poi Aromatic Heterocyclic Chemistry David T. Davies 0, S | | 0 Ly OXFORD SCIENCE PUBLICATIONS o e\ oyOXFORD CHEMISTRY PRIMERS FoundingfOrganie Editor STEPHEN G. DAVIES Usiverty of Oxtord| Anysical Cheeinry Editor RICHARD G.CONPTON Unieriy of Oxtord Inorganie Chemistey Editor JOHN EVANS Univer ef Southampton ‘Chemica! Enginetring Eeitor (WYNNE GLADDEN, Unversey of Cambetge TS. Thomas Oronie nih Themes of oon ad silicon 2 DT Davies Ammatic heretic chemisry 3 PUR Jenkins Ogynemctalc agent in sybsis 4 M,Ssindury Aromat heme LM Haron Polar earmnsemens ; {6 11 Donohoe Oxidation ard eduction in organic syubess 1 LU. Jones Amina acid and peptide ymhess Second edition 8 C.J Moody and G. H, Whitham Resctve intermediates GM. Momly and LM, Peach Fourdains of organic cherisry 10 R Henderson The mechanism ofeotions at ration metal sites 1 H.M. Carturight Applications of erica inifyence in cherry (M, Dochmann Orgunometllcs I: Compleses with runiion imctal-cwrbonsFoeds 13 M,Dochmann Ogonometlice 2: Complere with iranion inetal-corbonp-bonds 14 CE Houser Cluster molecules ofthe p-lock elements 1S N,J. Winter Chemica bonding 17 RS. Ward Bjfintonal conpounde 18 S.K Scot Oscillations, waves and chaos in chemical icles 19 TR Sofley Atom speci 20 1 Mana Chemica aspect of Basymtesit 21 B.G.Cox Modern liquid phase hinericr 22 A Marion Fractals in cherry 23 MT Weller Inergone material chemists 24 RB Wayne Chemiclintmmenttion 25 DLE. Fenton Biocoordinarionchemisry 26 W.G, Rchars and PR, Seon Enon lewls in atoms and smoleuler 27M Winter cBlock chemisry 28 DMP Mingos Essemias of inorganic chemitry 1 29 G.H. Grantand W.G. Richards Camputetionlchemisry 30 S.A.Lee and G, E. Robinson Process development: Fine chemicals Frost grams ia ilograms 31 CL. Wills and M.R. Wills Orgone yes 32 RL Hore Nuclear magnetic resonance 33 G.H. Whitham Orgonosulferchemizry 34 A.C, Fisher Elecrode dinanies 35. G.D. Meakins Functional groups: Characters end Interconversions 36 ALL Kirby Sereeletonic effets 37 RA.Cox lnradton io quantum theory and atom strture 38 RD. Bailey and K. M, Morgan Orgaroniogenchemisry 29 CE Wayne and RP Wayne Photochemistry 40 C.R Lawrence. A. Rodger and R.G. Compton Foundations o ipsa chemiary Oe $1 R.G.Compion and G. H. W Sanders Elecrade potentials 82 RB. Whaley Taw-phae flow and het wansfer ‘3 LM. Harwood and. DW. Claridge intedection to organic speciescopy CE Howsecrof Metal-meal bored carbon dimers and eusers 45H. Masi Meckanioms of ongani reactions 46 BC Witkin and RG. Wil : chemistry in biole snore 37. ones Coe carbon chemisry $8 - NB. Green Quantum meckanics 1: Foundations 49 US. Metalic Chemical revton engineering first couse $0 RLS. Winterton Heat rantfir SI N.C. Nowran Periadicig-and he sand Huck elements $2 RLW,Canall Chemical tensors 53M. Bowker The Basis and upplcaions of Aeterercous cetassit 54 M.C. Grose dlc chemi: 551M. Broan Noleelar specoscopy: 56 G.1 Price Mhermodhnamics of chemical processes 51 A.G. Howard Aquatic emironmenialchenisry 58 A.O.S, Muezek Sitsticelshemmadnamies 59 G.A.Atan and. J, Bames Surfaces 60) W. Clegg Crystal structure determin (LM. Brovard Rezction hamlet 62 A. Besdon /nnganicspeetrucopic methads {63 G. Proctor Steeoslecty in organi sythesis 64 C.M.A. Bretand A.M. 0, Bret Elecroarubsis 65. N.J.B, Green Quontum mechanics 2: The toolkit 66 D.M. BMingos Essential of inaganicchemitry 2 657 Fleming Prey reactions 68 N.S. Lawrence, J.D. Wachawan & R. G. Compton Foundation of phssical chemise Hoked examples 69-1 R.Chippefield Non-aqueous solvents 1 T.1.Mason Sonackemiatry 71 LMeCleveny Chemistry ofthe fstrow tranition metals 72 E.C.Consable Coortnation chemistry of macroyeie compounds 73 C.E-Houscroft The heaser dock meal: Aspects ofiargaic and coordination chemtry 74 RD. Bees, RA. Gale and D. K. Smith Supramolecular chemistry 76. N.Kaltoyanns and P Scot The felemtents 77 DS. Sivinand SG. Rewlings Foundations of tience mathematics 7B §, Ducket and B. Gilbert Foundations of spectroscopy 79 J.H, Atherton and K. 1. Carpenter Process development: Physicochemical coaceptt 80 Rede Levie Acid-base equilibria and trations 81H. Masil Siruture ond reactivity in organic chemistry 2 8 8 85 86 7 D.S.SiviaandS. G. Rawlings Foundations of science mathematics: Worked problems J: 1pgo NAR Speciroscopy in inorgonie chemise 2 Biggs Computer in chemistry DLL Waton andP Lorimer Polymers RA Davey and Garside From molecules to cnsillcers GM. Homby and JM. Peach Foundations ofrgonc chemin: Worked examples ‘88 M.1T. Robinson Organi serochemtsiry 89 HRN Jones Radiation het transfer 90 4, Saunders Top drugs—topsyntheric routes ‘LM, 1 Peckins Radical chemisry: The fundamentals 92 B3.Hore,1.A, Jones, and S. Wimperis NAIR: The tolit 93 G.A.D Richie and DS. Siva Foundaon of psc fr chia 94 M.J. Winter and J Andrew Foundations of inorganic chemise 95 J. Robertson Protecting group chem 96 R. Whyman Apliedorgenometallic chem and cuss 97 J.S. Ogden lnroduction 1 molecular symmetry 98 C.M, Dobson, A.J Prat and JA. Gerrard Bioorganic chemists 99 B.G. Davis and A.J Fairbanks Carbohydrate Chemis’ EE re ee ere eee Pete Cee EEE reer reee Hee beetAromatic Heterocyclic Chemistry David T. Davies ‘SmithKine Beecham Pharmaceuticals, Hartow, Essex. OXFORD UNIVERSITY PRESSOXFORD [UNIVERSITY PRESS Great Clarendon Street, Oxford OX2 6DP it i versity of Oxford. versity Press is a department of the University ; 1 foes Tathuiersty’s objective of excellence in research, scholarship, ‘and education by publishing worldwide in Oxford New York ; ‘Auckland Cape Town Dares Salaam Hong Kong Kerachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Dethi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Sly Japan South Korea Poland Portugal ‘Singapore Switzerland Thailand Turkey Ukraine Vietnam Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries Published in the United States by Oxford University Press Inc., New York. © David T. Davies, 1992 ‘The moral rights of the author have been asserted Database right Oxford University Press (maker) Reprinted 2011 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transinitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, or under tetms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction ‘outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this book in any other binding or cover And you must impose this same condition on any acquirer ISBN 978-0:19-855660-2 Printed and bound in Great Britain by CPI Antony Rowe, Chippenham and Eastbourne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 sightimpossible to dojustice to inatext 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. . T would like to thank my friends and colleagues at SmithKline Beecham Pharmaceuticals for their helpful comments, including Angela Gadre, Clare Hayward, Chris Johnsoa, Helen Morgan and vacation students Peter Ainsworth and Francis Montgomery. I am similarly grateful to Prit Shah and colleagues of Glaxo Group Research. Iam iadebted 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. D.T.D. Harlow June 1991To JulieZFS eewaunwn Contents Introduction Pyrroles, thiophenes, and furans Oxazoles, imidazoles, and thiazoles Isoxazoles, pyrazoles, and isothiazoles Pyridines Quinotines and isoquinolines Indoles Five- membered ring heterocycles with three or four heteroatoms Six-membered ring heterocycles containing one oxygen atom Pyrimidines Answers to problems Index 20 28 BeR 61 67 BB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 (eg. 1.4), organic conductors (e.g. 1.5), and, of course, pharmaceutical products such as the anti-ulcer drug 1.6, a x 3 xan &> a re wl tha mAg ENT Sy Net 0 - uM 9 13 1.2 Aromaticity and heteroaromaticity ‘Any ring system containing at least one heteroatom (ie. an atom other than carbon ~ typically nitrogen, oxygen, or sulphur) can be described as heterocyclic. This broad definition encompasses both aromatic heterocycles (uch as pyridine $.1) and their non-aromatic counterparts (piperidine 1.7). N’ H 5A W 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. POOR, The compound numbering system in this chapter is not as odd as it might seem, For more on compound 5.1 see Chapter §, etc.2 Introduction " " 0. 4, H “oC if 1 — 1H " wy H ey i " H 180 tab u rs = 19 re sin benzene are sp” hybridised, and the hydrogen ay aunties same pane asthe carbon atoms, The remaining six p orbitals ma Tight angles to the plane ofthe ring and contain six ™ electrons, Benzene fulfils the Hitckel criteria for aromaticity as applied to cyclic polyenes containing 4n + 2 electrons (where n=l in this case) in filled p orbits lap. ough wo mesa representations 1.83, can be drawn for benzene, this does not imply two rapidly-interconverting forms. Rather, the six lectrons are delocalised in molecular orbitals resulting in an annular electron ‘loud 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 equivalny (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 impacted 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 (ie. non-delocalised structure 1.8a) by around 150 kJ mot-!, 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 sp? hybridised nitrogen atom, Consequently, pyridine has a lone pair of electrons instead of a hydrogen atom, However the six 7 electrons are essentially unchanged, and the pyridine isarelatively aromatic heterocycle. y oO S N’ " H 5A. 24 A difficulty arises with five-membered heterocycles such as pyrrole, which at first sight would appear to have only four m electrons, 1wo short of the 4 + 2 Hiickel criteria for aromaticity. The nitrogen atom is sp” 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. G 5 ° U \ = = Opt Ge + B+ O-G HoaAromatic heterocyclic chemistry 3 ‘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 ‘eam’ aromaticity by delocalisation of a lone pair of electrons from the heteroatom. oc wm & & FY N" Ne N’ H H H SA 10.1 61 a 32 87 ‘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 2.32 As delocalisation results in electron loss from