摘要:

ISSN 1350-4894 COGSE6 3 (6) 447-568 (1996) Contemporary Organic Synthesis A journal of current developments in Organic Synthesis V O L U M E 3 N U M B E R 6 CONTENTS 0 Me f - - - 0 73 PdCI2(MeCN), (1 equiv.) El3N (8 equiv.) HCOpH (3 equiv.) The intramolecular Heck reaction By Susan E. Gibson (nCe Thomas) and Richard J. Middleton Reviewing the literature published up to the end of 1995 447 74 I Saturated and partially unsaturated 473 carbocycles By Kevin I. Booker-Milburn and Andrew Sharpe Reviewing the literature published between May 1995 and April 1996 Ts-H PhSeCI, NEt3 SePh + R(unsat)-M Synthesis of thiols, selenols, sulfides, 499 selenides, sulfoxides, selenoxides, sulfones and selenones By Christopher M. Rayner Reviewing the literature published between March 1995 and May 1996 The synthesis of carbocyclic aromatic 535 systems By Andrew C.Williams Reviewing the literature published between I January 1992 and 31 December 1995Cumulative Contents of Volume 3 Number 1 1 19 41 6.5 Stoichiometric applications of organotransition metal complexes in organic synthesis (1 September 1994 to 30 April 1995) Timothy J. Donohoe Saturated and partially unsaturated carbocycles (January 1994 to April 1995) Christopher D. J. Boden and Gerald Pattenden The enediyne and dienediyne based antitumour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 1 (up to 15 October 1995) Hervk Lhermitte and David S. Grierson Alcohols, ethers and phenols (August 1993 to February 1995) C. S. Hau, Ashley N. Jarvis and Joseph B.Sweeney Number 2 93 The enediyne and dienediyne based antitumour antibiotics. Methodology and strategies for total synthesis and construction of bioactive analogues. Part 2 (up to 15 November 199.5) HervC Lhermitte and David S. Grierson 12.5 The discovery of fluconazole (up to December 1994) Ken Richardson 133 Organic halides (1 July 1994 to 30 June 1995) Stephen l? Marsden 151 Aldehydes and ketones (October 1994 to September 1995) Patrick G. Steel Number 3 173 201 229 243 Recent developments in chemical oligosaccharide synthesis (up to October 1995) Geert-Jan Boons Main group organometallics in synthesis (January 1994 to Junc 1995) Martin Wills Saturated oxygen heterocycles (October 1994 to September 199.5) Christopher J. Burns and Donald S.Middleton Carboxylic acids and esters (1 August 1994 to 31 July 1995) Tammy Ladduwahetty Number 4 259 Saturated nitrogen heterocycles (1995) Timothy Harrison 277 Catalytic applications of transition metals in organic synthesis (1 September 1994 to 31 October 1995) Graham J. Dawson, Justin F. Bower and Jonathan M. J. Williams 29.5 Saturated and unsaturated lactones ( 1 August 1994 to 31 October 199.5) Ian Collins 323 Amines and amides (1995) Michael North Number 5 345 373 397 433 Synthetic approaches to rapamycin (up to August 1995) Mark C. Norley Synthetic applications of flash vacuum pyrolysis (1990 to 1995) Hamish McNab Protecting groups (1995) Krzysztof Jarowicki and Philip Kocienski The synthesis of quinones (1 Jmuary 1991 to 31 December 1995) Peter T.Gallagher Number 6 447 473 499 535 The intramolecular Heck reaction (up to the end of 1995) Susan E. Gibson (nCe Thomas) and Richard J. Middleton Saturated and partially unsaturated carbocycles (Muy 1995 to April 1996) Kevin I. Booker-Milburn and Andrew Sharpe Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones (March 1995 to Muy 1996) Christopher M. Rayner The synthesis of carbocyclic aromatic systems ( l ~ i n u ~ i r y 1992 to Deccmbcv- 1995) Andrew C. Williams Articles that will appear in forthcoming issues include Synthetic developments in host-guest chemistry (Junuuy to December 199.5) Justin J. B. Perry and Jeremy D. Kilburn Asymmetric processes (Junuay lY94 to il1~ir-c.h 199-5) Andrew C. Regan Saturated and unsaturated hydrocarbons (Jonuury 1995 t o Muy 1996) David A. Entwhistle Applications o f stoichiometric organotransition metal complexes in organic synthesis ( M q 199.5 to April 1996) Timothy J. Donohoe, Paul M. Guyo, Peter R. Moore and Clare A. Stevenson

ISSN:1350-4894    

DOI:10.1039/CO99603FP019

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

280 H. Tani, S. Irie, K. Masumoto and N. Ono, Hetero- 281 S. Dhanalekshmi, C. S. Venkatachalam and K. K. cycles, 1993, 36, 1783. Balasubramian, J. Chem. SOC., Chem. Commun., 1994, 511. Chem. Soc., 1994, 116,6713. 1993,36, 1795. J. Chem. SOC., Perkin Fans. 1, 1995, 2855. 1994,352299. Chem., 1992,45, 1639. 282 W. Adam, M. Ahnveiler and D. Reinhardt, J. Am. 283 B. Alcaide, C. Biurran and J. Plumet, Heterocycles, 284 M. A. Brimble, S. J. Phythian and H. Prabaharan, 285 D. G. Barrett and S.H. Gellman, Tetrahedron Lett., 286 D. B. Clarke, J. R. Guild and R. T. Weavers, Aust. J. Williams: The synthesis of carbocyclic aromatic systems 287 H. R. Sonawane, S. N. Bellur and S. G. Sudrik, Ind. J. 288 E. V. Dehmlow and C. Bollmann, Tetrahedron, 1995, 289 G. P. Shkil and R. S. Sagitullin, Tetrahedron Lett., 290 H.A. Etman, Ind. J. Chem., Sect. B, 1995,34, 285. 291 T. Nakazawa, M. Ishihara, M. Jiguji, M. Yamaguici, Y. Sugihara and I. Murata, Tetrahedron Lett., 1992, 33, 6487. 292 H. Nishino, S. Kajikawa, Y. Hamada and K. Kuro- sawa, Tetrahedron Lett., 1995, 36, 5753. 293 R. F. C. Brown, F. W. Eastwood and J. M. Horvath, Aust. J. Chem., 1995, 48, 1055. Chem., Sect. B, 1992, 31, 606. 51, 3755. 1994,35, 2075. 567280 H. Tani, S. Irie, K. Masumoto and N. Ono, Hetero- 281 S. Dhanalekshmi, C. S. Venkatachalam and K. K. cycles, 1993, 36, 1783. Balasubramian, J. Chem. SOC., Chem. Commun., 1994, 511. Chem. Soc., 1994, 116,6713. 1993,36, 1795. J. Chem. SOC., Perkin Fans. 1, 1995, 2855. 1994,352299. Chem., 1992,45, 1639. 282 W. Adam, M. Ahnveiler and D. Reinhardt, J.Am. 283 B. Alcaide, C. Biurran and J. Plumet, Heterocycles, 284 M. A. Brimble, S. J. Phythian and H. Prabaharan, 285 D. G. Barrett and S.H. Gellman, Tetrahedron Lett., 286 D. B. Clarke, J. R. Guild and R. T. Weavers, Aust. J. Williams: The synthesis of carbocyclic aromatic systems 287 H. R. Sonawane, S. N. Bellur and S. G. Sudrik, Ind. J. 288 E. V. Dehmlow and C. Bollmann, Tetrahedron, 1995, 289 G. P. Shkil and R. S. Sagitullin, Tetrahedron Lett., 290 H. A. Etman, Ind. J. Chem., Sect. B, 1995,34, 285. 291 T. Nakazawa, M. Ishihara, M. Jiguji, M. Yamaguici, Y. Sugihara and I. Murata, Tetrahedron Lett., 1992, 33, 6487. 292 H. Nishino, S. Kajikawa, Y. Hamada and K. Kuro- sawa, Tetrahedron Lett., 1995, 36, 5753. 293 R. F. C. Brown, F. W. Eastwood and J.M. Horvath, Aust. J. Chem., 1995, 48, 1055. Chem., Sect. B, 1992, 31, 606. 51, 3755. 1994,35, 2075. 567280 H. Tani, S. Irie, K. Masumoto and N. Ono, Hetero- 281 S. Dhanalekshmi, C. S. Venkatachalam and K. K. cycles, 1993, 36, 1783. Balasubramian, J. Chem. SOC., Chem. Commun., 1994, 511. Chem. Soc., 1994, 116,6713. 1993,36, 1795. J. Chem. SOC., Perkin Fans. 1, 1995, 2855. 1994,352299. Chem., 1992,45, 1639. 282 W. Adam, M. Ahnveiler and D. Reinhardt, J. Am. 283 B. Alcaide, C. Biurran and J. Plumet, Heterocycles, 284 M. A. Brimble, S. J. Phythian and H. Prabaharan, 285 D. G. Barrett and S.H. Gellman, Tetrahedron Lett., 286 D. B. Clarke, J. R. Guild and R. T. Weavers, Aust. J. Williams: The synthesis of carbocyclic aromatic systems 287 H. R. Sonawane, S.N. Bellur and S. G. Sudrik, Ind. J. 288 E. V. Dehmlow and C. Bollmann, Tetrahedron, 1995, 289 G. P. Shkil and R. S. Sagitullin, Tetrahedron Lett., 290 H. A. Etman, Ind. J. Chem., Sect. B, 1995,34, 285. 291 T. Nakazawa, M. Ishihara, M. Jiguji, M. Yamaguici, Y. Sugihara and I. Murata, Tetrahedron Lett., 1992, 33, 6487. 292 H. Nishino, S. Kajikawa, Y. Hamada and K. Kuro- sawa, Tetrahedron Lett., 1995, 36, 5753. 293 R. F. C. Brown, F. W. Eastwood and J. M. Horvath, Aust. J. Chem., 1995, 48, 1055. Chem., Sect. B, 1992, 31, 606. 51, 3755. 1994,35, 2075. 567280 H. Tani, S. Irie, K. Masumoto and N. Ono, Hetero- 281 S. Dhanalekshmi, C. S. Venkatachalam and K. K. cycles, 1993, 36, 1783. Balasubramian, J. Chem. SOC., Chem. Commun., 1994, 511. Chem. Soc., 1994, 116,6713. 1993,36, 1795. J. Chem. SOC., Perkin Fans. 1, 1995, 2855. 1994,352299. Chem., 1992,45, 1639. 282 W. Adam, M. Ahnveiler and D. Reinhardt, J. Am. 283 B. Alcaide, C. Biurran and J. Plumet, Heterocycles, 284 M. A. Brimble, S. J. Phythian and H. Prabaharan, 285 D. G. Barrett and S.H. Gellman, Tetrahedron Lett., 286 D. B. Clarke, J. R. Guild and R. T. Weavers, Aust. J. Williams: The synthesis of carbocyclic aromatic systems 287 H. R. Sonawane, S. N. Bellur and S. G. Sudrik, Ind. J. 288 E. V. Dehmlow and C. Bollmann, Tetrahedron, 1995, 289 G. P. Shkil and R. S. Sagitullin, Tetrahedron Lett., 290 H. A. Etman, Ind. J. Chem., Sect. B, 1995,34, 285. 291 T. Nakazawa, M. Ishihara, M. Jiguji, M. Yamaguici, Y. Sugihara and I. Murata, Tetrahedron Lett., 1992, 33, 6487. 292 H. Nishino, S. Kajikawa, Y. Hamada and K. Kuro- sawa, Tetrahedron Lett., 1995, 36, 5753. 293 R. F. C. Brown, F. W. Eastwood and J. M. Horvath, Aust. J. Chem., 1995, 48, 1055. Chem., Sect. B, 1992, 31, 606. 51, 3755. 1994,35, 2075. 567

ISSN:1350-4894    

DOI:10.1039/CO99603BP021

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Contemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (nee Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board Professor E. J. Corey, Haward University Professor S. Hanessian, Universiti 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 Hyderahad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L.E. Overman, University of California, Iwine Professor L. F. Tietze, University of Giittingen California at Sun Diego, La Jolla 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 Dr Sheila R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK.Deputy Editor: Nicole Brooks. Production Editor: Nicola Coward. Technical Editor: Tony Breen. Tel +44 (0) 1223 420066 Fax +44 (0) 1223 420247 E-mail rscl @rsc.org RSC Server http://chemistry.rsc.org/rsc/ 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 1 HN, England. 1996 subscription rates: EEA E185, USA $350, Canada El90 (plus GST), Rest of the World 2190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December.Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices. Periodicals postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1996. 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 in Great Britain by Unicus Graphics Ltd, Horsham, West Sussex Printed in Great Britain by Whitstable Litho Ltd, Whitstable, KentContemporary Organic Synthesis Editorial Board Professor G.Pattenden, FRS (Chairman), University of Nottingham Professor P. D. Bailey, Heriot- Watt University Dr S. E. Gibson (nee Thomas), Imperial College of Science, Technology, and Medicine Professor P. J. Kocienski, University of Southampton Professor C. J. Moody, Loughborough University of Technology Professor E. J. Thomas, University of Manchester International Advisory Board PrGfessor E. J. Corey, Harvard University Professor S. Hanessian, Universiti de Montrial Professor M. Julia, Universiti de Paris X I (Paris-Sud) Professor P. D.Magnus, University of Texas at Austin Professor G. Mehta, University of Hyderabad Professor K. C. Nicolaou, The Scripps Research Institute and University of Professor R. Noyori, Nagoya University Professor L. E. Overman, University of California, Irvine Professor L. F. Tietze, University of Gottingen California at Sun Diego, La Jolla 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 Dr Sheila R.Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK. Deputy Editor: Nicole Brooks. Production Editor: Nicola Coward. Technical Editor: Tony Breen. Tel +44 (0) 1223 420066 Fax +44 (0) 1223 420247 E-mail rscl@rsc.org RSC Server http://chemistry.rsc.org/rsc/ 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.1996 subscription rates: EEA f185, USA $350, Canada El90 ‘(plus GST), Rest of the World f190. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October and December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NJ 07001, USA and at additional mailing offices. Periodicals postage is paid at Rahway, NJ. USA Postmaster: Send address changes to Contemporary Organic Synthesis, c/o Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey 07001. All other dispatches outside the UK are by Bulk Airmail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1996. 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 in Great Britain by Unicus Graphics Ltd, Horsham, West Sussex Printed in Great Britain by Whitstable Litho Ltd, Whitstable, Kent

ISSN:1350-4894    

DOI:10.1039/CO99603FX025

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

280 H. Tani, S. Irie, K. Masumoto and N. Ono, Hetero- 281 S. Dhanalekshmi, C. S. Venkatachalam and K. K. cycles, 1993, 36, 1783. Balasubramian, J. Chem. SOC., Chem. Commun., 1994, 511. Chem. Soc., 1994, 116,6713. 1993,36, 1795. J. Chem. SOC., Perkin Fans. 1, 1995, 2855. 1994,352299. Chem., 1992,45, 1639. 282 W. Adam, M. Ahnveiler and D. Reinhardt, J. Am. 283 B. Alcaide, C. Biurran and J. Plumet, Heterocycles, 284 M. A. Brimble, S. J. Phythian and H. Prabaharan, 285 D. G. Barrett and S.H. Gellman, Tetrahedron Lett., 286 D. B. Clarke, J. R. Guild and R. T. Weavers, Aust. J. Williams: The synthesis of carbocyclic aromatic systems 287 H. R. Sonawane, S. N. Bellur and S. G. Sudrik, Ind. J. 288 E. V. Dehmlow and C. Bollmann, Tetrahedron, 1995, 289 G. P. Shkil and R. S. Sagitullin, Tetrahedron Lett., 290 H.A. Etman, Ind. J. Chem., Sect. B, 1995,34, 285. 291 T. Nakazawa, M. Ishihara, M. Jiguji, M. Yamaguici, Y. Sugihara and I. Murata, Tetrahedron Lett., 1992, 33, 6487. 292 H. Nishino, S. Kajikawa, Y. Hamada and K. Kuro- sawa, Tetrahedron Lett., 1995, 36, 5753. 293 R. F. C. Brown, F. W. Eastwood and J. M. Horvath, Aust. J. Chem., 1995, 48, 1055. Chem., Sect. B, 1992, 31, 606. 51, 3755. 1994,35, 2075. 567280 H. Tani, S. Irie, K. Masumoto and N. Ono, Hetero- 281 S. Dhanalekshmi, C. S. Venkatachalam and K. K. cycles, 1993, 36, 1783. Balasubramian, J. Chem. SOC., Chem. Commun., 1994, 511. Chem. Soc., 1994, 116,6713. 1993,36, 1795. J. Chem. SOC., Perkin Fans. 1, 1995, 2855. 1994,352299. Chem., 1992,45, 1639. 282 W. Adam, M. Ahnveiler and D. Reinhardt, J. Am. 283 B. Alcaide, C. Biurran and J. Plumet, Heterocycles, 284 M. A. Brimble, S. J. Phythian and H. Prabaharan, 285 D. G. Barrett and S.H. Gellman, Tetrahedron Lett., 286 D. B. Clarke, J. R. Guild and R. T. Weavers, Aust. J. Williams: The synthesis of carbocyclic aromatic systems 287 H. R. Sonawane, S. N. Bellur and S. G. Sudrik, Ind. J. 288 E. V. Dehmlow and C. Bollmann, Tetrahedron, 1995, 289 G. P. Shkil and R. S. Sagitullin, Tetrahedron Lett., 290 H. A. Etman, Ind. J. Chem., Sect. B, 1995,34, 285. 291 T. Nakazawa, M. Ishihara, M. Jiguji, M. Yamaguici, Y. Sugihara and I. Murata, Tetrahedron Lett., 1992, 33, 6487. 292 H. Nishino, S. Kajikawa, Y. Hamada and K. Kuro- sawa, Tetrahedron Lett., 1995, 36, 5753. 293 R. F. C. Brown, F. W. Eastwood and J. M. Horvath, Aust. J. Chem., 1995, 48, 1055. Chem., Sect. B, 1992, 31, 606. 51, 3755. 1994,35, 2075. 567

