Table Of ContentBEST SYNTHETIC METHODS
Series Editors
A. R. Katritzky O. Meth-Cohn C. W. Rees
University of Florida Sunderland Polytechnic Imperial College of Science
Gainesville, Florida Sunderland and Technology
USA UK London, UK
Richard F. Heck, Palladium Reagents in Organic Syntheses, 1985
Alan H. Haines, Methods for the Oxidation of Organic Compounds: Alkanes, Alkenes, Alkynes,
and Arenes, 1985
Paul N. Rylander, Hydrogenation Methods, 1985
Ernest W. Colvin, Silicon Reagents in Organic Synthesis, 1988
Andrew Pelter, Keith Smith and Herbert C. Brown, Borane Reagents, 1988
Basil Wakefield, Organolithium Methods, 1988
Alan H. Haines, Methods for the Oxidation of Organic Compounds: Alcohols, Alcohol Derivatives,
Alkyl Halides, Nitroalkanes, Alkyl Azides, Carbonyl Compounds, Hydroxyarenes and
Aminoarenes, 1988
H. G. Davies, R. H. Green, D. R. Kelly and S. M. Roberts, Biotransformations in Preparative
Organic Chemistry: The Use of Isolated Enzymes and Whole Cell Systems, 1989
I. Ninomiya and T. Naito, Photochemical Synthesis, 1989
T. Shono, Electroorganic Synthesis, 1991
William B. Motherwell and David Crich, Free Radical Chain Reactions in Organic Synthesis, 1991
Free Radical Chain Reactions
in Organic Synthesis
William B. Motherwell and David Crich
Departments of Chemistry,
Imperial College of Science, Technology and Medicine,
and University College,
London, UK
ACADEMIC PRESS
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Copyright © 1992 by
ACADEMIC PRESS LIMITED
All Rights Reserved
No part of this book may be reproduced in any form by photostat, microfilm, or any other
means, without written permission from the publishers
This book is a guide providing general information concerning its subject matter; it is not a
procedural manual. Synthesis of chemicals is a rapidly changing field. The readers should consult
current procedural manuals for state-of-the-art instructions and applicable government safety
regulations. The publisher and the authors do not accept responsibility for any misuse of this
book, including its use as a procedural manual or as a source of specific instructions.
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
ISBN 0-12-508760-8
Typeset by Thomson Press (India) Limited, New Delhi,
Printed in Great Britain by St Edmundsbury Press, Bury, St. Edmonds Suffolk, UK.
"And now for the Initiation Ceremony"
Dedicated with admiration, gratitude and affection to
Professor Sir Derek Barton FRS
Foreword
There is a vast and often bewildering array of synthetic methods and reagents
available to organic chemists today. Many chemists have their own favoured
methods, old and new, for standard transformations, and these can vary
considerably from one laboratory to another. New and unfamiliar methods
may well allow a particular synthetic step to be done more readily and in
higher yield, but there is always some energy barrier associated with their
use for the first time. Furthermore, the very wealth of possibilities creates
an information-retrieval problem. How can we choose between all the
alternatives, and what are their real advantages and limitations? Where can
we find the precise experimental details, so often taken for granted by the
experts? There is therefore a constant demand for books on synthetic
methods, especially the more practical ones like Organic Syntheses, Organic
Reactions, and Reagents for Organic Synthesis, which are found in most
chemistry laboratories. We are convinced that there is a further need, still
largely unfulfilled, for a uniform series of books, each dealing concisely with
a particular topic from a practical point of view—a need, that is, for books
full of preparations, practical hints and detailed examples, all critically
assessed, and giving just the information needed to smooth our way painlessly
into the unfamiliar territory. Such books would obviously be a great help
to research students as well as to established organic chemists.
We have been very fortunate with the highly experienced and expert organic
chemists, who, agreeing with our objective, have written the first group of
volumes in this series. Best Synthetic Methods. We shall always be pleased
to receive comments from readers and suggestions for future volumes.
A. R. K., O. M.-C, C. W. R.
Preface
In recent times the myth of free radicals as highly reactive intermediates has
been exploded by the advent of rationally designed, highly efficient free radical
chain sequences permitting both the high yielding interconversion of
functional groups and the formation of carbon-carbon bonds under mild
neutral conditions. The extent of this change in perception is such that free
radical chain reactions can now be said to occupy an equal place in the
armoury of the synthetic organic chemist with long standing two electron
and concerted processes.
Several books and review articles dealing with various facets of this general
area have appeared: the intention of this particular volume, which we hope
will be useful to both the experienced practitioner and to the, as yet, un-
initiated, is to provide a guide to the more practical aspects of the subject.
This book does not seek to be comprehensive but rather to provide a
collection of tried and tested experimental parts as well as a selection of
methods of very recent vintage. We are only too well aware that free radical
chain processes of the S 1 type or those mediated by transition metal redox
RN
couples can, and in future may well, form the material for further volumes.
