diastereomer in high yield and selectivity. It appears that the sulfinyl oxygen atom plays a key role in the delivery of borohydride reagents to give products derived from a closed transition state, whereas L-Selectride reductions proceed via an open transition state.323 Nickel boride, generated in situ from nickel chloride and sodium borohydride, is an efficient reagent for debromination of vic-dibromides to the corresponding (E)-alkenes

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131

3 Oxidation and Reduction AcO

R∗ O

HN

H NaBH4

H

R

N+

O

OAc

B−

+ H NH

R∗

AcOH

AcO O

OAc R∗ NH+

AcO

B−

H AcOH

O+

HN

R∗

H NaBH4

OAc BH−

O+

NH+

R∗

AcOH

H H O

AcO

R∗ N

H AcOH

O+

OAc B−

R∗

NH+

Scheme 15

and for debromination with concomitant reduction to give dihydro products. Chalcone dibromides and other α,β-dibromo ketones undergo debromination with complete reduction to give alcohols or undergo debromination with selective reduction to give dihydrochalcones.324 With sodium borohydride and catalytic amounts of titanyl acetoacetonate, α,βunsaturated carbonyl compounds give allyl alcohols regioselectively, whereas αdiketones and acyloins are reduced to vicinal diols.325 Enantioselectivities in the reduction of acetophenone, catalysed by 1,3,2-oxazaborolidones, have been examined using the AM1-SCF MO method. The optimized geometries, thermal enthalpies, and entropies of R and S transition states in the stereo-controlling steps of the reduction have been obtained.326 Reaction of [2,3,4,5-Ph4 (η5 -C4 COH)Ru(CO)2 H] (HCPRH) with different imines afforded ruthenium–amine complexes at low temperatures. At higher temperatures in the presence of HCPRH, the complexes decomposed to give free amine. Electron-rich imines gave ruthenium–amine complexes with HCPRH at a lower temperature than did electron-deficient imines. The negligible deuterium isotope effect (kRuHOH /kRuDOD = 1.05) observed in the reaction of HCPRH with N -phenyl[1-(4-methoxyphenyl)ethylidene]amine shows that neither hydride (RuH) nor proton (OH) is transferred to the imine in the rate-determining step. These results are explained on the basis of an innersphere mechanism in which the substrate coordinates to ruthenium prior to hydrogen transfer.327 Non-activated aromatic and aliphatic esters have beeen efficiently hydrogenated to the corresponding alcohols under relatively mild, neutral conditions using a [2-(di-tbutylphosphinomethyl)-6-(diethylaminomethyl)pyridine]–ruthenium hydride complex

ee

Et2N

R

N

O

OR′

H

Ru

H

RCO2R′

CO

PBut2

Et2N

R

+H2

N

−R′·OH

NEt2

Ru

H t

RCHO

+H2

CO

PBu 2

RCH2 OH

Scheme 16

RCH(OH)OR′

CO

PBut2

CO

PBut2

OR′

H

Ru

H

H

Ru

O

N Et2

N

N

H

Et2N

N

R

N

N Et2

O

H

Ru

H

H

H

Ru

H

CO

PBut2

CO

PBut2

Et2N R

N O

H

Ru

H CO

PBut2

132 Organic Reaction Mechanisms 2006

133


as catalyst. This reaction involves an unusual aromatization–dearomatization sequence (Scheme 16).328 The stereochemistry of hydrogen transfer from [2,5-Ph2 -3,4-Tol2 (η5 -C4 COD)]Ru (CO)2 D to N -arylimines to give amine complexes was shown to be mostly trans stereospecific. Stereospecific hydrogen transfer is proposed to generate an amine and a coordinatively unsaturated ruthenium intermediate in close proximity. Coordination of the amine is proposed to occur faster than lone pair inversion of the amine. In contrast, hydrogen transfer to N -alkylimines is stereorandom. It is proposed that stereochemistry is lost in part due to the reversibility of the hydrogen transfer being faster than amine coordination.329

Hydrogenation A review of asymmetric hydrogenation of ketones with rhodium complexes as catalysts has been presented.330 A review of the developments in the asymmetric hydrogenation of ketones with ruthenium complexes as homogenous catalysts of hydrogenation, with particular emphasis on the work of Halpern, has been presented.331 A benzophenone-based ruthenium complex (15) afforded high enantioselectivity in the catalytic asymmetric ketone hydrogenation (up to 99% ee, >99% yield). It was found that chirality of benzophenone complexes can be controlled even in the solution phase.332

O

Ph2 Cl H2 N P Ru P N Ph2 Cl H2

ee

ee

Ph

Ph

(15)

Deuterium labeling experiments, kinetic studies, and rate law analysis have indicated that the (S)-BINAP–Ru-catalysed hydrogenation of 2-formyl-1-methylene-6,7dimethoxy-1,2,3,4-tetrahydroisoquinoline proceeds via a monohydride-unsaturated mechanism whereby the two protiums at the α- and β-positions of the enamide substrate are derived from two different hydrogen molecules. The overall rate is limited by the hydrogenolysis step.333 Ferrocene-based aminophosphines are shown to be effective ligands in the Ru(II)catalysed asymmetric hydrogenation of ketones. The enantioselectivity is mainly determined by the C-centred chirality of the ligands, but the planar chirality is also important, and (RC ,SFc )- or (SC ,RFc )- is the matched combination of chiralities.334 Dimethyl oxalate is selectively hydrogenated to methyl glycolate with Ru(acac)3 ,

ee

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Zn, and [MeC(CH2 SBu)3 ] as the catalyst system.335 Highly enantioselective (up to 93% ee) hydrogenation of an α-alkoxy ketone has been achieved using (phosphinoferrocenyl)oxazoline–ruthenium catalysts. Choice of appropriate solvent and base is essential for the success of this reaction.336 A new ruthenium catalyst (16) containing trans-1,2-diaminocyclohexane provided improvements in enantioselectivity to asymmetric ketone hydrogenation reactions using Ru–diamine catalysts. Substrates containing halogenated aryl rings are particularly compatible with this catalyst. However, α-chlorinated ketones remain resistant to reduction under any conditions.337

ee

ee

Br O O

NH2

P Ru O P O

NH2

Br

(16)

The role of base in the Noyori’s asymmetric hydrogenation of ketone catalysed by trans-Ru(diphosphine)Cl2 (diamine) has been evaluated. Several catalytic intermediates have been characterized and a mechanism (Scheme 17) has been presented.338 Deuterium labeling studies have shown that ruthenium–bis(phosphine)-catalysed enantioselective hydrogenation of α,β-unsaturated acids and esters follows two distinct mechanisms. In each case, a five-membered metallocycle intermediate is formed via alkene–hydride insertion. Hydrogenation of α,β-unsaturated acids proceeds via a heterolytic cleavage of dihydrogen, whereas hydrogenation of α,β-unsaturated esters proceeds via homolytic cleavage of dihydrogen.339 Rh and Ru complexes with electron-rich Tang-Phos and Duan-Phos catalyse a highly enantioselective hydrogenation of N -phthaloylenamides. In the hydrogenation of αarylenamides, up to 99% ee has been achieved though a moderate ee is obtained in the reduction of α-alkylenamides.340 Asymmetric hydrogenation of alkenes is efficiently catalysed by rhodium complexes with chiral diphosphite and diphosphoramidite ligands derived from BINOL or diphenylprolinol. Choice of a proper achiral backbone is crucial.341 Highly enantioselective hydrogenation of N -protected indoles was successfully achieved by use of the rhodium catalyst generated in situ from [Rh(nbd)2 ]SbF6 (nbd = norborna-2,5-diene)

ee

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ee ee

135

3 Oxidation and Reduction +

Ph2 P H

H2 N

Ph

Ru N H2

P Ph2 H

H

KOBut 1 equiv.

THF H2O

2-PrOH

Ph2 P H

H2 N

P Ph2

O

KOBut

Ph2 P H

2-PrOH

Ru

Ph

H2 N

Ru

THF

N H2

N P Ph2OH H2

KOBut 1 equiv. THF

Ru

THF (SiMe3)2NK NH

••

Ph2 P H Ru P Ph2

O

O

H2 N

H

Ph2 P Ru

H N

H2 N

P N Ph2 H

H OBut

Ru

NH

H

H

O

O

C

O

products

+

H2

Ph2 P H

H2 N

Ru P Ph2 H

N H

Scheme 17

and the chiral bisphosphine PhTRAP (17). Various 2-substituted N -acetylindoles are converted into the corresponding chiral indolines with up to 95% ee. The hydrogenations of 3-substituted N -tosylindoles yielded indolines possessing a stereogenic centre at the 3-position with high enantiomeric excesses (up to 98% ee).342

136

Organic Reaction Mechanisms 2006 H Me

Ph2P

Fe

Fe Me

H (17)

PPh2

A chiral diphosphonite, derived from BINOL (18) and with an achiral diphenyl ether backbone, is an excellent ligand for the iridium-catalysed asymmetric hydrogenation of quinolines. Enantioselectivities ranging from 90 to 94% were obtained.343

ee

O O

P

P

O

O

O

(18)

Mechanistic aspects of the hydrogenation of alkenes catalysed by iridium complexes with a new class of chiral phosphine–oxazoline ligands have been discussed and a selectivity model to help rationalize the results obtained has been presented.344 The complex [IrH2 (η6 -C6 H6 ) (i-Pr3 P)]BF4 is an effective catalyst for the hydrogenation of N -benzylideneaniline under mild conditions by what is postulated to be an outer-sphere, ionic, bifunctional mechanism.345 Under simple experimental conditions, the dinuclear complex [Ir2 (µ-H)(µ-Pz)2 H3 (NCMe)(i-Pr3 P)2 ] has been transformed into derivatives such as [Ir2 (µ-H)(µ-Pz)2 H2 (L)(NCMe)(i-Pr3 P)2 ]BF4 [L = η2 H2 , NH(Ph)CH2 Ph] or [Ir2 (µ-H)(µ-Pz)2 H2 (OSO2 CF3 )(NCMe)(i-Pr3 P)2 ], which are also very efficient catalyst precursors for the hydrogenation of N -benzylideneaniline through an ionic mechanism.346 The C2 -symmetric diphosphinite and C1 -symmetric phosphinite–phosphate ligands, based on a carbohydrate scaffold, and iridium complexes give catalyst precursors that are active in the hydrogenation of imines. Cationic iridium complexes gave rise to catalytic systems that were more active than the neutral iridium complexes. Enantioselectivities up to 76% were obtained.347 Hydrogenation of acyclic aromatic N -arylimines, to the corresponding optically active secondary amines with up to 99% ee, is catalysed by an iridium(I) complex

ee ee

137


of (S,S)-1,2-bis(t-butylmethylphosphino)ethane with tetrakis[3,5-bis(trifluoromethyl) phenyl]borate as the counterion. It has been suggested that the reaction proceeds through a four-membered transition state and the enantioselection is determined at the migratory insertion step.348 Near quantitative conversion and high ee (up to 89%) has been achieved in the asymmetric hydrogenation of methyl α-benzamidocinnamate employing ethylmethylimidazolium trifluoromethanesulfonate as sole reaction solvent using both the achiral and chiral Rh–phosphine catalysts.349 The hydrogenation of α,β-epoxy ketones is mediated by a catalytic amount of 1-benzyl-1,4-dihydronicotinamide (BNAH) or BNA+ Br− to form the corresponding β-hydroxy ketones in high yields. Na2 S2 O4 is used as the reducing agent to convert BNA+ Br− to BNAH. A radical mechanism has been proposed for this catalytic reaction.350 Moderate enantioselectivity is obtained in the hydrogenation of aryl alkyl ketones catalysed by [RuCl2 (p-cymeme)]2 and terpene-based β-amino alcohols.351

ee

ee

Transfer Hydrogenation Recent mechanistic studies on transition metal-catalysed hydrogen transfer reactions have been reviewed. Experimental and theoretical studies showed that hydrogen transfer reactions proceed through different pathways. For transition metals, hydridic routes are the most common. Within the hydridic family there are two main groups: the monohydride and dihydride routes. Experimentally, it was found that whereas rhodium and iridium catalysts favour the monohydride route, the mechanism for ruthenium catalysts proceeds by either pathway, depending on the ligands. A direct hydrogen transfer mechanism has been proposed for Meerwein–Ponndorf–Verley (MPV) reductions.352 Simulations based on kinetic modelling of the reduction of acetophenone with propan-2-ol, using polymer-enlarged and the unmodified catalysts, revealed that comparable performance cannot be obtained by batch operation. Polymer enlargement allowed a continuous operation of transfer hydrogenation in a chemical membrane reactor.353 High yields and enantiopurity have been realized by a highly diastereoselective MPV reduction of protected α-amino aromatic ketones using catalytic amounts of aluminium isopropoxide. The high anti selectivity resulted from the chelation of the nitrogen anion to the aluminium. In contrast, high syn selectivity was obtained with α-alkoxy ketones and other compounds via Felkin–Ahn control.354 A chiral Brønsted acid (19) catalyst system has been developed that induces cascade transfer hydrogenation to provide a direct access to a variety of 2-aryl- and Ar O O Ar (19)

P

O OH

de

138


2-alkyl-substituted tetrahydroquinolines with excellent enantioselectivities and good yields.355 The acid (19) is a highly efficient catalyst for transfer hydrogenation of various aryl-substituted benzoxazines, benzothiazines, and benzoxazinones. This method provides the corresponding dihydro-2H -benzoxazine and dihydro-2H -benzothiazines in good yields and with excellent enantioselectivities (93–99% ee). This methodology has been extended to the enantioselective synthesis of cyclic and linear aryl and heteroaryl glycine derivatives.356 A new catalyst salt (20) that consists of an achiral ammonium ion and a chiral phosphate anion and which catalyses highly enantioselective transfer hydrogenations of α,β-unsaturated aldehydes to the corresponding saturated derivatives has been developed. The underlying principle, namely asymmetric counteranion-directed catalysis, is claimed to be a new strategy for highly enantioselective synthesis.357 Pr i

ee

ee

ee

Pr i

O O

Pr i P

O O O−

N+ H2

Pr i

Pr i

Pr i

(20)

A mild, acid- and metal-free direct reductive amination of ketones has been achieved that relies on selective imine activation by hydrogen bond formation and utilizes the Hantzsch ester for transfer hydrogenation and catalytic amounts of thiourea as hydrogen bond donor. The mechanism in Scheme 18, supported by ab initio calculations, has been suggested.358 An enantioselective organocatalytic reductive amination has been achieved using Hantzsch ester for hydrogen transfer and compound (21) as catalyst. This mild and operationally simple fragment coupling has been accomplished with a wide range of ketones in combination with aryl and heterocyclic amines.359 A new, metal-free protocol involving (heteroaryl)oxazoline catalysts for the enantioselective reduction of aromatic ketones (up to 94% ee) and ketimines (up to 87% ee) with trichlorosilane has been developed. The reaction is characterized by an unusual, long-ranging chiral induction.The enantiodifferentiation is presumed to be aided by aromatic interactions between the catalyst and the substrate.360 Asymmetric reduction of N -arylketimines with trichlorosilane is catalysed by N -methyl-l-amino acid-derived Lewis-basic organocatalysts with high enantioselectivity (up to 92% ee).361 β,β-Disubstituted α,β-unsaturated ketones and esters are reduced with alkoxylhydrosilanes in the presence of chiral rhodium(2,6-bisoxazolinylphenyl) complexes to

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139

3 Oxidation and Reduction R

R

H

N R1

O R2

+

H N

R1

R2 H H

R

N N

R1

EtO2C

NH

CO2Et

S

R2 H

NH

H

NH

N H

H2N S H2N R R1 H R R1 H

H N

EtO2C

CO2Et

S R

2

NH2

N

NH R2 Scheme 18

SiPh3 O

O P

O

OH

SiPh3 (21)

give the corresponding ketones in high yields and high enantioselectivity (up to 98% ee). (EtO)2 MeSiH was proved to be the best hydrogen donor.362 Reduction of C(5)-substituted 2-hydroxychromans selectively provides 2,4-cischromans using large silane R3 SiH reductants and 2,4-trans-chromans using the smaller silane PhSiH3 . The stereochemical outcome has been rationalized on the basis of a Curtin–Hammett kinetic situation arising from hydride delivery to two different conformations of an intermediate oxocarbenium ion.363 Pentacoordinate chiral hydrosilanes were generated in situ from triethoxysilane and a C2 -symmetric ligand derived from bisproline (22). In the presence of a catalytic amount of the ligand, prochiral ketones were reduced in moderate yield with moderate enantioselectivity (up to 64% ee). Use of titanium tetrafluoride, a Lewis acid, along with complexes of (22) led to higher enantioselectivity and improved yields.364

ee

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140


O

O N H

N H

NH

HN (22)

l-Pipecolinic acid-derived formamides have been developed as highly efficient and enantioselective Lewis basic organo-catalysts for the reduction of N -arylimines with trichlorosilane. High isolated yields and enantioselectivities up to 96% are obtained under mild conditions with a large substrate spectrum.365 A one-pot reaction has been developed for the reduction of aldehydes, ketones, and primary, secondary and tertiary alcohols into their corresponding alkyl function using either diethylsilane or n-butylsilane as the reducing agent in the presence of the Lewis acid catalyst tris(pentafluorophenyl)borane; carbon–carbon double bonds remain unaffected.366 Aliphatic and aromatic polycarboxylic acids are also conveniently reduced to their corresponding alkanes using the same reagents and catalyst.367 Reductions of allylic carbonates, catalysed by Pd(OAc)2 –[(n-Bu3 PH)BF4 ], with formic acid–triethylamine show excellent diastereoselectivities. Selection of a proper protecting group, the stereochemistry of the aldol adduct, neighbouring substituents, and the alkene geometry can result in formation of three of the four possible diastereomeric triads, namely syn–syn, anti–syn, and anti–anti.368 Asymmetric reductions of various classes of fluoroalkyl ketones were achieved under transfer hydrogenation conditions. Chiral α-trifluoromethyl alcohols and their perfluoroalkyl higher homologues were prepared in excellent optical (up to 100% ee) and chemical yields (85–100%) through ketone reduction catalysed by Ru(II)–R2 NSO2 DPEN (0.05–0.5 mol%) complexes using formic acid–triethylamine in DMF. Possible transition states for the reaction have been suggested.369 The role of alkali metal cations in the [{RuCl2 (p-cymene)}2 ]-pseudo-dipeptidecatalysed enantioselective transfer hydrogenation of ketones with propan-2-ol has been examined. Lithium salts were shown to increase the enantioselectivity of the reaction when 2-PrONa or 2-PrOK was used as the base. An alternative reaction mechanism for the pseudo-dipeptide-based systems, in which the alkali metal cation is an important player in the ligand-assisted hydrogen-transfer step, has been proposed.370 Asymmetric transfer hydrogenation of cyclic imines and iminiums in water was carried out in high yields and enantioselectivities with sodium formate as the hydrogen source and CTAB as an additive, catalysed by a water-soluble and recyclable ruthenium(II) complex of the ligand (23).371 A class of simple, modular, and highly efficient α-amino acid amides ligands for Ruand Rh-catalysed asymmetric transfer hydrogenation of aromatic ketones in propan-2ol has been developed. A remarkable feature with these ligands is the switch of product enantioselectivity observed when the amide functionality is replaced by the corresponding thioamide. The results obtained have significant mechanistic implications

ee

de

ee

ee

ee

ee

141


SO3Na

NaO3S H2N

NHTs (23)

because they pinpoint the structural features which are essential for high catalytic activity and selectivity. Transition states for the reactions have been proposed.372 Anomalous concentration dependence observed in the asymmetric transfer hydrogenation of imines with formic acid, catalysed by chiral rhodium–diamine complexes, has been attributed to the participation of both reactant and product in the formation of formate salt. The probable resting state of the catalyst is a rhodium hydride species.373 An Rh(III)–tetramethylcyclopentadienyl complex containing a tethered functionality is found to give excellent results in the asymmetric transfer hydrogenation of ketones in both aqueous, using sodium formate, and formic acid–triethylamine media. Quantitative yields and almost 100% ees are obtained.374 α,β-Unsaturated acids and esters are reduced to the corresponding saturated acid derivatives by hydrogen transfer with formic acid in the presence of Rh(I) complexes with chiral ligand Ph-binepines, an axially chiral binaphthalene-type monodentate P -donor ligand. Up to 97% ees were obtained.375 Iridium–monotosylated ethylenediamine [Ts(en)] and Ir–CF3 Ts(en) are highly active and chemoselective catalysts for the aqueous-phase transfer hydrogenation of aldehydes using sodium formate as the hydrogen donor.376

ee

ee

ee

Other Reductions Reductive epoxide opening through single electron transfer has been reviewed. A number of electron-transfer reagents have been compared and a detailed report about titanocene complexes is included. The mechanism of the ring opening, established by cyclic voltammetry, kinetic measurements, DFT calculations, and synthetic studies, has been reported.377 The fundamental principles of catalytic asymmetric reactions have been reviewed. Various reactions including catalytic hydrogenation of alkenes, ketones, and imines, dihydroxylation and epoxidation, Diels–Alder reactions, and catalytic C−C bond formation have been discussed. Typical catalytic phenomena such as dynamic kinetic resolution, ligand-accelerated catalysis, non-linear effects, and asymmetric autocatalysis are considered.378 Investigation of the mechanism of nitrate reduction by Desulfovibrio desulfuricans nitrate reductase at various levels of theory has confirmed the utility of the orbital-free embedding method in the description of enzymatic processes.379 13 C Kinetic isotope effects (KIEs) of a xylose reductase-catalysed cinnamaldehyde reduction have been determined by 13 C NMR using competition reactions with reactants at natural 13 C abundance. The primary KIEs indicated that the chemical reaction steps are only partly rate limiting during reduction of aromatic aldehydes and slow steps occur outside the catalytic sequence. The aldo–keto reductase-catalysed

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142


reductions depend on a hydride transfer from NADH to the carbonyl group, which is not, however, the main step controlling the transformation rate.284 Reduction of activated carbonyl groups of α-keto esters, benzils, cyclohexane1,2-dione, and α-ketophosphonates by alkylphosphines afforded the corresponding α-hydroxy esters or ketones in good to excellent yields. A mechanism has been suggested on the basis of deuterium and 18 O labelling experiments.380 Reduction of multiple bonds with samarium diiodide has been reviewed. Chemoand stereo-selective reduction of various compounds such as conjugated alkenes, α,βunsaturated carboxylic acids, activated alkynes, carbonyl, azides, nitriles, and nitro compounds, under mild conditions, has been discussed. Recent developments in the use of samarium metal in this field have also been discussed.381 Electron-deficient imines are reduced with diethylzinc in the presence of Ni(acac)2 with up to 92% yield and moderate to excellent de. A plausible mechanism (Scheme 19) has been proposed on the basis of an NMR study.382 R1 R3

R1 R3

Sol

Sol R1

Ni(acac)2 + Et2Zn

+ Ni

Sol

R3

Sol

N EtZn

R1 R2

R3

H Ni Sol

Sol

R2 H

N

EtZn

R2

N

EtZn R1

R3

Et2Zn

Ni

R2

N

R2

N

Ni Sol

Sol

Scheme 19

Azoarenes are smoothly reduced to hydrazoarenes in excellent yields using tin and hydrazine hydrate. Formation of anilines is not involved.383 The rate of hydride transfer from 1-(p-substituted benzyl)-1,4-dihydronicotinamide (G-BNAH) to N -benzylphenothiazine radical cation (PTZ•+ ) decreases as the reaction temperature is increased. It has been attributed to G-BNAH and PTZ•+ forming a charge-transfer (CT) complex prior to the hydride transfer and the absolute value of the formation enthalpy for the CT complex being larger than the activation enthalpy of the CT complex. The Hammett reaction constant for the reaction is negative (ρ = −0.436). It has been suggested that the reaction of G-BNAH with PTZ•+ is initiated by a concerted hydride transfer via a CT complex.384

de

143


The regioselective debromination of substituted pentabromobenzenes with tBuONa–t-BuOH–DMSO is proposed to follow a halophilic mechanism via carbanions.385 Birch reductive alkylation of benzamide (24) was optimized to give the corresponding cyclohexa-1,4-diene products in 66–78% isolated yield and with high diastereoselectivity.386

de

OMe

NHCO2Me

N OMe O

OMOM (24)

It has been shown that the reductive ring opening of suitably constituted monocyclic alkylidenecyclopropyl ketones with lithium in liquid ammonia proceeds via distal cleavage and hence offers a novel regio- and stereo-selective route to thermodynamic enolates. Further, stereoelectronic factors dominate the ring opening in a fused bicyclic system, and the degree of regioselectivity is less than in the case of their cyclopropyl congeners.387 Reduction of perfluoroalkyl ketones with chiral lithium alkoxides gave chiral αperfluoroalkyl alcohols in high enantiomeric excesses. The order of steric effects on this reaction is estimated as C7 F15 > substituted phenyl > CF3 .388 An effective reductive coupling of primary, secondary, and tertiary alkyl bromides and iodides with a wide variety of conjugated alkenes such as acrylates, acrylonitrile, vinyl ketone, and vinyl sulfone in good to excellent yields has been accomplished in the presence of zinc, CoI2 –1,2-bis(diphenylphosphino)ethane complex, and water. The reaction appears to undergo an oxidative addition-driven route rather than a radical route. The reaction is proposed to involve a reduction of Co(II) to Co(I) by zinc followed by the oxidative addition of an alkyl halide to give an alkyl–cobalt(III) intermediate. Subsequent coordination of the conjugated alkene, insertion into the Co–alkyl bond, and protonation give rise to the final reductive coupling product. Co(I) is regenerated by the reduction of Co(III) with zinc powder.389 Reduction of diphenylbenzidine with arsenic(III) oxide shows a first-order dependence on hydrogen ions, As(III), and the substrate. The activation parameters have been determined.390 Carbonyl compounds and imines are reduced to the corresponding alcohols and amines, respectively, with a mixture of iron(II) chloride tetrahydrate, an excess of lithium powder, and a catalytic amount of 4,4 -di-t-butylbiphenyl. α,β-Unsaturated

ee

144


carbonyl compounds are reduced to the corresponding saturated alcohols. This reducing system exhibited good to excellent diastereoselectivity toward the reduction of different monocyclic and polycyclic ketones.391 A light-driven compound containing a photosensitizing tetraphenylporphyrin group linked to a diiron azadithiolate moiety (25) has been synthesized as a model compound of iron-only hydrogenases. This compound reduces protons photochemically to hydrogen.392

N

NH

HN

N

N S

S

(CO)3 Fe

Fe(CO)3 (25)

A comprehensive picture at the molecular level has been developed for the titanocene-mediated epoxide ring opening through electron transfer. The investigations, carried out by experimental and computational techniques, have shown that the most reactive Ti(II) species is the dimer in its half-open structure and that the selectivity of the ring opening is governed by steric effects.393

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3 Oxidation and Reduction 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260

149

Bernini, R., Mincione, E., Barontini, M., Fabrizi, G., Pasqualetti, M., and Tempesta, S., Tetrahedron, 62, 7733 (2006). Balogh-Hergovich, E. and Speier, G., Chem. Abs., 144, 69389 (2006). Zhang, J., Tang, Y., Xie, J.-q., Song, Z.-r., Wang, L., and Hu, C.-w., Chem. Abs., 144, 212347 (2006). Colladon, M., Scarso, A., Sgarbossa, P., Michelin, R. A., and Strukul, G., J. Am. Chem. Soc., 128, 14006 (2006). Berkessel, A. and Adrio, J. A., J. Am. Chem. Soc., 128, 13412 (2006). Zmitek, K., Zupan, M., Stavber, S., and Iskra, J., Org. Lett., 8, 2491 (2006). Goodman M. A. and Detty, M. R., Chem. Abs., 145, 124072 (2006). Jain, S. L., Sharma, V. B., and Sain, B., Tetrahedron, 62, 6841 (2006). Chica, A., Gatti, G., Moden, B., Marchese, L., and Iglesia, E., Chem. Eur. J., 12, 1960 (2006). Chatterjee, D., Basak, S., Mitra, A., Sengupta, A., Le Bras, J., and Muzart, J., Chem. Abs., 144, 390328 (2006). Liu, X., Li, Y., Wang, G., Chai, Z., Wu, Y., and Zhao, G., Tetrahedron: Asymmetry, 17, 750 (2006). Lattanzi, A. and Russo, A., Tetrahedron, 62, 12264 (2006). Kitayama, T., Furuya, A., Moriyama, C., Masuda, T., Fushimi, S., Yonekura, Y., Kubo, H., Kawai, Y., and Sawada, S., Tetrahedron: Asymmetry, 17, 2311 (2006). Cardellicchio, C., Omar, O. H., Naso, F., Capozzi, M. A. M., Capitelli, F., and Bertolasi, V., Tetrahedron: Asymmetry, 17, 223 (2006). Minatti, A. and Dotz, K. H., Eur. J. Org. Chem., 2006, 268. Frison, J.-C., Palazzi, C., and Bolm, C., Tetrahedron, 62, 6700 (2006). Lyle, M. P. A. and Wilson, P. D., Org. Biomol. Chem., 4, 41 (2006). Nagataki, T., Tachi Y., and Itoh, S., Chem. Commun. (Cambridge), 2006, 4016. Alvarez-Idaboy, J. R., Reyes, L., and Cruz, J., Org. Lett., 8, 1763 (2006). Grein, F., Chen, A. C., Edwards, D., and Crudden, C. M., J. Org. Chem., 71, 861 (2006). Shi, H., Zhang, Z., and Wang, Y., Chem. Abs., 144, 212327 (2006). Ginotra, S. K. and Singh, V. K., Org. Biomol. Chem., 4, 4370 (2006). Ginotra, S. K. and Singh, V. K., Tetrahedron, 62, 3573 (2006). Lobachev, V. L. and Rudakov, E. S., Chem. Abs., 144, 170542 (2006). Ottolina, G., de Gonzalo, G., and Carrea, G., Chem. Abs., 145, 145026 (2006). Erzen, E., Cerkovnik, J., and Plesnicar, B., Chem. Abs., 145, 145096 (2006). Alberti, M. N. and Orfanopoulos, M., Tetrahedron, 62, 10660 (2006). Bonesi, A. M., Manet, I., Freccero, M., Fagnoni, M., and Albini, A., Chem. Eur. J., 12, 4844 (2006). Zhang, D., Gao, R., Afzal, S., Vargas, M., Sharma, S., McCurdy, A., Yousufuddin, M., Stewart, T., Bau, R., and Selke, M., Org. Lett., 8, 5125 (2006). Ibrahem, I., Zhao, G.-L., Sunden, H., and Cordova, A., Tetrahedron Lett., 47, 4659 (2006). Zhang, D., Ye, B., Ho, D. G., Gao, R., and Selke., M., Tetrahedron, 62, 10729 (2006). Barnes, I., Hjorth, J., and Mihalopoulos, N., Chem. Rev., 106, 940 (2006). Xiang, J., Yu, L., Yu, Q., Hao, Z., Sun, M., and Lue, K., Chem. Abs., 144, 369436 (2006). Sheldon, R. A. and Arends, I. W. C. E., Chem. Abs., 145, 376693 (2006). Neumann, R. and Khenkin, A. M., Chem. Commun. (Cambridge), 2006, 2529. Olchanski, E. and Burcat, A., Int. J. Chem. Kinet., 38, 703 (2006). Hermans, I., Jacobs, P. A., and Peeters, J., Chem. Eur. J., 12, 4229 (2006). He, D., Ji, H., Luo, S., and Yuan, Q., Chem. Abs., 145, 292408 (2006). Kuznetsova, N. I., Kuznetsova, L. I., Kirillova, N. V., Detusheva, L. G., Likholobov, V. A., Khramov, M. I., and Ansel, J.-E., Chem. Abs., 144, 87760 (2006). Theyssen, N., Hou, Z., and Leitner, W., Chem. Eur. J., 12, 3401 (2006). Battin-Leclerc, F., Bounaceur, R., Belmekki, N., and Glaude, P. A., Int. J. Chem. Kinet., 38, 284 (2006). Nguyen, T. L., Peeters, J., and Vereecken, L., J. Phys. Chem. A, 110, 12166 (2006). Blanco, M. B., Cometto, P. M., Taccone, R. A., Lane, S. I., and Teruel, M. A., J. Phys. Org. Chem., 19, 752 (2006). Baik, J. S. and Lee, N. H., Chem. Abs., 145, 505054 (2006). Hammond, C. J., Smith, J. R. L., Nagatomi, E., Stark, M. S., and Waddington, D. J., New J. Chem., 30, 741 (2006). Voronina, S. G., Revkov, O. A., and Perkel, A. L., Chem. Abs., 145, 124068 (2006). Ozen, R. and Aydin, F., Monatsh. Chem., 137, 307 (2006). Ozen, R. and Kus, N. S., Monatsh. Chem., 137, 1597 (2006).

150 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307

Organic Reaction Mechanisms 2006 Kim, J., Li, H. B., Rosenthal, A. S., Sang, D., Shapiro, T. A., Bachi M. D., and Posner, G. H., Tetrahedron, 62, 4120 (2006). Weng, S.-S., Shen, M.-W., Kao, J.-Q., Munot, Y. S., and Chen, C.-T., Chem. Abs., 144, 488216 (2006). Ciriminna, R., Hesemann, P., Moreau, J. J. E., Carraro, M., Campestrini, S., and Pagliaro, M., Chem. Abs., 145, 210509 (2006). Jiang, N. and Ragauskas A. J., J. Org. Chem., 71, 7087 (2006). Minisci, F., Punta, C., and Recuperu, F., Chem. Abs., 145, 376692 (2006). Sun, H., Tang, Y.-Z., Wang, Z.-L., Pan, X.-M., Li, Z.-S., and Wang, R.-S., Chem. Abs., 144, 191726 (2006). Zierkiewicz, W. and Privalov, T., Chem. Abs., 144, 36013 (2006). Nielsen, R. J. and Goddard, W. A., J. Am. Chem. Soc., 128, 9651 (2006). Herrerıas, C. I., Zhang, T. Y., and Li, C.-J., Tetrahedron Lett., 47, 13 (2006). Backtorp, C., Wass, J. R. T. J., Panas, I., Skold, M., Borje, A., and Nyman, G., J. Phys. Chem. A, 110, 12204 (2006). Hassanein, M., Gerges, S., Abdo, M., and El-Khalafy, S., Chem. Abs., 144, 253715 (2006). Lee, J., Choe, J.-I., Jung, S., and Ham, S. W., Chem. Abs., 145, 292395 (2006). Rosado-Reyes, C. M., Francisco, J. S., Szente, J. J., Maricq, M. M., and Oestergaard, L. F., Chem. Abs., 144, 69451 (2006). Lenoir, D., Angew. Chem. Int. Ed., 45, 3206 (2006). Sheldon, R. A. and Arends, I. W. C. E., Chem. Abs., 144, 69404 (2006). Kerber, W. D., Chem. Abs., 144, 87840 (2006). Mai, C.-L. and Yeh, C.-Y., Chem. Abs., 145, 454563 (2006). Dick, A. R. and Sanford, M. S., Tetrahedron, 62, 2439 (2006). Breslow, R., J. Phys. Org. Chem., 19, 813 (2006). Pratviel, G. and Meunier, B., Chem. Eur. J., 12, 6018 (2006). Boyd, D. R. and Bugg, T. D. H., Org. Biomol. Chem., 4, 181 (2006). Sivaguru, J., Poon, T., Hooper, C., Saito, H., Solomon, M. R., Jockusch, S., Adam, W., Inoue Y., and Turro, N. J., Tetrahedron, 62, 10647 (2006). Okada, Y., Tanaka, K., Sato, E., and Okajima, H., Org. Biomol. Chem., 4, 4113 (2006). Brecker, L., Kogl, M. F., Tyl, C. E., Kratzer R., and Nidetzky, B., Tetrahedron Lett., 47, 4045 (2006). Henrikson, J. T., Grice, C. R., and Savage, P. E., J. Phys. Chem. A, 110, 3627 (2006). Guliants, V. V., Brongersma, H. H., Knoester, A., Gaffney, A. M, and Han, S., Chem. Abs., 145, 438224 (2006). Enescu, M. and Cardy, B., Chem. Phys. Chem., 7, 912 (2006). Kupan, A., Sauliere, A., Broussy, S., Seguy, C., Pratviel, G., and Meunier, B, Chem. Biol. Chem., 7, 125 (2006). Biosa, G., Bastianoni, S., and Rustici, M., Chem. Eur. J., 12, 3430 (2006). Cerny, M. A. and Hanzlik, R. P., J. Am. Chem. Soc., 128, 3346 (2006). Mihovilovic, M. D., Muller, B., Spina, M., Durrani, A. I., Stanetty, P., Dazinger, G., and Kirchner, K., Monatsh. Chem., 137, 785 (2006). Li, C., Wu, W., Kumar, D., and Shaik, S., J. Am. Chem. Soc., 128, 394 (2006). Liu, Y., Xie, G., Yamamoto, S., and Sueishi, Y., Chem. Abs., 145, 188296 (2006). Gonda, J., Martinkova, M., Raschmanova, J., and Balentova, E., Tetrahedron: Asymmetry, 17, 1875 (2006). Yuasa, J. and Fukuzumi, S., J. Am. Chem. Soc., 128, 14281 (2006). Scholte, A. A., An, M. H., and Snapper, M. L., Org. Lett., 8, 4759 (2006). Cho, C. S., Kim, D. Y., and Shim, S. C., Chem. Abs., 144, 87737 (2006). Kim, J., Suri, J. T., Cordes, D. B., and Singaram, B., Chem. Abs., 145, 356109 (2006). Abdel-Magid, A. F. and Mehrman, S. J., Chem. Abs., 145, 471033 (2006). Pasumansky, L., Goralski, C. T., and Singaram, B., Chem. Abs., 145, 376654 (2006). Verotta, L., Sterner, O., Appendino, G., Bombardelli, E., and Pilati, T., Eur. J. Org. Chem., 2006, 5479. Lange, D. A., Neudorfl, J.-M., and Goldfuss, B., Tetrahedron, 62, 3704 (2006). Utsugi, M., Miyano, M., and Nakada, M., Org. Lett., 8, 2973 (2006). Kreiselmeier, G., Frey, W., and Fohlisch, B., Tetrahedron, 62, 6029 (2006). Ren, Y., Tian, X., Sun, K., Xu, J., Xu, X., and Lu, S., Tetrahedron Lett., 47, 463 (2006). Chelucci, G., Baldino, S., and Chessa, S., Tetrahedron, 62, 619 (2006). Milczek, E. L., Palmiero, L., Sewell, S. L., and Knight, K. S., Chem. Abs., 145, 292390 (2006).

3 Oxidation and Reduction 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356

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Organic Reaction Mechanisms 2006 Mayer, S. and List, B., Angew. Chem. Int. Ed., 45, 4193 (2006). Menche, D., Hassfeld, J., Li, J., Menche, G., Ritter, A., and Rudolph, S., Org. Lett., 8, 741 (2006). Storer, R. I., Carrera, D. E., Ni, Y., and MacMillan, D. W. C., J. Am. Chem. Soc., 128, 84 (2006). Malkov, A. V., Liddon, A. J. P. S., Ramirez-Lopez, P., Bendova, L., Haigh, D., and Kocovsky, P., Angew. Chem. Int. Ed., 45, 1432 (2006). Malkov, A. V., Stoncius, S., MacDougall, K. N., Mariani, A., McGeoch, G. D., and Kocovsky, P., Tetrahedron, 62, 264 (2006). Kanazawa, Y., Tsuchiya, Y., Kobayashi, K., Shiomi, T., Itoh, J.-i., Kikuchi, M., Yamamoto, Y., and Nishiyama, H., Chem. Eur. J., 12, 63 (2006). Li, K., Vanka, K., Thompson, W. H., and Tunge, J. A., Org. Lett., 8, 4711 (2006). Gan, L. and Brook, M. A., Can. J. Chem., 84, 1416 (2006). Wang, Z, Ye, X., Wei, S. Wu, P., Zhang, A., and Sun, J., Org. Lett., 8, 999 (2006). Nimmagadda, R. D. and McRae, C., Tetrahedron Lett., 47, 5755 (2006). Nimmagadda, R. D. and McRae, C., Tetrahedron Lett., 47, 3505 (2006). Chau, A., Paquin, J.-F., and Lautens, M., J. Org. Chem., 71, 1924 (2006). Sterk, D., Stephan, M., and Mohar, B., Org. Lett., 8, 5935 (2006). Vastila, P., Zaitsev, A. B., Wettergren, J., Privalov, T., and Adolfsson, H., Chem. Eur. J., 12, 3218 (2006). Wu, J., Wang, F., Ma, Y., Cui, X., Cun, L., Zhu, J., Deng, J., and Yu, B., Chem. Commun. (Cambridge), 2006, 1766. Zaitsev, A. B. and Adolfsson, H., Org. Lett., 8, 5129 (2006). Blackmond, D. G., Ropic, M., and Stefinovic, M., Chem. Abs., 145, 45594 (2006). Matharu, D. S., Morris, D. J., Clarkson, G. J., and Wills, M., Chem. Commun. (Cambridge), 2006, 3232. Albericoa, E., Nieddub, I., Tarasb, R., and Gladiali, S., Helv. Chim. Acta, 89, 1716 (2006). Wu, X., Liu, J., Li, X., Zanotti-Gerosa, A., Hancock, F., Vinci, D., Ruan, J., and Xiao, J., Angew. Chem. Int. Ed., 45, 6718 (2006). Daasbjerg, K., Svith, H., Grimme, S., Gerenkamp, M., Mueck-Lichtenfeld, C., Gansaeuer, A., and Barchuk, A., Chem. Abs., 145, 376697 (2006). Muniz, K., Chem. Abs., 145, 27377 (2006). Leopoldini, M., Russo, N., Toscano, M., Dulak, M., and Wesolowski, T. A., Chem. Eur. J., 12, 2532 (2006). Zhang, W. and Shi, M., Chem. Commun. (Cambridge), 2006, 1218. Concellon, J. M. and Rodriguez-Solla, H., Eur. J. Org. Chem., 2006, 1613. Xiao, X., Wang, H., Huang, Z., Yang, J., Bian, X., and Qin, Y. Org. Lett., 8, 139 (2006). Dinesh, B., Abiraj, K., Srinivasa, G. R., and Gowda, D. C., J. Chem. Res. (S), 2006, 422. Zhu, X.-Q., Zhang, J.-Y., and Cheng, J.-P., J. Org. Chem., 71, 7007 (2006). Shishkin, V. N., Tarasova, I. V., and Butin, K. P., Chem. Abs., 145, 314368 (2006). Casimiro-Garcia, A. and Schultz, A. G., Tetrahedron Lett., 47, 2739 (2006). Motherwell, W. B. and Zuberi, S., Tetrahedron Lett., 47, 8789 (2006). Sokeirik, Y. S., Sato, K., Omote, M., Ando, A., and Kumadaki, I., Tetrahedron Lett., 47, 2821 (2006). Shukla, P., Hsu, Y.-C., and Cheng, C.-H., J. Org. Chem., 71, 655 (2006). Perveen, A. and Naqvi, I. I., Chem. Abs., 145, 454674 (2006). Moglie, Y., Alonso, F., Vitale, C., Yus, M., and Radivoy, G., Tetrahedron, 62, 2812 (2006). Song, L.-C., Tang, M.-Y., Su, F.-H., and Hu, Q.-M., Angew. Chem. Int. Ed., 45, 1130 (2006). Daasbjerg, K., Svith, H., Grimme, S., Gerenkamp, M., Mueck-Lichtenfeld, C., Gansaeuer, A., Barchuk, A., and Keller, F., Angew. Chem. Int. Ed., 45, 2041 (2006).

CHAPTER 4

Carbenes and Nitrenes M. Christlieb1 and E. Gras2 1

Gray Institute for Radiation Oncology and Biology, University of Oxford de Chimie de Coordination, Centre National de la Recherche Scientifique, Université de Toulouse

2 Laboratoire

Reviews . . . . . . . . . . . . Structure and Reactivity . . . Generation . . . . . . . . . . Metal-bound Carbenes . . . . Carbenes as Ligands . . Carbenes as Reagents . Addition and Fragmentation Insertion and Abstraction . . Rearrangement . . . . . . . . Nitrenes . . . . . . . . . . . . Nucleophilic Carbenes . . . . Electrophilic Carbenes . . . . Silylenes and Germylenes . . References . . . . . . . . . . .

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Reviews Diazirines are popular precursors for the formation of carbenes and a review of their synthesis and use has addressed the Graham reaction, the diazirine exchange reaction, and radical-initiated exchange in addition to mechanistic details of the diazirine exchange.1 Three Nobel Prize lectures have featured the metathesis reaction in detail, focusing on early results and development from a mechanistic point of view,2 the development of catalytic metathesis reactions,3 and the use of metathesis in the preparation of target molecules.4 Recent editions of Organic Reaction Mechanisms have highlighted a number of carbene and nitrene CH-insertion reactions. This field has now been reviewed with a focus on enantioselective reactions catalysed typically by dirhodium species.5 The use of C2 -symmetric ‘box’ ligands in asymmetric cyclopropanation reactions has been discussed in the context of a wider review of these ligands as a source of asymmetry.6 The chemistry of N -heterocyclic carbenes (NHCs) features strongly in the section on nucleophilic carbenes. In keeping with this interest, the chemistry and reactivity of these species have been reviewed.7 Their reactivity towards small molecules and Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd


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the relevance of the imidazolium salts to ionic liquids are highlighted. NHCs always feature strongly in this publication under the sections on metal-bound carbenes. Normally this is associated with synthesis and transition metals, but their involvement as ligands for f -block metals has been highlighted in a review that discusses NHCs with an alkoxide or amine tether, which allows the lability of the ligand to be studied.8 Silver is often used as a halophile. In the context of six-electron species, the role of silver atoms in carbene, nitrene, and silylene transfer reactions, including aziridination, CH insertion, ring expansion, and silacyclopropanation, has been reviewed.9 Carbenes can be highly reactive but modification of their chemistry through supramolecular encapsulation by cyclodextrins, hemicarcerands, and zeolites has been discussed in a microreview.10

Structure and Reactivity [1,3]Dithian-2-ylidene (2) has been trapped in argon and nitrogen and characterized by IR spectroscopy matrixes after high-vacuum flash pyrolysis (HVFP) of (1).11 The sulfur–carbene interaction has been investigated via DFT calculations. Precursor (1) was shown to be stable up to 100 K and to decompose under irradiation to CS2 and cyclopropane in a Corey–Winter-type reaction. Similar acyclic 1,3-heterocarbenes have also been observed and proved to decompose according to a different path. The conformations of dimethoxycarbene (4), generated from (3), were studied by IR spectroscopy and computations.12 Only s-trans,s-trans-(4)-(tt) and s-cis,s-trans-(4)(ct) were formed in the HVFP, the first being more stable due to dipole moment minimization. Computations have been carried out at the B3LYP/6–311+G(d,p) level of theory on ‘foiled’ carbene.13 Studies of the carbene π -orbital interaction have been achieved by determining stabilization energies, singlet–triplet gaps, and lowest transition states for a range of alkenylidenes. Stabilization is enhanced with ring strain and pyramidalization of the electron-rich double bond. In (5), the stabilization with respect to vinyl shift is expected to preclude the formation of (6) and should favour a retro-Skattebøl rearrangement to allene (7).

N

N

N

O

S

S

(1)

S

S

(2)

(6)

N

O

O

O

O

(3)

O

(4)-(tt)

(5)

+

O (4)-(ct)

(7)

O

155

4 Carbenes and Nitrenes

Theoretical studies indicate that the reaction between CH2 and SO proceeds by an attack on oxygen leading to HS and HCO.14 Similar studies on the reaction of CH2 with HNCO proposed three possible pathways giving different reaction outcomes.15 The singlet–triplet energy gap, the dimerization activation barrier, the 1,2-hydrogen shift, and intermolecular hydrogen transfer have been determined theoretically for a range of NHCs.16 Predictions of the hyperfine coupling constants of triplet carbene have been obtained by DFT calculations and compared with experimental ESR data.17

Generation Transient carbene (9) is expected to be a reaction intermediate in the transformation of butadiyne-linked triazene (8) to alkyne-linked bis-2H -indazoles (10).18 Experimental data and DFT calculations support carbene (9) as an intermediate in this stepwise, nonsynchronous coarctate reaction. Methoxy(methylthio)carbene (12) has been observed by UV photoelectron spectroscopy after gas-phase decomposition of oxadiazoline (11).19 The oxadiazoline (13) allows the generation of the acetoxy(methoxy)carbene (14).20 The reactivity of the latter with isocyanates has been explored. Such reactions generally yield methyl (acetylamino)oxoacetates (15). DFT calculations permitted interpretation of the experimental data.

NH2 N

N

N

N NH2

(8)

NH2 N N

NH2 N N N N

H2N N

H2N

N (10)

(9) O N N

Ac

O S O

N O

S

N Me

(11)

(12)

O O

O

O

Ar (13)

O

Ac R

N

CO2Me

Ac (14)

(15)

156


Cyclopropenylidenelithium (16) (the Yoshida–Weiss reagent) has for the first time been isolated and fully characterized.21 The impact of the counteranion is discussed. A new approach for the generation of NHCs has been reported using a cyclopentadiene(arene)iron complex (17).22 The method converts imidazolium to the free carbene in the presence of oxygen (peroxyradical anion is the base deprotonating the imidazolium salt). A colour change and precipitation of the oxidized iron complex are evidence for the reaction outcome.

Metal-bound Carbenes Carbenes as Ligands NHCs have become ligands almost as common as phosphines. This is widely exemplified in a book edited by Nolan.23 We will therefore limit this overview of ‘carbenes as ligands’ to unusual applications and significant publications regarding their coordination chemistry. The formation of a carbene from (18) in the coordination sphere of (PCy3 )2 RhCl has been studied experimentally and computationally.24 Evidence for an intramolecular C–H activation is provided by isotope labelling and reaction rate studies. These results have been further confirmed by DFT calculations. A wide array of ruthenium catalysts for alkene metathesis have been explored using DFT calculations in order to establish quantitative structure–activity and quantitative structure–properties relationships.25 It has been established that ligands stabilizing the high oxidation state of the intermediate metallacyclobutane (relative to the ruthenium carbene structure) give the most active catalysts. Such a stabilization is achieved for complexes incorporating electron-rich metal (strong σ -donation of the ligand and poor π -back-donation of the metal). Catalytic activity is also enhanced by the bulk of the dative ligand. A fluorine–ruthenium interaction is thought to enhance the catalytic activity of the fluorinated Grubbs II-type catalyst (19).26 This fluorine–ruthenium interaction is expected to take place upon phosphine dissociation. Interestingly, upon similar fluorine substitution, the Grubbs–Hoveyda-type catalyst (20) exhibits a native ruthenium–fluorine interaction but its catalytic activity is significantly decreased compared with the non-fluorinated counterpart. Grubbs–Hoveyda-type catalysts have been shown to have an enhanced activity (both in ring-closing metathesis and in crossmetathesis) when the standard isopropyl moiety is replaced by a 2-substituted methyl propanoate as in (21).27 Compound (21) is an air-stable complex and exhibits an additional coordination of the carbonyl.

Pri2N

+

NPri2

Fe

N

BF4−

N

Li (16)

(17)

(18)

157

4 Carbenes and Nitrenes F

F

F

F N

N

F

F Cl Cl

Ru

Cl

F

Ru

Cl

PriO

Ph

PCy3

MesN

NMes

N

N

(19)

Cl

F

MeO

Ru O Cl O

(20)

(21)

Reaction of ruthenium cyclopentadienyl bisacetonitrile carbene (22) with electronpoor acetylenes yields the allylcarbene (23).28 As evidenced from DFT calculations, the reaction is likely to proceed by NHC insertion into the ruthenium–carbene bond in the metallacyclopentatriene (24). An unexpected reaction of NHC in the coordination sphere of a metal has been disclosed.29 In this example, NHC is not coordinating the metal but is linked to a phosphorus atom with a shift of the carbene centre as shown in (25). Combination of an NHC and lithium hexamethyldisilyamide proved highly beneficial for the outcome of the titanium-catalysed hydroamination of alkynes (mainly terminal ones).30 High yields and complete Markovnikov regioselectivity have been observed. The NHC–Rh(I) (26) provided a highly efficient catalytic activity for cycloaddition towards cyclohexadienes and cycloheptadienes.31 The 4 + 2-cycloaddition can be carried out almost quantitatively both in intra- and inter-molecular fashion within minutes using 2 mol% of the catalyst; 30 min are required with 0.1 mol%. Similar efficiency (in turnover and yield) is achieved in the intramolecular 5 + 2cycloaddition. Interestingly, no intermolecular 5 + 2-cycloaddition occurs, starting materials being recovered unaltered. +

+

+

R′ CH3CN Ru CH3CN

R′

R′

Ru R N

NR RN Pri

Pri

(22)

R′

RN (23)

(24)

R′ = CO2Me, CO2Et, COMe Pri

Pri H RN

NR

Pri2N

Pri

Pri Rh Cl

P (OC)4Mn Mn(CO)4 (25)

NR RN

R′ R=

Ru

(26)

158


Carbenes as Reagents Methylidene–rare earth complexes (27) have been synthesized and fully characterized.32 In these complexes, the methylene should be seen as a doubly charged negative ligand. Nevertheless, these methylidene complexes react as Schrock-type nucleophilic carbenes, (27) therefore being analogous to the Tebbe reagent. Epimerization of vinylcyclopropanes by Grubbs I-type ruthenium catalysts (28) has been explored.33 The reaction can also be effected by the Grubbs–Hoveyda catalyst (29) provided that an additional phosphine is added. Mechanistic studies (experimental and theoretical) suggest that the epimerization goes through a ruthenacyclopentene intermediate (30). Rhodium-catalysed decomposition of methyl diazoacetate (1.2 equiv.) in the presence of 1,3-dithiolane yields mainly dithiane (31) as a mixture of diastereoisomers.34 Ring-expanded product (32) and ring-opened products (33) arising from a second condensation of the carbene are also isolated, albeit in low yield. Similar reactivity is observed with 1,3-oxathiolane. Cp*

THF *Cp Ln THF

Ln

Cl CH2 Cl

Cl Ln

Cp* THF

Cl

PCy3 Cl Ru Cl PCy3 Ph

(27)

H

O Pri

(28)

(29)

CO2Me

S [Ru]

PCy3 Cl Ru Cl

[Ru]

S

CO2Me R1 R2

1

*

*

R R2

S

(30)

(31)

S CO2Me (32)

MeO2C S MeO2C

S Ph (33)

The outcome of Rh(II)-catalysed 1,2-migration from variously substituted diazocarbonyl compounds (34) has been explored as a function of R and R .35 It appears that the steric effect overrides the electronic effect in the formation of alkenes (35a) and (35b).

159


Proline-derived Rh(I) catalyst (36) has been involved in ethyl diazoacetate polymerization.36 The poly(ethyl 2-ylideneacetate) polymers obtained are syndiotactic and have polydispersities slighter higher than 2. Interestingly, switching from rhodium to iridium leads to dimerization, no polymer being observed. Rhenium complex (37) has been used in the ring-opening metathesis polymerization of strained alkenes such as norbornene.37 The alkenes of the polymer backbone are predominantly Z, the polymer exhibiting high molecular weight and polydispersity. Gold(I)-catalysed cycloisomerizations of enynes (38) afford gold–carbene complexes (39) that have been trapped in an intramolecular fashion yielding highly strained tetracycles (40).38

R

O

R

Rh2(OAc)4

Ph

R′

Ph

R′

+

N2 (35a)

ON

Rh

R′

N H (36)

(35b)

[Au]

PR3 Re

O

Ph

(34)

ON

O

O

R

O

Au(I)

X

H

X

R

PR3 Ph

X

Y n

n

Y (37)

(38)

H (39)

(40)

Intermolecular trapping of carbene complexes (39) has also been reported. In this case, a second carbene (41) arising from a cyclopropyl shift from (39) can also be trapped to yield (42).39 DFT studies of the asymmetric cycloisomerization of enyne catalysed by PtCl2 have been carried out at the B3LYP/6–31G(d,p) level.40 The formation of the cyclopropylcarbene intermediate represents the chirality-limiting step. Rearrangements of 1,3-diynes (43) to dienynes (45a) and (45b) have been carried out; catalytically a metal–carbene intermediate (44) is likely to be involved.41 Interestingly, gold catalysis provides mainly (45a) whereas platinum catalysis under a CO atmosphere yields predominantly (45b). Intramolecular trapping of the transient carbene postulated above has also been achieved yielding polyunsaturated bicycles (47) from the diene–diyne precursor (46).42 The intramolecular cyclopropanation is preceded by a [1,3]-metallotropic shift.

ee

160


[Au]

H

OAc

R

X

R

X

AcO (41)

(42)

(43)

OAc OAc

[M] (44)

AcO OAc

OAc +

OAc

OAc OAc

(45a)

(46)

(45b)

OAc AcO

(47)

161


An overview describing the applications of group VI Fischer carbenes in carbo- and hetero-cyclization arising from the Barluenga group has appeared.43 The reactivity of alkenyl and alkynyl Fischer carbenes (48a) and (48b) with dimethylaminodiazafulvene (49) has been explored.44 A wide array of imidazole-containing polycycles are accessed in a highly convergent process. Reaction of crowded chromium alkenyl Fischer carbene (50) with bulky ketene acetals provides an interesting entry to 3-substituted pent-1-ynoate (53).45 Formation of the alkyne can be rationalized by a 1,4-nucleophilic addition of the ketene on the unsaturated carbene complex (crowded complexes will not undergo potential 1,2addition), following by oxonium (51) formation and fragmentation to a vinylidene carbene complex (52), which undergoes a 1,3-shift to the alkynylchromium complex leading the alkyne after reductive elimination. NMe2

OMe

OMe

(OC)5M

(OC)5M

N R

R

(48a)

(49)

(48b)

+

OPri

PriO

(OC)5Cr

OPri

O

−

OPri OPri

(OC)5Cr R1

R1

(50)

R

N

1

(51)

O

(OC)5Cr OPri

(53)

PriO OPri OPri

C R1 (52)

Chromium alkenyl Fischer carbenes have been shown to undergo a 3 + 2-cyclization with allenes under Rh(I) catalysis and a CO atmosphere, yielding 2-alkylidenecyclopentanone (54) after acidic hydrolysis.46 Reactions with electron-rich allenes are carried out with a neutral rhodium complex whereas electron-poor allenes require a

162


cationic rhodium complex. The mechanism is thought to proceed through a Cr–Rh metal exchange under the CO atmosphere followed by 4 + 2-metallacycloaddition and reductive elimination. Kinetics of the hydrolysis of chromium Fischer complexes (55)–(57) in a 50:50 water–acetonitrile medium have been studied.47 The rate-limiting step is the formation of (56), and the rate constant of the addition of water to the carbene is clearly controlled by the steric bulk of the R group in (55) varying from 5.3 to 0.01 l mol−1 s−1 . Intermolecular O–H insertions of phenyl diazoacetate with various alcohols have been reported to proceed with high enantioselectivities under catalysis by Cu(II) complexes of (58).48 The presence of water proved crucial to achieving high ees, which correlate linearly with catalyst ee. Moreover, a clear isotopic effect has been highlighted. The Rh(II)-catalysed intramolecular C–H insertion of diazoacetamide in water has been studied.49 This study assessed the factors governing the preferential intramolecular C–H insertion versus O–H insertion with the solvent. The hydrophobic/hydrophilic nature of the amide substituent appeared to be the most significant contribution driving the reaction towards C–H insertion. The nature of the rhodium catalyst precursor also modifies the reaction outcome [Rh2 (OAc)4 enhancing the O–H insertion]. Intermolecular C–H insertion of diazoacetate (59) into the bisallylic position of cyclohexa-1,4-dienes (60) followed by DDQ oxidation of the substituted cyclohexadiene gave the polysubstituted arenas (61) in medium to very good overall yields.50 O R4

O R (OC)5Cr

R3

R1

Ph

O R OH Ph

CH3CN H2O

(OC)5Cr

OH (OC)5Cr Ph

R2 (54)

R5

Fe N Fe

R1

R3

R5

CO2R6 N2

CO2R6

R1

R3

R2

R4

(59)

N R2

(58)

(57)

(56)

(55)

R4

(60)

then DDQ

(61)

1,4-Dihydropyrazines (62) have been accessed via double Rh(II)-catalysed N–H insertion of 2-diazocycloalkanedione (63) on anilines (64).51 Low yields are obtained as a consequence of inefficient double N–H insertion.

ee

163


Vinyldiazolactone (65), a stable vinylcarbene precursor, has been involved in C–H insertion with cyclohexadiene yielding the bicycle (66) with moderate yield and good ee, especially when azetidinone–rhodium complexes (67) were used.52 Competition between C–H insertion and cyclopropanation is always observed. The cyclopropanation reaction on classical alkenes is more efficient in terms of yields, de, and ee.

ee

R R

O O

N2

O

+

N n n

O

NH2

n

N H (62)

(64)

(63)

CO2R

O

O N2

O

N

O O

(65)

(66)

Rh2 4

(67)

Two DFT studies (one in Chinese and one in English) of the cyclopropanation of ethene with samarium(II) carbenoids have been reported.53,54 The reaction path is likely to involve a methylene transfer rather than a carbometallation with or without coordination of up to two THF molecules to the rare earth. Double cyclopropanation of furans and pyrroles with aryl diazoacetates catalysed by Rh2 (S-DOSP)4 have been reported to occur with opposite stereochemistry depending on the nature of the heterocycle.55 Better yields and ees are achieved for tricycles (69) derived from furan than for (68) derived from more bulky pyrroles. Monocyclopropanation (with high yields and ees) is achieved on the furan ring of benzofuran, whereas double cyclopropanation of the indole is observed. The effect of substrate structure on enantioselectivity has been explored for the catalytic intramolecular cyclopropanation reaction of α-diazo-β-keto arylsulfones.56 It has especially been shown that substitution of the phenyl ring by a methyl at the ortho position of the sulfonyl group dramatically increased the ees, with values up to 93%.

Addition and Fragmentation In contrast with its reaction with NHC, CO addition to acyclic and cyclic alkylaminocarbenes (70) forms aminoketenes (71).57 The structure of the ketene has been

ee

ee

164


fully studied (experimentally and theoretically). Involving the nitrogen in a cycle allowed its lone pair to conjugate with the ketene moiety; nevertheless, this interaction remains weak. The mechanism of the cycloaddition of singlet dimethylmethylene to acetone has been explored theoretically.58 The reaction is thought to proceed in two steps via a high-energy intermediate that isomerizes to the three-membered ring via an energy barrier of 22.2 kJ mol−1 . Additions of bromofluorocarbenes to 6-phenylbicyclo[3.2.0]hept-6-ene (72) have been shown to yield a mixture of various indanes (73), which probably arise from the formal ring expansion (cyclopropanation–ring opening) of (74) and (75), themselves coming from ring opening of the cyclopropane obtained by addition of the carbene to (72).59 H

MeO2C

H

CO2Me

Ar

Ar H

X

N H Boc

H

MeO2C

H

CO2Me

Ar

Ar H

X = O, NBoc

(68)

O

H

(69)

R1 R2

RnN

CO n = 1,2

R1 R2

RnN C O (71)

(70) Ph

Ph

Ph

F

Ph F

F

X X = F, Br (72)

(73)

(74)

(75)

4 -(2,2-Difluorospirocyclopropane) analogues (77) of nucleosides have been synthesized by addition of difluorocarbene to (76).60 Radical-mediated deoxygenation of the 2 -position leaves the difluorocyclopropane untouched whereas deoxygenation of the 3 -position induces a ring opening to (78). Difluoro(methylene)cyclopropanes have been obtained in modest yields from allene by difluorocarbene addition.61 The difluorocyclopropane moiety proved stable upon

165


functionalization of the remaining double bonds by Heck reaction or through lithiation. Ring opening was achieved using CuI–I2 . Fluorinated dihalocarbenes have been used as central synthons in the synthesis of fluorinated aromatics from cyclopentadienes.62 The reaction proceeds via a fluorinated fused bicyclic cyclopropane, which upon heating undergoes a ring opening to achieve the ring expansion of the second cycle. Ion pairs of similar structure are thought to be generated in polar solvents upon fragmentation of oxychlorocarbene (79), chlorocarbonate (80), and chlorosulfite (81).63 They all lead to similar mixtures of 2-chloro-5-norbornene (82) and 3-nortricyclyl chloride (83). The stereochemical outcome of the reaction is mainly due to the tight ion pair, implying least motion chloride return. F

F

F

B

O

F

B

O

O

(76)

B

O

OH

(77)

(78)

B = adenin-9-yl, cytosin-1-yl, utacil-1-yl O O Cl

X O

Cl

Cl

Cl (79)

(80): X = C (81): X = S

(82)

(83)

Insertion and Abstraction The insertion of an NHC (84) into a non-acidic CH bond has been studied in depth.64 The mechanism, kinetics, and catalysis by an amide base (K-HMDS) were all investigated. The carbene was found to be stable to dimerization and inserted slowly into a methyl CH bond of toluenes to give aminals (85). The rate of aminal formation was strongly dependent on the para-substituent (Hammett ρ − value of 4.8 ± 0.3). The rate-determining step is CH bond cleavage, which occurs with a late transition state. Abstraction reactions involving alkylidenecarbenes have been characterized by DFT methods.65 The transition states were examined at the B3LYP/6–311G(d,p) level of theory using the intrinsic reaction coordinate. The electronegativity of the substituents played an important role in predicting reactivity.

166


Intramolecular C–H insertion reactions, N–H insertion reactions, and intermolecular C–H insertion reactions of aminocyanocarbenes (NCC:NX2 , X = H, CH3 , CF3 ) have been studied using restricted and unrestricted CCD, CCSD, QCISD, B3LYP, and MP2 methods with the 6–31G(d), 6–311+G(d,p), cc-pVDZ, and cc-pVTZ basis sets. 66 HC:NH2 , NCC:NH2 , NCC:N(CH3 )2 , and NCC:N(CF3 )2 have singlet ground states.

Rearrangement Silver clusters 2.5 nm in diameter displayed unusual electrocatalytic properties in Wolff rearrangements of diazoketones.67 The reaction proceeds with electron transfer to and from the silver cluster. The presence of an α-ketocarbene/ketene was confirmed using pyridine as a nucleophilic probe and by UV–visible spectroscopy. Electrochemistry was used to support the role of the silver particles in the rearrangement. The rearrangement of 27 different singlet carbenes to alkenes (or their analogues) was studied by AM1 SCF-MO theory. Four effects were considered: bystander group(s) at the migration origin; various substituent groups at the migration terminus; variations in ring size for cyclic carbenes; and methyl migration instead of hydrogen.68 The interconversion of bicyclo[2.2.1]hept-2-yne (86) and 5-bicyclo[2.1.1]hexylidenecarbene (87) has been studied.69 The authors claim that their results, in combination with those of an earlier study, give unambiguous support for a rapid equilibrium between the cycloalkyne and the carbene. The results presented comprise careful analysis of product mixtures. The rearrangements of 3,3-diphenylcyclobutylidene (88) and 2,2-diphenylcyclobutylidene (89) are revealed to be affected significantly by the diphenyl substitution.70 The former undergoes a 1,2-hydrogen shift whereas the latter prefers a 1,2-carbon shift. The data were acquired by steady-state and LFP experiments and the mechanism was probed by MRMP2//MP2 calculations. Treatment of dihalospiropentanes (90) with alkyllithiums generates carbenoid species (91) following metal–halogen exchange.71 The carbenoids rearrange to cyclobutenes (92), which typically undergo a second lithium–halogen exchange before dimerizing in 44–75% yield. Ph N

N

PhMe

N

(84)

N

(85)

(86)

(87)

167

4 Carbenes and Nitrenes Ph

R1

Ph

X

Li

R1

X

X

MeLi

Ph Ph

R1 (88)

(89)

R1 (90)

(91)

R1

X

X

R1 (92)

Nitrenes A substantial 267-article review covers the theoretical treatment of nitrenes.72 Further reviews address the kinetics, spectroscopy, and computational chemistry of arylnitrenes73 and the generation of nitrene species catalysed by transition metal complexes.74 Optically active sulfonimidamides react with benzylic and allylic methylene groups to give the formal product of nitrene CH insertion.75 The reaction is catalysed by dirhodium complexes and delivers rather mixed results, both de and yield being substrate dependent. The authors finish the transformation by removing the sulfonimidamide by reduction to leave a benzylic or allylic amine. The singlet–triplet splitting energy was calculated for formylnitrene and for the syn- and anti -rotamers of carboxynitrene HOC(O)N: by the CCSD(T) method.76 The results were compared with DFT findings (which overestimate splitting) and with experimental data obtained by photolysis. The ring expansion of singlet ortho-substituted phenylnitrenes (93) (X = H, CH3 , CN, NH2 , NO2 , OH, F, SH, Cl) was studied by semiempirical AM1 SCF-MO methods.77 The two-step rearrangement involves nitrene atom insertion into the phenyl ring to give a bicyclic azirine intermediate (94), which undergoes electrocyclic ring opening to yield the monocyclic ketenimine product (95). The first step of azepine formation is predicted to be the rate-determining step and is favoured by electronwithdrawing substituents. The ring expansion is predicted to be favoured towards the unsubstituted side of the ring. The thermal Curtius rearrangement of formyl, acetyl, and benzoyl azides was studied by DFT.78 The authors conclude that the reaction occurs by a concerted mechanism and not by the alternative nitrene intermediate. 2,6-Difluorophenylnitrene was reinvestigated in Ar matrices at 10 K by UV–visible and IR spectroscopy. DFT and CASSCF/CASPT2 calculations were also used. Both

de

168


neutral rearrangement products (the bicyclic azirine and the cyclic ketenimine) of a phenylnitrene were prepared and characterized for the first time. X-irradiation was used to generate radical cations and it was shown that phenylnitrene and cyclic ketenimine yield stable radical cations, whereas the bicyclic azirine decays to both of these compounds on ionization.79 Sulfoximine- and phenanthrene-based N -alkoxyaziridines decompose under photochemical conditions to give oxynitrenes.80 The first EPR spectra of oxynitrenes were reported and were consistent with triplet ground states. Trapping and reactivity studies, nanosecond time-resolved IR investigations, and computational studies all support a triplet ground state. Argon matrix photolysis of tetrazolo[1,5-a]quinazoline/2-azidoquinazoline (96) gave a nitrene (97) which was observable by ESR, UV, and IR spectroscopy.81 The reactions of this nitrene were characterized and included fragmentation to radical species (98), rearrangement to cycloheptatetraene (99), and ring opening to a new nitrene (100).

N

N

X

X

(93)

(94)

N N

X

N

(95)

N

N N

N

N N (96)

(97)

N

N (100)

N

N

N N (99)

CN

N (98)

CN

A gold-catalysed nitrene transfer reaction gave aziridine products.82 The nitrene source was a sulfonamide in combination with a commercially available oxidant [PhI(OAc2 )]. The best catalyst was [Au(4,4 ,4 -tri-t-butyl-2,2 :6 ,2 -terpyridine)]OTf loaded at 3 mol%. The reaction worked well with mono- and di-substituted alkenes but not with alkenes fitted with electron-withdrawing groups. NsNH2 was by far the best nitrene source, other sulfonamides giving significantly worse results. The second aziridination reported in 2006 used a diphenylphosphoryl azide as the nitrene source and was catalysed by a cobalt–porphyrn complex.83 Yields were modest (< 68%) and the catalyst loading was relatively high at 5–10 mol%.


169

A Curtius rearrangement was reported as the key step in the synthesis of protected anilines and aromatic ureas.84 The reaction is a single step from the corresponding carboxylic acid and produces urea or aniline, depending on the conditions. A nitrene generated from the reaction of N -aminophthalimide (101) and PhI(OAc)2 was key to the metal-free ring expansion of alkylidenecyclopropanes (102) and an alkylidenecyclobutane.85 The authors propose two plausible mechanisms for these ring-expansion reactions: either an aziridine is formed which undergoes facile rearrangement to form the final 2,2-disubstituted cyclobutylidene hydrazine product (103), or reaction of the alkylidenecyclopropane with the nitrene generates an ionic or diradical species which rearranges. Nitrenes generated from PhINTs and copper acetoacetate react with thietanes to form isothiazolidines.86 The initially formed S–N donor–acceptor complex undergoes ring expansion with retention of stereochemistry. Yields range from 56 to 76%. An optically active ruthenium catalyst allows the asymmetric synthesis of aziridines from alkenes and sulfonylazides.87 Catalyst loadings are 0.1–2 mol% although the yields and ees are rather variable; at best the reaction works well, TsN3 and PhCCCH CH2 giving the corresponding aziridine in 98% yield and 98% ee. Use of 2-(trimethylsilyl)ethanesulfonyl (SES) azide and styrene gave good results for both yield (99%) and ee (92%), but the SES group is easily removed to give the unprotected aziridine.

ee

Nucleophilic Carbenes Asymmetric triazolium salts were employed in synthesis to catalyse benzoin reactions to give optically active benzo-fused cyclohexanes.88 The triazolium salts are loaded at 10–20 mol% and react in situ with base to give the NHCs, which are the real catalytic species. Yields of products were high (85–92%) and ees modest to good (61–98%). This report differs from those discussed in previous editions of ORM in that the benzoin reaction is intramolecular. A reaction with many of the same mechanistic features is the hydroacylation of α-keto esters with aldehydes.89 Choice of solvent switches the reaction between α-acyloxy- (in CH2 Cl2 ) and α-hydroxy ester products (in MeOH/EtOH). The process is tolerant of electron-rich aldehydes, but the yields are generally lower when electron-deficient systems are employed. Using a mixture of deuterated benzaldehyde and non-deuterated 4-methylbenzaldehyde gave all four possible products, implying a reversible reduction step separate from the acylation event. Closely related to hydroacylation is cyanosilylation.90–93 Yields were above 80% and catalyst loading was between 1 and 0.01 mol%. In one case the reactions were rendered mildly asymmetric by the use of C2 -symmetric NHCs. The formation of cyclopentenes from the reaction of α,β-unsaturated aldehydes with α,β-unsaturated ketones is catalysed by NHCs.94 Typical yields are 70–90%. Reaction of the carbene with the aldehyde reverses the polarity of the unsaturated aldehyde and allows the β-carbon to act as a nucleophile towards the β-carbon of the ketone. Thiazolium, imidazolium, and triazolium salts were each investigated as possible precatalysts for the ring opening of cyclopropanes (104) to give δ-ketoaldehydes (105).95 Catalyst loading was 5 mol%, the product chirality being derived from the starting material rather than the catalyst. Both diazolium and thiazolium salts were

ee

170


also used to ring open aziridines with aldehydes.96 At 20 mol% loading of the carbene precursor, the reaction only barely qualifies as catalytic; however, the reaction works well with a variety of aromatic and aliphatic aldehydes. The reactions were run in air and the products show attack by a carboxylic anion rather than the expected acyl anion. The authors note that exclusion of air yields the expected product of attack by acyl anions. In a second example, the NHC reacts with acid anhydrides to liberate the carboxylic anion, which acts as the nucleophile.97 O R

NPhth

1

N NH2

R1

R2

R2

O (101)

(102)

O

(103)

O

Ph

H

NHC

Ph

H O

Ph (104)

Ph

O

(105)

Chiral NHCs formed adducts with aldehydes that underwent enantioselective oxodiene Diels–Alder reactions with enones.98 The NHC only needed to be added at 0.5 mol% to achieve yields >70% and ees in the high 90s. The NHC class of nucleophilic carbenes are also bases. The proton–deuteron exchange of NHCs attached to macromolecules has been studied and the influence of counterion has been explored.99 Substitution, both directly on the imidazolium unit and on the pre-orientating calixarene backbone, was also studied. The results showed that substitution of the imidazolium salts has a large influence on the H–D exchange rates in wet methanol-d4 . These results were presented as having implications for Suzuki coupling. An unusual reaction of a diazolium salt was reported during an attempt to form copper complexes of the NHC.100 The isolated products showed ring expansion of the carbene to form six-membered lactams. The authors verified the product by X-ray crystallography and independent synthesis. It is not clear where the extra carbon comes from. The authors consider a possible mechanism involving a carbene dimer formation, but point out that the carbenes are very hindered. Possible reaction with atmospheric carbon dioxide was not considered. Direct oxidation of the carbene to give a urea is also noted. Diazolium and triazolium salts have been used in O- to C-acyl transfer reactions.101 The reaction works well (67–82% yield) in the presence of pyrrolidine > piperidine.7 Kinetic studies have also been reported of the selective substitution of chlorine at the 2-position in methyl 2,4-dichloro-3,5-dinitrobenzoate by aliphatic amines in methanol and in benzene. Here nucleophilic attack is rate limiting and the effect of variations in the nature of the nucleophile and solvent were discussed.8 The hydroxy-dehalogenation of activated haloarenes in alkaline water or water– DMF solvents has been shown to be accelerated by the addition of hydrogen peroxide. The mechanism is likely to involve aryl hydroperoxide intermediates.9 There has been a study of the phenoxy-denitration reactions of 4-nitrophthalonitrile by the Rphenol–potassium carbonate system in DMF and DMF–water solvents. The ratelimiting step is thought to depend on the substituent, R, in the phenol, and changes from phenol deprotonation with weakly acidic phenols to SN Ar substitution with more acidic phenols.10 Reaction of 4-substituted nitroarenes with alkanethiols in DMSO containing caesium carbonate may result in displacement of the nitro group. Dithiols may yield products resulting from substitutions by both thiol groups.11 The vicarious amination of nitrobenzene and 5- and 6-nitro-1-methylbenzimidazoles has been reported by use of 4-amino-1,2,4-triazole in DMSO containing potassium t-butoxide. In the case of the benzimidazoles the yield was increased on the addition of cuprous chloride and ESR spectroscopy indicated the presence of radical anions derived from the substrates.12 The oxidative substitution of hydrogen is an alternative to the vicarious mechanism when the nucleophile does not carry a good leaving group. Oxidative substitutions by phosphorus-stabilized carbanions have been reported and an example using a phosphazene derivative is shown in Scheme 2. The addition of dichlorodicyanobenzoquinone (DDQ) may aid the oxidation step.13 Substitution of hydrogen in nitroarenes by an oxazoline-stabilized carbanion has also been reported. Addition occurs para to the nitro group and oxidation of the anionic intermediate with DDQ yields substituted nitroarenes whereas oxidation with dimethyldioxirane (DMD) leads to substituted phenols.14 Deprotonation of pentafluoroacetonitrile by a guanidine-like base has been shown to yield a carbanion which will displace fluoride from a second molecule, resulting in the formation of a dimer. Further deprotonations may result in trimers and tetramers.15

O2N

(1)

NO2

O

NO2

NO2

NO2

+

NH2

R

+ B k−1

k1

O

k2

NO2

NH2

+

R

NO2

_

Scheme 1

O2N

O2N

O2N

O2N

+ B

NO2

NH

kBH+

kB

O 2N

NO2

R

O2N

NO2

+

O

NO2

_

NO2

NO2

OH

NH

R

NO2 + B

+ BH+

5 Nucleophilic Aromatic Substitution

177

178

Organic Reaction Mechanisms 2006 NP(O)(OPh)2 Me NP(O)(OPh)2 + Li+

Me

PPh2

_

PPh2 NO2

NO2 Scheme 2

There have been several reports of the use of intramolecular displacements of nitro groups in the synthesis of heterocyclic compounds. Thus, reaction16 of the intermediate (2) with a strong base in DMF results in the substitution of a nitro group by the amide function to yield a dibenzothiazepinone derivative (3). Nucleophilic addition across the double bond of 2,4,6-trinitrostyrene may occur with thiophenol, aniline, and aliphatic amines. The adducts so formed with primary amines may undergo intramolecular substitution of an o-nitro group to give N -substituted 4,6-dinitroindoles.17

O S

O

S

NHR NO2

N R

NO2

NO2 (3)

(2)

Reaction of 1,3,5-trinitrobenzene (TNB) with o-aminophenols in the presence of potassium carbonate in dipolar aprotic solvents has been shown to produce 1,3dinitrophenoxazines (5). This reaction is thought to involve nitro group displacement to yield intermediates (4), which undergo oxidative substitution of hydrogen by the amino group.18 The corresponding reaction of TNB with o-aminothiophenols yields 1,3-dinitrophenothiazine derivatives. O

O2N

R

O

O 2N

H2N NO2

NO2 (4)

N H (5)

R

179


The reaction of N -(2,4-dinitrophenyl)amino acids with base in aqueous dioxane has been shown to give benzimidazole N -oxides (7). The rate-determining step is likely to be formation of an N -alkylidene-2-nitrosoaniline intermediate (6), which is followed by rapid cyclization and decarboxylation.19 The loss of carbon dioxide from perbenzoate anions has been investigated by mass spectrometry and electronic structure calculations. The results, including isotopic labelling experiments, support a mechanism involving initial intramolecular nucleophilic attack at either the ortho- or ipso-ring positions. They also indicate that epoxides may be intermediates en route to the phenoxide products.20 There has also been a theoretical study of the formation of trichlorinated dibenzo-p-dioxins by reaction of 2,4,5-trichlorophenolate ions with 2,4-dichlorophenol.21 −

N

NH N

NO2 (6)

R

CRCO2

N

O

O

NO2 (7)

The kinetics of the piperidino-defluorination reaction of 1-fluoro-2,4-dinitrobenzene have been studied in non-aqueous reverse micelles consisting of ethylene glycol– AOT–n-heptane or DMF–AOT–n-heptane. The reaction, which is not base catalysed, is accelerated when DMF, a non-hydrogen bond donor solvent, is used in the micelle core.22 Catalysis by human glutathione S-transferase M 1a–1a of the reaction of glutathione with 1-chloro- and 1-fluoro-2,4-dinitrobenzenes has been investigated. Much stronger enzymatic catalysis was observed in the case of the dechlorination reaction than for the defluorination and a transition-state model was proposed.23 Both experimental and theoretical studies have been reported of fluoro-denitration and fluoro-dechlorination reactions using anhydrous tetrabutylammonium fluoride in DMSO. The absences of ion pairing and strong solvation are critical in contributing to the reactivity of the fluorinating agent.24 Quaternary ammonium salts derived from cinchona alkaloids have been shown to be effective catalysts in an improved asymmetric substitution reaction of β-dicarbonyl compounds with activated fluoroarenes. The products may be functionalized to yield spiro-oxindoles.25 There is continued expansion in the use of metals as catalysts in substitution reactions. Copper(I) iodide in the presence of N ,N -dimethylethylenediamine has been shown to be effective in the intramolecular substitution of aryl bromides carrying an o-1,3-dicarbonyl substituent; reaction may involve either an oxygen centre or a carbon centre of the dicarbonyl moiety.26 The reaction of aryl halides with sodium trifluoroacetate in the presence of copper(I) iodide may lead to the formation of the trifluoromethylated derivatives, possibly via CF3 CuI− as an intermediate.27 There have been theoretical calculations, PM3 and ab initio, on complexes formed from copper

180


chloride and bromobenzene in the presence of either quinolin-8-ol or bipyridyl.28 It has been shown that the use of copper(II) salts as catalysts with oxygen as the oxidant may be effective in the oxidative substitution of ring hydrogen by nucleophiles including halides and acetoxy ions; a mechanism involving single electron transfer (SET) is likely.29 Catalysis by cobalt(II) has been reported in the reaction of the aryl copper compound (8) with aryl fluorides to produce polyfunctional biophenyls.30 Cu(CN)MgCl

CN (8)

There has been a summary explaining how the use of reaction kinetics may help in the interpretation of complex catalytic reaction schemes; examples include palladiumcatalysed coupling reactions of aryl halides.31 A short review has been published on the use of hydrophilic ligands for palladium in aqueous-phase reactions involving aryl halides.32 A new palladium catalyst containing a rigid tripodal phosphorus-based ligand has been used successfully in Suzuki couplings, such as the reaction of 4bromoanisole with phenylboronic acid.33 The use of a new bulky phosphoramidate ligand for the palladium catalyst has been reported in the debromohydrogenation reaction of (9), the chromium tricarbonyl complex of dibromonaphthalene; the product is formed in a highly enantiomerically enriched form.34 Br

Br Cr(CO)3 (9)

Diastereoselectivity has also been achieved in the intramolecular double-Heck cyclizations of some cyclohexene diamides to form spirocyclic oxindoles; the structural features responsible for imparting diastereoselection in the first35 and second36 ringclosure reactions have been examined. The results of studies of the Heck vinylation of aryl bromides with 2-substituted enol ethers using a tetraphosphine–palladium catalyst have been reported; the stereoselectivity of the reaction depends on both steric and electronic factors with the Z-isomers being favoured for electron-rich or sterically congested aryl bromides.37 Use of a PdCl2 (PCy3 )2 catalyst in dioxane in the presence of caesium carbonate has been shown to allow the efficient coupling of aryl chlorides with alkenes to form the E-isomers; this catalyst system has the advantage that it

de

181


allows reaction with both electron-rich and electron-poor aryl chlorides under mild conditions.38 A procedure has been developed for the palladium-catalysed α-arylation of amides by aryl bromides using the zinc enolates of the amides. The reaction works well with bromoarenes carrying a variety of ring substituents and with bromopyridine. In addition, the reaction has been shown to be effective with morpholine amides to give products which are precursors for aldehydes and ketones.39 A new method has been reported for the allylation of aryl halides using homoallyl alcohols as the allyl source; the palladium-catalysed reaction, which may be both stereo- and regio-sepecific, uses a retro-allylation reaction to form a σ -allyl(aryl)palladium intermediate.40 A ruthenium catalyst derived from a secondary diaminophosphine oxide has been used successfully in the arylation of C–H bonds by aryl tosylates.41

Heterocyclic Systems Kinetic studies have been reported of the reactions of a series of 2-substituted-5nitrothiophenes (substituent = Br, OMe, OPh, OC6 H4 -4-NO2 ) with secondary amines in room-temperature ionic liquids. The kinetic behaviour is similar to that of the corresponding reactions in methanol so that most reactions do not show base catalysis. The observation that reactivity is higher in the ionic liquids than in methanol (or benzene) is attributed to relatively poor solvation of the reagents by the ionic liquids. As in conventional solvents, 2-bromo-3-nitrothiophene shows higher reactivity than 2-bromo-5-nitrothiophene.42 Solvent effects on the kinetics of the alkaline hydrolysis of 2-phenylthio-3,5-dinitropyridine in aqueous organic solvents have been analysed.43 Reaction of 9-chloroacridine with aryl sulfonyl hydrazides results in aminodechlorination to give the corresponding N -acridinylbenzenesulfonyl hydrazides; kinetic studies in methanol and DMSO have been reported.44 Reaction of electron-deficient heteroaryl chlorides with tertiary amines may proceed by quaternization and dealkylation, as shown in Scheme 3. These reactions occur under mild conditions, e.g. acetonitrile solvent at room temperature, and in THF may be accelerated by the addition of lithium chloride.45 A highly regioselective amination of 6-aryl-2,4-dichloropyrimidines has been developed using palladium catalysis. The reaction which works well with secondary aliphatic amines and with anilines gives the 4-substituted products.46 Palladium catalysis has also been used in the regioselective coupling of 2,3-dibromopyridine with a series Cl−

R2 R3

Cl N Ph

N + N

R2 N R3

R1

N+

N Ph

N

N N

Scheme 3

R2

R3

R1 N Ph

N N

+ R1Cl

de

182

Organic Reaction Mechanisms 2006 Br

Br

N

+ N

Br

Pd catalysis

N

H2N

N

N H Cu catalysis

N N

N

Scheme 4

of aminoazines including 2-aminopyridines. As shown in Scheme 4, the first step involves palladium-catalysed intermolecular aminodebromination whereas the second, intramolecular, step uses copper catalysis to form dipyrido[1,2-a:2 ,3 -d]imidazole.47 The regioselectivity in the methoxydefluorination reactions of difluoroquinolines has been examined.48 Studies of the substitution patterns in 2-cyano-3-nitroimidazole[1,2a]pyridine have shown that nitrogen and oxygen nucleophiles substitute the 2-cyano group whereas sulfur nucleophiles replace the 3-nitro group.49 4,5-Dicyanopyridazine may react with pyrrole and indole systems as a heterocyclic azadiene in IEDDA Diels–Alder reactions. However, in acetic acid as solvent reaction occurs by substitution of CN at the 4-position and intermediates such as (10) may be isolated.50 Reaction of dichloropyrazines with a dithiane anion in THF may result in a tele-substitution process, as shown in Scheme 5, in which initial nucleophilic attack occurs at an unsubstituted ring position. Deprotection of the substituted product yields the corresponding aldehydes.51

HN

CN

Me N

N CN (10)

Substitution of chloride in a variety of heterocyclic chlorides by esters, lactones, amides and lactams has been shown to occur in toluene in the presence of hexamethyldisilazide (NaHMDS) acting as a base.52 An example using a chlorothiadiazole derivative is shown in Scheme 6. There has been a report53 of a mild and convenient method for the introduction of tetrafluoroethyl substituents into nitrogen heterocycles using the reaction of hexafluoropropane with azine and azole N -oxides.

183

5 Nucleophilic Aromatic Substitution N Cl

N

N

Cl

H

N

+

S Cl

S Li

N

S

S

Cl H

S

S

−HCl

Cl

N

H

deprotection

Cl

N

CHO

N

H

Scheme 5

CO2But

Cl N

N

N S

O +

N S

CH3C OBut Scheme 6

A study of the effects of surfactants on the reaction of 2-(4-cyanophenoxy)quinoxaline with hydroxide ions has shown that rate accelerations caused by cetyltrialkylammonium chlorides may be due to reaction in premicellar aggregates or in micelles.54

Meisenheimer and Related Complexes 4,6-Dinitrobenzofuroxan (DNBF) is known as a superelectrophile due to its high reactivity both as an electrophile and in its pericyclic addition reactions. NMR studies show that reaction with 2-aminothiazole and its 4-methyl derivative yield anionic carbon-bonded adducts such as (11) by reaction at the 5-position, whereas the 4,5dimethyl derivative reacts via the exocyclic amino group. Kinetic studies of the first two compounds, both in acetonitrile and in 70:30 (v/v) water–DMSO, have been used to assess their carbon nucleophilicities and place them on the Mayr nucleophilicity scale.55 In a related study, the nucleophilic reactivity, in acetonitrile, of a series of indoles with both DNBF and with benzhydryl cations have been compared and used to determine nucleophilicity parameters for the indoles.56 There has been a comparison of the kinetics, in water over a wide pH range, of the formation of hydroxy adducts from 4,6-dinitrobenzofurazan (12) with those of its

184

Organic Reaction Mechanisms 2006 N H2N

O

H S O2N

N O N NO2_ (11)

HO O 2N

N X N

+

H2O

+

HO−

H

O2 N

N X

+ H+

N NO2−

NO2 (12), X = O (13), X = S (14), X = Se Scheme 7

sulfur (13) and selenium (14) analogues. As shown in Scheme 7, these reactions may involve the attack of water, producing a proton, or direct attack of hydroxide ions. The pKa values for these processes are 3.92 for (12), 6.34 for (13), and 7.86 for (14), showing (12) to be the strongest electrophile of the three. All three compounds also react with dienes to give Diels–Alder mono- or di-adducts and there is a relationship between this pericyclic reactivity and the ability to form σ -adducts. In turn, these abilities are inversely related to the degree of aromaticity in the heterocycles.57 The reaction of 7-chloro-4,6-dinitrobenzofurazan with 2-(4 -bromophenyl)indolizine has been shown to result in carbon–carbon bond formation by substitution of the 7chloro substituent.58 However, in the reaction of 7-chloro-4,6-dinitrobenzofuroxan the initial substitution is followed by intramolecular oxygen transfer from the N oxide function and by rearrangement to give the zwitterionic spiro-adduct (15). An Br

+

O O2N

N N O N

NO2− (15)

185


intramolecular substitution involving an oxygen–carbon spiro-adduct has been postulated59 during a stereoselective two-fold Wittig rearrangement in a 1,1 -binaphthyl derivative. The X-ray crystallographic structure of an anionic 1,3-dioxolane spiroadduct with a tetrabutylammonium cation has been reported and compared with the structure with a potassium cation.60

Benzyne and Related Intermediates There has been a summary of the use of insertion reactions of arynes into σ -bonds to prepare ortho-disubstituted arenes. A key to the success of these processes is the ability to generate benzyne under mild conditions by the reaction of readily available o-(trimethylsilyl)phenyl triflate with fluoride ions.61 Reaction of amines and their derivatives with benzynes generated in this way has been shown to be an efficient method for the production of N -arylated derivatives, as illustrated in Scheme 8. The method also works well in the O-arylation reactions of phenols and carboxylic acids.62 R

R

TMS +

PhNH2

CsF MeCN

OTf

NHPh

Scheme 8

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Pazo-Llorente, R., Maskill, H., Bravo-Diaz, C., and Gonzalez-Romero, E., Eur. J. Org. Chem., 2006, 2201. Beletskaya, I. P., Sigeev, A. S., Peregudov, A. S., and Petrovskii, P. V., Mendeleev Commun., 2006, 250. Bini, R., Chiappe, C., Marmugi, E., and Pieraccini, D., Chem. Commun. (Cambridge), 2006, 897. Wu, K., Dolbier, W. R., Battista, M. A., and Zhai, Y., Mendeleev Commun., 2006, 146. Vlasov, V. M., Chem. Abs., 146, 228709 (2006). Crampton, M. R., Emokpae, T. A., and Isanbor, C., J. Phys. Org. Chem., 19, 75 (2006). Crampton, M. R., Emokpae, T. A., Isanbor, C., Batsanov, A. S., Howard, J. A. K., and Mondal, R., Eur. J. Org. Chem., 2006, 1222. Fathalla, M. F. and Hamed, E. A., J. Chem. Res., 2006, 413. Cantrell, W. R., Bauta, W. E., and Engles, T., Tetrahedron Lett., 47, 4249 (2006). Plakhtinskii, V. V., Abramov, I. G., Abramova, M. B., and Yasinskii, O. A., Chem. Abs., 145, 27458 (2006). Kondoh, A., Yorimitsu, H., and Oshima, K., Tetrahedron, 62, 2357 (2006). Titova, I. A., Vakul’skaya, T. I., Larina, L. I., Mizandrontsev, M. I., Volkov, V. A., Dolgushin, G. V., and Lopyrev, V. A., Chem. Abs., 145, 7561 (2006). Andujar Sanchez, C. A., Iglesias, M. J., Lopez, J. G., Perez Alvarez, I. J., and Lopez Ortiz, F., Tetrahedron, 62, 3648 (2006). Makosza, M., Lorusso, P., and Troisi, L., Chem. Abs., 144, 273821 (2006). Gierczyk, B., Schroeder, G., and Brzezinski, B., Chem. Abs., 145, 314345 (2006). Smirnov, A. V., Kalandadze, L. S., Sakharov, V. N., and Dorogov, M. V., Mendeleev Commun., 2006, 262. Sapozhnikov, O. Yu., Mezhnev, V. V., Dutov, M. D., and Shevelev, S. A., Chem. Abs., 145, 188252 (2006). Dutov, M. D., Vorob’ev, S. S., Serushkina, O. V., Shevelev, S. A., Ugrak, B. I., and Kakala, V. V., Mendeleev Commun., 2006, 230.

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Bujan, E. I. and Salum, M. L., J. Phys. Org. Chem., 19, 187 (2006). Harman, D. G., Ramachandran, A., Gracanin, M., and Blanksby, S. J., J. Org. Chem., 71, 7996 (2006). Suarez, E., Suarez, D., Menendez, M. I., Lopez, R., and Sordo, T. L., ChemPhysChem, 7, 2331 (2006). Correa, N. M., Durantini, E. N., and Silber, J. J., J. Phys. Org. Chem., 19, 805 (2006). Patskovsky, Y., Patskovska, L., Almo, S. C., and Listowsky, I., Biochemistry, 45, 3852 (2006). Sun, H. and DiMagno, S. G., Angew. Chem. Int. Ed., 45, 2720 (2006). Kobbelgaard, S., Bella, M., and Jorgensen, K. A., J. Org. Chem., 71, 4980 (2006). Fang, Y. and Li, C., J. Org. Chem., 71, 6427 (2006). Chang, Y. and Cai, C., Chem. Abs., 144, 149861 (2006). Orlov, V. Yu., Krinitsina, G. V., and Milto, V. I., Chem. Abs., 144, 411981 (2006). Chen, X., Hao, X.-S., Goodhue, C. E., and Yu, J.-Q., J. Am. Chem. Soc., 128, 6790 (2006). Korn, T. J., Schade, M. A., Wirth, S., and Knochel, P., Org. Lett., 8, 725 (2006). Mathew, J. S., Klussman, M., Iwamura, H., Valera, F., Futran, A., Emanuelsson, E. A. C., and Blackmond, D. G., J. Org. Chem., 71, 4721 (2006). Shaughnessy, K. H., Eur. J. Org. Chem., 2006, 1827. Ciclosi, M., Lloret, J., Estevan, F., Lahuerta, P., Sanau, M., and Perez-Prieto, J., Angew. Chem. Int. Ed., 45, 6741 (2006). Kundig, E. P., Chaudhuri, P. D., House, D., and Bernardinelli, G., Angew. Chem. Int. Ed., 45, 1092 (2006). Overman, L. E. and Watson, D. A., J. Org. Chem., 71, 2587 (2006). Overman, L. E. and Watson, D. A., J. Org. Chem., 71, 2600 (2006). Battace, A., Zair, T., Doucet, H., and Santelli, M., Tetrahedron Lett., 47, 459 (2006). Yi, C. and Hua, R., Tetrahedron Lett., 47, 2573 (2006). Hama, T., Culkin, D. A., and Hartwig, J. F., J. Am. Chem. Soc., 128, 4976 (2006). Hayashi, S., Hirano, K., Yorimitsu, H., and Oshima, K., J. Am. Chem. Soc., 128, 2210 (2006). Ackermann, L., Althammer, A., and Born, R., Angew. Chem. Int. Ed., 45, 2619 (2006). D’Anna, F., Frenna, V., Noto, R., Pace, V., and Spinelli, D., J. Org. Chem., 71, 5144 (2006). Fathalla, M. F., Int. J. Chem. Kinet., 38, 159 (2006). Sondhi, S. M., Bhattacharjee, G., Jameel, R. K., Kumar, A., and Bajaj, K., Chem. Abs., 144, 170511 (2006). Hamilton, G. L. and Backes, B. J., Tetrahedron Lett., 47, 2229 (2006). Peng, Z.-H., Journet, M., and Humphrey, G., Org. Lett., 8, 395 (2006). Loones, K. T. J., Maes, B. U. W., Meyers, C., and Deruytter, J., J. Org. Chem., 71, 260 (2006). Politanskaya, LV., Malysheva, L. A., Beregovaya, I. V., Bagryanskaya, I. Y., Gatilov, Y. V., Malykhin, E. V., and Shteingarts, V. D., Chem. Abs., 145, 7560 (2006). Arias, L., Salgado-Zamora, H., Cervantes, H., Compos, E., Reyes, A., and Taylor, E. C., J. Heterocycl. Chem., 43, 565 (2006). Cecchi, M., Micoli, A., and Giorni, D., Tetrahedron, 62, 12281 (2006). Torr, J. E., Large, J. M., Horton, P. N., Hursthouse, M. B., and McDonald, E., Tetrahedron Lett., 47, 31 (2006). Shen, H. C., Ding, F.-X., and Colletti, S. L., Org. Lett., 8, 1447 (2006). Loska, R. and Makosza, M., Mendeleev. Commun., 2006, 161. Cuenca, A., Int. J. Chem. Kinet., 38, 510 (2006). Forlani, L., Tocke, A. L., Del Vecchio, E., Lakhdar, S., Goumont, R., and Terrier, F., J. Org. Chem., 71, 5527 (2206). Lakhdar, S., Westmaier, M., Terrier, F., Goumont, R., Boubaker, T., Ofial, A. R., and Mayr, H., J. Org. Chem., 71, 9088 (2006). Lakhdar, S., Goumont, R., Boubaker, T., Mokhtari, M., and Terrier, F., Org. Biomol. Chem., 4, 1910 (2006). Kurbatov, S., Tatarov, A., Minkin, V., Goumont, R., and Terrier, F., Chem. Commun. (Cambridge), 2006, 4279. Schlosser, M. and Bailly, F., J. Am. Chem. Soc., 128, 16042 (2006). Borbulevych, O. Ya., Chem. Abs., 144, 283498 (2006). Pena, D., Percy, D., and Guitian, E., Angew. Chem. Int. Ed., 45, 3579 (2006). Liu, Z. and Larock, R. C., J. Org. Chem., 71, 3198 (2006).

CHAPTER 6

Electrophilic Aromatic Substitution

R. G. Coombes Department of Chemistry, University College London General . . . . . . . . . . Halogenation . . . . . . . Nitration . . . . . . . . . Alkylation, Acylation, and Other Reactions . . . . . References . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Related Reactions . . . . . . . . . . . . . . . . . . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

. . . . . .

187 188 189 190 199 200

General The wide scope of application of the electrophilicity index of Parr, Szentpály, and Liu has been reviewed.1 Applications to electrophilic aromatic substitutions discussed are few. However, some alkylation and acylation reactions do correlate well with electrophilicity values. In the case of the nitration of toluene and chlorobenzene, correlation is not very good and it is suggested2 that electrophilicity is a kinetic quantity with inherent thermodynamic information. A quantitative description of the reactivity of monosubstituted benzenes to electrophilic substitution based on considerations of inductive effect parameters and conjugative effect parameters from the 13 C chemical shifts of the aromatic compounds has been proposed.3 MO calculations on the proton migration in the ipso adducts formed in the reaction of CH3 + and SiH3 + with benzene have been described.4 With SiH3 + the ipso adduct is the most stable of possible isomers, whereas for CH3 + the para-protonated isomer is the most stable. A DFT study of the reactivity of pyridine and the diazabenzenes towards electrophilic substitution, assuming frontier orbital control of the reactions, predicts their low reactivity as the HOMOs of these substrates are not π -orbitals.5 For pyridine-N oxide, however, the HOMO is an aromatic orbital. DFT studies giving Fukui indices predict6 the preferred sites of electrophilic attack on pyrrole, furan, and thiophene and calculation of the local softness of the reactive sites rationalizes relative reactivities. 2-Aminothiazole and its 4-methyl derivative react with the superelectrophilic 4,6dinitrobenzofuroxan at C(5) to form, for example, (1) in spite of them exhibiting higher nitrogen basicity than aniline.7 In the case of 4,5-dimethyl-2-aminothiazole, however, attack did occur at nitrogen. Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd


187

188

Organic Reaction Mechanisms 2006 NO2−

Me NO2

N O

5 +

N O−

S

H

NCl

Me +

O N Cl

O

N X

NH3 N

(1)

(2)

(3) a; X = H b; X = Cl

Halogenation A review indicates that only strong electrophilic fluorinating agents are suitable for the ipso fluorodesilylation of arylsilanes.8 Weaker N–F-type reagents, e.g. Selectfluor, give low yields together with side products. Kinetic isotope effect studies of the fluorination of aromatic compounds with N–F-type reagents are consistent with a polar SE Ar mechanism where the decomposition of the Wheland intermediate is not rate limiting.9 Studies of the fluorination of 1,3,5-trideuterobenzene demonstrated the occurrence of 1,2-hydrogen and deuterium migrations in the Wheland intermediates, the first time such a process has been demonstrated in electrophilic fluorination. The kinetics of the chlorination of phenol and 2-naphthol by 1,3-dichloro-5,5dimethylhydantoin (2) in aqueous acidic media have been interpreted10 in terms of an initial rate-limiting formation of a charge-transfer complex between the substrate and the chlorinating agent. A kinetic study of the chlorination of nine aryl ethers by 1-chlorobenzotriazole in acetic acid has also led to mechanistic conclusions.11 The direct iodination of aromatic compounds has been the subject of a review12 which, inter alia, points out that many of the novel modern methods are less successful with deactivated arenes than with activated aromatic compounds. A new reagent consisting of NaIO4 –KI–NaCl in aqueous acetic acid has been found to iodinate a number of activated aromatics, including even 2-nitroaniline.13 Reaction involving intermediate iodine monochloride is suggested. An MO theoretical study14 has been made of the iodination of pyridine, quinoline, and their N -oxides in neutral and protonated forms by a number of iodinating agents and direct iodination enthalpies have been calculated. The chlorination, bromination, and iodination of the proton sponge 5,6-bis(dimethylamine)acenaphthylene by halogens and by N -halosuccinimides have been studied.15 With bromine and iodine, reaction gives initial addition at C(1)=C(2). However, chlorination with N -chlorosuccinimide is directed ortho to the NMe2 groups, giving 4-chloro- or 4,7-dichloro-substituted derivatives in excellent yields. The scope of palladium-catalysed chelate-directed chlorination, bromination, and iodination of arenes using N -halosuccinimides has been explored.16 For example, compound (3a) forms (3b) in 95% yield on reaction with N -chlorosuccinimide in acetonitrile at 100 ◦ C in the presence of 1–2 mol% palladium acetate.

189

6 Electrophilic Aromatic Substitution

Nitration Theoretical calculations and gas-phase mass spectrometric studies have been performed for the reaction of naked and monosolvated nitronium ions with some monosubstituted aromatics, and these lead to a detailed mechanistic scheme for electrophilic aromatic nitration.17 The scheme comprises a continuum of pathways in which the single electron transfer and the classical polar mechanism are extremes. The importance of either mechanism depends on the ease of transfer of an electron from the substrate to the nitronium ion and this also governs the regioselectivity observed, meta-directing groups favouring the classical polar mechanism. MO calculations of the nitrations of benzyl alcohol and benzyl fluoride indicate18 that both have ortho–para-directing substituents but that the presence of the fluorine atom deactivates the system, whereas the hydroxyl group activates the system. The products and kinetics of nitration of chlorobenzene in a nitric acid–mineral acid system have been investigated19 to obtain information about possible adjustment of product ratio. The mononitration of phenols by a range of metal nitrates in acetone at 25 ◦ C in the necessary presence of catalytic p-toluenesulfonic acid gives highly regioselective ortho substitution, phenol, for example, giving an 85% yield of onitrophenol with Ni(II) nitrate.20 A PPh3 –Br2 –AgNO3 mixture stirred in acetonitrile at room temperature is a mild and effective chemoselective reagent for the nitration of aromatic amines.21 N -Methylaniline, for example, gives a 100% yield of nitro-N methylanilines (ortho:para = 15:78) even in the presence of anisole, which did not react. The nitration of triphenylamine derivatives by Cu(NO3 )2 in acetic anhydride at room temperature proceeds readily, introducing up to three nitro groups.22 Reaction NO2

O2N

NO2

Br N

OH OH OH OH

Br

NO2

O2N

NO2

(4)

(5) Ar

Me3SiO

Et2NSF3

R1 (6)

R2

ArH, r.t., 5 min

Ar or R1 (7)

R2

R2

R1 (8)

190


of 4,4 ,4 -tribromotriphenylamine gives a complicated mixture of products involving nitrodebromination on one or more rings and bromination at other sites [e.g. to form, inter alia, (4)]. The nitration of calix[4]arenes and calix[6]arenes by nitrogen dioxide to form p-nitro derivatives [e.g. (5) in 90% yield] has been investigated.23

Alkylation, Acylation, and Related Reactions MO calculations on the alkylation of aromatic compounds by alkyl halides catalysed by group 13 trihalides have shown that a pathway involving the dimeric form of the catalyst is more favourable, both thermodynamically and kinetically.24 This is in agreement with available experimental data suggesting the use of an excess of the metal halide (ratio close to 2:1). The reaction of tertiary cyclopropyl silyl ethers (6) with diethylaminosulfur trifluoride in an electron-rich aromatic compound (ArH) as solvent gives alkylated or cyclopropylated aromatic compounds [(7) or (8)].25 Compound (10), for example, is formed from (9) in furan. Enantioselective alkylation of simple aromatic ethers by ethyl 3,3,3-trifluoropyruvate (CF3 CO.CO2 Et) occurs using the Cu(OTf)3 complex (11) as a catalyst under solvent-free conditions [e.g. (12) from p-bromobenzyl phenyl ether in 91% ee].26 Me

p-MeOC6H4

Ph

p-MeOC6H4 O

(9)

Me

O

Me3SiO

(10)

O N

Ph

ee

N

Ph

Cu TfO OTf Ph (11)

p-BrC6H4CH2O

F3C

CO2Et OH (12)

A regioselective and highly syn-stereoselective catalyst-free intermolecular alkylation of aryl borates with aryl epoxides under mild, neutral conditions has been reported.27 The reaction of trans-stilbene oxide with tri(3,5-dimethylphenyl)borate gave a 38% yield (>95% syn) of the C-alkylated product (13), easily separated from the O-alkylated product(s). Triflic anhydride has been used to activate enones to nucleophilic attack by electron-rich arenes in the presence of a sterically hindered base.28 Resorcinol dimethyl ether, for example, reacted with cyclohex-2-en-1-one to

de

191

6 Electrophilic Aromatic Substitution Me

OTf

Ph

OMe HO

H Ph

H OH (13)

O

Me Ph

Me

MeO (14)

(15)

give a 45% yield of the enol triflate (14). Intramolecular examples of the reaction were also reported. The alkylation of phenol with t-butyl alcohol in supercritical water at 673 K produces some interesting results.29 The products are 2-isobutylphenol, 2-tbutylphenol, and 4-t-butylphenol. Isobutene is believed to be a reaction intermediate and the 2-isobutylphenol is formed by an anti-Markovnikov addition to the alkene in which the hydroxyl group participates. Propargylic alcohols bearing a terminal triple bond react with electron-rich aromatic compounds in the presence of thiolate-bridged diruthenium complexes to give the propargylated aromatic compounds.30 1-Phenylprop-2-yn-1-ol, for example, reacts with 2-methylfuran to form (15). Intramolecular examples of the reaction were also reported. The process is believed to involve electrophilic attack by the rutheniumstabilized propargyl cation. The [3]cumulene derivative (16) reacts with electron-rich heteroaromatics (e.g. furan) in the presence of 50 mol% Yb(OTf)3 to form the tetrasubstituted conjugated diene [e.g. (17)].31 Samarium diiodide has been investigated as a catalyst for reaction of various electron-rich aromatics with chelating electrophiles, e.g. alkyl 3,3,3trifluoropyruvates.32 With these electrophiles α-hydroxy esters are formed in good yield with complete regioselectivity [for example, (18) is formed from the methyl trifluoropyruvate and N ,N -dimethylaniline in 99% yield]. In reactions involving ethyl glyoxylate or a glyoxylic imine, α-hydroxy esters and α-amino esters are obtained, respectively, together with variable amounts of products resulting from further aromatic substitution [e.g. (19) from the former reactant with N ,N -dimethylaniline]. A review of catalytic protocols for the ring-closing alkylation and alkenylation reactions of arenes has appeared.33 Recent enantioselective strategies are covered and it is noted that the development of effective catalytic systems for practical stereoselective alkylations remains a challenge. 10-(3-Methoxybenzyl)-9,10-dihydroanthacen-9-ols (20) undergo a transannular ring closure in the presence of acid to form the corresponding homotriptycenes (21) in almost quantitative yields.34 Reaction of α-alkylcinnamaldehydes with ortho-esters, alcohols, or thiols in the presence of BF3 .OEt2 forms 1-alkoxy-2-alkylindenes [e.g. (22) from α-methylcinnamaldehyde and HC(OMe)3 ].35 It is suggested that initially alkoxylation of the carbonyl carbon of the aldehyde forms an acetal, which loses alkoxide to give a carbonium ion (23) and subsequently a geometric isomer (24) in which an intramolecular electrophilic substitution occurs to form the indene ring system.

ee

192


Ph

•

H

Me

•

Me

Ph

Ph

CHO

OH CF3 CO2Me

Me2N

CHO O

(16)

(17); E:Z = 1.0:2.0

(18) NMe2

Me2N

H

CO2Et

(19)

OMe OMe R2 R1

R2 R1

H+

Me OMe

OH (20) +

OMe +

Me

(21)

(22)

OMe

+

OMe

Me

(23)

Me

(24)

Superacid-catalysed intramolecular reactions of some dicationic electrophiles have been investigated.36 The positively charged centres migrate apart and this chemistry gives a new synthetic route to aza-polycyclic compounds. The polycyclic compound (26) can, for example, be formed from reaction of 2-phenyl-3-(1-hydroxy-2-phenylethyl)quinoline (25) with CF3 SO3 H at 25 ◦ C, loss of water and benzene being involved. Highly diastereoselective polycyclization of homo(polyprenyl)arenes [e.g. (27) →

de

193

6 Electrophilic Aromatic Substitution OH Ph N N

Ph

(25)

(26)

Me

Me SnCl4 −78 °C

4

H R3SiO Me

OSiR3 (2E)-2-, (2Z)-2- and 1-enyl mixture (27)

R = Pri

(28)

O Me

O Ph

Me

Ph

CF2 F

(29)

(30)

(28)] having terminal siloxyvinyl groups is catalysed by 10 mol% tin(IV) chloride.37 Structural variables, including the bulk of the silyl group, enabled the stereochemistry at C(4) to be altered. 2,2-Difluorovinyl ketones bearing an aryl group [e.g. (29)] undergo a facile electrophilic cyclization38 involving carbocations, which are stabilized by α-fluorine atoms, on treatment with a trimethylsilylating agent to form 4-fluorinated 3-acyl-1,2-dihydronaphthalenes [e.g. (30)]. Much work in the review period has concerned enantioselective substitution in five-membered heterocyclics. The enantioselective alkylation of some pyrroles by α,βunsaturated 2-acylimidazoles catalysed by the bis(oxazolinyl)pyridine–scandium(III) triflate complex (31) has been reported.39 Compound (33) is formed in 98% yield and 94% ee from the 2-acylimidazole (32) and pyrrole at −40 ◦ C. A series of enantiomerically pure aziridin-2-ylmethanols has been tested as catalysts in the alkylation of N -methylpyrrole and N -methylindole by α,β-unsaturated aldehydes.40 Enantiomeric excesses of up to 75% were observed for the alkylation of N -methylpyrrole by (E)-crotonaldehyde using (2S,3S)-3-methylazirin-2-yl(diphenyl)methanol TFA salt as catalyst to form (34). Novel axially chiral bis-arylthioureas [e.g. (35)] catalyse the asymmetric substitution of indole and N -methylindole by nitroalkenes.41 2-Nitroethenylcyclohexane is

ee ee

ee

194


O

O

N N

Sc

TfO

N OTf

OTf (31) H O

Me

N

O

Me N

N

N

Ph

N

Ph

(32)

(33) CF3

H N Me

Me

S

O

(34)

H N

F3C

N H

H N

N H

CF3

S CF3 (s-trans, cis) (35)

converted on reaction with N -methylindole into (36) with 43% ee. Zn(II) complexes of bisoxazolines [e.g. (37a)] catalyse the enantioselective alkylation of indoles by nitroalkenes giving products in up to 90% ee.42 Related catalysts [e.g. (38)] also catalyse the alkylation of indoles with nitroalkenes, this time in up to 98% ee.43 The catalyst is believed to act in a bidentate fashion, the nitroalkene being activated through coordination of the nitro group to the Lewis acid centre and the NH group in the catalyst acting as a donor for the NH · · · π (indole) interaction. Some bifunctional 6 -OH Cinchona alkaloid derivatives catalyse the enantioselective hydroxyalkylation of indoles by aldehydes and α-keto esters.44 Indole, for example, can react with ethyl glyoxylate to give mainly (39) in 93% ee. The enantioselective reaction of indoles with N -sulfonyl aldimines [e.g. (40)] is catalysed by the Cu(OTf)2 complex of (S)-benzylbisoxazoline (37b) to form 3-indolylmethanamine derivatives, in up to 96% ee [e.g. (41a)].45 Some 9-thiourea Cinchona alkaloids have been found to catalyse the formation of 3-indolylmethanamines [e.g. (41b)] from indoles and N -PhSO2 -phenylimines in ∼90% ee.46 Aryl- and alkyl-imines also give enantioselective reactions.

ee ee

ee

ee ee

195


Me NO2

Me O

O

N H

N

N

O

.Zn(OTf)2 N

N

O

R

R N

Ph

Ph

Ph

Ph

Me (36)

(37) a; R = Ph b; R = Bn

(38)

HO *

X

CO2Et

Ar NHX

N

*

Ar

N H

X = Ts or Ns

(39)

(40)

N H (41) a; X = Ts or Ns b; X = SO2Ph, Ar = Ph O

Me

Ph

Ph O Me O

O Me

Me

OH

Ph (42)

N H (43)

The reaction of (1R)-8-phenylmenthyl glyoxylate with various furans catalysed by SnCl4 or particularly magnesium salts (e.g. MgBr2 ) occurs with high yields and high diastereoselectivities (>90%) to form furan-2-ylhydroxyacetic acid esters [e.g. (42)].47 The heteropoly acids, H3 PMo12 O40 and H3 PW12 O40 , have been found to be excellent catalysts48 for the alkylation of a range of indoles and pyrrole by enones and β-nitrostyrene in water as solvent. Chalcone and indole form (43) at room temperature. Easy work-up was achieved without the use of organic solvents. The kinetics of reaction of four indoles with a number of benzhydryl cations has allowed the determination of the nucleophilicity parameters N and S for these reactions.49 Kinetic data from the reaction of a number of indoles with 4,6-dinitrobenzofuroxan then allow determination of their N values. Correlation of these data with those for protonation at C(3) of 5-substituted indoles and 5-substituted 2-methylindoles

de

196


demonstrates that the 2-methyl group sterically hinders the approach of 4,6-dinitrobenzofuroxan to the C(3) position. The quantitative data from reactions of indoles with some other electrophiles were also analysed by this reactivity parameter approach. Indoles are alkylated regioselectively by α,β-unsaturated acylbenzotriazoles (44) catalysed by samarium(III) iodide under reflux in THF to form new 3-substituted indoles [e.g. (45)].50 The formation of β-(3-indolyl)ketones from the alkylation of indoles by (E)-α,β-unsaturated ketones is effectively promoted by 30 mol% of equimolar pyrrolidine and perchloric acid in CH2 Cl2 .51 MO calculations have been reported on the alkylation52 of indole by dimethylalkylidenemalonates suggesting that the hydrogen-transfer process becomes rate limiting in alcoholic solvents. Reaction of the 1-acetylvinyl acrylates (46) with furan or thiophene in the presence of BF3 .Et2 O at −78 ◦ C occurred solely at C(2) in the vinyl moiety, this position being more reactive than C(3 ) in the acrylic moiety.53 MO calculations are in agreement with this regioselectivity.

R

O

O

N

R

N

N

N

R1

O

R2

O

N N N H (44)

3'

O

2

R1 = H, R2 = Me (46) R1 = Me, R2 = H

(45)

The competing pathways in the reactions of intermediate 1-alkylidene-2-oxyallyl cations (47) with furan have been investigated.54 Cycloaddition pathways compete with the electrophilic substitution pathway which initially forms the cation (48) from which a number of products may form. Recent progress in the palladium-catalysed direct arylation of simple arenes involving both intra- and inter-molecular reactions has been reviewed.55 The review includes a mention of mechanistic aspects. A new PdII -catalysed method for the direct 2arylation of indoles and pyrrole has been reported.56 This IMesPd(OAc)2 -catalysed

Ar

N H

• +

Me

+O

N

OR Me

Me

Pd

OR

Me

R = Me or SiMe3 (47)

(48)

(49)

I

197


reaction with [Ph2 I+ ][BF4 − ] gave regioselectively 2-substitution; the [Ph2 I+ ][BF4 − ] could be prepared in situ from PhB(OH)2 and PhI(OAc)2 . It is believed that initial electrophilic palladation at C(3) is a key step in these reactions. The reaction of an aryl(iodo)palladium(II)(bpy) complex (49) with 2,3-dibromothiophene in the presence of AgNO3 –KF gives arylation at C(5).57 It is suggested that electrophilic palladation, activated by the AgNO3 –KF, followed by reductive elimination, occurs. An experimental and theoretical study of some palladium-catalysed intramolecular arylation reactions, including the observation that (50) cyclizes mainly to (51), precludes an SE Ar mechanism and indicates that proton abstraction by a carbonate or related ligand occurs in the step which determines selectivity.58 Aryl tosylates have been shown to be arene arylating reagents in the presence of an optimized ruthenium catalyst and potassium carbonate in N -methylpyrrolidinone.59 The catalyst is prepared in situ from RuCl2 (p-cymene)2 and (52) and could, for example, catalyse the reaction between 2-oxazolinyltoluene and 4-methoxyphenyl tosylate to give (53). F

F F

F

F

F

Br (50) Pri

(51) Pri

H N

O P

O

N

N

OMe

Me

Pri

Pri (52)

(53)

The dehydrative acylation of arenes by carboxylic acids has been investigated with a range of Lewis and Brønsted acid catalysts at high temperatures. Eu(NTf)2 shows the best performance at 250 ◦ C and catalyses efficiently the acylation of alkyl- and alkoxybenzenes by aliphatic and aromatic carboxylic acids.60 HNTf2 is also a useful reagent, catalysing the acylation of anisole in refluxing toluene by carboxylic acids with azeotropic removal of water. Cyclopenta[c]pyran-3-yl derivatives (54a–c) are acylated by trifluoroacetic anhydride to form the 7-(trifluoroacetyl)cyclopenta[c]pyrans, although (54d) is the main product from (54b).61 Compound (54e), formed from (54c), readily undergoes further reaction to form the anions (55a) and (55b).

198

Organic Reaction Mechanisms 2006 CF3

O

•

R

R1

N−

O

O R2 O (54) a; b; c; d; e;

R1 = CO2Me, R2 = H R1 = CH2OH, R2 = H R1 = CN, R2 = H R1 = CH2COCF3, R2 = COCF3 R1 = CN, R2 = COCF3

CF3

(55) a; R = H b; R = COCF3

Details of the sequence of steps in the thionyl chloride-mediated transformation of 4-carboxy-3,4-dihydro-3-phenyl-1(2H )-isoquinolines into indeno[1,2-c]isoquinolones have been elucidated62 and it is confirmed that the dehydrogenation precedes the electrophilic cyclization [of (56)]. Intramolecular acylation in suitable aromatic aldehydes occurs in the presence of IPy2 BF4 and HBF4 to form benzocyclic ketones.63 For example, (58) can be formed by cyclization of (57) in 74% yield. Two plausible mechanistic pathways have been suggested. Cl

O

O

MeO

O N

MeO

OHC

Me

O

O (56)

(57)

NH

Ha

N H

HN

(58)

199


Other Reactions Recent experimental developments in coupling IR spectroscopy techniques with mass spectrometry, which allow the structural characterization of isolated and microsolvated protonated aromatic molecules in the gas phase have been summarized.64 Hydrogen–deuterium exchange has been observed at Ha in (59) and some closely related substrates when this ligand is complexed to CuI in [2 H6 ]acetone.65 The process is finely controlled by the precise coordination distance required to form agostic interaction between Cu(I) and the C–H bond and is believed to involve the enol form of [2 H6 ]acetone and a reversible Cu(I) to Cu(III) interconversion. Kinetic data for the ortho position azo coupling of substituted benzenediazonium cations with three activated naphthalene derivatives give good correlations with Hammett σ -values of the substituents66 and the data indicate a transition state near in energy to that of the Wheland intermediate. MO calculations67 on the trimethylsilylation of pyrrole and N -alkylpyrroles have been reported in full and studies of sulfonation by SO3 also pursued. Suggestions are made to reconcile the predictions as to regioselectivity with the experimentally observed β-substitution in the reactions. Studies of the chlorosulfonylation of calix[6]arenes have indicated the importance of ipso substitution involving displacement of But groups.68 When alternate OH substituents at the small rim are O-alkylated by a protonatable imidazole group (60), the units containing a methoxy group can be selectively chlorosulfonyldealkylated at room temperature [to give (61a)] and further reaction [to give (61b)] can take place at higher temperature.

N

N

+

N

Me

OMe

O

OMe

O

But

But

SO2Cl

R

Me

N

3 (60)

H 3X−

3

(61) a; R = But b; R = SO2Cl

Studies of the reactivity of 4,6-dinitrobenzofuroxan with substituted indoles have been mentioned above.49 Some reactions involving organometallic species are of interest. Protonation69 of (ArN=CMe–CMe=NAr)PtPh2 complexes yields Pt(II)phenyl–π -benzene complexes in non-coordinating solvents. The Pt(II) species undergo dynamic exchange processes involving C–H bond cleavage reactions probably involving Pt(IV) hydridodiphenyl

200


Me Me Me Me N N Na Zn But N But

N

N = N, N, N′, N′ (62)

Me Me Me Me N N Na Zn But N

NMe2 tetramethylethylenediamine (63)

intermediates giving large kinetic isotope effects. DFT calculations70 have shown that intramolecular hydrogen bonding to acetate can provide a low energy pathway to C–H activation of some aromatic systems with iridium where a {Cp∗ Ir(I)} moiety gives electrophilic activation of C–H bonds. The heterometallic species (62) induces meta deprotonation of N ,N -dimethylaniline, causing meta zincation to (63) and giving a proposed route to meta-substituted derivatives.71 The reagent can also effect dizincation and monozincation of naphthalene at the 2,6- and 2-positions, respectively.72

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Chattaraj, P. K., Sarkar, U., and Roy, D. R., Chem. Rev., 106, 2065 (2006). Chattaraj, P. K., Sarkar, U., Roy, D. R., Elango, M., Parthasarathi, R., and Subramanian, V., Chem. Abs., 145, 396875 (2006). Yang, J. and Yu, S., Chem. Abs., 145, 7668 (2006). Ignat’ev, I. S. and Kochina, T. A., Chem. Abs., 145, 7592 (2006). D’Auria, M., Chem. Abs., 144, 432332 (2006). Mekelleche, S. M., Ghomri, A., and Morell, C., Chem. Abs., 144, 330910 (2006). Forlani, L., Tocke, A. L., Del Vecchio, E., Lakhdar, S., Goumont, R., and Terrier, F., J. Org. Chem., 71, 5527 (2006). Tredwell, M. and Gouverneur, V., Org. Biomol. Chem., 4, 26 (2006). Borodkin, G. I., Zaikin, P. A., and Shubin, V. G., Tetrahedron Lett., 47, 2639 (2006). Rao, A. K. S., Sundar, B. S., and Radhakrishnamurti, P. S., Chem. Abs., 144, 191723 (2006). Kannappan, V. and Hemalatha, G., Chem. Abs., 144, 22485 (2006). Hanson, J. R., J. Chem. Res., 2006, 277. Emmanuvel, L., Shukla, R. K., Sudalai, A., Gurunath, S., and Sivaram, S., Tetrahedron Lett., 47, 4793 (2006). Siyanko, P. I. and Funk, A. A., Chem. Abs., 144, 128512 (2006). Mekh, M. A., Ozeryanskii, V. A., and Pozharskii, A. F., Tetrahedron, 62, 12288 (2006). Kalyani, D., Dick, A. R., Anani, W. Q., and Sanford, M. S., Tetrahedron, 62, 11483 (2006). de Queiroz, J. F., de M. Carneiro, J. W., Sabino, A. A., Sparrapan, R., Eberlin, M. N., and Esteves, P. M., J. Org. Chem., 71, 6192 (2006). Chen, L.-T. and Xiao, H.-M, Chem. Abs., 144, 330886 (2006). Dai, C.-b., Niu, H.-b., and Zhang, Y.-l., Chem. Abs., 144, 22497 (2006). Anuradha, V., Srinivas, P. V., Aparna, P., and Rao, J. M., Tetrahedron Lett., 47, 4933 (2006). Iranpoor, N., Firouzabadi, H., Nowrouzi, N., and Firouzabadi, D., Tetrahedron Lett., 47, 6879 (2006). Wu, X., Dube, M. A., and Fry, A. J., Tetrahedron Lett., 47, 7667 (2006). Yu, F.-J. Yang, H.-J., and Li, Y., Chem. Abs., 145, 376745 (2006). Volkov, A. N., Timoshkin, A. Y., and Suvorov, A. V., Chem. Abs., 144, 191719 (2006) Kirihara, M., Noguchi, T., Kakuda, H., Akimoto, T., Shimajiri, A., Morishita, M., Hatano, A., and Hirai, Y., Tetrahedron Lett., 47, 3777 (2006).

6 Electrophilic Aromatic Substitution 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 70 71 72

201

Zhao, J.-L., Liu, L., Sui, Y., Liu, Y.-L., Wang, D., and Chen, Y.-J., Org. Lett., 8, 6127 (2006). Bertolini, F., Crotti, P., Macchia, F., and Pineschi, M., Tetrahedron Lett., 47, 61 (2006). Grundl, M. A., Kaster A., Beaulieu, E. D., and Trauner, D., Org. Lett., 8, 5429 (2006). Sato, T., Ishiyama, Y., and Itoh, N., Chem. Lett., 35, 716 (2006). Inada, Y., Yoshikawa M., Milton, M. D., Nishibayashi, Y., and Uemura, S., Eur. J. Org. Chem., 2006, 881. Asakawa, T., Iinuma, M., Furuta, T., Fujii, S., Kan, T., and Tanaka, K., Chem. Lett., 35, 512 (2006). Soueidan, M., Collin, J., and Gil, R., Tetrahedron Lett., 47, 5467 (2006). Bandini, M., Emer, E., Tommasi, S., and Umani-Ronchi, A., Eur. J. Org. Chem., 2006, 3527. Gao, C., Cao, D., Xu, S., and Meier, H., J. Org. Chem., 71, 3071 (2006). Jobashi, T., Kawai, A., Kawai, S., Maeyama, K., Oike, H., Yoshida, Y., and Yonezawa, N., Tetrahedron, 62, 5717 (2006). Li A., Kindelin, P. J., and Klumpp, D. A., Org. Lett., 8, 1233 (2006). Uyanik, M., Ishihara, K., and Yamamoto, H., Org. Lett., 8, 5649 (2006). Ichikawa, J., Kaneko, M., Yokota, M., Itonaga, M., and Yokoyama, T., Org. Lett., 8, 3167 (2006). Evans, D. A. and Fandrick, K. R., Org. Lett., 8, 2249 (2006). Bonini, B. F., Capitò, E., Comes-Franchini, M., Fochi, M., Ricci, A., and Zwanenburg, B., Tetrahedron: Asymmetry, 17, 3135 (2006). Fleming, E. M., McCabe, T., and Connon, S. J., Tetrahedron Lett., 47, 7037 (2006). Jia, Y.-X., Zhu, S.-F., Yang, Y., and Zhou, Q.-L., J. Org. Chem., 71, 75 (2006). Lu, S.-F., Du, D.-M., and Xu, J., Org. Lett., 8, 2115 (2006). Li, H., Wang, Y.-Q., and Deng, L., Org. Lett., 8, 4063 (2006). Jia, Y.-X., Xie, J.-H, Duan, H.-F., Wang, L.-X., and Zhou Q.-L., Org. Lett., 8, 1621 (2006). Wang, Y.-Q., Song, J., Hong, R., Li, H., and Deng, L., J. Am. Chem. Soc., 128, 8156 (2006). Kwiatkowski, P., Majer, J., Chaladaj, W., and Jurczak, J., Org. Lett., 8, 5045 (2006). Azizi, N., Arynasab, F., and Saidi, M. R., Org. Biomol. Chem., 4, 4275 (2006). Lakhdar, S., Westermaier, M., Terrier, F., Goumont, R., Boubaker, T., Ofial, A. R., and Mayr, H., J. Org. Chem., 71, 9088 (2006). Zou, X., Wang, X., Cheng, C., Kong, L., and Mao, H., Tetrahedron Lett., 47, 3767 (2006). Li, D.-P., Guo, Y.-C., Ding, Y., and Xiao, W.-J., Chem. Commun. (Cambridge), 2006, 799. Wang, J.-Y., Fu, X.-H., Wu, T., Wang, J., Xiao, S.-X., and Hu, C.-W., Chem. Abs., 145, 396850 (2006). Herrera, R., Jiménez-Vázquez, H. A., Delgado, F., Söderberg, B. C. G., and Tamariz, J., Chem. Abs., 144, 412008 (2006). Fujita, M., Oshima, M., Okuno, S., Sugimura, T., and Okuyama, T., Org. Lett., 8, 4113 (2006). Campeau, L.-C. and Fagnou, K., Chem. Commun. (Cambridge), 2006, 1253. Deprez, N. R., Kalyani, D., Krause, A., and Sanford, M. S., J. Am. Chem. Soc., 128, 4972 (2006). Sugie, A., Kobayashi, K., Suzaki, Y., Osakada, K., and Mori, A., Chem. Lett., 35, 1100 (2006). Garcia-Cuadrado, D., Braga, A. A. C., Maseras, F., and Echavarren, A. M., J. Am. Chem. Soc., 128, 1066 (2006). Ackermann, L., Althammer, A., and Born, R., Angew. Chem. Int. Ed., 45, 2619 (2006). Kawamura, M., Cui, D.-M., and Shimada, S., Tetrahedron, 62, 9201 (2006). Güllük, E., Bogdan, E., and Christl, M., Eur. J. Org. Chem., 2006, 531. Xiao, X., Morrell, A., Fanwick, P. E., and Cushman, M., Tetrahedron, 62, 9705 (2006). Barluenga, J., Trincado, M., Rubio, E., and González, J. M., Angew. Chem. Int. Ed., 45, 3140 (2006). Dopfer, O., J. Phys. Org. Chem., 19, 540 (2006). Ribas, X., Xifra, R., Parella, T., Poater, A., Solà, M., and Llobet, A., Angew. Chem. Int. Ed., 45, 2941 (2006). Sallo, A., Crasmareanu, C., Simon, Z., and Raduly, S., Chem. Abs., 145, 314337 (2006). Belen’kii, L. I., Chuvylkin, N. D., Serykh, A. I., and Suslov, I. A., Chem. Abs., 145, 7562 (2006). Coquière, D., Cadeau, H., Rondelez, Y., Giorgi, M., and Reinaud, O., J. Org. Chem., 71, 4059 (2006). Wik, B. J., Lersch, M., Krivokapic, A., and Tilset, M., J. Am. Chem. Soc., 128, 2682 (2006). Davies, D. L., Donald, S. M. A., Al-Duaij, O., Macgregor, S. A., and Pölleth, M., J. Am. Chem. Soc., 128, 4210 (2006). Armstrong, D. R., Clegg, W., Dale, S. H., Hevia, E., Hogg, L. M., Honeyman, G. W., and Mulvey, R. E., Angew. Chem. Int. Ed., 45, 3775 (2006). Clegg, W., Dale, S. H., Hevia, E., Hogg, L. M., Honeyman, G. W., Mulvey, R. E., and O’Hara, C. T., Angew. Chem. Int. Ed., 45, 6548 (2006).

CHAPTER 7

Carbocations

R. A. McClelland Department of Chemistry, University of Toronto, Canada Introduction . . . . . . . . . . . . . . . . . . . . Alkyl and Cycloalkyl Carbenium Ions . . . . . . Benzyl Cations . . . . . . . . . . . . . . . . . . . Quinone Methides . . . . . . . . . . . . . . . . . Benzhydryl, Trityl, and Fluorenyl Cations . . . . Carbocation Reactivity–Quantitative Studies . . Oxonium Ions . . . . . . . . . . . . . . . . . . . . Carbocations Containing Sulfur . . . . . . . . . . Carbocations Containing Silicon . . . . . . . . . Halogenated Carbocations . . . . . . . . . . . . . Carbocations Containing Other Heteroatoms and Carbocations in Zeolites and Other Materials . . Allylic Systems . . . . . . . . . . . . . . . . . . . Vinyl Cations . . . . . . . . . . . . . . . . . . . . Aryl Cations . . . . . . . . . . . . . . . . . . . . Arenium Ions . . . . . . . . . . . . . . . . . . . . Nitrenium Ions . . . . . . . . . . . . . . . . . . . Aromatic Systems . . . . . . . . . . . . . . . . . Dications . . . . . . . . . . . . . . . . . . . . . . Polycyclic Systems . . . . . . . . . . . . . . . . . Carbonium (Bridged) Ions . . . . . . . . . . . . . Carbocations in Biosynthesis . . . . . . . . . . . Carbocations in Synthesis . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Metals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

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

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

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

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

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

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

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

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

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

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

203 204 205 206 207 208 209 210 211 211 212 212 213 214 214 215 216 217 218 220 221 222 224 225

Introduction Developments in the study of carbocations in superacid media over the past 30 years have been reviewed.1 The thermodynamics [G(g)] of the reaction R+ (g) + Rref OH(g) → ROH(g) + R+ ref (g) involving Rref = t-butyl and 21 R+ has been studied by high-level computation.2 A plot of G(g) versus G(solution) shows an excellent correlation, except for phenyl-substituted R+ , which form a separate correlation family. The magnitude of the most positive surface electrostatic potential was proposed as an effective measure of the stability of gas-phase carbocations, with results presented for a number of structurally diverse cations.3 The electrostatic potential directly Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd


203

204


addresses the issue of charge delocalization in the cation, and also relates carbocation stability solely to the properties of the ion, without the need to bring in other reference molecules. Density functional calculations of energy barriers for degenerate 1,2-shifts in long-lived carbocations were reported.4 When the shift involved a hydrocarbon migrant, there was good agreement with experimental data. Deviations were observed in the case of hydrogen and migrants containing heteroatoms and possible explanations presented. The effect of electrostatic interactions in stabilizing certain conformations of cations was reviewed.5 These conformational biases, along with stereoelectronic effects, were proposed to be controlling factors in determining the stereoselectivity of reactions involving carbocations. A review appeared discussing the development and use of superacids, with extremely high acidities in excess of many billion times that of concentrated sulfuric acid.6 The high acidity and extremely low nucleophilicity have made it possible to prepare in solution long-lived carbocations previously only considered as reactive intermediates. A critical analysis of the use of multi-parameter correlations of solvent effects on solvolytic reactivity appeared.7 It was suggested that some mechanistic conclusions are unreliable due to systematic errors caused by compensation effects and by comparisons between dissimilar processes. A review commentary considered recent findings of relevance to the mechanism of nucleophilic substitution reactions.8 Assigning a unimolecular ionization mechanism when racemization is experimentally observed was suggested to be flawed. Front-side bimolecular substitution can occur, especially with larger alkyl groups and with good leaving groups. The use of weakly coordinating anions [Al(ORF )4 ]− [RF = C(H)(CF3 )2 , C(CF3 )3 ] as counterions for the preparation of cation salts was reviewed.9 Carbocations that have been prepared and structurally characterized include C+ X3 (X = Br, Cl) and C+ (Br)(SBr)2 . The mechanisms of bioactivation of modulators of estrogen receptors were reviewed.10 Various electrophilic intermediates have been identified in these reactions, including carbocations and quinone methides.

Alkyl and Cycloalkyl Carbenium Ions A detailed kinetic study of the alkylation of benzene and alkylbenzenes by 1-adamantanol in sulfuric acid solutions was reported.11 The data clearly point to the 1-adamantyl cation as the intermediate alkylating species. A series of protonated epoxides and their ring-opened cations R2 C+ –CR 2 OH were investigated by a variety of computational methods, with the conclusion that the density functional B3LYP method provides poor agreement with methods such as MP2 and CCSD.12 The mechanism of the degenerate 1,5-hydride shift in 2,6-dimethyl-2-heptyl cations was investigated by computational methods.13 In addition to the two equivalent acyclic cations, the potential energy surface consists of a third minimum corresponding to a symmetrically µ-hydrido-bridged carbocation. Incorporation of solvent effects results in good agreement with experiment, for both the relative energies of the minima, and also the energy barriers separating them. The mechanism of the hydroxylation of simple alkanes by hydrogen peroxide in strong acid, investigated by density functional theory, was proposed to involve hydride transfer from the alkane to the superelectrophilic

205

7 Carbocations

HO–OH2 + .14 This reaction forms two water molecules and a carbenium ion, which is then hydrated to form the protonated alcohol. The degenerate gas-phase reactions between HF and protonated alkyl fluorides RFH+ (R = Me, Et, i-Pr, t-Bu) were investigated by ab initio methods.15 With the exception of MeFH+ , the protonated alkyl fluorides can be viewed as weak complexes of the carbocation R+ and HF. Both frontside and backside substitutions occur, supporting the proposal (see Introduction)8 that nucleophilic substitution reactions are better understood through such a competition as opposed to the traditional SN 1/SN 2 competition.