the heteroatom concemed, 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. N’ Ss 0" H 24 22 23 Tn fact the thomy problem as to how aromatic is a particular heterocycle or For a review on the concept of series of heterocycles has been a preoccupation of physical organic chemists femrenele wamatcly see 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 modem, 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4 Introduction The symbol = denotes a isconnection, an anaiytical process in which a structure is transformed into a suitable precursor ae reversible, but in practice if water o imine 112. All ese Tum (Zor instance by szeotropic distilation removed from the Cll foreed 10 completion. This type of reaction o¢g such reaetions Oren, ut in future will not be presented in such mechanism shown below and the many subsequent MEETAnISms. Condens Icha emechanisms will facilitate understanding of heteroey, Chemistry and organic chemistry in general ry R, R catalytic H! SN 20 + HN | a9 x Ra tn 110 Ry Li AH —H\H Is" Ne R, 7 ® ReO-H a ye 8 on EN oe x Rt RL % pa 13 14 us "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 ae 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. Retuming 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. ome he 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, 7 ‘COR NH, CO;Bt io Lo ‘ 7 : 0 19 120Aromatic heterocyclic chemistry 5 Ina 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, R Ron ~NH R-So Ni H 124 122 123 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, LO = Bre = Ro Ron ~Ol R ‘OH ‘1 ‘0 2: DO = Que ey R a ‘on ~SH ane ‘SH = Let us see how this disconnection approach can rationalize the synthesis of, pyrrole 2,16, AM ~~ . Wa y tale Se 6 2 ¢ 2} 216 + NH 126 Retrosynthetic analysis suggests a double condensation between diketone 1.26 and ammonia. Pyrrole 2.16 can actually be prepared if this way ~ sce 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 ge ec ce 1 0 0 LD NH; ae 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6 Introduction i ne correct oxidation level automatical Inthis Pat on ving pyrrole 2.16 directly. in ogra from the conden Hfford the correct oxidation level and an uns, cyclisation dos MM ased to achiove aromaticily. For instance, 15. Sperm ao to pyridines 1.29. HOH fo s ‘Ni; Coe OL R7SO O7-R R7 NTR RONAN : 128 1 arate keto, OXiiseg 1a sation-oxidation strategy include the synthesis 142) and syntheses of quinolines and isoquinoline, Chapter 6), Some examples of nucleophilic and electrophilic fragment Shown in Table 1.1. Several points arise from the table, ‘Consider acylating species such as acid chlorides. Acylation of diaming 1.30 intially gives amide 1.31 which undergoes a condensation to produce imidazole 1.32. The carbonyl moiety is acting exclusively as ay Examples of this cycl pyridotriazine 5.32 (page benzi celectropt ° we gahe — ‘NH, 130 However, delocalisation of the nitrogen lone pair in the amide linkage (see mesomeric representations 1.33a,b) produces a nucleophilic oxygen atom which can react with electrophiles as shown, ° 0° yh, Bgeh,, Y H 1330 H 1335 2° 7 o-E Baye anaied BAR,Aromatic heterocyclic chemistry 7 Nucleophilic fragments Table LA No. of ring atoms 1 NHy,HO,1,8 (see Chapters 2 and 5) 2 NONE: HN-OH (see pyratole and tsoxazole symihesis, Chapters) NH, NH Ni NH Ni 2 sAny stn sty Ay ony (see thiazole sythesis, Chapter 3,and pyrimidine synthecs, Chapter 10) a ce (see quinoline synthesis, Chapter 6} NE; COC tmnt te ch ‘NE Lyte he 5 CI (ee bags, Cate) 2 ‘Blectrophilic fragments Novtsingatms IL (X= leaving group, eg. Cl. see bensimidesole sythets, Chapter! 1 RSX and isoquinoline syuhess, Chapter 6) ° ° 2 “he (on {see thiazole sythesis, Chapter 3) x x °° a RyRy = allyl or O-allyt (see pyrazole and isoxazole symhests, Chapter 4, and pyrimidine syathess, Chapter 10) ‘Nucleophilic / Electrophitie fragments ‘No. of ring atoms _ 2 Aw, (see Chapter J and oxazole synthesis, Chapter 3) wpe ° any (ee lpr endear se, Co) we ° a (see extol sites, Chaper 3, and Keorr pyrrole ; AR gmt cre nN8 Introduction ‘Tho roaction of an acylting spacios with a nuctoophte Is shown below. the two-stage process is abbreviated thus: oh Onwe aay R® Noe p= ° R So RS Nuc R ° Au Nut "Noe this manner as, for example, in the acylation of any, “Amides can cyelize in rf acids 1.3410 afford oxazolidinone ° 0 9 a. excess J mgr, Ro Yee "Ur ° a ‘OH Mi 134 R us —— nse i i included in both electrophilic lating species are thus inc i Aeteoplieeecropilc categories in Table 1.1. For a related example see Js of oxazoles in Chapter 3. oe Me preutonyl ‘compounds, such as malonate derivatives, can also by i imply as a three-at classified under two categories. As well as reacting simp! i biselectrophilic fragment (asin the synthesis of barbiturate 10.25 (page 7p, an altemative reactivity is available, Condensation (by nucleophilic ancy) of the active methylene carbon and electrophilic reaction at just one of te carbonyl groups is a two-atom nucleophilic/electrophilic profile, as seen in the preparation of coumarin 9.16. ; : Oe OO oe on B07 HHO oo 9.16 - HOH ° on = Fo Noe B10 ‘These concepts of retrosynthesis and heterocycle construction will help pat the syntheses encountered in the following chapters into a brosder perspective, 1.4 References Textbooks Acheson, RM. (1967). An introduction to the chemistry of heterocyclic ‘compounds, (2nd edn). Wiley, New York. Paquette, L.A. (1966). Principles of modern heterocyclic chemistry. Benjamin, New York, Joule, JA. and Smith, G.F. (1979). Heterocyclic chemistry, (2nd ed). ‘Van Nostrand Reinhold, New York, Gilchrist, T.L, (1985). Heterocyclic chemistry. Longman, Harlow.Aromatic heterocyclic chemistry 9 ‘The first two (Acheson and Paquette) are still very good texts even today. OF the more recent pair, both are warmly recommended, Joule and Smith is possibly a more introductory text than Gilchrist, which contains many journal references and is pitched at the advanced undergraduate/posigraduate level. See Gilchrist for a discussion of the nucleophilic/electrophilic fragment approach to heterocyclic synthesis, Warren, S. (1978). Designing organic syntheses, p.150-172. Wiley, Chichester. Warren S. (1982), Organic synthesis - the disconnection approach, p. 3260-345. Wiley, Chichester. Reference books and series Coffey, S. (ed.) (1973 ~ 1986). Heterocyclic compounds (Vols. 4A - 4K of Rodd’ chemistry of carbon compounds). Elsevier, Amsterdam. Elderfield, R.C. (ed.) (1950 - 1967). Heterocyclic chemistry, Vols. 1 - 9. Wiley, New York. Katritzky, A.R. and Boulton, A.J. (ed) (1963 ~ 1989). Advances in heterocyclic chemistry, Vols. 1~ 45, Academic Press, Orlando. Katritzky, A.R. and Rees, C.W. (ed.) (1984). Comprehensive heterocyclic chemisiry, Vols. 1-8. Pergamon Press, Oxford. Katriteky, A.R. et al, (1991), Heterocycles, 32, 127-161 Sammes, P.G. (ed.) (1979). Heterocyclic chemistry (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis). Pergamon Press, Oxford. Weissburger, A. and Taylor, E.C. (ed.) (1950 ~ 1990). The chemistry of heterocyclic compounds. Wiley Interscience, New York. All of these sources contain excellent reviews on virtually every aspect of heterocyclic chemistry. In particular, Katritzky and Rees is a thoroughly comprehensive work. For those particularly interested in the synthesis of heterocycles as pharmaceutical agents see: Lednicer, D. and Mitscher, L.A. (197, 1980, 1984, and 1990). Organic chemistry of drug synthesis, Vols. 1-4. Wiley, New York. ental references Exp In this introductory text there is little detail regarding solvents, yields, workup procedures, etc. However, several chapters reference a relevant experimental procedure (taken from Organic syntheses or Vogel) which the student is strongly encouraged to read. For an excellent selection of experimental procedures for the synthesis of heterocycles see: Fumiss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989). Vogel's textbook of practical organic chemistry (Sth edn), pp. 1127 - 1194, Longman, Harlow.‘The numbering of heterocycles generally starts at the heteroatom H youu H Under extreme conditions of acidity pyrrole is protonated, but at the C2 position. LS No Na Note that protonation of the pyrrole nitrogen would lead to a ‘non-aromatic cation. 2. Pyrroles, thiophenes, and furans 2.1 Introduction i furan 2.3, are five-membered i pyrrole 2.1, thiophene 2.2, and red tin ereronromatic compounds containing one heteroatom, They derive thei, wromaticity from delocalisation of a lone pair of electrons from th heteroatom, Consequently the lone pair is not available for protonation ang rence these heterocycles are not basic. 