ISSN:1350-4894    

DOI:10.1039/CO99603BX027

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

The intramolecular Heck reaction SUSAN E. GIBSON (nee Thomas) and RICHARD J. MIDDLETON Department of Chemist4 Imperial College of Science, Technology and Medicine, South Kensington, London SW7 2AI: UK Reviewing the literature published up to the end of 1995 1 2 2.1 2.1.1 2.1.1.1 2.1.1.2 2.1.1.3 2.1.2 2.1.2.1 2.1.2.2 2.1.3 2.2 3 3.1 3.1.1 3.1.2 3.2 4 4.1 4.2 4.3 4.4 4.5 5 6 7 Introduction Synthesis of heterocycles Monocyclisations Five-membered ring formation Synthesis of indoles and related heterocycles Other nitrogen-containing rings Rings containing other heteroatoms Six-membered ring formation Nitrogen-containing rings Rings containing other heteroatoms Synthesis of medium and large rings Multiple cyclisations Synthesis of carbocycles Monocyclisations With P-hydride elimination With anion capture Multiple cyclisations Regio- and stereo-control Mode of cyclisation - endo or axo? Control of isomerisation and the r d e of additives Unexpected products Diastereocontrol Enantiocontrol Total syntheses Conclusion References 1 Introduction For most of the 1980s the Heck reaction was a well known but little used organometallic reaction.Broadly designated as the palladium catalysed arylation or vinylation of alkenes it had great potential in organic synthesis, but, perhaps due to recognised problems such as lack of regioselectivity and the necessity for harsh reaction conditions, only a few research groups pursued its promise. The intramolecular version of the reaction was almost unheard of until the mid-eighties, when the synthesis of heterocycles by this method started to be properly explored; and the question of whether carbocycles could be synthesised via the intramolecular Heck reaction was left virtually unanswered until the late eighties.Since this time, however, there has been an explosion of interest in the intramolecular Heck reaction, culminating in the last three years in its widespread application in total synthesis. catalysed reaction of a vinyl or aryl halide 1 with an alkene 2 to form a new carbon-carbon bond as in 3 together with the formation of a hydrogen halide as a by-product, was developed as long ago as the early 1970s.' The Heck reaction, defined as the palladium 1 2 The currently accepted mechanism of the reaction was defined in the 1970s2 and has remained unmodified in everything but detail since then.The first step is oxidative addition of a 14 electron palladium(0) species 4 to a bond joining a carbon atom to an appropriate group, usually a bromide, iodide or triflate, to form a carbon-palladium o-bond as in 5 . The carbon atom is usually part of an aryl or vinyl group as any sp' hybridised carbon atoms bearing hydrogen atoms P to the palladium atom would lead to facile P-hydride elimination. After coordination of an alkene to the palladium, carbopalladation leads to another carbon-palladium o-bonded complex 6 . Provided there is now an sp' hybridised hydrogen P to the palladium atom, then /I-hydride elimination will occur and the product of \ I d 6 Gibson: The intramolecular Heck reaction 447the reaction 7 will be released from the cycle.The palladium(ii) complex 8 thus formed then undergoes reductive elimination to regenerate the palladium(0) species 4 which can then continue round the catalytic cycle. lacking an appropriate fi-hydrogen then the complex may be long-lived and thus susceptible to a further cross-coupling reaction. This step may take place with the use of anionic or neutral nucleophiles as well as organometallics but the term ‘anion capture’ is generally used to avoid confusion with the Heck coupling steps. The group bonded to the unsaturated carbon atom which undergoes the oxidative addition step is usually iodide, bromide or, more recently, triflate. Chlorides do not give very good results although some success has been achieved with aroyl’ and benzyl chlorides4 The standard Heck conditions of catalytic quantities of palladium (usually palladium acetate) and an amine base in a polar aprotic solvent have been found to be widely applicable. (Phosphine ligands are necessary to aid the oxidative addition step in the case of bromides but not iodides.) The reaction generally requires high temperatures under these conditions.More recently, modification of the conditions by Jeffery et al.s through use of an inorganic base together with a phase transfer agent has allowed the Heck reaction to occur at lower temperatures. These have come to be known as the Jeffery conditions and have widened the scope and effectiveness of the Heck reaction still further. Other modifications to conditions have sometimes been found to be advantageous and these will be described later.Since the real upturn in interest in the Heck reaction in the last few years there have been several reviews of the Heck reaction and related palladium catalysed coupling reactions.6 In spite of the number of examples and specific features of the intramolecular reaction, however, there has been no comprehensive review devoted to this area to date, and thus such a review is undertaken herein. Due to the variety of Heck-type couplings that now exist some definition of the scope of the review is necessary. Therefore, for the purposes of this review, an intramolecular Heck reaction is defined as one where: 1) the first step in the catalytic cycle involves oxidative addition of palladium(0) into a carbon-heteroatom a-bond to form a carbon- palladium(1r) a-bond, and 2) the next step involves coordination to and the carbopalladation of an alkene, alkyne or allene which is part of the same molecule.intramolecular Heck reactions falling within the above definition leading to the synthesis of, first, heterocycles (Section 2) and then carbocycles (Section 3). Section 4 deals with several areas of specific interest in the intramolecular Heck reaction and Section 5 provides a few examples of the application of the reaction in the area of total synthesis. If the palladium in a complex similar to 6 is In the next two sections, we review all 2 Synthesis of heterocycles 2.1 Monocyclisations 2.1.1 Five-membered ring formation 2.1.1.1 Synthesis of indoles and related heterocycles This section deals with the synthesis of indoles and heterocycles containing the indole skeleton.There are more examples of the synthesis of indoles by the intramolecular Heck reaction than of any other group of compounds. This is mainly due to the immense importance of indoles as a species in biologically active compounds. Other, more practical, reasons for their prevalence are the commercial availability of ortho-iodo and ortho- bromo anilines 10 and the ease of forming carbon- nitrogen bonds, thereby giving rise to a wide variety of possible substrates 9 for the intramolecular Heck reaction. It is in these types of substrates that many of the steric and electronic factors which affect the Heck cyclisation have been explored. R3 R3 In 1977 Mori et al. reported the first intramolecular Heck cyclisations.’ They found that aryl bromide 12 could be cyclised to the indole 13 in 43% yield when reacted neat with palladium acetate (2 mol%)/triphenylphosphine (4 mol%) as the catalyst and TMEDA (2 equiv.) as the base.Under these conditions other by-products were also formed (such as the deallylated product l l ) , but these could be largely avoided through the use of DMF as a solvent. The aryl chloride was found to give no cyclised product due to the difficulty of the initial oxidative addition step. Also worth noting here is the fact that the initially formed double bond would be exocyclic but this completely isomerises in the reaction mixture to the more stable endocyclic position, probably through the re-addition of the HPdBr species and a second b-hydride elimination.This isomerisation can be prevented by the addition of silver salts which give the exocyclic isomers in good yields;8 the use of silver and other salts will be discussed later. aBr 11 /WE NHAc + __I V 1Z Br Me02C 702Me \ Ir ’ Pd(OAc)P, PPh3 l!, ,AN TMEDA (2 equiv.) 125 O C , 5 h AC Ac 4 Q 43% A- 448 Conternporaiy Oqanic SynthesisSubsequently, in 1979, Mori et al.9 and Heck et al.'" published syntheses of indolones using the standard conditions of catalytic palladium, with a phosphine as ligand and an organic base, usually triethylamine. In Heck's paper N-cinnamoyl- and N-(P-methylcinnamoy1)-o-bromoaniline 14 and 15 were cyclised to the benzylideneindolones 16 and 17 with 1 mol% palladium acetate and 4 mol% tri- o-tolylphosphine at 100 "C.(Tri-o-tolylphosphine is sometimes used in place of triphenylphosphine in order to prevent the formation of phosphonium salts.) Once again, the preference for 5-exo-trig cyclisation over 6-endo-trig cyclisation is observed and the factors influencing this preference in the Heck cyclisation will be examined later. A reversal of alkene stereochemistry is also seen and this reflects the necessity for palladium to adopt a .syn relationship to the P-hydrogen as in 18 before ,!I-hydride elimination can occur. Apparent exceptions to this rule will also be discussed later. aZLR Pd(OAc)2, P(o-Tol)s Et3N, MeCN, 100 "C H H 14 R = H 16 R = H, 58% 15 R=Me 17 R =Me, 21% R Ph PdBr Ph\ .z - -R 'I-- PdBr d o - d o - 16or17 H H 18 All the examples described so far involve alkenes conjugated to a carbonyl group, which is known to activate alkenes towards Heck insertion.In order to synthesise indoles by the cyclisation of unactivated N-allylanilines, Hegedus et al. found that sequential addition of the catalyst at various times over the course of the reaction gave much improved yields." The catalyst appears to become deactivated as the reaction proceeds, possibly through the formation of colloidal palladium; where the cyclisation occurred, as in, for example, the cyclisation of 19 to 20, yields Pd(0AC)z (3 X lye), E1,N (1.5 + 0.5 + 0.5 equiv.) MeCN. 110 "C, 72 h 87% 19 20 n Pd(0Ac)p (3 x lYo), A4 Et3N (1.5 + 0.5 + 0.5 equiv.) 21 MeCN. 110 "C, 72 h of 50-87% were observed. Several other points were noted. First, use of phosphines was necessary in the case of aryl bromides but not aryl iodides as might be expected from the intermolecular examples;" second, the reactions exhibited a clear preference again for the 5-exo over the 6-endo cyclisation; and third, the complete failure of N-cyclohexenylaniline 21 to react suggests a stereoelectronic constraint on the cyclisation.Although, for some substrates, the Heck cyclisation can tolerate various substituents on the aromatic ring and the alkene and give good yields of indoles under the right conditions,'3 it can also be very sensitive. Small changes in either the reaction conditions or steric or electronic factors in the substrate can have a huge effect on the yield of indole pr0du~ed.l~ For example, Hegedus et al. reported a case where acetate substituents on the aromatic ring of 22 gave a good yield of the indole 23 but when they were replaced with the more electron donating methoxy substituents as in 24 no cyclised product was obtained.'' Another good example of this sensitivity is provided by the cyclisation of aryl iodide 25 which gave indole 26 in very good yield,lb whilst under very similar conditions the similar substrate 27 gave only a poor yield of the desired product 28.17 L$ EtsN, Pd( OAC) MeCN, 2, P 50-1 (o-Tol), 10 "C DLy$ Ac Br 64% Br $, OAc OAc 22 23 24 C02Et a;yo2Et- Pd(OAc)p, 120 "C, EtsN, 3 h.88% DMF Q$C02Et H C02Et H 25 26 fOTHP <OTHP Pd(OAC)z, EtsN, DMF 1 10 "c, 25% H H &: 27 28 The attractiveness of this method of indole synthesis was improved further by Larock et a1.who found that the use of Jeffery's phase transfer conditions instead of the standard Heck conditions gave improved yields at lower temperatures." The conditions employed used 2 mol% palladium Gibson: The intramolecular Heck reaction 449acetate, 1 equivalent of tetrabutylammonium chloride, DMF as solvent and 2.5 equivalents of base (either sodium carbonate, triethylamine or sodium acetate). It was also noted that substitution on either nitrogen or the double bond slowed the reaction. Heck conditions and Jeffery conditions have been used several times over the past few years in the synthesis of simply substituted target indoles,” one such example being the synthesis of an analogue of sumatriptan 29.20 M e N H S E I F Pd(OAC)p, E13N M e N H S d ” w / DMF, A r 81% H O A C F 3 29 This methodology is not limited only to the formation of simple indoles as polycyclic fused ring and spirocyclic systems related to the indole system have also been synthesised.2’ The earliest examples were the syntheses of various carbazoles in 1980 by Iida et a1.22 but only poor yields were obtained.In 1987 Overman et al. published details of the synthesis of a number of spirocyclic indolones,” one of which was formed by cyclisation onto a tetrasubstituted alkene 30. Palladium catalysed arylations or vinylations of tetrasubstituted alkenes do not occur when performed intermolecularly and thus the versatility of the intramolecular reaction was again demonstrated. In recent years, Overman has shown that quaternary centres in oxindoles may be formed both diastereo~electively~~ and enantio~electively~~ as will be discussed later.5% Pd(OAC)p, 10% PPh3 0 2 equiv. Et3N * MeCN, 82 “C 56 h. 58% .Me 30 The versatility of this synthetic method has been extended still further by the use of the ‘anion capture’ methodology.26 Although there is one earlier example of hydride capture to give a 3,3-dimethylind0line,’~ the true scope of this method was first demonstrated by Grigg et al. who synthesised indole-related heterocycles by cyclisation onto geminally disubstituted alkenes with h ~ d r i d e , ~ ~ cyanidez8 and carbonylz9 capture, and onto alkynes with capture by organotin,” organozinc and organoboron reagents.” In one such example iodoaniline derivative 31 was cyclised to give the alkyl palladium species 33 which then underwent transmetallation with hexamethylditin, followed by a Stille type coupling to give 32.32 Luo et al.have recently reported conditions under which intramolecular cyclisations onto terminal alkynes such as 34 provide vinyl palladium intermediates 35 which may be trapped in situ with a wide range of organozinc reagents to provide products such as 36 in good yield.33 31 \ S02Ph 32 - J 33 / 34 36 72% 35 Finally, there have been several other palladium catalysed syntheses of indoles and related heterocycles which fall just outside the scope of this review but may be of interest to the reader.34 2.1.1.2 0 t her nit rogen-con taining rings Isoindolones were first synthesised by Grigg et al. as part of the work which demonstrated the feasibility of forming fused, spiro and bridged ring compounds by the intramolecular Heck rea~tion.~’ They were formed in good yields from vinyl amides of 2-iodobenzoic acids such as 37.As such amides are readily synthesised, a wide variety of substrates were thus available upon which a whole host of methodologies could be tested. Such vinyl amides were one of the main ways of testing the ‘anion capture’ methodology and were thus cyclised with hydride,” cyanide” and carb0ny1~~ capture. Furthermore, as bridgehead double bond formation is disfavoured, cyclisation onto amide substituted norbornenes provided a stable alkylpalladium intermediate which could then undergo organotid” or organoboron capture.31 Hence 37 was cyclised to 39 via 38 in good yield. Cyclisations onto dienes or allylic acetates gave n-allylpalladium complexes which then underwent capture with organozinc reagents”’ or carbon, nitrogen or oxygen nucleop hiles.36 For example, dienamide 40 was cyclised to 41.Other syntheses of isoindolones have been described, all occurring via 450 Contemporary Organic Synthesis37 \Ph 40 38 Pd(OAc)p, PPh3 2 equiv. NaCH(CN)2 MeCN, 80 "C 60% 39 A N Ph 41 _- 5-exo-trig cyclisations. '' Isoindolones have also been synthesised in studies on stereoselectivity3' and control of isomerisation7" and in the synthesis of indoloindoles via cyclisation onto an indole ring." The intramolecular Heck strategy has also been applied to the synthesis of a range of natural products featuring nitrogen-containing five membered rings such as camptothecin," magallane- sine," lentiginosine" and the mitoccnes."." A key step in the synthesis of an example of the latter was the cyclisation of an appropriately substituted N-vinyl- or N-allyl-bromoquinonc.For example, quinone 42 was cycliscd to the indolequinone 43 in excellent yield. The Heck cyclisation methodology 0 Meol?iBr Me0 *.I Pd(OAC)*, E13N * MeCN, 2 h, r.1. 97% 42 M e o w Me0 0 43 for the formation o f indoles has also been applied to thc synthesis of indole-type aromatic heterocycles where in place of a benzene ring there is a thiophene or selenophene to give thienopyrroles and s e 1 en o p y r r ol c s . ' ')" C y c 1 is at i o n s which construct n it rog e n - co n t a i n i ng heterocycles o n p re -for med indole rings as in thc synthesis of the indolo[3,2,1- i j ] [ 1,6)-naphthyridine ring system" and cyclisations onto the 2,3-double hond of i n d o l c ~ ~ ~ have been reported.Pyrrolidinones have also been formed from the Heck cyclisation of x-haloamides but only in poor to moderate Lastly, in a recent paper by Shibasaki c't ~ 1 . ' ~ the enantioselectivc formation of a five membered ring containing a nitrogen atom from B prochiral substrate was described; this work will be discussed morc fully I ate r . 2.1.1.3 Rings containing other heteroatoms This section is devoted almost exclusively to the formation of ox.ygcii-containir1~ rings. l'hc carlicst example involved the cyclisation of bromodialkenyl ethers and capture of the stable n-allylpalladium intermediate with a secondary amine, such as piper- idine.49 By this method, vinyl bromide 44 was cyclised to the 2,3-disubstituted dihydrofuran 46 via the n-allylpalladium intermediate 45 in good yield./-- Pd(OAC),, P(eT0l)3 O W 44 45 46- Larock et al. applied the conditions which had proved to be most successful for their synthesis of indoles'' to the synthesis of benzofurans.sO In this case, however, there is the complication that palladium(0) is known to react with aryl allyl ethers to give 7r-allylpalladium complexes. Together with one equivalent of sodium formate (whose rble may be to reduce any stable z-allylpalladium complexes that form thus releasing the palladium back into the catalytic cycle), the mild modified Jeffery conditions provided good yields of the desired benzofurans. In this manner iodoaryl allyl ether 47 gave 3-methyl- benzofuran 48.Negishi et al. also described the synthesis of bcnzofurans from aryl allyl ethers but used the standard Heck conditions. They obtained similar or slightly better yields but also obtained a mixture of isomers.5' P~(OAC)~, Na2C03 a:k Bu4NCI,HC02Na * DMF, 80 "C, 48 h 47 47% 48 Hoffmann el ai. described an intramolecular hydroarylation reaction on aryl ally1 ether 49 which gives the ABC ring system of the aflatoxins SO.'2 In this case there is n o syrz-[)-hydrogen for the palladium to eliminate arid so a hydride source was provided by preformed triethylammonium hydro- genformate. Pd(MeCN)2CI,, E13N H0 ~~ HC02H, DMF aLG0 50°C,3h 86% 49 50 Other benzofurans havc bcen synthesised by cycli- sations onto proximate alkynes with hydridc captures3 and spiro-fused benzofuran-2(3H)-ones have also been synthesised.2.i".s4 Recently an example of a cyclisation onto a carbohydrate template to form a fused five membered ring containing oxygen has also bccn The anion capture approach has been uscd by 1,arock et a!.in a synthesis of' prostaglandin-type corn pouri d s. "' I n t ra m ole cu I ar cycl i sa t ion of 5 1 leads to alkylpalladium intcrmcdiate 52 which lacks an appropriate syn-/&hydrogen for elimination and so is 3s IHO 51 PizNEt, DMF, 50 "C f l C O z E t o \ / b HO I . 53 42% available for anion capture. Both capture with alkenes (an intermolecular Heck) and organotin compounds (a Stille type coupling) have been used with alkenes giving the best results as exemplified by the synthesis of 53.There is only one publication, to date, on the synthesis of five-membered rings containing sulfur and this describes the synthesis of benzo- [blthiophenes by cyclisation of aryl allyl or aryl prop-2-ynyl thioethers." Although there are possible problems associated with the thiophilicity of palladium, under fairly standard Heck conditions at high temperature the desired benzothiophenes can be formed. For example, in a simple case, aryl allyl thioether 54 was cyclised to 3-rnethylbenzo[b]thio- phene 55 in good yield. tion is almost always preferred over 6-endo cyclisa- ion 15,35,58 the 6-endo cases must be dominated by other steric, electronic or stereoelectronic f d c t o r ~ . ~ ' ~ ~ ~ This topic will be dealt with more fully later. 6-Ex0 cyclisations of aryl bromides or iodides onto appropriately positioned alkenes can lead to substituted quinolines,lg as in the cyclisation of 56 to 57, or isoquinolines and related h e t e r o ~ y c l e s ~ ~ ~ ~ ~ " ~ ~ as in the cyclisation of 58 to 59.Where the alkene is itself part of a ring then spiro, fused23 or bridged35 rings may be formed as illustrated by the cyclisation of N-ally1 amide 60 to 61 in excellent yield. Fused ring systems have also been formed when the aryl iodide moiety was attached to the nitrogen atom of an indole ring bearing an alkene.45 When this methodology was directed towards the synthesis of dynemicin-A the fused quinolones 64 and 65 were successfully synthesised from 62.6' The BSA [N,O-bis(trimethylsilyl)acetamide] 63 was found to be crucial to the success of the cyclisation as it temporarily protects the secondary amide, a group which has been known to give problems in intra- molecular cyclisations.23 6-Ex0 cyclisation to form quinolones has also been employed in the total synthesis of (R, R)-crinan,62 racemic ly~oricidine~~ and ( + )-ly~oricidine.~~ Useful heterocycles can also be formed by 6-ex0 cyclisations onto in dole^.^^,^' Pd(OAc)p, Bu~NCI NaOAc. DMF I Et 57 55% 56 NH Pd(OAC)p, Bu~NCI Na2C03.DMF 54 a5 55 (J-j 80 "C, 24 h Pd(PPh&, Et3N MeCN, 140 "C. 15 h 70% 39% 58 59 2.1.2 Six-membered ring formation 2.1.2.1 Ni trogen-containing rings This section deals mainly with the synthesis of q N 9 ~~~K~~~ quinolines and isoquinolines and their partially either 6-endo or 6-ex0 cyclisations. As 5-exo cyclisa- 60 61 MeCN, 30-80 "C 88% 0 saturated analogues.These have been formed by 0 0 HN L Pd~(dba)~.CHCl~, P(*TOI)~ PII2NEt3, BSA-DMF (1:l) & 0 64 0 70 "C, 1 h 84% - n - o 62 5 : l BSA = N,Qbis(trimethyl)acetamide 63 452 Contemporary Organic SynthesisThe tandem cyclisation-‘anion capture’ methodo- logy can also be applied to the synthesis of six- membered rings containing nitrogen. This has been and capture with either h ~ d r i d e , ” . ~ ~ cyanide” or Et02C demonstrated by cyclisations onto proximate alkynes (PhaP)dPd, E13N organotin reagents3’ 6-Ex0 cyclisations of benzyl 73% halides onto alkenes with either hydride or sodium tetraphenylborate capture have also been used to prepare 3.3-disubstituted tetrahydroisoquinolines in good yield.4h Substituted piperidines may be synthesised by cyclisation of bromodialkenyl amines and subse- quent trapping of the n-allylpalladium intermediate with an in situ n~cleophile.“~ The cyclisation of an N-ally1 iodide onto a cyclic alkene to form a bridged ring product has also been successfully used in an approach to the Stlychnos alkaloid^.^^ Fused pyridi- nequinones have been synthesised as the minor product by a 6-endo cyclisation of bromoquinones where the major products were the desired indolo- quinones formed via the preferred 5-exo cyclisation.” 2.1.2.2 Rings containing other heteroatoms As for the five-membered rings, this section deals almost exclusively with the synthesis of oxygen- containing rings and again there are far fewer examples of this type than their nitrogen analogues.The earliest examples were reported by Heck et al.49 and included the cyclisation of a o-bromoaryl homoallyl ether 66 to give a mixture of isomers 67 and 68. 67 1 + Pd(OAc)l, P(eTo1)~ 47% EIsN, 100 “C, 48 h Br 28% 66 There was only one other publication in this area6’ until Negishi et ul. reported the synthesis of fused and spiro tetrahydrobenzopyrans from o-iodo- benzyl allyl ethers, and dihydropyrans from iododialkenyl ethers under standard Heck condi- tions.s’ On the whole, however, mixtures of isomers were formed. Overman et al. also used this method- ology (but with the addition of silver salts to prevent isomerisation) to form a spiro tetrahydrobenzopyran system in their total synthesis of (+)-tazettine and ( )-6a-epipreta~ettine.~~ Also under standard Heck conditions bromoaryl 69 gave tricyclic 70 in good yield.7o High temperatures were necessary to isomerise the double bond to the thermodynamically preferred (2) product.Other examples of the formation of oxygen-containing six-membered rings via the 6-ex0 cyclisation of aryl halides onto proxi- mate alkenes have been rep~rted.~”’’ cyclised onto an allyl ether in very good yield as a An iodopyridine derivative was successfully 69 70 key step in the synthesis of 20-(S)-~amptothecin.~* Six-membered cyclic ethers have also been formed by cyclisations of iodoaryls onto vinyl s~lfones’~ (such as the cyclisation of 71 to 72) and nitroalk- e n e ~ . ~ ~ In both cases the bromoaryl gave no cyclised product, the addition of silver salts gave improved yields and phosphines were necessary.It is worthy of note that a nonpolar solvent was found to give by far the best results for the cyclisation onto the nitroalkene. O*O Pd(PPh&, Et3N AgN03 (5 equiv.) MeCN, reflux, 3.5 h c w 97% o-oSo2Ph 71 S02Ph 72 A six-membered ring containing a nitrogen- oxygen bond has been synthesised by the intra- molecular Heck reaction in the synthesis of FR 900482 by Danishefsky et al.” This proceeded in excellent yield with a large excess of triethylamine but otherwise under standard Heck conditions. Lastly, a cyclisation of a sulfonamide by Grigg et al. gave a 1 : 1 mixture of 6-ex0 and 7-endo products with the nitrogen-sulfur bond as part of the bridged ~ystern.’~ Thus, together with the other examples, this demonstrates that the intramolecular Heck reaction can be used not only in the presence of carbon-heteroatom bonds but also heteroatom- heteroatom bonds.2.1.3 Synthesis of medium and large rings Due to there being relatively few examples, the synthesis of medium and large ring heterocycles via the intramolecular Heck reaction will be dealt with together in this section. (Some of the factors governing these cyclisations will be dealt with in more detail in Section 4.) The first example of the synthesis of a large ring by the intramolecular Heck reaction was reported in 1981 when the 16-membered lactone 74 was prepared from 73 in 55% yield.77 This reaction used one equivalent of palladium and a slow addition of the substrate 73 to the reaction mixture in order to prevent the forma- tion of dimers and oligomers by the intermolecular reaction.A seven-membered cyclic ether was formed by a 7-endo cyclisation with piperidine capture of a n-allylpalladium intermediate in the same manner as the capture of 45 to give 46.49 The ?’-ex0 cyclisation Gibson: The intramolecular Heck reaction 453II 1 0 II PdC12(MeCN)2 (1 equiv.) I fi HC02H (3 equiv.) I \ Et3N (8 equiv.) MeCN, 25 “C 55% Me 73 74 has been used to provide b e n z a ~ e p i n e s ~ ~ and cyclic etherS,jl amideS23,S3.7R and sulfonamides.‘3 In the last year, two reports of the synthesis of seven-, eight- and nine-membered rings using the Heck reaction have appeared. Gibson (nee Thomas) et al. cyclised aryl iodides tethered to dehydroala- nine units by two to four methylene groups 75 under anhydrous Jeffery conditions to give seven-, eight- and nine-membered rings 76 by endo ring clos~re.’~ Negishi et al.have synthesised seven-, eight- and nine-membered cyclic ethers by cyclisation onto allenes in reasonable yields but have found that the corresponding cyclisations onto alkenes only proceed in very poor yield.” Thus allene 77 cyclised to the eight-membered ring 78 in good yield but alkene 79 gave no isolated yield of 80. The reported results seem to indicate that allenes are more reactive than either alkenes or alkynes towards intramolecular carbopalladation and thus the versa- tility of the Heck reaction is increased still further. P~(OAC)~, NaHC03 Bu4NCI, 3 A mol. sieves 5 MeCN, 95 ‘C, 16.5 h n=1-3 7s 5b60% 76 0.05 M DMF. 100 “C 2 h, 52% 77 78 C12Pd(PPh3)2, K2CO3, 10 equiv.EtOH 0.05 M DMF, 100 “C 21 h 80 c 5% by NMR 79 Sundberg et aZ. have formed an eight-membered ring via an 8-endo cyclisation of a 3-iodo-(N)-methy- lindole onto a pendant alkene under Jeffery condi- tions.*’ Following this, in the last year, Rigby et al. have reported that, in the cyclisations of aryl iodides onto enamides to form medium sized rings, Jeffery conditions gave the product of endo cyclisation and standard Heck conditions gave the product of exo cycli~ation.~~ During the course of their investiga- tion, they formed both seven- and eight-membered rings containing nitrogen in good yield. Lastly, the synthesis of 16- to 22-membered lactones (also containing amide functionality) in 24 to 42% yield has been recently reported by Stocks et aLX2 They cyclised aryl iodides onto alkenes under standard Heck conditions; the tendency for large rings to form by exclusively endo cyclisations was noted.2.2 Multiple cyclisations The development of multiple Heck cyclisations in the synthesis of heterocycles has been carried out largely by the groups of Grigg and Overman. Bis- cyclisations were first reported by Overman et al. in 198Sg3 in the synthesis of spiro and fused ring systems. The importance of silver salts in promoting the desired reaction was also shown. The next several papers on the subject were by Grigg et al. who demonstrated the powerful nature of the methodology by combining a bis-cyclisation with an ‘anion capture’ ~tep.~~”,’~.*‘ Cirigg has coined several terms to describe the various species that must be present in a multiple Heck cyclisation.The ‘starter species’ is that into which palladium undergoes initial oxidative addition (e.g. an aryl or vinyl halide or triflate); the ‘relay species’, of which there may be more than one, is that which undergoes carbopalladation in a ring forming step (e.g. an alkene or alkyne) to give a carbopalladated intermediate; the ‘terminating species’ is that part of the substrate from which the palladium can return to the catalytic cycle by either b-hydride elimination or anion capture. There are two obvious but important restrictions that must be noted. Firstly, the relay species must be such that after carbopalladation, 1-hydride elimination cannot occur (e.g. an alkene must be appropriately substi- tuted).Secondly, anion capture must take place at a slower rate than the various cyclisation steps and thus alkynes are more likely to be successful as relay species due to their higher reactivity toward carbo- palladation than alkenes. in the synthesis of many varied ring structures. For example 81 was cyclised via 82 to 83 in good yield with hydride capture.27h The importance of using either silver or thallium salts was again demon- strated and the use of tetraethylammonium chloride This methodology has been successfully employed PdI 81 82 I I.. 83 454 Contemporary Oiganic Synthesisled to faster reaction times but also to an increased straightforward intermolecular Heck reaction with amount of premature capture product. The reactivity of certain alkylpalladium inter- mediates has also been demonstrated.".8' For example, after vinyl bromide 84 cyclised onto the proximal alkene to give a 'neopenty1'-palladium species, this then underwent another cyclisation to give the cyclopropane 85." Alkylpalladium inter- mediates will even undergo cyclisations onto aromatic rings, a process which has been termed 'Friedel-Crafts alkylation'.Spiroindolines have been synthesised by this method,s6 as have bridge~i-ring'~ and angularly fused-ring systems, as in the synthesis of 87 from 86.87 (&--Me H Pd(OAc)2, PPh3, KOAc, anisole 80 "C, 12 h 78% Ph02SN 84 Pd(OAC)p, PPhs TI2CO3, PhMe llO"C, 16h- 7&85% 85 /=3 87 86 The powerful nature of this methodology has been demonstrated further in a cascade cyclisation incorporating an intermolecular step." A 6-ex0 cycli- sation onto an appropriately positioned alkyne 88 provides the vinyl palladium intermediate 89 which can then undergo an intermolecular Heck reaction with norbornene to give 90.The alkylpalladium intermediate so formed cannot undergo P-hydride elimination and so cyclises to form a cyclopropane and another alkylpalladium intermediate 91 which can fi-eliminate to form the final product 92. An alkyne is necessary as the first relay species as it will undergo carbopalladation much more rapidly than an alkene, thus diminishing the importance of the IPd, ,H NMe Et3N, MeCN reflux 0 89 0 88 ia c-- \ \ 0 N. Me Me Me 40% 0 0 0 92 91 90 norbornene as a competing reaction. palladium catalysed cyclisation cascade of certain diene-ynes an electrocyclic ring closure can follow the 8-hydride elimination Thus dienyne 93 underwent palladium catalysed cyclisation to give 94 which then underwent electrocyclic ring closure to 95.De Meijere et al. have shown that in the 6 r 4 93 04 8- 94 95 Overman et al. have applied the palladium catalysed cascade cyclisation approach to the synthesis of spirocyclic polyethers.'" They found that the Jeffery conditions were the best for the synthesis of tricyclic diether 97 but gave only a poor yield when applied to the synthesis of tetracyclic triether 98. An important competing side reaction appears to be the palladium catalysed isomerisation of the allylic ether to the more stable enol ether moiety. 60% 96 97 ~ o T o T o 3 I \ as above 98 3 Synthesis of carbocycles 3.1 Monocyclisations 3.1.1 With fi-hydride elimination The intramolecular Heck reaction has been exploited far less in the synthesis of carbocycles than the synthesis of heterocycles.This was especially so in the earlier years of the 1980s. The imbalance is fast being remedied, however, as the reaction is applied not only to the synthesis of biologically interesting molecules, natural products, substituted aromatics etc., but also to cascade cyclisations. There is no synthetic reason why carbocycles may Gibson: The intramolecular Heck reaction 455not be as easily prepared by this reaction as hetero- cycles but it was not until the late 1980s that the area really started to flourish. In 1984 and then later in 1988 Grigg et al. reported the cyclisations of several substituted 2-brorno-x,w-diene~.'~ In 1987, as part of their paper on the synthesis of polycyclic systems containing quaternary centres, Overman et al.reported the formation of the fused ring carbocycle 100 from iodoarene 99.23 In 1988, Negishi et al. published their research on the formation of carbocycles by the cyclisation of iododiene~.'~ They found that the best conditions used triphenylphosphine as the ligand and a mixture of acetonitrile and THF as the solvent. Using dibenzylideneacetone as the Iigand gave a much slower reaction, again underlining the sensitive nature of this reaction to the conditions used. Pd(OAc)z, PPh3 MeCN, 30 h, 23 "C 71% 99 100 Concurrently, Larock et al. reported their study on the effect of different conditions on the forma- tion of carbocycles from iodoarene substituted alkenes.'? They found that in the cyclisation of iodoarene 101 to tricyclic 102 and 103, modified Jeffery conditions gave the desired product in good yield but as a mixture of the two double bond regioisomers in a 1 : 5.1 ratio.Overman's condi- tion~,'~ which had proved successful in the synthesis of spiro and fused ring systems, and controlled isomerisation with silver salts were found to slow the reaction down but at the same time gave a > 95 : 5 ratio of the two regioisomers. Standard Heck conditions do, however, give good yields of carbocycles with certain s ~ b s t r a t e s ~ ~ ' ~ ~ ~ although sometimes care in the choice of phosphine is neces- ~ a r y . ~ ~ i. 3% Pd(OAc)2, Bu~NCI, KOAC, DMF, ~ 5.1 2 days, 80 "C, 63% ii.1 % P~(OAC)~, 3% PPh3 + additions every 24 h, Ag2C03, MeCN, 80 "C, > 95 : 5 96 h, 72% A further paper by Negishi et al. in 1988 reported that the position of the doubIe bond in the cyclisa- tion product could sometimes be controlled by cyclising onto alkenes bearing carbonyl example, vinyl bromide 104 was cyclised to 105 in good yield under standard Heck conditions. Negishi et aZ. also examined the use of benzyl halides for the initial oxidative insertion step.& They found that benzyl chlorides gave the best results as iodides and bromides gave a greater amount of For Pd(OAc)Z, PPh3 NaHC03,DMF, * 8OoC, 36 h 0 68% 0 104 105 double bond regioisorners. The formation of five- and seven-membered ring carbocyclic products as well as a bis-cyclisation under standard Heck condi- tions were reported.For example, benzyl chloride 106 underwent 7-exo cyclisation to give 107 in good yield. Negishi et al. have also found that cyclisation of vinyl halides onto alkenes can sometimes lead to a cyclopropylcarbinyi-homoallyl rearrangement via a second cyclisation of an alkyl-palladium speces and so an initial 6-ex0 cyclisation can lead to a seven- membered ring and a 5-ao cyclisation to a six- membered ring. This rearrangement will be dealt with in more detail in Section 4.3. 106 107 The intramolecular Heck reaction was applied to the synthesis of bioactive molecules in an approach to the ergot alkaloids by Hegedus et al.98 Brorno- indoline 108 containing a monosubstituted alkene underwent 6-endo cyclisation to 109 in 50% yield under standard Heck conditions.This yield was increased to 64% in the case of the geminally disub- stituted alkene 110 which cyclised to 111. It appears to be the conjugation of the alkene in 110 to an electron withdrawing group rather than its disub- stitution which leads to the increase in yield, as cyclisation of r,P-unsaturated ketone 112 to 113 aIso proceeded smoothly. Br ylR A Pd(OAC)Z, Et3N P(eTol)s, MeCN Ts Ts 108 R = H 110 R=C02Et Go Ts 109 R = H, 50% 111 R = COP Et, 64"/0 Pd(OAC)*, Et3N P( ~ T O I ) ~ , MeCN Ts 691 112 113 Cyclisation onto allylic alcohols has also been reported.99 When a o cyclisation onto an allylic alcohol occurs the alkylpalladium intermediate can undergo fl-hydride elimination to form an enol. This enol can then tautomerise to the aldehyde as in the cyclisation of vinyl bromide 114 to cyclopentane 115.456 Contemporary Organic SynthesisE*2c?sco2Et Pd(OAC)*, PPh3 E'02cfico2E EtSN, MeCN 80°C,4h 60% HO CHO 114 115 Overman et ul. have more recently used vinyl and aryl triflates for the synthesis of cis angularly fused ring products. "') Although, for example, aryl triflate 116 cyclised in a 6-exo manner to give a mixture of regioisomers 117 and 118 in good yield, the condi- tions of the reaction required careful development. Bidentate phosphines were found to be necessary as monodentate phosphines gave only partial convcr- sion and amine bases were found to have a deleterious effect in giving less selectivity in the formation of the two isomcrs and also leading to the reduced product 119.