Benzyl Cations Cations (1)–(3) were observed in superacid upon addition of the appropriate alcohol precursors.16 Characterization by NMR and product analysis, combined with quantum chemical calculations, indicates that (3) has bishomoantiaromatic destabilization. Kinetics of the degenerate vinyl rearrangement of (4) to (5) (R1 , R2 , R3 = H or methyl) were studied by dynamic NMR spectroscopy.17–19 The presence of methyl groups in certain locations on the migrating vinyl group was shown to have a significant effect on the rate of migration. Two papers appeared discussing the formation of (6) by photoprotonation of 1,2-dihydroquinoline precursors in water and alcohol solvents.20,21 The cation (6) was observed with laser flash photolysis, and the kinetics of its further reactions were investigated. Photolysis of stilbenes in CF3 CH2 OH and (CF3 )2 CHOH results in addition of the solvent across the double bond.22 The proposed mechanism involves initial photoprotonation to form the cation ArCH+ –CH2 Ar . Transients identified as such cations were observed upon laser flash photolysis in (CF3 )2 CHOH. Chiral benzylic-type cations (7, various Ar) were obtained by acid treatment of the corresponding alcohol at low temperature, and observed to alkylate electron-rich aromatics Ar H to give products (8) with high facial diasetereoselectivity.23 This was R2

R3 b

a

+

R

(1), a = b = C–C (2), a = C=C, b = C–C (3), a = b = C=C

+

N R′

H (6)

1

R

R3

1 +

+

C6H4−4−F

R

R2

(4)

H

CMe3

+

C

C

Ar

H Ar

H Me

Ar′H (7)

(5)

CMe3 C

C

H Me

Ar′

(8)

206


proposed to arise via reaction of Ar H from the side opposite the t-butyl group in the favoured conformation (7). Naphthyl-1-methyl carbocations bearing dimethylamino and methoxy groups at positions 4 and/or 5 were obtained by treatment of the corresponding alcohol with acids, and the products of their subsequent reactions (mainly oligomers) determined.24 The acid-catalysed hydrolysis of the epoxide (9), and its diastereomer with the epoxide on the opposite face, were shown by azide trapping experiments to proceed via free carbocations [e.g. (10)].25 The lifetimes of these cations in water is of the order of 10 ns. A mechanistic study of the TiO2 -photosensitized oxidation of indane and some 1-hetero analogues appeared.26 The proposed mechanism involved several steps, with the product-forming intermediate being a benzylic carbocation formed by oxidation of the corresponding radical. Energy decomposition analysis based on density functional calculations was performed on a series of ortho-, meta-, and para-substituted benzylic cations.27 A reasonable correlation with Hammett σ and σ + constants was observed, especially for substituents with π -electrons. A computational study of benzyl cations substituted with substituents normally recognized as being π -accepting revealed that there was also a weak π -donating effect, in the order p-NO2 < pCHO < p-CN p-Cl.28 Ellipticine (11), a potent antineoplastic agent, forms covalent DNA adducts upon oxidation by cytochromes P450 and peroxidases. Two carbenium ions, ellipticine-12-ylium (12+ ) and ellipticine-13-ylium (13+ ), were proposed as reactive intermediates.29,30 CHa R

H

R H

H

H

N

+ +

O (9), R = MeO

(10)

H OH

N H

CHb

(11), a = b = 3 (12+), a = 2, b = 3 (13+), a = 3, b = 2

Quinone Methides o-Quinone methides with both electron-withdrawing and electron-donating substituents were studied by a combination of flash photolysis and product analysis, in the presence of various nucleophiles including nucleosides.31 Electron-withdrawing substituents significantly increase the reactivity of the quinone methide, and at the same time increase the stability of products, for example with nucleosides, since the reverse reaction regenerating the quinone methide is retarded. UV irradiation of racemic binaphthol derivatives results in quinone methides that were observed by laser flash photolysis.32 These quinone methides react with l-proline in a highly stereospecific manner to give adducts with >99% diastereoselectivity; these adducts can be further elaborated to single enantiomer binaphthol ligands. Radical formation from 3,5-di-t-butyl and

207

7 Carbocations

3,5-dimethoxy-4-hydroxycinnamic acids results in stable dimeric p-quinone methides with strong visible absorbance.33 The cyclopropyl quinone methide (14) is formed by elimination of a leaving group from the hydroquinone.34 Reactions with nucleophiles occur at the cyclopropyl group (as shown), rather than in the classic manner of quinone methides, i.e. at the C=C. Study of the products obtained with the diazoparaquinone antibiotics upon reductive activation led to the proposal of an o-quinone methide as a key intermediate.35 A reduced form of a fluoromethylnaphthoquinone eliminates HF giving an o-quinone methide, that functions as an irreversible suicide inhibitor of glutathione reductase.36 O

Me

MeO Me

Nu

Me

Me2N

NMe2 CHPh +

N OH (14)

(15)

Me

N+

N

Me CH2Ph

(16)

Benzhydryl, Trityl, and Fluorenyl Cations Recent advances in the chemistry of triaryl- and triheteroaryl-methanes were reviewed. A significant portion of the review considered carbocations.37 Cation (15) was observed in acidic solutions.38 This cation rearranged to (16) via an initial shift of hydride from one of the methyl groups of the NMe2 group adjacent to the carbocation centre, followed by cyclization of the neighbouring NMe2 onto the CH2 + so-formed in the hydride transfer. Reaction of benzophenone derivatives with 5-phenylbarbituric acids in the presence of triflic anhydride leads to regioselective formation of orthosubstituted products, the triaryl cation (17) when Ar is 4-Me2 NC6 H4 and the cyclic ether (18) when Ar has less electron-donating substituents.39 The cyclic ethers are converted to the cation upon treatment with strong acids. Highly stable cations [(19), R = (CH2 )n Me, n = 2, 5, 7], with pKR+ higher than 20, were shown to be useful as novel phase-transfer catalysts for several classical organic reactions.40 The stability of the cation under basic/nucleophilic conditions renders this novel use feasible. Photolysis of anthracene derivatives (20) in aqueous acetonitrile results in two intermediates arising by (formal) excited state intramolecular proton transfer, the zwitterionic cation (21) and the quinone methide (22).41 These intermediates were observed with laser flash photolysis. The radical cations of the sulfides Ph3 CSPh and Ph2 C(Me)SPh cleave the central C–S bond producing the carbocations Ph3 C+ or Ph2 C+ Me and the SPh radical.42 This process has been observed with laser flash photolysis and rate constants for the cleavage process determined. Photolysis of 3-(2,2,2-triphenylethoxy)-3chlorodiazirine gives 2,2,2-triphenylethoxychlorocarbene (Ph3 CCH2 –OC–Cl), which undergoes heterolytic fragmentation with 1,2-phenyl migration concomitant with loss of CO and chloride.43 This results in the cation Ph2 C+ CH2 Ph, followed by proton loss to give Ph2 C=CHPh. Very fast (ps, fs) laser flash photolysis reveals that 25% of the cation arises directly from the excited diazirine precursor, rather than the

208


O Ar

HOTf

C+ Ar HO

NH N R

O

Ar

N

R

NH

O

O

N R

N

O

(18)

R (19)

O−

OH H hn +

(20)

N +

Ar

(17)

R

R

R (21)

O + R H (22)

carbene. Using the ‘cation pool’ method, diarylcarbenium ions have been generated by anodic oxidation of diarylmethanes.44 The thus-generated cations react with various nucleophiles including allylsilanes, ketene silyl acetals and aromatic compounds in a synthetically useful manner. 9-Phenanthryl-type carbocations were proposed as intermediates in a complex transformation of the natural product benaphthamycin B, with support from quantum chemical calculations.45

Carbocation Reactivity–Quantitative Studies A review by Mayr and Ofial of the reactivity–selectivity principle included a number of examples of carbocation–nucleophile combinations.46 The conclusion was reached that a decrease in selectivity with increasing reactivity is expected only if diffusion control has been reached. In general, however, selectivity cannot decrease with increasing reactivity. Mayr’s group showed that nucleophilicity parameters N derived from the rate constants for carbocation–nucleophile combinations also hold for SN 2 reactions.47 The result is a general equation for polar reactions, log k = sE sN (E + N ), where sE and sN are electrophile- and nucleophile-specific slope parameters and E and N are electrophilicity and nucleophilicity parameters. This equation includes as special cases the Swain–Scott equation, the Ritchie single parameter relation, and the Mayr equation developed for carbocations, log k = sN (E + N ) (since sE ≈ 1 for carbocations). Back-to-back papers appeared discussing a quantitative nucleofugality scale.48,49 The analysis, presented in the first paper, was based on the kinetics of SN 1 ionization of benzhydryl derivatives; the second paper extended the discussion to other types of substrates. The data were correlated by the equation log ksol = sf (Nf + Ef ),

209

7 Carbocations

where ksol is the rate constant for ionization of R–X, Ef is an electrofuge-specific parameter dependent on R, and sf and Nf are nucleofuge-specific parameters dependent on X and, importantly, also on the solvent. Since sf ≈ 1, rate constants for solvolysis reactions can be estimated knowing the values of Nf and Ef . The threeparameter relation for ksol presented above was re-evaluated by Bentley, who proposed additivity methods for obtaining Ef and Nf parameters that avoided multi-parameter optimizations.50 The kinetics of the reactions between benzhydrylium ions and 11 carbanions (nitronates and malonates) led to the determination of nucleophilicity parameters N and s for the latter.51 The N parameters show poor correlations with the acidity constants of the conjugate CH acids, and also with Hammett σ − constants. Nucleophilicity parameters were determined for a series of substituted indoles,52 and for the azide ion in different alcohol solvents.53 A study of the kinetics of the gas-phase combinations of benzhydrylium cations with amine nucleophiles concluded that the Mayr equation, log k = s(E + N ), determined in solution also applies in the gas phase, albeit with different electrophilicity and nucleophilicity parameters E and N .54 The electrophilicity parameters E show a good correlation with those determined in solution, although the sensitivity to substituent change is considerably attenuated in the gas phase. A detailed review analysed the mechanism and kinetics of carbocationic polymerization.55 An attempt was made to explain the 104 –105 -fold discrepancy between propagation rate constants measured using (a) polymerization rates and (b) competition kinetics, where there is an assumption of diffusion limit trapping with nucleophiles. Kinetic hydrogen isotope effects were determined by computational methods for several identity hydride transfers involving carbenium ions, for example the hydride transfer between CF3 H and CF3 + , and the intramolecular hydride transfer in HCF2 –CF2 + .56 Correlations of the rates of solvolysis with solvent parameters show that 1- and 2-naphthoyl chlorides react by an ionization mechanism via an acylium ion intermediate.57

Oxonium Ions The zwitterion (23) was observed during the 2 + 2-cycloaddition reaction of the ketene (CF3 )2 C=C=O and CH2 =CHOEt.58 Thioacetal (24) reacted at low temperature with electrochemically generated (25) to give the cation (26), which was observed by NMR, and employed in synthetically useful reactions, e.g. with allyltrimethylsilane.59 The HCl-induced ring-opening reactions of (27) were explained by a competition between initial protonations at oxygen (a) leading to the cation (28) and carbon (b) leading to the cation (29).60 H O

+

−

OEt

OMe

H

OMe

(25)

H

F 3C

ArS(ArSSAr)+

R

SPh

R

+

CF3 (23)

(24)

(26)

210


a

b

OMe

+

OMe

OMe (27)

(28)

MeO

+

OMe

(29)

Conformational analysis of the arabinofuranosyl carbenium ion led to a model where the conformation was locked such that nucleophiles approached with a high selectivity from the β face.61 This prediction was borne out by synthesis, where excellent β selectivities with a variety of nucleophiles were observed. In conjunction with a systematic study of the C-glycosylations of mannose derivatives, conformational preferences of the intermediate oxocarbenium ions were investigated, along with the energetics of the transition states for nucleophilic addition to these cations.62 In a similar study, the stereoselectivity of the reactions of cyclohexanone acetals with thiophenyl groups (and other heteroatoms) was examined both experimentally and through computation.63 The trans selectivities were explained by the reactions of oxocarbenium ions, without the need to invoke episulfonium ions. In yet a further related paper, the nucleophilic substitution reactions of 4-substituted cyclohexanone acetals were examined, with the results being explained by the electronic nature of the 4-substitutent, and its preference for either the equatorial or axial position in the intermediate oxocarbenium ion.64 Stereoselective glycosylations were achieved by employing a chiral auxiliary at C(2) of a glycosyl donor.65 The mechanism proposed involved trans-fused or cis-fused dioxolenium ion intermediates, the nature of the fusion being controlled by the stereochemistry in the chiral donor. Density functional theory was employed to address the origin of stereoselectivity in intramolecular Diels–Alder reactions of vinyl oxocarbenium ions.66 Torsional steering, the preference for the staggered conformation about incipient σ -bonds, was found to determine the preferred transition states. Isotopic labelling experiments led to a mechanism for the racemization in Prins cyclization that involves an oxocarbenium ion intermediate undergoing a reversible oxonia-Cope rearrangement prior to nucleophilic capture.67 5 -Hydroxy-N -nitrosonornicotene undergoes decomposition in the presence of 2 -deoxyguanosine to give products with the nucleoside that are consistent with an oxocarbocation that reacts as an onium ion and a carbenium ion.68 A mechanistic study of the reversible oligomerization of cyclophane formaldehyde acetals concluded that the ring fusion/ring fission processes involve oxonium ion intermediates undergoing SN 2 reactions.69 The alternative pathway involving carbenium ions generated by SN 1 cleavage of oxonium ions is not consistent with the experimental data.

Carbocations Containing Sulfur The stabilization of carbocations by sulfur was studied by computational methods, and compared using isodesmic reactions to the stabilization by oxygen, fluorine,

211

7 Carbocations

and chlorine. Sulfur substitution stabilizes carbocations similar to oxygen, whereas halogen substitution leads to destabilization.70 The intermediate ArS+ (OE)CH2 R in the Pummerer reaction of sulfoxides ArSOCH2 R with electrophiles E+ fragments the CH2 –R bond to form the carbocation R+ when R+ is a very stable carbocation (pKR + > 14.5).71 A review of the Pummerer reaction has emphasized modern applications.72 Many of these take advantage of the sulfur-stabilized carbocation intermediate, and the possibility of reacting this with various nucleophiles in both interand intra-molecular reactions. Thioacetals (30) react with electrophiles to give cyclic ethers (32).73 The proposed mechanism involves an initial ring opening of the acetal to give the allylic sulfur-stabilized cation (31) that undergoes an intramolecular reaction with the neighbouring OH group, forming a six-membered ring as opposed to a four-membered ring. R3

R3

OH

OH

E+

R2 S

R3

R1

R1

R1

O

+

R2

R2

S

S

(30)

S(CH2)3SE

(CH2)3SE

(32)

(31)

Carbocations Containing Silicon The novel bridged disilyl cations (33), X = H, F, were synthesized as their B(C6 F5 )4 − salts and characterized by NMR and X-ray methods.74 In both cations the Si–X–Si linkage is symmetrical, corresponding to a single minimum potential. The novel cation (34), Ar = 2,6-i PrC6 H3 , with a formal divalent silicon was obtained as a B(C6 F5 )4 − salt.75 Bishomoaromatic stabilization energies [(35) → (36)] were obtained by computational methods; this study was part of a paper describing the experimental preparation of a zwitterionic analogue of such compounds (i.e. where X is boron).76

Me2Si

Me

+

X

+

SiMe2 Ar

N

Si

N

Ar

X

Me

+

Si

Me

+

Si

X

X

X Me

(33)

(34)

(35), X = C, Si

(36)

Halogenated Carbocations The cations CH2 I+ and CD2 I+ were observed in the gas phase, and their electronic spectra recorded.77 Quantum chemical calculations for semibullvalene bromination

212


show that the reaction involves concerted bromine addition and cyclopropane ring opening to form an allylic cation, without the intermediacy of either a bromonium ion or a cyclopropylcarbinyl cation.78 Under treatment with a Lewis acid (LA), 2,2difluorovinyl ketones bearing an aryl group form carbocations [e.g. (37)] stabilized by α-fluorines.79 These cations undergo Friedel–Crafts cyclization to give, after ketonization and loss of fluoride, dihydronaphthalenes such as (38). O-LA

O Me3C

+

(37)

Ph

Ph Me3C

CF2

F

Me3C

(38)

CMe3

+

C

C

Al

C Al

H −

H CMe3 CMe3

(39)

Carbocations Containing Other Heteroatoms and Metals The interesting zwitterionic compound (39) with the cationic component a butadien2-yl cation was obtained by reaction of 1,4-di(t-butyl)butadiyne with 2 mol of di(tbutyl)aluminium hydride, with the structure being established by X-ray analysis.80 The reactions of the 1,2-diferrocenyl-3-(methylthio)cyclopropenylium ion with carbanions derived from active methylene compounds were investigated.81 Products were derived by ring opening of the cyclopropene ring after the initial carbanion addition. The bis(ferrocenylethynyl)phenylmethylium cation (Fc–C≡C–)2 C+ Ph (Fc = ferrocenyl) was prepared.82 This cation proved to be much less stable than its bis-ethenyl analogue (Fc–CH=CH–)2 C+ Ph.

Carbocations in Zeolites and Other Materials The following papers relate to carbocation-mediated reactions catalysed by zeolites and other solid-state catalysts where the paper places a clear emphasis on mechanism, moreover, a mechanism with a carbocationic intermediate. Zeolite-catalysed reactions of n-butane, investigated through 13 C labelling, were rationalized in terms of rate-limiting hydride transfer between an initiating carbenium ion and the parent nbutane.83 Methanol is converted to hydrocarbons over zinc iodide at high temperature, with the highly branched alkane being formed with high selectivity.84 A mechanistic study, including various labelling experiments, proposed various carbocationic intermediates being formed through the methylation of alkenes. Gas-phase multiply methylated benzenium ions fragment by both loss of H2 and loss of methane, the latter being the dominant process for higher homologues.85 This latter finding is consistent with a proposed reaction cycle in the mechanism of the zeolite-catalysed conversion of methanol to hydrocarbons. Density functional computations and explicit-contact modelling were employed to investigate the mechanisms of β-scissions of chemisorbed carbenium ions, e.g. C5 H11 + → C2 H5 + + C3 H6 .86 Density functional theory was

213

7 Carbocations

employed to model the role of carbonium and carbenium ions in acid-catalysed hydrocarbon conversions that occur over phosphotungstic acid.87,88

Allylic Systems The singlet diradical (40), obtained by photolysis of a diazo precursor, was found to undergo C−OMe bond heterolysis in methanol to produce the allylic cation (41).89 Transient signals assigned to both the diradical and the cation were observed with laser flash photolysis. The gas-phase cyclobuten-3-yl cation was reacted with amine bases to give cyclobutadiene and with electron donors to give the cyclobuten-3-yl radical.90 The success or failure of these reactions, depending on the strength of the amine or electron donor, led to the experimental determination of the proton affinity of cyclobutadiene (undergoing protonation to form the cyclobuten-3-yl cation), and the ionization potential of the cyclobuten-3-yl radical (losing one electron to form the cyclobuten-3-yl cation). An (alkylidene)allyl cation R2 C=C+ −CH=COR was generated by Lewis-acid mediated ring-opening of the (alkylidene)cyclopropanone acetal.91 Reaction with (siloxy)alkenes gave products that are the results of nucleophilic addition to the sp2 centre of the cation, with no sign of nucleophilic addition at the sp centre. The oxyallyl cation (42) was obtained as an intermediate by acidic ring opening of an alkylidenecyclopropane acetal; this cation reacts with furan to give 3 + 2- and 4 + 3-cycloadducts, in addition to an electrophilic substitution product.92 Photolysis of cinnamyl acetates ArCH=CHCH2 OAc (Ar = 3- and 4-MeOC6 H4 ) in methanol solvent results in high yields of the ether products ArCH=CHCH2 OMe and ArCH(OCH3 )CH=CH2 .93 The cinnamyl cation ArCH=CHCH2 + is proposed as the intermediate, the cation forming by C–OAc bond heterolysis in the singlet excited state. Treatment of α-alkylcinnamaldehydes with orthoesters, alcohols and thiols in the presence of BF3 results in 1-alkoxy-2-alkylindenes.94 Mechanistic studies suggest a sequence of reactions, with a γ -alkoxyallyl cation as the key intermediate. A computational scheme expressing the wavefunction in terms of Lewis structures was tested on the allyl cation, leading to a resonance energy of 63 kcal mol−1 .95 Density functional theory was employed to investigate the Nazarov reaction, the cyclization of a 3-hydroxy- or 3-alkoxy-pentadienyl cation to a 2-hydroxy- or 2-alkoxy-cyclopentenyl cation.96 Of particular interest were the factors that control the torquoselectivity of the cyclization. Computation predicts that the aza-Nazarov reaction (43) → (44) proceeds with high exothermicity and a modest activation barrier; several experimental examples were then examined, verifying the prediction.97

OMe

MeO OMe Ar

Ar′

Ar

+

Ar′ +

OMe (40)

(41)

(42)

214

Organic Reaction Mechanisms 2006 OH

OH

+

+

+

(43)

+

n

N

N

n=1

(44)

(45)

(46)

Vinyl Cations Photochemical solvolysis of cyclopentene-1-I+ Ph and 1-cyclohexene-1-I+ Ph gave products consistent with the formation of the geometrically destabilized C5 - and C6 ring cations (45).98 Allylic products derived from the cation (46) were also observed with the C5 -ring system. These were argued to arise from a 1,3-hydride shift. Protonated polyacetylenes, observed in 6 K neon matrices, were shown to have the structure HC≡C(C≡C)n C+ =CH2 by analysis of their electronic and vibrational spectra.99 The protonation of arylethynyl halides or halogen addition to arylethynes was investigated through a computational study of the possible intermediates, an α-aryl-β-halovinyl cation, a β-aryl-α-halovinyl cation, a halogen-bridged cation, and a spirocyclic phenylbridged cation.100 Except with strongly electron-withdrawing substituents in the aryl ring, the β-aryl-α-halovinyl cation is the cation of lowest energy. The addition of HCl to two buta-1,3-diyne units held in close proximity results in a double cyclization leading to dichloro-substituted cyclooctatetraenes.101 A quantum chemical investigation of this process found several vinyl cations as energy minima. Vinyl cation (47), obtained by addition of the isopropyl cation to oct-4-yne, reacted in the presence of hydride donors to give cyclopentane (49).102 The mechanism proposed involved a concerted cyclization–hydride transfer resulting in the tertiary cyclic cation (48).

+

+

"H−"

H (47)

(48)

(49)

Aryl Cations The parent phenyl cation has been prepared in an argon matrix at 30 K, and characterized by IR spectroscopy.103 Co-deposition with nitrogen or carbon monoxide leads to a decrease in the IR signals for the phenyl cation, with new signals identified as being due to the products of addition of the diatomic nucleophiles, the benzenediazonium ion from N(2) or the benzoyl ion from CO. Nanosecond laser flash photolysis of neutral aqueous solutions of the quinolone antibacterial agent lomefloxacin and an 8-chloro analogue resulted in transients that, based on quenching by halide nucleophiles, were assigned to the aryl cations.104 Such cations may be responsible for the photosensitivity of this class of compounds. The dediazoniation of the 4-nitrobenzenediazonium

215

7 Carbocations

ion in acidic methanol–water mixtures was shown to involve a competition between homolysis and heterolysis, the latter proceeding by way of an aryl cation.105 Triplet aryl cations, obtained by acetone-sensitized irradiation of o-chlorophenyl allyl ethers, reacted to afford dihydrobenzofurans or chromanes through addition of the cation onto the tethered double bond either in 5-exo or 6-endo modes.106,107 Aryl cations (50), obtained by photoheterolysis of various precursors in acetonitrile–water, reacted with carboxyalkenes (51) to afford lactones (53) or (54) in good yield.108 A phenonium ion (52) was proposed as an intermediate. Y Y

+

+

COOH n

(52)

+

(50)

a (51)

n

HO

a

X = OH, OMe, NH2, NMe2

b

n=1

b

O n = 2, 3 Y

Y

O O O

n−1

O (53)

(54)

Arenium Ions A review summarized recent developments that have allowed the unambiguous structural characterization of arenium ions in the gas phase and under microsolvated conditions.109 C(5)-substituted 2,4,6-trimethylaminopyrimidines undergo protonation at the N(1) position and also at C(5), the latter resulting in the arenium cation (55).110 C(5) protonation is favoured over N(1) when R = alkyl, since the carbon protonation relieves steric congestion by pushing the alkyl group out of the plane of the aromatic ring. Cation (56), stabilized by palladium complexation, was obtained as its triflate salt, and characterized by NMR and X-ray methods.111 A solution of H3 O+ .CHB11 C11 − in benzene was obtained.112 IR spectroscopy suggests the formation of a trisolvated species H3 O+ .3C6 H6 with the three OH bonds hydrogen bonded to the benzene π system, i.e. as π complexes. A combined theoretical and gas-phase experimental study of the nitration of monosubstituted aromatics led to the proposal of a general mechanism whereby the polar Ingold–Hughes mechanism and single electron transfer are

216

Organic Reaction Mechanisms 2006 P Pd P

H R Me2N

NMe2 N

+

+

N But

NMe2 (55)

But OMe (56)

N +

OMe

(57)

extremes of a continuum.113 The fraction of each is determined by the ability of the aromatic compound to transfer an electron to the nitronium ion. A kinetic study of the electrophilic fluorination of aromatic compounds with NF reagents was reported.114 The results are consistent with rate-limiting formation of an arenium ion. An example of a 1,2-hydrogen shift in this intermediate was also revealed. A study of gas-phase toluenium ions formed by protonation of perdeuterated toluene provided evidence for the occurrence of ring hydrogen shifts, in particular evidence for the interconversion of isotopomers bearing either one D-atom and one H-atom or two D-atoms on the tetrahedral ring carbon.115 Benzenium ions bearing alkyl groups undergo carbon atom scrambling between ring carbons and the alkyl carbons.116 A theoretical study into this reaction has revealed that it occurs via a ring expansion into a seven-membered ring. A quantum chemical investigation was reported into the mechanism of the Scholl reaction, an intramolecular dehydrogenative aryl–aryl bond formation of synthetic utility in the preparation of oligophenylene compounds.117 The favoured mechanism involves ring protonation to form arenium ion intermediates, which react intramolecularly with neighbouring phenyl rings. The alkylation of phenol was investigated by density functional theory.118 A phenolic ether is the most energetically favourable product, but under acidic conditions the alkyl group migrates via arenium ions to form o- and p-alkylphenols. A picosecond time-resolved resonance Raman investigation of the photodeprotection reaction of p-hydroxyphenacyl diethyl phosphate led to the proposal of a short-lived ion pair, with phenonium ion characteristics.119

Nitrenium Ions The 2-methoxyazepinium ion (57), a nitrogen analogue of the tropylium ion, reacts with benzene to afford three products of electrophilic aromatic substitution (see arrows for position of attachment of phenyl ring).120 The result has been rationalized in terms of kinetic control based on the πLUMO of the cation. Laser flash photolysis was employed to investigate the reaction of the N -methyl-N -(4-biphenylyl)nitrenium ion with amino acids and protein.121 The electron-rich aromatic amino acids tryptophan and tyrosine, the sulfur-containing methionine and cysteine, and the basic lysine, histidine, and arginine all reacted, in competition with the solvent water, as did several representative proteins. Using laser flash photolysis, the kinetics of the reaction of the 2-fluorenylnitrenium ion with 2 -deoxyguanosine were determined as a function of solvent.122 Significant decreases in rate constant with decreasing solvent basicity were interpreted in terms of the importance of a hydrogen bonding

217

7 Carbocations

interaction in the transition state of the reaction. 2-Oxo-substituted arylazides such as 2-azidobenzaldehyde and 2-azidoacetophenone react with benzene in the presence of BF3 forming acridines.123 The proposed mechanism involves an arylnitrenium intermediate. Aminoflavone (58), an anticancer agent with potent growth inhibitory activity, was proposed to be metabolically activated to two arylnitrenium ions derived from the two NH2 groups present in the drug.124 The mutagenic potency of a series of heterocyclic amines found in cooked meat was evaluated and compared with structural features obtained by quantum chemical methods.125 One of the principal determinants of mutagenicity is the stability of the nitrenium ion. Azide trapping experiments show that 4 -X-4-biphenylyloxenium ions (X = H, Br, Me, MeO) are intermediates in the hydrolysis of 4-aryl-4-acetoxycyclohexa-2,5-dienones or O-(4-aryl)phenyl-N methanesulfonylhydroxylamines.126 With the assumption of diffusion control for the reaction with azide ion, the lifetimes of the cations in water range from 12 ns (X = H) to 18 µs (X = MeO). Various criteria suggest that the cations are more accurately described as 4-aryl-1-oxocyclohexa-2,5-dienyl carbocations. Phenoxonium cation (59), a vitamin E model, was obtained by treatment of the phenol precursor with NO+ SbF6 − in acetonitrile.127 The crystal structure of the SbF6 − salt showed bond lengths consistent with structure (60) as the major resonance contributor, with structure (59) of relatively minor importance (as also concluded in ref. 126). In a related paper, an electrochemical investigation of the oxidation of α-tocopherol and trolox led to the proposal of a mechanism involving the formation of an aryloxenium ion: carbenium ion intermediate.128 NH2

O+

O

O

F H3C

O F

NH2 (58)

+

F O

O

(59)

(60)

Aromatic Systems Cations (61),129 (62),130 and (63)131 were obtained as perchlorate or BF4 − salts. The cations were characterized by NMR and X-ray methods; reduction potentials and pKR + values were also determined. Density functional calculations were performed on the tropylium derivative (64), a number of substituted analogues, and a number of neutral systems.132 The objective was to assess the utility of NICS (nuclear independent chemical shift) as a probe for detecting/sensing variation in aromaticity due to transannular π –π interactions. A dicyanoheptafulvene has been prepared, with X-ray crystallographic analysis showing a significant contribution from the dipolar resonance contributor (65).133 Addition of acid results in the tropylium

218


+

PH

Me

N

N

+

R

O N Me

R (61), R = Me, Et, Prn

O

(62)

O Me

Me

N

N

+

O N

R

+ (63), R = Me, Ph

NC

−

(64)

D

CN

NC

CN

CF3COOD

+

+ NaHCO3

(65)

(66)

conjugate acid (66), which can be converted back to the zwitterionic form with base. The bis(diisopropylamino)cyclopropenium ion 2,3-Pri2 C3 H+ undergoes an acid–base reaction with KN(SiMe3 )2 , whereby the hydrogen on the ring is lost.134,135 The conjugate base is the bis(diisopropylamino)cyclopropenylidene carbene 2,3-Pri2 C3 :, and this can be isolated. Experimentally unknown monocyclic [11]annulenium ions were investigated by computational methods.136 Six minima were located, four being aromatic, one non-aromatic, and the sixth a Mobius antiaromatic species. The antiaromatic properties of the cyclopentadienyl cation and its analogue with one silicon were addressed, along with a number of neutral and anionic analogues.137 The objective was to evaluate the question of aromaticity through Pauling–Wheland resonance energies.

Dications Isoprenoid acyclic polyene carbocations with 6, 14, and 18 π -electrons were synthesized.138 Considering also previous data for carotenoid dications, an equation correlating λmax (ranging from 400 to 1100 nm) and the number of sp2 hybridized carbon atoms in the dication was developed. Dication (67) and an analogue with a different alkyl substitution pattern were prepared as PF6 − salts.139 These dications form

219

7 Carbocations

+

+

(67)

Ph

Ph Ph +

Ar

Ph

Ph

Ph Ph

Ar

Ph Ar

Ar

+

Ar

+

+

Ar

−2e− +2e−

(68)

Ar

Ar

+2e−

(69)

(70)

(71)

complexes with dibenzo-30-crown-10 and dibenzo-24-crown-8. The dication (68) exhibits an interesting two-electron reduction behaviour due to the close proximity of the two diarylmethyl cations, forming the acenaphthalene (69).140 The dication is therefore an efficient two-electron oxidizing agent, for example, oxidatively coupling N ,N -dialkylanilines at the para-position to form benzidines in excellent yield. In a related system, dienes (70), Ar = 4-Me2 N- and 4-MeOC6 H4 , were shown to undergo a reversible two-electron oxidation to give dications (71).141 The antiaromaticity of the dication (72) was demonstrated through magnetic criteria, 1 H NMR shifts, nucleus-independent chemical shifts (NICS), and magnetic susceptibility exaltation.142 Excellent agreement was seen in the calculated and experimental 1 H NMR shifts. Dications (73), with various Ar, were prepared to examine the response of the indenyl and fluorenyl cationic portions to magnetic measures of antiaromaticity.143 All measures supported antiaromaticity, with the indenyl ring system (even in the absence of the aryl substituent) being less aromatic than the fluorenyl ring system. This stands in contrast to the situation with the isolated monocations. The reactions of maleimide and phthalimide with cyclohexane and benzene under superelectrophilic activation were reported.144 For example, maleimide reacts with benzene in CF3 SO3 H to give predominantly a diphenyl derivative, with the proposed mechanism involving sequential Friedel–Crafts alkylation involving dications as the alkylating species. Dications such as (74)145 and (75)146 were obtained in the reversible two-electron electrochemical oxidation of alkene precursors. Superacid-promoted reactions of ammonium–carbocation dications show positive charge migration so as to separate the two positive charges in a predictable manner.147 This charge migration chemistry is the basis of new synthetic reactions, for example to prepare aza-polycyclic aromatic compounds. The reactions of quinidine acetate, epiquinidine, and its acetate in superacids were studied. After

220

Organic Reaction Mechanisms 2006 Ar +

+

+

+

(72)

(73) X

X

+ +

S

+

+

S

Me

Me

X X (75), X = OOCR, NHCOR, OAr

(74)

the two nitrogens have been protonated, alkene protonation leads to a trication that undergoes a series of relatively complex reactions, including rearrangements.148

Polycyclic Systems The acid-catalysed hydrolysis of 5-methoxyacenaphthylene 1,2-oxide was shown to proceed via the carbocation (76).149 This cation reacted with water to give an approximately 3:2 ratio of cis:trans diols, despite the trans-diol being substantially more stable. Hence, transition state effects, and not thermodynamic stability, determine the products. A computational investigation examined carbocations derived from oxidized benzo[a]anthracenes.150 Examples of cations considered are (77), derived by epoxidation and ring opening, and (78), derived by methyl oxidation and subsequent C−O bond heterolysis. H

H

OH

OH

+

Me

OMe (76)

(77)

+ +

CH2

Me (78)

221

7 Carbocations

Carbonium (Bridged) Ions A combined computational and experimental investigation of the protonation of adamantane was performed.151 Computations showed four stable structures, a van der Waals complex between the 1-adamantyl cation and H(2), two isomeric complexes between the 2-adamantyl cation and H(2), and a C-adamantonium ion formed by protonation of the C(1)–C(2) bond. Computational studies examined various aspects of the CH5 + cation – potential energy surface, including the pathways leading to the fragments CH3 + and H2 ,152 fluxionality including the effect of deuteration,153 and electron density charge topology as studied by Bader’s theory of atoms in molecules.154 Solvolysis of the mesylate (79) results in ring-opened products consistent with the bridged cation (80) as the intermediate.155 The exo-isomer of (79) undergoes solvolysis with direct displacement of the leaving group and complete retention of the bicyclic structure. The products obtained on the fragmentation of the oxochlorocarbenes (X = OCCl), chlorocarbonates [X = OC(=O)Cl] and chlorosulfites (X = OSOCl) of (81), (82), and (83) were determined.156 The fragmentation proceeds in polar solvents via a nortricyclyl cation:Z:chloride ion pair where the ions are separated by the spacer Z = CO, CO2 , or SO2 . For each of (81), (82), and (83), similar product distributions were observed with the three precursors. This indicates that similar ion pairs are formed. +

X

X CH2OMs (79)

(80)

(81)

(82) exo (83) endo

Hypercoordinate square-pyramidal carbocations C7 H9 + and C8 H9 + were examined computationally.157 For the former, (84) was found to be the minimum, and calculated 13 C NMR shifts were in good agreement with experimental values. For the latter, cations (85) and (86) were close in energy with a relative low barrier separating them. The calculated 13 C NMR shifts based on a weighted average of the two structures agreed with the experimental values. Quantum chemical calculations on carbonium ions containing hypercoordinated carbon atoms in distorted square-pyramidal geometries [e.g. (87)] were described.158 In addition, transition structures for reactions involving the intramolecular attack of tetracoordinated carbon on carbenium carbons (i.e. where the tetracoordinate carbon centre acts as a nucleophile) were located. A similar study examined a set of nonclassical carbocations with tetracoordinated protons ‘sandwiched’ between two carbon–carbon double bonds [e.g. (88)].159 The occurrence of five-centre, four-electron bonds was clearly demonstrated. Quantum chemical calculations have revealed an unusual rearrangement reaction of cyclopropylcarbinyl cations, a hybrid of a [1,2]-sigmatropic hydrogen shift and a two-electron electrocyclic ring opening.160 The term ‘hiscotropic’ was coined to describe the reaction, which occurs over potential energy surfaces that are complicated, in some cases with flat plateaux and even bifurcations. A series of caged hydrocarbon cations containing

222

Organic Reaction Mechanisms 2006 H +

+

C C

X (84), X = no bridge (85), X = CH2

(86)

(87)

+

H

H

CH2 H

+

H C

H C

CH2

C

C H

C H

(88)

hexa- and octa-coordinate carbon centres were designed computationally.161 For example, inserting C4+ into the centre of a caged system with four carbon–carbon double bonds held in close proximity is predicted to give an accessible tetracation where that central carbon is octacoordinate, being bonded to all eight of the alkene carbon atoms. Deamination of 1-alkyl-9-aminomethyltriptycenes was interpreted in terms of the loss of N2 from a primary alkane diazonium ion concomitant with participation of a C–H bond of the neighbouring C–H group to form a non-classical carbonium ion with a three-centre, two-electron bond.162 Non-classical carbonium ions such as corner-protonated cyclopropane were shown by computational methods to be excellent hydrogen bond donors to ammonia.163 The relevance of such interactions in enzyme-catalysed terpenoid biosynthesis was discussed.

Carbocations in Biosynthesis A quantum chemical investigation of the biosynthesis of farnesyl pyrophosphate through the condensation of isopentenyl pyrophosphate and dimethylallyl pyrophosphate suggests that the mechanism is concerted, although the transition state has carbocationic character.164 Quantum chemical calculations were performed on the cyclization of the farnesyl cation to the sesquiterpene pentalenene.165 Two distinct pathways with similar activation barriers were identified, each differing from previous proposed mechanisms, and each involving unusual carbocationic intermediates. Mechanisms previously proposed for enzyme-catalysed formation of the sesquiterpene trichodiene involve carbocation intermediates with a 1,4-hydride transfer as the key step, e.g. (89) → (90) → (91).166 Quantum chemical calculations, however, show a H

moves as H−

+

H

H

+

(90)

+

H (89), bisabolyl cation

moves as H+

(91), cuprenyl cation +

(92)

223

7 Carbocations

pathway (89) → (92) → (91) where hydrogen transfer as a proton is more favourable by over 10 kcal mol−1 . The energetics of a number of C30 H51 O+ intermediates in the cationic cyclization of oxidosqualene to lanosterol, lupeol, and hopen-3β-ol were obtained by quantum mechanical methods.167 The modest activation barriers so calculated combined with the exothermicity of the reactions led to the suggestion that the cationic intermediates do not require enzymatic stabilization. The reliability of quantum chemical methods for investigating such reactions was also addressed. Stereoisomeric alcohols (93) and (94) yielded identical ring-expansion products [e.g. (97)] on formation of carbocations.168 This is evidence of a stepwise reaction in sterol biosynthesis, whereby a tertiary cation [e.g. the model (95)] rearranges to a secondary cation (96)–an ‘anti-Markovnikov rearrangement’. The synthetic aspects of biomimetic cyclizations of isoprenoid polyenes were reviewed.169 Included was a detailed discussion of carbenium ion-initiated cyclizations, with a discussion of the different mechanisms that have been proposed. A novel biomimetic carbocation polyene cyclization of a daurichromenic ester was reported; an unusual 2 + 2-carbocation cyclization occurred as a side reaction.170 TiCl4

+

CMe2

CMe2OH (93), exo (94), endo

(95)

Cl

+

(96)

(97)

The diverse chemistry of the terpenoid cyclases was reviewed.171 These enzymes catalyze cyclization reactions occurring by way of carbocations, where on average twothirds of the carbon atoms of a linear polyisopropene undergo changes in bonding, hybridization, and/or configuration during the reaction. Type 2 isopentenyl diphosphate:dimethylallyl diphosphate isomerase, an enzyme that requires FMN for activity, was found to be irreversibly inhibited by an epoxide mechanism based inhibitor of the type 1 isomerase.172 This led to the suggestion that the type 2 isomerase proceeds via a carbocation intermediate, with a proposal that a reduced flavin stabilizes this intermediate. A mechanistic study of the conversion of oxidosqualene to marneral by an oxidosqualene cyclase led to the proposal that the triterpene arises by Grob fragmentation of an intermediate carbocation.173 A detailed mechanistic study was published employing deuterium isotope effects to examine the formation of the sesquiterpenes epiaristolochene and premnaspirodiene from farnesyl diphosphate catalysed by the appropriate enzymes.174 Several carbocation intermediates are involved in the transformations, and the results of this study are explained through consideration of their

224


conformations and stereoelectronic requirements in the course of proton transfers, rearrangements, and eliminations. Molecular modelling and site-directed mutagenesis were combined to examine the mechanism of terpene syntheses catalysed by maize sesquiterpene synthases, enzymes that produce 14 different olefinic sesquiterpenes.175 A bisabolyl cation is the key intermediate, and the study suggests that the steps in the reaction sequence are controlled by two active sites, with the conformation of this cation determining the pocket where the reaction occurs. The initial steps in the biosynthesis of artemisin were investigated by isotopic labelling.176 Three possible ring-closure mechanisms, two involving a bisabolyl carbocation and one involving a germacrenyl carbocation, were proposed and tested. Oxidosqualene–lanosterol cyclase mutants replacing a phenylalanine were described that generated different product profiles.177 The study supports a model whereby there is stabilization of carbocationic intermediates by cation–π interactions. A polar amino acid side-chain can replace the π -stabilizing group, but with product differentiation. A detailed structural investigation was reported for prephenate dehydratase, an enzyme that catalyses the conversion of prephenate to phenylpyruvate in a two-step sequence of dehydration–decarboxylation, with a carbocation intermediate proposed for the first step.178 The enzyme was proposed to function as an entropy trap, providing a highly pre-organized microenvironment that avoids the extensive solvent reorganization that accompanies carbocation formation. The stereochemistry in the acid-induced cyclization of a deuterium-labelled geranyl acetate was examined in solution and in zeolite Y.179 Whereas the solution reaction showed negligible diastereoselectivity, the zeolite reaction showed considerable stereoselective disposition. This was explained by the proximity of the nucleophilic C=C to the intermediate carbocation, as a result of confinement within the zeolite. A carbocation mechanism for the antimalarial activity of artemisinin was probed by computational methods.180 Although a number of cationic intermediates were shown to be possible, the conclusion was reached that the antimalarial activity is due to a radical pathway.

Carbocations in Synthesis Recently published intramolecular Friedel–Crafts-type alkylations were reviewed, with an emphasis on chemo-, regio-, and enantio-selective examples.181 Cyclopropanation reactions based on the γ -effect of tin on carbocationic intermediates were reviewed.182 A novel approach for C(sp3 )–H bond functionalization was reported, whereby a tertiary benzylic C–H bond is activated by transfer of the hydrogen as hydride ion to a metal coordinated centre, followed by intramolecular reaction of the so-formed carbocation.183 Benzyl, allyl, and propargyl cations can be formed and used in synthetically useful reactions by treatment of the appropriate alkoxide with BCl3 .184 Based on knowledge of the electrophilicity of the cations and the nucleophilicity parameters of the target and the solvent, certain allyl and benzyl halides were predicted to allylate or benzylate indoles in 80% aqueous acetone (and not react with the solvent) via an SN 1 mechanism, without the aid of a catalyst to generate the carbocation.185 This was borne out by experiment, where moderate to quantitative yields of products were obtained. Acid-catalysed reactions of 4,5-epoxy-9-trimethylsilyleudesmanes results in

7 Carbocations

225

rearrangement products determined by the stabilization of the rearranged carbocation by the silicon at its β-position.186 With the aid of deuterium labelling, mechanisms of the reactions of methylenecyclopropanes with aldehydes in the presence of BF3 .OEt2 were addressed, with several carbocations proposed as intermediates.187

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Organic Reaction Mechanisms 2006 Okazaki, T. and Laali, K. K., Org. Biomol. Chem., 4, 3085 (2006). Thanh, N. C., Miyatake, R., Kainuma, H., Kuroda, S., and Oda, M., Tetrahedron, 2006, 586 (2006). Lavallo, V., Canac, Y., Donnadieu, B., Schoeller, W. W., and Bertrand, G., Science, 312, 722 (2006). Lavallo, V., Ishida, Y., Donnadieu, B., and Bertrand, G., Angew. Chem. Int. Ed., 45, 6652 (2006). Warner, P. M., J. Org. Chem., 71, 9271 (2006). Mo., Y. and Schleyer, P. v. R., Chem. Eur. J., 12, 2009 (2006). Kildahl-Andersen, G., Anthonsen, T., and Liaaen-Jensen, S., Tetrahedron Lett., 47, 4693 (2006). Brule, C., Holmer, S., Krechanin, S., and Laali, K. K., Org. Biomol. Chem., 4, 3077 (2006). Saitoh, T., Yoshida, S., and Ichikawa, J., J. Org. Chem., 71, 6414 (2006). Suzuki, T., Iwashita, S., Yoshino, T., Kawai, H., Fujiwara, K., Ohkita, M., Tsuji, T., Ono, K., and Takenaka, M., Tetrahedron Lett., 47, 467 (2006). Mills, N. S. and Benish M., J. Org. Chem., 71, 2207 (2006). Mills, N. S., Llagostera, K. B., Tirla, C., Gordon, S. M., and Carpenetti, D., J. Org. Chem., 71, 7940 (2006). Koltunov, K. Y., Prakash, G. K. S., Rasul, G., and Olah, G. A., Eur. J. Org. Chem., 2006, 4861. Amriou, S., Wang, C., Batsanov, A. S., Bryce, M. R., Perepichka, D. F., Orti, E., Viruela, R., VidalGancedo, J., and Rovira, C., Chem. Eur. J., 12, 3389 (2006). Schreivogel, A., Maurer, J., Winter, R., Baro, A., and Laschat, S., Eur. J. Org. Chem., 2006, 3395. Li, A., Kindelin, P. J., and Klumpp, D. A., Org. Lett., 8, 1233 (2006). Debarge, S., Violeau, B., Jouannetaud, M.-P., Jacquesy, J.-C., and Cousson, A., Tetrahedron, 62, 662 (2006). Zhao, C. and Whalen, D. L., Chem. Res. Toxicol., 19, 217 (2006). Borosky, G. L. and Laali, K. K., Chem. Res. Toxicol., 19, 899 (2006). Davalos, J. Z., Herrero, R., Quintanilla, E., Jimenez, P., Gal, J.-F., Maria, P.-C., and Abboud, J.-L. M., Chem. Eur. J., 12, 5505 (2006). Jin, Z., Braams, B. J., and Bowman, J. M., J. Phys. Chem. A, 110, 1569 (2006). Johnson, L. M. and McCoy, A. B., J. Phys. Chem. A, 110, 8213 (2006). Okulik, N. B., Peruchena, N. M., and Jubert, A. H., J. Phys. Chem. A, 110, 9974 (2006). Bentley, T. W., Engels, B., Hupp, T., Bogdam, E., and Christl, M., J. Org. Chem., 71, 1018 (2006). Moss, R. A. and Fu, X., Tetrahedron Lett., 47, 357 (2006). Rasul, G., Prakash, G. K. S., and Olah, G. A., J. Phys. Chem. A, 110, 11320 (2006). Siebert M. R. and Tantillo, D. J., J. Org. Chem., 71, 645 (2006). Ponec, R., Bultinck, P., Gutta, P., and Tantillo, D. J., J. Phys. Chem. A, 110, 3785 (2006). Nouri, D. H. and Tantillo, D. J., J. Org. Chem., 71, 3686 (2006). Wang, Y., Huang, Y., and Liu, R., Chem. Eur. J., 12, 3610 (2006). Yamamoto, G., Koseki, A., Sugita, J., Mochida, H., and Minoura, M., Bull. Chem. Soc. Jpn, 79, 1585 (2006). Bojin, M. D. and Tantillo, D. J., J. Phys. Chem. A, 110, 4810 (2006). Sanchez, V. M., Crespo, A., Gutkind, J. S., and Turjanski, A. G., J. Phys. Chem. B , 110, 18052 (2006). Gutta, P. and Tantillo, D. J., J. Am. Chem. Soc., 128, 6172 (2006). Hong, Y. J. and Tantillo, D. J., Org. Lett., 8, 4601 (2006). Matsuda, S. P. T., Wilson, W. K., and Xiong, Q., Org. Biomol. Chem., 4, 530 (2006). Nishizawa, M., Asai, Y., and Imagawa, H., Org. Lett., 8, 5793 (2006). Brunoldi, E., Luparia, M., Porta, A., Zanoni, G., and Vidari, G., Curr. Org. Chem., 10, 2259 (2006); Chem. Abs., 146, 62928 (2007). Kurdyumov, A. V. and Hsung, R. P., J. Am. Chem. Soc., 128, 6272 (2006). Christianson, D. W., Chem. Rev., 106, 3412 (2006). Hoshino, T., Tamegai, H., Kakinuma, K., and Eguchi, T., Bioorg. Med. Chem., 14, 6555 (2006). Xiong, Q, Wilson, W. K., and Matsuda, S. P. T., Angew Chem. Int. Ed., 45, 1285 (2006). Schenk, D. J., Starks, C. M., Manna, K. R., Chappell, J., Noel, J. P., and Coates, R. M., Arch. Biochem. Biophys., 448, 31 (2006). Kollner, T. G., O’Maille, P. E., Gatto, N., Boland, W., Gershenzon, J., and Degenhardt, J., Arch. Biochem. Biophys., 448, 83 (2006). Kim, S.-H., Heo, K., Chang, Y.-J., Park, S.-H., Rhee, S.-K., and Kim, S.-U., J. Nat. Prod., 69, 758 (2006). Wu, T.-K., Liu, Y.-T., Chiu, F.-H., and Chang, C.-H., Org. Lett., 8, 4691 (2006). Kleeb, A. C., Kast, P., and Hilvert, D., Biochemistry, 45, 14101 (2006). Tsangarakis, C. and Stratakis, M., Eur. J. Org. Chem., 2006, 4435.

7 Carbocations 180 181 182 183 184 185 186 187

229

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CHAPTER 8

Nucleophilic Aliphatic Substitution

K. C. Westaway Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Canada SN Reactions Forming C–C Bonds . . . . . . . . . . . . . . . . Allylic and Vinylic Substitutions . . . . . . . . . . . . . . . . . Reactions of Cyclic Ethers . . . . . . . . . . . . . . . . . . . . . Aziridines and Other Small Ring Substitutions . . . . . . . . . Studies Using Kinetic Isotope Effects . . . . . . . . . . . . . . . Gas-phase Substitution Reactions . . . . . . . . . . . . . . . . . Nucleophilic Substitution on Elements Other than Carbon . . . Medium Effects/Solvent Effects . . . . . . . . . . . . . . . . . . Micelles and Phase-transfer Catalysis in Substitution Reactions Structural Effects . . . . . . . . . . . . . . . . . . . . . . . . . . Theoretical Studies . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Kinetic Studies . . . . . . . . . . . . . . . . . . . SN Reactions Producing Polymers . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

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

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

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

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

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

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

231 233 237 243 248 250 251 253 255 257 261 267 272 273

SN Reactions Forming C–C Bonds SN 2 products were obtained in good yield (83–99%) by highly regiospecific (79–98%) and enantiomeric specific (93–99.4% ee) reactions when variously substituted allylic chlorides were treated with a Grignard reagent in the presence of (1; Y = H) and ≤3 mol% of a copper thiophene carboxylate (CuTC) catalyst.1

Cl

+ RMgX

CuTC CH2Cl2 (1)

R

The alkylation of γ -acetoxy or γ ,γ -difluoro-α,β-unsaturated-δ-lactams (2) with Me3 CuLi2 .LiI.3LiBr and an alkyl halide2 gave mainly the 3,6-cis isomer (3) when the alkyl halide was small (MeI), but mainly the 3,6-trans isomer (4) when a bulky alkyl halide was used. Calculations at the B3LYP/6–31G(d) level of theory suggested the mechanism in Scheme 1 where the intermediate is stabilized by an interaction Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd


231

ee

de

232


Y (S) O

N

P

O

(S) Y

(1)

between a Cu or Li ion and the π -electrons of the benzene ring. Steric hindrance makes the transition state leading to the 3,6-cis product high energy when a bulky alkyl halide is used, so attack comes from the side opposite to the benzyl substituent. Total yields of 3,6-cis and 3,6-trans products ranged from 56 to 94%. A highly regiospecific SN 2 alkylation occurs when allyl carbonates (5) are reacted with an iron catalyst (Fec ) and PPh3 in DMF at 80 ◦ C.3 It appears the product is formed with retention of configuration at Cα . A possible mechanism (Scheme 2), involves two regioselective SN 2 reactions. X Y Ph Me

Me3CuLi2.LiI.3LiBr

N

−X−

O (2) X = OAc, Y = H X=Y=F Ph Ph M

Me N

I

O

Y

Ph Y

Me N

M

O Me

Y Me

N

Me

O (3) 3,6-cis Ph Me N O

Y

Ph

Ph Me N Y

O

Y Me

M M = Cu or Li

M I

Scheme 1

Me

N

Me

O (4) 3,6-trans

233

8 Nucleophilic Aliphatic Substitution O O

OR′

Fec

SN2′

R

O

−1

Fec

R +

−O

Nu NuH

OR′

SN2′

R

(5) Scheme 2

The formation of C–C bonds in SN reactions using ketone enolates as nucleophiles has been reviewed.4

Allylic and Vinylic Substitutions A wide range of substituted allyl carbonates have been found to undergo SN 2 reactions with potassium trialkylsilanoates in the presence of a chiral iridium catalyst regiospecificically (>99%) and with a very high (92–99%) enantioselectivity.5 Hydrolysis of the resulting silyl ethers gives chiral secondary alcohols in high yields. A new phosphoramidite ligand (1; Y = OMe), gives high enantioselectivities (92– 99% ee) and regioselectivities (99% SN 2 ) in iridium-catalysed allylic substitution reactions of carbonates and acetates with carbanion or primary amine nucleophiles.6 The new ligand also leads to a faster rate of reaction than other phosphoramidite ligands. The use of the o-diphenylphosphanylbenzoyl leaving group in copper-catalysed allylic substitution reactions with a Grignard reagent has been studied extensively.7 High SN 2 regiospecificity (≥95%) and complete stereospecificity are observed at room temperature when the solvent is a dichloromethane – diethyl ethyl mixture. A 31 P NMR study showed that there was a rapid ligand exchange on copper(I). This means that only 0.2 equiv. of catalyst is required for the reaction. The suggested mechanism, where two molecules of substrate become coordinated with the copper atom via their phosphorus atom, indicates that the reaction occurs via a syn-selective transfer to minimize A strain. The SN 1 hydrolysis of 5-methoxyacenaphthylene 1,2-oxide was found to occur preferentially via the 7.73 kcal mol−1 more stable carbenium ion,8 as confirmed by B3LYP/6–31G* calculation. The predominant formation of the less stable cis-diol is a consequence of kinetic control and explained by calculations at the MP2/6–31G*// MP2/6–31G* level of theory, which reveal the stabilizing influence of the hydrogen bonding that occurs between the attacking water molecule and the β-OH group on the carbenium ion in the transition state. The Taniaphos catalyst (6) has been found to give SN 2 products in excellent yields (90–98%) with a high enantioselectivity (90–98% ee) in the allylic substitution of several different leaving groups by Grignard reagents in the presence of CuBr.SMe2 in t-BuOMe at −78 ◦ C.9 . A detailed kinetic study10 of a palladium-catalysed reversible cis–trans isomerization of cyclic allylic benzoates has shown how a change to a better leaving group

ee ee

de

ee

234

Organic Reaction Mechanisms 2006 Me2N

Fe

PPh2 Ph2P (6)

increases the rate of the reaction, which proceeds by SN 2 substitution of intermediate cis and trans palladium complexes, for which the best catalyst is Pd0 (PPh3 )4 . The effect of added salts, the solvent, and the reaction temperature on the SN 2 reaction of silylated vinyloxiranes (7) with n-, s- and t-butyllithium has been investigated.11 Higher yields of the favoured Z-isomer were obtained at a lower temperature and when the base was t-butyllithium. Both the Z:E ratio (Z:E = 5.3) and the yield (99%) were slightly greater when the solvent was Et2 O rather than pentane. Adding LiCl, BF3 , or tetramethylethylenediamine to the solvent reversed the Z:E ratio, giving Z:E = 1:2.3 with LiCl, 1:3.4 with BF3 and 1:3.5 with tetramethylethylenediamine, by changing the coordination with the oxirane oxygen. The results have been discussed with reference to alternative inter- and intra-molecular mechanisms, (Schemes 3 and 4, respectively) Intramolecular Li

Bu

O Li Bu

Hb

O

TBS

TBS

Ha (7) H+

TBS

TBS = t−BuSiMe2

Bu OH

Scheme 3 Intermolecular Bu

Li

Bu

O

Li O 3

Hb TBS

2

3

Hb TBS

C2–C3 rotation

Ha H+

TBS

Ha

Bu OH

Scheme 4

2

Bu-Li

ee

de

235

8 Nucleophilic Aliphatic Substitution

Allylic alcohols can be converted in high yield (74–94%) to the corresponding linear allylic trifluoroborate salts in two steps: by treatment with [B(OH)2 ]2 , p-toluenesulfonic acid and a Pd–selenium complex catalyst, in DMSO–MeOH, and then by KHF2 .12 The reaction is probably successful because the poor OH leaving group is converted to the excellent leaving group OBOH(OH2 )B(OH)2 in the first step. Allylic alkylations (Scheme 5) using Grignard reagents and the Lewis base imidazolinium chloride (8) have been found to give 82% of the SN 2 product with a 97% ee.13 Ph

Ph N

O

+

Cl−

N

O

HO

(8)

Cl + PriMgCl

RO

ee

RO

THF

R = t-Bu, Me

Me

Me

Pri

Scheme 5

A mechanism has been proposed for the syn-SN allylic substitution of α-cyanoacetals with alkyllithium reagents.14 The matched (9) and mismatched (11) substrates gave different products [98% (10) and 85% (12), respectively] when treated with lithium di-t-butyl biphenylide (LiDBB) in THF at −78 ◦ C as shown in Schemes 6 and 7. The spiroether effect is the controlling factor in determining the products. Matched: Me

‡

Me O Ph

H

O

LiDBB

OMe R

CN (9)

O

−78 °C

O Ph

H Li

O R

Me O

syn-SN′

Ph

O

H H (10) Scheme 6

R

Me

de

236


Mismatched:

‡

Me O O

O

OMe LiDBB

Ph

H

H Li

−78 °C

R

CN (11)

Ph

Me O

R O

Me

Me O

O

SN′

Ph

H H

R

R = CH2CH2CH2Ph

(12) Scheme 7

The effect of leaving group, solvent, base, temperature, and ligands on the apparent SN 2 allylic arylation of cis-cyclopent-2-ene-1,4-diethylcarbonate with arylboronic acids [ArB(OH)2 ] and a rhodium(I) catalyst has been reported.15 The best conditions gave good to excellent yields with a high regiospecificity (>90%) and high enantioselectivity (84–92%). Two possible mechanisms, one requiring two substitution reactions and the other an addition – elimination mechanism, are discussed. The regioselective and enantiospecific allylic substitution of alkyl-substituted allyl benzoates and carbamates with (Me2 PhSi)2 Zn and CuI has been shown to occur by an oxidative addition – reduction elimination mechanism rather than an SN 2 mechanism.16 A natural bond orbital-based CI/MP through-space/bond interaction analysis of the SN 2 reaction between allyl bromide and ammonia17 showed that allyl bromide reacted faster than propyl bromide because the σ − π * and π − σ * interactions stabilize the allyl bromide transition state equally. Two reactions related to allylic substitution have used propargyl compounds as substrates. The SN 2 reaction between gem-difluoropropargyl bromide and a Grignard reagent is highly regiospecific if the reaction is carried out in the presence of a copper (I) halide catalyst.18 Control experiments have shown that a magnesium organocuprate intermediate formed in the initial SN 2 reaction, undergoes a reductive elimination giving the difluoroallene. Ab initio calculations indicate the reaction occurs at C(3), the most positive site in the substrate, as revealed by the NBO (natural bond order) charge densities. The difluoroallene is often unstable and reacts further giving a monofluoride as the final product. The yields of difluoroallene range from 37 to 94%. Finally, the SN reaction of propargylic alcohols [R1 R2 C(OH)C≡CR3 ] in refluxing acetonitrile has been found to occur in good (50–90%) yields when catalysed by

ee

ee


237

p-toluenesulfonic acid.19 Nucleophiles, including alcohols, amines, thiols, sulfonamides, allyltrimethyl silane, and even aromatic and heteroaromatic compounds, can be used in this reaction. The product obtained using tertiary propargyl alcohol was racemic, indicating that at least this reaction occurred by an SN 1 mechanism. Four reviews on allylic and vinyl substitution have been published.20–23 The use of pentamethylcyclopentadienylruthenium catalysts for the SN reactions of allyl substrates has been reviewed.20 The SN reactions of allyl substrates in the presence of ruthenium catalysts occur primarily at the most substituted position of the allylic group. All the catalysts involve formation of an intermediate where the allyl compound becomes associated with the Ru atom in the catalyst. The regiospecificity (50–98%) depends on the structure of the allylic substrate, the nucleophile, the solvent, the temperature, and the catalyst. These catalysts have also been used for protection of allylic alcohol and amino groups. Some of the reactions are stereospecific. An excellent review21 outlining the mechanism of diphenylphosphinobenzoic acidbased palladium-catalysed asymmetric substitution of allyl compounds with nucleophiles has been published. The mechanistic model developed for these reactions allows one to predict the stereochemistry of the product(s). The use of C2 -symmetric chiral bis(oxazolines) in allylic substitutions has also been reviewed.22 The SN V2 reactions of vinylic compounds have been reviewed.23 An SN Vσ (an in-plane attack at the σ * orbital giving inversion of configuration) and an SN Vπ mechanism (an out-of-plane attack on the π * orbital giving retention of configuration) have been found with vinyl iodonium salts. Finally, three other allylic substitution reactions1–3 have been reported.

Reactions of Cyclic Ethers Virtually all of the studies using cyclic ethers have been carried out on epoxides. For example, an investigation of the effect of changing the acid, the silyl triflate and the solvent showed that the bishomoepoxy alcohol (13) can be converted in high yield to the 6-endo-cyclic ether (15) rather than the normal 5-exo-cyclic ether (14) by reaction with trifluoromethanesulfonic acid, triisopropylsilyl triflate, and 2,6-lutidine in nitromethane (Scheme 8).24 The regioselective production of the 6-endo-cyclic ether (15) is favoured when the partial positive charge is stabilized on a tertiary carbon and steric hindrance of the trialkyl silyl triflate leaving group in the transition state makes formation of the 5-exo-ether unfavourable. Cyclic voltammetry, kinetic studies, and DFT calculations using a BP functional and the TZVP basis set showed that the major pathway of the non-regiospecific zinc-reduced titanocene-mediated ring opening of epoxides was initiated by a titanium dimer-epoxide compound that reacted in a rate-determining electron transfer mechanism.25 The calculations showed that the transition state is early so the stereoselectivity is determined by steric effects rather than by the stability of intermediate radicals. This was confirmed by studies with more sterically crowded catalysts. The ring opening of aryloxiranes with 3,5-dinitrobenzoic acid (HA) in acetonitrile has a Hammett ρ + = −2.9 and a transition state where Cα –O cleavage is greater than

238


O OH (13) H

CF3SO3 H R3SiOTf 2,6-Lutidine

+

R R δ+

O

Si

δ−

‡

R

OTf

R

R

O

OH

OH

Si

δ−

‡

OTf R

δ+

steric hindrance

OSiR3 O

O

O SiR3 (14) 5-exo

(15) 6-endo Scheme 8

the formation of the new O–Cα bond.26 Since the reaction is first order in the oxirane and second order in the acid, it has been suggested that pre-equilibrium association with HA is followed by attack of a second HA at the benzyl carbon. The much slower rate found when a more electron-withdrawing substituent is on the aryl ring was due to a large decrease in S = (i.e. much more negative) coupled with a small decrease in H = and suggests a later transition state. Catalytic amounts of tin(II) chloride have been found to give good yields (72–86%) of the trans-amino alcohols when oxiranes have been treated with aromatic amines in acetonitrile at room temperature.27 Only the reaction with styrene oxide was regiospecific with the amine adding to the benzylic carbon of the epoxide ring. An investigation of the effect of various catalysts, the solvent, and alkyl groups on the oxirane ring28 has shown that for ring opening with cyanide ion the best yields are obtained when the catalyst is (16) and the solvent is ethylene glycol. The reactions are regiospecific at the least substituted carbon and occur rapidly at room temperature,

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giving the trans-β-hydroxynitrile in high yields (80–93%). The results imply that the reaction occurs by an SN 2 mechanism.

N

de

N Co

O

O (16)

An investigation of various catalysts, the solvent, and the additive used in the mesostilbene oxide enantioselective ring opening with anilines at room temperature has been carried out.29 The best catalyst, solvent, and additive proved to be (17), toluene and triphenylphosphane, respectively. The reaction gave 95% of the syn-β-amino alcohol with 78% ee. A single recrystallization increased the enantiomeric excess to 98%. The catalyst is recyclable.

O O

O Ti

Ti O

ee

O O

(17)

The major products of the SN 2 reaction between the sulfur of thiocamphor (18) and (R)-2-vinyloxirane (19) form regioselectively at the most hindered carbon when the reaction is carried out in the presence of the Lewis acids ZnCl2 , SiO2 , or SnCl4 .30 When the reaction is carried out under basic conditions with NaH in anhydrous THF, however, the major product is formed when the sulfur of the enethiolate ion attacks the least substituted carbon in an SN 2 reaction (Scheme 9). The initial products from both reactions react further giving more complex products. gem-Difluorinated vinyloxiranes (20) undergo SN 2 reactions when treated with HF–pyridine in CH2 Cl2 at 0 ◦ C.31 Most of the reactions are stereoselective giving only the E-isomer (21). Treatment of the gem-difluorinated vinyloxiranes (20) with DIBAL-H or BH3 .THF (Scheme 11) gave the ring-opened allylic alcohol with high stereoselectivity. DIBAL-H gave mainly the E-isomer (22) and BH3 .THF gave only the Z-isomer (23) in most of the reactions. The Z-isomer is favoured when the reducing agent has small ligands (BH3 ) while the E-product is found when the ligands are large, i.e. in DIBAL-H. Both the fluorination and the reduction reactions are feasible because the CF2 carbon of the substrate has a significant positive charge. When treated with 3,5-dimethylpyrazole, epoxyvinyl sulfones (24) are converted to (25) by an SN 2 reaction that is both regiospecific and stereospecific.32 The product

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+ S Lewis acid

O

O

S

O

+

NaH

S

THF

(18)

(19) S OH Scheme 9

O R

F−

+

CF2

HF

H d R O d+

OH F F

Pyridine

R

(20)

CF3 (21)

Scheme 10

H ML2 or CF2 H

CF2

CHF2

DIBAL-H

O

O

R

R

M L L

R

(20)

OH (22)

F

O R

CF2

BH3.THF

O R

H B H F H

(20)

CHF2 R

OH (23)

Scheme 11

241


can be methylated in a second regio- and stereo-specific SN 2 reaction with MeMgBr (Scheme 12) to give >95% yield with 95% of (26) with the methyl group syn to the OH group. Surprisingly, when the temperature of the methylation was lowered to 0 ◦ C, the syn:anti ratio decreased from 20:1 to 1:1 and it was reduced further to 1:4 at −45 ◦ C. This temperature dependence was attributed to an equilibrium between two conformations of the magnesium alkoxide intermediates in the methylation reaction. PhSO2

SO2Ph N N O

3,5-dimethylpyrazole, toluene, 65 °C

OH

TBSO

TBSO (24)

(25) SO2Ph Me MeMgBr, Et2O

OH

−78 °C to r.t.

TBSO (26) Scheme 12

The ring opening of hindered 1,2-disubstituted epoxides by a copper-catalysed Grignard reagent generates two stereogenic centres with a high regiospecificity and in reasonable yields (60–85%).33 When the cis-prop-1-enyl Grignard reagent was used, only the cis-product was obtained, whereas when the trans-prop-1-enyl Grignard reagent was used, some of the cis-product was obtained as a consequence of isomerization during the formation of the Grignard reagent. Carbanions generated from fluorinated sulfones react regiospecifically and in high yield at the least hindered carbon of an epoxide.34 The reactivity of the fluorinated nucleophile decreases from (PhSO2 )2 CF− to PhSO2 CFH− to PhSO2 CF− 2 as expected considering the strong electron-withdrawing effect of the F. PhSO2 CCl− 2 also reacted with epoxides regiospecifically in good yield. Only (PhSO2 )2 CF− reacted with a 2substituted N -tosylaziridine. An NMR study35 using the labelled epoxide (28) has shown that both the ringopening reaction by a rhodium tetraphenylporphyrin (27) and re-formation of the epoxide under basic conditions occur with inversion of configuration at the least substituted carbon (Scheme 13). This has been taken as evidence that both reactions occur by an SN 2-type mechanism. Bromodimethylsulfonium bromide36 reacts regiospecifically at the least substituted carbon of epoxides and aziridines in a few minutes at room temperature. The only exception is when a phenyl group is on one of the carbons of the epoxide or aziridine

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−

N N

I

Rh

N +

N

D

O

D

EtOH

C 4H 9

H

(27)

H

H

C4H9 OH H RhIII

(28) O− D

KOBut/18-crown-6

H

RhIII

H C4H9

D

O

H C4H9

H (28)

Scheme 13

ring. Since the nucleophile attacks the benzyl carbon of the ring in these reactions, it was suggested they occurred via the benzyl carbenium ion. The other reactions presumably occur via an SN 2 mechanism, since trans-products were obtained from bicyclic substrates. The SN 2 reaction between ethylene oxide and guanine has been modelled using HF/6–311++G(2d,2p), B3LYP/6–311++G(2d,2p), and semiempirical AM1 and PM3 calculations.37 The effect of adding water as the solvent was considered using the solvent reaction field (SCRF) and Langevine dipole (LD) methods. The HF and semiempirical methods gave similar values for the G = , whereas the DFT calculations gave a significantly lower value. Adding solvent stabilized the transition state more than the reactants, thereby reducing G = . Only the HF-LD method gave a value for G = close to the experimental value. The DFT calculations gave too small a value for G = , and the semiempirical methods gave a value that was too large. The geometries and energies of the complexes formed between BF3 and MeOH, HOAc, dimethyl ether, diethyl ether, and ethylene oxide have been determined at the MP2/6–311++G(3df,2pd) and B3LYP/6–311++G(3df,2pd) levels of theory.38 BF3 forms bimolecular complexes with the lone pairs of electrons on the oxygen of dimethyl and diethyl ethers, MeOH, HOAc, and ethylene oxide. The tightest and loosest complexes are with diethyl ether and ethylene oxide, respectively. Higher levels of theory lead to shorter B–O distances in these complexes and the formation of F · · · H hydrogen bond(s) is primarily responsible for their stability. BF3 also forms two trimolecular complexes: a BF3 (MeOH)2 complex at high MeOH concentrations and a very stable HOAc(BF3 )2 complex in HOAc. Because the complex formed between ethylene oxide and BF3 is less stable than the complexes with the other reagents, it was concluded that BF3 does not coordinate with the epoxide oxygen

243


in non-protogenic solvents, but activates the nucleophile, in the SN 2 ring opening of ethylene oxide. The mechanisms and the regio- and stereo-selectivity of epoxide reactions have been reviewed.39 The review also covers the role of epoxides in biologically important reactions. The achiral and chiral catalysts used in these reactions are discussed. A second review40 discusses the ring-opening reactions of oxiranes with carbon nucleophiles. The reactions of larger cyclic ethers have also been investigated. A comparative study41 of the ring-opening reaction between several B-bromoboranes and 2-methyltetrahydrofuran has established that the most regioselective reagent, (MeO)2 BBr, gave 91% of the primary bromide when it was mixed with the substrate at −78 ◦ C and warmed slowly to room temperature. The authors suggested that oxygen coordination with boron was followed by concerted intramolecular substitution by Br with C–O bond cleavage; the resulting OB(OMe)2 group is then hydrolysed to OH. The nucleophilic substitution reaction of 10-oxa-2-azatricyclo[5.2.1.01,5 ]decane (29) promoted by Rh(I) has been investigated.42 The reactions, which occur with a high regiospecificity and stereoselectivity, give only or predominately (31) with the nucleophile cis to the OH group generated from the 10-oxa oxygen in the ring-opening reaction. A possible mechanism is shown in Scheme 14 for reactions using alcohols, amines, and phenylboronic acid as the nucleophile. 5,5-Dimethyl-2-phenyl-1,3,2dioxaborinane was thought to react by a different mechanism. O−

OH Nu

O

R

[Rh(COD)Cl]2

+

R

BocN O

(29)

R

−Rh (I)Lm

LmRh BocN

NuH

BocN O

(30)

O (31)

Scheme 14

Aziridines and Other Small Ring Substitutions Several studies on the reactions and preparation of aziridines have been published. The ring opening of 2-substituted aziridines, accomplished by first converting them into aziridinium salts by reaction with a benzyl bromide and then attack of the bromide counter ion, gave only one bromide in a regio- and stereo-specific reaction.43 Since attack by the bromide ion of the aziridinium salt only occurred at the most substituted carbon with an inversion of stereochemistry, it was concluded the reaction occurred by an SN 2 mechanism. This was supported by calculations at the MPWB1K/6–31+G(d) level of theory for reactions featuring two solvating acetonitrile molecules embedded in an acetonitrile matrix. New ligands for a polymetallic Gd catalyst used in the ring opening of mesoaziridines with trimethylsilyl cyanide and 2,6-dimethylphenol have been developed.44

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The new ligand–catalyst complex is huge with a metal:ligand ratio of 3:4 and two free OH groups. The yields of nitrile vary from 83 to 99% with an ee ≥95%. An N -heterocyclic carbene (similar to that in Scheme 15) has proved to be an effective catalyst for the nucleophilic ring opening of N -tosylaziridines by silylated nucleophiles (Me3 SiX, X = N3 , Cl, I).45 Yields range from 89 to 99% for reaction at the least substituted carbon, except when a phenyl group on one of the carbons of the aziridine ring induces predominant attack at the benzyl carbon. The stereochemistry is consistent with the SN 2 mechanism and THF was found to be the best solvent for the reaction. Carbene-catalysed substitution of N -tosylaziridines with aldehydes46 bearing both electron-withdrawing and electron-donating substituents has been reported to give good to excellent yields (50–90%) of β-amino esters by highly regiospecific reaction at the least substituted carbon of the aziridine (with one exception). A possible mechanism (Scheme 15) has been proposed. Intermediacy of the carboxylate anion has been ruled out. Mes Cl−

Mes

N+

K2CO3

H

RCHO

:

N

N

Mes

N+

Ts

O−

Mes Mes

R

N

−

H

Mes R NHTs

NTs N

O Mes

N

R

N

Mes

Mes N+

Mes

N

N+

O2

NHTs N

O

Mes

R

O −

Mes

OO

Mes N+ 2

R

R NHTs

N Mes

NHTs

O O

O O −

Scheme 15

The unactivated aziridine-2-carboxylic acid methyl ester was found to react with two molecules of aromatic thiol.47 Initial ring opening is followed by a faster reaction (since little mono substitution product is found), probably involving formation of an episulfonium ion which is then ring opened by the second ArSH. The same result

ee

245


was found when aziridine-2,3-dicarboxylic acid diethyl ester was the substrate. No catalyst or solvent was required for these reactions. DMSO has been found to catalyse the SN reactions of aziridines with aromatic thiols and amines, and trimethylsilyl azide and chloride.48 The reactions occur in good to excellent yields (73–97%) with high regiospecificity and stereoselectivity. Unless there is a phenyl substituent on the aziridine ring, the attack is completely at the least substituted carbon giving only the trans-isomer as the product. Phenylsubstituted aziridines undergo nucleophilic attack at both ring carbons. DMSO does not cause reaction in the absence of the nucleophile, suggesting that the role of the solvent is to activate the nucleophile. Aliphatic amines and thiols react slowly. The products of alkylation of N -sulfonyl-protected aziridines (32) by alkyllithiums are unstable and undergo subsequent rapid elimination; a possible mechanism for the reaction is shown in Scheme 16.49 −

Li MeO

NTs

MeO

RLi

MeO

NTs−

MeO

R

R −Li+

MeO MeO

de

Li NLiTs

(32) R −MeOLi

MeO

NHTs

Scheme 16

The ring-opening substitution of N -Boc-azabenznorbornadiene (33) with rhodium catalysts and aliphatic and aromatic amines gives chiral 1,2-diamino compounds (34), usually in high yields and enantioselectivities.50 The effects of using different catalysts, additives, solvents, and substrate structures on the reaction have been investigated. A possible mechanism involves ring opening of the azanorbornadiene ring by the catalyst followed by an SN 2 reaction. An SN 2 reaction with anchimeric assistance (via formation of a bicyclic aziridinium ion intermediate) has been proposed for the nucleophilic substitution of trans-2substituted 3-piperidinol mesylates by nitrogen nucleophiles with retention of trans Boc

Rhc

N Rh cat.

Boc N

R1R2NH

R1R2N HN

(33) Scheme 17

Boc (34)

ee

246


stereochemistry.51 The reaction is both stereospecific and regiospecific when the 2substituent is phenyl but not when it is methyl. The cis-stereoisomer is thought to be formed in a direct SN 2 displacement of the mesylate group that competes with the formation of the aziridine ring intermediate. Two other reports of reactions involving aziridines34,36 have been discussed above. Calculations at the MP2(Full)/6–31++G(d,p)//MP2(Full)/6–31+G(d) level of theory were used to investigate the SN reactions between ammonia and aziridine, azetidine, methylethylamine, and four fluorinated derivatives of aziridine.52 The results show that aziridine and azetidine have strain energies of 27.3 and 25.2 kcal mol−1 , respectively, and that as a consequence they react 7.76 × 1023 and 2.30 × 1017 times faster with ammonia than does the methylene group of methylethylamine. However, even after subtracting the effect due to the release of ring strain, aziridine still reacts much faster than the other two substrates. This is because the electrostatic attraction of the charges in the product-like dipolar transition state are much greater for aziridine. For fluoro-substituted aziridines, the strain energy in the ring increases from the trans-2,3- at 35.4 kcal mol−1 , to the monosubstititued, to the cis-2,3- to the 2,2difluoroaziridine at 42.9 kcal mol−1 , all having a much higher strain energy than unsubstituted aziridine. The rate of the SN 2 reaction with NH3 at C(3) increased from the cis-2,3-, to the monosubstituted, to the trans-2,3- to the 2,2-difluoroaziridine. The last compound reacted fastest due to the greater stabilization of the negative charge on the leaving group by the fluorines and to the electrostatic interaction between the fluorine and the NH3 hydrogens in the transition state. trans-2,3-Difluoroaziridine reacts faster than the cis-isomer because the fluorine is closer to the imine hydrogen in the trans-transition state and because the encounter complex for the trans-substrate is higher energy. Adding an N -acetyl group to aziridine increases the rate 3 × 1018 fold by equally decreasing the basicity of the leaving group (making a better leaving group) and increasing the ring strain in the substrate. The substituent effects on the geometry of the N -substituted aziridine ring, the N -inversion energy barriers, and the transition states and activation energies for ring-opening reactions of aziridines by cyanide ion, have been calculated at the B3LYP/6–31+G* level of theory.53 Electron-withdrawing groups on the ring nitrogen, especially those with a C=O or S=O or a phenyl group, stabilize incipient negative charge and thereby induce a faster reaction via an earlier, planar, transition state. Adding an electron-withdrawing C=OCH3 group to one of the carbons of the aziridine ring switches the reaction from the least substituted carbon (CH2 ) to the more substituted carbon (CHC=OCH3 ). A method of preparing either cis- or trans-aziridine carboxylates (39) from N diphenylphosphinylimines (37) and the chiral enolate (36) derived from N -bromoacetyl 2S-2,10-camphorsultam (35) has been reported.54 When the arylimine is substituted in the ortho-position, the product is either a mixture of cis- and trans-aziridine or only the trans-isomer. When the ortho-substituent is H or NO2 , only a cis-aziridine is obtained. The suggested mechanism is partially shown in Scheme 18. Both steric and inductive effects of the ortho- substituent affect the stereochemistry of the addition complex (38) and the stereochemistry of the final aziridine.

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8 Nucleophilic Aliphatic Substitution R

O (35)

(37)

N

Br

THF

S

O

O

.−.

LiHMDS

N

Br

OH

O

S

O O

O (36)

Dpp =

O

Dpp

Dpp

N H

N

S

NDpp

P Ph2

1. LiOH

R

N

2. HCl

R

HO2C

O (38)

(39)

Scheme 18

Two reviews, one on the use of C2 -symmetric chiral bis(oxazolines) in the preparation of aziridines55 and the other discussing the ring opening of aziridines with carbon nucleophiles,40 have been published. Two papers discussing the reactions of azetidines follow. N -Activated azetidines are converted into aminoalkenes in a regiospecific ring opening at the benzyl carbon when treated with allylsilanes and BF3 ·OEt2 in dichloromethane (Scheme 19).56 O Ph Me3Si

+

−

Ar

Ph

S N

NSO2Ar

O +

BF3 (40) Me3Si

H2O

H Ph

NSO2Ar

(41)

Scheme 19

248


The regiospecificity of the ring-opening SN 2 reactions of di- and tri-substituted azetidinium ions with azide ion, benzylamine, acetate ion, and alkoxide ions has also been investigated.57 The products depend on the degree of substitution on the ring, the group on C(2), the nucleophilic atom and the configuration of the substituents on the ring. Epimerization at C(2) also affects the regiospecificity of these SN 2 reactions. Although the product composition is governed by several factors, 2,3-disubstituted azetidinium ions usually react exclusively at C(4) whereas trisubstituted isomers react at C(2). B3LYP/6–31G(d) calculations successfully predict the products of these reactions. Finally, 1,1-dinitrocyclopropane reacts readily with C, N, O, and S nucleophiles opening the ring.58 The yields of 1,1-dinitropropanes range from moderate (50%) to high (88%). When aliphatic amine nucleophiles are used, zwitterionic compounds are produced.

Studies Using Kinetic Isotope Effects The perdeutero KIEs for the reactions between methyl, ethyl, isopropyl and t-butyl chlorides and ClO− , measured in the gas phase using a tandem flowing afterglowselected ion flow tube mass spectrometer, increased from 0.85 ± 0.01 to 0.99 ± 0.01 to 1.72 ± 0.05 to 2.31 ± 0.12, respectively.59 The reactions with isopropyl and t-butyl chloride obviously occur mainly by the E2 pathway whereas methyl chloride obviously reacts by an SN 2 mechanism. The calculated reaction efficiencies for the SN 2 and E2 reactions between ethyl chloride and ClO− have been found to be 2 and 26%, respectively, and the corresponding KIEs were 0.60 and 3.1, respectively, at the MP2/ADZP level of theory.60 An overall KIE of 2.4 was predicted for the gas-phase reaction. The small experimental KIE of 0.99 for the perdeuteroethyl chloride reaction indicates that the SN 2 channel is much more important than the calculations suggest. The discrepancy between the experiment and the calculations was attributed to the difficulty in calculating the barrier height for the two reactions accurately. Six different kinetic isotope effects for the SN 2 reaction between cyanide ion and ethyl chloride were measured in DMSO and in THF to learn how the change in solvent affected the structure of the transition state.61 The secondary α- and β-deuterium, the α-carbon, the k 11 /k 14 nucleophile carbon, the nucleophile nitrogen, and the chlorine leaving group kinetic isotope effects for the reaction showed that the transition state in THF was only slightly tighter than that in DMSO, with very slightly shorter NC–Cα and Cα –Cl bonds. This change in transition-state structure supports the earlier contention that the transition states for SN 2 reactions where the nucleophile and the leaving group have the same charge would not be affected significantly by a change in solvent.62 The results also suggest that the failure of theoretical calculations to reproduce the experimental KIEs in DMSO was not due to a lack of solvent modeling in the calculations.63 The large, inverse, solvent kinetic isotope effects, kCH3 OD/ kCD3 OD = 0.84 and kCH3 OH/ kCD3 OH = 0.74 found in the reaction (Scheme 20) of methanol with the intermediate aziridine (44) produced in the reaction between tetramethylethylene (43) and N -phenyltriazolinedione (42),64 supported the existence of a tight SN 2-type transition state (45) with extensive O–C bond formation in the ring-opening step of the reaction,

249


i.e. these KIEs were attributed to the lesser steric hindrance with the smaller deuterated solvent. The KIEs of kCH3 OD/ kCD3 OD = 0.72 and kCH3 OH/ kCD3 OH = 0.81 found in the reaction with trimethylethylene were taken as evidence of a looser transition state. Ph O

Ph

O N N

+

N (42)

O N

O

+

slow

N

−

CH3(CD3)OH

N

(43) (44) ‡

Ph

O N

O

d+ N

d− N

H

Od H

Ph

CH3(CD3)

O N

O− d

O

NH N

+

OCH3(CD3)

CH3(CD3)

(45)

(46) Scheme 20

The formation of organic fluorides has been a difficult undertaking. However, an investigation of the effect of the solvent, leaving group, and source of the fluoride ion has shown that using tetrabutylammonium fluoride or CsF in t-amyl alcohol is able to convert arene sulfonates into fluorides rapidly at 90 ◦ C in excellent yields (>80%).65 Since the half-life of 18 F is only 110 min, this is an important advance as it allows one to label compounds with 18 F for PET studies. The transition structures and secondary α-deuterium and solvent KIEs were calculated for the SN 2 reactions of fluoride ion (solvated by water, MeOH, or HF) with methyl chloride, bromide, and iodide at the B3LYP/6–31++G(d,p) and MP2/6–31++G(d,p) levels of theory.66 The rotational, vibrational, and translational contributions to the KIEs were also determined. One observation is that the KIEs calculated using the DFT method do not agree with the experimental KIEs. This is because the B3LYP/6–31++G(d,p) level of theory gives less inverse contributions from the out-of-plane bending vibrations. The solvent KIEs (kCH3 OH /kCD3 OD ≈ 0.6) are substantially more inverse than the secondary α-deuterium KIEs (kCH3 X /kCD3 X ≈ 0.8) and the KIEs found by deuterating the methyl group of MeOH (kCH3 OH /kCD3 OH ) are also fairly large and inverse at approximately 0.8. The product of the translational, rotational, and low-frequency vibrational contributions to the total KIE is small and normal whereas the remaining vibrational contribution to the KIEs is large and inverse. It is interesting that the solvent molecule in these calculations increases the steric crowding in the transition state, making the out-of-plane bending

250


contribution to the KIE and the total KIE more inverse. The solvent KIE arises mainly from the change in the OH stretching vibration in water due to loss of the hydrogen bond to the F− ion on going to the transition state. The important discovery however, is that transition-state theory cannot be used to predict either the solvent or the secondary α-deuterium KIEs for fast reactions having small or negative free energies of activation; thus, the calculated KIEs for the slow methyl chloride reaction agree with experiment very well whereas the calculated KIEs for the faster reactions with methyl bromide and especially methyl iodide are much more inverse than the experimental values. This is because the slow step of the fast reactions is the collision of the reactants and not passing over the transition state as transition-state theory requires. Finally, reviews discussing nucleophile carbon k 11 /k 14 ,67 nitrogen k 14 /k 15 ,68 and secondary α-deuterium69 kinetic isotope effects in SN 2 reactions have been published.

Gas-phase Substitution Reactions The substituent effect on the stereochemistry of the SN 1 methanolysis (using Me18 OH+ 2 ) of the pure stereoisomers of 1-arylethanols has been studied at different temperatures in the gas phase in the presence of triethylamine (to absorb the proton released in the SN 1 reaction) and methyl fluoride (to ensure complete thermalization).70 The product with a retained stereochemistry is formed preferentially at or near room temperature in every case. Transition state (47) is favoured for carbenium ions with electron-withdrawing substituents where the greater positive charge on Cα increases the strength of the partial bond between the nucleophiles and Cα . The inverted product is believed to arise from transition state (48) that can form with more stable carbenium ions and those reacting at higher temperatures where the bonding to the nucleophiles is weaker. In fact, a racemic product is obtained at higher temperatures in the reaction where the para-substituent is H. The results are compared with those from similar reactions in solution. H d− H

Me

‡

‡

H

* Me O

* O d+ H Me

H

O H

CF3

d+ H

Me H O H * = 18O

Me (47)

(48)

The SN 2 transition states and the encounter complexes for back- and front-side attack in the gas-phase reactions between X:− and CF3 X have been calculated at the

251


B3LYP/6–311+G(3df)//B3LYP/6–311+G(d) level of theory and determined experimentally using pulsed-ionization high-pressure mass spectrometry.71 The front-side encounter complexes are more stable than the back-side complexes, probably due to the electrostatic repulsion between the nucleophile and the negatively charged fluorines in the back-side complexes. In spite of this, the reactions all occurred via backside attack from the back-side [X–CF3 –X]− encounter complex because the back– side transition states were approximately 20 kcal mol−1 more stable than the front-side transition states. Where it could be checked, the theoretical and experimental values of H ◦ and S ◦ for formation of the encounter complexes agreed very well. Since the Cl:− + CF3 Br SN 2 reaction is described very well by Marcus theory, it is suggested the reaction is initiated by an electron transfer. The perdeutero KIEs measured for the gas-phase reactions between methyl-, ethyl-, isopropyl- and t-butyl-chlorides and ClO− 59 are discussed above.

Nucleophilic Substitution on Elements Other than Carbon Possible mechanisms have been suggested for the alkaline hydrolysis of 5-(N -bromo) iminothianthrene (49) and its cis- and trans-10-oxide and 10,10-dioxide derivatives.72 The base compound (49) and the cis-10 oxide undergo both changes shown in Scheme 21; i.e., formation of (50) by substitution at bromine and oxidation at sulfur. The trans10-oxide and the 10,10-dioxide derivatives either react at bromine only or undergo both the reaction at bromine and at sulfur. S

S

MeOH / KOH aq 60 °C

S

S

BrN

HN (49)

O (50)

Scheme 21

The mechanism of the SN hydrolysis reaction at silicon removing the 5 -t-butyldimethylsilyl group of 3-spiro-5 -(4 -acylamino-1 , 2 -oxathiole-2 , 2 -dioxide) nucleoside derivatives (51) involves neighbouring group participation by the N–H hydrogen of the 4 -acylamino group (Scheme 22).73 Calculations at the B3LYP/6–31+(d) level of theory on modified substrates showed that the 4 -N–H bond was longer, the H–O distance from the 4 -N–H to the O of the 5 -silyloxy group was shorter, and the 5 -Si–O bond was longer in the substrates with a more electron-withdrawing group on the oxygen on the 4 -carbonyl group. All of these factors should increase the reactivity in agreement with experiment. Finally, the greater reactivity found in the most polar solvent tested, DMSO–water, is expected given the proposed mechanism. The potential energy surfaces for the SN 2 reactions at carbon, silicon, and phosphorus have been calculated using the Amsterdam Density Functional method with the

252


O

:OH2

H d+ H O

N H

O

N

O DMSO

N

R

R

H 2O

O

S O O O (51)

O d−

OSi

N

Si O H N

Si O

‡

O

N

O

S O O O

O

OSi

O N HO H N

O

N

O

R O

S O O O (52)

OSi

Scheme 22

OLYP/TZ2P functional.74 The identity reactions where the leaving group was Cl− , OH− and OCH− 3 were investigated. Whereas the SN 2 reaction at carbon showed the expected two encounter complexes and one transition state, the reactions at silicon and phosphorus formed one stable encounter complex and no transition state. Although increasing either the steric crowding slightly or the coordination number on phosphorus does not change the mechanism, increasing both the coordination number and the steric crowding markedly causes the energy of the transition complex to increase and leads to a triple-well potential energy surface. However, adding a more electronegative atom to the phosphorus, i.e. changing a Cl to F, or changing to a better nucleophile, led to a reaction with the formation of a stable encounter complex and no central barrier. An activation strain model was used to illustrate how steric strain and electronic effects affect the central barrier for these reactions. A review75 of the SN reactions at neutral nitrogen, oxygen, and sulfur has been published. The substitution reactions at nitrogen and oxygen predicted by theory and found experimentally occur by an SN 2 mechanism and are faster than the corresponding reactions at carbon. The SN reactions at sulfur, on the other hand, mostly occur by an addition–elimination mechanism, although some SN 2 mechanisms have been


253

suggested. The stereochemistry and mechanisms of the SN reactions at carbon and nitrogen that occur when the nucleophile is an ion pair rather than a free ion, are also included.

Medium Effects/Solvent Effects The effect of high concentrations of MClO4 , M(ClO4 )2 , and R4 NX salts on SN 1 and SN 2 hydrolyses in aqueous sulfolane has been investigated.76 In the SN 1 reaction of 1-adamantyl chloride and 2-adamantyl bromide, increasing the concentration of either MClO4 or M(ClO4 )2 causes a large increase in rate. In fact, the order of rate increase with concentration was Na+ < Li+ < Mg2+ = Ba2+ . The cation was thought to provide electrophilic catalysis in the removal of the leaving group (carbenium ion formation) and by changing the bulk properties of the solvent into those of a non-aqueous solvent. The addition of R4 NX salts decreased the rate of reaction − − − of both adamantyl substrates with the order ClO− 4 < Br < Cl < TsO by decreasing the activity of the water acting as a nucleophile. Increasing the length of the carbon chains in the ammonium ion also decreased the rate of the SN 1 reaction. Cobalt and particularly nickel salts were effective in accelerating the SN 1 reaction of 1-adamantyl chloride. The rates of the SN 2 reactions of n-hexyl halides and tosylate decreased slightly on addition of high concentrations of metal and ammonium perchlorates. The effect was attributed to a decrease in the activity of the water nucleophile. However, adding ammonium halides can either increase (by converting R–Cl into R–Br) or decrease (by converting R–Br into R–Cl) the rates of reaction by introducing a competing SN 2 halide exchange reaction. Raman spectroscopy was used to show that adding salts or organic solvents or increasing the temperature broke up the hydrogen-bonding network in the bulk water solvent. The energy barriers and solvent effects for the SN 2 identity reactions of methyl halides have been calculated in the gas phase and in aqueous solution using several valence bond PCM methods.77 The breathing orbital valence bond (BOVB) and the valence bond-polarized continuum (VBPCM//BOVB) model reproduced the experimental reaction barriers, (F > Cl > Br > I) the solvation energies of X− (F− > Cl− > Br− > I− ) and the theoretical quantum mechanical results very well. The triple-ion VB structure makes the most important contribution to the transition-state wavefunction in the gas phase and this contribution is even greater in solution. The results shed light on the origin of the barrier heights and the solvent effects on these reactions. The nucleophilicity of chloride ion in the SN 2 reaction with methyl benzenesulfonate was found to decrease as the solvent was changed from cyclohexane to acetone to butan-2-one to DMF to acetonitrile to methanol.78 Activation parameters in each solvent are reported. The effect of solvent on the SN 2 reaction between methyl iodide and 2-amino-1methylbenzimidazole has been investigated experimentally in acetonitrile and in the gas phase at two different levels of theory, B3LYP/[6–311++G(3df,3pd)/LanL2DZ]// B3LYP/[6–31G(d)/LanL2DZ] and B3LYP/[6–311++G(3df,3pd)/LanL2DZ]//B3LYP/ [6–31+G(d)/LanL2DZ].79 The effect of the acetonitrile was determined using the

254


PCM model. AIM calculations were also used to investigate hydrogen bonding in each intermediate. The experimental and theoretical results are in excellent agreement. The calculations also indicate the reaction will be much faster in acetonitrile than in the gas phase, as one would expect for a process forming ionic products. The energies and structures of the transition states and the activation parameters for the SN 2 reactions between para-substituted benzyl bromides and bromide ion or pyridine have been calculated at the B3LYP/6–31G(d) level of theory in the gas phase and in acetone using the PCM model.80 The charges, bond lengths, and bond angles for the transition states for reaction in the gas phase and in acetone correlated with the Hammett σ and σ + constants, respectively. An electron-withdrawing para-substitutent leads to a tighter transition state in the gas phase. The substituent effects are larger and the transition states looser in acetone. In the gas phase, both G = and H = correlated with σ whereas in solution both the calculated and experimental G = and H = were a maximum when the para-substituent was H, i.e. both electron-donating and electron-withdrawing substituents increased the rate of reaction with bromide ion. The calculated G = and H = are smaller than the experimental values. This was attributed to the form of the bromide ion, i.e. a free ion in the calculations and an ion pair in acetone. The reactions with pyridine have different transition states in the gas phase and in solution, i.e. the transition states are central in acetone and methanol but product-like in the gas phase. This is attributed to the attraction of the developing positive and negative charges on these transition states in the gas phase. The calculated changes in geometry of the transition states and in G = and H = correlate with σ in the gas phase but σ + in solution. As in the reaction with bromide ion, however, the G = and H = values in acetone are maximum when the para-substituent is H. Also, the substituent effect is again greater in solution than in the gas phase. Finally, the failure of the calculations, even at higher levels of theory, to calculate the breaks in the G = and H = versus Hammett substituent constants in solution suggests that solvation effects play an important role in these reactions. Finally, the substituent effects on the pyridine nucleophile are smaller than those on the substrate and both the calculated and experimental G = and H = correlate with the corresponding σ values. A better nucleophile leads to a later transition state. The rate of the SN 2 reaction between benzyl bromide and benzimidazole in 11 solvents was found to vary with two properties of the solvent: the polarizability and the hydrogen bond acceptor (basicity), with a slightly stronger correlation with the polarizability of the solvent.81 The importance of the polarizability is due to the need to solvate the developing positive charge on the nitrogen nucleophile in the transition state. The hydrogen bond acceptor ability is required for solvating the developing negative charge on the bromide ion in the transition state. The G = values become smaller and the S = values more negative when the solvent is changed from methanol to most other solvents. This behaviour is found because of the developing charges in the transition state. The usual V-shaped Hammett ρ plot with the slowest reaction for the unsubstituted benzyl bromide was observed for the reaction. Finally, the reaction is less affected by substituents at higher temperatures.


255

The rate of the SN 2 reaction between p-nitrobenzyl bromide and 2-mercaptobenzoxazole has been measured in 14 protic and dipolar aprotic solvents.82 The rates correlated strongly with the electron pair accepting ability and the hydrogen bond accepting ability of the solvent, with the former being almost twice as important as the latter. The transition state is more highly solvated than the reactants. The solvent hydrogen bond accepting ability is important because it solvates the developing chloride ion and the electron pair accepting ability is important because it solvates the developing positive charge on the sulfur nucleophile. The G = values are effectively independent of the solvent. The solvolysis of trimethylsilyl trifluoromethanesulfonate has been determined in several solvents and solvent mixtures.83 The two-term Grunwald–Winstein equation indicated that the rates were strongly dependent on the nucleophilicity and only slightly dependent on the ionizing power of the solvent. This, and the large negative S = found in four solvents, suggest the reactions occur by an SN 2 mechanism. The trimethylsilyl group does not affect the rate appreciably, probably because the steric and electronic effects of the trimethylsilyl group are almost equal. The rate of the solvolysis reaction between 3-methyl-3-chlorobut-1-ene and 13 different alcohols correlated (r = 0.977) with the solvent’s ET value.84 The weak negative correlation with solvent nucleophilicity and the first-order kinetics was taken as evidence that the reaction occurs via an SN 1 mechanism. A detailed reassessment of several multi-parameter correlations describing the solvent effects on the rates of four solvolytic SN reactions has shown that great caution should be exercised when using these relationships.85 The conclusions based on the multi-parameter correlations are not reliable because (i) both random and systematic errors have been underestimated, (ii) mechanisms may change when different substrates are involved, (iii) data extrapolated from different temperatures, and (iv) only small numbers of samples have been used in establishing these relationships. The N/s values [where log k = s(E + N )] for several carbanion (nitronate and malonic acid derivatives) nucleophiles have been determined using benzhydrilium ions in MeOH–acetonitrile (9:91 v/v) and compared with the corresponding values in H2 O and in DMSO.86 With one exception, − CH(CN)2 , the nucleophilicity increases from water to MeOH to DMSO by varying amounts. The difference in behaviour is attributed to solvation rather than to the basicity of the anions. Finally, a study in which six different kinetic isotope effects for the SN 2 reaction between cyanide ion and ethyl chloride were measured in DMSO and in THF has shown that the transition state in THF was only slightly tighter than that in DMSO with very slightly shorter NC–Cα and Cα –Cl bonds,61 and another on the effect of the solvent, leaving group, and source of the fluoride ion in synthesizing organic fluorides is discussed above.65

Micelles and Phase-transfer Catalysis in Substitution Reactions Several studies have examined the effect of micelles on the rates of SN reactions. The SN 2 reactions of (53), (54), and (55) with bromide ion have been studied in wet CH2 Cl2

256


in the presence of the reversed micelles formed from cetyltrimethylammonium bromide (CTA), cetyltripropylammonium bromide (CTPA), and tetra-n-butylammonium bromide (TBA).87 The rates of (53) and (54) increase markedly in the presence of the micelles whereas the rate of (55) does not, presumably because the positive (55) does not interact with the cationic micelle. It is suggested that (55) reacts fastest because of the ionic attraction between the charges on the substrate and the bromide ion; (53) reacts the slowest. The rate of reaction of (55) decreases as the micelles change from TBA to CTPA to CTA. This occurs because the bromide ion interacts more strongly with the ammonium ion when the head group is smaller. Adding more water to the reaction mixture reduces the rate of all three reactions until the ratio {[H2 O]/[CTA]} = w0 ≈ 6, where ‘water pool’ reverse micelles form. The initial decrease in rate on adding water presumably occurs because water solvates the bromide ion by hydrogen bonding. Adding water does not change the relative reactivity of (53)–(55). SO3Me SO3Me −O

SO3Me 3S +NMe

(53)

(54)

3

(55)

The effect of different cationic micelles on the SN 2 reaction between methyl 4nitrobenzenesulfonate and bromide ion has been studied.88 The micelle systems were hexadecyltributylammonium bromide and four alkyltriphenylphosphonium bromides featuring C10 -, C12 -, C14 -, and C16 -alkyltriphenylphosphonium groups, respectively. As expected, the rate of reaction increases with increase in the surfactant concentration and the hydrophobic chain length of the surfactant for all of the surfactants tested. However, the rate increases are greater with the alkyltriphenylphosphonium bromides. Reasons for this are suggested. Two mixed micelle systems investigated had slower rates and showed non-ideal behaviour. Only a mixed micelle system of two triphenylphosphonium salts showed ideal behaviour. Molecular modeling at the HF/6–31+G* level of theory using a single surfactant molecule suggested that the superior catalysis of the alkyltriphenylphosphonium bromides was due to (i) the phosphorus being positively charged whereas the nitrogen is negatively charged in the ammonium salt surfactants because its positive charge is distributed over its substituent groups and/or (ii) the bromide ion interacting less strongly with the alkyltriphenylphosphonium head group due to steric hindrance with the phenyl substituents; this allows more room for substrate binding. Adding more tetradecyltrimethylamonium bromide micelles to the SN 2 reaction between methyl naphthalene-2-sulfonate in aqueous DMSO increases the rate by (i) increasing the amount of substrate in the micelle where the bromide ion concentration is high, (ii) increasing the electrophilic interaction of the ammonium head groups with the developing naphthalene-2-sulfonate ion, and (iii) disrupting the hydration shell around the bromide ion nucleophile. However, increasing the proportion of DMSO

257


decreases the catalytic effect of the micelles.89 This occurs because (i) the substrate does not bind to the micelles as well at higher [DMSO], where the bulk phase becomes a better solvent for the substrate, and (ii) the micelles become smaller, i.e. they ionize more, so less substrate is bound in the micelles, thereby reducing the amount of reaction catalysed by the micelle. The rate constant for the SN 2 reaction in the micelle is not affected significantly by the amount of DMSO in the solvent. Three papers have reported on phase-transfer types of catalysis. The ionic liquid butylmethylimidazolium tetrachloroferrate catalyses the biphasic SN reaction between primary and secondary alkyl halides with β-hydrogens and the Grignard reagent pFC6 H4 MgBr.90 The yields ranged from 60 to 89%. The other two papers have investigated the catalytic effect of 1,4-benzenedimethanol on the SN 2 reaction between acetate ion and ethyl chloride in DMSO.91,92 Calculations using the ONIOM[CCSD(T)/6–311+G(2df,2p):MP2/6–31+G(d)] level of theory and the PCM solvent continuum model suggest that the overall effect of the catalyst is to reduce G = by 5.9 kcal mol−1 by stabilizing the transition state (56), even though the catalyst also stabilizes the acetate ion. Another advantage of this type of catalysis is that it should reduce the amount of any competing E2 reaction. These calculations also suggest that the catalysis of the SN 2 reaction between alkyl chlorides and acetate ion by 1,4-benzenedimethanol will be more effective for primary alkyl chlorides than for secondary alkyl chlorides.92 The catalytic effect in DMSO is smaller for secondary chlorides, i.e. the catalyst reduces G = by 4.7 kcal mol−1 for the propyl chloride reaction whereas it reduces G = by only 0.6 kcal mol−1 for the isopropyl chloride reaction. The catalytic effect is smaller for isopropyl chloride because (i) the transition state is looser and solvation of the nucleophiles in the transition state is greater making catalysis less important and (ii) increasing steric hindrance between the substrate and the catalyst makes catalyst binding weaker. H 2C

CH2

O

O H

H H Nu d−

C R1

X d−

R2 = H, R

R2 (56)

Structural Effects The effect of changing the nucleophile in an SN reaction continues to attract considerable interest. A study of the rates of the SN 2 reactions between S-methyldibenzothiophenium ion or methyl iodide and many nucleophiles93 has shown that the

258


nucleophilicity towards Csp2 and Csp3 are closely related. This has led to the suggestion of a new equation, log k = sE sN (E + N ), where sE is the electrophile specific slope, sN is the nucleophile specific slope, E is the electrophilicity parameter and N is the nucleophilicity parameter, relating nucleophilicity to reactivity. It is important to note that this equation encompasses the familiar log k = sN (E + N ) used for the SN 1 reactions of benzyhydryl substrates, etc., when sE = 1.0, the familiar Swain–Scott equation when sN = 0.6, and the Ritchie equation when sE = 1.0 and sN = 0.6. Some possible limitations for the new equation are suggested. A log ks = sf (Ef + Nf ) equation relating the rate of solvolyses to the nucleofugality (the leaving group ability) of a leaving group in a specific solvent and from a specific substrate has been proposed,94 where Nf and sf are nucleofuge-specific parameters and Ef is an electrofuge-specific parameter. The nucleofugality, Nf , which varies with the substrate, leaving group, and solvent, is found from ks by setting sf = 1.00 and Ef = 0.00 for the 4, 4 -diansylcarbenium ion and the leaving group Cl− in ethanol at 25 ◦ C. Nf values were reported for TsO− , Br− , Cl− , CF3 CO− 2 , 3,5-dinitrobenzoate and p-nitrobenzoate in EtOH, 80% EtOH–water, MeOH, TFE, and 80 and 90% acetone–water. Ef values were also found for several substituted benzhydryl carbenium ions. The solvent effect on the ionization rates ks for benzhydryl-LG correlates with the negative charge density on the leaving group (LG) and falls in the order R-Cl > R-Br ≈ R-OTs > R-CF3 CO2 > R-3,5-dinitrobenzoate. The Ef value correlates very well (r 2 = 0.992) with the Hammett σ value and inversely with the electrophilicity parameter (r 2 = 0.996) E from the log k = s(N + E) equation. In a second publication, Ef and Nf values for the log ks = sf (Ef + Nf ) equation have been determined for many new carbenium ions and leaving groups in different solvents.95 An analysis of the data indicated that sf was equal to or near 1.0 for most SN 1 reactions and that compounds having (Ef + Nf ) > −2 solvolyse with halflives of −6.5 solvolyse with half-lives of >1 month. Substrates with intermediate values of (Ef + Nf ) react at measureable rates at 25 ◦ C. Hence, one can use the Nf and Ef values to determine if a substrate will be stable during purification and or a synthetic transformation or whether it will undergo solvolyses too fast to be purified or reacted. A critical analysis of the log ks = sf (Ef + Nf ) equation has been published96 and new equations that provide more reliable Ef and Nf values have been suggested. The proposed Ef and Nf values are Ef = log kRCl/EtOH/25 ◦ C – 1.87 and Nf = 6.14 + log kBX/any solvent/25 ◦ C , where RCl and BX are chlorides and benzhydryl substrates, respectively. A new equation, log kt-alkylX/any solvent − Ef + Nf where Nf = 3.90 + Yany solvent + log k(X/Cl) is proposed for the solvolysis of t-butyl chloride and similar substrates. The nucleophilicity scale based on the stretching frequency of the hydrogen bond between a nucleophile and an acid (Nu–HX) 97 was tested against experiment using the hard acids HF, HCN, and BF3 and the soft acid BH3 .98 The correlation with the hard acids is excellent but fails when a soft acid is used. A new nucleophilicity index, ω− = 12 [(µA − µB )2 /(ηA + ηB )2 ]ηA , where µA , and µB , are the chemical potentials of the nucleophilic and electrophilic molecules, respectively, and ηA and ηB are their respective hardnesses, has been proposed. This gives the relative nucleophilicity that is


259

based on the electrophile used. The µ and η values are found using the frozen orbital and finite difference approximation, respectively. The new nucleophilicity scale has been tested using gas-phase SN 2 reactions of MeCl, MeBr and MeOCOCF3 . The reaction efficiency, the rate of reaction/rate of collision, correlated with ω− for the MeCl and MeBr reactions (r = 0.980 and 0.923, respectively) but less well for the MeOCOCF3 reactions where r = 0.851. The potential energy profiles of 18 identity SN 2 reactions of methyl substrates − − − − − − − − where the nucleophile is NH− 2 , OH , F , PH2 , SH , Cl , AsH2 , SeH , or Br and their protonated (neutral) form, have been estimated in the gas phase using G2 quantum-chemical calculations.99 The barrier heights, which are calculated to within 10 kJ mol−1 , and the geometry of the transition states, are very similar for anionic and neutral nucleophiles. The width and height of the central barrier and the imaginary frequency vary significantly with the nucleophile. The barrier height decreases from left to right in the periodic table and is related inversely to the ionization energy of the nucleophile. Reactions where the substrate has a greater charge separation have lower central barriers due to decreased electron repulsion in the transition state. Where they form, the front-side encounter complexes (CH3 –X–X) are more stable than the − − − back-side encounter complexes. However, PH− 2 , SH , AsH2 and SeH do not form an encounter complex. The SN 2 transition states, however, display the normal Walden inversion. The C–X bond length in both the reactants and transition states decreases as the nucleophilic atom moves from right to left and up a column in the periodic table. The C–X transition state bond length increases with the height of the central barrier for both the neutral and negative nucleophiles. Finally, it is suggested that nucleophilicity is determined by two factors, exothermicity of the reaction (basicity of the nucleophile) and the intrinsic reactivity (barrier height) of the nucleophile. Intrinsic nucleophilicity will dominate for thermal neutral and slightly exothermic reactions while nucleophilicity will be related to basicity in very exothermic reactions. A kinetic study showed the SN reactions between meta- and para-substituted pyridines and para-substituted α-chloroacetanilides (57; R = H) were faster than those with para-substituted N -methyl-α-chloroacetanilides (57; R = Me).100 Also, the small and negative cross-interaction constants (ρXY = −0.06 and −0.10, respectively) and the small Brønsted βX coefficients (0.30 and 0.32, respectively) for the two sets of substrates and the failure of the reactivity–selectivity principle suggest the mechanism involves a slow nucleophilic attack on the carbonyl carbon followed by a rapid concerted transfer of the nucleophile and expulsion of the leaving group from intermediate (58) (Scheme 23). The N -methyl substrate reacts slower because the methyl group reduces the positive charge on the carbonyl carbon in the rate-determining step of the reaction. A kinetic study in 50% aqueous DMSO has shown that the first step in the threestep mechanism (Scheme 24) proposed for the SN V reaction between para-substituted (methylthio)benzylidene Meldrum’s acids (61) and four aliphatic primary amines is rate determining.101 The evidence supporting this mechanism is that the reactions are second order kinetically and show no base catalysis. A value of βnuc = 0.32 for the reaction with primary amines is smaller than the βnuc = 0.41 found for the reaction with the less reactive secondary amines, indicating that N–Cα bond formation is more

260


R YC6H4

O

R O− Cl + NC5H4X

N C CH2

slow

YC6H4

R = H, Me

N C CH2Cl +

(57)

NC5H4X

(58) d− d− O Cl

R YC6H4

R YC6H4

N C CH2 d2+ NC H X

O +

− NC5H4X + Cl

N C CH2

5 4

(60)

(59) Scheme 23

advanced in the transition state of the latter reaction. This is a Hammond–Leffler effect. Hammett plots found by changing the Z substituent gave ρ = 0.40 for the reaction with butylamine. Larger Hammett ρ values were found for the reaction with piperidine and oxygen and sulfur nucleophiles, confirming an earlier transition state with less N–Cα bond formation and less positive charge on nitrogen in the butylamine (the primary amine) reaction. The Hammett ρ values for the SN 2 reaction between diphenylamine and parasubstituted benzyl bromides in methanol decrease from 0.64 to 0.10 as the reaction Z

Z O

MeS

C

O

O

Me

slow

O

Me

RNH2

C

MeS

C

C

+

RNH2

O (61)

−

O

Me

O

Me

O

Z Z O −

H+

MeS

C RNH

C

O −

O O

Me

− MeS−

Me

O Scheme 24

C RNH

O

Me

O

Me

C O

261


temperature increases from 298 to 313 K.102 This suggests that the isokinetic temperature (where the substituent effect = 0.0) is 315 K. The H = values vary directly with the S = values for these reactions. The solvolysis rates of 2-(dimethylphenylsilyl)-1-(Y-phenyl)ethyl 3,5-dinitrobenzoates (62) in 60% aqueous ethanol were analysed using using the Yukawa–Tsuno equation.103 The ρ value of −2.95 with r ≈ 1.04 found by changing the α-aryl substituent was much smaller than the ρ value of −5.45 found for the corresponding non-silylated system. This, the fact that the rate constant for the silylated substrate was >105 -fold faster than the rate of the non-silylated compound, and the small α value of 0.52 found from the log(kY /kH )Si = α log(kY /kH )non-Si plot was taken as evidence that the reaction of the silyl compound occurred via a tight transition state with significant neighbouring silyl participation (Scheme 25). Ph

Ph

Ph MeSiMe H H Ar H O TNB (62)

MeSiMe slow

H

EtOH / H2O

H

+

H Ar (63)

NuH

MeSiMe H H Ar H Nu (64)

Ar = Y.C6H4 TNB = 3,5-trinitrobenzoyl Scheme 25

The SN reactions of cyclohexanone acetals substituted at C(2) with sulfur, iodine, or chlorine are thought to occur when the nucleophile attacks the oxocarbenium ion intermediate with the substituent on C(2) in an axial conformation.104 The most stereospecific reactions (i.e. ≥92% trans), were when the substituent at C(2) was sulfur. This mechanism (Scheme 26) is supported by HF/6–31G* calculations that show the oxocarbenium ion (66) with the sulfur at C(2) in the axial position to be the most stable, and by the high yield of the trans-isomer (67) in the products. Finally, the substituent effects on the geometry of the N -substituted aziridine ring, the N -inversion energy barriers, and the ring opening reactions of aziridines by cyanide ion53 have been discussed

Theoretical Studies Most of these theoretical investigations have been carried out using methyl compounds as the substrate. For example, the SN 2 reaction between OH− and methyl chloride has been investigated for non-linear and linear collisions using ab initio molecular dynamics calculations.105 The potential energy surface was calculated at the MP2/6–311++G(2df,2pd) level of theory and the collision energy was set at 25 kcal mol−1 . The results for 495 trajectories indicated that the reactants pass from the initial encounter complex to the transition state in 0.02 ps and to the product encounter

262

Organic Reaction Mechanisms 2006 SPh

SPh OMe

But

BF3.OEt2

But

+

OMe

OMe (66)

(65)

Nu−

SPh OMe

But Nu (67) Scheme 26

complex in another 0.04 ps. The total reaction is over in 0.30 ps. Some of the energy is transferred into the internal modes of the product while 72% goes to translational motion of the products. The populations of the translational energies are different for the linear and non-linear collisions, being broader for the non-linear collisions. Although the maximum translational energy is normally found for a collinear reaction, the maximum translational energy in this reaction occurs when the incoming nucle˚ from the straight line defined by the linear transition state geometry. ophile is ∼1.2 A This is because the transition state is slightly bent with an O–C–Cl angle of 183.1◦ . B3LYP/6–311++G**-level calculations have been used to predict the structure of the encounter complex (68) for the SN 2 reaction between F− and methyl chloride in the presence of one molecule of water.106 Structure (68) was chosen as the encounter complex even though it does not have the lowest energy, but because it has the greatest negative charge on fluorine. Structure (69) is the encounter complex for the reverse reaction.

C

1.841

1.434 C

F

Cl

1.099

1.090

2.256

2.274 1.851

Na

0.977 F

O

2.252 O

1.998

Na (68)

2.242

2.525 Cl

0.984

0.960

2.246 (69)

2.763

263


The SN 2 reactions of a free cyanate ion or a lithium isocyanate ion pair with methyl halides have been investigated at the MP2/6–311+G(d,p) level of theory.107 Although the ion-pair reactions are slower than the free-ion reactions, the calculated H = decreases in the order MeF > MeCl > MeBr > MeI as expected for both the free-ion and ion-pair reactions. The calculations also show that both the free-ion and ion-pair reactions occur with inversion, rather than with retention of configuration, via the transition states (70) and (71), respectively. In both the free-ion and ion-pair reactions, the percentage extension of the C–X bond in the transition state decreases when a better leaving group is used, i.e. the transition state is earlier for leaving groups having a smaller C–X bond dissociation energy. Finally, including the solvent DMSO in calculations using the PCM approach leads to a much slower reaction with a looser transition state but does not change the mechanism of either the free ion or the ion pair reaction. In agreement with experiment, the calculations predict that the only product in the gas phase and in solution will be methyl isocyanate. Li

O N

C

X

C X

C

N

O

C

(70)

(71)

The SN 2 reaction between lithium isothiocyanate ion pair and methyl fluoride has been calculated at the MP2(full)/6–311+G**//HF/6–311+G** level of theory in the gas phase and in acetone using the PCM model.108 Both the gas phase and acetone reactions occur with inversion, rather than retention, of configuration. However, the transition states and products are different in the gas phase and in solution; methyl thiocyanate is formed in the gas phase by transition state (72) whereas methyl isothiocyanate is formed much more slowly in acetone via the looser transition state (73).

N

2.038

S

Li

C 136.8 S

1.714

2.053

(72)

Li

C

F

2.545

2.834

147.8

N

1.722 F

2.136

2.091

(73)

264


The mechanism for the fluorination of methanol by diethylaminosulfur triflouride (74) has been investigated in the gas phase and in dichloromethane using the RHF and B3LYP methods with the 6–31G+** basis set and truncated structures for the reactants.109 Solvent effects were calculated using the PCM approach. Truncating the reactant did not affect the results significantly. The results suggest that fluorination occurs via an SN 2 mechanism in both the gas phase and dichloromethane, (Scheme 27). F

F Et2N

S

F + MeOH

Et2N

S F

F (74)

F− SN2

F

F Et2N

H O

OMe + HF

S F

Me

−

F Et2 N

S

O Me

F

F

F MeF

+

Et2N

S

O

F Scheme 27

A direct dynamics simulation of the SN 2 identity reaction of CD3 Cl at the MP2/6– 31G* level of theory110 found that the dynamics of the trajectories from the transition state were inconsistent with both RRKM and transition state theory. The reaction force, the negative derivative of the potential energy along the intrinsic reaction coordinate, for the gas-phase SN 2 reaction between water and methyl chloride has been calculated at the B3LYP/6–31G* level of theory.111 The calculations show that there are four different regions for the reaction force of an SN 2 reaction (Fig. 1). These are: (1) a preparation region leading to a minimum value of the reaction force where the reactants become orientated for reaction, which requires an expenditure of force, (2) an increasing reaction force to a value of zero at the transition state as the driving force for the reaction begins to be realized, (3) an increase in the reaction force as the structural changes for the reaction are completed and the driving force for the reaction is maximized, and (4) a relaxation region to a reaction force of zero as the molecules relax to their equilibrium state. In region 1–2, the C–Cl bond lengthens, the carbon approaches planarity, and hydrogen bonds between the Cl and a H on water and between the O and a methyl H begin to form. In region 2–3, to C–O bond begins to form, the C–Cl bond continues to lengthen, and the hydrogen bond between Cl and a H on water strengthens. In region 3–4, the new O–C bond formation, the C–Cl bond rupture, and the Cl–H bond formation are completed. In region 4, the molecules relax to their equilibrium energies. The changes in charge density of the atoms, the charge separation during the reaction, the electrostatic potential, and the average ionization energy of the system all reach their maximum values at the end

265

Force


0.0

1

2 3 4 Intrinsic reaction coordinate

Figure 8.1

of region 3. It is worth noting that the maximum rate of change in these properties occurs at the transition state. MP2/6–31++G(d,p) and G3m calculations of the identity reactions between protonated methyl, ethyl, isopropyl, and t-butyl amines, alcohols, and fluorides led the author to suggest that the SN 1–SN 2 model needs to be rethought.112,113 Two problems have been identified. First, while simple theory predicts the reactivity decreases from methyl to ethyl to isopropyl to t-butyl for steric reasons, the calculations indicated this order was only found for the reactions with NH3 . The order when water is the nucleophile was t-butyl > isopropyl > methyl > ethyl and the fluoride ion reactions all occurred at nearly the same rate. Another problem was that the preference for back-side attack decreases in the order methyl > ethyl > secondary > tertiary for the reaction with NH3 and water, whereas even the protonated methyl fluoride reacts by a front-side attack. In fact, front-side attack becomes more favourable as the size of the alkyl group increases and a better leaving group is used. This suggests that the SN reactions of secondary and particularly tertiary substrates with very good leaving groups may occur by front-side attack. Front-side attack has also been observed for other SN 2 processes with special structural properties. The SN reactions between HF and protonated methyl, ethyl, isopropyl, and t-butyl fluorides in the gas phase have been examined at the MP2/6–31++G(d,p) level of theory.112,113 The reaction of CH3 FH+ clearly occurs via back-side attack as the transition state for this process is of lower energy than the transition state for frontside attack. The EtFH+ can react via a more stable back-side SN 2 reaction or an SN 1 reaction via front-side attack since the SN 1 pathway is 4.4 kJ mol−1 lower in energy. No SN 2 path could be found for i-PrFH+ and the front- and back-side pathways had equal activation energies for t-BuFH+ , which effectively reacts by an SN 1 mechanism. The conclusion is that the preference for back-side attack is reduced as the size of

266


the alkyl group and the leaving group ability increase. Again, it is concluded that the results of SN reactions should be understood by a competition between front- and back-side attack rather than from competing SN 1 and SN 2 mechanisms. A comparative static (time-independent) and dynamic (time-dependent) conversion of the transition state for the gas-phase methyl chloride identity SN 2 reaction into the product ion–molecule complex has been carried out using the hybrid PBE0 functional and the 6–31+G(d,p) basis set.114 The static approach follows the intrinsic reaction coordinate while the dynamic approach is based on the atom-centred density matrix propagation (ADMP) model and quantum chemical topology (QCT) analyses. A three step-electron charge-transfer mechanism has been proposed for the static process whereas a five-step electron charge-transfer mechanism is required for the dynamic pathway where there is a stronger electron exchange leading to a maximization of both covalent and non-covalent interactions during the formation of the product ion–molecule complex. The QCT approach reveals the crucial role of the electron charge transfers during the reaction. Other calculations using more complex substrates have been undertaken. Two of these deal with the reactions of polyfluorosulfonate esters. The SN reaction between CF3 CH2 OSO2 R and F− could occur at either the Cα H2 carbon or at the more positive S.115 DFT calculations at three different levels of theory up to B3LYP/6–311++G** have confirmed the experimental observations that the reaction only gives the product resulting from F− attack at Cα . Although the energies of the transition states for Cα and S attack are virtually identical, the energy from the encounter complex to the transition state for attack at Cα is 2.2 kcal mol−1 less than that for attack at S. More important, however, is that attack by F− at S is reversible whereas that at Cα is not. Therefore, the product will only be that from attack at Cα . It is worth noting that interaction between the attacking fluoride ion and the Cβ F3 carbon stabilizes the transition state for reaction at Cα . Calculations using the PCM approach show that the reaction is at Cα in both cyclohexane and DMSO and is faster in DMSO. Finally, the calculations suggest that the SN 2 reaction between fluoride ion and perfluoro isomer (CF3 CF2 OSO2 CF3 ) occurs via a front-side SN 2 reaction at S displacing a CF3 CF2 O− anion.115,116 The transition state for attack at S is of lower energy than that for attack at Cα because the attacking fluoride ion can still be stabilized by an interaction with the carbon of the terminal CF3 group and because of the better leaving group. The SN 2 reaction at S is irreversible because the CF3 CF2 O− anion undergoes a rapid decomposition to CF3 COF + F− . The SN 2 portion of the substitution reaction converting chlorosuccinate dianion into malic acid involves the formation of either an α- or a β-lactone intermediate.117 PCM/B3LYP/6–31+G* calculations have shown that the reaction in water goes via the β-lactone with a central transition state where the C–Cl and C–O bond orders are 0.37 and 0.43, respectively. The transition state for the formation of the α-lactone is product-like with C–Cl and C–O bond orders of 0.1 and 0.7, respectively. The βlactone route is favoured because (i) the O–C–Cl bond angle of 174◦ in the transition state forming the β-lactone is much greater than the 139◦ required for forming the α-lactone, (ii) there is less ring strain in the earlier transition state in the β-lactone reaction, and (iii) the coulombic repulsion between the negative charges in the substrate


267

are relieved on going to the transition state. The α-lactone route is favoured in the gas phase because the unfavourable electronic interaction between the negative chlorine and carboxylate oxygens on the adjacent carbon is reduced as the α-lactone is formed. The different mechanisms in the gas phase and in solution show that solvent plays a very important role in this reaction. Calculations at the B3LYP and MP2 levels of theory with the 6–31+G* basis set were used to model the SN 2 reactions of the intermediates formed when alkyllithiums were reacted with several 1,1-dibromo- and 1,1-dichloro-alkenes.118 The calculations showed, correctly, that the most sterically constrained halogen was attacked in the first step of the reaction and that the intramolecular substitution reaction in the second step of the reaction occurred by an SN 2 mechanism. Other theoretical studies discussed above include investigations of the potential energy profiles of 18 gas-phase identity SN 2 reactions of methyl substrates using G2 quantum-chemical calculations,99 the transition structures, and secondary α-deuterium and solvent KIEs for the SN 2 reaction between microsolvated fluoride ion and methyl halides,66 the SN 2 reaction between ethylene oxide and guanine,37 the complexes formed between BF3 and MeOH, HOAc, dimethyl ether, diethyl ether, and ethylene oxide,38 the testing of a new nucleophilicity scale,98 the potential energy surfaces for the SN 2 reactions at carbon, silicon, and phosphorus,74 and a natural bond orbitalbased CI/MP through-space/bond interaction analysis of the SN 2 reaction between allyl bromide and ammonia.17

Miscellaneous Kinetic Studies The solvolysis of (S)-1-(3-nitrophenyl)ethyl tosylate, 18 O-labelled in the sulfonyl oxygens of the tosylate group, in 50% v/v aqueous trifluoroethanol has been investigated.119 The rate constants kisom , krac , and ksolv (where kisom is the rate constant for the exchange of the 16 O oxygen bonded to the carbon in the substrate with an 18 O oxygen on the sulfur of the leaving tosylate group, krac is the rate constant for conversion of the S to the R stereoisomer, and ksolv is the rate constant for the formation of the solvolysis product) were determined for the reaction. It was concluded that the reaction cannot go via a carbenium ion pair intermediate, for two reasons. First, the ratio kisom /krac ≈ 80 and the maximum kisom /krac was estimated to be ∼ 7 for a reaction going via an ion-pair intermediate. The carbenium ion-pair mechanism was also eliminated as a possibility because ksolv /kisom ≈ 260. Since kisom = 1.5 × 1010 s−1 and ksolv /kisom ≈ 260, ksolv would be greater than the diffusion controlled limit. Since this is not possible, a new mechanism (Scheme 28) in which solvent reorganization occurs before the ionization step has been proposed for this reaction. Finally, it is suggested the 16 O– 18 O isomerization occurs on a flat energy surface, i.e. with no acti− vation energy, via a [C+· α OSO2 Ar] intermediate that forms by stretching the Cα –O bond in the substrate. The rate constants and equilibrium constants for the formation of THF from butane1,4-diol in water have been measured at temperatures between 200 and 350 ◦ C.120 Although the reaction is reversible, the yield of THF at 350 ◦ C is 94%. The reaction rate increased with decreasing pH at all temperatures, although the change in rate with

268


O H O H

H

H

O

O O H H H

kas

H

H

C X

H C X

O

H

H

H

k1 k−1

O H H H O H

O H C

+

X−

H O

O

ks

H

H

H +

O C

H X−

H Scheme 28

decreasing pH at near-neutral conditions was very small. Adding CO2 to the reaction increased the rate two and three times at 250 and 300 ◦ C, respectively, by forming H2 CO3 and decreasing the pH. However, the effect of adding CO2 was smaller than expected because the kinetic order with respect to H+ was only ∼0.4. This indicates that water can be the source of the proton needed for the reaction. The mechanism involves three steps: (1) protonation of the diol by water or H+ , (2) a rate-determining cyclization to form the protonated THF, and (3) deprotonation to give THF. Kinetic equations and the rate constant and activation energy for each step of the reaction are given. The effect on the solvolysis rate of replacing a methyl group of cumyl chloride with an ethyl, isopropyl, or t-butyl group has been determined in 90% aqueous acetone and 90% aqueous acetonitrile.121 The greater reduction in the rate of reaction with increasing size of the replacing group (by 3.5 with ethyl to 625 times with t-butyl) in 90% aqueous acetone correlates (r = 0.991) with Charlton’s steric factor. This reduction in rate has been attributed to a steric effect that reduces the planarity and the resonance stabilization of the developing carbenium ion in the transition state rather than to a small electronic effect. Although the reaction is 10 times faster in the more polar solvent (90% aqueous acetonitrile), as one would expect, the reduction in rate with increasing size of the substituting group is effectively identical with that found in 90% aqueous acetone and the correlation with Charlton’s steric factors is even higher at 0.995. Changing one of the methyl groups on the substrate to ethyl does not change the Hammett ρ + value significantly. This shows that adding the ethyl group does not affect the stabilization of the developing carbenium ion by the benzene ring significantly. The rates for the SN 2 reactions of seven different anionic nucleophiles (Cl− , Br− , I− , OAc− , CN− , SCN− and trifluoromethylacetate− ) with methyl p-nitrobenzenesulfonate have been determined in CH2 Cl2 , MeOH, DMSO, and three ionic liquid solvents.122 The reactivity was not correlated with the dielectric constant for the solvents as predicted by the Hughes–Ingold rules and a different nucleophilic order was found in

269


each solvent. Moreover, the change in rate from MeOH (the slowest) to DMSO (the fastest) varied with the nucleophile, e.g. the rate for SCN− increased only 13-fold whereas that for acetate ion increased 6471-fold. The rates for each nucleophile were examined using the three-parameter Kamlet–Taft equation that is based on the ability of the solvent to form hydrogen bonds (α), the ability of the solvent to accept a hydrogen bond (β) and the polarizability of the solvent (π *). There was a strong negative correlation with α for all the nucleophiles, i.e. the rate decreases as the solvent becomes more able to hydrogen bond to the negative nucleophile. Also, as expected, the dependence on α increases with the hardness of the nucleophile. Large positive correlations with π * were found for three nucleophiles (CN− , OAc− , and TFA− ), whereas I− and OAc− had weak positive correlations with β. Neither H = nor S = correlated with the parameters in the Kamlet–Taft equation. However, the S = values were generally more negative for the ionic liquid reactions, suggesting that the anionic nucleophiles were maximally solvated by the corresponding cations in the ionic liquids. Triphenylverdazyl (75) has been proposed as a trapping reagent for solvent-separated ion pairs.123 The results obtained in a study of the SN reaction of benzhydryl bromide in anhydrous acetonitrile124 showed that alkylation of (75) rarely occurs; rather, it reacts with HBr formed when traces of water in the solvent react with the alkyl halide or its carbenium ion. Other arguments against the hypothesis that triphenylverdazyl is a trapping agent for solvent-separated ion pairs are given. Ph RX + 2

N Ph

Ph N

N

N

•

N Ph

Ph

N

Ph N N

R Ph

+ Ph

N

N

N

N+

+ Br− Ph

(75)

An extensive review with many examples125 shows that the reactivity–selectivity principle cannot be used to predict the selectivity of a reaction except in unique systems where one reaction is close to or diffusion controlled. The relative importance of the Hammond effect and the frontier-orbital effects determines the reactivity–selectivity relationship that will be found in a particular system. The review also concludes that the Hammond–Leffler α-value cannot be used as an indicator of transition-state structure. A kinetic study126 has shown that the rate constants for SN 1 hydrolysis of imidazolidin-4-ones (76) via the neutral substrate and after protonation at either the N(1) or the carbonyl oxygen (78) (Scheme 29) are similar. Theoretical calculations at the AM1 and B3LYP/6–31G* levels of theory have shown that the barrier to reaction is much smaller for both the O and N protonated pathways in the gas phase. This is due to the high energy of the ionic intermediate (77) formed in the reaction of the neutral substrate, i.e. the doubly charged intermediate would be solvated and therefore of lower energy in solution where the rate constants for the neutral and protonated reactions are similar. Although the calculations were unable to indicate whether the

270

Organic Reaction Mechanisms 2006 d−

O

R4

R4 d− N

N R

R1

2

O +H+

R2

R

1

−H

N R3 H

HO

+

R2

OH

R4

OH

N

N

+

fast

R

d+ NH

R2

1

d+

N R3 H (78)

R1

R3

O

R4 R2

H2O

(77) R4

N

R1

R3

(76) R4

d+ NH

R2 d+

N R3 H

O

R1

N H

R2

O +

R1 NH

H2N

R3

O R3

N R4 H

Scheme 29

O or N protonation mechanism was the lowest energy pathway, the authors preferred the O protonation mechanism, via (78). Steric effects at N(1) and C(2) were found to have a significant effect on the rate of reaction. The cyclic sulfamidate (79) reacts with a host of neutral and anionic sulfur nucleophiles to give an excellent yield (84–99%) of product (80).127 1,8-Diazabicyclo[5.4.0] undec-7-ene (DBU) was added to ionize the neutral nucleophiles. All the reactions proceed with an inversion of configuration at the quaternary carbon even when tertiary alkanethiols are used. Therefore, since a kinetic study showed that the reaction is first order in both the nucleophile and (79), an SN 2 mechanism applies. MeO O O

MeO

O N

RS−

S O Me

O

MeO N

HN Me RS

O

MeO N Me

(79)

O

Me (80)

The strong Lewis acid niobium(V) pentachloride has been found to be an effective reagent for the monodealkylation of diethers with two alkyl–aryl linkages.128

271


The reaction always occurs at the most sterically crowded alkyl group and the alkyl group reactivity decreases in the order benzyl > ethyl > methyl. This suggests that the reaction proceeds via an SN 1 mechanism. Also, the reaction occurs in high yield (≥84%) only when the ether groups are in close proximity or when another group that can coordinate with niobium, e.g. a −CO2 Me group, is close to the ether group. The reaction occurs in high yield whether electron-withdrawing or -donating groups are adjacent to the ether groups. The proposed mechanism is illustrated in Scheme 30 for reaction of 1,2-dimethoxybenzene, for which proposed intermediates have been detected using NMR spectroscopy. Me OMe

Cl

O NbCl5

NbCl4

OMe

O Me

Me O

Cl

MeCl

O NbCl4

NbCl4 O Me

O

H2O

OH OMe

Me

Scheme 30

The best solvent, temperature, and Lewis acid conditions for the SN reactions of (RS )-1-(2-nitrobenzenesulfonyl)- and (RS )-1-(4-nitrobenzenesulfonyl)-3-methoxy1,2,3,5-tetrahydro-4,1-benzoxazepines with silylated 5-fluorouracil and uracil129 proved to be SnCl4 at 50 ◦ C in MeCN. The more nucleophilic silylated uracil reacts faster at its N(3) atom giving mainly the cyclic O,N -acetal (by C–OMe cleavage). The silylated 5-fluorouracil, on the other hand, reacts at its less sterically hindered N(1) atom and gives mainly an acyclic product (by ring C–O cleavage). Calculations at the HF/6–31G** level of theory support the experimental observations. A highly enantioselective dehydrobrominative cyclization of α-amino acid derivatives (81) that can occur with either retention or inversion of configuration130 has been reported. Simply changing the counterion of the amide ion base and the solvent from sodium or potassium amide in DMF or THF to lithium amide in THF or toluene changes the reaction from one with retention of configuration to one with inversion of configuration (Scheme 31). Both reactions are highly enantioselective (most give >90% ee) and in high yield (usually >90%). The commonly used bases were potassium hexamethyldisilazide and lithium 2,2,6,6-tetramethylpiperidide. By varying the number of carbons in the (CH2 )n Br group, one can obtain four-, five-, or sixmembered ring products. The products from these reactions can be easily converted into α,α-disubstituted α-amino acids.

ee

272

Organic Reaction Mechanisms 2006 CO2Et R

K amide

R

CO2Et N

Boc

or Na amide

N Boc

(CH2)n

retention R

(CH2)n−Br

Li amide

EtO2C N Boc

(CH2)n

inversion

Scheme 31

The mechanism of the N 6 -acyladenine and silylating method for the ribosylation of adenine has been determined.131 The kinetic product formed by ribosylation at N(1) has been isolated. The reaction occurs here because the N(7) position is sterically hindered. The effect of (i) the distance between the side-chain phenyl and the α-chiral reaction centre, (ii) the distance between the 4-methoxyphenyl ring and the nitrogen atom, and (iii) the effect of adding TADDOL in the BTPP base-catalysed formation of the β-lactam (83) from (82) was investigated.132 The most enantioselective reaction (74% ee) occurred when n = 0 and m = 1. TADDOL had a variable effect on the enantioselectivity but had a negative effect on the enantioselectivity in the reaction with n = 0 and m = 1. Reasons for the observed enantioselectivities are presented.

(CH2)n N

Cl

(CH2)n

CO2Me (CH2)m

CO2Me BTPP

N O

(CH2)m

O

OMe (82)

OMe (83)

Recent advances in the scope and mechanisms of Pummerer-type reactions have been reviewed.133

SN Reactions Producing Polymers Polyetherols are formed by reaction of hydroxymethyl derivatives of uric acid and ethylene oxide or propylene oxide. A kinetic study of the simple model reaction134

ee


273

between the tetrakis(hydroxymethyl)uric acid and oxirane indicated that the reaction occurred by a four step mechanism. This mechanism involves (i) release of formaldehyde from a nitrogen in the substrate forming an NH (imide) group on the uric acid derivative, (ii) a proton transfer from the imide group to the oxirane forming an imide ion–protonated oxirane ion pair, (iii) the rate-determining attack of an oxygen of a hydroxymethyl group on the substrate on the carbon of the protonated oxirane (an SN 2 reaction) adding the oxirane to the hydroxymethyl group of the substrate and (iv) transfer of the proton from the protonated product to the N:− group of the imide ion re-forming the imide.