This is a task which we leave for others.
In the final analysis, the writing of a book is not only a labour but also
a test of love. Given that the dedicatee once informed one of the authors
that "those who can, do, those who can't, review," we hope that we may be
forgiven. We are especially grateful to our friend Dr Tom Purcell, whose
modesty forbade him to append his name to the cartoon which we
commissioned from him. Finally, we would like to thank those of our
colleagues, and, in particular, Dr Stephen Caddick, Dr Robyn S.
Hay-Motherwell and Dr A. M. K. Pennell who have provided invaluable
assistance in the painstaking task of checking this work.
WILLIAM B. MOTHERWELL
DAVID CRICH
Detailed Contents
1 Some basic concepts of free radical chain reactions 1
1.1 Introduction 1
1.2 The advantages 1
1.3 The relative "character" of various radical species 2
1.3.1 Reactivity as a function of the nature of the atom
containing the unpaired electron 2
1.3.2 Character variations within carbon centred radicals . . .. 4
1.4 Determinant factors in the production of a successful free radical
chain reaction 7
1.5 The initiation ceremony 10
1.6 Strategy and design in synthetic sequences involving carbon
centred radical reactions 12
1.6.1 Chemoselectivity in functional group interconversions . .. 12
1.6.2 Stereoselectivity in carbon-carbon bond forming reactions . 14
1.6.3 Retrosynthetic carbon-carbon bond disconnections . . .. 17
1.7 Some practical guidelines 19
1.7.1 Initiators 20
1.7.2 Solvents 20
1.7.3 The correct order of addition of reagents 20
1.7.4 Removal of organotin residues 21
1.7.5 The role of oxygen in free radical reactions 24
1.8 Overview and perspectives 24
References 25
2 Books and review articles 27
2.1 Some earlier basic texts and reviews (pre-1980) 27
2.2 General books and reviews (post-1980) 28
2.3 Recent books and articles dealing with more specific aspects
of free radical reactions 28
3 Substitution reactions 29
3.1 Dehalogenation (RX -► RH, X = halogen) 29
3.1.1 Selection of the organostannane 29
3.1.2 Selection of the halogen atom 30
3.1.3 Choice of solvent and relative concentrations 30
xii DETAILED CONTENTS
3.1.4 Reactivity and selectivity as a function of substrate structure 30
General procedure for dehalogenation
reactions (RX RH) without rearrangement . . . 36
Photochemically induced organostannane dehaloge-
nation of 4-bromotoluene—a typical procedure . . . 36
Preparation of 2-acetoxy-l-chloroethene 36
3.2 Deoxygenation reactions (ROH RH) 37
3.2.1 Introduction. The development of the thiocarbonyl
ester method (Barton-McCombie deoxygenation) 37
3.2.1.1 Practical requirements 38
(a) Xanthate esters (X = SMe) 38
(b) Thiocarbonyl imidazolide derivatives
(X — l-imidazolyl) 39
(c) Thionobenzoate esters (X = Ph) 39
(d) Phenoxythiocarbonyl derivatives (X = OPh) . . 39
3.2.2 Deoxygenation of primary alcohols via thiocarbonyl
derivatives 3399
n-Octadecane from the thionobenzoate derivative
of n-octadecanol 40
3.2.3 Deoxygenation of secondary alcohol thionocarbonyl derivatives 40
Deoxygenation of 3ß-thiobenzyloxy-5(x-cholestane—
a typical procedure 47
3.2.4 Tertiary alcohol deoxygenation 47
General procedure for the deoxygenation of alcohols
via in situ formation of oxalyl thiohydroxamates . . 50
3.2.5 Regioselective deoxygenation of 1,2- and 1,3-diol cyclic
thionocarbonates 50
Preparation of 5-deoxy-l,2-0-isopropylidene-3-0
methyl-D-xy\ohexofuranose 52
3.2.6 Deoxygenation of p-toluenesulphonate esters with tri-n-
butylstannane via in situ iodide formation 52
General procedure for the deoxygenation of p-
toluenesulphonate esters 53
3.2.7 Deoxygenation of carboxylic acid esters 53
Preparation of cyclododecane—a typical procedure. 54
3.2.7.1 Deoxygenation of carbohydrate α-acetyl tertiary
benzoates 55
Preparation of 3-C-acetyl-3-deoxy-l,2; D-5,6-di-0-
isopropylidene-a-D-d\\ofuranose 55
3.2.8 Selective deoxygenation of tertiary and allylic alcohols
via mixed methyl oxalate esters 56
3.2.9 Deoxygenation reactions based on chloroformate and
