Aromatic Heterocyclic Chemistry David T. Babies SmithKline Beecham Pharmaceuticals, Harlow, Essex Series sponsor: S E I M E CA ZENECA is a major international company active in four main areas of business: Pharmaceuticals, Agrochemicals and Seeds, Specialty Chemicals, and Biological Products. ZENECA's skill and innovative ideas in organic chemistry and bioscience create products and services which improve the world's health, nutrition, environment, and quality of life. ZENECA is committed to the support of education in chemistry. OXFORD NEW YORK TOKYO OXFORD UNIVERSITY PRESS Oxford University Press, Walton Street, Oxford 0X2 6DP Oxford New York Athens Auckland Bangkok Bombay Calcutta Cape Town Dar es Salaam Delhi Florence Hong Kong Istanbul Karachi Kuala Lumpur Madras Madrid Melbourne Mexico City Nairobi Paris Singapore Taipei Tokyo Toronto and associated companies in Berlin Ibadan Oxford is a trademark of Oxford University Press Published in the United States by Oxford University Press Inc., New York © David T. Davies, 1992 First published 1992 Reprinted 1993 (with corrections), 1994, 1995 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, without the prior permission in writing of Oxford University Press. Within the UK, exceptions are allowed in respect of any fair dealing for the purpose of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act, 1988, or in the case of reprographic reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms and in other countries should be sent to the Rights Department, Oxford University Press, at the address above. This book is sold subject to the condition that it shall not, by way of trade or otherwise, be lent, re-sold, hired out, or otherwise circulated without the publisher's prior consent in any form of binding or cover other than that in which it is published and without a similar condition including this condition being imposed on the subsequent purchaser. A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data Davies, David T. Aromatic heterocyclic chemistry/David T. Davies. I. Heterocyclic chemistry. I. Title. QD400.D38 1991 547'.S9-dc20 91-34831 ISBN 0 19 855660 8 (Pbk) Printed in Great Britain by The Bath Press, Avon Series Editor's Foreword Aromatic heterocyclic chemistry is an enormous and complex subject of great industrial and academic significance. A number of the molecules of life are derived from aromatic heterocycles and many important pharmaceutical and agrochemical compounds are based on aromatic heterocycles. Consequently, the importance of aromatic heterocyclic chemistry has stimulated a vast amount of synthetic and theoretical work in the area. Oxford Chemistry Primers have been designed to provide concise introductions relevant to all students of chemistry, and contain only the essential material that would be covered in an 8-10 lecture course. In this primer David Davies has produced an excellent introduction to aromatic heterocyclic chemistry that should stimulate any reader to explore further into this vast topic. This primer will be of interest to apprentice and master chemist alike. Stephen G. Davies The Dyson Perrins Laboratory, University of Oxford Preface Heterocyclic chemistry is a vast discipline and at first sight impossible to do justice to in a text of this size. The aim of this book is to present only the essential features of the more important ring systems. Many reaction mechanisms are discussed in detail and several complete syntheses of heterocycles are presented. I hope that the reader will find this text both interesting and instructive, and that it will provide the platform for further study of this fascinating subject. I would like to thank my friends and colleagues at SmithKline Beecham Pharmaceuticals for their helpful comments, including Angela Gadre, Clare Hayward, Chris Johnson, Helen Morgan and vacation students Peter Ainsworth and Francis Montgomery. I am similarly grateful to Prit Shah and colleagues of Glaxo Group Research. I am indebted to Roger Martin of SmithKline Beecham Pharmaceuticals for helping me with the chemical structure drawing package. Professor Gurnos Jones made several helpful comments. Finally, I would like to thank the Series Editor, Steve Davies, for his advice and encouragement, as well as his acceptance of an industrial scientist to write an academic text. Harlow D.T.D. June 1991 To Julie Contents 1 Introduction 1 2 Pyrroles, thiophenes, and furans 10 3 Oxazoles, imidazoles, and thiazoles 20 4 Isoxazoles, pyrazoles, and isothiazoles 28 5 Pyridines 35 6 Quinolines and isoquinolines 46 7 Indoles 53 8 Five-membered ring heterocycles with three or four heteroatoms 61 9 Six-membered ring heterocycles containing one oxygen atom 67 10 Pyrimidines 73 1S Answers to problems 