Organic Reaction Mechanisms 2016 9781119288732, 1119288738

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ORGANIC REACTION MECHANISMS ⋅ 2016

ORGANIC REACTION MECHANISMS ⋅ 2016 An annual survey covering the literature dated January to December 2016

Edited by

A. C. Knipe University of Ulster Northern Ireland

This edition first published 2020 © 2020 by John Wiley & Sons Ltd. All rights reserved. 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 A. C. Knipe to be identified as the editor 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. Limit of Liability/Disclaimer of Warranty: While the publisher and the editor have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the editor shall be liable for damages arising herefrom. If professional advice or other expert assistance is required, the services of a competent professional should be sought. 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 editor 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 editor 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 Print ISBN: 978-1-119-28864-0 Printed and bound by CPI Group (UK) Ltd, Croydon, CR0 4YY Typeset in 10/12pt TimesLTStd by SPi Global, Chennai, India. 10 9 8 7 6 5 4 3 2 1

Contributors

K. K. BANERJI

Department of Chemistry, J. N. V. University, Jodhpur, India

C. T. BEDFORD

Department of Chemistry, University College London, London, UK

M. L. BIRSA

Faculty of Chemistry, ‘Al. I. Cuza’ University of Iasi, Iasi, Romania

J. M. COXON

Department of Chemistry, University of Canterbury, Christchurch, New Zealand

M. R. CRAMPTON

Department of Chemistry, University of Durham, Durham, UK

N. DENNIS

3 Camphor Laurel Court, Stretton, Queensland, Australia

D. A. KLUMPP

Department of Chemistry, Northern Illinois University, DeKalb, IL, USA

ˇ ´ P. KOCOVSK Y

Department of Organic Chemistry, Charles University, Czech Republic and Department of Organic Chemistry, Stockholm University, Sweden

M. G. MOLONEY

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK

B. A. MURRAY

Department of Science, Technological University of Dublin (TU Dublin), Dublin, Ireland

K. C. WESTAWAY

Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada

v

Preface The present volume, the 52nd in the series, surveys research on organic reaction mechanisms described in the available literature dated 2016. 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, enzymology, 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. All the chapters have been written by the members of a team of experienced ORM contributors who have submitted authoritative reviews over many years. We are naturally pleased to benefit from such commitment and consequent awareness of developing trends in the title area. Particularly noteworthy in recent years has been a major impact on directed organic synthesis through mechanistic studies which enable optimization of ligand design for highly selective transition metal catalysts. In view of the considerable interest in the 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). Although every effort was made to reduce the delay between the title year and the publication date, circumstances beyond the editor’s control again resulted in the late arrival of a substantial chapter which made it impossible to regain our optimum production schedule. Steps have been taken to reduce the knock-on effect of this occurrence. I wish to thank the staff of John Wiley & Sons and our expert contributors for their efforts to ensure that the review standards of this series are sustained. A.C.K.

vii

Contents 1. Reactions of Aldehydes and Ketones and Their Derivatives by B. A. Murray . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives by C. T. Bedford . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Oxidation and Reduction by K. K. Banerji . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Carbenes and Nitrenes by M. G. Moloney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Aromatic Substitution by M. R. Crampton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Carbocations by D. A. Klumpp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Nucleophilic Aliphatic Substitution by K. C. Westaway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Carbanions and Electrophilic Aliphatic Substitution by M. L. Birsa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Elimination Reactions by M. L. Birsa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Addition Reactions: Polar Addition by P. Koˇcovsk´y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Addition Reactions: Cycloaddition by N. Dennis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. Molecular Rearrangements by J. M. Coxon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ix

1

71 97 201 247 337 369 423 449 463 661 697 781 833

CHAPTER 1

Reactions of Aldehydes and Ketones and Their Derivatives

B. A. Murray Department of Science, Technological University of Dublin (TU Dublin), Dublin, Ireland Formation and Reactions of Acetals and Related Species . . . . . . . . . . . . Reactions of Glucosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactions of Ketenes and Related Cumulenes . . . . . . . . . . . . . . . . . . . Formation and Reactions of Nitrogen Derivatives . . . . . . . . . . . . . . . . . Imines: Synthesis, and General and Iminium Chemistry . . . . . . . . . . . Mannich, Mannich-type, and Nitro-Mannich Reactions . . . . . . . . . . . Other ‘Name’ Reactions of Imines . . . . . . . . . . . . . . . . . . . . . . Stereoselective Hydrogenation of Imines, and Other Reductive Processes . . Stereoselective Allyl-, Aryl-, Alkenyl-, and Alkynyl-ations of Imines . . . . Other Stereoselective Reactions of Imines . . . . . . . . . . . . . . . . . . Other Reactions of Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . Oximes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hydrazones and Related Species . . . . . . . . . . . . . . . . . . . . . . . C–C Bond Formation and Fission: Aldol and Related Reactions . . . . . . . . Reviews of Aldols, and General Reviews of Asymmetric Catalysis . . . . . Asymmetric Aldols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Mukaiyama Aldol . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Morita–Baylis–Hillman Reaction . . . . . . . . . . . . . . . . . . . . Other Aldol-type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . Allylation and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . Alkynylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Benzoin and Stetter Reactions . . . . . . . . . . . . . . . . . . . . . . The Michael Addition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous Condensations . . . . . . . . . . . . . . . . . . . . . . . . . Other Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Addition of Organozincs . . . . . . . . . . . . . . . . . . . . . . . . . . . Arylations, and Addition of Other Organometallics, Including Grignards . . The Wittig and Other Olefinations . . . . . . . . . . . . . . . . . . . . . . Hydrosilylation, Hydrophosphonylation, Hydroboration, and Hydroacylation Formation of Cyanohydrins, Cyanosilylation, and other Cyanations . . . . . 𝛼-Aminations and Related Reactions . . . . . . . . . . . . . . . . . . . . . Enolization, Reactions of Enolates, and Related Reactions . . . . . . . . . . . . 𝛼-Halogenation, 𝛼-Alkylation, and Other 𝛼-Substitutions . . . . . . . . . . Oxidation and Reduction of Carbonyl Compounds . . . . . . . . . . . . . . . . Oxidation of Aldehydes to Acids . . . . . . . . . . . . . . . . . . . . . . . Other Oxidations and Oxidative Processes . . . . . . . . . . . . . . . . . . Reduction Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organic Reaction Mechanisms 2016, First Edition. Edited by A. C. Knipe. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

1

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

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

2 5 7 8 8 10 14 15 17 18 20 22 24 27 27 28 31 31 32 33 34 36 36 38 41 41 42 43 45 47 48 48 50 51 51 52 54

2

Organic Reaction Mechanisms 2016

Miscellaneous Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

56 59 62

Formation and Reactions of Acetals and Related Species 𝛾,𝛿-Unsaturated aldehydes (e.g. 1) undergo endo-selective Prins bicyclization with aldehydes to give dioxabicyclo[2.2.2]octanes (2) in high de and ee. Glyoxylic esters work well (i.e. R = COCO2 Et), with induction by a chiral BINOL-derived N-triflylphosphoramide at ambient temperature.1

R–CHO

O

(S)

O

O

(1)

(S) (R)

R (2)

Organocatalytic enantioselective routes to two classes of cyclic acetals have been described. Chiral 5,5-fused tetrahydrofurobenzofurans (bearing two stereocentres) and 5,6-bridged methanobenzodioxepines (bearing three) have been prepared from hydroxyarenes and 𝛾-keto-enals. Using diphenylprolinol TMS ether as catalyst, very low loadings are required for these very efficient iminium catalyses. The pathways have been probed using DFT.2 Treatment of 𝛼-diazo-𝛽-ketoesters (3) with cyclic ketones, lactones, or carbonates (4; X, Y = CH2 ,O n = 0–3) yields spiro ketals, orthoesters, or orthocarbonates (5). The key first step of diazo decomposition requires a catalyst combination of 1,10phenanthroline and a ruthenium salt, [CpRu(MeCN)3 ]+ [BAr4 ]− , where Ar = 3,5bis(trifluoromethyl)phenyl.3

R2

O R1O

O

+

X

Y

N2

( )n

(3)

(4)

R2

O

O

ee 

R1O

O Y

O X (5)

( )n

Spiroacetalization of two enol ethers (6; n = 1 or 2) has been the subject of a QM/ MM study which compares two catalysts: a chiral phosphoric acid and a chiral imidodiphosphoric acid with a much more confined ‘active site’. For the first catalyst (a BINAP–phosphoric acid with buttressing anthracenes), the ee is only 1% for the formation of the 5,5-spiro-system (7; n = 1): the substrate is small, fits inside, and induction is negligible. In the second catalyst, the ee goes up to 92%, reflecting a confinement effect. The 6,6-reaction (7; n = 2) shows a slightly higher ee of 95% for the second catalyst.4

ee 

3

1 Reactions of Aldehydes and Ketones and Their Derivatives O

( )n

( )n O

OH

O ( )n

( )n (6)

(7)

Vinyl propynyl acetals (8) can be rearranged to yield catechol ethers (9) using gold(I) in 1,2-dichloroethane (DCE) at 25 ∘ C. Alkyne activation triggers nucleophilic addition of acetal oxygen, setting up an equilibrium mixture of oxonium ions of similar stability. These can be considered as ‘kinetically self-sorted’ by the next step: highly exothermic cyclization. Computations support this view, as the barriers between the oxonium ions are low, so the system can be considered as an example of dynamic covalent chemistry (DCC), where the fast equilibration acts like an ‘error-checking’ process. The alkene ‘linker’ in the substrate can be replaced by an aromatic (or heteroaromatic), resulting in naphthyl analogues, etc. Syntheses of the substrate acetals (8) are also described.5 PMP OR OR AuI/AgNTf2

OMe

O

O

OMe

Cl–CH2–CH2–Cl

OMe (8)

(9)

(10)

OH

Enantiomeric acetals (10) show a surprising difference under reductive cleavage by diisobutylaluminium hydride. The 𝛼-acetal (PMP behind) is converted to a PMB ether, while the 𝛽-acetal is resistant [but can be opened with Na(CN)BH3 /TMS–Cl].6 Substituted benzothiophenes have been prepared from substituted thiophenoxyacetaldehyde diethyl acetals, X–C6 H4 –S–CH2 –CH(OEt)2 , in the presence of polyphosphoric acid. The mechanisms have been probed by way of kinetic and computational studies.7 Proline catalyses reaction of dihydroxyacetone isopropylidene acetal (11) with enantiopure 𝛼-silyloxy aldehyde (12) to give a single isomer (13) cross-aldol product in 91% yield in a substantially aqueous medium at ambient temperature. This result has now been investigated by NMR spectroscopy, monitoring individual steps, allowing the role of water to be better understood. It is found that proline ‘protects’ aldehyde (12) as an oxazolidinone, but this means that the catalyst is effectively ‘trapped’ by aldehyde (12) … , but the high water content helps avoid this. Water also mediates prolyl group exchanges, and opposes dehydration of the aldol. NMR also allowed detection of a ‘wanted’ intermediate, an enamine of the adduct (14). The authors count two unfavourable effects of water countervailed by four favourable ones.8 BINOL-based trifluoromethyl aryl ketones (15; R = H or CH2 OMe) act as fluorescence sensors for 1,2-diamines in organic solvents, with a dramatic increase at 375 nm and a decrease at 500 nm. Little effect is seen with other diamines (or monoamines), so

de 

4

Organic Reaction Mechanisms 2016 O

O

O

OH 3S

OTBDPS

O

O

O

(12)

CO2H OH

N

OTBDPS

O

O

proline DMSO/H2O/r.t.

(11)

5S

4R

OTBDPS

O

(13)

(14)

diketones (15) can act as highly selective ratiometric sensors for 1,2-diamines, especially ethylenediamine. UV and NMR studies suggest formation of a hemiaminal (16) at the electron-deficient carbonyl, with stabilization by hydrogen bonding from the second nitrogen. Such a non-covalent interaction is absent for a monoamine, and would be poorly optimized for a longer diamine. Job plots for the fluorescence interaction suggest an unexpected 1:4 stoichiometry (rather than 1:2), indicating that the phenolic oxygens can also hydrogen-bond 1,2-diamines.9 OH H NR22

R1 (17)

O CF3 HO H O

OR OR

H C

NH2

R1

NR22 (19)

Ar N F 3C (16) O

O

CF3 R1 (15)

O

NR22 (E-18)

NR22

R1 (Z-18)

Alkynylhemiaminals (17) can be prepared from propargyl aldehydes, or oxidatively from propargyl alcohols. The Meyer–Schuster reaction was then studied for stereoselective synthesis of 𝛽-enaminones (18). Catalysed by Brønsted acids, the selectivity of this rearrangement has now been found to be very simply tuneable: benzoic acid gives (Z-18), while tosic acid gives (E-18). The key step is the protonation of the allenol intermediate (19). The mechanism is supported by 18 O-labelling experiments.10 2-Substituted 2H-chromenes (20) have been prepared via aniline-catalysed nucleophilic attack on ortho-hydroxycinnamaldehydes, via N,O-acetals. The cyclization– substitution cascade accommodates a broad range of nucleophiles including indoles, pyrroles, phenols, and silyl enol ethers.11

de 

5

1 Reactions of Aldehydes and Ketones and Their Derivatives MeO

Ph S

MeO O

S

Nu MeO

Ph

(20)

(21)

Enantioselective aminomethylation of 𝛼,𝛽-unsaturated aldehydes, R–CH=CHCHO, by an N,O-acetal, Bn2 N–CH2 –OMe, to give a 𝛽 2 -amino ester, R–CH2 –*CH(CH2 NBn2 ) –CO2 Me, has been reported to occur under NHC/Brønsted acid dual catalysis, but a theoretical investigation has surprisingly uncovered a specific role for the Brønsted base, refining the mechanism to an NHC/Brønsted acid/Brønsted base multi-catalysis.12 For a reactivity scale for N,O-acetals, see the ‘𝛼-Aminations’ section. A bifunctional tertiary-amide squaramide catalyst allows highly enantioselective addition of methyl thioglycolate (HS–CH2 CO2 Me) to N-Boc aldimines, giving a range of chiral N,S-acetals.13 3,4,5-Trimethoxybenzaldehyde undergoes reversible dithioacetal formation (21) with 2-phenylethanethiol under mild acidic conditions. Subsequent exchange with other thiols and disulfides suggests that the methodology may be useful in DCC.14 Multi-substituted furans (22) have been prepared from 𝛽-chlorovinyl dithianes (23), using a cyclization with aromatic aldehydes under mild metal-free conditions. The tactic involves the dithiane inducing a cycloaddition–aromatization sequence. The strong base dehydrochlorinates (23), giving an allenyldithiane donor (separately isolable), which – on reaction with aldehyde – yields a spirodihydrofuran (24). Protonation then drives aromatization. The disulfide side-chain of the product (22) is easily removed, if desired, using Raney nickel/ethanol reflux.15 HS O

S

1. tBuOK; 2. HCl workup

Ar1 (22)

S

Ar2-CHO

Cl

S Ar1

Ar1

ee 

O

Ar2 Ar2

ee 

S

S

H (23)

(24)

Reactions of Glucosides Transition-metal catalysis of glycosylation is the subject of a comprehensive review (196 references), including recent advances in stereoselective syntheses of O-, N-, C-, and Sglycosides.16 The use of a sulfoxide as a glycosyl donor is 30 years old, and their initial use as anomeric leaving groups has expanded into other roles in glycosylations. A review examines the mechanistic aspects (55 references).17 Chemical derivatization of sulfated glycosaminoglycans has been reviewed (220 references).18

de  de 

6

Organic Reaction Mechanisms 2016

The origin of 𝛼-(1,2-cis) selectivity in galactosyl and galactosaminyl donors with a di-tert-butylsilylene (DTBS) group has been probed by experiment and computation. The major factors found were (i) generation of an oxocarbenium ion and through-space stabilization thereof by electron donation from O(4) and O(6), (ii) a 4,6-O-silylene structure, and (iii) steric hindrance by bulky substituents.19 Glycosyl methanesulfonates undergo regio- and stereo-selective couplings with partially protected pyranoside and furanoside acceptors. In a notable example, a somewhat 𝛼-selective process (2:1) is switched to being 𝛽-selective (10:1) in the presence of a rigid biarylborinic acid (25). Reaction progress kinetic analysis and EXSY (exchange spectroscopy) NMR have been used to probe uncatalysed and catalysed mechanisms.20 O

O

B

D HO R R (26)

OH

(25)

D

de 

de 

O

chiral BINAP– phosphoric acid

O R R (27)

Anomeric sulfonium ions can act as glycosyl donors for stereoselective installation of 1,2-cis glycosides, but their mechanism is not well characterized. Derivatization, NMR kinetics, and computation have examined non-sulfur analogues to help pin down the role of sulfur. It appears that a sulfonium ion is formed as a trans-decalin ring system that can undergo glycosylation through a bimolecular mechanism, with the sulfonium ion forming a hydrogen-bonded complex with the acceptor that undergoes SN 2-like glycosylation to give 𝛼-anomeric product.21 A popular urea organocatalyst, N,N’-bis[3,5-bis(trifluoromethyl)phenyl]urea, has been employed in stereoselective Koenigs–Knorr glycosylations, avoiding methods involving heavy metals. For dealing with the low 𝛼-selectivity found with perbenzylated donors, addition of tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP) greatly improved results. The effect of both additives has been ascribed in part to hydrogen-bonding effects, supported by 1 H NMR studies.22 Nucleophile-directed stereocontrol over glycosylations has been developed using geminally difluorinated nucleophiles such as HO–CH2 –CF2 –CH2 –NBnCbz. The two fluorines lower the oxygen nucleophilicity and reverse the stereoselectivity to preferentially form cis-glycosides.23 1-O-Acetylfuranoses and pyranose 1,2-orthoesters act as excellent glycosyl donors when activated by a gold(III)/phenylacetylene relay, with a preference for 1,2-transglycoside products.24 Iodonium ions, generated from N-iodosuccinimide and triflic acid, promote glycosylation of disarmed glycosyl bromide, avoiding the need for heavy-metal salts.25 A new stereoselective synthesis of 𝛽-mannopyranosides employs anomeric Oalkylation of mannopyranoside-derived lactols, exploiting a kinetic anomeric effect and chelation by caesium.26

de 

de 

de 

1 Reactions of Aldehydes and Ketones and Their Derivatives

7

Radicamine A and B are azasugars, and their fluorinated derivatives have been prepared from a d-arabinose-derived cyclic nitrone. Their ability to inhibit glycosidases has been tested.27 Stereoselectivity of chiral phosphoric acid-catalysed spiroketalization of deuteriumlabelled cyclic enol ethers (e.g. 26 → 27) has been probed by experiment and computation. Long-lived oxocarbenium intermediates were ruled out, and Hammett analysis of the kinetics revealed accumulation of positive charge at the transition state. Secondary kinetic isotope effects (KIEs) are reported. Computations, including molecular dynamic simulations, suggest an asynchronous concerted route with a TS lifetime of about 500 fs.28 Reactive boron species are useful in sensing applications of d-fructose. A kinetic study examined phenylboronic acid and its 2-methyl and 2-isopropyl derivatives, plus 1-hydroxy-3H-2,1-benzoxaborole. Both boronic acids and boronate ions were reactive towards d-fructose, the latter more so.29 Oxidative NHC catalysis has been used for regio- and chemo-selective functionalization of carbohydrates.30 The valuable feedstock, furfural (furan-2-carboxaldehyde), can be generated from xylose under hydrothermal conditions. A DFT study identifies xylulose as a likely intermediate, with water lowering the TS barrier by 12.8 kJ mol−1 compared to the gas phase. Explicit participation of a water molecule results in the replacement of four-membered transition states for several steps with less-strained six-membered ones.31 DFT has been used to study the iridium-catalysed chemoselective C(1)–O reduction of glucose with silene.32

Reactions of Ketenes and Related Cumulenes The first ketene N,S-acetal was reported in 1956, and their chemistry is the subject of a comprehensive review (234 references).33 Several candidates for prebiotic interstellar chemistry have been examined. Ketenimine and methyleneimine, identified in interstellar space, have been proposed as precursors of prebiotic species. Second-order Moller–Plesset perturbation theory (MP2) has been employed to investigate their reactivity, with pericyclic reactions giving rise to five-membered cyclic carbene intermediates, leading – through subsequent hydrogen transfers – to pyrazoles and imidazoles.34 In similar studies, the cycloaddition of ketenimine with various unsaturated compounds shows that five-membered cyclic carbenes appear achievable with acetonitrile, leading to 3-methylpyrazole and 2-methylimidazole,35 while reaction with hydrogen cyanide can give pyrazole and imidazole via similar processes,36 and reaction with ethyne or ethene gives pyrroles or pyrrolines, respectively.37 O-Silyl cyanohydrins (28) can be converted to silyloxy-N-silylketenimines (29) in situ, but these in turn convert to 𝛼-ketoamides (30) on brief exposure to air. A 3-imino-1,2dioxetane (31), formed spontaneously by triplet oxygen, is postulated to explain the facile oxidation of (29). The cases reported involve R being an aryl or vinyl substituent.38

de  ee 

8

Organic Reaction Mechanisms 2016

TBSO

H

R

CN

O

OTBS R

NaHDMS

C

R

ambient

N TIPS (29)

−80 °C

(28)

H N

air

TIPS–Cl

TIPS

O (30) O

O O R TBSO

N TIPS

NTs (32)

(31)

R

𝛼-Addition of aldehydes (e.g. Pr–CHO) across allenamides, H2 C=C=CH–N(R)Ts, gives aldehyde–enamine derivatives (32).39 Catalysis is by gold(I) and a diarylprolinol silyl ether: the former activates the allenamide, and the latter the aldehyde. Such catalysts also render the reaction enantioselective.40

Formation and Reactions of Nitrogen Derivatives Imines: Synthesis, and General and Iminium Chemistry A ‘new’ synthesis of N-sulfonyl arylaldimines, Ar–CH=N–SO2 R, has been reported41a … it having ‘failed’ in 1960.41b Simply heating an arylaldehyde with a sulfinylisocyanate, RO2 S–N=C=O (neat, or in a solvent), gives the sulfinylimine, with loss of CO2 driving the process. Neither catalyst nor additive is required. For the example of paratolualdehyde and tosylisocyanate, refluxing in DCE at 90 ∘ C for 40 min delivers 93% yield (after recrystallization). 2 + 2-Cycloaddition via a cyclic carbonate-type intermediate (33) is discussed.41a O O

Ar

N SO2R

Ar (33)

X N (34)

The kinetics of condensation of 4-methoxybenzaldehyde with 2-aminobenzamide have been measured using formic acid as both catalyst and solvent.42 Benzimidazoles (34; X = NH) are easily prepared by condensation of ortho-phenylenediamine with aryl aldehydes using TiCl3 OTf in ethanol at ambient temperature. Similarly, ortho-aminophenol yields benzoxazoles (34; X = O).43 A dehydrogenative cross-coupling strategy converts 1,2,3,4-tetrahydroquinolines (35) into 3-benzylquinolines (36), using an aldehyde, a simple ruthenium catalyst, and oxygen. The transformation is equivalent to 𝛽-benzylation of quinolines. Control experiments helped establish the mechanism: radicals were ruled out as scavengers

9

1 Reactions of Aldehydes and Ketones and Their Derivatives

had no effect, and quinoline would not react with benzaldehydes (or benzyl alcohols). Critically, enamine (37) would, identifying it as an intermediate, and showing that reaction with benzaldehyde precedes the second dehydrogenation of the ring.44 R2–CHO

R1 N H

R2

R1

[RuCl2(p-cymene)]2

R1 N H

N

O2/120 °C

(35)

(36)

(37)

Trifluoromethyl ketimines, R–C(CF3 )=N–CH2 –Ar, have been enantioselectively isomerized via symmetric proton transfer, using a chiral cinchonium betaine catalyst. The tautomeric products, R–CH(CF3 )–N=CHAr, afford access to optically active trifluoromethylated amines,45 with the overall process mimicking transamination. 2-Methoxyimidoyl-oxiranes (38) have been prepared diastereoselectively by trapping 𝛼-phosphonyloxy enolates with aldehydes (Ar2 –CHO). Dimethyl phosphite initiates coupling of an 𝛼-keto N-tert-butylsulfinyl imidate, Ar1 –CO–C(OMe)=NS(O)–But , initiating a cascade sequence. A [1,2]-phospha-Brook rearrangement follows, to give the 𝛼-phosphonyloxy enolate. This Darzens-type process for preparing epoxides via 𝛼-phosphonyloxy enolates and aldehydes can be viewed as the oxygen analogue of the corresponding reaction with aldimines to give aziridines.46 R1 But

O S Ar1 N OMe

O

−

O

Ar H

de 

CO2H N

2

ee 

NH R2

HO +

N H (38)

(39)

Novel chiral pyridoxamines catalyse enantioselective transamination. The biometric process converts 𝛼-keto acids (R1 –CO–CO2 H) to 𝛼-amino acids in up to 87% ee, using amino-diphenyl acetic acid [2,2-diphenylglycine, Ph2 C(NH2 )CO2 H] as amine donor, driven by loss of CO2 , with benzophenone as the other by-product, in aqueous methanol at ambient temperature. The pyridoxamine catalyst is proposed to condense with the 𝛼-keto acid to give a ketimine which undergoes asymmetric 1,3-proton transfer tautomerization to an aldimine. Hydrolysis then gives the 𝛼-amino acid, with a pyridoxal as by-product. The proton transfer may involve a pyridinium-stabilized azaallyl anion (39).47 Copper(I) coupling of a ketone, R1 –CO–CH2 –CH2 –(CH2 )n –Cl (n = 1, 2), a primary amine, R2 –NH2 , and a terminal alkyne, H–C≡C–R3 , yields 2-alkynyl N-heterocycles

ee 

10

Organic Reaction Mechanisms 2016 R3 R1 R1

N

( )n

( )n N+ R2

X

−

R2 (40)

(41)

(40) in up to 98% yield, via in situ generation of a cyclic ketiminium species (41), which is more reactive towards alkynylation than acyclic analogues.48 A salicylaldehyde derivative has been used in an oxidative kinetic resolution of indolines with a chiral phosphoric acid catalyst. A self-redox process of the iminium intermediate is described.49 A DFT study has examined Jorgensen–Hayashi-type amines as catalysts of iminiumtype additions of 𝛽-keto-sulfoxides and -sulfones to enals. High enantio- and diastereoselectivity is observed for the sulfoxides, but the de drops for the sulfones.50 Phosphate-mediated Pictet–Spengler cyclization has been studied by DFT and ab initio methods in vacuo and in acetonitrile. Examining the reactions of phenethylamine and its 3-hydroxy derivative with formaldehyde to give the corresponding tetrahydroisoquinoline was, with lower barriers in solution.51

ee  de  ee 

Mannich, Mannich-type, and Nitro-Mannich Reactions Free fluorinated amide enolates (42; R = H, alkyl, aryl) derived from 3-fluoroindolin-2 -one have been generated in situ by lithium-promoted detrifluoroacetylation of an 𝛼-fluoro-𝛽-ketoamide hydrate (43). Subsequent Mannich additions with sulfinylaldimines bearing fluoroalkyl groups are very clean, with up to 97% yield and >96% de of protected amine (44). Both steps take 5 min at 0 ∘ C. Deprotection then gives an 𝛼-fluoro-𝛽-(fluoroalkyl)-𝛽-aminoindolin-2-one.52 HO CF 3 HO F

LiBr

O N R (43)

O−

DIPEA

N R (42)

Rf

BuOtS-HN

F Rf

de 

F

SOBut

O N R (44)

The first organocatalysed direct Mannich reaction of unactivated 𝛼-styrylacetates adds them to N-tosyl benzaldimines to give N-tosyl 𝛽-amino esters. The cinchona alkaloid–urea catalyst employed gives yields/de/ee up to 84/92/97%.53 𝛼-Fluoroketones undergo Mannich reaction with N-tert-butylsulfinylimines in up to 98% de.54

de  ee  de 

11

1 Reactions of Aldehydes and Ketones and Their Derivatives

A diastereoselective Mannich reaction of an aromatic aldimine and a phenyl oxazolidine promoted by TiCl4 /R3 N stops at the titanium enolate stage unless a proton source is added. The process has been examined by low-temperature NMR, with acetic acid proving the best additive. The protocol, run slowly at −50 to −40 ∘ C, has to strike a fine balance, as direct protonation of the enolate reverts it to the reactant.55 A zinc–proline–phenol catalyst gives high de and ee in Mannich reactions of 𝛼-branched ketones with N-Boc aldimines, giving 𝛽-amino ketones with an all-carbon quaternary stereocentre in the 𝛼-position.56 A diastereo- and enantio-selective Mannich addition/cyclization reaction of 𝛼substituted isocyanoacetate ester pronucleophiles with ketimines employs a binary catalyst system of silver acetate and a cinchona-derived amino phosphine. An X-ray crystal structure of the amino phosphine/silver acetate complex, as well as 1 H and 31 P NMR studies, helps support a mechanistic proposal. The product imidazolines can be hydrolysed to give fully substituted 𝛼,𝛽-diamino acids.57 𝛼,𝛽-Tetrasubstituted imidazolines (45) are prepared from 𝛼-substituted 𝛼-isocyanoacetates [R4 –CH(CO2 R5 )–N+ ≡C− ] and ketimines (R1 R2 C=N–R3 ) via a Mannich reaction catalysed by a cinchona alkaloid/nickel(II)/Cs2 CO3 combination: typical yields/de/ee are in the 90s.58 R3

O N

N

R1

R4

R2

(45)

NHBoc C6H4-para-R (46)

de  ee 

de  ee  de  ee 

O F

CO2R5

de 

R1

SR2 I (47)

Functionalized propargylic amines have been prepared in high de and ee via a synselective Mannich reaction of enolizable aldehydes and C-alkynyl imines, catalysed by proline and an achiral aminal/urea co-catalyst.59 The enantioselective direct Mannich addition of ethyl acetoacetate to arylideneureas, Ar–CH=NCONH2 , has been used to explore non-covalent organocatalysis by networks of cooperative hydrogen bonds.60 𝛼-Fluoro aromatic ketones undergo zinc-catalysed Mannich reactions with N-Bocbenzaldimines to give protected 𝛽-fluoroamines (e.g. 46) with ee/de up to 99/95%.61 A syn-selective direct Mannich addition uses 𝛼-iodo thioesters (47) and sulfinyl imines to produce 𝛽-amino thioesters. Enolate formation is achieved by reductive soft enolization. The 𝛼-iodo thioester is a shelf-stable latent enolate.62 2,2,2-Trifluoroethanol (TFEA; pKa = 12.40) activates a one-pot reaction of 𝛽-nitroenamine (48), benzaldehyde, and piperidine to give a Mannich-like product (49). TFEA is believed to activate the aldehyde via its acidity and hydrogen-bonding ability, allowing it to react with piperidine to form an iminium ion, which then reacts with the iminium zwitterionic tautomer of enamine (48). Control experiments and MS detection of the first iminium intermediate support the mechanism.63 N-Aryl-3-hydroxyisoindolinones (50; R = OH) react with alkyl aryl ketones under Lewis acid-catalysed anhydrous conditions to give the corresponding substituted

de  ee  ee  de  ee  de 

12

Organic Reaction Mechanisms 2016

O2N

Pip

CHO +

HN

O2N

EtOH

+

NH

83%

N H

HN

(48)

NH (49)

isoindolinones (50; R = CH2 COPh for the case of acetophenone). Evidence for an N-acyliminium ion intermediate is presented.64 O N Ar

O

H

N ( )n

R

PG

HN ∗

CN

R

N

Cl

O NHBoc

Cl

R (50)

(51)

(52)

(53)

Simple cyclic amides with an electron-withdrawing group on nitrogen (51; n = 1–3) undergo direct catalytic asymmetric Mannich-type reaction with N-Boc aldimines. An electron-withdrawing group is not required at the 𝛼-position. Mannich adducts can then be further modified at the amide position, including removal of the 7-aza-indole moiety if desired. Catalysis is provided by copper(I) and Barton’s base (2-tert-butyl-1,1,3,3tetramethylguanidine), with chiral phosphines being employed for stereoselectivity.65 𝛼,𝛼-Dichloro-𝛽-aminonitriles (52) have been prepared via an enantioselective Mannich-type reaction of dichloroacetonitrile with protected aldimines, RCH=N–PG, using chiral bis(imidazoline) catalysts ‘pincing’ palladium. Silver acetate and potassium carbonate are also employed in a process which gives high yields and ees in THF at 0 ∘ C. At first sight, a strong base might appear to be indicated, but 𝛼,𝛼-dichloro carbanions (including the current one, − CCl2 CN) are unstable. So a weak base and palladium activation is the more effective strategy. The products (52) can be converted to 𝛽-amino-nitriles or -amides without loss of enantiopurity.66 A simple 𝛼,𝛽-unsaturated 𝛾-butyrolactam (53) undergoes a direct catalytic asymmetric Mannich-type addition reaction with an 𝛼-ethoxycarbonyl N-thiophosphinoyl ketimine, Ph–C(CO2 Et)=N–P(=S)Ph2 . Using copper(I) catalysis, a chiral diphosphine inducer, and triethylamine, ee up to 91% is achieved.67 Direct Mannich-type reactions generating both 𝛼- and 𝛽-amino esters from a range of carbonyl compounds and aldimines have been described. Using a sterically frustrated Lewis acid/Brønsted base pair, B(C6 F5 )3 /1,2,2,6,6-pentamethyl-piperidine, high des have been achieved under mild conditions.68

ee 

ee 

de 

13

1 Reactions of Aldehydes and Ketones and Their Derivatives

Aldimines of glycinates undergo catalytic enantioselective Mannich-type reaction with N-sulfonyl imines, using a chiral guanidine catalyst, in good yield and fair ee, providing a route to 𝛼,𝛽-diamino acids. Previous examples featured ketimines of glycinates.69 Enoldiazoacetamides (e.g. 54) undergo catalyst-controlled divergent reactions with nitrones: (i) a CuBF4 –bisoxazoline complex favours 3 + 3-cycloaddition, whereas (ii) CuOTf catalyses nearly exclusive Mannich addition in high yields. 1 H NMR and other evidence suggests that the first catalyst favours metal carbene generation within a few minutes, whereas the enoldiazoacetamide (54) is relatively inert in the presence of copper triflate on this timescale.70

Ph N

NEt2 N2

PO(OMe)2

(54)

(55)

Isoindolin-1-one-3-phosphonates (e.g. 55) are easily prepared at ambient temperature in 40 min under solvent- and catalyst-free conditions from three components: 2-formyl benzoic acid, benzylamine, and trimethyl phosphite (in this case). This version of the Kabachnik–Fields reaction shows de >94% for the 𝛼-methylbenzylamine case.71 A redox-annulation of a cyclic amine (56) and a 𝛽-keto-aldehyde (57) yields a benzo[a]quinolizine-2-one (58) in refluxing acetic acid/toluene with moderate to good de. The new intramolecular redox-Mannich process probably involves azomethine ylides as intermediates. Products such as (58) are known to be in equilibrium with the corresponding ring-opened isoquinolinium ions, so the diastereoselective ratio of the products likely represents the equilibrium ratio. In a sample case, the diastereomers were separated and both subjected to the reaction conditions, resulting in identical de.72 O

O

MeO H

MeO NH

MeO (56)

ee 

O

OTBS O

MeO

de 

(57)

N H (58)

O

3-En-1-ynamides (e.g. 59) undergo gold-catalysed imination/Mannich cascades in a one-pot reaction with benzaldehyde and aniline, giving 1,5-iminoamines (60) with some diastereoselectivity. Control experiments show that gold-catalysed aminations of the

de 

de 

14

Organic Reaction Mechanisms 2016

enynamides (59) yield 𝛼-imino allylgold intermediates. Substrates such as (59) give (anti-60) products, whereas if the alkene is cyclic, syn-selectivity is obtained.73 Me

Ts N

Ph

Me (59)

Ph

Ph–CHO Ph–NH2

Ph

N H

Me

N

Ph N

Ph

de 

Ts

Me (60)

Other ‘Name’ Reactions of Imines Aza-Henry reaction of a nitroalkane with an isatin-derived N-Boc ketimine is catalysed by a quinine derivative, giving high ee. DFT has been used to probe the origin of the selectivity. C–C bond formation is found to be both the rate-determining and the stereo-controlled steps. Multiple non-covalent interactions, including classical and non-classical hydrogen bonds and anion· · ·𝜋 interactions, act cooperatively to give the high reactivity and high ee.74 DFT has been used to probe chiral hydrogenbonding catalysts of aza-Henry reactions. The results highlight the role of cooperative effects arising from non-covalent attractions as a vital factor governing stereoinduction, whereas unfavourable steric interactions were the dominant factor controlling diastereoselection.75 A self-catalysed aza-Henry reaction of ethyl nitroacetate on chiral trifluoromethyl aldimines, F3 C–CH=N–R*, works without solvent. The product 𝛽-amino 𝛼-nitro trifluoromethyl esters are easily reduced to 𝛼,𝛽-diamino acid esters. The reactions can also be catalysed by Lewis acids such as ZrCl4 or AlCl3 .76 New recyclable polymer-supported chiral thioureas have been tested in solvent-free aza-Henry and nitro-Michael additions, giving good ees at low catalyst loading.77 An iminium activation of aromatic aldehydes has been exploited in an organocatalytic domino aza-Michael–Henry reaction of N-(2-formylphenyl)sulfonamides with trans-𝛽nitro olefins, to give 3-nitro-1,2-dihydroquinolines (61) in high yields and up to 88% ee at ambient temperature.78 In an exploration of carbene catalysis ‘beyond NHCs’, a cyclopropenylidene has been tested in aza-Morita–Baylis–Hillman (aza-MBH) reactions, using an umpolung strategy. Bis(dialkylamino)cyclopropenylidenes (‘BAC’s, 62), first isolated in 2006, are easily synthesized and stable, and are among the least hindered carbenes as the bulky dialkylaminos are nevertheless far from the carbene centre. They are stronger 𝛿-donors than NHCs, and comparable 𝜋-donors. In a model aza-MBH test of N-tosylbenzaldimine and cyclopent-2-enone with DBU as base, BAC (62; R = Pri ) indeed proved superior to NHCs, CAACs [cyclic(alkyl)(amino)carbenes], and P- or N-centred Lewis bases.79 Sulfonated benzaldimines with an ortho-alkynyl moiety undergo enantioselective azaMBH reactions with enones in one pot, using a combined chiral phosphine/gold catalysis, to give dihydroisoquinolines.80 MO6-2X calculations on a model aza-MBH reaction have identified a pathway with explicit involvement of formic acid in the rate-determining step. Substrate and medium

ee  de  ee 

de  ee 

ee 

ee 

15

1 Reactions of Aldehydes and Ketones and Their Derivatives NO2 N Ts (61)

R2

X

OH

R R2N

NR2 (62)

N (63)

N R

Cbz

R1

(64)

dependence have also been studied and compared with previous work, revealing considerable mechanistic complexity.81

Stereoselective Hydrogenation of Imines, and Other Reductive Processes Ruthenium–sulfur complexes have been used to catalyse reduction of ketimines, Ar1 C(Me)=NAr2 , by either hydrogenation or transfer hydrogenation, and via different types of mechanism: cooperative activation of dihydrogen or hydride and proton.82 Hydrogenation of N-benzylidene-tert-butylamines by tris(2,6-difluorophenyl)boron via frustrated Lewis pair (FLP) catalysis has been studied for 16 ring-substituted imines. pKa values for the imines were determined quantum-chemically and correlate directly with those of the corresponding amines. Structure–reactivity relationships are discussed in terms of ΔpKa and Hammett’s 𝜎 parameter, or with measured rate constants.83 The reduction potentials of 30 N-(phenylethylene)anilines, X–C6 H4 –C(Me)=N– C6 H4 –Y, have been determined. As the radical anion product has an electronic distribution which is like that of the excited state, the authors suggest that Hammett parameters are insufficient or inadequate for describing the substituent effects, and so they employ excited-state substituent constants instead.84 Sulfinamide phosphinates have been used as chiral catalysts for enantioselective reduction of imines.85 The design of new sugar-based ligands for asymmetric transfer hydrogenation from readily available feedstocks is the subject of a short review.86 Asymmetric transfer hydrogenation of 1-methyl-3,4-dihydroisoquinoline and its 6,7dimethoxy derivative shows unusual ee behaviour when catalysed by a cyclopentadienyl iridium diamine in formic acid/trimethylamine. Initially the product amines are predominantly (R)-, with >90% ee, but this decreases over time. It is not due to product racemization, but rather due to a difference in kinetics of the formation of the enantiomers: (R)- follows first-order, while (S)- is zero order. The results are accounted for by a difference in the rate-determining steps of the routes to the enantiomers.87 N-Substituted diarylmethanimines, Ar1 Ar2 C=N–CH2 –R (R = H, Me, CO2 R), have been enantioselectively hydrogenated (30 atm/1,4-dioxane/ambient) using iridium complexed with a chiral ferrocene biphosphine. Yields are near-quantitative, with ees from 94% to 99.4%, and turnover numbers of up to 4000. Catalyst loading was typically 0.025 mol%.88 C,N-Diarylketimines, Ar1 –C(Me)=N–Ar2 , undergo asymmetric transfer hydrogenation using ammonia borane (H3 N⋅BH3 ) as hydrogen source, giving the corresponding amines in up to 95% ee. The catalysis is by a very simple FLP: Pier’s borane

ee  ee 

ee 

ee 

16

Organic Reaction Mechanisms 2016

[HB(C6 H5 )2 ] and (R)-tert-butylsulfinamide, with pyridine as an additive. Evidence from computation, NMR, and control experiments suggests an eight-membered cyclic transition state.89 Chiral diamine Noyori–Ikariya ruthenium(II) and rhodium(III) half-sandwich complexes catalyse hydrogenation of cyclic imines in high ee, with TFA employed to activate the substrates. Transfer hydrogenation, using formic acid/triethylamine, is also successful for some of the catalysts. Inert atmospheres are not required.90 Asymmetric hydrogenation of imines contained within seven-membered rings (63; X = O, CH2 , NMe, S, and SO2 ) is catalysed by iridium(I) complexed with ‘P–OP’ (phosphine–phosphite) ligands on BINOL scaffolds. DFT has helped identify N–H· · · Cl, C–H· · ·𝜋, and C–H· · ·H–Ir non-covalent interactions which may be responsible for the ee.91 2-Pyridyl ketones are converted to chiral diaza ligands via reductive amination with anilines, using a Hantzsch ester as reductant and a buttressed BINAP–phosphoric acid auxiliary as catalyst, with yield/ee up to 98/94%.92 Using isopropanol as a hydrogen source and a new moisture- and air-stable ruthenium catalyst, benzylideneanilines formed in situ are reduced to amines in high yield.93 Quinolines have been directly alkylated by aldehydes (R1 –CHO) via acylquinolinium ions generated using benzyl chloroformate, avoiding the need for N,O-acetals. In situ reduction with borohydride gives diastereomeric 1,2-dihydro-quinolines (64) in fair to good yield, up to 66% syn-de, and up to 99% ee, with typically ca 10–20% of the 1,4dihydro-isomer. Selectivity is induced by a commercially available diarylprolinol TMS ether. Products (64) can also be efficiently re-aromatized if desired.94 Without the need for liquids or noble metals, 5 mol% zinc acetate catalyses hydrosilylation of N-tert-butylsulfinylimines in up to 98% de, using triethoxysilane as hydrogen source; the reaction works well for both aromatic and aliphatic ketimines.95 Decarboxylative trichloromethylation of N-sulfonyl aldimines yields trichloromethyl sulfonamides. No catalysis as such was required: the reaction (followed by IR) works in DMSO at ambient temperature. High diastereoselectivity can be achieved, and solvent effects have been explored.96 A C2 -symmetric diastereomeric secondary amine (65) has been prepared by reductive self-condensation of unsubstituted acetophenone imine [Ph–C(Me)=NH] using a Hantzsch ester as reductant, together with a buttressed BINAP–disulfonimide auxiliary as catalyst, in up to 98% de and 98% ee. The reaction was extended to N–H imines of substituted acetophenones, and to substrates with naphthalene or pyridine as the aromatic moiety.97 Ph Ph Ph

N H (65)

P

Ph

R1

O

P

Ph

R2 N

(66)

Ph

(67)

ee 

ee 

ee 

de  ee 

de 

de 

de  ee 

17

1 Reactions of Aldehydes and Ketones and Their Derivatives

Stereoselective Allyl-, Aryl-, Alkenyl-, and Alkynyl-ations of Imines Indium(III) triflate catalyses enantioselective allylation of isatin-derived ketimines via a chiral imidazolylpyridine ligand, using allyltributyltin as allylating agent.98 A copper-hydride catalyst allows homoallylic amines to be prepared from simple allenes and protected aldimines. Complementary conditions allow formation of either branched product with high syn-selectivity or linear product with exclusive E-selectivity, with high de in both cases.99 Allylrhodium species derived from 𝛿-trifluoroboryl-𝛽,𝛾-unsaturated esters react with imines to give products containing two new stereocentres and a Z-alkene. The selectivities observed have been rationalized in terms of rhodium ‘chain walking’ towards the ester.100 N-Me–BIPAM, a chiral bis(phosphorimidite) containing two BINAPs, induces enantioselective arylation of aliphatic N-sulfonyl aldimines by arylboronic acids under rhodium(I) catalysis.101 Copper-catalysed intermolecular enantioselective addition of styrenes to imines has been achieved under mild conditions, with the styrene featuring as a latent carbanion equivalent via a benzylcopper derivative. The reaction depends on chemoselective hydrocupration of the styrene (over the imine), and mechanistic studies indicate how the bis(diphenylphospholano)ethane (66) ligand achieves this.102 2-Substituted 3H-indol-3-ones (67) undergo enantioselective aza-Friedel–Crafts reaction with pyrroles or indoles with an imidazoline–BINAP–phosphoric acid catalyst.103 Substituted cyclic tosylhydrazones (e.g. 68) undergo regio- and stereo-selective reductive coupling with a boronic acid. This stereoselective C(sp3 )–C(sp2 ) bond-forming reaction works for 2-substituted cyclopentanone-derived hydrazones as well, but not for acyclic substrates. DFT calculations indicate an asynchronous concerted TS leading to the intermediate allyl boronic acid, with an equatorial trajectory determining the stereoselectivity en route to alkene (69).104 R2 NNHTs

O

Ar

(68)

R1 (69)

de  ee 

ee 

ee 

de 

Ar

(72) cinchona PTC

B(OH)2

de 

R3

R2

N R1

ee 

R1

R2 (71)

KOH (aq.)

N

O

∗

R1

R2

R3

(70)

𝛿-Keto-imines (70), related to 𝛾-aminoketones, have been generated chemo-, regio-, diastereo-, and enantio-selectively by an umpolung reaction of simple ketimines (71) and enones (72), using a phase-transfer catalysis based on a cinchona alkaloid.105 Chiral propargylamines have been prepared by catalytic asymmetric Friedel–Craftstype arylations of C-alkynyl imines. The approach is complementary to previously developed alkylations and alkynylations.106

de  ee 

ee 

18

Organic Reaction Mechanisms 2016

Other Stereoselective Reactions of Imines Enantio-enriched 𝛼-(silyloxy)-𝛽-amino amides (73) can be prepared in up to 99% yield and 95% de via a three-component reaction: a silyllithium (PhMe2 SiLi) initiates coupling of an 𝛼-ketoamide (e.g. Ar1 –CO–CO–N-piperidinyl) with an aryl N-tertbutylsulfinylimine [Ar2 –CH=N–*S(O)– t Bu]. Nucleophile addition of the silyllithium to the ketone group is followed by 1,2-Brook rearrangement generating a nucleophilic enolate which reacts with the chiral sulfinylimine.107 O N

HN

NR2 But

R1

CO2R3

H R1

NR2 O

CO2R3 CN

O Ar2 1 PhMe2SiO Ar (73)

H–CH 2CN

de 

Ph (75)

(74)

Cl (76)

Regio-, chemo-, and diastereo-selective assembly of branched 𝛼,𝛽-substituted𝛾-boryl homoallylic amines has been achieved by a three-component coupling of allenes, bis(pinacolato)diboron, and imines. Alternatively, oxidative workup yields 𝛼-substituted-𝛽-amino ketones, that is, the Mannich adducts. Computational studies examining the catalysis suggest that the high de arises from imine complexation of an allylcopper intermediate.108 A copper-diphosphine catalyses C-addition of diborylmethanes to N-tert-butylsulfinyl aldimines to give 𝛽-aminoboronates in up to 98% de.109 A highly diastereo- and enantio-selective copper-catalysed borylative coupling of 1,3dienes and aldimines yields branched homoallylic amines.110 Esters of 𝛼,𝛼-disubstituted 𝛼-amino acids (74) have been prepared with enantioenrichment by direct addition of acetonitrile to 𝛼-iminoesters (75), using a chiral NHC complex of iridium(I) and Barton’s base. Trials of the N-substituent eventually identified the thiophosphinoyl group [–P(=S)Ph2 ] as one which gave reasonable yield and fair ee.111 Cyclobutenones (e.g. 76) undergo C–C bond activation by NHC catalysts, yielding an NHC-bound vinyl enolate which can then undergo ring expansion with an electrophilic sulfonyl imine to give six-membered lactams. With a suitable chiral NHC, good ees and des are achievable. DFT calculations have been used to confirm the mechanism and understand the stereoselectivities. Several non-covalent interactions (C–H· · ·O, C–H· · ·𝜋, lone pair· · ·𝜋) assist the major pathway.112 Reaction of imines (77) with methanesulfonyl sulfene (78) is a method of preparing four-membered trans-𝛽-sultams (79). This [2 + 2]-annulation works at 20 ∘ C, but the annuloselectivity changes towards six-membered 1,2,4-thiadiazine 1,1-dioxides (80, i.e. 4-aza-𝛿-sultams) at −78 ∘ C, with diverse configurations.113 Thermal decomposition of Meldrum’s acid yields acyl ketenes as demonstrated by their stereoselective 2 + 2-cycloaddition to chiral aldimines to give 3-acyl-𝛽-lactams.114

de  de  de  ee 

ee 

de  ee  de  ee  de 

19

1 Reactions of Aldehydes and Ketones and Their Derivatives O O S

R1

O S O

O S

+20 °C

N

O

R2

(79)

O S

H

R1

H

−78 °C

+ N

O

(78)

R2

H O

R2

O

(77)

R1 H

N

S

S O

H R1 N

R2

O

(80)

Lithium enolates of pyroglutaminol undergo aza-aldol addition with simple aldimines in >99% de.115 As part of a special issue ‘Computational Catalysis for Organic Synthesis’, enantioselectivity of addition of nucleophiles to imines has been studied for catalyses by chiral BINAPs. While appropriate computations can be time-consuming, the authors have also used their results to generate a practical predictive model allowing fast and easy prediction of the stereochemical outcome.116 The same issue provides a progress report on asymmetric organocatalysis by cinchona alkaloids.117 A phosphine-catalysed, highly enantioselective umpolung addition of trifluoromethyl ketimines to MBH carbonates allows access to trifluoromethyl amines with a chiral tertiary stereocentre.118 Enantioselective hydrophosphonylation of N-benzylimines, isatin-derived ketimines, and isatins has been effected in high yield and ee (92% and 99%) using dimethyl phosphite and a titanium(IV)-salen complex.119 Pyrazole–amino oxindole adducts (81) have been prepared enantioselectively from isatin-derived N-Boc ketimines and pyrazolones, using a chiral thiourea catalyst, followed by in situ treatment with Ac2 O/Et3 N.120

Me

N

HN R

(R)

S(=O)2-But SiMe2Ph

O

ee 

ee 

O

OH

N

Bn (81)

ee 

Ph

OAc O

ee  ee 

Ph

N

BocHN

N

de 

(82)

(83)

OMe

Enantio-enriched N-tert-butylsulfonyl-𝛼-amido silanes (82) react with aldehydes, ketones, imines, and 𝛼,𝛽-unsaturated esters in the presence of caesium fluoride to give the coupling products with up to 89% retentive enantiospecificity. The intermediates have been investigated by 19 F– 29 Si multiple-quantum coherence 2D NMR spectroscopy, which helped to identify fluorosilicate intermediates. The method results in relatively little reaction flux via a reactive carbanion, which would tend to lead to racemization.121

ee 

20

Organic Reaction Mechanisms 2016

A benzylidene erythrosyl imine derivative (83) undergoes a range of 4𝜋 + 2𝜋cycloadditions with dienophiles to give 1,2,3,4-tetrahydroquinoline derivatives. The facial selectivity is discussed.122 Activated 𝛼-silylimines, TMS–CH2 –N=C(Me)–CO2 Et, undergo an enantioselective silver-catalysed 1,3-dipolar cycloaddition with trisubstituted olefins to give 𝛼quaternary-carbon-rich bi- and tri-cycles, using chiral diphosphine inducers.123 3-(Benzimidazolyl)acetic acids react with cyclic imines to give azaspirocycles diastereoselectively. The metal-free approach uses propylphosphonic anhydride and Hunig’s base and has been extended to 2- and 3-pyrrolyl acetic acids. N-Acyliminium ion intermediates are discussed.124 2,4,5-Triaryl-1,3- and spiro-oxindolyl oxazolidines have been prepared via dirhodium tetraacetate-catalysed coupling of methyl phenyldiazoacetate [Ph–C(=N2 )–CO2 Me], an aldehyde, and an N-tosylimine (Ar–CH=NTs), in good yields and des. A 1,3-dipolar addition of a carbonyl ylide (formed in situ from the diazoacetate and aldehyde) to the imine is proposed.125 A three-component reaction of a diazo-ester, Ar1 –C(=N2 )–CO2 Me, an aldehyde, Ar2 CHO, and a carbonate, H2 N–CO2 R, yields 𝛽-hydroxyl-𝛼-amino acid derivatives (84) in good yields and high des. Proceeding at ambient temperature under Rh2 (OAc)4 / InCl3 co-catalysis (a transition metal/Lewis acid strategy), a carbonate ammonium ylide (85, and/or its enolate form) is proposed: the aldehyde would trap this to give (84).126 +

OH

CO2Me Ar1 (84)

Ar1

O

−

O I

N R

(86)

de 

(85)

O S

de 

CO2Me RhLn

Cyclic aldimine and ketimine derivatives (86) undergo aza-Reformatsky reaction with ethyl iodoacetate to give 𝛽-amino ester derivatives (87). Moving to five-membered cyclic N-sulfonyl ketimines (i.e. 86 with omission of the phenolic oxygen), the reaction also works with good ee.127 O

de 

CO2 R

H 2N NHCO2R

Ar2

de 

CO2Et

O

O S

NH

Me2Zn/chiral ligand

CO2Et R (87)

Other Reactions of Imines The familiar need for low temperatures, exclusion of water and air, toxic organic solvents, and long reaction times for unactivated substrates has been set aside in the addition

ee 

21

1 Reactions of Aldehydes and Ketones and Their Derivatives

of n-butyllithium and Grignards to imines and quinolines. For example, n-BuLi has been added to benzylideneaniline (PhCH=NPh) at ambient temperature in an aprotic solvent under air, giving a 98% yield of the amine [PhCH(Bu)NH–Ph] in 3 s. The key modification to familiar protocols is the use of deep eutectic solvents (DESs) … which are also green and biorenewable. In this case, a 1:2 mixture of choline chloride, HOCH2 CH2 NMe3 + Cl− , and glycerol was used, that is a hydrogen bond acceptor and donor. No additives are required, and processes such as tautomerism, reduction, or coupling do not compete. All such processes – and hydrolysis of the organometallic – are obviated by the extreme kinetic anionic activation of the alkylating agent.128 3 + 2-Cycloadditions of an azomethine imine with N-vinyl pyrrole or N-vinyl tetrahydroindole have been studied by DFT. They are meta- but not stereo-selective.129 A one-step access to fused 𝛽-lactams has been achieved via bicyclic annulation of imines with 𝛼,𝛽-unsaturated esters. The C–H activation process is catalysed by manganese, works for both ket- and ald-imines, and shows good functional group tolerance. A five-membered azamanganacycle is implicated as a key intermediate.130 trans-𝛽-Lactams (e.g. 88) have been made from an enal (trans-EtO2 C–CH=CH– CHO) and an enamine (trans,trans-Ph–N=CH–CH=CH–C6 H4 -para-NO2 ), using a cooperative catalysis of a chiral NHC and a Brønsted acid. The NHC activates the enal to give a Breslow intermediate, while the acid protonates the imine nitrogen. A DFT study has identified CH· · ·𝜋, N–H· · ·O, and 𝜋–𝜋 non-covalent interactions in the stereocontrolling step that help explain the experimentally observed des and ees.131

O

Cl

R2

N

R1

R3 N

Ph

[Pd]/base

R2

(89) R1

R3

EtO2C NO2 (88)

N H (90)

Easily prepared N-(chloroaryl)ketimines (89) undergo intramolecular 𝛼-arylation in 1,4-dioxane, using sodium tert-butoxide as base and a palladium cinnamyl complex as catalyst. The products (90) are useful N-unprotected indoles, and the corresponding aza-indoles can be prepared using a pyridinylimine instead of the arylimine. DFT calculations tend to rule out a Heck-like pathway; instead, imine deprotonation is followed by palladium-catalysed 𝛼-arylation and reductive elimination.132 3-Methyleneisoindolin-1-ones (91) have been prepared by a novel rhodium-catalysed oxidative cyclocarbonylation of ketimines (92) using CO, a reaction which involves two C–H cleavages (one sp2 and one sp3 ). Experimental data and DFT calculations indicate initial imine–enamine tautomerization followed by N–H bond breaking, activation of the aryl hydrogen and CO insertion, and finally reductive elimination.133 𝛾-Hydroxy-𝛼,𝛽-unsaturated ketones undergo a novel DBU-catalysed cycloaddition with cyclic N-sulfinylimines to give polyheterotricyclic 1,3-oxazolidines.134

de  ee 

22

Organic Reaction Mechanisms 2016 R2

R2

H

N

R3

[Rh]

R1

CO; [O]

R3

H

N R1 O

(92)

(91)

Enamine and allylic amine derivatives have been prepared via palladium-catalysed C–H arylation of 𝛼,𝛽-unsaturated imines.135 N-Boc-imines, generated from aldehydes (RCHO), form 𝛼-(N-Boc)aminoamides by treatment with N,N-dimethylcarbonyl(trimethyl)silane, TMS–C(=O)–NMe2 , in anhydrous benzene at 60 ∘ C, without catalyst. The carbamoylsilane is proposed to react in its nucleophilic carbene form (93).136 NHS(=O)- But TMS

O

N

∗

Ar

∗

R1

R1

N (93)

R2

R2

(95)

(94)

Zinc-promoted aza-Barbier reaction of N-tert-butylsulfinyl ketimines yields chiral homoallylic–homopropargylic amines with two contiguous chiral centres (94).137 Copper(I) iodide catalyses annulation of aromatic alkynyl imines (95) with diazo compounds, R3 –C(=N2 )–CO2 R4 , giving quinolines with a pendant ester at C(4). It is suggested that initial coupling of reactants by copper is followed by metal extrusion to give an allene, which then electrocyclizes.138 A range of bench-stable 𝛼,𝛼-bis(trimethylsilyl)toluene reagents, Ar–CH(TMS)2 , undergo stereoselective aza-Peterson olefinations with aldimines, R–CH=N–X, to give stilbenes, Ar–CH=CH–R, in good to excellent yields, using TMSO− /Bn4 N+ as Lewis base activator (THF/20 ∘ C/1–3 h). A striking difference is found between simple N-substituted imines (e.g. X = Ph) and sulfinyl imines [X = S(O)-But ] … the former give up to 99:1 E:Z ratio, while the latter switch over to 5:95. Additions of this type to N-sulfinyl imines tend to be highly diastereoselective, which may help to account for the mechanistic switchover.139

Oximes The use of O-acyl oximes in N-heterocyclic synthesis in the presence of transition metal catalysis has been reviewed.140 Benzaldehyde oximes (96) provide two new routes to isoquinolines: a homocoupling of two equivalents (97) or a cyclization with vinyl azide (98). These [3 + 3]-type

de 

23

1 Reactions of Aldehydes and Ketones and Their Derivatives

and [4 + 2]-type cyclizations are both catalysed by palladium(II) acetate, with the homocoupling requiring 130 ∘ C, while the azide requires only 90 ∘ C (and thus does not face competition from homocoupling). Ketoximes such as acetophenone oxime also work, to give methyl-substitution on the heterocyclic ring.141 R R

Ph

N3

N

N [Pd]

R Ph

NOH

[Pd]

R (98)

(96)

(97)

Aldoximes can be isomerized to amides under mild conditions of ethanolic reflux using copper(II) acetate, with a typical yield of 10% after 12 h for the case of parachlorobenzaldoxime. However, addition of 0.05 equiv of acetonitrile raises this to 82%. Comparable results are found for representative aryl, heteroaryl, and alkyl substrates, with superior yields found for the 2-furyl and 2-thiophenyl cases, both possessing a heteroatom lone pair ortho to the oximido group.142 An oxime ether C=N bond has been carboacylated via C–C activation of a pendant benzocyclobutenone (99; ‘A–B’ = a linker such as O–CH2 ). The C(1)–C(2) bond of the cyclobutanone is activated by low-valent rhodium, leading to metal insertion, with either 𝜂 1 -coordination to nitrogen or 𝜂 2 -coordination to the C=N bond. Extrusion of rhodium and rearrangement gives isoquinolinones (100) in up to 99% ee.143 A

B

N R O

X

A B

OMe RhI,

R

L*

N

O

X (99)

OMe

(100)

Isonitrosoacetophenone (101) reacts with an ethanolamine (102; R = H) to give oxiimine alcohol (103). With a phenyl substituent in the amine (102; R = Ph), the product (103) apparently rearranges to amido alcohol (104). However, computations suggest that the barrier to simple rearrangement is too high to be consistent with the mild conditions. The immediate and rearranged products are potentially useful as bi- or poly-dentate ligands.144 High-level DFT calculations have been used to probe oxime–nitrone tautomerism for arylamidoximes, with evidence for involvement of two oxime molecules, rather than the commonly accepted thermal 1,2-H-shift. It is also suggested to play a role in their reaction with 1,2-diaza-1,3-dienes to give O-substituted oximes (precursors to 1,2,4oxadiazines). Thus, the tautomerism is implicated in a nucleophilic addition reaction of an oxime.145

de  ee 

24

Organic Reaction Mechanisms 2016 R

R H 2N

OH

(102) O HON

OH

OH

−HCN

N

EtOH/ 25 °C/ 4h

R

H

HON

(101)

H N O

H

(103)

(104)

A computational study of copper-catalysed skeletal rearrangements of O-propargyl oximes, R–CH=N–O–CH2 –C≡CH, highlights a common initial stepwise 2,3-rearrangement to generate an N-allenylnitrone. Its subsequent reactivity depends on the nature of R: azete oxides or amidodienes are formed if it is an electron-poor or electron-rich aryl group, while pyridine N-oxides are obtained from olefinic R groups.146 Acetaldehyde has been ammoximated using in situ-generated hydroxylamine (NH2 OH), prepared using ammonia and a titanium silicalite/H2 O2 oxidation system. A ReactIR15 spectrometer was used for in situ monitoring.147 Aryltetrazoles (105) have been prepared in one pot from benzaldehydes, using (i) hydroxylamine hydrochloride to give the oxime, then (ii) P2 O5 to dehydrate to the nitrile, and (iii) sodium azide to give (105) via 3 + 2-cycloaddition. Less wasteful and safer than other methods, the mechanism has been demonstrated by isolation of the oxime and nitrile intermediates by appropriate quenchings.148 NNHTs

HN N Ar

N N (105)

R1

R2 (106)

O R3

O

R2 CF3

R1

Ts

R3 CF3

(107)

N N

CF3

R2 −O

R3

R1 (108)

Hydrazones and Related Species An epoxidation reaction of trifluoromethylketones with N-tosylhydrazones (106) under transition metal-free conditions has been reported, giving tetrasubstituted trifluoro-methylated oxiranes (107) in up to 97% yield and 95% de. An unprecedented nucleophilic addition process is proposed, supported by the isolation of an O-anionic intermediate (108) which was characterized by NMR and HRMS.149 Electrophilic trifluoromethylation of carbonyl compounds and their nitrogen surrogates under copper catalysis has been reviewed, including umpolung examples such as aldehyde hydrazones and the contrast between enones and hydrazones of enones.150 Phenyliodonium diacetate, PhI(OAc)2 , mediates carbotrifluoromethylation of aldehyde-derived N-acylhydrazones by TMS–CF3 .151 4-Bromoisatin (109) couples with 2-amino-5-methyl-N′ -phenylbenzohydrazide (110) to give 1-amino-5-phenyl-indazolo[3,2-b]quinazolin-7(5H)-one (111), catalysed by

de  de  ee 

25

1 Reactions of Aldehydes and Ketones and Their Derivatives Br

O

O Me

N H

H N

NH2

O

Ph

O Me

Ph N

N H

N

N

(109) CuI/base

H 2N

(110)

(111)

CuI/Cs2 CO3 . Based on control experiments, a domino condensation/cyclization/C–N bond Ullmann coupling/ring opening/decarboxylation is proposed.152 2-Formylaryl tosylate (112) undergoes a palladium-catalysed three-component cycloaminocarbonylation with hydrazine and carbon monoxide to give phthalazinone (113). Subsequent treatments lead to hydralazine hydrochloride (114), a hypertensive drug.153

CHO OTs (112)

N

CO BocNHNH2

NH

N 1. POCl3; 2.. H2NNH2; 3. HCl (aq.)

DBU

O (113)

N HN

+

NH2 Cl−

(114)

The acetohydrazone function has been used as a transient directing group for arylation of unactivated C(sp3 )–H bonds. ortho-Tolualdehydes (115) react with iodobenzenes (Ar–I) in refluxing aqueous acid in the presence of acetohydrazide (AcNH–NH2 ; 20 mol%) and palladium(II) to give 2-benzylbenzaldehydes (116). The activation and transient directing effect depends on two equilibria: (115) ↔ (117) and (117) ↔ (118). Silver acetate acts as oxidant, and the solvent was optimized as 1:1 H2 O:AcOH, with water content promoting hydrolysis of the acetylhydrazone and increasing yield of (116). The intermediacy of (118) is consistent with the reaction failing for ortho-substituted aryl iodides.154 Hydrazones derived from aldehydes, R1 –CH=N–NR2 R3 , undergo copper(II)catalysed C(sp2 )–H difluoroalkylation by difluoroalkyl bromides (e.g. BrCF2 CO2 Et) to give the corresponding ketone-derived hydrazine [in this case, R1 –C(CF2 CO2 Et)=N– NR2 R3 ] in up to 99% yield, with a diboron as reductant. Evidence for a fluoroalkyl radical is shown.155 The effect of substituents on cyclizations of 2-pyridylhydrazones has been reported.156 4-Alkyl- or 4-aryl-aminophtalazin-1(1H)-ones (119) have been made regioselectively from 2-formylbenzoic acids [or the equivalent 3-hydroxyisobenzofuran-1(3H)-ones] by reaction with hydrazine, with subsequent 4-bromination followed by 4-amination.157 Rhodium(I) catalyses reaction of arylboronates (120) with N-tosyl-hydrazone derivatives of trifluoromethylketones, Ar1 –C(CF3 )=N–NHTs, to give 1,1-fluoro-2,2-diarylalkenes, Ar1 –C(=CF2 )–Ar2 . The method exploits Rh(I)–carbene insertion followed by 𝛽-fluoride elimination.158

26

Organic Reaction Mechanisms 2016 R

R

CHO

N CH3

H N O

CH3

(115)

Me

(117)

R N

H N

Pd O C H2 L

R

CHO

Me C H2

(118)

Ar

(116)

NHR2 N

R1

NH

O Ar2 Br O

O (119)

(120)

N

N N

Ph (121)

2-Hydrazinopyridines undergo one-pot KI-catalysed oxidative cyclization with 𝛼-keto acids to give 1,2,4-triazolo[4,3-a]pyridines (121), using tert-butylhydroperoxide (TBHP) as terminal oxidant. A mechanism is described in which the initial condensation product of the reactants is oxidized by hypoiodate (OI− ), generated from iodide and TBHP.159 2-Hydrazinopyridines also undergo a similar condensation with aldehydes to give 1,2,4-[4,3-a]pyridines via an iodine-mediated oxidative cyclization in one pot, without the need for isolation of the hydrazine intermediate formed by the initial condensation with aldehydes. Aryl, alkyl, and 𝛼,𝛽-unsaturated aldehydes all work well.160 An acetophenone-derived N-tosylhydrazone, Ph–C(Me)=N–NHTs, can N-alkylate benzamide to give PhCONHCH(Me)Ph in refluxing THF, using CuI/But OLi under argon, with tetrabutylammonium iodide helping to raise the yield. The strong base can deprotonate the amide, generating a strong nucleophile. A wide range of structural changes such as benzamide C- and N-substitution and variation of carbon substituents in the hydrazone is tolerated. A one-pot version from acetophenone and H2 N–NHTs has been developed.161 Appropriate hydrazones (122) can be oxidatively cyclized to pyrazoles or fused 1,2,4triazole (123). A review (93 references) focuses on the use of hypervalent iodine(III) reagents such as PhI(OAc)2 to effect tandem in situ generation of N-heteroaryl nitrilimines, which convert via 1,5-electrocyclization to triazoles (123). Isomeric 1,2,3-triazole

27

1 Reactions of Aldehydes and Ketones and Their Derivatives

cases are also described. Such hypervalent iodine reagents score strongly on their oxidizing properties, environmentally benign character, and commercial availability.162 H N

N N

N

N H (122)

R

N R (123)

O

R2

R1 N

CO2Et

(124)

Aldehyde-derived hydrazones, R1 –CH=NNR2 2 , have been converted to functionalized difluoromethylketone hydrazones, R1 –C(CF2 –G)=NNR2 2 (where G = functional group), by reaction with bromodifluoromethylated compounds, BrCF2 –G. The C(sp2 )– H insertion process is catalysed by palladium(0), and may involve a radical/SET mechanism via a difluoroalkyl radical. The method allows access to 𝛼,𝛼-difluoro-𝛽ketoesters and 𝛼,𝛼-difluoroketones.163 A thermodynamic and kinetic study of the mechanism of formation of six semicarbazones by DFT identified two transition states, the first for a bimolecular process, and the second being unimolecular.164 Azomethine ylide N-oxides (nitrone ylides), R1 –CH=M+ (− O− )–CH2 CO2 Et, undergo cycloaddition with aldehydes (R2 –CHO), to give trans-2-alkyl-3-oxazolines (124) with complete stereoselectivity. n-Butyllithium (20 mol%) catalyses the reaction, whereas stoichiometric amounts inhibit. Spectroscopic and computational studies identify that trace water is required in the mechanism, and how too much butyllithium diverts the reaction towards transoximation.165 Aldehydes and ketones can be methylenated through their N-sulfonylhydrazones, using copper(I) catalysis and dimethylsulfone, Me2 S(=O)2 . The reaction proceeds via formation of a copper(I) carbene followed by its migratory insertion. Extending the reaction, trifluoromethyl alkyl sulfones, F3 C–S(=O)2 –R, insert the R group.166

C–C Bond Formation and Fission: Aldol and Related Reactions Reviews of Aldols, and General Reviews of Asymmetric Catalysis Despite its importance, controversies still remain concerning the precise mechanism of the aldol condensation. For the case of the base-catalysed reaction of benzaldehydes with acetophenones to produce chalcones (in water), the complete energy profile has now been reported. The rate-limiting step is the final loss of hydroxide and formation of the C=C bond. This is based on a study of partitioning ratios of intermediate ketals and on solvent KIEs, with condensations being faster in D2 O than in H2 O, regardless of substitution.167 A computational study of the proline-catalysed aldol reaction suggests that one-way transition state analysis is unsuitable. With significant competition between kinetic and thermodynamic effects, the integration of a system of kinetic differential equations associated with the multiple equilibrating reactions successfully rationalized the chemical

28

Organic Reaction Mechanisms 2016

and stereochemical data for the reaction.168 An ab initio and DFT study has investigated differences in the catalytic behaviour of proline in water, DMSO, and a range of organic solvents, including some apparently contradictory results in the literature.169 A selective review considers the fundamentals of organocatalysis, emphasizing systems other than prolines, cinchona alkaloids, and binaphthyls (well covered elsewhere). Comparisons and contrasts with metal and enzyme catalysts are drawn, including the fact that organocatalysts are typically smaller, cheaper, and more stable than enzymes.170 A short review describes organo-SOMO (singly occupied molecular orbital) activation of enamine/iminium-based organocatalytic transformations to synthesize chiral carbonyl compounds.171 The use of N-allenyl amides and O-allenyl ethers in enantioselective catalysis is the subject of a short review.172 In a new approach to unexplained results in asymmetric aminocatalysis, ‘downstream species’ and their kinetic and thermodynamic effects have been proposed as forming a second hierarchical level for selection control, where the first level is the steric facial discrimination in the attack of the enamine on an electrophile, that is the stereogenic bond-forming step. NMR characterization of intermediates has been used to explore the new paradigm, where such species can either enhance or erode the selectivity established at the first level. As the critical parameters may not be the same at the two levels, this has important implications for optimal design, and indeed for other types of catalysis.173 An ONIOM study has been carried out on the TS of an organocatalytic asymmetric direct aldol where an ionic-liquid-supported benzoic acid is employed. The acid appears to act as direct proton donor in the TS, with direct counterion involvement also likely.174 A copper-catalysed retro-aldol reaction of 𝛽-hydroxy ketones or nitriles with aldehydes provides chemo- and stereo-selective access to (E)-enones and (E)-acrylonitriles.175 A bulky trisalkylgallium, Ga(CH2 –TMS)3 , is a viable Lewis acid partner for 1,3-bis(tbutyl)imidazole-2-ylidene as an FLP for activation of aldehydes and ketones. Neither can activate carbonyl sufficiently on its own, and an NMR study, backed up by DFT calculations, has examined the complex equilibria involved in their interaction with various types of substrates.176 Ferrocenecarboxaldehyde, in the presence of NaOH, catalyses direct 𝛽-alkylation of 1-phenylethanol by benzyl alcohol. DFT calculations indicate an initial hydride transfer as rate-determining step, followed by a cross-aldol condensation and a reduction.177

ee  ee  de  ee  de  ee  ee 

ee 

ee 

Asymmetric Aldols Aldol reactions of pentafluorosulfanyl acetic acid esters (125; R1 = octyl, benzyl) with both aromatic and aliphatic aldehydes give excellent anti-selectivity (126, determined by X-ray crystallography) in a process mediated by dicyclohexylchloroborane.178 Organocatalyses of aldols of acetone with ortho-sulfur-substituted benzaldehydes (127) have been studied for R = SMe and S+ (–O− )–Me (racemic, and R- and S-enantiomers). The sulfinyl group could control the enantioselectivity via a 1,4-induction.179 A combination of a simple Brønsted acid, TFA, and an amino acid, (R)-5,5-dimethyl -thiazolidinium-4-carboxylate (128), has been reported as a synergistic catalyst system for asymmetric List–Lerner–Barbas aldol reactions, giving yield/de/ee

de  de  ee 

29

1 Reactions of Aldehydes and Ketones and Their Derivatives 1. Et3N/ Cy2BCl; 1

F5S

CO2R

(125)

2. R2-CHO

CHO

OH R2

S

CO2R1 R

SF5 (126)

(127)

N H

CO2H (128)

up to 95/99/99% in DMSO at ambient temperature.180 New BINAP-based chiral bifunctional organocatalysts have been designed for water-mediated versions of the List–Lerner–Barbas aldol, giving yields up to 98% and ees up to 99%.181 A biphasic micellar medium of water, acetone, and aldehyde has been used to examine the effect of a single chiral catalyst (from a suite of hydroxy proline derivatives) as modulated by acidity/basicity changes effected by addition of achiral salts. For example, acidic conditions (using NH4 Cl) gave (R)-product, while basic media (using carboxylates) enriched the (S)-. That the medium is micellar is essential, and some salts only render the reaction enantioselective when they are used in concentrations that have a salting-out effect that causes a phase break. Similarly, the catalyst can have two roles: a ‘physical’ one stabilizing the biphasic system, and a ‘chemical’ one catalysing the reaction.182 DFT calculations have been employed to search for transition states of aldol reactions catalysed by vicinal diamines. A cyclic transition state with a nine-membered hydrogenbonded ring has been identified.183 A primary amino amide organocatalyst gives yield/de/ee up to 99/98/99%(syn) in aldols of isatins with ketones.184 ReaxFF, a reactive force-field model, has been used to probe the proline-catalysed aldol reaction, and in particular the role of water molecules.185 A model aldol using acetone as donor and para-substituted benzaldehydes (H, Me, and NO2 ) as acceptors has been studied using DFT at the B3LYP/6-31G(d,p) level, with a dipeptide catalyst (S)-Pro-(S)-Asp. An s-trans-enamine route with ee >99% was found to be highly favourable, with validation via use of CAM-B3LYP and M06-2X methods (within the same basis set). Solvation effects were explored using a polarizable continuum model, with DMSO and water found to be useful solvents. The identified parameters (in terms of catalyst and solvents) undoubtedly have green potential.186 Functionalized 𝛼-keto amides, R1 2 NCOCOCH2 OR2 , undergo direct asymmetric cross-aldol with aldehydes (R3 –CHO) to generate highly functionalized products with two stereocentres, R1 2 NCOCO*CH(OR2 ) and *CH(OH)–R3 , via a bifunctional Brønsted base.187 Naphthamide (129) is axially chiral, with the Ar–CO bond rotationally restricted by the ortho- and peri-substituents. Such an atropisomer may have catalytic and other uses as a stable, spatially organized, chiral scaffold. A stereoselective arene-forming aldol condensation has been reported to generate such structures in up to 98% ee from a glyoxylic amide substrate (130) in minutes at ambient temperature, using a tetrazole derivative of proline (131) as organocatalyst. Thermal isomerization indicates Ar–CO rotational barriers of the order of 113 kJ mol−1 (R1 = 5-Me; R2 = R3 = Pri ), and the aldehyde functionality conveniently allows for onward derivatization.188

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Organic Reaction Mechanisms 2016 CHO H N N H

R1

(131)

O 2

R

O

N

N N N

R1 CHO

−H2O

R3

R2

O

R3

N

R3

R3

(130)

(129)

Bifunctional chiral thioureas have been used to react 𝛽-nitro oxindoles with aldehydes to give 3-spiro-𝛼-alkylidene-𝛾-butyrolactone oxindoles (132) enantio- and diastereoselectively, via an aldol/lactonization/elimination domino sequence.189

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O R2

OH

O ∗

O

∗

OH

R1 O N Boc (132)

(133)

3-Alkylidene oxindoles and isatins undergo a highly enantioselective vinylogous aldol-cyclization cascade, using bifunctional organocatalysis, to give spiro-oxindole dihydro-pyranones.190 A carboxylic acid-selective aldol reaction mediated by boron and a mild base (DBU) has been reported. As an example, benzaldehyde reacts with propanoic acid to give 3-hydroxy-2-methyl-3-phenylpropanoic acid (133) in 96% yield and >90% syn de. The method uses BH3 ⋅SMe2 and DBU in toluene, and a tosyl-leucine as catalyst. The electron-withdrawing N-sulfonyl amino acid ligates the boron, increasing its Lewis acidity. The aldol proceeds exclusively at the 𝛼-position of the carboxyl group even in the presence of amide, ester, or ketone groups, all of which have lower pKa values for their 𝛼-protons.191 C2 -Symmetric chiral bisoxazolines act as hydrogen-bond-acceptor catalysts in decarboxylative aldols of 𝛽-ketoacids, R1 COCH2 CO2 H, with trifluoroacetaldehyde hemiacetals, F3 C–CH(OH)–OR2 , giving trifluoromethylated alcohols, R1 COCH2 CH(OH)– CF3 , in up to 98% yield and 95% ee.192 Gold catalyses a cascade Friedel–Crafts alkylation/aldol annulation which yields indenol and tetrahydronaphthalenol derivatives with two adjacent quaternary stereocentres.193

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1 Reactions of Aldehydes and Ketones and Their Derivatives

The Mukaiyama Aldol Recent advances in ‘supersilyl’ systems – those bearing tris(trimethylsilyl)silyl groups – have been described as the second generation of the Mukaiyama aldol: the authors focus on stereoselective aldol reactions involving aldehyde-derived supersilyl enol ethers.194 The origin of the observed diastereo- and enantio-selectivity in Yamamoto’s chiral (acyloxy)borane(CAB)-catalysed Mukaiyama aldol reaction has been probed computationally. The CAB ligands are conformationally flexible and far from the forming C–C bond, making the high de and ee more remarkable. To cope with this, Q2MM has been used for extensive sampling of the transition state conformations using a first-order transition state field. A closed transition state structure was calculated to be 3.3 kJ mol−1 more stable than the open one commonly invoked for this reaction.195 Protected 𝛽-hydroxy acylsilanes have been converted by two complementary methods into E- or Z-silyl enol ethers, which were then applied to Mukaiyama aldols to give 𝛽-hydroxy ketone diastereomers.196 A thiourea-catalysed Mukaiyama-type aldol is further catalysed by nitro compounds, even nitromethane. Nitro group-mediated silyl cation transfer is proposed, and is supported by 29 Si NMR monitoring. The process is convenient: it does not require low temperature, inert atmosphere, nor aqueous workup.197 Chiral allenoates have been prepared in high yield and excellent regio-, diastereo-, and enantio-selectivity following the development of an alkynylogous Mukaiyama aldol reaction built around a newly designed chiral BINAP–disulfonimide with heavy orthobuttressing.198 Fully substituted acyclic enolates of ketones have been formed as single regio- and stereo-isomers through a reaction sequence of metallation of an enol carbonate, carbonyl addition, followed by a carbamoyl transfer. The enolates, in turn, can serve as substrates for Makaiyama aldols, or for reaction with imines to give Mannich-type products.199

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The Morita–Baylis–Hillman Reaction Intramolecular MBH reaction of 𝛽,𝛽-disubstituted enones (134) has been employed in an enantioselective organocatalytic approach to cyclopenta[b]annulated arenes and heteroarenes (135).200 O

HO R3

Ar

R2 O (134)

R1

Ar

R3

∗

R2 R1

O (135)

An ionic thiourea-based organocatalyst (136) further accelerates DABCO-catalysed MBH reaction of benzaldehyde and cyclohex-2-en-1-one. Being a solid at ambient

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Organic Reaction Mechanisms 2016 CF3 N

S F3C

N H

+

PF6 −

N H

(136)

temperature, it is not an ‘ionic liquid’, but it is ionophilic and readily dissolves in IL media. Such reactions thus conveniently allow recyclability of both catalyst and solvent, with the process also proving suitable for microwave heating. The charged intermediates of the MBH reaction are stabilized by the medium.201 Asymmetric MBH reaction of methyl acrylate with aldehydes has been investigated by MS screening of the back reaction (including deuteration studies), assisting development of better catalysts. Together with kinetic measurements, the evidence points to the aldol step being rate- and enantioselectivity-determining, and not the subsequent proton transfer.202

ee 

Other Aldol-type Reactions Aldehydes have been catalytically inserted into dihalonitroacetophenones (137; X = F or Cl) via a mild sequential bond scission/aldol reaction/acyl transfer; yields of up to 99% and 100% atom efficiency are achieved. Initial cleavage generates a nitronate (138) which undergoes Lewis acid-catalysed addition to the aldehyde to give the nitro alcohol. Finally, benzoylation (to give 139) renders the sequence irreversible and regenerates the bond scission and acyl transfer agent. The method avoids elevated temperatures, transition-metal catalysts, and excesses of any reactants.203 O O NO2

Ph

R1–CHO

+

N

2

LiBr/R 3N

X X

X

−

X

O −

O

O R1

Ph NO2

X X (137)

(138)

(139)

A new catalytic system has been developed for the copper-mediated Henry reaction. Thirty-three 5-cis-substituted prolinamines were screened, with the best giving 99% ee with a broad variety of aldehydes. The 5-cis-position needs an aryl or bulky alkyl substituent, but bulk at nitrogen lowers ee (and the reaction rate). The reaction has also been rendered diastereoselective.204 A novel copper/samarium/aminophenol sulfonamide–BINAP complex catalyses a one-pot anti-selective Henry reaction, with yields/de/ee up to 99/94/98%. ESI-MS confirms the monomeric form of the complex as the active form.205

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1 Reactions of Aldehydes and Ketones and Their Derivatives

Novel disite chiral phase transfer catalysts derived from cinchona alkaloids give yields and ee up to 99% in Henry reactions of nitromethane with a wide variety of aldehyde types, at ambient temperature.206 Dendronized piperidine has been prepared and tested, proving to be an effective and recyclable catalyst for the Henry reaction.207 𝛼-Amino-oxy ketones (140) have been prepared in near-quantitative yield and up to 99% ee via an O-nitroso aldol reaction of alkenyl trifluoroacetates (141) with nitrosoarenes. Proceeding via in situ generated chiral silver enolates, the reaction is also regioselective, with the isomeric N-adduct typically present at 95% de, and >99% ee.239 𝛼,𝛽-Unsaturated 𝛼-keto esters, R1 –CH=CH–CO–CO2 R2 , undergo asymmetric Michael addition to give a 𝛽-chiral product, R–*CHNu–CH2 –CO–CO2 R2 . Asymmetric trans-amination with a benzylamine (Ar–CH2 –NH2 ) gives the corresponding 𝛼,𝛾-dichiral esters, R–*CHNu–CH2 –*CH(NH2 )–CO2 R2 . A one-pot sequential Michael/transamination process with 1,3-cyclohexanediones as nucleophiles (with an additional cyclization) has now been developed to give optically active hydroquinoline2-carboxylates.240 Bench-stable N-acylimidazoles act as ammonium enolate precursors under mild basefree conditions in the presence of catalytic isothiourea hydrochlorides. Enantioselective Michael addition–cyclizations using different 𝛼,𝛽-unsaturated Michael acceptors yield dihydropyranones and dihydropyridinones with de/ee of up to 90/98%. Reaction Progress Kinetic Analysis has helped characterize an ‘imidazolium effect’.241

Miscellaneous Condensations Lawsone (2-hydroxy-1,4-naphthoquinone, 161) undergoes acid-catalysed Knoevenagel condensation with benzaldehyde to give 6H-dibenzo[b,h]xanthenes (162). Eight new aryl-substituted derivatives have been prepared under solvent-free conditions and characterized spectroscopically, confirming that this ortho–para-xanthene structure (162) is formed in all cases. A computational investigation of this preference suggests that it is thermodynamic in origin, with (162) being more stable than the ortho–ortho- or para–para-alternatives.242 O

O OH

O

Ph–CHO H+

O O (161)

O

Ph

O

(162)

A mechanism has been proposed for imidazolium-based ILs, notably 1-methoxyethyl3-methylimidazolium trifluoroacetate (163), promoting Knoevenagel condensation.243

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1 Reactions of Aldehydes and Ketones and Their Derivatives S −

O2C CF3 +

Me

N

N

HN O

NH

Me CO2Me

F

(163)

(164)

Knoevenagel condensation of aromatic bisulfite adducts with 2,4-thiazolidine–dione in toluene yields 5-arylidenethiazolidine-2,4-diones, mediated by POCl3 . A wide range of experimental techniques has been used to show that in situ reaction of the bisulfite adduct yields the parent aldehyde as intermediate prior to C–C bond formation. Addition of phosphorus oxychloride causes a fast cleavage of the C–S bond.244 The Biginelli reaction has been reviewed.245 A highly enantioselective version of the Biginelli assembles 6-isopropyl-3,4-dihydropyrimidines (164) from 4-fluorobenzaldehyde, thiourea, and methyl isobutyrylacetate (Pri –CO–CH2 –CO2 Me). The reaction proceeds at 25 ∘ C in toluene, using a self-assembled methanoproline–thiourea organocatalyst.246 An asymmetric Biginelli-type reaction of a ketone couples an isatin with urea and an alkyl acetoacetate. Up to 80% ee was achieved using a BINOL-derived phosphoric acid catalyst. The products – spiro(indoline–pyrimidine)dione derivatives – were characterized by NMR and X-ray crystallography.247 An imidazolium salt with a pendant ester at C(4) (165) has been prepared by retroClaisen reaction of a para-quinone derivative (166). While a catalyst is not required, Lewis acids – especially silver acetate – markedly accelerate the reaction. Nucleophilic attack of the alcohol on the carbonyl group is proposed, with activation of the carbonyl by binding of silver. 1 H NMR spectra in methanol-d4 and related deuteration experiments, together with MS and IR spectra, support the mechanism.248 OMe O

Mes N +

N Mes (165)

Br− H

O

Mes

N

+

+

N

N

2 × MeOH/50 °C 1.5 h/AgOAc

Mes

N H Mes

O

(Br−)2 H

Mes

(166)

2-Substituted quinazolinones (e.g. 167) have been prepared using an iron(III)catalysed tandem reaction of 2-aminobenzamides with 1,3-diketones via condensation, intra-molecular nucleophilic addition, and C–C bond cleavage. The green protocol uses cheap ferric chloride in aqueous poly(ethylene glycol) under oxidant-free conditions at 100 ∘ C for 24 h; the sample reaction with pentane-2,4-dione gives a 91% yield.249 Salicylaldehyde condenses with cyclic 1,3-diones [e.g. dimedone (175)/2 equiv] to give 1-oxo-hexahydroxanthenes (168). As above, FeCl3 ⋅6H2 O (10 mol%) operates as a green catalyst, giving 97% isolated yield in water at ambient temperature after 30 min.250

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Organic Reaction Mechanisms 2016 R O O

HO O

NH

S O NH S O

O

O R

N O (167)

(168)

(169)

A three-component synthesis of pyrrolo[1,2-a]indoles has been developed, using indole-2-carboxaldehyde, an amine, and an enol ether. Very high ees have been achieved by changing BINOL-derived phosphoric acid catalysts to a BINAP–disulfonimide (169; R = H). The multidentate nature of the disulfonimide is invoked to explain the high selectivity, possessing as it does an acidic site, two basic sites, and multiple hydrogen-bonding sites. Very usefully, buttressing the ortho-positions (e.g. 169; R = Ar) gives enantioinversion.251 A one-pot synthesis of pyrrolyl-ketones (170) from 𝛽-enaminones (171) and arylglyoxals (as their hydrates) is mediated by triphenylphosphine, giving high yields in acetonitrile in 20 min at ambient temperature, via a cyclic phosphonium betaine intermediate.252 O O

NHR

Me

O

OH

Ar

OH

Me PPh3

(171)

ee 

Me

Me NR (+ O=PPh3) Ar (170)

1-Methyl-2,8-dioxabicyclo[3.3.0]oct-4-ene-3,7-dione (172) has been prepared by acid-catalysed condensation of glyoxylic acid and levulinic acid (4-oxobutanoic acid), with the levulinic acid enolizing to the 3-position (and not the 5-position).253 Chiral multifunctional tetrahydroindeno[1,2-c]furan-1-ones (173) have been prepared enantioselectively as single diastereomers in up to 82% yield from 2aroylvinyl-cinnamaldehydes and benzaldehydes, with a dual chiral NHC/Lewis acid catalysis.254 A new bis(N-bromosulfonamide) reagent, N,2-dibromo-6-chloro-3,4-dihydro-2Hbenzo[e][1,2,4]thiadiazine-7-sulfonamide 1,1-dioxide (174), catalyses condensation of dimedone (175) with arylaldehydes to give 9-aryl-1,8-dioxo-octahydroxanthenes (176). The reaction involves the in situ generation of Br+ from the catalyst.255 Symmetrical and unsymmetrical 𝛼-diones such as butanedione and pentan-2,3-dione undergo Friedländer synthesis with ortho-aminoarylketones, giving 2-acetyl-quinolines and 2-propanoyl-quinolines, respectively. The reactions are catalysed by TFA, are

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1 Reactions of Aldehydes and Ketones and Their Derivatives Ar Me O

H

O

O

O

X

O (172)

(173)

O

O

H

Y

O

O

BrHN

O

O O S NBr

S

O

2×

O

Ar

O

N H

(175)

(174)

O

Ar–CHO/90 °C/solvent-free

(176)

regioselective, and the products have been characterized by IR and NMR, with the mechanism scrutinized by several levels of theory.256 An organocatalytic asymmetric domino reaction of 𝛾-nitroketones with enones yields functionalized cyclohexanes with four contiguous stereocentres with yield/de/ee up to 91/95/93%, using a chiral thiourea catalyst.257

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Other Addition Reactions Addition of Organozincs A chiral amino-thiol derived from camphor (177) is an efficient catalyst-ligand in enantioselective addition of organozincs to benzaldehyde, and to 𝛼-ketoesters. Its superiority to the corresponding amino-alcohol has been investigated.258

N

O

SH (177)

Soai’s asymmetric autocatalytic addition of diisopropylzinc to pyrimidinyl aldehyde (178) has been demonstrated with a miniscule perturbation of an otherwise symmetrical organocatalyst. Isotopic 15 N monosubstitution of meso-N,N,N′ ,N′ -tetramethyl-2,3butane-diamine (179) to give [15 N](R)-179 or [15 N](S)-179 was confirmed by 13 C NMR, where the signal of the carbon bearing the nitrogen is split and isotopically shifted. In the test reaction, ees of 16–45% were observed for alcohol (180), using (separate) samples of

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Organic Reaction Mechanisms 2016 Me2N

N But

S

N

R

CHO

But

N (178)

NMe2 ∗

N (179)

OH

(180)

the isotopically chiral diamines synthesized by two distinct routes. As previously found for Soai catalysts, reapplication of the isolated alcohol (180) to the aldehyde (178) raised the ee to >99.5%.259 Copper(I) and chiral NHCs bearing a pyridyl group catalyse 1,2-addition of dialkylzincs to the imine of 𝛽-aryl-𝛼,𝛽-unsaturated N-tosylaldimines, Ar–CH=CH–CH=N–Ts, in up to 91% ee.260 DFT and ONIOM calculations have been used to probe the mechanism of the enantioselective addition of diethyl- and dimethyl-zinc to aldehydes in the presence of nickel(II) complexes of chiral 𝛼-amino amides.261 Other reports on dialkylzincs deal with new ligands based on (+)- and (−)-𝛼-pinene,262 rigid o-xylylene-type chiral 1,4-amino alcohols,263 a reusable MeO–PEG2000 -supported chiral ferrocenyl oxazoline carbinol ligand,264 and chiral 2∘ and 3∘ aziridine alcohols.265

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Arylations, and Addition of Other Organometallics, Including Grignards Recent advances in metal-catalysed intramolecular aryl additions have been reviewed, focusing on 1-aminotetraline, 1-aminoindene, and benzocycloalkanol structures.266 Rhodium(I) catalyses arylation of mono- and di-fluoromethyl ketones, Ar1 –CO–CHF2 and Ar1 –CO–CH2 F, by boronic acids, Ar2 –B(OH)2 , to give the corresponding alcohols, Ar1 Ar2 C(OH)CHF2 and Ar1 Ar2 C(OH)CH2 F, in good to excellent yields in toluene at 100 ∘ C, in the presence of potassium carbonate. Branched ketones such as 𝛼-fluoro-𝛼methylacetophenone also work, but acetophenone itself does not: a minimum of one fluorine is required. Interestingly, three fluorines lower the reactivity, with the additional electronic effect of a third fluorine outweighed by an unfavourable steric effect.267 Chiral titanium catalysts derived from H8 -BINOL ligands prove more enantioselective for arylation of aldehydes when one of the tetrahydronaphthalenes of the H8 -BINOL is ‘buttressed’ with a 3,5-disubstituted phenyl group, particularly with large groups such as tert-butyl or 9-anthracenyl.268 Chiral homoallylic amides have been prepared in high de via a one-pot, threecomponent reaction of readily available N-phosphonyl amides, aliphatic aldehydes, and allylmagnesium bromide. A key step is the addition of the Grignard to an N-phosphonyl hemiaminal (not isolated).269 Copper(I)-catalysed enantioselective addition of organomagnesium reagents to ketones to give chiral 3∘ alcohols is the subject of a short review (35 references).270 2,3-Disubstituted indoles (182) have been prepared regio- and chemo-specifically from isatins (181) by reacting the carbonyl groups in turn. Grignard reagents, RMgX, react with the ketone to yield oxindoles. These in turn are reduced with Schwartz’s reagent, Cp2 Zr(H)Cl, and subjected to nucleophilic addition and dehydration, all in one pot.271

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1 Reactions of Aldehydes and Ketones and Their Derivatives O

R O

Nu

N Br

N Br

(181)

(182)

Cheap, commercially available d-TADDOL and (S)-BINOL are efficient chiral ligands for addition of aldehydes to alkyllithiums, giving the corresponding secondary alcohols with yields/ee up to 92/94% under convenient and mild conditions.272 With chiral induction by an Ar-BINMOL ligand, addition of organolithiums to aldehydes still suffers from low ee when titanium tetraisopropanoxide is employed. Reasoning that chloride is more labile, TiCl(OPri )3 has been successfully deployed to produce highly enantioselective addition of organolithiums (including MeLi) to a wide range of aromatic and aliphatic aldehydes, tolerating halogen and nitrile functionalities.273 𝛽,𝛾-Unsaturated ketones have been prepared via an umpolung strategy: nucleophilic 𝛽-alkenylation of N-alkoxyenamines. The latter are prepared in situ from ketones and isoxazolidine by means of alkenyl aluminium reagents.274

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The Wittig and Other Olefinations Triphenylphosphine oxide, Ph3 P=O, frequently the waste by-product of Wittig reactions, can activate bromination of alkenes. Combining these observations, a one-pot stereoselective synthesis of 𝛼,𝛽-dibromoesters (183) from aldehydes has been developed, using an ester Wittig reagent (184). The trans-dibromoesters (183) are obtained in up to 88% yield and >90% de. A version with an 𝛼,𝛽-unsaturated enal gives the corresponding trans,cis,trans-𝛼,𝛽,𝛾,𝜎-tetrabromoester with comparable yields and des.275 OR2 Ph3P O (184)

Br R1–CHO

O

1

O 2

R

OR

P Ph

Br (183)

(185)

The mechanism of the Wittig reaction of a stabilized ylide with benzaldehyde has been modelled ‘on water’, using a gas hydrate structure of 20 water molecules as a surface, allowing non-bonding interactions over a large area to be captured by the calculation. The cis-selective version is accelerated more than the trans-, apparently as it has a greater number of such stabilizing interactions. Contrasts are also drawn with the neat reaction.276 Gas-phase Wittig reactions of 2,2-dimethylcyclopentanone have been studied at the B3LYP/6-31G*t level of theory. Using ylides, X3 P=CHR, to examine non-stabilized, semi-stabilized, and stabilized cases (R = Me, Ph, and CO2 Me, respectively), high Eselectivity was observed, apparently via the salt-free oxaphosphetane mechanism.277

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Organic Reaction Mechanisms 2016

Aldehyde olefination has been effected with ethyl diazoacetate, using a combination of an iron(II)/NHC complex and triphenylphosphine as catalysts. The Wittig-like process exhibits excellent E-selectivity. Generation of a phosphorus ylide is considered to arise via a metal carbene, (NHC)Fe(IV)=CH(CO2 Et), or a phosphazine, Ph3 P=N–N=CH(CO2 Et).278 Carbazole ligands have been prepared via a domino Wittig/Diels Alder reaction.279 A base-free catalytic Wittig reaction has been developed for synthesis of highly functionalized alkenes. Taking the model reaction of benzaldehyde with diethyl maleate, optimization experiments have led to a protocol of maleate (1.1 equiv), pre-catalyst phosphine oxide (185; 0.05 mol), (MeO)3 SiH (3.0 mol), and Brønsted acid (PhCO2 H, 0.05 mol) in toluene at 100 ∘ C for 14 h. Yield is quantitative, with an E/Z-ratio of 88/12.280 A new direct nucleophilic difluoromethylation of aldehydes and ketones has been identified in a diversion of a Wittig. Difluoromethyl triphenylphosphonium bromide (DFPB, Ph3 P+ CHF2 Br− ) had previously been employed in Wittig reactions, where treatment with a suitable base such as DBU yielded the betaine, Ph3 P+ CF2 − , allowing difluoroolefination. But if the base is changed to caesium carbonate, the Wittig fails and instead formal addition of difluoromethane occurs: R1 –CO–R2 → R1 –C(OH)(CHF2 )–R2 . As to the mechanism, it appears that the carbonate may act as a nucleophile rather than as a base, attacking DFPB (whose phosphonium centre would be expected to have a high affinity for oxygen) to give the pentacoordinate Ph3 P(OCO2 − )CHF2 Cs+ , which then reacts with the carbonyl compound, with loss of triphenylphosphine oxide, Ph3 P=O, and CO2 .281 A ruthenium(II)–sulfonamide (186) catalyses direct condensation of toluene with benzaldehyde to give trans-stilbene (trans-Ph–CH=CH–Ph). The catalyst is much more sophisticated than it first appears, with the 𝜂 6 -tolyl ‘ligand’ and sulfonamide ‘counterion’ both apparently participating in C–C covalent bond making and breaking, with the latter also acting as a base facilitating benzylic C–H bond breaking. In situ formation of an imine, Ph–CH=N–Ts, is proposed to lead to attachment to the ligand’s benzylic methyl, followed by elimination and release of stilbene. The method also converts paraxylene and two moles of aldehyde to para-distyrylbenzene.282 OMe HO Ru+

−

NHTs

O N Me

(186)

(187)

A chiral N,N′ -dioxide/Mg(OTf)2 complex catalyses an asymmetric carbonyl-ene reaction of N-methylisatin with an alkyl enol ether such as 2-methoxypropene, giving (R)-product (187) in 98% yield and >99% ee. A computational investigation of the mechanism and of the origin of the stereoselectivity highlights the ability of the

1 Reactions of Aldehydes and Ketones and Their Derivatives

45

magnesium to form a hexacoordinate species, binding to the isatin’s oxygen and also generating a more polar process with lower activation barriers. The study also came up with a design proposal, suggesting that the catalyst’s N-oxide functions might profitably be replaced with phosphorus donors.283 An MPZ/6-31G(d) study of high-temperature thermolysis of 2-methylbutanal reproduced experimental rate constants. The retro-ene mechanism involves two steps: (i) cleavage to 1-propenol and ethene via a six-membered transition state, followed by (ii) ketonization (of propenol) via a four-membered transition state, both steps being highly synchronous and concerted. Comparisons with 2-pentanone, 3-hydroxy-2-methylpropanal, and 4-hydroxy-2-butanone are also detailed.284 Diarylmethanones (benzophenones) react with hexachlorodisilane, Si2 Cl6 , to give tetra-aryl ethenes in good yields. The carbonyl groups are proposed to act as Lewis bases, initially generating low-valent species such as SiCl2 , leading the authors to describe it as a ‘Sila-McMurry’ reaction, by analogy with the classical process involving TiCl2 . Benzopinacolones are then formed and can be isolated. The reaction fails if the aryl is very sterically demanding or has strongly electron-withdrawing groups. As the reactions take up to 3 days at 160 ∘ C, identification of Lewis base catalysts would extend their utility.285 For a methylenation of aldehydes and ketones via their N-sulfonylhydrazones, see the ‘Hydrazones and Related Species’ section.

Hydrosilylation, Hydrophosphonylation, Hydroboration, and Hydroacylation A bifunctional Lewis acid catalyses hydrosilylation of benzaldehyde and triethylsilane and is proposed to do so by simple ‘double activation’ (188). The corresponding monostibonium cation, Ph3 MeSb+ , is not an effective catalyst. Direct observation of such activation of a carbonyl group via antimony ligands is provided by isolation and X-ray crystallographic analysis of the corresponding 𝜇2 -adduct of DMF.286 HSiEt3

Ph

Me Me + O + Ph Sb Sb Ph Ph Ph ( −OTf) 2 (188)

Bn

NH

HN Bn

(189)

An air-stable and green chiral zinc complex has been used in asymmetric reduction of the C=N bond. N-Phosphinylimines are hydrosilylated by polymethylhydrosiloxane (PMHS) or triethoxysilane in the presence of (R,R)-N,N′ -dibenzyl-1,2-diphenylethane1,2-diamine (189) and zinc acetate with yields/ee up to 96/97% in THF/methanol at ambient temperature in 1 day.287 Silyl formates have been employed as hydrosilane surrogates: they can effect chemoselective reduction of various aldehyde types by transfer hydrosilylation under ruthenium

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catalysis. Mechanistic investigations show that genuine hydrosilane species are avoided. Instead, a decarboxylation/insertion/transmetallation route has been identified.288 Catalysis of hydrosilylation of ketones by the high-valent molybdenum(VI)–dioxo complex, MoO2 Cl2 , had been thought to occur via a [2 + 2]-addition pathway, but a reinvestigation by DFT suggests an ionic outer-sphere route involving a novel SN 2@Si transition state. An interesting comparison is drawn with the catalysis of hydrosilylation by Lewis acids such as B(C6 F5 )3 .289 1,2-Dicarbonyl compounds have been hydrosilylated enantioselectively using chiral FLP catalysts to deliver 𝛼-hydroxy ketones and esters in up to 98/99% yield/ee. Although 3 equiv of dimethylphenylsilane was employed, no diol by-products were observed.290 A new nickel–pyridine–bisulidine complex asymmetrically hydrophosphonylates aldehydes, giving 𝛼-hydroxy phosphonates in up to 99% yield and 97% ee.291 An unactivated ketone ortho-tethered to a boronic acid (190) undergoes intramolecular addition to give 3-hydroxy-2,3-dihydrobenzofurans (191). Using rhodium with a chiral SOL (sulfur-based olefin ligand) gave yields and ee of up to 98/98%.292 B(OH)2 R1

R2

O

HO

[Rh]/SOL* K2HPO4/ toluene/r.t.

ee 

R2

R1 O

O (190)

ee 

(191)

Nucleophilic borylation of the carbonyl group of aldehydes has been achieved regioand enantio-selectively using bulky diphosphine/borylcopper(I) catalysts which exert a notable polarizing effect. Up to 96% ee was obtained.293 Light alkali metal hydridotriphenylborates, M[HBPh3 ] (M = Li, Na, K), complexed with a simple triamine, efficiently catalyse chemoselective hydroboration of aldehydes and ketones, and of carbon dioxide.294 A copper carbene complex catalyses hydroboration of aldehydes and ketones at ambient temperature with only 0.1 mol% catalyst loading, giving turnover frequencies >6000 h−1 , and leaving alkenes, nitriles, esters, and allyl chlorides untouched.295 A diastereodivergent strategy for constructing bicyclic 𝛾-lactones (anti-192 and syn-192) bearing quaternary centres uses intramolecular hydroacylation of 𝛾,𝛾-diketoaldehydes (193), catalysed by rhodium complexed with a chiral ferrocenyl diphosphorus ligand. Stereoselection can be achieved by kinetic control: (anti-192) is obtained at 10 ∘ C with ees typically 90–99%, whereas (syn-192) is formed at 80 ∘ C, usually in >99% ee.296 Cobalt(I) catalyses enantioselective intramolecular hydroacylation of ketones and alkenes, giving phthalide or indanone products, depending on the choice of cobalt ligand. DFT results indicate hydrogen migration as both the rate- and stereo-determining steps.297 A nickel-catalysed hydroacylation of styrenes with simple aldehydes allows selective preparation of branched ketones in near-quantitative yields with branched:linear ratios of up to 99:1. Using an Ni(COD)2 /PCy3 catalyst system in refluxing dioxane, NMR and

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1 Reactions of Aldehydes and Ketones and Their Derivatives O Bn O

(193)

CHO O

RhI

O

O Bn O

JoSPOphos ligand

(anti-192)

+

Bn O

O

(syn-192)

isotopic labelling studies (backed up by calculations) suggest reversible formation of an acyl–nickel–alkyl intermediate, with aldehyde C–H bond transfer to a co-ordinated alkene without oxidative addition.298 Rhodium(I) catalysts incorporating tight diphosphine ligands such as dppm (bis(diphenylphosphino)methane) couple aldehydes and propargyl amines to give linear hydroacylation adducts, R2 –CO–C(R3 )=CH–CH(R4 )–NHR1 . In situ treatment with tosic acid triggers cyclization to pyrroles. The corresponding sequence using allylic amines produces dihydropyrroles.299 DFT has been used to study the mechanisms of ruthenium(II)-catalysed hydroacylation of isoprene with benzaldehyde and with its three methoxy-substituted isomers.300

ee 

Formation of Cyanohydrins, Cyanosilylation, and other Cyanations Cyclic 2-fluoroketones have been converted to their TMS- or TBS-protected cyanohydrins in good yield and de, using TMSCN or TBSCN and a Lewis base. Reagent and base selection allow access to both stereoisomers: TMSCN/DIPEA gives cis, while TBSCN/ methoxide gives trans.301 A cyanide-free synthesis of O-trityl-protected cyanohydrins from aldehydes uses trityl isocyanide (Ph3 C–N+ ≡C:− ) with diphenyl phosphite as catalyst in an ‘interrupted Passerini-type reaction’ in which the reagent attacks the phosphoric acid-activated aldehyde, the trityl cation is lost (but presumably into a tight ion pair) to give the simple cyanohydrin, and then the trityl cation recombines at oxygen. Use of chiral phosphoric acid organocatalysts renders the reaction enantioselective.302 Ketones have been enantioselectively cyanosilylated with lithium dicyanotrimethylsilicate(IV), Li+ [Me3 Si(CN)2 ]− , and a catalytic lithium BINOL–phosphate–phenolate salt.303 New aluminium hydride species catalyse addition of TMS–cyanide to aldehydes.304 A study of the mechanism of a dual Lewis acid/Lewis base-catalysed acylcyanation of benzaldehydes by acyl cyanides (R–CO–CN) has been undertaken. The chiral 𝛼-cyano ester products (194; a.k.a. O-acylated cyanohydrins) are useful synthetic building blocks. A Hammett correlation analysis, variation of catalyst structure, and low-temperature NMR experiments point to a mechanistic switchover. The Lewis base activates the acyl cyanide, releasing cyanide ion and a powerful acylating agent. Lewis acid activation of the aldehyde facilitates addition of the cyanide ion, which is then followed by Oacylation. For less-reactive aldehydes, addition of cyanide is rate determining, whereas the addition is rapid and reversible for electron-deficient aldehydes, where acylation becomes rate limiting. The catalyst resting state is a titanium complex off the catalytic

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Organic Reaction Mechanisms 2016

2

O

R

CO2Et

O O

R

∗

Ph

CN

O

N R1

R1

R2 NH

R1 R2

CO2Et

NH

N CO2Et

(194)

(195)

(196)

cycle. Its stability is the likely reason for high catalyst loading being required for an effective process.305 𝛽-Ketonitriles have been produced by electrophilic cyanation of boron enolates with either tosyl cyanide or N-cyano-N-phenyl-p-toluenesulfonamide [Ts–N(Ph)CN, NCTS]. An enantioselective example is described.306

ee 

ee 

𝛼-Aminations and Related Reactions 13 C-

and 2 H-KIEs have been combined with computations to reveal the mechanism of enamine formation in proline-catalysed 𝛼-amination of aldehydes. The results support the formation of enamine being rate determining, but calculated and measured KIEs are inconsistent with enamine being formed by intermolecular deprotonation of an iminium carboxylate. Rather, the KIEs are consistent with E2 elimination catalysed by a bifunctional base to directly form N-protonated enamine from an oxazolidinone, indicating that oxazolidinones are non-parasitic intermediates.307 Direct catalytic 𝛼-amido-alkylation of carbonyl donors (ketones and aldehydes) with unbiased N,O-acetals at ambient temperature has been carried out using tin(IV) triflimidate as its dimethyl sulfoxide adduct, Sn(NTf)4 ⋅(DMSO)4 , acting as a Lewis superacid. As part of their determination of the reaction scope, the authors constructed reactivity scales for the reactants, that is for N,O-acetals and especially for ketones. The latter scale should be more generally useful for other 𝛼-functionalizations of ketones.308 Amino acid-substituted imidazoles (195) have been prepared in high yield from 2-oxoaldehydes, R1 –CO–CHO, and ethyl esters of amino acids, R2 –*CH(NH2 )–CO2 Et (two moles each), using selenium dioxide/pyridine in acetonitrile at ambient temperature, with regioselectivity. Control experiments suggest an intermediate with two full amino acid moieties (196, confirmed by MS), which must then undergo C–N cleavage.309

ee 

Enolization, Reactions of Enolates, and Related Reactions Enolizable anhydrides (e.g. 197) have been found to undergo asymmetric formal cycloadditions with activated ketones to give highly functionalized lactone–esters (198) in high yield/de/ee, using cinchona alkaloid-based catalysts.310 Specific anion effects on the kinetics of the iodination of acetone in acidic media have been reported, with the sequence of the mixed constant, k1 K, being HBr < HCl ≪

de  ee 

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1 Reactions of Aldehydes and Ketones and Their Derivatives O

O O

O

F3C

O

O

Ph

CF3 Ph CO2Me

chiral catalyst/ TMS–CH=N2 /MeOH

(197)

(198)

HClO4 < HF < H2 SO4 < H3 PO4 . (The order of the reaction with respect to acetone is close to unity, and practically unaffected by the composition of the acid). The rate variations are explained in terms of a combination of the interaction of the anions with the solvent (reflected in their Gibbs free energy of hydration), and the specific stabilization of the reaction intermediate. The multi-functional oxygenated anions are three of the top four, presumably through hydrogen-bonding interactions such as (199).311

+

Me

−

O H O Me

−

H O (199)

O S

Mn(CO)2

H C

O

C

R

H

F2HC-O

O

−

O (200)

(201)

While conjugated alkynyl aldehydes, R–CH2 –C≡C–CHO, do not normally isomerize to their thermodynamically less-stable allenal isomers, R–CH=C=CH–CHO, organomanganese complexation facilitates the process. Using a chiral cinchonidinium salt under weakly basic conditions, a cumulenolate intermediate (200) can form, and asymmetric protonation then yields the allenal (still complexed by manganese) in up to 92% yield and up to 83% ee.312 The preference for enolate anions to undergo O- rather than C-alkylation in the gas phase has been studied computationally for the model SN 2 reaction of the enolate of acetaldehyde reacting with methyl fluoride. Using a number of methods, the separate contributions of resonance and inductive effects to raising the barrier were calculated. Both increase the energy, but resonance is the dominant effect, with C-methylation raising the barrier about twice as much.313 An S-difluoromethyl sulfonium salt has been used for O-difluoromethylation. The reaction has now been studied for cyclic and acyclic diones, producing, for example, (201) from 1,3-cyclohexanedione. Previously, the mechanism was ascribed to the reagent directly transferring the CHF2 group, but a difluorocarbene process has now been found to also operate.314 A pentacoordinate bis(difluoromethyl)silicate anion, [Me3 Si(CHF2 )2 ]− , has been observed by activation of Me3 SiCHF2 with a nucleophilic alkali-metal salt and 18crown-6. It can be used for nucleophilic difluoromethylation of enolizable ketones. The anion has been characterized by 19 F, 29 Si, and 1 H NMR, and its reactivity characterized by variable-temperature and deuteration NMR experiments. The new anionic reagent

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Organic Reaction Mechanisms 2016

is conveniently used in 1,2-dimethoxyethane (DME) solvent at ambient temperature, stabilized by the [(18-crown-6)Cs]+ counterion generated from inexpensive caesium fluoride.315

𝛼-Halogenation, 𝛼-Alkylation, and Other 𝛼-Substitutions Starting from a simple aldehyde, R1 –CH2 –CHO, a four-step reaction sequence of chlorination (with a chiral catalyst), oxidation, substitution, and cyclization leads to enantioenriched 2-oxopiperazines (202) in up to 93% yield and 95% ee. A previously elusive epoxy lactone intermediate (203) is proposed and has been identified by HRMS.316 R2 R3 R3

N N

RL O R1

O R

(202)

N Boc

R2 (203)

R1 F

1

O

O

CHO

RS

ee 

(204)

R2 n

(205)

Trichloromethylsulfonyl chloride, Cl3 C–S(=O)2 –Cl, efficiently 𝛼-chlorinates aldehydes in up to 99% yield, with minimal dichlorination. Greener than many other chlorinating agents, the whole protocol is quite benign: DME/water at ambient temperature for 2 h, with pyrrolidine and 2,6-dimethylpyridine as bases. A simple proline derivative renders the reaction highly enantioselective.317 A catalyst-controlled diastereodivergent synthesis of substituted 𝛽-fluoropyrrolidines has been developed. Starting from N-protected 𝛽-aldehyde (204), fluorination with Nfluorobenzenesulfonimide [NFSI: FN(SO2 Ph)2 ] places the fluorine syn- to the large substituent (RL ) if a simple chiral pyrrolidine organocatalyst is employed (giving up to 98% de), while a readily available imidazoline completely reverses the selectivity to anti- (again, up to 98%).318 𝛼-Fluoro-indanones (205; R1 = H or C(OH)2 –CF3 ) have been enantioselectively 𝛼-arylated (to give 205: R1 = Ar), using an aryl bromide (or triflate) and base, and a palladium/BINOL-phosphine catalyst. 72 examples are reported, with yields of 63–91% and ees of 80–94%. For the 𝛼-fluorotetralone case (i.e. n = 0), the reaction works better with the loss of trifluoroacetate. Heteroaryl bromides also work.319 Chiral 𝛾-nitroaldehydes (e.g. 206) are accessible via organocatalytic Michael addition of aldehydes to nitroalkenes. NFSI has now been used to 𝛼-fluorinate them in a reaction which proceeds via a chiral trisubstituted enamine, with catalysis by a diarylprolinol TMS ether. NMR and computational studies have identified several kinetic and thermodynamic factors controlling the enantio- and diastereo-selectivities achieved. The fluorination has also been incorporated into a one-pot version of Michael preparation of (206).320 Chromones (e.g. 207) have been prepared in one pot from ortho-chlorobenzoyl chloride and (in this case) ethyl benzoylacetate, using a strong base/weak base protocol

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1 Reactions of Aldehydes and Ketones and Their Derivatives O

O

Ph

O

NO2

H

OEt

(S)

O (206)

Ph

(207)

(NaOBut /Cs2 CO3 ), in dimethylacetamide solvent. The formal 3 + 3-cycloaddition consists of sequential C-acylation and O-arylation.321 Preparation of 𝛼-benzyl-𝛼,𝛼-difluoroketones, Ar–CH2 –CF2 –CO–R, has been achieved by palladium-catalysed decarboxylation of a related 𝛽-ketoester, Ar–CH2 –OC (=O)–CF2 –CO–R, a strategy which circumvents the intrinsically poor reactivity of the enolates of 𝛼,𝛼-difluoro-ketones.322 Tsuji–Trost-type direct 𝛼-allylation of 𝛼-branched aldehydes uses a synergistic organocatalysis by a Brønsted acid and an amine.323 Ketones have been 𝛼-allylated stereoselectively via their sulfinylimine derivatives using palladium catalysis and triphenylphosphine. The S-chiral auxiliary can be quantitatively removed by in situ hydrolysis without racemization.324 An indanone with a pendant ester (208) undergoes an intramolecular enolate Calkylation to give a C2 -symmetric 2,2′ -spirobi-indanone (209) in up to 94% ee, using a chiral counterion to control the ee. The reaction works for Ar = Ph, but pentafluorophenyl is superior. A range of substituents is tolerated, with different substituents allowing access to unsymmetric variants of (209).325 O

chiral quinolinium catalyst;

Ar O O

O

K3PO4

O (208)

(209)

Transition metal-catalysed C-alkylation of ketones and secondary alcohols, with alcohols, avoids organometallic and other environmentally unfriendly agents. A review details recent advances (since 2009) in the ‘borrowing hydrogen’ or ‘hydrogen auto-transfer’ involved in these processes.326 A synergistic rhodium(III)/amine catalysis is ascribed to the high ee obtained in alkylation of aldehydes with 𝛼,𝛽-unsaturated 2-acylimidazoles.327

Oxidation and Reduction of Carbonyl Compounds Oxidation of Aldehydes to Acids Several papers deal with the conversion of aldehydes to carboxylic acids, or oxidation to the acid level, such as anhydride or nitrile formation.

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Organic Reaction Mechanisms 2016

A kinetic study of the oxidation of 2,4-dichlorobenzaldehyde by potassium permanganate in sulfuric acid exhibited first-order kinetics with respect to all three; salt and temperature effects were also investigated.328 The effect of magnesium hydroxide on the oxidation of furfural has been studied by experiment, IR, and Gaussian calculations. Selective oxidation of the aldehyde group leads to 2-formyloxyfuran as a crucial intermediate. Magnesium hydroxide helps to suppress ring oxidation, enhancing selectivities towards 2(5H)-furanone (45%) and succinic acid (38%). The reaction was found to be homogeneous.329 The simplest Criegee intermediate (210, also known as the Criegee biradical or zwitterion) has been studied in the gas phase for its reactions with acetaldehyde and acetone, from 298 to 500 K and 4–50 mmHg. At room temperature, the rates are ca. two orders of magnitude greater than those of alkenes, with the aldehyde four times faster than the ketone. A theoretical analysis points to an inner 1,3-cycloaddition transition state in the rate-limiting step.330 −

+

−

O

+

H2C O

O

H N

O

H2C O Cl

N

O N

Cl

O (210)

(211)

B97D computation shows that NHC-catalysed chemoselective ring opening of N-tosyl aziridines with aldehyde under aerobic conditions involves rate-determining ring-opening to give the carboxylate product, with the oxygen atom derived from molecular oxygen.331 A green method for making anhydrides from aldehydes uses cross-dehydrogenative coupling (CDC). Employing TBHP as oxidant and tetrabutylammonium iodide as catalyst, the mechanism the authors favour generates acyl and carboxyl radicals, which combine.332 Hydroxylamine–O-sulfonic acid (H2 N–OSO3 H) converts aldehydes to nitriles in water at 50 ∘ C in high yields. Acetic acid boosts the yields, and indeed ordinary vinegar gives a 94% yield of 3-phenylpropionitrile from 3-phenylpropionic acid. The free oxime gives very low yield when exposed to the reaction conditions, so it appears that direct formation of the (organic) hydroxylamine–O-sulfonic acid (R–CH=N–O–SO3 H) occurs, followed by elimination of sulfuric acid. A wide range of functional groups are tolerated, and hindered aldehydes and enals work well.333

Other Oxidations and Oxidative Processes Several reports deal with oxidation of ketones. Dichloroisocyanuric acid (DCICA, 211) oxidizes aromatic ketones such as acetophenone and desoxybenzoin (PhCOCH2 R; R = H, Ph) in aqueous acetic/perchloric acid media. A kinetic study indicates that enol tautomers and protonated ketones

53

1 Reactions of Aldehydes and Ketones and Their Derivatives

both participate. For example, the conjugate acid of the ketone gives rise to the enol in a rate-determining step. Added chloride ions divert the reaction, with molecular chlorine species (from HOCl via DCICA) reacting with protonated ketone (again, rate determining).334 Acetophenone has been oxidized by N-bromosaccharin in a kinetic study in aqueous acetic acid media. Addition of mercury(II) acetate, and of saccharin, has been investigated, as have the roles of cationic and anionic micelles.335 Copper-catalysed oxidation of ketones, R1 –CO–CHR2 R3 , with molecular oxygen can result in 𝛼-hydroxylation, or else C–C cleavage to a shorter ketone (R2 –CO–R3 ) and an acid (R1 –CO2 H). An experimental and computational study suggests a common key intermediate, that is an 𝛼-peroxo ketone. The factors that then affect its fate are examined in detail, including the roles of the copper catalyst, the structure of the substrate, the nature of the solvent, and the type of base employed.336 1,3-Disubstituted imidazo[1,5-a]pyridines (212) have been prepared from 2-aroylpyridines (213) via a copper/iodine co-catalysed decarboxylative cyclization with an 𝛼-amino acid. The 2-aroyl-quinoline reactant can give the corresponding benzo-fused version of (212). Di-tert-butyl peroxide serves as oxidant.337

CO2H

Ar +

N

R O (213)

NH2

Cu(OTf)2/I2/DTBP

Ar

N

−CO2, −H2O

N R (212)

A number of other reactions described involve aldehydes being oxidatively coupled. A biomimetic domino amination–oxygenation has been developed for direct amidation of aldehydes under metal-free conditions, using air as oxidant. 9-Aminofluorene acts as a pyridoxamine 5′ -phosphate equivalent to convert an aldehyde, RCHO, to a 1∘ amide, RCONH2 . Appropriate N-substitution of the fluorene gives the corresponding 2∘ amide. An azomethine ylide route is supported. Labelling studies are also instructive: H2 18 O does not incorporate oxygen into the amide, though some 18 O shows up in the fluorenone by-product. In contrast, the use of 18 O2 results in 100% incorporation: indeed, this is now proposed as an efficient method of so labelling amides.338 A range of quinazolines (214) have been prepared in up to quantitative yield from 2-aminobenzamides and aldehydes (RCHO, or the corresponding alcohol, RCH2 OH), using a vanadium catalysis and aerobic oxidation. The VO(acac)2 catalyst and relatively benign conditions (refluxing DCE, 1 atm O2 , 2 h) avoid more toxic oxidants, sensitive hydroperoxides, expensive metal catalysts, and so on. It is likely that oxygen converts V4+ to V5+ species, and the latter then has two functions: (i) oxidation of alcohol to aldehyde (if required), followed (after aminal formation) by (ii) oxidation of the aminal to the quinazolinone.339 Redox-neutral aromatization of cyclic amines with aldehydes [e.g. pyrrole (215) + benzaldehyde → 1,3-dibenzylpyrrole (216)] has been studied by computation and by interception of reactive intermediates which include azomethine ylides and enamines.

54

Organic Reaction Mechanisms 2016 Ph O

Bn

toluene

NH N

R

(214)

N H (215)

200 °C /20 h

+

+

N N Bn (216)

Ph

−

(217)

N Ph

−

(218)

The former were confirmed by trapping them via intermolecular 3 + 2-cycloaddition with N-methylmaleimide: simple (217) and conjugated (218) cases were identified. The original reaction conditions of 200 ∘ C for 20 h have been modified to a milder version (toluene reflux with acetic acid catalysis), and such acid catalysis has also been investigated computationally. Formation of acetylated N,O-acetals is implicated.340

Reduction Reactions A review examines the current understanding of enantioselective reduction of prochiral aromatic ketones by Noyori and Nayari–Ikariya bifunctional catalysts, two of the bestbehaved catalytic systems: they deliver up to 99.9% ee with very low catalyst loading of ca. 10−5 mol%.341 The use of phosphine-free tethered ruthenium(II) catalysts for asymmetric reduction of ketones and imines has been reviewed. Systems related to the commonly used TsDPENliganded catalyst [Ru(II)/N-tosyl-1,2-diphenylethylene-1,2-diamine] are described, as well as closely related Rh(III) and Ir(III) catalysts.342 An amine(imine)diphosphine iron pre-catalyst is a highly efficient promoter of asymmetric transfer hydrogenation of ketones such as acetophenone, when suitably activated with base. A detailed study has characterized the catalysis via 1 H NMR (including nuclear Overhauser effects), MS, X-ray crystallography, and IR, supported by DFT studies.343 Several asymmetric transfer hydrogenations were carried out on ketones in formic acid/triethylamine, using ruthenium catalysts. New 𝛾-sultam-cored N,N-ligands were used for hydrogenation of ketones, including the first report of a dynamic kinetic resolution of a 𝛾-keto ester.344 Bifunctional oxo-tethered ruthenium complexes were used for reduction of unsymmetrical benzophenones where the asymmetry is steric in nature (e.g. mono-ortho-substituted substrates), or electronic. The reaction was extended beyond benzene derivatives to, for example, phenyl 2-thienyl ketone and to benzoylferrocene.345 CF3 -substituted 1,3-diols [e.g. PhCH(OH)CH2 CH(OH)CF3 ] have been prepared in high yield and excellent enantiopurity from the corresponding diketones. Milder conditions allow isolation of the intermediate keto-alcohol, again in high enantiopurity. A dynamic kinetic resolution is invoked, with impressive results of 100% conversion and de and ee >99.9% after one recrystallization in some cases.346 Silyl enol ethers undergo FLP-catalysed transfer hydrogenation using 𝛾-terpinene as hydrogen surrogate, and B(C6 F5 )3 and TMP (2,2,6,6-tetramethylpiperidine) as the Lewis acid and Lewis base.347

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1 Reactions of Aldehydes and Ketones and Their Derivatives

A readily available ruthenium(II) catalyst has been used for hydrogenation of aldehydes, with optimization of conditions (no base, no solvent) giving turnover number up to 340 000. Alkenes and ketones are unaffected, and glucose is efficiently reduced. Theoretical studies identify the hydrogenation itself as rate determining, rather than the H2 activation step.348 Reductive amination of ketones such as acetophenone is catalysed by a nickel(II)biphosphine in up to 91% ee, using an aniline as the amine, and formic acid as a safe surrogate for hydrogen. The product, Ph–*CHMe–NH–Ar, can alternatively be obtained in protected form (Ph–*CHMe–NH–NHBz) if benzhydrazide (H2 N–NHBz) is used instead of aniline, typically also raising the ee. A double-reductive amination, using ortho-diaminobenzene and an 𝛼-keto-aldehyde, gives quinoxalines which are readily reducible in situ to their tetrahydro analogues in good to excellent ee.349 Enantiopure 𝛽-arylamines (219) have been prepared via another direct asymmetric reductive amination of the corresponding arylacetones. Catalysed by iridium complexed to an axially chiral phosphoramidite in the presence of H2 /Ti(OPri )4 /TFA, ees of up to 99% were achieved, with turnover numbers of up to 20 000. Diphenylmethylamine (i.e. 𝛼-phenylbenzylamine) serves as a convenient nitrogen source, with its steric bulk ensuring considerably higher enantioselectivity compared to benzylamine itself.350 O ∗

R

ee 

N(iPr)2

Me HO

HN (219)

CHPh2

R

O (220)

O (221)

The use of samarium(II) iodide to mediate reductive couplings of aldehydes with substituted acrylates yields dihydrofuran-2(3H)-one derivatives (𝛾-butyrolactones, e.g. 220). However, complications include self-dimerization of some aliphatic aldehydes and low diastereoselectivity in the products. Now, new acrylates derived from 2-amido arenols such as N,N-diisopropyl-2-hydroxy-benzamide (221) help minimize these problems in two ways. Firstly, they enable preferential conjugate reduction of acrylates, thus diminishing aldehyde self-dimerization. Secondly, they facilitate an eight-membered ring [using the carbonyl oxygen of the amide and samarium(III)], leading to a bicyclic TS which sets up highly diastereoselective protonation of the samarium(III) enolate intermediate.351 Aldehyde–alkyne reductive couplings with silanes produce 𝛽-siloxyalkene derivatives, R1 –CH(OSiR2 3 )–CR3 =CHR4 , with R1 , R2 , and R3 /R4 derived from aldehyde, silane, and alkyne, respectively. DFT has been used to investigate NHC–Ni(0) catalysis of the reaction, with variations of the bulk of NHC ligands and R2 groups. Changing the regioselectivity (i.e. swapping R3 and R4 in the product) can be controlled by bulking up any of the three reactants or the NHC.352 The synthesis of tertiary arylamines via Lewis acid-catalysed direct reductive Nalkylation of secondary amines with aryl ketones has been achieved using tin(II)/PMHS,

de 

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Organic Reaction Mechanisms 2016

but through an alternative carbocationic pathway, rather than by reductive amination. Control experiments and testing of the reaction with cation traps have been used to support the mechanism.353 An in-depth computational study of the mechanism of thionation of carbonyl compounds with Lawesson’s reagent has been undertaken. Following dissociation of the reagent, two steps are involved: (i) concerted cycloaddition of the monomer and carbonyl to form a four-membered intermediate and (ii) cycloreversion leading to the thiocarbonyl derivative and phenyl(thioxo)phosphine oxide. The second step is rate limiting, and the overall mechanism resembles that of the lithium salt-free Wittig. Amides are the most reactive. Substituent effects – both steric and electronic – are significant in aldehydes and ketones, but not in amides or esters.354

Miscellaneous Cyclizations Diastereoselective formation of useful tricyclics (223) has been achieved by platinumcatalysed addition of aldehydes such as cinnamaldehyde to 1,6-enynes (e.g. 222).355 Ar

Ph Ts

cis-[Pt(PPh3)Cl2]

N

PhCH=CHCHO

Ph (222)

AgOTf

Ts

N

O Ph (223)

de 

O

O

Ar

Ar

O (224)

Acetophenones, Ar1 COCH3 , undergo a [1 + 1 + 1]-cyclotrimerization to give a single trans-stereoisomer (224), involving a copper-catalysed sixfold C(sp3 )–H bond functionalization. In a test of possible intermediacy, the 1,4-diketone, Ar1 COCH2 CH2 COAr1 (formed by dimerization of the acetophenone), could either dehydrogenate (to the enedione, trans-ArCOCH=CHCOAr) or could react with a different acetophenone (Ar2 COCH3 ) to give a mixed version of (224). The proposed mechanism involves all three species, and appears to be radical in nature, with scavengers like TEMPO suppressing cyclopropane formation.356 Reaction of sulfur ylide (225) with 𝛼,𝛽-unsaturated aldehyde (226) in the presence of (S)-indoline-2-carboxylic acid (227) catalyst gives cyclopropane (228) in 73% yield, with ee = 89% and de = 93%. Mechanistic proposals to date conflict, and do not fully explain the experimental behaviour. A computational study has now identified several strong hydrogen bond interactions between the reactants. The overall enantioselectivity depends on the relative energy of the two reaction steps, averaged over the relative populations of the iminium intermediates initially formed.357 meso-Cyclopropyl carbaldehydes (229) undergo organocatalysed 1,3-chlorochalcogenation to give regio-, diastereo-, and enantio-selective ring opening, producing highly functionalized aldehydes (230). The chalcogen substituent, R2 , can be alkyl, aryl, or CO2 Me. A merged iminium–enamine catalysis by the chiral imidazolidinone inducers is proposed.358

de 

de  ee 

57

1 Reactions of Aldehydes and Ketones and Their Derivatives O O

O

O +

S

Ph

+

−

N H

Ph

(R) (S)

OH

(227)

Ph

O (225)

(226)

CHO

1

R

R

R32NH

(229)

H (228)

R1

R2–Ch–Cl (Ch = S, Se); 1

Ph

(R)

O

Ch–R2

Cl

N

CHO R1

X

(230)

R1 R2

N (231)

Useful chalcones, trans-R1 –C6 H4 –CO–CH=CH–C6 H4 –R2 , have been prepared by a copper-catalysed A3 -coupling/isomerization/hydrolysis sequence, starting from benzaldehydes and terminal alkynes.359 N-Aryl-enaminone cyclization to give indoles has been studied by DFT. Deprotonation of the enaminone sets up a copper(I) catalysis – using Cu+ –phenanthroline – with binding of the metal ion dramatically increasing the acidity at the carbon adjacent to the ketone.360 Quinazolin-4(3H)-ones (231; X = CH) or pyrido[2,3-d]pyrimidin-4(3H)-ones have been prepared from easily available 2-halobenzamides (or 2-halonicotinamides), aldehydes (R2 CHO), and sodium azide. The reaction is catalysed by copper(I)/ proline, and can be conveniently carried out in DMSO at 80 ∘ C under air. An SnAr/reduction/cyclization/oxidation sequence is proposed. Control experiments confirmed the first steps, namely azide-for-halide substitution, followed by azide-to-amino reduction.361 Highly functionalized pyrano[3,4-c]pyrrole derivatives (232) have been prepared in a cascade reaction of simple ketones, R1 –CO–CH2 R2 , and tetracyanoethene, followed by an aldehyde, R3 –CHO, using acetic acid medium at 70 ∘ C. A single diastereomer is typically isolated, and significant progress on elucidation of the mechanism has been achieved through isolation of intermediates.362 R2 R1

CN O −C

N

O R3 (232)

CN NH 2

R4

Ts

R3–COMe

N

N +

R3–COMe; R2–NH2

R1

N

R3

R2 (233)

The classical Radziszewski reaction generates tetrasubstituted imidazoles (233) from an aldehyde (R1 –CHO), ammonia, a 1∘ amine (R2 –NH2 ), and an 𝛼-dione

58

Organic Reaction Mechanisms 2016

(R3 –CO–CO–R4 ). In a new variant, an imidazolyl methyl ketone (233; R1 = R3 –CO, R4 = H) derives its three ring carbons and acyl side-chain from two molecules of a methyl ketone, with the nitrogens provided by an aniline (i.e. R2 = Ar) and tosylmethyl isocyanide. So the methyl ketone substitutes for the roles of the 𝛼-dione and the aldehyde. This formal [2 + 1 + 1 + 1]-annulation is mediated by iodine in DMSO at 100 ∘ C. Mechanistic studies for the case of acetophenone (i.e. R3 = Ph) and derivatives show that the hydrate [Ph–CO–CH(OH)2 ] and iodine are competent substrates, as is 𝛼-iodoacetophenone (Ph–CO–CH2 I) in the absence of iodine. In contrast, the 𝛼-amino aldehyde fails, ruling out 3 + 2-cycloaddition.363 Furan-2(5H)-ones substituted in the 3,4,5-positions have been synthesized from benzaldehyde, 4-ethylaniline, and diethyl acetylenedicarboxylate (DEAD). Solvent effects on the kinetics and mechanism have been explored: current and previous studies examined ethanol (close to neutrality) versus formic acid. Using UV–visible stopped-flow spectrophotometry, the reaction in ethanol was second order (in aldehyde and amine), whereas the second-order dependence in formic acid was on amine and DEAD.364 The fact that a strained amide (e.g. azetidinone 234) could act as a formal dipole (235) and hence react with a dipolarophile has been tested with eight putative dipolarophiles. One such dipolarophile – ethyl glyoxylate (236) – was found to react with lactam (237) to give ring-expanded product, 1,3-oxazinan-6-one (238), using 4-pyrrolidinopyridine (PPY, a hyper-nucleophilic Lewis base) as catalyst. The method does not work for Ntosylpyrrolin-2-one, emphasizing the requirement for ring strain or tension.365 O O

O

O

O

+

OEt

?

O

O

N

−

N

N

EWG

Ph

Ns

(236)

(235)

CO2Et

N Ns

EWG (234)

Ph

(238)

(237)

Activation of ortho-(bromomethyl)benzaldehyde (239) with an NHC provides a new route to ortho-quinodimethane intermediates (240), via a 1,4-elimination. Trapping with a variety of ketone types yields substituted 1-isochromanones (241) via a [4 + 2]annulation. Several examples use cyclic ketones to generate spiroproducts. Analogues of Breslow intermediates have been isolated. Chiral NHCs give enantio-enriched product.366 +

O

O

NHC H

−

NHC

O

O R1

O R2

R1 R2

Br (239)

(240)

(241)

ee 

59

1 Reactions of Aldehydes and Ketones and Their Derivatives

Quinolyl-peri-ketones (242; R = electron-donating group) undergo interconversion of their aryl moiety (to give 242 with R = electron-withdrawing group) by reaction with boronic acids, EWG–C6 H4 –B(OH)2 , in the presence of a rhodium catalyst. This implicates a rhodacycle intermediate (243). Some silyl ketones can act as substrates, and use of methylboronic acid (in the presence of potassium carbonate) allows preparation of methyl quinolyl ketones.367 Me R

R

O

N

O Rh

N

N H (242)

(243)

O Ar (244)

Two reports describe access to rings with >6 carbons via in situ benzyne insertions. Nonacyclic dibenzo[1,5]oxazonines (244) have been prepared in one pot by a threecomponent reaction of N-methylindoline, ortho-(trimethylsilyl)phenyl triflate, and an aromatic aldehyde. Using caesium fluoride and 18-crown-6 in refluxing THF, the reaction proceeds via fluoride-generated benzyne. Changing the starting heterocycle to Nmethyl-tetrahydroquinoline gives the corresponding 10-membered ring.368 Medium-ring-fused benzocarbocycles occur widely in natural products and chiral ligands. Benzocyclic ketones (245; n = 1–5) provide a useful entry point, via fluoridecatalysed insertion of arene derivatives (246) into unactivated benzylic C–C bonds to give dibenzocarbocycles (247). The reaction also works for 𝛼-arylcycloalkanones, to give monobenzocarbocycles with an aryl substituent on the enlarged ring. However, simple cycloalkanones fail, suggesting that benzofusion or aryl substitution is essential for C–C activation. This suggests a mechanism in which the enolate (from benzylic deprotonation) reacts with benzyne (from 246, via fluoride ion) yielding an 𝛼-phenylsubstituted carbanion (248), which would undergo ring closure to a cyclobutene followed by ringexpanding re-ketonization.369 O n

TMS

O

n

O

− TfO

(245)

(246)

(247)

(248)

Other Reactions Alkynals with an appropriate leaving group (249) have been converted to 𝛼fluoroallenoates (250) in up to 98% yield, under very mild conditions. The leaving

60

Organic Reaction Mechanisms 2016

group was optimized as methyl carbonate. The NHC is proposed to form a Breslowtype intermediate, with loss of the leaving group then giving a cumulenol, which is intercepted by NFSI followed by ethanolysis to yield product (250) and NHC.370 R1 MeO2CO R2

O H

NFSI NHC NaHCO3 EtOH/r.t.

R1

F C

R2

(249)

CO2Et (250)

Propargylic CF3 -substituted tertiary alcohols have been obtained in high yield and ee by base-free addition of terminal ynamides to trifluoromethyl ketones.371 A three-component cobalt(III)-catalysed C–H bond addition across two different partners has been reported. 𝛼,𝛽-Unsaturated amide (251, C–H highlighted) adds to diene (252) with further reaction with an aldehyde to give (253) with high regio- and stereoselectivity with the formation of two new C–C 𝜎-bonds and 4–6 new stereocentres. The diene and aldehyde react synergistically: neither undergoes C–H addition alone. A mechanism involving a Co(III)–allyl intermediate (supported by X-ray characterization of same) is further backed up by the observed transfer of stereochemistry, and by KIEs. Enamide (251) can be substituted by arylamides.372 R4 R3

N

R4 O H

2

R

RE

+ RZ

R1 (251)

5

R –CHO

R3

N

RZ O

H

R5

R2 R1

(252)

RE

OH (253)

Arylpropiolic acids, Ar–C≡C–CO2 H, undergo a copper(I)/silver(I)-mediated decarboxylative trifluoromethylation with TMS–CF3 /KF/phen to give the trifluoromethyl alkynes, Ar–C≡C–CF3 . The reaction proceeds at ambient temperature under nitrogen in DMF in a few hours. The silver is proposed to form a salt with the acid and then decarboxylate it. Fluoride anion displaces F3 C− from TMS–CF3 , delivering it to phen-complexed copper(I), which then transmetallates, followed by reductive elimination.373 Readily available trifluoromethylketones react with aldehydes to yield difluoromethylene compounds, using a diboron reductant [bis(pinacolato)diboron] in the presence of sodium tert-butoxide. Catalysed by copper(I) complexed with phenanthroline, the copper difluoroenolate generated in situ tends to give the cross-adducts preferentially, and a mechanistic study rationalized this selectivity.374 Benzaldehydes are converted to benzophenones via Ir(III)- and Rh(III)-catalysed, directing-group-assisted C–H arylation with diaryliodonium salts, Mes–I(OTf)–Ar.375

ee 

de 

61

1 Reactions of Aldehydes and Ketones and Their Derivatives

An indium(III)-catalysed C(sp3 )–H alkenylation of 2-methylquinoline with benzaldehyde gives alkene (254) in 88% yield. A range of aza-arenes can be employed, and other electrophiles such as aldimines and enones can substitute for the aldehyde.376

O N

N R (254)

(255)

A combined experimental and computational study of Lewis acid-promoted hydroxylation reactions between aldehydes and arenes or heteroarenes has drawn up ‘league tables’ of activation barriers and adduct stabilities for all three components, that is aldehyde, (hetero)arene, and Lewis acid. A particular focus on tin(IV) species includes detailed 119 Sn NMR data on complexation-induced chemical shift changes.377 An interesting side-reaction of an aldehyde group has been identified in rutheniumcatalysed cyclization. If R = H (aldehyde, 255), a cationic vinylidene complex formed between the alkyne and ruthenium is then diverted via reaction with the pendant aldehyde. No such reaction is seen with ketone or ester (255; R = Me or OMe).378 The use of the Kulinkovich–de Mejiere reaction of alkenes and amides, constrained by the limitations imposed by Bredt’s Rule, yields carbocyclic amino ketones.379 Cyanomethylation of aldehydes is catalysed by nickel pincer complexes under basefree conditions. The carbon-bound cyanomethyl complex, [Ni]–CH2 C≡N, was originally thought to be the active catalyst, but DFT calculations suggest that it has to convert to the less-stable nitrogen-bound isomer, [Ni]-N=C=CH2 . The latter then reacts with aldehyde to give an alkoxide, which reacts with acetonitrile.380 Benzaldehydes with an ortho-group (256; X = electron withdrawing) undergo iridiumcatalysed sp2 C–H amidation to give the N-tosylate in the other ortho-position (257) in up to 92% yield. The reaction can be carried out with stoichiometric addition of an aniline, that is by pre-preparing the aldimine, whose nitrogen then steers C-iridation to give (258), an intermediate characterized by X-ray crystallography. Subsequent reaction with tosylazide and acid workup generates the protected aminobenzene product (257). The aniline can also be used catalytically, generating the imine for in situ reaction. Kinetic studies and Hammett plots for both the imines (𝜌 = −0.64) and azides (𝜌 = −1.40) indicate that electron-donating para-substituents in both rings cause the

O

H

H

[*CpIrCl2]2 AgI/TsN3 ArNH2 (cat.) 100 °C/air

X

L

Ar

+

Ir Cp*

2. 2 M HCl

H

H X

X (256)

O 1. TsN3;

(258)

(257)

NHTs

62

Organic Reaction Mechanisms 2016

reaction to accelerate, probably by enhancing coordination to the iridium. An sp3 case using Ar–N=CH–C(Me2 )–CH2 –H as substrate also works, in 50% yield.381 Chiral NHCs cross-couple enamides and aldehydes, giving enantioselective formation of N-protected amines bearing a quaternary carbon centre.382 3-Amino-1,4-diynes (259) have been prepared from propargylaldehydes and secondary amines, using coupling by copper(I) iodide in refluxing DCE, in the presence of triphenylphosphine and oxygen. A wide range of both symmetrical (R1 = R2 ) and unsymmetrical cases are reported, and copper–alkyne intermediates, R1 –C≡C–Cu–L, are implicated.383 R3

N

R3

R1

R2 (259)

A newly reported DFT method, M11-L, has been used to investigate formyl transfer between an aldehyde and an alkene, activated by rhodium. 𝛽-Hydride elimination is found to be rate determining for the whole catalytic cycle. Calculations suggest that alkynes or ring-strained olefins should be good formyl acceptors.384 A base-metal cooperative catalysis has been developed to secure a mild dehydroformylation process.385 SF5 -containing diarylmethanols have been prepared, racemically and enantioselectively, by metal-catalysed addition of arylboronic acids to meta- and para-(pentafluorosulfur)benzaldehydes.386 Optically pure P-chiral H-phosphinates have been added diastereoselectively to aldehydes to give 𝛼-hydroxyphosphinates, using rhodium or iridium catalysts. This Pudovik-type reaction probably proceeds via hydridometal complexes which favour electron-deficient substrates; ketones, being less electrophilic, fail.387 A tripeptide, H-d-Pro-Pro-Asn-NH2 , catalyses asymmetric conjugate additions of aldehydes to maleimide. 1 H NMR, X-ray crystallographic, and DFT investigations have helped identify its conformational properties and its hydrogen-bonding interactions with maleimide. High yields and de/ees of up to 90/98% were achieved.388

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Tajbakhsh, M., Heidary, M., Hosseinzadeh, R., and Amiri, M. A., Tetrahedron Lett., 57, 141 (2016). Galvan, A., Gonzalez-Perez, A. B., Alvarez, R., de Lera, A. R., Fananas, F. J., and Rodriguez, F., Angew. Chem. Int. Ed., 55, 3428 (2016). Masoudi, M. and Anary-Abbasinejad, M., Tetrahedron Lett., 57, 103 (2016). Amarasekara, A. S. and Ha, U., Tetrahedron Lett., 57, 2598 (2016). Wang, G., Wang, Z.-Y., Niu, S.-S., Rao, Y., and Cheng, Y., J. Org. Chem., 81, 8276 (2016). Khazaei, A., Abbasi, F., and Moosavi-Zare, A. R., Res. Chem. Intermed., 42, 6719 (2016). Satheeshkumar, R., Shankar, R., Kaminsky, W., and Karnam Jayarampillai, R. P., Chem. Select, 1, 6823 (2016). Yu, L., Yang, Z., Peng, J., and Li, P., Eur. J. Org. Chem., 2016, 535 (2016). Wu, H.-L., Wu, P.-Y., Cheng, Y.-N., and Uang, B.-J., Tetrahedron, 72, 2656 (2016). Matsumoto, A., Ozaki, H., Harada, S., Tada, K., Ayugase, T., Ozawa, H., Kawasaki, T., and Soai, K., Angew. Chem. Int. Ed., 55, 15246 (2016). Soeta, T., Ishizaka, T., and Ukaji, Y., J. Org. Chem., 81, 2817 (2016). Escorihuela, J., Burguete, M. I., Ujaque, G., Lledós, A., and Luis, S. V., Org. Biomol. Chem., 14, 11125 (2016). Frensch, G., Labes, R., Wosch, C. L., Munaretto, L. d. S., Salomé, K. S., Guerrero, P. G., and Marques, F. A., Tetrahedron Lett., 57, 420 (2016). Asami, M., Hasome, A., Yachi, N., Hosoda, N., Yamaguchi, Y., and Ito, S., Tetrahedron: Asymmetry, 27, 322 (2016). Zhao, W.-X., Liu, G.-J., Wang, J., Li, F., and Liu, L., Tetrahedron: Asymmetry, 27, 1139 (2016). Wujkowska, Z., Jarzynski, S., Pieczonka, A. M., Lesniak, S., and Rachwalski, M., Tetrahedron: Asymmetry, 27, 1238 (2016). Burke, A. J., Tetrahedron Lett., 57, 1197 (2016). Dobson, L. S. and Pattison, G., Chem. Commun. (Cambridge), 52, 11116 (2016). Hayashi, Y., Yamamura, N., Kusakawa, T., and Harada, T., Chem.-Eur. J., 22, 12095 (2016). Qiao, S., Pindi, S., Spigener, P. T., Jiang, B., and Li, G., Tetrahedron Lett., 57, 619 (2016). Rong, J., Pellegrini, T., and Harutyunyan, S. R., Chem.-Eur. J., 22, 3558 (2016). Ulikowski, A. and Furman, B., Org. Lett., 18, 149 (2016). Zong, H., Huang, H., and Song, L., Tetrahedron: Asymmetry, 27, 1069 (2016). Veguillas, M., Sola, R., Shaw, L., and Macia, B., Eur. J. Org. Chem., 2016, 1788 (2016). Nandi, R. K., Takeda, N., Ueda, M., and Miyata, O., Tetrahedron Lett., 57, 2269 (2016). Yu, T.-Y., Wei, H., Luo, Y.-C., Wang, Y., Wang, Z.-Y., and Xu, P.-F., J. Org. Chem., 81, 2730 (2016). Ayub, K. and Ludwig, R., RSC Adv., 6, 23448 (2016). Jarwal, N., Meena, J. S., and Thankachan, P. P., Comput. Theor. Chem., 1093, 29 (2016). Karaca, O., Anneser, M. R., Kueck, J. W., Lindhorst, A. C., Cokoja, M., and Kuehn, F. E., J. Catal., 344, 213 (2016). Tilve, S. G., Torney, P. S., Patre, R. E., Kamat, D. P., Srinivasan, B. R., and Zubkov, F. I., Tetrahedron Lett., 57, 2266 (2016). Schirmer, M.-L., Adomeit, S., Spannenberg, A., and Werner, T., Chem.-Eur. J., 22, 2458 (2016). Deng, Z., Lin, J.-H., Cai, J., and Xiao, J.-C., Org. Lett., 18, 3206 (2016). Takemoto, S., Shibata, E., Nakajima, M., Yumoto, Y., Shimamato, M., and Matsuzaka, H., J. Am. Chem. Soc., 138, 14836 (2016). Wang, J., Su, Z., Yang, N., and Hu, C., J. Org. Chem., 81, 6444 (2016). Ruiz, P., Castro, M., Lopez, S., Zapata, A., Quijano, J., and Notario, R., Struct. Chem., 27, 1373 (2016). Moxter, M., Tillmann, J., Füser, M., Bolte, M., Lerner, H.-W., and Wagner, M., Chem.-Eur. J., 22, 16028 (2016). Hirai, M., Cho, J., and Gabbai, F. P., Chem.-Eur. J., 22, 6537 (2016). Bezlada, A., Szewczyk, M., and Mlynarski, J., J. Org. Chem., 81, 336 (2016). Chauvier, C., Thuery, P., and Cantat, T., Angew. Chem. Int. Ed., 55, 14096 (2016). Ning, X., Wang, J., and Wei, H., J. Phys. Chem. A, 120, 4167 (2016). Ren, X. and Du, H., J. Am. Chem. Soc., 138, 810 (2016). Zeng, Y., Deng, P., Zhang, S., Yan, H., Liang, G., Xiong, Y., and Zhou, H., Org. Biomol. Chem., 14, 9221 (2016). Zhu, D.-X., Chen, W.-W., and Xu, M.-H., Tetrahedron, 72, 2637 (2016). Kubota, K., Jin, M., and Ito, H., Organometallics, 35, 1376 (2016). Mukherjee, D., Osseili, H., Spaniol, T. P., and Okuda, J., J. Am. Chem. Soc., 138, 10790 (2016). Bagherzadeh, S. and Mankad, N. P., Chem. Commun. (Cambridge), 52, 3844 (2016). Wu, X., Chen, Z., Bai, Y.-B., and Dong, V. M., J. Am. Chem. Soc., 138, 12013 (2016).

