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 (ne6 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, Hawurd University Professor S. Hanessian, Universite' de Montre'al Professor M. Julia, Universitk de Paris XI (Paris-Sud) Professor P. D. Magnus, University of Taus 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, Iwine Professor L. F. Tietze, University of Gbttingen 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 the Senior Editor (Reviews), Books and Reviews Department, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF.Members of the Royal Society of Chemistry may subscribe to Contemporary Organic Synthesis by placing their orders on the Annual Subscription renewal forms in the usual way. All other orders accompanied with payment should be sent directly to The Royal Society of Chemistry, The Distribution Centre, Blackhorse Road, Letchworth, Herts SG6 lHN, England. 1995 subscription rate: EEA E165, USA $303, Canada El73 (plus GST), Rest of the World E173. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October, December. Airfreight and mailing in the USA by Mercury Airfreight International Ltd, 2323 Randolph Avenue, Avenel, New Jersey, NY 07001 USA and at additional mailing offices. Second class 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 Armail within Europe and Accelerated Surface Post outside Europe. 0 The Royal Society of Chemistry, 1995 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of the publishers. Typeset by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho LtdContemporary Organic Synthesis Editorial Board Professor G. Pattenden, FRS (Chairman), University of Nottingham Professor P.D. Bailey, Heriot- Watt University Dr S. E. Gibson (neC 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, Harvard University Professor S. Hanessian, Universitk de Montrkal Professor M. Julia, Universitk de Paris XI (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 S. R. Buxton, Managing Editor, Organic Publications, The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 4WF, UK. 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. 1995 subscription rate: EEA f165, USA $303, Canada El73 (plus GST), Rest of the World f173. Contemporary Organic Synthesis is published 6 times a year in February, April, June, August, October, 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. Second class 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, 1995 All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form, or by any means, electronic, mechanical, photographic, recording or otherwise, without the prior permission of the publishers. Typeset in Great Britain by Unicus Graphics Ltd Printed in Great Britain by Whitstable Litho Ltd

ISSN:1350-4894    

DOI:10.1039/CO99502FX021

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

EUCHEM Conference on Tycloadditions and Related Reactions: Theory and Practice” Vulcano Island, Italy, 21-24 June, 1995 Address for Correspondence: Prof. Mario Gattuso - Universith di Messina Dpt di Chimica Organica e Biologica - Salita Spemne 31, S. Agata 98166 MESSINA, Italy - FAX +39 90 392840EUCHEM Conference on Tycloadditions and Related Reactions: Theory and Practice” Vulcano Island, Italy, 21-24 June, 1995 Address for Correspondence: Prof. Mario Gattuso - Universith di Messina Dpt di Chimica Organica e Biologica - Salita Spemne 31, S. Agata 98166 MESSINA, Italy - FAX +39 90 392840

ISSN:1350-4894    

DOI:10.1039/CO99502BX023

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

ISSN 1350-4894 COGSE6 2 (5) 289-364 (1995) Contemporary Organic Synthesis A journal of current developments in Organic Synthesis VOLUME 2 NUMBER 5 CONTENTS Synthetic developments in host-guest 289 chemistry By James Dowden, Jeremy D. Kilbum, and Paul Wright Reviewing the literature published in 1994 MeS )=NAC02Et R' 9- "- & d' Protecting groups 315 By Knysztof Jarowicki and Philip Kocienski Revkwing the literature published in 1994 Synthesis of aromatic heterocycles 337 By Thomas L. Gilchrist Reviewing the literature published between July 1993 and Februaly I995 Nitro and related compounds 357 By Graeme Robertson Reviewing the literature published between December 1993 and May 1995Cumulative Contents of Volume 2 Number 1 1 Aromatic heterocycles as intermediates in natural product synthesis (up to the end of 1993) Michael Shipman 19 The hydrometallation, carbometallation, and metallometallation of heteroalkynes (up to August 1994) Sharon Casson and Philip Kocienski 35 Serotonin, sumatriptan, and the management of migraine Alexander Oxford 43 Stoichiometric organotransition metal complexes in organic synthesis ( I September 1993 to 31 August 1994) Julian Blagg Number 2 65 Catalytic applications of transition metals in organic synthesis (1 September 1993 to 31 August 1994) Christopher G.Frost and Jonathan M. J. Williams 85 Organic halides (1 July 1993 to 30 June 1994) Peter L. Spargo 107 Carboxylic acids and esters (1 January 1993 to 31 July 1994) T. Harrison and T. Laduwahetty 121 Hypervalent iodine in organic synthesis: a-functionalization of carbonyl compounds (up to February 1995) Om Prakash, Neena Saini, Madan €! Tanwar, and M.Moriarty Number 3 133 Saturated and unsaturated lactones (1 January 1993 to 31 July 1994) T. Laduwahetty 151 Aldehydes and ketones (July 1993 to September 1994) Patrick G. Steel 173 a-Cation equivalents of amino acids (up to the end of 1994) Patrick D. Bailey, Andrew N. Boa, and Joanne Clayson 189 Saturated oxygen heterocycles (1 April 1993 to 30 September 1994) Christopher J. Burns Number 4 209 Saturated nitrogen heterocycles (June 1993 to December 1994) Timothy Harrison 225 Synthesis and use of cyclic peroxides (January 1992 to January 1993) K . J . McCullough 251 Recent advances in organofluorine chemistv (January 1992 to April 1995) Jonathan M.Percy 269 Amines and amides (1994) Michael North Number 5 289 Synthetic developments in host-guest chemistry (1994) James Dowden, Jeremy D. Kilbun, and Paul Wright 315 Protecting groups (1994) Krzysztof Jarowicki and Philip Kocienski 337 Synthesis of aromatic heterocycles (July 1993 to February 1995) Thomas L. Gilchrist 357 Nitro and related compounds (December 1993 to May 1995) Graeme Robertson Articles that will appear in forthcoming issues include Dispiroketals: A new functional group for organic synthesis Steven V. Ley, Robert Downham, Paul J. Edwards, Jean E. Innes and Martin Woods Methods for the asymmetric preparation of amines Anders Johansson Synthesis of thiols, suifides, sulfoxides and sulfones Christopher M. Rayner Saturated and unsaturated hydrocarbons Richard €! C. Cousins Stoichiometric applications of organotransition metal complexes in organic synthesis Timothy J. Donohoe Saturated and partially unsaturated carbocycles Christopher D. J. Boden and Gerald Pattenden Alcohols, ethers and phenols C. S. Hau, Ashley N. Jarvis and J. B. Sweeney The discovery of fluconazole K. Richardson

ISSN:1350-4894    

DOI:10.1039/CO99502FP025

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

128 G. Handke and N. Krause, Tetrahedron Lett., 1993,34, 129 C. Darcel, S. Bartsch, C. Bruneau and P.H. Dixeuf, 130 T. Moriya, N. Miyaura and A. Suzuki, Synlett, 1994, 131 H. Bienaym6, Tetrahedron Lett., 1994,35,7387. 132 Y.S. Lee, K.H. Nam, S.H. Jung and H. Park, 133 P. Rochet, J-M. Vatkle and J. Go&, Synthesis, 1994, 134 H-F. Chow, X-P. Cao and M. Leung, J. Chem. SOC., 135 F. Toda, K. Tanaka and H. Nawata, J. Chem. SOC., 136 B.J.L. Royles and D.M. Smith, J. Chem. SOC., Perkin 137 V. Ratovelomanana, Y. Rollin, C. GCbkhenne, 6037. Synlett, 1994, 457. 149. Synthesis, 1994, 792. 795. Chem. Commun., 1994,2121. Perkin Trans. 1, 1994, 2043. Trans. 1, 1994, 355. C. Gosmini and J. Perichon, Tetrahedron Lett., 1994, 35, 4777. 138 D. Grandjean, P. Pale and J. Chuche, Tetrahedron Lett., 1994,35, 3529.139 K. Kusuda, K. Kawamura, Y. Ueno and T. Toru, Tetrahedron Lett., 1993, 34, 6587. 140 K. Miwa, T. Aoyama and T. Shioiri, Synlett, 1994, 107. 141 G.G. Melikyan, R.C. Combs, J. Lamirand, M. Khan and K.M. Nicholas, Tetrahedron Lett., 1994, 35, 363. 142 K. Iida and M. Hirama, J. Am. Chem. SOC., 1994,116, 10310. 143 M. Yoshimatsu, H. Yamada, H. Shimizu and T. Kataoka, J. Chem. SOC., Chem. Commun., 1994, 2107. Lett., 1993, 34, 5403. Tetrahedron Lett., 1994,35, 7615. 5975. 59, 6877. SOC., Chem. Commun., 1994, 1845. 1829. 4738. 713. 144 M. Alami, F. Ferri and G. Linstrumelle, Tetrahedron 145 T. Mandai, Y. Tsujiguchi, S. Matsuoka and J. Tsuji, 146 S. Ikeda and Y. Sato, J. Am. Chem. SOC., 1994, 116, 147 S. Ikeda, D.-M. Cui and Y. Sato, J. 0 ~ .Chem., 1994, 148 C. Darcel, C. Bruneau and P.H. Dixeuf, J. Chem. 149 K.K. Wang and Z. Wang, Tetrahedron Lett., 1994,35, 150 Z. Wang and K.K. Wang, J. 0%. Chem., 1994,59, 151 M.E. Maier and D. Langenbacher, Synlett, 1994, 152 J. Isihara, N. Kanoh, A. Fukuzawa and A. Murai, 153 K.K. Wang, Z. Wang and Y.G. Gu, Tetrahedron Lett., 154 H. Hopf and M. Theurig,Angew. Chem., Znt. Ed. 155 M. Moniatte, M. Eckhardt, K. Brickmann, Chem. Lett., 1994, 1563. 1993,34,8391. Engl., 1994,33, 1099. R. Bruckner and J. Suffert, Tetrahedron Lett., 1994, 35, 1965. Tetrahedron Lett., 1994, 35, 5689. Tetrahedron Lett., 1994, 35, 5645. 50,5335. 156 M. Yamaguchi, K. Omata and M. Hirama, 157 C. Meyer, I. Marek, J-F. Normant and N. Platzer, 158 D. Chemin and G. Linstrumelle, Tetrahedron, 1994, 159 S.A.Hitchcock, S.H. Boyer, M.Y. Chu-Moyer, S.H. Olson and S. J. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994, 33, 858. 160 T. Brandstetter and M.E. Maier, Tetrahedron, 1994, 50, 1435. 161 H. Audrain, T. Skrydstrup, G. Ulibarri, C. Riche, A. Chiaroni and D.S. Grierson, Tetrahedron, 1994, 50, 1469. K.M. Pham, D.M. Vyas and M.D. Wittman, Tetrahedron, 1994, 50, 1519. 482. 35, 37. 35, 2655. Tetrahedron Lett., 1994,35, 7997. R.A. Fairhurst, J. Chem. SOC., Chem. Commun., 1994, 1543. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994,33, 2477. 169 M.D. Shair, T. Yoon and S.J. Danishefsky, J. 0%. Chem., 1994,59,3755. 170 M.F. Braiia, M. Moran, M.J.P. de Vega and I. Pita- Romero, Tetrahedron Lett., 1994,35, 8655. 171 K. Toshima, K. Yanagawa, K. Ohta, T. Kano and M.Nakata, Tetrahedron Lett., 1994, 35, 1573. 172 P. Magnus, Tetrahedron, 1994,50, 1397. 173 D. Elbaum, T.B. Nguyen, W.L. Jorgensen and S.L. 162 J.F. Kadow, D.J. Cook, T.W. Doyle, D.R. Langley, 163 T. Nishikawa, S. Shibuya and M. Isobe, Synlett, 1994, 164 J.M. Nuss and M.M. Murphy, Tetrahedron Lett., 1994, 165 R.S. Huber and G.B. Jones, Tetrahedron Lett., 1994, 166 T. Nishikawa, M. Yoshikai, K. Obi and M. Isobe, 167 P. Magnus, D. Parry, T. Iliadis, S.A. Eisenbeis and 168 M.D. Shair, T. Yoon, T-C. Chou and S.J. Schreiber, Tetrahedron, 1994,50, 1503. Cousins: Saturated and unsaturated hydrocarbons 461128 G. Handke and N. Krause, Tetrahedron Lett., 1993,34, 129 C. Darcel, S. Bartsch, C. Bruneau and P.H. Dixeuf, 130 T. Moriya, N. Miyaura and A. Suzuki, Synlett, 1994, 131 H.Bienaym6, Tetrahedron Lett., 1994,35,7387. 132 Y.S. Lee, K.H. Nam, S.H. Jung and H. Park, 133 P. Rochet, J-M. Vatkle and J. Go&, Synthesis, 1994, 134 H-F. Chow, X-P. Cao and M. Leung, J. Chem. SOC., 135 F. Toda, K. Tanaka and H. Nawata, J. Chem. SOC., 136 B.J.L. Royles and D.M. Smith, J. Chem. SOC., Perkin 137 V. Ratovelomanana, Y. Rollin, C. GCbkhenne, 6037. Synlett, 1994, 457. 149. Synthesis, 1994, 792. 795. Chem. Commun., 1994,2121. Perkin Trans. 1, 1994, 2043. Trans. 1, 1994, 355. C. Gosmini and J. Perichon, Tetrahedron Lett., 1994, 35, 4777. 138 D. Grandjean, P. Pale and J. Chuche, Tetrahedron Lett., 1994,35, 3529. 139 K. Kusuda, K. Kawamura, Y. Ueno and T. Toru, Tetrahedron Lett., 1993, 34, 6587. 140 K. Miwa, T. Aoyama and T. Shioiri, Synlett, 1994, 107.141 G.G. Melikyan, R.C. Combs, J. Lamirand, M. Khan and K.M. Nicholas, Tetrahedron Lett., 1994, 35, 363. 142 K. Iida and M. Hirama, J. Am. Chem. SOC., 1994,116, 10310. 143 M. Yoshimatsu, H. Yamada, H. Shimizu and T. Kataoka, J. Chem. SOC., Chem. Commun., 1994, 2107. Lett., 1993, 34, 5403. Tetrahedron Lett., 1994,35, 7615. 5975. 59, 6877. SOC., Chem. Commun., 1994, 1845. 1829. 4738. 713. 144 M. Alami, F. Ferri and G. Linstrumelle, Tetrahedron 145 T. Mandai, Y. Tsujiguchi, S. Matsuoka and J. Tsuji, 146 S. Ikeda and Y. Sato, J. Am. Chem. SOC., 1994, 116, 147 S. Ikeda, D.-M. Cui and Y. Sato, J. 0 ~ . Chem., 1994, 148 C. Darcel, C. Bruneau and P.H. Dixeuf, J. Chem. 149 K.K. Wang and Z. Wang, Tetrahedron Lett., 1994,35, 150 Z. Wang and K.K. Wang, J. 0%. Chem., 1994,59, 151 M.E.Maier and D. Langenbacher, Synlett, 1994, 152 J. Isihara, N. Kanoh, A. Fukuzawa and A. Murai, 153 K.K. Wang, Z. Wang and Y.G. Gu, Tetrahedron Lett., 154 H. Hopf and M. Theurig,Angew. Chem., Znt. Ed. 155 M. Moniatte, M. Eckhardt, K. Brickmann, Chem. Lett., 1994, 1563. 1993,34,8391. Engl., 1994,33, 1099. R. Bruckner and J. Suffert, Tetrahedron Lett., 1994, 35, 1965. Tetrahedron Lett., 1994, 35, 5689. Tetrahedron Lett., 1994, 35, 5645. 50,5335. 156 M. Yamaguchi, K. Omata and M. Hirama, 157 C. Meyer, I. Marek, J-F. Normant and N. Platzer, 158 D. Chemin and G. Linstrumelle, Tetrahedron, 1994, 159 S.A. Hitchcock, S.H. Boyer, M.Y. Chu-Moyer, S.H. Olson and S. J. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994, 33, 858. 160 T. Brandstetter and M.E.Maier, Tetrahedron, 1994, 50, 1435. 161 H. Audrain, T. Skrydstrup, G. Ulibarri, C. Riche, A. Chiaroni and D.S. Grierson, Tetrahedron, 1994, 50, 1469. K.M. Pham, D.M. Vyas and M.D. Wittman, Tetrahedron, 1994, 50, 1519. 482. 35, 37. 35, 2655. Tetrahedron Lett., 1994,35, 7997. R.A. Fairhurst, J. Chem. SOC., Chem. Commun., 1994, 1543. Danishefsky, Angew. Chem., Znt. Ed. Engl., 1994,33, 2477. 169 M.D. Shair, T. Yoon and S.J. Danishefsky, J. 0%. Chem., 1994,59,3755. 170 M.F. Braiia, M. Moran, M.J.P. de Vega and I. Pita- Romero, Tetrahedron Lett., 1994,35, 8655. 171 K. Toshima, K. Yanagawa, K. Ohta, T. Kano and M. Nakata, Tetrahedron Lett., 1994, 35, 1573. 172 P. Magnus, Tetrahedron, 1994,50, 1397. 173 D. Elbaum, T.B. Nguyen, W.L. Jorgensen and S.L. 162 J.F. Kadow, D.J. Cook, T.W. Doyle, D.R. Langley, 163 T. Nishikawa, S. Shibuya and M. Isobe, Synlett, 1994, 164 J.M. Nuss and M.M. Murphy, Tetrahedron Lett., 1994, 165 R.S. Huber and G.B. Jones, Tetrahedron Lett., 1994, 166 T. Nishikawa, M. Yoshikai, K. Obi and M. Isobe, 167 P. Magnus, D. Parry, T. Iliadis, S.A. Eisenbeis and 168 M.D. Shair, T. Yoon, T-C. Chou and S.J. Schreiber, Tetrahedron, 1994,50, 1503. Cousins: Saturated and unsaturated hydrocarbons 461