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Organic Reaction Mechanisms 2006 Kas’yan, L. I., Kas’yan, A. O., and Okovityi, S. I., Russ. J. Org. Chem., 42, 307 (2006). Pineschi, M., Eur. J. Org. Chem., 2006, 4979. Roy, C. D., Aust. J. Chem., 59, 657 (2006). Padwa, A. and Wang, Q., J. Org. Chem., 71, 3210 (2006). D’hooghe, M., Spybroeck, V. V., Waroquier, M., and De Kimpe, N., Chem. Commun., 2006, 1554. Fujimori, I., Mita, T., Maki, K., Shiro, M., Sato, A., Furusho, S., Kanai, M., and Shibasaki, M., J. Am. Chem. Soc., 128, 16438 (2006). Wu, J., Sun, X., Ye, S., and Sun, W., Tetrahedron Lett., 47, 4813 (2006). Liu, Y., Li, R., Yue, L., Li, B., Chen, Y., Wu, Y., and Ding, L., Org. Lett., 8, 1521 (2006). Ingebrigtsen, T. and Lejon, T., Tetrahedron Lett., 47, 3949 (2006). Wu, J., Sun, X., and Sun, W., Org. Biomol. Chem., 4, 4231 (2006). ˇ Hodgson, D. M., Stefane, B., Miles, T. J., and Witherington, J., J. Org. Chem., 71, 8510 (2006). Cho, Y., Zunic, V., Senboku, H., Olsen, M., and Lautens, M., J. Am. Chem. Soc., 128, 6837 (2006). Liu, L.-X. and Huang, P-Q., Tetrahedron: Asymmetry, 17, 3265 (2006). Banks, H. D., J. Org. Chem., 71, 8089 (2006). Park, G., Kim, S., and Kang, H., Bull, Korean Chem. Soc., 26, 1339 (2005). Sweeney, J. B., Cantrill, A. A., Drew, M. G. B., McLaren, A. B., and Thobhani, S., Tetrahedron, 62, 3694 (2006). Desimoni, G., Faita, G., and Jørgensen, K. A., Chem. Rev., 106, 3561 (2006). Domostoj, M., Ungureanu, I., Schoenfelder, A., Klotz, P., and Mann, A., Tetrahedron Lett., 47, 2205 (2006). Couty, F., David, O., Durrat, F., Evano, G., Lakhdar, S., Marrot, J., and Vargas-Sanchez, M., Eur. J. Org. Chem., 3479 (2006). Budynina, E. M., Ivanova, O. A., Averina, E. B., Kuznetsova, T. S., and Zefirov, N. S., Tetrahedron Lett., 47, 647 (2006). Villano, S. M., Kato, S., and Bierbaum, V. M., J. Am. Chem. Soc., 128, 736 (2006). Hu, W. P. and Truhlar, D. G., J. Am. Chem. Soc., 118, 860 (1996). Fang, Y., MacMillar, S., Eriksson, J., Kołodziejska-Huben, M., Dybała-Defratyka, A., Paneth, P., Matsson, O., and Westaway, K. C., J. Org. Chem., 71, 4742 (2006). Westaway, K. C., Can. J. Chem., 56, 2691 (1978). Fang, Y., Gao, Y., Ryberg, P., Eriksson, J., Kolodziejska-Huben, M., Dybala-Defratyka, A., Madhavan, S., Danielsson, R., Paneth, P., Matsson, O., and Westaway, K. C., Chem. Eur. J., 9, 2696 (2003). Syrgiannis, Z. and Elemes, Y., Tetrahedron Lett., 47, 6831 (2006). Kim, D. W., Ahn, D., Oh, Y., Lee, S., Kil, H. S., Oh, S. J., Lee, S. J., Kim, J. S., Ryu, J. S., Moon, D. H., and Chi, D. Y., J. Am. Chem. Soc., 128, 16394 (2006). Davico, G. E., J. Phys. Chem. A, 110, 13112 (2006). Matsson, O., in Isotope Effects in Chemistry and Biology (Eds Kohen, A. and Limbach, H.-H.), CRC Press, Boca Raton, FL, 2006, pp. 423–427. Anderson, V. E., Cassano, A. G., and Harris, M. E., in Isotope Effects in Chemistry and Biology (Eds Kohen, A. and Limbach, H.-H.), CRC Press, Boca Raton, FL, 2006, pp. 908–909. Henge, A. C., in Isotope Effects in Chemistry and Biology (Eds Kohen, A. and Limbach, H.-H.), CRC Press, Boca Raton, FL, 2006, pp. 968–969. Filippi, A., Fraschetti, C., Renzi, G., Roselli, G., and Speranza., M., Chem. Eur. J., 12, 7913 (2006). Bogdanov, B. and McMahon, T. B., J. Phys. Chem. A, 110, 1350 (2006). Kawaguchi, H., Nakajima, A., Fujii, T., Kim, B. J., Hashimoto, J., Fujimoto, A., Yoshimura, T., and Morita, H., Tetrahedron, 62, 10907 (2006). de Castro, S., Lozano, A., Jimeno, M., Pérez-Pérez, M., San-Félix, A., Camarasa, M., and Velázquez, S., J. Org. Chem., 71, 1407 (2006). van Bochove, M. A., Swart, M., and Bickelhaupt, F. M., J. Am. Chem. Soc., 128, 10738 (2006). Ren, Y. and Chu, S., J. Theor. Comput. Chem., 5, 121 (2006). Hojo, M., Ueda, T., Ueno, E., Hamasaki, T., and Fujimura, D., Bull. Chem. Soc. Jpn, 79, 751 (2006). Song, L., Wu, W., Hiberty, P. C., and Shaik, S., Chem. Eur. J., 12, 7458 (2006). Lai, G.-h., Hu, K.-c., Zhou, R.-x., and Zheng, X.-m., Zhejiang Daxue Xuebao, 32, 562 (2005). Melo, A., Alfaia, A. J. I., Reis, J. C. R., and Calado, A. R. T., J. Phys. Chem. B , 110, 1877, (2006). ¨ and Kucsman, A., ´ Eur. J. Org. Chem., 2006, 5570. Ruff, F., Farkas, O., Reddy, S. R. and Manikyamba, P., Indian J. Chem. A, 45A, 1844 (2006). Reddy, S. R., Kalyani, P., and Manikyamba, P., J. Chem. Res. (S), 2006, 354.

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Kevill, D. N., Goken, E. G., and Park, B.-C., J. Chem. Res. (S), 2006, 173. Ponomarev, N. E., Zaliznyi, V. V., and Dvorko, G. F., Russ. J. Gen. Chem., 75, 1430 (2005). Bentley, T. W. and Garley, M. S., J. Phys. Org. Chem., 19, 341 (2006). Phan, T. B. and Mayr, H., Eur. J. Org. Chem., 2006, 2530. Brinchi, L., Germani, R., Savelli, G., and Spreti, N., Eur. J. Org. Chem., 2006, 4270. Mohareb, M. M., Ghosh, K. K., Orlova, G., and Palepu, R. M., J. Phys. Org. Chem., 19, 281 (2006). Moyá, M. L., Rodr´ıguez, A., Muñoz, M., del Mar Graciani, M., and Fernández, G., J. Phys. Org. Chem., 19, 676 (2006). Bica, K. and Gaertner, P., Org. Lett., 8, 733 (2006). Pliego, J. R., J. Mol. Cataly. A: Chem., 239, 228 (2005). Pliego, J. R., Org. Biomol. Chem., 4, 1667 (2006). Phan, T. B., Breugst, M., and Mayer, H., Angew. Chem. Int. Ed., 45, 3869 (2006). Denegri, B., Streiter, A., Jur´ıc, S., Ofial, A. R., Kronja, O., and Mayer, H., Chem. Eur. J., 12, 1648 (2006). Denegri, B., Ofial, A. R., Jur´ıc, S., Streiter, A., Kronja, O., and Mayer, H., Chem. Eur. J., 12, 1657 (2006). Bentley, T. W., Chem. Eur. J., 12, 6514 (2006). Legon, A. C. and Millen, D. J., J. Am. Chem. Soc., 109, 356 (1987). Jaramillo, P., Pérez, P., Contreras, R., Tiznado, W., and Fuentealba, P., J. Phys. Chem. A, 110, 8181 (2006). Uggerud, E., Chem. Eur. J., 12, 1127 (2006). Dey, S., Adhikary, K. K., Kim, C. K., Lee, B.-S., and Lee, H. W., Bull. Korean Chem. Soc., 26, 776 (2005). Ali, M., Biswas, S., Rappoport, Z., and Bernasconi, C. F., J. Phys. Org. Chem., 19, 647 (2006). Reddy, S. R. and Manikyamba, P., J. Chem. Sci., Bangalore, India, 118, 257 (2006). Fujio, M., Umezaki, Y., Alam, M. A., Kikukawa, K., Fujiyama, R., and Tsuno, Y., Bull. Chem. Soc. Jpn, 79, 1091 (2006). Billings, S. B. and Woerpel, K. A., J. Org. Chem., 71, 5171 (2006). Tachikawa, H. and Igarashi, M., Chem. Phys. 324, 639 (2006). Jeon, J.-H., Oh, Y.-H., Chung, S.-Y., Ahn, D.-S., Park, S.-W., and Lee, S., Bull. Korean Chem. Soc., 26, 2081 (2005). Sun, Y.-X., Ren, Y., Wong, N.-B., Chu, S.-Y., and Xue, Y., Int. J. Quantum Chem., 106, 1653 (2006). Ren, Y., Li, M., Wong, N.-B., and Chu, S.-Y, J. Mol. Model., 12, 182 (2006). Baptista, L., Bauerfeldt, G. F., Arbilla, G., and Silva, E. C., Theochem, 761, 73 (2006). Cheon, S., Song, K., and Hase, W. L., Theochem, 771, 27 (2006). Politzer, P., Burda, J. V., Concha, M. C., Lane, P., and Murray, J. S., J. Phys. Chem. A, 110, 756 (2006). Uggerud. E., J. Phys. Org. Chem., 19, 461 (2006). Laerdahl, J. K., Civcir, P. U., Bache-Andreassen, L., and Uggerud, E., Org. Biomol. Chem., 4, 135 (2006). Joubert, L., Pavone, M., Barone, V., and Adamo, C., J. Chem. Theory Comput., 2, 1220 (2006). Guo, L., Yu, Z.-H., Zhu, S.-Z., and Chen, Q.-Y., Theochem, 730, 143 (2005). Guo, L., Yu, Z.-H., Zhu, S.-Z., and Chen, Q.-Y., Huaxue Xuebao, 63, 897 (2005). Buchanan, J. G., Diggle, R. A., Ruggiero, G. D., and Williams, I. H., Chem. Commun., 2006, 1106. Ando, K., J. Org. Chem., 71, 1837 (2006). Tsuji, Y. and Richard, J. P., J. Am. Chem. Soc., 128, 17139 (2006). Hunter, S. E., Ehrenberger, C, E., and Savage, P. E., J. Org. Chem., 71, 6229 (2006). Balachandran, S. and Devi, R. S., Asian J. Chem., 17, 2589 (2005). Crowhurst, L., Falcone, R., Lancaster, N. L., Llopis-Mestre, V., and Welton, T., J. Org. Chem., 71, 8847 (2006). Dvorko, G. F., Ponomareva, E. A., and Pervishko, T. L., Reakts. Sposobn. Org. Soedin., 17, 434 (1980). Serebryakov, I. M., Kryzhanovskaya, E. B., Dzhurinskaya, S. S., Kladova, A. V., and Azarova, E. A., Russ. J. Gen. Chem., 75, 1331 (2005). Mayr, H. and Ofial, A. R., Angew. Chem. Int. Ed., 45, 1844 (2006). Chambel, P., Capela, R., Lopes, F., Iley, J., Morais, J., Gouveia, L., Gomes, J. R. B., Gomes, P., and Moreira, R., Tetrahedron, 62, 9883 (2006). Avenoza, A., Busto, J. H., Jiménez-Osés, G., and Peregrina, J. M., J. Org. Chem., 71, 1692 (2006).

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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 . . . . . . . . . . Organolithium species . . . . . . . Directed lithiation . . . . . . Addition and other reactions Organomagnesium species . . . . . Organozinc species . . . . . . . . . Other organometallic species . . . . Proton-transfer Reactions . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . Electrophilic Aliphatic Substitution . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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277 279 279 283 285 285 285 287 291 294 297 298 300 301 302

Carbanion Structure and Stability The linear correlation between the Eπ values for meta- and para-substituted benzylic anions and the Hammett σ constants has suggested that π conjugation may be used to explain the influence of substituents which have π orbitals.1 The structure of n-butyllithium in mixtures of ethers and 1,2-diamines has been investigated.2 Solutions in TMEDA–THF (TMEDA = N ,N ,N ,N -tetramethylethylenediamine) are not amenable to detailed investigation because of rapid ligand exchange. TMCDA–THF mixtures (TMCDA = trans-N ,N ,N ,N -tetramethylcyclohexanediamine) afford clean assignments for a mixture of homo- and hetero-solvated dimers but demonstrate poor control over structure. TMCDA–tetrahydropyran (THP) mixtures and TMEDA–Et2 O mixtures afford clean structural assignments and also excellent structural control. Rate studies of the 1,2-addition of n-BuLi using TMCDA– THP mixtures revealed cooperative solvation in which both THP and TMCDA coordinate to lithium at the monomer- and dimer-based transition structures. The molecular geometries of nitrogen squaric acid and its dimeric derivatives have been optimized at RHF/6–311+G∗∗ and RB3LYP/6–311+G∗∗ levels of theory.3 The Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd


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geometric, energetic, and magnetic criteria have indicated that nitrogen squaric acid is aromatic, and the dimer should be considered as only partly aromatic. The IR spectra and structures of the free tricyanomethanide carbanion and its potassium ion pair have been studied by both spectroscopic experiment and DFT B3LYP force field computations.4 According to the computations, the conversion of the free tricyanomethanide carbanion into an ion pair results in essential changes in the lowerfrequency vibration. The experimental geometry agrees with an ion-pair structure with K+ along the C–C≡N axis. The basicity of the anion CH2 X− , as a function of X, has been found to decrease in groups 16 (from OH to SH), 15 (from NH2 to PH2 ), and 14 (from CH3 to SiH3 ), because the α-stabilization of CH2 X− increases.5 In contrast, the basicity of CH2 X− along the series X = F, Cl, Br, I does not decrease, as commonly assumed. Fluorine has been found more effective than the heavier halogens for α-stabilization of carbanions. Various cross-conjugated enediynes undergo ‘Bergman-type’ cycloaromatizations upon reduction with potassium metal, generating anions of fulvenes and fulvalene derivatives (Scheme 1).6 Not all cross-conjugated enediynes yield cyclized dianions upon reduction; some give uncyclized, Y-shaped, cross-conjugated dianions, whereas others apparently yield radical anions that either dimerize or persist as monomers. TMS

TMS

TMS

TMS

K, +2H THF

Scheme 1

The reduction of several annelated corannulene derivatives has been performed using lithium and potassium metals.7 It has been found that annelation affects the annulenic character of corannulene by changing its charge distribution; the dianions of derivatives that are annelated with six-membered rings have less annulenic character and are less paratropic than corannulene dianion. A systematic density functional theory level investigation of differently substituted pyridinium methylides has been carried out to determine the role of Cylidic lone-pairassociated hyperconjugative and negative hyperconjugative interactions in deciding conformational preferences.8 Deviation from the coplanar orientation of the carbanionic centre with the pyridine ring and its substituent dependence have been found to correlate well with the relative opportunities for conjugative and negative hyperconjugative interactions of an ylidic moiety with different substituent groups present at the ylidic carbon. The aromaticity of the dianion (1) and the antiaromaticity of the correponding dication of tetrabenzo[5.5]fulvalene have been evaluated through magnetic criteria, 1 H

279

9 Carbanions and Electrophilic Aliphatic Substitution

NMR shifts, nucleus-independent chemical shifts, NICS, and magnetic susceptibility exaltation, .9 It has been found that counterions play a more important role in the behavior of dianions than dications, as shown by the improvement in the agreement of experimental and calculated shifts for dianions with the inclusion of counterions.

_ _

(1)

Carbanion Reactions Enolates and Related Species The preparation of α-lithio aldehydes, α-lithio ketones, and related compounds and their applications to organic synthesis has been reviewed.10 The Tsuji–Trost allylic alkylation with ketone enolates has been highlighted.11 Alkali metal counterion has been found to control the enolate protonation stereoselectivity.12 This remarkable phenomenon has been reported for lithium and potassium enolates of a norborneol derivative. The molecular mechanisms for the nucleophilic addition of lithium enolates and silyl ketene acetals to nitrones in the absence and in the presence of a Lewis acid catalyst to give isoxazolidin-5-ones or hydroxylamines have been investigated by DFT methods at the B3LYP/6–31G∗ level.13 An analysis of the global electrophilicity of the reagents accounts for the strong electrophile activation of the Lewis acid-coordinated nitrone, and the analysis of the local indices leads to an explanation for the experimentally observed regioselectivity. A density functional study of enantioselectivity in the 2-methylproline-catalysed αalkylation of aldehydes has been reported.14 On the basis of the computed barriers and transition states, an explanation has been provided for the remarkable and unexpected increase in enantioselectivity that is observed when using 2-methylproline instead of proline as the catalyst. The independent generation and reactivity of allenic enolates has been investigated.15 Under kinetic conditions, these highly reactive species are protonated in the α,β –π plane with preference (E) to the larger β group. Under thermodynamic conditions, addition/elimination equilibrates the two product stereoisomers. The kinetic protonation stereochemistry has been found a function of solvent, proton donor, and donor concentration. The alkylation of cis- and trans-4-fluoro-N -Boc-l-proline methyl esters has been examined by exposing their lithium enolates to a range of alkylating agents.16 The process showed a high degree of facial diastereoselectivity, invariably giving rise to products bearing the alkyl group anti with respect to the fluorine atom.

ee

de

de

280


The mechanism of the Perkin condensation involving benzal acetate has been revised.17 It has been demonstrated that the enolate of the gem-diacetate derived from the aromatic aldehyde and acetic anhydride–rather than the enolate of acetic anhydride itself–adds to the aldehyde in the key step. The deprotonation of the diacetate to the enolate appeared to be assisted electrophilically by the neighbouring acetate group. The origin of the diastereoselective alkylation of enolates of oxazolopiperidones (2) and (3) has been studied by means of theoretical calculations and experimental assays.18 For the unsubstituted oxazolopiperidone, the alkylation with methyl chloride is predicted to afford mainly the exo product, a finding further corroborated from the analysis of the experimental outcome obtained in the reaction of the racemic oxazolopiperidone. However, such a preference can be drastically altered by the presence of substituents attached to the fused ring. Ph O

Ph N

O

O

N

R

O

R

(2)

(3)

The Claisen-type condensation reaction of cyclic vinylogous carboxylic acid triflates with lithium enolates and their analogues has provided acyclic alkynes bearing a 1,3diketone-type moiety.19 The reaction mechanism has been proposed to proceed via a 1,2-addition of the enolate to the vinylogous acyl triflate, followed by fragmentation of the aldolate intermediate (Scheme 2).

R′ O

OLi R

n

R′

O

OTf

O

OLi R

R′ n

OTf

O

R

n

n = 1, 2 Scheme 2

A kinetic and mechanistic study of substituent effects in the nucleophilic acyl group has been performed for the Claisen-like condensation of a series of 1-arylacetyl6-acetyl-3,4,7,8-tetramethylglycolurils.20 The reactions proceeded in virtually quantitative yield and are highly regioselective. The results have been explained by a mechanism in which deprotonation of the substrates is rate limiting; thus, deprotonation of the arylacetyl groups is favoured.

de

281


The first E-selective Knoevenagel condensation of acetoacetic derivatives has been developed by using TEMPO for the acylated substituent.21 Alternatively, Z-selective Knoevenagel condensation was achieved by use of amide analogues including the Weinreb amide. The mechanism of Morita–Baylis–Hillman (MBH) alkylation has been investigated.22 An MBH intermediate exhibiting unprecedented trans geometry of the phosphonium salt and acyl group has been isolated for the first time. (S)-3-(N -Isopropyl-N -3-pyridinylaminomethyl)BINOL (4) has been established as an efficient asymmetric bifunctional organocatalyst for the aza-MBH reaction.23 The acid–base functionalities cooperate in substrate activation and fixing of the organocatalyst conformation to promote the reaction with high enantiocontrol.

de

de

ee

Me N OH OH

(4)

N

N N H

N HN N

(5)

Asymmetric organocatalytic conjugate addition of malonates to enones has been performed using a proline tetrazole catalyst (5).24 The reaction has provided good results for a range of substrates, furnishing the products in good yield with good to high enantioselectivities. The regio- and stereo-selective rhodium-catalysed allylic alkylations of chelated enolates have been investigated.25 It has been found that the Rh-catalysed allylic alkylation is as efficient and versatile as the Pd-catalysed version. In reactions of chelated enolates with suitable protecting groups, high yields and selectivities were obtained, and the regioselectivity can be directed by the reaction parameters. A simple method for the direct catalytic allylic alkylation of aldehydes and cyclic ketones has been developed.26 The direct catalytic highly chemo- and regio-selective intermolecular α-allylic alkylation reaction has been mediated by an unprecedented combination of palladium and enamine catalysis which furnishes α-allylic alkylated aldehydes and cyclic ketones in high yield. Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on α,β-unsaturated esters.27 Michael adducts have been obtained in ees up to 76% combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction has been found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent. The copper-catalysed asymmetric conjugate addition of dialkylzinc leads to homochiral zinc enolates.28 These intermediates have been trapped in situ with activated allylic electrophiles, without the need for additional palladium catalysis (Scheme 3).

ee de

ee

ee

282


O

OZnR + R2Zn

EWG LG

L*, CuX Et2O

n

EWG

O

R

n

R

n

Ph n = 1, 2 L* =

O O

P N Ph

Scheme 3

High trans selectivity (85:15 to 100:0) and excellent enantioselectivities (up to 99%) have been reported. The synthesis of chiral syn-β-amino esters has been performed by the addition of titanium ester enolates to aldimines containing a chiral α-methylbenzylamine moiety.29 The reactions take place in high yields and diastereomeric ratios (up to 96:4). A series of diaryl-2-pyrrolidinemethanols have been tested as catalysts for the enantioselective Michael addition of malonate esters to nitroalkenes.30 Bis-(3,5-dimethylphenyl)[(S)-pyrrolidin-2-yl]methanol (6), easily prepared from l-proline, has been found the most efficient bifunctional organocatalyst, providing up to 56% ee.

But

S

HO N H NH2

(6 )

N H

N H

de

de

ee

Me N

Bn

O

( 7)

The highly enantioselective direct conjugate addition of ketones to nitroalkenes has been promoted by a chiral primary amine–thiourea catalyst (7).31 The observed anti diastereoselectivity has suggested participation of a (Z)-enamine intermediate, given the complementary diastereoselectivity obtained in analogous reactions involving (E)enamines generated from secondary amine catalysts. Asymmetric 1,4-addition of various malonates to enones has been carried out using tetrabutylammonium tetrahydroborate (TBATB) in the presence of a chiral ligand.32 11 B NMR spectroscopic studies have explained the unexpected reactivity through the

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predominant formation of an aminodiol-modified borate complex in the presence of a hydride acceptor. Significant mechanistic insights into the DABCO-catalysed isomerization of γ hydroxy-α,β-alkynyl esters to γ -oxo-α,β-trans-alkenyl esters have been reported.33 The reaction mechanism involves cumulene formation, protonation with the conjugate acid of the amine, and protonation of the resulting allenol with water.

Heteroatom-stabilized Species The epoxy-Ramberg–Bäcklund reaction (ERBR) has been used for the conversion of α,β-epoxy sulfones into a range of mono-, di-, and tri-substituted allylic alcohols.34 Modification of this method has permitted the preparation of enantio-enriched allylic alcohols following the diastereoselective epoxidation of enantio-enriched vinyl sulfones that were accessed efficiently from the chiral pool. Vicarious nucleophilic substitution reactions of azolopyridazines have been found to be controlled by methyl substituents.35 On treatment with bromomethyl phenyl sulfone in DMSO–t-BuOK, azolopyridazines yield mainly typical reaction products, whereas 7-methylazolopyridazines under the same conditions undergo annulation. These competitive reactions illustrate the role of charge distribution and steric hindrance for the course of the nucleophilic substitution. The stereocontrolled synthesis of functionalized lactams has been achieved via sulfur-stabilized enolates.36 Thio-substituted enolates were the reagents of choice as these proved to be more generally applicable than the corresponding sulfoxidesubstituted enolates. The lithium enolate formed from methyl S-trityl mercaptoacetate (8) has been Calkylated in high yield at or below −40 ◦ C (Scheme 4).37 At higher temperatures, the [1,2]-thio-Wittig rearrangement of the enolate was the predominant process. ESR evidence has indicated that the rearrangement occurred by a radical mechanism.

Ph Ph

Ph

Ph

Ph

Ph

1. base

S (8)

CO2Me

2. RX

and / or RS

CO2Me

Ph

Ph

Ph

R S

CO2Me

RX = DOAc, MeI, BnBr, MeO2CCH2Br Scheme 4

Stabilized sulfonium ylides react with cyclopentenone to give the corresponding cyclopropane with high diastereoselectivity as a result of base- or ylide-mediated equilibration of the intermediate betaine.38 When using chiral sulfonium ylides, betaine equilibration compromises enantioselectivity, because whereas one diastereomer ring closes rapidly, the other diastereomer undergoes epimerization at the ester stereocentre, ultimately leading to the opposite enantiomer of the cyclopropane. The salt-free Wittig reaction of non-, semi-, and stabilized ylides has been investigated on realistic systems using density functional theory (DFT) calculations, including

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continuum solvation.39 The results provided unequivocal support for the generally accepted mechanism and are in very good agreement with experimental selectivities. The E/Z selectivity of non- and semi-stabilized ylides cannot be fully understood without considering the energy of the elimination TS. The existence of oxaarsetanes during an arsa-Wittig reaction has been proved by 1 H and 17 O NMR spectroscopy.40 75 As NMR spectra were obtained from the corresponding arsonium salts and arsane oxides. It has been shown that the reaction mechanism of the arsa-Wittig reaction is identical with that of the phospha-Wittig reaction. The regioselective functionalization of nitrobenzene and benzonitrile derivatives has been performed via nucleophilic aromatic substitution of hydrogen by phosphorusstabilized carbanions.41 Lithium phosphazenes have been found to be the most suitable nucleophiles for the substitution of hydrogen in nitrobenzene. This method represents a convenient alternative to the vicarious nucleophilic substitution for the synthesis of benzylic phosphorus derivatives using phosphorus-stabilized anions that do not bear a leaving group at the carbanionic centre. The catalytic asymmetric Henry reaction has been reviewed.42 Mild and efficient enantioselective nitroaldol reactions of nitromethane with various aldehydes have been catalysed by chiral copper Schiff-base complexes yielding the corresponding adducts with high yields and good enantiometric excess.43,44 5-Pyrrolidin-2-yltetrazole has been found to be a versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones.45 Using this catalyst, this transformation requires short reaction times, tolerates a broad substrate scope, and possibly proceeds via generation of an iminium species. A highly diastereo- and enantio-selective formal conjugate addition of nitroalkanes to nitroalkenes has been achieved using a chiral ammonium bifluoride catalyst (9).46 This strategy provides a reliable route to optically active 1,3-dinitro compounds. F 3C X

Ar

de

ee

de ee

CF3

HF2− +

N CF3

Ar = X

Ar (9) X = H, CF3

CF3

An enantioselective aza-Henry reaction has been performed in the presence of zinc triflate and N -methylephedrine.47 This method features tolerance to imines that bear aryl groups of diverse electronic nature and substitution patterns. It has been reported that yield and diastereoselectivity in reactions of aryl-stabilized ammonium ylides with aldehydes are strongly influenced by the nature of the amine and the ylide substituent (Scheme 5).48 Electron-deficient aromatics, which are able to

ee

de

285


N

+

Cl

_

+ PhCHO

R N N

+

Cl

O

ButOK THF

Ph

Ar

_

R Scheme 5

stabilize the ylide, give good yields, whereas electron-rich aromatics, which destabilize the ylide, give poor yields. DFT calculations are consistent with a mechanism in which reversibility in betaine formation is finely balanced due to the high barrier to ring closure.

Organometallic Species Organolithium species Volume 8a of the Science of Synthesis series has reviewed the synthesis and applications in organic synthesis of the following organolithium compounds: alkyl- and cycloalkyl-lithium,49 alkenyllithium,50 allyllithium,51 benzyllithium and (lithiomethyl) hetarenes,52 β-lithiocarboxylic acids and related compounds,53 and bis(organosulfanyl)- and bis(organoselanyl)-methyllithium compounds.54 Directed lithiation A new route to bridgehead alkenes based on a deprotonation reaction has been established.55 The deprotonation of 9-oxabicyclo[3.3.1]nonadiene (10) with t-BuLi–TMEDA occurs selectively in the allylic position. While (10) has four allyl positions, only one bridgehead proton is removed, as demonstrated by quenching with Me3 SnCl, Me3 SiOTf, and Me3 PbCl (Scheme 6). The lithiation/boronation of 1,4-dihalobenzenes (Hal = F, Cl, Br) bearing various functional groups in the 2-position has been investigated using lithium diisopropylamide as the metalating agent and trialkyl borate B(OR)3 as the electrophile.56 It has been demonstrated that sufficient steric hindrance precludes effective ortho-lithiation at the 3-position. In such cases, a strong meta-directing effect of an oxygen- or sulfur-based substituent (OMe, OSiMe3 , SMe), resulting in the preferred formation of 2,6-disubstituted 1,4-dihalobenzenes has been observed. The role of aggregates and mixed aggregates on the lithium diisopropylamidemediated anionic Fries rearrangements of aryl carbamates (Scheme 7) has been described.57 Substituents at the meta-position of the arene (X = H, OMe, F) and the

286


(10) O

− H+

O

O Me3SnCl

_

_

SnMe3 Scheme 6

NR2 O

NR2

O

O LDA

X

O

OH

O

Li X

NR2 X

Scheme 7

dialkylamino moiety of the carbamate (Me2 N, Et2 N, and i-Pr2 N) markedly influence the relative rates of ortho-lithiation and subsequent Fries rearrangement. By treatment with s-BuLi–TMEDA at −78 ◦ C, unprotected 2-methoxybenzoic acid has been deprotonated exclusively in the position ortho to the carboxylate.58 A reversal of regioselectivity is observed when the acid has been treated with n-BuLi–t-BuOK. These results are of general utility for the one-pot preparation of a variety of very simple 3- and 6-substituted 2-methoxybenzoic acids that are not easily accessible by conventional means. The expedient and regioselective metalation of unprotected biphenyl-2-, -3-, and -4-carboxylic acids has been reported.59 Unprotected biphenyl-2-carboxylic acid has been cleanly metalated with sec-butyllithium at the position adjacent to the carboxylate and can then be subjected to site-selective electrophilic substitution (Scheme 8). The remote C(2 )-position has been attacked by the superbasic mixture of n-BuLi and t-BuOK (LICKOR) in THF or benzene. The resulting dianion cyclizes to give the fluorenone skeleton. The mechanism of the metalation of homologous compounds, 2-(pyridin-3-yl)benzoic acid derivatives, with strong bases has also been discussed.60 The regioselectivity in lithiation of 1-methylpyrazole has been investigated by experimental, DFT and multinuclear NMR studies.61 In THF, 1-methylpyrazole reacts initially at the exocyclic α-position, to give an α-lithiated species which forms the thermodynamic product C(5)-Li in an intermolecular reaction. A coordination from N(2) to lithium apparently favours formation of the kinetic product α-Li.

287

9 Carbanions and Electrophilic Aliphatic Substitution E 1. BusLi (2.2 equiv.), −78 °C, THF

COOH

1. LICKOR (3.5 equiv.) 2. H+

2. EX, −78 °C 3. H+

3 COOH 2'

1. LICKOR (3.5 equiv.), 60 °C, benzene 2. BunLi (2 equiv.), r.t. to 60 °C

E

O

3. EX, r.t. 4. H+

Scheme 8

Lithiation of 5-bromonicotinic acid protected as a secondary or tertiary amide and also (4,4 -dimethyl)oxazoline (11) with lithium amides has been reported.62 The unusual C(2) and C(4) regioselective lithiation of 3-bromo-5-(4,4 -dimethyl)oxazolinylpyridine using LTMP versus LDA has been observed, providing a new route to substituted nicotinic acid scaffolds. LDA (100%) N Br

O N

LTMP (100%) (11)

The synthesis of new 4,6-disubstituted dihydrodipyridopyrazines has been performed starting from corresponding carboxaldehydes via lithiation directed by αaminoalkoxides.63 N ,N ,N -trimethylethylenediamine has been used as the amine component for in situ formation of the α-aminoalkoxides. ortho-Metalation of enantiopure sulfoxides has been described for aromatic and ferrocenyl derivatives.64,65 New aminosulfoxides have been obtained with complete diastereocontrol when Dpp or Boc groups were used (dr > 98:2).

Addition and other reactions The relative basicities of solutions of n-BuLi in cyclohexane as a function of the addition of increasing increments of THF or TMEDA have been assessed.66 By measuring the rates of loss of chlorobenzene in the varied media

de

288


and also by certain 7 Li NMR studies, a gradual, controlled increase in the basicity of n-BuLi in cyclohexane with increasing increments of THF or TMEDA has been observed. Transition structures for the lithium–bromine exchange reaction of 1,1-dibromoalkenes with methyllithium have been located by both the B3LYP and the MP2 levels of theory with the 6–31+G∗ basis set.67 The reaction with methyllithium dimer gave similar results with lower activation energies. These calculations predict both the kinetic and the thermodynamic stereoselectivity correctly. It has been found that predominantly the sterically more constrained bromine atom of 1,1-dibromoalkenes reacted with alkyllithium (dimer) in the kinetic condition. It has been demonstrated that lithium–bromine exchange of a representative aryl bromide, 1-bromo-4-t-butylbenzene, may be accomplished in high yield at 0 ◦ C, a temperature significantly higher than that normally used for the process.68 The reaction has been performed with 2 equiv. of t-BuLi in heptane in a predominantly hydrocarbon medium containing a small (1% v/v) to modest (10% v/v) quantity of any of a variety of ethers (Et2 O, THF, THP, or MTBE). The exchange reaction between 1-bromo-4-tbutylbenzene and n-BuLi, which is slow in pure diethyl ether, proceeds in high yield in a hydrocarbon medium containing a small amount (1% v/v) of THF. The carbolithiation of six- to nine-membered 3-methylenecycloalka-1,4-dienes has been investigated and shown to be an exceptionally facile and general process.69 Primary, secondary, and tertiary organolithium reagents may be employed for carbolithiation of cyclic trienes with uniform efficiency, generating cyclic pentadienyl carbanions. The six-electron pentadienyl systems display unique reactivity as a function of ring size. The cyclopropyl effect has controlled the regioselectivity of the cross-coupling reactions of propargylic/allenylic metallic species with electrophiles afford alkynic cyclopropanes (Scheme 9).70 Cyclopropyl ring strain, which makes the formation of vinylidenecyclopropanes unfavourable, is believed to control the regioselectivity. E Ph 1. BunLi, r.t. Ph

2. EX, r.t. Ph Scheme 9

The mechanism of acylation of lithium phenylacetylide with a Weinreb amide has been investigated (Scheme 10).71 Dimeric lithium acetylide has reacted via a monosolvated monomer-based transition structure. The robust tetrahedral intermediate (12) forms sequentially a C(1) 2:2 mixed tetramer with the excess lithium acetylide and a 1:3 (alkoxide-rich) mixed tetramer. The stabilities of the mixed tetramers are consistent with a pronounced autoinhibition.

289

9 Carbanions and Electrophilic Aliphatic Substitution O

Ph

O N

OMe

Me

O

PhCCLi THF, −50 °C

Li N

OMe Ph

Me (12) Scheme 10

The regioselective reaction of trans-2-(t-butyldimethylsilyl)-3-vinyloxirane (13) with primary, secondary, and tertiary butyllithium has proceeded in a SN 2 fashion and allowed the formation of α-silylated allylic alcohols with diastereomeric ratios of over 7:1 in favour of the (Z)-alkenes (Scheme 11).72 A study of the effect of temperature, time, addition of salt, and polarity of the solvent on the diastereoselectivity of the reaction has been described. But

O Si

RLi, TMEDA

But

Et2O

(13)

de

Si

R OH

R = Bun, Bus, But Scheme 11

A mechanistic study of the Wittig rearrangement of lithiated allyl aryl ethers has been reported.73 At −75 ◦ C, α-lithiated allyl phenyl ether undergoes mainly the [1,2]Wittig rearrangement to afford, after acidic hydrolysis, 1-phenylprop-2-en-1-ol as the main product. A second metalation taking place at one of the ortho positions is the sole competing side reaction. Both the significant decrease of the isomerization rate upon the introduction of a t-butyl substituent in the para position of the aromatic ring and the complete absence of [1,4] rearrangement products suggest an intramolecular addition/elimination process bringing about the aryl migration. Studies on the deprotonation and subsequent [1,4]-Wittig rearrangement of αbenzyloxyallylsilanes have shown that the two processes are separate rather than concerted events.74 The presence of anion-stabilizing groups on the migrating substituent could be detrimental to the success of the reaction. Several asymmetric 1,2-additions of various organolithium reagents (methyllithium, n-butyllithium, phenyllithium, lithioacetonitrile, lithium n-propylacetylide, and lithium phenylacetylide) to aldehydes result in decent to excellent ees (65–98%) when performed in the presence of a chiral lithium amido sulfide [e.g. (14)].75 The chiral lithium amido sulfides invariably have exhibited higher levels of enantioselectivity compared to the structurally similar chiral lithium amido ethers and the chiral lithium amide without a chelating group. The first highly diastereoselective, one-pot organometallic addition and hydride reduction reactions (>95% de) involving three symmetry-equivalent carbonyl centres

de

ee

de

290


NLi

S

(14) H

Me

OMe O

O

H

MeO

OMe H

Me

−78 °C, 3 h

Me

OMe O

F TH

LiA

Me

MeO

Me

MeO

O

O

Me

HO

CH3Li, THF

, lH 4

0 °C

,3

OMe OH

OMe OH

anti, syn > 95% de

h

OMe O Scheme 12

have been described (Scheme 12).76 Three-fold methyllithium addition to 2,4,6trimethoxybenzene-1,3,5-tricarbaldehyde gives the anti,syn-triol exclusively; addition of HMPA to the reaction or replacement of the substrate’s methoxy groups with ethyl groups affords a statistical 3:1 (anti,syn:syn,syn) diastereomeric product ratio. Analogous asymmetric induction has been found upon hydride reduction of the complementary triketone, 2,4,6-trimethoxybenzene-1,3,5-triethanone (Scheme 12). Chelation and steric (gearing) effects about the crowded aromatic core contributed to the observed stereoselectivity. The reactions of ketone dilithio α,β-dianions with imines and hydrazones have been investigated.77 The nucleophilic addition reaction to C−N double bonds took place selectively at the β-position of dianions to form lithium (Z)-enolates containing a lithium amide portion, which is then transformed into γ -amino ketones and related compounds by the subsequent reaction with electrophiles. The effect of donor ligands on the addition of PhLi to (E)-cinnamaldehyde in THF, under conditions that lead the reaction towards the production of 1,3-diphenylpropanone, has been studied.78 It has been observed that in the presence of TMEDA and HMPT, the rate of that reaction becomes slower than in the absence of ligands; the effect of HMPA was even more spectacular: at concentration ratios [HMPA]:[PhLi] ≥ 4 the reaction becomes almost completely inhibited. As an extension of the above

291


study, in situ addition of an organolithium reagent into the N=O bond leads to an almost quantitative conversion into the corresponding hydrazone.79 Intramolecular hydroamination of cyclohexa-2,5-dienes has afforded the corresponding bicyclic allylic amines with high selectivity (Scheme 13).80 The reaction does not proceed through a direct hydroamination of one of the diastereotopic alkenes but more likely involves a diastereoselective protonation of a pentadienyl anion, followed by addition of a lithium amide across the double bond of the resulting 1,3-diene and a highly regioselective protonation of the final allylic anion.

R

H N

R

Ph BunLi

(20 mol%)

Ph

N

THF

MeO

MeO de > 95% Scheme 13

It has been demonstrated that α-alkyl-α-amino-N -[(silyl)methyl]-β-lactams can be regarded as new N -methyl-β-lactam cryptocarbanion sources.81 Compared with previously reported nonenolate N -benzyl-β-lactams, the α-lithiated derivatives of N [(silyl)methyl]-β-lactams are remarkably stable, with no apparent tendency to nucleophilic ring opening or ring cycloexpansion side-reactions. According to MO calculations and experimental observations, the origin of such stability seems to lie primarily on the coordination of the lithium cation by the β-lactam carbonyl and, to a lesser extent, on the ‘α-effect’ of the trimethylsilyl groups.

Organomagnesium species Efficient procedures for the shifting of alkyl magnesiate–dialkyl magnesiate equilibria by additives or the alternative direct preparations of dialkyl magnesiates have been developed.82 Compounds (15) and (16) has displayed exceptional reactivities for otherwise challenging Br–Mg exchange reactions, thus giving dialkyl magnesiates general synthetic value. Bus2Mg · LiCl (1 M solution) (15)

Pri MgCl

Pri2Mg · LiCl Me (16)

(17)

Pri Me

MgCl (18)

The direct synthesis of Grignard reagents from enantiomerically pure alkyl halides has always resulted in a 1:1 ratio of the two possible epimers.83 Once formed, the two components of the reagent are configurationally stable. If the reactivity of the two epimers differs significantly, as in the case of MenMgCl (17) and NeomMgCl

292


(18), it is possible to use each component selectively in reactions with electrophiles. This can be achieved by using thermodynamic/kinetic control of the reaction, altering temperature, solvent polarity, and stoichiometry. Grignard reagents have been generated from magnesium and organic iodides in the ionic liquid n-butylpyridinium tetrafluoroborate, [bpy][BF4 ], and they showed different reactivity from classical Grignard reagents in organic solvents.84 Readily available THF solutions of LnCl3 .2LiCl (Ln = La, Ce, Nd) have been found to be superior promoters for the addition of various organometallic reagents to ketones.85 They also catalyse efficiently the addition of organomagnesium compounds to imines. The mechanism of the enantioselective 1,4-addition of Grignard reagents to α,βunsaturated carbonyl compounds promoted by copper complexes of chiral ferrocenyl diphosphines has been explored through kinetic, spectroscopic, and electrochemical analysis.86 On the basis of these studies, a structure of the active catalyst is proposed. The roles of the solvent, copper halide, and the Grignard reagent have been examined. An efficient way to create, enantioselectively, all-carbon quaternary centres, by the unprecedented asymmetric conjugate addition of Grignard reagents to enones has been developed using a copper catalyst and a chiral diaminocarbene ligand of the corresponding salt (19) or (20).87 H Ar

N

+

OH

BF4 N

ee

PF6

H

Ar R

Ph

ee

N

+

N

Ph (19)

(20)

Sequential carbonyl addition–conjugate addition of Grignard reagents to 3-oxocyclohex-1-ene-1-carbonitrile has generated C-magnesiated nitriles whose alkylation stereoselectivities intimately depend on the nature of the electrophile.88 The alkylation of these C-magnesiated nitriles with alkyl halides, sulfonates, and unstrained ketones occurs with the retention of the C–Mg configuration, whereas aldehyde and acyl cyanide acylations proceed with inversion of the stereochemistry (Scheme 14). Mechanistic probes indicated that the stereoselectivity is controlled by stereoelectronic effects for most electrophiles, except allylic, benzylic, and cyclopropyl halides, where single electron transfer processes intervene. A ferrocenyl catalyst system able to perform highly enantioselective Cu-catalysed allylic alkylations with Grignard reagents has been described.89 The alkylated products have been obtained in high yields with good to excellent enantioselectivities (ee up to 98%). The o-diphenylphosphanylbenzoyl (o-DPPB) group has been explored as a directing leaving group in copper-mediated and copper-catalysed allylic substitution with Grignard reagents.90 Complete control of chemo-, regio- and stereo-selectivity with complete syn-1,3-chirality transfer has been observed as a result of the directed nature

ee

293

9 Carbanions and Electrophilic Aliphatic Substitution CN

O

R1MgX R2MgX

Mg CN R2

R1

O

R4

CN

R3X or

O OH

R3 CN R2

R1 retension

OH

or

CN R2

R1

R4 O

inversion

Scheme 14

of the reaction. No excess of organometallic reagent is required and the directing group can be recovered quantitatively. Hindered protected and unprotected epoxy alcohols have been regioselectively cleaved using copper-catalysed cis- and trans-prop-1-enylmagnesium bromide (Scheme 15).91 The reactions exhibited good yield and excellent regioselectivity in systems where organocuprates and organoalanes failed. The cis Grignard reagent displayed no double-bond isomerization, whereas the trans isomer showed partial trans-to-cis equilibration, which has been minimized by controlling the reagent formation conditions. O R2 R1

MgBr , THF CuI, Et2O, −78 °C

cis trans

OH R1 R2 syn/cis anti/cis

Scheme 15

A copper-free catalytic enantioselective addition to γ -chloro-α,β-unsaturated esters has been developed in the presence of N -heterocyclic carbenes.92 The activation of Grignard reagents has been achieved using a Lewis base. The ionic liquid butylmethylimidazolium tetrachloroferrate (bmim-FeCl4 ) has been found to be a very effective and completely air-stable catalyst for the biphasic Grignard cross-coupling with primary and secondary alkyl halides bearing β-hydrogens.93 The ionic liquid catalyst has been successfully recycled four times. The addition of Grignard reagents to chiral trifluoromethyl t-butyl sulfinimine– ethanol adducts has afforded protected trifluoromethylamines in high yields with good

ee

de

294


to excellent diastereoselectivities.94 The stereochemical outcome of the addition has been opposite to that expected via a chelation controlled transition state.

Organozinc species Recent trends in enantioselective diorganozinc additions to aldehydes and developments in the use of dialkylzincs in radical reactions have been reviewed.95,96 Grid-based QSSR methods have been used to predict catalyst enantioselectivities with a high degree of accuracy and precision.97 The empirical models are easily assembled from a small set of ligands and their experimentally measured selectivities such as might be determined in preliminary screening. Relatively quick theoretical calculations provide models that allow a researcher to readily distinguish poorly, moderately, and highly selective catalysts, e.g. for asymmetric addition of Et2 Zn to PhCHO. The first enantioselective one-pot, three-component imino Reformatsky reactions have been reviewed.98 (−)-N ,N -Dimethylaminoisoborneol has been found to be an excellent ligand for the enantioselective addition of Reformatsky reagents to aromatic and aliphatic aldehydes.99 Enantioselectivities up to 93% ee have been obtained with sulfur-containing aldehydes. Directed metalation using alkali metal-mediated zincation has been developed for mono- and poly-cyclic aromatic derivatives.100,101 Asymmetric 1,4-addition of arylzinc chlorides to (E)-3-arylpropenals has proceeded with high enantioselectivity in the presence of a rhodium–(R)-binap catalyst and chlorotrimethylsilane.102 The corresponding 3,3-diarylpropanals were obtained in high yields and excellent enantiomeric excess (98–99% ee). A Et2 Zn–(S, S)-linked-BINOL (21) complex has been found suitable for chemoselective enolate formation from a hydroxy ketone in the presence of isomerizable aliphatic N -diphenylphosphinoylimines.103 The reaction proceeded smoothly and βalkyl-β-amino-α-hydroxy ketones were obtained in good yield and high enantioselectivity (up to 99% ee). A titanium complex derived from 3-(3,5-diphenylphenyl)BINOL (22) has exhibited an enhanced catalytic activity in the asymmetric alkylation of aldehydes, allowing the reduction of the catalyst amount to less than 1 mol% without deterioration in enantioselectivity.104 Ph

O

Ph

OH HO

OH

OH HO

OH

(21)

(22)

ee

ee

ee ee

ee

ee

ee

295


A binol derivative (23) has allowed high enantioselectivities in the reaction of diphenylzinc with both aliphatic and aromatic aldehydes.105 Unlike other catalysts developed for the addition of diphenylzinc, the use of (23) avoids the need for additive and gives excellent results at room temperature.

N

ee

O Ph

OH

N

OH

Ph HO N

O

(23)

(24)

The direct addition of in situ-prepared arylzinc to aldehydes with chiral binaphthylderived amino alcohols (24) as catalysts has afforded optically active diarylmethanols in high yields and with excellent enantioselectivities (up to 99% ee).106 By using a single catalyst, both enantiomers of many pharmaceutically interesting diarylmethanols can be obtained by the proper combination of various arylzinc reagents with different aldehydes. The synthesis of a new enantiopure, conformationally constrained 1,4-amino alcohol (25) has been reported, starting from commercially available reagents from the chiral pool.107 This 1,4-amino alcohol has been used as a chiral ligand in the addition of Et2 Zn to aldehydes (best ee 98%) and in the synthesis of chiral propargylic alcohols (best ee 70%) by alkynylzinc species. O Me N

O HO

(25)

ee

ee

O R2N OH

NR2 = pyrrolidine, piperidine, morpholine

(26)

A de novo structural class of chiral amino alcohol catalysts has been identified through a synergistic effort combining novel architectures from 4 + 3-cycloadditions and quantum mechanical interaction field predictions that closely match subsequent experimental measurements.108 On the basis of the assignment of absolute configuration of the resulting alcohol, a stereochemical model using ligand (26) has been proposed. Primary, secondary, and tertiary γ -amino alcohols (27–30) have been used as chiral catalysts in the enantioselective addition of diethylzinc to aromatic aldehydes.109 The first evidence of the substituent-dependent enantioselectivity of 1,3-amino alcohol catalysts has been observed, and the phenomenon interpreted by using molecular modeling at the ab initio level.

ee

296

Organic Reaction Mechanisms 2006 NH2

NHCH2Ph

OH

OH

H

H

(27)

(28)

NHMe

NMe2

OH

OH

H

H

(29)

(30)

A series of chiral (3R,5R)-dihydroxypiperidine derivatives have been conveniently prepared from trans-4-hydroxy-l-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal.110 The compound (31) has been found to show the best asymmetric induction in promoting the addition of Et2 Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee. Ph HO

OTr N Bn

O

Ph OH

N

OH

Ph

Ph

Ph (31)

(32)

ee

(33)

The chiral ligands (32) and (33) have been used as catalysts in the enantioselective addition of Et2 Zn to benzaldehyde.111 It has been observed that the presence of the cyclohexane core gave better enantioselection, presumably owing to a more rigid transition state for the addition reaction in the former ligand. Novel norephedrine-based chiral ligands with multiple stereogenic centers have been conveniently prepared from norephedrine and N -substituted pyrrole.112 These novel chiral ligands have been used to catalyse the enantioselective addition of diethylzinc to aldehydes and to chalcone in high yields and with good to high enantioselectivities. The absolute configuration of products has been found to be affected by the stereogenic centres on the norephedrine part of the novel chiral ligands. A practical and general alkynylation of aromatic and α,β-unsaturated aldehydes using a proline-derived dinuclear zinc catalyst system has been reported (Scheme 16).113 The reaction proceeds with slightly higher enantiomeric excess at increased temperatures. Interestingly, electron-donating substituents have been found to be beneficial for both the yield and selectivity. Substituents in the ortho positions of the benzaldehyde raised both yields and ees.

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ee

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297

9 Carbanions and Electrophilic Aliphatic Substitution O

OH H

+

R

Me2Zn, toluene L* (10 mol%)

R

MeO

Meo HO

HO Ph Ph

N

OH

N

Ph Ph

L* =

Scheme 16

The direct strong steric interaction between substrate substituents and ligand substituents has been demonstrated in asymmetric addition of diethylzinc to aldehydes catalysed by sterically congested ferrocenyl aziridino alcohol derivatives.114 In addition, this non-bonded steric repulsion influenced enantioselectivities significantly, and even led to inversion of the absolute configuration. This fact was further confirmed by theoretical calculations and the design of a new chiral ferrocenyl aziridino alcohol ligand. New chiral Schiff base catalysts for the enantioselective addition of diethylzinc reagents to aldehydes have been developed.115,116 The reaction of aldehyde with diethylzinc in the presence of 1–2 mol% of the chiral Schiff base catalyst has provided the corresponding secondary alcohol with excellent enantiomeric excess (up to 96% ee). Enantioselective addition of diethylzinc to aldehydes has been catalyzed by diastereomeric monosubstituted [2.2]paracyclophane-based N ,O-ligands.117 A remarkable cooperative effect of planar and central chiralities has been observed. The enantioselective addition of dialkylzinc to imine derivatives has been performed using copper,118,119 titanium,120 and rhodium catalysts;121 high yields and excellent enantiocontrol (up to 99% ee) have been achieved.

Other organometallic species Volume 8b of the Science of Synthesis series has reviewed the synthesis and applications in organic synthesis of the following organosodium compounds: alkylsodium,122 alkenylsodium,123 sodium acetylides,124 allylsodium,125 arylsodium compounds and sodium cyclopentadienide,126 benzylsodium compounds,127 1,1-disubstituted organosodium compounds,128 1-monosubstituted organosodium compounds,129 and α-sodio aldehydes, α-sodio ketones, and related compounds;130 the volume also includes a review of the synthesis of organometallic compounds of rubidium and caesium and their applications to organic synthesis.131 The rhodium-catalysed addition of alkynes to 1,2-diketones, 1,2-keto esters, and aldehydes has provided a method for the synthesis of tertiary alkynyl alcohols under

ee

ee

ee ee

298


HO

HO 7

O

Rh(acac)(CO)2 (3 mol%) L* (9 mol%)

+

THF, 40 °C

HO O

7

O

O L* = O

P(But)2 Scheme 17

mild conditions (Scheme 17).132 The reaction tolerates many functional groups (such as carboxylic acids) that are incompatible with other methods. The alkyne addition reaction proceeded best using bulky phosphine ligands such as 2-(di-t-butylphosphino) biphenyl. This method fills a void in the more common zinc-catalysed processes, which give poor yields with enolizable 1,2-dicarbonyl substrates. The enantioselective addition of allylstannanes to glyoxylates and glyoxals, and also simple aromatic and aliphatic aldehydes, catalysed by chiral (salen)Cr(III) complexes, has been studied.133 The reaction proceeded smoothly for the reactive 2-oxoaldehydes and allyltributyltin in the presence of small amounts (1–2 mol%) of (salen)Cr(III)BF4 under mild, undemanding conditions. The stereochemical results have been rationalized on the basis of the proposed model.

Proton-transfer Reactions Enthalpies of activation, transition-state geometries, and primary semi-classical (without tunneling) kinetic isotope effects (KIEs) have been calculated for 11 bimolecular identity proton-transfer reactions, four intramolecular proton transfers, four nonidentity proton-transfer reactions, 11 identity hydride transfers, and two 1,2-intramolecular hydride shifts at the HF/6–311+G∗∗ , MP2/6–311+G∗∗ , and B3LYP/6–311++ G∗∗ levels.134 It has been found that the KIEs are systematically smaller for hydride transfers than for proton transfers. The differences between proton and hydride transfers have been rationalized by modeling the central ·C· · ·H· · ·C· unit of a protontransfer transition state as a four-electron, three-centre (4-e 3-c) system and the same unit of a hydride-transfer transition state as a 2-e 3-c system. The intrinsic acidity of dimethylhalonium ions has been determined, both by theoretical methods and by gas-phase reactions of the isolated ions with pyridine bases.135 The calculated geometry of the dimethylhalonium ions shows a bent structure with the C–X–C angle decreasing in the order Cl > Br > I. Thermochemical calculations for the reaction of the dimethylhalonium ions with pyridine, 2,6-dimethylpyridine, and 2,6-di-t-butylpyridine indicated that proton transfer, with the formation of the dimethylhalonium ylide, is endothermic, whereas methyl transfer, with formation of methyl halide, is exothermic. The endothermicities for proton transfer are, nevertheless,

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299


dependent on the steric hindrance of the base. The bulkier the bases, the less endothermic is the proton-transfer reaction. A novel example of a vinylic hydrogen more reactive than a benzylic hydrogen has been found by treatment of a twisted styrene derivative (34) with a strong base followed by D2 O quenching.136 A correlation between the reactivity of the vinyl hydrogens and the magnitude of the twist has been presented. The highly reactive vinyl hydrogens could be rationalized by considering the novel orbital interaction between the π ∗ orbital of the benzene ring and the σ orbital of the vinylic C–H bond in the twisted styrene derivatives. Base H

H OSiEt3 (34)

A study on how the difference in the aromaticity between (35) and (36) may affect the intrinsic barriers to proton transfer has been reported (Scheme 18).137 The intrinsic barriers for the deprotonation of the thiophene derivative by amines and OH− have been found to be somewhat higher than for the furan analogue. This result has been attributed to a combination of steric, inductive, and π -donor effects which overshadow the aromaticity effect.

H O

B

δ

_

+

B

O

X X = O (35) X = S (36)

δ

H

X +

+ +

BH

O

+

_

X

+

∆G0+ (35) < ∆G0+ (36) Scheme 18

Rates of hydrogen exchange reactions promoted by methanolic sodium methoxide have been compared with gas-phase acidities, for fluorinated aromatic compounds.138 Experimental hydrogen isotope effects of near unity found for 14 of the fluorinated benzylic compounds and pentafluorobenzene suggest that the amount of internal return associated with the exchange process is substantial. Density functional calculations using B3LYP/6–31+G(d,p) have been reported for the reactions of methanolic sodium methoxide with C6 F5 H, C6 H5 CH(CF3 )2 , C6 H5 CHClCF3 , and 9-phenylfluorene. Asymmetric protonation of lithium enolates has been examined using commercially available amino acid derivatives as chiral proton sources.139 Among the amino acid

300


derivatives tested, N -β-l-aspartyl-l-phenylalanine methyl ester has been found to cause significant asymmetric induction in the protonation of lithium enolates. The enantiomeric excess (up to 88% ee) of the products obtained in the presence of a catalytic amount of the chiral proton source has been higher than those obtained in the stoichiometric reaction.

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Miscellaneous The asymmetric ring opening of epoxides and aziridines with carbon nucleophiles has been reviewed.140 A computational investigation of the mechanism and diastereoselectivity of aziridine formation from sulfur ylides and imines has been performed using DFT methods including a continuum model of solvent.141 The results are in very good agreement with observed cis/trans selectivities. This study has shown that betaine formation is non-reversible and that the transition-state structures are governed by the steric strain induced by the N -sulfonyl group. Theoretical calculations at the B3LYP/6–31+G(d), MP2/6–31+G(d), and G3(MP2) levels have been carried out to understand the alternative reaction pathways–the cyclopropyl ring cleavage (RC) and the retrocycloaddition reaction (rCA)–of a constrained tricyanocyclopropyl anionic derivative.142 The more energetically favourable path has been found to be the RC process, a formally ‘forbidden’ rearrangement yielding an allylic anion system via a concerted transition structure, in agreement with experimental outcomes. An explanation for the low energy barrier associated with RC was furnished on the analysis of the evolution of the twisting (dis-/conrotatory) motions of cyano substituents in the cyclopropyl ring and also on the number and type of electron pairs provided by the electron localization function. The nucleophilicity parameters for carbanions of nitronates and malonic acid derivatives have been investigated.143 The nucleophilic reactivities do not correlate with the acidity constants of the conjugate CH acids, and from the poor correlation of the reactivities of the substituted α-nitrobenzyl anions with Hammett’s σ -constants it can be inferred that the nucleophilic reactivities are strongly controlled by solvation. Rate constants have been measured for the capture of para-substituted phenylchlorocarbenes by chloride ions to form aryldichloromethide carbanions and for the additions of these carbanions to acrylonitrile.144 A conventional interpretation of the Hammett correlations has suggested that the reactions of carbenes with Cl− traverse ‘early’ transition states. The catalytic enantioselective crossed aldehyde–ketone benzoin cyclization has been reported.145 The reactions have been performed in the presence of Rovis’ aminoindanolderived chiral triazolium salts (37) as catalysts with excellent enantioselectivities (up to 99% ee) (Scheme 19). The reactive species in fluoride-mediated carbon–carbon bond-forming reactions has been investigated.146 The regio- and diastereo-selectivities of silanes reacting with cyclohexenone in the presence of a catalytic amount of fluoride have been compared with the reactivity of analogous solvent-separated lithium ion pairs. Closely analogous behaviour has been observed, showing that carbanions and not siliconate complexes are the reactive species in the fluoride-catalysed reactions.

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ee

301

9 Carbanions and Electrophilic Aliphatic Substitution Ph + N N (37), base

N

*

O

O

THF

R

CI−

O

O HO R up to 99% ee

(37) Scheme 19

Recent advances in the Stevens rearrangement of ammonium ylides have been reviewed in terms of application to the synthesis of alkaloid natural products.147 The generation and reactivity of conjugated azomethine ylides has been reviewed.148 1,3-Dipolar cycloaddition and 1,5- and 1,7-electrocyclizations have been described as powerful strategies for the synthesis of monocyclic and annulated five- and sevenmembered nitrogen heterocyclic compounds. The synthesis, isolation, and characterization of the first stable aliphatic bromonium ylides (38) have been reported (Scheme 20).149 The bromonium ylides (38) selectively undergo transfer of the aryl group to nitrogen heterocycles, such as pyridines, yielding N -arylpyridinium salts. F RSO2

RSO2

Br F

_

MeCN 0 °C

+

RSO2

RSO2

CF3 R = CF3, CF3(CF2)3

+

Br

(38)

CF3

Scheme 20

Electrophilic Aliphatic Substitution The enantioselective α-fluorination of carbonyl compounds has been highlighted.150–152 The catalytic asymmetric fluorination of various substrates has also been reviewed.153,154 The asymmetric fluorination of β-keto esters has been performed in the presence of various catalysts, such as CpTiCl3 ,155 chiral rare earth perfluorinated organophosphates,156 and chiral palladium complexes.157 The structural and stereochemical aspects of the enantioselective halogenation of 1,3-dicarbonyl compounds catalysed by Ti(TADDOLato) complexes have been reported.158 The observed absolute configuration at the fluorinated stereogenic centre has

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ee

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302


been found to match the one inferred from the structural analysis of the Ti(TADDOLato) complexes. Enantioselective α-amination of carbonyl compounds has been promoted by lazetidinecarboxylic acid,159 axially chiral guanidine derivative,160 and chiral palladium complexes.161

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139 140 141

Organic Reaction Mechanisms 2006 Demel, P., Keller, M., and Breit, B., Chem. Eur. J., 12, 6669 (2006). Rodriguez, D., Mulero, M., and Prieto, J. A., J. Org. Chem., 71, 5826 (2006). Lee, Y. and Hoveyda, A. H., J. Am. Chem. Soc., 128, 15604 (2006). Bica, K. and Gaertner, P., Org. Lett., 8, 733 (2006). Kuduk, S. D., Di Marco, C. N., Pitzenberger, S. M., and Tsou, N., Tetrahedron Lett., 47, 2377 (2006). Dimitrov, V. and Kostova, K., Chem. Abs., 145, 7476 (2006). Bazin, S., Feray, L., and Bertrand, M. P., Chem. Abs., 145, 82775 (2006). Ianni, J. C., Annamalai, V., Phuan, P.-W., Panda, M., and Kozlowski, M. C., Angew. Chem. Int. Ed., 45, 5502 (2006). Cozzi, P. G. and Rivalta, E., Pure Appl. Chem., 78, 287 (2006). Kloetzing, R. J., Thaler, T., and Knochel, P., Org. Lett., 8, 1125 (2006). Armstrong, D. R., Clegg, W., Dale, S. H., Hevia, E., Hogg, L. M., Honeyman, G. W., and Mulvey, R. E., Angew. Chem. Int. Ed., 45, 3775 (2006). Clegg, W., Dale, S. H., Hevia, E., Hogg, L. M., Honeyman, G. W., Mulvey, R. E., and O’Hara, C. T., Angew. Chem. Int. Ed., 45, 6548 (2006). Tokunaga, N. and Hayashi, T., Tetrahedron: Asymmetry, 17, 607 (2006). Yamaguchi, A., Matsunaga, S., and Shibasaki, M., Tetrahedron Lett., 47, 3985 (2006). Harada, T. and Kanda, K., Org. Lett., 8, 3817 (2006). Qin, Y.-C. and Pu, L., Angew. Chem. Int. Ed., 45, 273 (2006). Lu, G., Kwong, F. Y., Ruan, J.-W., Li, Y.-M., and Chan, A. S. C., Chem. Eur. J., 12, 4115 (2006). Scarpi, D., Lo Galbo, F., and Guarna, A., Tetrahedron: Asymmetry, 17, 1409 (2006). Huang, J., Ianni, J. C., Antoline, J. E., Hsung, R. P., and Kozlowski, M. C., Org. Lett., 8, 1565 (2006). Szakonyi, Z., Balazs, A., Martinek, T. A., and Fulop, F., Tetrahedron: Asymmetry, 17, 199 (2006). Roudeau, R., Pardo, D. G., and Cossy, J., Tetrahedron, 62, 2388 (2006). Mastranzo, V. M., Santacruz, E., Huelgas, G., Paz, E., Sosa-Rivadeneyra, M. V., Bernes, S., Juaristi, E., Quintero, L., and Anaya de Parrodi, C., Tetrahedron: Asymmetry, 17, 1663 (2006). Unaleroglu, C., Aydin, A. E., and Demir, A. S., Tetrahedron: Asymmetry, 17, 742 (2006). Trost, B. M., Weiss, A. H., and von Wangelin, A. J., J. Am. Chem. Soc., 128, 8 (2006). Wang, M.-C., Hou, X.-H., Chi, C.-X., and Tang, M.-S., Tetrahedron: Asymmetry, 17, 2126 (2006). Tanaka, T., Yasuda, Y., and Hayashi, M., J. Org. Chem., 71, 7091 (2006). Cozzi, P. G. and Kotrusz, P., J. Am. Chem. Soc., 128, 4940 (2006). Sugiyama, S., Aoki, Y. and Ishii, K., Tetrahedron: Asymmetry, 17, 2847 (2006). Palacios, F. and Vicario, J., Org. Lett., 8, 5405 (2006). Lauzon, C. and Charette, A. B., Org. Lett., 8, 2743 (2006). Basra, S., Fennie, M. W., and Kozlowski, M. C., Org. Lett., 8, 2659 (2006). Nishimura, T., Yasuhara, Y., and Hayashi, T., Org. Lett., 8, 979 (2006). Mordini, A. and Valacchi, M., Chem. Abs., 145, 504985 (2006). Mordini, A. and Valacchi, M., Chem. Abs., 145, 504986 (2006). Mordini, A. and Valacchi, M., Chem. Abs., 145, 504987 (2006). Mordini, A. and Valacchi, M., Chem. Abs., 145, 504988 (2006). Mordini, A. and Valacchi, M., Chem. Abs., 145, 504989 (2006). Mordini, A. and Valacchi, M., Chem. Abs., 145, 504990 (2006). Lazny, R., Chem. Abs., 145, 504991 (2006). Lazny, R., Chem. Abs., 145, 504992 (2006). Juaristi, E. and Melgar-Fernandez, R., Chem. Abs., 145, 504993 (2006). Streitwieser, A. and Xie, L., Chem. Abs., 145, 504998 (2006). Dhondi, P. K. and Chisholm, J. D., Org. Lett., 8, 67 (2006). Kwiatkowski, P., Chaladaj, W., and Jurczak, J., Tetrahedron, 62, 5116 (2006). Gronert, S. and Keeffe, J. R., J. Org. Chem., 71, 5959 (2006). Noronha, L. A., Judson, T. J. L., Dias, J. F., Santos, L. S., Eberlin, M. N., and Mota, C. J. A., J. Org. Chem., 71, 2625 (2006). Mori, H., Matsuo, T., Yoshioka, Y., and Katsumura, S., J. Org. Chem., 71, 9004 (2006). Bernasconi, C. F. and Zheng, H., J. Org. Chem., 71, 8203 (2006). DeTuri, V. F., Koch, H. F., Koch, J. G., Lodder, G., Mishima, M., Zuilhof, H., Abrams, N. M., Anders, C. E., Biffinger, J. C., Han, P., Kurland, A. R., Nichols, J. M., Ruminski, A. M., Smith, P. R., and Vasey, K. D., J. Phys. Org. Chem., 19, 308 (2006). Mitsuhashi, K., Ito, R., Arai, T., and Yanagisawa, A., Org. Lett., 8, 67 (2006). Pineschi, M., Eur. J. Org. Chem., 2006, 4979. Robiette, R., J. Org. Chem., 71, 754 (2006).

9 Carbanions and Electrophilic Aliphatic Substitution 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161

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Polo, V., Domingo, L. R., and Andres, J., J. Org. Chem., 71, 754 (2006). Phan, T. B. and Mayr, H., Eur. J. Org. Chem., 2006, 2530. Moss, R. A. and Tian, J., Org. Lett., 8, 67 (2006). Takikawa, H., Hachisu, Y., Bode, J. W., and Suzuki, K., Angew. Chem. Int. Ed., 45, 3492 (2006). Biddle, M. M. and Reich, H. J., J. Org. Chem., 71, 4031 (2006). Vanecko, J. A., Wan, H., and West, F. G., Tetrahedron, 62, 1043 (2006). Pinho e Melo, T. M. V. D., Eur. J. Org. Chem., 2006, 2873. Ochiai, M., Tada, N., Murai, K., Goto, S., and Shiro, M., J. Am. Chem. Soc., 128, 9608 (2006). Pihko, P. M., Angew. Chem. Int. Ed., 45, 544 (2006). Prakash, G. K. S. and Beier, P., Angew. Chem. Int. Ed., 45, 2172 (2006). Marigo, M. and Jorgensen, K. A., Chem. Commun., 2006, 2001. Bobbio, C. and Gouverneur, V., Org. Biomol. Chem., 4, 2065 (2006). Tredwell, M. and Gouverneur, V., Org. Biomol. Chem., 4, 26 (2006). Huber, D. P., Stanek, K., and Togni, A., Tetrahedron: Asymmetry, 17, 658 (2006). Suzuki, S., Furuno, H., Yokoyama, Y., and Inanaga, J., Tetrahedron: Asymmetry, 17, 504 (2006). Hamashima, Y., Suzuki, T., Takano, H., Shimura, Y., Tsuchiya, Y., Moriya, K.-i., Goto, T., and Sodeoka, M., Tetrahedron, 62, 7168 (2006). Perseghini, M., Massaccesi, M., Liu, Y., and Togni, A., Tetrahedron, 62, 7180 (2006). Thomassigny, C., Prim, D., and Greck, C., Tetrahedron Lett., 47, 1117 (2006). Terada, M., Nakano, M., and Ube, H., J. Am. Chem. Soc., 128, 16044 (2006). Kang, Y. K. and Kim, D. Y., Tetrahedron Lett., 47, 4565 (2006).

CHAPTER 10

Elimination Reactions

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

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307 307 308 309 309 309 311 312 314 315

E1cB Mechanisms The mechanistic borderline between E2 and E1cB mechanisms has been studied under various conditions.1,2 The mechanism of the elimination reaction of 2-(2-fluoroethyl)1-methylpyridinium has been explored explored by Car–Parrinello molecular dynamics in aqueous solution.3 The results indicated that the reaction mechanism effectively evolves through the potential energy region of the carbanion: the carbon–fluoride bond breaks only after the carbon-hydrogen bond.

E2 Mechanisms It has been found that dehydrobromination of 9-bromo-9,9 -bifluorenyl derivatives (Scheme 1) occurred by E2 elimination, suggesting that the configuration of 9bromo-9,9 -bifluorenyl isomers determined the stereochemistry of the product.4 Facile isomerization of the 9,9 -bifluorenylidenes formed may give the observed stereoselectivity depending on the length of the acyl side-chain. The nature of the transition state for the E2 reaction of some 3-thiophenoxypropanones in aprotic solvents has been investigated.5 The linear free energy correlation and the calculated activation parameters H = and S = of the reactions suggested an unequal and synchronous E2cB mechanism via base-catalysed amine-elimination reaction. Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd


307

de

308

Organic Reaction Mechanisms 2006 (R)

(R)

Br Br

KOH

R

KOH

R

(R)

R R = Ac R = St

(R) Z : E = 30 : 70 Z : E = 90 : 10

Scheme 1

The competition between nucleophilic substitution and base-induced elimination in the gas phase has been studied using deuterium kinetic isotope effects (KIE).6 The overall reaction rate constants and KIE have been measured for the reactions of RCl + ClO− (R = Me, Et, i-Pr, and t-Bu). As the extent of substitution in the alkyl chloride increases, the KIE effects become increasingly more normal. These results indicated that the E2 pathway becomes the dominant channel as the alkyl group becomes more sterically hindered.

Solvolytic Reactions High-level ab initio calculations have shown that the SN 2 reaction of the cyanide ion with ethyl chloride is catalysed by 1,4-benzenedimethanol in dipolar aprotic solvents through selective two hydrogen bonds.7 In non-polar solvents, combined with phasetransfer catalysis, the 1,4-benzenedimethanol could replace some water molecules hydrating the cyanide ion and induce a substantial rate acceleration effect. Cope elimination reactions of threo- and erythro-N ,N -dimethyl-3-phenyl-2-butylamine oxide have been investigated using QM/MM calculations in water, THF, and DMSO.8 The aprotic solvents provided rate accelerations of up to 106-fold. It has been found that the amine oxide oxygen is the acceptor of three hydrogen bonds from water molecules for the reactant but only one or two weaker ones at the transition state. Solvent effects on the kinetics and mechanism of unimolecular heterolysis of commercial organohalogen compounds have been investigated.9–11 The reaction rate is satisfactorily correlated by parameters for polarity, electrophilicity, and cohesion of the solvent, whereas the solvent nucleophilicity and polarizability exert no effect. The solvent effect of ionic liquids on the decarboxylation of 1,3-dimethylorotic acid and its analogue has been investigated.12 The rate acceleration observed has been attributed to stabilization of the zwitterionic intermediates by the charged groups available in these special solvents.

309

10 Elimination Reactions

Pyrolytic Reactions Cycloreversions Density functional theory studies of intramolecular retro-ene reactions of allyldiazenes have shown that the reaction is a concerted process involving a six-centre cyclic transition state.13 The cis- and trans-allyldiazenes can interconvert by rotation around the double bond or by nitrogen inversion, it being predicted that nitrogen inversion is favoured. Experimental and theoretical results have revealed the influence of a neighbouring cyclopropane ring in a retro-Diels–Alder reaction at lower temperature.14 The lower kinetic barrier for this reaction has been attributed to stabilization of the transition state by orbital interactions involving the cyclopropane bond orbitals. An improved retro-cycloaddition of pyrrolidinofullerenes has been carried out in presence of metal Lewis acids.15 The experimental data suggested that thermal treatment leads to the formation of the azomethine ylide, which is efficiently trapped by the dipolarophile that is present in the reaction medium. A strained azo-bridged tricyclic system (1) undergoes a selective retro ‘inverse electron-demand’ Diels–Alder reaction on heating, leading through a cascade of tautomeric and sigmatropic shifts to the pyridazine derivative (2) (Scheme 2).16 The proposed mechanism was supported by quantum chemical calculations and experimental evidence. E

N N

E

110 –150 °C or pyrolysis

N

E

O E = COOMe

(1)

N N E (2)

Scheme 2

Acid Derivatives An ab initio study on the unimolecular elimination reactions of methacrylonitrile has revealed a direct four-centre elimination of HCN and three-centre elimination of H2 channels.17 A methylcyanoethylidene intermediate has also been identified. Decarboxylation of pyruvic acid and its isomers, including the enol tautomers and enantiomeric lactone structures, has been investigated at the B3LYP/6–311++G(3df, 3pd) level.18 It has been found that a keto form with trans Cmethyl Cketo Cacid Ohydroxyl and cis Cketo Cacid OH, and with one methyl hydrogen in a synperiplanar position with respect to the keto oxygen, is the most stable. The unimolecular reactivities of a range of perbenzoate anions have been investigated in the gas phase by electrospray ionization tandem mass spectrometry.19 The

310


O

O

O−

O−

O

O

−

O

−

ortho

O

O

−CO2

ipso ‡

O O

O

O

O−

−

O

O −

O O

−

O

−CO2

Scheme 3

combination of substituent studies and electronic structure calculation have revealed competing ortho and ipso mechanisms that have similar activation energies directly influenced by the nature and position of substituents on the aromatic ring (Scheme 3). These data also indicated that the loss of carbon dioxide does not lead directly to the phenoxide product ions but rather proceeds via initial epoxidation of the benzene ring forming benzene oxide or oxepin anions that may subsequently rearrange to the global minimum. Gas-phase elimination reactions of ethyl esters of α- and β-amino acids have been investigated in a static reaction system.20,21 The first step of decomposition of these esters is formation of the corresponding carboxylic acids and ethylene through a concerted six-membered cyclic transition state. The intermediate β-amino acids decarboxylate via a semipolar six-membered cyclic transition state. Activation barriers for geometric isomerism and tautomerization have been studied for carbamic acid and its mono- and di-chalcogenide analogues, H2 NC(=X)YH (X, Y = O, S, Se), at the B3LYP/6–31+G∗ , MP2/6–31+G∗ , and G2MP2 theoretical levels.22 The studies have indicated that carbamic acid with higher chalcogen prefers chalcogen at the chalcogenol position. Decomposition of carbamic acid and its analogues is believed to occur by a two-step pathway. The gas-phase unimolecular elimination reactions of 2-substituted ethyl N ,N dimethylcarbamates23,24 and several heterocyclic carbamates25 have been studied using the Möller–Plesset MP2/6–31G method. On the basis of these calculations, the mechanism appears to be concerted, asynchronous, through a six-membered cyclic transitionstate structure. Theoretical studies on the gas-phase elimination of 2-substituted alkylethyl methylcarbonates were performed at the B3LYP/6–31G∗ and B3LYP/6–31+G∗∗ levels of theory.26 The results of these calculations provide additional evidence that the mechanism for carbonates with a Cβ –H bond proceeds through a concerted non-synchronous

311


six-membered cyclic transition state to produce methylcarbonic acid and the corresponding alkene. The unstable intermediate, methylcarbonic acid, rapidly decomposes through a four-membered cyclic transition state to methanol and carbon dioxide. Theoretical evidence for the thermal decomposition mechanism for ethyl oxamate, ethyl oxanilate, and ethyl N ,N -dimethyl oxamate have been provided.27 Ethyl oxamate and ethyl oxanilate undergo rapid decarbonylation to give the corresponding carbamates. Ethyl N ,N -dimethyloxamate elimination reaction yields in one step, through a six-membered cyclic transition state, dimethyloxamic acid and ethylene gas.

Other Pyrolytic Reactions The Arrhenius parameters for the gas-phase unimolecular structural isomerizations of 1,1,2-trimethylcyclopropane28 to three isomeric methylpentenes and two dimethylbutenes, and of 1,1,2,2-tetramethylcyclopropane29 to 2,4-dimethylpent-2-ene have been determined over a wide range of temperatures. Despite previous reports on substantial decreases in activation energies for structural isomerizations of methylsubstituted cyclopropanes, this study has revealed that the trend does not continue beyond dimethylcyclopropane isomerization. Activation energies and rate constants calculated for the thermolysis of α-hydroxyaldehydes at the MP2/6–311++G(d,p)//MP2(FC)/6–31G(d) level indicate that the thermolysis of α-hydroxyaldehydes is slower than the thermolysis of similar α-hydroxy ketones.30 A positive inductive effect due to methyl groups, at either C(3) or C(4), accelerates the reaction with respect to the unsubstituted α-hydroxyaldehyde; the effect at C(4) is greater than that at C(3). Kinetics of the gas-phase elimination of 2-hydroxynitroalkanes have been investigated at the MP2/6–31G∗ level of theory.31 The thermal elimination of 2-hydroxynitroalkanes occurs in a retro-aldol type of mechanism with a six-membered transition state structure characterized by the transference of the hydroxyl hydrogen to the nitro group to give acetaldehyde and the corresponding nitroalkane for the secondary substrates and acetone and nitromethane for the tertiary substrate. Sulfenic acid (3) has been synthesized in the gas phase by low-pressure, hightemperature pyrolysis of di-t-butyl sulfoxide (4) and characterized by means of matrix isolation and gas-phase IR spectroscopy (Scheme 4).32 The mechanism of formation of (3) by flash pyrolysis of (4) has been studied by quantum chemical calculations, and different pyrolysis experiments monitored by mass spectrometry. In agreement H H2C Me

H

O S

Me Me

500 °C

H2C Me SOH

−

Me

H 1150 °C −

S O

Me

Me (4)

(5) Scheme 4

(3)

H

312


with theoretical and experimental results, (3) appears to be formed through several successive unimolecular steps via the primary decomposition product t-BuSOH (5). A series of cyano(arylcarbamoyl)phosphorus ylides (6) and cyano(arylthiocarbamoyl)phosphorus ylides (7) have been prepared and fully characterized.33 Pyrolytic reaction products obtained by FVP have shown that thermal extrusion of Ph3 PO or Ph3 PS occurs (Scheme 5). Kinetic study of the gas-phase pyrolysis of each ylide by a static method showed that these reactions are unimolecular and first order with no significant substituent effect, but the thiocarbamoyl ylides (7) react 40–65 times more rapidly than their carbamoyl analogues (6). Ph3P X

CN N H

FVP, 500 °C

Ph

Ph3P X + PhHN

CN

PhNH2

(6) X = O (7) X = S Scheme 5

Elimination Reactions in Synthesis Metathesis of alkenes has been reviewed in terms of cross-metathesis, ring opening and closing, disproportionation, transmutation, and self-metathesis.34 A review on catalytic processes involving β-carbon elimination has summarized recent progress on palladium-catalysed C–C bond cleavage in various cyclic and acyclic systems.35 The salt-free Wittig reaction of non-, semi-, and stabilized ylides has been investigated on realistic systems using DFT calculations, including continuum solvation.36 These results provided unequivocal support for the generally accepted mechanism and are in very good agreement with experimental selectivities. Intermolecular aza-Wittig reaction has been described for the one-step synthesis of pyrazolo[1,5-a]pyrimidine and imidazo[1,2-b]pyrazole derivatives.37 The asymmetric synthesis of β-quaternary azacycles has been accomplished by aza-Wittig reaction mediated by chiral phosphorus(III) reagents.38 The existence of oxaarsetanes during an arsa-Wittig reaction has been proved by 1 H and 17 O NMR spectroscopy.39 75 As NMR spectra were obtained from the corresponding arsonium salts and arsane oxides. It has been demonstrated by various NMR methods that the mechanism of the arsa-Wittig reaction is identical to that of the phospha-Wittig reaction. Pentacoordinate 1,2-oxastibetane (8) has been successfully synthesized by the reactions of the corresponding bromo-2-hydroxyalkylstiboranes with NaH.40 3-Phenyl1,2-oxastibetane decomposed to give the corresponding oxirane with retention of configuration as the sole product, in sharp contrast to the result of the thermolysis of the 1,2-oxaphosphetane bearing the Martin ligand (Scheme 6). Thermolysis of the 3-phenyl-1,2-oxastibetane in the presence of LiBr and LiBPh4 .3DME gave selectively the oxirane with inversion of configuration and the corresponding alkene as the main product, respectively.

313

10 Elimination Reactions F3C CF3 O

O

∆

Ph

Sb Ar

O

Ph F3C

CF3 Ph

H Ph

(8) Scheme 6

A variety of α,β-epoxy sulfones have been converted into a range of mono-, di-, and tri-substituted allylic alcohols using the epoxy-Ramberg–Bäcklund reaction (ERBR) (Scheme 7).41 Modification of this method has enabled the preparation of enantioenriched allylic alcohols following the diastereoselective epoxidation of enantioenriched vinyl sulfones that were accessed efficiently from the chiral pool. R1 R

R2

S H O2

R1 O

R3

base

R2

O−

R

H+ −SO2

R4

S O2

R4

R3

R1

HO R3 R4

R

R2

ee de

R, R1, R2, R3, R4 = alkyl, aryl Scheme 7

A reaction of dibromoacetic acid with different aldehydes promoted by SmI2 , followed by an elimination reaction also promoted by samarium diiodide, affords (E)α,β-unsaturated carboxylic acids with total stereoselectivity (Scheme 8).42 A mechanism that involves chelation of the Sm(III) centre with the oxygen atom of the alcohol group through a six-membered chair-like transition state has been described. O

O R

R

+

O

SmI2

Br

OH

de

R

OH

Br Scheme 8

A highly Z-selective olefination of α-oxy and α-amino ketones via ynolate anions has been reported (Scheme 9).43 The stereocontrol mechanism has been explained by orbital interactions between the s orbital of the breaking C–O bond or π orbital of the enolate and the s ∗ orbital of the C–O or C–N bonds of the substituent in the ring opening of the β-lactone enolate intermediates, and/or the chelation to lithium. A clean and reagent-free generation of highly strained cycloalkynes from bi-3H diazirin-3-yls has been described.44 A new synthesis of alkynes has been achieved by

de

314

Organic Reaction Mechanisms 2006 R1

OLi

O R1

OLi +

R2

R3

R2

O R

R 1,

R2,

R3

R1

COOLi

R2

R3

3

= alkyl

Scheme 9

Br Br

R2

base DMF, 80 °C

OR1

R2 OR1

R1, R2 = alkyl, aryl Scheme 10

treatment of 1,2-dibromoalkanes with 5 equiv. of DBU (Scheme 10).45 The inductive effect of oxygen substitution at the C(3) position plays a critical role in proton abstraction. An unusual dehydroxymethylation has been observed in an acyclic primary alcoholic system.46 The relief of steric congestion has been considered as the primary driving force in this reaction. A new and readily available catalytic system has been developed to open the cyclopropane ring in 4 + 2 + 2-homo-Diels–Alder cycloadducts formed by reaction of norbornadienes and buta-1,3-diene.47 The cobalt-mediated homo-Diels–Alder reaction followed by this PtCl2 -promoted isomerization is a key step in the efficient route to bicyclo[5.3.0]decanes. A novel system for the enantioconvergent decarboxylative protonation of racemic β-keto esters has been developed.48 The reaction tolerates a variety of substitution and functionality and delivers products of high enantiopurity in excellent yield. The enantioinduction in the observed protonated products is consistent with the intermediacy of an enolate that is intimately associated with a chiral Pd complex. The molecular mechanism of the Hoffmann elimination involving (N -Cl)-N -methylethanolamine has been theoretically characterized by using DFT at the B3LYP/ 6–31++G∗∗ computing level.49 The role of water as a solvent has been analysed by using both discrete and hybrid discrete–continuum models. The rearrangement proceeds by a water-assisted asynchronous concerted mechanism.

ee

Other Reactions The enantioselective palladium-catalysed decarboxylative allylic alkylation has been highlighted.50

ee


315

Ultrafast molecular elimination of iodine from IF2 C–CF2 I has been studied using the velocity map ion imaging technique in combination with femtosecond pump–probe laser excitation.51 By varying the femtosecond delay between pump and probe pulse, it has been found that elimination of molecular iodine is a concerted process, although the two carbon–iodine bonds are not broken synchronously. Experimental rate constants, kinetic isotope effects and chemical branching ratios for the CF3 CFClCH3 -d0 , -d1 , -d2 , and -d3 molecules have been experimentally measured and interpreted using statistical unimolecular reaction rate theory.52 The structural properties of the transition states needed for the theory have been calculated by DFT at the B3PW91/6–31G(d ,p ) level. A kinetic study of the aminolysis of substituted (methylthio)benzylidene Meldrum’s acids with aliphatic primary amines in aqueous DMSO has been reported.53 With all amines the reactions are strictly second order and proceed via a three-step mechanism. The effects of the addition of sugars, long-tailed n-alkyl pyranosides, n-alkyl glycerol ethers and n-alcohols on the properties of di-n-hexadecyldimethylammonium bromide (DHAB) vesicles have been studied.54 Upon addition of most additives, an inhibiting effect on the decarboxylation reaction of 6-nitrobenzisoxazole-3-carboxylate anion has been observed relative to the reaction in vesicles without any additive. The largest inhibition was observed in the case of cholesterol. A significant acceleration of the electrocyclic ring opening of benzocyclobutene derivatives has been disclosed under the influence of a β-silicon atom.55 This effect has been associated with the adjacent anion-driven electrocyclic reactions such as oxy-Cope rearrangement. A convenient route to trivinylphosphine has been developed by thiol elimination from tris[2-(phenylthio)ethyl]phosphine oxide.56 The reaction mechanism involves a phosphoryl-stabilized carbanion, from which benzene thiolate anion is eliminated.

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Pyun, S. Y. and Cho, B. R., Chem. Abs., 144, 232584 (2005). D’Anna, F., Frenna, V., Pace, V., and Noto, R., Tetrahedron, 62, 1690 (2006). De Angelis, F., Tarantelli, F., and Alunni, S., Chem. Abs., 145, 124002 (2006). Oota, A., Imai, T., Yamazaki, A., Oba, T., Karikomi, M., and Minabe, M., Bull. Chem. Soc. Jpn, 79, 333 (2006). Ismail, A. M., Elba, M. E., and El-Sadany, S. K., Chem. Abs., 144, 369488 (2005). Villano, S. M., Kato, S., and Bierbaum, V. M., J. Am. Chem. Soc., 128, 736 (2006). Almerindo, G. I. and Pliego, J. R., Chem. Abs., 145, 124037 (2006). Acevedo, O. and Jorgensen, W. L., J. Am. Chem. Soc., 128, 6141 (2006). Ponomarev, N. E., Zalinznyi, V. V., and Dvorko, G. F., Chem. Abs., 145, 82854 (2006). Vasil’kevich, A. I., Ponomareva, E. A., and Dvorko, G. F., Chem. Abs., 145, 62435 (2006). Ponomarev, N. E., Zalinznyi, V. V., and Dvorko, G. F., Chem. Abs., 145, 62434 (2006). Wong, F. M. and Wu, W., Bioorg. Chem., 34, 99 (2006). Jabbari, A., Sorensen, E. J., and Houk, K. N., Org. Lett., 8, 3105 (2006). Kotha, S., Banerjee, S., Patil, M. P., and Sunoj, R. B., Org. Biomol. Chem., 4, 1854 (2006). Martin, N., Altable, M., Filippone, S., Martin-Domenech, A., Echegoyen, L., and Cardona, C. M., Angew. Chem. Int. Ed., 45, 110 (2006). Novak, Z., Vincze, Z., Czegeny, Z., Magyarfalvi, G., Smith, D. M., and Kotschy, A., Eur. J. Org. Chem., 2006, 3358. Oh, C. Y., Park, T. J., and Kim, H. L., Chem. Abs., 144, 350177 (2005). Kakkar, R., Pathak, M., and Radhika, N. P., Org. Biomol. Chem., 4, 886 (2006).

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Harman, D. G., Ramachandran, A., Gracanin, M., and Blanksby, S. J., J. Org. Chem., 71, 7996 (2006). Chuchani, G., Herize, A., Dominguez, R. M., Rotinov, A., and Tosta, M., J. Phys. Org. Chem., 19, 326 (2006). Monsalve, A., Rosas, F., Tosta, M., Herize, A., Dominguez, R. M., Brusco, D., and Chuchani, G., Int. J. Chem. Kinet., 38, 106 (2006). Kaur, D., Kaur, R. P., and Kaur, P., Bull. Chem. Soc. Jpn, 79, 1869 (2006). Ruiz, C., Argenis, J., Lorono, M., Cordova, T., and Chuchani, G., Chem. Abs., 145, 488844 (2006). Marcano, B., Carlos, J., Lorono, M., Cordova, T., and Chuchani, G., Chem. Abs., 145, 376712 (2006). Graterol, M., Cordova, T., and Chuchani, G., J. Phys. Org. Chem., 19, 700 (2006). Anez, R., Herize, A., Sierraalta, A., Cordova, T., and Chuchani, G., Int. J. Chem. Kinet., 38, 184 (2006). Mora, J. R., Lorono, M., Cordova, T., and Chuchani, G., J. Phys. Org. Chem., 19, 503 (2006). Lewis, D. K., Hughes, S. V., Miller, J. D., Schlier, J., Wilkinson, K. A., Wilkinson, S. R., and Kalra, B. L., Int. J. Chem. Kinet., 38, 475 (2006). Lewis, D. K., Gray, T., Katsva, V., Parcella, K., Schlier, J., Kalra, B. L., Cho, J., and Mish, D., Int. J. Chem. Kinet., 38, 483 (2006). Castillo, N. and Boyd, R. J., J. Phys. Chem. A, 110, 8710 (2006). Anez, R., Izquierdo, R., Vidal, A., Cordova, T., Sierraalta, A., and Chuchani, G., J. Phys. Org. Chem., 19, 836 (2006). Beckers, H., Esser, S., Metzroth, T., Behnke, M., Willner, H., Gauss, J., and Hahn, J., Chem. Eur. J., 12, 832 (2006). Aitken, R. A., Al-Awadi, N. A., El-Dusouqui, O. M. E., Farrell, D. M. M., and Kumar, A., Int. J. Chem. Kinet., 38, 496 (2006). Dwyer, C. L., Chem. Abs., 145, 471037 (2006). Satoh, T. and Miura, M., Chem. Abs., 145, 1046753 (2006). Robiette, R., Richardson, J., Aggarwal, V. K., and Harvey, J. N., J. Am. Chem. Soc., 128, 2394 (2006). Barsy, M. A. and El-Rady, E. A., Chem. Abs., 145, 210988 (2006). Lertpibulpanya, D., Marsden, S. P., Rodriguez-Garcia, I., and Kilner, C. A., Angew. Chem. Int. Ed., 45, 5000 (2006). Raeck, C. and Berger, S., Eur. J. Org. Chem., 2006, 4934. Uchiyama, Y., Kano, N., and Kawashima, T., J. Org. Chem., 71, 659 (2006). Evans, P., Johnson, P., and Taylor, R. J. K., Eur. J. Org. Chem., 2006, 1740. Concellon, J. M. and Concellon, C., J. Org. Chem., 71, 1728 (2006). Shindo, M., Yoshikawa, T., Itou, Y., Mori, S., Nishii, T., and Shishido, K., Chem. Eur. J., 12, 524 (2006). Al-Omari, M., Banert, K., and Hagedorn, M., Angew. Chem. Int. Ed., 45, 309 (2006). Kutsumura, N., Yokoyama, T., Ohgiya, T., and Nishiyama, S., Tetrahedron Lett., 47, 4133 (2006). Peng, L., Ma, M., Zhang, X., Zhang, S., and Wang, J., Tetrahedron Lett., 47, 8175 (2006). Hours, A. E. and Snyder, J. K., Tetrahedron Lett., 47, 675 (2006). Mohr, J. T., Nishimata, T., Behenna, D. C., and Stoltz, B. M., J. Am. Chem. Soc., 128, 11348 (2006). Ramos, D. R., Castillo R., Canle L. M., Garcia, M. V., Andres, J., and Santaballa, J. A., Chem. Abs., 145, 454643 (2006). You, S.-L. and Dai, L.-X., Angew. Chem. Int. Ed., 45, 5246 (2006). Roeterdink, W. G., Rijs, A. M., and Janssen, M. H. M., J. Am. Chem. Soc., 128, 576 (2006). Zhu, L., Simmons, J. G., Burgin, M. O., Setser, D. W., and Holmes, B. E., J. Phys. Chem. A, 110, 1506 (2006). Ali, M., Biswas, S., Rappoport, Z., and Bernasconi, C. F., J. Phys. Org. Chem., 19, 647 (2006). Jongejan, M. G. M., Klijn, J. E., and Engberts, J. B. F. N., J. Phys. Org. Chem., 19, 249 (2006). Matsuya, Y., Ohsawa, N., and Nemoto, H., J. Am. Chem. Soc., 128, 412 (2006). Gusarova, N. K., Chernysheva, N. A., Arbuzova, S. N., Bogdanova, M. V., Ivanova, N. I., Kudryavtsev, A. A., and Trofimov, B. A., Chem. Abs., 146, 62794 (2006).

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 Brønsted Acids . . . . . . . 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . .

317 318 318

. . . . . . .

321 322 324 324 340 341 341

. . . .

353 361 368 372

Reviews During the coverage period of this chapter, reviews have appeared on the following topics: gold-catalysed hydroamination of C–C multiple bonds;1 mechanism of hydrosilylation;2 hydrostannation of activated alkynes mediated by Stryker’s reagent;3 synthesis, hydrometallation, and carbometallation of fluoroalkylated alkynes;4 C2 symmetrical bis(oxazoline) ligands in asymmetric catalysis;5 enantioselective dihydroxylation of alkenes by osmium complexes;6 transition metal-catalysed carbochalcogenation of alkynes;7 synthesis of fine chemicals by the conjugate addition of nitroalkanes to electrophilic alkenes;8 asymmetric aza-Michael reaction;9 one-pot coupling of α,β-unsaturated carbonyl compounds bearing a chalcogen group and electrophiles using a Lewis acid;10 the phospha-Michael addition in organic synthesis;11 enantioselective 1,4-conjugate addition catalysed by Cu complexes;12 and asymmetric synthesis using environmentally friendly reagents and catalyst versus kinetic resolution.13



317

ee

ee

318


Electrophilic Additions A study of the reactions of a series of gas-phase cations (NH4 + , H3 O+ , SF3 + , CF3 + , CF+ , SF5 + , SF2 + , SF+ , CF2 + , SF4 + , O2 + , Xe+ , N2 O+ , CO2 + , Kr+ , CO+ , N+ , N2 + , Ar+ , F+ , and Ne+ ) with the three structural isomers of dichloroethene, i.e. CH2 =CCl2 , cis-ClCH=CHCl, and trans-ClCH=CHCl, has been reported.14 The recombination energy (RE) of these ions spans the range 4.7–21.6 eV. Reaction rate coefficients and product branching ratios have been measured at 298 K in a selected ion flow tube (SIFT). Collisional rate coefficients were calculated by modified average dipole orientation (MADO) theory and compared with experimental data. Thermochemistry and mass balance have been used to predict the most feasible neutral products. Threshold photoelectron–photoion coincidence spectra have also been obtained for the three isomers of C2 H2 Cl2 with photon energies in the range 10–23 eV. The fragment ion branching ratios have been compared with those of the flow tube study to determine the importance of long-range charge transfer. A strong influence of the isomeric structure of dichloroethene on the products of ion–molecule reactions was observed for H3 O+ , CF3 + , and CF+ . For CH2 =CCl2 , the reaction with H3 O+ proceeds at the collisional rate with the only ionic product being 1,1-C2 H2 Cl2 H+ . However, the same reaction yields two more ionic products in the case of cis-1,2- and trans-ClCH=CHCl, but proceeds with only 14% and 18% efficiency, respectively. The CF3 + reaction proceeds with 56–80% efficiency, the only ionic product for CH2 =CCl2 being C2 H2 Cl+ formed via Cl− abstraction, whereas the only ionic product for both 1,2-isomers is CHCl2 + , corresponding to a breaking of the C=C double bond. Less profound isomeric effects, but still resulting in different products for CH2 =CCl2 and ClCH=CHCl isomers, have been found in the reactions of SF+ , CO2 + , CO+ , N2 + , and Ar+ . Although these five ions have REs above the ionization energy (IE) of any of the C2 H2 Cl2 isomers, and hence the threshold for long-range charge transfer, the results suggest that the formation of a collision complex at short range between these ions and C2 H2 Cl2 is responsible for the observed effects.14 An attempt has been made to analyse whether the electrophilicity index is a reliable descriptor of the kinetic behaviour. Relative experimental rates of Friedel–Crafts benzylation, acetylation, and benzoylation reactions were found to correlate well with the corresponding calculated electrophilicity values. In the case of chlorination of various substituted ethylenes and nitration of toluene and chlorobenzene, the correlation was generally poor but somewhat better in the case of the experimental and the calculated activation energies for selected Markovnikov and anti-Markovnikov addition reactions. Reaction electrophilicity, local electrophilicity, and activation hardness were used together to provide a transparent picture of reaction rates and also the orientation of aromatic electrophilic substitution reactions. Ambiguity in the definition of the electrophilicity was highlighted.15

Halogenation and Related Reactions Calculated equilibrium geometries, bond lengths, and charge densities have been compared for halonium ions (1–5; X = Cl or Br) derived from the addition of halogen electrophiles to fluoro-substituted terminal alkenes (R = alkyl or perfluoroalkyl with

319

11 Addition Reactions: Polar Addition

+

X

X

C

C

R

C

+

C

R (1)

X

X C

+

R (2)

+

C

C

X C

R (3)

+

C

C

R (4)

(5)

α- and β-substituents being H or F). The calculated structures were found to correlate with regiochemical product distributions from ring opening of halonium ions by anions or by methanol as solvent. Calculated halonium ion structures and the Hammond postulate were utilized to predict the regiochemical product distributions for reactions of halogens with fluoroalkenes that were not investigated experimentally.16 A mixture of molecular iodine and 4-iodotoluene difluoride has been found to generate in situ the couple ‘IF’, capable of adding to various alkenes and alkynes in a Markovnikov fashion in CH2 Cl2 at 0–5 ◦ C and with prevalent anti -stereoselectivity.17 The mechanism for bromination of semibullvalene has been proposed, based on quantum chemical calculations. The reaction pathway involves concerted bromine addition and cyclopropane ring opening to form an allylic cation, without the intermediacy of a bromonium or a cyclopropylcarbinyl cation.18 The extent of substitution to be attained in unsaturated and brominated dodecahedranes through electrophilic and radical bromination have been elucidated as part of an effort directed at the C20 fullerene.19 Full geometric optimization of endo-tricyclo[3.2.1.02,4 ]oct-6-ene (endo-TCO) by ab initio and DFT methods has demonstrated the endo-pyramidalization of the double bond and non-equivalence of its two faces, with the exo face having regions with much higher electron density (qi, HOMO) and more negative electrostatic potential. The endo-TCO–Br2 system was investigated at the B3LYP/6–311+G∗∗ level and the endo-TCO· · ·Br2 (exo) molecular complex was found to be considerably lower in energy than its endo-TCO· · ·Br2 (endo) stereoisomer, suggesting a high preference for the exo-facial selectivity. The study of the cationic intermediates of the bromination by ab initio and DFT methods revealed the bridged exo-bromonium cation to be relatively more stable than its endo counterpart. The non-classical rearranged cation was found to be the most stable ion among the cationic intermediates, implying that the ionic addition should occur via this cation.20 Similar geometric optimization has been reported for bicyclo[3.2.2]nona-6,8-diene (BND). The double bond situated in the opposite direction to the methylene group was found to be more exo-pyramidalized than the other double bond and the electron density (qi, HOMO) of the former double bond in HOMO of the molecule higher than that of the latter double bond. The exo and endo faces of exo-pyramidalized double bonds proved not to be equal and the electron density was found to be higher on the endo faces. The endo molecular complexes with bromine have been found by the HF/321G∗ method to be more stable than their exo congeners; this was attributed to electronic and steric factors. As a result, endo-facial stereoselectivity of bromination predominates.21 A related theoretical study of facial selectivity and regioselectivity of the electrophilic addition of chlorine to exo-tricyclo[4.2.1.02,5 ]nona-3,7-diene (exoTND) has also been reported.22

de

de

de

320


5,6-Bis(dimethylamino)acenaphthylene (6) has been shown to react with X2 (X = Cl, Br, I) and N -X-succinimides both as an electron-rich alkene and arene and as a proton sponge. Thus, addition of bromine or iodine to the C(1)=C(2) bond was found to be followed by immediate dehydrohalogenation, leading to the formation of the corresponding 1(2)-(di)halogenoacenaphthylenes in good yields. Reaction with chlorine allowed the isolation of only 1,4,7-trichloro-5,6-bis(dimethylamino)acenaphthylene. With N -halosuccinimides, the halogenation is directed mainly by the steric bulk of the entering halogen and then by solvent polarity, thus allowing a regioselective preparation of 1(2)- or 4(7)-(di)halides.23 Me2N

NMe2

O

O

Br O

O

NHAc

(6)

(7)

(8)

Metal triflates have been shown to catalyse 1,2-bromoazidation of alkenes R1 CH= CHR2 with N -bromosuccinimide (NBS) and trimethylsilyl azide (TMSN3 ). Among the metal triflates, (TfO)2 Zn was identified as the best catalyst. This catalytic process represents a highly regio- and stereo-selective and high-yielding method for the synthesis of anti -1,2-bromoazides R1 CH(N3 )–CH(Br)R2 from a variety of alkenes including α,β-unsaturated carbonyl compounds.24 A general process for haloamidation of alkenes has been developed, which is characterized by the addition of a bromine atom and an amide nitrogen in an anti sense to the olefinic double bond [(7) → (8)]. The process involves the use of an N -bromoamide and a Lewis acid as a source of Br+ , which reacts with the alkene. The amide group is derived from a nitrile and a water molecule, which serve as nucleophiles for the overall three-component reaction. The reaction has been shown to be general for a broad range of alkenes and nitriles; an analogous chloroamidation reaction has also been demonstrated.25 In order to explain the high stereocontrol occurring in the iodocyclization of 3acylamino-2-methylenealkanoates, the conformational space of the starting molecule and the potential energy surface (PES) for the cyclization reaction was explored at the DFT level; the polarized continuum formalism (PCM) for chloroform was used in order to consider the solvent effect. The observed stereoselection [(9) → (10)] was ascribed to a combination of the distribution of the near-attack conformations and the energy differences between the two possible and competitive cyclization pathways leading to cis and trans diastereoisomers.26 Bromination of 3,10-epoxycyclo[10.2.2.02,11 .04,9 ]hexadeca-4,6,8,13-tetraene (11) gave (12) and several by-products. Acid cleavage of corresponding epoxide proceeded in a similar fashion.27

de

321


O

R3 R3

H

NH N

R2O2C

O

I+

I R1

R1 (9)

CO2R2 (10)

O

O

Br

Br2

OH (12)

(11)

The iodocyclization reaction of diethyl β-allenic α,α-difluorophosphonates (13) using I2 or ICl as the electrophile has been reported to produce six-membered αdifluoromethylenephostones (14) in moderate to good yields with high regioselectivities under mild conditions.28

R1

F F

I •

O CF2 P(OEt)2

R2 (13)

I2 or ICl r.t.

R1 R2

O

P OEt O

(14)

Additions of ArSX, ArSeX, and Related Reagents with Electrophilic Sulfur The mechanism of selenocyclization of β,γ -unsaturated acids and their derivatives has been studied. The reactions of (E)-4-phenylbut-3-enoic acid and its silyl and alkyl esters (15; R = H, SiMe3 , alkyl) with benzeneselenenyl halide PhSeX (X = Cl, Br) have been examined by VT-NMR and in situ IR spectroscopic methods. Whereas the reactions of the acid in the presence of a base were irreproducible and complicated, reactions of the silyl esters were clean and spontaneously and quantitatively afforded the corresponding chloroselenylation adduct at −70 ◦ C as a single (Markovnikov) isomer. This adduct underwent three processes as the temperature was raised: (1) reversal to the starting materials, (2) isomerization to the anti-Markovnikov product, and (3) cyclization to the selenolactone (16). All of these processes are believed to proceed via a seleniranium ion, the intermediacy of which was established by independent synthesis and spectroscopic identification. The reversible formation of chloroselenide adducts was unambiguously established by crossover experiments. The reaction of (15) with PhSeBr was found to be rapid but thermodynamically unfavourable at room temperature.29

322

Organic Reaction Mechanisms 2006 Ph Ph

CO2R (15)

O

PhSeCl CH2Cl2 −78 °C to r.t.

O PhSe (16)

Regio- and diastereo-selective methoxyselenenylation of cinnamylamines attached to a chiral perhydrobenzoxazine (17) proceeds in high yields in dichloromethane– methanol. The diastereoselection is dependent on the temperature and the nature of the substituent at C(2) and can be rationalized by accepting a 1,4-asymmetric induction process after coordination of the selenium to the nitrogen atom of the allylamine system.30

de

R2 O N

SePh

PhSeCl

O N (17)

R1

MeO R2 (18)

Treatment of 2,3-allenoates R1 R2 C=C=C(R3 )CO2 Et with PhSeCl in the presence of water gives rise to β-organoselenium substituted butenolides via 5(O)π,n -endotrig cyclization.31,32 The yields of the products depend largely on the structures of 2,3-allenoates. The addition of water proved to be crucial for some of these electrophilic cyclizations. The reaction of simple unsubstituted methyl buta-2,3-dienoate afforded methyl 4-chloro-3-phenylselanylbut-2(Z)-enoate in good yield and with high stereoselectivity.31

Additions of Hydrogen Halides and Other Brønsted Acids Intermolecular Markovnikov-type addition of phenols (ArOH), carboxylic acids (RCO2 H), and protected amines (TsNH2 ) to alkenes, such as 4-MeOC6 H4 CH2 CH= CH2 , can be catalysed by triflic acid in low concentrations (1–5%). Functional groups, such as the methoxyl on aromatics, can be tolerated if the concentration of triflic acid and the reaction temperature are controlled appropriately. This reaction provides one of the simplest alkene addition methods and can serve as an alternative to metal-catalysed reactions.33 The kinetics of the hydration reaction of cyclopentene with a strongly acidic cationexchange resin as catalyst have been studied. Parameters of the intrinsic kinetics model were solved by the Gauss–Newton method based on the experimental data, after excluding the influence factors of internal and external diffusion.34 The anti-Markovnikov alkylation of phenol (PhOH) with t-butyl alcohol (t-BuOH) can be achieved in supercritical water at 673 K in the absence of an added catalyst.

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The reaction apparently proceeds via dehydration of t-BuOH to generate isobutene, which reacts with phenol to form 2-isobutylphenols as anti-Markovnikov products. The hydroxy group presumably participates in the anti-Markovnikov alkylation and is further assisted by the increased water density.35 Intermolecular additions of the O–H bonds of phenols and alcohols and the N–H bonds of sulfonamides and benzamide to alkenes catalysed by 1 mol% of triflic acid have been reported as tools for the synthesis of cyclic ethers and amines. This study contributed to defining the relationship between these reactions and those catalysed by metal triflates.36 The acid-induced cyclization of unsaturated thioacetals (19) gives anti-Markovnikov products (20), apparently involving sulfur elimination and readdition.37 R2

O

R2

Me

OH

H+

× R3

R1S

SR1

R3

R1S

R2

O

R3 R1S

SR1 (19)

SR1 (20)

Intermolecular hydroamination or hydroarylation reactions of norbornene and cyclohexadiene carried out with catalytic amounts of Brønsted or Lewis acid in ionic liquids have been found to provide higher selectivity and yields than those performed in classical organic solvents. This effect was attributed to the increases of the acidity of the medium and stabilization of ionic intermediates through the formation of supramolecular aggregates with the ionic liquid.38 The relationship between regioselectivity and acid–base effects in the cyclization of carboxylic acids with a pendant triple bond has been systematically investigated both experimentally and with the density functional theory calculations. Regiocontrolled cyclizations by acid or base catalyst has been developed [(21) → (22) or (23)].39 R

O O (22)

R base

R

acid

O OR1 (21)

O O (23)

An efficient protocol for Markovnikov-type addition of N -heterocycles (imidazole, pyrazole, pyrrole, etc.) to the electron-rich double bond of vinyl esters using ionic liquid as a catalyst has been reported.40 A highly regio- and stereo-selective Brønsted acid-catalysed addition of aromatic heterocycles, such as pyrroles, furans, and indoles, to ynamides RC≡CN(R)(EWG), catalysed by Tf2 NH at −35 ◦ C, has been developed as an equivalent of hydroarylation of ynamides.41

324


Additions of Electrophilic Carbon A highly diastereoselective polycyclization of homo(polyprenyl)arenes, such as (24), bearing terminal siloxyvinyl groups can be catalysed by tin(IV) chloride (10 mol%). The nucleophilicity and E geometry of the trisubstituted double bonds and a bulky silyl group favoured the formation of (25) (with the equatorial 4α-OSiR3 group). By contrast, the less nucleophilic double bond at the junction of the B/C rings (to be) and the Z geometry of the other double bond, in conjunction with the less steric hindrance of a silyl group, gave mainly the 4β-OSiR3 diastereoisomer.42

SnCl4 (10 mol%)

de

H

(But)Ph2 SiO

H

OSi Ph2(But) (25) (91:91dr)

(24)

Prins cyclization reaction of scalemic homoallylic alcohols (26) with aldehydes (R CHO), carried out in the presence of an acid catalyst (HX), affords tetrasubstituted tetrahydropyrans (27) (99% ee) with high stereoselectively in good yields (Scheme 1).43

OH

R′CHO

R (26)

H+ (cat.) −H2O

R′

+

O

R′

O

ee

R

R

Nu− Nu = AcO, TsO, F, Cl

Nu (27)

Scheme 1

Additions Initiated by Metals and Metal Ions as Electrophiles Hydroboration of bi(cyclopent-1-ene) and 3,3 -biindene with borane, thexylborane, or (−)-isopinocampheylborane afforded, after oxidation, the corresponding meso-1,4diols as the main products. No reaction was observed with 9-BBN.44 Alkynylboration has been achieved in the reaction of alkynyl(pinacol)boranes with alkynes in the presence of nickel catalysts, giving cis-1-borylbut-1-en-3-yne derivatives. 1-Arylalk-1-ynes underwent the alkynylboration regioselectively with the selective introduction of the alkynyl groups at their 1-positions, where the aryl groups were attached.45

de

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Rhodium-catalysed asymmetric cyclization/hydroboration followed either by Pdcatalysed arylation or by oxidation was applied to the synthesis of a number of chiral, non-racemic carbocycles and heterocycles. Thus, reaction of enyne (28) with catecholborane, catalysed by a 1:1 mixture of [Rh(COD)2 ]+ SbF6 − and (S)-BINAP (5 mol%), followed by Pd-catalysed arylation with p-IC6 H4 CF3 , afforded benzylidenecyclopentane (29) in 65% yield with 88% ee.46 MeO2C

Me

MeO2C (28) 1. R2BH, [(COD)2Rh]+SbF6− (5 mol%) (S)-BINAP (5 mol%)

MeO2C MeO2C

2. 4-IC6H4CF3 (AcO)2 Pd (5 mol%)

CF3 (29)

A highly enantioface-selective silaboration of chiral allenes (30) and (31) has been developed using a combination of a chiral silylborane, (−)-(34), and a chiral Pd–(R)-(35) catalyst (Scheme 2). The chiral reagent system efficiently controlled the stereochemistry of the new stereogenic centres even in the case of mismatched combinations.47 SiMe2Ph R

1

∗

(−)-(34) (R)-(35), [Pd]

•

R1

R2 (30)

∗

∗

P(pnd∗)

R2 (32)

SiMe2Ph R1

∗

•

as above

R2 (31)

R

1

∗

∗

B(pnd∗)

R2

(33)

O PhMe2Si

PPh2

B O

(34)

(35) Scheme 2

ee

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Mercuric triflate has been shown to be a powerful catalyst for the cyclization of alkynyl t-butylcarbonates (36) and (37) giving rise to cyclic enol carbonates under mild conditions. Internal alkynyl carbonate (36) afforded the endo-dig cyclization product (38) selectively, whereas terminal alkynyl carbonate (37) provided only the exo-dig product (39).48 ButO

O

C6H13

(TfO)2Hg (5 mol%)

O

CH2Cl2, r.t., 5 min

O

O (36)

ButO

C6H13

O

(38)

O

as above

O

O

10 min

O

O C6H13

C6H13 (37)

(39)

A remarkable acceleration by the phenyl-substituted silyl groups in hydroalumination and carbolithiation reactions of propargylic alcohols RR C(OH)C≡C–SiPh2 (t-Bu) has been reported. The results show that an aryl silyl group can act not only as a protecting group but also as an activating group of the alkynyl moiety.49 Thiolate ions RS− , generated in situ from dialkyl/diaryl disulfides RSSR by indium(I) iodide-promoted cleavage, add to a variety of styrenes ArCH=CH2 in an antiMarkovnikov manner, to produce linear thioethers ArCH2 CH2 SR in high yields.50 On the other hand, indium(III) chloride and indium(III) trifluoromethanesulfonate were found to catalyse a Markovnikov-type addition of thiolacetic acid to non-activated alkenes; thus, e.g., t-BuCH2 C(Me)=CH2 produced t-BuCH2 C(SAc)Me2 . The reaction is highly regioselective and can be run in the presence of 1 mol% of catalyst.51 An intramolecular addition of thiol to non-activated double bonds has also been reported.52 Indium(III) bromide has been employed in a novel cyclization of 2-alkynylaniline derivatives (40) to afford indoles (41).53 R InBr3 (5 mol%)

R N

NH

R′

R′ (40)

(41)

Indium trichloride was identified as an efficient catalyst for the atom-transfer cyclization of allylic halides with an alkyne pendant [(42) → (43)]. Mechanistic evidence supports a cationic reaction pathway with Lewis acid activation of the allylic halogen;

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11 Addition Reactions: Polar Addition X R

MeO2C

MeO2C

InCl3 (20 mol%) CH2Cl2, r.t. (75–97%)

MeO2C

MeO2C

X

(42)

R

(43)

concomitant nucleophilic attack by the alkyne and trapping the intermediate with halide leads to the atom transfer cyclization products. Depending on alkyne substitution, a bromine atom was transferred from the substrate or a chlorine atom was transferred from the solvent.54 Addition of 10 mol% of diphenyl diselenide to hydrostannylation reactions involving electron-rich alkenes resulted in a dramatic improvement in yield. For example, reaction of α-{[(t-butyl)dimethylsilyl]oxy}styrene with Ph3 SnH (1.1 equiv.) in the presence of PhSeSePh and 2,2 -azobis(2-methylpropanenitrile) (AIBN) afforded {2{[(t-butyl)dimethylsilyl]oxy}-2-phenylethyl}triphenylstannane in 95% yield after 2 h. This reaction is believed to benefit from the increased rate of H-atom transfer, resulting from the in situ-generated polarity-reversal catalyst benzeneselenol.55 Several neutral titanium complexes have been shown to catalyse intramolecular hydroamination reactions of alkenes. The corresponding pyrrolidine and piperidine products were formed in up to 97% yields. However, only the geminally disubstituted aminoalkenes were successfully cyclized (Thorpe–Ingold effect).56 A regioselective, alkoxide-directed carbometallation has been reported to occur in all cases at the site distal to the tethered alkoxide to produce functionalized tetrasubstituted 1,3-dienes [(44) → (45)].57 O R1

HO

Ti

1. BuLi 2. PriO

n

(44)

R2

OPri R3

i

Ti

OPr

R1

R3

R2

H+

R2

HO

R3 R1 (45)

5-Hexenylsilane was introduced as a co-monomer into the organotitanium-mediated polymerization of ethylene to produce silane-terminated ethylene–5-hexenylsilane copolymers. High activities and narrow polydispersities were observed in the polymerization–chain transfer process. Ethylene–5-hexenylsilane copolymer molecular weights

328


were found to be inversely proportional to 5-hexenylsilane concentration, supporting a silanolytic chain transfer mechanism. Control experiments indicate that the chain transfer mechanism for the organotitanium-mediated ethylene polymerization of 5hexenylsilane is significantly more efficient than that for n-hexylsilane. This study represents the first case in which a functionalized co-monomer is efficiently used to effect both propagation and chain transfer chemistry during alkene polymerization.58 Stereoselective synthesis of (Z)-α-arylsulfenylvinyl tellurides via hydrozirconation of alkynyltellurides has been reported.59 An ESI mass spectrometer coupled online to a microreactor was used to intercept the catalytically active cationic intermediates of the Ziegler–Natta polymerization of ethylene with the homogeneous catalyst system [Cp2 Zr(Me)Cl]–MAO (MAO = methylaluminoxane). For the first time these intermediates were studied directly in the solution and their catalytic activity proved.60 β-Hydrogen transfer to monomer has been identified as the dominant chain termination pathway for alkene polymerization promoted by group 4 metal catalysts; the transition state is characterized by a strong metal–hydrogen interaction. Further theoretical study of a series of homogeneous single-site polymerization catalysts revealed the existence of another transition state, competitive with the latter TS, which lacks direct metal–hydrogen interaction and strongly resembles that for the main group metal aluminium. The balance between the two reaction pathways is sensitive to the choice of metal and ligand structure.61 The reaction of ArI=NTs [Ar = 2-(t-butylsulfonyl)benzene; Ts = p-toluenesulfonyl] and (tpfc)Mn [tpfc = 5,10,15-tris(pentafluorophenyl)corrole] has been shown to afford the high-valent (tpfc)MnV =NTs on a stopped-flow time-scale. The reaction proceeds via the adduct [(tpfc)MnIII (ArINTs)], with formation constant K3 = (10 ± 2) × 103 l mol−1 . The latter species then undergoes a unimolecular group transfer to give (tpfc)MnV =NTs with the rate constant k4 = 0.26 ± 0.07 s−1 at 24.0 ◦ C. The complex (tpfc)Mn catalyses the [NTs] group transfer from ArINTs to styrene substrates with low catalyst loading and without requirement of excess olefin. The catalytic aziridination reaction is most efficient in benzene because solvents, such as toluene, undergo a competing hydrogen atom transfer, resulting in H2 NTs and lowered aziridine yields. The high-valent manganese imido complex (tpfc)Mn=NTs does not transfer its [NTs] group to styrene. Double-labelling experiments with ArINTs and ArINTstBu [TstBu = (p-t-butylphenyl)sulfonyl] established the source of [NR] transfer as a ‘third oxidant’, which is an adduct of Mn(V), [(tpfc)Mn(NTstBu )(ArINTs)]. Formation of this oxidant is rate limiting in catalysis.62 Iron salts (e.g. FeCl3 ) have been identified as new catalysts for intramolecular hydroamination. A number of olefinic tosylamides underwent the reaction at 80 ◦ C to form the corresponding the N -tosylpyrrolidine derivatives in good yield.63 The same salt can also catalyse Markovnikov addition of electron-rich arenes and heteroarenes to styrenes, giving rise to 1,1-diarylalkanes at 80 ◦ C.64 The aminochlorination of methylenecyclopropanes and vinylidenecyclopropanes has been explored with use of FeCl3 (20 mol%) as a Lewis acid catalyst in acetonitrile under convenient mild conditions. The aziridinium-based mechanism, accounting for

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both regio- and stereo-selectivity, has been studied in detail. A linear free-energy relationship of this reaction confirms consistency with the Hammett equation.65 For the first time, an enantioselective cobalt-catalysed hydrovinylation of styrene was achieved with a cobalt-based system bearing a chiral bis(phosphine)amide ligand to produce PhC∗ H(Me)CH=CH2 .66 1-Alkylstyrenes PhC(R)=CH2 undergo efficient hydrovinylation (coupling with ethylene) in the presence of 1 mol% of a nickel catalyst prepared from [(allyl)NiBr]2 , Na+ BAr4 − (Ar = 3,5-bistrifluoromethylphenyl), and phosphoramidite ligands (derived from enantiopure binaphthols and 1-methylbenzylamines), giving products PhC∗ (R) (Me)CH=CH2 in excellent yields and enantioselectivities. The products contain a quaternary centre with two versatile latent functionalities, an arene and a vinyl group, useful for further synthetic elaborations.67 Aryl cyanides add to norbornene and norbornadiene under nickel catalysis to give (2R ∗ ,3S ∗ )-3-aryl-2-cyanobicyclo[2.2.1]heptanes and (2R ∗ ,3S ∗ )-3-aryl-2-cyanobicyclo[2.2.1]hept-5-enes in good yields with a broad substrate scope. On the other hand, the reaction of an aryl cyanide with triethoxy(vinyl)silane gives a Heck-type arylation product, suggesting the arylnickelation pathway in the catalytic cycle.68 Nickel(0)-catalysed hydrocyanation of certain 1,3-dienes with 1,2-bisdiarylphosphinites as chiral ligands has been developed as an efficient method. Thus, 1-phenylbuta-1,3-diene, 1-vinyl-3,4-dihydronaphthalene, and 1-vinylindene undergo highly regioselective hydrocyanation under ambient conditions to give exclusively the 1,2adducts in good to excellent yields. Using bis-1,2-diarylphosphinites derived from d-glucose, the highest (to-date) enantioselectivities for asymmetric hydrocyanation of 1,3-dienes (70–83% ee) have been obtained.69 Allyl cyanides can be added across alkynes in the presence of a nickel catalyst prepared from (COD)2 Ni and (4-CF3 C6 H4 )3 P in situ to give functionalized di- or tri-substituted acrylonitriles in a highly stereoselective manner, presumably via π allylnickel intermediates. α-Siloxyallyl cyanides also react at the γ -position of a cyano group with both internal and terminal alkynes to give silyl enol ethers, which can be converted into the corresponding aldehydes or ketones upon hydrolysis.70 Nickel-catalysed coupling of enynes (46) with allyl chlorides has been reported to occur in the presence of zinc; the reaction gives rise to the cyclic products (47) in good yields.71

Cl

(COD)2Ni, Ph3P Zn

+

MeCN, r.t.

(46)

(47)

Nickel complexes catalyse hydroheteroarylation of alkynes (49) at 35 ◦ C. Selective activation of an Ar–H bond over an Ar–CN bond of N -protected 3-cyanoindoles (48) can be achieved by a judicious choice of ligand and/or an N -protecting group.

ee

ee

ee

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Organic Reaction Mechanisms 2006 CN +

Pr

Pr

N R (48a), R = Me (48b), R = CO2Me Cy3P 35 °C

a

b

(49)

Me3P 100 °C

Pr Pr

CN

CN

Pr N Me (50)

Pr

N CO2Me (51)

Thus, the former reaction is promoted by the bulky tri(cyclopentyl)phosphine ligand, Cyp3 P, with N -methylindole derivative (48a), giving rise to (50). By contrast, Me3 P as ligand and carbamate protecting group (48b) favour the CN activation to afford adduct (51). The catalysis is applicable to a diverse range of heteroarenes to afford cis-hydroheteroarylation products in a highly chemo- and stereo-selective manner. Excellent regioselectivity was observed with unsymmetrical alkynes, which gave the corresponding heteroaryl-substituted ethenes with the larger substituent trans to the aryl group.72 The Pd[(−)-sparteine]Cl2 complex catalyses the formation of dialkyl acetals ArC (OMe)2 Me from styrene derivatives ArCH=CH2 with Markovnikov regioselectivity. Initial mechanistic studies indicate that the reaction proceeds through an enol ether intermediate and a Pd hydride.73 Pd(II)-catalysed acetalization of terminal alkenes with electron-withdrawing groups CH2 =CHX (X = CO2 -alkyl, CN) has been reported to proceed smoothly in supercritical carbon dioxide under an oxygen atmosphere to produce (RO)2 CHCH2 X; polystyrene-supported benzoquinone (PS-BQ) or CuII (CuI ) chloride were employed as co-catalyst. The higher selectivity was achieved, without any chlorinated by-product detected, when using PS-BQ instead of the copper salts. PS-BQ was recycled with excellent catalytic activity remaining after each simple filtration. The chloride ion was shown to be a promoter. Different acetalization mechanisms were found to operate as a function of the subtle relationship of the chloride ion and BQ to the catalytic activity of PdCl2 –PS-BQ, PdII –CuCl2 , or (AcO)2 Pd–PS-BQ.74 The first example of intermolecular Pd-catalysed aminoacetoxylation of alkenes, such as (52), with phthalimide as the nitrogen source and PhI(OAc)2 as the stoichiometric oxidant and source of acetate has been reported. The reaction is highly regio- and diastereo-selective; mechanistic studies revealed that the reaction proceeds

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via syn-aminopalladation of the alkene [(52) → (53)], followed by oxidative cleavage of the intermediate Pd–C bond in the Pd(IV) intermediate (54) with an unusual inversion of stereochemistry to produce the threo-isomer (55).75,76 The reaction is believed to commence by steering the approach of palladium by the alkoxy group [(56) →→ (57); R = Ar, Me, PhCH2 ; R = Me, PhCH2 ].75 O +

Ph

PhI(OAc)2

HN

(52)

Pd2+ (cat.)

[PdII]

NPhth

Ph

OMe (53)

O

PhI (OAc)2

O AcO

[(AcO)2PdIV] N

SN2

O Ph

NPhth

Ph

OMe AcO− (54)

OMe (55) O

R

R N

PdLn

R′O

OAc

R′O (56)

N

O O

O

R OR′ (57)

A very active catalyst for intermolecular hydroamination of vinylarenes and dienes (Scheme 3) can be generated from [(η3 -allyl)PdCl]2 (with or without added TfOAg) or [(CH3 CN)4 Pd](BF4 )2 and Xantphos [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene], which forms complexes with large P–Pd–P bite angles. The additions occur in the presence of potentially reactive functional groups, such as ketones with enolizable hydrogens, free hydroxyls, carboxyls, amides, nitriles, and esters. Studies on the rate of the C–N bond-forming step that occurs by attack of amine on an η3 -phenethyl and an η3 -allyl complex were conducted to determine the effect of the bite angle on the rate of this nucleophilic attack. Studies on model η3 -benzyl complexes containing various bisphosphines showed that the nucleophilic attack was faster for complexes with larger P–Pd–P bite angles. Studies of substituted unsymmetrical and unsubstituted symmetrical η3 -allyl complexes showed that nucleophilic attack on complexes ligated

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Organic Reaction Mechanisms 2006 + HX

Ph

X−

L2Pd°

L2Pd+ ArNH2

ArNH •

Ph

HX Scheme 3

by Xantphos was faster than on complexes bearing ligands with smaller bite angles and that nucleophilic attack on unsymmetrical allyl complexes with larger bite angle ligands was faster than on unsymmetrical allyl complexes with smaller bite angle ligands. However, monitoring of catalytic reactions of dienes by 31 P NMR spectroscopy showed that the concentration of active catalyst was the major factor that controlled rates for the reactions of symmetrical dienes catalysed by complexes of phosphines with smaller bite angles. The identity of the counterion also affected the rate of attack: reactions of allylpalladium complexes with chloride counterion occurred faster than reactions of allylpalladium complexes with triflate or tetrafluoroborate counterion. As often observed before, the dynamics of the allyl and benzyl complexes were also found to be dependent on the identity of the counterion.77 A facile intramolecular hydroamination of unactivated alkenes (58), catalysed by the palladium complex (60), has been reported to take place at room temperature. The formation of hydroamination products (59) rather than oxidative amination products is believed to be due to the use of a tridentate ligand, which effectively inhibits β-hydride elimination.78 O

O

PPh2

R N H

N

(60)

R

N

Pd2+

2 BF4 −

n

n

PPh2 (58)

(59)

(60)

The intramolecular Pd-catalysed carboetherification of alkenes (61) affords 2-indan1-yltetrahydrofuran products (62)/(63) in moderate to good yields with good to excellent levels of diastereoselectivity. The stereochemical outcome of these reactions is dependent on the structure of the Pd catalyst. Use of Cy3 P or [(4-MeO)C6 H4 ]3 P as the ligand for Pd leads to syn addition of the arene and the oxygen atom across the double bond giving (62), whereas the use of (±)-BINAP or DPP–benzene affords products (63) of anti addition. This catalyst-induced change in stereochemistry apparently originates from a change in reaction mechanism. The anti addition product is believed

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Br

OH

(61) (4-MeOC6H4)3P

(dba)3Pd2

O (62) (8:1)

(+)-BINAP

ButONa toluene 105 °C

O (63) (18:1)

to arise from Wacker-type anti-oxypalladation, whereas the syn addition product is assumed to be derived from an unprecedented transannular alkene insertion of an 11-membered Pd(Ar)(OR) complex.79 Phenylacetylenes substituted in the ortho-position with tethered amide functionality undergo an intramolecular endo-dig addition of the amide group to the C≡C in the presence of 5% (Ph3 P)2 Pd(OAc)2 and KOH. This methodology is suitable for the synthesis of 3-benzazepinone.80 N,N -Dichloro-p-toluenesulfonamide (TsNCl2 ) has been found to be an efficient nitrogen source for the aziridination of unfunctionalized alkenes using palladium catalysts. Among the palladium salts, (AcO)2 Pd was the most effective catalyst.81 An enantioselective silaboration of allenes (65) was attained by using the achiral silylborane (64) in the presence of a palladium catalyst bearing the chiral monodentate phosphine ligand (R)-(67). The enantioselectivity depends on the steric bulk of the allene substituents: 91–93% ee (R = t- and s-alkyl), 88–90% ee (R = aryl), and 80–82% ee (R = prim-alkyl and Me) at 0 ◦ C.82 Ligand effects on ethylene migratory insertion into a series of cationic phenylpalladium complexes (a model for Heck reaction) with diverse bidentate phosphine ligands have been studied by using the density functional methods. For the complexes with n-membered ring ligands (n = 4–6), a correlation was found between the ring size and the insertion barrier. This behaviour was explained by considering the P–Pd–P bite angle. In the case of complexes with ligands of different rigidity, almost no difference was found for the insertion barriers. Furthermore, the bidentate phosphine ligands were systematically substituted by Me, t-Bu, F, and Ph groups. It was found that the electron-donating substituents increased the insertion barrier, whereas the electron-withdrawing groups decreased it. The substantial increase of insertion barrier by the t-Bu group indicated that steric bulk also had a great effect on the migratory insertion.83 The Heck addition of aryl iodides (ArI) to CH2 =CHCH(OH)CF2 CO2 Et can be catalysed by (AcO)2 Pd in the presence of Et3 N under standard conditions.84 The

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Organic Reaction Mechanisms 2006 SiMe2Ph

O PhMe2Si

B

(dba)3Pd2 (2 mol%)

O (64) +

R

(67)

B

toluene 0 °C

O

O

•

R (65)

(66) Me P 2

Me (67)

Herrmann–Beller phosphapalladacycle has been reported to catalyse the addition of terminal alkynes across one double bond of norbornadiene to afford exo-alk5-ynylbicyclo[2.2.1]hept-2-enes. Insights into the mechanism of this reaction have been presented.85 Palladium-catalysed allylation of alkynes RC≡CR with allyl alcohol in aqueous media gives 1,4-dienes RC(Cl)=C(R )CH2 CH=CH2 with high regioand stereo-selectivity. A mechanism has been proposed, which involves competition between π -allylpalladation through cleavage of the C–O bond and the insertion of an alkene.86 Palladium-catalysed addition of terminal alkynes to cyclopropenes affords alkynylcyclopropanes under mild conditions; a number of functional groups (esters, carboxylic acids, aldehydes, and alcohols) are tolerated.87 A highly efficient and regioselective methoxycarbonylation of terminal alkyl- and aryl-alkenes (RCH=CH2 ) can be attained via a palladium–salicylic borate-catalysed protocol. The substrates include aliphatic alkenes, allylbenzenes, and styrene derivatives. The regioselectivity, in favour of the linear esters RCH2 CH2 CO2 Me, is up to quantitative, which is unprecedented in the case of styrenes.88 Palladium–monophosphine complexes catalyse trans-selective arylative, alkenylative, and alkylative cyclization reactions of alkynals [e.g. (68)] and alkynones with organoboronic reagents. These reactions afford six-membered allylic alcohols (69) and/or their five-membered counterparts (70), whose ratios are dramatically affected Ar

Ar ArB(OH)2

ArB(OH)2

(Ph3P)4Pd

(dba)3Pd2

OH

OH (69)

(68)

O

(70)

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by alkyne substituents and by the phosphine ligand. The remarkable trans selectivity of the process results from the novel reaction mechanism involving oxidative addition without oxametallacycle formation.89 By using Josiphos ligands, palladium-catalysed hydrophosphorylation of norbornenes with hydrogen phosphonates proceeds efficiently to give the corresponding phosphonates in high enantioselectivities.90 The rate of cyclotrimerization of PhC≡CMe catalysed by the camphor-derived complexes of PdCl2 has been found to be highly dependent on the R group, decreasing in the order R = Me2 N, i-Pr, C6 H5 . The effects of geometric and/or electronic parameters on the catalytic activity of the complexes were evaluated on the basis of X-ray and electrochemical data.91 The anti-Markovnikov hydration of terminal alkynes RC≡CH to give aldehydes RCH2 CH=O can be catalysed by complexes derived in situ from the air-stable ruthenium complex [CpRu(η6 -naphthalene)]PF6 and 6-aryl-2-diphenylphosphinopyridines. Increasing the size of the ligand C(6) aryl group in the order Ph < mesityl < 2,4,6triisopropylphenyl < (2,4,6-triphenyl)phenyl gave hydration catalysts of the highest activity known to date.92 Ruthenium complexes bearing bidentate ligands, generated by the self-assembly of monodentate ligands through complementary hydrogen bonding have been employed as catalysts in the regioselective hydration of terminal alkynes to produce the corresponding aldehydes.93 A catalytic amount of ruthenium(III) acetylacetonate (2 mol%) [Ru(acac)3 ] permits solvent-free tetrahydropyranylation of various types of alcohols and phenols at ambient temperature in moderate to excellent yields.94 Hydroamidation of alkenes with N-substituted formamides has been performed with dodecacarbonyltriruthenium [Ru3 (CO)12 ] at 180 ◦ C under an N2 or CO atmosphere in toluene and in a series of ionic liquids. Yields of 99% with 94–97% exo selectivity were obtained for the addition of N -methylformamide to 2-norbornene under CO both in toluene and in the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [bmim][NTf2 ]. The presence of CO or a phosphine is necessary for the reaction to occur, with CO being more effective than Ph3 P in all ionic liquids investigated. Acceptable yields were attained at low pressures, in contrast to most reported instances of hydroamidation. Conversion and selectivity decrease with increasing steric bulk of the N-formamide substituent; disubstituted formamides are inactive. Of the terminal alkenes investigated, only styrene can be hydroamidated.95 The complex formed in situ from bis(2-methylallyl)cycloocta-1,5-dieneruthenium(II) [(COD)Ru[met]2 ], a phosphine, and (TfO)3 Sc has been found to catalyse efficiently the anti-Markovnikov addition of imides (RCO)2 NH to terminal alkynes R C≡CH to produce enimides R CH=CHN(OCR)2 . Depending on the phosphine employed, E- and Z-isomers can be accessed stereoselectively.96 The presence of catalytic amounts of halide salts (e.g. Bu4 NI) was found to enhance dramatically the efficiency of hydroesterification of alkenes (e.g. cyclohexenone) and alkynes catalysed by [(CO)12 Ru3 ] in the presence of the chelating 2-pyridylmethyl formate (2-C5 H4 NCH2 OCHO). On the basis of IR and NMR studies, the halide effect

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on the reaction was attributed mainly to the facile dissociation of the trirutheniumcarbonyl precursor into the presumed active metal species. With these milder conditions, the substrate scope has been significantly broadened.97 A synthesis of the Annonaceous acetogenin asimicin and a side-chain analogue has been achieved by a highly convergent route in which Grubbs cross-metathesis played a key role.98 In the presence of a catalytic amount of a ruthenium complex coordinated to PBu3 , alkynylstannanes (R1 C≡CSnBu3 ) have been found to add to terminal alkynes (R2 C≡CH) with a 1,2-shift of the stannyl group to give (E)- and (Z)-1-tributylstannylbut-1-en-3-ynes [Bu3 SnC(R1 )=CHC≡CR2 ]. Various combinations of substrates having an aromatic and/or aliphatic substituent can be used, and the stereochemical outcome depends largely on the character of these substituents. The reaction of aliphatic terminal alkynes proceeds stereoselectively, and R1 determines the configuration: E for R1 = alkyl and Z for R1 = aryl. By contrast, the reaction of arylalkynes gave a mixture of stereoisomers irrespective of the character of substituent R1 . Ruthenium–β-stannylvinylidene complexes generated from a ruthenium complex and an alkynylstannane with migration of the stannyl group are believed to be key intermediates, which insert into the C–H bond of terminal alkynes to give the corresponding stannylenynes. DFT calculation clearly showed that the 1,2-shift of the stannyl group on formation of ruthenium–β-stannylvinylidene complexes is more facile than the corresponding 1,2-hydrogen shift of the coordinating terminal alkynes.99 Rhodium(III) tetra(p-sulfonatophenyl)porphyrin [(TSPP)Rh] aquo and hydroxo complexes react with a series of alkenes in water to form β-hydroxyalkyl coordination compounds. Addition reactions of (TSPP)Rh-OH to unactivated terminal alkenes CH2 =CHR invariably occur with both kinetic and thermodynamic preferences to place rhodium on the terminal carbon to form (TSPP)Rh–CH2 CH(OH)R complexes. Acrylic and styrenic alkenes initially react to place rhodium on the terminal carbon to form [Rh]–CH2 CH(OH)R as the kinetically preferred isomer, but subsequently proceed to an equilibrium distribution of regioisomers where [Rh]–CH(CH2 OH)R is the predominant thermodynamic product. Equilibrium constants for reactions of the diaquo rhodium(III) compound [(TSPP)RhIII (H2 O)2 ]3− in water with a series of terminal alkenes that form β-hydroxyalkyl complexes were directly evaluated and used in deriving thermodynamic values for addition of the Rh–OH unit to alkenes. The G◦ for reactions of the Rh–OH unit with alkenes in water was found to be approximately 3 kcal mol−1 less favourable than the comparable Rh–H reactions in water.100 The intramolecular anti-Markovnikov hydroamination of 1-(3-aminopropyl)vinylarenes (71; R = H, Me, CH2 OMe, CH2 OTBS) in the presence of a rhodium catalyst to form 3-arylpiperidines (72) has been reported. In contrast to intermolecular hydroamination of vinylarenes, which occurs in high yields in the presence of rhodium catalysts

R NHMe

Ph (71)

Me N

[(COD)Rh(DPPB)]BF4 (5 mol%) THF, 70 °C, 18 h

Ph

R (72)

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containing DPEphos, the intramolecular reaction occurred in high yield in the presence of [Rh(COD)(DPPB)]BF4 as catalyst. Reactants with substituents β- to the nitrogen produced 3,5-disubstituted piperidines with high yields and high diastereoisoisomeric excess. The regiochemistry of these cyclizations contrasts with the regiochemistry of intramolecular hydroaminations catalysed by lanthanide complexes, group III metal complexes, and platinum complexes, all of which have been reported previously to form cyclization products via Markovnikov addition.101 Hydroformylation of 2-phenylsulfonyl-substituted norbornene (73) and norbornadiene derivatives, catalysed by the unmodified (acac)Rh(CO)2 , has been reported to give, under standard conditions, exo-norbornane- and exo-norbornene-carboxaldehydes. The steric properties of the sulfonyl substituent, rather than its electronic effects, are believed to control the regioselectivity of the process.102 (acac) Rh(CO)2 H2, CO (1:1), 5 atm

SO2Ph

toluene, 60 °C, 15 h

de

OHC + SO2Ph

OHC

SO2Ph

(73)

A comprehensive theoretical investigation into the mechanism of the Rh(I)-catalysed hydroformylation of 1-phenyl-1-(4-pyridyl)ethene, employing a non-local density functional method (B3LYP), has been carried out. The calculations have demonstrated that the overall catalytic cycle is strongly exothermic by >90 kJ mol−1 , and the ratelimiting step is the oxidative addition of H2 . The regioselectivity originates from the alkene insertion into the Rh–H bond. 3-Phenyl-3-(4-pyridyl)propanal, the predominant product, is formed as a result of both thermodynamic and kinetic control, in agreement with experimental studies.103 The hydroformylation of linalool using [(AcO)Rh(COD)]2 as a catalyst precursor in the presence of triphenylphosphine or various diphosphines leads mainly to a mixture of cis and trans isomers of the corresponding hemiacetal, formally arising from the intramolecular cyclization of the primarily formed hydroxyaldehyde. An unexpected effect of the phosphorus ligands on the reaction rate was observed. With unmodified systems, linalool shows a very low reactivity under the hydroformylation conditions, probably due to the chelation of rhodium by the substrate. The introduction of (di)phosphine and the increase in its concentration exerts a great accelerating effect so that under optimized conditions (40–50 ◦ C and 20 atm of CO–H2 ) a virtually complete conversion of linalool has been achieved in 4–6 h. A good control of chemo- and stereo-selectivity was attained through the appropriate choice of reaction variables. Each of the two hemiacetal isomers can be obtained in ca 95% chemo- and 85% stereo-selectivity.104 The new hybrid phosphorus ligand (74), prepared from NOBIN (2-amino-2 -hydroxy-1,1 -binaphthyl),105 has been reported to exhibit excellent enantioselectivities (up to 99% ee) in the Rh-catalysed asymmetric hydroformylations of styrene derivatives and vinyl acetate.106 A range of high-yielding quaternary selective hydroformylation reactions have been performed in the presence of a reactive phosphane-modified rhodium catalyst at

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Et N

O P

PPh2

O

(74)

near ambient temperature; a range of unsaturated esters R1 R2 C=C(R3 )CO2 Me have been hydroformylated with high regioselectivity towards the α-position to produce R1 R2 CHC(R3 )(CHO)CO2 Me.107 Hydrogenation of a mixture of styrenes ArCH=CH2 (or reactive alkenes, such as norbornene or ethylene) and symmetric or mixed carboxylic anhydrides [(RCO)2 O or (RCO)O(COR )] in the presence of cationic rhodium catalysts ligated by triphenylarsine (Ph3 As), generates hydroacylation products ArCH(Me)COR as single regioisomers in high yields.108 Asymmetric hydroarylation of diphenylphosphinylallenes [Ph2 P(O)]C(R)=C=CH2 with arylboronic acids ArB(OH)2 , catalysed by an Rh–BINAP complex, has been shown to proceed in high yields with high regio- and enantio-selectivity to afford chiral allylphosphine oxides [Ph2 P(O)]CH(R)C(Ar)=CH2 of up to 98% ee. A π -allylrhodium complex has been identified as the key intermediate.109 Rhodium(I)-catalysed inter- and intra-molecular addition of 3,4-dihydroquinazolines to unactivated alkenes has been reported.110 The iridium-catalysed hydrosilylation of alkynes in the presence of 4,4 ,5,5 -tetramethylbiphosphinine (tmbp) has been explored and shown to proceed effectively to afford β-(E)-vinylsilanes with high selectivity in moderate to high yields, whereas a similar hydrosilylation in the absence of tmbp produced β-(Z)-vinylsilanes. This stereoselectivity reversal is believed to be a function of the electron-withdrawing properties of tmbp coordinated to iridium.111 The hydrosilylation of styrenes ArCH=CH2 with silanes R3 SiH can be catalysed by (CO)5 ReBr in toluene at 120 ◦ C to produce anti-Markovnikov adducts ArCH2 CH2 SiR3 in good to high yields.112 The same complex has been shown to catalyse an antiMarkovnikov addition of Et2 NH and CO2 to terminal alkynes RC≡CH (110 ◦ C, 24 h), affording E–Z mixtures of alkenyl carbamates RCH=COCONEt2 .113 1,2-Hydroxysulfenylation of alkenes R1 CH=CHR2 with disulfides R3 SSR3 can be catalysed by (bipy)CuI in DMF–AcOH in air to produce the corresponding 1,2acetoxysulfides R1 CH(OAc)CH(SR3 )R2 with high anti selectivity.114 Ph3 PAuOTf has been shown to catalyse intra- and inter-molecular hydroamination of unactivated alkenes with sulfonamides in a Markovnikov fashion.115 The same complex catalyses hydroamination of 1,3-dienes with carbamates (e.g. PhCH2 OCONH2 ) and sulfonamides at room temperature.116 An intramolecular version of the hydroamination with the Cbz group (benzyloxycarbonyl) has also been reported. The latter

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reaction is catalysed by a mixture of [{(tBu)2 (o-biphenyl)P}Au]Cl and TfOAg to produce the corresponding pyrrolidines.117 Selective activation of alkyne functions of enynes to give products either of alkoxycyclization or of exo- and endo-skeletal rearrangement can be achieved by using alkynophilic cationic gold(I) complexes. The endocyclic cyclization catalysed by gold(I) proceeds via a mechanism different from those known for Pd(II), Hg(II), or Rh(I) catalysts.118 The key step in the gold-catalysed cycloisomerization of enynes (75) is believed to be the nucleophilic attack at the Au-coordinated C≡C triple bond to form a vinylic gold intermediate (76) that is eventually converted into the final product (77).119 Me OAc

O

(Ph3P)AuCl (2 mol%) AgSbF6 (2 mol%)

O

CH2Cl2, r.t.