78 Index 87 1. Introduction 1.1 Heterocyclic chemistry Heterocyclic chemistry is a large and important branch of organic chemistry. Heterocycles occur in nature, for instance in nucleic acids (see Chapter 10) and indole alkaloids (see Chapter 7). Synthetic heterocycles have widespread uses as herbicides (e.g. 1.1), fungicides (e.g. 1.2), insecticides (e.g. 1.3), dyes (e.g. 1.4), organic conductors (e.g. 1.5), and, of course, pharmaceutical products such as the anti-ulcer drug 1.6. N-N C1 A O / ^ Cl n - S ^ W * *1 1/ \ s r * „ / 7 fT t X H A- P h ^ o' EtN^N NEt / ^ Y ^O ^^ U 11 O 1.2 1.3 1.2 Aromaticity and heteroaromaticity Any ring system containing at least one heteroatom (i.e. an atom other than The compound numbering system in this chapter is not as odd as it carbon - typically nitrogen, oxygen, or sulphur) can be described as might seem. For more on heterocyclic. This broad definition encompasses both aromatic heterocycles compound 5.1 see Chapter 5, etc. (such as pyridine 5.1) and their non-aromatic counterparts (piperidine 1.7). N N H 5.1 1.7 Aromatic heterocycles are described as being heteroaromatic, and we shall concentrate on these systems in this book at the expense of more saturated systems. Let us now consider the concept of aromaticity with regard to benzene. H H, „H H" ^H H 1.8a The carbon atoms in benzene are sp2 hybridised, and the hydrogen atoms are in the same plane as the carbon atoms. The remaining six p orbitals are at right angles to the plane of the ring and contain six n electrons. Benzene fulfils the Hiickel criteria for aromaticity as applied to cyclic polyenes containing 4n + 2 electrons (where n-1 in this case) in filled p orbitals capable of overlap. Although two mesomeric representations 1.8a,b can be drawn for benzene, this does not imply two rapidly-interconverting forms. Rather, the six 7t electrons are delocalised in molecular orbitals resulting in an annular electron cloud above and below the plane of the ring. Benzene can also be represented by structure 1.9, which emphasises the cyclical arrangement of electrons. In agreement with this theory, the carbon-carbon bond lengths are all equivalent (0.14 nm) and intermediate between that of a single (0.154 nm) and double (0.133 nm) carbon-carbon bond. The extra thermodynamic stabilisation imparted to benzene by this phenomenon of electron delocalisation, called 'resonance', can be determined indirectly. Real, delocalised benzene is thermodynamically more stable than a theoretical cyclohexatriene molecule (i.e. non-delocalised structure 1.8a) by around 150 kJ mol"1. How does this concept of aromaticity apply to typical heterocycles such as pyridine 5.1 and pyrrole 2.1? Pyridine can formally be derived from benzene by replacement of a CH unit by an sp2 hybridised nitrogen atom. Consequently, pyridine has a lone pair of electrons instead of a hydrogen atom. However the six 7t electrons are essentially unchanged, and the pyridine is a relatively aromatic heterocycle. Q N H S.l 2.1 A difficulty arises with five-membered heterocycles such as pyrrole, which at first sight would appear to have only four n electrons, two short of the 4n + 2 Hiickel criteria for aromaticity. The nitrogen atom is sp2 hybridised and formally contains a lone pair of electrons in the remaining p orbital at right angles to the ring. However, the system is delocalised, as shown below. t> o —o © ©N ©N ©N YWj H 2.1 H H H Thus, delocalisation of the nitrogen lone pair completes the sextet of electrons required for aromaticity. These two examples illustrate the point that certain heterocycles (closely analogous to benzene and naphthalene) such as pyridine 5.1, pyrimidine 10.1, and quinoline 6.1 are aromatic 'by right' whereas other heterocycles such as pyrrole 2.1, imidazole 3.2, and triazole 8.7 have to 'earn' aromaticity by delocalisation of a lone pair of electrons from the heteroatom. 5.1 10.1 6.1 2.1 3.2 8.7 What are the consequences of this concept of lone pair delocalisation for a related series of heterocycles such as pyrrole 2.1, thiophene 2.2, and furan 2.3? As delocalisation results in electron loss from the heteroatom concerned, the extent of delocalisation (and hence aromaticity) will vary with the electronegativity of the heteroatom. The highly electronegative oxygen atom in furan holds on to electron density more strongly than the heteroatom in thiophene or pyrrole. Furan is generally considered to have a non-aromatic electron distribution fairly close to that depicted by structure 2.3. Q o o H 2.2 2.3 2.1 In fact the thorny problem as to how aromatic is a particular heterocycle or For a review on the concept of heterocyclic aromaticity see series of heterocycles has been a preoccupation of physical organic chemists Katritzky et a! (1991). for some time. Bond lengths, heats of combustion, spectroscopic data, and theoretically-calculated resonance energies have all been invoked, but an absolute measure of aromaticity remains elusive. Nevertheless, trends regarding relative aromaticity will be alluded to in this text as they arise. 