ISSN:1350-4894    

DOI:10.1039/CO99502BP027

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Synthetic developments in host-guest chemistry JAMES DOWDEN, JEREMY D. KILBURN, and PAUL WRIGHT Department of Chemistry, University of Southampton, Southampton, SO1 7 lBJ, UK Reviewing the literature published between January and December 1994 Continuing the coverage in Contemporary Organic Synthesis, 1994, 1, 259 1 2 2.1 2.2 2.3 2.4 3 3.1 3.1.1 3.1.2 3.1.3 3.2 3.3 3.4 4 4.1 4.2 4.3 5 5.1 5.2 6 7 Introduction Crown ethers and cryptands Crown ethers Azacrown ethers and related compounds Thiacrown ethers Crypt ands Calixarenes Calix[4]arenes Modifications to the lower rim Modifications to the upper rim Other modifications Calix[6]arenes Calix[8]arenes Double calixarenes Cyclophanes All carbon cyclophanes Heteroatom-containing cyclophanes Cage-type cyclophanes Cleft receptors and molecular bowls Cleft receptors Molecular bowls Self-assembling receptors References 1 Introduction The study of artificial receptors is critical to our understanding of molecular recognition phenomena, and leads to the design and synthesis of supramolecular materials with tailored properties.Not surprisingly, much of the interest in this area focuses on the recognition properties of the receptors, a subject which is frequently reviewed in the literature. However, before the properties of a new receptor can be investigated, the receptor must, of course, be synthesized. The importance of efficient synthesis in this area cannot be overstated if sufficient material is to be obtained for study, in a realistic time-span. Receptor synthesis is often far from trivial, particularly for the synthesis of large macrocyclic compounds, and can rival natural product synthesis in complexity and elegance.The purpose of this article is to review developments in host-guest chemistry, over the period January to December 1994, with the emphasis on the synthetic aspects. As before,' the review is divided into sections using conventional categorization of the type of receptor concerned, but because, increasingly, receptors are being prepared with features of more than one structural type, these categorizations become somewhat arbitrary! 2 Crown ethers and cryptands 2.1 Crown ethers Two reviews on crown ethers have appeared this year dealing with bis- and oligo-(benzocrown ethers)' and metallomacrocycles based on, and incorporating, crown ether^.^ Chiral crown ethers are of interest because of their enantioselective binding properties.A crown ether incorporating a glucose unit has been synthesized in six steps from a-ally1 glucopyranoside 1 (Scheme l).4 The diallyl derivative 2 was subjected to ozonolysis followed by reductive work-up to give diol3 in 79% yield. The macrocycle 5 was then formed in 34% yield by reaction of 3 with triethylene glycol ditosylate 4 and sodium hydride in refluxing tetrahydrofuran. 1 5 (34%) 2 (i) O,, MeOH, -78 "C (ii) NaBH., NaH, THF 70 "C, 24 hr - C O T S L O T S OH 3 (79%) 4 Scheme 1 The synthesis of large crown ethers can be problematic, but Gibson has reported' full details of an approach to the synthesis of 30-72 membered crown ethers by combining oligo(ethy1ene glycols) and oligo(ethy1ene glycol) ditosylates to give the [ 1 + 11 or [2 + 21 condensation products 8 or 9 (Scheme 2).In order to maximize the yield of the Dowden, Kilhurn, and Wright: Synthetic developments in host-guest chemistry 289HO(CH2CHZO)a H + TsO(CH2CH20)b TS 6 7 [1+1] 8 [2+2] 9 Scheme 2 [2 + 21 product 9, 0.5 equivalents of ditosylate was added slowly to the dialkoxide before dilution of the mixture and addition of a further 0.5 equivalents of ditosylate. The readily available starting materials and the ability to optimize the reaction conditions allow the preparation of large crown ethers on a 100 g scale. synthesized by reaction of malonyl chloride with the corresponding diol (Scheme 3).6 Triphenyl antimony was used to template the preferred formation of the [1+ 11 product 11 relative to the [2+2] product 12.Armed crown ethers 11 and 12 have been 10 0-0 11 (40%) + 12 (15%) Scheme 3 A [2 + 21 intramolecular cyclization reaction was used to prepare a novel crown ether derivative with two cation ligating side-chains (Scheme 4).' The key [2 + 21 cyclization gave the 'crownophane' intermediate 15 in 95% yield and was subsequently converted into 16, which displayed a particular selectivity for Ag' ions. of furan with hydroxymethylfuran, in the presence of boron trifluoride etherate, giving the trifuran 19 and difuran 20 in 20 and 28% yields respectively.8 The difuran could then be cyclized by treatment with boron trifluoride etherate and dimethoxymethane to give the 'calkfuran' 21 in 6% yield (Scheme 5).Cyclic oligofurans have been prepared by reaction X 13 O V 0 0-0 /o 0, 16 Reagents: (i) 1.3-dioxane-5,5-methand, NaH, THF; (ii) hu (>28C)nrn), MeCN. N,; (iii) steps Scheme 4 17 18 OH 10 eq. 19 (20%) + ) - 20 (28%) 21 (6%) Scheme 5 Other functionalities have been incorporated within the ring of the crown system, including thiophene' and disulfide bonds," the latter being synthesized by closure of the S-S bond using benzyltriethylammonium tetrathiomolybdate (C6H5CH2NEt3)2M~S4. The synthesis of a series of perfluoro crown ether based macrocycles" and crowns with pendant sugars12 have also been reported. 2.2 Azacrown ethers and related compounds Simple azacrowns may be regarded as nitrogen analogues of crown ethers with the potential for incorporating additional functionality on the nitrogen atoms. As with large crown ethers, the synthesis of large azamacrocycles can be difficult. To overcome the unfavourable entropy associated with large ring formation, relatively rigid six-membered rings have been incorporated within the macro~ycle.'"'~ Thus, reaction of triamine 22 with ditosylate 23 forms the intermediate 24, containing two piperazine rings, which can then be incorporated into the macrocycle 27 by standard methodology, giving a reasonable yield of 19% for the final cyclization (Scheme 6).290 Contemporary Organic Synthesisn Me-,N + Ts-,N - k-,N 22 23 24 R = TS (74%) 25R=H (72%) Me-N N-Me 27R=Ts (19%) 28R=H (62%) Scheme 6 Using more flexible precursors, the combination of a dihalogenoalkane with an N-pertriflated polyamine gave either the [ 1 + 11 or the [2 + 21 cyclization products 31 and 33, depending on the nature and concentration of reactants." Using potassium carbonate and the o, o '-dibromoalkanes at a concentration of 0.05 M in DMF, reaction with the N, N '-triflated amines gave the [ 1 + 11 product 31.However, reaction with o, a'-diodoalkanes, at higher concentrations (0.2 M), gave predominantly the [2 + 21 product 33. Subsequent deprotection with lithiumfliquid ammonia gave the corresponding azamacrocycles in good yield (5570%) (Scheme 7). A novel approach to azamacrocycles with substitution on the carbon backbone involves the complete reduction of polypeptide macrocycles.'6 29 30 31 [ltl] product n =1,2 (50%) r / - T f L L T f Tf -N + 29 Reagents: (i) K&03, Scheme 7 I 3 32 DMF, & Peptide synthesis is well established and allows straightforward preparation of the linear precursor 34 which can be cyclized with diphenylphosphoryl azide in yields ranging from 30-78%, depending on the nature of the substituents (amino acids that have been used in this approach include glycine, alanine, 0-benzyltyrosine and 0-benzylserine) (Scheme 8).Reduction with lithium aluminium hydride then gave the desired azamacrocycles 36 with yields generally greater than 55%. 34 -20 -0°C LiAH, THF 35 (30-78%) 36 (23-71%) Scheme 8 In related work, also relying on amide bond formation and subsequent reduction, Lennon et ul." have prepared azamacrocycles by condensation of bis(ch1oroacetamides) of chiral diamines with tris(N- tosy1)diethylenetriamine dianion.binaphthyl derivative (S)-37 and (R,R)-1,2-diamino- 1 ,Zdiphenylethylene 38 using imine formation (Scheme 9).18 (R)-37 reacted with 38, under the same conditions, to give polymeric material. This result was attributed to the ends of the growing Macrocycle 39 has been synthesized from the H p 0 H ( S ) - 37 - 4H20 - + HzN NHZ (R, R ) - 38 H 33 [2+2] produd (70%) 39 (42?!) [2+2] product Scheme 9 Dowden, Kilbum, and Wright: Synthetic developments in host-guest chemistry 291chain being far apart in the case of (4-37, but close enough together to close the macrocycle in the case of (Sb37. @CH(OEt)z OHC . I Azamacrocycles can, of course, be readily substituted on the nitrogen atoms as well as the carbon backbone. This is most generally achieved by simple alkylation or acylation followed by reduction as exemplified recently by the incorporation of catechols onto diaza-18-crown-6.19 Anthraquinone substituted crown ethers have been prepared in reasonable yield by reaction of fluoro- anthraquinones with monosubstituted diaza- crowns.2o Monofunctionalization of polyamine compounds can, however, be difficult due to the potential for multiple alkylation.Luis21 has reported the selective monoalkylation of the polyamine heterophane 40, with a stoichiometric amount of allyl bromide. In the presence of one equivalent of Zn2+, the coordination of three of the nitrogens to the zinc leaves one of the benzylic nitrogen atoms free to react with the allyl bromide, giving a 60% yield of the monoalkylated product 41 (Scheme 10).' N H ~ 40 Scheme 10 Phosphorus containing receptors are rare but a review covering a wide range of macrocycles based on phosphorus has been published.22 New macrocycles containing a combination of nitrogen, phosphorus, and silicon have been prepared, beginning with the lithiation of heterocycles 42 and coupling with appropriate silanes. Subsequent acetal hydrolysis gave the bis(heteroary1)silanes 43 in 95% yield, which on reaction with phosphono- dihydrazides gave the [2 + 21 macrocycles 44 in quantitative yield (Scheme ll).23 Metallic analogues of the classic crown ethers have also been reported, comprised of electrophilic mercury centres supported by a carborane skeleton. Icosahedral carborane cZoso-1,2-C2BloH12 45 was lithiated at the vertices by treatment with two equivalents of butyl lithium.Reaction with mercury halides gave tetrameric 47, while reaction with mercury acetate gave the trimer 46 (Scheme 12).24 The charge-reversed analogues of crown ethers were able to bind halide anions, and indeed the synthesis of 47 appeared to be templated by the iodide anion. 2.3 Thiacrown ethers 42 X = O x = s 43 X = 0 (95%) x = s (95%) (iii) 44 X=O,Y=O X=S,Y=O X=S,Y=S Reagents: (i) (a) Bu"Li (1.2 eq.), Et20, -15 "C - r.t.; (b) Me$3i(OEt)z, (c) H,O; (i) 6 N HCI, Et20, reflux; (iii) PhP(Y)[NMeNH&, CHCl3, r.t., 24 hr Scheme 11 45 , \HS& I 46 47 X = Br, CI, I Scheme 12 several reports of new strategies for the synthesis of such compounds this year. Condensation of dithiols 48 with aldehydes has been used to prepare sulfur crowns containing thioacetal units.25 Under appropriate conditions the [2+2] products 50 can be obtained in reasonable yields (Scheme 13).The same authors have described the synthesis of larger macrocyclic sulfur crown ethers (up to 24-membered rings), in good yields, using the conventional condensation of caesium dithiolates with appropriate dibromides.26 azacrown ethers) has been developed based upon condensation of the hypervalent sulfur-containing tetraazapentalene 51 with suitable i~othiocyanates.~' For example, condensation of 51 with diisothiocyanate 52 gave the thiocrown ether 53 in An unusual approach to azathiocrown ethers (and Thiacrown ethers are of interest because of the soft character of the ligating sites and there have been 45% yield.The hyplrvalent sulfur could be removed by treatment with sodium borohydride giving 54, 292 Contemporary Organic Synthesis48 49 50 Reagents: (i)PhCHO, C6H6. TsOH, 80 "C, 8 hr; or - 49 (2%) t 50 (62%) PhCHO, MeOH, HCI, 5&!55 "C, 50 hr - 49 (85%) + 50 (3%) Scheme 13 (,',!3 SCN 52 -(s PhH, 50 "C, 45 hr N-S-N S & W S NaBH4 U J SANANAS U 54 OH 56 n = 1 (46%) 55 59 /I = 1 (32%) n = 2 (19%) 58 n = 1 (16%) n = 2 (22%) Reagents: (i) 0,, NaBH,; (ii) TsCI, py, CH,CI,; (iii) Bun4NBr, NaHCO,, butan-2-one, reflux, 4 hr; (iv) Na,S, aq. EtOH, reflux; (v) Na, NH,; (vi) 0,; (vii) TsCI, DMAP, CH,CI,; (viii) AcSK, DMF; (ix) Me,SCI, Nal, MeCN; (x) NaOEt, CICH2CH20H; (xi) SOCI,; (xii) MeSNa, EtOH, MeCN Scheme 14 Scheme 15 incorporating two thiourea moieties, in 57% yield.(Scheme 14). A stereospecific synthesis of non-macrocyclic thioether ligands 59 (strictly thiopodands) has been reported." Protected cis-dihydroxycycloalkenes 55 were converted into thiopyrans 56 (Scheme 15). Activation of the secondary hydroxy groups of 56 was not practical with the ring sulfur atom in the reduced form because of rearrangements that are known to occur in such systems. Temporary oxidation to the sulfoxide 57 allowed the preparation of the required cis-ditosylates. Subsequent displacement with thioacetate gave the core structure with three sulfur atoms and the required configuration. After reduction of the sulfoxide the synthesis of 59 was completed in a straightforward manner. 2.4 Cryptands Novel cryptands have been prepared by bridging azacrowns 66 with the 1,lO-phenanthroline moiety 67 (Scheme 16).*' Starting from iminodiacetic acid, conversion into a cyclic anhydride followed by opening with dibenzylethylenediamine gave 64 in 82% yield.Reaction with a further equivalent of dibenzylethylenediamine and DPPA, followed by deprotection gave the azacrown 66. Further reaction with 2,9-bis(bromome t hy1)- 1,lO-phenant hroline 67 then gave the sodium bromide complexes of the [1+ 11 cryptand 68 (6%) and the [2+2] cryptand 69 (45%). A novel cryptand has been reported which exhibits selective binding of calcium and strontium cations with associated changes in the absorbance spectrum resulting from isomerization of the host on binding.3o Reduction of lactone 70 and functionalization gave hydroxyaldehyde 72 which was condensed with iodide 73 to give 74 (Scheme 17).Reaction of 74 with diazacrown ethers then gave cryptands such as 75, by a combination of amine and amide formation, in 18% yield. Chelators for tribasic cations, such as Fe3+ and In", have possible use in treatment of iron overload disease, as NMR contrast agents, and for radioimaging. The novel cryptand 81, incorporating hydroxamate functionality, has been synthesized by Hider, and the formation of 1 : 1 complexes with Fe3+ and In3+ has been ~tudied.~' Monoprotected 76 was coupled to the bis acid chloride 77 at high dilution in 50% yield (Scheme 18). Deprotection and acylation of the pendant nitrogen with 6-chlorohexanoyl chloride was followed by cyclization (at high dilution) to give the macro- bicycle 80 in 40% yield.Removal of the benzyl Dowden, Kilbum, and Wright: Synthetic developments in host-guest chemistry 293b 3 0 2 H 60 62 + 63 64 (82%) 67 Bn\ 66, K2C03 MeCN c n ?" 68 [1+1] (6%) 0 Bn Bn 0 I 69 [2+2] (45%) Scheme 16 groups required a two-step procedure. Reaction with dimethyl boron bromide followed by hydrogenation over palladium gave host 81 with free hydroxamate donor groups. A polyazacryptand has been prepared, templated by Co3+. Stereospecific sequential condensation of paraformaldehyde and propionaldehyde with a tripodal bis(triamine), in the presence of Co3+, led to intermediate 83 with encapsulation of the metal (Scheme 19). Subsequent reduction of the imines gave the hexaazabicycle 84 which had unusual structural and chromophore electron properties.32 Derivatization of the known polyazacryptand 85 with boron-tetrahydrofuran gave the adduct 86 in # "."u ? O b H L o , p - 9 74 u 75 (18%) Reagents: (i) LiAH,, THF, reflux, 48 hr; (ii) Buw, CICH20Me; (iii) Buki, Me2NCHO; ( i ) HCI, W H ; (v) HNO,; (vi) EtOH, 3 hr; (vii) 1 ,lO-diaza-[18)Croww6, P-chloro -1-rnethylpyridinium iodide, Et3N, CH& reflux, 3 hr Scheme 17 Boc 1 76 C,H, pyddine, 5 OC / hgh dilution 77 Scheme 18 79 294 Contemporary Organic Synthesis82 I - 83 (20-25%) 84 (>95%) Reagents: (i) ECHO, (CH20),, MeCN, Et,N, 2 hr, r.t.; (ii) NaBH,, pH 9-10,20 min, r.t. Scheme 19 3+ 77% yield (Scheme 20).33 The novel host 86 was found to bind small anionic guests (such as chloride and cyanide) by ion-dipole interactions. The selective complexation of anions by neutral receptors carries its own challenges and has been the subject of a recent Scheme 20 BH3 86 (77%) Novel cryptands based on amino acids with a phosphodiester linkage have been described.35 Thus, Boc-L-Ser(Bn)-OH 87 was coupled with an excess of diethylene glycol, followed by a second coupling with Boc-D-Ser(Bn)-OH, and the product carried through to the (R,S)-macrocycle 88 (Scheme 21).Deprotection and subsequent reaction of 89 with a phosphorodichlorite linked the two serine side- chains. Oxidation at phosphorus with meta chloroperbenzoic acid gave cryptand 90 (31% yield) which could be converted into the water soluble sodium salt 91. The corresponding (S, S)-macrocycle 92 could not, however, be crosslinked in the same way. A somewhat different cryptand containing phosphorus has been synthesized by a [2+3] <OBn 87 (R, S)-89 R = H (ii), (iii) Reagents: (i) H2.10% PdC; (ii) DIPEA, pCIC,H4CHzOPC12; (iii) m-CPBA (iv) 10%Pd/C, Hz, NaOAc, Bu'OH, H,O; (v) Sephadex LD-20 Scheme 21 cyclocondensation between the phosphotri- hydrazides 93 and the dialdehydes 94.36 The reaction gave good yields of the cryptands 95 (Scheme 22) when carried out in tetrahydrofuran with 4 molecular sieves. This methodology has been developed further to give a range of similar compounds.37 93 x = s 94 x=s x = o x=o 4 A molecular sieves, THF 24 hr, r.t. I 95 x = s, Y = s (60%) X = S , Y = 0 (6OYo) X = 0, Y = 0 (50%) Scheme 22 Dowden, Kilbum, and Wright: Synthetic developments in host-guest chemistry 295Relatively rigid ‘cryptaspherands’ 98 have been prepared by treating the appropriate dioxa- or oxa- alkanediamine 96 with two equivalents of 2,6-bis[3- (bromomethyl)-2-methoxy-5-met hyl- phenyll-4-methylanisole 97 and sodium carbonate in acetonitrile (Scheme 23).38 Me Me\ Me Me Me‘ Me 98 A = (CH2)20(CH2)20(CH2)2 (58%) A = (CH2)3O(CH2)2O(CH2)3 (53%) A = (CH2)30(CH2)3 (68%) Scheme 23 Water-soluble, non-ionic calixarenes are of interest as potential molecular receptors for highly polar organic molecules, such as amino acids and carbohydrates, in water. With this in mind Dondoni and Ungaro have introduced sugar moieties to both the lower and upper rim of calix[4]arenes.Lower rim functionalization was achieved by Mitsonobu glycosylation, for example reaction of calix[4]arene 99 with tetraacetyl-a, P-D-glucoside 100 in toluene gave a 1 : 1 mixture of a, P-bisglucoside 101 and a, a-bisglucoside 102 in 50% overall yield (Scheme 24).4* & OH 99 A.\ I OAc OAc I 101 a,&bisglucoside 1.5 eq. DEAD, m3r, toluene, r.1. * A c o S O H AcO + ’OAc 102 a,a-bisglucoside /”” AcO I I 101 : 102 1 : 1 ( W h overall) Scheme 24 3 Calixarenes 3.1 Calix[4] arenes 3.1.1 Modifications to the lower rim Modification of the lower rim of calixarenes is particularly attractive since it can be achieved by straightforward alkylation of the phenolic oxygens. The complete and partial alkylation of the free phenolic oxygens has already been examined in great detail and procedures for selective alkylation have been established. Pappalardo has now published an extensive study on the mixed alkylation of calix[4]arenes using a range of alkylating agents to generate chiral binding environment^.