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1 Reactions of Aldehydes and Ketones and Their Derivatives 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345

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Meng, Q. and Wang, F., J. Molec. Model., 22, 1 (2016). Xiao, L.-J., Fu, X.-N., Zhou, M.-J., Xie, J.-H., Wang, L.-X., Xu, X.-F., and Zhou, Q.-L., J. Am. Chem. Soc., 138, 2957 (2016). Majhail, M. K., Ylioja, P. M., and Willis, M. C., Chem.-Eur. J., 22, 7879 (2016). Meng, Q., Su, P., Wang, F., and Zhu, S., J. Theor. Comput. Chem., 15, 1650019 (2016). Brawley, K. K. and Davis, T. A., Tetrahedron Lett., 57, 2161 (2016). Cioc, R. C., Schuckman, P., Preschel, H. D., Vlaar, T., Ruijter, E., and Orru, R. V. A., Org. Lett., 18, 3562 (2016). Hatano, M., Yamakawa, K., Kawai, T., Horibe, T., and Ishihara, K., Angew. Chem. Int. Ed., 55, 4021 (2016). Yang, Z., Yi, Y., Zhong, M., De, S., Mondal, T., Koley, D., Ma, X., Zhang, D., and Roesky, H. W., Chem.-Eur. J., 22, 6932 (2016). Nash, A. L., Hertzberg, R., Wen, Y.-Q., Dahlgren, B., Brinck, T., and Moberg, C., Chem.-Eur. J., 22, 3821 (2016). Kiyokawa, K., Nagata, T., and Minakata, S., Angew. Chem. Int. Ed., 55, 10458 (2016). Ashley, M. A., Hirschi, J. S., Izzo, J. A., and Vetticat, M. J., J. Am. Chem. Soc., 138, 1756 (2016). Touati, B., El Bouakher, A., Taillier, C., Othman, R. B., Trabelsi-Ayadi, M., Antoniotti, S., Dunach, E., and Dalla, V., Chem.-Eur. J., 22, 6012 (2016). Padala, A. K., Kumar, R. R., Athimoolam, S., and Ahmed, Q. N., Org. Lett., 18, 96 (2016). Cornaggia, C., Gundala, S., Manoni, F., Gopalasetty, N., and Connon, S. J., Org. Biomol. Chem., 14, 3040 (2016). Lo Nostro, P., Mazzini, V., Ninham, B. W., Ambrosi, M., Dei, L., and Baglioni, P., ChemPhysChem, 17, 2567 (2016). Roy, A., Bhat, B. A., and Lepore, S. D., Org. Lett., 18, 1230 (2016). Seitz, C. G., Zhang, H., Mo, Y., and Karty, J. M., J. Org. Chem., 81, 3711 (2016). Yue, C.-B., Lin, J.-H., Cai, J., Zhang, C.-P., Zhao, G., Xiao, J.-C., and Li, H. F., RSC Adv., 6, 35705 (2016). Chen, D., Ni, C., Zhao, Y., Cai, X., Li, X., Xiao, P., and Hu, J., Angew. Chem. Int. Ed., 55, 12632 (2016). Kaplaneris, N., Spyropoulos, C., Kokotou, M. G., and Kokotos, C. G., Org. Lett., 18, 5800 (2016). Jimeno, C., Cao, L., and Renaud, P., J. Org. Chem., 81, 1251 (2016). Fjelbye, K., Marigo, M., Clausen, R. P., and Juhl, K., Org. Lett., 18, 1170 (2016). Jiao, Z., Beiger, J. J., Jin, Y., Ge, S., Zhou, J. S., and Hartwig, J. F., J. Am. Chem. Soc., 138, 15980 (2016). Emma, M. G., Lombardo, M., Trombini, C., and Quintavalla, A., Eur. J. Org. Chem., 2016, 3223 (2016). Dong, Q., Shen, H.-C., and Jiang, M., Tetrahedron Lett., 57, 2116 (2016). Yang, M.-H., Hunt, J. R., Sharifi, N., and Altman, R. A., Angew. Chem. Int. Ed., 55, 9080 (2016). Stanek, F. and Stodulski, M., Eur. J. Org. Chem., 2016, 4768 (2016). Li, J., Jiang, S., Procopiou, G., Stockman, R. A., and Yang, G., Eur. J. Org. Chem., 2016, 3500 (2016). Rahemtulla, B. F., Clark, H. F., and Smith, M. D., Angew. Chem. Int. Ed., 55, 13180 (2016). Huang, F., Liu, Z., and Yu, Z., Angew. Chem. Int. Ed., 55, 862 (2016). Gong, J., Li, K., Qurban, S., and Kang, Q., Chin. J. Chem., 34, 1225 (2016). Pakhare, S. B., Ubale, M., Gawai, J., and Farooqui, M., J. Adv. Sci. Res., 6, 01 (2015). Xiang, X., Zhang, B., Ding, G., Cui, J., Zheng, H., and Zhu, Y., Catal. Commun., 86, 41 (2016). Elsamra, R. M. I., Jalan, A., Buras, Z. J., Middaugh, J. E., and Green, W. H., Int. J. Chem. Kinet., 48, 474 (2016). Liu, C., Han, P., Liu, Y., and Tang, M., Theor. Chem. Acc., 135, 1 (2016). Singha, R., Ghosh, M., Nuree, Y., and Ray, J. K., Tetrahedron Lett., 57, 1325 (2016). Quinn, D. J., Haun, G. J., and Moura-Letts, G., Tetrahedron Lett., 57, 3844 (2016). Kumar, Y. L., Nadh, R. V., and Radhakrishnamurti, P. S., Russ. J. Phys. Chem. A, 90, 552 (2016). Sharma, V. K., Jain, I., Singh, P., and Sharma, K., Chem. Sci. Trans., 4, 890 (2015). Tsang, A. S.-K., Kapat, A., and Schoenebeck, F., J. Am. Chem. Soc., 138, 518 (2016). Wang, H., Xu, W., Xin, L., Liu, W., Wang, Z., and Xu, K., J. Org. Chem., 81, 3681 (2016). Ghosh, S. and Jana, C. K., Org. Lett., 18, 5788 (2016). Bie, Z., Li, G., Wang, L., Wang, L., Lv, Y., Niu, J., and Gao, S., Tetrahedron Lett., 57, 4935 (2016). Ma, L., Paul, A., Breugst, M., and Seidel, D., Chem.-Eur. J., 22, 18179 (2016). Dub, P. A. and Gordon, J. C., Dalton Trans., 45, 6756 (2016). Nedden, H. G., Zanotti-Gerosa, A., and Wills, M., Chem. Record, 16, 2619 (2016). Zuo, W., Prokopchuk, D. E., Lough, A. J., and Morris, R. H., ACS Catal., 6, 301 (2016). Rast, S., Modec, B., Stephan, M., and Mohar, B., Org. Biomol. Chem., 14, 2112 (2016). Touge, T., Nara, H., Fujiwhara, M., Kayaki, Y., and Ikariya, T., J. Am. Chem. Soc., 138, 10084 (2016).

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Cotman, A. E., Cahard, D., and Mohar, B., Angew. Chem. Int. Ed., 55, 5294 (2016). Khan, I., Reed-Berendt, B. G., Melen, R. L., and Morrill, L. C., Chem.-Eur. J., 22, 14717 (2016). Tan, X., Wang, G., Zhu, Z., Ren, C., Zhou, J., Lv, H., Zhang, X., Chung, L. W., Zhang, L., and Zhang, X., Org. Lett., 18, 1518 (2016). Yang, P., Lim, L. H., Chuanprasit, P., Hirao, H., and Zhou, J., Angew. Chem. Int. Ed., 55, 12083 (2016). Huang, H., Liu, X., Zhou, L., Chang, M., and Zhang, X., Angew. Chem. Int. Ed., 55, 5309 (2016). Lai, Y., Sun, L., Sit, M. K., Wang, Y., and Dai, W.-M., Tetrahedron, 72, 664 (2016). Liu, T. and Bi, S., Organometallics, 35, 1114 (2016). Nayal, O. S., Thakur, M. S., Bhatt, V., Kumar, M., Kumar, N., Singh, B., and Sharma, U., Chem. Commun. (Cambridge), 52, 9648 (2016). Legnani, L., Toma, L., Caramella, P., Chiacchio, M. A., Giofre, S., Delso, I., Tejero, T., and Merino, P., J. Org. Chem., 81, 7733 (2016). Fourmy, K., El Louz, M., Mallet-Ladeira, S., Daran, J.-C., Dechy-Cabaret, O., and Gouygou, M., Dalton Trans., 45, 13294 (2016). Manna, S. and Antonchick, A. P., Angew. Chem. Int. Ed., 55, 5290 (2016). Georgieva, M. K., Duarte, F. J. S., and Santos, A. G., Org. Biomol. Chem., 14, 5965 (2016). Wallbaum, J., Garve, L. K. B., Jones, P. G., and Werz, D. B., Chem.-Eur. J., 22, 18756 (2016). Zhao, Y. and Song, Q., Org. Chem. Front., 3, 294 (2016). Bernardo, C. E. P. and Silva, P. J., Royal Soc. Open Sci., 3, 150582 (2016). Li, T., Chen, M., Yang, L., Xiong, Z., Wang, Y., Li, F., and Chen, D., Tetrahedron, 72, 868 (2016). Ievlev, M. Y., Ershov, O. V., and Tafeenko, V. A., Org. Lett., 18, 1940 (2016). Zhang, J., Gao, Q., Wu, X., Geng, X., Wu, Y.-D., and Wu, A., Org. Lett., 18, 1686 (2016). Habibi-Khorassani, S. M., Shahraki, M., and Dehdab, M., Chem. Select, 1, 6069 (2016). Barbier, V., Marrot, J., Couty, F., and David, O. R. P., Eur. J. Org. Chem., 2016, 549 (2016). Janssen-Müller, D., Singha, S., Olyschläger, T., Daniliuc, C.-G., and Glorius, F., Org. Lett., 18, 4444 (2016). Dennis, J. M., Compagner, C. T., Dorn, S. K., and Johnson, J. B., Org. Lett., 18, 3334 (2016). Okuma, K., Kinoshita, H., Nagahora, N., and Shioji, K., Eur. J. Org. Chem., 2016, 2264 (2016). Rao, B., Tang, J., Wei, Y., and Zeng, X., Chem.-Asian J., 11, 991 (2016). Wang, X., Wu, Z., and Wang, J., Org. Lett., 18, 576 (2016). Cook, A. M. and Wolf, C., Angew. Chem. Int. Ed., 55, 2929 (2016). Boerth, J. A., Maity, S., Williams, S. K., Mercado, B. Q., and Ellman, J. A., Angew. Chem. Int. Ed., 55, 12650 (2016). Yang, L., Jiang, L., Li, Y., Fu, X., Zhang, R., Jin, K., and Duan, C., Tetrahedron, 72, 3858 (2016). Doi, R., Ohashi, M., and Ogoshi, S., Angew. Chem. Int. Ed., 55, 341 (2016). Yang, X., Wang, H., Zhou, X., and Li, X., Org. Biomol. Chem., 14, 5233 (2016). Jamal, Z., Teo, Y.-C., and Lim, G. S., Tetrahedron, 72, 2132 (2016). Pratihar, S., Org. Biomol. Chem., 14, 2854 (2016). Chia, P.-Y., Huang, S.-L., Liu, Y. H., and Lin, Y.-C., Chem.-Asian J., 11, 1098 (2016). Finn, P. B., Derstine, B. P., and Sieburth, S. M. N., Angew. Chem. Int. Ed., 55, 2536 (2016). Ariafard, A., Ghari, H., Khaledi, Y., Hossein Bagi, A., Wierenga, T. S., Gardiner, M. G., and Canty, A. J., ACS Catal., 6, 60 (2016). Zhang, Y.-F., Wu, B., and Shi, Z.-J., Chem.-Eur. J., 22, 17808 (2016). Wu, J., Zhao, C., and Wang, J., J. Am. Chem. Soc., 138, 4706 (2016). Choi, Y.-J. and Jang, H.-Y., Eur. J. Org. Chem., 2016, 3047 (2016). Luo, X., Bai, R., Liu, S., Shan, C., Chen, C., and Lan, Y., J. Org. Chem., 81, 2320 (2016). Abrams, D. J., West, J. G., and Sorensen, E. J., Chem. Sci. [Ahead of Print 2016], 8, 1954 (2017). Desroches, J., Tremblay, A., and Paquin, J.-F., Org. Biomol. Chem., 14, 8764 (2016). Li, Q., Chen, T., Xu, Q., and Han, L.-B., Chem.-Eur. J., 22, 6213 (2016). Grünenfelder, C. E., Kisunzu, J. K., and Wennemers, H., Angew. Chem. Int. Ed., 55, 8571 (2016).

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CHAPTER 2

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

C. T. Bedford Department of Chemistry, University College London, London, UK 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 Anhydrides . . . . . . . . . . . . . . . . . . . (d) Amides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (e) Carbonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (f) Thioesters and Thiocarbonates . . . . . . . . . . . . . . . . . . . (g) Thioamides and Thioacyl Halides . . . . . . . . . . . . . . . . . Phosphoric Acids and their Derivatives . . . . . . . . . . . . . . . . . . (a) Phosphinic Acids . . . . . . . . . . . . . . . . . . . . . . . . . (b) Phosphoryl and Thiophosphoryl Halides . . . . . . . . . . . . . INTRAMOLECULAR CATALYSIS AND NEIGHBOURING GROUP PARTICIPATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BIOLOGICALLY SIGNIFICANT REACTIONS . . . . . . . . . . . . . Carboxylic Acids and their Derivatives . . . . . . . . . . . . . . . . . . (a) Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (b) Amides and Peptides . . . . . . . . . . . . . . . . . . . . . . . Phosphoric Acids and their Derivatives . . . . . . . . . . . . . . . . . . (a) Phosphates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (b) Phosphoramidates . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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83 87 87 87 88 91 91 95 96

INTERMOLECULAR CATALYSIS AND REACTIONS

Carboxylic Acids and their Derivatives (a) Acids Kinetic studies of the reaction of diazodiphenylmethane, Ph2 CN2 , with a series of 5substituted orotic acids (1; X = Bui , Bu, Et, Me, NH2 OH, H, Cl, Br, NO2 ) permitted evaluation of the ‘ortho effect’ using the Charton model and a comparison with similar Organic Reaction Mechanisms 2016, First Edition. Edited by A. C. Knipe. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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Organic Reaction Mechanisms 2016 O X

HN O

CO2H

N H (1)

data from an earlier study of O-substituted benzoic acids. The results showed that the ortho-polar effect for both series was dominant, with only a low significance of the orthosteric effect.1 A mechanistic study of the Ph3 P–I2 /Et3 N-mediated aryl esterification reaction (Scheme 1) investigated the effects of the order of addition and the efficiency of the process using the results of a series of 11 variously substituted phenols (3) in reaction with benzoic acid (2; X = H), and the results of the reaction of a series of variously substituted benzoic acids (2) with 3-nitrophenol (3; Ar = 3-NO2 –C6 H4 ). To elucidate the nature of the intermediate in the process, the reaction between benzoic acid (2; X = H) and 3-nitrophenol (3; Ar = 3-NO2 -C6 H4 ) was followed by 31 P and 1 H NMR. The results led to the following proposed mechanism (Scheme 2). Nucleophilic attack of the Ph3 P upon iodine yields pentavalent triphenylphosphine diiodide (4) and a triphenylphosphonium salt (5). Upon addition of the reactive phenol, phosphorane (6) could be formed before subsequent reaction with a carboxylic acid in the presence of a base to generate the aryloxyphosphonium salt (7). Since the SN 2 displacement of a carboxylate ion at the sp2 -centre of (7) is highly unlikely, the more plausible pathway leading to the ester product would be through intermediate (8) or an acyloxyphosphonium salt (9) which could be present in equilibrium with (8). Intramolecular substitution at the acyl group within phosphorene (8) could give rise to ester bond formation (path a). Alternatively, the direct nucleophilic attack of a phenolate anion onto the carbonyl carbon of (9) could also lead to an ester product (path b). Through the intermediacy of an acyloxyphosphonium salt (9), anhydride formation could take place in competition with the esterification reaction (path c). In cases where anhydride formation was not observed (e.g. acidic carboxylic acids and phenols), the reaction is more likely to proceed through path a rather than path b as commonly proposed in other phosphine-mediated esterifications.2 Theoretical studies of the uncatalysed esterification of acetic acid by MeOH in the gas phase revealed the possible cyclic conformations that may occur during experiments at O

O OH + ArOH

X (2)

Ph3P, I2 Et3N, CH2Cl2

(3) Scheme 1

X

OAr

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

I2

Ph3P

I Ph3P

+

Ph3P

I

H I

−

O

ArOH

Ph3P

I

I (4)

RCO2H Et3N

−

+

Ar

I (6)

(5) OAr

+

Ph3P OAr

Ph3P

−

R O

OCOR

O path a

R

OAr

O

(7)

(8) path b

O + − OAr

Ph3P

R O

RCOO path c

O

−

R

O

R

O (9) Scheme 2

simple ratios of reactants. The calculated free energy of activation, 36 kcal mol−1 , was in good agreement with the experimental data.3

(b) Esters (i) Transesterification An anchimerically assisted regioselective transesterification of a dimethyl ester to an alkyl methyl ester and an intramolecular transesterification of an aromatic ester mediated by an adjacent HO group are described in full in the section devoted to ‘Intramolecular Catalysis and Neighbouring Group Participation’. (ii) Solvolysis reactions Although both cationic and anionic components of an ionic liquid (IL) can catalyse the hydrolysis of esters by acting, respectively, as a general acid and a general base, the most effective IL catalysts, unsurprisingly, are those that are a combination of a strong acid and a strong base. Now, an extensive experimental and theoretical (density functional theory (DFT) calculations) study of a large series of 13 ILs showed that 1-butyl-3-methylimidozolium acetate [Bmim]OAc was a very effective catalyst since it was composed of the strongest acid and strongest base of those tested. The mechanism proposed for the process (Scheme 3) takes the form of the well-known general acid/general base catalysis of the hydrolysis of an ester. The acidic 2-proton of [Bmim] forms a hydrogen bond with (and activates) the CO group of the ester R1 CO2 R2 , and

74

C 4H9

Organic Reaction Mechanisms 2016

O

+

N

N

−O

H O

C 4H 9

O

+

N

N

−O

H

H

R1

O−

O

H

N

H

OR2

OR2

R1

R1

H

(11)

+

N

O OH OR2

R1

(10)

C 4H 9

O

H

H

O

O

+

C 4H 9 N

N

O

C 4H 9

+

N

N

O

H

−O

H

O

R2 OH

O

OH

Scheme 3

R1

−

OH OR2 (12)

H

O

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

75

AcO− attacks one hydrogen of water, facilitating its attack upon the C–O group. This leads, via a transition state (10), to a TI (11) which is still hydrogen-bonded to [Bmim] and to the formation of acetic acid. The collapse of TI (11) is facilitated by protonation of the departing OR2 group by the proton of acetic acid and yields, via transition state (12), hydrolysis products, acid (R1 CO2 H), and alcohol (R2 OH) with regeneration of [Bmim] and AcO− .4

(iii) Aminolysis reactions Kinetic studies of the aminolysis of 4-nitrophenyl acetate (13) by a series of cyclic secondary amines (14) in several ILs and in MeCN at 293–313 K were reported (Scheme 4). The cationic components of the ILs were 1-butyl-3-methylimidazolium (Bmim) (15), 1-butyl-2,3-dimethylimidazolium (Bm2 im) (16), and 1-hexyl-3-methylimidazolium (Hmim) (17), and the anionic components were BF4 − , PF6 − , trifluoromethylsulfonate (OTf), or bis(trifluoromethylsulfonyl)imide (NTf2 ) (18). Not all combinations were evaluated. For reaction with piperidine (14; X = CH2 ), [Bmim]PF6 , [Bmim]BF4 , [Bmim]OTf, [Bmim]NTf2 , [Bm2 im]NTf2 , and [Hmim] NTf2 , the measured ΔH≠ and ΔS≠ values were in the range 18–32 kJ mol−1 and (−130)–(−176) J K mol−1 , respectively, quite close to values found for MeCN, 18.9 kJ mol−1 and −174 J K mol−1 . By measuring the rates of aminolysis at 298 K of 4-nitrophenyl acetate (13) by piperidine (14; X = CH2 ), morpholine (14; X = O), 1-formypiperazine (14; X = NCHO), and 1-(2-hydroxyethyl)piperazine (14; X = NCH2 CH2 OH) in [Bmim]NTf2 , [Bm2 im]NTf2 and [Bmim]PF6 , a series of Brønsted plots were obtained with 𝛽 = 0.68, 0.38, 0.41, respectively, for the three ILs. For MeCN, 𝛽 = 0.56. These values are in the range expected for a concerted mechanism (0.3–0.8), and the authors thus concluded that the aminolyses of 4-nitrophenyl acetate (13) in the ILs and in MeCN are concerted.5 OH O Me

X

NO2

O

+

Me

N H

O (13)

N

+ X NO2

(14) Scheme 4

+

Bu

N Me

N

[Bmim] (15)

+

Bu

N

N Me

+

Hexyl

N Me

N

Me [Bm2im]

[Hmim]

(16)

(17)

O

−

N

O

S F3C S CF3 O O [NTf2] (18)

76

Organic Reaction Mechanisms 2016

(c) Acyl Halides and Anhydrides Theoretical studies of the uncatalysed esterification of acetyl fluoride, chloride, bromide, and iodide by MeOH in the gas phase have revealed the possible cyclic conformations that may occur during experiments at simple ratios of reactants. The calculated free energy of activation for acetyl chloride, 21 kcal mol−1 , was in good agreement with the experimental data.3 The 1:1 reactions of a dialkylsilylene (19) with benzoyl (20; X = H), 4-methylbenzoyl (20; X = Me), and 4-trifluoromethylbenzoyl chloride (20; X = CF3 ) in hexane at 243 K afforded the corresponding benzoyl(chloro)silanes (21; X = H, Me, CF3 ) in high yields, indicating that the C(carbonyl)–Cl bond is much more reactive than the carbonyl group (Scheme 5). No significant difference was observed in the reactivity among the benzoyl chlorides (20; X = H, Me, CF3 ). Even when a twofold excess of (19) was used in reaction with each benzoyl chloride (20; X = H, Me, CF3 ), the corresponding benzoyl(chloro)silane (21; X = H, Me, CF3 ) was obtained as the sole product. The expected reactions at the C=O group of (20) with silylene (19) would be prohibited due to the steric effects of the bulky silylene moiety of (19). Two mechanisms appear probable (Scheme 6), each involving initial formation of a silylene–ArCOCl complex (22). A concerted pathway would proceed via a three-centre TS (23), whereas facile heterolysis of the Cl–C=O bond of the complex (22), facilitated by the silylene acting as a Lewis base to activate the Cl–C=O bond, would yield transiently an ion-pair (24) which would recombine in a solvent cage to give the product (21).6 Monoacylation of long-chain linear diols is invariably accompanied by overacylation affording the diacetylated product. For example, treatment of 1,5-pentanediol (25) Me3Si

Me3Si

SiMe3 Si:

+

Cl X

SiMe3 Cl Si

hexane, −30 °C

O SiMe3

Me3Si

O SiMe3

Me3Si

(19)

X

(20)

(21) Scheme 5

O

Cl

R2Si: (19)

ArCOCl

R2Si

𝛿−

𝛿+

Ar

R2Si

O

Cl

C (23)

C Ar

−

(22)

(21) +

R2SiCl

O

C Ar

(24) Scheme 6

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

77

with isobutyric anhydride (Pri CO)2 O in the presence of the typical acylation catalyst, 4-dimethylaminopyridine (DMAP) (28), in CHCl3 at 213 K afforded the monoacylate (26) and diacylate (27) in a 1.7:1 ratio (Scheme 7). Some improvement of the ratio of products (to 3.5:1) could be achieved using 6 equiv of the anhydride. A highly ramified version of DMAP in which the 4-N,N-dimethyl group of the pyridine ring is replaced by a trans-2,5-disubstituted pyrrolidine (29; R = H) has been shown to catalyse highly selective monoacylation of 1,5-pentanediol (25) in CHCl3 at 213 K (mono-/di-acylate = 31:1). The structural groupings crucial to this selectivity are the two esterified l-tryptophan residues attached by carbonyl linkages at positions 2 and 5 of the pyrrolidine ring, which of course renders the catalyst chiral. The NH groups of the indolyl residues in (29) are also important for catalysis, as shown by testing the selectivity of the N,N-dimethyl derivative (29; R = Me) and observing the mono/di-acylate ratio drop to 8:1. The C2 -symmetry of catalyst (29; R = H) is also very important, for the corresponding C1 -symmetrical catalyst (30) yielded a selectivity ratio of only 10:1. For both C1 - and C2 -symmetrical catalysts, the amide C=O groups attached to the pyrrolidine ring are important in the selective monoacylation, but an increase of the selectivity is shown only by the C2 -symmetrical catalyst (29; R = H). DFT calculations were able to elucidate the origin of the precise molecular recognition of the 1,5-diol and the TS stabilization effects of the C2 -symmetrical catalyst (29; R = H).7

(d) Amides An intramolecular transamidation of an aromatic ester mediated by an adjacent HO group is described in full in the section devoted to ‘Intramolecular Catalysis and Neighbouring Group Participation’.

(e) Carbonates Theoretical studies of the aminolysis of ethylene carbonate by methylamine in dioxane using the supermolecule method concluded that for calculation of the relative energies of individual reaction steps it is sufficient to consider just one solvent molecule.8 Kinetic NMR studies of the hydrolysis of a series of X-benzyl phenyl carbonates (31; X = 4-CF3 , 4-Br, H, 4-Me, 3-MeO, 4-MeO, 3,4-(OMe)2 ) catalysed by 1,4-diazobicyclo [2.2.2]octane (DABCO) (32) (5 equiv) (Scheme 8) in DMSO-d6 /D2 O (4:1) at 313 K showed that EDGs accelerated the reaction. The rates of hydrolysis of all the X-benzyl phenyl carbonates (31) were 11- to 44-fold greater than that of an alkyl phenyl carbonate, and this was attributed to stabilization of the TS by cation–TI interactions by the benzyl group (33). The proposed mechanism (Scheme 9) involves rate-determining initial attack of the benzyl phenyl carbonates (31) by DABCO (32) to form, via transition state (33), a quaternary intermediate (34) with expulsion of phenoxide. This is followed by their rapid hydrolysis (D2 O) to benzyl alcohol, phenol, DABCO, and CO2 .9 Aminolysis of a series of 12 Y-phenyl phenyl carbonates (35) by 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in H2 O/DMSO (4:1) at 298 K (Scheme 10) proceeded via a concerted mechanism, a conclusion based on (i) a linear Brønsted-type plot

78

Organic Reaction Mechanisms 2016

HO

OH

catalyst or reagent

HO

+

OCOR

RCOO

OCOR

RCO-X

(25)

(26)

O H17C8O Me

N

Me

(27)

O H N

5

H N

2

N

OC8H17

H N N

O

O

N

NH N

N (28)

(29) Scheme 7

OC8H17

O NR

RN

O

(30)

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

79

δ−

O− δ+

O O

X

Ph

O

OPh

Nu

(31)

O

(33)

O R

O

O

N

Ph +

(31)

+ D2O

N

DMSO-d6

R

OD + PhOD + CO2 + (32)

(32) Scheme 8

N

O +

Ph

O

O

Ar

N

N

Ar

N

Ar

+

+ PhO−

N

(31)

O (34)

(32)

+ D2O + PhO− fast

+

slow

N

O

OD + PhOD + CO2 +

Ar

N N

O

O

Scheme 9

O PhO C O

+ N Y

(35)

N

O + PhO C N

N

=

+ −O Y

(DBU)

N Scheme 10

80

Organic Reaction Mechanisms 2016

with 𝛽 lg = −0.48; (ii) an excellent linear correlation in the Yukawa–Tsuno plot with 𝜌Y = 1.27 and r = 0.57; and (iii) the unlikelihood of formation of a zwitterionic TI owing to steric hindrance by the bulky DBU.10

(f) Thioesters and Thiocarbonates Comparison of the rates of aminolysis in MeCN at 298 K of O-2-pyridyl (36) and O-4pyridyl thionobenzoate (37) by a series of cyclic secondary amines (piperidine, morpholine, piperazine, and 3-methylpiperidine) showed that the O-2-pyridyl isomer is faster by a factor of 7–10.11,12 Aminolysis of both isomers proceeds via a mechanism that involves a catalysed and an uncatalysed route. The first step in the mechanism of the O-2pyridyl isomer (36) (Scheme 11) is formation of a zwitterionic TI, T± . The uncatalysed pathway proceeds via a six-membered cyclic transition state (38) in which the proton transfer from the aminium moiety to the N atom of the leaving group occurs simultaneously with expulsion of the leaving group. In the catalysed reaction, a second amine molecule deprotonates the aminium moiety of T± as a general base catalyst, again via a six-membered transition state (39).11 Although the latter process also occurs in the catalysed reaction of the O-4-pyridyl isomer (37), no intramolecular assistance is available for the uncatalysed route from T± , and the transition state (40) lacks the stabilizing six-membered feature of that of its O-2-pyridyl isomer.12 It seems probable that the difference in energy of the two transition states accounts for the greater reactivity of the O-2-pyridyl isomer (36). S Ph

S Ph

C O

C O

N

N (36)

(37)

The aminolysis of thioesters and thiocarbonates was reviewed.13

(g) Thioamides and Thioacyl Halides Theoretical studies of the water-assisted and unassisted enolization of formamide HCONH2 and thioformamide HCSNH2 concluded that the presence of one molecule of water reduces the activation energy of each process by a factor of 2. In the unassisted process for each amide, a cyclic four-membered transition state (41; X = O, S) is required (Scheme 12), but in the water-assisted process, a much less-strained six-membered transition state (42; X = O, S) prevails (Scheme 13).14 Kinetic studies of the solvolysis at 298 K in more than 20 solvent mixtures or pure solvents of 4-methylthiobenzoyl chloride (43) concluded that the reactions proceeded via an ionization pathway (SN 1), based on a good linear plot using the extended Grunwald–Winstein equations, a kinetic solvent isotope effect of kMeOH /kMeOD = 1.42, and activation parameters consistent with such a mechanism, ΔH‡ = 16.2–17.6 kJ mol−1 and ΔS‡ = (−16.5)–(−7.2) J K mol−1 .15

81

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

𝛿−

S Ar uncat.

C OPy

Ar

𝛿−

O 𝛿+

N

S−

S Ar

C

𝛿+

−OPy

N

H

Ar

S H+ C N

(38)

C OPy

S

+

Ph

HN

+ HN

𝛿−

T± cat.

Py =

HN

N

Ar

C N

O 𝛿+

H (39)

Scheme 11

+

S H N

− HN

Ar

C N + HOPy

𝛿−

C OPy HN

Py

S

𝛿−

(40)

82

Organic Reaction Mechanisms 2016

H

C

H C

NH

X

NH

X

H

H

H

C

NH

XH

(41) Scheme 12

H

H C

NH

X+

H

H

H C

NH

X

O

C NH + XH OH2

H H

O

H

H (42) Scheme 13

MeS

COCl (43)

Phosphoric Acids and their Derivatives (a) Phosphinic Acids Theoretical calculations on the esterification (BuOH) and amidation (BuNH2 ) of three cyclic phosphinic acids, 1-hydroxy-3-methyl-3-phospholene 1-oxide (44) and cisand trans-1-hydroxy-3,4-methylphospholone 1-oxide (45, 46), promoted by trimeric propylphosphonic acid anhydride (T3P) (47) showed that the mechanism (Scheme 14) involved attack of the six-membered ring of T3P (47) by the HO group of the phosphinic acids (44–46) to give a phosphinotriphosphonate which suffers a displacement of the triphosphonyl moiety by BuOH or BuNH2 to yield, respectively, a cyclic butyl phosphinate (48) or a cyclic N-butyl phosphinamide (49).16 Me

Me

Me

Me

Me

O Pr

HO

P (44)

O

HO

P

O

HO

(45)

P (46)

O

P O O

O P

P O

O Pr

Pr

(47)

(b) Phosphoryl and Thiophosphoryl Halides Aminolysis of 4-chlorophenyl-4-methoxyphenylchlorophosphate (50) by a series of substituted pyridines (51; X = 4-MeO, 4-Me, H, 3-Ph, 3-Ac) at 278 K in MeCN (Scheme 15)

83

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

P HO

P

O + (47)

O O

(44–46)

P

P O Pr

O

Pr

P

BuOH

Pr O

O

P

BuO (48)

BuNH2

OH

O

O

P BuNH

O (49)

Scheme 14

X

Cl Cl

O

P

OMe +

O

O

N

(50)

(51)

O Cl

O

P N

O +

OMe Cl−

X Scheme 15

yielded a Brønsted plot having 𝛽 x = 1.18, which, together with other data, pointed to an SN 2(P) process.17 A review covering the period 1994–2014 of the mechanisms of aminolysis of thiophosphinyl, thiophosphonyl, and thiophosphoryl chlorides appeared.18 INTRAMOLECULAR CATALYSIS AND NEIGHBOURING GROUP PARTICIPATION A series of 1-cyanocyclopropane-1-carboxylates (52) in which the aryl groups (Ar1 , Ar2 ) could possess electron-donating or -withdrawing groups were selectively hydrolysed to the 1-carboxamidocyclopropane-1-carboxylates (53) when heated at reflux for 18 h in an ethanolic solution containing 2 equiv of hydroxylamine hydrochloride and 2 equiv of sodium acetate (Scheme 16). It would be very feasible for NH2 OH to react with the Ar2 CO group to form an oxime. Indeed, this is the first step in the mechanism proposed by the authors.19 In the second step, the HO group of the oxime is shown adding to the cyano group. This is clearly impossible since the cyano group is trans to the Ar2 CO group. Instead, a much more likely mechanism can be delineated if one

84

Organic Reaction Mechanisms 2016 Ar1

Ar1 HONH HCl (2 equiv) Na OAc (2 equiv) 2•

CN

H H Ar2CO

CO2Et

CONH2

H H

EtOH/Δ, 18 h

Ar2CO

(52)

CO2Et (53)

Scheme 16

molecule of NH2 OH adds to the cyano group and another to the carboxyethyl group. The order of addition is immaterial, so for clarity the initial addition of NH2 OH is shown in Scheme 17 to be to the cyano group. Since the distal substituents on the cyclopropane ring are not involved in the intramolecular mechanism, they have been omitted from Scheme 17. Addition of NH2 OH to the cyano group of the 1-cyanocyclopropane-1carboxylate (54) yields an imine (55) which adds water to give a TI (56). The product of addition of NH2 OH to the carboxyethyl group of the TI (56) is an intermediate (57) which is set up to facilitate, via two six-membered rings, an intramolecular double proton transfer which yields the 1-carboxamidocyclopropane-1-carboxylate (58) with the regeneration of the carboxyethyl group and two molecules of NH2 OH. N

NH NH2OH

C

NHOH

HO

H2 O

CO2Et

CO2Et (54) H

C

C

NH2 NHOH

NH2OH

CO2Et

(55)

(56) O

O NH2 NHOH

HON H EtO

O

H

−2NH2OH

NH2 EtO

(57)

O (58)

Scheme 17

An efficient and highly regioselective hydrolysis of the 2-methoxycarbonyl group of 12 variously substituted dimethyl 3-benzamidophthalates (59) to the corresponding 2-carboxylated monomethyl esters (60) was achieved by treatment with 1 M KOH methanolic solution for 15 min at reflux (Scheme 18). Yields of the corresponding 2-carboxylated monomethyl ester (60) from one small series (59; R1 = Me, R2 = MeCO) were consistently about 84% whether the Ar group contained an EDG (e.g. Ar = 4MeO-C6 H4 -) or an EWG (e.g. Ar = 4-Cl-C6 H4 -, 4-NO2 -C6 H4 -). Nor for the series where the Ar substituent was simply phenyl (59; R1 = Me, Ar = Ph) did the yields change appreciably when R2 was either an EDG (e.g. 4-Me, 4-MeO, and 3,4-(MeO)2 )

85

2 Reactions of Carboxylic, Phosphoric, and Sulfonic Acids and their Derivatives CO2Me 1 M KOH/MeOH or MeCN reflux

CO2Me R1

CO2Me

R2

NH

R1

CO2H

CO2H

R1

CO2H

R2

NH

or R2

NH O

Ar

O

(60)

O (59)

(61)

CO2Me

Ar 3

10 mol% R ONa R3OH, reflux

1

O

R1

CO2R3

R

NH O (62)

Ar

OMe OMe

1 2

R2 R2

Ar

𝛿+

3

N

O

𝛿−

H

COAr (63)

Scheme 18

or an EWG (e.g. 4-MeCO and 4-PhCO). No selectivity was observed when a non-protic solvent such as MeCN replaced MeOH, and in a slower reaction (60 min) both ester groupings were hydrolysed in this solvent to yield the corresponding dicarboxylic acid (61) (Scheme 18). The regioselectivity of the C(2) over the C(1) ester group hydrolysis in (59) can be explained by the anchimeric assistance of the neighbouring 3-benzamido group. Intramolecular hydrogen bonding between the NH proton and the C=O group of the C-2 methoxycarbonyl group to form a six-membered ring (63) renders the C=O group more electrophilic and consequently more reactive to nucleophiles. Support for this proposal was obtained by subjecting the N-methyl derivative (59; R1 = Me, R2 = 4-MeO-C6 H4 -, Ar = Ph; Me for H) to similar conditions and observing a complex mixture of products. Another factor, the result of steric effects, is the C(1) methoxycarbonyl group which is forced to be perpendicular to the aromatic ring [see (63)], rendering it less exposed to nucleophilic attack. The necessity for a protic solvent could be explained by an effective H-bond-driven solvation of the C(2) carboxylate in monoester (60) which, accompanied by steric hindrance of vicinal substituents, renders attack of the solvated nucleophile at the C(1) methoxycarbonyl group less favourable. A selective transesterification of the diester (59; R1 = Me, R2 = 4-MeO-C6 H4 -, Ar = Ph) (and several other diesters) could be achieved by replacing MeO – /MeOH with either EtO– /EtOH or But O– /But OH, the products being, respectively, the 2-ethoxycarbonyl ester (62; R1 = Me, R2 = 4-MeO-C6 H4 -, R3 = Et, Ar = Ph) or the 2-t-butoxycarbonyl ester (62; R1 = Me, R2 = 4-MeO-C6 H4 -, R3 = But , Ar = Ph) (Scheme 18).20 Selective hydrolysis at pH 8.5 of 2,5,6-trimethoxycarbonyl-3-hydroxypyridine (64) in dioxane–water at 333 K yielded 2-carboxy-5,6-dimethoxycarbonyl-3-hydroxypyridine (65) (Scheme 19). Selective transesterification of (64) with primary and secondary alcohols (ROH) to the triester (65; CO2 R for CO2 H) and selective amidation with

86

Organic Reaction Mechanisms 2016 MeO2C

OH

MeO2C

N

pH 8.5

CO2Me

MeO2C

OH

MeO2C

N

(64)

R1R2NH

CO2H

(65)

EtN(Pr i)2

MeO2C

OH

MeO2C

CONR1R2

N (66)

Scheme 19

primary and secondary amines to the corresponding amide (66; R1 = alkyl, R2 = H; R1 , R2 = alkyl) were also achievable if diisopropylethylamine was present as a basic catalyst (Scheme 19). The presence of the 5,6-trimethoxycarbonyl groups acted as an internal control, the two ester groups remaining intact throughout. Guided by the well-known precedent of the intramolecularly-assisted alkaline hydrolysis of alkyl esters of salicylic acid, the authors proposed a mechanism (Scheme 20) in which the phenate (67) of the substrate (64) acts as a general base in an intramolecular catalytic O−

O H

N

C O

Y R′

N−

OMe

(67)

YR′ OMe

(68)

O− N

O

C

H

MeOH

CYR′

O N−

O (70)

O

(69)

YR′ = OH, OR, NR2, NH2 Scheme 20

C

H OMe YR′

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

87

process. In the general case, the phenate attacks the proton of water, alcohol, or amine (R′ YH), facilitating the attack of each upon the C=O group of the ester. The resultant TI (68) undergoes a rotation to a conformation (69) in which the phenolic proton is able to protonate the departing methoxy group, thereby facilitating the formation of the product (70).21 BIOLOGICALLY SIGNIFICANT REACTIONS

Carboxylic Acids and their Derivatives (a) Acids The enzymatic conversion of acids into amides was reviewed, with special emphasis on two processes that occur outside of the ribosome, B, C in Scheme 21. In the ribosomally guided process of peptide synthesis, activation of the carboxyl group occurs via reaction with ATP to form an acyl adenylate (71) (A, path a in Scheme 21). This is acted upon by a thiol group of an acyl carrier protein to generate a thioester which in turn reacts with an amino group of an amino acid. A non-ribosomal variant of the initial activation is formation of an acyl phosphate (72) via expulsion of ADP from ATP (A, path b in Scheme 21). This is frequently the route by which the substrate (ester or amide) (73; LG = OR, NR2 ) PPi

(A)

O

O O

a

R1

O

LG 1 AMP R

(71)

P

O ADP

LG

O

O R1

LG

R2 NH2

OH b

O

O Ad

O−

ATP

R1

P

O

OH

O−

Pi

R1

N H

R2

(72) (B) O R1

HO LG

ENZ

LG

R2 NH2

O R1

(73)

O

O

ENZ

(74)

ENZ

R1

N H

R2

HO

(C)

R1

R2 NH2

O

O R1

OH

OMe

AdoMet (75) Scheme 21

MeOH

O R1

N H

R2

88

Organic Reaction Mechanisms 2016

for process B is formed (Scheme 21). In that process, amide formation occurs via initial reaction of a serine residue of an enzyme (HO-Enz) upon (73; LG = OR, NR2 ) to generate an acyl enzyme (74) which suffers attack by an amine R2 NH2 to form the amide. A much more recent finding is simple activation of an acid to a methyl ester (75) via a methyltransferase that employs S-adenosylmethionine (AdoMet) as cofactor and thence enzyme-catalysed displacement of MeOH by an amine R2 NH2 (C in Scheme 21).22

(b) Amides and Peptides The mechanisms of metal-assisted peptide bond hydrolysis were reviewed.20 The majority of mechanisms reported so far are based on the Lewis acidity of the metal ion. In an alternative hydrolysis reaction, metal ions such as Cu(II), Ni(II), and Pd(II) play a structural role by forming a square planar complex with Ser/Thr-His or a Ser/Thr-Xaa-His sequence, which enables an N → O rearrangement of the acyl moiety in the peptide bond downstream from the Ser/Thr residue. Toxicological implications of the Ni(II) reactions were discussed.23 If pyridine possesses at its 2,6-positions two methylene groups that are each linked to the 6-amino group of two modified 𝛽-cyclodextrins (𝛽-CD), a Cu(II) complex (76) (CuL1 ) can form that has the 𝛽-CD moieties in a back-to-back relationship. However, if the linkages are to the 3-amino group of a modified 𝛽-CD, the 𝛽-CD moieties of the Cu(II) complex (77) (CuL2 ) are in a face-to-face relationship. In the jargon of CD chemistry, the two complexes possess different cavity orientations and should bind substrates with differing efficiencies. This was what was observed when, as hydrolase models, CuL1 showed higher catalytic efficiency and more pronounced enantioselectivity than ′ CuL2 in the hydrolysis of the 4-nitrophenyl (Np) esters of N-Boc-N -Boc-lysine (78; R = (CH2 )4 NHCO2 But ) and of N-Boc-alanine (78; R = Me) (Scheme 22). Moreover, the former ester with the longer alkyl chain showed twice the enantiomer selectivity of the latter.24

N

N

NH

NH

Cu H 2O

NH

NH

Cu OH2

H2O

OH2

CuL1

CuL2

(76)

(77)

The site-specific hydrolysis of peptide bonds at glutamic acid (Glu) under neutral aqueous condition has been developed.8 It involves the selective conversion of a Glu residue in a peptide (79) into a pyroglutamyl (pGlu) imide (82), via the acyl bromide (80) (path a, Scheme 23), which is activated towards hydrolysis of the adjacent peptide bond yielding the N-terminal fragment (83) and a pGlu imide-containing C-terminal

ee 

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

NO2

O R (L or D)

*

HN

O

O

CuL1 or CuL2

O

H2O

R

NO2

*

(L or D)

O(H) +

HN

O

(H)O

O O

(78) Scheme 22

H N

O

O

O

H N

N H

N H

activation

A

O path a

O

path b

O OH

Br

path b

(79) H N

(80)

O

imide path a formation

N

O

O

HN

(81) O

N O O O H H (82) hydrolysis

O H N

OH O (83) Scheme 23

89

N H

O (84)

90

Organic Reaction Mechanisms 2016

fragment (84) (Scheme 23). The reagent effecting this ground-breaking methodology is bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (85) with catal′ ysis by N,N -diisopropylamine. In the development stages, an alternative reaction of the acyl bromide (80) (path b) to yield a six-membered ring (81) was observed, but optimization of the process virtually eliminated formation of this dead-end product. A model hexapeptide, Fmoc-Val-Ala-Glu-Arg-Ph-Ala-NH2 was used initially to validate the process, the products being identified by HPLC-MS. Studies of other model peptides showed that virtually all other amino acid residues were unaffected, including notably the lower homologue of Glu, aspartic acid (Asp).25

N N

− P+ −Br PF6

N

(85)

Constructing peptides, especially linking two large peptides, is termed ligation. The classic native chemical ligation (NCL) exploits the special reactivity of the thiol group of an N-terminal cysteine residue, H2 N–CH(CH2 SH)–CO–, of one of the components. Now, in a promising new development, the special reactivity of the hydroxyl group of an N-terminal serine (Ser) residue, H2 N–CH(CH2 OH)–CO–, of one of the components is exploited in a process called serine peptide assembly (SPA). The key fragment of the terminal Ser residue involved in the chemistry of the SPA process is the 1,2hydroxyamine, H2 NCHR.CH2 OH. Early extensive experimentation had established that an activated ester would react with a 1,2-hydroxyamine, most effectively in a non-protic solvent, in a two-step process involving initial transesterification followed by attack of the NH2 group upon the C=O group in an intramolecular rearrangement to yield an activator O

R2 O

R1

O

H2N

R2 OH

H2N

O R1

H N

HO R2 (86)

Scheme 24

O R1

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

91

amide (86) (Scheme 24). This process is counterintuitive given that an amino group is always considered a better nucleophile than a hydroxyl group. However, based on many model experiments, the authors rationalized the reaction by invoking hard acid–hard base theory and concluded that the hard electrophile, C=O, is reacting preferentially with the harder nucleophile, the OH group. Many variants of activated ester were investigated, and the ester of choice was the 2,2,2-trifluoroethyl ester, RCOCH2 CF3 . Thus, as an example of SPA (Scheme 25), N-acetylvaline (Ac-Val) (87) was reacted with 2,2,2trifluoroethyl triflate (88) in MeCN in the presence of CsCO3 for 3 h at room temperature to yield its 2,2,2-trifluoroethyl ester (89). This ester (89) was treated with Ser-Ph–OMe (90) in EtAc at room temperature for 36 h to give Ac-Val-Ser-Ph-OMe (91), this reaction occurring via initial attack of the serine HO group upon the C=O group of (89), followed by the intramolecular attack of the NH2 group of the Ser residue upon the ester C=O group, as in Scheme 24. Another factor influencing the preferential transesterification is the presence of an internal hydrogen bond between the amine and the OH group (92). This could explain the preference for non-polar solvents, as they do not compete with the internal nitrogen as H-bond acceptors.26 O

H N

OH + CF3CH2OS2CF3

O

H N

CsCO3

OCH2CF3

MeCN

O

O (87)

(88)

(89) +

H2N

CH2OH H N

EtAc

CO2Me

36 h

Ph

O (90) H N O

O N H

CH2OH H N O

H CO2Me Ph

(91)

:NH2

O

R2 R1 (92)

Scheme 25

Phosphoric Acids and their Derivatives (a) Phosphates DFT calculations were used to investigate the reaction mechanisms of phosphodiester hydrolysis and transesterification catalysed by a dinuclear zinc complex of 2-(Nisopropyl-N((2-pyridyl)methyl)-aminomethyl)-6-(N-(carboxylmethyl)-N-((2-pyridyl)

92

Organic Reaction Mechanisms 2016

methyl)aminomethyl)-4-methylphenol (IPCPMP) (93), mimicking the active site of zinc phosphotriesterase. The substrates bis(2,4-dinitrophenyl) phosphate (BDNPP) (94) and 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP) (95) were employed as analogues of DNA and RNA, respectively. A number of different mechanistic proposals were considered, with the active catalyst harbouring either one or two hydroxide ions. It was concluded that for both reactions the catalyst has only one hydroxide bound, as this option yielded lower overall energy barriers. For BDNPP (94) hydrolysis, it was suggested that the hydroxide acts as the nucleophile in the reaction, attacking the phosphorus centre of the substrate. For HPNP (95) transesterification, on the other hand, the hydroxide was proposed to act as a Brønsted base, deprotonating the alcohol moiety of the substrate, which in turn performed the nucleophilic attack. The calculated overall barriers were in good agreement with measured rates. Both reactions were found to proceed by essentially concerted associative mechanisms, and it was demonstrated that two consecutive catalytic cycles needed to be considered in order to determine the rate-determining free energy barrier.27 NO2

NO2

N

O N

−O

O−

O

O2N

N CO2−

O

P

NO2 (94)

N OH

(93) H3C

O −O

P

O O

(95)

NO2

Quantum mechanical methods were used to define the hydrolytic cleavage mechanism of bis(2,4-dinitrophenyl) phosphate (BDNPP) (94) by a dinuclear copper(II) complex (96) formed from 4-methyl-2,6-bis[(6-methyl-1,4-diazepane)iminomethyl]phenol. CH3

N

O

N

CuII Cu II NH NH O NH H HN (96)

93

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

O 2N N 2+ O

−O

N Cu N N N O H O− O O2N P O O 2+

N Cu

O2 N

O 2N (97)

N O N N Cu Cu N N N H O O O2N O2N O P O O NO2

(99)

NO2

O2N

N 2+ O 2+ N N Cu Cu N N N O O H P O2N O O

NO2

O 2N

(98)

(100)

O O− HO P O N 2+ O N Cu N

N Cu N N O H 2+

+

O2 N

NO2 (101) Scheme 26

(102)

94

Organic Reaction Mechanisms 2016

The results showed that the mechanism is concerted and is of the SN 2(P) type involving the direct attack of the 𝜇-OH bridge between the two copper(II) ions upon the phosphoryl centre (Scheme 26). Initially, there is monodentate coordination of BDNPP (94) to the dinuclear copper(II) complex to form (97). Such coordination promotes the phosphorus atom activation in BDNPP, and the nucleophile (𝜇-OH bridge) becomes more labile to facilitate the nucleophilic attack. This attack leads to a pentacoordinate TS (98) from which dinitrophenol (99) was expelled to form complex (100), which rapidly dissembles to 2,4-dinitrophenyl phosphate (102) with regeneration of the dinuclear Cu(II) complex (101).28 An assessment of the catalytic proficiencies of 1-, 2-, and 4-methylimidazole (103, 104, 105) was made by the determination of their reactivity towards the triester, diethyl 2,4-dinitrophenyl phosphate (107) in aqueous solution, and a comparison was made with that of imidazole (106). All isomers (108) reacted with the triester (107) to give a diethyl phosphoramidate (109) with expulsion of 2,4-dinitrophenol (110) via an SN 2(P) mechanism (Scheme 27). The phosphoramidate (109) is short-lived and rapidly breaks down to diethyl phosphate (111) with regeneration of the imidazole (108). Progress of the catalytical hydrolysis of the triester (107) by 1-, 2-, and 4-methylimidazole (103, 104, 105) was followed by 31 P NMR in buffered solutions at pH 8.5. This permitted the detection and rate of formation of the corresponding phosphoramidate (109) and its rapid decomposition to diethyl phosphate (111). The most and least proficient catalysts were the 4-isomer (105) and the 2-isomer (104). The relative numerical reactivities towards the triester (107) were found to be 2-Me-IMZ (104):1-Me-IMZ (103):IMZ (106): 4-Me-IMZ (105) 1:2.90:4.02:6.30.29 Me

Me N

N

(EtO) 2 P

Me

N H

N H

(103)

(104) Me

NO 2

O

+ N

O

N N H

N H

(105)

(106)

Me NH

N

NO2 N P(OEt) 2 + O

NO 2 (107)

N

(108)

(109)

NO2 (110)

H2O

HO P(OEt) 2 O (111) Scheme 27

HO

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

95

(b) Phosphoramidates An experimental and computational study was reported of the hydrolysis of guanosine 5′ -phosphoroimidazolide (ImpG) (112) (Scheme 28) as a model for the role that phosphoroimidazolides play in several enzymatic phosphoryl transfer reactions. To obtain insight into the transition state structures, the leaving group kinetic isotope effect (KIE) was determined by mass spectrometry using 15 N-labelled ImpG (112). The observed KIE for the hydrolysis was 15 k = 1.019 ± 0.002, and this suggested that the rate-determining step in the mechanism (Scheme 29) involves extensive scissile bond fission of (113) and an AN DN mechanism with a loose transition state (114). Using 18 O-labelled ImpG (112) (label absent from the P–O–CH linkage), the observed 2 KIE for the hydrolysis of ImpG (112) was 18 k = 1.002 ± 0.003, and this pointed to O + HN

N

P O−

O O

G

HO

H2O

O OH OH

+ HN

(112)

P

O

G

O−

O OH OH

NH

Scheme 28

pathway A without concomitant proton transfer HO+ loose ANDN

H O−

extensive P N bond breaking O

1.82

P −O

N

HO

P

N

NH+

P

HO H

P

N

NH+

O OR (115) Scheme 29

−

O−

+ N

OH OR (117)

tight ANDN minor P N bond breaking

NH

O− OR

O pathway B HO with concomitant proton transfer

OR (113)

+ N

(116)

H − O OR (114)

NH+

O P

NH

96

Organic Reaction Mechanisms 2016

the phosphate remaining deprotonated at the rate-limiting step. This result appeared to rule out the intervention of transition state (115) which features protonation of the phosphoryl group and only minor P–N bond breaking (Scheme 29). Extensive quantum mechanical calculations also supported the involvement of the transition state (114) with extensive P–N bond breaking and pointed to two alternatives for its progression to products, via a zwitterionic intermediate (116) (pathway A) or via a concomitant proton transfer (pathway B) (117) (Scheme 29).30

REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Assaleh, F. H., Marinkovic, A. D., Nikolic, J. B., Drmanic, S. Z., Brkovic, D., Prlainovic, N., and Jovanovic, B. Z., Int. J. Chem. Kinet., 48, 367 (2016). Phakhodee, W., Duangkamol, C., and Pattarawarapan, M., Tetrahedron Lett., 57, 2087 (2016). Lawal, M. M., Govender, T., Maguire, G. E. M., Honarparvar, B., and Kruger, H. G., J. Mol. Model., 22, 1 (2016). Yu, X., Wang, M., and Huang, X., J. Mol. Liquids, 216, 354 (2016). Pavez, P., Millan, D., Rojas, M., Morales, J. I., and Santos, J. G., Int. J. Chem. Kinet., 48, 337 (2016). Xiao, X.-Q., Liu, X., Lu, Q., Li, Z., Lai, G., and Kira, M., Molecules, 21, 1376/1–1376/10 (2016). Imayoshi, A., Yamanaka, M., Sato, M., Yoshida, K., Furuta, T., Ueda, Y., and Kawabata, T., Adv. Synth. Catal., 358, 1337 (2016). Zabalov, M. V. and Tiger, R. P., Russ. Chem. Bull., 65, 631 (2016). Reddy, G. R., Avadhani, A. S., and Rajaram, S., J. Org. Chem., 81, 4134 (2016). Park, K.-H., Kim, M.-Y., and Um, I.-H., Bull. Korean Chem. Soc., 37, 77 (2016). Kim, M.-Y. and Um, I.-H., Bull. Korean Chem. Soc., 37, 1401 (2016). Um, I.-H., Kim, M.-Y., and Lee, J.-I., Bull. Korean Chem. Soc., 37, 1577 (2016). Dey, S., Am. J. Chem., 5, 55 (2015). Guzman-Angel, D., Inostroza-Rivera, R., Gutierrez-Oliva, S., Herrera, B., and Toro-Labbe, A., Theor. Chem. Acc., 135 (2), 1 (2016). Ryu, Z.-H. and Park, K.-H., Bull. Korean Chem. Soc., 37, 561 (2016). Ábrányi-Balogh, P., Jablonkai, E., Henyecz, R., Milen, M., and Keglevich, G., Curr. Org. Chem., 20, 1135 (2016). Lumbiny, B. J., Hui, Z., Islam, M. A., Quader, M. A., and Rahman, M., J. Phys.: Conf. Series, 495(Int. Conf. Sci. Eng. Math., Chem., Phys., 2014), 12004/1–12004/9, 9 (2014). Dey, S., Am. J. Chem., 5, 49 (2015). Liu, J., Zhang, F., Wang, T., Qing, X., and Wang, C., J. Chem. Res., 40, 694 (2016). Krivec, M., Perdih, F., Koˇsmrlj, J., and Kocevar, M., J. Org. Chem., 81, 5732 (2016). Wojtas, K. P., Lu, J.-Y., Krahn, D., and Arndt, H.-D., Chem.-Asian J., 11, 2859 (2016). Goswami, A. and Van Lanen, S. G., Mol. BioSyst., 11, 338 (2015). Wezynfeld, N. E., Fraczyk, T., and Bal, W., Coord. Chem. Rev., 327–328, 166 (2016). Xue, S.-S., Zhao, M., Lan, J.-X., Ye, R.-R., Li, Y., Ji, L.-N., and Mao, Z.-W., J. Mol. Catal. A: Chem., 424, 297 (2016). Nalbone, J. M., Lahankar, N., Buissereth, L., and Raj, M., Org. Lett., 18, 1186 (2016). Pirrung, M. C. and Schreihans, R. S., Eur. J. Org. Chem., 2016, 5633. Daver, H., Das, B., Nordlander, E., and Himo, F., Inorg. Chem., 55, 1872 (2016). Esteves, L. F., Rey, N. A., Dos Santos, H. F., and Costa, L. A. S., Inorg. Chem., 55, 2806 (2016). Campos, R. B., Menezes, L. R. A., Barison, A., Tantillo, D. J., and Orth, E. S., Chem.-Eur. J., 22, 15521 (2016). Li, L., Lelyveld, V. S., Prywes, N., and Szostak, J. W., J. Am. Chem. Soc., 138, 3986 (2016).

CHAPTER 3

Oxidation and Reduction

K. K. Banerji Department of Chemistry, J. N. V. University, Jodhpur, India Oxidation by Metal Ions and Related Species . . . . . . . . Chromium, Manganese, Nickel, and Cobalt . . . . . . Copper, Silver, Gold, and Thallium . . . . . . . . . . . Cerium, Tungsten, Molybdenum, and Vanadium . . . . Palladium, Iridium, Ruthenium, Rhodium, and Platinum Group VIII Metals . . . . . . . . . . . . . . . . . . . . Oxidation by Compounds of Non-metallic Elements . . . . Nitrogen and Sulfur . . . . . . . . . . . . . . . . . . . Halogens . . . . . . . . . . . . . . . . . . . . . . . . . Ozonolysis and Ozonation . . . . . . . . . . . . . . . . . . . Peracids and Peroxides . . . . . . . . . . . . . . . . . . . . Photo-oxygenation and Singlet Oxygen . . . . . . . . . . . Triplet Oxygen and Autoxidation . . . . . . . . . . . . . . . Other Oxidations . . . . . . . . . . . . . . . . . . . . . . . . Reduction by Complex Metal Hydrides . . . . . . . . . . . Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . Transfer Hydrogenation . . . . . . . . . . . . . . . . . . . . Other Reductions . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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97 97 100 105 107 115 117 117 121 131 131 143 143 155 159 162 172 183 189

Oxidation by Metal Ions and Related Species Chromium, Manganese, Nickel, and Cobalt Kinetic and activation parameters of oxidation of malic acid by benzyltrimethylammonium fluorochromate1 and morpholinium fluorochromate (MFC),2 picolinic acid (PA)-catalysed oxidation of some 𝛼-hydroxy acids with triethylammonium fluorochromate,3 primary aliphatic alcohols by MFC,4 thiolactic, thiomalic, and thioglycolic acids with quinaldinium fluorochromate,5 phenylalanine by pyridinium chlorochromate,6 𝛼-hydroxy acids and their Co(III) complexes by quinoxalinium chlorochromate,7 alanine and phenylalanine with pyridinium dichromate,8 vanillin,9 and clindamycin phosphate10 by Cr(VI), aliphatic secondary alcohols by tetrakis(pyridine)silver dichromate,11 and PA-promoted oxidation of phenylsulfinylacetic acid with Cr(VI)12 have been determined, and the mechanisms are proposed. Michaelis–Menten-type kinetics were observed with respect to sulfide in Organic Reaction Mechanisms 2016, First Edition. Edited by A. C. Knipe. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

97

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Organic Reaction Mechanisms 2016

the oxidation of some substituted aryl methyl sulfides13 and dimethyl-, dipropyl-, and diphenyl-sulfides14 by benzimidazolium dichromate. Activation parameters have been determined, and a mechanism is proposed. In the oxidation of substituted phenylmercaptoacetic acids (PMAAs) by oxo(salen) chromium(V) complexes, in the presence of different ligand oxides (LOs), the reactive intermediate in the catalytic cycle is O=Cr(V)(salen)+ –LO. Both electron-donating and -withdrawing substituents in the reductant and oxidant increase the rate. Two different mechanisms have been postulated, a direct oxygen atom transfer for PMAAs with electron-withdrawing substituents and a single electron-transfer (SET) for PMAAs with electron-donating substituents.15 Autocatalysis by Mn(II) has been observed in permanganate oxidation of some straight chain amino acids in moderately concentrated sulfuric acid medium. The rate constants of the uncatalysed oxidation of glycine, l-𝛼-amino-n-butyric acid, l-norleucine, and l-𝛼-amino-n-heptanoic acid satisfy Taft’s equation involving the inductive factor. The rate constants of the catalytic pathway satisfy Taft’ biparametric equation comprising inductive and steric factors. Amino acid–Mn(II) complexes were studied using density functional theory (DFT). Results show that such a complex is less stable than reactants.16 The autocatalytic behaviour of the oxidation of thiamine hydrochloride by the permanganate ion in aqueous sulfuric acid is due to the (4-methylthiazol-5-yl)acetic acid, a product formed from the oxidation of the substrate. Added Mn(II) has no effect on the rate. The activation parameters with respect to the slow step and reaction constants involved in the mechanism have been determined.17 The kinetics of oxidation of pyridine to pyridine-N-oxide,18 caffeine,19 2,4-dichlorobenzaldehyde,20 and of 4-hydroxyacetophenone21 with acid permanganate has been studied. The activation parameters have been determined, and suitable mechanisms have been postulated. The kinetics and activation parameters of the uncatalysed and ruthenium(III)-catalysed oxidation of aspartame,22 lomefloxacin,23 and of atropine24 by potassium permanganate in aqueous alkaline medium have been determined and plausible mechanisms suggested. Hammett correlations, isotopic (18 O) labelling, and other experiments showed that the nature of oxidizing species in enantioselective epoxidations of olefin catalysed by aminopyridine manganese(II) complexes, [LMn(II)(OTf)2 ], changes with different terminal oxidants. An addition of co-catalytic additives such as carboxylic acid or water dramatically changes the catalytic behaviour of the catalyst system. In the presence of chiral additive Boc-protected (l)-proline, achiral Mn aminopyridine complexes catalyse the epoxidation of chalcone in an enantioselective manner, representing a rare example of chiral environment amplification.25 Manganese(V) nitrido complex, [MnV (N)(CN)4 ]2− , efficiently catalyses the oxidation of alkanes by periodate. Excellent yields of alcohols and ketones (>95%) are obtained with a maximum turnover number (TON) of 3000. A kinetic isotope effect (KIE) of 4.7 has been obtained in oxidation of an equimolar mixture of cyclohexane and cyclohexane-d12 . A mechanism has been proposed in which O-atom transfer from IO4 − to [Mn(N)(CN)4 ]2− occurs in the first step which is rate-determining. The resulting [MnVII (N)(O)(CN)4 ]2− then oxidizes the alkane via a H-atom abstraction/O-rebound mechanism to give the alcohol (Scheme 1).26

ee 

99

3 Oxidation and Reduction

IO3− −

IO4

NC

N CN

N

2−

NC

RH

MnVII NC CN CN

H-atom abstraction

2−

NC

MnV CN NC

ROH

OH

N

2−

MnVI R NC CN CN

R NC

N OH

O

2−

H

MnV

Orebound

NC CN CN Scheme 1

A nickel/N-heterocyclic carbene (NHC) system for regioselective oxidative annulation of benzamides by double C–H bond activation and concomitant alkyne insertion has been described. The catalytic reaction requires a bidentate directing group, such as an 8-aminoquinoline, embedded in the benzamide. Various 5,6,7,8-tetrasubstitutedN-(quinolin-8-yl)-1-naphthamides as well as phenanthrene and benzo[h]quinoline amide derivatives can be prepared. Reaction of a deuterated benzamide yielded a KIE close to one indicating that C–H cleavage is not involved in the rate-determining step. A Ni(0)/Ni(II) cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two-component coupling partner and as a hydrogen acceptor.27 A nickel(II)-catalysed alkynylation/annulations cascade via double C–H cleavage has been successfully achieved. The catalytic system tolerates a broad range of amides and terminal alkynes. Oxygen has been used as the terminal oxidant. Reaction of 2-benzamidopyridine-1-oxide and its d5 analogue resulted in an intermolecular KIE of 2.4, illustrating that the cleavage of o-sp2 C–H bonds of amides may play an important role in the catalytic system. A catalytic cycle, which involves an initial coordination of the Ni(II) species with 2-benzamidopyridine 1-oxide followed by C–H activation, has been proposed.28 Cobalt(III)-catalysed intramolecular C–H/N–H cross-dehydrogenative coupling (CDC) of ortho-alkenylanilines and of ortho-alkenylphenols has been developed utilizing oxygen as a terminal oxidant and Cu(II) acetate as a co-catalyst. Preliminary mechanistic investigations revealed that a radical pathway is not favoured. Reaction in the presence of D2 O indicated that the reaction involves initial Co–C bond formation through a reversible C–H bond activation. Formation of a cobaltacycle intermediate has been postulated.29 A mild Co(III)-catalysed oxidative annulation of N-arylureas and internal alkynes to yield indoles has been developed. The use of less electrophilic ureas other than acetamides as directing groups is crucial for the reaction. Indoles were successfully obtained from a broad range of substrates in moderate to high yields with ortho-regioselectivity. Both electron-donating and -withdrawing substituents are tolerated. Ag2 CO3 has been used as a terminal oxidant to regenerate Co(III) catalyst.

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Organic Reaction Mechanisms 2016

Two separate experiments using 1,1-dimethyl-3-phenylurea and 1,1-dimethyl-3phenylurea-d5 were carried out from which KIE values of 1.6 and 3.3 were found, indicating that C–H activation is the likely turnover limiting step in the coupling process. A mechanism has been suggested.30 A cobalt-catalysed, aerobic oxidative dehydrogenative formal [4+2] reaction of N,N-dimethylanilines with dihydrofuran has been reported. The reaction proceeds through cobalt-catalysed dehydrogenation of tertiary amines followed by nucleophilic addition/intramolecular cyclization with dihydrofuran to afford hexahydrofuroquinoline motifs in good yields. No reaction occurs in the presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) or 2,6-di-t-butyl-4-methylphenol (BHT), which indicates a radical pathway in the reaction. The reaction is proposed to be initiated by generation of a cobalt(III) peroxide radical by a combination of molecular oxygen with cobalt(II), which may abstract a hydrogen atom from N,N-dimethylaniline to form a radical intermediate.31 Kinetic and activation parameters of the oxidation of n-propyl mercaptan with chloridotetraphenylporphyrinatocobalt(III) in the absence of oxygen have been determined, and a mechanism is proposed.32

Copper, Silver, Gold, and Thallium Methodologies of computational studies of homogeneous gold catalysis have been reviewed. It has been pointed out that a representative number of current mechanistic studies still use methods which have been reported as inappropriate and inaccurate for this purpose. A number of recent mechanistic studies where computational chemistry has provided relevant insights into non-conventional reaction paths, unexpected selectivities, or novel reactivity have been discussed.33 Arylamines and cyclic ketones undergo a Pd(OAc)2 -catalysed oxidation with copper(II) acetate to deliver carbazoles in moderate to good yields. The protocol involves a domino reaction via a dehydrogenative aromatization and a dual sp2 C–H functionalization process under ligand-free conditions. A primary KIE value of 2.45 was observed for the competition reaction between diphenylamine and diphenylamined5 , which revealed that the C–H bond cleavage is involved in the rate-determining step. A plausible mechanism has been suggested.34 Pd(II)-catalysed peroxide-free ortho-aroylation of directing arenes has been developed via CDC in the presence of the terminal oxidant Cu(OAc)2 ⋅H2 O. ortho-Aroylation of 2-phenylbenzothiazoles proceeds via decarbonylation of the in situ generated phenylglyoxal, which is obtained from 2-acetoxyacetophenone in the presence of the oxidant. However, changing the oxidant to CuX2 (X = Cl, Br) provided exclusively di-ortho-halogenated 2-arylbenzothiazoles. During the halogenation, CuX2 served the dual role of a halogen source as well as a co-oxidant. It has been proposed that cyclopalladation of 2-phenylbenzothiazole leads to the formation of an intermediate followed by the insertion of an aroyl moiety obtained via decarbonylation of phenylglyoxal to form another intermediate. In the final stage, reductive elimination gave an ortho-aroylated product releasing Pd(0), which was oxidized to Pd(II) by air/Cu(OAc)2 for the next catalytic cycle.35 DFT and kinetic Monte Carlo calculations of Cu-catalysed CDC of thiazoles with THF, mediated by peroxydisulfate (PDS), showed that the previously proposed concerted

3 Oxidation and Reduction

101

metallation–deprotonation mechanism is unfavourable. In the proposed mechanism, the Cu(II) catalyst first combines with the thiazoles, forming an organocopper species that then binds to the THF radical. The rate-limiting step, C–C bond formation, is realized through an intramolecular structural rearrangement. THF radical is likely to be generated through sulfate radical anion, obtained by the dissociation of PDS ion.36 Rhodium(III)-catalysed oxidative annulation reactions of pyridinium trifluoromethanesulfonate salts with alkynes, leading to substituted indolizines by cleavage of sp2 C–H/ sp3 C–H bonds, have been developed. KIE experiments yielded kH /kD values of 2.3 for both the competitive and parallel reactions. It indicated that the cleavage of the C–H bond of pyridine ring may have been involved in the rate-determining step. Cu(II) acetate was used as a terminal oxidant. A mechanism which involves a C–H bond activation to generate a six-membered rhodacyclic intermediate has been proposed.37 A simple method for the efficient synthesis of highly substituted pyrido[1,2a]quinolinium- and quinolizino-[3,4,5,6-ija]quinolinium-based polyheteroaromatic compounds via [Cp*RhCl2 ]2 -catalysed multiple C–H activation oxidative annulation reactions has been developed. Copper(II) acetate is the terminal oxidant. Deuterium KIE experiments indicated that cleavage of the C–H bond of the phenyl ring is not involved in the rate-determining step. The initial step is likely to be an ortho-C–H bond activation directed by the coordinated pyridine-based carbene ligand affording a five-membered cyclometallated intermediate.38 The cascade oxidative annulation reactions of aryl imidazoles with two molecules of alkynes via multiple C–H activation proceed efficiently in the presence of [Cp*RhCl2 ]2 and Cu(OAc)2 ⋅H2 O to give substituted benzo[ij]imidazo[2,1,5-de]quinolizine-based polyheteroaromatic compounds. This method is compatible with various functional groups. H/D exchange experiments indicated that imidazole C–H and phenyl ring C–H activations are reversible. A KIE (kH /kD = 2.2) indicated that the cleavage of the phenyl ring C–H bond is probably involved in the rate-determining step. A mechanism has been proposed.39 Rh(III)catalysed carbocyclization reactions of 3-(indolin-1-yl)-3-oxopropanenitriles with alkynes and alkenes yield 1,7-fused indolines through oxidative C–H activation. The reactions proceeded with a broad range of substrates. For alkynes, almost all products are highly regio- and stereo-selective. Electron-rich alkynes could undergo oxidative coupling to form a polycyclic compound. For alkenes, the Rh(III)-catalysed carbocyclization is through sp2 C–H/sp3 C–H oxidative coupling. Copper(II) acetate has been used as a stoichiometric oxidant. A probable mechanism has been proposed.40 The regioselectivity of cyclopropane ring-opening and product distributions in the oxidative ring-opening reactions of benzene-fused bicyclic cyclopropyl silyl ethers, promoted by copper(II) tetrafluoroborate, were found to be highly dependent on the nature of the solvent. In alcohols, dimeric substances arising from external bond cleavage are major products. Radical rearrangement products are also formed in solvents such as ether and ethyl acetate. On the contrary, nucleophile addition to carbocation intermediates, generated by internal bond cleavage, occurs mainly in reactions taking place in acetonitrile. It has been proposed that the observed solvent effects that govern the reaction pathways followed are a consequence of varying solvation of copper intermediates, which governs their reactivity and redox properties. A mechanism has been suggested.41 DFT calculations indicated a new cooperative reductive-elimination mechanism for

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Organic Reaction Mechanisms 2016

rhodium-catalysed oxidative coupling of benzoic acid and alkynes in the presence of Cu(II) acetate as an oxidant. According to this mechanism the oxidizing agent participates directly in the reductive-elimination process by taking one electron already in the reductive-elimination transition state itself. In this way, the rhodium(I) oxidation state is never reached. In this case, the copper acetate oxidant plays a key role in the reductive-elimination step, which takes place through a transition state containing both rhodium and copper centres. This cooperative reductive-elimination step is not accessible with a generic oxidant, which is in agreement with available experimental data.42 Highly substituted anthracenes have been synthesized, in satisfactory to good yields, by a rhodium-catalysed oxidative benzannulation of N-adamantyl-1-naphthylamines with internal alkynes in the presence of Cu(II) acetate as an oxidant. Experimental results indicate that the metallation is directed by the amide group and that cyclorhodation is a reversible process in the absence of an alkyne under the protonic conditions. A plausible catalytic cycle, involving six-membered rhodacyclic intermediate formation, has been proposed.43 A Cu(OTf)2 -catalysed enantioselective cross-coupling of a sp3 C–H moiety (Narylglycine ester) with a sp C–H component (terminal alkyne) using molecular oxygen as the terminal oxidant is an efficient approach for rapid preparation of a diverse array of optically active non-natural 𝛼-amino acids. Experiments showed that 𝛼-imino esters are intermediates in this reaction. A preliminary model for enantioinduction has been presented.44 8-Aminoquinoline-directed amination of 𝛽-sp3 C–H bonds of 𝛼,𝛼-disubstituted propionic amides by alkylamines such as morpholine mediated by Cu(OAc)2 and oxygen has been reported. The preliminary data of parallel intermolecular KIE experiments (kH /kD = 2.7) implied that the cleavage of the 𝛽-sp3 C–H bond occurred as the rate-determining step. It was found that TEMPO inhibited the reaction completely, suggesting that a radical pathway is involved. A mechanism involving an initial complexation of N-(quinolin-8-yl)pivalamide with Cu(OAc)2 to generate an intermediate followed by a base-assisted sp3 C–H activation to produce another Cu(II) intermediate has been postulated.45 A copper(II)-mediated regioselective N-arylation of azoles has been developed using 8-aminoquinoline amide as a directing group. This reaction shows a broad substrate scope with different azoles such as pyrroles, indoles, pyrazoles, and carbazole with good yields. A mechanism involving formation of a copper(II) species by a reaction of azole with Cu(OAc)2 , in the presence of base, has been suggested (Scheme 2).46 The products of oxidative coupling of variously substituted racemic [2.2]paracyclophane-derived phenols in the presence of CuCl(OH)⋅TMEDA are solvent-dependent. In MeOH it leads predominantly or exclusively to ortho-cyclohexadienones of (Rp*,Rp*) relative configuration, while in CH2 Cl2 the respective dimeric para-cyclohexadienones are obtained as mixtures of two diastereomers, namely chiral (Sp*,Rc*,Rc*,Sp*) and meso-(Rp,Sc,Rc,Sp). The enantiomerically pure phenol of (Sp) configuration gives rise to the single (Sp,Rc,Rc,Sp) diastereomer.47 CuI/2-(diphenylphosphino)-N,Ndimethylaniline (PN-1)-catalysed oxidative cross-coupling (OCC) of alkyl-, aryl-, and alkynyl-aluminium reagents with aryl and heteroaryl halides and vinyl bromides afforded the cross-coupled products in good to excellent yields. Radical clock experiment with a radical probe indicated that the reaction does not involve free aryl radicals

ee 

ee  de 

103

3 Oxidation and Reduction Cu(OAc)2

O +

N H

N Cs2CO3

CsHCO3 + CsOAc

N

Cs2CO3

N H

−CsHCO 3 −CsOAc

CuOAc

O

O N N

CuII N

Cu(OAc)2

N

CuOAc

CuIII

N AcO

O N N

CuIII N

Cs2CO3

N

−CsHCO3 −CsOAc

O H+ Cu+

N H N N

Scheme 2

and radical anions as intermediates. The reaction constant (𝜌 = 1.06) obtained from a linear Hammett plot of the reaction of Ph3 Al with p-substituted iodoarenes suggests that the reaction follows an oxidative addition–reductive elimination pathway. A catalytic cycle has been proposed (Scheme 3).48 The kinetics and activation parameters of the oxidation of aspartame,49 piperazine,50 and of norfloxacin51 by diperiodatocuprate(III) (DPC) in aqueous alkaline medium have been determined. The results indicated that [Cu(H2 IO6 )(H2 O)2 ] is the reactive species of Cu(III). Probable mechanisms have been proposed. The kinetics and activation parameters of the Os(VIII)-catalysed oxidation of l-glutamic acid with DPC have been determined. [Cu(H2 IO6 )(H2 O)2 ] and [OsO4 (OH)2 ]2− have been postulated as the reactive species of DPC and Os(VIII).52 The kinetics and activation parameters of oxidation of neopentyl glycol and 1,3-butanediol by ditelluratocuprate(III) in alkaline medium have been determined, and a mechanism is proposed.53 The palladium-catalysed CDC of N-alkylpyrroles and pyridine N-oxides gave the corresponding pyrrolylpyridine N-oxides. Cu(OAc)2 ⋅H2 O as a co-catalyst with air as the terminal oxidant led to preferential coupling in the 𝛽-position, whereas using AgOAc as the stoichiometric oxidant resulted in preferential coupling in the 𝛼-position. Reaction of deuterium-labelled N-benzylpyrrole is indicated against a reversible C–H activation of the pyrrole. For pyridine N-oxide, the observed KIEs of kH /kD > 2.0 are consistent with rate-limiting C–H activation of pyridine N-oxide likely by a concerted metallation–deprotonation mechanism. For pyrrole, small KIEs of kH /kD ≈ 0.9–1.5 are

104

Organic Reaction Mechanisms 2016 [R3AlCl]− Li+

R3Al + LiCl

[R2Al(Cl)(X)]− Li+

(PN-1)Cu-R

(PN-1)Cu-X

R1-X R-R1 R1 X = I, Br, Cl

(PN-1) Cu

R

X Scheme 3

observed, consistent with electrophilic functionalization of the pyrrole, by SE Ar-like metallation or by carbometallation.54 A double C–H activation of 2-coumarins and 2-pyrones has been developed using palladium(II) acetate as the catalyst and Ag2 O as an oxidant. Excellent regioselectivity on the pyrones and good yields have been achieved. Isotope effect experiments indicated that C(3)–H cleavage is not rate-determining. An initial palladation–protodepalladation of the C(3)–H bond to give an intermediate as the first step has been proposed.55 A Rh(III)-catalysed C–H activation/cyclization of oximes and alkenes for facile and regioselective access to isoquinolines has been developed. A large primary KIE value (kH /kD = 2.8) was obtained, suggesting that C–H bond cleavage occurs during the rate-determining step. It has been proposed that the reaction is initiated by a generation of [Cp*Rh(III)] from [Cp*RhCl2 ]2 and Ag2 CO3 .56 A one-pot oxidation/cycloaddition cascade for the synthesis of 2,4-diaryl chromans has been developed. The reaction involves in situ oxidative generation of the unstable o-quinone methides, using silver oxide, followed by endoselective 4 + 2-cycloaddition with styrenes.57 Chiral 𝛼-amino phosphonates have been synthesized by enantioselective C–H phosphonylation of allylamine with phosphite in the presence of a chiral Brønsted acid catalyst. The reaction involves a direct C–H oxidation with silver carbonate and asymmetric phosphonylation with high enantioselectivity (up to 92% ee). It is proposed that initially, allylimine is generated in situ from allylamine via C–H oxidation. Next, a chiral Brønsted acid activates the phosphite and allylimine to form a nine-membered transition state, wherein the chiral phosphoric acid works as a bifunctional catalyst. It promotes the phosphite to attack the allylimine from the re face and increases the enantioselectivity by proximity effect. Finally, protonation gives rise to the desired product, and the catalytic cycle completes.58

ee 

3 Oxidation and Reduction

105

Unprotected 2-alkynylanilines are converted to benzisoxazole derivatives in moderate to good yields through Ag-catalysed domino oxidation. The gold-catalysed process, on the other hand, yielded functionalized 4H-benzo[d][1,3]oxazin-4-one. Potassium peroxymonosulfate (PMS) has been used as the terminal oxidant. The addition of TEMPO had a slight influence but did not interrupt the reaction, thus suggesting that radical intermediates were not involved in the process. Plausible mechanisms have been suggested.59 Oxidation of picolinic acid hydrazide,60 m-toluic acid hydrazide,61 benzoic, pmethoxy-, and p-chloro-benzoic acid hydrazides,62 and p-hydroxybenzoic acid hydrazide63 by thallium(III) in acid medium is proposed to proceed through formation of an intermediate complex with the reactant, which decomposes in subsequent steps to give the product. Effect of acrylonitrile showed that there is no formation of free radicals. The activation parameters were determined, and suitable mechanisms have been proposed.

Cerium, Tungsten, Molybdenum, and Vanadium The use of Mo(V) reagents, in particular MoCl5 , in organic synthesis has been surveyed. Their unique high oxidative power combined with exquisite Lewis acid properties has been discussed. Their uses in C–C bond formation through inter- and intra-molecular oxidative coupling leading sometimes to selective formation of five- to eight-membered ring systems have been mentioned. Mechanistic aspects of the reactions of Mo(V) reagents have been emphasized.64 A ceric ammonium nitrate-promoted dehydrogenative coupling of various 1,2diarylethylenes led to the formation of phenanthrenes and other biaryl compounds. Preliminary mechanistic investigation by EPR spectroscopy and DFT calculations indicated that an electron transfer (ET) from methoxyarene to cerium leads to cationic radical formation, which further proceeds to intramolecular coupling (Scheme 4).65 The kinetic and activation parameters of oxidation of methylaminopyrazole formamidine,66 𝜄- and 𝜆-carrageenans as sulfated polysaccharides,67 aminotriazole formamidine,68 and Ru(III)-catalysed oxidation of N-(2-hydroxyethyl)phthalimide69 by cerium(IV) have been obtained and mechanisms suggested. Based on a combined study including synthetic investigations, electrochemical measurements, EPR spectroscopy, DFT calculations, and mass spectrometry, a mechanistic scenario for the dehydrogenative coupling of arenes by molybdenum pentachloride has been proposed. It has been suggested that MoCl5 acts as a one-electron oxidant in the absence of TiCl4 and as two-electron oxidant in the presence of TiCl4 (Scheme 5).70 DFT calculations of oxidation of olefins with MoO2 Cl2 and WO2 Cl2 revealed that formation of epoxide from these reactions is not very feasible by any of the postulated paths. An epoxide precursor may arise via initial [3+2]O ,Cl addition of ethene to MoO2 Cl2 and WO2 Cl2 to form an intermediate, followed by rearrangement to form the precursor, from which the epoxide can be generated by hydrolysis.71 In the oxidation of 2-mercaptoethanol and 2-mercaptoethylamine with heteropoly 11-tungsto-1-vanadophosphate anion, [PV(V)W11 O40 ]4− , the oxidant undergoes a one-electron reduction to [PV(IV)W11 O40 ]5− , while the thiols are oxidized to the

106

Organic Reaction Mechanisms 2016

R1

R1

R1 − H+

Ce4+

R2

Ce4+

H

−e

−e

R2

R2

+

R1

·

H R2 − H+

R1

R2

Scheme 4

MeO MeO MeO MoCl5

OMe

MeO

+

SET

OMe

MeO

MeO

MeO

reduction during

OMe

aqueous workup

Scheme 5

MeO

+

OMe

3 Oxidation and Reduction

107

corresponding disulfides. It has been shown that both the undissociated thiol (RSH) and thiolate ion (RS− ) are reactive species. It has been proposed that generation of RS radical from RSH proceeds via a separated–concerted proton–ET mechanism. The reaction of thiolate ion is a simple outer-sphere ET reaction.72

Palladium, Iridium, Ruthenium, Rhodium, and Platinum Mechanistic studies on Pd-catalysed C–C cross-coupling reactions via DFT calculations have been reviewed. The review includes a brief introduction of fundamental steps involved in these reactions such as oxidative addition, transmetallation, and reductive elimination. Recent progress on theoretical studies of palladium-catalysed carbon–carbon cross-coupling reactions, including the C–C bond formation via C–H bond activation, decarboxylation, Pd(II)/Pd(IV) catalytic cycle, and double palladium catalysis, has been discussed.73 Significant developments in the field of palladium-catalysed cross-coupling reactions in ionic liquids (IL) have been reviewed. The beneficial effect of the IL in terms of activity, selectivity, and recyclability has been commented upon for all types of reactions discussed. Insights into the reaction mechanisms revealed that the effect of the IL on C–C bond forming reactions manifests itself not only in the lowering of energy of polar transition states or intermediates involved in the catalytic cycles but also in the stabilization of palladium nanoparticles, the synthesis of molecular Pd complexes with the IL anions, the enhancement of the chemical reactivity of reactants, and others.74 Recent advances in the utility of the oxidative boron Heck reaction in enantioselective Heck-type couplings have been reviewed. It has been pointed out that oxidative boron Heck reaction, using Pd(II) catalysts, overcomes several limitations of the traditional Pd(0)-catalysed Heck coupling and has subsequently allowed for intermolecular couplings of challenging systems such as cyclic enones, acyclic alkenes, and even site selectively on remote alkenes.75 Palladium(II) carboxylate salts have been shown to catalyse the oxidation of various hydroquinones to benzoquinones (BQs) in the presence of t-butyl hydroperoxide (TBHP). This catalytic system has been integrated into the oxidative 1,4-functionalization of cyclic 1,3-dienes where the palladium plays a dual role, catalysing both the diene oxidation itself and the regeneration of the active quinone oxidant, which is required for diene functionalization.76 Treatment of alkynes with catalytic amounts of Pd(OAc)2 and (diacetoxyiodo)benzene (PIDA) in DMSO afforded (Z)-𝛼-acetoxylated enones, in one step, with high selectivity. Mechanistic studies, including the use of 18 O-labelled DMSO, revealed that the ketone-oxygen atom in the product originates from DMSO. It has been suggested that initially a Wacker-type nucleophilic attack by DMSO on the palladium(II)-activated alkyne provides a vinylpalladium(II) intermediate (Scheme 6). This palladium(II) species is oxidized by PIDA to a vinylpalladium(IV) intermediate, which can undergo 𝛽-hydride elimination (path A) or reductive elimination (path B).77 Selective Pd-catalysed oxidative sp2 C–H acetoxylation/pivaloxylation of arenes and certain alkenes has been achieved featuring the unconventional role of a simple triazole scaffold as a modular and selective directing group. This protocol has wide group tolerance, sites electivity, and directing group and substrate-controlled regioselectivity.

ee 

108

Organic Reaction Mechanisms 2016

R Ar

S

O

DMSO Pd(OAc)2

+

PdII

AcO−

AcO PhI

OAc

S

+

Ar

•

−

R

+

R PdIV OAc OAc

path A 𝛽-H-elim.

O Ar

S

Ar

R

Ar

O

O

PhI(OAc)2

R

Pd(OAc)2 HOAC

OAc

OAc + Me2S

S

− OAc

H

O HOAc

+

Ar

path B red. elm.

R OAc

Pd(OAc)2

Scheme 6

PIDA has been used as terminal oxidant.78 The first step in the Pd(OAc)2 -catalysed C(3)-selective alkenylation of 7-azaindoles, performed in the presence of PPh3 as the ligand, Cu(OTf)2 as an oxidative co-catalyst, and molecular oxygen as the terminal oxidant, is proposed to be electrophilic palladation of 7-azaindole at the C(3)-position generating a palladated intermediate.79 A direct intermolecular allylic amidation of electron-deficient tautomerizable N-heterocycles has been reported via allylic C–H activation of terminal olefins with a PdCl2 catalyst. The reaction proceeded with high chemo- (N vs. O), regio- (linear vs. branched), and stereo-selectivity (E vs. Z) for a variety of N-heterocycles and terminal olefins. Mechanistic investigation and stoichiometric studies validate the sulfoxide-ligand-assisted allylic C–H bond cleavage to form a 𝜋-allylpalladium intermediate in the reaction pathway.80 Palladium(II)-catalysed enantioselective C–H olefination of 𝛼-hydroxy and 𝛼-amino phenylacetic acids by kinetic resolution has been achieved using a mono-N-protected amino acid ligand. Acrylates were excellent coupling partners. Oxygen has been used as the terminal oxidant. Two possible transitions states have been proposed and discussed.81 A palladium-catalysed oxidative borylation of enallenes has been developed for the selective formation of cyclobutene derivatives and fully substituted alkenylboron compounds. Cyclobutenes are formed as the exclusive products in MeOH in the presence of water and triethylamine (TEA), whereas the use of acetic acid leads to

109

3 Oxidation and Reduction CO2−

N Ph

N +H+

Ph

− CO2

N

NH air/AgOAc

Ph

0

R

−N2

Pd

+ HOAc

Ph-PdII-OAc AcO H

PdII R

Ph

OAc Pd

Ph

R

II

R Scheme 7

alkenylboron compounds. It has been suggested that the reaction of Pd(OAc)2 with enallene is likely to form a vinylpalladium intermediate through allene attack involving allenic C–H bond cleavage, which is promoted by the coordination of allene and olefin to Pd(II). This vinylpalladium could undergo an olefin insertion to form cyclobutene intermediate. Subsequent transmetallation of the cyclobutene intermediate with B2 pin2 would produce another intermediate, which upon reductive elimination would give the target cyclobutene derivative. Transmetallation of the vinylpalladium intermediate with B2 pin2 , followed by reductive elimination, would give the alkenylboron product.82 A new version of the Mizoroki–Heck reaction proceeding via phenyldiazenes has been developed. Phenyldiazenes, generated in situ from azocarboxylates, reacted with styrenes, acrylates, and acrylamides with full E/Z selectivity using palladium(II) acetate in the presence of silver(I) acetate or hydrogen peroxide (HP) as oxidant. HP is found to be a cheap and broadly applicable alternative for the established silver(I) system. A mechanism has been proposed (Scheme 7).83 A new intramolecular palladium(II)-based catalytic system that triggers aminopalladation/dehydropalladation of N-sulfonylalkenylamides to give the corresponding methylidene 𝛾-lactams has been reported. Molecular oxygen is used as the terminal oxidant. This new procedure opens the way to aminopalladation/proxicyclic 𝛽-dehydropalladation, a sequence hitherto regarded as forbidden for these substrates. A catalytic cycle has been proposed on the basis of experimental results as well as DFT calculations. In the catalytic cycle, triphenylphosphine is proposed to prevent coordination between a sulfonyl oxygen and palladium favouring the anti-aminopalladation process and allowing the syn-periplanar H–C–C–Pd arrangement needed for the subsequent dehydropalladation step.84

110

Organic Reaction Mechanisms 2016

An acceptorless coupling of o-aminobenzamides with methanol has been accomplished in the presence of the metal–ligand bifunctional catalyst [Cp*Ir(2,2′ -bpyO) (H2 O)] to deliver quinazolinones. A plausible mechanism comprising two cycles has been proposed. In the first cycle, the bipyridonate ligand accepted a proton in the step of the activation of methanol to give methoxy iridium species, which underwent 𝛽-hydrogen elimination to afford an iridium hydride species and formaldehyde. Accompanied by simultaneous transfer from the hydroxyl proton on the bipyridine ligand and the hydride on the iridium, hydrogen gas is released, and the catalytic species is regenerated. Furthermore, the condensation between o-aminobenzamides and formaldehyde occurred to give 2,3-dihydroquinazolinones. In the second cycle, reaction of the resulting 2,3-dihydroquinazolinones and the methoxy iridium species affords an amino iridium species, which undergoes 𝛽-hydrogen elimination to afford the iridium hydride species with the liberation of quinazolinones as products.85 In the presence of water soluble catalyst, [Cp*Ir(6,6′ -(OH)2 bpy)(H2 O)][OTf]2 , an acceptorless dehydrogenative cyclization of o-aminobenzyl alcohols with methyl ketones results in the construction of quinolines. Two possible mechanisms, with common initiation, have been proposed. In the presence of an excess amount of strong base, the catalyst is likely to be transformed to neutral complex [Cp*Ir(2,2′ -bpyO)-(H2 O)] and anionic complex [Cp*Ir(2,2′ -bpyO) (OH)]− via multiple deprotonations. Accompanied by the activation of alcohols, the ligand accepted a proton to afford an alkoxy iridium species, which then undergoes 𝛽-hydrogen elimination to give iridium hydride species and aldehydes. The possible paths thereafter have been discussed.86 The [RuCl2 (p-cymene)]2 -catalysed C–H activation and annulation reaction of salicylaldehydes and disubstituted alkynes afforded chromones in high yields. A KIE of 1.4 was obtained for the reaction of deuterated salicylaldehyde, which indicates that C–H bond cleavage might be involved in the rate-limiting step.87 A Ru-catalysed highly selective synthesis of 3,4-dihydroisoquinolines or isoquinolines has been accomplished via a redox-divergent hydrogen-retentive or -releasing coupling of diarylmethanimine and 1,2-diarylacetylene. High cis-selectivity of 3,4-dihydroisoquinolines has been observed. The chemoselectivity depends on the solvent. Annulation in 1,4-dioxane gives a cisdihydroquinoline, while DMSO as the solvent results in hydrogen-releasing coupling to an isoquinoline. Primary mechanistic investigations indicate that the sequence of the major pathway involves Ru-catalysed C–H activation, alkyne insertion, and subsequent 6𝜋-electrocyclization.88 A protocol for synthesis of urea directly from methanol and amine has been archived. The reaction produces hydrogen as the sole by-product. Commercially available ruthenium pincer complexes were used as catalysts. Unsymmetrical urea derivatives were also successfully obtained. It is postulated that the primary amine oxidatively couples with formaldehyde, which is formed from dehydrogenation of methanol, to generate the formamide. Subsequent nucleophilic attack of an amine on the formamide generates the hemiaminal analogue, which is further dehydrogenated to the urea (Scheme 8).89 Hydroquinone (H2 Q) is readily oxidized by a (salen)ruthenium(VI) nitrido complex in the presence of pyridine to give BQ. The oxidation of H2 Q-d6 gave KIE of 1.03, which indicates that O–H or C–H bond cleavage does not occur in the rate-limiting step. DFT calculations indicated that an initial electrophilic ring-attack by the Ru-complex

111

3 Oxidation and Reduction −H2

−H2

[Ru]H2

[Ru] CH3OH

O

R1-NH2

H

H

OH R1

N H

[Ru]H2

[Ru]

H

−H2

OH R2

O R1

N H

H

N H

R3

R1

N H

R2

N

[Ru]

O

[Ru]H2 R

3

R

1

N H

N

R2

R3

Scheme 8

generates an Ru(IV) imido intermediate. This is followed by a rapid proton transfer from –OH to imido to generate a Ru(IV) amido species, which then undergoes concerted C–N bond cleavage and proton transfer from the other –OH to pyridine to generate another intermediate, which then spontaneously accepts the proton from pyridine-H+ to yield the product.90 A four-electron oxidation of phenols by a (salen)ruthenium(VI) nitrido complex in methanol, in the presence of pyridine, to afford (salen)ruthenium(II)-BQimine complexes has been reported. No KIE was found when C6 H5 OD in CD3 OD or C6 D5 OH in CH3 OH was used as substrate, suggesting that no O–H or C–H bond cleavage occurs in the rate-determining step. Mechanistic studies indicate that this reaction occurs in two phases. The first phase is proposed to be a two-ET process that involves electrophilic attack by R≡N at the phenol aromatic ring, followed by proton shift to generate an Ru(IV) p-hydroxyanilido intermediate. In the second phase, the intermediate undergoes intramolecular two-ET, followed by rapid deprotonation to give the Ru(II) BQ imine product (Scheme 9).91 DFT calculations of dehydrogenation of primary alcohol to ester, catalysed by a ruthenium(II)–PNN pincer complex, indicated that the catalytic cycle includes three stages. First, alcohol dehydrogenation to form aldehyde, then coupling of aldehyde with alcohol to give hemiacetal or ester, and finally, hemiacetal dehydrogenates to form ester. Two dehydrogenation reactions occur via the 𝛽-H elimination mechanism. At the second stage, the coupling reaction requires alcohol or the ruthenium catalyst as mediator. The formation of hemiacetal through the alcohol-mediated pathway is kinetically favourable than the ruthenium catalyst-mediated one.92 Two competitive cycles have been explored by DFT calculations for dehydrogenation of formic acid catalysed by two Ru-phosphine complexes. It has been found that a cycle, which starts with a direct hydride transfer from formate ion to the Ru-centre, releasing carbon dioxide, followed by generation of hydrogen, is more accessible than a cycle in which neutral formic acid approaches the catalyst to produce a hydrogen molecule prior to carbon dioxide generation via 𝛽-hydride elimination.93 Computations by DFT

112

Organic Reaction Mechanisms 2016 +

1st Phase

OH H

+

N

OH

RuVI

N

+

Ru

MeOH

H

H+ shift IV

fast

N RuIV

MeOH

MeOH py

py

+

OH OH

RuVI

OH

H

+

N

+

OH

N

+

H+ shift

RuIV

py

H

fast

+

N RuIV

py py

2nd phase OH H

+

+

OH H

H

N

N

py

RuIV py

O

II

Ru py

N RuII

+ pyH+

py

The Salen ligand is omitted for clarity py = pyridine Scheme 9

method M11-L of Ru-catalysed arylation of ortho C–H bonds directed by a bidentate 8-aminoquinoline moiety indicate that the initial step for this reaction is catalyst loading by electrophilic deprotonation to generate a substrate coordinated Ru(II) intermediate. The catalytic cycle includes electrophilic deprotonation by carbonate, oxidative addition of bromobenzene, reductive elimination to form a new aryl–aryl bond, proton transfer to release the product, and ligand exchange to regenerate the initial Ru(II) intermediate. Theoretical calculations suggest that the oxidative addition of bromobenzene is the rate-determining step of the whole catalytic cycle.94 A mechanism has been proposed on the basis of DFT calculations of the dehydrogenation of methanol

3 Oxidation and Reduction

113

catalysed by ruthenium pincer catalysts. The mechanism involves a methanol-catalysed dehydrogenation of ruthenium hydride intermediate and pre-protonation of the pincer ligand present therein. This mechanism is kinetically favoured over the previously proposed ones and more consistent with the optimal experimental condition where strong base and neat methanol solvent are used.95 Ruthenium-catalysed decarboxylative oxidative C–H functionalizations which furnish meta-substituted arenes have been described. The ruthenium(II) bis(carboxylate) catalysis is highly chemo-, positional-, and regio-selective and proceeds with ample substrate scope, including substrates without an activating ortho substituent. The unique versatility of the ruthenium(II) bis(carboxylate) complex [Ru(O2 CMes)2 (p-cymene)] is reflected in the oxidative olefinations with alkenes as well as the redox-neutral hydroarylations of alkynes. Kinetic studies involving the evolution of carbon dioxide indicated that CO2 is formed during the course of the C–H functionalization. A KIE of kH /kD ≫ 2.6 confirmed kinetic relevance of C–H ruthenation process.96 Selective ortho-olefination of 2-arylbenzo[d]oxazoles with alkenes enabled by Cp*Rh(III) has been achieved. This protocol features broad functional group tolerance, high regioselectivity, and high yields. The molecular structure of the m-fluorosubstituted olefination product confirms regioselective C–H activation/olefination at the more hindered site in cases where the m-F atom or heteroatom substituent existed. Intermolecular competition studies and KIE experiments imply that the oxidative olefination process occurs via an electrophilic C–H activation pathway. It has been proposed that initially C–H activation of 2-arylbenzoxazole formed a five-membered rhodacycle species, followed by elimination of HX through chelation-directed C–H activation.97 Spirocyclic sultams and heterobiaryls have been synthesized through a CDC strategy using N-sulfonylketimine and 2-methylthiophene with [Cp*RhCl2 ]2 as the catalyst and PIDA as the terminal oxidant. This method employs N-sulfonylimine, a weak coordinating group, as an efficient directing group to assist C–H activation. It has been found that in an H/D exchange experiment between the substrate and 10 equiv. of D2 O, 18% D was introduced into the two ortho-positions of the ketimine aryl ring indicating that a reversible C–H cleavage is involved in the reaction. An intramolecular competition reaction between N-sulfonylketimine and its deuterated analogue showed a KIE of 1.2, illustrating that the rate-limiting step does not involve the C–H cleavage.98 DFT calculations of the Rh-catalysed dehydrogenative aryl–aryl bond formation reactions showed that the reaction comprised three steps, two consecutive C–H bond activations followed by the final reductive elimination. The study indicated that PivO− anion plays an important role in activating the C–H bond.99 Styryl azides undergo a smooth reaction by a SET-controlled intramolecular rearrangement in the presence of a Rh(II) complex, producing a series of indole-fused azetidines and 1H-carbazoles or related derivatives in moderate to good yields. Radical inhibitors such as TEMPO, BHT, or hydroquinone interrupt the outcome of the reaction. Among the radical trapping products, evidence for Rh2 (III)(II) nitrene radicals has been found. These results support the assumption that the reaction starts from the Rh2 (III)(II) nitrene radical intermediate. DFT calculations of the key step explain that cyclization and SET pathways are controlled by a designed radical clock.100 Rh(III)-catalysed synthesis of mesoionic heterocycles has been achieved via C–H activation of sydnones

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and oxidative coupling with internal alkynes. An intermolecular competition between two different alkynes showed that the electron-rich one reacted preferentially. H/D exchange reactions have been carried out for sydnone in the presence of alkyne, but no deteurium was incorporated into the product. On the other hand, H/D exchange of the syndone has been observed at the 4-position in the absence of any diphenylacetylene, indicating that the C(4)–H cleavage is reversible. A KIE of kH /kD = 4.0 has been obtained, suggesting that C–H bond cleavage is involved in the turnover-limiting step. A mechanism involving initial cyclometallation of the sydnone to form a rhodacyclic intermediate, which undergoes nitrogen decoordination and rollover C–H activation to give a Rh(III) diaryl intermediate, has been proposed. 101 An efficient Rh(III)-catalysed direct ortho-C–H olefination of acetanilides with vinyl acetate provides a straightforward pathway to a series of (E)-2-acetamidostyryl acetates. The reaction sequence for this 𝛽-selective Heck-type coupling is coordination of a directing amide group with the Cp*Rh(III) centre, cyclometallation giving a six-membered rhodium intermediate, regioselective insertion of vinyl acetate into the Rh–C bond to afford a rhodacycle, and 𝛽-hydrogen elimination. The rhodium catalyst is regenerated through the oxidation of the Rh–H intermediate by oxygen and Cu(OAc)2 .102 The C(2)-symmetric bisphosphine ligand, BINAP, is found to be effective in controlling enantioselectivity in the rhodiumcatalysed synthesis of spiro-9-silabifluorenes through dehydrogenative silylation. The axially chiral spiro-9-silabifluorenes were obtained in excellent yields with high ee. The reaction proceeded through two consecutive dehydrogenative silylations, and the absolute configuration was determined in the first silylative cyclization.103 Anthranil has been employed as the nitrogen source in the Rh(III)-catalysed sp3 C–H aryl amination reaction. This C–H amination reaction exhibits broad substrate scope without using any external oxidants. Mechanistic studies including rhodacycle intermediates, H–D exchange, KIE experiments, and in situ IR indicated that at first, the reactive Rh species activates the sp3 C–H bond of 8-methylquinoline to give an intermediate, and then coordination of anthranil takes place to afford another intermediate. Next, N–O bond cleavage occurs to generate a Rh(V)-nitrenoid species. Subsequent nitrenoid insertion into the Rh–C bond leads to an (amido)rhodium complex. Finally, the amination product is released through protodemetallation with the regeneration of the Rh(III) species.104 Kinetic and activation parameters of silver(I)-catalysed oxidation of l-asparagine and l-histidine, with hexachloroplatinate(IV) ion, have been determined and a mechanism suggested.105 Dibenzosilole derivatives are obtained in good yields in intramolecular dehydrogenative cyclization of 2-(dialkylsilyl)biaryls, in the presence of a catalytic amount of platinum(II) chloride and potassium tris(3,5dimethyl-1-pyrazolyl)borohydride. When a deuterated substrate was subjected to the platinum-catalysed cyclization, an intramolecular KIE of 2.4 was found. This suggests that the C–H bond activation step is rate-determining for the present cyclization. It has been suggested that the initial step involves formation of a Pt(IV) silyl dihydride complex, which loses hydrogen followed by intermolecular oxidative addition of the aromatic C–H bond to the Pt(II) centre. Subsequent reductive elimination of the C–Si bond leads to a Pt(II) hydride complex from which the product is eliminated.106

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Group VIII Metals Recent developments of iron-catalysed CDC reactions including the reaction mechanism and the role of the iron species in the catalytic cycle have been reviewed.107 The development of catalysis by rhenium, molybdenum, and iron complexes in epoxidation reactions has been reviewed. Recent emergence of highly active molybdenum and iron catalysts with high turnover frequencies has been discussed. The use of cheaper, more readily available metals and the challenges of using base metals in catalysis have also been discussed.108 A ferric chloride-mediated oxidative spirocyclization for construction of a new class of dispiro-linked 𝜋-conjugated molecules, dispiro[fluorene-9,5′ -indeno[2,1a]indene-10′ ,9′′ -fluorene]s, has been reported. The combination of FeCl3 with FeO(OH) triggered an unprecedented double one-electron oxidation of difluorenylidene diarylethanes to afford the corresponding dispirocycles in high yields. It has been suggested that FeCl3 induces double one-electron oxidations to more-electron-rich of the two C=C bonds of the diene moiety to give a radical cation species, which can exist as a dication intermediate.109 An efficient synthesis of complex 3-arylated 3,4-dihydro-1,4-benzoxazin-2-one derivatives via ferrous chloride-catalysed oxidative sp3 C–H functionalization of benzoxazin-2-ones and indoles with excellent functional group tolerance has been achieved. TBHP is used as a terminal oxidant. The protocol constructs alkyl–aryl C(sp3 )–C(sp2 ) bonds under mild reaction conditions. Addition of TEMPO completely inhibited the reaction. A one-electron oxidation mechanism has been proposed.110 The presence of steric hindrance triggers different reaction pathways in the intramolecular oxidative aromatic coupling of tetraarylpyrrolo[3,2-b]pyrroles with ferric chloride and leads to the formation of a fluorene moiety and a new cationic 𝜋-system linked together by a spiro carbon atom. Computational studies with Truhlar’s unrestricted M05-2X DFT functional with the 6-31G(d) basis set have rationalized these results.111 Conformationally constrained methionine analogues embedded within a norbornane framework, that is, 2,6-endo, endo-, and 2,6-exo, and endo-pyrrolidine amide thiomethyl bicyclo[2.2.1]heptanes, have been synthesized. Oxidation of both methionine analogues in the Fenton oxidation yielded some sulfoxide. In addition, the oxidation of the endo, endo derivative generated a vinyl sulfide, while the exo, endo derivative was converted into a ketone, indicating a selective influence of a sulfuroxygen two-centre-three-electron bond on product formation. Mechanistic details of product formation were investigated through the incorporation of stable isotopes.112 A DFT study of mechanisms for dehydrogenation and hydrogenation of Nheterocycles using PNP-pincer-supported iron catalysts revealed that mechanism for catalysed dehydrogenation of a 1,2,3,4-tetrahydroquinoline (THQ) substrate to quinoline (Q) involves two main steps: (i) dehydrogenation of THQ to 3,4-dihydroquinoline (34DHQ) and (ii) dehydrogenation of 34DHQ to Q. In each dehydrogenation step, the proton is transferred from the substrate to the N of the PNP ligand of the catalyst. However, the mechanism for hydrogenation of Q involves the initial formation of 14DHQ, which can easily isomerize to 34DHQ with the assistance of a t-butoxide base. Finally, 34DHQ is dehydrogenated to THQ.113 FT cyclotron resonance mass

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spectrometry has been used to provide rate constants and product distributions for the aromatic hydroxylation by iron(IV)-oxo porphyrin cation radical. Product distributions and KIE studies implicated a rate-determining aromatic hydroxylation reaction that correlates with the ionization energy of the substrate, and no evidence of aliphatic hydroxylation products was observed. Computational studies on a model complex confirmed the experimental hypothesis of dominant aromatic over aliphatic hydroxylation and showed that the lack of an axial ligand affects the aliphatic pathways. Aromatic hydroxylation rates correlate with the ionization energy of the substrate as well as with the electron affinity of the oxidant.114 The oxidation of a series of aryl diphenylmethyl sulfides (4-X-C6 H4 SCH(C6 H5 )2 , where X = OCH3 CH3 , H, and CF3 ), promoted by the non-haem iron(IV)-oxo complex [(N4Py)FeIV O]2+ alone115 and of aryl 1-methyl-1-phenylethyl sulfides116 promoted by [(N4Py)FeIV =O]2+ and [(Bn-TPEN)FeIV =O]2+ occurs by an ET-oxygen rebound mechanism, leading to corresponding sulfoxides accompanied by products derived from 𝛼-C–S fragmentation of sulfide radical cations. The rate constants for the oxygen rebound process have been determined from the fragmentation rate constants of the radical cations and the S-oxidation/fragmentation product ratios. The fragmentation/S-oxidation product ratios regularly increase through a decrease in the electron-donating power of the aryl substituents, that is, by increasing the fragmentation rate constants of the radical cations. A non-haem, iron(III)/(thymine-1-acetate) catalyst together with HP as oxidant is efficient in oxidative C–H activation of alkanes. Although having a higher preference for tertiary C–H bonds, the catalyst also oxidizes aliphatic secondary C–H bonds into carbonyl compounds with good to excellent conversions. On the basis of isotopic labelling, kinetic studies, and spectroscopic measurements, it has been concluded that in the presence of thymine-1-acetate ligand, high-valent iron-peroxo species are generated from the low spin Fe(III) complex with HP as a terminal oxidant. A rapid exchange of the FeOOH oxygen atom with H2 18 O showed that the reaction follows a mechanism in which an exogenous water molecule assists the hydrogen transfer from the coordinated water molecule to the oxo group. The results support the mechanism where the iron-oxo species are formed via water-assisted heterolysis of O–O bond, and the carbonyl bond is formed via the oxygen either from HP or water.117 Redox-neutral [4 + 2] annulations of N–H imines and internal alkynes have been developed by employing iron carbonyl catalysis. The reaction features only cis-stereoselectivity. Intramolecular, intermolecular, and parallel-reaction KIE values are 3.7, 2.6, and 2.6, respectively. These results indicate that the C–H bond cleavage may be involved in the turnover-limiting step or in a prior step with a lower activation barrier. DFT calculations and experimental studies reveal an oxidative addition mechanism for C–H bond activation to afford a dinuclear ferracycle and a synergetic diiron-promoted H-transfer to the alkyne as the turnover-determining step.118 Kinetic and activation parameters of the oxidation of methylaminopyrazole,119 levofloxacin,120 glycylglycine,121 Ru(III)-catalysed oxidation of l-lysine,122 Pd(II)catalysed oxidation of l-tryptophan,123 and of N,N-dimethyl-N′ -(4H-1,2,4-triazol-3-yl) formamidine, both uncatalysed and Ru(III)-catalysed,124 by hexacyanoferrate(III) have been determined and interpreted.

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One of the many mechanisms postulated for aliphatic and aromatic hydroxylation by cytochromes P450 invokes an arene oxide and/or its oxepin tautomer as the key intermediate. Identification of a P450-generated arene oxide as a product of in vitro oxidation of t-butylbenzene has been reported. Computations (CBS–QB3) indicated that the arene oxide and oxepin have similar stabilities to other arene oxides/oxepins implicated, but not detected, in P450-mediated transformations, suggesting that arene oxides can be unstable terminal products of P450-catalysed aromatic oxidations.125 The kinetics and mechanism of Os(VIII)-promoted oxidation of crotonic acid in alkaline solution have been investigated. Potassium iodate has been used as a terminal oxidant. [OSO4 (OH)2 ]2− is postulated as the reactive species of Os(VIII). A suitable mechanism has been proposed.126

Oxidation by Compounds of Non-metallic Elements Nitrogen and Sulfur Developments in the oxidations of amines catalysed by TEMPO and related catalytic systems have been reviewed. The most important feature of these systems is that, with slight modifications in the reaction media, amines are selectively oxidized to either an imine or nitrile. Progress made towards the oxidation of various benzylic, allylic, and aliphatic amines and possible reaction mechanism are discussed.127 The recent developments in asymmetric allylic amination reactions including the most important methods and their mechanistic aspects have been reviewed with an aim to provide insight into their current scope and limitations.128 Skraup reaction affording quinoline has been investigated computationally. First, two reaction channels up to the 1,2-dihydroquinoline were considered, one involving acrolein and the other a direct linkage of aniline and glycerol. The channel without acrolein is calculated to be more likely. Secondly, the oxidation process of 1,2dihydroquinoline to quinoline was examined with and without the oxidizing agent, nitrobenzene. With it, the hydride-shift path was obtained, and it is likely energetically. Proton transfer was found to be the primary driving force of the Skraup reaction.129 Chiral bifunctional urea-containing ammonium salts were found to be very efficient catalysts for asymmetric 𝛼-hydroxylation reactions of 𝛽-ketoesters with oxaziridines under base-free conditions with enantiomeric ratios up to 99:1. The reaction is accompanied by a simultaneous kinetic resolution of the oxaziridine, and a pronounced match–mismatch scenario of the catalyst with the oxaziridine seems to play a crucial role in this reaction. A plausible bifunctional transition state model has been obtained by means of DFT calculations.130 The treatment of cyclic thioureas with the aluminium(I) compound NacNacAl (NacNac = [ArNC(Me)CHC-(Me)NAr]− , Ar = 2,6-Pri 2 C6 H3 ) resulted in oxidative cleavage of the C=S bond and the formation of a monomeric aluminium complex with an Al=S double bond, stabilized by NHC. The aluminium compound also reacts with triphenylphosphine sulfide in a similar manner, which resulted in cleavage of the P=S bond and production of the adduct [NacNacAl=S(S=PPh3 )]. The Al=S double bond in

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the product reacts with phenyl isothiocyanate to furnish a cycloaddition product and a zwitterion as a result of coupling between the liberated carbene and PhN=C=S. The nature of the Al=S bond in the product has also been probed by DFT calculations.131 A transition-metal-free nitration of alkenes with sodium nitrite in the presence of PDS and TEMPO has been developed. The reaction provides for stereoselective synthesis of (E)-nitroalkenes with moderate to good yields. Moreover, the nitration processes of (E)and (Z)-stilbene are also studied; even though the proportion of substrates is different, the E/Z ratio of the products is basically the same. Addition of BHT leads to almost complete inhibition of the reaction. This result indicated that the reaction presumably follows a radical pathway. In the absence of TEMPO, no reaction takes place. Further, the intermediate TEMPOH was also detected by GC–MS. Based on the experimental observations, a possible reaction mechanism has been proposed (Scheme 10).132 NO2−

[O]

S2O8−

R1

NO2

R2 R3

R1 NO2

R2 H

TEMPO

R3

R1

TEMPOH

NO2

R2 R3

Scheme 10

Synthetic and computational aspects of the oxidative ring-opening of cyclic ethers, facilitated by 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (4-NHAc-TEMPO+ BF4 − ), have been studied. The computations aided in the understanding of the limitations of the methodology. DFT calculations revealed that the cationic species formed after hydride transfer is comparably stable. The calculated energy valley indicated that the reactive cationic intermediate is relatively long-lived, enabling it to undergo undesired side reactions such as the polymerization. This correlated well with the observed experimental results.133 A metal-free oxidative CDC of N-aryl tetrahydroisoquinolines and 2-methylazaarenes in water has been developed. 4-NHAc-TEMPO+ BF4 − has been employed as a mild oxidant that can be recovered and reused directly. The reaction, involving a C(sp3 )–C(sp3 ) bond formation, proceeds through an iminium ion generated in situ followed by condensation with various nucleophiles, providing the desired products in moderate to good yields.134 Azaadamantane-type oxoammonium salts react with cycloalkenes to afford 1,3cycloalkadienes through N-preferential ene-like addition followed by Cope elimination. It has been suggested that the cycloalkene reacts with the oxoammonium salt through a group-transfer reaction to form an N-hydroxyammonium species. In this step, C–N bond formation occurs preferentially. After treatment with 1,8-diazabicyclo[5.4.0]undec-7ene (DBU), the N-hydroxyammonium species forms an amine N-oxide, which undergoes Cope elimination to give the corresponding 1,3-cycloalkadiene and hydroxylamine.135 Two intermediates, 1,5-dinitroso-3,7-dinitro-1,3,5,7-tetraazacyclooctane and 1-nitroso3,5,7-trinitro-1,3,5,7-tetraazacyclooctane, have been isolated and characterized in the synthesis of 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane from the nitrolysis of 3,7-dinitro-1,3,5,7-tetraazabicyclo[3.3.1]nonane (DPT). It is proposed that electrophilic

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NO2 + and NO+ from HNO3 and N2 O4 might attack nitrogen atoms at positions 3 and 7 of DPT to form the cations of the intermediates, and then H2 O attacked the bridge carbon atoms of DPT to produce the intermediates.136 Tetrahydroquinolines, in excellent yields, have been prepared by direct cyclization of N-methylanilines with maleimides mediated by PDS as a radical surrogate. The protocol involves sequential formation of C(sp3 )–C(sp2 ) and C(sp2 )–C(sp2 ) bonds in a one-pot procedure at room temperature. It has been suggested that PDS on interaction with solvent homolyses into two KSO4 radicals, which abstracts a hydrogen atom from N-methylaniline to convert it into an N-methylaniline radical. This radical attacks on the C=C bond of maleimide.137 A palladium-catalysed C–H acylation reaction of Nnitrosoanilines with 𝛼-oxocarboxylic acids has been developed. The reaction proceeded smoothly with PDS as the oxidant to afford acylated N-nitrosoanilines in moderate to good yields with a broad substrate scope and good regioselectivity.138 Secondary C–H bonds in a series of phthaloyl protected primary amines and amino acid derivatives have been oxidized, with PDS/molecular oxygen, to carbonyl compounds with good regioselectivities. This method has been applied to oxidize tertiary C–H bonds also. 18 O-labelling experiments showed that the oxygen atom came from water, rather than from oxygen or PDS. The addition of TEMPO shuts down the reaction, indicating that a radical pathway is involved. These data as well as the fact that the reaction also takes place well under nitrogen indicated that oxygen did not play a key role. A mechanism involving pyrolysis of PDS to generate sulfate radical anions has been postulated.139 Oxidation of chromenes catalysed by several iminium salt catalysts yielded different products depending on the solvent. In non-aqueous solvents, with tetraphenylphosphonium monoperoxysulfate as the oxidant, epoxides were obtained with up to 99% ee. Reaction under aqueous conditions, with triple salt Oxone as a stoichiometric oxidant in the presence of a base, could induce in situ hydrolysis of the epoxides, giving the corresponding diol products with ees up to 71%.140 The degradation of 1,1,1-trichloroethane (TCA), involving both oxidation and reduction processes, has been investigated with an application of the PDS-zero-valent iron (ZVI) system through batch experiments. The results showed that TCA was stable in the presence of ZVI alone for 12 h and degraded with the addition of PDS. A two-stage process involving PDS oxidation and ZVI reduction is operative during TCA degradation. Sulfate and hydroxyl radicals are present during the first stage (0–2 h) but are absent in the second-stage (2–12 h) when PDS has exhausted.141 The kinetics of oxidation 1,10-phenanthroline (phen) by PMS features a complex pH dependence. In 1.00 M H2 SO4 , 1,10-phenanthroline-mono-N-oxide (phenO) is the sole product of the reaction. The rate of the N-oxidation is highly dependent on the pH with a maximum at pH ≫ 6.7. The formation of phenO occurs via two parallel pathways, the rate constant of the oxidation of phen is significantly larger than that of Hphen+ because the two nitrogen atoms are open to oxidative attack in the deprotonated substrate while an internal hydrogen bond hinders the oxidation of the protonated form. With an excess of PMS, four consecutive oxidation steps were found in nearly neutral solutions. In the early stage of the reaction, the stepwise oxidation results in the formation of phenO, which is converted into 1,10-phenanthroline-N,N′ -dioxide (phenO2 ) in the second step. The formation of phenO2 was confirmed by 1 H NMR and ESI-MS methods.142

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New biaryl iminium salt catalysts, containing additional substitution in the heterocyclic ring, have been synthesized and their use for enantioselective alkene epoxidation with PMS as oxidant has been explored. It is observed that the presence of additional methyl substituents adjacent to the nitrogen atom in the heterocyclic ring provided improvements in enantioselectivities in the reaction. 𝛼-Methylated octahydrobinaphthyl catalyst gave the best results of this series with enantioselectivities of up to 97% ee. DFT calculations clearly suggested a parallel pattern of dihedral angles between the iminium parents and the putative derived oxaziridinium oxidative intermediates. This postulation is supported by experimental results also.143 The oxidation of thiourea (TU) with PMS is catalysed by [Ru(III)(edta)(H2 O)]− . Spectral and kinetic data are suggestive of a catalytic pathway involving rapid formation of a [Ru(III)(edta)(TU)]− intermediate complex followed by the oxidation of the coordinated TU. A mechanism has been presented.144 The kinetics of oxidation of arabinose, fructose, and lactose by PDS145 and of Mn(II)-catalysed oxidation of a gabapentin by PMS146 has been determined and interpreted. Sulfur ylides, generated from benzyne and sulfoxides through the S–O bond insertion and deprotonation, react with carbonyl compounds to form epoxides, This one-pot reaction proceeds under mild and base-free conditions, providing a convenient way to introduce the substituted methylene groups onto the carbonyl carbon. For example, Kobayashi benzyne precursor, 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, and benzyl phenyl sulfoxide have been used to generate sulfur ylide, which reacts with N-methylisatin to yield an epoxide.147 A variety of different N-sulfonyl protected 𝛼-amino aryl ketones have been synthesized in good to excellent yields by a 2-methylquinoline promoted room-temperature oxidative ring-opening of Nsulfonylaziridines with DMSO. A mechanism in which initially nucleophilic oxygen atom of DMSO regiospecifically attacks the benzylic carbon of the N-sulfonyl aziridine to furnish a zwitterionic intermediate has been proposed.148 DMSO acts as the solvent, oxidant, and oxygen source in the iodine-catalysed direct conversion of cyclohexanones to substituted catechols. Use of 18 O-labeling indicated that the additional oxygen atom in the catechol product originates from DMSO. DFT calculations supported a possible reaction pathway for the formation of catechol. Initial electrophilic iodization of cyclohexanone, by the iodine catalyst, affords 𝛼-iodocyclohexanone; Kornblum oxidation then generates 1,2-cyclohexanedione which undergoes 𝛼-iodization to give an intermediate, which subsequently eliminates hydrogen iodide and then tautomerizes to afford catechol products.149 A para-selective C−C bond coupling between phenols (sp2 C) and aryl methyl ketones (sp3 C), which results in the formation of 4-hydroxybenzil derivatives, has been achieved. Results of an isotope-labelling experiment conducted with H2 18 O showed that the ratio of 16 O and 18 O-labelled product was 1.83:1, which indicated that H2 O is involved in the reaction, and phenylglyoxal monohydrate can be seen as the intermediate. Further mechanistic investigations indicated that the combination of HI with DMSO realized the oxidative carbonylation of aryl methyl ketones, while boric acid acted as a dual-functional relay reagent to promote this transformation.150

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Halogens Advances in iodine(III)-mediated halogenations have been reviewed. The ability of halogenated iodanes to trigger novel reactivities and selectivities has been highlighted. Selected examples of chemo-, regio-, and stereo-selective iodine(III)-mediated brominations, chlorinations, and fluorinations have been discussed, which showed the diverse and often unique reactivities and selectivities that can be unlocked by iodine(III)mediated halogenations.151 The synthetic utilities of hypervalent iodine reagents for the metal-free oxidative biaryl coupling have been reviewed. The challenges encountered in OCC of non-activated aromatic substrates and the mechanistic aspects of reaction of hypervalent iodine reagents have been discussed.152 The oxidation of 1-aminoalkylphosphonic acids with bromine water, chlorine water, and iodine water leads to the formation of phosphoric(IV) acid, as a result of a halogenpromoted cleavage of the 𝛼-C–P bond, accompanied by nitrogen release. The rates of reactions of bromine and chlorine are comparable but that of iodine is relatively much slower.153 A highly regioselective oxidative annulation of aryl sulfonamides with both internal and terminal alkynes has been achieved using sodium chlorate as an efficient oxidant in the cobalt-catalysed C–H activation. The reaction has been extended to the annulations of benzamide also. Addition of radical inhibitors such as BHT and TEMPO exhibited significant suppression effect on the reaction, thus indicating that a radical process might be involved. It is proposed that initial coordination of cobalt complex to the aryl sulfonamide leads to a Co(III) species, which then undergoes C–H metallation and alkyne insertion to deliver a seven-membered metallacycle intermediate. Subsequent reductive elimination affords the desired sultam product and releases the Co(I) species. Finally, the reoxidation of Co(I) to the reactive Co(III) species by chlorate completes the catalytic cycle.154 Oxidation of flavonoids from flavonol subclass with hypochlorous acid has been studied by stopped-flow spectrophotometry. A mechanism of the oxidation at physiological pH has been proposed, and biological consequences of this reaction are discussed. Slightly higher antioxidant activity, compared to parent compounds, was observed for flavonols after their reaction with equimolar or moderate excess of HOCl, whereas flavonols treated with high molar excess of HOCl exhibited decrease in antioxidant activity.155 A procedure for selective dual sp3 C–H functionalization at the 𝛼-and 𝛽-positions of cyclic amines to their corresponding 3-alkoxyamine lactams has been reported. The protocol, which involves the use of NaClO2 /TEMPO/NaClO in either aqueous or organic solvent, allows not only the 𝛼-C–H oxidation but also the subsequent functionalization of the unreactive 𝛽-methylene group in a tandem manner. A mechanism involving formation of an enamine as the key intermediate has been suggested.156 The reaction mechanisms, kinetic studies, and the optimization of the synthetic parameters of a new way of preparing pyrazolidine by intramolecular Raschig amination using 1,3-diaminopropane and sodium hypochlorite have been described. An experimentally validated kinetic model has been proposed.157 Simple aldehydes have been converted into enantioenriched 2-oxopiperazines by a four-step reaction sequence comprising chlorination, oxidation, substitution,

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and cyclization. Chlorination with chloroquinone in conjunction with MacMillan’s third-generation catalyst coupled with oxidation by sodium chlorite afforded 𝛼chloroheptanoic acid almost quantitatively. This chlorination protocol provided high levels of asymmetric induction. Treatment of this acid with diamine led to a moderate yield of 2-oxopiperazine with 93% ee. The reaction mechanism has been studied, and the previously elusive epoxy lactone intermediate was identified by HRMS.158 The kinetics and activation parameters of oxidation of benzyl alcohol by hypochlorite,159 aliphatic primary alcohols with 1-chlorobenzimidazole,160 3-benzoylpropionic acid,161 citric acid,162 and Os(VIII)-catalysed oxidation of 2-methyl-1-propanol and 2-methyl-1-butanol163 by N-chloroacetamide, aromatic ketones by dichloroisocyanuric acid,164 amoxicillin,165 substituted anilines,166 and osmium(VIII)-catalysed oxidation of glutamic acid167 by chloramine-T (CAT), metformin168 and substituted 1H-imidazoles169 by chloramine-B (CAB) have been determined, and the suitable mechanisms are proposed. Oxidation of pregabalin with CAT in alkaline solutions, uncatalysed and catalysed by RuCl3 , OsO4 , and by both RuCl3 and OsO4 , has been studied kinetically. It was found that combined catalysts exert a synergistic effect and enhances the rate tremendously. A mechanism has been put forward and kinetic models deduced.170 Iodine-catalysed oxidation of N-substituted indoles using CAB resulted in corresponding isatins in moderate to excellent yields. Introduction of TEMPO to the reaction system did not have any effect, which demonstrated that a radical pathway is not involved in the reaction. Mechanistic studies suggested that the two oxygen atoms of the isatin might have originated from the water. A mechanism involving an interaction of CAB with iodine to generate the active species N-chloro-N-iodobenzenesulfonamide has been suggested.171 Kinetic and activation parameters of the Rh(III)-catalysed oxidation of trehalose,172 1,2-propanediol,173 and monoethanolamine174 by N-bromosuccinimide, tartaric acid by N-bromonicotinamide,175 acetophenone by N-bromosaccharin,176 and Pd(II)-catalysed oxidation of alanine by N-bromoacetamide177 have been obtained and plausible mechanisms postulated. Benzyl alcohols have been oxidized to aldehydes with 1,3-dibromo5,5-dimethylhydantoin and a variety of cyclodextrin additives in aqueous solutions. This reaction proceeds with moderate to good yields for a broad scope of benzyl alcohol substrates, with the cyclodextrin acting to enhance the desired reactivity and limit undesired aromatic bromination side products.178 The stoichiometry of oxidation of d-penicillamine (Depen) by acidic bromate is 1:1, in which Depen is oxidized to the sulfonic acid with no cleavage of the C–S bond to yield sulfate. The oxidation takes place through addition of oxygen atoms to the sulfur centre to successively yield sulfenic and sulfinic acids before the product sulfonic acid. The reaction of bromine with Depen gives a stoichiometry of 3:1 with the same sulfonic acid product. This reaction is so fast that it is essentially diffusion controlled.179 The kinetics and activation parameters of the 13-vanadomanganate(IV)-catalysed oxidation of benzoic acid hydrazide by bromate have been determined, and a mechanism is proposed.180 A discussion is presented of the kinetics of chemical reactions as well as some thermodynamic considerations important to the appearance of temporal oscillations and

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123

other nonlinear dynamic behaviours, for example deterministic chaos. The behaviour, chemical details, and mechanism of the oscillatory Belousov–Zhabotinsky reaction (BZR) have been described. Experimental and mathematical evidences have indicated that BZR does indeed exhibit deterministic chaos when run in a flow reactor. The origin of this chaos seems to be in toroidal dynamics in which flow-driven oscillations in the control species bromomalonic acid couple with the BZR limit cycle.181 A one-pot procedure has been developed for the selective assembly of complex bicyclic structures, tetrahydrofurodioxoles, by the oxidation of 2-allyl-1,3-diketones with HP and iodine. It has been suggested that the first step involves the reaction of iodine with a double bond to form iodonium cation, which undergoes cyclization to tetrahydrofuran intermediate. Addition of HP to this intermediate followed by cyclization gives the bicyclic compound.182 Arylenols have been converted to 𝛽-keto sulfones in a one-pot reaction using sodium sulfinates as sulfonating agents and iodine as an oxidizing reagent. The oxidation is both base- and metal-free. It has been proposed that initially molecular iodine reacts with sodium sulfinate to give sulfonyl iodide, which undergoes homolysis to generate sulfonyl radical and iodine radical. The addition of sulfonyl radical to arylenol acetate forms a radical intermediate, which combines with iodine radical to yield an 𝛼-iodoacetate. The 𝛼-iodoacetate hydrolyses to give the desired 𝛽-keto sulfones.183 Substituted 2-aminoimidazo[1,2-a]pyridine frameworks have been synthesized by addition of arylamines to nitriles followed by iodine/KImediated oxidative cyclization.184 An intramolecular C–H functionalization reaction of N-aryl enamines has been carried out with molecular iodine as the sole oxidant in the presence of copper(I) iodide. This method is compatible with both N-heteroaryl- and N-aryl-substituted enamines and produces diverse imidazo[1,2-a]pyridine and indole derivatives via iodine-mediated oxidative C–N and C–C bond formation, respectively. The proposed mechanism is depicted in Scheme 11.185 An I2 /KI-promoted oxidative C–C bond formation reaction from sp3 C–H and sp2 C–H bonds has been used to construct quinazoline skeletons from N,N′ -disubstituted amidines in moderate to good yields. A mechanism has been proposed.186 A metal-free intermolecular formal [3 + 2] heterocyclization between triethylammonium thiolates and aryl hydrazines has been achieved using the combination of I2 and O2 as efficient oxidation sources, to yield new densely functionalized 1,2,3-thiadiazoles with good to excellent yields. Addition of TEMPO or BHT to the reaction gives complex mixtures without observation of the desired product, suggesting a possible radical process. The desired product is also not observed under argon conditions, indicating that oxygen plays a key role in this reaction. A mechanism has been suggested.187 A CDC of Betti bases, promoted by iodine and TBHP, resulted in intramolecular oxidation of sp3 C–H bond 𝛼- to tertiary amine to yield 1,3-oxazines. A variety of Betti bases of naphthol and phenol having cyclic as well as acyclic t-amine moieties have been employed as the starting materials. The Betti bases of naphthol produce a single diastereomer of oxazine, whereas phenolic Betti bases give diastereomeric mixtures. Addition of a radical scavenger such as BHT or TEMPO has no effect on the reaction. Thus, a radical pathway is unlikely. It has been suggested that I+ is the active oxidizing species.188 1,3,5-Trisubstituted 1,2,4-triazoles have been synthesized from hydrazones and aliphatic amines through iodine/TBHP-mediated aerobic oxidation. The reaction

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Organic Reaction Mechanisms 2016

Me

I2

N

I

O

O Me

N

Me

I

CuI

Base

N

N H

N H

H

O Me

N

Cu N

O −CuI

Me

N

O

Cu

N N Scheme 11

Base

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3 Oxidation and Reduction

proceeds through a cascade sequence of C–H functionalization, double C–N bonds formation, and oxidative aromatization. An acyclic intermediate has been captured by carrying out the reaction for a shorter duration. A mechanism has been suggested.189 An I2 /TBHP-mediated intramolecular dehydrogenative coupling reaction has been developed for the synthesis of a library of 5,11-dialkylindolo[3,2-c]quinoline salts and 5,7-dimethylindolo[2,3-c]quinoline salts. The annulation reaction is followed by aromatization to yield tetracycles in good yield. It has been suggested that initially iodine coordinates with N,N-dimethyl-2-(1-methyl-1H-indol-2-yl)aniline through the tertiary amine moiety, which is then oxidized with TBHP to give an N-iodo species and hypoiodite ion. The hypoiodite anion then abstracts the proton from the N-iodo species to give iminium species, which then undergoes intramolecular nucleophilic attack followed by loss of a molecule of HI and further oxidation to yield the product.190 An iodine-catalysed CDC reaction of N-alkyl amides and azoles has been reported. The catalytic system provides an efficient method for introducing amides onto azoles, especially onto benzotriazoles.191 1,2,4-Triazolo[4,3-a]pyridines and related heterocycles have been synthesized through condensation of aryl hydrazines with a variety of aromatic, aliphatic, and 𝛼,𝛽-unsaturated aldehydes followed by iodine-mediated oxidative cyclization. A possible mechanism has been proposed (Scheme 12).192 Base I

H

NHNH2

N

PhCHO

N

I

I N

N

Ph

N

N

N N Ph

H

Ph

N

N

N +

N

Base

N Ph

Scheme 12

An iodine-promoted highly chemo- and site-selective C–H/C–H OCC of unprotected anilines and methyl ketones furnishes the C(4)-dicarbonylation of anilines in moderate to good yields. Co-product hydrogen iodide acts as a catalyst in the reaction. The salient feature of this approach is C–H functionalization rather than N–H functionalization of unprotected anilines. Controlled experiments showed intermediacy of 2iodoaniline, phenylglyoxal, and phenacyl iodine in the transformation. A mechanism has been postulated.193 Molecular structures of the most prominent chiral non-racemic hypervalent iodine(III) reagents have been elucidated (1). The formation of a chirally induced supramolecular scaffold based on a selective hydrogen-bonding arrangement provides an explanation for the consistently high asymmetric induction with these reagents. As an exploratory

126

Organic Reaction Mechanisms 2016 OO Ar O

N

H

O

I

O

O

H O

N

Ar O

Ar = 2,4,6,-Pri3C6H2 or 2,6-Pri2C6H3 (1)

example, their scope as chiral catalysts has been extended to the enantioselective dioxygenation of alkenes. A series of terminal styrenes undergo oxidation to the corresponding vicinal diacetoxylation products and provide the proof of principle for a truly intermolecular asymmetric alkene oxidation under iodine(I/III) catalysis.194 A series of 1-(𝛼-aminoalkyl)-2-naphthols have been synthesized via three-component Betti reaction of 𝛽-naphthol, aldehyde, and cyclic secondary amine. The subsequent oxidation of 1-(𝛼-aminoalkyl)-2-naphthols with PIDA resulted in the formation of 1,3naphthoxazines. This reaction demonstrates the formation of C–O bond via CDC under transition metal-free conditions. A tentative mechanism for dehydrogenative C–O bond formation using PIDA has been suggested (Scheme 13).195 Hydrazone-based exo-directing groups have been developed for the Pd-catalysed functionalization of unactivated primary 𝛽-C–H bonds of aliphatic amines. These directing groups are shown to promote the site- and chemo-selective 𝛽-acetoxylation and tosyloxylation via five-membered exo-palladacycles with PIDA as the terminal oxidant.196 Oxidation of phenols with PIDA in methanol followed by reaction with ethyl glycinate hydrochloride, TEA, and 5% water yields corresponding anilines. Similarly, if the oxidation is followed by treatment with hydroxylamine sulfate and pyridine, then nitrosobenzenes are formed. This ipso-oxidative aromatic substitution process results in the formation of products in good yields under metal-free conditions. It has been proposed that the reactions proceed through a monoketal intermediate (Scheme 14).197 An iodine(III)-mediated synthesis of substituted phenanthrenes from ortho-vinylated biaryl derivatives through highly 6-endo-trig selective oxidative intramolecular arene–alkene coupling has been reported. Preliminary mechanistic investigations indicated that the reaction presumably proceeds via activation of the alkene moiety followed by a Friedel–Crafts-type electrophilic aromatic substitution at the adjacent arene ring.198 An iodine-mediated intramolecular aryl C–H amination reaction for the synthesis of benzimidazole has been reported. It works well with both N-aryl-substituted amidines and 2-aminopyridines to produce 1H-benzo[d]imidazole and pyrido[1,2a]benzimidazole derivatives, respectively.199 An intramolecular electrophilic N–H and C–H bond functionalization between the aniline and acetylene led to regioselective synthesis of 2,3-diarylated indoles. This methodology employs the concept of a traceless sulfonyl tether. Hypervalent iodine reagents have been identified as suitable promoters for stoichiometric and catalytic transformations. A Hammett correlation resulted in a 𝜌 value of −0.35, which indicated that the slow step of the overall reaction

ee 

127

3 Oxidation and Reduction

N

Ar

OAc O

H

I

OAc

Ar

ligand exchange

N O

−AcOH

OAc

ligand exchange

I Ph

Ph

Ar

+ N

H I O

Ph

− OAc

reductive elimination

Ar

+ N

Ar O−

−PhI

Scheme 13

trapping of imminium ion

N O

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Organic Reaction Mechanisms 2016

N H 2N

HN

CO2Et

CO2Et

OR

ROH

O

PIDA ROH

N

OR

NH2

H2O

O

OH

CO2Et

OH N

H2NOH

OR Scheme 14

ROH

O

CO2Et

3 Oxidation and Reduction

129

belongs to one of the electrophilic cyclization events. The reaction is initiated by an interaction between the hypervalent iodine reagent and the substrate, most probably through the formation of I–N bond. The heterolytic cleavage of this bond results in the generation of an electrophilic nitrogen species, which on attack by the acetylene moiety triggers a 5-exo-dig cyclization to yield a vinylic cation. This vinylic cation undergoes further cyclization by nucleophilic attack of the aromatic ring of the aniline followed by rearomatization of the resulting cationic intermediate.200 Mechanism of oxidation of primary nitroalkanes into amides, which entailed mixing an iodonium source with an amine, base, and oxygen, has been investigated. It has been concluded that an amine–iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both 𝛼-iodo- and 𝛼,𝛼-diiodonitroalkanes. The congested, tetrahedral diiodinated nitroalkane rearranges in a homogenic, anaerobic manner to form the nitrite ester. The nitrite ester reacts with nucleophilic amines in a traditional manner.201 Mild and efficient synthesis of benzophenones via Ir(III)- and Rh(III)-catalysed, directing group-assisted formyl C–H arylation of benzaldehydes has been achieved using p-tolyl(mesityl)iodonium triflate, in which Rh(III) and Ir(III) catalysts exhibited a complementary substrate scope. Use of a deuterated aldehyde indicated that the C–H activation process is irreversible and cleavage of the C–H bond might be involved in the rate-limiting step. The proposed mechanism (Scheme 15) involves a cyclometallation of the aldehyde with the active catalyst RhCp*(OAc)2 to afford a rhodacyclic intermediate.202 In a Wacker-type oxidative amination of unactivated internal alkenes, the combination of a simple copper salt, without additional ligand, as the catalyst and Dess–Martin periodinane as the oxidant promotes efficiently the oxidative amination of allylic carbamates and ureas bearing di- and tri-substituted alkenes, leading to oxazolidinones and imidazolidinones. The reaction showed excellent diastereoselectivity and is fully compatible with enantioenriched substrates without racemization. Preliminary mechanistic studies suggested a hybrid radical-organometallic mechanism involving an amidyl radical cyclization to form the key C–N bond.203 A hypervalent iodine-promoted stereoselective oxidative rearrangement of 1,1-disubstituted alkenes provides access to enantioenriched 𝛼-arylated ketones from readily accessible alkenes without the use of transition metals. A possible mechanistic pathway has been proposed.204 Terminal alkynes undergo homo-coupling with acetoxy-benzoiodoxole in the presence of strong bases such as nbutyllithium or lithium bis(trimethylsilyl)amide in high yields. It has been suggested that half of the starting alkyne adds to the iodinium reagent first, giving an electrophilic alkyne-transfer reagent which is then attacked by the remaining alkyne, which is present as the Li-acetylide.205 Computations with the M06 functional have been carried out on the reaction between PhI(N(SO2 Me)2 )2 and three different representative substrates viz. styrene, 𝛼-methylstyrene, and (E)-methylstilbene. All reactions start with electrophilic attack by a cationic [PhIN(SO2 Me)2 ]+ unit on the double bond and formation of an intermediate with a single C–I bond and a planar sp2 carbocationic centre. The major path, leading

130

Organic Reaction Mechanisms 2016 O

O

H

Ar NHTs

NHTs RhCp*(OAc) 2 2AcOH

AcOH Ar

O O Cp* Rh N OAc Ts

* Rh Cp

N Ts

TfO−

Mes

OTf I

Ar

Ar OAc−

O Cp* Rh N OTf Ts

MesI

O Ar Rh

OTf

Cp* Ts Scheme 15

to 1,2-diamination, proceeds through a mechanism in which the bissulfonimide initially adds to the alkene through an oxygen atom of one sulfonyl group. This behaviour is now corroborated by experimental evidence. An alternative path, leading to an allylic amination product, takes place through deprotonation at an allylic C–H position in the common intermediate.206 Sodium periodate causes direct oxidative lactonization of alkenoic acids catalysed by triflic acid. Sodium periodate works not only as an oxidant but also as an active reagent and directly mediates the lactonization. Acetic anhydride was found to be a necessary reagent for high conversions. A mechanism in which a key intermediate is generated from the acetylation of periodate ion followed by its protonation to form a cationic iodine centre, which is captured by the C=C bond to give an onium intermediate, has been proposed.207 The kinetics and activation parameters of the oxidation of glycine, alanine, and valine with N-iodosuccinimide,208 Mn(II)-catalysed oxidation of 3,5-xylidine209 and l-cysteine with periodate,210 and Ir(III)-catalysed oxidation of d-xylose by sodium metaperiodate211 have been determined, and the suitable mechanisms are proposed.