43 4 3 slo sl’. US: Hu! s 24 22 23 ‘The basis and extent of their aromaticity is discussed in Chapter 1. In summary, the capacity for the lone pair on a particular heteroatom to be delocalised is inversely related to the electronegativity of the heteroatom. For instance, furan is the least aromatic of the trio because oxygen has the greatest electronegativity and hence mesomeric representations 2.4b-e make relatively less of a contribution to the electronic structure of furan than they do in the cases of pyrrole and thiophene. The order of aromaticity is furan < pyrrole < thiophene. We shall see later how this variation in aromaticity affects the reactivities of these three related heterocycles. CS = = 6, e | (+ Dove of D a &) al) e eS eS 24 2b 2de 24d de X=NH,S,O A small number of simple pyrroles such as 2,5 and 2.6 occur naturally. Far more important are the tetramic pyrrole derivatives (porphyrins) such as chlorophyll-a 2.7 and haem 2.8, , a oy bi 1 OH ze a sy rH aN 2Aromatic heterocyclic chemistry 11 Cot I CO} 28 Acetylenic thiophene 2.9, found in some species of higher plants, is one of the few naturally-occurring thiophenes. However, the thiophene ring is used in several important pharmaceutical products, such as the penicillin antibiotic 2.10. COM yy oe OMe Zs c 5 eX o CO>,H 240 23 S In contrast to the pyrrole and thiophene series, the furan nucleus occurs in many plant-derived terpenes such as 2.11. The most important furan- containing drug is 2.12, which reduces gastric acid secretion and is important in the treatment of ulcers, 2.2. Synthesis of pyrroles, thlophenes, and furans We shall first examine a general synthesis applicable to all three heterocycles, then consider two specific syntheses of pyrroles. Retrosynthetic cleavage of a carbon-heteroatom bond in 2.13 gives enol 2.14 which is equivalent to ketone 2.15. Repeating the process gives us a 1 4-dicarbonyl compound and the heteroatom-containing fragment such as a primary amine or hydrogen sulphide. Chlorophyl-a Is a plant pigment Involved in the crucial photosynthotic process in which the energy of sunlight is hamessed to incorporate carbon dloxlde into plant metabolism, Haem, however, Is fundamental to mammalian biology, being the ‘oxygen-binding component of haemoglobin. Oxygen absorbed ‘rom the air is transported around the body while temporary co- cordinated to the Iron atom of haemoglobin, which occurs in the red blood cells. Torpenes are plant-derived natural products constructed of ‘multiples of the five-carbon hydrocarbon isoprene.1d Pyrnotes, thigphones, at eens a) BOR ROM : ee ==,0 = — inl \ OM \ vont x & Xu ¥ FANS vv the Paat-Kove syothesis, This is a gy ited only by the aecessibilty’ OF the ye “Whe fonwant prowess is ha ataightionwant syattiesis ti Aicarbonyt precuTsos. » ‘ho mechanism is iistatedd by wr oh fo 282, Co the preparation of 2$stimettyt ox @®a, \: byte 2.18 and is Sin BO u consecutive confensations, NM ‘l ou i Wate LOS Hane Ul Se . OF v " ty 26 nthesis can similarly be applied 10 thiophenes, eg, “The Paat-Rnore coanpornds 2.17 = 2.20, PSS; pou us PSs US — sa, O mn Cen « \ Ph C \~~coai wCI AV 7 A th On Ni 5 tN. COs xy 220 When hytrogen sulphide is the heteroatom source the mechanism is similar to the pyrrote ease, sy a nk ye oe GQ) Px wv a0 NX . nh X, ANS Py e= ol MN SA gH NS POS NS 27 However, the situation is slightly different when phosphorus (\) sulphide is used, This wagent converts ketones to thioketones, by exchange ‘ofa phosphorus-sulphur double bond with a carbon-oxyigen double band, “ x eK PYG hey 3 SS sAromatic heterocyclic chemistry 13 For instance, in the synthesis of 2.19, the 1,4-diketone is converted into the corresponding 1,4-dithioketone followed by loss of hydrogen sulphide, PSs = 1s ‘The mechanism of the cyclisation mi em > mS NL, Stops siar oat! ophone 0° ss Ss 247. 2 Our retrosynthetic analysis of the Paal-Knorr synthesis leads to a problem ‘when applied to furan, as it implies addition of a water molecule, followed by elimination of two water molecules. In practice, simple dehydration of a 1,4- dicarbonyl compound leads to furans as in the preparation of 2.21. 1470, a BO, a Sanne Les i pao Ph pmo tH mag Tey Returning again to pyrroles, probably the most widely-used method for their preparation is the Knorr pyrrole synthesis, which is the condensation of a ketone 2.22 with an c-aminoketone 2,23 to give pyrrole 2.13, via enamine 2.24. A reasonable mechanism is shown below, although none of the intermediates is isolated. 23 ‘The c-aminoketones are often prepared by nitrosation of an active methylene group followed by reduction of the oxime to the amine (e.g. 2.25 to 2.26 to 2.27). ° Aron. She zemor Dhcoom | ae Aye 225 Sor Ny Wea uF A ACOH NH, 1A ian iad 2a As w-aminoketones are prone to self-condensation (see page 22 for a discussion of .-aminoketones), the initial condensation step is facilitated by Ro in 2.22 being an clectron-withdrawing group. This enhances the ‘electrophilic nature of the ketone carbonyl group thereby increasing the rate of the desired reaction, and favours enamine tautomer 2.24 over the imino14 Pyrroles, thiophenes, and furans Tho Knorr pyrrole synthosis consists of a kotone and amino condensing to give an enamine, followed by intramolecular cyclisation of this enamine onto the remaining ketone, Note that pyrrole reacts with ‘lectrophiles on carbon, like an enamine. of conjugation with the electron-withdrav in tnlom pprmotesyheses, showing the Key intermediate cm A selection es, js shown below: ° CO;Et Cone oe — Lo ag H,N~ ~cO,Et HCO NT COR, °. COXE 0. cdi. Ao HN’ H x CO;E Ox Glin CO OK cay — RS, Xo oso coe f Coens Ph. on Ph Ph. Os Ph mo Mle HSo | HNT TPR 7 ee 2.3 Electrophilic substitution of pyrrole, thiophene, and furan All three heterocycles undergo aromatic substitution reactions, though ter reactivities vary considerably. Let us consider a generalised mechanism and how the stability of the two possible intermediates affects the position of substitution, X=NHSO 2298 2298 ‘The intermediate derived from attack at the C2 position has great delocalisation of the positive charge (mesomeric forms 2.28a,b,c) than ts derived from attack at the C3.position (mesomeric forms 2.29a,b). As te charge is more extensively delocalised in the former, this intermediate lower energy. This in tum is reflected in a lower activation energy f° Pathway and manifested in a selectivity for electrophilic substitution 2 C2 position over the C3 position. The actual isomer ratio depends 0° heterocycle, the electrophile, and the precise conditions, although in m="! ases such reactions are virtually régiospecific, and only the C2 substié®Aromatic heterocyclic chemistry 15 jucts are isolated. Very reactive clectrophiles (such as the nitronium ion NO}*) exhibit lower selectivity because they tend to be less discriminating as to where they attack the heteroaromatic nucleus. ‘The case of electrophilic substitution is pyrrole > furan > thiophene > benzene. Pi Pyrrole is extremely reactive towards electrophiles while thiophene, the most aromatic of the trio, is much less reactive. At a very rough approximation, the reactivity of thiophene is of the order of a heteroatom- substituted benzene derivative such as phenol. Despite large differences in the rates of electrophilic substitutions there are some important aromatic, substitution reactions common to all three heterocycles. ‘The Vilsmeier reaction is the formylation of reactive aromatic compounds by using a combination of phosphorus oxychloride and N,N- dimethylformamide, followed by a hydrolytic workup. OY etexctosrocy OW x 2.10 X=NHSO H ‘The reaction proceeds by formation of the electrophilic Vilsmeier complex 2.30, followed by electrophilic substitution of the heterocycle. The formyl group is generated in the hydrolytic workup. Pyrrole, thiophene, and furan all undergo this formylation which is highly selective for the C2 position, mt. q ° a aia Bod @ ay ae See, a? 230 Sa nme, 1 All three heterocycles undergo sulphonation with the pyridine-sulphur trioxide complex. This behaves like a mild source of sulphur trioxide, enabling. the sulphonation to be carried out under essentially neutral Q : ee Furan and pyrrole are not stable to mineral acids, but acetyl nitrate can be used for the nitration of all three heterocycles. Da; -M a DB paek NO; To give a quantitative feel for these differences in reactivity, data for the bromination of thrae roprosontative dorivatives aro ‘shown below. cone In 14) cone _X— Relative Rate s 1 Oo 12x10 NH 56x1016 Pyrrotes, shiophenes, and furans ‘Tho formation of 2.92 rases an important theoretical point: because furan is not very aromatic and the driving force to ‘re- ‘aromatise’ by loss of a proton is ‘not very strong, cation 2.31 can bbe intercepted to give 2.92, This ‘behaviour is not observed with pyttola and thiophene. ‘Observe that etectophilic substitution occurs at the C3 Position when both the C2 and 05 Positions are blocked. ‘ils the mechanism shown above applic Lo pyrrole and thon nitration of furan with arising from attack of furan 2.33. ° ‘Thiophene, alkyl-substituted furans, and especially pyrrole, undrgy ‘acetate jon on the intermediate cation 2.31, 7, of 2.32 with pyridine eliminates the elements of acetic acid Producing Mannich reactions. HONE FV we QS ar On 7 Fi 1 t,o Ney 010, 1 cH,0 /iiMes rr AY seme aa ‘This involves condensation of the heterocycle, formaldehyde, and an amine 0" (usually a secondary amine) to give an aminomethyl derivative, AcOI eS rwgatscro SOs cH Rom Poh GE SS One Laren — Os CX c= NM, ot x’ ‘The Friedel-Crafis acylation and alkylation reactions are fundamen processes in aromatic chemistry. Pysroles and furans are not stable tot Lewis acids necessary for these reactions, but thiophenes are stable to Levit acids, and do undergo Friedel-Crafts acylation and alkylation, a s Pacoal ! \0 AICI, cHcoct ° ac Ebr AICh, \ he 1 acetyl nitrate gives the 2,5-addition produgr 12.3)Aromatic heterocyclic chemistry 17 The reactivity of all three heterocyles is considerably reduced when electron-withdrawing groups are present on the ring. This is important in the synthesis of pyrrole derivatives as it adds chemical stability to the ring, ‘enabling reactions to be performed in the presence of Lewis acids. NQ NO, q \ Ago N BFyOE, ( SU The regiochomistry of theso u o oF reactions is easily explained by rallonalisations from classical benzene chemisty, ie. electron- C\ we, TY varaving groups dest mot NO, BFsOE,” —\y7>NO, Hq CH,O a com 8 OO} HCI 37" COaNe oa 2.4 Anion chemistry of pyrroles, thiophenes, and furans Pyrrole has a weakly acidic hydrogen atom attached to the nitrogen (pKg= 17.5) and can be deprotonated by strong bases. The sodium and potassium salts are ionic in character and the naked anion tends to react on nitrogen as in the preparation of N-methyl pyrrole 2.34, The corresponding magnesium derivative 2.35 has more covalent character and tends to react more on carbon. than nitrogen, as in the preparation of pyrrole aldehyde 2.36 Q a OO Oo: nN a 3 ne 7 raat oO oe = Osh Oy a 235 N-methyl pyrrole 2.34, thiophene, and furan can be metallated at the C2 position with alkyl lithium reagents. This position is more activated to deprotonation than the C3 position because of the electron-withdrawing inductive effect of the heteroatom. The nucleophilic 2lthio species can then be reacted with various electrophiles, as in the preparation of 2.37, 2.38,18 Pyrroles, thiophenes, and furans ‘Tho precise nature of the carbon— lithium bond is beyond the scope of this book. Organofithium intermediates are hore ‘epresented as carbanion and cation to emphasis difloronces in Properties and roactivities as compared with full covatent bonds. ‘The alkyl group at the C2 position is not deprotonated in the second alkylation, Noto tho use of “CN as a synthon for "CO2H. and 2,39, Let us sce how this methodology can be applied to the synthesis of 2.42, a furan-containing mimic of a long-chain fatty acid. Deprotona bent furan and alkylation produces 2.39. A second deprotonation. ihe £2 position and alkylation gives bromide 2.40. Displacement of the affords nitrile 2.42, and acidic hydrolysis yields the target furan 2.42, : ICOpMe 71 & ba © eu? oe Od come Me Me ae 237 DO ™, Deue 2 OX 9 is S508 22 23s peDoli / CHy(CH)),Br Bull /B(CH).Br f\ ——— f\ —— ‘O CHYCHD.” ~o' CHy(CH)6 97 ~ (CHDBr 2 239 240 i 11,0 i \ exer o> ceapscogn Fee ca cry AM (CHD CN 0" 202 2aL 2.5 Problems ‘Tricyclic pyrrole derivative 2.43 is a drug currently under development for the treatment of schizophrenia. It is prepared by a Knorr pyrrole synthesis. What are the structures of the two starting materials required, and that of the intermediate enamine? 