(Amine bases arc thought to be hydride donors in palladium catalysed reactions."") Other bases also gave problems: silver salts led to decomposition of the starting material and bases such as sodium hydrogen carbonate gave side reactions such as the formation of 120. Lastly none of the desired product was observed at temperatures below 100 "C. With respect to tuning conditions, it has recently been shown that by varying the phosphine used, both the regio- and stereo-selectivity of an intramolecular Heck reaction can be altered.'"2 It is also worthy of mention that although almost none of the reactions indicated so far for the synthesis of carbocycles have used the Jeffery conditions, these can, in certain circum- stances, give excellent yields of carbocyclic products.'I)' W O B n TBDMSO 9, 116 R =OTf 119 R = H 120 R=OH Pd(dppb), KOAc Me2NCOMe, 120 "C 30 h, 68% 1 OTBDMS OTBDMS 117 20 : 1 118 Both medium and large ring carbocyclic products have been formed by the intramolccular Heck reaction. Although Roberts et al. had difficulty in controlling the regioselectivity of the reaction, they cyclised a bromoindolc onto a monosubstituted alkene to form, in a 2: 1 ratio, the 8-endo and 7-a0 products respectively in an 88% yield under standard Heck Negishi et al. have synthesised both medium and large ring carbocyclic products viu cyclisation onto both alkenes and allenes under high dilution Jeffery conditions.*' They found that they could only synthesise medium sized rings in very low yield with alkenes but that large rings, such as the 21-membered 121, could be prepared in good yield by this method.The large rings were formed almost exclusively in an endo fashion. The cyclisations with allenes proved to be very successful and 7- through 20-membered rings were formed, on the whole, in good to very good yields under high dilution Jeffcry conditions. For example, the 20-membered ring 123 was formed in 86% yield from allene 122. It was shown that carbon-carbon bond formation takes place at the central carbon atom of an allene to form a n-allylpalladium intermediate which can be trapped with a variety of nucleophilcs. Indeed intra- ClzPd(PPh& KzC03, Bu~NCI t DMF, 120 "C, 12 h 6670 ClzPd(PPh& K2CO3, Bu4NCI DMF, 120 "C, 5 h 66% E E 121 E 123 molecular nucleophilic capture can take place to afford another cyclisation.This is exemplified in the cyclisation of allene 124 to n-allylpalladium inter- mediate 125 which is then trapped with piperidine to form eight-membered ring 126. The rate of allene cyclisation was shown to be much faster than alkene cyclisation and it was proposed that it was due to this factor, rather than the lack of competing side reactions, that such good yields of large rings could be obtained. Lastly the geometry of the endocyclic double bond in the newly formed ring was shown to be (2) in eight- and less-membered rings, ( E ) in 1 1 - and more membered rings and to depend on other factors in nine- and ten-membered rings. Thus, the combination of allenes and the intramolecular Heck reaction appears to be a potentially excellent strategy for macrocyclic synthesis. the intramolecular asymmetric Heck reaction has involved the synthesis of carbocycle~.~' The majority of the work on the development of These will Gibson: Tjze intramolecular Heck reaction 4573.1.2 With anion capture Nuss et al. have described an approach to the skeleton of vitamin D3 which combines the intra- an anion capture that introduces the rest of the the vinylpalladium intermediate 134 which can then ClzPd(PPh3)~ II Kzco3, p i d Bu~NCI p i n DMF E molecular Heck cyclisation to form the A-ring with 66% E 80°C,Qh pi PtJ E 124 125 m01ecule."~ Cyclisation of the alkyne 133 leads to piperidine I E 126 undergocapture by the vinyltin reagent to give the product 135.TBSO- be discussed in detail later.Several total syntheses have employed the intramolecular Heck mediated formation of carbocycles as a key step: the synthesis of ( f )-y-apopicropodophyllin,'06 formed by a 6-end0 cyclisation; the synthesis of optically pure opioids,'"' via 6-a0 cyclisations; ( & )-duocarmycin,'"' via a 6-ex0 cyclisation; ( +)-aphidicolin,"l' via a 5-exo cyclisation; ( sation; taxol,"' via an 8-ex0 cyclisation and ( f)-dehydrot~bifoline,"~ via a 6-ex0 cyclisation. Several groups have synthesised variously substi- tuted and protected forms of the vitamin D1 A-ring via an intramolecular Heck 6-ex0 cyclisation."' The A-ring synthon 128 can be obtained by disconnec- tion of lr,25-dihydroxyvitamin D, 127 and the synthesis of 127 from 128 has been described.'14 The synthon 128 can itself be disconnected at the bond joining the two double bonds to reveal a substrate for the intramolecular Heck reaction where either C(5) or C(6) can bear the halide or triflate.Both approaches have been taken: for example, Shimizu under standard conditions with potassium acetate as base, whilst Hatakeyama et al. cyclised vinyl iodide 131 to 132 under similar conditions with triethyla- mine as base.'IY )-cis-trikentrin A,"" via a 5-a0 cycli- cyclised 129 to 130 in very good yield 113a.h 133 134 135 The earliest example of an intramolecular Heck carbocycle synthesis followed by anion capture was reported in 1983 by Heck et al. They cyclised bromodienes and captured the moderately stable n-ally1 palladium intermediate with piperidine thus forming five-membered rings.'I6 Several years later Grigg et al.exploited the tandem cyclisation-anion capture approach not only in the synthesis of heterocycles but also carbocycles. This was initially via 5-ex0 cyclisation onto 1,3-dienes followed by capture of the intermediate n-allylpalladium inter- mediate with either organotin reagents'" or carbon nucleophiles.36 Hydride capture has also been shown to be useful in the synthesis of carbocycles containing quaternary carbon centres.'I7 halides onto a range of terminally substituted alkynes followed by capture with phenylzinc chloride.Its They found that aryl iodides invariably gave better results than aryl bromides and that substitution on the alkyne can have a significant effect on the yield with the trimethylsilylated substrate giving only moderate yields.Thus 136- 138 were cyclised to 139-141 in the yields indicated. Wang et al. described the Heck cyclisation of aryl Y = halide or Off; 2 = H Y = H; 2 = halide or OTf n 127 128 roH C02Et Pd(PPh314 Et-N. MeCN 1\1, - Pd(0Ac)Z. PPh3 KzCO3, MeCN reflux TBSO'. &TBS 86% OT I c r r I -. -. 129 130 131 132 458 Contemporary Organic SynthesisI z 60% 68% 46% Negishi et al. studied the efficiency of various metals for the introduction of a range of organic functional groups in the anion capture process."9 As has been noted before, the main competing reaction in this process is anion capture of the initial inter- mediate formed by oxidative addition of palladium(0). The cyclisation reaction needs to occur significantly faster than this competing reaction for high yields of the desired product to be obtained.Alkynes (or even allenes) are therefore a better substrate for carbopalladation than alkenes and the vinylpalladium species thus formed is always stable enough to undergo anion capture. Negishi et al. therefore captured the product of an intra- molecular 5-exo cyclisation of an aryl iodide onto an alkyne with alkenyl-, alkynyl- and aryl-metals. They found that tin was good for introducing either alkenyl or alkynyl groups but that zirconocene chlor- ides were the best for alkenyls. They also found that the best metal for the introduction of aryl groups was aluminium and that organozincs reacted too fast and therefore gave too high a yield of the competing premature capture product. This methodology has been used in the construc- tion of the ene-yne system found in the neocarzinos- tatin chromophore. Torii et al.reported that cyclisation of the geminally dibrominated alkene 142 onto the proximate alkyne gave the vinylpalladium intermediate 143 which then underwent anion capture with the alkynylstannane to give 144 in reasonable yield.12" Palladium catalysed cross- coupling of 144 with another alkyne gave conjugated ene-yne 145. Thus two different acetylenic append- ages may be introduced by this technique. Nuss et al. found that with 1,l-diiodoalkenes the two possible organostannane coupling steps may occur in a one-pot reaction."' For example when diiodoalkene 146 was reacted in THF with 5 equiva- B n O e O T H P 144, 51 % \PdCI*(PPh&, CUI 145 HO I 1 46 Pd(PPh&, THF HO' 1 47 lents of the alkynylstannane then 147 could be formed in 32% yield.The earliest examples of the anion capture process involved, as mentioned previously, the trapping o f a n-ally1 intermediate by a secondary amine. In the last few years it has been shown that the formation of the intermediate n-ally1 complex is regiospecific and thus the product may be formed regioselectively.'*' Thus vinyl bromide 148 cyclises to 149 which then rearranges to 150. Intramolecular nucleophilic attack by the sulfonamide then generates 151 in good yield. Spirocyclic products may also be formed by this method. It is not only sulfonamides that can be used as nucleophiles. Carbon-centred nucleophiles derived from alkyl sulfonesl" and sc-substituted malonates have also been successfully intramolecular capture of n-allylpalladium inter- mediates formed by the intramolecular Heck reaction in their synthesis of morphine.'*5 In this case the internal nucleophile was a hydroxy group.Overman et a f . have used BrPd, 148 149 I 151 150 Lastly, a palladium catalysed rearrangement followed by an intramolecular Heck reaction has been reported by Watson et al. The palladium catalysed reaction of alkenyl ally1 ether 152 was expected to provide the product of a 7-ex0 cyclisa- tion, but in fact a palladium(0) catalysed 1,3-allyl shift occurred followed by a 5-exo cyclisation to give the spirocyciic product 153. I 152 153 Gibson: The intramolecular Heck reaction 4593.2 Multiple cyclisations The area of palladium catalysed cascade cyclisations is a relatively new and exciting one whereby, with the correctly tailored substrate, several rings may be formed in one reaction under diastereo- and, poten- tially, enantio-c~ntrol.'~~ Much of the initial work on multiple Heck cyclisations was performed in the area of heterocycle synthesis.In 1988, however, Overman et al. reported a series of bis-cyclisations from aryl iodides which formed spiro, fused and bridged ring compounds in good yields using silver carbonate as the base.'28 This was followed, in the next year, by a report of the use of vinyl triflates under standard Heck conditions in bis-cyclisations to form spiro carbocycles.'2y For example, vinyl triflate 154 was cyclised via alkylpalladium inter- mediate 155 to the tricyclic product 156 in good yield.Investigations into performing the cyclisation enantioselectively were also made. 72% 154 155 156 Negishi et al. used alkynes as the relay species with P-hydride elimination to form an alkene as the terminating step in a cascade cyclisation."" For example, the tricyclisation of vinyl iodide 157 to 158 was performed in excellent yield under standard Heck conditions.'31 As had been shown earlier in the synthesis of heterocycles, the 'neopenty1'-palladate intermediate is highly reactive and so, if the palladium is y to a double bond then a cyclopropane ring can be formed. Grigg et al. have demonstrated that this is the case in carbocyclic synthesis as well.85 MGN, reflux, 4 h 95% 1 57 158 De Meijere et al. have shown that palladium catalysed multiple cyclisations followed by a pericyclic reaction can be used in the construction of fused heterocyclic systems.89 Only moderate yields were obtained, however, and they propose that this was due to the presence of the oxygen atom as, in purely carbocyclic systems, very clean reactions may be obtained.132 The pericyclic reaction can take the form of either a 6n electrocyclic rearrangement to form a cyclohexadiene, or an intramolecular Diels-Alder to form a strained ring system.In a typical example, 159 underwent Pd(OAC)p, PPh3 KzCO3, MCN 130°C, 1 day Et02C E tO2C 159 160 Et02C C02Et 47% 161 palladium catalysed cyclisation to cislirans 160 and at the higher temperature of 130 "C trans 160 under- went a Diels-Alder cyclisation to give tetracyclic product 161.'33 cyclisations to the formation of pentacycles with carbonylative esterification as the termination step.134 As carbon monoxide insertion into a carbon-palladium rs bond and subsequent acyl palladation is a possibility in the presence of carbon monoxide then the relay species must be alkynes. This is because carbopalladation of alkynes occurs more quickly than insertion of carbon monoxide which occurs more quickly than carbopalladation of alkenes. Nucleophilic capture of the terminating acylpalladium species can be either intermolecular with, for instance, methanol or intramolecular with the use of a pendant hydroxy function to form a lactone.For example, vinyl iodide 162 was cyclised in good yield to the pentacyclic lactone 163. Negishi et al. have extended the area of multiple J>Bu ClpPd(PPh3)pp EtaN CO (1.1 atm), MeOH 7OOC.1 day * coyo It is also possible to form benzene rings through the use of multiple Heck cross-couplings.This can be done by either a mix of inter- and intra- molecular s t e p ~ ' ~ ' . ' ~ ~ or in a completely intra-molec- ular fashion.'36 For example, vinyl bromide 164 undergoes a Heck cyclisation to form a vinyl- palladium intermediate which then undergoes an intermolecular cross coupling with an alkyne 165 to form another vinyl palladium intermediate 166. This intermediate then undergoes either electrocyclic ring closure and palladium hydride elimination or 6-end0 carbopalladation to give the benzene deriva- 460 Contemporary Organic Synthesis\' DMF, 63% 164 Et2(HO)C = -.$ Et02C T? C02Et 1 68 C(OH)Et2 I Pd(OAC)z, PPh3 me K2C03, MeCN 120 "C, 67% Et02C C02Et 169 tive 167.This occurs with high regioselectivity.'3" In an intramolecular version enediyne 168 is cyclised to bisannelated benzene derivative 169 in good yield.'36 Finally, Overman's group have shown that the palladium catalysed cyclisation approach to the formation of carbocycles can be used successfully in the synthesis of natural products such as the synthesis of the scopadulcic acids.'37 4 Regio- and stereocontrol 4.1 Mode of cyclisation - endo or exo? There are several problems commonly associated with the Heck reaction, many of which have been at least partially overcome in the past few years. For example, reaction substrates were originally limited to aryl or vinyl bromides or iodides but more recently it was discovered that the often more accessible aryl or vinyl triflates may also bc used.138 Also, the previous general necessity for high reaction temperatures is now sometimes avoidable through the use of the Jeffery conditions.The problem of regioselectivity in the carbopalladation step is another area to which much attention has been paid as this is one of the most fundamentally important aspects of the Heck reaction. Before discussing the intramolecular reaction it is important to establish the factors influencing regio- selectivity in the intermolecular version. The Cabri- Hay ashi modelh". 1 ,139 for the coordination and carbopalladation steps will be very helpful to these discussions. (It is of note that the carbopalladation step is presented as irreversible in the Cabri- Hayashi model and that kinetic studies seem to provide some support for this hypothesis.'40) After oxidative addition to give complex 170 the reaction may take either Path A or B and the factor determining which occurs is the nature of 'X' in complex 170. If palladium undergoes oxidative addition into an aryl or vinyl halide bond then 'X' is a halide (usually either bromide or iodide) and the reaction proceeds down Path A. In order for the reacting alkene to coordinate to the palladium, then, due to the strong nature of the palladium- 166 1 67 > 98% regioselectivity /'- \ L, .L P4 I R X 170 H A 171 R Y 172 R halide bond, another ligand must dissociate as in 171. This may be a phosphine or a solvent molecule or if a chelating bisphosphine is present then one of its phosphorus atoms must dissociate before alkene coordination can take place.If 'X' is a triflate then Path B is followed. As the triflate group is only weakly coordinated to the palladium, it can dissociate to form the cationic complex 172 to which the alkene can then coordinate. In a simple reaction like that of an aryl iodide with an x-substituted alkene such as 174 then the reaction follows Path A and the alkene coordinates to give the neutral complex 171. In this case steric considerations dominate and the new carbon- carbon bond tends to be formed at the least substi- tuted end of the alkene to give disubstituted alkene 175. In the reaction of an aryl triflate with 174 the reaction follows path B to give cationic complex 172.The cationic nature of the palladium increases the polarisation of the double bond and so electronic factors dominate the carbopalladation step and the aryl group is transferred to the end of the alkene with the lowest electron density to give product 173. Thus it can be seen that the regio- selectivity of the intermolecular Heck reaction may be influenced by the choice of substrate for the reaction. &o",rOTf.Pdo doH ArI, Pdo L O H 'Ar Path B Path A / electronic steric Ar 175 173 control 174 control In the intramolecular version conformational constraints also exist, as well as the steric and electronic constraints already considered. The alkene should ideally be coplanar with the palladium and the carbon atom of the aryl or vinyl species, i.e.in an eclipsed conformation as Gibson: The intramolecular Heck reaction 46 1illustrated by 176 as opposed to a twisted conforma- tion 177. This is borne out by observation of inter- molecular reaction^'^' and Overman et al. have also provided evidence to support this theory in their synthesis of the Amaryllidaceae alkaloids where the eclipsed and twisted conformations would lead to different diastereomers of the p r o d ~ c t . ~ ~ ~ ~ " ~ Pd eclipsed 176 twisted 177 Accessing an eclipsed conformation in an inter- molecular reaction is not normally a problem and it is thus only the orientation of the alkene, which is governed by steric and/or electronic considerations, that determines the regioselectivity of the carbo- palladation step. In an intramolecular reaction, however, the alkene may be limited to only one eclipsed conformation due to the size and/or shape of the substrate.In this case only one of the possible regioisomers will be formed. In the formation of large rings via the intra- molecular Heck reaction, only endo selectivity has been observed to date.77*x0.82 Due to the large and flexible nature of the substrate very little conforma- tional constraint is present and so both possible eclipsed conformations of the alkene are accessible. The reaction therefore behaves in a manner similar to an intermolecular reaction. As all cases reported to date have employed Path A conditions, steric factors have dominated and endo cyclised products have been formed. As we move into the area of medium sized rings, there may still be a degree of flexibility in the substrate chain but now the conformational constraints become more important than they were for the larger rings and therefore it may prove energetically more difficult to adopt the alkene conformation favoured on steric or electronic grounds alone.A fine balance of steric, electronic and conformational influences may in fact lead to mixture of products. For example, in their synthesis of the conformationally constrained tryptophan derivatives,'04 Roberts et al. isolated a 2 : 1 mixture of the products 178 and 179/180 derived from 8-endo and 7-exo cyclisations respectively. For the synthesis of five-, six- and seven- membered rings, the reaction almost always occurs via the exo mode of cyclisation as conformational considerations now outweigh any steric or electronic factors in the system.It is possible, however, to construct substrates for the Heck reaction which give only the 6-endo cyclisation. For example, Hegedus et a/. observed exclusive 6-endo cyclisation of substrates such as 112 in their approach to the synthesis of ergot alkaloid^.'^ Other similar examples were reported by Black et al." in their cyclisations of 7-bromo-N-allylindoles. For example, 2 x 5 mol% Pd(OAc), 13 mol% (@TOI)~P H D H Et3N (2 equiv.), MeCN, 85 "C 2 x 3 h. 88% flNHCO2BZ C02Me +*.. H &j H 179 180 178: (179/180) = 2 : 1 cyclisation of the N-crotyl derivative 181 gave the tricyclic compound 182 in 94% yield. This particular preference for the endo cyclisation has been investi- gated more fully by Dankwardt et a1.2' who have shown that this selectivity occurs when the alkene component is an ally1 substituent on a ring fused to the aromatic ring bearing the halide and where the halide and the alkene are peri to each other as in 183.They have also shown that this high selectivity exists only when the ring fused to the aromatic ring is five-membered; with six-membered systems a mixture of ex0 and endo cyclised products is obtained. ?Me Ph J$& 43rn0l%Pd(OAc)~ Ph 73 rnol% (O-TOI)~P Me0 - EtsN, MeCN, 100 "C Ph ' N I Br \I 15h,94% Me0 181 \ 1\/1 182 p Br I Po 183 Although the structure of the substrate frequently dictates the regioselectivity of the intramolecular Heck reaction, it appears that sometimes the reaction conditions can be used to favour one mode of cyclisation or the other.For example, a study of the conversion of 184 to 185 and 186 suggests that small changes in catalyst concentration and base can lead to a reversal of regioseIectivity.3'"'" In one reaction (i), a 2: 1 :20 ratio of triphenylphosphine to palladium acetate to substrate with 2 equivalents of potassium carbonate gave a 2.5 : 1 ratio of exo:endo cyclised products. whilst, in a second reaction (ii), a 462 Contemporury Organic Synthesis5-eXO 6-endo -' ' M x h Me COPh i or ii 185 186 184 i. 5 mol% Pd(OAc)*, 10 mol% PPh3 2.5 I K2CO3 (2 equiv.), MeCN, 80 "C, 35 h, 73% ii. 10 mol% P~(OAC)~, 20 mol% PPh3 1 2.5 Et3N (2 equiv.), MeCN, 80 "C, 48 h, 81 % 2: 1 : 10 ratio of phosphine to palladium to substrate with 2 equivalents of triethylamine gave a 1 : 2.5 ratio of exo:endo products.Similarly, it has recently been shown that, for certain substrates, the use of the Jeffery conditions can lead to the formation of endo cyclised products whereas standard conditions yield ex0 cyclised products.s8h Thus aryl iodide 187 forms the seven-membered ring 188 under Jeffery conditions and the six-membered ring 189 under standard Heck conditions. XPd 1 90 C02Et m C 0 2 E t "0 191 t: i + Pd tI rn.m I1 r. C02Et C02Et t: Pd + I X Jeffery conditions NHCy Me0 Me0 standard conditions 6-ex0 32% 189 The regioselectivity of the intramolecular Heck reaction is thus still an area with many uncertainties. Although the structure of the substrate frequently dictates the regioselectivity, it is evident that when two competing pathways are energetically similar then the conditions may be altered to favour one mode of cyclisation over the other.Further rigorous studies are required before a clear understanding of the effects of any given variable will emerge. 4.2 Control of isomerisation and the rble of additives The question of regioselectivity arises not only in the carbopalladation step, as discussed above, but also in the P-hydride elimination step. Here the direction of elimination may be a problem as illus- trated by the potential conversion of intermediate 190 to either 191 or 192. Moreover, the palladium hydride formed from B-elimination may subse- quently coordinate to the newly-formed double bond to give 193, add again to give another alkyl- palladium intermediate 194, and re-eliminate with the formation of a different double bond.Repeti- tion of this process may lead to a variety of different products. The first problem is not as serious as the second as there is generally a preferred direction of elimination. It has been found, however, that both problems can be dealt with to a greater or lesser extent through the use of either silverI4' or thallium'33 salts. They are used to sequester halide ions from the palladium complex 170 formed in the initial oxida- tive addition step, thus forming a series of cationic palladium complexes. Due to its cationic nature the palladium not only coordinates the alkene more rapidly, hence partly explaining the rate enhancing effect of these salts, but it also effectively undergoes more selective P-hydride elimination.This may be explained by faster p-elimination and/or a shorter lifetime of the hydridopalladium species thus formed. The first reported use of silver salts to control isomerisation in the intramolecular Heck reaction was by Overman et aLz3 Since then their use has become more widespread in the synthesis of both hetero- and carbo-cycles in m ~ n o - ~ ~ " " ~ ~ and poly- c y c ~ ~ s a ~ ~ o n s ~ X ~ . l ~ ~ . 1 " 6 . ~ 3 7 A good example of their use is in the control of isomerisation in the synthesis of 3-meth~leneindolines.~ Without silver salts the cycli- sation of 195 would form substituted indole 197 via initial elimination followed by re-addition of the hydridopalladium species and re-elimination to bring the double bond into conjugation with the aromatic ring.With the addition of silver carbonate, however, exclusive formation of the desired exo- methyleneindoline 196 was achieved. Gibson: The intramolecular Heck reaction 4633% Pd(OAc)2,6% PPh3 d( S02Ph a:T Ag2C03 (2 equiv.), DMF * S02Ph ~ t . . 5 h, 80% 1 95 196 ($ 0% S02Ph 197 Denmark et al. found that not only were silver salts necessary for good yields of the desired products from intramolecular Heck arylations of nitroalkenes, but also that the nature of the anion was very important.74 For instance, silver carbonate worked well but silver nitrate gave none of the desired product. The importance of the anion has also been noted in asymmetric cyclisations but, as yet, there is little understanding of its r6le. The use of silver salts with vinyl triflates has led to decom- position of the starting material."" (However, silver salts should not be necessary in such cases, as when triflate is used as the leaving group then the reaction should follow Path B of the Cabri-Hayashi model to form a cationic palladium complex anyway.) Thallium salts have been found to have a similar effect to silver salts and have been exploited in the intramolecular Heck reaction, predominantly by Grigg, in nion~cyclisations,~~~~~~~'~~~~~~ and polycyclisa- Tietze et al.have found that ally1 silanes may be used to control isomerisation.j3 Under Jeffery condi- tions the silyl group eliminates, but with the addition of silver oxide P-hydride elimination occurs to yield vinyl silanes as in the cyclisation of 198 to 199.t ions.29.S7.8S L S i M e , I R Jeffery conditions, R = H 198 with Ag20, R = SiMe3 199 Finally, the addition of water to the reaction mixture when a phase transfer agent is has been found to accelerate the reactionSs and in one case its presence was essential for the reaction to proceed."" 4.3 Unexpected products Occasionally, the products formed from a Heck reaction do not fit the accepted mechanism. Often there is a reasonably obvious explanation but sometimes the proposed explanation raises as many questions as it answers. One of the very earliest examples of an unexpected product involved an attempted cyclisa- tion of anilide 200 to quinolone 201 by Heck et al.'" The isomeric quinolone actually formed, 204, was clearly not produced via the usual mechanism and so an alternative mechanism was proposed. This relied on the preferential formation of the 5-exo intermediate 202. Lacking P-hydrogen atoms, the palladium undergoes a P-carbonyl elimination to form an acylpalladium intermediate 203 which then cyclises via a 6-endo process to form 204.H H 200 201 202 \ / the 203 An interesting rearrangement was discovered by Rawal et al. in their efforts directed towards the synthesis of Strychnos alka10ids.l~~ At first sight, the cyclisation of 205 appeared to have proceeded via a 7-endo route to give 206 in pxeference to the 6-ex0 product, but on further inspection, the geometry of the exocyclic double bond is seen to be incorrect for such a cyclisation. It was therefore poposed that the cyclisation had occurred via the 6-ex0 mode but that the alkylpalladium intermediate thus formed had not undergone the expected /I-hydride elimination but instead formed a six-membered palladocycle with the neighbouring carbamate group'46 to give 207.This intermediate could then rearrange with the aid of the pendant exocyclic double bond via the cyclopropylcarbinylpalladate intermediate 208 to form the alkylpalladium intermediate 209 and the observed product 206. Examples of homoallyl- palladate-cyclopropylcarbinylpalladate rearrange- m e n t ~ ' ' ~ have also been observed by Negishi et al. during the course of studies on the cyclisations of vinyl halides onto geminally disubstituted terminal a1 kenes. ')7 sation should result in an alkylpalladium inter- mediate lacking a syn P-hydrogen atom for elimination and yet elimination still occurs.The reasons for this are varied. In cyclisations onto alkenes coordinated to carbonyl groups then oxo- n-allylpalladium intermediates have been through which the palladium can orient itself syrz to a P-hydrogen. Where the alkyl- palladium intermediate has palladium bound to a In several other cases the apparent mode of cycli- i nvoked 1 Ojg.7 lh.94U 464 Contemporay Organic SynthesisMe02C I Me026 H 205 1 t 206 In a recent example, 5-exo cyclisation of 213 gave 214 when stoichiometric amounts of palladium acetate and triphenylphosphine were used with a large excess of triethylamine in refluxing THF.’” It was proposed that the alkylpalladium intermediate underwent intramolecular oxidative addition into the benzylic carbon-hydrogen bond to form 215 which then underwent sequential reductive elimina- tion and P-hydride elimination of the palladium.Pd(OAC)P, PPh3 EtsN,THF * reflux, 10 h PdI Me CJ2Me 207 \ Me02C / 209 Me02C 208 benzylic carbon then ‘stereomutation’ has been proposed to allow syn P-hydride eliminati~n.””.~~ In syntheses of lycoricidine63.3,64 6-ex0 cyclisation is apparently followed by anti P-hydride elimination to give the desired product and so an intermediate such as 210 is proposed which would lead to the product via a reductive elimination step. E O M O M NMPM 210 MPM = CH2C6H4(pOMe) Danishefsky et al. have reported the formation of an aldehyde via cyclisation onto an enol ether.”” They propose that the elimination of palladium from 211 occurs via an ‘Arbuzov-like unravelling’ to give aldehyde 212.OMe CHO 21 1 21 2 6i Br 21 5 Lastly an example of what appears 21 4 // to be syn dealkoxypalladation has been reported.55 Although for palladium( 11) this is unprecedented, an example of syn elimination of palladium(0) from a p-hydroxy organopalladium intermediate is known.’4x 3.4 Diastereocontrol The intramolecular Heck reaction is often highly diastereoselective as has been shown in Overman’s elegant synthesis of scopadulcic acid The use of chiral auxiliaries in providing stereocontrol, however, has not received much attention. Grigg et al. have shown that amino ethers may be effective chiral auxiliaries for the Heck reaction.’8 Thus, in the cyclisation of iodoarene 216 onto the pendant cycloalkene, no diastereoselectivity was observed for the two chiral auxiliaries indicated when achiral phosphines were used, but when (S)-BINAP was used diastereoselectivities of between 48 and 55% were achieved.When the acyclic alkene 217 bearing SAMP (or RAMP) as the chiral auxiliary was 21 6 0 with (S )-BINAP when R = SAMP, de = 48% when R = CH(Ph)CH20Me, de = 55% 0 OMe de > 95% Gibson: The iritramolecular Heck reaction 465subjected to standard cyclisation conditions, diaster- eoselectivities of 95% were achieved with achiral p hosp hines. In the cyclisation of dienyne 218 carried out by de Meijere et al. 133 the stereoselectivity of the final electrocyclisation step is controlled by the pendant chiral ether to give a diastereomeric excess of > 95%. yh lO%Pd(OAC)p ph 20% PPh3 Et02C EQC OMe 21 8 Overman et al.have reported an example where the diastereoselectivity of an intramolecular Heck reaction was controlled by the conditions used.24h Thus, when triethylamine was used as the base in the cyclisation of aryl bromide 219, an 89: 11 ratio of 220 to 221 was formed in very good yield. With silver phosphate as the base, however, a 3:97 ratio of 220 to 221 was formed in good yield. Their proposal to account for this reversal in stereose- lectivity was that the cationic palladium inter- mediate formed by the action of the silver salts can coordinate to both alkenes present in the substrate to form intermediate 222 and therefore carbopalla- dation is directed in this case onto the upper face of the alkene. SEM \\ O v N , .\ O A k J i - 4 21 9 Dr Br’ 222 4.5 Enantiocontrol I TNSE5 0 Me02C’ w:‘“ Br’ 221 I The area of the asymmetric intramolecular Heck reaction has been explored mainly by the Shibasaki group. They have shown that prochiral vinyl iodides and vinyl triflates can be cyclised to products with high optical purity in the presence of enantiopure phosphines. For vinyl iodides the addition of silver salts is important to obtain a good eelo5” as would be expected from the Cabri-Hayashi model.When a chiral bisphosphine is used, obviously the highest degree of influence over the enantioselectivity of the reaction is exerted when both phosphorus atoms are bound to the palladium atom. For this to be the case when the palladium coordinates to the alkene, the reaction must proceed along Path B. It was also found that the nature of the silver anion was very important and that silver phosphate gave the best results.The best phosphine for this reaction has been found to be the BINAP ligand and better ees were obtained when the preformed palladium dichloride- BINAP catalyst was The best solvents were polar and aprotic and N-methylpyrrolidinone was found to give consistently good results. The use of calcium carbonate as an additional base was also beneficial.1o5e Under these conditions vinyl iodide 223 was cyclised to 224 in good yield and with a good ee.Iosd Tris(dibenzy1ideneacetone)bispalladium has also been found to be a good catalyst for asymmetric Heck reactions of vinyl iodides. Experi- mentation with various ligands and salts often proves beneficial as in the synthesis of indolizi- dines48 where BPPFOF { 1-[ 1 ‘,2-bis(diphenyl- phosphino)ferrocenyl]ethanol} was found to be the best chiral ligand and silver-zeolite the best source of silver ions.,OTBDMS ,OTBDMS 10% PdCld(R )-binap] CaC03 (2.2 equiv.) NMP, 60 “C, 100 h 87% 0e OAc 67% OAc 223 224 It has also been found that the use of vinyl triflates, which obviates the need for silver salts, gives good enantioselectivities with BINAP as the ligand.lo5‘ When used with a phase transfer agent such as tetrabutylammonium acetate then the cycli- sation can be followed by anion capture with the acetate anion as in the conversion of 225 to 226.’05c6 It has been found that nonpolar solvents give the best results when triflates are used’05g and under such conditions, with THF as the solvent and potas- sium carbonate as the base, asymmetric quaternary centres can be formed as in the cyclisation of aryl triflate 227 to tetrahydronaphthalene 228.105”.i*k 1.7% Pd(OAc)p, 2.1% (3-BINAP BulNOAc (1.7 equiv.), DMSO Me 20 “C, 2.5 h, 89% Me 80% ee 225 226 3% Pd~(dba)~ K2C03, THF 8Yo (R)-BINAP m 9 227 50 “C, 336 h.97% OTBDPS 466 Contemporary Organic SynthesisThe solvent that gave the highest ees with triflates was 1,2-dichloroethane but under the standard range of conditions only a poor conversion of starting material was possible. This conversion was improved, however, upon the addition of alcohols, the most effective being pinacol or the acetate anion."" It appears that Pdo is oxidised readily in 1,2-dichloroethane to Pd"C12L, and that the addition of pinacol or potassium acetate prevents this process.Thus a new set of conditions have been developed for the intramolecular asymmetric Heck reaction of triflates: namely, palladium acetate as the catalyst, BINAP as the chiral ligand, two equiva- lents of potassium carbonate as the base together with either 15 equivalents of pinacol or one equiva- lent of potassium acetate in 1,2-dichloroethane. Overman et al. have obtained extremely interesting results in their syntheses of indolones with asymmetric induction.2' With the same enantiomer of a chiral ligand (BINAP) they have obtained either enantiomer of the cyclic product derived from 229 by varying the conditions used. With silver phosphate as the base and dimethylace- tamide as solvent both significant ee's and yields of the (S)-indolone can be obtained, whilst with 1,2,2,6,6-pentamethylpiperidine and no silver salt present the (R)-indolone can also be formed in significant ee.Overman et al. have also carried out a bis-cyclisation with moderate enantio~electivity,"~ but although enantioselective polycyclisations are in principle a very powerful technique, this area is still largely unexplored. 5% Pd2(dba)3 (9-(+) 71%ee I 81% 229 10% Pd2(dba)3 c 20% (R)-BINAP 0 MeCONMe2, 80 "C, 140 h Me Me Me Tietze et al. have combined asymmetric conditions with their use of ally1 silanes for controlling the regioselectivity of the elimination step to create an asymmetric intramolecular Heck reaction of use in their total synthesis of a norsesquiterpene."'.1"5' In the key step, aryl iodide 230 was cyclised to 231 in excellent yield and enan tioselectivi ty.The asymmetric intramolecular Heck reaction is thus fast becoming a very useful and reliable 2.5% Pd2(dba)3.CHC13 91% Me 92% ee 230 231 catalytic asymmetric carbon-carbon bond forming reaction. 5 Total syntheses In the last three years the intramolecular Heck reaction has been widely used in the total synthesis of natural products with the ring generated being both hetero~yclic~~,~'.~~-~~.~~' and carbocy- described which demonstrate the versatility of the intramolecular Heck reaction. The total synthesis of taxol 233 has been described by Danishefsky et al. in a series of papers."' The key step in this synthesis was the closure of the eight-membered ring via an intra- molecular Heck reaction of the vinyl triflate 232.The closure was achieved in 49% yield under fairly standard conditions and clearly demonstrated the utility of the reaction for the cyclisations of highly functionalised substrates. In this section, four examples are clic.43.1U5.1 12.125.127h.137 90"C,49% WH 'r c A/ 1- 1 '' 232 0 OH 232 BzHN u 0 233 The synthesis of morphine 237 by Overman et al. has as its key step an intramolecular Heck reaction followed by an intramolecular anion capture process.'25 Thus, aryl iodide 234 undergoes a stereo- selective Heck cyclisation onto a 1,3-diene to form the n-allylpalladium intermediate 235 which is then captured by an appropriately positioned hydroxy group to give the pentacyclic product 236. has been demonstrated by the synthesis of scopa- dulcic acid A 240 by Overman et al.synthesis vinyl iodide 238 undergoes regioselective bis-cyclisation to give tricyclic 239. The synthesis of (+)-vernolepin 243 by Shibaski et al. 1('5' corresponds to the first asymmetric total synthesis of this molecule and demonstrates the usefulness of the asymmetric intramolecular Heck reaction. Using the conditions described earlier The usefulness of the polycyclisation methodology In this Gibson: The intramolecular Heck reaction 467235 -PdI 237 236 TBDMSO 238 \ A / 239 OH HO 240 5% Pd(OAc)p, 10% (R)-BINAP K2CO3 (2 equiv.), KOAC (1 equiv.) CICH2CH2Ci. 60 "C. 41 h H 70% TfO 241 86%ee 242 / 0 -+y 0 243 (potassium acetate as the additive and 1,2-dichloro- ethane as the solvent) vinyltriflate 241 was cyclised to bicyclic product 242 in 70% yield and 86% ee.6 Conclusion In the past few years, the intramolecular Heck reaction has started to reveal its full potential as a powerful tool for the synthetic chemist interested in constructing heterocyclic and carbocyclic compounds. 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ISSN:1350-4894    