3 Oxidation and Reduction

131

Ozonolysis and Ozonation A Criegee intermediate (CI) of gas-phase ozonolysis of ethylene has been detected experimentally using FT microwave spectroscopy and a modified pulsed nozzle, which combines high reactant concentrations with rapid sampling and sensitive detection. Nine other product species of the reaction have also been detected, including formaldehyde, formic acid, dioxirane, and ethylene ozonide. The presence of all these species has been attributed to the unimolecular and bimolecular reactions of the CI.212 A new flow system to measure the pressure dependence of stabilization of Criegee intermediate has been developed. The technique depends on the high sensitivity and precision of chemical ionization mass spectrometry for sulfuric acid measurements to obtain pressure falloff curves with unprecedented precision and demonstrated the system using the well-studied and highly symmetrical reaction of ozone with tetramethyl ethylene. The yields of stabilized CI depend nearly linearly on pressure.213 In the ozonation reactions of benzo and dibenzo derivatives of pyrrole, furan, and thiophene, peroxide compounds have been detected as the products. The kinetics of ozonolytic reactions of benzologues of five-membered hetarenes has been investigated, and a mechanism of the interaction is proposed.214 Ozonolysis of methoxybenzene (MB) has been investigated using the quantum chemical methods [M06-2X/aug-cc-pVDZ//M06-2X/6-31+g(d,p)] and Rice–Ramsperger– Kassel–Marcus theory. The results showed that ozone addition to the methoxysubstituted carbon dominates the entrance channel of MB with ozone, and the total rate coefficient of the reactions has been calculated. The bimolecular rate constants show positive dependence on temperature and negligible dependence on pressure. The atmospheric lifetime of MB determined by ozone has been calculated considering the typical concentration of ozone in atmosphere.215 The mechanism of ozonation of benzothiophene and its derivatives has been studied by DFT, considering the solvation effect in acetonitrile. Two pathways are proposed for ozonation of benzothiophene; that through the Criegee mechanism was found to be favoured.216 Rate constants for oxidation of hexenols with ozone have been determined. Calculations in terms of DFT, transition-state theory, and at the BH&HLYP/6-31+G(d,p) level of theory indicated that the calculated rate constants are in good agreement with the experimental data, and the reactivity of hexenols with ozone showed a strong dependence on their chemical structure based on the theoretical results. Lifetimes of the hexenols, with respect to their reactions with some important atmospheric oxidants such as ozone, OH, and NO3 radicals, have also been discussed.217

Peracids and Peroxides Rearrangement reactions of peroxides such as the Baeyer–Villiger, Criegee, Hock, Kornblum–DeLaMare, Dakin, Elbs, Schenck, Smith, Wieland, Story, and other unnamed rearrangement reactions have been reviewed.218 Recent developments in ruthenium-catalysed alkene epoxidations have been reviewed. Catalyst development, structural studies, and mechanistic investigations of catalytic cycles have been emphasized. It has been observed that the reactions often feature a Ru(IV) oxo or Ru(VI) dioxo species as the catalytically active species from which oxygen transfer to the

132

Organic Reaction Mechanisms 2016

alkene is suggested to occur via a concerted mechanism.219 State of art of C–H and C=C oxidations catalysed by non-haem iron complexes with HP as the oxidant have been reviewed. Optimization of ligand structure and the use of bulky carboxylic acids as co-ligands, leading to highly enantioselective epoxidation of olefins providing a highly modular and tunable catalytic system, have been discussed.220 The ammoximation of acetaldehyde to its oxime in the titanium silicalite-1/HP system was investigated using an in situ IR spectrometer. It has been found that ammonia is first oxidized to NH2 OH, and it then reacts with the aldehyde.221 Bulky iron complexes were prepared by introducing trialkylsilyl groups at the meta-position of the pyridines in tetradentate aminopyridine ligands. These complexes catalyse the site-selective oxidation of alkyl C–H bonds with HP under mild conditions with high product yields, an enhanced preferential oxidation of secondary over tertiary C–H bonds, and the ability to perform site-selective oxidation of methylenic sites in terpenoid and steroidal substrates. The site-selective oxidation at C(6)- and C(12)-methylenic sites in steroidal substrates is shown to be governed by the chirality of the catalysts.222 High enantioselectivities have been achieved in the tungstate-catalysed oxidation of phenyl and heterocyclic sulfides with HP under mild conditions. The active ion-pair catalyst was identified to be bisguanidinium phosphatobisperoxotungstate using Raman spectroscopy and computational studies.223 It has been observed that Pd1 O4 single sites anchored on the internal surface of micropores of a microporous silicate exhibit high selectivity and activity in transforming methane to methanol in aqueous phase through partial oxidation of methane with HP. The selectivity for methanol production remains at 86.4%, while the activity for methanol production at 95 ∘ C is about 2.78 molecules per Pd1 O4 site per second when 2.0 wt% CuO is used as a co-catalyst. Thermodynamic calculations suggested that the reaction towards methanol production is highly favourable compared to formation of a by-product, methyl peroxide.224 The asymmetric epoxidation of 𝛼,𝛽unsaturated aldehydes by HP, catalysed by a spiro-pyrrolidine-derived organocatalyst, has been accomplished with good diastereoselectivities (up to dr > 20:1) and with high to excellent enantioselectivities (up to 99% ee). It has been suggested that firstly, an iminium ion is formed by dehydration of an 𝛼,𝛽-unsaturated aldehyde with the catalyst. Next, the iminium ion is attacked by HP, leading to an enamine intermediate. Finally, the formation of the epoxide takes place by an attack of the nucleophilic enamine carbon atom on the electrophilic oxygen atom. Due to the steric hindrance caused by the bulky silyl ether from the Si-face, the nucleophilic HP could only approach the iminium ion from the Re-face, thus affording the (S,R)-epoxide.225 Asymmetric Baeyer–Villiger (BV) oxidation of structurally diverse 3-substituted cyclobutanones with HP is catalysed by an assembly of a chiral flavinium and a cinchona alkaloid dimer. This catalyst provides good to excellent enantioselectivities (up to 98:2 er). A transition state, which explains the selectivity, has been proposed.226 Both inner sphere and intermediate sphere mechanisms have been analysed by DFT calculations, in the presence and absence of pyridine-2-carboxylic acid, in Zn(II)-catalysed oxidation of benzylic alcohols to aldehyde and ester by HP. An intermediate sphere mechanism involving the transfer of hydrogen from alcohol to HP was found to be preferred over the competitive inner sphere mechanism involving 𝛽-hydride elimination. Pyridine-2-carboxylic acid remarkably decreases the activation

ee 

ee 

ee  de  ee 

3 Oxidation and Reduction

133

barriers for the intermediate sphere pathway, whereas a less-pronounced inverse effect is observed for the inner sphere mechanism.227 DFT calculations of olefin epoxidation with HP catalysed by aqua-coordinated sandwich-type polyoxometallates (POMs), {[WZnTM2 (H2 O)2 ](ZnW9 O34 )2 }n− [TM = Rh(III), Pd(II), and Pt(II)], showed that the reaction proceeds through a two-step mechanism, activation of HP and oxygen transfer. The aqua-coordinated complexes show two distinct HP activation pathways, two-step and concerted. The concerted processes are more facile.228 A novel family of manganese(II) complexes bearing chiral aminopyridine ligands that possessed additional aromatic groups and strong donating dimethylamino groups have been synthesized and characterized. These manganese complexes exhibited efficient activities in the asymmetric epoxidation of various olefins, such as styrene derivatives (up to 93% ee) with HP as the oxidant and a catalytic amount of carboxylic acid as the additive.229 An OCC of phenols and anilines in the presence of silver nitrate and HP results in the formation of 2′ -aminophenyl-2-ols. This reaction is selective towards the creation of a new C–C bond at the ortho-position of both amine and hydroxyl functional groups in the respective starting materials. Electron-withdrawing groups in aniline slow down the reaction, whereas electron-donating groups have the opposite effect. The electronic nature of substituent on phenol has little effect on the reaction. It has been proposed that phenol is oxidized to an electrophilic radical intermediate and aniline acts as a nucleophile.230 A catalyst, generated in situ from a Mn(II) salt, pyridine-2-carboxylic acid, and a ketone promote efficient oxidation of alkenes, alkanes, and alcohols with HP. It is shown that the equilibrium between the ketone co-catalyst and HP is central to the catalytic activity observed and that a gemhydroxylhydroperoxy species is responsible for generating the active form of the manganese catalyst. The apparent order with respect to the substrate is zero, consistent with rate-limiting formation of highly reactive manganese species.231 The anion of the isoalloxazinium catalysts has been found to play an important role in the catalytic efficiency of the oxidation of the sulfides with HP, and the rate followed the order TfO− ≫ ClO4 − > CH3 SO3 − ≫ TsO− > CF3 CO2 − ≫ CH3 CO2 − , indicating that the counter anions forming stronger conjugated acids accelerated the reaction rate. The riboflavin-derived isoalloxazinium triflate salt was chosen as a readily accessible flavin with an efficient catalytic activity. It has been found that the isoalloxazinium triflate is an excellent organocatalyst for chemoselective oxidation of a sulfide to a sulfoxide, BV reaction of a cyclobutanone to a 𝛾-butyrolactone, Dakin reaction of an arylaldehyde to a phenol, and oxidation of an aldehyde to a carboxylic acid using HP as a terminal oxidant under mild conditions.232 Hydroperoxovanadium(V)-salophen has been identified as the active oxidizing species in the oxidative decarboxylation of a series of phenylsulfinylacetic acids (PSAA) by HP with four oxovanadium(IV)-salophen catalysts. A Hammett correlation displays a nonlinear downward curvature, which consists of two intersecting straight lines. Based on the observed substituent effects and the spectral changes, a mechanism involving electrophilic attack of PSAA on the nucleophilic peroxo oxygen atom of the vanadium complex in the rate-determining step followed by an oxygen atom transfer has been proposed.233 Addition of magnesium hydroxide in the oxidation of furfural with HP suppresses the oxidation of the furan ring and

ee 

134

Organic Reaction Mechanisms 2016

enhanced selectivities of 2(5H)-furanone and succinic acid. 2-Formyloxyfuran, arising out of selective oxidation of –HC=O group in furfural, is a crucial intermediate.234 cis-Hydroxido-aquoosmium(III) complex supported by a macrocyclic tetradentate ligand catalyses the stereoselective oxidative cyclization of 1,5-dienes to give tetrahydrofuran derivatives with cis–syn conformation in modest to high yields using HP as the terminal oxidant in an aqueous media. It is suggested that initially HP oxidizes the starting Os(III) complex to generate an active Os(V) oxidant, which binds to a 1,5diene in a 3 + 2-cycloaddition manner to produce the cis-dihydroxy-5,6-alkene and the osmium(III) complex. The dihydroxy alkene is then converted to cis–syn tetrahydrofuran derivatives.235 A mononuclear non-haem manganese complex bearing a tetradentate N4 ligand is a highly efficient catalyst in the epoxidation of olefins by aqueous HP and many other oxidants in the presence of sulfuric acid. The effect of sulfuric acid on the epoxidation by various oxidants suggests that a common epoxidizing intermediate is generated in the reactions of the catalyst and the oxidants. In the epoxidation of styrene under optimal conditions, a significant amount of 18 O-incorporation from H2 18 O into the styrene oxide was observed demonstrating that a high valent Mn-oxo species was indeed formed as an epoxidizing intermediate in the reaction (Scheme 16a). Use of 18 O-labelled cumene hydroperoxide (CHP) (cumyl-18 O18 OH) as a terminal oxidant resulted in the products epoxide and cumyl alcohol with the same amount of 18 O derived from the oxidant showing that the source of oxygen atom in the products was the CHP, not molecular oxygen (Scheme 16b).236 Direct asymmetric synthesis of N-chiral amine oxides has been accomplished (up to 91:9 er) by means of a bimetallic titanium catalyst and an N,O-ligand (2). A (a) 16O

16O

16OH−

H

16O

MnV

MnIII

18O

H218O

MnV

18

16O

H+

(b) Me

Me 18

18O

O

MnIII

Ph

Ph

Ph

Me

18

Me

18O−

Me

O

OH

Me 18O

MnV Scheme 16

18

O

de 

135

3 Oxidation and Reduction

hydroxy group situated at the 𝛾-position of the nitrogen-stereocentre enables the desired N-oxidation through dynamic kinetic resolution of the trivalent amine substrates. The terminal oxidant was TBHP. The method was further extended to the kinetic resolution of racemic 𝛾-amino alcohols with a pre-existing stereocentre, giving an important class of enantioenriched (up to 99.9:0.1 er) building blocks.237

But

N OH

OH OH

OH N

But

(2)

Functionalized 2H-azirines have been synthesized by OCC of enamines with carboxylic acid mediated by potassium iodide and TBHP. This one-pot procedure, leading to the formation of C–O and C–N bonds, showed broad functional group tolerance, good reaction yields, short reaction time, and high atom economy. Addition of BHT and TEMPO inhibited the formation of the desired product, indicating a radical pathway. Experiments showed that OCC of enamines with carboxylic acid occurs before the formation of azirine ring (Scheme 17).238 A CDC of aldehydes and heterocycles, using N-chlorosuccinimde (NCS) and TBHP, resulted in the acylation of the heterocycles. When the reaction was carried out in the presence of BHT or TEMPO, the acylated product was not formed, indicating that the reaction proceeds via a radical pathway. It is proposed that TBHP forms t-butyloxy radical and hydroxyl radical, in the presence of NCS, which abstracts the proton from the aldehyde to form an acyl radical. Further, the addition of acyl radical to heteroarene forms an amidyl radical. Finally, t-butyloxy radical or hydroxyl radical abstracts a hydrogen radical from the amidyl radical to furnish the acylated product.239 An OCC of aryl alkyl ketones with alkyl/aryl H-phosphonates and H-phosphine oxides using tetrabutylammonium iodide (TBAI) as catalyst in the presence of TBHP as terminal oxidant in aqueous media results in the formation of a wide range of ketol phosphates and phosphinates in moderate to good yields. A tentative mechanism in which t-butyloxy radical, generated from iodide ion and TBHP, abstracts a hydrogen from the ketone to form a radical, which subsequently is converted by a SET to a carbocation, has been proposed.240 An intramolecular radical cascade of the 𝛼-cyano𝛼-TMS/aryl-capped alkynyl aryl alkyl ketones, promoted by oxidant TBHP under catalysis with TBAI, has been developed, which culminates in the construction of a variety of [6,6,5] tricyclic frameworks containing a high level of functionalization. The cascade process is proposed to be initiated with abstracting H-atom, 𝛼 to both

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Organic Reaction Mechanisms 2016

+ − OH

ButO

ButOOH

I−

1/2 I2

H2O + ButOO

ButOOH + HO

O

ButO

NH2

Ph

O

Ph

RCOO

RCOOH

NH2

Ph

Ph O

Ph

Ph O

O

R H O

+

HN

O R

O

I

Ph

Ph

R

I

I

+

O

H

N

−HI

Ph

Ph O

O R Scheme 17

O

I

HN

1/2 I2

t

Bu OO

+

O

N Ph

Ph O R

O

O

3 Oxidation and Reduction

137

cyano and carbonyl groups, by the free radical species t-BuO⋅ or t-BuOO⋅ generated by a catalytic cycle of TBHP and TBAI. The initial 𝛼-keto radical intermediate thus formed might undergo an intramolecular 5-exo-dig cyclization to produce a vinyl radical intermediate which, by the ensuing 6-endo-trig addition, gives rise to a cyclic pentadienyl radical; this may afford the desired rearomatization product by aromatic homolytic substitution.241 An oxidative coupling of isocyanide and toluene derivatives using TBAI as a catalyst and TBHP leads to the formation of benzamide derivatives. A radical pathway is indicated by a complete inhibition of reaction by TEMPO. The reaction of toluene-[methyl-13 C(1)] proceeded readily to give the amide-[carbonyl13 C(1)] product, which clearly indicated that the carbon of the isocyano group is eliminated during the reaction. A plausible mechanism has been proposed.242 Efficient C–P bond formation between N-aryltetrahydroisoquinoline and diethyl phosphate, in the presence of N,N-bis[3,5-bis(trifluoromethyl)phenyl]thiourea as a catalyst and TBHP as the terminal oxidant, results in 𝛼-aminophosphonic derivatives in good yields. A plausible mechanism, based on earlier reports, has been postulated.243 Chromenes are converted to the corresponding flavones in good to excellent yields by TBHP with copper(II) bromide as a catalyst. The reaction shows excellent reactivity and functional group tolerance. A tentative mechanism has been proposed (Scheme 18).244 Experimental and DFT calculations indicated that activation of N-aryl tetrahydroisoquinolines in oxidative coupling reactions using CuBr as catalyst and TBHP follows a hydrogen atom transfer (HAT) mechanism. Hammett plots, a direct time-resolved kinetic study and DFT calculations showed that HAT is mostly mediated by t-butoxyl radicals and only to a lesser extent by t-butylperoxyl radicals (Scheme 19).245 An efficient synthesis of 3-trifluoromethylthiospiro[4,5]trienones through a radical oxidative dearomatization process with AgSCF3 has been reported. This reaction is promoted by a combination of PDS and TBHP. The oxygen atom in the product comes from the TBHP. This protocol provides a novel route to SCF3 -substituted spirocyclic compounds via the formation of one C–SCF3 bond, one C–C bond, and one C–O double bond in a single step. The reactions were found to be inhibited by TEMPO or BHT, which implied that the reaction may proceed by a radical pathway. The reaction sequence starts with an addition of the trifluoromethylthio radical, which is generated from AgSCF3 and PDS, onto the alkynyl bond to afford a vinyl radical. This radical undergoes an intramolecular cyclization to give another radical intermediate which is trapped by the t-butylperoxy radical before elimination of t-BuOH to generate the desired product.246 Cobalt(II)-TBHP-mediated oxidative annulations of aromatic tertiary amines with a typical electron-deficient alkene, N-arylated or N-alkylated maleimide derivative, lead to the formation of tricyclic tetrahydroquinolines. This oxidizing system could also be applied to annulation with an electron-rich alkene, 3,4-dihydropyrane. Decrease in the yield of the product on addition of BHT indicates that the reaction involves a radical pathway via a SET.247 Synthesis of 4H-3,1-benzoxazin-4-ones has been realized by an intramolecular oxidative cyclization of N-(2-formylphenyl)amides through an oxidative C(sp2 )–O(sp2 ) bond-forming reaction, mediated by TBHP/CoCl2 . The reaction is hampered by an addition of TEMPO, and a mechanism has been formulated that involves radical intermediates (Scheme 20).248

138

Organic Reaction Mechanisms 2016 ButOOH

ButO

CuIII –OH

CuII ButOOH

ButOO + H2O

O

But

O ButO

ButOO

ButOH

O

H

O O

ButOH

O

O

Scheme 18

ButOH

ButO HAT

N

N

HAT

Ar ButOO

N Ar

Ar

Nu

ButOH Scheme 19

Co(salen)-catalysed C–H activation and peroxidation of 2-oxindoles provides a new pathway for the synthesis of biologically active 3-peroxy-2-oxindoles. TBHP or CHP has been used as an oxidant. A KIE, kH /kD = 2.4, has been observed. A radical reaction pathway has been proposed. Initially, the cobalt complex catalyses the homolytic

139

3 Oxidation and Reduction O heating

ButOOH

O

ButO N H

R

O CoIII – OH

CoII O

O

O N

N H

O

R

O R

N H

H2O

R

Scheme 20

decomposition of the peroxide, generating the highly reactive Co(III)OH species, which reacted very rapidly with a second peroxide molecule to give Co(III)OOR. The latter dissociates to the ROO⋅ radical while generating the starting Co(II) species. The resulting RO⋅ radical abstracts the 𝛼-carbonyl hydrogen of 2-oxindole to form a radical intermediate, which further undergoes a selective cross-coupling with the longer lived ROO⋅ radical to give the product.249 DFT calculations indicated operation of a two-step oxidation mechanism in the Zn(II)catalysed oxidative amidation of benzylic alcohols with amines. Oxidation of benzyl alcohol to benzaldehyde is the first step. In the next step, hemiaminal generated from the aldehyde is converted to amide through oxidation. TBHP was the terminal oxidant. The respective activation barriers suggest that the outer sphere mechanism is more plausible than the inner sphere.250 An NHC-catalysed benzylic sp3 C–H bond activation of alkylarenes and N-benzylamines under metal-free conditions has been developed. This organocatalysed oxidation afforded the corresponding carbonyl derivatives in good to excellent yields. A variety of alkylarenes and N-benzylamines are tolerated under the optimized reaction conditions. TBHP is the terminal oxidant. DFT calculations at the M06-2X/6-31g(d,p) level of theory showed that the benzylic C–H bond is activated through nucleophilic attack of the free carbene on the benzylic C (Scheme 21).251 An oxidative dearomatization of 2-arylindole via Pd-catalysed C–H peroxygenation, coupled with cascade transformation, provides a new route to access indolin-3-ones bearing a C(2)-quaternary functionality, including a chiral centre. The method is chemo- and regio-selective, compatible with versatile substrates and uses MnO2 as a co-catalyst and TBHP as an oxidant. A mechanism has been outlined, which involves an initial electrophilic palladation of indole, reaction with TBHP, and reductive elimination to yield indole 3-t-butylperoxide.252

140

Organic Reaction Mechanisms 2016 Ar N+ Cl− N Ar Base

Ar HO

N

H

ButOH +

R

Ar

Ar

R

N Ar Ar H

N Ar

Ar R N

O

N

H

O

H

N

Ar H R

Ar But

Ar Ar N H

O

O

N

But

H

Ar H R

Ar HO Ar

H R

O + H

O

O

Bu

+ ButOH + H2O

t

Ar

R

Scheme 21

Two non-haem iron complexes showed efficient catalysis in oxidation of various alcohols to the corresponding carbonyl products using TBHP as an oxidant in the presence of N-hydroxyphthalimide (NHPI) under mild conditions. Studies of Hammett correlation, deuterium isotope effects, and the use of 2-methyl-1-phenylprop-2-yl hydroperoxide as a guide to mechanism suggested that the reactive oxidants are possibly FeIV =O species, alkoxy radical, and phthalimide N-oxyl radical.253 A CDC reaction between N-arylglycine esters and phenols or 1,3,5-trimethoxybenzene catalysed by Cu(II), with di-t-butyl peroxide (DTBP) as an oxidant, leads to 𝛼-aryl 𝛼amino acid esters with high ortho-regioselectivities in a moderate to excellent yield, which is reduced dramatically in the presence of BHT, suggesting operation of a radical pathway. A possible mechanism involving aromatic electrophilic substitution is proposed (Scheme 22).254

141

3 Oxidation and Reduction SET

Ar

O

H N

ButO

Ar

OEt H

H N

O OEt

CuII

CuI

ButOH ButOOBut

ButO + ButO−

Ar

O

H N +

OEt

Ar

H N +

O OH

Ar

O

H N

OEt

H

OEt

OH +

−H+

Ar

H N

O OEt OH

Scheme 22

Optically active rotaxane amine N-oxides have been synthesized in up to 95% diastereomeric excess and up to 99% yield via the oxidation of the t-amine moiety of the axle component of the rotaxanes having a chiral crown ether wheel via the effective through-space chirality transfer. The oxidant was dimethyldioxirane. Higher diastereoselectivity was observed with the rotaxane possessing the rigid skeleton and the N-benzyl substituent. The optimized structures suggested an (R)-configuration at the nitrogen centre.255 BV oxidation of N-aryl-3-(arylimino)-3H-indol-2-amines with m-chloroperbenzoic acid (m-CPBA) resulted in the formation of 1,4-benzoxazines and corresponding N-oxide in a temperature dependent ratio. Thus, the N-oxide predominates at room temperature, but 1,4-benzoxazines are a major product component at –20 ∘ C. A mechanism for the formation of 1,4-benzoxazines is shown in Scheme 23.256 The selective elimination of selenoxide from 1,2-bis[4-(trimethylsilyl)phenylseleno] alkanes, resulting in the exclusive formation of (E)-alkenyl selenoxides via a 1,2bisselenoxide intermediate, has been studied. The oxidation of 1,2-bis[4-(trimethylsilyl)phenylseleno] alkanes with one equivalent of m-CPBA resulted in the non-selective

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Organic Reaction Mechanisms 2016 O Ar

N

Ar

O

N NH Ar

H

O

O

Ar

N

O

Ar1

O

1

NH N Ar1

Ar

= 3-Cl-C6H4 Ar O N

N NH Ar

Scheme 23

formation of several arylseleno alkene derivatives, and it has been shown that the elimination of the corresponding 1,2-bisselenoxide proceeded with high regio- and stereo-selectivity. 77 Se NMR and computational studies have been described.257 An oxidation process that selectively produces two different fused polycyclic products from electron-rich tetraarylethylenes bearing two furan rings has been disclosed. The reaction selectivity could be switched by applying different oxidants. A tricyclic compound was isolated as the sole product when m-CPBA was used as the oxidant. Another product, indenone, was obtained instead when FeCl3 was applied as the oxidant. It has been suggested that both the reactions were triggered through oxidation of furyl group to 2-buten-1,4-dione.258 Arylated quinines have been synthesized through a one-pot oxidation of phenols/naphthols with m-CPBA, followed by triflic acid-catalysed arylation with electron-rich arenes.259 C(3)-Symmetric chiral trisimidazolines with m-CPBA promoted the organocatalytic oxidation of N-sulfonyl ketimine. The imidazoline catalysis produced oxaziridines bearing a tetrasubstituted carbon stereogenic centre in high yields with up to 87% ee. 1 H NMR studies indicated that an ion pair is formed between the catalyst and m-CPBA. It was further observed that in this process, an electron-deficient group tends to accelerate the reaction rate. It has been proposed that initially, one imidazoline nitrogen atom in the catalyst is protonated by m-CPBA, whereas the other imidazoline group coordinates to the oxygen atom of the peroxy carbonyl group, leading to tight-ion-pair aggregation. Next, attack of the generated chiral oxidant to ketimine forms oxaziridine through an 𝛼-aminoperoxy intermediate. After the oxaziridination, m-CBA is released from imidazoline because m-CBA is insoluble under the optimized conditions. The chiral peracid species was regenerated from imidazoline with m-CPBA.260 An in situ generated catalyst system based on Mn(CF3 SO3 )2 , picolinic acid, and peracetic acid rapidly converts a large number of olefins to their epoxides, with

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3 Oxidation and Reduction

143

remarkable oxidant efficiency and no evidence of radical behaviour. Competition experiments indicate an electrophilic active oxidant, proposed to be a high-valent Mn=O species. Intramolecular competition with geranyl acetate, which contains two alkene moieties with similar steric properties but differentiated electronic properties, indicates preferential oxidation of the more electron-rich alkene.261 Pd(II)-catalysed CDC of methyl N-phthaloyl dehydroalanine esters with simple aromatic hydrocarbons generates stereoselectively Z-dehydrophenylalanine skeletons in an atom economical manner. The reaction, which involves the cleavage of two sp2 C–H bonds followed by a C–C bond formation, uses Pd(OAc)2 as the catalyst together with t-butylperoxybenzoate as the terminal oxidant and 3,5-dichloropyridine as the ligand.262 Formation of an iron(III) peroxo species-5-oxo acid complex has been postulated in the iron(II)-catalysed oxidation of substituted 5-oxo acids with perborate in acid solution. HP is the reactive species. A mechanism has been proposed.263 A double BV reaction of quinizarin dimethyl ether with sodium perborate tetrahydrate directly provides the dibenzo[b,f ][1,4]-dioxocin-6,11-dione ring system. This methodology provides rapid access to 1,2,3,4-tetraoxygenated benzenes.264 The kinetics of the oxidation of methyl phenyl sulfide by peroxoborate anions indicates that the reactivity of the peroxoborate anions is much higher than that of HP. When water is replaced by aqueous-alcohol mixtures as a solvent, the reaction rate decreases.265 A (1S)-(−)-2,10-camphorsultambased highly stereoselective 𝛼-hydroxylation of amides has been developed to deliver the desired products in good yield and excellent diastereoselectivity (>20/1). Davis oxaziridine has been used as the oxidant, and sodium bis(trimethylsilyl)amide has been added as a salt.266

Photo-oxygenation and Singlet Oxygen The optimal geometry and energy parameters for five electronic states of the singlet oxygen and ethylene system that characterize the elementary reactions of two-step 1,2addition giving the dioxetane molecule have been calculated using various quantum chemical methods. The first step of the reaction is found to pass through the ethylene perepoxide intermediate. Results calculated by the higher level methods (QCISD, CCSD, and CASSCF) and the standard methods (DFT and MPn) correspond to experimental estimates.267 Simulation of oxidation reactions of substituted ethylene and butadiene with singlet oxygen has revealed many competing routes. The largest product variety is obtained for butadiene and methyl derivatives of ethylene. For butadiene, along with 1,2-cycloaddition reactions resulting in four-membered dioxetane, six-membered cyclic epidioxides and diepoxide products with two three-membered rings may form. The formation of hydroperoxides along with 1,2-addition products is also possible for all methyl derivatives of ethylene. Formation conditions and relative stability of the noted products have been discussed in each case.268

Triplet Oxygen and Autoxidation Advances made by combining method development in organic synthesis with detailed mechanistic studies have been summarized. The discovery of an unexpected autoxidative coupling reaction led, by virtue of an ever increased understanding of its

de 

de 

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Organic Reaction Mechanisms 2016

mechanism, to a strategy for green C–H functionalization reactions, novel modes of radical generation, addition reactions of ketones to alkenes, and new insights into an old reaction, the BV oxidation.269 Advances in organic synthesis during the period 2004–2016 involving metal-free alkene oxygenation-based carbonyl generation have been reviewed; oxygenations involving both full and partial cleavage of the C=C double bond are included.270 Siloxy-N-silylketenimines generated in situ from O-silyl cyanohydrins have been converted to 𝛼-ketoamides by brief exposure to air or oxygen. Oxidation under extremely mild conditions can be explained by assuming the intermediacy of a 3-imino1,2-dioxetane derivative generated via triplet–singlet intersystem crossing after the reaction of siloxy-N-silylketenimines with triplet oxygen. Addition of triplet oxygen to siloxy-N-silylketenimine affords a biradical intermediate that, through triplet–singlet intersystem crossing, leads to a 3-imino-1,2-dioxetane derivative which collapses to 𝛼-ketoamide and silyl ester via reductive cleavage of the peroxide bond.271 Primary alcohols react with 2-aminobenzamides under oxygen in a one-pot, catalyst-free, and environment friendly reaction to yield 4(3H)-quinazolinones in satisfactory to good yields. Background experiments indicated that possibly three distinct reaction mechanisms are operative.272 A theoretical and experimental study of oxidation of acetylene with HO2 and O2 at intermediate temperatures and high pressure indicated that the C2 H2 + HO2 reaction involves nine pressure- and temperature-dependent product channels, with formation of triplet CHCHO being dominant under most conditions. Model predictions are generally in satisfactory agreement with the experimental data. Acetylene is mostly consumed by recombination with H to form vinyl or with OH to form a CHCHOH adduct. Both C2 H3 and CHCHOH then react primarily with oxygen. The CHCHOH + O2 reaction leads to formation of significant amounts of glyoxal and formic acid, and the oxidation chemistry of these intermediates is important for the overall reaction.273 The kinetics of chain initiation during the auto-oxidation of some unsaturated compounds in solvents of different polarity has been studied. A data array composed of chain initiation rate constants of bi- and tri-molecular reactions has been obtained. It was shown that in some cases, the polarity of the medium is the key factor defining the initiation mechanism.274 Auto-oxidation mediated hydroxysulfenylation of electron-deficient and electron-rich olefins with phenthiols has been achieved. The method illustrates a selective and convenient synthesis of complex 𝛽-hydroxysulfides using oxygen as both the oxidant and the oxygen source under mild transition-metal-free conditions. Addition of TEMPO inhibited the formation of hydroxysulfenylation product. A mechanism has been proposed (Scheme 24).275 Regioselective synthesis of 4-hydroxybiphenyl-2-carboxylates via a base-mediated oxygenative [3 + 3] benzannulation reaction of 𝛼,𝛽-unsaturated aldehydes and 𝛾phosphonyl crotonates has been reported. A hydroxyl group is installed in the final product on the originally phosphorus-bound carbon via a novel oxygenative and dehydrogenative transformation. The reaction proceeds rapidly, uses atmospheric oxygen as an oxidant, and affords good yields of substituted biaryl phenols. A probable mechanism, involving an initial C–C bond-forming Michael addition of the phosphonate anion to the enal to afford an acylic intermediate, has been suggested.276

145

3 Oxidation and Reduction O

+O2 SH

O

S

S

OOH

O O

S

O2 O

O

SH

O

O

S

4-Me-C6H4S

HO

PPh3

S

P(O)Ph3

HO

O

O O

O O

Scheme 24

An aldehyde-selective Wacker-type oxidation of allylic fluorides proceeds with a nitrite catalyst. The method affords a direct route to 𝛽-fluorinated aldehydes. Allylic fluorides bearing a variety of functional groups are transformed in high yield with very high regioselectivity. Individual rate comparisons of the two compounds showed that the more electron-deficient fluorinated olefin reacts at an accelerated rate relative to the unfunctionalized olefin. Preliminary mechanistic studies are consistent with inductive effects having a significant influence on both the regioselectivity and rate of oxidation.277 Aerobic oxidation of aldehydes to carboxylic acids has been realized using 9-azabicyclo[3.3.1]nonan-3-one N-oxyl and NaNO2 as the optimal nitroxyl and NOx sources, respectively.278 N,N′ -Diphenyl-p-benzoquinonediimine is reported to work as a redox-active organocatalyst for the oxidative homo-coupling of aryl- and alkenyl-magnesium compounds under molecular oxygen. The catalytic cycle was formally monitored by 1 H NMR experiments.279 Direct amidation of aldehydes, involving RNH transfer from secondary amines to produce secondary amides, under metal-free conditions employing molecular oxygen as the oxidant has been achieved. 9-Aminofluorene derivatives acted as pyridoxamine5-phosphate equivalents for efficient and chemoselective amine-transfer oxygenation reaction. In the presence of 18 O2 , 18 O-amide was formed with excellent (95%) isotopic purity. It has been proposed that condensation of aldehyde and 9-aminofluorenyl derivative occurs to provide corresponding aldimine. TEA-promoted deprotonation of aldimine furnished stabilized azomethine anion. The anion reacted with molecular oxygen to provide a hydroperoxide or its regioisomer. The hydroperoxide could react

146

Organic Reaction Mechanisms 2016

further to furnish the corresponding dioxazolidine, which on subsequent thermal decomposition would provide the desired amide and 9-fluorenone.280 The effect of 2-thio-6-aminouracil on the free-radical chain oxidation of 1,4-dioxane with oxygen has been investigated. The presence of a thiocarbonyl group in the 2position of the uracil ring makes 6-aminouracil highly reactive towards 1,4-dioxane peroxy radicals. The stoichiometric inhibition factor f = 1.1 ± 0.1 has been determined.281 A wide range of phenylethanol derivatives with a variety of functional groups have been effectively synthesized by a highly selective radical dioxygenation of alkenes using NHPI and N-hydroxybenzotriazole and oxygen with 5–10 mol% of TBHP as a catalyst. Oxygen is found to be essential for the reaction. Further, in the presence of TEMPO, the target product is not formed indicating a radical pathway. It has been suggested that initially NHPI reacts with TBHP to form a radical, which reacts with the alkene.282 A DFT computational study of the mechanisms for preparation of benzoxazole gave a significant insight into the amine–aldehyde condensation, cyanide ion-catalysed dehydrogenation, and final cyclization reactions. Cyanide ion was found to trigger involvement of oxygen atoms in the aerobic oxidative dehydrogenation at the 𝛼-carbon instead of catalysing the direct cyclization expected by Baldwin’s 5-exotet rule. This facilitates triplet oxygen dehydrogenation because of the captodative effect to stabilize the intermediates, which reduces the activation energy to make the reaction progress smoothly. In addition, a trace amount of water will assist the proton to transfer from the hydroxyl group primarily but not from imine N-atom.283 Ethyl 2-arylhydrazinecarboxylates work as organocatalysts for Mitsunobu reactions because they provide ethyl 2-arylazocarboxylates through aerobic oxidation with a catalytic amount of iron phthalocyanine. Investigation of the catalytic properties of ethyl 2-arylhydrazinecarboxylates and the corresponding azo forms led to the discovery of a new catalyst, ethyl 2-(4-cyanophenyl) hydrazinecarboxylates, which expanded the scope of substrates. Mechanistic study of the Mitsunobu reaction with these new reagents strongly suggested the formation of betaine intermediates as in typical Mitsunobu reactions.284 Copper-catalysed aerobic oxygenation and cyclization of indoles with oxime acetates yields pyrazolo[1,5-a]indole derivatives. This protocol represents an elegant example of N(1)-, C(2)-, and C(3)-trifunctionalization of indoles in one-pot. Radical scavenger, such as BHT and BQ, prevented the desired transformation completely. These observations indicate that the oxygenation of indole probably proceeds via a radical intermediate. Oximes, as internal oxidant, have been demonstrated to initiate aerobic oxidation and thereby provide a new oxidative pattern for C–H functionalization.285 Primary 𝛼-ketoamides have been synthesized by copper(II)-catalysed oxidation of benzylimidates with molecular oxygen. The reaction proceeds through cleavage of two benzylic C–H bonds and one C–O bond of the benzylimidates with liberation of alcohol as a by-product. Effect of radical scavengers indicates that the reaction is likely to involve a radical pathway. Formation of the superoxide radical was detected by EPR measurements also. The reaction is proposed to be initiated by coordination of Cu(II) salt with the –NH group of benzylimidate to generate animinyl copper(II) species, which could be oxidized to superoxide radical via radical pathway under molecular oxygen.286 Cu-catalysed oxidation of ketones with oxygen can lead to

3 Oxidation and Reduction

147

either an 𝛼-C–C bond cleavage or C–H hydroxylation to form 𝛼-hydroxy ketone. Experimental and computational studies suggest that both C–C cleavage and C–H hydroxylation proceed via a common key intermediate, that is an 𝛼-peroxo ketone. The fate of this peroxide dictates the ultimate product selectivity. It has been found that the use of 1,3,4,6,7,8-hexahydro-2H-pyrimido [1,2-a]pyrimidine (hppH) as base and DMSO as solvent along with copper(I) oxide as catalyst selectively yield C–H hydroxylated product. The base hppH acts also as a reductant of the peroxide to the corresponding 𝛼-hydroxy ketone. The likely competitive pathway is the cleavage of peroxide to the 𝛼-oxy radical, which is computationally predicted to spontaneously trigger C–C bond cleavage.287 In the presence of catalyst Cu(phen)Cl2 , in conjunction with di-t-butyl hydrazinedicarboxylate and an inorganic base, alcohols and secondary amines react to form amides, in moderate to excellent yields, using air as the terminal oxidant. In the presence of a suitable base, alcohol is rapidly oxidized to aldehyde. Reaction with the aldehyde C–H(D) resulted in a KIE of kH /kD of 2.4 ± 0.2. This primary KIE is consistent with benzylic C–H bond cleavage in the rate-determining step of amide formation. A Hammett study of rates of reaction of substituted benzaldehydes with piperidine suggests that significant anionic character develops at the benzylic position during the formal oxidation step; the value of 𝜌 = 2.6 is consistent with a deprotonation rather than hydrogen atom or hydride abstraction.288 The mechanism of the Cu(II)-catalysed benzylic oxygenation of (aryl)(heteroaryl)methanes with oxygen has been studied using in situ IR monitoring, continuous-wave and pulsed ESR, and DFT calculations. It has been concluded that both mono- and di-nuclear copper species act as catalysts.289 An efficient coppercatalysed selective cross-coupling of imidazo[1,2-a]pyridines with methyl hetarenes, using molecular oxygen, has resulted in a new route to synthesize the C(3)-carbonyl imidazo[1,2-a]pyridine derivative. 18 O-labelling experiments indicated that the oxygen of the products originated from molecular oxygen. Use of TEMPO or BHT indicated that there is a radical pathway in this reaction. A mechanism has been proposed (Scheme 25).290 Arylsilanes undergo trifluoromethylation with [(phen)CuCF3 ] as the CF3 source under mild, oxidative conditions with high functional-group compatibility. Ariel oxygen is the oxidant in this system.291 Imidazole[1,2-a]pyridines have been synthesized through aerobic copper-catalysed intramolecular C–N bond forming cross-coupling reactions of enaminones via sp2 C–H amination. It has been suggested that the enaminone first reacts with Cu(I), with the assistance of the N-chelating site in the pyridine ring, to give a cuprous intermediate. This intermediate undergoes aerobic oxidation to a Cu(III) intermediate. Finally, the Cu(III) species on reductive elimination yield the target product and Cu(I).292 Aerobic oxidation of amines to either nitriles or imines with simple copper catalysts under mild conditions has been reported. It has been observed that use of CuI leads to the formation of nitriles, whereas that of CuPF6 yields iminies. Kinetic analysis showed a rate dependence on the amine for both CuI- and CuPF6 mediated oxidation, but there was an absence of a KIE in the relative rates of oxidation for RCH2 NH2 and RCD2 NH2 . These results suggest that substrate coordination, rather than C–H bond cleavage, is rate-determining during catalysis. However, substitution of amine-hydrogens with deuterium resulted in an inverse KIE of 0.8 with

148

Organic Reaction Mechanisms 2016

CuII, O2

TFA

N

N+ H

F3CCO2−

SET

+ H2C

N

N

N

N

N+ H

HN +

(3) SET

O

O

O2

N HN +

N

SET

N HN +

N

N

(3) O

OH

N N

O N

HN +

N Scheme 25

N

N

HN +

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149

both the counterions. A preliminary mechanism involving a rate-determining formation of a polyamine–Cu–O2 complex has been suggested.293 Copper-bpy-catalysed coupling of thiols/disulfides with amines leads to the formation of sulfinamides in excellent yields. The procedure was found to be promoted by the addition of water and NH4 PF6 under aerobic conditions. Mechanistic studies indicated that the presence of oxygen was necessary for the reaction to occur successfully and that the sulfur–nitrogen bond is not formed via a free radical pathway. The presence of NH4 PF6 and iodonium ion promotes the reaction. The oxygen atom of the sulfinamide was found to be introduced by the addition of water. A plausible mechanism has been suggested.294 Copper(II) acetate under aerobic conditions catalyses the formation of 5,5′ -bis(1,2,3-triazole)s from organic azides and terminal alkynes. This reaction is an oxidative extension of the widely used copper-catalysed azide−alkyne cycloaddition. The inclusion of potassium carbonate as an additive and methanol or ethanol as the solvent, and in many instances an atmosphere of oxygen, promote the oxidative reaction to afford 5,5′ -bis(1,2,3-triazole)s. It has been suggested that the triazolide intermediate from the copper(I)-catalysed azide–alkyne cycloaddition reaction could be oxidatively coupled to afford 5,5′ -bistriazole.295 An effective aerobic OCC of amines using alloxan and a Cu(I) salt as catalysts has been reported. Mechanistic investigations point towards a complex reaction manifold with evidence that supports a catalytic cycle that does not proceed through a quinone–imine step. This dual catalyst system effects the diimide-mediated hydrogenation reactions of alkenes and alkynes also.296 Coppercatalysed C–H activation in thiophenol in the presence of arylboronic acid and oxygen led to a sequential C–H activation and S-arylation. The use of 18 O isotope-labelled water with regular oxygen gave the product with only 16 O on the phenol. As the reaction does not proceed under nitrogen, it is highly likely that the hydroxyl oxygen originated from molecular oxygen. Mechanistic investigation revealed the disulfide intermediate to be the key component in directing C–H oxidation.297 Quinoline-type N-oxides undergo a dual C–H/N–H CDC with sulfoximines that leads to N-(hetero)arylsulfoximines in high yields with a catalytic amount of CuBr in air. The method does not require any additional ligand, base, reactivity modifier, or oxidant. It has been suggested that first a metallated intermediate is generated upon reaction of heteroaromatic N-oxide with copper(I) bromide. After coordination of the sulfoximine to give a complex, an aerobic oxidation occurs leading to Cu(III) species. Subsequent reductive elimination releases the product and regenerates the Cu(I) catalyst.298 The generation of HP and hydroxyl radical during the oxidation of l-ascorbic acid (LAA) by oxygen with copper as a catalyst was investigated to set up the O2 /Cu/LAA process with benzoic acid (BA) as a probe reagent. HP that is generated undergoes an intramolecular two-ET and is further activated by the intermediate cuprous copper to yield hydroxyl radical, resulting in significant degradation of BA. Dehydroascorbic acid, 2,3-diketogulonic acid, and l-xylosone are the predominant products from the oxidation of LAA.299 The possible transition states of C–H activation on the dehydrogenative coupling of arenes with alcohols employing Ag(I) additives and oxygen as an oxidant have been investigated using B3LYP DFT. The AgOTf salt with Cu(OAc)2 was identified as the most active catalyst. The facile occurrence of the studied reactions is supported by the low activation energies of their respective transition states.300 In the presence of AgOTf

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and triflic acid, anilines, aryl aldehydes, cyclohexanecarboxaldehyde, and alcohols undergo regioselective aerobic cyclocondensation reactions to yield substituted quinolines. KIE and competition reactions using preformed imines and reactions of potential intermediates in the cyclocondensation have been used to suggest a mechanism for the reaction.301 A new NHPI-Co(II)-catalysed protocol, mechanistically involving a sequence of 𝛼-hydrogen abstraction, 5-exo-dig cyclization, oxygen capture, hydrogen transfer, and 1,4-dehydration, has been developed to facilitate an efficient aerobic oxidation of aryl-, silyl-, and alkyl-capped alkynyl 𝛼-cyano alkanone systems to the corresponding highly functionalized products. It is proposed that the chain reaction is initiated by abstracting hydrogen 𝛼 to the cyano and ketone group via a phthalimide N-oxyl radical, generated under catalysis with Co(II)/NHPI in the presence of oxygen to form a radical intermediate, which could immediately undergo 5-exo-dig addition to produce a vinyl radical. Subsequently, an oxygen molecule is captured by the vinyl radical to provide vinyl peroxyl radical by which the hydrogen of NHPI is abstracted to form hydroperoxide followed by 1,4-dehydration to give the product and restart the catalytic cycle.302 An aerobic Co(OAc)2 -catalysed C–H functionalization of benzamides, possessing a bidentate 2-pyridyl-N-oxide group, chemoselectively delivered the six-membered isoquinolone product. The oxidation strategy proved viable with various internal and terminal alkynes through kinetically relevant C–H cobaltation, providing access to a large number of isoquinolone derivatives. DFT calculations suggested that electronic effects controlled the regioselectivity of the alkyne insertion step.303 In the presence of Co(II)-catalyst, aryl gem-disubstituted conjugated alkenols underwent oxidative cyclization affording 2,5,5-trisubstituted tetrahydrofurans in reasonable yields and good diastereoselectivities using the reductive termination variation of the Mukaiyama aerobic oxidative reaction. Under oxidative termination, the same alkenols produced diols and ketonic by-products via the double hydration and 𝛽-scission competing pathways. Oxygen activation of cobalt(II) in a superoxo-binding mode provides a stronger oxidant, which converts the olefin into radical cation. The lowest energy chair-like conformer for the radical cation has been proposed based on the experimentally observed diastereoselectivities.304 Oxidative C–H/C–H bond arylation of unactivated arenes has been achieved using [Co(acac)3 ] as catalyst, Mn(OAc)2 ⋅4H2 O as the cooxidant, and oxygen as the terminal oxidant. KIE studies suggest that C–H bond cleavage is not involved in the rate-limiting step. Two different pathways, namely, a single-electron-transmetallation process and a concerted metallation–deprotonation process, have been proposed to be involved to activate two different inert aromatic C–H bonds.305 Kinetics, activation parameters, and equilibrium constants of the oxidation of 2-mercaptoethanol with oxygen in the presence of cobalt(II)histidine complex have been determined. Oxygen does not directly react with 2-mercaptoethanol but reacted in the form of an adduct with cobalt(II)histidine complex. A mechanism has been proposed.306 DFT computational investigation showed that in the manganese-catalysed homocoupling reaction of aryl Grignard reagents, RMgX, using atmospheric oxygen as an oxidant, an oxo-complex MnR2 O2 , where the oxygen molecule is 𝜂 2 -bonded to the metal, is obtained. The free energy barrier for the subsequent reductive elimination, key-step

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of the cycle, is the result of a complex interplay between electronic and steric effects and, in the case of aryl groups, strongly depends on the nature of the substituent and its position on the phenyl ring.307 The oxidation scheme of 𝛽-isophorone (𝛽-IP) catalysed by iron(III) acetylacetonate using molecular oxygen can be simplified to two parallel reactions. 𝛽-IP on oxidation gave keto-isophorone (KIP) and 4-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one (HIP) along with little isomerization product 𝛼-isophorone (𝛼-IP). Rates were explored under the mass transfer reaction kinetic regime and activation parameters for the oxidation to KIP and HIP have been determined. The intrinsic kinetics equations for oxidation of 𝛽-IP to KIP and HIP have been obtained.308 A t-butyl nitrite/TEMPO radical/FeCl3 catalyst system has been developed to activate molecular oxygen for the aerobic dihydroxylation of the side chain of desmosterol acetate. Formation of C-(24) and C-(25) oxysterols has been achieved with 100% diastereomeric excess and excellent yields. A mechanism for the catalytic aerobic oxidation has also been proposed.309 1,2-Dicarbonylated benzo[d]imidazo[2,1-b]thiazoles have been synthesized through a FeCl3 -catalysed CDC of benzo[d]imidazo[2,1-b]thiazoles and oxoaldehydes under ambient air. An array of C(3)-dicarbonylated derivatives with broad functionalities have been synthesized in high yields. The reaction proceeded in equal ease in the presence of radical scavengers such as TEMPO, BHT, and BQ. A non-radical mechanism has been proposed.310 Computation studies of the aerobic oxidation of 5-hydroxymethylfurfural (HMF) to 2,5-diformylfuran in DMSO catalysed by Keggin heteropolyacid (H3 PMo12 O40 ) at the M06/6-31++G(d,p), Lanl2dz level indicated that the oxidation of HMF involves two main reaction steps viz., cleavage of the O–H bond in the hydroxyl group and cleavage of the C–H bond in the methylene group of HMF. The turnover frequency determining the transition state was the first-step, C–H bond cleavage in the methylene group of HMF. The value of the KIE (kH /kD ) is predicted to be about 4.2–5.9 over the temperature range 373–433 K.311 An efficient direct aerobic oxidative olefination of the methyl group of 2-methylquinolines with benzylamines in the presence of a rare-earth-metal Lewis acid catalyst to give 2-styrylquinolines has been developed. Preliminary mechanistic studies revealed that the oxidative olefination reaction proceeds through a Lewis acid-catalysed 2-methylquinolinealdehyde condensation and an amine–aldehyde condensation.312 A new Ce(IV) complex bearing a dianionic pentadentate ligand with an N3 O2 donor set has been prepared. This complex in the presence of TEMPO and 4A molecular sieves has been found to serve as a catalyst for the oxidation of arylmethanols using oxygen as an oxidant. The observed reaction rates for p-substituted benzyl alcohols correlated reasonably well with the Hammett 𝜎 p parameters, providing a 𝜌 value of −0.77, which implies radical intermediate formation at the benzylic position of the substrate in the transition state for the oxidation process. A mechanism based on isolation and reactivity study of a trivalent cerium complex, its side-on peroxo adduct, and the hydroxobridged Ce(IV) complex as key intermediates during the catalytic cycle has been proposed.313 Pd-catalysed aerobic [4 + 2] annulation of o-vinylanilines and alkynes with the aid of a copper salt and oxygen has been developed. This protocol enables rapid assembly of quinolines via C–N, C–C bond formations and aerobic C–C bond cleavage. Only a trace

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amount of desired product was detected when TEMPO or BHT was employed, which indicates that the transformation might involve a radical process. A mechanism has been suggested.314 Pd(OAc)2 /Cu(OAc)2 -catalysed oxidation of 𝛼-bisabolol by molecular oxygen under chloride-free non-acidic conditions gives exclusively the products resulting from the interaction of palladium with a sterically encumbered internal acyclic double bond. No concomitant oxidation of the endocyclic double bond occurs.315 Pd/Ag synergistic catalysis in the direct carbonylation of sp2 C–H bonds utilizing DMF as the carbon source under oxygen has been demonstrated in the synthesis of pyrido-fused quinazolinone and phenanthridinone scaffolds. Control experiments indicated that the carbon of the carbonyl group is derived from the methyl group of DMF and the oxygen originates from oxygen. Absence of a KIE indicates that C–H bond cleavage of the arenes is not the rate-limiting step.316 Pyrrolidine and indoline derivatives have been synthesized by a palladium-catalysed mild intramolecular aminoacetoxylation using molecular oxygen as the oxidant. A catalytic NOx species acts as an ET mediator to access a high-valent palladium intermediate as the presumed active oxidant (Scheme 26).317 NHAc PdII

NHAc

Me Me

O

II

Pd

+

N

N

O

Me AcOH

N Ac N

NO2

O

Ac2O

PdII

PdIV

OAc

NO 1/2 O2

Scheme 26

A palladium-catalysed direct thioetherification of quinolone derivatives with diaryl disulfides through decarboxylative C–S coupling has been achieved. The reaction proceeds smoothly under air in the presence of Pd(OAc)2 , phosphine, and Ag2 CO3 in DMSO. When some radical scavengers such as TEMPO or hydroquinone are present, the coupling product is not detected. It has been suggested that initially, an organometallic intermediate forms via decarboxylation reaction with silver salt. Subsequently, Pd(II) reacts with the diaryl disulfides to generate Pd(II)–sulfide species. After this, an aryl Pd(II) species is produced by a transmetallation reaction. Finally,

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the reductive elimination of the aryl Pd(II) species gives the target product and the Pd(0) species, which is converted by oxygen to Pd(II), thereby maintaining the catalytic cycle.318 A homogeneous Pd(II) catalyst, utilizing an amine ligand, TMEDA, converts terminal alkynes and alcohols to 2-alkynoates in high yields by an oxidative carbonylation process. This protocol has an increased substrate scope, avoids large excesses of alcohol substrate, and uses a desirable solvent. The catalyst employs oxygen as the terminal oxidant and can be operated under safer gas mixtures.319 The catalyst [(neocuproine)Pd(OAc)]2 [OTf]2 is known to catalyse aerobic oxidation of alcohols, However, high Pd loadings up to 10 mol% are required. This is caused in part by concomitant autoxidation of the ligand. It has been found that deuteration of the methyl substituents in neocuproine allowed the development of a catalyst system that increased the TON by 1.6–1.8 times. The turnover frequency of the catalyst is similar, as expected, but as inactivation of the catalyst through unwanted intramolecular C–H activation is retarded by the KIE, the deuterated catalyst has a longer lifetime.320 An effective Pd/C-catalysed oxidative N-dealkylation/carbonylation of various aliphatic as well as cyclic tertiary amines with alkynes has been described. The selective sp3 C−N bond activation of tertiary amines at the less steric side uses oxygen as a sole oxidant, and a plausible reaction pathway for the reaction is discussed.321 Oxidative N-dealkylation/carbonylation of tertiary amines using molecular oxygen as a sole oxidant and a Pd/C catalyst leads to the formation of tertiary amides. This protocol is free from ligands, additives, bases, and co-catalysts. Different tertiary amines as well as aryl iodides have been examined for this transformation, providing desired products in good to excellent yield. A probable mechanism has been suggested (Scheme 27).322 O R3R2N

ArI + CO

Pd0 Ar

O Pd I Ar

O R3R2N

R1CH2-NR2R3

Pd O

Ar

Pd I

Ar R1CHO 2 HI + 1/2 O2 = H2O + I2

Ar

R2

O Pd

N

R

R3R2N=CH-R1 +

H

3

R1

HI

Scheme 27

A regioselective catalytic CDC between simple thiols and enamines to construct 𝛽-amino sulfides has been achieved through the palladium-catalysed sp2 C–H functionalization with Cu(II) acetate and oxygen as oxidants. An external phosphine ligand

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was added to prevent poisoning of the palladium catalyst by the sulfuric reagents. The results of DFT calculation are consistent with formation of the E isomers of the 𝛽-amino sulfides, as found by experiment. A plausible Heck-type mechanism has been proposed.323 [RuCl2 (p-cymene)]2 -catalysed CDC reaction of various 1,2,3,4-tetrahydroquinolines and aryl aldehydes, in the presence of oxygen as an oxidant, resulted in the formation of 𝛽-benzylated quinolines. The reaction exhibited excellent functional group tolerance and chemoselectivity. Addition of BHT and ethene-1,1-diyldibenzene had little influence on product yields showing that reaction via a radical pathway is less likely. Mechanistic investigations support a monodehydrogenation-triggered 𝛽-benzylation mode of reaction.324 An efficient ruthenium-catalysed oxidation protocol, which enables smooth oxidation of a wide variety of primary, as well as secondary benzylic, allylic, heterocyclic, and aliphatic, alcohols with molecular oxygen as the primary oxidant, has been developed. Deuterium labelling studies on RCH2 OH and RCD2 OH revealed an intermolecular KIE of kH /kD = 6.73 indicative of rate-determining C–H bond cleavage. Oxidation of radical clock substrate cyclobutanol as a mechanistic probe yielded the 2e-oxidation product, cyclobutanone, exclusively, without any of the ring opening product 4-hydroxybutanal. Radical scavenger, TEMPO, did not affect the reaction rate. A mechanism involving in situ formation of an oxo–ruthenium intermediate as the active catalytic species in the cycle has been proposed (Scheme 28).325 Rhodium and copper efficiently co-catalysed C–H bond activation and annulations, involving an imidate ester and an alkyl azide, for the construction of quinazolines. [RuIIH(CO)Cl(PPh3)3] O2 PPh3

H2 O

PPh3

PPh3=O

[RuIIH(CO)Cl(PPh3)2] O2 O

OH2

[RuIVH(CO)Cl(PPh3)2]

[RuIIH(CO)Cl(PPh3)2]

ArCH2OH ArCHO

rate determining step

OH [RuIIH(CO)Cl(PPh3)2] +

+ [ArCHOH] Scheme 28

3 Oxidation and Reduction

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This [4 + 2] annulation strategy utilizing alkyl azides as the carbon-heteroatom synthons shows high efficiency in the synthesis of six-membered benzoheterocycles containing two heteroatoms. This aerobic oxidation protocol produces only nitrogen and water as by-products. Controlled experiments with benzonitrile, benzylamine, and benzoyl azide showed that these compounds are not intermediates in this reaction. A mechanism involving a rhodacyclic intermediate has been proposed.326

Other Oxidations Recent work on oxygenation of hydrocarbons, both saturated and aromatic, and other C–H compounds has been reviewed. Applications of new metal complexes and catalytic systems, soluble as well as solid, are discussed, and various oxidants such as molecular oxygen, HP, alkyl peroxides, and peroxy acids have been mentioned.327 Recent progress on precious-metal and transition-metal oxide catalyst systems for the oxidation of formaldehyde has been reviewed. Topics such as properties of oxidants, structure–activity relationships, and factors influencing the catalytic activity and reaction mechanism are discussed. Future prospects and directions for the development of such catalysts are also covered.328 Recent advances in the chemistry of Ni–NHC species have been reviewed. Novel Ni–NHC-catalysed transformations such as the CDC of aldehydes and amines or alcohols, the hydroamination of alkenes, hydroimination of alkynes, a one-step indoline synthesis, Tishchenko reactions, borylation of unsaturated C–C bonds and arenes, borylative cleavage of C–N bonds, hydrosilylation of C–O and C–N multiple bonds, reductive cleavage of aromatic C–O bonds, and anaerobic oxidation of alcohols have been discussed with a special emphasis on mechanistic apects.329 The work done in the area of pyrrole oxidation has been reviewed. Use of peroxide, singlet oxygen, hypervalent iodine reagents, a range of organic and inorganic oxidants, and electrochemical approaches are discussed. It has been pointed out that if substrates and oxidants are appropriately matched, good yields of synthetically useful intermediates can be obtained from oxidation of pyrrole.330 Recent achievements in the transition-metal-mediated CDC amination reactions with two types of hydrocarbon substrates, direct amination of acidic C–H bonds with parent amines and chelationassisted CDC amination/amidation of nonacidic C–H bonds, have been reviewed. Mechanistic aspects are also briefly delineated in representative amination reactions to provide insights for the future development of highly practical and environmentally benign processes.331 Computational studies on the dehydrogenation of amine-borane and alcohols and on the catalytic hydrogenation of carbon dioxide and small organic carbonyl compounds have been reviewed, with an emphasis on elucidating reaction mechanisms and predicting new catalytic reactions, and some general ideas for the design of high-efficiency, low-cost transition-metal complexes for hydrogenation and dehydrogenation reactions are provided.332 DFT calculations of dehydrogenation of formic acid catalysed by the bis(imino) pyridine-ligated aluminium hydride complex (PDI2− )Al(THF)H (PDI = bis(imino) pyridine) revealed that the reaction comprises two stages, catalyst activation and the catalytic cycle. The catalyst activation begins with O–H bond cleavage of HCOOH promoted by Al–ligand cooperation, followed by formic acid-assisted Al–H bond

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cleavage, and protonation of the imine carbon atom of the bis(imino)pyridine ligand. The imine carbon atom protonation step is relatively more difficult than the former two steps. The active catalyst of formic acid dehydrogenation is the aluminium complex with three HCOO− units and a twice-protonated PDI ligand. The catalytic cycle includes 𝛽-hydride elimination of (H,H PDI)Al(OOCH)3 to produce CO2 , and the formed (H,H PDI)Al(OOCH)2 H mediates formic acid to release hydrogen.333 Quinones are important organic oxidants, and they are susceptible to activation towards ET through hydrogen bonding. This effect of hydrogen bond donors (HBDs) has been observed for Lewis basic, weakly oxidizing quinines, but comparable activation is not readily achieved when more reactive and synthetically useful electron-deficient quinines are used. HBD-coupled ET as a strategy to activate electron-deficient quinines has been successfully employed. It has been discovered that certain dicationic HBDs have an exceptionally large effect on the rate and thermodynamics of ET and that these HBDs can be used as catalysts in a quinone-mediated model synthetic transformation.334 An organic halide has been utilized as an oxidant for Pd-catalysed CDC reactions. This class of oxidant enables the CDC of pyridines and provides a new convergent synthetic strategy as well as divergent access to various heterobiaryl structures. The regioselectivity of the pyridine functionalization site can be controlled by the choice of organic halides. The CDC reactions of pyridines with benzoxazoles took place at the C(3)-position of pyridine cores with aryl bromides, while the use of benzyl bromide completely switched the regiochemical outcome to the C(2)-selective CDC pathway.335 An organoiron catalyst combined with a mild organic oxidant, 1,2-dichloropropane, promotes both C–H bond cleavage and C–N bond formation and forms 2-pyridones and isoquinolones from an alkene- or arylamide and an internal alkyne, respectively. An unsymmetrical alkyne gives the pyridone derivative with high regioselectivity; this could be due to the sensitivity of the reaction to steric effects because of the compact size of iron.336 Mode-specific reactions of nonsilylated and silylated allenes with 2,3-dichloro5,6-dicyanobenzoquinone (DDQ) and/or TBHP in the presence of an iron catalyst have been reported. Trisubstituted allenes containing geminal aryl–aryl or aryl–alkyl substitution patterns provide indene/indanone derivatives, whereas silyl-substituted allenes, regardless of the nature of the other substituents, consistently generate 1,3-enynes as the major products with DDQ, and t-butylpropargylic peroxides with TBHP. The formation of different putative cationic intermediates from nonsilylated and silylated allenes is strongly supported by DFT calculations. A plausible mechanism for this iron-catalysed propargylic peroxide formation has been proposed.337 An efficient synthesis of 1-substituted barbaralones by gold(I)-catalysed oxidative cyclization of 7-(substituted ethynyl)-1,3,5-cycloheptatrienes has been achieved. The oxidants used were diphenyl sulfoxide and N-oxides of pyridine and substituted pyridines. This method has allowed accomplishment of the shortest syntheses of bullvalene and other substituted bullvalenes and a readily accessible route to complex cage-type structures by further gold(I)-catalysed reactions.338 An organocatalytic domino 𝛼-amination/oxidative coupling/cyclization of thioamides to azodicarboxylates has been achieved. The asymmetric reaction is smoothly effected using oxygen as the oxidant as well as using N-bromosuccinimide. This domino reaction affords chiral spiroannulated 1,2,3-thiadiazoles in high yields and enantioselectivities in

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the presence of an easily available organic catalyst. Added TEMPO had not much effect on the reaction. Thus, the reaction is not likely to involve a radical process.339 A CuBr/IMes⋅HCl [IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]-catalysed oxidative vicinal diphosphination of styrenes with diphenyl(trimethylsilyl)phosphine proceeds in the presence of LiOBut and a pyridine N-oxide/MnO2 combined oxidant to give the corresponding 1,2-bis(diphenylphosphino)ethanes in good yields. It has been proposed that CuBr is initially converted into IMesCuOBut by salt metathesis of LiOBut and coordination of the IMes generated in situ. Subsequently, a ligand exchange, driven by formation of an O–Si bond, forms IMesCuPPh2 (Scheme 29).340 Me3Si-OBut

Me3Si-PPh2, pyridine N-oxide and/or MnO2

IMesCuPPh2

Me3Si-PPh2 IMes.HCl LiOBut

CuBr

IMesCuX(PPh2)n

IMesCuOBut

Ph LiX

PPh2 IMesCuX LiOBut

Ph

PPh2

X=Br, Cl, or OSiMe3

Scheme 29

Using a strongly electron-donating, three coordinate, and sterically encumbered Ndonor ligand base, reduced titanium complex (ket guan)(𝜂 6 -ImDipp N)Ti has been synthesized. Although bond metrics support a formal Ti(IV) oxidation state assignment, this complex behaves as a masked form of low-coordinate Ti(II). It effects the intramolecular dehydrogenation of a peripheral isopropyl group upon standing in solution to give (ImDipp N)[(2,6-Pri 2 C6 H3 N)(2-Pri C6 H3 -6-(𝜂 2 -CH3 CCH2 )N)C-(NCBut 2 )]Ti, a transformation that can be reversed upon addition of hydrogen. Spectroscopic evidence points to a rare instance of sp3 C–H oxidative addition across titanium as a key step. Moreover, treatment with cyclohexene gives cyclohexane via transfer hydrogenation (TH). This dual reactivity is unprecedented for the early-metals but well established for the later d-block elements.341 The decay of 2,2-diphenyl-1-picrylhydrazyl (dpph) in absolute ethanol and in the presence of curcumin, 4-methylcurcumin, 4,4-dimethylcurcumin, or curcumin 4′ -methyl ether follows bi-exponential kinetics. The kinetics of the oxidation is compatible with a two-step process in which an intermediate accumulates in a reversible first step followed by an irreversible process. It has been hypothesized that the intermediate is a 𝜋-stacked complex, formed between one curcumin anion and the picryl moiety of dpph, in which

ee 

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an intra-complex ET from the anion takes place. Comparison of the kinetics of curcumin 4′ ,4′′ -dimethyl ether, curcumin 4′ -methyl ether, and curcumin indicated that the ET process is accompanied by a simultaneous proton transfer from the phenolic OHs to the bulk solvent, that is a separated coupled proton–ET.342 Regularities in liquid-phase oxidation in the alkyl aromatic hydrocarbons and their cyclohexyl derivatives to hydroperoxides in the presence of phthalimide catalysts have been studied. It is established that NHPI increases the speed of oxidation of these hydrocarbons and provides high selectivity of formation of their hydroperoxides.343 The mechanistic aspects of ethylene addition to MO2 (CH2 )(CH3 ) (M = Co, Rh, Ir) have been investigated with a Hartree–Fock/DFT hybrid functional at the MO6/ LACVP* and B3LYP/LACVP* levels of theory to elucidate the reaction pathways on the singlet, doublet, and triplet potential energy surfaces. The reactions of olefins with the cobalt dioxo complex have lower activation barriers for the preferred [3 + 2] and [2 + 2] addition pathways as compared to those of the rhodium and iridium systems. This implies that the cobalt complexes may be better catalysts for the specific oxidation reactions of olefins than the rhodium and iridium complexes are.344 DFT calculations of the ruthenium- and rhodium-catalysed oxidative spiroannulation of naphthols and phenols with alkynes showed that the reaction undergoes O–H deprotonation/sp2 C–H bond cleavage through a concerted metallation–deprotonation mechanism/migratory insertion of the alkyne into the metal–C bond to deliver the eight-membered metallacycle. However, the dearomatization through the originally proposed enol–keto tautomerization/C–C reductive elimination is calculated to be kinetically inaccessible. Alternatively, an unusual metallacyclopropene, generated from the isomerization of the eight-membered metallacycle through rotation of the C–C double bond, has been identified as a key intermediate to account for the experimental results. The calculations reproduce quite well the experimentally observed formal 5 + 2-cycloaddition in the rhodium-catalysed oxidative annulation of 2-vinylphenols with alkynes.345 An overall 4𝜋 + 2𝜋-cycloaddition reaction that generates a different, highly reactive intermediate known as an 𝛼,3-dehydrotoluene has been reported. This species is in the same oxidation state as a benzyne. Similar to benzynes, 𝛼,3-dehydrotoluenes can be captured by various trapping agents to produce structurally diverse products that are complementary to those arising from the hexadehydro-Diels–Alder process. This cycloisomerization process has been named as pentadehydro-Diels–Alder process.346 Investigation of the role of alkali in liquid-phase catalytic oxidation of p-cresols to p-hydroxyl aromatic aldehydes indicated that p-cresols were activated by alkali to form phenolate salt. It was also found that excess alkali improved the selectivity of aldehyde by inhibiting the formation of dimeric side products. The detection of trace acid during the oxidation of p-cresols suggested the phenoxy radical mechanism rather than the classic benzyl radical mechanism proposed for interpreting the oxidation of non-hydroxyl aromatic hydrocarbons.347 Primary alcohols have been reacted with hydroxide and the ruthenium complex [RuCl2 (IPri )(p-cymene)] to afford carboxylic acids and dihydrogen. The KIE has been determined to be 0.67 using 1-butanol as the substrate. A plausible catalytic cycle has been characterized by DFT/B3LYP-D3 and involved coordination of the alcohol to the metal, 𝛽-hydride elimination, hydroxide attack on the coordinated aldehyde, and a second 𝛽-hydride elimination to furnish the carboxylate.348

3 Oxidation and Reduction

159

Rate coefficients for reactions of OH and Cl radicals with vinyl and allyl butyrate have been determined, using the relative method, and reactivity trends and atmospheric lifetimes of esters have been determined. Butyric acid and polyfunctional compounds are products of the reactions of vinyl and allyl butyrate, respectively, and a general mechanism has been proposed.349 Structurally tunable boron complexes supported by N-heterocyclic imine ligands have been synthesized. By linking one such imine unit with an electron-deficient borane, a new class of intramolecular frustrated Lewis pair (FLP) has been developed that has the ability to rapidly dehydrogenate various amine-boranes under ambient conditions and instigate their dehydrocoupling.350 An unstable cyclic intermediate, formed by the base-mediated C-arylation of 2-nitro-N-alkyl-N-(2-oxo-2-phenylethyl) benzenesulfonamides and subsequent N–N bond formation, has been converted to 2-alkyl-2H-indazol-3-yl benzoates. The transformation occurred via the acid-mediated intramolecular BV oxidation of a ketone to an ester in which N-oxide served as the internal oxidant. No external oxidant was used. This synthetic route provides access to 2-alkyl-2H-indazol-3-yl benzoates and 2-alkyl-1,2-dihydro-3H-indazol-3-ones.351 DFT calculations of the mechanism of oxidative addition of chlorobenzene to abnormal NHC-Pd complexes in a Suzuki–Miyaura cross-coupling reaction showed that the dimeric Pd(II) system, used in experiments, is a pre-catalyst. Active catalyst is generated in situ in a base-assisted reaction. Formation of the Pd(0) catalyst from the Pd(II) species was found to be energetically demanding, and a Pd(II)/PD(IV) pathway is found to be more favourable. Three possible pathways have been examined.352 A borane-catalysed, metal-free acceptorless dehydrogenation of saturated N-heterocycles has been reported. Tris(pentafluorophenyl)borane has been identified as a versatile catalyst, which afforded several synthetically important N-heteroarenes in up to quantitative yield. This metal-free catalytic system exhibited a uniquely high tolerance towards sulfur functionalities and demonstrated superior reactivity in the synthesis of benzothiazoles compared to conventional metal-catalysed systems.353 N-Protected indulines and other substrate classes have been synthesized by an acceptorless dehydrogenation of heterocycles catalysed by FLPs. Liberation of hydrogen with concomitant oxidation proceeds in excellent yields. The mechanism has been elucidated through KIE, characterization of reaction intermediates by NMR spectroscopy and X-ray crystal analysis, and by quantum-mechanical calculations. Hydrogen liberation from the ammonium hydridoborate intermediate is the rate-determining step of the oxidation. The addition of a weaker Lewis acid as a hydride shuttle increased the reaction rate.354

Reduction by Complex Metal Hydrides A novel B–B bond activation mode has been designed by DFT calculation and verified experimentally. In this new mode, two molecules of the Lewis base, 4-cyanopyridine, are coordinated to the two boron atoms of bis(pinacolato)diboron, B2 (pin)2 , and then the B–B bond is homolytically cleaved to generate two boryl radicals which are stabilized by the captodative effect and confirmed by free-radical trapping and EPR experiments. With this novel activation mode, the catalytic reduction of azo compounds and quinones, and deoxygenation of sulfoxides to sulfides, was achieved under mild conditions.355 DFT

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calculations on the Suzuki–Miyaura coupling of N-benzyl-N-t-butoxycarbonyl amides with pinacolato boronate, in the presence of K3 PO4 and water, showed that the most favourable pathway comprises four basic steps viz., oxidative addition, protonation, transmetallation, and reductive elimination. Base K3 PO4 and water play crucial roles in the rate-determining transmetallation step.356 A computational study of the regioand stereo-selectivity of hydroboration of dienes showed that 1,3-cyclohexadiene does not follow the anti-Markovnikov rule. This has been attributed to stabilization of the transition state due to conjugation with the allyl double bond and the specific geometric features of the cyclohexane ring. The stereoselective outcome of the reaction is governed by Re-face attack and steric influences of substituents on the diene.357 Aromatic 𝛼,𝛽-unsaturated carbonyl compounds undergo copper(I) iodide-catalysed conjugate addition of B2 pin2 and reduction to give saturated carbonyl compounds in excellent yields. Formation of a borylated copper enolate intermediate has been proposed (Scheme 30).358 O

Cu-B(pin)2 Ph

R

B2(pin)2 base Ph B(pin)2

CuI proton source

O R

O Cs2CO3

Ph

R

MeOH

R

Cu

Ph O

B(pin)2

Scheme 30

Simple ruthenium precursor [Ru(p-cymene)Cl2 ]2 -catalysed regioselective 1,4-dearomatization of pyridine derivatives using pinacolborane has been reported. Tricyclohexyl phosphine (PCy3 ) has been found to be a highly suitable ligand. Two catalytic intermediates, [Ru(p-cymene)Cl2 py] and [Ru(p-cymene)Cl2 (PCy3 )], involved in this process have been identified, independently synthesized, characterized, and further used directly as effective catalysts. Two other catalytic intermediates, [Ru(p-cymene)Cl2 (py)(PCy3 )] and [Ru(p-cymene)(H)Cl(py)(PCy3 )], were identified in solution. The active catalytic intermediate is the last mentioned complex. It is proposed to achieve regioselective 1,4-hydroboration of pyridine compounds by undergoing intramolecular selective

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3 Oxidation and Reduction

1,5-hydride transfer.359 Diborane-mediated deoxygenation of o-nitrostyrenes, in the presence of potassium fluoride, results in the formation of indoles through a reductivecyclization reaction which benefits from electron withdrawal by para substituents, as evidenced by a Hammett 𝜌-value of +0.97. It has been suggested that generation of a nitrosoarene borane and a borate anion is followed by reaction with a second equivalent of B2 pin2 whereupon KF-mediated deboronation produces a nitrosyl anion. Cyclization with the o-alkenyl substituent is proposed to occur through a 6𝜋-electron-5-atom electrocyclization. The resulting C(3)-benzyl anion then eliminates OBpin to produce 2H-indole from which the indole product is obtained by a 1,5-hydride shift.360 Light alkali metal hydridotriphenylborates M[HBPh3 ] (M = Li, Na, K), characterized as tris{2-(dimethylamino)ethyl}amine (L) complexes, [(L)M]-[HBPh3 ], act as efficient catalysts for the chemoselective hydroboration of a wide range of aldehydes and ketones using pinacolborane, HBpin. Carbonyl compounds such as benzophenone and benzaldehyde are readily inserted into the B–H bonds to give alkoxyborates, which were characterized in situ by solution NMR spectroscopy. These compounds also catalyse the hydroborative reduction of CO2 to give formoxyborane HCO2 Bpin without any over-reduction.361 A series of base-stabilized silylium species have been synthesized and their reactivity towards CO2 explored, resulting in characterization of a novel N/Si+ FLP-CO2 adduct (3). These silicon species are active catalysts in the hydroboration of CO2 to the methoxide level with 9-borabicyclo[3.3.1]nonane, catecholborane, and pinacolborane. Both experiments and DFT calculations indicated active participation of FLP-CO2 adduct in the catalysis. Depending on the nature of the hydroborane reductant, two distinct mechanisms have been unveiled.362 R O

C N

O +

Si

R

N

N (3)

Diastereoselective hydroboration of 5-enoglycopyranosides is a crucial step of the synthesis of l-pyranosides from d-sugar. It has been demonstrated that the reactions of various suitably protected 5-enopyranosides with borane afforded mixtures of d-gluco and l-ido pyranosides in a ratio highly dependent on the protecting groups used at C(4) of the glucose substrate. It was revealed that the reaction of 𝛼-configured monosaccharides and disaccharides possessing small substituents at C(4) (OH, OMe) delivers l-ido pyranosides with high yield and stereoselectivities. Particularly, application of these guidelines for the hydroboration of methyl 2,3-O-methyl-6-deoxy-𝛼-d-xylohex-5-enopyranoside resulted in exclusive formation of l-ido product. It is rational as the formation of required l-ido product occurs via the attack of electrophile at C(5) from the opposite side to the C(4) substituent as well as the anomeric substituent at C(1).363

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A sequential retro-Henry reduction of 2-nitroalcohols by sodium borohydride results in the formation of corresponding alcohols and nitroalkanes in 77–99% yield. The reaction is useful in chemoselective reduction of 𝛼,𝛽-unsaturated aldehydes and ring opening of cyclic t-𝛽-nitroalcohols to open chain sec-nitroalcohols. Experimental studies on the mechanism of reaction showed that sodium borohydride may be reducing the aldehyde formed initially, via retro-Henry reaction of 2-nitroalcohols, catalysed by in situ-generated base, to alcohol.364 Primary alcohols have been deoxygenated cleanly and in yields of 60–95% by reduction of derived diphenyl phosphate esters with lithium triethylborohydride in THF at room temperature (Scheme 31). Selective deoxygenation of a primary alcohol in the presence of a secondary alcohol was demonstrated.365 O (PhO)2P(O)Cl

HO

R

−HCl

O

P O

O

R

H

−

BEt3 Li+

H

R

Scheme 31

A series of C(5)-bromo-d-glucuronides were subjected to tributyltin hydride-mediated radical reduction to give a mixture of l-ido and d-gluco configured products. It was found that the diastereomeric product ratio was dependent on the reaction temperature and the nature and configuration of the anomeric substituent. The reduction of the C(5)-bromo-d-glucuronyl 𝛽-fluoride gave exclusively the l-ido product, whereas the Omethyl or O-acetyl derivatives led to isomeric mixtures of both the l-ido and d-gluco products in different ratios. DFT calculations show that the l-ido selectivity obtained with the 𝛽-F derivative originates from a combination of a transition state gauche effect and an Sn–F interaction.366

Hydrogenation The current level of understanding of the mechanism of enantioselective hydrogenation and TH of aromatic ketones with pioneering prototypes of bifunctional catalysts, the Noyori and Noyori–Ikariya complexes, has been reviewed. The concept of metal–ligand cooperation has been expanded, and the term ‘cooperative ligand’ has been redefined, and H− /H+ outer-sphere hydrogenation as a novel paradigm in outer-sphere hydrogenation has been explained.367 Catalytic hydrogenolysis of the C–C 𝜎 bond as an alternative reduction methodology has been reviewed. It has been pointed out that strategies beyond ring-strain relief and chelation-assistance are still to be explored and that the catalytic hydrogenolysis of unfunctionalized C(sp3 )–C(sp3 ) bond in a selective manner under mild conditions is the ultimate challenge in this area.368 The design, synthesis, and applications of tethered versions of the Ru(II)/N-tosyl-1,2diphenylethylene-1,2-diamine (TsDPEN) class of catalysts that are commonly used for asymmetric hydrogenation (AH) and asymmetric transfer hydrogenation (ATH) of

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ketones and imines have been reviewed. The review covers key aspects of the reaction mechanisms and examples of applications. In addition, closely related catalysts based on Rh(III) and Ir(III) are also described.369 Advances in the construction of chiral heterocycles and carbocycles, including cyclic amines, ethers, alcohols, and alkanes, via the AH of non-aromatic cyclic substrates, including prochiral cyclic imines, ketones, and alkenes, using appropriate transition-metal complexes, have been reviewed. Various challenges in the field are also discussed.370 DFT-B3LYP method calculations of the hydrogenation mechanism and energy of Cn and Cn Hn fullerene cages, where n = 20–60, revealed that the stable hydrogenation sites on the Cn fullerene cages are 5/5/5 and 5/6/5/ and on the Cn Hn fullerene cages are 6/6/6, 6/7/6, and 6/7/5. The energy required to initiate hydrogen migration on the surface of Cn fullerene cages between two metastable structures of C54 H has also been calculated.371 Activation of hydrogen by geminal aminoborane-based FLPs has been computated by DFT. It is found that the activation barrier of this process and the geometry of the corresponding transition states strongly depend on the nature of the substituents directly attached either to the acidic or the basic centres of the FLPs. An activation strain model of reactivity combined with the energy decomposition analysis method suggested a highly orbital-controlled mechanism where the degree of charge transfer cooperativity between the most important donor–acceptor orbital interactions, namely LP(N) → 𝜎 * (H2 ) and 𝜎(H2 ) → p𝜋 (B), along the reaction coordinate constitutes a suitable indicator of the reaction barrier.372 Kinetics of the autoinduced FLP-catalysed hydrogenation of several benzene-ring substituted N-benzylidene-t-butylamines with less Lewis acidic B(2,6-F2 C6 H3 )3 and hydrogen has been studied. The pKa values for imines and for the corresponding amines were determined by quantum-mechanical methods and provided a direct proportional relationship. Correlation of the two rate constants k1 (simple catalytic cycle) and k2 (autoinduced catalytic cycle) with pKa difference between imine and amine pairs or Hammett’s 𝜎 value served as useful parameters to establish a structure–reactivity relationship for the FLP-catalysed hydrogenation of imines. The values of Hammett’s 𝜌, −3.77 for imines and −1.67 for amines, indicate increasing incipient positive charge in concert with stabilization of the protonated species.373 A nickel complex with NHC has been shown to catalyse selectively C–O bond hydrogenolysis of aryl methyl ether to yield arene and alcohol. DFT calculations showed that the catalytic cycle comprises four steps, the C–O bond oxidative addition being rate-determining. Aromatic C–O bond cleavage is more favourable than the aliphatic C–O bond cleavage, as evidenced by formation of arene and alcohol experimentally.374 DFT calculations of the Ni–NHC-catalysed hydrogenolysis of aryl ethers suggest a new mechanistic pathway which involves coordination of the excess base (t-BuO− ) to facilitate the rate-determining C–O activation step, dissociation of the ArO–ligand bond, hydrogen activation through a Ni–OBut bond to give t-BuOH, and finally reductive elimination to afford the arene product (Scheme 32).375 DFT calculations of hydrogenation of propylene catalysed by a series of aliphatic PNP cobalt pincer complexes, [(PNRPPri )CoH]+ and [(PNPPri )CoH], revealed that a propylene molecule first inserts into the Co–H bond to form a Co–C bond. Then, a hydrogen molecule is inserted into the Co–C bond for the formation and release of

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Organic Reaction Mechanisms 2016 t-BuO− L

ButOH

PhH

Ni

Ph H excess base

Ni(L)OBut PhOPh L

PhO Ph Ni OBut

L Ph But

Ni O

H

PhO−

L S NAr-like

H

Ph-Ni-OBut OPh

L Ph-Ni-OBut H2

PhO− Scheme 32

propane. The mechanism of acceptorless dehydrogenation of alcohols, using these catalysts, has also been elucidated.376 Use of chiral oxazoline iminopyridine–cobalt complexes as precatalysts and NaHBEt3 as catalyst in the AH of 1,1-diarylethenes resulted in the synthesis of various chiral 1,1-diarylethanes with excellent enantioselectivities (up to 99% ee). A unique o-chloride effect leading to high enantioselectivity was observed.377 High activities and enantioselectivities were observed in the AH of substituted benzofused five-, six-, and seven-membered alkenes with a C(1)-symmetric bis(imino)pyridine cobalt catalyst. The stereochemical outcome was dependent on both the ring size and exo/endo disposition. Deuterium-labelling experiments support a rapid and reversible 2,1-insertion that is unproductive for generating alkane product but accounts for the unusual isotopic distribution in deuterated alkanes. Analysis of the stereochemical outcome of the hydrogenated products coupled with isotopic labelling, stoichiometric, and kinetic studies established 1,2-alkene insertion as both turnover limiting and enantiodetermining. A stereochemical model accounting for the preferred antipodes of the alkanes is proposed and relies on the subtle influence of the achiral aryl imine substituent on the cobalt catalyst.378 Hydrogenation of C=C, C=N, and C=O bonds has been achieved using readily accessible and inexpensive Pri 3 SnOTf as a main-group Lewis acid (LA) catalyst, along with 2,4,6-trimethylpyridine as a base. Hydrogenation of C=O by this protocol displays an unparalleled level of tolerance to water. A mechanism involving a hydride transfer to the ketone-LA adducts has been suggested (Scheme 33).379 Iron-based homogeneous catalysts bearing a bis(phosphino)amine pincer ligand promote hydrogenation of alkenes containing polarized C=C double bonds. Electronwithdrawing p-substituents in styrene enhance the rate. The reaction is tolerant of

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3 Oxidation and Reduction Pri3SnOTf Me2CO

Pri3SnH

Pri3SnOTf + LB

+

Pri3Sn

O Pri3SnOTf

Me HO Me

Me

H Me

Pri3SnH + LB+ −H − OTf

− OTf

SnPri3 Me Me

O H Me

Me O Pri3Sn

LB+ −H

H

+

O

OTf Me

H2

H Me

− OTf

LB

LB = 2,4,6-trimethylpyridine Scheme 33

ester, cyano, and N-heterocycle functions. A stepwise metal–ligand cooperative pathway of Fe–H hydride transfer, resulting in an ionic intermediate, followed by N–H proton transfer from the pincer ligand to form the hydrogenated product, has been suggested.380 Mechanisms associated with the hydrogenation of alkenes catalysed by the iron complex Fe(cis-CO)2 {o-(SiMe2 )2 C6 H4 }2 (H)2 have been investigated by DFT calculations. The exchange of a 1,2-bis(dimethylsilyl)benzene ligand with ethylene and hydrogen gives a disilaferracycle bearing 𝜂 2 -(CH2 =CH2 ) and 𝜂 2 -H2 ligands. The catalytic cycle initiated from the disilaferracycle involves cleavage of a H–H linkage assisted by an Fe–Si bond to form Fe–H and 𝜂 1 -(H–Si) moieties, hydrogen migration from the Fe–H group to the 𝜂 2 -(CH2 =CH2 ) ligand (which accomplishes the insertion of ethylene into the Fe–H bond), and reaction of the resulting 𝛽-agostic ethyl moiety with the 𝜂 2 -(H–Si) group to form ethane on the iron atom. The reactions correspond to the 𝜎-complex-assisted metathesis mechanisms.381 The combination of Mn(CO)5 Br with [HN(CH2 CH2 P(Et)2 )2 ] leads to a mixture of cationic and neutral manganese PNP pincer complexes, which catalyse hydrogenation of various ester substrates, including aromatic and aliphatic esters as well as diesters and lactones. Based on computational studies, a mechanism has been suggested (Scheme 34).382 A chemoselective C–O bond cleavage of the ester alkyl side chain of 𝛼-acyloxy ketones has been realized by a highly efficient palladium-catalysed hydrogenolysis. A variety of substrates have been investigated with almost quantitative conversions.

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Organic Reaction Mechanisms 2016 H H O Ph O Ph

MeOH

H

E

N

OMe

CO

E

Ph

H

H

OH OMe

Ph

CO H2

H

O

Mn

E

N

Ph

H OH

Mn E = PEt2

E

CO CO

Scheme 34

Furthermore, a kinetic resolution of 𝛼-acyloxy ketones has been developed by enantioselective hydrogenolysis with good yields and up to 99% ee.383 Linear chiral alkyl-substituted fluorinated hydrazines have been synthesized through AH of N-acylhydrazones, catalysed by [Pd(R)-TBMSegPhos(OCOCF3 )2 ] in excellent yields with up to 94% enantioselectivity. The reductive amination between trifluoromethyl-substituted ketones and benzohydrazides was also achieved with slightly lower enantioselectivity.384 Kinetics of Pd-catalysed hydrogenolysis of Nbenzyl-4-fluoroaniline has been investigated in a semi-batch reactor. The effects of various operating parameters have been examined to identify factors that influence the reaction pathways. Langmuir–Hinshelwood mechanistic models are evaluated by regressing the experimental data to determine the appropriate reaction expression for the debenzylation reaction. Kinetics of defluorination of 4-fluoroaniline has also been obtained.385 A number of cyclic prochiral olefins have been hydrogenated successfully (>99 conversion, up to >99% ee) using novel N,P-ligated iridium catalysts. The substituent on the aryl ring flanking the imidazole ring of the ligand was found to have a significant influence on the enantioselectivity of the catalyst, a 2,4-dimethylaryl group being most effective. Minimally functionalized substrates and those having functional groups not directly attached to the cycle are hydrogenated rapidly and with high ee. Substrates having functional groups and heterocycles attached to the unsaturated cycle are hydrogenated more slowly, but high enantioselectivity is maintained. Mechanistic insight aided in rationalizing the stereochemical outcome of the reaction.386 An iridium complex of a monodentate phosphoramidite ligand catalyses a highly efficient and direct asymmetric reductive amination of arylacetones to yield enantiomerically pure 𝛽-arylamines. The complex exhibits superb reactivity (TONs of up to 20 000) and enantioselectivity (up to 99% ee). TFA as an additive significantly improved the reaction rate and enantioselectivity.387 It has been observed that the MaxPHOX–Ir catalyst system provides a high selectivity in the AH of cyclic enamides derived from 𝛼- and 𝛽-tetralones, outperforming Ru and Rh catalysts. These results indicate that iridium catalysts can be proficient in

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3 Oxidation and Reduction

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the reduction of alkenes bearing metal-coordinating groups. For the present system, selectivity was pressure dependent; in most cases, lowering of the hydrogen pressure to 3 bar resulted in an increase in enantioselectivity.388 The catalytic AH of alkyl quinoxaline-2-carboxylates has been achieved in the presence of in situ generated iridium catalysts bearing chiral phosphines. A series of ligands were screened using an automated high-throughput platform. Atropisomeric ligands appeared to be the most suitable ones for this transformation. High conversions (up to 97%) could be obtained. The highest enantioselectivity of 74% ee was attained for the hydrogenation of methyl quinoxalin-2-carboxylate with a 10 mol% catalyst loading.389 Hydrogenation of unfunctionalized exocyclic C=C bonds has been carried through an iridium-catalysed process using an axially flexible chiral phosphine–oxazoline ligand to provide the desired chiral 1-benzyl-2,3-dihydro-1H-indene products with up to 98% ee. The additive acetate ion plays an important role in the high enantioselectivity of the reaction.390 Stable cationic iridium (COD) (COD = cis-cycloocta-1,5-diene) complexes with different P,S ligands are found to be good pre-catalysts for the AH of minimally functionalized olefins in terms of activities and enantioselectivities. For many substrates, the ligand fine-tuning enabled achievement of good to excellent levels of enantioselectivity, underlining their promising potential.391 Iridium(I) complexes with phosphine-phosphate (P-OP) ligands efficiently catalyse the AH of diverse seven-membered C=N-containing heterocyclic compounds with up to 97% ee. The enantioselectivity has been rationalized by means of DFT calculations, which identified the position of the Cl ligand in the catalytically relevant iridium structures and a number of non-covalent interactions as key features in rationalizing the stereochemical outcome of the reactions with the ligands.392 N-Benzyl-2-arylpyridinium bromides are hydrogenated with full conversion and good enantioselectivity in the presence of an iridium catalyst based on a mixture of a chiral monodentate phosphoramidite and an achiral phosphine. Kinetic measurements and isotopic-labelling experiments suggest that the hydrogenation starts with a 1,4-hydride addition and that the enantiodiscriminating step involves the reduction of an iminium intermediate.393 The directed chemoselective hydrogenation of olefins has been achieved using iridium(I) catalysts, which feature a tuned NHC/phosphine ligand combination. This selective reduction process has been demonstrated in a wide array of solvents, including more environmentally acceptable media.394 The iridium catalyst, [IrCl(COD)]2 -phosphine-I2 , selectively hydrogenated isoxazolium triflates to isoxazolines or isoxazolidines. High to good enantioselectivity is achieved when an optically active phosphine–oxazoline ligand is used. Mechanistic studies indicate that the hydridoiridium(III) species preferentially delivers its hydride to the C(5) atom of the isoxazole ring. The hydride attack leads to the formation of the chiral isoxazolidine via a 3-isoxazoline intermediate. In the selective formation of 4-isoxazolines, hydride attack at the C(5) atom may be obstructed by steric hindrance from the 5-aryl substituent.395 An iridium complex with a chiral spiro amino-phosphine ligand having a dimethyl group at the benzylic position efficiently catalysed the hydrogenation of both 𝛽-aryl-𝛽-methyl-nitroalkenes and 𝛽-alkyl-𝛽-methyl-nitroalkenes to the corresponding saturated nitroalkanes in excellent yields (up to 96%) and enantioselectivity (up to 94% ee).396 A series of modular and electron-donating tridentate ferrocene aminophosphoxazoline ligands have been successfully developed and used in iridium-catalysed

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Organic Reaction Mechanisms 2016

AH of simple ketones to afford corresponding enantiomerically enriched alcohols under mild conditions with superb activities and excellent enantioselectivities (up to 1 000 000˜TON, up to >99% ee, and full conversion). DFT calculations have been applied to gain insights into mechanism and the origins of enantioselectivity.397 Computational studies showed that enantioselective hydrogenation of linear enones, catalysed by iridium complexes that bear a chiral P,N ligand, involves a coordination of the substrate. In the favoured pathway, iridium stays in the +3 oxidation state throughout the entire catalytic cycle. The calculated path rationalizes the observed enantioselectivities and allows the development of a predictive quadrant model for this class of substrate-ligand.398 High-level ab initio coupled cluster and DFT calculations with a simplified model of Pfaltz’s Ir/P,N-type catalyst, for all four previously proposed Ir(I)/Ir(III) and Ir(III)/Ir(V) mechanisms of olefin hydrogenation, have been compared. The three best-performing density functionals (DFs) are B2-PLYP, BP86, and TPSSh; double-hybrid functional B2-PLYP-D3 has a balanced and outstanding performance, whereas BP86-D3 and TPSSh-D3 methods have outstanding but relatively less uniform performances.399 A wide range of 1,8-naphthyridine derivatives have been effectively hydrogenated to give 1,2,3,4-tetrahydro-1,8-naphthyridines with up to 99% ee and full conversions in the presence of chiral cationic ruthenium diamine complexes as catalyst. A cyclic 10membered transition structure with the participation of the TfO anion for the AH of 1,8-naphthyridines has been proposed. For substrates bearing an alkyl or aryl group at the 2-position, the enantioselectivity originates from the CH-𝜋 interaction between the 𝜂 6 -arene ligand in the ruthenium complex and the fused pyridine ring.400 The development of a tailored tridentate ligand, triphos 𝜂 4 -trimethylenemethane, enabled the synthesis of a molecular ruthenium-triphos catalyst, which avoids dimerization as the major deactivation pathway. This resulted in a significant improvement in the performance of this catalyst in ester hydrogenation, and the challenging reduction of lactams to cyclic amines has been achieved.401 The 𝜂 6 -arene/N-methylsulfonyldiamine-Ru(II)-BF4 complex (4)-catalysed AH of 2-substituted unprotected indoles in weakly acidic hexafluoroisopropanol (HFIP) gives optically active indoline compounds with up to >99% ee. Halogen atoms and synthetically important protecting groups, for example, silyl ether, acetal, benzyl ether, and ester, are tolerated. Deuterium-labelling experimental results proved that unprotected indoles are activated in the weakly acidic HFIP solvent to form an iminium intermediate, and these complexes hydrogenate the iminium intermediate quite effectively to provide asymmetric indoline synthesis. This highly efficient AH is Rn

RO2S

N

Ru BF 4 H N Me

Ph Ph (4)

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3 Oxidation and Reduction

169

believed to occur through cooperation between ruthenium-hydride and amine-NH in the concerto catalysis. A transition state has been proposed.402 Enantio- and diastereo-selective hydrogenation of 𝛽-keto-𝛾-lactams with a rutheniumBINAP catalyst, involving dynamic kinetic resolution, has been employed to provide a general, asymmetric approach to 𝛽-hydroxy-𝛾-lactams. Full conversion to the desired 𝛽-hydroxy-𝛾-lactams was achieved with high diastereoselectivity (up to >98% de) by addition of catalytic HCl and LiCl, while 𝛽-branching of the ketone substituent demonstrated a pronounced effect on the modest to excellent enantioselectivity (up to 97% ee) obtained.403 A novel AH of vinylthioethers has been developed using a Ru(II)-NHC catalyst prepared in situ from [Ru(COD)(2-methylallyl)2 ], (R,R)-SINpEt⋅HBF4 , and KOBut . This method provides an efficient approach to optically active 1,5-benzothiazepines featuring stereocentres with C–S bonds. Excellent enantioselectivities (up to 95% ee) and yields (up to 99%) were obtained for a variety of substrates bearing a range of useful functional groups.404 Hydrogenation cum alkoxylation and amination of substituted phthalimides/succinimides using a [Ru/Triphos]-based catalyst system has been reported. N-Substituted phthalimides react with a wide range of alcohols and amines, thus affording the corresponding 2-substituted isoindolinones in good to excellent yields. For aryl-ring substituted phthalimides, an excellent selectivity for the reduction of one of the carbonyl groups has also been achieved. This methodology avoids hydrogenation of the aromatic ring.405 Cyclic tertiary amines have been synthesized by hydrogenation of simple lactam substrates and secondary alcohols in high yield with excellent selectivity using the [Ru(triphos-xyl)(tmm)] catalyst. Mechanistic investigations suggested an initial C−N bond cleavage, followed by N-alkylation of the amino alcohols, thus yielding, formally, C=O bond cleavage products. An alcohol can also be used as a hydrogen transfer reagent.406 A highly enantioselective synthesis of indolines by AH of 1H-indoles and 3H-indoles at ambient temperature and pressure, catalysed by chiral phosphine-free cationic ruthenium complexes, has been developed. Excellent enantio- and diastereo-selectivities (up to >99% ee, >20:1 dr) were obtained for a wide range of indole derivatives. On reduction of 2-methylindole with D2 , the incorporation of deuterium was observed only at the 2-position. Results indicate that the reaction proceeds through the generation of an iminium salt, on C(3) protonation by the in situ generated TfOH acid, which is subsequently reduced by the ruthenium complex to afford the desired indolines.407 A DFT study of the formation of ethanol on hydrogenation of ethyl acetate catalysed by Gusev’s SNS ruthenium complexes indicated a direct hydride transfer involving two cascade catalytic cycles via the intermediate aldehyde. In the first cycle, three different pathways for the key step of C–OEt bond cleavage have been discussed. It was found that the ion-pair-mediated metathesis pathway has the lowest energy barrier. However, the direct hydride transfer from ruthenium to the carbonyl carbon atom was still the rate-determining step. The proposed mechanism features ethanol-assisted proton transfer for hydrogen cleavage.408 A ruthenium(II) complex with 1,3-bis(diphenylphosphino)propane has been developed for the catalytic highly chemoselective hydrogenation of aldehydes with a TON up to 340 000. It can be performed without base and solvent and tolerates the presence of alkenyl and ketone groups. DFT calculations, using the B3LYP-D3 method, revealed

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that the hydrogenation step is rate-determining, not the carboxylate-assisted hydrogen activation step.409 Imines have been subjected to hydrogenation and TH, catalysed by tethered Ru–S complexes. 1,5-Dimethoxycyclohexa-1,4-diene and a Hantzsch ester have been employed as the source of dihydrogen in the TH. Quantum chemical calculations indicated that the two processes follow different mechanisms. In the hydrogenation reaction, the cationic Ru–S complex activates dihydrogen cooperatively to afford the adduct H–Ru⋅⋅⋅S–H. In the TH reaction, the same complex acts as a Lewis acid. Hydride abstraction from the dihydrogen source yields a neutral Ru–H complex and the corresponding Wheland intermediate, and then dihydrogen is released after a facile proton/hydride recombination. With an imine substrate present, proton transfer onto the imine nitrogen from either the protonated sulfur atom or the Wheland complex is followed by hydride transfer from the neutral Ru–H complex to arrive at the amine product.410 Rhodium complex with a chiral f-spiroPhos ligand efficiently catalyses AH of N-substituted diarylmethanimines to chiral diarylmethylamines,411 𝛼,𝛽-unsaturated nitriles bearing an ester or amide group to the corresponding chiral nitriles,412 and 𝛽-aryloxy/alkoxy cinnamic nitriles and esters to chiral 𝛽-oxyfunctionalized nitriles413 with excellent enantioselectivities (>99% ee) and high TON (4000–50 000). AH of 4-substituted cyclic enamido esters for the preparation of 4-substituted oxazolinones catalysed by Rh/TangPhos complex has been carried out with good enantioselectivities and high yields.414 AH of unprotected 𝛽-enamine phosphonates to free 𝛽-amino phosphonates directly with good enantioselectivities (80–86% ee) and high conversions (>99% conversion) has been achieved with Rh-TaniaPhos catalyst.415 AH of 𝛽-amino nitroolefins has been achieved by rhodium/bis(phosphine)-thiourea with excellent enantioselectivities and yields (up to 96% ee, 96% yield, TON up to 1000) under mild conditions.416 Chenphos/Rh complex serves as a highly efficient catalyst system for AH of 𝛼-oxy functionalized 𝛼,𝛽-unsaturated carboxylic acids under mild conditions in trifluoroethanol. The control experiments indicated that the ionic interaction between the ligand and the substrate plays a vital role in achieving high enantioselectivities in a suitable solvent.417 [Rh(COD)Cl]2 /ZhaoPhos-catalysed AH of 𝛼,𝛽-unsaturated carbonyl compounds, such as amides and esters, has been achieved with high enantiomeric excess. The substrate scope for this chemical transformation is broad with various substituents at the 𝛽-position. Control experiments revealed that each unit of the ligand ZhaoPhos is irreplaceable. Mechanistic investigations support a traditional innersphere mechanism. A ligand–substrate coordinating complex (5) involving a secondary interaction between the thiourea and the carbonyl substrate has been proposed.418 Catalysed by a rhodium complex of P-stereogenic diphosphine ligand, trichickenfootphos, AH of racemic aldimines via dynamic kinetic resolution has been realized for the preparation of chiral arylglycines with good yields and enantioselectivities. Under optimized conditions, a conversion of 47% (with 75% ee) and a 47% recovery ( with 59% ee) of the starting material was obtained.419 In Rh-catalysed hydrogenation of quinoline, the active catalytic species is formed by the coordination of two molecules of quinoline with the pre-catalyst. Partial hydrogenation of one coordinated quinoline yields a complex containing a 1,2-dihydroquinoline ligand which is then subject to a ratedetermining hydrogenation.420 A bis(phosphine)/triflatosilyl pincer-type Rh(I) complex

ee 

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171

3 Oxidation and Reduction CF3 F 3C S

NH H2N

N H

O

CH3

H

H3C

P Ph

Fe

Rh H

P Cl (5)

can reversibly store 1 equiv. of hydrogen across the Si–Rh bond upon triflate migration from silicon to rhodium. The triflatosilyl complex serves as an effective precatalyst for norbornene hydrogenation, but Si–OTf bond cleavage is not implicated in the major catalytic pathway. The combined experimental and DFT computation findings suggested possible strategies for metal/silicon cooperation in catalytic processes.421 A range of N-benzylated 3-substituted pyridinium salts undergo a Rh-JosiPhos-catalysed AH to piperidines with ee values up to 90%. A mechanistic study involving isolation of the various reaction intermediates and isotopic-labelling experiments found that the added base acts as a scavenger of the acid produced. It has been suggested that initially a 1,2-hydride addition at the C(2) position takes place (Scheme 35).422 Ph +

Br−

N Bn

Ph [Rh]-H

enantiodetermining step

Ph

[Rh]−H, H2

N Bn

N Bn ii. [Rh]-H

i. tautomerizatio

Ph N Bn Scheme 35

Catalyzed by a rhodium complex of P-stereogenic diphosphine ligand (R)-2-t-butylmethylphosphino-3-(di-t-butylphosphino)quinoxaline ((R)-3H-QuinoxP*) (6), fivemembered cyclic 𝛼-dehydroamino ketones bearing endocyclic vinyl and endocyclic

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keto-carbonyl groups undergo sequential AH to give chiral cyclic trans-𝛽-amino alcohols with two contiguous stereocentres in quantitative conversions, excellent enantioselectivities, and good diastereoselectivities. Control experiments have shown that synthesis of cyclic trans-𝛽-amino alcohols includes two sequential AH steps with the C=C bond being reduced more rapidly than the C=O bond.423

ee  de 

+

P

N

Rh

COD SbF − 6

P

N Me

COD = cis-1, 5-cyclooctadiene (6)

A new series of chloride-bridged dinuclear rhodium(III) complexes have been synthesized from the rhodium(I) precursor [RhCl(COD)]2 , chiral diphosphine ligands, and hydrochloric acid. The complexes act as efficient catalysts for AH of alkenes, allylic alcohols, alkenylboranes, and unsaturated cyclic sulfones. It has been proposed that the monohydride rhodium(III) complex acted as an active species in a process involving hydride attack of simple olefins as its key step.424 Rhodium/DuanPhos-catalysed AH of aliphatic 𝛼-dehydroamino ketones afforded chiral 𝛼-amino ketones in high yields and excellent enantioselectives (up to 99% ee). 𝛼-Amino ketones have been reduced further to chiral 𝛽-amino alcohols by LiAlH(t-BuO)3 with good yields.425 Rhodium(I) alkene complexes of an NNN-pincer ligand catalyse the hydrogenation of alkenes. The terminal or resting state of the catalyst, which exhibits a very upfield Rh–hydride 1 H NMR chemical shift, has been isolated, and a synthetic cycle for regenerating the catalytically active species has been established. In the hydrogenation of diphenylacetylene, the exclusive formation of the trans-stilbene complex suggests that stereoselective hydrogenations of more complicated alkynes are possible.426 AH of 𝛼,𝛽-unsaturated N-acylpyrazoles using a Rh/bisphosphine-thiourea (ZhaoPhos) catalytic system leads to products with high yields and excellent enantioselectivities (up to 97% yield, 99% ee). The pyrazole moiety played an important role in providing hydrogen-bond acceptor sites, which is critical for achieving high reactivities and enantioselectivities.427

Transfer Hydrogenation The progress on the use of sugar-based ligands in ruthenium- and rhodium-catalysed ATH reactions has been reviewed. It has been pointed out that such ligands are readily available, highly functionalized, and their modular constructions are easy. Series of chiral ligands can be screened in the search for high activities and selectivities for each type of substrate.428 Many efforts made to render the well-known stoichiometric phosphinepromoted reactions, such as the Wittig, Mitsunobu, Staudinger, Appel reactions, and

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3 Oxidation and Reduction O (C6F5)2BH +

O S

N H

B(C6F5)2 But

NHAr1 Ar

Me

S

NH2

NH2 H S C6F5 B O But C6F5

NH3-BH3

But

But

NAr1 Ar

H N H

Ar1

S

N

O

C B H Ar Me C6F5

C6F5

Me

Scheme 36

others, catalytic in phosphine have been reviewed. Regeneration of the active catalyst was possible using reagents that reduce in situ the phosphine oxide formed during the reaction. Mostly silanes were used as the stoichiometric reductant.429 A cobalt-catalysed chemodivergent TH of nitriles to synthesize primary, secondary, and tertiary amines, using ammonia borane as a hydrogen donor, has been reported. Mechanistic studies revealed the homogeneous nature of these cobalt catalysis systems and operation of an inner-sphere mechanism without the metal–ligand cooperativity.430 A cobalt-catalysed stereodivergent TH of alkynes to Z- and E-alkenes using ammonia borane as a hydrogen donor has been reported. Effective selectivity control is achieved based on a rational catalyst design. Experimental results indicate that the E/Z selectivity is well controlled by the levels of steric hindrance of cobalt catalysts. This mild system allows for the TH of alkynes bearing a wide range of functional groups in good yields. A preliminary mechanistic study revealed that E-alkene product was generated via sequential alkyne hydrogenation to give Z-alkene intermediate, followed by a Z to E alkene isomerization process. It has been hypothesized that cobalt dichloride complexes are reduced by ammonia borane to generate catalytically active cobalt hydride complexes.431 ATH of imines with ammonia borane as hydrogen source, Piers’ borane, chiral t-butylsulfinamide, and pyridine additive furnished optically active amines in 78–99% yields with 84–95% ees. A catalytic pathway for this reaction involving an eight-membered hydrogen transfer transition state is depicted in Scheme 36.432 TH of various N-heteroaromatic compounds has been achieved with Pd(II) as a catalyst, B2 pin2 as a mediator, and water as both solvent and hydrogen donor. A myriad of N-heteroaromatic compounds are selectively reduced with a broad functional groups tolerance in good to excellent yields. Mechanistic studies suggested that the new protons in products are from water, and Pd−H might be the key intermediate with B2 pin2 as the water activator.433 A variety of N-heterocycles have been hydrogenated mediated by

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Organic Reaction Mechanisms 2016

diboronic acid with water as the hydrogen source. Complete incorporation of deuterium from stoichiometric D2 O onto substrates confirmed the sources of H/D atom. HRMS and computational results showed the existence of key intermediates in the reaction of 2-methylquinoline, diboronic acid, and water. Mechanistic studies revealed that the reduction proceeds with initial 1,2-addition, where diboronic acid synergistically activates substrates and water via a six-membered ring transition state.434 Alkenes and alkynes are directly reduced by water or D2 O in a Pd/C-catalysed and diboron-mediated TH. This reaction has been conducted on a broad variety of alkenes and alkynes at ambient temperature. Under the optimal reaction condition, reduction of diphenylacetylene in the presence of an equimolar mixture of H2 O and D2 O revealed a primary KIE of 5.6 for the reaction. Mechanistic experiments suggest that this reaction involves a hydrogen atom transfer from water that generates a Pd–hydride intermediate.435 A combination of two iron complexes viz., Funk’s modified version of Knölker’s iron hydride complex and Fe(acac)3 , serving different roles is the key to success of the ironcatalysed TH of N-aryl and N-alkyl imines using 2-propanol as the hydrogen donor. The use of a Lewis acid as an activator not only led to efficient TH but also showed potential in enantioselective transformation. The proposed mechanism is depicted in Scheme 37.436 Ruthenium complex, [(𝜂 6 -cymene)Ru(Cl)-(dpmpy)]+ {dpmpy = 2-[2-(dimethylamino)pyrimidin-4-yl]pyridine}, catalyses the reductive amination of aromatic aldehydes through in situ generated imines with 2-propanol as the hydrogen source following a TH mechanism. According to mechanistic studies performed on the TH activity of this catalyst, its activation takes place in situ by rollover cyclometallation. This generates a carbanion coordinated to ruthenium, which acts as the base that keeps the catalysis running.437 The canonical SN 2 behaviour displayed by alcohols and activated alkyl halides in basic media (O-alkylation) is superseded by a pathway leading to carbinol C-alkylation under the conditions of rhodium-catalysed TH with 2-propanol as the hydrogen source. Racemic and asymmetric propargylations take place. It has been suggested that catalysis is initiated by addition of 3-chloropropyne to the rhodium complex to form the 𝜂 1 -allenylrhodium(III) complex, which underwent substitution with the alcohol to form the rhodium(III) alkoxide complex.438 An efficient method for the C–N bond reduction of aromatic and benzylic ammonium triflates using a nickel(0) catalyst and sodium isopropoxide as a reducing reagent has been developed. Reduction of the biphenyl ammonium triflate with deuterated sodium isopropoxide resulted in the formation of deuterated biphenyl product in excellent yield, which confirmed that sodium isopropoxide was the hydrogen donor of the reduction reaction. Reduction with i-PrONa-d7 resulted in a KIE of 1.06, suggesting that the 𝛽-hydride elimination is not rate-determining. It has been suggested that oxidative addition of the ammonium triflates to the Ni(0) catalyst starts the catalytic cycle. Anion displacement and 𝛽-H elimination produce a nickel hydride intermediate, which could easily undergo the reductive elimination to give the reduced product and regenerate the reactive Ni(0) species.439 In the base catalysis of TH of ketones with two amine(imine)diphosphine iron pre-catalysts, treatment of the complexes with at least 2 equiv. of strong base such as t-BuOK generates the active from of the catalysts. In less basic solution, the pre-catalysts react with the hydrogen source, 2-propanol, to form an inactive neutral bis(amido) iron complex. The structure of the transition state for the reaction

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3 Oxidation and Reduction TMS O TMS

Fe

N

OC CO

Ph

heat

PhCN

TMS O Fe OC

NHR3 R1

TMS

CO

OH

R2 R3

LA N R1

O R2

LA= Lewis acid

TMS

= vacant site

O TMS Fe H

OC CO Scheme 37

of the amine hydrido iron catalyst with acetophenone has been modelled using DFT calculations.440 The molybdate-catalysed transfer hydrodeoxygenation (HDO) of benzyl alcohol to toluene driven by oxidation of the solvent 2-propanol to acetone has been investigated using a combination of experimental and computational methods. A Hammett study that compared the relative rates for the transfer HDO of five para-substituted benzylic alcohols has been carried out. DFT calculations suggest that a transition state with significant loss of aromaticity contributes to the lack of linearity observed in the Hammett study. In the reaction of PhCD2 OH, the toluene formed was PhCD3 , the benzaldehyde was PhCDO, and the bibenzyl was PhCD2 CD2 Ph. A KIE of greater than one was observed, which is indicative of C–H/D bond breakage in the

176

Organic Reaction Mechanisms 2016

rate-determining step. It has been proposed that the Mo(IV) moiety can oxidatively form a 𝜋-benzyl complex with the benzylic alcohol, which can undergo a reductive TH, after isomerization to an 𝛼-benzyl complex, with concomitant reduction of Mo(VI) to Mo(IV), thus closing the catalytic cycle of the reaction.441 Osmium(0) complexes derived from Os3 (CO)12 and XPhos (2-dicyclohexylphosphino-2′ ,4′ ,6′ -triisopropylbiphenyl) catalyse the TH cum C−C coupling of ethylene and higher 𝛼-olefins with diverse vicinally dioxygenated hydrocarbons. Coupling may be conducted in a redox-neutral mode using 𝛼-ketols or 𝛼-hydroxy esters as reactants or in oxidative or reductive modes using 1,2-diols or 1,2-diones as reactants, respectively. The collective data suggest that increased 𝜋-backbonding at the stage of the osmium(0)–olefin 𝜋-complex plays a critical role in facilitating alkene–carbonyl oxidative coupling, as does the use of transient vicinal dicarbonyl partners, which have relatively low-lying LUMO energies. Experimental data, including deuterium labelling studies, are consistent with a catalytic mechanism involving olefin–dione oxidative coupling to form an oxa-osmacyclopentane, which upon reductive cleavage via hydrogen transfer from the secondary alcohol reactant releases the product of carbinol C-alkylation with regeneration of the ketone.442 DFT investigation of the reaction mechanism of deoxydehydration reactions of allyl alcohols with 1-butanol as reductant in the presence of methyltrioxorhenium(VII) catalyst revealed that a direct two-step pathway (Scheme 38) has lower activation barriers as compared to a three-step pathway involving [1,3]-transposition of allylic alcohols.443 HO

OH O

Re O

OH

Re

O

O HO

OH

O

O

Re O

O

+ 2 H2O H Scheme 38

A series of chiral cis-epoxy naphthoquinols with three contiguous stereocentres are obtained by asymmetric reductive desymmetrization of meso-epoxy naphthoquinones with Ru(OTf)((R,R)-TsDPEN) in ethanol and in the presence of hydrogen. Excellent enantioselectivities (96–99% ee) and diastereoselectivities (8:1–15:1) are obtained. Deuterium-labelling experiments with D2 and ethanol-d6 indicated that the transformation proceeds via a combined AH and ATH mode, both catalysed by TsDPEN−Ru, and ATH plays a dominant role.444 An asymmetric reductive amination of ketones using both arylamines and benzhydrazide in the presence of nickel catalysts has been developed. A one-pot synthesis of tetrahydroquinoxalines was also developed starting directly from 𝛼-ketoaldehydes and 1,2-diaminobenzene. Formic acid was used as source of hydrogen. Strongly 𝜎-donating bis(alkylphosphine)s are crucial ancillary ligands for both stereoselective hydride insertion and decarboxylation of the formate. The most suitable ligand for

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177

3 Oxidation and Reduction Ph

Ph P

P Ph Ph (7)

stereoselectivity is Ph-BPE (7). Simulation of hydride insertion of a cationic complex of [(R)-Ph-BPE)](hydrido)nickel(II) into a bound N-phenylketimine derived from acetophenone was performed by ONIOM(QM:QM′ ) method. Two diastereomeric transition-state structures have been determined and their energies are 2.1 kcal mol−1 apart, which is consistent with the observed 76% ee.445 Selective transfer semihydrogenation of alkynes to yield alkenes was achieved with commercial first- and second-generation Hoveyda−Grubbs catalysts and formic acid as a hydrogen donor. In the reduction of diphenylacetylene, first-generation ruthenium– benzylidene complexes, containing aliphatic phosphine ligands, favour production of (Z)-stilbene, while the second-generation benzylidene complexes, bearing the NHC ligand, promote production of (E)-stilbene from diphenylacetylene. Substrates containing various functional groups, both electron-donating and -withdrawing, are tolerated. (Z)Stilbene seems to be in all cases the initial product of the reaction that undergoes, with time, isomerization to more thermodynamically stable (E)-stilbene.446 Olefins have been reduced to saturated hydrocarbons using formic acid in water and palladium(II) as a catalyst. Xanthophos has been found as the most suitable ligand. The reaction protocol leads to excellent yields and high chemoselectivity. It has been tentatively suggested that an oxidative addition of formic acid to Pd(0) results in the formation a palladium hydride complex, which hydropalladated the olefin substrate to afford new hydrido palladium complex. Upon reductive elimination, this complex gave the expected saturated compound with regeneration of Pd(0) catalyst.447 An ATH of diaryl ketones, promoted by bifunctional Ru complexes with an etherial linkage between 1,2-diphenylethylenediamine (DPEN) and 𝜂 6 -arene ligands, has been developed. Because of the effective discrimination of substituents at the ortho-position on the aryl group, unsymmetrical benzophenones are reduced by formic acid and TEA with an excellent enantioselectivity. For the non-ortho-substituted benzophenones, the oxotethered catalyst electronically discerned biased substrates, resulting in chiral diarylmethanols with >99% ee.448 CF3 -substituted 1,3-diols have been stereoselectively prepared in excellent enantiopurity and high yield from CF3 substituted diketones by ATH in formic acid/TEA catalysed by Ru(II) complexes with DPEN–SO2 N–(Me)(CH2 )3 (𝜂 6 -Tol) and piperidino-SO2 DPEN–(CH2 )3 (𝜂 6 -Ph) conjugate ligands. The intermediate mono-reduced alcohol was also obtained in very high enantiopurity by applying milder reaction conditions. In particular, CF3 C(O)substituted benzofused cyclic ketones underwent either a single or a double dynamic kinetic resolution during their reduction.449 The ATH of 1-methyl-3,4dihydroisoquinoline and its 6,7-dimethoxy substituted derivative, with formic acid/TEA as hydrogen source and using the iridium complex of pentamethyl-cyclopentadiene and (S,S)-1,2-diphenyl-N′ -tosylethane-1,2-diamine as a catalyst, showed an unusual

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Organic Reaction Mechanisms 2016

ee profile for the product amines. The reactions initially give predominantly the R-enantiomer of the chiral amine products with >90% ee, but it then decreases significantly during the reaction. The decrease in ee is not due to racemization of the product amine, but because the rate of formation of the R-enantiomer follows first-order kinetics, whereas that for the S-enantiomer is zero-order. This difference in reaction order explains the change in selectivity as the reaction proceeds. The rate of formation of the R-enantiomer decreases exponentially with time, while that for the S-enantiomer it remains constant. A reaction scheme is proposed which requires rate-limiting hydride transfer from the iridium hydride to the iminium ion for the first-order rate of formation of the R-enantiomer amine and rate-limiting dissociation of the product for the zero-order rate of formation of the S-enantiomer.450 New enantiopure syn- and anti-3-(𝛼-aminobenzyl)-benzo-𝛾-sultam ligands have been synthesized and used in the Ru(II)-catalysed ATH of ketones using formic acid/TEA. In particular, benzo-fused cyclic ketones based on 1-indanone or 𝛼-tetralone afforded excellent enantioselectivities. The ATH rate and enantioselectivity using the syn isomer of ligand are better than with the anti isomer.451 Cyclohexa-1,4-dienes have been introduced to Brønsted acid-catalysed TH as an alternative to the widely used Hantzsch dihydropyridines. There is not much advantage over established protocols for the reduction of imines, including examples of reductive amination. However, the use of cyclohexa-1,4-dienes makes the ambient-temperature hydrogenation of structurally and electronically unbiased alkenes possible.452 An improved synthesis of the bis-methylamido Hantzsch dihydropyridine has been described. The Hantzsch amide is demonstrated to be an effective TH reagent using 𝛼,𝛽-unsaturated ketones as the test case. The major advantage of this reagent is the ease of removal. Unreacted Hantzsch amide and the bis-methylamidopyridine by-product can be removed easily by aqueous acidic extraction, whereas Hantsch ester and its by-product require column chromatography for removal.453 Reductive condensation of N−H imines under the influence of a disulfonamide catalyst (8), using Hantzsch ester as hydrogen source,

NO2

NO2 SO2 NH SO2 NO2

NO2 (8)

ee 

ee 

179

3 Oxidation and Reduction

leads to the facile formation of several C(2)-symmetric secondary amines in good yields with high diastereo- and enantio-selectivity.454 Chiral phosphoric acid-catalysed ATH of 3-tosylaminoquinolines, with Hantzsch dihydropyridine, results in the formation of 3-aminotetrahydroquinolines with high yields and high enantioselectivity.455 A chiral phosphoric acid-catalysed one-pot enantioselective reductive amination of 2-pyridyl ketones, with Hantzsch ester as hydrogen source, provided chiral pyridine-based ligands in excellent yields with high enantioselectivities (up to 98% yield, 94% ee). Computational studies on the key intermediate imine and transition state of the hydride transfer process revealed that the nitrogen atom of the pyridyl ring might be an important factor to significantly promote both the reaction activity and enantioselectivity (Scheme 39).456 Kinetic resolution of axially chiral 5- or 8-substituted quinoline derivatives has been achieved through ATH of the heteroaromatic moiety, simultaneously obtaining two kinds of axially chiral skeletons with a selectivity factor of up to 209. A chiral phosphoric acid (9) was used as catalyst and a Hantzsch ester (10) as a hydrogen source.457

R

OH

Me

N

P

N

O R

H

Me

N

Ar

O P O

N

Ar Imine intermediate

H

H

R′ Me

R′ N H

Me

H N

R′

Me

Me

H H

R′ R′ Me

O P

N

R′

OH

Me

R

Me

N HN

Scheme 39

Ar

ee  de  ee 

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180

Organic Reaction Mechanisms 2016 Ph O O O Ph (9)

P

O

O OH

MeO

OMe Prn

N H (10)

Prn

A new type of chiral sulfinamide phosphinate catalyst with up to three stereogenic centres has been synthesized. The naphthyl derivative is a highly efficient organocatalyst for ATH of imine, leading to a wide range of arylmethylamines in high yields with up to 99% ee. Trichlorosilane has been used as a source of hydrogen. A tentative explanatory model of the observed stereoselection has been presented.458 Reductive cross-coupling of aryl bromides and conjugated arylalkenes or internal alkynes with hydrosilanes by cooperative palladium/copper catalysis has been developed, resulting in the highly regioselective formation of various 1,1-diarylalkanes. Mechanistic studies revealed that stereoinvertive transmetallation including dissociation of one phosphane is the likely rate-determining step.459 DFT calculations have been performed to study the mechanism of Ir(III) pincer complex-catalysed chemoselective C(1)–O hydrosilylative reduction of glucose. The mechanisms for reduction of the external and internal C(1)–O (i.e. C(1)–Oext and C(1)–Oint ) on the C(1)–MeO-substituted glucose (i.e. 1 Me) and C(1)–Me2 EtSiO-substituted glucose (i.e. 1 Si) have been investigated. The results show that both mechanisms proceed with initial concerted silyl transfer and subsequent C(1)–Oext or C(1)–Oint bond cleavage and hydride transfer steps. In the hydride transfer step, the Ir–H moiety acts as the hydride source. The C(1)–O cleavage is the rate-determining step of the overall mechanism.460 The Ir-catalysed reductive formation of functionalized nitrones from N-hydroxyamides takes place through two types of iridium-catalysed reactions including dehydrosilylation and hydrosilylation using the Vaska complex [IrCl(CO)(PPh3 )2 ] and (Me2 HSi)2 O. The method showed high chemoselectivity in the presence of sensitive functional groups, such as methyl esters. 1 H NMR studies strongly supported generation of an N-siloxyamide and an N,O-acetal as the actual intermediates.461 Nickel complexes with sterically demanding NHC ligands catalyse hydrogenolysis of arenols through the use of hydrosilane as a reductant. This protocol allows selective cleavage of Ar–O bonds of arenols over aryl and benzyl ethers. It has been suggested that the dehydrogenative silylation of arenols first proceeds by nickel catalysis to give aryl silyl ether with evolution of hydrogen (Scheme 40).462 Cobalt-cyclometallated bis-NHC-dinitrogen complex catalyses highly chemo- and regio-selective anti-Markovnikov hydrosilylation of terminal monosubstituted alkenes containing hydroxy, carbonyl, and nitrile functional groups, producing n-alkylsilanes and 𝜔-silyl alcohols, aldehydes, and nitriles. The reaction exhibited broad functional group tolerance. Multinuclear NMR studies of reactive intermediates have given insights into the mechanism.463 Zinc acetate complex with (R,R)-N,N′ -dibenzyl-1,2diphenylethane-1,2-diamine has been used as a catalyst for the hydrosilylation of

181

3 Oxidation and Reduction

R

OH R

L

+ H-Si

LNi0

LNi

Ni

−H2

0

H

R

OSi R

Si

O

Si L Ni

H-Si R

OSi

Scheme 40

various imines. Secondary amines are obtained in excellent yields (up to 96%) and enantioselectivity (up to 97% ee). It has been suggested that the first amount of silane is used for the formation of the Zn-hydrido species.464 DFT calculations have been used to rationalize the impact of NHC ligands and silane on the reversal of regioselectivity and alteration of the rate-limiting step in the (NHC)Ni(0)-catalysed aldehyde–alkyne reductive couplings with silanes as the reducing agent. The regioselectivity reversal is found to be related to switching of the steric effect, from the aldehyde-phenyl hindrance with the adjacent alkyne substituent to the NHC ligand hindrance with the adjacent alkyne substituent, when the NHC ligand employed is changed from small to large. Alteration of rate-limiting step is caused by strong steric effects induced when bulkier silanes are used.465 The reduction and reductive addition, formal hydroamination, of functionalized nitroarenes has been achieved using an iron(III) catalyst and silane. The reduction was chemoselective for nitro groups over an array of reactive functionalities. The high activity of this catalyst also facilitated a follow-on reaction in the reductive addition of nitroarenes to alkenes, giving efficient formal hydroamination of olefins under mild conditions.466 A variety of N-(t-butylsulfinyl)imines are reduced in the presence of a catalytic amount of zinc acetate to provide the corresponding secondary amines in high yields with excellent diastereoselectivities (up to 98% de) using triethoxysilane as a hydrogen source. It has been suggested that the reaction proceeds through a six-membered cyclic transition state, in which zinc coordinates to the sulfinyl oxygen and participates in the delivery of the hydride.467 Trichlorosilane-mediated nitro group reduction is supposed to occur through the generation of a Si(II) reducing species. The correlation between ΔΔG‡ and the 𝜎 H Hammett constants of the different nitrobenzenes indicated that electron-poor nitro groups were reduced faster, thus suggesting a nucleophilic species as the active reducing agent. Quantum mechanical

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Organic Reaction Mechanisms 2016

calculations, and spectroscopic and other experimental data, strongly suggest the tertiary amine-stabilized dichlorosilylene to be the most probable reducing agent.468 A combination of PhSiH3 and [Mo(VI)Cl2 O2 (H2 O)2 ] proved to be highly efficient for the deoxygenation of a large variety of diaryl ketones and acetophenones to give the corresponding alkanes in good to excellent yields. Carrying out the reaction with the deuterated silane resulted in introduction of two deuterium atoms into the product, which suggests that the reductive deoxygenation of the carbonyl group involves reduction of the ketone to the corresponding alcohol, followed by deoxygenation of the alcohol to the alkane by reaction with the deuterated silane.469 A variety of aldehydes have been chemoselectively reduced by transfer hydrosilylation using triorganosilyl formates and a newly developed ruthenium catalyst. The catalyst was synthesized by treating [Ru(Me-allyl)2 (COD)] with 2 equiv. of acetic acid and 1 equiv. of triphos in THF. A collection of different functionalized aldehydes successfully underwent transfer hydrosilylation in excellent yields. The para-substituted benzaldehydes bearing halogens, ether, thioether, or alkyl groups were fully hydrosilylated into the silyl ethers. Oxidizing functionalities such as ketone, ester, cyano, or nitro groups were well tolerated, and the reactions proceeded chemoselectively in excellent yields. DFT investigations have shown that the mechanism involves a sequence of decarboxylation/insertion/transmetallation steps, thereby avoiding genuine hydrosilane intermediates.470 Ruthenium alkylidenes catalyses regio- and stereo-selective dehydrogenative silylation and hydrosilylation of vinylarenes with alkoxysilanes. Varying the ligands on ruthenium alkylidenes permits selective access to either (E)-vinylsilanes or 𝛽-alkylsilanes with high regio- and stereo-control. cis,cis-1,5-Cyclooctadiene was identified as the most effective sacrificial hydrogen acceptor for the dehydrogenative silylation of vinylarenes, which allows use of a nearly equimolar ratio of alkenes and silanes. Analysis of the products in parallel KIE experiments with HSiMe(OTMS)2 and DSiMe(OTMS)2 established a significant KIE (kH /kD = 3.2). An intermolecular KIE experiment using [2,2-D2 ]styrene and [2,2-H2 ]styrene displayed minimal isotopic selectivity (kH /kD = 1.3), suggesting that direct C–H activation/silylation to afford vinylsilane is unlikely. These indicate that the Si–H bond cleavage to generate the putative ruthenium silyl complex and HCl is the turnover-limiting step, which is consistent with observation of Ru alkylidene as the resting state.471 Twelve P-chiral phosphine oxides, screened for their ability to act as a chiral Lewis base catalyst for the asymmetric hydrosilylation of ketimines, provide chiral amines in good conversion and yield, but with relatively poor enantioselectivity (ee 99:1), whereas (519) is obtained with R1 = Me and R2 = ArCH2 (91:9).344 The alkyne–alkyne coupling of Me3 SiC≡CR1 with R2 C≡CCH2 CH2 OLi (generated from the alcohol and n-BuLi), mediated by (i-PrO)4 Ti at –20 ∘ C, has been reported to produce Me3 SiCH=C(R1 )–C(R2 )=CHCH2 CH2 OH, whose yield can be dramatically improved by Me3 SiCl as an additive. A plausible mechanism was proposed, including the initial formation of a titanacyclopropene from Me3 SiC≡CR1 , in which one of the two remaining (i-PrO) groups is replaced by the Li-alkoxide of the second reactant, so that the rest of the domino sequence occurs in the coordination sphere of Ti as an intramolecular event.345

552

Organic Reaction Mechanisms 2016

Titanium-catalysed multicomponent coupling of terminal alkynes R1 C≡CH, isonitriles R2 N≡C, and primary amines R3 NH2 in toluene at 100 ∘ C has been reported to generate R3 N=CH–C(R1 )=CHNHR2 as intermediates, which can be converted into pyrroles derivatives on reaction with esters of 𝛼-amino acids.346 A mixture of Cp2 TiCl2 (10 mol%), EtAlCl2 , and Mg has been shown to promote a coupling of symmetrical alkynes RC≡CR with c-PrCO2 Me, affording 2,3-dialkyl-l,4dicyclopropylbutane-1,4-diones (c-PrCO)–C(R)H–CH(R)–CO(c-Pr). DFT calculations shed light on some of the mechanistic features.347

(xvi) Chromium A combination of triazacyclohexane chromium complexes with MAO has been shown to catalyse the selective trimerization of 1-pentene, 1-hexene, and 1-octene with unprecedented efficiency, reaching nearly 5000 turnovers in 1 h. Model studies and stoichiometric experiments suggest that the reaction operates via a metallacyclic mechanism.348 (xvii) Magnesium According to 1 H– 13 C HMBC and HSQC spectroscopy, magnesium complexes, such as (523), undergo a coordination–decoordination in THF; no Schlenk-type ligand redistribution was observed. These findings, together with stoichiometric and kinetic experiments, shed light on the mechanism of hydroamination of amino alkenes, for example, (CH2 =CHCH2 )2 C(Me)CH2 NH2 , which was found to produce (524) and (525).349 SiMe2 (Pri)2N

Mg+ (523)

NPh2

N H (524)

N (525)

The addition of H2 GeFMgF to ethylene (C2 H4 ) has been shown to proceed via one of the two possible channels by QCISD calculations with the 6-311++G (d,p) basis set. With a PCM model, THF was predicted to accelerate the reaction.350

(xviii) Aluminium The mechanism of catalytic hydroalumination of 𝛼-olefins with alkylalanes has been investigated by mathematical modelling for the individual reactions, which allowed estimation of the kinetic parameters and activating energies, so that possible pathways could be formulated.351 Calculations using the M06-2X and QCISD methods have demonstrated that for the addition of H2 SiAlCl3 to ethylene, the pathway involving one TS≠ is thermodynamically more feasible than that with two TS≠ . Furthermore, PCM modelling predicts that the reaction is more likely to proceed in vacuum than in CH2 Cl2 .352 The reaction of ethynylstyrenes (526) with a substoichiometric amount of DIBAL-H has been reported to produce 1,2,3-trisubstituted naphthalenes (528). This interesting

553

10 Addition Reactions: Polar Addition

benzocyclization is believed to be initiated by a regioselective trans-hydroalumination of the alkyne moiety, generating alkenylaluminium intermediate (527), which then undergoes a sequence of intramolecular carboalumination, skeletal rearrangement, and dehydroalumination.353 In contrast to this mechanism, cis-hydroalumination with DIBAL-H was also observed, as mentioned in the subchapter on boron.132 R1

R1 R2

R2

R1 R2

DIBAL-H (0.5 equiv)

Al(Bui)2

octane 100 °C

SiMe3

SiMe3

SiMe3

(526)

(527)

(528)

(xix) Gold Hydrothiolation of terminal alkenes R1 CH=CH2 with R2 SH has been found to proceed readily in the presence of Ph3 PAuNTf2 (2 mol%) in THF at 45 ∘ C, giving rise to anti-Markovnikov products R1 CH2 –CH2 SR2 . Formation of the tetranuclear intermediate [(Ph3 P)Au]4 (NTf2 )2 (SPh)2 has been detected by 31 P NMR and confirmed by X-ray analysis, which suggests that the reaction starts with 𝜂 2 -coordination of [Au]-SR2 to the alkene, and the resulting complex (Ph3 P)(Tf2 N)Au(SR2 )(alkene) then undergoes a [2 + 2] syn-addition to generate R1 CH[Au]–CH2 SR2 . Subsequent protodeauration then gives the final product.354 Benzotriazole (529a) as ligand has been found to decelerate decomposition of gold catalysts. As a result, addition of terminal alkenes RC≡CH to vinyl ethers, such as dihydropyran, catalysed by [(ArO)3 P](529a)AuOTf (3 mol%), readily afforded the expected products, for example, (530) at r.t. This protocol was expanded to the Ferrier-type alkynylation of glycals. Mechanistic investigation revealed the formation of acetylide RC≡C[Au] as the key intermediate.355 R N N N (529a) R = H (529b) R = Me

O (530)

R

DFT calculation on the Au(I)-catalysed hydroamination of alkylidenecyclopropanes (531) revealed two competing pathways: (a) the C=C bond activation (532) affording the alkene hydroamination product (535) and (b) the three-membered-ring activation (536) giving rise to allylic amines (537). Route (a) consists of three steps: C–N bond formation (532) → (533), C–C bond rotation (533) → (534a), and the rate-limiting protodeauration

de 

554

Organic Reaction Mechanisms 2016 + +

H

Au L (a)

R (531)

NHR2

+

NHR2

R2NH

Au+ L

R

R

(532)

R

AuL (533)

AuL (534a)

(b)

NR2 LAu

NR2 H

R2N R

+

R2NH

R

Au

R (536)

(537)

(535)

(534b)

via (534b). Path (b) occurs via the rate-limiting ring-opening (531) → (536), followed by C–N bond formation and protodeauration.356 Gold(I)-catalysed hydroarylation of alkylidenecyclopropanes (538) with indole derivatives (539) has been reported to afford the anti-Markovnikov products (540), presumably via an analogous mechanism.357 R (IPr)Au (OTf) (5 mol%)

+

R N Me

(538)

(539)

H

N

THF, 20–40 °C

H (540)

A systematic study of the addition of O-, N-, and C-nucleophiles to alkynes, catalysed by LAuOTf, has demonstrated that Lewis or BA co-catalysts, such as (TfO)3 Ga, (TfO)3 In, or TfOH, can significantly increase the catalyst turnover of some reactions. The origin of this effect is not clear but can be attributed either to the coordination to the anion (TfO− ) of the catalyst, that is, [LAu(OTf)· · ·MX] for Lewis and [LAu(OTf)· · ·H–A] for BAs, or the protodeauration of the (vinyl)[Au] intermediate.358 A DFT study on the Au(I)-catalysed twofold hydroarylation of terminal alkyne MeC≡CH with pyrrole (C4 H4 NH), giving rise to the Markovnikov product Me2 C(2C4 H3 NH), revealed that both steps proceed via a Friedel–Crafts-type mechanism. However, while the first hydroarylation is directly promoted by Au(I), the second hydroarylation is promoted by a proton released through interaction of the alkene intermediate with gold-bound AcOH.359 Methoxylation of 3-hexyne, catalysed by (IPr)AuX complexes, affords EtC(OMe)2 Pr. Experimental and computational study revealed that the anion X− plays an active role in all steps, that is, in the pre-equilibrium, nucleophilic attack, and protodeauration. The fact that the medium-coordinating anions (MsO− and TsO− ) give the best results was rationalized as follows: (i) the pre-equilibrium is shifted towards the outer sphere ionpair;

555

10 Addition Reactions: Polar Addition

Tol

Fluorescence intensity

[(LAu)2C LAu+

N R2P

B F2

CC6H4R]+

R= NO2 H NMe2

N

(541a) R = P h (541b) R = Cy

LAuCl LAu(SPh)

L

L = (541b) Figure 1

(ii) the basicity of X− promotes the nucleophilic attack; and (iii) the catalyst deactivation is inhibited. Furthermore, MsO− and TsO− , being highly symmetric tridentate anions, apparently destabilize the unreactive tricoordinated gold species, which may be formed by planar anions, such as TFA− . Notably, alcohols with poor nucleophilicity exhibit a large difference in reactivity.360 The fluorescence intensity of the Au(I) complexes with bodipy-tagged phosphines (541) has been shown to be dependent on the electron density at the Au atom (Figure 1). This finding is likely to become a valuable tool for monitoring the changes in the coordination sphere of the metal in monitoring a variety of reactions.361 Addition of primary amines R2 NH2 to terminal acetylenes R1 C≡CH, catalysed by the anti-Bredt diaminocarbene–gold(I) complexes (542), has been reported to produce imines R1 C(CH3 )=NR2 as a result of the initial Markovnikov addition, followed by enamine → imine tautomerization.297 By contrast, enamines were isolated from the reaction catalysed by Cu(II).296 Another Au(I) catalyst for the conversion of terminal alkynes Ar1 C≡CH into imines Ar1 C(CH3 )=NAr2 has been generated in situ from the ligand precursor (543) and gold(I) complex (544). DFT calculations revealed that the cyclopropenium counterion in (544) imparts the complex stability through H-bonding and other non-covalent interactions.362 The addition of o-phenylendiamine 2-NH2 C6 H4 NH2 to propargylic alcohols R1 C≡CCH(OH)R2 , catalysed by [(JohnPhos)(MeCN)Au][SbF6 ] in CH2 Cl2 at 60 ∘ C, affords 1,5-benzodiazepines (545), presumably via a domino hydroamination– substitution process.363 Addition of 3-substituted indoles as nucleophiles to ynamides, for example, PhC≡C–N(Me)Ts, catalysed by [(JonPhos)Au][NTf2 ] in DCE at 80 ∘ C, gives rise to (546). An initial reaction of the electrophilic 𝜂 2 -Au complex of the ynamide at the 3-position of indole, followed by a well-precedented rearrangement to 2-position, is envisaged as a plausible mechanism.364 The cross-dimerization of terminal alkynes PhC≡CH and HexC≡CH, catalysed by an AuCl (1 mol%) complex with a phosphorous cavitand ligand in the presence of TfOAg,

556

Organic Reaction Mechanisms 2016 O NPr2i Me N N

N

N

R

N Au N

+

+

−

O

NPr2i

O H

2 BF4

N Me

O

NPr2i

+

AuCl

NPr2i (543)

(542) H N

N H

(544)

R2

R Ph N H

R1

(545)

NMe Ts

(546)

has been reported, resulting in the formation of PhC≡C–C(Hex)=CH2 in preference to homodimerization products.365,366 The XPhos-benzimidazole complex [(247a)(529a/b)Au][OTf] (1 mol%) has been reported to catalyse the addition of propargyl alcohols, such as (547) (96% ee), to terminal alkynes, for example, (548). The initially generated Markovnikov adduct (549) undergoes a spontaneous Claisen rearrangement, so that allenic ketone (550) was obtained as the final product with 91% ee. Note that this chirality self-immolative process was accompanied by only a marginal loss of stereointegrity.367 Ph OH +

Pr Ph

[(247a)(529a/b)Au] [OTf]

O

Ph toluene, 45 °C

(548)

Pr Ph

(547)

(549) O

Ph

•

Pr

Ph (550)

The (IPr)Au(OTf) complex has been found to catalyse the transformation of aminaloalkynes (551) into indolizidines (555) (n = 1). The reaction is believed to proceed as a domino process (Scheme 15) involving hydroaminoalkoxylation generating (553) via (552), followed by Petasis–Ferrier transformation via (554). This protocol was also successfully applied for the synthesis of quinolizidines (555) (n = 2).368

ee 

557

10 Addition Reactions: Polar Addition ( )n O

N

( )n OH

R Au+

(IPr)Au OTf (3 mol%)

+

O

OH

N

5 Å MS DCE, 80 °C, 12 h

O

N

R

(551) n = 1, 2 R = H, alkyl

(552)

( )n O

O

R Au+

AuL

(553)

( )n

H R

N

O

AuL R

+

N

O (555)

O (554)

Scheme 15

The Au(I)-catalysed rearrangement of aromatic methoxypropynyl acetal (556), giving rise to 1,2-dialkoxynaphthalenes (560), draws from the same portfolio and was rationalized using DFT calculations as follows: the initial attack by Au+ triggers an intramolecular relocation of the MeO group of the acetal, generating the trans-adduct (557). Its rotamer (557′ ) then undergoes a highly exothermic cyclization, and the arising aurated intermediate (558) is stabilized by forming the 𝜂 2 -Au–enol ether complex (559), from which the final product (560) is obtained by aromatization via a 1,4-elimination of methanol, concomitantly releasing Au(I) for the next catalytic cycle.369 The new C2 symmetric (NHC)AuCl complex (561) (5 mol%) has been shown to catalyse the cyclization of the 1,6-ene–yne (PhO2 S)2 C(CH2 C≡CPh)CH2 CH=CMe2 in the presence of Tf2 NAg (5 mol%) in CH2 Cl2 –MeOH (2:1) at r.t. to produce (562) with mere ee 44% ee.370  The 6(C)-exo-dig cyclization of MeC≡CCH2 N(Ts)(CH2 )2 CH=CHOTIPS to produce the piperidine derivative (563) has been accomplished with (JohnPhos)(MeCN)Au(SbF6 ) complex as catalyst (5 mol%) in CH2 Cl2 at r.t.371 The domino 5(C)-exo-dig ring closure of [(2-HOCH2 )C6 H4 C≡CCH2 ]2 C(CO2 Me)2 , followed by Prins-type cyclization, has been shown to occur in the presence of Ph3 PAuNTf2 as catalyst in CH2 Cl2 at r.t., giving rise to (564).372 Hydration of alkyne Ph2 P(O)NH–CH(Ar)-C≡CR, catalysed by NaAuIII Cl4 ⋅2H2 O (10 mol%) in EtOH–H2 O–CH2 Cl2 at r.t., has been reported to proceed regioselectively, affording ketone Ph2 P(O)NH–CH(Ar)–CH2 –COR, presumably as a result of steering the catalyst approach by coordination to the neighbouring group (565). The carbonyl oxygen originates from water, as shown by a labelling experiment using H2 18 O.373 A hydroxyl-assisted hydration of the C≡C bond in Ar1 CH=CHCH(OH)CH2 C≡CAr2 , followed by allylic substitution with a suitable O-, N-, and/or C-nucleophile, catalysed by Ph3 PAuCl (5 mol%) in the presence of Tf2 NAg (5 mol%) in CH2 Cl2 at r.t.,

558

Organic Reaction Mechanisms 2016 MeO

Au+ OMe

OMe (556) Ph3PAuCl (5 mol%) Tf2NAg (5 mol%)

DCE, r.t., 20 min

MeO

MeO

AuL

OMe

AuL +

+

OMe

MeO

(557)

(557')

MeO

MeO

OMe

MeO

H OMe

OMe

+

OMe

Au+ L AuL MeO

(560)

(559)

MeO (558)

has been shown to afford 𝛾-functionalized ketones Ar1 CH=CHCH(Nu)CH2 CH2 COAr2 with some preference over their isomer Ar1 CH(Nu)CH=CHCH2 CH2 COAr2 , depending on the nucleophile. The allylic substitution is believed to proceed via allylic radical, arising from the Au-coordinated product of the initial cyclization.374 Cyclization of homopropargylic sulfonamides RCH(NHTs)CH2 C≡CH with Selectfluor, catalysed by the gold(I)–BrettPhos complex (218)AuNTf2 (5 mol%) in the presence of Et3 N (2 mol%) in DCE at 60 ∘ C, affords 3-fluoropyrrolidinols (566) with >10:1 dr. The reaction is believed to proceed via an Au-promoted 5(N)-endo-dig cyclization, followed by fluorination and hydration of the resulting pyrroline. The related Aucatalysed reaction of the same substrate with NIS afforded 3,3-diiodopyrrolidin-2-ols (567) with >50:1 dr.375 Carboxylative cyclization of propargylic amines R1 C≡CCH2 NHR2 with CO2 (1 atm) to produce 2-oxazolidinones (568) has been attained with a dendritic (NHC)AuCl catalyst in water at r.t.376 A computational study has revealed the likely mechanism of the cyclization of (NHC)Au–C≡C(CH2 )4 OTs that affords (569). The 𝜋-back-bonding in the starting complex was found to be of importance.377

de 

559

10 Addition Reactions: Polar Addition Ph Ph Pri

PhO2S

OMe

AuCl

PhO2S

Ph

N N

Pri (561)

Ph

Ts N

O (562)

Ph

Ph P O N AuCl3

O

(563)

Ph

MeO2C

R

Ts N

Ar

MeO2C

OH R2 R1

O

R (565)

(564) R1

18OH

2

(566) R1 = H, R2 = F (567) R1 = R2 = I

Ar N O

N O

(568)

R2

N

Au

OTs

Ar

(569) Ar = 2,6-(Pri)2C6H3

MeO

PPh2

MeO

PPh2

(570)

Cyclization of the 3-indolylynamide (571), catalysed by (Ph3 P)AuSbF6 in DCE at 25 ∘ C, has been reported to provide the spirocyclic pyrrolidinoindolines (574). The proposed mechanism involves formation of the Au-associated keteneiminium (572), followed by a 5(C)-endo-trig cyclization to generate (573), whose further cyclization in the 5(O)-exo-trig manner gives the final product (574). With the diphosphine ligand (570), the latter product was obtained in 60% ee. In the presence of BF3 ⋅Et2 O the reaction does not stop at (574) but continues via fragmentation to generate the intermediate indolenium alcohol (575). Subsequent stereoselective 1,5-hydride transfer (as shown by deuterium labelling) resulted in the formation of enone (576) as the final product.378 A bimetallic Au(I)/Ni(II) domino reaction of alkynyl alcohols or tosylamides (577) (X = O and NTs) with 𝛽,𝛾-unsaturated 𝛼-keto esters (578) afforded spiroketals and spiroaminals (579) with 80 to >99% ee. This one-pot reaction proceeds via a 5(O)-exo-dig initial cyclization of (577), catalysed by Ph3 PAuCl, followed by a conjugate addition/spirocyclization with (578), catalysed by a complex generated from Ni(ClO4 )2 ⋅6H2 O (2.5 mol%) with the N,N′ -dioxide ligand (580), to complete the formation of (579) with 80 to >99% ee. A model to rationalize the asymmetric induction was proposed.379

ee 

ee 

560

Organic Reaction Mechanisms 2016 Ts Ts

N

N

DCE, −20 °C, 30 min

HO

N Me

Ph

HO

[Au]

(5 mol%)

Au+ N Me

•

(570), Au2(BF4)2

(571) R = Alkyl, Ar

Ph

(572)

Ts

N

Ts

N

[Au]

H+ +

Ph

O

N Me

N HO Me

L.A.

(574)

(573)

N

+

Ts

N O Ph

H

N Me

Ph

L.A.

1,5 H-shift

H O H

N Me

(575)

Ts

Ph

(576)

XH (Ph3P)AuCl (1 mol%) Ni(ClO4)2•6H2O (2.5 mol%)

(577) +

X O

(580) (2.5 mol%)

O

CHCl3, 35 °C

R

CO2Me

R

CO2Me (579)

(578) +

N O−

O Ar

N H

N

O

−O

H N

(580) Ar = 2,6-(Pr i)2C6H3

Ar

561

10 Addition Reactions: Polar Addition

Hydrosulfoximation of ynamides ArC≡CN(Ts)Me with sulfoximines Ph2 S(O)=NH, co-catalysed by Ph3 PAuCl (5 mol%) and TfOAg (10 mol%) in DCE at 40 ∘ C, has been reported to produce N-alkenylated sulfoximidoyl derivatives ArCH=C[N(Ts)Me]N= S(O)Ph2 , typically with ∼2:1 (E/Z) stereoselectivity. Subsequent oxidation with H2 O2 , catalysed by (p-cymene)RuCl2 (5 mol%) in CH2 Cl2 /MeCN at r.t. under aerobic conditions, proceeds via dihydroxylation of the C=C bond, followed by cleavage of the resulting diol to afford the urea-type sulfoximines Me(Ts)N–CO–N=S(O)Ph2 .380 The Au/Ag co-catalysed reaction of anthranils (581) with alkynes RC≡CH [R = alkyl, Ar, and N(Ts)Me] in the presence of MsOH (10 mol%) has been reported to produce 7-acylindoles (585) as a result of opening the original isoxazole ring and Friedel–Crafts attack at the neighbouring position. The mechanism was formulated as follows: coordination of [Au+ ] to the C≡C bond, followed by the isoxazole nitrogen nucleophilic attack, generates the Markovnikov-type iminium adduct (582), whose electrocyclic opening results in the formation of metallocarbene (583). Subsequent intramolecular Friedel–Crafts reaction gives the 𝜂 1 -Au complex (584) that undergoes protodeauration (with MsOH) to afford (585) as the final product.381 H

N: O

[Au]

(IPr)AuCl (5 mol%) Tf2NAg (5 mol%)

+

R

Au+

PhCF3, −20 °C, 1 h or 65 °C, 4 h

(581)

+

N

R

O (582)

[Au] [Au] R

R

N H

N H+

O

O

(585)

(584)

N

R

O (583)

1,6-Diynes, such as (586), with the propargylic carbonate group have been reported to undergo an Au/Ag-catalysed double cyclization, initiated by the 5(O)-exo-dig process at the propargyl moiety to generate (587), followed by a second 6(C)-exo-dig cyclization and subsequent deauration to produce (588). The latter mechanism is supported by DFT calculations.382 An interesting diversity has been reported for the oxidative cyclization of alkynyl anilines (589), mediated by oxone (KHSO5 ), which turned out to be catalyst dependent. Thus, with Au(III), the reaction proceeds via the 5(N)-endo-dig cyclization, and the arising indole (590) is oxidized to produce 4H-benzo[d][1,3]oxazin-4-ones (591). On the other hand, with Ag(I), the reaction involves the oxidation of the NH2 group followed by

de 

562

Organic Reaction Mechanisms 2016 OBut O

O

BnO Au+

BnO

O O

(JohnPhos)AuCl (8 mol%)

O

BnO

AgSbF6 (32 mol%) PriOH, DCE r.t., 24 h

BnO Au+

(586)

(587) O O O

BnO BnO (588) Au+

R

O

R

oxone (2 equiv) MeCN, 80 °C

NH2

O

[Au]

NaAuCl4•2H2O (5 mol%)

(589)

N H

N

(590)

(591)

R

AgNO3 (10 mol%) oxone (2 equiv) MeCN, H2O, 60 °C

R

O N (592)

O

R O

N (593)

a multistep cyclization of the arising nitroso intermediate (592) to afford benzisoxazoles (593). However, the yields are generally moderate owing to the formation of various amounts of byproducts, depending on the electronics of the substituents.383 The AuCl-catalysed aminoalkynylation of alkynes (594) with TIPS–EBX (595) has been reported to produce quinazolinols (596) as a result of the 6(N)-endo-trig cyclization, followed by transfer of the alkyne group from the reagent to the organogold intermediate.384

563

10 Addition Reactions: Polar Addition

(Pri)3Si MeO

N

O

I

+

R

O AuCl (5 mol%) MeCN, MeOH (95:5) 50 °C, 24 h

(594)

O

(595)

N R

Si(Pri)3 (596)

The 5(C)-endo-dig carbocyclization of o-alkynylaryl 𝛼-diazoesters 2-(RC≡C)C6 H4 C (CO2 Me)=N2 in conjunction with arylation by electron-rich aromatics, such as phenols (PhOH), anisole, and indole, catalysed by Ph3 PAuOTf (5 mol%) in CH2 Cl2 at r.t., has been developed as a method for the synthesis of indene derivatives (597). The reaction is believed to commence with the formation of metallocarbene from the starting diazo derivative, followed by a Friedel–Crafts-type attack on the PhOH and Au-assisted cyclization.385 NR2

OH N CO2Me

O

O R

Ar

O Ar

HO

R (597)

(598)

(599)

O-Allyl hydroxamates RC≡CCONH–OCH2 CH=CH2 undergo 5(O)-endo-dig cyclization, catalysed by PicAuCl2 in refluxing CH2 Cl2 , followed by a [3,3] sigmatropic rearrangement of the arising oxonium intermediate to produce 3-hydroxyisoxazoles (598) as a result of the final aromatization with a concomitant deauration.386 The Au-catalysed ring-closing oxyboration of alkynes was discussed in the subchapter on boron.144 A domino homodimerization of o-alkynylbenzaldehydes 2-(ArC≡C)C6 H4 CHO with secondary amines R2 NH, catalysed by L(MeCN)AuCl (L = 2-Ph-C6 H4 PCy2 ) (5 mol%)

564

Organic Reaction Mechanisms 2016

and AuSbF6 in DCE at 70 ∘ C, has been reported to produce the tetracyclic aminal (599). The reaction was rationalized as proceeding via a sequence of 6(O)-endo-digcyclization, initiated by Au(I), amine addition to the resulting oxonium intermediate, protodeauration, and a [4 + 2]-cycloaddition of the product of the latter step with another molecule of the oxonium intermediate.387 An intramolecular domino hydroamination/Michael addition of (600), affording the fused tetrahydrocarbazole derivative (602) with 76–93% ee, has been accomplished using a combination of (IPr)Au(NCMe) and the BINOL-derived phosphoric acid (603a) as catalysts. The reactive intermediate (601) was isolated in some instances.388 H+ Au+

O

(IPr)Au (NCMe) (5 mol%)

O

(603) (5 mol%) DCE, −20 to −10 °C NH2

MeO

N H

MeO

(600)

(601) (603) Ar O O

O

P

O

H

OH MeO N H

Ar (603a) Ar = 9-anthranyl (603b) Ar = 3,5-(CF3)2C6H3

(602)

The aza-Nazarov-type reaction of enynamides R1 CH=C(R2 )C≡CN(R3 )Ms with benzyl azides ArCH2 N3 , catalysed by (IPr)AuNTf2 (10 mol%) in the presence of 3 Å MS in DCE at 60 ∘ C, has been reported to produce 2-amidopyrroles (604). DFT calculations were employed to shed light on the mechanism, in particular the high regioselectivity.389 R2 Ms R1

N

N

R3 Ar (604)

ee 

565

10 Addition Reactions: Polar Addition

N-Propargyl pyrrole hydrazones (605) undergo an Au(III)-catalysed 6(N)-endo-dig cyclization to produce azomethine imines (606).390 NHTs N N

R

AuCl3 or (TfO)3Au

+

N

CHCl3, r.t.