Ph

Ph

[Au]

(75)

Me AcO

Me O

O

+

O

O

Ph Ph

[Au−]

Ph

[Au]

(77)

(76)

The cationic binuclear complex [(Mes3 PAu)2 Cl]BF4 has been found to catalyse the reaction of 2-methyl- or 2-pentyl-furan (78) with phenylacetylene, pent-1-yne, or hept-1-yne (79) to afford the products of a twofold hydroarylation of the alkyne (80).120

R

+

Au(I)

R′

50 °C, 7 d

O (78)

(79)

R

O

O

R

R′ (80)

The Bi(OTf)3 –Cu(CH3 CN)4 PF6 system has been reported to promote efficiently an intermolecular 1:1 hydroamination of 1,3-dienes R1 CH=CHCH=CHR2 with various carbamates, sulfonamides, and carboxamides to afford allylic amines in Markovnikov

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fashion and in good yields (≤96%). The reaction proceeded with 0.5–10 mol% catalyst loading at 25–100 ◦ C (generally at 50 ◦ C) in 1,4-dioxane within 24 h. Mechanistic studies led to the formulation of a plausible mechanism.121 In the presence of BiCl3 , the hydroarylation of styrenes Ar C(R)=CH2 with electronrich arenes ArH afforded Markovnikov adducts Ar C(R)(Ar)Me selectively in good to high yields as a result of the C–H activation of ArH. Under arene-free conditions, the intermolecular hydroarylation of α-substituted styrenes and subsequent intramolecular hydroarylation produced the cyclic dimers of α-substituted styrenes in good yields.122,123 Ytterbium and lutetium ionic complexes, derived from enantiopure substituted (R)binaphthylamine ligands of the general formula [Li(THF)n ][Ln[(R)C20 H12 (NR)2 ]2 ], have been investigated as catalysts for hydroamination/cyclization of several unsaturated amines CH2 =CH(CH2 )n C(R2 )CH2 NH2 (n = 1 or 2). Complexes with isopropyl or cyclohexyl substituents on nitrogen atoms were found to be efficient catalysts for the formation of N-containing heterocycles under mild conditions with enantiomeric excesses up to 78%.124 The complete catalytic reaction course for the intramolecular hydroamination/ cyclization of hepta-4,5-dien-1-ylamine in the presence of a prototypical [(η5 -Me5 C5 )2 LuCH(SiMe3 )2 ] precatalyst has been critically scrutinized by employing a reliable DFT method.125

Miscellaneous Electrophilic Additions 1,1-Bis(trimethylsilyl)-2-adamantylidenesilane, a stabilized silene, has been generated by photolysis of a novel trisilacyclobutane derivative in various solvents and studied directly by kinetic UV spectrophotometry. The latter silene decays with secondorder kinetics in a degassed hexane solution at 23 ◦ C (k/ = 8.6 × 10−6 cm s−1 ) via a head-to-head dimerization. It reacts rapidly with oxygen [k(25 ◦ C) ≈ 3 × 105 l mol−1 s−1 ] but ∼10 orders of magnitude more slowly with MeOH than other silenes that have been studied previously. The data are consistent with a mechanism involving reaction with the hydrogen-bonded dimer of the alcohol [i.e. (MeOH)2 ] (k = 40 ± 3 l mol−1 s−1 ; kH /kD = 1.7 ± 0.2). The stable analogue of silene, namely 1t-butyldimethylsilyl-1-trimethylsilyl-2-adamantylidenesilane, reacts ∼50 times more slowly, but via the same mechanism. The mechanism for addition of water and methanol to both silenes and 1,1-bis(silyl)-2,2-dimethylsilene has been studied computationally at the B3LYP/6–31G(d) and MP2/6–31G(d) levels. Hydrogen-bonded complexes with monomeric and dimeric methanol, in which the Si=C bond acts as a nucleophile, have been located computationally for all three silenes. Reaction pathways have been characterized for the reaction of the three silenes with monomeric and dimeric ROH, which reveal significantly lower barriers for the reaction with the dimeric form of the alcohol in each case. The calculations indicate that t-butyldimethylsilyl-1-trimethylsilyl-2-adamantylidenesilane should be ∼40-fold less reactive toward dimeric MeOH than 1,1-bis(trimethylsilyl)-2-adamantylidenesilane, in excellent agreement with the ∼50-fold difference in the experimental rate constants for reaction in hexane solution.126

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Nucleophilic Additions Additions to Multiple Bonds Conjugated with C=O A study of the aminolysis of substituted (methylthio)benzylidene Meldrum’s acids (81; Z = MeO, Me, H, Br, CF3 ) with a series of aliphatic primary amines in aqueous DMSO revealed second-order overall kinetics, i.e. first order in (81) and first order in the amine. A three-step mechanism has been proposed, the first step being the ratelimiting addition of amines to form the tetrahedral intermediate which is followed by fast acid–base equilibration and then formation of (82) by a fast expulsion of the leaving group, catalysed by RNH3 + or H2 O.127 Z Z

O O O

MeS O

O

RCH2NH2 k1 k−1

O MeS

C +

PhCH2NH

O O

(81)

Z

O O O

RCH2NH O (82)

The kinetics of the addition of N-acetyl-l-cysteine, N-acetylcysteamine, and N 2 acetyl-l-lysine (NAL) to p-methoxycinnamate, p-methoxycinnamide, anthranilate, and crotonyl or sorboyl thiol ester have been studied, and the thiol addition products identified. The reaction rates increased at higher pH and the crotyl thiol ester was found to be 7.9 times more reactive than a sorboyl thiol ester toward N -acetyl-lcysteine addition. These unsaturated thiol esters may serve as a means of covalently binding UVA and UVB sunscreens to the outer layer of skin to provide long-lasting protection.128 Addition of thiophenols to chalcones in [bmim]PF6 , catalysed by l-proline and cinchonine in CH2 Cl2 , afforded products with ≤16% and 26% ee, respectively. The latter addition also occurred in neat ionic liquids in the absence of the latter catalysts but the rate of the reaction depended considerably on the structure of the ionic liquid.129 In the conjugate addition of thiols to α,β-unsaturated carbonyl compounds, carried out in aqueous conditions, water was found to play a dual role in simultaneously activating the α,β-unsaturated carbonyl compound and the thiol.130

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While the Michael-type addition of thiolates to α,β-conjugate systems is expected to proceed faster if the thio donor contains an electron-rich group or the enone acceptor is highly electron deficient, the hard–soft acid–base (HSAB) principle predicts that this reaction is favoured when a soft–soft interaction between the reactants takes place. To analyse the apparent discrepancy, the effect of charge transfer of a para-substituent on the softness of sulfur in thiophenols, as well as its impact in the conjugate addition to cyclohex-2-en-1-one, has been investigated. Experiments-in-competition, net charge of the X-groups at the para-position of the aromatic ring, the global and local softness at sulfur, and the electrophilicity, obtained by density functional theory (DFT), revealed that the reaction is faster for electron-attracting thiophenols, as the softness at sulfur increases by delocalization of the charge through the aromatic ring.131 The asymmetric conjugate addition of thiophenol to (E)-3-crotonoyloxazolidin-2one, catalysed by the scandium(III) triflate complex of Ph–PYBOX, gave the corresponding adduct in 66% ee. Lanthanoid triflates gave lower enantioselectivities (≤28% ee).132 Enantiopure α,β-unsaturated δ-lactams react stereoselectively with carbon-, nitrogen-, sulfur-, and oxygen-centred nucleophiles [N3 − , Me(CH2 )11 S− , MeO− , and nBu− ]. The synthetic potential of these conjugate additions has been demonstrated through the synthesis of two new substituted indolizidines, (7R)-7-amino-8-deoxyswainsonine and (7R)-7-acetylaminoswainsonin.133 The stereochemical outcome of the conjugate addition of sulfur-stabilized nucleophiles to the δ-lactam unit of tetrahydrobenzo[a]benzoquinolizines (83) has been shown to depend on the nature of the substituent at the angular position (R1 ); thus, 2,11b-cis or 2,11b-trans diastereoisomers (84) and (85) can be obtained selectively.134 MeO

MeO N

MeO

R

1

O

MeO

N R

O

1

E

2

RS

−

R2S (84)

R2S (83)

SR2

or MeO MeO

N R

O

1

E R2S

SR2

(85)

The intramolecular thia-anti-Michael addition has been reported to occur on treatment of dithiolane (86) with aliphatic primary amines, which produced a series of

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11 Addition Reactions: Polar Addition O

O

O

O

+

R1

NHR2 S

(−R3NH3)

R1

R3NH2 DMSO

S

NHR2 S

−

(86)

O

S

O

O

O

3

R1

NHR2 −

O

R1

NHR2 −

NHR3

S

R NH2

S

S

O NHR2

R1 S NHR3 (87)

tetrasubstituted thiophene derivatives (87). Here, the amine played the dual role of a base and a nucleophile. The intramolecular thia-anti-Michael addition, as the key step, proceeded in a regioselective manner; a plausible mechanism was proposed.135 Cerium(IV) ammonium nitrate (CAN) has been reported to catalyse a facile and efficient aza-Michael addition of aromatic and aliphatic amines to α,β-unsaturated esters in the absence of solvent under ultrasound irradiation.136 α,β-Unsaturated ketones react in aqueous solutions under these conditions but only with aliphatic (not aromatic) amines.137 The basic ionic liquid [Bmim]OH has been introduced as a catalyst for the azaMichael addition of aromatic amines and N -heterocycles to cyclic or acyclic ketones under solvent-free conditions.138 An efficient and highly selective synthesis of bicyclic-α-keto aziridines (89) from 2-bromocyclopent-2-enone (88) and aliphatic primary amines, mediated by phasetransfer catalysts (PTCs) in water at room temperature, has been demonstrated.139 Energy profiles for alternative intramolecular cyclizations of 4-(aminoalkyl)-oquinones (90); (n = 1–3) have been calculated using the AM1 method and ab initio energies of the transition states have been determined. In all the cases, cyclization at position 5 to form (91) occurs via a significantly lower energy transition state

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O RNH2

Br

TBAB, H2O r.t.

NR

(88)

(89)

O

HO n 5

O

n

NH2

N H

HO

(90)

(91)

than cyclization at position 3, consistent with experimental observations. Optimal trajectories for attack have been determined from a study of the reactions of methylamine with 4-methyl-o-quinone. For cyclization of aminoalkyl derivatives deviation from the optimal direction is smaller for reaction at position 5 but constraint on angle of attack only partially accounts for the regioselectivity. Intrinsic differences in the electronic energies of the alternative transition states appear to be the main contributor to regioselectivity. The relative energies of transition states can be modified by variation of the substituent at position 4. The calculations suggest that seven-membered ring formation may occur via a boat transition state and steric hindrance in the sevenmembered transition states may account for the experimentally observed influence of N -substituents on the mode of reaction.140 A double aza-Michael addition was enforced by high pressure in the reaction of primary amines with the α,β-unsaturated bis ester (92) to afford the azanorbornyl derivatives (93).141 R CO2Me

N

RNH2

CO2Me

11 kbar, r.t. MeOH

MeO2C

MeO2C (92)

(93)

α-Ketoaziridines have been obtained via a novel amine-promoted direct aziridination of chalcones ArCH=CHCOAr using an aminimide, generated in situ from a tertiary amine and O-mesitylenesulfonylhydroxylamine, NH2 OSO2 C6 H2 Me3 , in the presence of a base. The aziridination proceeds well in the presence of a catalytic amount of the tertiary amine; non-racemic aziridines were obtained by using a chiral amine.142 Addition of a variety of alcohols R3 OH to enones R2 CH=CHCOR1 was observed to occur in the presence of secondary amines R3 R4 NH and acids as catalysts (30 mol% each) at room temperature via the in situ-generated iminiums R2 CH=CHC(R1 )=N+ R3 R4 .143

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Imidazolidinone (94.pTSA) has been developed as an enantioselective organocatalyst for the addition of various silyloxycarbamate nucleophiles (e.g. BnOCONHOTBS, having a raised HOMO) to a range of α,β-unsaturated aldehydes RCH=CHCH=O, affording β-aminoaldehydes (96) (≤96% ee), which can be converted into β-amino acids (97) in two steps. The reaction proceeds via the corresponding iminium species (95) with a lowered LUMO.144 Me N

O Ph

RCH=CHCHO

But

O

Me N

Ph

But

N H (94) TBSO

O

Me N

Ph

But

N

ee

N

R

••

R

N Bn O

H O (95)

Cbz

1. NaClO2 2. Zn

NH CO2H

R

Cbz

N

OTBS

R

(97)

O (96)

The asymmetric domino reactions between 2-mercaptobenzaldehyde and α,βunsaturated aldehydes proceed with excellent chemo- and enantio-selectivities in the presence of (99) (20 mol%) as organocatalyst to afford 2H -1-benzothiopyrans (98) in high yields with 91–98% ee.145 O

O H

SH

O H

+ R

ee

H

(99) (20 mol%) (ArCO2H (20 mol%)

N H

∗

S (98)

R

Ar Ar

OSiMe3 (99; Ar = 3,5-(CF3)2 C6H3)

5-Pyrrolidin-2-yltetrazole (100) (15 mol%), in conjunction with the chiral piperazine (101) (1 equiv.), has been shown to catalyse the asymmetric conjugate addition

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of nitroalkanes RR CHNO2 to enones. The addition requires short reaction times, tolerates a broad substrate scope, and is believed to proceed via an iminium species.146 The same organocatalyst, in the presence of piperidine, has been employed to promote a highly enantioselective addition of malonates to enones.147 H N

Ph

Ph

N N H

N N N H (100)

Ph N

HO

N H (101)

ee

OH

(102)

HO Ph

RO

Ph N H

N

OH N (103)

(104; R = 9-phenanthryl)

Significant rate acceleration of metal-catalysed Michael addition reactions of βdicarbonyls to α,β-enones in water was observed upon addition of dibasic ligands. Ytterbium triflate and TMEDA was the most effective combination leading to a nearly 20-fold faster reaction than in the absence of ligand.148 Asymmetric 1,4-addition of various malonates to enones has been carried out using Bu4 N+ BH4 − in the presence of a chiral ligand, such as (R,R)-(102). The Michael adducts were formed in good yields (61–67%) with moderate enantioselectivity at 0 ◦ C. 11 B NMR spectroscopy suggests that the reaction proceeds via the formation of an aminodiol borate complex.149 Selective and efficient Michael additions of heterocyclic enamines (e.g. indoles, pyrroles, and pyrazoles) to enones can be catalysed by ZrCl4 (2 mol%).150 Michael addition of α-cyanoketene-S,S-acetals (RS)2 C=CHCN to enones R1 CH=CHCOR2 can be promoted by TiCl4 .151 Addition of the lithium enolate, generated from (2S,5S)cis-1,3-dioxolan-4-one, which in turn was prepared from (S)-mandelic acid and pivalaldehyde, to several 2-arylidene-1,3-diketones, gives the Michael adducts in good yields and diastereoselectivities.152 The first highly regio-, chemo-, diastereo-, and enantio-selective vinylogous Michael addition of α,α-dicyanoalkenes to α,β-unsaturated aldehydes employs salts of α,αdiarylprolinol (103) (20 mol%) as organocatalysts. The reaction presumably involves the formation of an iminium species from the aldehyde as the first step of the cascade.153 The catalytic application of l-proline in the asymmetric Michael addition of unmodified aldehydes or ketones with nitroalkenes in ionic liquids has been studied. The

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1R,2S configuration of the Michael adduct resulting from the reaction of cyclohexanone with β-nitrostyrene indicates the Re-face attack on β-nitrostyrene by an enamine intermediate. The enantioselectivities observed (≤70% ee) were rather modest.154 The conjugate addition of cyclic or acyclic α-substituted β-keto esters to α,βunsaturated ketones can be achieved with good diastereo- and enantio-selectivity (≤98% ee) by using derivatives of Cinchona alkaloids, such as (104), a chiral organocatalysts.155 Highly enantioselective Michael addition of silyl nitronates (105) to cyclic α,βunsaturated ketones (106; n = 0–2) has been accomplished by the utilization of N spiro C2 -symmetric chiral quaternary ammonium bifluoride (108) as an organocatalyst, offering a new route to the enol silyl ethers of scalemic γ -nitro ketones (107; 70–90% ee).156

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OSiMe3 −

O

N

R

R (105)

n

(R,R)-(108)(2 mol%)

n

+

OSiMe3

O O2N

(106)

(107)

HF2−

Ar +

N

Ar (108; Ar = 3,5-[3,5(CF3)2C6H3]C6H3)

Allylic C–C bond-forming addition of activated alkylidenes RCH2 CH=C(CN) CO2 R to acrolein has been achieved with good yield and regio- and enantio-selectivity in the presence of Cinchona alkaloid-derived organocatalysts. The reaction is characterized by an unusual α-selectivity of the C–C bond-forming step and represents an example of deconjugative Michael addition.157 A thiourea-catalysed asymmetric Michael addition of activated methylene compounds to α,β-unsaturated imides, derived from 2-pyrrolidinone and 2-methoxybenzamide (109), has been developed. In the case of 2-pyrrolidinone derivatives, the reaction with malononitrile proceeded in toluene with high enantioselectivity, providing the Michael adducts in good yields. However, the nucleophiles that could be used for this reaction were limited to malononitrile due to poor reactivity of the substrate. Further examination revealed that N -alkenoyl-2-methoxybenzamide (109) was the best substrate among the corresponding benzamide derivatives bearing different substituents on the aromatic ring. Indeed, several activated methylene compounds, such as malononitrile, methyl α-cyanoacetate, and nitromethane, could be employed as nucleophiles to give the Michael adducts (110) in good to excellent yields with

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O

EtO2C CN

R

N H

CO2Et

CN

N H

R

MeO

O

O

MeO (110)

(109) CF3 S F3C

N H

N H

NMe2

(111)

up to 93% ee. Spectroscopic experiments revealed that this enhanced reactivity can be attributed to the intramolecular hydrogen bonding between the N–H of the imide and the methoxy group of the benzamide moiety. Thus, the key to the success of the catalytic enantioselective Michael addition is a dual activation of the substrate by both intramolecular hydrogen bonding in the imide and intermolecular hydrogen bonding with the bifunctional thiourea catalyst (111), in addition to the activation of a nucleophile by the tertiary amino group of (111).158 The chiral thiourea catalyst (111) has also been used for the enantioselective Michael addition of thioacetic acid to enones (≤63% ee).159 The Cinchona alkaloid-derived thiourea (112), has been developed as an organocatalyst for conjugate addition of a wide range of nucleophilic enol species to enones. The reaction is characterized by high enantioselectivities and mild reaction condition.160

N

H N

H N

ee

ee

ee

CF3

H MeO

S CF3

N (112)

Diastereo- and enantio-selective cascade of Michael addition and lactonization between various silyl enolates derived from phenyl carboxylates and α,β-unsaturated ketones were successfully carried out by using an efficient organic catalyst, a cinchonidine-derived chiral quaternary ammonium phenoxide. In this asymmetric domino reaction, the corresponding trans-3,4-dihydropyran-2-ones were obtained in high yields with almost complete diastereoselectivities and good to excellent enantioselectivities.161

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d-Camphorsulfonic acid (d-CSA) was identified as catalyst for the enantioselective Michael-type Friedel–Crafts reactions of indoles with aromatic enones ArCH= CHCOAr to afford the corresponding β-indolyl ketones in excellent yields and moderate enantioselectivities. A surprising synergistic effect was discovered between [Bmim] Br and d-CSA, which may originate from the catalytic Lewis acid activation of the Brønsted acid.162 Heteropoly acids can catalyse conjugate addition of indoles and pyrrole to unsaturated carbonyl compounds and nitroalkene in water at ambient temperature in good to excellent yields.163 Reactions of indoles and α,β-unsaturated ketones can also be catalysed by using gallium triiodide (10 mol%) to give the corresponding Michael adducts in good to excellent yields.164 Finally, the Na[AuCl4 ].2H2 O-catalysed addition of 7-azaindole derivatives to α,β-enones has been described and factors directing the C(3) versus N (1)-alkylation reaction on the 7-azaindole nucleus were explored. Thus, the reaction of 7-azaindole with β-unsubstituted α,β-enones afforded 1-substituted-7azaindoles through an aza-Michael-type reaction. By contrast, 6-substituted 7-azaindoles underwent a regioselective C(3) alkylation. In analogy, the Na[AuCl4 ].2H2 Ocatalysed reaction of 7-azaindole derivatives with β-aryl-substituted α,β-enones gave 3-substituted 7-azaindoles in moderate to satisfactory yields and the reaction of 1substituted 7-azaindoles with α,β-enones allowed an easy entry to 1,3-disubstituted 7-azaindoles in moderate to high yields.165 Simple bis(oxazoline) ligands, especially azabis(oxazolines), can catalyse the addition of indoles to benzylidene malonates in up to 99% ee, provided that excess of the chiral ligand is avoided.166 The paradigm followed in many asymmetric catalytic reactions that an excess of the chiral ligand with respect to the metal should improve enantioselectivity because the background reaction catalysed by a free metal is suppressed, was shown not to be applicable here,166 which might call for revisiting some of the many copper(II)–bis(oxazoline)-catalysed processes known. Enantioselective additions of pyrroles and indoles to α,β-unsaturated 2-acylimidazoles catalysed by the bis(oxazolinyl)pyridine–scandium(III) triflate complex have been accomplished.167 HF calculations with the 6–31G(d) basis set were used to study the mechanism of the Michael addition (or Friedel–Crafts alkylation) reaction of indole with dimethyl alkylidenemalonate. This reaction proceeds through two transition states, TS1 and TS2 : in the first step, assumed to be rate determining, the new C–C bond is formed, whereas in the second step, proton transfer from indole to malonate occurs with the formation of the new C–H bond. The calculations show that the transfer and interaction of the π -electrons in the reactant molecules may play an important role in the cleavage of the original C=C bond and the formation of the new bonds (C–C and C–H); the electron transfer is believed to be the driving force for the reaction to occur. The solvent effects (alcohol vs 1,2-dichloroethane) were elucidated with single-point energy calculations at the MP2/6–311+G(d,p) level, using the polarized continuum model (PCM) implemented in the Gaussian 03 package. The PCM results indicate that the energy barriers of the reaction are reduced in the presence of solvents, and the proton of the alcohol may participate in the H-transfer process, thereafter making this step a rate-determining event in alcohol as solvent. By contrast, dichloroethane has little influence on the reaction pathway compared with that taking place in the

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gas phase. The calculated results explain why a deuterated product is formed if this reaction takes place in CH3 OD.168 Cobalt(II) complexes prepared in situ from (AcO)2 Co and two novel chiral spiro nitrogen-containing ligands, 7,7 -bis(2-pyridinecarboxamido)-1,1 -spirobiindane (SIPAD) and 7,7 -bis(2-quinolinecarboxamido)-1,1 -spirobiindane (SIQAD), are efficient catalysts for the asymmetric Michael addition of malonates to chalcone derivatives. The alkylation products were obtained in high yields with moderate enantioselectives.169 Triflic anhydride has been shown to activate enones (113) with an electron-rich aromatic pendant to undergo a Friedel–Crafts-like cyclization, affording the cyclic enol triflate (114).170

O

Tf2O

OTf

base

(113)

(114)

The Morita–Baylis–Hillman reaction can be accelerated by a catalytic amount of lithium bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent-free medium.171 A study of the effect of the Michael acceptor configuration on the efficiency of intramolecular Morita–Baylis–Hillman reactions has been performed. Enones containing a pendant aldehyde moiety attached at the β-position of the alkene group were employed as substrates and the reactions were catalysed by a phosphine. In all cases examined, with Ph3 P as the catalyst, cyclization of (Z)-alkene (117) gave 2.5–8.5 times higher yield than with the E-isomer (115) under identical reaction conditions, both affording the same product (116). Steric effects are believed to be the source of this difference in reactivity.172 O

HO

O

O

Ph3P

O

R

Ph3P

R

slow

R

fast

O (115)

(116)

(117)

With the weakly basic counterion produced in the Morita–Baylis–Hillman alkylation and allylation [(118) → (120)], the reaction can be stopped after electrophilic attack on the zwitterionic enolate and the intermediate (119) isolated. The trans configuration of (119) suggests that there is no electrostatic interaction between phosphorus and oxygen in the zwitterionic enolate that undergoes alkylation, thus giving a new mechanistic insight into the Morita–Baylis–Hillman reaction.173 1,3-Bis[2-(naphthalene-2-yloxy)propyl]imidazolium bromide has been reported as a new ionic liquid catalyst promoting the Morita–Baylis–Hillman reaction of various arylaldehydes in the absence of solvents.174

ee

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11 Addition Reactions: Polar Addition Br

KOH, H2O Et3BuN+ Cl−

Me3P ButOH

O

+

Me3P Br−

Ph (118)

CH2Cl2

O

O

Ph

Ph

(119)

(120)

Using electrospray ionization mass spectrometry in both positive and negative ion modes, the on-line scanning of the Morita–Baylis–Hillman reaction in the presence of imidazolium ionic liquids has been investigated. The interception of several supramolecular species indicated that ionic liquids co-catalyse the reactions by activating the aldehyde toward nucleophilic enolate attack and by stabilizing the zwitterionic species that act as the main intermediates.175 The aza-Baylis–Hillman reaction of 4-X-C6 H4 CH=NTs with CH2 =CHCOMe, catalysed by Ph3 P in the newly designed chiral ionic liquid (121), derived from l-(−)malic acid, gave products with up to 84% ee. This example represents the first highly enantioselective asymmetric reaction in which a chiral medium is the sole source of chirality.176 HO2C

CO2H O

ee

+

−

(C8H17)3NMe3

O

B O

O

O

O (121)

A series of N -p-nitrobenzenesulfonylimines have been reported to undergo asymmetric aza-Morita–Baylis–Hillman reactions with methyl acrylate mediated by DABCO in the presence of chiral thiourea organocatalysts with unprecedented levels of enantioselectivity (87–99% ee), albeit only in modest yields (25–49%). Isolation of a DABCO–acrylate–imine adduct as a key intermediate, kinetic investigation, and isotopic labelling, have been employed to determine the mechanism.177 Intramolecular hydrogen bonding has been proposed to facilitate nucleophilic addition of sulfones to the Morita–Baylis–Hillman adducts in a single step to produce the substituted allyl sulfones.178 A direct asymmetric reductive Mannich-type reaction that allows for the formation of three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity (10:1 to 50:1 dr; 96–99% ee) has been presented (Scheme 4). The reaction commences with the formation of the corresponding iminium ion from aldehyde (122) and prolinol catalyst (125), followed by conjugate reduction with Hantzsch ester (123) to generate an enamine, which then undergoes Mannich reaction with imine (124) to produce (126).179

ee

ee de

352

Organic Reaction Mechanisms 2006 H H Me Ph

EtO2C

O

CO2Et

+

MeO +

N H

H

(122)

N H (124)

(123) Ph N H

CO2Et

Ph

OH

(10 mol%)

(125)

OMe Me HN R

CO2Et O (126)

Scheme 4

Nucleophilic addition of α-halo-4-tolylsulfonyl methyl anions to quinone methides has been reported to afford three kinds of products as a result of domino reactions. Two of them were identified as rearrangement products and one as the vicarious nucleophilic substitution (VNS) product. An unexpected 1,2-migration of the tosyl group was observed.180 The kinetics of the addition of aniline (PhNH2 ) to ethyl propiolate (HC≡CCO2 Et) in DMSO as solvent has been studied by spectrophotometry at 399 nm using the variable time method. The initial rate method was employed to determine the order of the reaction with respect to the reactants, and a pseudo-first-order method was used to calculate the rate constant. The Arrhenius equation log k = 6.07 − (12.96/2.303RT ) was obtained; the activation parameters, Ea , H = , G = , and S = at 300 K were found to be 12.96, 13.55, 23.31 kcal mol−1 and −32.76 cal mol−1 K−1 , respectively. The results revealed a first-order reaction with respect to both aniline and ethyl propiolate. In addition, combination of the experimental results and calculations using density functional theory (DFT) at the B3LYP/6–31G∗ level, a mechanism for this reaction was proposed.181 An efficient double conjugate addition of ethane and propane dithiols in the presence of sodium methoxide to propargylic carbonyl compounds (127) has been developed. The corresponding amino-substituted propargylic aldehydes afforded piperidine derivatives.182

353

11 Addition Reactions: Polar Addition O OH R

R′ (127)

n HS SH MeONa

R′ = H, alkyl

R′ = O-alkyl

n

S

R

O OH (128)

n

S

S

R

O

S

O

R

(129)

Additions to Multiple Bonds Activated by Other Electron-withdrawing Groups Nucleophilic addition reactions of para-substituted benzylamines (XC6 H4 CH2 NH2 ) to α-phenyl-β-thiophenylacrylonitriles [Y(C4 SH2 )CH=C(CN)C6 H4 Y ] have been studied in acetonitrile at 25.0, 30.0, and 35.0 ◦ C. The reactions apparently take place in a single step in which the Cβ –N bond formation and proton transfer to Cα of α-phenyl-β-thiophenylacrylonitriles occur concurrently with a four-membered cyclic transition structure. These mechanistic conclusions were deduced from the following: (i) the large negative ρX and large positive ρY values; (ii) the negative sign and large value of the cross-interaction constants (ρXY ); (iii) the normal kinetic isotope effects (kH /kD > 1.0); and (iv) relatively low H = and large negative S = values.183 Investigation of the stereochemistry of the nucleophilic addition of amines to 1,3dienylsulfone revealed that the Z/E ratios of the resulting allylic sulfones varied with amines, solvents, temperature, and concentrations. The predominant formation of (Z)isomer was rationalized by a ‘syn-effect’, which could be mainly regarded as a result of the n/σ → π ∗ interactions.184 The Michael addition of oxygen nucleophiles to vinyl sulfones185 and the addition of dimethyl malonate and ethyl cyanoacetate to α,β-unsaturated sulfones in the presence of Triton-B and K2 CO3 have been studied.186 The relative Michael-acceptor abilities of a variety of substituted aromatic and aliphatic nitroalkenes have been elucidated by computational methods. Several global and local reactivity indices were evaluated with the incorporation of the natural charge obtained from natural bond orbital (NBO) analysis. Natural charges at the carbon atom β to the NO2 group and the condensed Fukui functions derived by this method were found to be consistent with the reactivity.187 Secondary acyclic formamides RNHCH=O can serve as efficient N -nucleophiles in the addition to nitroalkenes R1 CH=C(R2 )NO2 to afford the corresponding Michael adducts in good yields.188

de

354


A diastereoselective version of the latter Michael-like addition employed cyclic amides, oxazolidinones, and thiazolidinones (130; X = O or S) to afford the respective adducts (131) with 92% de (X = O) and >99% de (X = S), respectively.189 O Ph

X

N H

O

NO2

+ CF3

de

O

Ph

N

NO2

CF3 (130)

(131)

Michael addition of β-keto esters to nitroalkenes catalysed by TfOAg.PPh3 has been reported to proceed efficiently only in water.190 The α-addition of alkyl or aryl thionucleophiles R1 SH to β-nitroacrylates R2 (NO2 ) C=CCO2 R3 in THF in the presence of Et3 N or DBU does not stop at β-nitroα-thioalkanoates R2 CH(NO2 )CH(SR1 )CO2 R3 , but proceeds further with concomitant elimination of nitrous acid to afford α-thioacrylates R2 CH=C(SR1 )CO2 R3 .191 The organocatalytic asymmetric Michael addition of aldehydes RCH2 CH=O to β-nitroacrolein dimethyl acetal [(MeO)2 CHCH=CHNO2 ] has been studied in detail. ee The reaction took place with excellent yields and good stereoselectivities (≤88% ee) when a chiral β-amino alcohol, such as l-prolinol (10 mol%), was employed as the catalyst.192 On the other hand, bis(3,5-dimethylphenyl)(pyrrolidin-2-yl)methanol (30 mol%), readily obtained from l-proline, catalysed Michael addition of malonates to nitroalkenes with only ≤56% ee.193 Another Michael addition of aldehydes to nitrostyrenes using a series of chiral 2-trimethylsilanyloxymethylpyrrolidine-based de dendronic catalysts has been described. Good yields (≤82%), and high diastereo- ee selectivities (up to syn:anti = 95:5) and enantioselectivities (≤99% ee) have been 194 obtained. With the proline-derived bifunctional catalyst (134) having long hydrophobic alkyl chains, Michael addition of ketones and aldehydes (132) to β-nitrostyrenes (133) can be performed in brine or seawater without addition of organic solvents. The products (135) were obtained in excellent yields (≤99%) with high enantiomeric excess (≤96% de and ≤97% ee), even when only an equal molar ratio of the donor to acceptor was used.195 N(C10H21)2

O2N

O

N H

+

R1

Ar

R2 (132)

(133)

(134)

CF3CO2H (0.1 equiv.) brine, 25 °C

O

Ar NO2

R1 R2 (135)

Pyrrolidine-based diamine (136) and triamine derivatives that incorporate the secondary diamine motif have been developed as additional organocatalysts for the highly diastereoselective and enantioselective Michael addition of cyclic ketones to

355

11 Addition Reactions: Polar Addition O

H N

NHR N H

N H (136)

N H

N

SO2CF3

(138)

Ph Ph (137)

N N H

N

BF4−

(139)

R1

OH

+

Bun

H N N H

NR2R3

H 2N O

O (140)

N

(141)

N

NH (142)

2-nitrovinylarenes. The highest selectivities were obtained when these catalysts were used in conjunction with Brønsted acids.196 Catalyst (137) promotes the Michael addition of aldehydes to nitroalkenes with the lowest catalyst loading and lowest stoichiometric ratio of reactant aldehyde reported to date.197 (S)-Pyrrolidinesulfonamide (138) represents another addition to the portfolio of the organocatalysts for the latter reaction; mechanistic studies have been conducted to understand the origin of its high catalytic activities.198 The functionalized chiral ionic liquid (139) can also act as a highly efficient and reusable organocatalyst for the asymmetric Michael addition of ketones and aldehydes to nitroalkenes.199 The same catalyst also works in water in the absence of organic solvents or other additives.200 The l-prolinamide (140) represents another variation of bifunctional catalysts for the direct Michael addition of ketones to β-nitrostyrenes with ≤94% de and ≤80% ee.201 Amides (141), derived from primary amino acids, catalyse the enantioselective addition of ketones to nitroalkenes with high stereocontrol (>38:1 dr; ≤99% ee).202 Triamine (142) has been reported to catalyse the Michael addition of cyclic ketones to nitroalkenes with high diastereoselectivity (≤99:1) and enantioselectivity (≤91% ee).203 The organocatalytic asymmetric Michael addition of 2,2-dimethyl-1,3-dioxan-5-one (143) to various nitroalkenes (144), using a number of proline-based catalysts, afforded

de ee de ee

356


O +

O

NO2

R

O

NO2 O

(143)

R

organocatalyst

(144)

O (145)

polyfunctional nitro ketones (145). Reverse diastereoselectivity was observed with the diphenylprolinol catalyst (103), and the best diastereoisomeric and enantiomeric excesses were achieved with the sulfonamide catalyst (138) (84–98% de; 81–86% ee).204 Primary amine–thiourea derivative (146) has been developed as an active and highly enantioselective catalyst for the conjugate addition of ketones to nitroalkenes. The reaction is characterized by a broad substrate spectrum, with nitroalkenes bearing either aromatic or aliphatic substituents and a wide variety of ketones. Ethyl ketones react preferentially, generating anti -configured products with good to excellent diastereoselectivity. An enamine mechanism has been suggested, with cooperative activation of the electrophile by the thiourea and of the ketone by the primary amino group.205 But

Me Bn

N O

ee de ee

de

S N H

N H

NH2

(146)

The mechanism of enantioselective Michael addition of acetylacetone (147) to β-nitrostyrene (148), catalysed by a thiourea-based chiral bifunctional organocatalyst (149), has been investigated theoretically, using DFT calculations. A systematic conformational analysis was presented for the catalyst; both substrates apparently coordinate preferentially via bidentate hydrogen bonds. The deprotonation of the enol form of acetylacetone by the amino group of the catalyst occurs easily, leading to an ion pair characterized by multiple H-bonds also involving the thiourea unit. Two distinct reaction pathways were explored toward the formation of the Michael adduct that differ in the mode of the electrophile activation: (1) one which involves a bidentate hydrogen bonding of the electrophilic partner (151), while the approaching nucleophile is directed by the hydrogen bonding from the protonated Me2 N group; (2) an opposite scenario, where the nucleophile is bonded by the protons of the thiourea moiety (152), while the protonated Me2 N group steers the approach of the electrophile. Both reaction channels were shown to be consistent with the notion of non-covalent organocatalysis in that the transition states leading to the Michael adduct are stabilized by extensive H-bonded networks. The comparison of the energetics for the two pathways showed the latter mechanism (152) to be slightly lower in energy and, therefore, more likely.206 A similar study has been reported for the bifunctional catalysis by urea.207

ee

357

11 Addition Reactions: Polar Addition O O

O

O

(149)

+

NO2

Ph (147)

NO2

∗

R

(148)

(150)

CF3 S CF3

N H

N H

NOCl2

(149) S

S

Ar N

N+

H

H

O H

N

H

O O −N O

Ar N

N

H

H O

O

N

H

O

N

Ph

Ph (151)

+

O

H

(152)

The chiral thiourea catalyst (153) (15 mol%) and AcOH−H2 O additive converts ketones into addition products with nitro ketones in high yields (82–99%) and enantioselectivities (90–99%).208 The transition-state geometries for formation of R- and S- enantiomers suggest that only one oxygen atom of the nitro group is coordinated to the thiourea moiety of this catalyst.209 This is in conflict with the earlier working hypotheses, which involve a bonding of both oxygens, but in agreement with the most recent calculations by another group (see above206 ). The theoretical and experimental ee values showed good agreement, demonstrating the predictive power of the calculations.209 Ph

S

CF3

Ph H2N

N H

ee

N H

S

NH (153)

N H

N H

CF3

(154)

The proline-derived thiourea organocatalyst (154) (20 mol%) in conjunction with n-butyric acid (10 mol%) exhibited high stereoselectivity (≤99:1 syn:anti and ≤98%

de

358


ee) in the asymmetric Michael additions of cyclohexanone to both aryl and alkyl nitroalkenes.210 The axially chiral guanidine catalyst (155) (0.4–5 mol%) has been developed to facilitate the highly enantioselective Michael addition of 1,3-dicarbonyl compounds to a broad range of conjugated nitroalkenes (≤98% ee).211 Ph Ph

Ar H N

HO

OH

ee ee

Ph Ph

OH NMe

N

N

N H Ar

Me (156)

(155; Ar = 3,5-(3,5-ButC6H3)C6H3)

The bis-prolinol-derived phenol (156) has been designed to facilitate the formation of heterodinuclear complexes based upon the large difference in pKa of the phenolic OH group and the tertiary OH groups. The first examples of its application involve hydroxyacetophenones (157) as donors in the asymmetric Michael addition to nitroalkene acceptors (158); the best stereocontrol was observed with a zinc– magnesium dinuclear complex, where enantiomeric excesses ranged up to 92% for the major anti diastereoisomer (159).212 O +

Ph OH (157)

NO2

O (158)

Et2Zn (5 mol%) Bu2Mg (5 mol%) MeCN, toluene, hexane

OCH2Ph

O

(156) (5 mol%)

CH2Ph

ee

NO2

Ph OH (159)

The chiral quaternary ammonium bifluoride (162) has been shown to catalyse a highly diastereo- and enantio-selective conjugate addition of silyl nitronates (160) to nitroalkenes, giving rise to 1,3-dinitro compounds (161) (76–96% ee).213 Direct nucleophilic acylation of nitroalkenes (164), promoted by a combination of fluoride anion and thiourea catalyst (165), has been developed, using the thiazolium derivative (163) as the umpolung reagent (≤20:1 dr; 74% ee).214 Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of N -heterocycles, such as benztriazole, to nitroalkenes in moderate to high enantioselectivities (≤94% ee).215 The thiourea derivative (149) catalysed Michael addition of thioacetic acid to a range of trans-β-nitrostyrenes to afford RCH(SAc)– CH2 NO2 (≤70% ee).216 The thiourea derivative (149) and its congeners have been identified as efficient organocatalysts for the Michael addition of α-substituted cyanoacetates RCH(CN)CO2 Et to vinyl sulfones CH2 =C(R)SO2 Ph (72–96% ee).217

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359

11 Addition Reactions: Polar Addition OSiMe3 N

+

O

R1

−

+

NO2

R2

NO2

(162) THF, −78°C, 1 h

R1 (160)

NO2

R2

(161) F3C

−

HF2

Ar +

N

F3C

Ar (162; Ar = 3,5-(3,5-ButC6H3)2C6H3) R1

X3SiO

S

R1

Me

+

MeN

+

(165) Me4N+F−

NO2

R2

CH2Cl2 −40 °C

R3

O NO2

R2 R3

Me (163)

(164) N

CF3 S F3 C

N H

OMe N H

N

(165)

A highly enantioselective and diastereoselective addition of trisubstituted carbon donors, such as (166), to 2-chloroacrylonitrile (167), catalysed by bifunctional Cinchona alkaloid catalysts, e.g. (169), has been reported as the first example of an asymmetric cascade that includes conjugate addition and protonation with efficient catalytic control at two non-adjacent stereocentres (168).218 Conditions were found under which 2,4,6-trinitrostyrene adds nucleophiles (thiophenol, aniline, and aliphatic amines) at the vinyl moiety to form the corresponding β-X-ethyl-2,4,6-trinitrobenzenes (X = PhS, PhNH, or R2 N). In the reactions with primary aromatic amines, the initially formed adducts undergo an intramolecular replacement of the nitro group followed by aromatization of the indolines, giving rise to the corresponding N -substituted 4,6-dinitroindoles.219 The formation of imidazo[1,2-c]pyrimidines (171) via a ring closure of 2-(2-sulfonylimino-1,2-dihydro-1-pyrimidinyl)acetamides (170) has been studied using DFT methods, which revealed the requirement for Brønsted acid catalysis.220

ee de

360


O Cl

+

CN

∗

∗

Cl

CN (166)

CN

CN

(167)

(168) (7:1 dr; 91% ee)

HO RO N N (169; R = 9-phenanthryl) HN+Me3 N

NSO2Me

H N

N

NSO2Me N

Ph H2N

Ph HN

O (170)

O (171)

Experimental and theoretical study of the Diels–Alder reactions of the furans and methyl 3-nitroacrylate has demonstrated that the initial cycloadducts arise via a concerted mechanism. The latter adducts then undergo retro-Diels–Alder reactions to give the Michael adducts via a stepwise mechanism. To account for the selectivity observed in these additions, the frontier molecular orbitals were examined and the transition states were located by employing density functional calculation at the B3LYP/6–31G∗ level. The experimentally observed regio- and stereo-selectivities were explained by a comparison of the calculated activation energies, which ranged from 11 to 18 kcal mol−1 for the individual isomers. The s-cis forms of the dienophile were found to be more stable than the s-trans forms, both in the ground state and in the transition state. Furthermore, the endo transition structures for the ester group exhibited a lower energy barrier by 0.3 kcal mol−1 than their exo counterparts, a value that is in disagreement with the experimental results. The presence of the nitro group in the dienophile may play an important role in determining the selectivity. Attempts to find a stepwise mechanism leading to the Diels–Alder adduct via a zwitterion were unsuccessful. Two stepwise processes were found, which lead to the formation of Michael adducts generated via an electrophilic attack by the nitroacrylate at the α-position of the furan ring, and an intramolecular proton transfer mediated by the formation of a four-membered structure. The potential energies for these reactions showed values in the range 11–17 kcal mol−1 for the first step and 41–51 kcal mol−1 for the proton transfer. Solvent effects in chloroform on the Michael addition did not

361


appear in the electrophilic attack step (less than 4 kcal mol−1 ) but the transition state of the latter process was stabilized by 6–13 kcal mol−1 .221

Additions of Organometallics to Activated Double Bonds The effect of donor ligands, usually expected to enhance the reactivity of organolithiums, was studied in the case of the addition of PhLi to (E)-cinnamaldehyde in THF, under conditions that lead to 1,3-diphenylpropanone. TMEDA and HMPT were found to decelerate the reaction and with an [HMPA]:[PhLi] ratio ≥4, the reaction became almost completely inhibited. These results show the complexity of solvation effects and the specificity of the substrate–reagent–ligand–solvent interactions.222 Organolithium reagents undergo highly regio- and diastereo-selective 1,4-addition to α.β-unsaturated amides (172) derived from (S,S)-(+)-pseudoephedrine, furnishing the corresponding β-alkyl-substituted adducts in excellent yields and diastereoselectivities. Furthermore, the intermediate lithium enolates, generated in the conjugate addition step, undergo a highly diastereoselective alkylation reaction to afford α,β-dialkylsubstituted amides (173) in high yields.223 R2

O R1

N Me (172)

Ph

1. R2Li, LiCl 2. R3X

OH

de

O

R1 R3

N Me

Ph OH

(173)

Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on α,β-unsaturated esters. Michael adducts were obtained in up to 76% ee by combining a lithium enolate and a chiral 3-aminopyrrolidine lithium amide. The sense of the induction was found to be determined by both the relative configuration of the stereogenic centres borne by the amide and the solvent in which the reaction was conducted.224 A new study has revealed that allylmagnesium, allylindium, and allylbismuth generally exhibit a preference for axial addition to cyclohexenones (in the 1,2-addition). Allylmagnesium was found to be the most stereoselective reagent. Reactions with carvone (an α-methylated enone) were most selective, except that allylbismuth was inert to this substrate.225 A simple trick proved generally valuable for asymmetric copper-catalysed conjugate addition reactions: it was found that the enantioselectivities of Et2 Zn or Me3 Al reagents in reaction with α-halo enones, carried out in the presence of chiral phosphorimidite ligands, were dramatically improved upon the addition of styrene, which acts as a radical scavenger to suppress the competitive non-asymmetric radical pathway.226 The copper-catalysed asymmetric conjugate addition of dialkylzinc to enones (174; n = 1 or 2) generates homochiral zinc enolates (175), which can be trapped in situ with activated allylic electrophiles to produce (176). High trans selectivity (85:15 to

ee

ee

ee

362


O

EWG

R2Zn (1.2 equiv.) CuX, (177)

X

Et2O n

R

n

(174)

EWG

O

OZnR

R

n

(175)

(176) Ph

O P

N

O Ph (177)

>99:1) and excellent enantioselectivities (91–99% ee) were attained in the presence of ligand (177).227 The new tridentate aminohydroxyphosphine ligand (178) has been developed for the copper-catalysed asymmetric conjugate addition of organozinc reagents to acyclic α,β-unsaturated carbonyl compounds R1 CH=CHCO2 R2 ; the addition is characterized by high enantioselectivity (≤98% ee). Theoretical analysis suggests that the C–C bond formation takes place through a highly ordered transition state by the coordination of the phosphorus and nitrogen atoms to the copper(III) and zinc(II) atoms, respectively, and of the oxygen anion to both the metal centers.228 Ph2P

Me

OH N(CH2Ph)2 Me (178)

Fe

(179)

ee

Me NMe2

PPh2

de

PR2 Fe

PPh2

(180)

The copper-catalysed enantioselective 1,4-conjugate addition of Et2 Zn to chalcones was investigated in the presence of a catalytic amount of N,P -ferrocenyl ligand (179) with central and planar chirality under mild conditions (0 ◦ C to room temperature). Chalcones with ortho-substituents (from ortho-substituted benzaldehydes and acetophenones) exhibited a dramatic improvement in the enantioselectivities (≤92% ee).229 The mechanism of the enantioselective 1,4-addition of Grignard reagents to α,βunsaturated carbonyl compounds (Scheme 5; R1 = alkyl; R2 = alkyl, OR3 ), promoted by copper complexes of chiral ferrocenyl diphosphines (180), has been explored using kinetic, spectroscopic, and electrochemical analysis. The roles of the solvent, copper halide, and the Grignard reagent have been thoroughly examined. Kinetic studies support a reductive elimination as the rate-limiting step, in which the chiral catalyst,

ee

ee

363


the substrate, and the Grignard reagent are involved. The thermodynamic activation parameters were determined from the temperature dependence of the reaction rate. The putative active species and the catalytic cycle of the reaction (Scheme 5) were proposed.230 P P

Cu R1

Br Br

Cu

P

P

P

P

OMgBr

CuBr

P P O

R2

Cu

R1MgBr

R1 Br

MgBr

R2 Scheme 5

The copper-catalysed asymmetric conjugate addition of Grignard reagents to trisubstituted cyclic enones, carried out in the presence of a chiral carbene ligand, generated in situ from (181), afforded enantioenriched all-carbon quaternary centres with up to 96% ee. Interestingly, this is the only method that allows the addition of PhMgX to these enones.231 Another example of the Cu-catalysed enantioselective conjugate additions of alkyl- and aryl-zinc reagents to cyclic β-substituted enones utilized the chiral NHC-based Cu complex (2.5–15 mol%), generated from the silver precursor (182). The latter reaction afforded the products bearing all-carbon quaternary stereogenic centres in 67–98% yield and in 74–97% ee. Mechanistic models accounting for the observed levels and trends in enantioselectivity were provided.232 The CuH-catalysed asymmetric conjugate reduction of (E)- and (Z)-β-silyl-α,βunsaturated esters PhMe2 SiC(R)=CHCO2 R has been developed. Using polymethylhydrosiloxane (PMHS) as a stoichiometric source of hydride and the in situ-generated CuH ligated by the JOSIPHOS analogue PPF–P(t-Bu)2 (183), highly enantioselective 1,4-reductions were attained. By contrast, the SEGPHOS analogue (184) gave inferior results.233 A highly enantioselective synthesis of α-dehydroamino acids (186) with a stereogenic centre at the γ -position has been developed, which employs a copper-catalysed asymmetric conjugate addition of diethylzinc to α,β-unsaturated imines (185) with the TADDOL-derived phosphoramidite (187) as a chiral ligand.234 The reaction of allyl carbamates (189) with activated enones (188) catalysed by (Ph3 P)4 Pd in THF proceeded smoothly at room temperature to give the corresponding α,β-bis-adducts (190) in high yields.235 1,4-Addition of arylboronic acids to α,β-unsaturated ketones can be catalysed by palladium(0)–phosphine complexes with chloroform in the presence of a base. It is remarkable that the palladium(0) complexes are inactive in the absence of chloroform.236 Palladium acetate–bipyridine complex has been reported to catalyse conjugate addition of arylboronic acids to α,β-unsaturated carbonyl compounds in aqueous media with high yields.237

ee

ee

ee

364


Ph

PF6− +

N

N

Ag

OH

H

+

N

N

O (181)

O

Ag

N +

Ph

N Ph (182) But

O

PBut2 Fe

OMe

O

Me

PPh2 O

P

But

P

But

O

2

OMe But

(183)

2

(184)

R2 R1

EtO2C

R2

Et2Zn (MeCN)2CuPF6

N

(187) toluene, −30 °C

(185)

Ph

O

O

O

P

(186)

Ph

(187)

NMe2

Et R1

EtO2C

Ph

O

Ph

N

365


O

O

O

O

CN +

R1

N

CN

(Ph3P)4Pd

O

O

THF r.t. 12 h

R2

N

R1

R2 (188)

(189)

(190)

Alkynes in combination with a catalytic amount of a nickel complex have been found to catalyse the conjugate addition of arylboron reagents to α,β-unsaturated carbonyl compounds.238 An efficient cobalt-catalysed conjugate addition of functionalized aryl derivatives ArX (X = Cl, Br, OTf) to Michael acceptors CH2 =CHZ (Z = CO2 Et, CN, CONMe2 ) has been developed, using (2,2 -bipyridine)CoBr2 as a particularly suitable catalyst. This procedure permits the synthesis of compounds resulting from 1,4-addition in good to excellent yields. The versatility of this original process represents a simple alternative to most known methods using organometallic reagents.239 A kinetic study of the Rh–BINAP-catalysed 1,4-addition of phenylboronic acid using reaction calorimetry revealed that the catalytically inactive dimeric hydroxorhodium complex [Rh(OH){(R)-BINAP}]2 (191) is the resting state (Scheme 6). A negative non-linear effect in eeprod and an amplified reaction rate were predicted and observed in the present reaction system that is characterized by the preferential formation of the homochiral (191) dimer.240 PhB(OH)2

ee

B(OH)3 k1

[Rh]

H O O H (191)

Kdimer

[Rh]

[Rh]

8 × 102 l mol−1

OH Sol

[Rh] k2

Ph Sol

O O Ph

[Rh] = (R)-Binap Rh Sol = Solvent

k1 = 0.5 mol l−1s−1

Scheme 6

The rhodium-catalysed enantioselective 1,4-addition of arylboronic acids to the bifunctional Michael acceptors (192) in the presence of phosphoramidites (194) occurs regioselectively at the endocyclic C=C bond and in up to 95% ee. The presence of KOH is required to increase the reactivity so that less boronic acid and lower reaction temperatures can be used.241

ee

366


R1

O

O

ArB(OH)2 (acac)Rh(C2H4)2

R2

R1

O P

R2

NEt2

O

(194), KOH

Ar (192)

(193)

(194)

Asymmetric 1,4-addition of Ar1 ZnCl to (E)-3-arylpropenals (Ar2 CH=CHCH=O) proceeded with high enantioselectivity in the presence of Me3 SiCl and [(R)-BINAP– RhCl]2 as catalyst in THF at room temperature to afford, after hydrolysis, the corresponding 3,3-diarylpropanals in 98–99% ee. The presence of the chlorosilane is essential to attain high yields (55–80%).242 A highly enantioselective 1,4-addition of aryltrialkoxysilanes ArSi(OR)3 to α,βunsaturated esters and amides RCH=COX (X = OR , NR R ) was catalysed by a chiral rhodium complex generated from [(MeCN)2 Rh(COD)]BF4 and (S)-BINAP in aqueous dioxane.243 The choice of the organometallic nucleophile (Zn, B, or Si) has been shown to facilitate the straightforward conversion of enone (195) into the opposite diastereoisomers of 2-substituted pyrrolizidinones (196)/(197) via the rhodium-catalysed 1,4-addition reaction.244 H

H Ar

ArZnCl [Rh]

N

N

O

ArB(OH)2 or ArSi (OR)3

H

[Rh]

N (197)

A rhodium-catalysed asymmetric 1,4-addition of arylboronic acids to substituted maleimides (198) has been described. The regioselectivity in this reaction is controlled by the choice of ligand (dienes or bisphosphines); 1,4-adducts with a quaternary stereocentre (199) can be obtained with high regioselectivity (87%) and enantioselectivity (≤97% ee) when (R)-H8 -BINAP is employed as ligand.245 O

O PhB(OH)2 [Rh](2.5 mol%)

Et O (198)

(R)-H8-BINAP

de

O

(195)

NBn

ee

Ar

O

(196)

ee

NBn Et Ph

O (199)

ee

367


An unusual rhodium-catalysed addition of a dienylboronate ester to highly strained alkenes, such as norbornene, has been reported, resulting in the formation of vinylcyclopropane-fused tricyclic products (Scheme 7). Preliminary mechanistic studies have been presented.246 CO2But (pin)B

ButO2C

[(COD)RhCl] 2 Bu3t P+H Br4−

+

Scheme 7

A chiral cationic rhodium complex has been shown to catalyse the enantioselective conjugate addition of silyl anion equivalents to cyclic α,β-unsaturated ketones and esters, thus providing a facile access to chiral organosilicon compounds.247 The silylformylation of functionalized alk-1-ynes X(CH2 )n CR1 R2 C≡CH with ArMe2 SiH and CO, catalysed by Rh4 (CO)12 , affords the corresponding (Z)-βsilylalkenals X(CH2 )n CR1 R2 C(CHO)=CHSiMe2 Ar in high yields under mild conditions.248 The catalytic 1,6-addition of arylboronic acids to electron-deficient dienes, such as (E,E)-MeCH=CHCH=CHCOMe, was realized by use of an iridium catalyst. High yields of the corresponding δ-arylated carbonyl compounds were obtained with perfect 1,6-selectivity.249 The conjugate addition of alkynylboronates (200) to enones, catalysed by binaphthol organocatalysts (i.e., in the absence of any metal catalysts), has been studied theoretically with DFT methods. The high reactivity of the alkynylboronate derived from binaphthol seems to arise from electronic effects since its acidic boron atom binds tightly to the enone carbonyl and lowers the activation energy of the alkynylboration step. Steric clashes between the atoms of the ligands on boron and the enone have been invoked to account for the observed facial diastereoselectivity. The competing hetero-Diels–Alder reactions appear to be kinetically disfavoured relative to alkynylborations.250 R3 (PriO)2B

O

R3

O

(200)

R1

R2

3,3′-X2 – BINOL

R1

R2

Indium(I) iodide has been shown to promote the cleavage of dialkyl disulfides, generating thiolate anions that then undergo facile addition to α,β-unsaturated ketones,

ee

de

de

368


aldehydes, carboxylic esters, and nitriles under neutral conditions, producing the corresponding β-keto sulfides or β-cyano sulfides. This strategy has also been used for the regioselective nucleophilic ring opening of epoxides by thiolate anions in the presence of indium(III) chloride, affording β-hydroxyphenyl sulfides.251 An asymmetric synthesis of 1,3-dinitro compounds through Michael addition of nitroalkanes R1 CH2 NO2 to nitroalkenes R2 CH=CHNO2 , catalysed by C2 -symmetric chiral tridentate bis(oxazoline) and bis(thiazoline) complexes of Et2 Zn, has been reported to occur with high enantioselectivities (≤95% ee).252 The reaction of cinnamate esters with lithium pentamethylcyclopentadienide in the presence of chlorodiethylaluminium provides the corresponding 1,4-adducts in high yield.253 An expedient method for the preparation of isochromene carboxylates (203) has been developed, which relies on the regioselective 1,6-addition of various nucleophiles, such as Grignard reagents, alkoxides, and cyanide, to benzopyranylidenetungsten(0) complexes (201), followed by iodine oxidation of the addition intermediates (202).254 DFT calculations have been carried out to rationalize the unusual switch in stereoselectivity, where ynone and ynoate substrates exhibit opposite stereochemical preferences in the stannylcupration.255 R1

R1 O

R2 O

R2M

M+ W−(CO)5

W(CO)5 (201)

(202)

R1

R2

Et3N, MeOH, I2 −78 °C

O CO2Me (203)

Miscellaneous Nucleophilic Additions Whereas acid-catalysed cyclization of (21) undergoes the 6-endo-dig cyclization to afford (23), as discussed earlier, application of a base results in the formation of (22) as a product of 5-exo-dig ring closure.39 A dimeric proline-derived diamidobinaphthyl dilithium salt has been introduced as the first example of a chiral main group metal-based catalyst for asymmetric hydroamination–cyclization reactions of aminoalkenes.256 Intramolecular hydroamination of cyclohexa-2,5-dienes (204) mediated by Bun Li has been reported to produce the corresponding bicyclic allylic amines (205) with high

ee

369


selectivity (≤95%). A mechanistic study has demonstrated that the reaction does not proceed through a direct hydroamination of one of the diastereotopic C=C bonds but more likely involves a diastereoselective protonation of the intermediate pentadienyl anion, followed by addition of a lithium amide across the double bond of the resulting 1,3-diene, and subsequent highly regioselective protonation of the final allylic anion.257 R

Ph

Ph

R

N H

de

N

BunLi (20 mol%) THF

OMe

OMe

(204)

(205)

In the presence of 1-hexynyllithium (0.2–0.6 equiv.), 1,ω-diiodoalk-1-ynes (206); Y = O, CH2 ; n = 1, 2) undergo a new type of cyclization reaction with retention of the two iodine atoms to afford (diiodomethylene)cycloalkanes (207).258 I

BuC

CLi

(0.2–0.6 equiv.)

Y

I

n

I

Y

I

n

(206)

(207)

A catalytic asymmetric amination of enecarbamates has been attained using a chiral Cu(II) complex of diamine (210) as catalyst. Thus, azodicarboxylates have been shown to react with various enecarbamates (208) derived from aromatic and aliphatic ketones and aldehydes to provide acylimines (209) in good yields with high enantioselectivity (≤99% ee). The catalyst loading required for high enantioselectivity was generally low (0.2 mol% in some cases).259 O RO2C

N N

CO2R

OR3

HN

+

R2

(TfO)2 Cu (210)

R1 RO2C

toluene, −20 °C

RO2C

1

R2

N NH

N

R

(208)

(209)

PhCH2N H HNCH2Ph (210)

CO2R3

ee

370


Tetrasubstituted alkenes (214) were obtained with high Z selectivity (>99:1) by reaction of ynolates (211) with α-oxy- and α-amino-ketones (212; X = OR, NR2 ) at room temperature. According to experimental and theoretical studies, the high Z selectivity is induced by orbital interactions in the ring opening of the β-lactone enolate intermediate (213), rather than by the initially presumed chelation of the lithium atom.260 OLi OLi

+

X

X

X (211)

CO2Li

O

O

de

(212)

(213)

(214)

A novel ring-expansion protocol has been developed, based on the conjugate additions of cyclic allylamines (215) to (p-toluenesulfonyl)ethyne (216), followed by aza-Cope rearrangement of the resulting zwitterions (217), to afford medium- and large-ring cyclic amines (218) under remarkably mild conditions.261 n +

n

+

H

Ts

N Bn (215)

(216)

N Bn

_

Ts (217)

n

N

Ts

Bn (218)

The alkylideneallyl cation, generated from the Lewis acid-mediated ring-opening reaction of alkylidenecyclopropanone acetal, has been employed in the reaction with siloxyalkenes to give 3 + 2-cycloaddition and acyclic addition products. All products resulted from a nucleophilic addition to the sp2 centre of the alkylideneallyl cation, with no sign of the nucleophilic addition to the sp centre. The regioselectivity was found to be independent of the electronic and steric effects of siloxyalkene nucleophiles, and appears compatible with the charge distribution of the allylic cation.262 Chiral bicyclic guanidine (221) has been identified as an excellent catalyst for reactions between anthrones (219) and various dienophiles, such as (220). The catalyst can tolerate a range of substituents and substitution patterns, making several anthrone derivatives suitable for this reaction. Both Diels–Alder and Michael adducts were obtained in excellent yields, high regioselectivities, and high enantioselectivities (≤99% ee). This is the first case of a highly enantioselective base-catalysed anthrone Diels–Alder reaction.263 A nucleophilic addition of bis(TMS) ketene acetals to pyridines (223), aided by acylation of the pyridine nitrogen with methyl chloroformate, has been reported to produce the 1,4-adduct (224).264

ee

371


O

O

N

+ Cl

O

N

Bn

Bn

NBu

N

O Cl

(221) (10 mol%)

NBn

Cl

CH2Cl2, −20 °C, 4 h (92%; 99% ee)

O

Cl (219)

OH

(220)

(222) O R1

R

R1

OSiMe3

R2

OSiMe3

R2

OH

R

MeOCOCl

N

N O

(223)

OMe (224)

Triphenylphosphine was employed as a nucleophilic catalyst for the umpolung addition of azoles (225) to the electron-deficient allenes (226; R1 = H, R2 = OEt, R3 = H, Et) to afford the addition products (227). This organocatalytic methodology has been extended to addition–cyclization reactions between electron-deficient allenes or alkynes and pyrrole-2-carboxaldehyde in the presence of a catalytic amount of tributylphosphine, giving the substituted indolizine-7-carboxylates (228; R2 = OEt, Me; R3 = H, Et).265 COR2

X X +

X N H (225)

R

R3 (226)

Ph3P (10 mol%) CH2Cl2, r.t.

X X

Bu3P(30 mol%) MECN, r.t.

COR2

COR2

X N

N R

•

R3 (227)

R3 (228)

Arynes, generated in situ from o-silylaryl triflates (229), undergo ene reaction with alkynes (230) possessing propargylic hydrogen in the presence of KF–18-crown-6 in

372

Organic Reaction Mechanisms 2006 R1 R

OTf

1

•

R2

KF, 18-crown-6

+

THF, r.t. 6 h

SiMe3 R2 (229)

(230)

(231)

THF at room temperature to produce substituted phenylallenes (231). Various arynes and terminal and internal alkynes can be used. The reaction of alkyne without propargylic hydrogen gave an acetylenic C–H addition product (a phenylalkyne) and a dehydro-Diels–Alder product (a phenanthrene).266

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374

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

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11 Addition Reactions: Polar Addition 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171

375

Riegert, D., Collin, J., Meddour, A., Schulz, E., and Trifonov, A., J. Org. Chem., 71, 2514 (2006). Tobisch, S., Chem. Eur. J., 12, 2520 (2006). Leigh, W. J., Owens, T. R., Bendikov, M., Zade, S. S., and Apeloig, Y., J. Am. Chem. Soc., 128, 10772 (2006). Ali, M., Biswas, S., Rappoport, Z., and Bernasconi, C. F., J. Phys. Org. Chem., 19, 647 (2006). Hartman, R. F. and Rose, S. D., J. Org. Chem., 71, 6342 (2006). ˇ and Kotrusz, P., Org. Biomol. Chem., 4, 1420 (2006). Meˇciarová, M., Toma, S., Khatik, G. L., Kumar, R., and Chakraborti, A. K., Org. Lett., 8, 2433 (2006). Meza, R., Gordillo, B., and Galván, M., Int. J. Quantum Chem., 104, 29 (2005); Chem. Abs., 144, 69427 (2006). Sauerland, S. J. K., Kiljunen, E., and Koskinen, A. M. P., Tetrahedron Lett., 47, 1291 (2006). Tinarelli, A., and Paolucci, C., J. Org. Chem., 71, 6630 (2006). Garc´ıa, E., Lete, E., and Sotomayor, N., J. Org. Chem., 71, 6776 (2006). Li, Y., Liang, F., Bi, X., and Liu, Q., J. Org. Chem., 71, 8006 (2006). Duan, Z., Xuan, X., Li, T., Yang, C., and Wu, Y., Tetrahedron Lett., 47, 5433 (2006). Varala, R., Sreelatha, N., and Adapa, S. R., Synlett, 2006, 1549; Chem. Abs., 145, 335400 (2006). Yang, L., Xu, L.-W., Zhou, W., Li, L., and Xia, C.-G., Tetrahedron Lett., 47, 7723 (2006). Mekonnen, A. and Carlson, R., Tetrahedron, 62, 852 (2006). Land, E. J., Ramsden, C. A., and Riley, P. A., Tetrahedron, 62, 4884 (2006). Rulev, A. Yu., Yenil, N., Pesquet, A., Oulyadi, H., and Maddaluno, J., Tetrahedron, 62, 5411 (2006). Shen, Y.-M., Zhao, M.-X., Xu, J., and Shi, Y., Angew. Chem. Int. Ed., 45, 8005 (2006). Ramachary, D. B. and Mondal, R., Tetrahedron Lett ., 47, 7689 (2006). Chen, Y. K., Yoshida, M., and MacMillan, D. W. C., J. Am. Chem. Soc., 128, 9328 (2006). Rios, R., Sundén, H., Ibrahem, I., Zhao, G.-L., Eriksson, L., and Córdova, A., Tetrahedron Lett., 47, 8547 (2006). Mitchell, C. E. T., Brenner, S. E., Garc´ıa-Fortanet, J., and Ley, S. V., Org. Biomol. Chem., 4, 2039 (2006). Knudsen, K. R., Mitchell, C. E. T., and Ley, S. V., Chem. Commun., 2006, 66. Ding, R., Katebzadeh, K., Roman, L., Bergquist, K.-E., and Lindström, U. M., J. Org. Chem., 71, 352 (2006). Abraham, S. and Sundararajan, G., Tetrahedron, 62, 1474 (2006). Kumar, V., Kaur, S., and Kumar, S., Tetrahedron Lett., 47, 7001 (2006). Yin, Y., Zhang, Q., Li, J., Sun, S., and Liu, Q., Tetrahedron Lett., 47, 6071 (2006). Blay, G., Fernández, I., Molina, E., Muñoz, M. C., Pedro, J. R., and Vila, C., Tetrahedron, 62, 8069 (2006). Xie, J.-W., Yue, L., Xue, D., Ma, X.-L., Chen, Y.-C., Wu, Y., Zhu, J., and Jin-Gen Deng, J.-G., Chem. Commun., 2006, 1563. Luo, Sh.-P., Wang, L.-P., Yue, H.-D., Le, Zh.-G., Yang, W.-L., Xu, D.-Q., and Xu, Zh.-Y., Huaxue Xuebao, 64, 1483 (2006); Chem. Abs., 145, 314329 (2006). Wu, F., Li, H., Hong, R., and Deng, L., Angew. Chem. Int. Ed., 45, 947 (2006). Ooi, T., Doda, K., Takada, S., and Maruoka, K., Tetrahedron Lett., 47, 145 (2006). Bell, M., Frisch, K., and Jørgensen, K. A., J. Org. Chem., 71, 5407 (2006). Inokuma, T., Hoashi, Y., and Takemoto, Y., J. Am. Chem. Soc., 128, 9413 (2006). Li, H., Zu, L., Wang, J., and Wang, W., Tetrahedron Lett., 47, 3145 (2006). Wang, J., Li, H., Zu, L., Jiang, W., Xie, H., Duan, W., and Wang, W., J. Am. Chem. Soc., 128, 12652 (2006). Tozawa, T., Yamane, Y., and Mukaiyama, T., Chem. Lett., 35, 360 (2006). Zhou, W., Xu, L.-W., Li, L., Yang, L., and Xia, C.-G., Eur. J. Org. Chem., 2006, 5225. Azizi, N., Arynasab, F., and Saidi, M. R., Org. Biomol. Chem., 4, 4275 (2006). Huang, Z.-H., Zou, J. P., and Jiang, W.-Q., Tetrahedron Lett., 47, 7965 (2006). Alfonsi, M., Arcadi, A., Bianchi, G., Marinelli, F., and Nardini, A., Eur. J. Org. Chem., 2006, 2393. Rasappan, R., Hager, M., Gissibl, A., and Reiser, O., Org. Lett., 8, 6099 (2006). Evans, D. A. and Fandrick, K. R., Org. Lett., 8, 2249 (2006). Wang, J.-Y., Fu, X.-H., Wu, T., Wang, J., Xiao, Sh.-X., and Hu, Ch.-W., Huaxue Xuebao, 64, 727 (2006); Chem. Abs., 145, 396850 (2006). Chen, C., Zhu, S.-F., Wu, X.-Y., and Zhou, Q.-L., Tetrahedron: Asymmetry, 17, 2761 (2006). Grundl, M. A., Kaster, A., Beaulieu, E. D., and Trauner, D., Org. Lett., 8, 5429 (2006). Mamaghani, M., Radmogadam, K., and Badrian, A., Asian J. Chem., 18, 840 (2006); Chem. Abs., 145, 376743 (2006).

376 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215

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11 Addition Reactions: Polar Addition 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262

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378 263 264 265 266

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CHAPTER 12

Addition Reactions: Cycloaddition N. Dennis Stretton, Brisbane, Queensland, Australia 2 + 2-Cycloaddition . . . . . 2 + 3-Cycloaddition . . . . . 2 + 4-Cycloaddition . . . . . Miscellaneous Cycloadditions References . . . . . . . . . . .

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. . . . .

381 386 397 406 413

The thermal intramolecular 2 + 2-cycloaddition of 4,4 -disubstituted-2,2 -bis(phenylethynyl)biphenyls (1) yielded the intermediate 1,2-diphenylcyclobuta[1]phenanthrenes (2), which could be trapped with 2,3,4,5-tetraphenylcyclopenta-2,4-dione (3) to produce the Diels–Alder adduct (4). Thermal decarbonylative ring opening of (4) gave 9,10,11,12,13,14-hexaphenylcycloocta[1]phenanthrenes (5) as the final product in 12– 23% yield (Scheme 1).1 The reaction of 1-lithiobuta-1,3-dienes with aromatic nitriles produced substituted pyridines, pyrroles, and/or linear butadienylimines in good to excellent yields. The competition between 5-exo and 6-endo cyclization is responsible for the formation of either pyrroles or pyridines.2 The thermal intramolecular cycloaddition of 2-(allenyl)phenylazides furnished C(2)–C(3) and N–C(2) cyclopentannelated indoles via a cascade cyclization sequence involving an initial 3 + 2-cycloaddition, a nitrogen extrusion and a ring formation.3 The acid-catalysed ring opening of alkylidenecyclopropanone acetal (6) produced 1-alkylidene-2-oxyallyl cation (7), which reacted with furan to yield both 3 + 2-(8) and 4 + 3-(9) cycloadducts (Scheme 2).4 The 1,3-dipolar cycloaddition of azomethine ylides from sarcosine, with (E)-3-furfurylindene-4-chromanone and (E)-furfurylidene1-tetralone, formed spiropyrrolidines which undergo Diels–Alder addition with DMAD to give dispiropyrrolobicyclo[2.2.1]heptanes in good yields.5 The tandem double intramolecular 4 + 3/3 + 2-cycloaddition of the nitroalkene (10) produced the nitroso acetal (11) in 77% yield. Further functional group manipulations allowed for the conversion to the partial core (12) of the complex polycyclic alkaloid daphnilactone B in high yield (Scheme 3).6 The tandem intramolecular 4 + 2/3 + 2cycloaddition cascade of 1,3,4-oxadiazoles (13) to polycyclic adducts (14) was investigated by considering the tethered initiating dienophile, the tethered dipolarophile, the 1,3,4-oxadiazole C(2) and C(5) substituents, the tether lengths and sites, and the central heterocycle (Scheme 4).7 Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd


379

380

Organic Reaction Mechanisms 2006 R

R

Ph

Ph 260 ˚C

Ph

Ph

R

R R = H, I, CO2Me (1)

(2) O Ph

Ph

Ph

Ph

(3)

R Ph

Ph

Ph

Ph

Ph

Ph

Ph

OC

Ph

Ph R

Ph

R

Ph Ph

R

12–23%

(4)

(5) Scheme 1

furan

Me

OR Me

Me OR R = Me, SiMe3 (6)

HCI

+

O

O

OR

Me

+

O Me Me

O

Me

Me (7)

(8) Scheme 2

(9)

381

12 Addition Reactions: Cycloaddition

Me O

+

N

Me

−

MeO2C

CO2Me

O

N

O

AlMe3, toluene

O

−76 °C, 25 min

H

77%

Me Me (11)

(10)

Me

N H

HO (12) Scheme 3

O O N N

R O N

N N

CH2

o-Cl2-C6H4, 180 °C, 3−24 h

Me CO2Me R = H, Et (13)

O

R

N Me (14) Scheme 4

The [Rh(NHC)Cl(COD)]/AgSbF6 -catalysed intramolecular 4 + 2-cycloaddition of dienynes and the intramolecular 5 + 2-cycloaddition of alkyne vinylcyclopropanes formed the corresponding bicyclic cycloadducts in 91–99% yields within 10 min.8

2 + 2-Cycloaddition CR-CCSD(T) calculations of the 2 + 2-cycloaddition of cyclopentyne to ethylene indicate a highly exothermic (Gr 298 = −68 kcal mol−1 ) reaction and a predominately

382


concerted process with a relatively low activation barrier.9 Triflic imide (Tf2 NH) promoted the 2 + 2-cycloaddition of allylsilanes with electron-deficient alkenes leading to substituted cyclobutanes. Silyl triflic imide acts as the actual catalyst in this reaction.10 The first linear free energy relationship for the thermal cyclodimerization of aromatic trifluorovinyl ethers to 1,2-disubstituted perfluorocyclobutyl compounds has been reported.11 The thermal intramolecular 2 + 2-cycloadditions of fuller-1,6enynes in toluene produce fused cyclobutenes as stable solids in very high yields.12 3 H NMR spectroscopy has been used successfully to determine the regioselectivity of the 2 + 2-photocycloaddition of enones to fullerene, C70 . The major method of photocycloaddition involves addition to the C(1)–C(2) bond of the ovoid fullerene.13 The intramolecular 2 + 2-cycloadditions of α-substituted enones are solvent controlled. In aprotic solvents, 2 -hydroxyenones underwent cycloaddition in a manner consistent with the presence of an intramolecular H-bond between the carbonyl group and the tether’s hydroxyl group. In protic solvents, the disruption of the intramolecular H-bond produced products with complementary diastereoselectivity.14 The photochemical intramolecular 2 + 2-cycloaddition of diphenylbicyclo[3.2.0]oct3-ene-2,5-diones (15, 16) produced pentacyclotetradeca-10,12-diene-2,7-diones (17, 18), respectively. These reactions involve a triplet 1,4-biradical intermediate derived from the spin-inverted excited triplet state of the primary 1:1 adducts (Scheme 5).15 Photoinduced 2 + 2-cycloadditions of N -methylnaphthalene-1,8-dicarboximide with alkynes take place at the naphthalene C(1)=C(2) bond to give cyclobutane adducts. Experiments show that these reactions proceed from the π π ∗ singlet excited state O 1

R

O

R4

1

R

R4

Ph R2

R3

Ph

R2

R3 O (16)

O (15)

hn C6H6

O R

R4

1

hn C6H6

O

O R3 Ph

R2

Ph Ph

R

R4

1

R3

R2 Ph

(17)

(18) Scheme 5

O

de

383


of the naphthalene.16 Direct excitation of stilbenes and the selective excitation of the charge-transfer (CT) complex at various temperatures succeeded in diastereodifferentiating the 2 + 2-photocycloadditions of (E)- and (Z)-stilbenes to bis[(R)-1methylpropyl]fumarate to produce p-truxinates.17 The diastereoselective transannular 2 + 2-photocycloaddition of ascorbic acid derivatives (19) produced polyoxacyclic structures (20, 21) in high yields with high diastereocontrol. The adducts will be tested as chiral ligands for enantioselective reactions (Scheme 6).18 Me

Me

O

O O

Me

Me

O

O

O O

de ee

O O

O (20) hν

O

O

+

MeCN, 5 °C

Me O

Me O O

(19) O

O O

(21) Scheme 6

The TFA treatment of daurichromenic acid ester (22) produced the cyclobutane (23) as the major product via a Gassman-like cationic 2 + 2-cycloaddition. Further manipulation of adduct (23) yielded rhododaurichromanic acid A (24) (Scheme 7).19 Ruthenium-catalysed 2 + 2-cycloadditions of norbornenes with alkynes produced the corresponding exo-cyclobutenes in good yields. Regioselectivity was observed with various substituents on the C(2) position of the norbornenes.20,21 The chiral Rhcatalysed enantioselective 2 + 2-cycloaddition of alkynyl esters with norbornene yielded chiral tri- and tetra-cyclic cyclobutenes in moderate to high ee.22 The bis(imino) pyridine iron bis(dinitrogen) complex catalysed the 2 + 2-cycloaddition of α,ω-dienes to produce the corresponding bicyclo[3.2.0] ring compounds. The redox activity of the bis(imino)pyridine ligand to maintain the ferrous oxidation state throughout the catalytic cycle has been shown to be important for reaction.23 Ruthenium-catalysed 2 + 2-cycloaddition of C(1)-substituted 7-oxanorbornadienes with alkynes at 65 ◦ C produced cyclobutene cycloadducts in moderate to good yields.24–26 A new chiral copper

ee

384

Organic Reaction Mechanisms 2006 CO2Me HO

CO2Me

Me HO O2CCF3 O

Me

H

TFA

H

Me H

(22)

O Me

(23)

CO2H HO

Me

H H

Me H

O Me

(24) Scheme 7

O X N N

O

Cu X

O O (25)

catalyst (25) promotes the 2 + 2-cycloaddition of 2-methoxycarbonylcyclopent-2-en1-one with thioalkynes to produce substituted bicyclo[3.2.0]hept-6-enes in 67% yield and 73% ee. This catalytic system was applied to the enantioselective total synthesis of the marine prostanoid tricycloclavulone.27 An ab initio study of the 2 + 2-cycloadditions of allene to isocyanic acid and ketene to vinylimine found the reactions to be concerted and mostly asynchronous.28,29 The diastereoselective 2 + 2-cycloaddition of dichloroketene with a chiral enol ether (26) produced the cyclobutanone (27), which leads to a key intermediate (28) in the total synthesis of the natural alkaloid (−)-Swainsonine (29) (Scheme 8).30 The

ee

de

385

12 Addition Reactions: Cycloaddition Cl DCK

OR*

95%

H *RO H (27)

(26) R*

O

Cl

= (S)-CH(Me)C6H2(i-Pr)3

O N

HO

NH *

RO

HO

H

(29)

H OH (−)-Swainsonine

OH (28)

Scheme 8

repeated 2 + 2-cycloaddition of benzyne with ketene silyl acetals provided a route to polyoxygenated tricyclobutabenzenes, e.g. tetraketone.31 The reaction of crossconjugated azatrienes (30) with conjugated ketenes (31) produced the intermediate 2 + 2-cycloadducts (3,4,4-trisubstituted-2-azetidinones) (32), which readily underwent Cope rearrangement to substituted 5,6-dihydro-1H -azocinones (33) in high yields (Scheme 9).32 The origin of the relative stereoselectivity of the β-lactam formation in the Staudinger reaction has been investigated by using detailed Hammett analyses. The stereoselectivity is generated as a result of the competition between the direct ring closure and the isomerization of the imine moiety in the zwitterionic intermediate.33 (R)-2,2-Diphenylcyclopentanol has been used as a successful chiral auxiliary in the 2 + 2-cycloaddition of dichloroketene with acyclic enoxy-lactones.34 The 2 + 2cycloaddition of ynamides with ketenes produced a variety of substituted 3-aminocyclobut-2-en-1-ones in good yields.35 Mesoionic 1,3-dioxolium-4-olates (34) readily ring open to acyloxyphenylketenes (35), which can be trapped with ketenophiles (dihydrofuran, carbodiimides, and imines) to yield 2 + 2-cycloadducts [e.g. (36), (37)] (Scheme 10).36 The 2 + 2-cycloaddition of four-membered endocyclic enamides (azetidines) to dichloroketene provides a new synthesis of substituted azetidine-3-carboxylic acid derivatives of interest in biological chemistry.37 The reaction of 2-(phenylamino)- and 2-(dimethylamino)-thiazoles (38) with DMAD produced dimethyl 6-(phenylamino)- and 6-(dimethylamino)-3,4-pyridinedicarboxylates exclusively. The intermediate 2 + 2-cycloadduct (39) undergoes ring opening, 6π -electrocyclization with the extrusion of sulfur to produce the final pyridine derivatives (40) (Scheme 11).38

386


N

Ar

Ar

R R

O

N

R

R

(30) +

CH2Cl2, r.t.

O C R

C

(32) Me

R

(31) O

Ar

R

N

R

72–89%

R (33)

Scheme 9

2 + 3-Cycloaddition SCS-MP2 and the new perturbative B2-PLYP density functional methods provide accurate reaction barriers and outperform MP2 and B3-LYP methods when applied to the 1,3-dipolar cycloaddition reactions of ethylene and acetylene.39 Phosphepine has been shown to catalyse the asymmetric 3 + 2-cycloaddition of allenes with a variety of enones (e.g. chalcones) to produce highly functionalized cyclopentenes with good enantiomeric excess.40 The AuPPh3 SbF6 complex catalysed the intramolecular 3 + 2cycloaddition of unactivated arenyne- (or enyne)-yne functionalities under ambient conditions.41 A review of the use of Rh(I)-catalysed 3 + 2-cycloadditions of diaryland arylalkyl-cyclopropenones and aryl-, heteroaryl-, and dialkyl-substituted alkynes to synthesise cyclopentadienones for use in the synthesis of natural products, polymers, dendrimers, and antigen-presenting scaffolds has been presented.42

ee

387

12 Addition Reactions: Cycloaddition Ar

O−

Ar +

O

C O O

O

O

C6H6

Ar

Ar (34)

(35)

R N

N

R O

Ar

O

OCOAr

R

Ar

O

N

OCOAr

N R

O (37)

(36) Scheme 10

R2N

R2N S N

DMAD

S

H CO2Me

N R1

R1

CO2Me

R1

= CH=CHAr, Ar or Me R2 = Me or Ar (38)

(39)

CO2Me CO2Me R2N

Scheme 11

N (40)

R1

388


In the absence of a Lewis acid promoter, the 2 + 3-reaction between p-quinone monoimide and azadienes, e.g. α,β-unsaturated hydrazones yielded 2,3-dihydrobenzofurans in moderate to excellent yields when the dienophile was maintained at low concentration.43 A DFT study of the 1,3-dipolar cycloaddition of benzonitrile N -oxides with 9methylenephthalimidines showed a concerted reaction with highly asynchronous transition states.44 The 3 + 2-cycloaddition of aryl nitrile oxides with acetyl- and benzylprotected exo-glucals or benzoylated β-d-glucopyranosyl cyanide produced glucosederived spiroisoxazolines and 3-aryl-5-C-glucosyl-1,2,4-oxadiazoles. The removal of the protecting groups provided water-soluble products, which were evaluated as glycogen phosphorylase inhibitors.45 The 1,3-dipolar cycloaddition of pentafluorophenylsubstituted imines with nitrile oxides formed pentafluoro-1,2,4-oxadiazoles in moderate to good yields.46 The 1,3-dipolar cycloadditions of stable nitrile oxides (42) with indole o-quinodimethanes (41) produced the exo-anti -dispiroisoxazolines (43–46) in

Ar–C

+

N–O−

(42) 150 °C, 3 h

N R (41)

Ar

Ar N O O

N O

+

Ar

N

N

O N

N

Ar

R

R

(43)

(44)

Ar N R N O

N

Ar

N

O N Ar

N

R HO

R (45)

(46) Scheme 12

de


389

moderate to good yields (25–47%) (Scheme 12).47 The intramolecular 1,3-dipolar cycloaddition of nitrile oxides, nitrones, and nitrile imines provided a synthesis of tetrahydroisoxazolo-, dihydroisoxazolo-, and dihydropyrazolo-fused pyrano[2,3-b] quinolines.48 The thermal and microwave 1,3-dipolar cycloaddition of adamantylidenefulvene with aryl- and alkyl-nitrile oxides gave 1:1 cycloadducts, as major adducts, and four other 1:2 minor cycloadducts. The use of cyclodextrins was shown to enhance the regio- and stereo-selectivity of the cycloadditions.49 The intramolecular 1,3-dipolar cycloadditions of homochiral nitrilimines derived from methyl esters of glycine, l-alanine, l-phenylalanine, and (S)-2-phenylglycine produced enantiopure 2,3,3a,4,5,6-hexahydropyrrolo[3,4-c]pyrazoles in fair to good overall product yields.50 The thermal reaction of diphenylnitrilimine with N substituted benzimidazoles (47) produced N ,N -disubstituted o-phenylenediamines (51). The reaction involved two 1,3-dipolar cycloadditions with two nitrilimine moieties yielding adducts (48–50), followed by a ring opening of the azolic ring of (50) (Scheme 13).51 The chemo-, regio-, and stereo-selective 1,3-dipolar cycloaddition of C-aryl-N phenylnitrones with 3,5-bis(arylidine)-1-methylpiperidin-4-ones produced mono- and bis-spiroisoxazolidines, with the former predominating.52 The 1,3-dipolar cycloaddition of five-membered cyclic nitrones with α,β-unsaturated γ -lactones provides an interesting example of a double asymmetric induction.53 Eu(fod)3 catalysed the 1,3-dipolar cycloaddition of α-alkoxycarbonylnitrones with vinyl ethers to give transisoxazolidines in a highly stereoselective manner.54 The bis(oxazolinyl)pyridine– cerium(IV) triflate complex (52) catalysed the enantioselective nitrone cycloaddition of β-substituted α,β-unsaturated 2-acylimidazoles to produce isoxazolidines products which can be effectively converted to β -hydroxy-β-amino acid derivatives.55 The intramolecular nitrone–alkene cycloaddition of nitrones (53) derived from hept6-enoses produced fused isoxazolidines (54) (Scheme 14). The effect of blocking groups, the stereochemistry of the substituents and the reaction solvent on the regioand stereo-selectivity of the cycloadditions has been investigated.56 The 1,3-dipolar cycloaddition of cyclic nitrones with free and Pt-bound nitriles has been investigated by theoretical methods at different levels of theory. The coordination of an RCN to a Pt centre provides an even higher activation effect upon cycloaddition in comparison with the introduction of a strong electron accepting group R such as CF3 .57 3-Substituted 1,2-diphenylcyclopropenes and 3,3-disubstituted cyclopropenes reacted with carbonyl ylides, derived by dirhodium tetraacetate-catalysed decomposition of diazocarbonyl precursors, to produce 8-azatricyclo[3.2.1.02,4 ]octanes and 9-oxatricyclo[3.3.1.02,4 ]nonanes.58 Chiral 5-ethoxy-3-p-tolylsulfinylfuran-2(5H )-ones (55) reacted with 2-benzopyrylium-4-olate (56) to give 4,10-epoxybenzo[4,5]cyclohepta[1,2-c]furan-3,9-diones (57, 58) in good to moderate yields with high regioselectivity (Scheme 15).59 2,6-Bis(oxazolinyl)pyridine–lanthanoid complexes catalysed the asymmetric 3 + 2-cycloaddition reactions of 2-benzopyrilium-4-olates with 3-(alk-2enoyl)-2-oxazolidinones to yield cycloadducts, substituted (2-oxazolidinoyl)carbonyl8-oxabenzo[c]bicyclo[3.2.1]octan-2-ones with high enantioselectivity (96% ee) and endo selectivity (>99:1).60 The 3 + 2-cycloaddition of mesoionic acyclic C-nucleoside 1,3-thiazolium-4-olates (59), derived from δ-gluconolactone, with acetylenic (60) and

ee

ee de

390

Organic Reaction Mechanisms 2006 Ph +

−

N

N

Ph C N N Ph

N

Ph H H

N

N THF, reflux, 24 h

R

N

N

N

R

O Me

O

Me

(47)

(48)

Ph

N

Ph

N

Ph

N

+

N

C

N N

Ph N

Ph Ph N N N

H NHR

−

Ph

Me

N O

NHR (49)

Ph N Me

O (50)

N

Ph H N

N

N Ph

Ph NHR

(51) Scheme 13

O Ph

N Ph

O

N Ce (OTf)4 (52)

Ph

N Ph

Ph

N

N

Me O

391

12 Addition Reactions: Cycloaddition O− N+

Me

OH

O MeO Me

O

Me

O

CH2Cl2

MeO Me

OMe

Me

N

OH

Me OMe 43%

(53)

(54) Scheme 14

O

O

O

Tol

H

H

OEt

S

O

O

O MeO

H O SOTol (57) anti-exo

OEt (55) +

+

THF, r.t.

O O O

OMe SOTol

H

OMe +

H O O H OEt (58) anti-endo

O− (56) Scheme 15

olefinic dipolarophiles produced substituted 2-aza-7-thiabicyclo[2.2.1]heptenes (61) and heptanes. On sulfur extrusion, the cycloadducts formed enantiomerically pure acyclic C-nucleosides (62) containing a pyridin-2-one moiety. These cycloadditions proved to be regioselective but showed no facial selectivity (Scheme 16).61 The palladium-catalysed intramolecular 3 + 2-cycloaddition of alk-5-enylidenecyclopropanes produced a variety of bicyclo[3.3.0]octane systems with up to three stereocentres.62 The oxidative addition of cyclopropyl phenyl ketone to Ni(Pcy3 ) gave nickeladihydropyran, which is a key intermediate in the Ni(0)-catalysed homo-

392

Organic Reaction Mechanisms 2006 OAc

OAc

CO2Me S

AcO OAc OAc N Me

Ph

heat

+

+

O

−

R

(59)

(60) R = H, CO2Me

Ph

CO2Me

CO2Me

O Me

O

Me

N

R R*

N *R

S

R

R* = D-gluco-(CHOAc)4-CH2OH

(62)

(61) Scheme 16

or hetero-cycloaddition to give substituted cyclopentanes having two carbonyl substituents at the 1,3-position.63 The palladium-catalysed asymmetric 3 + 2-trimethylenemethane cycloaddition of 3-acetoxy-2-trimethylsilylmethylprop-1-ene with di- and tri-substituted alkenes produced exo-methylenecyclopentanes in 59–99% yields and enantiomeric excesses from 58 to 92% ee.64 In the absence of organic solvents, Sc(OTf)3 catalysed the cycloaddition of aziridines to nitriles to produce substituted imidazolines in good to excellent yields at room temperature and in an air atmosphere. The reaction is believed to progress through a highly reactive cationic intermediate in which the aziridine nitrogen is coordinated to Sc(OTf)3 .65 The phosphine-catalysed enantioselective 3 + 2-cycloaddition of buta2,3-dienoates with arylimines yielded 2-aryl-3-pyrrolidines with 64% ee.66 Supercritical carbon dioxide with a minute co-solvent addition is an effective medium for the 1,3-dipolar cycloaddition of azomethine ylides with DMAD to produce substituted pyrroles.67 The 1,3-dipolar cycloaddition of nitrile ylides [e.g. benzonitrile (4-nitrobenzylide) and 4-nitrobenzonitrile(benzylide)] with acrylamides provided a synthesis of 3,4-dihydro-2H -pyrroles with moderate to good yields.68 The Pt(II)or Au(III)-catalysed 3 + 2-cycloaddition of the transition metal-containing azomethine ylide (63) with electron-rich alkenes provided a carbene complex (64), which yields tricyclic indoles (65) having a substituent at 3-position (Scheme 17).69 The 1,3dipolar cycloadditions of azomethine ylides with aryl vinyl sulfones are catalysed by Cu(MeCN)4 ClO4 –Taniaphos with nearly complete exo- selectivity and enantioselectivities up to 85% ee.70 The 3 + 2-cycloaddition of benzo[b]thiophene 1,1-dioxide

ee

ee

de ee

393

12 Addition Reactions: Cycloaddition Ph Ph N

PtCl2 (3 mol%)

N+

MS5A, toluene 50 °C

OTIPS [Pt]−

OTIPS

(63) OBut toluene

Ph

Ph 1,2-migration

N

OBut

N

OBut OTIPS

Pt

OTIPS

[Pt]

(65) 73%

(64) Scheme 17

with stabilized and non-stabilized azomethine ylides yielded new pyrrolo derivatives of benzo[b]thiophene 1,1-dioxide.71 3-Methylsulfanyl-2-arylazo-3-(pyrrolidin-1yl)acrylonitriles reacted with N -substituted maleimides to form 3 + 2-cycloadducts, 3-methylenepyrrolizidines, via pyrrolidine-derived azomethine ylides.72 N -(Porphyrin2-ylmethyl)glycine is a precursor of the azomethine ylide (66), which underwent 3 + 2-cycloaddition with meso-tetrakis(pentafluorophenyl)porphyrin (67) and tetraazaporphine (68) to yield porphyrin–chlorin (69) and porphyrin–tetraazachlorin (70) dyads, respectively (Scheme 18).73 The reaction of alkene-tethered α-ketocarboxylic acid derivatives (71) with monosubstituted hydrazines (72) produced azomethine imines (73). These dipoles underwent thermal or Lewis acid-catalysed intramolecular 1,3diploar cycloaddition to produce highly substituted cis-cyclopentapyrazolidines (74). This work was directed towards the total synthesis of the diguanidine alkaloid massadine (Scheme 19).74 For the first time, the Cu(I)-catalysed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with nitroalkenes has been reported. By using electron-rich or electron-deficient aryl groups on the P atom of the chiral P ,N ferrocenyl ligands, high yields of either exo- or endo-adducts can be obtained, respectively.75 The 1,3-dipolar cycloadditions of the imines of 2-amino-γ -lactones and thiolactones are catalysed by a mixture of AgOAc or Ag2 O and NEt3 or DBU to produce spiro-lactone/thiolactone cycloadducts as single cycloadducts in good yields. In all cases, the imines generated the corresponding metallo-azomethine ylide stereoselectively.76

de

Ph

Ph

N

N

N

Ni

N

N

N

N

C 6 F5

C 6 F5

(68)

H N

N H

(66) +

N

(67) +

H N

N H

N

N

N

Ph

Ph

N

N

+

C 6 F5

C6 F 5

−

120 °C 1,2-dichlorobenzene

CH2

CH2

1,2-dichlorobenzene

120 °C

N

N

Scheme 18

Ph

Ph

Ph

Ph

N

Ni

N

N

Ni

N

N

N

Ph

Ph

Ph

Ph

(70)

N

(69)

N

N

N

N

N

C6F5

C 6 F5

H N

N H

H N

N H

N

N

N

N

C6F5

C6 F 5


395

12 Addition Reactions: Cycloaddition O

O MeO2C

H2NHN

NH2

(72)

CO2Pri

citric acid, ButOH, 110 °C

OMe (71)

S

O

i H CO2Pr N H N

HN

OMe

+

HN MeO2C

O

Ph N− CO2Pri

OMe

(74) 93%

(73) Scheme 19

The 1,3-dipolar cycloaddition of homochiral 1-benzyl-2-phenyl-3-oxidopyridinium betaine with electron-withdrawing alkenes produced 8-azabicyclo[3.2.1]oct-3-en-2ones. Excellent diastereofacial selectivity was exhibited for the major 6-exo cycloadducts.77 The enantioselective 1,3-dipolar cycloaddition of the 3-oxidopyrylium betaine (75) with methyl cinnamate in the presence of a Brønsted acid, TADDOL, produced the key intermediate cycloadduct (76). Further elaboration of the intermediate (76) achieved the synthesis of the natural products rocaglaol (77) and rocaglamide (78) in good yields and high ee (Scheme 20).78 The intramolecular Diels–Alder reaction of N -alkoxycarbonyl-2,3-dihydropyridinium cation (79) gave exclusively the endoadduct (80), which could be converted to the tricyclic compound (81) possessing symbioimine stereochemistry (Scheme 21).79 It has been reported that the cycloaddition of arylimines with nitrosoalkenes proceeds in a 3 + 2-manner, whereas alkylimines cycloadd to nitrosoalkenes in a competitive 3 + 2- and 4 + 2-manner.80 The alkylative 3 + 2-cycloaddition of nitrosoarenes with alkynes, phenylacetylene and methyl propiolate, in the presence of K2 CO3 – Me2 SO4 produced N -methoxyindoles in high yields. This procedure has been used to prepare the Wasabi phytoalexins, 3-carboxy-N -alkoxyindoles.81 A kinetic study of the primary 1,3-dipolar cycloaddition of meta- and parasubstituted diphenyldiazomethanes with fullerenes C60 and C70 , showed that fullerene C60 was ca 1.5 times more reactive than C70 .82 The copper-catalysed 3 + 2-cycloaddition of N -benzyl-N -tosylynamides with azides yielded 1-substituted 4-amino1,2,3-triazoles in high yields and high regioselectivity.83 The CuSO4 .5H2 O-catalysed 3 + 2-cycloadducts of benzyl azide with terminal di-, tri-, and tetra-ynes produced 4-alkynyl, 4-butadiynyl-, and 4-hexatriynyl-triazoles in good yields. No evidence of multiple addition to the polyyne framework was observed.84 The Cp∗ RuCl(PPh3 )2 catalysed 3 + 2-cycloaddition of azides to unsymmetrical internal alkynes in refluxing benzene formed 1,4,5-trisubstituted-1,2,3-triazoles in good yields.85 A titanium

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Organic Reaction Mechanisms 2006 OMe OH methyl cinnamate hν > 350 nm TADDOL

O− +

MeO

toluene–CH2Cl2, −70 °C

O OMe (75)

HO OMe HO

OMe OH O

R

MeO

O

MeO

CO2Me

O

OMe OMe

(77) R = H, rocaglaol (78) R = H, CONMe2, rocaglamid

(76)

Scheme 20

RO2C

Me

+

N

RO2C

Ar

Me

+

N

H

CH2Cl2

H (80)

(79) CF3CO2−

H

Me

+

N

H

H

Ar

H (81) Scheme 21

H

Ar

397


BINOL-catalysed enantioselective 1,3-dipolar cycloaddition between α-substituted acroleins and alkyl diazoacetates yielded chiral 2-pyrazolines with 95% ee. This methodology has been used to synthesise manzacidin A.86

ee

2 + 4-Cycloaddition The activation enthalpies for the Diels–Alder reactions of cyclopentadiene and 9,10dimethylanthracene with cyanoalkenes have been computed by the Hartree–Fock quantum method and a variety of density functionals (B3LYP, BPW91, and WPW1K) and compared with experimental data. This work identified significant errors in B3LYP activation enthalpies involving cyano groups, whereas HF and WPW1K reproduce substituent effects fairly accurately.87 The halogenation of dienes is beneficial in Diels–Alder reactions, increasing both the rates and yields of these reactions. The trifluoromethyl group shows comparable effects to halogen at the 2-position of furan.88 Also, the incorporation of a halogen in the 3- or 5-position of N -alkenyl-substituted furanylamides increased the reaction rate of the intramolecular Diels–Alder reactions.89 In a recent re-examination of the thermolysis of benzocyclobutenes for the in situ generation of o-quinodimethanes, the resultant IMDA diastereoselectivity was highly dependent on the nature of the hydroxyl protective group.90 The intramolecular 4 + 2cycloaddition of o-quinodimethanes (83), derived from ene-bis(sulfinylallenes) (82), with electron-deficient and electron-rich alkenes produced the corresponding polycyclic aromatic compounds (84) (Scheme 22).91 The enantioselective Diels–Alder S(O)Ph R1

C CH2 C CH2

R2 S(O)Ph (82)

THF

S(O)Ph

S(O)Ph

R1

CH2

X

R2

CH2

THF

R1

X

R2

Y

Y

S(O)Ph

S(O)Ph

(83)

(84) Scheme 22

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reaction of o-quinodimethanes with fumaric acid esters was achieved by utilizing diisopropyl (R,R)-tartrate as a chiral auxiliary.92 DFT studies have been used to investigate the 4 + 2-cycloaddition of ethyl 3,3difluoro-2-(N ,N -diethylcarbamoyloxy)prop-2-enoate with furan and substituted furans in the presence of tin(IV) catalyst. In the presence of SnCl4 and polar solvents, a twostep reaction was predicted.93 The catalytic effect of Lewis acids in the Diels–Alder reaction between methylacrolein derivatives and cyclopentadiene can be explained through the analysis of the electrophilicity effect of the regents and the molecular structure of the corresponding transition structures.94 The chiral auxiliary (85), derived from levoglucosenone, has been used as a chiral template in the Diels–Alder reaction of the corresponding acrylic ester derivative with cyclopentadiene. The reaction showed excellent diastereoselective excess with Et2 AlCl even at room temperature.95 The Diels–Alder reactions of 3-phosphonopropenoyl derivatives of 1,3-oxazolidin2-ones with cyclic and acyclic dienes are highly stereoselective.96 The Diels–Alder cycloadditions of the natural cyclolignins thuriferic acid and epithuriferic acid with cyclopentadiene have been reinvestigated. In the case of thuriferic acid (86), all four possible α,β-isomers (87–90) were isolated and characterized, while with epithuriferic acid only the β-isomers were isolated and identified (Scheme 23).97 The cycloaddition of zirconacyclopentadienes to p-quinones in the presence of CuCl–p-chloranil produced higher p-dihydroquinones in high yields (65–79%).98 The intramolecular 4 + 2-cycloaddition of reactions of N -(o-ethynyl)phenylynamides with arylynamides yielded carbazoles and benzannulated and heteroannulated carbazoles in moderate to good yields.99 Aromatic ketones have been used as photosensitizers in the Diels–Alder reactions between indoles and cyclohexa-1,3-dienes (CHD). Theoretical calculations support a stepwise mechanism involving a triplet ternary complex arising from a nearly barrierless reaction between CHD and the exciplex.100

HO

ee

de

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H

(85)

The influence of Lewis acids on the 4 + 2-cycloaddition of (2R,2 R)-N ,N -fumaroylbis[fenchane-8,2-sultam] with cyclopentadiene and cyclohexadiene was investigated by IR studies of the sultam compexes with various Lewis acids.101 The first enantioselective silicon Lewis acid catalyst (91) catalysed the Diels–Alder cycloaddition of methacrolein and cyclopentadiene with 94% ee.102 [AlCl3 + 2THF] is a new and efficient catalytic system for the Diels–Alder cycloaddition of α,β-unsaturated carbonyl compounds with dienes under solvent-free conditions.103 Dendritic copper(II) triflate catalysts with a 2,2 -bipyridine core (92) increased the chemical yields of Diels–Alder adducts.104

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12 Addition Reactions: Cycloaddition O

CO2Me

MeO

1. cyclopentadiene 2. CH2N2

OMe OMe (86) O

O O CO2Me

MeO

O

+

OMe

CO2Me

MeO

OMe (87) a-exo

OMe

OMe (88) b-exo

O

O

O

O

O

CO2Me

MeO

O

+

OMe

CO2Me

MeO

OMe (89) b-endo

OMe (90) a-endo Scheme 23

Ts Cl

N

Si O N

(91)

OMe

400

Organic Reaction Mechanisms 2006 Me

O

O C O H2

Me

O

Me

C H2

O

O n

N

Me n

N Cu (OTf)2

n = 1, 2, 3 (92)

The key intermediate (94), in the projected synthesis of the antibiotic branimycin, was prepared by the transannular Diels–Alder reaction of the macrocyclic tetraene (93) in 70% yield (Scheme 24).105 The hypervalent iodine-mediated oxidative dearomatization–Diels–Alder cascade was investigated as a means of preparing the [2.2.2]bicyclic core of the natural product tashironin. Trapping of allyl alcohols during the oxidative dearomatization of phenol (95) produced the desired five-membered acetal (96), whereas trapping of the allenyl alcohols resulted in the undesired six-membered acetal (97) (Scheme 25).106 The configuration of the stereogenic C(3) centre bearing the protected hydroxyl group is crucial to the diastereoselectivity in the IMDA reaction of (E,E,E)-nona-1,6,8-trienes leading to products containing the bicyclo[4.3.0]non2-ene carbon skeleton.107 A DFT study of the intramolecular Diels–Alder reaction of vinyloxocarbenium ions has shown that torsional steering is responsible for the stereoselectivity exhibited during cycloaddition.108

de

H xylenes

O

BHT, reflux

O

O

70%

MeO

O

H

(93)

O O

MeO (94) Scheme 24

Binuclear complexes with calixarene-like [M2 (µ-L ) (L1 )] structures have been used to accelerate the Diels–Alder reaction between sorbic acid and acrylonitrile. The reaction between the coordinated sorbinate co-ligand and acrylonitrile is controlled by the binding cavity of the complexes and is highly regioselective.109 Treating serum albumins, BSA or HAS, with phthalocyanine–Cu(II) complexes produced Lewis acid catalysts for highly enantioselective Diels–Alder reactions of azalactones with cyclopentadiene in aqueous medium.110 The l-DOPA-derived monopeptide (Y = NR2 )–Cu(II) complex (98) catalysed the enantioselective Diels–Alder reaction of α,β-unsaturated

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12 Addition Reactions: Cycloaddition OH OBn

Br

OTs (95) CH2 CHCH2OH Phl(CO2CF3)2

CH2 C C(Me)CH2OH Phl(CO2CF3)2

O

O O

OBn

O Br

OBn

Br Me

Me OTs

Me OTs

(96)

(97) Scheme 25

MeO

OMe

Me

OMe OMe

N

N

O

Cu2+

Y Z

NH N

O

O

Me

N H R1

H Cu2+ (98)

(99)

1-acyl-3,5-dimethylpyrazoles with cyclopentadiene. A transition-state assembly (99) has been proposed based on the crystal structure of known bis(l-tyrosino)–Cu(II) complex.111 A chiral Sn(IV) aryl oxide has been designed as a mild Lewis acid catalyst for enantioselective Diels–Alder reactions of cyclopentadiene with α,β-unsaturated aldehydes.112 The hyperbaric 4 + 2-cycloaddition of 1,2,4-trioxegenated 1,3-dienes with dienophiles, N -phenylmaleimide, and methyl and phenyl acrylates produced the expected endo-cycloadducts with excellent stereo- and regio-control.113 The high-pressure Diels–Alder reactions of 3-substituted coumarins with methylbuta-1,3-dienes in water formed tetrahydro-6H -benzo[c]chromen-6-ones in high yields (85–95%).114 Hydrophobic effects have been shown to dominate the geometries of the transition states for the simple Diels–Alder reactions of cyclopentadiene and methyl acrylates

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in water.115 In salt solutions, hydrophobic effects are dominant over secondary orbital interactions for Diels–Alder reactions between cyclopentadiene and methyl transcrotonate.116 Protic imidazolium ionic liquids have been used as reaction media for the Diels–Alder reaction of cyclopentadiene with dimethyl maleate and methyl acrylate.117 The AuCl-catalysed 4 + 2-cycloaddition of benzyne with o-alkynyl(oxo)benzenes produced anthracene derivatives having a ketone in the 9-position, in good to high yields under mild conditions.118 Hypervalent iodine compounds, [5-acyl-2-(trimethylsilyl)]iodonium triflates, readily yielded acylbenzynes which could be trapped with furan.119 Both DMAD and benzyne reacted with borabenzene to yield substituted borabarrelenes and borabenzobarrelenes, respectively.120 A DFT study of the Lewis acid-catalysed hetero-Diels–Alder reaction of vinylallenes with aldehydes found that the reaction proceeds via a highly asynchronous polar transition state; endo –exo mixtures were obtained in all cases.121 A computational study at the B3LYP/TZVP//B3LYP6–31G∗ level of the hetero-cycloadditions of o-thioquinones with 1,3-dienes has been published. The 2 + 4-cycloadditions are favoured kinetically, whereas the 4 + 2-cycloadditions are favoured thermodynamically.122 Hetero-Diels–Alder reactions, e.g. between Danishefsky’s diene and benzaldehyde, are effectively catalysed by cage-shaped borate esters, although openshaped borates are not catalytic.123 The chiral copper(II) Schiff base complexes (100) catalysed the enantio- and diastereo-selective hetero-Diels–Alder reactions of Brassard diene with aldehydes to produce 5-methyl-containing α,β-unsaturated δ-lactones in moderate yields, high enantioselectivites (>99% ee) and excellent diastereoselectivities (99:1 anti :syn).124 The TADDOL-catalysed enantioselective oxa-Diels–Alder reaction of Danishefsky’s diene with benzaldehyde produced 2-phenyl-2,3-dihydro4H -pyran-4-one, through hydrogen-bonding activation, in moderate yield and good enantioselectivity. Calculations at the B3LYP/31G∗ :PM3 level indicated that this reaction proceeds through a concerted method via an asynchronous and zwitterionic TS.125 The chiral N -heterocyclic carbene-catalysed 1-oxadiene Diels–Alder reaction of unsaturated α-keto esters with dienes derived from α-chloroaldehydes formed 3,4,6trisubstituted dihydropyran-2-ones in 70–95% yields and up to 99% ee. The reaction conditions are mild using 1 mol% N -mesityltriazolium salt as precatalyst in EtOAc

N But

OH R R = But, adam (100)

OH

de

ee de ee

ee

403


CH2

CH-EDG

CHCl3, 60 °C, 20 h

O

S

H O GDE

(101)

S

(102) Scheme 26

at room temperature.126 The inverse-electron-demand hetero-Diels–Alder reaction of paracyclophane-o-thioquinone (101) with electron-rich alkenes produced the expected benzoxathiin cycloadducts (102) with complete control of regio- and stereo-chemistry (Scheme 26).127 The hetero-Diels–Alder reaction between 1-aza-3-siloxybuta-1,3-dienes, including α,β-unsaturated oximes and hydrazones, with electron-deficient alkynes yielded triand tetra-substituted pyridines containing a C(3) oxygen functionality. These investigations were directed towards the total synthesis of nosiheptide.128 A highly regio-, diastereo-, and enantio-selective aza hetero-Diels–Alder reaction has been developed using 2-azopyridine and silver(I)–BINAP (2:1) catalyst to produce a number of chiral 1,4-diamines of pharmaceutical importance.129 A detailed study of the diastereoselective Diels–Alder reactions of N -sulfonyl-1-azabuta-1,3-dienes with optically active enol ethers has highlighted a number of previously unexplored asymmetric auxiliaries for use in the 1-azadiene Diels–Alder reaction.130 DFT and ab initio studies of the cycloaddition reaction between methyleneketene and cyclopentadiene indicated that the norbornene adduct is the primary reaction product from a 1,2-addition.131 The thermal 4 + 2-cycloaddition of o-xylylenes (104) with β-nitro-meso-tetraphenylporphyrin (103) produced a high yield of the chlorin (105) together with low yields of the naphthoporphyrin (106) and the bis-naphthoporphyrin (107). These reactions allow access to chlorins, bacteriochlorins, and isobacteriochlorins having biological activity (Scheme 27).132 The key marine metabolite oroidin (108) underwent Diels–Alder cycloaddition with electron-poor dienophiles, maleimide, and N -phenylmaleimide (109), to form cycloadducts (110) in good yields (54% and 45%, respectively) (Scheme 28).133 The normally sluggish Diels–Alder cycloaddition between cyclohexa-1,3-diene and various enones and enals can be activated by precoordination of the diene to a π -basic molybdenum complex [TpMo(NO)MeIm(η-cyclohexadiene)].134 The 4 + 2cycloaddition of cyclohexa-2,4-dienones with electron-deficient 2π -dienophiles produced bridged bicyclo[2.2.2]octenones. Triplet-sensitized irradiation of these bridged bicyclooctenones produced bicyclo[3.3.0]octanoids, whereas direct irradiation yielded bicyclo[4.2.0]octanes.135 Cinchona alkaloid derivatives catalysed the enantioselective 4 + 2-cycloaddition of o-quinones with ketene enolates to produce chiral o-quinone cycloadducts in high ee

de

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Ph

Ph

Ph

Ph

N H

N H N

N

(104)

H N

NO2

N

N H N

reflux, argon

Ph

Ph

H

NO2 Ph

Ph

(103)

(105) 56% + Ph

Ph N H N

N H N

Ph

Ph

(107) 17% + Ph

Ph N H N

N H N Ph

Ph (106) 19%

Scheme 27

and good to excellent yields. The cycloadducts can be readily converted into optically active α-hydroxy esters in the presence of ceric ammonium nitrate.136 Lewis acid co-catalysts [Zn(OTf)2 –Sc(OTf)3 ] are extremely effective in catalysing the enantioselective inverse-electron-demand hetero-Diels–Alder reaction of ketene enolates with o-benzoquinonediimides to give biologically active quinoxalinones in high yields and >99% ee.137 The 4 + 2-cycloaddition of o-quinone methides with substituted 2-aminooxazoles produced a variety of benzopyrans.138 DFT has been used to investigate the Diels–Alder reactions of cyclopentadiene with α,β-unsaturated aldehydes and ketones organocatalysed by MacMillan’s chiral

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12 Addition Reactions: Cycloaddition Br N Br

NH2

H N

N H

N H

O (108) O N R O

(109) R = H, Ph

R

O N

Br Br

N NH2

H H N

N H O

H

H

O

N H

(110)

R = H, 54% R = Ph, 45%

Scheme 28

imidazolidinones.139 A DFT study of the Diels–Alder reaction of 2-methylacrolein and cyclopentadiene catalysed by cationic oxazaborolidine Lewis acids showed that the reaction is stepwise and not concerted as exhibited in the absence of the catalyst.140 Binaphthyl-based diamine salts (111) are organocatalysts in the Diels–Alder reaction between cinnamaldehyde and cyclopentadiene producing the corresponding exocycloadduct as the major isomer with 92% ee.141 Aziridin-2-ylmethanol salts are effective organocatalysts for the Diels–Alder reactions of N -methylpyrrole and N methylindole with ees ranging from 10 to 66%.142 The chiral bicyclic guanidine (112) catalysed the Diels–Alder reaction between substituted anthrones and dienophiles, e.g. maleimides, to form cycloadducts in excellent yields, with high regioselectivities and high enantioselectivities.143 Phosphonium salts derived from dioxaphosphacycles behaved as organocatalysts in the Diels–Alder reaction of cyclopentadiene with dienophiles.144 A chiral indium(III) complex in [hmim][PF6 − ] ionic liquid catalysed the enantioselective Diels–Alder reactions of 2-methacrolein and 2-bromoacrolein with dienes to produce cycloadducts in good yields and high enantioselectivities.145 In the presence of chiral 1,1 -binaphthyl-2,2 -diammonium salt catalysts in EtCN at −75 ◦ C, the Diels–Alder reaction of α-(cyclohexanecarbonyloxy)acrolein with cyclopentadiene produced the cycloadducts in 88% yield with 92% exo-isomer and 91% ee.146

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Organic Reaction Mechanisms 2006 But

NHMe p-TsOH.H2O NHMe

But (111)

N

Bn N H

Bn N

(112)

A phosphoric acid diester, derived from (R)-BINOL, catalysed the inverse-electrondemand aza-Diels–Alder reaction of aldimines with enol ethers to produce tetrahydroquinoline derivatives with excellent enantioselectivity.147 The aza hetero-Diels–Alder reaction of aromatic aldimines with cyclohexenones in the presence of a chiral phosphoric acid, derived from 3,3-di(4-chloropheneyl)-H8 -BINOL, proceeded with good yields and enantioselectivity.148 TMBOTf catalysed the aza-Diels–Alder reactions of sulfinimines with Rawal diene to produce enantiomerically enriched dihydropyridones with ee up to 90%.149 Triflic imide catalysed the Diels–Alder reaction of 2-siloxydienes to aldimines to produce substituted piperidin-4-ones.150 The CANinitiated aza-Diels–Alder reaction of N -arylimines with N -vinylpyrrolid-2-one or N -methyl-N -vinylacetamide formed the corresponding 2,4-cis-4-amido-N -yl tetrahydroquinoline derivatives in good yields.151 A DFT investigation of the Diels–Alder reactions of substituted triazolo[3,2-d][1,4,2]diazaphospholes with buta-1,3-diene and isoprene revealed concerted mechanisms via asynchronous transition states.152 The inverse-electron-demand Diels–Alder reactions of 3-methylsulfinyl-6-methylthio-1, 2,4,5-tetrazine and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl-1,2,4,5-tetrazine are regioselective, producing a single cycloadduct in each case.153 Allenyltrimethylsilylthioketenes undergo 4 + 2-cycloaddition with imines to produce the corresponding δ-thiolactones, which can be converted into (±)-lupinine in six steps.154

Miscellaneous Cycloadditions The [RhCl(CO)2 ]2 -catalysed intramolecular 2 + 2 + 1-cycloaddition of allenes (113) produced bicyclo[4.3.0]non-1(9)-en-8-ones (114) and also the bicyclo[5.3.0]dec-1(10)en-9-ones (115) (Scheme 29).155

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12 Addition Reactions: Cycloaddition PhO2S

H

•

H

n

N Ts (113) [RhCl(CO)2]2 CO (5 atm) toluene, 120 °C

n=1

n=2

[RhCl(CO)2]2 CO (5 atm) toluene, 120 °C

SO2Ph

SO2Ph O

TsN

O Tsn

H (114)

H (115) Scheme 29

R1 R

1

R2

[Rh(COD)2]BF4 + tolBINAP (10 mol%)

Z

DCE, 60 °C

Z

∗

∗

R2 (116)

(117) Scheme 30

The enantioselective Rh-catalysed intramolecular 2 + 2 + 2-cycloaddition reaction of 1,4-dienynes (116) yielded strained multicyclic compounds (117) with quaternary carbon stereocentres in high enantiomeric excess (Scheme 30).156 Again, the rhodium-catalysed double 2 + 2 + 2-cycloaddition of ether-linked tetraynes produced tetra-ortho-substituted axially chiral biaryls with up to 99% ee.157 [Ir(cod)Cl]2 –DPPE is an effective catalyst for the 2 + 2 + 2-cycloaddition of α,ω-diynes with monoynes to give polysubstituted benzene derivatives.158,159 However, a rhodium-catalysed enantioselective intermolecular 2 + 2 + 2-cycloaddition of 1,6-diynes with trimethylsilylynamides readily yielded axially chiral anilides with 98% ee.160 The nickel-mediated regioselective 2 + 2 + 2-cycloaddition reaction of carboryne with alkenes produced highly substituted benzocarboranes via the Ni–carboryne intermediate [(η2 -C2 B10 H10 ) Ni(PPh3 )2 ].161 The Ni(0)–NHC-catalysed intermolecular 2 + 2 + 2-cycloaddition of diynes (118) with nitriles (119) formed pyridines (120) in reasonable yields (up to 100%) (Scheme 31).162 The Ni(0)Ln -catalysed 2 + 2 + 2-cycloaddition of one alkyne and two isocyanates formed pyrimidinediones in appreciable amounts.163 The regio- and enantio-selective rhodium-catalysed 2 + 2 + 2-cycloaddition of alkenyl

ee

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Organic Reaction Mechanisms 2006 +

N

Cl−

N

10 mol%

Ni(acac)2 5 mol% BuLi 25 mol%

R1 + R2 CN

X

R1 N

X

hexanes, r.t.

R1

R2 1

(118)

R (120)

(119) Scheme 31

O

C

+ OMe

N

H2C

OMe (121)

5 mol% [Rh(C2H4)2Cl]2 10 mol% (−)-L5 toluene, 110 °C

(122) OMe

OMe

MeO

MeO

N

N HO

O

H (124)

H (123)

Scheme 32

isocyanates (122) with terminal alkynes (121) produced quinazolinones (123), which are key intermediates in the total synthesis of the alkaloid (+)-lasubine II (124) (Scheme 32).164,165 The enantioselective [Rh(cod){(S)-xylyl-binap}]BF4 catalysed 2 + 2 + 2-cycloaddition of 1,6-diynes with α-methylene lactones and cyclic ketones formed chiral spirocyclic compounds.166 Mono- and di-nuclear titanium complexes of p-t-butylthiacalix[4]arene are efficient catalysts for the 2 + 2 + 2-cyclotrimerization of terminal alkynes to produce 1,3,5-trisubstituted benzenes regioselectively.167 The diastereoselective cobalt(I)-mediated 2 + 2 + 2-cycloaddition of allenediynes (125) with a pre-existing D-ring led to cycloadducts (126) possessing the skeletons of 11-aryl steroids (127) (Scheme 33).168

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Me

•

Ph Me

O

Me O

Ph CpCo(Co)2

Me

xylenes, hν, heat 60%

CoCp (125)

(126) SiO2 90% CH2Cl2

Me O

Ph Me

(127)

Scheme 33

The nickel-catalysed 3 + 1 + 1-cycloaddition of alkenyl Fischer carbene complexes with methylenecyclopropanes produced the methylenecyclopentanone in high yields.169 The nickel-catalysed three-component 3 + 2 + 2-cocyclization of ethyl cyclopropylideneacetate with two alkynes gave cycloheptadienes in good yields and high chemo- and regio-selectivity.170 The palladium [Pd(Ph3 )4 ]-catalysed 3 + 3-cycloaddition of trimethylenemethane with azomethineimines produced hexahydropyridazine derivatives under mild conditions (40 ◦ C).171 The Lewis acid-catalysed formal oxa-[3 + 3]-cycloaddition of α,βunsaturated aldehydes with 6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and vinylogous silyl esters yielded a variety of pyrones at room temperature.172 Crotonaldehyde has been converted to 6-hydroxy-4-methylcyclohex-1-enecarboxaldehyde by an enantioselective 3 + 3-cycloaddition catalysed by proline. This methodology was used in the synthesis of (−)-isopulegol hydrate, (−)-cubebaol, and (−)-6-hydroxy-4methylcyclohex-1-ene-1-methanol acetate, an intermediate in the total synthesis of the alkaloid magellanine.173 The Ni(COD)2 -catalysed 4 + 2 + 1-cycloaddition of (trimethylsilyl)diazomethane with dienynes readily produced carbo-, oxa-, and aza-cyclic adducts. Evidence has been supplied for a mechanism involving a 3 + 3-sigmatropic rearrangement of intermediate divinylcyclopropanes.174 The rhodium(I)-catalysed 4 + 2 + 2-cycloaddition of diene-enes (128) and alkynes (129) resulted in the preparation of cyclooctadienes (130, 131) in high yields (Scheme 34).175 The Ni(0)-catalysed intermolecular formal 4 + 2 + 2-annulation of cyclobutanones with 1,6- and 1,7-diynes gave bicyclic eight-membered ring ketones via a β-elimination for ring expansion.176 The Lewis acid-catalysed 4 + 3-cycloaddition of furan with chiral allylic dioxolans produced cycloadducts with high diastereoselectivity.177 Theoretical calculations have

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Organic Reaction Mechanisms 2006 OMe

H E E H MeO

(130)

+

E

Pri

[RhCl(CO)2]2 AgSbF

E

+

85%

OMe

H E

(129)

(128)

E H

Pri (131)

Scheme 34

Me

R1

Me R2 Ni(COD)2–PO(o-biph)3 (1:3)

Me

toluene, 85 °C

(132)

(133) m-CPBA NaHCO3, CH2Cl2 −78 to −20 °C 88%

Me

Me

Me H2 (1 atm) RhCl(PPh3)3

Me

Me

benzene 95%

O

O

(135)

(134) Scheme 35

411


shown that the key 4 + 4-cycloaddition in the biosynthesis of epoxytwinol A consists of three consecutive steps involving biradical intermediates. The first step is the formation of the C(8)–C(8 ) bond generating a biradical intermediate. Next, rotation about the C(8)–C(8 ) bond occurs, and finally the C(1)–C(1 ) bond is formed.178 A novel type of nickel(0)-catalysed intramolecular 4 + 4-cycloaddition of the (Z)-bis-diene (132) yielded the cyclooctadiene cycloadduct (133), which was converted to the tricyclic sesquiterpene (±)-salsolene oxide (135) in two chemoselective steps via intermediate (134) (Scheme 35).179 The photochemical diastereoselective 4 + 4-cycloaddition of the fused bicyclic pyran-2-ones (136), with pendant furan side-chains and a stereogenic centre adjacent to the pyranone ring oxygen, furnished the corresponding lactone bridged 5–8–5 cycloadducts (137–139) in good yields. These cycloadducts are suitable intermediates in the total synthesis of traversianal and related fusicoccin fungal metabolites (Scheme 36).180 The photocycloaddition of anthracene derivatives to anthracene produced only 4 + 4-cross-cyclomer adducts under selective excitation conditions.181 The intermolecular 1,5-dipolar cycloaddition of tungsten-containing vinylazomethine ylides with ketene acetals produced azepino[1,2-a]indole derivatives in good

RO O

O hn, Pyrex

O

O

hexanes 90% (R = TBDPS)

O

(136)

RO O

O

O O

O (137) + RO

RO O

O

O

+

O

O

O

O O

O (139)

O (138) Scheme 36

de

412

Organic Reaction Mechanisms 2006 OMe R1

(OC)5Cr +

X

R2

CHO (140)

(141) OMe R

OMe

1

R1 + X X

R2

2

OH

R (142)

(143)

Scheme 37

R2 R2

O− +

O

R3

R3 O

+

CHCl3

R1

R1 (146)

(144)

(145)

R1 = H, alkyl

R2 = R3 = H, alkyl, aryl

R2

1,6-H shift

R3

H

R2 DMAD

O

MeO2C R1 CO2Me

O

R1

O

−

H2C

+

N Bn H2C

R3

R3

R1

O

(148) R2

O

N Bn

O (149)

Scheme 38

CH2Cl2

(147) 45–83%

O


413

yields.182 [{(R)-BINAP}Rh]+ SbF6 − catalysed the intramolecular 5 + 2-cycloaddition of vinylcyclopropanes with π -systems to produce bicyclic cycloadducts in high yields and high enantioselectivities.183 Alkynylphenylcarbene complexes (141) and alkynylheteroaromatic carboxaldehydes (140) underwent net 5 + 5-cycloaddition to form heterocycle-annulated phenanthrenes (142, 143) (Scheme 37).184 The cobalt(I)-catalysed 6 + 2-cycloadditions of cyclooctatetraene with monosubstituted alkynes produced monosubstituted bicyclo[4.2.2]deca-2,4,7,8-tetraenes in good yields.185 The 6 + 3-cycloaddition of fulvenes (145) with 3-oxidopyrylium betaines (144) formed 5–8 fused oxa-bridged cyclooctanoids (146, 147), which can be manipulated by cycloaddition reactions to produce key intermediates (148, 149) for the synthesis of fused cyclooctanoid natural products e.g. lancifodilactones (Scheme 38).186,187

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416 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179

Organic Reaction Mechanisms 2006 Kawasaki, M. and Yamamoto, H., J. Am. Chem. Soc., 128, 16482 (2006). Clark, R. C., Pfeiffer, S. S., and Boger, D. L., J. Am. Chem. Soc., 128, 2587 (2006). Sheng, Y. and Leszczynski, J., Tetrahedron, 62, 7014 (2006). Ostrowski, S. and Wyre¸bek, P., Tetrahedron Lett., 47, 8437 (2006). Poverlein, C., Breckle, G., and Lindel, T., Org. Lett., 8, 819 (2006). Liu, W., You, F., Mocella, C. J., and Harman, W. D., J. Am. Chem. Soc., 128, 1426 (2006). Singh, V. and Pal, S., and Mobin, S. M., J. Org. Chem., 71, 3014 (2006). Bekele, T., Shah, M. H., Wolfer, J., Abraham, C. J., Weatherwax, A., and Lectka, T., J. Am. Chem. Soc., 128, 1810 (2006). Abraham, C. J., Paull, G. H., Scerba, M. T., Grebinski, J. W., and Lectka, T., J. Am. Chem. Soc., 128, 13370 (2006). Lindsey, C. C. and Pettus, T. R. R., Tetrahedron Lett., 47, 201 (2006). Gordillo, R. and Houk, K. N., J. Am. Chem. Soc., 128, 3543 (2006). Pi, Z. and Li, S., J. Phys. Chem. A, 110, 9225 (2006). Kano, T., Tanaka, Y. Y., and Maruoka, K., Org. Lett., 8, 2687 (2006). Bonini, B. F., Capitò, E., Comes-Franchini, M., Fochi, M., Ricci, A., and Zwanenburgh, B., Tetrahedron: Asymmetry, 17, 3135 (2006). Shen, J., Nguyen, T. T., Goh, Y.-P., Ye, W., Fu, X., Xu, J., and Tan, C.-H., J. Am. Chem. Soc., 128, 13692 (2006). Terada, M. and Kouchi, M., Tetrahedron, 62, 401 (2006). Fu, F., Teo, Y.-C., and Loh, T. P., Org. Lett., 8, 5999 (2006). Sakakura, A., Suzuki, K., Nakano, K., and Ishihara, K., Org. Lett., 8, 2229 (2006). Akiyama, T., Morita, H., and Fuchibe, K., J. Am. Chem. Soc., 128, 13070 (2006). Liu, H., Cun, L.-F., Mi, A.-Q., Jiang, Y.-Z., and Gong, L.-Z., Org. Lett., 8, 6023 (2006). Kawe¸cki, R., Tetrahedron: Asymmetry, 17, 1420 (2006). Takasu, K., Shindoh, N., Tokuyama, H., and Ihara, M., Tetrahedron, 62, 11900 (2006). Han, B., Jia, X.-D., Jin, X.-L., Zhou, Y.-L., Yang, L., Liu, Z.-L., and Yu, W., Tetrahedron Lett., 47, 3545 (2006). Bansal, R. K., Gupta, N., and Kumawat, S. K., Tetrahedron, 62, 1548 (2006). Hamasaki, A., Ducray, R., and Boger, D. L., J. Org. Chem., 71, 185 (2006). Aoyaga, S., Hakoishi, M., Suzuki, M., Nakanoya, Y., Shimada, K., and Takikawa, Y., Tetrahedron Lett., 47, 7763 (2006). Inagaki, F. and Mukai, C., Org. Lett., 8, 1217 (2006). Shibata, T. and Tahara, Y.-k., J. Am. Chem. Soc., 128, 11766 (2006). Nishida, G., Suzuki, N., Noguchi, K., and Tanaka, K., Org. Lett., 8, 3489 (2006). Kezuka, S., Tanaka, S., Ohe, T., Nakaya, Y., and Takeuchi, R., J. Org. Chem., 71, 543 (2006). Shibata, T., Tsuchikama, T., and Otsuka, M., Tetrahedron: Asymmetry, 17, 614 (2006). Tanaka, K., Takeishi, K., and Noguchi, K., J. Am. Chem. Soc., 128, 4586 (2006). Deng, L., Chan, H.-S., and Xie, Z., J. Am. Chem. Soc., 128, 7728 (2006). Tekavec, T. N., Zuo, G., Simon, K., and Louie, J., J. Org. Chem., 71, 5834 (2006). Duong, H. A. and Louie, J., Tetrahedron, 62, 7552 (2006). Yu, R. T. and Rovis, T., J. Am. Chem. Soc., 128, 12370 (2006). Yu, R. T. and Rovis, T., J. Am. Chem. Soc., 128, 2782 (2006). Tsuchikama, K., Kuwata, Y., and Shibata, T., J. Am. Chem. Soc., 128, 13686 (2006). Morohashi, M., Yokomakura, K., Hattori, T., and Miyano, S., Tetrahedron Lett., 47, 1157 (2006). Petit, M., Aubert, C., and Malacria, M., Tetrahedron, 62, 10582 (2006). Kamikawa, K., Shimizu, Y., Takemoto, S., and Matsuzaka, H., Org. Lett., 8, 4011 (2006). Komagawa, S. and Saito, S., Angew. Chem. Int. Ed., 45, 2446 (2006). Shintani, R. and Hayashi, T., J. Am. Chem. Soc., 128, 6330 (2006). Kurdyumov, A. V., Lin, N., Hsung, R. P., Gullickson, G. C., Cole, K. P., Sydorenko, N., and Swidorski, J. J., Org. Lett., 8, 191 (2006). Hong, B.-C., Wu, M.-F., Tseng, H.-C., and Liao, J.-H., Org. Lett., 8, 2217 (2006). Ni, Y. and Montgomery, J., J. Am. Chem. Soc., 128, 2609 (2006). Wender, P. A. and Christy, J. P., J. Am. Chem. Soc., 128, 5354 (2006). Murakama, M., Ashida, S., and Matsuda, T., J. Am. Chem. Soc., 128, 2166 (2006). Harmata, M., Brackley, J. A., and Barnes, C. L., Tetrahedron Lett., 47, 8151 (2006). Shiina, I., Uchimaru, T., Shoji, M., Kakeya, H., Osada, H., and Hayashi, Y., Org. Lett., 8, 1041 (2006). Wender, P. A., Croatt, M. P., and Witulski, B., Tetrahedron, 62, 7505 (2006).