DOI:10.1039/CO9960300447

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

~~ Saturated and partially unsaturated carbocycles KEVIN I. BOOKER-MILBURN and ANDREW SHARPE School of Chemical Sciences, University of East Anglia, Nonvich, Nogolk NR4 7TJ, UK Reviewing the literature published between May 1995 and April 1996 Continuing the coverage in Contemporary Organic Synthesis, 1996, 3, 19 1 1.1 1.1.1 1.1.2 1.2 1.3 2 2.1 2.2 3 3.1 3.2 3.2.1 3.2.2 3.2.3 3.2.4 3.3 3.4 4 4.1 4.2 4.3 4.4 4.5 5 5.1 5.2 6 7 8 Three-membered rings Metal carbenoid-based methods From dihaloalkanes From diazocarbonyl compounds Anion-based and related methods 0 ther met hods Four-membered rings Photochemical met hods 0 t her met hods Five-membered rings Free radical methods Me tal-based met hods Cobalt Palladium and nickel Zirconium and titanium Other metals Anion-based methods Cycloadditions, rearrangements and ring expansions Six-membered rings Diels-Alder reactions Free radical cyclisations Transition metal-mediated cyclisations Cationic cyclisations Other routes Seven-membered rings Cycloadditions and annulations Other methods Eight-membered rings Nine-membered and larger rings References optically active cyclopropanes.For example, Charette and Lebel' have reported the diastereo- selective cyclopropanation of allylic alcohols 1 using the modified Simmons-Smith reagent of diethylzinc and diiodomethane to give the desired products 2 in high yields and very high diastereomeric excesses superior to those obtained using the corresponding samarium-based cyclopropanation. Landais and Parra-Rapado' have used the same reagent to study 1,2-asymmetric induction in 2-silylalk-3-enols 3; similarly the resulting cyclopropanes 4 were obtained in high yields and high diastereomeric excesses.i. Etgn, CH2C12 - ')&R4 ii. CH212 R2 "J R4 R2 R3 1 2 Yield of syn syn : anti 86% 7: 1 97% 200: 1 96% 200: 1 R' = H; R2 = Ph; R3 = H; R4 = Me R1 = H; R2 = Ph; R3 = H; R4 = P i R' = Ph(CH2)2; R2 = H; R3 = H; R4 = Me SiMe2Ph SiMe2Ph Yield of anti anti : syn 1 Three-membered rings 1.1 Metal carbenoid-based methods 1.1.1 From dihaloalkanes The zinc carbenoid Simmons-Smith cyclopropana- tion remains one of the most useful methods available for the construction of the three- membered ring. Recent work has concentrated on the use of allylic or homoallylic alcohols to facilitate asymmetric induction; this coupled with the use of a chiral auxiliary has resulted in the preparation of Two research groups (Kobayash? and Charette4) have reported the Lewis acid-catalysed cyclo- propanation of the allylic alcohol 5 ; in both cases titanium tetrachloride was used as the Lewis acid and a good yield of the cyclopropylmethanol 6 was obtained.This principle was extended by both research groups to give enantioselection by the use of a chiral Lewis acid. Kobayashi used the Lewis acid 8 which was formed in situ from the C2 symmetric disulfonamide 7, whereas Charette used the titanium derivative 9. High yields of 6 were obtained with moderate to good enantiomeric excesses. Booker-Milburn and Sharpe: Saturated and partially unsaturated carbocycles 473LOH ii. C H ~ I ~ iii. Lewis acid Cu'Tf (5 mol%) ligand (15 rnol%) CHzCIz ooc+rt 05% 77% ee v 5 6 Lewis Yield ee acid 8 75% 68% 9 80% 90% H NHS02Ph Gyph Zn S02Ph a H NHS02Ph 7 8 9 1.1.2 From diazocarbonyl compounds The second metal carbenoid-based method of cyclo- propanation is by the treatment of an alkene with diazocarbonyl compounds in the presence of a metal catalyst. Demonceau and co-workers have demonstrated the use of the ruthenium-phosphine complex 11 and the osmium-phosphine complex 12 as catalysts5." as well as the osmium-aryl complex 137.Good yields of the product 10 were only achieved using styrene systems.Various research groups have been active in the dcvelopment of chiral catalysts for both intra- and inter-molecular enantioselective alkene-diazocarbonyl cyclo- propanations. The semicorrin-copper complex 16 has been reported' to effect the conversion of substrate 14 into the cyclopropyl ketone 15 in moderate yield with very good enantiomeric catalyst - phYco2Et Ph \= + N2CHC02Et 10 Catalyst Yield 12 OSCI2(PPhJ2 52% 11 RuCIp(PPh3 2 93% 13 [O~C1~(Cisopropyltoluene)]~ 59% 14 15 CN I CN 16 R = CMe20H excesses.A cobalt-salen complex, viz 18, has been reported' to catalyse the reaction between styrene and tert-butyl diazoacetate giving cyclopropanes 17a,b in good yield with good ee; a similar reaction has been described'" using an iron porphyrin as the catalyst. Shibasaki et aE." in their synthesis of the phorbol CD-ring skeleton have demonstrated an asymmetric intramolecular cyclopropanation of the enol silyl ether 19 using the chiral ligand 21 coupled with a copper catalyst to give the desired bicyclo- [4.1.0]heptane system 20 in very good yield and good ee.Doyle and Protopopova'2 have used the standard dirhodium tetraacetate catalyst in macro- cyclic lactone formation (22423). Finally, all four Ph L 17a catalyst CH2CIrMeOH rt, 24 h, 76% 1 + hYco2But 17b trans: cis 98 : 2 73% ee 18 N2' 4 0 OSiMe, 19 H H CMe3 CMe, 20 21 22 23 474 Contemporary Organic Synthesisdiastereomers of 4-(carboxymethy1)proline have been prepared via a dirhodium tetraacetate-induced cycIopropanation'-'. 1.2 Anion-based and related methods The familiar trimethylsulfoxonium ylide has been used by Gibson and co-workers14 as a reagent to convert the CrO complex 24 into the cyclopropane 25 in moderate yield. As a chiral alternative to the more usual trimethylsulfoxonium ylide, Hanessian et u1.l' have developed the new reagent 28 to prepare diastereomerically pure cyclopropyl ketones 27 from cqfi-unsaturated ketones such as 26.In the field of intramolecular anion reactions Nelson and Warren" have prepared cyclopropyl ketones 30 stereo- selectively from phosphine oxides 29. An intra- Me2(0)SCH2 61% 24 25 8 Me 28 BuLi, THF, -78 "C 73% 26 27 92%de 0 BU'OH Ph 29 30 R =Bu 83% trans: cis >95: 5 R = Ph 62% trans: cis >95: 5 molecular nucleophilic displacement has been used by Wicha et al. " to produce functionalised cyclo- propanes such as 32 from the iodide 31; elimination of benzenesulfinic acid from 32 then gave the cyclo- propene 33 in good yield. An intramolecular epoxide-ring opening has been reported]' in the enantioselective synthesis of cyclopropane a-amino acids, and a novel anion-induced ring contraction of cyclobutanes has been used as the key step in a preparation of an unusual cyclopropane nucleoside.19 Finally, Genet and co-workers"' have reported an asymmetric synthesis of the cis- and trans-vinylcyclopropanes 35 from the corresponding allylic esters 34.1.3 Other methods Two novel methods of cyclopropane ring formation starting from /I-haloesters have recently been N~N(S~MEI~)~ PhS02 C6H6 PhSO2 =!3iPh3 57% 32 trans : cis >96 : 4 31 BuLi 72% Et vSiPh3 33 34 35 reported. Thus, Tamaru et al." have developed a synthesis of the cyclopropane ketals 37a,b via a silyl chloride promoted cyclisation from /I-iodo esters such as 36 (moderate yields and stereoselectivities are obtained).Along similar lines, Fukuzawa et a1.22 found that treatment of 3-bromo esters 38 with a Grignard reagent -samarium iodide couple led to cyclopropanols 39 in excellent yield (this method has been adapted with less success to the prepara- tion of other cycloalkanols). Two other closely related methods of cyclopropanol formation, both utilising a titanium reagent, have recently been reported.'-' For example Cha and co-worker~~~ prepared the fused ring systems 41 from o-vinyl esters 40 via an intramolecular Kulinkovich hydroxycyclopropanation. The same research group has also rep~rted'~ the diastereoselective synthesis 0 i. Zn(Cu), THF ii. TBDMSCI I 36 37a 37b trans: cis = 12 : 1 RMgBr t ,xO" SmI2 (2 =I.) Br-C02Et THF-H MPA -78 "C -+ rt 38 39 R = BU 99% R = cyclohexyl 95% R = phenyl 99% OH 40 41 n = l 55% n = 2 62% n = 3 17% n = 4 0% Booker-Milburn and Shurpe: Saturated and partial& unsaturated carbocycles 475of cis- 1,2-dialkenylcyclopropanols using an intermolecular variation.The Cp2TiC12 complex has been used by Takeda et aLZ6 in the desulfuritive cyclopropanation of substituted 1,3-dithianes such as 42. A general method of small ring formation has been reported by Rieke and Sell27 in which, for example the cyclopropane 44 is prepared in good yield by reaction between Rieke barium, strontium, magnesium or calcium, the butadiene 43 and dichloromethane. A very neat synthesis of the cyclo- propane 46 has been described by Suzuki and co-workers28 starting from the homoallylic alcohol 45.This methodology has been used in the synthesis of a cyclopropane-containing icosanoid.29 Finally, a novel and highly efficient cyclopropane ring synthesis has been reported by Yus and Guijarro3" in which a 1,3-diol 47 is converted into a substituted cyclopropane 49 through the corresponding cyclic sulfate 48. CppTiC12 BULI (2 eq.) A * Ph3P Ph Ph 77% 42 M' ____f Ph A P h CHpClp 43 Brio+ 45 Ph - r v Ph 44 M=Ba 67% M = Sr 55% M=Ca 47% M=Mg 76% 46 0, ,o ,/s: 0 OH OH i. SOCI~, CCI~ I i. Li. 4.4'-di-tert-butvl- I biphenyl (cat.), YHF. o "C ii. H 2 0 "k R2 R3 49 Yield of 48 Yield of 49 R' = H; R2 = Me; R3 = CH2Ph 81% 60% 95% 84% R'R2 = CH2CH2CH2CH2; R3 = CH2Ph 93% 91 O/O R' = Me, R2 = CH2Ph; R3 = H 2 Four-membered rings 2.1 Photochemical methods The temporary silicon tether has again been used to good effect in [2 + 21 photocycloadditions.For example, Fleming et aZ. found that irradiation of the tethered enyne alkoxysilanes 50 followed by desilylation of the photoadducts led to high yields of the functionalised cyclobutene diols 51 with excellent levels of regio- and stereo-control.31 Overall the temporary silicon tether allows the synthesis of 'intermolecular' [2 + 21 photocyclo- adducts with the regio- and stereo-control normally associated with the intramolecular variant. Interestingly the diphenyl diyne 52 gave the naphthalene derivative 53 via an alternative cyclo- addition involving one of the phenyl moieties. Booker-Milburn et aZ.32 have reported that 3,4,5,6-tetrahydrophthalic anhydride 54 and the corresponding imide 55 underwent highly stereo- selective intermolecular [2 + 21 photocycloadditions with a variety of alkenols.For example irradiation of 54 with but-2-ene-174-diol gave the cyclobutane lactone 56 as a single product in excellent yield via spontaneous lactonisation of the initially formed cyclobutane anhydride. Irradiation of 55 with ally1 alcohol for example gave the diastereomeric cyclobutane imides 57 and 58 with a high de of 10 : 1. Similarly, a number of cyclobutene-anhydrides and imides were prepared in good yield by [2+2] photocycloadditions of 54 and 55 with a variety of acetylenic alcohols. Studies of the scope for intramolecular [2 + 21 photocycloadditions in synthesis have continued in earnest and a number of interesting examples have been reported over the review period.For example, Tenaglia and Barillk33 found that irradiation of the allenyl pyrone acetals 59 gave the corresponding exu-methylenecyclo- 50 L A 1 NH~F " O X HO 51 R=Ph 80% R=C02Me 75% ,Ph 52 53 476 Contemporary Organic Synthesis0 55 1.5 q H O v o H - hv. MeCN. 4 h, 83% 54 0 1.5 eq. doH hv, MeCN, 70 rnin, 89% 54, X L O 55, X=NH -O*l HO- 1 1 56 .&+:& HO- 1O:l 57 58 59 I I 60 n = i , R = M e 81% n = 2 , R = H 46% n = 2. R = Me 60% n = l , R = H 99% butanes 60 in good yield with excellent stereo- selectivity. In a study of the radical fragmentation of cyclobutanes, Reckwith and co-worked" found that irradiation of the pyridone 61 gave the highly functionaliscd cyclobutanc 62, as a single diastoreomer, in exccllcnt yield.In their studies towards as t e r i scan o 1 i de Boo ke r - M i 1 burn an d Cow c I 1 '' found t h at in t r am o I e cu 1 ar p h o t ocyclo - addition o f the x,/hnsaturated acid 63 gave the fused cyclobutane 64 with complete stereocontrol. Finally, Haddad and Abramovich"" have reported moderato to good diastereocontrol on irradiation of alkcnyl tethered cyclic acetals. 61 hv, Pyrex, MeCN c 76% H02C 63 62 R=HorMe H& H C02H 64 2.2 Other methods Padwa et al." have reported a very useful therrnal [2 + 2) cycloaddition reaction involving prop-2-ynyl sulfones. For example reaction of the alcohol 65 with benzenesulfenyl chloride gave the correspond- ing prop-2-ynyl sulfoxide which was then oxidised to the sulfone 66. Heating 66 with tricthylamine led to the metliylenecyclobutane 68 in excellent yield via thermal [2 + 21 cycloaddition of the transient allenyl sulfone 67.The Lewis acid promoted tandem intra- molecular Michael-aldol reactions of keto esters have bcen further investigated by FukumotoJX and a number of new examples reported (69-+70 and 71 4 7 2 ) . Jun has reported'" an interesting new i. PhSCI, Et3N ~ ii. Oxone@ \ \ \\ 65 \\ 66 EtSN, 80 "C 68 95% 67 TMSI or Bu2BOTf --OTMS 69 70 71 72 cyclobutane ring-forming process involving the reaction of quinoline-7-carbaldchydc with the Rh' bis-alkene dimer 73. The reaction probably proceeds by oxidative insertion of Rh into the aldehyde C-H bond followed by reductive cyclisation on treatment with trimethyl phosphite. Silyl substitution of vinyl allenes has been found to have a remarkable effect o n the rate and equilibrium of electrocyclisation; thus Ito et a/.'"' have found that a number of silyl substituted rnethylenecyclobutenes can be prepared in good yield under mild conditions (74-75).3 Five-membered rings 3.1 Free radical methods Free radical cyclisations remain a very popular method of tive-membered ring synthcsis; new work Boo kt.I--hlilhurri u t i d Sli urpe: Su tii ra t ed and partially u 11 sa ti iru t ed c-u rhocycles 477CHO I 2 73 I P(OMe)3, EtpO 82% Me H’ 83: 17 R’ -R’ SiRZ3 heat, xylene, 2 h 6 examples, 8549% 74 75 in this area comprises novel methodology, the use of chiral reagents to confer stereoselectivity and the application of existing methods to natural product synthesis. Two interesting developments reported recently involve the translocation via a 1,5-hydrogen abstraction by an aryl radical to form an alkyl radical which then undergoes cyclisation.For example Murphy and Roome” have generated aryl radicals from arenediazonium salts, such as 77, in the presence of tetrathiofulvalene 76 to afford ring systems, such as 78, in good yields. Curran and Xu41 have demonstrated the viability of a protccting- translocating group that generates a radical in the P-position relative to a protected alcohol, such that o-bromo-p-methoxyphenyl ethers 79 are converted successfully into cyclopentanes 80. Fu and Hays43 have described the use of catalytic tributyltin hydride for the radical-mediated reductive Bu3SnH Et02C Fe AlBN CGH6 R P OMe 79 cyclisations of enaIs arid enones, such as 81, giving good yields of cyclopentanes, e.g.82a,b. As alternative radical-generating methods, Chuang and Wang44 have reported the use of sodium toluene- p-sulfinate, while Hatem et al.4s have proposed the use of toluene-p-sulfonyl bromide in the cyclisations of allylallenes. Booker-Milburn and have published full experimental details of their iron( uI)-mcdiatcd ring expansion-cyclisation technique for the formation of [n.3.0] systems from cyclopropyl ethers. Enholm and Jia4’ have also made use of the radical ring openings of functionalised cyclopropanes; thus generation of the O-stannyl radical from the cyclopentanone 83 results in a fragmentation-cyclisation sequence of reactions to produce the angular triquinane skeleton 84. The same research group4’ has also studied the reactions of allylic O-stannyl radicals and excellent yields of cyclisation products 86a,b were achieved using tributyltin hydride radical-generation from the a,P-unsaturated ketone 85.Two examples of stercoselective radical cyclisations using a chiral aluminium-based Lewis acid have been reported by Nishida and co-workers.“””) Curran and Martinez- L 77 E t0pC & EtO& OMe - 45% t-- 1 ,&hydrogen abstraction I r 78 - Et02C E*2cT0 80 R = H 44% 89 : 11 cis: trans R = Br 71% 81 : 19 cis: trans 478 Con tetnporaiy Organic SynthesisC02Et BuoSnH (5 mol%) H o . , 6 C O 2 : a ''U PhSiH, AlBN * 0 71% 81 Bu3SnH AlBN C6H6 80 c 03 1.6: 1 82a 82b J 93% v H a4 0 A 193% 86a 86b 3 : 1 G r a d ' have used the unimolecular chain reactions of silicon hydrides such as 87 to give exclusively the E-alkene cyclisation product 88 (this methodology has also been applied to the synthesis of six- membered rings).The same principlei' has been utiliscd to prepare alkenes 90a,b predominantly as the Z-isomer 90a from the enantiomcrically pure alkyne-tethered oxime ethers 89. The final area of research involving free radicals that has attracted much interest is tandem cyclisations and cascade reactions. Pattendcn and Hayes" have dcviscd elegant methodology in which the sclcnoester 91 is convcrted into the bicyclic ketonc 94 in very good yield via the a,[,'-unsaturatcd acyl radical 92 and the 80% 87 88 BnO-N- W"" O X 0 89 H + O X 0 90a (Z) 69% 3% R = H 70% R=Ac R=TBDMS 45% 14% 91 90b (E) MOM0 Go 92 I 93 94 x-ketene alkyl radical 93.This is the first reported example of radical cyclisation onto a ketenc. An example of the unusual 5-endo-trig cyclisation in a radical cascade has been demonstrated by Malacrio and B ~ g e n ~ ~ in which alkynes 95 are converted into cyclopentanols 96 in very good yield. The uses of tandem radical cyclisations in natural product synthesis have been reported in the synthesis of ( & )-Y- and [Hiotol,55 and by Hoffmann and Booker-Milhurn and Sharp: Saturated and partially unsaturated carbocycles 47995 7 SiMe3 96 1 R' R2 (R4 R5) R3 Yield P i p i H Me BU' 88% p i PI-' H Me TMS 69% Et Et H H Bu' 21% Weltering" in their synthesis of dioxatriquinanes and doubly annulated glycosides. 3.2 Metal-based methods 3.2.1 Cobalt As in previous years the most commonly reported cobalt-based cyclisation method has been the Pauson-Khand reaction (PKR).Perhaps the most important recent development in the PKR has been reported by Livinghouse and Pagenkopf' who have found that under photochemical conditions the reaction can be made catalytic in cobalt with only 5 mol% Co,(CO), required. Cazes et af.58 have studied the intermolecular PKR with allenic compounds, and Veretenov and co-~orkers'~ have used the PKR to synthesise linearly fused triquinanes. Paquette and Borelly"" have prepared the angularly fused triquinane 98 from the cyclopentene 97 in their approach to the CD diquinane substructure 99 of 97 -+ 85% OTBDMS 98 OM@ Me 99 R'O R1O'* eR2 100 i. Co2(CO)e ii. A or B A 101 H A: MeCN, A 8: Me3N0, THF, rt R' = TBDMS; R2 = TMS 100 : 0 93% (A) R' = H; R2= Ph 92: 8 81% (B) R' = TBDMS; R2 = Bu' 97 : 3 84% (6) kalmanol.A highly diastereoselectivc construction of optically active bicyclo[3.3.0]octenones 101 from enynes 100 by an intramolecular PKR has been reported by Mukai et uf.61 Other uses of cobalt have been reported by Tyrrell and co-workersh2 who have utilized the intramolecular Nicholas reaction in an approach to fused carbocycles such as 103 from the alkynyl enol ether 102. Takacs and Mehrma# have developed the cobalt-mcdiated reductive cyclisation of ene dienes 104 to cyclopentanes, e.g. 105. 3.2.2 Palladium and nickel The familiar palladium-catalysed coupling of alkenes has been well represented in the literature recently, particularly in the area of natural product synthesis.On the methodology side, Larock and GuoM have studied the annulation of oxygen- substituted dienes with aryl iodides leading to benzo-fused cyclopentanes in excellent yield. The same research group" has also reacted aryl iodides 106 with vinylic cyclopropanes, including 107, to give benzo-fused cyclopentanes such as 108. The stereo- chemistry of the product 110 resulting from intra- molecular asymmetric allylation of the chiral enamine 109 has been investigated with some success by Hiroi and co-workers,b6 and Yamamoto 102 H 103 104 105 R=CHzPh 86% R = C02Et 74% 480 Contt.mporury Organic SynthesisC02Et I 106 107 Pd(0Ac) , NaOAc. Bu4NCI DMF. 3 Jays, a0 o c , 82% 108 i. Pd(dba)2 MeCN 82 "C + ii. 10% HCI 80% ee 65% 109 110 et aL6' have demonstrated a tandem palladium(o)- catalysed cyclization of 6-(alk-2-enyl)octa-2,7-dienyl acetate 111 giving the diquinane 112 with high diastereoselectivity.Palladium-catalysed cyclisation reactions directed towards the synthesis of natural products have been reported from the research groups of Fukumoto,"."' Shirahama"' (in their synthesis of kainic acid analogues) and Kihayashi" in which under controlled conditions the enyne 113 was found to give predominantly the single isomer 114, a key intermediate used in their synthesis of ( + )-streptazolin 115. Two research groups have studied organozinc/catalytic nickel(())-promotcd cyclisations. Thus, Knochel and Stadtmiiller7' have < OAc 111 112 Me 113 114 utilized this methodology in asymmetric syntheses of ( +)-methyl epijasmonate and (-)-methyl cucurbate, whereas Montgomery and Sauchenk~''.~~ have examined the cyclizations of bis-enones and the alkynyl enones 116 leading to products 117 in which the substituted double bonds have been introduced in a stereoselective manner.116 117 R=Me 82% R=Ph 61% 3.2.3 Zirconium and titanium The zirconium-mediated intramolecular cyclisation of 1,6-dienes, enynes and diynes is a well-known method for the formation of cyclopentanes proceding via zirconobicycles. Recently new methodology has been developed by Sato and co-workers7' in which the established zirconium reagent is replaced by a new titanium reagent, viz. a titanobicycle. Thus the diene 118 is converted in high yield into the cyclopentane 119 upon treatment with titanium tetraisopropoxide and iso-propyl- magnesium chloride.As with zirconium, the intermediate metallobicycle can be reacted with carbon monoxide to give a bicyclo[3.3.0]octanone; one advantage over zirconium is that single terminal alkynes can be used in the cyclisation. Sato's group have extended this work to include the stereo- selective synthesis of cycloalkylamines from unsaturated imines7' as well as to the cyclisation of conjugated dienes with alkyne~;'~ in the latter case it was found that the intermediate titanobicycle 121 derived from 120 reacts exclusively with electro- philes such as benzaldehyde through the allylic double bond to give the corresponding cyclopentane Ti(OPr'), Pr'MgCI * BnoxY BnO 77% BnO 118 119 B n O S Ti(OPr'), BnO* SiMea ::) - Ti-3 BnO , Pr'MgCI BnO .120 k 121 PhCHO 96% I BnO 122 Booker- M i l h rn and Sh arpe: Sa tit ra ted a ii d part ia /ly ii n sa tu ra ten ca rhocycles 48 1122 in excellent yield. Along similar lines, Buchwald and ~o-workers’~ have shown that dicyclopentene- titanium dichloride and butyllithium form a suitable alternative catalyst for the synthesis of bicyclic cyclopentenones and allylic amides; thus the enyne 123 can be converted into the amide 124 or the a,P-unsubstituted ketone 125. Zirconium-based cyclisations in conjunction with the zinca-cne-allene reaction have been used to synthesise linear and angular triquinane skeletons stereo~electively.~’ Returning to titanium-based methods, two research groups have studied the reductive cyclisations of &&-unsaturated ketones and aldehydes.Buchwald and Kablaoui””.“’ for instance have used a titanium catalyst with diphenyphosphine to prepare the cyclopentanol 127 from the enone 126, whereas Crowe and co-workers82’R’ have developed similar methodology that includes a carbon monoxide insertion reaction to synthesise fused bicyclic j+utyrolactones, such as 129, from enones e.g. 128. Ph cPh 123 i. Cp2TiCI2 BuLi ii. Et3SiCN D PPh3 toluene 64% 126 q y NH OAMe 124 & SiEt3 H30+ 66% I Ph do H 125 &Me 127 128 129 3.2.4 Other metals The familiar samarium diiodide coupling reactions of aldehydes and ketones with alkenes have been used for the synthesis of cyclopentanols notably by Holzaffel et al. 84 in their stereoselective synthesis from carbohydrates; this methodology has been extended to oxime ethers for the synthesis of aminocyclopentenols.85 Bennett and co-workersfi6 have used samarium diiodide to effect the trans- formation of alkynyl bromides to cyclopentanes i n very good yields.Forsyth and Huang” have reported the spirocarbomercuriation of a silyl enol ether in their synthesis of the spirocyclic sesquiterpenes erythrodiene and spirojatamol. Rieke et aLSS have reacted substituted (but-2-ene-1,4-diyl)magnesium complexes with carboxylic esters and lactones to generate cyclopentanols. In the field of alkene metathesis, Nugent et al.’” have used a tungsten catalyst to synthesize enantiomerically pure cycloalkenes e.g. 131 from the simple dienes 130, and Grubbs and Fuyimurago have had modest success with asymmetric ring-closure reactions using a chiral molybdenum catalyst.Finally, Taber and You” have used a diastereoselective rhodium carbenoid C-H insertion reaction (132 + 133) in their approach to the synthesis of the dendrobatid alkaloid 25 1 F. ArO.0 CI c, ,w.iAr (2 mol%) 1,2,Qtrichlorobenzene, 90 “C. 68% 130 Ar = 2,6-dibromophenyl 131 0 w, cat. Rh octanoate, CH2C12 89% Me02C 132 133 3.3 Anion-based methods Once again there have been many reports of five- membered ring synthesis using anion-based mcthods, including the standard aldol, Michael and Dieckman-like reactions, those of note leading to the syntheses of ( & )-Ia~rene’~ and ( & )-a~amide.’~,’~ There have also been a number of more novel methods including the reagent 134 devised by Katritzky et al.” to effect the transformation of esters 135 into 2-ethoxycyclopent-2-enones 136.Krief and co-workers’b have reported the stereo- selective synthesis of 1,2-dialkyl-l-phcnylcyclo- pentanes 138 by intramolecular carbolithiation of vinyl sulfides 137, and Taguchi et a1.” have used the chiral titanium reagent 141 to effect the catalytic asymmetric iodocarbocyclisation of diesters 139 to cyclopentane lactones 140, both in very good yield and with high ees. There have been several rcports of anion-based annulations, including two based on aldol condensations coupled with Wittig or Horner- Emrnons reactions to make 4-hydroxycyclopent- 2-en-1-ones 144. Thus, Bonadies et a1 ” have reacted diketones 142 with phosphonates 143 to achieve this 482 Contemporary Organic Synthesis134 1 NaH Ar&OEt 136 Ar = Ph 62% Ar = pMeOC6H4 57% Ar = pCIC6H4 55% t PhIGNOTf 86% SnBu3 1 45 Ill -Art +I " I ' Ph 146 LiN(SiMe& 66% &Me I Ts 1 47 i. BuLi Me,, PhMe Me., PhMe A particularly interesting and unusual example has - &sph + &SPh been devised by Padwa and co-workers'"' in which an a-diazo-yamido ketone such as 148 is treated 1 37 138 cisp : cisa = 3 : 1 C02Bn cat. 141, 12, CH,CI, 94% ee d C 0 2 B n 139 P6 Ph p{ 'Ph 140 141 ? LiOH*H,z j$,, "4~1 + (Me0)2P T R 2 MeOH " OH 0 0 142 143 144 R' = Et; R2= H R' = Ph; R2 = H R' = Ph; R2 = Bu 52% 64% 60% with rhodium( 11) acetate and an electron-deficient alkene or alkyne to give a spiro-epoxy cyclopentane such as 149.Lu and Zhang"'-' have developed a phosphine-catalysed cycloaddition reaction between buta-2,3-dienoate and electron-deficient alkenes, while Kurajima et af.104 have used the silyl enol ether 150 to prepare cyclopentanones from alkenes.A synthesis of diquinanes has been achieved by Iwato et af. Io5 using a novel cation radical-mediated intra- molecular [3 + 21 cycloaddition of cyclopropyl sulfides (151 +152a,b). Motherwell et af.'"6 have continued to develop their intramolecular [3 + 21 cycloaddi tions involving cyclopropanes which under palladium catalysis are converted into bicyclic systems. Lautens and c o - ~ o r k e r s ~ " ~ ~ ' ~ ) ~ have made cxtensive studies on cobalt- and nickel-catalysed [27r + 27r + 2711 cycloadditions; thus for instance bicyclo[2.2.l]hepta-2,5-diene 153 is converted into the enantiomerically pure cycloadducts 154 using Co(acac), in conjunction with a chiral phosphine ligand.Weinreb and co-workcrs1"" have reported a novel ene reaction involving allenylsilancs to synthe- sise cyclopentanols and cyclohexanols, while Normant et al." have used a similar zinca-ene-allene reaction t o prepare, for example, the cyclopentane 156 from the silylalkyne 155 in very good yield; this Yh Me, ,Ph 0 0 0 end, whereas Hatanaka and co-workers')' have reacted a phosphorane with chiral glyoxals. Another annulation reaction leading to the synthesis of bicyclic conjugated enediones has been described by G hera and co-workers.""' Finally, in a carbene-based cyclisation, Feldman et al."" have reacted the stannane 145) with base to produce the nitrogen- Ph * Rh" +HN2 0 70% Ph I alkynyliodonium salt 146 (derived from the alkynyl- 148 149 containing bicycle 147.OTlPS R MeS+OAc -2 EtAIC12 C10H21 CHzCIz 3.4 Cycloaddi tians, rearrangements and ring expansions 150 Many research groups have been active in the area o f five-membered ring formation viu cycloadditions. R = Ph 66% 89: 11 R = SPh 80% >99: 1 483151 + 153 3 b*SiMe3 155 T SiMe, 156 152a 152b 3 : 1 Co(aca& Et2AICI R' 154 C6H6 R = BU 83% 91% ee R = (CH2j40Ac 85% 85% ee i. Bu'Li THF * ii. ZnBr2 CuCN 72% SiMe3 TZnBr SiMe3 sequence in conjunction with zirconium chemistry has led to the synthesis of linear and angular tri- quinane carbon skeletons. An alternative synthesis of triquinancs has been devised by Moore and Santora'"' which features a novel tandem oxy-Cope- transannular ring closure to prepare, for example, the triquinane 158 from the ketone 157.Paquette and Doyen"' have continued to explore the fasci- nating chemistry of squarate esters to achieve full control of regioselectivity in their synthesis of linear and angular polyquinanes (159-+160). In the field of ring expansions, Fitjer et al."' have successfully prepared cyclopentanones from cyclobutyl phenyl sulfides (an asymmetric method has also been described), and Fukuzawa and Tsuchimoto] I ' have * Me3SiO& iii.NaHC03 ii. warm to rt Me3Si0 1 L 157 1 0 &p '0 H _67% Me3Sy@) 0 H HO- 159 1 60 developed a facile conversion of cyclobutanones into cyclopentanones using samarium diiodide and diiodomethane. Finally, Fukumoto et ~ l . " ' . " ~ have prepared cyclopentanones from vinyl cyclobutanols.4 Six-membered rings 4.1 Diels-Alder reactions The Diels-Alder reaction has continued to be the premier method for the formation of six-membered carbocycles, and again much work has been focused towards developing new methods for the construc- tion of enantiomerically pure cyclohexenes. The interest in asymmetric catalysis using binaphthol ligands has continued."" For example the cyclo- additions of eight different dienophiles were found to give very high ees with the boron-derived catalyst 161 and a number of cyclic and acyclic dienes."' Posner et a/.'1s have reported that the pyrone 162 undergoes cnantioselective cycloaddition using a BINOL [1.1 '-bi(2-naphthol)]-Ti catalyst. A very interesting kinetic resolution was reported by Larsen et al.ll' during the synthesis of angucyclinone antibiotics. It was found that brief exposure ( < 2 min) of 5-hydroxy-naphtho-l,4-quinone and the rucernic diene 163, to a catalyst prepared from (S)-3,3'-diphenyl-l,1 '-binaphthalene-2,2'-diol and borane, gave the Diels-Alder adduct 164 in good yield and greater than 98% ee.The use of chiral auxiliaries and diastereocontrol has continued to attract attention. For example Sommakia and Berliner have demonstrated"" that treatment of the acetals 165 with fluoroboric acid yields the cyclohex- enes 167 viu highly diastereosclective Diels-Alder cycloaddition of the vinyloxocarbenium ions 166. The continued interest of Agganval et ul.]" in chiral CF, 161 C02Me i. 1.3 eq. (R)-(+)-BINOL-TiC12(OPr')2 50 "C, toluene -oy&!: ii, _,OR ,-30°C 0 9243% ee o6 162 R = CH,naphthyl, SiMe2Bu' 158 4 84 Con temporary Orgu ri ic Synthesis@ :yMe I OMe OH 0 (*)-163 BH3-THF.(S)-3,3'-diphenyC1 ,l'- binaphthalene-2,2'-diol AcOH, THF, -78 "C, c2 min 69% 1 &M:8yoee \ OH 0 H : OMe 164 &OTOEt HBF4-OMe2 R' R' H 165 166 ii, TsOH, MeOH 0 R2 d=y;H 167 4&74% high des (20-2OO:l) sulfoxides has led to some promising results with the use of the enantiomerically pure sulfoxide 168 as a chiral ketene equivalent in diastereoselective Diels- Alder reactions. An entry to enantiomerically pure decalin structures has been reported by Chapleur and co-workers'" via the diastereoselectivc intra- molecular reaction of the carbohydrate derived triene 169. An interesting use of the retro Diels- n 4 EtCN, 83% rt, 18 h o--sTs-o >97:3 168 OTMS EtCN, rt, 2 h M%:20 0 >97:3 0 169 PhMe, 155°C hydroquinone 75% I Bu'02C 0 Alder reaction has been described in an enantio- selective synthesis"' of calcitriol.The toluene-p-sulfonyl selenoacetylene 170 has proved to be a useful masked ketene equivalent in a number of Diels-Alder reactions with unactivated dienes, leading to excellent yields of cycloadducts under mild conditions.I2" Grieco el af. 125.'26 have continued to report on the excellent results obtained with lithium perchlorate-accelerated Diels-Alder reactions. Of particular note is the use of LiNTf2 as a safer and equally efficient alternative to LiC104.'" Okamura et al.'2x have demonstrated that 3-hydroxy- 2-pyrone undergoes a base-catalysed Diels-Alder reaction with a number of dienophiles without the the need for high pressure e.g.171+172a,b. Furthermore, the resulting cycloadducts can be isolated without extrusion of CO?. Funk and Yost have shown that 2-acyloxyacroleins are excellent dienophiles for a number of different diene systems. Most importantly the tetrasubstituted dienes 173 lead to excellent yields of Diels-Alder cycloadducts under SnCI, catalysis, thus providing rapid access to functionalised Taxol A ring synthons."" R- f, + 1 - R - sTs -.-a \\ SePh 0 SePh 170 -C02Me '&C02Me - Et3N, CHC13, 12 h, 98% HO Ho C02Me OH 171 172a 172b (1 1:l) R' 3:l PhMe-CHzCI2 0 R2 0 173 R' = CH2C02Me; R2 = C5H1, 95% R' = OCOCSH11; R2 = OPr' 90% Booker-Milburn and Sharpe: Saturated and partially unsaturated carbocycles 485486 The intramolecular Diels-Alder (IMDA) reaction continues to be one of the most useful strategies in target molecule synthesis and a number of signifi- cant examples have been reported over the review period.Taber's synthesis of r-dictyopterol involved an efficient construction of the decalin framework via IMDA reaction of the vinylsilane 174 followed by Wittig olefination and oxidative desilylation.'"' Singleton and LeeI3' have continued their studies on the use of vinylboranes in the Diels-Alder reaction and have found that hydroboration of the acetylene 175 followed by IMDA of the intermediate vinyl- borane 176 yields the hydroxylated decalin 177 after oxidative work-up, all in a one pot reaction. It is interesting to note that 175 itself is constructed in good yield in a one pot reaction.In an approach towards the diterpene skeleton of the radarins either geometrical isomer of the tetraene 178 was found to undergo IMDA leading to the highly functionalised skeleton 179.'32 Baldwin and SiMezPh 250 "C ___) 0 c I 174 (E:Z = 4:l) i. Wittig ii. [O] t OH co-workcrs'33 have demonstratcd the viabiliy of an IMDA in the proposed biosynthesis of himgravine (180+181), and Deslongchanips and Hall'34 have used a tandem transannular Diels-Alder-aldol cyclisation sequence to good effect in a stereo- controlled approach towards ( + )-aphidicolin (182483). The temporary silicon connection has again been used as a powerful tool in the stereo- controlled formation of highly functionalised cyclo- hexenes.'35 For example Luh et a1.'36 found that the siloxane tethered bis-dienes 184 underwent IMDA reaction followcd by oxidative desilylation to yield the highly functionalised trans-cyclohex-3-ene- 1,2-diols 185 with complete stereocontrol.Finally, Stork and Chan13' have reported the remarkable observation that a magnesium or aluminium atom can serve as a temporary connection in an IMDA reaction, leading to good yields and stereoselectivi- ties. One of the fascinating features of this reaction is that it allows for the cycloaddition of unactivated , 0 180 TMSOCH2CH20TMS TMSOTf, CH~CIZ, -78 + 20 "C 2 h, 53% I &o H , ' 0 a-dictyopterol 181 i. (C6HI1)2BH, THF ii. 75 "C, 2.5 h 0 210"C, 18h, Et3N, PhMe 54% P TIPSO TIPSO 175 176 182 183 N aB 034H20 1 p 2 4542% R 184 177 KHCO3, H 0 2 , M~OH-T~F then KF, 7&75% SPh R 185 178 179 Z = 55%, E = 82% R = Ph, 4-MeOC6H4, Z-MeOC,H,, PhCH=CH Con temporury Orgartic Synthesis80 "C, 1 h Me / Me Me dienes and dienophiles under mild conditions.The reaction of 186 with vinylmagnesium bromide is illustrative. 4.2 Free radical cyclisation Nishida and co-workersI3' have reported the first example of an enantioselective radical cyclisation controlled by a chiral aluminium reagent. For cxample treatment of the vinyl iodide 187 with tributyltin hydride and triethylborane in the presence of the binaphthol catalyst 189 gave the methylenecyclohexcne 188 in 63% yield with an ee of 48%. Although in absolute terms this ee is moderate, the fact that enantioselectivity in a prochiral h-exu radical cyclisation (k, - 5.4 x 10' s - I ) can be controlled by added external Lewis acid is impressive.Chelation controlled 6-ex0 radical cyclisations of chiral oxazolidinone-derived alk- 2-enamides were found to proceed in good yield with moderate diastereoselect ion. I ") Pat t enden and ~ o - w ~ r k e t - s ~ ~ " papers o n their successful 6-endo multiple radical cyclisation reactions of polyenes (e.g 190+ 191). In a similar vein Zuretic et ~ 1 . " ' have shown that the Mn"' oxidativc cyclisation of the polyene 192 gives the tricyclic system 193 with excellent stereoselec- tivity. In an approach towards the huperzine skeleton White and Jeffrey"4 found that Mn"' oxida- have published a series of full I (c-Hex)02C 187 Et3B, Bu3SnH, 189 dry air, 63% CH~CIZ, -78 "C "i) 108 48% ee 190 Bu3SnH, AlBN 72% 1 191 f l Mn(0Ac)39 ~ ~ ~ 2 s 0 Et02C Et02C 'H 192 193 M~(OAC)~, Cu(OAc)z, HOAc, 33% EtHN 194 195 @/ 0 Bu3SnH, AlBN PhMe, 55% + fiH 0 SnBu3 196 197 C02Et COZEt - O T oa Bu3SnH,;N PhH.80 OC 198 199 tive cyclisation of the amide 194 gave the [3.3.1] bicyclic system 195. The rather unusual deethylation was a result of a sequence involving 1,5-hydrogen abstaction, oxidation, hydroxylation and loss of ace t alde hyde . A 6-endo r ad ical cy clisat ion, initiated by addition of thc tributylstannyl radical to an acety- Icnc. has been used in an approach to forskolin ( 196+197).145 Addition of Bu3Sn. to the carbonyl oxygen of the diquinane 198 followed by /$scission of the adjacent cyclopropane bond has been shown to provide novel access to the [3.2.1] ring system 199."" 4.3 Transition metal mediated cyclisations Balme et ul.terminated carbocyclisation for the formation of functionalised lactones. For example, treatment of have reported a useful palladium Booker- Mil bu rn a 11 (1 Sti (I rpe: Su tu ra t ed n ri ti partially U I I sn t i d ra t ed ca rbocy cles 487the carboxylic acid 200 with palladium acetate in the presence of base leads to the lactone 202 via cyclisa- tion of the Pd" intermediate 201. Malacria and co-~orkers'"~'~~ have used the Vollhardt cobalt mediated cycloaddition to good effect in the rapid construction of complex terpene skeletons. The rhodium-catalysed generation of sulfonium ylides from diazo esters, and the subsequent [2,3] sigma- tropic rearrangement "" have proved useful in the synthesis of highly functionalised cyclohexanones, as well as in a key step (203-204) in an approach to vernolepin'".A novel and very useful annulation (205 -207) reaction involving Fischer carbene '0 200 201 mo \ - Qf& 0 202 70% 4 examples C02Me Me0 203 10% Rh~(0Ac)d PhH. 80 "C, 77% 204 Mef + 205 111 Ph OMe 206 I.+ Me0 207 4 examples complexes and dienes leads to highly functionalised tricyclic ring systems in a one pot ~equence.'~' The reaction is thought to proceed via an initial [4 + 21 cycloaddition followed by benzannulation to yield the enarnine 206. Grubbs et al.'', have continued to report on the success of their ruthenium-catalysed metathesis reaction for the formation of fused 6,5- and 6,6-systems. Helquist et al. lS4 have demonstrated that iron carbene complexes undergo cationic polyene cyclisations leading to fused 6,6-systems (208-210).A useful feature of these reactions is that the intermediate iron complex 209 can be used to introduce further functionality into the cyclised products. Me30+ BF4-, MeN02 &25'C,2h = $@ H Cp(OC)2Fe Cp(OC)2Fe SPh 208 209 rn R 21 0 4.4 Cationic cyclisations Lewis acid-catalysed cyclohexane ring formation reactions have continued to attract interest and a number of research groups have reported significant results over the review period. For example, Jung et ~ 1 . l ~ ~ have shown that the allylsilane cyclisation of the Sharpless derived epoxy alcohol 211 leads to the enantiomerically pure diol 212 in good yield upon treatment with diethylaluminium fluoride. A similar BF,-catalysed allylsilane ring-opening reaction of an aziridine 213 was used to construct the amino substituted cyclohexanes 214a,b.Is6 Majetich and SieselI5' have used a BF,-catalysed cyclisation in their synthesis of nimbidiol.Cationic cyclisation of SiMe? 21 1 21 2 rSiMe3 2.7: 1 21 3 21 4a 214b 488 Contemporary Organic Synthesisthe silyl enol ether 215 gave the intermediate vinyl- mercury species 216 which underwent transmetalla- tion with palladium followed by carbonylation to yield the [3.3.1] bicyclic ketoester 2l7.Is8 Ley and co-workers'" have again used the selenium mediated cationic cyclisation to good effect in an approach towards the insect antifeedant jodrcllin (218+219). A high yielding iodine mediated trans- annular cyclisation of the bis-acetylene 220 has been shown to lead to the symmetrically functionalised'h" decalin system 221.OTMS w' 'Me HgC12,HMDS ~ \/"'Me 21 5 q 0 OH 21 8 220 CH& 21 6 PdCl CUC12 Lici, t o , M ~ O H M e O k i 0 I Me 21 7 i. NPSP, Znlp, CHpCIz, 95% ii. TBHP. Ti(OOPr')4, dihydropyran, CHzCIz, 95% 219 I 221 4.5 Other routes Yamaguchi et a1 16' have found that conjugate addition of hydride to the bis-a, /&unsaturated ester 222 promotes a Michael ring closure to form the cyclohexane diester 223 in good yield. In a similar vein Crimmins and co-workers'62 have reported on a useful annulation reaction involving the conjugate addition of zinc-copper reagents to acetylenic esters (224-+225). Functionalised 6,6-bicyclic systems have been constructed using a novel dehydrative cyclisa- tion of allylic alcohols under Mitsunobu conditions (226+227).Ih3 Mangion et al.Ih4 have demonstrated that the diene 228 undergoes a stereoselective photosensitised [4 + 21 cycloaddition to give the tricyclic system 229 in excellent yield.Paquette and Tsui'"-' have once again demonstrated the power of the anionic oxy Cope-rearrangemcnt for thc construction of complex carbocyclic structures from simple precursors. Thus, in their approach to the diterpene kaurane, the requisite dienol 230 was readily available in enantiomerically pure form and \CO2Me fJ' L-Selectride? d , . c o 2 u e THF, 4 0 "C, 82% 222 223 COVE1 IZnCu A C O z E t THF, EtpO, TMSCI. HMPA, 5040% R 224 225 H QSO Ph DEAD, Me3P, PhH S02Ph 82% - S02Ph2 HO S02Ph 226 227 Ph 228 hv, MeCN, PhH, 1,4-dicyanobenzene, 87% 1 G Ph 'H 229 \/ KH, 18-crown-6 THF, 80% H 0 / 230 231 1 0 232 underwent smooth rearrangement to the enone 232 via elimination from the intermediate enolate 231.The same research group reported the use of a stereoeontrolled oxonium ion-activated pinacol ring expansion (233+234) as the key step in the construction of ( + )-grindelic acid.'" Finally, Brown Hooker-Milbum und Shape: Saturated arid partially urisatiirated carhncycles 489490 CSA, CH2Cl2,20 "C 10 min. 76% 233 234 i. (ipc)BClp (cat.), Me3SiH, Et20 ii. 0.25 eq. LiAIHI iv. CI2CHOMe, Bu'OLi v. H202, NaOAc 0 235 236 77%; 299% ee and selective synthesis of trans-decalone 236, which involves treatment of the allylcyclohexene 235 with a remarkable succession of five different reagents resulting in an overall yield of 76% and an ee 2 99%.have reported a practical enantio- 5 Seven-membered rings 5.1 Cycloaddi t ions and annula t ion s The most frequently reported method for the synthesis of seven-membered rjngs has been via [3 + 41 cycloadditions or annulations. Harmata have been particularly prolific in the field of intramolecular cycloadditions; for example treat- ment of the ally1 alcohol 237 with triflourornethanc- sulfonic anhydride and 2,b-lutidine resulted in the formation of the bicycle 238 via cycloaddition of the intermediate vinylthionium ion. The tricycle 240 was prepared in high yield by Lewis acid-induced forma- tion of the alkoxyallylic cation from the enol ether 239. Molander and Ea~twood'~' have reported that the reaction of diones 241 with the bis(trimethy1- sj1yl)enol ether 242 gives the familiar oxygen- bridged carbocycle 243 which can then be readily converted into the cycloheptane 244.This method has also been adapted to [3 + 51 annulations. Takeda and co-worker~'~' have described the reaction of the the silane 245 with the lithium enolates of %,,%unsaturated ketones 246 to give the desired 168-I70 S S P h 237 PhS02 (3 Tf 0 cl-f$32 2,Wutidine -78 "C 63% & R3 PhS R' 0 241 TMSOTf 1 T M 4 E e 242 0 r R3 1 L 0 243 11 n H O G R2 R' 0 OLi 245 246 1 -80 -30 "C 0 TBDMSO 6; \ TMS 247 R' = H; R2 = CH2CH2Me; R3 = H R' = H; R2 = Me; R3 = Me R'R2 = CH2CH2CH2; R3 = H 73% 65% 73% products 247 in good yield. IIigher order cycloaddi- tions have also featured in the preparation of seven- membered rings. Lautens et ~ 1 . " ) ~ in their studies of the reactions of bicyclo[2.2.l]hepta-2,5-diene 248 have demonstrated the asymmetric [2n + 2n + 4x1 cycloaddition with diencs 249 using a cobalt catalyst and the chiral ligand R-l,2-bis(diphcnylphos- (aSPh 238 Ph2Pj-PPh2 Et AlCl &-HI3 R 248 249 B R 239 240 P-H : a-H = 2.4 : 1 Con temporary Orgu n ic Synthesis R=Me 66% 72%ee R = (CH2)30Ac 52% 73% ee\ / 80 “C R=Me 88% d R = H 84% 250 251 phino)propane (intramolecular cycloadditions have also been examined).Finally in this area, Rigby and co-worker~’~~ have described the intramolecular thermal cycloadditions of cycloheptatrienones 250 to give exclusively the exo product 251 in high yield, as well as the analogous photochemical and thermal cycloadditions of the corresponding chromium(o)tri- carbonyl complexes.5.2 Other methods Another popular method of seven-membered carbo- cycle synthesis is the Cope rearrangement of divinyl- cyclopropanes; the synthesis of the fused carbocycle 253 from the cyclopropane 252 is an example of the work of Cha et ~ 1 . ‘ ~ in this field. Along similar lines, Rarluenga and co-w~rkers”~ have prepared cyclo- heptane- 1,3-diones 256 from 2-arninobuta- 1,3-dienes 254 and vinylchromium Fischer-type carbenes 255 in very good yields; the total synthesis of desmarestene has also been reported175 using Cope rearrangement methodology. Alkene metathesis has also been used in the construction of seven-membered rings. For example Blechert et al. 17” have investigated the use of both rhenium 258 and ruthenium 261 catalysts in the synthesis of hydroazulenes e.g.259 from the I OTIPS 77% I J 1 ‘ TBDMSO TDMS C6H6 A \ heat 81% . OTBDMS OTBDMS 253 252 __c Ph 0‘ 254 255 256 R’ = Me; R2 = 2‘-furyl 82% R’ = CH2Ph; R2 = Ph 76% ? Me - 9:: 0 0 0 0 II 258 h 1.1.2-trichlorotrifluoroethane) A -. . . \ / 80q0 X V 257 259 cyclopentane 257. Grubbs et al.Is3 have also used the ruthenium catalyst 261 in their studies on the metathesis of dienynes, such as 260, to give fused bicyclic [n.m. 01 rings ( e g 262) in very good yields. Using an alternative stratcgy, Dowd and Zhang177 have extended their work on free radical ring expan- sions of fused cyclobutanones to fused rnethylene- cyclobutanes; for example 263 gave the 260 262 W”‘ 263 Bu3SnH 1 AIBN 91% 264 9218 cycloheptane 264 on treatment with tributyltin hydride and AIBN. Banwell and Ca~neron”~ have utilised a Beckwith-Dowd ring expansion in their enantioselective synthesis of the carbon skeleton of the sesquiterpene rnanicol. Also in the field of ring expansions Little et UE.~’~) have used a diyl cycloaddi- tion-fragmentation route to obtain bicyclic ring systems such as 265. This route has also been modified to include the synthesis of eight- and nine- membered rings.The radical tandem ring expan- sion-cyclisations of cyclopropylsilyl ethers described by 13ooker-Milburn and Thompson“6 also provides a facile entry into 7,s-bicyclic ring systems. New methodology for the synthesis of medium-sized rings in which cyclic /,’-keto phosphonates 266 are reacted with dimethyl acetylenedicarboxylate t o give good yields of the two-carbon ring-expanded products 267 has been developed.’”) The novel cyclisation of 2,3-epoxy alcohols reported by Marson and co-workers’” result in the formation polyfunctional seven-membered rings in excellent yiclds (2684269).The enantioselective synthesis of Rooker-Milburn and Sharpe: Saturated and partially unsuturuted curlwcycles 49 IL 266 0 268 qco2,. C4Me & - 94% H C02Me 1 i. Li, NH3, -78 "C ii. NH4CI, H20 72% .C02Me 265 OH C02Me ii. i. base Me02C-C02Me * n( @C02Me n=l 54% n=2 52% n = 3 60% n=4 57% OH OH I TiCI4 CH2CI2 98% 'cl 269 bicyclic tetrahydrofurancarbaldehydes from chiral 3-stannylbut-1 -enyl carbamates by tandem homoaldol-aldol reaction has been reported by Hoppe and co-workers (270+271).'8' Finally, Shea et a1.lg3 have developed a simple fused cycloheptane and cyclooctane synthesis by subjecting 272 to ozonolysis followed by an intramolecular aldol condensation to give, for example, the [5.3.0] bicyclic system 273 in excellent overall yield.This bridged-to-fused ring interchange methodology has been used in a neat total synthesis of the sesqui- terpene 1ed01.~~~ - Ph Bu& OCb 270 BF39Et PiOH quantitative I 94% ee H<,Me Cb = carbamoyl 271 6 Eight-membered rings Once again, this year has seen a heightened level of interest in eight-membered carbocycle constructions due to the intense synthetic activity towards Taxol and its congeners. Thus Danishefsky et al. have described the total synthesis of baccatin 111*85 and constructs"' using an intramolecular Heck reaction to construct the eight-membered B-ring (274+275). Blechert et al.'" have used a novel TMSI-promoted ring enlargement process (276+277) for the forma- tion of the taxane A,B-ring system.Swindell and his co-workers1"8-'90 have continued to publish promising results towards the taxanes using Ti- or Sm-mediated pinacol ring closure. Magnus et al.'"' have constructed the B,C-ring of the taxanes using an extremely efficient semi-pinacol type ring expan- sion under acid conditions (278+279). The seven- membered precursor 278 was readily constructed by pyrylium ylide cycloaddition. The cycloaddition chemistry of chromium carbonyl complexes has 0 OTBDMS 272 0 O'TBDMS 273 6' 274 0 275 H6 277 276 OTf 278 279 492 Contemporary Organic Synthesisbeen admirably demonstrated by Rigby et al.over the past few years and has recently been used to great effect in the construction of the taxane skeleton. For example, the photochemical [6 + 41 cycloaddition between the chromium tricarbonyl complex 280 and the diene 281 led to the adduct 282 which after some functional group interconver- sions gave the ketol epoxide 283. This epoxide was then subjected to an x-ketol rearrangement by treat- ment with aluminium isopropoxide which resulted in the formation of the taxane A,B-rings 284 in good yield.'" Other contributions to the formation of the taxane B-ring have come from a number of labora- tories including those of Wender,lg3 Kumar,lg4 Miesch,'" Paquette"' and Magnus.19"Finally, Nicolaou and Gray'9X have published a highly readable and personal account of their successful Taxol synthesis.280 282 Me& t(OP&.PhH M e w X = H 81% X=OT6S 65% H " H \x 284 283 A number of other cyclooctane-containing natural products have been investigated over the review period. For example Paquette and co-worker~'~~ reported full details of their ( + )-acetoxycrenulide synthesis which involved an oxidation-Claisen sequence as the key step (285-286). Booker- Milburn and Sharpe'" have described an approach to the related pachylactone skeleton where the key step involved an electrocyclic ring opening of the cyclobutene 287 followed by spontaneous lactonisa- tion to yield the cyclooctane 288. Borrelly and Paquette'"' also described a very neat Tebbe- Claisen sequence for the rapid construction of the kalmanol skeleton (2894290).An interesting Lewis acid mediated fragmentation-cyclisation sequence has been used as the key step in the synthesis of ( )-tetramethylmediterraneol B (291 -+292).*02 Me . . SePh TBSO "H 'Me TBSO 'Me 285 286 i. hv, prop-2-ynyl alcohol 77% ii. MeOH, cat. H'. 24 h 0 84% C02Me 287 xylene, reflux. 24 h 84% 1 C02Me 288 Me H I H B - O B n ' " S 0 - - ~ M e 0 0 Me' \ Me 289 i. Tebbe ii. pcymene, 120-130 "C 86% I TBSO-- OBn n Me U 290 291 I O---Lewis acid I L 1 J '0 292 Molander and EastwoodZu3 have used a [3 + 5 J cyclo- addition (293-294) as the key step in their total synthesis of (+)-dactyl01 . Piers and R ~ m e r o ~ " ~ have reported a useful oxidative cyclisation of bis-alkenyl- stannanes for the formation of carbocycles of various sizes. For example the bis-alkenylstannane 295 underwent oxidative coupling on treatment with CuCl in DMF to give the 6,8-system 296 in excellent yield.Booker-Milburn and Cowel13s used a novel aza deMayo reaction in their approach towards the Booker- Mil hu rn and Shave: Saturated and part ia li) unsaturated carbocy cles 493r " R 0 LHMDS, HMPA, THF Br 302 303 R = H; 95% R = CHZOTBDPS; 93% \ 293 ' 294 CO&t Me CrCl DM&O,307$ NiCh mMe Me0 OH Me0 ; ( I CHO .D 07% SnBu3 295 296 304 305 0 "a ii. i.Ru04 2 M H2SO4 d H-@ 2:, H N=C=O 55% ten-membered ring of the potent anti-inflammatory marine diterpenoid solenolide F (304 -305). Dowd and Zhang2'" have described a useful double ring expansion procedure for the formation of 11- and 12-membered rings. For example reductive cyclisa- tion ring expansion of the cyclobutanone 306 leads to the 6,8-system 307, which after Grob fragmenta- tion gives the 12-membered enone 308.Finally, Ma and Negishi211have disclosed exciting results on the cyclic carbopalladation of to-haloallenes. This promises to be a general route towards aryl fused medium and large rings and provides ready access 0 298 297 asteriscanolide skeleton (2974298). Further studies have been reported towards cyclooctane-containing lignans using biomimetic oxidative phenolic coupling catalysed by either ferric perchlorate2"s or phenyl- iodonium bis(trifluoroacetate).206 7 Nine-membered and larger rings Pfander et d 2 0 7 have used a Grob fragmentation of the toluene-p-sulfonate 300 [derived from (-)-HoJosParrish ketone 2991 in their synthesis of the optically active trans-cyclononenc 301.Continued studies towards the enediyne antitumour agents have yielded a number of new methods for ring closure. 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ISSN:1350-4894    

