摘要:

Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Dr S . E. Thomas, Imperial College of Science, Technology, and Medicine Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S . Hanessian, Universite' de Montrial Professor M. Julia, Universiti de Paris XI (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, Scripps Research Institute, La Jolla Professor R. Noyori, Nagoya University Professor L.E. Overman, University of California, Irvine Professor L. F. Tietze, University of Gottingen Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity, and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently, so too will modern aspects of strategy and computer aided design, biotransformations, and protecting group protocols. Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis, and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment, and new materials, will also be encompassed.Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although the majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication. In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way.All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1994 subscription rate: EC &150, USA $282, Canada S 169 (plus GST ),-Rest of the World E 16 1. Air freight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont 1103; USA Postmaster, send address changes to Contemporary Organic Synthesis, Publications Expediting Inc. Second class postage is paid at Jamaica, New York 1143 1. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe.0 The Royal Society of Chemistry, 1994 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho LtdContemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Dr S: E. Thomas, Imperial College of Science, Technology, and Medicine Professor E. J.Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Harvard University Professor S. Hanessian, Universiti de Montrkal Professor M. Julia, Universiti de Paris XI (Paris-Sud) Professor P. D. Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, Scripps Research Institute, La Jolla Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Irvine Professor L. F. Tietze, University of Gottingen Contemporary Organic Synthesis is a bimonthly journal which aims to review and provide perspective in all aspects of methodology, selectivity, and efficiency in contemporary synthesis. As well as covering all the principles and methods in functional group chemistry and interconversions, organometallic chemistry and asymmetric synthesis will feature prominently, so too will modern aspects of strategy and computer aided design, biotransformations, and protecting group protocols.Special methods and techniques, such as sonochemistry, FVP, electroorganic synthesis, and supported catalysis will be included as occasional articles, and the manner in which synthesis addresses problems and provides solutions in biology, medicine, agriculture, the environment, and new materials, will also be encompassed. Contemporary Organic Synthesis aims to be proactive, drawing attention to new opportunities and new directions, providing timely information to the synthetic chemist who needs to keep abreast of developments in the field. Although th2 majority of articles are intended to be specially commissioned, the Society is always prepared to consider offers of articles for publication.In such cases a short synopsis, rather than the completed article, should be submitted to the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF. Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre. Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1994 subscription rate: EC &150, USA $282, Canada E 169 (plus GST ), Rest of the World E 16 1. Air freight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont 1 103; USA Postmaster, send address changes to Contemporary Organic Synthesis, Publications Expediting Inc. Second class postage is paid at Jamaica, New York 1143 1. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1994 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho Ltd

ISSN:1350-4894    

DOI:10.1039/CO99401FX009

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

HAZARDS IN THE CHEMICAL LABORATORY Royal Society of Chemistry, Turpin Distribution Services Ltd, Blackhorse Road, Letchworth, Herts SG6 IHN, United Kingdom. CHEMISTRY Information Services II I 5th Edition ‘. . . easy to read, an excellent reference text, and a worthwhile investment .’ Journal of the American Chemical Society reviewing the 4th Edition. The new edition of this essential laboratory handbook is the ‘key’ requirement for all research, development, production, analytical and teaching laboratories worldwide. The 5th Edition provides: 0 a quick guide to the hazardous properties of 1339 substances (over 800 more than were covered in the previous edition) details of the latest UK and EC regulations an extremely useful emergency action check list - users can fill in their own key contacts for hospitals, fire etc.handy tables, symbols and statistics for ease of reference 0 a description of the American scene, including US legislation and safety practices - highlighting differences between the UWEC and USA PVC Protective Binding xx + 676 pages New features include: expanded ‘Yellow Pages’ section on hazardous substances, providing immediate information on hazardous properties, recommended control procedures and safety measures complete guide to labelling requirements to comply with EC directives and UK legislation, including the risk and safety phrases that must appear 0 chapter on electrical hazards 0 index to ‘Yellow Pages’ section, with synonyms of compounds 0 index to CAS Registry Numbers ISBN 0 85186 229 2 (1992) Price f45.00 If you have not yet ordered your copy of the NEW edition, do so now! Why take chances? Be informed and safe.5I To order, please contact: Telephone: +44 (0)462 672555 Fax: +44 (0)462 486947. 1350-4894C199411.1-9HAZARDS IN THE CHEMICAL LABORATORY Royal Society of Chemistry, Turpin Distribution Services Ltd, Blackhorse Road, Letchworth, Herts SG6 IHN, United Kingdom. CHEMISTRY Information Services II I 5th Edition ‘. . . easy to read, an excellent reference text, and a worthwhile investment .’ Journal of the American Chemical Society reviewing the 4th Edition. The new edition of this essential laboratory handbook is the ‘key’ requirement for all research, development, production, analytical and teaching laboratories worldwide. The 5th Edition provides: 0 a quick guide to the hazardous properties of 1339 substances (over 800 more than were covered in the previous edition) details of the latest UK and EC regulations an extremely useful emergency action check list - users can fill in their own key contacts for hospitals, fire etc.handy tables, symbols and statistics for ease of reference 0 a description of the American scene, including US legislation and safety practices - highlighting differences between the UWEC and USA PVC Protective Binding xx + 676 pages New features include: expanded ‘Yellow Pages’ section on hazardous substances, providing immediate information on hazardous properties, recommended control procedures and safety measures complete guide to labelling requirements to comply with EC directives and UK legislation, including the risk and safety phrases that must appear 0 chapter on electrical hazards 0 index to ‘Yellow Pages’ section, with synonyms of compounds 0 index to CAS Registry Numbers ISBN 0 85186 229 2 (1992) Price f45.00 If you have not yet ordered your copy of the NEW edition, do so now! Why take chances? Be informed and safe. 5I To order, please contact: Telephone: +44 (0)462 672555 Fax: +44 (0)462 486947. 1350-4894C199411.1-9