^^ Other recent work has focused on extending these ideas by alkylating with other reagents; for example, tetra 0- alkylation of p-t-butylcalix[4]arene with 4-bromo- butyronitrile, followed by reduction and reaction with alkyl and aryl (thio)isocyanates gave a series of thiourea derivatives that could form hydrogen bonds with spherical anions.4o Grigg has developed a luminescent pH sensor by O-alkylation of one or two of the free phenolic oxygens with bromomethylbipyridine, and subsequent formation of a trisbipyridylruthenium(I1) complex to act as the luminophore.The remaining free phenolic oxygens act as the acid-base sites.41 Another popular method for the introduction of functional variety at the lower rim has been to convert known calix[4]arene carboxylic acid derivatives into acid chlorides, and to introduce novel moieties by amide or ester formation.Shinkai has used this approach to develop ditopic ligands that can bind both hard metal cations such as Na’, and soft metal cations such as Ag’. Functionalization of the lower rim was achieved by formation of the tetra(acid chloride) from p-t- butylt e t rakis- (carboxymet hoxy)calix[ 41 arene and subsequent reaction with EtS(CH2),NH2.43 Similarly, reaction of 2-hydroxy-5(4‘-nitro- pheny1azo)benzyl alcohols with a calixarene tetraacid chloride gave a tetraphenylazophenol derivative in 80% yield, which could be used as a visual indicator for gaseous a m i n e ~ .~ ~ It has been shown that exceptional selectivity for binding sodium over potassium metal ions can be accomplished by bridging calix[4]arenes with polyether chains.45 To this end Shinkai has carried out a thorough study of the product distribution for the reaction of calk[4]arene tetrol and 3,6-dioxo- catane-1,8-ditosylate. Weak bases such as M2CO3 (where M = K, Na) lead to 1,3-bridging in agreement with previous findings for general 0- 296 Contemporary Organic Synthesisalkylations. However, a strong template effect was observed for alkali metal hydrides. LiH led to 1,3-bridging while NaH and KH encouraged reaction at the proximal phenolic oxygen, giving rise to 1,2-bridging.4h Related to this work, Vicens has described the synthesis of doubly bridged calixarenes 105 in the 1,3-alternate conformation by alkylation of calix[4]arene 99 with bistosylate 104 (Scheme 25).47 aCHO OH 104 Scheme 25 I 1 P 0) \ 99,K&O, MeCN.reflux 0 105 n = 125% n=217% Reinhoudt has prepared a series of calixpherands, that form kinetically stable complexes with alkali metal ions, by bridging p-t-butylcalix[4]arene with rn-terphenyl units. Previous attempts at synthesis using high dilution techniques only gave poor yields, but addition of a solution of the rn-terphenyl dibromide, without high dilution, to the polyanion of p-t-butylcalix[4]arene, formed using five equivalents of sodium hydride, gave the diametrically bridged molecule in an improved 80% yield. The second, bridge-forming alkylation is only possible with the distal phenol, since alkylation on the more reactive proximal phenol is prevented by the rigidity of the rn-terphenyl. It is thought that sodium acts as a metal template in the reaction since, with potassium hydride as base to generate the polyanion, the resulting calixspherands were produced in very low yields.48 A Suzuki cross- coupling was used to prepare rn-terphenyl 107 which MOM0 OMe 9 + - * (9 Pd(Ph3P)4, Na2C03 (ii) HCI, MeOH (iii) PBq 107 (29%) Me' 106 J Me But BUbu' But 108 4 0 7 , 5 eq. NaH, 3 mol%l8-crom-6 (v) Mel, KOBU' (vi) K&05 MeOH, H,O (vii) DCC.N-hydroxysuccinimide (viii) LMWP, dioxanhrate buffer 109 Scheme 26 110 I , I 111 R = p N H p 0 1 high dilution, THF 112 (8%) Scheme 27 Dowden, Kilbum, and Wright: Synthetic developments in host-guest chemistT 297was then linked to calix[4]arene 108 using the above methodology (Scheme 26).After protection of the phenols and ester hydrolysis the resulting calixpherand could be coupled to low molecular weight proteins (LMWP) to give 109 in good yield. By attaching egg-white lysozyme the calixspherand and entrapped Rb+ (or the radioactive isotope) could be delivered to a specific organ, in this case kidney, in an approach to tracing bloodflow through specific organs.49 tetraphenylporphyrin, 112 (Scheme 27), by functionalization of 5,10,15,20-tetrakis (2-aminopheny1)porphyrin with L-alanine and subsequent coupling, under high dilution conditions, to the calix[4]arene tetraacid chloride 110. The chiral, C4 symmetric receptor 112 with a hard-soft ditopic binding site was obtained in 8% yield.” Shinkai has formed a calix[4]arene-capped (iii) Me2NH.HCHO. THF (iv) Mel, DMSO (v) Nu- 3.1.2 Modifications to the upper rim Structural extension of the upper rim provides calixarenes with much deeper pockets, and functionalization that can be further developed into binding sites. Thus, Lin has isolated all the possible derivatives of the diazo-coupling reaction between calix[4]arene and the diazonium salts of 6-amino- 1,3-benzodioxin - a reaction that showed little se~ectivity.~’ Gutsche has made a thorough study of the ‘quinonemethide’ route to upper-rim substituted calk[ 41 arenes. Aminome t hylation of calix[4] arene 99, followed by quarternization with Me1 and treatment with various nucleophiles, gives a flexible route to para-substitution at the upper rim (Scheme 28).If the aminomethylation was carried out in THF/HOAc reaction took place at all available positions giving 114. However, with no HOAc present, aminomethylation occurred at just one position, giving 1K5* When CN- was the Qqpp HO HO OH OH 1 13 (88%) 1 Nu- 115 (48-88%) 114 (2%88%0) Scheme 28 nucleophile, p-cyanomethyl calix[4]arene was formed, and subsequent reaction with strong base and benzyl halides gave rise to a variety of heavily substituted calix[4]arenes with deep pockets. Both cone and 1,3 alternate conformations could be obtained depending on the synthetic protocol employed.53 The synthetic utility of these compounds has been further extended by using aromatic aldehydes in aldol condensations with the p-cyanome t hyl ~alix[4]arenes.’~ Kovalev has described the synthesis of adamantyl substituted upper rim calix[4]arenes 117 (Scheme 29).Direct reaction of various l-hydroxy- adamantanes 116 with calix[4]arene 99 in trifluoroacetic acid gave the tetraadamantyl calix[4]arene in 75% yield. The low nucleophilicity but high solvating ability of TFA made it an excellent medium for this reaction.55 pcHJ OH 99 116 CF3COfl pxylene 50-55’c pc3 OH 117 R=H (95%) R = P f (90%) R = p i (70%) Scheme 29 Sutherland has prepared a calix[4]arene derivative with cation binding sites at both the upper and lower rim, giving rise to strong co-operativity in the binding of alkali metal cations. Bromination of the cone conformer of the known tetrabenzylether of calix[4]arene, followed by Suzuki-arylation with benzyloxyboronic acid gave 119.Debenzylation, and alkylation of all eight hydroxy groups with N,N- diethylchloroacetamide in the presence of sodium iodide, gave the novel derivative 120 (Scheme 30).5h Pdo 118 + RO OR OR OR Scheme 30 Reinhoudt has synthesized calix[4]arene salenes 123 that act as neutral bifunctional receptors for NaH2P04. The receptors contain an immobilized Lewis acidic U02-centre as well as amido units that 298 Contemporary Organic Synthesiscan act as hydrogen bonding sites for anions, and showed a high selectivity for dihydrogen phosphate, with the calix[4]arene unit providing a binding site for a sodium cation. 1,3-Diarninocalix[4]aren'e 121 was reacted with chloroacetylchloride, followed by alkylation with 2-(2-allyloxy)-3-hydroxybenzaldehyde in the presence of K2C03.Palladium-catalysed deallylation of 122 gave a bis-aldehyde which on reaction with cis-l,2-diaminocyclohexane and U02- (OAC)~.H~O gave the receptor 123 in 15% yield (Scheme 31).57 I) CICH&OCI, EtSN, CH&Iz OH, K2C03, KI, MeCN 121 ,CHO OHC, 0 NH 122 (384%) %(OAc)Zv Ph3P, NEt3, HCO2H UO~(OAC)~~H,O, EtOH (iv) cis- cydohexa-1 ,2-diamine. OR oWRRO 123 (9-15%) Scheme 31 3.1.3 Other modifications An alternative method for obtaining novel calixarenes is to go back to the synthesis of the calixarene itself. Thus calix[4]arenes 125 have been prepared bearing aryl groups on the methylene bridges, in diametrical positions, starting from 2,2' dihydroxytriphenylmethanes 124. The triphenylmet hanes are readily produced by the directed ortho-regioselective alkylation of bromomagnesium phenolates with various aromatic aldehydes (Scheme 32).Acid-promoted macrocyclization of 124 with formaldehyde gave calix[4]arenes 125 in moderate yields.5s Bohmer using a 2 + 2 condensation of a bisbromomethylated biaryl fragment 127 with a second biaryl unit 126, although reaction conditions were not described (Scheme 33).59 Calix[4]resorcinane octamethyl ethers have been synthesized in almost quantitative yield by treatment of 2,4-dirnethoxybenzylalcohol with 5% TFN CHC1,.6" A novel route, that offers considerable A related strategy has been recently reported by OMgBr CHO R2 124 (4690%) CHzO, BFa.Et20 CH2CIz, r.t. c- R2 125 R' = But, R2 = H (27%, 1 :1 cis:trans ) = NO, (18%, trans only) R' = But, Scheme 32 1 R3 1 R3 126 + M e Me 127 Scheme 33 128 (20.35%) flexibility in the variation of the functionality at the methylene bridge, has been developed for calix[4]resorcinanes. The reaction of 2,4-dimethoxy- cinnamates with BF3.Et20 gave good yields of the calix[4]resorcinanes 129, as a mixture of stereoisomers (Scheme 34).61 M e O w O M e BF3.Et20 OMe '7' C02R 129 (6840%) Scheme 34 3.2 Calix[6]arenes In comparison with calix[4]arenes7 much less attention has been paid to the calix[6]arenes, although larger ions can be bound within the cavity Dowden, Kilburn, and Wright: Synthetic developments in host-guest chemistry 299of the latter.The controlled derivatization of the calix[6]arenes is vital for their development as molecular building blocks. 1,3,5-regioselective 0- alkylation provides C3 symmetric points of attachment but, previously, only methyl iodide gave good yields for such alkylations.This has now been successfully extended to other alkyl iodides and para-substituted benzyl bromides, by reaction with p-t-butylcalix[6]arene in the presence of a weak base such as K2C03 or C S F . ~ ~ Shinkai has completed a thorough study on the synthetic strategies, including direct methylation and protection-deprotection methods, leading to all possible 0-methylated derivatives of hexa-t-butylcalix[6]arene hex01.~~ discourages their use as platforms for binding arrays, but capping of the lower or upper rim restricts conformational freedom and provides necessary preorganization. Such capped calixarenes can provide derivatives with c6 or c3 symmetry, suitable for the recognition of ammonium cations.Reinhoudt has developed a three point capping between p-t-butylcalix[6]arene and a cyclo- triveratrylene to form a crypto-calix[6]arene 133. Coupling various veratryl units 131 to 1,3,5-trimethoxy-p-t-butylcalix[6]arene 130, using Cs2C03 in DMF, gave the precursors 132 in 70-90% yields (Scheme 35). Slow addition of a 0.1 M solution of 132, in glacial acetic acid, to an ice- cooled mixture of glacial acetic acid and perchloric The greater flexibility of calix[6]arenes 130 Br (x-0 + @OMe CSCO,, DMF. 'OH 60-80 "C 131 But But I I \ t H 2 m OMe /J x \ \ x x 133 (3@73%) Scheme 35 glacial acetic perchloric acid X = (CH,), (n = 1-4) or X = (CH20CH2), (n = 1,2) acid (2: 1, v/v) gave the capped products 133 in yields varying from 30-73%, after purification.@ Shinkai has also capped the lower rim by high dilution esterification of calix[6]arene tris(acid chloride) 135 with tris(2-hydroxyethyl)isocyanurate, to give 136 (Scheme 36).65 0 HOHzCHzC,N)(N,CH2CH20H O & A O I CH,CH,OH 134 + 136 135 Reagents: (i) pyridine, THF Scheme 36 The same group has successfully capped the upper rim.Treatment of 1,3,5-trimethoxy-p-t- butylcalix[6]arene 130 with AlC13, in the presence of nitromethane in benzene, gave selective di-t- butylation of the free phenols, which were then protected by methylation. Chloromethylation at the free para-positions, and high dilution intramolecular coupling with 1,3,5-tris(sulfanylmethyl)benzene gave the capped calix[6]arene 138 in 28% yield (Scheme 37)? But BU' CH2CI 1 130 BU' I 138 (28%) Scheme 37 Other modifications to calix[6]arenes include the formation of a mono(indoani1ine) derivative by reaction of calix[6]arene with 4-diethylamino- 300 Contemporary Organic Synthesis2-methylaniline hydrochloride, in the presence of K3Fe(CN6), to give a UO,’ sensitive chromophore in 53% yield.67 Complete removal of the six hydroxy groups of calix[6]arene has been successfully achieved by phosphorylation, followed by reduction with K/NH3, to give the corresponding metacyclophane.6s Biali has extended his work, on the oxidation of calix[4]arenes, to calix[6]arenes, and has described the synthesis of trisspirodienones 140 (Scheme 38).Mild oxidation of calix[6]arene 139 with phenyl trimethylammonium tribromide and aqueous NaOH gave the major chiral spirodienone derivatives 140 in 44% overall yield providing a potential route to calix[6]arenes selectively functionalized in intra- or extra-annular positions.69 2.2 eq.1.4-bis- (brmmthyl)bonzene Cs$Os TIiF, rdlux, 24 h. But \ 141 R’ = CI-~~CO~BU‘ 6 ut 142 R’ = CH2C02But, $ = pCHLC6ti4CH2Br NaOH. H@ Scheme 39 Scheme 38 140 (29%) + isomer (1 5%) 3.3 Calix[8] arenes The calix[8]arenes bear all the same challenges as the calix[6]arenes. Neri has completed a thorough study of the substitution patterns obtained from 0- alkylation reactions. Strong base-mediated reactions give rise to good yields of octa-substituted calix[8]arenes while weak base gives more complex mixtures from which 1,3,5,7-tetraethers with C4 symmetry were generally obtained in up to 49% yield.However, when Me1 was the electrophile, no C4 symmetric tetraethers were detected, instead the 1,2,4-trimethoxy and 1,2,3,4-tetrarnethoxy derivatives were isolated as the main product^.^' The same group has synthesized the first example of a 1,5 intramolecularly bridged calix[8]arene 142 by reaction of 141 with 1,4-bis(bromomethyl)benzene using Cs2C03 as base (Scheme 39). The products are conformationally frozen into a double conical shape. 71 Calix[8]arene has also been capped with 4,4’-diazophenyls potentially leading to novel chromogenic calix[8]arenes, although the regioselectivity of the capping is unclear from this A water soluble p-t-butylcalix[8]arene has been prepared by reaction with ethylene oxide, resulting in functionalization of the lower rim with polyoxyethylene chains.74 3.4 Double calixarenes Calixarenes can be linked together to form bis- calixarenes that provide large, rigid cavities.An octathio-bis-calixarene, for example, was generated by replacement of the t-butyl groups with thiomethyls and bridging by reaction with CH212 under high dilution conditions, with yields between 26-30% for the final step.” Ziessel has prepared a family of calix[4]arene podands and bis- calix[4]arenes by selective alkylation of p-t-butyl- calix[4]arene with 5,5’-substituted-2,2’-bi- pyridine building blocks in the search for lanthanide receptors.76 The first examples of ‘head-to-tail’ linked bis-calixarenes 146 have been synthesized, with the dipole moments of the two calixarene units linked up in an additive manner.77 1,3-Dialkylation of p-t-butylcalix[4]arene 108 with two equivalents of tosylate 143 gave 145 after deprotection.Condensation of 145 with bis-bromomethyl p-cresol in glacial acetic acid gave the head-to-tail linked calixarene 146 in 4-5% yield (Scheme 40). In a single experiment Reinhoudt has generated two large calixarene-based receptors resulting from an intramolecular cyclization and a dimerization. Coupling of calix[4]arene 147 with 148 gave the 1 : 1 adduct 149 exclusively as the endo-isomer shown (Scheme 41). Reduction of the nitro groups and condensation of the resulting amines with chloroacetylchloride gave 150. Removal of the silyl protecting groups and stirring for 48 hours with Cs2C03 and KI then led to two products.The first, Dowden, Kilburn, and Wright: Synthetic developments in host-guest chemistry 301108 146 (46%) Scheme 40 OR OR obtained in 26% yield, was the highly symmetrical 'holand' 151, comprised of two opposed calix[4]arene and two cavitand moieties, which produces a cavity of nanometre proportion^.^' The second product, in 27% yield, was a calix[4]arene based cancerand 152. Complexes with this carcerand showed novel stereoisomerism ('carceroisomerism') as a result of hindered rotation of guest molecules in the carcerand cavity.79 The same group has also reported the formation of a biscalix[4]arene-tetraarylporphyrin 154, by refluxing 1,3-bisaldehyde calix[4]arenes 153 with pyrrole in propionic acid, in a reaction which gave just one of the possible rotational isomers in 3-5% yield (Scheme 42).*' 1,3-Alternate conformers of calix[4]arenes lend themselves to the construction of materials by formation of rods and tubes.The observation of metal tunnelling through calix[4]arenes8' has led Shinkai to synthesize n-basic 'nano-tubes' by linking 1,3-alternate calix[4]arene units.** Chloromethyl substitution at the para-positions of a 1,3-alternate conformer of calix[4]arene provided the basic building block 155. Reaction of 155 with a bisphenol provided the linking unit 157, while terminal units 156 were prepared by capping 155 with catechol. Controlled capping and linking of these units provided the 'nano-tube' 158 in 17% yield (Scheme 43). Finally, a triscalix[4]arene has been prepared by linking three p-t-butylcalix[4]arene units with two silicon atoms.Reaction of p-t-butylcalix[4]arene 108 with 1.2 equivalents of SiC14 and five equivalents of NaH in THF for 1 hour gave a tridirectional multicavity receptor in 69% yield.83 (Biscalixarenes linked by non-covalent interactions are described in the final section of this review.) 147 148 (i) KI. MeCN (ii) TBDMSCI, EfN. DMAP 1 (I) Raney NI, hydrazine 149 R = NOp (41v0) (ii) C1CH2COC1 150 R = NHCOCHgI (1 oovo) (i) CsF, DMF (ii) CS&O, KI Pro Pro 151 (26%) + LO 152 (27%) Scheme 41 302 Contemporary Organic SynthesisOPP mopr CHO CHO H-! N-H I propionic acle. refiux 153 154 (4%) Scheme 42 CIH C CH CI A< 4 Cyclophanes Several reviews on the subject of cyclophanes have appeared in the literature recently, dealing with the chemistry of [ l,]orthocy~lophanes,~~ the synthesis of small cyclophane~,'~ and the intramolecular [2 + 21 photocycloaddition of vinylarenes to give cyclop hanes .86 4.1 All carbon cyclophanes Some new work has been reported in this area this year, including synthesis of metacyclophanes which incorporate crown ether-type f~nctionality.'~ Rajca has described a novel route to [l.l.l.l]meta- cyclophanes, such as 164, starting from 1,3,5-tribromo- benzene (Scheme 44)." Mono lithiation of tribromobenzene and condensation with ethyl H2C CHp I \ x x 9 Q CIH2C CH2CI 156 k 160 R1=OH, p = B r (86%) (')' E 161 R' = H, R~ = ~r (as%) 159 (iii) 162 R' = HI R2 = CHO (61%) CH20-X-OH CH20-X-OH I I x I CH2X XH2C I I 9 P R2 R' Br Br HO-X-H2C CH20-X-OH 157 (39%) H2b CH2 x = a+e 0 0 I I 8 Reagents: (i) catechd, K2C03, Nal, acetone; (ii) bsphenol HO-X-OH, K2C03, acetone; (iii) K2C03, Nal, acetone 158 (17%) Scheme 43 RZ 163 R' = OH, R2 = Br (40%) 164 R' =H, #=CHO Reagents: (i) Bu'Li, Et20 (ii) HC02Me; (iii) red P, 4, AcOH; (iv) Buki, THF; (v) PhMeNCHO; (vi) 162 Scheme 44 Dowden, Kilburn, and Wright: Synthetic developments in host-guest chemistry 303formate gave 160 which was transformed, again by partial lithiation, to give 162.A similar sequence coupled 161 and 162 to give 163 and subsequently 164 after a final lithiation. Polyoxo[ l,]orthocyclophanes ('ketonands') have been synthesized by exhaustive oxidation of all the methylenes in odd numbered [ l,]orthocyclo- phanes." Thus, treatment of 165 with pyridinium chlorochromate, followed by further oxidation with ceric ammonium nitrate in hot acetic acid gave ketonand 166 in 66% yield (Scheme 45).165 166 (66%) Reagents: (i) Pyridinium chlorochromate (ii) Ceric ammonium nitrate, AcOH, 80 "C, 1 day Scheme 45 4.2 Heteroatom-containing cyclophanes Two syntheses of cyclophanes incorporating carbamate functionality have been described using the condensation of appropriate diols with diisocyanate~.