N

− N Ts

R

AuIII (605)

(606)

A one-pot combination of the phosphines-catalysed Morita–Baylis–Hillman reaction of tosyl imides (607) with enones (608), followed by the gold-catalysed 6(N)-endo-dig cyclization to the pendant alkyne group, has been shown to afford dihydroisoquinolines (609). By employing MOP (610) as the catalyst for first step and the gold-t-BuXPhos complex (247b)(MeCN)AuSbF6 for the second, the products were obtained with 85–97% ee.391 N

Ts

O O +

1. (610) (20 mol%) THF, −15 °C, 36 h 2. (247b) (MeCN)AuSbF6 THF, 80 °C, 2 h

N

Ph (607)

Ts Ph

(608)

(609) OH PAr2

(610)

The gold(I)-catalysed 5(N)-endo-dig hydroamination of alkynes (611) has been found to be accompanied by the N-to-O-1,5-Ts migration, affording (612). In the presence of m-nitrophenol, the Ts group migrates to its hydroxyl, so that ketone (613) is obtained instead (under essentially identical conditions), together with ArOTs.392 O

OTs (Ph3P)Au NTf2

( )n N

CH2Cl2, 30 °C

R (612)

O (Cy3P)Au NTf2

( )n N

R 3-(NO2)C6H4OH Ts

(611) n = 1–3

+ ArOTs ( )n N

DCE, 30 °C

R (613)

ee 

566

Organic Reaction Mechanisms 2016

The Au(I)-catalysed rearrangement of 2-alkynyl-N-propargylanilines (614), affording (619), has been submitted to DFT calculation in order to rationalize the mechanism and the kinetics. According to this analysis, the reaction commences with the 5(N)-endo-dig cyclization, followed by a [3,3]-sigmatropic rearrangement of the resulting intermediate (615) to generate allene (616). Subsequent activation of the allene moiety with Au(I) via TS≠ (617) triggers a Nazarov-type cyclization, and the arising allylic cation (618) undergoes cyclization and protodeauration to give the final product (619). Formation of allene (616) was found to be rate limiting.393 OH

N Me

Et

(614) PriOH, 40–60 °C (IPr)AuSbF6 (5 mol%) 1–2 h

Au+ Et

•

[Au] OH +

N

N Me

Et

Me (615)

OH

(616)

[Au] Et

Et

[Au] O

+

Et

OH

N Me

N Me

N Me

(619)

(618)

(617)

OH

The stoichiometric reaction of allenol HOCH2 C(Ph)2 CH2 CH=C=CHMe with (L)AuOTs [L = P(t-Bu)2 o-biphenyl] has been found to proceed via a rapid and reversible 5(O)-exo-trig cyclization generating (620a) (Z/E ≥25:1), followed by a rate-limiting

567

10 Addition Reactions: Polar Addition

and stereochemically determining protodeauration, which gives (620b) (Z/E = 5:13). By contrast, cyclization of the homologous allenol HOCH2 C(Ph)2 CH2 CH2 CH=C=CHMe turned out to involve a rate-limiting 6(O)-exo-trig cyclization, followed by a rapid protodeauration.394 Alkoxylation of allenes, such as (R)-MeCH=C=CHCH2 OBz (98% ee), with alcohols, for example, BnOH, catalysed by (IPr)AuCl (10 mol%) and TfOAg (10 mol%) in DMF at 0 ∘ C, afforded allylic ethers (R)-MeCH(OBn)–CH=CHCH2 OBz with 96% ee. A plausible mechanism was proposed.395

de 

ee 

AuCl N

Ph Ph H N

O M

N H

H N

N H

N AuCl

(620a) M = AuL (620b) M = H

(621)

N H

Ph Ph OR

(622a) R = TIPS (620b) R = TMS

Hydroamidation of racemic allene PhCH=C=CHMe with BocNH2 , catalysed by (621) (5 mol%) and TfOAg (12 mol%) in dioxane at r.t., afforded (S)-PhCH= CH–CH(NHBoc)Me with 89% ee. By contrast, with Me3 SiN3 as the nucleophile and TFA, the opposite enantiomer (R)-PhCH=CH–CH(N3 )Me was formed (90% ee).396 Double catalysis with the prolinol derivative (622a) (20 mol%) and (IPr)AuNTf2 (5 mol%) in MeCN at r.t. allowed the addition of aldehydes RCH2 CH=O (via enamine intermediate) to allene Me(Ts)NCH=C=CH2 . The products Me(Ts)NCH=CH–CH2 CH (R)CH=O were obtained with 68–82% ee.397 Similar enantioselectivities (30–83% ee) were attained with (622b).398 A gold(I)-catalysed triple cyclization of the allene derivative (623) has been employed for the construction of the bicyclo[6.3.0]undecane ring systems spanned by an oxygen bridge (626). The proposed mechanism involves the initial 5(C)-exo-trig cyclization followed by a neighbouring carbonyl participation, which generates the oxonium ion (624). Its quenching via another ring closure forms metallocarbene (625), whose deauration gives rise to the final product (626).399

ee 

ee 

568

Organic Reaction Mechanisms 2016 Au+ •

(IPr)(MeCN)AuSbF6 (3 mol%)

E E

CH2Cl2, 23 °C

AuL

E

+O

E

O (623) E = CO2Me

(624)

LAu+ E

O

E

E

O

E H (626)

(625)

Another cooperative Au(I)/Ag(I) system, using [2-Ph-C6 H4 PCy2 ]AuCl (5 mol%) and TfOAg (10 mol%), has been shown to catalyse the reaction of enyne (627) with allenamide (631) to produce (635) in DCE at 25 ∘ C. The reaction was conjectured to proceed via two catalytic cycles (Scheme 16): one, in which silver effects the initial 5(N)-endo-dig ring closure via (628) to generate the silver-bound benzylic cation (629). In the meantime, the gold cycle starts with the activation of the allenamide (631) via (632) to generate the 𝛼-gold en-iminium (633), whose hydrolysis provides the 𝛼-gold enal (634). At this point the two cycles merge in a nucleophilic attack of the latter species (634) at (629), which generates the Michael adduct (630), whose protodemetallation then gives rise to the final product (635).400

(xx) Silver Hydrofluorination of alkynamides (436) and (438) with Et3 N⋅3HF, catalysed by Cu(I), can also be catalysed by Ag(I), as discussed in the subchapter on copper.299 The intramolecular hydroamination of tosyl-protected N-allylguanidines CH2 = CHCH2 N(Bn)C(NH2 )=NTs, catalysed by AgNO3 (15 mol%) in the presence of O2 or air and t-BuONa in chlorobenzene at 80 ∘ C, has been reported to produce cyclic guanidines (636) in essentially quantitative yield as a result of 5(N)-exo-trig cyclization. Interestingly, under anaerobic conditions with 10 mol% of AgNO3 , the reaction reached 60% conversion; full conversion was attained with 1 equiv of AgNO3 . These results show that O2 is not strictly required for the reaction to proceed, but the mechanism was not elaborated any further.401

569

10 Addition Reactions: Polar Addition N

Ph Ag+ N

Ph

Ph (628) Ph

Ph (627)

N

Ag

Ag+

Ag cycle +

Ph

Ph N

(629) Ph

CHO

N

Ag Ph

AuLn O

(635)

Ph (630)

O AuLn Au+ Ln

Au cycle

(634)

Ph N Ts

+

H PhNHTs

•

Ph H2 O

+

N

(631)

Ph

Ts

N AuLn

(633)

•

Ts +

Au Ln

(632) Scheme 16

570

Organic Reaction Mechanisms 2016

N

Ts

Ar

Ph O

BnN

F

NH N Ts

(636)

(637)

R

O

R S (638)

NPh

(639)

Another 5(N)-endo-trig hydroamination has been described for 𝛽,𝛽-difluoro-osulfonamidostyrenes, 2-(TsNH)C6 H4 C(R)=CF2 , which in the presence of AgSbF6 (10 mol%) and BSA (1 equiv) in boiling (CF3 )2 CHOH (HFIP) afforded 2-fluoroindoles (637). A plausible mechanism was proposed, including the 𝛽-fluoride elimination and the role of BSA as a base, which enables the NHTs group deprotonation and consequently the Ag+ -assisted cyclization.402 A remarkable control of the regioselectivity by variation of the reaction conditions has been reported for hydrotrifluoromethylthiolation of terminal alkynes ArC≡CH with AgSCF3 (1.5 equiv) in the presence of K2 S2 O8 (3.0 equiv). Thus, with CuCl (10 mol%) and H2 O (3 equiv) in DCE at 100 ∘ C, ArC≡CH afforded the Markovnikov products ArC(SCF3 )=CH2 . By contrast, anti-Markovnikov isomers RCH=CH(SCF3 ) were formed (E/Z ∼1:1 to ∼2:1) in the absence of CuCl and H2 O but in the presence of phen (10 mol%) and HMPA (50 mol%) in DMF at 80 ∘ C. The latter result apparently originates from a radical mechanism, for which some evidence was obtained from radical-trapping experiments, deuterium labelling, and KIE.403 The three-component reaction of terminal alkynes ArC≡CH with PhNCS and epoxides (638), catalysed by Ag2 CO3 in the presence of 3 Å MS in dioxane at 55 ∘ C, has been reported to produce 1,4-oxathian-3-imine derivatives (639).404 The Ag(I)-catalysed oxidative cyclization of alkynyl anilines (589), affording benzisoxazoles (593), has been discussed in the subchapter on gold.383 The mechanism of the related 6(N)-endo-trig oxidative cyclization of alkynylimine (640) with NFSI, catalysed by AgNO3 , involves the following steps: fast, Ag-assisted amination, generating the mesoionic Ag-carbene complex (641); rate-limiting fluorination to form (642); and the final elimination of isobutene, which affords the fluorinated isoquinoline (643).81 An Au(I)-catalysed domino reaction of alkynylaniline derivatives (644) with the donor–acceptor cyclopropanes (645) has been reported to produce the 2,3-disubstituted indoles (646) as a result of the Ag-mediated 5(N)-endo-dig cyclization of (644) followed by a ring-opening reaction of the resulting organosilver intermediate with (645).405 The silver-catalysed cyclization of o-alkynylbenzohydroxamic acids, such as (647), can be driven to either O- or N-cyclization and the consequent formation of either (650) or (653) by tuning the reaction conditions. Thus, with Ag2 O in EtOH, the hydroxamic moiety is presumably coordinated to [Ag], and the Ag-assisted hydroamination of the C≡C bond proceeds in a 5(O)-exo-dig manner to generate the Ag–vinyl complex (649), whose protodeargentation affords (650) as the final product. On the other hand, in the

de 

571

10 Addition Reactions: Polar Addition AgNO3

Ag+

Bun

N

F

But

NFSI AgNO3 (cat)

Bun +

Li2CO3, DMA

N

F

(640)

But

(641)

Bun

Bun

N

N

(643)

+

But

(642)

Ph

NHBn

CH(CO2Me)2

Ar

(644) AgSbF6 (10 mol%)

+ CO2Me CO2Me

DCE, 60 °C 3–12 h

Ph N Bn (646)

Ar (645) Ar = PMP

presence of silver imidazolate polymer [ImAg]n and, in particular, an excess of Ph3 P, (647) is converted into (651), which prefers the 5(N)-exo-dig cyclization, affording the structural isomer (653).406 Trifluoromethylthiolation of the propargylic alcohols 2-(HX)C6 H4 C≡CC(OH)Ph2 (X = O or NTs) with AgSCF3 (1.2 equiv) in the presence of BF3 ⋅Et2 O (1.5 equiv) in MeCN at r.t. has been found to produce the trifluoromethylthiochromene (654) and dihydroquinoline (655), respectively. Formation of the propargylic cation 2-(XH)C6 H4 C≡CC+ Ph2 can be envisaged at the outset of the reaction as a result of the action of BF3 . Subsequent rearrangement to allenic cation 2(XH)C6 H4 C+ =C=C(OH)Ph2 would then set the scene for the addition of Ag+− SCF3 , followed by a 6(X)-endo-trig cyclization and protodeargentation.407

572

Organic Reaction Mechanisms 2016

O

OBn

N N H

OBn

[Ag]

O

Ag2O (5 mol%)

N OBn O

EtOH, r.t.

OMe

OMe Ag

(647)

OMe X (649) X = [Ag] (650) X = H

+

(648)

[ImAg]n (5 mol%) Ph3P (2 equiv) EtOH, 70 °C

H + PPh3 O − OBn N [Ag]

O N OBn OMe

OMe Ag+ (651)

X (652) X = [Ag] (653) X = H SCF3

X

O

Ph Ph

(654) X = O (655) X = NTs

SCF3 R (656)

Br2Ga

O

OMe

EtO (657)

Trifluoromethylthiolation of aromatic alkynones C6 H5 COC≡CR (R = Ar, HetAr, and alkyl) with AgSCF3 and K2 S2 O8 (2 equiv) in the presence of NaHCO3 (1.5 equiv) in DMSO at 80 ∘ C afforded 2-(trifluoromethylthio)-indenones (656). The reaction apparently proceeds via a radical mechanism involving the initial generation of CF3 S∙ by a SET between AgSCF3 and K2 S2 O8 , radical addition across the C≡C bond to form the vinyl radical C6 H5 COC(SCF3 )=C∙ R, cyclization to the C6 H5 group, and subsequent oxidation of the resulting radical with K2 S2 O8 to the corresponding phenyl cation and its final aromatization.408

(xxi) Manganese MnI2 has been shown to catalyse the intramolecular iodoamination of amino alkenes R2 NHCH2 C(R1 )2 (CH2 )n CH=CH2 (n = 1 and 2; R1 = H, Me, and Ph; R2 Bn, Pri , and

573

10 Addition Reactions: Polar Addition

Ts) with NaI in the presence of NaHSO4 in EtOH at 35 ∘ C under aerobic conditions to produce mixtures of the corresponding piperidines and pyrrolidines as a result of the endo-trig and exo-trig cyclization, respectively. Furthermore, the 5(N)-exo-trig products were found to readily isomerize to 6(N)-endo-trig derivatives, presumably via aziridine intermediates. A mechanism assuming coordination of Mn to the amino group and chelation of the resulting complex –N(R)MnI to the C=C bond and consequently a syndelivery of the iodine and amino group to the C=C bond has been proposed; however, no compelling evidence was presented.409

(xxii) Gallium The reaction of silyl ketene acetals, such as Me2 C=C(OMe)OSiMe3 , with vinyl ethers, for example, CH2 =CHOEt, has been reported to occur in the presence of GaBr3 (10 mol%) in DCE at 80 ∘ C, affording CH2 =CHC(Me)2 CO2 Me. Based on monitoring the reaction by 1 H NMR, this outcome was rationalized as follows: GaBr3 , being a Lewis acid, activates the vinyl ether by coordination, which is followed by a nucleophilic attack of the ketene acetal to generate chelate (657), from which the final product is formed by a turnover-limiting elimination. The reaction of vinyl esters CH2 =CHOCOR proceeds in a similar way but differs in that it is now the initial GaB3 -assisted nucleophilic attack (carbogallation) that becomes turnover limiting. Stereospecific deuterium labelling of the vinyl ether, namely trans-DHC=CHOPh, has demonstrated the anti-stereochemistry of the carbogallation.410 (xxiii) Indium InBr3 (10 mol%) has been reported to catalyse the three-component coupling of terminal alkynes R1 C≡CH with primary amines R2 NH2 and Me3 SiCN in toluene at r.t., affording quaternary 𝛼-aminonitriles R1 C(CN)(NHR2 )CH3 in reminiscence of Strecker reaction. The transformation is assumed to commence as an In(III)-assisted hydroamination generating enamine R1 C(NHR2 )=CH2 , followed by its isomerization into imine RC(CH3 )=NR2 , and subsequent nucleophilic addition of Me3 SiCN. An intramolecular version, using RNH(CH2 )3 C≡CH, was found to proceed readily via a 5(N)-exo-dig cyclization.411 A domino halocyclization of N-propargylic sulfonylhydrazones, such as (658), mediated by InX3 (X = I, Br, and Cl), has been developed as a new route to 5,6dihydropyrazolo[5,1-a]isoquinolines (659). A plausible mechanism was proposed.412 Ar

I

N

Ar

NTs InI3 (1 equiv)

In3+

N

Ph

DCE, 70 °C

Ph (658)

(659)

N

de 

574

Organic Reaction Mechanisms 2016

(xxiv) Bismuth Stoichiometric BiCl3 (2 equiv) has been reported to effect trifluoromethylthioarylation of (3-arylprop-2-ynyl)oxybenzenes 4-Me-C6 H4 OCH2 C≡CPh and related substrates with PhNHSCF3 to afford 3-(trifluoromethyl)thiochromenes (660). Preliminary mechanistic studies suggest that the reaction is initiated by the activation of the reactant with BiCl3 , followed by an electrophilic attack of ‘CF3 S+ ’ at the C≡C. The resulting species then undergoes a Friedel–Crafts-type cyclization.413

Ph

Ph Me

R SCF3 M Ph

O Ar (660)

Ar Ar

(661) (662a) M = Sm, R = H, Ar = 2-(Me2N)C6H4 (662b) M = La, R = SiMe3, Ar = 2-(Me2N)C6H4

(xxv) Lanthanides The NHC–ytterbium(II) amide (IMe4 )2 Yb[N(SiMe3 )2 ]2 (IMe4 = 1,3,4,5-tetramethylimidazo-2-ylidene) has been reported to catalyse hydrophosphination of styrenes ArC=CH2 with Ph2 PH at r.t. to 60 ∘ C (depending on the electronics of Ar) to afford ArCH2 CH2 PPh2 . Mechanistic studies revealed that the latter complex is actually a pre-catalyst, from which the catalytic species (IMe4 )3 Yb(PPh3 )2 is formed in situ.414 An intramolecular alkyne–hydroarylation of 2-Ph–C6 H4 C≡C–Ar, giving rise to (661), has been attained with (TfO)3 Nd (5 mol%) in MeNO2 at 115 ∘ C; the newly formed aromatic ring is highlighted. A plausible mechanism, including an initial coordination of Nd3+ to the C≡C bond, was proposed, based on deuterium labelling and KIE.415 Hydroamination of substrates as sensitive as cyclopropenes (663) with secondary amines, for example, morpholine, has been attained with Sm and La Cp complexes (662a) and (662b). The resulting amines (664) were obtained with 82–99% ee and up to >20:1 dr. A plausible catalytic cycle, assuming a syn-addition of the Sm–N species across the C=C bond was proposed, which also addressed the stereochemical issues.416 R O R

Ar

+ N H

(663)

(662) (5 mol%) toluene, 25 °C 12 h

N O (664)

Ar

ee  de 

575

10 Addition Reactions: Polar Addition

Miscellaneous Electrophilic Additions FLP (C6 F5 )3 P/P(But )3 (10 mol%) has been reported to catalyse the addition of perfluorinated primary iodides Rf I to alkenes RCH=CH2 in CH2 Cl2 at r.t., affording RCH(I)–CH2 Rf . Mechanistic studies were inconclusive.417 The reaction of methylenecyclopropanes (C2 H4 )=CR2 with Me3 S–Rf (2 equiv), catalysed by CuI (10 mol%) in the presence of Cs2 CO3 in dioxane at 60 ∘ C, afforded ICH2 CH2 C(Rf )=CR2 as a result of the fluoroalkyl radical-mediated ring opening. In a similar way, Me3 Si–CF3 , in combination with PhI(OAc)2 , produced AcOCH2 CH2 C(Rf )=CR2 .418 Cyclic ethers (667a) have been synthesized by the Pd(II)-catalysed oxidative cyclization of carboxylic acids bearing a directing group (665a), which steers the catalyst approach and enables the crucial C(sp3 )–H activation. Lactones (667b) were obtained from the corresponding acids (665b) in the same way. A plausible mechanism, featuring the Pd(IV) chelate (666) as the key intermediate, was proposed.419 X

X OH

( )n

H H N

O N

O

(AcO)2Pd (10 mol%) PhI(OAc)2 (3 equiv)

( )n

NaHCO3 (2 equiv) toluene 105 °C, 24 h

OAc Pd

N

N O

(665a) X = H2, n = 1,2 (665b) X = O, n = 1,2

(666) X

( )n

O H N

N

O (667a) X = H2, n = 1,2 (667b) X = O, n = 1,2

N-Heterocyclic alkenes (669) have been shown to catalyse the carboxylative cyclization of propargyl alcohol (668) with CO2 , affording vinyl carbonates (671). DFT calculations revealed that the reaction is likely to proceed via an ion pair mechanism, according to which (669) is protonated by the OH of the propargyl alcohol, which triggers the reaction via the ion pair intermediate (670), stabilized by favourable orbital and charge interactions. The cation moiety in (670), which is aromatic, is the key feature that drives the reaction through a thermodynamically suitable channel. These calculations thus predict that the strongly electron donating and bulky N-substituents R1 /R2 should improve the catalytic activity of (669).420

576

Organic Reaction Mechanisms 2016

R1

HO

N

N

R2

R1

N

H

H

R2 O

(669)

H+

H O − O

CO2

(668)

N

−(669)

O

O

O (670)

(671)

The solvent-free one-pot reaction of primary amines RNH2 (2 equiv) with carbon disulfide CS2 (2 equiv) and dimethyl acetylene dicarboxylate MeO2 CC≡CCO2 Me (1 equiv) has been reported to produce birhodanine (672).421 O R

S

S

S

N

(Pri)3Si

13

C C

SPh

(Pri)3Si

C

13

C SPh

N

S O

R

(672)

(673a)

(673b)

The reaction of thiols, such as PhSH, with ethynylbenziodoxolone (595) labelled with at the CSi(Pri )3 terminus gave a 1:1.2 mixture of (673a) and (673b), which corresponds to two pathways, namely the 𝛼-addition followed by elimination and 𝛽-addition followed by 1,2-shift.422 Annulation of cyclic 𝛽-dicarbonyls (674) with propargylic alcohols (675), catalysed by Pd/BINAP and B(OH)3 , has been reported to produce (677), presumably via (676). The activation role of B(OH)3 in the formation of the 𝜋-allyl complex has been demonstrated.423 13 C

O

O

(674) X = CH2, O

O

OH

(AcO)2Pd (10 mol%) BINAP (20 mol%)

Ar

B(OH))3Pd (20 mol%) dioxane, 100 °C

+ Ar

X R

Ar

B(OH)3

Pd+

X O Ar

R

(675)

(676)

O

Ar

X R

Ar O

(677) X = CH2, O

577

10 Addition Reactions: Polar Addition

A [3 + 2] annulation of 2-alkynyl pyrrole PyrC≡CAr with isothiocyanates RNCS, promoted by K2 CO3 , has been shown to produce 1H,3H-pyrrolo[1,2-c]thiazol-3-imine (678).424 A metal-free addition of arylsulfonamide ArSO2 NHR to benzyne C6 H4 gives biaryls 2-Ar–C6 H4 NHR as a result of Truce–Smiles rearrangement.425 Ph

Ar SCF3 S

N

S

I N R

O

Ph

+

−OTf

CF3

(678)

(679)

Ar (681)

(680)

Addition of CF3 SAg to benzyne has been shown to generate the 1,2-adduct (679), which in the presence of PhC≡CI was converted into (680) in one pot, all in MeCN at r.t. The latter salt can serve as a potent trifluoromethylating reagent.426 Another transition metal-free reaction of benzyne C6 H4 with 𝛼-aryl ketones ArCH2 COPh, promoted by CsF, proceeds as an insertion of benzyne into the C–CO bond, giving rise to 2-benzylphenyl ketones (681) in DMF at r.t.427 The Pd-catalysed ring-closing addition of benzyne to ortho-iodo cinnamates (297), providing phenanthrolines (299), was discussed in the subchapter on palladium.225 The benzyne derivatives, such as (683), generated by a thermal cycloisomerization of triyne (682), have been reported to react with (684) and other cyclic sulfides to generate ylide (685), which abstract a proton from weak acids, such as (Boc)2 NH, and the resulting sulfonium species (686) undergoes a ring opening to produce (687).428 S

O

O SiMe3

Δ

HN

SiMe3

SiMe3

O

H

Me

Me (684) HN

HN

+

Me

S H

(682)

(683)

−

(685) HN(Boc)2

O

SiMe3

O N(Boc)2

HN

SiMe3 Me

HN

+

S (687)

S (686)

− N(Boc)

2

578

Organic Reaction Mechanisms 2016

Addition of diarylphosphine oxides Ar2 P(O)H to azobenzenes Ar′ N=NAr′ has been shown to proceed in the presence of Cs2 CO3 in MeCN at 100 ∘ C, affording the Psubstituted hydrazines Ar′ NH–N(P(O)Ar2 Ar′ .429

Nucleophilic Additions Linear dependences of the internal enthalpy constants 𝛿ΔHint ≠ on the 𝛿ΔG≠ and the Hammett 𝜌 constants have been found for the Michael-type additions to activated alkenes and alkynes.430

Additions to Multiple Bonds Conjugated with C=O DFT calculations revealed that the catalytic effect of iodine in nucleophilic additions to 𝛼,𝛽-unsaturated carbonyls and nitrostyrenes originates from the halogen bonding to the Michael acceptor (685), which results in the reduction of activation energies ΔG≠ by 1.8–7.6 kcal mol−1 .431

(i) Nitrogen nucleophiles A detailed computational study and kinetic analysis of the aza-Michael addition of primary and secondary amines to acrylates in aprotic solvents at M06-2X/6-311+G(d,p) level with CBS-QB3 corrections for solvation using COSMO-RS, and including diffusional contributions for the coupled encounter pair model, has been presented. The microkinetic model thus created proved to be in excellent agreement with experimental data obtained by GC analysis. These efforts allowed to formulate the following overall picture for the aza-Michael addition of RNH2 and RR′ NH to CH2 =CHCO2 Et: the favoured mechanism involves the conjugate addition to generate the zwitterionic enolate R2 NH+ CH2 CH=C(O− )OEt (which is in an equilibrium with the reactants), followed by a rate-controlling amine-assisted proton transfer (limited by diffusion) to the enolate carbon, affording the singly substituted product R2 NCH2 CH2 CO2 Et. The alternative Oprotonation, generating the corresponding enol R2 NH+ CH2 CH=C(OH)OEt, becomes competitive if bulkier substituents are present in the amine or at the double bond of the acrylate. Primary amines react faster than secondary amines due to an increased solvation of the zwitterionic intermediate and less sterically hindered proton transfer.432 Tautomerization of alkylbenzoquinones (C6 H4 O2 )CH2 R1 to the corresponding quinone methide has been reported to allow trapping by an amines R2 RR NH2 nucleophile, which results in the formation of benzylic amines (689). The reaction is promoted by tertiary amines in protic solvents under mild conditions.433 HO

R1

Nu H H

O H (688)

NR2R3

I—I

R HO (689)

579

10 Addition Reactions: Polar Addition

1,6-Conjugate addition of primary and secondary amines to cyclohexadienone (690) has been shown to produce aryl benzyl amines (691). In analogy, addition of phenols gives the corresponding aryl benzyl ethers.434 Cl

CO2Me

CO2Me

O

HO

RR′NH K2CO3, Me2CO r.t., 2–9 h

MeO

NRR′

MeO

Cl

Cl

(690)

(691)

The evergreen aza-Michael addition of lithium amides, generated from the enantiopure N-benzyl phenethyl amine PhCH(Me)NBn, has continued with 𝛽 ′ -amino-𝛼,𝛽unsaturated ester as acceptors.435 The syn-selective addition of primary and secondary amines RR′ NH to the mannitolderived (E)- and (Z)-enoates has been reported to afford the aza-Michael adducts (692). DBU accelerates the reaction, and (Z)-enoates exhibit higher stereoselectivity.436

de 

Ph O

N

O CO2Et RR′N (692)

N

N N

R

COR′ (693)

N R

Ph O

(694)

Aza-Michael addition of aromatic amines and aromatic aza-heterocycles to electrondeficient alkenes RCH=CHX (X = COEt, CO2 Me, SO2 Ph, and CN), catalysed by CuCl and t-BuOK in the presence of DEPPhos or dppbz, afforded the expected products.437 Imidazo[1,2-a]pyridines (693) were obtained via a one-pot I2 -induced aerobic oxidative addition of 𝛼-aminopyridines to chalcones RCH=CHCOR′ , mediated by AlCl3 .438 Addition of 3-substituted imidazo[4,5-b]pyridines to 1,3-diphenylprop-2-yn-1-one PhC≡CCOPh in refluxing MeCN/H2 O has been reported to produce pyrido[2,3b][1,4]diazocin-9-ones (694) in 8 days as a result of the ring opening of the imidazole moiety.439 Triphenylphosphine (10 mol%) has been shown to catalyse the (Z) → (E) isomerization of alkylideneoxazolones. The more reactive (E)-isomer (695) thus generated undergoes an enantioselective addition of hydroxylamines, catalysed by the BINOL-derived phosphoric acid (603a), to produce the anti-𝛼,𝛽-diamino acid derivatives (696).440 The chemoselectivity of the addition of isothiocyanate PhNCS to 2′ -amino chalcones 2′ -NH2 C6 H4 CH=CHCOR can be controlled by the solvent: thus, 3,4dihydroquinazoline-2-thiones (697) were obtained in CH2 Cl2 at 40 ∘ C in 12–36 h, as a result of the aza-Michael reaction, whereas thia-Michael addition was favoured by DMSO at r.t., resulting in the formation of 2-imino[1,3]benzothiazines (698) within 1–3 h.441

ee  de 

580

Organic Reaction Mechanisms 2016 R

Boc O O

N

N (603a) (4 mol%)

+

Boc

N H

OH

R

O

CH2Cl r.t., 24 h

Ar

O

HN

O Ar

(695)

(696) O

O R

N N (697)

R N

Ph S

CO2R

S N H (698)

N

Ph N (699)

Double Michael addition of tetrahydrodiazocines to chiral propiolic esters HC≡CCO2 R* has been reported to afford Tröger base (699) with ≤74:26 dr. Protic solvents facilitate the first intermolecular step.442 Conjugate addition of anilines XC6 H4 NH2 to 3-butyn-2-one HC≡CCOMe in EtOH gives enaminones (XC6 H4 NH)CH=CHCOMe, which exhibit dynamic E/Z interconversion, as revealed by in situ FTIR, with 𝜈 CO = 1670 and 𝜈 CO = 1640 for (E) and (Z) isomers, respectively. The (Z) isomers seem to prevail,443 possibly due to the intramolecular hydrogen bonding. The reaction of tertiary amines Et3 N with 2-propiolylazulene 2-(HC≡CCO)Az generates the ammonium enolate Et3 N+ CH=C=CO− Az, which upon the elimination of CH2 =CH2 gives trans-enaminone Et2 NCH=CHCOAz. The reaction is accompanied by colour changes.444 The three-component reaction of phosphine chalcogenides RR′ P(H)=X (X = O and S), quinoline, and alkyl propiolates HC≡CCO2 R′′ has been shown to produce adducts (700) in reminiscence of Reisert reaction. Isoquinoline and acetylene dicarboxylates react in a similar way.445 The reaction of o-phenylenediamine with ynones PhC≡CCOAr generates benzodiazepines (701), which under O2 atmosphere and in the presence of t-BuOK in DMSO undergo oxidation of the CH2 group, followed by extrusion of CO2 , giving rise to quinoxalines (702) in one pot. A radical mechanism was excluded.446 A three-component reaction of guanidines, R2 NHC(NR2 )=NH, trichloroacetonitrile Cl3 CC≡N, and acetylenic esters R′ C≡CCO2 Me, carried out at r.t. in CH2 Cl2 , resulted in the formation of pyrimidines (703).447 The reaction of acetylenic aldehydes 2-(OHC)C6 H4 C≡CCO2 Me with NH2 OH has been found to involve an aza-Michael cyclization, producing N-hydroxy-2.3-dihydroisoindolin-1-ones (704), presumably via nitrone intermediates.448

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581

10 Addition Reactions: Polar Addition Ar

N X PRR′

N

N

N

Ar

N

Ph

Ph

CO2R′′ (700)

(701)

NR2

O

R2

CO2Me

N Cl3C

(702)

X

N OH N

R′

N S

R1 CO2Me

(703)

(704)

Ar (705) X = O, NH, NCN, NAr

1,2-Thiazines (705) were obtained from sulfone analogues Y=S(Me)(R1 )=NH (Y = O, HN, NCN, and ArN) and alkynones R2 C≡COAr via a domino Michael addition–cyclization–dehydration.449

(ii) Oxygen nucleophiles Cyclohexadienone (690) undergoes 1,6-conjugate addition of phenols (ArOH) in a similar way as discussed for the addition of amines, affording aryl benzyl ethers.434 The macrocyclic hydroxy enone (706) has been found to readily undergo a reversible transannular oxa-conjugate addition, giving rise to a mixture of the cis-pyran (707) and its trans-isomer (9:1). The reaction is thermodynamically controlled, with (707) being lower in energy by 1.4 kcal mol−1 , owing to the fact that the trans-isomer can only exist in a twisted-boat conformation of the pyran ring, as shown by calculations.450

O

O

de 

O H O

O O O

O (706)

(707)

The reaction of quinols with trifluoromethyl ketones ArCOCF3 in CH2 Cl2 , catalysed by (DHQ)2 PHAL, afforded 1,3-dioxolanes (708) at r.t. over 3 days with ≤80% ee and ≤97:3 dr as a result of ketalization followed by oxa-Michael cyclization.451

ee  de 

582

Organic Reaction Mechanisms 2016 O

R

O O F3C

Ar

(708)

Reaction of the N-methylquinolinium salt (709) with NaOH has been reported to produce betaine (711), presumably via the cyclized intermediate (710). DFT calculations suggest that the C≡C bond is distorted towards the transoid geometry. By contrast, under acidic conditions the reaction afforded isochromene (712).452 HO−

HO

NaOH

O −

+

N

H

H OH

O

Me

−O

+

N

OH

H

Me (709)

(710)

H+

− OH−

O −

O +

O

O

+

N

N Me (712)

Me (711)

(iii) Sulfur and selene nucleophiles Michael addition of thiols Ar2 SH to cinnamic acids and esters Ar1 CH=CHCO2 R, and enones, catalysed by the cinchonidinium salt (713) (6 mol%) in the presence of TBAF (20 mol%) in water, has been reported to produce sulfides (714) with 91–100% ee.453

ee 

583

10 Addition Reactions: Polar Addition

+

SAr2

Br−

N

Ar

CO2R

Ar1

OR N (713) R = CH2CH=CH2

(714)

DFT calculation shed light on the reversibility of the Michael addition of thiols (MeSH as a model for cysteine) to Michael acceptors, namely PhCH=CHCO2 Me and PhCH=CHCN versus the doubly activated derivative (E)-PhCH=C(CN)CO2 Me. The reversibility observed for the latter substrate was attributed to the much lower energy of the TS≠ (7.2 kcal mol−1 ) as compared to the former two substrates (17.0 and 15.7 kcal mol−1 , respectively), where the stabilization by just one EWG group is weaker.454 Addition of thiols RSH to Michael acceptor (715) has been reported to afford adducts (716). The stereochemistry corresponds to the protonation of the intermediate enolate from the concave side, which proceeds through a TS≠ , which is by 1.5 kcal mol−1 lower in energy than that corresponding to the convex side protonation, as revealed by calculations at the PCMTHF/M06-2X/6-31+G(d,p) level.455 O O

SR

O N

O O

MeO

RSH Et3N THF, 25 °C

O

N

O O

MeO (715)

(716)

Calculations have revealed that Michael addition of MeSH to 𝛼-substituted acrylates CH2 =C(X)CO2 Me (X = F, Cl, Me, H, CN, and NO2 ) is a highly non-synchronous process.456 Calculations show that stereochemistry of the addition of thioacetic acid to the paraquinone methides (717), catalysed by the BINOL-derived phosphoric acid (603a), is controlled by the unique involvement of a molecule of water that provides an unprecedented O–H· · ·𝜋 interaction with the aromatic nucleus of the catalyst in the TS≠ (719). Experiments further showed that while the Michael adduct (718) is obtained in 92% ee in the presence of 2–10 mol% of water, the enantioselectivity drops to mere 40% ee in ee its absence.457  2 1 Addition of thiols R SH to 𝛼,𝛽-unsaturated N-acylpyrazoles R CH=CHCO(pyrazolyl), catalysed by the iridium complex (720a), only works for R2 = Ar. However, introduction of the N-pyrrolidine moiety into the catalyst, as in (720b), which increased the complex basicity by 3 pKa units, has been shown to extend the scope of the catalyst to aliphatic thiols (R2 = alkyl).458

584

Organic Reaction Mechanisms 2016 O But

OH But

(603a) (2 mol%)

O +

H2O (10 mol%)

CH3

SH

CCl4, 25 °C 48 h

O

Ar

Ar

S

(717)

CH3

(718)

H O O

O P

O

O H

O

H

H

S

CH3 Ar

O

H

(719)

N C

X N

Ir N

C N

R2

EWG R1

N N H

(720a) X = H (720b) X = N-pyrrolidyl

S

CHO

Ph (721)

Michael–aldol domino reaction of 2-mercaptobenzaldehyde with 𝛽-indole-𝛽-CF3 enones as Michael acceptors, catalysed by various cinchona-derived squaramides,  ee afforded the 2-CF3 -2-indole-substituted thiochromanes with >20:1 dr and 96% ee.459  de DABCO has been reported to catalyse the reaction of mercaptoacetaldehyde HSCH2 CH=O (which exists as a cyclic dimer) with 1,3-enynes R1 CH=C(EWG)C≡CR2 . The initially generated Michael intermediate then undergoes a 5-exo-dig carbocyclization, followed by air oxidation, to afford the tetrasubstituted thiophenes (721).460 The thia-Michael addition, resulting in the formation of 2-imino[1,3]benzothiazines (698), was mentioned earlier.441

585

10 Addition Reactions: Polar Addition

(iv) Phosphorus nucleophiles The Michael addition of 2-(Ph2 P)C6 H4 CO2 H to CH2 =CHCO2 H has been found to be 1.4–2.1 faster than the addition of Ph3 P, which implies participation of the neighbouring CO2 H group of the former reagent in stabilization of the intermediate zwitterion by intramolecular hydrogen bonding to the carbonyl oxygen of the acrylic acid as a proton acceptor.461 Amine-catalysed phospha-Michael addition of N-heterocyclic phosphine thioureas (722) to cinnamaldehyde PhCH=CHCH=O and other 𝛼,𝛽-unsaturated aldehydes and ketones has been reported to produce (723) upon the loss of the thiourea moiety.462 O

Ph N

P

O

N H

N

Ph Ph

N H

+

N

CHO

Ph

O

CHO

P Ph

N

Ph

Ph (722)

(723)

Addition of (RO)2 POH to p-quinone methides, such as (717), catalysed by the Nheterocyclic carbene (724), has been shown to afford 1,6-adducts (725).463 Hydrophosphination of enones with R2 PH, catalysed by Pd(II), will be detailed in the subchapter on metal-catalysed nucleophilic addition.464 OH But Mes

N

+

But

N Mes CO2− Ar

(724)

P(O)(OR)2 (725)

(v) Halogen nucleophiles Titanium tetraiodide has been shown to mediate the iodide addition to enynes (726). The resulting allenic enolates (727) can be trapped with aldehydes or imines, thus effecting aldol and Mannich reaction, respectively.465 O−

O Ph

OEt OEt (726)

TiI4 (1.3 equiv)

Ph

•

I

CH2Cl2, −50 °C

EtO (727)

OEt

586

Organic Reaction Mechanisms 2016

(vi) Hydride as nucleophile Hydrosilylation of 𝛼,𝛽-unsaturated esters and amides R1 CH=CHCOX (X = OR2 and NR2 2 ) with R3 3 SiH, catalysed by (C6 F5 )3 B, has been found to first generate silyl enols R1 CH2 CH=CO(SiR3 3 )X, which gradually taumerize to afford the 𝛼-silyl carbonyl derivatives R1 CH2 CH(SiR3 3 )–COX.466 (vii) Carbon nucleophiles Michael addition of MeNO2 and other nitroalkanes to enones ArCH=CHCOMe, catalysed by 9-amino(9-deoxy)-epi-quinine (728a) (20 mol%) in the presence of proton sponge or DBU or another base (20 mol%) and PhCO2 H (40 mol%) at 30 ∘ C over 96 h (the nitroalkane also serving as a solvent), gives rise to (S)-ArCH(CH2 NO2 )–CHCOMe with 65–99% ee. The reaction is assumed to proceed via the corresponding imine intermediate, where the protonated quinuclidine steers the nitroalkane by hydrogen bonding to the NO2 group.467 However, this reviewer is concerned with the composition of the reaction mixture: note that half of the PhCO2 H is neutralized with the proton sponge, which leaves the remaining 20% of the acid free to protonate the quinuclidine nitrogen. Would just adding only 20 mol% of PhCO2 H (without the base) be sufficient for the reaction to proceed? MeO

OH

O O

X O

N

N O NH2

O

O

O

N Ph (728a) X = MeO (728b) X = H

(729)

But

N

But

MeO N

O M H O

O O But

N

HN

H N

O

O

N

But (730) M = Yb, Y, Sc

CF3

(731)

CF3

ee 

587

10 Addition Reactions: Polar Addition

Michael addition of CH2 (CO2 Et)2 , AcOCH(CO2 Et)2 , and other malonate esters to chalcones Ar1 CH=CHCOAr2 under the conditions of phase-transfer catalysis using Na2 CO3 (2 equiv) and the glucose-derived azacrown ether (729) (15 mol%) in Et2 O–THF (4:1) proceeded with 33–99% ee.468 The same reaction, catalysed by the dimeric complex (730) (M = YbIII , YIII , and ScIII ), afforded the products with 77–90% ee.469 Michael addition of dimethylallyl malonate CH2 =CHCH2 CH(CO2 Me)2 to endotricyclo[5.2.1.02,6 ]deca-4,8-dien-4-bromo-3-one has been reported to proceed readily at r.t. over 30 min in the presence of DBU and water (1 equiv each).470 Michael addition of C-, N-, O-, and S-nucleophiles to CH2 =C(F)COR (R = Alk and Ph) also readily proceeds in the presence of a base (Et3 N, K2 CO3 , DBU, etc.).471 The quinine-derived squaramide (731) (10 mol%) has been found to catalyse the Michael addition of ArCH(CN)CO2 But to CH2 =C(Me)COC(Me)2 OH in DCE at 50 ∘ C, affording (But O2 C)(Ar)C*(CN)–CH2 –C*H(Me)COC(Me)2 OH with 90:10 to 98:2 dr and 91–98% ee. The initial nucleophilic addition, creating the first chiral centre, is believed to be stereocontrolled by the hydrogen bonding between the two NH groups of the catalyst and the C=O of the Michael acceptor, together with the steering of the nucleophile by hydrogen bonding between the C=O and the protonated quinuclidine nitrogen. The final protonation of the arising enolate occurs by abstracting the proton from the quinuclidinium moiety.472 A domino Michael addition of cyclic silyl ketene acetal (732) to a 𝛽-substituted-𝛼alkoxycarbonyl-cyclopentenone (733), catalysed by the Lewis acidic Cu(II), has been reported to afford (734).473

OBn

Me3Si

CH2Cl2

O O O

O (732)

ee  de 

O

(TfO)2Cu

O

O

ee 

CO2Me OBn

CO2Me O

ee 

(733)

(734)

The racemic Michael adduct with two adjacent chiral centres (735) was obtained diastereoisomerically almost pure (>20:1 dr) by addition of the alanine-derived azlactone to dibenzylidene acetone in the presence of the galactose-derived organocatalyst (736) (20 mol%) in CH2 Cl2 at r.t. over 24 h.474 Addition of the enantiopure (R)-N-tert-butanesulfinyl imidates RCH2 C(OMe)=NS(O) But , deprotonated by LDA, to 𝛼,𝛽-unsaturated pyrazolidinone resulted in the formation of pyrazolidinones (737) at −78 ∘ C in THF with ≤97:3 dr.475 Deprotonation of allylic ethers (738) (R = Me, i-Pr, and c-Hex) with LDA triggered the Michael 4(C)-exo-trig cyclization, giving rise to oxetanes (739) as single diastereoisomers. The benzylic congeners of (738) behaved in the same way. An alternative pathway, starting with deprotonation of the 𝛾-position, followed by Wittig [2,3] rearrangement, which is known for the substrates with R = H, was not observed, presumably due to the enhanced steric congestion.476

de 

de 

de 

588

Organic Reaction Mechanisms 2016

PMB

O O

Ph

O

O

CO2H PMB N

NH

CO2Me

O

O Ph

O N

Ph

O

N

O

OMe

R O

N

+

S

But

−O

(735)

(736)

(737)

CO2Me LDA

O

N R

(738)

N

CO2Me

THF −78 °C → r.t.

R O (739)

Sequential Mukaiyama–Michael reaction, induced by the carbon acid (740) and combining two different Michael acceptors, can be regarded as an illustration of the power domino reactions (Scheme 17): In the first step, (740) protonates the silyl ketene acetal (741), generating the stabilized anion (742) and the oxonium species (743). The latter transient intermediate then transfers the TBS group onto the 𝛼,𝛽-unsaturated lactone (744), and the resulting activated oxonium species (745) undergoes Michael addition with another molecule of (741) to generate the silyl ketene acetal (746). The latter intermediate then reacts with enones as second Michael acceptors (e.g., MVK) to give (747) as the final product.477 (2-Aminoaryl)divinyl ketones (748) have been reported to undergo a domino process (Scheme 18), commencing with the initial Michael addition of MeNO2 and other nucleophiles in the presence of DBU. The first step thus generates the Michael adduct (749), whose deprotonation allows the 6(C)-endo-trig Michael cyclization. The resulting cyclohexane derivative (750) undergoes an intramolecular hemiaminalization to afford 3,4-benzomorphan (751) as the final product with high diastereoselectivity.478 Mixed anhydrides (752) (R1 = Ar, HetAr, and alkenyl), generated from the corresponding acids and t-BuCOCl, have been reported to react with the saccharine-derived Michael acceptors (753) in the presence of the thiourea-derived organocatalyst (755), affording lactams (754) with 80:20 to 95:5 dr and 40–99% ee.479 A related cyclization, employing ent-(755) and its analogues as organocatalysts, has also been successful (>95:5 dr and ≥95% ee).480

de  ee  de  ee  de 

589

10 Addition Reactions: Polar Addition OH O O − S CF3

OH OTBS H

(740)

Tf

O (741) +

O

S O

O

(743)

TBS O

(743)

OEt

CF3

(742)

O

OTBS

+ H

O H

OEt HO Tf

+

O

TBS O

(741)

(− CH3CO2Et)

EtO (744)

(745)

O

O (746)

O O O

EtO2C (747) Scheme 17

Triflic acid TfOH (10% in pyridine) has been shown to undergo a 1,6-addition to 1,5diarylpent-2-en-4-yn-1-ones Ar1 –C≡CCH=CHCOAr2 , which gives butadienyl triflates Ar1 -C(OTf)=CHCH=CHCOAr2 at r.t. in 15 min. If carried out in neat TfOH, the latter product undergoes further cyclization.481,482 Ylide (757), generated from the corresponding sulfonium bromide by deprotonation with DBU, has been shown to react with the sterically hindered p-quinone methides (756) in CHCl3 upon the formation of the spirocyclic cyclopropanes (758) with >20 dr.483 Addition of vinyl azide CH2 =C(Ph)N− –N+ 2 to 𝛼,𝛽-unsaturated esters, such as PhCH=C(CO2 Me)2 , catalysed by TiCl4 at 40 ∘ C in CH2 Cl2 , afforded pyrroline (759).484

de 

590

Organic Reaction Mechanisms 2016 O

O

H2N

H 2N

CH3NO2 DBU (1 equiv)

Ar

Ar

MeCN, r.t.

NO2

(748)

(749) DBU

O OH H 2N

HN Ar O2N

Ar NO2

(751)

(750) Scheme 18

O R1

N

O But

O

+

(752)

O S O

R2 (753)

(755) (5 mol%) CH2Cl2 r.t. or −78 °C

N O R1

O N

S O

Ph

N

S (755)

R2 (754)

Another synthesis of pyrrolines, namely (760), was attained via a Michael addition of the glycine-derived Schiff base 4-Me-C6 H4 C=NCH2 CO2 Me to chalcones Ar1 CH=CHCOAr2 , catalysed by the silver complex of Xing-Phos (761) in the presence of HCl. The resulting cis-diastereoisomer (760) was obtained with ≤97% ee as a kinetic product that can be isomerized to the trans-isomer by DBU.485

ee  de 

591

10 Addition Reactions: Polar Addition But

But +

O Ar

−

CO2Et

CO2Et O

+

SMe2

But (756)

But

Ph

(758)

Ar1 O

Ph

N

Ar

(757)

CO2Et CO2Et

Ar2

(759)

CO2Me

N

H N

S t

Bu

PPh2 Ph

(760)

N(Pri)2

O

(761)

Vinylogous Michael addition of 𝛾-butyrolactones (763) to 𝛼,𝛽-unsaturated 7azaindoline amides (762), catalysed by the Lewis-acidic copper(I)-complex of (R)-xylyl-BINAP (766) in the presence of a Brønsted base, afforded the adduct (765) with >20:1 dr and ≤95% ee. The Cu(I) chelate (764) was intercepted as an intermediate by NMR spectroscopy.486 CuL N

O N

R2 R1 + O O

(762)

(MeCN)4CuPF6 (1 mol%) (766) (1.2 mol%)

N

O R1

N

(Me2N)2C=NBut (5 mol%) THF, − 40 °C

(764)

(763)

PAr2

N

O

R1

PAr2 N

(766) Ar = 3,5-xylyl

R2 (765)

O O

The anion generated by deprotonation of (R)-PhSO(NTs)CH2 Cl with LiHMDS has been reported to react with the 𝛼,𝛽-unsaturated Weinreb amides RCH=CHCON(Me) OMe, affording (sulfonimidoyl)cyclopropanes (767) via a selective C–Cl bond cleavage in the final cyclization step with >99:1 de. Here, the Weinreb amide group, together with the counterion, play the key role for the reaction to proceed this way. On the other

ee  de 

592

Organic Reaction Mechanisms 2016

hand, the reaction of the same nucleophile with PhCH=C(CN)2 gives rise to (768) (62–72% ee) as a result of the C–S bond cleavage in the final cyclization.487 TsN Ph

S

O

Cl

O R1 O

O

R

N

OH

CN

Ph CN

Me (767)

R2

X

(768)

(769) X = CH2, (CH 2)2, NTs

The triflic acid-catalysed cyclization of enynes R1 C≡CCH2 CH2 (X)CH=CHCOR2 affords diketones (769). The reaction is initiated by protonation of the carbonyl group, followed by an exo-trig cyclization with the C≡C bond serving as a Michael nucleophile. The resulting cyclic vinyl cation is quenched by water, which creates the second carbonyl.488 Conjugate addition of 𝛽-dicarbonyls, such as (771), to enynes (770) has been shown to proceed with a C–C bond fragmentation and ring expansion via (772) → (773) → (774) to produce (775).489 O−

O

•

CO2Et

Ph

+

Cs2CO3 (1.5 equiv)

O

O

DMA, 30 °C

Ar (770)

Ph

(771)

(772)

O− O

Ph

Ar CO2Et

CO2Et

O

O

OEt

Ar

Ar Ph

Ph HO

O −O

Ph

OEt

O (775)

(774) (773)

Enolates generated from aryl ketones (777) have been reported to add across the C≡C bond of 2-fluorophenylacetylenes (776). Subsequent in situ enolization of the resulting adduct (778) and its trans/cis isomerization to generate (779) is followed, under harsh conditions, by an SN Ar cyclization to produce benzoxepines (780).490 Calculations using the B3LYP method and 6-311++G(d,p) basis set shed light on the reaction of Ph3 P and dialkyl acetylenedicarboxylates in the presence of thiols, such as

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10 Addition Reactions: Polar Addition

O Ar

F (776)

Ar

ButOK

+

DMSO 120 °C, 1–12 h

O

F

(777)

(778) base

O

F

−O

Ar

(780)

Ar

(779)

2-NH2 C6 H4 SH or amines RR′ NH (as S–H and N–H acids, respectively). The first step, that is, the ylide formation, was found to be rate limiting in both instances.491,492 The reaction of 2H-pyrido[1,2-a]pyrimidine-2,4(3H)-dione, isocyanides R1 NC, and dialkylacetylenedicarboxylates R2 O2 CC≡CCO2 R2 in DMF at 100 ∘ C has been reported to produce tricyclic fused pyrano[2,3-d]pyrido[1,2-a]pyrimidines as a result of the initial isonitrile addition across the C≡C, followed by deprotonation of the 𝛽-dicarbonyl moiety and cyclization.493 In a related study, reaction of R1 NC, R2 O2 CC≡CCO2 R2 , MeCOCH2 CO2 Et, and N2 H4 has been shown to produce pyrazolo[1,2-a]pyrazoles (781). With PhNHNH2 employed instead of N2 H4 , the reaction afforded pyrano[2,3-c]pyrazoles.494 R1NH

O Ar

N

R2O2C

N

R2O2C

NHR3 R1 N

O

O

O O

R2

H N

O R

(781)

(782) Ar = N-heteroaryl

(783)

A domino Ugi/Michael reaction of (N-HetAr)CH=O, R1 NH2 , RC≡CCO2 H, and carried out in MeOH at r.t. or 50 ∘ C, opened a new access to 𝛼,𝛽-unsaturated 𝛾-lactams (782) with 5-endo-dig cyclization as the key step.495 R3 NC,

Enamines Mechanistic investigation of the organocatalysed Michael, Mannich, and aldol reactions revealed a rapid 16 O/18 O exchange in the presence of H2 18 O. Therefore, the use of H2 18 O would be inappropriate for distinguishing between the enamine and enol pathways.496

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Organic Reaction Mechanisms 2016

Aldehydes RCH2 CH2 CH=O, which form, in situ, the corresponding enamine with the tripeptide catalyst d-Pro-Pro-Asn-NH2 ⋅TFA (5 mol%), have been shown to react with unprotected maleimide in the presence of N-methylmorpholine (5 mol%) in CHCl3 /MeOH (1:1), to afford the Michael adducts (783) with ≤94:6 dr and ≤98% ee. Hydrogen bonding between the catalyst and maleimide is believed to be key for the reaction to proceed efficiently.497 Diphenylprolinol silyl ether (784a) (2 mol%) has been reported to catalyse the addition of MeNO2 to 4-Cl–C6 H4 CH=CHCH=O in the presence of HCO2 H (20 mol%) in MeOH at r.t. over 40 h. The resulting Michael product (785) was obtained with 92% ee. Notably, the starting aldehyde was obtained in the same pot prior to the Michael addition by aldol condensation of 4-Cl–C6 H4 CHO with acetaldehyde, catalysed by DBU (20 mol%). And still in the same pot, the Michael product was oxidized with NaClO2 , and the resulting acid was hydrogenated on Raney-Ni, again in the same pot, to afford baclofen, a GABAB receptor agonist.498 The bifunctional primary amine (786) has been shown to catalyse addition of 𝛼-branched aldehydes R2 CHCH=O to N-substituted maleimides with 60–89% ee.499

ee  de 

ee  ee 

O Ar N H

Ar OR

(784a) R = SiMe3, Ar = Ph (784b) R = H, Ar = Ph

N H

NO2

Ar

H2N

N H

(785)

C12H25

O

N

H

N H (786)

O EWG

HN

SO2

(787)

X (788) X = H (789) X = NHR

𝛼-Activated propionic aldehydes MeCH(EWG)CHO (EWG = CO2 R, COSEt, and CN) were added to cyclohexenone in a reaction catalysed by the proline-derived sulfonamide (787), giving rise to bicyclo[2.2.2]octanes (788) with ≤20:1 dr and ≤56% ee. Analogous amines (789) (≤20:1 dr, ≤92% ee) were obtained when additional primary amines RNH2 were present in the reaction mixture.500 The cinchonine-derived primary amine (793) has been reported to catalyse the addition of enones (791) (via enamine) to indanedione (790), that affords the spiro derivatives (792) with up to >20:1 dr and ≤99% ee. Their enantiomers were obtained from the reaction catalysed by the quinine-derived amine (728a).501

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595

10 Addition Reactions: Polar Addition O

O

R1 +

2 O R

(793) (cat) 2-(NO2)C6H4CO2H (cat)

R2

O

CH2Cl2, 30 °C

O R1

O (791)

(790)

(792)

O NH2

H N

N

O (793)

R2

O

S O

HN R1 (795)

Ph

O (794)

O

R2S

R N

Ar

O R1 (796)

Iminiums Formation of the Michael adducts (785)498 was included in the previous subchapter. The helical peptide Trp-Trp-[Leu-Leu–NH–(C5 H8 )CO]2 OMe (20 mol%), which can form the corresponding imine intermediate with enones R1 CH=CHCOR2 through its terminal NH2 group, has been shown to catalyse Michael addition of RCH2 NO2 and 𝛽-dicarbonyls in the presence of PhCO2 H (100 mol%) in THF at 40 ∘ C. The respective products were obtained with 80–99% ee.502 The proline-derived sulfonamide (787) has successfully catalysed the Michael addition of azlacones to cyclic and non-cyclic enones, affording products, such as (794), with >20:1 dr and 24–94% ee.503 Michael addition of isorhodamines to 𝛼,𝛽-unsaturated aldehydes R1 CH=CHCH=O, catalysed by (784a) (10 mol%) in toluene at r.t., afforded thiazolone (795) with up to >99% ee.504 Vinylogous Michael addition of 𝛾-substituted aryl enones ArCOCH=CHCH2 R1 to 𝛼,𝛽-unsaturated aldehydes R2 CH=CHCH=O, catalysed by ent-(784a) and carried out in the presence of Et3 N and PhCH2 CH2 CO2 H in MeOH at r.t. over 3 d, afforded (796) with 87–98% ee, presumably as single diastereoisomer.505 A computational study506 has disputed the previously proposed507 directing electrostatic interaction of the negative carboxylate group of the iminium intermediate (797) with the positive thionium moiety of ylide (798) in the cyclopropanation reaction that

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Organic Reaction Mechanisms 2016

gives (799). The latter effect was supposed to reduce the activation energy.507 However, the calculations506 suggest that the selectivity of this reaction originates from several strong hydrogen bonding interactions between the two reacting species, while little evidence was found for the electrostatic interaction. These hydrogen bonds do not seem to accelerate the reaction by lowering the activation energy of the RLS but rather by promoting efficient reaction trajectories via a long-range complexation of the reactants. Furthermore, the cyclopropanation proceeds via a two-step mechanism, and the overall enantioselectivity is dependent on the relative energies of the two steps, averaged by the relative populations of the initially formed iminium intermediates (797).506 CO2− O

+

Ph

O

N

+ Ph

+

Me2S

−

Ph O

H Ph

(797)

(798)

(799)

The benzylic chloride 2,4-(NO2 )2 C6 H3 CH2 Cl, an ambident reagent (both nucleophilic and electrophilic), has been found to enable cyclopropanation of enals RCH=CHCH=O, catalysed by (784a) (20 mol%) in the presence of (Pri )2 NEt in CHCl3 at 0 ∘ C. The cyclopropyl derivatives (800) were obtained with 1:1:1 to 9:2:1 dr and ≤99% ee.508

ee  de 

CH O

R O2N

NO2 (800)

Densely substituted pyrrolidines (807) have been synthesized from enals (801) and imine (803) on a domino reaction catalysed by (784a) (5 mol%) in toluene at r.t. over 12–48 h (Scheme 19). The whole process starts with the formation of the iminium salt (802), whose OH− deprotonates the trifluoromethyl imine (803). The subsequent Michael addition (804), stereocontrolled by the bulky group of the catalyst, generates enamine (805), which undergoes an intramolecular Mannich reaction, giving rise to (806), hydrolysis of which gives (807) as the final product.509 Michael addition of 𝛼-angelica lactone (808) to enones (809), catalysed by the quinine-derived primary amine (728a), has been shown to produce 𝛾,𝛾-disubstituted butenolides (810) with 1:1–12:1 dr and 97–99% ee when carried out in the presence of 2-hydronaphthoic acid (Scheme 20). On treatment with rac-(812), the latter products undergo an intramolecular Michael addition, to afford hexahydrobenzofuran-2(3H)-ones (811).510

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597

10 Addition Reactions: Polar Addition O H

Ar

E F 3C

N H

E

N H

(807)

Ph Ph O

Ar

OH

(801)

(784a)

H2O HO− N

+

Ar

R

+

N

R

(802)

Ar H E F3C

N H

F3C

E

N

E E

(803)

(806)

N

R

Ar F3C

+

Ar

N −

N

E

F3C

N

R

E E

(804)

E

(805) E = CO2Et Scheme 19

The ring-closing Friedel–Crafts-type 1,4-addition of (813), catalysed by the cinchonidine-derived primary amine (728b), has been developed as a new route to spiroindanes (814) that were obtained in ≤95% ee.511 The organocatalytic Michael–Michael–Henry domino reaction of 2-methylcyclopentane-1,3-dione, RCH=CHNO2 , and CH2 =CHCH=O, catalysed by the prolinol derivative (784b) (20 mol%) in MeCN–H2 O (1:2) at 20 ∘ C over 7–12 h, has resulted in the formation of the Hajos–Parish-type products (816) with 90–94% ee. A plausible mechanism, via TS≠ (815) in the early key step, has been proposed.512 The Michael addition of 2-methyl-cyclohexa-1,3-dione (Nu) to ynal (817) (Scheme 21) can be directed towards the production of either (E)- or (Z)-enals (819)/(821) by the organocatalyst: Thus, with the bulky TMS-prolinol catalyst (784a), the allenic enamine, initially generated by the Michael addition of Nu to the corresponding iminium intermediate, is protonated from the less-hindered side (818) to produce (819). By contrast, in the case of the free prolinol congener (784b), it is its own proton that is delivered (820), which gives rise to (821).513

ee 

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de 

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Organic Reaction Mechanisms 2016

O

O

O

+

R

(808)

R

O

(728a) (20 mol%) 2-(OH)-NaphthCO2H (60 mol%) toluene, r.t., 72 h

(809)

O

O

(810) rac-(812) (10 mol%) toluene, 40 °C, 48 h

R O

S Ar

N H

O N H (812)

O

H

NH2

(811)

Scheme 20

O

( )n

OH

OH

(728b) (30 mol%) ()

H2O (1 equiv)

R

OH

O H O n

4·Br C6H4OH (1 equiv) benzene, 65 °C

HO (813)

(814)

Ph Ph N H H R

NO2 O

Me O

OHC

H

H

R

Me O

O2N

O (815)

(816)

OH

599

10 Addition Reactions: Polar Addition O Ph H (817) (784b)

(784a) NuH

N Ph Ph Me3SiO

H

N

H+ Ph Ph

•

Ph

Nu

O H Ph

(818)

H •

Nu

(820)

O

Ph

O H

H

Nu

Ph

(819)

Nu (821)

Scheme 21

Ureas, Squaramides, and Related Catalysts Michael addition of malononitriles R1 CH(CN)2 (R1 = H, Bn) to 𝛼,𝛽-unsaturated pyrazolamides R2 CH=CHCOPyr (R2 = Me and H; Pyr = N-pyrrazolyl), catalysed by the bifunctional thiourea (822a) (10 mol%) in toluene at 15 ∘ C over 168 h, afforded (823) with 80–95% ee.514 Correlation of steric and electronic parameters of tertiary amine thiourea catalysts, using Hammett 𝜎-constants and experimental ΔΔG≠ values obtained from the addition of benzofuran-2-ones to alkyl 2-phthalimidoacrylates, has evolved into a model allowing prediction of the stereoselectivity. 3,5-Bis(trifluoromethyl)benzyl- and methylsubstituted tertiary amine thioureas (824) and (825) were identified as particularly suitable catalysts.515 The multifunctional thiourea derivative (826), which features a phosphonium unit, has been developed as a catalyst for the Michael addition of malonates XCH(CO2 Me)2 (X = H, Me, and F) to chalcones R1 CH=CHCOR2 . With 3 mol% of the catalyst in the presence of K2 CO3 (2 equiv) in mesitylene at 0 ∘ C, the products were obtained with 86–99% ee. The phosphonium moiety is believed to coordinate the enolate of the 𝛽dicarbonyl nucleophile and steer the direction of its attack to the chalcone acceptor.516

ee 

ee 

600

Organic Reaction Mechanisms 2016 CF3 S F3C

N H

NC N H

( )n

(823)

NMe2

N

N H

NMe2

NH

(825) Ph

O

S

Me

N H

(824)

Ph

Br−

N H

+

Ph

P

Ph Ph

CF3

NH

Ph H2N

O2N

N

S

N H F3C

O N

S F3C

CN

R2

N

(822a) n = 1 (822b) n = 2

R1

(826)

CF3

S N H

N H

Ph

(827)

While pyrrolidine and other secondary amines are known to convert 𝛼-substituted ketones, such as 2-methyl-cyclohexanone (828), into the less-substituted enamines (in analogy to kinetic enolates generated by LDA), primary amines tend to favour the formation of the more substituted enamines. The latter enamines, generated stoichiometrically, can react as nucleophiles with Michael acceptors (Pfay-d’Angelo reaction). A catalytic version of this process has now been developed, which relies on the thiourea derivative (827) featuring a primary amino group (Scheme 22). Thus, on encounter with the catalyst (827) (20 mol%), ketone (828) forms imine (829), whose tautomerization generates the more substituted enamine (830) [in preference to its isomer (831)], which then reacts with acrylate (832) and other activated alkenes to generate the Michael adduct (833), hydrolysis of which gives rise to the 𝛼,𝛼-disubstituted cyclohexanone (834). Observation of KIE, in conjunction with computational analysis, revealed the details of the reaction mechanism and allowed the formulation of the TS≠ (835) that accounts for the stereochemistry of the reaction. The reaction proceeds in toluene at 90 ∘ C over 48 h and affords the Michael products with 72–98 ee.517 Thiourea (836) (20 mol%), bearing a phosphine pendant, has been reported to catalyse the 1,6-conjugate addition of 1,1-dicyanoalkenes to para-quinone methides in the

ee 

601

10 Addition Reactions: Polar Addition O O CO2Me Ph R

(828)

(827)

(834)

Ph

NH

Ph

N

S

H

N

Ph

H Ph

H N

N O

H

MeO

H2O R Ph

NH

Ph

N

(835)

(829)

CO2Me

(833)

R

R

Ph

NH

Ph

NH

Ph

NH

Ph

NH

CO2Me (832) (830)

(831)

Scheme 22

presence of Et3 N in Et2 O at −40 ∘ C over 48 h, producing (837) with >20:1 dr and (typically) 90–99% ee. The reaction is believed to involve hydrogen bonding of the carbonyl of the acceptor by the thiourea moiety, the phosphine group acting as a base in deprotonation of the dicyanoalkene and directing the Si-face attack on the Michael acceptor (838).518,519 Another thiourea with a phosphorus pendant (839) has been utilized in a different way: Here, (839) actually served as a stoichiometric reagent to effect a phospha-Michael addition of maleimides, affording (840).520 Michael addition of 3-isothiocyanatooxindoles (842) to arylidene malonates (843), catalysed by the epi-quinine-derived thiourea (841), has been reported to produce spirooxindoles (844) with 85:15 to 98:2 dr and 94–99% ee (Scheme 23). The TS≠ is believed to involve coordination of the enolate derived from (842) with the protonated quinuclidine moiety of the catalyst and, at the same time, steering the approach of the electrophile (843) by double hydrogen bonding to the thiourea segment (845). Enantiomers of the products were obtained with the pseudo-enantiomeric epiquinidine-derived analogue of (841).521

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602

Organic Reaction Mechanisms 2016 NC

CF3

N H

N H

But H OH

PPh2

But

(836)

(837)

Ph Ph P

Ph

Ar

Ph

S F 3C

CN

NC −

NC

Si-face attack

H But

N H

H

O

S

Ph

But

N H F3C

(838)

CF3

MeO

O R N

P

O

N H

NR

N

O N H

Ph

R N

N R′ P NR

NH N

S

NH

O

F3C (839)

(840)

CF3 (841)

Michael-type cyclization of 2-(PhCOCH2 O)C6 H4 CH=CHCOPh and its congeners, catalysed by the Takemoto original thiourea (846) (5 mol%) in toluene at 50 ∘ C, afforded 2,3-disubstituted trans-2,3-dihydrobenzofurans (847) with ≤96:4 de and ≤90% ee.522 A domino reaction between 𝛾-nitro ketones RCO(CH2 )3 NO2 and 𝛼,𝛽-unsaturated ketones Ar1 CH=CHCOAr2 , catalysed by the Takemoto thiourea (822b) (10 mol%) in AcOEt at 50 ∘ C, afforded the functionalized cyclohexanes (848). The reaction commences with the Michael addition of the 𝛾-carbon of the pronucleophile (due to the activation of the CH2 NO2 group by the catalyst) and is completed by cyclization of the resulting enolate.523

ee  de 

603

10 Addition Reactions: Polar Addition S NCS

CO2Et CO2Et

N R O

+

N Me (842)

CO2Et

(841) (20 mol%)

CO2Et

toluene 0 °C, 10 h

R O N Me

(843)

(844) S Ar S

O

C

Q

N

N

H

H

N

−

+

N H

O

O

NMe R (845) Scheme 23

O

CF3

O Ph

S F 3C

N H

N H

Ph NMe2

(846) O

O

Ar2 Ar1 NO2

O

(847)

R

H O R

(848)

O CO2Et

N H (849)

CO2But

N Ac

R

O

(850)

1,3-Cyclohexanediones have been shown to undergo an organocatalysed one-pot domino Michael/transamination/cyclization reaction with 𝛽,𝛾-unsaturated 𝛼-ketoesters RCH=CHCOCO2 But , BnNH2 , and DBU in DCE at r.t. to afford hydroquinoline-2carboxylates (849). In the presence of squaramide (851a), the products were obtained with ≤11:1 dr and ≤98% ee.524

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Organic Reaction Mechanisms 2016

On the same tune, squaramide (851b) has been reported to catalyse the addition of 1-acetylindolin-3-ones to 𝛼-ketoesters RCH=CHCOCO2 Et in CH2 Cl2 at 20 ∘ C, giving rise to indolinones (850) with >19:1 dr and 94–99% ee. Hydrogen bonding between the squaramide moiety and the 𝛼-dicarbonyl unit of the acceptor, and steering the approaching enolate by the protonated pyrrolidine nitrogen of the catalyst, in a similar way as shown in Scheme 23, is assumed.525 O

O

F3C

O

NH F3C

N H

O But

F 3C

Ph Ph

N H

N H

NMe2 F 3C

(851a)

ee  de 

N

(851b)

CF3 O

O

N H

N H

S

But

O N R′

N R

F3C

N H

O

(852)

NMe2

(853) O

O Ph

F3C

N H

N H

MeN

CF3 (854)

Vinylogous Michael addition of 𝛼,𝛽-unsaturated 𝛾-butyrolactams to 2-enoylpyridines RCH=CHCO(2-Py), catalysed by the quinine-derived squaramide (731) in mesitylene at 40 ∘ C, has been reported to produce adducts (852) with ≤99:1 dr and ≤99% ee.526 The [4 + 2] annulation of malononitrile and 5-ylidenethiazol-4-ones (855), catalysed by squaramide (853), has been reported to produce 7H-pyrano[2,3-d]thiazoles (856) with 55–99% ee.527 The proline-derived squaramide (854) has been reported to catalyse the vinylogous Michael addition of pyrazolones (858) to oxindolyliedene 𝛼-keto esters (857), which afforded dihydrospiro[indoline-3,4′ -pyrano[2,3-c]pyrazole] derivatives (859) with >20:1 dr and 83–99% ee. The squaramide moiety of the catalyst is assumed to coordinate the 𝛼-keto segment of (857), whereas the protonated pyrrolidine nitrogen steers the approach of the enolized pyrazolene from the Si-face.528 Other spiroxoindole derivatives, such as (860) and (861), were obtained from isatine derivatives and appropriate maleimide-derived nucleophiles, on a Michael addition catalysed by the quinine-derived squaramides (862) and (731), respectively, all with >99:1 dr and ≤98% ee.529,530

ee  de  ee 

ee  de  ee  de 

605

10 Addition Reactions: Polar Addition Ar

Ar

S + CH2(CN)2

R N

R

Et2O, 20 °C

O

CN

S

(853) (10 mol%)

N

O

(855)

NH2

(856) R2

O R2

EtO2C

O

HO

N N

N

O R3 N

R3 1

R1

R

(858)

(857) Boc N

O

MeO2C

(859)

O

R2 O

MeO

N

S

O

N

NH

R O

O

N Boc

N

(860)

(861)

O

N H

O

R2

Ts N

R1

N N

O (864)

O O Ar

(865)

N

O R

N H

(863)

O

CF3

(862)

O

N H

CF3

N

R1

O

H N

H N

F3C

F3C

N

CH2Cl2, r.t.

O

N

EtO2C

(854) (5 mol%)

+

O

N N+ Ar

(866a) Ar = 2,4,6-(Cl)3−C6H2 (866b) Ar = 2,4,6-Me3−C6H2

606

Organic Reaction Mechanisms 2016

Vinylogous Michael addition of enones and enoates TsNHCH2 CH=CHCOR to vinylidene pyrazolones, catalysed by (863) (5 mol%) in CHCl3 at r.t., afforded spiro-pyrrolidine–pyrazolones (864) with ≤20:1 dr and ≤98% ee.531 The quinine-derived squaramide (731), whose structure is not revealed in the paper but was obtained from the author on request, is claimed to be superior to the related thiourea catalysts for the intramolecular oxa-Michael reaction of 2(O=CHCH2 )C6 H4 CH=CHCOAr, which afforded isochromenes (865) with ≤95% ee.532

Carbenes The NHC, generated by deprotonation of (866a) with t-BuOK, has been reported to catalyse the desymmetrizing Stetter-type reaction of (867), producing tetralones (868) with 3:1 to 6:1 dr and 85–98% ee.533 EtO2

CO2Et

CO2Et O

(866a) (20 mol%) ButOK (20 mol%)

O

EtO2C

toluene, −20 °C

(867)

(868)

The 𝛼,𝛽-unsaturated phenolic esters (869) have been shown to undergo an intramolecular phenylation, cooperatively catalysed by NHC (872) and K+ , affording (871). Mechanistic studies demonstrated the key role of the potassium ion in the cyclization process (870).534 Mes N+

R (872) K+

O

O

(869)

R O−

N Mes

O K+ (870)

R

Mes

N

N

(872)

Mes

O (871)

O

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ee 

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607

10 Addition Reactions: Polar Addition

Phase Transfer The cinchonine-derived ammonium salt (876a) was employed as a phase-transfer catalyst for the umpolung addition of imines (873) to enones (874). The corresponding Michael products (875) were obtained with 90% ee.535 In a similar manner, (876b) has been shown to catalyse addition of the glycine-derived imine (878) to quinone methides (877) (R1 = Me, t-Bu; R2 = alkyl, At, and HetAr), which gave rise to the tyrosine derivatives (879) with >20:1 dr and 92–99% ee.536

ee  ee  de 

Ar Ar N

(876a) (0.2 mol%) N Me

O

+

KOH (10 mol%)

Me

toluene −50 °C, 3 h

CF3

(873) Ar = 4-NO 2-C6H4

(874)

O CF3 (875)

X OR2

R1 = N

N R1,

Br−

+

O

R1 Cl

R2

–to the right, X = H (876a) (876b) R1 = 9-anthryl, R2 = alkyl, X = H (876c) R1 = Ph, R2 = H, X = MeO

O R1

R1 +

N CPh2 CO2But

N Ph

1. (876b) (10 mol%) Cs2CO3 (1.1 equiv) toluene, −40 °C

Ph N

R1

HO R1

NH2

2. 1 M HCl, THF 0 °C

R2

R2 (877)

R2 =

(878)

CO2But

(879)

Others Catalysts Qunine (880a) (15 mol%) has been found to catalyse the Michael addition of 𝛽-naphthols to 2,6-dichlorobenzoquinone in THF at 4 ∘ C, producing biaryls (881) with ≤86% ee. DFT calculations suggest that the reaction proceeds via TS≠ (882) where two hydrogen bondings are crucial for steering the reactants.537

ee 

608

Organic Reaction Mechanisms 2016 Cl HO

R 1O N

Cl

OH OH

OR2 N (880a) R1 = Me, R2 = H (880b) R1 = H, R2 = 2-Naphth (880c) R1 = H, R2 = Bu (880d) R1 = Me, R2 = 2,4,6-(Pri)3C6H2

R

(881)

OMe O

H

N

Br− N

H

+

Ph O

OMe

O

NH NH

O

CF3

P Ph2

F

CF3

O Cl

Cl O (882)

(883)

Bisamide (883) (5 mol%), featuring a phosphonium moiety, can catalyse the double Michael addition of MeO2 CCH=CHCH2 CH(CO2 Bn)2 to oxindolyliedene esters in the presence of K2 CO3 in mesitylene at 0 ∘ C, which affords the spirocyclic indoles, such as (884) with 12:1 to >19:1 dr and 82–99% ee. The reaction is believed to involve activation of the reactants by hydrogen bonding and phosphonium-to-enolate interactions (885).538 Modified quinidine analogues with contracted or expanded quinuclidine moiety have been synthesized as organocatalyst for the Michael addition of C- and S-nucleophiles to enones, but the enantioselectivities attained turned out range from only 6% to 82% ee.539 The bisguanidinium salt (886) has been designed as a multifunctional organocatalyst for the reaction of isocyanates R1 N=C=O with 2-hydroxyphenyl-substituted enones 2HO–C6 H4 CH=CHCOR2 , which afforded 1,3-benzoxazin-2-ones (887) with ≤95% ee as a result of carbamate formation followed by an intramolecular Michael addition.540

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10 Addition Reactions: Polar Addition

O OEt CO2Bn

BnO2C

N

Bn EtO2C

O

H

O

O

MeO2C

N

−

Bn

H N

Ph

+

P O Ph Ph

BnO

(884)

N O

OBn

O

CO2Me

F

CF3

(885)

CF3

R2

O N

N H

N

H

N

N

N CyNH

O N

Cy

Cy

R1

HNCy O

(886)

O

(887)

(viii) Morita–Baylis–Hillman reaction (MBH) DFT calculations of the MBH cyclization of N-allyl 𝛼-amino nitriles (888), catalysed by Bu3 P, which affords pyrrolidines (889), have demonstrated that the TS≠ for this reaction is of considerably lower energy than that leading to the 5-exo-trig attack on the ester group. Furthermore, a C–H· · ·𝜋 interaction apparently favours the formation of (889) over its diastereoisomer.541 R2 R1

CO2Me

N CN (888)

Bu3P

R2

CO2Me N

R1 CN (889)

DFT/M06-2X calculations revealed the explicit role of formic acid as co-catalyst in the RLS of the aza-MBH reaction.542 A new bio-inspired organocatalyst, featuring the cysteine and acridinone units, has been designed for the MBH 𝛼-functionalization of mesityl oxide Me2 C=CHCOMe and other enones with alkylating agents RX. A synergistic hydrogen bonding of the substrate and thia-Michael addition as the starting point (890) are assumed.543

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Organic Reaction Mechanisms 2016 O

N H

NH

H

HN

O P

O

O

Ph

NH

HS

CO2Me (890)

(891)

The twisted phosphine (891) has been designed as a catalyst of the MBH reaction of the isatine-derived imine (892) with allenes (893), effecting an overall [3 + 2] annulation to produce 3,2′ -pyrrolidinyl spirooxindoles (894) with 94–99% ee.544 EtO2C

N Boc O N Me (892)

ee 

R •

CO2Et

(891) (20 mol%)

NBoc

toluene, r.t.

O N Me

(893)

(894)

Another [3 + 2] annulation, catalysed by the quinine derivative (895), opened a route to spirooxindoles (896) (>19:1 dr, ≤99% ee). Here, DFT calculations shed light on the mechanism and selectivity of this domino process.545 Catalysis by PhMe2 P (10 mol%) enabled the MBH-type acylcyanation of alkynoates Ar1 C≡CCO2 Et with acyl cyanides, such as Ar2 COCN, in toluene at 60 ∘ C, to produce adducts (897) (Z:E = 85:15).546 The same phosphine (5 mol%) has been shown to catalyse the cyclization of 𝛼-nitroethylallenic esters CH2 =C=C(CO2 Et)CH(R)CH2 NO2 in MeCN at r.t., which afforded (Z)-furan-2(3H)-one oximes (898).547

Additions to Multiple Bonds Activated by Other Electron-withdrawing Groups (i) Vinylsulfone, vinylselenone, and vinylsulfoxide acceptors Kinetic studies of the reactions of CH2 =CHSO2 F and PhCH=CHSO2 F with sulfonium ylides ArCOCH− S+ Me2 and their pyridinium congeners revealed that the SO2 F group activates C=C bonds 106 to 108 times more strongly towards nucleophilic attack than the SO2 Ph or SO2 Tol groups. In the lg k = sN (N + E) equation, the electrophilicity parameter was found to be E = −12.09, showing that these alkenes are among the strongest Michael acceptors on the electrophilicity scale.548

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10 Addition Reactions: Polar Addition O

O

HO

S

Ph

N

O N O N

N Me (895)

(896) MenthO2C

NC Ar2

R

HO N

CO2Et

O

O

(2-Naphth) CO2Et

CO2But

N

NH

S

Ar1

(897)

F3C

(898) R

O

(899)

N

CF3

CN

SO2Ph O

R

SO2Ph

Ph2P

N

O Ni

PPh2

R

N CMe (900)

(901)

CO2Et

(902)

Vinylsulfones RCH=CHSO2 Ar have been reported to exhibit large differences in the kinetics of hydrothiolation with PhCH2 CH2 SH as a function of the electronic properties of the Ar group, with the t1/2 = 360 min and 7 min for Ar = 4-MeOC6 H4 and 4-CF3 C6 H4 , respectively. The nucleophilic attack, generating the carbanion intermediate, was identified as the RLS.260 Addition of the amino alcohol PhCH2 CH(NH2 )CH2 OH to vinyl sulfone CH2 = CHSO2 R, catalysed by AcOAg (3 mol%), dppe (3 mol%), and KHDMS (4 mol%) in DMF at −20 ∘ C, has been reported to proceed selectively as an oxa-Michael addition, giving rise to PhCH2 CH(NH2 )CH2 CH2 O–CH2 CHSO2 R. The latter selectivity seems to stem from the hydroxyl deprotonation with KHDMS, together with the O/N chelation of Ag+ . The latter effect is apparently responsible for the selectivity of the addition of HO(CH2 )2 CH(NH2 )CH2 OH, which adds by the OH proximal to the NH2 group.549 Addition of aldehydes RCH2 CH=O to sulfones CH2 =C(SO2 Ph)2 , catalysed by the thiourea derivative (899), gave adducts (900) with ≤78% ee.550 The quinine derivative epi-(880b) has been reported to catalyse the Michael addition of 𝛼-alkylsubstituted 𝛼-nitroacetates RCH(NO2 )CO2 Me to vinyl selenone CH2 =CHSeO2 Ph with 82–96% ee.551

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Organic Reaction Mechanisms 2016

(ii) Acrylonitrile acceptors The Michael-type hydroamination of acrylonitrile and its congeners R1 CH=C(R2 )CN with amines R3 R4 NH, catalysed by the nickel(II) complex (901) (1 mol%), has been found to proceed via an outer-sphere nucleophilic attack on the cationic adduct of the nitrile-coordinated substrate. The cationic nitrile adducts constitute the resting state in the catalytic manifold.552 Addition of ethyl isocyanoacetate (CN)CH2 CO2 Et to (Z)-3-substituted-2-(4pyridyl)-acrylonitriles (4-Py)C(CN)=CHR, catalysed by N-benzylquinidinium bromide (876c) (10 mol%) in the presence of K2 CO3 in CH2 Cl2 , and followed by the (i-Pr)2 NEt-mediated ring closure, gave 1-pyrrolines (902) with 70–94% ee.553 The Michael addition of 2-(Ph2 P)C6 H4 CO2 H to various Michael acceptors was discussed in the subchapter on Michael addition to 𝛼,𝛽-unsaturated carbonyl compounds.461 Addition of the anion generated from (R)-PhSO(NTs)CH2 Cl to PhCH=C(CN)2 was mentioned in connection with the addition to the 𝛼,𝛽-unsaturated Weinreb amides.487 The anion generated from 2-nitrobenzylcyanide 2-NO2 –C6 H4 CH2 CN by deprotonation with NaH in THF has been reported to react with CH2 =CHCN upon the formation of 4-cyanoquinoline-N-oxide (903) featuring a CN− group departure.554 The addition of dithiocarbamates RNHC(S)SNEt3 to 2-[bis(methylthio)-methylene] malononitrile (MeCS)2 C=C(CN)2 in DMF at 100 ∘ C produced 1,3-thiazine-2-thione derivatives (904).555 (iii) Nitroalkene acceptors Addition of dimethyl malonate CH2 (CO2 Me)2 to ArCH=CHNO2 , catalysed by the Werner complex (905) (10 mol%) in CH2 Cl2 at r.t., has been shown to afford the corresponding products with 90–99% ee. Crystallographic analysis provided a starting point for speculations regarding the transition state.556 The morpholine-derived enamines have been reported to undergo Michael addition to 3-nitroindoles, affording the dearomatized products (906) in a totally regio- and diastereo-selective manner. By contrast, the analogous 3-nitrobenzofuran affords dienylphenol.557 The epi-quinine derivative (907) (1–5 mol%) has been shown to catalyse the vinylogous addition of furanones (763) to 𝛽-substituted nitrostyrenes EtO2 C–C(Ar)=CHNO2 . The resulting adducts (908) were obtained with >98:2 dr and 95–98% ee. The proposed mechanism assumes an initial Michael addition of the quinuclidine moiety to the nitrostyrene, which generates the ammonium intermediate, whose structure was optimized by calculations at the B3LYP/6-31G(d) level. However, the subsequent replacement of the ammonium leaving group by the dienolate generated from the furanone (763) via an SN 2 process at the tertiary centre seems unlikely.558 Addition of 2-acetyl azaarenes, such as 2-acetyl thiazole, to (E)-(CF3 )C(Ar)=CHNO2 , catalysed by the complex generated from (acac)2 Ni and the BOX ligand (909), afforded (910) with 93–99% ee in i-PrOH at 0 ∘ C. The reaction proceeds via an attack from the Re-face and is believed to involve the coordination of the reactants to the nickel centre (911).559

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10 Addition Reactions: Polar Addition CN HN + N

R

SMe H 2N

S

N

H2N

NH2 H2 N

NMe2

Co3+

O−

S

N NH2 H2

(903)

(904)

(905)

O2N H H

OH

Ar N

N

O

O

N

Ts

O

CO2Et NO2

R

Ar

N

O (906)

(907)

(908)

N O

O

O

S N

O

N

Ph

O

NO2 Ph Ar

CF3

N Ph

N

O Ph O Ni N Ar O N S CF3

(909)

(910)

(911) Cl

NO2

NO2

Me3SiCl2Br

X (912) X = CH2, O

Bu4NF, THF −78 °C

Cl

X (913)

The reaction of Me3 SiCCl2 Br with nitroalkenes, such as (912), in the presence of Bu4 N+ F− in THF at −78 ∘ C, has been reported to result in the formation of the dichlorocyclopyl derivatives (913). Probing the mechanism by NMR spectroscopy at low temperature and DFT calculations suggest formation of the ‘ate’ species [Me3 SiF(nitronate)]− , which on heating at 10–20 ∘ C extrudes Me3 SiF with a concomitant formation of (913).560

614

Organic Reaction Mechanisms 2016 E NO2

Ar HN

N

Ar

OH

N N E

Cs2CO3

+

H

O

MeCN Mw, 100 °C

E

E (914) E = CO2Pri

(915)

𝜔-Nitrostyrenes ArCH=CHNO2 have been shown to undergo an MBH-like 𝛼hydrazination with azodicarboxylates EN=NE (E = CO2 Pri ), catalysed by imidazole. The products (914) can further react with phenol PhOH to afford hydrazinodihydrofurans (915), as a result of the initial Michael addition to (914), followed by extrusion of the NO2 group and final cyclization.561 Thia-Michael addition of R3 SLi to nitroalkenes R1 CH=C(R2 )NO2 generates the sixmembered chelate (916), protonation of which is subjected to stereoelectronic control: pseudoaxial attack by H+ thus gives rise to the anti-configured products (917).562 −O

+

N

O

NO2 H+

Li S

R2

de 

R3

−78 °C

R1

R2

R3S

R1 (916)

(917)

Enamines A simple model was employed to shed light on the diastereoselectivity of the addition of aldehydes RCH2 CHO (via enamine) to nitroalkenes, which gives the syn-configured product (919) with aliphatic aldehyde (R = Bu), whereas the benzylic counterpart (R = Ph) affords mainly the anti-diastereoisomer (921). A detailed in situ NMR investigation of the stoichiometric system containing PhCH=CHNO2 and the enamine prepared from RCH2 CHO and pyrrolidine demonstrated that the addition initially generates the iminium ion (918) that is directly hydrolysed in the case of R = Bu, so that the configuration of the final product reflects that of the initially formed iminium species (918). On the other hand, the phenyl derivative (R = Ph) encourages equilibration via enamine (920), which allows the formation of (921).563 Pyrrolidine–HOBt (922) (10 mol%) in THF has been employed as an organocatalyst for the addition of cyclohexanone to 𝜔-nitrostyrenes (water, r.t.). The expected syn adducts were obtained with 7:3 to 98:2 dr and 81–95% ee.564 Addition of aliphatic aldehydes RCH2 CHO to ArCH=CHNO2 , catalysed by indolinol (923) (20 mol%) in aq. NaCl at 0 ∘ C, proceeded with 84–99% ee.565 Dipeptide (924) (5 mol%), together with PhCO2 H (10 mol%), catalysed Michael addition of the branched aldehydes RR′ CH2 CHO to ArCH=CHNO2 in toluene at r.t. affording the syn-configured products with 4:1 to 94:6 dr and 63–91% ee. The reaction is believed to involve activation of the NO2 group by hydrogen bonding to the phenylglycine moiety of the catalyst.

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10 Addition Reactions: Polar Addition

+

N R

Ph H

R = Bu

H R

O 2N

Ph

O

NO2 (918)

(919)

R = Ph

N

Ph

O

R H O 2N

Ph

R

NO2 (920)

(921)

However, this mechanism would require formation of the cis-configured enamine from the proline segment,566 which seems to contradict the current beliefs. Finally, the benzimidazole-derived diamine (786) (10 mol%) has been reported to catalyse the addition of Me2 CHCHO to ArCH=CHNO2 in CH2 Cl2 at 25 ∘ C with 74–92% ee.499

Iminiums Iminium activation of 2-(TsNH)C6 H4 CHO by the hydroxy proline-derived amide (925) (20 mol%) in the presence of p-nitrophenol (20 mol%) and MS in CHCl3 at r.t. triggered the domino aza-Michael–Henry reaction with ArCH=CHNO2 . The resulting 3-nitro-1,2-dihydroquinolines (926) were obtained with 52–88% ee.567 Ureas and squaramides Comparison of the activity of the thiourea catalysts (927a) and (927b) with a CH3 and CF3 group, respectively, for the addition of MeCOCH2 COMe to PhCH=CHNO2 , has revealed the following (both experimentally and theoretically): in addition to the established N–H· · ·O bonding between the catalyst and the reactants, the former catalyst contributes by strong C–H· · ·F interaction (928), whereas the latter relies on the C–H· · ·𝜋 interaction (929) with the substrate.568 The glucose-derived thiourea (930) (10 mol%) has been shown to catalyse the addition of cyclohexanone to RCH=CHNO2 (R = Ar, HetAr, and Pri ) in the presence of Et3 N (neat, −10 ∘ C) giving rise to (931) with 80:10 to 99:1 dr and 88–95% ee.569 Michael addition of CH2 (COSPh)2 to RCH=CHNO2 (R = Ar and Alk), catalysed by the prolinederived urea (932) (5 mol%) in toluene at 25 ∘ C, proceeded with 73–99% ee.570 The

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Organic Reaction Mechanisms 2016 O

H O

N

N H

N H H

N N (922)

OH

O

R1

N N H

R2

O

S

Me

N

H

N

N

H

H

H O

CPh3

N H

NMe2

(927a) R1 = CF3, R2 = aryl, But (927b) R2 = CH3, R2 = aryl, But

O −

F

H

Me +

F

O +N

−

S

F

Me +

NH

S N H

Ar

(926)

(925)

O

(924)

NO2 N H

N H

N

(923)

HO

Ph

Me

N

N

N

H

H

H O

O − −

(928)

O +N

H

O

Me

H

O

H

(929)

calix[4]arene equipped with two chiral thiourea units (10 mol%) has been reported to catalyse the addition of CH2 (CO2 Me)2 to ArCH=CHNO2 in MeCN, affording Michael products with 85–94% ee.571 The quinine-derived thiourea (933) (20 mol%) has been shown to catalyse the addition of PhCH2 C(O)–P(O)(OEt)2 to ArCH=CHNO2 in CHCl3 at 0 ∘ C, which yields (934a) with 4:1 to 92:8 dr and 79–94% ee. The latter products were in situ converted into the stable esters (934b) on treatment with EtOH and DBU at 0 ∘ C.572 The valine-derived thiourea anchored to the Merrifield resin (935) has been employed for the Michael addition of cyclic ketones and lactones to ArCH=CHNO2 , which produces (936) with >98:2 dr and ≤92% ee.573 Michael addition of 3-pyrrolyloxindoles to 𝛽-phthalimidonitroethene (Phth)NCH= CHNO2 , catalysed by thiourea (937) (5 mol%) in mesitylene at −40 ∘ C, afforded 3,3′ disubstituted oxindoles (938) with 87:13–99:1 dr and 77–98% ee.574 Thiourea (939) has been employed as a catalyst (15 mol%) for the addition of 𝛼(PhS)cyclobutanone to ArCH=CHNO2 (in toluene at r.t.), which afforded (940) with

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10 Addition Reactions: Polar Addition CF3

O O

S F3C

N H

N H

O

R NO2

O

HNBn

(930)

(931) CF3 S F3C

N H

Ph N H

H N Me

(932) MeO N

N

O

O

N H HN

Ph S

Ar

Ar

R NO2

NH

(933) 3,5-(CF3)2C6H2

(934a) R = P(O)(OEt)2 (934b) R = OEt

96:4 to 99:1 dr and 92–98% ee. The reaction is believed to proceed via the enamine intermediate, generated from the catalyst NH2 group and the ketone (941).575 Addition of Me2 C=CHCHO to 2-nitroallylic acetates ArCH=C(NO2 )CH2 OAc, catalysed by (942) in toluene at 35 ∘ C, afforded the cyclohexenes (943) with 88–98% ee. The mechanism apparently involves the formation of initial enamine from the aldehyde and the pyrrole moiety of the catalyst, its addition to the 𝛽-nitrostyrene, followed by elimination of AcOH, and the ring-closing enamine addition across the nitroalkene group.576 Addition of 3-methyl-1-phenyl pyrazol-5-one to the same 2-nitroallylic acetates ArCH=C(NO2 )CH2 OAc, catalysed by squaramide (944) (20 mol%) in the presence of K2 HPO4 (5 mol%) in CH2 Cl2 at 25 ∘ C, afforded 1,4,5,6-tetrahydropyrano[2,3c]pyrazoles (945) with 87–97% ee as a result of the initial Si-face attack by pyrazole on the Michael acceptor, followed by a ring closure via the AcO group displacement with the OH group of the pyrazole moiety.577 The quinine-derived squaramide (946a) (note the benzylamine moiety instead of the usual aniline unit) has been identified as an optimal catalyst (1 mol%) for the vinylogous Michael addition of 3-methyl-2-pyrazol-5-one to 𝛽-nitrostyrenes ArCH=CHNO2 . The resulting pyrazoles (947) were obtained with 35–83% ee. Activation of the NO2 group by hydrogen bonding with the two NH2 groups of the squaramide moiety and hydrogen bonding of the nucleophilic reactant with the quinuclidine nitrogen is assumed.578

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Organic Reaction Mechanisms 2016

CF3 Ar

O

S

NO2 F 3C

N H

X

N H (935)

Ph

N Me

(936) NO2

S

Me

R

( )n

N Me

N N

N H

N H

O N Me (938)

NMe 2

(937)

S R

O Me Bn

N

S

H

Ar

N

N H

O

N H

−

O

PhS NH2

N

O S

Ar (941)

CF3 CHO

S N H

Ar HN

NO2

(942)

(943)

CF3 O

F 3C

N H

O N H

Me

Ph Ph N

Ar NO2

N N

O

Ph (944)

HN

Ph

(940)

N H

+

NO2

(939)

F3C

N H

(945)

619

10 Addition Reactions: Polar Addition R MeO

Ar

CF3 N

R

H N

H N

O

HN

CF3

N

NO2 OH N

O

(946a) R = CH2 = CH (946b) R = Et S N H

Me2N

(947)

Ph Ph

N H

NO2 CO2But (949)

R1

NHTs

(948) 0.5 TFA

O

CF3

O Ph

N H

NH

N H

F 3C 2

O

O

N H

N H

O2N Ar

O

CF3

CO2Me

R

N R R

N

(951)

(950)

O

R2

O

O

(952)

OH

N H (953)

Me

N Boc

O2N Ar (954)

Addition of alkynyl 𝛽-keto esters R1 C≡CCOCH2 CO2 But to nitroalkenes (R1 , R2 = Ar, and Alk), catalysed by thiourea (948) (10 mol%) in CH2 Cl2 , resulted in the formation of the Michael adducts (949) with 93–99% ee.579 The thiourea with a phosphorus pendant (839) has been shown to add580 to RCH=CHNO2 in a similar way as described earlier for 𝛼,𝛽-unsaturated carbonyls.520 The proline-derived squaramide (950) (10 mol%) has been employed as a catalyst for the addition of cyclic ketones, such as cyclohexanone, to ArC=CHNO2 , which resulted in the formation of (931) with ≤97:3 dr and ≤96% ee.581 R2 CH=CHNO2

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Organic Reaction Mechanisms 2016

Addition of cyclohexane-1,3-diones to 𝛽-CF3 -𝛽-disubstituted nitroalkenes (E)CF3 C(Ar)=CHNO2 , catalysed by squaramide (951) (10 mol%) in CH2 Cl2 at −10 ∘ C, afforded hydroxyimino tetrahydrobenzofuranones (952) with 58–89% ee.582 Squaramide epi-(946a) (5 mol%) has been shown to catalyse the formation of substituted dihydroquinolines (953) with 90–99% ee on Michael addition of methyl acetoacetate MeCOCH2 CO2 Me to 2-(BocNH)–C6 H4 CH=CHNO2 , followed by a TFAcatalysed cylization.583 Addition of 𝛼-alkylidene succinimides to nitrostyrenes ArCH=CHNO2 , catalysed by the dihydroquinine-derived squaramide (862a) (5 mol%) in CHCl3 at −10 ∘ C, afforded (954) with 74:26 to >99:1 dr and 87–99% ee.584 A domino reaction, including vinylogous Michael addition and Henry cyclization, has been reported for the combination of 1,3-indandione-derived pronucleophiles (955) with nitroalkenes (956), catalysed by the quinine-derived squaramide (731). The resulting tetrahydrofluoren-9-ones (957), containing four consecutive chiral centres, were obtained as single diastereoisomers(!) with 92–98% ee.585

ee 

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O Ar1

O Ar1

NO2

+ Ar2

xylenes 30 °C, 24 h

Ar2

O (955)

(731) (5 mol%)

(956)

NO2 (957)

Catalyst (862b) was employed for the addition of 4-hydroxycoumarin to 𝛽nitrostyrenes, which afforded (958) with 53–81% ee. Computational analysis led to the formulation of two most likely transition states, which differ by 0.1 kcal mol−1 only: (i) the Papai–Soós model with the squaramide bidentate hydrogen bonding of the nucleophilic coumarine, while the protonated quinuclidine moiety of the catalyst directs the approach of the Michael acceptor by hydrogen bonding of one of the oxygens of the NO2 group; (ii) the Takemoto model, which suggests the opposite mode of hydrogen bonding, that is, the bidentate binding of the NO2 group to the squaramide unit, while the protonated quinuclidine nitrogen binds the coumarine enolate. In agreement with the experiment, the former model suggests the formation of (R)-(–)-(958), whereas the latter model would favour its enantiomer.586 Nevertheless, this reviewer feels that the experimentally observed enantioselectivity would require a larger difference in the energies of these two transition states. Furthermore, it is pertinent to note that the absolute configuration of the product was established computationally from its optical rotation rather than experimentally.586 Michael addition of the same 4-hydroxycoumarin and its analogues to branched nitroenynes (E)-ArCH=C(NO2 )C≡CR, catalysed by (731) (5 mol%) in CH2 Cl2 at 0 ∘ C, followed by the oxa-Michael cyclization of the initially formed allenic adduct and subsequent alkene isomerization, catalysed by DABCO, resulted in the formation

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10 Addition Reactions: Polar Addition

of (Z)-2-methylenepyrans (959) with 6:1 to >20:1 dr and 92–99% ee.587 The related reaction of 2-hydroxy-1,4-naphthoquinones and nitroenynes RC≡CCH=CHNO2 , catalysed by the Takemoto-like squaramide (951) (0.5 mol%) and TfOAg (15 mol%) in CH2 Cl2 at r.t., afforded 4H-pyranonaphthoquinones (960) with 89–99% ee.588 R OH

Ar

O

O

(958)

O

O

(959) X = O, NMe2

NO2

(960) O

R3

O

Ar2

O2N

O

N N

Ar1

R1 R (961)

N Ts (963)

(962) Ph

Ph

O R1

N H NO2

O

+N

R2

O−

O

N N+

−O

Me N

(967)

Ph

Ar

N Ph

ButS

O (966)

O2 N

N

O 2N

CH3 (965)

Fe

CN

Ar

H

Cy

(964)

Ph2P

NO2

R

OEt

O

2

O

R

Ar

O X

O2N

O

NO2

O

NO2

N

CO2Me

Ph (968)

Addition of pyrazolones (858) to 2-alkynyl nitrostyrenes 2-(R1 C≡C)C6 H4 CH= CHNO2 , catalysed by epi-(946b) (1 mol%) in conjunction with Ag2 O (3 mol%), produces spiropyrazolones (961) with 8:1 to 30:1 dr and 42–98% ee. The role of Ag(I) is to activate the C≡C towards the 5(C)𝜋 -exo-dig cyclization of the initially formed

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Organic Reaction Mechanisms 2016

Michael addition intermediate. Activation of the nitroalkene by hydrogen bonding between the squaramide NH groups of the catalyst and both oxygens of the NO2 group is assumed, together with the hydrogen bonding of the enol tautomer of the pyrazolone to the quinuclidine nitrogen, which dictates the Si-face approach to the acceptor.589

Carbenes The NHC, generated by deprotonation of (866b) with K3 PO4 , has been reported to catalyse the domino reaction of enals Ar1 CH=CHCHO and 2-nitroallylic acetates Ar2 CH=C(NO2 )CH2 OAc in CHCl3 –EtOH (10:1) at −60 ∘ C to produce the tetrasubstituted cyclopentanes (962) with 13:1 to >20:1 dr and 72–96% ee. The reaction is believed to proceed via homoenolate/enolate intermediates and the final displacement of the catalyst with EtOH, which forms the ester group of the final product.590 Others Addition of 𝛽-dicarbonyls, such as MeCOCH2 COMe, to (3-indolyl)nitroalkenes, catalysed by the quinine derivative (880c) (10 mol%) in THF in the presence of MS at r.t., has been shown to produce adducts (963) with 69–98% ee. The TS≠ , optimized using DFT calculations at 21.01 kcal mol−1 , suggests activation of the NO2 by hydrogen bonding with the phenolic group of the catalyst, while the enol form of the 𝛽-carbonyl reactant is hydrogen-bonded to the quinuclidine nitrogen.591 The quinine derivative epi-(880d) has been found to be one of the rare catalysts to promote the addition of 5-substituted 2(3H)-furanones to nitroalkenes R1 CH=CHNO2 in an anti-manner, giving rise to (964) with ≥98:2 de and 85–97% ee. The catalyst loading can be as low as 0.1 mol%, which corresponds to TON = 890 – quite remarkable for an organocatalyst.592 The proline-derived bis-N-oxide (965) (10 mol%) has been reported to catalyse the addition of 𝛼-cyano ketones RCOCH2 CN to bromonitrostyrenes ArCH=C(Br)NO2 in toluene at −60 ∘ C. In the presence of proton sponge, the initial Michael adduct undergoes cyclization to afford dihydrofurans (966) with >95:5 dr and 84–93 % ee.593 Addition of the glycine-derived imine PhCH=N–CH2 CO2 Me to nitrostyrenes ArCH=CHNO2 , catalysed by a complex generated from AcOAg and (967) (5 mol%) in dioxane at r.t., afforded polysubstituted proline esters (968) with 89:11 to 98:2 de and 80–98% ee.594 A nickel-catalysed domino vinylogous Mukaiyama 1,6-Michael/Michael addition of 2-silyloxyfuran (970) to N-sulfonyl-1-aza-1,3-dienes (969) has been reported to produce the fused piperidine/butyrolactones (971).595 Ts

Ts Ar2

N

+

OTBS O

Ar1 (969)

Ni(ClO4) (5 mol%)

Ar

2

N

O

MeCN, 80 °C

O Ar2

(970)

H

H

(971)

ee 

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10 Addition Reactions: Polar Addition

(iv) Vinyl phosphates The reaction of primary amines RNH2 (2 equiv) with cis-5-chloro-1-pentenylphosphonate Cl(CH2 )3 CH=CHP(O)(OEt)2 at reflux resulted in the formation of pyrrolidinylmethylphosphonates (972). The reaction is believed to proceed via the initial Michael addition, followed by 5(N)-exo-tet ring closure.596 O P(OEt)2

R 2P

O

O P

N

R2P

O

O P

But Me

But Me

R (972) R = alkyl, Ar

(973)

(974)

The phosphorus nucleophiles R2 P(O)H, deprotonated with LDA in THF, can be added to cyclohexen-1-ylphosphine oxide to afford the trans-adducts (973). On the other hand, its diastereoisomer (974) was obtained when t-BuOK was used as a base in DMF, owing to a double isomerization of the carbanion intermediate, as shown by NMR analysis.597

(v) Other electron-withdrawing activators Cyclic enol ethers (976) have been shown to add to the non-symmetric diarylmethylium salts containing the protonated indole moiety (975) in CH2 Cl2 at r.t. in the presence of 2,6-di-t-butyl-4-methylpyridine (DTBMP; to prevent acidic hydrolysis of (976)), producing (977) with ca 3:1 dr. The diastereoselectivity was rationalized by DFT calculations.598 Ar

Ar

O

OSiMe3 +

BF4−

N H (975)

Me

+

( )n (976)

N H

( )n Me

(977)

The TMEDA-catalysed reaction of allenoate (978) with 1-aza-1,3-diene (979) commences with an MBH-type process, and the resulting intermediate (980) undergoes cyclization to generate (981), followed by 1,3-hydrogen shift and desulfonation to produce the pyridine derivative (982). According to DFT calculations,599 the rate-limiting 1,3-hydrogen shift precedes the cyclization, which is in conflict with the previously suggested mechanism.600 The calculations also show that TMEDA not only serves as a Lewis base to activate the allenoate (978), but also as a BA/base to mediate the 1,3hydrogen shift process, which lowers its barriers and thus accelerates the reaction.599

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de 

624

Organic Reaction Mechanisms 2016 CO2Bn

+cat

•

ArSO2

(978) N

Ph

CO2Me

TMEDA

ArSO2

OBn CO2Et

Ph

(979)

(980)

CO2Bn N

CO2Et

Ph

O−

NH

CO2Bn ArSO2

CO2Et

N Ph

(982)

(981)

The NHC-catalysed addition of enals, such as cinnamaldehyde PhCH=CHCHO, to azoalkene (986), generated from ClCH2 C(Ph)=NNHBoc, can be directed towards the [4 + 3] and [4 + 1] products (989) and (990), respectively, by the catalyst (Scheme 24). Thus, catalyst (983) favours the [4 + 3] product (989) (9:1), whereas the [4 + 1] product (990) is obtained with catalyst (984). Calculations, employing distortion–interaction analysis, suggest that the initial catalyst adduct, which can be portrayed by its two resonance form (985a) and (985b), can react with azoalkene (986) via two different transition states (987) and (988), whose relative energies are a function of the catalyst substitution pattern.601 Nitrosoallenes (992), a novel species generated in situ from allenyl N-hydroxysulfonamides (991) on reaction with TBAF, have been shown to undergo a Michael addition of various N-, O-, and S-, and C-nucleophiles to afford the 𝛼-functionalized enoximes (993). The presence of DIAD as a scavenger of the Ts− , generated along the first step, proved to be of key importance.602

Additions of Organometallics to Activated Double Bonds (i) Lithium Cyclization of pyridones with a vinyliodide pendant at the nitrogen (994) to afford izidines (996) as single diastereoisomers has been attained via a halogen–Li exchange on treatment with t-BuLi. The reaction is believed to proceed via an axial attack at the C=C bond (295). Isomeric vinyl halides (997) afforded the corresponding exo-methylene products (998).603 (ii) Magnesium The aza-Michael addition of lithium amides to 𝛽 ′ -amino-𝛼,𝛽-unsaturated ester as acceptors has also been reported for the analogous magnesium amides.435

de 

625

10 Addition Reactions: Polar Addition O

O Ph

N

N

N

N

N

N Ar

(983) Ar = 2,4,6-Me3C6H2

Ar (984) Ar = 2,6-(MeO)2C6H3

OH

OH

−

Ph

X

−

Ph

(985a)

X

(985b) NBoc

N Ph (986)

Boc N N

Boc N

H

Ph

H

N

O

O Ph

X

X Ph (987)

Boc N

(988)

O N

N Ph

Boc N Ph

Ph Ph (989)

(990) Scheme 24

(iii) Boron Addition of ArB(OH)2 to 𝛼,𝛽-unsaturated amides, such as N-alkyl maleimide, catalysed by (AcO)2 Pd/bipy, has been optimized (AcOH–THF–H2 O, 80 ∘ C).604 In a similar way, addition of ArB(OH)2 to alkylchromones was attained with (CF3 CO2 )2 Pd as catalyst in an aqueous solution of CF3 CO2 Na at 60 ∘ C.605

626

Organic Reaction Mechanisms 2016

F− O

TBS

N

Bun

Ts

O TBAF DIAD

•

Ph

Bun

THF 0 °C, 10 min

Ph

( )n

R

•

ButLi (2 equiv)

Nu Ph Ph (993)

R

O

N ( )n

THF, −78 °C 1h

O

( )n

Li

(994) O

I N

N R (996)

(995)

( )n

N

Bun

Ph

(992) O

N

Nu

Ph

(991) I

HO

N

ButLi (2 equiv)

H

THF, −78 °C 1h

O

( )n N

R

R (998)

(997)

The reaction of (pin)B–B(pin) with 𝛼,𝛽-unsaturated carbonyl compounds R1 CH=CHCOR2 , catalysed by CuI (2 mol%) in the presence of K2 CO3 and MeOH in THF at r.t., afforded the expected addition products (pin)BCHR1 CH2 COR2 . However, replacement of K2 CO3 with Cs2 CO3 resulted in the subsequent protodeboration, giving rise to the reduced products R1 CH2 CH2 COR2 .606 Addition of (pin)B–B(pin) to 𝛼,𝛽-unsaturated ketones and esters ArCH=C(X)COR (R = Me and OR′ ; X = Me, OMe, NHAc, and Cl), catalysed by a complex generated from CuCl (10 mol%), (S)-(R)-ppfa (999) (20 mol%), and Tf2 NAg (10 mol%) in the presence of CF3 CH2 OH or t-BuOH and a 4 Å MS in toluene at r.t., has been reported to afford the syn-configured kinetic products (1000) with 3:1 to 70:1 dr and 78–98% ee. Equilibration to the thermodynamically more stable anti-isomer (e.g., from 12:1 to 1:4) has been observed to occur in the presence of t-BuONa. The concomitant presence of Tf2 NAg and alcohols was identified as the key feature for achieving high catalytic activity and enantio- and diastereo-selectivity.607 (pin)B

Me2N Fe Me

PPh2

O

Ar

R X

(999)

(1000)

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10 Addition Reactions: Polar Addition

Hydroboration of HC≡CCO2 Me with the Ru/BH3 -thiazole complex (1001) has been found to result in the formation of the Markovnikov adduct and its anti-Markovnikov isomer. Both of these novel 𝜂 4 -𝜎,𝜋-borataallyl complexes exhibit agostic interactions (1002).608 CO2Me

H OC Cp*

Ru

BH2

H

N

N

S

S S

S

(1001)

(1002)

H N

O B B O

BH

Cp*Ru

N H (1003)

H N

R B

O X

N H (1004)

Addition of pinB–Bdan (1003) to acetylenic esters and amides RC≡CCOX, catalysed by CuSO4 in the presence of 4-picoline, proceeds in aqueous conditions (H2 O–EtOH 9:1) at 50 ∘ C, giving rise to the (Z)-𝛽-boryl enoates and primary, secondary, and tertiary enamides, respectively (1004).609

(iv) Copper 1 H NMR investigation of the Cu(I)-catalysed addition of EtMgBr to (2R)-Ncinnamoylbornane-10,2-sultam derivatives led to the revision of the configuration of the resulting N,OAc-ketene acetal. Furthermore, 19 F NMR spectroscopy was employed to correct and improve the linear correlation between the diastereoselectivity and the 𝜎 para Hammett electronic parameters of the Michael acceptor.610 The Cu(I)-catalysed borylation of R1 CH=CHCOR2 was mentioned in the paragraph dedicated to boron.606 The addition of arylboron reagents (PhBO)3 to chalcones Ar1 CH=CHCOAr2 , catalysed by a complex generated from (TfOCu)2 Tol (5 mol%) and phosphoramidite (1005) (6 mol%), carried out in the presence of AcOK in toluene at 10–110 ∘ C, afforded (1006) with 82–98% ee. Mechanistic studies, including DFT calculations, revealed a rare 1,4insertion of arylcopper(I), which generates the corresponding O-bound copper enolates (1007) (ΔG≠ = 13 kcal mol−1 for Ar1 = p-Tol, Ar2 = Ph). The latter species then undergoes transmetallation with (PhBO)3 to generate (1005)2 CuPh (ΔG≠ = 23 kcal mol−1 ) in continuation of the catalytic cycle. This new mechanism is fundamentally different from the classical oxidative addition followed by reductive elimination.611

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Organic Reaction Mechanisms 2016

L O

P

Ph

N

O

O

Ar1

Cu

O

Ar2 Ar1

(1005)

(1006)

O O

O P

N

(1007)

N

R1 R2

(1008)

Ar2

(1009)

Nu

MeO

PAr2

MeO

PAr2

(1010a) Ar = 3,5-But2-4(MeO)C6H2 (1010b) Ar = 3, 4,5-(MeO)3C6H2

Addition of Et2 Zn to chalcones, catalysed by a complex generated from (TfO)2 Cu and phosphoramidite (1008), afforded the expected products with 39–93% ee.612 The reaction of enones R1 CH=CHCOR2 with N-acyloxyamines ArCO–ONR2 , in particular N-benzoyloxymorpholine, catalysed by CuI/bipy (20 mol%) in dioxane at 80 ∘ C, has been reported to afford the anti-configured oxyamination products R1 CH(NR2 )–CH(O2 CAr)COR2 with high regioselectivity.613 Copper iodide can catalyse the conjugate addition of nucleophiles NuH (first being deprotonated by LDA or NaH) to isocyano enones R2 CH=C(N≡C)COR1 . The reaction proceeds via the expected enolates R2 CH(Nu)–C(N≡CCuLn )=C(R1 )O− M+ with the isonitrile group coordinated to Cu(I), which is followed by cyclization, giving rise to oxazoles (1009).614 The complex generated from [(MeCN)4 Cu]BF4 and MeOBIPHEP (1010a) has been shown to catalyse the alkynylation of 1,1,1-trifluoromethyl enones R1 CH=CHCOCF3 with terminal alkynes R2 C≡CH, affording R2 C≡CCH(R1 )CH2 COCF3 with 90–98% ee. The corresponding diynes R2 C≡CC≡CH reacted in a similar way.615 At long last, the intermediate 𝜂 2 -Cu complex (1011), assumed to feature in the conjugate addition of Bu2 CuLi to trans-(NC)CH=CH(CN) and other 𝛼,𝛽-unsaturated nitriles, has been intercepted by electrospray ionization mass spectrometry (ESI MS) and further characterized by quantum-chemical calculations.616

ee 

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10 Addition Reactions: Polar Addition

NC

−

CuBu2

Ph

N

−

PF6 N Mes +

CO2Me

Ph CN

OH

(1011)

(1012)

CO2Me (1013)

O Ar

O

R1 N

N Fe

(1014)

F 3C

R2 CO2Me

(1015)

Enantioselective 1,6-conjugate addition of allenes, such as (pin)BCH=C=CH2 , to acyclic 𝛼,𝛽,𝛾,𝛿-doubly unsaturated acceptors, for example, PhCH=CHCH=C(CO2 Et)2 , has been attained with a catalyst generated from CuCl (5 mol%), (1012) (5 mol%), and t-BuONa (20 mol%) in the presence of PhONa in THF at 22 ∘ C. With the aid of theoretical methods, the reaction was found to proceed via the 𝜂 2 -Cu complex at the 𝛼,𝛽-double bond, which undergoes a rearrangement to afford the 1,6-adduct (1013) with ≤95% ee rather than its 1,4-isomer.617 Fullerenes equipped with pendants containing –C≡CH groups and N-maleimide moiety were sequentially functionalized with azides R1 –N3 followed by Michael addition of thiols R2 SH, such as cysteine, to provide fullerodendrimes.618 The reaction of propargylamine HC≡CCH2 NH2 with ferrocenyl alkynones [Fer]C≡CCOAr has been shown to generate the corresponding N-propargylic 𝛽enaminones, which undergo cyclization in the presence of CuCl in DMF at 110 ∘ C, affording 2-ferrocenylpyridines (1014).619 A simple assembly of the CF3 -substituted pyrrolo[1,2-a]quinolines (1015) from quinoline, terminal alkynes R2 C≡CH, and CF3 C≡CCO2 Me has been attained in two steps. In the first, catalysed by CuI in CH2 Cl2 at r.t., the quinoline is added to the electron-deficient propiolate, and the resulting Michael zwitterion undergoes a nucleophilic addition of the acetylide (arising from the alkyne and CuI) to the C=N+ bond. The subsequent cyclization proceeds with CuBr2 , air, and DMAP in DMSO at 80 ∘ C.620 The reaction of H-phosphonates (EtO)2 P(O)H with activated enynes R1 C≡CCH= C(COR2 )2 , catalysed by CuBr, was dealt with in the subchapter on electrophilic Cu-catalysed reactions.306 The addition of (pin)B–SiMe2 Ph to allenoates R1 R2 C=C=CHCO2 R3 , catalysed by CuSO4 in the presence of 𝛾-picoline in water at r.t., delivered the (E)-configured

ee 

630

Organic Reaction Mechanisms 2016

𝛽-silylated products R1 R2 C=C(SiMe2 Ph)–CH2 CO2 R3 . The reaction is believed to proceed via an initial conversion of (pin)B–SiMe2 Ph into LCuII SiMe2 Ph, which then undergoes a regioselective syn-addition across the 𝛼,𝛽-double bond of the allene, followed by hydrolysis of the Cu(II)-enolate, giving rise to the final product.621

(v) Palladium The optimized, Pd(II)-catalysed conjugate addition of ArB(OH)2 to N-substituted maleimides604 and chromones605 was mentioned in the subchapter on boron. The reaction of arylboronic acids with 2-alkylenecyclobutanones (1016) has been reported not to produce the corresponding 1,4-adducts. Instead, the reaction commences with 1,2-addition, and the resulting adduct (1017) undergoes a ring opening with insertion of Pd to generate the vinylpalladium intermediate, from which the (Z)-configured 𝛾,𝛿-unsaturated ketones (1019) were obtained as a result of protonolysis. Other pathways were excluded by control experiments.622

de 

de 

[Pd] O

Ph

ArB(OH)2 (dba)3Pd2, Cy3P K2CO3, dioxane 100 °C

(1016)

O Ph

O

Ph

Ar

(1017)

[Pd] O

Ph Ph

Ar

(1019)

(1018)

The pincer complex (1020) was employed as a catalyst for the hydrophosphination of 𝛼,𝛽-unsaturated enones bearing 𝛽-(2-pyridyl) substituents (2-Py)CH=CHCOR1 with ArR2 PH (R2 = Ar or i-Pr), which afforded (1021) with 92–99% ee.464 ArRP N Ph2P

Pd

O R′

PPh2

OAc (1020)

(1021)

The combined catalysis by thiourea (836) and (dba)3 Pd2 , of the addition vinylcyclopropanes to quinone methides, producing (837), was commented on in the subchapter on thiourea catalysts.518,519

ee 

631

10 Addition Reactions: Polar Addition

Aromatic diazonium salts ArN2 BF4 have been shown to undergo a Heck coupling with vinylsulfamides CH2 =CHSO2 N(Me)Bn, catalysed by (AcO)2 Pd (5 mol%) in MeOH at 20 ∘ C, to afford the styryl derivatives ArCH=CHSO2 N(Me)Bn.623 The Pd-catalysed reaction of indole derivatives with internal alkyne esters Ar2 C≡CCO2 Me, which proceeds via (1022), gives pyrroloindoles (1023).624 Me

Me

Ar1 N

(AcO)2Pd Cs2CO3

O

DMF 70 °C

CO2Me

H Ar2

Ar1 OH

N Ar2

Pd (OAc)2

(1022)

CO2Me

(1023)

A domino carbopalladation/C–H activation protocol has been developed, which relies on the addition of nucleophilic azoles (1024) to propiolic amides (1025), producing indolones (1026). The corresponding acrylic amides react in a similar way.625 Ar

Ph N N Ar

X

H

+

I N R

(1024) X = O, S

(AcO)2Pd (10 mol%) Ph3P (20 mol%)

(1025)

O

N

de 

N

X

Ph

Cs2CO3, toluene 100 °C

O N R (1026)

The reaction of indoles with alkynyl-substituted aryl aldehydes 2-(O=HC)C6 H4 C≡ C(EWG), catalysed by (AcO)2 Pd (8 mol%) in CH2 Cl2 at r.t., has been reported to yield the indole-substituted indanones (1027). A plausible mechanism has been proposed.626

(vi) Ruthenium The Phebox ruthenium complex (1028) was employed as a catalyst to effect the three-component coupling of terminal alkynes R1 C≡CH, enones CH2 =CHCOR2 , and aldehydes R3 CHO, which afforded the Morita–Baylis–Hillman-like products (1029), though with a rather low stereoselectivity (1:1 to 3:1 anti/syn dr and 32–79% ee for the anti-diastereoisomer).627 Benzamides PhCONHR have been shown to undergo addition to maleimides, catalysed by (p-cymene)2 RuCl (5 mol%) in the presence of AgBF4 (20 mol%), (AcO)2 Cu, and AcOH in DCE at 100 ∘ C, affording (1030) as a result of the amide-directed orthopalladation, followed by Heck-type addition.628 The hydroboration of HC≡CCO2 Me with the Ru/BH3 –thiazole complex (1001) has been discussed earlier in the subchapter on boron.608

ee  de 

632

Organic Reaction Mechanisms 2016 Me

O

Me OH

EWG

O

R3

CO Ru

N Ph

O

O

O

O

N R

Me

(1027)

(1028)

R2

N Ph

R1 (1029)

O NMe H

O

N R (1030)

CO2(2-Naphth) O

MeO (1031)

(vii) Rhodium Enones R1 CH=CHCOCH2 CHR2 (first generated in situ from R1 CH(SEt)CH2 CH=O on an Rh-catalysed carbonylation of terminal alkenes CH2 =CHR2 , followed by sulfide elimination) undergo addition of ArB(OH)2 , catalysed by the Rh complex of the chiral diene (1031), to afford 𝛽-aryl ketones R1 CH(Ar)CH2 COCH2 CH2 R2 with 89–96% ee.629 The phellandrene–abietic acid-derived ligand (1032) was employed in a similar way for the Rh-catalysed addition of ArB(OH)2 to ArCH=CHNO2 .630 Ligand (1033) represents yet another variation, which offers ≥90:10 dr and >99% ee for the arylation of 2,2-dialkyl cyclopent-4-ene-1,3-diones.631 Other diene ligands, namely (1034a)632 and (1034b),633 have been developed for the substrates that include cyclic N-sulfonyl ketimines (with ≤99% ee for the addition of ArB(OH)2 )632 and 𝛼,𝛽-unsaturated lactones (95–98% ee for the addition of terminal alkynes).633 The complex generated from [(C2 H4 )2 RhCl]2 and the novel proline-derived phosphines-alkene ligand (1035), whose function can be modulated by the Ar group, has been developed as a catalyst for the arylation of cyclic enones, 𝛼,𝛽-unsaturated esters, and 𝜔-nitrostyrene RCH=CH(EWG) with ArB(OH)2 to afford the adducts RCH(Ar)CH2 (EWG) with 70–93% ee. The mechanism was established by computational methods.634 Sulfurous diamide–alkene (1036) has also been successful for the same purpose (with ≤96% ee).635 The Rh-catalysed addition of ArZnCl to thiochromones will be discussed in the subchapter on organozinc additions.636 Enol carbamates (1037) undergo directed C–H activation at the vinyl group rather than at the aromatic ortho-position, as demonstrated by the Rh-catalysed addition to maleimide (1038), which gave rise to (1039).637 A similar reaction has been attained with acrylamides R1 CH=CHCONHR2 (R1 = H, alkyl, and Ar; R2 = H, i-Pr, and Bn), where the cis-H underwent activation.638

ee  ee  de  ee  ee 

ee  ee 

633

10 Addition Reactions: Polar Addition

O

O N H H

O

(1032)

(1033) Ph

Ar2

Ph

N

Ph

N

S

N Ph2P

Ar1

Ar

Ph

(1034a) Ar1 = Ph, Ar2 = 4-(CF3)C6H4 (1034b) Ar1 = Ar2 = ferrocenyl (1034c) Ar1 = Ar2 = Ph

(1035)

(1036)

O O

O NMe2 H

R1

[Cp*RhCl)2 (2.5 mol%) AgSbF6 (20 mol%)

O +

N

R2

Me2N

O O

PivOH (2 equiv) DCE, −70 °C

O (1037)

O

O R1

(1038)

N R2

(1039)

Directed C–H activation in the addition of arenes, such as (2-pyridyl)C6 H5 , to the bis-Michael acceptors RCOCH=CHCH2 XCH2 CH=CHCO2 Et (X = CH2 , NTs, and O), followed by a BnNH2 -promoted cyclization, has been reported to afford (1040). The reaction is believed to commence with addition of the metallated arene to the enone moiety; the resulting enolate then reacts with BnNH2 to generate the corresponding enamine, whose intramolecular Michael addition gives the final cyclic product (1040).639 (2-Pyridyl)C6 H5 has also been shown to add to enones F3 CCH=CHCOAr upon the Rhactivation of the ortho-position.640

X

N

EtO2C R

O

(1040)

634

Organic Reaction Mechanisms 2016

An interesting C–H activation was accomplished with aryloxymethyltrifluoroborates (1041); here, the initial transmetallation generates the rhodium complex (1042), which undergoes a 1,4-shift to form the ortho-metallated intermediate (1043) that adds to enones. When carried out in the presence of the diene ligand (1034c), the resulting product (1044) was obtained with 98 to ≥99.5% ee. The small isotope effect kH /kD = 1.1, observed for the substrate (1041) with a perdeuterated aromatic ring, shows that the C–H activation is not rate limiting.641 [(1034c)RhCl]2 5 mol%

O

BF3K

Cs2CO3, 100 °C

(1041)

[Rh] O (1042)

O O

[Rh] OMe (1044)

OMe (1043)

The ortho-quinone methide (1046), arising from ortho-hydroxy benzhydryl alcohol (1045) on reaction with the BINOL-derived phosphoric acid (603b) (5 mol%) (Scheme 25), has been reported to react with the metallocarbene (1048), generated from the diazo derivative (1047) and [(AcO)4 Rh2 ] (2 mol%), via the oxonium ylide (1049). Apparently, the key moment here is the interaction of (1046) with (1049) via the hydrogen bonding with (603b). The resulting adduct (1050) is then cyclized to the final hemiketal (1051).642 The outcome of the reaction of O-substituted N-hydroxybenzamides (1052) with 1,6enyne (1053) (Scheme 26) is known to be dependent on the O-substituent: the substrates with R = t-BuCO (1052a) give rise to (1056), whereas with R = Me (1052b), the reaction is driven to (1059). DFT calculations have now shed new light onto the mechanism. Thus, in the case of the pivalate (1052a), the reaction commences with the ortho-C–H activation, followed by addition to the C≡C bond, generating the pivalate chelated complex (1054), which then undergoes an intramolecular N-Michael addition (1055) to produce (1056). With R = Me (1052b), which does not offer the same chelation as the pivalate, the Rh is coordinated to the amide nitrogen instead (1057), whose formation is followed by a C-Michael addition (1058), affording (1059).643 The electron-deficient CpE -rhodium(III) complex (1060) has been reported to catalyse the domino [2+2+2] annulation–lactamization of acetanilide C6 H5 NHAc with two molecules of alkynoate R1 C≡CCO2 R2 via a consecutive cleavage of two adjacent C–H bonds (o- and m-) of the anilide to give benzo[cd]indolones (1061). The four newly formed bonds in the latter formula are highlighted.644

ee 

635

10 Addition Reactions: Polar Addition Ar1

O OH

*

O O

O

P

OH

OH

CO2R

Ar2

(1045)

CO2R

Ar2

(1048)

(603b)

N2

[(AcO)4Rh2]2

H2O Ar1 Ar2 O

+

H HO

Ar1

O [Rh]− CO2Me O

(1046)

O

[Rh]

OH Ar2

H

O P

O

(1047)

OH CO2R O

(1050) (1049)

O

Ar1

*

O

OH CO2R Ar2 OH

(1051) Scheme 25

(viii) Iridium Addition of (i-Pr)3 C≡CH to cis-enamides RCH=CHNH(COAr), catalysed by [(COD)Ir(1062)]OTf (5 mol%) in CHCl3 at 60 ∘ C, has been reported to produce homopropargyl amides (1064) with 5–92% ee. The regioselectivity is believed to be controlled by coordination of Ir to the amide carbonyl (1063).645 A related reaction of 𝛼,𝛽-unsaturated amides, such as R1 CH2 CH=CHCONHR2 , catalysed by the Ir-Segphos complex generated from (COD)2 IrOTf and (217b), afforded the 𝛾-alkynylated products (i-Pr)3 SiC≡C–C(R1 )CH2 CH2 CONHR2 with 84–96 ee.646 (ix) Manganese Addition of acetyl acetone MeCOCH2 COMe to alkenes Ar1 CH=CHAr2 (e.g., Ar1 = pO2 N–C6 H4 ; Ar2 = p-MeO–C6 H4 ), mediated by (AcO)3 Mn, afforded the cis-configured dihydrofuran derivatives (1065). The mechanism was assessed by a combination of experimental and theoretical studies.647 (x) Titanium The reaction of cyclic enones, in particular chromones, with acrylonitrile CH2 =CHCN, catalysed by Cp2 TiIII Cl, which in turn was generated from Cp2 TiIV Cl2 (10 mol%) on

ee 

ee 

de 

636

Organic Reaction Mechanisms 2016 O

O N H

OR

+ O Me

(1052a) R = Piv (1052b) R = Me

(1053) [Cp*RhCl2)2 R = Me

R = Piv O

But

O

O

N

N

Rh O Cp*

OMe Cp* Rh

O

O

O

Me

Me

(1054)

(1057) O

Cp* O

O

OPiv O

OMe N

Rh

Rh

Cp*

O

N O

O Me

Me (1058)

(1055)

O O

N H

O N

H H

O

Me O

O Me (1059)

(1056) Scheme 26

OMe

637

10 Addition Reactions: Polar Addition CO2R2 CO2Et

Ph

Ph R1

EtO2C

Cl Rh

N

Cl

O Ar

Ir

(1061)

P * P

(1062)

Si(Pri)3

Si(Pri)3

O Ar

N H

Ph

Ph

Ac

2

(1060) H

P

P

O

N H

R (1063)

R (1064) C6F5

O

O

Me

OH

Me

O

OH

Ar1

O

Ar2

R

CN C6F5

(1065)

(1066) R1

(1067) O

O F3C R2

R3 (1068)

S

Ar

(1069)

reduction with Zn or Mn (2 equiv), gave the formal 1,4-adducts (1066). However, the reaction proceeds in a radical way via the initially generated Ti(IV)-enolate radical, which adds across the acrylate double bond in a radical manner.648

(xi) Zinc The enantioselective Cu(II)-catalysed addition of Et2 Zn to chalcones, using the BINOLderived phosphoramidite (1008), was dealt with in the subchapter on copper.612 With an analogous phosphoramidite ligand, the maximum of 64% ee was attained.649

ee 

638

Organic Reaction Mechanisms 2016

Terminal acetylenes R1 C≡CH can be added to 𝛽-substituted-𝛽-trifluoromethyl enones (F3 C)(R2 )C=CHCOAr in the presence of a catalyst generated from Et2 Zn and the BINOL derivative (1067) in toluene at 37 ∘ C. The resulting 𝛽-propargylic ketones (1068) were obtained with 60–90% ee.650 The addition of ArZnCl to thiochromones, catalysed by a complex generated from [(COD)RhCl]2 and (R)-3,4,5-(MeO)3 -BIPHEP (1010b) in the presence of Me3 SiCl in THF at r.t., afforded thioflavanones (1069) with 83–95% ee.636 The 1,4- versus 1,6-selectivity of the addition of organozincates [R-Zn(CH2 SiMe3 )2 ]− , generated from RMgX, ZnCl2 , and Me3 SiCH2 MgCl, to polyconjugated esters, can be controlled by a combination of the solvent and the substituent at the terminus of the conjugated system. Thus, with Ph at the terminus and in THF at −78 ∘ C, the 1,4-addition is preferred, apparently as a result of the formation of the tight ionpair (1070). By contrast, with EtO at the terminus (which affects the electronics) and added HMPA, the system works via the loose ionpair (1071), favouring the 1,6-addition.651 (HMPA)n XMg+ O

M −

O

EtO

Zn

OEt

R

R′

O

R′ EtO

O OEt

R Ph

−

R′

Zn

R′

EtO (1070)

(1071) M = MgX or Li

The reaction of nitrones (1072) with terminal alkynes, mediated by Me2 Zn, has been shown to produce 2H-tetrahydro-4,6-dioxo-1,2-oxazines (1073), the core moiety of antibiotics, such as alchivemycin.652 O

O

MeO + −

O

OMe

N

+

O

Me2Zn

R

N

toluene r.t.

OMe

R (1072)

(1073)

(xii) Gold Calculations using the MP2 method have shown that hydroarylation of alkenes with furans, catalysed by AuCl3 , proceeds via direct auration and that hydrogen bonds are an important factor in stabilization of the intermediates.653

ee 

ee 

639

10 Addition Reactions: Polar Addition

Oxindolylidine acetates have been reported to undergo a double addition of isonitriles, catalysed by KAuCl4 in toluene. The reaction outcome was found to be temperature dependent, and a plausible mechanism was proposed.654 1-(N-Tosylazetidin-2-yl) ynones (1074) undergo a gold(I)-catalysed rearrangement on a nucleophilic attack with NuH (ROH, BnNH2 , PhNH2 , EtSH, indole, etc.) to produce N-tosylpyrrolin-4-ones (1075).655 [Au+ ]

O

NuH LAuNTf2 (5 mol%)

N NuH

R

Ts

O

R N

CH2Cl2, r.t.

Ts (1075)

Nu

(1074)

The Au(I)-catalysed intramolecular domino hydroamination/Michael addition of (600), which affords tetrahydrocarbazoles (602), was discussed earlier.388

Miscellaneous Nucleophilic Additions The reaction of cyclopropyl bromides (1076) with t-BuOK has been reported to produce the cis-fused cyclic ethers (1078). The reaction proceeds via cyclopropene (1077) with exo-trig cyclization including coordination of K+ to the amide carbonyl and the alkoxide anion, as confirmed by QST2 calculations at b3lyp 6-311++G** level.656 O Me

R

Bu OK 18-crown-6 (cat)

( )n

THF

N Br

t

O N

−

O

Me

R ( )n

HO (1076) n = 0–2

Me

R

O

(1077)

N O

( )n (1078)

Triazoles have been developed as surprisingly efficient C–H hydrogen bond donors for anion binding, such as Cl– generated in the Reissert-type reaction (1079). When applied as catalyst (10 mol%) for the addition of Cl3 CCH2 OCOCl and the ketene acetal CH2 =C(OPri )OTBS to isoquinoline, it was found to shield one of the faces of the isoquinoline substrate, resulting in the formation of (1080) in ca 75% ee.657

ee 

640

Organic Reaction Mechanisms 2016

N N

MeO

N

N H

N

N N

Cl−

N

OMe

H

H

H

N

N

N N

CF3 F3C F3C

CF3 (1079)

N PriO2C

O

CCl3

O (1080)

The reaction of 𝛼,𝛽-unsaturated amides CH2 =C(R)CONEt2 with Zhdankin’s azidoiodine(III) reagent (1081) and SOCl2 , catalysed by Cu2 O in AcOEt at r.t., has been designed as a new method for chloroazidation of electron-poor alkenes. The reaction gives rise to N3 CH2 C(Cl)(R)CONEt2 and is believed to proceed in a radical way.658 Terminal alkynes RC≡CH (R = Ar and alkyl) have been shown to react with 2 equiv of H-phosphine oxide Ph2 P(O)H in the presence of t-BuOK (10 mol%) in THF at 70 ∘ C, affording (1082). A plausible catalytic cycle was formulated, which includes the initial nucleophilic addition of the anion Ph2 P(O)− to the unsubstituted terminus of the alkyne molecule.659 Treatment of alkynic phosphonates (EtO)2 (O)PC≡CCH2 NPhth at r.t. with a base, such as Cs2 CO3 , generates the novel 3-imidoallenylphosphonates (EtO)2 (O)PC=C=CNPhth, which can be trapped by nucleophiles, such as alcohol ROH, to give 𝛽-alkoxylation products (1083).660 The formal [4 + 2] addition of PhN=NCOPh to allenes MeCH=C=CHCO2 Et, catalysed by DMAP, has been shown by DFT calculations to actually proceed as a four-step event, commencing with a nucleophilic addition of DMAP to the central carbon, followed by a nucleophilic addition of the resulting zwitterion to the N=N bond of the other reactant, 6(O)-exo-trig cyclization, and elimination of DMAP to afford (1084).661 Regio- and stereo-selectivity of nucleophilic addition to vinyl epoxides derived from cyclohexadiene, glycal, and imino glycal (1085) have now been rationalized using the

641

10 Addition Reactions: Polar Addition N3

I

O P(O)Ph2

R (1081)

(EtO)2P

NPhth RO

(1082)

Me Ph

O

P(O)Ph2

O

(1083)

CO2Et

N

O N

O R

X 1

4

Ph (1084)

3

2

(1085a) X = CH2 (1085b) X = O (1085c) X = NCbz

HSAB theory and molecular electrostatic potential (MEP), namely by a combination of the usual parameters for softness (Fukui indexes) and hardness (atomic charges) and novel parameters, obtained from the MEP on the van der Waals surface (ESP indexes). As expected, under neutral conditions, C(1) was identified as a softer centre than C(3) in the cyclohexadiene derivative (1085a), but oxirane activation with an electrophile levels the softness and shifts hardness from C(3) to C(1). With the heterocycles (1085b) and (1085c), C(1) is a harder centre than C(3). Rationalization of the prevailing syn-C(1) selectivity observed with glycal and iminoglycal epoxides (1085b) and (1085c) versus the anti-C(3)-selectivity observed with carbocycles was also given. The ESP indexes were identified as suitable parameters to account for stereoselectivity and more reliable as hardness descriptors than the atomic charges.662

Acronyms acac BA BARF BBN BIBOP BINAM BINAP BINOL BIPHEP Bmim B2 pin2 or pin2 B2 p-BQ BSA

Acetylacetone Brønsted acid Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate 9-Borabicyclo[3.3.1]nonane Ligands (324a,b) [1,1′ -Binaphthalene]-2,2′ -diamine 2,2′ -Bis(diphenylphosphino)-1,1′ -binaphthyl 1,1′ -Bi-2-naphthol Formula (1010b) 1-Butyl-3-methylimidazolium hexafluorophosphate; bis(oxazoline) ligand, for example, formula (909) Bis(pinacolato)diboron p-Benzoquinone N,O-Bis(trimethylsilyl)acetamide

642 BTA Cat CBS-QB3 COD COE CpE Cpx CT Cy p-Cym Cy-Xanphos DABCO dan DBDMH DBU DCE DCDMH DHP (DHQD)2 PHAL (DHQ)2 PHAL DIAD DIOP DMAc DMAP DMB DMEDA DMPU DMSO DPEPHOS dpm dppe dppb dF ppb dppbz dppf dpph dppm dppp dpppf DTBM DTBM-BINAP DTBM-Garphos DTBM-SEGPHOS

Organic Reaction Mechanisms 2016 Benzotriazole Catechol, catecholato Computational method 1,5-Cyclooctadiene Cyclooctene Ligand in formula (1060) Ligand in formula (373) Thiophene carboxylate Cyclohexyl p-Cymene Formula (148b) 1,4-Diazabicyclo[2.2.2]octane 1,8-Diaminonaphthyl 1,3-Dibromo-5,5-dimethylhydantoin 1,8-Diazobicycloundec-7-ene 1,2-Dichloroethane 1,3-Dichloro-5,5-dimethylhydantoin 3,4-Dihydro-2H-pyran Dihydroquinidine 1,4-phthalazinediyl diether Dihydroquinine 1,4-phthalazinediyl diether Diisopropyl azodicarboxylate 2,3-O-Isopropylidene-2,3-dihydroxy-1,4bis(diphenylphosphino)butane N,N-Dimethylacetamide 4-Dimethylaminopyridine 2,4-Dimethoxybenzyl N,N′ -Dimethylethylenediamine 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone Dimethyl sulfoxide Formula (156) 2,2′ -Dipyridylmethane 1,2-Bis(diphenylphosphino)ethane 1,4-Bis(diphenylphosphino)butane 1,4-Bis[di(pentafluorophenyl)phosphino]butane 1,2-Bis(diphenylphosphino)benzene 1,1′ -Bis(diphenylphosphino)ferrocene 1,6-Bis(diphenylphosphino)hexane 1,1-Bis(diphenylphosphino)methane 1,3-Bis(diphenylphosphino)propane 1,1′ -Bis(diphenylphosphino)ferrocene 3,5-Di-tert-butyl-4-methoxy Formula (9) Formula (353) 5,5′ -Bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]4,4′ -di-1,3-benzodioxole; formula (217a)

10 Addition Reactions: Polar Addition DTBP Duphos EDG ESI MS ESP EWG FLP FTIR Fxyl HB HFIP HMDS HSAB HTIB Ind IPr

643

2,6-Di-tert-butylpyridine Formula (197) Electron-donating group Electrospray ionization mass spectrometry Electrostatic potential Electron-withdrawing group Frustrated Lewis pair Fourier-transform infrared spectroscopy 3,5-(CF3 )2 C6 H3 Hydrogen bonding 1,1,1,3,3,3-Hexafluoropropan-2-ol Hexamethyldisilazane Hard and soft acids and bases (principle) PhI(OH)Ts 𝜂 5 -Indenyl 1,3-Bis(2,6-diisopropylphenyl)imidazolium-derived carbene ligand ISIPHOS Ligand (317) JohnPhos 2-Ph-C6 H4 P(t-Bu)2 JoSPOphos Formula (354) KIE Kinetic isotope effect KHMDS Potassium bis(trimethylsilyl)amide LDA Lithium diisopropylamide LiHMDS Potassium bis(trimethylsilyl)amide m-CPBA or MCPBA m-Chloroperoxybenzoic acid MAO Methylaluminoxane MBH Morita–Baylis–Hillman reaction MEP Molecular electrostatic potential Mes Mesityl MeOBIPHEP Formula (1010) MOP Formula (610) MS Mass spectrometry or molecular sieves MVK Methylvinyl ketone NBO Computational method NCS N-Chlorosuccinimide NHC N-Heterocyclic carbene nbd Norbornadiene NBP N-Bromophthalimide NBS N-Bromosuccinimide NFSI N-Fluorobenzenesulfonimide NIS N-Iodosuccinimide NMR Nuclear magnetic resonance Oxone KHSO5 PBE Computational method PEPPSI-IPr–Pd Formula (171)

644 Phebox Phen PIC PIDA PIFA Pin PMHS PMP ppfa Py PPTS RLS SEGPHOS Selectfluor Senphos Siphos SET SIMES SPhos TBAF TBDPS TBS or TBDMS t-BuXPhos TFA THF TIPS-EBX TMEDA TMG TOF Xantphos XAS Xing-Phos XPhos XRD XtalFluor-E Yanphos

Organic Reaction Mechanisms 2016 Ligand in formula (1028) Phenanthroline 2-Picolinate Diacetoxy iodobenzene Bis(trifluoroacetoxy)iodo)benzene Pinacol, pinacolato Polymethylhydrosiloxane p-Methoxyphenyl Formula (999) Pyridinyl Pyridinium toluenesulfonate Rate-limiting step 5,5′ -Bis(diphenylphosphino)-4,4′ -bi-1,3-benzodioxole 1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate Formula (157) Formula (237) Single-electron transfer Formula (512) 2-Dicyclohexylphosphino-2′ ,6′ -dimethoxybiphenyl Tetrabutylammonium fluoride tert-Butyldiphenylsilyl tert-Butyldimethylsilyl Ligand (247b) Trifluoroacetic acid or acetate CF3 CO2 H or CF3 CO2 − Tetrahydrofuran 1-[(Triisopropylsilyl)-ethynyl]-1,2-benziodoxol-3(1H)-one (595) N,N,N′ ,N′ -Tetramethylethylenediamine Tetramethyl guanidine Turnover frequency Formula (148a) X-ray absorption spectroscopy Formula (761) Ligand (247a) X-ray diffraction Mixture of compounds (467) and (468) Ligand (323)

Acronyms and Abbreviations http://acronyms.thefreedictionary.com/DPPB

10 Addition Reactions: Polar Addition

645

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 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

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10 Addition Reactions: Polar Addition 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240

649

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650 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288

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10 Addition Reactions: Polar Addition 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335

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652 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383

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10 Addition Reactions: Polar Addition 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429

653

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10 Addition Reactions: Polar Addition 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516

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10 Addition Reactions: Polar Addition 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605

657

Donadío, L. G., Galetti, M. A., Giorgi, G., Rasparini, M., and Comin, M. J., J. Org. Chem., 81, 7952 (2016). Kumar, T. P., Prasad, S. S., Haribabu, K., Kumar, V. N., and Reddy, C. S., Tetrahedron: Asymmetry, 27, 1133 (2016). Hu, X., Wei, Y.-F., Wu, N., Jiang, Z., Liu, C., and Luo, R.-S., Tetrahedron: Asymmetry, 27, 420 (2016). Xu, D., Wang, J., Yan, L., Yuan, M., Xie, X., and Wang, Y., Tetrahedron: Asymmetry, 27, 1121 (2016). Luo, H., Yan, X., Chen, L., Li, Y., Liu, N., and Yin, G., Eur. J. Org. Chem., 2016, 1702. Jiménez, E. I., Vallejo-Narváez, W. I., Román-Chavarría, C. A., Vazquez-Chavez, J., Rocha-Rinza, T., and Hernández-Rodríguez, M., J. Org. Chem., 81, 7419 (2016). Azad, C. S., Khan, I. A., and Narula, A. K., Org. Biomol. Chem., 14, 11454 (2016). Jin, H., Kim, S. T., Hwang, G.-S., and Ryu, D. H., J. Org. Chem., 81, 3263 (2016). Durmaz, M., Tataroglu, A., Yilmaz, H., and Sirit, A., Tetrahedron: Asymmetry, 27, 148 (2016). Zhang, M. L., Chen, L., You, Y., Wang, Z.-H., Yue, D.-F., Zhang, X.-M., Xu, X.-Y., and Yuan, W.-C., Tetrahedron, 72, 2677 (2016). Andrés, J. M., de La Cruz, N., Valle, M., and Pedrosa, R., ChemPlusChem, 81, 86 (2016). You, Y., Wu, Z.-J., Chen, J.-F., Wang, Z.-H., Xu, X.-Y., Zhang, X.-M., and Yuan, W.-C., J. Org. Chem., 81, 5759 (2016). Luridiana, A., Frongia, A., Aitken, D. J., Guillot, R., Sarais, G., and Secci, F., Org. Biomol. Chem., 14, 3394 (2016). Xiao, W., Yin, X., Zhou, Z., Du, W., and Chen, Y.-C., Org. Lett., 18, 116 (2016). Xie, J., Sha, F., and Wu, X.-Y., Tetrahedron, 72, 4047 (2016). Rao, K. S., Ramesh, P., Trivedi, R., and Kantam, M. L., Tetrahedron Lett., 57, 1227 (2016). Liu, W., Zou, L., Fu, B., Wang, X., Wang, K., Sun, Z., Peng, F., Wang, W., and Shao, Z., J. Org. Chem., 81, 8296 (2016). Huang, H., Palmas, J., and Kang, J. Y., J. Org. Chem., 81, 11932 (2016). Kucherenko, A. S., Lisnyak, V. G., Kostenko, A. A., Kochetkov, S. V., and Zlotin, S. G., Org. Biomol. Chem., 14, 9751 (2016). Liu, W., Lai, X., Zha, G., Xu, Y., Sun, P., Xia, T., and Shen, Y., Org. Biomol. Chem., 14, 3603 (2016). Kumar, A. S., Reddy, T. P., Madhavachary, R., and Ramachary, D. B., Org. Biomol. Chem., 14, 5494 (2016). Zhao, B.-L., Zhang, D., Liu, L., and Du, D.-M., Org. Biomol. Chem., 14, 6337 (2016). Möhlmann, L., Chang, G.-H., Reddy, G. M., Lee, C.-J., and Lin, W., Org. Lett., 18, 688 (2016). Wolf, F. F., Klare, H., and Goldfuss, B., J. Org. Chem., 81, 1762 (2016). Gurubrahamam, R., Gao, B.-F., Chen, Y. M., Chan, Y.-T., Tsai, M.-K., and Chen, K., Org. Lett., 18, 3098 (2016). Kaya, U., Chauhan, P., Hack, D., Deckers, K., Puttreddy, R., Rissanen, K., and Enders, D., Chem. Commun. (Cambridge), 52, 1669 (2016). Hack, D., Dürr, A. B., Deckers, K., Chauhan, P., Seling, N., Rübenach, L., Mertens, L., Raabe, G., Schoenebeck, F., and Enders, D., Angew. Chem. Int. Ed., 55, 1797 (2016). Shu, T., Ni, Q., Song, X., Zhao, K., Wu, T., Puttreddy, R., Rissanen, K., and Enders, D., Chem. Commun. (Cambridge), 52, 2609 (2016). Kaur, J., Islam, N., Kumar, A., Bhardwaj, V. K., and Chimni, S. S., Tetrahedron, 72, 8042 (2016). Sekikawa, T., Kitaguchi, T., Kitaura, H., Minami, T., and Hatanaka, Y., Org. Lett., 18, 646 (2016). Feng, J., Yuan, X., Luo, W., Lin, L., Liu, X., and Feng, X., Chem.-Eur. J., 22, 15650 (2016). Kimura, M., Matsuda, Y., Koizumi, A., Tokumitsu, C., Tokoro, Y., and Fukuzawa, S., Tetrahedron, 72, 2666 (2016). Liu, K., Chang, X., and Wang, C.-J., Org. Lett., 18, 6288 (2016). Al Quntar, A. A. A. and Dewik, H., Tetrahedron Lett., 57, 189 (2016). Jakli´nska, M., Cordier, M., and Stankeviˇc, M., J. Org. Chem., 81, 1378 (2016). Barbero, M., Cadamuro, S., Dughera, S., Ghigo, G., Marabello, D., and Morgante, P., Tetrahedron Lett., 57, 4758 (2016). Qiao, Y., Yang, W., Wei, D., and Chang, J., RSC Adv., 6, 70723 (2016). Shi, Z. G. and Loh, T.-P., Angew. Chem. Int. Ed., 52, 8584 (2013). Liu, T., Han, S., Li, Y., and Bi, S., J. Org. Chem., 81, 9775 (2016). Tanimoto, H., Yokoyama, K., Mizutani, Y., Shitaoka, T., Morimoto, T., Nishiyama, Y., and Kakiuchi, K., J. Org. Chem., 81, 559 (2016). ̇ Lipner, G., Ulikowski, A., Domzalska, A., and Furman, B., Tetrahedron, 72, 7125 (2016). Ji, J., Yang, Z., Liu, R., Ni, X., Lin, S., and Pan, Q., Tetrahedron Lett., 57, 2723 (2016). Gerten, A. L. and Stanley, L. M., Tetrahedron Lett., 57, 5460 (2016).