ISSN:1350-4894    

DOI:10.1039/CO99401BX011

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Recent developments in indole ring synthesis-methodology and applications* GORDON W. GRIBBLE Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA Reviewing the literature published between 1990 and 1993 1 2 2.1 2.1.1 2.1.2 2.1.3 2.2 2.3 2.4 3 3.1 3.2 3.3 3.4 4 4.1 4.2 4.3 4.3.1 4.3.2 4.3.3 4.4 4.5 5 5.1 5.2 5.3 5.4 6 6.1 6.2 7 8 8.1 8.1.1 8.1.2 8.2 8.3 8.3.1 8.3.2 8.4 9 9.1 Introduction Sigmatropic rearrangements Fischer indole synthesis Methodology Applications Mechanism Gassman indole synthesis Bartoli indole synthesis Miscellaneous sigmatropic rearrangements Nucleophilic cyclization Madelung indole synthesis Schmid indole synthesis Wender indole synthesis Couture indole synthesis Electrophilic cyclization Bischler indole synthesis Nordlander indole synthesis Nitrene cyclization Cadogan-Sundberg indole synthesis Sundberg indole synthesis Hemetsberger indole synthesis Queguiner azacarbazole synthesis Miscellaneous electrophilic cyclizations Reductive cyclization 0, B-Dinitrostyrene reductive cyclization Reissert indole synthesis Leimgruber-Batcho indole synthesis Makosza indole synthesis Oxidative cyclization Watanabe indole synthesis Miscellaneous oxidative cyclizations Radical cyclization Metal-catalysed indole syntheses Palladium Larock indole-indoline synthesis Miscellaneous Rhodium and ruthenium Titanium Furstner indole synthesis Miscellaneous Zirconium Cycloaddition and electrocyclization Diels-Alder cycloaddition *Dedicated to the memory of Professor Manfred E.Mueller, San Francisco City College, 191 1-1992.9.2 10 10.1 10.1.1 10.1.2 10.2 10.3 10.3.1 10.3.2 11 11.1 11.2 11.3 12 13 Photoelectrocyclization Indoles from pyrroles Electrophilic cyclization Natsume indole synthesis Miscellaneous Palladium-catalysed cyclization Cycloaddition routes From vinylpyrroles From pyrrole-2,3-quinodimethanes Aryne intermediates Aryne Diels-Alder cycloaddition Nucleophilic cyclization of arynes Miscellaneous aryne cyclizations Miscellaneous indole syntheses References 1 Introduction Ever since the early studies, more than 100 years ago, by Baeyer' and others on the chemistry of indigo, isatin, and related compounds, indole and its myriad derivatives-both natural and unnatural-have captured the imagination of organic chemists, especially with regard to syntheses of the indole ring Because the present review is restricted to coverage of the 1990-1993 literature, some excellent indole syntheses that were not utilized during this period are not covered herein (e.g., those of Houlihan,8 Saegusa,' and Smithlo).Furthermore, with a few exceptions, syntheses of oxindoles, indolines, isatins, indoxyls, and related indole analogues, like carbazoles and carbolines, could not be included for reasons of space. This was unfortunate, since, for example, several excellent new oxindole syntheses have been reported during this period.11-14 The organization of this review follows the type of reaction involved in the key step. In some cases, new or previously unnamed syntheses are named according to their discoverer( s) and/or developer( s). 2 Sigmatropic rearrangements 2.1 Fischer indole synthesis Despite its myriad complications, rearrangements, and mechanistic mysteries, the Fischer indole synthesis, in which the key step is a [3,3]-sigmatropic rearrangement, remains the epitome of indole ring construction methods, and an exhaustive review is Gribble: Recent developments in indole ring synthesis-methodology and applications 145available.' Nevertheless, recent years have seen several improvements and novel applications of this classical reaction,16.' as well as new mechanistic surprises.2.1.1 Methodology The use of zeolites improves the regioselectivity in the Fischer indolization of phenylhydrazones from unsymmetrical ketones (Scheme l),l*> l9 and Eaton's reagent (P,O,/MeSO,H) is highly regioselective in furnishing the 3-unsubstituted indole (Scheme 2).20 H 90 : 10 Scheme 1 CI /o' CI loo : 1 02NmcH' H C3H7 Scheme 3 X = H, OMe, Br, NO2 microwave 7346% 96%HCO&I 2rnin- 1 Scheme 4 his work on the Fischer indole construction of the 7,12-dihydropyrido[3,2-b: 5,4-b']diindole ring system from 4-OXO- 1,2,3,4-tetrahydro-B-~arbolines.~~ Sol1 and his colleagues at Wyeth-Ayerst have made extensive use of the Fischer reaction with dihydrofuran to synthesize etodolac derivatives (Scheme 5),27 and a Mexican group has developed a protocol that avoids pyrazole formation in the preparation of (P-oxo)indol-3-yl ketones.28 Reagents: (i) 0 0 , HCI, THF; (ii) ZnCh, (HOCH& 170 "C Scheme 5 Scheme 2 Katritzky has found that the combination of (85% H,PO,)/toluene is crucial to a greatly improved preparation of nitroindoles (Scheme 3),21 and Abramovitch used 96% HC02H and microwave irradiation to synthesize efficiently 1,2,3,4-tetrahydro- 1 -oxo-B-carbolines (Scheme 4).22 2.1.2 Applications Thummel and his colleagues have made excellent use of the Fischer indole reaction in their syntheses of 'polyaza cavities' such as pyrido[ 3,2-g]indoles and higher condensed molecule^.^^-^^ Cook has reviewed Likewise, an excellent new procedure for the synthesis of ethyl 3,3-dimethyl- 3 H-indole-2-carboxylate has been reported (Scheme 6).29 OMo" (iHiii) 4796 EtO 0 Reagents: (i) PSMgCI; (ii) PhNHNH,; (iii) HCI EtOH A Scheme 6 Black and co-workers have used the Japp-Klingemann reaction as an entry to certain phenylhydrazones which were then converted into 7-substituted (heterocyclic) indoles (Scheme 7).30 146 Contemporary Organic SynthesisppA :% I 'N 2? / Et Scheme 7 Not surprisingly, the Fischer indole synthesis continues to find employment in the indole alkaloid field.In an elegant total synthesis of ( - )-physovenine, an alkaloid of the calabar bean, Takano et al. utilized a non-acidic Fischer indolization as a key step in their sequence (Scheme 8).3 1 Scheme 8 This group used the same strategy in a synthesis of several cuparene se~quiterpenes.~~ Bosch and his colleagues have employed the Fischer indole synthesis in an approach to da~ycarpidone,~~ and Hart has utilized this indolization in the context of gelsemine model studies.34 Finally, the Fischer reaction was used to prepare fused indoles such as the indolo[3,2-b]indole ring system (e.g., 1 35) and the 5,10-dihydroindeno[ 1,2-b]indole ring system (e.g., z3(j).I TS 1 ' H Me 2 2.1.3 Mechanism Since this review is primarily directed at the synthesis of indoles, the discussion of mechanistic abnormalities in the Fischer indolization will be brief. Luis and Burguete have discovered a large amount (up to 40%) of the 1,2-methyl migration product 3 during the course of a study (Scheme 9),37 and a similar substrate was found by an Italian group to give the rearranged product 4 (Scheme N-N Me 0 M% HCOzH g,% 1' 3 60 : 40 Scheme 9 Ma~--cH' 0 A N ) H 4 Scheme I 0 Ishii and co-workers have extensively investigated the Fischer indolization reactions of the arylhydrazones of ethyl pyruvate, uncovering abnormal pathways and isolating multiple products from some substrate~.~~-~l Likewise, in cyclic systems, one often encounters unusual reaction pathways (Scheme 1 1)."2 Scheme 11 PPA A 65% QPh Q 9APh NH A detailed mechanistic study by Hughes and Zhao has revealed that in strong acid, such as MeS03H, the benzene ring of the phenylhydrazone can be Gribble: Recent developments in indole ring synthesis-methodology and applications 147protonated and that tautomerization of the hydrazone is rate limiting.43 Another careful investigation provides evidence, including ’ 5N labelling experiments, for the interesting pathway shown in Scheme 1 2,44 leading to the unexpected product 5 , which is formed in addition to the expected (major) product 6.(i) Raney Ni EtOH (ii) pTsOH,PhH (iii) pTsOH,MeCN CI /o‘ I TFA Scheme 1 Q - J I CO2H H 5 2 2.2 Gassman indole synthesis Scheme 13 The elegant Gassman indole synthesis,45 which features a [ 2,3]-sigmatropic rearrangement, has been employed only sparingly in recent years.Smith has used this methodology in the first reported syntheses of the alkaloids ( + )-paspalkine and ( + )-paspalfie, the indole-forming step of which is depicted in Scheme 13.“6 Ts Scheme 14 2.3 Bartoli indole synthesis A Japanese group has extended the Gassman protocol in a clever of the azasulfonium salt and its rearrangement to 7, these workers found that acid treatment of the derived sulfonamides smoothly leads to indoles (Scheme 14), presumably via an episulfonium intermediate. A wide range of indoles were prepared in yields up to 95% (e.g., 5-OMe, 5-Me, 5C1, 5-N02, 7-OMe, 7-C1, and 7-Me).Following the preparation One of the most exciting recent developments in indole ring construction is the elegant discovery made by Bartoli and his co-workers that nitroarenes and nitrosoarenes react with vinyl Grignard reagents to afford indoles (Schemes 15 and 16).48-50 The scope, limitations, and mechanism of these reactions have been explored in substantial detail by Bartoli. The mechanism suggested by Bartoli for the nitrosoarene case is shown in Scheme 1 7.49 148 Contemporary Organic Synthesis3eq. P M g B r 4147% NO2 X X = Me, Br, CI. F. OSiMe3 Scheme 15 Scheme 16 L r L MgBr WTMS N I MgBr H Scheme 17 The Bartoli indole synthesis has been found to be far superior to the Gassman synthesis for the preparation of 7-hydroxyindole 8, as shown in Scheme Noteworthy is the use of the benzhydryl protecting group which was preferable to benzyl in the Grignard step.(9 9- NO2 70% 9- 0 NO2 OH PhAPh (ii) 574b I (iii) 92 - ce.9046 OH 8 Ph Reagents: (i) Ph2CHBr, K2CO3, Acetone; (ii) 3 eqeMgBr,THF; (iii) H2, Pd(OH)2, MeOH td, 50 psi Scheme 18 This same group of researchers adapted the Bartoli synthesis to an excellent preparation of 7-formylindole 9 (Scheme 19), in 68% overall yield on a 70-gram scale.52 NO2 BunOH 9- NO2 pTSA to1 aq. HCI THF 68% overall 97 * CHO 9 Scheme 19 However, in a recent synthesis of the topoisomerase I1 inhibitor BE 10988, Moody found that the Bartoli indole synthesis did not provide the requisite 5,7-dioxygenated indole starting material.53 2.4 Miscellaneous sigmatropic rearrangements A [3,3]-sigmatropic rearrangement is the crux of a short synthesis of the benz[g]indole 10 (Scheme 20),54 and a [2,3]-sigmatropic rearrangement sets up the final indolization in the allene 1 1 (Scheme 2 3 Nucleophilic cyclization 3.1 Madelung indole synthesis Like the Fischer and Bischler indole syntheses, the Madelung indole synthesis has had a long, rich history since its discovery some 80 years ago.56 This cyclization method, involving the reaction of ortho-alkylanilides with strong base at high temperatures, has seen a number of improvements over the years.For example, Bartoli has reported the intramolecular Peterson olefination of ortho-trimethylsilylmethyl anilides under mild conditions (Scheme 22),57 and, more recently, he extended this methodology to the synthesis of N-unsubstituted indoles (Scheme 23).5* C02Me _.a N M o H ,,": Q N - 0 ' Et3N '1/1 98% Scheme 20 Gribble: Recent developments in indole ring synthesis-methodology and applications 149PhSCl 1%; 78% 11 03%I (0 LDA, THF. - 20 "C to r.t. (ii) aq. HCI Scheme 21 Ac SOPh TMS I Scheme 22 Scheme 23 H X = OMe, Ph, Me R' = Ph, At, Me, Bu' @ = Me, alkyl R = Ph, Ar Mild conditions also prevail in a directed-metalation route to Madelung-reaction type intermediates, as shown in Scheme 24.59,60 Several substituted indoles were prepared in this study. Moreover, the employment of Weinreb's amides allowed for the construction of 2-substituted indoles by trifluoroacetic acid induced cyclization and deprotection of 12 (Scheme 25).5yJ'0 r 1 DMF 85% 1 0- L!C!.THF 90% a--- I OH kO2Bu' C02But Scheme 24 Li 1 O Y e H 12 H Scheme 25 Despite these modernizations, the classic Madelung cyclization still finds use in indole ring construction. Thus, an Italian group found the Madelung indole synthesis to be the choice method for the preparation of the antithrombotic-drug-candidate precursor 13 (Scheme 26)."' 13 Scheme 26 Bergman has developed several variations of the Madelung rection to craft nitroindoles (Schemes 27 and 28);62 many examples are described and the mechanism is discussed in this yo2 yo2 Scheme 27 150 Contemporary Organic Synthesis3.4 Couture indole synthesis Couture and his group have described a simple indole synthesis based on the Wittig-Homer reaction.6'~~~ The cyclization is extremely general and high-yielding, affording a variety of indole types (Schemes 3 1-33). The nature of the base dramatically affects the outcome of the reaction (6, Schemes 32 and 33).- DMF A1 R' Scheme 28 3.2 Schmid indole synthesis CONE12 *a--Jw A p(o)ph2 In what might be construed as a 'reverse-Madelung' indole synthesis, Molina has utilized a reaction, which was originally discovered by Greuter and S~hmid,6~ to prepare indolo[ 1,2-c]quinazoline precursors such as 14 (Scheme 29)."4 aN A P(0)Ph2 A Reagents: (i) Bu"Li, lHF, - 78 "C; (ii) H20 Scheme 31 Ph Scheme 29 Scheme 32 3.3 Wender indole synthesis closure and deh~dration.~~ Sainsbury and his & Me Me The Wender indole synthesis involves the ortho-lithiation of N-phenylamides followed by reaction with a-haloketones and subsequent ring co-workers have explored both the Bischler and Wender indole syntheses in order to prepare dihydroindenoindoles such as 15, but only the latter - a-fi (i) KHMDS, THF, -10% !j2% (li) aq.HCI Y y-P(0)Ph2 Scheme 33 method worked reasonably addition of ceric chloride somewhat suppressed the They found that the 4 Electrophilic cyclization enolate formation side-reaction (Scheme 30). 4.1 Bischler indole synthesis The venerable Bischler indole synthesi~~'.~~ and its several variations involve the electrophilic cyclization of a-arylaminoketones or their synthetic equivalents. In a study of indole-based conducting polymers and CC- 1065 analogues, Dmitrienko and co-workers used the Bischler indole synthesis to prepare the two pyrroloindole ring systems 16 and 17 (Schemes 34 and 35).71 The mode of cyclization in each case was correctly predicted by FMO analysis.oBr NH _____c ( i ) l (4 Q(r,Li O&F3 oAcF3 37% (14 H3C 1 Q--+ 8 --ct H2NfJTLCH3 - NH&NJCH3 CH3 BU~OH CH3 HOAC A H ' NH H H oAcF3 40% 16 15 Scheme 34 Scheme 30 Scheme 35 Grib ble: Recent developments in indole ring synthesis-methodology and applications 151Basanagoudar deployed the Bischler indole synthesis as the key step (Scheme 36) in the preparation of several dimepino[ 1,2-a]indoles 1 8.72 kH2CH2CN kH2CH2CN 18 (R' =CHI, Ph R2 = H, CH3, OM, OEt R3 = CH3, Ph) H H 22 4.2 Nordlander indole synthesis The Nordlander modification of the Bischler indole synthesis involves a combination of trifluoroacetic acid ("FA) and trifluoroacetic anhydride (TFAA) to effect cyclization of an N-trifluoroacetyl-2-anilino acetal ( 19) to the corresponding N-trifluoroacetylindole 20 (Scheme 37).73 X- croEt - TFA F A A A I I OACF3 19 Scheme 37 A slightly different version of the Nordlander's route used zinc chloride in a synthesis of the topoisomerase I1 inhibitor BE 10988 2 1, although the yield of the indole-ring forming step (Scheme 38) was only m0dest.7~ 0 S+ AC Reagents: (i) BrCH2CH(OEt),, Na&03, EtOH; (ii) TFAA, Et3N; (iii) TFA, TFAA; (iv) DDQ, PhH, A: (v) KOH, MeOH 21 Scheme 38 The Nordlander cyclization was employed by Dmitrienko to fashion the pyrroloindole ring system 22 as shown in Scheme 39.71 I Q J I AC Scheme 36 Scheme 39 Earlier, Sundberg developed an important modification of the Nordlander indole synthesis, which employs TiCl, in the cyclization of N-methylsulfonyl-2-anilino acetal~.~~ 4.3 Nitrene cyclization Several different approaches to the generation and cyclization of nitrenes to indoles have been explored over the years.As a result, this strategy has emerged as a powerful indole construction method. 4.3.1 Cadogan-Sundberg indole synthesis C a d ~ g a n ~ ~ and S ~ n d b e r g ~ ~ discovered, independently, that o-nitrostilbenes and o-nitrostyrenes are deoxygenated by triethyl phosphite to a nitrene (or equivalent) which then cyclizes to form the indole ring. The cyclization of a-nitrostilbene was also reported.76 Several variations of this reaction have been described in recent years. Thus, o-nitrostilbene is deoxygenated and cyclized to 2-phenylindole with a ruthenium catalyst (Scheme 40),78 and b-nitrostyrenes and dialkyl phosphites give rise to 3-dialkoxyphosphoryl- 1 -hydroxyindoles (Scheme 4 1).7y Scheme 40 Russell and co-workers have reported the conversion of 2-nitro- 1,l -diphenylethylene derivatives to 3-phenylindoles as shown (Scheme 42).80 Likewise, Gelmi and his colleagues have employed this indole ring construction to prepare (unexpectedly) a series of azepino[l,2-a]indoles (e.g., 25) by rearrangement of the initially formed indolylpyranones 24 which were prepared from 23 (Scheme 43).81 152 Contemporary Organic SynthesisScheme 41 II R3 OH R’ = Ph, OEt, OPS R2 = Et, PS R3= H, Me R4 = Me, Et mo; QJT-JPh X H 24 h X = H, 90% X = PhS, 99Yo X = Buts, 95% Scheme 42 undergo smooth thermolysis to afford indole-2-carboxylates has proven to be very useful in a number of instances.The reaction is exceptionally clean and the yields are high (Scheme 45).85 Moreover, the a-azidocinnamates are readily prepared by base condensation of ethyl azidoacetate with the appropriate benzaldehyde. CO2Et Xyl 9048% A H X = 4-Me, 4-CI,4-Br, 4-OMe, &Me, M I , 6-Br, &0Me, 6-F Scheme 45 The Hemetsberger indole synthesis afforded an entry to 2-cyano-4-hydroxyindole 26 in 30% overall yield from salicylaldehyde (Scheme 46).86 Indole 26 is useful in the preparation of cyanopindolol and other pharmaceuticals . Thermolysis of 27 was the key manoeuvre in the synthesis of the marine indoles ( k )-cis- 28 and ( k )-trans-trikentrin A, as summarized for the former in Scheme 47.87 It is important to note that no isoquinoline ring formation, by insertion into the benzylic CH, group, was observed.23 Scheme 43 24 25 4.3.2 Sundberg indole Synthesis v Although several groups, apparently simultaneously, discovered that o-azidostyrenes and /3-azidostyrenes could be converted to indoles on pyrolysis,82 S ~ n d b e r g ~ ~ and Hemetsberger ( vide infra ) developed these observations into useful indole construction methods. Thus, Sundberg reported that the OH OBn OBn thermolysis of o-azidostirenes gives rise to indoles, apparently via nitrene formation and electrophilic cyclization (Scheme 44).83 However, this reaction was not particularly successful in a bis-azide appli~ation.~~ CONH:! H H 26 rpf 81Yo 0-J H P f Scheme 46 Scheme 44 In earlier work, it was found that thermolysis of 4.3.3 Hemetsberger indole synthesis azide 29 leads to indole 30 in high yield (Scheme 48).@ However, on exposure to triethyl phosphite, 29 is converted into aziridine 3 1, presumably via Although a relatively recent indole synthesis, the discovery by Hemetsberger that a-azidocinnamates iminophosphorane formation and attack on the epoxide.Grib ble: Recent developments in indole ring synthesis-methodoloa and applications i53Bu"8nH A 1 8256 r.t. N&H&O& NaOEt 1 P h S e N b 0 (i) aq. KOH, dioxane 74% (ii) N P 1 f 28 Scheme 47 30 29 31 ph Scheme 48 4.4 Queguiner azacarbazole synthesis Queguiner and his colleagues have reported a remarkable cyclization to a pyridine (pyridinium) ring leading to an excellent p-carboline synthesis (Scheme 49).8y This protocol has also been applied to azacarbazoles in general.yo The biaryl substrates are neatly crafted using a combination of palladium-catalysed cross-coupling and directed-metalation technologies.R = Ph, Ppyr, 2-thienyl, Me, Et, CN Scheme 49 4.5 Miscellaneous electrophilic cyclizations Mercuric acetate smoothly transforms amine 32 into tetrahydrocarbazole 33 (Scheme 50).y1 The starting amino olefin was prepared via an amino Claisen rearrangement. A novel amidoselenation reaction was found to be very effective in the cyclization of amidostilbene 34 to indole 35 (Scheme 51).y2 n 32 33 Scheme 50 Mea-ph NHAc 34 t AC 35 Scheme 51 The use of PhSeBr was less effective. An accidental discovery has led to a new indole ring synthesis (Scheme 52).y3 The starting materials 36 were prepared from substituted methyl anthranilates.In the key acid-promoted cyclization of 37 --* 38, it was found that H,S prevents the formation of the 3-chloro derivatives. CHo MeS(0)CHfiMe - x- p r NHTs NHTs Triton B 5!%88% 36 37 Scheme 52 X-gJ-T-7 SMe Ts 38 X = H, 5-M, 6-CI, dBr, 5-Br 154 Contemporary Organic SynthesisIn a most unusual role for benzoquinone, Echavarren reported the novel indole synthesis shown in Scheme 53,”4 in which hydroquinone is isolated in 62% yield. A fascinating mechanism is proposed by Echavarren for this transformation. KBH, r N ” M % NH 0 A Ph PrbH r.t. 9% wN”Me. OAPh Scheme 53 5 Reductive cyclization 5.1 0, p-Dinitrostyrene reductive cyclization The ancient reductive cyclization of o,P-dinitrostyrenes to indoles continues to enjoy popularity-both in application and methodological improvements.Three separate groups have utilized this indole ring construction to craft methoxyindoles. Both Fe/HOAc and NaBH,/Pd/C are reported to furnish 4,7-dimethoxyindole 40 in good yield from the corresponding dinitro precursor 39 (Scheme 54).9s HOAc 71Ya OMe OMe 39 Scheme 54 40 Indole 40 was also synthesized on an industrial scale, using catalytic hydrogenation in the key step.96 This latter method was employed in the first synthesis of the potent insect antifeedant dithyreanitrile 41 as summarized in Scheme 55.y7 The use of TiCl, to cyclize o,p-dinitrostyrene to indole has been described,y8 and this cyclization has been accomplished using electrolysis, as has the conversion of 2-nitrophenylpyruvic acid to indole-2-carboxylic acid, in modest yields.9y 5.2 Reissert indole synthesis The classic Reissert indole synthesis, involving the reductive cyclization of o-nitrophenylpyruvic acid to indole-2-carboxylic acid, has been largely supplanted by newer methods, although a number of modifications and variations have been described in recent years.A series of substituted 2-nitrophenyl- acetaldehyde acetals, prepared from the OMe OMe R 61% (lli) I 81% (vi) 1 Reagents: ( i ) CH3N02, NaOH, MeOH; (ii) Ac20, NaOAc, A; (iii) HP, 10% Pd-C, HOAc, EtOAc; (iv) (COCI), Et20, 0 “C; (v) NH,OH, 0 “C; (vi) TMSSMe, F3B.0Et2, MeCN; (vii) POC13, pyr, 0 “C Scheme 55 corresponding styrenes, was cyclized to indoles (Schemes 56).loo Castedo and colleagues published a new route to benzo[ blcarbazoles and indeno[ 1,2-b]indoles using a simple reductive-cyclization protocol.101 An example of each is shown in Schemes 57 and 58, respectively.CH(OR)2 Fe HOAc 1 746% - X - I EtOH HCI I H R = Me, Et, But, Bun X = H, 4-OMe, 4-Me, 4-CI, 5-OMe, &Me Scheme 56 OMe g H Scheme 57 Gribble: Recent developments in indole ring synthesis-methodology and applications 155156 .I- - NO2 0 H Scheme 58 The use of a twin Reissert-like indole synthesis was employed to build the indolo[3,2-b]indole ring system 42 for use as a spin-containing unit for polaronic magnetic materials (Scheme 59).84 HOAc HCI S ~ C I ~ 80% 1 67% H 42 Scheme 59 5.3 Leimgruber-Batcho indole synthesis Since its inception some 20 years ago, the Leimgruber-Batcho indole synthesis has enjoyed great success in the preparation of benzene ring substituted indoles.102-104 Modified versions now exist.'05 In the original synthesis, illustrated in Scheme 60 for the preparation of 6-metho~yindole,'~~ the appropriate nitrotoluene is condensed with DMF-acetal to afford the anticipated P-dialkylamino-2-nitrostyrene.Hydrogenation gives 6-methoxyindole in 76% yield for the two steps. DMF H 105% * Me0 Me0 H Scheme 60 Contemporary Organic Synthesis Stanetty and Koller used the Leimgruber-Batcho protocol to synthesize indoles 43 and 45. By performing the reductive cyclization at room temperature in THF, these workers could isolate N-hydroxyindoles 44 and 46.1°7 43 R = H 44 R=OH 45 R = H 46 R=OH Macor and his team at Pfizer have synthesized several rigid analogues of serotonin, such as 47, using the Leimgruber-Batcho method.'08 Another group has utilized nickel boride in the reductive cyclization step (Scheme 6 1) in a synthesis of a metabolite of an ergoline derivative.10y H 47 -N- -N- 1 110°C BnO &"" NO2 75% (two steps) Scheme 61 In an important extension of the Leimgruber-Batcho methodology, an Italian group was able to prepare the 2,3-disubstituted indole 48 as shown in Scheme 62.61 5.4 Makosza indole synthesis An excellent reductive cyclization protocol, which was developed by Makosza,"O has been exploited extensively by Macor and his colleagues to synthesize both indoles and 4 - a ~ a i n d o l e s .