2. Why is pyrrole aldehyde 2.44 less reactive to nucleophiles than, say, benzaldehyde? Why is pyrrole alcohol 2.45 readily polymerised on exposure toacid?Aromatic heterocyclic chemistry 19 3, Nitration of furan with nitronium tetraftuoroborate produces nitrofuran 2.33 directly. Contrast this result to the two stage reaction necessary with acetyl nitrate, page 16, Explain these observations. . oe & oS Me, 22 233 4, What is the mechanism of this reaction? OY poor, oy, ff \ ~xa, s Ss ‘AIG 22 2.6 References Dean, F.M. (1982). Adv. heterocyclic chem, 30, 167; 31, 237 (furans), Gronowitz, S. (ed.) (1985). In Thiophene and its derivatives (The chemistry of heterocyclic compounds fed, A. Weissburger and E.C. Taylor}, Vol. 44). Wiley Interscience, New York. Furniss, B.S., Hannaford, A.J., Smith, P.W,G, and Tatchell, A.R. (1989). Vogel's textbook of practical organic chemistry (5th edn), p.1148 (preparation of pyrrole 2.16), Longman, Harlow. Jackson, AH, (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis) (pyrroles). Pergamon Press, Oxford. Jones, RA. (ed.) (1990). In Pyrroles (The chemistry of heterocyclic compounds (ed. A. Weissburger and E.C, Taylor}, Vol 48, Part 1). Wiley Interscience, New York. Jones, R.A. and Bean, G.P. (1977). The chemistry of pyrroles. Academic Press, London. Jones, E. and Moodie, LM. (1970). Org. syn., 50, 104 (C2 metallation of thiophene). Katritaky, A.R. and Rees, C.W. (ed.) (1984). Comprehensive heterocyclic chemistry, Vol. 4, Part 3. (five-membered rings with one heteroatom). Pergamon Press, Oxford. Meth-Cohn, O. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis), p.737 (thiophenes). Pergamon Press, Oxford. Sargent, M.V. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis), p.693 (furans). Pergamon Press, Oxford. Silverstein, R.M., Ryskiewicz, E.B., and Willard, C. (1963). Organic ‘syntheses, Coll. Vol. IV, 831 (Vilsmeier formylation of pyrrole).The biosynthesis of histamine involves decarboxylation of the amino acid histidine. 3. Oxazoles, imidazoles, and thiazoles 3.1 Introduction Oxazole 3.1, imidazole 3.2, and thiazole 3.3 are the parent structures of related series of 1,3-azoles containing a nitrogen atom plus a second heteroatom in a five-membered ring. 3 3 4oN aN sll Sa sl Sa 07 87 a 33 ‘They are isomeric with the 1,2-azoles isoxazole, pyrazole, and isothiazole (see Chapter 4). Their aromaticity derives from delocalisation of a lone pair from the second heteroatom, 3.4a-e. e ah Ne x a on G7 & - QO ++ Lp — Oe 34a 3Ab 34e 346 ‘34e XeO.NHS ‘The imidazole ring occurs naturally in histamine 3.5, an important mediator of inflammation and gastric acid secretion. A quaternised thiazole ting is found in the essential vitamin thiamin 3.6. There are few naturally occurring oxazoles, apart from some secondary metabolites from plant and fungal sources. NH, ® ‘th i IES \ 0 WA x 35 3.6 Oxazole, imidazole, and thiazole can be formally derived from furan, pyrrole, and thiophene respectively by replacement of a CH group by & nitrogen atom at the 3 position. The presence of this pyridine-like nitrogen deactivates the 1,3-azoles towards electrophilic attack and increases their susceptibility towards nucleophilic attack (sec later), ‘These 1,3-azoles can be viewed as hybrids between furan, pyrrole, or thiophene, and pyridine,‘Aromatic heterocyclic chemistry 21 Imidazole (pX'j=7.0) is more basic than oxazole (pk4=0.8) or thiazole (pK,=2.5). This increased basicity arises from the greater electron-releasing capacity of two nitrogen atoms relative to a combination of nitrogen and a heteroatom of higher electronegativity. Also note that a symmetrical resonance-stabilised cation 3.7a,b is formed. ce ex e O~| Ow O : x % i ii an Furthermore, certain substituted imidazoles can exist in two tautomeric forms. N nt Bev 38 39 For instance, the imidazole shown above exists as a rapidly equilibrating mixture of 4-methyl 3.8 and S-methyl 3.9 tautomers, and is referred to as 4(5)-methylimidazole. [t must again be stressed that tautomerisation and resonance are totally different. Mesomeric representations 3.7a,b are not interconverting like tautomers 3.8 and 3.9; this is simply a means to deseribe an intermediate hybrid structure, 3.2. Synthesis of oxazoles Retrosynthetic cleavage of the carbon-oxygen bond in generalised oxazole 3.10 produces iminoalcohol 3.11 (better represented in the amide form * PS" TY" 7 SR om on (O° 32 340 3b 4. rk YS 3.12). Similar tautomerisation of the enol group gives an actual intermediate 3.13, and disconnection of the amide linkage reveals ‘aminoketone 3.15 and an acylating species 3.14 such as an acid chloride. The forward process, eyclocondensation of amides 3.13 to yield oxazoles 3.10, is known as the Robinson-Gabriel synthesis. ‘The statommont that oxazole has a pK, of 0.8 means that ho protonated form of oxazole is a vory strong acid. Therefore oxazole (as the tree base) is a vory weak base indeed.22 Oxazoles, imidazoles, and thiazoles wk Rog R Ry hooRS x ~% 1,0 va —— Rk R—> £ ke B eo rate i 3s 313 3.10 In practice the dehydration can be achieved with a broad range of acids or ‘cid anhydrides, such as phosphoric acid, phosphorus oxychloride, phosgene (COCIg), and thiony! chloride, An example of the mechanism is shown below for thionyl chloride and involves activation of the amide to imidoly} halide 3.16 then intramolecular attack by the enotic form of the ketone. H ‘ ~ éy R NY UR, NR; NO _LRy Re NWR -HO Tr Sey Rasy Sy) Bee FY "Oe te eT eh a, RO we S2OR ROMS = S02 RYO Ry 333 a a a6 a0 ‘The aminoketones themselves can be prepared by a number of methods. A typical route is illustrated by the synthesis of anti-inflammatory drug 3.23. ~ Be, Bray Ms ape “cme + — = pH SO. Pro PaO Ha PASO. aa7 aus 349 320 ° EGN (eq) coe | Ph, Ph. N N 4 cost rs NOH x Poa, N aAgrcom tid yA we Ph 323 ‘3.22 32k Drugs which reduce inflammation are often used to troat tho symptoms of arthritis, Bromination of ketone 3.17 gives 3.18 which can be converted to azide 3.19. Hydrogenation of 3.19 in the presence of hydrochloric acid affords aminoketone hydrochloride salt 3.20, Such aminoketones are often isolated as the corresponding salts because. the free aminoketones are prone 10 dimerisation, having both nucleophilic and electrophilic centres. (Fot 3 common altemative preparation of aminoketones, see the Knorr py‘role bie Chapter 2.) Liberation of the free base of 3.20 in the presence of i ‘an chloride affords amide 3.21 which is cyclised to oxazole 3.22. Ester 'ydrolysis then affords the biologically-active carboxylic acid 3.23. 3.3 Synthesls of imidazoles Although there are seve outstanding method, ral ways of preparing imidazoles, there is no one One useful synthesis is the condensation of # 1-2Aromatic heterocyclic chemisiry 23 icarbonyl compound with ammonium acetate and an aldehyde, as in the preparation of imidazole 3.25. ME Boo, ‘A reasonable rationalisation is a eyclocondensation type of process to give 3.24 followed by irreversible tautomerisation to 3.25, 0 om ome ea ne 98 why, one Wy RUNS RO ey na} Ray Ser" ba Se a fort is os 324 3.4 Synthesis of thlazoles Retrosynthetic disconnection of the nitrogen-carbon bond in thiazole 3.26 leads formally to enol 3.27 which is equivalent to ketone 3.28. This can be derived from haloketone 3.29 and thioamide 3.30. a, N Oy ° oO Nit mo = TRS x aon ashe, wy shay ax sy 327 328 329 330 X-C1Be 326 “The forward process is the Hantzsch synthesis of thiazoles which, despite its antiquity (it is around 100 years old), is still very widely used. Nik _ por wT ake, y y wae O& exten crite ‘much more nuctoophilicthan 3at ‘carbonyl compounds because ‘The mechanism for the formation of thiazole 3.31 involves initial oftholower oloctronogatvity cof sulphur as compared to nucleophilic attack by sulphur followed by a cyclocondensation, eon24 Oxazoles, imidazoles, and thiazoles wD) rN ony Oe yl a m0 v3 Gy par En OL ver TAN wes aa ‘The thioamides themselves are conveniently prepared from the corresponding aimides by treatment with phosphorus (V) sulphide (see the Paal—Knorr synthesis of thiophenes, Chapter 2, for this type of conversion). A variation of the Hantzsch reaction utilises thioureas, where R3 in 3.30 is a nitrogen and not a earbon substituent. For instance, thiourea itself is used in the preparation of 2-aminothiazoles such as 3.32. 