12 Addition Reactions: Cycloaddition 180 181 182 183 184 185 186 187

417

Song, D., McDonald, R., and West, F. G., Org. Lett., 8, 4075 (2006). Bailey, D. and Williams, V. E., J. Org. Chem., 71, 5778 (2006). Kusama, H., Suzuki, Y., Takaya, J., and Iwasawa, N., Org. Lett., 8, 895 (2006). Wender, P. A., Haustedt, L. O., Lim, J., Love, J. A., Williams, T. J., and Yoon, J.-Y., J. Am. Chem. Soc., 128, 6302 (2006). Zhang, Y. and Herndon, J. W., Tetrahedron Lett., 47, 5303 (2006). Achard, M., Mosrin, M., Tenaglia, A., and Buono, G., J. Org. Chem., 71, 2907 (2006). Krishnan, K. S., Smitha, M., Suresh, E., and Radhakrishnan, K. V., Tetrahedron, 62, 12345 (2006). Krishnan, K. S., Sajishi, V. S., Anas, S., Suresh, C. H., Bhadbhade, M. M., Bhosekar, G. V., and Radhakrishnan, K. V., Tetrahedron, 62, 5952 (2006).

CHAPTER 13

Molecular Rearrangements: Part 1. Pericyclic Reactions

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 . . . . . Other [n,m]-Sigmatropic Rearrangements . [1,n]-Sigmatropic Rearrangements . . . . . Vinylcyclopropane–Cyclopentene, Bergman, Diradical Rearrangements . . . . . . . . . . Electrocyclic Rearrangements . . . . . . . . Ene Reactions . . . . . . . . . . . . . . . . . Tandem Pericyclic Rearrangements . . . . . References . . . . . . . . . . . . . . . . . . .

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

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

. . . . . . .

. . . . . . .

420 420 421 426 431 433 433

. . . . .

. . . . .

435 437 441 442 448

A new type of rearrangement, dubbed ‘hiscotropic’, has been predicted by DFT calculations to occur, albeit with a high energy barrier. The reaction has been described as a fusion of a two-electron electrocyclic ring opening and a [1,2]-hydrogen shift to an adjacent carbocation, and the calculations have shown that the two processes occur in an asynchronous, concerted fashion, and share a p-type orbital in the single transition state.1 The aromaticities of symmetry-allowed and -forbidden transition states for electrocyclic reactions and sigmatropic rearrangements involving two, four, and six π -electrons, and Diels–Alder cycloadditions, have been investigated by ab initio CASSCF calculations and analysis based on an index of deviation from aromaticity. The order of the aromaticity levels was found to correspond to the energy barriers for some of the reactions studied, and also to the ‘allowed’ or ‘forbidden’ nature of the transition states.2 The uses of catalytic metal vinylidene complexes in electrocyclization, [1,5]-hydrogen shift reactions, and 2 + 2-cycloadditions, and the mechanisms of these transformations, have been reviewed.3



419

420


[3,3]-Sigmatropic Rearrangements A review of the use of Pd(II) catalysis for the acceleration of the Cope, Claisen, and aza-Claisen rearrangements has focused on the mechanism of catalysis, stereochemical outcome and synthetic applications of these reactions.4

All-carbon Pericyclic Systems The Cope rearrangements of a series of 1(5)-monosubstituted and 1,5-disubstituted semibullvalenes have been investigated by ab initio quantum methods. In the monosubstituted series, the results were found to be in accordance with Hoffmann’s predictions, depending on the electronic nature of the substituents. In the disubstituted series, rearrangement barriers have been shown to be lowered by π -donor groups, and the position of equilibrium was found to correlate with the BCO stabilization effects of the substituents.5 A DFT investigation of the Cope rearrangement of the cyclobiphenalenyl (1) has shown it to occur via the unusual diradical (2), stabilized by π -dimerization, and having an unusually long inter-phenalenyl distance (comparable ˚ 6 to the inter-allyl distance in a classical Cope rearrangement) of ∼2.8 A.

(1)

(2)

Calculations of the interactions between matured catalytic antibody AZ28 and the different conformers and enantiomers of 2,5-diaryl-hexa-1,5-dien-3-ol, allowing for the flexibility of the antibody, have reproduced, qualitatively only, the observed selectivity of the antibody for the S,equatorial substrate.7 Doubly α,β-unsaturated N -arylimines (3) have been shown to react with α,β-unsaturated ketenes to give azocinones (4),

O

•

Ar2 R +

Ar2

2+2

N

Ar1

1

R Ar1

Ar1 (3)

Ar

Ar2

O N [3,3]

Ar

1

O

N

R Ar1 (4)

de

13 Molecular Rearrangements: Part 1. Pericyclic Reactions

421

in which any aromatic ring(s) may bear a para-substituent. The mechanism shown, involving 2 + 2-cycloaddition followed by a facile ring-expanding Cope rearrangement, has been supported by AM1 calculations.8

One Heteroatom The Claisen rearrangement of allyl vinyl ether has been studied using a combination of spin-coupled modern valence bond theory and DFT. These calculations have suggested a non-synchronous, concerted, homolytic mechanism in which aromaticity is achieved but not at the transition state.9 A range of 3-alkylidene-2-oxabicyclo[2.2.2]oct-5ene derivatives has been shown to undergo thermal or Lewis acid-catalysed Claisen rearrangement giving bicyclo[4.2.0]oct-5-en-2-one derivatives. The rate of rearrangement was found to correlate qualitatively with the electron donor ability of an aromatic substituent on the exo-methylene group. The related 3-dichloromethylene2-oxabicyclo[2.2.1]hept-5-ene could not be isolated, the observed product of its attempted synthesis by elimination being 3,3-dichlorobicyclo[3.2.0]hept-5-ene-2-one. These results are consistent with the related Claisen rearrangement believed to follow 4 + 2-cycloaddition of ketene derivatives to cyclopentadiene, the sequence leading to the observed products of this cycloaddition, the bicyclo[3.2.0]hept-5-en-2-one derivatives.10 The decarboxylative Claisen rearrangement of allylic tosylacetate (5) and methyl tosylmalonate derivatives has been extensively studied. In the tosylacetate series, it has been found that acetate ions, base and a silylating agent, preferably N ,Obis(trimethylsilyl)acetamide (BSA), are all necessary, but in only catalytic quantities provided that BSA is used. Potassium acetate has been shown to be a suitable base. In the absence of acetate ion, ketene acetal formation and Claisen rearrangement have been found to proceed, but without the final decarboxylation. These findings have been interpreted in terms of a proposed catalytic cycle (Scheme 1). By contrast, in the methyl tosylmalonate series, rapid room temperature rearrangement and decarboxylation have been shown to occur using either BSA–KOAc or DBU–TMSOTf reagent systems, but a stoichiometric amount of silylating agent has been found to be necessary. In this case, it has been proposed that decarboxylative silatropic retro-ene rearrangement can occur without the need for the acetate catalyst.11 Bismuth triflate has been shown to be an effective catalyst for the Claisen rearrangement of allyl naphthyl ether derivatives in refluxing acetonitrile, giving exclusively oallylnaphthol derivatives. Vinylic substitution has been found to cause competing [1,3]sigmatropic migration of the allyl group. Although 1,4-diallyloxynaphthalene has been shown to undergo Claisen rearrangement of both substituents, this did not occur cleanly for either 1,5- or 2,5-diallylnaphthol, where single rearrangement was found to compete. Clean double [3,3]-sigmatropic rearrangement to give p-allylnaphthol derivatives was found to occur, as expected, with 2-substituted 1-allylnaphthol derivatives.12 The asymmetric Claisen rearrangement of 2-allyloxyindolin-3-one derivative (6) has been investigated. Treatment with a weak base such as DBN has been found to give only modest enantioselectivity; this has been attributed to competition between chair-like and boat-like transition states as shown in Scheme 2. By contrast, the corresponding

ee

422

Organic Reaction Mechanisms 2006 K+

OSiMe3

+

OSiMe3 −

KOAc

Me3SiN

+

Me3SiOAc

Me3SiN O

Ts

Ts

O

R

R (5)

K+

O −

+ Me3SiOAc

Me3Sin

CO2

and/or K+(5−H)−

O + KOAc

Me3SiN H

OSiMe3 Ts

OSiMe3 Ts

[3,3]

O

R

O

R

Scheme 1 (n-C6H13) O

H (n-C6H13)

HO DBN

O

O

N

N

Ac (R)-(6)

Ac

H

via

OH

or (n-C6H13) Ac

OH Ac

N

+ enantiomer

N

O

O H

Scheme 2

(n-C6H13)


423

TMS enol ether has been shown to rearrange with good enantioselectivity, presumably because the boat-shaped transition state is sterically disfavoured. Rearrangement of the enantiomeric starting material has been used as a key step in a total synthesis of (+)-alline.13 Ring-expanding Claisen rearrangements of some 1-vinyl-5-methylene-glucose and -mannose derivatives have been found to occur either on strong heating or, in one case, by Lewis acid treatment, to give protected 2,3,4-trioxygenated cyclooct-5-en1-ones. Since the Lewis acid used was TRIBAL, this rearrangement was found to be accompanied by stereoselective reduction to the corresponding cyclooctenol.14 Total diastereoselectivity has been found to occur in an Mg(II)-promoted Claisen rearrangement of some sugar-derived enol ethers. Treatment of 2-substituted 1-chloro1-isopropoxycarbonyl epoxides (7) with MgI2 –Mg followed by allyl bromide–HMPA was found to generate a mixture of allyl enol ethers (9), α-keto esters (10), and βallyl α-keto esters (11), formed as single diastereomers from sugar derivatives (7a) or (7b). Although esters (11) could be derived by C-allylation of magnesium enolates (8), these have previously been shown to undergo exclusively O-allylation. This, and the total stereoselectivity of the reaction, have led to a proposed mechanism involving O-allylation followed by Claisen rearrangement with a chair-shaped transition state having the Mg-coordinated ring oxygen, and the allyl group, both avoiding close contact with the isopropylidene protecting group(s) on the sugar moiety R, as shown in Scheme 3.15 Ireland–Claisen ester enolate rearrangements have been shown to occur readily in conjugated dienes bearing an internal acetoxymethylene substituent, giving conjugated dienes bearing an internal CH2 CH2 CO2 H or CH2 CH2 CO2 Me substituent. A wide range of initial diene substitution patterns has been found to be compatible with the rearrangement. With an enantiomerically enriched starting material, however, some loss of chirality has been observed, and attributed to competing chair- and boat-like transition states.16 Tertiary cyclic α-vinylamines (12) have been shown to undergo four-atom ring expansion on treatment with alkynyl p-toluenesulfonate, giving medium- or largering amines (13). The reaction, which has been found to be generally stereoselective, although the alkene stereochemistry could not always be determined, has been presumed to occur by nucleophilic addition followed by a rapid zwitterionic formal [3,3]-sigmatropic rearrangement as shown in Scheme 4, although no intermediates could be trapped or detected, so it remains unclear whether the rearrangement is concerted.17 The rearrangements of some di- and tetra-N -allyldibenzotetraazafulvalenes (15), generated in situ by deprotonation of N -allylbenzimidazolium halides (14), have been investigated experimentally and by DFT calculations. Deprotonation of N ,N -diallylbenzimidazolium and N -allyl-N -methylbenzimidazolium halides (14) has been found to give a mixture of rearrangement products (17) and deallylation products (18), whereas with N -allyl-N -benzylbenzimidazolium and N ,N -diprenylbenzimidazolium ions only the debenzylation or deprenylation products (18) have been observed. DFT calculations have suggested that all these reactions occur by radical mechanisms via intermediates (16) as shown in Scheme 5, unlike the corresponding rearrangements

ee

de

O

O

Cl

O

(11)

R

O

(7)

R

O

O

H

H

(i)

(iii)

I

Cl

O

O

Mg

O

O

R

O

I

R

O H I

Cl

I

Mg

O

O

O

(ii)

(8)

Scheme 3

Mg

Cl

O

R

O

R

O

H

H

(iii)

(iii)

O

O

(10)

R

O

(9)

O

O H

O O O

c; R = (Me)2CH

b; R =

O

O

OBn

O

O O

(i) Mg/MgI2 (1 equiv. of each), Et2O (ii) allyl bromide, HMPA (both in excess) (iii) H2O

R

O

a; R =


425


H

R1

Ts

X

+

R

R2

+

N

X

R1

N Bn

Ts

R2

N

X

R2

−

Bn

Bn

1

Ts

(13)

R1 = H, Me R2 = H, Me, vinyl X = CH2, (CH2)2, (CH2)3, (CH2)9, or CH2O

(12)

Scheme 4

R

R N H

+

N

(i)

N

N

N

X−

R

N

R′

R′ (14)

R′

(15) •

−R

(i) 2 NaH

R

R R

N

N

N

•

•

+R

N

N

N

R′

N

N R′

R′

R′

(16)

(17)

•

−R

R

R = allyl or prenyl R′ = Me, allyl, benzyl, or prenyl

N

N

N

N

R (18) Scheme 5

426


of non-benzannulated tetraazafulvalenes, which are believed to involve pericyclic Claisen-like rearrangements.18 Homoallylic alcohols (19), which are also homoallylic sulfones, have been shown to react with aldehydes (20) under acidic conditions to produce dienes (22), which are allylic sulfones, via an oxonia-Cope rearrangement and elimination of the resulting oxonium ion. The rearrangement has often been found to proceed with excellent diastereoselectivity, which has been accounted for with a chair-like transition state. Thus anti -alcohols (19) have been shown to give (all-E)-sulfones (22), whereas syn(19) has been found to give (2Z,4E)-sulfones (22). Some erosion of stereoselectivity has been observed, however, from starting materials having a vinyl substituent and a tertiary allylic centre. Although the aldehyde appears mechanistically to be a catalyst, higher yields have been obtained using stoichiometric amounts. Further studies have revealed that the electronic nature of aldehyde (20), and of the aromatic ring adjacent to the alcohol in (19), influence the course of the reaction, with the more electron rich of the two being incorporated into the product. This has been attributed to a combination of fragmentation of alcohol (19), generating the corresponding benzaldehyde derivative (23) as shown in Scheme 6, and the relative abilities of the two aldehyde moieties to stabilize the adjacent oxonium ion in intermediates (21) and (24). The fragmentation has been supported by the recovery of more than the starting amount of aldehyde in some cases, when Ar1 = Ar2 .19 A new mechanism for loss of optical purity in Prins cyclizations has been elucidated using 2 H and 13 C labelling, supported by structural modification and calculations. The mechanism involves 2-oxonia-Cope rearrangements via (Z)-oxocarbenium ion intermediates, as shown in Scheme 7. It has been shown that racemization can be suppressed by conditions or structural features which slow the Cope rearrangement in either forward or reverse directions, since the [3,3]-sigmatropic rearrangement must occur many times before reaction via the less favoured (Z)-oxocarbenium ion becomes important.20

Two or More Heteroatoms Arylpropargyl acetates have been shown to produce indenyl acetates on treatment with AgBF4 and an AuCl complex of a sterically demanding N -heterocyclic carbene ligand. In view of the occasional observation of allene by-products, and of various regioisomeric byproducts, a mechanism has been proposed involving Au coordination to the alkyne, rearrangement to an allene by acetate migration, and hydroarylation of the gold-coordinated allene. The acetate migration may formally occur by either two [1,2]-migrations with a vinyl acetate intermediate or a single [1,3]- or [3,3]rearrangement.21 The synthesis of N -arylindoles from N ,N -diaryl-N -trifluoroacetyl enehydrazines, a process analogous to the Fischer indole synthesis, has been studied in various solvents, including water, and in solvent-free conditions. Solvent polarity, or presence, appears to have had little influence on the reaction course. The N -TFA group has been found to be necessary for efficient reaction, with less electron-withdrawing substituents giving slower reactions, and triflyl diverting the reaction course after the

de

Ar1

R

+

(23)

Ar1

O

O

(ii)

(20)

+ Ar2 R SO2Ph

(anti-19)

OH

Ar1

(i)

Ar1

O

+

Ar2 +

R

R

SO2Ph

R SO2Ph

(21)

Ar1

H

Scheme 6

O

(24)

Ar1

H

SO2Ph

O

+

[(E,E)22]

R

Ar1

R

SO2Ph

SO2Ph

(i) H+, C6H6, reflux (ii) (19), H+, C6H6, reflux

Ar2

Ar2

H H


427

428

Organic Reaction Mechanisms 2006 Nu R2

R1

O

+

H

H

(ii)

R2

H

(iii)

OAc R

2

(i)

R

O

+

R2

1

Nu

R1

O H

H

R1

O

(ii)

R2

R1

O

H

(iv)

+

H R2

R1

O H

H

(iii)

R1

O

H

+

R2

H

(v)

R1

H

R2

O H

H

+

H (ii)

(i) acid (ii) Prins cyclization with nucleophile Nu− (iii) 2-oxonia-Cope rearrangement (iv) E/Z isomerization (v) C-C bond rotation

Nu

R2

O

R1

Scheme 7

initial [3,3]-sigmatropic rearrangement. Formation of N -arylindoles has been shown to occur readily when the N -vinyl group of the starting enehydrazine was acyclic or part of a six-membered ring, but required higher temperatures when it was in a fivemembered ring. In these cases, it was found possible to isolate instead the indoline intermediates, prior to elimination of trifluoroacetamide. Indole formation has been shown to be accelerated by an electron-donating N -aryl substituent, and retarded by an electron-withdrawing one. With ortho- and meta-substituents, the reaction has been found generally to lack regioselectivity, although electron-deficient ortho-substituted starting materials have unexpectedly been found to give only 7-substituted indoline products. Product distributions observed with electron-rich ortho-substituents have been attributed to competing chair- and boat-like transition states for the initial [3,3]sigmatropic rearrangement.22 Some ester- or aldehyde-substituted bicyclo[2.2.2]oct-2-ene and bicyclo[2.2.1]hept2-ene systems (25) have been shown to undergo nitrosation adjacent to the carbonyl group followed by [3,3]-sigmatropic rearrangement to give oxazine products (26).23 Stereodefined monoprotected allylic 1,2-diol (27) and its diastereomer have been converted into stereodefined propenylimidazolidinone (30) and its diastereomer by

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13 Molecular Rearrangements: Part 1. Pericyclic Reactions X

X

Rn X

(i)

Rn

C(O)R′

C(O)R′

Rn O

O R′ (25)

O

N

N

(26)

(i) 1. Base, Me3SiCl; 2. i-C5H11ONO, TiCl4

X = CH2, (CH2)2

OPMB

OPMB

OPMB

(i)

OH N (27)

O

C

N

C

O

(28) (ii)

OPMB (i) 1. CCl3CONCO, CH2Cl2; 2. K2CO3, MeOH; 3. PPh3, CBr4, Et3N, CH2Cl2 (ii) PhCH2OH, Bu3SnOCH2Ph (iii) DDQ, CH2Cl2, H2O

HN

Cbz (iii)

OH

HN

Cbz (i)

O Cbz

N

N

NH HN (30)

C

Cbz

O

N

HN

C

Cbz (29)

O

430


successive diastereoselective [3,3]-sigmatropic rearrangements of the initially formed allylic cyanates (28), (29), or their diastereomers as shown.24 The stereoselectivity of the MOM ether-directed, transition metal-catalysed azaClaisen rearrangement of O-(4-methoxymethoxypent-2-en-1-yl) trichloroacetimidate to N -(4-methoxymethoxypent-1-en-3-yl) trichloroacetimidate has been studied under various conditions. A range of Pd(II) and Pt(II) catalysts have all been shown to give ∼10:1 diastereoselectivity, whereas Ni(II), Ru(II) and Hg(II) complexes have been shown to have no catalytic activity. An Au(II) catalyst gave lower selectivity, whereas thermal reaction has been shown to give very little selectivity. Solvent polarity and metal-coordinating ability have been found to have a greater effect on reaction stereoselectivity, with toluene giving greatest selectivity and an ionic liquid least, which is consistent with selectivity being largely influenced by coordination of the metal to the alkene and the ether oxygen.25 Similarly, use of toluene as solvent has been found to give good diastereoselectivities in the rearrangements of trichloroacetimidates of 4-alkyl-(2E,4S,5R)-5-methoxymethoxyhex-2-en-1-ol. In these cases, the more remote MOM ether has been found to give little or no Pd coordination and diastereoselectivity in THF, with the low selectivities observed being attributed to allylic strain from the closer chiral centre.26 A Pd(II)-catalysed formal [3,3]-sigmatropic rearrangement has been used to convert 4-THP protected, 3-substituted but-2-en-1,4-diols, via their N -PMP trifluoroacetimidate derivatives, into THP-protected, 2-substituted N -p-methoxyphenyl-N trifluoroacetyl-2-aminobut-3-en-1-ols, which are quaternary α-vinylglycine precursors, usually in excellent yields.27 Enantioselective aza-Claisen rearrangement of N -pmethoxyphenyl trifluoroacetimidates has been shown to be catalysed by ferrocenyl– Pd(II) complexes (31). It has been found that the catalysts may be optimized to suit the alkene geometry in the substrate by varying the ferrocenyl substituent R; best results have been obtained using E-substrates and the pentaphenylcyclopentadienyl-derived catalyst.28

de

de

2

Ph ••••••

N N

Ph p-TolO2S

R

Pd X

Fe

R R

R R (31)

Allyloxyphosphonium ylids (32), generated in situ, have been shown to undergo [3,3]-sigmatropic rearrangements readily on heating to give phosphonate derivatives (33) in good yields. Diastereoselectivity has been found to be low; following DFT calculations, this has been attributed to the small energy gap between axial and equatorial ylid substituents, because of the long P–C ylid bond.29

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13 Molecular Rearrangements: Part 1. Pericyclic Reactions R1

OH R2

R3

(i)

+ O

EtO2C O

+

P

O

−

O

R

3

(ii)

R2

PCl O

R3

R1

(32) (i) 1. Et3N 2. EtO2CCHN2, Fe(III) (cat.) (ii) heat

EtO2C O

R1 P O R2 O (33)

[2,3]-Sigmatropic Rearrangements The [2,3]-Wittig rearrangements of cinnamyloxyacetone and various analogues into syn-4-hydroxy-3-phenylhex-1-en-5-one and analogues has been shown to be catalysed by pyrrolidine, allowing the rearrangements to be carried out at or well below room temperature, provided that methanol is used as solvent. A range of substitution patterns has been found to be tolerated, and chirality transfer from an α-chiral ether starting material was found to be effectively complete. A chiral pyrrolidine derivative has been shown to give moderate enantiomeric induction. In contrast to reactions in other solvents, the rearrangements have been found to be syn selective in every case, except for rearrangement of 5-triisopropylsilylpent-4-yn-2-enyloxyacetone, which was not diastereoselective. A possible catalytic cycle and transition-state model have been proposed, in which the sigmatropic rearrangement occurs from an enamine, with hydrogen bonding from the ether to the methanolic solvent playing an important rôle in determining transition-state geometry.30 Vinyl epoxide derivatives have been shown to undergo ring expansion to 3,6dihydropyran-2-carboxylates on treatment with diazoacetate esters and a Cu(II) catalyst, presumably by [2,3]-sigmatropic rearrangement of the resulting oxonium ylids. 1,2-trans-Disubstituted epoxides have been found to give exclusively 2,6-transdisubstituted dihydropyrans, but it has been shown that only 1,2-trans-divinylsubstituted epoxides gave useful yields of the dihydropyran products; with other substituents, deoxygenation to penta-1,3-dienes was found to compete. These results are consistent with [2,3]-sigmatropic rearrangement of the initally formed oxonium ylid via a boat-shaped transition state, with a requirement for a vinyl substituent cis to the alkoxycarbonylmethyne substituent on the epoxide.31 Ring expansions of ylids (35) or (37), generated by deprotonation of alk-2-enylazetidinium salts (34), to alk-3-enylpyrrolidines (36) or azepanes (38) respectively, have been investigated. KHMDS treatment of N -benzyl-N -methylalk-2-enyl-3-phenylazetidinium triflates (34; R1 = H) has been found to give N -methylalk-3-enyl-2,4diphenylpyrrolidines (36) in good to excellent yields but with very variable stereoselectivity, via a [1,2]-Stevens rearrangement. By contrast, KHMDS treatment of N -benzylN -ethoxycarbonylmethylalk-2-enyl-3-phenylazetidinium salts (34; R1 = CO2 Et) has been shown to give N -benzyl-2-ethoxycarbonyl-6-phenylazepane derivatives (38),

ee de

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Ph

R2 N

N

Ph Ph

Me

−

Ph

Me (36)

(35)

R2

+

R

+

(i)

2

N R1

Ph

R2

TfO− (34)

Ph

(ii)

Ph R2

+

N

N Ph

(i) KHMDS; R1 = H (ii) KHMDS; R1 = CO2Et

CO2Et

−

CO2Et

Ph

(37)

(38)

again with variable stereoselectivity, by a [2,3]-sigmatropic rearrangement of the intermediate ylid (37). The contrasting behaviour of these two groups of substrates has been attributed to the cis or trans relationship between the anion and the vinyl group in the ylids (35) and (37).32 A DFT study of the [2,3]-sigmatropic rearrangements of some hydrogen and alkyl prop-3-enyl sulfoxides to the corresponding prop-3-enyl sulfenates has found the rearrangements to be concerted, with the competing exo and endo transition states very close in energy.33 Enantiomerically pure branched allylic alkyl sulfides (39) have been shown to give N -allylic-N -Boc-sulfimides (40) via a [2,3]-sigmatropic rearrangement, with essentially complete transfer of chirality, on treatment with N Boc-3,3-di(ethoxycarbonyl)oxaziridine.34

n-C6H13S

R2

+ R1

(39)

O N EtO2C

Boc

n-C6H13S

N

Boc R2 R1

CO2Et (40)

A mild method for thiol allylation has been developed based on the [2,3]-sigmatropic rearrangement of allylic disulfides. Treatment of a thiol, which may be sugar-derived or a protected or unprotected cysteine-containing peptide, with an allylic pyridyl or benzothiazolyl disulfide, followed by a thiophilic phosphine, has been shown to result in transfer of the allylic group to the thiol with allylic transposition.35 The analogous [2,3]-rearrangement of allylic selenosulfides has also been shown to be a suitable method for the same conversions. In these cases, with Se-allylic selenium Bunte salts such as allyl–Se–SO3 K as the allylic reagents, the allylic transposition has been found to occur slowly but spontaneously at room temperature even in the absence

ee


433

of the phosphine.36 It has further been shown that the allyl sulfides resulting from these two rearrangements, which have usually been cysteine-derived, react with diazo compounds in the presence of catalytic amounts of Rh2 (OAc)4 by a further [2,3]sigmatropic sulfonium ylid rearrangement to give α-substituted homoallylic sulfides in moderate yields. The reaction has been shown to be compatible with peptides bearing allyl sulfides, and with diazo compounds derived from fatty acids or mono- or di-saccharides, but not with tryptophan, as the indole system apparently competes with the sulfide for the carbenoid moiety.37

Other [n,m]-Sigmatropic Rearrangements It has been shown that a single ortho or meta substituent on either aromatic ring can suppress formation of byproducts in the [5,5]-sigmatropic rearrangements of aryl hydrazides (readily prepared by Pd-catalysed coupling reactions), allowing clean formation of benzidine derivatives. The reaction has been shown to be extendible to double and triple [5,5]-sigmatropic rearrangements.38

[1,n]-Sigmatropic Rearrangements An asymmetric [1,2]-Wagner–Meerwein shift has been achieved under Pd catalysis, allowing ring expansion of 1-(alkyloxyallenyl)cyclobutanol and simple derivatives to 2-alkyloxy-2-vinylcyclopentanones. A mechanistic rationale for the high ee values observed has been proposed, based on the C2 -symmetry of the chiral ligands used.39 A dynamic NMR study of the stepwise, cationic [1,2]-migrations of differently substituted vinyl groups on 9,10-dimethyl-9-vinylphenanthrenium derivatives has found that prop-2-enyl and trans-but-2-en-2-yl groups migrate at comparable rates, but, unexpectedly, nearly 105 times more slowly than vinyl or cis-but-2-en-2-yl groups. This slow migration has not been explained.40 [1,3]-Sigmatropic migrations of the nitroso group in the systems ON–X–CH=X (X = O, S, Se, NH, CH2 ) have been studied by DFT methods.41 Treatment of silyl ethers of allyl alcohol, and some simple derivatives, with t-BuLi in THF–HMPA, followed by a suitable electrophile, has been shown to give the 1,4retro-Brook rearrangement products, which are ethers, carbonates or carbamates of 3-trialkylsilylprop-1-en-1-ol. With Et3 Si as the migrating group, it has been found necessary to use t-BuMe2 SiOTf as electrophile to suppress 1,2-silyl migration, but with t-BuPh2 Si or t-BuPh(MeO)Si as migrating groups a wider range of electrophiles has been shown to be suitable, with no competing 1,2-rearrangement observed. In the last case, rearrangement has been shown to proceed with retention of configuration at Si, although only moderate asymmetric induction to an adjacent chiral carbon could be achieved. A possible transition state has been proposed.42 It has been shown that treatment of α-benzyloxyallyltrimethylsilane with strong base (s-BuLi) at low temperatures results in exclusive formation of the [1,4]-Wittig rearrangement product, the enolate of 4-phenylbutanoyltrimethylsilane, which can be protonated or trapped with a range of electrophiles. By contrast, when weaker bases

ee

ee

434


needing higher temperatures for complete deprotonation were used, a [1,2]-Wittig rearrangement has been found to compete. This has been interpreted as evidence for the [1,4]-rearrangement occuring via a concerted pathway.43 A DFT study on thermal aryl migration in two aryliodonium ylids has suggested that the mechanism in each case is a concerted, single-step process involving a five-membered cyclic transition state, FMO controlled by an intramolecular HOMO–LUMO interaction. The ylids studied were the phenyliodonium ylids of cyclohexane-1,3-dione and 2-amino-1,4diquinone; the lower energy barrier calculated for the latter is in line with previous experimental observations.44 DFT studies on [1,5]-hydrogen shifts in cyclopentadiene and 2-fluorocyclopentadiene have suggested that the reactions may be enhanced in polar solvents.45 Kinetic studies of the [1,5]-hydrogen shift in deuterated 2-methyl-10-methylenebicyclo[4.4.0] dec-1-ene, a cisoid-locked (Z)-penta-1,3-diene, have allowed calculations of deuterium kinetic isotope effects and Arrhenius parameters for this reaction, but little or no evidence for any influence of tunnelling has been obtained.46 A kinetic study of gasphase thermal [1,5]-hydrogen shifts in monodeuterated cis,cis-cyclonona-1,3-dienes has allowed calculation of activation parameters. A parallel DFT study, which has given excellent agreement with the experimental results, has highlighted the importance of conformational flexibility in this complex system.47 Contrasting [1,5]-sigmatropic rearrangements have been observed on heating 4-tbutyl-2,7-dimethoxy-2H -azepine and 4-t-butyl-7-methoxy-2-propylthio-2H -azepine. In the former case, an equilibrium mixture of 4- and 5-t-butyl-2,7-dimethoxy-3H azepines has been found to be formed rapidly. This has been attributed to a [1,5]hydrogen shift followed by a very rapid second [1,5]-hydrogen shift. In the latter case, a 1:1 mixture of 3- and 7-propylthio-5-t-butyl-2-methoxy-3H -azepines has been observed, and attributed to competing [1,5]-hydrogen and [1,5]-propylthio sigmatropic shifts. Further studies have shown the rates of these competing reactions to be little affected by changes in solvent polarity, and the activation parameters to be similar, and consistent with concerted pericyclic mechanisms. The figures have been qualitatively supported by DFT analysis, which has also shown a much higher activation energy for [1,5]-methoxy shift (which has not been observed). It has therefore been concluded that both [1,5]-hydrogen and [1,5]-propylthio shifts are pericyclic in nature. This is apparently the first such [1,5]-alkylthio migration.48 NMR and DFT methods have been used to study [1,5]-silatropic shifts in 1,3and 1,1-bis(trialkylsilyl)indene derivatives, and to compare these with silyl migration in 1-trimethylsilylindene. In the last compound, the apparent [1,3]-trimethylsilyl migration is known to occur by two sequential [1,5]-migrations, with an unstable 2-trimethylsilylisoindene intermediate. Further silyl substitution has been found to destabilize this intermediate, slowing the overall migration considerably. In addition, replacement of trimethylsilyl by either allyldimethylsilyl or hex-5-enyldimethylsilyl groups has been shown both to slow the rearrangement and to reduce the proportion of the 1,1-disilylindene derivative in the equilibrium mixture. Curiously, silyl migration has not been observed in 1-(pent-5-enyl)-3-allyldimethylsilylindene, so a still higher energy barrier to silyl migration has been presumed in this case.49


435

Vinylcyclopropane–Cyclopentene, Bergman, Di-π-methane, and Related Diradical Rearrangements The evidence behind a proposed possible mechanism for a new dihalocyclopropane– (dihalomethyl)vinyl rearrangement has been reviewed.50 1-Chloro-1-fluoro-2-vinylcyclopropane and its 2-methyl derivative have been shown to give a mixture of butadiene derivatives as well as 4-chloro-4-fluorocyclopentene, or its 1-methyl derivative, on pyrolysis. The product mixture has been attributed to competition between homolytic C(1)–C(2) cleavage, leading to the cyclopentene products, and C(2)–C(3) cleavage, with concerted or subsequent [1,2]-chloro migration, leading to the butadiene products. The various possible butadiene products are themselves interconvertible by [1,3]and [1,5]-chloro migrations. The competition between ring-opening modes has been attributed to the contrast between the ability of Cl to stabilize an adjacent radical, and the ability of F to destabilize the bond opposite it in a three-membererd ring.51 The vinylcyclobutane–cyclohexene rearrangement has been studied using DFT and CASSCF methods. The rearrangement has been found to proceed via diradical species on an almost flat potential energy surface. Although the lowest energy pathway has been shown to be the symmetry-allowed suprafacial route with inversion of configuration at C(4), stationary points for other possible pathways have been found to be only slightly higher in energy, explaining the formation of other products; these include butadiene and ethene, because of a merger of the potential surface with that for the stepwise cycloaddition of those two molecules.52 An extensive kinetic study of the evolution of four enantiomerically pure 2 thujenes, cis- and trans-1-isopropyl-4-methylbicyclo[3.1.0]hex-2-enes and exo- and endo-3-iso-propyl-6-methylbicyclo[3.1.0]hex-2-enes, into optically pure trans-3-isopropyl-5-vinylcyclopentene, has allowed the calculation of 12 specific rate constants, and a greater understanding of the diradical caldera involved in these transformations.53 Rate constants for thermal isomerizations of [2-2 H]-1-(E)-propenylcyclobutanes to [42 H]-3-methylcyclohexenes have been measured, and compared with those of related systems.54 A modern re-evaluation of stereochemical and mechanistic aspects of the thermal stereomutations and [1,3]-carbon sigmatropic shifts of 2 H-labelled (Z)ethylidene-2-methylcyclobutanes has been performed.55 Kinetic studies on the thermal conversion of 2 H-labelled bicyclo[4.2.2]oct-2-ene to norbornene have found reaction to occur largely by homolysis of the C(1)–C(8) bond in the four-membered ring. This contrasts with the homolysis of the ring fusion bond observed in bicyclo[3.2.0]hept2-ene.56 Kinetic and DFT studies have found that the rapid cycloaromatization of 2,3diethynyl-1-methoxybenzene compared with 1,2-diethynylbenzene can be attributed to intramolecular hydrogen abstraction by the p-benzyne diradical intermediate from the OMe substituent. This has been shown to render the cyclization effectively irreversible by leading to a more stable diradical, and may have significant implications for the action of therapeutic enediynes.57 In general, the Bergman cycloaromatizations of 1-substituted 2,3-diethynylbenzenes have been found to be highly sensitive to the nature of the ortho-substituent, but the measurements and even the relative trends

436


have been found to be highly dependent on the experimental method used for the assessment. DFT and Møller–Plesset second-order perturbation theory calculations have been used to support the experimentally obtained rate constants and activation energies.58 DFT studies on heteroatom diallenes have found, in line with previous experimental data, that biradical cyclization to a five-membered heteroaromatic ring is the preferred reaction pathway, although protonation of the heteroatom has been found to promote a competing cyclization to a six-membered, initially biradical, ring.59 Fused bicyclic (thio)acetals (41) having a pendant diazo ketone have been shown to rearrange to ether-bridged tricyclic ketones (42) on treatment with Cu(hfacac)2 by oxonium ylid formation and [1,2]-Stevens rearrangement as shown in Scheme 8. In the six-membered ring series, where only endo starting materials were available, the rearrangement has been found to be clean and usually totally stereoselective. In the five-membered ring endo compounds, stereoselectivity has been found to be significantly reduced, whereas in the five-membered ring exo-thioacetals, sulfonium ylid formation has been shown to compete, giving additional products (43) in varying amounts. Several possible explanations for the variation in stereoselectivity have been proposed, including involvement of the copper catalyst in the migration; slow cyclization with the [3.2.1] bridged system as compared with the [4.2.1] case, allowing more bond rotation; and greater ring strain release from the [3.3.0] ylids than from the [4.3.0] ylids, again allowing more bond rotation.60 O

O

O N2

O

MLn MLn

O

X n

X

−

O+

−MLn

X

n

n

(41)

O

O

O •

O

STol

O n

H (43)

(42) X = OMe, STol Scheme 8

O •

X n = 1 or 2

n

X

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437

Electrocyclic Rearrangements The potential energy surfaces for the four-electron electrocyclizations of vinylallene and bisallene have been investigated by ab initio CASSCF calculations and CiLC-IRC analysis. The orthogonality of the allene π systems has been found to break down near the transition state, allowing considerable interactions between the formally orthogonal orbitals. The energy barriers for both reactions have been found to be significantly lower than for the cyclization of butadiene, which has been attributed to these interactions, but like butadiene, conrotatory pathways have been found for these reactions.61 The isomers of cycloheptadiene and bicyclo[2.2.0]hept-6-ene and their interconversion pathways have been investigated by multireference SCF methods. (E,E)-Cyclohepta-1,3-diene (44) has been found to occupy a shallow potential well, and to be barely conjugated. The calculated energy barriers, in kcal mol−1 , are summarized in Scheme 9.62 H (iii) (i) (iv)

H (vi)

(44)

H (ii) (v)

Energy barriers in kcal mol−1 (i) 7.2 (ii) 13.0 (iii) 12.7 (iv) 20 (v) 27.4 (vi) 48.2

H Scheme 9

The ring opening of cis-bicyclo[4.2.0]oct-7-ene to cis,cis-cycloocta-1,3-diene has been found to occur by a symmetry-allowed conrotatory ring opening followed by double bond isomerization, using an apparently highly accurate combination of DFT, CASSCF, coupled cluster and multi-reference Møller–Plesset calculations.63 DFT studies on Nazarov reactions in which one alkene forms part of a six-membered carbo- or oxa-cycle have demonstrated the role of the ring oxygen atom in stabilizing the cationic transition state. The reactions have been further found to occur preferentially via a twist-boat conformation of the developing five-membered ring, and the observed 2,5-trans selectivity has been explained by the torquoselectivity associated with the twist-boat shaped transition state.64 The aza-Nazarov cyclization of 1-azapenta-1,4-dien-3-ones has been studied both by G3 level calculations and experimentally. 1-Amino- and 1-alkoxy-substituted derivatives, including some with extended conjugation, have been shown to cyclize readily to 1-amino- or 1-alkoxy-3-

de

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hydroxypyrrole derivatives, and both theoretical and NMR studies have supported a cationic aza-Nazarov mechanism.65 The electron localization function has been used in a further attempt to distinguish pericyclic and pseudopericyclic reactions, the latter having been defined as having significant discontinuities in electron density around the cyclic transition state. These calculations have shown the pericyclic nature of butadiene ring closure, a Claisen rearrangement, and ring closure of hepta-1,3,5,6-tetraene, and the pseudopericyclic nature of the cycloaddition of acetylketene to acetone and of two electrocyclic processes. The controversial ring closures of hexa-2,4,5-trienal and its imine have by this analysis been found to be pseudopericyclic reactions.66 Diazo compounds (46) have been shown to react with α-thioxo ketones (45; X = O) and α-thioxothioamides (45; X = S, R2 = NMe2 ) to give unstable α-(thio)carbonyl thiocarbonyl ylids (47), which can cyclize by either four- or six-electron electrocyclization. 1,5-Dipolar (six-electron) electrocyclization has been found to be the major or exclusive pathway, giving either 1,3-oxathioles (48; X = O) or 1,3-dithioles (48; X = S). Except with diazo(diphenyl)methane (46; R3 = R4 = Ph), 1,3-dipolar (4-electron) electrocyclization has been shown to compete, giving alkenes (50) by sulfur extrusion from the initially formed thiiranes (49). When diazacyclohexane [46; R3 = R4 = (CH2 )5 ] was used, however, neither electrocyclization pathway was observed. Instead, the products have been found to be thioethers (51), arising from [1,4]-hydrogen migration in thiocarbonyl ylids (47).67 Significant torquoselectivity has been observed in the six-electron electrocyclization of 1-azatrienes prepared in situ from a chiral crotonaldehyde derivative and a βamino α,β-unsaturated carbonyl compound, and so having chiral centre(s) outside the pericyclic system at the C-terminus. Equilibration studies have suggested that although the cyclization may be reversible under the reaction conditions, the torquoselectivity is probably mainly kinetic in origin, and a transition-state model has been proposed to account for the observed selectivity, based on steric interactions between the nitrogen substituent and the groups at the chiral centre(s).68 Various α,β-unsaturated esters (52) have been shown to react with dimethyl diazomalonate in the presence of Cu(acac)2 to give a variety of γ -lactone derivatives by [1,5]-electrocyclization of the initially formed α,β-unsaturated carbonyl ylid (53). The immediate ring closure products (54) have been found to suffer a range of fates, including hydration, hydrolysis, and capture by a second equivalent of carbenoid, some of which are outlined in Scheme 10.69 Using DFT calculations and natural bond orbital analysis, it has been shown that in substituted oxazoles, a C(2)-amino substituent and a C(5)-alkoxy substituent interact independently with orthogonal orbital systems to reduce the energy barrier to ring opening of the oxazole to a carbonyl-substituted nitrile ylid. Thus the lone pair on a C(2)-amino group has been found to conjugate in the plane of the ring with C(2) and with lone pairs on the ring N and O atoms. By contrast, a C(5)-alkoxy substituent has been shown to donate its lone pair to the π system orthogonal to the opening ring. The two effects on the transition state and product energies have been found to be almost additive.70

de

439

13 Molecular Rearrangements: Part 1. Pericyclic Reactions X S

R2 R1 (45)

X N N

+ N2 R

R4

R2 S

R1

3

R4

R4

S

X

X

X (i)

+

S

R2 R1

R2

R1

X = O, S

−N2

(46)

R3

R3

(i) 6-electron electrocyclization (ii) 4-electron electrocyclization (iii) R4 = H; −S (iv) R3, R4 = (CH2)5; [1,4]-H migration

R3

−

(iv)

S

R2 R1

R4

(47)

(51)

(48) (ii)

X

X S

R2 R1 R3 (49)

R4

(iii)

R2

R3 R1 (50)

DFT studies have highlighted the rôle which can be played by a molecular container in the eight-electron electrocyclic ring expansion of bicyclo[4.1.0]heptatriene to cyclohepta-1,2,4,6-tetraene.71 Azomethine ylids (56) generated from isoquinolinium salts (55) bearing a diphenylvinyl substituent in the 2-position have been shown to form tetrahydro[5,6]azepino[2,1-a]isoquinolines (57) by a [1,7]-electrocyclization, followed by either a [1,5]-prototropic shift, or proton migration under the prevailing basic conditions. The sequence has been found to give good yields in general, but has been shown to be blocked if the side-chain is unable to adopt a suitable conformation, as for example with a naphthalene side-chain.72 2-Bromo-3-(o-styryl)cyclopentenone (58) and various derivatives and analogues have been shown to react with base in trifluoroethanol to produce tricyclic products (60) by electrocyclization of antiaromatic cyclopentadienone intermediates (59) as shown. The loss of antiaromaticity as the transition state develops has been confirmed by DFT calculations, which have also suggested that the regioisomeric ring closure on to C(2) of the enone, which has not been observed, would be associated with an increase in antiaromaticity going into the transition state.73

(52)

R1

OEt

R1

MeO2C

R2

OEt

O

O

O

MeO2C CO2Me

R2

O

(i)

(53)

R1

O+ OEt

R1

MeO2C

R2

HO

O

OMe

O

OEt

MeO2C CO2Me

R2

MeO2C

CO2Me

−

(54)

R1

O OEt

Scheme 10

MeO2C

R2 R CO2Me

1

O OEt

MeO2C CO2Me

R2

MeO2C CO2Me

O

(i) (MeO2C)2CN2, Cu(acac)2, C6H6, reflux

R1

O

MeO2C

R2

R CO2Me

1

O O

MeO2C CO2Me

R2

MeO2C CO2Me


441


MeO

MeO +

N

MeO Br−

R

+

N

MeO

(i)

R −

Ph Ph

Ph

(55)

(56)

(i) Et3N, MeOH MeO MeO

N

R H

H

Ph (57)

O

O−

O

O

Br (i)

H

H +

O F3C (58)

(59)

(i) Et3N, F3CCH2OH, heat

(60)

Ene Reactions Ene-allenes (61) having a two-carbon bridge have been found to be good substrates under relatively mild conditions for ene reactions giving dienes (62), albeit with 2 + 2-cycloadducts (63) formed as minor byproducts in most cases.74 Treatment of 2,5bis(methoxycarbonyl)-3,4-diphenylcyclopentadienone (64) with non-hindered propargylic alcohols has been shown to give, primarily or exclusively, bicyclic cyclopenta[b] furan-4-one derivatives (65), formally the products of 1,4-nucleophilic attack followed by ene reaction. As steric hindrance increases, Diels–Alder cycloaddition has been found to compete with this sequence, either directly or following 1,4-nucleophilic attack, giving products (66) and/or (67), respectively. Product (65a) has been shown, by X-ray crystallography, to have an (E)-exo-methylene bond, and a hydrogen bond between the second alcohol and the enone, as shown. This has led to the proposal that

442

Organic Reaction Mechanisms 2006 EtO2C CO2Et

EtO2C (i)

n

R

•

3

R4

+ R3 R4

R4 R1

(i) DMF, 120 °C, 24–108 h

(61)

R1

O

R

R1 (63)

HO

R2

O Z Z

Z

+

Ph

R2

Ph

Ph

R1

O

Ph

Ph

O

(65a)

(65)

(64)

R2

2

(62)

O

OH

CO2Et

H

Z Z

Z

Ph

n

R

R1

n

3

R2

EtO2C

CO2Et

Z = CO2Me throughout O

Z

Ph

O

Ph O

Ph

Z

Z R1

R2

O R2 R1

(66)

(67)

the formal ene rearrangement, at least in the presence of a second –OH group, occurs in a stepwise fashion, promoted by intramolecular hydrogen bonding.75

Tandem Pericyclic Rearrangements Formal 1,2-prenyl migration in suitably protected tryptamine and tryptophan derivatives bearing a prenyl substituent on the indole nitrogen has been studied experimentally and using DFT calculations. The rearrangement has been shown to proceed under Brønsted acid conditions, but better yields, and in the tryptophan derivative better ees, have been obtained using a large excess of Lewis acid. DFT calculations have suggested that the migration involves charge separation to an allyl-like partial carbocation, which is stabilized by π -stacking over the indole ring. This has been found to favour sequential [3,3]-sigmatropic migration to C(3a) of the indole, [3,3]sigmatropic migration to C(2) of the indole, and finally a [1,5]-hydrogen shift from C(2) to the indole nitrogen.76 Suitably substituted propargyl vinyl ether derivatives (68) have been shown to transform into 2,4,6-trisubstituted 5-ethoxycarbonyl 2H pyrans (70) on sequential treatment with AgSbF6 and DBU. The reaction has been

443


R1

R1 CO2Et

O

(i)

CO2Et

O

R (68)

CO2Et

O •

R2

R1

R3

R2

3

R3 (69)

R2

R1 (i) 1. AsSbF6 (5 mol%), 2. DBU (5 mol%)

CO2Et

O R2

R3 (70)

Scheme 11

proposed to occur by a silver-catalysed propargyl Claisen rearrangement, followed by base-catalysed allylic transposition, and finally six-electron electrocyclization, as shown in Scheme 11. This mechanism has been supported by the isolation in two cases of the conjugated dienone (69).77 Alkynyl propargyl sulfides have been shown to rearrange on heating by a [3,3]sigmatropic rearrangement–four-electron electrocyclic ring closure sequence. When both alkynes bear terminal substituents, the product 4-methylenecyclobutenethiones have been found to be isolable in moderate to good yields, and it has been shown that an intermediate allenylthioketene can be trapped using diethylamine. Absence of a terminal substituent on the propargyl group has been found to destabilize the 4-methylenecyclobutenethione, but in one case has allowed isolation instead of the allenylthioketene.78 It has been shown that 2-(4 -aryloxybut-2 -ynylthio)-1-acetylindoles rearrange to 9-acetyl-4-(4 -aryloxymethyl)-2,9-dihydrothiopyrano[2,3-b]indoles on refluxing in chlorobenzene. On stronger heating, or under Lewis acid catalysis, these products have been shown to rearrange to substituted 7-acetyl-11c-methyl-4b,5, 7,11c-tetrahydro[1]benzofuro[2 3 :4,5]thiopyrano[2,3-b]indole derivatives. The first rearrangement has been accounted for by sequential [3,3]-sigmatropic thio-Claisen rearrangement in the (but-2-ynylthio)indole moiety, thioenol tautomerization, [1,5]hydrogen shift, and six-electron electrocyclization, and the second by [3,3]-sigmatropic Claisen rearrangement of the (alk-2-ynyloxy)arene fragment followed by keto–enol tautomerization and 5-exo-trig cyclization.79 It has further been shown that 2-(4 aryloxybut-2 -ynylthio)-1-methylindoles, on mild oxidation followed by gentle heating, rearrange to 2-aryloxymethyl-3-hydroxymethyl-8-methylthieno[2,3-b]indole derivatives. This rearrangement has been attributed to the following reaction sequence: [2,3]-sigmatropic rearrangement of the corresponding sulfoxide; [3,3]-sigmatropic rearrangement of the resulting allenyl intermediate; thioenol tautomerization with

(73)

H

H

(71)

OH

OH

H

O

O

(v)

(i)

SPh H

H

(72)

H

OSPh

O

(iv)

(ii)

O

PhS

SPh

PhS

O

Scheme 12

SPh SPh O O (i) PhSCl, Et3N, THF (ii) double [2,3]-sigmatropic rearrangement (iii) 6-electron electrocyclization (iv) 4+2 cycloaddition (v) Raney-Ni, THF, reflux

O

PhSO

O

O

•

(iii)

•

O

O


445


5-exo-trig attack of sulfur on the carbonyl carbon thus formed; and finally SN 2 conversion of the resulting monothiohemiacetal into an allylic alcohol. Isolation, in two cases, of the last-mentioned intermediate in this sequence has supported this proposed mechanism.80 A tandem sequence of double [2,3]-sigmatropic rearrangement–six-electron electrocyclization–4 + 2-cycloaddition has been shown to convert acyclic ene-bis(propargyl alcohols) such as (71), via the corresponding bis-sulfenic ethers such as (72), into anthracene (with an intermolecular final cycloaddition) or phenanthrene or related (with an intramolecular cycloaddition) skeletons. The sequence is illustrated in Scheme 12 for synthesis of a steroid skeleton, estra-1,3,5(10)-trien-17-one (73).81 Heating (thio)acetal N -arylketenimines (74a,b) or acetal-bearing N -arylcarbodiimides (74c) has been found to produce spiro[1,3-dioxolane-2,4 (3 H )-quinolines] (76a), or the corresponding spirodithiolane (76b) or quinazoline (76c) derivatives, respectively. The proposed mechanistic sequence involves a [1,5]-hydrogen shift to the central carbon of the cumulene system giving (75), followed by six-electron electrocyclization to the new heterocycle, as shown in Scheme 13. This mechanism has been supported by DFT calculations, which have suggested that the [1,5]-hydrogen shift is rate limiting. The sequence has been found to proceed most readily for the acetal ketenimines, and least readily for the carbodiimides, so that thioacetal-bearing carbodiimides (74; X = S, Y = NAr) have been shown to be unreactive. The (thio)acetal group has been shown to be required for the reaction to proceed, and it has been suggested that hyperconjugative interactions between the O or S lone pairs and the C–H σ ∗ orbital weaken the C–H bond and allow the hydride shift to occur.82

R

X

1

H N R

2

X

X

C

(i)

R

1

(ii)

X

Y

X

R1

X Y

Y N R

(74)

N

2

H

(75) a; X = O, Y = CPhR3 b; X = S, Y = CPhR3 c; X = O, Y = NAr

R

H

2

(76) (i) [1,5]-hydrogen shift (ii) 6-electron electrocyclization

Scheme 13

Derivatives of 3-allyl-4-(dialkylallenyl)furan-2(5H )-one (77) have been shown to rearrange on heating to give fused bicyclic cyclooctatriene derivatives (78) in moderate to excellent yields. Although the products are formally those of an ene reaction between allyl and allene groups, two alternative mechanisms have been proposed: either direct [1,5]-hydrogen shift followed by eight-electron electrocyclization, or initial 2 + 2-cycloaddition followed by [1,5]-hydrogen shift and six-electron electrocyclic ring opening, as shown in Scheme 14. The last pathway has been supported not only by the known tendency of allenes to undergo 2 + 2-cycloaddition, but

R1

O

EtN

R2

O O

O

(79)

O

(77)

H

•

Me H

H

R4

R3

(ii)

(i)

R1

R2

R2

O

O

R1

O

O

R4

R3

R4

R3

O

R1 R2

R2

O O

R1

Scheme 14

(iv)

(ii)

O

(78)

(iii)

R4

R3

(i) 2+2 cycloaddition (ii) [1,5]-hydrogen shift (iii) 6-electron electrocyclic rearrangement (iv) 8-electron electrocyclization

R4

R3


(80)

N

R1R2N

RRN

1 2

S

N

(83)

R3

R4

R

3

R4

CO2Me

CO2Me

CO2Me

+

CO2Me

N

S

R3

R3

R4

(81)

N

Scheme 15

R1R2N

RRN

1 2

S

R4

CO2Me

CO2Me

CO2Me

CO2Me

RRN

1 2

RRN

1 2

+

R3

R4

R3

−

(82)

N

S

N

S

R4

CO2Me

CO2Me

CO2Me

CO2Me


447

448


also by the Diels–Alder trapping of intermediate (79) in the related conversion of 3-(dimethylallenyl)-2-(methallyl)cyclohex-2-enone into 4,4,6-trimethylbicyclo[6.4.0] dodeca-1(8),2,6-trien-9-one.83 Benzocyclobutenone and derivatives have been shown to react with diazomethylene anions to give 2,3-benzodiazepines under very mild conditions. A mechanism has been proposed which involves four-electron electrocyclic ring opening of the initial alkoxide, with important acceleration by the alkoxide anion. Torquoselectivity to set up an eight-electron electrocyclic ring closure to the benzodiazepine enolate has been attributed to the strong preference of the alkoxide anion for outward rotation. This mechanism has been supported by isolation of one of the β-diazo alcohols, and its conversion to a benzodiazepine on LDA treatment.84 Various 2-aminothiazoles (80) have been found to react with dimethyl acetylenedicarboxylate to produce dimethyl 2-amino-4,5-pyridinedicarboxylates (83). A mechanism has been proposed and supported experimentally and computationally, and is shown in Scheme 15. Polar stepwise 2 + 2-cycloaddition has been suggested to generate bicycle (81), which has been isolated in one case. Although symmetry-allowed four-electron electrocyclic ring opening of (81) would be conrotatory and lead to a trans-alkene, it has been suggested that a symmetry-allowed disrotatory six-electron, five-atom, dipolar electrocyclic ring opening of the thiazole portion could lead to the all-cis-thiazepine (82). This proposal has experimental support from two sources. Electron-deficient substituents at C(4) have been observed to retard the overall reaction, perhaps by destabilizing the positive charge developing next to the N atom in the polar ring opening. Also, bicycle (81) has been shown to transform into the corresponding pyridine (83) on heating, but not in the presence of acid, suggesting the importance of a free exocyclic amine. Six-electron eletrocyclization of thiazepine (82), followed by sulfur extrusion, has been proposed for the generation of the observed pyridine products (83).85

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450 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85


Cavalli, A., Masetti, M., Recanatini, M., Prandi, C., Guarna, A., and Occhiato, E. G., Chem. Eur. J., 12, 2836 (2006). Dieker, J., Fröhlich, R., and Würthwein, E.-U., Eur. J. Org. Chem., 5339 (2006). Matito, E. , Poater, J., Duran, M., and Solà, M., ChemPhysChem, 7, 111 (2006). Egli, D. H., Linden, A., and Heimgartner, H., Helv. Chim. Acta, 89, 1910 (2006). Sydorenko, N., Hsung, R. P., and Vera, E. L., Org. Lett., 8, 2611 (2006). Anaç, O., Güngör, F. S¸., and Merey, G., Helv. Chim. Acta, 89, 1231 (2006). Fukushima, K. and Iwahashi, H., Chem. Lett., 35, 1242 (2006). Yang, Z. Y., Wang, X. L., Wang, J., Zhang, J. C., and Cao, W. L., Chem. Abs., 144, 467717 (2006). Tóth, J., Dancsó, A., Blaskó, G., T˝oke, L., Groundwater, P. W., and Nyerges, M., Tetrahedron, 62, 5725 (2006). Harmata, M., Zheng, P., Schreiner, P. R., and Navarro-Vázquez, A., Angew. Chem. Int. Ed., 45, 1966 (2006). Närhi, K., Franzén, J., and Bäckvall, J.-E., J. Org. Chem., 71, 2914 (2006). Yamaguchi, K., Utsumi, K., Yoshitake, Y., and Harano, K., Tetrahedron Lett., 47, 4235 (2006). Cardoso, A. S. P., Marques, M. M. B., Srinivasan, N., Prabhakar, S., Lobo, A. M., and Rzepa, H. S., Org. Biomol. Chem., 4, 3966 (2006). Menz, H. and Kirsch, S. F., Org. Lett., 8, 4795 (2006). Aoyagi, S., Sugimura, K., Kanno, N., Watanabe, D., Shimada, K., and Takikawa, Y., Chem. Lett., 35, 992 (2006). Majumdar, K. C. and Alam, S., J. Chem. Res., 281 (2006). Majumdar, K. C. and Alam, S., J. Chem. Res., 289 (2006). Kitagaki, S., Ohdachi, K., Katoh, K., and Mukai, C., Org. Lett., 8, 95 (2006). ´ Org. Lett., 8, 5645 (2006). Alajar´ın, M., Bonillo, B., Ort´ın, M.-M., Sánchez-Andrada, P., and Vidal, A., Ma, S. and Gu, Z., J. Am. Chem. Soc., 128, 4942 (2006). Matsuya, Y., Ohsawa, N., and Nemoto, H., J. Am. Chem. Soc., 128, 13072 (2006). Alajar´ın, M., Cabrera, J., Pastor, A., Sánchez-Andrada, P., and Bautista, D., J. Org. Chem., 71, 5328 (2006).

CHAPTER 14

Molecular Rearrangements: Part 2. Other Reactions

A. Brandi1 and M. Gensini2 1

Department of Organic Chemistry ‘Ugo Schiff’, University of Florence, Italy of Chemistry, Menarini Ricerche SpA, Florence, Italy

2 Department

Aromatic Rearrangements . . . . . . . . . . . . . . . . . . . . Benzene Derivatives . . . . . . . . . . . . . . . . . . . . Ionic Rearrangements . . . . . . . . . . . . . . . . . . . . . . Anionic Rearrangements . . . . . . . . . . . . . . . . . . Cationic Rearrangements . . . . . . . . . . . . . . . . . . Rearrangements Involving Electron-deficient Heteroatoms Rearrangement Involving Organometallic Compounds . . . . Rearrangements Involving Ring Opening . . . . . . . . . . . Isomerizations . . . . . . . . . . . . . . . . . . . . . . . . . . Tautomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . Radical Rearrangements . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

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

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

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

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

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

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

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

451 451 453 453 461 470 477 488 494 502 503 508

Aromatic Rearrangements Benzene Derivatives The formation of α-phenyl-β-halovinyl cation, β-phenyl-α-halovinyl cation, and also the halogen-bridged and the spirocyclic phenyl-bridged cations, as intermediates of protonation of phenylethynyl halides, or of halogen addition to phenylethynes, has been evaluated by DFT at the B3LYP/6–31+G(d) level and, for comparison in representative cases, by B3LYP/6-311++G(d,p).1 Structural and mechanistic studies of the lithium diisopropylamide (LDA)-mediated anionic Fries rearrangements of aryl carbamates have been described.2 Substituents at the meta position of the arene (H, OMe, F) and the dialkylamino moiety of the carbamate (Me2 N, Et2 N, and i-Pr2 N) markedly influence the relative rates of ortholithiation and subsequent Fries rearrangement. The mechanism of the Fries rearrangement of aryl formates promoted by boron trichloride has been studied by means of 1 H, 2 H, and 11 B NMR spectroscopy and DFT calculations.3 After the formation of a 1:1 substrate – Lewis acid adduct, the rearrangement proceeds in two steps, beginning with the cleavage of the ester bond and the release of formyl chloride in situ, which, in turn, acts as a formylating agent, introducing Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd


451

452


O

R1 R2

n

R3 Br

‡

R2

R1

+

Hg(OTf)2 THF, 0 °C

R

3

n

n = 0, 1, 2 (1)

H

O H

O

R1 n

R3

R2

Scheme 1

an aldehydic functionality into the aromatic ring. A synthetically useful Wagner– Meerwein rearrangement of α-quaternary β-bromovinyl methyl ethers (1) promoted by Hg(OTf)2 has been developed (Scheme 1).4 It is noteworthy that the E- and Z-isomer ratios of the double bonds in substrates have little effect on the stereochemistry of the product double bonds. This rearrangement afforded not only an excellent method to place an aryl group at the γ -position of α,β-unsaturated aldehydes, but also a convenient synthetic approach to some natural skeletons with a tricyclic aromatic system. 1,3-Diphenylisobenzofuran Diels–Alder cycloadducts, with n-butyl- and phenyl-substituted acetylenic sulfones, underwent various types of rearrangements under pyrolytic, acid-catalysed, and photochemical conditions.5 Dibenzoylketene has been reported to undergo degenerate 1,3-shifts of the phenyl group between acyl and ketene carbon atoms in the gas phase under vacuum thermolysis (FVT) conditions, but not in solution at 110–145 ◦ C.6 Imidoyl(benzoyl)ketene undergoes a degenerate 1,3-shift of the phenyl group on FVT. Calculations of the transition states for the transformations at the B3LYP/6–31G∗∗ level of theory are in agreement with the observed reaction preferences. A mechanistic study on the [1,2] Wittig rearrangement of α-lithiated allyl phenyl ethers (2) affording, after acidic hydrolysis, 1-phenylprop-2-en-1-ol (5) as the main product, has been reported (Scheme 2).7 Although the two competing intermediates, the hypothetical ketyl–aryl radical pair (4) and the oxaspirooctadienyllithium (3), are not the rate-determining transition states, they should lie at almost the same energetic level. The rearrangement is in accord with the intramolecular nucleophilic addition/elimination mechanism rather than with homolytic cleavage/recombination.

453

14 Molecular Rearrangements: Part 2. Other Reactions Li •

O

+

R

•

(4) R OLi Li

O Li

R

O

R (3)

(2)

HCl BusLi

O

OH R R (5) Scheme 2

Ionic Rearrangements Anionic Rearrangements A novel reaction of pyroglutamate (6) and an isocyanate promoted by NaH in THF leads to functionalized hydantoins (7) in good yields. The reaction involves the ring closure of intermediate (8) by a nucleophilic attack on the carbonyl of the ester function followed by expulsion of an alkoxide anion resulting in the formation of the bicyclic intermediate (9). The alkoxide anion in turn can open this bicyclic intermediate with formation of anions (10) and (11) leading to the final racemic hydantoins (7) (Scheme 3).8 Highly substituted hydantoins (13) can be obtained in similar yield and very mild conditions starting from pyroglutamates (12) (Scheme 3). The base-catalysed acyl transfer (Baker–Venkataraman reaction) of enantiopure 2acetyl-1-hydroxyanthraquinone esters of 2-methylbutanoic acid or of O-allyllactic acid produces the respective 1,3-diketones, precursors of anthra[1,2-b]pyran antibiotics, without any racemization.9 The acetylation of p-t-butyl[3.1.3.1]homooxacalixarene with acetyl chloride and CsF as a base takes place through an equilibrium with the occurrence of both intraand inter-molecular acyl transfers. Control of the reaction conditions allows the various acetyl derivatives to be obtained.10

ee

454

Organic Reaction Mechanisms 2006 R1O2C

O

R2NCX

OR1 N H

NaH

HN

O (6)

R1O2C

R1O2C

OR1 N X

N

O

2

R

(8)

−

H

N R2

N

O

−

N R2

X (7) 42–89%

O O

OR1

N

N R2

EtO2C

NaH

N R2

X (11) R1 O

R2NCO

OEt

HN

X (10)

R1

N H

O−

O

−

X

(9)

O

R1 = Me, Et, Bn R2 = Ph, Bn, 2-Cl-Et, allyl X = O, S

O

HN

N R2

O O (13) 45–70%

(12)

R1 = H, Me, Cl R2 = Pr, Ph, Bn

Scheme 3

Base-catalysed benzil–benzilic acid rearrangement and the methyl analogue were investigated by DFT calculations. The reaction paths of the rearrangement were investigated in term of FMO theory, in particular the carbanion [1,2]-migration that was calculated to be the rate-determining step.11 The double α-ketol rearrangement of (1S, 2R,4R)-2-acetyl-1-vinyl-2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptane in the NaH– THF is reported.12 Adducts of potassium enolate of (E/Z)-4-phenylbut-3-en-2-one with 6-aryl-3,4-disubstituted-2H -pyran-2-ones rearrange affording highly functionalized (E)-stilbenes and 4-aryl-6-styrylpyran-2-ylidineacetonitriles by two different reaction paths.13 N -Carbamoyldiarylamines (14) have been shown to undergo a new anionic ortho N Fries rearrangement to anthranilamides with good to excellent regioselectivity and in synthetically useful yields (Scheme 4).14 The t-butyllithium or LDA-mediated direct ortho-metallation strategy applied to substituted N -carbamoyldiarylamines (14a–c)

ee

OMe Et2N

N

O

Et2N

O

OPri

(14)

N

OPri

R

90%

2. NaH, DMF, MeI

1. LiTMP, 0 °C, THF

B = LDA–THF 0 °C r.t.

OMe

N Me

O

OPri

Scheme 4

Et2N

OPri

81% 90% 92% 94% 87% 97% 59% 6% 54% 4% 75% 7% 73% 47%

(15)

Et2N

N H

A: B: b: R = 3-Cl A: B: c: R = 4-Cl A: B: d: R = 3-OMe A: B: e: R = 4-OMe A: B: f: R = 3,5-OMe A: B: g: R = 2-Ph A: B:

a: R = H

A = t-BuLi–TMEDA–Et2O −78 °C r.t.

A or B

+

26% 90% 35% 90% 14% 90% 19% 51%

Et2N

90%

Tf2O, CH2Cl2 0 °C r.t.

O

R

(16)

OMe

O

N H

(17)

N Me

O

OPri

R

OPri

14 Molecular Rearrangements: Part 2. Other Reactions

455

456


leads regioselectively to anthranilamides (15a–c), whereas (14d–g) give both (15d–g) and (16d–g) with varied regioselectivity accordingly to the base used. The strategy can be applied efficiently to the synthesis of acridone (17), an intermediate for the synthesis of acridone and pyranoacridone alkaloids. Lithiation of aryltriazenes followed by treatment with an electrophile provides a new approach to benzylamines. The regioselectivity of the reaction can be controlled by means of the substituents on the aryl group. The reaction consists of an intramolecular carbon–carbon bond formation with the aryl ring of a lithiated alkyl group on a 3nitrogen atom, a 1,2-proton shift, demonstrated by deuterium substitution, and the subsequent release of nitrogen gas.15 New P -stereogenic (o-hydroxyaryl)diazaphospholidines, in the form of their borane complexes (19), have been synthesized in a totally diastereoselective manner by a P–O to P–C migration rearrangement of (o-bromoaryloxy)diazaphospholidine–borane complexes (18) mediated by t-BuLi (Scheme 5).16 The stereoselective rearrangement, confirmed by X-ray diffraction study of the structures of the product (21) and its precursor (20), occurs with clean retention of the phosphorus configuration. A review on anionotropic 1,2-rearrangements of borate complexes evidences the most important factors that are responsible for which group migrates, by showing a broad spectrum of reactions involving borate complexes.17

R

BH3

Br BH3 P O

N N

1. t-BuLi 2. H2O

Ph R = H, Me, Ph, Cl, F, t-Bu, OMe

(18)

P

R

N N

OH Ph (19) 70–86% BH3

Br BH3 P O

1. t-BuLi

N

P

2. H2O

N

N OH

Ph (20)

N

Ph

(21) 40% Scheme 5

The rate constants, thermodynamic parameters of activation, equilibrium constant, and the isomerization enthalpy for conversion of cholest-5-en-3-one to cholest-4-en-3one catalysed by EtONa in absolute ethanol were determined by classic and multivariate kinetic methodologies. The multivariate modelling kinetic treatment allowed the concentrations of the species involved to be calculated, revealed the 3,5-dienolate to be a highly reactive intermediate, and was able to discriminate among several applicable mechanisms, thereby supporting the one comprising two reversible steps.18

de

457


A desymmetrization of cyclohexa-2,5-dienes (22) and (24), obtained by Birch reductive alkylation, through a diastereoselective intramolecular hydroamination led with high selectivity to the corresponding bicyclic allylic amines (23) and (25) (Scheme 6).19 Ph R

Ph

R1

N H

N

n-BuLi 20 mol%

MeO

THF, 20 °C, 4 h

MeO

(22)

(23) R = Ph 95% >97:3 R = 3,5-(MeO)2Ph 46% >97:3 82% >97:3 R = CH2OBn

n-BuLi 20 mol%

Ph

Ph

THF, 20 °C, 4 h

N H

N

OR OR (25) R = Me 26% 90:10 R = MOM 73% 95:5

(24)

Ph R

R

N H

n-BuLi

Ph H N Li O

MeO

Me (22)

(26)

Ph N Li O Me (27) Scheme 6

R

R1

Ph N −

OMe

Li+ (28)

de

458


The mechanism does not proceed through a direct hydroamination of one of the diastereotopic alkenes, but involves a series of very selective processes including a deprotonation of (22), diastereoselective protonation of (26), intramolecular addition of lithium amide (27) to the 1,3-diene moiety, and final regioselective protonation of the allyl anion (28), all mediated by a substoichiometric amount of n-BuLi. The aza-Payne rearrangement of activated N -Ts-α,α-disubstituted-aziridinemethanols, induced by NaOH in the mixed solvent t-BuOH–H2 O–THF (4:5:1) or NaH in the mixed solvent THF–HMPA (10:1), and also some N -Boc-α,α-disubstitutedaziridinemethanols with the latter reagent–solvent combination, provides the corresponding epoxides in up to 99% yield.20 Treatment of 1,6:2,3-dianhydro- and 1,6:3,4-dianhydro-β-d-hexopyranoses with aqueous NaOH or NaI in acetone caused epoxide or pseudo-epoxide migration giving equilibrium mixtures. Experimental data were compared with DFT calculations and the role of chair–boat equilibration of 1,6-anhydro-3-deoxy-3-halo-β-d-glucopyranoses was analysed.21 The generation of a carbanion by a conjugate addition of the lithium enolates of 2-chloroacetates and 2-chloroacetamide to an enoate system, bearing an epoxysilane moiety at the vinylogous α-position (29), can induce epoxysilane rearrangement to afford highly functionalized cyclopropane derivatives (30) in good to excellent yields (Scheme 7).22 With acetamides the reaction is diastereoselective. The domino process involves Michael addition of the enolate followed by ring opening of the epoxide (31) to give intermediate (32). The exclusive formation of the internal (Z)-alkene in the reactions of both ester and amide enolates is warranted by the fast-reacting silicate intermediate (33) in an s-cis-diene conformation. Metal alkoxides, such as sodium benzylate, in catalytic amounts promote the [2,3]Wittig rearrangement of silyl enolates (34), to afford the corresponding rearrangement product (35) in good yields at room temperature (Scheme 8).23 It has been demonstrated that the oxygen anion of initially formed product (36) effectively catalysed the [2,3]-Wittig rearrangement as a Lewis base. Other Lewisbase catalysts such as lithio or sodio 2-pyrrolidone promote the same [2,3]-Wittig rearrangement of silyl enolates generated from α-allyloxy ketones, whereas rearrangements of enolates from α-allyloxy esters were efficiently catalysed by ammonium 4-methoxybenzoate.24 The [1,2]-Wittig rearrangement of several benzylic chloromethyl ethers by a 4,4 di-t-butylbiphenyl (DTBB)-catalysed chlorine–lithium exchange has been carried out for the first time. Homobenzylic alcohols were obtained efficiently in good yields apart from a few cases.25 A twofold [1,2]-Wittig rearrangement of bis-O-allyl-1,1 binaphthalene-2,2 -diol (BINOL) occurs at −75 ◦ C with the LIC–KOR mixture (butyllithium + potassium t-butoxide) in 72% yield and with an unprecedented diastereoselectivity.26 By X-ray crystallography, the axial chirality (M) was found to be associated with the S-configuration of the oxygen-bearing side-chain and the P -helicity with the R-configuration. Benzyloxyallylsilane, treated with s-BuLi, undergoes an unusually rapid and efficient [1,4]-Wittig rearrangement. Results of a study of trapping

de

de

459

14 Molecular Rearrangements: Part 2. Other Reactions CO2Et CO2Et O

2

ClCH(R )COR

1

COR1

KHDMS or LDA, THF, −80 to −70 °C

R2 OSiMe2But

ButMe2Si (29)

(30) 67–100%

R1 = OEt, NEt2 R2 = H, Me, n-Bu, Ph, Cl

O

OM OM Cl

(29)

Y

OEt

OEt

O

COY

O

COY Si −

ButMe2Si

Cl

Me2But

(31)

Cl (32)

OM OEt (30)

COY Cl

ButMe2SiO (33)

Scheme 7

the intermediate α-carbanion with TMSCl prior to rearrangement indicate that αdeprotonation and bond reorganization are separate events.27 Adducts (38) of 2-substituted cyclohexanones (37) with lithium α-sulfinyl carbanion of 1-chloroethyl p-tolyl sulfoxide treated with LDA or t-BuMgCl give lithium or magnesium alkoxides, which on treatment with t-BuLi or i-PrMgCl afford onecarbon ring-expanded 2,7-disubstituted cycloheptanones (39) through β-oxido carbenoids (Scheme 9).28 Interestingly, 2,3-disubstituted cycloheptanones were obtained in trace amounts or were not obtained at all. The enolate intermediates of this reaction are able to be trapped with electrophiles to give 2,2,7-trisubstituted cycloheptanones in moderate to good yields. Treatment of 1-chloro-2-methylalkenyl p-tolyl sulfoxides with N -lithio-2-piperidone in THF at room temperature resulted in the formation of 1-chloro-2-(hydroxymethyl)alkenyl p-tolyl sulfides in good yields. The reaction is the first example of the Mislow–Braverman–Evans rearrangement retaining the sulfur atom on the original carbon.29

(34)

R

R

DMF

(36)

O

OM

(34)

O

OSiMe3

R DMF

Scheme 8

O

O

Si

O O

Na+

−

R = H, OMe, CN

2. H+

1. M-OBn cat. DMF, r.t., 1 h R

OH

(34)

R

(35) 76–98%

O

(35)

O OH


461

14 Molecular Rearrangements: Part 2. Other Reactions Me O R

Me TolS(O)

(O)STol Cl

HO

R

CClLi

X X (37)

X X (38)

1. LDA or t-BuMgCl 2. t-BuLi or i-PrMgCl THF, 30 min, −70 or 0 °C 3. H+

R = Me, c-Hex, Ph X = H, OCH2CH2O

O R

Me

X

X

(39) 62–87%

Scheme 9

The reaction of 2-(diphenylmethylene)thietan-3-one with 1,2,4,5-tetrazines in KOH– MeOH–THF gives 4H -pyrazolo[5,1-c]thiazines. This novel condensation reaction proceeds via the intermediacy of an 8-(diphenylmethylene)-2H -1,4,5-thiadiazocin7(8H )-one, which undergoes a multi-step rearrangement including a rare anti-Michael addition.30

Cationic Rearrangements Superacid-promoted dicationic species containing heteroaromatic rings, where positive charge centres migrate through consecutive deprotonation–reprotonation steps, undergo cyclization reactions followed by aromatization and superacid-promoted elimination of benzene (Scheme 10).31 The process leads to the synthesis of aza-polycyclic aromatic compounds in moderate to good yields. Seven examples include pirazole, oxazole, and thiazole heterocycles. The unique electrocatalytic role of benzoic acid-protected silver nanoclusters in the Wolff rearrangement of α-diazo ketones has been disclosed. The presence of a Agn 0 /Agn + redox couple facilitates a non-classical electron-transfer process, involving chemical reactions interposed between two electron-transfer steps occurring in opposite directions.32 A new rearrangement of fused tetracyclic heterocycles, obtained by criss-cross intramolecular cycloadditions of homoallenylazines (40), mediated by HCl in MeOH, leads to high yields of cage compounds (42) after reduction with NaBH3 CN (Scheme 11).33 The decarboxymethylation of substituted α-hydroxy-α-carbomethoxy hexacyclic substituted ketones (43), one of these used as an advanced intermediate in the synthesis of the alkaloid aspidophytine, can be effected by heating with MgI2 in CH3 CN in good yields (75–84%) (Scheme 12).34 The reaction was shown to proceed through a novel α-hydroxy β-dicarbonyl to α-ketol ester rearrangement mechanism, which is supported by the isolation of the carbonate (45) intermediate. The BF3 -promoted rearrangement of several 4,5-epoxy-9-trimethylsilyldecalines having different relative stereochemistry and substitution at the oxirane ring is described. The presence of the silicon at C(9) favours two different main reaction pathways

462

Organic Reaction Mechanisms 2006 OH

Ph CF3SO3H

N

−C6H6 −H2O

Ph

N 63% Me

Ph

OH

Ph

CF3SO3H −C6H6 −H2O

Me N

N 93%

Ph +

−C6H6 −H2O

7 examples 41–93% yield

CF3SO3H

Ph

Ph

Me

+

Ph Me +

Me N+

N+

H

H

H N

Scheme 10

C

N N

C

145 °C

N

R

(40)

R

N

(41) 1. HCl, MeOH

2. NaBH3CN

R

R = Ph 86% R = Bn 77% R = morpholinomethyl 82%

Scheme 11

R

NH N H (42)

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14 Molecular Rearrangements: Part 2. Other Reactions O

O N

MeO

N H Me OMe

N

O

O

O OH CO2Me

MeO

N H Me OH OMe

(43)

O

O

O

(46)

I Mg

O

O

OMgI O

O

O OMe

OMe

(44)

(45) Scheme 12

involving bridgehead-methyl or C(1)-methylene migration through the stabilization of a carbocation intermediate. The synthetic utility of these rearrangements is shown by the synthesis of natural (−)-aristolochene.35 The acid-catalysed conversion of isotwistanol skeleton to the tricyclo[5.2.1.04,8 ]decane skeleton has provided support for the proposed biosynthesis of allopupukeananes from pupukeananes.36 The isomerization of trans-3-deutero-r-1-methyl-cis-2-phenylcyclopropan-1-ol to three isomeric cyclopropanols was facilitated by reaction with a mixture of Ti(O-i-Pr)4 and BF3 .OEt2 . The more Lewis acidic Cl2 Ti(O-i-Pr)2 is able to catalyse the same reaction in the absence of BF3 .OEt2 . A reversible ring opening to a β-titanaketone is involved in this rearrangement. The mechanism proposed is able to explain both retention and inversion of configuration at the carbon bearing phenyl for these isomerization processes that involve ring opening and ring closure.37 A microporous metal–organic framework [Cu3 (btc)2 ] (BTC = benzene-1,3,5-tricarboxylate) is a highly selective Lewis acid catalyst for the isomerization of terpene derivatives, such as the rearrangement of α-pinene oxide to campholenic aldehyde and the cyclization of citronellal to isopulegol. By using the ethylene ketal of 2-bromopropiophenone as a test substrate, it was demonstrated that the active sites in [Cu3 (btc)2 ] are hard Lewis acids.38 The protonation and acid-catalysed rearrangements of a tricyclo[4.2.2.22,5 ]dodeca3,7,9,11-tetraene scaffold were studied.39 The fragmentations of 3-nortricyclyl, exo5-norbornen-2-yl, and endo-5-norbornen-2-yl oxychlorocarbenes, chlorocarbonates, and chlorosulfites in polar solvents proceed via similar ion pairs to mixtures of exo-2-chloro-5-norbornene and 3-nortricyclyl chloride. The stereochemical course of

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the conversions is mainly determined by least motion chloride return in ion-pair intermediates.40 A theoretical investigation of the isomerization pathways from the norbornadiene to the cycloheptatriene radical cation has been carried out.41 In the synthesis of (+)-anatoxin-a from S-(−)-pyroglutamic acid, an unexpected inversion of chirality, leading to (−)-N -Ts-anatoxin-a (48), was found to be the result of a skeletal rearrangement of 9-azabicyclo[4.2.1]nonene derivative (47) at the stage of the oxymercuration of diene (Scheme 13).42 NTs

NTs

ee

NTs

Hg(OAc)2 +

+

O AcOHg

H H

AcOHg

(47) NTs

NTs

NTs

O

1. NaBH4 2. Dess–Martin

OH

O (−)-N-Ts-anatoxin-α

AcOHg

(48) Scheme 13

Treatment of 1-indanols and 1-tetralols with hydrogen peroxide under acidic conditions caused substitution and hydroperoxide rearrangement to yield chroman-2-yl hydroperoxides or open-chain unsaturated geminal bis-hydroperoxides.43 2-(Arylmethylene)cyclopropylcarbinols in acetonitrile give the corresponding ring-enlarged N -(3arylmethylidenecyclobutyl)acetamides in good yields under the catalysis of trifluoromethansulfonic acid.44 Ionic liquid 1-methylpentylimidazolium bromide ([pmim]Br), catalyses, under sonication without solvent, the rearrangement of cyclopropylcarbinol derivatives to substituted all-trans-buta-1,3-dienes.45 N -Acetylated 2,4,5-triphenylimidazolinium salts give an unprecedented acid-catalysed rearrangement leading to the N -benzoylated 2-methyl-4,5-diphenylimidazolinium salts.46 Several tetrasubstituted cyclopentanes (51) can be prepared in four steps from cyclopentadiene in good overall yield (30%) by the acid-catalysed rearrangement of epoxide (49) followed by a regio- and stereo-selective nucleophilic attack, with control of the relative configuration of four contigous stereogenic centres in a single operation (Scheme 14).47 Participation of the nitrogen lone pair is likely to stabilize the cation intermediate (50). The Lewis acid-promoted rearrangement of 2,2,3,3-tetrasubstituted 2,3-epoxyalcohol derivatives, which have only a slight difference in stability of carbocation at the C(2) or C(3) positions, proceeds through the C(3) carbocation. With

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14 Molecular Rearrangements: Part 2. Other Reactions HO

N

CO2Bn N CO2Bn

O N

CO2Bn N CO2Bn

H+ NuH

Nu +

(49)

N

CO2Bn N CO2Bn

(49–68%) H2, PtO2 AcOH

OH HO +

N

Nu−

CO2Bn N CO2Bn

H2N

NH2

Nu (51)

(50)

Nu = Cl, Br, OH, MeO, R

Scheme 14

SnCl4 as the LA, control of stereochemistry of the rearranged products is obtained only by changing the type of the protecting group.48 The semi-pinacol rearrangement of alkenyl-substituted 2,3-epoxycyclopentanols gives stereoselectively α-alkenylated cyclopentanones.49 Epoxides undergo an efficient and selective rearrangement to give carbonyl compounds (Meinwald rearrangement) in excellent yields by the catalysis of copper tetrafluoborate [Cu(BF4 )2 .nH2 O].50 An efficient one-pot domino procedure for allylation and propargylation of aryl epoxides has been developed by using SnCl2 to promote the epoxide rearrangement and Pd(0) or Pd(II) to catalyse the allylation or propargylation, respectively, with allyl or propargyl bromides.51 The adduct of cycloaddition of cyclohexadiene with 1,4-dihydronaphthalene-1,4-epoxide (52) by reaction with 1.1 equiv. of Br2 afforded two main products, (53) and (54), in which a 1,5-oxygen migration has occurred (Scheme 15).52 With excess of Br2 , further bromination products of the central ring were obtained. 3-N -Aryl-2-oxindoles (55) undergo Hofmann–Martius rearrangement under acidcatalysed conditions, in contrast to their 3-O analogues (Scheme 16).53 The thermal O

O Br2 1.1 equiv.

Br +

CCl4

(52)

HO Br

HO (53) 31%

Scheme 15

(54) 56%

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Organic Reaction Mechanisms 2006 NH2

Ph N H

O Ph

(56) 35% +

CF3CO2H (cat.)

PhHN

25 °C

Ph

N H

O

(55)

H2N

N H

O (57) 30%

NHMe Ph

O Ph

Me

(59) 55% or 30% + Ph

CF3CO2H (cat.) 25 °C or 80 °C, toluene

PhN O

N H (58)

N H

MeHN

O (60) 25% or 37%

N H

Scheme 16

(and acid-catalysed) rearrangement is possible only with N -methyl-substituted compound (58). Higher regioselectivity is obtained with substituted N -aryls. The dissociative mechanism of the process, evident from the formation of ortho- (56) and para-substituted (57) rearrangement products, was also confirmed by crossover experiments. An unusual transannular cyclization catalysed by TMSOTf occurs in a 14-membered marine cembranoid sarcophytoxide (61), together with an epoxide–ketone rearrangement (Scheme 17).54 The concomitant opening of the epoxide ring in (61) creates flexibility, thereby permitting intermolecular ring closure. It should be noted that the pinacol-type epoxide ring rearrangement gives in this case the β-methyl that is anomalous according to the attack of the hydride of the leaving C–O bond from the back side.

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O

O

O TMSOTf 0.5 equiv. benzene, r.t.

(61) −TMSOH

+

OTMS

O

OTMS

O H

Scheme 17

(−)-Modhephene (62)

(−)-Isocomene (64)

(63)

Scheme 18

The rearrangement of (−)-modhephene (62) to a (−)-triquinane (63) through acid catalysis has been demonstrated (Scheme 18).55 The rearrangement involved protonation, 1,2 s-bond and methyl shifts, and deprotonation. Monitoring by 1 H NMR suggested the (−)-isocomene (64) as an intermediate, further proved by transformation of natural (64) to (63).

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Organic Reaction Mechanisms 2006 O 6 M HCl reflux 24 h

N

N O Ph

Ph (65)

(66) 90% OH

(65)

OH H2O

H+ +N

OH + NH

Ph OH

O

O NH

Ph

OH

OH

(66)

N

NH

OH Ph

Ph

Ph

(67)

(68) Scheme 19

A selective high-yielding (90%) acid-catalysed ring contraction of 1-benzyl-2methyl-3-piperidone (65) to 1-benzyl-2-acetylpyrrolidine (66) occurs by refluxing in 6 m HCl for 24 h (Scheme 19).56 2-Dimethyl-substituted or 2-unsubstituted-3piperidone do not give the rearrangement under the same conditions. The process appears to be thermodynamically controlled. Kinetic studies and the synthesis of a competent intermediate suggest that the process evolves through a reverse Amadori rearrangement giving an open-chain intermediate (67) that closes to the five-membered pyrrolidine (68) at high temperature and to the piperidone (65) at room temperature. The mixture of products obtained by the reaction of 1-substituted 3-alkyl/aryl-3-amino1H ,3H -quinoline-2,4-diones with nitrourea rearranges in boiling acetic acid to give a mixture of ring-contracted indol-2-ones.57 The ring expansion of a tertiary cation into an unstable secondary cation, the so-called anti-Markovnikov rearrangement, has been studied as a mean to understand the nature, concerted or stepwise, of the correlated natural process of sterol biosynthesis.58 TiCl4 (2 equiv.) at −78 ◦ C is able to promote the rearrangement of cyclopentyldimethylmethanol (69) to the chlorocyclohexane (70) (eq. 1, Scheme 20), whereas BF3 .Et2 O gives only deprotonation products of the isomerized carbocation. Both diastereoisomers of bicyclic alcohol (72), expressly designed to study the stereochemical outcome of the rearrangement, give the same ring-enlarged product (73) under the same conditions (eq. 2, Scheme 20). Optically pure compound (74) gives, at room temperature, ring-enlarged diastereomeric products (75) and (76) in racemic form (eq. 3, Scheme 20).

469


OH

BF3·Et2O

TiCl4

CH2Cl2 0 °C

CH2Cl2 −78 °C

(71) 90% exo:endo 2:1

Cl

(69) H

(70) 71% H

OH

TiCl4 CH2Cl2 −78 °C

(2)

H

(73) TiCl4

OAc

(R)-(74)

Cl

H (72)

OH

(1)

Cl

CH2Cl2, r.t. 93%

OAc

+

Cl

(3)

OAc rac-(75) 7

rac-(76) :

3

Scheme 20

These results demonstrate that the products of the rearrangement do not reflect the stereochemistry of the starting materials, as would be expected in a concerted anti-Markovnikov rearrangement. Therefore, the processes studied occur via a totally cationic stepwise mechanism, suggesting the same mechanism for sterol biosynthesis. Energy profiles of cyclization energies for the cationic cyclization of oxidosqualene to lupeol, lanosterol, and hopen-3b-ol were calculated by DFT methods. The profiles indicated that rings A and B form more exergonically than rings C and D owing to a better arrangement of cation-stabilizing methyls in the early annulations.59 The authors warn that molecular modelling results revealed systematic errors in energy calculations from B3LYP and other quantum mechanical methods. This type of B3LYP error appears to affect many transformations involving the conversion of C=C or C=O bonds to two single bonds. This problem is manifest in the molecular modelling literature but has seldom been recognized. A quantum chemical study of solvent and substituent effects on the 1,5-hydride shift in 2,6-dimethyl-2-heptyl cations has been also carried out.60 A novel solvolysis reaction of a tetrahydropyranyl mesylate has been demonstrated.61 α-Phenylated 1,8-bis(dimethylamino)-2-naphthylmethyl carbocations have been shown to rearrange into 1,1,3-trimethyl-2,3-dihydropirimidinium cations through an intramolecular hydride shift from the 1-NMe2 group.62 The racemization of solvated product (79), obtained as a single diastereomer, suggests that the intermediate tetrahydropyranyl cation (78) is a common intermediate for consecutive Grob fragmentations and 2-oxonia-Cope and Prins cyclizations (Scheme 21).

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Organic Reaction Mechanisms 2006 OMs

O

Bn

(77) 91% ee TFA

OH +

1. CF3CO2−

O

Bn

2. K2CO3

O

(78)

Bn

rac-(79)

Grob fragmentations

Prins cyclization

2-oxonia-Cope +O

Bn

O+

(80)

Bn

(81) Scheme 21

The data collected are consistent with an asynchronous mechanism of the Grob fragmentation. The ring expansion of the spirocyclohexadienone system of quinolinone (82) can occur under both acidic and anionic conditions, leading to different tricyclic fused compounds (Scheme 22).63 Under acidic conditions, the more nucleophilic C-aromatic carbon of (84) migrates to form the benzoazepinone (85). Under basic conditions, the more acidic quinolinone protons drive the rearrangement to (83). Reaction of quinidine and epiquinidine and its acetates with HF–SbF5 affords gemdifluoro compounds also with quinuclidine ring rearrangement.64

Rearrangements Involving Electron-deficient Heteroatoms The Pummerer reaction can be oriented towards two different chemical pathways through the careful selection of the β-carbon substituent moieties. Highly stabilizing carbocation substituents, i.e. leading to carbocations of pKR+ values higher than 14.5, promote Pummerer fragmentation reactions (Cα –Cβ bond rupture), whereas the others giving pKR+ < 14.5 lead to the usual Pummerer rearrangement.65 A Pummerer-like rearrangement of heterocycles (87) containing selenium and sulfur leads to thio- or

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O

HO

PTSA–Toluene

t-BuOK–THF

N (83)

O

N

O

N

(82)

O

(86)

+ O H

HO

H +

N (84)

O

N

O

(85)

Scheme 22

seleno-sugars (90) involving linear ozonide acetates (88) as putative intermediates (Scheme 23).66 Trapping experiments with rubrene and electron paramagnetic resonance studies with the radical trap DMPO have been performed to probe whether the rearrangement proceeded heterolytically via extrusion of singlet oxygen or homolytically via the generation of radical species. A new transition state of the addition step in the Baeyer–Villiger rearrangement has been found.67 The role of proton acceptor is played by the carbonyl oxygen atom and the free energy barrier is 12.7 kcal mol−1 lower than that previously reported. Prins–pinacol reactions of cyclohexyl- and cyclopentyl-triisopropylsilyloxy ethers having (2Z)-(6,6-dimethoxyhexylidene) or (2Z)-(5,5-dimethoxypentylidene) side-chains, promoted by SnCl4 , has been employed to provide bicyclic products in which five-, six-, or seven-membered rings are joined by a C–C single bond.68 A very efficient process for the Curtius rearrangement that allows the direct conversion of aromatic carboxylic acids into carbamates and ureas has been developed.69 This process is based on the use of various commercially available chloroformates and sodium azide, which presumably generate the corresponding azidoformate. The formate serves to activate the carboxylic acids and as a source of nucleophilic alkoxide. A cavity-containing metal–ligand assembly has been used as a catalytic host for the 3-aza Cope rearrangement of allyl enammonium cations.70 Upon binding, the rates of rearrangements are

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X

X

R

Ac2O

OAc

O3

AcO

n

AcO

OAc

OAc

n

OAc

X = S, Se n = 0, 1

(87)

OAc

(90)

O O O O R

+

X

R

H

X

+

−OAc

AcO

n

AcO

OAc

n

OAc

OAc

OAc (88)

(89) Scheme 23

accelerated for all substrates studied up to 850-fold. Activation parameters were measured for three enammonium cations in order to understand the origins of acceleration. Those parameters reveal that the supramolecular structure is able to reduce both the entropic and enthalpic barriers for rearrangement and is highly sensitive to small structural changes of the substrate. The space-restrictive cavity preferentially binds closely packed, preorganized substrate conformations, which resemble the conformations of the transition states. Attached rings in which both rings are chiral can be prepared in this fashion with high stereoselectivity and moderate enantiospecificity. A facile synthesis of five membered antiviral azasugars (94), which involves an exo-imino to endo-iminocyclitol rearrangement, has been reported (Scheme 24).71 The mechanism of conversion of (91) to (94) shows that the key step is the intramolecular 5-exo-tet ring opening of the epoxide with inversion of configuration at C(4). The exo-imino to endo-iminocyclitol process works equally efficiently in the d- and l-hexose series, with the interesting consequence that a double inversion occurs at two carbon atoms, C(4) and C(5). The reaction of fluoroalkanesulfonyl azides (95) with cycloalkenyl ether and ynamine have been studied (Scheme 25).72 Ring-contracted N -fluoroalkanesulfonyl amidine analogues (97) were obtained when (95) was reacted with cycloalkenyl vinyl ethers at 0 ◦ C. Two novel ring-contracting rearrangements of 3-amino-4-(arylamino)1H -isochromen-1-ones (98) yielding 1-(arylamino)-3-oxo-1,3-dihydroisobenzofuran1-carboxamides (99) and 2-aryl-3-oxo-2,3-dihydro-1H -isoindole-1-carboxamides (100) have been described (Scheme 26).73

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H

OH

O

MsO

H NH3

R O

MsO

4

NH2

O

R

O

O

(91)

−MsOH

O

(92) H

O

H 4

N

O

N

HO

R

R

H

O

O

(93)

O

(94)

Scheme 24

OEt SO2Rf N N N

OEt RfSO2N3

+ n

(95)

n

OEt SO2Rf N− n

N2 +

(96) N −N2

SO2Rf OEt

n−1

(97)

Scheme 25

Two factors effect the second transformation in an appreciable yield, the I2 –Et3 N system and Cu2+ (CuBr2 and CuCl2 ) salts. Apparently, an oxidative step is required to effect the opening of the electron-rich diaminopyran-2-one ring. The driving force for both reactions is the formation of a primary amide from a cyclic O-acyl imidate. An efficient synthesis of 2-aryl-1-benzazocines via Beckmann rearrangement of 5H -benzocyclohepten-5-one oxime mesylates has been described using aryl Grignard reagents to induce the rearrangement directly without any additional protic agent.74 Iodotrimethylsilane has also been employed to promote Beckmann rearrangement of

474

Organic Reaction Mechanisms 2006 Ar

N

R

Ar

N

NH2

−

O O−

R Ar

NH2

O S+ O

O

(99)

S (98)

O

N

−Me2S

CONH2

O O

R

+

R

R NH NH2

−e−

NH

H

•

N+

O

H

O

O

O +Nu−

CONH2 •

R R

N

−NuH

NH •

CONH2 O

Nu O

+e− +H+

+e− +H+

R

CONH2 R N

NH −NuH

CONH2 Nu

O (100) Scheme 26

O

475


the mesylates, followed by the treatment of the intermediate imidoyl iodide with phenylmagnesium bromide to complete the synthesis of benzazocines. The first generation of organophosphinic chloride systems, commercially available BOP–Cl or BOP-Cl–ZnCl2 , has been developed for highly effective catalysis of the Beckmann rearrangement of ketoximes to corresponding amides (Scheme 27).75 OH N R1

R2

BOP-Clcat

OBOP

R1

N R1

R2

BOPO

N R2

H+ R2

R1 N O

P

O N O R1 O

O

N

O−

+

O

H N

O

R2 R1 OH

NH

N R2

R1

R2

Scheme 27

The Lewis acid ZnCl2 has been used as co-catalyst in order to use a lower catalyst loading. The rearrangement of α-chlorocyclobutanone oximes, derivatives of steroids, has been described as characterized by a Beckmann fragmentation–substitution.76 The results are interpreted in terms of structural and stereoelectronic effects and are supported by AM1 calculations. The stability of the transient carbocations appears to play the major role in reactions leading to the abnormal Beckmann rearrangement products. [2,3]-Sigmatropic rearrangements of allylic ammonium ylides derived from glycinoylcamphorsultams have been described as highly selective in terms of relative and absolute stereocontrol only when acyclic alkenes are present.77 When chiral esters of ylids derived from N -methyltetrahydropyridine undergo rearrangement, the reactions show exclusive cis stereoselectivity but the products are obtained with virtually

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no absolute stereocontrol. A review has summarized recent developments in the field of Schmidt reactions.78 Fused carbocyclic compounds possessing seven- and eightmembered rings can be constructed from allylic ethers in a stereoselective manner by tandem carbenoid generation, ylide formation, and [2,3] rearrangement.79 The relative configurations of the stereogenic centres in the substrates have an important influence on the course of the rearrangement reaction: reactions of substrates possessing favourable relative stereochemistries deliver exceptionally high yields of the required [2,3] rearrangement products. A useful method for the stereoselective synthesis of trifluoromethyl 1,4-oxathiolane through ring expansion of 1,3-oxathiolane ylide using trifluoromethyl diazoacetate in the presence of Rh2 (OAc)4 has been presented.80 The mechanistic possibilities of the triazolinedione–alkene ene reaction have been tested by the use of the vinylcyclopropyl moiety as an efficient probe.81 In non-hydroxylic solvents, this reaction afforded only the ene adducts via a closed three-membered aziridinium imide intermediate, whereas in hydroxylic solvents a dipolar intermediate is favoured and trapped by the cyclopropyl moiety to form the corresponding cyclopropyl-rearranged solvent-trapped adducts. An explanation of the unexpected low phenyl migratory aptitude observed in reactions of mixed alkyl–arylboranes with benzylic sulfur ylides has been reported (Scheme 28).82 OH

BEtPh −

p-Tol

+

S

p-Tol

Et +

p-Tol

Et 65%

B

Ph

Et (101)

Et

OH

BEt2 (102) p-Tol

Ph

p-Tol

Ph 28%

Scheme 28

Reaction of ylide (101) with borane (102) gave predominantly the product resulting from alkyl migration: a 2.3:1 ratio in favour of ethyl migration over phenyl migration was observed. The authors have shown that the following factors impact on which group migrates in mixed aryl–dialkylborates: (i) conformation of the ate complex (there is a preference for the phenyl group to be syn to the sulfonium group because of stabilizing electrostatic interactions and this favours alkyl group migration); (ii) the presence of a phenyl group on boron inherently impedes the migration of the other (alkyl) groups; (iii) the phenyl group is usually a better migrating group than methyl because it can stabilize the transition state by donation of an electron pair ∗ from its π system into the σC1−S orbital (neighbouring effect), but this effect is highly attenuated when the migrating terminus C(1) is less electrophilic (e.g. when R = Ph); and (iv) steric effects also play a role. Larger groups will suffer increased barrier to migration when the migrating terminus is hindered. Boron trifluoride and indium(III)

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trifluoromethanesulfonate have been used to catalyse efficiently the isomerization of thionolactones to thiolactones in good yields.83 This reaction, when applied to an optically active γ -thionolactone, proceeds with a complete inversion of configuration by using BF3 .Et2 O. It has been reported84 that ionic liquid-promoted Michaelis–Arbuzov rearrangement can be performed at room temperature in a short period and without any protective atmosphere of an inert gas. A review of the catalytic use of Lewis acid for the functionalization of C(sp 3 )–H bonds through formation of iminium and oxonium ions has appeared.85

ee

Rearrangement Involving Organometallic Compounds Mild Ni(0)-catalysed rearrangements of 1-acyl-2-vinylcyclopropanes to substituted dihydrofurans have been developed.86 The room temperature isomerizations afford dihydrofuran products in high yield. A highly substituted, stereochemically defined cyclopropane has been employed in the rearrangement to evaluate the reaction mechanism. The Cu(II)-catalysed cycloisomerization of tertiary 5-en-1-yn-3-ols with a 1,2-alkyl shift affords stereoselectively tri- and tetra-cyclic compounds of high molecular complexity (Scheme 29).87 A proposed mechanism has been outlined in which HO

O Cu(BF4)(MeCN)4 (1 mol%) toluene 70 °C, 4 h

85%

O

OH [Cu]

OH

OH [Cu]− +

Scheme 29

[Cu]

[Cu]−

ee

(103)

O

OH

PdCl2

O (104)

OH

O

PdClLn

(107)

O

Scheme 30

PdCl2

O (105)

OH

PdII

1. b-hydride elimination 2. isomerization

Wacker oxidation

PdII Wacker oxidation

(108)

O

(106)

O

O

O


479


the cyclopropanation precedes the skeletal rearrangement and the perfect stereocontrol of the cyclopropanation with respect to the orientation of the acetylene unit has been supported. A novel method for the synthesis of five- to seven-membered α-alkylidene lactams by the palladium-catalysed intramolecular cyanoamidation of alkynyl and alkenyl cyanoformamides has been developed.88 The reaction proceeded exclusively in a 5exo mode, giving the corresponding (Z)-alkenes as major products. Electroneutral cyclopropane rings can be catalytically activated using PdCl2 to give lactams and lactones.89 Six-membered derivatives are always the major products. Interesting mechanistic trends have been uncovered, pointing toward dependence of the cyclopropane activation pathway on nearby substituents, as shown in Scheme 30 for one model reaction. The α-methylstyrene derivative (105) was detected by 1 H NMR during the cyclization of (103), suggesting that a possible pathway in the case of carboxylic acid-containing substrates is Pd(II)-catalysed isomerization of the cyclopropane ring to the branched alkene followed by a Wacker oxidation. However, the formation of (108) can also be explained by direct carboxypalladation followed by β-hydride elimination and subsequent alkene isomerization. The carboxypalladation is expected to occur upon initial coordination of Pd(II) to the more electron rich distal C–C bond of the arylcyclopropane. A versatile palladium-catalysed ring enlargement reaction where arylidenecyclopropanes are converted into the corresponding cyclobutene compounds has been reported (Scheme 31).90 A plausible mechanism for the unusual ring enlargement (D)H Pd(OAc)2, MBrn

Ar

Ar

(114)

H(D) (109)

PdBr2

PdBr

H(D) Ar

Ar PdBr2

Br H(D)

(113)

(110) H(D) Ar

PdBrH(D)

PdBr Ar

Br

Br (111)

(112) Scheme 31

480


of (109) to (114) shows the regioselective bromopalladation of arylidenecyclopropane (109) with PdBr2 , which might be produced in situ from Pd(OAc)2 and MBrn (M = Cu, Zn, Mg, Li), to afford intermediate (110). Intermediate (110) undergoes βhydrogen elimination to form intermediate (111), which subsequently generates palladium carbenoid (112) via hydropalladation with a reversed regioselectivity. Via an α-bromo migration, (112) is transformed to a palladium carbene (113), which yields the product (114) and regenerates the palladium bromide catalyst. To test the plausibility of this proposed mechanism, a deuterium labelling experiment has been performed. The mechanism of cycloisomerization of hepta-1,6-dienes catalysed by [(t-BuCN)2 PdCl2 ] has been investigated by isotopic labelling and by study of the reactions of dimethyl 1-arylhept-1,6-dienyl-4,4-dicarboxylates and dimethyl hept-1,5-dienyl-4,4dicarboxylate.91 The mechanism proposed involves the generation of a monochlorobearing palladium hydride which undergoes a simple hydropalladation, carbopalladation, Pd/H dyotropy, β-H elimination sequence. A key point that emerges is that chelation of the 1,6-diene at various stages in the mechanism plays an important role in determining the regioselectivity of the reaction. Cyclization reactions on 6-[(2hydroxyphenyl)ethynyl]purines, 6-[(2-hydroxymethylphenyl)ethynyl]purines, and 6[(2-hydroxyphenyl)propyn-1-yl]purines have been studied.92 6-(2-Benzofuryl)purines are readily available via a one-pot Sonogashira coupling–cyclization between 6iodopurine and 2-ethynylphenol. When the same reaction was performed with o(hydroxymethyl)ethynylbenzene, 6-[isobenzofuran-1(3H )-ylidenemethyl]purine was formed, mainly as the E-isomer. Acid-catalysed isomerization of the E-compound afforded the Z-isomer. The latter compound was also formed from a two-step reaction: Sonogashira coupling with O-silylated alkyne followed by deprotection and subsequent 5-exo cyclization. Sonogashira coupling between 6-halopurines and 2propynylphenol gave only the alkyne coupling product and no cyclization took place. The activation of alkylidenecyclopropanes with catalytic amounts of PtCl2 or, preferentially, PtCl2 –CO (1 atm), undergoes ring expansion to substituted cyclobutenes.93 The platinum-catalysed intramolecular domino annulation reaction of o-alkynylbenzaldehydes has been described as a versatile approach to naphthalenes with annulated carbocycles or heterocycles of various sizes (Scheme 32).94 A plausible mechanism for the platinum(II)-catalysed annulation reaction shows that the double annulation process most probably proceeds through the benzopyrylium cation (117), which results from the nucleophilic attack of the carbonyl oxygen at the alkyne, activated by the Lewisacidic platinum salt. A subsequent intramolecular Huisgen-type 3 + 2-cycloaddition of the second alkyne is assumed to generate intermediate (118). Rearrangement to (119) and the formal 4 + 2-cycloaddition product (118) leads to the aromatized final (116), liberating the active catalyst. In the case of FeCl3 as the Lewis acid, we assume that intermediate (118) is oxidatively transformed to (121). An efficient method for pentannulation using acyloxy-functionalized pyrans that evolve from readily available propargylic esters has been developed. Utilizing a range of epoxides, pentannulation is achieved using PtCl2 to obtain bicycles containing a

481

14 Molecular Rearrangements: Part 2. Other Reactions O H Pt(II)

O

O O (115)

(116) −MXn

MXn

O+

+

O

O

O+

O

− −

−MX

MXn

MXn

n

O

(120)

(117) [3+2]

+

O

M = Fe

O

M = Pt

O O

O O (121)

MXn (118)

O

−MX

n

(119)

Scheme 32

tertiary stereocentre.95 A facile annulation reaction catalysed by AuI or AuIII species of alkyne-tethered indoles forming six-, seven-, and eight-membered annulated indoles has been reported.96 A cationic AuI complex has been described as the best catalysts for the formation of six- and seven-membered rings through 6-endo-dig, 6-exo-dig, and 7-exo-dig cyclizations. Indoloazocines have been obtained with AuCl3 as catalyst through a rare 8-endo-dig process. An exhaustive study of the cyclization of 1,6-enynes with different gold(I) complexes in the presence of alcohols results in cyclized products alkoxy- or hydroxy-functionalized or in their skeletal rearrangement products.97 Gold(I) complexes are selective alkynophilic catalysts, promoting reactions through the exclusive coordination of the metal complex to the alkyne of

482


the enyne. With these catalysts, the first examples of skeletal rearrangement of enynes by the endocyclic cyclization pathway have been documented. This endocyclic cyclization proceeds by a mechanism different from those followed in the presence of PdII , HgII , or RhI catalysts. The mechanistic puzzle of transition metal-catalysed skeletal rearrangements of enynes has been outlined.98 Three pathways actually compete in metal-catalysed cyclizations of enynes in which the metal selectively activates the alkyne: an endocyclic process and two exocyclic cyclizations, one proceeding by anti attack of the alkene and a second one resulting in a syn addition. Although cyclobutenes may be formed in transition metal-catalysed cyclization of some enynes, particularly, 1,7-enynes, these compounds are not necessarily the intermediates in the skeletal rearrangement. Cyclobutenes are formed by ring expansion of syn-cyclopropyl metal–carbenes formed in the syn pathway. The mechanism of the stereospecific gold(I)-catalysed Rautenstrauch rearrangement of (E)-1-ethynyl-2-methylbut-2-enyl acetate to 3,4-dimethylcyclopent-2-enone has been computationally addressed using DFT (B3LYP/6–31G∗ , SDD for Au).99 The results indicate that the bond formation event follows the Au(I)-induced acetyl transfer to the vicinal alkyne and that it is the helicity of the pentadienyl cation intermediate which keeps memory of the chiral information. The fidelity of the centre-to-helix-to-centre chirality transfer requires that the rates of helix interconversion and pivaloyl rotation are slower than the cyclization, as calculations predict. A highly efficient synthesis of α-alkylidene or benzylidene β-diketones from readily available propargylic esters has been developed.100 The proposed key transformation is a novel intramolecular acyl migration to nucleophilic AuIII –C(sp 2 ) bonds (Scheme 33). The propargylic ester (122) undergoes an initial Au-catalysed 3,3rearrangement to form carboxyallene (123), which can be further activated by the same AuIII catalyst in situ. The resulting intermediate (124) has been shown to react efficiently with nucleophiles at the oxocarbenium moiety; however, in the absence of suitable nucleophiles, an acyl group migration ensues as the nucleophilic AuIII –C(sp 2 ) attacks the acyl carbonyl group intramolecularly, generating a tetrahedral intermediate (125). The collapse of (125) results in α-ylidene β-diketone (126) with concomitant regeneration of the Au catalyst. The formation of the double bond isomer of (126) is most likely due to isomerization catalysed by either AuIII or H+ . The same authors have developed a unique Au-catalysed 1,5-enyne cycloisomerization involving carboxy group migration and Au-mediated C–C single bond formation.101 A highly efficient and general method for the diastereoselective synthesis of eightmembered carbocycles (133) based on a new tandem platinum- or gold-catalysed cycloisomerization–Prins-type cyclization reaction of alkynol (127) has been developed (Scheme 34).102 The reaction is initiated by coordination of the platinum or gold complex to the triple bond of the starting alkynol (127) to form intermediate (128) according to the Dewar–Chatt–Duncanson model. Intramolecular addition of the hydroxy group to the internal carbon atom of the triple bond generates (129). Migration of the hydrogen atom from the oxygen to the metal atom then leads to the formation of hydride complex (130), which, after reductive elimination, produces the exocyclic enol ether (131) and regenerates the catalytic species. At this point, the

de

de

R1

R2

O

O

R

AuIII or H+

R1

R

1

O

(122)

R2

R

AuIII

O

R2 (126)

O

O

R

R1 (125)

R R2

AuIII

Scheme 33

O

+

O

R1

+

O

AuIII

AuIII

O

R

R1

R2

(124)

O

+

R

R2

AuIII

O

R O

• R1 (123)

O R2 AuIII


483

R

R

(127)

OH

(128)

OH

MLn

R

+

(129)

O

H

−

MLn

6-exo cycloisomerization

MLn

(130)

Scheme 34

R

O

R

MLn

(131) H

O

R

Prins-type cyclization

MeOH

(133)

O

OMe

(132)

+

O

−OMe


485


second part of the tandem sequence–the Prins-type cyclization–is initiated. In the alcohol solvent an equilibrium between intermediate (131) and oxocarbenium ion (132) is likely to occur. This oxocarbenium ion may exist as an ion pair with the counterion, which also serves as the nucleophile. The cyclization step is believed to proceed through a chair-like transition state, thereby favouring nucleophilic trapping from an equatorial trajectory. This is consistent with the configuration of the stereogenic centres observed in the final products (133). The first examples of gold-catalysed cycloisomerizations of 1,6-ene-ynamides that lead to substituted cyclobutanones or azabicyclic compounds, depending on the substitution pattern, and proceed with high level of diastereoselectivity has been reported.103 The gold-catalysed cycloisomerization of various α-aminoallenes affords the corresponding 3-pyrrolines in good to high chemical yields and – if the amino group is unprotected – with complete axis-to-centre chirality transfer.104 In cases involving N -protected substrates, an interesting dependence of the chirality transfer on the protecting group was observed. Gold(I) precatalysts such as AuCl and AuI are extremely reactive and dramatically shorten the reaction times for the intramolecular hydroamination of unprotected α-aminoallenes. Mechanistic studies with stoichiometric amounts of AuBr3 suggest that a gold(I) compound (formed by oxidation of the aminoallene) is the catalytically active species even if the reaction is started with a gold(III) precatalyst. A cationic phosphinegold(I)-catalysed tandem cyclopropanation–hydroarylation reaction, which produces formal 4 + 3-annulation products from vinyl arenes and propargyl esters, has been developed.105 The cyclopropanation represents the first intermolecular reaction of diynyl esters and proceeds with excellent regio- and diastereo-control. 7-Azanorbornenes undergo ring opening/ring closing metathesis upon treatment with the second-generation Grubbs catalyst to give hexahydroindoline derivatives.106 A new concept of diastereoselective ring-rearrangement metathesis has been developed for the synthesis of various carbo- and hetero-cycles (134) and (135) (Scheme 35).107 A strong influence of the substitution pattern of the directing stereocentre on R

R

*

X

n

*

X

Ru, Mo catalyst m

m

m

n

* m

(134) R

R

*

X

n

*

X

Ru, Mo catalyst

*

m m

X = CH2, N, O

Scheme 35

(135)

n

de

de

de

de

486


the configuration of the new stereocentre has been observed. The diastereoselectivity depended on the precatalyst applied. An efficient and regioselective synthesis of isomeric fluorinated lactam derivatives through a ring-closing metathesis reaction or a tandem ring-closing metathesis–isomerization protocol has been reported.108 The presence of the gem-difluoro moiety in the starting materials exerts a pivotal effect by directing the isomerization step. A formal total synthesis of eleutherobin using the ring-closing metathesis reaction of a densely functionalized diene as the key step has been reported.109 The unusual kinetically controlled ring-closing metathesis stereochemical outcome has been investigated using computational methods. Semiempirical PM3 calculations have shown that the E-isomers of the 10-membered carbocycles resulting from the RCM reaction are less thermodynamically stable than the Z-isomers. Alkene metathesis catalysts containing chiral, monodentate N -heterocyclic carbenes (NHC) have been synthesized and their application to asymmetric ring-closing metathesis has been studied.110 Two proposed models for the formation of the observed products have been discussed: if the incoming alkene binds cis to the NHC, the stereodefining interaction is the face of the ruthenium to which the olefin binds; if the incoming alkene binds trans to the NHC, the stereodefining interaction is the position of the alkylidene under the N -bound aryl ring. In both cases, the position of the pendent alkene in the forming ring also plays an important role in the transition state. The direct rearrangement of the allenylidene–ruthenium complex into an indenylidene–ruthenium derivative has been studied.111 It has been established that this acidpromoted reaction involves electrophilic alkenylcarbyne–ruthenium intermediate formation. The in situ-prepared indenylidene–ruthenium complexes are efficient catalyst precursors for ring-opening metathesis polymerization of cyclooctene and cyclopentene. The late transition metals have been demonstrated to be able to induce unprecedented reactivity in methyl aromatic ethers that have their ortho-positions blocked by methyl substituents.112 DFT calculation have shown that the 1,2-shift of the stannyl group on formation of ruthenium–β-stannylvinylidene complexes is more facile than the corresponding 1,2-hydrogen shift of the coordinating terminal alkynes.113 The ruthenium-catalysed cyclization of a propargylic alcohol with an oxabenzonorbornene in methanol leads to an unexpected isochromene framework.114 The catalytic cycle that leads to this product is believed to implicate an oxidative cyclization of the two unsaturated partners with the ruthenium catalyst, followed by a β-hydride elimination, tautomerization and hydroruthenation. The ruthenacyclobutane obtained further undergoes 2 + 2-cycloreversion to form an Ru–carbene intermediate that uncommonly rearranges through a [1,3]-alkoxide shift and finally reductively eliminates to produce the desired compound. Iodonium ylides (136), generated in situ with bisacetoxyiodobenzene, are converted to allyl- or benzyl-substituted oxonium or sulfonium ylides (137) via rhodium- or copper-catalysed carbene transfer.115 Such ylides undergo [1,2]- or [2,3]-rearrangement to the corresponding 2-substituted heterocycles (138). An example of the rhodiumcatalysed reaction is reported in Scheme 36. It has been demonstrated that, in addition to electronic factors, steric factors play an even more important role in affecting the 1,2-migratory aptitude in rhodium

de

de

de

487


X

O

Rh2(OAc)4 or Cu(hfacac)2

CO2Me N2

O

−

MLn

+

X = O, S

CO2Me

CO2Me

X

X

R

R

R

(137)

(136)

(138)

Scheme 36

N

N2

N EtO2C

S R

S

O

N

N

CO2Et

Rh2OAc4 (1–2 mol%) xylenes, reflux

E

S R

S

O

E E

E R

R

(139)

(140)

Scheme 37

(II)–carbene reactions.116 New benzimidazolidinone cyclophanes (140) have been synthesized from (139) through a rhodium(II)–carbene-mediated double Stevens rearrangement employed as a ring expansion technique (Scheme 37).117 The insertion is highly regioselective and provides access to larger carbocyclic cyclophanes after sulfur atom extrusion. An efficient rearrangement of 1,3-diynes possessing propargylic heteroatom substituents to functionalized 1,5-dien-3-ynes in the presence of electrophilic transition metal catalysts has been demonstrated.118 The mechanism of bond reorganization process is most consistent with the involvement of the formation of putative platinum and gold carbene species followed by its metallotropic [1,3]-shift. The same authors have demonstrated that 1,3-diynes behave in predictable yet distinctive manners compared to simple enynes under electrophilic transition metalmediated reaction conditions. This characteristic behaviour of 1,3-diynes is presumably caused by the slightly electron-withdrawing nature of the alkynyl substituent, which not only renders preferentially the formation of 5-exo-type alkylidenes but also allows for the subsequent [1,3]-metallotropic shift. Several salient features of reactions with this functionality include the following: (a) an acetate is more reactive than the tethered alkene as an initiator, generating [1,2]-acetate migrated alkylidene intermediate, whereas an alkene is a better terminator than an acetate/bromide to generate the cyclopropane moiety; (b) allene products are not formed at all under current reaction conditions; (c) 5-exo/6-endo-type alkylidene formation depends on the heteroatom substituent in the tether; (d) facile metallotropic [1,3]-shift of the intermediate alkylidenes occurred whenever possible.

488


O

OH

O

O

R OEt

OEt HO

O

+

OEt

R O−

ReI R

(3-b)

HO

OEt (4-a)

HO

R

Re R

(2-b)

O

O

OEt

OEt (2-a)

O

Re

HO+ R

(3-a)

O OEt

Re R O− OEt

Scheme 38

A rhenium catalyst promoted insertion of terminal alkynes into a carbon–carbon single bond next to a carbonyl group of non-strained cyclic compounds under mild conditions (Scheme 38).119 The proposed reaction mechanism is as follows: (1) the formation of a rhenacyclopentene intermediate by the reaction of a rhenium catalyst, β-keto ester, and terminal alkyne. After the formation of the rhenacyclopentene intermediate, there are two possible pathways; the difference is the timing of reductive elimination. Path A: (2-a) ring opening by a retro-aldol reaction; (3-a) isomerization; (4-a) reductive elimination. Path B: (2-b) reductive elimination; (3-b) ring opening by a retro-aldol reaction; (4-b) isomerization. 1-Phenoxyocta-2,7-diene in the presence of rhenium- or tungsten-based catalysts affords ortho-substituted phenols with a Claisen-type mechanism, whereas the metathesis of the internal double bond exclusively occurs with Grubbs catalysts.120 The reductive olefination of aldehydes via chromium Brook rearrangement has been reported.121 The [1,5]-Brook rearrangement to give silyl ethers has been reported to proceed efficiently with sodium and potassium bases.122

Rearrangements Involving Ring Opening 1-Acyloxybenzocyclobutenes, having an α,β-unsaturated carbonyl group at the C(1) position, undergo the periselective thermal ring expansion to give 2-benzoxocin

489


derivatives in high yields.123 The asymmetric epoxidation of benzylidenecyclobutane and subsequent epoxide rearrangement to 2-arylcyclopentanones (143) and (146) with either inversion or retention of configuration using Et2 AlCl or LiI has been reported (Scheme 39).124

O

pathway a

Ar

O

LA O+

inversion

Ar

LA

Ar (141)

pathway b

(142)

(143)

LiI inversion

I

O

I inversion

OLi (144)

Ar

LiO (145)

Ar

Ar (146)

Scheme 39

The rearrangement with Et2 AlCl is likely to go through a concerted process with inversion of the configuration (pathway a). Slightly more enantioselectivity is lost for epoxides with electron-donating groups, such as the 4-MeOPh moiety, during the rearrangement. This lowered enantioselectivity could be because of the competition from a stepwise SN 1-type process via a carbocation which is stabilized by electron-donating groups. The rearrangement with LiI is likely to go via intermediate (144) with double inversion (pathway b). A simple one-pot procedure for ring enlargement of α-chloromethyl N -containing heterocycles has been developed.125 By reaction of chloromethyltetrahydroisoquinoline and its thieno analogue with benzyl or allyl bromide under basic conditions, ring expansion and N -substitution were achieved simultaneously. The key to the transformation was proposed to involve the formation of aziridinium salt and subsequent bond breaking between the nitrogen and tertiary carbon atoms. The ring expansion of isopropenyldihydrofuran derivatives has been described for the synthesis of oxepinolactones.126 The metal-free ring expansions of alkylidenecyclopropanes and an alkylidenecyclobutane (147) mediated by a phtalimidonitrene, generated from N -aminophthalimide (148) and bisacetoxyiodobenzene, has been described for the synthesis of aryl-substituted cyclobutylidene and cyclopentylidene hydrazine derivatives (149) obtained in good to excellent yields (Scheme 40).127 Two plausible mechanisms for these ring-expansion reactions have been proposed. First, N -aminophthalimide reacts with diacetoxyiodobenzene to generate the active nitrene equivalent (150). Intermediate (150) then assumed to react with alkylidenecyclopropane in two paths. In path A, the reaction of alkylidenecyclopropane with (150)

ee

490


NPhth

R1 n

R2

PhI(OAc)2

N NH2

+

CH2Cl2, r.t., 2 h

O (147)

n = 1 or 2 R1 = Ar, alkyl R2 = Ar, alkyl

(148)

Phth-NH2

R1

n

R2 Yield: 45–98% (149)

H

+

PhI(OAc)2

Phth

N OAc (150) R1 R2

B

Phth NPhth R1 R2

A

Phth

N*

N *

R1

R1 R2

(152)

R2 (151)

Scheme 40

generates the corresponding aziridine (151), which undergoes a facile rearrangement to form the final 2,2-disubstituted cyclobutylidene hydrazine product via an ionic or diradical intermediate (152). Alternatively, in path B, reaction of alkylidenecyclopropane with (150) directly generates intermediate (152), which then undergoes a cation- or radical-induced ring-expansion rearrangement to furnish the final product. Intermediates (152) have not yet been distinguished as ionic or diradical species. The hydrazinolysis reaction of 5-perfluoroalkyl-1,2,4-oxadiazoles with hydrazine or methylhydrazine as bidentate nucleophiles has been studied (Scheme 41).128 The reaction occurred through the addition of the bidentate nucleophile to the C(5)–N(4) double bond of the 1,2,4-oxadiazole followed by ring opening and ring closure involving the second nucleophilic site of the reagent to give fluorinated 1,2,3- and 1,2,4-triazoles, (Z)-oximes of 1,2,4-triazin-5-ones and 5-hydroxylamino-1,2,4-triazin-6-ones. The observed regioselectivity shows the preferential attack of the NH2 end of the methylhydrazine on the C(5). A new tandem cleavage–cyclization reaction of tetrahydroisoquinoline derivatives has been reported for the synthesis of benzoazocines.129 A novel and readily available method for the synthesis of pyrroles possessing substituents with various groups via thermal rearrangement of iminocyclopropenes has been developed.130 The regioselectivity in this iminocyclopropene rearrangement has also been disclosed. New perspectives on Boekelheide–Fedoruk ring expansions have

491


HO

O

OEt OH

N

OEt N

N

N

Rf NH HO

N

Rf

N

OEt

O

Rf

RHN

N

N

R

H

Rf = CF3, C3F7, C7F15

HO

NH O

N Rf

N

N

R

Scheme 41

been outlined for the reactions of 1-substituted-imidazolium-3-dicyanomethanilides with maleic anhydride.131 5,7-Diaryl-2-fluoro-4H -1,3-diazepines (156) have been synthesized from 3-aryl-substituted 2H -azirines (153) and difluorocarbene.132 The reaction involves isomerization of azirinium ylide (154) into a 2-aza-1,3-diene (155) which undergoes 4 + 2-cycloaddition with the starting azirine (153) followed by ring expansion and dehydrofluorination (Scheme 42).

N

Ar

+

CF2

N

Ar

(153)

CF2 N

−

CF2

Ar

(154) Ar Ar

N

(155) Ar

N

F

N

F

N F

Ar

N Ar (156)

Scheme 42

A new ring transformation of 1,2,3-thiadiazoles into furan-2-carbothioamides has been described.133 An unprecedented rearrangement of 5,5-diazidobarbituric acids to parabanic, tetrazoles and benzyl allophanate has been reported.134 Computational data for the energetics of internal nucleophilic reactions, both in ring-opening reactions

492


where strain energy is released and in model, strain-free systems has been reported.135 The authors show that in internal nucleophilic ring-opening reactions the exothermicity of the internal reaction is much reduced compared with the same ring opening induced by an external nucleophile. Upon treatment with BF3 .Et2 O at low temperature, enantiopure benzyl-type ethers of arylglycidols (157), with electron-withdrawing substituents at the skeletal aryl group and electron-donating substituents at the benzyl group, undergo stereospecific rearrangements of Friedel–Crafts type, leading to enantiopure 4-diarylmethyl-1,3-dioxolanes (158) or to enantiopure trans-4,5-disubstituted tetrahydrobenzo[c]oxepin-4-ols (159) (Scheme 43).136 The course of the reactions is controlled by the substitution pattern at the benzyl ether. Whereas benzylic systems activated toward ipso substitution afford diarylmethanes through a Friedel–Crafts reaction followed by fragmentation, benzylic systems activated toward ortho attack lead to enantiopure oxepinols (159) through a 7-endo-tet ring closure of Friedel–Crafts type. The epoxy-Ramberg–Bäcklund reaction has been outlined, in which α,β-epoxy sulfones are converted into a range of mono-, di-, and tri-substituted allylic alcohols, on treatment with a base.137 Modification of this method allowed the preparation of enantio-enriched allylic alcohols following the diastereoselective epoxidation of enantio-enriched vinyl sulfones that were accessed efficiently from the chiral pool.

de

ee

BF3.Et2O (ortho activation)

O

EDG

O

O O EWG (158)

EDG

EWG

O BF3.Et2O (ipso activation)

HO

(157) EDG EWG (159) Scheme 43

The oxidation of 2-alkoxy-3,4-dihydro-2H -pyrans with dimethyldioxirane followed by Jones oxidation, which leads to rearrangement and stereocontrolled formation of 4,5-cis-disubstituted tetrahydrofuranones, has been reported.138 Ring-opening reactions of 2-cyclohexylidene-3,3-dimethylcyclopropanone acetal (160) has been reported to be readily induced by treatment of hydrogen chloride in various solvents, and leads to a mixture of isomeric ketones (161) and (163) and ester (162) in different ratios and yields depending on the solvent used (Scheme 44).139 Bond cleavage takes place at the C(1)–C(2) or C(2)–C(3) bond, and the ratio of C(1)–C(2) to C(2)–C(3) cleavages changes from >99:1 to NaH > LiH. Among the various amines tested, only aliphatic 1,2diamines exhibited the activity for the isomerization. Electron paramagnetic resonance (EPR) and UV–visible spectroscopic experiments on the active species suggest that the isomerization of 5-vinyl-2-norbornene proceeds through a radical mechanism.167 3-Vinylmethylenecyclobutane (205) rearrangement has an experimental activation energy of 35.7 kcal mol−1 , which is comparable to the energy expected for the homolysis of one of the endocyclic allylic C–C bonds, and is therefore expected to give rise to diradical pathways and non-concerted reaction products. In contrast, the highly substituted 3-vinylmethylenecyclobutane (203) was found to rearrange stereoselectively to give the [3,3]-sigmatropic shift product (204) in greater than 90% yield (Scheme 56). To determine the nature of the mechanism, the effects of substituents, and the cause of the observed stereoselectivity, a theoretical study using density functional theory (B3LYP) and complete active space ab initio methods (CASSCF and CASPT2) has been carried out for the parent 3-vinylmethylenecyclobutane (205) rearrangement and also for substituted models for the stereoselective rearrangement of (203) to (204).168 Calculations indicate that for the parent compound (205), transition structures and diradical intermediates are very comparable in energy, and that diradical intermediates (206) and (207) (Scheme 56) have substantial conformational freedom and very low barriers for forming stereo- and regio-isomeric forms of the ring-enlarged product (208). In the substituted system, stereoelectronic effects of the trialkylsiloxy group and the ester and methyl substituents on the methylene group all conspire to cause a reaction that occurs by distinct bond-cleavage and bond-formation events, nevertheless exhibiting the high stereo- and regio-selectivity that is the usual feature

504

Organic Reaction Mechanisms 2006 Br H N

O N H

HN

H N

HN

NH2 N H NH NH2

N H

O Br sceptrin (199) MW, H2O, 200 °C, 5 min

Br O

H N

N H

HN

N H

H N

HN

•

H2N

Br O N H

+

+

N H

H2N

Br O

HN N H

H N +

H N

NH2

+

NH

HN H N

HN

+

N H

HN

NH2

(200)

NH

HN

NH

NH

•

O Br

+

H N

O

N H

HN O

Br

Br nagelamide E (201)

ageliferin (202)

2%

40% Scheme 55

+

NH2

505

14 Molecular Rearrangements: Part 2. Other Reactions Me EtO2C

CO2Et

100–135 °C

R2 OSiR13

a: R1 = Me; R2 = Ph b: R1 = t-Bu; R2 = Me

(203)

•

OSiR13 (204)

• •

•

(205)

Me H R2

(206)

(207)

(208)

Scheme 56

of concerted processes. Dynamics simulations of the four-fold degenerate rearrangement of bicyclo[3.1.0]hex-2-ene, which yields a non-statistical product distribution, were carried out. The simulated product ratio agrees with experiment and is found to be entirely dynamically determined. A geometric model is produced to estimate qualitatively the dynamically determined product ratio independently of trajectory calculations. The characteristics of this rearrangement are expected also to apply to others involving modestly stabilized diradical intermediates.169 Addition of O-centred radicals XO• to cyclodecyn-5-one (209) leads to the isomeric vinyl radicals (210) and (214) that undergo transannular cyclization on to the carbonyl group. The resulting allyloxyl radicals (211) and (215) subsequently attack the C=C bond in a 3-exo fashion to give the X-oxy radical intermediates that decompose into the isomeric α,β-epoxy ketones (213) and (217) by release of a radical X• (Scheme 57). When this reaction was performed with NO3 • , (213) and (217) were exclusively formed. With other radicals, such as the hydroxyl (HO• ) or the sulfate radical anion (SO4 • ), or organic O-centred radicals, such as acyloxyl [RC(O)O• ] or alkoxyacyloxyl radicals [ROC(O)O• ], a third product, identified as the spirodiketone (220), formed through β-cleavage in (215) followed by cyclization and homolytic fragmentation. The finding that the yield of (220) was regularly significantly higher than 50% suggested that, as the initial radical attack should occur with equal probability, the initial radical addition should be reversible and the vinyl radical (210) should directly rearrange to (214). Therefore, the 1,2-nitroxyl and 1,2-acetoxyl rearrangements of β-(nitroxy)vinyl and β-(acetoxy)vinyl radicals (221) and (222), respectively, have been studied for the gas phase by various ab initio and density functional methods (Scheme 58).170 The calculations lead to the conclusion that, in the case of the NO3 • -induced radical oxygenation of cycloalkyne (209), all processes following the initial NO3 • addition are fast and irreversible, because the terminating homolytic scission of the O–N bond requires practically no activation energy. Therefore, a 1,2rearrangement of the nitrate moiety in a vinyl radical has no time to occur. In contrast,

(209)

O

XO

XO•

•

•

O (214)

•

XO

(210)

OX

O

OX

OX

(218)

O

Scheme 57

•

(215)

O•

(211)

O•

OX •

O

O

•

OX

(219)

•

OX

(216)

(212)

O

OX

X•

X•

X•

O

O

O

(220)

O

(217)

(213)

O

O



507

in radical oxygenations involving acetoxyl (and other O-centred) radicals, the final homolytic cleavage of the O–C bond is the rate-determining step. In these systems, all cyclization steps are reversible, especially the 1,2-rearrangement of the acetoxy group in the vinyl radicals (221) and (222). The final product ratio (213):(217):(220) reflects, therefore, the relative rates between the various competing processes. The calculations showed a significant method-dependent outcome that should be taken into account in similar studies. Z

Z

Y O

O Y O

O

(221)

(222) Scheme 58

The radical reaction of a series of N -(2-bromoallyl)-N -methylarylcarboxamides promoted by Bu3 SnH–AIBN led to the production of 4-aryl-1-methylpyrrolidin-2ones and directly reduced materials in comparable yields (30–40%). A cascade process, involving sequential 5-exo-trig spirocyclization on the aryl ring, β-scission, and 5-endo-trig cyclization of the resulting acyl radical, is proposed to explain the pyrrolidinone products.171 The lithium enolate formed from methyl S-trityl mercaptoacetate can be C-alkylated in high yield at or below −40 ◦ C, but at higher temperatures the [1,2]-thio-Wittig rearrangement of the enolate is the predominant process leading to S-alkylated tritylacetate. ESR experiments indicate that this rearrangement occurs by a radical mechanism involving the homolytic cleavage of the S-trityl bond followed by C–C bond formation and S-alkylation.172 The cathodic reduction or a base treatment of a 1-cyanomethyltetrahydrothiophenonium salt gave the stabilized ylide, which reacted with benzaldehyde to give 3-hydroxy-3-phenylpropionitrile. In the absence of benzaldehyde, the ring-expanded product 2-cyanotetrahydrothiopyran was obtained through a [1,2]-Stevens rearrangement in excellent yield (92%) by both methods. The reaction mechanism was investigated by using B3LYP density functional calculations and is proposed to be radical.173 Aza-enediynes (C,N -dialkynylimines) (223) undergo thermal aza-Bergman rearrangement to β-alkynyl acrylonitriles through 2,5didehydropyridine intermediates (226). Certain aza-enediynes, particularly in more concentrated solutions, undergo a parallel conversion to fumaronitrile (225) and (Z)enediynes (224). Kinetic and labelling studies indicate that the conversion to enediyne is second order in aza-enediyne and proceeds by a series of ‘head-to-tail’ coupling and fragmentations (Scheme 59).174 1,2-Dialkynylimidazoles, another type of aza-enediynes, by thermolysis (80–100 ◦ C) in chlorobenzene or CH2 Cl2 , or in DMF containing 1 equiv. of HCl, afford 5chloroimidazo[1,2-a]-pyridine products deriving from the HCl trapping of the azaBergman cyclization product.175 In search of new cyclizations, a computational study of the thermal rearrangements of 3-heteroatom-pent-1-en-4-yn-1-ones, enyne-ketenes

508


R 55 °C

N

Ph R

Ph (223)

CN

NC

Ph

+

120 mM

R

Ph

Ph (224) 47–68% R = Me, Ph, p-MeC6H4

(225) 35–44%

80 °C 0.45 mM R = Ph

•

N Ph

•

N Ph

Ph

Ph

Ph Ph

(226)

(227) 85% Scheme 59

containing a variable heteroatom or carbon group at the 3-position, was carried out at the BLYP/6–311+G∗ //BLYP/6–31G∗ level of theory. While cyclizations to oxohetero-cyclopentadiendiyl (2,6-cyclization) are most favourable and predicted to be experimentally feasible for X = CH− , NH, O, and S, protonation of these substituents raises the corresponding 2,6-cyclization barriers. Cyclizations to homoaromatic oxacyclohexadienediyl (1,6-cyclization) are highly improbable due to competition with other low-lying alternative pathways.176 Treatment of various o-methoxy-substituted aryltriazenes with methyl iodide in a sealed tube at 120–130 ◦ C gave aryl iodides together with 1,5-hydrogen atom transfer (originating from an o-triazene alkyl chain) products in excellent yields and roughly 1:1 ratio. The replacement of an orthohydrogen by a methoxy group has a crucial effect on the decomposition of triazene and particularly on the formation of 1,5-hydrogen atom transfer products. More than likely, 1,5-H shift reactions can be attributed to a radical mechanism mediated by iodine anion.177 A reinvestigation of 2,6-difluorophenylnitrene, both experimentally and computationally, showed that it can be selectively and completely transformed into its two isomers, the bicyclic azirine and the cyclic ketenimine, by light of suitable wavelengths. All three isomers are ionized in Ar matrices, but only the phenylnitrene and the cyclic ketenimine yield stable radical cations, whereas the bicyclic azirine decays to both of these compounds on ionization. The cyclic ketenimine yields a novel aromatic azatropylium-type radical cation.178

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512 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178

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Author Index In this index bold figures relate to chapter numbers. roman figures are reference numbers.