~ ~ ~ ~ ~ ~ ~ Two examples are48% 48 Scheme 62 listed in Schemes 63 and 64.A key feature of the first synthesis is the use of the Makosza 'Vicarious Nucleophilic Aromatic Substitution Reaction' (VNASR)' lo, Macor's second application featured the use of a carbon acid in the Mitsunobu reaction to lead eventually to 3-substituted indoles (Scheme 64). to install the acetonitrile side chain. Scheme 63 58% 9h H Scheme 64 6 Oxidative cyclization 6.1 Watanabe indole synthesis In an extension of their earlier reported method of indole synthesis from anilines, glycols, and a ruthenium catalyst,' l4l1 l5 Watanabe and co-workers have described the intramolecular version of this reaction.' l6 Thus, condensation of 2-nitrotoluenes with formaldehyde affords, after reduction, the requisite 2-aminophenethyl alcohols 49.Exposure of the latter to a homogeneous ruthenium catalyst gave the corresponding indoles 50 in excellent yields (Scheme 65). 2m1% R~C12(PPh3)3 ' - W o H t o l ~ 50 73-10096 NH2 49 R = dBr, 4-CI,6CI, 5-OMe. &Me Scheme 65 A one-step version of this synthesis was also discovered. Thus, treatment of 2-nitrophenethyl alcohol with a mixture of Rh/C and RuCl,(PPh,), in the presence of H, afforded indole in 96% yield.' l6 Not surprisingly, indoline was oxidized to indole ( 100°/~) with RuC12( PPh,), in refluxing toluene. This Watanabe indole synthesis was used successfully in an elegant synthesis of the teleocidin analogue 56, as outlined in Scheme 66.' l7 Although attempts to apply the Leimgruber-Batcho indole ring synthesis to dinitro 5 1 failed, this compound was converted in excellent yield to amino alcohol 54 via 52 and 53.A Watanabe oxidative cyclization afforded the desired indole 55 which was further transformed into the target molecule 56. 6.2 Miscellaneous oxidative cyclizations Although a relatively unexplored synthetic route to indoles, oxidative cyclization does play an important role in the biosynthesis of the melanin pigments. Carpender has developed carefully defined conditions for the synthesis of 58, a stable protected form of N-methyl-5,6-dihydroxyindole 57, which is a precursor to melanin polymers (Scheme 67).'18 Manganese dioxide has also been used in the oxidative cyclization of tricarbonyliron-cyclohexadiene complexes, leading to carbazoles.' l91l2O For example, Knolker applied this method to a B 5 9 synthesis of 4-deoxycarbazomycin (Scheme 68).120 A Japanese group has discovered a very efficient oxidative cyclization route to 5-hydroxyindoles, involving the cyclization of aminoethyl-p-benzoquinones (Scheme 69).121 Gribble: Recent developments in indole ring synthesk-methodology and applications 157NHC02Et C m E t c N* 95% cyclohexene EtOH Triton4 N02 DMSO 51 52 NHC02Et I coH NH2 several steps 7 c--- tol A 78% 56 Scheme 66 55 54 HO HO w N H C H 3 % 1-2 min.HO I 95% R = TMSCH2CH20CO Scheme 69 A*n- Y ACQ The latter are prepared by oxidation of the appropriate 1,4-dioxygenated benzene with phenyliodine bis( trifluoroacetate). 58 cH3 Scheme 67 7 Radical cyclization In recent times, radical cyclizations have pervaded all aspects of organic synthesis and the construction of the indole ring is no exception.Most of the pre-1990 work involved the synthesis of dihydroindoles,’** and, even since then, only a few methods have been developed that provide indoles directly. radical cyclization of 2-bromoacetanilides (Scheme 70), conditions that also induce ring closure to dihydroindoles (Scheme 7 1).123 A nickel catalyst in conjunction with electrolysis has been reported to convert bromoaniline 60 to 3-methylindole 6 1 (Scheme 72).124 Samarium iodide is a useful reagent for effecting the QMe Me 47% Ac Scheme 70 o - - - O M e Me H N-Ph H r.t. he 59 59% Scheme 71 Scheme 68 Contemporary Organic Synthesis 158f CHo Qc&cl H 60 H 61 (56%) 28% Scheme 72 Similarly, the following reactions lead to oxindoles or reduced versions thereof. It is worth noting that in Scheme 73 there is no cyclization into the ally1 unit (rationalized using conformational argurnent~),'~~ and the first example of a 5-endo-trig radical cyclization is presented in Scheme 74.126 The former research group has used this strategy in a synthesis of the alkaloid h0r~filine.l~~ Scheme 73 Boger and his colleagues have designed a 5-exo-trig radical cyclization in an improved synthesis of CBI, an analogue of a CC-1065 subunit.128 Thus, the precursor 62 was rapidly assembled from 1,3-dihydroxynaphthalene and underwent closure to 63 in nearly quantitative yield (Scheme 75).8: {OTHP {OTHP ' Bun3SnH / pfHA En0 ' - Y ' Y C02But BnO COPBU' 97% 62 63 Scheme 75 Parsons et al. have presented an elegant tandem radical cyclization leading to lysergic acid derivatives.12Y The precursor 64 was fashioned as shown and then smoothly converted into a mixture of two diastereomers 65 (Scheme 76).The use of Se-phenyl-p-tolueneselenosulfonate in a novel free radical selenosulfonylation cyclization to the perhydroindole ring system 66 has been described (Scheme 77).130 AC "oTNOMe A + td Meo2cv0Me - I AC 64 Me02Cfl'cH3 I Ac 65 Scheme 76 I AC S02T0l I PhH A (57- Y C02Me 66 aNr Tdszh- 94% C02Me Scheme 77 An earlier indole synthesis developed by Katritzky131 has been extended and improved by Barker and St01-r.'~~ Thus, flash vacuum pyrolysis (FVP) of N-vinylbenzotriazoles affords indoles (Schemes 78 and 79), although the reaction often leads to side products in other cases. The same reaction as applied to N-arylbenzotriazoles to give carbazoles (the Graebe-Ullmann reaction) has R A H R = n-Pen (56%) R = Ph (67%) Scheme 78 42% H n-C5H11 Scheme 79 Gribble: Recent developments in indole ring synthesis-methodology and applications 159been recently extended to produce ~arbolines.'~~J~~ In a variation of this diradical generation and cyclization, Edstrom and Yuan have photolysed triazolyluracils to afford p yrrolo [ 2,3 - d] pyrimidines.8 Metal-catalysed indole syntheses 8.1 Palladium Applications of palladium in organic synthesis have assumed enormous proportions in the past ten years. For example, palladium-catalysed cross-coupling reactions provide facile syntheses of a variety of structures. Likewise, palladium has found important uses in indole synthesis, both in the indole-ring forming step and in the synthesis of precursor compounds.136 8.1.1 Larock indole-indoline synthesis The pioneer in this area has been Larock, and, since his first paper (eg., Scheme 80),137 he has described several applications to the synthesis of indolines and indoles (Schemes 81-83).13s-141 The reaction with unsymmetrical alkynes (i.e., Scheme 83) gives predominantly the 2-substituted indole.H H Reagents: 2 mol % P~(OAC)~, DMF, Na2C03, Bu",NCI, 25 OC Scheme 80 Ac Reagents: P~(OAC)~, Na2C03, Ph3P, Bun4NCI, DMF, 100 "C -Bun Scheme 81 QJ1 NHTs +(D I TS Reagents: P~(OAC)~, Ph3P, Na2C03, DMF, Bun4NCI, 100 O C 0--JR3 R2 A1 R' = H, Me, Ac, TS R2 = Ph, n-Pr, t-Bu, TMS, CH2W R' = Me, Et, Ph, n-Pr, CH&H Reagents: Pd(OAc),, Bu"~NCI, DMF, K2CO3, 100 "C Scheme 83 Other groups have exploited Larock's conditions to construct more complex indoles (Schemes 84 and 85).142-144 ? CBZ-N Et3N A CBZ-N H Scheme 84 40% D Na-- SiMqBu' OACMe3 Reagents: Me2ButSiC3CH20H, P~(OAC)~, Bun4NCI, KOAc.100 "C Scheme 85 In a synthesis of the CC-l065/duocarmycin pharmacophore 67, Sakamoto and co-workers found that silver carbonate prevented tautomerism to the indole derivative (Scheme 86).145 Grigg has described a carbomethoxylation variation (Scheme 87),'& and Genet has utilized the water-soluble palladium( 0 ) catalyst prepared in situ from trisodium 3,3',3"-phosphinetriyltribenzene- sulfonate (TPFTS) and palladium(r1) acetate.14' 160 Scheme 82 Contemporary Organic SynthesisR 0 R=H (80%) R = OMe (73%) S02Ph 67 Reagents: P~(OAC)~, PhsP, DMF, Ag2C03, r.t. Scheme 86 S02Ph S02Ph Reagents: PdCL,(PPb)2, WAC, CO, MeOH Scheme 87 Yamanaka and his colleagues studied exhaustively the palladium-catalysed cyclization of b-( 2-halopheny1)amino substituted a, #bunsaturated ketones and esters to 2,3-disubstituted indoles (Scheme 88).14* 0 0 H X = Br, I H R' = HI Me, C02Et, Ph R2 = Me, Ph, OM, OEt R', R2 = -(CH2)3- Reagents: P~(OAC)~, Et3N, ( ~ T O I ) ~ P , DMF, A Scheme 88 8.1.2 Miscellaneous An interesting variation that leads to 3-vinyl- and 3-aryl-indoles has been reported by an Italian group (Scheme 89),149 and the use of palladium in the reductive heterocyclization of o-nitrostyrenes has been discovered (Scheme 9O).l5O The palladium-catalysed cross-coupling of aryl bromides with organostannanes has led to an efficient indole synthesis (Scheme 9 l ) , l including a short synthesis of the pyrrolophenanthridine alkaloid hippadine 68.15* Backvall has devised a palladium-catalysed intramolecular 1,4-addition to cyclic 1,3-dienes (Scheme 92),153 including the extension of this reaction to syntheses of a- and y-1y~orane.l~~ D C Z C - P h + ' N-COCF3 H H Scheme 89 75% H Scheme 90 Ac 68 Ac Reagents: (i) Bun3SnCH=CHOEt, PdC12(PPh3)2, DMF, EhNCI, 100 "C; (ii) pTsOH, PhH Scheme 91 Pd(0Ac)z acetone HOAc r.i.LiCl benzoquinone .. H I Ts 90% Scheme 92 8.2 Rhodium and ruthenium Rhodium acetate smoothly converts diazo compounds into the corresponding 3-acylindoles (Scheme 93),' 55 and a ruthenium catalyst was superior to palladium in the conversion of amino alcohols to 2-phenylindoles (Scheme 94),lS6 in a variation of the Watanabe indole synthesis (vide supra).Gribble: Recent developments in indole ring synthesis-methodology and applications 1610 0 A Scheme 93 Scheme 94 A R = Me, Bn 8.3 Titanium 8.3.1 Furstner indole synthesis Furstner forged a wide range of indoles using titanium/graphite in an intramolecular version of the McMurry coupling reaction (Schemes 95-97).157-15y R' = H, Me, Ph, t-Bu, 2-thienyl, Ar R2 = H, Me, Ph Scheme 95 V Scheme 96 Ph c'&:mo*y CH3 4 eq. Tl-graphke] c'Q--iph '13 CO2Et CH3 70 Scheme 97 162 Contemporary Organic Synthesis 69 The starting ketoamides are readily prepared by acylation of the corresponding aromatic amines. For example, the crowded 2-phenyl-3-t-butylindole was synthesized in 84% yield.lSs These researchers also prepared the Pakistan drug salvadoricine 69 (Scheme 96) and the diazepam precursor 70 (Scheme 97).lSy 8.3.2 Miscellaneous A different use of titanium was reported by a Japanese group.160 This involves the generation of a Ti-isocyanate complex and its reaction with a bromo ketone to effect indole formation (Scheme 98).Reagents: TiCI3, COP, NO, Mg, Pd(PPh&,THF, NMP, 100 OC Scheme 98 8.4 Zirconium Buchwald has uncovered a novel indole ring construction involving sequential alkene insertion with a zirconium complex (Scheme 99).161 Subsequent manipulation of 71 gave indole 73 via an ene reaction on the surprisingly stable indole tautomer 72. 2eq.Bu'Li Cp$r(Me)CI THF An Bn I &--- _DBu to1 A &- I Bn 72 71 I 100% Bn I Bergman discovered the remarkable set of transformations shown in Scheme 100, involving alkyne addition to a hydrazidozirconocene complex, leading eventually to indoles 74 in excellent yields.16*R Cpgr=N-NPh2 7249% RCECR 5%HCI 8146% l R F;r 74 R = Et, Ph, ptd Scheme 100 9 Cycloaddition and electrocyclization 9.1 Diels-Alder cycloaddition Boger has applied his earlier developed tetrazine cycloaddition methodology to a clever synthesis of the marine alkaloids cis- 28 and trans-trikentrin A (Scheme 101).163 The indole-forming step is the intramolecular cycloaddition of allene pyridazine 75 -, 76. SMe A Y' IY NYN SMe A PhH f.t.(ii) HOAc PhH 85% I " N \ SMe 76 75 28 Scheme 101 The powerful intramolecular Diels-Alder cycloaddition of vinylketenimines developed by G h o ~ e z ' ~ ~ has been extended by two research groups.Molina discovered a one-pot synthesis of various fused indoles and ~arbolines.'~~-l~~ For example, benz[ flindoles 78 are available from vinylketenimines 77, which in turn are formed by the reaction between an iminophosphorane and an isocyanate (Scheme 102), in what is a consecutive Staudinger, aza-Wittig, intramolecular Diels-Alder sequence.168 r.t. Ar = Ph, dMeOPh, 4-CIPh, 4-NO2Ph, 3-theny1, 4-pyridyl M d z 27-59% overall I @-- Ph 78 Scheme 102 td Similar chemistry was discovered independently by a Japanese group, leading to a one-pot synthesis of a-carbolines and pyridocarbolines (Scheme 103).16y The intermediate carbodiimide 79 could be isolated. H Scheme 103 9.2 P ho toelec t roc y clization The well-known Chapman photocyclization of N-arylenamines to dihydroindoles 70 has been Gribble: Recent developments in indole ring synthesis-methodology and applications 163employed by a Barcelona group to construct Aspidospem alkaloid intermediates (Scheme 1O4).l7l Similarly, a simple photochemical route to ellipticine-precursor carbazoles has been reported by a British group (Scheme 105).17* Me0&CH=C=CHC02Me 85% Scheme 104 Me Me Scheme 105 10 Indoles from pyrroles The obvious close chemical relationship between pyrroles and indoles has made the former an attractive substrate for indole ring construction, and many examples have been reported recently.10.1 Electrophilic cyclization 10.1.1 Natsume indole synthesis In a series of elegant papers, rich in chemical detail, Natsume arid his colleagues have synthesized a number of different indoles and indole natural products, including a janthitrem G model system,173 herbindoles A, B, and C,174 (S)-pindol~l,~~~> 176 pend~lmycin,~~~ trikentrin~,~~~? 17y alkoxyindoles,lgO 4-substituted indoles,lgl and fused indoles.lS2 As can be seen from the simple example in Scheme 106,173 + n 0-0 9- A Me Ts 75% Scheme 106 the key step is intramolecular electrophilic cyclization of C-2 of a pyrrole ring, followed by functionality manipulation and adjustment.The initial site of intermolecular electrophilic substitution (C-2 or C-3) is controlled by the nature of the Lewis acid. 10.1.2 Miscellaneous Using chemistry similar to that of Natsume, Trost had previously reported the conversion of pyrrole thioketal 80 into indole 81 (Scheme 1O7),ls3 and Kozikowski has synthzsized several lyngbyatoxin A analogues (e.g., 82), utilizing a pyrrole cyclization strategy (Scheme 1O8).ls4 Y Y H OH I" Me 81 OH i" 82 Scheme 108 As it has been over the years, the synthesis of 7- (and 4-) oxo-4,5,6,7-tetrahydroindoles as indole precursors continues to be an important route to indoles.For example, an Australian group has described a simple synthesis of N-benzyl- 7-0~0-4,5,6,7-tetrahydroindole 83 (Scheme 1O9).lg5 4-0~0-4,5,6,7-tetrahydroindole 84 to fashion 4-alkylthioindoles (Scheme 1 previously been converted to chuangxinmycin. Ishibashi employed a Natsume-type protocol to synthesize 4-substituted indoles, including (S)-pindolol and ( & )-~huangxinmycin.'~~ An example is shown in Scheme 11 1.Tobinaga and co-workers used Ester 85 had 164 Contemporary Organic SynthesisQ o :;" * pyH 0 70% O B f l 63 Scheme 109 (Ar = pCIPh) Scheme 11 1 (9 MeMgBr,THF A (ii) pTSA A- Y SOpPh 10.2 Palladium-catalysed cyclization Palladium has also been employed to spark the cyclization of a pyrrole to an indole (Schemes 1 12 and 1 13).188318y The latter study also included the synthesis of carbazoles from indolylallyl acetates by cyclocarbonylation. 8y OAc 57% Scheme 11 3 OAc CH20CHa 10.3 Cycloaddition routes 10.3.1 From vinylpyrroles The Diels-Alder cycloaddition of vinyl heterocycles has long been a fascination to organic chemists. Not surprisingly, this motif is an important route to indoles from 2- and 3-vinyl-pyrroles.For an important and elegant earlier study leading to the synthesis of 4-acylindoles see Muchowski and Scheller. lyo Recent examples are summarized in Schemes 114-1 16.iy1-'94 Unfortunately, yields are low to modest, and there is clearly room for improvement in this approach to indoles. TMSO CO2Et Scheme 114 4Tg NaH BnCl Y Me OH C02Et [%I SBn I Scheme 115 07 SO2Ph H O ~ ~ O A c 3396 * $7 SO2Ph Me02C C02Me Scheme 1 12 Scheme 11 6 Gribble: Recent developments in indole ring synthesis-methodology00 and applications Br TS 1651 0.3.2 From pyrrole-2,3-quinodimethanes The generation and Diels-Alder trapping of 2,3-dimethylene-2,3 -dihy dro p yrrole (pyrrole-2,3-quinodimethane) 86, or their synthetic analogues 87, is a tantalizing route to indoles. derivatives of 86 during the pyrolysis and subsequent trapping of thieno[3,4-b]pyrrole- 1,l-dioxides such as 88 (Scheme 1 17).lY5 Chou and Chang have apparently generated 75% Me S02Ph 88 Me S02Ph Scheme 117 Van Leusen has reported several approaches for the generation of pyrrole-2,3-quinomethanes, one of which is illustrated in Scheme 11 8; a reaction that leads to indole 89 and the novel compound 90.1g6 phTNo2 Me PhNOz A 1 89 (21%) Scheme 118 90 (50%) In a comprehensive set of papers, Moody et al.have elegantly illustrated the use of cycloaddition chemistry, involving both 1,5-dihydropyrano[ 3,4-b]pyrrol-5( 1 H)-ones and 1,6-dihydropyrano[4,3-b]pyrrol-6( 1 H)-ones in a new and powerful syntheses of in dole^.'^^-^^^ These synthetic analogues of pyrrole-2,3-quinodimethane 86 are readily prepared from the corresponding pyrroleacetic acids.Several examples are shown in Schemes 119-121. Et Et Scheme 119 TMSC 3CCOzEt yJ-- Y COp-BU' PhC' * Et02C 64% 0 co& ( isomer observed; >20:1) Scheme 120 (C H2)4C 3 C H .-8;;11 78% M e S02Ph Me S02Ph Scheme 121 Frey and Eger have uncovered a novel synthesis of 2-amino-3-cyanodihydroindol-5-ones via a cycloaddition of pyrroles such as 9 1 with dimethyl acetylenedicarboxylate (DMAD) (Scheme 1 22).200 OMAD ov~lcN HOAc M e NH2 25% NH2 M e 1 An 41% Me02C P f 91 Scheme 122 11 Aryne intermediates Given the enormous utility of benzyne and other arynes in organic synthesis, especially within the realm of cycloaddition chemistry, it is not surprising that these highly reactive intermediates have been exploited in indole ring construction.1 1.1 Aryne Diels-Alder cycloaddition An intramolecular aryne cycloaddition has been devised to synthesize the ergot skeleton, as shown in Scheme 123.201 Thus, the precursor 92 was crafted in high yield and then treated with lithium 2,2,6,6-tetramethylpiperidide (LTMP) to give directly 93 in 30% yield. 166 Contemporary Organic Synthesis92 0 H 93 Scheme 123 11.2 Nucleophilic cyclization of arynes In an extension of a reaction first reported in 1975 by the same group, a French team used the complex base NaNH,-t-BuONa to synthesize several indoles via arynic cyclization, two of which are illustrated in Schemes 124 and 125.,02 Quenching with CI I- (i) NaNH2. NaOBu', THF 20°C (ii) Hfl "eoaT- Scheme 124 H CI Scheme 125 dimethylsulfate instead of water provides the corresponding N-methylindole. to prepare carbazoles, including the alkaloids glycozolinine 94 and glycozolidine 95F03 Similarly, this arynic cyclization approach was used H073---cH3 H H 95 1 1.3 Miscellaneous aryne cyclizations Flash vacuum pyrolysis of quinoline- 3,4-dic arboxy lic anhydrides at 800°C affords fused indole derivatives in variable yields.*04 The intermediacy and rearrangement of an aryne is postulated to account for these remarkable reactions in the two cases shown in Schemes 126 and 127.4 ' 000°C 0.05 TOK ' Scheme 126 O+? m-40% Scheme 127 12 Miscellaneous indole syntheses Fadda has described a remarkable synthesis of indoles from the consecutive rearrangement of N-alkylpyridinium salts to indolizines and then to indoles by ring opening and recyclization (Scheme 128).,05 This sequence is limited to nitroindoles thus far.The mechanism of an earlier reported synthesis of indoles by the reaction of 3-nitropyridinium salts with N-alkylketimines (Scheme 129) has been discussed at length.206 This remarkable transformation affords a powerful route to polyalkylindoles. Gribble: Recent developments in indole ring synthesis-methodology and applications 167aq. NaOH 02Na-$- H R = Me, Ph, Bu' Scheme 128 CH3 Scheme 129 Makosza has discovered a facile synthesis of N-hydroxy-2-vinylindoles that involves a novel cyclization reaction (Scheme 1 30).207 The requisite starting materials were prepared via cyanomethylation of nitroarenes in the vicarious nucleophilic substitution reaction,l13 followed by alkylation.The N-hydroxyindoles can be reduced to the corresponding indoles (Zn, HOAc, reflux). CN $ (if) 3441% 1 R' = CI, Br, OMe R2 = H, Me R3= H, Ph OH Reagents: (i) BCH2CHR2=CHF?, K2CO3. BU",NI, CH3CN; (ii) TMSCI, EtsN, DMF, r.t. Scheme 130 A Russian research group has explored the use of metal oxides (Zn, Cr, Fe, Al) as catalysts in the high temperature conversion of ketimines to indoles (Scheme 131).208 Interestingly, 3-methyl-2-phenylindole is an intermediate in the formation of 2-phenylindole. H Scheme 131 Satomura reported an intriguing cyclization of in situ generated 0-vinylazoarenes leading to N-amino-5-hydroxyindoles, which can be reduced to the corresponding 5-hydroxyindoles (Scheme 1 32)?09 I r 1 2%HCI 80% I H073---JCH3* EtOH H00-100% kHPh H Scheme 132 5- endo-dig cyclization reaction, originally developed by Yamanaka,210 to achieve a total synthesis of the alkaloid ( - )-goniomitine.211 The key precursor 96 was prepared via palladium-catalysed cross-coupling (Scheme 133).Takano and co-workers have used a novel SXiH CO2Et 96 70% 11% Scheme 133 168 Contemporary Organic SynthesisIn a reaction thought to proceed via an a-aminocarbene intermediate, Li and Vasella have reported the synthesis of the cyclopropylindole shown in Scheme 134.212 COpEt N=N NHAc Br Ac Ar = 4-NO2Ph Scheme 134 13 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 A. Baeyer, Chem. Ber., 1880,13,2254. R.J. Sundberg, ‘The Chemistry of Indoles’, Academic Press, New York, 1970, Chapter 111. R.K. Brown, ‘Indoles, The Chemistry of Heterocyclic Compounds’, ed.W. J. Houlihan, Interscience, 1972, Vol. 25, part 1, Chapter 11. R. J. Sundberg, in ‘Comprehensive Heterocyclic Chemistry’, ed. A.R. Katritzky, C.W. Rees, C.W. Bird, and G.W.H. Cheeseman, Pergamon, Oxford, 1984, Vol. G.P. Ellis, in ‘The Chemistry of Heterocyclic Compounds’, Wiley, Chichester, 1992, Vol. 47, part 2. M. Alvarez, M. Salas, and J.A. Joule, Heterocycles, 1991,32,1391. For ongoing reviews including indole ring syntheses, the reader is referred to (a) ‘Progress in Heterocyclic Chemistry’, ed. H. Suschitzky and E.F.V. Scriven, Pergamon Press, Oxford, Vols. 1-5; and (b) ‘Annual Reports in Organic Synthesis’, Academic Press, San Diego. For two excellent introductions to the synthesis of indoles, see (a) J.A.Joule and G.F. Smith, ‘Heterocyclic Chemistry’, 2nd edition, Van Nostrand Reinhold, London, 1979; (b) T.L. Gilchrist, ‘Heterocyclic Chemistry’, Longman, Essex, 1985. W. J . Houlihan, V.A. Parrino, and Y. 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ISSN:1350-4894    