6 NH TS Noo! ve — eof J sAm k Seater oH 332, 3.5 Electrophilic substitution reactions of oxazoles, imidazoles, and thiazoles ine, not only does The 1,3-azoles are not very reactive towards electrophilic attack due to the As with pyr the electronegative ona atom deactivating effect of the pyridine-like nitrogen. However, electron-donating ee arumertelesde groups can facilitate electrophilic attack, as in the preparation of oxazoles conditions of mary electrephiic 3.34 and 3.35. Dimethylamino oxazole 3,33 is essentially functioning like reactions the azole ritrogen isan enamine in this reaction, protonated. Tho azolium cation is relatively inert to further attack by (_ a positively charged electrophilo. rm, on Kcr, cry r NORCO aS © cE @, lt MS oon a4 MeNTp ro” Ph MeaNF S07 Ph MeN x © x y~ ER Me _= oS ——+ me, OFS No, Ss“ghome BAve og ose 338 Imidazole can be nitrated under forcing conditions, nitration remarkably ‘occurring on the imidazolium cation 3.7a,b, giving nitroimidazole 3.36 after Joss of two protons. N NG N eG Poy us a6 o un n Ww NO: on kop N i \ W Som — "Ee aah No NAromatic heterocyclic chemistry 25 3.6 Anton chemistry of oxazoles, imidazoles, and thiazoles ‘The C2 position of 1,3-azoles is particularly clectron-deficient because of the electron-withdrawing effect of the adjacent heteroatoms. The acidity of the protons at this position is such that deprotonation can be achieved with strong bases to give nucleophilic carbanions 3.37 which can be quenched with electrophiles producing substituted 1,3-azoles 3.38. No N @ N ry 2, Co u0e # Oya @ (eu = Oo Similarly, alkyl groups at the C2 positions (but not the C4 or C5 positions) There is a usef analogy Fal a F betwaen resonance-stabilised ‘can be deprotonated giving carbanions 3.39a,b which can also be quenched 2°72" s90' and an ester with electrophiles to afford 1,3-azoles 3.40. arorate anion. Note that in both cases the negative charge can be delocalised onto a heteroatom. Napa Ne x? 0] 2 7X Ch CX ae OY ee Oe & 3.40, RO e X=ONRS 3398 3.39 Some examples of both the above types of reactivity are given below ‘e x x C3} wpa Ox sos x Batewcn” Sw hs My " x ae TS eo TaaibeHd s m sua Oa TI we. TYE = Ph mags se ag 3H017140 ON Tae” yen wo Figvo Ne ‘2Mel26 Oxazoles, imidazoles, and thiazoles ‘Onco again this reactivity parallels certain features of carbonyl ‘chomistry. Compare the reaction of aniline with chioroformates, below. 3.7 Nucleophilic aromatic substitution of oxazoles, Imidazoles, and thlazoles We have previously discussed the reduced reactivity to clectrophiles of oxarole, imidazole, and thiazole, as compared to furan, pyrrole, and thiophene, which results from the presence of the pyridine-like nitrogen tigrn. This behaviour is paralleled by inereased reactivity to nucleophiles. Nucleophitie tack on furan, pyerole, and thiophene derivatives only occurs hen an additional activating group is present, as in the displacement reaction giving thiophene 3.41. 18 KS Gil Ge 2 Soy aS au, D oN” SS" NO, ~S 80 BAL ‘The nitro group plays a key role as an electron-acceptor in this reaction, which also illustrates the fact that imidazole is a good nucleophile. However, no activation is necessary with 2-halo-1,3-azoles, which ean react with nucleophiles, as shown by the preparations of 3.42 and 3.43. Ph Ph gs Ph. TER te Te eT rao Pao Sup PhS SNHPh 3.42 TaNPh e £ ay He ff Noda 3? a Ce Ox oa 3.8 Problems 1, Suggest a synthesis of oxazole 3.33. “ Aon 3s MeN 2. A less general synthesis of oxazoles isthe condensation of bromoketones with aides. What is the mechanism forthe formation of oxazole 3.44? How does 34 relate fo the oxazole which might be prepared from the ame y conversion to th ing ami formylation, andeyclocondensation? *PONGIPE aminokerone, N- ° Jk Ph Pi a ir Br Heat o> 34Aromatic heterocyclic chemistry 2 3. Carboxylic acid 3.46 has been extensively used in the preparation of semi-synthetic penicillins and cephalosporins. Devise a synthesis of 3.46 from ester 3.45. 3.9 References Campbell, M.M. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis) p. 962 (oxazoles) and p. 967 (thiazoles). Pergamon Press, Oxford. Fumiss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989). Vogel's textbook of practical organic chemistry (Sth edn), p.1153 {preparation of aminothiazole 3.32). Longman, Harlow. Grimmett, M.R. (1970). Adv. heterocyclic chem., 12, 103 (imidazoles). Grimmett, M.R. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Ollis), p:357 (imidazoles). Pergamon Press, Oxford. Grimmett, M.R. (1980). Adv. heterocyclic chem, 27, 241 (imidazoles). Lakhan, R. and Ternai, B, (1974). Adv. heterocyclic chem., 17, 99 (oxazoles). Metzger, J.V. (1979). In Thiazole and its derivatives (The chemistry of heterocyclic compounds (ed. A. Weissburger and E.C. Taylor], Vol. 34). Wiley Interscience, New York. ‘Turchi, LJ. (1986). In Oxazoles (The chemistry of heterocyclic compounds [ed. A. Weissburger and E.C. Taylor], Vol. 45). Wiley Interscience, New York, Turcl LJ. and Dewar, M.J.S. (1975), Chem. rev. ,75, 389 (oxazoles).4, Isoxazoles, pyrazoles, and isothiazoles thiazole 4.3 are the parent structures of having a nitrogen atom plus one other bered ring. Isoxazole 4.1, pyrazole 4.2, and iso the 1,2-azole family of! heterocycles, heteroatom in a 1,2-telationship in a five-ment 43 43 43 71 i" { sQ na sC XN. ee 4 s: 42 43 4a ‘The aromatic sextet is completed by delocalisation of the lone pair from the second heteroatom, 4.4a-e. Consequently, as in pyridine, the nitrogen atoms of the 1,2-azoles have a lone pair available for protonation. However the 1,2- azoles are significantly less basic than the 1,3-azoles because of the electron- withdrawing effect of the adjacent heteroatom, Isoxazole and isothiazole are essentially non-basic heterocycles (pKqs <0), and even pyrazole (pK g=2.5) is a much weaker base than the corresponding 1,3-azole imidazole (pK = eg _ Oy ae Gea Oh ae Che oe oh x" x* s Ne ae Ny ® @ eS 8 4 sa Ba ana é x=onts ). As with substituted imidazoles, substituted pyrazoles may exist as @ mixture of tautomers. 5-Methyl pyrazole 4,5, is oF taro 15 and 3. asap equlibraing mixture in sation, tnd PaaeTe AG ex ee rere tnepeerenAromatic heterocyclic chemistry 29 4,1 Synthesis of isoxazoles and pyrazoles - Retrosynthetic disconnection of generalised 1,2-azole 4.7 gives initially 4.8 which would exist as ketone 4.9, This in tum is clearly derived from 1,3- diketone 4.10, a Ry R, Rs Ry Rs 411 4, 1 HNO = rs = Lh. = a 42 HANNE Ron bog RNo Saat No a NSH 4 49 4.0 In practice hydroxylamine and hydrazine are very reactive nucleophiles, far more so than might be expected trom . z consideration of simple physical This analysis suggests that condensation of 4.10 with hydroxylamine 4.11, parameters. The inceased hydrazine 4.12, or thiohydroxylamine 4.13 should give the corresponding _ucleophilicity of a heteroatom 1,2-az0le. This approzch represents an important route to isoxazoles and When Bonded to 8 second pyrazoles, but thiohydroxylamine 4.13, although known, is far too unstable _hereoatom is know as tho for synthetic purposes. The synthesis of isothiazoles will be mentioned later. Sheet. For a theofe! - lisation ot the fect ir ‘The mechanism of the forward process is illustrated by the preparation of ‘ewe ar tontier obits coe, isoxazole 4.14 and is simply two consecutive condensations, Fleming, 1976. xe H ag nw mm ~ ety AK AB me PEG XL NL re 07 © HN-Oi Won ‘s as Note that if hydroxylamine or a substituted hydrazine is condensed with an unsymmetrical diketone (4.10, where Rj and R3 ate different) then a regioisomeric mixture of isoxazoles or pyrazoles may result. However a single regioisomer may predominate where there is an inherent bias. °o oO ‘The general reactions of HgNOH Ry Rs Bs H.NOH = ns a * Das Ry Ro" RON" oo ke ‘and HoNNHR with unsymmetrical 3 RBs diketones are shown here, HNNER = Ry Ry i \, + Ry ROONT RW R For instance, the preparation of isoxazole 4.17 is virtually regiospecitic because the reaction commences with the more nucleophilic heteroatom (i.e. nitrogen) attacking the more electrophilic ketone (activated by the electron withdrawing inductive effect of the adjacent ester group). The reader is encouraged to consider the regiochemical bias in the preparation of isoxazole 4,15 and pyrazole 4.16.30 Isoxazoles, pyrazoles, and isothiazoles oo O 1 NO; oo = - ( M0" NO, ‘MEO! Ads oN won, 35 ~~ 4 AX BE AG hoot KN =H,0 0" ‘The other important isoxazole synthesis involves the concerted {3#2) cycloaddition reaction of nitrile oxides 4.18 with either alkynes 4.19 o alkyne equivalents 4.20, Ry Ry Ry Ry —* as Ra? Fa oo OW ey nf x A : R a re) R RA _ 6 ACoo ~7 °° 1 . . X=0Ac.NMez,NOz ails range of nitrile oxides is known (R3 = H, aryl, alkyl, esters 2 le method of choice for the preparation of simple nitrile oxides (®3* + aryl) is oxidation of the corresponding oxime: halide. Non -OH Ay A ok 2.8 as ——— or)several wemts can be used (lead Sowwoeinimids, chloting, ete). A mest gre eonbtur hypochlorite tetntisetare, 4 et Ee iMuetearcd Beko bo —— REN a0 Xe ay the synthesis of isoxazole 4.28, a drug for the ircatcut of bronchial asthma, The most direct preparation of icoxarolyl jeune 4.24 is the cycloaddition of unstable bromonittils ovide 4.22 prepa in situ by dohylrobromination of 4.21) with scetylenis ketone 424, ive the regioselectivity of this reaction. Both electron-donating and clectron-withdrawing groups on the acetylenic components in stich cyclondultions tend to occur at the C5 position in the final isoxazole and not at CA. Bromination of ketone 4.24 affords bromoketone 4.23 which is 6 Bo mem | = mn. Br Alt it Br, i ow Ne > = a ‘4 07 Nr ‘0 Or 4at 2 aa 0 aos 0 an sam / a be . ™\ Nas 7 nat NY - NL —_— N ° ithe 0 N 3 " \ on 7 ™ 428 47 426 ou reduced with sodium borohydride to give bromohydrin 4.26, Treatment with a strong base produces epoxide 4.27 via the intermediate alkoxide, and nucleophilic opening of this epoxide at the least sterically hindered position affords the target drug 4.28, 4,2 Synthesis of Isothlazoles Isothiazoles are usually prepared by routes involving formation of the nitrogen-sulphur bond in the