A Abad, A., 12, 97 Abbas, M., 14, 9 Abbasoglu, R., 11, 20–22 Abboud, J.-L.M., 7, 2 Abboud, K.A., 9, 22; 11, 173 Abdel-Magid, A.F., 1, 333; 3, 299 Abdi, S.H.R., 8, 29 Abdo, M., 3, 271 Abdul-Rahim, O., 1, 236; 9, 76 Abe, M., 7, 89 Aberg, J.B., 3, 327 Abhilash, K.G., 7, 37 Abiko, Y., 1, 255 Abiraj, K., 3, 46, 383 Abraham, C.J., 12, 136, 137 Abraham, S., 9, 32; 11, 149 Abramov, I.G., 5, 10 Abramova, M.B., 5, 10 Abrams, N.M., 9, 138 Abu Bakar, M.D., 1, 242 Abu-Omar, M.M., 11, 62 Aceña, J.L., 14, 108 Acevedo, O., 10, 8 Achard, M., 12, 185 Acharya, S., 2, 109 Ackermann, L., 5, 41; 6, 59 Adair, G.R.A., 3, 320 Adam, W., 3, 282 Adamo, C., 8, 114 Adapa, S.R., 1, 155; 8, 27; 11, 94, 137 Adhikary, K.K., 8, 100 Adlhart, C., 4, 37 Adolfsson, H., 1, 306, 313; 3, 370, 372 Adrio, J.A., 3, 217 Afonso, C.A.M., 4, 49 Afonso, M.M., 12, 121 Afzal, S., 3, 241; 14, 154 Agama, K., 7, 124 Aggarwal, V.K., 1, 238, 274; 9, 38, 39, 48; 10, 36; 14, 17, 82 Aghapoor, K., 1, 281 Aghmiz, M., 3, 347 Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd

Aguayo, R., 2, 47 Aguilar, A.M., 1, 126 Ahlquist, M., 11, 255 Ahmed, N., 2, 91 Ahn, D., 8, 65 Ahn, D.-S., 8, 106 Ai, Z., 12, 98 Aikawa, K., 3, 332 A¨ıssa, C., 14, 93 Aitken, R.A., 10, 33 Aizman, A., 2, 50, 51 Aizpurua, J.M., 9, 81 Akimoto, T., 6, 25 Akindele, T., 1, 42 Akiyama, T., 1, 65; 12, 147 Akram, M., 1, 21 Akullian, L.C., 1, 136 Akulova, L.V., 14, 12 Alabugin, I.V., 13, 57, 58 Alaerts, L., 14, 38 Alajar´ın, M., 12, 38; 13, 82, 85 Alam, M.A., 8, 103 Alam, M.M., 8, 27 Alam, S., 13, 79, 80 Al-Awadi, N.A., 10, 33 Alberico, E., 11, 102 Albericoa, E., 3, 375 Alberti, M.N., 3, 239 Albini, A., 3, 240; 7, 106–108 Albuquerque, L., 2, 85 Alder, R.W., 4, 64 Al-Duaij, O., 6, 70 Alexakis, A., 1, 39; 8, 1, 6; 9, 28, 87; 11, 226, 227, 231 Alfaia, A.J.I., 8, 79 Alfonsi, M., 11, 165 Algi, F., 4, 59 Ali, M., 8, 101; 10, 53; 11, 127 Ali, M.S., 3, 61 Ali, S.A., 11, 76 Aliaga, M., 2, 30, 54 Ali-zade, N.I., 3, 211 Aljarilla, A., 1, 246 Allaert, B., 14, 8 Almasi, D., 1, 204; 11, 202 Almeida, W.P., 11, 175 Edited by A. C. Knipe

513

Almerindo, G.I., 10, 7 Almo, S.C., 5, 23 Al-Omari, M., 10, 44 Alonso, D.A., 1, 204; 11, 202 Alonso, F., 1, 326; 3, 391 Alper, H., 11, 88 Altabe, M., 12, 12 Altable, M., 10, 15 Althammer, A., 5, 41; 6, 59 Altundas¸, A., 11, 27; 14, 52 Alunni, S., 10, 3 Alvarez, R., 14, 99 ´ Alvarez-Guti´ errez, J.M., 8, 19 Alvarez-Idaboy, J.R., 3, 231; 14, 67 Alves, C.N., 12, 94 Amat, M., 9, 18 Amatore, C., 8, 10 Amatore, M., 11, 239 Amedjkouh, M., 1, 113 Amemiya, R., 1, 290 Amer, A.A., 4, 104; 14, 132 Ameta, R.C., 3, 66 Amin, S.B., 11, 58 Ammal, S.C., 1, 23 Amriou, S., 7, 145 Amseis, P., 7, 76 An, H.-Y., 12, 16 An, M.H., 3, 296 Anaç, O., 13, 69 Ananda, S., 3, 135 Anani, W.Q., 6, 16 Anas, S., 12, 187 Anaya de Parrodi, C., 9, 111 Anders, C.E., 9, 138 Andersen, N.G., 3, 323 Anderson, V.E., 1, 208; 2, 10; 8, 68 Andersson, P.G., 1, 51; 3, 344, 352 Ando, A., 1, 316; 3, 388 Ando, F., 14, 173 Ando, H., 2, 7 Ando, K., 8, 118; 9, 67 Andrés, C., 11, 30 Andres, G.O., 2, 17 Andres, J., 9, 142; 10, 49

514 Andrés, J., 12, 94; 13, 7 Andres, J.L., 1, 50; 3, 345 Andrievsky, A., 2, 102 Andujar Sanchez, C.A., 5, 13 Andujar Sanchez, C.M., 9, 41 Anez, R., 10, 26, 31 Angelis, Y.S., 14, 81 Anghel, D.F., 2, 64 Anilkumar, G., 3, 95, 96 Anke, A., 3, 95 Annaka, K., 11, 53 Annalakshmi, S., 2, 63 Annamalai, V., 1, 215; 9, 97 Ansel, J.-E., 3, 251 Anthonsen, T., 7, 138 Antoline, J.E., 1, 216; 9, 108 Antonchick, A.P., 3, 355, 356 Antonio Urbano, A., 3, 114 Anuradha, V., 6, 20 Anwander, R., 4, 32 Aoki, Y., 1, 220; 8, 17; 9, 117; 12, 119 Aoyaga, S., 12, 154 Aoyagi, S., 13, 78 Aoyama, T., 1, 243; 4, 92 Aparna, P., 6, 20 Apeloig, Y., 1, 57; 11, 126 Aponick, A., 8, 21 Appendino, G., 3, 301 Aprahamian, I., 9, 7 Arai, S., 8, 128 Arai, T., 1, 292, 294; 9, 139 Araki, S., 1, 63 Aranzaes, J.R., 4, 22 Araujo, M., 2, 44 Arbilla, G., 8, 109 Arbuzova, S.N., 10, 56 Arcadi, A., 11, 165 Ardura, D., 2, 90 Arends, I.W.C.E., 3, 200, 246, 275 Arévalo, M.J., 12, 61 Argenis, J., 10, 23 Arias, L., 5, 49 Ariffin, A., 2, 37, 39 Arion, V.B., 12, 105 Arisandy, C., 7, 82 Arlt, D., 4, 27 Armstrong, A., 3, 120, 121; 13, 34; 14, 138 Armstrong, D.R., 6, 71; 9, 100 Armstrong, J.D., 3, 354 Arnaut, L.G., 12, 67 Arndtsen, B.A., 1, 79 Arno, M., 9, 13 Arnold, K., 2, 1 Arnold, P.L., 4, 8 Arnott, G., 1, 214 Aronica, L.A., 11, 248 Arrayás, R.G., 12, 70

Author Index Arroyo, P., 12, 44 Arstad, B., 7, 116 Artamoshkin, V.G., 7, 17, 19; 13, 40 Arumugham, M.N., 3, 74 Arunachalam, S., 3, 74 Arynasab, F., 6, 48; 11, 163 Arzumanov, S.S., 7, 83 Asahara, H., 12, 15 Asai, T., 14, 173 Asai, Y., 7, 168; 14, 58 Asakawa, N., 14, 28 Asakawa, T., 6, 31 Asano, Y., 1, 251 Asao, N., 12, 118 Ashby, M.T., 3, 206 Ashida, S., 1, 197; 12, 176 Astruc, D., 4, 22 Auberson, Y.P., 9, 16 Aubert, C., 12, 168 Auer, G., 11, 247 Augustin, M., 11, 231 Avakyan, V.E., 13, 41 ´ Avalos, M., 12, 61 Avenoza, A., 8, 127 Averina, E.B., 4, 71; 8, 58; 14, 141, 145 Avey, A.A., 1, 352 Aydin, A.E., 1, 223; 9, 112 Aydin, F., 3, 259 Aye, Y., 1, 181 Azap, C., 1, 67 Azarova, E.A., 8, 124 Azizi, N., 6, 48; 11, 163 Azzaoui, B.E., 12, 51

B Baati, R., 1, 189; 14, 121 Baba, A., 12, 123 Baba, A.R., 3, 46 Babiano, R., 12, 61 Baboo, R., 3, 93 Baceiredo, A., 1, 266 Bach, T., 2, 3; 7, 23 Bache-Andreassen, L., 7, 15; 8, 113 Bachi, M.D., 3, 261 Bachie, M., 1, 280 Bachiocchi, E., 7, 42 Back, T.G., 11, 261; 13, 17; 14, 5 Backes, B.J., 5, 45 Backinowsky, L.V., 7, 81 Backtorp, C., 3, 270 Bäckvall, J.-E., 3, 327, 352; 13, 74 Bader, S.J., 12, 14 Badia, D., 11, 9 Bad´ıa, D., 11, 192, 223 Badorrey, R., 9, 86; 11, 230

Badrian, A., 11, 171 Bae, J.Y., 14, 167 Bae, S.-K., 2, 27, 58 Baek, M.-H., 2, 48 Bagan, X., 1, 266 Bagaria, P., 1, 1 Baghdasarian, G., 7, 64 Bagmar, M., 3, 25 Bagno, A., 14, 3 Bagnoli, L., 1, 6 Bagryanskaya, I.Y., 5, 48 Bahrami, H., 3, 43 Bahrami, K., 3, 205 Bai, H.-T., 4, 14 Bai, J., 1, 106 Bai, T.S.J., 3, 17, 34 Bai, X., 14, 125 Baiazitov, R.Y., 12, 6 Baik, J.S., 3, 256 Baik, M.-H., 9, 69 Bailey, D., 12, 181 Bailey, W.F., 9, 68 Bailly, F., 5, 59; 14, 26 Bajaj, K., 5, 44 Bakalbassis, E.G., 13, 44 Bakar, M.D.A., 4, 93 Bakken, V., 14, 92 Bakulev, V.A., 12, 72; 14, 133 Bal, S., 2, 66 Balachandran, S., 8, 121 Balaiah, A., 11, 186 Balamurugan, R., 1, 209 Balazs, A., 1, 218; 9, 109 Balci, M., 4, 59 Baldino, S., 3, 306 Baldwin, J.E., 13, 47, 54–56; 14, 150 Balensiefer, T., 4, 88 Balentova, E., 3, 294 Balija, A.M., 1, 3; 11, 73 Ball, R.G., 12, 77 Balle, T., 9, 61 Ballini, R., 11, 8 Bally, T., 4, 76, 79; 14, 178 Balogh-Hergovich, E., 3, 214 Bancu, M., 9, 7 Bandini, M., 1, 321; 3, 314; 6, 33; 7, 181 Banerjee, S., 10, 14; 14, 45 Banerji, K.K., 3, 4 Banert, K., 10, 44 Bang, H.Y., 2, 45 Banks, H.D., 8, 52 Bansal, R.K., 12, 152 Bao, W., 1, 338 Baptista, L., 8, 109 Baragona, F., 12, 43 Baran, A., 2, 64 Baran, P.S., 14, 166

515

Author Index Barbas, C.F., 1, 26, 111, 203; 11, 195 Barchuk, A., 3, 377, 393; 8, 25; 11, 108 Barlan, A.U., 3, 78, 79 Barlow, S., 7, 82 Barluenga, J., 1, 272; 4, 43, 44, 46; 6, 63; 14, 102 Barma, D., 1, 189; 14, 121 Barman, J., 2, 109 Barnes, C.L., 12, 177 Barnes, I., 3, 244 Baro, A., 7, 146 Barone, V., 8, 114 Barontini, M., 3, 213 Barret, R., 12, 43 Barros, H.J.V., 11, 104 Barsy, M.A., 1, 240; 10, 37 Bartoli, G., 2, 42 Barua, N.C., 1, 141; 9, 42 Baruah, B., 12, 48 Basak, A., 3, 78, 79 Basak, S., 3, 222 Basaric, N., 7, 41 Basavaiah, D., 3, 312, 313 Basch, H., 14, 135 Basilio, N., 2, 65 Basra, S., 1, 41; 9, 120 Bassioni, G., 9, 55 Bastianoni, S., 3, 289 Baszczyˇnski, O., 11, 44 Batalov, A., 7, 99 Bathala, R.M., 13, 33 Batsanov, A.S., 5, 7; 7, 145 Battace, A., 5, 37 Battin-Leclerc, F., 3, 253 Battista, M.A., 5, 4 Bau, R., 3, 241; 14, 154 Bauer, H., 7, 36 Bauer, M., 7, 39 Bauerfeldt, G.F., 8, 109 Baumann, T., 1, 280 Bauta, W.E., 5, 9 Bautista, D., 12, 38; 13, 85 Baymak, M.S., 1, 91 Bazin, S., 9, 96 Beaulieu, E.D., 6, 28; 11, 170 Becker, E., 4, 28 Beckers, H., 10, 32 Beckmann, J., 9, 83 Bednarek, P., 4, 81 Begtrup, M., 9, 61 Behenna, D.C., 10, 48 Behnke, M., 10, 32 Beier, P., 9, 151 Bekdemir, Y., 2, 62 Bekele, T., 12, 136 Belanger, A.P., 9, 7 Belanger, G., 1, 278 Belanger, J.M.R., 13, 50

Belen’kii, L.I., 6, 67 Beletskaya, I.P., 5, 2 Bell, A.T., 3, 82 Bell, M., 11, 157 Bella, M., 5, 25 Bellan, J., 12, 51 Beller, M., 3, 95, 96; 11, 64 Belmekki, N., 3, 253 Belskaia, N.P., 12, 72 Belyakov, P.A., 1, 78 Benagalia, M., 1, 117 Benaglia, M., 1, 301 Ben-David, Y., 3, 328 Bendikov, M., 11, 126 Bendova, L., 1, 262; 3, 360 Benet-Buchholz, J., 14, 136 Benish, M., 7, 142; 9, 9 Benito, A., 9, 81 Benltifa, M., 12, 45 Bennet, A.J., 1, 10 Bentley, T.W., 7, 7, 50, 155; 8, 85, 96 Bercaw, J.E., 7, 84 Beregovaya, I.V., 5, 48 Berestneva, T.K., 7, 81 Berg, T.C., 14, 92 Bergens, S.H., 1, 308; 3, 338, 339 Berger, S., 9, 40; 10, 39 Bergman, R.G., 4, 24; 11, 110; 14, 70 Bergquist, K.-E., 11, 148 Berke, H., 4, 37 Berkessel, A., 3, 198, 217 Berkowitz, D.B., 13, 27 Berlin, J.M., 14, 110 Bernardinelli, G., 5, 34 Bernasconi, C.F., 8, 101; 9, 137; 10, 53; 11, 127 Berndt, A., 7, 76 Bernes, S., 1, 213; 9, 111 Bernini, R., 3, 213 Bertha, F., 2, 94 Berthet, J., 3, 154 Berti, P.J., 2, 97 Bertolasi, V., 3, 226 Bertolini, F., 6, 27 Bertolli, P., 9, 37; 14, 172 Bertrán, J., 13, 7 Bertrand, G., 4, 21, 57; 7, 134, 135 Bertrand, M.P., 9, 96 Bessolo, J., 2, 47 Beth, E.B., 3, 349 Bettoni, M., 7, 26 Bhadbhade, M.M., 12, 187 Bharadwaj, A.R., 1, 166 Bharadwaj, S., 3, 66 Bhargava, G., 12, 32; 13, 8 Bhattacharjee, G., 5, 44

Bhattacharyya, J., 3, 45 Bhattacharyya, R., 3, 77 Bhor, S., 3, 95, 96 Bhosekar, G.V., 12, 187 Bhowmick, M., 11, 24 Bhuvaneshwari, D.S., 3, 18, 19 Bhuyan, P.J., 12, 48 Bi, X., 11, 135 Biaggi, C., 1, 301 Bian, X., 1, 53; 3, 382 Bianchi, G., 11, 165 Bica, K., 8, 90; 9, 93 Bickelhaupt, F.M., 8, 74; 9, 5 Biddick, N.A., 13, 31 Biddle, M.M., 9, 146 Bieniek, M., 4, 27 Bierbaum, V.M., 8, 59; 10, 6 Biermann, U., 7, 102 Biffinger, J.C., 9, 138 Bikzhanova, G.A., 1, 48; 3, 329 Billings, S.B., 7, 63; 8, 104 Bilthoven, N., 9, 49–51 Binev, I.G., 9, 4 Bini, R., 5, 3 Bio, M., 3, 336 Biosa, G., 3, 289 Bisai, A., 1, 185 Bish, G., 11, 244 Bishop, R.L., 1, 293; 9, 12 Biswas, S., 8, 101; 10, 53; 11, 127 Bitter, I., 3, 166 Bjorgen, M., 7, 85 Bjorsvik, H.-R., 4, 25 Black, D.A., 1, 79 Blacker, A.J., 3, 112 Blackmond, D.G., 3, 373; 5, 31 Blacque, O., 4, 37 Blagg, B.S.J., 12, 7 Blanchot, M., 11, 96 Blanco, M.B., 3, 255 Blanco, M.C., 11, 120 Blanksby, S.J., 5, 20; 10, 19 Blaskó, G., 13, 72 Blay, G., 1, 143, 228; 7, 186; 9, 44; 11, 152; 14, 35 Blechert, S., 14, 107 Bloemberg, T.G., 4, 36 Blum, J., 1, 36 Blumberger, J., 2, 34, 35 Boa, A.N., 12, 71 Boardman, B., 3, 335 Boatz, J.A., 11, 16 Bobbio, C., 9, 153 Boche, G., 9, 5 Bode, C.M., 1, 71 Bode, J.W., 1, 267; 4, 95, 98; 9, 145; 12, 126 Bogdam, E., 7, 155 Bogdan, E., 6, 61

516 Bogdanov, B., 8, 71 Bogdanova, M.V., 10, 56 Boger, D.L., 12, 7, 130, 153 Boggs, M.E., 2, 31; 7, 57 Böhrsch, V., 14, 107 Bois, J.D., 3, 180 Boiteau, L., 2, 87 Bojin, M.D., 7, 163 Boland, W., 7, 175 Bolm, C., 1, 137, 284, 346; 3, 228 Bols, M., 3, 209 Bolte, M., 7, 74 Bolton, J.L., 7, 10 Bombardelli, E., 3, 301 Bonache, M.A., 8, 132 Bondarev, O., 3, 341 Bonesi, A.M., 3, 240 Bongardt, T., 7, 73; 11, 37 Bongini, A., 1, 350 Bonillo, B., 13, 82 Bonin, M., 14, 47 Bonini, B.F., 6, 40; 12, 142 Bonini, C., 3, 41 Bonneau, A.-L., 9, 62 Bonneau, R., 4, 103 Boons, G.-J., 7, 61, 65 Booth, R.A., 11, 182 Borboa, L.G., 2, 88 Borbulevych, O. Ya., 5, 60 Borden, W.T., 4, 72; 14, 146 Borella, S., 7, 184 Borhan, B., 3, 101 Borisova, T.N., 14, 129 Borje, A., 3, 270 Born, R., 5, 41; 6, 59 Borodkin, G.I., 6, 9; 7, 114 Boros, E., 2, 94 Borosky, G.L., 7, 150 Borovlev, I.V., 7, 24 Boruwa, J., 1, 141; 9, 42 Boryski, J., 8, 131 Bosca, F., 7, 104 Bosch, J., 9, 18 Bosco, M., 2, 42 Bosica, G., 11, 8 Bottoni, A., 1, 321; 3, 314 Boubaker, T., 5, 56, 57; 6, 49; 7, 52 Bou Laouz, A., 13, 50 Boumbia, M.L., 12, 51 Bounaceur, R., 3, 253 Bouquillon, S., 14, 120 Bourceanu, G., 3, 166 Bourgeois, D., 13, 11 Bournaud, C., 14, 47 Bouwkamp, M.W., 12, 23 Bower, J.F., 9, 36 Bowerman, C., 1, 205 Bowman, A.C., 12, 23

Author Index Bowman, J.M., 7, 152 Bowman, R.K., 14, 86 Boyd, D.R., 3, 281 Boyd, R.J., 10, 30 Boyle, K.L., 3, 349 Braams, B.J., 7, 152 Brackley, J.A., 12, 177 Braga, A.A.C., 6, 58 Braieda, B., 7, 95 Branchadell, V., 1, 266 Brandao, T.A.S., 2, 14 Brandariz, I., 2, 75 Brandsma, L., 9, 49–51 Brandt, P., 3, 352 Branzˇa-Nichita, N., 14, 71 Brase, S., 1, 280 Braun, M., 8, 4; 9, 11 Bravo-Diaz, C., 5, 1; 7, 105 Bray, K.L., 14, 91 Brebion, F., 13, 35, 37 Brecker, L., 3, 284 Breckle, G., 12, 133 Breit, B., 8, 7; 9, 90; 11, 93 Breitenlechner, S., 2, 3 Brenner, S.E., 9, 45; 11, 146 Breslow, R., 3, 279 Breugst, M., 7, 47; 8, 93 Brewer, M., 1, 93; 3, 111 Brinchi, L., 8, 87 Brinck, T., 7, 3 Brinker, U.H., 4, 10, 13; 14, 163 Brinkmann, C., 11, 96 Broggini, G., 12, 81 Brongersma, H.H., 3, 286 Brook, M.A., 1, 265; 3, 364 Broussy, S., 3, 288 Brouwer, C., 11, 33, 116 Brown, M.K., 11, 232 Brown, R.S., 2, 106 Brown, S., 9, 66 Brown, S.N., 1, 287 Browne, W.R., 9, 86; 11, 230 Bruckmann, A., 1, 161; 11, 176 Brud, A., 11, 180 Brule, C., 7, 139 Bruneau, C., 8, 20 Brunoldi, E., 7, 169 Brusco, D., 10, 21 Bryce, M.R., 7, 145 Brym, M., 7, 75 Brzezinski, B., 5, 15 Buchanan, J.G., 2, 2; 8, 117 Buckley, B.R., 3, 112 Budˇesˇ´ınský, M., 14, 21 Budynina, E.M., 8, 58 Budzelaar, P.H.M., 11, 61 Bugg, T.D.H., 3, 281 Bui, B.H., 13, 59; 14, 176 Bujan, E.I., 5, 19 Bujok, R., 4, 27

Bukowski, M.R., 3, 83 Bultinck, P., 7, 159 Buncel, E., 2, 18, 19 Bunuel, E., 4, 38 Buono, G., 11, 85; 12, 185; 14, 16 Burcat, A., 3, 248 Burda, J.V., 8, 111 Burger, M., 3, 167 Burgin, M.O., 10, 52 Burke, C.P., 3, 117 Burke, L.A., 14, 131 Burnell, D.J., 11, 225 Burtoloso, A.C.B., 12, 37 Burton, R.R., 12, 25 Buscemi, S., 14, 128 Bushmelev, V.A., 7, 17–19; 13, 40 Busico, V., 4, 36 Buskens, P., 1, 161; 11, 176 Busto, J.H., 8, 127 Butin, K.P., 3, 385 Butler, R.N., 14, 131 Butterfield, A.M., 1, 205 Buttero, P.D., 3, 322 Bykowski, D., 4, 52 Bła˙zej, S., 11, 180 Błaszczyk, K., 14, 76

C Cabaj, M., 4, 27 Cabanas, B., 3, 89 Cabello, N., 1, 39 Cabrera, J., 12, 38; 13, 85 Cacciapaglia, R., 2, 105; 7, 69 Cachau, R.E., 8, 38 Cadeau, H., 6, 68 Caggiano, L., 14, 109 Cai, C., 5, 27 Cai, M., 11, 59 Cai, Z., 2, 115 Cai, Z.-T., 2, 60 Caine, D., 1, 234; 9, 10, 53 Calado, A.R.T., 8, 79 Caliando, B.J., 3, 180 Calvaleiro, J.A.S., 12, 73 Camacho, M.E., 3, 107 Camarasa, M., 8, 73 Campbell, A.D., 3, 100 Campbell, C., 7, 118 Campbell, E., 2, 33 Campbell, L., 1, 312 Campeau, L.-C., 6, 55 Campestrini, S., 3, 263 Campodonico, P.R., 2, 30, 40, 50, 51 Campomanes, P., 2, 90 Campos, J.M., 8, 129 Canac, Y., 4, 57; 7, 134 Canal, J.P., 4, 7

517

Author Index Candeias, N.R., 4, 49 Canedo, M.M., 14, 18 Canle, L.M., 10, 49 Cantrell, W.R., 5, 9 Cantrill, A.A., 1, 61; 8, 54 Cao, C.-L., 1, 202; 11, 210 Cao, D., 6, 34; 14, 39 Cao, W.L., 13, 71 Capela, R., 8, 126 Capitelli, F., 3, 226 Capitò, E., 6, 40; 12, 142 Caporusso, A.M., 11, 248 Capozzi, M.A.M., 3, 226 Cappuccio, F., 3, 353 Cappucio, F., 1, 310 Cardellicchio, C., 3, 226 Cardenas, D.J., 4, 38 Cardona, C.M., 10, 15 Cardona, L., 7, 186; 14, 35 Cardoso, A.S.P., 13, 76 Cardy, B., 3, 287 Carlier, P.R., 7, 12 Carlone, A., 2, 42 Carlos, J., 10, 24 Carlson, R., 11, 139 Carmeli, M., 1, 80 Carmona, E., 14, 112 Carneiro, A.S., 12, 94 Carneiro, J.W., 6, 17; 7, 113 Carpenetti, D., 7, 143 Carra, C., 4, 79; 14, 178 Carraro, M., 3, 263 Carrea, G., 3, 237 Carreira, E.M., 8, 5 Carreno, M.C., 3, 114 Carrera, D.E., 3, 359 Carretero, J.C., 1, 29; 12, 70 Carrillo, L., 11, 9, 192, 223 Carrion, M.D., 3, 107 Carroll, A., 9, 66 Carty, A.J., 4, 29 Carvalho, N.F.N.N., 11, 91 Casas, J., 1, 24 Casey, C.P., 1, 48; 3, 329; 14, 37 Casimiro-Garcia, A., 3, 386 Casnati, A., 2, 105 Cassano, A.G., 1, 208; 2, 10; 8, 68 Castanet, A.-S., 9, 58–60 Castarlenas, R., 14, 111 Castedo, L., 1, 348; 12, 62, 99 Castellano, R.K., 1, 236; 9, 76 Castillo, N., 10, 30 Castillo, R., 10, 49 Castillon, S., 3, 347 Castoldi, D., 14, 109 Castro, E.A., 2, 30, 40, 47, 54, 76 Catino, A.J., 1, 35

Cativiela, C., 8, 132 Caubere, P., 9, 63 Cavaleiro, J.A.S., 3, 49 Cavalli, A., 7, 96; 13, 64 Cavillo, J.E., 13, 33 Cazorla, A.M., 1, 266 Cecchi, M., 5, 50 Ceccon, J., 12, 30 Cee, V.J., 1, 130, 154 Cerkovnik, J., 3, 196, 238 ˇ y, M., 14, 21 Cern´ Cerny, M.A., 3, 290 ˇ y, V., 11, 25, 32 Cern´ Cervantes, H., 5, 49 Cha, C., 14, 75 Chai, Z., 3, 223 Chaikovskaya, O.N., 7, 20 Chaki, N.K., 4, 67; 14, 32 Chakraborti, A.K., 11, 130 Chakraborty, D., 7, 118 Chakthong, S., 9, 36 Chaladaj, W., 1, 171; 6, 47; 9, 133 Challinor, L., 13, 34 Chambel, P., 8, 126 Champeau, R.M., 3, 188 Chan, A., 1, 257; 4, 89 Chan, A.S.C., 1, 230; 3, 331; 9, 106 Chan, H.-S., 12, 161 Chan, T.H., 3, 110; 9, 84 Chan, W.S., 7, 119 Chandrasekhar, S., 1, 103, 270; 9, 17; 11, 178 Chang, C.-H., 7, 177 Chang, S., 11, 97 Chang, W.-X., 1, 170 Chang, Y., 5, 27 Chang, Y.-J., 7, 176 Chao, I., 12, 49 Chapman, T.M., 8, 15 Chappell, J., 7, 174 Chapuis, C., 12, 101 Chaquin, P., 11, 264 Charette, A.B., 1, 16; 9, 119 Chatani, N., 1, 8; 7, 183; 14, 85 Chattaraj, P.K., 1, 298; 6, 1, 2; 11, 15 Chatterjee, D., 3, 222 Chatterjee, S., 2, 109 Chattopadhyaya, J., 2, 109 Chau, A., 3, 368 Chaubey, G.S., 1, 340; 3, 10, 11, 13, 14 Chaudhary, P., 1, 342; 3, 29 Chaudhuri, P.D., 5, 34 Chauhan, M., 3, 90, 92 Chauvin, Y., 4, 2 Chavan, S.P., 4, 67; 14, 32 Chavan, V.B., 4, 67; 14, 32

Che, Q., 12, 79 Chellamani, A., 3, 44 Chelucci, G., 3, 306 Chempath, A., 3, 82 Chen, A.C., 1, 344; 3, 232 Chen, C., 7, 124; 11, 169; 12, 98 Chen, C.-H., 9, 3 Chen, C.-T., 3, 262 Chen, F.-L., 1, 14 Chen, G., 11, 31, 84 Chen, H., 1, 4, 5, 268 Chen, J., 1, 222; 11, 59 Chen, J.-H., 1, 169 Chen, J.-R., 1, 109 Chen, K., 1, 168, 169, 327 Chen, L.-T., 6, 18 Chen, M., 9, 20 Chen, P., 4, 37 Chen, P.-C., 12, 41 Chen, Q., 11, 83 Chen, Q.-Y., 4, 61; 8, 115, 116 Chen, W., 1, 309; 3, 173, 334 Chen, X., 1, 96, 253; 3, 53; 5, 29 Chen, X.-X., 4, 53, 54 Chen, Y., 4, 85; 8, 46; 14, 127 Chen, Y.-C., 4, 96; 11, 153, 217 Chen, Y.-J., 6, 26 Chen, Y.K., 11, 144 Chen, Z., 1, 33 Chen, Z.-T., 1, 239 Cheng, C., 1, 114; 6, 50 Cheng, C.-H., 3, 389; 11, 266 Cheng, E.W.C., 12, 96 Cheng, F., 1, 9; 3, 309 Cheng, J., 1, 291 Cheng, J.-J., 9, 3 Cheng, J.-P., 3, 384; 11, 199, 200 Cheng, L., 1, 149, 150 Cheng, M.-J., 11, 266 Cheng, Z.-L., 4, 61 Cheon, S., 8, 110 Cheong, M., 14, 167 Cheong, P.H.-Y., 1, 26; 3, 202 Chernysheva, N.A., 10, 56 Chessa, S., 3, 306 Chevallier, F., 11, 93 Chi, C.-X., 1, 217; 9, 114 Chi, D.Y., 8, 65 Chiang, S.-M., 1, 13, 14 Chiappe, C., 5, 3 Chiavarino, B., 7, 115 Chiba, K., 12, 123 Chiba, T., 8, 31 Chica, A., 3, 221 Chimni, S.S., 1, 107 Chin, A.O., 2, 102 Chirik, P.J., 12, 23 Chishima, H., 1, 211

518 Chisholm, J.D., 1, 148, 194; 9, 132; 11, 87 Chiu, F.-H., 7, 177 Chiu, P., 11, 3 Chiummiento, L., 3, 41 Chmielewski, M., 12, 53 Ch.O., 11, 186 Cho, B.R., 10, 1 Cho, C.-G., 13, 38 Cho, C.S., 3, 297 Cho, E.J., 4, 41, 42; 14, 118 Cho, J., 10, 29; 14, 147 Cho, Y., 8, 50 Choe, J.-I., 3, 272 Choi, S.Y., 4, 31; 12, 8 Chojnacka, A., 12, 101 Chongthu, L., 3, 8 Chotii, K.Y., 2, 23 Chouhan, K., 1, 89; 3, 23, 26 Chow, M.S., 3, 85 Chow, S., 11, 204 Choytun, N., 1, 10 Christianson, D.W., 7, 171 Christl, M., 6, 61; 7, 155 Christoforou, A., 3, 109 Christy, J.P., 12, 175 Chu, J.-H., 12, 49 Chu, S., 8, 75 Chu, S.-Y., 8, 107, 108; 11, 266 Chu, Y., 1, 88; 3, 310 Chuchani, G., 10, 20, 21, 23–27, 31 Chughtai, M.J., 3, 100 Chun, S.-M., 2, 58 Chung, C.K., 1, 28 Chung, H., 14, 138 Chung, L.W., 1, 264 Chung, M.-K., 1, 187 Chung, S.-Y., 8, 106 Chung, W., 1, 247 Chung, W.-S., 12, 49 Chung, Y.K., 4, 31; 12, 8 Chupakhin, O.N., 1, 66 Chuvylkin, N.D., 6, 67 Chuzel, O., 1, 157 Cibulka, R., 2, 71 Ciclosi, M., 5, 33 Cimarelli, C., 1, 320; 3, 321 Cintas, C., 12, 61 Cintrat, J.-C., 12, 83 Ciriminna, R., 3, 263 Civcir, P.U., 7, 15; 8, 113 Claeys, D.D., 14, 8 Clark, D.A., 13, 16 Clark, J.S., 14, 79 Clark, R.C., 12, 130 Clark, S., 12, 71 Clarke, M.L., 11, 107 Clarkson, G.J., 1, 315; 3, 374

Author Index Claver, C., 3, 347 Clavier, H., 9, 87; 11, 231 Clegg, W., 6, 71, 72; 9, 100, 101 Cleland, W.W., 2, 33 Clemens, N., 14, 46 Climent, E., 1, 143; 9, 44 Clyburne, J.A.C., 4, 7 Coates, R.M., 1, 184; 7, 174 Cochran, B.M., 11, 78 Coe, D.M., 1, 176 Coelho, F., 11, 175 Cohen, T., 3, 173 Coichev, N., 3, 76 Cole, K.P., 12, 172 Collado, A.M., 7, 186; 14, 35 Colladon, M., 3, 216 Colleredo-Mels, S., 7, 31 Colletti, S.L., 5, 52 Collin, J., 6, 32; 11, 124 Colloredo-Mels, S., 7, 32 Collum, D.B., 1, 37; 9, 2, 57, 71; 14, 2 Colvin, M.E., 7, 125 Colyer, J.T., 3, 323 Comba, P., 3, 83 Comes-Franchini, M., 6, 40; 12, 142 Comesse, S., 14, 63 Cometto, P.M., 3, 255 Compain, P., 3, 178 Compos, E., 5, 49 Concellon, C., 10, 42 Concellon, J.M., 3, 381; 10, 42 Concha, M.C., 8, 111 Connon, S.J., 2, 89; 6, 41 Conrad, K.M., 3, 354 Consorti, C.S., 11, 175 Constantieux, T., 14, 16 Conte, P., 11, 17 Contini, A., 12, 122 Contreras, R., 2, 40, 50, 51; 8, 98 Conza, M., 1, 274; 9, 48 Cook, G.R., 11, 54 Cook, S.P., 12, 106 Cooke, R.S., 13, 34 Cooks, R.G., 1, 4, 5 Cooper, D.L., 13, 9 Coquière, D., 6, 68 Cordes, D.B., 1, 317; 3, 298 Cordoba, R., 1, 246 Cordonier, C.E.J., 7, 120 Cordova, A., 1, 24, 34, 120, 121, 201, 300; 3, 204, 242; 9, 26; 11, 145, 179, 201 Cordova, T., 10, 23–27, 31 Corey, E.J., 11, 25 Corminboeuf, C., 8, 6 Cornelissen, L.L.J.M., 3, 103 Correa, A., 9, 86; 11, 230

Correa, N.M., 5, 22 Correiga, C.R.D., 12, 37 Cos¸kun, N., 14, 142 Coss´ıo, F.P., 14, 161 Cossu, S., 11, 102 Cossy, J., 1, 212; 9, 110; 14, 103 Costa, A.M., 14, 109 Coste, G., 1, 7 Cottet, H., 2, 87 Coulombel’, L., 11, 52 Courillon, C., 8, 11; 9, 72 Cousson, A., 7, 148; 14, 64 Coutrot, P., 13, 15 Couty, F., 8, 57; 13, 32 Couty, S., 14, 103 Cozzi, F., 1, 301 Cozzi, P.G., 1, 20, 226, 321; 3, 314; 9, 98, 116 Craig, D., 13, 11 Cramer, C.J., 1, 154 Crampton, M.R., 5, 6, 7 Crasmareanu, C., 6, 66 Crauste, C., 13, 15 Crawford, K.R., 12, 89 Crawford, T.D., 7, 12 Crawley, M.L., 3, 97 Cremer, D., 3, 196 Crespo, A., 7, 164 Crestoni, M.E., 7, 115 Crevisy, C., 1, 156 Crich, D., 13, 35–37 Cristau, H.-J., 11, 265 Croatt, M.P., 12, 179 Cross, D.J., 1, 312 Cross, R.J., 12, 13 Crotti, P., 6, 27 Crowhurst, L., 8, 122 Crudden, C.M., 1, 344; 3, 232 Cruz, J., 3, 231; 14, 67 Csaky, A.G., 1, 246 Cuenca, A., 5, 54 Cuerdo, L., 9, 81 Cui, D.-M., 6, 60 Cui, J., 1, 206 Cui, S.-L., 1, 195 Cui, X., 1, 49; 3, 371 Culkin, D.A., 5, 39 Culver, J.P., 9, 66 Cun, L., 1, 49; 3, 371 Cun, L.-F., 1, 105, 149, 150; 11, 203; 12, 148 Cunningham, D., 14, 131 Cuperly, D., 1, 156 Cuquerella, M.C., 7, 104 Curci, R., 3, 197 Curtis, N.R., 12, 77 Cushman, M., 6, 62 Czegeny, Z., 10, 16 Czira, G., 2, 94

519

Author Index D Daasbjerg, K., 3, 377, 393; 8, 25 D’Accolti, L., 3, 197 Daglen, B.C., 1, 205 Dai, C.-b., 6, 19 Dai, G.-L., 4, 65 Dai, L.-X., 10, 50 Dai, S., 14, 74 Dai, Y., 11, 2 Dakternieks, D., 9, 83 Dalaigh, C.O., 2, 89 Dale, S.H., 6, 71, 72; 9, 100, 101 Daley, C.J.A., 3, 339 Dalpozzo, R., 1, 15; 2, 42 Damez, C., 14, 120 Dancsó, A., 13, 72 Danger, G., 2, 87 Danheiser, R.L., 12, 35 Danielsson, R., 8, 63 Danishefsky, S.J., 3, 202; 12, 106 D’Anna, F., 5, 42; 10, 2; 14, 155 Daquino, C., 7, 33 Darabi, H.R., 1, 281 Darbre, T., 1, 98 Darsigny, V., 1, 278 Das, A., 14, 45 Das, A.K., 3, 30 Das, B., 8, 36 Das, K., 3, 39 Das, S., 3, 5, 12, 45 Dasaundhi, R.A., 2, 12 Dascombe, M.J., 7, 180 da Silva, D., 2, 100 Da Silva, J.G., 11, 104 DaSilveira Neto, B.A., 11, 38, 175 Dauban, P., 4, 75 d’Augustin, M., 9, 87 D’Auria, M., 6, 5 Davalos, J.Z., 7, 151 Davico, G.E., 8, 66 David, O., 8, 57 Davies, B., 2, 1 Davies, D.L., 6, 70 Davies, H.M.L., 4, 5, 55 Davioud-Charvet, E., 7, 36 Davis, C.E., 1, 184 Davis, R.J., 7, 87, 88 Davis, S.R., 13, 62 Day, M.W., 4, 26 Dazinger, G., 1, 345; 3, 291; 4, 28 De, A., 9, 59 de, M., 6, 17; 7, 113 De Angelis, F., 10, 3 Debarge, S., 7, 148; 14, 64 De Benassuti, L., 12, 50 de Bruin, B., 4, 36

de Castro, S., 8, 73 DeChristopher, B.A., 13, 31 Decker, A., 3, 85 Defieber, C., 8, 5 de Frémont, P., 13, 21 Degenhardt, J., 7, 175 de Gonzalo, G., 3, 237 de Groot, A., 14, 140 Degryarev, A.V., 7, 38 Degtyarev, A.V., 14, 62 Dehaen, W., 12, 72; 14, 133 Dejaegere, A., 2, 99 De Kimpe, N., 8, 43 Delalu, H., 3, 154 de Laorden, C.L., 3, 83 Del Buttero, P., 12, 50 del Carmen Hita, M., 1, 116 de Lera, A.R., 13, 63; 14, 99 Delgado, F., 6, 53 Delgardo, A., 12, 62 Del Giacco, T., 7, 26, 42 del Mar Graciani, M., 8, 89 del Olmo, E., 12, 97 del Pozo, C., 14, 108 Del Vecchio, E., 5, 55; 6, 7 Demappa, T., 3, 146 Demel, P., 8, 7; 9, 90 Demerseman, B., 8, 20 Demeter, A., 7, 110 Demir, A.S., 1, 223; 9, 112 Denegri, B., 7, 48, 49; 8, 94, 95 Denehy, E., 2, 113 Denekamp, C., 7, 54 Deng, G., 1, 76 Deng, J., 1, 49; 3, 340, 371 Deng, J.-G., 11, 153 Deng, L., 1, 27, 145, 254; 6, 44, 46; 11, 155, 218; 12, 161 Deng, W.-P., 14, 75 De Nino, A., 1, 15 Denise, B., 11, 264 Denmark, S.E., 1, 17, 176, 247; 11, 29; 12, 6 Deora, N., 7, 12 de Parrodi, C.A., 1, 213 Deprez, N.R., 6, 56 de Queiroz, J.F., 6, 17; 7, 113 de Rossi, R.H., 2, 17; 4, 47 Deruytter, J., 5, 47 Deryabina, T.G., 12, 72 Deschamp, J., 1, 157 Deshpande, S.S., 12, 115 Desimoni, G., 1, 133; 4, 6; 8, 22, 55; 11, 5 Detty, M.R., 3, 219 DeTuri, V.F., 9, 138 Detusheva, L.G., 3, 251 Deutsch, C., 3, 36 Devi, R.S., 8, 121 Devipriya, S., 4, 86

De Vos, D.E., 14, 38 de Vries, J.G., 1, 285, 314 Dey, S., 8, 100 Deyhimi, N.F., 11, 181 Dhariwal, V., 1, 89; 3, 28 Dhondi, P.K., 1, 194; 9, 132 D’hooghe, M., 8, 43 Dhusia, M., 3, 68, 69 Diaconescu, P.L., 7, 84 Dias, J.F., 9, 135 Dias, L.C., 1, 126 Diaz, N., 2, 90 Diaz, Y., 3, 347 Diaz-Gavilán, M., 8, 129 Diaz-Torres, E., 13, 50 Dichiarante, V., 7, 106, 107 Dick, A.R., 3, 278; 6, 16 Dickerson, T.J., 1, 112 Dickie, D.A., 4, 7 Didierjean, C., 13, 15 Diedrich, C., 13, 18 Diéguez, A., 14, 102 Dieker, J., 7, 97; 13, 65 Dieltiens, N., 14, 8 Diesen, J.S., 1, 51; 3, 344 Dietrich, H.M., 4, 32 Dietzel, P., 9, 66 Diev, V.V., 12, 58 D´ıez-González, S., 13, 21 Diggle, R.A., 2, 2; 8, 117 Dilman, A.D., 1, 57, 78 DiMagno, S.G., 5, 24 Di Marco, C.N., 9, 94 Dimitrov, V., 1, 231; 9, 95 Dimtsas, J., 12, 47 Dinda, S., 3, 77 Diner, P., 1, 113 Dinesh, B., 3, 383 Ding, F.-X., 5, 52 Ding, H., 1, 95 Ding, K., 12, 125 Ding, L., 1, 170; 8, 46 Ding, L.-N., 1, 108 Ding, L.-S., 4, 96; 11, 217 Ding, R., 11, 148 Ding, X., 4, 82 Ding, Y., 6, 51 Disadee, W., 1, 275 Di Stefano, S., 7, 69 Ditrich, K., 3, 123; 8, 6 Diver, S.T., 13, 16; 14, 117 Dixit, V.K., 2, 55 Dixneuf, P.H., 14, 111 Dixon, D.J., 1, 233 Dkhar, P.G.S., 4, 68, 77 Doan, L., 7, 25 Dobler, C., 3, 95, 96 Dobrowolski, J.C., 12, 28, 29 Docherty, G.F., 1, 311; 3, 337 Dockendorff, C., 8, 15

520 Doda, K., 9, 46; 11, 156, 213 Dodd, R.H., 4, 75 Doering, W., 13, 46, 53 Dolbier, W.R., 1, 282; 5, 4 Dolby, L.J., 1, 352 Dolgushin, G.V., 5, 12 Domingo, L.R., 2, 40; 9, 13, 142; 11, 220; 12, 44, 94, 100 Dominguez, R.M., 10, 20, 21 Dominguez-Fernandez, B., 3, 121 Dominiak, P.M., 4, 55 Domostoj, M., 8, 56 Donahue, J.P., 14, 152 Donald, S.M.A., 6, 70 Dondi, R., 7, 31 Dong, C., 1, 76 Dong, C.Q., 3, 64 Dong, S., 1, 293; 9, 12 Donnadieu, B., 4, 21, 57; 7, 134, 135 Donohoe, T.J., 3, 100 Donovan, P.M., 9, 6 Dooley, C.J., 1, 11 Dopfer, O., 6, 64; 7, 109, 115 Dore, M., 1, 278 Doria, F., 7, 32 Doris, E., 14, 63 Dorogov, M.V., 5, 16 Dos Santos, E.N., 11, 104 Dotz, K.H., 3, 227 Doubleday, C., 14, 169 Doucet, H., 5, 37 Dowers, T.S., 7, 10 Doye, S., 11, 56 Doyle, M.P., 1, 35; 4, 52 Draˇc´ınský, M., 7, 30; 14, 21 Drager, M., 9, 83 Dreessen, S., 7, 73 Dreeßen, S., 11, 37 Drew, M.G.B., 1, 61; 7, 180; 8, 54 Driess, M., 7, 75 Drudis-Sole, G., 3, 98; 11, 6 Drysdale, M.J., 14, 79 D’Souza, M.J., 2, 31, 59; 7, 57 Du, D.-M., 1, 81; 6, 43; 11, 252 Du, H., 12, 125 Du, L., 2, 70 Du, Y., 7, 119 Duan, H.-F., 6, 45 Duan, W., 11, 160 Duan, W.-L., 11, 245 Duan, Z., 11, 136 Duarte, M.T., 11, 91 Dube, M.A., 6, 22 Dubé, P., 14, 105 Dubs, C., 1, 74

Author Index Ducray, R., 12, 153 Dudley, G.B., 9, 19 Duguet, N., 9, 27; 11, 224 Dulak, M., 3, 379 Dumbrava, I.G., 4, 107 Duñach, E., 2, 49; 11, 51, 52; 14, 83 Dunetz, J.R., 12, 35 Duong, H.A., 12, 163 Dupont, J., 11, 38, 175 Duran, M., 13, 66 Durantini, E.N., 5, 22 Durrani, A.I., 1, 345; 3, 291 Durrat, F., 8, 57; 13, 32 Dussault, P.H., 3, 189, 190 Duthie, A., 9, 83 Dutov, M.D., 5, 17, 18; 11, 219 Dvorak, M., 2, 102 Dvorko, G.F., 8, 84, 123; 10, 9–11 Dwyer, C.L., 10, 34 Dybala-Defratyka, A., 8, 61, 63 Dyker, G., 14, 94 Dyudya, L.V., 14, 133 Dzeidzic, P., 1, 121 Dzhurinskaya, S.S., 8, 124 Dziedzic, P., 1, 120 Dzik, W.I., 4, 36 Dˇzoganová, M., 14, 21

E East, A.L.L., 7, 86 East, S.P., 14, 79 Eastman, K.J., 7, 35 Ebata, S., 11, 68 Eberlin, M.N., 1, 4, 5; 6, 17; 7, 113; 9, 135; 11, 38, 175 Ebrahimi, R., 3, 20 Echavarren, A.M., 4, 38, 39; 6, 58; 11, 118; 14, 96–98 Echegoyen, L., 10, 15 Echevarria, G.R., 2, 76 Eckschlager, T., 7, 30 Eduarda, M., 2, 44 Edwards, D., 1, 344; 3, 232 Edwards, M.G., 11, 29 Egawa, H., 13, 24 Egli, D.H., 13, 67 Egorov, I.N., 1, 66 Eguchi, T., 7, 172 Ehlers, A.W., 12, 39 Ehrenberger, C, E., 8, 120 Eilerman, S., 9, 66 Elango, K.P., 3, 18, 19 Elango, M., 1, 298; 6, 2; 11, 15 El-Awa, A., 8, 32 Elba, M.E., 10, 5 El-Dusouqui, O.M.E., 10, 33 Elemes, Y., 3, 109; 8, 64

El-Khalafy, S., 3, 271 Elkhatib, M., 3, 154 Ell, A.H., 3, 327 Ellervik, U., 1, 9; 3, 309 Elliott, G.I., 12, 7 Ellis, D.A., 1, 211 Ellis-Holder, K.K., 14, 117 Ellman, J.A., 4, 24; 11, 110 El-Rady, E.A., 1, 240; 10, 37 El-Sadany, S.K., 10, 5 Elsegood, M.R.J., 4, 100 El Seoud, O.A., 2, 15 Emanuelsson, E.A.C., 5, 31 Emer, E., 6, 33; 7, 181 Emmanuvel, L., 6, 13 Emokpae, T.A., 5, 6, 7 Enders, D., 4, 88; 11, 11, 204 Enescu, M., 3, 287 Engberts, J.B.F.N., 10, 54 Engels, B., 7, 155 England, M.D., 8, 35 Engles, T., 5, 9 Engstroem, A., 2, 109 Ensing, B., 2, 35 Entrena, A., 3, 107; 8, 129 Enugala, R., 1, 155; 8, 27 Epishina, M.A., 14, 156 Erikson, J., 1, 232; 9, 75 Eriksson, J., 8, 61, 63 Eriksson, L., 3, 327; 11, 145 Erin, A.S., 1, 351 Erzen, E., 3, 238 Escolano, C., 9, 18 Esfandiara, S., 1, 352 Eshdat, L., 9, 6 Espinosa, A., 3, 107; 8, 129 Essassi, E.M., 12, 51 Esser, B., 7, 101 Esser, S., 10, 32 Estevan, F., 5, 33 Esteves, P.M., 6, 17; 7, 113 Etxebarria, J., 11, 9 Evano, G., 8, 57; 13, 32 Evans, B., 13, 30 Evans, D.A., 1, 130, 154, 181; 6, 39; 11, 167; 12, 55 Evans, G.J.S., 1, 56 Evans, P., 9, 34; 10, 41; 11, 185; 14, 137

F Fabrizi, G., 3, 213 Faggi, C., 12, 127 Faglioni, F., 7, 118 Fagnoni, M., 3, 240; 7, 106–108 Fagnou, K., 6, 55 Fahlbusch, T., 4, 99 Faita, G., 1, 133; 4, 6; 8, 22, 55; 11, 5 Falciola, C.A., 8, 1

521

Author Index Falck, J.R., 1, 189; 14, 121 Falcone, R., 8, 122 Falk, H., 3, 195 Falson, C.T., 1, 83 Falvey, D.E., 7, 121 Fan, J., 1, 224, 323 Fan, J.-f., 3, 326 Fan, Q., 12, 124 Fañanás, F.J., 14, 102 Fandrick, K.R., 6, 39; 11, 167; 12, 55 Fang, D., 11, 34 Fang, G.Y., 14, 17, 82 Fang, R., 4, 53, 54, 65 Fang, X., 11, 84 Fang, Y., 5, 26; 8, 61, 63 Fanjul, S., 1, 124 Fanning, A.-M., 2, 107 Fanning, K.N., 13, 4 Fanwick, P.E., 6, 62 Farina, V., 4, 33 ¨ 8, 80 Farkas, O., Farley, R.D., 9, 37; 14, 172 Farrell, D.M.M., 10, 33 Farris, I., 14, 87 Fathalia, M.F., 1, 353 Fathalla, M.F., 5, 8, 43 Fatma, W., 1, 22 Fattahi, A., 7, 90 Faul, M.M., 3, 323 Faza, O.N., 13, 63; 14, 99 Fedé, J.-M., 13, 54 Fedorov, A., 8, 30 Fedunov, R.G., 2, 38 Fehr, C., 14, 87 Feldman, K.S., 7, 35, 72; 8, 133; 12, 3 Feller, A., 2, 94 Fellows, C.M., 11, 95 Felzmann, W., 12, 105 Femet, B., 12, 43 Feng, D., 2, 115 Feng, D.-C., 2, 60 Feng, F.-M., 2, 78, 79 Feng, G., 2, 103, 104 Feng, L., 14, 174 Feng, S., 14, 162 Feng, X., 1, 70, 250, 253; 3, 106, 181; 12, 124 Fennie, M.W., 1, 41; 9, 120 Feray, L., 9, 96 Ferenc, D., 14, 73 Ferguson, M.L., 13, 29 Feringa, B.L., 1, 172, 285, 314; 8, 9; 9, 86, 89; 11, 230 Fernández, A., 14, 102 Fernández, G., 8, 89 Fernández, I., 1, 143, 228, 246; 7, 27; 9, 1, 44; 11, 152; 14, 161

Fernandez, X., 2, 49; 14, 83 Fernandez-Ibanez, M.A., 1, 138 Ferrer, C., 14, 96 Fetter, J., 2, 94 Fiaud, J., 8, 10 Fiedler, D., 14, 70 Figadere, B., 1, 123 Figueras, S., 1, 127 Filatova, E.A., 7, 24 Filippi, A., 8, 70 Filippi, J.-J., 2, 49; 14, 83 Filippone, S., 10, 15 Fillipone, S., 12, 12 Filosa, R., 9, 16 Finaru, A.-L., 9, 63 Fiorini, D., 11, 8 Firouzabadi, D., 6, 21 Firouzabadi, H., 6, 21 Fischer, C.B., 2, 32 Fischer, D.F., 13, 28 Fischmeister, C., 14, 111 Fishbein, J.C., 1, 58 Fleming, E.M., 6, 41 Fleming, F.F., 9, 88 Fleming, S.A., 7, 93 Fletcher, M.D., 9, 37; 12, 128; 14, 172 Flores-Michel, L.S., 1, 94 Fochi, M., 6, 40; 12, 142 Fohlisch, B., 3, 304 Ford, L., 11, 55 Forester, C.D., 3, 191 Forlani, L., 5, 55; 6, 7 Formoso, E., 2, 92 Fornarini, S., 7, 115 Foti, M.C., 7, 33 Fowler, T.G., 13, 10 Fraile, A., 12, 59 Fraleonic-Morgera, A., 7, 123 Framski, G., 8, 131 Francisco, J.S., 3, 273 Franck, X., 1, 123 Frank, M., 4, 99 Frank, M.A., 7, 70 Frankenfield, K.N., 7, 31 Franzén, J., 13, 74 Fraschetti, C., 8, 70 Frasson, C.M.L., 2, 14 Fratila, R.M., 9, 81 Freccero, M., 3, 240; 7, 31, 32 Frech, C.M., 4, 37 Freeman, F., 4, 66; 13, 33 Frei, E., 7, 29, 30 Frelek, J., 1, 140 Frenking, G., 7, 27; 9, 1 Frenna, V., 5, 42; 10, 2; 14, 155 Freude, D., 7, 83 Frey, W., 3, 304 Friestad, G.K., 1, 95 Fringuelli, F., 12, 103

Frisch, K., 11, 157 Frison, J.-C., 1, 346; 3, 228 Fritz-Wolf, K., 7, 36 Fröhlich, R., 7, 97; 13, 65 Frost, C.F., 11, 244 Fruchier, A., 13, 15 Fruit, C., 4, 75 Fry, A.J., 6, 22 Fu, A., 1, 299; 9, 14 Fu, C., 8, 30; 11, 31 Fu, F., 12, 145 Fu, G.C., 1, 64; 4, 48; 12, 40 Fu, H., 7, 124 Fu, J., 1, 176 Fu, X., 4, 63; 7, 43, 156; 11, 100, 263; 12, 143; 14, 40 Fu, X.-H., 6, 52; 11, 168 Fu, Y., 3, 350; 11, 83 Fu, Y.-Q., 1, 108 Fuchibe, K., 1, 65; 12, 147 Fuchs, J.R., 12, 7 Fuchs, P., 8, 32 Fuentealba, P., 2, 40; 8, 98 Fugiwara, Y., 12, 119 Fujii, N., 8, 2 Fujii, S., 6, 31 Fujii, T., 8, 72 Fujimori, I., 8, 44 Fujimoto, A., 8, 72 Fujimoto, K., 4, 70; 14, 143 Fujimura, D., 8, 76 Fujinami, S., 3, 52 Fujio, M., 2, 21; 8, 103 Fujioka, H., 14, 48 Fujisawa, H., 1, 30; 14, 23, 24 Fujita, K.-i., 12, 104 Fujita, M., 6, 54; 7, 60, 91, 92; 11, 262; 12, 4; 14, 139 Fujiwara, K., 7, 91, 141; 11, 262 Fujiyama, R., 8, 103 Fukuda, Y., 1, 243; 4, 92 Fukushima, K., 13, 70 Fukuyama, T., 1, 84 Fukuzumi, S., 3, 295 Fulara, J., 7, 99 Fullam, E., 7, 82 Fülöp, F., 1, 218; 9, 109; 14, 164, 165 Funabiki, K., 1, 97 Funicello, M., 3, 41 Funk, A.A., 6, 14 Funk, T.W., 14, 110 Fur, L.N., 9, 64 Fürstner, A., 14, 93 Furukawa, T., 1, 72 Furuno, H., 9, 156 Furusho, S., 8, 44 Furuta, T., 6, 31 Furutachi, H., 3, 52

522 Furuya, A., 3, 225 Fusco, C., 3, 197 Fushimi, M., 12, 111 Fushimi, S., 3, 225 Fustero, S., 14, 108 Futran, A., 5, 31

G Gabaldon, R.E., 3, 89 Gaertner, P., 8, 90; 9, 93 Gaffney, A.M., 3, 286 Gal, J.-F., 7, 151 Galbiati, F., 4, 50 Galeazzi, R., 11, 26 Gallagher, B., 1, 310; 3, 353 Gallagher, T., 9, 36 Gallo, M.A., 3, 107; 8, 129 Gallou, F., 1, 244; 4, 90 Galván, M., 11, 131 Gan, C., 1, 144; 9, 43 Gan, L., 1, 265; 3, 364 Ganaev, A.M., 7, 4, 17–19 Ganem, B., 1, 276 Ganesan, S.S., 1, 32; 9, 29 Ganesh, J.K., 14, 48 Gansaeuer, A., 3, 377, 393 Gansäuer, A., 8, 25 Gao, C., 6, 34; 14, 39 Gao, G.-Y., 4, 83 Gao, L.-G., 4, 53, 54 Gao, R., 3, 241, 243; 14, 154 Gao, S.-H., 14, 4 Gao, W., 3, 340 Gao, X., 11, 25 Gao, Y., 8, 63 Garc´ıa, B., 2, 86; 7, 186; 14, 35 Garcia, C., 1, 329 Garc´ıa, E., 11, 134 Garcia, M.M., 7, 81 Garcia, M.V., 10, 49 Garcia, R., 12, 62 Garcia-Cuadrado, D., 6, 58 Garcia-Flores, F., 1, 94 Garc´ıa-Fortanet, J., 9, 45; 11, 146 Garcia Lopez, J., 9, 41 Garc´ıa-López, M.T., 8, 132 Garcia-Rio, L., 2, 30, 40, 65 Garc´ıa-Rodr´ıguez, J., 4, 44 Garcia Ruano, J.L., 1, 138 Garel, J., 2, 83 Garg, D., 3, 175, 176 Garg, G., 3, 67 Garg, R., 9, 8 Garley, M.S., 7, 7; 8, 85 Garst, M.E., 1, 352 Garvey, D.S., 11, 76 Gati, T., 7, 110 Gatilov, Y.V., 5, 48 Gatti, G., 3, 221

Author Index Gatto, N., 7, 175 Gaunt, M.J., 11, 182; 13, 30 Gausepohl, R., 1, 161; 11, 176 Gauss, J., 10, 32 Gauthier, D.A., 2, 98 Gavin, H.A., 14, 131 Gazitua, M., 2, 54 Gdaniec, M., 8, 131 Gdaniec, Z., 8, 131 Gebhardt, P., 7, 45 Geiseler, G., 7, 76 Gembicky, M., 1, 205 Genaev, A.M., 13, 40 Geng, Z.-Y., 4, 53, 54, 65 Gennari, C., 14, 109 George, L., 4, 81; 14, 6 Gerard, B., 12, 78 Gerber-Lemaire, S., 1, 7 Gerchikov, A.Y., 3, 193 Gerenkamp, M., 3, 377, 393; 8, 25 Gergely, J., 12, 74 Gerges, S., 3, 271 Gerini, M.F., 7, 42 Germani, R., 8, 87 Gershenzon, J., 7, 175 Ghammami, S., 3, 20, 21 Gharah, N., 3, 77 Gharib, F., 3, 20 Ghomri, A., 6, 6 Ghosh, K., 2, 66 Ghosh, K.K., 2, 67; 8, 88 Gichuhi, A., 14, 149 Gierczyk, B., 5, 15 Gil, R., 6, 32 Gilbert, B.C., 3, 208 Gilbert, J.C., 4, 69 Gilday, J.P., 14, 151 Giles, R.L., 2, 1 Gilla, S., 1, 39 Gin, D.L., 2, 110 Ginesta, X., 14, 17 Ginotra, S.K., 1, 104; 3, 234, 235 Giordano, L., 11, 85 Giorgi, G., 14, 128 Giorgi, M., 6, 68 Giorni, D., 5, 50 Giovannetti, D., 3, 49 Girotti, R., 12, 103, 114 Gissibl, A., 11, 166 Giuli, S., 1, 320; 3, 321 Gladiali, S., 3, 375 Gladysz, J.A., 3, 183 Glaude, P.A., 3, 253 Gleason, D.C., 11, 16 Gleiter, R., 7, 101; 12, 58 Glover, S.A., 7, 126 Glukhareva, T.V., 14, 133

Goc-MacieJewska, I., 12, 117 Goddard, J.D., 12, 21 Goddard, W.A., 3, 268; 7, 118 Goeddel, D., 3, 119 Goekjian, P.G., 12, 45 Goel, A., 3, 90–92 Goeppert, A., 7, 6, 23 Gogoi, N., 1, 141; 9, 42 Goh, Y.-P., 11, 263; 12, 143 Gois, P.M.P., 4, 49 Gokavi, G.S., 3, 165 Goken, E.G., 8, 83 Goldfuss, B., 3, 302 Gomarooni, M., 4, 66 Gomes, J.R.B., 8, 126 Gomes, P., 8, 126 Gomes, P.J.S., 12, 67 Gómez, C., 14, 25 Gomez, G.R., 1, 246 Gomez Arrayas, R., 1, 29 Gómez-Bengoa, E., 11, 197 Gomez-Esque, A., 9, 18 Gomez Pardo, D., 1, 212 Gomez-Tagle, P., 2, 101 Gómez-Vidal, J.A., 8, 129 Goncalves, M-. H., 3, 113 Goncalves-Maia, R., 2, 85 Gonda, J., 3, 294 Gong, L.-Z., 1, 105, 149, 150; 11, 203; 12, 148 Gonzalez, A.S., 1, 29 Gonzalez, F.J., 7, 124 González, J.M., 1, 272; 6, 63 González-Béjar, M., 12, 100 González-Hernández, J.L., 14, 18 Gonzalez-Lopez, M., 3, 114 González-Muñiz, R., 8, 132 González-Rodriguez, C., 1, 348 Gonzalez-Romero, E., 5, 1; 7, 105 González-Rosende, M.E., 11, 220 Gonzalez-Sabin, J., 2, 80 Goodhue, C.E., 3, 53; 5, 29 Goodman, J.M., 1, 125; 11, 250 Goodman, M.A., 3, 219 Goossen, K., 11, 96 Goossen, L.J., 11, 96 Gopalakrishnan, M., 3, 31 Gopalsamuthiram, V., 4, 45 Goralski, C.T., 3, 300 Gordillo, B., 11, 131 Gordillo, R., 12, 139 Gordon, S.M., 7, 143 Gorin, D.J., 14, 105 Gornitzka, H., 12, 51 Gosmini, C., 11, 239 Goto, S., 9, 149

523

Author Index Goto, T., 9, 157 Gotoh, H., 1, 99 Gotor, V., 2, 80 Gou, S., 1, 253 Gould, I.R., 7, 43 Goumans, T.P.M., 12, 39 Goumont, R., 5, 55–58; 6, 7, 49; 7, 52 Gouveia, L., 8, 126 Gouverneur, V., 6, 8; 9, 153, 154 Gowda, C.C., 3, 155 Gowda, D.C., 3, 46, 163, 383 Gowda, N.S.L., 3, 163 Grabovskiy, S.A., 3, 203 Gracanin, M., 5, 20; 10, 19 Grach, G., 1, 38; 9, 65 Graham, A.E., 14, 50 Graham, T.W., 4, 29 Grampp, G., 12, 16 Granader, J., 9, 75 Granados, A.M., 4, 47 Granander, J., 1, 232 Grande, C., 14, 18 Grange, E., 9, 38 Grass, S., 3, 113 Graterol, M., 10, 25 Gray, T., 10, 29; 14, 147 Grebinski, J.W., 12, 137 Greck, C., 9, 159 Greco, M.N., 2, 98 Greco, T., 14, 43 Gree, R., 1, 156 Green, I., 14, 9 Green, M.J., 11, 88 Greene, A.E., 12, 30 Gregor, T., 12, 109 Grein, F., 1, 344; 3, 232 Greiner, L., 1, 307; 3, 351 Grela, K., 4, 27 Grellepois, F., 13, 11 Grice, C.R., 3, 285 Griedel, B.D., 1, 176 Griffin, D., 3, 100 Griffith, G.A., 1, 288; 12, 93 Grig-Alexa, I.-C., 9, 63 Grigg, R., 12, 76 Grimme, S., 3, 377, 393; 8, 25; 12, 39; 13, 18 Grinberg, N., 4, 33 Grishin, Y.K., 4, 71; 14, 141, 145 Grison, C., 13, 15 Gritsan, N.P., 4, 72, 73, 76 Groen, M.B., 14, 140 Groendyke, T.M., 13, 29 Gromak, V.V., 14, 140 Gronert, S., 7, 56; 9, 134 Gronheid, R., 7, 98 Grosjean, C., 2, 1

Groszek, G., 11, 180 Groundwater, P.W., 13, 72 Groves, J.T., 8, 35 Grubbs, R.H., 4, 4, 26; 7, 84; 14, 110 Grundl, M.A., 6, 28; 11, 170 Grundy, E.C., 7, 93 Grunenberg, J., 7, 80 Grutters, M.M.P., 11, 66 Gryko, D., 1, 110 Gu, Y., 1, 183 Gu, Z., 11, 119; 13, 83 Guarna, A., 1, 225; 7, 96; 9, 107; 13, 64 Güell, M., 12, 12 Gueyrard, D., 12, 45 Guha, S.K., 11, 184 Guillaumet, G., 9, 63 Guillena, G., 1, 116 Guillot, R., 12, 52 Guillouzic, A.-F., 11, 265 Guionneau, P., 4, 103 Guitian, E., 5, 61 Guiu, E., 3, 347 Guizzetti, S., 1, 117 Guliants, V.V., 3, 286 Gulias, M., 12, 62 Gullickson, G.C., 12, 172 Güllük, E., 6, 61 Gundersen, L.-L., 14, 92 Guner, V.A., 12, 87 Güngör, F. S¸., 13, 69 Gunnlaugsson, T., 2, 107 Guo, H., 11, 198 Guo, H.-M., 1, 149, 150 Guo, L., 8, 115, 116 Guo, Q.-X., 11, 83 Guo, S., 11, 34 Guo, W.-H., 4, 16 Guo, Y., 2, 24 Guo, Y.-C., 6, 51 Guofu, Q., 14, 20 Gupta, A., 1, 209 Gupta, M.K., 3, 160 Gupta, N., 9, 8; 12, 152 Gurunath, S., 6, 13 Gusarova, N.K., 10, 56 Gusevskaya, E.V., 11, 104 Guthikonda, K., 3, 180 Gutkind, J.S., 7, 164 Gutta, P., 7, 159, 165 Guzei, I.A., 1, 48; 3, 329

H Hachisu, Y., 1, 267; 9, 145 Hadad, C.M., 4, 80 Haddad, N., 4, 33 Haddadin, M.J., 14, 30 Hafren, J., 1, 121 Hagadorn, J.R., 2, 110

Hagedorn, M., 10, 44 Hager, M., 11, 166 Hahn, F.E., 13, 18 Hahn, J., 10, 32 Haigh, D., 1, 262; 3, 360 Hailun, R., 3, 106 Háj´ıcˇ ek, J., 11, 76 Hajra, A., 11, 228 Hajra, S., 11, 24 Hakoishi, M., 12, 154 Halder, R., 1, 73; 9, 47 Haley, M.M., 4, 18; 14, 144 Hall, D.G., 1, 174 Hall, M.H., 14, 149 Ham, J.E., 3, 191 Ham, S.W., 3, 272 Hama, T., 5, 39 Hamaguchi, M., 12, 36 Hamann, H.-J., 14, 43 Hamasaki, A., 12, 153 Hamasaki, T., 8, 76 Hamashima, Y., 1, 74; 9, 157 Hamblett, C.L., 12, 102 Hamed, E.A., 5, 8 Hamilton, G.L., 5, 45 Hamilton, R.J., 1, 308; 3, 338 Hammond, C.J., 3, 257 Hammond, G.B., 8, 18 Hampel, F., 11, 256 Hampl, F., 2, 71 Hamura, T., 12, 31; 14, 123 Hamza, A., 11, 206 Han, B., 12, 151 Han, H., 11, 97 Han, I.S., 7, 28 Han, J., 11, 81 Han, J.-Y., 2, 19, 28 Han, L.-B., 11, 90 Han, P., 1, 347; 3, 199; 9, 138 Han, S., 3, 286 Han, X., 11, 1, 117; 12, 46 Han, Y., 8, 35 Hanagiri, S., 7, 60; 14, 139 Hanbing, T., 14, 20 Hancock, F., 3, 376 Hannedouche, J., 1, 157 Hanson, J.R., 6, 12 Hanton, M.J., 3, 335 Hanuˇs, V., 11, 105 Hanusek, J., 2, 53 Hanzlik, R.P., 3, 290 Hao, X.-S., 3, 53; 5, 29 Hao, Z., 3, 245 Harada, S., 1, 33 Harada, T., 1, 221; 9, 104; 11, 258 Harano, K., 13, 75 Harden, J.D., 4, 83 Harger, M.J.P., 2, 56 Hargrave, J.D., 11, 244

524 Harikengaram, S., 3, 44 Harman, D.G., 5, 20; 10, 19 Harman, W.D., 12, 134 Harmata, M., 12, 177; 13, 73; 14, 177 Harris, M.E., 1, 208; 2, 10; 8, 68 Harris, T., 7, 118 Harrison, P.H.M., 1, 268; 9, 20 Harrison-Marchand, A., 9, 27; 11, 224; 12, 113 Hart, A.C., 1, 273 Hartman, R.F., 11, 128 Hartwig, J.F., 5, 39; 11, 36, 77, 101 Harutyunyan, S.R., 9, 86; 11, 230 Harvey, J.N., 1, 238; 9, 39; 10, 36; 14, 82 Hase, W.L., 8, 110 Hasegawa, M., 12, 27 Hasegawa, T., 7, 58 Hashimoto, J., 8, 72 Hashimoto, S., 1, 131 Hashimoto, T., 12, 86 Hashimoto, Y., 1, 146; 3, 308 Hashmi, A.S.K., 11, 120 Hassanein, M., 3, 271 Hassfeld, J., 1, 334; 3, 358 Hatano, A., 6, 25 Hatch, F.T., 7, 125 Hattori, H., 12, 104 Hattori, M., 7, 89 Hattori, T., 12, 167 Hatzimimikou, D., 12, 47 Haustedt, L.O., 12, 183 Hawkins, M.J., 2, 98 Haxell, T.F.N., 9, 22; 11, 173 Hayashi, M., 1, 219; 9, 115 Hayashi, R., 11, 54 Hayashi, S., 1, 173; 5, 40 Hayashi, T., 1, 40, 180; 3, 331; 7, 89; 9, 102, 121; 11, 95, 109, 238, 240, 242, 245, 249; 12, 171 Hayashi, Y., 1, 99; 2, 84; 12, 178; 14, 158 Hayes, A.G., 4, 18; 14, 144 He, C., 4, 9, 82; 11, 33, 115, 116 He, D., 3, 250 He, L., 1, 105 He, M., 2, 115; 4, 98; 12, 126 He, M.-X., 2, 60 He, P., 14, 72 He, Q., 9, 70 He, X., 1, 142, 287; 3, 110 He, Z., 14, 89 Heasley, V.L., 11, 16 Heathcock, C.H., 11, 76 Hecht, S.S., 7, 68

Author Index Hedley, S.J., 4, 55 Heimgartner, H., 8, 30; 13, 67 Heller, S.T., 1, 297 Hemalatha, G., 6, 11 Henderson, K.W., 1, 287 Hendriksen, C., 4, 36 Henge, A.C., 8, 69 Hengge, A.C., 2, 6, 112 Henin, F., 14, 120 Henrikson, J.T., 3, 285 Heo, K., 7, 176 Hepp, A., 7, 80 Herges, R., 4, 18; 14, 144 Herize, A., 10, 20, 21, 26 Hermann, H.L., 9, 5 Hermans, I., 3, 249 Hernandez-Olmos, V., 1, 143; 9, 44 Herndon, J.W., 12, 184 Herrerıas, C.I., 3, 269 Herrera, R., 6, 53 Herrero, H., 3, 86 Herrero, R., 7, 2, 151 Herrero-Gómez, E., 4, 39; 11, 118; 14, 97 Herrmann, R., 11, 91 Herschlag, D., 2, 73 Herson, P., 11, 264 Hesemann, P., 3, 263 Hess, B.A., 13, 47 Hess, K., 4, 18; 14, 144 Hester, D.K., 12, 3 Hetterscheid, D.G.H., 4, 36 Hevia, E., 6, 71, 72; 9, 100, 101 Heydenreich, M., 14, 165 Hiberty, P.C., 8, 77 Higashi, T., 12, 82 Hildebrandt, D., 14, 94 Hill, J.G., 13, 9 Hillier, I.H., 1, 288; 12, 93 Hilmersson, G., 1, 232; 9, 75 Hilt, G., 4, 50 Hilvert, D., 7, 178 Hinds, S., 1, 11 Hintermann, L., 11, 92 Hioki, K., 2, 93 Hirabayashi, S., 11, 109 Hirai, Y., 6, 25; 14, 126 Hiraiwa, Y., 1, 132 Hiran, B.L., 1, 341, 342; 3, 29, 47, 48, 125 Hirano, K., 1, 173; 5, 40 Hirao, K., 1, 2 Hirashita, T., 1, 63 Hirata, Y., 11, 70 Hirayama, T., 13, 13 Hird, A.W., 11, 232 Hiremath, C.V., 3, 55, 57 Hiremath, G.C., 3, 54 Hiroi, K., 14, 130

Hiroya, K., 11, 39 Hirsch, A.K.H., 11, 182 Hisaindee, S., 11, 212 Hiyama, T., 11, 68, 70, 72 Hjorth, J., 3, 244 Ho, C.-Y., 1, 188 Ho, D.G., 3, 243 Hoarau, C., 9, 62 Hoashi, Y., 11, 158 Hobson, S.J., 14, 153 Hodgson, D.M., 8, 49 Hoffmann, S., 1, 332 Hofmann, M., 7, 76 Hogg, L.M., 6, 71, 72; 9, 100, 101 Hojo, M., 8, 76 Holˇcapeck, M., 14, 57 Holder, C., 9, 16 Holman, R.W., 9, 66 Holmer, S., 7, 139 Holmes, B.E., 10, 52 Holtgrewe, C., 13, 18 Honda, T., 3, 179 Honeyman, G.W., 6, 71, 72; 9, 100, 101 Hong, B.-C., 12, 173 Hong, J.A., 8, 18 Hong, R., 6, 46; 11, 155 Hong, W., 12, 75 Hong, X., 12, 98; 14, 34, 177 Hong, Y.-T., 11, 108 Hong, Y.J., 7, 166 Honma, Y., 11, 243 Hooper, C., 3, 282 Hope, H., 14, 30 Hopf, H., 9, 6 Horii, A., 1, 167; 9, 23 Horrillo Mart´ınez, P., 11, 256 Horton, P.N., 5, 51; 9, 37; 14, 172 Hoshino, T., 7, 172 Hosokawa, N., 12, 10 Hosoya, Y., 12, 107 Hou, X.-H., 1, 217; 9, 114 Hou, X.-L., 12, 75 Hou, Z., 3, 252 Houk, K.N., 1, 26; 3, 202; 7, 66; 10, 13; 12, 87–89, 108, 139; 13, 52; 14, 166, 168, 169 House, D., 5, 34 Houson, I., 1, 312 Hoveyda, A.H., 1, 136; 8, 13; 9, 92; 11, 232 Howard, J.A.K., 5, 7 Howell, G.P., 1, 172 Howells, D.M., 14, 17 Hoyuelos, F.J., 2, 86 Hoz, S., 14, 135 Hoza, I., 14, 57

525

Author Index Hrovat, D.A., 14, 146 Hsu, Y.-C., 3, 389 Hsung, R.P., 1, 216; 7, 170; 9, 108; 12, 19, 172; 13, 68 Hu, C., 1, 70; 2, 68 Hu, C.-H., 4, 16 Hu, C.-W., 3, 215; 6, 52 Hu, Ch.-W., 11, 168 Hu, J., 8, 34 Hu, K.-c., 8, 78 Hu, Q.-M., 3, 392 Hu, W., 2, 69 Hu, W.P., 8, 60 Hu, X.-D., 14, 4 Hu, Y., 1, 293; 9, 12 Hua, R., 5, 38; 11, 112, 113, 122 Huang, A.C., 13, 33 Huang, H., 9, 31; 11, 205 Huang, J., 1, 216, 323; 3, 326; 9, 108; 11, 86; 13, 6 Huang, J.-W., 7, 187 Huang, P.-M., 1, 13, 14 Huang, P-Q., 8, 51 Huang, R., 1, 164; 11, 172 Huang, X., 1, 250 Huang, X.-R., 4, 14 Huang, Y., 7, 161 Huang, Z., 1, 53; 2, 68; 3, 382 Huang, Z.-H., 11, 164 Huard, K., 4, 74 Huber, D.P., 9, 155 Huelgas, G., 1, 213; 9, 111 Huffman, M.A., 3, 354 Hüggenberg, W., 14, 94 Hughes, S.V., 10, 28; 14, 148 Hugl, H., 3, 95, 96 Hui, A., 1, 224 Huibers, M., 3, 184 Huijbers, J.P.J., 3, 103 Hulme, A.N., 1, 124 Hultzsch, K.C., 11, 256 Humbel, S., 7, 95 Humphrey, G., 5, 46 Hunger, M., 7, 83 Hunkler, D., 11, 19 Hunter, R., 1, 214 Hunter, S.E., 8, 120 Huo, S., 3, 51 Huo, S.-Y., 3, 58–60 Huo, Z., 11, 235 Hupp, T., 7, 155 Hurley, M.D., 1, 211 Hurst, T.E., 12, 128 Hursthouse, M.B., 5, 51; 9, 37; 14, 172 Huttenhain, S.H., 1, 322; 3, 311 Hutton, T.K., 13, 36 Hwang, J., 11, 183

Hwang, S.-J., 2, 18, 48 Hynes, S.J., 2, 89

I Iafe, R.G., 7, 66 Ianni, J.C., 1, 215, 216; 9, 97, 108 Ibeas, S., 2, 86 Ibrahem, I., 1, 24, 120, 300; 3, 204, 242; 9, 26; 11, 145 Ibusuki, Y., 12, 31 Ichikawa, J., 6, 38; 7, 79, 140 Ichikawa, Y., 13, 24 Igarashi, K., 7, 131 Igarashi, M., 8, 105 Igawa, K., 11, 49 Iglesia, E., 3, 221 Iglesias, M.J., 5, 13; 9, 41 Iglesias-Martinez, E., 2, 75 Ignatenko, A.V., 13, 51 Ignat’ev, I.S., 6, 4 Iguchi, K., 12, 27 Ihara, M., 12, 10, 150 Iinuma, M., 6, 31 Iizuka, M., 11, 236 Ijsselstijn, M., 12, 83 Ikeda, S., 11, 71 Ikeno, T., 1, 318; 3, 316; 12, 56 Ikuta, T., 2, 93 Iley, J., 2, 44; 8, 126 Illa, O., 1, 266 Ilyashenko, G., 1, 252 Imagawa, H., 7, 168; 11, 48; 14, 58 Imagawa, Y., 1, 63 Imai, T., 10, 4 Imai, Y., 12, 54 Imamoto, T., 1, 52, 263; 3, 348 Inaba, M., 4, 70; 14, 143 Inada, Y., 6, 30 Inagaki, F., 12, 155 Inanaga, J., 9, 156 Inanaga, K., 12, 10 Incarvito, C.D., 11, 77 Ingebrigtsen, T., 8, 47 Inoguchi, R., 14, 48 Inokuchi, E., 8, 2 Inokuchi, T., 1, 269; 9, 21 Inokuma, T., 11, 158 Inomata, K., 1, 43; 11, 184; 12, 92 Inoue, K., 12, 60 Inoue, M., 1, 179, 180 Inoue, Y., 3, 282; 11, 243; 12, 17 Ionescu, E., 4, 17 Iovescu, A., 2, 64 Iranpoor, N., 6, 21

Isanbor, C., 5, 6, 7 Ishibashi, H., 12, 54 Ishida, Y., 4, 21; 7, 135 Ishihara, K., 1, 132; 6, 37; 11, 42; 12, 111, 146 Ishihara, T., 11, 4 Ishii, K., 1, 220; 9, 117 Ishii, S., 1, 243; 4, 92 Ishikawa, H., 12, 7 Ishikawa, T., 1, 275 Ishiyama, Y., 6, 29; 11, 35 Ishizuka, T., 1, 131 Iskra, J., 1, 337; 3, 218 Islam, M., 3, 30 Islas-González, G., 14, 136 Ismail, A.M., 1, 353; 10, 5 Ismail, F.M.D., 7, 180 Isobe, M., 13, 24 Isomura, E., 11, 111 Isshiki, S., 12, 119 Isshiki, T., 1, 191 Ito, H., 12, 27 Ito, J., 1, 160 Ito, R., 1, 292; 9, 139 Ito, T., 3, 342; 13, 24 Ito, Y., 3, 342; 11, 236 Itoh, J., 1, 65 Itoh, J.-i., 3, 362 Itoh, K., 11, 221 Itoh, N., 6, 29; 11, 35 Itoh, S., 3, 52, 230 Itoh, T., 1, 263 Itonaga, M., 6, 38; 7, 79 Itou, Y., 10, 43; 11, 260 Ivanov, Yu.A., 7, 20 Ivanova, N.I., 10, 56 Ivanova, O.A., 8, 58 Iwadate, N., 1, 52; 3, 348 Iwahashi, H., 13, 70 Iwamura, H., 5, 31; 11, 240 Iwasawa, N., 11, 254; 12, 69, 182 Iwashita, S., 7, 141 Iyama, Y., 12, 36 Iyoda, M., 11, 111 Iza, A., 11, 223 Izquierdo, R., 10, 31

J Jabbari, A., 10, 13 Jackson, T.K., 13, 33 Jacobs, P.A., 3, 249; 14, 38 Jacobsen, E.N., 1, 162; 9, 31; 11, 177, 205 Jacobsen, H., 14, 152 Jacquesy, J.-C., 7, 148; 14, 64 Jadhav, D.N., 1, 296 Jagadeesh, B., 11, 178 Jagadeesh, R.V., 3, 133, 134, 139, 142, 145, 155, 174

526 Jagadeshwar, V., 11, 178 Jagt, R.B.C., 1, 285 Jagtap, S.B., 1, 44 Jain, B., 3, 62 Jain, S., 3, 47 Jain, S.L., 3, 220 Jaky, M., 3, 37, 38 Jameel, R.K., 5, 44 Jamieson, A.G., 13, 4, 25 Jamison, T.F., 1, 188, 198, 328 Janda, K.D., 1, 112 Janik, M.J., 7, 87, 88 Jankowska, J., 1, 134 Jankowski, C.K., 13, 50 Jansa, P., 2, 53 Janssen, M.H.M., 10, 51 Janus, E., 12, 117 Jaramillo, P., 8, 98 Jaroszewski, J.W., 9, 61 Jary, W.G., 3, 195 Jasra, R.V., 8, 29 Jasti, R., 7, 67; 13, 20; 14, 61 Jautze, S., 13, 28 Jayanth, T.T., 11, 266 Jayashankaran, J., 12, 5 Jean, L., 12, 66 Jebria, A.-B., 3, 194 Jee, J., 3, 104, 105 Jeganmohan, M., 11, 266 Jellema, E., 4, 36 Jemmis, E.D., 1, 151 Jenkins, S.I., 1, 268 Jensen, V.R., 4, 25 Jeon, H.-B., 14, 56 Jeon, J.-H., 8, 106 Jeon, S.-E., 2, 26, 41 Ji, H., 3, 250 Ji, Y., 1, 127 Jia, X.-D., 12, 151 Jia, Y.-X., 6, 42, 45 Jiang, F., 1, 114 Jiang, H., 11, 86; 12, 46 Jiang, H.-F., 11, 74 Jiang, J., 1, 250 Jiang, J.-L., 11, 113 Jiang, J.-X., 3, 318 Jiang, L., 11, 217 Jiang, N., 3, 264 Jiang, Q.M., 3, 63 Jiang, W., 11, 160 Jiang, W.-Q., 11, 164 Jiang, Y.-Z., 1, 105, 149, 150; 11, 203; 12, 148 Jiang, Z., 1, 118 Jiao, H., 3, 95, 96 Jiao, L., 1, 81; 4, 85; 12, 33; 14, 127 Jiao, N., 12, 110

Author Index Jiménez, D., 14, 108 Jiménez, J.L., 12, 61 Jimenez, P., 7, 151 Jiménez-Nún˜ ez, E., 4, 38; 11, 118; 14, 97, 98 Jiménez-Osés, G., 8, 127 Jiménez-Vázquez, H.A., 6, 53 Jimeno, M., 8, 73 Jin, J., 12, 11 Jin, L., 2, 24 Jin, P., 7, 3 Jin, X.-L., 12, 151 Jin, Z., 7, 152 Jin, Z.-Z., 1, 289 Jobashi, T., 6, 35; 7, 94 Jockusch, S., 3, 282 John, M., 1, 205 Johns, A.M., 11, 77 Johnson, E.C.B., 2, 81 Johnson, J.S., 14, 86 Johnson, L.M., 7, 153 Johnson, P., 9, 34; 10, 41; 14, 137 Johnson, W.L., 7, 126 Johnsson, R., 1, 9; 3, 309 Jones, G.O., 12, 87 Jones, J.E., 4, 83 Jones, M.P., 7, 126 Jongejan, M.G.M., 10, 54 Jonnalagadda, S.B., 3, 132 Jordan, K.P., 9, 68 Jordan, R.W., 12, 21, 26 Jørgensen, K.A., 1, 260; 4, 6; 5, 25; 8, 22, 55; 9, 152; 11, 5, 157 Jorgensen, W.L., 10, 8 Jose, T.P., 3, 88, 94 Joseph, J., 1, 151 Joseph-Nathan, P., 14, 55 Joshi, B.P., 1, 237 Jouannetaud, M.-P., 7, 148; 14, 64 Joubert, L., 8, 114 Journet, M., 5, 46 Jovel, I., 11, 64 Juaristi, E., 1, 94, 213; 9, 111, 130 Jubert, A.H., 7, 154 Judson, T.J.L., 9, 135 Jung, I.G., 4, 31; 12, 8 Jung, M.E., 14, 168 Jung, S., 3, 272 Jung, S.-Y., 13, 19 Jurczak, J., 1, 171; 6, 47; 9, 133; 12, 101 Jurczak, M., 12, 53 Jur´ıc, S., 7, 48, 49; 8, 94, 95 Jürs, S., 13, 14 Jutand, A., 8, 10

K Kaavi, J.A., 1, 101 Kabalka, G.W., 7, 184 Kabal’nova, N.N., 3, 203 Kabilan, S., 3, 162 Kache, R., 1, 189; 14, 121 Kadam, R., 2, 55 Kadowaki, A., 11, 188; 12, 81 Kagan, H.B., 12, 52 Kainuma, H., 7, 133 Kajioka, T., 7, 129 Kajtar-Peredy, M., 2, 94 Kakala, V.V., 5, 18 Kakehi, A., 12, 60 Kakeya, H., 12, 178 Kakinuma, K., 7, 172 Kakkar, R., 10, 18 Kakuda, H., 6, 25 Kalandadze, L.S., 5, 16 Kalantre, V.A., 3, 165 Kalbarczyk, K., 13, 16 Kalberg, C.S., 3, 349 Kalita, P.K., 12, 48 Kalra, B.L., 10, 28, 29; 14, 147, 148 Kalsotra, B.L., 3, 22 Kalyani, D., 6, 16, 56 Kalyani, P., 8, 82 Kalyankar, S.N., 3, 33 Kam, K., 1, 268 Kambe, N., 11, 7 Kamijo, S., 9, 19 Kamikawa, K., 12, 169 Kamimura, A., 11, 188 Kamisaki, H., 14, 88 Kampf, J.W., 11, 79 Kan, J.T.W., 7, 119 Kan, T., 6, 31 Kanai, M., 1, 46, 129, 158, 159, 178; 8, 44 Kanazawa, Y., 3, 362 Kanda, K., 1, 221; 9, 104 Kandpal, B.M., 3, 324 Kaneda, K., 3, 342 Kaneko, M., 6, 38; 7, 79 Kaneko, N., 1, 283 Kang, G.-L., 2, 69 Kang, H., 8, 53 Kang, H.-M., 13, 38 Kang, Y.-B., 1, 77 Kang, Y.K., 1, 259; 9, 161 Kannappan, V., 6, 11 Kanno, N., 13, 78 Kano, N., 10, 40 Kano, T., 1, 245, 261; 4, 91; 12, 86, 112, 141 Kanthak, M., 14, 94 Kantlehner, W., 14, 3 Kanyiva, K.S., 11, 72 Kao, J.-Q., 3, 262

527

Author Index Kapoor, K.K., 3, 320 Kappe, T., 14, 134 Karadakov, P.B., 13, 9 Karbarz, M., 7, 128 Karch, R., 11, 96 Karikomi, M., 10, 4 Karimov, R.R., 4, 71; 14, 141, 145 Karni, M., 1, 57 Karplus, M., 2, 99 Karri, P., 1, 270; 9, 17 Karunakaran, C., 3, 128 Kashiwabara, M., 3, 342 Käss, S., 12, 109 Kass, S.R., 7, 90 Kast, P., 7, 178 Kaster, A., 6, 28; 11, 170 Kas’yan, A.O., 8, 39 Kas’yan, L.I., 8, 39 Kataoka, K., 1, 182; 11, 43 Kataoka, T., 1, 163; 11, 10 Katebzadeh, K., 11, 148 Kato, S., 8, 59; 10, 6 Kato, Y., 1, 251 Katoh, K., 12, 91; 13, 81 Katrusiak, A., 9, 35 Katsuaki, K., 3, 181 Katsuki, T., 3, 73; 4, 87 Katsumura, S., 9, 136 Katsva, V., 10, 29; 14, 147 Kaur, D., 10, 22 Kaur, P., 10, 22 Kaur, R.P., 10, 22 Kaur, S., 11, 150 Kavala, V., 1, 1 Kawabata, H., 4, 87 Kawabata, T., 8, 130 Kawachi, A., 12, 22 Kawafuchi, H., 1, 269; 9, 21 Kawaguchi, H., 8, 72 Kawahata, M., 1, 275; 14, 22 Kawai, A., 6, 35; 7, 94 Kawai, H., 7, 141 Kawai, S., 6, 35; 7, 94 Kawai, Y., 3, 225 Kawakami, S., 8, 130 Kawakami, T., 1, 68 Kawakami, Y., 11, 99; 14, 113 Kawamura, M., 6, 60 Kawano, N., 14, 123 Kawano, Y., 1, 283 Kawasaki, M., 1, 68; 12, 129 Kawasaki, T., 1, 227; 13, 13 Kawashima, T., 10, 40 Kawata, A., 14, 119 Kawatkar, S., 7, 61 Kawe¸cki, R., 12, 149 Kay, R.D., 7, 84 Kazmaier, U., 9, 25 Keay, B.A., 12, 120

Kebede, N., 4, 80 Keeffe, J.R., 7, 56; 9, 134 Kehrli, S., 9, 87; 11, 231 Keller, F., 3, 393; 8, 25 Keller, M., 8, 7; 9, 90; 11, 19 Kelley, S.O., 1, 11 Kemsley, J.N., 3, 85 Kenny, J.A., 1, 312 Kent, S.B.H., 2, 81 Kerber, W.D., 3, 276 Kermani, S., 3, 194 Kersting, B., 12, 109 Kertesz, M., 13, 6 Kerwin, S.M., 14, 174, 175 Kevill, D.N., 2, 31, 59; 7, 57; 8, 83 Kezuka, S., 12, 158 Khan, M.N., 2, 37, 39 Khan, N.H., 8, 29 Khan, Z., 1, 22; 3, 61 Khanduala, A., 3, 131 Khare, P., 3, 164 Khatik, G.L., 11, 130 Khattab, A.F., 14, 134 Khazaei, A., 3, 172 Khdour, O., 7, 34 Khedar Nasser Akhmed, K., 2, 38 Khenkin, A.M., 3, 247 Khlebnikov, A.F., 4, 104; 14, 132 Khodaskar, S.N., 3, 33 Khodot, E.N., 7, 20, 21 Khong, A.M., 12, 13 Khot, V., 7, 65 Khramov, M.I., 3, 251 Khripach, V.A., 14, 140 Khurana, J.M., 3, 324 Kibbee, S.P., 12, 21 Kiemele, L.A., 2, 110 Kieninger, M., 8, 38 Kikuchi, M., 3, 362 Kikukawa, K., 8, 103 Kil, H.S., 8, 65 Kildahl-Andersen, G., 7, 138 Kiljunen, E., 11, 132 Kilner, C.A., 1, 241; 10, 38 Kim, B.J., 8, 72 Kim, C.K., 7, 28; 8, 100 Kim, D., 3, 315 Kim, D.-S., 14, 122 Kim, D.W., 8, 65 Kim, D.Y., 1, 259; 3, 297; 9, 161 Kim, E.Y., 2, 41 Kim, H.-J., 1, 58 Kim, H.-Y., 13, 38 Kim, H.L., 10, 17 Kim, H.S., 14, 167

Kim, J., 1, 317, 319; 3, 261, 298, 319 Kim, J.-H., 7, 65 Kim, J.S., 8, 65 Kim, K.-C., 7, 112 Kim, M., 4, 41, 42; 14, 118 Kim, S., 8, 53 Kim, S.-H., 7, 176 Kim, S.-U., 7, 176 Kim, S.S., 1, 248, 249 Kim, W.-S., 14, 122 Kim, W.R., 2, 61 Kimura, M., 7, 120; 13, 48 Kimura, T., 2, 84; 14, 158 Kimura, Y., 13, 22 Kina, A., 11, 240 Kindelin, P.J., 1, 302; 6, 36; 7, 147; 14, 31 Kinder, R.E., 11, 46 Kinel, A., 12, 9 King, B.T., 7, 117 Kinzel, T., 1, 175 Kiprof, P., 7, 70 Kiran, T.S., 3, 55–57 Kiranmayee, S.R.T., 2, 11 Kirby, A.J., 2, 100 Kirchner, K., 1, 345; 3, 291; 4, 28 Kirihara, M., 6, 25 Kirillova, N.V., 3, 251 Kirsch, S.F., 13, 77 Kirubasankar, P., 3, 162 Kischel, J., 11, 64 Kishimoto, S., 11, 221 Kiso, Y., 2, 84; 14, 158 Kita, P., 3, 75 Kita, Y., 14, 42, 48 Kitagaki, S., 12, 91; 13, 81 Kitagawa, T., 3, 52 Kitajima, A., 1, 8 Kitamura, H., 12, 82 Kitamura, M., 3, 333 Kitamura, T., 12, 119; 14, 42 Kitaura, K., 8, 2 Kitayama, T., 3, 225 Kitazawa, T., 1, 193 Kitazume, T., 8, 31 Kitching, S., 7, 84 Kitoh, K., 11, 221 Kivala, M., 2, 71 Kiyotami, T., 12, 54 Kizirian, J.-C., 1, 39 Kladova, A.V., 8, 124 Klaehn, M., 2, 95 Klankermayer, J., 1, 161; 11, 176 Klásek, A., 14, 57 Klauber, D.J., 3, 100 Klawonn, M., 3, 95, 96 Kleeb, A.C., 7, 178

528 Klein, M.L., 2, 34, 35 Kleinen, J., 1, 161; 11, 176 Kleinpeter, E., 14, 165 Kletskii, M.E., 13, 41 Klijn, J.E., 10, 54 Klimova, E.I., 7, 81 Klinkel, K.L., 2, 110 Kloetzing, R.J., 1, 271; 9, 99 Klotz, P., 8, 56 Klumpp, D.A., 1, 302; 6, 36; 7, 147; 14, 31 Klussman, M., 5, 31 Klys, A., 4, 19 Knight, K.S., 3, 307 Knize, M.G., 7, 125 Knochel, P., 1, 271; 5, 30; 9, 82, 85, 99 Knochnel, P., 1, 235 Knoester, A., 3, 286 Knothe, L., 11, 19 Knudsen, K.R., 1, 122; 9, 24; 11, 147 Ko, S.-H., 2, 27 Kobayashi, K., 3, 362; 6, 57 Kobayashi, M., 1, 43 Kobayashi, S., 1, 128, 183; 11, 190, 259 Kobayashi, T., 11, 95 Kobayashi, Y., 14, 88 Kobbelgaard, S., 5, 25 Kobino, M., 3, 52 Koch, A., 14, 165 Koch, H.F., 9, 138 Koch, J.G., 9, 138 Koch, R., 7, 102 Kochina, T.A., 6, 4 Kock, R., 7, 45 Koˇcovský, P., 1, 262; 3, 360, 361; 11, 25, 32, 76, 105 Kodess, M.I., 12, 72 Koenig, H., 14, 76 Kofoed, J., 1, 98 Kogl, M.F., 3, 284 Köhler, F., 4, 18; 14, 144 Kohler, F.H., 9, 55 Kohnen, A.L., 12, 35 Koide, K., 9, 33; 14, 160 Koizumi, S., 4, 30 Koketsu, J., 14, 173 Kokubo, K., 12, 82 Kokumai, T., 1, 191 Kokura, A., 1, 318; 3, 316 Kolakowski, R.V., 2, 46 Kolboe, S., 7, 85, 116 Kollar, L., 1, 258 Kollenz, G., 14, 6 Kollner, T.G., 7, 175 Kolodziejska-Huben, M., 8, 63 Koltunov, K.Y., 7, 144

Author Index Komagawa, S., 12, 170 Komatsu, M., 1, 82; 9, 77 Komeyama, K., 4, 30; 11, 63 Komissarov, V.D., 3, 187, 192, 193 Konakahara, T., 11, 53 Kondo, K., 1, 243; 4, 92 Kondo, S., 3, 73 Kondo, Y., 1, 349; 11, 89 Kondoh, A., 5, 11 Kong, L., 6, 50 Konishi, S., 12, 112 Konishi, T., 1, 245; 4, 91; 12, 112 Konno, T., 11, 4 Koo, I.S., 2, 25, 45, 61; 11, 183 Koo, S., 13, 19 Kopf, J.R., 4, 34 Kopp, F., 1, 235; 9, 85 Koppel, I., 2, 20 Koppel, I.A., 2, 16 Koprowski, M., 3, 50 Korapala, C.S., 1, 95 Korn, T.J., 5, 30 Koseki, A., 7, 162 Koseki, S., 4, 70; 14, 143 Koskinen, A.M.P., 11, 132 Kostikov, R.R., 4, 34; 12, 58 Kostova, K., 1, 231; 9, 95 Kotha, S., 10, 14 Kothari, A., 3, 4 Kothari, S., 3, 4, 159, 175, 176 Kotrusz, P., 1, 226; 9, 116; 11, 129 Kotschy, A., 10, 16 Kotsuki, H., 13, 24 Kouchi, M., 12, 144 Kovalenko, S.V., 13, 58 Kovalenko, V.V., 2, 23 Kovalevsky, A.Y., 14, 117 Kovár, M., 14, 57 Kozlowski, M.C., 1, 41, 215, 216; 9, 97, 108, 120 Kołodziejska-Huben, M., 8, 61 Krafft, M.E., 9, 22; 11, 173 Kraka, E., 3, 196 Kral, V., 2, 102 Kralova, J., 2, 102 Kraml, C.M., 1, 177 Kranjc, A., 8, 37 Krasovskiy, A., 1, 235; 9, 82, 85 Kraszni, M., 2, 9 Kratzer, R., 3, 284 Krause, A., 6, 56 Krause, N., 11, 241; 14, 104 Krawczyk, E., 3, 50 Krechanin, S., 7, 139 Kreiselmeier, G., 3, 304

Kress, R., 14, 3 Kribber, T., 11, 92 Krinitsina, G.V., 5, 28 Krische, M.J., 11, 108 Krishna, G.G., 1, 147 Krishnaiah, M., 8, 36 Krishnamurthy, V., 13, 35, 36 Krishnan, K.S., 12, 186, 187 Krishnasmy, K., 3, 162 Krivdin, L.B., 14, 157 Krivokapic, A., 6, 69 Krohn, K., 14, 9 Kronja, O., 7, 48, 49; 8, 94, 95 Kropotina, P.E., 14, 133 Krossing, I., 7, 9 Kroulik, J., 7, 117 Krupková, A., 11, 44 Kryzhanovskaya, E.B., 8, 124 Kubo, H., 3, 225 Kubota, K., 12, 102 Kubota, Y., 13, 48 Kuchto, A.I., 14, 140 Kuck, D., 7, 85 ´ 8, 80 Kucsman, A., Kudryavtsev, A.A., 10, 56 Kuduk, S.D., 9, 94 Kuhn, F.E., 1, 186 Kuhner, S., 7, 36 Kukreja, G., 3, 324 Kukushkin, V.Y., 12, 57 Kulagowski, J.J., 12, 77 Kulikov, A.S., 14, 156 Kulikova, L.N., 14, 129 Kulkami, A.A., 13, 16 Kulkarni, A.S., 3, 35 Kulkarni, N.A., 1, 168, 327 Kumadaki, I., 1, 316; 3, 388 Kumar, A., 5, 44; 10, 33; 12, 115, 116 Kumar, D., 3, 292 Kumar, N. ,V., 1, 209 Kumar, R., 11, 130; 14, 13 Kumar, R.R., 12, 52 Kumar, S., 2, 13; 3, 69, 93; 11, 150 Kumar, S.S., 12, 5 Kumar, V., 11, 150 Kumara, M.N., 3, 163 Kumaraguru, N., 3, 74 Kumarn, S., 1, 87 Kumawat, S.K., 12, 152 Kundig, E.P., 5, 34 Kuninobu, Y., 14, 119 Kunishima, M., 2, 93 Kuniyasu, H., 11, 7 Kupan, A., 3, 288 Kurbatov, S., 5, 58 Kurdyumov, A.V., 7, 170; 12, 19, 172 Kureshy, R.I., 8, 29

529

Author Index Kurkovskaya, L.N., 7, 21 Kurland, A.R., 9, 138 Kuroda, S., 7, 129, 133 Kurosawa, H., 12, 63 Kurth, M.J., 12, 68; 14, 30 Kurts, A.L., 1, 351 Kus, N.S., 3, 260 Kusama, H., 11, 254; 12, 69, 182 Kusumi, T., 14, 54 Kutsumura, N., 10, 45 Kutuk, H., 2, 62 Kuwano, R., 3, 342 Kuwata, Y., 12, 166 Kuzmin, V.A., 7, 21 Kuznetsov, M.L., 12, 57 Kuznetsova, L.I., 3, 251 Kuznetsova, N.I., 3, 251 Kuznetsova, T.S., 8, 58 Kuznetzova, T.S., 4, 71; 14, 141, 145 Kvaskoff, D., 4, 81 Kv´ıcˇ ala, J., 11, 44 Kwak, J.M., 1, 248, 249 Kwiatkowski, P., 1, 171; 6, 47; 9, 133 Kwok, W.M., 7, 119 Kwong, C.K.-W., 1, 164; 11, 172 Kwong, F.Y., 1, 230; 9, 106 Kwong, H.-K., 3, 40 Kyong, J.B., 2, 59

L Laali, K.K., 7, 100, 132, 139, 150; 14, 1 Labinger, J.A., 7, 84 Labonne, A., 11, 92 Lacerda, P.S.S., 12, 73 Lacour, J., 3, 113, 123; 7, 40, 71; 14, 65 La Cruz, T.E., 8, 14 Laerdahl, J.K., 7, 15; 8, 113 Lafe, R.G., 12, 108 Lagarkha, R., 3, 160 Lagt, R.B.C., 1, 314 Lahuerta, P., 5, 33 Lai, A.J., 1, 177 Lai, C., 2, 33 Lai, C.-L., 4, 16 Lai, G., 1, 144; 9, 43 Lai, G.-h., 8, 78 Lakhdar, S., 5, 55–57; 6, 7, 49; 7, 52; 8, 57 Lakshmi Kantam, M., 1, 147 Laleu, B., 7, 71; 14, 65 Lalmalsawmi, H., 3, 8 Lam, T.Y., 12, 35 Lam, W.W.Y., 3, 40 Lamanna, G., 12, 127

Lamei, W., 14, 20 Lammertsma, K., 12, 39 Lampkins, A.J., 1, 236; 9, 76 Lancaster, N.L., 8, 122 Land, E.J., 11, 140 Landais, Y., 9, 80; 11, 257; 14, 19 Landgraff, S., 12, 16 Lane, P., 8, 111 Lane, S.I., 3, 255 Lang, H., 7, 39 Lang, K., 2, 102 Lang, S., 14, 78 Lange, D.A., 3, 302 Langer, M., 1, 137 Lannou, M.-I., 11, 11 Lanzalunga, O., 7, 42 Lapis, A.A.M., 11, 38 Lara, P., 14, 112 Large, J.M., 5, 51 Larina, L.I., 5, 12 Larock, R.C., 5, 62 Larsson, P.-E., 14, 41 Laschat, S., 7, 146 Laso, A., 1, 73; 9, 47 Lattanzi, A., 3, 224; 9, 30; 11, 193 Lau, E.Y., 7, 125 Lau, S., 1, 302 Lau, T.-C., 3, 40 Laue, S., 1, 307; 3, 351 Lauper, C., 3, 123 Laurikainen, K.M., 1, 101 Lautens, M., 3, 368; 8, 15, 50; 11, 246 Lauzon, C., 1, 16; 9, 119 Lavallo, V., 4, 21, 57; 7, 134, 135 Lavandera, I., 2, 80 Lavigne, G., 4, 27 Law, M.C., 9, 84 Lawrence, R.M., 9, 36 Lazny, R., 9, 128, 129 Le, Zh.-G., 11, 154 Leal, J.M., 2, 86 Lebeau, L., 11, 189 Lebel, H., 4, 74, 84; 14, 69 Leber, P.A., 13, 56 Lebeuf, R., 9, 80; 11, 257; 14, 19 Le Bras, J., 3, 222 Leclerc, F., 2, 99 Lectard, S., 4, 74 Lectka, T., 12, 136, 137 Lee, B.-S., 7, 28; 8, 100 Lee, B.Y., 4, 31 Lee, C., 1, 177 Lee, C.-C., 12, 1 Lee, C.-H., 14, 167 Lee, C.-T., 11, 233

Lee, Lee, Lee, Lee,

C.B., 3, 97 C.M., 3, 122 C.W., 3, 152 D., 3, 315; 4, 41, 42; 14, 118 Lee, G.-H., 12, 1, 49 Lee, H., 14, 167 Lee, H.G., 1, 264 Lee, H.W., 7, 28; 8, 100 Lee, I., 2, 25; 11, 183 Lee, J., 3, 272 Lee, J.-Y., 2, 21, 27 Lee, J.M., 11, 97 Lee, J.M.N., 3, 40 Lee, J.P., 2, 45, 61 Lee, J.S., 14, 167 Lee, K.-S., 11, 232 Lee, L.-C., 1, 169, 327 Lee, M.-T., 4, 16 Lee, N.H., 3, 256 Lee, S., 3, 182; 8, 65, 106 Lee, S.B., 7, 127 Lee, S.H., 1, 249 Lee, S.I., 4, 31; 12, 8 Lee, S.J., 8, 65 Lee, S.Y., 14, 167 Lee, Y., 8, 13; 9, 92 Lee, Y.H., 2, 29, 61 Le Fur, N., 1, 75 Legon, A.C., 8, 97 Legros, J., 8, 10 Le Guevel, E., 2, 111 Lehman, J.J., 11, 16 Lehmann, C.W., 1, 161; 11, 176 Lehnert, N., 3, 85 Lei, L., 1, 142 Leigh, W.J., 4, 105, 107; 11, 126 Leighton, J.L., 1, 45; 12, 102 Leino, R., 13, 49 Leis, J.R., 2, 30, 40 Leitner, W., 1, 161; 3, 252; 11, 176 Leitus, G., 3, 328; 7, 111 Lejon, T., 8, 47 Lemaire, J., 7, 115 Lemek, T., 11, 180 Lendero, N., 3, 196 Lenoir, D., 3, 274 Lenska, B., 2, 23 Lenzen, A., 11, 11 Leo, G.C., 2, 98 Leogane, O., 4, 74, 84; 14, 69 Leone, S., 12, 122 Leoni, A., 3, 49 Leopoldini, M., 3, 379 Le Quement, S., 11, 255 Lerebours, R., 1, 286 Lersch, M., 6, 69 Lertpibulpanya, D., 1, 241; 10, 38

530 Lesage, D., 13, 50 Leshcheva, I.F., 1, 351 Leszczynski, J., 12, 131 Lete, E., 11, 134 Lett, R., 12, 90 Letzel, M., 7, 85 Leung, L.T., 11, 3 Leung, M.-k., 12, 1 Levi Mortera, S., 14, 10 Levin, V.V., 1, 57, 78 Levina, I.I., 7, 20, 21 Levina, L., 1, 11 Lewandowska, E., 11, 191 Lewis, B.E., 1, 10 Lewis, D.K., 10, 28, 29; 14, 147, 148 Lewis, J.C., 4, 24 Ley, S.V., 1, 87, 122; 9, 24, 45; 11, 146, 147, 182 Li, A., 6, 36; 7, 147; 14, 31 Li, B., 8, 46; 11, 122 Li, B.-J., 4, 96; 11, 217 Li, C., 3, 292; 5, 26 Li, C.-J., 1, 343; 3, 269 Li, Ch., 11, 12 Li, D.-P., 6, 51 Li, F., 11, 2 Li, G., 11, 65, 81 Li, G.-R., 1, 239 Li, H., 1, 145; 6, 44, 46; 11, 155, 159, 160, 198, 215, 216; 13, 27 Li, H.B., 2, 78, 79; 3, 261 Li, J., 1, 170, 334; 3, 358; 11, 151 Li, J.-L., 4, 14 Li, J.-M., 2, 69 Li, J.-Z., 2, 78, 79 Li, K., 3, 363; 11, 226 Li, L., 2, 96; 4, 15; 11, 138, 162 Li, L.-C., 3, 317, 318 Li, M., 1, 222; 4, 40; 8, 108; 11, 103 Li, P., 4, 106 Li, Q., 7, 86; 11, 65 Li, R., 4, 96; 8, 46; 11, 217 Li, S., 11, 100; 12, 140 Li, S.-M., 3, 58, 59 Li, S.-X., 2, 78, 79 Li, T., 11, 136 Li, W., 2, 4 Li, W.-D.Z., 1, 277 Li, W.-S., 12, 49 Li, X., 3, 343, 376; 7, 84 Li, X.-Y., 1, 109 Li, Y., 1, 200; 3, 65, 223; 6, 23; 8, 34; 11, 81, 135, 194 Li, Y.-M., 1, 230; 9, 106

Author Index Li, Y.-X., 1, 106 Li, Y.L., 1, 152 Li, Z., 1, 86; 2, 96; 4, 9, 82; 11, 33 Li, Z.-C., 1, 108 Li, Z.-L., 1, 239 Li, Z.-S., 3, 266 Liaaen-Jensen, S., 7, 138 Lian, J.J., 12, 41 Liang, C., 4, 75 Liang, F., 11, 135 Liang, Y., 1, 81; 4, 85; 12, 33; 14, 127 Liang, Z., 1, 118 Liao, J.-H., 12, 173 Liao, Z., 1, 206 Liddle, S.T., 4, 8 Liddon, A.J.P.S., 1, 262; 3, 360 Liebscher, J., 14, 43 Lienke, A., 3, 83 Liese, A., 1, 307; 3, 351 Light, M.E., 12, 61 Likholobov, V.A., 3, 251 Liljefors, T., 9, 61 Lillo, V.J., 14, 25 Lim, J., 12, 183 Lim, Y.-K., 13, 38 Lima, M.F., 2, 100 Limbach, M., 1, 119 Limberg, C., 3, 83 Lin, B.-L., 11, 83 Lin, C.-Y., 1, 165; 11, 174 Lin, L., 12, 124 Lin, N., 12, 172 Lin, S., 11, 237 Lin, X.-F., 1, 195; 11, 40 Lin, Y., 11, 28 Lin, Y.-P., 12, 41 Lin, Y.-S., 1, 165; 11, 174 Lin, Z., 1, 264; 3, 40 Linares, M., 7, 95 Lindel, T., 12, 133 Linden, A., 9, 81; 13, 67 Lindsay Smith, J.R., 3, 208 Lindsey, C.C., 12, 138 Lindström, U.M., 11, 148 Lipinski, R., 1, 110 Lipkind, M.B., 13, 51 Lipshutz, B.H., 11, 233 Lis, L., 7, 90 List, B., 1, 60, 299, 332; 3, 357; 9, 14 Listowsky, I., 5, 23 Listratova, A.V., 14, 129 Little, S., 7, 36 Liu, B.-K., 11, 40 Liu, C., 4, 61; 11, 207 Liu, C.-W., 1, 165; 11, 174 Liu, D., 1, 88; 3, 40, 310 Liu, F., 2, 70

Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu, Liu,

F.-A., 1, 106 G., 11, 75; 12, 2 H., 3, 51; 12, 148 J., 3, 376 J.-K., 3, 317 J.-T., 11, 28 L., 6, 26; 11, 83; 12, 2 L.-P., 14, 90 L.-T., 11, 229 L.-X., 8, 51 P., 12, 21 Q., 11, 12, 135, 151 Q.-J., 12, 16 R., 7, 161 R.-S., 12, 41 S., 1, 190; 11, 199, 200 S.-Y., 1, 64 T.-Y., 11, 217 W., 12, 134 X., 1, 250; 3, 223; 4, 45; 11, 218 Liu, X.-Y., 1, 200; 11, 194 Liu, Y., 1, 330; 3, 293; 4, 80; 8, 46; 9, 158 Liu, Y.-C., 3, 350 Liu, Y.-H., 12, 1 Liu, Y.-K., 4, 96 Liu, Y.-L., 6, 26 Liu, Y.-T., 7, 177 Liu, Z., 5, 62; 14, 106 Liu, Z.-L., 12, 151 Llagostera, K.B., 7, 143 Llamas, T., 12, 70 Lledos, A., 11, 6 Llobet, A., 6, 65 Llopis-Mestre, V., 8, 122 Lloret, J., 5, 33 Lloyd-Jones, G.C., 4, 64; 14, 91 Lo, M.M.-C., 1, 64 Lobachev, V.L., 3, 212, 236 Lobkovsky, E., 1, 37; 12, 23 Lobo, A.M., 13, 76 Locatelli, M., 2, 42 Lodder, G., 7, 98; 9, 138 Lo Galbo, F., 1, 225; 9, 107 Loh, T.P., 12, 145 Lohier, J.-F., 1, 38; 9, 65 Lollmahomed, F., 4, 107 Lomberget, T., 12, 43 Loncke, P.G., 2, 97 Long, J., 11, 217 Loones, K.T.J., 5, 47 Loos, C., 11, 56 Lopes, F., 8, 126 López, C.S., 13, 63 López, F., 8, 9; 9, 86, 89; 11, 230 Lopez, J.A., 3, 346 Lopez, J.G., 5, 13 Lopez, L.A., 4, 46

531

Author Index Lopez, R., 1, 73; 2, 90; 5, 21; 9, 47 López, S., 4, 38, 39; 11, 118; 14, 97, 98 Lopez, X., 2, 92, 99 Lopez-Cara, L.C., 3, 107 Lopez-Mercado, A.Z., 13, 33 Lopez Ortiz, F., 1, 246; 5, 13; 9, 41 López-Pérez, J.L., 12, 97 Lopyrev, V.A., 5, 12 Lorenc, M., 11, 105 Lorono, M., 10, 23, 24, 27 Lorusso, P., 5, 14 Loska, R., 5, 53 Lou, B., 11, 198 Lou, S., 1, 25 Louie, J., 12, 162, 163 Love, J.A., 12, 183 Lowdon, T.R., 3, 208 Lozano, A., 8, 73 Lozano, O., 9, 18 Lu, C.-D., 13, 23 Lu, G., 1, 230; 9, 106 Lu, H., 14, 149 Lu, L., 3, 173 Lu, S., 1, 325; 3, 305 Lu, S.-F., 6, 43; 11, 252 Lu, X., 4, 58; 11, 237 Lu, Y., 1, 118, 323; 3, 326 Lu, Z.-L., 2, 106 Lubczak, J., 8, 134 Lucas, A.C., 1, 233 Lucero, C.G., 7, 62 Luckhurst, C.A., 1, 233 Luczak, J., 3, 50 Luderer, M.R., 9, 68 Lue, K., 3, 245 Lue, L.-L., 4, 65 Lue, X., 1, 347; 3, 199 Lugan, N., 4, 27 Luk, T., 3, 122 Lukyanets, E.A., 12, 73 Lulinski, S., 9, 56 Luo, F.-T., 1, 18 Luo, H., 1, 86 Luo, S., 3, 250; 11, 199, 200 Luo, Sh.-P., 11, 154 Luo, W., 1, 206 Luo, X., 11, 103 Luparia, M., 7, 169 Lupattelli, P., 3, 41 Luque, F.J., 9, 18 Lutz, F., 1, 227 Luu, T., 12, 84 Luxenburger, A., 1, 293; 9, 12 Luzgin, M.V., 7, 83 Lyˇcka, A., 14, 57 Lyer, M.R., 12, 3 Lyle, M.P.A., 3, 229

Lynch, V., 2, 102 Lyngdoh, R.H.D., 4, 68, 77 Lyon, C., 1, 266 Lyothier, I., 8, 5 Lyssenko, K.A., 14, 156 Ło˙zyński, M., 12, 117

M Ma, Ma, Ma, Ma, Ma,

C., 7, 119 L., 4, 85; 14, 127 M., 1, 210; 10, 46 Q., 7, 118 S., 9, 70; 11, 31, 119; 13, 83 Ma, X.-L., 11, 153 Ma, Y., 1, 49; 3, 371 Ma, Z., 14, 74 Mabry, J., 1, 276 Mabury, S.A., 1, 211 Macaluso, G., 14, 155 Macchia, F., 6, 27 MacDougall, K.N., 3, 361 Macgregor, S.A., 6, 70 Machacek, M.R., 8, 21 Machado, M.S., 7, 71; 14, 65 Machiguchi, T., 7, 58 Maciá, B., 14, 25 MacMillan, D.W.C., 3, 182, 359; 11, 144 MacMillar, S., 8, 61 MacNeil, D.D., 1, 11 MacNeil, S.L., 14, 14 Maddaluno, J., 9, 27; 11, 141, 224; 12, 113 Madhavan, S., 8, 63 Mae, M., 8, 18 Maeda, Y., 1, 243; 4, 92 Maekawa, M., 1, 42 Maemets, V., 2, 20 Maes, B.U.W., 5, 47 Maestro, M.A., 14, 136 Maestro, M.C., 1, 138 Maeyama, K., 6, 35; 7, 94 MaGee, D.I., 12, 34 Magerlein, W., 3, 95, 96 Magers, D.H., 13, 62 Magnus, P., 14, 53 Magull, J., 4, 34 Magyarfalvi, G., 10, 16 Mahajan, D., 1, 107 Mahajan, M.P., 12, 32, 80; 13, 8 Mahanti, M.K., 1, 340; 3, 5–15 Maharana, P., 3, 131 Mahendra, K.N., 3, 142 Maher, D.J., 2, 89 Maheswaran, H., 1, 147 Mai, C.-L., 3, 277 Maia, H.L.S., 2, 85 Maier, J.P., 7, 99 Maier, T.C., 4, 48

Mairata i Payeras, A., 3, 208 Maiti, S.K., 3, 77 Maitre, P., 7, 115 Majer, J., 6, 47 Majireck, M.M., 12, 85 Majumdar, K.C., 13, 79, 80 Mak, X.Y., 12, 35 Makarova, E.A., 12, 73 Makhova, N.N., 14, 156 Maki, K., 8, 44 Makino, S., 1, 46 Makosza, M., 5, 14, 53 Malacria, M., 8, 11; 9, 72; 12, 168 Maleczka, R.E., 9, 74; 13, 43; 14, 27 Maletesti, N., 12, 71 Malhotra, S.V., 1, 324 Malkani, R.K., 1, 342; 3, 29, 47 Mal’kina, A.G., 1, 199 Malkov, A.V., 1, 262; 3, 360, 361 Mallais, T.C., 12, 34 Mallik, S., 3, 62 Maluszko, J., 7, 128 Malykhin, E.V., 5, 48 Malysheva, L.A., 5, 48 Mamaghani, M., 11, 171 Man, S., 14, 33 Mancuso, J., 11, 246 Mandal, T., 11, 50, 251 Mandalia, R.T., 12, 96 Mandolini, L., 2, 105; 7, 69 Manesh, A.A., 3, 172 Manet, I., 3, 240 Mani, K., 1, 9; 3, 309 Manian, R.D.R.S., 12, 5 Manikyamba, P., 3, 185; 8, 81, 82, 102 Mann, A., 8, 56 Mann, I., 1, 312 Manna, K.R., 7, 174 Manoharan, M., 13, 57, 58 Manuzi, A., 3, 184 Mao, H., 6, 50 Mapp, A.K., 13, 29 Marcano, B., 10, 24 March, S., 9, 28; 11, 227 Marchese, L., 3, 221 Marchetti, M., 11, 102 Marco-Aleizandre, A., 1, 228 Marek, R., 14, 33 Mareque-Rivas, J.C., 2, 103, 104 Maria, P.-C., 7, 151 Mariani, A., 3, 361 Maricq, M.M., 3, 273 Marié, J., 8, 11 Marie, J.-C., 9, 72 Marigo, M., 1, 260; 9, 152 Marinelli, F., 11, 165

532 Marinescu, L.G., 3, 209 Marinetti, A., 12, 66 Marini, F., 1, 6 Marion, N., 13, 21 Marks, T.J., 11, 58 Marlier, J.F., 2, 33 Marmsäter, F.P., 13, 60 Marmugi, E., 5, 3 Marques, M.M.B., 13, 76 Marquez, R., 14, 153 Marrocchi, A., 12, 114, 127 Marrot, J., 8, 57; 13, 32 Marsais, F., 9, 62 Marsden, S.P., 1, 241; 10, 38 Marsella, M.J., 1, 303 Marshall, J.A., 11, 98 Martasek, P., 2, 102 Martelli, G., 11, 26 Marti, S., 13, 7 Martin, D., 9, 87; 11, 231 Martin, J.W., 1, 211 Martin, M., 1, 50; 3, 345, 346 Mart´ın, M.R., 12, 59 Mart´ın, N., 10, 15; 12, 12 Martin, O.R., 3, 178 Martin, V.S., 1, 329 Martina, S.L.X., 1, 314 Mart´ın-Domenech, A., 10, 15; 12, 12 Martinek, T.A., 1, 218; 9, 109 Mart´ınez, A., 3, 113; 8, 19 Mart´ınez, S., 4, 43, 44 Mart´ınez-Esperón, M.F., 12, 99 Martinkova, M., 3, 294 Marullo, S., 14, 155 Maruoka, K., 1, 245, 261; 4, 91; 9, 46; 11, 156, 213; 12, 86, 112, 141 Marwaha, A., 12, 80 Maryanoff, B., 2, 98 Masamune, S., 11, 76 Mas-Balleste, R., 3, 83 Mascarenas, J.L., 12, 62 Masci, B., 14, 10 Mase, N., 1, 111, 203; 11, 195 Maseras, F., 3, 98; 6, 58; 11, 6 Masetti, M., 7, 96; 13, 64 Maskill, H., 5, 1; 7, 105 Massa, W., 7, 76 Massaccesi, M., 9, 158 Mastranzo, V.M., 1, 213; 9, 111 Mastryukova, T.A., 14, 84 Masuda, T., 3, 225 Masuyama, A., 7, 89 Matar, M., 7, 80 Matharu, D.S., 1, 315; 3, 374 Mathew, J.S., 5, 31 Mathew, S.C., 7, 37 Mathiyalagan, N., 3, 147, 150, 151

Author Index Matito, E. , 13, 66 Matsson, O., 8, 61, 63, 67 Matsubara, H., 1, 83, 84 Matsubara, R., 11, 259 Matsubara, T., 11, 99; 14, 113 Matsuda, H., 1, 68 Matsuda, S., 8, 130; 14, 48 Matsuda, S.P.T., 7, 167, 173; 14, 59 Matsuda, T., 1, 197, 336; 12, 176 Matsui, K., 1, 167; 9, 23 Matsui, M., 1, 97 Matsumoto, K., 3, 73; 7, 59 Matsumoto, M., 1, 182; 11, 43 Matsumoto, T., 3, 52; 12, 31; 14, 123 Matsumoto, Y., 11, 39 Matsumura, T., 12, 107 Matsunaga, N., 4, 80 Matsunaga, S., 1, 31, 33, 255; 9, 103; 11, 121 Matsuo, K., 14, 15 Matsuo, T., 9, 136 Matsuoka, K., 14, 54 Matsuya, Y., 10, 55; 13, 84 Matsuzaka, H., 12, 169 Mattson, A.E., 11, 214 Matveeva, E.D., 1, 351 Matveeva, E.V., 14, 84 Mauduit, M., 9, 87; 11, 231 Maulik, P.R., 14, 13 Maurer, J., 7, 146 Mavalangi, S.K., 3, 42 Mavri, J., 8, 37 Maxwell, C.I., 2, 106 Mayanna, S.M., 3, 155 Mayer, H., 8, 93–95 Mayer, S., 3, 357 Mayhew, C.A., 11, 14 Mayo, P.D.M., 12, 34 Mayr, H., 5, 56; 6, 49; 7, 46–49, 51–53, 185; 8, 86, 125; 9, 143 Mbafor, W., 1, 309; 3, 334 McArdle, P., 14, 131 McCabe, T., 2, 89; 6, 41 McCaw, C.J.A., 2, 114 McClelland, R.A., 7, 122 McClure, B., 9, 66 McCoy, A.B., 7, 153 McCurdy, A., 3, 241; 14, 154 McDonald, E., 5, 51 McDonald, R., 12, 84, 180 McDonald, R.S., 1, 268; 9, 20 McGeoch, G.D., 3, 361 McGilvra, J.D., 1, 135 McIntee, E.J., 7, 68 McKee, V., 4, 100

McLaren, A.B., 1, 61; 8, 54 McMahon, T.B., 8, 71 McNally, A., 13, 30 McRae, C., 1, 331; 3, 366, 367 McWilliams, J.C., 3, 336 Meˇciarová, M., 11, 129 Meddour, A., 11, 124 Medebielle, M., 1, 282 Meenakshisundaram, S., 3, 32 Meenakshisundaram, S.P., 3, 31 Meetsma, A., 9, 86; 11, 230 Mehler, G., 3, 341 Mehrkhodavandi, P., 7, 84 Mehrman, S.J., 1, 333; 3, 299 Meier, H., 6, 34; 14, 39 Meier, T., 8, 4; 9, 11 Mej´ıa-Oneto, J.M., 14, 34 Mejuto, J.C., 2, 65 Mekelleche, S.M., 6, 6 Mekh, M.A., 6, 15; 11, 23 Mekonnen, A., 11, 139 Mel, K., 14, 76 Melchiorre, P., 2, 42 Melgar-Fernandez, R., 9, 130 Mella, M., 7, 106, 107 Melo, A., 8, 79 Menard, F., 1, 278; 8, 15 Menche, D., 1, 334; 3, 358 Menche, G., 1, 334; 3, 358 Mendiguch´ıa, P., 11, 30 Menendez, M.I., 2, 90; 5, 21 Meng, L., 7, 124 Meng, Q., 4, 40 Meng, X.-G., 2, 69 Meng, Z., 2, 68 Menichetti, S., 12, 122, 127 Mensah., L., 8, 10 Menz, H., 13, 77 Menzek, A., 11, 27 Menzeka, A., 14, 52 Mercero, J.M., 2, 92 Mereiter, K., 4, 28 Merey, G., 13, 69 Merino, P., 9, 13 Mertins, K., 11, 64 Mery, D., 4, 22 Merz, M., 3, 83 Meseguer, B., 3, 347 Metcalfe, J., 7, 180 Metz, R., 3, 154 Metzger, J.O., 7, 102; 11, 60 Metzner, P., 1, 38, 75; 9, 64, 65 Metzroth, T., 10, 32 Meuller, C., 3, 103 Meunier, B., 3, 280, 288 Meyer, C., 14, 103 Meyer, G., 8, 10 Meyers, C., 5, 47

533

Author Index Meza, R., 11, 131 Mezhnev, V.V., 5, 17; 11, 219 Mi, A.-Q., 1, 105, 149, 150; 11, 203; 12, 148 Mi, X., 11, 199, 200 Micalizio, G.C., 11, 57 Miceli, A.P., 4, 80 Michael, F.E., 11, 78 Michel, P., 1, 122 Michelin, R.A., 3, 216 Micoli, A., 5, 50 Micouin, L., 14, 47 Mielgo, A., 11, 197 Mieusset, J.-L., 4, 13; 12, 105; 14, 163 Miftakhov, M.S., 14, 12 Mihai, D.M., 2, 64 Mihalopoulos, N., 3, 244 Mihovilovic, M.D., 1, 345; 3, 291 Mii, H., 1, 245; 4, 91 Mikami, K., 3, 332 Mikhailov, V.A., 11, 14 Mikhaleva, A.I., 14, 157 Milczek, E.L., 3, 307 Miles, R.B., 1, 184 Miles, T.J., 8, 49; 12, 128 Militzer, C., 3, 347 Millen, D.J., 8, 97 Miller, J.D., 10, 28; 14, 148 Miller, K.M., 1, 198 Miller, S.R., 7, 70 Mills, A.M., 3, 103 Mills, N.S., 7, 142, 143; 9, 9 Milstein, D., 3, 328; 7, 111 Milto, V.I., 5, 28 Milton, M.D., 6, 30 Min, J.-H., 13, 19 Minabe, M., 10, 4 Minakata, S., 1, 82; 9, 77 Minato, T., 7, 58 Minatti, A., 3, 227 Mincione, E., 3, 213 Minisci, F., 3, 265 Minkin, V., 5, 58 Minnaard, A.J., 1, 172, 285, 314; 8, 9; 9, 86, 89; 11, 230 Minoura, M., 7, 162 Minowa, T., 1, 193 Minuti, L., 12, 114, 127 Minyaev, R.M., 13, 41 Mioskowski, C., 1, 189; 11, 189; 14, 121 Miranda, J.I., 9, 81 Miranda, M.A., 7, 104; 12, 100 Mirazi, N., 3, 87 Miscione, G.P., 1, 321; 3, 314 Mish, D., 10, 29; 14, 147 Mishima, M., 2, 28; 9, 138 Mishra, B.K., 3, 1–3

Mishra, K.K., 3, 126, 127 Mishra, M.K., 3, 25, 27 Mishra, P., 3, 23, 24, 81 Mishra, S.K., 2, 12; 3, 84 Mishra, S.P., 3, 136–138 Misra, M., 3, 149 Mita, M., 12, 54 Mita, T., 8, 44 Mitan, C.I., 14, 71 Mitchell, C.E.T., 9, 24, 45; 11, 146, 147 Mitchell, C.H., 7, 31 Mitchell, D., 11, 80 Mitra, A., 3, 222 Mitsuhashi, K., 1, 292; 9, 139 Mitsumoto, Y., 7, 131 Miura, M., 10, 35 Miyabe, H., 1, 72, 85 Miyagawa, T., 14, 29 Miyake, Y., 1, 290; 11, 111 Miyano, M., 3, 303 Miyano, S., 12, 167 Miyashita, Y., 12, 69 Miyata, M., 13, 22 Miyata, O., 13, 22 Miyatake, R., 7, 133 Miyazawa, M., 14, 126 Mizandrontsev, M.I., 5, 12 Mizumoto, M., 8, 2 Mizunashi, K., 11, 258 Mloston, G., 4, 11, 12 Mlynarski, J., 1, 134, 139, 140 Mlynarski, S.L., 2, 59 Mo., Y., 7, 137 Mobbili, G., 11, 26 Mobin, S.M., 12, 135 Mocella, C.J., 12, 134 Mochida, H., 7, 162 Mochizuki, E., 12, 15 Moden, B., 3, 221 Modi, K., 1, 135 Moglie, Y., 1, 326; 3, 391 Mohamed, M.F., 2, 106 Mohamed, M.M.A., 2, 77 Mohana, K.N., 3, 135, 143, 144 Mohar, B., 3, 369 Mohareb, M.M., 8, 88 Mohr, J.T., 10, 48 Moir, J.H., 13, 34 Moisan, L., 14, 63 Moiseev, A.G., 4, 105 Mojovic, L., 1, 38; 9, 64, 65 Mojovoc, L., 1, 75 Mokhtari, M., 5, 57 Molchanov, A.P., 4, 34; 12, 58 Molina, E., 11, 152 Moliner, V., 13, 7 Moloney, E.M., 14, 131 Molotov, S.I., 14, 156 Molteni, G., 3, 322; 12, 50

Monakov, Y.B., 3, 187 Monari, M., 1, 321; 3, 314 Mondal, R., 5, 7; 11, 143 Monguchi, D., 8, 130 Monsalve, A., 10, 21 Montgomery, J., 1, 196; 12, 174 Moody, C.J., 12, 128 Moon, D.H., 8, 65 Mora, J.R., 10, 27 Moradian, M., 8, 28 Morais, J., 8, 126 Moraleda, D., 1, 304 Moralee, A.C., 12, 93 Morales-R´ıos, M.S., 14, 55 Mordini, A., 9, 122–127 Moreau, J.J.E., 3, 263 Moreau, M., 7, 55 Moreira, R., 8, 126 Morell, C., 6, 6 Moreno, R.M., 1, 279 Morgan, J.B., 12, 74 Morganti, S., 14, 155 Mori, A., 6, 57 Mori, H., 9, 136 Mori, M., 14, 42 Mori, S., 10, 43; 11, 260 Mori, T., 12, 17 Moriarty, R.M., 14, 71 Morie, Y., 4, 102 Morimoto, H., 1, 33 Morimoto, T., 11, 63 Morimoto, Y., 8, 24 Morishita, M., 6, 25 Morita, H., 8, 72; 12, 147 Morita, J., 2, 93 Morita, M., 12, 54 Morita, N., 14, 104 Morita, R., 11, 99; 14, 113 Morita, Y., 7, 58 Moriya, K.-i., 9, 157 Moriya, T., 2, 93 Moriyama, C., 3, 225 Moriyama, K., 8, 130 Morohashi, M., 12, 167 Morrell, A., 6, 62 Morris, D.J., 1, 315; 3, 374 Morris, G.E., 7, 84 Morris, J.J., 1, 287 Morrow, J.R., 2, 108 Mortier, J., 9, 58–60 Morzherin, Y.Y., 14, 133 Moseley, J.D., 14, 151 Moslin, R.M., 1, 198, 328 Mosrin, M., 12, 185 Moss, R.A., 4, 1, 63; 7, 43, 156; 9, 144; 14, 40 Mota, C.J.A., 9, 135 Motevalli, M., 1, 252; 12, 96 Motherwell, W.B., 3, 387 Mothia, B., 12, 96

534 Motoki, R., 1, 178 Mott, K., 3, 189, 190 Mountford, D.M., 13, 11 Moutiers, G., 2, 111 Moya, H.D., 3, 76 Moyá, M.L., 8, 89 Moyano, A., 1, 279 Mozzanti, A., 14, 128 Msaddek, M., 12, 45 Mucientes, A.E., 3, 86, 89 Mück-Lichtenfeld, C., 3, 377, 393; 8, 25; 12, 39 Muhlthau, F., 7, 23 Mujika, J.I., 2, 92 Mukai, C., 12, 91, 155; 13, 81 Mukaiyama, T., 1, 30, 193, 283; 11, 161; 14, 23, 24 Mukarakate, C., 7, 77 Mukhopadhyay, S., 3, 45 Mulero, M., 8, 33; 9, 91 Mulla, R.M., 3, 54 Muller, B., 1, 345; 3, 291 Müller, C., 11, 56, 66 Müller, I.M., 14, 94 Müller, P., 4, 75; 7, 2 Muller, R.P., 7, 118 Muller, T., 7, 74 Mulvey, R.E., 6, 71, 72; 9, 100, 101 Mulzer, J., 12, 105 Munakata, T., 14, 54 Muniz, K., 1, 207; 3, 378 Munot, Y.S., 3, 262 Muñoz, M., 8, 89 Muñoz, M.C., 11, 152 Muñoz, M.P., 4, 38; 14, 91, 97 Murai, K., 9, 149 Murakama, M., 12, 176 Murakami, M., 1, 197, 336 Muraki, T., 12, 104 Muramatsu, K., 1, 242; 4, 93, 102; 11, 258 Murphy, G.K., 13, 60; 14, 115 Murphy, J.A., 14, 78 Murray, J., 3, 208 Murray, J.S., 7, 3; 8, 111 Murthy, A.S.A., 3, 141 Muzart, J., 3, 222; 14, 120 Mwene-Mbeja, T.M., 13, 12 Myahkostupov, M., 7, 43

N Nachtigall, F.M., 11, 38 Nachtsheim, B.J., 11, 123 Nadipuram, A.K., 14, 175 Nadkarni, D.V., 14, 56 Naeimi, H., 8, 28 Nag, P.P., 9, 69 Nagaoka, M., 13, 13 Nagarajn, S., 3, 31

Author Index Nagasawa, K., 1, 146 Nagata, M., 12, 63 Nagata, Y., 11, 188 Nagataki, T., 3, 230 Nagatomi, E., 3, 257 Nagatomo, S., 3, 52 Nagaya, H., 1, 97 Nagy, P., 3, 206 Nagy-Ungvarai, Z., 3, 167 Naik, S., 1, 1 Nair, S.M., 4, 86 Nair, V., 4, 86, 94; 7, 37 Naito, T., 13, 22 Nájera, C., 1, 116, 204; 11, 202 Najera Domingo, C., 9, 54 Naka, K., 8, 17 Nakada, M., 1, 179; 3, 303; 4, 56; 12, 107 Nakai, T., 13, 42 Nakai, Y., 1, 111 Nakajima, A., 8, 72 Nakajima, K., 11, 261; 13, 17 Nakajima, M., 1, 131 Nakajima, N., 7, 129 Nakamura, E., 11, 228 Nakamura, S., 1, 69 Nakano, K., 12, 146; 13, 24 Nakano, M., 9, 160 Nakanoya, Y., 12, 154 Nakao, Y., 11, 68, 70, 72 Nakashima, H., 1, 69 Nakaya, Y., 12, 158 Nakayama, K., 11, 99; 14, 113 Nakazaki, A., 13, 42 Nakhla, J.S., 11, 79 Nalwaya, N., 1, 341 Namba, K., 1, 68 Nambi, K., 1, 339; 3, 153 Namboothiri, I.N.N., 11, 187 Nanda, S., 1, 251 Nandibewoor, S.T., 3, 42, 54–57, 88, 94 Nantz, M.H., 14, 30 Naota, T., 1, 153 Napolitano, E., 4, 33 Naqvi, I.I., 3, 390 Nardi, M., 1, 15 Nardini, A., 11, 165 Närhi, K., 13, 74 Narsihmulu, Ch., 1, 103; 11, 178 Narui, R., 1, 263 Narumi, T., 8, 2 Naso, F., 3, 226 Natale, D., 2, 104 Natarajan, S.R., 1, 297 Nath, D.C.D., 11, 95 Navarro-Vázquez, A., 13, 73 Naya, S., 7, 130, 131