~,~' Azacyclophanes such as 170 and 171 have been prepared using a Baylis-Hillman reaction (Scheme 46).92 Dialdehyde 167 was reacted with methyl acrylate in the presence of DABCO, or 3-quinuclidinol, for 1-14 days at room temperature, to give 168 which was subsequently acylated. The resulting diacetate 169, on treatment with ammonia CHO DABCO MeO& C02Me CHO 167 168 R = H JA&I,E~~N 169 R=Ac NH, M d H 1 c--- High dilution NH co2Me c0,Me 171 (95%) 170 (28%) Scheme 46 in methanol, gave the cyclophane 170 in 28% yield.Further reaction of 170 with another equivalent of 169 in reluxing acetonitrile (high dilution) led to the macrobicyclic cryptophane 171 in 95% yield. An extensive study on the conformation of this and other cyclophanes was reported. Lindner. Thus, reaction of bistriflates 172 with Na,[Os(CO),] gave the ortho-, meta-, and para- diosmacyclophanes 173-175 in reasonable yields (Scheme 72). Thermolabile diferracyclophanes, such as 176, could be obtained in the same way, and reacted with CO to give the corresponding cyclic diketones 177.9' Novel metallocyclophanes have been reported by 1 72 Og0 co - 173 ortho (46%) 174 meta (77%) 175 para (78%) [os] = Os(CO), p 177 (38% from meta 174) 176 [Fe] = Fe(CO), Scheme 47 4.3 Cage-type cyclophanes A tricyclic cyclophane able to selectively bind cholesterol in water has been reported by Diederich.The key step was the Pdo-catalysed Stille coupling of equimolar amounts of bis(tributylstanny1)acetylene and dibromocyclophane 178, which can be prepared in multigram quantities starting from 2-bromo- 6-ethoxynaphthalene (Scheme 48).94 The reaction produced the chiral D2-symmetrical macrotricycle 179 selectively in 14% yield and none of the possible achiral isomer with C2h symmetry. Reduction of 179 with lithium aluminium hydride, followed by quaternization with ethyl iodide and ion exchange chromatography, afforded the water-soluble receptor 181 (Scheme 48).been synthesized via a triple condensation of hexabromide 184 with catechol derivative 185 (Scheme 49).95 Double protection of 182 as the THP ether, followed by reaction with 1,3,5-tris(bromomethyl)benzene gave 183. The protected alcohols were converted into bromides and the resulting hexabromide 184 was then reacted to give 186 using CsC03 as base. Subsequent ester hydrolysis gave receptor 187. A basket like macrotricyclic cyclophane 187 has 304 Contemporary Organic SynthesisOMe R Br 178 R R --J (ii) 179 R = AC (14%) 180 R = Et (59%) 181 R = Et,' CT ( 7 8 a (ii9 Reagents: (0 B u 3 S ~ S n B u 3 , [Pd(PPh,)4], 2,6-di-t-butyC pcresol. OMF, 110 "C. pressure bottle, 2 days; (ii) LiAH,, Et20, 20 "C, 12 hr.; (iii) (a) EtL CHC13, 20 "C, 4 days, (b) Dowex resin (CT) eluent H20/MeOH (1 :1) Scheme 48 5 Cleft receptors and molecular bowls Among the most interesting host-guest molecules are receptors that have novel structures designed to possess the preorganization required for the recognition of specific guest molecules.These structures often bear only a passing resemblance to those already discussed in this review. 5.1 Cleft receptors One of the most important concepts in the design of a receptor is the preorganization of binding groups. The synthetically most accessible means is to generate a cleft in which convergent binding sites are constrained by a rigid spacer. The strategy often results in strong and highly selective binding. A good example is the C3-symmetric cleft 190, constructed to bind cis-1,3,5-cyclohexane tri(carboxy1ic acid).The desired three point recognition was provided by three amido pyridine units attached, by an adaptation of the Weinreb procedure, to the C3-symmetric base 189, which, in turn, was synthesized from 4-acetylmethylsalicylate 188 in four steps (Scheme 50).9h f OH HO HonCoz- co&e 1 85 183 R = OTHP (18%) (iii) L 1 8 4 R = Br (74%) NaOH, W H 186 R = CO,Me (31 %) c 187 X = C0,- Na' (51 %) Reagents: (i) THP, pyridinium ptoluene sulphonate; (ii)l,3,5tris(brom~methyl)benzene, NaH, THF-DMF, -2 "C, 20 hr.; (iii) PPh3, CBr,; ( i ) Cs2C03, 185, acetone, reflux, high dilution Scheme 49 Rebek has previously demonstrated the usefulness of his rigid receptors and this family has since been extended further by condensation of xanthine derivatives with aromatic dianhydrides, to give cleft receptors that provide a deeper cavity with restricted internal rotation, and are straightforward to deri~atize.~~ Nolte has expanded the scope of his molecular clip receptors, by functionalization of the basic clip receptor with two bispyrazole ligands, to give a dicopper(rr) pyrazole complex which could selectively oxidize benzylic alcohols.98 receptors that bind N-benzyloxyaminoacids, based on the chromenone derivative 191, which is easily prepared from the nitro derivative of 2-hydroxy- acetophenone.Thus, for example, the phosphoramide 192 and the sulfonamide 193 were each prepared in three steps in reasonable yields (Scheme 51).99,100 Very similar structures were employed in the generation of lactone receptors that were able to catalyse the nucleophilic addition of pyrrolidine to 2-(5H)-furanone."' The same group has also Morhn has recently generated a family of Dowden, Kilburn, and Wright: Synthetic developments in host-guest chemistry 305MeO& 6 OH 1 88 c-$ O=(N-H OH W 2 C HO Pf C0,Me 189 (61%) H " V o H 190 (26%) "6r Reagents: (i) SiCI,/EtOH; (ii) BrCHCH=CH,, Cs,CO, DMF, acetone, reflux; (iii) N,N-dimethylaniline, reflux; (iv) H2, Pd/C 10%; (v) 3 eq.Me,AI, then Me,Ai~-amino-Bmethylpyridine complex, benzene, reflux Scheme 50 methane sulfonic acid) to produce the symmetric bislactam 196 in 57% total yield (Scheme 52).'02 194 195 (24%) Reagents: (i) Me02CC('C4Hg)2COCI; 0aBut 196 (57%) (ii) hydrolysis; (iii) Eaton's reagent (P205, 7.5 wt % in MeS0,H) Scheme 52 Related structures have been devised by Kelly103 and showed high affinity for isophthalate and 1 ,3-C6H,[ P( OH)02]-.The 2,3-substituted naphthalene 197 was reduced, nitrated, and reduced again to give 198, after protection of the amine groups (Scheme 53). Lithiation and reaction with methyl formate gave the bisnaphthyl derivative 199, which, after oxidation and deprotection, underwent tin tetrachloride mediated ring closure in 93% yield, and led ultimately to the highly preorganized bisurea 200. 0 191 0 192 R = (EtO),PO (77%) 193 R = H11CeNHSOZ (64%) Reagents: (i) (EtO),POCI; (ii) NaOH, EtOH; (iii) dhexadecyloxy -1- naphthylamine, CMC; (w) H11C6NHS0&I, pytidne Scheme 51 developed a novel receptor for dibutylmalonic acid. a-Tetralone was converted into diamine 195, which served as the core unit for a series of highly preorganized receptors.The most effective of these was formed by acylation of the amine groups with the chloride of dibutylmalonic acid mono- methylester, hydrolysis, and final treatment with Eaton's reagent (phosphorus pentoxide, 7.5 wt% in 1 97 N H k 198 (26%) OH I 4 NH HN NHBoc NHBoc Reagents: (i) H,, Raney Nickel; (ii) HNO,, H2S04; (Hi) H, Raney Nickel; ( i i ) (60c)~O; (v) (a ) 3 eq. MeLi; ( b ) 4 eq. BuLh (c) methyl formate; (vi) PDC; (vii) TMSI; (viii) SnCI,; (ix) BH,: (x) Bu"NC0. Scheme 53 306 Contemporary Organic SynthesisPolycyclic pyridines have also been the basis of a series of receptors developed by Anslyn, and designed to recognize cyclitols and phosphodiesters.For example, diketone 201 was diformylated and condensed with ethyl 2,2-diaminopropenoate to give receptor 202 in 45% yield (Scheme 54).'04 C02 Et 0 0 201 NH2 202 (45%) Reagents: (i) (Me0)2CHNMe2, DMF; (ii) HCI, H20; (iii) ethyl 2,2-diaminopropenoate Scheme 54 A modified receptor 208 was also synthesized using a lengthier route. Thus, cycloheptanone derivative 203 was formylated and condensed with the 2,2-diaminopropenoate derivative 204, to give the bicyclic pyridine 205, in 57% yield. Oxidative cleavage of the alkene and enamine formation, followed by treatment with ethylglyoxalate, gave 207. Reaction of 207 with a further equivalent of enamine 206 in THF, and cyclization of the central pyridine ring with ammonium acetate in acetic acid gave, after deprotection, the receptor 208 in moderate yield (Scheme 55).'" This linear route NHDMBn ' f'h (i) (ii) (Me0)&HNMc,, HCI DMF Em2c&ph c 203 BnMDHN t c o 2 204 205 (57%) tr 1 (iv) Os04 Nal0, (v) TMS-pyrroldine NHDMBn NHDMBn (vii) (vi) ethylglyox.a?%o TsOH \ CO2Et 206 207 (67% from 205) (viii) 206.THF \ (u)HCl . (xi) CF3C02H (x) NHdOAc, WAC H2N NH2 208 m = n = 3 (30%) 209 m =1,n =2 Scheme 55 also allowed the synthesis of a related unsymmetrical cleft 209."' Reinhoudt has developed metalloreceptors such as 212106-108 for the recognition of phosphates. The metalloreceptors were obtained by derivatization of key precursor 210 with various pendant amides, by alkylation of the hydroxy function. Deallylation and reaction with 1,2-diaminocyclohexane or diaminobenzene, and subsequent addition of UO,(OAC)~ .2H20, gave the metalloclefts in good yields.In one example a ditopic receptor 212 was constructed by functionalization of 210 with thymine (Scheme 56). The molecule showed strong association with adenosine monophosphate in d,-DMSO. CHO A FHO I &IH 21 0 0 0 212 (74%) Scheme 56 Molecular tweezers are of interest as mimics of antitumour antibiotics, and Harmata has developed a novel, chiral tweezer based upon Kagan's ether. m-Hydroxybenzaldehyde was converted in six steps into the dibenzofuran derivative 213. Treatment with tosic acid, followed by SnC14, gave the Kagan ether 214 in 68% yield. Conversion into the triflate ester 215 and homocoupling, using a Stille protocol, gave the biaryl216 in 34% yield (Scheme 57).'09 5.2 Molecular bowls Cram has continued his studies of hemi- carcerands."O Thus, hemicarcerand 218 was prepared by reaction of the tetrol217 with T s O C H 2 s C H 2 0 T s in 2- 10% yield (Scheme 58). Reaction of cis-C1CH2CH==CHCH2C1 with tetrol 217 gave the corresponding hemicarcerand in 25% yield.Trapped guest solvent molecules were not released on reduction of the unsaturated bonds around the equator. '11 Still has continued to synthesize an impressive range of receptors for the recognition of peptide Dowden, Kilburn, and Wright: Synthetic developments in host-guest chemistry 307HoucHo OMe (i) TsOH, CH2CI2 (ii) SnCI,, CH2C12, 21 3 214 R=OCHZPh (68%) 215 R = OTf (89%) (iii) H2, PdC (iv) Tfg, collidine, CHS12,O "C w 216 (34%) Scheme 57 sequences. The previously reported receptor 219 has now been functionalized with a dye molecule (Scheme 59) and the resulting coloured host molecule 220 was introduced to a binary encoded combinatorial library of - 50 000 tripeptides. The most tightly bound tripeptide beads became brightly coloured, allowing easy identification and thus provided an extremely efficient assay for the binding characteristics of such receptors, and, in this case, uncovered unexpectedly selectivity for binding certain peptide sequences."' This technique has also been employed in the elucidation of the peptide binding preferences of a new receptor 224.The molecule is closely related to receptor 220, differing by the introduction of naphthyl groups in place of benzyl aromatic spacers, around the rim of the receptor, thus widening the binding site, and again providing a highly selective receptor for tripeptides, particularly those with an internal L-Pro unit.The synthesis began with a Friedel-Crafts cyclization of the Stobbe derived half-ester 221 to give the naphthyl unit which was elaborated to 222 (Scheme 60). Macrolactamization with PriNEt gave 223 in 50% yield, which was then tagged with a dye molecule to give 224.'13 also been prepared by much shorter routes than those described above. Coupling three equivalents of pentafluorophenyl dimethyl trimesate 226 to one equivalent to 1,3,5 - t ri( aminome t hy1)- benzene 225 gave 227 in 78% yield. After conversion into the activated ester, 228, three-fold coupling with (3R, 4R)-3,4-diaminopyrrolidine 229 (linked to the Dye Disperse Red by a succinyl Related C3-symmetric 'cup-shaped' receptors have 21 7 - TsO OTs C+CO,, cat.KI, DMF, 60 "C. 5 days 1 218 (2-10%) Scheme 58 R Reagents: (i) Pd(Ph3P),, dimedone; (ii) Bu,NF, RMs Scheme 59 308 Contemporary Organic SynthesisReagents: (i) PS2EtN; (ii) Pd(Ph3P),, dimedone; (iii) Bu,NF, ROMs 225 / R'O& 227 R' = Me (78%) 228 R' = C6F5 (30%) 230 R2 = CO(CH&CO,-Dye (26%) Scheme 61 Scheme 60 spacer) gave the receptor 230 in 26% yield (Scheme 61).' l 4 macrotricycles, previously prepared in a remarkable one-step synthesis by reaction of the tris(acid chloride) of trimesic acid (A) with diamino- cyclohexane (B). Similar reaction of the tris(acid chloride) or trimesic acid with a series of diamines gave a number of novel receptors structures with subtle variations in their binding ~electivities."~ A structurally distinct &B6 system - a tetrahedral receptor - has now been synthesized, using a strategy very similar to that in Scheme 61.Trimesic acid dimethyl ester was coupled (DCC) with monoprotected 1,2-diaminocyclohexane to give 23 1. Three equivalents of deprotected 231 were then coupled with one equivalent of trimesic acid tris( acid chloride) yielding 232 (Scheme 62). Conversion into the hexapentafluorophenyl ester 233 and then treatment with three equivalents of the diamine 229 gave the desired dye-tagged, macrotricyclization product 234 in 51% yield. This Still has extended his work on &B6 new receptor also showed selectivity in the binding of certain tripeptides.'16 Still has also used the combinatorial technique to generate a library of - lo4 receptors based on a peptidosteroid structure.This library could then be assayed for binding activity with arbitrarily selected dye-tagged substrate^."^ Chamberlin has also synthesized novel macrocycles designed to bind to peptides, and the chiral C2 macrolactams 238 did bind cyclic dipeptides enantioselectivity (Scheme 63). Starting from bromo aldehyde 235, the terphenyl236 could be prepared on large-scale via an aryl lithium addition to benzoquinone. Terphenyl236 was further elaborated using Horner-Emmons chemistry and hydrogenation of the resulting olefins, to give the precursor 237 as a 1: 1 mixture of (S,S)- and (R, S)-diastereoisomers. The first olefination reaction of 236 with phosphonate 239 gave a greater than statistical yield (75%) of mono-alkene product.The diastereoisomers of 237 could be separated by column chromatography, after manipulation of the protecting groups, and were separately subjected to Dowden, Kilbum, and Wright: Synthetic developments in host-guest chemistry 309I 231 C02Me ,C02R' H-N R'02C 6" 'CO, R' PriEtN 234 R2 = CO(CH,),CO,-Dye (51 %) Scheme 62 macrolactamization which was successfully carried out using the BOP coupling reagent in yields of 10-20%.' l8 A crown ether based peptide receptor 245 has also been synthesized, using an adapted Stille procedure to bring about 4,4'-biaryl formation in the ring-closing step. 1,10-Diaza-l8-crown-6 243 was first monoalkylated with an aryl stannane 240. A second alkylation with bromide 242, generated from p-bromobenzyl alcohol 241 in five steps, gave the cyclization precursor 244.Macrocyclization using Pd(PPh& and potassium carbonate in DMF gave 245 in 15% yield (Scheme 64).'19 6 Self-assembling receptors Complex assemblies can be achieved by employing non-covalent interactions. This aspect of molecular design is called self-assembly and can significantly reduce the number of synthetic steps required to develop a receptor. The hydrogen bond has been used by Gokel for the preparation of molecular boxes and results of 237 H Bu' 0 F 2 H 0 H- Q Q 238 (or diastereoisomer) (1 0.20%) Reagents: (i) MeOH, H'; (ii) Bu"Li, THF, -78 "C; (iii) 1,4 benzoquinone; (iv) 47% HI, THF, 0 "C; (v) NaOMe, THF, Boc-VaCNHCH(C02Me)PO(OEt)2 (239); (vi) LOH, MeOH, H,O; (vii) Et02CCH2PO(OEt)2, DBU, CH2C12; (viii) HP, 5% R K , 2 atm.; (ix) Me2NH, Et3N, HOBT, EDC; (x) TFA, CH2C12, flash chromatography; (xi) LiOH, MeOH; (xii) BOP, P+,EtN, THF, 0 "C, 1 mmol concentration Scheme 63 this work are described in detail.12' Complementary adenine and thymine nucleotide bases were attached by flexible spacers to 1,10-diaza-18-crown-6.An induced fit ternary complex 246 was formed between these fragments with suitable diammonium salts as guests (Scheme 65). Hydrogen bonding interactions between carboxylic acid and pyridyl groups have been used to assemble a molecular capsule 250 from two calix[4]arenes. The two calixarenes, 248 and 249, were both prepared from the formyl calix[4]arene 247 (Scheme 66) and formed a dimeric structure involving four hydrogen bonds.121 metal co-ordination.Calix[4]arene 251 was bisfunctionalized at distal positions of the upper rim, using established procedures. Complexation of 252 with copper(I1) gave the dimerized complex 253 in 50% yield (Scheme 67).'22 pyridine ligands perpendicular to zinc porphyrins to generate a dimeric receptor 256. The cavity defined by the dimer has inwardly directed hydrogen bond recognition sites which were used to bind terephthallic acid derivatives. Incorporation of a A biscalix[4]arene has also been assembled using Hunter has exploited the co-ordination of 3 10 Contemporary Organic SynthesisScheme 64 Me 246 Scheme 65 2,6-pyridinedicarboxylamide moiety into monomeric unit 255 orientates the covalently linked pyridine and porphyrin at the approximately 90" angle necessary for dimerization, using internal hydrogen bonds to stabilize such a conformation.Reaction of the porphyrin derived amine 254 with pyridine- 2,6-dicarbonyl chloride, and 4-aminopyridine7 gave 255 in 65% yield (Scheme 68). Complexation with Zn" gave 256 in 91% yield which exists as a self- assembled dimer at concentrations 10-7-10-2 M, at room temperature, in chlorinated organic solvents. 23 phenanthroline derivative 258 by coordination with Hamilton has coupled two units of simple 253 (50%) Scheme 67 Cu'. The resulting distorted tetrahedral bisphenanthroline complex 259 is chiral, and places the acylaminopyridine moieties in the appropriate orientation for binding dicarboxylic acids. The key subunit 258 was prepared by double arylation of 1,lO-phenanthroline 257 (Scheme 69).'24 even further, allowing preparation of macrocyclic receptors with a minimal amount of organic ~ynthesis.'~~ For example, tetranuclear cationic molecular boxes have been assembled from 4,4'-bipyridine and square-planar platinum( 11) and palladium( 11) complexes 260.The assembly process The structural role of metals has been extended Dowden, Kilburn, and Wright: Synthetic developments in host-guest chemistry 311ph, ,Ph d 254 (9%overall) Q t I P d 0 256 R = @6H&jH11 (91%) Scheme 68 8 \ 257 259.glutaric acid complex Scheme 69 p i b h 260 (M = Pd, Pt) L t , - P h Ph P h C p d Ph' 261 M = Pd (96%) 262 M = R (87%) Scheme 70 CFSSOa- gave 261 and 262, which were soluble in most organic solvents, in excellent yields (Scheme 70).7 References 1 J.D. Kilburn and H.K. Patel, Contemp. 0%. Synth., 1994, 1, 259. 2 H. An, J.S. Bradshaw, R.M. Izatt, and Z. Yan, Chem. 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ISSN:1350-4894    