DOI:10.1039/CO9960300473

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones CHRISTOPHER M. RAYNER School of Chemistry, Universiy of Lceds, Leeds LS2 YJ7: UK Reviewing the literature published between March 1995 and May 1996 Continuing the coverage in Contemporary Organic Synthesis, 1995, 2, 409 1 2 2.1 2.2 2.3 2.4 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 6 Introduction Synthesis of thiols and disulfides, selenols and diselenides, sulfides and selenides Simple alkanethiols and dialkyl disulfides, alkaneselenols and dialkyl diselenides, dialkyl sulfides and selenides Unsaturated thiols, disulfides, selenols, diselenides, sulfides and selenides Substituted thiols and disulfides, selenols and diselenides, sulfides and selenides Thiols, disulfides, selenols, diselenides, sulfides and selenides as mediators of asymmetric transformations Synthesis of sulfoxides Oxidation of sulfides and selenides Non-stereoselective oxidation Stereoselective oxidation Enantioselective oxidation Non-oxidative sulfoxide and selenoxide synthesis General methods for sulfoxide and selenoxide synthesis Functionalised sulfoxides and selenoxides Unsaturated sulfoxides and selenoxides Synthesis of Sulfones and Selenones Oxidation of sulfides and sulfoxides Non-oxidative sulfone synthesis General methods for sulfone synthesis Functionalised sulfones U ns a t u r a t e d s ul fone s Conclusion References 1 Introduction This review continues from t h e previous ones published in 1994' and 1995.* It covers new methods for the synthesis of acyclic thiols, sulfides, sulfoxides and sulfones. In addition, the coverage has now been extended to include the analogous selenium derivatives.Cyclic systems will be covered else- where. A similar format has been adopted to that of the previous review in that it is divided into three sections: thiols, selenols, sulfides and selenides; sulfoxides and selenoxides; and sulfones and selenones. Each section begins with synthetic routes to simple systems, and then goes on to consider methods leading to more complex, polyfunctional molecules. Considerable emphasis has been placed on stereo- and enantio-selective reactions, reflecting the current interest in this area. chemistry has been published which is suitable for undergraduates, postgraduates and anyone involved in research needing to refresh their knowledge of this area3 Reviews on S-cationoid reagents in organic synthesis' and recent advances in synthetic reactions using organoselenium reagents have been published.s The latter includes sections on the addition of electrophilic selenium species to double bonds, including asymmetric processes, and catalytic oxyselenation and intramolecular oxyselenation re actions .A new introductory text on organosulfur 2 Synthesis of thiols and disulfides, selenols and diselenides, sulfides and selenides Methods of preparation, reactions and physico- chemical properties of sulfides have recently been reviewed.6 The chemistry of disulfides has also been r~viewed,~ as have applications of organosulfur compounds' and elemental selenium9 in organic synthesis.The origins of acidity trends for sulfides and oxidised derivatives"'.' I and radical stabilities' ' have also been investigated. 2.1 Simple alkanethiols, dialkyl disulfides, alkaneselenols, dialkyl diselenides, dialkylsulfides and selenides The reactions of alkyl halides and related electro- philes with nuclcophilic sulfur or selenium species are amongst the most established methods of sulfide and selcnide synthesis. Recent advances have been reported which include the use of borohydride exchange resin (BER) which promotes reaction between thiols and alkyl halides or epoxides to form unsymmetrical sulfides.".'3 The use of hydrosulfide exchange resin, prepared from the chloride form of Amberlitc IRA-400 and sodium hydrosulfide, can be used for the direct synthesis of thiols from alkyl halides (cJ: Scheme Sl)." Addition of triethylamine Ruyner: Synthesis of thiols, selenols, sulfides, selenides, sidfoxides, selenoxides, sulfones and seleriories 499hydrochloride minimises formation of the more usual symmetrical sulfide products.Benzyl sulfides can be prepared by reaction of thiols with benzyl chloride in the presence of montmorillonite- 3-aminopropyl(triethoxy)silane.” Alternatively, benzyl thioacetate in the presence of NaOH and methanol generates phenylmethanethiolate which reacts with alkyl halides to give benzyl thioethers (Scheme l ) . I 6 . I 7 Symmetrical dibenzyl diselenides can be synthesised from elemental selenium, NaOH and benzyl halides under phase transfer conditions using polyethylene glycol (PEG) (Scheme 2).IX Diselenides can also be formed directly using elemental selenium and zinc in the presence of sodium hydroxide, reacting with either alkyl halides, nitrohaloaromatics and acyl halides (Scheme 3).19 Bis(benzyltriethy1ammonium) tetrathiomolybdate20.2’ reacts with alkyl halides and toluene-p-sulfonates to form disulfides directly and has found particular application in macrocyclic disulfide synthesis (Scheme 4), whereas sodium sulfide adsorbed on 0 NaOH.MeOH PhASAMe * [ PhASNa] Scheme 1 NaOH, PEG-400 ArnX + 2se CsH6.65’C ArAS&Sed Ar Scheme 2 Scheme 3 0 C6H&H2NEt3)2MOS4 1 &iCI3 y z J , 25 “C 7-20 membered rings 0 Scheme 4 500 Contemporary Organic Synthesis alumina has been used for the synthesis of macrocyclic sulfides (Scheme 5).22323 The reaction of alcohols with o-N~~C,H,S~CN under Mitsunobu conditions24 results in formation of the selenide with clean inversion of stereochemistry (Scheme has also been reported that zeolites catalyse the formation of thiols and sulfides by reaction between alcohols and hydrogen sulfide.26 It Scheme 5 BnO HO Me0 OMe OMe Scheme 6 A new method of selenolate generation relies on a thiolate-diselenide exchange reaction using the sodium salt of N-acetylcysteine (Scheme 7).The produced benzeneselenolate reacts with various electrophiles, including alkyl halides, epoxides and epoxy ketones in high yields.27 The major byproduct is the disodium salt of cystine, which is easily removed due to its high water solubility. Tin- lithium exchange can be used to prepare bis(lithiomethy1) sulfide, an unusually stable 1,3-dilithiated synthetic building block which reacts with electrophiles such as dimethylphenylsilyl chloride to give symmetrical sulfide products (Scheme 8).’? A novel route to unsymmetrical dithia compounds relies on cleavage of a disulfide by a nucleophilic reagent such as an organolithium, followed by trapping of the intermediate thiolate with an alkyl halide (Scheme 9).28 disulfides and diselenides to alkenes provides a The photochemically initiated radical addition of Na02C 2 )‘*\sH + PhSeSePh NHAC MeOH, H20 NaOH, pH 9.2 I PhSeR Scheme 7i.Na2S/A1203 S Bu3Sn-1 ii. 6uLi (2 equiv.) [ >i] 1 Me2PhSiCI (2 equiv.) PhMe2Si 7 PhMe2Si S Scheme 8 i. RLi, THF, -78 "C to rt ,, ii.RBr, rt 5-8% A Scheme 9 route to 1-thio-2-seleno substituted systems. Interestingly, the reaction is much more efficient if mixed PhSSPh-PhSeSePh reagents are used rather than individual disulfides or diselenides; however high regioselectivity is possible with a wide variety of substrates (Scheme The photochemical degradation of [bis( 1-adamant-3-yl-carbony1oxy)- iodolbenzene in the presence of disulfides provides a route to adamantyl sulfides (Scheme 11).3" Other hindered sulfides can be prepared by ligand transfer of aryl thiocyanates with higher order cyanocuprate reagents (Scheme 12).3' The reaction can be carried out in the presence of reactive groups such as aldehydes, halides and NHBoc, but nitro groups are reduced under the reaction conditions.With simple Grignard reagents, thiols are the major products. - T S P h hv, 45 "C SePh 89% Scheme 10 P hI(0COAd)z Scheme 11 + RSSR 0 AdSR + PhI + AdC02H 2340% Ad =D R = alkyl, aryl Organic thiocyanates undergo reductive dimerisa- tion to give disulfides using bis(benzyltriethy1- ammonium) tetrathiomolybdate. A wide range of structures and functional groups can be tolerated in this reaction (cf. Scheme 4).20-21732 Similarly, seleno- cyanates can be converted to diselenides using hydride reducing agents ([diisobutylaluminium hydride (DIBAL-H), LiEt,BH] even in the presence of sensitive functionality such as ketones and alkyl bromides." Use of excess reagent however does result in reduction of carbonyl groups. Other recently reported methods of symmetrical disulfide synthesis include the reductive cleavage of Bunte salts (RSS0,Na) derived from primary alkyl halides using samarium( 11) iodide;" methanolysis of thioacetates and disproportionation catalysed by nickel boride, generated in situ from nickel( 1 1 ) acetate and borohydride exchange resin (BER);3s and the copper catalysed disproportionation of thiols using copper(I1) sulfate and BER.36 Thioacetates can be converted into thiols using palladium catalysed methanolysis with BER." This has also led to the development of a one pot synthesis of thiols from alkyl halides, using thioacetate exchange resin to prepare the initial thioacetate intermediate, then followed by BER, MeOH and Pd(OAc)2 for the hydrolysis (Scheme 13).Unsymmetrical disulfides can be prepared by the reaction of dithioperoxyesters (formed by oxidation of dithiocarboxylic esters and rearrangement of the intermediate S-oxide) with thiols (Scheme 14).38 i. @AM03 AcS, MeOH ii.@-&Me3 B H I , Pd(OAc)2, R-X - RSH heat, MeOH 87-97'7'' Scheme 13 lrt, 15-20d 0 42-86% I Scheme 14 Various reagents have been developed to oxidise 0 thiols to disulfides. These include methyltrichloro- Me0 Meoq SCN silane with diphenyl sulfoxide, which regioselectively couples two cysteine residues of human endothelin- 1 in quantitative yield;39 2,2'-dithiobis(5-nitro- pyridine) 1 and the corresponding sulfenyl chloride, which have also found application in peptide ~hemistry;~' and 2-mercaptobenzothiazole 2 which has been shown to be useful in the synthesis of a H Me0 SBu' 'H (Bu')~CU(CN)L~~ -78 "C, THF 65% Scheme 12 Rayner: Synthesis of thiols, selenols, sulfides, selenides, suljoxides, selenoxides, suljones and selenones 501wide variety of symmetrical and unsymmetrical disulfides.41 An interesting enantioselective thiol synthesis by thione-thiol rearrangement catalysed by optically active pyridine N-oxides has been reported (Scheme 15).42 Low enantioselectivities have so far been achieved; however the use of diastereomeric mixtures of N-oxides and elevated temperatures may in part be responsible for this.1 2 n CH3 S 6- - R 100 "C, 24 h 1 H2N -OH 55% overall CH3 RASH up to 38% optical purity R = Et, Ph Scheme 15 One final method of synthesis of simple sulfides is by the reduction of sulfoxides. The metal ion mediated deoxygenation of sulfoxides has been reviewed.43 Ammonium iodide has been reported for the reduction of methionine sulfoxides in peptides containing cysteine and cystine residues,44 and dimethyl sulfoxide reductase from Rhodobucter sphaeroides f.s.denitrificans will reduce predomin- antly the S-enantiomer of racemic methyl phenyl sulfoxide to give thioanisole, although the unreduced optically active sulfoxide is of greater synthetic i n t e r e ~ t . ~ ~ 2.2 Unsaturated thiols, disulfides, selenols, diselenides, sulfides and selenides The reaction of arene diazonium salts with sulfur based nucleophiles provides a route to the corresponding aryl thioethers. Bis(benzyltriethy1- ammonium) tetrathiomolybdate can be used, usually to give the disulfide, but thiols can be obtained in some cases (Scheme 16).'"'' To introduce selenium, reduction of amorphous selenium with SmI, gives the diselenide dianion which reacts with aryl diazonium compounds to give the corresponding diselenides (Scheme 17).46 The diselenide dianion generated using zinc, NaOH and elemental selenium reacts with halonitroaromatics also to form aryl diselenides (cf.Scheme 3).19 The direct nucleophilic sulfenylation and thiocyanation of phenolic ethers using hypervalent iodine(ii1) provides an attractive route to aryl Scheme 16 SH Adz+ BF4- - ArSeSeAr THF se + Sm12 - lsez-1 DMF, 0 "C Scheme 17 sulfides. The reaction is believed to proceed by addition of the nucleophilic sulfur species (either a thiol, or its S-trimethylsilyl thioether) to the cation radical of the phenolic ether (Scheme 18).47 Alternatively, palladium-catalysed coupling of a variety of aromatic iodides with thiols (cysteine derivatives) provides access to mercapturic acid (N-acetylcysteine) derivatives in good yield (Scheme 19).48 The choice of catalyst is crucial for the success of this reaction with tris(dibenzy1ideneacetone)- dipalladium [Pd2(dba),] modified with 1,l '-bis(dipheny1phosphino)ferrocene (dppf) giving by far the best yields, but only if the catalyst is stirred at room temperature with the aromatic iodide for 15 min prior to addition of the thiol.OMe OMe 0 P h 1 ( 1 ~ ~ F & (CF&CHOH * qSph X = H, SiMe3, 61% 62% Pr' P i Scheme 18 * xSAr ArI, Pd2(dba)3, dppf 1 -methyl-2-pyrrolidinone NEt3, 60 "C AcHN C02Me 5948% Scheme 19 A tandem Pummerer rearrangement-Diels-Alder reaction sequence can be used for the preparation of a-thio-substituted naphthalene derivatives (Scheme 20).49 A variety of dienophiles can be used, allowing considerable variation in substitution on the new ring.A very versatile method of construct- ing conjugated arenethiols is by palladium-mediated Heck coupling of thiophenols. Choice of S-protecting group is important for the efficiency of this process, and of a variety investigated (Me, Bn, 502 Contemporary Organic Synthesissulfide, when treated with base, isomerises to the acetylenic sulfide which can then be stereoselectively converted into either the E-vinyl sulfide using LiA1H4, or the Z-vinyl sulfide using DIBAL. Reductive removal of the propyl group ( Li-NH3) gives the ethenethiolates with retention of double bond geometry. The ethenethiolates can be dimerised to the disulfides using MeS0,CI (Scheme 22).Unsymmetrical E,Z isomers can also be accessed by isolating the sulfenylsulfonate intermediates and reacting them with the appropriate ethenethiolate. Reaction between 1,l-dichloroethene and thiophenol results in formation of 2-1,2-bis(phenyl- sulfeny1)ethene in high yield (Scheme 23).“ Alternatively, thiols react with 1,172-trichloroethene via dichloroethyne to give acetylenic sulfides which can be further functionalised in one pot by lithiation and reaction with electrophiles, to give a variety of substituted acetylenic sulfides. Subsequent reduction with either LiA1H4 or LiA1H(OBu‘)3-CuBr gives the E- or 2-vinylic sulfides respectively (Scheme Acetylenic sulfides can undergo hydrozirconation followed by transmetallation to give vinyl cuprate reagents which undergo Michael additions to enones (Scheme 25).55 This has been exploited in the synthesis of prostaglandin analogues such as ( +)-15-thia-15-deoxy PGE, methyl ester.Hydrozirconation can also be used for vinyl selenide synthesis. Treatment of terminal alkynes with Schwartz’s reagent (Cp,ZrHCI) selectively generates the E-vinylzirconocene intermediate, which reacts stereospecifically with diselenides to form vinyl selenides in good overall yield (Scheme 26).” Palladium catalysed coupling of 1 -bromo- 1 -phenylthioethene to an organoborane generated in situ by hydroboration of a terminal alkene with 9-borabicyclo[3.3. llnonane (9-BBN) provides a route to a wide variety of vinyl sulfides, and has been used as a key step in the synthesis of laurencin (Scheme 27).s7 P-Sulfonylacrylates and b-sulfonyldienamides react with thiolate nucleophiles to give [j-thioacryl- ates and d-thiodienamides respectively, by stereospecific addition-elimination (Schemes 28 This reaction is successful for a wide variety of substrates, including relatively hindered thiols.The reagent 1 -(phenylseleno)-2-(p-tolyl- and 29)..iS.SS ocIo- Ph P h 0 2 S 4 y SFt 6 Scheme 20 Pd(PPh3)2C12, CUI THF, PiZNEt, 50 “C I 99% I O + O S R R = A c i. EtZNH, CHC13, 50 “C ii. Zn, HOAc, CH2C12 8&%% R = H Scheme 21 CPh3 and Ac) the acetyl derivative was found to be best for the coupling reaction and also for deprotec- tion to the thiol (Scheme zl).”’ (-)-Menthy1 chloroformate has recently been introduced as a new reagent for the resolution of 1,l ’-binaphtha- lene-2,2’-dithiol by derivatisation and fractional recrystallisation of the menthyl thiocarbonate esters.” Subsequent hydrolysis gives a high yield of the required dithiol of excellent enantiomeric purity.Some useful methods of stereoselective vinyl sulfide synthesis are demonstrated by approaches to alkenyl prop- 1 -enyl disulfides.” Prop-2-ynyl propyl B~ PrSNa H = ’ 94% H = ’ “Pr MeONa. MeOH (0.5 equii.) LiAIHl 61 -82% 81 Yo Dr I , heat,36h * H3C*s’ DIBAL I 75% 85% I - - i. LdNH3 - Men SPr ii. MeSOaCl Men s-s- Me (0.5 equi;.) 61 -82% Scheme 22 Rayrier: Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selerioxides, sulfones and selenones 503cs,, heat, 2 h m N R 2 PT-2;;; TsvNR2 0 PhCH2Sv 0 NR2 31 43% 0 H202, AcOH EtONa, EtOH 85% SPh 95% CI + PhSH heat, 36 ht 42-65X 1 ph2s:a I Bu3SnH CH&12, rt.5 min. 1 00% Scheme 23 LWH, 91 % i. KH, MeOH (cat.) CI H RSH * RS-R' R = CsHI1, R' = Me ii. BuLi iii. R X 72-92% 72% CuBr, 20 OC Scheme 24 i. CwrHCl ii. MeLi,CuCN L H+ SCSH 1 1 Scheme 25 THF, -7W-50 "c 70% overall 6240% . L Scheme 26 OTBDMS SPh OTBDMS I I 91% Scheme 27 0 0 Scheme 29 sulfony1)ethyne 3 is a novel acetylenic sulfone that can undergo both normal and anti-Michael nucleophilic addition, and as such can be used to prepare a wide variety of substituted selenides and sulfides (Scheme 30)" Organocuprate reagents tend to add with Michael-type regioselectivity, whereas thiolate and selenolate nucleophiles tend to give mainly products of anti-Michael addition to the double bond relative to the sulfone.The precise reason for the change in regiochemistry for the nucleophilic addition is unclear at present. It has also been shown that 3 can act as a dienophile.61 Wittig-Horner methodology has been applied to the synthesis of vinyl sulfides. This can involve either phosphono sulfoxide-derived (Scheme 31),62 or phosphono sulfide-derived (Scheme 32)63 reagents. In the case of the former, use of the bis(2,2,2-trifluoroethyl)phosphono sulfoxide derivative leads to high 2-selectivity, the initially formed vinyl sulfoxide being subsequently reduced to the corresponding sulfide under mild conditions with t ributylp hosp hine. Diet hy lp hosp hono sulfoxides have also been used for the synthesis of unsaturated selenides, however little control of double bond geometry is possible and the products are 1 : 1 mixtures of E and 2 isomers (Scheme 33).@ I NaSEt Tsv PhSeCI.NEt3 Et20, rt Ts+H -Ts*SePh- / SePh 97% I N a s : z * T ~ F / SePh SePh 62% Scheme 30 0 0 i. KHMDS,lM-6 ii. ArCHO, -78 "C, THF 1 03% Scheme 28 Scheme 31 504 Contemporary Organic Synthesisi. LDA,-lOO°C ii. RCHO 0, u:qR i. separation ~~k~ 89X ii. NaH,THF HO Major diastereoisomer Scheme 32 i. Buli. THF, -78 "C ii. PhSeBr 72-76% I Scheme 33 The reaction of sulfoxides with magnesium amides provides a novel route to vinyl sulfides. A number of byproducts can also be formed during the reaction, including dithioacetals (Scheme 34).65 The allylation of silyl enol ethers and a variety of similar compounds, with Pummerer generated vinyl thionium ions provides a versatile method for the synthesis of polyfunctional vinyl sulfides (Scheme 35).66 Vinylic bis-thioethers can be synthesised from aromatic a-bromo ketones using the appropriate thiol in the presence of 2,6-lutidine (2,6-dimethyl- p~ridine).~~ The presence of HBr is essential for efficient reaction; if excess 2,6-lutidine is used then products resulting from simple thiolate displacement of the bromide are produced (Scheme 36).4R2NH-2EtMgBr Ph0'\Et Et20,O "C+rt * phxs% R*NH= f 72% Scheme 34 0 TMSOTf, PipNEt L Ph' :,),,SiMes CH2CI2, -78 OC Scheme 35 PrSH 2,blutidine (0.35 equiv.) e 60% No, Scheme 36 Ally1 sulfides and selenides are available by Lewis acid-induced cleavage of the corresponding S , O- and Se,O-acetals respectively, in the presence of an allyl-stannane or -silane (Scheme 37).6* In the case of S,O-acetals, selective C-0 bond cleavage is observed with TiCl, as the Lewis acid, however no analogous reaction is observed with a similar selenium based system.Instead, selective cleavage of the C-0 bond of the Se,O-acetal is achieved using BBr3 to give an intermediate a-bromo selenide, which then reacts under Lewis acid conditions SPh Tic14 (1.3 equiv.) SPh 54"b SnC14 (2 equiv.) H 3 Scheme 37 Rayner: Synthesis of thiols, selenols, suljides, selenides, sulfoxides, selenoxides, sulfones and selenones 505(SnC1,) with allyltrimethylsilane to give the desired allyl selenide. Ally1 sulfides can also be prepared in some cases by acid catalysed rearrangement of a 2,3-epoxy sulfide and elimination (Scheme 38).69 Alternatively, a-lithio-y-methoxyallyl phenyl sulfide will regioselectively add in a Michael fashion to enones resulting in allyl sulfide formation (Scheme 39).70 The intermediate enolate can be further reacted with electrophiles to form highly substituted ketones with good stereochemical control.The use of the triphenyltin enolate however would appear to be essential for an efficient alkylation step. Finally, sigmatropic rearrangements have been used in unsaturated sulfide synthesis. The 3-thio- Claisen rearrangement of an allyl vinyl sulfonium ion leads to formation of a sulfenium ion which can be trapped by appropriate nucleophiles (Scheme 40).7' Alternatively, the use of a chiral rhenium r ~ h .1 ( P O H Scheme 38 Scheme 39 I fast Scheme 40 I ON- - -Re- - -PPh3 ButOK, THF, -80 OC R' = H, 85%, \ - R2 = CH3, 97:3 stereoselectivw I ON- --Re- - -PPh3 BU'OK, THF. -80 "C ON- - -Re- - - PP h3 Scheme 41 auxiliary allows access to a variety of unsaturated thiols via the 2,3-sigmatropic rearrangement of ylides derived from complexes with diallyl, diprop- 2-ynyl and dibenzyl sulfide (Scheme 41).72 The i. Bu'Li, HMPA ii. T B D M S O - 0 0 - %oMe authors report that the rhenium auxiliary is easily -OM* * resolved and can be recycled. PhS TBDMSO' iii. PhBSnCl iv. R I *% PhS 2.3 Substituted thiols and disulfides, selenols and diselenides, sulfides and selenides Mixed 0,s- and 0,Se-acetals can be prepared by oxidation of dialkyl ethers using iodobenzene diacetate in the presence of a disulfide or diselenide (Scheme 42).73 Alternatively, electrochemical oxidation of a thioether in acetic acid provides access to a-acetoxy sulfides which, with suitable substituents, can undergo Lewis acid-induced cyclisation to an oxathiolane (Scheme 43).74 Another very versatile route to S,O-acetals is by Pummerer rearrangement.This has been particularly useful with the development of the asymmetric Pummerer reaction, where chirality in the original sulfoxide is relayed to the product S,O-acetal chiral centre (Scheme 44). This reaction has recently been reviewed.75 Other routes to a-acetoxy sulfides include treatment of a dithioacetal with mercuric acetate (Scheme 45),76*77 other Pummerer rearrangements (Scheme 46),"-'" and acetylation of a hemithioacetal (Scheme 46).78*79 It has recently been shown that a-acetoxy sulfides can be efficiently resolved by treatment with Pseudomonas jluorescens lipase (PFL) (Scheme 47).78*x" A further develop- R = 506 Contemporary Organic SynthesisSePh PhI(OAc)z, PhSeSePh B u ' / O V Bu' Oo, Me NaN3, rt 90% Scheme 42 R2 R2 ' ' y S + R i Pt electrode, -20- " y S A R ' AcONa,AcOH 4140% * R3 OAc R3 Scheme 43 ?- R S+ - *'pTol BF&Etp CHPCIz, heat 5-3% I Me0 &JOEt OAc Pseudomonas fluorescens lipase pH7 buffer, 30 "C, Bu'OMe I 49% yield, ~ 9 5 % ee OAc L OH J NH2 4 Scheme 47 95% >90% 88 I 0 ,,,JyS, 0 OEt y \pTol OTBDMS ment of this involves the dynamic kinetic resolution (DKR) of an epimerising hemithioacetal by ZnIp (cat.), MeCN Scheme 44 EtsY SEt EtS-OAc single diastereoisomer Scheme 45 i.CH~CI~, 4 A sieves ii. AcpO. pyridine, DMAP / 7449% Scheme 46 enzymatic acylation allowing up to 100% yield of resolved a-acetoxy sulfide (Scheme 48),79 rather than the 50% limit on yield for most enzymatic resolutions. Hemithioacetals can be made to epimerise using SO2 which plays a crucial role in the DKR process. In contrast, optically active hemithioacetals are sufficiently configurationally stable under acid conditions to allow cyclisation onto an adjacent acetal functionality to form oxathiolanes and oxathianes of high enantiomeric excess (Scheme 47)'" This has been exploited in a synthesis of the antiviral agent Lamivudine (3TC) 4.'l Finally, (ary1thio)nitrooxiranes can be accessed by nucleophilic epoxidation of the corresponding nitroalkene (Scheme 49).82 In some cases, significant stereoselectivity can be achieved, and this can be reversed by changing the metal counter-ion.One of the classic methods for the synthesis of fi-hydroxy sulfides and selenides is the nucleophilic ring opening of epoxides with thiolate and selenolate nucleophiles respectively. Recent developments include the use of thiol-diselenide exchange for the generation of benzeneselenolate using N-acetylcysteine and diphenyl diselenide (cf Scheme 7);27 silica gelx3 and polyethylene glycol (PEG)84 catalysis for the addition of thiophenol to epoxides (Scheme SO); and the use of hydrosulfide exchange resin, prepared from the chloride form of Amberlite IRA-400 and sodium hydrosulfide, for the direct synthesis of P-hydroxy thiols from epoxides (Scheme 51).14 Addition of triethylamine hydrochloride minimises formation of the more usual symmetrical sulfide products.The addition of chiral selenolates to prochiral epoxides proceeds with moderate to excellent stereoselectivity (Scheme 52).'5-'7 The selenolate can be generated from the corresponding diselenide using either LiA1H4 or NaBH,. Rayner: Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones 507Scheme 48 BubOM, THF, -78 "C 1 5 6 M = Li, 60% (after separation), ratio 5:6 5:l M = K, 63% (after separation), ratio 5:6 1 :6.5 Scheme 49 4' PhSH,PEG-4000 I Ph E S P h CHzCl2,2 h Ph 72% Scheme 50 Scheme 51 sek Scheme 52 i. LiAIH,, THF ii. Cyclohexene oxide, -20 "C 82%, 69% de e M? )-NMe2 HO An alternative approach to P-hydroxy sulfides and selenides is by oxysulfenylation and oxyselenylation of alkenes.This is illustrated by a recent example where N-(pheny1seleno)phthalirnide (NPSP) adds to alkenes in the presence of water to give a B-hydroxy selenide as a mixture of diastereoisomers (Scheme 53).88 Interestingly, if phenyl selenyl chloride is used instead of NPSP then simple addition is observed with no incorporation of water. Phenylselenyl nitrate can be generated in situ from diphenyl diselenide and NOz. It is a novel oxyselenylating agent, and adds to alkenes to give P-phenylseleno nitrates which are readily hydrolysed to the corresponding alcohols by silica gel (Scheme 54).89 The reagent (2,4,6-triisopropylphenyl)selenyl bromide has recently been introduced, and reportedly gives up to a 10- to 100-fold increase in stereoselectivity for selenylation reactions relative to PhSeCl and NPSP.w Asymmetric selenylating agents have also recently appeared, and can be used for P-alkoxy selenide synthesis.Selenylation of styrene with chiral selenyl trifluorornethanesulfonate 7 in the presence of methanol gives moderate to good levels of diastereoselectivity (Scheme SS)." The selenyl- 0 0 Scheme 53 CHCl R% ON02 PhSeSePh + NO2 L[ 0-25 "C PhSeONOP] - R L S e P h Si02 57-77% I OH R L S e P h Scheme 54 R ? i. (-)-DIPXI ii. NaH, R'X iii. Bu'Li, Se I i. lor2 ii. AgOTf R 1 1 R r 7 (-)-DIP-CI = (-)-B-chlorodiisopinocampheylborane Scheme 55 508 Contemporary Organic Synthesisating agent is generated in situ from the corre- sponding diselenide.In an approach to the synthesis of ( + )-samin, a diastereomeric ratio of up to 16 : 1 was achieved for addition to alkene 8 using a related system (Scheme 56).92 Selenyl bromides having chiral C2-symmetric pyrrolidine rings have also been investigated as asymmetric selenylating agents and give poor to moderate stereoselectivity in a seleno- methoxylation reaction (Scheme 57).93 A practical synthesis of the asymmetric selenylating agent 9 has been reported which is a significant improvement on the originally reported procedure (Scheme 58).94 An interesting deprotection reaction of P-hydroxy aryl selenides has been reported (Scheme 59). Photolysis of a phenylselenoalkane results in i. Br2 ii.AgOTf iii. 8, -100 "C, 15 min. iv.c-*= , -100 oc, 3 h 4" i@= OH 56% ArA'.O/ 161 diastereomeric ratio Scheme 56 pCt R2NH, DMF NaHCO, 80 "C sej-, 4849% R' R P h P h R2N= rx;'p Scheme 57 $, 0 81%, i. (+)-DIP-Cl, 99?h 88 THF, -25 "C 41:; B~ ii. NaH, EtI, 83Oh D \ / set2 iii. Bu'Li, Se, NaOH (cat.) 70-76%, >99% ee Me 9 Me (+)-DIP-CI = (+)-B-chlorodiisopinocampheylborane cleavage of the Se-aryl bond rather than the alkyl- Se bond which often occurs using conventional reductive cleavage protocols (Birch reduction). Olefinic byproducts are also formed in this react ion .95 Reduction of a P-keto sulfide using baker's yeast provides access to optically active P-hydroxy sulfides in good yield and with high enantioselectivity (Scheme 60).96 Dihydroxylation of an ally1 sulfide provides a route to P,y-dihydroxy sulfides using a modified Sharpless-style racemic dihydroxylation procedure (Scheme 61).97 Nucleophilic displacement of a glycerol-derived toluene-p-sulfonate by phenyl- methanethiolate provides access to related systems.Interestingly, alcohol protection and subsequent treatment of the benzyl thioether with tributyltin hydride produces a nucleophilic tributylstannyl sulfide which reacts with sugar derived electrophiles with good control of anomer selectivity (Scheme 62) .9s form via the Sharpless asymmetric epoxidation, represent new readily available synthons for use in asymmetric synthesis. On treatment with Lewis acids, they rearrange to the corresponding thi- iranium ions which can be trapped with various nitrogen-based nu~leophiles.~' Recent developments include the use of imines as synthetic equivalents of simple primary amines for overall clean monoalkyl- ation with the thiiranium ion intermediates.'"" The initially produced iminium ions are isolable, but are 2,3-Epoxy sulfides, available in an optically active ASph 0 baker's yeast ?H &SPh 80% 91% ee VO(acac)2 TBHP, CHpClp 74% 3: 1 diastereoselectivity I i.Ms20. NEt3 -'\ph -ii. DBU 76% I i. LiHMDS, THF I ii. O0 47% Scheme 60 Scheme 58 fYSePh hv, NEt3, MeCN Scheme 59 0 U u MeS02NH2, K2CO3 Bu'OH, H20 96% Scheme 61 Rayner: Synthesis of thiols, selenols, suljides, selenides, sulfoxides, selenoxides, surfones and selenones 509c HO $oc16H3 PhCH2SLi HO i. Mel. NaH THF. rt ii. Bu3SnH, AIBN B u ~ N ~ S O ~ C6H6. heat, 3 h Scheme 62 usually hydrolysed immediately to form the required secondary amines (Scheme 63).By comparison, with amino ester nucleophiles, polyalkylation is not a problem, and the free amines can be used with moderate to good efficiency (Scheme 63)."' In the absence of nucleophiles, related thiiranium ion intermediates undergo elimination to give allylic P-hydroxy sulfide derivatives (Scheme 38).69 to aldehydes also provides a route to /I-hydroxy selenides (Scheme 64).Io2 In this case, the organo- lithium species is generated from the selenoacetal and adds to the aldehyde to give a single stereo- isomer of the product. The enantioselective aldol reaction between benzaldehyde and P-thio-substi- tuted silyl enol ethers, catalysed by a chiral Sn" The nucleophilic addition of a-metallo selenides R3 R1 S' TMSOTf -78 "C, CHpClp .R4 I R2 OH K2co3 bq.1 R1+N0~4 3h,rt H 4446% S R3 TBDPSO 3H ( P h S e ) 2 C H 2 , B u L f o ~ THF, -78 80% "C *.H SePh 'CH3 'CH3 Scheme 64 complex, also allows access to P-hydroxy sulfide derivatives with good control of both relative and absolute stereochemistry. Interestingly, products with opposite absolute configuration can be obtained by relatively minor modification of the chiral ligand (Scheme 65).'03 Mixed 0,Se-acetals have been used for radical mediated phenylseleno group transfer reactions, adding to a wide variety of electron-rich and electron-deficient alkenes under photochemical initiation (Scheme 66).1049'0' Related systems involving sulfur stabilised radicals also add to electron-deficient alkenes with phenyl selenide transfer (Scheme 67).'"' A new route to substituted phenylmethanethiols involves the reductive ring opening of thiophthalan (dihydro-2-benzothiophene), and quenching of the resulting dianion with electrophiles such as water, aldehydes and ketones (Scheme 68).l"' Related Sn(OTf), BU~S~(OAC)~ I ligand 68%, 19:81 syn:anti P h V S E t 83% ee with ligand = SBu' Me OR Scheme 65 PMPO PMPO SePh " SOpP h Me02CA SeP h 4670 Me02C Bu3SnH, AIBN + @S02PhL 92% 1 PMPO &so2,, H? CAN Me02C hS02Ph Me02C Scheme 63 Scheme 66 5 10 Contemporaly Organic Synthesis0 n 0 baker's yeast PhS glucose, H20, pH 7 * PhS 'OBu SePh Scheme 67 Li, THF, -78 "C [ ErLi] biphenyl (cat.) as 4,4'-di-tert-butyl-* i.R'COR~ ii. H20 l 4249% ot"" Scheme 68 OMe I L OMe 1 10 Me OMe MeWOSiMe3 79% >99:1 stereoselectivity SMes I % Me Me OMe Scheme 69 systems can also be prepared by an alternative route (Scheme 69) which also allows for remote stereo- control by neighbouring group participation of the sulfenyl In this case the reaction proceeds via the cyclic sulfonium salt 10 which accounts for the stereochemical outcome of the reaction.Optically active y- and d-hydroxy sulfides can be produced in high enantiomeric excess by baker's yeast reduction of the corresponding ketone (Scheme 7O).Io9 Alternatively, y-hydroxy sulfides can be prepared by ring opening of (S)-( -)-propylene oxide with phenylthiomethyllithium (Scheme 7O),"" or the Lewis acid catalysed ring opening of oxetanes by lithium thiolates (Scheme 71).11" Finally, the dilithium salt of phenylselenoacetic acid reacts with epoxides to form y-hydroxy selenide derivatives (Scheme 72)."' The use of maleic acid in the work up procedure prevents lactonisation observed with stronger acids. 70%, 96% ee I O h I -:: P hSCH2Li i PhSCu, -78 "C 99%, 97% 88 Scheme 70 RSH, BuLi THF.-78 "C OH BFs.OEt2 Scheme 71 i. LDA (2 equiv.) OLi SePh PhSenC02H ii. BnO [ BnOAC02L] i. maleic acid, -15 "C ii. CH2N2 >72% overall I OH SePh BnO &C02Me Scheme 72 The synthesis of (R)- or (S)-2-~ulfanylpropanoic acid from ethyl lactate relies on clean inversion of configuration of the derived methanesulfonate using caesium acetate in DMF. Conventional acid or base hydrolysis of the ethyl ester usually results in some degree of racemisation, however hydrolysis using pig liver esterase (PLE) at neutral pH alleviates this problem (Scheme 73).Il2 Subsequent thioester hydrolysis is readily achieved using aqueous ammonia.The ring opening of trifluoromethyl- substituted epoxy ethers by thiolates leads to a-thiotrifluoromethyl ketones in good to moderate yield (Scheme 74).'13 Alternatively, samarium iodide induces coupling between selenyl bromides and a-bromo ketones to give or-selenyl ketones (Scheme 75).'14 Both Sm12 and Sm13 can be used to induce this reaction. OMS SAC SH i. PLE, pH 7 CsAc, DMF MeAC02Etp MeAC02Et ii. NH3, H2: MeAC02H Scheme 73 Rayner: Synthesis of thiols, selenols, suljides, selenides, sislfoxides, selenoxides, sulfones and selenones 511SR2 H 0 CF R lWoE: R'"'" 49-88"b 0 Scheme 74 &OM. Ar L B r SrnX2, RSeBr MeCN * Ar L S e R 58-72% Scheme 75 Reaction of the lithium enolate of camphor with elemental selenium results in formation of camphoryl diselenide in good yield (Scheme 76); however related reactions usually give more complex results."' Alternative new selenium transfer reagents such as PhSO2SeC1 and PhS02SeSeS02Ph have been developed which help alleviate some of these problems.'I6 The reaction between a-thio'"' or a-selenoenolates" ' with electrophiles (Schemes 65 and 72) and radical mediated phenyl selenide transfer (Schemes 66 and 67)'04*10h also provide routes to related compounds, and have been discussed previously.i. LDA, THF.40 "C ii. Se iii. H', air 76Oh Et02C.. SR' 97:3 diastereomeric ratio Scheme 77 N2CHCO2E1, CH2C12 V N .'$ PhX PhAXxPh 0-0 X=S, Se Bu' CuOTf Bur diastereomeric mixture up to 69:31 (best case) up to 41% ee, X = Se up to 20% ee, X = S Scheme 78 MeOH, 65 "C X = C02R, CONR2, CN 6597% Scheme 76 Scheme 79 Sigmatropic rearrangements have also be used to access carbonyl compounds with r-thio substituents.The [2,3]-sigmatropic rearrangement of sulfonium ylides leads to the formation of E-homoallylic sulfides with a high degree of stereocontrol (Scheme 77).' l7 Alternatively, enantioselective carbenoid addition to allylic sulfides and selenides and subse- quent [2,3]-sigmatropic rearrangement also allows access to similar compounds but with lower stereo- selectivity (Scheme 78)."* A number of different chiral catalysts were investigated, but all gave the products as a mixture of diastereomers.a, @-unsaturated carbonyl compounds is the most common method of synthesising P-thiocarbonyl compounds. Reaction of a thioacetate with boro- hydride exchange resin and Pd" catalysis generates a thiolate which efficiently adds to cqp-unsaturated esters, amides and nitriles (Scheme 79).*19 Addition of potassium thiolates and selenolates to a, P-unsat- urated nitriles have also been reported,"" as have similar additions to more complex substrates (Scheme SO).'?' Additions to a,P-unsaturated ketones have been discussed previously (Schemes 39 and 70).70,'09 Diastereoselective addition of sulfur The addition of thiolate nucleophiles to Scheme 80 nucleophiles to chiral Michael acceptors have also been reported. The use of y-(trityloxymethy1)- y-butyrolactams (Scheme 81)"' and oxazolidinones (Scheme 82)'" as chiral auxiliaries both give high levels of stereoselection. In the more complex example of the asymmetric Bayliss-Hillman reaction, the enolate formed after initial thiolate or selenolate addition to an r, P-unsaturated ketone can react with aldehydes to give mainly the syn- diastereomeric aldol-like product of moderate to excellent enantiomeric excess (Scheme 83).'24 Finally, the Lewis acid mediated reaction between 5 12 Contemporary Organic Synthesis.k P h3C0 -, Ph&O--, ' I 7 PhSH. PhSLi (cat.) Mg(C104)2, EtCN, -78 "c' Ph SPh 0 0 6 1: WX, W:I stereoselectivity Scheme 81 0 0 0 n o RCOSH up to 97: 1 VN$' (orRSH,TiCI4) * R P ~ - stereOseiectivity Ph'. Scheme 82 mainly syn 50-96Yo ee n = 0, X = 0,6&89% 88 n = 1, X = 0 or 2,64-80% ee 12 = Scheme 85 The synthesis of selenium substituted cyclo- propanes has been described using two different methods.The first involves the 12 + 11 cycloaddition of 1-seleno-2-silylethenes to unsaturated carbonyl compounds. Poor to moderate yields of the products can be isolated (Scheme 86).127 Alternatively, the phenylselenyl chloride-mediated cyclofunctionalisa- tion of y, &unsaturated carbonyl compounds also allows access to similar systems in good to moderate yield, and with high stereoselectivity (Scheme 87).12* If N-phenylselenophthalimide (NPSP) is used rather than PhSeC1, then simple a-selenylation of the carbonyl group is observed. Scheme 83 SePh sulfides and silyl enol ethers provides an alternative route to P-thio carbonyl compounds (Scheme 45) .76*77 Routes to other carbonyl containing sulfides and selenides have also been reported.An interesting reaction is the ozonolysis of unsaturated selenides. The carbon-carbon double bond is cleaved in the usual manner, and the selenide is also oxidised to the selenoxide. Under reductive work-up conditions (PPh3), the ozonide is cleaved as usual, however excess reducing agent also results in reduction of the selenoxide back to the selenide. The latter reaction is much faster than any competing selen- oxide elimination. Thus the overall transformation is selective cleavage of the carbon-carbon double bond in the presence of the selenide (Scheme 84).12' Asymmetric rhodium( 1)-catalysed hydroformylation of sulfur-containing alkenes can be used to make a variety of sulfur-substituted sulfides (Scheme 85).'26 High enantiomeric excesses can be achieved using the (R,S)-BINAPHOS ligand 12.7 SePh i. O3 (excess), -78 "C, CH2C12 ii. PPh3 (excess), -78 "C+rt I 93% H Scheme 84 + SnCi4 ____c R 1142% SiMe3 d Scheme 86 n 0 * Me+SePh L-;a;Cl, NaH, THF Me V 72%, 96% de Scheme 87 The Pummerer rearrangment of P-amido sulfox- ides leads to the formation of enantiomerically enriched P-lactams containing S , N-acetal function- ality (Scheme 88).75.129 The use of a benzylidene N, S-acetal to protect cysteine through subsequent synthetic manipulations has also been reported (Scheme 89).13' This methodology was used in an enantioselective synthesis of ( + )-biotin. Other new protection reagents for cysteine have also been introduced.13' - 84%, 80% 88 Scheme 88 Rayner: Synthesis of thiols, selenols, suljides, selenides, suvoxides, selenoxides, sulfones and selenones 513**C02H i.BH3*Me2S, THF, 82% ph--< 3 ii. Swem oxidation, 81; S Ph3P(CH2)&02H Br- / + LDA (2 equiv.), THF, rt ii. H~o+/ B o c H N , - * ~ c 0 2 H HS Scheme 89 Conjugate addition of thiols to a,P-unsaturated nitro compounds followed by reduction of the nitro group allows access to /3-amino sulfides in good overall yield (Scheme 90).132 Related compounds can be obtained in an optically active form from the corresponding amino alcohols by methanesulfonate (Scheme 91)1”3 or toluene-p-sulfonate (Scheme 92)’34 formation and thiolate displacement, or using PBu” and a diary1 disulfide on the free alcohol (Scheme 0 SPh i.MeN02, MeNH2*HCI H KzCO3, EtOH ii. PhSH, heat Me0 82% overall Me0 Zn, HCI 1 AcOH 81% SPh Me0 JpNH2 93).’”’ Alternatively, palladium-catalysed arylation of cysteine derivatives can be used to synthesise similar compounds as previously discussed (Scheme 19).48 The preparation of protected lanthionine (the monosulfide analogue of cystine) derivatives, has been achieved by selective ring opening of serine P-lactones by cysteine thiolates (Scheme 94).”‘ Use of Cs2C03 as base is crucial for this reaction as it cleanly gives 0-alkyl fission of the P-lactone ring, whereas other bases investigated led to 0-acyl fission. The preparation of more complex peptides where disulfide bonds have been replaced by thioether linkages have also been reported including an HIV-1 protease analogue which retains its enzymatic activity after modificatior~,~~’ and the cyclic 10 residue peptide CI-oxytocin.l3* Other new methods for the preparation of large cyclic disulfide peptides have also been r e ~ 0 r t e d .I ~ ~ PBu3 A~S/YCO‘~~ NHBoc + THF, pyridinr NHBoc Scheme 93 Scheme 94 Scheme 90 i. MsCI, NEt3 4 A sieves, 8847% JoH CH2C’2’ooC * Ph NHBoc NHBoc ii. EtSH, NaH Ph THF, heat, 100% Scheme 91 L O H i. LiAIH4, THF, heat H2N Aco2H ii. BocpO, Pr‘2NEt, EtOA: B ~ ~ H N Ph i. TsCI, pyridine ii. RSNa 1 L S R LiAlH4, THF, heat MeHN E S R * BocHN R = Me, Ph, Bur co + “ t N H B 0 c 0 OMe 0 CS~CO~, DMF 50-92% I FO2H VHBOC CbzHN A 4 S + ( O M e 0 The nucleophilic ring cleavage of L-homoserine lactone derivatives by selenolate can be used to prepare selenium containing amino acids.Use of the diselenide and NaBH4 to generate the nucleo- philic selenolate anion is crucial to the success of the reaction as alternative sources of selenolate led to significant racemisation (Scheme 95).14’ The coupling of amino esters with thiiranium ions derived from homochiral 2,3-epoxy sulfides under Lewis acid conditions has been reported, and provides a route to novel stereochemically defined sulfur containing amino acid derivatives (Scheme 63)*99.1” I I 7 PhSeSePh PhSe/\ Ph2CHovNHBac O V N H B O C NaBH4.DMF * Ph2CN2 83% 0 0 Scheme 92 Scheme 95 5 14 Contemporary Organic SynthesisNucleophilic ring opening of N-acylaziridines by thiolates can also lead to formation of p-amino sulfides. In the example given (Scheme 96) the product is formed as a single regioisomer, although lower selectivities are observed in other case^.'