DOI:10.1039/CO9940100145

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Saturated and unsaturated hydrocarbons R.P.C. COUSINS Glaxo Research and Development Ltd, Greenford Road, Greenford, Middlesex UB6 OHE, UK Reviewing the literature published between 1 July 1992 and 1 September 1993 1 2 3 3.1 3.2 4 5 6 7 8 9 10 Saturated hydrocarbons Olefinic hydrocarbons Stereoselective simultaneous formation of sp3 and sp2 centres Claisen rearrangements Wittig rearrangements Conjugated dienes Non-conjugated dienes Poly enes Allenes Alkynes Enynes References 1 Saturated hydrocarbons Further developments of radical deoxygenation methodology have included approaches to dideoxygenations, as well as dehalogenation and deaminati~n,'-~ whilst an electroreductive deoxygenation of a-methylsulfonyloxyesters via a catalytic selenation-deselenation sequence has also been rep~rted.~ Radical decarboxylation procedures allow stereoselective alkylations with activated olefins of tartaric acid derived radicals, with retention of configuration (Scheme 1 )." B yJ ' 84% Scheme 1 Direct desulfonylations using magnesium in ethanol with catalytic mercuric chloride proceed in excellent yield,' and a mild procedure for the decarbonylation of aldehydes at room temperature in the presence of catalytic Rh( PPh,),Cl and stoichiometric diphenylphosphorylazide has been reported.8 ag-unsaturated carbonyl compounds has been achieved using an oxygen-activated palladium catalyst for ketones: SmI,-HMPA for esters, acids, amides, and anhydrides,'* and with CO and H,O in the presence of RhJCO),, for esters and ketones.l1 nitro olefins produce polyfunctional nitroalkanes in high yields (Scheme 2),12 and functionalized dialkylzinc reagents treated with Me,Cu( CN) (MgCl), in DMPU have been shown to undergo cross-coupling reactions with alkyl iodides in excellent yields (Scheme 3).13 The selective reduction of the double bond in The additions of copper-zinc reagents to a variety of p p b N o 2 + EtO&(CH2)&u(CN)ZnI t JwN22Et PP 94% Scheme 2 PhAN-OAc Tf 87% Scheme 3 A new procedure for the transmetallation of organoboron derivatives with Et,Zn or Me,Zn allows access to the corresponding dialkylzinc reagents, which are not readily available by standard methods (Scheme 4).14 (I) Eta.CUCN.2LICI - (CH2)gOTIPS 83% Scheme 4 In addition, a method allowing the insertion of zinc dust into primary alkyl chlorides, bromides, sulfonates, or phosphates has been reported with a variety of adducts prepared under copper ~atalysis;'~ Pd" Cousins: Saturated and unsaturated hydrocarbons 173catalysis enables the facile formation of akyl zinc iodides in the synthesis of cyclopentylmethyl zinc iodides, which were then subsequently further derivatized (Scheme 5).16 CO2Et phw 73% Scheme 5 The application of alkenyl zinc reagents in the preparation of functionalized carbocycles has also been reported, as has the use of o-alkenylalkyllithiums derived from the corresponding methyl selenide for the preparation of cyclopentanes.' Organomanganese chloride reagents have been found to be chemoselective and high yielding when applied under copper catalysis at room temperature to the preparation of a range of functionalized alkanes, and minimal /?-elimination was observed (Scheme 6).19 Alkylzirconium derivatives obtained from the hydrozirconation of olefins have been alkylated in the presence of catalytic CuCN with activated halides or phosphonates (Scheme 7).,O Scheme 6 cat.CuCN eBr 1 Y O T i P S R4 = T O T I P S Scheme 7 2 Olefinic hydrocarbons Transfer hydrogenations of alkynes in the presence of a Pdo catalyst have been shown to proceed in a highly stereoselective manner to afford Z-alkenes,,l as do new catalysts under standard hydrogenation conditions.22.23 The nickel-catalysed reductive cleavage of cyclic enol ethers with a Grignard reagent, however, produces the corresponding E-alkenes (Scheme 8).24 R=&" Scheme 8 A number of elimination procedures have been published during the period of this review, including the dehydration of benzylic and tertiary alcohols using molybdenum acetylacet~nate,~~ and a two-fold extrusion reaction of 1,3,4-thiadiazolines 1 which provides stereoselectively unhindered Z-olefins (Scheme 9)F6 1 H R R HH E:Z = 1:6 Scheme 9 An efficient decarbonylation-dehydration of aliphatic carboxylic acids using Pd- and Rh-based catalysts provides terminal ole fin^,^^ and the conversion of cis-vicinal dimethanesulfonates with alkali metal tellurides or selenides leads to the corresponding olefin.28 Acetonides, together with cyclic carbonates or sulfites of y, 6-dihydroxy-E- aB unsaturated esters undergo reductive cleavage with SmI, to give d-hydroxy-E-/?y-unsaturated esters in good yield (the use of magnesium affords the fully saturated ester) (Scheme 1 O).2y OH C0,Me ?> R- X = C(CH&, CO, SO Scheme 10 R = BnOCH, Methyl xanthate derivatives of #I-hydroxy sulfones have been shown to undergo radical deoxygenation to yield the corresponding olefin in a modified Julia olefination, where the reductive elimination of the sulfone moiety can often be problematic (Scheme 1 11.30 S PhgiiH, AIBN.toluene (CH2)6CH3 Scheme 11 Enantiomerically pure N-tosyl homoallylic amines are obtained via a three component coupling reaction between a (phenylsulfony1)-methane, enantiomerically pure N-tosylaziridines, and aldehydes to give 174 Contemporary Organic Synthesis/?-hydroxysulfones, which yield the corresponding olefins under Julia reductive elimination conditions (Scheme 1 2).31 (I) Bull (I0 dR Pls PhSO2 w Phs02Me (iii) BuU (hr) R'CHO Na(H9) R =TBDPSOCH2 I R' = ~C&43- R' ) Z S 45% E:Z = 3 1 Scheme 12 Horner- Wittig eliminations of p-hydroxyphosphine oxides in a variety of substrates has permitted the stereoselective synthesis of allylic and homoallylic mines, and non-conjugated unsaturated carboxylic and erthyro- and threo-phosphinyl alcohols provide E- and 2-alkenes, respectively, by an anti-elimination under acidic conditions, ih contrast to the Horner-Wittig syn-eliminations (Scheme 1 3)?5 E:Z >95:5 56% R=Bn €:Z = 1090 50% Scheme 13 The use of K,C03 and MeCN in Horner-Wadsworth-Emmons olefinations involving B-ketophosphonates prevents racemization of chiral centres in base sensitive pho~phonates.~~ The Wittig olefination reaction continues to be among the most popular methods for preparing alkene double bonds, but control of stereochemistry remains the key issue.A new one-pot, three-component procedure where the carbonyl moiety is derived from DMF has been reported to proceed with variable stereocontrol, but the best results were obtained with stabilized ylides and phosphonate esters (Scheme 14).37 &Ph3&H2(CH2),CH3 + BunLi CH3(CH2h3 Bun d E:Z < 595 69% Scheme 14 The bicyclic non-stabilized ylide 2 reacts with aldehydes to afford E-alkenes with high stereoselectivity; however, an inexpensive source of 2 is required before it becomes a general reagent.38 a 2 The application of cyclodextrin to the olefination reactions of aromatic aldehydes leads to only limited stereoc~ntrol,~~ but tris( 2-methoxy- methoxypheny1)-phosphine has given good selectivities when employed with stabilized, a-heterosubstituted ylides.4O.41 A new method for the construction of geometrically pure alkene double bonds has been reported where, having prepared the key dibromide 3 exclusively as the 2-isomer, selective functionalization of both the bromide and the silicon atoms allowed elaboration to a number of derivatives (Scheme 1 5).42 NBS TMS- PhH(Wet)' TMSyBT Br Bu&uLI~(CN) 2 eq. i 97% Scheme 15 73% The number of procedures that utilize transition metals in the synthesis of double bonds continues to increase, including the isomerization of endocyclic double bonds to an ex0 position via a palladium-catalysed hydrogenolysis of allylic formates, sulfones, and nitro the palladium-catalysed coupling of organoboron-derivatives with 1 -alkenyl-triflate~~~ and the development of a pdo water soluble catalyst enabled Heck, boronic acid, and alkynyl coupling reactions, as well as allylic substitutions, to be carried out in aqueous media.45 The preparation of stereo-defined, functionalized olefins has become increasingly important because of their application in transition metal mediated couplings, and a number of new procedures for the preparation of these useful intermediates have been published; for example, the cross-coupling of alkynes and alkenes in the presence of Zr-complexes leads to the formation of zirconacyclopentenes which, following alcoholysis and iodination, afford stereoselectively trisubstituted alkenyl iodides - (Scheme 16).46,47 The conversion of aldehydes into E-alkenyl stannanes, including a facile one-pot procedure using chromium chemistry (Scheme 1 7),4874y of acyltins to vinyltins with phosphorus ylide~,~O and of tin-alkynes to 2-alkenyl stannanes using zirconium chemistry (Scheme 18),51 have all been reported.Stannyl-cupration of acetylenes followed by quenching with a suitable electrophile affords substituted vinyl stannanes (Scheme 19).52 Cousins: Saturated and unsaturated hydrocarbons 175TMS I MeOH 1, I PP I TMS 75% (68%) €:Z = 6.63 Scheme 21 Scheme 16 3 Stereoselective simultaneous formation of sp3 and sp2 centres \ SnBu, Bu3SnCHBr2. LiI CaH17CHo CrQ,25- 60% Scheme 17 R = PhCH,O(CH& 90% Scheme 18 (0 Bu~Sn(M)CuCNU2 Bu3Sn c (ii) ethybne oxide S#=- Scheme 19 3.1 Claisen rearrangements The synthetic utility of the Claisen rearrangement is further demonstrated this year in its application to the preparation of a number of different classes of compounds, including y, 6-unsaturated- aldehyde^,^^ y, d-unsaturated-trifluoromethylketones,56 bicyclic lac tone^,^' branched chain ~-myo-inositols,~~ and cembranoid~;~~ as well as its application in a general method of iterative cyclopentannulation.6O The Ireland-Claisen rearrangement of allylic acrylates via phosphonium-substituted ester enolates has been achieved using only catalytic trialkylphosphine (Scheme 22),6l and optically active Z-vinylsilanes rearrange to anti-a-alkoxy-b-silyl-E-hexanoates with high diastereoselectivity (Scheme 23).6* 0 L Vinyl silanes have been prepared from a range of carbonyl compounds with the titanium (IV) reagent 4 (Scheme 20),53 and a series of vinyl iodides are available through the action of TMSI on the appropriate vinyl phosphate which in turn are obtained from the corresponding ketones (Scheme 2 1 ).54 Scheme 22 Z€ = 1A.5 79% Scheme 20 Contemporary Organic Synthesis 0.1 eq.P(C~H~I)S TESCI, DBU I ---r 84% y S i M e r P h (I) LW(TMSI2 OMe 1 68% Scheme 23 The aza-Claisen rearrangement of enolates of the N-crotyl derivatives of glycolamide and glycinamide proceeds with high syn: anti selectivity, and the procedure has been developed using a chiral auxiliary to enable the synthesis of a-hydroxy and a-amino acids (Scheme 24).63 176r 89% I - LHMDS Scheme 24 Very mild, essentially neutral, conditions are reported to enable the 3-aza-Claisen rearrangement of N-ally1 amides, using I,, P(OEt),, and Et3N.64 The stereoselective construction of the Z- or E-double bond in the ten-membered thiolcarbonates 5 can be achieved by controlling chair-like transition states in the [3,3]-sigmatropic rearrangement of eight-membered thionocarbonates.The subsequent reductive desulfurization of 5 then affords tri- or tetra-substituted olefins (Scheme 25).65 r Bu 1 SU" 7 90% Scheme 25 -OH O d Further studies on the thio-Claisen rearrangement illustrated that modest diastereoselectivity can be achieved.66-68 A study of the [ 3,3]-sigmatropic rearrangement of chiral trichloroacetimidic esters has found that palladium catalysis enables stereoselective synthesis of the dipeptide bioisostere 6 (Scheme 26).69 The interesting metalla-Claisen rearrangement involving 7 has enabled the stereoselective preparation of compounds with two adjacent stereocentres under very mild conditions (Scheme 2 7).70 U U Scheme 27 3.2 Wittig rearrangements The [2,3] Wittig rearrangement has been applied to a number of different targets, including subunits of herbimycin A71 and rapamy~in,'~ both from D-glucose, and to the preparation of the 4C-hydroxymethyl-hex-2-enopyranoside 8 (Scheme 28),73 as well as to the synthesis of the racemic Ireland alcohol where the key reaction was a titaniurn-mediated rearrangement of 9 (Scheme 29).74 ,OTBDPS ,OTBDPS 8 Bu3SnCH,0 Scheme 28 7J.i- OBn 0 53% Scheme 29 The use of a tandem [2,3]-Wittig rearrangement followed by an anionic oxy-Cope rearrangement of propargyl ethers has enabled the synthesis of key precursors to ( + )-faranal and ( - )-anti~-hiene.~~ The application of [2,3]-Wittig rearrangement to ( l-cyclopenteny1)methyl propargyl ethers was found to proceed with good stereocontrol (Scheme 30).76 Cousins: Saturated and unsaturated hydrocarbons 177A series of alkene dipeptide isosteres has been prepared using a Wittig-Still rearrangement (Scheme 3 1),77 and the application of the rearrangement to tertiary allylic ethers has allowed the preparation of geometrically defined tetrasubstituted olefins with modest stereocontrol (Scheme 32).78 Ph TIN >y\\ - BuLi H 07S"BU TIN OH H Scheme 31 MOMO Bun M e 4 Me' 0 I (I) MeLl (H) PtCOCl 1 OBZ I MOMO Bu" OBz Mew + Me Me rile 80% (4:l) Scheme 32 Further studies on the mechanism of the Wittig rearrangement suggest that the lithium-bearing terminus undergoes inversion rather than retention, as demonstrated by the use of enantiomerically defined a-(ally1oxy)stannanes (Scheme 33).79 Scheme 33 4 Conjugated dienes Further extensions of the Stille methodology have been reported in the synthesis of 1,3-dienes, such as the stereocontrolled synthesis of enantiomerically pure dienylsulfoxidess0 or the use of alkenyl( pheny1)iodonium salts in cross-coupling reactions.81 Two examples of macrocyclizations have been published using in one case a direct intramolecular Stille coupling in a synthesis of the polyene macrolactam leinamycin,8* and in the other an insertion of the enedistannane 10 in a synthesis of rapamycin (Scheme 34).83 Me..28% Scheme 34 An interesting communication has demonstrated that intramolecular coupling reactions of vinyl stannanes and vinyl halides can be achieved with just stoichiometric Cul C1 in DMF, without any palladium cataly~t.8~ A palladium-catalysed coupling reaction of /?-stannylenoates with /?-triflylenoates provides electron-deficient 1,3-diene~,~~ and the successful coupling of 2,2-difluorovinylboranes and vinyl halides to afford 1,1 ,-difluoro- 1,3-dienes has been reported.86 The synthesis of the chiral A-ring synthon for 1 a,2/?,25-trihydroxyvitamin D, was achieved using a palladium-catalysed cyclization of the 2-vinyl iodide 11 derived from D-mannitol (Scheme 35).87 OH OH 58% 11 Scheme 35 The Pd-Cu catalysed reaction of the chiral vinyl iodide 12 with methyl dec-9-ynoate followed by selective reduction has afforded methyl coriolate (Scheme 36).88 178 Contemporary Organic SynthesisCH3(CH2)4 Y- I EtO 7 OH 12 (1)- (CHd7COAe (ii) CUI Pd(PPh& ,J'CO2M, I OH 76% lzn mcqMe OH 73% Scheme 36 A number of procedures involving the conversion of carbonyl moieties into 1,3 dienes, including the use of lithiodienol ethers 13 (Scheme 37)*' and 80% Scheme 37 3-iodo-3-trimethylsilylallylic phosphonium ylide 14 to furnish 1 -iodo- 1 -trimethylsilyl- 1,3-dienes with high stereoselectivity (Scheme 38),y0 have been reported.14 R = n-C~H13- Scheme 38 I 71 Yo 3E : 32 = 7822 Two methodologies utilizing vinologous Peterson olefination of aldehydes were reported, one in which a chromium-mediated coupling reaction of 1 -bromo-3-trimethylsilylpropene affords allylic hydroxysilanes and subsequently 1,3-dienes.This approach takes advantage of the chemoselectivity of chromium organometallics (Scheme 39)." Similarly, the coupling of trimethylsilyl- 1 -propenyl-zirconocene chloride 15 with aldehydes in the presence of AgC104 followed by 1,4-eliminations has provided 1,3-dienes (Scheme 40).927y3 y-Trimethylsilyl crotonaldimine 16 enables a fluoride-mediated four-carbon homologation of aldehydes (Scheme 4 1),y4 and the condensation of the allylborane 17 with heterocyclic aldehydes followed by base induced Peterson olefination leads to 1,3-diene derivatives (Scheme 42).'5 A variety of 2-phenylthio- 1,3-dienes have been prepared through the palladium-catalysed 72% HCI.THF 1 quant. €:Z = 9:l Scheme 39 15 80% E:Z = 98:2 R = MeO,C(CH2),- Scheme 40 -"+ RCHO + Me3Si R = V C H 0 16 (i) CsF DMSO (il) ZnCk? 1 -CHO R 8Q% Scheme 41 17 R = O C H O Scheme 42 I.