DOI:10.1039/CO9950200289

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Protecting groups KRZYSZTOF JAROWICKI and PHILIP KOCIENSKI Department of Chemistry, The Universiy, Southampton SO1 7 lBJ, UK Reviewing the literature published in 1994 1 2 2.1 2.2 2.3 2.4 3 4 5 6 7 7.1 7.2 8 9 10 Introduction Hydroxyl protecting groups Esters Silyl ethers Alkyl ethers Alkoxyalkyl ethers Thiol protecting groups Diol protecting groups Carboxyl protecting groups Phosphate protecting groups Carbonyl protecting groups 0,O-Acetals S, S-Acetals Amino protecting groups Books and Reviews References 1 Introduction The following review covers new developments in protecting group methodology which appeared in 1994. The review is not comprehensive but a selection of methods which we deemed interesting or useful. In addition to examples gleaned from casual reading, the references were selected through a Science Citation Index search based on the root words block, protect, and cleavage.The review is organized according to the functional groups protected with emphasis being placed on deprotection conditions. In the accompanying schemes, transformations for which the scale is specified imply that full experimental details were provided in the original reference. 2 Hydroxyl protecting groups 2.1 Esters Biotransformations continue to make significant contributions to protecting goup technology. For example, the acetyl esterase enzyme from the flavedo of oranges chemo- and regio-selectively removes acetyl groups from carbohydrates and nucleosides (Scheme l).' However, the exquisite gentleness and selectivity of the reaction exacts its price: 350 rnL of solvent are needed for 1 mmol of substrate.In another example, Fujii and co-workers2 reported a simple strategy for the generation of catalytic antibodies which can regioselectively and stereoselectively deprotect acylated carbohydrates. 0 OAc Acetyl esterase (20 units) 0.15 M NaCl(350 rnL) pH I 6.5 (adjusted with 0.02 M NaOH), r.t. 52% (1 rnmol scale) I 0 OH Scheme 1 Magnesium metal in methanol (i.e. magnesium methoxide) deprotects alkyl esters selectively by transesterification in the order p-nitro- benzoate > acetate >benzoate > pivaloate 9 trifluoroacetam ide (Scheme 2)3. 6 O M e HO Mg (3.0 eq.) NHCOCF3 BtO *oMe NHCOCF3 MeOH, 9196 r.t., 13 hr. * Scheme 2 Electrochemical methods are not a stock in trade of the typical synthetic chemist but two recent reports amply illustrate the potential of the method.In the first report, a new route to semisynthetic docetaxel analogues (Scheme 3) was accomplished by the selective electrochemical cleavage of the 2-benzoate as the key rea~tion.~ The optimized electrochemical reduction of 1 in a mixture of methanol and acetonitrile in the presence of tetraethylammonium acetate and acetate buffer at E-2.0 to -2.05 V versus SCE (5.5 F mol-' used) gave the 2-debenzoyl taxoid 2 in 79% yield on a 30 g scale. In the second example, electrochemical reductive cleavage was a ploy used to selectively remove only one of the tosyl groups from the bistosylate 3 during a synthesis of the furobenzofuran precursors of the carcinogenic aflatoxins 13' (Scheme 4). Jarowicki and Kocienski: Protecting groups 315FOCH20Me O A P h Q OMe 1 0 +2 e (-205 V ks SCE) c+ - 5.5 F mi-' EbNBF4 (0.1 M) EtNOAc (0.05 M) MeOH-MeCN (1:l) 79% (30 Q -1 FOCH20Me 2 OMe Scheme 3 TsO 0 $0- Pd(0Ac)flPTS (12) (5 d%) HNEt2 (5 q.) C3HFN (3 ml), H2O (0.5 ml) 20 min, r.t.1 1ooo/. (I mnol scale) 9" Ph+ Scheme 5 2.2 Silyl ethers Selective cleavage of primary and secondary TMS, TIPS, TBS, and TBDPS ethers has been accomplished with neutral alumina by stirring in the presence of a non-polar solvent like hexane.8 The deprotection rate depends on the steric bulk of the silicon substituents, following the order TMS + TBS -TIPS > TBDPS. The procedure can discriminate between different silyl groups located at equivalent positions of the same molecule, affording the corresponding monoprotected alcohols in very good yields.Potassium carbonate/Kriptofix 222 deprotects phenolic silyl ethers' and under these conditions the alkanolic silyl ethers remain unaffected. On the other hand PPTS or BF3 - OEt, removes only alcoholic silyl ethers (Scheme 6). -1 275 V TEAB, MeCN, 20 hr. 63X (3.62 mmol scale) i TsO Scheme 4 Genet and co-worker~~'~ have reported the removal of allyloxycarbonyl (Aloc) groups from protected alcohols using a water soluble Pd' catalyst [prepared in situ from Pd(OAc)* and trisodium 3,3',3"-phosphinetriyltribenzenesulfonate (TPPTS)] with diethylamine as ally1 scavenger. Scheme 5 illustrates the selective deprotection of an Aloc group without affecting a neighbouring dimethylallylcarbamate. The best result is obtained in a biphasic butyronitrile-water system with 5% of Pdo.Scheme 6 0 K&03 (0.5 mmol) Kryptofa 222 (0.065 mmol) MeCN (0.5 mL), 55 "C, 2 hr. 1 72% (0.13 mmol scale) PPTS (0.1 eq.) EtOH, 50 "C, 1 hr. or r.t., 70% BF@Et, (2 q.) 0 I 316 Contemporary Organic SynthesisPirrung and co-workers" reported a new method of deprotecting nucleosides and nucleotides bearing silyl protecting groups using commercially available triethylamine trihydrofluoride (Scheme 7). Work-up is accomplished by simple evaporation and chromatography thereby avoiding aqueous work-up. Excess triethylamine was added before work-up in some cases, but products of depurination were not observed even in its absence despite the seemingly acidic nature of the reagent. It is also harmless to pivaloyl, allyl, dimethoxybenzoin (DMB), and cyanoethyl protection.EtaNWF (4-10 q.) THF, 8-1 6 hr. 1 61% DMB = dimethoxybenzoin Scheme 7 During a recent synthesis of the antibiotic tunicamycin, Myers, and co-workers" required mild and efficient methods for the large-scale deprotection of anomeric TBS ethers. The first procedure (Scheme 8) uses triethylamine trihydrofluoride to accomplish the task in 97% yield. The second procedure effected deprotection of the pure a-glycoside 4 in quanatitative yield using the trihydrate of KF in MeOH but the product was obtained as a mixture of anomers (a : /.? = 2 : 1). Note the selective removal of the anomeric TBS ether in the case of 4. Kremsky and Sinha12 have reported that TBS and TIPS ethers can be removed from nucleosides under mild conditions by treatment with a mixture of potassium fluoride trihydrate and 18-crown-6 in DMF or THF at room temperature.Both acid and base-labile protecting groups are unaffected. are readily cleaved at room temperature using HF generated in situ from the reaction of BF3.0Et2 with 4-methoxy~alicylaldehyde.'~ The reaction time needed for complete deprotection is faster than t -Butyldiphenylsilyl ethers or triphenylsilyl ethers Et$+3HF (250 mmd) MeCN (120 mL) r.t., 6 hr. 67% (28.6 mmol scale) I 4 KF3H20 (1 27.5 mmd) MoOH (100 ml) rl., 6.5 hr. 100% (23.3 mmol scale) I OBOM O W BzO..flNPhth ym PhSel= 0 .'OH OLO* 0 OH a : g = 2 : 1 Scheme 8 TBAF or BF, - OEt, alone. t-Butyldiphenylsilyl ethers are usually more difficult to cleave than t-butyldimethylsilyl ethers - especially in acid - but Scheme 9 shows a selective deprotection of a primary TBDPS ether in the presence of a secondary TBS ether using 10% NaOH in relwring MeOH.14 Bu$Ae2Si0--{-r - OSi Ph2Bu' 10% NaOH in MeOH (I0 ml) A, 3 hr.87% (2 mmol scale) I Bu'Me2Si0 - - { -7 - - OH Scheme 9 A new silylation of base-sensitive alcohols has been described by Tanabe and co-worker~.'~ The procedure uses silazanes in the presence of a catalytic amount ( - 0.02 eq.) of tetrabutyl- ammonium fluoride (TBAF) (Scheme 10). The use of more hindered silazanes such as the bissilyl derivative of 5,5 -dimethylhydantoin allows regioselective TMS or TBDMS protection of primary hydroxy groups in the presence of secondary and tertiary ones. The same research group also found that hydrosilanes and disilanes can be used instead of silazanes in TBAF-catalysed protection of primary and secondary alcohols.'6 TMS protected alcohols can be prepared directly from carbonyl compounds via reductive silylation.l7 The procedure is limited to ketones and nonenolizable aldehydes and is accomplished by treating them with lithium hydride, TMSCl and a Jarowicki and Kocienski: Protecting groups 317O H 0 N ~ N T M S \-I 2 eq. TBAF (0.02 eq.) DMF, r f , 1 hr. 88% Scheme 10 0 lln (UH), (1.5 eq.) ?TMS -0"' &Sic1 (1.5 q.) Zn(OSOzMe)z (0.01 eq.) CH&h (30 mL), 28 "C, 50 hr. 50% (50.7 r n d scak) 1 mmol 5 <OH 6 7 L = coordinating liiand, X = CI, Br 8 catalytic amount of zinc salts or zinc powder (Scheme 11). groups in butane-1,2,4-triolS was achieved via st annanediyl acetal methodology.l8 Although stannanediyl acetal formation can give either 6 or 7, silylation (TBDMSC1, 1.2 eq.) occurs exclusively at the primary hydroxy of the 1,3-diol system to give 8 in ~ 9 9 % yield (Scheme 12); however, acylation, tosylation, and benzylation occur preferentially at the primary hydroxy group of the 1,2-diol system to give 9, 10, and 11 respectively. The silylation of hindered alcohols is greatly accelerated by the use of silyl triflates in place of the chlorides. The one silyl protecting group for which the triflate procedure is precluded is the t-butyl- diphenylsilyl group whose triflate cannot be prepared in the usual way owing to easy protiodesilylation of the aromatic rings. However, the rate of silylation with t-BuPh,SiCl can be boosted with the aid of silver nitrate." In the example shown in Scheme 13, silylation of an equatorial hydroxyl occurred preferentially over its adjacent axial neighbour.Regioselective protection of the primary hydroxy 2.3 Alkyl ethers Methyl aryl ethers can be demethylated" using 1,- Selectride and SuperHydride (Scheme 14). L- Selectride is the more effective reagent while electron-poor arenes work best. Ethyl ethers react 0 R = Ac, 71% 10 R = Ts, 72% 12 R=TBS,O% 11 R = Bn, 70% Scheme 11 Scheme 12 Bu'Ph#lCI (56 rnmd) AgN03 (52 rnmol) F'yr (0.215 mol) ''6- 'OMe THF 70% (20 (43 ml), mmol r.t., scale: 3 hr. Scheme 13 LiaHauS3 (1.1 eq.) in THF 67"C,3d 92% or b LIBHE13 (1.5 q.) in THF EtO 67 "C, 5 d EtO 88% Scheme 14 much slower than methyl ethers so selective deprotection is possible.the dynemicins, Myers and co-workers*' encountered problems with the lability of the dimethyl acetal function in 13 (Scheme 15) whilst removing the robust phenolic methyl group using sodium thioethoxide in hot DMF. These workers found that prior conversion of the free hydroxy function in the substrate into the magnesium salt 14 During a synthesis of quinone imine precursors to 3 18 Contemporaiy Organic Synthesis13 EtMgBr 1 1 14 Scheme 15 by reaction with EtMgBr afforded protection for the dimethylacetal under the strenuous conditions of nucleophilic demethylation. functions in polyoxygenated natural products and their precursors can be very inefficient. Evans and co-workers22 systematically investigated some of the known mild methods in the search for optimum conditions.Scheme 16 depicts two of the procedures which were especially fruitful. Both methods suffer from the high cost of the bases required. For all its simplicity, the 0-methylation of alcohol MeOTf (1 5 eq.) CHCI+ 60 "C, 6.3 hr. 2.&dCt-butyl4mthylWldi110 (30 bq.) R = M e Scheme 16 The allyl group in its various guises has gained favour as a hydroxyl protecting group due to its stability under basic and acidic conditions. Zhu and c o - ~ o r k e r s ~ ~ reported a way of removing this group from protected phenols using sodium borohydride and a catalytic amount of Pd(PPh3)4 (Scheme 17). A range of reducible functional groups are compatible like nitro groups, acetals, carboxylic acids, nitriles, carbamates, and imides.However, allyl esters are cleaved selectively in the presence of allyl ethers. Ph Ph NaBH, (0.287 ml) THF (2 mL) 1 hr., r.t. 97% (0.10 mmol scale) Pd(PPh& (0.02 w.) - Scheme 17 Ho$ph Benzyl ethers are amongst the oldest and most often used protecting groups typically removed by hydrogenolysis or dissolving metal reduction. A study on the oxidative debenzylation using dimethyldioxirane carried out by Csuk and co- w o r k e r ~ ~ ~ showed that the reaction proceeds well with benzyl ethers of primary and secondary alcohols and the method is compatible with silyl ethers (Scheme 18). Isopropylidiene acetals are stable but benzylidene acetals are cleaved. The deprotection of p-bromo, p-cyano and 2-naphthyl- methyl ethers can also be accomplished. Due to its R = -CH,Ph, -CHrpBr-CeH4 -CH2-2-Napht hyl -CH2-pCN-CeH, dimdhyldioxirane (60 ml of ca 0.1 M acetone Pdutkn) CH&12 (10 ml), 48 h, r.t.85-80% (1 mmd scale) Scheme 18 1,2-ck-arrangement and the stereoelectronically disfavoured anomeric equatorial C-0 linkage, construction of /?-mannosides based on conventional technology is difficult to achieve. Ito and Ogawa have recently devised an ingenious solution to the problem (Scheme 19) by using the well known oxidative lability of p-methoxybenzyl ethers to create a temporary anchor that fixes the position of the nucleophilic partner in a p-methoxyphenyl a~etal.*~ In the subsequent glycosidation step the Jarowicki and Kocienski: Protecting groups 319OMe I BnO BnO x F (0.16 mmol) Dw (0.10 mmol) 4 A MS (0.3 g) _____t CHZCI, (2.5 d) BnO \ BnO 74*& overall Scheme 19 ROH (0.121 mnol) _____c OMe I I &On (0.24 mnol). SnCl, (0.24 mmd) 2.6-difBu-4-Mepyr (0.24 mmo9 4 A MS (0.3 g), Et,O (I0 mL), r.t, 2.4 hr.OMe I + OMe BnO BnO BnO Bno neighbouring acetal ensures delivery of the nucleophilic partner from the P-face giving an intermediate whose capture by water results in stereospecific formation of the desired P-mannoside. A recent synthesis of the thrombin inhibitor cyclotheonamide B (15) was notable for the use of the simultaneous deprotection of an arginine 4-methoxy-2,3,6-trimethylbenzenesulfonyl group and a phenolic 2,6-dichlorobenzyl ether using trifluoroacetic acid in the presence of thioanisole as a carbocation scavenger.26 Both protecting groups survived dilute HCl in dioxane, LiOH in aqueous THF, TMSOTf (used to remove a Boc group), TBAF (used to cleave a trimethylsilylethyl ester), and a Dess-Martin oxidation (Scheme 20).Falck and c o - ~ o r k e r s ~ ~ have described a novel protecting group for primary and secondary alcohols prepared from commercial 1,1,1,3,3,3-hexafluoro- 2-phenylisopropyl (HIP) alcohol using DEAD and Ph3P (Scheme 21). The oustanding chemical resistance of the HIP group compares favourably with other standard ether protectors such as methyl, benzyl, and trityl. HIP ethers are stable over an unusually broad pH range as well as being resistant to oxidants, nucleophiles (MeLi, N2H4), Lewis acids (BF3 * OEt,), and various reducing agents. However, lithium aluminium hydride causes partial ( < 30%) cleavage of primary HIP ethers under forcing conditions.Results from the selective removal of several representative alcohol protecting groups in the presence of a HIP moiety are summarized in Table 1. The susceptibility of trifluoromethyl ethers to lithium naphthalenide (LiNaphth) can be exploited for the preferential deprotection of HIP ethers in the presence of other protecting groups. Many common functional groups such as amides, carboxylic acids, unconjugated olefins, and HN HNANH, 15 Scheme 20 320 Contemporary Organic Synthesis0- / PhcHo (1.2 eq.) I O- TMSOTf (2 q.) I I bMe PhC(CF&OH (1.2 MI) DEAD (1.5 mmol) Ph3P( 1.5 mmol) PhH (2 ml) 83% (1 mmol scale) 1 OH F3C CF3 x;DoXpn OM* Scheme 21 PhC(CF3)20-(CH&OPG -PG PM=(CF3)20-(CH2)80H - LIN apht h \ HO(CH2)eO-PG Table 1 PG removal ~~~ ~~ HIP' Yield removal Entry PG Reaction conditions Tmr.