cyclisation step. This is often set up by oxidation of the sulphur atom, as in the conversion of thioamide 4.29 to isothiazale 4.30.32 Isoxazoles, pyrazoles, and isothiazoles 43 Electrophilic substitution of isoxazoles, pyrazoles, and isothiazoles ‘The presence of a pyridine-like nitrogen in the 1,2-azoles makes them markedly less reactive towards electrophilic substitution than furan, pyrrole, and thiophene, (The same effect was noted for the 1,3-azoles in Chapter3) Nevertheless, electrophilic substitution is known in 1,2-azoles, occurring principally at the C4 position. This selectivity is reminiscent of pyridine chemistry where the position meta to the electronegative nitrogen atom is the least deactivated’ (see Chapter 5). ‘mr Be mn Bry HEN Hp? nN & NO Ce Br Br in By HYG -u® NS Rene SN EK Ne 1 Nitration and suiphonation of 1,2-azoles under vigorous conditions art also known, as in the preparation of 4-nitropyrazole 4.31, * x 6 NO, y HNO, MT Ne “Dy e EXe Xz = x — Ko Se] Ny ee a * Sd As we hi . _ As we have seen with other el i Sto he eed reparation ot ‘troduction of an electron-donating group on ne imidazole 2:36, substitution, as in the eee facile bromination of aminoisothiazole 4.32.Aromatic heterocyclic chemistry 33 1 ° &s nul uted \, (COE eo 6 OX, wei, 2 of te aS nN e wh TB ue ek Uk LS wh ast th Ph mh This useful methodology (complementary to the C4 selectivity of normal electrophilic substitution) is not applicable to isoxazole chemistry because the intermediate anions (such as 4.35) are rather unstable and decompose via oxygen-nitrogen cleavage. rh Ph Ph Ph noi 1° OR oa PG | + mew 2 0, Cs — | 43s However, alkyl groups at the C5 position of isoxazoles can be deprotonated and reacted with electrophiles. V nBuli Note the analogy to tho anions: AG 8. poh 28. Sint on Dimethyl isoxazole 4.14 can be selectively deprotonated at the CS methyl rx SS group, nearer the more electronegative oxygen atom. Although simple g 4 N ° deprotonation cannot afford an entry into C4 substitution in this system, it is, ° possible to generate a carbanion at the C4 position in a roundabout fashion. } Bromination of 4.14 affords the C4-functionalised isoxazole 4.36. Metal~ halogen exchange With 1-butyllithium at low temperature (-78°C) generates EX Ss carbanion 4.37 which can be quenched with electrophiles to give isoxazoles such as 4,38. omc Interestingly, 1, 3, S-rimethyl pyrazolo is deprotonated on the = CoH 7 Nemethy! group, facilitating y My emu, pail r t 120, 7%, reaction with electrophites at this -N position. 0" 438 4.5 Problems nb 1, What is the mechanism for the formation of isothiazolone 4.39? Mi 6 9 =< t NH} $s Y aaas34 Isoxazoles, pyrazoles, and isothiazoles 2. What general strategy might be employed to convert pyrazole to alcohol 4.40, a potent inhibitor of steroid biosynthesis. CX 9, 1 LN oo 1 1 3. What is the product resulting from oxidation of 4.41? H at car H HO. NaOH Ae 108 x ak 4. A synthesis of 2-cyanocyclohexanone 4.45 from cyclohexanone is shown below. Formylation of cyclohexanone produces a mixture of keto/enol tautomers 4.42 and 4.43, the equilibrium lying to the side of the enol 4.42. ‘Treatment with hydroxylamine affords isoxazole 4.44, and base-induced fragmentation of the isoxazole ring affords 4.45. Explain the regioselectivity of the isoxazole formation, and the mechanism of the fragmentation process. X i a7 ~oe >on H NiO cx Ost OC OC Oh, ae 7 NaOEr ‘O 0 JN -2NHG7H,O - 442 443 ase 0 445 4.6 References Campbell, MM. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D. Olt), p.993 (isoxazoles) and p.1009 (isothiazoles). Pergamon Press, Oxford. Fleming, 1. (1976). Frontier orbitals and organic chemical reactions, p77. Wiley, Chichester. Furniss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989), In Vogel's textbook of practical organic chemistry (Sth edn), P.1149 (preparation of 3,5-dimethylpyrazole). Longman, Harlow. Grimmett, M.R. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W.D- Ollis), p.357 (pyrazoles). Pergamon Press, Oxford. Kochetkov, N.K. and Sokolov, $.D. (1963). Adv. heterocyclic chent.,2s 365 (isoxazoles). Kost, A.N, and Grandberg, 1.1. (1966). Adv. heterocyclic chet 6, 347 (pyrzoles). Slack, R. and Wooldrige, K.R.U. (sothiazotes), Wakefield, B.I. and Wright, D.J, (1979), Adv. heterocyclic chem. 25. 147 (isoxazoles). (1965). Adv, heterocyclic chem., 4, 1075. Pyridines 5.1 Introduction Pyridine 5.1 is a polar liquid (b.p. 115°C) which is miscible with both organic solvents and water. It can formally be derived from benzene by replacement of a CH group by a nitrogen atom, Pyridine is a highly aromatic heterocycle, but the effect of the heteroatom makes its chemistry quite distinct from that of benzene. The aromatic sextet of six 7 electrons is complete without invoking participation of the lone pair on the nitrogen. This is in direct contrast with the situation in pyrrole (Chapter 2) where the aromatic sextet includes the lone pair on the nitrogen, Hence the lone pair of pyridine is available for bonding without disturbing the aromaticity of the ring. Pyridine is moderately basic (pK,=5.2) and can be quatemised with alkylating agents to form pyridinium salts 5.2. Pyridine also forms complexes with Lewis acids such as sulphur trioxide, This complex 5.3 is a” mild source of sulphur trioxide for sulphonation reactions (see Chapter 2). oy 53 so? “The effect of the heteroatom is to make the pyridine ring very unreactive to normal electrophilic aromatic substitution. Conversely. pyridines are susceptible to nucleophilic attack. These topics are discussed later. 5.2 Synthesis of pyridines Our retrosynthetic analysis of generalised pyridine 5.4 commences with an adjustment of the oxidation level to produce dihydropyridine 5.5. This molecule can now be disconnected very readily. Cleavage of the carbon— heteroatom bonds in the usual way leaves dienol 5.6 which exists as diketone 5.7. The 1,5-dicarbonyl relationship can be derived from a Michael reaction of ketone 5.8 and enone 5.9, which in turn can arise from condensation of aldehyde 5.10 and ketone 5.11.36 Pyridines Note that in this example Ry and Ry are ethyl esters, 50 the adjacent carbon Is actually an active methylone group. The higher acidity and henco ‘nucleophilcity of these centres faciitates the reaction sequence, Bs Ry HH ® 7 R Ry S i | = l =— Ryn? Rs RY N@ Rs — NBs a SA ad R 50 A £ Ro’ u RAN Re \ + <= + L RS. RY SO ones mR SAL = = ‘These processes are facilitated when Ro and Rg are electron-withdrawing groups such as esters. Furthermore, when ketones 5.11 and 5.8 are the sam, wwe have the basis for the classical Hantzsch pyridine synthesis. o 6s 57 ° ° o oO L Vy ‘OB a cA no on 510 AS ee eT 2 N (-2H) NW’ 3 a S12 513 For instance, condensation of ethyl acetoacetate, formaldehyde, and ammonia gives dihydropyridine 5.12 which is readily oxidised with nitric acid (0 give pyridine 5.23. Although the precise details of this multicomponest condensation are not known, a reasonable pathway is shown below. ° “ a CO,Et CO;Et — [ 1 Kea : olow oro 0 an MR? EA 2 Co,e 3 ° tom 3 > = oT) NiAromatic heterocyclic chemistry 37 ‘Some examples of dihycropyridines prepared in this way are shown below. (Che student is encouraged to work out the aldehydes used in each case.) mz 1 as being intermediates f th ‘dines, these Aeonsoquonce ofthe asymmatry As well as being intermediates for the synthesis of pyridin ae eee dihydropyridines are themselves an important class of heterocycles, For . instance, dihydropyridine 5.14 is a drug for lowering blood pressure, In the corre Hono fe ods ommed synthesis of 5.14 note that carrying out the Hantzsch synthesis stepwise allows for the preparation of an unsymmetrical dihydropyridine, having both methyl and an ethyl ester. ° ° EO) 0, .CO;Me > ee OG 0 0 wm «=O VO =a —_—_ Presiding” 0) 10” BO" OMe =H,0 Heat lJ ‘0 WN HO Sie 5.3 Electrophilic substitution of pyridines Pyridine is virtually inert to aromatic electrophilic substitution. Consider nitration of pyridine by nitric acid. First, as pyridine is a moderate base, it will be almost completely protonated by the acid, making it much less susceptible to electrophilic attack. Second, addition of the electrophile to the small amount of unprotonated pyridine present in solution is not a facile process. ‘Attack of the electrophile at the C2 or C4 position results in an intermediate cation with partial positive charge on the electronegative nitrogen atom, This is clearly not energetically favourable when compared to C3 substitution, where no partial positive charge resides on nitrogen. In fact the product of C3 substitution, nitropyridine 5.15, can be isolated from the ‘exhaustive nitration of pyridine, but only in poor yield.38 Pyridines C-atkylation of a sterically: hindered phenotate anion, 2) <— 0. = w4— 0: on Although better results have been achieved with the sulphonation of pyridine to give the sulphonic acid 5.16, electrophilic substitutions on an inactivated pyridine ring are in general not preparatively useful. Ww 515 a Pyridine can be activated to electrophilic substitution by conversion to pyridine N-oxide 5.17. At first sight it is curious to consider oxidation (i. electron loss) as a means of activating a system to electrophilic substitution, but 5.17 can act rather like a sterically-hindered phenolate anion towards electrophiles, producing intermediate 5.18 which then loses a proton 10 give substituted N-oxide 5.19. For this methodology to be useful it is of course necessary to remove the activating oxygen atom. This ean be done with phosphorus trichloride, which becomes oxidised to phosphorus oxychloride. . (0) (~ — 2 sar Nt 59 ek)Aromatic heterocyclic chemistry 39 For instance, 4-nitropyridine 5.20 can be prepared from pyridine in three steps by this methodology. NO} No, SS Ho: HNO, SS) Pay ~ q oe AcOH l A H,SO, l (7 q ‘F WN’ ve a Ne N 547 00 oe Pyridine N-oxides can also be converted into synthetically useful 2- chloropyridines 