- ">)==(== H 83% E:Z= 2:98 Cousins: Saturated and unsaturated hydrocarbons 179cross-coupling reaction of a-allenyl acetates under nonbasic conditions.Y6 Substituted 1,3-dienes are also prepared by the reductive elimination of allylic nitro derivatives (Scheme 43),Y7 and 1,4-di&oxy- 1,3-dienes can be prepared stereoselectively by the thermolysis of molybdenum carbene complexes in the presence of propargyl ethers instead of the expected cyclic ethers (Scheme 44).Y8 A range of 2,3-disubstituted- 1,3-butadienes have been prepared from organotin and butadienyl-lithium reagents."Y ,OAc ?Ac alkylation of a terminal acetylene and subsequent selective reduction to give an E,Z-l,6-diene system.lo2 Newer approaches that have been published include the 1,4-elimination of l-methoxymethyl- 2-( trimethylsilylmethyl)cyclo-butanes, promoted with catalytic ZnBr,, to furnish 1,2,5 -trisubstituted- 1,5-dienes stereoselectively (Scheme 46).lo3 I Ph Scheme 43 I Ph 61 % OMe 62% Scheme 44 Several 1,3-cyclohexadienedicarboxylate esters of high stereopurity have been prepared with the new dienophile benzyl methyl-( S)-2-( p-tolylsulfiny1)- maleate 18 through a TiCl, promoted Diels-Alder reaction, followed by spontaneous sulfinyl elimination (Scheme 45).loo i a I r.t.t Me0 aco2Bn *'C02Bn Scheme 45 5 Non-conjugated dienes A typical approach to the synthesis of non-conjugated diene systems is illustrated in the synthesis of eicopentaenoic acid where ozonolysis, selective reduction, and Wittig reactions are used to produce the required 2-skipped diene.lol Another example is the preparation of a sex pheromone through the ZnBr2 0.1 eq.1 -Ph 95% €2 = 9416 Scheme 46 Additions of alkenes to acetylenes in the presence of catalytic Cp( C0D)RuCl affords 1,4-dienes (Scheme 47)lo4 and the cross-coupling under palladium catalysis of alkenyl( pheny1)iodonium salts with ally1 stannanes (Scheme 48) also leads to 1,4-diene~.~l R = (CH2)4C02CH3 Scheme 47 I +BF4- I Ph 72% Ph \\ 72% Scheme 48 6 Polyenes The use of acetylenic coupling reactions with vinyl halides leading to 1,3-enynes and subsequent stereoselective reduction is illustrated well in a new synthesis of lipoxin B, .lo5 The coupling reaction between a terminal acetylene and a propargyl chloride under mild conditions in the presence of only CuI, NaI, and K2C03 has allowed the preparation of hepoxilin B, epimers (Scheme 49) using the same overall strategy.O6 The straightforward derivatization of aldehydes with preformed reagents is a common approach, and is demonstrated in the use of the d-alkoxydienyl zirconocene complex 19 which enables a four-carbon homologation reaction which can be used in an iterative manner (Scheme 5O).lo7 The development of 180 Contemporary Organic Synthesis+ c02Me 9% HZ. Undlar 1 OH 95% Scheme 49 19 (i) RCHO, AgC104 (ii) Ha0 + I -CHO R R = (CH2)&02Me 80% Scheme 50 a synthetic equivalent to o-lithio dehydrocitral20 has enabled the expedient preparation of retinoid aldehydes (Scheme 51),lo8 and a reaction sequence involving Arbuzov rearrangement of ally1 phosphites followed by Horner-Wadsworth-Emmons olefination provides substituted trienes and tetraenes stereoselectively from aldehydes.loy Straightforward Wittig olefinations have also been used in the preparation of polyene oligomers.llOp 20 6870 Scheme 51 The synthesis of carotenoid alkylidene butenolides has now been developed, utilizing sulfone chemistry in order to avoid the more drastic reaction conditions required by Wittig chemistry.112 The use of alternative radical ring-opening reactions of vinylcyclopropanes has allowed the stereocontrolled elaboration of the diterpene casbene 2 1 into a number of different cembranes.' ' 7 b v 7 21 A stereoselective synthesis of conjugated all-E trienes uses Na( Hg) amalgam for a reductive elimination of 1,6-dibenzoate-2,4-dienes instead of low-valent titanium and is thus more tolerant of other functional groups present (Scheme 5 2), 4-1 has been described. 97% Scheme 52 A cuprate coupling reaction with the alkyl diiodide 22 has formed the key step in a synthesis of ( - )-C,,-botryococcene 23,' l 8 and the carbocupration of acetylene followed by in situ coupling with chlorobutadiene in the presence of catalytic NiCl,(PPh,)2 has facilitated the stereoselective addition of a triene unit onto a Grignard reagent (Scheme 53).' l 9 22 23 65% Scheme 53 Cousins: Saturated and unsaturated hydrocarbons 181182 The palladium-catalysed cross-coupling reaction of the organozinc 24 without protecting groups has been used in an approach to the synthesis of carotenoids and retinoids (Scheme 54).12* I Scheme 54 24 68% >96%z An extension of intramolecular cyclizations of 1,6-eneynes containing a terminal acetylene has afforded triene units stereoselectively when the reactions are carried out in the presence of a vinyl halide under palladium catalysis (Scheme 55).121 The importance of Stille coupling methodology in polyene synthesis is further demonstrated in a syntheses of the C-1-C-14-tetraene nitrile unit of calyculin A122*123 and for stable linear p01yenes.l~~ 62% Scheme 55 The additions of functionalized propargylic halides to aldehydes or ketones have been accomplished in the presence of CrCl, to give functionalized allenic derivatives not normally accessible by this type of approach (Scheme 58).127 OH WHO R = n-pent Scheme 58 92% Simple additions of propargylic halides, tosylates, and acetates to terminal alkynes in the presence of Pdo lead efficiently to conjugated allenynes (Scheme 59),12* and a series of allenol lactones have been prepared from propargylic acetates and 4-pentynoic acid, also using palladium ~ata1ysis.l~~ The palladium-catalysed conversions of terminal propargylic formates 25 into terminal allenes have also been reported (Scheme 6O).l3O Bu Et R = (CHd2OH Scheme 59 7 Allenes The use of propargylic derivatives as precursors to allenic moieties is further illustrated by the synthesis of terminal allenes from the action of lithium butyl( pheny1thio)cuprate on propargylic acetates (Scheme 56).125 The hydrostannation of propargylic alcohols, and subsequent deoxystannylation, produces allenes in a two-step, one-pot operation (Scheme 57).'26 Scheme 56 OH OH Bu&H AlBN * SnBu3 R t k.- Me -R Scheme 57 Contemporary Organic Synthesis 81 % Scheme 60 R' 86% I wo Two examples of the synthesis of allenes using [ 2,3]-sigmatropic rearrangements have been published.One example uses cyclicpropargylsulfonium ylides and affords terminal allenic lactones (Scheme 61),131 and another utilized a dienylselenide to furnish an allenic system which was then applied in a synthesis of an anti-fungal agent.132 A [ 2 + 21 cycloreversion reaction involving a-alkylidene-p-lactones has allowed the preparation of substituted allenes (Scheme 62),133 and a procedure for the synthesis of isocyanate substituted allenes has been published.134 The use of Raney nickel for the desulfurization of dithiolanes such as 26 has extended this approach to 1,3-butatrienes, to include alkyl substituted systems (Scheme 63).1350 0 I-( phenylsulfony1)- 1 -alkynes from aldehydes or E-caprolactone via /?-ketosulfones (Scheme 65),137 unsymmetrical 1,2-bis-( perfluoro)ethynes via dehydr~iodination,'~~ chiral propargylic amines by the conversion of optically active amine aldehydes using dimethyl diazoph~sphonate,~ 3y 3-acetoxy-3-alkoxy propynes through hypervalent iodine oxidation of alkoxy allenes.140 (i) BoLi (iii) PDC COpEt PhS02Me(li)o R 70'%0 R = Me2CHCH2- I Scheme 61 RCHO '.",,, Scheme 65 H Et t R-EQPh 84% Homopropargylic alcohols have been synthesized from the allenylboration of aldehydes and ketones,14' whereas y-hydroxy alkynes are derived from the dichloromethylene derivatives of lactones by reductive elimination with lithium metal.142 Alkynyl alcohols have been produced from a-chloroenones which are themselves derived from the aldol condensation of 1-bromo- 1-chloro ketones followed by deh~drati0n.l~~ The preparation of ethyl arylpropiolates is possible mCPBA A &M* c----- R.qo H Me R 4 H R = C-CgHir 69% Scheme 62 using palladium-cataly sed cross-coupling reactions of terminal alkynes with aryl iodides.144 In a number of other studies success without palladium catalysis was reported such as the coupling between aryl- or vinyl-halides and terminal alkynes using catalytic S ' K P 3 CuI-2PPh3 .145 Similarly, the condensation of terminal '}*( - d='='s~ functionalized alkynes with propargylic tosylates or chlorides using K2C03, NaI, and CuI at room temperat~re,'~~ and with CuI, Na2C03, and Bu4NC1 at room temperature have been rep91ted.l~~ The potential use of these last two routes as a convenient stereoselective route into skipped diynes, triynes, 95% X X X = CI, &, OTS R- Pr' 26 ( W o ) Scheme 63 8 Alkynes The preparation of 1,2-disubstituted alkynes by decarboxylation-hydrogenolysis of propargyl formates is of great synthetic importance given the ease of formation of the latter (Scheme 64).130 WHO dienes, and trienes cannot be ignored. dilithium salts of terminal alkynes has been reported, along with the preparation of a series of symmetrically disubstituted diacetylenes with polychlorophenyl rings as side groups, and linear polyether chains as spacer^.'^^^'^^ There is much interest in the properties of polyacetylenic compounds and this is reflected in the growing number of preparations reported, such as the synthesis of hexabutadiynylbenzene via palladium-catalysed coupling of terminal alkynyl units, 50 whereas copper catalysis proved much more successful in the synthesis of tribenzocyclotriyne.' 51 The successful synthesis of a series of selectively The synthesis of a range of cyclic diakynes using the R = GH13 Scheme 64 Synthetic procedures for the preparation of a number of acetylene derivatives have been published, including: chloroacetylene,' 36 89% protected tetraethynylethenes, such as 27, has allowed the preparation of [ 181- and [ 121-annulenes to be completed via oxidative cyclization, and also of mono cross-conjugated compounds.' 527 ' 53 The synthesis of stable tetraethynyl-butatriene has been described, along with the total synthesis of tetraethynyl-methane 28, which is quite an Cousins: Saturated and unsaturated hydrocarbons 183achievement considering the steric demands of the quarternary ~ e n t r e .l ~ ~ ~ l ~ ~ The syntheses of diethyl-dipropargyl- and tetrapropargyl-methane have also been published.156 A general asymmetric approach towards the synthesis of cis-epoxy polynes, which are naturally occurring antifeedants, has been described and uses optically pure (2R, 3S)-5-bromo-2,3-epoxyy- 4-pentyn- 1-01 29 as the key intermediate in a copper-catalysed cross-coupling reaction with terminal alkynes.57p 58 H 29 9 Enynes The direct coupling of terminal alkynes with vinyl iodides using catalytic CuI-PPh, in the presence of K2C03 affords eneynes with retention of configuration and without the need for palladium catalysis.15Y Similarly, the derivatization of 1-iodoalkynes, mediated with catalytic Py2BF4-HBF4, affords head to tail eneynes (Scheme 66).160 The enyne sulfide 30 is readily converted into 1,3-diene derivatives which lead to 2-enyne products following the elimination of ethanethiol with excess sodamide (Scheme 67).16' R 32% Scheme 66 80% 30 (ZS -9) Rx lm "H2 R-=i SEt R y - H 63% 79% R = 3-pyridyl Scheme 67 Disubstituted propynyl alcohols can be dehydrated using PdCl,( FTh,), and SnC1, under neutral conditions to afford 2-but-3-en-1-ynes.16, E-Conjugated eneynes bearing an acetal function on the allylic, propargylic, homoallylic, or homopropargylic position were prepared by the facile palladium-catalysed coupling of the corresponding vinyl tins with 1-bromo-alk- 1-ynes.16, Elaboration of eneyne linchpins such as 3 1 using palladium catalysis and en01 triflates has enabled the rapid building of polyenyne structures (Scheme 68).164 OTf + Bu3Sn 0- 7 R 31 R = SiMe3 90% Scheme 68 The preparation of a range of skipped cyclic ene- and diene-diynes by the addition of dilithium salts of diterminal enediynes to the appropriate dihalogenides has been re~0rted.I~~ The addition of alkynylalanes to alkylidene-malonates followed by palladium-catalysed allylation allows the construction of 1,6-eneynes in a single operation (Scheme 69).166 OAIEt2 <OTBDMS 54% Scheme 69 The discovery of powerful anti-tumour antibiotic enediyne natural products has stimulated considerable interest, since their complex structures and mode of action are novel and their biological activity is potent.There has been an ever increasing number of publications about these exquisite molecules, ranging 184 Contemporary Organic Synthesisfrom model studies to total synthesis. Thus, the synthesis of enediynes by the reaction of bicycloalkenyldiiodinium salts with lithiumalkynyl cup rate^,'^^ and the conversion of the diiodide 32 into enediynes using palladium-mediated chemistry has been reported (Scheme 70),168 along with an analogous approach using a dibromide.16Y HO fil P B BU&+ OTBDMS OTBDMS OTBDMS 32 3270 Scheme 70 The consecutive palladium-catalysed coupling reactions of the E-bis( enoltriflate) 33 with two different alkynes in a one-pot reaction have afforded mixtures of dienediynes with some degree of selectivity (Scheme 71),170 and application of this approach with 2-enoltriflate 34 has realized the successful synthesis of chiral dienediynes (Scheme 72).l7' TfO, &oTf An interesting conversion of dulcitol35 into the 2-hex-3-ene- 1,5-diyne unit has been published. It uses a Corey-Winter reaction involving the elimination of thionocarbonate for the introduction of the ene unit (Scheme 73).17* HO OH OPBDMS HO OH Me 35 OPBDMS 84% Scheme 73 The enzymatic conversion of the anthraquinone 36 into the enediyne 37 has been reported (Scheme 74),17, as has the conversion of o-dibromobenzene, using palladium catalysis, into the diyne 38 which was eventually elaborated to CDP1,-enediyne.74 33 0 OMe 38 62% R' = TBDPSOCHp R2 = MPOCH2 Scheme 71 wo CUI 1 0 OMe 37 Scheme 74 b H 38 The first total synthesis of calicheamicin yll has been reported,175 and a number of different approaches to the core structures of these molecules have been published. An allylic diazene rearrangement was used in a synthesis of the tricyclic core of dynemi~in,'~~ and a [2,3]-Wittig rearrangement of a Cousins: Saturated and unsaturated hydrocarbons 185cyclic enediyne ether was used in a synthesis of a bicyclic core.' 77 A n intramolecular [3,4]-ene reaction has provided a bicyclic subunit of these anti-tumour agents,178 and a preparation of the bicyclic enediyne 39 has been achieved using a series of iron-, copper-, titanium-, silicon-, and palladium-mediated reactions (Scheme 7 5).17y (9 CUCNLh(+TMS), - (i9 KF. MeOH 64% kH 83% 39 (rnY0) Scheme 75 The conversion of propargylic aldehydes into acyl substituted enediynes has been achieved using enolates derived from a-trimethylsilyl-a-allenyl carbonyl compounds (Scheme 76),' 8o and enediyne synthons like 40 have been utilized in the preparation of a new class of enediyne compound, where the final cyclization was mediated by chromium salts (Scheme 77).181 (ii) H30 + 62% Scheme 76 H J R = ButPh2Si, d3Si 40 60% Scheme 77 10 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 References D.H.R.Barton, D.O. Jang, and J.Cs. Jaszberenyi, Tetrahedron, 1993,49,2793. D.H.R. Barton, J. Dorchak, and J.Cs. Jaszberenyi, Tetrahedron, 1992,48,7435. D.H.R Barton, S.I. Parekh, and C.-L. Tse, Tetrahedron Lett., 1993,34,2733. D.H.R. Barton, D.O. Jang, and J.Cs. Jaszberenyi, Tetrahedron Lett., 1992,33,5709. T. Inokuchi, T. Sugimoto, M. Kusmoto, and S. Torii, Bull. Chem. Soc. Jpn., 1992,65,3200. D.H.R. Barton, A. Gateau-Olesker, S.D. Gero, B. Lacher, C. 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ISSN:1350-4894    