("A) yield ("A) I 1 Tr SnC12, CH2CI2 4 a9 a1 2 THP pTsOH,MeOH 1 93 89 3 MEM Me,SiiI,Nal/MeCN 6 88 86 4 Bn PdC, HAeOH 1 91 71 5 MPM DDQ,CH,CIf120 3 92 74 6 t-BuPh2Si Bu~NF, THF 1 95 73 7 Bz KOH, MeOH 97 0 'HIP = -C(CF&Ph acetylenes are compatible with the HIP deprotection conditions whilst others, e.g. esters, epoxides, ketones, and halides, are labile. With stoichiometric LiNaphth, deprotection is rapid ( < 1 h) even at - 78 "C; on a preparative scale, the cleavage is more conveniently conducted using Li sand and a catalytic amount of naphthalene, although the reaction requires more time to reach completion. ethers of primary and secondary alkyl alcohols has been reported by Hatakeyama and co-workers*' (Scheme 22).Ester, lactone, and glycosidic acetal functionalities are unaffected. of small organic molecules has stimulated a fresh Direct preparation of benzyl ethers from of TMS The growing interest in the solid phase synthesis Scheme 22 appraisal of traditional organic synthesis in a polymeric environment. One such recent study examined Horner-Emmons and conjugate addition chemistry on short aliphatic chains linked to a solid support (Scheme 23). Reaction of butane-1,4-diol with the tritylated3' polystyrene 16 gave the monoprotected alcohol 17 which was converted into the adduct 18 using traditional organic transformations without any penalty in efficiency. Release of the adduct was accomplished by simply treating the polymer beads with formic acid in THF at room temperature.Having validated the basic protocol, the authors extended their study to the generation of combinatorial libraries. 2.4 Alkoxyalkyl ethers Tetrahydropyranyl (THP) ethers can be selectively cleaved in the presence of TBS ethers, MOM ethers, benzyl ethers, and mesitylene acetals using RESIN Ph Ph 16 RESIN (i) PyrSOs DMSO (ii) PbP=CH-COMe * Ph RESIN I 17 PhSH, NaOMe (cat.) THF, r.t., 2 d REFIN THF H r.t.. 2 hr. 18 Scheme 23 Jarowicki and Kocienski: Protecting groups 32110 mol% BF3 - OEt, in dichloromethane containing EtSH as a carbocation scavenger; BBr3, ZnCl,, and H p o (i) ml,, cHZcl2, 0 “c, 50 ZnBr, also 24. OMEM 73% OH An example is shown in Scheme (19 pH 7.0 phosphate buffer EtSH4HZCIz (5% V/V) ../Oh 92% HA H ATBS Scheme 24 Tanemura and co-workers3’ have reported that THP ethers can be deprotected with DDQ in methanol-water solution giving the parent alcohols in very good yields.Sonnet’s33 one-pot direct conversion of tetrahydropyranyl ethers into bromoalkanes using Ph3P - Br, complex was used in quadruplicate for the conversion shown in Scheme 25.34 Ph3PBr2 (8.56 mmol) r.t., 16 hr. 81% (1.43 mmol scale) CHzCIz (40 ml) Scheme 25 A tetrahydropyranylation of primary and secondary alcohols using (zinc chloride)- impregnated alumina3’ is mild (room temperature), solvent free, and the procedure does not need an aqueous work-up. Deprotection of the homochiral MEM ether 19 was complicated by racemization owing to reversible intramolecular transesterification. Schroer and Welzel found that racemization could be prevented by using a phosphate buffer (pH 7.0) during work- up.36 Even then the product must be immediately used in the next step if the valuable stereogenicity is to be preserved (Scheme 26).During a synthesis of the antifungal polyene macrolide roxaticin (24) (Scheme 27), Rychnovsky and H ~ y e ~ ~ were faced with the daunting task of selectively releasing and distinguishing only the first two of the nine hydroxy functions (at C-1 and C-3) in the fully protected intermediate 20. The 19 no racemization I with buffer work-up I Scheme 26 successful three-step protocol involved first selective electrophilic cleavage of the terminal dioxane ring using TESOTf at elevated temperature thereby placing a TES group at C-1 and an isopropenyl ether at C-3.The isopropenyl ether was then cleaved in the second step using Os04 and finally the C-3 hydroxyl function was reprotected by reaction with 1,3-benzodithiolyl tetrafluoroborate (21) according to the procedure of Sekine and Hata.38. The resultant 1,3-benzodithiolan-2-yl (BDT) ether was stable to the conditions required to remove the TES ether of intermediate 22 in preparation for construction of the macrocycle in intermediate 23. In the final step of the synthesis, the remaining three dioxane rings and the BDT ether were cleaved using an acid ion-exchange resin in MeOH. 3 Thiol protecting groups For the synthesis of the highly labile antibiotic thiarubrine A (28) (Scheme 28), Koreeda and Yang3’ required a method for introducing a protected thiol which could be carried through the synthesis unscathed until the end.The 2-(trimethylsily1)ethyl group which had previously served well in the protection of esters and alcohols (in the form of the SEM group) was chosen for its robust character. Thus, a double base-catalysed addition of 2-(trimethylsily1)ethanethiol to the diyne 25 gave the symmetrical dienedithiol derivative 26 in excellent yield. After further elaboration to the triyne 27, the two thiol functions were released by treatment with TBAF and the construction of the 1,Zdithiine ring completed by oxidation with iodine to give the target in 53% yield for the two steps. Guibk and c o - ~ o r k e r s ~ ~ reported a new allylic protecting group for thiols in general and cysteine in paticular - allyloxycarbonylaminomethyl (Allocam).S-Allocam derivatives are readily prepared by acid- catalysed condensation of thiols with allyl N- hydroxymethyl carbamate 29 (Scheme 29). Deprotection can be achieved using a palladium catalyst, tributyltin hydride, and acetic acid - the latter being essential to prevent formation of allyl thioethers. The reaction leads to a mixture of the thiol, its tributyltin derivative, and minor amounts of disulfide. For the sake of convenience, the crude reaction mixtures were therefore treated with iodine and the deprotected products isolated as their disulfide derivatives. S-Allocam derivatives are stable under the basic deprotection conditions of 322 Contemporary Organic SynthesisI I TESOTf (318 mmd) Pt2NEt (530 mmol) CH2Cb (0.5 ml) 11o”c,2ohr. 20 I : I 22 \ I Q r 1 1 OsO, (30 pL of 2.5% inBu’OH) Pyr (20 pL), CDC13 (2.5 mL) 60% (53pmolscalc) J BF4- 21 I I I I 1 I I I i Dowex Wm-1x (10 mg) MeOH (2 mL) 1 .5 hr., r.t.23 24 Scheme 27 SiMe3 I I Me3SCHgHSH (2.2 eq.) I I KOH (cat.), DMF, r.t, 2 hr. [ 25 :: 87% -:$< 26 SiMe3 I I I I 28 Scheme 28 TBAF (8 eq.) 3A MS, THF, r.t., 1 hr. - I 2 (10 cq.) r.t., 30 mn. 53% 27 Fmoc derivatives but only marginally stable in the acidic conditions of But ester and Boc removal. 4 Diol protecting groups Selective cleavage of an acetonide in the presence of two MOM ethers, a Troc group, and a Boc group was accomplished with the aid of ferric chloride adsorbed onto silica gel (Scheme 30).4’ to efficiently cleave a terminal acetonide in the presence of an internal acetonide (Scheme 31).42 The Ley group has devised new methods for the simultaneous protection of two adjacent hydroxyl functions in carbohydrate derivative^.^^ For example, cyclohexane-1,2-diacetals allow protection of diequatorial 1 ,Zdiols especially in manno-type sugars where regioselective introduction of 3,4-protection is difficult.For rhamnosides4 this was, until now, only possible by a four-step sequence. In the example shown (Scheme 32), the requisite protection was accomplished by acid- cat alysed transacetaliza t ion between methyl a-mannoside (31) and 1,1,2,2-tetramethoxy- cyclohexane (30). In this case, vicinal protection Dowex 50W-X8 in 90% methanol has been shown Jarowicki and Kocienski: Protecting groups 32329 Bu3SnH (4.4 m 9 AcOH (8 mmol) CH&la 20 min, r.t.PdCldPPh& (0.08 mm~l) NHBoc T MeOOC &s.sOycoo-.. 4 I2 (0.5 -4.1 = Y O o M e NHBoc NHBoc 100% (2 mmol scale) FeCb / SiO, (0.3 mmol) CHC13, r.t., 15 hr. 86% (0.9 mmd scale) R = H, SnBu:, Scheme 29 Scheme 30 Scheme 31 DOWX 5ow-xa (110 w/w%) 80% MbOH 32 hr., r.t., 93% 1 A NH includes a minor amount of axial-equatorial protection of the 2,3-hydroxyls as well. The resultant cyclohexane-1,Zdiacetals 32 are readily deprotected on brief treatment with trifluoroacetic acid/water (19 : 1). On the other hand the protection of D-gluco- pyranose 34 (Scheme 33) presents problems, because here all secondary OH groups are trans- diequatorially arranged; thus tetramethoxy- cyclohexane 30 gives a mixture of 2,3- and 3,4-protected glucosides.If, however, the homochiral bis-dihydropyran 33 is used, one regioisomer (35) can be prepared in high yield.45 5 Carboxyl protecting groups The very high nucleophilicity of caesium phenylthi~late~~ was used to cleave both a hindered methyl ester and a methyl carbonate in the tetraprenylbenzoquinol derivative 36 (Scheme 34) under comparatively mild conditions (DMF, + HCIo3 OM9 OMe 24 4 mmal 17.8 mmol 30 31 HC(OM43 (2 ml) MeOH (25 mL) CSA (1.33 mmol), A T 698.77 7 6101.40 \ - Me&) I 11% 6 99.22 6111.23 32 (48%) Scheme 32 324 Contemporary Organic SynthesisPh I Scheme 33 OMe 36 PhSH (0.3 mL) 85 "c, 3 hr. 01% (0.3 ml scale) cw(se"mT' Yh OMe 37 Scheme 34 85 0C).47 The phenolic methyl ether in the product 37 survived unscathed. Chlorotetaine is an irreversible inhibitor of glucosamine-6-phosphate synthetase and thereby interferes with cell wall biosynthesis.The terminal steps of a synthesis of chlorotetaine are shown in Scheme 35 in which deprotection of an N-terminal amino group is a prelude to the final enzymatic hydrolysis of a methyl ester function.48 Critical to the success of the synthesis was the suppression of easy racemization at the ring juncture in the ester hydrolysis step by using porcine pancreatic lipase. deprotecting benzyl esters under neutral conditions using N-bromosuccinimide and dibenzoyl peroxide in carbon tetra~hloride.4~ It provides an alternative method to hydrogenolysis but it fails when the substrate contains a tertiary amide functionality. The 2-methoxyethoxy (MEM) group is a well known protector for alcohols but its use in the protection of carboxylic acids is rare.Scheme 36 depicts the deprotection of a MEM ester 38 under Anson and Montana reported a way of Scheme 35 (i) CF3COOH (3.1 mL) anisole (0.3 rrl) (ii) porcine pancreatic #pass pH 7.5 phosphate buffer 23 'c, 4.5 hr. 55% (0.62 mmol scale) CH&12 (0.6 ml), 0 "c, I h no racemization 0 COOH CbzHN OMe 38 MgBrz-EtzO ( 5 eq.) r.t.. 26 hr. ph\ CbzHN OMe OMe Scheme 36 mild conditions without harm to the Cbz or Boc groups and without racemization of the arylglycine units.50 MEM esters can also be cleaved readily on treatment with AlC1,-N,N-dimethylaniline in dichloromethane to give the parent carboxylic acid in high yield51 and the same conditions can be used to cleave methyl, benzyl, methoxymethyl, met hylt hiomethyl, and p-( trimet hylsilyl) ethoxymethyl esters as well.Jarowicki and Kocienski: Protecting groups 325The Kunz group has been at the forefront of development of new strategies and tactics for the synthesis of glycopeptides which compound all the difficulties inherent in manipulating acid-sensitive carbohydrates and base-sensitive peptides. A noteworthy new tactic from these workers52 uses lipase M from Mucor javanicw for the hydrolysis of the C-terminus of peptide components of glycopeptides as illustrated by the model shown in Scheme 37. 2-[2-Methoxyethoxy]ethyl (MEE) esters are especially valuable substrates because they confer wetability and solubility in water and so ensure that the esters of hydrophobic peptide sequences will be hydrolysable.Moreover, lipases generally lack protease activity making them selective for hydrolysis of ester functions only. Scheme 37 Reductive cleavage of 2,2,2-trichloroethyl esters and carbamates is usually accomplished with Zn in the presence of a proton source such as NH4Cl or acetic acid. However, in a recent synthesis of the potent phospholipase A2 inhibitor thielocin Alb, a 2,2,2-trichloroethyl ester was cleaved from the complex substrate 39 using cadmium in a mixture of DMF and acetic acid (Scheme 3!Q5' Of the many approaches toward the development of useful protecting groups for peptide synthesis, the concept of converting a stable protecting group into a labile protecting group (relay deprote~tion~~) has been fruitful. The same concept can be applied to linkers for solid phase peptide synthesis in which the linker also serves as a C-terminal protecting group.A recent synthesis of y-endorphin by Kiso and co- w o r k e r ~ ~ ~ adapted a relay deprotection strategy based on the p-(methylsulfiny1)benzyl (Msob) group of Samanen and Brandiess6 for the design of a new linker: 4 (2,5-dimet hyl-4-methylsulfinylpheny1)- 4-hydroxybutanoic acid (DSB) (40) (Scheme 39). The linker was appended to an aminomethylated polystyrene-resin and then coupled with C-terminal amino acid Boc-Leu to give 41. The acid stability of p(methylsulfiny1)benzyl type groups enabled selective removal of the Boc-protecting group from reagent 41 which could be used in solid phase peptide synthesis to prepare the protected resin- bound peptide 42. The deprotection of all protecting groups as well as the cleavage of the peptide from the resin was achieved in one-pot by reductive acidolysis using tetrachlorosilane, thioanisole, anisole, and trifluoroacetic acid.Under these conditions all Msob-derived protecting groups were smoothly reduced to the corresponding labile sulfide form and then cleaved by acidolysis to give y-endorphin in 62% yield. In a recent solid phase synthesis of arylacetic acids,57 a linker was required with the seemingly irreconcilable property of being stable towards the basic conditions of enolate alkylation and Suzuki coupling but also labile towards cleavage with hydroxide or amines. A relay deprotection approach based on Kenner's N-acylsulfonamide linker5* served the purpose as shown in Scheme 40.Under basic conditions the arylsulfonamide (pK, 2.5) is deprotonated and hence inert towards nucleophilic attack during the alkylation (43-+44) and Suzuki coupling (44 +45) steps. However, cleavage from the resin was accomplished by first converting the N-acylsulfonamide 45 into its N-methylated derivative 46 which is now quite labile towards nucleophilic attack. Cleavage of peptide segments linked to resins by allyl linkers using hydrostannolytic allyl transfer was originally reported by L ~ f f e t . ~ ~ Giralt and co- workersm showed that the procedure (which uses tributyltin hydride in presence of (Ph3P)4PdC12) is compatible with Fmoc protecting groups. Alternatively, the cleavage reaction may be carried out using N-methylaniline in a 2 : 2: 1 mixture of 0 Cd (50 q.), DMF-HOAc (1:l) 25 "C, 15 hr.R = H Scheme 38 326 Contemporary Organic Synthesis(i) HWESIN, PiflEt, BOP ( 8 ) B d e u , DIPCDI, DMAP \ HN Q. OH 41 SoYdPhaos i HN\o Pe#ide Synthesis i NH-RESIN I 0 Msob OMS& Msob Msob Msob I 1 1 I I I I Msz Boc-Tyr-Gl y-G l y - P h e - M e t - T h r S e r - G I ~ ~ r ~ l ~ T ~ - P ~ e ~ V a ~ T h r ~ e ~ 42 I I Msob Msz I HN\ SCb, thioanizds (100 eq.) aniook (100 q.), TFNCH& (9 : I) 25 "c, 3 hr., ( 6 s from 41) Msz I pMcSOC&t4CH,0C0 9 NH-RESIN Scheme 39 REFIN YHZ REFIN y 2 REFIN y 2 HNYo - Pd(PPhd4, hk&HCH*BN NafiO3 - Q Q THF, A (i) LDA, THF, 0 'c (ii) 43 44 I 45 A Ho% A Ho- Q 46 A Scheme 40 Jarowicki and Kocienski: Protecting groups 327DMSO/THF/OS M HCl in the presence of (Ph,P),Pd.The weaker basicity of the N-methyl- aniline compared with the usual morpholine suppresses competing deprotection of Fmoc groups. Genet and co-workers6 devised a water soluble Pdo catalyst [prepared in situ from Pd(OAc)2 and trisodium 3,3',3"-phosphinetriyltribenzenesulfonate (TPPTS)] which can be used to deprotect base sensitive penem allyl ester 47 (Scheme 41). The free carboxylic acid 48 was obtained in high yield and almost pure form by simple evaporation. and is thus compatible with other acid- or base- sensitive functional groups. Recently a comprehensive studyM revealed that bis(tributy1tin) oxide shows a high level of chemoselectivity between methyl and ethyl esters versus t-butyl esters and lactones. (Pivaloy1oxy)methyl carboxylates can also be cleaved in the presence of the base sensitive P-lactam moiety (Scheme 43).However, sterically hindered esters do not cleave and the method is not compatible with a fluoroalkyl group. 