5.21 (see later). R R S Sy O — Qn— dies, Ne Ng oN ES Oe b 2) sat Pe ava a7"Sa or ae Another spproach to electrophilic substitution involves the chemistry of 2-pyridone 5.22 and 4-pyridone 5.23. These are the tautomeric forms of 2- and 4-hydroxypyridine respectively. They exist exclusively in the pyridone form, the hydrogen atom being attached to the nitrogen atom, not the ‘oxygen. Their electronic structures are not adequately described by a single valence representation, the lone pair from the nitrogen atom being detocalised to a considerable extent onto the oxygen atom, as in mesomeric tepresentations 5.22a and 5.232. . Ca = CL Qed Hosa H sa3 ° 08 Co—-Os) [O-—¢ NSO Ng 7! N’ NS A sz 5.2304 Both pyridones can react with electrophiles at positions ortho and para to the activating oxygen atom. For instance, 4-pyridone reacts with electrophiles at the C3 position (the mechanism can be formulated from liate 5.24, As with pyridine Neoxides, reaction with phosphorus oxychloride gives _useful chloropyridines 5.25. We shall see the utility of 2- and 4-chloropyridines in the next section.40 Pyridines ‘The actual mechanism is ‘complicated. Hydrogen gas i evolved, but in really free sodium hydride is never generated. Seo McGill and Rappa (1988), Pyridine can be attacked by nucleophiles at the C2/C6 and C4 positions ina manner analogous to the addition of nucleophiles to a carbonyl group ina 1,2 oF 1,4 fashion, Attack at the C3/C5 positions is not favoured because the negative charge on the intermediate cannot be delocalised onto tke electronegative nitrogen atom. So & G-F N e e x x Cente | Bod oh Qe) tod ox g a0 xe nuceoptit Under conditions of high temperatures the intermediate anion aromatise by loss of a hydride ion, even though it is a very poot ei pyridine ant oduct ie ion kup a This is illustrated by the Chichibabin reaction of rencini {2 Produce 2-aminopyridine §.26, The immediate wayne eh the sodium salt of 5.26, as the eliminated hyd regenerates tion OF this sodium salt during the aqueous 8° "generates 5,26, A simplistic rationale is shown below. Sy os> (Lm. 7S Me 9, N’ — Nalt A Ag. workup: ny SOW nat,Aromatic heterocyclic chemistry 41 ‘These nucleophilic substitution reactions are much more facile when better Jeaving groups (c.g, halide ions instead of hydride ions) are employed. X= Nucleophile Nucleophilic substitutions are widely used in pyridine chemistry. Some examples are shown below. a RA Cea, Om oO 1 Qa, ‘NH i SEt oo, O¢ n7Nq 7 ri NZ @ mn sine Sonam AN CAS O., (2 a 7 N’ NZ neN fw OS ~a ‘OMe 2° (S) ee ous OL Nor Ww section, we shall consider the synthesis of fungal drug. This synthesis illustrates Finally, before leaving pytidotriazine 5.32, potential ant features of both electrophilic and nucleophilic pyridine chemistry, Nitration of 4-pyridone 5.23 gives 5.28, and reaction with phosphorus oxychloride affords chloropyridine 5.29. This pyridone-chloropyridine conversion activates the system to nucleophilic attack by hydrazine, affording, 5.30, The nitro group also facilitates nucleophilic attack by dclocalisation of negative charge in the intermediate,42 Pyridines BN HN HY Pe ay-N [cl NH ¥,0° amt /f OE, oe Avro, so? eo |= ff <> ( x? 2 Ww WN 530 sa i ino, and condensation produce jon, reduction of nitro to amino, ; Tadaaive 31, This system is readily dehydrogenated i minome deide ta afford the fully aromatic heterorycle 5.32. Note ow ree agi easy ‘can be used to form a quite complex heterocycle. sin 3 NH, Heat (~Hf,0) cy . —_—— 2 Ni 5.5 Anion chemistry of pyridines ‘We earlier drew a parallel between nucleophilic attack on the C2/C6 and a Positions of pyridine and 1,2 and 1, iti i sroup. This analogy can be extende f alkyl substituents st the C2/C6 and C4 positions, Sy S ( 1 — f we N 0 Just 48 a carbonyl group stabilises an Guplsts anion, so the anion derived from 2 ‘localisation ofthe negative charge onto u e as a! ‘adjacent negative charge -anethyl pyridine is stabilise he electronegative nitroge?Aromatic heterocyclic chemistry 43 [A similar argument holds for 4-methy\ pyridine. These stabilised anions can ‘hon react with the usual range of electrophiles, Navi, PE : 1602 ei a” Ch om oO : co; az e oH CA 0 GL Aa oe poe Noe 2HC Na® Oo Rant, S Met ya x Dialkyl pyridine $,33 is selectively deprotonated at the C4 alkyl group, illustrating the greater acidity of this position over the C3 position. With regard to ring deprotonation, however, there are relatively few examples known for simple pyridines, in contrast to the extensive chemistry developed for the five-membered ring heterocycles. This is because the resultant organometallic species are good nucleophiles, and because pyridines are also moderate electrophiles, polymerisation problems are often encountered. More success has been achieved with substituted pyridines having an ortho activating substituent (e.g. -CONHR, -NHCOR, -OMe, -CHNR2 etc). These substituents increase the rate of kinetic deprotonation and stabilise the intermediate organolithium species by coor ition. For instance, 4-aminopyridine 5.34 can be converted to amide 5,35 which, on treatment with two equivalents of butyl lithium, gives organometallic species §.36. Formylation of the more reactive anion (the carbanion) then re~ protonation of the amide anion gives 5.37. Acidic hydrolysis removes the activating group to release pyridine aldehyde 5.38. Sy The negative charge resulting {rom deprotonation of the ethyl methylene group of 5.33 cannot be delocalisad onto the nitrogen atom,idines 44 Py ‘The motalation proceeds by initial oprotonation of the amido followed by ortho-directed deprotonation at the C3 position to produce the pseudo six- ‘membered ring organolit species 8.36. Hint. Start by acotylating tho to givo a quaternary cationic spoctes. How can doprotonation alford a ‘aucloophilic enamina-like system? My, uN CS) sso oO ati Ean iva WZ af 7 (Besser) 534 5.35 L 1.7 ~NMe 2.HCL/Hz0 Ni 0 uno ° Sy H HCI cone.) Sch I i l 2 cat 2 nv N 538 337 5.6 Problems 1, What is the mechanism of this reaction? a A HORT EOR ri ‘Coset 2. ‘The condensation of active methyl groups with aldehydes can be catalysed with acetic anhydride as well as base. Suggest a possible mechanism. Ph 2 tS PhCHO S x7 Ae,0/ AcOH Uo N’ 3. Rationalise the formation of lactone 5.40 from pycidyl amide 5.39. ae one saee anes one ~ Leeanaat a LB, ZpMeocetsco ~ ny Shisosino ( T° sa 0 ve sao 4. Some pyridine N-oxide: interest in sheit own righ Ubetic intermediates, line N-oxide S41Aromatic heterocyclic chemistry 45 claimed to be useful for the treatment of senile dementia. What are the ‘mechanisms of the pyridone-forming step and the final displacement? ° ° ; OE CN CN ON L 1 £ cy sock, CO oa A Ge on C) / . 8 'N” = a to LL 2 <—t 2 : : 5.7 References ‘Abramovitch, R.A. (1974), In Pyridine and its derivatives (The chemistry of heterocyclic compounds [ed. A. Weissburger and B.C. Taylor], Vol. 14, Supplement Parts 1-4). Wiley Interscience, New York, Eisner, V. and Kuthum, J. (1972). Chem. rev., 72, 1 (dihydropyridines), Furiss, B.S., Hannaford, A.J., Smith, P.W.G,, and Tatchell, A.R. (1989). Vogel's textbook of practical organic chemistry (Sth edn), p.1168 (preparation of pyridine 5.13). Longman, Harlow. Klinsberg, E. (1974), In Pyridine and its derivatives (The chemistry of heterocyclic compounds {ed. A. Weissburger and E.C. Taylor], Vol. 14, Pants { 4), Wiley Interscience, New York. McGill, C.K. and Rappa, A. (1988). Adv. heserocyelic chem., 44, 3. Smith, DM. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol. ‘4of Comprehensive organic chemistry, ed. D, Barton and W.D. Ollis), p.3. Pergamon Press, Oxford.6. Quinolines and isoquinolines 6-4 Introduction Quinoline 6.1 and isoquinoline 6.2 are two isomeric heterocyclic systens, Quinoline and isoquincline can which can be envisaged as being constructed from the fusion of a benzene also be viewed as being formally Fin at the C2/C3 and C3/C4 positions of pyridine respectively. They are served rom naphihalene both ten r-electron aromatic heterocycles. Like pyridine, they are modemtely basic (pKa quinoline = 4.9, pKa isoquinoline = 5.1). Indeed quinoline i sometimes used asa high boiling-point (237°C) basic solvent, 4 soa 3 6 S3 6 s 7 ar 1 ZN 2 Nt 1 61 5 q 62 Note the numbering system for isoquinoline ‘As with pyridine, the nitrogen atoms of quinoline and isoquinoline exch bear a lone pair of electrons not involved in aromatic bonding which can te protonated, alkylated, or complexed to Lewis acids. This chapter should be read in conjunction with the chapter on pyridines as several points discussed at length there are also relevant to the chemistry of quinoline and isoquinoline. 