658 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653

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10 Addition Reactions: Polar Addition 654 655 656 657 658 659 660 661 662

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CHAPTER 11

Addition Reactions: Cycloaddition

N. Dennis 3 Camphor Laurel Court, Stretton, Queensland, Australia

2 + 2-Cycloaddition 2 + 3-Cycloaddition 2 + 4-Cycloaddition Miscellaneous . . . References . . . . .

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664 666 674 684 693

Tetrafluorothiophene S,S-dioxide is a potent cycloaddend that reacts as a Diels–Alder diene, a dienophile, and a 2 + 2-addend. Both Diels–Alder and 2 + 2-cycloadditions can occur with terminal alkynes.1 A tandem rhodium-catalysed C–H activation/intramolecular Diels–Alder reaction/ 1,3-dipolar cycloaddition cascade process involving a diazole (1) and an eneyne (2) has yielded a decahydropyrene (3) with high stereoselectivity (Scheme 1).2 Unsymmetrical aryl (mesityl) iodonium salts (4) are precursors of arynes for 1,3-dipolar and 4 + 2-cycloaddition reactions with azides and furans, respectively.3 Mechanistic studies on the Garratt–Braverman cyclization reactions have shown that for bis-propargyl ethers, an anionic 4 + 2-cyclization is involved. However, for bis-propargyl sulfones, a diradical mechanism is proposed.4 The 2 + 2-cycloaddition of N-alkyl imines with methanesulfonyl sulfene at 20 ∘ C yielded trans-𝛽-sultams in up to 69% yields. However, at low temperatures of −78 ∘ C, a 2 + 2 + 2-cycloaddition with N-methyl imines produced 1,2,4-thiadiazine 1,1-dioxides (4-aza-𝛿-sultams) in up to 80% yields.5 The Pd(0)-catalysed intermolecular 2 + 2 + 1- and 2 + 2 + 2-carbocycloadditions of (1,n)-diynes (n = 6–9) with bromophenols provide an efficient route to tricyclic scaffolds possessing a quaternary carbon centre.6 The BF3 ⋅OEt2 -mediated formal 4 + 2- and 5 + 2-cycloaddition reactions of 4-alkenols (5) with veratrol (6) produced substituted tetralins (7) and benzosuberans (8), respectively, in good yields (Scheme 2).7 Formal 4 + 1-/4 + 3-cycloaddition reactions of diazo esters with hexahydro-1,3,4triazines have been accomplished using a gold complex. The reactions provide evidence of the involvement of a gold metalloenolcarbene intermediate (9). Mechanistic studies indicate that the triazines react directly with the metal carbene.8 Organic Reaction Mechanisms 2016, First Edition. Edited by A. C. Knipe. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

661

de 

de 

662

Organic Reaction Mechanisms 2016 CO2Et

EtO2C 1. [Cp*Rh(MeCN)3](SbF6)2 PhOCH2CO2H, AgOAc DCE, 100 °C, 11 h

N O

+

N

2. K2CO3 Ph mesitylene, 240 °C, 10 h

Ph

(1)

O

Ph

(2)

(3)

ortho C−H activation

3+2

CO2Et

EtO2C N O

+

O

N

−

Ph

Ph

Ph

Ph

CO2Et

4+2

O

−N2

N N

Ph

Ph

Scheme 1 −

OTs

I+ R H (4)

SMe

663

11 Addition Reactions: Cycloaddition Y Me

Ar

MeO

OMe (7)

BF3• OEt2 (R = H)

Y + Ar

OH R

R

OMe OMe

(5)

BF3• OEt2 (R = Me)

(6)

Y Me

Ar

Me

MeO

OMe (8)

Scheme 2

OSi R1

OSi 1

CO2Et

CO2Et

R

+

[Au] Si = TBS, TIPS, TPDPS (9)

−

[Au]

664

Organic Reaction Mechanisms 2016

2 + 2-Cycloaddition An extensive review of 2 + 2-cycloaddition reactions of allenes, allenenes, allenamides, ketenes, alkynes, siloxy alkynes, phenylthioacetylene, and ynamides promoted by metalbased catalysts has been published.9 A further review covers all recent aspects of the 2 + 2-photocycloaddition chemistry of synthetically relevant regio- and stereo-selective reactions for the past 20 years (1995–2015). Copper(I) and photoinduced electron transfer (PET) catalysis together with direct excitation or sensitization are discussed.10 The iminium-ion-catalysed 2 + 2-cycloaddition of 𝛼,𝛽-unsaturated aldehydes with alkenyl phenols produced highly functionalized head-to-tail coupled chiral cyclobutanes with high regiospecificity.11 The intramolecular 2 + 2-cycloaddition of allenylic esters (10) yielded various trispirocyclic derivatives (11) containing a cyclobutane ring. The process is highly regiospecific under mild reaction conditions (Scheme 3).12,13 O

de 

O

O O O O THF, 60 °C, Ar

C Ph

Ph

Ph

Ph

Ph Ph

(10)

(11) Scheme 3

A key step in the total synthesis of the sesquiterpenes Rumphellaone A and Hushinone is the gold(I)-catalysed 2 + 2-macrocycloaddition of a 1,10-enyne ((R)-6-(2-ethynyl)benzyloxy-2-methylhept-2-ene) (12) to produce the intermediate ((2aS,5R)-2,2, 5-trimethyl-2,2a,3,4,5,7-hexahydrobenzo[c]cyclobuta[e]oxonine) (13) in a 75% average yield (Scheme 4).14 The chiral N,N′ -dioxide-Zn(II)(NTf2 )2 -catalysed 2 + 2cycloaddition of alkynones with cyclic enol silyl ethers yielded fully substituted cyclobutenes with high enantioselectivity (up to 97% ee). Both terminal and internal alkynes react in this cycloaddition.15

[Au]-catalysed

O

O

H (12)

(13) Scheme 4

de 

ee 

665

11 Addition Reactions: Cycloaddition

The intramolecular 2 + 2-cycloaddition reaction of alkynone–vinylidenecyclopropanes (14) produced cyclobutene-containing spiro[2.3]hexenes (15) fused with six- or seven-membered carbo- or heterocycles in good to excellent yields (Scheme 5).16 The Rh-catalysed intermolecular head-to-head 2 + 2-cycloaddition of allenamides formed trans-dimethylenecyclobutane-1,2-diamine derivatives in good yields (63–89%) with high regio- and stereo-selectivity.17 The regio- and stereo-selective intermolecular  de 2 + 2-cycloaddition of C60 (16) with allenol esters (17) (formed in situ from propargylic esters) produced alkylidenecyclobutane-annelated fullerenes (18). A reaction mechanism involving a radical-ion pair formation by a single election transfer (SET) process has been proposed (Scheme 6).18 The 2 + 2-cycloaddition of terminal alkenes with allenoates yielded 1,3-disubstituted cyclobutanes in high yields.19 R1

R1 C

X

O DCE, 80 °C

n

X

R2

n

R2

O

(14)

(15)

R1 = alkyl; R2 = alkyl, Ar X = TsN, BsN, PhSO2N, O, (BnOCH2)2C n = 1, 2 Scheme 5

Ph +

C

BocO (16)

Ph

1,2-dichlorobenzene

Bu

Bu

OBoc (18)

(17) Scheme 6

The 2 + 2-cycloaddition of ketenes with chiral acyclic enol ethers yielded chiral densely substituted cyclobutanones with high stereoselectivity.20 The Lewis acidpromoted 2 + 2-cycloaddition of monosubstituted aryl ketones with alkenes produced cyclobutanones in unusually high yields. The success of this reaction is due to the formation of a highly reactive intermediate monosubstituted ketene–Lewis acid adduct.21 The reaction of arylaldehydes with sulfonylisocyanates produced N-sulfonylimines via an initial 2 + 2-cycloaddition followed by the release of carbon dioxide.22

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Organic Reaction Mechanisms 2016

The 2 + 2-cycloaddition reaction of carbodiimides (19) to 1,3-N-triflyl-1-azabutadienes (20) formed N-{[1-alkyl-4-(alkylimino)azetidin-3-ylidine]methyl}triflamides (21) via the unusual reaction of carbodiimides with the C=C bond of the diene (Scheme 7).23 The rare 2 + 2-photocycloaddition reaction of N-arylsulfonyl imines with styrene derivatives and benzofurans yielded azetidine derivatives with high stereoselectivity under ambient conditions.24 The diastereoselective 1,4-diazabicyclo[2.2.2]octane (DABCO)-catalysed 2 + 2-cycloaddition of isatin-derived ketimines (22) with allenoates (23) provided chiral spirooxindole-fused 4-methyleneazetidines (24). The stereodirecting effect of the bulky tert-butanesulfinyl chiral auxiliary was used to access single diastereoisomers in this process (Scheme 8).25 Meldrum’s acid derivatives have been used to generate acyl ketenes which readily undergo stereoselective 2 + 2-cycloaddition with chiral aldimines to furnish optically active cis- and trans-𝛽-lactams.26

2 + 3-Cycloaddition An extensive review of the progress in 1,3-dipolar cycloadditions in the recent decade has been published. A variety of dipole intermediates including azomethine ylides, münchnones, azomethine imines, nitrones, carbonyl ylides, nitrile ylides, nitrile imines, nitrile oxides, and diazoalkanes were investigated.27 Tf

R1

NR2

TfHN

N

N

+

C

R1

N R1

Me

(19)

(20)

N

Me

R2

R2

(21)

R1 = Pri, c-Hex; R2 = H, Me; Tf = CF3SO2 Scheme 7

R3

But O

But

S +

R2

CO2R4

C

O N

S

R3

N

DABCO (20 mol%) THF, r.t., 24 h

H2C

N O

R2 N R1

R1 (22)

O

CO2R4

(24)

(23)

up to 97% yield dr > 99:1 Scheme 8

de 

ee  de  de 

667

11 Addition Reactions: Cycloaddition

The tricyclohexylphosphine-catalysed 1,3-dipolar cycloaddition of (E)-alkyl 5substituted phenylpent-4-en-2-ynoates with C60 produced cyclopentenofullerenes. An initial 1,3-addition of phosphines to the 𝛼-carbons of the enynolates generated the 1,3-dipole.28 Air-stable ferrocenylphosphines (25) promote the asymmetric 3 + 2-cycloaddition of Morita–Baylis–Hillman carbonates with maleimides to yield the corresponding bicyclic imides in high yields (67–99%) and high enantioselectivity (84–99% ee).29

ee 

O N H Fe

S

Cl

PPh2

(25)

The palladium/organocatalyst-promoted asymmetric 3 + 2-cycloaddition of vinylcyclopropanes with 𝛼,𝛽-unsaturated aldehydes formed cyclopentanes containing up to four stereocentres in high yields and selectivities.30 The Sc(OTf)3 -catalysed cycloaddition of alkynylcyclopropane ketones with e-rich aromatic ketones produced 2,5-trans-2,3,3,5-tetrasubstituted tetrahydrofurans containing a quaternary carbon centre in high-to-excellent yields (up to 95%) with good diastereoselectivities.31 Benzothiazoles and cyclopropane-1,1-dicarboxylates undergo 1,3-dipolar cycloadditions to produce hydropyrrolo[2,1-b]thiazole adducts in high yields (up to 97%) and excellent enantioselectivity (up to 97% ee).32 The phosphine (28)-mediated 3 + 2-cycloaddition of isatin-derived ketimines (26) with simple and 𝛾-substituted allenoates (27) formed 3,2′ -pyrrolidinyl spirooxindoles (29) in high yields (up to 85%) with excellent enantioselectivity (98% ee) (Scheme 9).33 The chiral N,N′ -dioxide/Ni(II)-catalysed 3 + 2-cycloaddition of oxiranes with heterosubstituted alkenes yielded chiral tetrahydrofurans in high yields (up to 99%) with high diastereo- (92:8 dr) and enantio-selectivity (99% ee).34 The intermolecular Lewis acid-catalysed 3 + 2-cycloaddition of epoxides with styrenes formed substituted tetrahydrofurans through a mechanism involving cationic intermediates. The reaction showed complete control of regioselectivity and high diastereoselectivity.35 Again, the BuOK/BEt3 -catalysed 1,3-dipolar cycloaddition of 3-substituted indoles (30) with vinyl epoxides (31; X = O) and vinyl aziridines (31; X = N) formed furoindolines (32; X = O) and pyrroloindolines (32; X = N), respectively, in high yields (up to 96%) and excellent diastereoselectivity (9:1 dr) (Scheme 10).36 The metal-catalysed 1,3-dipolar cycloaddition of alkenyl arenes with azomethine ylides produced exo- or endo-4-aryl pyrrolidine cycloadducts, depending on the nature of the catalytic system used.37 The (R,R)-Me-Duphos/AgF-catalysed 3 + 2cycloaddition of nitroalkenes with acyclic azomethine ylides, derived from 𝛼-imino𝛾-lactones, formed spiro-nitroprolinate cycloadducts in good to moderate yields (40–73%) and with both high diastereoselectivity and enantioselectivity.38 When imidazoline-aminophenol (IAP)/Ni(OAc)2 or bis(imidazolidine)pyridine/Cu(OTf)2

ee  de  de 

ee  de  ee  de  ee  de  de 

de 

de 

ee  de 

668

Organic Reaction Mechanisms 2016 N Boc OTBS

R1

PPh2

O O

N

NH

R2

Boc (26) F3C

+

BocN

CF3

(28) catalyst (10 mol%)

R2

•

CO2Bn

CO2Bn O

R1 N

toluene, 0 °C, 5 min to 2 h

Boc (29)

(27)

up to 85% yield >98% ee Scheme 9

R2

R2 R3

R1

+

X

t-BuOK BEt3

N

X N

R3

H

H (30)

R

1

(31)

(32)

X = NTs, O Scheme 10

complexes are used to react imidolyl nitroalkenes with azomethine ylides, exo- and endo-indolyl-pyrrolidines are produced, respectively.39 2,5-Diaryl fulleropyrrolidines are readily produced by the reaction of [60]fullerene with aromatic aldehydes and arylmethanamines via an intermediate azomethine ylide. N-Unsubstituted arylmethanamines yielded cis-cycloadducts, while N-substituted arylmethanamines always produced trans-isomers.40 When a chiral cyclopropenimine Brønsted base (35) is used as the catalyst, the reaction of 2-acyl cycloheptatrienes (33) with azomethine ylides (34) produced only 3 + 2-cycloadducts (36) in high yields and up to 99% ee. Coordination of the azomethine ylide and the 2-acyl cycloheptatriene to the chiral organosuperbase is responsible for the observed configuration of the adducts (Scheme 11).41 The copper(I)-catalysed 1,3-dipolar cycloaddition of racemic tropanes with azomethine ylides, derived from glycine ester imines, formed cycloadducts with a maximum of eight stereocentres. This procedure allows for the production of two enantiopure products in a one-pot reaction with only one chiral catalyst.42 The enantioselective 1,3dipolar cycloaddition of azomethine ylides with methyleneindolinones formed chiral

de 

de 

ee  de 

ee 

669

11 Addition Reactions: Cycloaddition R1

O

Bn OH

N

(33) Cy2N

+

(35)

CO2But HN

NCy2

CO2But

H

1. Et2O, −20 °C, overnight 2. TsCl, Et3N, DMAP, 20 h, r.t.

N

Ts

+

−

R1

Ar

O

Ar

(36)

(34)

up to 90% yield Scheme 11

spiro[pyrrolidine-3,3′ -oxindoles] in good yields (80–99%) with excellent enantioselectivity (up to 99% ee and >19:1 dr). Thiourea-quaternary ammonium salts (37) were used as effective phase-transfer catalysts.43 +

N S

ee  de 

CF3

Br−

NH CF3

NH O2N (37)

Taniaphos/AgF-, Xing-Phos/AgF-, and (S)-TF-BiphamPhos/AgOAc-catalysts successfully promote the enantioselective 1,3-dipolar cycloaddition of acyclic azomethine ylides with substituted maleimides to produce octahydropyrrolo[3,4-c]pyrrole derivatives in high yields with good levels of enantioselectivity.44 – 46 The one-step 1,3-dipolar cycloaddition reactions of stabilized pyridinium ylides (38) with substituted 3-phenylpropionaldehydes (39) yielded indolizine-1-carbaldehydes (40) in high yields (up to 83%) (Scheme 12).47 Again, the FeCl3 -catalysed 3 + 2cycloaddition of pyridinium-1-yl(quinolin-2-yl)methanide with 𝛼,𝛽-unsaturated ketones produced aryl(2-aryl-3-(quinolin-2-yl)indolizin-1-yl)methanones.48 The copper(I)-catalysed 3 + 2-cycloaddition of hydrazones with nitroolefins produced 1,3,4-trisubstituted and 1,3,4,5-tetrasubstituted pyrazoles in high yields (up to 95%) with

ee 

670

Organic Reaction Mechanisms 2016

R Cs2CO3 (1.1 equiv)

+

+

MeCN, r.t.

N

CHO

N CHO

−

CHCOAr

ArOC

(38)

R (40)

(39) Scheme 12

R

H N

N

Ts

(41) R = aryl, heteroaryl, alkyl, benzyl, carbocyclic +

n

X

Y

I2 (20 mol%) TBHP (2 equiv)

n

X CH2Cl2, r.t.

N

N

Y N N

R (43)

(42) X = CH, N Y = CH, NMe, S n = 0, 1

up to 96% yield

Scheme 13

high regioselectivity.49 Also, the I2 -TBHP (tert-butylhydroperoxide)-catalysed cycloaddition of N-tosylhydrazones (41) with a variety of aromatic N-heterocycles (42) yielded 4,3-fused 1,2,4-triazoles (43) in excellent yields and high regioselectivity (Scheme 13).50 N,N′ -Cyclic azomethine imines react with e-deficient alkynes51 and ynolates,52 ketenes,53 and iminooxindoles54 to produce N,N-bicyclic pyrazolidinones, bicyclic pyrazolidinones, and oxindole spiro-N,N-bicyclic heterocycles, respectively. C,N-Cyclic azomethine imines react with enecarbamates,55 𝛿-acetoxyallenoates,56 and ketenes57 to form dinitrogen-fused heterocyclic adducts in good to high yields. Pyrrole-fused C,Ncyclic azomethine imines (45) react with various dienophiles (46) to yield cycloadducts (47) having a pyrazolopyrrolopyrazine skeleton. The azomethine imines were prepared from C(2)-substituted pyrrole hydrazones (44) in the presence of AuCl3 or AgOSO2 CF3 catalysts (Scheme 14).58 The thermal diastereoselective 3 + 2-cycloaddition of N-iminoquinazoline ylides with allenoates produced tetrahydropyrazoloquinazoline derivatives in good to excellent yields (up to 99%).59

671

11 Addition Reactions: Cycloaddition X −

N

N

NTs

+

AuCl3 or AgOSO2CF3

X

+

N

N N

N

N

Me

NHTs

Me (44)

(45)

(46)

(47)

Scheme 14

Pyrroloindoline analogues were prepared at room temperature and in mixed solvents by the 1,3-dipolar cycloaddition of aza-oxyallyl cations with C(3)-substituted indoles.60 The 3 + 2-cycloaddition of aza-oxyallyl cation intermediates with carbonyl compounds yielded 4-oxazolidinones in good yields (up to 98%) and diastereoselectivities.61,62 The oxidative diaza-3 + 2-cycloaddition of substituted indoles (48) with diaza-oxyallyl cations (49) furnished highly functionalized imidazoloindolines (50) in high yields (up to 85%) (Scheme 15).63 BnO R2

R2 +

R3 N

O BnO

N

PhI(OAc)2

OBn

N

TFP–Na/TFP

R1 (48)

O

N N

R3 N

H

OBn

R1 (49)

(50) Scheme 15

Stabilized C(4)-acyl münchnones readily reacted with terminal alkynes to yield cycloadducts which readily decarboxylate to form densely substituted pyrroles with high regioselectivity.64 A multi-functional organocatalyst (51) was shown to be highly effective in the 3 + 2cycloaddition of enynones (2-(1-alkynyl)-2-alken-1-ones) with alkanes nitro to produce 2,3-dihydroisoxazoles enantioselectively (63–99%).65 O R

O N

N OH (51)

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de 

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Organic Reaction Mechanisms 2016

Diazoacetamides readily undergo 1,3-dipolar cycloadditions with oxanorbornadienes (OND) and ethyl 4,4,4-trifluoro-2-butynoate. The rate of cycloaddition of the latter dienophile is 35-fold faster than that of OND analogues because of the favourable interactions with the fluoro groups.66 The first 1,3-dipolar cycloaddition reaction of 1,2-cyclohexadiene with acyclic nitrones produced isoxazolidine adducts in moderate to high yields (62–92%).67 The synthesis of hexahydro-3H-xantheno[1,2-c]isoxazoles was achieved by the intramolecular 1,3-dipolar cycloaddition of alkene-tethered chromene nitrones. The reactions are highly diastereoselective.68 The Cu(I)-catalysed Kinugasa reaction between alkynes and acyclic nitrones produced 𝛼-methylene- and 𝛼-alkylidene-𝛽-lactams via an initial 3 + 2 cycloaddition.69 – 71 The stereoselective 3 + 2-cycloaddition reactions of carbohydrate-derived acyclic nitrones with thioketones formed 1,4,2-oxathiazolidine derivatives with high stereospecificity (>99:1 dr) and high yields (up to 97%).72 The intramolecular 3 + 2-cycloaddition of the nitrile oxide (52) yielded the oxazoline (53), a key intermediate in the total synthesis of the macrolide, (−)-11𝛽hydroxycurvularin (54) (Scheme 16).73 The 3 + 2-cycloaddition of in situ prepared aromatic nitriles with 1-phenyl-1,2-dihydro-pyridazine-3,6-dionyl N-glycosides produced enantiopure isoxazolines substituted with carbohydrate analogues. The 𝜋-facial selectivity of these reactions is controlled by the carbohydrate group.74 The 1,3-dipolar cycloaddition of nitrile oxides with 𝛼,𝛽-acetylenic aldehydes yielded isoxazoles in good yields (60–80%) with high regioselectivity.75 Also, hypervalent iodine-mediated cycloaddition of nitrile oxides with acetylenes yielded 3,4-disubstituted and 3,4,5-trisubstituted isoxazoles under catalyst-free conditions.76 O

O

O

O

BnO

BnO +

OBn

N

O

−

OBn

(52)

N O (53)

O

O

HO

O

OH

(54) Scheme 16

OH

de 

de 

673

11 Addition Reactions: Cycloaddition

The 1,3-dipolar cycloaddition of the in situ generated nitrile oxides with 2-(1,2,3thiadiazol-5-yl)enamines and 3-(1,2,3-triazol-4-yl)enaminones produced 3-aryl-4(1,2,3-thiadiazol-5-yl)- and [4-(1,2,3-triazol-4-yl)carbonyl]isoxazoles, respectively, in high yields.77 The intramolecular 1,3-dipolar cycloaddition of bis-aldimines (55) with in situ generated nitrile oxides (56) formed N,N-bis(2-(4-(3,4-di-substituted phenyl-4,5-dihydro-1,2,4-oxadiazol-5-yl)phenoxy)ethyl)anilines (57) in moderate yields (Scheme 17).78 R1

R1 N

N N

O

O

(55)

+

R2

CH2Cl2

C

N

−

O

(56)

R

R1

R1

2

R2

N

N

N

N O

O O

N

O

(57) Scheme 17

The initial cross-dimerization of isocyanides (58) with 2-isocyanochalcones (59) formed 1,4-diazabutatrienes (60) which underwent intramolecular hetero-3 + 2cycloaddition to produce the cycloadducts (61), followed by a 1,3-proton shift, to form pyrrolo[3,4-b]indoles (62) in moderate to high yields (Scheme 18).79 The CuClcatalysed 3 + 2-cycloaddition reaction of 2-haloaryl isothiocyanates with isocyanides produced 5H-benzo[d]imidazo[5,1-b]thiazoles in good to excellent yields.80 The metal-free 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-promoted organoclick reaction of organic azides with electron-deficient olefins yielded disubstitutedand trisubstituted 1,2,3-triazoles in aqueous medium. The reaction is important as aryl, alkyl, and benzyl azides can be used as substrates.81 Sodium azide reacted with 1,3-diynes to produce 5-substituted-4-acetylene-1H-1,2,3-triazoles in 75–99% yields.82

674

Organic Reaction Mechanisms 2016 O

R2 R2

O heterodimerization

R1 N C: + N

(58)

C

N

C:

C

R1 N

(60)

(59)

3 + 2-cycloaddition

R2

O

R1 N

R2

O

+

H 1,3-proton shift

N H

R1

N C− N

(62)

(61) Scheme 18

The copper (I)-catalysed alkyne–azide cycloaddition (CuAAC) of alkyne–fullerenes with organic azides produced 1,2,3-triazolofullerone derivatives as intermediates in the synthesis of ferrodendrimers.83 Again, the tandem CuAAC/alkynylation reaction of organic azides with various alkynes and bromoalkynes produced 5-alkynyl-1,2,3triazoles.84 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) readily catalyses the 3 + 2-cycloaddition reactions of aryl azides with a variety of quinones in polyethylene glycol-400 (PEG400) solvent to produce 1,2,3-triazoles in high yields and short reaction times.85 Deep eutectic solvents (DES) are active promotors of the 1,3-dipolar cycloaddition between organic azides and 𝛽-enaminones yielding 4-acyl-1-substituted-1,2,3-triazoles.86

2 + 4-Cycloaddition Recent progress in the dehydro-Diels–Alder reactions initiated by heat, microwaves, bases, transition metals, or photochemical conditions has been extensively reviewed.87 A new supersaturated solvent consisting of carbohydrates, organic acids, and organic ketones in water was found to accelerate Diels–Alder reactions between cyclopentadiene and methyl acrylate by several times at room temperature.88

675

11 Addition Reactions: Cycloaddition

The chiral pyridinium phosphoramides (63) are a new class of chiral Brønsted acid catalysts for the enantioselective Diels–Alder reaction of 1-amido-dienes with various dienophiles including N-unsubstituted maleimides and benzoquinones.89 The AlCl3 catalysed 4 + 2-cycloaddition of 1,2-azaborines with N-methylmaleimide is a concerted reaction leading exclusively to endo-cycloadducts.90 The Lewis acid-catalysed 4 + 2cycloaddition reaction of aryl allenes with simple acrylates yielded bi- and tri-cyclic dihydronaphthalene derivatives.91 The chiral phosphine (66)-catalysed asymmetric 4 + 2-cycloaddition of barbiturate-derived alkenes (64) with 𝛼-substituted allenoates (65) produced spirobarbiturates (67) in good to excellent yields (59–95%) with excellent diastereo- and enantio-selectivities (Scheme 19).92 The normal-electron-demand Diels–Alder reaction of e-rich 2-vinylindenes with dienophiles yielded functionalized tetrahydrofluorenes.93 Ar O O

de 

ee  de 

R O P

+

N H

N H

−

OTf

Ar (63)

But OMe

P Bu

O Me

N

N

R2

Me

O

O

(66) CO2Et

+ C

(20 mol%)

O N

O R1

N Me O R2

4 Å MS, toluene, 60 °C

CO2Et

R1 (64)

Me

t

(67)

(65)

56–95% yield 90–99% ee, >20:1 dr Scheme 19

The key step in the total synthesis of the trans-decalin core (70) of Australifungin involves the intramolecular 4 + 2-cycloaddition of a nitroalkene dienophile (69) prepared from the 𝛽,𝛽 ′ -branched aldehyde (68) (Scheme 20).94 The high-pressure/

de 

676

Organic Reaction Mechanisms 2016 O

H

OMOM Me H

Me

C6H13

C6H13

H

OPMB

OPMB Me

Me

O2N

(68)

(69)

PMB = p-methoxybenzyl

OMOM Me H H O2N

C6H13

H H

OPMB Me

(70) Scheme 20

Lewis acid-catalysed 4 + 2-cycloaddition reaction of 4-carbomethoxyethynyl[2,2] paracyclophane (71) with methyl-1,3-butadienes (72) produced cyclohexadienylparacyclophanes (73) which were readily oxidized to the corresponding 4-aryl [2,2]paracyclophanes (74) with DDQ (Scheme 21).95 The enantioselectivity of the Diels–Alder reaction of anthrone enolates with maleimides can be controlled by the nature of the organocatalyst used. When organocatalysts with pyridine, quinolone, or 1,3,4-oxadiazole achiral heterocyclic subunits are used, the resultant cycloadducts have an (S,S)-configuration. However, when the organocatalysts have a benzotriazole subunit, the cycloadducts have a (R,R)configuration.96 The Diels–Alder reaction between dibutyl vinylboronate and cyclopentadiene is accelerated by 𝛼-hydroxy acids such as (S)-mandelic acid.97 The organocatalytic formal 4 + 2-cycloaddition of nitroalkenes with cyclopentadiene carboxylates produced bicyclo[2.2.1]heptane-1-carboxylates under mild conditions with good yields and high enantioselectivity.98 The organocatalytic formal 4 + 2-cycloaddition of 2,4-dienals with 3-nitroindoles yielded chiral dihydrocarbazole scaffolds in moderate to good yields (up to 87%) and high enantioselectivity (up to 97% ee). The reaction proceeds through a cycloaddition/elimination cascade under mild conditions.99 A key step in the total synthesis of the marine hydroid Annulin B (77) was the regioselective Diels–Alder reaction of pyranobenzoquinone dienophile (75) with a silyl ketene acetal diene (76) (Scheme 22).100

ee 

ee 

ee 

677

11 Addition Reactions: Cycloaddition R3 8 kbar, EtAlCl2

+ R2

55–78%

CO2Me

R1

R1 CO2Me R3 (71)

(72)

R2

(73)

R1, R2, R3 = H, Me oxidation

93–99%

CO2Me R1 R3

R2

(74) Scheme 21

The primary 𝛽-amino alcohol-catalysed Diels–Alder reaction of 3-hydroxy-2-pyridones with N-substituted maleimides formed isoquinuclidines with excellent yields (up to 95%) and high enantioselectivities (up to 98%) under mild reaction conditions.101 The organocatalytic asymmetric 4 + 2-cycloaddition of 5H-oxazol-4-ones with Nsubstituted maleimides yielded chiral oxo-bridged piperidine-fused succinimides in good yields (up to 88%) and excellent enantioselectivities (up to >99% ee).102 The intramolecular base-promoted Diels–Alder reaction of a furanyl group and an e-deficient cyclopropane moiety (78) formed tetracyclic compounds (79) in high yields and high diastereoselectivity. Selective reduction of these adducts with Zn/acetic acid produced octahydro-1H-cyclohepta[c]furan-1-ones (80), the key core structure of Lactarane and Marasmane sesquiterpenes (Scheme 23).103 The 4 + 2-cycloadditions of trans-oxasilacycloheptenes with dienes are fast, high yielding, and, generally, stereoselective reactions. These seven-membered-ring trans-alkenes are more reactive in Diels–Alder reactions than trans-cyclooctenes.104 The Diels–Alder cycloaddition of arynes with 2-vinylpyrroles yielded benzo[e]indoles with good yields and high stereoselectivities. The arynes selectively reacted with the external vinyl group instead of the pyrrole ring when CHPh2 was used as the Nprotecting group.105 The Diels–Alder reaction of 9-nitroanthracenes with tetrabromobenzyne produced sterically crowded 9-nitrotriptycenes.106

ee 

ee 

de 

678

Organic Reaction Mechanisms 2016 O

OMe Me

Me

O

+ Me3SiO

CO2Me O O Me

Me

Me (76)

(75)

OH

O O

Me

Me CO2Me O

Me O Me

Me

(77) Scheme 22

O

O

Ar

O

O

Cl (78) reflux

Cs2CO3, THF

O

O

O O

Ar

Zn/acetic acid

O

Ar

O

O

(79)

(80)

up to 80% yield up to > 20:1 dr

up to 60% yield 4:1 dr Scheme 23

O

679

11 Addition Reactions: Cycloaddition

Chiral N,N′ -dioxide (85)/nickel(II) complex-catalysed asymmetric Diels–Alder reactions of cyclopentadiene with 2,3-dioxopyrrolidines (81) and 2-alkenoyl pyridines (83) yielded chiral bridged adducts (82, 84), respectively, in high yields (up to 97%) with excellent enantio- and diastereo-selectivity (97% ee, 95:5 dr) (Scheme 24).107 The asymmetric trienamine-catalysed Diels–Alder reactions of 𝛽-trifluoromethyl (CF3 ) eneones with 2,4-dienals yielded normal-electron-demand cycloadducts which could be reduced to cis- and trans-fused octahydroisoquinolines with a stereogenic CF3 group. Trienamine catalysts with a chiral secondary amine were used to activate this reaction.108 The intermolecular Diels–Alder reactions of multi-substituted acyclic dienes with geometrical isomers of 𝛼,𝛽-enals produced substituted cyclohex-3-enecarbaldehydes. The dienes were shown to react selectively with the Z-isomer of the 𝛼,𝛽-enals.109 O

O

N Bn

de 

O

O

cyclopentadiene L-RaPr2/Ni(OTf) 2 (1:1, 10 mol%)

ee  de 

N Bn

ClCH2CH2Cl, 30 °C

R1

R1 (81)

(82) R2 O

O

cyclopentadiene L-RaPr2/Ni(OTf) 2 (1:1, 10 mol%)

N

N

ClCH2CH2Cl, 30 °C

R2 (83)

(84)

+

O Ar

+

N N H

N −

O−

O

(85)

O H N

Ar

L-RaPr2

Scheme 24

An efficient chiral boron complex-promoted asymmetric Diels–Alder reaction of 2′ -hydroxychalcones with acyclic or cyclic dienes produced substituted cyclohexene skeletons important in the total synthesis of Diels–Alder-type natural products including (−)-nicolaioidesin C and (−)-panduratine A.110 Again, the intermolecular Diels–Alder reactions of germinal bis(silyl) dienes with 𝛼,𝛽-unsaturated carbonyl compounds

ee 

680

Organic Reaction Mechanisms 2016

yielded ortho-trans-cyclohexenes in good yields, high exo-selectivity, and high enantioselectivity.111 The enantioselective 𝛼,𝛼-diphenylprolinol TMS ether-catalysed 4 + 2-cycloaddition of inolyl ortho-quinodimethanes (86) with aromatic enals (87) produces highly enantioenriched 2,9-dihydro-1H-carbazole-3-carboxaldehydes (88) in high yields (48–80%) and high enantioselectivity (up to >99% ee) (Scheme 25).112 The chiral N,N′ -dioxide/yttrium triflate complex-catalysed 4 + 2-cycloaddition of silyloxyvinylindoles with 𝛽,𝛾-unsaturated 𝛼-ketoesters yielded optically active carbazole derivatives with three contiguous stereocentres in high yields (47–98%) and high enantioselectivity (84–99% ee) under mild conditions.113,114

ee  de  ee 

ee  de 

NC CN

N

R1

R2 (86) + O

CHO diarylpropinol–TMS ether/(Pri)2NEt catalyst

R1 3

R

R

(87)

R3

N 2

(88) Scheme 25

The intramolecular aza-Diels–Alder reaction of unactivated 2H-azirines with unactivated dienes furnished aziridine-containing trans-fused tricyclic adducts with excellent stereospecificity. A variety of trans 5-6-3, 6-6-3, and 7-6-3 tricycles containing a fused aziridine have been prepared.115 The aza-Diels–Alder reaction of imines with Danishefsky diene produced substituted 2,3-dihydropyridinones in the presence of a piperidinederived tetraalkylammonium salt with a non-coordinating counterion.116 The base (KOH)-promoted metal-free 4 + 2-cycloaddition of azadienes with internal alkynes formed functionalized quinolones in up to 87% yield. The azadienes were generated in situ from o-aminobenzyl alcohols.117,118 The N-heterocyclic carbene-catalysed 4 + 2-cycloaddition of saccharine-derived 1-azadienes with unsaturated aldehydes produced saccharine-derived dihydropyridinones in excellent yields (up to 98%) and excellent cis-selectivity and enantioselectivity (99% ee).119 The intramolecular Cu(I)-catalysed aza-Diels–Alder reaction of azadienes with alkynes (89) followed by halogenation yielded 7-chloro-6H-chromeno[4,3-b]quinolones (90) in moderate yields under mild conditions (Scheme 26).120,121 The inverse-electrondemand 4 + 2-cycloaddition of d-erythrosyl aromatic imine with e-rich alkenes

de 

ee  de 

681

11 Addition Reactions: Cycloaddition X Y

Y

R2

Cu2O (10 mol%)

N

R1

N

R1

chloranil

R2

(90)

(89)

X = Cl, Br; Y = O, S Scheme 26

produced 2-alkylpolyol 1,2,3,4-tetrahydroquinolines with total facial selectivity.122 Again, the inverse-electron-demand aza-Diels–Alder reaction of substituted arynes with ethyl(arylimino)acetates formed N-aryl dihydrophenanthidine derivatives in moderate to high yields (up to 88%) at room temperature.123 The organocatalytic 4 + 2cycloaddition of o-N-Cbz-amino-𝛽-nitrostyrene (91) with benzoxathiazine 2,2-dioxides (92) yielded enantioenriched benzosulfamidate-fused tetrahydroquinazolines (94) in high yields. A novel chiral quinine-derived squaramide organocatalyst (93) was used in this reaction (Scheme 27).124 A palladium-catalysed asymmetric decarboxylative 4 + 2-cycloaddition reaction of vinyl benzoxazinanones with nitroacrylates formed chiral tetrahydroquinoline derivatives with high yields (68–99%) with 98% ee and 95:5 NO2 R1 NHCbz F3C

(91)

OMe H

+

N

NH HN N

O

O S

CF3

N

O

O

O

O2N O

(93) 20 mol%

R2

CHCl3, r.t.

N

R1

O S

O

N Cbz (94) yield up to 85% dr up to >20:1 er up to 69:31

(92)

Scheme 27

R2

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Organic Reaction Mechanisms 2016

dr. A new hybrid P,S-ligand (95), derived from a chiral 𝛽-amino sulfide and diphenyl phosphite, was used to form the palladium complex catalyst.125 R1 O P O

ee 

R2 *

*

N

S

Me

Bn

(95)

The Cs2 CO3 -promoted 4 + 2-cycloaddition of azoalkenes with enol diazoacetates produced tetrahydropyridazinyl-substituted diazoacetates. However, when the 4 + 2cycloaddition is promoted by Rh2 (OAc)4 , bicyclo[4.1.0]tetrahydropyridazines are formed via intermediate donor–acceptor cyclopropenes.126 The Lewis acid-catalysed 4 + 2-cycloaddition reaction of 3-ethoxycyclobutanones with azobenzenes yielded 2,3-dihydro-pyridazin-4-(1H)-ones in high yields (97%). EtAlCl2 -activated ring cleavage of the butanone produced a zwitterionic intermediate which reacted with the azobenzenes to form the desired cycloadducts after elimination of alcohol.127 The copper-catalysed hetero-Diels–Alder reaction of Danishefsky’s diene with glyoxals yielded biologically active dihydropyrones with high enantioselectivity (up to 96% ee).128 The inverse-electron-demand oxa-Diels–Alder reaction of allylic ketones with 𝛼-cyano-𝛼,𝛽-unsaturated ketones formed substituted dihydropyrans with excellent enantio- and diastereo-selectivity. A cinchona-derived primary amine (96) was used as an efficient dienamine catalyst.129 Two consecutive 4 + 2-cycloaddition reactions yielded hexahydro-2H-chromenes (101) with high enantio-, regio-, and diastereo-selectivity. The initial cycloaddition between ethyl-2,3-butadienoate (97) and the substituted dienones (98) formed substituted vinylidene dihydropyrans (99). Subsequent cycloaddition with various dienophiles (100) yielded the desired hexahydro2H-chromenes (101) (Scheme 28).130 The phosphine-catalysed 4 + 2-cycloaddition of 3-aroylcoumarins with allenoates produced dihydrocoumarin-fused dihydropyrans in high yields (up to 94%) and excellent enantioselectivities (up to 94% ee). A dipeptide phosphine catalyst was used in this synthesis.131 The diamine-catalysed 4 + 2cycloaddition of (Z)-arylidenylpyrazolones with 𝛼,𝛽-unsaturated aldehydes yielded substituted 2-((4R,5R,6R)-1,4,5,6-tetrahydropyrano[2,3-c]pyrazole-6-yl)-aldehydes in high yields (up to 87%) and high enantioselectivities (up to 99% ee).132 The one-pot 4 + 2-cycloaddition of o-quinone methides with substituted alkenes produced 2,4-diarylchromans with high endo-selectivity.133,134 The related 4 + 2cycloaddition of 2,3-dihydro-1H-furan with o-hydroxybenzaldimine yielded trans- and cis-fused furanobenzopyrans, depending on the catalyst and the reaction conditions.135 The AlCl3 -catalysed cycloaddition reaction of ynamides (102) with o-quinone methides (103) yielded 4-amino-2H-chromenes (104) and 2-amino-4H-chromenes (105) in high yields (up to 95%). When terminally unsubstituted ynamides (102, R3 = H) are

ee 

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683

11 Addition Reactions: Cycloaddition

OMe CO2H

N

OH NH2 N But (96)

R2

O CO2Et 10 mol% catalyst

+

C

heat, r.t., 8–72 h

R1

R2

(97)

(98)

(2–5 equiv)

(1 equiv)

R1

O

CO2Et

(99)

EWG

R3

(100) R3

R1

H

R2

O

CO2Et

(101) up to 98% ee 98:2 dr Scheme 28

used, only 2-amino-4H-chromenes (105) are formed (Scheme 29).136 When o-quinone methides react with azalactones, in the presence of Brønsted acid and a chiral guanidine base, dihydrocoumarin derivatives are formed in high yields (up to 99%) and high enantioselectivity (96:4 er).137 The phosphine-catalysed 4 + 2-cycloaddition of thiazolederived alkenes with allenoates produced 6,7-dihydro-5H-pyrrano[2,3-d]thiazole in high to excellent yields. When the chiral catalyst, Kwon’s phosphine, was used, optically active products were produced in good yields and excellent enantioselectivities.138

ee 

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Organic Reaction Mechanisms 2016 H

O

O

R1

O

R3 N

(104)

EWG

R2

AlCl3 (0.2 equiv) R3 = alkyl, aryl, TIPS

EWG

N

R2

O

O +

O R1

R3 (102)

AlCl3 (0.2 equiv) R3 = H

(103)

EWG O

O

N

R2

O R1 (105) Scheme 29

The 4 + 2-cycloaddition of cyclic 𝛼,𝛼 ′ -dioxoketene, indanedioneketene (106), with e-rich dienophiles (e.g. enol ethers) (107) yielded unstable 2,3-dihydro-2-alkoxyindeno[1,2-b]pyrano-4,5-diones (108). Under thermal conditions, these cycloadducts tautomerize to alkoxyallylidene-indenedione derivatives (109) (Scheme 30).139 The enantioselective copper(II)-catalysed formal 4 + 2-cycloaddition of oaminophenol derivatives with propargylic esters produced chiral 2,3,4-trisubstituted 3,4-dihydro-2H-1,4-benzoxazines in high yields and excellent enantioselectivities (up to 97% ee). A substituted 6-imino-2,4-cyclohexadien-1-one is believed to be the active diene intermediate.140

Miscellaneous The catalytic 2 + 2 + 1-cycloaddition of diynes (110) with sulfur produced fused thiophenes (113). N-(p-Chlorophenyl)methylbenzoxazole-2-thione (112) was used as the sulfur atom donor in DMF at 80 ∘ C. A cationic ruthenacycle (111) has been proposed for this catalytic process (Scheme 31).141 A mini-review of the participation of alkenes, alkynes, and allenes in 2 + 2 + 2cyclotrimerization reactions to produce cyclohexadienes and other polycycles has

ee 

685

11 Addition Reactions: Cycloaddition

O

O C O

+

R1HC CHOR2

O CH2Cl2, heat

R1 O

O

OR2 (107)

(106)

(108)

CH2Cl2 , heat

O OH R1 O (109) Scheme 30

+ R R R

cat. CpRu+

RuCp

DMF, 80 °C

R (110)

(111)

O S N Cl

R

(112) S R (113) Scheme 31

OR2

686

Organic Reaction Mechanisms 2016

been published.142 The gold-catalysed 2 + 2 + 2-cyclotrimerization of sulfonylallenamides yielded cyclotrimers which were readily converted into aromatic derivatives in the presence of NaOH. The reaction mechanism involves an initial electrophilic activation of an allenamide by coordination with gold.143 A cationic rhodium(I)/(S)-H8 -BINAP (2,2′ -bis(biphenylphosphanyl)-1,1′ binaphthalene) (116) complex catalyses the 2 + 2 + 2-cycloaddition reaction of 1,6-enynes (114) with cyclopropylideneacetamides (115) to form spirocyclohexenes (117) in moderate to high yields (up to 77%) and excellent enantioselectivities (up to >99% ee) (Scheme 32).144 Again, the 2 + 2 + 2-cycloaddition reactions of 1,6-enynes with e-rich alkenes, enamides, and vinyl carbonates yielded the corresponding cyclohexenylamines and cyclohexenols in moderate yields and with high enantioselectivity (>99% ee).145

ee 

ee 

R1 Z PPh2

R2

PPh2

(114) +

(S)-H8-BINAP

O

R1

(116) 3

N R4

R

O

2

[Ru(cod) ]/BF4/(S)-H8-BINAP catalyst

N Z

R3

R4

CH2Cl2, r.t.

R2 (117)

(115)

up to 77% yield up to >99% ee Scheme 32

The cationic rhodium(I)-BINAP complex catalyses the 2 + 2 + 2-cycloaddition– aromatization of 1,6-diynes with cyclic enol ethers (2,3-dihydrofuran and dihydropyran) producing protected and unprotected aryl alkanols in good yields (up to 97%) and high enantioselectivity (>99% ee).146,147 Also, 2 + 2 + 2-cycloaddition reaction of allenynes with alkynes yielded polysubstituted benzene-fused bicyclic derivatives in high yields (up to 99%) and with high chemo- and regio-selectivity.148 Transition metal-free formal 2 + 2 + 2-cycloadditions of alkynes, triynes, and oligoalkynes have been reviewed. This review discusses the mechanistic course of these reactions.149 The chiral Rh-catalysed intramolecular 2 + 2 + 2-cycloaddition reaction of amino acid-tethered triynes (118) yielded chiral-tethered aminoindan carboxylic acid derivatives (119) with excellent enantiomeric excess. Further hydrolysis with NaOH produced chiral carboxylic acids (120) in good to high yields (Scheme 33).150

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11 Addition Reactions: Cycloaddition R2 O O O O

R1

CbzHN

R1 (118)

R1 = Me, Ar; R2 = H, Me

chiral Rh cat.

R1

O O

O

R1 2

R

R2

R4O2C

O CbzHN

R3HN

CO2R4

R1

R1

(119)

(120)

up to > 99% ee

R1 = Cbz, H; R4 = H, Me Scheme 33

H

H H

MeO

MeO

+

OMe R1

R2

(121)

(122)

MeO R2

[Co] cat.

H

MeO OMe R1 R2

R2

(123) Scheme 34

The cobalt-catalysed intermolecular 2 + 2 + 2-alkyne cyclotrimerization of dialyne (121) with alkynes (122) yielded 6,7-cyclopropylallocolchicinoids (123) (Scheme 34).151 The synthesis of multi-substituted tribenzoheteropins, including tribenzothiepins, tribenzothiepin S,S-dioxide, and dibenzoselenepin, has been achieved. The intermolecular 2 + 2 + 2-cycloaddition of diphenyl-sulfide-tethered diynes or 2-phenyl sulfanylbenzene tethered diynes with monoalkynes produced the desired tribenzothiepins with good to excellent enantioselectivity under mild conditions.152

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Organic Reaction Mechanisms 2016

The Brønsted-acid catalysed formal intermolecular 2 + 2 + 2-cycloaddition of heteroalkynes with nitriles yielded highly substituted pyridines in high yields under mild conditions. The reaction mechanism involves an initial addition of a cyanoalkyne to an intermediate stabilized keteniminium or ketenethionium species followed by a formal cycloaddition.153 The gold(I)-catalysed intermolecular 2 + 2 + 2-cycloaddition reaction of unsubstituted or methyl-substituted ynamides with nitriles yielded 6-substituted 2,4-diaminopyridines in high yields. The reaction is applicable to a variety of nitriles and tosylamide-derived ynamides. When e-rich mesylamide-derived ynamides are used, aminopyrimidines are formed.154,155 The Ni/BPh3 -catalysed 2 + 2 + 2-cycloaddition of alkyne–nitriles with alkynes yielded fused pyridines regioselectively under mild conditions. A key reaction intermediate in this reaction is believed to be an azanickelacycle.156 The iridium-catalysed cycloaddition reaction of 𝛼,𝜔-diynes with acyl cyanides formed acylpyridines in high yields (>99%).157 The cationic rhodium(I)/(S)-H8 -BINAP complex-catalysed atroposelective 2 + 2 + 2-cycloaddition of (o-halophenyl)diynes with acylnitriles produced axially chiral 3-(2-halophenyl)pyridines. The regio- and enantio-selectivity of this reaction depends on the ortho-substituents on the phenyl group of the diynes.158 The FeI2 -catalysed 2 + 2 + 2-cycloaddition reaction of diynes (124) with siloxyphosphaethynes (125) yielded 2-phosphaphenol derivatives (126) in moderate yields (16–52%). Siloxyphosphaethynes were formed from phosphaethynolate and silyl triflates in situ (Scheme 35).159 +

X

(124)

P

OSiR3

FeI2 (20 mol%) m-xylene, 140 °C, 16 h

ee 

P

X

OSiR3 (126)

(125)

16–52% yield Scheme 35

The ruthenium[C5 Me5 Ru(cod)Cl]-catalysed 3 + 2 + 2-cycloaddition of 2H-azirines with diynes formed fused azepine derivatives in moderate yields. A key intermediate in this reaction sequence is an eight-membered ruthenacycle.160 The 3 + 3-cycloaddition of nitrilimines with donor–acceptor cyclopropanes produced tetrahydropyridazines in high yields (up to 92%). The nitrilimines were prepared in situ from hydrazonyl chlorides at room temperature.161 The Cu(I)tetrafluoroborate/bisoxazoline complex-catalysed 3 + 3-cycloaddition reaction of enoldiazoacetamides with nitrones yielded substituted 3,6-dihydro-2H-1,2oxazine derivatives with excellent yields and enantioselectivity. When Cu(I) triflate is used as the catalyst, only Mannich addition products were isolated.162 The base-catalysed 3 + 3-cycloaddition reaction of isoquinoline N-oxides with azaoxyallyl cations yielded 1,11b-dihydro[1,2,4]oxadiazino[3,2a]isoquinoline-2(3H)-ones when the base used is sodium carbonate. However, when caesium carbonate is used, the products are 2-(isoquinoline-1-yloxy)acetamides. The azaoxyallyl cations are generated in situ from 𝛼-bromohydroxamate.163 A phosphine-catalysed 3 + 3-cycloaddition reaction of azomethine imines (127) with ynones (128) yielded hydropyridazine

ee 

689

11 Addition Reactions: Cycloaddition

+

N N

R2

O

O

PPh3

+

−

O R1

N N Ar

R1

Ar (127)

R2 (128)

O (129)

up to 85% yield Scheme 36

derivatives (129) in excellent yields (up to 85%) and with high stereoselectivities (Scheme 36).164 The Cu(I)-catalysed 4 + 1-cycloaddition of sodium bromodifluoroacetate with silyl dienol ethers formed 4,4-difluorocyclopent-1-en-1-yl silyl ethers in moderate yields (59–76%). The annulation reaction is presumed to proceed via a copper(I) difluorocarbene complex.165 The iridium-catalysed intermolecular formal 4 + 1cycloaddition reaction of diphenylenes (130) with monosubstituted alkenes (131) yielded 9,9-disubstituted fluorenes (132) in moderate to high yields (up to 99%). The cycloaddition is thought to involve a C–C bond cleavage, alkene insertion, 𝛽-hydrogen elimination, intramolecular alkene insertion, and followed by a reductive elimination (Scheme 37).166

R2 +

de 

R1 [Ir(cod)Cl]2 (10 mol%) xylene, 135 °C, 24 h

1

R

Me

R2

(130)

(131)

(132)

R1 = H, Ph, Ms, TMS

R2 = aryl, alkyl, SiR3

up to 99% yield

Scheme 37

A key step in the asymmetric synthesis of the sesquiterpene (−)-Englerin A (135) is the platinum-catalysed intramolecular 4 + 3-cycloaddition reaction of allenediene (133) to form the trans-fused bicyclic guaiane skeleton (134) with complete diastereoselectivity (Scheme 38).167 An important step in the synthesis of polyfunctionalized acetallic tetrahydropyrans involves the 4 + 3-cycloaddition of 2-methoxyfurans with oxyallyl cations to produce substituted 1-methoxy-8-oxabicyclo[3.2.1]oct-6-en-3-ones. Further oxidative and/or reductive ozonolysis yielded 2-methoxytetrahydropyrans with high regio- and stereo-selectivity.168 The rhodium-catalysed 4 + 3-cycloaddition reaction of mono-, di-, and trisubstituted furans (136) with cyclic donor–acceptor diazocarboxylates (137) produced

de 

de 

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Organic Reaction Mechanisms 2016

X

C

X

cat.

H

H (133)

(134) 99% ee

O O H

Ph

O

O

OH

O H (135) (−)-Englerin A Scheme 38

H O R

Rh2(OAc)4

+ TBSO

N2 EtO2C

(136)

R O

(137)

TBSO EtO C 2 (138) 50–68% yield

Scheme 39

functionalized bicyclo[5.3.0]decane derivatives (138) having the 5/7-fused ring framework present in many natural products, for example, Phorbol and Ingenol (Scheme 39).169 The Lewis acid-catalysed 4 + 3-cycloaddition reaction of propargyl alcohols with azides produced imine-based indole azepines in satisfactory yields.170 The formal 4 + 3-cycloaddition reaction of amphiphilic benzodithioloimines with donor–acceptor cyclopropanes formed dithiepine derivatives in 27–91% yields. The

de 

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11 Addition Reactions: Cycloaddition

benzodithioloimines were used as surrogates for the intermediate benzothioquinones.171 Oxaphosphirane complexes (139) react with tetrachloro-o-benzoquinones (140) to form benzo-1,3,6,2-trioxaphosphepine complexes (141). This regioselective formal 4 + 3-cycloaddition reaction involves a sequence of three consecutive steps involving a ditopic van der Waals complex (Scheme 40).172 R

(OC)5M P Cl R

(OC)5M P

Ph

Cl

Cl

Cl

O

+

O H

Cl

O (139)

Ph

toluene, r.t.

O H

O

O

Cl

Cl Cl (141)

(140) Scheme 40

The fluorinated alcohol-mediated formal 4 + 3-cycloaddition reaction of cyclopentadiene with 3-indolylmethanols in hexafluoroisopropanol (HFIP) produced cyclohepta[b]indole derivatives in high yields. The hydrogen bonding offered by the HFIP during the reaction decreases the reaction barrier and stabilizes the reaction transition state.173 The N-heterocyclic carbine-catalysed 4 + 3-annelation of 5-alkenyl thiazolones with enals formed thiazole-fused 𝜀-lactones in high yields (64–90%) and with excellent diastereo- and enantio-selectivities (up to >20:1 dr, 99% ee).174 The Fe2 (CO)9 -mediated 5 + 1-cycloaddition of vinylcyclopropanes with carbon monoxide produced 𝛼,𝛽-cyclohexenones without the need for photo-irradiation conditions.175 A key step in the formal synthesis of the alkaloid (−)-galanthamine is the Rh-catalysed 5 + 1-cycloaddition of di- and tri-substituted allenylcyclopropanes with CO to produce functionalized 2-methylidene-3,4-cyclohexinones in good yields and under mild conditions (60 ∘ C).176 The intramolecular rhodium(I)-catalysed 5 + 2-cycloaddition reaction with concomitant 1,2-acyloxy migration between 3-acyloxy-1,4-enyne and alkyne (142) formed bicyclo[5.3.0]decatrienes (143) in moderate to high yields (41–85%). The bicyclo[5.3.0]decane skeleton is present in a variety of sesquiterpene natural products (Scheme 41).177 The novel 8 + 2-cycloaddition reaction of dienylfurans (144) with e-deficient alkynes, for example, DMAD, formed an 8 + 2-cycloadduct (145) under solvent-free conditions. Further treatment with a Lewis acid base yielded hydronaphthalenes (146) via a ring opening-isomerization process (Scheme 42).178 The formal cycloaddition between vinylphenylfurans (147) and DMAD yielded 8 + 2-cycloadducts, epoxyphenanthrenes (148). The mechanism involved a tandem 4 + 2-/diradical alkene–alkene coupling followed by a [1,3]-H shift. The expected 8 + 2-intermediate, o-quinodimethane, was not involved (Scheme 43).179

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Organic Reaction Mechanisms 2016

AcO OAc

O

O

[Rh(cod)2]BF4 CH2Cl2, r.t., −50 °C, 8–20 h

R R (142)

(143) Scheme 41

CO2Et

CO2Et

CO2Et DMAD

Et3N/ DBU dioxane

O

80 °C, heat

O

O

CO2Me CO2Me

CO2Me

MeO2C DMAD = dimethylacetylenedicarboxylate (144)

(146)

(145) Scheme 42

O

CO2Me CO2Me

DMAD toluene, heat

1,3-H shift

DMAD

CO2Me CO2Me O

H

(148)

(147)

4+2

O

alkene–alkene coupling

CO2Me CO2Me O

diradical intermediate Scheme 43

11 Addition Reactions: Cycloaddition

693

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 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

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694 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 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90

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11 Addition Reactions: Cycloaddition 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134

695

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696 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179

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CHAPTER 12

Molecular Rearrangements

J. M. Coxon Department of Chemistry, University of Canterbury, Christchurch, New Zealand Pericyclic Reactions . . . . . . . . . . . . . . . . . . . Sigmatropic . . . . . . . . . . . . . . . . . . . . [1,3]-Sigmatropic . . . . . . . . . . . . . [1,4]-Sigmatropic . . . . . . . . . . . . . [3,3]-Sigmatropic, Cope Claisen . . . . . [5,5]-Sigmatropic . . . . . . . . . . . . . [2,3]-Sigmatropic . . . . . . . . . . . . . Electrocyclic . . . . . . . . . . . . . . . . . . . . Cycloaddition . . . . . . . . . . . . . . . . . . . Molecular Rearrangements . . . . . . . . . . . . . . . Rearrangement . . . . . . . . . . . . . . . . . . Ring Expansion, Ring Opening, and Ring Closing Radical . . . . . . . . . . . . . . . . . . . . . . . Thermal . . . . . . . . . . . . . . . . . . . . . . Oxidation . . . . . . . . . . . . . . . . . . . . . Phosphorous, Boron Sulfur, and Silicon . . . . . Carbene and Nitrene . . . . . . . . . . . . . . . . Acid Promoted . . . . . . . . . . . . . . . . . . Addition . . . . . . . . . . . . . . . . . . . . . . Metathesis . . . . . . . . . . . . . . . . . . . . . Ylide . . . . . . . . . . . . . . . . . . . . . . . . Metal-Induced Reactions . . . . . . . . . . . . . . . . Copper . . . . . . . . . . . . . . . . . . . . . . . Gold . . . . . . . . . . . . . . . . . . . . . . . . Hafnium . . . . . . . . . . . . . . . . . . . . . . Iridium . . . . . . . . . . . . . . . . . . . . . . . Iron . . . . . . . . . . . . . . . . . . . . . . . . Rhodium . . . . . . . . . . . . . . . . . . . . . . Ruthenium . . . . . . . . . . . . . . . . . . . . . Palladium . . . . . . . . . . . . . . . . . . . . . Platinum . . . . . . . . . . . . . . . . . . . . . . Silver . . . . . . . . . . . . . . . . . . . . . . . Named Reactions . . . . . . . . . . . . . . . . . . . . . Alder-Ene . . . . . . . . . . . . . . . . . . . . . von Auwers . . . . . . . . . . . . . . . . . . . . Bayer–Villiger . . . . . . . . . . . . . . . . . . . Beckmann . . . . . . . . . . . . . . . . . . . . . Brook . . . . . . . . . . . . . . . . . . . . . . . Organic Reaction Mechanisms 2016, First Edition. Edited by A. C. Knipe. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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Organic Reaction Mechanisms 2016

Curtius . . . . . . Friedel–Crafts . . Hauser–Kraus . . Ichikawa . . . . . Kinugasa . . . . . Lossen . . . . . . Meyer–Schuster . Michael . . . . . Newman–Kwart . Overman . . . . . Piancatelli . . . . Pinacol . . . . . . Pauson Khand . . Schmidt . . . . . Smiles . . . . . . Sommelet–Hauser Stevens . . . . . . Suzuki–Miyaura . Ugi . . . . . . . . Wittig . . . . . . Computation . . . . . . Miscellaneous . . . . . References . . . . . . .

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752 752 752 755 755 756 756 757 757 757 759 760 760 761 761 761 762 762 763 763 764 765 775

Pericyclic Reactions Sigmatropic [1,3]-Sigmatropic The bent bond/antiperiplanar hypothesis has been applied to the analysis of thermal [1,3]-sigmatropic alkyl shifts for which there is some evidence that they proceed through diradical intermediates. For the thermolysis of cyclic molecules, the preferred generation of pyramidal allyl radicals in staggered conformations is postulated and accounts for the preference of suprafacial rearrangement pathways as well as the extent of inversion or retention of configuration at the migrating carbons (Scheme 1).1 H

H H

H H

H H H

H

H

H H

H

Scheme 1

The rearrangement of 2-vinyl aziridine 2-carboxylates to chiral cyclic sulfoximines has been reported for the stereospecific synthesis of substituted cyclic sulfoximines (Scheme 2).2

699

12 Molecular Rearrangements

−O

O− +

S N

Mes N

Mes

S +

CO2Me CO2Me Scheme 2

The regioselectivity of the o-semidine, p-semidine, and diphenyline rearrangements of unsymmetrical N,N′ -diarylhydrazines indicates that the electron-rich nitrogen atom is first protonated, and then the electron-poor non-protonated nitrogen atom undergoes an N[1,3]-sigmatropic shift to the ortho-position of the electron-rich aryl rings, generating key intermediates. The intermediates can undergo a direct proton transfer to give o-semidines, or a second N[1,3]-shift of the electron-poor nitrogen atom and then proton transfer to furnish p-semidines, or a [3,3]-sigmatropic shift and subsequent proton transfer to yield diphenylines (Scheme 3).3 NH2

EDG

H2N

EDG

EDG

+

NH2

H2N NH

EWG

or NH2

EWG

NH

EWG

EDG or

NH

EWG

Scheme 3

A borylation/ortho-cyanation/allyl group transfer cascade initiated by a coppercatalysed electrophilic dearomatization has been reported to involve a regio- and stereo-specific 1,3-transposition of the allyl fragment facilitated by an aromatizationdriven Cope rearrangement (Scheme 4).4

[1,4]-Sigmatropic Epimerization of the 𝛼-stereocentre of sugar nitrones has been suggested to involve a [1,4]-sigmatropic rearrangement (Scheme 5).5 [3,3]-Sigmatropic, Cope Claisen Acyclic and cyclic acyl hydrazides have been reported to catalyse a Cope rearrangement of 1,5-hexadiene-2-carboxaldehydes via iminium ion formation (Scheme 6).6 A Cope rearrangement of 1,5-hexadiene-2-carboxaldehydes in the presence of a diazepane catalyst has been reported to offer chiral selection.7 An enantioselective

de 

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Organic Reaction Mechanisms 2016 CuLi BPin BPin-CuLi

Ts

N

CN

Ph

BPin BPin CN CN Scheme 4

H O + N

O O OH

HO

H O

−

+ N

O

O

OH HO

OH

+ N

O

N

O−

OH

−

O

OH

HO

O

OH HO

Scheme 5

𝛾-alkylation of 𝛼,𝛽-unsaturated malonates and ketoesters is reported to involve a regio- and enantio-selective iridium-catalysed 𝛼-alkylation of an extended enolate and subsequent translocation of chirality to the 𝛾-position via a Cope rearrangement (Scheme 7).8 A computational study to establish the potential use of halogen bonding interactions to accelerate and control Diels–Alder reaction, Claisen rearrangement, and Cope-type

ee 

701

12 Molecular Rearrangements R O

H R

N

+

R H

R

R

N

+

R

Scheme 6

MeO2C

H

CO2Me

X n

R CO2Me

R

CO2Me

X

n

X = CH2, O, S, NBn n = 0, 1, 2 Scheme 7

hydroamination with a triarylbenzene tripodal organocatalyst has been reported.9 A phosphine-catalysed 1,4-addition of allyl malononitrile to an alkynoate followed by Cope rearrangement results in two-directional carbon chain elongation on the alkynoate (Scheme 8).10 An asymmetric propargyl Claisen rearrangement has been reported to give chiral allene products along with enantiomerically enriched substrate (Scheme 9).11 An efficient reductive Claisen rearrangement, catalysed by in situ generated copper hydride and stoichiometric in diethoxymethylsilane, has been reported to result in stereospecific rearrangement via a chair transition state of (E)-silyl ketene acetals intermediates and not via the copper enolates (Scheme 10).12 An intramolecular ketene aza-Claisen rearrangement has been reported for the stereoselective synthesis of 𝛼-ally-𝛼-cyano-lactams from N-allyl amino esters (Scheme 11).13 A synthesis of 2,3-diallyl-1,4-quinone derivatives via a Diels–Alder reaction, Claisen rearrangement, and retro-Diels–Alder reaction has been reported (Scheme 12).14 Syntheses of oxepine-, oxocine-, oxepinone-, and dioxocine-angularly annulated flavone skeletons have been reported combining a Claisen rearrangement and ringclosing metathesis (Scheme 13).15 The Claisen rearrangement of allyl phenyl ether to 6-(prop-2-en-1-yl) cyclohexa-2,4dien-1-one has been studied by means of bonding evolution theory, which combines the topological analysis of the electron localization function and catastrophe theory.16 An asymmetric synthesis of 𝛼-amino allylsilane derivatives involving a [3,3]-allyl cyanate sigmatropic rearrangement from enantioenriched 𝛾-hydroxy alkenylsilyl compounds has been reported (Scheme 14).17

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702

Organic Reaction Mechanisms 2016 O H H

H CO2Et

CN

(ii) Cope

(i) CN

O H H

CO2Et

H

NC

CN

Scheme 8

X O R1

X

H

R3

chiral

R4

recognition

R

R3

R4

•

X R2

R2

R3

O

+ R1

O

R4 R2

Scheme 9

O

O O

O

n

n

Pr

Pr

Scheme 10

An acid-catalysed arylation of aromatic C–H bonds in phenols and naphthols has been reported for the preparation of non-C2 -symmetrical, atropoisomeric 1,1′ -linked functionalized biaryls. Density-functional calculations suggest that the quinone and iminoquinone monoacetal coupling partners are exclusively arylated at their 𝛼-position by

703

12 Molecular Rearrangements R2

O

CN

N

CO2Et

1,2

CN

1. base

R1

N

2. carbonyl diimidazole

1,2

R1

R2 Scheme 11

X

O

O R R

O

R R

O Scheme 12

HO

O

Ph

O

O

O

H(Me)

Ph H(Me)

O

O

O O

O

Ph H(Me)

O Scheme 13

an asynchronous [3,3]-sigmatropic rearrangement of a mixed acetal species which is formed in situ under the reaction conditions (Scheme 15).18 Oxyarylation of electron-poor alkynes with pyridine N-oxides has been reported to give meta-substituted pyridines (Scheme 16).19

704

Organic Reaction Mechanisms 2016 NH2 O R′3Si

NCO

O

R′3Si

R

R

RH

R2 H

N

O

R′3Si

R

Scheme 14

MeO

O OH +

OH OH

MeO OMe

Scheme 15

R1

CO2Et

+

O

+

N O−

R1

N

Scheme 16

A regiocontrolled dehydrogenative C–H/C–H cross-coupling of aryl sulfoxides with phenols has been reported. Because the reaction takes place through an interrupted Pummerer reaction followed by sulfonium-tethered [3,3]-sigmatropic rearrangement, the C–H/C–H coupling takes place exclusively between the ortho positions of both substrates (Scheme 17).20 Reactions of in situ generated 𝛼-isocyanato allylboronic esters and aldehydes have been shown to give seven-membered-ring enecarbamates with high levels of diastereoand enantio-control (Scheme 18).21

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12 Molecular Rearrangements

R S O

+

R SR OH

S

OH

O

+

Scheme 17

R1

OH

O B

1

R

OCONH2

R2CHO

O

H

R1

R2

N

O O

Scheme 18

[5,5]-Sigmatropic When treated with dilute inorganic acid 4-alkyl-substituted N,N′ -diarylhydrazines undergo [5,5]-sigmatropic rearrangement to give 4-(4′ -aminophenyl)-4-alkylcyclohexa2,5-dienimines (Scheme 19).22 NH H N

H+

N

R

H

R

NH2 Scheme 19

[2,3]-Sigmatropic Using 2-(trimethylsilyl)aryl triflates as aryne precursors, a range of tertiary allylic amines bearing electron-withdrawing groups undergo [2,3]-sigmatropic rearrangement to give homoallylic amines (Scheme 20).23

TMS N R1

EWG R2

+

N OTf Scheme 20

R

1

R2 EWG

706

Organic Reaction Mechanisms 2016

Electrocyclic Benzyl nitriles containing an alkenyl or aryl groups at the ortho position give aryl amines under silylation conditions. The reaction is thought to proceed via in situ generation of an N-silyl ketene imine followed by 6𝜋-electrocyclization and aromatization (Scheme 21).24 OP

OP CN

OP C

H N

N

SiR3

COCF3

Scheme 21

Computational studies suggest that a reaction cascade to substituted cyclooctatetraenes proceeds by a 8𝜋-electrocyclization reaction (Scheme 22).25 O O

O

O

O

O

Br

R1 R1 R2

R2 Scheme 22

Cycloaddition Reaction of spiro[2,4]hepta-4,6-dien-1-ylmethanol with phenyltriazolinedione gives 4-phenyl-1-[(3aR(S),6S(R))-6-tetrahydro-1H-cyclopenta[b]cyclopropa[c]furan-6-yl]1,2,4-triazolidine-3,5-dione.26 Diethyl 2-(dicyanomethylene)malonate has been reported to undergo formal 3 + 2-cycloaddition–rearrangement cascades with alkynes to provide the penta-2,4-dien-1-one adducts.27 Copper triflate catalysis of a [3 + 2] annulation of propargylic acetates with N-alkylanilines in the presence of trimethylsilyl chloride gives 2,3-disubstituted indoles (Scheme 23).28 R2

R2 + NHR1

N AcO

Ar Scheme 23

R

Ar

707

12 Molecular Rearrangements

In the presence of O2 and an IPrCuCl additive [3 + 2]-annulation of N-hydroxyaniline with nitrosobenzenes gives isoxazolidin-5-ols which on heating with DBU give indoles (Scheme 24).29

•

HO

N O R′

N Ar

OH

ArN

R

+

O

NHAr

R N H

R′

R

N O R′

Scheme 24

Substituted hydronaphthalenes have been reported to be prepared via a tandem [8 + 2] cycloaddition and base-catalysed rearrangement process using dienylfurans and electron-deficient alkynes. A base-catalysed alkene positional isomerization followed by disrotatory electrocyclic ring closure was proposed for the key reaction step that converts 8 + 2-cycloadducts to hydronaphthalenes. The products undergo selective ring opening–isomerization processes upon reaction with Lewis acids (Scheme 25).30

O

CO2Et

O MeO2C

CO2Me

CO2Et CO2Me CO2Me

CO2Et O

CO2Me CO2Me Scheme 25

708

Organic Reaction Mechanisms 2016

Syntheses of polycyclic systems related to conidiogenol, crinipellin, and crotogoudin have been reported from simple aromatic precursors involving oxidative dearomatization, tandem retro-Diels–Alder/Diels–Alder reaction, and photoreaction (Scheme 26).31 CO2Et

OH

H

OH

n

O

CO2R

O

H

X Scheme 26

Molecular Rearrangements Rearrangement An enantioselective pinacol rearrangement of functionalized (E)-2-butene-1,4-diols in the presence of a catalytic amount of a chiral BINOL-derived N-triflyl phosphoramide has been reported to rearrange with enantiomeric selectivity to 𝛽,𝛾-unsaturated ketones (Scheme 27).32 OH R

R

Ar

ee 

O Ar

B*H

Ar

*

R

OH

R

Ar

Scheme 27

2-(2-Cyanoethyl)aziridines and 2-aryl-3-(2-cyanoethyl)aziridines undergo In(OTf)3 mediated regio- and stereo-selective ring rearrangement with LiAlH4 to give 2-(aminomethyl)pyrrolidines and 3-aminopiperidines, respectively (Scheme 28).33 Ph

H N

N

de 

Ph N

CN Scheme 28

The synthesis of 6-arylpyridin-3-ols has been achieved by the oxidative rearrangement of (5-arylfurfuryl)amines (Scheme 29).34 Treatment of several Diels–Alder adducts of cyclopropenecarboxylates and 1,3diarylisobenzofurans with a strong acid results in a skeletal rearrangement to give 4,8b-dihydro-3aH-indeno[1,2-b]furans (Scheme 30).35

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12 Molecular Rearrangements Ar

O

Ar

N

NH2 OH Scheme 29

O

Ph

Ph

Ph

CO2Me

Ph

O CO2Me +

Ph Ph

Ph

O

Ph

Ph

CO2Me

Scheme 30

A series of p-terphenyl-based macrocycles have been synthesized. Biaryl bonds of the nonplanar p-terphenyl nuclei were constructed using 1,4-diketones as surrogates to strained arene units. Under protic acid-mediated dehydrative aromatization conditions, the central and most strained benzene ring of the p-terphenyl systems was susceptible to rearrangement reactions but overcome by a dehydrative aromatization protocol using the Burgess reagent.36 Experimental and theoretical investigations into the phenyliodine bis(trifluoroacetate)-mediated reaction of N-arylcinnamamide to produce 3-arylquinolin-2-one derivatives have been reported to involve a mechanism of oxidative annulation, followed by aryl migration (Scheme 31).37 Ar′

Ar Ar′

Ar Ph N

O

N

O

Scheme 31

The degenerate rearrangement in the 21-homododecahedryl cation has been investigated by computational methods, and it has been reported that complete scrambling can be achieved by the combination of two barrierless processes. The first one is a ‘rotation’ of one of the six-membered rings via a 0.8 kcal mol−1 barrier, and the second is a slower interconvertion between two hyperconjomers via an out-of-plane methine bending (ΔG‡ = 4.0 kcal mol−1 ).38 Computational studies of the FeBr3 -catalysed skeletal rearrangements of 2-cyclohexanal,2-p-C6 H4 OMe-propylaldehyde and 2-phenyl,2-pC6 H4 OMe-propylaldehyde show that for the former the [1,2]-group shift (first step) is rate determining, while for the latter the [1,2]-H shift (second step) is rate determining (Scheme 32).39

710

Organic Reaction Mechanisms 2016

R2

Me

O

R1

R2

Me

H

H

O R1

Scheme 32

R1

R1 OH O

O OH

Scheme 33

Bismuth(III) triflate is reported as a catalyst for the ring rearrangement of tertiary allylic alcohols to give polysubstituted cyclopentenones with a high degree of diastereoselectivity (Scheme 33).40 The synthesis of secondary benzylic alcohols via sodium amalgam-mediated desulfonylative reduction of 𝛽-ketosulfones (a Bouveault–Blanc-type reduction) has been reported (Scheme 34).41 O

O S

Ar

OH R

Ar

O

Scheme 34

A synthesis of lingzhiol has been achieved via a Brønsted acid-catalysed semi-pinacol rearrangement of a glycidyl alcohol intermediate (Scheme 35).42 OH MeO

HO HO

O

O

O

CO2Me HO

MeO Scheme 35

O

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711

12 Molecular Rearrangements O

H O

O

O

H O

BnO

H

O O

OBn

O H

HO

OH

O Scheme 36

A synthetic strategy for the asymmetric total synthesis of ascospiroketals A and B has been reported which involves ring contraction rearrangement of the 10-membered lactone to the tricyclic spiroketal cis-fused 𝛾-lactone core (Scheme 36).43 The total synthesis of (−)-cardiopetaline has been reported involving a Wagner– Meerwein rearrangement of a sulfonyloxirane enabling the construction of the bicyclo[3.2.1] system (Scheme 37).44 SO2Ph MOMO

MOMO

O

O Et

Et

N

N OMe

Scheme 37

A domino reaction intended to give oxazolidin-4-ones from 𝛼-bromoamido alcohol in the presence of KNaCO3 and water with Michael acceptors results in molecular rearrangement (Scheme 38).45 O

O

R1

R2

O R1

OEt +

O

O Br R3

N H

N

R2

O O

OH

R3

O

Scheme 38

Tricyclic structures have been synthesized from 7𝛽-hydroxy-9-oxolongipin-2-en-1one by a reaction involving Wagner–Meerwein rearrangements (Scheme 39).46

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Organic Reaction Mechanisms 2016 15

O 1

2

11

12

3

4

9

1

2

11

10 8

6 7

3

13

10

9

8 5

O

O

O

OH

10

OH

4

5

6

1

2

+

3

4

9

11 5

8

O O

6 7

7

14

Scheme 39

CO2Me Ph

MeO2C

CO2Me

CO2Me

Ph

+

CO2Me CO2Me

OH

Ph + OH

Scheme 40

Lewis acid-catalysed reactions of 2-substituted cyclopropane 1,1-dicarboxylates with 2-naphthols occur with Bi(OTf)3 to give dehydrative 3 + 2-cyclopentannulation and formation of naphthalene-fused cyclopentanes. With Sc(OTf)3 Friedel–Crafts-type addition of 2-naphthols to cyclopropanes occurs to give 2-naphthols (Scheme 40).47

Ring Expansion, Ring Opening, and Ring Closing Benzo-fused nitrogen heterocycles such as indolines and tetrahydroquinolines undergo ring expansion through deprotonation of their benzylic urea derivatives with LDA in the presence of N,N′ -dimethylpropylideneurea to give benzodiazepines and benzodiazocines (Scheme 41).48 n N Ph

N

NH

n+3

base

N

O Ph

R

O

R

n = 5–9 Scheme 41

Ring expansion of propargyl alcohol-substituted aziridines has been reported by using a ruthenium cyclopentadienyl phosphine complex (Scheme 42).49

713

12 Molecular Rearrangements R

OH

R

R [Ru] R

N Bn

OMe N +

Bn

Scheme 42

X Ar

CO2R

TfOH

Ar

O

CO2R

O Scheme 43

A synthetic strategy was reported for the construction of alkyl 5-arylfuran-2carboxylates from alkyl 1-alkoxy-2-aroylcyclopropanecarboxylates. These donor– acceptor cyclopropanes undergo a ring-opening reaction or/and cycloisomerization reaction. Alkyl 5-arylfuran-2-carboxylates result in the presence of triflic acid (Scheme 43), whereas alkyl 2,5-dioxo-5-phenylpentanoate is the major product in other protic acids and Lewis acids.50 An extensive review of ring-opening, cycloaddition, and rearrangement reactions of nitrogen-substituted cyclopropane derivatives has been published.51 A site-selective silylation of C(sp3 )–H bonds mediated by a [1,5]-hydrogen transfer has been reported to occur selectively at the 𝛼-position of benzamides in the presence of tert-butylmagnesium chloride and a catalytic amount of a 4,4′ -di-tert-butylbipyridine ligand, resulting in 𝛼-sila benzamides. (Scheme 44).52 O

H N

F

O R

R3Si–Cl

H

SiR3 N

H

R

H

Scheme 44

A Lewis pair-catalysed cycloisomerization of a series of 1,5-enynes has been reported to proceed via 𝜋-activation of the alkyne and 5-endo-dig cyclization with the adjacent alkene (Scheme 45).53 A silver-catalysed cycloisomerization reaction of a series of o-alkynylbenzohydroxamic acids results in 5-exo-dig and 6-endo-dig modes of cyclization (Scheme 46).54 An Fe(OTf)3 -catalysed 1,5-enyne cycloisomerization via a 5-endo-dig cyclization is reported for the synthesis of 3-(1-indenyl)indole derivatives (Scheme 47).55 An arylsulfonyl radical-triggered desulfonylation of N-aryl-N-arylsulfonylacrylamides gives sulfonylated amides through 5-exo-trig cyclization, desulfonylation, and aryl migration sequence (Scheme 48).56

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Organic Reaction Mechanisms 2016 R1

R2

R2

R1 B(C6F5)3/PPh3

R3 R3 Scheme 45 1 N OR

O

O

1

N

OR

N OR1

+

O

H

R2

R2

R2 Scheme 46

R2

H R2

R1

R1 H

N

N

Ts

Ts Scheme 47

Ar1 O 2S

O N

O +

Ar3 H2N NH

SO2

Ar2

Radical

Ar2

Ar3

N H

Ar1

SO2

Scheme 48

Breslow postulated that key intermediates in thiamine-catalysed enzymatic pathways included an N-heterocyclic carbene and an enaminol. It has now been reported that Breslow intermediates that bear radical-stabilizing N substituents undergo facile homolytic C–N bond scission to give products of formal [1,3] rearrangement rather than undergoing benzoin condensation.57

715

12 Molecular Rearrangements

Thermal A synthesis of orthogonally functionalized naphthalenes from indanones has been reported by thermally induced fragmentation of a cyclopropane indanone with a simultaneous 1,2-chloride shift (Scheme 49).58 OH

O

R

R O

OMe OMe Cl

Cl

O

Scheme 49

Pentasubstituted aromatic rings have been prepared by the thermolysis of suitably substituted alkynes under microwave conditions (Scheme 50).59 OTBS

O O O

O

O Scheme 50

Flash vacuum pyrolysis of benz[a]azulene has been reported to give phenanthrene and 2-ethynylbiphenyl, and cyclohepta[b]indole similarly gives phenanthridine and 2-cyanobiphenyl. The reactions involve a norcaradiene–vinylidene mechanism of the azulene–naphthalene rearrangement (Scheme 51).60

Scheme 51

A cascade (cyclo)isomerization/elimination to give isoquinoline derivatives has been suggested to involve an allenylpyridine as an intermediate (Scheme 52).61

Oxidation A stereoselective hypervalent iodine-promoted oxidative rearrangement of 1,1disubstituted alkenes provides access to enantio-enriched 𝛼-arylated ketones (Scheme 53).62

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Organic Reaction Mechanisms 2016 SPh N

N

SPh

H

N

SPh

H N

Scheme 52

O

R1

R2

R1

Ar

*

R2

Ar Scheme 53

A chiral lactic acid-based iodine(III)-mediated rearrangement of arylketones in the presence of orthoesters has been reported to give enantioselectivity 𝛼-arylated esters (Scheme 54).63 O

O MeO

Ph

Ph Scheme 54

An oxidative rearrangement of spiro tetrahydroisoquinolines to give fused tetrahydroisoquinolines has been reported using in situ generated N-chloroamines. The reaction proceeds via chlorination of an amine, a 1,2-carbon to nitrogen migration, and nucleophilic trapping of a ketiminium ion intermediate (Scheme 55).64 An iodine-catalysed oxidation of 2,3-dihydrowogonin to negletein has been reported that comprises a Wessely–Moser rearrangement associated not with an O-demethylation but with an oxygen to oxygen methyl shift (Scheme 56).65 Medium-sized cyclic ethers have been synthesized via oxidative rearrangement of benzylic tertiary alcohols (Scheme 57).66

ee 

717

12 Molecular Rearrangements

NH

N Nu n

n

Scheme 55

MeO HO

MeO

Ph

O

O

Ph

HO HO

HO

O

O

Scheme 56

CF3

HO R

R O O

[(Py+ )2IPh] 2 OTf −

Ar

X

n

Ar

X

CF3 n

Scheme 57

Oxidative rearrangement of 2-(2-aminobenzyl)furans has been reported to give 2-(2acylvinyl)indoles (Scheme 58).67 R2

R2 O

R1

O R1

N

NH

Ts

Ts Scheme 58

A hypervalent iodine(III)-intermediated oxidative rearrangement of 3-hydroxybut-2enimidates to give oxazoles has been reported (Scheme 59).68

Phosphorous, Boron Sulfur, and Silicon Low-temperature generation of P-nitroxyl phosphane by the reaction of Ph2 PH, with two equivalents of TEMPO, has been reported which upon warming decomposed to P-nitroxyl phosphane P-oxide (Scheme 60).69

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Organic Reaction Mechanisms 2016 NH Ar

OH

R1 R2

O

O N Ar

R1

O

O

R2

O

Scheme 59

N

O

P

Ph

N

Ph

O

Ph P

Ph

O Scheme 60

An efficient synthetic method for 2,3-allenylamides having oxygen functionality at the 2-position has been reported utilizing a [1,2]-phospha-Brook rearrangement under Brønsted base conditions. The 2,3-allenylamides undergo gold-catalysed cycloisomerization to form 2-aminofurans (Scheme 61).70 O R R1

2

O

O

R

HP(OR4)2

N O

R

3

[1,2]-phosphaBrook

R1

OP(OR4)2

2

N

•

O

R3 H

O Au(PPh3)NTf2 cycloisomerization

(EtO)2PO R2 N

O

R3

R1 Scheme 61

A series of heteroleptic boranes and borenium cations have been reported to react with various propargyl esters and carbamates to give allyl-boron and boronium compounds through complex rearrangement reactions (Scheme 62).71 Asymmetric cyclopropanation of vinylphosphonates with (S)-dimethylsulfonium(ptolylsulfinyl)methylide in the presence of base and subsequent stereoselective methylation provides substituted cyclopropylphosphonates (Scheme 63).72 Coupling of 𝛼-ketoesters with imines initiated by diethyl phosphite in the presence of alkaline metal hexamethyldisilazides has been reported to occur by addition of diethyl phosphite to the 𝛼-ketoester, followed by a [1,2]-phosphonate/phosphate rearrangement,

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719

12 Molecular Rearrangements

I

O

(C6F5)2B

+

R

R1

C6F5

R2

C6F5 C F 6 5 R

B

O R1

C6F5

I

O R2

Scheme 62

O O

O

(RO)2P

X

+

p-Tol

+

S

S

(RO)2P

BF4−

X

S

p-Tol

O Scheme 63

to generate 𝛼-phosphonyloxy enolates that are intercepted by imines to give syn-𝛼hydroxy-𝛽-amino acids or trans-aziridine-2-carboxylates (Scheme 64).73

O H

OEt OEt

P

PG = p-MeOPhSO2 NaN(SiMe3)2 then H+

O R

HN EtO2C

de 

SO2PMP R′

(EtO)2(O)P O R

CO2Et

N

PG

PG = Ph2P(O) LiN(SiMe3)2 then H+

R′

P(O)Ph2 N

EtO2C R

H R′

Scheme 64

An aryl to vinyl palladium 1,4-migration has been reported. The generated alkenyl palladium species was trapped by diboron reagents under Miyaura borylation conditions providing for the synthesis of 𝛽,𝛽-disubstituted vinylboronates (Scheme 65).74 High-throughput experimentation has been used to define stereoconvergent Suzuki– Miyaura cross-coupling conditions to give (Z)-𝛼-methyl-𝛽-cyclopropylcinnamates, and subsequent ruthenium-catalysed asymmetric hydrogenation provided enantiopure 𝛼-methyl-𝛽-cyclopropyldihydrocinnamates (Scheme 66).75

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720

Organic Reaction Mechanisms 2016 R1

R1

R1

Pd0

PdII PdII

Br

B2(pin)2

B(pin)

Scheme 65

R R

OTs (Z)

CO2Me (Z)

B(OH)2

Me

Pd-catalyzed

CO2Me

Me

Ru-catalyzed

R

(R)

(S)

CO2Me

Me Scheme 66

Catalytic amounts of a nickel pincer complex and NaOBut have been reported for the synthesis of alkyl hydrosilanes from alkenes and alkoxy hydrosilanes, leading to the replacement of flammable Me2 SiH2 , MeSiH3 , and SiH4 by Me2 (MeO)SiH, Me(EtO)2 SiH, and (MeO)3 SiH in hydrosilylation reactions of alkenes (Scheme 67).76 A bora-Brook rearrangement, that is, the migration of boryl group from a carbon to an oxygen atom in an isolated 𝛼-boryl-substituted alkoxide, has been examined to establish factors for the acceleration of the reaction (Scheme 68).77

721

12 Molecular Rearrangements

Me N O

n=2

Cl Pri

Men(R′O)3-nSiH + R

R

O

N Ni N

Si Me

Pri

n=1

Si

R

H n=0

Si

R

H Me H R H R

Scheme 67

Ar

OH Ar Ar

N

B

N base

H

O

B

Ar

N

N Ar

Ar

H

H

Scheme 68

The C4 -bridged unsaturated phosphane/borane Lewis pairs have been reported to undergo borane-induced phosphane addition to acetylenic esters or ketones to give heterocyclic 10-membered intermediates that undergo phospha-Claisen-type rearrangement to give phosphanyl pentadienes (Scheme 69).78

de 

O R1 R2

R2P

B(C6F5)2

+

−

R2P R1

−

B(C6F5)2

B(C6F5)2 •

O R2

O+

R 2P R1

R2

Scheme 69

An aryne 1,2,3-trisubstitution with aryl allyl sulfoxides has been reported having C–S, C–O, and C–C bonds on the benzene ring. Mechanistic study suggests a cascade formal [2 + 2] reaction of aryne with the S=O bond, an allyl S → O migration, and a Claisen rearrangement (Scheme 70).79 The thermal-induced 1,3- and 1,5-sulfonyl migration reactions of sulfonamides show that N-arenesulfonylphenothiazines and N-arenesulfonylphenoxazines can undergo 1,3and 1,5-sulfonyl migrations to give aryl sulfone involving homolytic cleavage of the sulfonamide bond and intermolecular radical–radical coupling (Scheme 71).80

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Organic Reaction Mechanisms 2016 Ar

R′

+

Ar

S

R2

O

R3

S

R4X

R

R1

H

R4

O R3

R1 R2

Scheme 70

X

X

N

N

SO2Ar

SO2Ar

ArO2S +

H

X N H

Scheme 71

Carbene and Nitrene Flash vacuum pyrolysis of 1-(5-13 C-5-tetrazolyl)isoquinoline generates 1-(13 Cdiazomethyl)isoquinoline, and 1-isoquinolyl-(13 C-carbene) undergoes carbene–nitrene rearrangement to 2-naphthylnitrene which then undergoes ring contraction by two parallel paths (Scheme 72).81 * CH

*

* N

N

*

* CN N

*

N

* N

Scheme 72

A synthesis of 3-aminofurans has been reported that involves a tandem reaction sequence through rhodium(II) carbene O–H bond insertion, thermal propargyl-Claisen rearrangement, and gold(I)-catalysed intramolecular cyclization (Scheme 73).82 The reaction of phosphanyl ketenes, (NHP)–P=C=O (NHP = N-heterocyclic phosphenium), with N-heterocyclic carbenes leads to phosphaheteroallenes (NHP)–O= P=C=NHC in which the PCO unit has been isomerized to OP, and a mechanism

723

12 Molecular Rearrangements R2 TsHN

N

N

N

Ts

R1

O

R1 + OH

R2 Scheme 73

has been proposed.83 Photolysis of carbamoyl azides provides carbamoylnitrenes, and subsequent visible-light irradiation causes rearrangement into aminoisocyanates (Scheme 74).84 O R2N

O

hv

N3

−N2

R2N

hv

N

N C O R2N

R = H, Me hv

−CO

O Me2N

NCO

Scheme 74

The mass spectrometric fragmentation of 15 N-labelled 2-pyridylnitrene radical cation has been reported. The nitrogen atoms become equivalent prior to fragmentation in the mass spectrometer (Scheme 75).85

Acid Promoted Acid-promoted bicyclization of alkynes to polycyclic compounds has been reported to proceed through two C–C bonds formed on remote alkyl C–H bonds by long-distance cationic rearrangement (Scheme 76).86 Carboamination of unactivated alkynes towards substituted quinolines has been reported in the presence of a Brønsted acid catalyst. The reaction proceeds via a highly reactive vinyl cation in a C–C bond formation, a Schmidt reaction sequence (Scheme 77).87 Intramolecular cycloisomerizations of nitrogen-tethered cyclopropenes with indole in the presence of Brønsted acids have been reported to proceed via the same pathway but stop at different stages depending on substitution to give azocino[5,4-b]indole and (epiminoethano)cyclopenta[b]indole (Scheme 78).88

724

Organic Reaction Mechanisms 2016

hv or Δ

FVP

N

N N N

N

N3

hv or Δ

N

N

hv or Δ

N

N

N Δ

hv

N Δ

hv or Δ

RH

CN Δ

N H

Δ

N H

CN

Δ

CN

N Δ

CN Scheme 75

CN

N

NH2

725

12 Molecular Rearrangements 1 1

2

H

3

2 6

R

4

R1

3

R

4

5

5

(1)

6

R1

(2) Scheme 76

R1

OH R1

R2

R2

R3

N3

N

R3

Scheme 77

Sulfur-mediated allylic C–H amination of alkenes has been reported to involve anti-Markovnikov rearrangement from secondary to a primary carbocation or to a primary triflate.89 Brønsted acid-promoted nucleophilic attack of propargylic alcohols during the Meyer–Schuster rearrangement has been reported. Reverse polarization of the intermediate allenyl cation was effected by employing a cis-enoate-assisted strategy (Scheme 79).90 An acid-promoted cascade [3 + 2] annulation strategy for the synthesis of naphthoand benzofurans involves an alkoxyfuranylallene intermediate generated from Z-enoate propargylic alcohols via a Meyer–Schuster rearrangement of the 1,2-bis-electrophile and 𝛽-naphthols as the 1,3-bisnucleophile (Scheme 80).91 A synthesis of the biologically active (+)-CP-99,994 has been reported with the key step, a ring-expansion rearrangement in which threo-fused monosubstituted prolinol was transformed to 2,3- disubstituted piperidine with a cis-relationship and without loss of optical purity.92

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Addition Tricyclic-bridged heterocyclic systems can be prepared from sequential 1,4- and 1,2addition reactions of allyl and 3-substituted allylsilanes to indolizidine and quinolizidine 𝛼,𝛽-unsaturated N-acyliminium ions. The reactions involve an N-assisted, transannular 1,5-hydride shift (Scheme 81).93 Reaction of electron-deficient alkenes with donor-activated and -unactivated alkynes results in a 3 + 2-cycloaddition–rearrangement cascade to give penta-2,4-dien-1-ones (Scheme 82).94

Metathesis para-Quinone methides activated by Lewis acid react with diazo compounds and lead to nitrogen extrusion and tetrasubstituted alkenes, while diazo-oxindole gives quinolinones (Scheme 83).95

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Organic Reaction Mechanisms 2016

NR1 CO2R3 R=H

2

R N

CO2R3

R1

2

R

N X

CO2R3

N H

R

X = Boc or TIPS R1 = Ts, Ns or Bs R2 = alkyl or halogen R3 = Me or Et

CO2R3

NHR1 O

CO2R3 R = aryl

R2

CO2R3 N H

Scheme 78

NR1

Ph

H+

Ph N H

727

12 Molecular Rearrangements CO2Et OH R3

R2 MsOH

CO2Et

R3

ArH

R2

O Ar

Scheme 79

R3 2 3

1

OH

HO

R2

R2

1

R3

2

RO2C

3

O O OR Scheme 80

BnO

BnO BF3• Et2O

HO

Me

O

N

+

D

O

N

Me TMS

D

D

D

shift 1.5−H

BnO

BnO

D Me

O

N

−H+

D

D Me

O

N+ D

Scheme 81

Ylide The generation of 11–21-membered intramolecular macrocyclic sulfonium ylides using catalytic Rh2 (OAc)4 has been reported.96 A computational study of the mechanism of the reaction of ethyl acetoacetate with Martin’s sulfurane and a mixture of diphenyl sulfide and triflic anhydride has been reported.97

728

Organic Reaction Mechanisms 2016 CN NC

CO2Et

NC

NC

CO2Et

EtO2C

+

Ph

OEt

Ph

O

Scheme 82

But

HO

R2

N2

Bu

R3O2C

O t

t

R4

*

But

Bu

R3O2C R4 N2

* R2

But

R2

R3

OH

O N

But

*

R3 N

O

Scheme 83

Metal-Induced Reactions Copper The synthesis of di- and tri-substituted pyrroles via copper-catalysed cyclization of ethyl allenoates with activated isocyanides has been reported featuring a skeletal rearrangement in which the aryl sulfonyl moiety migrates to the 𝛾-carbon of the starting allenoate (Scheme 84).98 A regiodivergent [2,3]- and [1,2]-rearrangement of iodonium ylides are reported to be controlled by copper catalysts bearing different ligands. In the presence of a 2,2′ -dipyridyl ligand, diazoesters and allylic iodides react via a [2,3]-rearrangement pathway, while a phosphine ligand favours the formation of the [1,2]-rearrangement (Scheme 85).99 A synthesis of 𝛾,𝛿-unsaturated 𝛼-nitrogenated aldehydes involves a copper-coupling reaction between 𝛽-iodoenamide derivatives and allylic alcohols to generate 𝛽allyloxyenamide derivatives which on heating undergoes Claisen rearrangement (Scheme 86).100

729

12 Molecular Rearrangements

R1 R1

H

CO2R

EWG

Cu2O

•

CO2R

R2

+

N H

R2 CN

EWG Scheme 84

N

R

N

Br

3

Br

R3

I

R1

R2

CuPF6 I

R1

CO2But

R2 +

N2

CO2But

R3

CuPF6

I

R1

CO2But

OMe

R2

P MeO

OMe

Scheme 85 R5

R3 R4

R2

N

I

COR1

CuI

R3

R5

OH

R2

R4 N COR1

R1 = alkyl, O-alkyl R2 = alkyl, aryl Scheme 86

O

R3

R5 Δ

R2

R4 N COR1

O

730

Organic Reaction Mechanisms 2016

A copper-catalysed cascade reaction providing in situ generation of nitrilium from a nitrile ylide and subsequent Mumm rearrangement of carboxylic acid, nitrile, and diazo compounds has been reported to give unsymmetrical diacylglycine esters (Scheme 87).101 O N2

O OR3

H

R1CO2H R2CN

R1

OR3

N R2

O

O

Scheme 87

A synthesis of polycyclic compounds from linear diynes and diaryliodonium salts has been reported by Cu-catalysed arylation of alkynes and the generation of two vinyl carbocation intermediates that subsequently react with arene groups (Scheme 88).102 R1

n

R1

n

R2 R2 n = 1 or 2

Ar Scheme 88

4-Imino tetrahydropyridine derivatives are formed from 𝛽-enaminones and sulfonyl azides and involve sequential copper-catalysed ketenimine formation and intramolecular hydrovinylation (Scheme 89).103 O R3SO2N3 CuI

1

R

R2

N H

O

N

R2

N H

SO2R3

R1

Scheme 89

Gold 1-Azabicycloalkane derivatives have been synthesized through a gold(I)-catalysed desulfonylative cyclization strategy. An ammoniumation reaction of ynones substituted at the 1-position with an N-sulfonyl azacycle occurs by intramolecular cyclization of the sulfonamide moiety onto the triple bond (Scheme 90).104

731

12 Molecular Rearrangements R O

O SO2R

N

[Au]+

[Au]

H

+ N

R SO2R

ArylOH

heat

O ArylOSO2R

+

OSO2R H

N

H

N

R

R

Scheme 90

EtO2C

NR R

O

1

EtO2C

NHR KAuCl4 reflux

R NC +

R1

O N Pg

N H 95°

EtO2C

KAuCl4

NHR O

R1 N H

NR

Scheme 91

A selective double insertion of isocyanides with the aid of potassium tetrachloroaurate(III) has been reported to provide polycyclic skeletons (Scheme 91).105 An intramolecular cyclization of ortho-O-propargyl-1-one-substituted arylaldehydes has been reported to give aroylbenzo[b]oxepin-3-one via a gold-catalysed oxidation of the internal alkyne moiety followed by an intramolecular condensation (Scheme 92).106

732

Organic Reaction Mechanisms 2016 O R1 O

R2

O

R2

O

O

O

R1 Scheme 92

Gold-catalysed, regioselective cycloisomerization of N-(o-alkynylaryl)-N-vinyl sulfonamides gives 2-sulfonylmethyl-1-benzoazepines via a 7-endo-dig-selective cyclization that proceeds via the incorporation of an exocyclic double bond by a labile 1-benzoazepine intermediate (Scheme 93).107 Sonogashira coupling

Ar Ar

I + NHMs

SO2R

N Ms Br

SO2R AuI

Ar

N Ms

SO2R

Scheme 93

A gold(I)-catalysed cycloisomerization of 1-en-3,9-diyne esters to spiro[4.4]non-2ene-substituted 1,2-dihydronaphthalenes involves a gold-catalysed 1,3-acyloxy migration/Nazarov cyclization followed by a formal 4 + 2-cycloaddition to give the tetracarbocyclic product (Scheme 94).108 An Au(I)-catalysed tandem 1,3-acyloxy migration/double cyclopropanation of 1-ene4,9-diyne and 1-ene-4,10-diyne esters gives tetracyclodecene and tetracycloundecene derivatives (Scheme 95).109 A gold-catalysed sequential reaction of O-allyl hydroxamates bearing an alkyne moiety gives 3-hydroxyisoxazoles and isoxazole-3-ones and involves cyclization and rearrangement (Scheme 96).110 Pericyclic reactions bypass high-energy reactive intermediates by synchronizing bond formation and bond cleavage, and two strategies for uncoupling these two processes

733

12 Molecular Rearrangements R2 R1OCO

R

R2

OCOR1

2

OCOR1 [Au]+

R3 R3

R3 Scheme 94

R1OCO

R3

R2

H

OCOR1

[Au]+

( )n ( )n

R3

R2

n = 1, 2 Scheme 95

HN

O

N PicAuCl2

O

O R

HO

R Scheme 96

have been reported by combining Au(I) catalysis with electronic and stereoelectronic factors. The combination of Au(I) catalysis and C–F-mediated stereoelectronic gating in a gold(I)-catalysed allenyl Cope rearrangement has been reported to delay the central bond scission, opening access to the interrupted Cope rearrangements and expanding the scope of this classic reaction to the design of new cascade transformations.111 The synthesis of substituted 2-cyclopentenones has been reported using a gold(I) catalyst and a proton source (Scheme 97).112 O

O O

R3 But PPh3AuNTf2

R1 R2

R3 Scheme 97

R2

R1

734

Organic Reaction Mechanisms 2016

An early and late transition-metal relay catalysis has been developed by combining a gold-catalysed cycloisomerization and a Yb(OTf)3 -catalysed diastereoselective 3 + 2cycloaddition with aziridines in a selective C–C-bond cleavage mode (Scheme 98).113 Ts

XH

N

+ Ph

COOEt

X

Ph3PAuNTf2 Yb(OTf)3

COOEt

COOEt COOEt

NTs

X = O, NTs Ph Scheme 98

Au(I)-catalysed reaction of 2-propargyloxypyridines has been reported to give N-alkylated 2-pyridones from 5-exo and 6-endo addition of the nitrogen to the alkyne (Scheme 99).114 R3 Au I

R2

R4OH

N

R3

R1

O

N

O R1

OR4 R2

Scheme 99

Gold-catalysed cyclization of various furan-ynes with a propargyl carbonate or ester moiety has been reported for the synthesis of a series of polycyclic aromatic ring systems. The reactions are rationalized by a tandem gold-catalysed 3,3-rearrangement of the propargyl carboxylate moiety in furan-yne substrates to form an allenic intermediate, followed by an intramolecular Diels–Alder reaction and subsequent ring-opening of the oxa-bridged cycloadduct (Scheme 100).115 A synthesis of bicyclo[2.2.1]hept-2-en-7-ones involving a gold(I)-catalysed Rautenstrauch rearrangement followed by Brønsted acid-mediated 3 + 2-cycloaddition/ deacetylation of 1,8-diynyl vinyl acetates has been reported (Scheme 101).116 A regiospecific synthesis of bicyclic furopyran derivatives has been reported via a gold(I)-catalysed propargyl-Claisen rearrangement/6-endo-trig cyclization of propargyl vinyl ethers. The introduction of angle strain into the substrates alters the reaction’s regioselectivity (Scheme 102).117 Gold mesoionic carbenes having a chiral sulfoxide group attached to the C(4) position of the five-membered ring have been used as catalysts in the cycloisomerization of enynes. The sulfoxide moiety plays a key role in their activity and the N(1)-substituent in control of the regioselectivity of these processes (Scheme 103).118

735

12 Molecular Rearrangements OCO2Me R1

MeO2CO

R1

•

LAu+

O

O

R2

R2

[4+2]

MeO2CO

R1 R2

Scheme 100

R2

O

AcO

Ph3PAuNTf2

( )3

R2

R1 R1

Ar

Ar

Scheme 101

PPh3 R

Au O

+

Ph3PAuNTf2

R O

6-endo-trig

R′

O H

O

O O

O

O

O

Scheme 102

Phenylpropargyl diazoacetates have been reported to exist in equilibrium with 1-phenyl-1,2-dien-1-yl diazoacetate – allenes by 1,3-acyloxy migration catalysed by gold(I) or gold(III) compounds which react with the 𝜋-donor rather than with the diazo group. Rearrangement occurs to give 1,5-dihydro-4H-pyrazol-4-ones (Scheme 104).119

736

Organic Reaction Mechanisms 2016

Control of activity

O S

R

ClAu

MeO2C

R1

MeO2C

N

CO2Me

N N

MeO2C R2

Control of 5-exo vs 6-exo

R2 R3

R3 + R2

MeO2C MeO2C Scheme 103

N2 O

Ar1 O

Ar2

AuCH(C4H8S)

2 O Ar

Ar1

O N

N H

•

Ar2

N2 O

Ar1

2 O Ar

O

O N

Scheme 104

N H

Ar1

R3

737

12 Molecular Rearrangements

A synthesis of indolizidines and quinolizidines from aminaloalkynes via a gold(I)catalysed hydroaminaloxylation and Petasis–Ferrier rearrangement cascade has been reported (Scheme 105).120 n

n

H

cat.

O

N

OH

R

IPrAuOTf

O

R

N

O

n = 0,1; R = H, alkyl and aryl Scheme 105

A gold(I)-catalysed cycloisomerization of indolyl-1,6-enynes via 5-exo-dig cyclization yields indole polycyclic scaffolds that can undergo a 2 + 2 + 2-cycloaddition reaction with aldehydes to give tracyclic indoles (Scheme 106).121 LAu H R1

AuL+

N

N

R1

R1

R1 R2CHO

R2 N O H

R1 R1

Scheme 106

Chiral monodentate phosphines based on ortho-disubstituted ferrocene units have been used for the synthesis of gold(I) complexes that are catalysts for the cycloisomerization of 3-hydroxy-1,5-enynes to bicyclo[3.1.0]hexanones (Scheme 107).122 The gold(I)-catalysed dehydrogenative cycloisomerization of cyclopropane-tethered 1,5-enynes has been reported to give multi-substituted benzenes including benzocyclobutenes (Scheme 108).123 A gold(I)-catalysed substituent-controlled strategy for the stereoselective synthesis of bicyclic furan and pyran derivatives has been reported and the mechanism studied by deuterium labelling experiments (Scheme 109).124

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Organic Reaction Mechanisms 2016 Ar P

AuCl

O

Fe R R

HO Me

Me

Ph

[AgX]

Ph Scheme 107 n

R2

R2

n

PPh3AuCl/AgSbF6

R1

R1

n = 1, 2,3 Scheme 108

R

X O

R′ H X = O, S

Nuc O

O

Au(I)+ Nuc-H

O

O

Nuc

Me

R′′

H O

Au(I)+

O

Nuc-H

O

O

Scheme 109

A gold-catalysed rearrangement of propargyl esters followed by allene–ene cyclization has been reported to give bicyclic [4.4.0] dihydronaphthalenes. The reaction involves ligand-controlled preferential activation of the alkene over the allene (Scheme 110).125 PivO R

R

[Au]

X

X

OPiv +

X

OPiv R

X = CH2, O, N Scheme 110

A gold-catalysed cyclization of 1,6-diynyl dithioacetals has been reported to give diverse-substituted benzo[a]fluorene derivatives by 1,2-sulfur migration of a propargyl dithioacetal moiety to generate a vinyl gold carbene followed by carbene transfer to the remaining alkyne and aromatic substitution (Scheme 111).126

739

12 Molecular Rearrangements

S

S

S

S

[Au]

R1 R R2

R2

R1 = aryl, R2 = aryl, alkyl

Au+L

Scheme 111

Hafnium In the presence of hafnium(IV) triflate, a variety of 2,3-unsaturated-O- and S-glycosides have been obtained by stereoselective glycosylation of 3,4,6-tri-O-acetyl-d-glucal and hexa-O-acetyl-d-lactal (Scheme 112).127 OAc

OAc +

O

RO AcO

RXH (X = O- or S-)

Hf(OTf)4

O

RO

XR O- or S-glycosides

R=Ac, Glucal R=Gal, Lactal Scheme 112

Iridium Asymmetric synthesis of indole-annulated medium-sized-ring compounds has been reported through an iridium-catalysed allylic dearomatization/retro-Mannich/hydrolysis cascade (Scheme 113).128 Ph

m

m

NH

N N H

[Ir] n

n

OCO2Me

N H

Scheme 113

Iron Treatment of enynes with alkyl-Grignard reagents in the presence of catalytic amounts of Fe(acac)3 has been reported to result in formation of two new C–C bonds while a C–Z bond in the substrate is ruptured (Scheme 114).129

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Organic Reaction Mechanisms 2016

O

MgCl

COOMe

O

COOMe Fe

Fe(acac)3

R

R

OH COOMe

Scheme 114

Rhodium Allylrhodium species from 𝛿-trifluoroboryl 𝛽,𝛾-unsaturated esters undergo chain walking towards the ester moiety. The resulting allylrhodium species react with imines to give products containing two new stereocentres and a Z-alkene (Scheme 115).130

O O S N

O

+ EtO

BF3K

[{Rh(cod)Cl}2]

Me

R

O O S NH H O

OEt

Me

Scheme 115

Highly functionalized 4-bromo-1,2-dihydroisoquinolines have been prepared from 4(2-(bromomethyl)phenyl)-1-sulfonyl-1,2,3-triazoles. A bromonium ylide has been proposed as the key intermediate formed by intramolecular nucleophilic attack of the benzyl bromide on the 𝛼-imino rhodium carbine (Scheme 116).131 A rhodium(II)-catalysed or thermally induced intramolecular alkoxy group migration of N-sulfonyl-1,2,3-triazoles has been developed for the synthesis of 1,2-dihydroisoquinoline and 1-indanone derivatives. N-Sulfonyl keteneimine is the key intermediate for the synthesis of dihydroisoquinoline, whereas the aza-vinyl carbene intermediate results in the formation of 1-indanone (Scheme 117).132

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12 Molecular Rearrangements [Rh]

N N N Ms

NMs

[Rh]

Br

Br

Br

[Rh] NMs [Rh]

N

+

Br

Ms Scheme 116

R4

R4

3

R3

3

R

R

NR1

OR2

R4

+

NHR1

NR1 OR2

N N

O

RhII −N2

R4

R3

+

R4

R3

+

2

OR2

OR

−

−

Rh

N R1

Rh

N R1

Scheme 117

A rhodium(I)-catalysed reaction of (E)-1,6-enynes has been reported to undergo enantioselective cycloisomerization (Scheme 118).133 The treatment of benzylallene-substituted internal alkynes with [RhCl(CO)2 ]2 effects cycloisomerization by C(sp2 )–H bond activation to produce hexahydrophenanthrene derivatives. The reaction proceeds through formation of a rhodabicyclo[4.3.0] intermediate, 𝜎-bond metathesis between the C(sp2 )–H bond on the benzene ring and the C(sp2 )–Rh(III) bond, and isomerization between three 𝜎-, 𝜋-, and 𝜎-allylrhodium(III) species (Scheme 119).134

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742

Organic Reaction Mechanisms 2016 R1

R2

R1 R2

RhI/L*

* X

X X = NR2, O, C(CO2Et)2 Scheme 118

Y •

RhI

X

Y X

R1

R1 Scheme 119

Nitrone-directing groups have been explored in rhodium(III)-catalysed C–H activation of arenes and couplings with cyclopropenones. N-tert-Butyl nitrones with a small ortho substituent are coupled to give 1-naphthols, while nitrones with a bulky group follow a C–H acylation/[3 + 2] dipolar addition pathway to give bicyclics (Scheme 120).135 Ph

O [[RhCpCl2]2] AgSbF6

+ O– H

Ph

Ph

Ph OH

Scheme 120

The Rh(III)-catalysed oxidative C–H allylation of N-acetylbenzamides with 1,3dienes is reported. The presence of an allylic hydrogen cis to the less-substituted alkene of the 1,3-diene is important for reaction, and a mechanism involving an allyl-to-allyl 1,4-Rh(III) migration has been proposed (Scheme 121).136 An Rh-catalysed enantioselective cycloisomerization of 𝛼,𝜔-heptadienes to cyclohex3-enecarbaldehyde has been reported. Various 𝛼,𝛼-bisallylaldehydes rearrange to generate six-membered rings by a mechanism triggered by aldehyde C–H bond activation. Mechanistic studies suggest a pathway involving regioselective carbometallation and endocyclic 𝛽-hydride elimination (Scheme 122).137 A rearrangement of 3,3-dimethylcyclopropenylmethyl esters, catalysed by [Rh2 (OAc)4 ], proceeds through the rhodium carbenoid intermediate and gives alkylidenecyclopropanes that possess an enol carboxylate (Scheme 123).138

ee 

743

12 Molecular Rearrangements O Cl

O

NHAc Cu(OAc)2 [RhIII]

H

NHAc swap [Rh] H

+ Cl

H Ph Ph

O NHAc H Ph

Cl Scheme 121

O R

O R H

H

Rh/L*

H

Ar = L* =

But

PAr2

OMe

PAr2 But Scheme 122

A cationic rhodium(I)/BINAP complex has been reported as a catalyst for the cycloisomerization of 2-silylethynylphenols, leading to 3-silylbenzofurans via 1,2-silicon migration (Scheme 124).139 Skeletal reorganization of benzofused spiro[3.3]heptanes has been reported using rhodium(I) catalysts. The reaction of benzofused 2-(2-pyridylmethylene)spiro[3.3]

744

Organic Reaction Mechanisms 2016

R′′

3

2

R′′ 1

R′′ [Rh]

R

4

[Rh2(OAc)4]

H O

2

3

1

O

O

R′

R′′ 4

R

R

O

2

H

1 4

O

R′

R′

R′′

3

R

O R′

Scheme 123

C

C

SiR3

SiR3

R6

C

R5

X

Rh(I)+/ catalyst

XH

C H R4

X = O, NH Scheme 124

heptanes proceeds via sequential C–C bond oxidative addition and 𝛽-carbon elimination in contrast to benzofused spiro[3.3]heptan-2-ols which undergo two consecutive 𝛽-carbon elimination processes, in both cases, giving naphthalenes (Scheme 125).140 OH

R

R

Scheme 125

An Rh(II)/Brønsted acid-catalysed tandem benzannulation of oxindoles with enaldiazo carbonyls led to the formation of 1-hydroxy-2-acylcarbazoles and involves a formal insertion of a rhodium enalcarbenoid into an oxindole sp2 C–O bond, an oxa-Michael addition, Friedel–Crafts reaction, and a semi-pinacol-type 1,2-carbonyl migration (Scheme 126).141 O O N2 N O

R

O R

N

H

H Scheme 126

OH

745

12 Molecular Rearrangements

The Rh(II)-catalysed sulfur ylide [1,2]-rearrangement of carbenoids generated from aryldiazoacetates has been reported via N–S bond insertion. This is a sulfur ylide [1,2]rearrangement undergoing N–S bond insertion (Scheme 127).142 N2

O

O OR2

N O

SR +

OR2

Rh2(OAc)4

O R

O

1

N SR

Ar

O Scheme 127

Ruthenium A ruthenium complex has been reported to catalyse cycloisomerization of 2,2′ diethynylbiphenyls to 9-ethynylphenanthrenes cleaving the carbon–carbon triple bond of the original ethynyl group. A metal–vinylidene complex is generated from one of the two ethynyl groups, and its carbon–carbon double bond undergoes a 2 + 2-cycloaddition with the other ethynyl group to form a cyclobutene. The phenanthrene skeleton results from electrocyclic ring opening of the cyclobutene moiety (Scheme 128).143 1,3-Oxazaheterocycles have been reported by Ru–H/Brønsted acid catalysis in a reaction that involves a long distance chain-walking process. The acid is responsible for generation of an electrophilic iminium ion which is trapped intramolecularly by the alcohol (Scheme 129).144 A comparison of the Ru(II)-catalysed rearrangements of allenyl- and alkynylcyclopropanols to cyclopentenones has been reported (Scheme 130).145

Palladium An enantioselective method is reported with palladium catalysts that transform achiral allylic alcohols and N-tosylisocyanate into enantioenriched N-tosyl-protected allylic amines via an allylic carbamate intermediate. The latter can undergo a [3,3]-rearrangement (Scheme 131).146 When an allenic sulfone is treated with a palladium catalyst in the presence of a weak acid, isomerization to a 1-arylsulfonyl 1,3-diene has been reported to occur (Scheme 132).147 A carbonylative esterification reaction between aryl bromides and alcohols promoted by Pd/C and NaF in the presence of oxiranes occurs with the latter serving as a source of carbon monoxide by conversion to aldehydes through a palladium-promoted 1,2 hydride shift pathway (Scheme 133).148 A new method for the synthesis of benzoxepines via migratory insertion into a palladium carbene followed by C–C bond cleavage has been reported (Scheme 134).149 An intramolecular palladium-catalysed alkyne–alkyne coupling has been reported for the synthesis of a strained 1,3-bridged macrocyclic enyne (Scheme 135).150

ee 

746

Organic Reaction Mechanisms 2016

•

Ru

Ru

•

Ru

Scheme 128

R2

R1

OH

R1

p

R3

n

N m

O

RuH2(CO)(PPh3)3

p

m

R3

PG

R2

N

n

PG Scheme 129

O

OH •

R

R1

RuII InIII

OH RuII InIII

R1

R1 R Scheme 130

R

747

12 Molecular Rearrangements

O p-Ts

N H

p-Ts O

NH

+

p-Ts-NH2

Prn

Prn Scheme 131

ArO2S

ArO2S •

ArO2S

[Pd]

R2 [Pd–H]

R2

R2

R1

R1

R

1

Scheme 132

O

+

ArBr

R1

+

O

Pd/C

R2OH

base

Ar

O

R2

+

R1CH3

Scheme 133

NNHTs R

R

Ar

PdX

Ar

R

[Pd] Ar–X

O

O

EWG

O

EWG

EWG

Scheme 134

H

O

OAc

OAc

O

H

O

O

Scheme 135

748

Organic Reaction Mechanisms 2016

An oxy-palladation formal Wagner–Meerwein rearrangement and fluorination cascade has been reported for the preparation of fluorinated oxazolidine-2,4-diones and oxazolidin-2-ones. The reaction is initiated by anti-oxy-palladation of the alkene, followed by oxidative generation of an alkyl Pd(IV) intermediate and a concerted migration–fluorination (Scheme 136).151 F R

N

ButO

X Pd(OAc)2

R N

PdIV

R N

X

R′

O

O

O

F

O

O

R′

X

R′

X = CH2, CO Rm = alkyl, aryl Scheme 136

Spirocyclic imine derivatives have been reported by a Pd(II)-catalysed dearomatization reaction of N-aryl ureas with alkynes (Scheme 137).152 Ar H N

N

+

Ar

Ar

Ar Ar

Ar

[Pd]

N

N

O O Scheme 137

Platinum An enyne scaffold was reported using platinum catalysis to give regioselective cycloisomerizations to produce cyclopropane sesquiterpenoids A (Scheme 138).153

HO

HO O

H O O

Scheme 138

Silver A silver-catalysed cyclization of propargyl benzoates has been reported for the synthesis of pyran ring systems (Scheme 139).154

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749

12 Molecular Rearrangements

R′

R

OH

R′

* R′′

R * *

AgBF4

*

R′′

OBz * R′′′

O * R′′′

OBz Scheme 139

An AgOTf-catalysed [3,3]-sigmatropic rearrangement/1,3-H shift/6𝜋 azaelectrocyclization cascade reaction of N-propargylic hydrazones has been developed to provide a synthetic route to polysubstituted 1,6-dihydropyridazines (Scheme 140).155 R3

N

N

R2

R3

AgOTf

R4

R4

R1

N

N

R2 R1

Scheme 140

A silver-catalysed tandem reaction of tosylmethyl isocyanide with 2-methyleneindene1,3-diones has been reported to give benzo[f]indole-4,9-diones. The mechanism suggested involves 3 + 2-cycloaddition – imidoyl anion cyclization – ring opening of cyclopropanolate, and aromatization (Scheme 141).156 O

O R1

R2

+ CN

R1

AgOAc

C

Ts

O

R2 N H

O Scheme 141

A silver-catalysed isocyanide–isocyanide [3 + 2] cross-cycloaddition reaction has been reported to give 1,4,5-trisubstituted imidazoles. 1,2-Migration of sulfonyl, alkoxycaybonyl, and carbamoyl groups occurs during the cyclization process (Scheme 142).157 A synthesis of imidazoles by Ag2 CO3 -mediated coupling of vinyl azides with secondary amines allows the formation of three new C–N bonds by cascade reactions that involve sp3 C–H functionalization (Scheme 143).158 An AgOTf-catalysed tandem intramolecular transannulation of ((2-alkynyl)aryl) cyclopropyl ketones has been reported to give 2,3-dihydronaphtho[1,2-b]furans

750

Organic Reaction Mechanisms 2016

Ar

+

NC

CN

R

N [Ag]

R

N Ar

Y

Y

Y = Ts, CO2R, CONR1R2 Scheme 142

O N

+

NH

N3

Cl

O

N

Cl Scheme 143

O

Ar O

Ar 1

R

R1 R2

R2 Scheme 144

featuring a regioselective alkyne hydration, cyclopropylketone-2,3-dyhydrofuran rearrangement, and benzannulation (Scheme 144).159 Computational studies of silver-mediated geminal difluorination of styrenes demonstrate an ‘F-coordination’ model that is energetically preferred over the commonly accepted ‘O-coordination’ model (Scheme 145).160 F

I

O

+

F AgBF4

F Scheme 145

Named Reactions Alder-Ene A range of trifluoromethylthiolated benzolactams and benzolactones have been formed from 1,3,8-triynes and AgSCF3 via an initial Alder-ene reaction, 1,4-addition of

751

12 Molecular Rearrangements

AgSCF3 , and a series of bond-reorganizations that include double-bond migration, 6𝜋-electrocyclization, and a [1,3]-H shift (Scheme 146).161 R2

O

O

SCF3 R

AgSCF3

Z

R2 or

Z R

SCF3

O 2

Z

1

R3

R3

R3

R1

R1

Scheme 146

von Auwers 3-Methylene-1,4-cyclohexadienes possessing an alkoxycarbonyl substituent in position 6 have been reported to undergo thermal rearrangement and aromatization to provide arylacetates by a radical chain mechanism (Scheme 147).162 O

O

O

O Scheme 147

Bayer–Villiger 1,4-Benzoxazines have been synthesized by a Baeyer–Villiger oxidation reaction (Scheme 148).163 Ar

Ar N R

Ar NH

m-CPBA

N

R

O

N

N

N H

Ar

Scheme 148

Beckmann The Beckmann rearrangement of ketoximes has been reported mediated by ammonium persulfate–dimethyl sulfoxide and involves a radical pathway (Scheme 149).164 A microwave-assisted N-fluorobenzenesulfonimide/Lewis acid-catalysed Beckmann rearrangement has been reported (Scheme 149).165

752

Organic Reaction Mechanisms 2016 O

OH N

(NH4)2 S2O8

Ar/R Ar/R

R′/Ar′

N

R′/Ar′

H Scheme 149

Brook The combined regio- and stereo-selective carbometallation of cyclopropenyl amide, followed by the addition of an acyl silane, has been reported to give polysubstituted cyclopropyl diastereoisomers which on warming undergo Brook rearrangement with inversion of configuration to give enantiomeric-selective 𝛿-ketoamides (Scheme 150).166 A zinc-Brook rearrangement of enantiomerically enriched 𝛼-hydroxy allylsilanes has been reported to produce a chiral allylzinc intermediate which reacts with retention of configuration in the presence of an electrophile. A six-membered transition state leads to the transfer of chirality (Scheme 151).167 A stereospecific Brook rearrangement/trapping sequence initiated by the formation of a zinc alkoxide from an enantioenriched (hydroxyallyl)silane has been reported. The chiral carbanion resulting from the Brook rearrangement is trapped intermolecularly by carbonyl electrophiles with complete transfer of chirality (Scheme 152).168 A coupling reaction of 𝛼-ketoesters, imines, and diethyl phosphite under Brønsted base catalysis has been reported to involve generation of ester enolates via the chemo-selective addition of diethyl phosphite to give 𝛼-ketoesters followed by a [1,2]-phospha-Brook rearrangement and the trapping of the resulting enolates by imines (Scheme 153).169 A type II anion relay comprising a Brook rearrangement has been initiated by a stabilized tetrahedral intermediate generated by nucleophilic addition to a Weinreb amide (Scheme 154).170

Curtius A Curtius-like rearrangement of hydroxamates to isocyanates has been reported from a reaction initiated from an iron(II)–nitrenoid complex generated by the iron(II)-catalysed cleavage of N–O bonds of functionalized hydroxamates (Scheme 155).171

Friedel–Crafts o-Alkynyldihydrochalcones when treated with a catalytic amount of anhydrous FeCl3 in refluxing 1,2-dichloroethane are reported to undergo a tandem Conia–ene and Friedel–Crafts reactions to yield benzo[b]fluorene derivatives (Scheme 156).172

Hauser–Kraus Hauser–Kraus annulation of sulfonylphthalides with conjugated nitroalkenes furnishes naphthoquinones. However, by employing nitroalkenes bearing an additional nucleophilic site results in [4 + 4] annulation, leading to complex fused and spiro heterocycles

ee  de 

ee 

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753

12 Molecular Rearrangements

R3

O Me2N

R1 R2 O H3O+

O

NMe2 R3

O Me2N

R1

R1 R2 OSiR43

H2O

O

O

NMe2 R3

NMe2

R1

R1 R2

O

[M]

O

NMe2

[M]O

SiR43 1

O[M]

R2 R3

SiR43

R

R2 Scheme 150

OSiR43 R3

[M]

Me2N

R3 R1 R2 OSiR43

754

Organic Reaction Mechanisms 2016

OH H 3C

Et2Zn

Et2Zn

Et

OSiPh2Me

H3C

SiPh2Mn PhCOCl

MePh2SiO2

Et

CH3

Et Ph

H3C

CH3

O

CH3

Scheme 151

O Cy

OH

Cu-L*

SiPh2Me BuiMgBr Cy

OSiPh2Me

Et2Zn

SiPh2Me Bui

E

Cy

E+

Bui

E = carbonyl electrophiles Scheme 152

BnO2C − O

O

R1

BnO2C

H P(OEt)2

P(OEt)2 O

O

N

BnO2C − R1 R2

O

R1

HN

Ts

BnO2C H

R1

(EtO)2PO

P(OEt)2

Ts R2

O

O Scheme 153 −

ASG

O

O

Nu−

R1SO

ASG

SiR3 2

R

ASG

Brook

−

E+

R1SO

ASG

Nu

2

SiR3 2

Nu

R

E Nu

2

R

Scheme 154

H N

Ar

O

R1

O Scheme 155

Ar

N C O

R

755

12 Molecular Rearrangements

R3 R2

FeCl3

Ar/R

R1 Z

R3

R2 Ar/R

R1 Z

O

Z = H, CH(CO2Et)2 Scheme 156

through a cascade process involving Michael addition, Dieckmann cyclization, and a series of eliminations and rearrangements.173

Ichikawa An approach to 𝛼,𝛼-disubstituted 𝛼-amino acids has been reported that involves allyl cyanate-to-isocyanate rearrangement. The allyl isocyanates can be trapped with nucleophiles to provide N-functionalized allylamines (Scheme 157).174

R

O R

NH2 O

1. TFAA, TEA 2. Nu

O Nu: alcohols, amines, Grignard reagents, organolithium reagents

Nu

R

N H

O Nu

R

R R N H

OH O

Scheme 157

Kinugasa The regioselective reactions of fluorinated nitrones with alkynes (Kinugasa reaction) to give 𝛽-lactams were studied in the presence of Cu(I) iodide and TEA as a base and in the presence of enantiomerically pure ligands and result in enantiomerically enriched products (Scheme 158).175

ee 

756

Organic Reaction Mechanisms 2016 −

O

+

N

Bn

Ph

Bn

O

Bn

N

+

F3C

+ Ph

F3C

O N

F3C

Ph

Scheme 158

Lossen Aromatic and aliphatic hydroxamic acids have been reported to be converted to primary amines via a base-mediated rearrangement that involves an isocyanate intermediate (Scheme 159).176 O RNH2 R

NHOH Scheme 159

Divergent reactivity of an indole glucosinolate has been reported to give Lossen or Neber rearrangement products (Scheme 160).177 HO

HO

OCH3

N

•

HO HO

S

O MeO OH

S

•

Lossen type

N H repalexin A

TFA

N

OSO3

O

HO HO

O MeO

S

•N

Neber type

N I-Boc

K2CO3

N H

Scheme 160

Meyer–Schuster A regio- and chemo-selective oxidative cycloisomerization reaction of acyclic 1,5diynols gives benzo[b]fluorenones in a reaction considered to involve a Meyer–Schuster rearrangement combined with an oxidative radical cyclization (Scheme 161).178 A triazole acetyl gold(III) complex has been shown to be an effective catalyst in Meyer–Schuster rearrangement of propargyl alcohols (Scheme 162).179 A synthesis of azines via the reaction of propargyl alcohols and isatin hydrazones in the presence of iodine has been reported (Scheme 163).180

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12 Molecular Rearrangements HO

R4

O het

R1

het

DDQ

R3 R2

R

1

R4

het

het

R2

R3 Scheme 161

O

N

OH

Cl Au

O

Cl

Bu

O Bu

PicAuCl2

Scheme 162

Synthesis of Z-𝛽-aryl-𝛼,𝛽-unsaturated esters from 1-aryl-3-phenoxy propargyl alcohols has been reported via a BF3 -mediated syn-selective Meyer–Schuster rearrangement and considered to involve an electrophilic borylation of an allene intermediate as the key step to kinetically control the stereoselectivity (Scheme 164).181

de 

Michael A phosphine-catalysed intramolecular cyclization of 𝛼-nitroethylallenic esters has been reported for the stereoselective syntheses of (Z)-furan-2(3H)-one oxime derivatives and involves a phosphine-catalysed Michael addition of an alkylideneazinate and rearrangement of the cyclic nitronate to the 𝛼-nitrosodihydrofuran (Scheme 165).182

Newman–Kwart The thione–thiol Newman–Kwart rearrangement of di- and tetra(thiocarbamoyl) dinaphthylmethanes and octa(thiocarbamoyl)resorcinarenes has been reported to give cyclic and acyclic thioaromatic compounds (Scheme 166).183

Overman Sulfinyl trichloroacetamides result by a stereoselective Overman rearrangement; bisallylic substrates lead to amido 2-sulfinyl butadienes (Scheme 167).184

de 

758

Organic Reaction Mechanisms 2016

R4

R4 R3

4

R

N

R1

R4

I

R3

R4

OH I2 (2.5 equiv)

I2 (1.0 equiv)

+

N

N

R1

H

N

NH2

R1 N

R4

R3

N

O

N

R2

R2 N 2

R

Scheme 163

O

O

759

12 Molecular Rearrangements OH BF3 • OEt2

Ar

Ar

OEt O

OPh Scheme 164

R1

NO2 R1

HO MePh2P

R2

OR3 O

OR3

•

N

O

O R2

Scheme 165

S

S

S

S S

S S

S R

R

R

R

R=CH3CH2Ph Scheme 166

R2 O HO

R2

O

S

Cl3C p-Tol

R1

N

O

H

S

p-Tol

R1 Scheme 167

Piancatelli An organocatalytic enantioselective aza-Piancatelli rearrangement has been reported to give chiral 4-amino-2-cyclopentenone (Scheme 168).185 A catalytic asymmetric Piancatelli reaction using a chiral Brønsted acid of furylcarbinols with aniline derivatives gives aminocyclopentenones.186

ee  ee 

760

Organic Reaction Mechanisms 2016 OH

O

R

HA

H2O

A−

+

−

A

O

R′ NH2

+

+

O

R′H2N

R′HN

R

HO

R

R A−

H

R

O R

O

−HA

+

R′HN A

R +

4π conr

OH

R′HN +

−

A−

NHR′ Scheme 168

Pinacol A Prins pinacol-type rearrangement followed by C(4)–OBn participation in a cascade manner has been reported to provide access to tetrahydrofuran-fused bridged bicyclic ketals (Scheme 169).187

BnO

O OH

BnO

O

O +

BnO

O

H BnO

OBn (3)

O (5a)

Scheme 169

Pauson Khand The use of a Pauson–Khand reaction in synthesis has been reported.188

761

12 Molecular Rearrangements

N

O

N N N

TMSN3

Scheme 170

Schmidt The Schmidt reaction of TMSN3 with ketones in the presence of triflic acid has been reported to give tetrazoles (Scheme 170).189

Smiles A synthesis of indole-fused dibenzo[b,f][1,4]oxazepines from 2-(1H-indol-2-yl)phenol and 1,2-dihalobenzenes or 2-halonitroarenes has been reported and considered to involve a Smiles rearrangement (Scheme 171).190 Ar3 Z X

Z Ar3

Ar2

+

Ar1

N H

N

K3PO4

Ar2

Y

HO Z = CH, N

O

Ar1

X, Y = F, Cl, NO2 Scheme 171

Sommelet–Hauser The base-induced Sommelet–Hauser rearrangement of azetidine-2-carboxylic acid ester-derived ammonium salts to give 2-aryl-substituted derivatives has been reported. The ring-strain of four-membered N-heterocycles enables generation of the ylide intermediate (Scheme 172).191

CO2But +

N

CO2But OTf − ButOK

N

R1

R1 R3

R2

R3 Scheme 172

R2

762

Organic Reaction Mechanisms 2016

Stevens The construction of quaternary 𝛼-benzyl- and 𝛼-allyl-𝛼-methylamino cyclobutanones, via a sequential methylation/sigmatropic rearrangement, has been reported (Scheme 173).192 N

O

H N

Alk/Aryl

N

N O Ar

N

HN

Alk/Aryl Ar

NH2

N

Scheme 173

Arynes undergo a [2,3] Stevens rearrangement with tertiary allylic amines to give homoallylic amines with the nitrogen ylide intermediate generated by the N-arylation of allyl amines (Scheme 174).193

N

TMS

R

N

R

+ OTf Scheme 174

A [2,3]-Stevens rearrangement has been reported in a synthesis of octahydro-2H-2,8methanoquinolizines (Scheme 175).194

Suzuki–Miyaura A synthesis of triazolopyridopyrimidines via a Suzuki–Miyaura coupling has been reported (Scheme 176).195 Pyrimido[4,5-e]tetrazolo[5,1-b][1,3,4]thiadiazine derivatives have been prepared through heterocyclization of 5-bromo-4,6-dichloropyrimidine with sodium 1-amino1H-tetrazole-5-thiolate via an S–N-type Smiles rearrangement.196

763

12 Molecular Rearrangements

3′

1′ CO2Me 2′ − N I 2 1+

O

N N

H

NO2 CO2Me

Scheme 175

N N

Cl

N

(Het)ArB(OH)2

N

Pd0

N

N N

N

(Het)Aryl N

(Het)Aryl

or

N

N

N

N N

N

Scheme 176

Ugi An intermolecular Ugi reaction of 2-(1-(aminomethyl)cyclohexyl)acetic acid (gabapentin) with aromatic aldehydes and cyclohexyl isocyanide has been reported to give N-cyclohexyl-2-(3-oxo-2-azaspiro[4,5]decan-2-yl)-2-aryl acetamides (Scheme 177).197 R

HOOC

NH2

CHO +

+

N C

O

N O

HN

R R = H, 4-OH, CH3, OCH3, F, Br, Cl, 2-Cl, 3-OH, 4-NO 2, 3-NO2 Scheme 177

Wittig Treatment of aryl benzyl ethers with t-BuLi selectively gives organolithiums that can be trapped with electrophiles before they can undergo [1,2]-Wittig rearrangement. A concerted anionic intramolecular addition/elimination sequence and a radical dissociation/recombination sequence are suggested to explain the tendency of migration for aryl groups (Scheme 178).198

764

Organic Reaction Mechanisms 2016 E∗

Li

BunLi

Ph

O

E Ph

O Ph

O

Ph OLi Scheme 178

A squaramide-catalysed enantioselective organocatalytic [2,3]-rearrangement of oxindoles has been reported to give 3-hydroxy 3-substituted oxindoles (Scheme 179).199 Ar

Ar

R1

O N R2

Ar

HO

O

HO

R1

O N R2

+

R1

O N R2

Scheme 179

Computation The mechanisms of isonitrosoacetophenone with ethanolamine and 1-phenylethanolamine have been investigated computationally to establish why unexpected rearrangement products occur.200 A computational study of bispropargyl substrates – sulfone, sulfide, ether, amine, and methane – towards Garratt–Braverman cyclization has been reported.201 Computational studies have been presented to rationalize the reluctance of pyridinylidenes to undergo aromatization.202 Computational studies have been reported in an attempt to establish the role of protonated cyclopropane structures in carbocation rearrangements, and the authors conclude that intermediates are neither edge protonated nor corner protonated but are ‘closed’ structures mesomeric between these two.203 High-level computational studies have been reported to examine electrocyclic rearrangements involving a 1,2,4,6-heptatetraene skeleton to determine which, if any, are pseudopericyclic as opposed to pericyclic.204 Experimental and computational studies of atropisomerization of 7,8-diallyl-5-benzyl-7,8-dihydrodibenzo[e,g][1,4]diazocin6(5H)-one have been reported.205 The mechanism of NHC-catalysed annulation reactions involving an 𝛼,𝛽-unsaturated acyl azolium and 𝛽-naphthol has been studied using computational methods. The relative Gibbs free energy of stereoisomeric transition states, present in the 1,4-additions, accounts for the experimentally observed stereoselectivity.206 A computational study has been reported of allyl thiocyanates that undergo sigmatropic rearrangement including the rearrangement of 1-[(E)-3thiocyanoprop-1-en-1-yl]adamantane to 1-(1-isothiocyanoprop-2-en-1-yl)adamantine (Scheme 180).207

ee 

765

12 Molecular Rearrangements N C SCN

NCS S CH2

−

Δ

or

and

Br

SCN

−

+

NCS

Scheme 180

Computational studies of gold-catalysed rearrangement of propargylic esters that can result in 1,3-acyloxy migration to form allenes, or undergo 1,2-acyloxy migration to access gold-carbenoids, have been reported to rationalize the rearrangement selectivity. Substrates with a major resonance contributor A prefer 5-exo-dig cyclization (1,2-migration), while those with a major resonance contributor B prefer 6-endo-dig cyclization (1,3-migration) (Scheme 181).208 A

CH4

O

5-oxo-dig cyclization

O

O

O

O

Au

+

Me

But

6-endo-dig cyclization

+

Au

CO2Me

O

BH3

H

R3

+

Au

R3

Cl CF3

R3

OMe

Scheme 181

Heathcock’s amazing cyclization/rearrangement cascade for formation of Daphniphyllum alkaloids has been studied by computational methods which are consistent with a two-step pathway involving a Diels–Alder cycloaddition and an ene reaction (Scheme 182).209

Miscellaneous The use of sugar-based ligands on asymmetric transfer hydrogenation for synthesizing enantiopure alcohols has been reviewed.52 An enantioselective two-step protocol for the synthesis of 1H-pyrrol-3(2H)-one derivatives from 2,3-diketoesters has been reported (Scheme 183).210

ee 

766

Organic Reaction Mechanisms 2016 R

R

+

N +

N

Scheme 182

O

R2O2C

O

O OR2

R1

+

L-proline

HO OH

R2O2C

H X

R1OC OH

X

+ R1OC OH

O

X

H

O

Scheme 183

Treatment of methyl 4,6-diaryl-5-oxa-6-azaspiro[2.4]heptane-1-carboxylates with zinc in acetic acid leads to cleavage of the N–O bond in the isoxazolidine ring and formation of 1,3-amino alcohols that cyclize to give bi- or tri-cyclic lactams or lactones with retention of the three-membered ring (Scheme 184).211 H H H

O

COOMe H

Ph

Cl

N MeOC(O) HO

Ph

NHPh

Ph +

Cl Ph

Cl

O O

H NHPh

Scheme 184

Azidocyanation of unactivated alkenes has been reported by intramolecular distal cyano migration combined with alkene difunctionalization (Scheme 185).212 A fluoride-anion-induced, regioselective ring expansion of benzocyclic ketones and 𝛼-aryl cycloketones has been reported to occur via insertion of arynes into unactivated benzylic C–C bonds to give medium ring-fused benzocarbocycles (Scheme 186).213 Coupling of arynes, aromatic tertiary amines, and CO2 has been reported to give 2arylamino benzoates via a nitrogen to oxygen alkyl migration or 2-aminoaryl benzoates by aryl to aryl amino group migration, depending on the substitution of the amines (Scheme 187).214

767

12 Molecular Rearrangements

O

HO CN N3

R

R

R′

n

N3

+

R′

n

CN Scheme 185

n

O

O TMS

+

F

+

or

O

n

or

TfO

O

Ar n

n

Ar n = 1, 2 Scheme 186

R3 N R

R2 O

O

R1

F−

R2

TMS +

R

N

R3

OTf

R1 = electron-poor groups

R1

CO2 F−

O

R2 O

R N

R3

R1 R1 = electron-rich/neutral groups Scheme 187

768

Organic Reaction Mechanisms 2016

A bench-stable cyclic hypervalent iodine(III) fluoro reagent has been used for the preparation of 4-fluoro-1,3-benzoxazepines starting from styrenes. The reaction is thought to proceed by an unusual fluorination/1,2-aryl migration/cyclization cascade (Scheme 188).215 R3

R4

R5 R3

R4

F

+

R5

O

NH

R2

R2 R1

N

R1

O Scheme 188

A formal [1 + 4]-annulation of 𝛼-dicarbonyl compounds with 1,1-dicyano-1,3-dienes has been reported to give cyclopentenimines and cyclopentenones through a P(NMe2 )3 mediated cyclopropanation followed by a base-catalysed cyclopropane rearrangement (Scheme 189).216 Ar2 O

NC

O

CN

+ 1

2

R

R

CN

P(NMe2)3

Ar2

NH

Ar1

Ar1

R1 COR2

Scheme 189

N-Linked benzamidines have been prepared from a regiospecific rearrangement of quinazolinones (Scheme 190).217 O

O

O R

HO X

Ph

N

H3C

X BOC

X = CH2 or O n = 1.2

Ph

N

N

n

N

N H

R

N

n

NHCH3

X

CH3

n

Scheme 190

Zinc-catalysed [4 + 2]-annulation reactions of disubstituted N-hydroxy allenylamines with nitrosoarenes are reported to give 1,2-oxazinan-3-ones. Nitrosobenzene can also

769

12 Molecular Rearrangements

HN

R2 •

OH

+

R1

N Ar

O N

Lewis acid

O

R2

R

Ar

N

R1

R

O Scheme 191

implement this annulation through a radical annulation path, but Zn(OTf)2 or AgOTf improves the efficiency of the [4 + 2]-annulation (Scheme 191).218 The synthesis of 1,2,3-triazole derivatives and 1,2,3-triazolium salts that contain an organometallic group at the N-1, N-2, or N-3 position has been reported (Scheme 192).219 Ph

Ph RI

N N

Mn(CO)3

N

Δ

N

Mn(CO)3

(1)

+

N I−

N

Ph +

R

+

N

R

N

( 2)

N

(3)

R I−

Scheme 192

A synthesis of N-(2-hydroxyaryl)benzotriazoles via O-arylation of Nhydroxybenzotriazoles with diaryliodonium salts and sequential N–O bond cleavage has been reported. The [3,3]-rearrangement of N–O bond cleavage is reported to take place on N rather than C (Scheme 193).220

R C

N3 Ar2IOTf N2 N OH

R C

N3 N2 N 1 O

C [3,3]

N N

R N

3′

OH

1′ 2′

R1

R1

Scheme 193

The preparation of 3,3-disubstituted 2-oxindoles from 2-substituted indoles has been reported to involve an iminium-intermediate-triggered 1,2-rearrangement and requires a trace amount of water for subsequent oxidation (Scheme 194).221 The synthesis of trans-oxazolidines by the regio- and stereo-controlled reaction of NHketoaziridines with phenylisocyanate has been reported and a mechanism proposed.222 Aryl- or vinyl-substituted bis-propargyl ethers upon treatment with base generally form

770

Organic Reaction Mechanisms 2016 alkyl/aryl

aryl/alkyl

Y

Y

O

N

N

R

R

R = alkyl, aryl, H Y = hydroxymethyl, ester, aldehyde, ketone Scheme 194

phthalans, but it is reported that several aryl/vinyl bis-propargyl ethers with one of the acetylenic arms with 2-tetrahydropyranyloxy methyl or ethoxy methyl groups have been shown to undergo an intramolecular 1,5-H shift pathway (Scheme 195).223

O R

KOBut

X

R

O

X + O

R X Scheme 195

3-Diphenylprop-2-yn-1-one has been inserted into 3-substituted imidazo[4,5b]pyridines to give pyrido[2,3-b][1,4]diazocin-9-ones (Scheme 196).224 The insertion of alkynes into carbon–carbon 𝜎-bonds of unstrained cyclic 𝛽-dicarbonyl compounds has been reported (Scheme 197).225 Cleavage of the carbon–carbon triple bonds of alkynes has been reported leading to arylnitriles (Scheme 198).226 A cascade trifunctionalization of alkynoates with N-iodosuccinimide has been reported to preceed through iodination, aryl migration, and decarboxylation followed by a second iodination (Scheme 199).227 The synthesis of coumarin derivatives by Brønsted acid-mediated condensation and intramolecular cyclization of phenols and propiolic acids has been reported (Scheme 200).228

771

12 Molecular Rearrangements

O

N +

N

+

Ph

N

H 2O

Ph

R = Me, Bn R Ph

Ph

Ph

N

N +

N

Ph

N R

H

O

N R

N

O O Scheme 196

O H1

R2 +

O O

O

OEt

R2

O OEt

Cs2C3

R1 HO

Scheme 197

N + ButONO

BnNHCH3

Scheme 198

The reaction of 𝛼,𝛽-disubstituted (E)-o-(trimethylsilylethynyl)styrenes with a diisobutylaluminum hydride has been reported to give 1,2,3-trisubstituted naphthalenes. The benzocyclization is initiated by hydroalumination of the alkyne and gives naphthalenes through intramolecular carboalumination, skeletal rearrangement, and dehydroalumination (Scheme 201).229 The rearrangement of 4-oxobutane-1,1,2,2-tetracarbonitriles to give the penta-1,3diene-1,1,3-tricarbonitrile moiety, accompanied by elongation of the carbon chain via

772

Organic Reaction Mechanisms 2016 I R1

I

O O

R2

+

N

+

R2

I

CO2

O O

R1 R1 = aryl, alkyl

Scheme 199

R2

O R1

+

TfOH

HO

R1

OH

R2

O

O

Scheme 200

R2

R1

R1

R1

R2

R2 DIBAL-H

Al SiMe3

SiMe3

SiMe3 Al = Bu2i Al Scheme 201

CN NC C O

CN CN

CN

AcONH4

CN CN

CN

N O

NH2 HO

N H

CN

Scheme 202

introduction of the cyano group carbon atom to the carbon skeleton, has been reported (Scheme 202).230 The synthesis of cyclopentene-fused chromene derivatives from strained phenolsubstituted fulvene-derived bicyclic hydrazines has been reported proceeding through base catalysed sequential intramolecular ring opening and ring closure of azabicyclic akenes (Scheme 203).231

773

12 Molecular Rearrangements R

− N E

OH

OH

N

N

+

N E

E

E Pri,

But,

E = CO2Et, CO2 CO2 CO2Bn R = H, Me, But, OMe, Cl, Br, NO2

EHN

N E

R O

H

Scheme 203

6-Amino-2,3-dihydro-4-pyridinethiones have been reported from N-(3-butenyl) thioureas. The thioureas are transformed into iodocyclothiocarbamates which subsequently give cyclic thioenol esters after base-mediated HI elimination. These esters readily undergo a base-mediated thioenolate–carbodiimide rearrangement, accompanied by C–S bond cleavage and C–C bond formation, to finally give 6-amino-2,3-dihydropyridine-4thiones (Scheme 204).232 The synthesis and base-mediated rearrangement of 3-acetyl-2-methyl-3,4-dihydro2H-1,2,3-benzothiadiazine 1,1-dioxides have been reported (Scheme 205).233 A base-promoted ring expansion of 3-amino-4-hydroxyhexahydropyrimidine-2thiones to give 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones has been reported to proceed through the fast formation of intermediate acyclic isomers of pyrimidines followed by slow cyclization into triazepines (Scheme 206).234 A synthesis of 6-amino-2,3-dihydro-4-pyridinones from homoallylamines involving NBS-mediated cyclization of N-(3-butenyl)ureas to 6-(bromomethyl)-2iminourethanes, dehydrohalogenation, and subsequent rearrangement has been reported (Scheme 207).235 Two core-switching rearrangements to natural product-like scaffolds have been reported and the deviation from planarity of the central N-acyl urea carbonyl suggested to dictate the reaction outcome (Scheme 208).236 A transformation has been reported of 3-furylphthalides into 3-(3-oxoalkyl) isocoumarins mediated by a red phosphorus/iodine system (Scheme 209).237

774

Organic Reaction Mechanisms 2016

S S N H

R2

S

1. I2

R1 N H

R3

R1

2. DIPEA

N H

R2

N

R3

R1 R2

NHR3

N H

ButOK

S− K+

S R1

N− K+

N

R2

R1 R2

R3

N

•

NR3

Scheme 204

Cl Cl

O O S NH N R

R = H, Me, Et, Ph

2. acetylation

Cl Cl

1. reduction

O O O S N

Cl Cl

N R

Cl

O O S N

O O

Cl

S N

N O

R

O

R O

Scheme 205

NH

775

12 Molecular Rearrangements

R3

R1 R S

C

N

N2H+

O

R1

OH

R

R3 N

R3

R2

R2

R2

R1 R

Base

N

H

N HN

NH2 S

NH S

Scheme 206

O O

R1

1. NBS

N

R2

N

R3 2. tBnok

R1 NHR3

N

R2

H Scheme 207

O

O

O OH

O N

N

Nu−

N

O

N

O O

Nu

Scheme 208

R O O R O

O O O Scheme 209

References 1 2 3 4

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780 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219

220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237

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Author Index In this index bold figures relate to chapter numbers, roman figures are reference numbers.