1.3 Synthesis of heterocycles There are many syntheses of the major heterocycles and they are often complementary in that they afford different substitution patterns on the ring. Most of the synthetic methods we shall examine are fairly classical (indeed some are decidedly ancient!) although many of the specific examples are quite modern. Many classical syntheses of heterocycles revolve around the condensation reaction in its various guises. Let us consider the mechanism of a simple acid-catalysed condensation, that of generalised ketone 1.10 and amine 1.11 to give imine 1.12. Protonation of the ketone oxygen atom activates the ketone to nucleophilic attack by the amine. Loss of a proton from 1.13 produces neutral intermediate 1.14. A second protonation, once again on the oxygen atom affords 1.15, which on loss of a water molecule and a proton gives the imine 1.12. All these steps are reversible, but in practice if water can be removed from the equilibrium (for instance by azeotropic distillation) then such reactions can be forced to completion. This type of reaction occurs many times in this text, but in future will not be presented in such detail. The student is strongly advised to work through, using pen and paper, the mechanism shown below and the many subsequent mechanisms. Confidence with reaction mechanisms will facilitate understanding of heterocyclic chemistry and organic chemistry in general. Ri catalytic H + H2N-R2 /=N-R2 1.12 -H,0 1.10 R! 1.11 -H,0 j+H® -H Rl r>„H -H V" +H® K-l i Kj i H,N - R, Rl r2^h r2 R2 1.13 1.14 1.15 The disconnection approach to synthesis essentially involves working backwards from a target compound in a logical manner (so-called retrosynthesis), so that a number of possible routes and starting materials are suggested. This approach has been applied mainly to alicyclic, carbocyclic, and saturated heterocyclic systems. Retrosynthetic analyses are presented in this text not as an all-embracing answer to synthetic problems, but rather as an aid to understanding the actual construction of unsaturated heterocycles. Returning to the condensation presented above, this leads to an important disconnection. The imine-like linkage present in several heterocycles (generalised structure 1.16) can arise from cyclisation of 1.17, containing amino and carbonyl functionalities. The symbol => denotes a disconnection, an analytical process in which a structure is -NH, transformed into a suitable N' precursor 1.16 1.17 Now consider condensation of ammonia with ketoester 1.18. The isolated product is not imine 1.19 but the thermodynamically more stable enamine tautomer 1.20 which has a conjugated double bond system and a strong intramolecular hydrogen-bond. Although not a heterocyclic example, 1.20 illustrates that an enamine-like linkage, as in generalised heterocycle 1.21, is also accessible by a condensation reaction. In a retrosynthetic sense, formal hydrolysis of the carbon-nitrogen bond of 1.21 reveals enol 1.22 which would exist as the more stable ketone tautomer 1.23. Note that in the hydrolytic disconnection step the carbon becomes attached to a hydroxy group and the nitrogen to a hydrogen atom - there is no change in the oxidation levels of carbon or nitrogen. H 1.21 1.22 1.23 Unlike our initial imine disconnection which is restricted to nitrogen heterocycles (with one or two specific exceptions such as pyrylium salts, see Chapter 9), the heteroatom in the enamine or enamine-like disconnection could be divalent. Therefore this disconnection is also applicable to oxygen- and sulphur-containing heterocycles, typified by 1.24 and 1.25. 1.25 Let us see how this disconnection approach can rationalize the synthesis of pyrrole 2.16. 2.16 + NH 1.26 3 Retrosynthetic analysis suggests a double condensation between diketone 1.26 and ammonia. Pyrrole 2.16 can actually be prepared if this way - see Chapter 2.2. Another aid to understanding heterocyclic synthesis in general is the fact that a large number of five- and six-membered heterocycles can be constructed from various combinations of small acyclic molecules by complementary matching of nucleophilic and electrophilic functionality. C-C ©C C© 1.26 o o t-e3 2 NH NH, Returning to the synthesis of pyrrole 2.16, diketone 1.26 can be regarded as a four-carbon bis-electrophilic fragment and ammonia, in this instance, as a bis-nucleophilic nitrogen fragment. Ammonia can form up to three bonds in a nucleophilic manner.