^' The facial selectivity for the reduction of a-(fluoroalky1)- b-sulfinylenamines using K- or L-Selectride, is controlled by the sulfoxide, and proceeds with high diastereoselectivity.The product can then be converted into a p-amino sulfide by reduction of the sulfoxide under standard conditions (Scheme 97).142 The synthesis of new chiral diselenides derived from a-methylbenzylamine has been reported. ortho- Lithiation, directed by the tertiary amino group, and reaction with selenium, results in diselenide forma- tion, which can be further functionalised to give a variety of new chiral selenides (Scheme 98).87 A related approach has also been adopted for the synthesis of chiral ferrocene-derived diselenides (Scheme 99).85,86.143.144 NaBH4 Meovo CHC13, EtSH, -50 BF3.OEt2 "C+tl ~ MeoYo AcHN SEt Ac 80% Scheme 96 !J2 K-selectride ~ pTol ' CF3 THF pTol' Up t0 75% 93:7 diastereoselectivity TMSCI, Nal MeCN, 0 "C 74% 1 NH2 pTol 0saCF3 Scheme 97 R = Me, Et, (CH& I se6 Scheme 98 Scheme 99 2.4 Thiols, disulfides, selenols, diselenides, sulfides and selenides as mediators of asymmetric transformations There have been a number of reports of the use of organo-sulfur and -selenium compounds for control- ling asymmetric induction in new enantioselective processes.Whilst it is beyond the scope of this review to discuss these processes in any detail, the potential importance of this area warrants a brief discussion of the structural classes of the organo- sulfur and -selenium compounds used, and the types of reaction that have been reported.When their preparation involves new synthetic methodology, this has been included in the relevant section of the review. reagents to aldehydes can be catalysed by a number of sulfur- and selenium-containing moieties. Recent developments include thiols and the related disulfides 13,145 14,146.147 and 15,14' and various amino selenides (Scheme 98)87 and ferrocenyl selenides (Scheme 52)8s986 which have been discussed previously. Asymmetric seleno-etherification and -esterification reactions have received considerable recent attention. This includes the use of C2-sym- metrical pyrrolidine-derived selenides (Scheme 57),93*149 various a-methylbenzyl alcohol derived selenides (Schemes 55, 56 and 58),9',92,9"."0 and ferrocenyl selenides (Scheme 99).143.144*'s1 Such ferro- cenyl selenides have also found application in asymmetric selenoxide elimination ~ h e m i s t r y ' ~ ~ ~ ' " ~ and/or stereoselective [2,3]-sigmatropic rearrangements.152*153 The enantioselective addition of organozinc Ph Ph n 13 F ' h Y Me SH 14 (sri- N Me 15 Some new sulfur containing chiral ligands have found application in palladium-catalysed allylic substitution reaction of allylic acetates, including 16,154 17lSs and the C2-symmetric bis-sulfoxide-Pd" complex 18.156 The asymmetric synthesis of epoxides from carbonyl compounds and sulfur ylides has also been further reported. The chiral sulfides 19,Is7 201s8 and 21,1s9 give low to excellent enantiomeric excess in the product epoxides, with 21 inducing asymmetry in a catalytic asymmetric epoxidation.IhO Other applications include the use of y-hydroxy selenoxides'b1.'62 and [j-hydroxy sulfoxides'63 for the Rayner: Synthesis of thiols, selenols, suljides, selenides, sulfoxides, selenoxides, sulfones and selenones\ rn 0 0 OH 16 II II * PhO*s'czr,s-*Ph NaOCI, TEMPO 23 ph/SM,Sxph KBr, Bu4NCI Scheme 100 19 20 18 21 enantioselective protonation of prochiral enolates, and the use of a novel C3-symmetric sulfur-based chiral stationary phase for the resolution of amino acid derivative^.'^^ 3 Synthesis of sulfoxides and selenoxides 3.1 Oxidation of sulfides and selenides The preparation of sulfoxides and selenoxides by oxidation of the corresponding sulfides and selenides respectively, continues to be an important area of research.This section is divided into three parts. The first is concerned with new methods of oxidation where chirality is not addressed. The second part is concerned with diastereoselective processes, whereas the final part concentrates on new methods for enantioselective oxidation. 3.1.1 Non-stereoselective oxidation New methods for the oxidation of simple sulfides to sulfoxides have been reported. These include methyltrioxorhenium( VI 11) with H202165 (significant amounts of sulfone by-products formed in some cases); the novel palladium catalyst 22 with O2 (1 atm);'66 various Mn"', Fe"', Co" and Ni" complexes with air, O2 or PhIO as re oxidant^;'^' tert- butyl hydroperoxide (TBHP) with silicz + pl;"' 2,2,6,6-tetramethylpiperidin-l-yloxy free 'iadical (TEMPO) 23 and NaOCl (Scheme I2;I7" fluorooxaziridines such as 24; 17' salts between selenoxides and sulfonic acids;*72 and electrolysis in the presence of meso-tetraphenylporphyrinato- manganese(rI1) chloride and 02, which is a model system for electrocatalytic cytochrome P-450 ~xidation.'~' HgO and 22 a 0 23 4 YHg F3cxcF3 HO OOH C3F7 I= 24 25 A review on a-hydroxy hydroperoxides (eg.25) as oxygen transfer reagents in organic synthesis includes a section on sulfur 0xidati0n.I~~ Mechanistic studies on sulfur oxidation using transition metal peroxide c~mplexes,"~ per acid^,'^^ 102,177 (methyl- trifluorornethyl)dio~irane,'~~ O2 with N02,179 and MOO~*HMPT'*' have also been reported. A comparative study on the oxidation of thianthrene derivatives with chromyl chloride ( Cr02C12), benzyl- triethylammonium permanganate and ruthenium tetraoxide, has been published,'*' as has a study on the oxidation of S, S-acetals using varying equiva- lents of dimethyldioxirane (DMDO).IH2 Little sulfone product is observed until > 2 equiv.of DMDO are used. Thioether-containing chromium carbene complexes undergo chemoselective oxida- tion to the sulfoxide using oxaziridines (Scheme 101).'83 An interesting new method for the oxidation of cysteine derivatives uses diphenyl sulfoxide as stoichiometric oxidant in the presence of a rhenium catalyst (Scheme 102).1"4 Excellent yields are obtained, with no overoxidation to the corre- sponding sulfone. Finally, a simple and efficient preparation of 3-aryl-3-trifluoromethyl-3H-diazirinyl sulfoxides relies on Bu'OC1 oxidation of an aryl sulfide with concomitant oxidation of the diaziridine to the diazirine (Scheme 103).'*' 0 i.BuLi. THF. -78 "C ( c o ) 5 c r q ii. PhSSPh, -20 "Cc (C0)5Cr<Sph Me 56% do& Ph I Ts' 1 CH2CI2,O"C 70% Scheme 101 516 Contemporary Organic SynthesisScheme 102 HN-NH N =N \ / S - M ~ 4 equiv., n = 2, 0348% ,?-Me Scheme 103 3.1.2 Stereoselective oxidation There have been a limited number of studies on the diastereoselective oxidation of sulfides to sulfoxides. Oxidation of a P-hydroq sulfide using VO( acac)' with TBHP as stoichiometric oxidant provides moderate stereoselectivity for sulfoxide formation (Scheme 60)96 whereas camphor-derived sulfides, oxidised using MCPBA, give high diastereoselec- tivity when the reaction is carried out at -78 "C (Scheme 104).'8" The oxidation of bis-phenylthioalk- anes with TEMPO and NaOCl (Scheme 100) proceeds to give the meso-disulfoxide with 90-98% distereosele~tivityl~~ although the actual cause of this stereoselectivity is unclear at present.&sR Me MCPBA CH2C12, -78 "C 1 1 : 1 diastereoselectivity 96% '4 i. Buli, THF, -78 "C ii. PhC02Me 74% Conditions THF, -78 "C I 26 27 DIBAL 3: 97 Scheme 104 3.1.3 Enantioselective oxidation The enantioselective oxidation of sulfides to sulfox- ides continues to be a popular and important area of organosulfur chemistry, and has been included in a recent review.lR7 The reagent (S)-a-methoxy- phenylacetic acid 28 has been introduced as a new chiral NMR shift reagent for the determination of the enantiomeric excess of sulfoxides.lR8 HO L P h OMe Me02C, Me *fie OOH 30 There are four main methods used for asymmetric sulfur oxidation. These are systems based on modified Sharpless asymmetric epoxida- tion conditions, further developed by Kagan and Modena; other metal catalysed oxidations such as the (salen)manganese( 111) complexes of Jacobsen and Katsuki; oxaziridines developed by Davis; and enzymatic procedures. These are now well estab- lished and have been discussed in previous reviews of this series.',' However significant improvements and applications will be included here. Optimised conditions for the enantioselective oxidation of alkyl aryl sulfides developed by Kagan have been reported.'*' The catalyst system is prepared from Ti(OPr'),, diethyl tartrate and water in the ratio 1 : 2: 1 , with cumene hydroperoxide (CHP) as the stoichiometric oxidant at -20 "C in CH2C12.More recently, the fury1 hydroperoxide 29 has been introduced as an alternative to more usual hydroperoxides (CHP, TBHP) for use in the titanium catalysed oxidation procedures and can give excellent enantioselectivity for sulfur oxidation (74-91% ee)."' The kinetic resolution of racemic sulfoxides using a modified Sharpless procedure has been reported, one enantiomer being oxidised to the sulfone, the slower reacting enantiomer remaining with poor to excellent enantiomeric excess (Scheme 105). Full details on the catalytic oxidation of sulfides using the (salen)manganese( 111) complex 30 and Scheme 105 Ruyner: Synthesis of thiols, selenols, suljides, selenides, suvoxides, selenoxides, sulfones and selenones 517iodosobenzene have been reported.Low to excellent enantiomeric excesses can be obtained for the oxidation of aryl alkyl thioether~.'~~ Related p-0x0 aldiminato manganese( III) complexes have also recently been reported, which are capable of asymmetric sulfur oxidation with O2 (1 atrn) as stoichiometric oxidant in the presence of pivalalde- hyde (Scheme 106).193.'93 pJs.Me X (CCH3)3CCH0, O2 (1 atm), rt c P 4693% 6 7 2 % ee Scheme 106 Recent developments on the use of oxaziridines and related compounds have led to catalytic asymmetric processes where the effective oxidising agent is generated in situ from an N-sulfonylimine and hydrogen peroxide.Interestingly, when the (3,3-dimethoxycamphorylsulfonyl)oxaziridine 31 or the corresponding imine precursor is used in the oxidation reaction, the same enantiopreference is observed. However, for the simple (camphoryl- su1fonyl)oxaziridine 32, opposite enantioselect ion is observed depending on whether the oxaziridine is used stoichiometrically, or the imine is used catalyticaIIy with hydrogen peroxide reoxidant (Scheme 107).195 This suggests that in the case of 32, 0 H202, DBU 0 I I R/S. 'Me 32-98% ee CH&I2, rt 4 Me 31 R = OMe 32R=H Scheme 107 PhSAr I I RHS'Me i. 4-cyanopyridine, (-)-menthol chlorobenzotriazole. DMF. -30 "C different active oxidants are operating in each case, either the parent oxaziridine, or an a-hydroperox- yamine generated in situ from hydrogen peroxide and the i r n i ~ ~ e .' ~ ~ Mechanistic studies on oxaziridine oxidations of sulfides have also been p~bIished.'~' A somewhat different approach to asymmetric chemical oxidation of sulfides has been applied to the synthesis of the xanthine dehydrogenase inhibitor (S)-( -)-BOF-4272 (Scheme 108). The process relies on the reaction of the required sulfide precursor with menthol and chlorobenzotriazole to give two diastereomeric sulfoxonium salts, one of which crystallises with high diastereomeric purity as the nitrate salt, the other remaining in solution. Subsequent conversion of the individual salts into the sulfoxide, either by hydrolysis (inversion of configuration) or thermolysis (retention of configuration) leads to the same desired sulfoxide whose enantiomeric purity can be further enriched by recrystallisation if There has been significant progress on the biochemical asymmetric oxidation of sulfides. The whole cell oxidation of aryl alkyl sulfides using Acinetobacter sp.NCIMB 9871 is only slightly less enantioselective than if the purified cyclohexanone monooxygenase (CMO) from the same species is similar substrates but with mostly opposite enantio- selectivity. CMO can also be used to oxidise benzyl alkyl sulfides with up to 96% ee,200*201 and dithio- acetals to form the mono S-oxide ( > 98% ee) along with a small amount of sulfone (8%).2"2 The fungus Heiminthospoiiiim sp. 4671 has been used to oxidise a wide variety of para-disubstituted benzyl methyl sulfides, including trifluoromethyl, halo, hydroxy, methoxy, acetoxy, nitro, cyano, amino, acetamido, acyl and carboxylic acid substituents with 52-98% ee*2"? The same species, along with Mortierella isabel- Zina ATCC 42613, has also been used to oxidise isothiocyanato sulfides and related compounds in approaches to the synthesis of ( -)-sulforaphane 33.Note this paper also corrects previous erroneous stereochemical assignments.'" The use of baker's yeast Saccharomyes cereiisiae NCYC73 for the oxidation of methyl aryl sulfides has been reported. The reaction involves the use of whole cells and Pseiidornonas sp. NCIMB 9872 oxidises Phc s- AF !. crystalline 1 + KOH, H20, DMF INVERSION I heat, 5 0 4 0 "C, 2 h Pk-4'- -Ar !m remzins in mother liquor 30%, ca. 40% 80 RETENTION - f - l Ph--S--Ar (S)-(-)-BOF-4272 Scheme 108 5 18 Contemporay Organic Synthesisgives the product sulfoxide in good yield and with high stereosele~tivity.~"~~~~ Toluene and naphtha- lene deoxygenases have been shown to oxidise alkyl aryl sulfides to give mainly the (S)-sulfoxide with high enantioselectivity.2"X Chloroperoxidases have also been investigated,2"Y*210 and can give mainly the (R)-sulfoxide (>98% ee) for the oxidation of aryl alkyl sulfides,208 and have also be used to prepare more complex aromatic cyclic sulfoxides of up to 99% ee.*'" Finally, in a rather different approach, the enantioselective reduction of racemic methyl phenyl sulfoxide by dimethyl sulfoxide reductase from Rhodobacter sphaeroides f.s.denitrificans leads to predominantly the (R)-sulfoxide by preferential reduction of the (S)-enantiomer to thioani~ole.~~ 3.2 Non-oxidative sulfoxide and selenoxide synthesis 3.2.1 General methods for sulfoxide and selenoxide synthesis A review on recent advances in asymmetric synthesis using organochalcogen compounds includes sections on the synthesis and utility of chiral sulfoxides and ~elenoxides."~ A review on the synthesis of sulfoxide-based ferrocenes using chiral sulfites, sulfinates and by asymmetric oxidation, has also been published.2" Studies on the stereo- chemistry of a-sulfinyl carbanions have also been An improved synthesis of methyl benzenesulfinate has been reported (Scheme 109).*13 The product reacts with various kinds of carbonyl compounds under basic conditions to produce P-carbonyl sulfox- ides in good yield.0 0 >90% Ph03'\0 Scheme 109 The reaction of resolved sulfinate esters (or their equivalents) with nucleophiles continues to be an important approach for the synthesis of optically active sulfoxides. Methods for large scale syntheses of both enantiomers of methyl p-tolyl sulfoxide from diacetone-D-glucose are significant improvements on procedures reported previously (Scheme 110).132 The required diastereomerically pure methanesulfinate or toluene-p-sulfinate ester precursors are readily prepared from diacetone-D-glucose and the appro- priate sulfinyl Menthyl sulfinate esters continue to be useful precursors for the synthesis of optically active s ~ l f o x i d e s . ~ ~ ~ - ~ ~ ~ Resolved sulfina- R = pT01 PTol\S,Me i. MeMgI ii. TFA, MeCN, H20 0 6 80% R = M e i.pTolMgBr ii. TFA, MeCN, H20 I 80% Me. ,pTol f 0 Scheme 110 i. MeMgI, 0 'C F.l O i ? S. dyNswpToi ii. Na2HP04 * Me0 'pTol R 9597% ee Scheme 111 CBH~~OH, TFA toluene, 0 "C 72%, >95% ee Ar -OCsHI Scheme 112 Scheme 113 mides can also be used in a conceptually similar approach (Scheme 111),219 and can also be used to synthesise new chiral sulfinate esters which in turn can provide access to optically active sulfoxides (Scheme 1 12).220 Camphor derived cyclic sulfinates react with organometallic reagents to give 10-isobornyl sulfoxides (Scheme 113).22' Finally, the use of sulfonic acid salts for the characterisation of selenoxides, including X-ray crystallography, have been reported, and overcome a number of problems associated with the instability of ~elenoxides."~ Recent FT-IR studies of related complexes between sulfoxides and sulfonic acids have also been reported.222 Rayner: Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones 519r Na 1 i.LDA, THF n P N 3.2.2 Functionalised sulfoxides The condensation between an a-metallo sulfoxide and a carboxylic acid derivative is one of the main methods for the preparation of P-keto sulfoxides. Recently N-acylimidazoles have been shown to be superior to a variety of carboxylic acid derivatives for this kind of reaction (Scheme 114 cf. Scheme 104).223 Other more complex carboxylic acid deriva- tives such as or-chloro-a-fluoroethyl acetate can also be rearrangement of a chloro alkoxide produced from the reaction between a ketone and the anion of an a-chlorosulfoxide (Scheme 115).225.22h Note that there is effectively a one carbon homologation of the ketone and, in the case of aryl alkyl ketones, the carbon is inserted between the carbonyl group and the aromatic ring.An alternative approach relies on the 0 ' \o DIBAL PTOI" pTol@' 9a%, sayo de DIBAL, ZnC12 I i. MeLi (2 equiv.),THF, -78 "C 1 ii. FIX, -78 "C-xt OH pTol ' 9a%, sayo de R 60-8570 Scheme 114 r n i 0 i. LDA, THF, I 0 to- I It HMPA. -78+30 "C Ph'svc' ii. [CHs(CH2)&0 Ph' Scheme 115 (Et02C)2CHBr R pTol NaH, THF, 0 "C t 45% 67% diastereoselectivity 0 0 R*I C02Et C02Et Scheme 116 The reduction of P-keto sulfoxides using DIBAL or DIBAL-ZnC12 is a well established method for the synthesis of diastereomerically pure P-hydroxy sulfoxides, the two reagent systems giving comple- mentary stereoselectivity. This methodology has been used for the synthesis of a variety of types of compound including or-unsubstituted aldol adducts (Scheme 114);223 (-)-(lR, 3R,5S)-endo-1,3-di- methyl-2,9-dioxabicyclo[3.3.3 Jnonane 34, an insect pheromone;229 the lactonic acid moiety 35 of ( + )-compactin and ( + )-mevinolin;"" the spiroketal (2R,5 S , 7R)-2,7-dimet hyl- 1,6-dioxaspir0[4.4]nonane 36;23' allylic alcohols;232 1,2-di01s;~~~ and or-substituted P-hydroxy ~ulfoxides.~~~ Similar methodology has also been adapted for use with P-keto sulfoxides derived from camphor (Scheme 104) achieving equally high stereocontro1.'X6 The addition of diazo- methane to P-keto sulfoxides has also been investi- gated, and proceeds with modest diastereoselectivity to give 2,3-epoxy sulfoxides (Scheme 117)."j 34 36 pTol S T O H 8 0 CH2N2 MeOH or Et20 I 4w3% 1 : 2.3 (MeOH) 1 : 2.9 (Et20) Scheme 117 The synthesis of optically active acyl(sulfiny1)- cyclopropane derivatives by addition of bromo- malonate to a-acyl vinylic sulfoxides proceeds with moderate stereoselectivity and yield.The stereo- chemical outcome can be rationalised by steric interaction between the p-tolyl group of the sulfoxide and the electrophilic tetrasubstituted carbon atom (Scheme 1 16).2279228 The other main method for the preparation of P-hydroxy sulfoxides is by addition of an a-lithio sulfoxide to a carbonyl compound. This kind of reaction has been used as one of the main coupling reactions in an approach to the synthesis of ampho- tericin B (Scheme 118) although problems of stereo- 520 Contemporaly Organic Synthesism Brio O K 0 OH i.PhSSPh, PBu3, DMF ii. MMPP, EtOH, HzO 1 i. LDA, THF, -78 "C :."rri, 66% O K 0 Scheme 118 control during C-C bond formation are not addressed.236 The addition of x-lithio sulfoxides to fluoroalkyl vinylogous esters occurs with excellent regioselectivity (exclusive 1,2-addition), but poor diastereoselectivity (Scheme 119).237 Usc of non- fluorinated carbonyl compounds gives more complex results. An alternative route to B-Auoroalkyl sulfox- ides is by conjugate addition of an ester enolate to /{-trifluoromethyl-@,/?-unsaturated sulfoxides (Scheme 120).'" High regio- and stereo-selectivity are observed in this case. Scheme 11 9 Scheme 120 Further functionalisation of 11-hydroxy sulfoxides by dianion formation and alkylation is also possible although poor stereocontrol is generally observed (Scheme 1 14).L23 Better stereoselectivity can be obtained for the allylation or deuteriation of /hhydroxy-a-sulfinyl radicals generated using azoiso- butyronitrile (AIBN) on the corresponding selenide (Scheme 121).210 The choice of protecting group plays a crucial role in the stereoselectivity of the reaction.With the free alcohol, the syn product predominates, whereas for the TBDMS-protected alcohol, high nnti selectivity is observed. Bu3SnD, AlBN CeH8,lO "C SYn anti R = H, 97%, 64:36 syn:anfi R = TBDMS, 51%, 10:90 syn:anfi Scheme 121 Relatively few new routes to [hmino sulfoxides have been reported.The addition of a-lithio methyl phcnyl sulfoxide to oxaziridines provides a route to [i-hydroxyamino sulfoxides in good yield and with moderate diastcreocontrol (Scheme 122).24" The reduction of cr-(fluoroalky1)-B-sulfinylenamines with K- or L-Selectride(") proceeds with high diastereo- selectivity (Scheme 97).14' In the enantioselective synthesis of the tetrahydroisoquinoline (R)-( + )- carncgine, the acid catalysed cyclisation of a [1-amino-H,p-unsaturated sulfoxide onto an indole proceeds to give a single diastereomeric product in good overall yield (Scheme 123).24' ? Me/ *P h it LDA, THF, -78 "C ii.ph, 0 03% 67:33 diastereoselectivity Scheme 122 M e o d N > ' w A r 0 e N Ar = O"02-C6H4 Me0 A r 4 ? ll Me0 0 TFA, CHC13.0 "C 65% Me0 Me0 (@-(+)-carnegine Scheme 123 3.2.3 Unsaturated sulfoxides and selenoxides The elimination of watcr from a b-hydroxy sulfoxide is one of the main methods !;;7ihe synthesis of a, P-unsaturated suIfoxidesoh.-'..-. and can also allow access to dienyl sulfoxides (Scheme 124).234."2 If a homochiral P-hydroxy sulfide is used as starting Rayrzer: Synthesis of ttziol.s, selenols, sidjides, selenides, suljbxides, seknoxides, sulforzes and selenones 52 1i.MeI, NaH, THF, 65% * H P ' \ p T o I ii. CuSO4. Me2C0, 1OOoh OMe 0 1 i. BULL THF, -78 "C ii. RCHO conditions: 1 V 7 % BuLi, THF, 5% ee Mainly €-isomer DBU, UCI, MeCN, >98% ee I 0 I 40-70% 9 X \pTol Scheme 124 material, the alcohol moiety can be used to control the absolute stereochemistry at sulfur in a diastereo- selective thioether oxidation to give an intermediate P-hydroxy sulfoxide.Subsequent dehydration then gives an optically active a, P-unsaturated sulfoxide (Scheme 60).9h Alternatively, the P-hydroxy sulfoxide precursors are commonly obtained by reduction of the corresponding P-keto sulfoxides (e.g. Schemes 104 and 114).'"6,22' Full details of eliminative routes to y-hydroxy-a,P-unsaturated sulfoxides from 2,3-epoxy sulfoxides and 2,3-dihydroxy sulfoxides have been p~blished.~~' Such compounds can also be accessed by baker's yeast reduction of a y-keto- a, @-unsaturated sulfoxide although yields are low (19%) and stereoselectivities only moderate (64% de, >55% ee);"' or alternatively condensation of an aldehyde with a dithioacetal bis-S-oxide. In the latter synthesis, dehydration occurs followed by a double bond migration to allow a subsequent Evans-Mislow rearrangement, which in the presence of a thiophile gives the y-hydroxy- a, P-unsaturated sulfoxide as a mixture of diastereo- isomers (Scheme 125).245 The condensation of an 3-chloro sulfoxide anion with a carbonyl compound followed by dehydration leads to formation of 1-chlorovinyl sulfoxides (Scheme 126).246 The OH P-Tol, s=o R'R~CHCHO (s.o piperidine. MeCN 4 1-10d 8 pTol 50-96% R ~ = H PCC.NaOAc CHpCI2 0 I 68-8770 0 Scheme 125 kc' i. LDA, THF, -78 "C ? ii. R2CO. 97% p ~ o l N s V c ' iii. AQO. pyridine. DMAP. 94%- S-pTo' iv. NaH, DBU, THF, 83% d' R = (CH2)14 chemoselective oxidation of vinyl sulfides using perfluorooxaziridines also provides a route to a,P-unsaturated sulfoxide~.'~' The Horner- Wadsworth-Emmons reaction and related procedures, have been widely used for a,P-unsaturated sulfoxide synthesis by condensation of a sulfinyl phosphonate with an aldehyde (Scheme 127).247,24R This can allow access to both E- and Z-alkenes (Scheme 31)."' In some cases, sulfoxide racemisation can occur2423247 however changing the base and/or substrate can in many cases alleviate such problems.f/ i. conditions s / t t N ~ - P(0Me)2 ii. MeO2CCHO * p ~ o l w ~ 0 pTol S\pTol N R' Scheme 127 Sulfinyl phosphonates can be used to prepare a,P-unsaturated sulfoxides and selenoxides by an alternative route (Scheme 33).64 Treatment with base followed by reaction with PhSeBr introduces a phenylseleno substituent to give the key synthetic intermediate. Subsequent oxidation of the selenide and selenoxide elimination leads to formation of an unsaturated sulfinyl phosphonate, or alternatively, sulfoxide elimination by thermolysis gives the corre- sponding unsaturated selenide which can be oxidised to analogous phosphoryl selenoxide.Similar procedures involving mixed S , Se-acetals have also been used to prepare camphor-derived a,P-unsaturated sulfoxides (Scheme 128).249 0 90438% R = H, neopentyl MCPBA I -7hO "C i. LDA, THF, -78 "C ii. PhSeBr I 8142% Scheme 126 Scheme 128 522 Contemporary Organic SynthesisThe synthesis of cx-methylene-P-hydroxy sulfoxides has been reported by regioselective photooxidation (Schenck reaction) of racemic vinyl sulfoxides (Scheme 129).250 The intermediate hydroperoxide can be isolated, or is readily reduced using tri- phenylphosphine.The use of chiral sulfoxides as stereocontrolling elements in SN2' reactions has also been reported. This methodology has been applied to a formal synthesis of brassinolide (Scheme 130) .25 ' Scheme 129 Me 1 1 -.-- i. Ms20, pyridine, 0 "C, 84% *-.- * St ii. MeCuCNLi, THF, 76% St " I I I St = Scheme 130 100% de @ OMe The palladium-mediated cross-coupling of vinyl stannanes with halovinyl sulfoxides has been exploited in the synthesis of a wide variety of 2-sulfinyl-substituted butadienes (Scheme 131).2'2 Similar methodology has also been used to access related systems (Scheme 132), however these undergo Diels-Alder dimerisation under the reaction conditions to give cycloadducts with remarkably high diastereoselection.25' The preparation of (phenylsulfiny1)phenols from arenesulfinates using a 'thia-Fries' rearrangment has been reported (Scheme 133)."4 An interesting enzyme-mediated kinetic resolution of the related methyl arenesulfinates by hydrolysis of pendant acetoxy groups provides access to these types of compounds in an optically active form (Scheme 134).'j5 A number of enzymes were investigated for this transformation, with cholesterol esterase (CE) giving the best results.Alternative routes to optic- ally active diary1 sulfoxides have been reported which rely on the use of menthyl toluene-p-sulfinate &SnBu3 Pd2(dba)3-CHC13 BHT, DMF. heat 1 81% f Scheme 131 pSnBu3 Pd(PPh3)4 * [ q : N - E I toluene, heat 0- 0- 0 Et/ sole product .Et Scheme 132 OH f ! o's, Ph OH 0 PhSOCl ~ R 87-92% ) / 7240% R R AIC13 ~ bsXph / / pyridine, THF CH2C12,25 "C Scheme 133 OAc f +&s*sy OH f &'\Me Me cholesterol esterase 50% conversion 62% ee 66% ee Scheme 134 to control the absolute stereochemistry of the sulfoxide.This allows access to quinol and quinone derivatives (Scheme 135),II6 and 2- or 3-sulfinyl- furans (Scheme 136).2'7 The use of unsaturated sulfoxides as dienophiles, dienes and dipolarophiles in cycloadditions has continued to be an important area of research, and the use of the (2-exo-hydroxy-10-borny1)sulfinyl Rayner: Synthesis of thiols, selenols, su@des, selenides, sulfoxides, selenoxides, sulfones and selenones 523?Me 9 ?Me 70% 1 OMe 1 OMe Ago, HN03 dioxane, rt 81 YO 0 Scheme 135 '2 i.Buli,THF ii. MgBr2.0Et2, Et20 iii. (-)-(SJ-menthyl-gtoluene sulfinate 6 86% Scheme 136 group and derivatives in Diels-Alder reactions and applications in natural product synthesis has been reviewed.256 Whilst it is beyond the scope of this review to give a detailed account of this area of chemistry, a brief discussion of the kinds of systems which have been investigated will be included.Syntheses of many of these compounds have been reported previously; any important new synthetic routes have been discussed above. The 1,3-dipolar cycloaddition of 2 - a , p-unsatu- rated sulfoxide 37 and a nitrone has been used in a synthesis of ( + )-~edridine."~ The acetylenic sulfoxide 38 has also been used in a 1,3-dipolar cycloaddition with a n i t r ~ n e . ~ ~ ~ Acetylenic sulfinates 39 have also been investigated as dienophile~.~~' The asymmetric Diels-Alder reactions of more complex a-sulfinyl acrylates including 40,*15 and related 37 (+)-sedridine 38 0 39 40 0 0 41 42 camphor derived systems (Scheme 128)24y have also been reported.The 3-(p-tolylsulfinyl)furan-2-carbal- dehyde 41 has been used as a hetero-Diels-Alder d i e n ~ p h i l e , ~ ~ ' ~ ~ ~ ~ whereas the allenic trichloromethyl sulfoxide 42 undergoes conventional [4 + 21 cyclo- addition with cyclopentadiene to give predominantly endo cycloadducts.261 Various quinone derived sulfoxides have also been used as dienophiles (e.g. 43262 and Scheme 135).216q26' Further studies on the use of 1- and 2-sulfinyl- 1,3-dienes in cycloadditions have been reported (Schemes 124, 131 and 132).24292523253-264 More recently, the use of 3-vinylsulfinylindoles as 4n components in Diels-Alder reactions has been reported (Scheme 127).248 4 Synthesis of sulfones and selenones Although this section is supposed to include methods for the synthesis of selenones as well as sulfones, very little literature has been published on them, and they have found only limited synthetic utility and so will not be discussed in any detail here.4.1 Oxidation of sulfides and sulfoxides The use of tert-butyl hydroperoxide (TBHP) in the presence of Si02 or A1203 after prolonged reaction times will efficiently oxidise alkyl and aryl sulfides to the corresponding sulfones.168 Dimethyldioxirane (DMDO) has also been used for sulfone formation in cephalosp~rins,~~~ ketene S, S-acetals,IX2 and thioether-containing chromium carbene complexes ( c j Scheme 101).2"6 Related mechanistic studies have also appeared.17"'7x The oxidation of vinyl sulfides using MCPBA or perfluoroxaziridines provides a route to vinyl sulfone~.'~~ A review of r-hydroxy hydroperoxides (e.g 25) as oxygen transfer reagents in organic synthesis includes a section on sulfone formation.174 Electron deficient sulfides can be oxidised to sulfones using HOFOM~CN.'~~ 4.2 Non-oxidative sulfone synthesis 4.2.1 General methods for sulfone synthesis A novel approach to sugar-derived sulfones utilises the benzothiazol-2-yl (Btz) group, which on treat- ment with sodium methoxide liberates a sulfinate anion, which can then react with electrophiles to give the desired products (Scheme 137).268 The Btz Scheme 137 i.MeONa, MeOH ii. RX 3748% 0 2 524 Contemporary Organic Synthesisgroup is originally introduced onto the sugar moiety by Mitsunobu reaction of the sugar alcohol and benzothiazole-2-thiol followed by oxidation. The copper-assisted displacement reaction of non- activated iodoarenes with arenesulfinates provides a convenient synthetic route to unsymmetrical diary1 sulfones (Scheme 138).269 Low yields are obtained with the corresponding bromoarenes although the use of copper( 1 1 ) bis(4-methylbenzenesulfinate) catalyst led to considerably improved yields in some cases. The asymmetric palladium-catalysed sulfonyl- ation of s(,y-disubstituted allylic acetates has been investigated with a wide variety of chiral phosphine ligands. It was found that although moderate levels of asymmetric induction were observed with most of the ligands investigated, (S)-( - )-2,2'-bis(diphenyl- phosphin0)-1,l-binaphthyl [ (S)-BINAP 441 gave highest selectivity for cy, 1'-diphenyl allylic acetates, whereas (S)-N, N-dimethyl-1-[ (R)-l',2-bis(diphenyl- p hosp hino)ferrocenyl]e thylamine [ (S)-( R)-BPPFA 451 was superior for r-methyl-yphenyl allylic acetates (Scheme 139).27') Cur.DMF, heat 46-94% Arl + Ar'S02Na * ArS02Ar' Scheme 138 R1- R2 PhS02Na, [PdCl(r-allyl)12 * R1* R2 I OAc q PPh2 ligand 14-68% I S02Ph R1 = R2 = Ph, ligand = (S)-BINAP, 98% ee R' = Ph, R2 = Me, ligand = (S)-(R)-BPPFA, 44% ee soPPh2 (S)-BINAP 44 (9-( R)-BPPFA 45 Scheme 139 4.2.2 Functionalised sulfones PhS02CH2CN Ph2Bu'sio&~ ADDP, PMe3- Ph2ButSi0 imidazole, 40 "C 82% I S02Ph Scheme 140 p ! ! 0 2 P l ] -S02Ph BuLi (2.2.equiv.) THF. TMEDA, -78 "C c'-cI 0 oc+rt, 75% I Scheme 141 of oxiranes by sodium sulfinate resulting in the synthesis of (3-hydroxy sulfones in good yield (Scheme 142).84 An alternative well-established method for the preparation of p-hydroxy sulfones is by condensation of an a-sulfonyl anion with a carbonyl compound. For example, o-bromophenyl methyl sulfone can be lithiated and undergoes clean 1,2-addition to cx, P-unsaturated aldehydes (Scheme 143).'73 The alkoxide intermediate is benzoylated and the product can then undergo radical cyclisation to give a benzo-fused seven-membered ring sulfone. The anion derived from [(methoxymethyl)sulfonyl]- benzene has also been reported to add to ketones (Scheme 144).274 The use of a Schwesinger phospha- Scheme 142 Me,S ii.slHo +Bin * OBz O2 iii. PhCOCl 72% 0 2 I The Mitsunobu reaction of alcohols with phenyl- sulfonylacetonitrile, using trimethylphosphine and 1,1'-( azodicarbony1)dipiperidine (ADDP) provides a versatile method for preparing functionalised sulfones (Scheme 140)."' With unreactive alcohol substrates, the reaction can be carried out at 40 "C in the presence of imidazole to improve yields. The reaction of cx, r-dilithiated ally1 phenyl sulfone with E-1,4-dichlorobut-2-ene gives divinyl-substituted cyclopropyl sulfones with a high degree of stereo- Scheme 143 * ,YH control (Scheme 141).272 On thermolysis, the products undergo Cope rearrangment to form cyclo- heptadienyl sulfones. 6442% Me0 S02Ph catalyse the regioselective nucleophilic ring opening i.BuLi. THF, -78 "C ii. R'R*CO MeOnS02Ph Poly(ethy1ene glycol) (PEG) is reported to Scheme 143 Bu3SnH 1 AlBN 58% I Rayner: Synthesis of thiols, selenols, su@des, selenides, suljioxides, selenoxides, suljiones and selenones 525zene base (Bu'P,) with Me3SiC1 quench gives signifi- cantly higher diastereoselectivity than other bases for the addition of a-sulfonyl anions to isopropyl- ideneglyceraldehyde (Scheme 145).275 This is rationalised by Bu'P, being a strong cation free base, which results in the formation of a 'naked' a-sulfonyl carbanion that adds to carbonyl groups with enhanced stereoselectivity. An alternative diastereoselective approach to P-hydroxy sulfones relies on the threo-selective reduction of P-keto sulfones using NaBH,-CeCl, (Scheme 146).276 The precursor is prepared by oxidation of a diastereo- meric mixture of P-hydroxy sulfones resulting from non-stereoselective addition of an a-sulfonyl anion to an aldehyde.Other related non-stereoselective processes have been reported,277 including the reaction of the dianion of a /?-amino sulfone, which adds to aldehydes to give a 1 : 1 mixture of diastereomeric P-hydroxy sulfones (Scheme 147) .278 Immobilised Candida antarctica lipase (Novozyme 435) will catalyse the stereoselective esterification (vinyl acetate) of a P-hydroxy sulfone, or the hydro- lysis of the corresponding racemic acetate with up to 99% enantiomeric excess in the products (Scheme 148).279 It has also been reported that enzymatic reduction of y-methyl-@-keto sulfones using Candida R, f i i.Burp4 S Ph 0 2 O2 OH iii. Me3SiCl 8349% diastereoselectivity 95-1 00% Scheme 145 i. PDC, 4 A sieves, CHpClp ii. NaBH4, CeCl3, MeOH 63-89% i. BuLi, TsCI, THF ii. NaOEt, EtOH 5 146% OTBDMS up to 1O:l z : E Scheme 146 Ph, I\ 4-(MeO)C6H4CH2NH2 Ph,S/\/NHPMB s \ c 0 2 TFA (cat.), THF 0 2 i. BuLi (2 equiv.), ii. RCHO THF, -78 "C I 6 1 -92% Ph ,S&NHPMB 0 2 Scheme 147 R R = Me, Bn Candida anfarctica lipase (Novozyme 435) I P O A c Scheme 148 i. BuLi. THF ii. BF3*0Et2, Scheme 149 zeylanoides or a variety of other enzymes can give excellent enantioselectivity. However conversions are generally low and limit the synthetic utility.Z8o carried out by reaction of an a-sulfonyl anion with an epoxide. This has been exploited in the synthesis of complex natural products, including key steps in the synthesis of ( + )-bullatacin,28' and ( + ) -tauto- mycin (Scheme 149); note that in the latter case the reaction is catalysed by the addition of BF3*OEt2.282 Another impressive example is the reaction between an ally1 sulfonyl anion and a diepoxide which gives a single product in excellent overall yield (Scheme 150).28' A rather different approach to yhydroxy The synthesis of 11-hydroxy sulfones is usually 526 Contemporary Organic Synthesissulfones is the stereoselective radical addition to 3-hydroxy- 1 -( methylt hio)- 1 -(p-tolylsu1fonyl)alk- 1 -enes.Excellent yields and high stereoselectivity ( > 95 : 5 ) are observed (Scheme 151).IS4 tion of the corresponding sulfide using MCPBA or oxaziridines have been r~ported.'~'~**~ Phenyl- sulfonylethene can also be prepared from thiophenol and 2-chloroethanol and oxidation;2xs and p-tolylsulfonylethene, from sodium toluene- p-sulfinate and 1 -bromo-2-chloroethane.The p-tolyl- sulfonylethene can subsequently be converted to E-l,2-bis(p-tolylsulfonyl)ethene by addition of HO--& toluene-p-sulfonyl iodide and dehydroiodination (Scheme 153)."' Similar reactions have also been reported for other electron deficient alkenes (Scheme 29)," and simple terminal alkenes (Scheme OBn P i. BuLi. THF. -78 "C -S02Ph ii. o, 0 W O B n (0.5 equiv. relative to sulfone) 95% (based on epoxide) so2 Ph' Scheme 150 154) .290 OH SMe OH i. Pr'OH, hv, Ph2C0, 97% R d s , p T o l ii. RdNi (W2), EtOH. 7 i ' ~ R ~ S - P T 0 ' 0 2 : 0 2 /T\ OH Scheme 151 There has been relatively little published on the synthesis of amino sulfones.The conjugate addition of an amine to a vinyl sulfone provides a route to {;-amino sulfones (Scheme 147).17* These can then be further functionalised by dianion formation and alkylation x-to the sulfone group. In an approach to the synthesis of /$-branched rx-amino acids, the addition of a chiral bis-lactim ether glycine synthon to an x,{&unsaturated sulfonc proceeds with high stereoselectivity (Scheme 152).2*5 OEt PhS02 ) Ph I Li I Et20, THF -70 "C 74% 9O:lO stereoselectivity Scheme 153 71% Scheme 154 The use of x-sulfonyl phosphonates for the synthesis of a wide variety of x,/hnsaturated sulfones has been reported (Scheme 155).2y' Intro- duction of the phosphonate group improves stereo- selectivity in the double bond formation.A variety of se I en i um - and s u 1 fur -su bs t i t u t e d 2, /j- unsaturated sulfones have been synthesised from 1 -(phenyl- seleno)-2-(p-tolylsuIfonyl)ethyne 3, a novel acetylenic sulfone that undergoes both normal and anti-Michael nucleophilic additions (Scheme 30).'(' Generally good to excellent control of double bond geometry is possible. Scheme 152 4.2.3 Unsaturated sulfones A review of new synthetic methods exploiting x,/j-unsaturated sulfones during the synthesis of a natural product has been published.2sh An inexpen- sive procedure for the preparation of Z- 1,2-bis- (phenylsu1fonyl)ethene and phenylsulfonylethene from 1,l -dichloroethene and thiophenol has been reported (Scheme 23).53 The initial 1,2-bis-thioether product is oxidised to the bis-sulfone which can be selectively monodesulfonylated using Bu7SnH.Other routes to x,{hnsaturated sulfones by oxida- Scheme 155 Br i. PhS02Na, DMSO ii. LDA, THF, (Et0)2POCI S02Ph I i. BuLi, THF, MeCHO ii. PhCOCl iii. B U ~ K , THF 1 S02Ph -7J Rayner: Synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones 527Recently, the isolation of stable episulfones has led to increased interest in their synthetic potential. The base-mediated ring opening of episulfones leads to the formation of alkenylsulfinates which can undergo in situ alkylation leading to sulfone forma- tion (Scheme High E-selectivity is observed, and the final alkylation reaction is most successful with reactive alkyl halides.i. LDA, THF, -78 "C 4048% R R - >20:1 E : z Scheme 156 The p-elimination reactions of /3-hydroxy sulfone derivatives provides one of the most versatile methods for a,P-unsaturated sulfone synthesis. For example, 2,3-epoxy sulfones, when treated with base result in formation of y-hydroxy-z, P-unsaturated sulfones (Scheme 157).293 Further details on earlier examples of this reaction have also been rep~rted.'~' A particularly elegant method of controlling the double bond geometry during elimination to form an a,P-unsaturated sulfone is by controlling the relative stereochemistry of phenylsulfonyl group and the alcohol leaving group. Reduction of a P-keto sulfone using NaBH4-CeCl3 provides selectively the threo p-hydroxy sulfone.Subsequent E,-type elimi- nation leads to predominantly the Z-a,P-unsaturated sulfones (up to 10: 1) which can be separated from E-isomer by chromatography (Scheme 146).27"."9' OH BuLi, THF, 6OYo -60 "C+ +S02Ph Me Scheme 157 Iron-mediated allylic substitution reactions of y-alkoxy-a,p-unsaturated sulfones have been shown to occur with complete chirality transfer, and lead to the synthesis of functionalised 1)-substituted a, P-unsaturated sulfones of high enantiomeric purity (Scheme 158).294 Thermal sulfinate-sulfone rearrangement of allylic sulfinates leads to the formation of allyl sulfones (Scheme 159).295*296 If optically active sulfinates are used then the product allyl sulfones retain some of the optical purity after rearrangement. The allyl sulfone anion is a versatile synthetic building block for the preparation of a variety of functionalised allyl sulfones.In many cases, the a-sulfonyl anion is stabilised by coordination of an adjacent heteroatom (Cl, 0, N) to the metal counterion (usually lithium). This can then go on to react with electrophiles in good yield (Scheme 160) *297-299 One of the most important reactions of cx,p-unsat- urated sulfones is their Diels-Alder reaction. Whilst it is beyond the scope of this review to discuss this \ S02Ph i. Fe2(CO)9, CO, hexane Me OBn Fe(co)4 >99% de and ee ii. recrystallisation - 65% OBn HBF4. Et20 96% S02Ph i. RCu(CN)ZnBr Me S02Ph ii. CAN, H20 w CH2CH2CN 81% Fe(C0)4 >96% ee Scheme 158 + Et2Nm S+-pTol BF3-OEt2, toluene I 96% A O A c 96% ee DMF, 100 "C 95% 5T 40% ee OAc ' I Scheme 159 pTolYs O 4 x i.BuLi, THF, DMPU, -78 "C ii. E+ E X X = CI, OH, NHBn E+ = RHal, RCHO Scheme 160 in detail, a brief discussion of some of the substrates that have been investigated will follow. The intra- molecular cycloaddition of a variety of trienyl sulfones have been investigated (Scheme 155).276*291 The cycloaddition reactions of 1-(phenylse1eno)- 2-(p-tolylsulfonyl)ethyneh' and 1-(trimethylsily1)- 2-(phenyl~ulfonyl)ethyne"~ have been studied, the latter acting as a new acetylene equivalent in the Diels-Alder reaction. Divinyl sulfone has been shown to be a useful reagent for 173-azaprotio cyclo- transfer- 1,3-dipolar cycloadditions of oximes."" l-(Trifluoromethyl)-2-(phenylsulfonyl)ethene has also been investigated as a 1,3-dip0larophile.'~~ Allenic trichloromethyl sulfones undergo conven- tional [4 + 21 cycloadditions with dienes such as cyclopentadiene, and give much greater endo-selec- tivity than the corresponding allenic phenyl sulfones.261 E-Bis(phenylsu1fonyl)ethene has been shown to be an efficient dieneophile for reaction with isobenzofurans (Scheme 20).49 Finally, one of the most interesting examples of x,P-unsaturated sulfone cycloaddition is by long range activation of the sulfonyl dienophile via its oxosulfoxonium salt.528 Contemporary Organic SynthesisBF3.0Et2 (cat.) + I CHC13 0 0 = : 4 Scheme 161 J 1 70% o = E \ a I 0 This is formed by a reversible Lewis acid-catalysed reaction between the sulfone moiety and a suitably positioned epoxide (Scheme 161).”’3 5 Conclusion Organo-sulfur and -selenium chemistry continues to play a crucial role in organic synthesis, particularly with the new stereoselective and asymmetric pro- cesses being developed.I hope this review will encourage the further development and exploitation of these methods in the future. 6 References 1 C. 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ISSN:1350-4894    