DOI:10.1039/CO9940100173

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

~~ Thiols, sulfides, sulfoxides, and sulfones CHRISTOPHER M. RAYNER School of Chemistry, University of Leeds, Lee& LS2 9JT, UK Reviewing the literature published between July 1992 and September 1993 1 2 2.1 2.2 2.3 2.4 2.5 3 3.1 3.1.1 3.1.2 3.1.3 3.2 3.2.1 3.2.2 3.2.3 4 4.1 4.2 4.2.1 4.2.2 4.2.3 5 Introduction Synthesis of thiols and sulfides Simple alkylthiols and diakylsulfides Substituted thiols and sulfides Ally1 and benzyl thiols and sulfides Vinyl and aryl sulfides Alkynyl sulfides Synthesis of sulfoxides Oxidation of sulfides Non-stereoselective oxidation Stereoselective oxidation Enantioselective oxidation Non-oxidative sulfoxide synthesis General methods for sulfoxide synthesis Functionalized sulfoxides Unsaturated sulfoxides Synthesis of sulfones Oxidation of sulfides Non-oxidative sulfone synthesis General methods for sulfone synthesis Functionalized sulfones Unsaturated sulfones References 1 Introduction This review covers new methods for the synthesis of acyclic thiols, sulfides, sulfoxides, and sulfones.Cyclic systems will be covered elsewhere. The review is divided into three sections: thiols and sulfides, sulfoxides, and sulfones. Each section begins with synthetic routes to simple systems, and then goes on to consider more complex, polyfunctional molecules. Considerable emphasis has been placed on stereo- and enantio-selective methods, reflecting the current interest in this area. 2 Synthesis of thiols and sulfides 2.1 Simple alkylthiols and dialkylsulfides One of the simplest, well established procedures for the preparation of sulfides is the alkylation of thiols with alkyl halides, or their equivalent.Improved procedures for this reaction have been reported. The bis( dipheny1phosphino)methane platinum (11) complex 1 catalyses the reaction between thiols and alkyl 1 halides for the preparation of unsymmetrical sulfides and thioacetals.' It has also been reported that ultrasound can accelerate reactions between thiols and alkyl and aralkyl halides in the presence of K2C03 in DME2 Treatment of hydrogen sulfide with ethyl magnesium bromide generates S( MgBr),, which is an effective reagent for the synthesis of a wide variety of symmetrical sulfides when treated with appropriate electrophiles (Scheme The reduction of sulfoxides using sodium iodide and a sulfonic acid catalyst also provides access to sulfides, the procedure being particularly efficient for the reduction of benzylic sulfoxides which can often be pr~blematic.~ A particularly useful one-pot preparation of sulfides from carbonyl compounds uses boron trifluoride monohydrate to catalyse the addition of a thiol to the carbonyl group to form a hemithioacetal, which is reduced in situ using triethylsilane to give unsymmetrical sulfides in good overall yields (Scheme 2).The reaction is successful even with hindered thiols (e.g. BU'SH).~ A related procedure has also been reported where replacement of Et3SiH with an aromatic nucleophile leads to products resulting from electrophilic aromatic substitution? r 7 Scheme 2 + t Rayner: Thiols, sulfides, sulfoxides, and sulfones 191Similar thioalkylation of electron-rich aromatic compounds has also been achieved using a-( benzotriazol- 1 -yl)benzyl phenyl sulfide under Lewis acidic conditions (Scheme 3).' (i) PPh3.(PrbcoN)~ CH@SH. THF RASPh R*SPh (ii) LiAIH4. Et@ Scheme 3 An adaptation of Corey 's oxazaborolidine-based asymmetric reducing agent has led to the development of a route to homochiral benzylic thiols8 Enantioselective reduction of a prochiral ketone gives the alcohol ( > 96% e.e.), which is converted to the thiol with clean inversion of configuration via an intermediate thioester and reduction (Scheme 4). 0 OH \ I Bu Scheme 4 2.2 Substituted thiols and sulfides The nucleophilic ring-opening of epoxides is a well known method for the preparation of #&hydroxysulfides.A recent study on the role of metal salts in promoting this reaction has shown that magnesium and lithium perchlorate are effective, with the former showing particularly useful regioselectivity (Scheme 5)? The use of proton exchanged X-type zeolite as a catalyst for this reaction has also been demonstrated, and is a superior catalyst to sulfuric acid.1° The direct conversion of a number of different B-alkoxyalcohols to the corresponding /3-alkoxysulfides, using a disulfide and a phosphine, has been reported (Scheme 6).l 1 ~ 1 2 The Lewis acid &SR R * R RSSR. PBu~ Scheme 6 catalysed reaction of a-sulfenyl acetals with silylated carbon nucleophiles provides a route to /?-alkoxysulfides with high diastereoselectivity (Scheme 7). The reaction is believed to proceed via sN2 displacement on the acetabLewis acid complex rather than an thiiranium ion.process, or an intermediate SR + + *But OSiMe3 OMe TMSOTf. MeCN 1 %But OMe 0 up to 98:2 anti:syn Scheme 7 In a related process, the highly regioselective reaction of allylic acetates with silylated carbon nucleophiles directed by a sulfenyl group gives moderate to good yields of addition products, with predominant a-attack (Scheme 8), rationalized by V S P h + -<"' OAc OSiMe3 TMSOTi (0.1 eq.) - 78 C + r.t. 1 A But L S P h a-attack a:y 94:6 yattack Scheme 8 consideration of an intermediate vinylthiiranium ion 2.14 The sulfoboration of cyclic ethers using bis( 1,5-cyclooctanediylboryl)sulfide 3 (R = 9-BRN) gives a preparative route to mercaptoalkanols (Scheme 9). Cleavage initially forms a boryl complex, which on decomplexation gives the desired thi01.l~ The a-thioalkylation of zinc enolates of a, a-disubstituted ketones has been reported using a-chlorosulfides under Lewis acidic conditions, giving good to moderate yields of p-( ary1thio)ketones (Scheme 10).l6 192 Contemporary Organic Synthesis3 H O W N H 2 + H O W S H Scheme 9 : u CI Scheme 10 2.3 Ally1 and benzyl thiols and sulfides The synthesis of allylaryl sulfides by palladium (0)-mediated alkylation of arylthiols with allylic carbonates gives primarily the product of substitution at the less-hindered carbon atom of the allylic carbonate (Scheme 11).Double bond geometry is lost THF,6O"c Scheme 11 in the case of Z-allylic carbonates, but otherwise the reaction proceeds well.17 The direct synthesis of allyl, benzyl, and cinnamyl sulfides and thiols from the corresponding alcohols under Lewis acidic catalysis has been reported.Again, the major product in all cases is that resulting from introduction of the sulfide group at the less-hindered carbon of the allylic system (Scheme 12). A mixture of double bond isomers is formed in cases where allylic rearrangement is observed. R'-oH (i) F3B.0Et2, CH&12 OH Scheme 12 Unactivated primary alcohols remain unaffected by this reaction. Inversion of stereochemistry is observed at secondary centres, and the reaction works equally well with thiols or their trimethylsilyl ethers as the nucleophile. Use of bis( trimethylsilyl) sulfide provides direct access to allylic thiols (Scheme 1 2).l8 The reaction of arylthiostannanes with benzyl bromide provide a route to unsymmetrical sulfides, although at present examples are limited (Scheme 13).19 PhS-CH2Ph CsF (cat.) PhSSnPh3 + PhCH2Br Scheme 13 An alternative approach for the synthesis of allyl sulfides is the addition of allyl silane derivatives to bis( ary1)thioketones (Scheme 14).Dialkylthioketones are rather unreactive in this reaction.20 The use of TBAF at room temperature or TASF at - 78°C as catalyst is required, and the reaction is successful for a range of silane systems. 2.4 Vinyl and aryl sulfides The reaction of trimethylsilyl thioethers with trimethylsilyl enol ethers under Lewis acidic catalysis provides a useful approach for the synthesis of vinyl sulfides from ketones and aldehydes (Scheme 15).OSiMe3 Sd "+ R3 R'SSiMe3. F3B.0Et2 R1+R3 R2 R2 Scheme 15 Reaction of a$-unsaturated carbonyl compounds with phenylthiotrimethylsilane (two equivalents) also allows efficient access to 1,3-bis( pheny1thio)propenes (Scheme 1 6).21 Polyunsaturated sulfides can be prepared from the appropriate vinyl silanes by treatment with a sulfenyl halide. The double bond geometry of the vinyl sulfide product is opposite to that of the original vinyl silane (Scheme 1 7).22 0 SPh Scheme 16 Scheme 17 Treatment of a /3-alkoxy sulfide with strong base induces /3-elimination to produce vinyl sulfides. Moderate to excellent control of geometry of the new double bond is possible, and is substrate dependent. This method also provides access to y-hydroxy vinyl sulfides by elimination of B, y-dialkoxy sulfides or /3, y-epoxy sulfides (Scheme 18).12,23 An alternative approach to y-hydroxy vinyl sulfides is by reaction of alkynyl sulfides with carbonyl compounds mediated by low-valent tantalum, generated in situ using TaCl, and zinc (Scheme 19).24 This selectively gives the E-double bond isomer (usually > 99 : 1) via the intermediate tantalum complex 4.1.7:l to 99:l €:Z Scheme 18 Rayner: Thiols, sulfides, sulfoxides, and sulfones 193(iii) NaOH.k@ 4 Scheme 19 The reaction of 1,2-propadienylsulfides with aldehydes and acetals under Lewis acidic conditions provides a route to substituted dienyl sulfides (Scheme 20). The allenic sulfide precursors are significantly more reactive than the corresponding allenic 0-ethe1-s.~~ OH SMe SMe RCHO, F3B.OEt2 R+Ph Scheme 20 Phthalimidosulfenyl chloride reacts with alkynes with formation of the E-vinylchlorosulfenimide.Substitution of the phthalimido residue by acetylide then provides access to alkynylvinyl sulfides in good overall yield (Scheme 2 1 ).26 E-2-Iodoethynyl sulfides have been prepared by zirconium-catalysed addition of N-iodosuccinimide to a terminal alkyne, with full control of double bond geometry (Scheme 22).27 Scheme 21 Scheme 22 The displacement of fluoride from activated fluoroaromatics using an aromatic thiol and KF-alumina with 18-crown-6 provides a route to unsymmetrical diary1 thioethers in excellent yield (Scheme 23).28 Similar products have also been prepared by an electrophilic aromatic substitution reaction of a sulfenium ion equivalent, generated from a disulfide using the acidic catalyst SbClJAgSbF,.The para-disubstituted isomers, where appropriate, are the main products of this reaction (Scheme 24).2y Scheme 23 SbCls. AgSbFG RSSR + A N c RSAr c'-cl A Scheme 24 The ortho-sulfenylation of N , N-dimethyl- 1 -phenylethylamine by lithiation and quench with a disulfide provides a route to alkylaryl sulfides in good overall yield (Scheme 25).30 RSSR 0°C I Scheme 25 2.5 Alkynyl sulfides The reaction of acetylide anions with sulfenylsulfonium salts, generated in situ from a disulfide and methyl iodide, provides an efficient route to alkynyl sulfides. The reaction is successful with a range of functionalized acetylide nucleophiles (Scheme 26).31 The copper ( I ) iodide catalysed reaction of disulfides (and diselenides) with alkynyl bromides in HMPA provides direct access to both aryl- and alkyl-alkynyl sulfides (Scheme 27).32 The preparation of alkyl ethynyl sulfides has been reported.27 Condensation of acetaldehyde with a thiol and HCl generates an a-chlorosulfide.This reacts with bromine to form a vicinal-dibromide, which is eliminated under strongly basic conditions to give an alkyl ethynyl sulfide (Scheme 28). The synthesis of alkynyl vinyl sulfides by nucleophilic displacement of phthalimide from a phthalimidosulfenate has been described previously (Scheme 2 1 ).26 Scheme 26 Scheme 27 194 Contemporary Organic SynthesisScheme 28 N~tBO3.4Hfl AcOH I 3 Synthesis of sulfoxides 3.1 Oxidation of sulfides The oxidation of sulfides continues to be one of the most important routes for the preparation of sulfoxides.Whilst there are already many known oxidants that will carry out this process, more appear every year, along with applications of previously reported reagents. Important recent advances have been made in the enantioselective oxidation of prochiral sulfides to the corresponding sulfoxides, and a separate section will be dedicated to this area. 3.1.1 Non-stereoselective oxidation A considerable number of new, non-stereoselective oxidizing agents have been reported for the oxidation of sulfides to sulfoxides. These include [R~(bpy),(0)PR,][C10,],~~ VOCl,/TBHP on montrnorill~nite,~~ Zn( B~O,),/ACOH,~~ H,O,-Urea/phthalic anhydride (utilizes a stable, inexpensive, and easy to handle source of H,0,),36 oxone on wet alumina (no overoxidation, alcohols and alkenes ~naffected),,~ Na2B,0, (particularly good for p-di~ulfoxides),~~ and o-iodosylbenzoic acid/H,SO, .3y The dramatic effect of alcohols, particularly methanol, on selectivity in the photo-oxidations of sulfides has also been reported.40 N-Phenylsulfonyloxaziridines are superior reagents to MCPBA and oxone for the oxidation of alkynylsulfides to alKynylsulf~xides.~~~~ 3.1.2 Stereoselective oxidation Me \ 1 Me 1 I A 6- m7md.e. 0’ Scheme 30 The use of MOO,( acac), and TBHP as a diastereoselective oxidant has been reported, however, selectivity and yield are modest (Scheme 3 1 ).Use of MMPP provides selective access to the trans-isomer as the cis-isomer rearranges under these reaction conditions. For the oxidation of a series of p- and y-hydroxy sulfides, VO( acac),/TBHP gives moderate to good diastereoselectivity (Scheme 32).,, Q -O-j-CMe Me There have been a number of reports of diastereosekctive oxidation of sulfides to sulfoxides.These often involve an adjacent functional group to cis, 36% Scheme 31 1 + ’0- trans, 6% which the oxidant can bind, thus delivering its oxygen ‘intramolecularly’. Good examples of this are the 2-exo-hydroxybornyl systems, with a sulfide in where oxidation provides exclusively one substituents (including vinyl groups) in good yield (Scheme 29).,l Protection of the alcohol as its MOM ether reduces diastereoselectivity to 30% d.e. 0- VO(~C~C)~,TBHP ?H I 2:l ?H position 10, derived from camphor- 1 0-sulfonic acid, &s\p~d CH&l2,- 20 “c &skp~oi diastereomeric product for a variety of sulfur PT0ks VO(a~ac)= TBHP PTd.s+.o- 5:l LOH CH&. - 20 .c‘ &OH OH \., R Stereochemistry at sulfur not determined Scheme 32 Scheme 29 Sulfides prepared from a-methylbenzylamine by ortho-lithiation and disulfide quench can be stereoselectively oxidized with NaB0,.4H20 with up to 77% d.e.(Scheme 30).,O Organic peracids were ineffective as diastereoselective oxidants. 3.1.3 Enantioselective oxidation Potentially the most useful method for the preparation of enantiomerically pure sulfoxides is asymmetric oxidation. This area rightly continues to attract considerable attention. A number of reviews in this Rayner: Thiols, sulfides, sulfoxides, and sulfones 195area have appeared, including oxidation using chloroperoxidase and horseradish peroxidase enzyme~,4~ strapped prophyrin catalyst^,,^ and N-( phenylsulfonyl )( 3,3-dicNorocamphoryl)oxaziridine 5 (Davis ~xaziridine)?~ 0' 5 Further details on the Davis oxaziridine have been reported.46 It has also been included in comparative studies with the Kagan oxidation [Ti(OPr'),, DET, cumene hydroperoxide, H,O] and fungal cultures for the preparation of vinyl sulf~xides,~~ and with the Kagan oxidation for the synthesis of substituted arylalkyl and methylalkyl sulfoxides.' In general the selectivity observed using the different oxidation procedures is very substrate dependent, however, the alternative procedures frequently provide complementary selectivity.For example, the Kagan oxidation gives good selectivity for methylalkyl sulfides but poor selectivity for phenylalkyl sulfides, whereas the Davis oxaziridine gives good selectivity for phenylalkyl sulfides but poor selectivity for methylalkyl sulfides (Scheme 33).' 0- CHs12;- 20 "C 5:l selectivity 0- 1 3 1 selectivity Scheme 33 New methods for asymmetric oxidation have been reported.A Japanese patent describes the use of iron-porphyrin catalysts with up to 46% e.e.48 A series of manganese( salen) catalysts (2-3 mol.%) and H,O, oxidize a range of arylalkyl sulfides in 34-68%e.e. and 80-95% yield, the best catalyst being 6, derived from enantiomerically pure H Q H 6 trans- 1,2-diamino~yclohexane.~~ Modest to good selectivity has also been observed for the preparation of arylmethyl sulfoxides using Ti( OR'), modified with R-( + )-binaphthol, with TBHP as oxidant.As with other related systems (Kagan oxidation) the addition of water (one equivalent relative to substrate) is of crucial importance for good selectivity (Scheme 34).50 Scheme 34 Enzymatic systems have also been reported. Chloroperoxidase from Caldariomyces furnago has been used in conjunction with chiral peroxides, which undergo kinetic resolution during asymmetric S-oxidation. A series of substituted arylmethyl sulfoxides can be prepared with 97-1 OO%e.e. (Scheme 35).51 The dramatic effect of substrate structure on enantioselectivity using cyclohexanone monooxygenase from Acinetobacter has been reported for a series of alkylaryl- and dialkyl-sulfides (3-99%e.e.)