A Abaev, V.T., 12, 237 Abba, H., 1, 164 Abbasi, F., 1, 255; 10, 94 Abbiati, G., 4, 131; 5, 564; 7, 76; 10, 364 Abdel-Halim, H.M., 3, 24 Abdel-Maksoud, K., 3, 357; 10, 114 Abdi, S.H.R., 1, 119; 5, 250 Abdoli-Senejani, M., 10, 94 Abe, T., 12, 24 Abi, T.G., 5, 420 Abilov, Z.A., 5, 581 Abozeid, M.A., 3, 260 Abrams, D.J., 1, 385 Abrams, M.L., 3, 278 Ábrányi-Balogh, P., 2, 16; 4, 45 Abualreish, M.J.A., 3, 145 Acerete, R., 6, 50 Achard, T., 1, 3; 4, 105 Acharya, A., 6, 79; 11, 61, 63 Achrainer, F., 7, 36 Ackermann, L., 3, 96, 303; 5, 291, 326, 378, 382, 481, 545, 552 Acocella, M.R., 1, 179 Adamek, J., 11, 71 Adamkiewicz, A., 1, 95; 3, 467 Adamo, M.F.A., 10, 553 Addante, V., 8, 44 Addy, P.S., 12, 223 Adeel, M., 5, 354 Adei, E., 3, 71, 344 Adib, M., 1, 71 Adili, A., 1, 212; 10, 184 Adimurthy, S., 4, 56 Adiyala, P.R., 12, 158 Adly, F.G., 4, 86 Adolfsson, H., 3, 474 Adomeit, S., 1, 280; 9, 18 Adrio, J., 11, 37 Affron, D.P., 5, 341 Afonin, A.V., 4, 177; 10, 439, 445; 12, 224 Agapie, T., 5, 278 Agarwal, R., 3, 209

Agasti, S., 5, 413 Agbossou-Niedercorn, F., 3, 389; 10, 37 Aggarwal, T., 5, 437; 10, 216 Aggarwal, V.K., 7, 126 Agrawal, A., 3, 18 Aguilar-Calderon, J.R., 3, 341 Ahamed, A.J., 11, 50 Ahlemeyer, N.A., 9, 38 Ahmed, B.M., 8, 1, 116 Ahmed, I., 3, 344 Ahmed, Q.N., 1, 309 Ahmed, S., 5, 581 Ahuja, B.B., 3, 475 Aida, Y., 11, 146, 147 Aihara, Y., 3, 27; 5, 379; 10, 341 Aikawa, K., 5, 308, 309 Aillerie, A., 3, 455 Aissa, A., 3, 145 Aithangani, S.K., 5, 49 Aitken, D.J., 10, 575 Aizpurua, J.M., 3, 78 Ajitha, M.J., 5, 163 Akagawa, K., 10, 502 Akazome, M., 10, 65 Akbar, S., 5, 221; 12, 172 Akdag, A., 10, 647 Akhmedov, N.G., 5, 427; 10, 128, 145, 282, 367; 12, 125 Akimoto, R., 7, 47; 8, 50 Akiyama, T., 1, 49; 3, 498; 5, 444 Akula, R., 9, 30 Alabugin, I.V., 1, 5; 10, 369; 12, 111 Alahmdi, M., 3, 140 Alam, M.I., 9, 7, 8 Alami, M., 5, 155 Alamsetti, S.K., 10, 642 Alanthadka, A., 3, 251; 4, 159 Alarcon, K., 5, 37 Albanov, A.I., 10, 445 Al-Bonayan, A., 3, 119 Albrecht, M., 5, 89 Albugin, I.V., 6, 71 Alcazar, J.J., 9, 12, 15 Al-Duaij, O.K., 11, 74 Alemán, J., 1, 50; 10, 513

Organic Reaction Mechanisms 2016, First Edition. Edited by A. C. Knipe. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

781

Alexakis, A., 10, 510 Alexy, E.J., 7, 20; 12, 8 Alfahemi, J., 3, 9 Alfahmi, J., 3, 66 Alford, J.S., 4, 91 Algarra, M., 5, 91 Al-Ghreizat, S.K., 3, 24 Alhaji, N.M.I., 3, 1, 2 Al-hunaiti, A., 3, 117 Ali, M.A., 5, 183 Aliaga, M.E., 5, 37 Aliakbar, K., 4, 143 Alimova, A.Z., 7, 105 Ali Tabarki, M., 10, 89 Alivaisi, R., 10, 447 Al-Jaroudi, Z., 1, 64 Allain, M., 5, 238 Allan, J.E., 3, 264 Allard, E., 10, 618; 11, 83 Allegretti, P.A., 4, 139; 10, 228 Allen, C., 3, 479 Allen, L.A.T., 12, 59 Allin, S.M., 3, 143 Al-Lohedan, H.A., 3, 306 Allu, S., 4, 81 Allu, S.R., 5, 114 Almallah, Z., 3, 119 Almansour, A.I., 3, 43 Al-Mourabit, A., 3, 488; 5, 44 Almstead, D.K., 6, 114; 7, 100 Alnasleh, B.K., 10, 656 Al-Othman, Z.A., 3, 306 Alper, H., 11, 125 Al Quntar, A.A.A., 7, 154; 10, 596 Alt, I.T., 5, 168 Altass, H.M., 3, 105 Althagafi, I., 3, 9, 66, 67 Altman, R.A., 1, 322 Alvarado, C., 1, 50 Alvarez, E., 1, 85; 3, 458; 5, 465 Alvarez, R., 1, 251; 5, 257 Alvarez, S., 5, 257 Alvarez-Casao, Y., 5, 465 Alvaro, C.E.S., 5, 41 Alves, M.J., 1, 122; 11, 122 Alves, T.M.F., 3, 304

782 Alwarsh, S., 12, 57 Aly, A.A., 10, 555 Alzueta, M.U., 3, 273 Amaiz, L.V., 9, 15 Amant, A.H.S., 5, 46 Amarante, G.W., 1, 96; 10, 474 Amarasekara, A.S., 1, 253 Amaro-Luis, J.M., 6, 91; 12, 46 Amatore, M., 5, 565 Amaya, T., 3, 279 Ambrosi, M., 1, 311 Ametovski, A., 4, 224 Amiri, M.A., 1, 250 Ammar, H.B., 5, 588 Amr, F.I., 1, 120 Amzallag, V., 4, 140 An, F., 4, 141 An, K., 5, 304 An, R., 10, 83 An, W., 3, 283 An, X.-M., 10, 412; 12, 155 An, Y., 10, 213; 11, 163 An, Z., 5, 163 Anami, T., 5, 446; 10, 217 Anand, M., 5, 175 Anand, R.V., 4, 160; 10, 463 Ananda, S., 3, 121 Anary-Abbasinejad, M., 1, 252 Anbarasan, P., 3, 29 Anbarasan, S., 3, 15 Anderson, C.E., 12, 114 Andersson, P.G., 3, 77, 386 Andò, S., 10, 209 Ando, H., 1, 19 Ando, M., 1, 38; 3, 271 Ando, W., 10, 154 Andreev, P.Y., 3, 214 Andreini, M., 10, 557 Andrés, J.M., 1, 77; 10, 573 Andres, P., 12, 21 Andrew, J.P., 12, 59 Andrews, B.I., 7, 110 Andriyankova, L.V., 4, 177; 10, 439; 12, 224 Aneesh, P.V., 6, 106 Anezaki, S., 4, 228; 7, 33 Angnes, R.A., 5, 354 Anilkumar, G., 3, 219; 5, 420; 7, 59 Anitha, T., 3, 240 Anjaiah, B., 5, 128 Anju, R.S., 10, 608 Annadi, K., 4, 14 Anneser, M.R., 1, 278; 4, 203 Annunziata, R., 3, 468 Ano, T., 5, 368; 10, 329 Anoop, A., 12, 201, 223 Antenucci, A., 10, 537 Antol, I., 6, 23

Author Index Antonchick, A.P., 1, 356; 4, 252; 11, 42 Antoniotti, S., 1, 308 Antonov, A.S., 5, 45 Antonov, D.Y., 3, 47 Anumandla, D., 11, 63 Aoki, T., 12, 70 Aono, T., 4, 51; 11, 165 Aoyama, H., 12, 64 Aponick, A., 5, 354 Arai, T., 3, 402; 5, 547; 11, 39 Araque, M., 3, 389 Arcadi, A., 3, 59; 10, 383 Archambeau, A., 12, 138 Arda, A., 6, 51 Arde, P., 4, 160; 10, 463 Arguelles, A.J., 1, 28; 6, 109 Ariafard, A., 1, 380; 3, 495; 5, 224, 540; 10, 359 Ariga, G.G., 3, 51 Arii, H., 6, 36 Arimitsu, K., 3, 226, 257 Ariyama, K., 3, 459 Arlow, S.I., 5, 307 Arman, H., 1, 70; 4, 61, 84; 11, 126, 162; 12, 119, 210 Arman, H.D., 1, 53 Armand, J.R., 5, 136 Armenise, N., 3, 320 Armenta, F., 5, 126 Armstrong, A., 1, 173; 5, 54 Armstrong, D.R., 1, 176 Armylisas, A.H.N., 3, 140 Arndt, H.-D., 2, 21 Arndt, S., 5, 540; 6, 70; 12, 112 Arndtsen, B.A., 3, 293; 5, 499 Arnó, M., 4, 172; 12, 206 Arnold, A.M., 3, 151; 8, 120; 10, 78; 12, 215 Arnold, N., 4, 259 Arokianathar, J.N., 5, 478 Aronoff, M.R., 11, 66 Arora, R., 4, 41 Arpa, E.M., 1, 50 Arriola, D.J., 5, 84 Arteaga, F.A., 1, 65 Arthoba Nayaka, Y., 3, 165 Artigas, M.J., 4, 208; 10, 251 Aruma, A.N., 10, 429 Arumugam, N., 3, 43 Asachenko, A.F., 4, 190; 5, 64 Asada, T., 4, 161 Asadbegi, S., 10, 421 Asami, M., 1, 263; 4, 228; 7, 33; 8, 61 Asao, N., 3, 109 Ascic, E., 5, 256; 6, 107 Asensio, G., 6, 50 Asghar, B.H., 3, 105 Ashe, M., 7, 94; 10, 508

Ashley, A.E., 3, 379 Ashley, M.A., 1, 307 Ashokkumar, V., 1, 181 Ashtekar, K.D., 10, 32; 11, 130 Asiri, A.M., 3, 146, 167 Asmus, S., 5, 83; 10, 657 Assaleh, F.H., 2, 1 Assempour, N., 3, 256; 12, 163 Ataualpa, A.C., 5, 392 Athimoolam, S., 1, 309 Atman, N.V., 3, 47 Atodiresei, I., 12, 186 Atzrodt, J., 5, 282 Au, C.-T., 7, 111 Aubé, J., 5, 268; 12, 189, 217 Aubert, C., 5, 565 Audran, G., 6, 15 Augros, D., 5, 119, 120 Augur, D.J., 7, 125 Aurell, M.J., 4, 172; 12, 206 Aursnes, M., 10, 36, 68 Avadhani, A.S., 2, 9 Avalani, J.R., 10, 453 Avello, M.G., 4, 136; 12, 118 Avenoza, A., 10, 455 Avila, E.P., 1, 96 Aviyente, V., 1, 117; 10, 26 Avrorin, V.V., 6, 3 Awata, A., 11, 39 Ayala, C.E., 6, 40, 82 Aydillo, C., 10, 455 Aylward, N., 4, 240; 12, 81 Ayub, K., 1, 276; 3, 227, 250, 478; 8, 25; 9, 17 Ayugase, T., 1, 259 Ayyagari, N., 5, 205; 10, 561 Azad, C.S., 10, 569 Azizi, N., 10, 94 Azizian, J., 1, 43 Azizoglu, A., 9, 43 Azizollahi, H., 5, 38 Azizollahia, H., 12, 196 Azum, N., 3, 167 Azumaya, I., 7, 124

B Ba, F., 5, 434; 10, 415 Baba, A., 7, 102; 9, 26; 10, 410 BabaAhmadi, R., 3, 495 Babinszki, B., 5, 48 Babu, K.R., 10, 434 Babu, M.H., 12, 181 Babu, S.A., 5, 144 Baceiredo, A., 4, 260, 261 Bach, T., 5, 328; 11, 10 Bachle, F., 1, 202 Back, D.F., 5, 433; 10, 88 Bäckvall, J.-E., 3, 77, 82; 7, 55; 10, 148, 220, 223 Baczko, K., 10, 618; 11, 83

783

Author Index Badani, P.M., 11, 96 Badiola, E., 10, 472 Badji´c, J.D., 10, 44 Bae, J.M., 3, 253 Baell, J.B., 5, 21 Bag, S., 5, 413; 11, 4 Bagga, M.M., 10, 324 Bagherzadeh, S., 1, 295; 4, 185 Bagi, A.H., 5, 540 Bagle, P.N., 6, 75; 10, 400 Baglioni, P., 1, 311 Bagryanskaya, I.Y., 4, 177; 10, 439; 12, 224 Bähr, S., 10, 417 Bahrami, H., 3, 16 Bahri, J., 10, 309 Bai, B., 3, 328 Bai, D.-C., 1, 211; 4, 196 Bai, L., 11, 6 Bai, R., 1, 384 Bai, S., 4, 68; 5, 559 Bai, X., 3, 485; 5, 94; 9, 47; 10, 320 Bai, X.-F., 10, 485; 11, 45 Bai, X.-Y., 10, 645, 646 Bai, Y.-B., 1, 296 Bai, Z.-J., 1, 159 Baidoo, J., 3, 71 Baidoo, K., 5, 85 Baidya, M., 5, 156, 171 Baiju, T.V., 10, 246; 12, 231 Baik, M.-H., 5, 190 Bailey, W.F., 3, 127; 9, 48 Baimuratov, M.R., 12, 207 Baire, B., 10, 105; 12, 90, 91 Bajaj, H.C., 1, 119; 5, 250 Bakalbassis, E.G., 11, 139 Bakavoli, M., 5, 38 Bakavolia, M., 12, 196 Baker, R.T., 4, 178 Bakhtin, S.G., 7, 69 Bakkali-Hassani, C., 4, 157 Bakó, P., 10, 468 Bakulev, V.A., 11, 77 Bal, W., 2, 23 Bala, M.D., 5, 63 Bala, R.S., 3, 211 Balakrishna, B., 1, 91; 3, 392 Balamurugan, R., 8, 46 Balan, G.A., 3, 114 Balanta, A., 10, 125 Balaraman, E., 5, 425, 426 Balasubramanian, S., 10, 470 Balci, E., 10, 390 Balci, M., 10, 647; 11, 58 Ballesteros, A., 1, 39; 10, 397 Bamberger, J., 5, 83; 10, 657 Bandini, M., 1, 172; 8, 111; 10, 22 Bandosz, T.J., 5, 91

Banerjee, A., 3, 35; 5, 59, 134 Banerjee, D., 3, 244; 10, 220 Banerjee, P., 7, 83 Banik, B.K., 7, 148 Banik, S.M., 10, 71, 76 Bantreil, X., 10, 406; 12, 54 Bao, M., 3, 43; 11, 120 Bao, X., 8, 122, 123; 10, 197 Bao, Z., 3, 243 Baralle, A., 4, 189; 5, 71, 415 Barattucci, A., 11, 95 Barber, J.S., 11, 67 Barbero, A., 6, 66 Barbero, M., 10, 598 Barbier, V., 1, 365 Barbieri, A., 3, 115, 116 Barbosa, Q.P.S., 1, 226 Barcellos, J.C.F., 10, 436 Barham, J.P., 5, 10 Barik, S., 5, 250 Barison, A., 2, 29 Barnes, C.L., 7, 61 Barone, I., 10, 209 Barrio, P., 10, 358 Barrios Antúnez, D.-J., 8, 10; 10, 522 Barroso, R., 4, 36 Barroso, S., 5, 195 Barroso-Flores, J., 12, 202 Barsu, N., 5, 381; 8, 105; 9, 37; 10, 337 Bartelson, A.L., 3, 127 Bartlett, C.J., 3, 143 Bartoccini, F., 3, 262 Bartok, M., 1, 182 Bartolotti, L., 10, 90 Baruah, P.K., 3, 188 Baruah, S., 3, 87 Basak, A., 1, 174; 11, 4; 12, 223 Bashpa, P., 3, 159 Basnet, P., 5, 319 Bassu, N., 5, 566 Batashev, S.A., 10, 168 Bateman, L.M., 3, 55 Batista, G.M.F., 10, 474 Batsyts, S., 10, 452 Baudoin, O., 1, 150 Bauer, J.M., 12, 146 Baumann, C., 5, 318 Baumgartel, P.G., 7, 125 Bauza, A., 1, 91; 3, 392 Bayle, A., 8, 133 Bayrak, C., 12, 26 Beaud, R., 5, 220; 10, 326 Beaver, M.G., 6, 53 Becerra-Cely, L., 7, 156 Bechtoldt, A., 3, 96 Beck, T.M., 8, 12; 10, 252, 253 Beckendorf, S., 5, 83; 10, 657 Becker, J., 12, 60

Becker, P., 5, 226; 10, 104 Bedell, T.A., 10, 473 Bedford, R.B., 7, 168 Bedini, E., 1, 18 Bégué, D., 4, 238, 243; 12, 84, 85 Behera, T.K., 12, 31 Behrends, I., 10, 417 Beier, P., 8, 124 Beiger, J.J., 1, 319; 5, 346 Bekker, A., 5, 194 Belaid, S., 5, 155 Belanzoni, P., 4, 211; 10, 360 Belaud-Rotureau, M., 5, 73 Belen’kii, L.I., 5, 13, 14 Beletskaya, I.P., 5, 87 Belhomme, M.-C., 4, 114 Beliaev, N.A., 11, 77 Belikov, M.Y., 12, 230 Belitz, F., 5, 489 Bella, M., 10, 537 Beller, G., 3, 142 Beller, M., 3, 382, 405; 10, 167 Bellina, F., 5, 571, 577 Bellomo, A., 5, 390; 7, 39, 40 Bellows, S.M., 3, 380 Belmont, P., 10, 406; 12, 54 Belmore, K., 12, 145 Beloomo, A., 1, 135 Belpassi, L., 4, 211; 10, 360 Beltran, R., 10, 55 Belyaeva, K.V., 4, 177; 10, 439; 12, 224 Benaglia, M., 1, 168; 3, 468 Bender, C.F., 10, 226 Bengali, A.A., 5, 499 Bengtsson, C., 7, 167 Benharref, A., 4, 19, 20; 12, 195 Benischke, A.D., 5, 336 Benkö, Z., 4, 163; 12, 83 Benmahdjoub, S., 5, 155 Bennasar, M.-L., 4, 115 Bennet, A.J., 7, 97 Benohoud, M., 10, 496 Benoit, D.M., 10, 125 Benoit, E., 7, 53 Bentabed-Ababsa, G., 5, 275 Bera, S., 1, 30; 4, 225 Bergero, F.D., 5, 41 Berges, J., 5, 6 Bergman, J., 7, 167 Berhault, Y., 5, 277 Berionni, G., 6, 9 Berkessa, S.C., 3, 230 Berkovitz, T., 1, 199 Bernárdez, R., 12, 144 Bernardo, C.E.P., 1, 360 Bernhardt, P.V., 11, 169 Beromi, M.M., 5, 472 Beronzini, G., 8, 108 Berritt, S., 1, 135; 5, 390

784 Berry, J.F., 4, 249 Berski, S., 12, 16 Berthel, J.H.J., 5, 477 Berthelot-Brehier, A., 5, 119, 120 Berthet, J.-C., 3, 362 Berton, J.K.E.T., 10, 660 Bertounesque, E., 8, 118 Bertrand, G., 4, 10, 163, 181; 10, 297; 12, 83 Besbes, R., 10, 89 Besnard, C., 10, 510 Besora, M., 11, 135 Bespal’ko, Y.N., 7, 69 Besset, T., 8, 133 Bettadapur, K.R., 5, 365, 555; 10, 628 Beutel, B., 10, 471 Beyzaei, H., 5, 38; 12, 196 Bezlada, A., 1, 287; 3, 464 Bhadra, S., 3, 237 Bhagavathy, G.V., 3, 112 Bhanage, B.M., 3, 321, 322; 5, 523 Bhanuchandra, M., 5, 71, 81 Bharathiraja, G., 10, 460 Bhardwaj, V.K., 10, 591 Bhaskara Rao, V.U., 3, 65 Bhaskararao, B., 5, 143 Bhat, B.A., 1, 312 Bhatt, V., 1, 353; 6, 57 Bhattacharyya, A., 7, 78 Bhojgude, S.S., 5, 104, 110; 12, 214 Bhunia, S.K., 5, 394 Bhuvanesh, N., 10, 556 Bi, H.-Y., 12, 220 Bi, S., 1, 352; 3, 465; 4, 171; 10, 393, 601 Bi, S.A., 12, 39 Bi, X., 3, 484; 6, 97; 10, 19; 12, 157 Biafora, A., 5, 430, 489; 10, 236 Bialy, L., 9, 36; 10, 227 Bian, G., 10, 314 Bian, Y., 5, 172 Bian, Z., 5, 387 Biasiolo, L., 4, 211; 10, 360 Bichler, P., 10, 260 Bichovski, P., 3, 493; 10, 648 Bickelhaupt, F.M., 7, 104, 109, 146 Bidal, Y.D., 4, 181 Bie, Z., 1, 339 Bielawski, C.W., 4, 148 Bierzynski, I.R., 12, 204 Bietti, M., 3, 245 Bihani, M., 1, 53 Bihari, T., 5, 48 Bihelovic, F., 10, 382 Bija, A.T., 5, 204

Author Index Bijanzadeh, H.R., 1, 71 Biju, A.T., 4, 219; 5, 104, 109, 110; 12, 47, 193, 214 Bijudas, K., 3, 159 Billard, T., 7, 133 Billow, B.S., 10, 346 Binnani, C., 5, 474, 490 Biosca, M., 3, 391 Birman, V.B., 6, 96; 9, 38; 12, 42 Bisai, A., 6, 68 Bismuto, A., 1, 132; 10, 132 Bispo, B.A.D., 3, 304 Bissember, A.C., 3, 330 Biswal, H.S., 3, 23 Biswas, A., 4, 69; 5, 544 Biswas, S., 5, 20, 375; 7, 130 Bjornberg, C., 10, 520 Bjorsvik, H.-R., 5, 460 Blacker, A.J., 1, 87; 3, 450 Blackmond, D.G., 1, 173 Blanc, A., 10, 392, 655; 12, 104 Blanc, R., 5, 195 Blanchard, F., 10, 55 Blanco, M.B., 3, 349 Blasik, Z.E., 8, 124 Blay, G., 1, 120; 5, 249; 8, 63; 10, 615, 650 Błaziak, K., 7, 108; 8, 6 Bleriot, Y., 6, 51 Blieck, R., 10, 309 Blom, J., 11, 41 Blond, A., 1, 198 Blond, G., 12, 25 Blouin, S., 12, 25 Blum, S.A., 10, 141–144 Bobbink, F.D., 4, 176 Bobbitt, J.M., 3, 127 Bobritskaya, E.V., 3, 32 Bochat, A.J., 10, 120 Bochkarev, V.V., 5, 51 Boda, R., 10, 624 Boddy, C.N., 10, 450 Boerth, J.A., 1, 372; 5, 369 Boess, E., 3, 245 Boga, C., 5, 88 Bogachenkov, A.S., 6, 47 Bohle, D.S., 3, 230 Bohmann, R.A., 10, 449 Bois, J.D., 3, 261 Boitsov, V.M., 5, 218; 6, 86 Bok, K.H., 3, 253 Bokach, N.A., 5, 428; 10, 14 Bokka, A., 3, 471 Bolcic, F.M., 5, 41 Bolm, C., 3, 298, 398; 5, 226; 10, 59, 104, 449 Bolte, M., 1, 285; 4, 258 Bonaccorsi, P.M., 11, 95 Bonacorso, H.G., 11, 86 Bonet, A., 10, 125

Bonifazi, D., 7, 162 Bonmerad, B., 5, 155 Boobalan, R., 5, 424 Boodram, J., 3, 357; 10, 114 Boominathan, S.S.K., 3, 259; 5, 209 Boons, G.-J., 1, 21; 7, 128 Bootsma, A.N., 12, 114 Bora, P.P., 11, 17 Bora, U., 5, 414 Border, S.E., 10, 44 Borges, B.H.F., 10, 436 Borhan, B., 10, 32; 11, 130 Borisov, Y.A., 12, 219 Borodina, T.N., 10, 445 Borpatra, P.J., 3, 188 Borra, S., 12, 158 Borrego, L.G., 1, 85; 3, 458 Borthakur, U., 10, 42 Bortoli, M., 7, 109 Bortolini, O., 1, 230, 231 Bose, D., 1, 214 Bose, S., 11, 175 Botla, V., 5, 141 Botteselle, G.V., 9, 41 Bottoni, A., 3, 307; 8, 48 Bouakher, A.E., 12, 45 Bouazza, F., 10, 47 Boubaker, T., 5, 3 Boughdiri, S., 7, 2 Bougrine, A.J., 3, 157 Bouillon, M.E., 12, 22 Bouisseau, A., 10, 629 Boumediene, M., 12, 162 Bour, C., 1, 238 Bourderioux, A., 10, 406; 12, 54 Bourdreux, F., 10, 618; 11, 83 Bousquet, T., 3, 455 Bouyssi, D., 1, 150, 163 Bower, J.F., 5, 303; 10, 13 Boyarskaya, I.A., 5, 22, 243, 245; 6, 28, 45–47; 10, 481 Boyarskii, V.P., 5, 22 Boyarskiy, V.P., 5, 428; 6, 47; 10, 14 Boyle, G.M., 11, 169 Boyle, J.W., 12, 108 Brabham, R., 1, 17 Brachet, E., 10, 406; 12, 54 Braddock, D.C., 5, 54 Bradley, L., 12, 36 Braga, A.A.C., 1, 81; 4, 197; 5, 354, 392; 10, 53, 542 Braga, A.L., 9, 41 Bragoni, V., 5, 430; 10, 236 Brahim, M., 5, 588 Brahmanandan, A., 5, 139 Brånalt, J., 7, 167 Branchadell, V., 4, 260 Brand, H., 10, 616

785

Author Index Brase, S., 10, 555 Brassard, C.J., 3, 295 Brauns, M., 1, 214 Braunschweig, H., 4, 144, 259 Braunstein, P., 4, 212 Bravo-Diaz, C., 5, 4 Brawley, K.K., 1, 301 Braybrook, C., 4, 238; 12, 85 Brechbiel, M.W., 5, 85 Breder, A., 3, 198; 5, 230 Breit, B., 8, 12; 10, 252, 253, 255, 262–265 Breman, A.C., 10, 539 Bremond, E., 3, 391 Bremond, P., 6, 15 Brennan, C., 5, 54 Brenner-Moyer, S.E., 10, 505 Breslavskaya, N.N., 3, 267, 268; 10, 113 Breugst, M., 1, 214, 340; 4, 141; 6, 7; 10, 431 Breunig, M., 12, 194 Breuning, M., 1, 204 Breuring, M., 8, 30 Brewer, C.R., 3, 295 Brewitz, L., 1, 65 Brian, J.-D., 5, 155 Briggs, R.A., 10, 125 Brigou, B., 5, 19 Brimble, M.A., 7, 62 Brinck, T., 1, 305 Brindani, N., 11, 112 Brinker, U.H., 4, 9 Britton, R., 8, 130 Brkovic, D., 2, 1 Bronner, S.M., 4, 30 Brooner, R.E.M., 10, 394 Brothers, E.N., 5, 292, 499 Brown, A.B., 10, 555 Brown, G.G., 3, 212 Brown, J.A., 3, 394 Brown, J.M., 5, 295 Brown, M., 3, 204; 12, 62 Brown, M.K., 11, 19, 21, 91 Brown, T.J., 10, 226, 394 Browne, W.R., 3, 231 Bruk, L.G., 10, 23 Bruneau, A., 5, 155 Brunner, A., 1, 220; 10, 237 Brunner, C., 10, 78; 12, 215 Brunner, H., 10, 623 Brunskill, A., 1, 55 Bryliakov, K.P., 3, 25 Bu, Q., 5, 552 Bubnov, Y.N., 12, 232, 235 Buccolini, G., 1, 132 Buchwald, S., 1, 99 Buchwald, S.L., 1, 102; 5, 67, 349; 10, 9, 174, 285, 311 Buda, S., 6, 54

Budinska, A., 8, 124 Budnikova, Y.H., 5, 192 Budynina, E.M., 7, 90 Buevich, A.V., 12, 205 Buissereth, L., 2, 25 Bujok, R., 5, 75; 10, 554 Bukhryakov, K.V., 1, 197 Bull, J.A., 5, 206, 341 Bull, S.D., 10, 448 Bulut, S., 4, 176 Bunno, Y., 5, 380 Bunrit, A., 7, 130 Buras, Z.J., 1, 330 Bures, J., 5, 479 Burguete, M.I., 1, 261; 8, 54 Burk, M.T., 10, 50 Burke, A.J., 1, 266; 5, 301 Bürki, C., 6, 70; 12, 112 Burmistrov, V.A., 3, 32 Burns, D.J., 12, 136 Burov, O.N., 5, 43, 78; 7, 86 Burroughs, L., 10, 560 Burtolos, A.C.B., 4, 17 Busacca, C.A., 5, 534; 7, 91 Buscagan, T.M., 6, 53 Busico, V., 4, 211; 10, 360 Buslov, I., 12, 76 Busto, J.H., 10, 455 Butcher, T.W., 10, 128, 283 Butin, A.V., 12, 237 Butt, N.A., 3, 370 Butts, C.P., 10, 274, 275 Byers, J.A., 8, 73 Byrne, P.A., 6, 7, 8; 8, 28

C Cabal, M.-P., 4, 36 Caballero-Garc´ıa, G., 12, 202 Cabellos, J.L., 6, 63, 87, 95; 12, 38 Caboni, P., 12, 192 Cabrero-Antonino, J.R., 3, 405 Cacchi, S., 10, 363 Cadamuro, S., 10, 598 Cahard, D., 1, 346; 3, 449; 5, 149 Cahiez, G., 3, 307; 8, 48 Cai, C., 1, 98; 10, 99, 156 Cai, G., 7, 6 Cai, H., 3, 191 Cai, J., 1, 140, 281, 314; 3, 285; 4, 39; 7, 160 Cai, L., 10, 547; 12, 182 Cai, M., 5, 501; 11, 80 Cai, P.-J., 5, 258 Cai, S.-H., 7, 19; 8, 93; 11, 109 Cai, X., 1, 315; 7, 56 Cai, Y., 3, 36; 4, 62; 12, 186 Cai, Z.-J., 5, 436; 10, 208 Cailly, T., 5, 277 Cajaiba, J., 1, 96

Calderone, J.A., 10, 621 Calhorda, M.J., 3, 84 Calvaresi, M., 3, 307; 8, 48 Camacho, R., 10, 349 Cambeiro, X.C., 5, 478 Campa de la, R., 8, 36 Campbell, A.D., 5, 285 Campeau, L.-C., 3, 378; 12, 75 Campos, B.B., 5, 91 Campos, R.B., 2, 29 Campos, V.R., 1, 242 Cannas, D.M., 3, 262 Cano, J., 10, 349 Canta, M., 3, 222 Cantat, T., 1, 288; 3, 362, 470 Cantillo, D., 9, 39 Canty, A.J., 1, 380 Cao, B., 7, 114 Cao, C., 1, 84; 3, 492 Cao, C.-T., 1, 84; 3, 492 Cao, D., 8, 14; 10, 516, 538 Cao, G., 1, 151 Cao, H., 3, 97, 215, 290; 5, 405 Cao, J., 3, 355; 6, 100; 10, 163, 314; 11, 49 Cao, L., 1, 317 Cao, M., 3, 415 Cao, P., 1, 110; 4, 31 Cao, Q., 3, 319 Cao, S., 7, 46; 10, 403 Cao, T., 8, 69; 10, 342 Cao, W., 7, 51; 10, 620 Cao, X., 5, 283 Cao, Y., 4, 122 Cao, Y.-C., 4, 193; 5, 463 Cao, Z., 1, 74, 84; 3, 492; 6, 73; 8, 29; 10, 372 Cao, Z.-C., 7, 52 Capet, F., 3, 455 Capperucci, A., 9, 41 Capriati, V., 8, 44 Caputo, C.B., 5, 198 Caramella, P., 1, 354 Caramenti, P., 10, 422 Carbery, D.R., 3, 296 Carboni, A., 5, 467 Carboni, B., 12, 17, 21 Caretti, I., 3, 289 Cari, R., 10, 537 Cariou, K., 10, 55 Carlotti, S., 4, 157 Carmona, D., 5, 549 Carmona, R.C., 5, 355 Carnaghan, E.R., 3, 133 Carneiro, J.W.M., 1, 242 Carneiro, P.F., 1, 242 Carneros, H., 1, 8 Carr, B., 3, 277; 10, 166 Carrascosa, E., 7, 135 Carreaux, F., 12, 17, 21

786 Carreira, E.M., 5, 431; 9, 24 Carreno, M.C., 5, 257 Carreras, J., 6, 74; 10, 399 Carret, S., 11, 20 Carretero, J.C., 11, 37 Carson, F., 3, 494 Cartaya, L., 9, 15 Carter, R.G., 1, 236; 10, 500, 517; 12, 154 Carvalho, C., 11, 100 Casimiro, M., 8, 38 Cassani, C., 8, 108 Cassidy, J.S., 10, 345 Castanet, A.-S., 5, 73 Castarlenas, R., 4, 208; 10, 251 Castelli, U., 10, 47 Castro, C., 5, 327 Castro, L.C.M., 3, 27 Castro, M., 1, 284; 9, 14 Castro-Alvarez, A., 1, 8 Catak, S., 1, 117; 5, 19; 10, 26 Catalano, S., 10, 209 Caumes, X., 7, 29 Cavalcanti, I.H., 1, 226 Cavallo, L., 1, 132; 4, 231; 8, 107; 10, 273 Cavender, H., 10, 21 Caylan, E., 11, 70 Cayuelas, A., 11, 38, 44 Cazin, C.S.J., 4, 181 Ceccon, J., 6, 74; 10, 399 Cella, S., 5, 481 Ceotto, M., 1, 168 Cera, G., 5, 378 Cerisoli, L., 1, 189 Cerminara, I., 1, 7; 5, 233 Cerulli, V., 10, 553 Cespedes, D., 5, 37 Cetinkaya, B., 4, 188 Cetinkaya, Y., 10, 647 Ceyhan, S., 10, 647 Cha, J.K., 12, 145 Chabrier, A., 5, 155 Chachignon, H., 5, 149 Chachkov, D.V., 7, 105 Chacón-Morales, P.A., 6, 91; 12, 46 Chafaa, F., 1, 129 Chagarovskiy, A.O., 7, 90 Chai, Y., 7, 56 Chakrabarty, K., 1, 174 Chakrabarty, S., 5, 115 Chakraborty, S., 3, 380 Chakravarty, M., 5, 201 Chambers, S.J., 1, 124 Chamorro, E., 4, 29 Chamorro-Arenas, D., 3, 156 Champiré, A., 12, 195 Chan, A.S.C., 5, 162

Author Index Chan, C.-K., 6, 80; 7, 132; 8, 21; 12, 41 Chan, J.Z., 1, 68 Chan, K.S., 3, 368 Chan, P.W.H., 4, 132; 12, 108, 109, 116 Chan, V.S., 3, 288; 4, 104; 5, 36 Chan, W.-L., 11, 33, 131 Chan, Y., 3, 140, 143 Chan, Y.-T., 1, 233; 10, 587 Chand, S., 4, 69; 5, 544 Chand, S.S., 10, 291 Chandna, N., 5, 570; 10, 300 Chandra, S., 3, 325; 7, 148 Chandra, S.K., 10, 51 Chandrasekaran, S., 3, 7 Chandrasekha, A., 5, 447 Chandrasekhar, S., 1, 196 Chandrasekharam, M., 5, 141 Chang, C.-H., 1, 190 Chang, D., 4, 174 Chang, F., 7, 89 Chang, G.-H., 10, 585 Chang, H., 5, 585 Chang, H.-K., 1, 233 Chang, J., 1, 160; 3, 184–186, 192, 199; 4, 167; 5, 445; 10, 214, 599; 11, 136, 155 Chang, K.-L., 1, 167 Chang, M., 1, 350; 3, 387 Chang, M.-Y., 6, 80; 7, 132; 8, 21; 11, 7; 12, 41 Chang, N.-Y., 5, 211 Chang, S., 3, 331; 4, 79, 184; 5, 180, 190, 386, 500; 7, 35; 10, 466 Chang, W., 10, 175, 176, 304, 374 Chang, X., 3, 91; 10, 595 Chang, Y.-Y., 10, 378 Chanthamath, S., 7, 95 Chao, A., 5, 77; 10, 614 Chapellas, F., 10, 557 Chapman, R.S.L., 10, 448 Chapuis, C., 10, 610 Charaschanya, M., 12, 189 Charette, A.B., 4, 85 Charpentier, J., 8, 124 Charushin, V.N., 5, 74 Chataigner, I., 10, 557 Chatalova-Sazepin, C., 10, 292 Chatani, N., 3, 27; 4, 97; 5, 325, 379, 476; 10, 341 Chattaraj, P.K., 7, 83 Chatterjee, B., 3, 359 Chatterjee, D., 3, 144 Chatterjee, I., 3, 452 Chaudhari, T.Y., 8, 64; 10, 317 Chaudhary, V., 3, 252 Chaudhuri, S., 3, 178

Chauhan, P., 10, 588, 589 Chauvier, C., 1, 288; 3, 470 Chavda, M.K., 7, 31; 8, 15 Che, C.-M., 3, 91 Che, X., 3, 139 Chee, K.W., 5, 345 Chee, M.A., 10, 394 Chelli, S., 6, 11 Chelouan, A., 1, 85; 3, 458 Chemla, F., 5, 565; 10, 315 Chen, B., 1, 110, 211; 4, 196, 245 Chen, C., 1, 384; 3, 282, 377, 397; 6, 101, 103; 10, 249, 343; 12, 86, 102, 109 Chen, C.-N., 1, 84; 3, 492 Chen, C.-Y., 3, 259; 5, 209 Chen, D., 1, 211, 315, 361; 4, 196; 5, 57, 330, 331; 10, 136, 632 Chen, D.-K., 10, 218 Chen, D.-Q., 3, 246 Chen, D.-Z., 5, 179 Chen, F., 3, 31, 110, 275, 400, 407; 5, 151; 7, 139; 10, 408; 11, 78 Chen, G., 4, 13, 40; 5, 340, 347; 8, 74, 92 Chen, G.-G., 5, 239 Chen, G.-H., 3, 139 Chen, G.-Q., 12, 78, 123 Chen, G.-S., 7, 30 Chen, H., 3, 118, 399; 5, 314, 427, 438; 6, 101; 10, 77, 218, 323; 11, 156; 12, 86, 115 Chen, J., 1, 65, 136; 3, 377, 383, 423, 444; 4, 31, 37, 96; 5, 65, 116, 459; 7, 25, 51, 131, 139; 10, 428, 620; 12, 82, 101 Chen, J.-F., 10, 574 Chen, J.-Q., 8, 127 Chen, K., 1, 233; 3, 100, 258, 347; 4, 66, 100; 5, 305; 10, 587; 11, 179 Chen, K.-L., 5, 234 Chen, K.-Q., 4, 220; 11, 174 Chen, L., 1, 78; 3, 26; 4, 52; 6, 100; 7, 111; 10, 31, 314, 567, 572, 658 Chen, M., 1, 361; 4, 127; 5, 57; 10, 211; 12, 126 Chen, M.-W., 3, 384, 457 Chen, N., 10, 562 Chen, N.-Y., 3, 431 Chen, P., 1, 118, 149; 3, 356; 7, 38; 9, 31; 10, 137, 169, 182 Chen, Q., 1, 234, 235; 5, 145; 10, 548, 634, 635

787

Author Index Chen, Q.-A., 5, 197 Chen, R., 1, 166; 3, 56; 4, 63; 5, 403 Chen, S., 3, 246, 356; 5, 33, 216, 454, 470; 10, 259, 321, 525; 11, 123 Chen, S.-S., 5, 376; 10, 185 Chen, S.B., 6, 111 Chen, T., 1, 98, 387; 9, 19; 10, 33, 659 Chen, W., 1, 41, 72, 219; 3, 283, 417; 4, 242; 5, 191; 7, 21; 8, 101; 11, 22, 34 Chen, W.-W., 1, 292; 5, 371; 10, 632 Chen, X., 1, 9, 54; 3, 332, 376, 408; 4, 68, 122, 132, 145, 163, 167; 5, 23, 55, 487, 510, 511, 559; 8, 9; 11, 47, 153; 12, 19, 83, 109, 116 Chen, X.-M., 3, 207 Chen, X.-Q., 11, 54, 114 Chen, X.-Z., 3, 309 Chen, Y., 1, 233; 3, 285; 4, 54; 5, 158, 258, 508; 10, 306; 12, 165, 216 Chen, Y.-C., 3, 98; 6, 78; 10, 545, 576; 11, 108, 129 Chen, Y.-H., 6, 80; 12, 74 Chen, Y.-L., 11, 154 Chen, Y.-Q., 8, 70 Chen, Y.-X., 7, 30 Chen, Y.-Y., 5, 234 Chen, Y.M., 10, 587 Chen, Z., 1, 296; 3, 189, 308, 347; 4, 221; 5, 397, 512; 6, 99; 10, 57, 106, 254, 380; 12, 137, 178 Chen, Z.-P., 3, 384 Chen, Z.-X., 1, 74; 3, 36; 8, 29; 12, 23 Cheng, B., 12, 3 Cheng, B.-Y., 6, 115; 11, 36 Cheng, C., 3, 291; 5, 306; 7, 51 Cheng, C.-H., 5, 332, 424; 10, 335, 338 Cheng, G., 1, 138; 4, 60; 7, 74; 9, 40; 10, 446 Cheng, G.-J., 10, 182 Cheng, J., 4, 158; 10, 158, 352, 534 Cheng, J.-B., 10, 350 Cheng, J.-P., 8, 125, 131; 10, 79, 457, 515; 12, 160 Cheng, L., 3, 249, 396 Cheng, M., 12, 117, 124, 165 Cheng, M.-X., 3, 58 Cheng, P., 5, 215 Cheng, P.T.W., 8, 92 Cheng, Q., 4, 233; 7, 22, 23

Cheng, Q.-Q., 1, 70; 4, 61, 84; 11, 162 Cheng, W., 4, 92; 12, 131 Cheng, X., 4, 96; 5, 397; 10, 459; 12, 82 Cheng, X.-F., 5, 150 Cheng, Y., 1, 254; 3, 150; 4, 216, 230; 5, 592; 10, 80 Cheng, Y.-C., 5, 211; 7, 132; 8, 21; 11, 7 Cheng, Y.-N., 1, 258; 8, 57 Cheng-Yong Su, C.-Y., 4, 145 Chennamsetti, H., 4, 78 Chennamsettiai, H., 12, 141 Cheong, P.-H.Y., 1, 236; 10, 25, 517 Chernikova, I.B., 10, 49 Chernyshev, V.V., 3, 182; 10, 58 Chesa, J.F., 11, 168 Chesse, M., 5, 119, 120, 411 Chetcuti, M.J., 3, 329; 4, 198 Cheurfa, Z., 1, 156 Chevalier, Y., 5, 417 Chevallier, F., 5, 275 Chi, Y., 3, 491; 9, 42 Chia, P.-Y., 1, 378; 4, 108 Chiacchio, M.A., 1, 354 Chiarini, M., 3, 59; 10, 383 Chiba, K., 9, 26; 10, 410 Chiba, M., 5, 272 Chiba, S., 10, 77, 484 Chida, N., 3, 461 Chien, T.-C., 10, 308 Chikhi, S., 5, 578 Chimatadar, S., 3, 17, 22 Chimatadar, S.A., 3, 10, 51, 69, 120 Chimni, S.S., 10, 591 Chin, K.F., 3, 223 Chinthapally, K., 4, 74 Chipanina, N.A., 1, 237 Chipiso, K., 3, 179 Chiranjeevi, B., 5, 141 Chirik, P.J., 3, 378; 8, 106; 10, 155 Chisholm, D.R., 10, 443 Chithiraikumar, C., 1, 181 Chiu, P., 12, 12 Cho, B.R., 9, 3 Cho, J., 1, 286 Cho, S.H., 1, 109; 7, 9; 8, 100 Cho, Y.J., 1, 10 Chobanov, N.M., 10, 347 Choe, H., 11, 73 Choe, Y.-K., 10, 154 Choi, C., 5, 206 Choi, H., 5, 227, 536; 12, 228 Choi, M., 5, 188, 384, 553; 10, 637 Choi, Y.-J., 1, 383; 8, 81

Cholkar, K., 3, 121 Chong, E., 10, 144 Chong, S., 1, 151 Choppin, S., 5, 119, 120, 467 Choquette, K.A., 4, 64 Chorro, T.H.D., 5, 355 Chou, C.-H., 5, 234 Choudhary, A., 3, 4 Choudhury, S.K., 8, 118 Chow, C.H.E., 4, 214 Chow, S., 3, 125; 11, 169 Chowdhury, R., 10, 521 Chowdhury, S., 3, 365; 11, 27 Chrisholm, J.D., 6, 58 Christensen, M., 12, 75 Christianson, D.W., 6, 5 Chu, C.K., 3, 277; 10, 166 Chu, L., 3, 81 Chu, T., 3, 131 Chu, W.-D., 4, 65; 8, 22; 10, 483 Chu, Z.J., 5, 90 Chua, Y.-Y., 4, 204; 5, 498; 8, 49 Chuang, S.-C., 11, 28 Chuanprasit, P., 1, 349; 3, 445 Chucani, G., 9, 12 Chuchani, G., 9, 15 Chung, L.W., 1, 348; 3, 375, 409; 4, 202; 5, 298; 8, 113; 10, 8 Chupakhin, O.N., 5, 74 Churcher, I., 12, 2 Chuvylkin, N.D., 5, 13, 14 Ci, C., 3, 228 Cicco, L., 8, 44 Cid, M.M., 1, 146 Ciesielski, J., 4, 254 Cinar, M.E., 4, 21 Cino, S., 5, 88 Cioc, R.C., 1, 302 Ciofini, I., 5, 6, 520 C´ısaˇrová, I., 10, 274 Cisnetti, F., 4, 212 Cividino, P., 11, 20 Clark, H.F., 1, 325 Clark, R.J., 3, 295 Clarke, C., 10, 340 Clarke, L.-A., 3, 403 Clarke, Z.J.F., 3, 230 Clausen, R.P., 1, 318; 8, 129 Clavier, G., 10, 618; 11, 83 Clayden, J., 5, 82; 12, 48 Clemenceau, A., 10, 551 Cleveland, A.H., 6, 41 Clift, M.D., 10, 433 Clive, D.J.L., 7, 140; 8, 112 Clizbe, E.A., 3, 128 Clososki, G.C., 4, 4 Cloutier, M., 7, 27 Clyburne, J.A.C., 1, 201 Cobb, K.M., 5, 320; 7, 5 Cochran, K.H., 10, 90

788 Codée, J.D.C., 7, 127 Coeffard, V., 1, 238 Coelho, F., 1, 81; 10, 542 Coffinet, M., 10, 37 Cokoja, M., 1, 278; 4, 203 Colacot, T.-J., 5, 66 Coleman, M.G., 4, 5 Coll, M., 3, 391 Collados, J.F., 8, 4; 12, 168 Colletto, C., 5, 575 Collot, V., 5, 277 Collum, D.B., 1, 115 Colobert, F., 5, 119, 411, 467 Colomer, I., 12, 184 Coltart, D.M., 1, 62 Combee, L.A., 11, 35 Comesana, M.G., 4, 248 Comesse, S., 12, 45 Comin, M.J., 10, 563 Compagner, C.T., 1, 367 Company, A., 5, 140, 442; 8, 104; 10, 336 Conde, A., 4, 42 Cong, H., 11, 46 Congcong Liu, C., 12, 39 Conner, M.L., 11, 19, 91 Connon, S.J., 1, 310 Constant, C., 10, 618 Contreras-Caceres, R., 5, 91 Cook, A.M., 1, 371; 8, 56 Cook, G.R., 3, 80 Coon, T., 5, 342; 8, 89 Coote, M.L., 11, 102 Cordes, D.B., 4, 181 Cordier, M., 10, 597 Cordova, T., 9, 15 Cordova-Sintjago, T., 9, 12 Cornaggia, C., 1, 310 Corominas, A., 11, 168 Corpet, M., 1, 132 Corral-Bautista, F., 6, 10; 7, 122 Correa, A., 3, 78 Correa, C.C., 1, 96 Correia, C.R.D., 5, 354, 355 Corzana, F., 10, 455 Corzo, H.H., 12, 36 Cosme, P., 10, 107 Coss´ıo, F., 12, 21 Coss´ıo, F.P., 11, 37, 38, 44; 12, 17 Cossy, J., 12, 138 Costa, I., 4, 248 Costa, L.A.S., 2, 28; 7, 98 Costa, M.O., 3, 304 Costa, P.R.R., 1, 232; 10, 436, 499 Costant, C., 11, 83 Costas, M., 3, 220, 222; 4, 42 Côté-Raiche, A., 4, 30

Author Index Cotman, A.E., 1, 346; 3, 449 Cotugno, P., 3, 74 Couce-Rios, A., 10, 244 Coulthard, G., 1, 124; 5, 10 Courant, T., 4, 89 Coussanes, G., 9, 1 Couto, T.R., 1, 226 Couto, U.R., 7, 80 Couty, F., 1, 365; 7, 86 Cowley, M.J., 10, 132 Cox, P.A., 5, 285 Coxon, A.G.N., 10, 348 Cozzi, F., 3, 468 Cozzi, P.G., 1, 94 Cramer, D.L., 1, 30; 4, 225 Cramer, N., 5, 453; 10, 270 Cresswell, A.J., 5, 589 Crestoni, M.E., 3, 114 Crich, D., 6, 54 Crisenza, G.E.M., 5, 303; 10, 13 Crochet, A., 4, 107 Crocker, R.D., 4, 11; 10, 27 Croft, R.A., 5, 206 Crotti, P., 10, 662 Cruz, F.A., 10, 254 Csák¨y, A.G., 6, 89; 7, 88 Csampai, A., 10, 93 Cuenca, T., 10, 349 Cuerda-Correa, E.M., 3, 23 Cui, B., 10, 409 Cui, C., 4, 209; 10, 414 Cui, H.-L., 11, 51 Cui, J., 1, 329; 3, 234 Cui, K.J., 3, 136 Cui, L., 10, 527 Cui, P.-P., 5, 492 Cui, S., 3, 56; 5, 403; 10, 319; 12, 95, 117, 124 Cui, X., 1, 138; 4, 60; 5, 181, 510, 511, 546; 9, 40; 10, 446 Cui, Y., 10, 314 Cui, Y.-M., 6, 100; 10, 31, 163, 485 Cummings, S.P., 3, 435 Cundari, T.R., 3, 380; 4, 197; 5, 68, 392; 10, 313 Cupioli, E., 5, 253 Curcio, M., 1, 132 Curiel Tejeda, J.E., 4, 241 Curnow, O.J., 6, 22 Curti, C., 11, 112 Cussj, O., 3, 220 Cusso, O., 3, 222 Cvengroˇs, J., 10, 442 Cypryk, M., 12, 72 Cyr, P., 4, 30 Cyranski, M.K., 3, 111 Czaban-Jozwiak, J., 5, 76 Czakó, G., 7, 135, 136 Czarnocki, Z., 5, 582

Czechtizky, W., 9, 36; 10, 227 Czekelius, C., 10, 417 Czerwi´nska, K., 12, 5

D Da, Y.-X., 5, 56 da Cunha, A.M., 3, 315 D’Acunto, M., 4, 80 Dahlgren, B., 1, 305 Dahlstrand, C., 7, 130 Dai, B., 4, 151; 5, 61, 399; 9, 20 Dai, G.-F., 10, 464 Dai, H., 5, 385; 9, 6 Dai, H.-X., 8, 92 Dai, J., 1, 106; 5, 247; 10, 175, 176 Dai, J.-X., 10, 293 Dai, K., 5, 398 Dai, L.-X., 4, 233; 7, 23; 12, 128 Dai, M., 4, 26 Dai, W., 7, 46; 10, 403 Dai, W.-M., 1, 351 Dai, X., 5, 210; 10, 82 Dai, Y., 9, 10 Dai, Z., 9, 10 Dakshayani, S., 3, 166, 170 D’Alessio, L., 1, 7; 5, 233 Dalipe, A., 10, 46 Dalla, V., 1, 308 D’Amora, A., 4, 211; 10, 360 D’Amore, L., 4, 211; 10, 360 Dang, L., 5, 135, 454; 10, 259; 12, 133 Dang, M., 10, 266 Dang, Y., 4, 187; 10, 102 Dang, Z.-M., 5, 591 Dangarh, B.K., 3, 8 Dangat, Y.B., 5, 576 Dange, N.S., 6, 40 D’Angelo, K.A., 1, 20 Daniels, M.H., 5, 136 Danikiewicz, W., 3, 111; 7, 108; 8, 6 Daniliuc, C., 1, 178, 366; 3, 404; 4, 15, 153, 229; 7, 96; 8, 20; 10, 45, 129, 195; 12, 78 Dannenberg, C.A., 3, 298 Danodia, A.K., 10, 66 Daoust, B., 12, 100 Daran, J.-C., 1, 355 Darehkordi, A., 12, 197 Dargelos, A., 4, 238; 12, 85 Daru, A., 1, 145 Das, B., 2, 27 Das, D., 4, 69; 5, 544 Das, D.K., 4, 227; 10, 533 Das, E., 12, 223 Das, G.K., 1, 174 Das, J., 11, 4; 12, 223 Das, M., 1, 139; 9, 21

789

Author Index Das, P., 3, 79, 316; 5, 62, 556 Das, R., 5, 410 Das, S., 4, 176 Das, T., 3, 65 Das, U., 10, 501 da Silva, F.D., 1, 242 Dateer, R.B., 4, 79 Dauban, P., 4, 254 D’Auria, M., 1, 7; 5, 233 Davari, M.D., 3, 16 Daver, H., 2, 27 Davey, J.A., 10, 450 David, O.R.P., 1, 365 Davies, H.M.L., 4, 91; 11, 169 Davies, R.P., 5, 54 Davies, S.G., 10, 435 Davis, A.J., 10, 141, 143 Davis, T.A., 1, 301 Davis-Gilbert, Z.-W., 10, 344 Dawande, S.G., 4, 77; 5, 558; 12, 159 Day, B.M., 4, 150 Day, D.P., 4, 132; 12, 116 Day, V.W., 12, 189 De, S., 1, 304; 3, 352; 4, 192 De, U., 5, 188 Deacy, A.C., 3, 379 de Alaniz, J.R., 5, 46 Dean, W.M., 8, 51 De Angelis, A., 5, 66 Deasy, R.E., 3, 403 de Azambuja, F., 5, 355 Deb, I., 5, 531 Deb, M.L., 3, 188 de Boer, J.W., 3, 231 Debrouwer, W., 10, 660 De Carlo Chimienti, R., 3, 115 Dechy-Cabaret, O., 1, 355 Deckers, K., 10, 588, 589 de Cózar, A., 7, 104; 11, 37, 38, 44 Decreau, R., 5, 133 Dedeoglu, B., 1, 117; 10, 26 Deetz, A.M., 3, 421 de Fernandes, T.A., 10, 499 de Figueiredo, R.M., 5, 253 de Fremont, P., 4, 212 Dehdab, M., 1, 364 Dehghani, M., 10, 11 Deh-Lee, A.M., 9, 5 De Houwer, J., 3, 289 Dei, L., 1, 311 De Jesús, M., 7, 61 Deka, M.J., 10, 42 De Kimpe, N., 7, 81; 12, 33 de la Campa, R., 1, 57 de La Cruz, N., 1, 77; 10, 573 Delalu, H., 3, 157 de la Pradilla, R.F., 12, 118, 184 Delarmelina, M., 1, 242

de la Torre, M.C., 4, 136; 12, 118 Delbrouck, J.A., 7, 60 de Lera, A.R., 1, 251 Del Fiandra, C., 10, 553 Delforge, A., 7, 162 Delgado, N., 5, 10 Delgado-Abad, T., 6, 50 de Lima Batista, A.P., 1, 81; 10, 542 Dell’Acqua, M., 4, 131; 5, 564; 7, 76; 10, 364 Dell’Anna, M.M., 3, 74 Delley, B., 10, 90 Del Rio, N., 4, 261 Delso, I., 1, 165, 354; 8, 35 De Luca, G., 10, 209 Del Vecchio, L., 3, 59; 10, 383 Del Zotto, A., 4, 211; 10, 360 Demchuk, D.V., 3, 218 Demchuk, O.M., 5, 461 Demertzidou, V.P., 6, 94; 12, 153 Demmer, C.S., 7, 53 De Munck, L., 1, 127 Deng, C.-L., 5, 151; 10, 408 Deng, G., 1, 141 Deng, G.-J., 1, 140; 3, 285 Deng, H., 10, 620 Deng, J., 4, 253; 10, 247 Deng, L., 1, 45, 105, 143; 10, 535 Deng, P., 1, 205, 291; 8, 32 Deng, Q.-M., 5, 263 Deng, W., 10, 130, 131 Deng, W.-P., 4, 94 Deng, X., 4, 187; 10, 102; 12, 133 Deng, X.-Y., 4, 113 Deng, Y., 3, 216; 4, 68, 84; 5, 161, 200, 559; 10, 314; 11, 126; 12, 113 Deng, Y.-H., 8, 22; 10, 483, 536 Deng, Z., 1, 281 Deng, Z.-Q., 1, 175; 9, 25 Deng, Z.-X., 10, 503 Deniau, E., 10, 37 Denis, M., 3, 320 Denmark, S.E., 10, 50 Dennis, J.M., 1, 367 Depken, C., 3, 198; 5, 230 de Prevoisin, G., 10, 172 Deprez, B., 8, 87 DeProft, F., 5, 19 Dequirez, G., 4, 254 Derat, E., 5, 565 Derdau, V., 5, 282 Derdour, A., 5, 275 De Risi, C., 1, 231 Derksen, D.J., 5, 98 Derosa, J., 10, 198 Derstine, B.P., 1, 379 Déry, M., 4, 140

DeSarkar, S., 5, 334 Desire, J., 6, 51 Deslongchamps, G., 12, 1 Deslongchamps, P., 6, 52; 12, 1 Desmet, G.B., 10, 432 de Souza, I.F., 1, 96 de Souza, R.O.M.A., 1, 96 Desroches, J., 1, 386 Desrosiers, J.-N., 5, 375, 466 Desyatin, V.G., 1, 197 de Talence, V.L., 3, 455 Dethe, D.H., 10, 624 Dethlefsen, J.R., 3, 441 Detmar, E., 10, 431 Devaraj, K., 5, 538 Devi, E.S., 3, 251; 4, 159 Devi, M., 6, 14 Devi, R.A., 3, 162 Devi, S., 5, 93 Devi, S.S., 3, 263 de Vilela, G.V.M.A., 10, 436 de Visser, S.P., 3, 114 De Voss, J.J., 3, 125 de Vries, J.G., 3, 320, 393, 422 Dewar, A., 5, 414 Dewhurst, R.D., 4, 144 Dewik, H., 7, 154; 10, 596 Dey, A., 5, 299, 413 Dey, C., 5, 205; 10, 561 Dey, S., 2, 13, 18; 3, 475 Dhar, T.G.M., 8, 92 Dhara, S., 5, 108 Dhawa, U., 5, 412 Dherbassy, Q., 5, 411 Dhokale, R.A., 5, 105 D’hooge, D.R., 10, 432 D’hooghe, M., 7, 81; 12, 33 Diab, S., 10, 557 Dias, A.G., 10, 436 Dias, R.M.P., 4, 17 D´ıaz-Requejo, M.M., 4, 42, 210 Diaz-Tendero, S., 1, 50 Di Bussolo, V., 10, 662 Di Carmine, G., 1, 230, 231 Dickie, D.A., 5, 319 Diederich, F., 12, 27, 94 Diéguez, M., 1, 86; 3, 391, 428 Diesendruck, C.E., 5, 108 Diez-Varga, A., 6, 66 Di Giuseppe, A., 4, 208; 10, 251 Dilger, A.K., 6, 114; 7, 100 Dilman, A.D., 4, 38; 8, 26 Dine, A.N.E., 11, 69 Dinesh, T.K., 10, 470 Ding, A., 5, 434; 10, 415 Ding, C.-H., 1, 211; 4, 196 Ding, C.-K., 10, 412; 12, 155 Ding, F., 12, 98 Ding, G., 1, 329; 3, 234 Ding, J., 5, 532

790 Ding, K., 10, 467 Ding, Q., 5, 152; 10, 413 Ding, R., 1, 203; 7, 166 Ding, S., 10, 160, 367 Ding, X., 4, 94; 5, 471; 10, 458; 11, 130 Ding, Y.-L., 4, 216; 10, 1 Ding, Y.-S., 3, 88 Ding, Z.-C., 10, 412; 12, 155 Dinh, A.N., 5, 126 Di Sabato, A., 10, 537 Dissanayake, A.A., 10, 346 Ditchfield, R., 6, 49 Diver, S.T., 4, 109 Dixon, D.J., 1, 57; 8, 36 Djebbar, S., 5, 578 Djerourou, A., 1, 129 Do, D., 5, 242; 6, 81 Dobhal, B., 3, 21 Dobrzycki, L., 3, 111 Dobson, L.S., 1, 267 Dodd, R.H., 10, 55 Dodo, K., 5, 435 Dogadina, A.V., 6, 47 Dohi, T., 3, 152 Doi, M., 10, 502 Doi, N., 10, 386; 12, 110 Doi, R., 1, 374; 4, 32; 7, 43; 8, 86 Doi, T., 10, 146 Dokli, I., 9, 35 Dolan, N.S., 4, 249, 250 Dolensk´y, B., 7, 151 Dolfen, J., 7, 81; 12, 33 Dolin, S.P., 3, 267, 268; 10, 113 Domingo, L.R., 1, 129; 4, 29, 172; 12, 206 Dom´ınguez, G., 11, 142 Dom˙zalska, A., 10, 603 Donad´ıo, L.G., 10, 563 Donahue, N.M., 3, 213 Donau, C.A., 8, 44 Donckele, E.J., 12, 27, 94 Dong, B., 3, 358; 10, 606 Dong, G., 1, 143; 3, 196; 5, 353; 10, 504 Dong, J., 1, 33; 3, 31, 110 Dong, J.J., 3, 231 Dong, K., 11, 126 Dong, L., 5, 404, 407, 455, 557; 8, 71; 10, 267; 11, 2 Dong, N., 10, 457 Dong, Q., 1, 321; 10, 298 Dong, V.M., 1, 296; 10, 254; 12, 137 Dong, W., 3, 189 Dong, X., 4, 154 Dong, X.-Q., 3, 397, 414–416, 427; 10, 249 Dong, Y., 5, 103 Dong, Z., 10, 459

Author Index Donnell, T.M., 3, 421 Donnelly, J.V.G., 3, 296 Donohoe, G.C., 10, 128 Doran, R., 9, 30 Dorcet, V., 5, 275; 11, 69; 12, 21 Dorn, S.K., 1, 367 Dorogan, I.V., 7, 86 Dorta, R., 4, 231; 10, 273 Dosa, Z., 10, 93 dos Passos Gomes, G., 1, 5; 10, 369 Dos Santos, H.F., 2, 28; 7, 98 dos Santos Comprido, L.N., 10, 377 Dou, X., 10, 631, 633 Doubleday, C., 8, 110 Doucat, H., 5, 578 Doucet, H., 5, 588 Dowley, M.J.H., 3, 296 Doyle, A.G., 4, 64 Doyle, M.P., 1, 70; 4, 61, 84; 11, 126, 162; 12, 119, 210 Drabowicz, J., 3, 153 Drapeau, M.P., 5, 294 Dreher, S.D., 7, 40 Dreier, A.-L., 1, 178; 8, 20 Driver, T.G., 3, 360; 4, 255 Drmanic, S.Z., 2, 1 Drouillat, B., 7, 86 Drover, M.W., 10, 280 Du, C., 3, 28, 305; 5, 486; 12, 124, 165 Du, D.-M., 10, 529–531, 584 Du, G., 1, 228 Du, G.-F., 4, 151; 9, 20 Du, H., 1, 89, 290; 3, 432; 6, 44; 12, 89 Du, J.-Y., 8, 22; 10, 483 Du, L., 10, 643 Du, S., 10, 661 Du, T., 12, 23 Du, W., 10, 545, 576; 11, 108, 129 Du, X., 10, 151 Du, X.-H., 5, 258 Du, Y., 3, 248; 5, 335; 10, 303; 12, 37 Du, Z., 5, 387 Duan, C., 1, 373 Duan, D.-Z., 1, 159 Duan, J.-X., 4, 72 Duan, M., 3, 397 Duan, W.-L., 10, 464 Duan, X., 3, 238 Duan, Y., 4, 44; 10, 393 Duangkamol, C., 2, 2 Duarte, F.J.S., 1, 357; 3, 84; 10, 506 Duarte, T.N., 10, 474 Duarte, V.C.M., 1, 122; 11, 122

Dub, P.A., 1, 341; 3, 367 Dudding, T., 1, 75; 6, 20; 10, 362 Dudley, G., 12, 61 Dudzik, A., 5, 4 Dughera, S., 10, 598 Dumeignil, F., 3, 389 Dumont, C., 3, 455 Dunach, E., 1, 308 Du˜nachand, E., 12, 40 Duncan, J.A., 12, 204 Duncan, L.R.H., 6, 14 Duncan, N., 4, 137; 8, 80 Dunn, V., 10, 187 Duong, H.A., 4, 204; 5, 498; 8, 49 Du Prez, F.E., 10, 432 Durgannavar, A.K., 3, 10 Durgaprasad, M., 6, 106 Durlak, P., 12, 16 Durmaz, M., 10, 571 Dürr, A.B., 5, 32; 7, 42; 10, 589 Dutton, J., 12, 2 Dwight, T.A., 7, 147 Dwivedi, A.D., 5, 474 Dyson, P.J., 4, 176 Dzhemilev, U.M., 10, 347 Dzhevakov, P.B., 4, 190; 5, 64

E East, A.L.L., 6, 16, 62; 12, 203 Eastgate, M.D., 3, 76 Easwaramoorthy, D., 3, 162 Eaton, P.E., 6, 88 Ebe, Y., 5, 370; 10, 277 Ebisawa, K., 5, 368; 10, 329 Ebrahimpour, Z., 5, 38 Ebrahimpoura, Z., 12, 196 Echavarren, A.M., 3, 338; 6, 74; 10, 399; 11, 14 Echave, H., 1, 187 Echeverria, P.-G., 12, 129 Eckermann, R., 12, 194 Edor, J., 3, 71 Edouard, G.A., 5, 278 Efimov, I.V., 11, 77 Efremova, M.M., 12, 35 Egami, H., 10, 38 Egger, L., 1, 3; 4, 105 Eguchi, S., 10, 423 Ehlert, C., 5, 356 Ehm, C., 5, 86; 7, 49 Eichman, C.C., 10, 193 Eisenburger, L., 6, 9 Eisenreich, W., 10, 159 Eisink, N.N.H.M., 3, 320 Eivazzadeh-Keihan, R., 10, 447 Ekebergh, A., 7, 155 Elaieb, F., 5, 458 El Ali, B., 10, 178 Elangovan, J., 11, 81

791

Author Index Elangovan, S., 3, 382 El-Barbary, A.A., 3, 371 El Bouakher, A., 1, 308 El Dine, A.N., 11, 70 El Hajbi, A., 4, 19, 20 El Hajj, A., 3, 157 El Kaim, L., 5, 520 Elkanzi, N.A.A., 10, 555 El Kazzouli, S., 5, 535 El Khafib, M., 5, 344 Ellern, A., 10, 243 Ellman, J.A., 1, 372; 5, 369; 10, 639 El Louz, M., 1, 355 Ellwart, M., 7, 36 El Malah, T., 10, 555 El-Mansy, M.F., 10, 500 Elsamra, R.M.I., 1, 330 Elumalai, V., 5, 460 Emayavaramban, B., 3, 487 Emma, M.G., 1, 320; 8, 128 Emu, T., 7, 63 Enders, D., 1, 239; 10, 509, 588–590 Endo, K., 4, 138 Endo, N., 10, 365, 366 Engel, J., 3, 398 Engelhardt, T.B., 10, 234 Engle, K.M., 10, 170, 171, 198 Enomoto, K., 12, 28 Entsminger, S.W., 3, 463; 4, 205 Eppe, G., 12, 166 Epping, R., 7, 65 Erb, W., 5, 273 Erbing, E., 3, 494 Erdei, A., 4, 206 Erfan, S., 5, 522 Erker, G., 7, 96; 10, 129; 12, 78 Ermolenko, C., 5, 44 Ermolenko, L., 3, 488 Ershov, O.V., 1, 362; 12, 230 Escalante, A.M., 1, 14 Escorihuela, J., 1, 261; 8, 54 Escudero-Adán, E.C., 7, 18, 64, 65 Esmaeili, A.A., 10, 493 Espeel, P., 10, 432 Espinal-Viguri, M., 10, 118 Espinosa, A., 11, 172 Espinosa, S., 7, 61 Ess, D.H., 12, 18 Estepa, B., 5, 465 Esteres da Silva, J.C.G., 5, 91 Esteves, L.F., 2, 28; 7, 98 Evano, G., 6, 84; 7, 53 Evans, D.J., 4, 150 Evans, P.A., 1, 218; 3, 128; 8, 8 Ezernitskaya, M.G., 12, 219

F Fabian, I., 3, 142 Fabis, F., 5, 277 Fabre, I., 5, 6 Fabrizi, G., 10, 363 Fair, J.D., 9, 48 Fairlamb, I.J.S., 3, 495 Fairlamb, J.S., 5, 572 Faizi, D.J., 10, 141, 143 Fakhari, A.R., 10, 493 Falconer, R.L., 10, 140 Falivene, L., 4, 231; 10, 273 Falk, I.D., 11, 35 Fallan, C., 8, 10; 10, 522 Fallon, B.J., 5, 565 Faltracco, M., 11, 25 Fan, B., 7, 25 Fan, C.-A., 8, 22; 10, 483, 536 Fan, D., 3, 419 Fan, H., 3, 86 Fan, J., 5, 235; 10, 86 Fan, M., 5, 30 Fan, M.-J., 1, 159; 11, 12, 13 Fan, Q.-H., 3, 400, 407 Fan, R.-J., 5, 263 Fan, S.-Q., 6, 115 Fan, T., 3, 73; 5, 79; 6, 37; 8, 76 Fan, W., 3, 187 Fan, X., 5, 323, 527 Fan, Y., 5, 280; 11, 49 Fan, Z., 5, 138 Fananas, F.J., 1, 251; 5, 327 Fa˜nanás-Mastral, M., 7, 12; 12, 144 Fandrick, K.R., 10, 240 Fang, B., 3, 217 Fang, D., 3, 358; 10, 606 Fang, D.-C., 5, 293 Fang, G., 8, 14; 10, 516 Fang, H., 5, 539 Fang, J., 8, 127 Fang, J.-F., 5, 493 Fang, K., 10, 504 Fang, L., 3, 134 Fang, M., 3, 483 Fang, R., 4, 174 Fang, S., 5, 158 Fang, T., 1, 21; 3, 308; 7, 128 Fang, W., 3, 73; 4, 122, 126; 8, 76; 12, 123 Fang, X., 1, 228; 4, 227; 7, 70; 10, 533 Fang, Y., 3, 483; 7, 44, 75 Fang, Z., 7, 68 Fanning, D., 5, 342; 8, 89 Fantin, G., 1, 231 Farès, F., 11, 69 Farina, V., 5, 195 Farmer, M.E., 5, 174; 8, 70 Farokhi, S.A., 3, 19

Farook, N.A.M., 3, 161 Farooq, U., 10, 61 Farooqui, M., 1, 328; 3, 20, 21 Farre, A., 10, 125 Farrell, M., 12, 170 Farren-Dai, M., 7, 97 Fascione, M.A., 1, 17 Faseke, V.C., 1, 188 Fatima, I., 1, 148 Fatkhutdinov, A.R., 10, 461 Fausto, R., 4, 239 Favero, L., 10, 662 Fawzy, A., 3, 9, 66–68, 105, 119, 123, 124, 496 Faza, O.N., 3, 33; 4, 248; 10, 16 Fazzini, S., 5, 88 Fedik, N.S., 5, 43 Fedorov, O.V., 4, 38 Fedoseev, S.V., 12, 230 Fehler, S.K., 3, 83 Fei, N., 7, 169 Feldt, M., 5, 552 Feng, B., 5, 448; 10, 200; 11, 125 Feng, B.-X., 1, 13 Feng, C., 7, 19; 8, 93; 10, 478, 613 Feng, C.-T., 5, 269 Feng, H., 4, 70 Feng, J., 10, 593 Feng, S., 4, 52, 71, 73; 7, 106 Feng, W., 1, 177 Feng, W.-C., 3, 249 Feng, X., 7, 89; 10, 379, 540, 593; 11, 15, 34, 107, 113; 12, 11 Feng, Y., 1, 63; 5, 181, 541, 546; 10, 653 Feng, Z., 4, 35; 5, 311 Fengg, C.-G., 12, 74 Fensterbank, H., 10, 618; 11, 83 Ferguson, M.J., 3, 350 Feringa, B., 5, 316 Feringa, B.L., 4, 200; 7, 12 Ferkinghoff, K., 4, 144 Fernandes, A.C., 3, 469 Fernandes, T. de A., 1, 232 Fernandes, T.A., 3, 469 Fernandez, G.E., 3, 435 Fernández, I., 1, 85; 3, 372, 458; 4, 115; 11, 90 Fernandez, J.J., 5, 327 Fernandez, R., 5, 416, 465 Fernández-Casado, J., 1, 40; 10, 398 Fernández de la Pradilla, R., 4, 136 Fernández-Herrera, M.A., 6, 63, 87, 95; 12, 38 Fernandez-Salas, J.A., 5, 153 Ferreira, E.M., 4, 139; 10, 228

792 Ferreira, F., 5, 565; 10, 315 Ferreira, J., 1, 122; 11, 122 Ferreira, M.A.B., 3, 304 Ferreira, V.F., 1, 242 Ferrer, S., 3, 338 Ferro, V., 3, 366 Fesenko, A.A., 12, 234 Fettinger, J.C., 10, 117 Feula, G., 3, 293 Field, R.J., 3, 181 Field, R.W., 3, 212 Fier, P.S., 5, 25 Filatov, A.S., 6, 86 Fini, F., 3, 262 Finn, P.B., 1, 379 Fiorani, G., 7, 65 Fioravanti, S., 1, 76 Fiser, B., 1, 232; 10, 499 Fisher, H.C., 5, 297; 8, 77 Fisk, J.S., 5, 580 Fitzpatrick, K.P., 10, 193 Fjelbye, K., 1, 318; 8, 129 Fleet, G.W.J., 1, 27 Fleige, M., 10, 133 Fleischer, I., 10, 177 Flematti, G.R., 3, 264 Fleming, F.F., 5, 77; 10, 614 Fletcher, A.M., 10, 435 Fletcher, S.P., 7, 34 Fleurat-Lessard, P., 5, 520 Fleury, F., 3, 182; 10, 58 Floquet, S., 1, 238 Florent, J.-C., 8, 118 Flörke, U., 3, 354; 12, 53 Fogagnolo, M., 1, 230 Follet, E., 6, 12 Font, D., 3, 222 Font-Bardia, M., 11, 168 Fopp, C., 10, 315 Forbes, A.M., 5, 503 Forlani, L., 5, 88 Fornarini, S., 3, 114 Fortes, A.G., 1, 122; 11, 122 Fortier, S., 3, 341 Fossey, C., 5, 277 Foti, M.C., 3, 342 Fotie, J., 3, 230 Fourmy, K., 1, 355 Fout, A.R., 3, 463; 4, 205; 10, 152 Fra, L., 3, 200; 10, 67 Fraboni, A.J., 10, 505 Fraczyk, T., 2, 23 France, S., 6, 85 Franchino, A., 1, 57; 8, 36 Franck, P., 1, 48; 8, 83 Franckeviˇcius, V., 7, 50 Franczyk, T.S., 3, 288 Franke, R., 10, 167 Franzen, J., 6, 113

Author Index Franzen, S., 10, 90 Franzmann, P., 3, 70 Franzoni, I., 5, 351 Fraser, C., 7, 161 Frazier, C.P., 3, 197; 5, 46 Freese, T., 10, 452 Freitag, F., 1, 204; 8, 30 Freitas, J.C.R., 1, 226 Freitas, J.J.R., 1, 226 Frenkel, A.I., 3, 224 Frenking, G., 10, 318 Frensch, G., 1, 262; 8, 58 Frere, P., 5, 238 Frey, W., 1, 214; 12, 146 Frias, M., 1, 50 Friedfeld, M.R., 3, 378 Friedrich, A., 5, 477 Friese, F.W., 1, 178; 8, 20 Frihed, T.G., 3, 477; 10, 6 Friis, S.D., 5, 349; 10, 174 Frings, M., 10, 59 Fristrup, P., 3, 348, 441 Frizzo, C.P., 11, 86 Froese, R.D.J., 5, 84 Fröhlich, R., 6, 25 Fromm, K.M., 4, 107 Fronczek, F.R., 5, 548; 6, 39–41, 82 Frongia, A., 10, 575; 12, 192 Frontera, A., 1, 91; 3, 392 Fruchauf, K.R., 5, 46 Fructos, M.R., 4, 210; 11, 9 Fruehauf, K.R., 3, 197 Frutos, M., 4, 136; 12, 118 Fruzi´nski, A., 11, 72 Fu, B., 4, 256; 10, 258, 559, 579 Fu, C., 5, 228; 6, 72 Fu, G., 10, 165 Fu, H., 4, 99, 100, 245; 5, 429; 7, 114 Fu, J.-G., 11, 98 Fu, K., 11, 107, 113 Fu, S., 3, 430, 431; 5, 518 Fu, X., 1, 373; 5, 451; 10, 643 Fu, X.-L., 10, 70 Fu, X.-N., 1, 298; 10, 339 Fu, Y., 1, 32; 3, 95, 333, 396, 460; 5, 147; 7, 11; 10, 98, 121 Fu, Z., 10, 101 Fuchibe, K., 4, 51; 11, 165 Fuchter, M.J., 3, 379 Fujii, A., 4, 162; 5, 229 Fujimoto, K., 12, 20 Fujino, Y., 5, 252; 10, 511 Fujioka, H., 3, 260; 12, 64 Fujita, K., 3, 461; 4, 162; 10, 376 Fujita, M., 5, 254; 10, 60 Fujita, T., 9, 33; 10, 402 Fujiwara, K., 10, 354

Fujiwhara, M., 1, 345; 3, 448 Fukui, M., 10, 644 Fukumoto, Y., 4, 97 Fukuyama, A., 10, 328 Fukuyama, T., 6, 90; 12, 44 Fukuzawa, S., 10, 594 Fülöp, F., 7, 153 Funes-Ardoiz, I., 3, 42, 206; 4, 46; 7, 145; 10, 62 Funicello, M., 1, 7; 5, 233 Furkert, D.P., 7, 62 Furlan, R.L.E., 1, 14 Furman, B., 1, 271; 10, 603; 11, 71 Fürst, M.C.D., 12, 34 Fürstner, A., 3, 477; 10, 6; 12, 129 Furukawa, A., 4, 93 Furukawa, T., 5, 476 Furusawa, T., 5, 516 Furuta, T., 2, 7 Furuyama, T., 11, 101 Fuse, S., 5, 276 Füser, M., 1, 285; 4, 258 Fustero, S., 7, 153; 10, 471 Futamura, T., 7, 16; 8, 95 Futemma, T., 6, 26

G Gabbai, F.P., 1, 286 Gabidullin, B., 3, 131 Gabidullin, B.M., 4, 178 Gable, R.W., 5, 21 Gäbler, C., 10, 233 Gabriele, B., 10, 209 Gabsi, W., 5, 3 Gackstatter, A., 4, 259 Gadakh, S.K., 3, 475 Gade, A.B., 10, 368; 12, 120 Gagne, M.R., 6, 93; 10, 15 Gagne, R., 3, 224 Gagnot, G., 10, 199 Gai, X., 11, 131 Gai, Y., 3, 217 Gaillard, B., 10, 392; 12, 104 Gajewski, P., 3, 393, 422 Galabov, B., 5, 11 Galetti, M.A., 10, 563 Galindo, J.F., 7, 118 Gallagher, T., 7, 168 Gallegos, C., 10, 349 Gallucci, J., 10, 44 Galvan, A., 1, 251 Gamba, I., 5, 442; 8, 104; 10, 336 Gambacorta, A., 5, 253 Gamba-Sánchez, D., 7, 156 Gandeepan, P., 5, 332, 424; 10, 335 Gandon, V., 1, 238; 4, 254; 7, 29; 12, 25, 122

793

Author Index Gang, T.G., 10, 1 Gangaprasad, D., 11, 81 Ganguly, B., 5, 250 Ganss, S., 10, 265 Ganzmann, C., 10, 556 Gao, B., 1, 133; 4, 54; 5, 519; 10, 306 Gao, B.-F., 10, 587 Gao, G., 3, 360 Gao, G.-L., 5, 594 Gao, H., 12, 18 Gao, J., 5, 114; 10, 218 Gao, J.-M., 10, 39 Gao, J.-R., 5, 262, 263, 567; 8, 96; 10, 438 Gao, K., 5, 352 Gao, L., 5, 387; 7, 163; 9, 10 Gao, M., 10, 629 Gao, P., 1, 159; 3, 246; 5, 496 Gao, Q., 1, 363; 3, 193 Gao, S., 1, 339 Gao, T., 11, 47, 75 Gao, W., 3, 425; 5, 585 Gao, X., 5, 374; 11, 59 Gao, Y., 1, 166; 3, 270, 273; 4, 63; 5, 397 Gao, Y.-N., 1, 80 Gao, Y.N., 10, 391 Gao, Y.Q., 3, 139 Gao, Z., 5, 217; 7, 40; 11, 138 Garad, D.N., 5, 377; 10, 192 Garbe, M., 3, 382 Garc´ıa, J.M., 10, 472 Garcia, F., 11, 168 Garcia-Alvarez, J., 1, 128; 8, 45 Garcia-Castro, M., 10, 544 Garcia-Garcia, C., 5, 257 Garcia-Orduna, P., 5, 549 Garcia-Rodeja, Y., 11, 90 Garcia-Rodriguez, J., 4, 47 Garc´ıa-Ruano, J.L., 10, 513 Gardiner, M.G., 1, 380; 4, 86 Garg, N.K., 5, 95, 122; 11, 67 Garlets, Z.J., 10, 190, 401 Garve, L.K.B., 1, 358; 10, 87; 11, 161, 171 Gary, N.K., 5, 375 Gasonoo, M., 5, 242; 6, 48, 81 Gasperi, T., 5, 253 Gates, P.J., 5, 538 Gati, W., 1, 194 Gaus, K., 9, 1 Gautam, K.S., 6, 96; 12, 42 Gautier, A., 4, 212 Gawai, J., 1, 328; 3, 20 Gayner, E.R., 10, 480 Gazvoda, M., 3, 284; 7, 119 Ge, C., 3, 297; 5, 34, 262 Ge, H., 4, 62 Ge, L., 7, 51

Ge, Q., 3, 38, 39 Ge, S., 1, 319; 5, 346; 8, 109; 11, 15 Ge, X., 5, 55; 10, 268 Ge, Z., 5, 423 Ge, Z.X., 3, 136 Gebauer, K., 12, 7 Gebbink, R.J.M.K., 3, 222 Gebicka, L., 3, 155 Geerlings, P., 5, 19 Gehrtz, P.H., 10, 177 Gekhman, A.E., 3, 267, 268; 10, 113 Gelat, F., 10, 37 Gelbaum, C., 5, 580 Genc, S., 5, 133 Geng, H., 5, 240 Geng, X., 1, 363; 3, 193 Geng, Y., 5, 112 Geng, Z., 5, 70 Genji, I., 12, 92 Gennari, C., 3, 393, 422 Gensch, T., 5, 157 Georgieva, M.K., 1, 357; 10, 506 Georgiou, I., 7, 162 Gerhardt, C., 1, 220 Gerten, A.L., 10, 605 Gervay-Hague, J., 7, 158 Gessner, V.H., 4, 101 Gestin, J.-F., 5, 85 Gevorgyan, V., 4, 90; 5, 329 Ghanbari, M., 3, 256; 12, 163 Ghanem, A., 4, 86 Ghari, H., 1, 380; 5, 540 Gheewala, C., 12, 184 Ghigo, G., 10, 598 Ghisu, L., 12, 192 Gholami, H., 11, 130 Gholap, S.S., 4, 182; 8, 67; 10, 310 Ghorai, J., 3, 29 Ghorai, M.K., 5, 60, 203; 7, 77, 78 Ghorai, P., 10, 532 Ghosh, A., 1, 174; 7, 83; 12, 154 Ghosh, D., 4, 194; 5, 569; 10, 203 Ghosh, K., 5, 366, 367; 10, 230, 231 Ghosh, M., 1, 332 Ghosh, S., 1, 338; 3, 280; 10, 608 Ghosh, S.J., 5, 569 Ghosh, S.K., 4, 194; 10, 203, 521, 556 Giacco, T.D., 3, 115, 116 Giacinto, P., 3, 307; 8, 48 Giedyk, M., 4, 43 Gigot, E., 5, 133

Gilani, M.A., 3, 250 Gilbert, B.B., 10, 50 Gildner, P.G., 5, 66; 7, 165 Gilheany, D.G., 8, 28 Gillingham, D., 7, 169 Gilmour, R., 10, 72 Gil-Negrete, J.M., 6, 56 Gimadieva, A.R., 3, 281 Gimenez-Lopez, J., 3, 273 Gimeno, M.C., 1, 248 Ginotra, S.K., 8, 64; 10, 317 Giofre, S., 1, 354 Giordano, C., 10, 209 Giordano, L., 10, 238 Giorgi, G., 10, 563 Giovannini, P.P., 1, 230, 231 Giraldo, C., 10, 456 Giri, R., 3, 48; 5, 319 Gjmez, A.B., 3, 494 Gladysz, J.A., 10, 556 Glarborg, P., 3, 273 Glass, R.S., 3, 112 Gleason, J.L., 12, 6 Glenadel, Q., 7, 133 Glorius, F., 1, 366; 3, 404; 4, 153, 229; 5, 157; 10, 133 Godovikov, I.A., 3, 47; 12, 235 Goeke, A., 1, 1; 10, 109 Goff, R.L., 12, 45 Goggiamani, A., 10, 363 Gogoi, S., 3, 87 Gogoll, A., 10, 187 Gogula, T., 12, 15 Goh, K.K.K., 7, 161 Gohier, F., 5, 238 Gokavi, G.S., 3, 180 Gold, B., 11, 66 Golden, J.E., 12, 217 Goldfuss, B., 10, 586 Goldsmith, C.F., 3, 273 Goliszewska, K., 4, 43 Gollmar, J.M., 3, 486 Golovanov, A.A., 6, 46; 10, 481, 482 Golz, C., 1, 123; 10, 544; 11, 42 Gomes, G. d. P., 6, 71 Gómez, A.B., 7, 101 Gómez, S., 10, 456 Gomez, L., 5, 53 Gomez-Bautista, D., 10, 157 Gómez-Bengoa, E., 1, 232; 10, 499 Gonçalves, J.R., 10, 474 Goncalves, A.-M., 10, 618; 11, 83 Gonda, Z., 5, 48 Gong, C., 10, 48 Gong, H., 3, 481, 482; 5, 396 Gong, J., 1, 327; 3, 191 Gong, J.-X., 10, 378

794 Gong, L., 10, 458 Gong, L.-Z., 1, 212; 4, 123, 129; 5, 225; 10, 184 Gong, M., 5, 213 Gong, X., 10, 211 Gong, Y., 11, 103; 12, 50 Gonnade, R.G., 4, 219; 5, 109, 110, 204, 576; 6, 75; 10, 400; 12, 47, 193, 214 Gonzales, M.M., 9, 9 Gonzales-Nunez, M.E., 6, 50 González, J., 4, 46, 47, 134 González, J.M., 10, 397; 11, 143 González, L., 12, 19 González, M.A.C., 7, 101 González, R., 7, 118 Gonzalez, J.M., 1, 39 Gonzalez Comesana, M., 1, 146 Gonzalez-Esguevillas, M., 1, 135; 5, 390 Gonzalez-Perez, A.B., 1, 251 Goodman, J.M., 1, 116 Goossen, L.J., 5, 294, 395, 430, 489 Gooßen, L.J., 10, 236 Gopal, K., 5, 160 Gopalan, G., 10, 291 Gopalasetty, N., 1, 310 Gopalkrishnan, B., 5, 144 Gopal Reddy, S., 6, 106 Gorden, J.D., 12, 36 Gordon, J.C., 1, 341; 3, 367 Gordon, M.S., 7, 138 Gore, B.S., 5, 5; 10, 111 Gorelsky, S.I., 4, 178 Gornitzka, H., 4, 136; 12, 118 Gorobets, E., 5, 98 Gosmini, C., 5, 336 Goswami, A., 2, 22 Goswami, G., 3, 4 Gou, Q., 3, 45 Goudar, S.C., 3, 69 Goumont, R., 5, 3 Gounder, R., 3, 385 Gour, S., 3, 21 Gouygou, M., 1, 355 Govender, T., 2, 3 Gowda, J.I., 3, 49 Gowda, N.M.M., 3, 121 Goya, T., 12, 143 Grˆıtzmacher, H., 4, 163 Graham, T.J.A., 4, 64 Grandclaudon, C., 5, 131; 10, 69 Grange, R.L., 3, 128 Gratia, S., 4, 109 Gray, A., 4, 124 Gray, E.E., 4, 64 Gray, K.V., 5, 82; 12, 48 Greaney, M.F., 10, 425 Greck, C., 1, 238

Author Index Gredicak, M., 9, 35 Grée, D., 11, 70 Grée, R., 1, 196; 11, 69, 70 Green, R.A., 12, 59 Green, W.H., 1, 330 Greenhalgh, M.D., 8, 10; 10, 522 Greer, A., 8, 110 Greer, E.M., 8, 110 Grela, K., 3, 446 Griffiths, G.J., 1, 221 Grimaud, L., 5, 6, 520, 577 Grimblat, N., 5, 265; 11, 97 Grimm, C.C., 3, 230 Grimme, S., 1, 82; 3, 354, 410; 12, 53, 69 Grinberg, N., 5, 375, 466 Grinenko, E.V., 5, 244; 6, 32, 33; 9, 4 Grisel, J., 11, 20 Grolleau, J., 5, 238 Gross, A.K., 3, 486 Grossmann, A.S., 12, 58 Grubbs, R.H., 3, 277, 317; 10, 166, 191 Gruden, M., 10, 382 Grugel, C.P., 10, 255 Grün, A., 10, 468 Grünenfelder, C.E., 1, 388; 10, 497 Grützmacher, H., 4, 145 Gryko, D., 4, 43 Gryko, D.T., 3, 111 Gryszel, M., 12, 5 Gu, B., 5, 228 Gu, C.-Z., 4, 151; 9, 20 Gu, D.-W., 1, 222; 8, 85 Gu, J., 10, 156 Gu, K., 3, 243 Gu, Q., 5, 514 Gu, R., 5, 106; 12, 79 Gu, T., 7, 3 Gu, X., 3, 141, 217 Gu, Y., 1, 21; 7, 128; 12, 23 Gu, Y.-C., 4, 44 Gu, Z.-Y., 5, 484 Gualandi, A., 1, 94 Gualtierotti, J.-B., 4, 200; 5, 316 Guan, B.-T., 3, 439 Guan, C.S., 10, 313 Guan, H., 4, 213; 10, 81 Guan, W., 5, 15 Guan, Y.-Q., 12, 133 Guang, J., 1, 53 Guarnaccio, A., 1, 7; 5, 233 Gubaidullin, I.M., 10, 351 Gubaidullin, R.R., 10, 347 Guchhait, S.K., 3, 252 Guduguntla, S., 7, 12 Guell, I., 5, 53 Guénée, L., 1, 3; 4, 105

Guerard, F., 5, 85 Guerra, C.F., 7, 104 Guerrero, P.G., 1, 262; 8, 58 Gui, Q., 5, 487 Guidetti, F., 1, 23 Guignard, R.F., 12, 162 Guillaumet, G., 5, 535 Guillot, R., 5, 220, 236; 10, 326, 327, 575 Guin, M., 3, 121 Guiry, P.J., 9, 30 Gulden, D., 1, 214 Gulder, T., 3, 151; 8, 120; 10, 78; 12, 215 Gulias, M., 11, 167 Gulko, C., 5, 50 Gunaga, P., 1, 157 Gunanathan, C., 3, 359 Gund, M., 4, 140 Gundala, S., 1, 310 Guntreddi, T., 5, 480 Guo, B., 6, 72; 10, 424 Guo, C., 3, 132; 12, 165 Guo, D.-S., 10, 204 Guo, F., 10, 634, 635 Guo, H., 5, 304, 387, 434; 7, 136; 10, 415; 11, 47, 59, 75, 92, 138 Guo, H.-M., 11, 32 Guo, J., 3, 171; 5, 114; 8, 131; 10, 161; 12, 11 Guo, L., 5, 317, 318, 539 Guo, L.-P., 4, 72 Guo, P., 5, 509 Guo, Q., 1, 136; 10, 505 Guo, R., 10, 84 Guo, S., 3, 191; 5, 304, 527; 7, 67; 10, 540 Guo, T., 5, 360, 537; 10, 640 Guo, W., 6, 59; 7, 18, 64, 139; 12, 161 Guo, X., 3, 141; 7, 67; 10, 541 Guo, X.-H., 7, 68 Guo, X.-S., 3, 147 Guo, X.-X., 1, 222; 8, 85 Guo, Y., 5, 148; 8, 132; 10, 268 Gupta, A., 3, 122 Gupta, D., 3, 126 Gupta, K., 5, 474 Gupta, N.R., 10, 496 Gupta, S., 9, 7, 8 Gupta, V., 3, 65 Gurak, J.A., 10, 170, 171 Gurbuz, N., 4, 188 Gurjar, J., 10, 532 Gurka, A.A., 1, 182 Gurubrahamam, R., 1, 233; 10, 587 Gurung, L., 5, 167 Gurung, S.K., 3, 48

795

Author Index Gurzhig, V.V., 5, 218 Gusarova, N.K., 10, 445 Gusevskaya, E.V., 3, 315 Gustafson, J.L., 5, 126 Gutierrez, D.A., 5, 177 Gutierrez, O., 4, 255 Gutiérrez-Jiménez, M.I., 10, 455 Gutierrez-Oliva, S., 2, 14 Guzei, I.A., 4, 250 Guzik, P., 12, 5 Guzman-Angel, D., 2, 14 Guzov, E.A., 9, 2 Gyanchander, E., 12, 145 Gyüjtö, I., 12, 233

H Ha, T.M., 10, 292 Ha, U., 1, 253 Haas, D., 5, 573 Haas, T.M., 3, 493; 10, 648 Habibi, A., 10, 493 Habibi-Khorassani, S.M., 1, 42, 364 Hachem, A., 11, 69, 70 Hachiya, I., 1, 209; 10, 465 Hack, D., 10, 588, 589 Hackenberger, D., 5, 395, 489 Haddad, N., 5, 375, 466 Haddon, R.C., 7, 142 Hagashi, Y., 5, 574 Hage, R., 3, 231 Hagerman, C.E., 10, 406; 12, 54 Hai, L., 5, 270 Haider, M.A., 9, 7, 8 Haimov, E., 1, 199 Haines, R.S., 6, 18; 7, 116 Hajek, P., 8, 124 Hajra, A., 3, 310; 5, 271; 10, 51 Hakala, J.P., 3, 213 Halauko, Y.S., 5, 275 Haley, C.K., 5, 111 Hall, D.G., 1, 215; 6, 112 Hall, J.E., 5, 82; 12, 48 Hall, M.B., 5, 292 Hall, M.G.H., 5, 137 Halldin, C., 7, 101 Halliday, C.J.V., 10, 18 Halperin, H.M., 5, 321 Halskov, K.S., 11, 30 Halvagar, M.R., 11, 48 Hamachi, Y., 10, 411 Hamada, Y., 5, 300, 435 Hamadi, N.B., 11, 74 Hamaguchi, H., 5, 29 Hamashima, Y., 10, 38 Hamdan, L., 3, 357; 10, 114 Hamel, J.-D., 7, 27 Hamilton, T.G., 10, 128 Hamlin, T.A., 3, 133 Hammal, R., 4, 19, 20

Hammann, J.M., 5, 573 Hammond, G.B., 7, 80; 10, 358 Hampton, C.S., 12, 147 Han, B., 10, 288 Han, F.-S., 1, 161 Han, J., 1, 52; 4, 37; 5, 261, 469, 529; 8, 18; 10, 358, 620; 11, 110; 12, 227 Han, J.-L., 1, 190 Han, J.T., 10, 289 Han, L., 1, 63; 11, 6; 12, 216 Han, L.-B., 1, 387; 4, 55; 9, 19; 10, 659 Han, L.-L., 10, 261 Han, M., 11, 115; 12, 13 Han, P., 1, 331; 4, 16 Han, Q., 5, 518 Han, R., 4, 236; 11, 57 Han, R.-Z., 11, 115 Han, S., 1, 246; 4, 171; 5, 187, 361, 384, 553; 10, 245, 601, 637 Han, S.-J., 7, 43 Han, S.-L., 5, 537 Han, S.-M., 10, 261 Han, S.H., 5, 187, 361, 384, 553; 10, 245, 637, 638 Han, S.J., 1, 10 Han, X., 4, 50; 5, 568; 10, 206, 626; 11, 33, 131 Han, Y.-P., 10, 407; 11, 170 Han, Z., 10, 249 Han, Z.-Y., 1, 212; 4, 129; 5, 225, 376; 10, 184, 185, 388; 12, 133 Hanagadakar, M.S., 3, 23 Hanakawa, T., 7, 16; 8, 95 Handa, S., 5, 68 Hang, F., 10, 136 Hang, Z., 1, 246 Hanna, L.E., 5, 322 Hanninen, M.M., 3, 426 Hansen, C.L., 5, 256; 6, 107 Hansen, T., 7, 127 Hansen, T.V., 10, 36, 68 Hansmann, M.M., 12, 71 Hanuman Reddy, V., 6, 64, 106 Hao, J., 3, 328 Hao, W., 3, 491; 5, 92, 501; 9, 42; 11, 80 Hao, W.-J., 12, 56 Hao, X.-Q., 3, 28; 5, 173; 7, 32 Hao, Z., 11, 134, 173 Hapke, M., 11, 149 Haque, H.N., 3, 306 Hara, H., 11, 146 Hara, O., 11, 89 Harabuchi, Y., 7, 138 Harada, A., 4, 217; 5, 550; 7, 28 Harada, S., 1, 259

Harada, T., 1, 268; 5, 348 Harakat, D., 10, 291 Hardee, D.J., 3, 334 Hardman-Baldwin, A.M., 10, 110 Hare, S.R., 6, 6 Hari, D.P., 4, 57; 5, 421; 8, 119; 10, 3 Hari, T.P.A., 10, 450 Haribabu, K., 10, 564 Harjani, J.R., 5, 21 Harmata, M., 12, 147 Harms, K., 1, 224 Harode, M., 12, 159 Harper, J.B., 6, 18; 7, 116, 117 Harrath, K., 7, 2 Harris, R.J., 4, 3; 6, 2 Harris, T., 1, 5; 6, 71; 10, 369 Harris, T.V., 4, 34; 7, 144; 8, 126 Harrison, J.G., 4, 255 Harrity, J.P.A., 5, 178; 9, 36; 10, 227; 11, 64 Hartigan, E.M., 3, 293 Hartley, W.C., 11, 64 Hartmann, R.W., 12, 19 Hartwig, J., 8, 100 Hartwig, J.F., 1, 219, 319; 3, 291; 5, 306, 307, 346, 388; 7, 21; 8, 101, 103; 10, 283 Harutyunyan, S.R., 1, 270; 8, 4, 47; 12, 168 Harvey, J.N., 7, 126 Hase, W.L., 7, 137 Hasegawa, E., 3, 41 Hasegawa, J.-y., 7, 63 Hasegawa, Y., 10, 29 Hashemi, H., 3, 273 Hashimoto, T., 11, 157 Hashimoto, Y., 7, 157 Hashizuma, D., 5, 99 Hashizume, D., 4, 261 Hashmi, A.S.K., 4, 121, 128; 5, 540; 6, 70; 8, 79; 10, 377, 381; 12, 71, 112 Hashmi, M.A., 3, 250, 478 Hasome, A., 1, 263; 8, 61 Hassam, M., 6, 65; 12, 187 Hassan, R.M., 3, 67 Hastings, B.T., 1, 68 Hata, T., 4, 93 Hatakeyama, T., 5, 287, 584 Hatanaka, M., 4, 34; 7, 144; 8, 126 Hatanaka, Y., 8, 13; 10, 558, 592 Hatano, M., 1, 303; 5, 370; 8, 52, 102; 10, 277, 651 Hattori, T., 5, 272 Haubenreisser, S., 3, 194; 10, 4 Haufe, G., 1, 178; 8, 20; 10, 471 Haun, G.J., 1, 333

796 Havama, M., 11, 18 Haven, T., 5, 378 Hawker, R.R., 7, 117 Hayashi, M., 10, 328 Hayashi, S., 4, 32 Hayashi, T., 5, 362; 10, 631, 633, 641 Hayashi, Y., 1, 268; 3, 201; 5, 348; 10, 496, 498 Haydl, A.M., 10, 262, 264 Hayes, P.G., 3, 426 Hazai, L., 4, 45 Hazama, Y., 5, 100 Hazari, N., 5, 472 Hazra, C.K., 5, 411 Hazra, M., 8, 39; 10, 649 Hazra, S., 4, 161 He, G., 1, 147; 3, 221; 5, 340, 347; 10, 86, 299 He, H., 5, 24; 10, 490 He, J., 4, 92; 5, 101, 174; 8, 92; 12, 131 He, K.-H., 3, 88 He, L., 4, 13, 151, 236; 9, 20; 11, 57 He, M., 1, 69; 3, 215; 5, 145 He, Q., 5, 7 He, R., 3, 118; 5, 438; 10, 323 He, S., 6, 10; 7, 122 He, S.-G., 6, 35 He, W., 1, 35–37; 4, 22–24; 5, 304, 408; 10, 101, 272, 298; 12, 3 He, X., 5, 172, 457 He, Y., 1, 88; 3, 407, 411; 5, 114, 554; 8, 122; 11, 111, 123; 12, 68 He, Y.-M., 3, 400 He, Y.-T., 5, 223; 10, 302 He, Z., 7, 25; 8, 17; 10, 195; 12, 216 Hedhli, A., 5, 458 Hedidi, M., 5, 275 Heerdt, G., 5, 355 Hegde, M.S., 3, 52 Heidary, M., 1, 250 Heijnen, D., 4, 200; 5, 316 Heimgartner, H., 4, 18; 12, 175 Heinrich, M., 10, 262 Heinrich, M.R., 3, 83; 12, 34 Heinze, K., 3, 70 Helquist, P., 1, 195 Hemmert, C., 4, 136; 12, 118 Hemming, O.B., 4, 150 Hemric, B.N., 10, 287 Hennecke, U., 10, 45 Hennig, L., 1, 156 Henrion, M., 3, 329; 4, 198 Henrion, S., 12, 17 Henry, J.L., 6, 40, 82

Author Index Henry, R., 5, 36 Henyecz, R., 2, 16 Heo, J., 5, 190 Hepburn, H.B., 1, 100; 12, 130 Heravi, M.M., 10, 11 Hermández-Diaz, C., 11, 143 Hermann, M., 10, 318 Hernandez-Linares, M.A., 6, 95 Hernández-Rodr´ıguez, M., 10, 568 Hernan-Gomez, A., 1, 128; 8, 45 Herndon, J.W., 11, 178; 12, 30 Herrebout, W.A., 3, 289 Herrera, B., 2, 14 Herrero, M., 6, 66 Hertsen, D., 5, 19 Hertzberg, R., 1, 305 Hessz, D., 10, 468 Heugebaert, T.S.A., 10, 660 Heurich, T., 12, 69 Hevia, E., 1, 128, 176; 8, 45 Heyte, S., 3, 389 Hida, S., 3, 424 Hie, L., 5, 375 Hiemstra, H., 10, 539 Hierso, J.-C., 5, 133 Higashida, K., 3, 424 Higashihara, K., 3, 424 Higashimae, S., 10, 354 Higuchi, Y., 10, 196 Hikawa, H., 7, 124 Hilario-Martinez, J.C., 6, 95 Hilinski, M.K., 11, 35 Hilmersson, G., 7, 155 Hilpert, L.J., 10, 264 Himo, F., 2, 27; 7, 130 Hintermann, L., 1, 220; 10, 237 Hirai, M., 1, 286 Hirai, N., 10, 353; 12, 229 Hiran, B.L., 3, 6 Hirano, K., 3, 340; 4, 186; 5, 449; 7, 4; 8, 94; 10, 123, 294 Hirao, H., 1, 349; 3, 223, 445; 10, 611 Hirao, T., 3, 279 Hirner, J.J., 10, 142 Hirose, D., 3, 284; 7, 119 Hiroya, K., 5, 368; 10, 328, 329 Hirsch, M., 5, 108 Hirschbeck, V., 10, 177 Hirschi, J.S., 1, 307 Hitchcock, S.R., 7, 31; 8, 15 Hiyama, T., 5, 446; 10, 217 Ho, G.-M., 10, 476 Ho, P.-H., 10, 305 Hocek, M., 10, 222 Hochlaf, M., 7, 2 Hofkens, J., 6, 30 Hohloch, S., 4, 147 Holden, B., 5, 580

Holden, C.M., 10, 425 Holstein, S.A., 3, 479 Honarparvar, B., 2, 3 Honda, K., 4, 34; 7, 144; 8, 126; 12, 176 Hong, A.Y., 7, 20; 12, 8 Hong, B.-C., 8, 16; 10, 512 Hong, G., 3, 312; 10, 429 Hong, R., 3, 266 Hong, S., 5, 536; 10, 130, 131; 12, 161 Hong, S.H., 3, 89 Hong, W.-X., 3, 57; 11, 133 Hong, Y., 3, 444 Honma, H., 5, 368; 10, 329 Hooker, J.M., 5, 18 Hopfl, H., 3, 156 Hoque, E., 5, 412 Horibe, T., 1, 303 Horiuchi, Y., 5, 69 Hornillos, V., 4, 200; 5, 316, 416; 7, 12 Horvath, H., 4, 206 Hosek, J., 4, 110 Hoshimoto, Y., 4, 161 Hoshino, Y., 10, 644; 12, 176 Hoshiya, N., 8, 88 Hosoda, N., 1, 263; 8, 61 Hosoya, T., 5, 99, 100 Hossein Bagi, A., 1, 380 Hosseinzadeh, R., 1, 250 Hosseyni, S., 10, 355, 367; 12, 125 Hossian, A., 5, 394 Hou, C., 4, 244; 12, 208 Hou, G., 1, 88; 3, 411–413 Hou, H., 3, 291; 5, 306 Hou, L., 10, 266 Hou, S., 12, 3 Hou, W., 4, 70 Hou, X., 10, 559 Hou, X.-F., 3, 97; 5, 405 Hou, X.-L., 1, 211; 4, 196 Hou, Z., 4, 182; 5, 16; 8, 67; 10, 310, 416 Houghton, M.J., 1, 115 Houk, K.N., 1, 170, 183; 7, 120, 140, 147; 8, 112; 10, 454; 11, 67, 177 Hoveyda, A.H., 1, 213; 7, 14; 10, 617 Howard, J.K., 3, 330 Howell, A.R., 5, 534 Hoye, T.R., 3, 346; 5, 116; 10, 428 Hrudka, J.J., 12, 61 Hsiao, C.-C., 5, 317 Hsieh, K.-H., 10, 501 Hsu, C.-P., 3, 139 Hsu, W.-H., 11, 28

797

Author Index Hu, B., 10, 379 Hu, C., 1, 283; 3, 217; 10, 429; 11, 111 Hu, C.-H., 4, 195; 5, 393 Hu, C.-W., 3, 311 Hu, D., 3, 292 Hu, F., 4, 48, 53; 5, 40, 491; 6, 19; 10, 235; 12, 190 Hu, G., 5, 94 Hu, H., 4, 209; 7, 37; 10, 199, 414; 11, 29; 12, 11 Hu, J., 1, 315; 4, 51, 199, 256; 8, 19; 10, 39, 258, 426, 487; 11, 103, 165 Hu, J.-Y., 5, 223; 10, 302 Hu, L., 1, 9, 105, 154; 5, 315, 339, 487; 7, 139; 10, 535 Hu, P., 6, 42; 10, 325 Hu, P.P., 5, 90 Hu, Q., 3, 423 Hu, Q.-T., 3, 282 Hu, R., 10, 165 Hu, S., 5, 16 Hu, S.-B., 3, 384, 457 Hu, T.-J., 12, 74 Hu, W., 1, 126; 3, 297; 4, 54, 82, 154; 5, 34, 130; 10, 306; 12, 68 Hu, W.-P., 3, 259; 5, 5; 10, 111 Hu, W.-R., 5, 209 Hu, X., 1, 243; 3, 416, 427; 4, 68; 5, 182, 559; 7, 15; 8, 7; 10, 297, 565; 12, 76 Hu, X.-G., 7, 68 Hu, X.-P., 11, 140 Hu, X.-Q., 10, 441 Hu, Y., 1, 41, 130, 151; 3, 38; 5, 497; 9, 10; 10, 458; 11, 22, 128 Hu, Y.-C., 4, 193; 5, 463 Hu, Z., 1, 160; 3, 186, 192; 10, 257; 11, 79 Hua, C., 5, 509 Hua, H.-L., 5, 223; 10, 302 Hua, M., 5, 92 Hua, R., 10, 424 Hua, Y.-Z., 5, 264 Huang, B., 4, 133, 256; 5, 359; 10, 258, 385; 12, 95 Huang, C., 11, 75 Huang, C.Z., 5, 90 Huang, D., 1, 41, 151; 4, 175; 5, 497; 11, 22 Huang, F., 1, 326; 3, 476; 5, 179 Huang, G., 3, 345; 4, 111; 7, 130; 10, 278, 279; 11, 49 Huang, H., 1, 11, 133, 140, 272, 350; 3, 285, 387; 5, 519; 7, 51, 134; 8, 43; 10, 40, 84, 86, 299, 462, 580

Huang, H.-X., 10, 475 Huang, J., 1, 227; 7, 51, 112; 10, 84, 296, 380 Huang, J.-K., 3, 302 Huang, J.-W., 5, 508 Huang, K., 4, 76; 7, 61; 10, 304, 374 Huang, K.W., 5, 163 Huang, L., 3, 191, 314; 4, 128; 5, 430; 10, 202, 205, 236, 381; 12, 128 Huang, M., 5, 213 Huang, P.-Q., 5, 240, 241 Huang, Q., 5, 507, 518 Huang, S.-L., 1, 378; 4, 108 Huang, T.-Z., 5, 258 Huang, W., 1, 21, 46; 3, 224; 7, 128 Huang, W.-S., 10, 31 Huang, W.-Y., 1, 233 Huang, X., 1, 177; 2, 4; 4, 13, 40, 96; 5, 23, 228; 6, 72; 10, 545; 12, 82 Huang, X.C., 3, 136 Huang, Y., 5, 31, 145; 7, 75, 85, 159; 8, 23; 10, 633; 11, 164 Huang, Y.-H., 5, 240, 241; 12, 41 Huang, Y.-S., 11, 40 Huang, Z., 3, 196, 293; 5, 27, 96, 539; 7, 163; 9, 29; 10, 151, 162 Huang, Z.-B., 5, 529 Huang, Z.-D., 7, 166 Huang, Z.-Z., 3, 254; 5, 212 Huang, Z.L., 5, 454; 10, 259 Hubin, P.O., 1, 185 Hübner, E.G., 10, 452 Huck, C.J., 1, 115 Huestis, M.P., 5, 409 Hughes, N.L., 3, 319 Hui, X.-P., 4, 222 Hui, Z., 2, 17; 7, 99 Hullaert, J., 6, 76 Hullatti, P.K., 3, 69 Hume, P.A., 7, 62 Hummel, J.R., 5, 369 Humne, V.T., 12, 164 Hung, C., 1, 61 Hung, C.-I., 1, 56 Hunt, J.R., 1, 322 Huo, C., 3, 31, 110, 275 Huo, P., 5, 457 Huo, S., 7, 125 Huple, D.B., 4, 135 Hurley, P.B., 8, 121 Hussain, M.I., 12, 68 Hussein, M., 11, 69 Hutchings, M., 10, 61 Huynh, K., 4, 139; 10, 228 Hwang, G.-S., 10, 570

Hwang, H.T., 3, 385 Hyogo, M., 5, 290

I Iadonisi, A., 1, 18 Iazzetti, A., 10, 363 Ibrahim, A.D., 3, 463; 4, 205; 10, 152 Ibrahim, H., 4, 212; 5, 63 Ibsen, L., 11, 41 Ichikawa, J., 4, 51; 9, 33; 10, 402; 11, 165 Idris, S., 1, 164 Idttalbe, N., 10, 618; 11, 83 Ievlev, M.Y., 1, 362; 12, 230 Igawa, K., 5, 229 Igei, M., 5, 38 Igeia, M., 12, 196 Iglesias, M., 10, 157 Iglesias, M.J., 8, 38 Iglesias-Siguenza, J., 5, 416, 465 Ignat’ev, N.V., 10, 2 Iida, H., 3, 232 Ikariya, T., 1, 345; 3, 448 Ikeda, K., 7, 16; 8, 95 Ikeda, R., 3, 395 Ikeda, T., 10, 146 Ikemoto, K., 10, 29 Ikonnikov, N.S., 12, 219 Ilies, L., 3, 336; 5, 324 Il’in, A.V., 10, 461 Ilovaisky, A.I., 10, 58 Ilovaisky, A.L., 3, 182 Imagawa, H., 5, 229 Imamoto, T., 5, 69 Imamura, A., 1, 19 Imaoka, H., 9, 26; 10, 410 Imayoshi, A., 2, 7 Inada, T., 11, 24 Inamo, M., 1, 29 Inamoto, K., 5, 528; 10, 256 Incerti-Pradillos, C.-A., 10, 340 Ingemann, S., 10, 539 Inman, M., 11, 100 Inostroza-Rivera, R., 2, 14 Inoue, H., 5, 252; 10, 511 Inoue, K., 10, 376 Inturi, S.B., 11, 50 Iqbal, J., 3, 250, 478; 5, 581 Iranpoor, N., 5, 522 Irastorza, A., 3, 78 Iriarte, I., 10, 472 Irwin, L.C., 4, 241 Isaac, K., 10, 315 Ise, Y., 10, 256 Isenegger, P.G., 1, 202 Ishida, H., 1, 19 Ishida, S., 5, 284 Ishihara, K., 1, 29, 303; 3, 194; 8, 52; 10, 4, 43, 651

798 Ishii, K., 5, 308, 309 Ishikawa, R., 4, 149 Ishikawa, S., 12, 70 Ishikawa, T., 3, 232 Ishikura, M., 10, 301 Ishitsuka, T., 10, 179 Ishizaka, T., 1, 260; 8, 66 Ishmaeva, E.A., 7, 105 Ishmuratov, G.Y., 10, 96 Islam, M.A., 2, 17; 7, 99 Islam, N., 10, 591 Islam, S., 5, 575 Isono, T., 10, 477 Issaian, A., 10, 141 Itami, K., 3, 335; 5, 165, 579, 584 Itatsu, Y., 5, 252; 10, 511 Itazaki, M., 3, 107 Ito, F., 12, 77 Ito, H., 1, 293; 5, 286; 10, 116 Ito, J., 1, 225; 10, 627 Ito, S., 1, 209, 263; 8, 61; 10, 465 Itoh, S., 3, 235, 313 Ivanon, A.Y., 6, 28 Ivanov, A.Y., 5, 245; 6, 46; 10, 481 Ivanov, K.L., 7, 90 Ivanova, N.I., 10, 445 Ivanshkina, E., 5, 194 Ivashkevich, O.A., 5, 275 Ivashkin, P., 4, 85 Ivkovic, B., 10, 550 Iwabuchi, Y., 3, 135; 9, 22 Iwaki, R., 1, 27 Iwamoto, H., 3, 41; 10, 116 Iwamoto, T., 5, 284 Iwanaga, M., 1, 58 Iwasa, S., 7, 95 Iwasa, T., 1, 184 Iwasaki, H., 4, 149 Iwasaki, M., 10, 199 Iwasaki, S., 4, 32 Iwasaki, T., 7, 47; 8, 50 Iwasawa, T., 10, 365, 366 Iwata, K., 7, 93 Iwatsuki, S., 1, 29 Iyori, Y., 4, 97 Iyun, J.F., 3, 210 Izadyar, M., 7, 115 Izumi, K., 5, 286 Izumi, S., 10, 440 Izzo, J.A., 1, 307; 3, 130

J Jablonkai, E., 2, 16 Jackl, M.K., 5, 122 Jackowski, O., 10, 315 Jackson, J.E., 10, 32 Jackstell, R., 10, 167

Author Index Jacobsen, E.N., 3, 334; 10, 71, 76 Jacquemin, D., 1, 185 Jadidi, K., 3, 256; 12, 163 Jafari, B., 5, 132 Jaferian, G., 3, 16 Jaganathan, A., 5, 580 Jagannadham, V., 7, 129 Jager, M., 3, 320 Jaglinski, T.C., 3, 486 Jagtub, R.A., 5, 576 Jain, I., 1, 335; 3, 176 Jain, N., 5, 570; 10, 300 Jain, P., 5, 174, 594 Jaiswal, G., 5, 425 Jaiswal, Y., 5, 482 Jakhar, A., 1, 119 Jakli´nska, M., 10, 597 Jakobsche, C.E., 7, 125 Jalal, S., 12, 55 Jalan, A., 1, 330 Jalife, S., 6, 63, 87; 12, 38 Jamal, Z., 1, 376 Jamieson, M.L., 7, 62 Jamison, T.F., 1, 199 Jana, C.K., 1, 338; 3, 280 Jana, R., 5, 170, 394 Jana, S., 10, 51; 12, 201, 223 Jana, U., 12, 55 Jandl, C., 10, 159 Jang, H.-Y., 1, 10, 383; 8, 81 Jang, J., 5, 418 Jang, W.J., 10, 135, 289 Janich, S., 10, 41 Janjetovic, M., 7, 155 Janni, M., 5, 279 Janssen-Müller, D., 1, 366; 4, 153 Janzen, D.E., 3, 421 Jaque, P., 3, 372 Jarhad, D.B., 12, 31 Jaroschik, F., 10, 291 Järving, I., 12, 199 Jarvo, E.R., 5, 322 Jarwal, N., 1, 277 Jarzynski, S., 1, 265; 8, 59 Jaˇs´ık, J., 4, 124 Jasi´nski, M., 11, 72 Jasinski, R.A., 9, 11 Jaszczuk, K., 5, 4 Jattinagoudar, L., 3, 22 Jeanne-Julien, L., 7, 29 Jedrysiak, R.G., 5, 52 Jeffrey, C.S., 6, 79; 11, 61, 63 Jena, H.S., 3, 424 Jenkins, H.A., 11, 11 Jensen, F., 1, 2; 5, 251; 11, 99 Jeon, H.J., 5, 526 Jeon, J., 3, 471 Jeon, M., 5, 187, 188, 553 Jeon, T., 5, 361

Jeong, S.A., 7, 39 Jeong, T., 5, 384; 10, 637 Jeschke, J., 10, 233, 234 Jessing, M., 5, 12 Jesús Durán-Pe˜na, M., 10, 560 Jha, A., 1, 64 Ji, C., 3, 377 Ji, D., 3, 43; 5, 172 Ji, E., 5, 61 Ji, G., 4, 52 Ji, J., 10, 604 Ji, L.-N., 2, 24 Ji, S.-J., 5, 436, 484; 10, 208 Ji, W., 5, 200; 6, 77; 11, 60 Ji, X., 3, 285; 10, 403 Ji, Y., 3, 457 Jia, C., 1, 138; 4, 60 Jia, F., 7, 7 Jia, F.-C., 5, 58 Jia, J., 3, 132; 5, 40, 483, 521; 12, 113, 190 Jia, J.-H., 10, 438 Jia, M., 4, 1 Jia, P., 7, 85; 8, 23 Jia, S., 9, 10 Jia, T., 3, 118; 5, 438; 10, 323 Jia, X., 3, 242; 10, 654; 12, 98, 105 Jia, Y.-M., 1, 27 Jia, Y.-X., 5, 262, 263, 567; 8, 96 Jia, Z.-L., 8, 127 Jian, N.-G., 7, 32 Jiang, B., 1, 269; 3, 187; 12, 56 Jiang, C., 5, 304, 397, 408, 514; 10, 137, 272; 12, 117 Jiang, D.-e., 7, 142 Jiang, H., 1, 44, 141, 149; 3, 258, 314, 324; 4, 54, 66, 68, 100, 244; 5, 24, 161, 202, 330, 331, 559; 6, 59; 7, 39, 40, 75; 8, 92; 9, 31; 10, 186, 202, 205, 213, 306, 490; 11, 99 Jiang, H.-C., 10, 122 Jiang, J., 3, 36, 418; 5, 161; 10, 298; 11, 80; 12, 73, 208 Jiang, J.-H., 3, 259; 5, 209 Jiang, K., 6, 78 Jiang, L., 1, 106, 110, 373; 5, 247; 11, 47, 75 Jiang, L.L., 5, 454; 10, 259 Jiang, M., 1, 321; 3, 216 Jiang, P., 12, 152 Jiang, Q., 3, 132; 5, 360; 10, 640 Jiang, R., 5, 448; 10, 200 Jiang, S., 1, 324; 7, 17 Jiang, T., 3, 77

799

Author Index Jiang, X., 1, 219; 7, 21; 8, 101; 10, 28; 12, 221 Jiang, Y., 3, 323; 5, 30, 512; 12, 132 Jiang, Y.-J., 5, 147 Jiang, Y.-N., 10, 412 Jiang, Y.-Y., 3, 95; 10, 121, 393 Jiang, Z., 3, 134; 8, 7; 10, 565; 11, 102 Jiang, Z.-X., 10, 658 Jiao, H., 3, 382 Jiao, J., 5, 165, 579 Jiao, N., 3, 104, 149, 326; 5, 184, 439; 10, 333 Jiao, P., 12, 3 Jiao, X., 5, 346 Jiao, Z., 1, 319; 5, 345 Jijy, E., 10, 246 Jiménez, A., 4, 36 Jiménez, E.I., 10, 568 Jimenez, M.V., 10, 157 Jiménez, T., 6, 74; 10, 399 Jimenez-Jimenez, J., 5, 91 Jiménez-Osés, G., 7, 140; 8, 112; 10, 455 Jimeno, C., 1, 317 Jin, C., 4, 83; 12, 142 Jin, D.-P., 3, 246; 10, 407; 11, 170 Jin, E., 5, 260 Jin, H., 1, 147; 3, 221; 4, 128; 10, 218, 381, 570 Jin, K., 1, 373 Jin, M., 1, 293 Jin, M.Y., 8, 62; 10, 636 Jin, Q.-W., 11, 43 Jin, R., 5, 387, 434; 10, 415 Jin, S., 12, 117, 124 Jin, T., 3, 109; 10, 545 Jin, W., 4, 82 Jin, X., 3, 483; 7, 44; 10, 86 Jin, Y., 1, 319; 5, 346, 500 Jin, Z., 5, 112; 6, 95 Jing, C., 4, 84 Jing, Q.-W., 10, 412 Jing, Y., 3, 376, 408 Jirak, J.G., 4, 250 Jo, H., 5, 188, 384, 553; 10, 637 Johannes, L., 8, 118 Johansson, M.J., 7, 101 John, J., 10, 291 John, M.P., 3, 296; 5, 10 Johnson, J.B., 1, 367 Johnson, J.S., 10, 144 Johnson, K.F., 10, 243 Johnson, M.W., 4, 234; 10, 396 Johnson, T., 3, 499 Johnston, R.C., 1, 236; 10, 25, 517 Johnstone, T.C., 10, 140

Jones, A.C., 10, 17 Jones, A.M., 12, 236 Jones, A.X., 11, 110 Jones, C., 10, 318 Jones, D.R., 12, 59 Jones, G.A., 3, 143 Jones, L., 5, 274 Jones, P.G., 1, 358; 10, 87; 11, 161, 171 Jones, S., 3, 472 Jones, W.D., 3, 380 Jones-Mensah, E., 5, 503 Joo, F., 4, 206 Jordan, F., 3, 153 Jordi Burés, J., 1, 173 Jørgensen, K.A., 1, 2; 5, 251; 11, 30, 41, 99 Jorgensen, M., 5, 12 Joseph, B., 10, 608 Joseph, N., 10, 246 Joshi, A., 4, 56 Joshi, P.R., 3, 276 Joshi, P.S., 3, 49 Jovanovic, B.Z., 2, 1 Jovanovic, P., 10, 550 Jover, J., 5, 289 Ju, L.-C., 12, 155 Ju, T., 10, 286 Jubault, P., 4, 85 Juds, C., 5, 538 Juhl, K., 1, 318; 8, 129 Julia-Hernandez, F., 5, 478, 575 Jun, C.-H., 12, 148 Jung, D.J., 5, 526 Jung, K.W., 10, 172 Jung, M.E., 7, 147 Jung, Y.H., 5, 361, 384; 10, 245 Junge, K., 3, 382, 405 Juste-Navarro, V., 1, 165; 8, 35

K Kaabel, S., 12, 199 Kacer, P., 1, 90 Kachala, V.V., 5, 232 Kacka, A.B., 9, 11 Kadam, S.D., 3, 180 Kadu, R., 8, 117 Kaga, A., 10, 77 Kaib, P.S.J., 1, 216, 217; 6, 108 Kaicharla, T., 5, 109; 12, 47, 193 Kaichurla, T., 5, 204 Kainz, M.A., 7, 135 Kaiser, D., 10, 103 Kaiser, R.P., 5, 288 Kaishap, P.P., 3, 87 Kaithal, A., 3, 359 Kakaawla, T.K., 11, 64 Kakde, B.N., 6, 68 Kakino, J., 5, 547 Kakiuchi, K., 5, 516; 10, 602

Kakkar, R., 4, 41 Kalaria, P.N., 10, 453 Kalbandhe, A.H., 3, 195 Kaldre, D., 12, 6 Kaldun, J., 1, 204; 8, 30 Kale, R., 5, 205; 10, 561 Kalepu, J., 12, 159 Kaliappan, K.P., 5, 59 Kalita, B., 11, 50 Kállay, M., 10, 468 Kalow, J.A., 4, 64 Kalshetti, R.G., 5, 166; 10, 56 Kalsi, D., 5, 381; 9, 37 Kalvet, I., 5, 32, 317; 7, 42 Kamal, A., 12, 158 Kamal, R., 1, 162 Kamat, D.P., 1, 279 Kamath, R.V., 5, 109; 12, 193 Kambe, N., 7, 47; 8, 50 Kamble, S.P., 3, 475; 5, 166; 10, 56 Kameyama, R., 3, 459 Kamijo, K., 12, 10 Kamijo, S., 12, 10 Kamik, A.V., 11, 96 Kamimura, A., 12, 34 Kaminsky, W., 1, 256 Kanai, M., 1, 191; 3, 353; 5, 72, 214, 380, 391 Kanaura, M., 10, 365, 366 Kancherla, R., 5, 413 Kancheva, V.D., 3, 342 Kandekar, S., 3, 252 Kane, R.G., 5, 10 Kaneda, A., 5, 435 Kaneko, S., 11, 116 Kaneshiro, K., 10, 172 Kanetake, T., 3, 235 Kang, C., 5, 387 Kang, D., 5, 536 Kang, J., 5, 176 Kang, J.Y., 1, 210, 236; 10, 462, 500, 517, 520, 580 Kang, K., 7, 8 Kang, Q., 1, 327; 11, 17 Kang, S., 10, 221, 437 Kang, T., 11, 15 Kang, X., 5, 16; 10, 321 Kang, Y.-B., 3, 207 Kang, Y.-W., 1, 10 Kang, Y.K., 11, 73 Kanger, T., 12, 199 Kannaboina, P., 3, 79; 5, 62, 556 Kanno, H., 12, 139 Kanomata, K., 10, 91, 92 Kantam, M.L., 10, 578 Kanyiva, K.S., 8, 39; 10, 649; 11, 150, 152, 166 Kao, T.-T., 3, 241, 302 Kapat, A., 1, 336; 3, 287

800 Kaplaneris, N., 1, 316; 3, 158 Kaplon, K., 5, 461 Kappe, C.O., 9, 39 Kapras, V., 10, 222 Kapur, M., 5, 139, 410, 551 Karaca, E.O., 4, 188 Karaca, O., 1, 278; 4, 203 Karad, S.C., 4, 191 Karade, N.N., 3, 195 Karadeniz, E., 10, 619 Karaghiosoff, K., 6, 8; 8, 44 Karakus, M., 12, 26 Karam, O., 10, 47 Karbalaie-Reza, M., 5, 533 Karkhelikar, M.V., 7, 152; 10, 64 Karmakar, A.C., 1, 244 Karmakar, R., 10, 405; 12, 161 Karmakar, U., 4, 69; 5, 544 Karnam Jayarampillai, R.P., 1, 256 Karre, N., 1, 196 Karthikeyan, K., 11, 81 Kartika, R., 6, 39–41, 82 Kartnaller, V., 1, 96 Karty, J.M., 1, 313; 7, 141; 8, 5 Karunakar, G.V., 12, 106 Kasai, Y., 5, 229 Kashima, K., 11, 158 Kashyap, M., 3, 252 Kasper, J.B., 3, 231 Kass, S.A., 5, 246 Kastenschmidt, A.M., 3, 486 Kästner, J., 4, 121; 8, 79; 10, 377 Kasuga, Y., 12, 20 Katahara, S., 3, 461 Katano, M., 10, 411 Katayama, T., 5, 287 Kato, A., 1, 27 Kato, K., 6, 24; 8, 3; 11, 157; 12, 143 Kato, N., 1, 101; 5, 372 Kato, T., 4, 155, 260, 261 Katsumata, H., 5, 444 Katukojvala, S., 4, 77, 78; 5, 558; 12, 141, 159 Kaufman, T.S., 5, 265 Kaupmees, K., 1, 83; 3, 373 Kaur, J., 10, 543, 591 Kaur, M., 5, 117 Kaur, S., 10, 543 Kaushik, R.D., 3, 209 Kavitha, C.V., 7, 78 Kavthe, R.D., 7, 24; 8, 99 Kawabata, T., 2, 7 Kawaguchi, Y., 11, 148; 12, 134 Kawahata, M., 1, 38; 3, 271 Kawai, R., 10, 328 Kawai, T., 1, 303 Kawano, Y., 4, 32 Kawasaki, I., 3, 257

Author Index Kawasaki, T., 1, 259 Kawashima, H., 5, 9; 7, 41; 8, 41, 55 Kawashima, T., 6, 36 Kawato, Y., 10, 38 Kawatsura, M., 7, 16; 8, 95 Kaya, U., 10, 588 Kaya, Y., 1, 144; 12, 200 Kayaki, S., 1, 209; 10, 465 Kayaki, Y., 1, 345; 3, 448; 5, 281 Kayal, U., 3, 244 Kayalvizhi, K., 3, 1, 2 Kazakova, A.N., 5, 245; 6, 28 Kazin, V.N., 9, 2 Ke, M., 1, 155 Ke, S., 11, 12 Ke, X., 11, 177 Ke, Z., 4, 244; 5, 161; 10, 34 Keaveney, S.T., 6, 18; 7, 116 Keay, B.A., 5, 98 Kee, C.W., 12, 9 Keene, C., 12, 18 Keesara, S., 5, 462 Kegl, T., 5, 524 Keglevich, G., 2, 16; 10, 468 Keglevich, P., 4, 45 Kehr, G., 7, 96; 10, 129; 12, 78 Keipert, K., 7, 138 Kelbysheva, E.S., 12, 219 Kelkar, A.H., 7, 135 Keller, M., 3, 493; 10, 648 Keller, S.C., 12, 76 Kelley, B.T., 12, 66 Kelley, P., 5, 278 Kelly, C.B., 3, 133 Kemper, S., 10, 115 Kennedy, A.R., 1, 128, 176; 8, 45 Kerdphon, S., 3, 386 Kern, N., 10, 392; 12, 104 Kerner, C., 1, 93; 3, 437 Kerr, M.A., 4, 241 Kerr, R.W.F., 10, 480 Kerr, W.A., 3, 394 Kerr, W.J., 5, 282 Kerrigan, N.J., 11, 53 Kesavan, V., 10, 528 Kesava-Reddy, N., 1, 123 Kesharwani, T., 10, 63 Keshri, P., 5, 365; 10, 628 Keskin, S., 10, 390; 11, 58 Kessler, S.N., 7, 55 Khafizova, L.O., 10, 347 Khaibulova, T.S., 5, 22 Khairou, K., 3, 9 Khake, S.M., 5, 576 Khaledi, Y., 1, 380; 5, 540 Khan, A., 3, 146, 167 Khan, A.A.P., 3, 167 Khan, F.A., 10, 434 Khan, I., 1, 347

Khan, I.A., 10, 569 Khan, K.M., 1, 148 Khan, M., 10, 30 Khan, N.H., 1, 119; 5, 250 Khan, S.B., 3, 167 Khan, T.S., 9, 7, 8 Khandavilli, U.B.R., 3, 403 Khandelwal, C.L., 3, 18 Khanna, G., 11, 85 Kharnaior, K.S., 6, 14 Khazaei, A., 1, 255 Khelifi, C., 7, 29 Khezemi, L., 11, 74 Khiar, N., 1, 85; 3, 458 Khlebnikov, A.F., 4, 18 Khlebnikova, E., 5, 194 Khodja, M., 1, 156 Khomutnyk, Y.Y., 1, 28; 6, 109 Khorief Nacereddine, A., 1, 129 Khose, V.N., 11, 96 Khrakovsky, D.A., 4, 234; 10, 396 Khrapova, K.O., 10, 445 Khrustalev, V.N., 12, 235 Khullar, S., 5, 530 Khuntwal, J., 3, 6 Khurana, J.M., 11, 85 Khursan, S.L., 10, 49 Kibriya, G., 3, 310; 5, 271 Kiemele, E.R., 10, 260 Kikkawa, S., 7, 124 Kikuchi, H., 10, 328 Kikuchi, S., 10, 65 Kilbinger, A.F.M., 4, 107 Kim, B.-S., 5, 338; 7, 45 Kim, C., 3, 253; 11, 75 Kim, C.K., 5, 541; 10, 653 Kim, D., 6, 24; 8, 3 Kim, D.-S., 12, 148 Kim, G., 10, 437 Kim, H., 3, 331; 7, 8; 10, 282; 11, 124 Kim, H.S., 5, 188 Kim, I.S., 5, 187, 188, 361, 384, 553; 10, 245, 637, 638 Kim, J., 1, 109; 3, 253; 5, 227, 418; 7, 8, 9; 12, 228 Kim, J.K., 5, 213 Kim, J.N., 5, 237; 9, 34 Kim, K.H., 8, 27; 9, 34 Kim, M., 5, 26; 10, 221 Kim, M.-Y., 2, 10–12 Kim, N., 8, 27; 10, 289 Kim, S., 5, 26; 10, 437 Kim, S.-G., 11, 124 Kim, S.H., 3, 89 Kim, S.M., 10, 307 Kim, S.T., 10, 570 Kim, S.Y., 5, 237; 8, 27; 9, 34 Kim, W., 6, 24; 8, 3

801

Author Index Kim, W.Y., 7, 8 Kim, Y., 4, 247; 5, 180; 10, 172, 466 Kimachi, T., 10, 256 Kimm, M., 12, 199 Kimura, J., 1, 184 Kimura, K., 8, 11 Kimura, M., 10, 594 Kimura, Y., 11, 146 King, C., 1, 41 King, J.M., 7, 31; 8, 15 King, R., 3, 296 King, S.M., 5, 67 Kinoshita, H., 1, 368; 5, 118; 10, 353; 12, 229 Kinoshita, T., 4, 161 Kira, M., 2, 6; 4, 257 Kiran, I.N.C., 11, 123 Kiranmye, T., 11, 81 Kischkewitz, M., 4, 15; 10, 471 Kishi, K., 3, 260 Kiso, M., 1, 19 Kiss, L., 7, 153 Kisu, H., 12, 77 Kisunzu, J.K., 1, 388; 10, 497 Kita, K., 5, 435 Kita, Y., 3, 152, 424; 7, 24; 8, 99; 9, 26; 10, 410 Kitagawa, O., 10, 210 Kitagawa, T., 6, 26 Kitaguchi, T., 8, 13; 10, 558, 592 Kitajima, M., 10, 371 Kitamura, C., 11, 89 Kitaura, H., 8, 13; 10, 558, 592 Kiyokawa, K., 1, 306 Klankermayer, J., 3, 401, 406 Klaper, M., 9, 44 Klare, H., 10, 586 Klare, H.F.T., 5, 196, 197; 6, 25; 10, 115 Klauck, F.J.R., 5, 157 Kleij, A.W., 7, 18, 64, 65 Klein, J.C., 11, 94 Klein, J.E.M.N., 4, 121; 8, 79; 10, 377 Kletskii, M., 7, 86 Kletskii, M.E., 5, 43, 78 Klier, L., 1, 2; 5, 251 Klimochkin, Y.N., 12, 207 Klimova, T.A., 5, 51 Klumpp, D.A., 5, 242; 6, 48, 81 Klussmann, M., 3, 245, 269 Knauber, T., 5, 337 Knezz, S.N., 4, 239 Knizia, G., 4, 121; 8, 79; 10, 377 Knochel, P., 5, 195, 336, 573; 7, 36 Knoll, I., 5, 336 Knott, J.P., 3, 426 Ko, C.-T., 10, 501

Kobayashi, N., 11, 101 Kobayashi, O., 10, 477 Kobayashi, S., 3, 461; 6, 7 Kobayashi, Y., 7, 41; 8, 41; 10, 440 Kocevar, M., 2, 20 Kochetkov, S.V., 10, 581 Kochina, T.A., 6, 3 Kochly, E.D., 9, 5 Koˇcovsk´y, P., 10, 187, 222, 274, 275 Koga, Y., 4, 149 Kohari, Y., 1, 184; 3, 106; 5, 290; 11, 101 Kohn, R.D., 10, 348 Kohrt, S., 10, 442 Koifman, O.I., 3, 32 Koizumi, A., 10, 594 Kojima, M., 3, 353 Kokotos, C.G., 1, 316; 3, 158 Kokotou, M.G., 1, 316; 3, 158 Koksal, O., 5, 89 Kolarikova, V., 4, 110 Kolarski, D., 10, 382 Koledina, K.F., 10, 351 Koley, D., 1, 304; 3, 352; 4, 192 Koley, S., 11, 27 Kollar, L., 5, 524 Komagawa, S., 3, 257 Komata, Y., 7, 103 Konakahara, T., 12, 28 Kondo, H., 5, 149 Kondo, K., 12, 140 Kondo, M., 1, 66; 5, 586; 8, 98; 10, 224 Kondo, S., 10, 110 Kondo, Y., 5, 528 Kondoh, A., 8, 11; 12, 70, 169 Konev, M.O., 5, 322 Kong, D., 1, 88; 3, 411–413 Kong, D.-L., 3, 249 Kong, F., 5, 68; 10, 387 Kong, L., 3, 101; 5, 441, 543; 10, 332 Kong, L.-F., 12, 56 Kong, X., 3, 238 Kong, X.-w., 7, 48 Konno, M., 5, 272 Koperniku, A., 8, 121 Korenaga, T., 10, 91 Korica, N., 11, 169 Korkis, S.E., 12, 136 Kornmagalla, Y., 5, 379 Kornman, C.T., 10, 63 Korobkov, I., 4, 178 Korsakov, A., 5, 39 Koshel, G.N., 3, 343 Koˇsmrlj, J., 2, 20; 3, 284; 7, 119 Kostenko, A.A., 10, 581 Kostikov, R.R., 5, 218; 12, 35

Kostikova, R.R., 12, 211 Koszinowski, K., 3, 70; 10, 616 Kotai, L., 3, 11 Kothapalli, R.B., 8, 46 Kothari, S., 3, 13, 14 Kottari, N., 1, 23 Kouklovsky, C., 5, 220, 236; 10, 326, 327 Kovacs, S., 5, 48, 313 Kowalski, M.K., 12, 175 Krabbe, S.W., 3, 288; 4, 104 Kraetzschmar, F., 3, 198; 5, 230 Krafft, M.E., 12, 111 Krahn, D., 2, 21 Krainz, T., 11, 169 Krasavin, M., 5, 39 Krause, A.J., 3, 486 Krause, S.B., 10, 189 Krause, T., 5, 489 Krchnak, V., 3, 351 Kreiman, H.W., 12, 204 Kremer, A., 7, 162 Krenske, E.H., 3, 125, 366; 10, 454 Kress, S., 3, 499 Krische, M.J., 3, 438, 442; 7, 54; 10, 229 Krishnamoorthy, P., 3, 263 Krishnan, K.K., 7, 59 Krishnananthan, S., 1, 157 Kristensen, J.L., 5, 12 Kristianslund, R., 10, 68 Krivec, M., 2, 20 Krogh-Jespersen, K., 4, 6, 7 Kroner, K.M., 10, 128 Kruger, H.G., 2, 3 Krüger, J., 5, 86; 7, 49 Krupski, S., 7, 96 Kruszyk, M., 5, 12 Krych-Madej, J., 3, 155 Krysiak, J.A., 12, 72 Krzeszewski, M., 3, 111 Kseniya, V., 12, 224 Kuang, Z., 3, 360 Kubarev, A.V., 6, 30 Kubiak, R.W., 4, 91 Kubinyi, M., 10, 468 Kubota, A., 10, 38 Kubota, K., 1, 293; 10, 116 Kucherenko, A.S., 10, 581 Kudo, K., 10, 502 Kudzin, M.H., 3, 153 Kudzin, Z.H., 3, 153 Kueck, J.W., 1, 278; 3, 108; 4, 203 Kuehn, F.E., 1, 278; 3, 108; 4, 203 Kulkarni, R.M., 3, 23 Kumagai, N., 1, 67, 111; 4, 232; 10, 486

802 Kumagi, N., 1, 65 Kumar, A., 3, 177, 286; 5, 482, 530; 10, 495, 543, 591; 11, 88 Kumar, A.S., 10, 583 Kumar, D., 3, 80, 114 Kumar, G., 8, 64; 10, 317 Kumar, G.S., 5, 154, 551 Kumar, K., 1, 123; 10, 544; 12, 121 Kumar, K.A., 3, 79; 5, 62, 556 Kumar, K.P.V., 1, 244 Kumar, M., 1, 353; 5, 49; 6, 57; 10, 358, 521 Kumar, M.S., 5, 128 Kumar, N., 1, 353; 6, 57, 68 Kumar, N.Y.P., 3, 96 Kumar, P.S., 3, 240 Kumar, R., 1, 162; 3, 204; 4, 89, 161; 12, 62, 103 Kumar, R.A., 3, 240 Kumar, R.K., 3, 484; 6, 97; 10, 19; 12, 157 Kumar, R.R., 1, 309 Kumar, R.S., 3, 43 Kumar, S., 5, 437; 8, 117; 10, 66, 216 Kumar, T., 12, 173 Kumar, T.P., 10, 564 Kumar, V., 1, 162 Kumar, V.N., 10, 564 Kumar, Y., 3, 286; 5, 482; 10, 625 Kumar, Y.L., 1, 334; 3, 164 Kumari, E., 3, 209 Kumari, P., 5, 250 Kumari, S., 5, 530 Kumarswamyreddy, N., 10, 528 Kumatabara, Y., 11, 116 Kuninobo, Y., 5, 72, 214, 333, 391 Kuninobu, Y., 3, 103 Kuniyasu, H., 7, 47; 8, 50 Kuntze-Fechner, M.W., 5, 477 Kunz, R.K., 10, 507 Kuo, Y.-T., 4, 194; 5, 569; 10, 203 Kupfer, T., 4, 259 Kuppusamy, R., 10, 338 Kurandina, D., 4, 90 Kurata, H., 5, 432; 10, 164 Kurbatov, S.V., 5, 43, 78 Kureshy, R.I., 1, 119; 5, 250 Kurganova, E.A., 3, 343 Kuriakose, S., 6, 105 Kuriyama, M., 5, 29 Kuroda, K., 7, 103 Kurokhtina, A.A., 5, 456 Kurouchi, H., 6, 9 Kürti, L., 12, 18

Author Index Kurtoic, S.I., 10, 254 Kusakawa, T., 1, 268 Kusukawa, T., 5, 348 Kusy, R., 3, 446 Kuwano, R., 3, 395 Kuwano, S., 4, 156; 11, 39 Kuwata, S., 5, 281 Kuzhin, M.B., 9, 2 Kuzma, M., 1, 90 Kuznetsov, N.Y., 12, 232, 235 Kvaskoff, D., 4, 240; 12, 81 Kv´ıcˇ ala, J., 4, 110; 7, 151 Kwak, J.H., 5, 361, 384; 10, 245 Kwast, A., 5, 50 Kwon, E., 1, 184; 3, 201; 11, 101 Kwon, K., 8, 110 Kwon, O., 10, 547; 12, 182 Kwong, F.X., 5, 473

L Laabid, A., 12, 195 Laali, K.K., 6, 4 Labes, R., 1, 262; 8, 58 Lackner, S., 5, 326 Lacour, J., 1, 3; 3, 143; 4, 105 LaCroix, K., 10, 172 Lad, B.S., 4, 77, 78; 5, 558; 12, 141 Laezza, A., 1, 18 Lagarde, F., 3, 391 Lagishetti, C., 11, 123 Lagoutte, R., 10, 510 Laguna, A., 1, 248 Lahankar, N., 2, 25 Lahiri, G.K., 3, 325 Lahoz, F.J., 4, 208; 5, 549; 10, 251 Lai, G., 2, 6; 4, 257 Lai, J., 1, 15 Lai, X., 10, 582 Lai, Y., 1, 351; 10, 39 Lakhdar, S., 6, 11 Lakhtarenko, N.V., 3, 265 Lakshmi, J.K., 6, 106; 11, 68 Lal, K., 3, 6 Lalancette, R., 5, 505 Lalic, G., 4, 137; 8, 80; 10, 10, 295 Laloo, J.Z.A., 7, 146 Lam, B.Y., 5, 277 Lam, H.W., 1, 100; 10, 340; 12, 136 Lam, W.W.Y., 3, 90 Lam, Y., 1, 170, 183 Lam, Y.-h., 7, 120 Lamani, S., 3, 17 Lambert, K.M., 3, 127 Lambert, T.H., 6, 19 Lan, J., 4, 244; 5, 448, 507; 10, 200