Nebot, J., 1, 127 Nefedov, O.M., 4, 62; 13, 51 Neidhöfer, J., 14, 107 Nekipelova, T.D., 7, 20, 21 Nelyubina, Y.V., 14, 156 Nematollahi, D., 3, 87 Nemeth, B., 7, 110 Nemoto, H., 10, 55; 13, 84 Nemykin, V.N., 14, 8 Netsch, K.-P., 14, 6 Nettles, B.J., 1, 35 Neudorfl, J.-M., 3, 302 Neumann, R., 3, 247 Neurock, M., 7, 87, 88 Nevado, C., 11, 118; 14, 97 Neverov, A.A., 2, 106 Neves, M.G.P.M.S., 3, 49; 12, 73 Ng, S.-S., 1, 188 Ng, S.M., 12, 14 Ngono, C.J., 14, 16 Nguyen, T.-H., 9, 58 Nguyen, T.L., 3, 254 Nguyen, T.T., 11, 263; 12, 143 Ni, C., 8, 34 Ni, Y., 3, 359; 12, 174 Nicholas, K.M., 12, 81 Nichols, J.M., 1, 35; 9, 138 Nicolaou, G., 3, 109 Nicolas, C., 7, 40 Nicoletti, M., 1, 332 Nidetzky, B., 3, 284 Nie, X., 11, 12 Nieddub, I., 3, 375 Nielsen, O.J., 1, 211 Nielsen, R.J., 3, 268 Nielsen, T.E., 11, 255 Niemeier, O., 4, 88 Nieminen, V., 13, 49 Nieto, J., 11, 30 Nieto-Oberhuber, C., 4, 38, 39; 11, 118; 14, 97, 98 Nii, K., 14, 54 Niida, A., 8, 2 Nilsson, B.L., 2, 82 Nimmagadda, R.D., 1, 331; 3, 366, 367 Nishibayashi, Y., 6, 30 Nishida, A., 8, 128 Nishida, G., 12, 157 Nishii, T., 10, 43; 11, 260 Nishikawa, Y., 8, 24 Nishimata, T., 10, 48 Nishimura, T., 1, 40; 9, 121; 11, 109, 249; 12, 54 Nishimura, Y., 1, 290 Nishiwaki, K., 14, 15 Nishiyama, H., 1, 160; 3, 362 Nishiyama, M., 11, 48 Nishiyama, S., 10, 45

535

Author Index Nishizawa, M., 7, 168; 11, 48; 14, 58 Nitta, M., 7, 130, 131 Niu, H.-b., 6, 19 Noble, A.R., 13, 21 Noel, J.P., 7, 174 Noguchi, K., 12, 157, 160 Noguchi, M., 2, 84; 14, 158 Noguchi, T., 6, 25 Nokami, J., 1, 182; 11, 43 Nokami, T., 7, 44 Nolan, S.P., 4, 23; 13, 21 Noll, B.C., 1, 287 Nome, F., 2, 14, 100 Norberg, D., 14, 41 Norberto, F., 2, 44 Nori-Shargh, D., 11, 181 Noronha, L.A., 9, 135 Norrby, P.-O., 9, 61; 11, 255 Northrop, B.H., 13, 52; 14, 166 Nosyreva, V.V., 1, 199 Noszal, B., 2, 9 Noszticzius, Z., 3, 166 Noto, R., 5, 42; 10, 2 Nouri, D.H., 7, 160; 13, 1 Novak, M., 7, 126 Novak, Z., 10, 16 Novikov, M.S., 4, 104; 14, 132 Nowak, I., 4, 60 Nowrouzi, N., 6, 21 Nudelman, N.S., 9, 78, 79; 11, 222 Nummert, V., 2, 16, 20 Nunes, C.M., 12, 67 Nún˜ ez, A., 12, 59 Nunez, O., 2, 88 Nussbaum, R., 4, 79; 14, 178 Nuvala, S., 1, 155 Nyberg, A.I., 1, 101 Nyerges, M., 13, 72 Nygren, C.L., 4, 55 Nyman, G., 3, 270

O Oakes, J., 3, 208 Oba, T., 10, 4 O’Brien, J.E., 2, 89 Occhiato, E.G., 13, 64 Occhiato, R.G., 7, 96 Occhipinti, G., 4, 25 Ochiai, M., 7, 98; 9, 149 Oda, M., 7, 129, 133 Oda, S., 11, 68, 70, 72 Odashima, K., 11, 71 Ode, Y., 1, 182; 11, 43 O’Donoghue, A.M., 2, 108 Oestergaard, L.F., 3, 273 Oestreich, M., 8, 16; 11, 247 Ofial, A.R., 5, 56; 6, 49; 7, 46, 48, 49, 52; 8, 94, 95, 125

Ogawa, C., 1, 183 Ogawa, T., 14, 15 Ogoshi, S., 12, 63 Oh, C.Y., 10, 17 Oh, H.K., 2, 52 Oh, J.T., 13, 19 Oh, J.Y., 2, 52 Oh, S.J., 8, 65 Oh, Y., 2, 29; 8, 65 Oh, Y.-H., 8, 106 O’Hara, C.T., 6, 72; 9, 101 Ohara, N., 1, 111 Ohdachi, K., 12, 91; 13, 81 Ohe, T., 12, 158 Ohfune, Y., 1, 68 Ohgiya, T., 10, 45 Ohkita, M., 7, 141 Ohkuma, T., 1, 305 Ohmura, T., 11, 47, 82 Ohno, H., 8, 2 Ohsawa, N., 10, 55; 13, 84 Ohta, T., 11, 236 Ohtoshi, H., 7, 130 Oi, S., 11, 243 Oiarbide, M., 1, 73; 9, 47 Oike, H., 6, 35; 7, 94 Oisaki, K., 1, 46, 129, 158, 159 Oishi, S., 8, 2 Okada, Y., 3, 283 Okajima, H., 3, 283 Okajima, M., 7, 44 Okamoto, H., 7, 120; 13, 48 Okamoto, I., 12, 54 Okamoto, J., 7, 58 Okamoto, N., 13, 13; 14, 22 Okazaki, T., 7, 100, 132; 14, 1 Okazaki, Y., 14, 173 Okino, T., 1, 72 Okita, A., 11, 254 Okovityi, S.I., 8, 39 Okrent, R.A., 1, 352 Okulik, N.B., 7, 154 Okuno, S., 6, 54; 7, 92; 12, 4 Okuyama, T., 6, 54; 7, 60, 91, 92, 98; 8, 23; 11, 262; 12, 4; 14, 139 Olah, G.A., 7, 6, 23, 144, 157 Olchanski, E., 3, 248 O’Leary, D.J., 12, 78 Ollevier, T., 13, 12 Ollivier, C., 1, 304 Olmstead, M.M., 12, 68 Olsbye, U., 7, 85 Olsen, M., 8, 50 Olsson, V.J., 8, 12 Olszewski, T.K., 13, 15 O’Maille, P.E., 7, 175 O’Malley, D.P., 14, 166

Omar, O.H., 3, 226 Omote, M., 1, 316; 3, 388 Omura, K., 4, 87 Omura, S., 1, 82; 9, 77 Onel, L., 3, 166 Ono, K., 7, 141 Onyeozili, E.N., 9, 74; 13, 43; 14, 27 Ooi, T., 9, 46; 11, 156, 213; 14, 54 Oota, A., 10, 4 Opatz, T., 14, 73 Opazo, A., 2, 76 Optiz, A., 7, 45 Orena, M., 11, 26 Orendt, A.M., 3, 201 Orfanopoulos, M., 3, 239; 14, 81 Orimoto, Y., 8, 17 Orito, Y., 1, 131 Orlov, V. Yu., 5, 28 Orlova, G., 8, 88 Oro, L.A., 1, 50; 3, 345, 346 Orozco, M., 9, 18 Orti, E., 7, 145 Ort´ın, M.-M., 13, 82 Ortuno, R.M., 1, 266 Osada, H., 12, 178 Osakada, K., 6, 57 Osako, T., 3, 52 Osetrov, A.G., 1, 351 Oshima, K., 1, 173; 5, 11, 40; 11, 253 Oshima, M., 6, 54; 7, 92; 12, 4 Oshima, T., 12, 15, 36, 82 Oshita, M., 1, 8 Os’kina, I.A., 2, 5 Oßwald, T., 11, 19 Ostrowski, S., 12, 132 Otaka, A., 8, 2 Otsuka, M., 12, 159 Otsuka, N., 1, 84 Ottolina, G., 3, 237 Oulyadi, H., 11, 141 Ouyang, A., 7, 34 Ouyang, X.-Y., 11, 74 Overkleeft, H.S., 7, 98 Overman, L.E., 5, 35, 36; 12, 74; 14, 68 Owens, T.R., 11, 126 Owen-Smith, G.J.J., 4, 64 Ozawa, H., 11, 39 Ozawa, T., 3, 73 Ozen, R., 3, 259, 260 Ozeryanskii, V.A., 6, 15; 7, 38; 11, 23; 14, 62

P Pace, A., 14, 128 Pace, V., 5, 42; 10, 2; 14, 155 Padhy, A., 3, 131

536 Padmaja, A., 11, 186 Padmavathi, V., 11, 186 Padwa, A., 8, 42; 12, 89; 14, 34 Page, M.I., 2, 91 Page, P.C.B., 3, 112, 113 Pagliaro, M., 3, 263 Pais, A.A.C.C., 12, 67 Pal, B., 3, 102 Pal, S., 12, 135 Palacios, F., 9, 118; 11, 234 Palacios, J.C., 12, 61 Palaniappan, A.N., 3, 16 Palazzi, C., 1, 346; 3, 228 Palenzuela, J.A., 12, 121 Palepu, R., 2, 66 Palepu, R.M., 8, 88 Palfey, B., 7, 36 Palframan, M.J., 14, 171 Palmieri, A., 11, 8 Palmieri, G., 1, 320; 3, 321 Palmiero, L., 3, 307 Palmisano, G., 12, 81 Palmucci, C., 11, 220 Palomo, C., 1, 73; 9, 47, 81; 11, 197 Palumbo Piccionello, A., 14, 128 Pamplona, T., 2, 44 Pan, X.-M., 3, 266 Pan, Y., 11, 81 Panas, I., 3, 270 Panchenko, B.V., 2, 43 Panda, M., 1, 215; 9, 97 Panda, R., 3, 124 Pandey, M.K., 1, 185 Pandya, K., 11, 196 Paneque, M., 14, 112 Paneth, P., 8, 61, 63 Pang, Q.-H., 2, 69 Panigada, L., 14, 109 Panisch, R., 7, 74 Pansare, S.V., 11, 196 Panunzi, B., 11, 17 Panunzio, M., 1, 350 Paolucci, C., 11, 133 Paoniczek, K., 12, 53 Pápai, I., 11, 206 Pape, T., 13, 18 Paquette, L.A., 1, 273, 293; 9, 12 Paquin, J.-F., 3, 368 Paradela, C., 9, 37; 14, 172 Parasuk, V., 13, 45 Parcella, K., 10, 29; 14, 147 Pardo, D.G., 9, 110 Pare, B., 3, 132 Pare, J.R.J., 13, 50 Parella, T., 6, 65 Parihar, P.S., 2, 55 Paris, J.-M., 11, 189

Author Index Pariza, R., 3, 188 Park, B.-C., 2, 59; 8, 83 Park, E.J., 2, 48; 11, 97 Park, G., 8, 53 Park, H.-R., 2, 41 Park, J.H., 4, 31; 12, 8 Park, K.-H., 2, 59 Park, S.-H., 7, 176 Park, S.-W., 8, 106 Park, S.J., 14, 167 Park, S.Y., 4, 31; 12, 8 Park, T.J., 10, 17 Parker, V.D., 2, 8 Parkes, M.A., 11, 14 Parlier, A., 11, 264 Parmon, V.N., 7, 83 Parrish, D., 14, 71 Parthasarathi, R., 1, 298; 6, 2; 11, 15 Parvez, M., 11, 261; 12, 120; 13, 17; 14, 5 Paryzek, Z., 14, 76 Pas, E., 1, 213 Pascal, R., 2, 87 Pasqualetti, M., 3, 213 Pastor, A., 12, 38; 13, 85 Pasumansky, L., 3, 300 Patanwadia, Y., 12, 96 Patel, B.K., 1, 1, 2 Patel, N.T., 3, 33, 35 Patel, S., 3, 1–3 Pathak, M., 10, 18 Patil, D.B., 3, 177 Patil, M.P., 10, 14 Patil, N.T., 11, 235 Paton, R.S., 1, 125 Patskovska, L., 5, 23 Patskovsky, Y., 5, 23 Paull, G.H., 12, 137 Pavam, C.H., 11, 175 Pavone, M., 8, 114 Pawar, S.S., 12, 115 Paxton, T.J., 12, 42 Paz, E., 9, 111 Paz Muñoz, M., 11, 118 Pazo-Llorente, R., 5, 1; 7, 105 Peach, P., 1, 312 Pedrech, A., 1, 268 Pedro, J.R., 1, 143, 228; 7, 186; 9, 44; 11, 152; 14, 35 Pedrosa, R., 11, 30 Peeters, J., 3, 249, 254 Pei, X., 13, 5 Pellegrinet, S.C., 11, 250 Peluso, P., 11, 102 Pena, D., 5, 61; 9, 86 Peña, D., 11, 230 Penedo, F., 2, 75 Peng, L., 1, 210; 10, 46 Peng, L.Z., 1, 152

Peng, Q., 12, 75 Peng, S.-M., 12, 1 Peng, Y., 1, 277 Peng, Z.-H., 5, 46 Penn, G., 14, 6 Penoni, A., 12, 81 Peppers, B.P., 14, 117 Percy, D., 5, 61 Percy, J.M., 1, 288; 12, 93 Peregrina, J.M., 8, 127 Peregudov, A.S., 5, 2 Pereira-Lima, S.M.M.A., 2, 85 Perepichka, D.F., 7, 145 Pérez, P., 8, 98 Perez Alvarez, I.J., 5, 13; 9, 41 Perez-Galan, P., 4, 39 Perez-Lorenzo, M., 2, 65 Pérez-Pérez, M., 8, 73 Pérez-Prieto, J., 5, 33; 12, 100 Periasamy, M., 1, 32; 9, 29 Pericàs, M.A., 14, 136 Périchon, J., 11, 239 Perkel, A.L., 3, 258 Pernak, J., 12, 117 Perseghini, M., 9, 158 Persiani, D., 14, 10 Peruchena, N.M., 7, 154 Perumal, P.T., 3, 72 Perumal, S., 12, 52 Perveen, A., 3, 390 Pervishko, T.L., 8, 123 Pesquet, A., 11, 141 Peters, R., 13, 28 Petersen, D., 14, 92 Petit, M., 12, 168 Petrignet, J., 1, 156 Petronijevic, F., 1, 273 Petrova, O.V., 14, 157 Petrovskii, P.V., 5, 2 Pettus, T.R.R., 12, 138 Pfeiffer, S.S., 12, 130 Phan, T.B., 7, 47, 51, 53; 8, 86, 93; 9, 143 Phares, K.R., 14, 71 Phillips, D.L., 7, 119 Phuan, P.-W., 1, 215; 9, 97 Phung, S., 13, 33 Pi, Z., 12, 140 Piatek, A.M., 12, 101 Pibiri, I., 14, 128 Piccinini, F., 1, 133 Picher, M.T., 12, 44 Pichon, N., 12, 113 Piecuch, P., 12, 9 Pieniazek, S.N., 12, 88, 89 Pieraccini, D., 5, 3 Pierciaccante, R., 3, 314 Pieriaccante, R., 1, 321 Pierini, A.B., 2, 17

537

Author Index Piermatti, O., 12, 114 Piers, W.E., 12, 120 Pignataro, L., 1, 117 Pihko, P.M., 1, 101, 295; 9, 150 Piirsalu, M., 2, 16, 20 Pikh, Z.G., 3, 210 Pilati, T., 3, 301 Pillinger, K.S., 14, 50 Pincock, J.A., 7, 22, 93 Pineschi, M., 6, 27; 8, 40; 9, 140 Pinho e Melo, T.M.V.D., 9, 148; 12, 67 Pinto, B.M., 14, 66 Pinto, F.C.S.C., 2, 85 Piotrowiak, P., 7, 43 Pitchumani, K., 2, 63 Pitcock, W.H., 9, 69 Pittman, C.U., 3, 317, 318 Pitzenberger, S.M., 9, 94 Piva, O., 12, 18 Pizzo, F., 12, 103, 114 Plakhtinskii, V.V., 5, 10 Platts, J.A., 1, 56 Platz, M.S., 4, 72, 73 Ple, N., 1, 38, 75; 9, 64, 65 Plesnicar, B., 3, 196, 238 Plesnikar, B., 3, 186 Pliego, J.R., 8, 91, 92; 10, 7 Plietker, B., 8, 3 Plöger, T., 14, 94 Plumet, J., 1, 246 Plush, S.E., 2, 107 Poater, A., 6, 65 Poater, J., 13, 66 Poblete, F.J., 3, 89 Poechlauer, P., 3, 195 Poelman, H., 14, 38 Pohani, P., 3, 24 Poisson, J.-F., 12, 30 Pol, P.D., 3, 42 Poláková, J., 11, 105 Polet, D., 8, 6 Politanskaya, LV., 5, 48 Politzer, P., 7, 3; 8, 111 Poljakova, J., 7, 30 Pölleth, M., 6, 70 Polo, V., 9, 142 Pommier, Y., 7, 124 Ponec, R., 7, 159 Ponomarev, N.E., 8, 84; 10, 9, 11 Ponomareva, E.A., 8, 123; 10, 10 Pons i Prats, R., 3, 208 Poon, T., 3, 282 Poonoth, M., 4, 94 Pooput, C., 1, 282 Popov, A.F., 2, 43 Porco, J.A., 12, 78 Port, M., 12, 90

Porta, A., 7, 169 Posner, G.H., 3, 261 Postigo, A., 7, 122 Potácˇ ek, M., 14, 33 Poturalski, M.J., 7, 126 Pour, M., 11, 32 Poveda, M.L., 14, 112 Poverenov, E., 7, 111 Poverlein, C., 12, 133 Powell, E.T., 2, 98 Powers, D.C., 13, 56 Pozharskii, A.F., 6, 15; 7, 24, 38; 11, 23; 14, 62 Prabaharan, R., 2, 104 Prabhakar, S., 13, 76 Prakash, G.K.S., 7, 1, 6, 23, 144, 157; 9, 151 Praly, J.-P., 12, 45 Prandi, C., 7, 96; 13, 64 Prasad, B.A.B., 14, 95 Prasad, D., 2, 12 Prasang, C., 7, 76 Prasanth, K.L., 1, 147 Pratap, R., 14, 13 Pratt, N.E., 1, 176 Pratviel, G., 3, 280, 288 Preda, D.V., 9, 7 Prieto, J.A., 8, 33; 9, 91 Prim, D., 9, 159 Prinzbach, H., 11, 19 Pritchina, E.A., 4, 76 Privalov, T., 1, 306; 3, 267, 327, 370 Priya, V., 3, 151 Procopio, A., 1, 15 Prodger, J.C., 1, 233 Prokop’eva, T.M., 2, 43 Protti, S., 7, 108 Pu, L., 1, 229; 9, 105 Puchberger, M., 4, 28 Puglisi, A., 1, 117 Pujanauski, B.G., 14, 95 Pullez, M., 3, 41 Punta, C., 3, 265 Purwar, M., 3, 68 Pushechnikov, A., 9, 15 Pyun, S.Y., 2, 108; 10, 1

Q Qi, C., 2, 115 Qi, C.-R., 11, 74 Qi, G., 1, 187 Qian, C., 11, 40 Qian, Y., 4, 15 Qin, B., 12, 124 Qin, C., 13, 62 Qin, H., 11, 121 Qin, S., 1, 70 Qin, S.-Y., 2, 78, 79 Qin, Y., 1, 53; 3, 382

Qin, Y.-C., 1, 229; 9, 105 Qin, Z.-H., 7, 10 Qu, B., 9, 2, 71 Qu, X., 2, 7 Que, L., 3, 83 Quiclet-Sire, B., 1, 92 Quinn, K.J., 13, 31 Quintanilla, E., 7, 2, 151 Quintero, L., 1, 213; 9, 111 Qwabe, L.Q., 3, 132

R Rabbat, P.M.A., 1, 45 Rabinovitz, M., 9, 6, 7 Rachid, B., 12, 51 Racz, K., 3, 167 Radhakrishnamurti, P.S., 3, 80, 129, 130; 6, 10 Radhakrishnan, K.V., 12, 186, 187 Radhika, N.P., 10, 18 Radivoy, G., 1, 326; 3, 391 Radmogadam, K., 11, 171 Raducan, M., 11, 118; 14, 97 Raduly, S., 6, 66 Raeck, C., 9, 40; 10, 39 Raffa, P., 11, 248 Ragauskas, A.J., 3, 264 Raghavan, A.S., 13, 47 Raghunathan, R., 12, 5 Raheem, I.T., 1, 162; 11, 177 Rahimizadeh, M., 1, 268 Rahmani, S., 3, 169 Rai, K.M.L., 3, 144 Rai, V., 11, 187 Raible, J., 3, 189, 190 Raimondi, L., 1, 301 Raines, R.T., 2, 82 Rainier, J.D., 3, 201; 14, 106 Raj, M., 1, 104 RajanBabu, T.V., 11, 67, 69 Rakhimov, A.I., 2, 38 Rakiel, B., 1, 140 Ram, V.J., 14, 13 Ramachandran, A., 5, 20; 10, 19 Ramachary, D.B., 1, 151; 11, 143 Ramasamy, V., 1, 339; 3, 153 Ramirez, A., 1, 37 Ramirez-Lopez, P., 1, 262; 3, 360 Ramnial, T., 4, 7 Ramos, D.R., 10, 49 Ramsden, C.A., 11, 140 Rangappa, K.S., 3, 163 Rani, E., 3, 5 Ranu, B.C., 11, 50, 251; 14, 45 Rao, A.K.S., 3, 80, 129, 130; 6, 10 Rao, J.M., 6, 20

538 Rao, K.V., 3, 312, 313 Rao, M.L.N., 1, 296 Rao, P.P., 3, 26 Rao, Y., 7, 61 Rappoport, Z., 8, 101; 10, 53; 11, 127 Rasappan, R., 11, 166 Raschmanova, J., 3, 294 Rassias, G.A., 3, 112 Rasul, G., 7, 144, 157 Rathgeb, X., 9, 28; 11, 227 Rathore, N., 3, 47 Rauniyar, V., 1, 174 Ravi, V.K., 1, 18 Ravikumar, K., 1, 147 Ravi Kumar, P., 14, 36 Rawal, V.H., 1, 135 Raymond, K.N., 14, 70 Rebek, J., 2, 74 Rebolledo, F., 2, 80 Reboul, V., 1, 38, 75; 9, 64, 65 Recanatini, M., 7, 96; 13, 64 Recuperu, F., 3, 265 Reddy, B., 11, 186 Reddy, B.S., 3, 312, 313 Reddy, K.V., 1, 103 Reddy, M.P.C., 3, 124 Reddy, N.R., 1, 103 Reddy, S.R., 8, 81, 82, 102 Red’ko, A.N., 2, 23 Redon, S., 12, 18 Reed, C.A., 7, 112 Reed, J.N., 9, 52 Reetz, M.T., 3, 341, 343; 12, 110 Reeves, J.T., 1, 244; 4, 90; 9, 69 Regás, D., 12, 121 Reich, H.J., 9, 146 Reich, N.W., 11, 33 Reid, S.A., 4, 17; 7, 77 Reinaud, O., 6, 68 Reingold, I.D., 1, 205 Reinhardt, L.A., 2, 33 Reinhoudt, D.N., 2, 105 Reis, J.C.R., 8, 79 Reisenauer, H.P., 4, 11, 12 Reiser, O., 11, 166 Reisinger, A., 7, 9 Rempala, P., 7, 117 Remy, P., 1, 137 Ren, J., 3, 317, 318 Ren, Y., 1, 325; 3, 305, 318; 8, 75, 107, 108 Renaud, J., 8, 20 Renault, L., 7, 93 Renzi, G., 8, 70 Revathi, S.K., 3, 135 Revkov, O.A., 3, 258 Reyes, A., 5, 49

Author Index Reyes, E., 1, 120; 11, 9, 192, 223 Reyes, L., 3, 231; 14, 67 Reyes-Trejo, B., 14, 55 Reymond, J.-L., 1, 98 Reynolds, T.E., 1, 166; 11, 214 Rhee, S.-K., 7, 176 Riant, O., 1, 157 Ribas, X., 6, 65 Ricci, A., 6, 40; 12, 142 Richard, J.P., 2, 108; 8, 119 Richardson, J., 1, 238; 3, 108; 9, 39; 10, 36 Riddell, N., 12, 20, 24 Riegert, D., 11, 124 Riera, A., 14, 136 Rijs, A.M., 10, 51 Riley, P.A., 11, 140 Rinaldi, S., 11, 26 Rios, R., 11, 145 Ritter, A., 1, 334; 3, 358 Ritter, T., 4, 26 Rivalta, E., 1, 20; 9, 98 Rivas-Nass, A., 11, 96 Rix, K., 4, 101; 14, 159 Robbins, A.M., 7, 3 Robert, F., 9, 80; 11, 257; 14, 19 Robert, N., 9, 62 Robert, P.S., 2, 76 Robert-Peillard, F., 4, 75 Roberts, J.C., 7, 22 Roberts, S.M., 1, 309; 3, 334 Roberts, S.W., 3, 201 Robertson, J., 13, 10; 14, 171 Robiette, R., 1, 62, 238, 274; 9, 39, 48, 141; 10, 36; 14, 82 Robins, M.J., 4, 60 Robinson, M.W.C., 14, 50 Robinson, T.V., 3, 99 Rode, J.E., 12, 28, 29 Rodr´ıguez, A., 8, 89 Rodr´ıguez, D., 8, 33; 9, 91; 12, 99 Rodr´ıguez, F., 8, 19; 14, 102 Rodriguez, S.J., 11, 16 Rodriguez-Dafonte, P., 2, 66, 111 Rodriguez-Garcia, I., 1, 241; 10, 38 Rodriguez-Solla, H., 3, 381 Roeterdink, W.G., 10, 51 Roff, G.J., 11, 107 Rogers, C.J., 1, 112 Rogov, V.A., 7, 83 Roig, R., 1, 288; 12, 93 Rokita, S.E., 7, 31 Rol, C., 7, 26 Roman, L., 11, 148 Romanski, J., 4, 11, 12 Romea, P., 1, 127

Roncoroni, M., 3, 322 Rondelez, Y., 6, 68 Ropic, M., 3, 373 Rosado-Reyes, C.M., 3, 273 Rosas, F., 10, 21 Rose, S.D., 11, 128 Roselli, G., 8, 70 Rosenberg, M. G., 4, 10 Rosenfeld, D.C., 11, 36 Rosenthal, A.S., 3, 261 Rosenthal, J., 12, 13 Roshan, R., 3, 161 Rosta, E., 2, 95 Rotinov, A., 10, 20 Roubelakis, M.M., 14, 81 Roudeau, R., 1, 212; 9, 110 Roussev, C.D., 2, 100 Rovira, C., 7, 145 Rovis, T., 12, 164, 165 Roy, C.D., 8, 41 Roy, D.R., 6, 1, 2; 11, 15 Roy, M.D., 1, 11 Roy, R.K., 1, 1, 2 Roy, S., 14, 51 Roy, U.K., 14, 51 Rozen, S., 1, 80 Rozental, E., 14, 135 Ruan, J., 3, 376 Ruan, J.-W., 1, 230; 9, 106 Ruano, J.L.G., 12, 59 Rub´ın, S.G., 1, 348 Rubio, E., 1, 272; 6, 63 Rudakov, E.S., 3, 212, 236; 7, 11 Rudler, H., 11, 264 Rudolph, J., 1, 284 Rudolph, S., 1, 334; 3, 358 Rueping, M., 1, 67, 322; 3, 311, 355, 356; 11, 123 Ruff, F., 8, 80 Ruggiero, G.D., 2, 2; 8, 117 Ruiz, C., 10, 23 Ruiz, J.M., 12, 121 Ruiz, M.C., 4, 45 Ruiz, N., 11, 9 Rulev, A. Yu., 11, 141 Ruminski, A.M., 9, 138 Rupertova, M., 7, 29 Rusakov, Y. Yu, 14, 157 Rusinov, V.L., 1, 66 Russo, A., 3, 224 Russo, B., 1, 15 Russo, N., 3, 379 Rustici, M., 3, 289 Rutjes, F.P.J.T., 3, 184 Ryabtsova, O.V., 7, 38; 14, 62 Ryan, J., 11, 57 Rybachenko, V.I., 2, 23 Ryberg, P., 8, 63

539

Author Index Rychnovsky, S.D., 7, 67; 8, 14; 13, 20; 14, 61 Ryslava, H., 7, 30 Ryu, I., 1, 82–84; 9, 77 Ryu, J.S., 8, 65 Ryu, W.S., 7, 28 Ryu, Z.H., 2, 29 Rzepa, H.S., 13, 76

S Saá, C., 1, 348; 12, 99; 13, 3 Sabatini, J.J., 11, 98 Sabino, A.A., 6, 17; 7, 113 Sackers, E., 11, 19 Sadeghy, B., 3, 21 Sadovaya, I.V., 8, 26 Sadovskii, Y.S., 2, 43 Sa-ei, K., 1, 196 Saenz, P., 8, 38 Sáez, J.A., 2, 40; 11, 220; 12, 44 Saha, B., 3, 30; 11, 69 Sahgal, S., 3, 68, 69 Saidi, M.R., 6, 48; 11, 163 Saielli, G., 14, 3 Saikia, P.P., 1, 141; 9, 42 Sain, B., 3, 220 Saint-Dizier, A., 11, 11 Saito, B., 3, 73 Saito, H., 3, 282; 12, 17 Saito, S., 1, 128; 12, 170 Saitoh, T., 7, 140 Sajishi, V.S., 12, 187 Sakai, H., 1, 68 Sakai, N., 11, 53 Sakai, S., 13, 2, 61 Sakakibara, T., 4, 70; 14, 143 Sakakura, A., 12, 146 Sakakura, T., 12, 104 Sakamoto, M., 12, 54 Sakamoto, S., 1, 191 Sakamoto, T., 11, 39 Sakharov, V.N., 5, 16 Salazar, V., 14, 112 Salbaek Andersen, M.P., 1, 211 Salgado-Zamora, H., 5, 49 Salhi-Benachenhou, N., 14, 41 Sallo, A., 6, 66 Salum, M.L., 5, 19 Salvadori.P., 11, 248 Salvio, R., 2, 105 Samaddar, P.R., 3, 39 Samanta, S., 1, 100 Samanta, S.S., 9, 59 Sambri, L., 2, 42 Samec, J.S.M., 3, 327, 352 Sanau, M., 5, 33 Sanchez, O., 3, 86 Sanchez, V.M., 7, 164

Sánchez-Andrada, P., 12, 38; 13, 82, 85 Sanchez Pelegri, A., 4, 100 Sánchez-Roselló, M., 14, 108 Sander, W., 7, 103 Sandlers, Y., 7, 54 San Feliciano, A., 12, 97 San-Félix, A., 8, 73 Sanford, M.S., 3, 278; 6, 16, 56; 8, 35 Sang, D., 3, 261 Sangji, S., 12, 78 Sankey, R.F., 14, 151 Santaballa, J.A., 10, 49 Santacruz, E., 1, 213; 9, 111 Santelli, M., 1, 304; 5, 37 Santhakumar, K., 3, 74 Santi, C., 1, 6 Santiago, F., 3, 89 Santos, J.G., 2, 30, 40, 47, 54, 76 Santos, L.L., 14, 112 Santos, L.S., 9, 135; 11, 175 Sanz, R., 8, 19 Sanz-Cervera, J.F., 14, 108 Sapozhnikov, O. Yu., 5, 17; 11, 219 Saraf, M., 3, 67 Saraf, S., 3, 67 Sararhi, N., 3, 32 Sarathi, N., 3, 31 Sargent, E.H., 1, 11 Saritha, B., 11, 178 Sarkar, U., 6, 1, 2; 11, 15 Sarker, M.A.B., 12, 76 Sarma, D., 12, 115, 116 Sarma, G.D., 11, 178 Sarotti, A.M., 12, 95 Sarpong, R., 14, 95 Sartori, A., 2, 105 Sasai, H., 1, 167; 9, 23 Sasaki, K., 1, 245; 4, 91 Sasaki, M., 14, 22 Sasamoto, N., 1, 74 Satake, K., 7, 120; 13, 48 Sathiyanarayanan, K., 3, 152 Satnami, M., 2, 66 Satnami, M.L., 2, 67 Sato, A., 8, 44 Sato, E., 3, 283 Sato, H., 14, 130 Sato, K., 1, 316; 3, 342, 388; 12, 118 Sato, M., 1, 242; 4, 93, 102 Sato, T., 6, 29; 11, 35, 243 Sato, Y., 14, 23, 24, 42 Satoh, J., 11, 68, 70 Satoh, T., 10, 35; 14, 28, 29 Satyanarayana, G., 14, 36 Sauerland, S.J.K., 11, 132

Sauers, R.R., 2, 46 Sauliere, A., 3, 288 Saunte, H., 3, 7, 9, 15 Savage, P.E., 3, 285; 8, 120 Savelli, G., 8, 87 Savelova, V.A., 2, 43 Sawada, S., 3, 225 Sawada, T., 11, 254 Sawada, Y., 3, 73 Saxena, A.K., 3, 93 Sayre, L.M., 14, 56 Scarpi, D., 1, 225; 9, 107 Scarponi, C., 1, 6 Scarso, A., 3, 216 Scerba, M.T., 12, 137 Schade, M.A., 5, 30 Schatz, J., 4, 99 Schaumann, E., 7, 73; 11, 37 Schaus, S.E., 1, 25, 71 Scheidt, K.A., 1, 166, 257; 4, 89; 11, 214 Scheidt, T., 11, 123 Scheisser, C.H., 1, 83 Schenk, D.J., 7, 174 Schenk, K., 9, 80; 11, 257; 14, 19 Schertzer, B., 13, 16 Scheschkewitz, D., 7, 76 Schiesser, C.H., 11, 55 Schirmer, R.H., 7, 36 Schleyer, P.v.R., 7, 137 Schlier, J., 10, 28, 29; 14, 147, 148 Schlosser, M., 5, 59; 9, 73; 14, 7, 26 Schmalle, H.W., 4, 37 Schmatz, S., 1, 175; 11, 209 Schmeiser, H.H., 7, 29 Schmidt, E.K.G., 13, 53 Schmidt, F., 1, 284 Schmidt, M.U., 1, 322; 3, 311 Schmidtmann, E.S., 8, 16 Schoeller, W. W., 4, 57 Schoeller, W.W., 7, 134 Schoenfelder, A., 8, 56 Schoepke, F.R., 1, 322; 3, 311 Scholte, A.A., 3, 296 Scholten, J.D., 11, 38 Schramm, V.L., 1, 10 Schreiber, S.L., 1, 55 Schreiner, P.R., 4, 11, 12; 13, 59, 73; 14, 176 Schreivogel, A., 7, 146 Schrock, R.R., 4, 3 Schroeder, G., 2, 23; 5, 15 Schubert, G., 11, 206 Schuhle, D.T., 4, 99 Schulenberg, N., 11, 56 Schulltz, M.J., 1, 3 Schultz, A.G., 3, 386

540 Schultz, M.J., 11, 73 Schulz, E., 11, 124 Schumann, H., 1, 36 Schuster, D.I., 12, 13 Schwartz, C., 3, 189, 190 Schweizer, W.B., 13, 28 Schwörer, U., 12, 64 Scolan, A.L.B., 3, 320 Scott, L.T., 9, 6, 7 Scott, M.S., 1, 233 Sebastiani, G.V., 7, 26 Sebelius, S., 8, 12 Sedenkova, K.N., 4, 71; 14, 141, 145 Sedlak, M., 2, 53 Sedmera, P., 11, 105 Segre, A., 4, 36 Séguin, E., 14, 38 Seguy, C., 3, 288 Seibert, K.A., 9, 22; 11, 173 Seike, N., 12, 82 Seki, S., 7, 89 Sekiguchi, O., 7, 85 Selander, N., 8, 12 Selke, M., 3, 241, 243; 14, 154 Selkti, M., 3, 178 Sen, P.K., 3, 39, 102 Senanayake, C.H., 1, 244; 4, 33, 90 Senboku, H., 8, 50 Senecal, T.D., 13, 29 Sengupta, A., 3, 222 Sen Gupta, K.K., 3, 102 Senthilkumar, S., 3, 16 Seoane, G., 8, 38 Seok, J.-A., 2, 26 Seon-Meniel, B., 1, 123 Sepúlveda-Arques, J., 11, 220 Serebryakov, I.M., 8, 124 Sereda, O., 14, 46 Serushkina, O.V., 5, 18 Serwatowski, J., 9, 56 Serykh, A.I., 6, 67 Sessler, J.L., 2, 102 Seth, S.K., 3, 91 Sethumadhavan, D., 4, 86 Seto, C.T., 1, 59 Setser, D.W., 10, 52 Setsune, J., 1, 63 Sewell, S.L., 3, 307 Sgarbossa, P., 3, 216 Shafikov, N.Y., 3, 193 Shah, K.K., 9, 8 Shah, M.H., 12, 136 Shaik, S., 3, 292; 8, 77 Shan, J., 3, 51 Shan, J.-H., 3, 58–60 Shan, Z., 1, 88, 102; 3, 310 Shangguan, N., 2, 46 Shankavaram, U., 7, 124

Author Index Shanmugam, P., 3, 72 Shannon, C., 14, 149 Shao, L.-X., 7, 187 Shapiro, T.A., 3, 261 Shaplov, A.S., 14, 84 Sharma, A., 1, 237 Sharma, A.K., 2, 55 Sharma, K., 3, 160 Sharma, M., 2, 72; 3, 22, 27 Sharma, P., 3, 324 Sharma, P.K., 1, 89, 90; 3, 23, 24, 26, 28, 160 Sharma, R.K., 3, 170, 171 Sharma, S., 3, 66, 241; 14, 154 Sharma, V., 3, 25, 27 Sharma, V.B., 3, 220 Sharma, V.K., 3, 84, 160 Sharon, O., 14, 109 Shaughnessy, K.H., 5, 32 Shaw, D.M., 1, 87; 11, 182 Sheikh, H.N., 3, 22 Shekhar, S., 11, 36 Sheldon, R.A., 3, 246, 275 Shellhamer, D.F., 11, 16 Shen, H.C., 5, 52 Shen, J., 11, 263; 12, 143 Shen, M.-W., 3, 262 Shen, S., 3, 51; 4, 33 Shen, S.-G., 3, 58–60 Shen, W., 4, 40 Shen, Y.-M., 3, 115, 116; 11, 142; 12, 16; 14, 124 Sheng, Y., 12, 131 Sheradsky, T., 9, 6, 7 Shevelev, S.A., 5, 17, 18; 11, 219 Shevlin, P., 14, 149 Shi, H., 3, 233; 7, 14 Shi, L., 1, 96 Shi, M., 1, 164, 256, 335; 3, 380; 7, 187; 11, 65, 172; 14, 44, 90 Shi, X.-X., 14, 75 Shi, Y., 3, 115–119; 11, 142; 14, 124 Shibasaki, M., 1, 31, 33, 46, 129, 158, 159, 178, 255; 8, 44; 9, 103; 11, 121 Shibata, D., 12, 91 Shibata, N., 1, 69 Shibata, T., 12, 22, 156, 159, 166 Shibuguchi, T., 1, 46 Shigehisa, H., 3, 179 Shigeno, M., 1, 336 Shigeta, K., 14, 15 Shiina, I., 12, 178 Shim, S.C., 3, 297 Shimada, K., 12, 154; 13, 78

Shimada, S., 6, 60 Shimajiri, A., 6, 25 Shimizu, Y., 12, 169 Shimura, Y., 9, 157 Shin, I.-J., 13, 38 Shin, J.-H., 7, 16 Shin, Y.-H., 2, 19, 28 Shinada, T., 1, 68 Shinde, C.P., 2, 57 Shindo, M., 10, 43; 11, 260 Shindoh, N., 12, 150 Shing, T.K.M., 12, 56 Shing, T.M.K., 3, 122 Shintani, R., 1, 180; 11, 245; 12, 171 Shiomi, T., 1, 160; 3, 362 Shiozawa, F., 11, 254 Shirakawa, E., 11, 99, 238; 14, 113 Shirakawa, S., 11, 190 Shirakura, M., 11, 45 Shiro, M., 8, 44; 9, 149; 12, 54 Shirtcliff, L.D., 4, 18; 14, 144 Shishido, K., 10, 43; 11, 260 Shishkin, V.N., 3, 385 Shivananda, K.N., 3, 142 Shnitko, I., 7, 99 Shoji, M., 1, 99; 12, 178 Shorger, N., 1, 341, 342; 3, 29 Shou, W.-S., 1, 19 Shoukry, A.A., 2, 77 Shoukry, M.M., 2, 77 Showalter, B.M., 4, 80 Shpan’ko, I.V., 8, 26 Shteingarts, V.D., 5, 48 Shu, L., 3, 119 Shubin, V.G., 6, 9; 7, 4, 17–19, 114; 13, 40 Shucai, L., 14, 20 Shukla, P., 3, 389 Shukla, R.K., 6, 13 Shukla, V.K., 3, 157 Siebert, M.R., 7, 158 Siehl, H.-U., 7, 13; 14, 60 Sierra, M.A., 14, 161 Sierraalta, A., 10, 26, 31 Sigeev, A.S., 5, 2 Sigman, M.S., 1, 3; 11, 73 Sigwalt, P., 7, 55 Silber, J.J., 5, 22 Silla, E., 13, 7 Silva, A.M.g., 12, 73 Silva, A.M.S., 12, 73 Silva, E.C., 8, 109 Silva Lopez, C., 14, 99 Silva Santos, L., 11, 60 Silver, S., 13, 49 Silverman, S.M., 12, 64 Sim, Y.-L., 2, 37 Simig, G., 2, 94

541

Author Index Simmons, J.G., 10, 52 Simon, K., 12, 162 Simon, Z., 6, 66 Simon-Trompler, E., 3, 37, 38 Singaram, B., 1, 310, 317, 319; 3, 298, 300, 319, 353 Singh, A., 2, 72; 3, 70, 71, 137, 138 Singh, A.K., 3, 69, 93, 140, 148, 168, 169 Singh, B., 3, 140, 148, 149, 168, 169 Singh, C., 3, 148 Singh, D.P., 2, 13 Singh, G.K., 2, 13 Singh, J., 3, 149 Singh, K.J., 9, 57; 14, 2 Singh, M.K., 2, 57 Singh, M.P., 3, 93 Singh, N.P., 1, 237 Singh, P., 2, 12, 72; 12, 32, 80; 13, 8 Singh, R., 2, 12 Singh, R.A., 3, 70, 71, 136–138, 156–158 Singh, R.K., 2, 57 Singh, R.T., 2, 12 Singh, S., 3, 62, 170; 8, 29 Singh, S.P., 3, 149, 168 Singh, V., 3, 140, 169; 12, 135 Singh, V.K., 1, 104, 185; 3, 234, 235 Sinha, A.K., 1, 237 Sinha, D., 11, 24 Sinha, R.P., 3, 161 Siska, S.J., 1, 130 Sivaguru, J., 3, 282 Sivaram, S., 6, 13 Siviero, F., 2, 15 Siyanko, P.I., 6, 14 Skibo, E.B., 7, 34 Sklenak, S., 3, 36 Skodane Foldes, R., 1, 258 Skold, M., 3, 270 Skrypka, A.V., 2, 43 Skwarczynski, M., 2, 84; 14, 158 Slatford, P.A., 14, 91 Slegt, M., 7, 98 Sloan, K.B., 2, 22 Slocum, D.W., 9, 66 Smentek, L., 13, 47 Smirnov, A.V., 5, 16 Smith, A.B., 14, 122 Smith, A.D., 4, 101; 14, 159 Smith, D.M., 7, 5; 10, 16 Smith, D.W., 12, 11 Smith, G.E., 2, 1 Smith, J.R.L., 3, 257 Smith, P.R., 9, 138 Smitha, M., 12, 186

Smits, J.M.M., 4, 36 Smrˇcina, M., 11, 105 Snape, T.J., 14, 49 Snapper, M.L., 1, 136; 3, 296; 12, 14 Sneddon, H.F., 11, 182 Snider, B.B., 12, 79 Snieckus, V., 14, 14 Snitman, D.L., 11, 76 Snyder, J.K., 10, 47 Soai, K., 1, 227 Sobenina, L.N., 14, 157 Sodeoka, M., 1, 74; 9, 157 Söderberg, B.C.G., 6, 53 Soellner, M.B., 2, 82 Soga, K., 7, 44 Sohma, Y., 2, 84; 14, 158 Sohn, S.S., 4, 95 Sohtome, Y., 1, 146 Sokeirik, Y.S., 1, 316; 3, 388 Sokol, W., 4, 20 Sokolova, I.V., 7, 20 Sokolova, T.V., 7, 20 Sola, E., 1, 50; 3, 345, 346 Solà, M., 6, 65; 12, 12; 13, 66 Solomoichenko, T.N., 2, 43 Solomon, E.I., 3, 85 Solomon, M.R., 3, 282 Soltani, B., 11, 181 Sommer, H., 14, 87 Somyo, T., 12, 123 Sonawane, H.R., 4, 67; 14, 32 Sondhi, S.M., 5, 44 Song, D., 12, 180 Song, H.-J., 12, 55 Song, J., 1, 27; 6, 46 Song, J.J., 1, 244; 4, 90 Song, K., 8, 110 Song, L., 8, 77 Song, L.-C., 3, 392 Song, W., 3, 65 Song, W.C., 3, 63 Song, W.Y., 3, 63, 64 Song, Z.-L., 14, 4 Song, Z.-r., 3, 215 Song, Z.J., 3, 336 Sonye, J.P., 9, 33; 14, 160 Soós, T., 11, 206 Sopkova-de Oliveira Santos, J., 1, 38; 9, 65 Sordo, T.L., 2, 90; 5, 21 Sorensen, E.J., 10, 13 Sorenson-Stowell, K., 2, 112 Sosa-Rivadeneyra, M.V., 1, 213; 9, 111 Soteras, I., 9, 18 Sotomayor, N., 11, 134 Soueidan, M., 6, 32 Soukup, T.S., 3, 323 Spanevello, R.A., 12, 95

Spange, S., 7, 39 Spannenberg, A., 3, 96 Sparrapan, R., 6, 17; 7, 113 Speier, G., 3, 214 Spek, A.L., 3, 103 Speranza., M., 8, 70 Spillane, W.J., 2, 114 Spina, M., 1, 345; 3, 291 Spinelli, D., 5, 42; 14, 128, 155 Spisani, R., 14, 155 Spraul, B.K., 12, 11 Spreti, N., 8, 87 Spybroeck, V.V., 8, 43 Spyroudis, S., 13, 44 Sreelatha, N., 11, 137 Sridhar, B., 1, 147 Sridharan, R., 3, 147, 150, 151 Srikrishna, A., 14, 36 Srinivas, P.V., 6, 20 Srinivasa, G.R., 3, 46, 383 Srinivasan, N., 13, 76 Srinivasan, S., 3, 16 Sriramula, Y., 3, 131 Sriramurthy, V., 1, 209 Srivastava, S., 3, 164, 170, 171 Srivastava, V.K., 3, 136–138, 157, 158 Stadler, D., 7, 23 Stahl, S.S., 11, 75 Stambuli, J.P., 12, 64 Stanek, K., 9, 155 Stanetty, P., 1, 345; 3, 291 Starikova, Z.A., 7, 24 Stark, M.S., 3, 257 Starks, C.M., 7, 174 Starova, G.L., 4, 34 Stavber, S., 1, 337; 3, 218 ˇ Stefane, B., 8, 49 Stefinovic, M., 3, 373 Steko, S., 12, 53 Stemmler, R.T., 1, 284 Stepakov, A.V., 4, 34 Stepan, A.F., 1, 122 Stepanov, A.G., 7, 83 Stephan, M., 3, 369 Stephanidou-Stephanatou, J., 12, 47 Stephenson, G.A., 11, 80 Sterba, V., 2, 53 Sterk, D., 3, 369 Sterner, O., 3, 301 Stevens, C.V., 14, 8 Steward, O.W., 9, 88 Stewart, A.J.W., 13, 11 Stewart, T., 3, 241; 14, 154 Stiborova, M., 7, 29, 30 Stinga, G., 2, 64 Stingl, V., 4, 28 Stiriba, S.-E., 12, 100 Stodulski, M., 1, 140

542 Stoltz, B.M., 10, 48 Stolz, D., 9, 25 Stoncius, S., 3, 361 Storer, R.I., 3, 359 Storozhakova, N.A., 2, 38 Stowers, K.J., 1, 3; 11, 73 Stoyanov, E., 14, 3 Stoyanov, E.S., 7, 112 Stoyanov, S.S., 9, 4 Stránská, D., 11, 44 Stratakis, M., 7, 179 Straub, B.F., 9, 82 Straub, C.S., 12, 89 Streiter, A., 7, 48, 49; 8, 94, 95 Streitwieser, A., 9, 131 Strotman, N.A., 14, 37 Struchkova, M.I., 1, 78 Strukul, G., 3, 216 Strunk, S., 9, 73; 14, 7 Strunz, G.M., 12, 34 Stryker, J.M., 1, 187 Su, F.-H., 3, 392 Su, X., 1, 176 Su, Z., 1, 70 Su, Z.-M., 1, 289 Suante, H., 3, 6, 8 Suárez, A.G., 12, 95 Suarez, D., 2, 90; 5, 21 Suarez, E., 5, 21 Suarez-Sobrino, A.L., 4, 44 Subbaiah, D.R.C.V., 11, 186 Subbalakshmi, R., 3, 17, 34 Subramanian, V., 1, 298; 6, 2; 11, 15 Sudalai, A., 6, 13 Sudo, Y., 8, 128 Sudrik, S.G., 4, 67; 14, 32 Sueishi, Y., 1, 330; 3, 293 Suen, Y.F., 14, 30 Suga, H., 12, 60 Suga, S., 7, 44, 59 Sugie, A., 6, 57 Sugimoto, H., 1, 69 Sugimura, K., 13, 78 Sugimura, T., 6, 54; 7, 92; 12, 4 Suginome, M., 11, 45, 47, 82 Sugiono, E., 1, 67 Sugita, J., 7, 162 Sugita, M., 1, 255 Sugiyama, S., 1, 220; 9, 117 Suh, J., 13, 33 Suhrada, C.P., 14, 168, 169 Sui, Y., 6, 26 Sui, Z., 4, 51 Sukhovatkin, V., 1, 11 Sultana, S.S., 1, 103 Sumiya, T., 1, 99 Sun, H., 3, 51, 266; 5, 24 Sun, H.-B., 11, 122 Sun, H.-W., 3, 58–60

Author Index Sun, J., 1, 54, 114; 3, 365 Sun, J.-Z., 4, 14 Sun, K., 1, 325; 3, 305 Sun, M., 3, 245 Sun, N., 1, 88; 3, 310 Sun, S., 2, 96; 11, 151 Sun, W., 1, 186; 8, 45, 48 Sun, X., 4, 97; 8, 45, 48; 12, 65 Sun, X.-L., 1, 77, 202; 11, 210 Sun, Y., 1, 323; 3, 336 Sun, Y.-p., 3, 326 Sun, Y.-X., 8, 107 Sundar, B.S., 6, 10 Sundararajan, G., 9, 32; 11, 149 Sundén, H., 1, 24; 3, 204, 242; 11, 145 Sunder, B.S., 3, 129, 130 Sunder, S.B., 3, 80 Sung, D.D., 2, 25; 11, 183 Sung, K., 1, 13, 14 Sunley, G.J., 7, 84 Sunoj, R.B., 10, 14 Suponitsky, K. Yu, 14, 156 Suresh, C.H., 12, 187 Suresh, E., 4, 94; 8, 29; 12, 186 Suresh, S., 1, 32; 9, 29; 12, 11 Suresha, N., 3, 134 Suri, J.T., 1, 317; 3, 298 Suseela, R., 3, 152 Suslov, I.A., 6, 67 Suszczynska, A., 1, 140 Sutherland, A., 13, 4, 25, 26 Suvorov, A.V., 6, 24 Suzaki, Y., 6, 57 Suzuki, K., 1, 267; 3, 73; 9, 145; 11, 71; 12, 31, 146; 14, 123 Suzuki, M., 3, 52; 12, 154 Suzuki, N., 12, 157 Suzuki, S., 9, 156 Suzuki, T., 7, 141; 9, 157; 12, 60, 107 Suzuki, Y., 1, 242; 4, 93, 102; 12, 182 Svelle, S., 7, 85 Svenda, J., 9, 36 Svith, H., 3, 377, 393; 8, 25 Swang, O., 7, 116 Swart, M., 8, 74 Sweeney, J.B., 1, 61; 8, 54; 14, 77 Swidorski, J.J., 12, 172 ´ Swierczy´ nski, D., 11, 180 Swift, M.D., 13, 26 Sydorenko, N., 12, 172; 13, 68 Sylvester, J., 3, 126, 127 Synácˇ ková, M., 11, 32 Syrgiannis, Z., 8, 64 Szabó, K., 8, 12 Szabo, K.J., 1, 47

Szakonyi, Z., 1, 218; 9, 109 Szammer, J., 3, 37 Szatmári, I., 14, 164, 165 Szente, J.J., 3, 273 Szeto, P., 9, 36

T Taccone, R.A., 3, 255 Tachi, Y., 3, 230 Tachikawa, H., 8, 105 Tada, N., 9, 149 Taft, B.J., 1, 11 Taft, B.R., 11, 233 Tagami, K., 14, 54 Tagawa, S., 7, 89 Tagliatesta, P., 3, 49 Tahara, Y.-k., 12, 156 Taira, A., 11, 243 Takabe, K., 1, 111, 203; 11, 195 Takada, S., 9, 46; 11, 156, 213 Takada, Y., 1, 173 Takahashi, E., 1, 30 Takahashi, J., 1, 99 Takahashi, K., 14, 15 Takahashi, Y., 4, 70; 12, 91; 14, 143 Takai, J., 1, 261 Takai, K., 1, 191; 14, 119 Takaki, K., 4, 30; 11, 63 Takami, K., 12, 22 Takamiya, W., 13, 13 Takano, H., 9, 157 Takasu, K., 12, 10, 150 Takaya, H., 1, 153 Takaya, J., 12, 69, 182 Takayama, J., 3, 179 Takeda, H., 4, 56 Takeda, K., 14, 22 Takeda, N., 13, 22 Takegami, A., 7, 89 Takeishi, K., 12, 160 Takemiya, A., 11, 36, 101 Takemoto, S., 12, 169 Takemoto, Y., 1, 72, 85; 11, 158; 13, 22; 14, 88 Takenaka, M., 7, 141 Takenaka, Y., 12, 27 Takeshi, O., 3, 330 Takeuchi, R., 12, 158 Takeya, T., 12, 54 Takikawa, H., 1, 267; 9, 145 Takikawa, Y., 12, 154; 13, 78 Takinami, M., 12, 92 Takizawa, S., 1, 167; 9, 23 Takuma, K., 11, 39 Talarico, G., 11, 61 Tam, W., 12, 20, 21, 24–26; 14, 114 Tamariz, J., 6, 53 Tamegai, H., 7, 172

543

Author Index Tammari, E., 3, 87 Tamura, O., 12, 54 Tan, C.-H., 11, 263; 12, 143 Tan, H.P.T., 14, 91 Tan, X., 4, 106 Tan, Z., 1, 244; 4, 90 Tanaka, F., 1, 26, 111, 203; 11, 195 Tanaka, K., 1, 167; 3, 283; 6, 31; 9, 23; 12, 157, 160 Tanaka, N., 11, 233; 12, 107 Tanaka, S., 1, 318; 3, 316; 12, 158; 14, 28 Tanaka, T., 1, 219; 8, 24; 9, 115 Tanaka, Y. Y., 12, 141 Tandon, P.K., 3, 68, 69, 93 Tang, D., 11, 103 Tang, J., 14, 90 Tang, L., 1, 170 Tang, M.-S., 1, 108, 217; 9, 114 Tang, M.-Y., 3, 392 Tang, O.N., 14, 151 Tang, Y., 1, 77, 202; 2, 79; 3, 215; 7, 118; 11, 210 Tang, Y.-Z., 3, 266 Tang, Z., 1, 105 Tanga, M.J., 7, 125 Tani, S., 2, 93 Taniguchi, H., 11, 82 Taniguchi, N., 11, 114 Tanner, D., 11, 255 Tantillo, D.J., 7, 78, 158–160, 163, 165, 166; 11, 18; 12, 68; 13, 1 Tao, C., 7, 77 Tao, F.-M., 3, 104, 105 Tao, H., 12, 7 Tao, J.-C., 1, 108 Tao, L., 2, 70 Tao, W.A., 1, 4, 5 Taraba, J., 14, 33 Taran, O., 2, 101 Tarantelli, F., 10, 3 Tarasb, R., 3, 375 Tarasova, I.V., 3, 385 Tartakovsky, V.A., 1, 78 Tatarov, A., 5, 58 Taticchi, A., 12, 127 Tavani, C., 14, 155 Tavassoli, A., 14, 77 Tawfik, D.S., 2, 83 Taylor, A.M., 1, 55 Taylor, D.K., 3, 99 Taylor, E.C., 5, 49 Taylor, R., 11, 185 Taylor, R.J.K., 9, 34; 10, 41; 14, 137 Taylor, S.A., 14, 66 Tchabanenko, K., 14, 171 Tedrow, J.S., 3, 323

Tejero, S., 1, 50; 3, 345, 346 Tejero, T., 9, 13 Tekavec, T.N., 12, 162 Tellers, D.M., 3, 336 Temperini, A., 1, 6 Tempesta, S., 3, 213 Tenaglia, A., 11, 85; 12, 185 Teng, W.-D., 1, 164; 11, 172 Teo, Y.-C., 12, 145 Terada, M., 9, 160; 11, 211; 12, 144 Terai, H., 1, 153 Terrier, F., 2, 111; 5, 55–58; 6, 7, 49; 7, 52 Teruel, M.A., 3, 255 Tesevic, V., 3, 183 Testaferri, L., 1, 6 Thaler, T., 1, 271; 9, 99 Thanh, N.C., 7, 129, 133 Thatcher, G.R.J., 7, 10 Thayumanavan, R., 1, 26 Theissmann, T., 3, 355, 356 Theyssen, N., 3, 252 Thibault-Starzyk, F., 14, 38 Thiel, W., 1, 299; 9, 14 Thiem, J., 13, 14 Thobhani, S., 1, 61; 8, 54 Thomas, J.D., 2, 22 Thomas, S., 7, 37 Thomas, S.I., 7, 121 Thomassigny, C., 9, 159 Thompson, W.H., 3, 363 Thomson, J.E., 4, 101; 14, 159 Thoniyot, P., 1, 310; 3, 353 Thuéry, P., 14, 10 Tian, G.-Q., 14, 44 Tian, J., 1, 255; 9, 144 Tian, S.-K., 1, 254 Tian, X., 1, 325; 3, 305 Tian, Z., 7, 90 Tidwell, T.T., 1, 12 Tiecco, M., 1, 6 Tiedemann, R., 7, 73; 11, 37 Tiekink, E.R.T., 3, 99 Tietze, L.F., 1, 175 Tiger, R.P., 4, 78 Tilly, D., 9, 59, 60 Tilset, M., 6, 69 Timerghazin, Q.K., 3, 203 Timmons, C., 11, 65, 81 Timoshkin, A.Y., 6, 24 Tinarelli, A., 11, 133 Ting, A., 1, 25, 71 Ting, H.-C., 12, 41 Tingoli, M., 11, 17 Tirla, C., 7, 143 Tissot-Croset, K., 8, 1, 6 Titov, A.A., 14, 129 Titova, I.A., 5, 12 Tiwari, B.K., 2, 55

Tiznado, W., 8, 98 Tobisch, S., 11, 125 Tobiso, M., 1, 8 Tobisu, M., 7, 183; 14, 85 Tocke, A.L., 5, 55; 6, 7 Toft, A., 1, 211 Togni, A., 9, 155, 158 Tohnai, N., 13, 22 Tojino, M., 1, 84 T˝oke, L., 13, 72 Tokunaga, N., 9, 102; 11, 242 Tokuyama, H., 12, 150 Toledano, C.A., 7, 81 ˇ 11, 129 Toma, S., Tomas, M., 4, 44, 46 Tomé, A.C., 12, 73 Tomida, N., 12, 36 Tomii, M., 3, 52 Tomioka, H., 4, 70; 14, 143 Tomioka, K., 1, 42; 9, 27; 11, 13, 224 Tomita, D., 1, 178 Tomita, T., 14, 42 Tomkinson, N.C.O., 1, 56 Tommasi, S., 6, 33; 7, 181 Tomooka, K., 11, 49; 13, 42 Tonokura, K., 1, 211 Tooze, R.P., 3, 335 Toppet, S., 12, 72 Tornroos, K.W., 4, 32 Torr, J.E., 5, 51 Toru, T., 1, 69 Toscanini, M., 1, 133 Toscano, J.P., 4, 80 Toscano, M., 3, 379 Toscano, R.A., 7, 81 Tosha, T., 3, 52 Tosta, M., 10, 20, 21 Toste, F.D., 14, 105 Tóth, D., 14, 164, 165 Tóth, J., 13, 72 Touge, T., 1, 294 Toulee, P.Y., 1, 285 Toumatsu, S., 1, 63 Toumieux, S., 3, 178 Toupet, L., 12, 113 Toy, P.H., 1, 164; 7, 119; 11, 172 Tozawa, T., 11, 161 Trauner, D., 6, 28; 11, 170 Travis, B.R., 3, 101 Tredwell, M., 6, 8; 9, 154 Treitel, N., 9, 6 Treweeke, N.R., 13, 34 Trifonov, A., 11, 124 Trifonova, A., 1, 51; 3, 344 Trimaco, P., 12, 122 Trincado, M., 1, 272; 6, 63 Trnka, T., 14, 21

544 Trofimov, B.A., 1, 199; 10, 56; 14, 157 Troisi, L., 5, 14 Trost, B.M., 1, 28, 192; 3, 97, 108; 8, 21; 9, 113; 11, 212; 12, 64; 13, 39 Trucks, G., 3, 36 Truhlar, D.G., 8, 60 Trukhaniva, N.V., 3, 192 Tsai, H.R., 1, 327 Tsai, T.Y.R., 1, 165; 11, 174 Tsang, J.S.W., 2, 106 Tsang, W.Y., 2, 91 Tsangarakis, C., 7, 179 Tse, M.K., 3, 95, 96 Tseng, H.-C., 12, 173 Tseng, N.-W., 11, 246 Tsenov, J.A., 9, 4 Tsiotra, E., 13, 44 Tsogoeva, S.B., 1, 44; 11, 208, 209 Tsoleridis, C.A., 12, 47 Tsou, N., 9, 94 Tsuchida, N., 14, 11, 126 Tsuchikama, K., 12, 166 Tsuchikama, T., 12, 159 Tsuchimoto, T., 11, 99; 14, 113 Tsuchiya, T., 3, 120, 121 Tsuchiya, Y., 3, 362; 9, 157 Tsuda, K., 3, 333 Tsuji, T., 7, 141 Tsuji, Y., 8, 119 Tsukamoto, H., 1, 349; 11, 89 Tsukamoto, M., 3, 333 Tsuno, Y., 2, 21; 8, 103 Tsvelikhovsky, D., 1, 36 Tu, Y.-Q., 14, 4 Tuckett, R.P., 11, 14 Tunçman, S., 14, 142 Tunge, J.A., 3, 363 Tuño´ n, I., 13, 7 Turck, A., 1, 38, 75; 9, 64, 65 Turconi, J., 11, 189 Tureˇcek, F., 11, 76 Turjanski, A.G., 7, 164 Turkoz, N., 2, 62 Turnbull, R., 14, 53 Turro, N.J., 3, 282 Tuttle, T., 3, 196 Tuwar, S.M., 3, 88, 94 Tykwinski, R.R., 9, 6; 12, 84 Tyl, C.E., 3, 284 Tyler-Mahon, A.R., 14, 91

U Ube, H., 9, 160; 11, 211 Uc, G.J., 4, 98; 12, 126 Uchimaru, T., 12, 178 Uchiyama, M., 11, 39 Uchiyama, Y., 10, 40

Author Index Udachin, K.A., 4, 29 Ueba, C., 8, 24 Ueda, M., 1, 261 Ueda, T., 8, 76 Ueki, H., 8, 31 Uekusa, H., 12, 31 Uemura, M., 11, 253 Uemura, S., 6, 30 Ueno, E., 8, 76 Ueno, T., 1, 349; 11, 89 Uggerud, E., 7, 8, 15, 85; 8, 99, 113 Uggerud.E., 8, 112 Ugrak, B.I., 5, 18 Uhl, W., 7, 80 Ujaque, G., 3, 98; 11, 6 Ukaji, Y., 1, 43; 11, 184; 12, 92 Ultman, J.S., 3, 194 Um, I.-H., 2, 18, 19, 21, 26–28, 41, 48, 58 Umani-Ronchi, A., 1, 321; 3, 314; 6, 33; 7, 181 Umeda, H., 4, 70; 14, 143 Umeda, K., 14, 126 Umeki, H., 1, 42 Umezaki, Y., 8, 103 Umezawa, T., 1, 68 Unaleroglu, C., 1, 223; 9, 112 Unarunothai, S., 13, 45 Ungaro, R., 2, 105 Ungureanu, I., 8, 56 Unni, A.K., 1, 135 Uno, H., 11, 188 Upadhyaya, P., 7, 68 Urbanczyk-Lipkowska, Z., 12, 53 Urbaneja, L.M., 11, 241 Uria, U., 11, 223 Urpi, F., 1, 127 Urushima, T., 1, 99 Usano, A., 1, 101 Usha, V., 1, 2; 3, 17, 34 Ushakov, I.A., 14, 157 Utsugi, M., 3, 303 Utsumi, K., 13, 75 Utsunomiya, M., 11, 36, 77 Uyanik, M., 6, 37; 11, 42

V Vacatello, M., 4, 36 Vaccaro, L., 12, 103, 114 Vachon, J., 3, 123 Vagner, P., 7, 84 Vaidya, J., 2, 67 Vakhitova, L.N., 2, 43 Vakul’skaya, T.I., 5, 12 Valacchi, M., 9, 122–127 Valdez, S.C., 1, 45 Valencia, D.O., 13, 33 Valentini, G., 11, 248

Valera, F., 5, 31 Van Axel Castelli, V., 4, 36 van Bochove, M.A., 8, 74 van Delft, F.L., 3, 184 van den Heuvel, A., 11, 182 van der Louw, J., 14, 140 van der Vlugt, D., 7, 98 van der Vlugt, J.I., 3, 103 van Duren, R., 3, 103 van Eck, E.R.H., 4, 36 Vanecko, J.A., 9, 147 van Halbeek, H.R., 14, 70 Van Hecke, K., 14, 133 Vanka, K., 3, 363 Vankatraman, S., 1, 17 Van Meervelt, L., 14, 133 Van Ornum, S.G., 3, 188 van Rensburg, H., 3, 335 van Wullen, C., 7, 75 van Zijl, A.W., 8, 9; 9, 89 Varala, R., 1, 155; 8, 27; 11, 94, 137 Varela, J.A., 1, 348; 13, 3 Vargas, M., 3, 241; 14, 154 Vargas-Sanchez, M., 8, 57 Vargas-Zuniga, I., 2, 101 Varlamov, A.V., 14, 129 Vasey, K.D., 9, 138 Vasikov, V.Z., 14, 12 Vasil’kevich, A.I., 10, 10 Vasquez, A., 9, 79 Vasquez, A.J., 9, 78 Vastila, P., 1, 306; 3, 370 Vaz, N., 3, 139 Vazquez, A.J., 11, 222 Vedeneev, A.A., 7, 21 Veerabhadraswamy, M., 3, 141 Veeraiah, M.K., 3, 141 Veerapen, N., 14, 66 Velázquez, S., 8, 73 Vellalath, S., 4, 94 Velthuisen, E.J., 14, 68 Venkataramnan, R., 3, 128 Venkatesham, U., 1, 169, 327 Venkateswarlu, K., 8, 36 Ventura, C., 2, 85 Ventura, D.L., 4, 55 Ventura, O.N., 8, 38 Vera, E.L., 13, 68 Vera, S., 11, 197 Vereecken, L., 3, 254 Verga, D., 7, 32 Verhagen, J., 1, 310; 3, 353 Verma, G.R., 3, 91 Verma, J., 3, 136–138, 156–158 Verma, P., 1, 341, 342; 3, 29 Verotta, L., 3, 301 Verpoort, F., 14, 8 Veszpremi, T., 7, 110 Vezin, H., 7, 36

545

Author Index Vicario, J., 9, 118; 11, 234 Vicario, J.L., 11, 9, 192, 223 Vicente, R., 4, 46 ´ 10, 31; 13, 82; 14, 9 Vidal, A., Vidal, S., 12, 45 Vidal-Gancedo, J., 7, 145 Vidari, G., 7, 169 Vidovic, D., 4, 34 Vieira, T.O., 11, 88 Viglianisi, C., 12, 122 Vijay, D., 11, 178 Vijayamohanan, K., 4, 67; 14, 32 Vijayaraj, C., 3, 150 Vila, C., 11, 152 Villalta, P.W., 7, 68 Villano, S.M., 8, 59; 10, 6 Villarreal, S., 3, 89 Villeneuve, K., 12, 24, 26; 14, 114 Vincent, M.A., 1, 288; 12, 93 Vinci, D., 3, 376 Vincze, Z., 10, 16 Vinogradov, A., 7, 80 Vinogradova, O.V., 7, 24 Violeau, B., 7, 148; 14, 64 Virieux, D., 11, 265 Viruela, R., 7, 145 Visky, D., 2, 9 Vistorobskii, N.V., 7, 24 Vitale, C., 1, 326; 3, 391 Vitz, J., 14, 9 Vivona, N., 14, 128 Vlasov, V.M., 2, 5; 5, 5 Vogl, N., 3, 198 Vogt, D., 3, 103; 11, 66 Vol. II., 11, 76 Volchkov, N.V., 4, 62; 13, 51 Volkov, A.N., 6, 24 Volkov, V.A., 5, 12 Volkova, L.K., 7, 11 Volz, H., 7, 16 von, E., 13, 46, 53 von Vacano, B., 9, 37; 14, 172 von Wangelin, A.J., 1, 192; 9, 113 Vorob’ev, S.S., 5, 18 Voronina, S.G., 3, 258 Voskressensky, L.G., 14, 129 Vostrikov, N.S., 14, 12 Vougioukalakis, G.C., 14, 81 Vovard, C., 14, 111 Vrˇcek, I.V., 7, 13; 14, 60 Vrˇcek, V., 7, 13; 14, 60 Vyas, R., 4, 83 ˇ 11, 105 Vyskoˇcil, S.,

W Wada, R., 1, 46

Wada, T., 12, 17 Waddington, D.J., 3, 257 Wagner, M., 14, 63 Waich, K., 4, 81 Wakabayashi, K., 3, 332 Walfort, B., 7, 39 Wallington, T.J., 1, 211 Wallner, O.A., 1, 47 Walls, S.B., 14, 79 Walsby, C.J., 14, 66 Walsgrove, T., 1, 312 Walter, C., 11, 247 Walters, R.S., 1, 205 Walton, P.H., 3, 208 Wan, H., 9, 147 Wandrey, C., 1, 307; 3, 351 Wang, A.-X., 14, 4 Wang, B., 1, 145; 3, 115, 116, 119; 14, 124 Wang, C., 1, 114; 7, 145; 12, 2 Wang, D., 4, 106; 6, 26 Wang, D.-M., 4, 65 Wang, F., 1, 49; 3, 371 Wang, G., 2, 4; 3, 223 Wang, H., 1, 53; 3, 382 Wang, J., 1, 76, 210; 4, 35; 6, 52; 10, 46; 11, 159, 160, 168, 198, 215, 216; 13, 71; 14, 116 Wang, J.-Y., 6, 52; 11, 168 Wang, L., 1, 250; 3, 215 Wang, L.-P., 11, 154 Wang, L.-X., 6, 45 Wang, M.-C., 1, 217; 9, 114; 11, 229 Wang, Q., 8, 42 Wang, R.-S., 3, 266 Wang, S., 1, 59, 115; 14, 100, 101 Wang, S.-G., 1, 327 Wang, S.-H., 14, 4 Wang, S.C., 7, 78; 11, 18 Wang, S.L.B., 4, 45 Wang, W., 7, 83; 11, 159, 160, 198, 215, 216 Wang, X., 6, 50; 12, 102 Wang, X.-D., 11, 229 Wang, X.-M., 1, 106 Wang, X.L., 13, 71 Wang, Y., 1, 27, 81; 3, 233; 4, 85; 7, 14, 126, 161; 11, 218; 14, 127 Wang, Y.-C., 4, 53, 54, 65 Wang, Y.-G., 1, 19, 195; 3, 36 Wang, Y.-Q., 6, 44, 46 Wang, Y.-Z., 1, 106 Wang, Z., 1, 54, 144, 224; 3, 365; 9, 43; 12, 2, 125 Wang, Z.-L., 3, 266 Wang, Z.-Y., 11, 74

Wangfeng, C., 3, 106 Wankhede, C.B., 3, 33 Wan.P., 7, 41 Warkentin, J., 4, 19, 20 Warner, P.M., 7, 136 Waroquier, M., 8, 43 Warshel, A., 2, 95 Wasai, K., 12, 119 Waser, M., 3, 195 Wass, J.R.T.J., 3, 270 Wasylenko, W.A., 4, 80 Watanabe, D., 13, 78 Watanabe, H., 3, 73 Watanabe, K., 1, 203; 11, 195 Watkinson, M., 1, 252 Watson, D.A., 5, 35, 36 Watson, G.W., 2, 89 Watts, C.C., 1, 310; 3, 353 Wayland, B.B., 11, 100 Weatherwax, A., 12, 136 Weaver, G.W., 4, 100 Weber, C., 7, 110 Weber, K., 11, 19 Weber, M., 2, 33 Webster, R.D., 7, 127 Weeden, J.A., 1, 148 Wehn, P.M., 3, 180 Wei, G., 9, 88 Wei, H., 14, 146 Wei, S., 1, 54, 114; 3, 365; 11, 208 Wei, W., 1, 43 Wei, X., 4, 33 Weidemann, S.H., 1, 33 Weinert, E.E., 7, 31 Weinreb, S.M., 12, 85 Weinstein, J., 7, 124 Wei-Optiz, D., 7, 45 Weiss, A.H., 1, 192; 9, 113 Weiss, M.E., 13, 28 We¨ıwer, M., 11, 51, 52 Wells, J.R., 3, 191 Welton, T., 8, 122 Wen, J., 1, 222 Wender, P.A., 12, 42, 175, 179, 183 Weng, S.-S., 3, 262 Wentrup, C., 4, 81; 14, 6 Werschkun, B., 13, 14 Werstiuk, N.H., 4, 19 Wesolowski, T.A., 3, 379 West, F.G., 9, 147; 12, 180; 13, 60; 14, 115 Westaway, K.C., 8, 61–63 Westermaier, M., 6, 49; 7, 52, 185 Westermann, B., 14, 9 Westmaier, M., 5, 56 Weston, M.H., 11, 261; 13, 17 Westwood, R., 12, 71

546 Wettergren, J., 1, 306; 3, 370 Whalen, D.L., 7, 25, 149; 8, 8 White, C.J., 2, 106 White, J.M., 2, 113 White, J.W., 1, 124 White, K., 1, 56 Whitehead, D.C., 3, 101 Whitfield, D., 7, 65 Whiting, A., 2, 1 Whittall, J., 1, 309; 3, 334 Wiberg, K.B., 3, 36 Widenhoefer, R.A., 11, 1, 46, 117 Wiedemann, S.H., 4, 24; 11, 110 Wik, B.J., 6, 69 Wiles, J.A., 3, 339 Wilhelm, R., 14, 46 Wilkinson, K.A., 10, 28; 14, 148 Wilkinson, S.R., 10, 28; 14, 148 Wille, U., 11, 55; 14, 170 Williams, A.J., 9, 36 Williams, D.R., 9, 69 Williams, I.H., 2, 2; 8, 117 Williams, J.M.J., 3, 320 Williams, L.J., 2, 46 Williams, N.H., 2, 103, 104 Williams, S.J., 2, 113 Williams, T.J., 12, 42, 183 Williams, V.E., 12, 181 Willis, A.C., 7, 127 Willner, H., 10, 32 Wills, M., 1, 311, 312, 315; 3, 337, 374 Wilmot, N., 1, 303 Wilson, B.J., 14, 14 Wilson, C., 14, 79 Wilson, J.E., 12, 40 Wilson, P.D., 3, 229 Wilson, W.K., 7, 167, 173; 14, 59 Winkler, M., 7, 103 Winter, R., 7, 146 Winzer, A., 7, 36 Wirth, S., 5, 30 Wisniewska, J., 3, 75 Witherington, J., 8, 49 Wittmann, M., 3, 166 Witulski, B., 12, 179 Wlosnewski, A., 14, 43 Woerpel, K.A., 7, 5, 62–64; 8, 104 Wolf, C., 1, 190, 286 Wolfe, J.P., 11, 79 Wolfer, J., 12, 136 Wolk, J.L., 14, 135 Won, K., 9, 20 Wong, A.W.F., 12, 56 Wong, F.M., 10, 12 Wong, K.-Y., 9, 84 Wong, N.-B., 8, 107, 108

Author Index Wong, O.A., 3, 118, 119 Wood, T.K., 12, 120 Woodward, G., 1, 311; 3, 337 Workman, J.A., 14, 77 Wörth, J., 11, 19 Worthington, P.A., 14, 91 Wu, B., 13, 27 Wu, F., 11, 84, 155 Wu, H., 13, 5 Wu, J., 1, 49, 86; 3, 371; 4, 97; 8, 45, 48; 11, 207; 12, 65 Wu, K., 5, 4 Wu, K.-H., 4, 52 Wu, M.-F., 12, 173 Wu, P., 1, 54; 3, 365 Wu, T., 6, 52; 11, 168 Wu, T.-K., 7, 177 Wu, W., 3, 292; 4, 58; 8, 77; 10, 12 Wu, W.-B., 11, 40 Wu, X., 1, 118, 289; 3, 376; 6, 22 Wu, X.-Y., 11, 169 Wu, Y., 1, 114, 115; 2, 24; 3, 223; 4, 96; 8, 46; 11, 136, 153, 217 Wu, Y.-D., 1, 264; 3, 350; 12, 75, 125 Wulff, W.D., 4, 45 Würthwein, E.-U., 7, 97; 13, 65; 12, 39 Wyatt, P.B., 12, 96 Wyre¸bek, P., 12, 132

Xie, J.-Q., 2, 78; 3, 215 Xie, J.-W., 11, 153 Xie, L., 9, 131 Xie, Y.-Z., 1, 289 Xie, Z., 12, 161 Xifra, R., 6, 65 Xin, Z., 13, 28 Xing, C., 14, 80 Xing, X.-N., 1, 109 Xiong, J., 2, 70 Xiong, Q., 7, 167, 173; 14, 59 Xiong, Y., 1, 253; 2, 36 Xu, B., 7, 187 Xu, D.-Q., 11, 154 Xu, H., 11, 199, 200 Xu, H.-J., 3, 350 Xu, J., 1, 81, 325; 3, 65, 305; 4, 85; 6, 43; 11, 142, 252, 263; 12, 33, 143; 14, 127 Xu, J.-H., 12, 16 Xu, J.-M., 11, 40 Xu, L.-W., 11, 138, 162 Xu, Q., 11, 90 Xu, S., 2, 32; 6, 34; 14, 39 Xu, X., 1, 72, 325; 3, 305 Xu, Y., 1, 120, 201, 311; 3, 337; 4, 33, 58; 11, 201, 264 Xu, Z., 11, 34 Xu, Zh.-Y., 11, 154 Xuan, X., 11, 136 Xue, C., 1, 18 Xue, D., 11, 153 Xue, Y., 2, 24; 8, 107 Xue, Z.-M., 9, 3

X Xi, C., 12, 98 Xi, Z., 12, 2 Xia, C.-G., 11, 138, 162 Xia, H.-G., 12, 65 Xian, M., 14, 122 Xiang, J., 3, 245; 14, 125 Xiang, Q., 2, 70 Xiangjing, Z., 3, 106 Xianming, H., 14, 20 Xiao, B., 11, 2 Xiao, F., 4, 35; 14, 116 Xiao, H., 6, 18 Xiao, J., 3, 376 Xiao, J.-C., 4, 61 Xiao, S.-X., 6, 52 Xiao, Sh.-X., 11, 168 Xiao, W.-J., 1, 109; 6, 51 Xiao, X., 1, 53; 3, 382; 6, 62 Xiao, Y., 1, 324 Xichun, F., 14, 20 Xie, D.-Q., 2, 24 Xie, G., 1, 330; 3, 293 Xie, H., 11, 160 Xie, J., 13, 39 Xie, J.-H., 6, 45

Y Yaakoubd, L., 2, 59 Yada, A., 11, 68 Yadav, V.K., 1, 209 Yaguchi, Y., 11, 211 Yajurvedi, D., 3, 28 Yalalov, D.A., 11, 209 Yamabe, S., 7, 58; 14, 11 Yamada, K., 1, 42 Yamada, T., 1, 318; 3, 316; 12, 56 Yamagiwa, N., 1, 255; 11, 121 Yamaguchi, A., 1, 31, 33; 9, 103 Yamaguchi, K., 1, 275; 13, 75; 14, 22 Yamaguchi, M., 1, 290 Yamaguchi, S., 14, 126 Yamaguchi, Y., 7, 131 Yamamoto, A., 11, 45 Yamamoto, G., 7, 162 Yamamoto, H., 1, 97, 132; 3, 78, 79; 6, 37; 11, 42, 48; 12, 129 Yamamoto, S., 1, 330; 3, 293 Yamamoto, T., 11, 236

547

Author Index Yamamoto, Y., 1, 42, 160; 3, 362; 4, 30; 11, 235 Yamamura, G., 1, 82 Yamamura, G.-h., 9, 77 Yamane, Y., 11, 161 Yamanoi, Y., 1, 263 Yamaoka, Y., 1, 85 Yamasaki, M., 12, 54 Yamasaki, S., 12, 123 Yamataka, H., 1, 23 Yamauchi, K., 4, 102 Yamazaki, A., 10, 4 Yamazaki, M., 11, 184 Yamazaki, S., 14, 11 Yan, G.-S., 2, 24 Yan, P., 3, 308 Yan, X.-X., 12, 75 Yan, Y., 11, 106 Yanada, R., 14, 88 Yanagisawa, A., 1, 292, 294; 9, 139 Yang, C., 11, 136 Yang, C.-G., 11, 33, 115 Yang, H., 1, 96; 7, 65 Yang, H.-J., 6, 23 Yang, J., 3, 382; 6, 3 Yang, J.-H., 1, 277 Yang, K., 2, 25; 11, 183 Yang, L., 11, 138, 162; 12, 151 Yang, M., 1, 347; 3, 199 Yang, M.-Y., 2, 108 Yang, Q., 3, 340 Yang, S.-R., 11, 74 Yang, S.-T., 1, 106 Yang, W.-L., 11, 154 Yang, X., 11, 84 Yang, Y., 6, 42 Yang, Y.-Y., 1, 19 Yang, Z.Y., 13, 71 Yang.J., 1, 53 Yao, M.-L., 7, 184 Yao, S., 7, 75 Yardley, V., 7, 36 Yasinskii, O.A., 5, 10 Yasuda, M., 12, 123 Yasuda, Y., 1, 219; 9, 115 Yasuhara, Y., 1, 40; 9, 121; 11, 109, 238, 249 Yatsimirsky, A.K., 2, 101 Yau, S.K.Y., 3, 40 Ye, B., 3, 243 Ye, C.M., 2, 39 Ye, M.-C., 1, 202; 11, 210 Ye, S., 4, 97; 8, 45 Ye, W., 11, 263; 12, 143 Ye, X., 1, 54; 3, 365 Yee, N.K., 1, 244; 4, 33, 90 Yeh, C.-Y., 3, 277 Yenil, N., 11, 141 Yeung, Y.-Y., 11, 25

Yi, C., 5, 38 Yilmaz, S.S., 11, 20, 22 Yin, J., 3, 354; 4, 69; 11, 87 Yin, Y., 11, 122, 151 Yiu, S.-M., 3, 40 Yoda, H., 1, 111, 203; 11, 195 Yokomakura, K., 12, 167 Yokota, M., 6, 38; 7, 79 Yokoyama, H., 14, 126 Yokoyama, T., 6, 38; 7, 79; 10, 45 Yokoyama, Y., 9, 156 Yonehara, M., 11, 39 Yonekura, Y., 3, 225 Yonezawa, N., 6, 35; 7, 94 Yong, K., 3, 108 Yoo, C.L., 12, 68 Yoo, W.-J., 1, 343 Yoon, J.-Y., 12, 183 Yorimitsu, H., 1, 173; 5, 11, 40; 11, 253 York, D.M., 2, 99 Yoshida, J., 7, 44, 59, 182 Yoshida, K., 1, 52, 263; 3, 348 Yoshida, M., 11, 144 Yoshida, S., 7, 140 Yoshida, Y., 6, 35; 7, 94 Yoshikai, N., 11, 228 Yoshikawa, M., 6, 30 Yoshikawa, T., 10, 43; 11, 260 Yoshimura, M., 3, 333 Yoshimura, T., 8, 72 Yoshino, T., 7, 141 Yoshioka, S., 1, 8; 12, 123 Yoshioka, Y., 9, 136 Yoshitaka, M., 3, 181 Yoshitake, Y., 13, 75 You, F., 12, 134 You, S.-L., 10, 50 You, T., 1, 222 Yousufuddin, M., 3, 241; 14, 154 Yu, B., 1, 49, 186; 3, 371 Yu, D., 14, 74 Yu, F.-J., 6, 23 Yu, G.-T., 4, 14 Yu, H., 4, 58 Yu, J.-K., 4, 14 Yu, J.-Q., 3, 53; 5, 29 Yu, L., 3, 245 Yu, L.-J., 2, 60 Yu, M., 1, 115 Yu, Q., 3, 245 Yu, R.T., 12, 164, 165 Yu, S., 6, 3; 11, 119 Yu, W., 12, 151 Yu, Y., 11, 80; 14, 162 Yu, Z.-H., 8, 115, 116 Yu, Z.-X., 4, 85; 14, 127 Yuan, D.-Y., 14, 4

Yuan, Q., 3, 250 Yuan, Y., 1, 177; 3, 119 Yuan, Z.-Q., 12, 7 Yuasa, J., 3, 295 Yudin, A.K., 14, 89 Yue, H.-D., 11, 154 Yue, L., 4, 96; 8, 46; 11, 153 Yukawa, T., 11, 70 Yun, H., 3, 202 Yun, J., 3, 315 Yus, M., 1, 326; 3, 391; 14, 25 Yus Astiz, M., 9, 54

Z Zabalov, M.V., 4, 78 Zabolotskikh, A.V., 13, 51 Zachová, H., 14, 33 Zaczek, A., 9, 56 Zade, S.S., 11, 126 Zahedi, M., 3, 43 Zaidi, N.H., 1, 21 Zaikin, P.A., 6, 9; 7, 114 Zair, T., 5, 37 Zaitsev, A.B., 1, 306, 313; 3, 370, 372 Zaja, M., 14, 17 Zakarian, A., 13, 23 Zalatan, J.G., 2, 73 Zalinznyi, V.V., 10, 9, 11 Zaliznyi, V.V., 8, 84 Zang, R., 2, 68 Zang, R.-R., 2, 69 Zanirato, P., 7, 123 Zanoni, G., 7, 169 Zanotti-Gerosa, A., 3, 376 Zaokov, G.E., 3, 192 Zapf, A., 11, 64 Zard, S.Z., 1, 92 Zare, K., 3, 20 Zdilla, M.J., 11, 62 Zefirov, N.S., 8, 58; 14, 141, 145 Zeidan, T.A., 13, 57, 58 Zelder, F.H., 2, 74 Zeng, X., 2, 68; 4, 33 Zeng, X.-C., 2, 69 Zeund, S.J., 1, 37 Zeynizadeh, B., 3, 325 Zhabinskii, V.N., 14, 140 Zhai, H., 14, 5 Zhai, Y., 5, 4 Zhan, C.-G., 2, 36 Zhang, A., 1, 54; 2, 96; 3, 365; 11, 67; 14, 174 Zhang, B., 1, 96 Zhang, D., 3, 241, 243; 11, 207; 14, 154 Zhang, H., 1, 26; 2, 7 Zhang, J., 1, 224; 3, 215, 328; 4, 40; 11, 33, 115

548 Zhang, J.-Y., 3, 384 Zhang, J.C., 13, 71 Zhang, K., 12, 75 Zhang, L., 4, 33; 11, 199; 14, 100, 101 Zhang, M., 3, 207 Zhang, P., 1, 347; 3, 199 Zhang, Q., 11, 151 Zhang, S., 1, 210; 4, 85; 10, 46; 14, 127 Zhang, S.-H., 1, 108 Zhang, S.-Q., 1, 106 Zhang, S.-W., 11, 252 Zhang, T., 13, 53 Zhang, T.Y., 3, 269 Zhang, W., 1, 256, 335; 3, 380 Zhang, X., 1, 210; 3, 340; 4, 51; 10, 46; 11, 106; 12, 125; 13, 5 Zhang, X.-H., 4, 53, 54, 65 Zhang, X.P., 4, 83 Zhang, Y., 1, 114, 115, 302, 338; 2, 70; 11, 41; 12, 75, 184 Zhang, Y.-l., 6, 19 Zhang, Z., 1, 144; 3, 233; 7, 14; 9, 43, 88 Zhao, C., 7, 149; 8, 8 Zhao, C.-G., 1, 100 Zhao, C.-Y., 4, 53, 54 Zhao, D., 1, 129, 158, 159 Zhao, G., 1, 115, 200; 3, 223; 11, 194 Zhao, G.-L., 1, 34; 3, 242; 11, 145, 179 Zhao, J., 12, 46 Zhao, J.-L., 6, 26 Zhao, J.-Y., 1, 289 Zhao, L., 11, 225

Author Index Zhao, M., 11, 84 Zhao, M.-X., 11, 142 Zhao, R., 3, 65 Zhao, R.H., 3, 63, 64 Zhao, S., 14, 56 Zhao, W.-G., 11, 112 Zhao, W.-J., 3, 58 Zhao, W.-X., 11, 229 Zhao, X., 3, 173; 13, 46 Zhao, Y., 2, 4 Zhao, Y.-L., 14, 168 Zhao, Z., 13, 62 Zhao, Z.Q., 1, 152 Zhdankin, V.V., 14, 8 Zheng, H., 9, 137 Zheng, J.-F., 1, 106 Zheng, L., 14, 125 Zheng, P., 13, 73; 14, 177 Zheng, X., 1, 4, 5 Zheng, X.-m., 8, 78 Zhi, S., 11, 81 Zhiburtovich, Y.Y., 14, 140 Zhou, B., 2, 78 Zhou, C., 2, 109 Zhou, F., 11, 34 Zhou, L., 11, 86 Zhou, M.-M., 1, 144; 9, 43 Zhou, P., 1, 239 Zhou, Q.-L., 6, 42, 45; 11, 169 Zhou, R.-x., 8, 78 Zhou, W., 11, 138, 162 Zhou, Y., 1, 102 Zhou, Y.-L., 11, 229; 12, 151 Zhou, Z.-Y., 1, 289 Zhu, H.-J., 3, 317, 318 Zhu, J., 1, 49; 2, 68; 3, 371; 11, 153

Zhu, L., 10, 52 Zhu, M., 14, 75 Zhu, M.-K., 11, 203 Zhu, R., 11, 207 Zhu, S., 12, 46; 14, 72, 80 Zhu, S.-F., 6, 42; 11, 169 Zhu, S.-Z., 8, 115, 116 Zhu, X., 7, 61 Zhu, X.-Q., 3, 384 Zhu, Y., 4, 15 Zhu, Z.-L., 2, 4 Zierkiewicz, W., 3, 267 Zimin, Y.S., 3, 187, 192, 193 Zimmerman, H.E., 1, 291; 9, 15 Zimtseva, G.P., 3, 212 Zink, C.N., 1, 58 Zipse, H., 2, 32 Zmitek, K., 1, 337; 3, 218 Zografos, A.L., 14, 166 Zoloff Michoff, M.E., 4, 47 Zou, J.P., 11, 164 Zou, W., 1, 24, 120, 121 Zou, X., 6, 50 Zou, Y., 13, 37 Zu, L., 11, 159, 160, 198, 215, 216 Zuberi, S., 3, 387 Zucco, C., 2, 14 Zuhl, A.M., 11, 214 Zuilhof, H., 7, 98; 9, 138 Zuman, P., 1, 91 Zunic, V., 8, 50 Zuo, G., 12, 162 Zupan, M., 1, 337; 3, 218 Zwanenburg, B., 6, 40 Zwanenburgh, B., 12, 142 Zwikker, J.W., 9, 49–51 Zyryanov, G.V., 1, 66

Subject Index A Ab initio calculations β-(acetoxy)vinyl radical rearrangements 505 acyl radical/imine additions 12 CASSCF AND CASPT2, for 3-vinylmethylenecyclobutane rearrangement 503 diethylzinc/aldehyde addition 28 metadynamics, formamide hydrolysis 60 β-(nitroxy)vinyl radical rearrangements 505 QM/MM free energy, phosphate monoester reactions 79 reductive amination 41 on SN 2 reactions 236 unimolecular elimination reactions 309 Abstraction, hydride 41 Acemethacin 75–6 Acetaldehyde-d1 , oxidation of 92 Acetalization, terminal alkene 330 Acetals 2–3 formation 191 Acetates, substitution reactions 233 Acetic anhydride acylation of 59 in choline acetylation 71 Acetophenones, chalcones from 362 Acetophenoximes, oxidation of 100 Acetoxy group, 1,2-rearrangements, vinyl radicals 507 β-(Acetoxy)vinyl radicals, rearrangements 505 Acetylacetone Michael addition of 356 oxidation of 95 N-Acetylated 2,4,5-triphenylimidazolinium salts 464 Acetylation Organic Reaction Mechanisms 2006.  2010 John Wiley & Sons, Ltd

of p-t-butyl[3.1.3.1]homooxacalixarene 453 of choline, with Ac2 O 71 Acetylcholine 71 N -Acetylcysteamine, addition of 341 N -Acetyl-l-cysteine, addition of 341 2-Acetyl-1-hydroxyanthraquinone esters 453 N 2 -Acetyl-l-lysine, addition of 341 1-Acetylvinyl acrylates reaction with furan 196 reaction with thiophene 196 Achmatowicz rearrangements 498 Acid anhydrides 58–9 Acid catalysis hydrolysis, formamide, KIE studies 59 rearrangements, tricyclo[4.2.2.22,5 ]dodeca3,7,9,11-tetraene 463 Acid halides 58–9 Acid hydrolysis acemethacin 76 1-azabicyclo[2.2.2]octan-2-one 77 indomethacin 76 3-methyl-δ-valerolactam 77 Acidity, thioamide 15 and hydrogenation 39 Acids, α,β-unsaturated, oxidation of 102 Acrolein, addition to 347 Acrylonitriles, substituted, formation of 329 Activated aromatics, iodination with 188 Activated bleomycin, oxidation with 101 Activation energy aziridine ring opening 246 lack of, 16 O-18 O isomerization 267 t-BuFH+ SN reactions 265 THF formation 268 Activation parameters aldehyde oxidation 42 Edited by A. C. Knipe

549

in aryloxirane ring opening 238 G = aziridine ring opening 246 ethylene oxide reactions 242 SN reactions at phosphorus 252 H = 238 S = 238 ketone alkaline hydrolysis 43 and sigmatropic shifts 434 solvent effects 254 see also G = ; H = ; S = Activation strain model 252 Activity alkali metal hydride 503 water, reaction rates, and R4 NX salts 253 Acylation 187 of alcohols, by anhydrides 59 by aliphatic carboxylic acids 197 of alkoxybenzenes 197 of alkylbenzenes 197 of anisole 197 of arenes 197 by aromatic carboxylic acids 197 by carboxylic acids 197 of cyclopenta[c]pyran-3-yl derivatives 197 Eu(NTf)2 catalysis 197 HBF4 in 198 HNTf2 in 197 intramolecular 198 IPy2 BF4 in 198 Lewis and Brønsted acid catalysis 197 by trifluoroacetic anhydride 197 7-(trifluoroacetyl)cyclopenta[c]pyrans formed by 197 Acylbenzotriazoles, α,β-unsaturated, alkylation of 196 Acylbenzynes, formation 402 1-Acyl-3,5-dimethylpyrazoles 401

550 Acyl group migration, 3,3-rearrangements with 482 2-Acylimidazole 193 Acylimines, formation of 369 Acyl migration, novel intramolecular 482 Acyloxyphenylketenes 385 Acyl radicals, 5-endo-trig cyclization 507 Acyl transfer product 500 α-Acylvinyl anion intermediates 21 1-Acyl-2-vinylcyclopropanes, rearrangement of 477 C-Adamantonium ions 221 2-Adamantyl bromide, SN 1 reaction 253 1-Adamantyl cation 204, 221 2-Adamantyl cation 221 1-Adamantyl chloride, SN 1 reaction 253 Adamantylidenefulvene, 1,3-dipolar cycloaddition of 389 Addition 1,2allylbismuth in 361 allylindium in 361 allylmagnesium in 361 1,4of ArI ZnCl 366 of arylboronic acids 365 of aryl derivatives 365 to (E)-3-arylpropenals 366 of aryltrialkoxysilanes 366 Cu complexes in 317 Grignard reagents 292, 362, 363, 368 Rh-BINAP catalysis 365 1,6arylboronic acids 367 nucleophiles 368 Aldol reactions see Aldol reactions of alkynes, to cyclopropenes 334 of arylboronic acids 363 carbenes in 163–5 carbonyl compounds 27–36 conjugate carbanions generated by 458 Cu complexes in 317 cycloaddition see Cycloaddition Michael see Michael addition nucleophilic see Nucleophilic additions

Subject Index organolithium species in 29, 287–91 organometallics in 6–7 organozincs in 27–9 polar see Polar addition Addition-elimination mechanism SN 2 substitutions 236 SN reactions at sulfur 252–3 1,4-Adducts, lithium pentamethylcyclopentadienide/cinnamate ester reactions give 368 Adenine, ribosylation of 272 5 -Adenosine monophosphate, hydrolysis of 79 Aerobic oxidation 121, 122–3 asymmetric 122 Aggregates, chiral lithium amide/enolate 361 Aggregation in aldehyde addition 28 NMR spectroscopy on 29 AgNO3 -KF, arylation with 197 Agostic interaction 199 [AlCl3 + 2THF], catalysis, cycloaddition 398 Alcohols allylic α,β-epoxy sulfone conversion gives 283 fluorinated vinyloxiranes give 239 trifluoroborate salts from 235 2-amino, carbonates of 74 γ -amino, catalysis with 295 t-butyl alkylation with 191 oxidation of 98 diols, oxidation of 97, 98, 101, 108 homoallylic, Prins cyclization 324 in intermolecular additions 323 oxidation of 91, 92, 93, 98, 99, 101, 104, 108 aerobic oxidation 122–3 Aldehydes addition 27–36 aldol reactions 14–21 Baylis-Hillman reactions 21–2 Michael addition 26 to nitroalkenes 355 alkylation 38, 193 alkynylations 25–6 allylation 22–4

aromatic, intramolecular acylation of 198 cinnamaldehyde, phenyllithium addition to 361 cycloisomerization 43 hetero-Diels-Alder reactions 43 hydroxyalkylation of 194 olefinations 24 oxidation 42, 93, 108 reduction 38, 41 α,β-unsaturated, alkylation of 193 Aldimines, N-sulfonyl, enantioselective reactions with 194 Aldolases, screening, in water 14 Aldol reactions 14–21 nitro 19 nitroso 19 stereoselective 14–18 Aldol-Tishchenko reaction 19 Alkali metal hydride, activity of 503 Alkaline hydrolysis aryl esters, ortho substituent effect in 57 N -benzylphthalimide 60 imides 60 rate prediction 55 Alkaline phosphatase 70 Alkaloid magellanine, synthesis 409 Alkanes, oxidation, with dioxiranes 113–14 Alkanethiols, oxidation of 107 Alkenes asymmetric epoxidation of 92, 106 asymmetric hydrogenation 134–5 cross-metathesis 312 dihydroxylations of 102 epoxidation of 92, 99, 100, 104–5, 106–7, 114 hydrogenation 134–5, 136 nitroalkenes, alkylation by 193, 194 oxidation of 95, 96, 100 polymerization, 5-hexenylsilane in 327–8 self-metathesis 312 Alkenylation 191 of arenes 191 by [3]cumulene 191 of electron-rich heteroaromatics 191 of furan 191

551

Subject Index Alkenylides, cyclic, computational study on 502 Alkoxides, 1,4-addition of 368 [1,3]-Alkoxide shift, Ru-carbene intermediate undergoes 486 1-Alkoxy-2-alkylindenes, intramolecular alkylation forms 191 γ -Alkoxyallyl cations, intermediate 213 Alkoxybenzenes, acylation of 197 N -Alkoxycarbonyl-2,3-dihydropyridinium cations 395 α-Alkoxycarbonylnitrones, 1,3-dipolar cycloaddition 389 2-Alkoxy-3,4-dihydro-2H pyrans, oxidation of 492 Alkoxylation 191 Alkyl-arylboranes, reactions of 476 Alkylation 187, 190–1 to 1-alkoxy-2-alkylindenes 191 by alkyl halide catalysts 190 α-, aldehydes 38 of arenes 191 of aryl borates 190 aryl epoxides in 190 by benzhydryl cations 195 Birch reductive 143, 457 bis(oxazolinyl)pyridinescandium(III) triflate complex catalysis 193 of p-bromobenzyl phenyl ether 190 with t-butyl alcohol 191 catalysts in 193–4 of chalcone 195 by (E)-crotonaldehyde 193 Cu(OTf)3 in 190 C- versus O- 38, 190 by cyclohex-2-en-1-one 190 diastereoselectivity 191 and diethylaminosulfur trifluoride 190 by dimethyl alkylidene malonates 196 of electron-rich aromatics 190, 191 enantioselectivity 193 and bis(oxazolinyl)pyridinescandium(III) triflate complex 193 and pyrrole 193 by enones 190, 195

of ethers, simple aromatic 190 by ethyl 3,3,3-trifluoropyruvate 190 by group 13 trihalides 190 to homotriptycenes 191 of indole 193, 194, 195, 196, 349 of indoles 194, 195, 196 of 10-(3-methoxybenzyl)9,10-dihydroanthacen9-ols 191 (2S,3S)-3-methylazirin-2yl(diphenyl)methanol TFA salt 193 of α-methylcinnamaldehyde 191 of N -methylindole 193–4 of N -methylpyrrole 193 molecular orbital calculations 190, 196 monodealkylation, of diethers 270–1 N -, ester aromatization in 103 by nitroalkenes 193, 194 by 2-nitroethenylcyclohexane 193 by β-nitrostyrene, in water 195 palladium catalysis 102 of phenol 191 by propargylic alcohols 191 of pyrroles 193, 195 rate limiting hydrogen transfer 196 regioselectivity in 190, 196 of resorcinol dimethyl ether 190 stereoselectivity in 190, 191 by trans-stilbene oxide 190 to 3-substituted indoles 196 in supercritical water 191 thiolate-bridged diruthenium complexes in 191 tri(3,5-dimethylphenyl)borate in 190 by triflic anhydride 190 by α,β-unsaturated acylbenzotriazoles 196 by α,β-unsaturated 2-acylimidazoles 193 of α,β-unsaturated aldehydes 193 by (E)-α,β-unsaturated ketones 196 Alkylbenzenes, acylation of 197 Alkyl carbenium ions 204–5 α-Alkylcinnamaldehydes 191 Alkyl halide catalysts, alkylation with 190

Alkylidenecyclobutanes, ring expansions 489 Alkylidenecyclopropanes 480 ring expansions 489 Alkylidenecyclopropanone acetal, ring opening of 370 α-Alkylidene lactams, synthesis 479 1-Alkylidene-2-oxyallyl cation 196, 379 Alkyl-imines, enantioselective reactions of 194 Alkyl mandalates, oxidation of 107 Alkyl migration, alkyl-aryl borane reactions with 476 Alkylphosphines, reduction with 142 N-Alkylpyrroles, trimethylsilylation of 199 1-Alkylstyrenes, hydrovinylation 329 Alkyl-substituted adducts 361 Alkyl 3,3,3-trifluoropyruvates 191 Alkyltriphenylphosphonium bromide micelles 256 Alkynals, cyclization, palladium-phosphine complexes in 334 Alkynes addition 334 to cyclopropenes 334 alkynylstannane addition to 336 allylation, Pd catalysis 334 allyl cyanide addition across 329 hydroesterification 335 terminal cycloaddition with 408 hydration of 335 Alkyne-tethered indoles, annulation reactions 481 Alkynones, cyclization, palladium-phosphine complexes in 334 Alkynylations, carbonyl compounds in 25–6 o-Alkynylbenzaldehydes, domino annulation 480 Alkynylboration 367 nickel catalysis 324 Alkynylboronates, addition of 367 Alkynyl t-butylcarbonates, cyclization of 326 Alkynylcyclopropanes, formation of 334

552 Alkynylphenylcarbene complexes 413 Alkynyl(pinacol)boranes, nickel catalysed reactions 324 Alkynylstannanes, addition to alkynes 336 Alkynyltellurides, hydrozirconation of 328 Allenes 2 + 2 + 1-cycloaddition 406 3 + 2-cycloaddition 386 azole addition to 371 gold-coordinated 426 silaboration of 325, 333 Allenic enolates, generation and reactivity 279 Allenylidene-ruthenium complexes, rearrangements 486 2-(Allenyl)phenylazides 379 Allyl acetate, hydroformylation, platinum catalysis 102 Allylamines 322, 370 Allylation of alkynes 334 carbonyl compounds in 22–4 Allyl benzoates, allylic substitutions 236 Allylbismuth, addition to cyclohexenones 361 Allyl bromide, SN 2 reactions 236 Allyl carbamates allylic substitutions 236 and enone reactions 363 Allyl carbonates, SN 2 substitutions 232, 233 Allyl chlorides, coupling with enynes 329 η3 -Allyl complexes 331–2 Allyl cyanides, addition across alkynes 329 Allyl enammonium cations, 3-aza Cope rearrangement 471 Allylic alcohol groups, protection of 237 Allylic alcohols allylic trifluoroborate salts from 235 α,β-epoxy sulfone conversion gives 283 fluorinated vinyloxiranes give 239 Allylic amines, diene hydroamination with 339–40, 368 Allylic ammonium ylides, rearrangement of 475

Subject Index Allylic benzoates 236 isomerization of 233–4 Allylic cations charge distribution 370 cyclopropane ring opening gives 319 Allylic chlorides, SN 2 products from 231 Allylic esters, oxidation of 103 Allylic geminal dicarboxylates, alkylation of 102 Allylic halides, cyclization 326 Allylic strain, selectivity and 430 Allylic substitutions 231–7 allyl benzoates in 236 allyl carbamates in 236 bis(oxazolines) in 237 copper catalysis 233, 236 of α-cyanoacetals 235 Grignard reagents in 233, 235 palladium catalysis 237 propargyl compounds in 236 reviews 237 taniaphos catalysis 233 Allylic systems, carbocation 213–14 Allylic transposition 432 Allylic trifluoroborate salts, formation of 235 Allylindium, addition to cyclohexenones 361 Allylmagnesium, addition to cyclohexenones 361 Allylnaphthol derivatives, formation of 421 π -Allylnickel intermediates in acrylonitrile formation 329 α-Allyloxy ester, enolate rearrangement gives 458 π -Allylpalladation 334 Allylpalladium complexes, nucleophilic attack with 332 π -Allylrhodium complex intermediate 338 Allylsilanes, 2 + 2-cycloaddition with 382 Allyl sulfones, formation of 351 α-effect 81, 84 DMSO influence on 57 α-profile, bell-shaped, and DMSO 57 Aluminium chloride see [AlCl3 + 2THF] AM1 calculations Beckmann fragmentationsubstitution 475 SN 1 hydrolysis, imidazolidin-4-ones 269

SN 2 reactions, ethylene oxide 242 Amadori rearrangements, reverse 468 Amides 74–7 formation 62 hydrogenation of 134 hydrolysis 59 nucleophile isotope effects 70 in intermolecular catalysis 59–60 Michael-like addition with 354 α,β-unsaturated addition 361 oxidation of 102 Weinreb 34 acylation with 288 Knoevenagel condensation with 281 Amidophosphonium salts, generation of 73 Amidosulfites 68 Amination of enecarbamates 369 reductive, Hantzsch ester in 138 Amine arms, appending to cyclen 83 Amines aromatic, nitration 189 cyclic 370 cyclohexa-2,5-diene hydroamination gives 368 in diene hydroamination 339–40 as nucleophiles 175 secondary S-(4-nitrophenyl) 4-methylthiobenzoate reactions with 62 oxidation of 108 in substituted Meldrum’s acid aminolysis 341 Aminimide, chalcone aziridination with 344 Aminoacetoxylation, alkene 330 Amino acids α-, oxidation of 107 βdecarboxylation 310 formation of 345 β -hydroxy-β-amino, derviatives 389 Amino alcohols γ -, catalysis with 295 carbonates of 74

553

Subject Index β-Aminoaldehydes, formation of 345 α-Aminoallenes 485 Aminochlorination 328 Aminodiol borate complex 346 α-Amino esters, formation of 191 Aminohydroxyphosphine ligands 362 Aminolysis aryl 2,4-dinitrophenyl carbonates 61 carbonates 61, 63 esters 71 intermolecular catalysis 58 4-nitrophenyl phenyl carbonate 63 4-nitrophenyl phenyl thionocarbonate 63 N-phenylthionocarbamates 64 substituted Meldrum’s acid 315, 341 Y-phenyl X-benzoates 58 Aminopalladation 331 6-Aminopenicillanic acid, oxidation of 95 3-Aminophenyl phosphate hydrolysis 66 3-Aminopyrrolidine lithium amide, addition with 361 2-Aminothiazole 187 Aminyl radical intermediates 12 Ammonium bifluoride, quaternary species, catalysis by 358 Ammonium 4-methoxybenzoate catalysis 458 Ammonium perchlorates, SN 2 reactions with 253 Ammonium salts, nucleophilic substitution with 179 Ammonium ylides benzaldehyde reactions 34–5 rearrangement of 301, 475 Ammonolysis, phenyl formate 58 Amoxicillin, oxidation of 95 Amsterdam Density Functional method 251–2 Anchimeric assistance in SN 2 reactions 245 Angle of attack, and cyclization of aminoalkyl derivatives 344 Anhydrides acetic 59, 71 acid 58–9 acylation of 59 in alcohol to ether conversions 61

of arylboronic acids 54 of carboxylic acids 54 Anionic rearrangements 453–61 ortho N -Fries rearrangement 454 Anionotropic 1,2-rearrangements, borate complexes in 456 Anisole acylation of 197 nitration with 189 Annulation, 4 + 2 + 2-, cyclobutanones in 409 Anomeric effects, in sugars, comparison with 39 Anthranilate, formation of 341 Anthranylamides, formation of 454 Anthrones, reactions with dienophiles 370 Antiaromaticity dications 219 intermediate electrocyclization 439 Antibodies, catalytic 420 Anti-Markovnikov reactions 321, 468, 469 alkynes in 335, 338 disulfide cleavage 326 hydroamination 336 hydrosilylation 338 imides in 335 2-isobutylphenol from 191, 323 phenol alkylation 322 in sterol biosynthesis 223 thioacetal cyclization 323 Antranylamides, formation of 454 Arene arylating reagents 197 Arenes acylation of 197 alkenylation of 191 alkylation of 191 arylation 196 epoxidation 499 halogenation of 188 in hydroarylation 340 see also Aromatics Arenium ions 215–16 ArI ZnCl, 1,4-addition 366 (ArN=CMe-CMe=NAr)PtPh2 complexes 199 Aromatics activated, iodination with 188 aldehydes, intramolecular acylation 198 alkenes, epoxidation 100 amines, nitration 189 carbocations 217–18

electron-rich alkenylation of 191 alkylation of 190, 191 ketones, in Diels-Alder reactions 398 monosubstituted benzenes, electrophilic aromatic substitution 187 oxidation of 96–7 rearrangements 451–3 see also Arenes Aromatization of indolines 359 Arrhenius equation 352 Arrhenius parameters 434 Arsa-Wittig reaction 284 NMR on 312 Arsenic(III) oxide, reduction with 143 ArSeX, additions of 321–2 ArSX, additions of 321–2 Arylation aryl(iodo)palladium(II)(byp) complex in 197 of 2,3-dibromothiophene 197 of indoles 196 intermolecular 196 intramolecular 196, 197 nucleophilic, benzaldehyde 36 palladium catalysis 196, 325 [Ph2 I+ ][BF4 − ] in 197 proton abstraction 197 of pyrrole 196 ruthenium 197 of simple arenes 196 by tosylates 197 2-Aryl-1-benzazocines, synthesis of 473 N -(Z-Aryl)-Y-benzenesulfinamides, hydrolysis of 68 Aryl borates, alkylation with 190 Arylboronic acids addition 363 1, 4- 365 1, 6- 367 rhodium catalysis 366 anhydrides of 54 hydroarylation with 338 Aryl cations 214–15 Aryl chloroformates 58 Aryl cyanides, addition with 329 Arylcyclopropane 479 Aryl 2,4-dinitrophenyl carbonates, aminolysis 61 Aryl epoxides, alkylation with 190 1-Arylethanols, SN 1 methanolysis of 250 Aryl ethers, chlorination of 188

554 Aryl formates, Fries rearrangements of 451 3-Aryl-5-C-glucosyl-1,2,4oxadiazoles 388 Aryl-imines, enantioselective reactions of 194 N-Arylimines, hydrogenation of 136–7 Aryl(iodo)palladium(II)(byp) complex, arylation with 197 2-(Arylmethylene)cyclopropylcarbinols 464 Arylnickelation pathway 329 Aryl nitrile oxides 388 Aryloxiranes, ring opening 237–8 C-Aryl-N -phenylnitrones, 1,3-dipolar cycloaddition of 389 Aryl phosphate monoesters 80 3-Arylpiperidines, formation of 336 (E)-3-Arylpropenals, addition to 366 2-Aryl-3-pyrrolidines 392 Aryl-stacking effects 16 11-Aryl steroids, formation of 408 Aryl-substituted [6,5] open fulleroids 498 3-Aryl-substituted 2H -azirines, synthesis with 491 Aryl tosylates 197 Aryltrialkoxysilanes, 1,4-addition of 366 Aryltriazenes, lithiation of 456 Arynes, in situ generation of 371 l-Ascorbic acid, oxidation of 100 Asimicin 336 A strain, minimizing, in SN 2 substitutions 233 Asymmetric aerobic oxidation 122 Asymmetric epoxidation, alkene 92, 106 Asymmetric Henry reaction 284 Asymmetric hydrogenation alkenes 134–5 ketones 133–4 quinolines 136 Asymmetric induction, Mukaiyama aldols in 18 Asymmetric oxidation 122, 123 Asymmetric transfer hydrogenation 141

Subject Index Asymmetric [1,2]-Wagner-Meerwein shifts 433 Atenolol, oxidation of 107 Atmospheric oxidation 120 Atom-centred density matrix propagation (ADMP) model 266 Atom-transfer cyclization, allylic halides 326 AuPPh3 SbF6 complex 386 Autocatalysts in aldehyde allylation 23 in iodination 38 pyrimidyl alcohols 29 Autoxidation 121, 122, 123 Axis-to-centre chirality transfer 485 Aza-Baylis-Hillman reactions 21, 22, 351 Aza-Bergman rearrangements 507 1-Azabicyclo[2.2.2]octan-2-one, acid hydrolysis 77 8-Azabicyclo[3.2.1]oct-3-en-2ones 395 9-Azabicyclo[4.2.1]nonene, rearrangement of 464 Azabis(oxazolines), catalysis by 349 Aza-Claisen rearrangements 430 Aza-Cope rearrangements of allyl enammonium cations 471 in ring expansion 370 Aza-Darzens reaction 10 Aza-Diels-Alder reactions 406 Aza-enediynes, thermal aza-Bergman rearrangements of 507 Aza-Henry reaction 284 Aza hetero-Diels-Alder reactions, aldimine 406 7-Azaindole derivatives, addition of 349 Aza-Michael addition 317 7-azaindole in 349 azanorbornyl derivatives from 344 cerium(IV) ammonium nitrate in 343 Aza-Nazarov cyclization 437 7-Azanorbornenes, ring opening/ring closing metathesis 485 Azanorbornyl derivatives, formation of 344 Aza-Payne rearrangements 458 Aza-polycyclic compound synthesis 192

Aza-Sakurai reaction 14 1-Aza-3-siloxybuta-1,3-dienes 403 2-Aza-7-thiabicyclo[2.2.1]heptenes 391 8-Azatricyclo[3.2.1.02,4 ]octanes 389 Azatropylium-type radical cations 508 Aza-Wittig reaction 30 synthesis with 312 Azeditidinones 78 Azepino[1,2-a]indole derivatives, formation of 411 Azetidine, SN reactions of 246 Azetidines 385 formation 6 Azetidinium ions 248 Azides, amides from 62 Azidoformate 471 Azines aromatic, nucleophilic addition to 10 formation of 13 Aziridination of chalcones 344 efficiency, in benzene 328 palladium catalysis 333 silver in 154 Aziridine, SN reactions with 246 Aziridine carboxylates, preparation 246 Aziridine-2-carboxylic acid methyl ester 244 Aziridinemethanols, disubstituted 458 Aziridine ring intermediate 246 Aziridines formation of 344 intermediate, SN 2 reactions 248–9 preparation 10, 243 reactions 241–2, 243–7 DMSO catalysis 245 ring opening 243, 244, 246, 247 synthesis of 343 Aziridine salts, ring opening with 243 Aziridinium ions, anchimeric assistance with 245 Aziridinium mechanism in aminochlorination 328–9 Aziridin-2-ylmethanols, alkylation with 193 Aziridin-2-ylmethanol salts 405 Azirines, allylaziridines prepared from 10

555

Subject Index 2,2 -Azobis(2-methylpropanenitrile), hydrostannylation with 327 Azocinones, formation of 420 Azo coupling 199 activated naphthalene derivatives in 199 of substituted benzenediazonium cations 199 transition states in 199 and Wheland intermediates 199 Azodicarboxylates, reactions with enecarbamates 369 Azoles, umpolung addition of 371 Azomethineimines, cycloaddition with 409 Azomethine ylides 494 cycloaddition 379, 392, 393

B B3LYP/6–311+F(d,p), on cyclic alkenylides 502 B3LYP calculations aziridine ring opening 246 B3LYP/6–311+F(d,p), on cyclic alkenylides 502 BF3 complexes 242 carbamic acid 310 cation formation 451 chalcogenide analogues 310 on cyclic alkenylides 502 cycloaddition 402 Diels-Alder reactions 397, 402 fluoride ions/methyl halide reactions 249 gas phase reactions 264 Hoffman elimination 314 lactam alkylation 231 lithium-bromide exchange reaction 288 methanol fluorination 264 methanolic sodium methoxide reactions 299 oxidosqualene cyclization 469 phenyl group 1,3-shifts 452 phosphate reactions 79 pyruvic acid decarboxylation 309 reaction pathways compared 300 SN 1 hydrolysis 233 imidazolidin-4-ones 269 SN 2 reactions alkyllithium/dihaloalkene intermediates 267 azetidinium ions 248

benzyl bromide and bromide/pyridine 254 chlorosuccinate dianions in 266 encounter complexes 262 ethylene oxide 242 methanol fluorination 264 methyl iodide 253–4 polyfluorosulfonate esters 266 water/methyl chloride 264 SN hydrolysis at silicon 251 Stevens rearrangement 507 transition states 315 tricyanomethanide carbanion structure 278 B3LYP/TZVP//B3LYP6–3G∗ studies, cycloaddition 402 B3PW91/6–31G(d ,p ), transition states 315 BAc 2 mechanisms carbamate reactions 65 in N -thiazolylcarbamate hydrolysis 61 Back-side attack gas-phase reactions 250–1, 265 SN reactions 265–6 Back-side encounter complexes 259 Bacteriochlorins, biological active 403 Bader’s theory 221 Baeyer-Villiger oxidation 42–3, 114, 118 rearrangements, transition steps 471 Baker-Venkataraman reaction 453 Barriers see Energy barriers Base catalysis benzil-benzilic acid rearrangement 454 in nucleophilic aromatic substitution 176 Basicity, solvent, and SN 2 reactions 254 Baylis-Hillman reactions see Morita-Baylis-Hillman reactions Beckmann fragmentation-substitution 475 Beckmann rearrangement 2-aryl-1-benzazocine synthesis 473 cyclohexanone oxime 13

iodotrimethylsilane promotes 473 of ketoximes 475 Belousov-Zhabotinsky (B-Z) reactions 110, 125 Bentley, carbocation reactivity and 209 Benzaldehydes, chalcones from 362 Benzamide, intermolecular additions with 323 3-Benzazepinone, synthesis of 333 Benzene in aza-polycyclic compound synthesis 192 electrophilic aromatic substitution 187 elimination, superacidpromoted 461 Benzene derivatives see Arenes; Aromatics Benzenediazonium ion 214 substituted 199 1,4-Benzenedimethanol, catalysis by 257 Benzeneselenenyl halide 321 Benzeneselenol catalysis, hydrostannylation with 327 Benzenium ions 212 carbon atom scrambling 216 Benzhydrilium ions 255 Benzhydryl bromide 269 Benzhydryl carbenium ions, Ef values 258 Benzhydryl cations 207–8 alkylation by 195 Benzhydrylium ions, kinetic studies 209 Benzil, base-catalysed rearrangement 454 Benzilic acid, base-catalysed rearrangement 454 Benzoates, allylic isomerization 233–4 substitutions 236 Benzoazocines, synthesis of 490 Benzocyclic ketones, formation of 198 Benzocyclobutene, ring opening of 315 5H -Benzocyclohepten-5-one oxime mesylates 473 6(2-Benzofuryl) purines 480 Benzoic acid, protecting silver nanoclusters 461 Benzoic acids, aryl esters of, hydrolysis 57 Benzoin, oxidation of 99

556 Benzoin reactions catalysis of 169 cyclization 33 Benzonitrile N -oxides 388 Benzopyranylidenetungsten(0)complexes, addition to 368 Benzopyrylium cations, annulation reactions with 480 2-Benzopyrylium-4-olates 389 Benzoquinone, catalysis by 330 Benzo[b]thiophene, cycloaddition of 392–3 2H -1-Benzothiopyrans, formation of 345 N -Benzoylated 2-methyl-4,5diphenylimidazolinium salts 464 N -Benzoyloxypyridinium salts 57 Benztriazole, Michael addition of 358 Benzyhydryl substrates 258 1-Benzyl-2-acetylpyrrolidine 468 Benzyl alcohol, nitration of 189 Benzylamines, addition reactions of 353 (S)-Benzylbisoxazoline, Cu(OTf)2 complex of 194 Benzyl cations 205–6 N -Benzyl-N -cyclopropylamine (BCP) 125 Benzyl fluoride, nitration of 189 Benzylidenecyclobutane, epoxydation of 489 N -Benzyl-N -(1 -methylcyclopropyl)amine 125 1-Benzyl-2-methyl-3-piperidone 468 N-Benzyl-3-oxo-β-sultam 86 Benzyloxyallylsilane, rearrangement of 458 3-(Benzyloxycarbonyl)amino6-methylsulfinyl-1,2,4,5tetrazine 406 1-Benzyl-2-phenyl-3-oxidopyridinium betaine 395 N-Benzylphthalimide, alkaline hydrolysis 60 Benzyltrimethylammonium chlorochromate 93 Benzyltrimethylammonium dichloroiodate 110 Benzyne 2 + 2-cycloaddition 385 borabenzene reactions with 402 insertion of sigma-bonds 185 Bergman rearrangements 435 aza- 507

Subject Index thermal aza-, aza-enediynes 507 Betaine, formation 10, 33, 35 βnuc values 259 β-Scissions, chemisorbed carbenium ions 212–13 BH3 -NMe3 -AlCl3 , reduction with 127 Bicyclic pyran-2-ones, cycloaddition of 411 Bicyclo[3.2.0]hept-6-enes 384 Bicyclo[3.3.0]octane systems 391 Bicyclo[3.3.0]octanoids 403 Bicyclo[4.2.0]octanes 403 Bicyclo[4.2.2]deca-2,4,7,8tetraenes 413 Bicyclo[4.3.0]non-2-ene carbon skeleton 400 Bicyclo[4.3.0]non-1(9)-en-8-ones 406 Bicyclo[5.3.0]dec-1(10)-en-9ones 406 Bidentate hydrogen bonds 356 Bidentate phosphine ligands, ethylene insertion with 333 Bifunctional catalysis 11 chiral BINOL 22 cyanation with 31 diamide 15 diamine 15 ketone addition 31 Mannich reactions 5 in Michael reactions 26 nitro aldol reactions 19 Biginelli synthesis 35 BINAP [{(R)-BINAP}Rh]+ SbF6 − , catalysis 413 [BINAP-RhCl]2 , 1,4-addition with 366 in hydroboration 325 Rh-BINAP, catalysis 338, 365 S-, rhodium complexes from 366 Binaphthols see BINOL Binaphthyl-based diamine salts, catalysis by 405 Binaphthyl phosphine derivatives, oxygen reaction with 499 BINOL alkynylboration with 367 catalysis 22, 367 aza-Morita-Baylis-Hillman reaction 281 1,3-dipolar cycloaddition 397

derivative, in diphenylzinc reactions 295 in enolate formation 294 phosphoramidite ligands from 329 Binuclear complexes, DielsAlder reactions with 400 Biologically significant reactions 70–86 Biosynthesis, carbocations in 222–4 (2,2 -Bipyridine)CoBr2 , addition with 365 Birch reductive alkylation 143, 457 [Bis(acetoxy)iodo]benzene, oxidation with 123 Bisallene, electrocyclizations of 437 Bis-arylthioureas, catalysis by 193 1,2-Bisdiarylphosphinites, hydrocyanation with 329 5,6-Bis(dimethylamine)acenaphthylene, halogenation of 188 Bishomoantiaromatic destabilization 205 Bishomoepoxy alcohol, conversion to ether 237 Bis-2H -indazoles, formation of 494 Bismuth hydroamination with 339–40 hydroarylation with 340 Bismuth(V) fluoride, oxidation with 100 Bis-naphthoporphyrins, formation 403 Bis(oxazoline) ligands 317, 349 Bis(oxazolines), aziridine preparation with 247 Bis(oxazolinyl)pyridine-cerium(IV) triflate complex 389 2,6-Bis(oxazolinyl)pyridinelanthanoid complexes 389 Bis(oxazolinyl)pyridinescandium(III) triflate complex, catalysis, alkylation 193 Bis(phosphine)amide ligand, cobalt in 329 Bisphosphines, nucleophilic attack and bite angle 331–2 Bis(thiazoline) complexes, catalysis with 368 Bite angle 331–2, 333 Bleomycin, oxidation with 101

557

Subject Index BLYP/6–311+G∗ //BLYP/6–31∗ level 508 Bmim, synergistic effect with d-camphorsulfonic acid 349 N-Boc-azabenznorbornadiene 245 Boekelheide-Fedoruk ring expansions 490–1 BOP-Cl, catalysis by 475 BOP-Cl-ZnCl2 , catalysis by 475 Borabarrelenes 402 Borabenzobarrelenes 402 Borane BH3 -NMe3 -AlCl3 , reduction with 127 hydroboration with 324 Boranes, alkyl-aryl, reactions of 476 Borate complexes, anionotropic 1,2-rearrangements of 456 Borates, aryl, alkylation with 190 Boron organometallic nucleophiles, enone conversion with 366 Boron trichloride, Fries rearrangements with 451 Boron trifluoride BF3 complexes 242, 267 BF3 .Et2 O, alkylation with 196 [BF3 -MnO4 ]− adduct 96 BF3 .OEt2 alkylation with 191 in isomerization reactions 63 rearrangements with 463 in 4,5-epoxy-9-trimethylsilyldecaline rearrangements 461 in lactone reactions 476–7 Boulton-Katritzky reaction 499 BPW91 (density functionals) 397 Breathing orbital valence bond (BOVB) model 253 Bromamine-B, oxidation with 109, 110 Bromamine-T, oxidation with 110 Bromate, oxidation with 110 Bromide, allyl, SN 2 reactions 236 Bromination 188, 190 by bromine 188 of endo-tricyclooctene 319 epoxycyclohexadecatetraene 320 palladium catalysis 188 radical, dodecahedranes 319

semibullvalene 211–12, 319 Bromine addition of 320 bromination by 188 substitution at 251 N -Bromoacetamide, oxidation with 109–10 (o-Bromoaryloxy)diazaphospholidine-borane complexes 456 1,2-Bromoazidation, alkene, catalysis 320 1,2-Bromoazides 320 N -Bromobenzamide, oxidation with 109 N -Bromo-N-benzoyl-4-toluenesulfonamide, oxidation with 110 p-Bromobenzyl phenyl ether, alkylation of 190 B-Bromoboranes, reactions 243 Bromonium ions, bromination without 212 N -Bromosuccinimide (NBS) 320 oxidation with 110 Brønsted acids 395 catalysis by 359 in Michael addition 355 Brønsted βX coefficients 259 Brook rearrangements 1,2-, α-hydroxypropargylsilanes in 21 1,5-, in aldehyde reductive olefination 488 in aldehyde olefination 24 retro- 433 Bu3 SnH-AlBN, promotion by 507 Bu4 NI, catalysis by 335 (t-BuCN)2 PdCl2 , catalysis by 480 s-BuLi, Wittig rearrangement with 458 Bun Li, hydroamination with 368 Buta-1,3-diene cycloadducts from 314 Diels-Alder reactions with 406 Buta-2,3-dienoate 322 cycloaddition of 392 Butane-1,2-diol, oxidation of 97, 98 Butane-1,3-diol, oxidation of 97 Butane-1,4-diol, oxidation of 98 Butane-2,3-diol oxidation of 101 reactions with hexacyanoferrate(III) 101 Butenolides, β-organoselenium substituted 322

p-t-Butyl[3.1.3.1]homooxacalixarene, acetylation of 453 t-Butyl alcohol alkylation with 191 oxidation of 98 4,4 -di-t-Butylbiphenyl catalysis 458 t-Butyl dicarbonate (Boc2 ) 61 t-Butyl hydroperoxide (TBHP), oxidation with 116 Butyllithium reagents 368 s-BuLi, Wittig rearrangement with 458 LIC-KOR mixture, Wittig rearrangements with 458 1-Butyl-3-methylimidazolium see Bmim 1-Butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [bmim][NTf2 ], hydroamidation with 335 t-Butyl peroxybenzoate, oxidation with 118 2-t-Butylphenol 191 4-t-Butylphenol 191 n-Butylsilane, reduction with 140 p-t-Butylthiacalix[4]arene, catalysis by 408 Butyltriphenylphosphonium dichromate, oxidation with 92 γ -Butyrolactam 76

C C2 -symmetric auxilliary 7, 14, 16, 18, 33 in ketone reduction 40 Calculations ab initio see Ab initio calculations AM1 Beckmann fragmentationsubstitution 475 SN 1 hydrolysis, imidazolidin-4-ones 269 SN 2 reactions, ethylene oxide 242 Amsterdam Density Functional method 251–2 B3LYP see B3LYP calculations BLYP/6–311+G∗ //BLYP/6– 31∗ level of theory, cyclizations 508

558 Calculations (contd.) CASPT2 and (4/4) CASSCF, geminal fluorine addition 496 CCSD(T)/6, and 1,4-benzenedimethanol catalysis 257 CR-CCSD(T), on 2 + 2-cycloaddition 381–2 G2MP2 carbamic acid 310 chalcogenide analogues 310 G2 quantum-chemical 259, 267 SN 2 reactions, potential energy surfaces 259 G3(MP2), reaction pathways compared 300 G3m , SN reactions, fluorides in, gas phase 265 HF/6, micelles 256 HF6, and SN reactions, silylated 5-fluorouracil 271 HF, SN 2 reactions, ethylene oxide 242 1,5-hydride shift 469 MP2 see MP2 calculations MPWB1K/6, in aziridine ring opening 243 PM3 242, 486 QM/MM 79, 308 QSSR methods, enantioselectivity predictions 294 RB3LYP/6–311+G∗∗ levels of theory, nitrogen squaric acid molecular geometries 277–8 RHF/6–311+G∗∗ , nitrogen squaric acid molecular geometries 277–8 SCS-MP2, on cycloaddition 386 semiempirical PM3, ring-closing metathesis 486 SN 2 reactions, methyl chloride 266 WPW1K (density functionals), DielsAlder reactions 397 see also Ab initio calculations; B3LYP calculations; Computational studies; DFT studies; Models Calix[4]arenes with [12]ane-N3 macrocycles, catalysis by 82

Subject Index nitration 190 Calix[6]arenes chlorosulfonylation of 199 chlorosulfonyldealkylation with 199 nitration 190 Calixarene backbone 170 Calixarene-like [M2 (µ-L )(L1 )] structures 400 Camphor derivatives, Pd complexes with 335 d-Camphorsulfonic acid, catalysis by 349 CAN-initiated aza-Diels-Alder reactions 406 Cannizaro oxidation 29 -Caprolactam 60 Carbamates 74 allylic substitutions 236 derivatives, from hydroxyamino acids 500 in diene hydroamination 339–40 enecarbamates, amination 369 and enone reactions 363 formation of 338 hydroamination of 338 N -thiazolylcarbamates, hydrolysis 61 thiocarbamates 64–5 N -Carbamoylalanine 76 N -Carbamoyldiarylamines 454 Carbanion [1,2]-migration 454 Carbanions as nucleophiles 233, 255 in nucleophilic aromatic substitution 176 reactions 279–98 with epoxides 241 structure and stability 277–9 Carbenes 153–4 abstraction reactions 165 addition reactions 163–5 catalysis, substitution 244 complexes, intermolecular trapping 159 in 1,3-diyne rearrangement 487 electrophilic 171 foiled 502 fragmentation 165 N -heterocyclic, catalysis by 244, 486 insertion reactions 165, 166 ligands 156–7, 363 metal-bound 156–63 nucleophilic 169–71 as reagents 158–63 rearrangements 166–7

rhodium(II)-carbene reactions 486–7 stability of 502 transfer reactions, silver in 154 Carbenium ions cyclo alkyl 204–5 diarylcarbenium ions 208 epoxide reactions involving 242 formation, and solvent effects 253 Nf (nucleofugality) 258 oxocarbenium ions 210, 485 resonance stabilization 268 transition states 250 and triphenylverdazyl reactions 269 Carbenoids Li-carbenoid intermediates 496 palladium, formation 480 samarium(II), cyclopropanation with 163 Carbocationic polymerization 209 Carbocation-nucleophile combinations 208 Carbocations 203–25 allylic systems 213–14 arenium ions 215–16 aromatic systems 217–18 aryl cations 214–15 benzyl cations 205–6 in biosynthesis 222–4 carbenium ions see Carbenium ions carbonium ions 191, 221–2 dications 218–20 fluorine substituents 193 halogenated 211–12 nitrenium ions 216–17 oxonium ions 209–10 polycyclic systems 220 quinone methides 206–7 reactivity, quantitative studies 208–9 silicon containing 211 sulfur containing 210–11 in synthesis 224–5 trityl cations 207–8 vinyl cations 214 in zeolites 212–13 see also Cations Carbochalcogenation, alkyne 317 Carbocycles, eight-membered, synthesis 482 Carboetherification, palladium catalysis of 332

559

Subject Index Carbolithiation, propargylic alcohol 326 Carbometallation alkoxide-directed 327 reviews of 317 Carbon, electrophilic, addition with 324 Carbonate group migration, hydroxyamino acids 500 Carbonates allyl, SN 2 substitutions 232, 233 of 2-amino alcohols 74 aminolysis 61 in biologically significant reactions 71–4 enol, formation of 326 4-nitrophenyl phenyl, aminolysis 63 oxidation of 103 sodium percarbonate 114, 116 thiocarbonates 62–4 Carbon dioxide, super-critical in alkene acetalization 330 cycloaddition with 392 Carbonium ions 191, 221–2 Carbon monoxide, N -methylformamide addition with 335 Carbon nucleophiles in aziridine ring opening 247 in oxirane ring opening 243 1,2-Carbon shifts 494 2,2-diphenylcyclobutylidene in 166 Carbonylation, synthesis with 32 Carbonyl ylides 389 Carboxamides, diene hydroamination with 339–40 Carboxenium ions 23 4-Carboxy-3,4-dihydro-3-phenyl1(2H )-isoquinolines 198 Carboxy group migration 482 N-Carboxylanhydride 76 Carboxylic acids in acylation 197 anhydrides of 54 cyclization of 323 in intermolecular catalysis 54–5 (4-Carboxylmethyl)thiophenol (MPAA) 72 Carboxypalladation 479 Carboxypeptidase, hydrolysis with 70 Carboxypeptidase A inhibitors 78 Carboxyvinyltransferases 80 Carotenoid dications 218

Car-Parrinello molecular dynamics simulation 59 Carvone, addition with 361 Cascade reactions anilines/aldehydes 4 silyl enolates in 348 Cascade transfer hydrogenation 137–8 Catalysis acid formamide hydrolysis 59 rearrangements 463 acylation, with HNTf2 197 by [AlCl3 + 2THF], cycloaddition 398 aldol reactions 16 in alkenylation 191 in alkylation 190, 191, 193–4 by ammonium 4-methoxybenzoate 458 arylation 196, 197 association-prefaced 68–70 autocatalysts see Autocatalysts aza-Claisen rearrangements 430 Beckmann rearrangements 475 by 1,4-benzenedimethanol 257 bifunctional see Bifunctional catalysis by BINAP 338, 365, 413 by BINOL 22, 281, 397 by bis-arylthioureas 193 bis(oxazolinyl)pyridinecerium(IV) triflate complex 389 bis(oxazolinyl)pyridinescandium(III) triflate complex 193 boron trifluoride lactone reactions 476–7 see also Boron trifluoride Brønsted acid 197 (t-BuCN)2 PdCl2 , hepta-1,6-diene cycloisomerization 480 4,4 -di-t-butylbiphenyl, chlorine-lithium exchange 458 by p-t-butylthiacalix[4]arene 408 C2 -symmetric auxiliary 7, 14, 16, 18, 33 in ketone reduction 40 by cerium(IV), Schiff base reactions 6 chiral 1,1 -binaphthyl-2,2 diammonium salt 405

by chiral 4-N ,N -dialkylaminopyridine acyltransfer 77 chiral Sn(IV) aryl oxide, in Diels-Alder reactions 401 cinchona alkaloid 11 aldol reactions 19 ketone cyanocarbonation 31 Mannich reactions 5 cinchonine 31, 341 copper in see Copper catalysis; Copper complexes Cp∗ RuCl(PPh3 )2 395 by CuSO4 .5H2 395 DABCO in 283, 351, 501 of Diels-Alder reactions 401, 402, 404–5, 406 by DMAP, anhydride acylation 59 by DMSO, aziridine reactions 245 L-DOPA-derived monopeptide (Y=NR2 )-Cu(II) complex 400 electrophilic, SN 1 reactions 253 and enantioselectivity 193–4 alkylation 193–4 aziridin-2-ylmethanols 193 and bis-arylthioureas 193 and bis(oxazolinyl)pyridinescandium(III) triflate complex 193 6 -OH Cinchona alkaloid derivatives 194 Cu(OTf)2 complex of (S)benzylbisoxazoline 194 hydroxyalkylation of indoles and aldehydes 194 2-methylproline 279 nitroalkenes 193–4 and pyrrole 193 by 9-thiourea Cinchona alkaloids 194 Zn(II) complexes of bisoxazolines 194 erbium(III) triflate, imine synthesis 3 by EtONa 456 by Eu(fod)3 , cycloaddition 389 by ferrocenyl-Pd(II) complexes 430 by gadolinium, aziridine ring opening 243 gold in see Gold catalysis