DOI:10.1039/CO9960300499

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

The synthesis of carbocyclic aromatic systems ANDREW C. WILLIAMS Lilly Research Centre Ltd, Erl Wood Manor; Windlesham, Surrey GU20 6PH, UK Reviewing the literature published between 1 January 1992 and 31 December 1995 1 2 2.1 2.2 2.3 2.4 3 3.1 3.1.1 3.1.1.1 3.1.1.2 3.1.1.3 3.1.1.4 3.1.2 3.1.2.1 3.1.2.2 3.1.2.3 3.1.2.4 3.2 4 5 6 7 Introduction Aromatisation reactions Dehydrogenation using noble metal catalysts Dehydrogenation using quinones Dehalogenation and dehydrohalogenation Other met hods Cycloadditions Simple cy cloadd it ions Intermolecular reactions Monocyclic systems Bicyclic systems Tricyclic systems Higher order systems Intramolecular cycloadditions M onocycl ic systems Bicyclic systems Tricyclic systems Higher order systems Transition metal-templated cycloadditions Base-catalysed condensations Acid-catalysed condensations Rearrangements References 1 Introduction This article is concerned solely with the de novo synthesis of carbocyclic aromatic rings and systems: modification of pre-existing rings by, for example, functional group interconversion or electrophilic substitution processes is beyond its scope.Furthermore, only the synthesis of non-charged systems is covered; aromatic species such as cyclopentadienyl anions, cycloheptatrienyl cations and their related analogues and homologues are intentionally omitted. Whilst they remain of interest from the point of view of defining the concept of aromaticity, and as test cases of bonding theory, the synthetic utility of, for example, higher annulenes is somewhat limited.For this reason, and because of space limitations, they are not discussed here. A number of reactions and processes which it might be thought would naturally fall within the area under discussion have been well reviewed in the literature very recently. These include the synthesis of aromatic systems from non-aromatic precursors, which is reviewed in Annual Reports on the Progress of Chemistry,‘-‘ and the conversion of enediynes to aromatics via Bergman cyclisation and related processes, which has been reviewed both elsewhere and in great detail in earlier editions of this j ~ u r n a l . ~ . ~ Similarly the benzannulation reaction of Fischer carbene complexes with alkynes to produce phenols has been excellently covered elsewhere.’ The volume of literature covering this topic, if one considers ‘synthesis’ of aromatic systems in its most general sense, is so vast that it would be most surprising if the synthetic methods discussed herein were not thought by some readers to reflect the subjective bias of the author.That may well be true, however, as wide a range of readily accessible literature sources as possible has been covered, focusing on the most synthetically useful, novel and interesting reactions, whilst trying to provide some level of historical context to the most recent applications of the more well established reagents and reactions. The wide range of reactions that might potentially be covered in this article have meant that it can in no way pretend to be comprehensive, and space limitations have meant that it has not been possible to give full reaction schemes for every cited reference.Readers should consult the references where closely related reactions or further uses of a particular reagent are indicated. 2 Aroma tisa t ion reactions The last chemical transformation involved in many synthetic sequences leading to an aromatic final product is very frequently an aromatisation. This may involve such processes as dehydrogenation, dehydration, reduction, oxidation (other than dehydrogenation), de halogenat ion and de hydro- halogenation. Where this occurs as a separate, well- defined step, and can therefore sensibly be considered a ‘reaction’ in its own right, it is discussed in this section. It will readily be apparent to the reader that it is not possible, in many cases, to divorce the aromatisation step from the preceding annulation steps of a reaction or sequence, and these cases are discussed later, under the general headings describing the ring-forming reactions.In these later sections, an attempt will be made to define at what point, and using which reagents, aromatisation is effected. Williams: The synthesis qf carbocyclic aromatic systems 5352.1 Dehydrogenation reactions using noble metal catalysts The 'traditional' hydrogenation catalysts have a long history of use as dehydrogenation catalysts for the aromatisation of, especially, six-membered alicyclic rings.'' Recent examples from the literature serve to show the continued utility of these substances, and to illustrate the directions in which the field is developing.5-Hydroxyquinolone 2 was prepared in quantitative yield by heating the ketone 1 with 10% palladium-on-charcoal at reflux in decalin for 144 hours." In related reactions the ketone 3 was converted in 53% yield to the naphthol 4, and the benzo[b][ 1,8]naphthyridine 6 prepared in 76% yield.I2.l3 More recent developments in catalysts are exemplified by the composite platinum-ruthenium catalyst 8 which has been described for the liquid- phase dehydrogenation of alkanes,I4 and the polystyrene-supported rhodium( H I ) chloride- quaternary ammonium ion pair, which efficiently catalysed the disproportionation of cyclohexadiene 10 to benzene 11 and cyclohexene 12.Is The use of platinum for a closely related transformation has recently been exemplified." 2.2 Aromatisations using quinones By far the most frequently used quinone in aromatisation reactions is DDQ (2,3-dichloro- 5,6-dicyano-1,4-benzoquinone).Suitable solvents are aromatic hydrocarbons at ambient to reflux temperatures, solvent and conditions being largely dictated by substrate solubility and susceptibility to oxidation. The following examples illustrate the range of substrates accepted by this reagent and the compatible functional groups."-" In the conversion of 13 to 14, it is interesting to note that aromatisa- tion is not accompanied by elimination of methanol. The oxidation of 15 to 16 is accompanied by a dienone-phenol rearrangement. Many further examples of the use of DDQ (illustrated by the conversions of 17 to 18, 19 to 20, 21 to 22) have been described.22-32 Me0 ,.C02Me Me0 C02Me mCoZMe DDQ (2 equiv.) C&, 20 h, reflux, 96 70 13 14 & \ / DDQ(7 C6H6,10 equiv.)* h, reflux, 63 YO OH 0 0 OH 15 16 0 OH decalin, reflux, 0 H 1 H 2 Me OH ye PH I t Me Me DDQ (1-1.5 equiv.) a 5-25 "C, 90 % ~ c o 2 B u ' C&, 5-90 illif;[ C02Bu' 1 -methylnaphthalene 0 reflux, 30 min, NP, Me0 OH 53% Me0 Bu 17 Bu 18 3 4 19 Me 5 Me 6 DDQ (2 equiv.) PhCH3,lOO % mco2Me Me02C MeO2C C02Me 20 DDQ Me Me 10 11 12 50% 50% POL = Polystyrene polymer support Me Me 21 22 536 Contemporary Otganic SynthesisOther quinones have been used less frequently. The isomeric quinones 23 and 24 were converted to maturone 25 and isomaturone 26 by chloranil (2,3,5,6-tetra~hloro-1,4-benzoquinone),~~ cyclo- hexenone 27 to 1,2,3,5-tetrasubstituted arene 28,'4 29 to steroid hydrocarbon 30 by a combination of chloranil and phenanthrenequinone," and 31 to 32 by chloranil.'" @&OH WoH 0 0 23 chloranil (5 equiv.) 25 + m-xvlene, 24 h, 140 "C Me 0 24 #OH Me 0 26 chloranil, ____) Ac20, PY / C02Et C02Et 0 27 OAc 28 H r r- @ \ \ Me 29 -@ / / Me 30 Me 31 Me 32 2.3 Dehalogenation and dehydrohalogenation These methods are discussed together due to their close mechanistic relationship and similarity in terms of reagents employed, reaction conditions and suitable substrates. The reductive defluorination of saturated perfluorocarbons to highly fluorinated aromatic compounds has recently been described." The perfluorophenanthrene 34 was prepared in 22% yield from the perfluoroalkane 33 using sodium- benzophenone. The authors also described the electrochemical reduction of this and closely related F F F Na, PhzCO THF,22% * F F F F 33 F Fx$ F + F 35 34 EtCECEt - Et F CI 36 NH3, Hz0, 25 "C, 92% dioxane, 1 Et F CI Et$TffNH2 F F 37 systems. A closely related reduction of perfluoro- methylcyclohexane has recently been described? Reaction of 36 with ammonia was accompanied by ring-opening and elimination of hydrogen fluoride, to give the amide 37 in 92% yield." Conversion of alcohol 38 to 4-methylaceto- phenone 41 was achieved in 73% yield: presumably the initial dehydrochlorination is followed by an aerial oxidation of the cyclohexadiene (Scheme l).4" Dehydrochlorination of the cyclohexene 42 gave the benzocyclopropane 43 in 43% 38 Scheme 1 A 0 39 40 I $ 41 CI 42 43 Williams: The synthesis of carbocyclic aromatic systems 537A common strategy employs a bromination- dehydrobromination sequence for the aromatisation of cyclohexanones and cyclohexenones in particular.Dehydrobromination of 44 with lithium bromide and lithium carbonate, in DMF at reflux, gave the sensitive 4-hydroxyindole 45 in excellent yield.j3 Similarly 46 gave 47 in 49% yield44 and 48 gave 49 in 68% yield.45 Further closely related reactions have been p~blished.~"~~ A number of examples of closely related iodination-dehydroidination sequences leading to 51, 53, 55, 57 and 59 have also been 0 OH CN H 44 H 45 0 OH Br2 (2 equiv.) OH Me /ooH AcOH * Me 602Me 46 C02Me 47 0 HO Meo2cb NBS, (PhC02i Meo2cb CCI4.20 h, 120 "C Me Me 48 49 C02Me Meo2c&oH CF3 A + * MeOH. 73% Me02c&0 C02Me CF3 50a NaOMe, I 2 Meo2c& C02Me 51 50b NaOEt, 12, Ir EtOH, -78 + 25 "C Eto2cn0 R' 52 a R'=Me b R' =CF3 c R' = C02Et Et02C R' 53 a 66% b 86% c 77% d 61% OH NaOEt, I*.Eto2cno R2 EtOH * 54 a R2=Me b R2=CF3 c R2=Ph I 55 a 78% b 65% c 64% 0 0 56 57 ' 0 0 M e N s 0 86% -- M e N p y H 0 0 58 59 2.4 Other methods Acid-catalysed dehydration? with or without concomitant skeletal rearrangement? has been used in a number of cases to effect aromatisation as in the conversion of 60 to 61, 62 to 63, 64 to 66, 67 to 68 and 69 to 70.52-6" The closely related loss of an alcohol is exemplified by the reduction-elimination of 71 to tetrahydroquinoline 726' and the loss of methanol from 73 and 75 to give 74 and 76.62 60 61 Me Me 0 HO Me 62 63 0 HO Me OH 0 HO Me Me 64 65 66 0 OH ii.i. MeLi H2S04 - WMe 0 Me 67 68 538 Contemporary Organic Synthesis0 {OH "'0"' Me Me ii. H2S04 - "aMe Me Me i. MeLi 0 69 Me 70 N/\ HN/\ HP, MeOH, Me0 6h,25'C, Me0 73% Me0 0 1 OMe CF3 71 B k N Me0 P OMe H 73 Me0 OMe 75 72 BZxNH Me OMe 74 BzNH PTSA PhCH3,40% OMe BZ = COPh 76 Related transformations, resulting in dihydro- benzofurans and tetrahydrofurans have recently appeared in the literature." Selenium dioxide and manganese dioxide have been used for the aromatisation of cyclohexenes 77 and 79 re~pectively."-~" Vanadium pentoxide on titanium dioxide in the presence of methanol effected alkylative aromatisation of cyclohexanone 81 to 2,6-dimethylphenol 82 in 100% conver~ion.'~ - ox SeO, (1-3 equiv.) TMS polyphosphate, CCI4, 18 h, reflux, 80-91% 77 78 a X = CO,H b X=CN c X=CI 0 MnO, 79 80 MeOH (10 equiv.), 10% V20EJTi02 E 38C-390 "C 81 82 Other oxidising agents which have found application are Jones' reagent," potassium oxide-chromium trioxide on ~arbon/alumina,~~ the [ PV2Mo,,,010]' heter~polyanion~" and molecular oxygen." It will be appreciated that the actual oxidant in the so-called 'spontaneous' aromatisations occurring following an annulation reaction is, for the most part, atmospheric oxygen, which probably makes it the most widely, but unwittingly, 'used' aromatisation reagent of all.One reductive aromatisation, of potential utility for the construction of highly functionalised benzonitriles has recently been described by Dani~hefsky.~? A quinone 83 is converted to a protected monocyanohydrin 84, which is then reduced with samarium(r1) iodide to yield a hydroxybenzonitrile 85 (Scheme 2); for unsym- metrical substrates excellent regioselectivity (1 0: 1 to 20:l) was obtained.Fused quinones such as 86 also gave the desired nitriles in good yield, as did phenanthrenequinone. 83 A = H, Me, OMe B = H, Me, OMe 0 84 85 7549% CN 0 OH 86 87 Scheme 2 3 Cycloadditions This constitutes perhaps one of the most active fields during the period under review. As will become apparent a large number of aromatic systems, both mono- and poly-cyclic, from simply to highly functionalised, may be prepared by this method. I n many cases an aromatisation step follows the construction of the carbon skeleton: this may be, for example, a DDQ oxidation, or elimination of a small molecule such as ethene, carbon dioxide, sulfur dioxide, nitrogen or water.The organisation of this section reflects a need at least to attempt some systematisation of the subject matter. 'Simple' cycloaddition reactions are discussed first, the namc having been chosen to differentiate them from the transition metal- templated reactions which follow. These two broad areas are further separated into inter- and intra- molecular reactions. and within each of thesc Williutn is: The syri tlz esis q f ' curboc ydic ummu tic systemssubsections the reactions are arranged according to the complexity of aromatic ring system constructed (mono-, bi-, tri-cyclic and higher order). The subject matter in the sub-sections is arranged approximately in order of increasing degree of substitution.3.1 Simple cycloadditions 3.1.1 Intermolecular reactions 3.1.1.1 Monocyclic systems aromatics include an intermediate 97 in an unambiguous synthesis of hericenone A,") daunomycinone," and the chlorophenols 100 and 102.s2 A recent example was employed in a synthesis of anacardic acids 103-105;*3 further examples of the use of this reaction may also be found.s4 zO:h ~ C02Me The simple [4+2] cycloaddition of a diene to an TMSO HO alkene or alkyne leads to a cyclohexene or cyclohexadiene. Clearly some aromatisation or 96 97 dehydrogenation must occur if an aromatic system is to result. As will be seen from the following of the carbon skeleton (see Section 2.2), or may examples, this may be effected by the addition of an agent such as DDQ subsequent to the construction occur by elimination of a small molecule subsequent C02Et ~ Me& C02Et TMSO Med -t I/ 120-140°C HO H pxylene to the cycloaddition process.The diene 88 under- 98 99 100 went smooth reaction with dimethyl acetylcne- dicarboxylate 89 (DMAD), to give a cyclohcxadiene which was aromatised, without isolation, by treatment with DDQ,7' to give the tetrasubstituted arene 90. Similarly the cyclobutene 91 underwent thermal cycloreversion to dime 92, which then underwent cycloaddition with DMAD followed by DDQ oxidation to give 93;7J a similar transforma- tion has recently been reported." Cycloaddition of fluorodiene 94 with DMAD, followed by loss of the elements of trimethylsilanol, gave fluoro diester 95 in 70% ~ i e l d . ' ~ A number of related reactions have been de~cribed.~'-~~ The Alder-Rickert reaction involves a [4 + 21 cycloaddition followed by a loss of an alkene, to give an aromatic system directly, even in the presence of groups which might eliminate under normal Diels-Alder conditions.Recent examples which illustate the utility of this process for the construction of highly functionalised CI pxylene OTMS 120-140 oc Me 101 OH b C O 2 " R' 103 a R' = (CH2)&H3 b R' = (CH2)&H3 C R' =(CHZ)~ U ( C H 2 ) 6 C H 3 OH 4 Me 102 ?H &cz Y Z-CH3 104 a Y = (CH2)7, Z = (CH2)3 b Y = (CH2)7, Z = (CH2)5 C02Me &or Y /X-CH3 Meox Me0 + rMe C02Me ii.DDQ - Meon Me0 C02Me i. heat 105 88 89 90 a X = (CH2)2, Y = (CH2)7 b X = (CH2)4, Y = (CH2)7 c: C02Me heatb-;;2Me $Me i. DMAD,89 C02Me Other small molecules may also be lost to give t aromatic products, one of the commonest being / C02Me carbon dioxide.The cycloaddition of a 2-pyrone with an alkyne followed by loss of carbon dioxide gives an aromatic species directly. The reaction is 91 92 93 generally less successful with alkenes, because the intermediate cyclohexadiene may itself react further with the alkene. A recent modification, which involves performing the cycloaddition in the presence of a dehydrogenation catalyst to aromatise the intermediate cyclohexadiene as soon as it is formed, overcomes this difficulty." By this route good yields of phenyl and biphenyl derivatives are __t ii. DDQ C02Me C02Me -a i. 89 ii. AICI3, PhMe, 16 h, 120 "C. 70% F 95 F fS 94 5 40 Con temporary Organic SynthesisMe02C no 1 06 10% PdC R'CH=CHR~ m-xylene or Me02C mesitylene or dodecane, 14Cb210 "C 107 5-20 h 2743% ii, R' =R2=Ph iii, R', ~2 = & iv, R' = 4-py, R2=H Scheme 3 obtained from readily available alkenes (Scheme 3).The Diels-Alder reactions of 2-pyrones have been reviewed.'6 Dihydrophthalate esters, or dihydro- phthalic acids, prepared by the electrochemical reduction of phthalates or phthalic acids, react with alkynes such as DMAD to yield a range of I ,2-disubstituted arenes and biaryl systems, with the elimination of dimethyl fumarate or fumaric acid (Scheme 4).x7 Loss of sulfur dioxide has been used as a means of aromatising [4+2] cycloadducts, for example in the conversion of 115 to 116 and 117;" a recent report describes the cycloadditions of thienopyrrole dioxides." The conversion of 115 to 116 also involves loss of one mole of benzenesulfinic acid.108 ;p -3 110 112 89 decalin, 2 h, 190 "C 89% 108 220 "C, 8 h, 90% qO2Et I l l decalin. C02Me C02Me 109 111 C02Et C02Et + 190 OC, 4 h, 87% C02Et 113 114 I I 115 116 C02Me C02Me 89 115 a;; 117 reflux 93% Aromatic systems have also been formed by loss of dimethylamine from [4 + 21 adducts,'" in related reactions by loss of pyrrolidine and morpholine,""3 and by addition of ally1 silanes to benzyl cations.94 A more complex loss still is involved in the conversion of 118 to 123. This proceeds as shown in Scheme 5, via [4 + 21 cycloaddition, fragmentation, Michael addition and ring closure.y5 Aromatisation of the initially formed cycloadduct 126 from diene 124 and 3-chlorocyclobutane-1,2-dione 125 was achieved by a bromination-dehydrobromhation sequence (Scheme 6);'6 the same group has reported further applications of this phenylethyne 130 and trimethylsilylethyne 132 react Alkynes such as U C02Me * Me2N Ly Do + 111 Me2N y H Me Me 118 119 120 C02Me I I C02Me C02Me 122 121 Me02C Me2N JF C02Me -Me 123 Scheme 4 Scheme 5 Williams: The synthesis of carbocyclic aromatic systems 54 1124 125 128 126 (& Br 127 Scheme 6 with 4,5-dicyanopyridazine 129 at 110 "C, in chloroform in a sealed tube, to give arenes 131 and 133 after loss of nitrogen.Alkenes such as 134 and 136 partially or completely aromatise after cycloaddition to give tetralin 135 and ester 137 (Scheme 7).98 Related cycloadditions of ynamines and pyridopyridazines have been reported.yy."'O Thermal cyclisations of enynones have been used in the synthesis of, for example, juncusol.'o' 100 OC + PhCECH CN sealed tube, Ph CN 131 68% 129 1 30 129 + TMSCZCH 7,% ;MS CN 1 32 1 33 CN 129 + o 20% 134 135 129 + rCOzMe CN 1 36 137 Scheme 7 3.1.1.2 Bicyclic systems Because of their wide occurrence in natural products, much interest and synthetic effort has been focused on developing synthetic routes to naphthoquinones and related molecules: many of these routes have involved cycloadditions.Reaction of 2,6-dichloro-l,4-benzoquinone 138 with Danishefsky diene 139, followed by mild acid 138 139 1 40 141 142 143 hydrolysis gave the 2-chloro-6-methoxy-8-hydroxy- naphthoquinone 140 in 83% yield.Io2 The bromo- quinone 143 was prepar<-:I similarly.This general approach is highly flexible, and capable of being adapted to produce a number of more highly substituted naphthoquinones (Scheme 8)."'"1"y have also found utility in this Pyrrolo- fused 2-pyrones { 1,6-dihydropyrano[4,3-b]pyrrol- 6-ones} such as 159 undergo cycloadditions with, for example, DMAD to give, after loss of carbon dioxide, substituted indoles exemplified by 160. " Another route to indoles involved the cycloaddition of N-phenylmaleimide 162 to the osmium- complexed vinylpyrrole 161, followed by decom- plexation and DDQ ~xidation."~ A completely substituted quinoline 165 has been prepared by the cycloaddition of DMAD and thiophene 164.'IS The aromatisation step involved here is extrusion of the ring sulfur atom from 166 with loss of the methyl- thio group. The Diels-Alder adducts of quinone imine ketal 167 with dienes 168 and 171 gave naphthalenes 170 and 173 in 91 and 36% yields.62 2,3-Disubstituted naphthalenes are also available from the cycloaddition of 2,3-naphthoquinodi- methanes and acrylates or maleates (Scheme 9).'16 The cycloaddition of DMAD-type dienophiles with isobenzofurans (and heteroaromatic analogues thereof), followed by acid-catalysed rearrangement is typified by the conversion of 179 to 180.'" Many further examples of this sequence have been reported in the review period.118-12' The Alder-Rickert reaction and variants thereof 3.1.1.3 Ricyclic systems Extending their work on the cycloadditions of 2,3-naphthoquinodimethanes to reactions with fumarates, followed by a DDQ aromatisation, Inanaga and co-workers have recently described a synthesis of 2,3-disubstituted anthracenes 181 (Scheme Polyhydroxylated anthraquinones occur widely in natural products, and many groups have devised synthetic strategies towards these targets based upon cycloadditions.122-'26 As part of their route to the pigments G-ZN and G-ZA Kelly and co-workers further elaborated the 3-chloro- 5-hydroxy-7-methoxyjuglone 140 to the anthra- 542 Contemporary Organic SynthesisTMS 0 MeO% OTMS TMS ref.103 * M e O d ' 0 Me Me 144 145 0 1 46 0 HO OMe OTMS Me02C M e : a + M e 0 5 ref. 105 * Meofi OMe Me02C OMe 147 139 1 48 clQc'+ Me0 ' M y OTMS * C ' Q y OH 0 + c y p 0 OH 138 149 0 0 150 151 TMSO 138 + M ~ o * ~ ~ ~ ~ + c l ~ c 4 H 9 OH 0 1 52 1 53 0 R2@c'+ R' T M T 0 R' 154 TMSO OTMS 155 0 156 a R'=H,R2=CI(~138) b R'=CI, R2=H c R' = H, R2 = OMe d R'=R2=OMe 0 yJ + TMxc4Hg * 7 MSU 138 I 1 - OTMS 0 157 158 Scheme 8 quinone 183."" The diene 182 can be prepared in a single step from commercially available ethyl a-ethylacetoacetate by deprotonation with LDA followed by quenching with chlorotrimethylsilane.Brassard and Couturier have described the construction of a number of closely related systems,Ios haematommone 188, ncLsolorinic acid 189, solorinic acid 191 and averythrin 190 amongst others (Scheme 11). Related routes to pachybasic acid, rhein, aloe-emodin, parietinic acid, emodic acid, fallacinol and citreorosein have also been reported.'*' Lehn has used a double quinone-diene cyclisation to produce building blocks for self assembled supramolecular rigid rods.of 4,5-dicyanopyridazine 129 with alkenes and alkynes (Section 3.1.1 .I) has been extended. The reaction Williams: The synthesis of carbocyclic aromatic systems 54389, reflux PhCI, * Me02C)JJQ Me02C Boc 0 Boc OAc 159 a R=Me b R = H 160 b 99% a 08% 161 162 163 ___) i. 89 M e 0 2 c p $ y c 0 2 M e C02Me ii. K2C03 C02Me DMSO Me02C 26% C02Me MeS 164 165 C02Me Meo2cq)(y C02Me Me02C via C02Mh' 1 66 fi+7 (@ - Me0 OMe Me0 OMe 167 168 - OMe 167 + OTMS 171 169 PTSA, touene, 25 "C, 91% 1 Bz-NH OMe 170 OTMS Me0 OMe 172 1 NHBz I OH OMe 1 73 OAc 174 0-25 "C, 63% 177 35% 176 178 13% Scheme 9 1 79 HCI I MeOH .OH E = C02Me 1 80 CO4e + - C02Me 60% 175 1 78 181 Scheme 10 Reaction with indoles 197a and 197b gave carbazoles 198a and 198b in 59 and 53% yield re~pectively.~~ A related reaction involves the addition of DMAD to quinoxalino-2,3-quinodi- methane.129 Ultrasound was used to promote the cycloaddition of o-quinone 200 with diene 199 in a 544 Contemporary Organic SynthesisMe0 Et 90% ~ fJyJEt Me0 Me0 OH 0 OTMS 182 1 83 0 140 wcl 0 184 f::MS TMSO 187 f::MS TMSO 1 87 OTMS P M e Me0 1 39 1 92 OMe TMSO OTMS 194 Scheme 11 C02Me OH \ C02Me ' OTMS OMe 0 OMe + k 185 1 86 HO 0 OH 0 C y # 4 - HO Jy$y OH OH / 0 0 156 R = H 158 R=C4Hg 188 R = H 189 R = C4H9 HO 0 OH HO OH 0 0 153 1 90 OH 0 HO 0 OH 0 Me0 OH 0 OH 0 158 191 HO 0 0 151 1 93 OH 0 * q+yoMe OH AcO 0 AcO 0 195 196 recent synthesis of ( + )-tanshindiol Reactions of the related tryptamine-4,5-dione have also been reported. 13' Aminocarbazoles have been synthesised by the addition of DMAD to 2,4-dihydropyrrolo[3,4- blindoles 203.'32 Vogel has described the use of his 'naked sugar' technology in a recent synthesis of a tetrahydronaphthacene.'"" 3.1.1.4 Higher-order polycyclic systems Building upon the use of halojuglones to prepare anthraquinones (Section 3.1.1.3), a recent report has detailed the cycloaddition of unsymmetrical quinones such as 205 with furanoquinodimethanes 206 to give anthraquinones 207 and 208.134 An Williams: The synthesis of carbocyclic aromatic systems 545CN CN k A 129 1 97 198 a R = H a 59% b R=Me b 53% BzO C02Me 199 200 1 uItm&nd 76% .Me #+&I: / / BzO C02Me BzO C02Me 201 202 201 : 202 = 2.5 : 1 Me Me O - d N T o I ii.PTSA. Q-oco2Me C0,Me I heat, 58% S02Ph 203 204 GBr \ + ' P C O 2 M e C02Me Br RO 0 I 205 a R = H b R=Ac 0 206 q$q-c02Me RO 0 C02Me 207 RO 0 &$q-c02Me 0 C02Me 208 a 72% 207:208=4:1 b 72% 207:208=3: 1 approach to unsymmetrically substituted triphenylenes has been de~cribed.'~~ 3.1.2 Intramolecular cycloadditions 3.1.2.1 Monocyclic systems Cyclisation of cyclopropane 209 to toluate 213 is thought to proceed via an ene-cope-dehydro- chlorination sequence (Scheme 12).136 Thermolysis of diesters 214 gave the substituted salicylates 215, probably via the en01.l~~ Coupling of the amino- silane 216 with alcohol 217, followed by intra- molecular Diels-Alder reaction, gave the tetrasubstituted arene 219 (accompanied by a larger quantity of unaromatised cy~lohexadiene).'~~ Cyclisation of the furan derivatives 220 and 222, followed by (or perhaps following?) a base-catalysed rearrangement, gave the phenols 221 and 223 in good yield^.'^^,'^' Later work by the same group showed that alkyne to allene isomerisation preceded Eto2c@e- CI 209 21 0 902Et -HCI - aMe -HCI - 21 3 Scheme 12 ArX C02Et Me /4=(c02Et 21 4 21 1 1 C02Et 6"' CI 212 vr heat OH 21 5 a Ar=Ph,X=O,R=H a 75% b Ar=Ph,X=O,R=Me b 29% c 56% c Ar = 4-MeOCsH4, X = 0, R = H d Ar=Ph,X=S,R=H d 43% e Ar = 4-CIC6H4, X = S, R = H e 61% Bu Me 216 217 J 21 8 21 9 546 Contemporary Organic Synthesisi. PhMe, reflux ii.B U ~ K , reflux HO 80% H 220 221 Me b 0 - l Me B U ~ K , BU'OH, HO SMe H SMe 222 223 cycloaddition, and that the final products were formed via zwitterionic intermediates (Scheme 13).'"' The related reaction of thiophenes, followed by oxidation and extrusion of sulfur dioxide, has been reported.*"2 Isomerisation of allene 231 to an alhyne, followed by cyclisation and loss of nitrogen gave dihydrobenzofuran 232.14' A number of synthetic strategies have been devised, mechanistic- ally based upon the enediyne antibiotics, whose synthesis and chemistry are reviewed in earlier editions of this jo~rnal."'"~ These are typified by the preparations of tetralone 233,'45 indanes 234,'45 235,14" 23614' and 23714' and steroid skeletons 239 KOBU' (cat.) M e S w $ BU'OH 0 =.4 225 a 80% b a m c 88% M:Q?-2 0 o+ 227 t - MeS-R' ' 0.; U 226 Ho+Q7R2 SMe 228 0 H d 229 a R3=H b R3=Me dB"l 230 PhMe, 20 h 200 "C 231 232 &02Me OMe TBSO 233 234 235 Mep \ M e m OMe Me Me 236 237 H 240 and 240 from 238.'49 Further related cyclisations have been rep~rted,'~'-''~ and a number of higher- order polycyclic aromatic systems p~epared."""