47 Pd(0AC)z (2 ml%) TPPTS (4 MI%), Et2NH (I0 eq.) MeCNIMcOWH20 1 hr., r.t, 03% I BmHND& 0 COOH (Bu,Sr1)~0 (0.2 mmol) Et@ (25 ml) 25 OC, 3 hr. 56% (0.1 mmd scale) Scheme 43 6 Phosphate protecting groups Scheme 41 Ally1 alk-2-ynoates can be readily converted into alk-2-ynoic acids by reaction with morpholine in the presence of a palladium-diphenylphosphinopropane catalyst, thus providing a deprotection of allyl esters of 2,2,3,3-tetradehydro-PGE1 (Scheme 42).6' Ruthenium-catalysed reductive cleavage of allylic esters with formic acid and triethylamine has also been reported.62 Bis(tributy1tin) oxide has been known for some time as a mild reagent for non-hydrolytic cleavage of carboxylic esters.63 The reaction is carried out in aprotic solvents under essentially neutral conditions dba = dibenzylideneacetone THF, 35 "C, 1 hr.0 -OH / T E S ~ dppp = 1,3-bis(diphenyIphosphino)propane Scheme 42 In 1971 Sheehad5 showed that 3',5'-dimeth- oxybenzoin (DMB) esters are photochemically cleaved with high quantum yield (0.64) to the corresponding carboxylic acid and the relatively inert 2-phenyl-5,7-dime t hoxybenzofuran (53). Givens66 and P i r r ~ n g ~ ~ have extended these observations to the protection of phosphotriesters. An asymmetric synthesis of 3',5'-dimethoxybenzoin (Scheme 44) via the benzaldehyde cyanohydrin minimizes the number of diastereoisomers created in the phosphorylation of chiral alcohols.Thus reaction of 49 with 2'-(cyanoethoxy)(N,N'- diisopropy1amino)chlorophosphine afforded the phosphoramidite 50 which then reacted with Boc- Ser-OMe to give the two diastereoisomeric phosphotriesters 51. Photodeprotection gave the desired phosphodiester 52 (85%) along with 53. Baldwin has used 3',5'-dimethoxybenzoin for the photolabile protection of inorganic phosphate.68 The allyl group in its many guises has rapidly gained favour for the protection of alcohols (allyl carbonates, allyl ethers), carboxylic acids (allyl esters), amines (allyl carbamates), and more recently, phosphate^.^^ Scheme 45 illustrates the value of the allyl group for the deprotection of complex substrates under very mild condition^.^' By using Pdo in a mixture of THF and acetic acid, 4 alcohol functions protected as their allyloxycarbonate (aloc derivatives) and two phosphotriesters protected and their allyl ester derivatives were deprotected simultaneously in 90% yield without injury to the remaining acid and base sensitive functionality.328 Contemporay Organic SynthesisMe0 g5% (8% e.e.) (1 80 m d scale) 85% (0.56 mmd scale) I MeO (i) hv (350 nm) PhH (10mL) 45 (ii) NEt:, Scheme 44 Scheme 45 I 51 Me0 (Ph2N-P(CI)OCH&H2CN (13.2 mmol) (PhpNEt (33 mmol) MeCN (50 mL), 0 "C, 1 hr. 66% (11 mmol scale) - (i) Boc-Ser-OMe (1.31 mmol) S@nitrophenyl)tetrazole (3.94 mmd) MeCN (30 ml), rA.. 30 min. (ii) 12, THF, 2,6-lutidine 45% (5 mmd scale) Me0 50 <NEt3 52 Mec, 53 OAll O-'f-ON 0 OH O.f-0" Jarowicki and Kocienski: Protecting groups 329The 2-(trimethylsily1)ethyl (TMSE) has been used successfully as a protecting group for phosphate monoester synthesis.71 It can be removed by treatment with tetrabutylammonium fluoride or HF in acetonitrile.Recently, Wada and Sekine have reported that TMSE is an effective protecting group for the internucleotidic phosphate in oligonucleotide ~ynthesis.~’ Reaction of protected phosphitylating reagent 55 (Scheme 46) with 5’-O-dimethoxy- tritylthymidine 54 afforded the phosphor- amidite building block 56 in 80-6% yield. The TMSE-phosphoramidite 56 was then condensed with thymidine 3’-O-succinate bound to controlled pore glass (CPG) 57 in the presence of 1 H- tetrazole. After oxidation with iodine and the subsequent capping reaction using acetic anhydride and DMAP, the protected dimer 58 was obtained in 99% yield.p-Nitrophenylethyl (Npe) groups are useful for phosphate protection during the preparation of oligonucleotides (Scheme 47).73 After phosphoramidite 59 was transformed into an oligonucleoside, the protecting group was removed using DBU. Npe protecting groups are superior to the 2-cyanoethyl group owing to diminished alkylation side-reaction during deprotection. 7 Carbonyl protecting groups 7.1 0,O-Acetals Aldehydes and ketones can be protected as p-me t hoxyp henyle t hylene ace t als and ke t als using DMTrO, OH 54 CHzCHzOH CH2CH20P(NPS& I I I 0 “c+ r.t.. 16 hr. I NO2 95% ( I 0 mmol scale) NO2 O M T ” W OH (0.66mmd) tetrazole (0.46 mmol) MeCN (I0 mL) 30 rnin., r.t.67% (0.83 mmd scale) 1 DMTrOtsl” 59 Scheme 47 bis-trimethylsilyl ether 60 and a catalytic amount of TMSI.74 Deprotection is accomplished under mild conditions with DDQ and water in dichloromethane. Other acetals and ketals are not affected (Scheme 48) ? TMSEO-P-NPS2 56 DMTr = 4,4’-dimethoxytrityl “w O-succinyCCPG 57 (i) 1Htetrazok (1 M in M N , 200 pmol), 5 min (i9 I2 (0.1 M in aqueous pyridine)), 1 min. (iii) Ac@, 0.1 M DMAP in pyridine, 2 mkr. >W %(using 20 pmol of 56 and 1 pmol57) ? TMSEO- k-okoJ” 0 bsuccinycCPG 58 Th = Thymine Scheme 46 330 Contemporary Organic SynthesisM e O w o m S oms Scheme 48 60 1.2 eq. TMSl (cat.), CH&lz (0.5 M) -78 + 0 "C 71% 82% HC(OMe)3 (376 mmol) PTSA (1.9 mmol) PhMe (50 mL) 97% (37.6 mmol scale) (€)-Me-CH=CH-CHO (51.8 mmol) PTSA (1.73 rnmol), PhMe (50 mL) r.t, 23 hr., r.t., 21 hr., 36% (34.6 mmol scale) 0 61 OH I MeO AD-mk-B (3.5 g) methanesulfonamide (2.50 mmol) BU'OH-H~O (1:1, 25 mL), rA., 48 hr.96% (250 mmol scale) + - Hz, Pd(OH)z. 50 p s i . MeOH, r.t., 48 hr. OH 0 OH Scheme 49 Wong and c o - ~ o r k e r s ~ ~ recently exploited the hydrogenolytic lability of 175-dihydro-3H-2,4-benzo- dioxepin derivatives for the preparation of some acid-labile dihydroxyaldehyde derivatives generated by the Sharpless asymmetric dihydroxylation as illustrated in Scheme 49. In the example shown, the required protected alkene 61 was generated in modest yield by acetal exchange with 3-methoxy- 1,5-dihydro-3H-2,4-benzodioxepin. Acid hydrolysis can also be used to release the aldehyde.The conversion of an aryl methyl group into a dioxolane is hardly a typical method but its feasibilty is illustrated by the two-step procedure shown in Scheme 50. The first step, a double radical bromination under photochemical conditions, converts 62 into the 172-dibromoalkane 63. In this case the bromination of the methyl group is accompanied by a small amount of bromination of the ester methylene function. In the second step, a double displacement of the bromine atoms in 63 by ethylene glycol at 160 "C produces the dioxolane 64 as a mixture of ethyl and hydroxyethyl esters.34 7.2 S,S-Acetals er I NBS (61.8 ml) CCl, (270 ml) - - 63 R = HI Br (85 : 1 5) cacos (75 ml) HO4H&H&H (120 ml) 160 "C, 3 hr. 5 48% (+29% Et ester) OH 64 Scheme 50 Direct conversion of the ketal function in 65 into a dithioketal moiety (Scheme 51)76 was accomplished with aluminium trichloride in order to minimalize the epimerization at C-(8) - a problem which attends other Lewis acids such as titanium tetrachloride.Deprotection of 173-dithianes to the corresponding carbonyl compounds has been achieved by treatment with 1.5 equivalents of DDQ in acetonitrile-water (9 : 1)77 and by irradiation Jarowicki and Kocienski: Protecting groups 331I 65 CFSCOOH (20 Id-) ankde (5.12 mmol) cH$3O,(l.l ml) r.t., 22 hr. 60% (1.28 mol scale) Small amount of C(8) epimer TBAF (1 .5 mmo9 DMF, 80 "c, 20 hr. 60% (0.5 mmol scale) H,NCH,CHflH, (0.15 mL) Scheme 51 ( y > 360 nm) of a dichloromethane solution of the dithioacetal or ketal with a pyrylium salt and molecular oxygen.78 8 Amino protecting groups Hydrazinolysis which is typically used to deprotect phthalimide derivatives can also be used to deprotect N-[ 1-(4,4-dimethyl-2,6-dioxocyclo- hexy1idene)ethyl (Dde) groups which are easily introduced by reaction of an amine (for example cadaverine as shown in Scheme 52) with 2-acetyldimedone (66).79 Dde groups are stable to 20% piperidine in DMF, the reagent frequently used to remove Fmoc groups, but is readily removed by 2% hydrazine in DMF within minutes.The driving force for the Dde deprotection is the formation of 3,6,6-trimethy1-4-0~0-4,5,6,7-tetra- hydro-lH-indazole and this can be monitored by the UV absorption at either 270 or 290 nm. The example shown in Scheme 52 comes from a synthesis of the spider toxins nephilatoxin-9 and -11. Two amine functions protected as their N- (3,4-dimethoxyphenyl)methyl derivatives in the pentacyclic tripyridine 67 (Scheme 53) were released on treatment with trifluoroacetic acid in the presence of anisole as a carbocation scavenger." [(trimethylsilyl)ethoxy]methyl (SEM) group from the indole derivative 68 (Scheme 54) using TBAF in THF gave poor yields" - a problem which had been previously encountered by others.82 The best and most consistent results were obtained by using Attempts to remove the 'COOEt Scheme 53 QyJyJ ' CN Scheme 54 66 Scheme 52 332 Contemporary Organic SynthesisTBAF in DMF in the presence of an excess of 0 eth~lenediamine.~~ (I) NaHMDS (4.4 mmo9 THF (4.4 mL), 15 min 929c (22 mmol scale) (4 eOc20 (2 ml) Waldman and co-workers reported’ the chemoselective enzymatic liberation of the amino functions present in the nucleobases of 0-acetylated nucleosides by penicillin G acylase mediated hydrolysis of the corresponding phenylacetamides (Scheme 55).Scheme 57 Pd(0Ac)pPTS (1:2,2.5 mot%) MeCN-Hfl (&I, 3.5 ml) HNEtz (5 -1) 30 m4. r.t. 0 OAc Penidlin G acylase pH 7.8, phosphate buffer 30 vol.% MeOH 0 I OAc Joulli6 and co-~orkers~’ reported that Fmoc can be removed from N-protected amino acids and dipeptides by potassium fluoride/l8-crown-6 in the presence of methyl, ethyl, t-butyl, benzyl, and p-methoxybenzyl esters. 2,2,5,7,8-pentamethylchroman-6-sulfonyl (pmc) group for the protection of the highly basic guanidine function in arginine based on earlier observations that electron donating substituents on arylsulfonamides greatly facilitate p r o t o n o l y ~ i s .~ ~ ~ ~ ~ Church and Young” have used the pmc group to activate an aziridine ring during nucleophilic cleavage with lithium trimethylsilylacetylide (Scheme 58). Simultaneous removal of the TMS, t-butyl ester, and pmc groups occurred in quantitative yield on treatment with trifluoroacetic acid to give the amino acid derivative 70. Ramage originally designed the Scheme 55 Allyloxycarbamate protected cephalosporin 69 (Scheme 56) are selectively and quantitatively cleaved using a Pdo water soluble catalyst [prepared in situ from Pd(OAc)2 and trisodium 3,3’,3’‘-phosphinetriyltribenzenesulfonate (TPPTS)] dimethylallyl carbo~ylate.~ A O H NH2 // under homogeneous conditions without affecting the 70 Scheme 58 okNf---- 0 Scheme 56 Aryl amines are converted into their Boc derivatives by treatment with two equivalents of sodium hexamethyldisilazide in THF followed by one equivalent of di-t-b~tylcarbonate.’~ This procedure works on a wide variety of both electron- rich and electron-deficient aryl amines (Scheme 57).A recent synthesis of spermine and spermidine analogues for use as tumour growth inhibitors made good strategic use of the trifluoromethanesulfonyl group as both a protecting group and an activating group (Scheme 59).89 The high acidity of the N- trifluoromethanesulfonamides of primary amines (pK, 7.5 compared with 11.7 for the corresponding tosyl derivatives) was sufficient to enable a double alkylation of the octane-198-diamine derivative 71 under Mitsunobu conditions.All four of the trifluoromet hanesulfonyl groups were then removed from the alkylation product 72 using sodium in a mixture of ammonia and t-BuOH to give the tetra- amine 73. Deprotection of N-( arylsulfony1)amines can be problematic. Electrolytic cleavage offers a method which tolerates a range of functionality. Thus, electrolysis of the N-tosylamide 74 (Scheme 60) gave the corresponding amine 75 in 90% yield.g0 Vedejs and Lin have also shown” that N-(arylsulfonyl) amines can be deprotected efficiently using Sm12 in a refluxing mixture of the substrate in THF and N, N ’-dimethylpropyleneurea (DMPU). Diary1 Jarowicki and Kocienski: Protecting groups 333\r?,s02cF3 LN/W2CF3 b o H CF@2 XN& (1 5 mmol) DEAD (1 5mnol) PhsP (15 mmOl) THF, r.t, 18 h 72% + NHS02C Fa I NHSO2CFa (yH2)6 71 (5 mmol) Na (OXC~OS), NH3 (106 mL) (em)@ (15 mnol), THF rR, 12 hr.54% overall (3 mmol scab) BdOH (!3 ml), -70 “c AH 73 Scheme 59 74 = Ts -1&55J 75 R=H (0.123 mmol scale) Scheme 60 disulfides and aryl mercaptans are amongst the sulfur-containing by-products. The study revealed that phenylsulfonyl groups cleave faster than tosyl groups but primary and secondary sulfonamides cleave at about the same rate. /?-Tosylethylamine 76 (Scheme 61) is a readily prepared reagent that can be used to synthesize N- tosylethyl-protected amido compounds, which can be deprotected with potassium t-buto~ide.~~ Thus, deprotection of /?-lactam 77 gave no evidence of ring-opening or epimerization. 9 Books and Reviews 1 ‘Protecting Groups’, P.J. Kocienski, 1994, Thieme Verlag, Stuttgart, 1994. 2 ‘Applications of Combinatorial Technologies to Drug Discovery, 1. Background and Peptide Combinatorial Libraries’, M.A. Gallop, R.W. Barrett, W. 3. Dower, S.P.A. Fodor, and E.M. Gordon, J. Med. Chem., 1994, 37, 1233. 3 ‘Applications of Combinatorial Technologies to Drug Discovery. 2. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions’, E.M. Gordon, R.W. Barrett, W.J. Dower, S.P.A. Fodor, and M.A. Gallop, J. Med. Chem., 1994,37, 1385. 4 ‘Convergent Solid-Phase Peptide Synthesis’, P. Lloyd- Williams, F. Albericio, and E. Giralt, Tetrahedron, 1993,49, 11065. 5 ‘Multi-step Deprotection for Peptide Chemistry’, M. Patek, Int. J. Peptide Protein Rex, 1993, 42, 97.6 ‘The Chemistry of 2-Oxazolines (1985-Present)’, T.G. Gant and A.I. Meyers, Tetrahedron, 1994,50,2297. 7 ‘Recent Progress in 0-Glycosylation Methods and Its Application to Natural Product Synthesis’, K. Toshima and K. Tatsuta, Chem. Rev., 1993,93, 1503. 8 ‘Enzymic Protecting Group Techniques’, H. Waldmann and D. Sebastian, Chem. Rev., 1994, 94, 911. 9 ‘Enzymes in Synthetic Organic Chemistry’, C.-H. Wong and G.M. Whitesides, Pergamon, Oxford, 1994. 10 ‘The Selective Blocking of Trans-Diequatorial, Vicinal Diols - Applications in the Synthesis of Chiral Building-Blocks and Complex Sugars, T. Ziegler, Angew. Chem., Int. Ed. 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ISSN:1350-4894    