?, It was shown that the substrate structure influenced not only the enantiomeric purity of the product, but also its absolute configuration.OOH + PhSCH3 PhACH3 Chloroperoxidase 46% of hydroperoxlde ?- I 62% 8.8. 71% 8.8. 86% 8.8. Scheme 35 3.2 Non-oxidative sulfoxide synthesis 3.2.1 General methods for sulfoxide synthesis An interesting new route for the synthesis of alkylaryl sulfoxides has been reported, using 2-trimethylsilylethy1 benzenesulfenate and an alkyl halide with fluoride catalysis. Alkylation of sulfur, with loss of trimethylsilyl fluoride and ethene, gives the sulfoxide (Scheme 36).53 Scheme 36 Most other reports in this area involve the preparation of homochiral sulfoxides. An extensive review of asymmetric carbon-carbon bond formation using sulfoxide stabilized carbanions has been published. This also includes a section on methods for the enantioselective synthesis of sulfoxide~.~~ The nucleophilic displacement at sulfur in a chiral sulfinate, or its equivalent, continues to be an efficient route for 196 Contemporary Organic Synthesissulfoxide synthesis.Alkane- and arene-sulfinates of diacetone-D-glucose (DAG) provide a general route to both sulfoxide enantiomers. Sulfinylation of DAG with a sulfinyl chloride provides access to either sulfinate diastereomer depending on the nature of the base catalyst. Use of ethyl diisopropylamine selectively gives the (S,)-alkanesulfinate, whereas pyridine gives the ( R,)-alkanesulfinate (Scheme 37).55 Treatment with organometallic reagents then proceeds with clean inversion of stereochemistry, and provides access to a wide variety of sulfoxides, particularly methylalkyl, methylaryl, or p-tolylalkyl, of high enantiomeric purity.DAG gives superior selectivities for sulfinate formation compared to menthol or cholesterol. Nu- I 6- I 0- (S&alkanesulfinate RSOCI, PriNEt MF,- 78' C I DAG-H RSOCI, pyridine MF. - 78 OC I ( Rs)-alkanesulfinate Scheme 37 A report describing the preparation of isomeric butylethyl sulfoxides using sulfinate methodology and Grignard reagents, strongly suggests that, in reactions where one partner (either the nucleophile or sulfinate) is particularly sterically hindered, overall retention of configuration at sulfur is observed, in contrast to inversion which is normally expected.56 In such cases therefore, caution should be exercised when assigning sulfur stereochemistry.In an extension of previous work, Evans has reported the use of homochiral N-sulfinyloxazolidinones for sulfoxide synthesis.57 They may be prepared either by sulfinylation of the parent oxazolidinone, or by oxidation of the appropriate sulfenimides. These reagents react readily with a wide variety of nucleophiles, including Grignard reagents, enolates, alkoxides, and amides to give sulfoxides, sulfinate esters, and sulfinamides in high yields and enantioselectivities (Scheme 38). These oxazolidinone-based reagents are > 100 times more reactive than menthyl sulfinate esters toward Grignard reagents. Raynec Thiols, sulfides, sulfoxides, and surones 0 0 Scheme 38 A related process involves the reaction of bromovinyl aryl sulfoxides and Grignard reagents for the preparation of homochiral sulfoxides.In this case, introduction of the nucleophile is accompanied by loss of ethyne and bromide (Scheme 39).58 The bromovinyl sulfoxide precursors are readily prepared by addition of bromine to a vinyl sulfoxide, followed by base-catalysed elimination. Br scheme39 3.2.2 Functionalized sulfoxides The preparation and uses of a-chlorosulfoxides have recently been revie~ed.~"~~ A recent paper has also described a one-pot synthesis of these reagents from the appropriate sulfides using sulfuryl chloride nitrate, generated in situ from sulfuryl chloride and silver (or potassium) nitrate (Scheme 40)."l a-Chlorosulfoxides, when treated with base and a carbonyl compound, provide a route to #?-ketosulfoxides. The reaction is believed to proceed via an a-sulfinyl carbenoid and 1,2-nucleophilic shift (Scheme 4 1).62 ? Cl Scheme 40 LDA - Scheme 41 The stereoselective reduction of #?-ketosulfoxides provides a route to #?-hydroxysulfoxides.Interestingly, the selectivity is relatively independent of stereochemistry of substituents in the a-position ( 1,2-asymmetric induction), and is governed almost exclusively by the sulfoxide stereochemistry ( 1,3-asymmetric induction) (Scheme 42).63 A related reduction using NaBH, gives the opposite diastereomer with only modest selectivity, but was the 197Scheme 42 d+ 6- 0 N ~ H ~ 1 0- OH 69:31 d.8. Scheme 43 best of a number of other reducing agents tried (Scheme 43).64 The addition of diethylaluminium cyanide to /l-ketosulfoxides shows very high levels of stereocontrol. Again 1,3-asymmetric induction is the dominant factor in controlling stereochemistry (Scheme 44).h5 Condensation of a /l-ketosulfoxide with benzylamine gives a B-iminosulfoxide, which can be reduced with DIBAL/ZnBr, with almost full stereocontrol to give the /l-aminosulfoxide.66 Reduction using L-Selectride gives almost complete reversal of selectivity (Scheme 45).EtdAICN R 'pTd Scheme 44 Scheme 45 group. This is illustrated by reduction of two diastereomeric substrates, differing in stereochemistry at the hydroxyl group but not the sulfoxide. Hydrogenation gives identical stereochemistry at the a-position for both compounds (Scheme 46).67 7 Scheme 46 Intramolecular nucleophilic addition of alkoxides to vinylsulfoxides provides a route to /l-alkoxysulfoxides.The cis-product is formed with up to 18 : 1 selectivity (Scheme 47).68 ds.trans,up to 18:l Scheme 47 3.2.3 Unsaturated sulfoxides The synthesis of unsaturated sulfoxides using selenoxide elimination methodology has been used for the preparation of ( + )-( S)- a-diethoxyphosphorylvinyl p-tolyl sulfoxide, a new chiral Michael acceptor and dienophile. Introduction of the selenide moiety is carried out by lithiation a-to the sulfoxide and quenching with phenylselenyl bromide. Oxidation to the selenoxide is then carried out using H202, with >96% d.e. elimination to the vinylsulfoxide following rapidly (Scheme 48).69 i Scheme 48 198 Hydrogenation of a-( hydroxyalkyl) vinyl sulfoxides with the rhodium complex 7 provides excellent stereocontrol at the new chiral centre, directed exclusively by the sulfoxide rather than hydroxyl The a-lithiation of vinylsulfoxides forms anions which are configurationally unstable, but react with electrophiles to give predominantly the E-isomer.Use Contemporary Organic Synthesisof an aldehyde as electrophile gives poor to good selectivity (Scheme 49).70 An alternative to this prokess involves lithiation of a B-alkoxy sulfoxide followed by quenching with a carbonyl electrophile and B-elimination, resulting in a one-pot synthesis of 1-acyl- and 1-hydroxyalkyl-vinylsulfoxides (Scheme 50).71 The starting material is readily prepared by addition of sodium ethoxide to p-tolyl vinyl sulfoxide. 9- pTd'sY% EorZ 1 (1) LDA (ii) RCHO 1 4555 to 86:14 selectivity Scheme 49 (I) LDA (2 eq.).M F pTol' 0- I Scheme SO The products of such a reaction using acetaldehyde as the electrophile, can be dehydrated to give 'remarkably stable' 2-sulfinyl butadienes (Scheme 5 1 )?* 0- I pTol' HO (9 MsCi - (ii) DABW 0- I pTol**sx R3 = TBDMS Scheme 53 The palladium-catalysed cross-coupling reaction of vinyl stannanes with B-halovinyl sulfoxides provides a route for the stereocontrolled synthesis of 1 -sulfinyl butadienes (Scheme 54).74 The stereochemistry of the halogen is retained in the product. A stereoselective route to 2-2-haloalkenyl sulfoxides by addition of zinc halides or sodium iodide to alkynyl sulfoxides enhances the synthetic utility of the cross-coupling pr~cedure.~~ s+-0- pTd' X = Br, I Scheme 54 R< R3 1-Sulfinyl-2-tributylstannyl alkenes have coupled with vinyl iodides, derived from nucleic acid bases, in a new approach to thymidylate synthetase inhibitors (Scheme 55).Again, full control over double bond geometry is possible.76 0 Pd*(dba)3 THF. NMP I Scheme 51 Similarly, the products of ester condensation can be converted into their trimethylsilyl enol ethers to form 2-sulfinyl-3-trimethylsilyloxy butadienes (Scheme S2). 1 -Sulfinyl-2-t-butyldimethylsilyloxy butadienes have also been prepared using related methodology (Scheme 53).73 Scheme 55 Condensation of sulfoxide-stabilized carbanions with aldehydes has been used for the synthesis of unsaturated sulfoxides Containing additional electron-withdrawing groups. These are of use as chiral dienophiles, enophiles, and Michael acceptors (Schemes 56 and 57).77978 0- I 4 Synthesis of sulfones pTdO's+v (i) NEt3, DMF p T d O * s + y 4.1 Oxidation of sulfides 0- I New procedures for the oxidation of sulfides to sulfones have been reported.A simple and efficient A (I) MeSiCi Me3Si A 0 Scheme 52 Rayner: Thioh, sulfides, sulfoxides, and sulfones 199NH2+ Aco- r.t. c 1 0- Scheme 56 0- 0 I I pTd' & - C02Bn + H J p 0 (i) NEts DMF (ii) MoL NaHC03 pyrrddhe DMF 1 p- Scheme 57 method utilizes a ruthenium tetraoxide catalyst with periodic acid reoxidant in a CCl,/CH,CN/H,O solvent A comparison of peroxymolybdenum complexes for this oxidation has shown that MoO,-H,O-HMPA is particularly useful, showing good chemoselectivity, allowing the preparation of hydrolytically and acid-sensitive sulfones.80 Sodium perborate in acetic acid is reported to be a good oxidizing agent for the preparation of electron-deficient sulfones by oxidation of the appropriate sulfide.8 4.2 Non-oxidative sulfone synthesis 4.2.1 General methods for sulfone synthesis The reductive addition of alkyl radicals to vinyl sulfones has been demonstrated.P hotolysis of iodonium carboxylates generates the radical which, in the presence of a hydrogen atom donor, adds to phenyl vinyl sulfone in moderate to excellent yield (Scheme 58).82 The hydroformylation of vinyl sulfones, catalysed by a zwitterionic rhodium complex gives excellent yields of a-formyl sulfones (Scheme 59).83 Treatment of phenyl alkyl sulfones with two equivalents of base results in lithiation a-to the sulfone Scheme 59 and in the ortho-position of the aromatic ring.The resulting dianion can be quenched with electrophiles (alkyl halides, esters, CO,, and Me3SiC1) in both positions. Two sequential, one-pot lithiations allows introduction of different electrophiles (Scheme 60).84 Scheme 60 (i)Bu"Li (2 eq.) (ii)BU"Li, COr 4 C 0 2 H 0=S\fm 0 4.2.2 Functionalized sulfones The asymmetric Michael addition of SAMP/RAMP hydrazones to vinyl sulfoxides leads to the enantioselective synthesis of 2-substituted 4-ketosulfones (Scheme 6 I)? High enantioselectivities are obtained in moderate to good overall yields. Scheme 61 The lipase PS-30 catalysed acylation of chiral y- and d-hydroxy sulfones allows resolution with enantioselectivity in the range 36-98% e.e. Lower selectivity is observed for 8-hydroxy sulfones, and systems containing relatively bulky substituents (R= ethyl, Ar = naphthyl) (Scheme 62).86,87 R &..O2M Lipase PS-30, Etfl OAC It 200 Scheme 58 Scheme 62 Contemporary Organic SynthesisMicrobiological reduction of #?- and y-ketosulfones, using Baker's yeast or a number of other organisms, provides access to #?- and y-hydroxysulfones respectively, with high enantioselectivity and yield.The control of absolute stereochemistry is possible by choice of micro-organism (Scheme 63).88 OH 0 I ~ 9 5 % 8.8. 99% yield OH >95% 8.8. 80% yield Scheme 63 The stereocontrolled reduction of ( a-hydroxyalky1)vinyl sulfones using the rhodium complex 7 has been reported. The very high levels of selectivity observed are accounted for by coordination of the reducing species to the adjacent hydroxyl group (Scheme 64).67 OH 6H 99% d.e.Scheme 64 Good levels of stereocontrol have been obtained in the nucleophilic epoxidation of a-( 1-hydroxyalky1)- a, #?-unsaturated sulfones using the lithium salt of t-butyl hydroperoxide. On the free alcohol, the syn-isomer is favoured, whereas on the triisopropylsilyl ether the anti-isomer is predominant (Scheme 65):' SYn Scheme 65 anti 4.2.3 Unsaturated sulfones Dilithiation of 2-( chloromethyl)-3-p-toluene- sulfonylpropene allows introduction of electrophiles a-to the sulfone group in moderate yields. Use of carbonyl electrophiles provides direct access to 3-sulfonyl-2,5 -dihydrofurans by intramolecular displacement of chloride (Scheme 66).'O A considerable number of other ally1 sulfones have been prepared by simple displacement of chloride from the same starting rnaterial.'l 3-Arylsulfonyl-2-[( trimethylsilyl)methyl]alkenes can be readily prepared by reaction of (trimethylsily1)methyl cuprates with the appropriate l-(arylsulfonyl)alka-l,2-dienes (Scheme 67).y2 The addition of sodium p-toluenesulfonate and iodine to terminal alkynes provides a route to (i)Bu"Li (2 eq.).DMPUr90 'c 1 - Scheme 66 E-2-iodo-1-tosyl-1-alkenes with full control of double bond geometry. These useful intermediates can be converted into Z-vinyl sulfones by reductive de-iodination, and into propargyl- and Z-ally1 sulfones by elimination and subsequent stereocontrolled hydrogenation, respectively (Scheme 68).y3 NEts, MeCN 1 Scheme 68 The resolution of y-hydroxy-a, #?-unsaturated phenyl sulfones using lipase from Pseudomonas cepacia proceeds with high enantioselectivity and yield with a variety of substrates (Scheme 69).87 The 2,3-sigmatropic rearrangement of #?-sulfonyl alkynyl carbinols allows access to 1,4-bis( phenylsulfony1)- 1,3-butadienes after subsequent, further oxidation (Scheme 70).Y4 A stereoselective route to E-( phenylsulfony1)enynes using vinyl sulfone chemistry has been reported.Treatment of a sulfone anion with an acetylenic Raynec Thioh, sulfides, sulfoxides, and sulfones 2018848% 9.9. >95% 9.9. 4-h yield 4748% yield Scheme 69 Scheme 70 aldehyde, followed by dehydration, selectively gives the trimethylsilyl (or t-butyldimethylsilyl) protected alkyne (Scheme 7 1 )? Scheme 71 Alkynyl sulfones may be prepared by dehydration of B-ketosulfones. The triple bond may then be moved out of conjugation with the sulfone by equilibration using catalytic potassium t-butoxide in t-butanol/THF (Scheme 72).y6 Scheme 72 5 References 1 P.C.B.Page, S.S.Klair,M.P.Brown, C.S.Smith, S.J. Maginn, and S. Mulley, Tetrahedron, 1992,48,5933. 2 J.M. Khurana and P.K. Sahoo, Synth. Commun., 1992, 22, 1691. 3 A.N. Nedugov and N.N. Pavlova, Zh. 0%. Chim, 1992, 28,1401. 4 J. Drabowicz, B. Dudzinski, and M . Mikolajczyk, Synlett, 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 1992,252. G.A. Olah, Q. Wang, N.J. Trivedi, and G.K.S. Prakash, Synthesis, 1992,465. G.A. Olah, Q. Wang, X. Li, and G.K.S. Prakash, Synlett, 1993,32. A.R. Katritzky, L.Xie, A.S. Afridi, W.-Q. Fan, and W. Kuzmierkiewicz, Synthesis, 1993,47. E. J. Corey and K.A. Cimprich, Tetrahedron Lett., 1992, 33,4099. M. Chini, P. Crotti, E. Giovani, F. Macchia, and M. Pineschi, Synlett, 1992,303. H. Takeuchi, K. Kitajima, Y. Yamamoto, and K. Mizuno, J. Chem. SOC., Perkin Trans. ZI, 1993, 199. C.M. Rayner, A.D. Westwell, and M.S. Sin, Tetrahedron Lett., 1992,33,7237. S. Takano, Y. Sughara, and K. Ogasawara, Synlett, 1992, 668. K. Kudo, Y. Hashimoto, M. Sukegawa, M. Hasegawa, and K. Saigo, J. Org. Chem., 1993,58,579. K . Kudo, Y. Hashimoto, H. Houchigai, M. Hasagawa, and K. Saigo, Bull. Chem. SOC. Jpn, 1993,66,848. R. Koster and R. Kucznierz, Liebigs Ann. Chim., 1992, 835. U. Groth, T. Huhn, and N. Richter, Liebigs Ann. Chim., 1993,49. C. Goux, P.Lhoste, and D. Sinou, Tetrahedron Lett., 1992,33,8099. S.-C.Tsay, L.C. Lin,P.A. Furth,C.C. Shum,D.B. King, S.F. Yu, B.-L. Chen, and J.R. Hwu, Synthesis, 1993,329. C.-J. Li and D.N. Harpp, Tetrahedron Lett., 1992,33, 7293. A. Capperucci, M.C. Ferrara, A. Degl'Innocenti, B.F. Bonini, G. Mazzanti, P. Zani, and A. Ricci, Synlett, 1992, 880. A. Degl'Innocenti, P. Ulivi, A. Capperucci, A. Mordini, G. 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Commun., 1993,23,765; see also J.E. Brumwell, N.S. Simpkins, and N.K. Terrett, Tetrahedron Lett., 1993,34, 12 19. 2169. 82 H. Togo, M. Aoki, and M. Yokoyama, Chem. Lett., 1993, 83 K. Totland and H. Alper, J. 0%. Chem., 1993,58,3326. 84 M.G. Cabiddu, S. Cabiddu, C. Fattuoni, C. Floris, G. Gelli, and S. Melis, P, S, Si, and rel. elem., 1992,70, 139. Tetrahedron, 1993,49, 1821. Tetrahedron, 1992,48,8891. 57,3867. Tetrahedron Asymm., 1993,4,239. A. McCamley, Tetrahedron Lett., 1992,33,6197. 6543. 5 179. 85 D. Enders, K. Papadopoulos, and E. Herdtweck, 86 H.K. Jacobs, B.H. Mueller, and AS. Gopalan, 87 J.C. Carretero and E. Dominguez, J. 0%. Chem., 1992, 88 S. Robin, F. Huet, A. Fauve, and H. Veschambre, 89 R.F.W. Jackson, S.P. Standen, W. Clegg, and 90 K. Najera and J.M. Sansano, Tetrahedron Lett., 1992,33, 91 K. Najera and J.M. Sansano, Tetrahedron, 1992,48, 92 M. Harmata and B.F. Herron, Synthesis, 1993,202. 93 N. Iwata, T. Morioka, T. Kobayashi, T. Asada, H. Kinoshita, and K. Inomata, Bull. Chem. SOC. Jpn, 1992,65,1379. Tetrahedron Lett., 1992,33,7303. 7775. 94 Z. Ni, X. Wang, A. Rodriguez, and A. Padwa, 95 A.B. Holmes and G.R. Pooley, Tetrahedron, 1992,48, 96 M.C. Clasby and D. Craig, Synlett, 1992,825. Rayner: Thiols, suljides, surfoxides, and surfones 203