6.2 Synthesis of quinolines and isoquinolines ines is exemplified by the reactionof 4 under acidic/oxidative conditions to produc? noon, eu OW 64 ~ —aoo NH, ty Tene H2S0, 8 Heat 61 At first sight this reacti sect heterocyclic 5 Feaction appears 10 be another one of those anit yAheses that owe more 1 Feat in i ‘0 alch ic, but the processes involved are relatively straightforward than 10 togAromatle heterocyclic chemistry 47 e HoH ine =", ‘On HO ‘on M0, h @ 6s e @ H =H O A Ae Mtg Oren es, 66 Protonation of glycerol 6.4 catalyses dehydration via secondary carbonium ion 6.5 to give enol 6.6. Acid catalysed climination of a second water molecule affords acrolein 6.7. Thus glycerol acts essentially as a protected form of acrofein, slowly releasing this unstable o,f-unsaturated aldehyde into Acrolen isa highly reactive olan the reaction medium, Better yields are realised with this approach than if that is prono to polymerisation, aorolein itself is present from the start, The reaction proceeds with a Michael addition of aniline 6.3 to acrolein, producing saturated aldchyde 6.8 which cyclises via an aromatic substitution reaction to alcohol 6.9, Acid-catalysed dehydration to 6.10 then oxidation yields quinoline 6.2. Nitrobenzene can be used as a mild oxidant, as ean iodine and ferric salts, ‘Some examples of the Skraup synthesis are shown below. = 09 oe 90 —_, NH OMe The key intermediates in the synthesis of isoquinolines are B- arylethylamines. For instance, acylation of B-phenylethylamine 6.11 gives amides of general structures 6.12 which can be cyclised with phosphorus oxychloride to produce dihydroisoquinoline 6,13. Better yields are obtained48 Quinolines and isoquinotines donating groups on the aromatic ring facilitating this sony with electron-donatir substitution cyclisation. xX RCOCL ae NH, Base ou X = Hlecwondonsing pubaient Pe st oN ‘Step RO. RO’ ofthe nturally-oceurring isoquinoline alkaloid 6.345 h,, 2. A synthesis might be used (0 accomplish each transformation? below. What reagents 10, RO. RO. SM ON NEz Stp3 RO’ nyt Step2 RO sot] z ‘OMe RO, 0, HO. O Step 6 Ci Step 5 OI 1 a RO A Ho RO « UO. Chen O., R=CHPh 6.7 References ‘Adams, R. and Sloan, A.W. (1941). Organic syntheses, Coll. Vol. 478 (areal blood-and-thunder preparation of quinoline). Claret, P.A. (1979). In Heterocyclic chemistry (ed. P.G. Sammes) (Vol.4 of Comprehensive organic chemistry, ed, D. Barton and W.D. Olli. 155 (quinolines) and p.205 (isoquinolines). Pergamon Press, Oxford. Fumiss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R. (1989) Vogel 's textbook of practical organic chemistry (Sth edn), p.1185 tather more safety-conscious preparation of quinoline). Longman, Harlow. Grethe, G. (ed.) (1981), In Isoquinolines (The chemistry of heterocyte compounds (ed. A. Weissburger and E.C. Taylor}, Vol. 3, Part 1). Wilt Interscience, New York. Jones, G. (1977, 1990). In Quinolines (The chemistry of heterocytt compounds [ed, A. Weissburger and E.C. Taylor], Vol. 32, Pas b> ond 3). Wiley Interscience, NewsYork, Xathawala, G.F., Coppola, G.M., and Schuster, HLF. (ed) (989 © Isoquinolines (The chemistry of heterocyclic compounds (6 * Wei: ste ebreer and EC. Taylor), Vol. 3, Part 2). Wiley Intersciens* Manske, synthesis Whaley, Wet and Govi ) WM. ovindachari, T.R, ve reat (ict Spengler symthesty n R (195E Organ reve HF. and Kalka, M. (1953). Organic reactions. 9 (sin? ons, pt7. Indoles 7A Introduction Fusion of a benzene ring onto the C2/C3 positions of pyrrole formally produces the corresponding benzopyrrole 7.1 known as indole. An analogous theoretical transformation can be envisaged to form benzofuran 7.2 and benzothiophene 7,3. This chapter will concentrate exclusively on indole, by far the most important member of this series, 4 5 2 ] Vs ] ® N’ 0 s 7 oH! 1 12 13 Indole is a ten-r electron aromatic system. As with pyrrole, delocalisation of the lone pair of electrons from the nitrogen atom is necessary for aromaticity. The single overall electronic structure of indole is not completely described by structure 7.1, because this implies localisation of the Jone pair on the nitrogen atom, Mesomeric representation 7.1a makes a contribution to the electronic structure of indole, as to a lesser extent do mesomerie representations where the negative charge occurs on the benzenoid ring, ° oI OO . . 1 12 TA Tia A consequence of this delocalisation is that the lone pair is not available for protonation under moderately acidic conditions so, like pyrrole, indole is another weakly basic heterocycle, Another similarity to pyrrole is that being an ‘electron-rich’ heterocycle indole easily undergoes aromatic electrophilic substitution, and is also rather unstable to oxidative (clectron-loss) conditions, However, an important difference emerges here, in that whereas Pyrrole preferentially reacts with electrophiles at the C2/CS positions, indole substitutes selectively at the C3 position. The reasons for this will be discussed later,54 Indoles Neurotransmitters are naturally- ‘occuring substances which effect ‘chemical communication between nerva calls by binding at specific sites on the coll surface called feceptars. jstoricaily, interest in indoles arose with the isolation ang canal embers of the enormous family of indole lal, cuch gs isergie acid 7.4. Many indole alkaloids possess interesting and sometimes ‘eeful biological activities. Although natural product chemistry is stl an ative area of primarily academic research, considerably more effort is expended nowadays in the preparation of indole derivatives as potential drug candidates. Following on from the observations that certain indole alkaloids or their semi-synthetic derivatives (e.g. lysergic acid diethylamide, LSD 7.5) have potent central nervous system activity, it was established that the simple indole 5-hydroxytryptamine 7.6 is a major neurotransmitter. Many indole derivatives which or block the binding of this neurotransmitter to its receptors have been synthesised and are beginning to find use in the treatment of various psychological disorders. ° x (Xue Ho. C A 1A X=0H ny 1S X=NBy ‘ N’ 16 H 7.2 Synthesis of indoles ‘As might be expected for a large branch of heterocyclic chemistry, many Syntheses of indoles have been developed. We shall restrict our discussion two, commencing with the widely-used Fischer synthesis. ‘The Fischer synthesis is the condensation of an aryl hydrazine with 4 ketone followed by cyclisation of th a idic candiions tive geen Of the resultant hydeazone under aci responding j ; 3 Of phenyl iioke pa Penang indole, a iMlustrated by the preparation wk Ph-N-NH, Ae a Ph-New. COU oF B 10 a SO a n Bh ZAC Ph 78 9 x ion stage is not asi , fist hygeine Seideatalyeed cauilibration between tah 5 a ‘ent n which is irreversible, is a concerted fong carbon-carbon bond, and breaking 9 aromatises by tautomerisation ne sens imine 7.11 immediately fo aniline 7.12, Fi id-catalysed ms indole Finally, acid-cataly 7.9, reminiscent of the last step of thAromatic heterocyclic chemistry 58 ne Le R X Hoo=w Ph Ph monn = iy AY = a8 (gt tan o, = 2 _ NH W ut " nt 70 \ mat =n —™ Oe — N’ Ph 'N’ Ph 79H i The electrocyctic reaction is very simi: Phenyl allyl ether 7.12 give phenol 213, nTyeamangement of Cop rarargement it YR O-ch- aor Oo ‘ - : So Some examples of the Fischer indole synthesis are shown below. by ™ So A Aza-Cope rearrangement VQ Ph N-NH, +, S\., ro. &d Q one Disza-Gopo rearangemont met o. oO y-Q a ° N Gy Seat H R SPh a ‘SPh Ph -N-NH, — I HN pg, Le x? 15 ‘McO. NMey ‘MeO, /NMe hy nat "CO 'N—NH, 0° = 'N’ y 7 . : : : + 2 — Ono F 'N — NH oO F N’ 3 , Y 1 An interesting regioselectivity question arises with the use of unsymmetrical ketone 7.14 to prepare indole 7.15. Two ene hydrazines 7.1656 Indoles Ce 47.47 can form, which would give rise 10 indoles 7.18 and 7.15 and 7. respectively. — BL 146 (major) Ph-N-ML JP x ‘SPh ‘ ", Gls He 7.47 (minor ) 18 In such cases the most thermodynamically stable ene hydrazine, ic. the one with the moze highly substituted double bond, forms preferentially. In this particular example there is also extra stabilisation derived from conjugation of the Ione pairs of electrons on the sulphur atom with the double bond, This regioselectivity in ene hydrazine formation is then reflected in the regioselectivity of indote formation. The more recent Leimgruber synthesis is illustrated by the aminomethylenation of nitrotoluene 7.19 to give 7.20, followed by hydrogenation to prodiice indole 7.1. Meo PME gay me a A NO, = No, PAVE ~ 720 ot The combination of formyl pyrrolidine acetal 7.21 and nitrotoluene 7.19 produces electrophilic cation 7.22 and nuck ili 1.23a,b which Teact together affording enamine 7.20. cxtanion 7288 ee «do 19 oc ON 0, \ o! Che OR, " fon 123 AeAromutie heterocyclic chemistry $1 Uystozenation of enamine 7.20 reduces the 24, thew elimination of pyrrotidine produces inde of this Ting closure step 0 the last step of the Fisher synthesis, In bot es the eventual C2 ea the ental SE karbon ton is formally at the earbonyl oxidation ee ce, es as ther an imine (Fischer synthesis) o unine (Leimgruber synthesis), Elimination of ammonia or pyrroli respectively is anatogous to a condensation proce: ‘water (as in the Knorr pyrrole synthesis), tka gronp le 7.1, Note the similarity ving aniline ne nvolving elimination of 0, poe, uw Kd é °. COL CO,Et TK oOo — oO ‘NO; oO 'N’ " J it NO} y 7.3 Electrophilic substitution of indoles As an electron-rich heterocycle, indole easily undergoes electrophilic substitution, However whereas pyrrole reacts preferentially at the C2/CS B ‘One explanation is that attack at C2 results in disruption of the aromaticity of the benzenoid ring, as in intermediate 7.25. This is therefore a high-onergy intermediate, and this reaction pathway is stower because the fist step is rate- determining. Also the C3 selectivity is in accord with the electrophite attacking the site of highest electron density on the ring, In essence, indole tends to react like an enamine towards electrophiles, with substitution58 Indoles ‘on, although substitution occurs at the C2 Position blocked. | : je to the mineral acid conditions for nitration, complex and the outcome is depender occurring at the C3 when the C3 position is Indole itself is unstable to the m nitration of substituted indoles is quite cise reaction conditions. ; ore rome indole readily undergoes the Mannich reaction affording ing aminomethyl derivative 7.26. A variety of nucleophiles can displace the amine via an elimination followed by a 1,4-addition reaction, as in the preparation of acetate 7.27. oo + ar ae ¥ TA 1.26 Fone @ ra? ch = Ny Ong NaOAc- oe owe N Ac0tt NZ N ot 6) This is the reactive electrophilic species of the Mannich reaction. H 127 me: ‘The Vilsmeier reaction proceeds extremely well with indoles giving ‘This is the reactive electrophilic aldehydes such as 7.28, species of the Vilsmeier reaction, HL @ ° SNM, of 1,POCI, /HCONMe, a ot ———_+ 7 2.420 'N’ z TA 128 contention ani usta synthetic intermediate, readily undergoing i . 's with active methyle1 jalonic acid and nivometian to pdaoe Ma one CompounES such 3m Ne ° CO N N70 NAOH ay ane 2Aromatic heterocyclic chemistry 59 ° oye ° 0 y

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