Lan, J.-X., 2, 24 Lan, X., 1, 47 Lan, Y., 1, 133, 384; 3, 94, 397; 4, 251; 5, 488, 519; 12, 117 Landge, V.G., 5, 425, 426 Landis, C.R., 3, 278 Lang, H., 10, 233, 234 Langer, P., 5, 132, 581 Langer, V., 10, 187, 274 Langote, S.R., 3, 49 Languet, K., 4, 8 Lanke, V., 5, 365, 555; 10, 628 Lanz, G., 1, 25 Lanzalunga, O., 3, 115, 116 Łapczy´nski, S., 12, 5 Lapi, A., 3, 115, 116 Lapointe, G., 5, 111 Lapointe, S., 10, 552 Lapuerta, I., 1, 59 Larina, A.G., 6, 86; 12, 35 Larina, E.V., 5, 456 Larra´naga, O., 11, 38, 44 Larrosa, I., 5, 478, 479, 575 Larsen, D.B., 3, 441 Larsen, M.A., 8, 100 Larson, A.J., 1, 53 Lasch, R., 3, 83 Laserna, V., 7, 64 Laskar, R.A., 5, 381; 9, 37 Lassaletta, J.M., 5, 416, 465 Lastovickova, D.N., 4, 148 Latif, M., 11, 73 Latronico, M., 3, 74 Lattanzi, A., 7, 58 Lau, K.-C., 3, 90; 7, 112 Lau, T.-C., 3, 26, 90, 91 Laub, H., 6, 7 Lauridsen, V.H., 1, 2; 5, 251; 11, 41 Lautens, M., 3, 499; 4, 112; 5, 586; 6, 70; 7, 70; 10, 224; 12, 112 Lavados, C.M., 11, 93 Lavinda, T.M., 6, 53 Lawal, M.M., 2, 3 Lawrence, S.E., 3, 403 Laws, A.P., 7, 110 Lawson, J.R., 12, 71 Layfield, R.A., 4, 150 Lazzara, P.R., 10, 193 Le, D.M., 3, 157 Le, T.-N., 3, 435 Leach, A.G., 5, 285 Leadbeater, N.E., 3, 133 Lear, M.J., 3, 201 Le Bras, J., 7, 1 Lebrun, S., 10, 37 Leclerc, M.C., 4, 178 Lecomte, M., 6, 84 Lectka, T., 5, 137

803

Author Index Le Darz, A., 10, 47 Lednev, S., 3, 274 Ledovskaka, M.S., 5, 218 Lee, A., 7, 8 Lee, A.-L., 3, 75; 5, 302; 10, 395 Lee, B.D., 10, 172 Lee, C.-J., 10, 501, 585 Lee, D., 3, 337; 12, 161 Lee, D.S., 10, 560 Lee, G.-H., 8, 16; 10, 512 Lee, H., 3, 337; 5, 375, 466 Lee, H.M., 4, 194, 195; 5, 393, 569; 10, 203 Lee, J., 8, 27; 9, 34; 11, 73; 12, 75 Lee, J.-H., 5, 418 Lee, J.-I., 2, 12 Lee, J.-Y., 4, 195; 5, 393 Lee, J.H., 10, 172 Lee, J.M., 1, 195 Lee, J.S., 5, 361, 553 Lee, J.Y., 10, 135; 11, 73 Lee, K., 5, 227; 12, 228 Lee, K.-H., 5, 284, 532 Lee, K.G.Z., 10, 34 Lee, M.E., 7, 106 Lee, M.M., 3, 253 Lee, R., 11, 102 Lee, S., 1, 217; 5, 418 Lee, S.-G., 5, 526 Lee, S.-Y., 5, 384; 10, 245 Lee, S.A., 3, 253 Lee, S.H., 10, 638 Lee, S.Y., 3, 253; 5, 388 Lee, T., 8, 103 Lee, W.-C.C., 5, 177 Lee, W.L., 10, 135 Lee, Y., 1, 109; 10, 437 Lee, Y.-M., 3, 236 Lee, Y.-S., 5, 85 Lefevre, G., 3, 362 Lefort, L., 3, 393, 422 Lefranc, A., 1, 82; 3, 410 Legnani, L., 1, 354 Le Grande, M.S., 5, 68 LeGrande Slaughter, M., 10, 387 Legros, J., 10, 557 Leherte, L., 1, 185 Lei, A., 5, 27 Lei, M., 1, 154; 5, 339; 10, 219 Lei, Q., 3, 73; 4, 122; 8, 76 Lei, S., 3, 290 Lei, X., 10, 652; 11, 110 Lei, Y., 11, 56 Leibeling, M., 12, 167 Leiendecker, M., 5, 317 Leitner, W., 3, 401 Lelyveld, V.S., 2, 30 Lemaire, S., 5, 195

Lemal, D.M., 11, 1 Lemière, G., 12, 40 Lemma, B.E., 4, 5 Lemon, N.J., 9, 5 Lempenauer, L., 12, 40 Lente, G., 3, 142 Lentz, D., 5, 86; 7, 49 Leonova, M.V., 12, 207 Lepore, S.D., 1, 312; 10, 107 Leppkes, J., 5, 86 Lerchen, A., 1, 61; 10, 471 Lerner, H.-W., 1, 285; 4, 258 Leroux, F.R., 5, 119, 120 Lesma, G., 1, 247; 11, 25 Lesniak, S., 1, 265; 8, 59 Lessi, M., 5, 571 Levens, A., 4, 141, 224 Levin, V.V., 8, 26 Levine, M., 3, 178 Levitsky, D.O., 3, 182; 10, 58 Lewis, W., 8, 51; 11, 100; 12, 2 Lhoste, J., 12, 45 Li, B., 1, 227; 3, 37–40; 5, 216, 401, 450, 507; 10, 138, 242, 296; 11, 54; 12, 23 Li, B.-J., 10, 645, 646 Li, C., 1, 152; 3, 242; 4, 40; 5, 79, 335; 6, 37, 78; 7, 3; 10, 213, 255, 654; 12, 105 Li, C.-H., 10, 305 Li, C.-J., 5, 235; 10, 97 Li, C.-L., 5, 502 Li, C.-Y., 4, 92; 12, 131 Li, D., 4, 243; 5, 513; 7, 82, 123; 12, 84, 171 Li, D.-Y., 4, 125, 126 Li, D.Y., 5, 454; 10, 259 Li, E., 1, 160; 3, 192 Li, F., 1, 134, 264, 361; 3, 85, 86, 242; 4, 226; 5, 57; 8, 60; 10, 451; 12, 152 Li, F.-B., 11, 40 Li, F.-H., 5, 436; 10, 208 Li, G., 1, 69, 89, 269, 339; 3, 187, 432, 500; 5, 182, 183, 222; 10, 316, 607; 12, 151 Li, G.-C., 5, 174 Li, H., 1, 11, 143, 211; 3, 189, 347; 4, 196, 243; 5, 58; 7, 131; 10, 98, 167, 219; 12, 84, 185 Li, H.-H., 10, 70 Li, H.F., 1, 314; 4, 39; 7, 160 Li, J., 1, 157, 324; 3, 201, 242, 314, 317, 328; 4, 95, 120, 253; 5, 70, 80, 270, 291, 457, 532, 560; 6, 17, 73; 7, 17, 44, 134; 10, 175, 176, 191, 202, 213, 247, 286,

304, 372, 374, 379, 643, 654; 12, 105, 154 Li, J.-H., 10, 531 Li, J.-M., 5, 162 Li, J.J., 5, 177 Li, K., 1, 327 Li, L., 1, 106; 2, 30; 3, 101, 292; 4, 130; 5, 102, 147, 247, 513; 10, 375, 485, 634, 635; 11, 128 Li, L.-H., 11, 170 Li, M., 1, 88; 3, 411–413; 4, 82, 174; 5, 148, 390, 585; 7, 45; 8, 125, 131, 132; 10, 169, 407 Li, M.-M., 8, 24 Li, N., 3, 447; 4, 129; 5, 225; 10, 388 Li, P., 1, 34, 35, 37, 257; 3, 416, 427; 4, 22, 24, 25, 28; 5, 314; 6, 44; 10, 523, 562; 12, 89 Li, P.-X., 3, 305; 5, 486 Li, P.-Z., 5, 474 Li, Q., 1, 31, 387; 3, 187, 497; 10, 158, 352 Li, Q.-Z., 10, 350 Li, R., 3, 483; 5, 373, 423; 7, 44; 10, 630; 12, 216 Li, R.-H., 10, 412; 12, 155 Li, S., 1, 89; 3, 355, 432; 5, 583; 6, 73; 10, 316, 372 Li, S.-Q., 3, 439 Li, S.-S., 3, 148; 5, 407, 557; 8, 71 Li, T., 1, 158, 361; 4, 88, 130; 5, 57; 10, 268; 11, 160 Li, T.-R., 6, 115; 8, 24; 11, 36, 125 Li, W., 3, 355, 404; 4, 175, 229; 5, 210; 7, 147; 9, 47; 10, 101, 158, 320, 352, 420; 11, 65, 87 Li, W.-H., 5, 407, 557 Li, W.-Z., 10, 350 Li, X., 1, 11, 13, 16, 26, 54, 141, 315, 375; 3, 101, 139, 149, 202, 215, 484; 4, 67, 106, 154, 251; 5, 17, 80, 185, 189, 215, 363, 400, 441, 448, 543, 561, 563, 585; 7, 6; 8, 9; 10, 200, 239, 332, 457, 467, 514, 515, 518, 617; 11, 110, 160, 177; 12, 135 Li, X.-H., 12, 220 Li, X.-X., 10, 70 Li, Y., 1, 9, 54, 78, 205, 228, 373; 2, 24; 3, 88, 94, 187, 224; 4, 12, 70, 106, 171, 220,

804 227, 251; 5, 77, 101, 102, 106, 115, 150, 181, 208, 213, 215, 335, 398, 421, 434, 470, 471, 488, 561; 7, 74, 87; 8, 9, 32, 119; 10, 3, 415, 459, 478, 489, 504, 533, 567, 601, 661; 11, 99, 128; 12, 79, 152, 208, 225 Li, Y.-H., 4, 129; 5, 225, 376; 10, 185 Li, Y.-J., 10, 438 Li, Y.-M., 5, 509; 10, 409 Li, Y.-m., 7, 48 Li, Y.-P., 3, 396; 10, 261 Li, Y.-X., 1, 27; 10, 407 Li, Y.-Y., 10, 476 Li, Z., 1, 1, 63, 105; 2, 6; 3, 134, 298, 314, 485; 4, 50, 145, 163, 222, 257; 5, 176, 269, 580; 7, 7, 80, 92; 9, 47; 10, 101, 109, 202, 320, 495, 535, 549; 11, 75; 12, 83 Li, Z.-H., 5, 399 Li, Z.-Q., 3, 147 Li, Z.-Y., 6, 35 Lian, X., 1, 246; 10, 379; 12, 165 Lian, X.-L., 4, 129; 5, 225 Liang, C., 3, 347 Liang, C.-F., 5, 234 Liang, D., 1, 1; 5, 215; 10, 109 Liang, G., 1, 291; 3, 323 Liang, H., 8, 127; 10, 28; 12, 39 Liang, H.-W., 3, 98 Liang, J., 3, 299 Liang, J.-H., 5, 65 Liang, K., 12, 171 Liang, L., 11, 164 Liang, M., 12, 113 Liang, T., 3, 438; 7, 54 Liang, W., 11, 159 Liang, X.-W., 5, 542; 10, 293 Liang, Y., 1, 15; 3, 149; 5, 7, 439, 521; 10, 333 Liang, Y.-F., 3, 149; 5, 545 Liang, Y.-M., 3, 246; 5, 223; 10, 302, 407; 11, 170 Liang, Y.-t., 7, 112 Liang, Z.-O., 11, 119 Liang, Z.-Q., 11, 174 Liao, D., 10, 652 Liao, H., 3, 318; 5, 159 Liao, J., 1, 110; 6, 59 Liao, J.-H., 8, 16; 10, 512 Liao, P., 3, 484; 12, 157 Liao, P.-Y., 10, 308 Liao, X., 4, 95, 253; 5, 33, 315; 6, 77; 11, 60 Liao, Y., 7, 89 Liao, Z.-Y., 10, 308

Author Index Liedos, A., 8, 54 Liffey, R.M., 12, 2 Lii, J.-H., 4, 195; 5, 393 Likhar, P.R., 7, 152; 10, 64 Lillo, V.J., 1, 60 Lim, G.S., 1, 376 Lim, J.W., 5, 237 Lim, L.H., 1, 349; 3, 445 Lima, E.S., 1, 242 Limanto, J., 1, 55 Lin, A., 4, 75; 5, 402; 10, 518, 519; 11, 62 Lin, B., 12, 165 Lin, C.-B., 10, 70 Lin, D., 5, 161 Lin, G.-O., 11, 98 Lin, G.-Q., 12, 74 Lin, H., 5, 455; 10, 267; 11, 2 Lin, J.-H., 1, 281, 314; 4, 39, 44, 113; 7, 160 Lin, K., 4, 102 Lin, L., 7, 89; 10, 379, 459, 540, 593; 11, 15, 107, 113; 12, 11 Lin, P.-C., 5, 234 Lin, Q., 1, 228; 4, 227; 10, 533 Lin, S., 1, 67, 111; 4, 232; 5, 278, 518; 10, 604, 607 Lin, W., 3, 102; 5, 406; 10, 501, 585 Lin, X., 3, 217; 4, 50, 245; 5, 260; 9, 40; 10, 446; 11, 111 Lin, Y., 1, 208; 12, 226 Lin, Y.-C., 1, 378; 4, 108; 12, 49 Lin, Y.-T., 3, 259; 5, 209 Lin, Z., 3, 216, 480; 4, 26; 5, 284 Lin, Z.H., 3, 136 Linden, A., 12, 175 Lindhorst, A.C., 1, 278; 4, 203 Lindsay, D.M., 5, 282 Ling, B., 10, 393 Ling, F., 10, 215 Lingampally, R., 10, 500 Linguerri, R., 7, 2 Linker, T., 9, 44 Liotta, C.L., 5, 580 Lipner, G., 10, 603 Lipschutz, M.I., 5, 103 Lisboa, M.P., 1, 23 Lisnyak, V.G., 10, 581 Lisovin, A.V., 5, 43, 78 List, B., 1, 97, 198, 216, 217; 3, 454; 6, 108 Liu, B., 1, 153; 3, 30, 299; 5, 423, 485, 525 Liu, C., 1, 31, 331; 3, 497; 4, 16, 122; 5, 470, 471, 505, 542; 6, 114; 7, 100; 8, 7; 10, 293, 565; 11, 135 Liu, C.-F., 5, 407

Liu, C.-G., 5, 484 Liu, C.-H., 11, 175, 176 Liu, C.-X., 11, 40 Liu, C.-Y., 10, 375; 11, 40 Liu, C.F., 5, 557 Liu, D., 3, 383 Liu, F., 10, 75, 101 Liu, F.-M., 11, 78 Liu, G., 4, 213; 5, 364; 10, 81, 169, 257, 271 Liu, G.-J., 1, 264; 8, 60 Liu, G.-Q., 10, 409 Liu, H., 1, 46, 107, 177, 207; 3, 99, 228; 4, 72; 5, 23, 40, 445, 494, 501; 8, 33, 121; 10, 28, 99, 214; 11, 92, 136; 12, 73, 190 Liu, H.-C., 11, 46 Liu, H.-M., 5, 537 Liu, H.-Y., 3, 147; 10, 204 Liu, J., 1, 1; 2, 19; 3, 104, 185, 199, 238, 386, 482; 4, 199; 5, 396; 8, 74; 10, 109, 167, 186, 473; 11, 6, 134, 173 Liu, J.-B., 5, 179 Liu, J.-H., 7, 11 Liu, J.-X., 3, 100 Liu, J.-Y., 5, 158 Liu, K., 3, 347; 10, 282, 595 Liu, K.-Y., 5, 235 Liu, L., 1, 134, 193, 216, 264; 3, 44, 249, 356; 4, 10, 12, 118, 119, 133, 163, 236; 5, 208, 358, 359, 496; 6, 104; 8, 60, 65; 10, 304, 374, 385, 451, 488, 530, 531, 584, 612; 11, 40, 57; 12, 37, 83 Liu, L.-C., 5, 304, 408; 10, 272 Liu, L.-J., 8, 40 Liu, L.-K., 12, 49 Liu, M., 1, 240; 10, 130, 131, 136, 524 Liu, N., 1, 78; 3, 238; 5, 61; 10, 504, 567 Liu, P., 3, 85, 171, 295; 5, 399; 10, 278, 393; 11, 177; 12, 52 Liu, P.N., 5, 454; 10, 259 Liu, Q., 1, 33, 239, 249; 3, 132, 430, 431; 5, 92; 10, 86, 487, 509; 11, 79; 12, 68 Liu, Q.-Q., 7, 68 Liu, Q.-R., 1, 211; 4, 196 Liu, Q.-S., 5, 493 Liu, R., 5, 266, 505; 10, 238, 604 Liu, R.-H., 10, 288 Liu, R.-R., 5, 262, 263, 567; 8, 96 Liu, R.-S., 1, 73; 4, 135; 11, 154; 12, 29, 218 Liu, R.Y., 1, 99; 10, 311

805

Author Index Liu, S., 1, 133, 384; 3, 54, 94, 397, 417; 4, 62, 76, 82, 238; 5, 488, 519, 593; 7, 114; 10, 100, 119, 467; 12, 85 Liu, S.-H., 5, 65, 459 Liu, S.-Y., 10, 138 Liu, T., 1, 15, 352; 3, 447, 465; 4, 171; 5, 152, 323; 10, 261, 413, 601 Liu, T.-T., 4, 193; 5, 463 Liu, T.-Y., 6, 78 Liu, W., 1, 337; 3, 300, 301; 5, 172, 382, 434, 457, 545; 10, 40, 97, 268, 415, 579, 582 Liu, W.-B., 7, 20; 12, 8 Liu, W.-J., 1, 137 Liu, W.J., 3, 136 Liu, X., 1, 47, 350; 2, 6; 3, 44, 171, 185, 387, 431; 4, 98, 257; 5, 163, 315, 317, 318, 323; 7, 89; 10, 83, 379, 459, 540, 593; 11, 15, 34, 107, 113; 12, 11, 152 Liu, X.-G., 5, 399 Liu, X.-W., 6, 69 Liu, X.-Y., 3, 246; 10, 475; 11, 170 Liu, Y., 1, 331; 3, 132, 292, 299, 390, 400, 419, 423, 444; 4, 16, 31, 118, 119, 127; 5, 65, 148, 266, 459, 505, 512, 537, 546, 563; 6, 55; 8, 132; 10, 34, 239, 393; 11, 92, 156; 12, 11, 39, 95, 115, 117, 124, 126, 127, 165, 208 Liu, Y.-H., 4, 108; 5, 305; 12, 49 Liu, Y.-J., 5, 305 Liu, Y.-Y., 7, 112; 11, 54 Liu, Y.A., 6, 77 Liu, Y.H., 1, 378 Liu, Z., 1, 65, 326; 3, 242, 476, 484; 4, 71, 73; 5, 440; 10, 170, 171, 198, 263, 334, 352; 11, 111; 12, 157 Liu, Z.-J., 3, 148; 5, 469 Liu, Z.-N., 3, 45 Liu, Z.-T., 5, 335, 398; 11, 140 Liu, Z.-W., 5, 235, 335, 398 Llacer, E., 1, 8 Lledós, A., 1, 261; 10, 244 Lloyd, M.G., 4, 80 Lloyd-Jones, G.C., 5, 285, 589; 10, 274, 275 Lo, P.-K., 3, 90 Locascio, T.M., 8, 97 Loh, C.C.J., 7, 70

Loh, T.-P., 3, 323; 7, 19, 166; 8, 93; 10, 181, 600, 613; 11, 109 Loim, N.M., 12, 219 Lok, C.K., 1, 68 Loman, J.J., 3, 133 Lombardo, M., 1, 189, 320; 8, 128 London, G., 1, 182 Longobardi, L.E., 10, 140 Lo Nostro, P., 1, 311 Lopatkiewicz, G., 3, 363 Lopes, J.L.C., 4, 4 Lopez, C.S., 3, 33; 10, 16 Lopez, E., 4, 134 López, F., 1, 40; 10, 398; 11, 167 Lopez, J.G., 8, 38 Lopez, L.A., 4, 134 Lopez, R., 1, 187 Lopez, S., 1, 284; 4, 27; 9, 14 Loreto, M.A., 5, 253 Lorion, M.M., 3, 84; 12, 236 Lorscheider, G., 5, 467 Losada-Barreiro, S., 5, 4 Loska, R., 5, 76 Lou, H., 5, 260 Lou, M.-M., 3, 147 Lough, A.J., 1, 343; 3, 440 Love, J.A., 10, 260, 280 Lovely, C.J., 10, 46 Lu, C., 5, 385; 9, 6; 10, 469 Lu, C.-D., 1, 46, 107; 12, 73 Lu, C.-J., 10, 218 Lu, D.-F., 10, 74 Lu, G., 5, 162, 280 Lu, H., 5, 27, 182, 183; 12, 151 Lu, I.-C., 4, 195; 5, 393 Lu, J., 3, 419; 5, 335, 398; 8, 31 Lu, J.-Y., 2, 21; 5, 335 Lu, K., 12, 98 Lu, L., 3, 85; 5, 148; 8, 132; 10, 186 Lu, L.-Q., 6, 115; 8, 24; 11, 36, 125 Lu, M., 1, 142 Lu, N., 5, 443; 10, 201 Lu, P., 4, 76 Lu, Q., 2, 6; 4, 257 Lu, Q.-Q., 3, 333 Lu, R., 12, 151 Lu, S., 3, 141, 485 Lu, X., 1, 79; 3, 203; 4, 130; 5, 364, 568; 7, 11, 51; 10, 206, 271, 389, 626 Lu, X.-Y., 7, 11 Lu, Y., 5, 492; 10, 631; 11, 15, 33, 107, 131 Lu, Z., 3, 377; 10, 161, 358; 12, 156 Luan, X., 11, 6

Luan, Z., 12, 208 Lübcke, M., 7, 101 Ludwig, R., 1, 276; 3, 227, 250; 8, 25; 9, 17 Lüerssen, H., 4, 240; 12, 81 Lugi¸nina, J., 7, 79 Lui, M.W., 3, 350 Luis, J.M., 5, 442; 8, 104; 10, 336 Luis, J.P., 4, 42 Luis, S.V., 1, 261; 8, 54 Luis-Barrera, J., 10, 513 Lujan-Montelongo, J.-A., 10, 614 Lumb, J.-P., 3, 293; 12, 150 Lumbiny, B.J., 2, 17; 7, 99 Lundgren, R.J., 5, 321 Luo, B., 4, 55 Luo, F.-X., 7, 52 Luo, G., 1, 147; 3, 221; 5, 16; 10, 321 Luo, H., 1, 78; 4, 66; 7, 56; 10, 567 Luo, H.-B., 5, 508, 514 Luo, J., 3, 266; 10, 83 Luo, K., 3, 434; 4, 99 Luo, L., 5, 16; 7, 57; 10, 321 Luo, M., 1, 63 Luo, R.-S., 8, 7; 10, 565 Luo, S., 1, 92; 3, 456 Luo, S.-P., 3, 431 Luo, W., 3, 132; 10, 593 Luo, X., 1, 384; 3, 94; 4, 13, 40; 5, 65, 459, 488 Luo, Y., 4, 193; 5, 16, 463; 10, 106, 321, 416, 634 Luo, Y.-C., 1, 275 Luo, Z., 4, 118; 5, 269 Luo, Z.-Y., 5, 514 Luong, T., 3, 442 Luping, L., 6, 108 Lupton, D.W., 4, 141, 215, 224 Luridiana, A., 10, 575 Lutter, F.H., 5, 573 Lutters, D., 4, 261 Lv, H., 1, 348; 3, 409, 425; 4, 102; 10, 239; 12, 133 Lv, S., 5, 270 Lv, X., 1, 118; 3, 92; 7, 38 Lv, Y., 1, 339 Lv, Z., 3, 184, 186, 199 Lvov, A.G., 5, 232 Lynam, J.M., 10, 18 Lynch, D., 3, 403 Lyssenko, K.A., 12, 232 Lyu, Y., 4, 175; 10, 420

M Ma, B., 4, 12, 133; 5, 208, 359; 10, 385

806 Ma, C., 4, 48, 53; 5, 40, 130, 258; 10, 215; 11, 49; 12, 190 Ma, D., 5, 30, 554 Ma, E., 7, 7; 9, 47; 10, 320 Ma, F., 1, 154; 5, 339 Ma, H., 1, 223; 10, 559; 11, 49 Ma, J., 3, 238, 258; 4, 99, 100; 5, 246; 7, 48 Ma, J.-A., 1, 192 Ma, J.-U., 1, 223 Ma, L., 1, 340; 3, 26, 90; 5, 150; 9, 47; 10, 320; 12, 101 Ma, M., 12, 101 Ma, M.-L., 1, 126 Ma, Q., 3, 217, 347 Ma, R.-S., 3, 58 Ma, S., 4, 1; 5, 228, 466; 6, 72; 8, 69; 10, 149, 316, 342 Ma, S.-T., 5, 269 Ma, T., 10, 70 Ma, W., 3, 400 Ma, X., 1, 142, 304; 5, 387; 7, 131; 10, 219, 634 Ma, X.-Y., 10, 536 Ma, Y., 11, 84 Ma, Y.-G., 1, 152 Maaliki, C., 5, 417 Macé, A., 12, 21 Macgregor, S.A., 3, 303; 10, 480 Machino, Y., 7, 124 Machtin, V., 3, 274 Macia, B., 1, 273; 8, 42 Mackey, K., 3, 55 MacMillan, D.W.C., 6, 114; 7, 100; 10, 507 MacNeil, C.S., 3, 426 MacRory, K., 1, 87; 3, 450 Madarasz, A., 10, 93 Maddox, S.M., 5, 126 Madhavachary, R., 10, 583 Madsen, R., 1, 25; 3, 348 Madura, I., 12, 5 Maeda, C., 7, 63 Maeda, K., 3, 235 Maeda, S., 7, 138 Maeda, Y., 6, 29 Maeno, M., 5, 149 Maes, B.U.W., 3, 289 Magarifuchi, D., 12, 10 Magauer, T., 12, 58 Magdum, P.A., 3, 50, 52 Magness, D.M., 5, 353 Magnus, N.A., 3, 403 Magolan, J., 5, 503 Maguire, A.R., 3, 403 Maguire, G.E.M., 2, 3 Mahajan, P.S., 12, 164 Maheswari, C.M., 11, 121 Maheswari, C.U., 3, 251; 4, 159; 10, 207

Author Index Mahmood, T., 3, 227, 250, 478 Mai, V.H., 4, 207 Mai, Y., 3, 290 Maiden, T.M.M., 5, 178 Maier, A.F.G., 3, 354 Mailikezati, M., 1, 92; 3, 456 Maiti, D., 3, 325; 5, 143, 299, 412, 413, 590 Maiti, G., 3, 244 Maitra, R., 4, 194; 5, 569; 10, 203 Maity, B., 3, 352; 4, 192 Maity, P., 10, 107 Maity, S., 1, 372; 5, 299, 412 Maixner, J., 1, 90 Maj, A.M., 3, 389 Majhail, M.K., 1, 299; 10, 250 Maji, A., 5, 143 Maji, T., 10, 241 Makarov, A.S., 12, 67 Makarov, I.S., 3, 348; 7, 36 Makiabadi, B., 10, 492 Mako, T.L., 8, 73 Makosza, M., 5, 75, 76 Makowiec, S., 1, 114; 11, 26 Mal, A., 5, 60; 7, 77 Malakar, S., 3, 245 Malamidou-Xenikaki, E., 11, 139 Malapit, C.A., 5, 534 Maldonado, A., 9, 15 Malekafzali, A., 10, 447 Maligres, P.E., 12, 75 Malik, P., 11, 172 Malik, V.S., 3, 3 Malinowski, M., 12, 5 Mal’kina, A.G., 4, 177; 10, 439; 12, 224 Malkov, A.V., 10, 222 Malladi, R.S., 3, 23 Mallapur, B.S., 3, 52 Mallet, C., 5, 238 Mallet-Ladeira, S., 1, 355 Mallick, A., 1, 24; 6, 69 Mallikharjunarao, Y., 1, 24 Malmedy, F., 12, 63 Malone, J.A., 6, 41 Maloney, K.M., 5, 25 Malter, M., 5, 467 Mamani, R., 3, 1, 2 Mamidipalli, P., 12, 161 Man, H.W., 5, 473 Man, K.Y., 3, 357; 10, 114 Man, W., 12, 131 Man, W.-L., 3, 90, 91 Man, Z., 4, 92 Manabe, K., 5, 444 Manche˜no, O.G., 5, 83; 10, 657 Mancuso, R., 10, 209 Mandal, A., 5, 156 Mandal, R., 5, 366; 10, 231

Mandal, S., 7, 83 Mandal, S.K., 5, 530 Mándi, A., 11, 150 Mandour, H.S.A., 7, 95 Mane, M.K., 6, 75 Mane, M.V., 5, 104; 10, 400 Mane, R.S., 3, 321, 322; 5, 523 Mane, V., 5, 205; 10, 561 Mangina, N.S.V.M.R., 12, 106 Manjunatha, A.S., 3, 166, 168, 169 Mankad, N.P., 1, 295; 4, 185 Manna, A., 11, 88 Manna, S., 1, 356 Manochitra, S., 3, 161 Manoni, E., 1, 172; 8, 111; 10, 22 Manoni, F., 1, 310 Manoury, E., 3, 391 Mansilla, J., 1, 60 Mansoor, S.S., 3, 3 Manzini, C., 5, 571 Mao, D., 3, 312 Mao, F., 5, 80 Mao, J., 3, 290, 347; 7, 39, 40 Mao, W., 10, 268 Mao, Z., 3, 56; 4, 96; 5, 403; 10, 635; 12, 82, 95 Mao, Z.-W., 2, 24 Marabello, D., 10, 598 Marchivie, M., 12, 195 Marder, T.B., 5, 477 Marek, I., 8, 75; 10, 21; 12, 166, 167 Marelli, E., 1, 132 Maresh, J., 1, 51 Margalef, J., 1, 86; 3, 428 Margarita, C., 3, 386 Margetic, D., 6, 23 Margulieux, G.W., 3, 378 Marianetti, G., 5, 571 Mariani, F., 4, 115 Marichev, K.O., 12, 119 Marigo, M., 1, 318; 8, 129 Marin, G.B., 10, 432 Marinelli, F., 3, 59; 10, 383 Marinetti, A., 12, 122 Marinez, E.R., 5, 167 Marinkovic, A.D., 2, 1 Marin-Luna, M., 4, 248 Marino, N., 10, 209 Marke, I., 1, 199 Markewich, D.J., 6, 16; 12, 203 Markosyan, A.I., 5, 232 Markov, A.A., 3, 267, 268; 10, 113 Markovi´c, Z.S., 10, 85 Marosvolgyi-Hasko, D., 5, 524 Marozsan, N., 4, 206 Marque, S.R.A., 6, 15 Marques, F.A., 1, 262; 8, 58

807

Author Index Marquez, E., 9, 12, 15 Marra, R.K.F., 1, 242 Marrot, J., 1, 365; 10, 47 Marshall, P., 3, 273 Marsini, M.A., 10, 473 Martel, A., 12, 45 Martin, A., 6, 51 Martin, D., 10, 297 Mart´ın, E., 7, 18, 64, 65 Martin, N., 9, 9 Martin, R.E., 8, 130 Martin-Diaconescu, V., 5, 442; 8, 104; 10, 336 Martin-Drumel, M.-A., 3, 212 Martinelli, J.R., 3, 385 Mart´ınez, C., 3, 194, 206; 7, 145; 10, 4, 62 Martinez, F., 7, 149 Mart´ınez, J.I., 1, 100; 12, 130 Martinez-Alvarez, R., 9, 9 Martinez-Ferrer, J., 6, 50 Mart´ınez-Guajardo, G., 6, 87; 12, 38 Martinez-Guardo, G., 6, 63 Mart´ınez-Otero, D., 12, 202 Mart´ınez-Rodr´ıguez, L., 7, 18 Martin-Matute, B., 3, 494 Martin-Mingot, A., 6, 51; 10, 47 Martins, M.A.P., 11, 86 Maruoka, K., 11, 24, 116 Marzo, L., 10, 513 Masa, H., 5, 69 Mas-Ballesté, R., 10, 513 Mascare˜nas, J.L., 1, 40; 10, 398; 11, 167 Maseras, F., 3, 42, 206; 5, 289; 7, 145; 10, 62; 11, 135 Mashima, K., 3, 313, 424, 473; 7, 24; 8, 99 Mashuta, M.S., 7, 80 Maslennikova, V.I., 12, 183 Masoodi, H.R., 10, 491 Masoudi, M., 1, 252 Massaro, N.P., 4, 74 Massi, A., 1, 230, 231 Massignan, L., 5, 545 Masters, J.T., 12, 150 Mastrorilli, P., 3, 74 Masu, H., 10, 65 Masuda, J.D., 1, 201 Masutomi, K., 11, 144, 145 Matano, Y., 12, 191 Mateo, P., 10, 406; 12, 54 Mathew, J., 10, 154 Mathew, T., 5, 167 Mathey, L., 3, 313 Mathur, A., 1, 157 Matlock, J.V., 5, 82; 12, 48 Mato, M., 11, 14 Matousek, V., 8, 124

Matovic, R., 10, 382 Matsnev, A.V., 1, 178; 8, 20 Matsubara, K., 4, 149 Matsubara, R., 11, 152 Matsubara, T., 3, 336 Matsuda, N., 1, 103; 5, 259 Matsuda, T., 12, 140, 143 Matsuda, Y., 10, 594 Matsui, K., 11, 141 Matsumoto, A., 1, 259 Matsumoto, K., 10, 423 Matsumoto, S., 3, 247; 4, 228; 7, 33; 10, 65 Matsumoto, T., 3, 461; 10, 477 Matsunaga, S., 5, 380 Matsunami, A., 5, 281 Matsuo, J.-i., 11, 127 Matsuo, Y., 11, 18 Matsuoka, H., 12, 69 Matsuoka, S., 4, 155 Matsuura, K., 12, 64 Matsuzaka, H., 1, 282 Matsuzawa, N., 1, 19 Matt, D., 5, 458 Mattson, A.E., 10, 110 Matulis, V.E., 5, 275 Matyas, C., 3, 125 Maulide, N., 6, 67; 10, 103; 11, 153; 12, 19 Maurin, J.K., 5, 582 Maurya, A.K., 5, 160 Maurya, R.A., 12, 158 Mawatari, Y., 1, 184 May, J.A., 6, 92 Mayer, P., 6, 11, 12; 10, 548 Mayr, H., 4, 141; 5, 95; 6, 7–13; 7, 122; 10, 548 Mazuela, J., 10, 220 Mazur, L., 5, 461 Mazzanti, A., 7, 94; 10, 508 Mazzini, V., 1, 311 Mazzonna, M., 3, 115, 116 McCammant, M.S., 10, 180 McCamnant, M.S., 5, 389 McCarthy, M.C., 3, 212 McCarty, Z.R., 4, 148 McClain, E.J., 10, 128 McDonald, R., 3, 350 McDouall, J.J.W., 1, 108; 10, 150 McGlacken, G.P., 3, 55 McGrath, T., 1, 201 McGregor, I., 3, 357; 10, 114 McHale, K.S.S., 7, 117 McIntosh, M.C., 12, 57 McKenzie, M.J., 3, 143 McKoy, A.M., 4, 5 McMahon, R.J., 4, 239 McMahon, T.C., 11, 67 McNulty, J., 11, 11 McQuilken, A.C., 10, 129

Méallet-Renault, R., 10, 618; 11, 83 Meanwell, M., 8, 130 Meany, F.B., 10, 143 Meazza, M., 7, 94; 10, 508 Meciarova, M., 1, 171 Mecozzi, F., 3, 231 Medaboina, D., 6, 64 Medina, J.M., 5, 122 Medley, J.W., 10, 71 Medvedev, J.J., 5, 243; 6, 45; 9, 39 Meena, J.S., 1, 277 Meena, M.L., 3, 6 Meggers, E., 1, 224; 10, 458 Mehrabi, T., 5, 224; 10, 359 Mehrdad, M., 3, 256; 12, 163 Mehta, G., 5, 107 Mei, G., 5, 457 Mei, H., 5, 261; 11, 113; 12, 227 Mei, R., 3, 303 Mei, S.-T., 3, 98 Meier, G.P., 5, 503 Meinds, T.G., 3, 231 Meise, K.J., 3, 486 Melaimi, M., 4, 181 Melen, R.L., 1, 347; 12, 71 Melillo, B., 12, 170 Melis, N., 12, 192 Mellerup, S.K., 10, 139 Mello, R., 6, 50 Melnikov, M.Y., 7, 90 Melot, R., 1, 163 Melvin, P.R., 5, 472 Men, Y., 11, 79 Mendez, I., 5, 549 Méndez, M., 9, 36; 10, 227 Mendis, C.H., 10, 241 Meneghetti, F., 1, 247 Menéndez, C., 11, 121 Menezes, L.R.A., 2, 29 Menezes da Silva, V.H., 4, 197; 5, 392; 10, 53 Meng, C., 1, 147; 3, 221 Meng, F., 10, 617 Meng, G., 5, 266, 475, 495, 504, 505 Meng, J., 4, 94; 5, 376; 10, 185 Meng, L., 8, 62; 10, 636 Meng, Q., 1, 297, 300; 10, 232, 330 Meng, W., 1, 89, 192; 3, 432; 6, 55; 11, 54; 12, 127 Meng, X., 6, 73; 10, 372 Meng, Z.H., 3, 136 Menges, N., 10, 390; 11, 58 Mengozzi, L., 1, 94 Menichetti, S., 9, 41 Menini, L., 3, 315 Meninno, S., 7, 58

808 Menon, R.S., 3, 276; 12, 107 Mensch, C., 3, 289 Menzek, A., 12, 26 Mercadante, M.A., 3, 133 Mercado, B.Q., 1, 372 Merino, G., 6, 63, 87, 95; 12, 38 Merino, P., 1, 145, 165, 354; 8, 35 Merkushev, A.A., 12, 67 Merner, B.L., 12, 36 Merritt, B.A., 4, 5 Mersmann, S., 3, 398 Mertens, L., 10, 589 Meshcheryakov, V.I., 1, 237 Meshram, H.M., 5, 154 Messaoudi, S., 5, 155 Meti, M.D., 3, 10, 69 Metta-Magana, A.J., 3, 341 Meudom, R., 12, 36 Meuresch, M., 3, 401, 406 Meyer, C., 12, 138 Meyer, H.H., 12, 22 Meyer, J., 7, 135 Mezei, G., 8, 1, 116 Mhaske, S.B., 5, 105, 377; 10, 192; 12, 164 Miao, B., 10, 316 Miao, C., 3, 229, 236; 7, 73 Miao, H., 5, 508 Miao, M., 3, 189; 4, 221, 223; 10, 106 Miao, W., 8, 19 Miao, Z., 4, 62; 10, 504 Miaskiewicz, S., 10, 392, 655; 12, 104 Micalizio, G.C., 10, 345 Miceli, M., 5, 253 Michael, C.D., 12, 34 Michalak, A., 11, 72 Michalak, M., 11, 71 Michelet, V., 3, 59; 5, 131; 10, 69, 383 Micheletti, G., 5, 88 Michon, C., 10, 37 Micouin, L., 4, 89 Middaugh, J.E., 1, 330 Midura, W.H., 12, 72 Midya, A., 10, 532 Midya, S.P., 5, 426 Mielgo, A., 10, 472 Mighion, J.D., 4, 91 Mikami, K., 4, 34; 5, 308, 309; 7, 144; 8, 126 Mikesell, J., 5, 350; 10, 188 Mikhailova, T.Y., 3, 267, 268; 10, 113 Miki, Y., 10, 294 Mikosch, R., 7, 137 Mikshiev, V.Y., 5, 45 Milan, M., 3, 222

Author Index Milen, M., 2, 16 Milenkovi´c, D.A., 10, 85 Miles, K.C., 3, 278 Milius, W., 12, 65 Millan, D., 2, 5 Milligan, J.A., 7, 91 Mills, J.L., 4, 5 Milo, A., 9, 46 Min, B.-H., 12, 148 Min, M., 5, 536 Min, Q.-Q., 4, 35; 5, 310, 311 Min, W., 6, 19 Minakata, S., 1, 306 Minakawa, M., 7, 16; 8, 95 Minami, H., 10, 301 Minami, T., 8, 13; 10, 558, 592 Minami, Y., 5, 446; 10, 217 Minenkov, Y., 1, 132 Ming, J., 5, 362; 10, 641 Ming, L., 11, 82 Minnaard, A.J., 3, 320 Minuti, L., 11, 95 Minyan, L., 1, 135 Mir, R., 6, 20; 10, 362 Miranda, M.F.F., 10, 436 Miranda-Quintana, R.A., 9, 9 Mirzaei, P., 1, 71 Misal Castro, L.C., 10, 341 Miscione, G.P., 3, 307; 8, 48 Mishiro, K., 6, 19 Mishra, A., 5, 531 Mishra, A.K., 5, 20 Mishra, N.K., 5, 187, 188, 553; 10, 245, 637, 638 Mishra, S.K., 3, 126, 173 Mita, T., 1, 121; 10, 196 Mitake, A., 11, 152 Mitra, N.K., 12, 36 Miura, H., 11, 157 Miura, K., 10, 353; 12, 229 Miura, M., 3, 340; 4, 186; 5, 146, 449; 7, 4; 8, 94; 10, 123, 294, 449 Miwa, Y., 10, 301 Miyagi, K., 5, 28; 10, 52 Miyamoto, H., 1, 213 Miyamoto, K., 4, 32 Miyata, O., 1, 274; 10, 386; 12, 110 Miyazaki, R., 7, 63 Miyazaki, T., 11, 39 Mizar, M., 10, 61 Mizoguchi, H., 10, 345 Mizota, I., 1, 209; 10, 465 Mizuguchi, T., 10, 423 Mizukami, A., 10, 256 Mizuno, M., 8, 52; 10, 651 Mizutani, Y., 10, 602 Mlosto´n, G., 12, 175 Mlosto´n, H.G., 11, 72

Mlynarski, J., 1, 95, 287; 3, 363, 464, 467 Mo, D.-L., 12, 220 Mo, F., 4, 65, 71, 73 Mo, W., 5, 283 Mo, X., 1, 215; 6, 112 Mo, Y., 1, 313; 5, 283; 7, 141; 8, 1, 5, 116 Moberg, C., 1, 305; 10, 147 Mobin, S.M., 5, 490; 12, 31 Möbus, J., 10, 133 Moccia, M., 10, 553 Mochida, K., 6, 36 Modak, M., 5, 413 Modec, B., 1, 344; 3, 451 Modrego, F.J., 10, 157 Moeljadi, A.M.P., 3, 223 Moghaddam, F.M., 5, 132 Moghaddam-Manesh, M., 5, 38; 12, 196 Mohamed, S., 3, 366 Mohammad, M., 5, 533 Mohammad, Z., 4, 143 Mohan, D.C., 4, 56 Mohanta, P.R., 3, 35; 5, 134 Mohanty, S., 1, 244 Mohapatra, P.P., 1, 64 Mohar, B., 1, 344, 346; 3, 449, 451 Möhlmann, L., 10, 585 Moiseeva, N.I., 3, 267, 268; 10, 113 Mokar, B.D., 4, 135 Mokhtari, N., 10, 47 Mokuya, A., 10, 210 Molander, G.A., 5, 344 Molchanov, A.P., 5, 218; 6, 86; 12, 35 Molchanova, A.P., 12, 211 Molina, K., 3, 420 Molinari, A., 1, 230 Moliterno, M., 10, 537 Molleti, N., 1, 210; 10, 520 Molnár, I.G., 10, 72 Molnar, A., 6, 61 Moncho, S., 5, 292, 499 Mondal, A., 5, 413 Mondal, M., 11, 53 Mondal, P.K., 6, 68 Mondal, S., 3, 310; 4, 219; 5, 271; 6, 63, 87; 10, 51; 12, 38 Mondal, T., 1, 304; 3, 352; 4, 192 Monde, K., 11, 150 Monge, D., 5, 465 Mongin, F., 5, 273, 275 Monir, K., 10, 51 Monnier, F., 10, 309 Monopoli, A., 3, 74 Monta˜na, A.M., 11, 168

809

Author Index Monteiro, N., 1, 150, 163 Montes, K., 6, 79; 11, 61 Moody, C.J., 11, 100 Moon, H.R., 5, 237 Moon, J.H., 10, 135 Moon, P.J., 5, 321 Moors, S.L.C., 5, 19 Moorthy, J.N., 1, 245 Moosavi-Movahedi, A.A., 3, 16 Moosavi-Zare, A.R., 1, 255 Mora, J.R., 9, 12, 15 Morad, M., 3, 66, 67 Moragas, T., 12, 2 Morales, J.I., 2, 5 Morán-Poladura, P., 1, 39; 10, 397 Mora-Radó, H., 9, 36; 10, 227 Morcillo, S.P., 1, 238 More, A.A., 11, 151 Morera-Boado, C., 9, 9 Moretti, E., 10, 537 Moretti, R.A., 3, 261 Morgante, P., 10, 598 Mori, A., 5, 574 Mori, S., 10, 179 Morimoto, N., 10, 95 Morimoto, T., 5, 516; 10, 602 Morimoto, Y., 3, 313; 10, 210 Morioku, K., 10, 95 Mori-Quiroz, L.M., 10, 433 Morita, N., 10, 38 Morita, T., 5, 276 Morita, Y., 1, 191 Moriyama, K., 5, 28; 10, 52 Moriyama, T., 12, 34 Morokuma, K., 4, 34; 7, 144; 8, 126 Morozov, O.S., 4, 190; 5, 64 Morozov, P.G., 5, 78 Morrill, L.A., 5, 95 Morrill, L.C., 1, 347 Morris, R.H., 1, 343; 3, 440 Morrison, A.E., 12, 61 Morsch, T., 3, 386 Morstein, J., 3, 291; 5, 306 Mortier, J., 5, 73 Mosaferi, E., 6, 31; 10, 108 Moselage, M., 5, 291 Moses, J.E., 5, 583 Mosesohn, K., 4, 109 Mosher, M.D., 5, 350; 10, 188 Moskalenko, I., 3, 274 Moss, R.A., 4, 6, 7 Motika, S.E., 10, 145 Motiwala, H.F., 12, 189 Mou, R.-Q., 10, 204 Moura-Letts, G., 1, 333 Moussallem, C., 5, 238 Mousseau, J.J., 5, 206

Moxter, M., 1, 285; 4, 258 Moyeux, A., 3, 307; 8, 48 Moynihan, H.A., 3, 403 Mozziconacci, O., 3, 112 Mu, J.R., 10, 1 Mu, Y., 4, 246; 5, 587 Mück-Lichtenfeld, C., 5, 115; 12, 78 Mudd, R.J., 3, 394 Mudit, D., 6, 116 Mujahid, M., 5, 437; 10, 216 Mukai, C., 11, 148; 12, 134 Mukai, M., 10, 328 Mukaiyama, T., 10, 496 Mukherjee, D., 1, 294; 3, 361, 473 Mukherjee, S., 4, 219 Mukhopadhyay, A., 1, 245 Muldoon, M.J., 3, 319 Müller, D.S., 8, 75 Müller, T., 4, 261 Muller, F., 1, 214 Munaretto, L. d. S., 1, 262 Munavalli, D.S., 3, 51 Munechika, A., 11, 18 Mu˜niz, K., 3, 194, 200, 206; 7, 145; 10, 4, 54, 62, 67 Mu˜noz, M.C., 1, 120, 127; 5, 249; 10, 615 Munoz-Hernandez, M.A., 6, 95 Munteanu, C., 3, 357; 10, 114 Murafuji, T., 12, 10 Murahashi, S.-I., 3, 232 Murai, K., 3, 260; 12, 64 Murai, M., 3, 103 Murakami, K., 3, 335; 5, 165, 579; 12, 20 Murakami, M., 12, 143 Murakami, N., 5, 380 Muralidhara, H.B., 3, 165 Muralirajan, K., 10, 338 Muraoka, S., 1, 225 Murata, M., 3, 106; 5, 290 Murata, Y., 10, 194 Murayama, H., 10, 546 Murie, V.E., 4, 4 Murphy, J.A., 5, 10 Murray, A.T., 3, 296 Murray, I.E., 3, 453 Murray, M., 10, 274, 275 Murugesan, S., 1, 206; 8, 34 Murugesapandian, B., 3, 313 Muslukhov, R.R., 10, 96 Musolino, S.F., 10, 480 Muthu, K., 3, 357; 10, 114 Muthukrishnan, I., 11, 121 Muthukumaran, B., 3, 263 Muthusamy, S., 12, 96, 180 Muto, K., 5, 584

Muzalevskiy, V.M., 5, 244; 6, 32, 33; 9, 4 Muzart, J., 7, 1 Myalochkin, D.L., 6, 3

N Nacci, A., 3, 74 Nadh, R.V., 1, 334; 3, 164 Naeimabadi, M., 11, 48 Naesborg, L., 5, 251 Nagahora, N., 1, 368; 5, 118 Nagai, H., 1, 191 Nagami, N., 5, 287 Nagamoto, M., 10, 276 Nagao, K., 10, 546 Nagao, Y., 10, 38 Nagarajaiah, H., 1, 245 Nagarajan, A., 3, 208 Nagarajan, S., 3, 251; 4, 159; 10, 207; 11, 121 Nagare, A.S., 11, 88 Nagarkar, A.A., 4, 107 Nagasawa, S., 3, 135; 9, 22 Nagase, M., 5, 72 Nagashima, H., 3, 381; 10, 153 Nagata, T., 1, 306 Nageswar Rao, D., 3, 316 Nagorny, P., 1, 28 Nagumo, R., 3, 41 Nagy, E., 10, 107 Naida, E., 11, 26 Naidu, V.R., 6, 113 Naik, P.N., 3, 51 Nairoukh, Z., 1, 199 Najda, E., 1, 114 Nájera, C., 1, 232; 10, 499; 11, 38, 44 Nakabayashi, K., 6, 36 Nakada, M., 4, 235; 10, 370 Nakagawa, M., 6, 26 Nakagawa, T., 11, 18 Nakajima, K., 10, 199; 11, 159 Nakajima, M., 1, 282 Nakajima, Y., 10, 154 Nakamara, S., 1, 66, 103 Nakamura, E., 3, 336; 5, 324 Nakamura, H., 3, 500; 5, 222, 276 Nakamura, K., 12, 139 Nakamura, S., 1, 58; 5, 259; 8, 98 Nakamura, Y., 5, 100; 11, 144 Nakamuro, T., 10, 173 Nakanishi, W., 4, 32 Nakano, H., 1, 184 Nakano, S., 5, 435; 11, 89 Nakano, T., 4, 138 Nakano, Y., 4, 215; 5, 35 Nakao, Y., 3, 459, 462; 10, 127 Nakashima, S., 1, 19 Nakata, K., 5, 207; 6, 43

810 Nakata, S., 11, 116 Nakatani, M., 5, 35 Nakatsuji, H., 10, 43 Nakatsuka, S., 5, 287 Nakazawa, H., 3, 107 Nakazono, K., 3, 255 Nakijima, K., 5, 287 Nalbantova, D., 5, 11 Nalbone, J.M., 2, 25 Nam, W., 3, 236 Namba, K., 10, 423 Namboothiri, I.N.N., 5, 205; 10, 561; 12, 173 Namikoshi, T., 3, 106 Na nakorn, R., 10, 199 Nandi, R.K., 1, 274; 5, 220, 236; 10, 326, 327 Nandi, S., 5, 590 Nandibewoor, S., 3, 22 Nandibewoor, S.T., 3, 10, 19, 49–52, 69, 120 Nanubolu, J.B., 3, 276; 6, 105; 12, 107 Nanya, A., 9, 32 Napolitano, E., 10, 662 Napolitano, J.G., 3, 288; 4, 104; 5, 36 Napoly, F., 5, 32; 7, 42 Nara, H., 1, 345; 3, 448 Narain, R., 10, 172 Naredla, R.R., 3, 346; 6, 48 Narkiewicz-Michalek, J., 5, 4 Narouei, Y., 1, 42 Narula, A.K., 10, 569 Naruse, Y., 10, 29 Nash, A.L., 1, 305 Nasibullina, R.A., 3, 281 Nasiri, B., 3, 495 Nasiri, F., 10, 421 Nathel, H.F.F., 5, 95 Natori, T., 11, 157 Nauton, L., 4, 212 Navale, G.R., 6, 117 Naveen, J.O.C., 5, 144 Navendu Jana, N., 4, 255 Navo, C.D., 10, 455 Nayak, A.N., 3, 121 Nayak, S.S., 3, 49 Nayal, O.S., 1, 353; 6, 57 Nazish, M., 1, 119 Ndassa, I.M., 5, 123, 124 Necas, D., 5, 288 Nechaev, M.S., 4, 190; 5, 64 Nedden, H.G., 1, 342; 3, 369 Negishi, E., 10, 20 Negrato, M., 4, 131; 5, 564; 7, 76; 10, 364 Nejad, N.K., 10, 494 Nelson, A.K., 10, 609 Nelson, B.M., 7, 31; 8, 15

Author Index Nelson, R., 1, 40; 10, 398; 11, 167 Nemcsok, T., 10, 468 Nemoto, K., 3, 41; 5, 272 Nemoto, T., 5, 300, 435 Nenajdenko, V.G., 5, 244, 245; 6, 28, 32, 33; 9, 4 Nesterov, V.N., 5, 68; 10, 387 Neubert, T., 5, 342; 8, 89 Neuenswander, S.A., 12, 217 Neuhaus, J.D., 8, 78 Neumann, C.N., 5, 18 Neumann, L.K., 5, 572 Newman, T., 6, 118 Newmeyer, B., 3, 197; 5, 46 Newson, H.L., 3, 264 Neyyappadath, R.M., 1, 132 Ng, E., 12, 12 Ng, T.W., 3, 436 Ngorny, P., 6, 109 Nguyen, D.-V., 12, 138 Nguyen, D.H., 10, 157 Nguyen, H., 1, 26 Nguyen, J., 4, 137; 8, 80 Nguyen, L., 3, 224 Nguyen, M.K., 10, 621 Nguyen, S., 1, 227; 10, 296 Nguyen, T., 4, 5 Nguyen, T.B., 3, 488; 5, 44 Nguyen, T.H., 5, 73 Nguyen, T.N., 6, 92 Nguyen, T.N.T., 7, 10 Nguyen, T.S., 6, 92 Nguyen, T.V., 10, 27 Ngwa, C., 1, 243 Ni, C., 1, 315; 4, 193; 5, 463; 8, 19 Ni, F., 10, 620 Ni, H., 11, 131 Ni, J., 5, 138 Ni, Q., 10, 590 Ni, S., 6, 113; 12, 227 Ni, S.-F., 12, 133 Ni, W., 5, 80 Ni, X., 10, 604 Ni, Z., 10, 238 Nichols, A.J., 11, 21 Nie, J., 1, 192 Nie, S.-Z., 8, 40 Niebuhr, R., 10, 61 Nieger, M., 10, 452 Nielsen, A.J., 11, 11 Nielsen, C.-D.T., 10, 611 Nielsen, M.K., 4, 64 Nielsen, R.P., 11, 99 Nielsen, T.E., 5, 256; 6, 107 Nieto, F.O.R., 12, 198 Nieto Faza, O., 1, 146 Niggemann, M., 6, 102; 12, 87 Niki, A., 3, 257

Nikishin, G.I., 3, 182; 10, 58 Nikitina, K.V., 12, 224 Nikitina, L.P., 4, 177; 10, 439 Nikolaev, V.A., 5, 243; 6, 45; 9, 39 Nikolic, J.B., 2, 1 Nikonov, G.I., 3, 131; 4, 207 Nilov, D.I., 5, 243; 6, 45 Nilova, A., 5, 97; 9, 28 Nilsson Lill, S.O., 6, 48 Ning, S., 10, 30 Ning, X., 1, 289 Ning, X.-S., 3, 207 Ninham, B.W., 1, 311 Ninkovic, D.B., 5, 292 Nisa, R.U., 3, 227, 250, 478 Nisha, K.J., 3, 159 Nishi, M., 5, 214 Nishibayashi, Y., 11, 159 Nishida, N., 5, 9; 8, 55 Nishide, K., 3, 257 Nishihara, Y., 10, 179, 199 Nishii, Y., 7, 93 Nishikawa, D., 10, 123, 294 Nishikawa, Y., 11, 89 Nishimine, T., 8, 37 Nishimoto, Y., 7, 102; 9, 26; 10, 410 Nishimura, R.H.V., 4, 4 Nishimura, T., 5, 370; 8, 102; 10, 276, 277 Nishimura, Y., 10, 199 Nishina, Y., 10, 95 Nishiura, M., 10, 416 Nishiyama, H., 1, 225; 10, 627 Nishiyama, Y., 5, 516; 6, 90; 10, 602; 12, 44 Nishizawa, M., 5, 229 Niu, J., 1, 339 Niu, J.-L., 3, 28, 305; 5, 173, 486 Niu, S.-S., 1, 254; 4, 230 Niu, Y., 10, 419; 12, 117, 124 Nivola, A., 11, 3 Nobushige, K., 5, 146 Nocera, D.G., 3, 334 Nocquet-Thibault, S., 10, 55 Noda, D., 10, 153 Nodwell, M.B., 8, 130 Noei, J., 1, 43 Noey, E.L., 7, 140; 8, 112 Nogi, K., 5, 71; 12, 20 Noguchi, K., 10, 644; 11, 144; 12, 139 Nojima, T., 9, 33; 10, 402 Nolan, M.-T., 3, 55 Nolan, S.P., 1, 132 Noll, B., 3, 341 Nolting, A., 12, 75 Nomoto, A., 10, 354 Nomura, K., 3, 232

811

Author Index Nonn, M., 7, 153 Nordlander, E., 2, 27 Norita, N., 10, 65 Noriyuki, Y., 12, 92 Noro, J., 1, 122; 11, 122 Norrby, P.-O., 1, 195; 3, 398 Nosova, V.E., 6, 86 Notario, R., 1, 284; 4, 27; 9, 13, 14 Novacek, J., 3, 130 Novak, Z., 5, 48, 313 Novikov, I.V., 3, 32 Novikov, R.A., 3, 182; 10, 58 Nozaki, K., 5, 284, 432; 10, 164; 12, 77 Noˇzinovi´c, S., 12, 69 Nudelman, N.S., 5, 41 Numano, M., 5, 287 Nunes, C.M., 4, 239 Nunes dos Santos Comprido, L., 4, 121 Nuree, Y., 1, 332 Nziko, V. d. P. N., 7, 143 Næsborg, L., 1, 2; 11, 30

O Obata, A., 3, 27; 10, 341 Obenauf, J., 12, 65 Obijalska, E., 12, 175 Obinata, S., 11, 150 Oblak, E.Z., 6, 114; 7, 100 Oble, J., 3, 84 Obligacion, J.V., 8, 106 Obradors, C., 11, 14 O’Brien, P., 1, 124 Ocando-Mavarez, E., 3, 420 Ochiai, M., 4, 32 Oda, H., 7, 24; 8, 99 Odani, A., 1, 29 Odell, B., 1, 57; 8, 36 Odom, A.L., 10, 346 Odriozola, J.M., 10, 472 Oestreich, M., 3, 410, 452; 5, 196, 197; 10, 7, 115, 315 Oestrich, M., 1, 82; 6, 25 Offield, A.C., 12, 119 Ofial, A.R., 6, 10, 11, 13; 7, 122 Ogawa, A., 10, 354 Ogawa, M., 5, 35 Ogawa, N., 7, 41; 8, 41 Ogawa, O., 10, 659 Ogba, O.M., 10, 25 Ogiwara, Y., 3, 247; 10, 411; 12, 28 Ogoshi, S., 1, 374; 4, 161; 8, 86 Ogura, Y., 10, 43 Oguri, R., 10, 627 Oh, J.S., 10, 638 Oh, K.H., 10, 307 Oh, Y., 5, 187, 188; 10, 245, 638

Ohara, M., 1, 103; 5, 259 Ohashi, M., 1, 374; 4, 161; 8, 86 Ohe, K., 9, 32 Ohgi, A., 3, 462 Ohkawa, H., 10, 328 Ohm, R.G., 5, 256; 6, 107 Ohmiya, H., 4, 217; 5, 550; 7, 13, 28; 8, 84; 10, 290, 546 Ohmura, T., 10, 281 Ohno, S., 10, 423 Ohsato, T., 5, 284 Ohshima, T., 10, 549 Ohtagaki, Y., 10, 127 Ohtsuka, N., 12, 176 Ohtsuki, A., 5, 476 Oiarbide, M., 1, 59; 10, 472 Oiler, J., 11, 47 Ojeda-Porras, A., 7, 156 Ojha, D.P., 10, 134 Okada, T., 5, 146 Okamoto, K., 9, 32 Okamoto, N., 7, 20; 10, 301; 12, 8 Okamoto, T., 1, 29 Okamoto, Y., 11, 148 Okamura, D., 10, 498 Okano, K., 5, 574 Okayasu, H., 10, 328 Okazaki, H., 7, 26 Okazaki, T., 6, 26 Okereke, S.E.O., 3, 210 Okita, A., 7, 102 Okoromoba, O.E., 7, 80 Okubo, R., 5, 272 Okuda, J., 1, 294; 3, 361, 473 Okuda, Y., 10, 179 Okugawa, Y., 3, 340; 4, 186 Okuma, K., 1, 368; 5, 118 Okuno, M., 12, 176 Okuno, Y., 5, 284 Okura, K., 5, 8, 9; 8, 53, 55 Okusu, S., 7, 26 Okuyama, Y., 1, 184; 11, 101 Olah, G.A., 5, 167; 6, 61 Oliphant, J., 7, 31; 8, 15 Oliveira, A.V.B., 1, 96 Oliveira, J.S., 5, 354 Oliveira, R.A., 1, 226 Olivier, S., 5, 238 Olivo, G., 3, 115, 116, 220 Olsen, L.B., 5, 256; 6, 107 Olsson, S.K., 7, 130 Olyschläger, T., 1, 366; 4, 153 Omurtag, P.S., 10, 432 Oniwa, K., 3, 109 Ono, H., 10, 38 Ono, T., 10, 496 Ono, Y., 7, 138 Onomura, O., 5, 29 Onozawa, S., 4, 162; 5, 272

ó Proinsias, K., 4, 43 Orebom, A., 3, 386 Orgue, S., 3, 388 Orian, L., 7, 109 Oriez, R., 4, 156 O’Riordan, T.J.C., 10, 479, 480 Orlandi, M., 1, 168; 3, 468 Oro, L.A., 4, 208; 10, 157, 251 Orr, R.K., 12, 75 Orrillo, A.G., 1, 14 Orru, R.V.A., 1, 302 Ortega, V., 7, 88 Ortega-Mart´ınez, A., 1, 232; 10, 499 Orth, E.S., 2, 29 Ortin, I., 1, 57; 8, 36 Ortiz, F.L., 8, 38 Ortiz, P., 8, 4; 12, 168 Ortiz, R., 11, 38 Ortiz-Marciales, M., 7, 61 Ortiz-Rujano, L., 5, 257 Osaka, A., 5, 352 Oˇseka, M., 12, 199 O’Shea, D.F., 1, 139; 9, 21 Osorio, E., 6, 63; 12, 38 Osorio-Nieto, U., 3, 156 Osseili, H., 1, 294; 3, 361 Osuka, A., 4, 189; 5, 71, 81, 415; 6, 24; 8, 3; 12, 20 O’Sullivan, A.C., 9, 1 Ota, T., 4, 32 Othman, R.B., 1, 308 Ototake, N., 10, 210 Otsuka, S., 5, 71; 12, 20 Ottenbacher, R.V., 3, 25 Otto, R., 7, 137 Ou, A., 4, 231; 10, 273 Ouyang, L., 5, 24; 10, 490 Ouyang, Q., 6, 78; 10, 545 Ouyang, Z., 4, 26 Overkleeft, H.S., 7, 127 Ovian, J.M., 3, 133 Ozaki, H., 1, 259 Ozawa, H., 1, 259 Ozawa, R., 12, 10 Ozdemir, I., 4, 188 Özer, M.S., 10, 390; 11, 58 Oziminski, W.P., 4, 142 Oznobikhina, L.P., 1, 237 Ozumerzifon, T.J., 4, 139; 10, 228

P Pace, V., 10, 207 Padala, A.K., 1, 309 Padgham, A.C., 12, 59 Paganoni, A., 7, 76 Page, M.I., 1, 87; 3, 450; 7, 110 Page, P.C.B., 3, 140, 143 Pahls, D.R., 5, 68

812 Pai, L.-X., 5, 542 Paik, K.C., 9, 3 Paisley, N.R., 3, 350 Pajkert, R., 5, 261 Pakhare, S.B., 1, 328; 3, 20 Pal, J., 5, 482 Pal, K., 4, 150 Palacios, L., 4, 208; 10, 251 Palani, N., 10, 470 Palani, V., 5, 116; 10, 428 Pale, P., 10, 392, 655; 12, 104 Paleta, O., 7, 151 Paley, D.W., 6, 19 Pallikonda, G., 5, 201 Palmas, J., 10, 580 Palmer, W.N., 8, 106 Palomo, C., 1, 59, 187; 10, 472 Pàmies, O., 1, 86; 3, 391, 428 Pan, C.-L., 5, 422 Pan, D., 10, 212 Pan, F., 5, 89; 10, 268 Pan, H., 1, 240; 10, 40, 524 Pan, H.-J., 3, 436 Pan, L., 5, 145 Pan, Q., 10, 604 Pan, Y., 1, 52; 5, 261; 8, 18; 12, 227 Pan, Y.-P., 11, 115 Panahi, F., 5, 522 Panday, D., 3, 13, 14 Pandey, A., 3, 122 Pandey, J., 5, 205; 10, 561 Pang, H.-L., 11, 54 Pang, W., 7, 32 Pang, Y., 12, 165 Paniagua, A., 7, 148 Panikorovsky, T.L., 5, 218 Pannecoucke, X., 4, 85; 8, 133 Panossian, A., 5, 119, 120 Papai, I., 10, 93 Pape, F., 4, 183; 7, 10 Pappas, I., 8, 106; 10, 155 Paquin, J.-F., 1, 386; 7, 27 Paradies, J., 1, 83; 3, 354, 373; 12, 53 Paraja, M., 4, 117 Parameswarappa, S.G., 1, 23 Pardasani, R.T., 5, 160 Pardo, L.M., 3, 55 Pareek, M., 1, 112, 131; 4, 168 Parella, T., 5, 442; 8, 104; 10, 336 Parent, J.-F., 6, 52 Parenti, K.R., 10, 190 Parhi, B., 10, 532 Parida, B.B., 8, 118 Parise, L., 1, 76 Park, B.Y., 3, 442 Park, H., 5, 26; 11, 73 Park, H.-S., 12, 148

Author Index Park, J., 1, 109; 4, 247; 5, 180, 361, 384, 553; 7, 9; 10, 172, 637 Park, J.-W., 12, 137 Park, J.K., 10, 307 Park, K.-H., 2, 10, 15; 7, 113 Park, S., 7, 9 Park, S.Y., 10, 307 Park, Y., 5, 190 Parra, R.D., 1, 51 Parreira, L.A., 3, 315 Parsons, P.G., 11, 169 Parsons, P.J., 12, 59 Parumala, S.K.R., 11, 76 Parvathaneni, S., 5, 462 Parvez, M., 5, 98 Parwaz Khan, A.A., 3, 146 Pascual-Escudero, A., 11, 37 Pashikanti, S., 10, 621 Pasko, C.M., 10, 346 Pasko, P.A., 10, 96 Pasquet, V., 3, 157 Passarelli, V., 5, 549 Pasturaud, K., 10, 557 Patel, B.K., 3, 35; 5, 134 Patel, K.H., 4, 191 Patel, M., 10, 66; 11, 117, 118 Patel, N.D., 5, 466 Patel, P., 4, 103 Patel, R., 3, 172 Patel, R.A., 6, 62 Patel, S.S., 5, 570; 10, 300 Patgar, M.B., 3, 120 Patgar, T.N., 3, 69 Pathare, R.S., 5, 160 Pati, K., 1, 5; 6, 71; 10, 369 Patil, D.G., 3, 50 Patil, M., 12, 97 Patil, N.T., 5, 562; 6, 75; 10, 368, 384, 400; 12, 120 Paton, R.S., 1, 4; 5, 536 Patra, T., 5, 413, 590 Patre, R.E., 1, 279 Pattar, V.P., 3, 50 Pattarawarapan, M., 2, 2 Patterson, S., 12, 236 Pattison, G., 1, 267 Paul, A., 1, 340 Paul, A.K., 5, 93 Paul, K., 12, 55 Paul, M., 3, 313 Paul, S., 3, 389 Pauson, P.L., 10, 324 Paveglio, G.C., 11, 86 Pavez, P., 2, 5; 5, 37 Pavlovi´c, R.Z., 10, 44, 85 Pawar, G.G., 5, 139 Pawliczek, M., 11, 171 Paz, B.M., 1, 2; 5, 251 Pazout, R., 1, 90

Peacock, L.R., 10, 448 Pechacek, J., 1, 90 Peck, C.L., 10, 609 Peddinti, R.K., 11, 76 Pedras, M.S.C., 12, 177 Pedraza-González, L., 7, 118 Pedro, J.R., 1, 120, 127; 5, 249; 8, 63; 10, 615, 650 Pedrosa, F.L., 3, 304 Pedrosa, R., 1, 77; 10, 573 Pegu, C.D., 3, 188 Pei, C., 11, 126 Pei, W., 1, 134 Pelagalli, A., 1, 76 Pelinski, L., 3, 455 Pellacani, L., 1, 76 Pellegrinet, S.C., 11, 97 Pellegrini, S., 3, 455 Pellegrini, T., 1, 270; 8, 47 Pelosi, G., 11, 112 Peltier, J.L., 4, 163; 12, 83 Pemberton, T.A., 6, 5 Pen, D., 10, 298 Peng, C., 10, 30; 11, 136 Peng, D., 10, 151 Peng, F., 10, 579 Peng, G., 7, 92 Peng, H., 5, 459; 7, 3; 10, 186 Peng, J., 1, 257; 6, 103; 10, 523; 12, 102 Peng, L.-J., 11, 51 Peng, Q., 5, 536 Peng, X., 12, 117, 124 Peng, Y., 5, 24; 10, 101, 490 Penkett, C.S., 12, 59 Perdih, F., 2, 20 Perego, L.A., 5, 6, 520, 577 Peregrina, J.M., 10, 455 Peregudov, A.S., 12, 219 Pereira, C.L., 1, 23 Pereshivko, O.P., 1, 227; 10, 296 Pérez, M., 5, 198, 199; 7, 150 Perez, P., 4, 29 Perez, P.J., 4, 210 Pérez-Aguilar, M.C., 1, 104; 3, 490; 4, 36 Pérez-Castells, J., 11, 142 Pérez-Galán, P., 12, 121 Perez-Luna, A., 5, 565; 10, 315 Perez-Torrente, J.J., 4, 208; 10, 157, 251 Pericàs, M.A., 11, 132 Periyasamy, S.K., 3, 5 Perna, F.M., 8, 44 Perrin, C.L., 1, 167 Perrin, L., 12, 167 Perrone, T.M., 10, 128 Perry, G.J.P., 5, 478 Perry, I.B., 1, 102; 10, 285 Peruncheralathan, S., 5, 279

813

Author Index Peshkov, A., 10, 495 Peshkov, V.A., 1, 227; 10, 296 Peters, B., 7, 70 Peters, B.K., 3, 386 Peters, R., 12, 146 Petersen, A.R., 3, 441 Petersen, J.L., 10, 128 Peterson, T.H., 5, 84 Petit, M., 5, 565 Petkovic, M., 10, 550 Petrone, D.A., 5, 586; 10, 224 Petrovic, P.V., 5, 292 Petter, R.C., 10, 454 Petzold, M., 11, 161 Pfaltz, A., 1, 202 Phakhodee, W., 2, 2 Pham, H.V., 11, 67 Pham, M.V., 5, 453; 10, 270 Pham, T.T., 11, 73 Phaomei, G., 8, 118 Phatake, R.S., 4, 103 Phelps, A.M., 4, 104 Phillips, D.L., 4, 98 Phillips, E.M., 5, 36 Phillips, N.A., 3, 379 Pi, Y.-X., 5, 65 Pia¸ tek, A., 10, 610 Piarulli, U., 3, 393, 422 Pieczonka, A.M., 1, 265; 8, 59 Pieczykolan, M., 12, 174 Piersanti, G., 3, 262 Pietrasiak, A., 8, 124 Pietrusiewicz, K.M., 5, 461 Pietruszka, J., 1, 214 Piettre, S.R., 10, 557 Piggott, M.J., 3, 264 Pignataro, L., 3, 393, 422 Pihko, P.M., 10, 246 Pike, R.A.S., 3, 48 Pilarski, L.T., 5, 538 Pimlott, S.L., 5, 129 Pimparkar, S., 5, 413 Pindi, S., 1, 269 Pi˜nero-Santiago, L.E., 7, 61 Ping, W., 12, 56 Pinheiro, D.L.J., 10, 474 Pinna, L., 11, 112 Pinter, B., 5, 19 Pinto, M.D.F.R., 1, 242 Piou, T., 10, 248 Pirnot, M.T., 5, 349; 10, 9, 174 Pirovano, V., 4, 131; 5, 564; 7, 76; 10, 364 Pirrung, M.C., 2, 26 Pirwerdjan, R., 5, 226; 10, 104 Pisa, O., 5, 42 Pisano, P.L., 11, 97 Pisella, G., 4, 112 Planar, O., 5, 140 Planas, F., 1, 8

Planas, O., 5, 442; 8, 104; 10, 336 Pla-Quintana, A., 4, 2 Platero-Prats, A.E., 3, 494 Plaza, M., 1, 104; 3, 490 Plé, K., 12, 195 Plenio, H., 10, 361 Plichta, K., 5, 50 Plietker, B., 5, 168 Pliss, E., 3, 274 Plummer, C.W., 12, 75 Poater, A., 4, 179; 8, 107 Poblador-Bahamonde, A.I., 5, 351 Poddar, J., 3, 357; 10, 114 Poethig, A., 10, 159 Pohl, E., 10, 443 Poirier, R.A., 3, 125 Poisson, J.-F., 11, 20 Poisson, T., 4, 85 Poittevin, C., 11, 20 Polganova, I., 5, 194 Poli, G., 3, 84 Poli, R., 3, 391 Pollet, P., 5, 580 Polley, A., 5, 170 Polo, A., 8, 107 Polo, V., 4, 208; 5, 549; 10, 178, 251 Polukeev, V.A., 5, 22 Pomaranski, P., 5, 582 Ponomarenko, M., 5, 261 Ponomarenko, M.V., 10, 2 Pons, A., 4, 85 Poole, J.S., 4, 237 Poonam Rao, A., 3, 11 Poplata, S., 11, 10 Popod’ko, N.R., 10, 347 Popov, A.F., 3, 265 Popp, B.V., 10, 128 Porcs-Makkay, M., 12, 233 Porez, P.J., 4, 42 Posevins, D., 6, 60; 7, 79 Postils, V., 4, 42 Pöthig, A., 5, 328; 10, 78; 12, 215 Potter, T.J., 10, 639 Poudel, P.P., 3, 226 Pozharskii, A.F., 5, 45 Prabhu, K.R., 3, 239; 5, 365; 10, 134, 628 Prabhu, R., 5, 555 Prabhu, R.N., 5, 419 Prajapati, S., 4, 77; 5, 558 Prakash, G.K.S., 5, 167; 6, 61; 9, 39 Prakash, P., 10, 246 Pramanik, S., 10, 532 Pranckevicius, C., 4, 10

Prasad, P.K., 5, 166; 7, 164; 10, 56 Prasad, S.S., 10, 564 Prasadrao, P.T.S.R.K., 3, 4 Prashanth, M.K., 3, 165 Pratihar, S., 1, 377; 5, 193 Prause, F., 1, 204; 8, 30 Preethanuj, P., 10, 291 PreFontaine, N.M., 12, 114 Premkumar, J.R., 5, 381, 566; 9, 37; 10, 337 Prendergast, A.M., 3, 55 Preschel, H.D., 1, 302 Presset, M., 1, 238 Presti, L.L., 11, 25 Presto, C.A., 3, 288 Preston, F.J., 10, 324 Prieto, A., 1, 150, 163; 11, 9 Priyadarshani, G., 3, 252 Prlainovic, N., 2, 1 Probst, N., 6, 51 Probst, N.P., 8, 87 Prochnow, T., 5, 433; 10, 88 Procopiou, G., 1, 324; 7, 17 Procopiou, P.A., 5, 178 Procter, D.J., 1, 108; 5, 153; 10, 150 Prokopchuk, D.E., 1, 343; 3, 440 Properzi, R., 1, 217 Prywes, N., 2, 30 Pu, F., 5, 235 Pu, L., 1, 9; 8, 68; 10, 373 Pu, M., 1, 186 Puente, A., 6, 10; 7, 122 Puerta-Oteo, R., 10, 157 Pugh, T., 4, 150 Puglisi, A., 10, 537 Pulido, F.J., 6, 66 Pulis, A.P., 5, 153 Punji, B., 5, 576 Punniyamurthy, T., 3, 46; 5, 169; 10, 460 Puri, S., 12, 181 Purohit, V.B., 4, 191 Pushpalatha, L., 3, 175 Putau, A., 10, 616 Puttaswamy, 3, 166, 168–170 Puttreddy, R., 10, 588, 590 Pyne, S.G., 6, 83; 12, 93 Pyun, S.Y., 9, 3

Q Qarah, A., 5, 242; 6, 81 Qi, C., 1, 149; 5, 24; 9, 31; 10, 490 Qi, C.-Z., 10, 356 Qi, F.-L., 1, 161 Qi, J., 3, 56; 5, 403; 10, 319 Qi, L., 7, 7, 37 Qi, N., 5, 114

814 Qi, X., 3, 94; 5, 488, 502; 10, 169 Qi, Y., 3, 92 Qi, Z., 4, 67, 106; 5, 17, 363, 400, 543; 12, 135 Qi, Z.-H., 3, 300 Qian, C., 3, 309; 5, 55 Qian, J., 4, 76; 5, 92 Qian, P., 10, 1 Qian, P.-C., 5, 151; 10, 408 Qian, Q., 10, 469 Qian, S.Y., 12, 57 Qian, X.-Y., 3, 203 Qian, Y., 5, 470 Qiao, H., 5, 176 Qiao, Q., 3, 328 Qiao, S., 1, 269; 10, 607 Qiao, Y., 4, 165, 167; 5, 216; 10, 541, 599; 11, 136 Qin, G., 7, 134 Qin, G.M., 3, 136 Qin, H.-L., 5, 468 Qin, H.-M., 11, 40 Qin, J., 3, 45 Qin, L., 5, 404; 8, 71; 12, 98 Qin, P., 1, 177 Qin, Y., 10, 475 Qin, Z., 10, 559 Qing, X., 2, 19 Qiu, B., 3, 229 Qiu, C., 3, 481 Qiu, D., 5, 101, 102, 106; 12, 79 Qiu, G., 5, 152; 10, 413 Qiu, H., 1, 193; 5, 358; 12, 119 Qiu, J.-K., 12, 56 Qiu, L., 1, 228; 7, 30 Qiu, S., 10, 299; 11, 102 Qiu, X., 5, 587 Qiu, Y., 3, 82; 10, 148, 223 Qiu, Y.-F., 5, 223; 10, 302, 407; 11, 170 Qiu, Z., 3, 141; 4, 253; 10, 247 Qu, B., 5, 466; 10, 240 Qu, D., 4, 72 Qu, G.-R., 11, 32 Qu, J., 6, 34; 8, 122, 123; 10, 321 Qu, M., 3, 88 Qu, P., 4, 52 Qu, Z.-W., 1, 82; 3, 354, 410; 12, 53, 69 Quader, M.A., 2, 17; 7, 99 Quan, M., 5, 113 Quan, X., 3, 77 Quan, Z., 3, 31 Quan, Z.-J., 5, 56 Quesnel, J.S., 5, 499 Quiambao, L.G., 3, 435 Quijano, J., 1, 284; 4, 27; 9, 13, 14 Quinn, D.J., 1, 333

Author Index Quintavalla, A., 1, 189, 320; 8, 128 Quintero, L., 3, 156; 5, 249 Qurban, S., 1, 327 Qureshi, Z., 4, 112

R Raabe, G., 5, 89; 10, 589 Rabten, W., 3, 386 Race, N.J., 10, 173 Rachwalski, M., 1, 265; 8, 59 Racys, D.T., 5, 129 Radhakrishnamurti, P.S., 1, 334; 3, 164, 174 Radhakrishnan, K.V., 10, 246, 291; 12, 231 Radia, R., 3, 357; 10, 114 Radius, U., 5, 477 Radl, S., 5, 42 Radulov, P.S., 3, 182; 10, 58 Rae, J., 1, 108; 10, 150 Rafferty, S.M., 10, 609 Rafiquee, M.Z.A., 3, 306 Rafsanjani, A.T., 12, 197 Raghuvanshi, K., 3, 96 Ragno, D., 1, 230, 231 Rahem, N., 12, 100 Rahemtulla, B.F., 1, 325 Rahimi, S., 5, 522 Rahman, M., 2, 17; 7, 99 Rahman, M.A., 8, 105 Rahman, M.M., 3, 167 Rahmani, S., 3, 172, 211 Rahn, C., 11, 130 Rai, A., 6, 21 Rai, R.K., 5, 474, 490 Rai, V.K., 6, 21 Raines, R.T., 11, 66 Rainoldi, G., 1, 247; 11, 25 Raisanen, M., 3, 117 Raj, J.P., 11, 81 Raj, M., 2, 25 Raja, A., 8, 16; 10, 512 Raja, G.C.E., 5, 418 Rajagopal, B., 5, 234 Rajamalli, P., 5, 332; 10, 335 Rajanna, K.C., 5, 128 Rajaram, S., 2, 9 Rajasekaran, K., 3, 72 Rajasekaran, P., 1, 24; 6, 65; 12, 187 Rajasekaran, T., 1, 125; 4, 87 Rajendran, P., 3, 159 Rajkumar, V., 5, 144 Rama, G., 12, 14 Ramachary, D.B., 1, 180; 10, 583 Ramakrishna, I., 5, 171 Ramakrishna, K., 4, 59 Ramalakshmi, R., 10, 608 Ramalho, T.C., 7, 104

Ramana, C.V., 4, 103; 11, 151 Ramana, D.V., 5, 141 Ramasami, P., 7, 146 Ramasastry, S.S.V., 1, 200 Ramb, D.C., 10, 471 Ramdass, A., 3, 15 Ramella, V., 10, 195 Ramesh, E., 5, 367; 10, 230 Ramesh, P., 10, 578 Ramesh, R., 5, 419 Rami Reddy, Y.V., 6, 64, 106 Ramirez-Lopez, P., 5, 416 Ramkumar, B., 3, 160 Ramkumar, V., 5, 447 Ramos, G. d. S., 6, 17 Ramos, S.B., 5, 41 Ramsden, C.A., 4, 142 Ran, Y., 3, 154; 4, 166 Rana, A., 4, 21 Rana, J., 5, 426 Rana, V.A., 3, 252 Ranieri, B., 11, 14 Rao, B., 1, 369; 10, 427; 12, 213 Rao, C., 9, 27; 10, 622 Rao, D.N., 5, 62 Rao, K.S., 10, 578 Rao, K.V.R., 5, 267 Rao, V.V., 7, 152; 10, 64 Rao, W., 12, 108, 109 Rao, Y., 1, 254; 4, 230; 5, 142; 8, 72, 90, 91 Rao, Y.J., 11, 68 Rapi, Z., 10, 468 Rasheed, S., 3, 316 Rasik, C.M., 11, 21 Rasmussen, C.T., 3, 273 Rasparini, M., 10, 563 Rassadin, V.A., 12, 51 Rassu, G., 11, 112 Rast, S., 1, 344; 3, 451 Rathnakumari, R.J.E., 3, 233 Rathore, K.S., 4, 78; 12, 141 Ratsch, F., 5, 220; 10, 326 Rauf, W., 5, 295 Raut, D.S., 10, 209 Raval, D.K., 4, 191; 10, 453 Ravasco, J.M.J.M., 1, 232; 10, 499 Ravi, M., 4, 81 Ravi, R., 7, 129 Ravichandran, C., 3, 162 Ravikumar, G., 12, 107 Ray, J.K., 1, 332 Ray, R., 3, 325 Read de Alaniz, J., 3, 197 Ready, J.M., 11, 52 Reamer, R.A., 1, 55 Reardon, M.B., 7, 125 Reay, A.J., 5, 572 Recio, R., 1, 85; 3, 458

815

Author Index Reddi, R.N., 5, 166; 7, 164; 10, 56 Reddy, A.C.S., 3, 29 Reddy, B.P., 5, 255 Reddy, B.V.S., 1, 125; 4, 87; 5, 255; 11, 68 Reddy, C.S., 10, 564 Reddy, E.P., 11, 68 Reddy, G.M., 10, 501, 585 Reddy, G.R., 2, 9 Reddy, K.R., 3, 240 Reddy, M.D., 5, 548 Reddy, M.K., 5, 171 Reddy, M.R., 5, 154 Reddy, M.S., 12, 103, 181 Reddy, P.V.G., 5, 255 Reddy, R.S., 11, 123 Reddy, S., 1, 244 Reddy, T.P., 10, 583 Reddy, U.V.S., 1, 184; 11, 101 Reed, P., 11, 130 Reed, R.I., 10, 324 Reed-Berendt, B.G., 1, 347 Reeder, A.T., 3, 472 Reekie, T.A., 12, 27, 94 Reeves, J.T., 5, 534 Regentová, D., 12, 2 Rehbein, J., 3, 204; 12, 62 Reibarkh, M., 1, 55 Reich, R.M., 3, 108 Reid, J.P., 1, 116 Reid, M., 5, 282 Reider, P.J., 10, 473 Reidy, C.P., 12, 114 Reinhard, F.G.C., 3, 114 Reinhardt, C.R., 3, 486 Remete, A.M., 7, 153 Ren, C., 1, 348; 3, 409 Ren, H., 3, 189; 10, 106 Ren, J., 3, 358; 10, 606; 11, 31 Ren, J.-W., 11, 114 Ren, L.-K., 3, 311 Ren, N., 1, 192 Ren, Q., 3, 243, 482; 5, 396 Ren, R., 10, 112; 12, 212 Ren, S., 10, 613 Ren, S.-J., 7, 112 Ren, W., 10, 175, 176 Ren, X., 1, 54, 290; 8, 9 Ren, X.-R., 10, 356 Ren, X.-T., 11, 115 Ren, Y., 1, 149; 5, 24, 483, 521; 7, 112; 9, 31; 10, 490 Renaud, P., 1, 317; 10, 124 Renga, J.M., 5, 84 Renom-Carrasco, M., 3, 393, 422 Repe´c, B., 7, 108; 8, 6 Repo, T., 3, 117 Rerat, A., 5, 336 Resende, J.A.L.C., 1, 242

Restrepo, A., 10, 456 Retailleau, P., 4, 254; 12, 122 Reutskaya, E., 5, 39 Reva, I., 4, 239 Rexit, A.A., 1, 92; 3, 456 Rexiti, R., 8, 31 Rey, N.A., 2, 28; 7, 98 Reyes, A., 7, 118 Reyes, M.L., 4, 260 Reyes-Lezama, M., 12, 202 Reyniers, M.-F., 10, 432 Rezaee, N., 4, 143 Rezaeian, M., 7, 115 Rhee, Y.-H., 4, 247; 10, 221 Rhyman, L., 7, 146 Ribagorda, M., 5, 257 Ribas, K., 5, 140 Ribas, X., 3, 222; 5, 53, 442; 8, 104; 10, 336 Ribblett, A.Q., 4, 237 Ricard, S., 12, 100 Richard, J.P., 6, 1 Richter, S.C., 5, 382 Rideau, E., 7, 34 Rieger, B., 10, 159 Rieger, E., 4, 157 Riera, A., 3, 388 Ries, U.J., 5, 466 Rigsbee, E.M., 11, 21 Rihak, K.J., 3, 330 Rintjema, J., 7, 65 Rios, R., 7, 94; 10, 508 Rios-Gutierrez, M., 1, 129; 4, 29 Ripsman, D., 6, 31; 10, 108 Rissanen, K., 5, 89; 10, 588, 590; 12, 199 Ristanovic, Z., 6, 30 Rit, R.K., 5, 366, 367; 10, 230, 231 Ritleng, V., 3, 329; 4, 198 Ritter, T., 5, 18 Rivard, E., 3, 350 Rivela, C., 3, 349 Rivero, A.R., 5, 338 Roberts, J., 3, 357; 10, 114 Roberts, P.M., 10, 435 Robertson, K.N., 1, 201 Robertson, N., 7, 80 Robiette, R., 7, 126 Roca-Lopez, D., 1, 145 Rocco, C., 3, 342 Rocha, M.V.J., 7, 104 Rocha-Rinza, T., 10, 568 Rodionov, A.N., 12, 219 Rodionov, V.O., 1, 197 Rodionova, A.S., 10, 168 Rodrigues, L.V., 11, 86 Rodr´ıguez, M., 4, 42 Rodriguez, F., 1, 251; 5, 327 Rodriguez, M.A., 4, 47

Rodriguez, R., 4, 260; 5, 549 Rodriguez, S., 5, 375, 466 Rodriguez-Castellon, E., 5, 91 Rodriguez-Escrich, C., 11, 132 Roeffaers, M.B.J., 6, 30 Roesky, H.W., 1, 304 Rogachev, A.Y., 6, 17 Roger, J., 5, 133 Roisnel, T., 1, 196; 5, 275; 11, 70; 12, 17 Roithová, J., 4, 124 Rojahn, P., 5, 282 Rojas, M., 2, 5 Romain, E., 10, 315 Román-Chavarr´ıa, C.A., 10, 568 Romero, E.O., 12, 114 Romero, R.M., 3, 206; 7, 145; 10, 54, 62 Romero-Ortega, M., 12, 202 Rominger, F., 4, 128; 10, 381; 12, 71 Rong, C., 1, 240; 10, 524 Rong, J., 1, 270; 8, 47 Rong, Z.-Q., 4, 214 Roozbin, F., 5, 522 Ros, A., 5, 416, 465 Rosales, M., 3, 420 Roscales, S., 6, 89 Roschenthaler, G.-V., 5, 261 Rose, J.J.S.J., 3, 233 Rosenberg, M.G., 4, 9 Rossi, E., 4, 131; 5, 564; 7, 76; 10, 364 Rossi, R., 5, 571 Roswell, C.A., 6, 93 Roszkowski, P., 5, 582 Roulland, E., 7, 29 Rout, L., 8, 118 Rout, S., 1, 53 Routaboul, L., 3, 391 Routier, S., 12, 195 Rovira, M., 5, 53 Rovis, T., 10, 248 Rowicki, T., 12, 5 Roy, A., 1, 312 Roy, A.K., 1, 244 Roy, B.N., 3, 163 Roy, M., 3, 487 Roy, R., 1, 24 Roy, T., 5, 109, 110, 204; 12, 47, 193, 214 Roy, T.K., 5, 160 Royappa, A.D., 10, 63 Royo, S., 10, 448 Rozen, S., 10, 73 Ruan, G.-Y., 3, 300 Ruan, P.-P., 10, 375, 389 Ruan, Z., 5, 326 Rub, M.A., 3, 167 Rübenach, L., 10, 589

816 Rubin, M., 10, 656 Rubina, M., 10, 656 Rubina, M.S., 4, 190; 5, 64 Rubio, E., 11, 143 Ruch, A.A., 5, 68; 10, 387 Ruchti, J., 5, 431; 9, 24 Ruck, R.T., 12, 75 Rucker, R., 10, 295 Rudolph, M., 4, 128; 10, 381 Rueda-Espinosa, J., 7, 156 Rueping, M., 5, 317, 318; 12, 186 Ruider, S.A., 12, 19 Ruijter, E., 1, 302 Ruiz, D.A., 4, 163; 12, 83 Ruiz, J., 1, 196 Ruiz, P., 1, 284; 4, 27; 9, 13, 14 Rukmangathan, M., 3, 160 Rullière, P., 11, 20 Runburg, R., 10, 172 Russell, C.A., 10, 140 Ryabchuk, P., 10, 50 Ryabukhin, D.S., 5, 244, 428; 6, 32, 33; 9, 4; 10, 14 Ryazantsev, M.N., 5, 218 Rybackova, M., 4, 110 Rybakov, V.B., 7, 90 Ryu, D.H., 10, 570 Ryu, I., 11, 18 Ryu, J.Y., 8, 27; 9, 34 Ryu, Z.-H., 2, 15; 7, 113 Rzewnicka, A., 12, 72

S Saá, C., 12, 144 Saa, J.M., 1, 60 Saad, S.M., 1, 148 Sabbasani, V.R., 3, 337 Sabbatani, J., 6, 67 Sabenya, G., 4, 42 Sacchetti, A., 1, 247 Sachan, R., 5, 188 Sader, C.A., 10, 240 Sadhu, P., 3, 46; 5, 169 Sadovaya, I.V., 7, 121 Saeednia, B., 5, 132 Saeki, R., 7, 41; 8, 41 Saffon-Merceron, N., 4, 260, 261 Safiullin, R.L., 3, 281 Saga, Y., 10, 659 Saget, T., 1, 56, 61 Saha, A., 5, 203 Saha, K., 10, 608 Sahin, ¸ E., 10, 390; 11, 58; 12, 26 Sahoo, A.K., 5, 366, 367; 10, 230, 231 Sahoo, H., 5, 156, 171 Sahoo, S.K., 5, 590 Saicic, R.N., 10, 382 Said, M.S., 6, 117 Saidulu, G., 3, 240

Author Index Saikia, A.K., 10, 42 Sailani, R., 3, 18 Sainna, M.A., 3, 114 Saisaha, P., 3, 231 Saito, A., 10, 210 Saito, K., 1, 49, 121; 3, 498 Saito, R., 7, 157 Saito, S., 9, 23; 10, 41 Sajjad, S., 3, 478 Sajo, I.E., 3, 11 Sakae, R., 10, 294 Sakagami, H., 3, 106 Sakaguchi, T., 11, 18 Sakai, M., 5, 446; 10, 217 Sakai, N., 3, 247; 10, 411; 12, 28 Sakai, S., 1, 19 Sakai, Y., 4, 32 Sakaino, H., 12, 77 Sakaki, S., 3, 459 Sakakura, A., 10, 43 Sakamoto, D., 10, 498 Sakamoto, R., 11, 24 Sakata, K., 1, 209; 10, 465 Sakhuja, R., 5, 530 Sakthivel, S., 8, 46 Sakurai, S., 11, 24 Salamone, M., 3, 115, 245 Sale, D., 5, 54 Saleh, A.I., 3, 24 Saleh, N., 3, 429 Salehan, F., 10, 493 Salin, A.V., 10, 24, 461 Salman, M., 3, 254; 5, 212 Salomé, K.S., 1, 262; 8, 58 Salomo, E., 3, 388 Salvio, R., 10, 537 Salyi, G., 5, 313 Salzman, R.M., 12, 161 Samanta, D., 4, 21 Samanta, R., 4, 69; 5, 544 Samanta, S., 3, 310; 5, 271, 582; 10, 51 Sambasivarao, K., 12, 14 Samec, J.S.M., 7, 130 Sameera, W.M.C., 3, 206; 7, 145; 10, 62 Sami, P., 3, 72 Samigullin, K., 10, 129 Samimi, H.A., 12, 222 Samineni, R., 5, 107 Sampedro, D., 3, 206; 4, 46; 7, 145; 10, 62 Samsonenko, D.G., 3, 25 Samzadeh-Kermani, A., 10, 404 Sanapo, G.F., 12, 100 Sanchez, D., 1, 8 Sandbeck, D.J.S., 6, 16; 12, 203 Sandoval-Ramirez, J., 6, 95 Sandridge, M.J., 6, 85 Sandtorv, A.H., 5, 47, 460

Sandzhieva, M., 6, 32, 33; 9, 4 Sandzhieva, M.A., 5, 243–245; 6, 28 Sang, X., 11, 80 Sanhueza, I.A., 5, 296 Sanjeev, R., 7, 129 Sankar, M.G., 10, 544 Sankararaman, S., 5, 447 Sansano, J.M., 1, 232; 10, 499; 11, 38, 44 Santamar´ıa, J., 4, 46, 47 Santas, J.G., 5, 37 Santelli, M., 6, 15 Santhini, P.V., 10, 291 Santhoshkumar, V., 3, 160 Santiago, C.B., 9, 46 Santilli, C., 3, 348 Santoro, O., 4, 181 Santos, A.G., 1, 357; 10, 506 Santos, J.G., 2, 5 Santos, W.L., 10, 609, 621 Santos Comprido dos, L.N., 8, 79 Santos Munaretto dos, L., 8, 58 Santra, S., 3, 310; 5, 271 Santra, S.K., 3, 35; 5, 134 Santrac, D., 5, 481 Santschi, N., 10, 442 Sanz, R., 7, 149; 12, 198 Sanz-Marco, A., 8, 63; 10, 615, 650 Sanzone, J.R., 11, 104 Sapegin, A., 5, 39 Sapre, J.V., 11, 96 Sapsford, J.S., 3, 379 Sarais, G., 10, 575 Sarandeses, L.A., 6, 56 Sarkar, B., 4, 147 Sarkar, D., 5, 329 Sarkar, P., 3, 144 Sarlah, D., 10, 5 Sarma, M., 5, 414 Sarotti, A.M., 5, 265; 11, 97 Sarpong, R., 11, 93 Sartillo-Piscil, F., 3, 156 Sas, W., 12, 5 Sasai, H., 3, 260 Sasaki, H., 3, 106 Sasaki, I., 5, 229 Sasaki, K., 7, 157 Sasaki, M., 1, 38; 3, 271 Sasaki, T., 5, 28; 10, 52 Sasaki, Y., 5, 272 Sasano, Y., 3, 135; 9, 22 Sasou, H., 5, 444 Satam, N., 12, 173 Satheeshkumar, R., 1, 256 Sathishkannan, G., 10, 460 Sato, H., 3, 442 Sato, J., 4, 162; 10, 376 Sato, K., 10, 154

817

Author Index Sato, M., 2, 7 Sato, T., 3, 461; 11, 152 Sato, Y., 1, 121; 10, 196, 659 Satoh, T., 5, 146, 449; 10, 477 Satoh, Y., 10, 328 Satpathi, B., 1, 200 Satsumov, E.T., 5, 243 Satumov, E.T., 6, 45 Sauer, C.S., 12, 34 Sauer, S.J., 1, 62 Saulnier, S., 6, 46; 10, 481, 482 Saunthwal, R.K., 5, 437; 10, 66, 216; 11, 117, 118 Sauter, B., 7, 169 Savanur, A., 3, 17 Savic, V., 10, 550 Savitha, G., 5, 238 Sawamura, M., 4, 217; 5, 550; 7, 13, 28; 8, 84; 10, 290, 546 Sawamura, Y., 10, 43 Sawant, D.M., 5, 160 Sawatlon, B., 3, 113 Sayaka, W., 12, 92 Sayyad, M., 5, 60; 7, 77 Sazonov, P.K., 5, 87 Scamp, R.J., 4, 249, 250 Scanlon, J., 8, 118 Scanlon, J.D., 10, 243 Scettri, A., 1, 179 Schaefer, H.F., 5, 11, 175; 8, 2 Schafer, L.L., 10, 280 Scharnagel, D., 1, 204; 8, 30 Schatte, G., 12, 177 Scheidt, K.A., 4, 180 Scheiner, S., 7, 143 Schiemann, O., 12, 69 Schirmer, M.-L., 1, 280; 9, 18 Schlangen, M., 4, 120 Schlepphorst, C., 3, 404; 4, 229 Schleyer, P. v. R., 5, 11; 8, 2 Schmid, M., 7, 70 Schmidt, A., 10, 452 Schmidt, A.F., 5, 456 Schmidt, B., 5, 356; 10, 623 Schmidt, M.A., 3, 76 Schmidt, R.K., 6, 25 Schmitt, W.W., 10, 357 Schmittel, M., 4, 21 Schmitz, P., 5, 467 Schnakenburg, G., 11, 172; 12, 69 Schneider, C., 10, 642; 12, 7 Schneider, E.A., 10, 243 Schneider, T., 3, 354 Schneider, U., 1, 79 Schobert, R., 12, 65 Schoenebeck, F., 1, 336; 3, 287; 5, 32, 296, 297, 317; 7, 42; 8, 77; 10, 589

Schomaker, J.M., 4, 104, 249, 250 Schoneich, C., 3, 112 Schörgenhumer, J., 3, 205 Schou, M., 7, 101 Schramm, M.P., 10, 365, 366 Schreihans, R.S., 2, 26 Schreiner, C., 5, 467 Schreyer, L., 1, 217 Schrievers, T., 4, 9 Schroeder, C.E., 12, 217 Schubert, M., 3, 64, 70 Schuckman, P., 1, 302 Schulte, A., 10, 41 Schulz, J., 4, 124 Schumacher, B.P., 10, 243 Schumann, B., 1, 23 Schuutznerova, E., 3, 351 Schwalm, C.S., 10, 173 Schwarz, H., 4, 120 Schweitzer-Chaput, B., 3, 269 Schwertz, G., 5, 411 Sciubba, F., 1, 76 Scotson, J.L., 7, 110 Scott, D.J., 3, 379 Sears, J.D., 10, 74 Sebesta, R., 1, 171 Secci, F., 10, 575; 12, 192 Seeberger, P.H., 1, 23 Seidel, D., 1, 72, 340; 6, 111 Seidl, T.L., 5, 97; 9, 28 Seidl, T.M., 11, 3 Seitz, C.G., 1, 313; 7, 141; 8, 5 Seiya, O., 6, 29 Sejbal, J., 10, 274 Sekar, K.G., 3, 5 Seki, C., 1, 184; 11, 101 Seki, T., 5, 286 Sekikawa, T., 8, 13; 10, 558, 592 Seling, N., 10, 589 Selkti, M., 10, 406; 12, 54 Sells, D., 3, 296 Selvakumar, K., 3, 72 Selvaraj, K., 12, 96, 180 Selvaraju, M., 10, 305 Selvi, N.T., 3, 12 Semba, K., 3, 459; 10, 127 Semenyuk, Y.P., 5, 78 Semeril, D., 5, 458 Sen, M., 5, 566; 8, 105; 10, 337 Senadi, G.C., 5, 5; 10, 111 Senanayake, C.H., 5, 375, 466, 534; 7, 91; 10, 240 Senol, H., 12, 26 Senoo, M., 4, 93 Sepahvand, H., 10, 494 Serafim, R.A.M., 5, 344 Seraphin-Hatcher, C., 1, 62 Sergeeva, E.V., 3, 47 Serguchev, Y.A., 10, 2

Serizawa, H., 5, 308, 309 Serkova, O.S., 12, 183 Servilha, B.M., 5, 354 Sestelo, J.P., 6, 56 Settle, C.A., 12, 204 Sevostyanova, N.T., 10, 168 Seyfried, M.S., 4, 18 Sha, F., 8, 31; 10, 577; 11, 105 Sha, Q., 12, 210 Sha, S.-C., 7, 39 Sha, W., 1, 52; 8, 18; 12, 227 Shaaban, S., 11, 153 Shaabani, A., 10, 494 Shafi, S.S., 3, 3 Shafran, Y.M., 11, 77 Shah, H.P., 5, 472 Shahraki, M., 1, 42, 364 Shaibakova, M.G., 10, 347 Shaikh, A.C., 5, 562; 10, 384 Shaikh, S.R., 6, 75; 10, 400 Shainyan, B.A., 1, 237; 11, 23 Shakoor, S.M.A., 5, 530 Shamsul, O.M., 3, 306 Shamsutdinova, F.G., 10, 461 Shan, C., 1, 384; 3, 94; 5, 488; 12, 117 Shan, G., 8, 72 Shan, J., 3, 53, 224 Shan, Y.-F., 11, 98 Shang, H., 1, 54; 8, 9 Shang, R., 5, 324 Shang, Y., 10, 538 Shang, Y.-J., 11, 43 Shang, Z., 5, 451 Shankar, R., 1, 256 Shanmugaprabha, T., 3, 72 Shao, M., 10, 620 Shao, P., 10, 343 Shao, X., 1, 63 Shao, Y., 12, 101 Shao, Z., 1, 106; 3, 430, 431; 5, 247; 10, 579 Sharif, M., 3, 250; 5, 581 Sharif, S.A.I., 5, 129 Sharifi, N., 1, 322 Sharma, A., 11, 76 Sharma, E., 5, 117 Sharma, G., 3, 11 Sharma, I., 4, 74 Sharma, K., 1, 335; 3, 176 Sharma, L.K., 5, 219 Sharma, N., 10, 625 Sharma, P., 3, 18; 11, 154; 12, 29, 218 Sharma, P.D., 3, 18 Sharma, P.K., 3, 11 Sharma, S., 5, 160, 187, 188, 361, 553; 10, 245, 637, 638 Sharma, U., 1, 353; 6, 57 Sharma, U.K., 10, 625

818 Sharma, V., 3, 4 Sharma, V.K., 1, 335; 3, 176 Sharplers, K.B., 5, 583 Shaver, M.P., 3, 466 Shaw, L., 1, 273; 8, 42 Shaw, M., 3, 286 Shcherbinin, V.A., 12, 237 She, X., 4, 236; 11, 57 Shearer, J.W., 5, 84 Sheikhi, E., 1, 71 Shekhar, S., 3, 288; 4, 104; 5, 36 Shen, A., 4, 193; 5, 463 Shen, B., 3, 37; 10, 540 Shen, C., 1, 234; 3, 318; 5, 113, 159, 163, 506; 10, 438 Shen, C.-H., 4, 130; 10, 375, 389 Shen, D., 1, 234, 235; 3, 229 Shen, G., 1, 249 Shen, H.-C., 1, 212, 321; 10, 184 Shen, J., 5, 546; 9, 40; 10, 446 Shen, J.-S., 4, 195; 5, 393 Shen, K., 10, 287 Shen, M.-H., 10, 137; 11, 115; 12, 13 Shen, M.-Z., 7, 32 Shen, P.-X., 5, 174 Shen, Q., 1, 134; 5, 148; 8, 132 Shen, R., 4, 55 Shen, X., 10, 487, 617 Shen, X.-J., 7, 32 Shen, Y., 5, 79, 177; 6, 37; 10, 582; 12, 95, 179 Shen, Z., 10, 39, 459 Sheng, C., 10, 504 Sheng, G., 4, 76 Sheng, W., 11, 130 Sheng, X.-H., 5, 179 Shepakov, A.V., 5, 218 Shevick, S.L., 4, 234; 10, 396 Shevlin, M., 3, 378; 12, 75 Shi, B.-F., 3, 30; 5, 305, 485 Shi, C., 11, 49 Shi, D.-H., 5, 21 Shi, F., 5, 79; 6, 37; 11, 137 Shi, F.-C., 1, 80; 10, 391 Shi, G., 5, 330, 331 Shi, H., 7, 46; 10, 478 Shi, J., 4, 12, 102; 5, 101, 102, 106, 208; 8, 92; 12, 79 Shi, J.-L., 6, 42; 10, 325; 11, 40 Shi, L., 5, 186; 10, 12; 12, 188 Shi, M., 1, 80; 3, 100; 4, 125, 126; 5, 164; 10, 122, 212, 391; 11, 16, 56; 12, 88, 123, 132 Shi, M.-L., 11, 129 Shi, S., 5, 475, 515 Shi, W.-M., 12, 220

Author Index Shi, X., 3, 297; 5, 34, 427; 10, 145, 355, 367; 12, 125, 179 Shi, X.-Q., 5, 258 Shi, X.-Y., 5, 235 Shi, Y., 1, 240; 4, 92; 7, 14; 10, 40, 175, 176, 524, 617; 12, 131 Shi, Z., 4, 199, 246; 5, 496, 587; 10, 100, 467, 514 Shi, Z.-J., 1, 381; 3, 139; 6, 42; 7, 52; 10, 325 Shi, Z.G., 10, 600 Shia, K.-S., 3, 241, 302 Shiaji, K., 5, 118 Shibasaki, M., 1, 65, 67, 111; 4, 232; 10, 486 Shibata, E., 1, 282 Shibata, N., 5, 149; 7, 26; 8, 37 Shibata, S., 4, 217; 5, 550; 7, 28 Shibata, T., 8, 39; 10, 649; 11, 150, 152, 166 Shibata, Y., 5, 383; 10, 644; 11, 144–147, 158; 12, 139 Shibatomi, K., 7, 95 Shibuya, M., 11, 141 Shidmoossavee, F.S., 7, 97 Shigehisa, H., 5, 368; 10, 328, 329 Shigeta, T., 5, 389 Shigitani, R., 5, 35 Shima, Y., 11, 127 Shimada, S., 10, 154; 12, 143 Shimamato, M., 1, 282 Shimbayashi, T., 9, 32 Shimi, M., 10, 246 Shimizu, M., 1, 29, 209; 5, 35; 10, 465 Shimizu, S., 10, 210 Shimizu, Y., 1, 191 Shimkin, K.W., 7, 165 Shimogaki, M., 5, 254; 10, 60 Shimojima, A., 7, 103 Shimonishi, J., 7, 63 Shimpi, R., 3, 21 Shin, H.Y., 7, 94; 10, 508 Shinde, D.R., 5, 426, 562; 6, 75; 10, 400 Shinde, P.S., 10, 384 Shinde, S.S., 6, 117; 7, 152; 10, 64 Shinohara, K., 5, 435 Shintani, R., 5, 432; 10, 164 Shioji, K., 1, 368 Shiota, Y., 3, 381 Shirai, T., 1, 101; 5, 372 Shirakawa, E., 5, 8, 9; 8, 53, 55 Shirakawa, S., 11, 116 Shirase, S., 3, 313, 473 Shiri, A., 5, 38

Shiria, A., 12, 196 Shirinian, V.Z., 5, 232 Shiro, M., 8, 37 Shiroudi, A., 9, 16 Shiryaev, V.A., 12, 207 Shishido, R., 5, 286 Shitaoka, T., 10, 602 Shoaib, K., 5, 581 Shoba, V.M., 10, 120 Shool, M., 10, 491, 492 Shpan’ko, I.V., 7, 121 Shpuntov, P.M., 12, 237 Shrestha, B., 3, 48 Shrinidhi, A., 3, 364 Shruthi, K.S., 1, 180 Shterenberg, A., 1, 199 Shu, C., 4, 130; 10, 375, 389 Shu, T., 10, 590 Shuai, L., 3, 98 Shukla, P., 6, 21 Shuler, S.A., 10, 189 Shuler, W.G., 11, 35 Shul’pin, G.B., 3, 327 Shurrush, K.A., 12, 167 Shutale, A.D., 12, 234 Shuto, S., 8, 88 Shved, E.N., 7, 69 Siaka, A., 1, 164 Siauciulis, M., 8, 51 Sibley, C.D., 10, 621 Siciliano, C., 11, 95 Sicker, D., 1, 156 Siddaraju, Y., 3, 239 Siddiqui, M.R., 3, 306 Sieber, J.D., 5, 466 Sieburth, S.M.N., 1, 379 Siegler, M.A., 5, 137 Sieler, J., 1, 156 Siero´n, L., 12, 72 Sierra, M.A., 4, 136; 12, 118 Sigman, M.S., 5, 389; 9, 46; 10, 173, 180 Sillanpää, R., 7, 153 Silva, L.C., 12, 198 Silva, L.F., 10, 53 Silva, P.J., 1, 360 Silva, V.H.M., 5, 354 Silva Lopez, C., 1, 146; 4, 248 Silvani, A., 1, 247; 11, 25 Silverio, D.L., 1, 213 Silvi, B., 5, 123, 124 Silvi, M., 10, 401 Sim, A.M., 10, 448 Sim, J.-T., 11, 124 Sima, J., 3, 141 Simal, C., 12, 184 Simanis, J.A., 3, 288 Simig, G., 12, 233 Simon, A., 1, 170, 183; 7, 120 Simon, L., 1, 4, 116

819

Author Index Simonetti, M., 5, 478 Simonetti, S.O., 5, 265 Simoyi, R.H., 3, 179 Simunek, O., 4, 110 Sinay, P., 6, 51 Sindhu, K.S., 3, 219; 5, 420 Sindu, K.S., 7, 59 Singal, P., 5, 137 Singarapu, K.K., 12, 107 Singer, R.D., 1, 201 Singh, A., 3, 163; 5, 117 Singh, A.K., 3, 172, 211 Singh, B., 1, 353; 3, 126, 173; 5, 93; 6, 57 Singh, B.B., 3, 52 Singh, B.K., 5, 170; 10, 625 Singh, G.P., 6, 65; 12, 187 Singh, H., 10, 543; 11, 85 Singh, J., 3, 209 Singh, K.N., 5, 480 Singh, K.W., 5, 117 Singh, M.S., 11, 27 Singh, P., 1, 335; 3, 176, 211; 5, 117; 10, 543 Singh, P.K., 6, 21 Singh, P.P., 5, 49 Singh, R.K., 3, 172 Singh, R.K.P., 5, 219 Singh, R.K.R., 1, 73 Singh, R.P., 3, 65; 10, 46 Singh, S.K., 5, 474, 490 Singh, V., 12, 31 Singh, V.K., 5, 219; 10, 405 Singha, R., 1, 332 Singha, S., 1, 366; 4, 153; 5, 143 Singhal, A., 11, 76 Sinha, A., 7, 161 Sinha, N., 9, 8 Sinotova, E.N., 6, 3 Sinyashin, O.G., 5, 192 Sipos, G., 4, 231; 10, 273 Siri, D., 6, 15 Sirick, A., 3, 274 Sirik, A.V., 9, 2 Sirit, A., 10, 571 Siriwardena, A., 5, 255 Sit, M.K., 1, 351 Sitte, N.A., 12, 53 Siva, A., 1, 181, 206; 8, 34 Sivasankar, C., 4, 59 Six, Y., 12, 51 Skelton, B.W., 3, 264; 4, 231; 10, 273 Sklute, G., 10, 21 Skoulika, S., 10, 447 Slagbrand, T., 3, 474 Slattery, C.N., 3, 403 Slavova-Kazakova, A., 3, 342 Slawin, A.M.Z., 4, 181; 8, 10; 10, 479, 480, 522; 12, 236

Slepukhin, P.A., 11, 77 Smeyanov, A., 10, 452 Smirnov, A., 5, 39 ˇ Smit, B.M., 10, 85 Smith, A.B., 12, 170 Smith, A.D., 1, 241; 8, 10; 10, 479, 480, 522 Smith, C.A., 10, 355 Smith, D., 1, 157 Smith, J.A., 3, 330 Smith, J.J., 1, 100; 12, 130 Smith, M.D., 1, 325 Smits, N.W.G., 7, 104 Smol’yakov, A.F., 12, 219 Smrˇcina, M., 10, 274 Smyth, L.A., 5, 36 Snadzhieva, M.A., 6, 45 Snyder, K.M., 1, 236; 10, 517 So, C.M., 5, 473 Soai, K., 1, 259 Soares, K., 10, 125 Sodeoka, M., 5, 435 Soeta, T., 1, 260; 8, 66 Sohail, M., 10, 30 Sohel, S.M.A., 10, 425 Sola, R., 1, 273; 8, 42 Soldi, R.A., 4, 4 Solé, D., 4, 115 Soler, M., 5, 53 Sollert, C., 5, 538 Soloshonok, V.A., 1, 52; 5, 261; 7, 26; 8, 18 Sombut, P., 4, 161 Son, K.I., 12, 80 Son, Y., 5, 418 Song, E.H., 3, 486 Song, H., 7, 136; 10, 475 Song, J., 3, 203; 4, 40; 5, 470, 471 Song, L., 1, 160, 272; 3, 147, 184, 192; 8, 43; 10, 149, 286 Song, L.-J., 10, 160 Song, M.-P., 3, 28, 305; 5, 173, 486; 7, 32 Song, Q., 1, 155, 359; 3, 360, 433; 5, 357, 404; 8, 82; 9, 27; 10, 126, 183, 622; 12, 226 Song, S., 3, 149; 7, 19; 8, 93; 10, 613 Song, T., 6, 55; 12, 127 Song, W., 11, 177 Song, X., 10, 590 Song, X.-Q., 11, 54 Song, X.-R., 10, 407; 11, 170 Song, Y., 8, 123 Song, Y.-C., 10, 464 Song, Y.-K., 5, 151; 10, 408 Song, Z., 4, 83, 122, 252; 7, 163; 11, 111; 12, 142

Soos, T., 10, 93 Sorensen, E.J., 1, 385; 10, 473 Soroka, L.S., 5, 51 Sorribes, I., 3, 405 Sot, P., 1, 90 Soto, C.F., 3, 125 Soudani, M., 4, 176 Soule, J.-F., 5, 578, 588 Sousa, S.C.A., 3, 469 Southgate, E.H., 10, 5 Souto, J.A., 3, 206; 7, 145; 10, 54, 62; 12, 2 Sowa, C., 10, 282 Spaniol, T.P., 1, 294; 3, 361 Spanka, M., 10, 642 Spannenberg, A., 1, 280; 3, 382; 5, 581; 9, 18; 10, 167 Sparr, C., 1, 188 Spears, J.A., 10, 46 Speciale, G., 7, 97 Speicher, A., 5, 467 Spencer, T.A., 6, 49 Sperandio, C., 10, 537 Sperger, T., 5, 296, 297; 8, 77 Spigener, P.T., 1, 269 Spinelli, S., 5, 88 Spino, C., 4, 140 Spitz, A.Z., 11, 21 Spoerlein-Guettler, C., 12, 65 Spreider, P.A., 10, 262 Spyropoulos, C., 1, 316; 3, 158 Spyroudis, S., 11, 139 Sridhar, B., 1, 125; 4, 87; 6, 64; 11, 68; 12, 106 Sridharan, V., 3, 251; 4, 159; 10, 207; 11, 121 Srifa, P., 7, 130 Srihari, P., 5, 107 Srinivas, P., 5, 128 Srinivasan, B.R., 1, 279 Srinivasan, K., 5, 221; 12, 172 Srivastava, A., 5, 570; 10, 300 Srivastava, A.K., 6, 105 Srivastava, J., 3, 172, 211 Srivastava, R., 3, 122, 211 Srivastava, S., 3, 211 Srivastava, V.P., 3, 183 Stack, T.D.P., 3, 261 Stahl, S.S., 3, 278 St Amant, A.H., 3, 197 ˇ Stambask´ y, J., 10, 222 Stamos, D., 5, 342; 8, 89 Standaert, R.F., 3, 365 Stanek, F., 1, 323 Stankeviˇc, M., 5, 231; 6, 38; 10, 597 Stanley, L.M., 10, 243, 605 Stappen, J.V., 8, 83 Starikova, Z.A., 3, 47 Stark, D.G., 1, 241; 10, 479, 480

820 Starova, G.L., 6, 86; 12, 35 Stawowska, K., 3, 155 Stecko, S., 12, 174 Stefano, S.D., 3, 115, 116 ˇ Stefko, M., 10, 222 Stei, M., 7, 135 Steib, A.K., 5, 195 Stenerson, Z.S., 3, 486 Stepakov, A.V., 6, 86; 12, 35 Stepakova, A.V., 12, 211 Stephan, D.W., 4, 10; 5, 198, 199; 6, 31; 7, 150; 10, 108, 133, 140 Stephan, M., 1, 344; 3, 451 Stephen, S.C., 10, 274, 275 Stepherson, J.R., 6, 39, 40, 82 Sterckx, H., 3, 289 Sterkhova, I.V., 11, 23 Stern, C., 10, 110 Stevens, C.V., 3, 153; 10, 660 St Germain, E., 10, 107 Stiebing, S., 5, 277 Stirling, A., 5, 48 Stirling, M.J., 1, 87; 3, 450 Stockman, R.A., 1, 324; 7, 17; 8, 51; 12, 2 Stodulski, M., 1, 323 Stohmann, C., 11, 42 Stok, J.E., 3, 125 Stokes, B.J., 3, 435 Stoltz, B.M., 3, 317; 5, 111; 7, 43; 10, 191; 12, 8 Stolz, B.M., 7, 20 Stopka, T., 6, 102; 12, 87 Storr, T.E., 8, 51 Straub, S.-D., 1, 93; 3, 437 Strelkova, T.V., 12, 219, 232 Streubel, R., 11, 172; 12, 69 Streuff, J., 3, 493; 10, 648 Strohmann, C., 1, 123; 10, 544 Struble, M.D., 5, 137 Struchkova, M.I., 4, 38; 8, 26 Strzelecka, D., 5, 461 Stuart, D.R., 5, 47, 97; 9, 28; 11, 3 Stucchi, M., 1, 247 Studer, A., 1, 30; 4, 15, 225; 5, 115; 10, 195, 322 Styduhar, E.D., 11, 67 Su, C.-Y., 4, 163; 12, 83 Su, F., 3, 102; 5, 404, 406 Su, G.-F., 12, 220 Su, H., 3, 443 Su, J.-H., 5, 173 Su, L., 5, 518 Su, P., 1, 300; 10, 232 Su, W., 7, 82; 10, 121 Su, X., 6, 101; 12, 86 Su, Y., 1, 151; 3, 110; 10, 367; 12, 125

Author Index Su, Z., 1, 283; 3, 228; 11, 111 Su, Z.-M., 5, 15 Suárez, A., 7, 149 Suárez, J., 12, 144 Suarez, M., 9, 9 Suarez-Sobrino, A.L., 4, 47 Subash, A., 3, 3 Subba Reddy, B.V., 6, 64, 106 Subbotin, A.N., 5, 13, 14 Subramani, K., 3, 7 Subramaniam, P., 3, 12, 15, 233 Subramanian, P., 5, 59 Subramian, R., 5, 482 Suc, J., 9, 35 Sudalai, A., 3, 475; 5, 166; 7, 164; 10, 56, 207 Sueda, T., 10, 301 Sueki, S., 5, 333, 391 Suess, A.M., 10, 10 Suffert, J., 12, 25 Sugawara, M., 1, 121 Sugaya, T., 1, 29 Sugheer, Z., 3, 250 Sugihara, S., 6, 29 Sugimoto, H., 3, 235 Sugimoto, M., 1, 66; 8, 98 Sugimura, T., 5, 254; 10, 60 Suginome, M., 10, 281 Sugirtha Devi, S., 3, 15 Sugita, S., 10, 386; 12, 110 Sugiya, M., 5, 69 Sugiyama, H., 10, 644; 11, 145, 147 Sugiyama, S., 10, 444 Sui, Q., 3, 141 Sui, Y., 1, 249 Suisse, I., 3, 389 Suleiman, R., 10, 178 Sulikowski, G.A., 1, 6 Sumida, T., 5, 99 Sumida, Y., 5, 99 Sun, B., 1, 65 Sun, B.-F., 11, 98 Sun, C., 10, 136 Sun, C.-M., 10, 305 Sun, C.-Y., 10, 70 Sun, C.-Z., 5, 179; 10, 204 Sun, C.L., 10, 1 Sun, D., 5, 507 Sun, D.-Q., 4, 220 Sun, D.L., 7, 147 Sun, F., 12, 152 Sun, G., 9, 10 Sun, G.-J., 11, 17 Sun, H., 3, 187; 4, 83; 5, 182; 10, 136, 409; 12, 113, 142 Sun, J., 3, 57, 215; 4, 154; 5, 248; 7, 72; 10, 160; 11, 8, 128, 133; 12, 185 Sun, K., 1, 177

Sun, L., 1, 22, 351; 5, 508 Sun, M., 5, 509 Sun, N., 4, 127; 10, 136; 12, 115, 126 Sun, P., 3, 171; 4, 75; 5, 402; 10, 582 Sun, Q., 6, 27; 7, 3 Sun, R., 3, 301; 11, 156; 12, 132 Sun, S., 5, 176; 11, 47, 75 Sun, T.-Y., 5, 142; 8, 90, 91 Sun, W., 3, 229, 236; 5, 470, 471, 509; 7, 73 Sun, W.-B., 11, 98 Sun, W.-Y., 5, 492 Sun, X., 3, 104; 6, 73; 7, 114; 10, 372 Sun, X.-Q., 11, 170 Sun, X.-T., 3, 434 Sun, X.-W., 1, 137 Sun, Y., 1, 93; 3, 356, 399, 437; 4, 62; 5, 216; 6, 101; 8, 91; 12, 86, 221 Sun, Y.-H., 5, 142 Sun, Y.B., 5, 500 Sun, Z., 1, 28, 107; 6, 109; 10, 579; 11, 59, 92, 138 Sunada, Y., 3, 381; 10, 153 Sunahara, K., 5, 574 Sundalam, S.K., 5, 97; 9, 28; 11, 3 Sundaraju, B., 5, 381 Sundararaju, B., 3, 487; 5, 566; 8, 105; 9, 37; 10, 337 Suneja, A., 10, 405 Sung, S., 5, 54 Sunoj, R.B., 1, 112, 131; 4, 168; 5, 143, 175 Suntrup, L., 4, 147 Suo, J.-F., 3, 28, 305; 5, 486 Supurgibekov, M.B., 9, 39 Surawatanawong, P., 3, 113, 374; 4, 201 Suresh, E., 12, 96, 180 Suresh, S., 12, 106 Susanta, D., 6, 116 Susick, R.B., 5, 122 Suta, K., 6, 60 Sutherland, A., 5, 129 Sutherland, D.R., 10, 395 Suvitha, A., 3, 251; 4, 159 Suwinski, J.W., 5, 52 Suzuki, H., 10, 95 Suzuki, K., 10, 371 Suzuki, M., 4, 155 Suzuki, N., 5, 207; 6, 43; 10, 139 Suzuki, R., 3, 279 Suzuki, T., 10, 328 Suzuki, Y., 1, 29; 4, 228; 5, 380, 435; 7, 33 Swamy, K.C.K., 4, 81

821

Author Index Swanson, S., 5, 178 Sweeney, G., 1, 87; 3, 450 Swenson, A.K., 4, 5 Swider, P., 3, 111 Syama Sundar, B., 3, 174 Szabó, I., 7, 135, 136 Szabó, K.J., 4, 114; 7, 71, 101 Szabo, M., 3, 142 Szántay, C., 4, 45 Szántay, C. Jr., 4, 45 Szczeptura, L.F., 8, 15 Szczepura, L.F., 7, 31 Szcze´sniak, P., 12, 174 Szewczyk, M., 1, 287; 3, 464 Szigetvári, A., 4, 45 Szilagyi, R.K., 10, 179 Szori, K., 1, 182 Szostak, J.W., 2, 30 Szostak, M., 5, 266, 429, 475, 491, 495, 504, 505, 515; 10, 235 Szostak, R., 5, 505 Szupiluk, A., 11, 106 Szymula, M., 5, 4

T Tabuchi, S., 7, 4; 8, 94 Tada, K., 1, 259 Tada, N., 4, 32 Tafeenko, V.A., 1, 362; 3, 182; 10, 58; 12, 230 Taha, M., 1, 148 Tahara, A., 3, 381; 10, 153 Tahara, Y.-k., 11, 150, 152 Tahira, K., 11, 89 Tahiri, N., 3, 320 Taillefer, M., 5, 6; 10, 309 Taillier, C., 1, 308 Taimoory, S.M., 1, 75 Taira, H., 8, 37 Tajbakhsh, M., 1, 250 Takacs, J.M., 10, 120 Takada, K., 10, 477 Takada, S., 7, 93 Takagi, H.D., 1, 29 Takahama, Y., 5, 383 Takahashi, T., 11, 101 Takahiro, N., 12, 92 Takai, K., 3, 103 Takanashi, N., 10, 371 Takano, H., 11, 166 Takao, K., 5, 252; 10, 511 Takasu, K., 4, 156 Takata, T., 3, 255 Takayama, H., 10, 371 Takayanagi, M., 12, 28 Takeda, K., 1, 38; 3, 271 Takeda, N., 1, 274; 10, 386; 12, 110 Takeishi, A., 1, 208

Takemoto, S., 1, 282 Takemoto, Y., 10, 440 Takenaka, K., 8, 88 Takeshi, N., 5, 290 Takeshita, M., 1, 184; 11, 101 Taketsugu, T., 7, 138 Takeuchi, R., 11, 157 Takeuchi, Y., 3, 103; 10, 95 Takimoto, M., 4, 182; 8, 67; 10, 310 Takise, R., 8, 92 Takizawa, M., 3, 106 Takizawa, S., 3, 260 Talipov, R.F., 10, 96 Talsi, E.P., 3, 25 Talukdar, R., 5, 203 Tamagawa, T., 5, 35 Tamai, T., 10, 354 Tamakuni, F., 5, 9; 8, 55 Tambar, U.K., 12, 99 Tamke, S., 12, 53 Tamura, K., 5, 69 Tamura, Y., 4, 97; 7, 103 Tan, C.-H., 3, 223 Tan, C.K., 10, 34 Tan, G., 5, 592 Tan, K.L., 5, 136 Tan, L., 1, 55; 4, 26; 5, 554; 10, 475 Tan, N., 1, 207; 8, 33 Tan, Q., 7, 125 Tan, R., 3, 417; 10, 240 Tan, T., 5, 320; 7, 5 Tan, W.W., 4, 58 Tan, X., 1, 34–37, 348; 3, 397, 409, 414; 4, 22–25, 28 Tan, Z., 1, 44; 3, 134, 324; 5, 487; 8, 74 Tanabe, H., 9, 33; 10, 402 Tanaka, H., 3, 381; 10, 196 Tanaka, K., 5, 383; 10, 644; 11, 144–147, 158; 12, 139 Tanaka, M., 10, 502 Tanaka, S., 3, 313; 5, 272 Tanaka, Y., 5, 272, 435 Tandon, V., 8, 64; 10, 317 Taneda, H., 5, 528 Tang, C., 3, 104, 149; 7, 56 Tang, E., 5, 210; 10, 82 Tang, G., 4, 251 Tang, G.-D., 5, 422 Tang, H.-T., 10, 412; 12, 155 Tang, J., 1, 369; 3, 110, 275; 5, 395, 583; 10, 427; 12, 52, 113, 213 Tang, J.-L., 11, 82 Tang, K.-L., 3, 88 Tang, L., 3, 34

Tang, M., 1, 12, 229, 331; 4, 16, 164, 166, 169, 170, 173; 8, 114, 115; 10, 541 Tang, P., 10, 475 Tang, S., 1, 15 Tang, W., 5, 464; 7, 3; 11, 177 Tang, X., 1, 141; 3, 217; 6, 59 Tang, X.-Y., 3, 100; 5, 164; 10, 122; 12, 88, 123, 132 Tang, Y., 3, 224, 272; 12, 39, 186 Tang, Z., 1, 69 Taniguchi, N., 3, 294 Taniguchi, T., 3, 284; 7, 119; 11, 150 Tanikawa, S., 7, 157 Tanimoto, H., 5, 516; 10, 602 Tanini, D., 9, 41 Tanino, K., 12, 24 Tanji, G., 12, 194 Tanner, D., 5, 256; 6, 107 Tanpure, S.D., 12, 164 Tanriver, G., 1, 117; 10, 26 Tantillo, D., 4, 255 Tantillo, D.J., 2, 29; 6, 6, 118; 12, 209 Tantirungrotechai, Y., 3, 374; 4, 201 Tao, A., 1, 216 Tao, C., 1, 47; 4, 234; 10, 396 Tao, F., 3, 224 Tao, H.-Y., 11, 46 Tao, J., 3, 92 Tao, K., 12, 10 Tao, L., 5, 527; 10, 620 Tao, X., 10, 489; 12, 225 Tao, Z.-L., 1, 212; 10, 184 Tap, A., 1, 198; 6, 108 Tarantelli, F., 4, 211; 10, 360 Tarao, A., 3, 257 Tarasenko, D.V., 12, 183 Tasserie, J., 12, 45 Tataroglu, A., 10, 571 Taton, D., 4, 157 Tatsumi, S., 5, 287 Tavakoli, G., 5, 132 Tawde, T.S., 11, 96 Tayama, E., 3, 41; 9, 23; 12, 191 Taylor, J.E., 1, 241; 10, 480 Taylor, M.S., 1, 20 Taylor, R.J.K., 1, 124; 4, 80 Tehrani, K.A., 1, 48; 3, 289; 8, 83 Teichert, J.F., 4, 183; 7, 10 Tejero, T., 1, 145, 165, 354; 8, 35 Telegina, L.N., 12, 219 Temkin, O.N., 10, 23 Temperini, A., 8, 44; 11, 95 Tenaglia, A., 10, 238 Teng, B., 3, 98 Teng, H.L., 10, 416 Teo, W.T., 4, 132; 12, 116

822 Teo, Y.-C., 1, 376 Terada, M., 8, 11; 10, 91, 92; 12, 169 Teradale, A., 3, 17 Teraoka, K., 10, 644; 11, 158 Terazawa, K., 11, 89 Terent’ev, A.O., 3, 182, 218; 10, 58 Terentis, A.C., 10, 107 Terida, M., 12, 70 Terrier, F., 5, 1, 78 Teruel, M.A., 3, 349 Teshome, A., 3, 441 Tessier, R., 7, 12 Testu, C., 5, 133 Thacker, N.C., 10, 120 Thackur, R., 5, 482 Thakar, M.S., 6, 57 Thakur, A.J., 5, 414 Thakur, M.S., 1, 353 Thakur, R., 3, 286 Thakur, S.S., 3, 8 Thamattoor, D.M., 4, 8 Thangaraj, M., 5, 104, 109, 204; 12, 47, 193 Thanh Nguyen, T.N., 4, 183 Thankachan, A.P., 3, 219; 5, 420 Thankachan, P.P., 1, 277 Thapa, S., 3, 48; 5, 319 Tharra, P., 10, 105; 12, 90, 91 Thery, V., 4, 212 Thétaz, C., 4, 240; 12, 81 Thibaudeau, S., 6, 51; 10, 47 Thibonnet, J., 5, 417 Thiel, N.O., 4, 183; 7, 10 Thiel, W., 3, 245; 12, 97 Thiel, W.R., 1, 93; 3, 437 Thiery, E., 5, 417 Thomas, M.D., 6, 116 Thomas, S.P., 3, 466; 10, 132 Thomas, T.J., 4, 5 Thompson, A.L., 1, 57; 8, 36 Thompson, S.K., 3, 346 Thompson, W.H., 10, 241 Thomson, J.E., 10, 435 Thorat, P.B., 3, 195 Thorat, S.H., 12, 103 Thornbury, R.T., 4, 234; 10, 396 Thrasher, J.S., 1, 178; 8, 20 Thuery, P., 1, 288; 3, 362, 470 Thulasiram, H.V., 6, 117 Thummanapelli, S.K., 12, 125 Tia, R., 3, 71, 344 Tian, C., 10, 458 Tian, H., 1, 240; 10, 40, 524 Tian, J.-M., 3, 225 Tian, L., 10, 654; 12, 105 Tian, P., 7, 19; 8, 93 Tian, S.-K., 12, 23 Tian, T., 11, 54

Author Index Tian, X., 3, 184; 10, 652 Tian, Y., 6, 34; 10, 654; 12, 105 Tian, Z., 7, 142 Tian, Z.-Y., 11, 179 Tiger, R.P., 2, 8 Tikad, A., 7, 60 Tikhov, R.M., 12, 232, 235 Tilley, T.D., 5, 103 Tillmann, J., 1, 285; 4, 258 Tilve, S.G., 1, 279; 3, 190 Timmerman, J.C., 10, 357 Tinnis, F., 3, 474 Tiˇslerová, I., 10, 274 Tisovsky, P., 1, 171 Tiwari, D.P., 5, 203 Tlili, A., 7, 133 To, C.T., 3, 368 To, Q.H., 12, 177 Tobisch, S., 10, 284 Tobisu, M., 5, 476 Toda, S., 10, 496 Togni, A., 8, 124 Togo, H., 5, 28; 10, 52 Tohjima, T., 10, 353; 12, 229 Tokiwa, M., 1, 184; 11, 101 Tokodai, N., 5, 286 Tokoro, Y., 10, 594 Tokumitsu, C., 10, 594; 11, 39 Tokunaga, E., 7, 26; 8, 37 Tolstikova, L.L., 11, 23 Tolstoy, P., 3, 494 Toma, E., 11, 130 Toma, L., 1, 354 Tong, H.-R., 5, 347 Tong, Q., 10, 205 Tong, R., 3, 480; 12, 43, 185 Tong, T.M.T., 7, 95 Tong, X., 10, 257, 266 Tong, X.-J., 11, 13 Tonks, I.A., 10, 344 Tonnaer, A.L., 10, 63 Tooriyama, S., 11, 146 Topchiy, M.A., 5, 64 Topchiy, M.A.A., 4, 190 Topolovˇcan, N., 10, 199 Torabi, P., 1, 43 Torigoe, T., 10, 281 Torker, S., 10, 617 Tormena, C.F., 7, 80 Torney, P.S., 1, 279 Toro-Labbe, A., 2, 14 Torres, Ò., 4, 2 Torres, A., 5, 37 Torres, G.M., 5, 499 Tortoreto, C., 1, 3; 4, 105 Tosi, F., 3, 468 Toste, F.D., 4, 234; 10, 396 Toth, B.L., 5, 313 Touati, B., 1, 308 Touchet, S., 12, 21

Touge, T., 1, 345; 3, 402, 448 Toullec, P.Y., 5, 131; 10, 69 Toyomoto, M., 7, 124 Trabelsi-Ayadi, M., 1, 308 Träff, A.M., 7, 155 Tran, H.T.Q., 8, 11 Tran, K., 7, 20; 12, 8 Tranb, T.Q., 12, 211 Trapp, N., 12, 27, 94 Treacy, S., 10, 155 Tremblay, A., 1, 386 Trieu-Van, T., 7, 126 Trifonov, A.L., 8, 26 Trinchillo, M., 4, 211; 10, 360 Tripathi, S., 3, 126, 173 Trivedi, R., 10, 578 Troadec, T., 4, 260 Trofimov, B.A., 4, 177; 10, 439, 445 Trofimov, L.P., 12, 224 Trombini, C., 1, 189, 320; 8, 128 Troshin, K., 6, 11 Trost, B.M., 1, 56, 61; 12, 150 Tröster, A., 11, 10 Truong, N., 1, 62 Trushkov, I.V., 7, 90; 12, 67 Tsai, M.-K., 1, 233; 10, 587 Tsang, A.-S.K., 1, 336; 3, 287 Tseng, C.-T., 3, 241, 302 Tseng, P.-Y., 11, 28 Tsoung, J., 4, 112 Tsovaltzi, E., 11, 139 Tsuchihashi, S., 5, 207; 6, 43 Tsuchimoto, T., 10, 376 Tsuji, Y., 6, 1 Tsukamoto, H., 10, 146 Tsurugi, H., 3, 313 Tu, D.-H., 5, 398 Tu, H.-C., 5, 234 Tu, H.-F., 5, 343 Tu, K.N., 10, 142, 144 Tu, S.-J., 5, 258; 12, 56 Tu, Y.-Q., 3, 225 Tucker, J., 5, 337 Tudge, M.T., 12, 75 Tugwell, T.H., 6, 82 Tukhvatshin, V.S., 10, 96 Tumma, N., 12, 145 Tuna, F., 3, 296 Tung, C.-H., 11, 84; 12, 113 Tunge, J.A., 8, 97; 10, 241 Tungen, J.E., 10, 36, 68 Tur, F., 11, 30, 99 Turcaud, S., 4, 89 Turecek, F., 4, 26 Turek, A.K., 3, 334 Turks, M., 6, 60; 7, 79 Turnbull, W.B., 1, 17 Turner, Z.R., 4, 146 Tussing, S., 1, 83; 3, 354, 373

823

Author Index Tuzi, A., 4, 211; 10, 360 Tyagi, D., 5, 474, 490 Tyagi, S., 5, 93 Tyan, Y.-C., 5, 234 Tyumkina, T.V., 10, 347 Tzeng, R.-J., 4, 195; 5, 393 Tzschucke, C.C., 3, 54; 4, 238; 5, 593; 12, 85

U Uang, B.-J., 1, 258; 8, 57 Ubale, M., 1, 328; 3, 20, 21 Ubukata, S., 1, 225; 10, 627 Uchida, K., 5, 100 Uchimoto, H., 3, 257 Uchiyama, M., 4, 32 Uchuskin, M.G., 12, 67 Udagawa, T., 1, 19 Ueda, A., 10, 502 Ueda, H., 9, 26; 10, 410 Ueda, M., 1, 274; 5, 229; 10, 386; 11, 18; 12, 110 Ueda, Y., 2, 7; 5, 290 Uehling, M., 10, 295 Uekusa, H., 10, 644; 11, 145, 147, 158 Uemura, T., 5, 325 Uenishi, J., 8, 88; 10, 194 Ujam, O.T., 3, 210 Ujaque, G., 1, 261; 8, 54; 10, 244 Ujwaldev, S.M., 3, 219; 7, 59 Ukaji, Y., 1, 260; 4, 138; 8, 66 Ukoha, P.O., 3, 210 Ulc, J., 5, 288 Ulikowski, A., 1, 271; 10, 603 Ullman, A.M., 3, 334 Ulmer, A., 3, 151; 8, 120; 10, 78; 12, 215 Um, I.-H., 2, 10–12 Um, J., 5, 126 Um, S.H., 5, 187 Umeno, T., 10, 502 Undeela, S., 12, 107 Ungarean, C.N., 10, 5 Unoh, Y., 5, 449; 10, 449 Unsworth, W.P., 1, 124; 4, 80 Unzner, T.A., 12, 58 Upadhyay, P., 3, 114 Urabe, H., 4, 93 Urabe, Y., 10, 154 Urbaniak, P., 3, 153 Urbano, J., 4, 210 Ursinyova, N., 7, 168 Urvashi, , 8, 64 Ushakov, I.A., 4, 177; 10, 439; 12, 224 Usui, K., 4, 235; 10, 370 Uwai, K., 1, 184; 11, 101 Uyeda, C., 4, 49 Uzairu, A., 1, 164

Uzelac, M., 1, 176 Uzule¸na, J., 7, 79

V Vaclavik, J., 1, 90; 8, 124 Vafaeezadeh, M., 5, 533 Vaillant, F.L., 12, 150 Vakhitova, L.N., 3, 265 Vakulin, I.V., 10, 96 Vala, C., 12, 195 Valdés, C., 1, 104; 3, 490; 4, 36, 117 Valentine, R., 10, 443 Valiente, M., 10, 349 Valkonen, A., 5, 89 Valle, M., 1, 77; 10, 573 Vallée, A., 10, 618; 11, 83 Vallee, Y., 5, 267 Vallejo, R., 3, 420 Vallejo-Narváez, W.I., 10, 568 Van Arman, S.A., 3, 453 Van Beej, W.E., 1, 48 Van Beek, W.E., 8, 83 Vandavasi, J.K., 3, 259; 5, 209 Van der Eycken, E.V., 10, 495, 625 van der Heijden, G., 10, 539 van der Marel, G.A., 7, 127 van der Mei, F.W., 1, 213 van der Vorm, S., 7, 127 Vander Wal, M.N., 6, 114; 7, 100 Van Doorslaer, S., 3, 289 Vanjari, R., 5, 480 Vanka, K., 3, 65; 5, 576; 10, 400 Vankar, Y.D., 1, 24; 6, 65; 12, 187 Vanke, K., 6, 75 Van Lanen, S.G., 2, 22 van Maarseveen, J.H., 10, 539 Van Speybroeck, V., 5, 19 Van Stappen, J., 1, 48 Varale, A.S., 3, 60–63 Varale, Y.S., 3, 62 Varela, J.A., 12, 144 Varga, S., 10, 93 Vargari, M.C., 1, 76 Varghese, B., 10, 608 Varma, A., 3, 385 Varughese, S., 10, 246; 12, 231 Vasilyev, A.V., 5, 243–245, 428; 6, 28, 32, 33, 45–47; 9, 4; 10, 14, 481, 482 Vasiuta, R., 10, 361 Vasyanina, L.K., 12, 183 Vats, T.K., 5, 531 Vaz, N., 3, 166, 168 Vazquez-Chavez, J., 10, 568 Vazquez-Romero, A., 3, 494

Vectariene, A., 5, 127 Veena, M.S., 3, 165 Veerasamy, N., 12, 154 Vega de la, M.G., 9, 9 Veguillas, M., 1, 273; 8, 42 Veiros, L.F., 10, 103 Vekariya, R.H., 5, 268 Velado, M., 12, 184 Velasco, R., 12, 198 Velez, E., 9, 13 Velikorechina, L.E., 5, 51 Vemula, S.R., 3, 80 Venkata Nadh, R., 3, 174 Venturini, A., 1, 230 Vera, S., 1, 59; 10, 472 Vercauteren, D.P., 1, 185 Verdaguer, X., 3, 388 Vereshchagina, Y.A., 7, 105 Verma, A.K., 5, 437; 10, 66, 216; 11, 117, 118 Verma, S., 1, 119 Vervisch, K., 7, 81; 12, 33 Vesper, C.M., 10, 189 Vetica, F., 5, 253 Vetticat, M.J., 1, 307 Vetticatt, M., 10, 32 Vetticatt, M.J., 3, 130 Vicente, R., 5, 327 Vidal, C., 1, 128; 8, 45 Vidal-Ferran, A., 1, 91; 3, 392 Vidhani, D.V., 12, 111 Viglianisi, C., 9, 41 Vignolle, J., 4, 157 Vijaya, P.K., 1, 206; 8, 34 Vijayan, A., 10, 246; 12, 231 Vil, V.A., 3, 218 Vila, C., 1, 120, 127; 5, 249; 8, 63; 10, 650 Vilarrasa, J., 1, 8 Vilhanova, B., 1, 90 Villalgordo, J.M., 12, 17 Villano, R., 1, 179 Vincent, G., 5, 220, 236; 10, 326, 327 Vincent, S.P., 7, 60 Vinoth, P., 10, 207; 11, 121 Vints, I., 10, 73 Visbal, R., 1, 248 Visco, M.D., 10, 110 Vishwakarma, R.A., 5, 49 Viso, A., 4, 136; 12, 118, 184 Vita, M.V., 5, 421; 8, 119; 10, 3 Vivekanand, T., 11, 121 Vivekanandan, K., 3, 208 Vizca´ıno-Milla, P., 1, 232; 10, 499 Vlaar, T., 1, 302 Vlasov, V.M., 10, 430 Voelter, W., 1, 148 Vogel, P., 1, 170; 7, 120

824 Voigt, C., 4, 259 Voituriez, A., 3, 429; 12, 122 Volatron, F., 5, 123, 124 Volk, B., 12, 233 Volkov, A., 3, 474 Volkov, P.A., 10, 445 Volkova, N.N., 11, 77 Vologzhanina, A.V., 3, 47 Volvoikar, P.S., 3, 190 vom Stein, T., 10, 133 von der Heiden, D., 10, 431 von Wolff, N., 3, 362 Vryhof, N.W., 12, 114 Vulovic, B., 10, 382 Vummaleti, S.V.C., 8, 107 Vyas, N., 3, 4 Vyboishchikov, S.F., 3, 131 ˇ 10, 274, 275 Vyskoˇcil, S.,

W Wˆınsche von Leupoldt, A., 3, 70 Wabaidur, S.M., 3, 306 Wada, H., 7, 103 Wade, K., 6, 61 Wagh, S.J., 11, 96 Waghmode, N.A., 3, 195 Wagner, M., 1, 285; 4, 258; 10, 129 Wakchaure, V.N., 1, 97, 198; 3, 454 Walden, D.M., 10, 25 Waldmann, H., 11, 42; 12, 121 Waldvogel, S.R., 3, 64, 70 Wallach, D.R., 6, 58 Wallbaum, J., 1, 358; 10, 87; 11, 171 Wallentin, C.-J., 8, 108 Walsh, P.J., 1, 135; 3, 491; 5, 338, 390; 7, 39, 40, 45; 9, 42 Walters, J.C., 12, 66 Walton, L., 12, 2 Wan, B., 11, 160 Wan, D., 5, 448; 10, 200 Wan, H., 4, 243; 5, 335; 12, 84 Wan, J.-P., 3, 270, 292 Wan, S.-H., 12, 49 Wan, X., 10, 39; 12, 101 Wan, Y., 10, 215 Wang, A., 1, 239; 10, 509 Wang, A.-Q., 10, 407 Wang, B., 1, 13, 110; 3, 37–40, 147, 186, 236; 5, 186, 398, 401, 450; 8, 122, 123; 10, 242, 416; 11, 59, 92; 12, 113 Wang, B.-Q., 6, 42; 10, 325 Wang, C., 1, 1, 130; 2, 19; 3, 118, 196; 4, 33, 222, 245; 5, 92, 213, 353, 438, 529; 7, 57;

Author Index 8, 109; 10, 109, 304, 323, 356; 11, 138, 160 Wang, C.-J., 7, 66; 10, 595; 11, 46 Wang, C.-M., 10, 503 Wang, C.-Q., 7, 19; 8, 93; 10, 267 Wang, D., 3, 249, 297; 4, 114; 5, 34; 6, 27; 7, 52; 8, 68; 10, 215; 12, 179 Wang, D.-C., 11, 32 Wang, D.-L., 11, 119 Wang, F., 1, 34, 297, 300; 3, 101; 4, 25; 5, 17, 189, 527; 10, 232, 330 Wang, F.-X., 10, 536 Wang, G., 1, 227, 254, 348; 3, 355, 409; 4, 216, 222, 230; 6, 103; 8, 31; 10, 229, 296, 379; 11, 156; 12, 102 Wang, G.-P., 11, 92 Wang, G.-W., 3, 138 Wang, H., 1, 337, 375; 3, 101, 147, 202, 216, 303; 4, 106; 5, 148, 347, 443, 471; 7, 48; 8, 14, 132; 10, 59, 97, 201, 218, 282, 304, 374, 419, 459, 516, 538; 11, 6; 12, 157 Wang, H.-J., 10, 475; 11, 40 Wang, H.-W., 5, 492 Wang, H.-Y., 7, 61; 11, 43 Wang, J., 1, 134, 158, 159, 166, 264, 283, 289, 370, 382; 3, 246, 457; 4, 33, 48, 52, 53, 63, 65, 71, 73, 88, 218, 226; 5, 106, 200, 408; 7, 82; 8, 60, 62; 10, 272, 451, 503, 562, 566, 636; 11, 47, 75, 120; 12, 43, 79, 80 Wang, J.-F., 11, 51 Wang, J.-J., 3, 259; 5, 5, 209; 10, 111 Wang, K., 1, 166; 4, 63; 5, 92; 7, 82; 10, 459, 579 Wang, K.-H., 1, 151 Wang, K.-K., 10, 545 Wang, L., 1, 118, 339; 3, 148, 312; 4, 6; 5, 7, 61, 94, 145, 181, 314, 387, 546; 7, 38, 82; 8, 72; 10, 129, 429; 11, 134, 173 Wang, L.-X., 1, 298; 10, 339 Wang, M., 1, 31, 110; 2, 4; 3, 150, 184, 497; 4, 214; 5, 96, 314; 9, 29 Wang, M.-C., 5, 264 Wang, M.-Y., 5, 158 Wang, M.-Z., 5, 53 Wang, M.H., 4, 180 Wang, N., 1, 34, 36, 37; 4, 23–25 Wang, N.-J., 3, 98