ISSN:1350-4894    

DOI:10.1039/CO9940100191

出版商:RSC    

年代:1994

数据来源: RSC

摘要:

Synthesis of five-membered aromatic heterocycles THOMAS L. GILCHRIST Chemistry Department, University of Liverpool, Liverpool L69 3BX, UK Reviewing the literature published between July 199 1 and June 1993 10 11 12 13 Introduction Furans and benzofurans Thiophenes and benzothiophenes Pyrroles Indoles Other fused pyrroles Oxazoles, isoxazoles, and benzoxazoles Thiazoles and selenazoles Pyrazoles, indazoles, imidazoles, and benzimidazoles Oxadiazoles Thiadiazoles, dithiazoles, and dithiadiazoles 1,2,4-Triazoles References 1 Introduction The aim of this review is to highlight advances in methods of formation of five-membered aromatic heterocycles. Because of the large number of publications the review has to be selective. In general, only methods which involve the construction of the ring systems, either from acyclic precursors or from other heterocycles, are covered: papers in which only functional group transformations are described are not included.The review is arranged according to the type of ring system being formed rather than according to the methods used. 2 Furans and benzofurans Several new furan syntheses involve a ring-forming step in which an oxygen-carbon bond is made by endo or ex0 cyclization of oxygen on to an sp hybridized carbon. Marshall and DuBay have described new routes to furans based on cyclization of unsaturated alcohols 1 with potassium t-butoxide.' A related route to furans is the ring opening and cyclization of the oxiranes 2 (Scheme l).2 The alcohols 1 are constructed by palladium-catalysed coupling of vinyl bromides or iodides with alkynes; a similar strategy is used to construct benzofurans from 2-iodophenol and alkynes (Scheme Z).394 Related routes to furans5 and to benzofurans6 which make use of palladium(0) coupling and cyclization are also shown in (Scheme 2).1 2 'OCH2Me Me R OCH20Me Reagents: (i) KOBU', BubH, 18-crown-6 Scheme 1 Reagents: (i) (Ph3P)zPdCh. CuI, M3N, 6060 "C, DMF (77%); (ii) Pd(PPh3),. K2C03, 60 "C. DMF (62%); (iii) Buli; (iv) Pd(PPha), (28%) Scheme 2 A simple route to 2-arylfurans (Scheme 3) makes use of the 1-benzotriazolyl function as an activating group and as a leaving group.7 A conceptually similar route to 2,3-disubstituted furans has also been described,* and 2,s-disubsituted furans have been prepared from the propargylic diols 3 by reductive cyclization with tributylphosphine and a palladium( 0 ) catalyst? Gilchrist: Synthesis of five-membered aromatic heterocycles 205Reagents: (i).BuLi, RCHO; (ii). NaOH, EtOH (R = Ph, 81% Scheme 3 R = 4CIC6H4,62% R = O-fut~~yl, 53%) B t ) e < L HO 3 Padwa and co-workers have used vinylsulfones 4 (X = Br, I) for the synthesis of several new trisubstituted furans. The sulfones 4, which are derived from benzenesulfonylallene by the addition of halogen, can react with enolate anions or their equivalent either by displacement of the allylic halide or by conjugate addition-elimination, the preference being determined by the choice of solvent and other reaction conditions.1°9 Two examples are shown in Scheme 4. The conjugate addition of enolate anions to vinyl sulfoxides has also been used as a route to trisubstituted furans: in this method, cyclization is achieved by Pummerer rearrangement of the intermediate sulfoxide (Scheme 5).12 J ' 0 Me QMe ' &OzPh, 1 Me tJ+=2ph Reagents: (i) (X = Br) MeCOCH2COMe, MeCN; (ii) K&O3 (77%); (iii) (X = I) l-(trimethykilybxy)cyclohexene, AgBF, (71%); (iv) Et3N (a%) Scheme 4 EtOZC, EtOzC, + Me G S P h Reagents: (i) ethyl 3oxobutanoate, NaOMe (83%); (u] (MeC0)20, Scheme 5 C13CC02H (84%); (iii) MCPBA (55%) Two further routes to trisubstituted furans which probably involve conjugate addition as a key step are illustrated in Scheme 6.a-Bromo-/3-alkoxyketones react with DBU to give trisubstituted furans 5 (35-7 l0/o): the reaction sequence shown has been suggested.13 Furans are also produced from ethynyl ketones 6 and aryl iodides by palladium-catalysed ~arbony1ation.l~ It is likely that conjugate addition of an intermediate acylpalladium iodide, ArCOPdI, to the triple bond provides the carbon framework.0- Br Br -* Me RO Me RO J RO RO 0 5 O=(-'R2 R' + ArI - " R2 $ k A r 6 Scheme 6 A useful synthesis of 2-fluoro-3-trifluoromethyl- furans 7 has been described starting from hexafluoroacetone (Scheme 7).15 The cyclization step can be represented as a 5-endo-trig process or, perhaps, better, as an electrocyclic reaction of the enolate anion. LFFhO F Ar F GAr 7 Reagents: (i) SnCI2 then heat (80-909'0); (ii) NaH M LDA (60-72%) Scheme 7 An electrocyclic process is also probably involved in the rather complex sequence by which 2-furanyloxiranes 8 are isomerized thermally to furo[3,4-blfurans 9 (Scheme 8).16 Several other unstable bicyclic furans, including thienofurans, furopyridines, and furoindoles, have been generated by acid catalysed cyclization: an example is shown in Scheme 9.17 Another route to fused furans is the intramolecular addition of acylcarbenoids to triple bonds: an example of the reaction is shown in Scheme 10 and several other types of polycyclic furans have been made using the same approach.'* Intramolecular radical addition reactions to carbon-carbon double bonds continue to provide useful routes to benzofurans." Normally such additions involve carbon radicals, but a flash pyrolytic route to benzofurans has been described in which an 206 Contemporary Organic Synthesis8 L + J 9 Scheme 8 Reagents: (i) CF3C02H; (ii) dimethyl acetylenedicarboxylate (88%.Scheme 9 Ar = 3,4dimethoxyphenyl) R Reagents: (i) Rh2(OAc),, 80 "C (>70%) Scheme 10 aryloxyl radical adds to a double bond at the ortho position.20 Another reaction which provides a good route to furans, benzofurans, and other heterocycles is intramolecular McMurry coupling of dicarbonyl compounds. For example, benzofurans were prepared in good yield by reductive cyclization of the ketoesters A method of preparing benzofurans and dibenzofurans has been described in which the six-membered ring is constructed from a chlorocyclobutenone 1 1 by palladium( 0 ) coupling to the five-membered heterocycle followed by ring expansion.22 3 Thiophenes and benzothiophenes Methods of preparation of ethenyl- and ethynyl-thiophenes have been reviewed.23 A general method of synthesis of 2,3-disubstituted thiophenes has been described starting from ketones.24 The method is illustrated in Scheme 11 for the preparation of 4,5,6,7-tetrahydrobenzothiophene; several other substituted thiophenes were prepared in an analogous manner from both cyclic and acyclic ketones.A procedure for preparing 3-substituted and 3,4-disubstituted thiophenes makes use of ketone dithioacetals 12 as starting materials. Reaction with diiodomethane and zinc-copper couple leads to the formation of 2-( methy1thio)thiophenes 13 from which the methylthio substituent can be selectively removed with Raney nickel.25 0 10 11 Reagents: (i) (Me3Si)2NLi. ZnC12; (ii) EtOC(=S)SCH2CH0 (660/): Scheme 11 (iii) conc.HCI (70V0) The strained thiophene 14 has been synthesized for the first time; the precursor was the diketone 15 which was subjected to reductive coupling and dehydration.*' Unlike most thiophenes, compound 14 participates as a diene in the Diels-Alder reaction under mild conditions. One of the products obtained from it by flash pyrolysis is benzo[ b Jthiophene (a reaction which presents a mechanistic challenge!). A variant of the long established route to 2,5-disubstituted thiophenes from 1,4-diketones has been described in which bis( trialkylstanny1)sulfides [( Bu,Sn),S, etc. ] have been used as the source of sulfur; thiophenes are formed in high yield in the presence of boron tri~hloride.~~ An improvement to the published experimental procedure for the preparation of 3-hydroxythiophene-2- carboxylic esters from P-ketoesters has been described.In the modified method a mixture of the ketoester, its corresponding alcohol, and thioacetic acid is treated with dry hydrogen chloride and the crude product mixture is then cyclized by reaction with the corresponding sodium alkoxide.28 An example is shown in Scheme 12. Thioacetic acid has also been used in the synthesis of ethyl thieno[2,3-dJthiazole-5-carboxylate 16 from the chloroaldehyde 1 7.29 The technique of directed lithiation is playing an increasing role in the synthesis of benzo fused heterocycles. An example is the synthesis of the sulfide 18 from N,N-dimethylbenzamide by directed lithiation followed by reaction of the lithio intermediate with sulfur then alkylation.This sulfide was then cyclized in high yield to 3-hydroxy-2-phenylbenzothiophene using potassium t-but~xide.~~ The cyclization requires the presence of both the sulfur atom and the phenyl group to provide activation to the methylene group in compound 18; a synthesis of the corresponding thieno[ 2,3- blpyridine was also successful. A related synthesis of naphtho[ 1,2-b Jthiophenes has been described.31 Gilchrist: Synthesis of five-membered aromatic heterocycles 2070 R x S M e Me& 12 14 Rg SMe 13 dSb 15 J W C 0 2 M e Reagents: (i) HSCH2C02H, MeOH, Dry HCI; (ii) NaOMe (85%) Scheme 12 Two reports have appeared of the preparation of benzo[ blthiophenes by the reaction of arylthio radicals with acetylenes. In one report, phenylthio radicals were generated from diphenyl disulfide at 150°C in the presence of phenylacetylenes (Scheme 13).32 In the other report, a gas-phase reaction between acetylene, hydrogen sulfide, and aryl chlorides or bromides was carried out and this gave benzothiophenes in good yield; arylthio radicals were suggested as intermediates in the reaction.33 16 17 i a Reagents: (i) Bu'OOBU', 150 OC Scheme 13 Some of the procedures described for furans in Section 2 have also been applied to thiophenes.These include the base-catalysed cyclization of thiols analogous to compound 1,34 and a route to benzothiophenes based on the coupling of the cyclobutenone 1 1 with 2-( tributyl~tanny1)thiophenes.~~ The Diels-Alder reaction shown in Scheme 9 provides a method of synthesis of benzothiophenes substituted in the six-membered ring.4 Pyrroles Reviews of the synthesis of the following pyrroles have appeared: ~inylpyrroles,~~ amin~pyrroles,~~ and 3-hydro~ypyrroles.~~ has proved to be the conjugate addition of the carbanion derived from tosylmethyl isocyanide (TOSMIC) to carbon-carbon double bonds followed by cyclization. A different use of TOSMIC has been described by van Leusen and co-workers in which it is first condensed with an aldehyde to produce an a#-unsaturated isonitrile; this then acts as the electrophilic partner in reactions leading to p y r r o l e ~ . ~ ~ , ~ ~ An example, shown in Scheme 14, is the synthesis of 3-cyano-4-phenylpyrrole in high yield from ethyl cyanoacetate. The use of the isonitrile (EtO),qO)CH,NC as a nucleophilic partner in pyrrole synthesis has also been described.4O A different endo cyclization procedure, which is claimed to be of wide scope, is illustrated in Scheme 15; the reaction can generally be carried out as a 'one-pot' Hydroformylation of propargylamines has provided an efficient synthesis of 3-phenylpyrrole and of several other pyrrole~;~~ a related method involves the use of propargylamines 19 which are converted into pyrroles 20 in moderate yield by conjugate addition followed by acylation (Scheme 1 6).43 catalysed decomposition of diazocarbonyl One of the best routes to 3,4-disubstituted pyrroles The use of acylcarbenoids, derived by rhodium(rr)- \ / Ts N H Reagents: (i) NaOEt (99%) Scheme 14 Reagents:(i) LDA, PhCN, BrCH2C ECH; (ii) EtBN (55%) Scheme 15 Me0 N(SiMe& 19 Reagents: (i).Me(Hex)CuLi; (ii) Scheme 16 MeO2C I R qMe H 20 RCOCl 208 Contemporary Organic Synthesiscompounds, in the synthesis of furans has already been referred to in Section 2. The methodology can be adapted to produce pyrroles: for example, the dihydrofuran 2 1 was prepared by carbenoid addition to ethyl vinyl ether and this was then converted into the pyrrole 22 (69%) by reaction with ammonium chl0ride.4~ A more complicated use of the carbenoid reaction in pyrrole synthesis is illustrated in Scheme 17: a 1,3-dipole is generated by intramolecular addition to the carbonyl group of an amide and this tautomerizes to an azomethine ylide, which can be intercepted conventionally by reaction with acetylenic esters. Several pyrrolecarboxylic esters with a variety of substituents have been prepared in good yield by this method.45 Rhodium-catalysed decomposition of diazoketones, ArCOCHN,, in the presence of benzonitrile provides a more direct route to nitrile ylides 23.These can be intercepted by dimethyl acetylenedicarboxylate to give pyrroles, although the major reaction is always electrocyclic ring-closure of the dipole to give a 2,5-diarylo~azole.4~ ,CO2Et ,CO2Et @CF3 Ph-ZEN-EHCOAr H EtO a C Fa 21 22 23 h + II Reagents: (i) Rh(OAc),; (in, dimethyl acetylenedicarboxylate (54V0) Scheme 17 A more efficient pyrrole synthesis based on nitrile ylide cycloaddition is shown in Scheme 18; this also illustrates another use of TOSMIC.47 2H-Azirines are known to give nitrile ylides upon irradiation but when the process is carried out in the presence of an electron-acceptor the intermediate generated is a radical cation, which reacts with dipolarophiles in a stepwise manner!8 An example of the synthesis of a pyrrole by this method is also shown in Scheme 18.MeS Azomethine ylides with appropriate leaving groups are, however, probably the most useful 1,3-dipoles for the synthesis of pyrroles. The transient intermediates shown in Scheme 17 are of this type and several others have been used recently. The species 2449 and 2550 were generated in situ and were intercepted efficiently by dimethyl acetylenedicarboxylate. A versatile procedure, described by Vedejs and Piotrowski, is the ring-opening of the oxazolium salts 26 by nucleophiles ( Z-).51 The azomethine ylides were then intercepted by acetylenic dipolarophiles, either inter- or intra-molecularly, to give a variety of polysubstituted pyrroles after the loss of the elements of HZ.25 27 28 30 29 Munchnones such as 27 can be regarded as stabilized azomethine ylides and their cycloaddition reactions provide good routes to polysubstituted pyrroles; several p-trifluoromethylpyrroles have been prepared by this method.52 The oxazolones 28 have also been used in pyrrole synthesis: reaction with a-chloroacrylonitrile gave /3-~yanopyrroles.~~ This reaction was interpreted as a stepwise Michael addition-elimination process rather than as a c ycloaddition. A rare example of Diels-Alder reaction of an imidazole is the intramolecular cycloaddition of compound 29, which takes place at 220°C to give the bicyclic pyrrole 30 in good yield.54 A Diels-Alder reaction is the first step in a useful synthesis of 3-fl~oropyrroles.~~ An example is shown in Scheme 19; nitrosobenzene was also used as the dienophile and gave 3-fluoro-l-phenylpyrrole by the same sequence.(ii) (iii) TsCH~NC - ('I hN, - [MeS-CEfi-eHTs] - MeS CI CH~TS H Reagents: (i) MeSCI; (ii) KOH, alumina; (iii) dethyl fumarate (68%); (iv) h. 1,4dicyanonaphthalene; Scheme 18 (v), dimethyl acetylenedicarboxylate (56%) Gilchrist: Synthesis of five-membered aromatic heterocycles 209210 E F b I OH Me3Si0 O-N Reagents: i, Et3N; ii, MeC02H aq. (7W0) Scheme 19 b An unusual synthesis of 2,3-diarylpyrroles has been described by Katritzky and co-workers and this is illustrated in Scheme 20.56 An ylide intermediate of a different kind is postulated in the route to pyrrole-2-carboxylic esters shown in Scheme 2 1 .57 This sequence can be carried out in one pot from the open chain species 3 1 and the overall yields are good.The loss of sulfur from the thiazines is a reaction which has been used before in pyrrole synthesis. Ph (Bt = 1 -benzotriazolyl) Reagents: (i) Ph3P = CH2, BuLi; (ii) PhCOCOPh (6Wo) Scheme 20 31 R3 v1 -‘C02Me I t R2 H I c02Me Reagents: (i) B T ~ ; (ii) Et3N Scheme 21 Conjugate addition-exo cyclization sequences are widely used in pyrrole synthesis and two of the many useful recent examples are illustrated in Schemes 22 and 23. The conjugated iminium salts 32 react with glycine ethyl ester and with N-methylglycine ethyl ester and the adducts are cyclized in the presence of sodium hydride to give pyrrole-2-carboxylic esters in good yield.5g A synthesis of 3-trifluoromethylpyrroles is achieved in good yield by conjugate addition to the enones 33.59 Several further examples of the synthesis of 1 -( methoxycarbony1amino)pyrroles by conjugate addition of carbanions to conjugated azoalkenes have also been described.6°J’1 Another reaction which is Contemporary Organic Synthesis proving to be quite versatile as a pyrrole synthesis is the conjugate addition of oximes to acetylenes followed by the sigmatropic rearrangement of the O-vinyloximes; a recent example is shown in Scheme 24.62 + + (I) * y + * 2 MeN-CO2Et ArY-NMe2 CI c10,- 32 AT QF,, Me Reagents: (i) MeNHCH2C02Et, NaH (67%.R = 4-CK6H4) Scheme 22 H Reagents: (i) (Me0)$HCH2NH2; (ii) CF3C02H aq.(87%) Scheme 23 + H-CEC-H - NOH I (AT = 4-biphenyl) Reagents: (i) KOH, Me2SO (68%) Scheme 24 Of all the methods available for pyrrole synthesis the Paal-Knorr procedure remains one of the most useful. An example of the synthesis of a highly functionalized,’ pentasubstituted pyrrole in good yield under carefully controlled conditions shows the versatility of the Paal-Knorr method.63 5 Indoles Two new and mechanistically interesting methods of synthesis of 2,3-disubstituted indoles from o-acetylbenzamides have been reported; they are illustrated in Scheme 25. One is an intramolecular McMurry coupling of the amide 34. This gives the indole in good yield; the coupling thus shows high chemoselectivity for the amide carbonyl despite the fact this functional group was previously believed to be inert in McMurry coupling, and despite the presence of a more activated carbonyl method the key step is the generation of an activated allene; this was achieved by a [2,3] sigmatropic rearrangement .6 Two other new indole syntheses based on o-substituted benzamides are shown in Scheme 26.The first makes use of directed lithiation into a 2-alkyl substituent and formylation of the alkyl-lithium intermediate. Several indoles were made in this way, including the 3,4-bridged compound 35.66 A Heck reaction is used in the second process to functionalize In the secondNHCOMe NHCOMe Me Me bWPh - &-"" NHCOMe COMe Reagents: (i) Tiigraphite; (ii) PhSCI, Et3N (93%) Scheme 25 a 2-ethyl substituent and to activate it to nucleophilic atta~k.6~ 2-Phenylindole has been prepared in good yield by palladium-catalysed reductive cyclization of 2-nitrostilbene, and other 2-substituted indoles were prepared by the same Activated 2-nitrostyrenes have also been used as precursors to l-hydroxyindoles (Scheme 27):' make use of quinones as intermediates.Two intramolecular reactions, both leading to Several indole syntheses have been reported which I 1" n n \COBu' 35 \COBu' Ar Reagents: (i) Bu'Li, TMEDA; (ii) DMF (88%); (iii) HCI (73%); (iv) ArI, Pd(PPh3)4, K2CO3, MeCN, 80 "C (80% for R = Ph, Ar = 4-CIC6H4) Scheme 26 CN CN Reagents: (i) K2CO3, MeOH (67%) Scheme 27 5,6-disubstituted indoles, are illustrated in Scheme 28. Epinine 36 was oxidized by manganese dioxide and intramolecular conjugate addition to the transient o-benzoquinone gave 1 -methyl- 5,6-dihydr0xyindole.~~ The amino protecting group was removed from the quinone 37, allowing the five-membered ring to form; dehydrogenation with palladium then gave 5-hydroxy- 6-methoxyindole in high yield.71 6-Hydroxy-3-nitro- indoles have also been isolated as products of the reactions of benzoquinone with nitroenamines, although the yields are (9 HO HO W N H M e - HO Me 36 37 Reagents: (i) Mn02, phosphate buffer (61 YO as diacetate); Scheme 28 The Fischer indole synthesis can be carried out in 96% formic acid under microwave irradiati~n.~~ A study of the mechanism of the Fischer indole synthesis has indicated that under strongly acidic conditions (phosphorus pentoxide in methanesulfonic acid) the intermediate which undergoes the [ 3,3] rearrangement is a dication 38 formed by protonation of the benzene ring.74 A method of synthesis of 2-substituted indoles from N-acyl-N-phenylhydroxylamines has been described which, it is suggested, also involves a [3,3] shift as a key step (Scheme 29).75 (ii) TsOH, MeCN; (iii) Pd/C (90%) 38 39 V0 1 Rvo 1 H Reagents: (i) heat, AIBN (82% for R = CH2Ph) Scheme 29 Gilchrist: Synthesis of Jive-membered aromatic heterocycles 211A method of indole synthesis first reported in 1989 is the reaction of nitrobenzenes with an excess of vinylmagnesium bromide.This procedure has now been adapted to provide a large scale preparation of 7-formylindole in good yield from 2-nitrobenzaldehyde dibutyl a ~ e t a 1 . ~ ~ six-membered ring on to a substituted pyrrole has the advantage that it is possible to control the substitution pattern in the carbocylic part of the indole.This approach has been adopted in the synthesis of different 4-substituted indoles starting with 3-acyl- 1 -arenesulf~nylpyrroles.~~-~~ An example is shown in Scheme 30. A similar approach to the synthesis of 2,7-disubstituted indoles has been described although the yields were low.8o The Diels-Alder reaction can also be used to construct the six-membered ring, as illustrated by the example in Scheme 3 1 .81 The approach to indoles of building up the TS Reagents: (0 H+, MeOH (82%) Scheme 30 (9 O m - \ S02Ph SO2Ph Reagents: (i) dimethyl acetylenedicarboxylate, PhCI, heat (58%) Scheme 31 6 Other fused pyrroles The reductive cyclization of 2-nitrosobiphenyl to carbazole is well known and a mechanism involving a nitrene intermediate has been postulated.Reaction of 2-nitrosobenzene with Ru3( CO), has been shown to give a nitrene complex 39, the structure of which was determined by X-ray analysis. This complex then gave carbazole when reacted with carbon monoxide.82 Some of the methods used for the preparation of indoles have been adapted to the preparation of aza-indoles (pyrrolopyridines) and other fused pyrroles. An example, shown in Scheme 32, is the preparation of a benzothienylpyrrole 40 by directed lithiation and cy~lization.~~ Another example is the construction of a 3-vinyl-2-aminopyridine by palladium coupling and its cyclization (Scheme 33).84 A conceptually novel approach to this ring system is also illustrated in the Scheme.Here, an intermediate N-lithiated imine is generated and then cyclized in the presence of more LDA on to the activated 2-position of ~ y r i d i n e . ~ ~ Several similar reactions, leading to other azaindoles, are described. A variety of methods has been used in an investigation of new and improved routes to 4-, 5, 6-, and 7-a~aindoles.~~ NHC02But NHC02Bu‘ & ‘ s 40 Reagents: (i) BuLi; (ii) P-chbrocydohexanone; (iii) KOH, MeOH (90%) Scheme 32 PYm Me N t Reagents: (i) ethynyltrimethylsilane, (Ph3P)2PdC12. Cul. Et3N, DMF; (ii) CuI, DMF, heat (40%); (iii) PhCN, LDA; (iv) LDA, H+, H20 (90%) Scheme 33 Padwa and co-workers have devised an indolizine synthesis (Scheme 34) as part of their continuing study of the applications of rhodium-catalysed reactions of diazoket~nes.~~ Another route to a special group of indolizines (and other 1,2-fused pyrroles) is also shown in the Scheme.This makes use of tris( alky1thio)cyclopropenium cations as miulating agents for 2-metallated aza heterocycles.88 7 Oxazoles, isoxazoles, and benzoxazoles Further examples have been reported of the preparation of oxazoles by the 1,5-dipolar cyclization of acylnitrile ylides; these intermediates were generated by the rhodium( u)-catalysed decomposition of diazo compounds in the presence of nit rile^.^^* 8y+90 These reactions can be carried out sequentially to provide a route to bis-oxazoles, as in the example shown in Scheme 35. 2 12 Contemporary Organic Synthesis&c02w SPS I SPS + A S P , PSS C104- 'SPS Reagents: (i) Rh,(OAc),; (ii) Scheme 34 DMAD, air (65%); (iii), (99%) N, OMe Reagents: ( i ) PhCN, Rh2(0COMe)4 (35%); (ii) (MeQC),C = N2 Scheme 35 RhANHCOC F3)4 (53%) Ph 4 Ph A range of trisubstituted oxazoles has been prepared in good yield by the route outlined in Scheme 36?lvY2 Three other methods for 2-methyloxazoles are illustrated in Scheme 37:Y3-95 the first is represented as a conjugate addition reaction to the vinyl sulfone and is analogous to the furan synthesis of Padwa and co-workers described in Section 2.Oxazole-4-carboxylic esters have been synthesized by cyclization of N-acylserine methyl esters 4 1 with diphenyl sulfoxide and triflic anhydride, followed by oxidation of the resulting oxazolines with nickel peroxide.'6 Oxazolines 42 are also formed by the reaction of the hydrazones 43 with wet silica.Y7 The mechanism of this unusual reaction has not been established but the C-2 methylene group is derived from the N-methyl substituent of the hydrazone.The oxazolines 42 were aromatized by reaction with phosphorus oxychloride and a base, giving 5-trifluoromethyloxazoles in good yield. The ketoamides 44 are produced by a three component reaction of arylglyoxals with carboxylic acids and isonitriles RNC; these compounds have been cyclized to oxazoles 45 in moderate yield with ammonium formate.'8.YY Reagents: (i) NaH, THF (94%); (ii) dphenylacetylene. MeCN; Scheme 37 (iii) H20, (iv) (75%); (v) Ph3PBr2, Et3N (61%) 0 41 42 43 44 45 2-Substituted oxazoles have been prepared in good yield by a reaction sequence (Scheme 38) with the retro Diels-Alder reaction as the final step.loO A method of preparation of 2-arylbenzoxazoles 46 from anilines 47 (X = F or OH) makes use of a palladium- catalysed N-acylation with aryl iodides and carbon monoxide followed by cyclization.lo1> lo2 The known method of preparation of 3,5-disubstituted isoxazoles from a,#?-unsaturated oximes has been carried out by using a new oxidant, Reagents: ( i ) pLi, (MeCO2)O; (ii) 600 "C/1 mmHg (72-80%) Scheme 36 213 Gilchrist: Svnthesis of five-membered aromatic heterocvclestetrakis( pyridine)cobalt( 11 )dichromate. O3 A different approach to 3,5-disubstituted isoxazoles 48 is the ex0 cyclization of oximes 49 of propargylic ketones with potassium carbonate.lo4 An unusual method of preparation of isoxazoles 50 is the reaction of monosubsituted acetylenes with nitric acid in the presence of the catalyst Bu,N+AuCI;.The ring system is produced by 1,3-dipolar cycloaddition of an intermediate acylnitrile oxide to the alkyne.lo5 A O H A O H NH2 NHCOR Reagents: (i) RCOCI; (ii) 195 "C (49-889'00) Scheme 38 k 46 47 49 50 8 Thiazoles and selenazoles Two approaches to the preparation of thiazoles from vinylsulfones are shown in Scheme 39."yY3 The methods are complementary in terms of the substitution pattern of the thiazoles. A modification of the Hantzsch thiazole synthesis has been described which avoids the need to use a-halocarbonyl compounds: instead, the carbonyl compound and the oxidant PhI(0H)OTs are used.lo6 An example is the preparation of the aminothiazole 5 1 (78%) from thiourea and hexane-2,5-dione.The corresponding selenadiazole was prepared in the same way. 9 Pyrazoles, indazoles, imidazoles, and be nz i m i d az o I e s The 1,3-dipolar cycloaddition of diazomethane to carbon-carbon multiple bonds provides one of the most straightforward methods of preparation of pyrazoles. Addition to vinylsulfones gives pyrazolines which can be converted into aromatic pyrazoles by reaction with a base.lo7 Further examples of the synthesis of pyrazoles using (trimethylsiy1)diazomethyl-lithium, Me,SiC( Li)N,, have been published.10s$ 1 Reagents: (i). MeCSNH2, DMF, pyridine (75%); Scheme 39 (ii) 12, NaS02Ph (95%) Two approaches to the bicylic pyrazole 52 have been described, one using the cycloaddition of diazomethane to a vinylsulfone (analogous to that described above)' lo and the other, condensation of the aldehyde 53 with t-butoxycarbonylhydrazine followed by S-oxidation."' Compound 52 was used as a precursor to new reactive dienes such as 54.Monosubstituted hydrazines have also been used to prepare pyrazoles from the alkenes YCH = C( COCF,), (Y = isobutoxy, ethylthio, or dimethylamino).l l2 Indazoles have been produced in good yield by the cyclization of acetophenone hydrazones 55 with polyphosphoric acid.' The azo compound 56 was cyclized to 3-phenyl- 1 -( 2,4,6-trichlorophenyl)indazole by reaction with antimony(v ) chloride.' l 4 Aminomalonamide, H,NCH( CONH,),, reacts with 1,2-diketone mono( phenylhydrazones) to give imidazole-2-carboxamides in moderate to good yield.' l5 51 52 53 RO Me Ph CI $$l e R N N H 2 PhXN 5N& CI CI 54 55 56 A large number of methods exists for the preparation of benzimidazoles from benzenes with ortho nitrogen substituents and some recent syntheses are based on this approach.' l 6 - I l 8 The intramolecular amination approach to fused pyrroles shown in 214 Contemporary Organic SynthesisScheme 33 has also been investigated as a method of preparation of fused imidazo1es.l lY It was less successful as a route to aminoazoles, although the imidazoquinoline 5 7 was prepared in moderate yield from 3-aminoquinoline.A route to imidazothiazoles 58 and other fused imidazoles has been described in which the imidazole ring is constructed by base- catalysed cyclization of the salts 59 followed by opening of the pyrrolidine ring.' 2o 57 58 COAr 59 10 Oxadiazoles The first 1,2,3-oxadiazole to be isolated is the naphtho fused compound 60; it is stable below - 20°C.121 Examples of another new class of heterocycles, 3,4,5-trisubstituted 1,2,4-0xadiazolium salts 6 1, have been prepared by the addition of isolable nitrile oxides to nitrilium salts.122 Further examples of the synthesis of 1,3,4-0xadizoles from acylhydrazines have been described.123. 124 60 61 1 1 Thiadiazoles, dithiazoles, and dithiadiazoles The cyclization of acylhydrazones of alkyl ketones with thionyl chloride (the Hurd-Mori reaction) represents the best general method of synthesis of 1,2,3-thiadiazoles. One problem with the procedure is that with unsymmetrical hydrazones (those having differently substituted methylene groups adjacent to the hydrazono group) the reaction often produces a mixture of isomeric thiadiazoles.A study of the effects of substituents has shown that the major product can, to some extent, be predicted on the basis of the relative rates of acid-catalysed enolization of the two methylene groups.125 An improved synthesis of 1,2,3-thiadiazole-4-carbaldehyde by the Hurd-Mori reaction has also been reported.126 A different approach to 1,2,3-thiadiazoles is the cycloaddition of diazomethane to compounds containing C=S bonds; examples of addition to ROCSCl and RSCSCl to give 5-subsituted 1,2,3-thiadiazoles have been described.' 27 Tetrasulfur tetranitride (S,N,) has proved to be a 1,2,5-thiadiazoles as the major products, but phenacyl chloride gave the 1,2,4-thiadiazole 62 (60%) in boiling chlorobenzene.128 Doubly alkylated 1,3,4-thiadiazolium salts 63 have been prepared for the first time by the cyclization of hydrazides 64 with triethyloxonium tetrafluoroborate.12' The reagent [SNS]+ AsF; has previously been shown to undergo cycloaddition to aliphatic alkynes and nitriles.It has now been shown to react with diphenylacetylene and with aromatic nitriles to give the heterocycles 65 and 66.130 0 62 63 64 65 66 12 1,2,4-Triazoles A useful route to disubstituted 1,2,4-triazoles is the reaction of N-cyanoisoureas and related compounds with hydrazine. 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ISSN:1350-4894    

DOI:10.1039/CO9940100205

出版商:RSC    

年代:1994

数据来源: RSC