~ Cyclisation of ester 241, followed by loss of the elements of isobutyric acid gave tetralone 242 in 24% yield.'j8 The triene 243, after in situ oxidation of the initially formed cycloadduct, gave the indane 244.'59 Because of its occurrence in a range of 241 242 QMe C6H6, 120 "c d 48 h, air, sealed tube, 42% Scheme 13 243 244 Williams: The synthesis of carbocyclic aromatic systems 547natural products, there is continued interest in novel syntheses of the indolo[2,3-a]carbazole skeleton. A recent approach involves Michael addition of the bisindolyl 245 to maleimide 246, elimination of benzenesulfinic acid, followed by photocyclisation with in situ oxidation to give 248.16' Closure of the central carbocyclic ring is a commonly employed strategy in this area.'61-166 SOpPh +OXLO !' L t - i R 245 246 a R=Me b R=Ph 1 a heat, sealed tube, MeCN b heat (80 "C) R R I & N N H H 248 a 90% b 80% hv EtOH - .fro H H 247 a 34% b 36% 3.1.2.2 Bicyclic systems Cyclisation of the silylene-protected 2-pyridone 249 followed by DDQ oxidation gave, after hydrolysis, the hydroxyisoquinolone 251, which was used in a synthesis of the DEF ring fragment of frederica- mycin As discussed in Sections 3.1.1.1 and 3.1.1.2, 2-pyrones will react with alkynes to give, after loss of carbon dioxide, benzenoid aromatics.In an intramolecular variant of this Moody and co-workers have prepared the substituted indole 253 from 1,5-dihydropyrano[3,4-b]pyrrol-5-one 252.'68 Conversion of ester 254 to enamine 255 by reaction with NJV-dime t hylformamide diet hyl ace t a1 was followed by intramolecular cyclisation and elimina- tion of dimethylamine, to give isoquinoline 256.'69 Conversion of amide 257 to tetrahydrobenzoquino- line 259 was effected via in situ formation of the isobenzofuran 258 and deh~drati0n.l~' Intra- molecular [2 + 21 cycloaddition and [1,5] sigmatropic hydrogen shifts in appropriately functionalised 2,3-naphthoquinodimethanes gave various 2,3-disub- stituted naphthalenes (Scheme 14).' l6 Tri-, tetra- and penta-substituted naphthalenes have been prepared by microwave irradiation of 4-aryl- 4-alkylhex-5-en-2-ones. ''I 3.1.2.3 Tricyclic systems In an extension of their intramolecular pyrone cycloaddition strategy, Moody and co-workers have Me, ,Me C02Me Me TMS TMS = 249 250 i.DDQ ii. H+ 1 Me 251 he SOpPh SOpPh 252 253 OEt OEt 254 255 COpEt I OEt 256 I C02Me- C02Me L 257 258 PTSA, dioxane I 0 0- hfc- = C F ~ ~ C F ~ Me0 f$ C02Me 259 548 Contemporary Organic Synthesis262 6% A L r 263 47% 266 L 264 265 Scheme 14 recently reported a carbazole ~ynthesis.'~~ Further intramolecular Diels-Alder approaches to carba- zoles have also been alkene 267 was followed by photocyclisation and aerial oxidation to give tricyclic 268.'75 Similarly 269 was converted to 270.176 Stilbene-phenanthrene cyclisation remains a frequently adopted approach to this ring system.*77~*7s Intramolecular cyclisation of benzynes to, for example, aristolactam 272 has been recently described.17' Substituted anthracenes and phenanthrenes have been prepared in reactions proceeding from didehydro[ lO]annulenes via diradical intermediates.IxO Isomerisation of 0 0 LDA.P Me0 35% 0 OoC' OMe 271 272 p Me\ c104- 273 ClO, 274 Me 267 268 Me addition-based strategies for the preparation of higher-order polycyclic aromatic hydrocarbons and helicenes have been e m p l ~ y e d . ' * ~ ~ ' ~ ~ 3.2 Ransition metal-templated cycloadditions A number of transition metals have been used to catalyse the conversion of three moles of alkyne into an arene. This may involve cyclisation of three molecules of a mono-alkyne, path A, or a diyne plus mono-alkyne cyclisation path B (Scheme 15).Ix6 There is a particularly large body of literature describing the use of cobalt carbonyl complexes €or these cyclisations, the wide scope of which is only hinted at by the examples s h o ~ n .' ~ ~ - ' ~ ~ Other metals which have been used include rhodium,'45 nickel'"6 and zirc~nium.'~~*''~ In the reaction of diyne 292 with tert-butyldimethylsilane 293, two moles of carbon monoxide were incorporated to produce the catechol derivative 294."' In a related reaction, allenylcyclopropanols were rearranged to 2,3-disub- stituted hydroquinones, with the incorporation of Me 269 270 3.1.2.4 Higher order polycyclic systems In a sequence entirely analogous to that discussed for 268 and 270 in 3.2.2.3, the quinolizinium salt 273 was cyclised to the 6-methylisoquinolino[7,8- a]quinolizinium salt 274 in excellent yield.'*' A halogen radical-initiated diyne cyclisation resulting in a range of polycyclic aromatic hydrocarbons has been reported.'*' A simple route from stilbenoids to extended aromatic hydrocarbons via cycloaddition- cyclodehydrogenation has been described.Ix3 Qclo- 549 Williams: The svnthesis of carbocyclic aromatic systemscoTMs SnBu3 P & + 111 reflux, octane, 46 h, 50% H SnBu3 285 286 287 BuLi THF, -78 "C 288 Scheme 15 rco2Me k C 0 2 M e 289 Ni(PPh3)4 + H A H + THF, 78% n;\OH 290 C02Me 291 80 "C, 48 h, 6070 276 H' 'H 275 Eto2YEt P(C-C6H11)3* Me CO (50 atm.), 20 h, 25-140 "C, -++H 74% TBSO OTBS Bu Bu 278 CoCP(C0)27 water 3 x BuCECH * supercritical + 277 95% Bu 279 278 : 279 = 3 : 1 Me 293 294 89, CuCI, LiCI, Et,& Me THF, 1 h, 25 'C; Bu 71 Yo Et Bu Bu 295 I Bu 296 A one mole of carbon phthalate 296 was produced in 71% yield by copper( 1)-catalysed cycloaddition of alkynes to zirconacyclopentadiene 295.'98 Tandem Stille coupling-intramolecular Heck vinylation of bis(tri- fluoromethanesulfonate) 297 with vinylstannane 298, under palladium(o) catalysis, gave a 55% yield of pentasubstituted arene 299.2"1 Other palladium(o)- mediated cyclisations converted bromoalkenes 300 The tetraalkyl- + TMS-CGC-TMS 282 281 OTf II r 8 1 I I TMs* TMS H H 283 Me 298 299 284 550 Contemporary Organic Synthesisrecent examples of this approach have appeared in the literature subsequent to this review.208-211 Et02C C02Et K 4 Base-catalysed condensations Malononitrile condensed with enone 313 with sodium methoxide in methanol to give aminodi- nitrile 315;"12 in a related reaction, cycloalkylidene malononitriles such as 316 condensed with aryl- methylenecyanoacetamides such as 317, to produce cycloalkano-fused arenes 318.*13 The pyridinium salt 319 condensed with malononitrile to give, after treatment with hydrazine, phenylenediamine 320.214 3,5-Bis(cycloalkylamino)biphenyls 323 were gener- ated by the reaction of the anion of enamino ester 321 with a-oxoketene-N,S-acetals 322."15 The anion 300 + T C0,Me Me02CQ Pd(0AC)p PPh3, KzC03, AgN03, MeCN, 3h, llO°C, sealed tube, * C02Me 56% 302 301 and 303 to indanes 302 and 3052023203 and triyne 306 to 307."02 Negishi has recently reported the intra- molecular Heck reaction of bromoarylallenes, giving substituted naphthalene^."^ The dirhenium carbonyl complex 308 coupled with two moles of methyl propiolate to give the rhenium aryl complex 31O.'Os The aminocarbene complexes 31 1 underwent cyclisation to the tetrahydroquinolines 312 upon heating.""' Allenes have been coupled with DMAD- type alkynes using palladium or platinum catalysts to give, after DDQ oxidation, 2,3,6,7-tetrasubsti- tuted naphthalene^.^'^ For further examples readers should refer to the excellent review of this area, to be found in Comprehensive Organometallic Chemistry II.lS6 The Dotz benzannnulation reactions of Fischer carbene complexes have been reviewed;' some very NaOMe, MeOH 3.5 h 0 oC-reflux Me Me 31 4 I -HCN y42 Me NcIYcN Me Br Eto2c&TMs Et02C - 31 5 piperidine, EtOH, 5 * h, refllux, 65% 31 6 + 40% Et-CEC-Et Et Et 305 r? 304 c0nh2 m N 31 8 31 7 HO i.CH2(CN)2, NaOH, H20 NC,&NH2 D Me02Cy Re(C0)4NCMe 308 (C0)4Re Me02C,qC02Me - + (W4Re C02Me H+C02Me 309 31 0 ii.N2H4*H20 M e y N H 2 CN 320 1 CI- Me NH2 31 9 Meo2clMe c" 321 LDA. TMEDA -110+25"CD Ar + I 323 31 1 31 2 a R=Ph b R = H c R=TMS a 59% b 22% C 29% 322 55 1 Williams: The synthesis of carbocyclic aromatic systemsof methyl propiolate 325 condensed with cyclo- hexenone 324 to give the dihydronaphthalene deriv- ative 326.216 Dihydroxyisoquinolone 328 was prepared in 76% yield by the Dieckmann cyclisation of keto ester 327.2'7 Related base-catalysed conden- sations converted pyrimidinedione 329 to thioethers 331 and 333,218 and pyrimidinecarboxylate 334 to diester 335.219 Hydroxyquinazolines were prepared in a similar manner.22" Ring closure of hemiacetal 336 to tetralone 337 was effected by treatment with potassium tert-butoxide in tert-butyl alcohol, with the loss of two moles of water.22' Heating the phos- phoranes 338 in chloroform or methanol led to the formation of substituted isophthalates 339.*** A general process for the preparation of 3-alkyl and 2,3-dialkyl-l-naphthols 341 by the base-catalysed cyclisation of alkynyl aceto- and propio-phenones 340 has been reported.22' Lithiation of 1,2-dimethyl- indole-3-carbaldehyde furnishes an indole-2,3-dieno- late, which has been trapped with a variety of Me Do 324 + LiCE C- C02Me 325 C02Me -L fi C02Me THF, 2 h, rt 31% Me 326 Et02C H O W * NH NH NaOEt, EtOH Me 12 h, 25 "C .... 0 0 HO 0 327 328 Me Me 329 330 331 -0TBS -0TBS 0 0 Me 336 337 C02Me CHC13 Me02C a C 0 2 M e - ph3p> MeOH or heal, R RF sealed tube - RF 338 339 a R = Me, RF = CF3 b R = Me, RF = C3F7 c R = P ~ , R F = C F ~ d R = Ph, RF = CsF7 0 KN(TMS)2 toluene R2 340 a R1=H, R2=Me b R' = H, R2 = C-CeH11 c R' = H, R2 = Bu' d R' = H, R2 = Bn e R'=H, R2=Ph f R'= Me, R2 = C6H13 341 a 74% b 92% c 75% d 95% e 0% f 70% alkynes and alkenes to give carbazoles and dihydro- carbazoles, through an anionic [4 + 21 cycloaddition or a tandem Michael-aldol process depending on your point of view.224 found wide application for the construction of complex natural product aglycones, for example in fredericamycin A,225 olivin226 and in the conversion of 347 to 349.227 A related condensation was employed in the synthesis of urdamycinone B."$ Intramolecular base-catalysed condensation, followed by reduction and dehydration, gave the ellipticine analogue 351.'29 Addition of anion 352 to enone 353, followed by loss of methanol and benze- nesulfenic acid, gave the methoxsalen precursor 354 in 77% yield.230 The same group reported a very similar route to benzoHindenone 356.23' Reaction of anions 357 with furanone 358, followed by dehydration and dehydrogenation gave the aryl- substituted nap ht hofuranones 359.232 Base-catalysed condensations of polyketides have 332 Me 333 M e 0 2 C T C 0 2 M e 0 HO 0 OMe HO OMe + MeOH M e o 2 c m 24 h, 25 "C ref.225 Me Me 344 Meo2cflo; 89 LDA, - Et20 -70 ~ c , 38% 334 335 Me Me02C 343 552 Contemporary Organic Synthesis?Me 345 - MeOAc, OMe Me BOMO OH 346 - M O M O ~ 0- 0- Me C02Et + UOEt 348 C02Et 1 347 :MOM 'OM'% Me Me 349 C02Me OMe SOPh I d & L i + 350 i.NaOH, M e H , H20, 0-20 "C ii. NaBH4, diglyme, 130 "C I OMe Me + go OMe 352 353 351 0% 354 OH SOgPh I e0- + 353 - hi+ 355 0 356 pcymene 357 358 359 a R=H,Ar=Ph b R=OMe,Ar= OMe \ OMe c R = OMe, Ar = qJ a 31% c 26% b 46% 5 Acid-catalysed condensations Treatment of the diene esters 360 with trimethylsilyl trifluoromethanesulfonate led to the formation of benzoates 361.'33 Cyclisation of ,&ionone 362 to tetralin 363 has been effected by a number of reagents, for example iodine"' and br~moform.'~' The yields are comparable to those obtained with toluene-p-sulfonic acid reported much earlier.'" As might be expected, Friedel-Crafts-based cyclisations have been widely employed for the construction of aromatic systems of various degrees of complexity.For example the dihydrobenzopyran 365 was obtained in 78% yield upon treatment of the acid 364 with oxalyl ~hloride,'~' and the indenes 367 and 369 from fulvenes 366 and 368.'3s Friedel-Crafts R' R' C02Et Me 'OZEt TMSOTf, CHpClp R2 P O M e \ 0 "C A3 360 A3 361 362 363 A. 12, 30 min, 11 0 "C, 80-95% B. CHBr,, icosane, Ar, 27 h, 20 "C, ultrasound, 79% c. PTSA (Cat), N2, reflux, 8 h, 95 yo Williams: The synthesis of carbocyclic aromatic systems 553364 OH 365 i. TMSCI, Et3N J D I ji. L M g C I , Et2O R ' W O T M S R2 OH - I 370 CDI (1.lequiv.) AC20 (1.5 equiv) DMAP, DBU Me K C 0 2 H 124h Me 366 367 CDI = 1,l -carbonyldiimidazole Me I 371 PTSA Me R' 372 368 369 reactions have been used to prepare anthrols, anthraquinones, indoles and ant hracene~.~"-*~~ Appropriately substituted dinitriles have been cyclised to cyanonaphthylamines with sulfuric A practical and efficient method for the benzannulation of ketones has been described, involving the addition of a Grignard reagent to a ketone, followed by acid-catalysed cyclisation (Scheme 16).244 The range of products accessible by this route is indicated by 373 to 381.The use of other Grignard reagents and cyclisation conditions is also discussed. Cyclisation of the acids 382 to the juglone precursors 383 was achieved in good yields. The juglones were used to prepare a range of naturally occurring anthraquinone-2-carboxylic acids (Section 3.1 . ~ 3 ) . ' * ~ Reaction of keto diester 384 with diacetal 385 in the presence of titanium(1v) chloride gave the 2-hydroxyisophthalate 386 in 58% yield.245 In a related condensation, tricarbonyl compounds reacted with enamin~amines.~~' Treatment of the anion of 3,5-dimethylisoxazole 388 with 3-oxoketene dithioacetals 387, followed by treatment with boron trifluoride, gave the benzoisoxazoles 389 in yields from 54 to 81%.?j7 A wide range of substituents R' was tolerated; 20 examples were quoted. The reaction failed for R' = R2 =Me; R' = Ph, R2 = Me and R' - R'=-(CH,),-. Four related demethylthio compounds 391 were also prepared by reaction of P-methylthioenones 390 with anion 388 (Scheme 17).Treatment of ketone 392 with toluene- p-sulfonic acid in refluxing toluene gave the indole 393 in 48% yield, together with 15% of the isomer were formed from their respective precursors;"" further indole syntheses closing the carbocyclic ring have been described.15' Treatment of cyclopropane- carbonyl chlorides 399 with arenes 400 and aluminium chloride gave aryl-substituted naphthols 401 in yields from 23 to 81% (Scheme 18).252 In related reactions aryl-substituted naphthols 404 and In a similar manner indoles 396 and 398 394.248.249 373 374 375 376 52% 76% 79% 74% Me Me Me 377 378 66% 89% 379 65% Me Me 380 86% 381 77% Scheme 16 OMe R' Me0 R' @ y C 0 2 " ~ x@co2Et X C02H R2 OMe Me0 OAc 382 a x = R ' = R ~ = H b X = CI, R' = R2 = H c X=R1=H,R2=Me d X = CI, R' = H, R2= Me e X = H, R' = Me, R2 = H f X = CI, R' = Me, R2 = H 383 a-e 6570% f 5% 554 Contemporary Organic Synthesis0 Et02C A C O p E t OH 384 TiCI,, (1 equiv.) I I EtO OEt 385 386 387 388 SMe RiAO 390 Scheme 17 389 A x x 399 400 X = CI, Br Y = H, CI, OMe R=H,Me Z = H, Me, CI, Br, 1-Me-2,6-CI2, 1,441, Scheme 18 391 Me S02Ph Me 392 ‘Me Me 393 48% 394 15% 395 396 cph o \ PhCH2SH PTSA, PhMe, Me & S02Ph Me S02Ph Me Me 397 398 a @Me) 44% b (or-Me) 16% 402 R’ = H, Me R2 = H, Me Y = H, 1,4-Me2 + 2Q-Y 403 401 R2 R’ 404 38-58% 0 OH 405 Y = H, 4-CI, 4-Me, 3-Me Z = H, 1 -Me-2,6-CI2 Scheme 19 406 407 23-56% 407 were also prepared (Scheme 19).In the first case intramolecular Friedel-Crafts reaction is followed by intermolecular; in the second case one intermolecular Friedel-Crafts reaction is followed by a second, then by an intramolecular Friedel- Crafts cyclisation. The final case supports the proposed mechanism, starting from independently prepared ketones 405 which would be intermediates in the conversion of 402 to 404.Acid-catalysed cycli- sation of quinol ketals 408 gave the phenanthrenes 409 in good yields.”3 Treatment of the imidazole 410 with acetic anhydride, followed by polyphos- phoric acid gave the naphthoimidazole 411 in almost quantitative yield:’j4 further examples of this approach have been cnol ether 412 with hydrogen chloride in acetic acid-acetic anhydride gave 1 -fluoroellipticine 413 in 54% yield.’” Enamino ketones 414 gave S-hydroxy- quinolones 415 upon treatment with concentrated hydrochloric acid.’” Acid treatment of the nitrile 416 gave a mixture of 5-hydroxy- and 5-dimethyl- amino-quinolones 417a and 417b. Mild acid treat- ment of 414a gave the dimeric tetracycle 418.”(’ Treatment of Williums: The synthesis of curhocyclic uromutic sytems 555Me0 R5 k4 MoMo OMe Ye Me0 M e o ~ ~ ~ \ HO 41 0 N SP h Ar i. AcBO ii. PPA Me0 Ar 41 1 Me F I I QJ-m - 54% H I OEt Ar = M a e - Me F 41 2 0 i. HCI, 12 h, 25 "C Rm ii. 10% KpC03(aq) 0 iii. AcOH 0 H H 41 5 Me2N 41 4 a R = H a 90% b R=Me b 77% 41 3 H? hcN AcOH, 45 reflux- h hcN 0 H Me2N ' N O H 41 6 41 7 a X=OH, 13% b X=NMe2, 34% 24h 0 Me2N H H 41 4a H CHO 41 8 6 Rearrangements Two groups, those of Liebeskind and Moore, have developed general routes to highly functionalised arenes based upon the rearrangement of cyclo- butenones substituted with unsaturated groups (Scheme 20). Flexible routes to the cyclisation precursors have been developed by both groups, allowing variation of the substituents R'-R'; space allows only an indication of the full scope of these processes.R1$R5 R2 R4 R3 41 9 420 R 2 v R 4 R 2 y R 4 R3 R3 422 421 Scheme 20 Coupling of the chlorocyclobutenones 423 with stannanes 424 under palladium catalysis gave unsat- urated cyclobutenones 425 which rearranged to the phenols 426 (Scheme 21).2'9 Methods for coupling chlorocyclobutenones with vinylzirconium reagents and subsequent rearrangement of the resulting products were also describcd. The method has also been applied to the benzannulation of aromatic heterocycles (Scheme 22),"') and has been used as an approach to the otherwise relatively inaccessiblc benzocyclobutenedione monoacetals 435 and 438 (Scheme 23).26' Examination of the general scheme (Scheme 20) shows that hydroquinones 422 (R3 =OH) and resorcinols 422 (R' or R' = OR) arc readily accessible.By making use of the conjugate addition of unsaturated organometallics 440 to cyclobutenediones 439, trapping of the enolatc so formed, and thermolysis, monoprotected catcchols 442 may be prepared (Scheme 24).'"' The scope o f this reaction variant is ilustrated in Schemes 25 to 27. By using metallated benzo- or naphtho- quinones, highly substituted naphtho- and anthra- quinones have been prepared.'"l Recent extensions to the work have been a general route to highly oxygenated, angularly fused polycyclic aromatic hydrocarbons 452,2h4 and acyl-substituted aromatics 453 and 454.''' Moore has described a method, based upon thc same general principle described abovc (Scheme 20) which allows the preparation of chlorophcnols 456 and chloronaphthols 458 (Scheme 28).2f'f' Prior displacement of the halogen substituted with alcohols and thiols gave, after rcarrangcmcnt.t tic 556 Contemporary Organic SynthesisR' + R(unsat)-M $R(unsat) R2 H 423 424 425 1 OH R'* R2 H 426 Scheme 21 427 428 R' = Me, Et, Bu , z = 0,s 10% tri(2-furyl)phosphine dioxane, 50-100 "c ii. Ac20, py "&TMS ' z R2 429 5&78% R' R2 424 426 Yield (%) OH a b C d e f 9 h i i K Me Me Me Me Me Bu Bu Bu Me Ph Me OPr' opi opi NBn, NBn2 Bu Bu Bu Ph Me @SnBu3 OEt A S n B u 3 PhSnMe3 @SnBu3 OEt A S n B u 3 &SnBu3 OEt A S n B u 3 PhSnMe3 &SnBu3 @SnBu3 67 55 53 62 74 74 54 77 75 75 Ph E t o F C O M e SnBu3 M e w M e Ph 50 naphthols 460 and 462.266 Rearrangement of alkynyl- substituted chlorocyclobutenones necessarily goes through a diradical of structure 465 (Scheme 29).'" The fate of this depends upon the nature of the substituents R' and R2.Thus, the dipentynylcyclo- butenone 466 gave 469 and 470 upon thermolysis, + B u 3 S n a R 3 R2 CI 427 430 R' = Me, Et, Ph, Bu , R2 = Et, Bu, Ph, OPS, Me R3 = H, Me z=o,s I OAc R'yJ--y3 R2 431 51 -94% SnBu3 427 R' = Me, Et R2 = Et, Ph 432 z=o.s t 433 60-78% Scheme 22 resulting from the two alternative modes of cyclisa- tion of the rearranged radical 468 (Scheme 29). The homologous compound 471 gave four products, again resulting from single hydrogen transfer-ring closure (474 and 475) or double hydrogen transfer (472 and 473). The isomeric cyclobutenone 476 gave the expected spiro compound 477 and alkene 478, none of the isomeric chromanol, and the radical fragmentation product 479.Thermolysis of diynes 480 gave only the cyclised products 481, resulting from ring closure of the rearranged prop-2-ynyl Williams: The synthesis of carbocyclic aromatic systems 557HO 03 03 427 434 R' = Me, Et, Bu, BuS,Bu',,Ph R2 = Me, Et, Bu, Ph, OPr' 435 56-99% OH 436 437 438 a R ' = R ~ = B U a 79% b R' = Ph, R2= Me 57% I b R' = Me, R2 = Ph c R'= Ph, R2= Me Scheme 23 R' 'OP 439 440 441 442 Scheme 24 radicals.267 A recent application of this approach to pyranoquinone synthesis has been reported.'@ The hydroxycyclobutanone 482 rearranged in 46% yield to hydroquinone 483.269 The alkynylmethylenecyclo- butene 484 rearranged, on heating in methanol, to the phenol 485 in 42% yield.The diradical 486 is thought to undergo [ 1,5] hydrogen atom migration to give a quinomethane which was trapped with solvent. Evidence for the intermediacy of diradical 486 came from the isolation, in 65% yield, of phenol 487, when the reaction was performed in cyclohexa- 1,4-diene, arising from hydrogen atom abstraction from the solvent (Scheme 30).270 Rearrangement of allene-substituted alkylidene cyclobutenes 488 gives benzocyclobutenes 489, via orthoquinodimethanes (Scheme 31).27' The geometrical isomers of starting materials 488 were cyclised independently, hence the ranges of yields quoted. The benzocyclobutene 489d was accompanied by 5% of phenol 490, which was thought to be derived from an orthoquinodi- methane by a [1,5] hydrogen shift.The furanohy- droquinone 492 was obtained in good yield upon thermolysis of cyclobutenone 491 in toluene.272 An application of this methodology to isochromanqui- none synthesis has been described (Scheme 32).273 The yields of hydroquinones were not quoted; those shown in Scheme 32 are minima, in that they repre- sent the isolated yield of quinone, after deprotection and oxidation. Recently, Moore has described a CUL, 443 444 445 Scheme 25 H? R2 "%(OP R' A1 446 Yield (%) R' 444 P 446 a Bu b Me c Me d Bu e Bu f Me 9 Me PCuMeCNLi, Ph,CuCNLi, Me0 o"FucNLi2 AC MEM MEM AC MEM MEM MEM OAc QoAc Bu Bu Me &OMEM Me Me Me Me Me OH ph*oH Bu B U 6 Bu Bu MEM MeO OH Me0 Me OH &:,.M 0 Me 95 95 64 83 83 82 64 strategy for the synthesis of naphthols complemen- tary to that of Liebe~kind,~~' which depends upon the reductive dehydroxylation of 4-hydroxycyclobu- tenones, rather than a palladium cross-coupling, for the construction of the cyclisation precursors (Scheme 33).274 An extension of this approach involves treating the cyclobutenones 502 with alkylli- thium reagents 503, to give the allenes 504, which thermolyse to give the acylnaphthalenes 505 in high yield (Scheme 34).275 The synthetic uses of cyclobu- tenones have been reviewed.2763277 In addition to the general methods described above, a number of reactions of more restricted utility have been reported.Thermal rearrangement of spirothioether 506 gave tetrahydrobenzothiepine 507 in 82% yield.278 Treatment of the thiazolidines 508 and 510 with N-bromosuccinimide in chloro- form gave the 2,3-dihydrobenzothiazines 509 and 511 in excellent yields:279 the authors also described the formation of phenothiazines.Under very similar 558 Contemporaiy Organic SynthesisCuLn %OMEM R2 R1 447 444 Scheme 26 H 448 R' 444 448 Yield (%) OH a Ph Ph2CuCNLi2 &:FM 69 OH CuLn 449 450 451 R' 0 0 HO R7 453 R' = Ph; R2,R3 = (CH2)5; R4 = H, OMe; R5 = H, OMe, NMe2; R4,R5 = benzo; R6 = H, OMe; R7 = H, OMe; R6,R7 = benzo; &91% OAc 454 R' = Me, Ph; R2= H, Bn; R3 = But, Bn; R2,R3 = (CH2)5; R4 = H, R5 = Me; R4,R5 = CH=CHO, SCH=CH, OCH2CH2,O(CH2)3; 82-1 00% HO Me0 reflux xylene CI 455 456 a R'=Ph, R2=R3=H b R' = Ph, R2 = Me, R3 = H c R' = Bu, R2 = Me, R3 = H d R'=Bu,R2=R3=Me e R' = BuCd, R2 = R3 = H f R' = PhC4, R2 = R3 = H a 80% b 65% c 87% d 59% e 48% f 45% Scheme 27 HO n * Rw reflux xylene guph Me0 R' R2 450 451 Yield (%) CI a Bu Me Me b2CuCNLi2 Me Bu 455 456 Meo CI h e OH a R=Bu b R=Me c R=B$ d R = PhC& e R=BuC=C b Me Bu Me ')3$uCNLip Me Bu a 62% b 34% c 80% e 78% d 76% HO c Ph H Ph2CuCNLi2 &OMEM 69 phflo - PhSH, Et*Ophflo - reflux p h ~ SPh xylene / / cI EtSN, 68% Ph Me0 SPh Ph Ph 457 R3 R4 R5 OAc PiOH, 1 Agz0 89% Ph 452 461 R' = Me, Ph; R2 = Me, OPi; R3 = Me, Et, Ph; R4 = Et, OPi; R5 = H, OAC; 17-96% Scheme 28 459 460 HO reflux xylene 74% Me0 bpi 462 Williams: The synthesis of carbocyclic aromatic systems 559R2 463 464 465 466 467 468 469 470 469:470=2: 1 Bu ?: heatxylene 55% ~ Me0 +H , + Me0 +H , + Me0 4 , + Meoh../ \ CI \ c1 \ c1 \ CI / Me Meo II Bu 471 472 473 474 475 471:472:473:474=1:1:1.3:2.5 Me Et heat, xylene * 55% Me0 CI + MeiEt Meo)kJ CI Me 476 477 478 + MeYEt " O q H CI 479 477:478:479=2:1 : 1 Scheme 29 Me0 Me0 R+(CH& M e o y o O M e Meow' Me0 :$'lH - Me$Bu Ph OH BU 480 a R = H b R=Ph Bu <OH - 481 a 87% b 76% OH Bul$ OH '7 / 485 CPh f ph MeQBu * MeQBu Ph OH Ph 487 OH 486 482 483 Scheme 30 560 Contemporary Organic Synthesis9' fy Me0 HO c P h a R ' R3SiH Rv ___) reflux " ' ~ - R3, R4 / / Ar - R2 R2 R2 TFA 64-96%0 \ OH 6049% R2 R3 1350 OR^ _ .. 488 489 a R' = Ph, R2 = R3 = H, R4 = Me, R5 = TMS a 49432% b R' = Ph, R2 = R3 = TMS, R4 = But, R5 = H C R' = C5H11, R2 = R3 = TMS, R4 = Bu', R5 = H b 4944% C 35% d R' = Ph, R2 = TMS, R3 = C3H7, R4 = Me, R5 = H d 30% Scheme 31 Me0 HO Ph* 0 5% Me0 TMS 490 / Me OH Me Me 491 492 OTIPS 493 a R'=R2=OMe b R' = Ph, R2 = OMe c R'=R2=OPi d R' = Ph, R2= OPi 8 R' = OPi, R2 = Ph ATIPS 495 HO Me OTIPS 494 a minimum38% b minimum50% c minimum61% d minimum7Ph 8 minimum70% PhNH Me Ph - pie% HO OTIPS 496 499 500 501 R' = Bu, Bus, BuGC, Ph, M e 0 9 Me0 R~ = opi, OMe, NH Scheme 33 R' & ___t R3Li R3yR' 503 \ Ar R20 Ar 6248% , 3 2 0 502 504 R' = Bu, MOM R3 = Bu, Ph R2 = Me, Pr' 9 3 fR' Ar = Ph, d , ($ ' m - ~ 4 , ~ 5 R20 \ / \ / OMe Me0 Me0 OMe R4,R5 = H, OMe 505 Scheme 34 '\ CN CN 506 507 Ac 508 509 Me0 Ac &q TMSO Mq \ / a;1.c02Me I 92% S 51 1 Q5**co2Me \ rMSO 0 0 OTIPS OTIPS 51 0 497 498 NBS, CHpCI, Do + HS-XH 60 5842% mi", 0 'CD a:] 51 2 51 3 51 4 R R=H,Me x = o , s Ill TIPS = sipi3 nanaomycin D Scheme 32 Williams: The synthesis of carbocyclic aromatic systems 561conditions cyclohexanones.512 were converted to 2,3-dihydro-l,4-benzodithiines and 1,4-benzoxa- thiines 514.280 The conversion of allenyl enol ether 515 to catechol 517 was initiated by treatment with cation radical 516;281 protected catechol 519 was formed upon rearrangement of epoxide 518.282 Treatment of Diels-Alder adduct 520 with a catalytic quantity of boron trifluoride in dichloro- methane at reflux gave a 99% yield of phthalate 521.283 The benzyne-derived cycloadduct 522 gave the naphthol 523 upon treatment with methanolic hydrogen Acid-catalysed rearrangement of methano[ lolannulene derivative 524 gave the naphthocyclopropanecarboxylate 525.285 Related acid-catalysed rearrangements forming substituted monocyclic arenes have been Acid- catalysed rearrangement of tetraene 526, using hydrobromic acid in acetic acid, gave the monoaro- matic steroid 527 in 72% yield.36 Reaction of dihalo- carbenes with alkylated cyclopentadienes gave halodialkylbenzenes, for example in the conversion of 528 to 529.2s8 Basic or nucleophilic rearrange- 51 5 51 7 51 8 51 9 O Y M e O Y M e C02Me C02Me BFpEt20 reflux, 2 h 99% 520 O Y OH OMe 521 Me? Me0 OH HCl(conc.aq.) Meom MeOH, 76% reflux * 522 523 C02Me AQO (1 equiv.) SnCl (2 equiv.) CH28I2, 30 min 0 "C C02Me 525 & 524 Et JMe / / 526 HBr (48% aq.) AcOH, 1 h reflux, 72% Et I 8 / 527 Me %Me Me CHC13 I x BnEt3N*Cr 528 529 & MeNH2, EtOH 90% ' Me 530 531 NaOH (20% as.) EtOH, N2 2 h, 45% CHO Me - 1 fl +N Me Me 532 533 OH O G O - 4 TFA 95% * o a - 534 535 ment of pyridinium salts has been used to prepare substituted nitroanilines (530 to 531)289 and indoles (532 to 533).290 Treatment of the oxaheptalenone 534 with trifluoroacetic acid gave the benzotropone 535 in 95% yield.29' Aryl-substituted naphthalenes have been prepared by the photolysis of 5'5-diaryl- 4,5-dihydrofuran~,~~~ and tri-substituted naphtha- lenes by pyrolysis of arylmethylidene Meldrum's acid.293 7 References 1 A.P. Charlton,Annu. Rep. bog. Chem., Sect. B, 05. Chem., 1992,89, 143. 562 Contemporary Organic Synthesis2 A. P. Charlton, Annu. Rep. Prog. Chem., Sect. B, 0%. Chem., 1992, 89, 161. 3 A. P. Charlton, Annu. 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ISSN:1350-4894    

DOI:10.1039/CO9960300535

出版商:RSC    

年代:1996

数据来源: RSC