560 Catalysis (contd.) Grubbs 156 in ring opening/ring closing metathesis 485 in terminal alkyne insertion 488 by guanidine 31 guanidine 31, 358, 370 H3 PMo12 O40 in 195 H3 PW12 O40 in 195 by N -heterocyclic carbenes 25, 30, 32, 244 decarbonylation 42 heteropoly acids in 195, 349 in hydroxyalkylation, of furans 195 by IMePd(OAc)2 196 imidazolidinones 405 immobilized catalysts, ester preparation 32 by indium(III) triflate 63, 326, 476–7 intermolecular 54–68 iodine in 38 iodinium species in, FriedelCrafts acylation 34 [Ir(cod)Cl]2 -DPPE 407 iridium in see Iridium catalysis by iron, SN 2 substitutions 232 Lewis acid see Lewis acids lithium cations, ketone hydrogenation 39 l-proline, Mannich reactions 5 magnesium in 195, 243, 358 Mannich reactions 16 by (2S,3S)-3-methylazirin2-yl(diphenyl)methanol TFA salt 193 micelles in 257 by microporous metal-organic framework [Cu3 (btc)2 ] 463 nickel in see Nickel catalysis; Nickel complexes organo see Organocatalysis in oxirane ring opening 238–9 oxovanadium, Mannich reactions 5 palladium in see Palladium catalysis; Palladium complexes phase-transfer 257 crown ethers and glymes 68 phosphepine, cycloaddition 386 phosphinegold(I), tandem cyclopropanationhydroarylation 485 platinum in 392

Subject Index hydroformylation 102 potassium cations in 26, 37 by prolinamides 15, 355 proline in see Proline catalysis prolinol in see Prolinol catalysts pyrrolidine and perchloric acid in CH2 Cl2 196 [RhCl(CO)2 ]2 , cycloadditions 406 rhenium 338 terminal alkyne insertion 488 rhodium see Rhodium catalysis; Rhodium complexes ruthenium see Ruthenium catalysis; Ruthenium complexes by samarium diiodide 191 by samarium(III) iodide 196 scandium(III) triflate 342, 349, 392 silyl triflic imide 382 sodium cations in 26 stilbene oxide ring opening 239 superacids, intramolecular reactions 192 by taniaphos, in SN 2 substitutions 233 thiourea 11, 21, 26, 358 addition with 347–8, 357 aza-Baylis-Hillman reactions 351 derivatives 356 reductive amination 41 by 9-thiourea Cinchona alkaloids 194 tin(II) chloride 238, 465 tin(IV) chloride 193, 195, 324, 465 titanocene, in epoxide ring-opening 237 TMBOTf, aza-Diels-Alder reactions 406 TMSOTf, transannular cyclization 466 p-toluenesulfonic acid 189 propargylic alcohol reactions 236–7 by triphenylphosphine 371 tungsten, terminal alkyne insertion 488 by water aldol reactions 16, 18 nitrosomorpholine reactions 9 of [2,3] Wittig rearrangements 458

by ytterbium triflate 191, 346 see also Precatalysts Catalytic antibodies 420 Catalytic autoxidation 121 Catecholborane, redox reactions with 129 Catechols, oxidation of 101 Cationic micelles, SN 2 reactions with 256 Cationic [1,2]-migrations, dynamic NMR study 433 Cationic oxazaborolidine Lewis acids 405 Cationic rearrangements 461–70 Cation-π interactions 224 Cation pool method, diarylcarbenium ions from 208 Cations allylic charge distribution 370 cyclopropane ring opening gives 319 azatropylium-type radical 508 highly stable 207 silyloxy 41 see also Carbocations; Metal ions Cavitand 71 13 C chemical shifts 187 CCSD(T)/6 calculations 257 Centre-to-helix-to-centre chirality transfer 482 Ceric ammonium nitrate cycloaddition with 404 oxidation with 99 Cerium(IV) catalysis, Schiff base reactions 6 oxidation with 98–9 Cerium(IV) ammonium nitrate, aza-Michael addition with 343 Cerium(IV) perchlorate, oxidation with 99 Cerium(IV) sulfate (Ce(SO4 )2 ), oxidation with 98 Cetyltrimethylammonium bromide 69, 70 Cetyltrimethylammonium dichromate, oxidation with 91 C-H activation in arene hydroarylation 340 in aromatic systems 200 and carbene formation 156 C-H addition 372 Chalcone, alkylation of 195 Chalcones aziridination of 344 Et2 Zn addition to 362

561

Subject Index thiophenol addition to 341 Charge distribution, allylic cation 370 Charge separation, rearrangements and 442 Charge-transfer complexes in chlorination 188 Charge transfer in dichloroethene/cation reactions 318 Charlton’s steric factor 268 Chelating electrophiles, substitution with 191 Chelation, rhodium, in linalool hydroformylation 337 Chemical potential, nucleophilicity index (ω− ) and 258 Chemical shifts, 13 C 187 CH-insertion reactions, carbene and nitrene 153 Chiral 401 Chiral benzylic-type cations 205 Chiral bicyclic guanidine, catalysis by 370 Chiral 1,1 -binaphthyl2,2 -diammonium salt 405 Chiral copper(II) Schiff base complexes 402 Chiral 4-N ,N -dialkylaminopyridine acyl-transfer catalysts 77 Chiral ferrocenyl diphosphines, addition with 362 Chiral induction 5 Chiral ionic liquids and aza-Baylis-Hillman reactions 351 Michael addition in 355 Chiral iridium catalysts 233 Chirality, planar, N ,P -ferrocenyl ligand with 362 Chirality transfer axis-to-centre 485 centre-to-helix-to-centre 482 Chiral ligands addition with 346 carbene 363 TADDOL-derived phosphoramidite 363 Chiral lithium amide 361 Chiral pyrrolidine derivatives 431 Chiral Sn(IV) aryl oxide, catalysis 401 Chiral thiourea-based catalysts 357 Chiral tridentate bis(oxazoline) catalysts 368 Chloramine, oxidation with 109

Chloramine-B, oxidation with 107–8, 110 Chloramine-T oxidation with 107–8, 110 sulfamidation with 36 Chloride counterions, nucleophilic attack with 332 Chlorination 188 of aryl ethers 188 charge-transfer complex formation in 188 by 1-chlorobenzotriazole 188 with N -chlorosuccinimide 188 by 1,3-dichloro-5,5dimethylhydantoin 188 kinetics 188 of 2-naphthol 188 palladium catalysis 188 of phenol 188 Chlorine, electrophilic addition 319 Chlorine leaving group KIE 248 Chlorine-lithium exchange 458 Chlorins 403 Chlorite, oxidation with 107 2-Chloroacetamide lithium enolates 458 α-Chloroacetanilides 259 2-Chloroacetate lithium enolates 458 2-Chloroacrylonitrile 359 Chloroamidation, alkene 320 Chlorobenzene, nitration 187, 189 1-Chlorobenzotriazole chlorination 188 oxidation with 109 cis-Chloro/bromo(dodecylamine)bis(ethylenediamine)cobalt(III) 99 Chlorodiethylaluminium 368 β-Chlorodiisopinocamphenylborane 126 2-Chloro-4,6-dimethoxy-striazine 77 1-Chloroethyl p-tolyl sulfoxide 459 Chloroform, palladium complexes with 363 Chloroformates, aryl, aminolysis 58 1-Chloro-2-(hydroxymethyl)alkenyl p-tolyl sulfides 459 1-Chloro-2-methylalkenyl p-tolyl sulfoxides 459 [1,2]-Chloro migrations 435 [1,3]-Chloro migrations 435 [1,5]-Chloro migrations 435

N-Chloronicotinamide 42 oxidation with 108 m-Chloroperbenzoic acid, oxidation with 118 Chloropromazine, oxidation of 100 Chlorosuccinate/malate, interconversion 54 Chlorosuccinates, dianion substitution 266 N -Chlorosuccinimide, chlorination with 188 Chlorosulfonylation of calix[6]arenes 199 ipso substitution in 199 Chlorosulfonyldealkylation 199 Cholesterol, oxidation of 91 Choline, acetylation of 71 Chroman-2-yl hydroperoxides 464 Chromenes, epoxidation of 106 Chromic acid, oxidation with 93–5 Chromium species, oxidation with 91–5 Cieplak model 27 Cieplak’s hyperconjugation hypothesis 27 CI/MP through-space/bond interaction analysis 236, 267 Cinchona alkaloids 347, 348, 358 catalysis 11, 194, 359 aldol reactions 19 ketone cyanocarbonation 31 Mannich reactions 5 derivatives 6 -OH 194 catalysis by 403–4 Cinchona alkaloids, see also Cinchonine catalysis Cinchonidine derivatives, catalysis by 348 Cinchonine catalysis 341 aldehyde cyanation 31 see also Cinchona alkaloids Cinnamaldehyde, phenyllithium addition to 361 Cinnamate esters 368 Cinnamylamines, methoxyselenenylation of 322 cis-Hydroheteroarylation products 330 Cl2 Ti(O-i-Pr)2 , rearrangements with 463 Claisen condensation 33 acyclic alkynes from 280 Claisen rearrangements asymmetric 421

562 Claisen rearrangements (contd.) aza 430 decarboxylative 421 Ireland, ester enolate 423 Mg(II) promoted 423 propargyl 443 ring-expanding 423 thio- 443 [6,6] Closed methanofullerenes, formation 498 CN activation 330 C-N bond formation 353 Coarctate reactions 496 Cobalt Co2+ complexes of N -methyldiethanolamine 69 Co(II) complexes in Michael addition 350 in phosphate hydrolysis 84 in nucleophilic aromatic substitution 179 oxidation with 99–100 in styrene hydrovinylation 329 C-O bond cleavage 80 Cocyclization, 3 + 2 + 2- 409 Collisions in SN 2 reactions 261 Computational studies on cyclic alkenylides 502 enolates and ketone complexes 36 phosphate monoesters 80 see also Calculations; DFT studies; Models Concerted mechanism, Diels-Alder reactions 360 Conjugate addition 1,4-, Cu complexes in 317 carbanions generated by 458 lactams 342 Conjugated dienes, epoxidation 106 Conjugate reduction 351 Conjugative effects 187 Conrotatory pathways 437 Cooperative activation, electrophile 356 Cooperative effects in aldehyde addition 28 Cope elimination, N ,N -dimethyl3-phenyl-2-butylamine oxide 308 Cope rearrangements 385 3-aza, of allyl enammonium cations 471 aza-, in ring expansion 370 oxocarbenium ions in 210 oxonia- 426 Copper

Subject Index Cu(II), phosphorus atoms coordinate to 362 hydroamination with 339 oxidation with 97 Copper(II)-bis(oxazoline), catalysis by 349 Copper catalysis 190, 194, 236, 363, 392, 395, 398, 463 addition 361–3 allylic substutions 233, 236 conjugate addition 361, 362 Cu(II) cycloisomerization 477 oxidation 97 CuII (CuI ) chloride 330 Cu(MeCN)4 ClO4 -Taniaphos 392 diethylzinc addition 363 hydroxysulfenylation 338 in nucleophilic aromatic substitution 179 oxirane ring opening 241 in reactions of arenediazonium ions 175 Copper complexes 1,4-addition with 317, 362 Cu3 (benzene-1,3,5-tricarboxylate)2 , catalysis by 463 Cu(II) complexes amination with 369 in phosphate hydrolysis 84 Schiff base 402 of N ,N ,N ,N -tetramethylethylenediamine 71 (µ-η2 :η2 -)peroxo)Cu(II)2 complex 97 NHC-based, in conjugate addition 363 oxidation with 119 Copper(I) halide, catalysis by 236 Copper hydride, catalysis, conjugate reduction 363 Copper sulfate pentahydrate (CuSO4 .5H2 0), catalysis 395 Copper tetrafluoborate [Cu(BF4 )2 .nH2 O] 465 Copper thiophene carboxylate (CuTC) catalyst 231 Corey-Chaykovsky reactions 35 Corey-Winter-type reaction 154 Corner-protonated cyclopropane 222 Counterion effect 37 Counterions in Morita-Baylis-Hillman reactions 350 in nucleophilic attack 332

Coupling of enynes and allyl chlorides 329 Cp∗ RuCl(PPh3 )2 , catalysis 395 CR-CCSD(T) calculations on cycloaddition 381–2 Cross-conjugated dianions 278 Cross-conjugated enediynes 278 4 + 4-Cross-cyclomer adducts 411 Cross-interaction constants 259 Cross-metathesis, alkene 312 (E)-Crotonaldehyde, alkylation by 193 Crotonic acid, oxidation of 108 Crotonyl thiol ester, formation of 341 Crotyl alcohol, oxidation of 99 Crown ethers [18]Crown-6 77, 371 side-arm on 77 as phase-transfer catalysts 68 (−)-Cubebaol, synthesis of 409 Cu(MeCN)4 ClO4 -Taniaphos, catalysis by 392 Cumene hydroperoxide, oxidation with 116–18 [3]Cumulene, alkenylation by 191 Cumyl chloride, solvolysis 268 Cu(OAc)2 494 Cu(OTf)2 complex of (S)-benzylbisoxazoline, catalysis 194 Cu(OTf)3 190 Curtius rearrangements 471 azides 167 Cyanides, addition with 329, 368 α-Cyanoacetals, substitutions with 235 Cyanoacylation, ketone 31 3-Cyanoindoles 329 Cyanosilylation 31 Cyclen, appending amine arms to 83 Cyclen-based lanthanide complexes 83 Cyclic alkenylides, computational study on 502 Cyclic allylamines, addition with 370 Cyclic amides, Michael-like addition with 354 Cyclic amines 370 Cyclic ethers 237–43 Cyclic ketenimine 508 Cyclic-2 ,3 -ribose phosphate, DFT studies 81 Cyclic voltammetry on epoxide ring-opening 237

563

Subject Index Cyclization 193, 198 acid-catalysed 368 of alkynyl t-butylcarbonates 326 of allylic halides 326 in arylation 197 carboxylic acids in 323 of 2,2-difluorovinyl ketones 193 of enynes 481–2 HBF4 in 198 IPy2 BF4 in 198 in linalool hydroformylation 337 of oxidosqualene 469 Prins see Prins cyclization transannular, TMSOTf catalysis 466 trimethylsilylating agent in 193 triphenylphosphine in 350 Cyclization energy, oxidosqualene 469 Cycloaddition 379–413 2 + 2- 379, 381–6 of allylsilanes 382 of benzyne 385 CR-CCSD(T) calculations on 381–2 of dichloroketene 384, 385 of fuller-1,6-enynes 382 Lewis acid promoted 494 of methoxycarbonylcyclopent-2-en-1-one 384 polar stepwise 448 2 + 2 + 1- 406 2 + 2 + 2intramolecular 407 [Ir(cod)Cl]2 -DPPE catalysis 407 2 + 3- 379, 386–97 2 + 4- 397–406 3 + 1 + 1-, nickel catalysed 409 3 + 2- 480 of allenes 386 Au(III) catalysis 392 of 2-benzopyrylium-4-olates 389 of buta-2,3-dienoates 392 products of 370 Pt(II) catalysis 392 Rh(I) catalysis 386 thiatriazolines from 62 3 + 3-, azomethineimines in 409 4 + 2azirines in 491 carbenes in 157

of cyclohexa-2,4-dienones 403 DFT studies 398 hyperbaric 401 imines 406 intramolecular 381, 397 Lewis acids in 398 of o-quinone methides 404 4 + 2 + 1- 409 4 + 2 + 2-, rhodium(I) catalysis 409 4 + 3-, of furan 409 4 + 3/3 + 2- 379 4 + 4- 411 intramolecular, nickel(0) catalysis 411 5 + 2-, intramolecular 381, 413 5 + 5- 413 6 + 2- 413 6 + 3-, fulvenes 413 1,3-dipolar see 1,3-Dipolar cycloaddition in furan/1-alkylidene2-oxyallyl cation reactions 196 intramolecular see Intramolecular cycloaddition Cycloadducts, 3 + 2- 395 Cycloalkanones, oxidation of 98 Cycloalkylation 190 Cyclo alkyl carbenium ions 204–5 Cyclobiphenalenyls, rearrangements of 420 Cyclobutanones, 4 + 2 + 2-annulation 409 Cyclobutenes in enyne cyclization 482 exo- 383 formation of 479, 496 substituted 480 Cyclobuten-3-yl cation 213 Cyclobutylidene, rearrangements of 494 Cyclobutylidene hydrazine derivatives, synthesis 489 Cyclodextrins 389 α-cyclodextrin 16 in hydrolysis 68 Cycloheptadienes, formation of 409 Cycloheptanones, disubstituted 459 Cycloheptatriene radical cation, formation of 464 Cyclohexa-2,5-dienes desymmetrization of 457 hydroamination 291, 368

Cyclohexa-2,4-dienones, cycloaddition with 403 α-(Cyclohexanecarbonyloxy)acrolein 405 Cyclohexanol, oxidation of 98 Cyclohexene, rearrangements with 503 Cyclohexenone 335 Cyclohex-2-en-1-one, alkylation by 190 2-Cyclohexylidene-3,3-dimethylcyclopropanone acetal 492 Cycloisomerization of α-aminoallenes 485 Cu(II) catalysis 477 of 1,6-eneynamides 485 of enynes 339, 482 gold catalysis 485 of hepta-1,6-dienes 480 and tandem Prins-type cyclization 482, 485 Cyclooctatetraene, 6 + 2-cycloaddition of 413 Cyclooctene oxidation of 100 polymerization 486 Cyclopentadiene in Diels-Alder reactions 401, 404–5 and methyleneketene cycloaddition 403 Cyclopentadienyl cations 218 Cyclopenta[c]pyran-3-yl derivatives 197 cis-Cyclopentapyrazolidines 393 Cyclopentene, polymerization of 486 Cyclopentenone, sulfonium ylide reactions with 283 Cyclopentyldimethylmethanol, rearrangements of 468 Cyclopentylidene hydrazine derivatives, synthesis 489 Cyclopropanation of furans 163 mechanism for 479 of pyrroles 163 and tandem hydroarylation 485 Cyclopropane corner-protonated 222 ring opening, allylic cation from 319

564 Cyclopropanes cyclopentenone/sulfonium ylide reactions give 283 isomerization 479 Cyclopropenes addition to alkynes 334 disubstituted 389 Cyclopropylation 190 Cyclopropylcarbinyl cations 221 absence, in semibullvalene bromination 212 Cyclopropyl effect 288 Cycloreversion 309 intermediate oxetane 494 Cyclotransferase, model 77 Cyclotrimerization, camphor/Pd catalysis of 335 Cysteine, oxidation of 108 Cytochrome P450 enzymes 125

D DABCO and aza-Baylis-Hillman reactions 351 and isomerization 501 ester isomerization 283 Danishefsky’s diene 402 Daphnilactone B 379 Darzens reaction, aza- 10 Daurichromenic acid ester 383 Decarboxylation Claisen rearrangements with 421 of β-keto acids 80 of perbenzoate ions 179 Decontamination, nerve agents and pesticides 84 Dediazoniation 175 Dehydration, phenol alkylation with 323 α-Dehydroamino acids, synthesis of 363 Dehydrobrominative cyclization 271 Dehydrogenation, thionyl chloride mediated 198 Dehydroxymethylation, primary alcohol 314 Dendrimers, catalysis with 16, 26 Dendronic catalysts 354 Density functional theory see DFT studies Dentritic copper(II) triflate, catalysis by 398 Deoximation, oxidative, kinetic studies 13 Dephosphonylation 80 Dess-Martin oxidations 124

Subject Index Desulfovibrio desulfuricans, reduction by 141 Desymmetrization of cyclohexa-2,5-dienes 457 of prochiral diketoazides 30 Deuterium isotope effects Claisen condensation 33 competition studied with 308 hydrogen shifts 434 secondary α- 248, 249, 250, 267 secondary β- 248 see also Perdeutero KIEs Deuterium labelling (2 H) alkyl chloride 13 carbonyl reduction 42 ring enlargement 480 styrene conversion to acetals 2 see also Labelling Deuterium migrations in fluorination 188 Dewar-Chatt-Duncanson model 482 DFT studies β-(acetoxy)vinyl radical rearrangements 505 alkylation 38 ammonium ylide/ benzaldehyde reactions 34–5 ammonolysis, of phenyl formate 58 B3LYP/6–31+G(d) level, for cation formation 451 B3LYP/6–31G∗ , Rautenstrauch rearrangements 482 B3LYP tricyanomethanide carbanion structure 278 for 3-vinylmethylenecyclobutane rearrangement 503 B3LYP and ab initio MP2, Newman-Kwart rearrangements 498 benzilic acid-benzil rearrangement 454 bicycloketone oxidation 43 carbon bond cleavage 494 C-H activation in aromatic systems 200 cyclic-2 ,3 -ribose phosphate in 81 cycloaddition 398 3 + 2- 62 Diels-Alder reactions 402, 404–5

electrophilic aromatic substitution 187 enols 37 epoxide migrations 458 epoxide ring-opening 237 ethylene phosphate in 81 ethyne-linked phenyltriazene formation 494 Fries rearrangements 451 gas-phase studies, hydrolysis of phenyl hydrogen-maleates 55 hetero-Diels-Alder reactions 402 hydrosilylation, carbonyl compounds 33 hyperfine coupling constants, carbenes 155 imine structures 6–7 iminium ion formation 9 keto-enol tautomerization 37 ketone reduction 40 β-(nitroxy)vinyl radical rearrangements 505 oxidosqualene cyclization energy 469 phosphine ligands, and ethylene insertion 333 proline catalysed aldol reactions 19 ruthenium-β-stannylvinylidene complexes, formation 486 SN 2 reactions, ethylene oxide 242 Stevens rearrangements 507 sulfonylimine allylation 8 β-sultam ring opening 68 type I-dyotropic 501 Wittig reactions 30 see also B3LYP; Calculations (Diacetoxy)iodobenzene, oxidation with 110 4-N ,N -Dialkylaminopyridine acyl-transfer catalysts 77 N ,N-Dialkylsulfamide 86 Diallenes, DFT studies on 436 Diamidobinaphthyle dilithium salt, proline-derived 368 Diamine salts, binaphthyl-based, catalysis by 405 1,6:2,3-Dianhydro-β-dhexopyranoses 458 1,6:2,4-Dianhydro-β-dhexopyranoses 458 Dianions α,β-, imine and hydrazone reactions with 290 cross-conjugated, formation 278

565

Subject Index 4,4 -Diansylcarbenium ion 258 Diarylamines, substituted, metallation with 454 5,7-Diaryl-2-fluoro-4H -1,3diazepines 491 Diarylmethanols, formation of 295 α,α-Diarylprolinol 77, 346 3,3-Diarylpropanals, formation of 366 Diastereoselectivity alkylation 191 and carbonyl compound reduction 38–41 Diazabenzenes, electrophilic substitution with 187 Diazirines as carbene precursors 153 Diazo intermediates in azine formation 13 α-Diazo ketones, Wolff rearrangement of 461 DIBAL, reduction with 126, 127 Dibenzotetraazafulvalenes, rearrangements of 423 Dibenzoylketene 452 Dibromoacetic acid 313 gem-Dibromospiropentanes, rearrangement with 494 2,3-Dibromothiophene, arylation with 197 Dicationic electrophiles 192 Dicationic intermediates 38 Dicationic species, superacid-promoted 461 Dications 218–20 1,3-Dichloro-5,5-dimethylhydantoin chlorination with 188 oxidation with 107 Dichloroketene 385 2 + 2-cycloaddition 384, 385 N ,N -Dichloro-p-toluenesulfonamide 333 α,α-Dicyanoalkenes, addition of 346 Diels-Alder adducts 370 1,3-diphenylisobenzofuran 452 Diels-Alder products 372 Diels-Alder reactions accelerating 400 [AlCl3 + 2THF] catalysis 398 azaCAN-initiated 406 inverse-electron-demand 406 aza hetero-, aldimines 406 of cyclopentadiene 397 DFT studies of 404–5

enantioselective 401 furans and nitroacrylate 360 heteroaldehydes in 43 1-aza-3-siloxybuta-1,3dienes in 403 chiral copper(II) Schiff base complexes catalyse 402 competing with alkynylboration step 367 paracyclophane-othioquinone 403 high-pressure 401 homo-, in bicyclo[5.3.0]decane formation 314 hydrophobic effects in 401–2 intramolecular 397 inverse electron-demand 309, 406 organocatalysis 404–5 retro- 309, 360 of N -sulfonyl-1-azabuta1,3-dienes 403 transannular 400 triflic imide in 406 Dienes conjugated, epoxidation 106 Danishefsky’s 402 Dienophiles, anthrone reactions with 370 Dienylboronate esters, addition of 367 1,3-Dienylsulfone, addition to 353 Diesterase activity 70 Diesters, phosphate 81–4 Diethers, monodealkylation of 270–1 Diethylaminosulfur trifluoride, alkylation with 190 Diethyl malonates, oxidation of 94 Diethylsilane, reduction with 140 Diethylzinc addition to imines 363 reduction with 142 Diffusion control, azide trapping experiments with 217 2,2-Difluorovinyl ketones, cyclization of 193 gem-Dihalogenospiropentanes, rearrangement of 496 Dihalospiropentanes, rearrangement of 494 Dihydric phenols, oxidation of 92 5,6-Dihydro-1H -azocinones 385

2,3-Dihydrobenzofurans 388 3,4-Dihydroisoquinoline-2oxides, rearrangement 494 1,4-Dihydronaphthalene-1,4epoxide 465 3,4-Dihydropyrimidin-2(1H )ones, oxidation of 99 p-Dihydroquinones 398 Dihydroxydiperiodatoargentate(III) 98 Dihydroxydiperiodatonickelate(IV) 97 Dihydroxyditelluratoargentate(III) 98 Dihydroxylation 102 of alkenes 102, 317 1,ω-Diiodoalk-1-ynes, cyclization of 369 Diisobutylaluminium hydride, reduction with 127 1,3-Diketones, oxidation of 96 Dimethyl acetylenedicarboxylate see DMAD Dimethyl alkylidene malonates, alkylation by 196 4-Dimethylaminopyridine see DMAP 4,5-Dimethyl-2-aminothiazole 187 N,N-Dimethylaniline reaction with methyl 3,3,3trifluoropyruvate 191 zincation of 200 Dimethyl-N,N -dichlorohydantoin, oxidation with 107 Dimethyl-N ,N -dichloroisocyanuric acid, oxidation with 107 Dimethyldioxirane epoxidation with 114 oxidation with 492 N,N-Dimethylethanolamine, esterification with 54 α,α-Dimethylglycines 74 5,5-Dimethyl-pyrroline N-oxide see DMPO N,N-Dimethylsulfamoyl chloride solvolysis 67

566 4,6-Dinitrobenzofuroxan electrophilic aromatic substitution with 187 formation of Diels-Alder adducts 184 formation of hydroxy-adduct 184 reactions with aminothiazoles 183 reactions with indoles 195–6, 199 substitution in 7-chloro derivatives 184 superelectrophilic 183, 197 1,3-Dinitro compounds, synthesis of 368 1,1-Dinitrocyclopropane 248 4,6-Dinitroindoles, N -substituted 359 2,4-Dinitrophenyl benzenesulfonate 67 2,4-Dinitrophenyl carbonates, aminolysis 61 Di(4-nitrophenyl) methylphosphonate, oximate anion reactions with 84 Di(4-nitrophenyl) phenylphosphonate, oximate anion reactions with 84 Di(p-nitrophenyl) phosphate 81 Diols, oxidation of 97, 98, 101, 108 Dioxaphosphacycles derived phosphonium salts 405 Dioxins 179 dihydroxylation of 102 Dioxiranes, oxidation with 113–14 Dioxocyclam, Ni(II) complexes with 69 Dioxygenase enzymes 124 Diperiodatoargentate(III), oxidation with 97 Diperiodatocuperate(III), oxidation with 97 (R)-2,2-Diphenylcyclopentanol 385 Diphenyl diselenide, hydrostannylation with 327 1,3-Diphenylisobenzofuran Diels-Alder cycloadducts 452 o-Diphenylphosphanylbenzoyl leaving group 233 Diphenylphosphinylallenes, hydroarylation 338 Diphenylprolinol catalyst 356 Diphenyl sulfoxide, oxidation of 107–8

Subject Index Diphosphines, hydroformylation with 337 1,3-Dipolar cycloaddition of adamantylidenefulvene 389 α-alkoxycarbonylnitrones 389 of C-aryl-N -phenylnitrones 389 of azomethine ylides 379, 392 of 1-benzyl-2-phenyl-3oxidopyridinium betaine 395 BINOL catalysis 397 of imines 393 Dipolar electrocyclic ring opening 448 1,5-Dipolar (six electron) electrocyclization 438 Diradical calderas, kinetic studies of 435 Diradical intermediates 505 Diradical pathways in 3-vinylmethylenecyclobutane rearrangement 503 Diradical processes, sceptrin rearrangements with 503 Diradical species, rearrangements with 435 Direct dynamics simulation 264 Directed lithiation 285–7 Dirhodium species, catalysis with 153 Disastereoselectivity in furan hydroxyalkylation 195 in furan-2-ylhydroxyacetic acid ester formation 195 Disilyl cations 211 exo-anti-Dispiroisoxazolines 388 Dispiropyrrolobicyclo[2.2.1]heptanes 379 Disrotatory ring opening 448 N -Ts-α,α-Disubstitutedaziridinemethanols 458 N -Boc-α,α-Disubstitutedaziridinemethanols 458 2,7-Disubstituted cycloheptanones 459 3,3-Disubstituted cyclopropenes 389 N ,N -Disubstituted o-phenylenediamines 389 Disulfides, hydroxysulfenylation with 338 Dithiolane, thiophene derviatives from 342–3 Divinylcyclopropanes, sigmatropic rearrangements 409

1,3-Diynes, rearrangement of 487 Di(zinc[9]ane-N3) complex, catalysis with 83 Di(zinc[12]ane-N3) complex, transesterification with 83 DMAD 379, 385 cycloaddition with 392 DMAP catalysis, anhydride acylation 59 DMPO radical traps 471 DMSO catalysis, aziridine reactions 245 DNAs, single-stranded 83–4 Dodecacarbonyltriruthenium, hydroamidation with 335 Domino reactions aldehydes in 345 annulation of o-alkynylbenzaldehydes 480 quinone methides in 352 L-DOPA-derived monopeptide (Y=NR2 )-Cu(II) complex 400 Double α-ketol rearrangement 454 Double SN 2-type process, in isomerization reactions 63 Double Stevens rearrangements, rhodium(II)-carbene mediation 487 DPEphos, vinylarene hydroamination with 337 Dual activation, substrate, Michael addition with 348 Dyads, porphyrin-based 393 Dynamic calculations, SN 2 reactions, methyl chloride 266 Dynamic kinetic resolution, reductive amination 41 Dynamic NMR study of cationic [1,2]-migrations 433 Dyotropic rearrangements 501

E E1cB mechanisms 307 in X-phenyl N-(4-thiocarboxamidophenyl)carbamate conversions 64 in N -thiazolylcarbamate hydrolysis 61 E2cB mechanisms 307 E2 mechanisms 307–8 chloride reactions 248 competing, and 1,4-benzenedimethanol catalysis 257 Eberlin reaction 2

567

Subject Index E (electrophilicity parameter) 258 Ef (electrofuge-specific parameter) 258 Efficiency, reaction 248, 259 Eight-membered carbocycles, synthesis 482 Electrocyclic rearrangements 437–41 Electrocyclic ring expansion 439 Electrocyclic ring opening 419 Electrocyclization [1,7]- 439 of bisallene 437 1,5-dipolar (six electron) 438 metal vinylidene complexes in 419 of vinylallene 437 Electron charge transfer mechanism 266 Electron-donating substituents 333 Electronic effects and SN reactions 252 trimethyl groups, and solvolysis rate 255 Electronic energies, transition state 344 Electronic interaction and lactone route 267 Electron-rich aromatics, alkylation of 190, 191 Electron Spin Resonance (ESR) data, carbene 155 Electron transfer in epoxide ring-opening 237 fulleroid rearrangements 498 gas-phase substitution 251 in nitration 189 Electrophile activation 356 Electrophilic addition 318–40 ArSeX in 321–2 ArSX in 321–2 electrophilic carbon in 324 halogenation, and related reactions 318–21 hydrogen halides in 322–3 metals in 324–40 Electrophilic aromatic substitution 187–200, 301–2 acylation 187, 197 alkenylation 191 alkylation 187, 190–1, 192, 193, 195, 196 aza-polycyclic compound synthesis 192 azo coupling, of substituted benzenediazonium cations 199

benzene in 187 bromination 188, 190 chelating electrophiles in 191 chlorination 188 chlorosulfonylation 199 conjugative effects 187 cycloalkylation 190 cyclopropylation 190 DFT studies 187 diazabenzenes in 187 dicationic electrophiles 192 electrophilicity index 187 enantioselectivity in 193–4 five-membered heterocyclic substitution 193 hydroxyalkylation 194 imines in 194 and indole 193 and indoles 194 and N -methylindole 193–4 and N -methylpyrrole 193 nitroalkenes in 193, 194 2-nitroethenylcyclohexane in 193 N -PhSO2 -phenylimines in 194 and N -sulfonyl aldimines 194 and α,β-unsaturated aldehydes 193 Zn(II) complexes of bisoxazolines 194 fluorination 188 fluorodesilylation 188 frontier orbital control in 187 Fukui indices 187 furan 187 halogenation 188 hydrogen-deuterium exchange 199 inductive effect parameters 187 iodination 188 ipso substitution in 199 molecular orbital calculations 187 of monosubstituted benzenes 187 nitration 187, 189–90 palladation 197 protonation 199 of 5-substituted indoles 195–6 of 5-substituted 2-methylindoles 195–6 proton migration 187 pyridine-N -oxide 187 pyrrole 187 reactivity parameters in 196

steric hindrance, methyl group 196 sulfonation 199 superelectrophilic 4,6-dinitrobenzofuroxan 187 thiophene 187 trimethylsilylation 199 Electrophilic carbenes 171 Electrophilic catalysis, SN 1 reactions 253 Electrophilic cyclization 322 Electrophilic fluorination, aromatic compound 216 Electrophilicity correlation with Hammett σ values 258 global descriptors 2 Electrophilicity index 187 Electrophilicity parameter (E) 258 Electrostatic potential, endo-tricyclooctene 319 Elimination 307–15 Cope, N ,N-dimethyl-3phenyl-2-butylamine oxide 308 in synthesis 312–14 Enamine catalysis in alkylation 38 in Michael reactions 26 Enamine mechanism 35 ketone/nitroalkene addition 356 Enamines in carbonyl reactions 10, 14 heterocyclic, addition of 346 substituted, generation 35 Enantioselectivity in aldehyde addition 28 in alkylation 191, 193–4 aziridin-2-ylmethanol 193 of p-bromobenzyl phenyl ether 190 Cu(OTf)3 in 190 by ethyl 3,3,3-trifluoropyruvate 190 of indoles 194 of simple aromatic ethers 190 in amide hydrogenation 134 in arene reactions 191 and Aza-Claisen rearrangements 430 carbonyl compound reduction 38–41 and 6 -OH Cinchona alkaloid derivatives 194 in ester aminolysis 71

568 Enantioselectivity (contd.) five-membered heterocyclic substitution 193 in imine reactions 194 in indole reactions 194 and pyrrole 193 Encounter complexes 252 aziridine reactions 246 methyl chloride reactions 261, 262 polyfluorosulfonate ester reactions 266 stability compared 259 6-Endo-dig cyclizations 481 7-Endo-tet ring closure 492 6-Endo-trig closing transition 503 5-Endo-trig cyclization 507 Ene-allenes, ene reactions with 441 Enecarbamates, amination 369 Enediynes, cross-conjugated, cycloaromatizations 278 Ene reactions 441–2 Energy activation see Activation energy cyclization, oxidosqualene in 469 electronic, transition state 344 free energy see G = Pauling-Wheland resonance, aromaticity from 218 photon, dichloroethene/cation reactions 318 potential energy surfaces see Potential energy surfaces solvation, halides in SN 2 reactions 253 strain energies, aziridines 246 Energy barriers 59, 246, 253 1,6-Eneynamides, cycloisomerization of 485 Enoate systems, addition with 458 Enolates 279–83, 361 rearrangements 458 Ireland-Claisen ester enolate 423 Enol carbonates, formation of 326 Enolization 36–7 Enol phosphates, oxidation of 97 Enol silyl ethers, new route to 347 Enones alkylation with 190, 195 nitroalkane addition to 346 Enthalpy see H =

Subject Index Entropy see S = Enynes coupling with allyl chlorides 329 cyclization of 481–2 cycloisomerization 159, 339, 482 5-En-1-yn-3-ols, cycloisomerization 477 Enzymes 70 aldolases, screening in water 14 alkaline phosphatase 70 carboxypeptidase, hydrolysis with 70 carboxypeptidase A inhibitors 78 cytochrome P450 125 dioxygenase 124 in nucleophilic aromatic substitution 179 reductase studies 141–2 Epimerization, azetidinium ion 248 Episulfonium ions, formation of 244 Epithuriferic acid 398 Epoxidation of alkenes 92, 99, 100, 104–5, 106–7, 114 of arenes 499 of benzylidenecyclobutane 489 of chromenes 106 of conjugated dienes 106 dimethyldioxirane in 114 oxone in 104–5, 106 Epoxide migration 458 Epoxides 241–3 acid cleavage of 320 aryl, alkylation with 190 pentannulation with 480 rearrangements 465 ring opening 141, 466 by thiolate ions 367–8 5-exo-tet 472 studies 237 see also Oxiranes 2,3-Epoxycyclopentanols, rearrangement of 465 α,β-Epoxy ketones, hydrogenation of 137 Epoxy-Ramberg-Bäcklund reaction 283, 313, 492 Epoxysilanes 458 α,β-Epoxy sulfones 283, 313, 492 4,5-Epoxy-9-trimethylsilyldecalines, rearrangement of 461

Epoxytwinol A, biosynthesis of 411 Epoxyvinyl sulfones, SN 2 reactions with 239, 241 ESR data, carbene 155 Esters 2-acetyl-1-hydroxyanthraquinone 453 α-allyloxy, enolate rearrangement gives 458 α-amino, formation 191 in biologically significant reactions 71–4 cinnamate, reaction with lithium pentamethylcyclopentadienide 368 enantioselective aminolysis of 71 furan-2-ylhydroxyacetic acid, formation of 195 hydrolysis, nucleophile isotope effects 70 α-hydroxy, formation 191 γ -hydroxy-α,β-acetylenic, isomerization 501 in intermolecular catalysis 55–8 in Ireland-Claisen ester enolate rearrangements 423 α-keto in hydroxyalkylation 194 oxidation of 96 linear, formation of 334 oxidation of 96, 103 phosphate diesters 81–4 phosphate monoesters 79–80 polyfluorosulfonate, SN reactions of 266 solvolysis, secondary isotope effects 55 spiroborate, reduction with 127 sulfamate 85 anti-cancer drugs 86 sulfate monoesters 85 Et2 Zn 368 conjugate addition with 361, 362 Ethanediol, oxidation of 98 Ethers alkylation of 190 monodealkylation of 270–1 aryl, chlorination of 188 p-bromobenzyl phenyl 190 chlorination of 188 cyclic 237–43

569

Subject Index diethers, monodealkylation of 270–1 enol silyl, new route to 347 α-lithiated allyl phenyl 452 resorcinol dimethyl ether 190 tertiary cyclopropyl silyl 190 see also Crown ethers Ethylene, polymerization 327–8 Ethylene oxide SN 2 reactions 242, 267 see also Oxirane Ethylene phosphate, DFT studies on 81 Ethyl glyoxylate 191 and indole reaction 194 5-Ethylidene-2-norbornene, formation of 503 Ethyl p-nitrophenyl phosphate 84 Ethyl 3,3,3-trifluoropyruvate 190 Ethyne-linked phenyltriazenes 494 Ethynylphenyltriazenes, homocoupling of 494 EtONa catalysis 456 ET values, solvent 255 Eu(fod)3 catalysis in cycloaddition 389 Eu(NTf)2 catalysis in acylation 197 Exo-2-chloro-5-norbornene 463 6-Exo-dig cyclizations 481 7-Exo-dig cyclizations 481 8-Exo-dig process 481 5-Exo-tet ring opening, epoxide 472 Exothermicity, nucleophilicity and 259 5-Exo-trig attack on sulfur 445 5-Exo-trig spirocyclization 507

F Facial selectivity, π- 18 Favorskii reactions 25–6 Felkin-Anh models 18, 20, 27 Femtosecond pump-probe laser excitation 315 Ferrocenyl diphosphines, chiral 362 N ,P -Ferrocenyl ligands 362 Ferrocenyl-Pd(II) complexes, catalysis by 430 Fischer carbenes 161, 409 Fischer indole synthesis 426 Five-membered heterocyclics, substitution in 193 Flash photolysis, benzyl cations in 205 Flash pyrolysis and carbene reactions 154

in sulfenic acid synthesis 311 Flash vacuum photolysis (FVP) 312 Flash vacuum thermolysis (FVT), phenyl group 1,3-shifts in 452 2-Fluorenylnitrenium ion 216 Fluorides, organic, formation 249 4-Fluorinated 3-acyl-1,2dihydronaphthalenes 193 Fluorinated aziridine 246 Fluorinated nucleophiles, epoxide reactions with 241 Fluorinated vinyloxiranes, ring-opening 239 Fluorination 188 α- 37 carbonyl compounds 301 electrophilic, aromatic compounds 216 hydrogen and deuterium migrations 188 kinetic isotope effects 188 N-F-type reagents 188 SE Ar mechanism 188 Selectfluor in 188 of 1,3,5-trideuterobenzene 188 Wheland intermediates 188 Fluorine 18 F, in PET studies 249 oxidation of 92 Fluoroalkanesulfonyl azides 472 Fluorodesilylation 188 Fluorogenic probes 14 Foiled carbenes 502 Formamide, hydrolysis of 59–60 Formamides as nucleophiles 353 N -substituted, hydroamidation with 335 Formates Fries rearrangements of 451 hydrolysis, nucleophile isotope effects 56 Formic acid 141 Formic acid-triethylamine hydrogenation with 141 reduction with 140 Formylating agents 451 Formyl chloride, in situ release of 451 Fragmentation, carbene 165 Free ion nucleophiles 253, 254, 263 Friedel-Crafts acylation, iodinium promotion of 34 Friedel-Crafts reactions 212 diarylmethanes formed with 492

enone cyclization 350 indoles in 349 Fries rearrangements N -, anionic ortho 454 of aryl formates 451 lithium diisopropylamide in 451 Frontier orbital theory 187 and reactivity-selectivity principle 269 Front-side attack 250–1, 265 Front-side encounter complexes 259 Front-side SN 2 reactions 266 d-Fructose, oxidation of 98 Fukui functions, nitroalkene 353 Fukui indices 187 Fullerenes C20 319 C60 , cycloaddition with 395 C70 382 cycloaddition with 395 methanofullerenes, [6,6] closed 498 Fuller-1,6-enynes, 2 + 2-cycloaddition 382 Fulleroids, aryl-substituted [6,5] open 498 Fulvenes, 6 + 3-cycloaddition 413 Fumaric acid, oxidation of 99 Functionalized hydantoins, formation of 453 Furan alkenylation of 191 with 1-alkylidene-2-oxyallyl cations 196 electrophilic aromatic substitution 187 reaction with 1-acetylvinyl acrylates 196 2-Furancarbonyl chloride, solvolysis 58–9 Furans addition of 323 hydroxyalkylation of 195 Furan-2-ylhydroxyacetic acid esters 195 Furfural, oxidation of 107 (E)-3-Furfurylindene-4chromanone 379 (E)-Furfurylindene-1-tetralone 379 Fusicoccin, synthesis of 411

G G2 calculations 259, 267 G2MP2 calculations, carbamic acid and chalcogenide analogues 310

570 G3(MP2) calculations, reaction pathways compared 300 G3m calculations, SN fluoride reactions 265 G = aziridine ring opening 246 and 1,4-benzenedimethanol catalysis 257 ethylene oxide reactions 242 HF/fluoride reactions 265–6 SN 2 reactions benzyl bromide and bromide/pyridine 254 nitrobenzyl bromide and mercaptobenzoxazole 255 SN reactions at phosphorus 252 solvent effects 254 Gadolinium, catalysis, aziridine ring opening 243 Gallium triiodide, catalysis by 349 Gas phase, protonated aromatic molecules in 199 Gas phase cations 318 Gas phase measurements 248, 251 Gas phase reactions 250–1, 254 1-arylethanol SN 1 methanolysis 250 lactone route 267 methanol fluorination 264 MP2 calculations on 265 SN 2 reactions 250–1 cyanate ion pairs in 263 cyanate/methyl halides 263 water/methyl chloride 264 SN reactions 265 Gauss-Newton method 322 Gearing effects, diastereoselectivity 29 Geminal bis-hydroperoxides, formation of 464 Geminal dicarboxylates, alkylation of 102 Gemini surfactant 69 Generation, carbene 155–6 Germylenes 171 Gibbs free energy see G = Glucose, anomerization of 3 d-Glucose, hydrocyanation with 329 Glutamic acid, oxidation of 108 Glycine methyl ester, hydrolysis 71 Glycogen phosphorylase inhibitors 388

Subject Index Glymes, phase-transfer catalysis with 68 Glyoxylic imines 191 Gold carbene species, rearrangement with 487 Gold catalysis 481 Au(III) 349 annulation reactions 481 cycloaddition 392 3,3-rearrangement 482 AuPPh3 SbF6 complex 386 cycloisomerization α-aminoallenes 485 1,6-eneynamides 485 1,5-enyne 482 in enyne cycloisomerization 159, 339, 482 hydroamination with 317, 338–9 hydroarylation with 339 nitrene transfer reaction 168 Gold complexes 386, 481 Gold-coordinated allenes 426 Gold(I) chloride precatalysts 485 Gold(II) chloride, catalysis 481 Gold iodide in annulation reactions 481 as gold(I) precatalysts 485 Graham reaction 153 Green chemistry and ketone oxidation 42 Grignard reagents addition with 29 1, 4- 292, 362, 363, 368 in allylic substitutions 233, 235 copper, oxirane ring opening 241 copper-catalysed allylic substitutions 233 copper (I) halide-catalysed substitutions 236 direct synthesis 291–2 in epoxyvinyl sulfone reactions 241 in SN 2 reactions 241 SN 2 substitutions with 231, 233, 235, 236 in SN reactions 257 Grob fragmentation 469–70 of carbocations 223 Gross-Butler equation 56 Group 4 metals, and β-hydrogen transfer, alkene polymerization 328 Group 13 trihalides, alkylation with 190 Group III metal complexes, hydroamination with 337

Group transfer in electrophilic addition 328 Group VIII metals, oxidation with 100–3 Grubbs catalysts carbene reactions 156 in ring opening/ring closing metathesis 485 in terminal alkyne insertion 488 Grubbs cross-metathesis 336 Grubbs-Hoveyda catalyst, carbene reactions 156 Grunwald-Winstein equation 67, 255 Guanidine 31, 358, 370 Guanine, SN 2 reactions with 242, 267

H

H = in aryloxirane ring opening 238 SN 2 reactions and anionic nucleophiles 269 benzyl bromide and bromide/pyridine 254 cyanate/methyl halides 263 Halides acid halides 58–9 alkyl, alkylation with 190 allylic, cyclization 326 group 13 tri-, alkylation with 190 m-hexyl, SN 2 reactions with 253 hydrogen, additions of 322–3 Haloamidation, alkene 320 α-Halo enones, conjugate addition with 361 Halogenated carbocations 211–12 Halogenation 188 of arenes 188 of 5,6-bis(dimethylamine)acenaphthylene 188 α-halogenation 37–8 by N-halogens 188 by N-halosuccinimides in 188 palladium-catalysed 188 proton sponge 188 and related reactions 318–21 Halogen-bridged cations 451 Halogens in oxidation 107–12 SN reactions at 251 see also Chlorine; Fluorine; Iodine

571

Subject Index Halonium ions, structure calculations 318–19 N -Halosuccinimides 188, 320 Hammett constants, SN 2 reactions, benzyl bromide/pyridine 254 Hammett equation/plots 254, 385 and aminochlorination 329 Claisen condensation 33 ketenimine series 3 SN V reactions, substituted Meldrum’s acid 260 Hammett ρ values aminal formation 165 ρ+ , aryloxirane ring opening 237–8 ρ + , cumyl chloride solvolysis 268 SN 2 reactions, diphenylamine/substituted benzyl bromides 260–1 SN V reactions 260 solvolysis 261 Hammett σ values azo coupling and transition states 199 correlation with electrophilicity 258 and σ + benzylic cations 206 SN 2 reactions 254 Hammond effect 269, 319 Hammond-Leffler effect 260, 269 Hantzsch ester 41, 351 reductive aminations with 138 Hardness, nucleophile 269 and nucleophilicity index (ω− ) 258 Hard-soft acid-base (HSAB) principle 342 Hartree-Fock quantum method, Diels-Alder reactions 397 HC(OMe)3 in alkylation 191 Head-to-tail coupling 507 Heck reaction 165, 180 of aryl iodides 333 model for 333 triethoxy(vinyl)silane/aryl cyanide reaction 329 Hemiaminals, as ketimine precursor 3 Henry reaction 284 Hepta-1,6-dienes, cycloisomerization of 480 Herrmann-Beller phosphapalladacycle 334 Hetereodinuclear complexes 358

Heteroarenes, hydroheteroarylation 330 Heteroatom-stabilized species 283–5 Heterocycles aza-Michael addition with 343 nucleophilic aromatic substitution 181–3 Pummerer rearrangements of 470–1 N -Heterocyclic carbenes 153 catalysis by 25, 30, 32, 244 decarbonylation 42 Cu complex, in conjugate addition 363 as metathesis catalysts 486 promote rearrangements 500 Heterocyclic enamimes, addition of 346 Hetero-Diels-Alder reactions aldehydes in 43 1-aza-3-siloxybuta-1,3-dienes in 403 chiral copper(II) Schiff base complexes in 402 competing with alkynylboration step 367 paracyclophane-o-thioquinone 403 Heteropoly acids, catalysis by 195, 349 Hexacyanoferrate(III), oxidation with 101–2 Hexahydroindoline derivatives, formation 485 Hexahydropyridazine derivatives, formation of 409 2,3,3a,4,5,6-Hexahydropyrrolo[3,4-c]pyrazoles 389 Hexaimidazolecobalt(III), oxidation with 100 Hexamine, oxidation of 96 9,10,11,12,13,14-Hexaphenylcycloocta[1]phenanthrenes 379 H-exchange 199 5-Hexenylsilane, polymerization with 327–8 m-Hexyl halides, SN 2 reactions with 253 1-Hexynyllithium, cyclization with 369 HF calculations micelles 256 SN 2 reactions, ethylene oxide 242 SN reactions cyclohexanone acetals 261 silylated 5-fluorouracil 271

HF-SbF5 , rearrangements with 470 Highly stable cations 207 Hiscotropic reactions 221 Hiscotropic rearrangements 419 [hmim][PF6 − ] ionic liquid 405 HNTf2 , acylation with 197 Hoffman elimination, DFT on 314 Hofmann-Martius rearrangement 465 Homoallenylazines, intramolecular cycloadditions of 461 Homoallylic alcohols, Prins cyclization 324 Homocoupling cyclobutenes dimers 496 ethynylphenyltriazenes 494 Homocysteine 73 Homo-Diels-Alder reactions 314 Homo(polyprenyl)arenes, polycyclization of 192 Homotriptycenes, formation of 191 H3 PMo12 O40 (heteropoly acid), catalysis by 195 H3 PW12 O40 (heteropoly acid), catalysis by 195 Hughes-Ingold rules 268–9 Hydantoins, formation of 453 Hydration, terminal alkyne 335 Hydration shell, bromide ion nucleophile 256 Hydrazine hydrate, reduction with 142 Hydrazones 13–14 Hydrices, Michler’s 41, 125 Hydride abstraction 41 β-Hydride elimination, inhibition of 332 Hydrides copper, conjugate reduction with 363 metal activity 503 reduction by 126–33 see also Anhydrides Hydride shifts 1,3-, and vinyl cations 214 1,5in dimethylheptyl cations 204 quantum chemical study of 469 intramolecular 469 Hydride transfer 1,4-, in sesquiterpene trichodiene formation 222

572 Hydride transfer (contd.) and zeolite-catalysed butane reactions 212 µ-Hydrido-bridged carbocations 204 Hydroacylation alkenes 31 carbonyls 31–2 Hydroalumination, propargylic alcohol 326 Hydroamidation, alkene 335 Hydroamination aminoalkenes 368 α-aminoallenes 485 anti-Markovnikov reactions 336 cyclohexadiene 323 cyclohexa-2,5-dienes 368 of dienes 331 copper and gold in 339 gold in 317, 338–9 group III metal complexes catalyse 337 intramolecular, iron salts in 328 lanthanide complexes catalyse 337 lutetium ionic complexes in 340 norbornene 323 palladium complexes catalyse 332, 337 titanium catalysis, alkenes 327 of vinylarenes 331 ytterbium complexes in 340 Hydroarylation bismuth in 340 cyclohexadiene 323 of diphenylphosphinylallenes 338 gold in 339 norbornene 323 and tandem cyclopropanation 485 ynamides 323 Hydroboration of acetophenone 127 borane in 324 (−)-isopinocampheylborane in 324 rhodium catalysis 325 thexylborane in 324 Hydrocyanation 30 1,2-bisdiarylphosphinites in 329 Hydroesterification, alkene 335 Hydroformylation 32, 337–8 of linalool 337 of norbornadiene derivatives 337

Subject Index phosphorus ligands in 337 rhodium in 337–8 synthesis with 32 Hydrogenation 133–41 of alkenes 134–5, 136 of amides 134 of N-arylimines 136–7 of α,β-epoxy ketones 137 of styrenes 338 transfer 137–41 of α,β-unsaturated acids 134 Hydrogen bonding and C-H activation 200 in Michael addition 348 and Morita-Baylis-Hillman adducts 351 and sigmatropic rearrangements 431 and solvents 269 Hydrogen-deuterium exchange 199 Hydrogen halides, additions of 322–3 Hydrogen migrations [1,4]- 438 fluorination 188 Hydrogen peroxide in epoxidation 114 alkene 99, 100 in nucleophilic substitutions 176 oxidation with 111, 114–15 aromatic compounds 96–7 cyclooctenes 100 Hydrogen phosphonates 335 Hydrogen shifts 1,2- 419, 494 and addition to alkynes 336 3,3-diphenylcyclobutylidene in 166 [1,5]- 419, 434, 508 Hydrogen transfer 137 1,5-, 508 alkylation 196 β-, alkene polymerization 328 in hydrostannylation 327 indole alkylation with 349 Hydroheteroarylation, alkynes, nickel catalysis 329 Hydrolysis acid-catalysed, formamide, KIE studies 59 alkaline aryl esters, ortho substituent effect in 57 N -benzylphthalimide 60 imides 60 rate prediction 55 of amides 59

nucleophile isotope effects 70 esters nucleophile isotope effects 70 ortho substituent effect in 57 silyl 233 formates, nucleophile isotope effects 56 N-propionyl-imidazole derivatives 61 N-thiazolylcarbamates 61 Hydrometallation, reviews of 317 Hydroperoxide ion 67 Hydrophobic effects in aldol reactions 16 and α-cyclodextrin 16 in Diels-Alder reactions 401–2 Hydrophosphorylation 335 Hydrosilanes, reduction with 139 Hydrosilylation carbonyl compounds 32–3 iridium catalysis 338 mechanism reviews 317 nitriles in 129 of styrenes 338 Hydrostannation, alkyne 317 Hydrostannylation, diphenyl diselenide in 327 Hydrovinylation, styrene 329 Hydroxamates, double-headed, reactivities 69 Hydroxamic acids 71 Hydroxyacetophenones 358 γ -Hydroxy-α,β-acetylenic esters 501 N-(2-Hydroxyacetyl)-2pyrrolidone 76 Hydroxy acids, oxidation of 101 α-Hydroxyaldehyde, thermolysis of 311 Hydroxyalkylation 194, 195 of aldehydes 194 disastereoselectivity in 195 of furans 195 of indoles 194 magnesium salt catalysis 195 MgBr2 catalysis 195 by (1R-)-8-phenylmenthyl glyoxylate 195 SnCl4 catalysis 195 β -Hydroxy-β-amino acid derviatives 389 Hydroxyamino acids, carbonate group migration 500 α-Hydroxy β-dicarbonyl rearrangement 461

573

Subject Index α-Hydroxy esters, formation of 191 N -(2-Hydroxyethyl)carbamates 74 Hydroxyl group, nitration with 189 6-Hydroxy-4-methylcyclohex-1enecarboxyaldehyde 409 (−)-6-Hydroxy-4-methylcyclohex-1-ene-1-methanol acetate, synthesis of 409 6[(2-Hydroxyphenyl)ethynyl] purines 480 N-(2-Hydroxyphenyl)phthalamic acid 60 2-Hydroxypropyl p-nitrophenyl phosphate 82, 83 1,2-Hydroxysulfenylation, disulfides in 338 Hydrozirconation 328 Hyperbaric 4 + 2-cycloaddition 401 Hypochlorous acid, oxidation with 107

I Ibuprofen, oxidation of 101 IMePd(OAc)2 , catalysis by 196 Imidazole, Markovnikov addition of 323 Imidazole groups 199 Imidazolidinone catalysis 345, 405 Imidazolium fluorochromate, oxidation with 93 Imidazolium salts 153, 169 Imides alkaline hydrolysis 60 anti-Markovnikov addition 335 triflic 382, 406 Imidoyl(benzoyl)ketene, phenyl group 1,3-shifts 452 Imines 3–12 enantioselective reactions of 194 glyoxylic 191 reduction of 8–9 synthesis and tautomerism 3–4 Iminium ions, formation of 351 Iminium species 9–10 in situ generation 344 in Michael addition 346 in nitroalkane addition 346 Iminocyclitol, rearrangements of 472 Iminocyclopropenes, rearrangement of 490

Iminophosphoranes, formation of 73 Immobilized catalysts 32 2-Indan-1-yltetrahydrofuran products 332 Indene ring system 191 Indeno[1,2-c]isoquinolones, formation of 198 Indenylidene-ruthenium complexes 486 Indium(III) bromide, cyclization with 326 Indium(III) chloride in epoxide ring opening 368 halide cyclization 326 thiolacetic acid addition 326 Indium(I) iodide 326, 367–8 Indium(III) triflate lactone reactions 476–7 thiolacetic acid addition 326 thionolactone isomerization 63 Indium(III) trifluoromethanesulfonate see Indium(III) triflate Indole alkylation of 193, 194, 195, 196 and ethyl glyoxylate reaction 194 hydroxyalkylation of 194 Indole o-quinodimethanes 388 Indoles 194, 195–6 addition of 323, 346, 348, 349 alkylation of 194, 195, 196 alkyne-tethered, annulation reactions 481 arylation of 196 enantioselective reactions 194 formation of 195–6, 326 hydroxyalkylation of 194 3-indolylmethanamines from 194 reactions with 4,6-dinitrobenzofuroxan 195–6, 199 3-substituted 196 5-substituted 195–6 Indolizidines, substituted, synthesis 342 Indolizine-7-carboxylates, formation of 371 Indoloazocines, formation 481 β-Indolyl ketones 196, 349 3-Indolylmethanamine derivatives 194 3-Indolylmethanamines 194 Indomethacin 75–6 Induction asymmetric 18, 322 chiral 5

see also Stereoinduction Inductive effects 246 Ingold-Hughes mechanism 215–16 Initial encounter complexes 261 Instantaneous rate constants 55 Interactions, transition state puckering and 30 Interconversion, malate/chlorosuccinate 54 Intermediates α-acylvinyl anions 21 diazo, in azine formation 13 dicationic 38 enamine 14 carbonyl transformations with 10 zwitterionic, in aza-Baylis-Hillman reactions 21 Intermolecular reactions 54–68 oxirane SN 2 234 Intramolecular alkylation 191 to 1-alkoxy-2-alkylindenes 191 to homotriptycenes 191 of 10-(3-methoxybenzyl)-9,10dihydroanthacen-9-ols 191 of α-methylcinnamaldehyde 191 Intramolecular arylation 197 Intramolecular cycloaddition 381, 397 2 + 2-, photochemical 382 2 + 2 + 2 - 407 3 + 2 - 391 4 + 2- 381, 397 4 + 4-, nickel(0) catalysis 411 5 + 2- 381, 413 of homoallenylazines 461 nickel(0) catalysis 411 of vinylcyclopropanes 413 Intramolecular Diels-Alder reactions 397 Intramolecular hydride shift 469 Intramolecular mechanisms, oxirane SN 2 reactions 234 Intramolecular O-N alkoxycarbonyl (carbonate → carbamate) migration 74 Intramolecular rearrangement, carbonates of 2-amino alcohols in 74 Intramolecular substitution cyclic ether reactions 243 molecular, indene rings from 191 nucleophilic aromatic 178

574 Intramolecular substitution (contd.) SN 2 mechanism, alkyllithium/dihaloalkene intermediates 267 Intrinsic nucleophilicity 259 Intrinsic reaction coordinates 264 Intrinsic reactivity 259 Inverse electron-demand Diels-Alder reactions 309, 406 N -Inversion energy barriers, aziridine ring opening 246 Iodate, oxidation with 111–12 Iodination 37–8, 188 α-iodination 37–8 by iodine 188 by iodine monochloride 188 molecular orbital calculations 188 by NaIO4 -KI-NaCL 188 of 2-nitroaniline 188 palladium catalysis 188 of pyridine 188 of pyridine N -oxide 188 of quinoline 188 of quinoline N -oxide 188 Iodine addition of 320 catalysis by 38 in situ IF generation with 319 iodination by 188 iodocyclization with 321 oxidation with 110, 368 Iodine monochloride iodination by 188 iodocyclization of diethyl allenic difluorophosphonates 321 Iodinium catalysts, Friedel-Crafts acylation with 34 Iodocyclization, stereocontrol in 320 Iodonium ylides, conversion of 486 Iodosobenzene, oxidation with 110 Iodotrimethylsilane, Beckmann rearrangements with 473 Ionic liquids in allylation, carbonyl compounds 22 in aza-Baylis-Hillman reactions 21, 351 Grignard cross-coupling, alkyl halides 293 in hydroamidation 323, 335

Subject Index in hydroarylation 323 and imidazolium salts 153 immobilized catalysts, ester preparation 32 in ketone reduction 40 1-methylpentylimidazolium bromide ([pmim]Br) 464 Michael addition in 346–7, 355 aza- 343 Michaelis-Arbuzov rearrangements in 477 in Morita-Baylis-Hillman reactions 21, 350 nucleophilic reactivities 175 as oxidizing agent 42 in phase-transfer catalysis 257 SN 2 reactions in, rates 268–9 and stereoselectivity 430 substitutions by amines in 181 thiophenol addition in 341 Ionic rearrangements 453–77 Ionization energy, nucleophile, in SN 2 reactions 259 Ion pairs interactions, in aza-Baylis-Hillman reactions 21 as nucleophiles, in SN reactions 253, 254, 263 trapping agents, triphenylverdazyl 269 Ionzation rates, benzhydryl leaving group 258 Ipso adducts, formation 187 Ipso substitution in chlorosulfonylation 199 and chlorosulfonyldealkylation 199 fluorodesilylation 188 [Ir(cod)Cl]2 -DPPE, catalysis by 407 Ireland-Claisen ester enolate rearrangements 423 Iridium catalysis 233 in arylboronic acid addition 367 hydrosilylation 338 in imine reduction 8 substitution, phosphoramidite ligands 233 Iron Fe(II), oxidation of 99 FeIII -OOH complex, oxidation by 101 ferrate(VI), oxidation with 101 intramolecular hydroamination 328

SN 2 substitution catalysis 232 Iron(III) chloride (FeCl3 ) 480 in aminochlorination 328 intramolecular hydroamination 328 IR spectroscopy for protonated aromatic molecules 199 on seleneocyclization 321 Isatins, oxidation of 108 Isobacteriochlorins 403 Isobutene intermediate 191 2-Isobutylphenol 191 2-Isobutylphenols, formation 323 Isobutyric anhydride, acylation of 59 Isochromene carboxylates, preparation of 368 Isocyanates, cycloaddition of 407–8 Isokinetic temperature, SN 2 reactions and 260–1 l-Isoleucine, oxidation of 96 Isomerizations 494–502 cyclopropane rings 479 Isonicotinate, oxidation of 97 (−)-Isopinocampheylborane 324 Isopropenyl chloroformate 58 Isotope effects nucleophile in aldehyde addition 27 and formate hydrolysis 56 primary, tautomerization 36 secondary, in amide hydrolysis 59 see also Kinetic isotope effects (KIEs) Isotopic labelling see Labelling Isovaleric anhydride, acylation of 59 trans-Isoxazolidines 389

J Josiphos 335 PPF-P(t-Bu)2 analogue for 363

K Kamlet-Taft equation 269 Ketene acetals, addition to pyridines 370 Ketene-Claisen reactions 3 Ketene-Cope reactions 3 Ketenes 3, 122 Ketenimines 3, 508 β-Keto acids, decarboxylation of 80 α-Ketoaziridines, formation of 344

575

Subject Index α-Keto esters 96 in hydroxyalkylation 194 α-Ketol ester 461 α-Ketol rearrangement, double 454 Ketone enolates, C-C bond formation using 233 Ketones addition 27–36 aldol reactions 14–21 Baylis-Hillman reactions 21–2 Michael additions 26–7 alkylation of 38, 196 alkynylations 25–6 allylation 22–4 aromatic, in Diels-Alder reactions 398 benzocyclic, formation of 198 condensation with sulfones 43 2,2-difluorovinyl, cyclization of 193 enolization 36–7 halogenation 37–8 hydrogenation 39–40, 133–4 α,β-epoxy ketones 137 nitro, formation of 356 oxidation 42–3, 92, 99, 100 1,3-diketones 96 reduction 38–42 (E)-α,β-unsaturated 196 β-Ketophosphonic acids 80 Ketoximes 94 Beckmann rearrangements 475 KIEs see Kinetic isotope effects Kinetic isotope effects (KIEs) aldehyde/chromate reactions 42 aqueous aldol catalysis 15 chlorine leaving group 248 deuterium Claisen condensation 33 competition studied with 308 hydrogen shifts 434 secondary α- 248, 249, 250, 267 secondary β- 248 fluorination 188 formamide hydrolysis 59 glucose anomerization 3 nucleophile carbon 248, 250 organometallic protonation 199–200 perdeutero, chloride reactions 248, 251 SN 2 reactions 248–50 cyanide ions and ethyl chloride 255

solvent, fluoride ions/methyl halide reactions 249, 267 see also Isotope effects Kinetic resolution 317 Kinetics [1,5]-hydrogen shifts 434 azo coupling, benzenediazonium cations 199 carbocation reactivity 208–9 chlorination 188 epoxide ring-opening 237 indoles/benzyhydryl cations reactions 195 and isomer preference 336 ring contractions 468 SN 1 hydrolysis 269 SN 2 reactions cyclic sulfamidate 270 rates and anionic nucleophiles 268 solvolysis, (S)-1-(3-nitrophenyl)ethyl tosylate 267 THF formation 267–8 Knoevenagel condensation 34 amide anologues in 281 K-Selectride 40

L Labelling aza-Baylis-Hillman reactions 351 deuterium (2 H) alkyl chloride 13 carbonyl reduction 42 ring enlargement 480 styrene conversion to acetals 2 hepta-1,6-diene cycloisomerization 480 oxygen (18 O) carbonyl reduction 42 solvolysis, (S)-1(3-nitrophenyl)ethyl tosylate 267 oxygen, in carbonyls 12 Lactams 77–9 α, β-unsaturated δ-, nucleophile reactions with 342 α-alkylidene, synthesis 479 β-, formation, TADDOL in 272 δ-, alkylation of 231 in intermolecular catalysis 59–60 Lactones 71–4

αin chlorosuccinate dianion substitution 266 in malate/chlorosuccinate interconversion 54 βin chlorosuccinate dianion substitution 266 enolate intermediate 370 in malate/chlorosuccinate interconversion 54 γ - 389 Lactonization, silyl enolates in 348 Lancifodilactones, synthesis of 413 Langevine dipole (LD) methods 242 Lanthanide complexes, hydroamination with 337 Lanthanoid triflate catalysis 342 (+)-Lasubine II, synthesis of 408 Lead tetraacetate, oxidation with 100 Leaving group effects benzhydryl leaving group 258 benzoate isomerization 233–4 organic fluoride formation 249 SN 1 reactions, solvolysis half-life 258 SN 2 reactions aziridine 246 cyanate/methyl halides 263 SN 2 substitutions 236 Leaving groups, o-diphenylphosphanylbenzoyl 233 l-Leucine, oxidation of 96 l-t-Leucine, oxidation of 96 Levoglucosenone 398 Lewis acids 197 cationic oxazaborolidine 405 in cycloaddition 398 2 + 2-, promotion 494 in Diels-Alder reactions 401 highly selective catalysis 463 in SN reactions 239 LIC-KOR mixture, Wittig rearrangements with 458 Ligands aminohydroxyphosphine 362 bidentate phosphine 333 bis(oxazoline) 317, 349 bis(phosphine)amide, cobalt in 329 carbene 156–7, 363 chiral 363 addition with 346 N ,P -ferrocenyl 362 Martin 312

576 Ligands (contd.) Me3 P 330 phosphine, and ethylene insertion 333 phosphoramidite 233, 329 phosphorus 337 tri(cyclopentyl)phosphine 330 tridentate palladium, in hydroamination 332 Linalool, hydroformylation of 337 Linear collisions in SN 2 reactions 261 α-Lithiated allyl phenyl ethers 452 Lithiation of aryltriazenes 456 directed 285–7 ortho- 7, 285 1-Lithiobuta-1,3-dienes 379 N -Lithio-2-piperidone 459 Lithio 2-pyrrolidone, catalysis by 458 Lithium chlorine-lithium exchange 458 in ketone hydrogenation 39 Li-carbenoid intermediates 496 reductive ring opening with 143 Lithium alkoxides 143 Lithium aluminium hydride, reduction with 126 Lithium amide, addition of 369 Lithium aminoborohydrides 126 Lithium diisopropylamide 451 Lithium enolates addition with 361 2-chloroacetamide 458 2-chloroacetate 458 protonation 299–300 Lithium pentamethylcyclopentadienide 368 Lithium α-sulfinyl carbanions 459 Lumiflavin, oxidation with 119 (±)-Lupinine, formation of 406 Lutetium ionic complexes 340

M Magnesium hydroxyalkylation with 195 Mg(II), Claisen rearrangements with 423 with zinc, dinuclear complex 358 Magnesium bromide (MgBr2 ), hydroxyalkylation with 195

Subject Index Malate/chlorosuccinate, interconversion 54 Maleic acid, oxidation of 99 l-(−)-Malic acid, chiral ionic liquid from 351 (S)-Mandelic acid 346 Manganese in electrophilic addition 328 imido complex 328 ions and related species, oxidation with 95–7 Manganese(III) acetate, oxidation with 96 Manganese dioxide (MnO2 ), oxidation with 124 Manganese(III) porphyrins, oxidation with 96–7 Manganese(III) pyrophosphate, oxidation with 96 Mannich reaction 5–6 stereocentres formed by 351 d-Mannitol 93 Manzacidin A 397 Marcus theory 251 Markovnikov isomers 321 Markovnikov reactions carbenes in 157 cyclization 337 N -heterocycles in 323 hydroamination 338, 339–40 Pd[(−)-sparteine]Cl2 complex in 330 of phenols 322 styrene addition 328 styrene hydroarylation 340 thiolacetic acid addition 326 Martin ligand, 1,2-oxaphosphetane with 312 Massadine 393 Mass spectrometry Morita-Baylis-Hillman reactions 351 nitration 189 protonated aromatic molecules 199 Ziegler-Natta polymerisation intermediates 328 Matrix isolation, characterization with 311 Mayr, reviews by 208 Mayr equation 208 Me3 Al, conjugate addition with 361 Me3 P ligand 330 Me18 OH2 + , methanolysis with 250 (MeCN)2 Rh(COD) 366 Medium effects 253–5 see also Solvent effects

Meerwein-Ponndorf-Verley (MPV) reductions 137 Meinwald rearrangements 465 Meisenheimer complexes 183–5 Meldola Blue, oxidation of 107 Meldrum’s acids, substituted, aminolysis of 315, 341 2-Mercaptobenzaldehyde in domino reactions 345 Mercury triflate (Hg(OTf)2 ) cyclization with 326 rearrangements with 452 O-Mesitylenesulfonylhydroxylamine 344 Mesoionic 1,3-dioxolium-4olates 385 ortho-Metalation, sulfoxides in 287 Metal hydrides activity of 503 reduction by 126–33 Metal ions in electrophilic addition 324–40 oxidation by 91–103 see also Cations Metallacyclobutane intermediate 156 Metallo-azomethine ylides 393 Metallotropic [1,3]-shift 487 Metal nitrates, nitration by 189 Metal perchlorates, SN 2 reactions with 253 Metals in electrophilic addition 324–40 ions see Metal ions Michael addition with 345 see also by name of metal Metal vinylidene complexes 419 Metaphosphate 80 Metathesis carbenes in 153 ring closure/opening 485, 486 self-, alkene 312 in terminal alkyne insertion 488 Methane, oxidation of 100 Methanofullerenes, [6,6] closed 498 Methanol, oxidation of 98 Methionine 93, 102 Methionine methyl ester hydrolysis 71 2-Methoxyazepinium ion 216 10-(3-Methoxybenzyl)-9,10dihydroanthacen-9-ols 191 Methoxycarbonylation 334 2-Methoxycarbonylcyclopent-2en-1-one 384

577

Subject Index p-Methoxycinnamate, formation 341 p-Methoxycinnamide, formation 341 N -Methoxyindoles 395 4-Methoxyphenyl tosylate 197 Methoxyselenenylation 322 [1,5]-Methoxy shifts 434 N -Methylaniline, nitration of 189 (2S,3S)-3-Methylazirin-2-yl(diphenyl)methanol TFA salt 193 1-Methylbenzylamines, phosphoramidite ligands from 329 S-Methyl chlorothioformate (MeSC(O)Cl) 65 α-Methylcinnamaldehyde, alkylation with 191 Methyl 8-dimethylamino1-naphthyl phosphate 81 S-Methyl 2,4-dinitrophenylthiocarbamate 64 Methylene Blue, reaction with thiourea 107 exo-Methylenecyclopentanes 392 Methylenecyclopentanone, formation of 409 Methylenecyclopropanes aminochlorination 328 cycloaddition with 409 ring enlargement 479 Methyleneketene, cycloaddition with 403 9-Methylenephthalimidines 388 N-Methylformamide, addition of 335 2-Methylfuran 191 N -Methylindole alkylation of 193–4 derivative 330 2-Methylindoles, 5-substituted 195–6 N -Methylnaphthalene-1,8dicarboximide 382 2-Methylpentane-2,4-diol, oxidation of 101 Methyl phosphate, hydrolysis of 79 2-Methylproline, enantioselectivity increase with 279 N -Methylpyrrole, alkylation of 193 3-Methylsulfinyl-6-methylthio1,2,4,5-tetrazine 406 2-Methyltetrahydrofuran 243 Methyl 3,3,3-trifluoropyruvate 191

3-Methyl-δ-valerolactam 77 N -Methyl-N-vinylacetamide 406 Micelles 255–7 ninhydrin reactions in 4 in nucleophilic heteroaromatic substitution 182 reverse 179, 256 in nucleophilic aromatic substitution 179 Michael addition aldehydes in 26 aza- 317 7-azaindole in 349 azanorbornyl derivatives from 344 cerium(IV) ammonium nitrate in 343 ketones in 26–7 metal-catalysis 346 thia-, thiophene derviatives 342–3 Michael adducts 360, 370 Michaelis-Arbuzov rearrangements 477 Michael-like addition, oxazolidinones in 354 Michler’s hydride 41 oxidation of 125 Microphases amine catalyst 15 in Michael reactions 26 Microporous metal-organic framework [Cu3 (btc)2 ] 463 Microreactors 328 Microscopic rate constants 55 Microwave 1,3-dipolar cycloaddition 389 Migrations 1,2carbanion 454 tosyl group 352 1,2-prenyl 442 1,2-silyl 433 [1,3]-trimethylsilyl 434 [1,4]-hydrogen 438 1,5-enyne cycloisomerization 482 [1,5]-oxygen 465 alkyl, aryl borane reactions 476 carbonate group, hydroxyamino acids 500 carboxy group 482 cationic [1,2]-, dynamic NMR study 433 chloro 435 epoxide 458 hydrogen 188, 438

phenyl, and alkyl-aryl borane reactions 476 proton 187 stannyl group 336 Migratory aptitudes, Baeyer-Villiger oxidation 42 Migratory insertion, ethylene 333 Mislow-Braverman-Evans rearrangement 459 Mixed anhydrides 54, 61 Mixed micelle systems 256 Mobius antiaromatic species 218 MO calculations see Molecular orbital (MO) calculations Models breathing orbital valence bond (BOVB) model 253 PCM see PCM model solvent reaction field (SCRF) 242 valence bond-polarized continuum (VBPCM//BOVB) 253 see also Calculations; Computational studies Molecular complexes, endo-tricyclooctene 319 Molecular modelling, ab initio 28 see also Calculations; Models Molecular orbital (MO) calculations alkylation 190, 196 C-H activation in aromatic systems 200 electrophilic aromatic substitution 187 iodination 188 ketone hydroboration 40 nitration 189 trimethylsilylation of N-alkylpyrroles 199 of pyrrole 199 see also Calculations Molecular oxygen, oxidation with 121, 123 Molecular rearrangements 451–508 anionic 453–61 aromatic 451–3 cationic 461–70 ionic 453–77 organometallic compounds 477–88 pericyclic molecular rearrangements 419–48 ring opening 488–94 see also Rearrangements

578 Molybdenum catalysts, oxidation with 100 Monodealkylation, diether 270–1 Monoesters phosphate 79–80 sulfate 85 Monosubstituted benzenes, electrophilic aromatic substitution 187 Morita-Baylis-Hillman adducts 351 Morita-Baylis-Hillman reactions 21, 281, 350–1 aza- 21, 22, 351 MP2/6–311++G(d,p)/MP2(FC)/ 6–31G(d), hydroxyaldehyde thermolysis 311 MP2 calculations on BF3 complexes 242 carbamic acid, and chalcogenide analogues 310 cyanate ion pairs/methyl fluoride 263 ethyl chloride reactions 248 fluoride ions/methyl halide 249 hydroxyaldehyde thermolysis 311 lithium-bromide exchange reaction 288 reaction pathways compared 300 SCS-MP2 calculations 386 SN 1 hydrolysis 233 SN 2 reactions alkyllithium/dihaloalkene intermediates 267 cyanate/methyl halides 263 direct dynamics simulation 264 methyl chloride 261 SN reactions 246 fluorides in, gas phase 265 and reactivity 265 MPWB1K/6 calculations, aziridine ring opening 243 Mukaiyama aldol reactions 18 Multiple bonds, additions to 341–52

N Naphthalene, zincation of 200 2-Naphthol, chlorination with 188 Naphthoporphyrins, formation of 403

Subject Index Naphthoxazine ring systems, tautomerism of 502 Native chemical ligation 71–2 Natural bond orbital analysis in carbonyl addition 27 CI/MP through-space/bond interaction 236, 267 Nazarov reaction 437 aza- 437 DFT for 213 Neighbouring group participation enol reactions 37 and Perkin condensation 34 silyl, in solvolysis 261 SN hydrolysis at silicon 251 Nerve agents, decontamination of 84 Newman-Kwart rearrangements 498 Nf (nucleofugality) 258 N-F-type reagents 188 NHC see N -Heterocyclic carbenes N-H insertion, dihydropyrazine from 162 Nickeladihydropyran 391 Nickel boride, reduction with 130–1 Nickel catalysis addition 365 in 1-alkylstyrene hydrovinylation 329 alkynylboration 324 allyl chlorides/enynes coupling 329 in allyl cyanide addition 329 in aryl cyanide addition 329 cycloaddition 409 hydroheteroarylation, of alkynes 329 Ni(0) hydrocyanation 329 intramolecular 4 + 4cycloaddition 411 rearrangements, 1-acyl-2vinylcyclopropanes 477 Ni(II), in imine reduction 8–9 Nickel complexes addition with 365 Ni2+ , of N-methyldiethanolamine 69 Ni(II), with dioxocyclam 69 oxidation with 97 Nickel(II) nitrate, nitration by 189 NIH rearrangement 499 Nile Blue, oxidation of 107

Niobium(V) pentachloride 270–1 Nitrates metal, nitration by 189 radicals, oxidation with 103 reduction 141 Nitration 187, 189–90 of aromatic amines 189 of benzyl alcohol 189 of benzyl fluoride 189 of calix[4]arenes 190 of calix[6]arenes 190 of catalytic p-toluenesulfonic acid 189 of chlorobenzene 187, 189 by Cu(NO3 )2 189 electron transfer 189 electrophilic aromatic substitution 187 fluorine atom substituent effects 189 hydroxyl group in 189 mass spectrometry 189 by metal nitrates 189 of N -methylaniline 189 MO calculations 189 by Ni(II) nitrate 189 in a nitric acid-mineral acid system 189 nitrodebromination 190 by nitrogen dioxide 190 to nitro-N-methylanilines 189 nitronium ion in 189 to o-nitrophenol 189 of phenol 189 of phenols 189 polar mechanism 189 by PPh3 -Br2 -AgNO3 189 regioselectivity in 189 of toluene 187 p-toluenesulfonic acid catalysis 189 of 4,4 ,4 -tribromotriphenylamine 190 of triphenylamine derivatives 189 Nitrenes 153–4, 167–9 Nitrenium ions 216–17 Nitrile oxides 388 aryl 388 Nitriles, α,β-unsaturated, oxidation of 102 Nitrile ylides, cycloaddition of 392 β-Nitroacrolein, addition to 354 3-Nitroacrylate, Diels-Alder reactions with 360 Nitro aldol reactions 19 Nitroalkanes, addition of 317, 346

579

Subject Index Nitroalkenes acylation of 358 addition to 353, 354, 355–6, 358, 368 by aldehydes 355 alkylation by 193, 194 in Michael addition 346–7, 358 acceptor abilities 353 2-Nitroaniline, iodination of 188 N -p-Nitrobenzenesulfonylimines 351 Nitrodebromination 190 2-Nitroethenylcyclohexane 193 Nitrogen carbonyl derivatives 3–14 see also Hydrazones; Imines; Oximes SN reactions at 252 Nitrogen dioxide nitration by 190 oxidation with 103 Nitrogen k 14 /k 15 KIE 250 Nitro-group displacement 178 Nitro ketones 356, 357 γ - 347 β-Nitro-meso-tetraphenylporphyrin 403 Nitro-N -methylanilines, nitration to 189 Nitrones, addition to 7 Nitronium ion 189 o-Nitrophenol, nitration to 189 4-Nitrophenyl benzoate 62 p-Nitrophenyl N ,N -dimethylcarbamate 61 4-Nitrophenyl diphenyl phosphate 70, 84 p-Nitrophenyl diphenyl phosphate 70, 84 p-Nitrophenyl ethylphosphonate 84 S-(4-Nitrophenyl) 4-methylthiobenzoate 62 4-Nitrophenyl phenyl carbonate, aminolysis 63 4-Nitrophenyl phenyl thionocarbonate, aminolysis 63 p-Nitrophenyl picolinate 69 4-Nitrophenyl 4-toluenesulfonate 67 O-4-Nitrophenyl X-thionobenzoates 62 Nitroso aldol reactions 19 Nitroso group, [1,3]-sigmatropic rearrangements 431 β-Nitrostyrene alkylation by 195

Michael addition with 347, 356 β-Nitrostyrenes, addition to 354, 355, 358 2-Nitrovinylarenes, addition to 354–5 β-(Nitroxy)vinyl radicals 505 NMR spectroscopy 75 As, on arsa-Wittig reaction 312 11 B, addition reactions 282–3, 346 diether monodealkylation 271 dynamic, cationic [1,2]-migrations 433 epoxide reactions 241 7 Li, n-BuLi basicity 288 17 O, arsa-Wittig reaction 312 31 P Cu-catalysed substitutions 233 diene reactions 332 seleneocyclization 321 N (nucleophilicity parameter) 258 (E,E,E)-Nona-1,6,8-trienes 400 Non-covalent organocatalysis 356 Non-linear collisions in SN 2 reactions 261 Non-linear effects aldehyde addition 28 autocatalysis by pyrimidyl alcohols 29 negative, phenylboronic acid addition 365 Norbornadiene addition to 334 aryl cyanides add to 329 isomerization of 464 Norbornadienes cycloadducts from 314 derivatives, hydroformylation 337 Norbornane-carboxaldehydes 337 Norbornene, addition to 329, 355, 367 Norbornene adduct 403 Norbornenylidene 502 l-Norleucine, oxidation of 96 Nortricyclyl cations 221 3-Nortricyclyl chloride 463 Nosiheptide, synthesis of 403 Novocaine, hydrolysis 71 Nuclear Magnetic Resonance see NMR spectroscopy Nucleofugality index, new empirical 64

Nucleofugality (Nf ), leaving group 258 Nucleofugality scale 208 Nucleophile carbon KIE 248, 250 Nucleophile isotope effects amide hydrolysis 70 ester hydrolysis 70 formate hydrolysis 56 phosphate hydrolysis 66 α-Nucleophile reactivities 69 Nucleophiles carbon in aziridine ring opening 247 in oxirane ring opening 243 fluorinated, epoxide reactions 241 hardness 258, 269 silylated, ring opening with 244 SN 2 substitutions 233 SN reactions 257–8, 259, 268–9 ion pairs 253, 254, 263 sulfur-stabilized 342 see also Grignard reagents Nucleophilic additions 341–72 to multiple bonds 341–60 conjugated with C=O 341–52 to activated double bonds 361–7 Nucleophilic aliphatic substitution 231–76 aziridines in 241–2, 243–7 C-C bond forming 231–3 cyclic ethers 237–43 on elements other than carbon 251–3 gas phase reactions 250–1 kinetic isotope effect studies 248–50 kinetic studies 272–3 micelles 255–7 polymers from 272–3 structure effects 257–61 theoretical studies 261–7 Nucleophilic aromatic substitution 175–85 base catalysis 176 in chromium tricarbonyl complex 180 heterocyclic systems 181–3 Meisenheimer complexes 183–5 nitro-group displacement 176 oxidative substitution of hydrogen 180 SN Ar mechanism 175–81

580 Nucleophilic arylation, benzaldehyde 36 Nucleophilic carbenes 169–71 Nucleophilicity 257–9, 268–9 and exothermicity 259 factors determining 259 and hydrogen bonding to acids 258 relative to electrophiles 258–9 solvent effects, carbanion nucleophiles 255 and solvolysis 255 Nucleophilicity index 64 ω− 258–9 Nucleophilicity parameter (N ) 258 carbocation-nucleophile combinations 208 indoles/benzyhydryl cations reactions 195 Nucleophilicity parameter (S) 195 Nucleophilicity scale 258–9, 267 Nucleophilic substitution aliphatic 231–76 aromatic 175–85 in carbocation reactions 204 Nucleosides 3 C-nucleosides 389

O Olefinations, aldehydes in 24 O(3 P) atoms, reactions of 122 o-Phenylenediamines, N ,N -disubstituted 389 Organic fluorides, formation 249 Organic solvents, absence of, cycloaddition 392 Organoboronic reagents, cyclization with 334 Organocatalysis 32 addition azole to allenes 371 Cinchona alkaloids 347, 348 malonates to enones 346 Michael addition 26, 346, 354–5, 356 thiourea 357 aldehyde domino reactions 345 aldol reactions 14–16, 19 alkylation 38 arylimine reduction 9 cascade 348 chiral bifunctional catalysts 356 Diels-Alder reactions 404–5 enamine-based 15 α-halogenation 37

Subject Index imidazolidinone catalysts 345 lactonization 348 non-covalent 356 oxazine preparation 13 proline, in aldol reactions 14–16 thiourea catalysts 351, 357 Organolithiums 285–91 addition of 29 to unsaturated amides 361 Organomagnesium species 291–4 addition with 29 see also Grignard reagents Organometallics 285–98 addition, imines 6–7 molecular rearrangements 477–88 nucleophiles, in enone conversion 366 titanium, in ethylene polymerization 327–8 see also Organolithiums; Organomagnesium species; Organozincs Organophosphorus pesticides, decontamination of 84 Organotitanium, polymerization with 327–8 Organozincs 294–7 addition of, carbonyl compounds 27–9 conjugate addition with 362 see also Et2 Zn Oroidin, cycloaddition with 403 Ortho-esters, reactions of 191 Ortho-metallation 454 Ortho substituent effect 57 Osmium, Os(VIII) catalytic activity 97 Osmium complexes, dihydroxylation with 102, 317 Osmium tetroxide 102 Out-of-plane bending 249–50 10-Oxa-2-azatricyclo[5.2.1.01,5 ]decane 243 Oxadiazoline, carbenes from 155 Oxalic acid, oxidation of 107 7-Oxanorbornadienes 383 1,2-Oxaphosphetane, Martin ligand bearing 312 1,2-Oxastibetane, decomposition 312 9-Oxatricyclo[3.3.1.02,4 ]nonanes 389 Oxazaborolidines, reduction with 126 Oxazines, preparation of 13

Oxazolidinones, addition with 354 2-Oxazolinyltoluene 197 Oxazolone intermediate 75 Oxepinols, formation of 492 Oxidation 91–126 aerobic 121 of anilines 93 atmospheric 120 Baeyer-Villiger see Baeyer-Villiger oxidation of carbonyl compounds 38–42 by metal ions, and related species 91–103 by non-metallic compounds 103–12 of ozone 113 Oxidative amination 432 Oxidative substitution, hydrogen 176 3-Oxidopyrylium betaine 395 Oxidosqualene, cyclization of 469 Oximes 13 Oxirane polyetherols from 273 see also Ethylene oxide Oxiranes 238–43 formation of 233 reactions 237, 241–2 tin(II) chloride catalysis 238 ring opening 238–9 carbon nucleophiles in 243 copper catalysis 241 in SN 2 substitutions 234 see also Aryloxiranes; Epoxides Oxocarbenium ions 210, 485 Oxo-diperoxo tungstate(VI), oxidation with 100 Oxone 104–7, 125 epoxidation with 104–5, 106–7 in p-quinol oxidative dearomatization 106 Oxonia-Cope rearrangements 426, 469 Oxonium ions 209–10 Oxonium ylides, formation of 486 Oxo(salen)Mn(V) complexes 96 Oxovanadium catalysis, Mannich reactions 5 Oxyallyl cation intermediate 213 Oxygen 16 O-18 O isomerization 267 ketene reaction with 122 oxidation with 121, 123 singlet 120

581

Subject Index SN reactions at 252 and subcritical water, redox reactions in 122 Oxygenation, phenol 123 Oxymercuration, diene 464 Ozonation 113 Ozone 112, 113 oxidation with 113, 124 Ozonolysis 112–13

P Palladation 197 Palladium acetate, catalysis by 188 Palladium carbenes, formation 480 Palladium carbenoids, formation 480 Palladium catalysis addition alkynes to cyclopropenes 334 arylboronic acid 363 Heck, aryl iodides 333 phenylacetylene amide group 333 alkylation 102 allylation, alkynes 334 aminoacetoxylation, alkenes 330 arylation 196, 197, 325 aziridination 333 benzoate isomerization 233–4 bromination 188 carbamate reactions 363 carboetherification, alkenes 332 chlorination 188 cycloaddition 391 halogenation 188 hydroamination 332 iodination 188 in nucleophilic aromatic substitution 179, 180, 182 Pd(II) alkene acetalization 330 cyclopropane ring isomerization 479 oxidation with 100 rearrangements 420 silaboration 325 substitutions 237 Palladium complexes acetate-bipyridine 363 with camphor derivatives 335 in hydroamination 332, 337 Pd[(−)-sparteine]Cl2 330 phosphine in 334 selenium in 235

transannular alkene insertion 333 Palladium hydride 330, 480 Palladium-salicylic borate 334 Paracetamol, oxidation of 97 Paracyclophane-o-thioquinone 403 Pauling-Wheland resonance energies 218 Pavelich-Taft dual substituent equation 13 Payne rearrangements, aza- 458 PBE0 functional 266 PBu3 , and ruthenium complexes, as catalysts 336 PCM model 54 for activation parameters 254 and 1,4-benzenedimethanol catalysis 257 SN 2 reactions acetonitrile in 254 benzyl bromide and bromide/pyridine 254 chlorosuccinate dianions in 266 cyanate ion pairs in 263 cyanate/methyl halides 263 methanol fluorination 263 polyfluorosulfonate esters 266 valence bond PCM methods 253 Pd/H dyotropy 480 Pd[(−)-sparteine]Cl2 complex 330 Pentachlorohydroxoplatinate(IV) 102 Pentacyclotetradeca-10,12diene-2,7-diones 382 Pentafluoro-1,2,4-oxadiazoles 388 Pentafluorophenylation 9, 11 Pentane-1,5-diol, oxidation of 101 Peptidases 70 Peptide-α-thioalkyl esters 72 Perborate, oxidation with 107 Perdeutero KIEs, chloride reactions 248, 251 Perfluoroalkylation 36 5-Perfluoroalkyl-1,2,4oxadiazoles 490 Perhydrobenzoxazines 322 Pericyclic molecular rearrangements 419–48 Periodate, oxidation with 111 Perkin condensation 34 benzal acetate in 280

Permanganate, oxidation with 95, 96 Peroxides oxidation with 114, 116 see also Hydrogen peroxide (µ-η2 :η2 -Peroxo)Cu(II)2 complex 97 Peroxomonosulfuric acid, oxidation with 107 Peroxydisulfate, oxidation with 107 Peroxynitrous acid, oxidation with 119 p-Peroxyquinols 106 Pesticides, decontamination of 84 Phase-transfer catalysis 257 in aziridine synthesis 343 crown ethers and glymes 68 PhB(OH)2 197 pH effect in THF formation 267–8 Phenanthrenes, formation of 413 9-Phenanthryl-type carbocations 208 Phenol alkylation 191 anti-Markovnikov reactions 322 chlorination with 188 nitration 189 Phenols intermolecular additions with 323 Markovnikov addition 322 nitration 189 Phenoxonium cations as vitamin E model 217 Phenylacetylenes 333 Phenylallenes, substituted 372 N-(X-Phenyl)amidosulfites 68 Phenyl benzoate, transesterification of 55 Y-Phenyl benzoates 66 N-Phenylbenzohydroxamate 69 Phenylboronic acid, addition of 365 4-Phenylbutanoic acid 54 Phenyl cations, preparation of 214 Phenylcycloalkanamines 71 Y-Phenyl diphenylphosphinates 66 Phenylenediamines, disubstituted 389 Phenyl formate ammonolysis 58 Phenyl group, 1,3-shifts 452 Z-Phenyl hydrogen-maleates 55 2-Phenyl-3-(1-hydroxy-2-phenylethyl)quinoline 192

582 Phenyllithium, addition to 361 (1R-)-8-Phenylmenthyl glyoxylate 195 S-Phenylmercaptoacetic acid, oxidation of 107, 108 Phenyl migrations in borane reactions 476 Phenylpalladium complexes 333 1-Phenylprop-2-en-1-ol 452 1-Phenylprop-2-yn-1-ol 191 Phenyl-substituted acetylenic sulfones 452 X-Phenyl N -(4-thiocarboxamidophenyl)carbamates 64 N -Phenylthionocarbamates, aminolysis 64 α-Phenyl-β-thiophenylacrylonitriles 353 Phenylthiourea, oxidation of 107 4-Phenyl-1,2,4-triazolin-3,5dione, oxidation with 124 N -Phenyltriazolinedione, oxidation with 103 Y-Phenyl X-benzoates, aminolysis of 58 PhI(OAc)2 197 in aminoacetoxylation 330 Phosphadioxirane intermediate 499 Phosphane-modified rhodium catalysts 337–8 Phosphatase, alkaline 70 Phosphatases 70 Phosphate dianions, hydrolysis 84–5 Phosphate diesters 81–4 Phosphate monoesters 79–80 Phosphates, intermolecular catalysis with 66–7 Phosphate triesters 84 Phospha-Wittig reaction 312 Phosphene intermediates 67 Phosphepine 386 Phosphinates, intermolecular catalysis with 66–7 Phosphinegold(I) catalysis 485 Phosphine ligands, ethylene insertion with 333 Phosphines, hydroamidation with 335 Phosphodiesters, transesterification of 82 Phosphoenoylpyruvate 80 Phosphonamidates 67 Phosphonate monoesters 79–80 Phosphonate triesters 84 Phosphonium salts 405 Phosphoramidates 67 Phosphoramidite ligands

Subject Index in 1-alkylstyrene hydrovinylation 329 in iridium catalysed substitution 233 TADDOL-derived 363 Phosphoramidites, addition with 365 Phosphorothioate monoester dianions 84–5 Phosphorus SN 2 reactions at 251–2, 267 SN reactions at 252 Phosphorus ligands 337 Phosphoryl transfer, enzyme 70 Phosphotransferases 70 Photochemical reactions rearrangements 452 fulleroid 498 Photocycloaddition 2 + 2- 382, 383 intramolecular 382 anthracene derivatives 411 Photoelectron spectroscopy, carbenes from 155 Photolysis, silenes from 340 Photon energies, dichloroethene/cation reactions 318 Photo-oxygenation 120 Photoprotonation 205 Photosensitizers, aromatic ketones as 398 PhSeCl 322 PhSeSePh, hydrostannylation with 327 N -PhSO2 -phenylimines 194 Phthalimide, aminoacetoxylation with 330 Phthalocyanine-Cu(II) complexes 400 Pinacol-type epoxide ring rearrangement 466 Piperazine catalysis 345 Piperidine in malonate/enone addition 346 in Y-phenyl X-benzoates aminolysis 58 Piperidine chlorochromate, oxidation with 93 Piperidines, hydroamination produces 327 Pivalic anhydride, acylation of 59 pKR + values, aromatic cation 217 Planar chirality, N ,P -ferrocenyl ligand with 362 Platinum carbene species, rearrangement with 487

Platinum catalysis hydroformylation 102 Pt(II), cycloaddition 392 Platinum(IV) hydridodiphenyl intermediates 199–200 Platinum(II)phenyl-π-benzene complexes 199, 200 PM3 calculations, SN 2 reactions 242 P-O bond cleavage 80 Polar addition 317–72 ArSeX in 321–2 ArSX in 321–2 electrophilic addition 318–40 electrophilic carbon in 324 halogenation 318–21 hydrogen halides in 322–3 metals in 324–40 nucleophilic additions 341–72 Polarizability, solvent 254, 269 Polar mechanism in nitration 189 Polar stepwise 2 + 2-cycloaddition 448 Poly[4-bis(acetoxy)iodo]styrene, oxidation with 123 Polycyclization, homo(polyprenyl)arene 192 Polydispersities in ethylene polymerization 327 Polyene carbocations, synthesis of 218 Polyetherols, formation of 272–3 Polyfluorosulfonate esters 266 Polymerization carbocationic 209 cyclooctene 486 cyclopentene 486 ethylene 327–8 polyetherols from 272–3 Ziegler-Natta 328 Polymerization-chain transfer process 327 Polymers polyetherols 272–3 see also Polymerization; Polypeptides Polymethylhydrosiloxane 363 Polymorphs 13 Polypeptides 74–7 Polyprenylarenes, polycyclization of 324 Porphyrin-chlorin 393 Porphyrin in complexes with rhodium(III) 336 Porphyrin-tetraazachlorin 393 N-(Porphyrin-2-ylmethyl)glycine 393

583

Subject Index Potassium cation, catalysis by 26, 37 Potential energy surfaces SN 2 reactions 251–2, 259, 267 methyl chloride 261 for vinylcyclobutanecyclohexene rearrangements 435 PPF-P(t-Bu)2 , JOSIPHOS analogue 363 Precatalysts, gold(I) 485 1,2-Prenyl migrations 442 Pressure effects, hydride transfer 41 Prins cyclization 426, 469 of homoallylic alcohols 324 racemization in 210 and tandem cycloisomerization 482, 485 Prins-pinacol reactions 471 l-Prolinamide, catalysis by 355 Prolinamides, catalysis by 15, 355 Proline, l- 5, 341, 346 Proline catalysis 341, 346 aldol reactions 14–16, 19 cycloaddition 409 derivatives 354, 355, 357 diamidobinaphthyl dilithium salt 368 dihydroxypiperidine 296 Mannich reactions 5 Prolinol catalysts 351 derivatives 358 l-prolinol 354 Promazine, oxidation of 100 Propane-1,2-diol, oxidation of 101 Propan-1-ol, oxidation of 95 Propan-2-ol, oxidation of 95 Propargylated aromatic compounds 191 Propargyl cations 224 Propargyl Claisen rearrangements 443 Propargyl compounds, substitutions with 236 Propargylic alcohols alkylation by 191 hydroalumination of 326 in SN 2 reactions 236–7 Propionic anhydride, acylation of 59 N-Propionyl-benzimidazole derivatives 61 N -Propionyl-imidazole derivatives 61 [1,5]-Propylthio sigmatropic shifts 434

Protecting groups carbamate 330 and 3-cyanoindoles 329 in hydroheteroarylation 329–30 Protic imidazolium ionic liquids 402 Protonation 199 of (ArN=CMe-CMe=NAr)PtPh2 complexes 199 of 5-substituted indoles 195–6 of 5-substituted 2-methylindoles 195–6 Proton inventory, KIE and 15 Proton migration 187 1,2-Proton shift 456 Proton sponge halogenation 188 Proton transfer 298–300 in benzylamine addition 353 Pseudoephedrine, amides derived from 361 Pseudopericyclic reactions 438 Pummerer rearrangements 470 of heterocycles 470–1 reviews 272 and modern applications 211 PYBOX and scandium(III) triflate, catalysis by 342 Pyramidalization, double bond 319 Pyrazole, Markovnikov addition of 323 Pyrazoles, addition of 323, 346 4-H -Pyrazolo[5,1-c]thiazines 461 Pyridazine rings 182 Pyridine in electrophilic aromatic substitution 187 iodination 188 Pyridinecarboxylic acids, oxidation of 92 Pyridine-N -oxide 187, 188 Pyridines 62 cycloaddition forms 407 ketene acetal addition to 370 Pyridinium ketoximes 70 Pyridinolysis 65 2-Pyridylmethyl formate 335 Pyrimidinediones, formation of 407 Pyrimidines, aminodechlorination of 181 Pyroglutamates, formation of 453 Pyrolysis, see also Flash pyrolysis

Pyrolytic reactions 309–12, 452 Pyrrole addition of 349 alkylation of 193 arylation of 196 electrophilic aromatic substitution 187 Markovnikov addition of 323 trimethylsilylation of 199 Pyrroles addition of 323, 346 alkylation of 193, 195 Pyrrolidines 327 derivatives, chiral 431 (S)-Pyrrolidinesulfonamide, catalysis by 354 5-Pyrrolidin-2-yltetrazole, catalysis by 345 Pyrrolizidinones, 2-substituted 366

Q QM/MM approach Cope elimination 308 phosphate monoester reactions 79 QSSR methods, enantioselectivity predictions with 294 Quantum chemical calculations 1,5-hydride shift 469 SN 2 reactions, potential energy surfaces 259 Quantum chemical topology (QCT), SN 2 reactions, methyl chloride 266 Quaternary ammonium bifluoride, addition with 347 Quaternary centres in alkylstyrene hydrovinylation product 329 Quinazolinones, formation 408 o-Quinodimethanes 397 Quinoline, iodination 188 Quinoline N-oxide 187 Quinolines, asymmetric hydrogenation 136 Quinolinium bromochromate 42, 93 oxidation with 93 Quinolinium dichromate 42 oxidation with 92 p-Quinols, oxidative dearomatization of 106 Quinone methides 206–7 o-, cycloaddition of 404 addition to 352

584 R Racemic hydantoins, formation of 453 Radical bromination, dodecahedranes 319 Radicals in epoxide ring-opening 237 in rearrangements 503–8 Radical traps, DMPO 471 Raman spectrscopy 253 Ramberg-Bäcklund reaction, epoxy- 313, 492 Rate constants instantaneous 55 solvolysis, (S)-1-(3nitrophenyl)ethyl tosylate 267 Rate prediction, ester hydrolysis 55 Rautenstrauch rearrangements 482 Rawal diene, aza-Diels-Alder reactions with 406 RB3LYP/6–311+G∗∗ levels of theory 277–8 Reaction calorimetry 365 Reaction coordinates, intrinsic 264 Reaction efficiency ethyl chloride reactions 248 and nucleophilicity index (ω− ) 259 Reaction force 264 Reactivity, quantitative studies on 208–9 Reactivity descriptors, global and local 38 Reactivity parameters, indole reactions 196 Reactivity-selectivity principle 259, 269 Mayr review of 208 Rearrangements 1,2acetoxy group, vinyl radicals 507 borate complexes 456 ylides 486 [1,5]-Brook, in olefination 488 [2,3]carbocycle compounds from 476 ylides 486 III catalysis 482 3,3-, Au Achmatowicz see Achmatowicz rearrangements Amadori see Amadori rearrangements anti-Markovnikov 468, 469

Subject Index aza-Payne 458 Baeyer-Villiger 471 Beckmann see Beckmann rearrangement Brook see Brook rearrangements carbenes 166–7 Claisen see Claisen rearrangements Cope see Cope rearrangements Curtius 167, 471 dyotropic thermal 501 Fries see Fries rearrangements gold(I) complexes in 339 Hofmann-Martius 465 Meinwald 465 Michaelis-Arbuzov 477 Mislow-Braverman-Evans 459 Newman-Kwart 498 NIH 499 of phenyl-substituted acetylenic sulfones 452 Pummerer see Pummerer rearrangements pyrolytic 452 radical 503–8 Rautenstrauch 482 retro-Skattebo[/]l 502 reverse Amadori, ring contractions 468 semi-pinacol 465 sigmatropic 409, 420–34 Skattebo[/]l 154 Stevens see Stevens rearrangements thermal aza-Bergman 507 type I-dyotropic 501 vinyl 205 Wagner-Meerwein 452 Wittig see Wittig rearrangements Wolff 3, 166, 461 see also Molecular rearrangements RED-AL, reduction with 126 Reductase 141–2 Reduction 141–4 by complex metal hydrides 126–33 of carbonyl compounds 38–42 of imines 8–9 see also Hydrogenation Reductive activation 207 Reductive alkylation, Birch 457 Reductive aminations, ester in 138 Reformatsky reaction, imino- 4 Reformatsky reagents 34

Regioselectivity in alkylation 190, 196 in arylation with [Ph2 I+ ][BF4 − ] 197 carbonyl reduction 38–41 in α-hydroxy ester formation 191 in sulfonation 199 in trimethylsilylation 199 Resolution, dynamic kinetic 41 Resonance stabilization, carbenium ion 268 Resorcinarenes 71 Resorcinol dimethyl ether 190 Retro-Brook rearrangement 433 Retro-Diels-Alder reactions 309, 360 Retro-ene reactions 421 DFT studies 309 Retro “inverse electron-demand” Diels-Alder reactions 309 Retro-Skattebo[/]l rearrangements 502 Reverse Amadori rearrangements, ring contractions 468 Reverse micelles 179, 256 Rhenium catalysis hydrosilylation 338 terminal alkyne insertion 488 RHF/6–311+G∗∗ levels of theory 277–8 Rhodium catalysis addition 1, 4- 366 to alkenes 338 arylboronic acid 365 of dienylboronate ester 367 of silyl anion equivalents 367 arylboronic acids 366 3-arylpiperidine formation 336–7 diazoacetate decomposition 158 dirhodium carbene reactions 153 nitrene reactions 153 epoxide reactions 241 hydroboration 325 hydroformylation 337–8 nucleophilic substitution 243 Rh4 , silylformylation 367 [RhCl(CO)2 ]2 , cycloadditions 406 Rh(I) in [BINAP-RhCl]2 366 cycloadditions 386, 409 in ring opening substitution 245

585

Subject Index SN 2 substitutions 236 in styrene hydrogenation 338 Rhodium complexes generated from (S)-BINAP 366 generated from (MeCN)2 Rh(COD) 366 Rh-BINAP 1,4-addition 365 hydroarylation with 338 Rh(III), with porphyrin 336 [Rh(NHC)Cl(COD)]/AgSbF6 381 Rhodium(II)-carbene reactions 486–7 Rhododaurichromanic acid A 383 Ribosylation, adenine 272 Rice-Ramsperger-Kassel-Marcus theory 264 Ring closure 7-endo-tet 492 metathesis 485, 486 and opening, 7-azanorbornenes 485 Ring contraction 472 of 1-benzyl-2-methyl-3piperidone 468 Ring enlargement, palladium catalysis 479 Ring expansion Boekelheide-Fedoruk 490–1 Claisen rearrangements 423 cyclic vinylamines 423 electrocyclic, molecular containers in 439 novel protocol 370 silver in 154 spirocyclohexadienone systems 470 Ring opening alkylidenecyclopropanone acetal 370 aryloxiranes 237–8 aziridines 243, 244, 246, 247 and closing, 7-azanorbornenes 485 cyclooctene polymerization 486 cyclopentene polymerization 486 electrocyclic 419 dipolar 448 epoxides 141, 237, 466 5-exo-tet 472 by thiolate ions 367–8 metathesis 485, 486 oxiranes 238–9, 241, 243 rearrangements involving 488–94

reductive 143 Ring rearrangements metathesis 485 pinacol-type epoxide rings 466 Ring strain aziridine reactions 246 lactones 266 Ritchie equation 258 Ritchie single parameter relation 208 RNAs, single-stranded 83–4 Rocaglamide, synthesis of 395 Rocaglaol, synthesis of 395 RRKM theory 264 Ruthenacyclobutane, carbenes from 486 Ruthenium-carbene intermediate 486 Ruthenium carbenes 156 Ruthenium catalysis 131–3, 335, 336 cycloaddition 383 in nucleophilic aromatic substitution 180 Ru(III) 97 Ru(VIII), oxidation with 101 SN reactions 237 Ruthenium complexes hydride 131–3 and PBu3 336 -β-stannylvinylidene 336, 486 Ruthenium(III) acetylacetonate catalysis 335

S

S = in aryloxirane ring opening 238 SN 2 reactions and anionic nucleophiles 269 diphenylamine/substituted benzyl bromides 261 solvent effects 254, 255 Sakurai reaction, aza- 14 (Salen)manganese(III) complex 97 Salicylic acids, oxidation of 92 (±)-Salsolene oxide, formation of 411 Salt effects SN 2 substitutions 234 SN reactions 253 Salt-free Wittig reaction 283–4, 312 Samarium(II) carbenoids, cyclopropanation with 163 Samarium(II) iodide (SmI2 ) 191

in dibromoacetic acid reactions 313 Samarium(III) iodide, catalysis by 196 Sapphyrins 81 Sarcosine 379 Sarin, oximate anion reactions with 84 Scandium, imide addition with 335 Scandium(III) triflate (Sc(OTf)3 ) 342, 349 in cycloaddition 392 Schiff base catalysis 297 Schmidt reactions 476 Scholl reaction, investigations of 216 Schrock-type nucleophilic carbenes 158 SCS-MP2 calculations 386 SE Ar mechanism 188, 197 Seawater in nitrostyrene addition 354 Secondary amines, oxidation of 108 Secondary isotope effects α-deuterium fluoride ions/methyl halide reactions 249, 267 SN 2 reactions 248, 249, 250 in amide hydrolysis 59 β-deuterium, SN 2 reactions 248 of enzymes, and phosphoryl transfer 70 in ester solvolysis 55 phosphate hydrolysis 66 Second generation Grubbs catalysts 485 SEGPHOS analogue 363 Selectfluor 188 Selectivity, π -facial 18 Seleneocyclization 321 Seleniranium ions 321 Selenium coordination of 322 Se(IV), tetrabutylammonium tribromide reaction 110 Selenoactones 321 Seleno-sugar heterocycles 470–1 Self-metathesis, alkene 312 Semibullvalene, bromination 211–12, 319 Semibullvalenes, rearrangements of 420 Semiempirical PM3 calculations 486 Semi-pinacol rearrangements 465

586 Shifts 1,2-, in carbocations 204 1,2-carbon 166, 494 1,2-proton 456 [1,2]-Wagner-Meerwein 433 1,3alkoxide 486 metallotropic 487 phenyl group 452 [1,3]-alkoxide shift, Ru-carbene intermediate 486 [1,5]-methoxy 434 [1,5]-silatropic 434 hydride see Hydride shifts hydrogen see Hydrogen shifts sigmatropic see Sigmatropic shifts Sigma-adducts 184 Sigma-complexes 183 Sigmatropic rearrangements 420–34 [1,3]-, nitroso group 431 [2,3]- 431–3 allylic ammonium ylides 475 3 + 3- 409 [3,3]- 420–31 double 421 [5,5]- 433 sulfonium ylide 433 Sigmatropic shifts [1,3]- 494 [1,3]-carbon 435 [3,3]- 503 [1,5]-propylthio 434 Silaboration, allene 325, 333 Silacyclopropanation, silver in 154 Silanes, reduction with 139 [1,5]-Silatropic shifts 434 Silenes, generation by photolysis 340 Silicate, hexacoordinate 11 Silicon carbocations containing 211 pentacoordinate species 9 SN reactions at 251, 252, 267 Silicon organometallic nucleophiles 366 Siloxyalkene nucleophiles 370 α-Siloxyallyl cyanides 329 Silver hydroamination with 339 oxidation with 97–8 precursors, in addition 363 Silver nanoclusters, benzoic acid protected 461 Silver triflate, Michael addition with 354

Subject Index Silyene transfer reactions, silver in 154 Silyl anion equivalents, addition of 367 o-Silylaryl triflates, arynes from 371 Silylated 5-fluorouracil 271 Silylated nucleophiles, ring opening with 244 Silylated uracil, SN reactions with 271 Silylboranes 325, 333 Silylenes 171 Silyl enolates 348 [2,3] Wittig rearrangements of 458 Silylformylation, Rh4 catalysis of 367 Silyl groups, as activating groups 326 1,2-Silyl migrations 433 Silyl nitronates, addition of 347, 358 Silyloxycarbamate nucleophiles 345 Silyloxy cations, reduction with 41 Silyl triflate 237 Silyl triflic imide 382 Singlet molecular oxygen 120 Singlet oxygen 120, 124 Singlet-triplet splitting, nitrene 167 Skattebo[/]l rearrangement 154 retro- 502 SN 1 reactions t-BuFH+ reactions 265 diether monodealkylation 271 epoxide reactions 242 hydrolysis B3LYP calculations on 233 imidazolidin-4-ones 269 salt effects 253 methanolysis, substituent effects 250 and solvent nucleophilicity 255 solvolysis half-life 258 SN 2 identity reactions methyl halide 253, 266 CD3 Cl direct dynamics simulation 264 potential energy surfaces 259 SN 2 mechanisms in aziridine ring opening 243 epoxide reactions 241, 242 at nitrogen and oxygen 252 SN 2 reactions

activation parameters 254 alkyllithium/dihaloalkene intermediates 267 allyl bromide/ammonia reaction, CI/MP analysis 236 anchimeric assistance 245 azetidinium ions 248 aziridine intermediates 248–9 aziridines 246 DMSO catalysis 245 1,4-benzenedimethanol catalysis 257 benzyl bromide and bromide/pyridine 254 carbonate alkylation 232 chloride ion nucleophilicity 253 chlorosuccinate dianions in 266 cyanate/methyl fluoride 263 cyanate/methyl halides 263 cyclic sulfamidate 270 N ,N-dimethylsulfamoyl chloride solvolyses 67 ethylene oxide/guanine 242, 267 ethylene oxide ring opening 243 fluoride ion/methyl halides 249, 267 fluoride ion/perfluoro isomer 266 F− /methyl chloride 262 halide exchange, competing 253 HF/fluorides, gas phase 265 hydrolysis, salt effects 253 in isomerization reactions 63 KIEs 248–50, 267 mesylates 245–6 methanol fluorination 264 methyl chloride reactions 248, 261–2, 266 and micelles 255–7 nitrobenzyl bromide and mercaptobenzoxazole 255 nucleophile effects 257–8 nucleophilicity scale for 259 polymers from 273 potential energy surfaces 251–2, 259, 267 rates, anionic nucleophiles 268–9 SN 2 reactions azanorbornadiene ring opening 245 butyllithiums in 289

587

Subject Index epoxyvinyl sulfones in 239, 241 vinyloxiranes 239 SN 2 substitutions allyl carbonate reactions 232, 233 allylic benzoate isomerizations 233–4 allylic chloride reactions 231 Grignard reagents in 231, 233, 235, 236 iridium catalysed 233 leaving group effects 236 phosphoramidite ligands in 233 solvent effects 236 SN 2 transition states, B3LYP calculations for 250–1 SN Ar mechanism 175–81 SN reactions at halogen 251 at nitrogen 252 at oxygen 252 at phosphorus 252 at silicon 251, 252 at sulfur 251, 252 and back-side attack 251 benzyl bromide and benzimidazole 254 forming C-C bonds 231–3 in oxirane ring opening 238–9 polymers from 272–3 ruthenium catalysts in 237 solvent effects 254, 271 trends, and front-side attack 265 vinyloxiranes in 239 see also SN 1 reactions; SN 2 reactions; SN 2 reactions SN V2 reactions, vinylic compounds in 237 SN Vπ mechanism 237 SN V reactions, substituted Meldrum’s acid 259 SN Vσ mechanism 237 Sodio 2-pyrrolidone catalysis 458 Sodium borohydride amide reactions with 129 reduction with 126, 130–1 Sodium cations, catalysis by 26 Sodium formate, hydrogenation with 140, 141 Sodium hydride, reduction with 127 Sodium perborate, oxidation with 116 Sodium percarbonate 114, 116

Sodium triacetoxyborohydride 126 Solvation, nucleophilicity and 255 Solvation effects 254, 361 Solvation energies, halide 253 Solvent effects 238, 239, 245, 248, 253–5, 258 in addition copper promoted 362 Michael 360–1 carbanion nucleophiles 255 chlorosuccinate dianion substitution 266–7 in cumyl chloride solvolysis 268 electron pair accepting ability 255 ether formation 237 ethylene oxide reactions 242 hydride transfer 41 hydrogen bond accepting ability 255 and ionzation rates, benzhydryl leaving group 258 multi-parameter correlations 255 in nucleophilic substitution 181 organic fluoride formation 249 oxime deoximation 13 in ring opening 244, 245 oxirane rings 238–9 SN 1 hydrolysis, imidazolidin-4-ones 269 SN 1 reactions, and solvolysis half-life 258 SN 2 reactions and anionic nucleophiles 268–9 benzyl bromide and benzimidazole 254 benzyl bromide and bromide/pyridine 254 cyanate/methyl halides 263 cyanide ions and ethyl chloride 255 methanol fluorination 264 methyl halides 253 and micelles 256–7 nitrobenzyl bromide and mercaptobenzoxazole 255 polyfluorosulfonate esters 266 SN 2 substitutions 234, 236 SN reactions 271

hydrolysis at silicon 251 and solvent ionizing power 255 solvolysis reactions 255 on solvolytic reactivity 204 in stilbene oxide ring opening 239 and transition states 248 Wittig reactions 30 see also Medium effects Solvent electrophlicity (E2 ), ester reactions 56 Solvent-free conditions Aza-Michael addition in 343 synthesis in 426 Solvent KIE fluoride ions/methyl halide reactions 249, 267 SN 2 reactions 248, 249 Solvent polarity and sigmatropic shifts 434 and stereoselectivity 430 Solvent reaction field (SCRF) modelling 242 Solvent reorganization, in solvolysis 267 Solvents absence of organic, cycloaddition 392 basicity 254 ET values 255 and hydrogen bonding 269 nucleophilicity 255 polarizability 254, 269 Solvent-separated ion pairs 269 Solvolysis t-butyl chloride, new log k equation 258 cumyl chloride 268 of 2-(dimethylphenylsilyl)1-(Y-phenyl)ethyl 3,5-dinitrobenzoates 261 esters, secondary isotope effects 55 half-life, and substrate choice 258 and intermolecular catalysis 55–8 of 3-methyl-3-chlorobut-1-ene 255 (S)-1-(3-nitrophenyl)ethyl tosylate 267 tetrahydropyranyl mesylate in 469 of trimethylsilyl trifluoromethanesulfonate 255 Solvolytic reactions 308

588 Soman, oximate anion reactions with 84 Sonogashira coupling 480 Sonogashira coupling-cyclization 480 d-Sorbitol 93 Sorboyl thiol ester, formation of 341 Spectrophotometry for aniline addition kinetics 352 Spiroborate esters, reduction with 127 Spirocyclic phenyl-bridged cations 451 Spirocyclohexadienone systems 470 Spirocyclopropane analogues, synthesis of 164 Spiroether effect 235 Spiroisooxazolines 388 Spiropyrrolidines 379 Square-pyramidal carbocations 221 SRN 1 mechanism 175 Stannylenynes, formation of 336 Static calculations, SN 2 reactions 266 Staudinger ligation, peptide fragments 73 Staudinger synthesis, of β-lactams 12 Steering the approach in aminopalladation 331 Stereoelectronic effects carbocation stereoselectivity 204 nucleophilic addition to ketones 39 P -Stereogenic (o-hydroxyaryl)diazaphospholidines 456 Stereoinduction 1,5-, boron aldol reactions 17 long-range 32 Stereoselectivity in alkylation 190, 191 in carbocation reactions 204 Steric crowding fluoride ions/methyl halide reactions 249–50 and SN reactions at phosphorus 252 Steric effects in aziridine carboxylate preparation 246 in cumyl chloride solvolysis 268 in epoxide ring-opening 237 SN 1 hydrolysis, imidazolidin-4-ones 270

Subject Index trimethyl groups, and solvolysis rate 255 Steric factors, Charlton’s 268 Steric hindrance in adenine ribosylation 272 in ether formation 237 methyl group 196 phenyl substituents 256 SN 2 reactions, aziridine intermediates 249 SN reactions, silylated 5-fluorouracil 271 and transition states 232 Steric strain, SN reactions 252 Steroids, 11-aryl, formation 408 Stevens rearrangements [1,2]- 431, 436, 507 ammonium ylides 301 double, rhodium(II)-carbene mediation 487 trans-Stilbene, oxidation of 94 Stilbene oxide trans-, alkylation by 190 ring opening 239 Stilbenes 383 (E)-, highly functionalized 454 Strain energies, aziridine 246 Strecker reactions 10–11 Structure effects in nucleophilic substitution 257–61 Stryker’s reagent 317 Styrene hydroamidation 335 hydroformylation, Pt catalysis 102 hydrovinylation 329 as substrate 328 Styrene oxide 238 Styrenes derivatives, in methoxycarbonylation 334 hydrogenation 338 in Markovnikov addition 328 Subcritical water, redox reactions in 122 Substituent effects azo coupling 199 cumyl chloride solvolysis 268 diether monodealkylation 271 in nitration 189 SN 2 reactions benzyl bromide and bromide/pyridine 254 diphenylamine/substituted benzyl bromides 260–1 SN reactions 259

solvolysis 261, 268 substituted Meldrum’s acid/amine reactions 259 Substituent equation, Pavelich-Taft 13 Substituent parameters 187 Substituted cyclobutenes 480 Substituted diarylamines, ortho-metallation with 454 N -Substituted 4,6-dinitroindoles 359 N -Substituted formamides, hydroamidation with 335 Substituted hydantoins, formation of 453 3-Substituted indoles, alkylation forms 196 5-Substituted indoles, protonation of 195–6 5-Substituted 2-methylindoles, protonation of 195–6 2-Substituted pyrrolizidinones, formation of 366 Substitution allylic see Allylic substitutions nucleophilic aliphatic see Nucleophilic aliphatic substitution nucleophilic aromatic 175–85 Sulfamate esters 85 anti-cancer drugs 86 Sulfamates 85–6 Sulfate monoesters 85 Sulfates 85–6 Sulfenic acid, synthesis of 311 Sulfides hydroxysulfenylation with 338 oxidation of 93, 103, 107 Sulfinamides 68 Sulfonamides in diene hydroamination 339–40 hydroamination of 338 in intermolecular additions 323 Sulfonates 67 Sulfonation 199 Sulfones α,β-epoxy 283, 313, 492 epoxyvinyl, SN 2 reactions with 239, 241 phenyl-substituted acetylenic 452 α,β-unsaturated, addition to 353 Sulfonium ylides formation of 486

589

Subject Index reactions with cyclopentenone 283 sigmatropic rearrangements 433 N-Sulfonyl aldimines, enantioselective reactions with 194 N-Sulfonyl-1-azabuta-1,3-dienes 403 N -Sulfonyl aziridines, alkylation of 245 Sulfonyl halides 67 Sulfoxides 1-chloroethyl p-tolyl 459 1-chloro-2-methylalkenyl p-tolyl 459 oxidation of 96 oxidation with 103 Sulfur carbocations containing 210–11 SN reactions at 251, 252 Sulfur extrusion 448 Sulfur-stabilized carbocations 211 Sulfur-stabilized nucleophiles 342 Sultam complexes, cycloaddition of 398 Sultams 68 β- 85–6 ring opening 68 Sunscreens 341 Superacids in benzene elimination 461 carbocations in 203 dicationic species 461 and intramolecular reactions 192 Supercritical carbon dioxide in alkene acetalization 330 cycloaddition with 392 Supercritical water alkylation in 191 oxidation with 124 phenol alkylation in 322 Superelectrophiles, 4,6dinitrobenzofuroxan 187 Superelectrophilic activation 219 Suprafacial route 435 Suzuki couplings 179 Swain-Scott equation 208, 258 (−)-Swainsonine, synthesis 384 Swainsonines, synthesis of 342 Swern oxidation 13, 104, 124 Symbioimine 395 Syn-effect, 1,3-dienylsulfone addition with 353 Syn selective rearrangements 431

Synthesis of benzoazocines 490 carbocations in 224–5 elimination reactions in 312–14 of pyrroles 490

T TADDOL in β-lactam formation 272 cycloaddition with 395 phosphoramidite derivative of 363 Tandem pericyclic rearrangements 442–8 Taniaphos catalysts 233 Tashironin, core of, preparation 400 Tautomerism 502 Tebbe reagents, carbene analogy with 158 Tellurides, synthesis of 328 Temperature effects SN 2 reactions 260–1 SN 2 reactions 234, 241 SN reactions 253, 254 in THF formation kinetics 267–8 Terminal alkynes, cycloaddition with 408 Tertiary cyclopropyl silyl ethers 190 Tetraalkylammonium bromide micelles 256 Tetraazaporphine 393 2,3,5,6-Tetrabromo-pbenzoquinone, oxidation with 125 Tetrabutylammonium tetrahydroborate 282–3 Tetrafluoroborate counterions 332 2,2,3,3,-Tetrafluoromethylenecyclopropane 496 Tetrahydrofuran (THF) 267–8, 398 Tetrahydropyrans, formation of 324 Tetrahydropyranylation 335 Tetrahydropyranyl cation intermediate 469 Tetraketone 385 N ,N ,N ,N -Tetrakis[(2benzimidazoyl)methyl]2-hydroxy-1,3-diaminopropane 84 meso-Tetrakis(pentafluorophenyl)porphyrin 393 Tetramethylammonium fluorochromate 93

1,1,2,2,-Tetramethylcyclopropane 496 N,N ,N,N -Tetramethylethylenediamine, Cu(II) complexes of 71 Tetrapeptides, oxidation of 96 2,3,4,5-Tetraphenylcyclopenta2,4-dione 379 2,2,3,3-Tetrasubstituted epoxyalcohol derivatives 464 Tetrazole 15 Thermal aza-Bergman rearrangements, aza-enediyne 507 Thexylborane, hydroboration with 324 THF [AlCl3 + 2THF] catalyst 398 formation, rate constants and equilibrium constants 267–8 Thia-Michael addition 342–3 Thiatriazolines 62 Thiazolidinones, addition with 354 Thiazolium derivative 358 1,3-Thiazolium-4-olates 389 Thiazolium salts, ring opening with 169 N -Thiazolylcarbamates, hydrolysis of 61 Thioacetals, cyclization of 323 Thioacetic acid, Michael addition of 358 Thio acids 62–4 oxidation of 92, 93 α-Thioacrylates, formation of 354 Thioacyl halides 64–5 Thioamides, acidity of 15 and hydrogenation 39 γ -Thiobutyrolactone 73 Thiocarbamates 64–5 Thiocarbonates 62–4 Thio-Claisen rearrangements 443 Thioenol tautomerization 443 Thioesters 62–4 Thioethers, formation of 326 Thiolacetic acid, Markovnikov addition with 326 Thiolactones 62–4, 73 formation of 63, 477 Thiolate-bridged diruthenium complexes 191 Thiolate ions 326, 367–8 Thiols addition products 341 oxidation of 103 water-soluble 72

590 Thionocarbamates, computational studies on 498 Thionolactones, isomerization of 63, 477 Thiophene derviatives, formation of 342–3 electrophilic aromatic substitution 187 nucleophilic aromatic substitution 181 reaction with 1-acetylvinyl acrylates 196 2-Thiophenecarbonyl chloride, solvolyses 59 Thiophenol, asymmetric addition of 342 Thiophenols 342 addition of 341 Thiophosphates 84–5 Thio-sugar heterocycles 470–1 Thiourea catalysis 11, 21, 26, 358 addition with 347–8, 357 aza-Baylis-Hillman reactions 351 derivatives 356 reductive amination 41 cooperative activation by 356 reaction with Methylene Blue 107 9-Thiourea Cinchona alkaloids 194 4-Thioxo-1H ,3H -quinazolin2-one 64 Thorpe-Ingold effect 327 Thuriferic acid 398 Tin(II) chloride (SnCl2 ) 238, 465 Tin(IV) aryl oxide, chiral 401 Tin(IV) chloride (SnCl4 ) 193 in hydroxyalkylation 195 in polyprenylarene polycyclization 324 rearrangements with 465 Ti(O-i-Pr)4 , rearrangements with 463 β-Titanaketone, ring opening gives 463 Titanium complexes in alkene hydroamination 327 oxidation with 99 Titanium ester enolates 282 Titanium(IV), Michael addition with 346 Titanium(IV) chloride (TiCl4 ) 468 Titanocene catalysis 237

Subject Index TMBOTf catalysis, aza-Diels-Alder reactions with 406 TMSOTf catalysis, transannular cyclization with 466 Toluene, nitration of 187 p-Toluenesulfonic acid 189, 236–7 Toluenium ions, gas-phase 216 Torquoselectivity in Nazarov reactions 437 Torsional steering 210 Tosylamides 328 Tosylate 253 N -Tosylaziridine 241 N -Tosylaziridines 244 [TpMo(NO)MeIm(η-cyclohexadiene)] complex 403 Transannular alkene insertion 333 Transannular cyclization 466 Transannular Diels-Alder reaction 400 Transesterification 55 phosphodiesters 82 of uridyl-3 5 -uridine (UpU) 82 Transfer hydrogenation 137–41 Transition states aryloxirane ring opening 238 aziridine reactions 246 back-side attack 251 chlorosuccinate dianion substitution 266 cumyl chloride solvolysis 268 epoxide ring-opening 237 ether formation 237 ethylene oxide reactions 242 fluoride ions/methyl halide reactions 249–50, 267 SN 1 hydrolysis 233 SN 1 methanolysis, 1-arylethanol 250 SN 2 reactions 249–50, 252 allyl bromide 236 aziridine 246 aziridine intermediates 249 B3LYP calculations 250–1 benzyl bromide and bromide/pyridine 254 cyanate ion pairs in 263 cyanate/methyl halides 263 fluoride ion/perfluoro isomer 266 methyl chloride 261–2 methyl halides 253 polyfluorosulfonate esters 266 solvation 255

Walden inversion 259 SN reactions, fluorides, gas phase 265 SN V reactions, substituted Meldrum’s acid 260 and solvent effect 248 stabilization, and 1,4-benzenedimethanol catalysis 257 and steric hindrance 232 Transition state theory 250, 264 Translational energies 262 Trapping agents, triphenylverdazyl 269 Traversianal, synthesis of 411 Triazolium salts, ring opening with 169 Triazolo[3,2-d][1,4,2]diazaphospholes 406 4,4 ,4 -Tribromotriphenylamine, nitration 190 Trichlorosilane, reduction with 138, 140 Tricyanomethanide carbanion 278 Tricyclo[4.2.2.22,5 ]dodeca3,7,9,11-tetraene 463 Tricyclo[5.2.1.04,8 ]decane 463 Tricycloclavulone 384 Tri(cyclopentyl)phosphine ligand 330 Tridentate bis(oxazoline) 368 Tridentate ligands, palladium complex 332 Tri(3,5-dimethylphenyl)borate 190 Triesters, phosphate 84 Triethoxy(vinyl)silane 329 Triflate counterions 332 Triflic acid, catalysis by 322, 323 Triflic anhydride 190, 350 Triflic imide 382, 406 Trifluoroacetic anhydride 197 7-(Trifluoroacetyl)cyclopenta[c]pyrans 197 Trifluoroborate salts, formation of 235 Trifluoromethylation 36 Trimethylchlorosilane (Me3 SiCl) 366 1,1,2-Trimethylcyclopropane isomerization 496 3 + 2-Trimethylenemethane cycloaddition 392 Trimethyl groups, solvolysis rate and 255 Trimethylsilylating agents 193 Trimethylsilylation 199 of N-alkylpyrroles 199

591

Subject Index of pyrrole 199 regioselectivity in 199 Trimethylsilyl azide (TMSN3 ) 320 [1,3]-Trimethylsilyl migration 434 1,3,5-Trinitrobenzene 178 2,4,6-Trinitrostyrene 359 Triphenylamine derivatives, nitration 189 Triphenylarsine (Ph3 As) 338 Triphenylphosphine (Ph3 P) in aza-Baylis-Hillman reactions 351 catalysis by 371 in hydroformylation 337 Michael addition with 354 in Morita-Baylis-Hillman reactions 350 Triphenyltin hydride, hydrostannylation with 327 Triphenylverdazyl as a trapping agent 269 Triplet arylnitrenium ions 217 Triquinane 467 Tris(oxalato)cobaltate, oxidation with 100 3,4,4-Trisubstituted-2-azetidinones 385 1,4,5-Trisubstituted-1,2,3triazoles 395 Trityl cations 207–8 Trivinylphosphine, formation of 315 Tropylium derivatives, DFT studies on 217 p-Truxinates 383 Tsuji-Trost allylic alkylation 279 Tungsten oxidation with 100 in terminal alkyne insertion 488 Tunnelling 36, 434 Type I-dyotropic rearrangements 501

U Ugi-Passerini reaction 74 Ultrasound irradiation, Michael addition with 343 Umpolung addition, azole 371 Umpolung allylation, aldehyde 23 Unsaturated acids α,βhydrogenation of 134 oxidation of 102 oxidation of 93

α,β-Unsaturated acylbenzotriazoles, alkylation of 196 α,β-Unsaturated 2-acylimidazoles, alkylation of 193 α,β-Unsaturated aldehydes, alkylation of 193 α,β-Unsaturated amides addition of 361 oxidation of 102 α,β-Unsaturated δ-lactams 342 (E)-α,β-Unsaturated ketones, alkylation by 196 α,β-Unsaturated nitriles, oxidation of 102 α,β-Unsaturated sulfones 353 Uridyl-3 5 -uridine (UpU) 82, 83

V Valence bond PCM methods 253 see also PCM model Valence bond-polarized continuum (VBPCM// BOVB) model 253 see also PCM model Velocity map ion imaging 315 Vibrational contribution to KIEs 249–50 Vicarious nucleophilic substitution 176, 352 Vinyl acetate, hydroformylation of 102 Vinylallene, electrocyclizations of 437 Vinylarenes, hydroamination of 336–7 Vinyl cations 214 Vinylcyclobutane-cyclohexene rearrangements 435, 503 Vinylcyclopropanes, intramolecular cycloaddition of 413 Vinylidenecyclopropanes 328 Vinylidenediamine intermediate 3 3-Vinylmethylenecyclobutane 503 5-Vinyl-2-norbornene isomerization 503 Vinylogous aldol reactions 18 Vinyloxiranes 239 Vinyloxocarbenium ions 210, 400 N -Vinylpyrrolid-2-one 406 Vinyl radicals 507 Vinyl rearrangement 205 Vinylsilanes 24, 338 Vinyl substitutions 234, 237, 259 Vinyl sulfones, addition to 353

W Wacker oxypalladation 333 Wagner-Meerwein rearrangements 452 asymmetric [1,2]- 433 Walden inversion 259 Water activity, reaction rates and R4 NX salts 253 catalysts aldol reactions 16, 18 nitrosomorpholine reactions 9 supercritical alkylation in 191 oxidation with 124 phenol alkylation in 322 Water pool reverse micelles 256 Weinreb amides 34 acylation with 288 Knoevenagel condensation with 281 Wheland intermediates 188 and Azo coupling 199 Willgerodt reaction 36 Wittig reaction arsa- 284 NMR on 312 aza- 30 synthesis with 312 DFT study 30 salt-free 283–4, 312 phospha 312 Wittig rearrangements 185 [1,2] 434 of bis-O-allyl-1,1 -binaphthalene-2,2 -diol 458 by 4,4 -di-t-butylbiphenyl catalysed chlorine-lithium exchange 458 α-lithiated allyl phenyl ethers 452 [1,2]-thio- 507 [1,4] 433 benzyloxyallylsilane 458 [2,3]- 431 [2,3], of silyl enolates 458 lithiated allyl aryl ethers in 289 Wolff rearrangement 3 of α-diazo ketones 461 silver clusters in 166 WPW1K (density functionals), Diels-Alder reactions 397

X Xantphos in nucleophilic attack 332

592 Y Ylides ammonium benzaldehyde reactions 34–5 rearrangement of 301, 475 azomethine 494 cycloaddition 379, 392, 393 carbonyl 389 guanidinium, in aziridination 35 iodonium, conversion of 486 nitrile, cycloaddition of 392 oxonium, formation of 486 rearrangement of 475, 486 sulfonium 283, 433, 486 Ynamides, addition of 323 Ynoate substrates 368 Ynolate anions, olefination of 313

Subject Index Ynolates, alkenes from 370 Ynone substrates 368 Yoshida-Weiss reagent 156 Ytterbium, aldol reactions with 19 Ytterbium complexes, hydroamination with 340 Ytterbium triflate (Yb(OTf)3 ) in alkenylation 191 in Michael addition 346 Yukawa-Tsuno equation 57

Z Zeolites, carbocations in 212–13 Ziegler-Natta polymerisation 328 Zinc and allyl chloride/enyne coupling 329 reagents of, addition 363 Zn(II), nitrogen atoms coordinate to 362

Zn-salen catalysis 71 Zincation 200 of N,N-dimethylaniline 200 of naphthalene 200 Zinc complexes zinc-magnesium dinuclear 358 Zn2+ , of N-methyldiethanolamine 69 Zn(II) of bisoxazolines 194 in phosphate hydrolysis 84 Zinc organometallic nucleophiles 366 Zinc triflate ((TfO)2 Zn) 320 [Zn(OTf)2 -Sc(OTf)plat3 ] 404 Zirconium (IV) catalysis 346 Zwitterionic cations, formation of 207 Zwitterionic enolates 350 Zwitterionic intermediates 21

Organic Reaction Mechanisms 2006 (Organic Reaction Mechanisms Series)

Organic Reaction Mechanisms , Organic Reaction Mechanisms, 1997

Organic Reaction Mechanisms, 2005 (Organic Reaction Mechanisms Series)