Wang, P., 5, 174; 7, 82, 166 Wang, P.-M., 5, 235 Wang, P.G., 6, 55; 12, 127 Wang, Q., 1, 1; 3, 53, 414, 425; 5, 164, 185, 189; 6, 110; 8, 24; 10, 98, 109, 145, 249, 287, 292, 467, 551; 11, 55, 125; 12, 32, 152 Wang, Q.-D., 3, 358; 10, 606 Wang, R., 1, 177; 3, 86, 413; 5, 448; 7, 82; 10, 200, 298, 459 Wang, R.-H., 5, 493 Wang, R.-W., 5, 310 Wang, S., 6, 69; 10, 139, 343; 11, 132 Wang, S.-F., 5, 234 Wang, S.-G., 5, 343 Wang, S.-H., 3, 225 Wang, S.-M., 5, 468 Wang, S.-Q., 10, 475 Wang, S.-S., 10, 503 Wang, S.-X., 5, 436 Wang, S.-Y., 5, 484; 10, 208 Wang, T., 2, 19; 3, 346; 8, 65; 10, 612 Wang, T.-Y., 4, 129; 5, 225 Wang, W., 1, 11, 34, 35, 37; 4, 22, 24, 25, 28; 5, 80, 210, 481; 10, 82, 504, 579; 11, 84 Wang, W.-Y., 1, 211; 4, 196 Wang, X., 1, 41, 370; 3, 149, 326; 4, 187; 5, 184, 217, 423, 497, 546; 9, 40; 10, 101, 102, 139, 322, 446, 579; 11, 22, 134, 173; 12, 165, 179 Wang, X.-C., 5, 56 Wang, X.-N., 5, 445; 10, 214; 11, 136, 155 Wang, X.-S., 1, 152; 5, 150 Wang, X.-W., 5, 264 Wang, X.-Y., 5, 468 Wang, Y., 1, 9, 12, 69, 74, 106, 229, 275, 351, 361; 3, 31, 40, 191, 236, 275, 283, 300; 4, 37, 76, 123, 151, 156, 164–166, 169, 170, 173; 5, 57, 247, 260, 280, 283, 450, 513; 7, 22, 136; 8, 29, 114, 115, 125; 9, 20; 10, 160, 242, 525, 527, 541, 566; 11, 6, 33, 55, 131; 12, 124, 221 Wang, Y.-G., 5, 567; 8, 96 Wang, Y.-H., 1, 161; 4, 130; 10, 389; 11, 140 Wang, Y.-M., 10, 9 Wang, Y.-N., 6, 115; 11, 36 Wang, Y.-X., 5, 493

825

Author Index Wang, Y.-Y., 5, 398; 10, 91 Wang, Z., 1, 337; 3, 34, 57, 238, 301; 5, 31, 182, 217, 248, 333, 335, 385, 391, 509; 7, 139; 9, 6; 10, 57, 268, 380; 11, 31, 103, 128, 133 Wang, Z.-F., 7, 66 Wang, Z.-H., 10, 526, 572, 574 Wang, Z.-X., 4, 187; 10, 102, 645, 646; 12, 220 Wang, Z.-Y., 1, 254, 275; 4, 216, 230 Wang, Z.-z., 3, 272 Wani, I.A., 5, 60; 7, 77 Wannere, C.S., 8, 2 Ward, J.-P.S., 12, 2 Ward, J.W., 5, 82; 12, 48 Warm, A., 1, 221 Warner, C.J.A., 3, 472 Warratz, S., 3, 303 Warren, T.H., 10, 129 Wasa, M., 1, 68 Waser, J., 4, 57; 5, 421; 8, 119; 10, 3, 422 Waser, M., 3, 130, 205 Watabe, Y., 9, 33; 10, 402 Watanabe, K., 12, 154, 191 Watanabe, S., 3, 106; 5, 290 Waterman, R., 4, 101 Wathier, M., 10, 260 Watkins, E.B., 5, 548 Watson, D.A., 7, 165; 10, 189 Watson, M.P., 5, 320; 7, 5 Weber, D., 10, 15 Webster, R.L., 10, 118 Webster, S., 10, 395 Weck, R., 5, 282 Weckhuysen, B.M., 6, 30 Wedler, H.B., 6, 118 Wee, A.G.H., 4, 14 Wei, B., 10, 239 Wei, D., 1, 12, 229; 4, 164–167, 169, 170, 173; 5, 173; 8, 114, 115; 10, 288, 541, 599 Wei, F., 5, 470; 11, 84 Wei, H., 1, 227, 275, 289; 10, 296 Wei, J., 3, 491; 5, 161; 9, 42 Wei, J.-F., 5, 235 Wei, J.-Q., 5, 239 Wei, K.-J., 5, 56 Wei, L., 3, 270; 7, 66 Wei, M., 3, 430 Wei, S., 8, 122, 123 Wei, T., 3, 447 Wei, W., 3, 171, 185, 199; 5, 585; 10, 518, 519 Wei, X.-G., 7, 112

Wei, Y., 1, 369; 3, 98, 100; 4, 125, 126; 10, 99, 212; 11, 125; 12, 123, 213 Wei, Y.-F., 8, 7; 10, 565 Wei, Z., 3, 318; 5, 159 Weibel, J.-M., 10, 392, 655; 12, 104 Weibel, T.J., 3, 486 Weiguo Cao, W., 4, 37 Weinhold, F., 10, 456 Weisel, M., 12, 75 Weismann, J., 4, 101 Weisshar, F., 3, 499 Wen, C., 3, 292 Wen, G., 1, 228 Wen, H., 10, 531 Wen, J., 3, 417, 418 Wen, L., 3, 34, 92 Wen, T.-B., 3, 102; 5, 406 Wen, X., 1, 136; 3, 104; 4, 83; 10, 247; 12, 142 Wen, Y., 10, 98 Wen, Y.-Q., 1, 305 Wen, Z., 5, 373; 10, 630 Wen, Z.K., 10, 181 Wencel-Delord, J., 5, 411 Wendel, D., 10, 159 Weng, J., 5, 162; 10, 90 Weng, J.-Q., 5, 263 Weng, Z., 4, 50; 5, 33; 7, 159 Wengryniuk, S.E., 12, 66 Wennemers, H., 1, 388; 10, 497 Wentrup, C., 4, 238, 240, 243; 12, 60, 81, 84, 85 Wenzler, M.E., 1, 6 Werner, T., 1, 280; 9, 18 Werner, V., 12, 167 Werz, D.B., 1, 358; 10, 87; 11, 161, 171 Wessig, P., 9, 44 West, J.G., 1, 385 West, T.H., 1, 241 Wester, R., 7, 135 Westhues, S., 3, 401, 406 Westwood, N.J., 12, 236 Wetzel, A., 7, 167 Wezynfeld, N.E., 2, 23 Wheeler, K.A., 11, 53 Whitaker, B.J., 5, 274 Whitaker, D., 5, 479 White, A.J.P., 12, 59 White, B.P., 6, 18; 7, 116 Whited, M.T., 3, 421 Whiteker, G.T., 5, 84, 580 Whiteoak, C.J., 5, 140, 442; 8, 104; 10, 336 Whiting, A., 10, 443 Whyte, A., 6, 70; 12, 112 Wickens, Z.K., 3, 277; 10, 166

Widenhoefer, R.A., 4, 3; 6, 2; 10, 226, 357, 394 Wielechowska, M., 12, 5 Wiemer, D.F., 3, 479 Wieneke, P., 12, 71 Wierenga, D.C., 12, 114 Wierenga, T.S., 1, 380 Wiest, J.M., 5, 328 Wiest, O., 1, 195; 10, 180 Wieting, J.M., 10, 110 Wiget, P.A., 11, 178; 12, 30 Wild, D.A., 3, 264 Wilke, B.I., 10, 450 Wilkerson-Hill, S.M., 4, 91; 11, 93 Wilking, M., 10, 45 Wilkins, L.C., 12, 71 Willand, N., 8, 87 Willans, C.E., 3, 495 Wille, U., 6, 83; 12, 93 William, R., 6, 69 Williams, C.M., 3, 125 Williams, D.R., 11, 94 Williams, G.M., 11, 169 Williams, L., 10, 282 Williams, M.J., 5, 472 Williams, N.H., 7, 123 Williams, R.E., 6, 61 Williams, S.J., 7, 97 Williams, S.K., 1, 372 Williamson, P., 10, 480 Willis, M.C., 1, 299; 8, 78; 10, 250, 629 Wills, M., 1, 342; 3, 369 Wills, V.S., 3, 479 Wilson, G.S., 3, 112 Winne, J.M., 6, 76 Winschel, G.A., 1, 28; 6, 109 Winterton, S.E., 11, 52 Wipf, P., 7, 91 Wirth, T., 3, 204; 10, 61; 12, 62, 63 Wititsuwannakul, T., 3, 374; 4, 201 Witte, M.D., 3, 320 Wlodarczyk, K., 5, 231; 6, 38 Wnuk, S.F., 5, 7 Wodrich, M.D., 10, 422 Woerly, E.M., 10, 76 Woerpel, K.A., 6, 53; 11, 104 Wojciechowski, K., 10, 554 Wojtas, K.P., 2, 21 Wojtas, L., 5, 427; 10, 145 Wolf, C., 1, 203, 371; 8, 56 Wolf, F., 5, 356; 10, 623 Wolf, F.F., 10, 586 Wolf, L.M., 3, 245 Wolfe, J.P., 10, 190, 401 Wolosewicz, K., 11, 71 Wolters, L.P., 7, 104, 109

826 Womack, C.C., 3, 212 Wong, C.-Y., 3, 91 Wong, K.C., 12, 12 Wong, M.W., 12, 9 Wong, W.-T., 12, 12 Wong, Y.-C., 3, 241, 302; 10, 35 Wong, Y.F., 3, 57; 5, 248; 11, 133 Woo, S.K., 3, 438; 7, 54 Wood, N.M., 3, 417 Woodward, S., 10, 560 Woof, C.R., 10, 118 Wosch, C.L., 1, 262; 8, 58 Wöste, T.H., 3, 194; 10, 4 Wouters, J., 7, 162 Wright, A.C., 5, 111 Wright, K., 10, 618; 11, 83 Wright, S.W., 1, 115 Wright, T.B., 1, 218; 8, 8 Wróbel, Z., 5, 50; 10, 554 Wu, A., 1, 363 Wu, A.-J., 11, 28 Wu, A.-X., 3, 150, 193; 5, 58 Wu, B., 1, 381; 4, 170; 5, 374; 8, 115 Wu, C., 4, 33, 253; 5, 200; 8, 109; 10, 101, 611 Wu, D., 3, 443; 5, 514 Wu, D.-R., 1, 157 Wu, F., 4, 242; 5, 191; 11, 179 Wu, G., 5, 200 Wu, H., 5, 471; 6, 110; 10, 137; 11, 115; 12, 32, 151 Wu, H.-L., 1, 258; 8, 57 Wu, H.-R., 3, 249 Wu, H.-S., 5, 483, 521 Wu, J., 1, 382; 3, 184, 185, 199; 4, 218; 5, 152, 323, 445; 10, 117, 211, 214, 312, 413; 11, 6, 136, 155, 163 Wu, K., 5, 360; 10, 640 Wu, L., 1, 69, 151; 3, 434; 5, 283, 407 Wu, M., 11, 47 Wu, N., 5, 373; 8, 7; 10, 565, 630 Wu, O., 11, 5 Wu, P., 5, 583; 9, 45 Wu, P.-Y., 1, 258; 8, 57 Wu, Q., 1, 113; 5, 79, 258, 387; 6, 37 Wu, Q.-G., 5, 65, 459 Wu, S., 3, 312; 10, 429, 504 Wu, S.-S., 5, 269 Wu, S.-W., 10, 75 Wu, T., 10, 590; 12, 171 Wu, W., 1, 141, 149; 3, 314, 397, 416; 4, 54, 100; 6, 59; 7, 6; 8, 1; 9, 31; 10, 202, 205, 213, 306, 403; 11, 34 Wu, X., 1, 22, 296, 363; 3, 193, 447; 7, 51

Author Index Wu, X.-D., 8, 68 Wu, X.-F., 5, 502, 506 Wu, X.-N., 4, 120 Wu, X.-Y., 1, 222; 5, 454; 8, 31, 85; 10, 259, 577; 11, 105 Wu, Y., 1, 45, 105; 3, 356; 4, 70, 75, 83, 213; 5, 70, 176, 213, 217, 270, 402, 508, 510, 511, 514, 592; 10, 81, 535; 11, 92; 12, 142 Wu, Y.-D., 1, 363; 3, 150, 193, 375; 4, 202; 5, 142, 298; 8, 113; 10, 8, 160, 180, 182; 12, 37 Wu, Z., 1, 370; 4, 133, 243; 5, 359; 10, 112, 385; 12, 84, 122, 212 Wu, Z.-J., 10, 526, 574 Wujkowska, Z., 1, 265; 8, 59 Wünsch, B., 10, 41 Wurm, F.R., 4, 157 Würthwein, E.-U., 10, 41

X Xi, C., 10, 343 Xi, H., 9, 47; 10, 320 Xi, J.-B., 1, 126 Xi, Y., 4, 245; 10, 283 Xi, Z., 3, 491; 9, 42 Xia, B., 11, 155 Xia, C., 3, 229, 236, 318; 5, 159; 7, 73; 12, 171 Xia, C.-G., 10, 485; 11, 45 Xia, F., 4, 118, 119 Xia, H., 4, 48; 11, 163 Xia, J., 3, 390 Xia, T., 10, 582 Xia, W., 5, 594; 10, 634 Xia, X.-F., 3, 282 Xia, Y., 3, 337; 4, 26, 48, 52, 53, 71, 73; 7, 89, 139; 12, 11, 161 Xia, Y.-Q., 5, 557 Xia, Y.-T., 3, 434 Xia, Z., 10, 39 Xiang, B., 5, 567; 8, 96 Xiang, J.-C., 3, 150 Xiang, S., 5, 518 Xiang, X., 1, 329; 3, 234 Xiao, B., 5, 147; 7, 11 Xiao, D., 3, 224 Xiao, F., 3, 285; 4, 256; 10, 258, 464 Xiao, H., 7, 48; 10, 229 Xiao, J., 3, 148; 9, 19; 11, 134, 173 Xiao, J.-A., 10, 503; 11, 114 Xiao, J.-C., 1, 281, 314; 4, 39, 44, 113; 7, 160 Xiao, K., 5, 471

Xiao, K.-J., 3, 81; 5, 241 Xiao, L.-J., 1, 298; 10, 339 Xiao, M., 1, 27 Xiao, P., 1, 315; 11, 111 Xiao, Q., 4, 52 Xiao, S.J., 5, 90 Xiao, W., 10, 576 Xiao, W.-J., 6, 115; 8, 24; 11, 36, 125 Xiao, X., 4, 244; 5, 161 Xiao, X.-Q., 2, 6; 4, 257; 8, 40 Xiao, Y., 10, 441; 11, 59, 92, 138 Xiao, Y.-C., 10, 147 Xiao, Y.-L., 5, 310 Xie, B., 7, 30 Xie, C., 1, 52; 5, 261; 8, 18; 12, 227 Xie, D., 1, 235 Xie, F., 5, 363, 422, 561; 12, 135, 165 Xie, H., 3, 73; 4, 122; 7, 131; 8, 65, 76; 10, 418, 612 Xie, J., 3, 90, 91; 4, 128; 7, 106, 137; 10, 48, 381, 577 Xie, J.-B., 10, 607 Xie, J.-H., 1, 298; 10, 339 Xie, J.-W., 3, 339; 5, 399 Xie, K., 5, 512 Xie, L., 10, 559 Xie, L.-G., 11, 153 Xie, M.-S., 11, 32 Xie, T., 10, 441 Xie, W., 4, 184; 5, 386; 7, 35; 10, 39 Xie, X., 4, 236; 10, 566; 11, 57, 156; 12, 115 Xie, Y., 3, 134, 397, 425; 4, 116; 5, 517, 563; 12, 149 Xie, Z., 3, 44 Xie, Z.-Z., 4, 72 Xin, L., 1, 337 Xin, M., 10, 438 Xin, T., 4, 83; 12, 142 Xing, D., 5, 130 Xing, F., 4, 151; 9, 20 Xing, H., 3, 243; 10, 658 Xing, J.-J., 11, 56 Xing, M.-M., 10, 438 Xing, Y., 11, 47, 75 Xiong, B., 5, 202; 7, 111 Xiong, D., 1, 106; 5, 247 Xiong, D.-C., 1, 22 Xiong, H.-Y., 8, 133 Xiong, M., 11, 156 Xiong, O., 11, 113 Xiong, P., 3, 203 Xiong, W., 5, 24; 10, 490 Xiong, X., 5, 125 Xiong, Y., 1, 205, 291; 8, 32; 12, 68

827

Author Index Xiong, Z., 1, 361; 5, 57 Xu, B., 3, 132, 293; 7, 80; 10, 100, 119, 358, 418; 12, 99 Xu, C., 5, 58, 148, 310, 427; 8, 132; 12, 98 Xu, D., 3, 229; 5, 434; 10, 415, 566 Xu, F., 3, 203; 11, 160 Xu, G., 5, 464; 10, 124; 11, 8 Xu, G.-Q., 8, 127 Xu, H., 4, 98; 5, 280; 10, 74, 106; 11, 42 Xu, H.-C., 3, 203 Xu, H.-D., 10, 137; 11, 115; 12, 13 Xu, J., 1, 113; 4, 221, 223; 5, 163; 6, 44; 7, 107; 10, 106, 562; 11, 5; 12, 3, 80, 89 Xu, J.-W., 3, 30 Xu, J.-X., 11, 45 Xu, J.-Z., 10, 163 Xu, K., 1, 337; 3, 255; 10, 268, 611 Xu, L., 3, 148, 375; 4, 202; 5, 181, 554; 8, 113; 10, 180; 11, 134, 173 Xu, L.-P., 7, 75 Xu, L.-W., 6, 100; 10, 31, 163, 485; 11, 45 Xu, M., 7, 125; 10, 451; 11, 31 Xu, M.-H., 1, 292; 3, 225; 5, 371; 10, 632 Xu, N., 1, 222; 8, 85 Xu, P., 1, 161, 246; 12, 50 Xu, P.-F., 1, 275; 8, 127; 10, 441 Xu, Q., 1, 80, 387; 7, 131; 10, 391; 11, 16, 56 Xu, Q.-L., 4, 83; 12, 18, 142 Xu, R., 3, 380 Xu, R.-Q., 5, 343, 542; 10, 293 Xu, S., 1, 166; 4, 63; 5, 94, 200; 10, 20, 138 Xu, T., 1, 143; 4, 213; 10, 81 Xu, T.-F., 5, 567; 8, 96 Xu, W., 1, 337; 4, 127; 5, 532; 7, 107; 10, 331; 12, 126 Xu, W.L., 4, 102 Xu, X., 1, 31, 33, 63, 147; 3, 221, 301, 497; 5, 451; 6, 34; 7, 25, 52, 87; 10, 186, 478, 518; 11, 79, 126, 177; 12, 156 Xu, X.-F., 1, 298; 10, 339 Xu, X.-Y., 7, 84; 10, 526, 572, 574 Xu, Y., 1, 9; 5, 172, 353; 6, 55; 10, 582, 643; 12, 57, 127, 152

Xu, Y.-H., 7, 166; 10, 181; 11, 109 Xu, Y.-J., 1, 46, 107; 5, 404; 10, 267; 12, 73 Xu, Z., 3, 109; 5, 172; 6, 100; 10, 31, 163, 485, 620; 11, 84, 120; 12, 113 Xu, Z.-Y., 3, 95; 8, 40; 10, 121 Xu, Z.B., 3, 136 Xuan, D., 5, 526 Xuan, Q., 3, 433 Xue, C., 12, 165 Xue, F., 5, 397; 8, 122 Xue, L., 1, 138; 4, 60 Xue, M., 3, 136 Xue, S.-S., 2, 24 Xue, X.-S., 5, 148; 8, 125, 131, 132; 10, 79, 457; 12, 160 Xue, Y., 1, 74; 3, 36; 8, 29 Xue, Z., 3, 415

Y Yachi, N., 1, 263; 8, 61 Yadav, A.K., 3, 137 Yadav, L.D.S., 3, 137, 183 Yadav, P., 8, 64; 10, 317 Yadav, R.N., 7, 148 Yadav, V.K., 3, 183 Yadov, M., 5, 49 Yadykov, A.V., 5, 232 Yaguchi, K., 10, 353; 12, 229 Yakovleva, M.P., 10, 96 Yakupova, L.R., 3, 281 Yalcouye, B., 5, 119, 120 Yamabe, S., 3, 129, 489 Yamada, K.-I., 4, 156 Yamada, S., 3, 335 Yamada, Y., 4, 149 Yamagata, A.D.G., 1, 57; 8, 36 Yamaguchi, J., 5, 584; 10, 444 Yamaguchi, K., 1, 38; 3, 257, 271 Yamaguchi, M., 5, 325, 444 Yamaguchi, S., 6, 36; 10, 139 Yamaguchi, T., 5, 379 Yamaguchi, Y., 1, 263; 4, 228; 7, 33; 8, 61 Yamaji, R., 1, 58 Yamakawa, K., 1, 303 Yamamoto, E., 5, 286 Yamamoto, H., 1, 194; 3, 237; 5, 229; 7, 57 Yamamoto, K., 3, 226; 4, 112 Yamamoto, T., 3, 112 Yamamoto, Y., 1, 101; 3, 43, 109; 5, 372; 11, 120, 141 Yamamura, M., 6, 36 Yamamura, N., 1, 268; 5, 348 Yamanaka, M., 2, 7 Yamane, Y., 5, 574 Yamaoka, Y., 4, 156

Yamasaki, N., 5, 229 Yamashita, J., 4, 32 Yamashita, M., 5, 284; 12, 77 Yamashita, S., 9, 33; 10, 402 Yamauchi, K., 3, 103 Yamazaki, A., 10, 328 Yamazaki, K., 11, 89 Yamazaki, S., 3, 129, 489 Yamin, B., 12, 222 Yaminova, L.V., 5, 232 Yan, B.-F., 10, 350 Yan, C., 3, 290; 5, 483 Yan, H., 1, 291; 5, 27, 385; 9, 6 Yan, J.-L., 3, 139 Yan, L., 3, 228; 10, 566 Yan, L.-K., 5, 15 Yan, M.-Q., 5, 65, 459 Yan, N., 7, 68 Yan, S.-S., 10, 286 Yan, S.-Y., 3, 30; 5, 305 Yan, T., 10, 79; 12, 160 Yan, W., 4, 122; 10, 459 Yan, X., 1, 78; 8, 22; 9, 47; 10, 320, 483, 536, 567 Yan, Y., 3, 301 Yan, Z., 5, 374 Yanada, R., 10, 301 Yanagi, T., 10, 276; 12, 20 Yanagisawa, A., 1, 208 Yanagisawa, K., 5, 476 Yanai, H., 10, 477 Yang, B., 3, 82; 10, 148, 223; 12, 151 Yang, B.-W., 10, 70 Yang, C., 3, 217; 10, 515; 11, 62 Yang, D., 4, 92; 7, 74, 82; 12, 131 Yang, D.-M., 5, 591 Yang, D.-S., 1, 159; 11, 12, 13 Yang, F., 5, 176; 10, 407 Yang, G., 1, 169, 324; 3, 390; 5, 113; 7, 17 Yang, H., 1, 207; 8, 33; 10, 503; 11, 114 Yang, H.-Q., 3, 311 Yang, H.S., 7, 94; 10, 508 Yang, J., 3, 266; 4, 48, 55; 9, 19; 10, 162; 12, 221 Yang, J.-M., 3, 358; 10, 606 Yang, J.W., 7, 94; 10, 508 Yang, K., 3, 238, 360; 5, 357; 10, 126, 183 Yang, K.-F., 10, 31 Yang, K.S., 10, 170, 171 Yang, L., 1, 361, 373; 5, 57 Yang, M., 3, 191; 7, 136 Yang, M.-H., 1, 322 Yang, M.-Y., 3, 88; 5, 235 Yang, N., 1, 283; 3, 407; 10, 420; 11, 111

828 Yang, P., 1, 349; 3, 445; 5, 343; 10, 101, 459 Yang, Q., 3, 58, 243; 4, 174 Yang, S., 1, 147, 228; 3, 221, 483; 4, 95, 227; 10, 213, 533, 643, 652; 11, 16 Yang, S.-D., 3, 58 Yang, T., 4, 75, 249; 5, 182, 402, 513, 560 Yang, T.-L., 5, 135 Yang, W., 4, 154; 5, 342; 7, 72, 74; 8, 89; 10, 599 Yang, W.-C., 3, 439 Yang, X., 1, 135, 375; 3, 101, 202, 332, 376, 408; 4, 8, 106; 5, 189, 239, 390, 464; 7, 45; 8, 72, 90, 91; 10, 467; 11, 137 Yang, Y., 1, 99, 102; 3, 34, 154, 318; 4, 26, 70; 5, 159, 445, 587; 10, 214, 239, 285, 311; 11, 54, 136; 12, 4, 155, 179 Yang, Y.-C., 5, 223; 10, 302 Yang, Y.-F., 12, 37 Yang, Y.-W., 3, 45 Yang, Z., 1, 113, 257, 304; 3, 407, 484; 5, 560; 7, 75; 9, 40; 10, 12, 86, 378, 446, 523, 562, 604, 658; 11, 5; 12, 3, 188 Yang, Z.-P., 10, 218 Yang, Z.-W., 5, 147; 11, 51 Yang, Z.-Y., 1, 192 Yano, R., 11, 157 Yano, Y., 6, 36 Yao, B., 7, 6 Yao, C.-S., 1, 152 Yao, C.-Z., 3, 207 Yao, H., 4, 75; 10, 518, 519; 11, 62 Yao, H.-C., 10, 646 Yao, J., 6, 101; 10, 504; 12, 86 Yao, J.-P., 3, 138 Yao, K., 3, 481 Yao, L., 3, 417; 7, 66; 8, 40; 10, 211; 11, 60 Yao, L.J., 10, 344 Yao, Q., 10, 39, 489; 12, 98, 225 Yao, T., 5, 121; 10, 225; 12, 217 Yao, W., 1, 68; 3, 297; 5, 34, 539; 11, 33 Yao, W.W., 5, 493 Yao, X., 5, 183 Yao, Y., 6, 27; 10, 469, 514 Yao, Z., 5, 518 Yao, Z.-J., 5, 239; 10, 130, 131 Yaqi Li, Y., 4, 145 Yaremenko, I.A., 3, 218 Yarkandi, N., 3, 119 Yarosh, E.V., 5, 456

Author Index Yashiro, K., 1, 209; 10, 465 Yasir, M., 4, 107 Yasuda, H., 4, 162; 10, 376; 11, 18 Yasuda, M., 7, 102; 9, 26; 10, 410 Yasuda, N., 5, 287 Yasuda, S., 11, 148; 12, 134 Yasuda, Y., 7, 13; 8, 84; 10, 290 Yates, B.F., 5, 540 Yavari, I., 10, 447; 11, 48 Yazaki, R., 10, 549 Yazici, A., 6, 83; 12, 93 Yazzaf, R., 1, 71 Ydhyam, S., 12, 145 Ye, J.-H., 10, 286 Ye, J.-L., 5, 240 Ye, K.-Y., 4, 233; 7, 23 Ye, L., 7, 19; 8, 93; 10, 467, 514, 613; 11, 179 Ye, L.-W., 4, 130; 10, 375, 389 Ye, M., 5, 493; 10, 98 Ye, R.-R., 2, 24 Ye, S., 4, 152, 220; 5, 342; 8, 89; 11, 119, 174 Ye, T.-Y., 10, 305 Ye, X., 3, 223; 5, 427 Ye, X.-S., 1, 22; 10, 419 Yedoyan, J., 1, 70; 4, 61; 11, 162 Yee, N.K., 5, 375, 466 Yeh, Y.-C., 3, 241 Yeo, H., 5, 402 Yepes, D., 3, 372 Yerneni, K., 3, 121 Yerrabelly, J.R., 12, 15 Yetra, S.R., 4, 219 Yeung, K., 1, 108; 10, 150 Yeung, S.Y., 3, 264 Yeung, Y.-Y., 5, 125; 10, 33, 34, 35 Yi, B., 1, 207; 8, 33 Yi, C., 5, 471 Yi, H., 5, 89 Yi, J.-C., 5, 542; 10, 293 Yi, L., 11, 174 Yi, N., 10, 298 Yi, P., 12, 221 Yi, S., 4, 54; 10, 306 Yi, W., 4, 102 Yi, Y., 1, 304 Yi, Y.-Q.-Q., 3, 439 Yi, Z., 1, 207; 8, 33 Yildiz, C.B., 9, 43 Yilmaz, H., 10, 571 Yin, B., 10, 186 Yin, G., 1, 78; 5, 32; 7, 42; 10, 189, 567 Yin, H., 3, 92, 308 Yin, L., 5, 501 Yin, Q., 5, 196; 10, 115

Yin, S.-F., 7, 111 Yin, X., 10, 576 Yin, Y., 1, 207; 8, 33 Yin, Z., 10, 117 Yin, Z.-B., 10, 286 Ying, J., 8, 68; 10, 373 Ying, W., 11, 178; 12, 30 Yip, S., 1, 157 Yiu, S.-M., 3, 90 Ylijoki, K.E.O., 5, 499 Ylioja, P.M., 1, 299; 10, 250 Yoda, N., 5, 435 Yogesh Kumar, K., 3, 165 Yohannes, Y., 3, 203 Yokoshima, S., 6, 90; 12, 44 Yokoyama, K., 10, 602 Yokoyama, Y., 5, 449 Yoo, K., 5, 26 Yorimitsu, H., 4, 189; 5, 71, 81, 352, 370, 415; 6, 24; 8, 3, 102; 10, 276, 277; 12, 20 Yoshida, K., 1, 208; 2, 7; 5, 252; 10, 511 Yoshida, M., 9, 32; 10, 423 Yoshida, S., 5, 100; 11, 18 Yoshida, T., 4, 235; 10, 370; 11, 144 Yoshidomi, T., 4, 91 Yoshikai, N., 4, 58; 10, 312, 331 Yoshikawa, M., 7, 103 Yoshikawa, N., 1, 55 Yoshimura, A., 10, 659 Yoshimura, F., 12, 24 Yoshino, T., 5, 380 Yoshizaki, S., 11, 144 Yoshizawa, K., 3, 381 You, C., 10, 239 You, J., 5, 448, 507, 592; 6, 73; 10, 200, 372 You, S.-L., 4, 233; 5, 343, 452, 542; 7, 22, 23; 10, 269, 293; 11, 32; 12, 128 You, X., 11, 156 You, X.-L., 11, 51 You, Y., 10, 526, 572, 574 Younesi, Y., 3, 495 Young, C.M., 1, 241; 10, 479 Young, M.C., 5, 353 Young, R.D., 7, 161 Yousefi, R., 10, 32 Yousufuddin, M., 10, 46; 12, 18 Yu, A., 3, 283 Yu, C., 1, 11; 5, 385; 9, 6 Yu, C.-Y., 1, 27 Yu, D.-G., 10, 286 Yu, F., 10, 169 Yu, F.-L., 1, 211; 4, 196 Yu, G.-A., 5, 65, 459 Yu, H., 1, 246; 3, 298

829

Author Index Yu, H.-Z., 1, 32; 3, 95, 333, 460; 5, 591; 10, 121, 356 Yu, J., 3, 248, 480; 10, 303 Yu, J.-Q., 3, 81; 5, 174, 342, 492, 594; 8, 70, 89, 92 Yu, K.-Y., 8, 22; 10, 483, 536 Yu, L., 1, 257; 10, 282, 314, 523 Yu, P., 7, 147; 12, 98, 221 Yu, R., 12, 152 Yu, S., 1, 9; 4, 67, 251; 5, 363, 400, 441, 543; 10, 80, 332; 11, 29; 12, 135 Yu, T.-Y., 1, 275 Yu, W., 1, 158, 160; 3, 184–186, 192, 199, 318; 4, 33, 88; 5, 159, 440; 10, 288, 334 Yu, X., 1, 9; 2, 4; 3, 43, 297; 4, 94; 5, 17, 34, 270; 11, 65, 120 Yu, X.-C., 7, 131 Yu, Y., 4, 40, 54, 96; 7, 67; 10, 306; 12, 82, 157 Yu, Y.-B., 3, 396 Yu, Z., 1, 193, 326; 3, 476; 4, 12, 118, 119; 5, 208, 358, 360; 6, 104; 10, 488, 640 Yu, Z.-X., 11, 175, 176, 179 Yu, Z.-Y., 10, 261 Yuan, B.-H., 1, 137 Yuan, C., 11, 59, 92, 138 Yuan, H., 1, 84; 3, 380, 492; 6, 98; 11, 79 Yuan, J., 4, 209; 5, 65, 459; 10, 414; 11, 105 Yuan, K., 10, 139 Yuan, M., 3, 483; 7, 44; 10, 566 Yuan, R., 10, 165 Yuan, S., 3, 308; 4, 221, 223 Yuan, W., 10, 149 Yuan, W.-C., 7, 84; 10, 526, 572, 574 Yuan, X., 10, 593; 11, 34, 108 Yuan, Y., 3, 98, 275; 4, 158; 5, 496; 10, 534; 11, 6 Yuan, Z., 1, 63; 4, 213; 10, 81, 519 Yuan, Z.-z., 7, 48 Yubune, T., 7, 93 Yue, C.-B., 1, 314; 4, 39; 7, 160 Yue, D.-F., 7, 84; 10, 526, 572 Yue, G., 10, 611 Yue, T., 3, 249 Yue, X., 5, 101 Yue, Z., 1, 118; 7, 38; 11, 65 Yuen, O.Y., 5, 473 Yugandhar, D., 6, 105 Yuihara, I., 12, 140 Yumagulov, R.A., 10, 49 Yumoto, Y., 1, 282

Yun, J., 10, 135, 289 Yun, S.Y., 12, 161 Yunis, R., 6, 22 Yunusov, M.S., 10, 49 Yurev, E., 5, 194 Yutaka, S., 12, 92 Yuvacharaskul, R., 10, 199

Z Zaafarany, I., 3, 9, 66, 119 Zabalov, M.V., 2, 8 Zadsirjan, V., 10, 11 Zaghi, A., 1, 230, 231 Zahedi, E., 9, 16 Zahedi, M., 3, 16 Zakarianezhad, M., 10, 491, 492 Zakaszewska, A., 1, 114; 11, 26 Zaki, H., 3, 178 Zambrano, V., 11, 112 Zammit, C.M., 10, 435 Zamora, M.T., 3, 426 Zanardi, F., 11, 112 Zanatta, N., 11, 86 Zand-Vakili, F., 12, 197 Zanna, N., 5, 88 Zanotti-Gerosa, A., 1, 342; 3, 369 Zapal, J., 1, 90 Zapata, A., 1, 284; 9, 14 Zapata, L.A., 4, 27 Zaragozá, R.J., 4, 172; 12, 206 Zarca, M., 4, 123 Zard, S.Z., 12, 162 Zargari, N., 10, 172 Zargarian, D., 10, 552 Zarick, S.D., 5, 292 Zatalochnaya, O.V., 5, 375 Zdvizhkov, A.T., 3, 182; 10, 58 Zeferino-Diaz, R., 6, 95 Zeidan, N., 5, 586; 10, 224 Zell, D., 5, 552 Zemtsov, A.A., 8, 26 Zeng, B.-B., 3, 358; 10, 606 Zeng, H., 10, 117; 11, 78 Zeng, J.-L., 1, 192 Zeng, K., 7, 111 Zeng, W., 4, 68, 244; 5, 161, 559 Zeng, X., 1, 234, 235, 369; 4, 243; 5, 497; 10, 48, 100, 119, 427; 12, 52, 84, 213 Zeng, X.-M., 3, 339 Zeng, Y., 1, 205, 291; 3, 447; 8, 32; 10, 426 Zeng, Y.-M., 1, 107 Zeni, G., 5, 433; 10, 88 Zeroual, A., 4, 19, 20 Zha, G., 10, 582 Zha, Z., 3, 34; 11, 128 Zhai, D.-D., 3, 439 Zhan, B.-B., 5, 485 Zhan, G., 11, 129

Zhan, Z.-P., 10, 412; 12, 155 Zhang, A., 1, 47; 5, 138 Zhang, B., 1, 329; 3, 234; 5, 312; 7, 11; 10, 219 Zhang, B.-S., 5, 223; 10, 302 Zhang, C., 1, 153; 3, 323; 5, 525, 554; 11, 31, 59 Zhang, C.-L., 4, 152, 220; 11, 119 Zhang, C.-P., 1, 314; 4, 39; 5, 468; 7, 160 Zhang, D., 1, 304; 5, 23; 10, 299, 475, 584; 12, 156 Zhang, E., 5, 583 Zhang, E.-G., 10, 515 Zhang, E.-L., 7, 131 Zhang, F., 2, 19; 12, 221 Zhang, F.-G., 3, 147; 12, 166 Zhang, F.-M., 3, 225 Zhang, G., 1, 228; 4, 227; 5, 217, 280, 430; 7, 67; 10, 117, 236, 419, 533; 12, 74 Zhang, G.-T., 5, 407, 557 Zhang, H., 1, 36, 37, 313; 3, 355, 447; 4, 23, 24, 217; 5, 121, 550; 6, 73; 7, 28, 141; 8, 1, 5, 92, 116; 10, 197, 225, 372, 620, 658 Zhang, H.-H., 5, 79; 6, 37 Zhang, H.-J., 3, 102; 5, 406 Zhang, H.-R., 10, 407; 11, 170 Zhang, J., 1, 118, 193, 363; 3, 139, 193, 299; 4, 12, 119, 133; 5, 208, 335, 358, 359, 399, 568; 6, 98, 104; 7, 38, 40, 44, 106; 8, 14; 10, 48, 163, 206, 283, 385, 488, 516, 538, 626; 11, 45, 65, 79, 87, 136, 155; 12, 23 Zhang, J.-C., 6, 42; 10, 325 Zhang, J.-F., 3, 97; 5, 405 Zhang, J.-X., 11, 43 Zhang, J.Z., 4, 118, 119 Zhang, K., 4, 75; 5, 402; 8, 24; 10, 547; 11, 62; 12, 182, 216 Zhang, L., 1, 33, 52, 224, 348; 3, 154, 266, 409, 434, 483; 4, 55, 65, 99, 100, 123, 129; 5, 90, 112, 225, 261, 280, 293, 509, 529; 6, 34; 7, 44, 56, 106; 8, 18; 10, 416, 634; 11, 178; 12, 30, 156, 157, 227 Zhang, L.-B., 5, 173 Zhang, L.-J., 10, 378 Zhang, L.-S., 3, 139 Zhang, M., 1, 44; 3, 132, 324, 345; 4, 111; 5, 33, 202, 210,

830 215; 7, 40; 10, 82, 158, 279, 352, 486 Zhang, M.-C., 11, 32 Zhang, M.-M., 11, 36 Zhang, M.-Q., 6, 35 Zhang, M.-X., 10, 350 Zhang, M.L., 10, 572 Zhang, N., 5, 114 Zhang, P., 3, 318; 4, 116; 5, 148, 159, 163; 8, 132; 12, 149 Zhang, P.-X., 5, 537 Zhang, Q., 1, 32; 3, 460; 5, 147, 513; 7, 56, 92; 11, 155 Zhang, Q.-W., 5, 304, 408; 10, 272 Zhang, R., 1, 373; 7, 30; 10, 299 Zhang, S., 1, 291; 3, 36, 215, 224, 417; 5, 202; 7, 6; 11, 128 Zhang, S.-H., 3, 225 Zhang, S.-J., 11, 108 Zhang, S.-K., 5, 173 Zhang, S.-L., 1, 175; 9, 25 Zhang, S.-Y., 10, 204 Zhang, T., 5, 182; 6, 35; 9, 10; 12, 37 Zhang, W., 1, 151, 229, 234; 3, 217, 299, 370, 383, 390, 419, 423, 444; 4, 164, 166, 169; 5, 113, 215, 217, 440; 8, 114; 10, 130, 131, 267, 334, 487, 504; 11, 57 Zhang, W.-D., 3, 88; 5, 485 Zhang, X., 1, 186, 195, 228, 348, 350; 3, 43, 148, 242, 295, 301, 387, 397, 409, 414–418, 425, 427, 481, 482; 4, 35, 98, 166; 5, 142, 298, 310–312, 340, 396, 469, 518; 9, 10; 10, 8, 83, 160, 180, 182, 239, 240, 249, 268; 11, 59; 12, 37, 68, 109, 156 Zhang, X.-F., 11, 40 Zhang, X.-G., 5, 151; 10, 408 Zhang, X.-M., 3, 225; 5, 557; 7, 84; 10, 526, 572, 574; 12, 133 Zhang, X.-Y., 3, 439 Zhang, X.-Z., 8, 22; 10, 483, 536 Zhang, X.R., 5, 500 Zhang, Y., 1, 11, 158, 166; 3, 104, 238, 299, 300, 443; 4, 33, 48, 52, 53, 63, 65, 71, 73, 88, 199; 5, 70, 200, 330, 331, 382, 440, 466, 539; 7, 3; 10, 30, 138, 151, 334, 504; 12, 179 Zhang, Y.-C., 11, 137

Author Index Zhang, Y.-F., 1, 381; 3, 139; 7, 52; 10, 632 Zhang, Z., 1, 158; 3, 243, 370, 383, 419, 423, 444; 4, 33, 65, 88, 95, 244, 253, 256; 5, 7, 56; 6, 44, 59; 7, 73, 87; 10, 101, 249, 258, 286, 424, 559; 12, 89 Zhang, Z.-C., 1, 137 Zhang, Z.-P., 10, 457 Zhang, Z.-Q., 7, 11 Zhang, Z.-X., 7, 75 Zhang, Z.-Z., 3, 30; 5, 305 Zhang-Negrerie, D., 3, 248; 10, 303; 12, 37 Zhao, A., 3, 132 Zhao, B., 1, 47; 5, 398; 10, 469 Zhao, B.-L., 10, 529, 530, 584 Zhao, C., 1, 382; 3, 118; 4, 98, 218, 226; 5, 408, 438; 6, 111; 10, 272, 323 Zhao, C.-Q., 8, 40 Zhao, C.Z., 12, 208 Zhao, D., 7, 67 Zhao, F., 1, 9; 5, 512; 10, 388 Zhao, G., 1, 69, 314; 4, 39; 7, 48, 160; 8, 14; 10, 516, 538; 11, 43 Zhao, H., 1, 177; 5, 216 Zhao, H.-W., 11, 54 Zhao, J., 3, 109, 355; 7, 71, 92; 12, 113 Zhao, J.-C.G., 1, 53 Zhao, J.-Q., 7, 84 Zhao, K., 1, 239; 10, 509, 590; 12, 37 Zhao, K.-Q., 6, 42; 10, 325 Zhao, L., 10, 318; 11, 138 Zhao, M., 2, 24 Zhao, Q., 3, 309, 416; 5, 148; 8, 132 Zhao, R., 8, 65; 10, 612 Zhao, S., 5, 485; 10, 441 Zhao, T., 3, 185 Zhao, W., 3, 86, 217; 6, 55; 8, 65; 10, 612; 12, 127 Zhao, W.-X., 1, 134, 264; 8, 60; 10, 451 Zhao, X., 1, 27; 3, 238; 5, 200; 7, 46; 10, 83, 84, 451; 11, 102, 113; 12, 98 Zhao, X.-l., 11, 177 Zhao, X.-M., 3, 28; 11, 82 Zhao, X.J., 5, 90 Zhao, Y., 1, 315, 359; 3, 99, 356, 436; 4, 199, 214, 242; 5, 27, 121, 191, 210, 474, 494, 529, 587; 8, 19, 82; 10, 82, 225, 489; 12, 225

Zhao, Y.-D., 11, 54 Zhao, Y.-H., 5, 537 Zhao, Z., 4, 227; 10, 467, 514, 533 Zhao, Z.-G., 10, 70 Zhao, Z.K., 10, 30 Zheng, B., 3, 76 Zheng, C., 5, 452; 8, 14; 10, 269, 516, 538 Zheng, C.-W., 11, 43 Zheng, D., 5, 323 Zheng, H., 1, 329; 3, 234, 459; 5, 31; 7, 159; 11, 107 Zheng, J., 3, 314; 4, 158; 5, 452; 10, 202, 269, 319, 534 Zheng, L., 4, 165, 170; 5, 70; 8, 115; 10, 541 Zheng, M., 10, 205 Zheng, N., 10, 378 Zheng, Q., 1, 243; 4, 82 Zheng, S., 10, 117 Zheng, S.-J., 5, 58 Zheng, W.-F., 11, 17 Zheng, X., 10, 240 Zheng, X.-W., 3, 99; 5, 494; 10, 261 Zheng, X.-X., 3, 28 Zheng, Y., 1, 223, 224; 5, 270; 6, 98; 7, 37; 10, 514 Zheng, Z.-b., 7, 87 Zheng, Z.-J., 6, 100; 10, 31, 163, 485 Zhi, Y., 1, 239; 10, 509 Zhong, G., 1, 234, 235 Zhong, M., 1, 304 Zhong, R., 3, 97; 5, 405 Zhong, W., 7, 37; 11, 29 Zhong, X., 10, 459 Zhong, X.-M., 10, 182 Zhong, X.-X., 11, 40 Zhou, B., 3, 358; 4, 70; 10, 79, 606; 12, 160 Zhou, C., 5, 560; 11, 21 Zhou, D., 3, 238 Zhou, F., 3, 360 Zhou, G., 10, 321, 634 Zhou, H., 1, 205, 249, 291; 3, 238; 8, 32; 11, 115 Zhou, J., 1, 74, 235, 348, 349; 3, 93, 409, 445; 5, 477; 8, 29; 10, 611 Zhou, J.-H., 11, 109 Zhou, J.P., 6, 88 Zhou, J.S., 1, 319; 5, 345, 346 Zhou, L., 1, 1, 169, 350; 3, 387; 4, 116; 10, 109; 11, 29, 87; 12, 149 Zhou, L.-J., 11, 137 Zhou, M., 3, 415, 416

831

Author Index Zhou, M.-J., 1, 298; 5, 135; 10, 339 Zhou, N.-N., 11, 12, 13 Zhou, P., 3, 299 Zhou, Q., 1, 158; 3, 97; 4, 65, 88; 5, 320, 405, 508; 7, 5 Zhou, Q.-F., 10, 547; 12, 182 Zhou, Q.-L., 1, 298; 3, 396; 10, 339; 11, 92 Zhou, R., 3, 216; 8, 17; 12, 216 Zhou, S., 3, 430; 4, 120; 5, 55 Zhou, S.-L., 11, 129 Zhou, T., 3, 40; 5, 401, 450; 10, 242 Zhou, W., 1, 207; 5, 30; 8, 33 Zhou, W.-J., 10, 286 Zhou, X., 1, 45, 153, 375; 3, 202, 479; 4, 251; 5, 189, 441, 525, 543; 7, 87, 114; 10, 332, 451; 11, 49 Zhou, Y., 3, 186, 258, 480; 7, 25, 111; 9, 27; 10, 424, 489, 622; 11, 107; 12, 225 Zhou, Y.-B., 12, 155 Zhou, Y.-G., 3, 384, 457; 5, 374 Zhou, Y.-P., 5, 158 Zhou, Y.-Y., 4, 49 Zhou, Z., 5, 364; 7, 6; 10, 271, 525, 527, 576 Zhou, Z.-F., 11, 114 Zhou, Z.-W., 5, 58 Zhu, B., 5, 15; 11, 102 Zhu, C., 1, 149; 3, 77, 82, 355; 4, 54, 246; 9, 31; 10, 112, 148, 223, 306; 11, 8; 12, 212 Zhu, C.-L., 10, 74 Zhu, D., 1, 26; 4, 99

Zhu, D.-X., 1, 292; 5, 371 Zhu, F.-L., 11, 140 Zhu, G., 5, 487; 10, 299 Zhu, H., 6, 99; 10, 86, 299; 12, 178 Zhu, H.-T., 11, 12, 13 Zhu, H.-Z., 5, 269 Zhu, J., 1, 16, 26, 246; 3, 356; 5, 198, 199; 6, 110; 7, 112, 150; 10, 292, 551; 11, 55; 12, 32 Zhu, K., 3, 466; 4, 158; 10, 534 Zhu, L., 1, 234; 3, 266, 295, 463; 4, 205; 7, 37; 10, 152; 11, 29; 12, 151 Zhu, P.-L., 12, 88 Zhu, Q., 5, 172; 7, 66 Zhu, Q.-N., 11, 137 Zhu, R., 1, 138; 4, 60 Zhu, R.-Y., 8, 70, 92 Zhu, S., 1, 300; 3, 258; 4, 66, 99, 100, 222; 10, 232; 11, 179 Zhu, S.-F., 3, 396; 11, 92 Zhu, S.-L., 3, 282 Zhu, W., 6, 27; 10, 469 Zhu, X., 1, 229; 3, 28, 305, 312; 4, 164; 5, 163, 173, 486; 7, 32, 114; 10, 429, 484; 12, 68 Zhu, X.-L., 5, 65 Zhu, X.-Y., 10, 407 Zhu, Y., 1, 329; 3, 234; 4, 166; 5, 176; 10, 459; 12, 50 Zhu, Y.-F., 10, 388 Zhu, Y.-Q., 5, 404 Zhu, Z., 1, 141, 348; 3, 191, 409, 414

Zhu, Z.-Q., 3, 254; 5, 212 Zhu, Z.-Z., 3, 100 Zhuang, Z., 11, 175 Zhuge, R., 3, 390 Zhuo, C.-X., 4, 233; 7, 23 Zhuravsky, R.P., 3, 47 Zhurkin, F.E., 7, 15 Zi, G., 1, 88; 3, 411–413 Zi, J., 1, 222; 8, 85 Ziegler, D.T., 3, 277; 10, 166 Zimmerman, P.M., 1, 28; 6, 109 Zimmet, A.J., 3, 453 Zipse, H., 7, 36 Ziyadova, T.M., 3, 32 Zlotin, S.G., 10, 581 Zografos, A.L., 6, 94; 12, 153 Zolali, A., 10, 421 Zolotarev, A.A., 6, 86 Zong, H., 1, 272; 8, 43 Zong, L., 3, 223 Zong, Z., 3, 485 Zora, M., 10, 619 Zou, D., 5, 70 Zou, H., 10, 298 Zou, K., 1, 249 Zou, L., 8, 122, 123; 10, 579 Zou, M., 3, 104, 149 Zou, X., 3, 494 Zou, Y., 1, 1; 10, 109; 12, 109 Zou, Y.Q., 11, 10 Zubkov, F.I., 1, 279 Zuccaccia, D., 10, 360 Zuo, W., 1, 343; 3, 440 Zuo, Y., 7, 106 Zuo, Z., 10, 162 Zurbano, M.M., 10, 455 Zurro, M., 5, 83; 10, 657

Subject Index

A Acetals, synthesis and reactions, 2–5 Acetanilides, oxidation, 114 Acetylation, carbocations, 338 Acetylene, oxidation, 144 2-Acetyl thiazoles, nucleophilic addition, 612 Acid catalysis, molecular rearrangements, 702–3, 723–5 Acrylonitriles, nucleophilic addition, 612 Acyclic diaminocarbenes (ADC), 220–1 Acyl anhydrides elimination reactions, 451 enolization and related reactions, 48 intermolecular catalysis and reactions, 76–7 nucleophilic addition, 588 Acylation, aromatic substitution, 270–80, 282–313 Acyl halides, intermolecular catalysis and reactions, 76–7 2-Acyl imidazoles, carbanions, 444 α-Acyloxy ketones, reduction, 165–6 3-Acyloxy-2-oxindoles, aromatic substitution, 256–7 2-(2-Acylvinyl)indoles, synthesis, 717 ADC see acyclic diaminocarbenes Addition aldehydes and ketones, 27–48 aldol and related reactions, 27–41 aromatic substitution, 261–2 carbanions, 426–7, 433–8 imines, 17–22 molecular rearrangements, 725 other addition reactions, 41–8 reviews, 465 see also cycloaddition; electrophilic addition; individual named reactions; individual reagents/classes; nucleophilic addition Adenosine triphosphate (ATP), 87–8 Adjacent lone pair (ALP) effect, 423 Alchivemycin, synthesis, 638 Alcohols, oxidation, 140, 149–50 Aldehydes, 1–70 acetals and related species, 2–5 aldol and related reactions, 27–41 alkynylations, 34–6 allylation and related reactions, 33–4 α-aminations and related reactions, 48

arylations, addition of organometallics, including Grignards, 42–3 asymmetric aldols, 28–30 benzoin and Stetter reactions, 36 C–C bond formation and fission, 27–41 cyanohydrins, cyanosilylation, and other cyanations, 47–8 cycloaddition, 675–6 enolization, reactions of enolates, and related reactions, 48–51 glucosides, 5–7 α-halogenation, α-alkylation, and other α-substitutions, 50–1 hydrazones and related species, 24–7 hydrosilylation, hydrophosphonylation, hydroboration, and hydroacylation, 45–7 imine synthesis and general chemistry, 8–10 ketenes and related cumulenes, 7–8 Mannich, Mannich-type, and nitro-Mannich reactions, 10–14 Michael addition, 36–8 miscellaneous condensations, 38–41 miscellaneous cyclizations, 56–9 Morita–Baylis–Hillman reaction, 31–2 Mukaiyama aldol, 31 nitrogen derivatives, 8–27 nucleophilic addition, 594, 611 organozincs, 41–2 other addition reactions, 41–8 other aldol-type reactions, 32–3 other name reactions of imines, 14–15 other reactions, 59–62 other reactions of imines, 20–22 other stereoselective reactions of imines, 18–20 oxidation, 121–2, 125, 135, 144–6 oxidation of aldehydes to acids, 51–2 oxidation of carbonyl compounds, 51–4 oximes, 22–4 reduction, 160–1, 169–70, 182 reduction of carbonyl compounds, 54–6 reviews of aldols and asymmetric catalysis, 27–8 stereoselective allyl-, aryl-, alkenyl-, and alkynyl-ations of imines, 17 stereoselective hydrogenation of imines and other reductive processes, 15–16 Wittig and other olefinations, 43–5

Organic Reaction Mechanisms 2016, First Edition. Edited by A. C. Knipe. © 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

833

834 Alder-ene reaction, 750–1 Aldimines, electrophilic addition, 540 Aldol reactions aldehydes and ketones, 27–41 alkynylations, 34–6 allylation and related reactions, 33–4 asymmetric aldols, 28–30 benzoin and Stetter reactions, 36 carbanions, 428, 443 elimination reactions, 454–5 Michael addition, 36–8 miscellaneous condensations, 38–41 Morita–Baylis–Hillman reaction, 31–2 Mukaiyama aldol, 31 other aldol-type reactions, 32–3 reviews of aldols and asymmetric catalysis, 27–8 Alkenes carbenes, 223 carbocations, 342 electrophilic addition, 465–6, 489–90, 496, 498–502, 519–20, 553 oxidation, 104–5, 107–8, 144, 146 reduction, 164–6, 174 Alkenoic acids, oxidation, 130 2-Alkenoyl pyridines, cycloaddition, 679 Alkenyl arenes, cycloaddition, 667–8 Alkenylation aldehydes and ketones, 17 aromatic substitution, 294–9 Alkenylboronic acids, reduction, 187 5-Alkenylhydantoins, electrophilic addition, 481 Alkenyl phenols, cycloaddition, 664 5-Alkenyl thiazolones, cycloaddition, 691 Alkoxamines, electrophilic addition, 526–7 Alkoxyallenes, electrophilic addition, 513 3-Alkoxyamine lactams, synthesis, 121 Alkoxy hydrosilanes, molecular rearrangements, 720–1 Alkoxylation, electrophilic addition, 567 Alkyl 5-arylfuran-2-carboxylates, synthesis, 713 Alkylation aldehydes and ketones, 50–1 aromatic substitution, 270–80, 282–313 carbanions, 441 Alkylbenzoquinones, nucleophilic addition, 578 2-Alkylenecyclobutanones, nucleophilic addition, 630 Alkyl halides, reduction, 184 Alkyl hydrosilanes, molecular rearrangements, 720–1 Alkylidenecyclobutanones, synthesis, 218–9 Alkylidenecyclopropanes electrophilic addition, 490, 553–4 synthesis, 742 Alkylideneoxazolones, nucleophilic addition, 579 Alkyllithiums see organolithiums 2-Alkyl-2-nitro-3-aryloxiranes, nucleophilic aliphatic substitution, 383–4 Alkylpyrazoles, carbanions, 443 Alkynals, reactions, 59–60

Subject Index Alkynamides, electrophilic addition, 537, 568 Alkynes carbenes, 212–3 carbocations, 350, 358–62 cycloaddition, 664, 672, 674, 686–7 electrophilic addition, 484–5, 491–4, 497–8, 507–513, 517–27, 530, 536–52, 555–65, 570–74 molecular rearrangements, 703–4, 715, 723–5, 744–7, 755–6 nucleophilic addition, 628, 631, 636–40 oxidation, 129 reduction, 173–4 Alkynoates, molecular rearrangements, 701–2 Alkynones, cycloaddition, 664–5 Alkynyl alcohols, electrophilic addition, 559–60 Alkynylanilines electrophilic addition, 488, 570 oxidation, 105 Alkynyl aryl ethers, electrophilic addition, 512 Alkynylation aldehydes and ketones, 17, 34–6 aromatic substitution, 268, 297–303, 317–19 carbanions, 437–40 𝜎-Alkynyl benzoates, electrophilic addition, 493 Alkynyl esters, carbanions, 426 Alkynylhemiaminals, synthesis, 4 Alkynylimines, electrophilic addition, 570 Alkynyl β-keto esters, nucleophilic addition, 619 Allenedienes, cycloaddition, 689 Allenes electrophilic addition, 495, 498, 524–8, 548, 566–7 nucleophilic addition, 610, 629 Allenic enamines, nucleophilic addition, 597 Allenic enolates, synthesis, 585 Allenol esters, cycloaddition, 665 2,3-Allenylamides, molecular rearrangements, 718 α-Ally-α-cyanolactams, synthesis, 701, 703 Allylamines, electrophilic addition, 532–3 Allylation aldehydes and ketones, 17, 33–4 aromatic substitution, 292–3 electrophilic addition, 519–20 Allyl butyrate, oxidation, 159 Allyl cyanates, molecular rearrangements, 755 Allylic alcohols carbanions, 441 molecular rearrangements, 710 nucleophilic aliphatic substitution, 371, 374 Allylic ethers, nucleophilic addition, 587 Allylic fluorides, oxidation, 145 Allylic ketones, cycloaddition, 682 Allylic substitutions, nucleophilic aliphatic substitution, 371–7 Allyl isocyanates, molecular rearrangements, 755 Allyl malononitrile, molecular rearrangements, 701–2 β-Allyloxyenamides, molecular rearrangements, 728–9

Subject Index ALP see adjacent lone pair Aluminium organocatalysis see organoaluminiums Amidation aromatic substitution, 268–9 oxidation, 155 Amides biologically significant reactions, 88–91 intermolecular catalysis and reactions, 77 nucleophilic aliphatic substitution, 414–5 oxidation, 99 reduction, 182–3 Amidines, electrophilic addition, 478 4-Amido-cinnolines, synthesis, 488 Amidofluorination, electrophilic addition, 477, 542 2-Amidopyrroles, synthesis, 564 Amidoselenenylation, electrophilic addition, 480 Amido 2-sulfinyl butadienes, synthesis, 757, 759 Aminaloalkynes, electrophilic addition, 556–7 Amination aldehydes and ketones, 48 aromatic substitution, 268–9 carbenes, 213–4 oxidation, 102, 126–30, 155–7 Amines nucleophilic addition, 594, 623 oxidation, 117 Amino acid-substituted imidazoles, synthesis, 48 Amino alcohols, nucleophilic addition, 611 1,4-Amino alcohols, synthesis, 436 1-(α-Aminoalkyl)-2-naphthols, synthesis, 126 Aminoalkynylation, electrophilic addition, 562–3 o-Aminobenzamides, oxidation, 110 2-Aminobenzimidazoles, aromatic substitution, 254 2-Aminobenzothiazoles, aromatic substitution, 266 2-(2-Aminobenzyl)furans, molecular rearrangements, 717 Aminoboration, electrophilic addition, 490 Aminocarbonylation, electrophilic addition, 498 Aminocyclization, electrophilic addition, 533 4-Amino-2-cyclopentenones, synthesis, 759–10 Aminocyclopentenones, synthesis, 759–10 Aminodechlorination, aromatic substitution, 252–3 3-Amino-1,4-diynes, synthesis, 62 Aminofluorination, electrophilic addition, 480 2-Aminofurans, synthesis, 718 3-Aminofurans, synthesis, 722–3 Aminoisocyanates, synthesis, 723 Aminolactonization, electrophilic addition, 533 Aminolysis reactions carboxylic acids and derivatives, 75–80 phosphoric acids and derivatives, 82–3 Aminomethylation, formation and reactions of acetals, 5 2-(Aminomethyl)pyrrolidines, synthesis, 708 α-Amino-oxy ketones, synthesis, 33 3-Aminopiperidines, synthesis, 708 Aminopyridines electrophilic addition, 471, 537 nucleophilic aliphatic substitution, 380 oxidation, 98

835 8-Aminoquinolines, aromatic substitution, 266–8, 273, 301 Aminosiloxycarbenes, 204 3-Aminotetrahydroquinolines, reduction, 179 Aminotriazole formamidine, oxidation, 105 Anhydrides see acyl anhydrides Anilines oxidation, 125, 133–4 synthesis, 126 Anilinopyrimidines, synthesis, 211 Anthranils, electrophilic addition, 561 Anthrone enolates, cycloaddition, 676 Arenes, oxidation, 107–8 Arenium ions, 345–6 Aromatic substitution, 247–335 alkylation and acylation, 270–80 alkylation, arylation, and acylation, 282–313 benzyne and related intermediates, 250, 258–62 bond formation to oxygen, nitrogen, sulfur, and phosphorus, 264–70 electrophilic substitution, 262–82 halogenation, 262–3 introduction and general, 247–9 Meisenheimer and related complexes, 249, 252, 258 nitration, 264 nucleophilic substitution, 249–62 other reactions, 280–82 SN Ar mechanism, 249–58 substitution on heterocyclic rings, 313–23 transition metal-catalysed C–C bond formation, 282–323 Aroylbenzo[b]oxepin-3-ones, synthesis, 731 Aryl alkyl ketones, oxidation, 100, 135–7 1-Aryl-1-alkynes, synthesis, 229 Aryl allylic halides, nucleophilic aliphatic substitution, 371–2 Aryl allyl sulfoxides, molecular rearrangements, 721–2 Arylamines oxidation, 100 synthesis, 55 α-Aryl α-amino acid esters, synthesis, 140–1 2-Arylaminobenzoates, synthesis, 260 2-Arylaminomethylbenzoates, synthesis, 260 Arylated cyclopropyl ketones, carbocations, 357 Arylation aldehydes and ketones, 17, 42–3 aromatic substitution, 282–313 imines, 21 molecular rearrangements, 702–3 Aryl azides, aromatic substitution, 269 2-Arylbenzoxazole, oxidation, 113

836 2-Aryl-3-(2-cyanoethyl)aziridines, molecular rearrangements, 708 Arylcyclopropenes, carbenes, 220 Aryldiazoacetates, carbenes, 212 Aryldibromothiophenes, synthesis, 320 Aryl difluoroamides, synthesis, 282–3 Aryl diphenylmethyl sulfides, oxidation, 116 Aryl enones, nucleophilic addition, 595 (5-Arylfurfuryl)amines, molecular rearrangements, 708–9 Aryl halides, aromatic substitution, 252–4, 257–8, 286–8, 294–5, 298–9, 304–313 Aryl imidamides, aromatic substitution, 295–6 2-Arylindoles, oxidation, 139 Aryl ketones molecular rearrangements, 716 nucleophilic addition, 592 nucleophilic aliphatic substitution, 409 Arylmethylamines, synthesis, 180 3-(Arylmethyl)benzofurans, synthesis, 530–1 β-Aryloxy aldehydes, synthesis, 500 Arylpropiolic acids, reactions, 60 2-Aryl pyridines, synthesis, 321 6-Arylpyridin-3-ols, synthesis, 708–9 Arylsilanes, oxidation, 147–8 3-Arylsuccinimides, aromatic substitution, 291 Aryl sulfinamides, aromatic substitution, 267 Aryl sulfonamides, oxidation, 121 Aryl sulfones, synthesis, 721–2 Aryl sulfoxides, molecular rearrangements, 705–6 1-Aryl-1,2,3,4-tetrahydroisoquinolines, synthesis, 261 Aryltetrazoles, synthesis, 24 Aryl vinylic ethers, nucleophilic aliphatic substitution, 379 Arynes, cycloaddition, 677 Ascospiroketals, synthesis, 711 ATP see adenosine triphosphate Autocatalysis, oxidation, 98 Autoxidation, 143–55 Azaadamantane-type oxoammonium salts, oxidation, 118–19 Aza-Barbier reaction, imines, 22 1-Azabicycloalkanes, synthesis, 730–1 Azadienes, cycloaddition, 680–1 Aza-Henry reaction, imines, 14 3-Azaindoles, aromatic substitution, 267 7-Azaindoles, oxidation, 108 Aza-Michael additions, nucleophilic addition, 578–80, 615 Aza-Michael–Henry reaction, imines, 14 Aza-Morita–Baylis–Hillman reaction, imines, 14–15 Aza-Nazarov-type reactions, electrophilic addition, 564 Aza-Peterson olefination elimination reactions, 453 imines, 22 Aza-Reformatsky reaction, imines, 20

Subject Index Azetidine-2-carboxylic acid esters, molecular rearrangements, 761 Azetidines cycloaddition, 666 nucleophilic aliphatic substitution, 390–1 Azetines, synthesis, 206 Azides aromatic substitution, 269 cycloaddition, 673–4 electrophilic addition, 522 nucleophilic aliphatic substitution, 381 Azidocyanation electrophilic addition, 488–9 molecular rearrangements, 766 3-Azidoindoles, synthesis, 472 Aziridines carbanions, 429, 435–6 carbenes, 209, 224 electrophilic addition, 478 molecular rearrangements, 712–13, 734 nucleophilic aliphatic substitution, 384–5, 387–90 Azirines elimination reactions, 456 synthesis, 135 Azlactones, electrophilic addition, 484 Azoalkenes, cycloaddition, 682 Azo-coupling, aromatic substitution, 247–8 Azodicarboxylates, oxidation, 156–7 Azoles carbenes, 232–3 nucleophilic addition, 631 Azomethine imines cycloaddition, 670, 688–9 synthesis, 565 Azomethine ylide N-oxides, carbanions, 431–2 Azomethine ylides cycloaddition, 667–9 elimination reactions, 460

B Baeyer–Villiger (BV) reaction molecular rearrangements, 751 oxidation, 132 Barbaralones, synthesis, 156 Base catalysis, molecular rearrangements, 707 BDNPP see bis(2,4-dinitrophenyl) phosphate Beckmann rearrangement, 751–2 Belousov–Zhabotinsky reaction (BZR), oxidation, 123 Benzaldehyde oximes, reactions, 22–3 Benzamides aromatic substitution, 307–8 nucleophilic addition, 631 oxidation, 99 synthesis, 137 2-Benzamidopyridine 1-oxide, oxidation, 99 Benz[a]azulenes, molecular rearrangements, 715 Benzenediazonium ions, aromatic substitution, 247–8

Subject Index Benzhydrilium ions, 338, 344 Benzimidazoles electrophilic addition, 556 synthesis, 8, 186–7 Benzisoxazoles electrophilic addition, 570 oxidation, 105 Benzo[b]thiophenes, synthesis, 474 Benzocarbocycles, synthesis, 59 Benzocyclic ketones, cyclization reactions, 59 Benzocyclobutenes, synthesis, 737–8 Benzocyclobutenols, electrophilic addition, 528 Benzodiazepines molecular rearrangements, 712 synthesis, 555, 580–1 Benzodiazocines, molecular rearrangements, 712 Benzodithioloimines, cycloaddition, 690–1 Benzo[b]fluorenes, molecular rearrangements, 752, 755 Benzo[b]fluorenones, molecular rearrangements, 756–7 Benzofurans electrophilic addition, 486, 507, 515 synthesis, 206, 220 Benzofused spiro[3.3]heptanes, molecular rearrangements, 743–4 Benzoimidazo[1,2-a]imidazolone, synthesis, 538–9 Benzo[e]indoles, synthesis, 677 Benzoin reaction, aldehydes and ketones, 36 Benzolactams, synthesis, 750–1 Benzolactones, synthesis, 750–1 Benzo[a]phenazines, synthesis, 512 Benzophenones, synthesis, 129 Benzophospholanes, synthesis, 275 Benzopyranes, synthesis, 471–2 Benzopyranyl acetals, carbocations, 347 Benzopyrylium triflates, electrophilic addition, 488 Benzoquinones, synthesis, 107 Benzo[b][1,4]selenazines, synthesis, 458–9 Benzotetracenes, aromatic substitution, 281–2 Benzothiazoles, aromatic substitution, 322 Benzothiophenes, synthesis, 276 Benzotriazoles electrophilic addition, 553 molecular rearrangements, 769 Benzoxasiloles, synthesis, 467 Benzoxazepines, electrophilic addition, 479 1,4-Benzoxazines oxidation, 141 synthesis, 751 1,3-Benzoxazin-2-ones, synthesis, 608 Benzoxepines, synthesis, 217, 592, 744–5 Benzyhydryl halides, electrophilic addition, 541 Benzyl alcohols, oxidation, 122 1-Benzyl-2-alkynylbenzenes, electrophilic addition, 483 Benzylation, carbanions, 428–9 α-Benzyl-𝛼,α-difluoroketones, synthesis, 51 Benzylic alcohols, molecular rearrangements, 710, 716

837 Benzylic amines, nucleophilic addition, 578 Benzylic arylsulfoxides, synthesis, 428–9 Benzylic ethers, electrophilic addition, 528 Benzyl nitriles, molecular rearrangements, 706 Benzynes aromatic substitution, 250, 258–62 electrophilic addition, 577 Bestmann–Ohira alkynylation, aldehydes and ketones, 34–5 Bicyclic [4.4.0] dihydronaphthalenes, synthesis, 738 Bicyclic pyranosides, carbocations, 346–7 Bicyclo[5.3.0]decane derivatives, synthesis, 690 Biginelli reaction, aldehydes and ketones, 39 Biologically significant reactions carbocations, 364 carboxylic acids and derivatives, 87–91 phosphoric acids and derivatives, 91–6 Bisallenes, electrophilic addition, 513, 531 Bisamides, nucleophilic addition, 608 Bis(2,4-dinitrophenyl) phosphate (BDNPP), 92–4 Bisguanadinium salts, nucleophilic addition, 608 Bismuth catalysis electrophilic addition, 574 molecular rearrangements, 710 Bisoxazolines aldol and related reactions, 30 carbenes, 208–9 Boracarboxylation, electrophilic addition, 491 Borylation aldehydes and ketones, 34 electrophilic addition, 491, 503 molecular rearrangements, 718–21 nucleophilic addition, 625–30 oxidation, 159 reduction, 159–61 see also hydroboration Breslow intermediates, molecular rearrangements, 714 Bridged bicyclic ketals, synthesis, 760 5,6-Bridged methanobenzodioxepines, formation, 2 Bromination, electrophilic addition, 465–70 Bromine, oxidation, 122 Bromoaminocyclization, electrophilic addition, 468 Bromochlorination, electrophilic addition, 466 2-Bromocyclopent-2-en-1-ones, synthesis, 218 Bromoetherification, electrophilic addition, 466–7 Bromolactamization, electrophilic addition, 468 Bromolactonization, electrophilic addition, 467 Bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBrop), 90 Brønsted acids cycloaddition, 675, 683, 688 electrophilic addition, 483–6 molecular rearrangements, 710, 723–5 Brook rearrangement, 720–1, 752–5 Butyrolactones, nucleophilic addition, 591, 622 BV see Baeyer–Villiger BZR see Belousov–Zhabotinsky reaction

838 C CAAC see cyclic (alkyl)(amino) carbenes Cage carboranes, aromatic substitution, 286 Carbanions, 423–48 addition and other reactions, 426–7, 433–4 directed lithiation, 432–3 electrophilic aliphatic substitution, 443–5 enolates and related species, 424–8 heteroatom-stabilized species, 428–32 miscellaneous, 442–3 nucleophilic aliphatic substitution, 398 organolithiums, 432–4 organomagnesiums, 434–5 organometallic species, 432–42 organozincs, 435–9 other organometallic species, 439–42 reactions, 424–32 structure and stability, 423–4 Carbazoles carbocations, 350–52 synthesis, 100, 218 Carbenes, 201–236 addition reactions, 46 aromatic substitution, 283, 289, 296 chiral NHC systems, 231–6 copper, 207–9, 226–7 electrophilic addition, 492, 528, 530, 538–9, 561–3, 567–8 gold, 217–20, 231 heterocyclic as ligands, 226–31 DFT analysis methods, 225–6 reactivity, 223–5 structure, 220–22 hydrazones, 25–6 imines, 14 iridium, 215 iron and cobalt, 230 metal-free carbenes: structure and reactivity, 202–6 metallated carbenes: structure and reactivity, 206–220 molecular rearrangements, 722–3, 734–47 nickel, 229–30 nucleophilic addition, 606, 622 nucleophilic aliphatic substitution, 394–5, 412 palladium, 217, 227–9 platinum, 220 reviews, 202 rhodium, 209–215, 230–1 ruthenium, 215–16, 230–1 silver, 220, 231 ytterbium, 231 see also N-heterocyclic carbenes Carboamidation, electrophilic addition, 505–7 Carbocations, 337–67 arenium ions, 345–6 aromatic and anti-aromatic systems, 339–40 asymmetric synthesis, 361–4 biosynthetic chemistry, 364

Subject Index electronic effects and structure, 338–9 introduction, 337 molecular rearrangements, 350, 356–8, 363–4, 730 new reactions and methods, 340–4 non-classical cations, 348 nucleophilic substitution, 346–7 propargyl and vinyl carbocations, 358–61 reactivity and electrophilicity, 338 ring-opening and ring-forming reactions, 348–57 superelectrophilic carbocations, 344–5 Carbodiimides, cycloaddition, 666 Carbonates, intermolecular catalysis and reactions, 77–80 Carbon monoxide ligands, aromatic substitution, 308–9, 311–12 1-Carboxamidocyclopropane-1-carboxylates, intramolecular catalysis, 83–4 Carboxylic acids and derivatives acids, 71–3, 87–8 acyl halides and anhydrides, 76–7 amides and peptides, 77, 88–91 aminolysis reactions, 75–6, 77–80 biologically significant reactions, 87–91 carbonates, 77–80 electrophilic addition, 517, 525, 533, 576 elimination reactions, 451–2 esters, 73–5 intermolecular catalysis and reactions, 71–82 intramolecular catalysis and neighbouring group participation, 83–7 nucleophilic addition, 588 oxidation of aldehydes to acids, 51–2 solvolysis reactions, 73–5 thioamides and thioacyl halides, 80–82 thioesters and thiocarbonates, 80 transesterification, 73 Cardiopetaline, synthesis, 356–7, 711 Carotol, synthesis, 220–1 CDC see cross-dehydrogenative coupling Cerium catalysis aromatic substitution, 280 oxidation, 105–6 Chalcones cyclization reactions, 56–7 nucleophilic addition, 628, 637 Chalk–Harrod mechanism, electrophilic addition, 529–30 Chlorination, electrophilic addition, 470–1 Chlorine, oxidation, 121–2 Chlorofluorination, electrophilic addition, 470 Chlorolactonization, electrophilic addition, 470–1 Chromenes molecular rearrangements, 772–3 oxidation, 119, 137 Chromenones, electrophilic addition, 488 Chromium catalysis electrophilic addition, 552 oxidation, 97–8 Chromones, synthesis, 50–1

Subject Index Cinchonium betaine catalysts, imines, 9 Cinnamyl alcohols, electrophilic addition, 466 CIPE see complex-induced proximity effect Cis-carbonyl epoxides, synthesis, 185–6 Cis-epoxy naphthoquinols, synthesis, 176 Claisen rearrangement, 259, 701–705, 721 Cobalt catalysis aromatic substitution, 270, 291–3, 299, 301, 307–8, 318 carbanions, 442 carbenes, 230 electrophilic addition, 495–6, 545–8 elimination reactions, 457 oxidation, 99–100, 121, 137–9, 150 reduction, 163–4, 170–1 Complex-induced proximity effect (CIPE), 461 Condensation reactions aldehydes and ketones, 38–41 hydrazones, 24–6 Cope elimination, oxidation, 118–19 Cope rearrangements, 699–702, 733 Copper catalysis aromatic substitution, 250–54, 266–9, 273–4, 279, 282–4, 295, 308–311, 314–19, 322–3 carbanions, 429–31, 439–40 carbenes, 207–9, 226–7 cycloaddition, 668–9, 674, 682, 684, 688–9 electrophilic addition, 485, 492, 532–40 elimination reactions, 454–5 molecular rearrangements, 706, 728–30 nucleophilic addition, 627–30 nucleophilic aliphatic substitution, 371–2, 375–6, 379–80 oxidation, 100–103, 146–50, 154–5 Corannulene cations, electronic effects and structure, 338–9 Coumarins, molecular rearrangements, 770, 772 Criegee intermediates aldehydes and ketones, 52 oxidation, 131 Cross-dehydrogenative coupling (CDC) aldehydes and ketones, 52 oxidation, 99–101, 103–4, 140, 143, 153–6 Cubyl cations, 356 Cumulenes, reactions, 7–8 Curcumins, oxidation, 157–8 Curtius rearrangement, 752, 754 Cyanations, aldehydes and ketones, 47–8 1-Cyanocyclopropane-1-carboxylates, intramolecular catalysis, 83–4 2-(2-Cyanoethyl)aziridines, molecular rearrangements, 708 Cyanohydrins, synthesis, 47–8 Cyanomethylation, aldehydes and ketones, 61 Cyanosilylation, aldehydes and ketones, 47–8 Cyclic 2-alkenyl aziridines, synthesis, 389, 429 Cyclic (alkyl)(amino) carbenes (CAAC), 222, 226–7 Cyclic amines, oxidation, 121 Cyclic anhydrides, carbocations, 343

839 Cyclic diarylmethanes, aromatic substitution, 257 Cyclic enol ethers, nucleophilic addition, 623 Cyclic ethers electrophilic addition, 575 nucleophilic aliphatic substitution, 381–6, 383 oxidation, 118 Cyclic ketiminium species, synthesis and reactions, 9–10, 17 Cyclic ketones, oxidation, 100 Cyclic silyl ketene acetals, nucleophilic addition, 587–9 Cyclic sulfamidates, nucleophilic aliphatic substitution, 417 Cyclic sulfoximines, molecular rearrangements, 697–8 Cyclic thioureas, oxidation, 117–18 Cyclic tosylhydrazones, reactions, 17 Cyclizations aldehydes and ketones, 2–4, 56–9 aromatic substitution, 256, 274–8, 289–92, 296, 299–301 carbanions, 426 carbenes, 206–212, 223–4, 231–2 carbocations, 348–63 electrophilic addition, 466–76, 480–83, 486–8, 493–5, 504–510, 521–33, 537–9, 544–9, 557–78 elimination reactions, 457 5-endo-dig cyclization, 486, 493, 545, 563, 565–70, 593, 713–14 6-endo-dig cyclization, 474, 486, 488, 493, 509–510, 537–8, 564–5, 570, 713–14, 734–5, 765 7-endo-dig cyclization, 483, 732 5-endo-trig cyclization, 457, 476, 480–1 6-endo-trig cyclization, 466, 468, 562–3, 571–3 5-exo-dig cyclization, 129, 150, 474, 494, 530–1, 557, 561, 571, 584, 621–2, 713–14, 737, 765 6-exo-dig cyclization, 561, 570–1 4-exo-trig cyclization, 587 5-exo-trig cyclization, 566–70, 573, 713–14 6-exo-trig cyclization, 525, 567, 640 hydrazones, 24–7 molecular rearrangements, 712–14, 730–44, 749–57, 765 nucleophilic addition, 581–4, 587–93, 597, 607–9, 621–5, 639–40 oxidation, 123–7, 129, 137, 150 Cycloaddition, 661–96 aldehydes and ketones, 5 aromatic substitution, 261–2, 284 carbanions, 431–2 carbenes, 204, 207–8, 218, 220–1, 225–7, 231 carbocations, 340, 349, 352–3, 358, 364 [1,2]-cycloadditions, 143, 204 [2+2]-cycloadditions, 18, 340, 458, 661, 664–6 [2+2+1]-cycloadditions, 661 [2+2+2]-cycloadditions, 661, 684–8, 737

840 Cycloaddition (continued) [3+2]-cycloadditions, 21, 24, 204, 220, 227, 284, 352–3, 364, 666–74, 706–7, 725, 734, 742, 749 [3+3]-cycloadditions, 208, 688–9 [4+1]-cycloadditions, 207, 218, 220–1, 239, 661, 689 [4+2]-cycloadditions, 104, 225, 231, 358, 564, 661, 663, 674–84, 732 [4+3]-cycloadditions, 661, 689–91 [5+2]-cycloadditions, 158, 661, 663, 691 [8+2]-cycloadditions, 707 electrophilic addition, 564 germylenes, 239 imines, 18–21 miscellaneous, 684–92 molecular rearrangements, 706–8, 725, 732–4, 737, 742, 749 oxidation, 104, 117–18, 143, 158 oximes, 24 1,3-Cycloalkadienes, synthesis, 454 Cycloalkenes, oxidation, 118–19 Cyclobutanes, cycloaddition, 664–5 Cyclobutenes, synthesis, 108–9 Cyclobutenones, reactions, 18 Cyclohepta[b]indoles, molecular rearrangements, 715 Cyclohepta-1,2,4,6-tetrenes, synthesis, 340 Cyclohexadienones, nucleophilic addition, 579, 581 1,3-Cyclohexanediones, nucleophilic addition, 603–4 Cyclooctatetraenes, molecular rearrangements, 706 Cyclopentadienes, cycloaddition, 675–6, 679, 691 Cyclopentene-fused chromenes, molecular rearrangements, 772–3 Cyclopropanation carbenes, 206–7, 212, 214–15 molecular rearrangements, 718–19, 768 nucleophilic addition, 595–6 nucleophilic aliphatic substitution, 392–3 Cyclopropane indanones, molecular rearrangements, 715 Cyclopropanes aromatic substitution, 271–2 carbanions, 440 carbocations, 338, 354–7 cyclization reactions, 56–7 cycloaddition, 688, 690–1 electrophilic addition, 490–1 molecular rearrangements, 713 nucleophilic aliphatic substitution, 384–5, 391–3 Cyclopropenes electrophilic addition, 574 nucleophilic addition, 639 nucleophilic aliphatic substitution, 392 Cyclopropenium ions, 339–40, 355–6 Cyclopropenones, aromatic substitution, 290–1 Cyclopropenylidenes, carbenes, 203–4 Cyclopropyl bromides, nucleophilic addition, 639 Cycloreversion, 450–1

Subject Index Cycloselenenylation, electrophilic addition, 481 Cysteine, aromatic substitution, 251–2 Cytochrome P450, oxidation, 117

D DCC see dynamic covalent chemistry Decarboxylation, elimination reactions, 451 Deep eutectic solvents (DES) cycloaddition, 674 reactions of imines, 21 Dehydrogenation, oxidation reaction mechanism, 111–13 Dehydrogenative cross-coupling, synthesis of imines, 8 Dehydrophenylalanines, synthesis, 143 Deltic guanidinium ions, 339 Density functional theory (DFT) addition reactions, 46–7 aldol and related reactions, 28–9, 33, 36 aromatic substitution, 248–9, 262–3, 268–70, 274–82, 301–2, 307–8, 311 carbanions, 425, 430, 442–3 carbenes, 203–4, 206, 214–19, 225–6, 231 carbocations, 357–8 carboxylic acids and derivatives, 73, 77 electrophilic addition, 483–4, 496–7, 502–3, 508, 513, 517–22, 529–30, 535–6, 544–7, 554, 564, 567, 575 elimination reactions, 450–1, 459–60 formation and reactions of acetals, 2 formation and reactions of imines, 10, 17–18, 21 glucosides, 7 hydrazones, 27 molecular rearrangements, 702–3 nitrenes, 237–8 nucleophilic addition, 578, 582–3, 592–3, 612, 622, 640 nucleophilic aliphatic substitution, 386, 403–4, 406–411 other reactions of aldehydes and ketones, 61–2 oxidation, 98, 105–7, 110–13, 118, 131–3, 137–9, 150–1, 155–9 oximes, 23 reduction, 159–60, 163, 168–70, 175–6, 180–82, 186–9 reduction reactions, 54–5 Deoxyfluorination, aromatic substitution, 249–50 DES see deep eutectic solvents DFT see density functional theory DHP see 3,4-dihydro-2H-pyran Diacylglycine esters, synthesis, 730 Dialkoxycarbenes, 220–1 Dialkylsilylenes, reactions with carboxylic acids and derivatives, 76 Diarylalkanes, synthesis, 180, 271, 288 Diaryl alkynes, synthesis, 298 2,5-Diaryl fulleropyrrolidines, cycloaddition, 668 Diarylhydrazines, molecular rearrangements, 699, 705 Diaryliodonium salts

841

Subject Index carbocations, 360 elimination reactions, 455 Diaryl ketones reduction, 177–8 synthesis, 309–311 Diarylmethylamines, reduction, 170 3,3-Diaryloxetanes, synthesis, 272 Diarylphosphine oxides, electrophilic addition, 578 Diarylphosphonates, synthesis, 224 Diaryl sulfides, aromatic substitution, 266 1,4-Diazabutatrienes, cycloaddition, 673 Diaza-Wittig process, elimination reactions, 458 Diazirines, synthesis, 202 Diazoacetamides, cycloaddition, 672 Diazocarboxylates, cycloaddition, 689–90 Diazo compounds carbenes, 215–16 molecular rearrangements, 725 α-Diazo-β-dicarbonyls, carbocations, 344 Diazo ketoesters, aromatic substitution, 295 Diazomethanes, carbenes, 203–4 Dibenzenesulfonimides, aromatic substitution, 265 Dibenzosiloles, synthesis, 114 Dibenzothiophene dioxides, aromatic substitution, 257 Dibutyl vinylboronate, cycloaddition, 676 𝛼,α-Dichloro-β-aminonitriles, synthesis, 12 Dicyclopentadien-1,8-one, elimination reactions, 452 Diels–Alder reaction carbocations, 364 cycloaddition, 661–2, 674–84 molecular rearrangements, 670–3, 708–9, 765 Dienes cycloaddition, 679–80, 682 electrophilic addition, 490–1, 503–4 gem-Difluoroalkenes, nucleophilic aliphatic substitution, 372–3, 378–9 Difluorocarbenes, 205–6 Dihydrobenzofurans electrophilic addition, 516 synthesis, 426 3,4-Dihydrocoumarins, synthesis, 224 Dihydrofurans, nucleophilic addition, 635 Dihydroisoquinolines molecular rearrangements, 740–1 synthesis, 110, 437, 565 2,3-Dihydroisoxazoles, cycloaddition, 671 1,2-Dihydronaphthalenes, electrophilic addition, 472 5,6-Dihydropyrazolo[5,1-a]isoquinolines, synthesis, 573 1,6-Dihydropyridazines, synthesis, 749 3,4-Dihydroquinazoline-2-thiones, synthesis, 579–80 2,3-Dihydroquinazolinones, synthesis, 110 Dihydroquinolines electrophilic addition, 571 nucleophilic addition, 620 oxidation, 117

cis-3,4-Dihydroquinolines, synthesis, 301 3,4-Dihydro-2H-pyran (DHP), electrophilic addition, 484 Diiminoisoindolines, synthesis, 294 2,3-Diketoesters, molecular rearrangements, 765–6 Diketones, synthesis, 592 Dimethylallyl malonate, nucleophilic addition, 587 Dioxabicyclo[2.2.2]octanes, synthesis, 2 Dioxanes, synthesis, 385 Dioxazolones, aromatic substitution, 270 1,2-Dioxolanes, synthesis, 472 1,3-Dioxolanes, synthesis, 581–2 2,3-Dioxopyrrolidines, cycloaddition, 679 Diperiodatocuprate(III) (DPC), oxidation, 103 Diphenylines, molecular rearrangements, 699 1,1-Disubstituted alkenes, molecular rearrangements, 715–16 1,3-Disubstituted imidazo[1,5-a]pyridines, synthesis, 53 2,3-Disubstituted indoles molecular rearrangements, 706 synthesis, 295–6 3,5-Disubstituted 2-isoxazolidines, synthesis, 504–5 3,4-Disubstituted 2-naphthylamines, synthesis, 494 3,3′ -Disubstituted oxindoles, nucleophilic addition, 616 Dithiocarbamates, nucleophilic addition, 612 Diynes carbocations, 360 cycloaddition, 684–6 electrophilic addition, 549–50, 561 nucleophilic addition, 628 DPC see diperiodatocuprate(III) Duff reaction, aromatic substitution, 279 Dynamic covalent chemistry (DCC), 3

E Electrocyclization, molecular rearrangements, 706 Electrophilic addition, 465–578 bromine, 465–70 carbon electrophilic additions, 487–8 chlorine, 470–1 fluorine, 476–80 halogenation and related reactions, 465–80 hydrogen halides and other Brønsted acids, 483–6 initiated by metals and metal ions as electrophiles, 489–574 aluminium, 552–3 bismuth, 574 boron, 489–95 chromium, 552 cobalt, 545–8 copper, 532–40 gallium, 573 germanium and tin, 542 gold, 553–68 indium, 573 iridium, 528–31 iron, 542–5 lanthanides, 574

842 Electrophilic addition (continued) magnesium, 552 manganese, 572–3 nickel, 548–50 osmium, 531 palladium, 498–514 platinum, 514–15 rhodium, 518–28 ruthenium, 516–18 silicon, 495–8 silver, 568–72 titanium, 550–2 zinc, 541–2 iodine, 471–6 Lewis acid mediated additions, 486–7 miscellaneous, 575–8 nitrogen electrophilic additions, 488 oxygen electrophilic additions, 489 sulfur and selenium electrophilic additions, 480–3 Electrophilic substitution alkylation and acylation, 270–80 aromatic substitution, 262–82 bond formation to O, S, N, P, 264–70 carbanions, 443–5 halogenation, 262–3 nitration, 264 other reactions, 280–2 oxidation, 129–30, 140–1 Electrophilic trifluoromethylation, hydrazones, 24 Elimination reactions, 449–62 acid derivatives, 451–2 cycloreversion, 450–1 E1cB and E2 mechanisms, 449 in synthesis, 452–9 other reactions, 459–61 oxygen derivatives, 452 pyrolytic reactions, 450–52 solvolytic reactions, 450 Enallenes, oxidation, 108–9 Enals, nucleophilic addition, 596 Enamides, electrophilic addition, 472 Enamines, nucleophilic addition, 593–5, 600, 614–15 Enaminones, carbocations, 343 Enecarbamates, synthesis, 705–6 Eneynyl ketones, carbenes, 207–8 5-Enoglycopyranosides, reduction, 161 Enolates carbanions, 424–8 reactions, 48–51 Enol carbamates electrophilic addition, 519–20 nucleophilic addition, 632 Enoldiazoacetamides carbenes, 208 reactions, 13 Enol ethers, cycloaddition, 665 Enolization, aldehydes and ketones, 48–51 Enones, nucleophilic addition, 594–5, 606, 628–32 Enoximes, synthesis, 624

Subject Index Enynamides electrophilic addition, 564 reactions, 13–14 Enynes carbocations, 360–1 cycloaddition, 686 electrophilic addition, 493–4, 518, 525, 538, 568 molecular rearrangements, 739–40 nucleophilic addition, 585, 592 synthesis, 185–6 Enynones carbocations, 345 cycloaddition, 671 Enzo[𝛼]quinolizine-2-ones, synthesis, 13 Epoxidation elimination reactions, 455–6 hydrazones, 24 oxidation, 105, 120, 134 Epoxides carbocations, 342 nucleophilic aliphatic substitution, 379, 381–5 reduction, 184 Epoxy naphthoquinols, synthesis, 176 Esters aminolysis reactions, 75–6 intermolecular catalysis and reactions, 73–5 phosphoric acids and derivatives, 82 solvolysis reactions, 73–5 transesterification, 73 Ethers, carbenes, 230 Ethoxyiodination, electrophilic addition, 472 3-Ethoxythiophene, aromatic substitution, 247–8 Ethyl diazoacetate, carbenes, 206 Ethylphosphonates, synthesis, 184–6 Ethynylstyrenes, electrophilic addition, 552–3 Europium catalysis, reduction, 188

F Farnesyl diphosphate (FFP), carbocations, 364 Ferrocenes carbocations, 340–1, 363 cycloaddition, 667 electrophilic addition, 524 molecular rearrangements, 737 nucleophilic addition, 626, 629 FFP see farnesyl diphosphate Flash vacuum pyrolysis, molecular rearrangements, 715 Flavonoids, oxidation, 121, 137 FLP see frustrated Lewis pair Fluorene-benzoxazines, synthesis, 300 Fluorinated nitrones, molecular rearrangements, 755–6 Fluorination carbenes, 205–6 electrophilic addition, 476–80 4-Fluoro-1,3-benzoxazepines, synthesis, 768 Fluorobenzyne, aromatic substitution, 258 α-Fluoro-indanones, reactions, 50 2-Fluoroindoles electrophilic addition, 570

843

Subject Index synthesis, 457 Fluorolactonization, electrophilic addition, 477–8 Friedel–Crafts reaction aldol and related reactions, 30 aromatic substitution, 271–5, 278–9, 281, 300, 308 carbanions, 445 carbocations, 341, 344–5, 350–1, 355, 360 imines, 17 molecular rearrangements, 752, 755 Friedländer synthesis, aldehydes and ketones, 40–1 Fries rearrangement, aromatic substitution, 261 Frustrated Lewis pair (FLP) catalysis aldol and related reactions, 28 imines, 15–16 oxidation, 159 reduction, 54, 163 Fullerenes cycloaddition, 665, 668 nucleophilic addition, 629 Furanones carbanions, 426–7 nucleophilic addition, 612 synthesis, 58 Furans, cycloaddition, 689–90 Furfural, synthesis, 188–9 Furfural imines, carbenes, 206 3-Furylphthalides, molecular rearrangements, 773, 775 Fused benzimidazoles, synthesis, 186–7 1,7-Fused indolines, synthesis, 302 5,5-Fused tetrahydrofurobenzofurans, synthesis, 2 3,4-Fused tricyclic indoles, synthesis, 300

G Gallium catalysis, electrophilic addition, 573 2-Geranylphenols, electrophilic addition, 468 Germanium catalysis, electrophilic addition, 542 Germylenes, 238–9 Glucosamine, aromatic substitution, 254 Glucosides, reactions, 5–7 Glucuronides, reduction, 162 Glycosyl cations, 346 Gold catalysis aromatic substitution, 289, 314–18, 322 carbanions, 439 carbenes, 217–20, 231 carbocations, 340, 342, 350–52, 357 cycloaddition, 686, 688 electrophilic addition, 494, 553–68 molecular rearrangements, 730–9 nucleophilic addition, 638–9 oxidation, 105, 156 Grignard reagents aldehydes and ketones, 42–3 carbanions, 434–5 imines, 21 molecular rearrangements, 739–40 nucleophilic aliphatic substitution, 371, 378–81, 385–6

H Hafnium catalysis carbocations, 347 molecular rearrangements, 739 Hajos–Parrish-type ketones, synthesis, 428 Haloalkynes, electrophilic addition, 484–5, 537 Halocyclization, electrophilic addition, 466–9, 473–6, 573 Halogenation aldehydes and ketones, 50–1 aromatic substitution, 262–3 bromine, 465–70 chlorine, 470–1 electrophilic addition, 465–80 fluorine, 476–80 iodine, 471–6 oxidation, 121–30 Hantzsch esters, reduction, 178–9 HAT see hydrogen atom transfer Hauser–Kraus reaction, 752–5 HBD see hydrogen bond donors HDO see hydrodexygenation Heck–Matsuda reaction, aromatic substitution, 288–9 Heck reaction aromatic substitution, 291–2, 297 elimination reactions, 450 nucleophilic addition, 631 oxidation, 107 Heck–Tsuji domino reaction, electrophilic addition, 504 Henry reaction aldol and related reactions, 32–3 carbanions, 430–1 Heterobiaryls, synthesis, 113 1,5-Hexadiene-2-carboxaldehydes, molecular rearrangements, 699–701 Hiyama–Denmark reaction, aromatic substitution, 304–5 HMF see 5-hydroxymethylfurfural Homocysteine, aromatic substitution, 251–2 Hosomi–Sakurai reaction, aldehydes and ketones, 34 HPNP see 2-hydroxypropyl-p-nitrophenyl phosphate Hydrazinodihydrofurans, synthesis, 614 Hydrazonamides, carbenes, 204 Hydrazones, 24–7 carbenes, 212, 217 cycloaddition, 669–70 synthesis, 542–3 β-Hydride elimination aromatic substitution, 289, 291–7 elimination reactions, 457, 459 oxidation, 107, 111, 132, 156, 158 Hydroacylation aldehydes and ketones, 45–7 electrophilic addition, 517, 519–20, 548 Hydroalkoxylation, electrophilic addition, 513, 545–6

844 Hydroallylation, electrophilic addition, 533 Hydroamidation, electrophilic addition, 567 Hydroamination aldehydes and ketones, 35 electrophilic addition, 499–500, 519, 532, 536, 538–9, 553–4, 564–5, 570–1, 574 molecular rearrangements, 701 nucleophilic addition, 639 Hydroarylation, electrophilic addition, 501, 516, 529–30, 535, 554 Hydroboration aldehydes and ketones, 45–7 electrophilic addition, 489–95 nucleophilic addition, 627, 631 reduction, 160–1 Hydrobromination, electrophilic addition, 535–6 Hydrocarbomethoxylation, electrophilic addition, 498 Hydrocarboxylation carbanions, 438 electrophilic addition, 549–50 Hydrodexygenation (HDO), 175–6 Hydrofluorination, electrophilic addition, 537, 568 Hydroformylation, electrophilic addition, 501–2, 518, 520 Hydrogenation, 162–72 aldehydes and ketones, 15–16, 54–5 mechanisms and catalysts, 163–72 reviews, 162–3 Hydrogen atom transfer (HAT) oxidation, 137 reduction, 164–5, 171 Hydrogen bond donors (HBD), oxidation, 156 Hydrogen halides, electrophilic addition, 483–6 Hydrogenolysis, carbenes, 230 Hydrolysis carboxylic acids and derivatives, 84–90 phosphoric acids and derivatives, 91–2 Hydrophosphination, nucleophilic addition, 585 Hydrophosphonylation aldehydes and ketones, 45–7 imines, 19 Hydropyridazines, cycloaddition, 688–9 Hydroquinoline-2-carboxylates, synthesis, 38 Hydroquinones, oxidation, 107, 110–11 Hydrosilylation aldehydes and ketones, 45–7 electrophilic addition, 495–8 nucleophilic addition, 586 reduction, 180–2 Hydrosulfonylation, electrophilic addition, 486 Hydrosulfoximation, electrophilic addition, 561 Hydrothiolation carbocations, 342 electrophilic addition, 486, 553 Hydrovinylation, molecular rearrangements, 730 Hydroxamates, molecular rearrangements, 752, 754 Hydroxamic acids, molecular rearrangements, 756 1-Hydroxy-2-acylcarbazoles, synthesis, 744 Hydroxyalkylation, aromatic substitution, 270–1

Subject Index 4-Hydroxybiphenyl-2-carboxylates, synthesis, 144 2′ -Hydroxychalcones, cycloaddition, 679–80 4-Hydroxycoumarins, nucleophilic addition, 620–1 3-Hydroxy-2,3-dihydrobenzofurans, synthesis, 46 Hydroxy enones, nucleophilic addition, 581 3-Hydroxyisoxazoles electrophilic addition, 563 molecular rearrangements, 732–3 Hydroxyketones, electrophilic addition, 531 β-Hydroxy-γ-lactams, synthesis, 169 5-Hydroxymethylfurfural (HMF), oxidation, 151 2-Hydroxypropyl-p-nitrophenyl phosphate (HPNP), 92 3-Hydroxy-2-pyridones, cycloaddition, 677 3-Hydroxy 3-substituted oxindoles, molecular rearrangements, 744, 764

I IBEX see (1-isobutoxy ethyl) carbodithiolate Ichikawa reaction, 755 IL see ionic liquids Imidamides, carbenes, 209–212 Imidazoles biologically significant reactions, 94 molecular rearrangements, 749–50 synthesis, 48, 57–8 Imidazolidine-2-thiones, synthesis, 483 Imidazolines, synthesis, 11 Imidazoloindolines, cycloaddition, 671 Imidazolopyridine, synthesis, 471 Imidazolylidenes, carbenes, 224–5 Imidazopyridines, synthesis, 53, 147–9, 256, 579 Imidazopyrrolopyrazines, synthesis, 215 Imines electrophilic addition, 532, 544 Mannich, Mannich-type, and nitro-Mannich reactions, 10–14 molecular rearrangements, 718–19, 752 other name reactions, 14–15 other reactions, 20–2 other stereoselective reactions, 18–20 reduction, 178–80 stereoselective allyl-, aryl-, alkenyl-, and alkynyl-ations, 17 stereoselective hydrogenation and other reductive processes, 15–16 synthesis and general chemistry, 8–10 Iminiums, nucleophilic addition, 595–9, 615 2-Imino[1,3]benzothiazines, synthesis, 579–80 Iminoisocoumarins, synthesis, 537–8 4-Imino tetrahydropyridine, synthesis, 730 Indanediones, nucleophilic addition, 594 Indanones formation and reactions, 51 nucleophilic addition, 631 Indazoles electrophilic addition, 484 synthesis, 289–90 Indenes, synthesis, 220, 474

Subject Index Indenones, synthesis, 301 3-(1-Indenyl)indoles, synthesis, 713–14 Indium catalysis, electrophilic addition, 573 Indole acetamides, electrophilic addition, 535 Indole-fused dibenzooxazepines, synthesis, 252, 761 Indole glucosinolates, molecular rearrangements, 756 Indolepiperazinones, synthesis, 374, 405 Indoles addition reactions, 42 aromatic substitution, 269, 273–5, 278–80, 295–6, 300, 316–19 carbanions, 441 carbenes, 209–212, 215–16, 218, 220, 235 carbocations, 343, 350–52 cycloaddition, 667, 671 electrophilic addition, 472, 507, 515, 535, 545, 554–5, 561–2 elimination reactions, 456–7 molecular rearrangements, 706–7, 713–14, 737, 739, 769–70 nitrenes, 237–8 nucleophilic aliphatic substitution, 374, 412 oxidation, 99–100, 139, 146–7 reduction, 169–70 Indolines aromatic substitution, 257, 274, 292, 294–5, 302 carbanions, 429 electrophilic addition, 516, 545 molecular rearrangements, 712 synthesis, 169–70 Indolinones cycloaddition, 668–9 nucleophilic addition, 604 Indolizidines carbocations, 352 synthesis, 556–7, 737, 769–70 Indolizines, synthesis, 539 Indoloazepinones, synthesis, 538 Indolones nucleophilic addition, 631 synthesis, 139 Indolopiperazinones, synthesis, 235 Indoloquinolines, synthesis, 269 2-Indolylmethanols, aromatic substitution, 256–7 Indolyl pyrroloindolines, synthesis, 314 3-Indolylynamides, electrophilic addition, 559–60 Iodination, electrophilic addition, 471–6 Iodine, oxidation, 121–30 Iodobenzene, aromatic substitution, 250 2-Iodobiphenyls, aromatic substitution, 285–6 Iodolactonization, electrophilic addition, 476 Iodonium ions aldehydes and ketones, 6 molecular rearrangements, 728 Ionic liquids carbocations, 339 elimination reactions, 450 nucleophilic aliphatic substitution, 400–1

845 Ionic liquids (IL), carboxylic acids and derivatives, 73–5 Ipso-borylated products, aromatic substitution, 255 Iridium catalysis aromatic substitution, 268–70, 281–2, 287 carbanions, 442 carbenes, 215 cycloaddition, 688–9 electrophilic addition, 528–31 elimination reactions, 456 molecular rearrangements, 739 nucleophilic addition, 635 nucleophilic aliphatic substitution, 373–4 oxidation, 110, 129–30 reduction, 166–8, 180 Iron catalysis aromatic substitution, 280 carbenes, 230 carbocations, 358 electrophilic addition, 542–5 elimination reactions, 460 molecular rearrangements, 739–40 nucleophilic aliphatic substitution, 379–81 oxidation, 115–16, 143 reduction, 165, 174, 181, 185 Isatin hydrazones, molecular rearrangements, 756–7 Isatins addition reactions, 44–5 carbenes, 233 (1-Isobutoxy ethyl) carbodithiolate (IBEX), carbocations, 341 1-Isochromanones, synthesis, 223 Isochromenes, nucleophilic addition, 582, 606 Isocoumarins, synthesis, 509–510 α-Isocyanato allylboronic acids, molecular rearrangements, 705–6 Isocyanides, cycloaddition, 673 Isoindolines, synthesis, 276, 311–13 Isoindolin-1-one-3-phosphonates, synthesis, 13 Isoindolinones, synthesis and reactions, 11–12 β-Isophorone, oxidation, 151 Isoquinoline N-oxides, cycloaddition, 688 Isoquinolines aromatic substitution, 274, 296–7 electrophilic addition, 573 molecular rearrangements, 715, 722 nucleophilic addition, 639–40 synthesis, 22–3, 104 Isoquinolinones, synthesis, 211, 213, 215 3-Isothiocyanatooxindoles, nucleophilic addition, 601 Isoxazole-3-ones, molecular rearrangements, 732–3 Isoxazoles aromatic substitution, 269, 280, 288 cycloaddition, 672–3 Isoxazolidines cycloaddition, 672 molecular rearrangements, 766 Isoxazolidin-5-ols, molecular rearrangements, 707

846 Isoxazolines elimination reactions, 451 reduction, 167 Isoxazolinofullerenes, elimination reactions, 451 Isoxazolones, elimination reactions, 456

J Jorgensen–Hayashi-type amines, formation and reactions of imines, 10

K Kabachnik–Fields reaction, aldehydes and ketones, 13 Ketenes carbocations, 340 cycloaddition, 665 reactions, 7–8 Ketenimines, molecular rearrangements, 730, 740 Ketimines cycloaddition, 667 electrophilic addition, 546 Ketiminium species, carbanions, 439 γ-Ketoaldehydes, carbocations, 356 Keto alkenes, electrophilic addition, 543–4 α-Ketoamides, synthesis, 144 Ketocarboxamides, synthesis, 312 α-Ketoesters, molecular rearrangements, 718–19, 752, 754 β-Ketoesters carbanions, 441 nucleophilic aliphatic substitution, 374 δ-Keto-imines, reactions, 17 Ketones, 1–70 acetals and related species, 2–5 aldol and related reactions, 27–41 alkynylations, 34–6 allylation and related reactions, 33–4 α-aminations and related reactions, 48 arylations, addition of organometallics, including Grignards, 42–3 asymmetric aldols, 28–30 benzoin and Stetter reactions, 36 carbanions, 428 C–C bond formation and fission, 27–41 cyanohydrins, cyanosilylation, and other cyanations, 47–8 enolization, reactions of enolates, and related reactions, 48–51 glucosides, 5–7 α-halogenation, α-alkylation, and other α-substitutions, 50–1 hydrazones and related species, 24–7 hydrosilylation, hydrophosphonylation, hydroboration, and hydroacylation, 45–7 imine synthesis and general chemistry, 8–10 ketenes and related cumulenes, 7–8 Mannich, Mannich-type, and nitro-Mannich reactions, 10–14 Michael addition, 36–8 miscellaneous condensations, 38–41

Subject Index miscellaneous cyclizations, 56–9 Morita–Baylis–Hillman reaction, 31–2 Mukaiyama aldol, 31 nitrogen derivatives, 8–27 organozincs, 41–2 other addition reactions, 41–8 other aldol-type reactions, 32–3 other name reactions of imines, 14–15 other oxidations and oxidative processes, 52–4 other reactions, 59–62 other reactions of imines, 20–2 other stereoselective reactions of imines, 18–20 oxidation, 100, 135–7, 146–7 oxidation of carbonyl compounds, 51–4 oximes, 22–4 reduction, 160–1, 165–72, 176–9, 182 reduction of carbonyl compounds, 54–6 reviews of aldols and asymmetric catalysis, 27–8 stereoselective allyl-, aryl-, alkenyl-, and alkynyl-ations of imines, 17 stereoselective hydrogenation of imines and other reductive processes, 15–16 synthesis, 276 Wittig and other olefinations, 43–5 β-Ketonitriles, synthesis, 48 β-Ketosulfones, molecular rearrangements, 710 β-Keto sulfoxonium ylides, carbenes, 203 Ketoximes, molecular rearrangements, 751–2 Kinetic isotope effects (KIE) aldehydes and ketones, 7, 48 aromatic substitution, 290, 296 carboxylic acids and derivatives, 80 nucleophilic aliphatic substitution, 370, 393–6 oxidation, 98–104, 110, 113–16, 138–9, 147–53, 158–9 phosphoric acids and derivatives, 95–6 reduction, 174–6, 181–2 Kinugasa reaction, 755–6 Knoevenagel condensation, aldehydes and ketones, 38–9 Koenigs–Knorr glycosylations, aldehydes and ketones, 6 Kulinkovich–de Mejiere reaction, 61

L LAA see L-ascorbic acid β-Lactams carbocations, 340 electrophilic addition, 528 molecular rearrangements, 755–6 Lactones electrophilic addition, 525, 575 molecular rearrangements, 712 nucleophilic addition, 596 oxidation, 130 synthesis, 291 Lanthanum catalysis, electrophilic addition, 574 L-ascorbic acid (LAA), oxidation, 149 Lewis acids cycloaddition, 665, 667, 675–6, 682, 690–1

Subject Index electrophilic addition, 486–7 molecular rearrangements, 712 Lingzhiol, synthesis, 710 Lithium organocatalysis see organolithiums Lossen rearrangement, 756 L-pyranosides, synthesis, 161

M Macrocycles electrophilic addition, 531 molecular rearrangements, 709, 727 nucleophilic addition, 581 Magnesium catalysis electrophilic addition, 552 nucleophilic addition, 624 see also Grignard reagents; organomagnesiums Maleimides cycloaddition, 669, 675–7 nucleophilic addition, 625, 632 Malonate esters, nucleophilic addition, 587 Malonates, nucleophilic addition, 599–601, 612 Manganese catalysis aromatic substitution, 286, 293 electrophilic addition, 572–3 nucleophilic addition, 635 oxidation, 98–9, 133–4, 142–3, 150–1 reduction, 165 Mannich reaction aldehydes and ketones, 10–14 carbanions, 425, 432, 441 MBH see Morita–Baylis–Hillman Meisenheimer complexes, aromatic substitution, 249, 252, 258 Menth-4-en-3-yl sulfoxide, electrophilic addition, 484 MEP see molecular electrostatic potential 2-Mercaptoethanol, oxidation, 105–7 2-Mercaptoethylamine, oxidation, 105–7 Meso-cyclopropyl aldehydes, electrophilic addition, 482 Mesoionic biscarbenes, 222 Mesoionic carbenes (MIC), 226–7, 231 molecular rearrangements, 734, 736 Meso-porphyrinylmethyl carbanion, 424 Metal-free carbenes, structure and reactivity, 202–6 Metallated carbenes, structure and reactivity, 206–220 Metathesis carbenes, 216 electrophilic addition, 491 elimination reactions, 460 molecular rearrangements, 725–8 Methoxybenzene, oxidation, 131 2-Methoxyimidoyl-oxiranes, synthesis, 9 Methoxylation, electrophilic addition, 554–5 Methylaminopyrazole formamidine, oxidation, 105 3-Methylene-1,4-cyclohexadienes, molecular rearrangements, 751 Methylenecyclopropanes, electrophilic addition, 575 3-Methyleneisoindolin-1-ones, synthesis, 21, 311

847 Methylidene γ-lactams, synthesis, 109 4-Methylthiobenzoyl chloride, nucleophilic aliphatic substitution, 399–400 2-Methyquinolines, oxidation, 151 Meyer–Schuster rearrangement, 358, 725, 756–9 MH see Mizoroki–Heck MIC see mesoionic carbenes Michael addition aldehydes and ketones, 36–8 carbanions, 426–7 molecular rearrangements, 757, 759 see also nucleophilic addition Mitsunobu reaction nucleophilic aliphatic substitution, 401 oxidation, 146 Miyaura reaction molecular rearrangements, 719–20 see also Suzuki–Miyaura reaction Mizoroki–Heck (MH) reaction aromatic substitution, 294–5 carbenes, 229 oxidation, 109 Molecular electrostatic potential (MEP), 641 Molecular rearrangements, 697–780 acid promoted, 702–3, 723–5 addition, 725 Alder-ene reaction, 750–1 aromatic substitution, 251–2, 259–61 Bayer–Villiger reaction, 751 Beckmann rearrangement, 751–2 Brook rearrangement, 720–1, 752–4 carbene and nitrene, 722–3 carbenes, 206 carbocations, 350, 356–8, 363–4 Claisen rearrangement, 259 computation, 764–5 Curtius rearrangement, 752, 754 cycloaddition, 706–8 electrocyclic reactions, 706 electrophilic addition, 485, 557, 566 Friedel–Crafts reactions, 752, 755 Fries rearrangement, 261 Hauser–Kraus reaction, 752–5 Ichikawa reaction, 756 Kinugasa reaction, 756–6 Lossen rearrangement, 756 metal-induced reactions, 728–50 copper, 728–30 gold, 730–9 hafnium, 739 iridium, 739 iron, 739–40 palladium, 744–7 platinum, 748 rhodium, 740–5 ruthenium, 744 silver, 748–50 metathesis, 725–8 Meyer–Schuster rearrangement, 358, 725, 756–9 Michael addition, 757, 759

848 Molecular rearrangements (continued) miscellaneous, 765–6 named reactions, 750–1 oxidation, 131–2, 715–17 Pauson–Khand reaction, 760 pericyclic reactions, 697–708 [1,3]-sigmatropic, 697–8 [1,4]-sigmatropic, 699 [2,3]-sigmatropic, 705 [3,3]-sigmatropic, 485, 566, 699–705, 749 [5,5]-sigmatropic, 705 phosphorus, boron, sulfur, and silicon, 717–22 Piancatelli rearrangement, 759–60 pinacol rearrangement, 363, 760 radical, 714 Rautenstrauch rearrangement, 350 rearrangement, 708–713 ring expansion, ring opening, and ring closing, 712–14 Schmidt reaction, 761 semipinacol rearrangement, 358, 710 Smiles rearrangement, 260, 761 Sommolet–Hauser rearrangement, 761 Stevens rearrangement, 762 Suzuki–Miyaura reaction, 762–3 thermal, 715 Ugi reaction, 763 von Auwers reaction, 751 Wagner–Meerwein rearrangement, 356–7, 711–13, 747 Wittig reaction, 763–4 Wolff rearrangement, 206 ylide, 727–8 Moller–Plesset perturbation theory (MP2), 7 Molybdenum catalysis oxidation, 105–6 reduction, 176, 181 Morita–Baylis–Hillman (MBH) reaction/products aldehydes and ketones, 31–2 carbanions, 430, 432 cycloaddition, 667 electrophilic addition, 565 elimination reactions, 457 nucleophilic addition, 609–610, 631 nucleophilic aliphatic substitution, 372, 376, 379 reactions of imines, 14–15 Morpholine, electrophilic addition, 479–80 MP2 see Moller–Plesset perturbation theory Mukaiyama aldols, formation and reactions, 31 Mukaiyama–Michael reaction, nucleophilic addition, 588, 622 Mumm rearrangement, 730

N N-acetyl indoles, electrophilic addition, 484 N-acyl ketimines, synthesis, 457 N-alkoxylactams, electrophilic addition, 527 N-alkoxy-substituted benzo[1,4]oxazepines, synthesis, 252 N-alkyl maleimides, nucleophilic addition, 625

Subject Index N-alkylpyrroles, oxidation, 103–4 N-alkynylated sulfoximines, electrophilic addition, 486 N-allyl α-amino nitriles, nucleophilic addition, 609 Naphthalenes, molecular rearrangements, 715 2-Naphthalenones, synthesis, 287 Naphthofurans, synthesis, 486 2-Naphthols, molecular rearrangements, 712 Naphthoquinones, molecular rearrangements, 752–5 1,8-Naphthyridines reactions, 35 reduction, 168–9 synthesis, 536 N-aryl hydroxamates, aromatic substitution, 260 N-aryl-3-hydroxyisoindolinones, reactions, 11–12 Native chemical ligation (NCL), 90 Natural bond orbital (NBO) charges, 460 Nazarov reaction, carbocations, 350 NBO see natural bond orbital N-(2-Bromobenzoyl)indoles, electrophilic addition, 514 N-bromosuccinimide (NBS), aromatic substitution, 263 NBS see N-bromosuccinimide NBSH see 2-nitrobenzenesulfonylhydrazide N-chiral amine oxides, synthesis, 134–5 N-chlorosuccinimide (NCS) aromatic substitution, 266 oxidation, 135 NCL see native chemical ligation NCS see N-chlorosuccinimide Negishi coupling, aromatic substitution, 319–20 Neighbouring group participation, carboxylic acids and derivatives, 83–7 Neodymium catalysis, aromatic substitution, 299–300 N-fluorobenzenesulfonimide (NFSI), carbanions, 444–5 N-fluorosuccinimide, aromatic substitution, 263 NFSI see N-fluorobenzenesulfonimide N-heterocyclic carbenes (NHC) aldol and related reactions, 33–4, 36 aromatic substitution, 254–5, 286–8, 293–5, 305, 308, 315–18 as ligands, 226–31 carbanions, 438–9, 443 chiral systems, 231–6 cyclization reactions, 58 cycloaddition, 691 DFT analysis methods, 225–6 elimination reactions, 453 formation and reactions of acetals, 5 molecular rearrangements, 714 nucleophilic addition, 606, 622, 624–5 nucleophilic aliphatic substitution, 371–2, 375–6 other reactions of aldehydes and ketones, 59–60, 62 oxidation, 99, 139, 155 reactions of imines, 14–15, 18, 21 reactivity, 223–5

Subject Index reduction, 177, 180–2 structure, 220–2 Nickel catalysis aromatic substitution, 250–1, 283–5, 293–4, 305–7 carbanions, 442–3 carbenes, 229–30 cycloaddition, 667 electrophilic addition, 548–50 elimination reactions, 453 molecular rearrangements, 720–1 nucleophilic addition, 622 nucleophilic aliphatic substitution, 374, 377–8 oxidation, 99, 155 reduction, 163, 174–5, 180–1, 184 N-iodosuccinimide, aromatic substitution, 262–3 Nitration, aromatic substitution, 264 Nitrenes, 201, 236–8 aromatic substitution, 267, 269 electrophilic addition, 550–1 molecular rearrangements, 722–3, 752 Nitrile oxides, cycloaddition, 672–3 Nitriles cycloaddition, 688 reduction, 173 Nitrile ylides, molecular rearrangements, 730 Nitrilimines, cycloaddition, 688 2-Nitroalcohols, reduction, 162 γ-Nitroaldehydes, synthesis, 50 Nitroalkanes nucleophilic addition, 586 nucleophilic aliphatic substitution, 416 oxidation, 129 Nitroalkenes carbanions, 426–8 cycloaddition, 675–6 elimination reactions, 451 molecular rearrangements, 752–5 nucleophilic addition, 612–17, 620–2 reduction, 167 synthesis, 118 2-Nitroallylic acetates, nucleophilic addition, 617, 622 Nitroarenes, aromatic substitution, 256 Nitrobenzene, reduction, 187 2-Nitrobenzenesulfonylhydrazide (NBSH), reduction, 184–6 Nitroenynes, nucleophilic addition, 620–1 Nitrogen ylides aromatic substitution, 259–60 molecular rearrangements, 762 3-Nitroindoles, nucleophilic addition, 612 γ-Nitro ketones, nucleophilic addition, 602 Nitro-Mannich reactions, aldehydes and ketones, 10–14 Nitro-Michael addition, carbanions, 426–7 Nitrones cycloaddition, 672, 688 electrophilic addition, 522 nucleophilic addition, 638

849 Nitrone ylides, hydrazones, 27 Nitrosoallenes, nucleophilic addition, 624 Nitrosobenzenes, molecular rearrangements, 768–9 α-Nitrosodihydrofurans, synthesis, 757, 759 Nitroxyl phosphanes, molecular rearrangements, 717–18 N-linked benzamidines, molecular rearrangements, 768 N-methyl indoles, aromatic substitution, 317 Non-classical cations, 348 Norbornene derivatives, electrophilic addition, 469, 491 2-Norbornyl cations, 348 N-propargyl pyrrole hydrazones, electrophilic addition, 565 N-substituted indoles, oxidation, 122 N-sulfonyl aldimines, reactions, 16 N-sulfonylalkenylamides, oxidation, 109 N-sulfonyl arylaldimines, synthesis, 8 N-sulfonyl-1,2,3-triazoles, aromatic substitution, 276 N-tert-butylsulfonyl-α-amido silanes, reactions, 19 N-tosylaziridines, nucleophilic aliphatic substitution, 387–8 Nucleophilic addition, 578–641 carbenes, 606, 622 enamines, 593–5, 600, 614–15 hydrogen halides and other Brønsted acids, 484 iminiums, 595–9, 615 miscellaneous, 639–41 organometallics to activated double bonds, 624–39 boron, 625–7 copper, 627–30 gold, 638–9 iridium, 635 lithium, 624 magnesium, 624 manganese, 635 palladium, 630–1 rhodium, 632–5 ruthenium, 631–2 titanium, 635–7 zinc, 637–8 other catalysts, 607–9, 622 phase transfer, 607 to multiple bonds activated by other EWGs, 610–24 acrylonitrile acceptors, 612 nitroalkene acceptors, 612–15 other electron-withdrawing activators, 623–4 vinyl phosphates, 623 vinylsulfone, vinylselenone, and vinylsulfoxide acceptors, 610–1 to multiple bonds conjugated with C=0, 578–610 carbon nucleophiles, 586–609 halogen nucleophiles, 585 hydride as nucleophile, 586 Morita–Baylis–Hillman reaction, 609–610 nitrogen nucleophiles, 578–81

850 Nucleophilic addition (continued) oxygen nucleophiles, 581–2 phosphorus nucleophiles, 585 sulfur and selene nucleophiles, 582–4 ureas, squaramides, and related catalysts, 599–606, 615–22 Nucleophilic aliphatic substitution, 369–421 allylic substitutions, 371–7 azetidine reactions, 390–1 aziridine reactions, 387–90 carbenes, 221–2 carboxylic acids and derivatives, 72, 80, 84–5 cyclopropane reactions, 391–3 kinetic isotope effects, 370, 393–6 medium effects/solvent effects, 399–401 miscellaneous kinetic and product studies, 411–14 on elements other than carbon, 396–9 reactions on nitrogen, 399 reactions on phosphorus, 398–9 reactions on silicon, 396–7 reactions on sulfur, selenium, and tellurium, 397–8 other, 414–17 oxidation, 129, 139 propargylic substitutions, 380–1 reactions forming C–C bonds, 369–70 reactions of cyclic ethers, 381–6, 383 SN 1 allylic substitutions, 371 carbocations, 346–7 kinetic isotope effects, 394–5 medium effects/solvent effects, 399–400 miscellaneous kinetic and product studies, 411–12 SN 2 allylic substitutions, 375–7 kinetic isotope effects, 393–4, 396 medium effects/solvent effects, 400–1 miscellaneous kinetic and product studies, 412–14 on elements other than carbon, 396–9 reactions forming C–C bonds, 370 structural effects, 402–5 theoretical studies, 406–411 SN 2′ allylic substitutions, 371–5 reactions forming C–C bonds, 370 structural effects, 405 SN i, on elements other than carbon, 397 structural effects, 401–6 theoretical studies, 406–411, 407 vinyl substitutions, 378–80 Nucleophilic aromatic substitution (SN Ar) aromatic substitution, 249–62 benzyne and related intermediates, 250, 258–62 mechanism, 249–58 Meisenheimer and related complexes, 249, 252, 258

Subject Index O OCC see oxidative cross-coupling O-diphenylphosphinobenzamide ligands, carbanions, 427 O-diphenylphosphinobenzoate ligands, carbanions, 427 O-iodoanilines, electrophilic addition, 504 Olefinations, aldehydes and ketones, 43–5 Olefin polycyclizations, carbocations, 342 Oligoalkynes, cycloaddition, 686–7 OND see oxanorbornadienes Organoaluminiums aromatic substitution, 284 electrophilic addition, 552–3 oxidation, 118–19 Organogalliums, elimination reactions, 455 Organolithiums addition and other reactions, 433–4 addition reactions, 43 aromatic substitution, 248, 255, 261, 284 carbanions, 432–4 directed lithiation, 432–3 elimination reactions, 461 nucleophilic addition, 624 reactions of hydrazones, 27 reactions of imines, 21 reduction, 187 see also Wittig reaction Organomagnesiums carbanions, 434–5 see also Grignard reagents Organoseleniums, aromatic substitution, 272–3 Organozincs addition to aldehydes and ketones, 41–2 aromatic substitution, 248, 319–20 carbanions, 435–9 electrophilic addition, 540–42 molecular rearrangements, 752 nucleophilic addition, 637–8 nucleophilic aliphatic substitution, 376 Ortho-iodo cinnamates, electrophilic addition, 514 Ortho-substituted phenols, synthesis, 203 Osmium catalysis electrophilic addition, 531 oxidation, 103, 117, 134 reduction, 176 Oxabenzonorbornadienes, nucleophilic aliphatic substitution, 385–6 Oxa-Diels–Alder reactions, cycloaddition, 682 Oxanorbornadienes (OND), cycloaddition, 672 Oxaphosphiranes, cycloaddition, 691 1,2-Oxazinan-3-ones, synthesis, 768–9 1,3-Oxazines, synthesis, 123 Oxaziridines nucleophilic aliphatic substitution, 388 synthesis, 142 Oxazoles nucleophilic addition, 628 synthesis, 717–18 Oxazolidine-2,4-diones

851

Subject Index molecular rearrangements, 748 synthesis, 482 Oxazolidines, carbenes, 212 Oxazolidinones electrophilic addition, 558–9 molecular rearrangements, 711, 748 synthesis, 225 Oxazolines carbanions, 431–2 cycloaddition, 672 electrophilic addition, 467 Oxetanes, nucleophilic aliphatic substitution, 384–5 Oxetan-3-ols, aromatic substitution, 272 Oxidation, 97–159 aldehydes and ketones, 51–4 cerium, tungsten, molybdenum, and vanadium, 105–7 chromium, manganese, nickel, and cobalt, 97–100, 133–4, 137–9, 142–3, 150–1, 155 compounds of non-metallic elements, 117–30 copper, silver, gold, and thallium, 100–5, 133, 137, 146–50, 154–6 electrophilic addition, 473, 476, 480, 520, 538, 549, 561–2, 575 group VIII metals, 115–17, 134, 143 halogen compounds, 121–30 metal ions and related species, 97–117 nitrogen and sulfur compounds, 117–20 other oxidations, 155–9 ozonolysis and ozonation, 131 palladium, iridium, ruthenium, rhodium, and platinum, 101–4, 107–116, 129–30, 143, 151–5, 159 peracids and peroxides, 131–43 photo-oxygenation and singlet oxygen, 143 triplet oxygen and autoxidation, 143–55 Oxidative addition aromatic substitution, 293, 297, 305, 308–9, 319–20 electrophilic addition, 503–4, 509 Oxidative boron Heck reaction, 107 Oxidative cross-coupling (OCC), 102, 107, 121, 125, 133–7 Oxidative cyclization hydrazones, 26 molecular rearrangements, 709, 715–17, 742 Oximes electrophilic addition, 525–6, 533 oxidation, 104 reactions, 22–4 synthesis, 132 Oxindole-α-hydroxyphosphonates, synthesis, 33 Oxindoles addition reactions, 42 aldol and related reactions, 30, 37 aromatic substitution, 292 molecular rearrangements, 744, 764, 769–70 nucleophilic addition, 616 oxidation, 138–9 synthesis, 211, 216

Oxindolylidine acetates, nucleophilic addition, 639 Oxiranes, aromatic substitution, 286 Oxocarbenium ions, 346–7, 349, 363 aldehydes and ketones, 6 1-Oxo-hexahydroxanthenes, synthesis, 39–40 Oxo-Pictet–Spengler reactions, carbocations, 363 2-Oxopiperazines, synthesis, 121–2 Oxyarylation, molecular rearrangements, 703–4 Oxyboration, electrophilic addition, 493–4 Ozonolysis and ozonation, 131

P Palladium catalysis aromatic substitution, 254–5, 261–5, 268, 280–323 carbanions, 440–1 carbenes, 217, 227–9 cycloaddition, 661, 667 electrophilic addition, 492, 494, 497–514 elimination reactions, 455 molecular rearrangements, 720, 744–7 nucleophilic addition, 630–1 nucleophilic aliphatic substitution, 369–72, 375–6, 378 oxidation, 104, 107–9, 116, 143, 151–3, 159 reduction, 166, 173–4, 183, 187–8 Pauson–Khand reaction, molecular rearrangements, 760 PBE molecular dynamics, carbocations, 338 P-cresols, oxidation, 158 Pentachloropyridine, aromatic substitution, 257–8 Peptides, biologically significant reactions, 88–91 Peracids and peroxides, oxidation reactions, 131–43 Perfluoroalkylation, aromatic substitution, 255 Perfluoroarylation, aromatic substitution, 255 Perhydroindoles, synthesis, 425 Pericyclic reactions, 697–708, 732–3 [1,3]-sigmatropic, 697–8 [1,4]-sigmatropic, 699 [2,3]-sigmatropic, 705 [3,3]-sigmatropic, 485, 566, 699–705, 749 [5,5]-sigmatropic, 705 PET see photoinduced electron transfer Petasis–Ferrier rearrangement, 737 Peterson olefination, elimination reactions, 453 Phase transfer catalysis, nucleophilic addition, 607 Phenanthrenes aromatic substitution, 261 synthesis, 126–7 Phenanthridinones, synthesis, 152 1,10-Phenanthroline, oxidation, 119 Phenanthrolines, synthesis, 514, 577 Phenols carbenes, 203 oxidation, 111, 126, 133–4 Phenylacetyl disulfides, nucleophilic aliphatic substitution, 398–9 Phenylalanines, synthesis, 208 Phenyl allyl ethers, nucleophilic aliphatic substitution, 371

852 2-Phenylbenzothiazoles, oxidation, 100 Phenylmercaptoacetic acids (PMAA), oxidation, 98 Phenylpropargyl diazoacetates, molecular rearrangements, 735–6 3-Phenylpropene, carbocations, 344 Phenylsulfinylacetic acids (PSAA), oxidation, 133–4 Phosphaalkynes, electrophilic addition, 493 Phosphanyl ketenes, molecular rearrangements, 722–3 Phosphates, biologically significant reactions, 91–4 Phosphine oxide carbocations, 343 Phosphinic acids, intermolecular catalysis and reactions, 82 Phosphite triesters, nucleophilic aliphatic substitution, 398–9 Phosphonoallenes, carbocations, 345 Phosphoramidates biologically significant reactions, 95–6 electrophilic addition, 530 Phosphoramidites carbanions, 432–3, 437–8 nucleophilic addition, 627–8, 637 Phosphoric acids and derivatives aromatic substitution, 277–8 biologically significant reactions, 91–6 intermolecular catalysis and reactions, 82–3 phosphates, 91–4 phosphinic acids, 82 phosphoramidates, 95–6 phosphoryl and thiophosphoryl halides, 82–3 Phosphoryl halides, intermolecular catalysis and reactions, 82–3 Photoinduced electron transfer (PET), cycloaddition, 664 Photo-oxygenation, 143 Piancatelli rearrangement, 759–60 Pictet–Spengler reaction carbocations, 363 formation and reactions of imines, 10 Pinacol rearrangement, 363, 760 Piperazinones, synthesis, 235, 374, 405 Piperidines nucleophilic addition, 622 synthesis, 354 Pivolyl triflate, elimination reactions, 450 Platinum catalysis aromatic substitution, 300 carbenes, 220 carbocations, 357 electrophilic addition, 514–15 molecular rearrangements, 748 oxidation, 107–114 PMAA see phenylmercaptoacetic acids PMS see potassium peroxymonosulfate Polyhydroxylated quinoxalines, synthesis, 278 Polyoxometallates (POM), oxidation, 133 Porphyrins, carbocations, 340–1 Potassium peroxymonosulfate (PMS), oxidation, 105

Subject Index Prins cyclization carbocations, 348–9, 352, 361–3 electrophilic addition, 487, 522 Propargyl alcohols, molecular rearrangements, 756–9 Propargyl benzoates, molecular rearrangements, 748–9 Propargyl carbamates, molecular rearrangements, 718–19 Propargyl carbocations, formation and reactivity, 358–61 Propargyl esters, molecular rearrangements, 718–19 Propargylic amines, electrophilic addition, 558–9 Propargylic aryl ethers, electrophilic addition, 471 Propargylic substitutions, nucleophilic aliphatic substitution, 380–1 2-Propargyloxypyridines, molecular rearrangements, 734 Propioloic amides, nucleophilic addition, 631 Propylene, reduction, 163–4 Protonated cyclopropanes, 338 PSAA see phenylsulfinylacetic acids PyBrop see bromo-tris(pyrrolidino)phosphonium hexafluorophosphate 4H-Pyranonaphthoquinones, nucleophilic addition, 621 Pyrano[3,4-c]pyrroles, synthesis, 57 Pyrans, molecular rearrangements, 748–9 Pyrazole–amino oxindole adducts, reactions, 19 Pyrazoles cycloaddition, 669–70 electrophilic addition, 484 nucleophilic addition, 617 Pyrazolidinones, synthesis, 587 Pyrazolones nucleophilic addition, 604, 617, 621–2 synthesis, 444 Pyrazolo[1,2-a]pyrazoles, synthesis, 593 Pyrazolo[2,3-c]pyrazoles, synthesis, 593 Pyridazines, synthesis, 458 Pyridine N-oxides molecular rearrangements, 703–4 oxidation, 103–4 Pyridines cycloaddition, 688 molecular rearrangements, 703–4 nucleophilic aliphatic substitution, 384, 393, 398–9 oxidation, 156 reduction, 160–1 Pyridinium phosphoramides, cycloaddition, 675 Pyrido-fused quinazolinones, synthesis, 152 Pyridones, nucleophilic addition, 624 Pyrido[2,3-d]pyrimidin-4(3H)-ones, synthesis, 57 2-Pyridyl ketones, reactions, 16 Pyridyl thionobenzoates, reactions, 80 Pyrolysis acid derivatives, 451–2 carbenes, 205 cycloreversion, 450–1

853

Subject Index elimination reactions, 450–2 oxygen derivatives, 452 Pyrrazoles, electrophilic addition, 524 Pyrrazolines, electrophilic addition, 486–7 Pyrroles carbenes, 216 cycloaddition, 671 electrophilic addition, 511, 554 molecular rearrangements, 728 nucleophilic aliphatic substitution, 374 oxidation, 155 Pyrrolidines nucleophilic addition, 596, 600, 609, 614–15 nucleophilic aliphatic substitution, 390–1 synthesis, 37–8 3,2′ -Pyrrolidinyl spirooxindoles cycloaddition, 667 synthesis, 610 Pyrrolines, synthesis, 590 Pyrroloindoles nucleophilic addition, 631 nucleophilic aliphatic substitution, 412 synthesis, 40, 273 Pyrroloindolines cycloaddition, 671 synthesis, 535 Pyrrolo[3,2-c]quinolines, synthesis, 284 Pyrrolo[1,2-a]quinolines, synthesis, 629 Pyrrolyl-ketones, synthesis, 40 3-Pyrrolyloxindoles, nucleophilic addition, 616 Pyrrolylpyridine N-oxides, synthesis, 103–4

Q Quantum mechanics/molecular mechanics (QM/MM) biologically significant reactions, 92–4, 96 elimination reactions, 451 formation and reactions of acetals, 2 oxidation, 131 reduction, 170, 181–2 Quaternary ammonium salts, aromatic substitution, 259–60 Quinazolines oxidation, 123 synthesis, 53, 154–5 Quinazolinones molecular rearrangements, 768 synthesis, 39–40, 57, 110, 254 Quinolines carbenes, 208 electrophilic addition, 509 oxidation, 117, 125 reactions, 16 reduction, 170–1 Quinolinones electrophilic addition, 472 synthesis, 725, 728 Quinolizidines, synthesis, 556–7, 737 Quinolones carbocations, 358

cycloaddition, 680–82 synthesis, 252–3 Quinolyl-peri-ketones, cyclization reactions, 59 Quinone methides cycloaddition, 682–3 molecular rearrangements, 725, 728 nucleophilic addition, 583, 585, 589, 607, 630, 635 Quinones oxidation, 156 synthesis, 39 Quinoxalines, synthesis, 278

R Radical anions, oxidation, 102–3 Radical molecular rearrangements, 714 Radziszewski reaction, aldehydes and ketones, 57–8 RAFT polymerization, carbocations, 341 Rautenstrauch rearrangement, carbocations, 350 Rearrangements see individual named reactions; molecular rearrangements Reduction aldehydes and ketones, 15–16, 54–6 carbenes, 229–30 complex metal hydrides, 159–62 hydrogenation, 162–72 other reductions, 183–9 transfer hydrogenation, 172–83 Reductive amination, aldehydes and ketones, 55 Reductive elimination, aromatic substitution, 293, 298–9, 307, 322–3 Reformatsky reaction carbanions, 437 electrophilic addition, 542 Retro-Diels–Alder reaction, elimination reactions, 450–1 Retro-Henry reaction, reduction, 162 Rhodium catalysis aromatic substitution, 268–9, 289–93, 295–7, 302–3, 308, 310–11, 315–17 carbanions, 425–6 carbenes, 209–215, 230–1 cycloaddition, 682, 686, 689–90 electrophilic addition, 518–28 elimination reactions, 454, 457 molecular rearrangements, 740–5 nucleophilic addition, 632–5 nucleophilic aliphatic substitution, 380, 384 oxidation, 101–2, 104, 113–14, 129, 154–5 reduction, 170–72, 174 Ring closure see cyclizations Ring expansion, molecular rearrangements, 712–14, 766, 773–4 Ring-opening reactions aromatic substitution, 261, 271–2 carbenes, 220, 224 carbocations, 354–7 electrophilic addition, 482–3 molecular rearrangements, 712–14

854 Ring-opening reactions (continued) nucleophilic aliphatic substitution, 381–90, 392, 397, 405–6 oxidation, 118 Rotaxane amine N-oxides, synthesis, 141 Ruppert–Prakash reagent, carbocations, 432 Ruthenium catalysis aromatic substitution, 264–5, 291, 297–9, 305–8, 312–16 carbenes, 215–16, 230–1 cycloaddition, 688 electrophilic addition, 493, 516–18 molecular rearrangements, 713, 744 nucleophilic addition, 631–2 oxidation, 110–13, 116, 154 reduction, 160–1, 168–70, 174, 176, 181–2, 184

S Sakurai–Prins cyclization, carbocations, 349 Salicylaldehydes electrophilic addition, 520 oxidation, 110 S-alkenyl sulfoximines, electrophilic addition, 472 Samarium catalysis, electrophilic addition, 574 Schmidt reaction, molecular rearrangements, 761 Selenoxides, oxidation, 141–2 Semipinacol rearrangement, 358, 710 Serine peptide assembly (SPA), 90 Sesquiterpenes cycloaddition, 689–92 molecular rearrangements, 748 SEY see single electron transfer α-Sila benzamides, synthesis, 713 Silaborative carbocyclization, electrophilic addition, 494–5, 513 Silacarboxylation, electrophilic addition, 498 Silver catalysis aromatic substitution, 262–3, 293–4 carbenes, 220, 231 electrophilic addition, 480, 568–72 molecular rearrangements, 713, 748–50 nucleophilic aliphatic substitution, 404 oxidation, 103–5, 133, 137, 149–50 Silylamination, aromatic substitution, 259 3-Silylbenzofurans, synthesis, 743–4 Silyl diethyl ethers, cycloaddition, 689 Silylenes, 238–9 Silyl enol ethers, carbenes, 208 Silylium ions, 342–3 Silyl ketene acetal dienes, cycloaddition, 676–7 Silyl ketene acetals molecular rearrangements, 701–2 nucleophilic addition, 587–9 Silyl ketene imines, molecular rearrangements, 706 Silyloxyallyl cations, 343–4 α-(Silyloxy)-β-amino amides, reactions, 18 Silylsilylene, electrophilic addition, 497 Single electron transfer (SET) aromatic substitution, 248, 264, 268, 273, 283, 285, 310

Subject Index cycloaddition, 665 electrophilic addition, 477 Singlet oxygen, 143 Skraup reaction, oxidation, 117 Smiles rearrangement, 260, 761 Solvolysis reactions carboxylic acids and derivatives, 73–5 elimination reactions, 450 nucleophilic aliphatic substitution, 399–401 Sommolet–Hauser rearrangement, 761 Sonogashira reaction, aromatic substitution, 301–2, 317 SPA see serine peptide assembly Spiroacetalization, aldehydes and ketones, 2 Spirocyclic cyclopropanes, nucleophilic addition, 589 Spirocyclic imines, molecular rearrangements, 748 Spirocyclic oxindole 2H-azirines, nucleophilic aliphatic substitution, 389 Spirocyclic oxindoles, synthesis, 37 Spirocyclic sultams, synthesis, 113 Spirocyclization carbenes, 233 electrophilic addition, 469, 545 Spiroindanes, synthesis, 278 3,3-Spiroindolines, synthesis, 276 Spirolactams, synthesis, 203 Spirooxindoles cycloaddition, 666–7 nucleophilic addition, 601, 604, 610 Spiropyrazolones, nucleophilic addition, 621–2 Spiro-9-silabifluorenes, synthesis, 114 Spirostan sapogenins, synthesis, 357–8 Spiro tetrahydroisoquinolines, molecular rearrangements, 716 Squaramides cycloaddition, 681 molecular rearrangements, 764 nucleophilic addition, 587, 603–6, 617–22 Stetter reaction, aldehydes and ketones, 36 Stevens rearrangement, 762 Stilbene, synthesis, 177 Styrenes carbenes, 227 carbocations, 341–2 electrophilic addition, 501–3 Styryl azides, oxidation, 113 α-Substituted aldehydes and ketones, 50–1 γ-Substituted aryl enones, nucleophilic addition, 595 Substituted benzothiophenes, synthesis, 3 α-Substituted ethylphosphonates, synthesis, 184–6 4-Substituted pyrazolones, synthesis, 444 2-Substituted thiochromenes, synthesis, 457 Sulfamidation, aromatic substitution, 269 Sulfinamides, synthesis, 149 Sulfinic acids electrophilic addition, 485 synthesis, 257 Sulfinyl trichloroacetamides, molecular rearrangements, 757, 759

Subject Index Sulfonamides aromatic substitution, 259, 268 carbocations, 347 electrophilic addition, 473, 558–9 molecular rearrangements, 721–2, 730–1 nucleophilic addition, 594–5 Sulfonic acids, electrophilic addition, 485 Sulfonium ions aldehydes and ketones, 6 molecular rearrangements, 705–6, 727–8 Sulfonylalkynamides, carbenes, 223–4 Sulfonylalkynols, carbenes, 223–4 Sulfonylallenamides, cycloaddition, 686 Sulfonylamides, electrophilic addition, 473 Sulfonylation, aromatic substitution, 266–7 Sulfonylaziridines, nucleophilic aliphatic substitution, 387 Sulfonyloxiranes carbocations, 356–7 molecular rearrangements, 711 Sulfonylphthalides, molecular rearrangements, 752–5 Sulfoxides aromatic substitution, 259 electrophilic addition, 485 Sulfoximes, synthesis, 237 Sulfoximines, molecular rearrangements, 697–8 Sulfur ylides aldehydes and ketones, 37, 56 aromatic substitution, 261 carbanions, 429 nucleophilic addition, 610 oxidation, 120 Sultams, electrophilic addition, 526 Superelectrophilic carbocations, 344–5 Suzuki coupling, aromatic substitution, 320–1 Suzuki–Miyaura reaction aromatic substitution, 284, 301, 303–7, 309, 321 carbenes, 229 molecular rearrangements, 720–1, 762–3 nucleophilic aliphatic substitution, 370, 404–5 reduction, 160

T Takemoto catalysts, nucleophilic addition, 602, 621 TBAI see tetrabutylammonium iodide Tertiary alkyl amines, synthesis, 347 Tertiary allylic alcohols, molecular rearrangements, 710 Tertiary allylic amines, molecular rearrangements, 762 Tertiary amines electrophilic addition, 471 molecular rearrangements, 705, 766 nucleophilic addition, 580 nucleophilic aliphatic substitution, 384, 398–9 Tertiary arylamines, synthesis, 55–6 Tertiary benzylic alcohols, molecular rearrangements, 710, 716

855 Tetrabutylammonium iodide (TBAI), oxidation, 135–7 Tetrahydrobenzofurans, synthesis, 277 Tetrahydrocarbazoles, nucleophilic addition, 639 Tetrahydrodiazocines, nucleophilic addition, 580 2H-Tetrahydro-4,6-dioxo-1,2-oxazines, synthesis, 638 Tetrahydrofurodioxoles, synthesis, 123 Tetrahydroindeno[1,2-c]furan-1-ones, synthesis, 40 Tetrahydroisoquinolines (THIQ) aromatic substitution, 261 carbocations, 339 molecular rearrangements, 716 reduction, 186–7 Tetrahydropyrazoloquinazolines, cycloaddition, 670 Tetrahydropyridines, synthesis, 354 Tetrahydroquinolines (THQ) aromatic substitution, 257 cycloaddition, 681–2 molecular rearrangements, 712 oxidation, 115–16, 119 Tetrahydroquinoxalines, synthesis, 176–7 Tetrahydrospiro[chroman-2,4′ -pyran]s, synthesis, 348 Tetralones electrophilic addition, 517 synthesis, 606 Tetramethoxyethylene, synthesis, 202 Tetrazoles, molecular rearrangements, 761 Thallium catalysis, oxidation, 105 Thermal molecular rearrangements, 715 1,2,3-Thiadiazoles, carbenes, 212–13 1,2-Thiazines, synthesis, 581 Thietanes, nucleophilic aliphatic substitution, 397 Thioacyl halides, intermolecular catalysis and reactions, 80–2 Thioalkynes, electrophilic addition, 497 Thioamides intermolecular catalysis and reactions, 80–2 oxidation, 156–7 Thioboration, electrophilic addition, 493 Thiocarbonates, intermolecular catalysis and reactions, 80 Thiocarbonylation, electrophilic addition, 502 Thiochromenes, synthesis, 457 Thioesters, intermolecular catalysis and reactions, 80 Thioflavanones, synthesis, 436–7 Thiophene-2-carboxamides, aromatic substitution, 322 Thiophenes, cycloaddition, 684–5 Thiophosphoryl halides, intermolecular catalysis and reactions, 82–3 Thioureas nucleophilic addition, 599–603, 615–19, 630 oxidation, 120 THIQ see tetrahydroisoquinolines THQ see tetrahydroquinolines

856 Tin triflate catalysis carbocations, 347, 350 electrophilic addition, 542 Titanium catalysis electrophilic addition, 550–2 nucleophilic addition, 635–7 reduction, 188 Titanocenes, nucleophilic aliphatic substitution, 379–80 Togni reaction, electrophilic addition, 532–3 Tosylamides, electrophilic addition, 559–60 Tosyl imides, electrophilic addition, 565 Trans-carbamates, synthesis, 382 Trans-2,3-disubstituted dihydrobenzofurans, synthesis, 426 Transesterification carboxylic acids and derivatives, 73, 85, 90–1 phosphoric acids and derivatives, 91–2 Transfer hydrogenation, 172–83 aldehydes and ketones, 15–16, 54 electrophilic addition, 516 mechanisms and catalysts, 173–83 oxidation reactions, 157 reviews, 172–3 Transition metal-catalysed C–C bond formation alkylation, arylation, and acylation, 282–313 aromatic substitution, 282–323 substitution on heterocyclic rings, 313–23 Trans-β-lactams, synthesis, 21 Triaryl-substituted cyclopentenones, synthesis, 275 Triazines aromatic substitution, 250 cycloaddition, 661 Triazoles aromatic substitution, 276 carbenes, 213, 220, 222 cycloaddition, 673–4 molecular rearrangements, 769 nucleophilic addition, 639–40 synthesis, 123–5 Triazolopyridopyrimidines, synthesis, 762 Tricyclic tetrahydroquinolines, synthesis, 137 Trifluoromethylation aromatic substitution, 282–3 carbenes, 207 Trifluoromethyl ketimines, reactions, 9 Trifluoromethylthiolation aromatic substitution, 250–1, 265 electrophilic addition, 571–4 3-Trifluoromethylthiospiro[4,5]trienones, synthesis, 137 Triplet oxygen, 143–55 1,3,5-Trisubstituted benzenes, synthesis, 223 2,4,5-Trisubstituted thiazoles, synthesis, 383–4 Trityl cation salts, 341 Triynes, cycloaddition, 686–7 Tsuji–Trost-type reactions, nucleophilic aliphatic substitution, 369–70 Tungsten catalysis, oxidation, 105–7

Subject Index U Ugi reaction, molecular rearrangements, 763 Ullazines, synthesi, 302 𝛼,β-Unsaturated aldehydes cycloaddition, 664, 667, 682 nucleophilic addition, 585, 595, 626 𝛼,β-Unsaturated amides, nucleophilic addition, 586, 625, 640 𝛼,β-Unsaturated enones, nucleophilic addition, 630 𝛼,β-Unsaturated esters, nucleophilic addition, 586, 626, 632 𝛽,γ-Unsaturated esters, molecular rearrangements, 740 𝛼,β-Unsaturated ketoesters, molecular rearrangements, 700 𝛼,β-Unsaturated ketones electrophilic addition, 477 nucleophilic addition, 585, 602, 626 reduction, 178–9 𝛽,γ-Unsaturated ketones, molecular rearrangements, 708 𝛾,δ-Unsaturated ketones, synthesis, 455 𝛼,β-Unsaturated lactones, nucleophilic addition, 632 𝛼,β-Unsaturated malonates, molecular rearrangements, 700 𝛼,β-Unsaturated oximes, nucleophilic aliphatic substitution, 381 𝛽,γ-Unsaturated oximes, electrophilic addition, 504–5 Ureas, nucleophilic addition, 599–603, 615–19, 630

V Vanadium catalysis, oxidation, 105–7 Vinyl arenes aromatic substitution, 295 synthesis, 184 Vinyl azides electrophilic addition, 477 nucleophilic addition, 589–90 2-Vinyl aziridine 2-carboxylates, molecular rearrangements, 697–8 Vinyl butyrate, oxidation, 159 Vinyl carbocations, formation and reactivity, 358–61 Vinylcyclopropanes cycloaddition, 667, 691 electrophilic addition, 507–8 nucleophilic addition, 630 Vinyl epoxides nucleophilic addition, 640–1 nucleophilic aliphatic substitution, 379 Vinyl halides, reduction, 184 Vinylidenecyclopropanes, carbenes, 218–19 Vinylindoles, electrophilic addition, 484 Vinyl phosphates, nucleophilic addition, 623 Vinylphosphonates, molecular rearrangements, 718–19 Vinyl propyl acetals, synthesis, 3 2-Vinylpyrroles, cycloaddition, 677 Vinylselenones, nucleophilic addition, 610–11

857

Subject Index Vinyl substitutions, nucleophilic aliphatic substitution, 378–80 Vinylsulfamides, nucleophilic addition, 631 Vinylsulfones, nucleophilic addition, 610–11 Vinylsulfoxides, nucleophilic addition, 610–11 Von Auwers reaction, 751

W Wagner–Meerwein rearrangement, 356–7, 711–13, 748 Wessely–Moser rearrangement, 716 Wittig reaction aldehydes and ketones, 43–5 carbanions, 429–30 elimination reactions, 452–3 molecular rearrangements, 762–3 Wolff rearrangement, 206

X Xanthenes carbocations, 341 synthesis, 38

Y Ynamides cycloaddition, 682 electrophilic addition, 541, 555, 561 Ynones, nucleophilic addition, 580 Ytterbium catalysis carbenes, 231 electrophilic addition, 574

Z Zinc catalysis aromatic substitution, 279 electrophilic addition, 541–2 oxidation, 132–3 see also organozincs Zwitterions aldehydes and ketones, 52 aromatic substitution, 259–60 carbenes, 221–2 electrophilic addition, 514–15

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