selenocarbonate derivatives 56
Deoxygenation of phenylselenocarbonates—
a typical procedure 57
3.3 Deamination reactions (RNH2->RH) 58
DETAILED CONTENTS xiii
3.3.1 Deamination via isocyanides, isothiocyanates and
isoselenocyanates 58
Preparation of n-octadecane from n-octadecylamine:
deamination of a primary isonitrile 62
Preparation of1,3,4,6-tetra-0-acetyl-2-deoxy-oc-D-
glucose: deamination of 2-amino-2-deoxy-0L-D-glucose 63
3.4 Denitration reactions (RN0 -> RH) 65
2
Method A. General procedure for the denitration
of tertiary nitro compounds 66
Method B. General procedure for the denitration
of secondary nitro compounds 66
3.5 Reductive homolytic cleavage of the carbon-sulphur bond 71
3.5.1 Introduction 71
3.5.2 Thiol desulphurization (RSH -> RH) 72
Preparation of n-octane from n-octyl mercaptan . . 72
Desulphurization of mercaptans 73
3.5.3 Reductive cleavage of sulphides 74
Desulphurization of 2,3-dimethyl-7-( 1-hydroxy-l-
methylethyl )-7-phenylthio-8-oxo-l -azabicyclo-
[4.2.0]octane 75
3.5.4 Reduction of dithioacetals 75
Desulphurization of l,4-dithiaspiro[4.5]decane . . 76
3.5.5 Reduction of thiocarbonyl groups (RCS->RCH) . . .. 77
2 2 2
3.6 Deselenation reactions 79
3.6.1 Introduction 79
3.6.2 Reductive cleavage of unsymmetrical selenides 79
General procedures for the reduction of alkyl
phenyl selenides 80
3.6.3 Reduction of selenoketals 82
3.6.4 Deselenation of acyl selenides 83
General procedures for the conversion of acyl
selenides to aldehydes or nor-alkanes 85
3.7 Decarboxylation reactions 85
3.7.1 Introduction 85
3.7.2 Nor-alkanes by reductive decarboxylation of O-acyl
thiodydroxamates (RC0H -+ RH) 88
2
Method A. Reductive decarboxylation using
tri-n-butylstannane and in situ generation of the
O-acyl thiohydroxamate from the acid chloride... 90
Method B. General procedure for the reductive
decarboxylation of carboxylic acids using in situ
generation from the acid chloride and t-butyl
mercaptan—normal addition 90
Method C. Reduction with t-butyl mercaptan—
inverse addition 91
xiv DETAILED CONTENTS
Method D. Reductive decarboxylation of bridgehead
dicarboxylic acid monoesters 91
Method E. General procedure for the reductive decar-
boxylation ofamino acid and peptide derivatives . . 92
3.7.3 Decarboxylative rearrangement of O-acyl thiohydroxamates 93
Method A. General procedure for decarboxylative
rearrangement to alkylpyridyl sulphides 96
Method B. Preparation of n-pentadecyl-2-pyridyl
sulphide by photolytic rearrangement 96
3.7.4 Decarboxylative halogenation (RC0H -> RY, Y = Cl, Br, I). 96
2
General method A. Decarboxylative chlorination (or
bromination) of aliphatic and alicyclic carboxylic
acids 97
General method B. Decarboxylative iodination
of aliphatic and alicyclic carboxylic acids 99
General method C. Decarboxylative bromination
of aromatic carboxylic acids 99
General method D. Decarboxylative iodination
of aromatic carboxylic acids 100
3.7.5 Decarboxylative chalcogenation (RC0H -► RSR', RSeR',
2
RTeR') 100
General procedure for decarboxylative chalcoge-
nation 102
Preparation of benzyl N-t-butoxycarbonylseleno-
methionate 103
3.7.6 Decarboxylative phosphonylation (RC0H -+ RPO(SPh)) . 103
2 2
3.7.7 Decarboxylative sulphonation (RC0H-► RS0Spy) 104
2 2
General method for the preparation of
thiosulphonates by decarboxylative sulphony-
lation of O-acyl thiohydroxamates 106
3.7.8 Decarboxylative hydroxylation (RC0H-► ROH) 107
2
General methods for the formation of
norhydroper oxides 109
General method for the reduction of
nor-hydroperoxides to nor-alcohols 110
General method for the fragmentation of
hydroperoxides with tosyl chloride and pyridine . . Ill
3.8 Functional group interchange using organometallic derivatives of
boron, mercury and cobalt 113
3.8.1 Introduction 113
3.8.2 Preparation of alcohol derivatives (R^ML,,-» ROH) . . .. 115
3.8.2.1 From organoboranes and organomercury
compounds 115
eis-, tmns-3-Benzyloxycarbonyl-4-hydroxymethyl-
6-methyl-tetrahydro-l ,3-oxazine 116
3.8.2.2 From organocobalt derivatives 117