DOI:10.1039/CO9950200315

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Synthesis of aromatic heterocycles THOMAS L. GILCHRIST Chemistry Department, University of Liverpool, Liverpool L69 3BX, UK Reviewing the literature published between July 1993 and February 1995 Continuing the coverage in Contemporary Organic Synthesis, 1994, 1, 205 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Introduction Furans and benzofurans Thiophenes and benzothiophenes Pyrroles Indoles Other fused pyrroles Oxazoles, thiazoles, benzoxazoles, and benzothiazoles Isoxazoles, isothiazoles, isoselenazoles, and fused analogues Imidazoles and benzimidazoles Pyrazoles and indazoles Thiadiazoles Triazoles and tetrazoles Pyrones, coumarins, and chromones Pyridines Quinolines and isoquinolines Pyrimidines and quinazolines Pyrazines, cinnolines, and triazines References 1 Introduction This is the second general survey in Contemporary Organic Synthesis of new and improved methods for the preparation of aromatic heterocycles.The first review' covered only five-membered aromatic heterocycles but this one also includes six- membered ring systems. As before, the methods discussed are those in which aromatic rings are produced from acyclic precursors or by ring interconversion; syntheses which involve functional group transformations on the existing ring system are excluded. Only the more common monocyclic and bicyclic ring systems are discussed system at ically . 2 Furans and benzofurans There have been further examples of the synthesis of furans by the intramolecular addition of an alkoxide anion to a carbon-carbon triple b ~ n d . ~ - ~ Marshall and co-workers have described a synthesis of 2,3-disubstituted furans by this method: an example is shown in Scheme L2 This method provided a route to rosefuran (1).The related ruthenium-catalysed cyclization shown in Scheme 1 is restricted to terminal alkynes. An intramolecular nucleophilic addition to a coordinated triple bond was propo~ed.~ Me MeO-0, 0 C02Me i Scheme 1 The ring expansion of alkynyloxiranes 2 to 2,3-disubstituted furans has been achieved by irradiation in the presence of molybdenum hexacarbonyl and triethylamine; the molybdenum complex 3 has been suggested as an intermediate (Scheme 2).6 The mercury(i1)-catalysed hydration of the triple bond of the oxiranes 4 provides a new synthesis of 2,5-disubstituted fur an^.^ 2 Scheme 2 Gilchrist: Synthesis of aromatic heterocycles 3370 0 5 0 0 6 I dCN used as the precursor to the 3-methylene- dihydrofuran 6, which can be isolated but which reacts readily with enophiles such as acrylonitrile (as shown) and diethyl azodicarboxylate to give 3-substituted furans.' The synthetic method for 2-alkyl-3-methylfurans 7 shown was also used as a route to rosefuran (1).l0 The new furan syntheses shown in Scheme 4 all make use of the arenesulfonyl group to activate an adjacent C-H bond and thereby to provide a route to an intermediate suitable for cy~lization.~'-'~ New ) - <"" RSH Me - Me Me Me Me 7 Scheme 3 (PhSe)2* (NH4)$&: Several useful furan syntheses which involve R3 R3 R' intermolecular addition reactions of alkynes are illustrated in Scheme 3.The rhodium carbenoid derived from 2-diazocyclohexane-l,3-dione reacts C02Me, COMe, 1-pyrrolyl) to give the furans 5 in moderate to good yield.8 Cyclohexane-l,3-dione is SiMe3 LDA w s i M e 3 with a range of acetylenes (X = OEt, SiMe3, R Scheme 5 R2 R2 BuLi. R%HO TscO,,Ph \ 0-Ph * R 2 A R i (i) NaHCO,, I, (ii) KOBu' PhS02 c t 2.2 BULiR2- Br PhS02 hOH PhSOp-R' 'OH PhS02 ,Ar 0 - II Et,N 0 0 * phso2~oPr 0 NHR + ArCOCHO.RNC Ph so2- O Scheme 4 338 Contemporary Organic Synthesismethods for the construction of hydroxyenones suitable for cyclization to fur an^",^^ include the addition of sulfur nucleophiles to 5-hydroxyhex- 3-yn-2-one (Scheme 5).16 Three other cyclization reactions which lead to the formation of furans in good yield are also shown in Scheme 5.17-19 A short and efficient synthesis of furan-3-carboxaldehyde from (Z)-but-2-ene-1,4-diol has been described2’ and 3,4-bis(trimethylsilyl)furan has been prepared in good yield by cycloaddition of bis(trimethylsily1)- acetylene to 4-phenylo~azole.~~ The endo cyclization of 2-alkynylphenols is an established route to benzofurans, but some new variants of the method have been The carbonylative cyclization illustrated in Scheme 6 leads to methyl benzofuran-3-carboxylates the same method has been used to prepare the analogous indole esters.8 Scheme 6 An unusual method for the preparation of benzofurans is the metathesis of aryl enol ethers 9 in the presence of a molybdenum alkylidene complex (Scheme 7).24 2-Benzylbenzofuran and 2-arylbenzofurans were prepared in high yield in this way.Another mechanistically interesting route, also illustrated in Scheme 7, is based on the palladium(0)-catalysed activation of methoxy groups. Thus, 3-benzyl-7-methoxybenzofuran 10 was prepared (56%) from 2,3-dimethoxyiodobenzene and P-br~mostyrene.~~ R 9 I q O M e &Me 1 Ph+B, 5690 O M e 10 Scheme 7 Gilchrist: Synthesis of aromatic heterocycles 3 Thiophenes and benzothiophenes There are several new methods for the preparation of thiophenes bearing specific substituents, and in which the five-membered ring is constructed from an acyclic precursor by the formation of a C-S bond (Scheme 8). A range of 3-bromothiophenes has been prepared by the addition of hydrogen bromide and deprotection of trityl sulfides such as 11.26 The ketones 12, which are prepared from hexafluoroacetone, react with phosphorus pentasulfide to give the thiophenes 13.The 2-fluoro substituent can be displaced by nucleophiles, thus providing a route to other 3-trifluoromethyl- thi~phenes.’~ 2,4-Dimorpholino-3,5-diphenylthio- phene, a rare example of a 2,4-diaminothiophene, was prepared in high yield by oxidation of the thioacrylmorpholide 14.28 R HBr, AcOH Et0mscph3 EtO R 11 c p4s10 F3cuAr F 12 13 14 Scheme 8 c CH212, ZMCU 0-OR SMe 15 ArkH2SH, KOH Ar’ = = Ar’ 16 Ar’ n I , HSCH2C02Me, MeONa 17 Cop Et (i) RCOS-K’ PPh3 BF4- (ii) DDQ * @-R 18 Scheme 9 339Some examples of the preparation of thiophenes by carbon-carbon bond formation are shown in Scheme 9.2-Alkoxythiophenes and 2-aryloxythiophenes 15 have been prepared from acylketene 0,s-acetals by reaction with diiodomet hane and zinc-copper couple.29 The addition of benzylthiols to diaryldiynes 16 has been used to prepare terthiophenes and other 2,5-diarylthiophene~.~' Methods for the preparation of esters 17 and 18 of thiophene-2- and 3-carboxylic acids are also i l l u ~ t r a t e d .~ ~ ? ~ ~ synthesis of 2-trimethylsilylbenzothiophene 19 (X = S) and other benzo fused heterocycles, including those with X = Se and X = Te. The method, outlined in Scheme 10, is based on a directed ortho lithiation reaction.33 Benzothiophenes have also been constructed from halobenzenes by palladium(0)-catalysed cy~lization~~ and by generation and cyclization of aryl radicals3' (Scheme 11). A synthesis of 3-chlorobenzothiophenes has been described starting from alkynylbenzenes; their 1 : 1 adducts with phthalimidosulfenyl chloride are cyclized by reaction with aluminium A general method has been described for the SiMe3 BuLi [ msiMe] OTJ SiMe3 19 Reagent: (i ) X = S; (PhS02)2S (62%); X = Se; red Se (67%) Scheme 10 Scheme 11 4 Pyrroles Activated isocyanides are useful starting materials for the preparation of pyrroles with specific substitution patterns.There are several new examples of the synthesis of pyrroles by conjugate addition of carbanions, derived from isocyanides, to conjugated a l k e n e ~ . ~ ' ~ ~ ~ The reaction between ethyl isocyanoacetate and a-fluorovinyl sulfoxides, which leads to P-fluoropyrroles 20 in moderate yield, is shown in Scheme 12.39 This is one of several methods of pyrrole ring synthesis which have been applied to the preparation of fl-flu~ropyrroles,~'-~~ and which include the first synthesis of 3,4-difl~oropyrrole.~~ R WF 20 Scheme 12 Cyclization reactions which lead to pyrroles by formation of a nitrogen to carbon bond are illustrated in Scheme 13.The palladium-catalysed cyclization leading to 3-methyl-1-tosylpyrrole 21 and to other N-tosylpyrroles is initiated by coordination of palladium(I1) to the double bond.43 N- Tosylpyrroles can also be prepared by the cycloaddition of dienes to N-tosylsufinylamine followed by base-catalysed ring contraction of the cycloadduct; the efficiency of the ring contraction step is significantly improved by using trimethyl phosphite as a ~o-reagent.~~ The cyclization of the 2-azidoacrylates 22 resembles the well established route to indole-2-carboxylic esters from alkyl a-azid~cinnamates.~' Me Me N HTs Ts 21 Me Me \R 22 I R I H Scheme 13 Further examples of the preparation of pyrroles by formation of C-N bonds are illustrated in Scheme 14.1-Substituted benzotriazoles are proving to be useful starting materials for the preparation of a variety of aromatic heterocycles. Examples of their use for the preparation of 2-arylpyrroles4' and of 1,2-diarylpyrrole~~~ have been described. The route to 172-diarylpyrroles from the enamine 23 (which is prepared from benzotriazole, acrolein, and morpholine) is shown in Scheme 14. There are also 340 Contemporary Organic Synthesisfurther examples of the preparation of N- aminopyrroles from azoalkenes by the addition of activated methylene compounds;48749 a route to benzoylpyrroles 24 is synthesis of pyrroles from ketoximes and alkynes, which proceeds by a [3,3]-sigmatropic rearrangement of 0-vinylketoximes followed by cyclization, has been reviewed." The useful method of (Bt = 1 -benzotriazolyl) Me 0 0 +Me02c4N~N.c02Bu' Me Me NHCO~BU' 24 Scheme 14 Pentacarbonylchromium carbene complexes have been used as starting materials for the preparation of several 1,2-diarylpyrrole~.~~~~~ The preparation of l-aryl-2,3-triphenylpyrroles from the complex 25 and Schiff bases of cinnamaldehyde is shown in Scheme 15.52 Some cyclization reactions which provide efficient routes to pyrroles of specific types are illustrated in Scheme 16.The cyclization of the imide 26 (and of its five-membered ring analogue) is brought about by reaction with tributyltrimethylsilylstannane and caesium fluoride, which in effect provide a source of the tributylstannyl anion.53 The enaminoketone 27 has proved to be a useful reagent for the preparation of a variety of aromatic heterocycles; its reaction with aminoacetaldehyde dimethyl acetal provided a good route to 3-trifl~oroacetylpyrrole.~~ The diesters 28 were prepared in good yield from a-amino carboxylic esters and DMAD.5' 2-Hydroxypyrroles have been prepared from phenylglyoxal by a reaction sequence analogous to that shown for hydroxyfurans in Scheme 4.56 Ph 25 0 26 Et2N & 0 27 YNH2 CO2Et Scheme 16 (i) Mq,SiSnBu+ CsF (ii) TsOH 74% - 0 0 Et02C C02Me NaOMe H 28 Dimethyl pyrrole-3,4-dicarboxylates are often most readily prepared from DMAD by Diels-Alder reaction with oxazoles or by a 1,3-dipolar cycloaddition reaction.The former method has been used to prepare the aminopyrrole 29 by the interception of a transient oxazole in solution.57 Analogous cycloaddition reactions of imidazoles are much more difficult to achieve but the bicyclic imidazoles 30 have been shown to give the pyrroles 31 in high yield with DMAD.58 The transient 29 30 Me02C 9'7 MeOpC Y TfO- 'SiMe3 L " L P h NHAr 33 Scheme 15 Scheme 17 Gilchrist: Synthesis of aromatic heterocycles 341triazolium ylides 32, which are generated as shown in Scheme 17, react with DMAD to give the pyrrole diesters 33.59 5 Indoles Methods for the synthesis of indoles have been reviewed separately in this journal?' best method for the preparation of many indole derivatives.Recent progress in the use of the method has been reviewed61 and the reaction has been used to prepare N,ZV-dimethyltryptamines62 and analogues of sumatriptan, used in the treatment of migraine.63 Organoaluminium amides such as 34 are effective catalysts for the Fischer indole synthesis and they enable indoles to be prepared regioselectively from ketone arylhydra~ones.6~ These catalysts control the regioselectivity by abstracting a proton from an a-methylene group anti to the hydrazone, as shown in Scheme 18. The stereochemistry of the starting hydrazone thus controls which indole will be formed when two are possible. The Fischer indole synthesis still represents the J C02Me C02Me Scheme 19 The Heck reaction of 2-iodoaniline derivatives and alkenes or alkynes provides a good route to 3-substituted indoles.Recent examples of the method include the synthesis of indole-3-acetic acid derivative^,^^ tryptophan and 3-alk-ylind0les.~' Palladium-catalysed carbonylative cycliiations of 2-alkynylaniline derivatives have been used for the preparation of 2-substituted 3-acylindoles, as shown in Scheme 20,72 and 2-substituted indole-3-carboxylic esters by a reaction sequence analogous to that shown in Scheme 6 for R3 R3 34 Scheme 18 dR' + R2X Pd', CO Scheme 20 0 '' Bu3SnH. AIBN, o-c::3 H Two related indole syntheses, which are postulated to go by sigmatropic rearrangement of N- aryl-0-vinylhydroxylamines, are shown in Scheme 19.65,66 Further examples of the construction of indoles from ketone N-arylimines by way of aryne intermediates have been described67 and details have been published" of the zirconium-catalysed provides a useful route to 3,4-disubstituted indoles."' R2Br, Pdo I QTJ*' cyclization of 2-bromo-N-allylanilines7 which H Scheme 21 342 Contemporary Organic Synthesisthe corresponding benz~furans.~~ A radical cyclization and palladium coupling sequence which leads to 2,3-disubstituted indoles is shown in Scheme 21.73 The 2-tributylstannylindoles formed by cyclization are used as partners in a palladium(0) coupling reactions to provide the final products in good yield.for the preparation of 2,3-disubstituted indoles which was described in the previous review' has been extended and the yields have been improved by using an active titanium catalyst prepared in sit^.^^ The Leimgruber-Batcho indole synthesis has also been extended by methoxycarbonylation of the enamine precursor before reductive ring closure (Scheme 22).75 The intramolecular McMurry coupling procedure OMe I H OMe Scheme 22 Some other cyclization routes to indoles are outlined in Scheme 23.An intramolecular Horner- Wittig method has been described for the preparation of N-alkylindoles with substituents at the 3-po~ition.~~ Marino and Hurt have shown that diisobutylaluminium hydride acts both as a selective method for the reduction of a cyano group to an imine and as a Lewis acid in a preparation of 5-alkoxy-3-methylind0les.~~ The catalyst PdC12(PPh3)2-SnC12 allows the reductive cyclization of 2-nitrostyrenes to indoles to be carried out in relatively mild condition^.^^ A new indole synthesis makes use of a Diels-Alder reaction to construct the six-membered ring and a cyclization of a vicinal tricarbonyl compound to produce the five- membered ring.79 A route to 5-hydroxyindoles has been described starting from 3-hydroxy~tyrenes;~~."' they react with arenediazonium salts and cyclize to give 1-arylamino-5-hydroxyindoles 35 in good yield (Scheme 24).The arylamino group can be removed by reduction using Raney nickel. The cycloaddition of the osmium complexed 3-isopropenylpyrrole 36 to N-phenylmaleimide proceeds in good yield and the indole 37 is isolated after oxidation of the intermediate cycloadduct.82 Moody and co-workers have provided further R' Me Bno&CN DIBALH 66% * BnoQ)-7--Me NHZ H # CO, PdC12(PPh~)2-SnCl,, Q7JR' R2 H NO2 9 0 ( i ) BuNH2 (ii) DDQ I Ql--7-J0" C0,Bu' Bu Scheme 23 NAr I H+ 35 Scheme 24 examples of the synthesis of indoles by cycloaddition of activated acetylenes to pyr anopyrrolones (Scheme 25).83 6 Other fused pyrroles A new method for the generation of N-t- butoxycarbonylisoindole 38 by intramolecular Gilchrist: Synthesis of aromatic heterocycles 343Me Ye 3-Substituted indolizines have been prepared by the generation of chlorocarbenes in the presence of 2-vinylpyridine. The reaction is envisaged to proceed by cyclization of intermediate pyridinium ylides followed by dehydrochlorination (Scheme 28).89 Indolizines are more commonly prepared by intermolecular cycloaddition of pyridinium ylides to olefinic dipolarophiles followed by oxidation of the adducts.It has been found that indolizines are obtained in good yield if the cycloaddition is carried out in the presence of the oxidant tetrapyridine- cobalt (11) dichromate.w The generality of a previously reported preparation of indolizines by thermal cyclization of 2-substituted pyridines 41 has been investigated.” 37 R’ R’ 0 R2 Meo Me02C 2c)$----j R2 R3 Scheme 25 cycloaddition is outlined in Scheme 26.84 The isoindole was intercepted by Diels-Alder cycloaddition to N-phenylmaleimide and to other dienophiles. YAC Bu‘O- - % NC02But NC02Bu‘ =.4 % - I_ 41 Scheme 28 7 Oxazoles, thiazoles, benzoxazoles, and benzo t hiazoles A synthesis of oxazole-and thiazole-4-carboxylic acid esters in good yield from the thioamide 42 is shown in Scheme 29.92 2-Substituted oxazole- 4,5-dicarboxylic esters have been prepared by thermal rearrangement of the imidates 43.93 38 Scheme 26 Details of the preparation of N-substituted furo[ 2,3-c]pyrroles 3985 and of t hieno[ 2,3-c:4,5 - c’ldipyrrole 4OS6 from furan and thiophene precursors have been published.Two high yielding preparations of pyrrolopyridines are outlined in Scheme 27.87,88 M%O’ BF,- MeS S )=NAC02Et R1 A H N AC02E1 R’ 42 HNwH 40 39 MeNCO. CO2Et Me Me02CL Me02C, Me02C< - 95 “c Me02C<vR 0-N 0 OEt 43 TClo PhH, COZEt OEt 80% CO2Et H Ts Scheme 27 Scheme 29 344 Contemporary OGanic SynthesisTwo methods for the preparation of oxazoles based on the use of acylaminomalonate esters94 or acylamino-P-ketoestersg5 are illustrated in Scheme 30. The latter were generated by oxidation of the corresponding P-hydroqamides and the Dess- Martin periodinane 44 was found to be the most efficient oxidant for this purpose.Further examples of the preparation of oxazoles by the rhodium(I1)- catalysed reaction of diazocarbonyl compounds with nitriles have been r e p ~ r t e d . ~ ~ . ~ ~ ' ~ ~ I (i) PhSCHzCl I Me02CY NH (ii) NCS MeO2C. 0 44 Scheme 30 2,4-Disubstituted 4,5-dihydrooxazoles can be prepared in high yield by sodium iodide catalysed ring expansion of N-acylaziridines; the dihydrooxazoles can be aromatized by oxidation using nickel per~dixe.~' The oxidation of dihydrooxazoles and dihydrothiazoles bearing chiral substituents at C-2 by t-butyl perbenzoate and copper( I) bromide proceeds in good yield when copper(r1)acetate is added as ~o-catalyst.~~ The conditions have also been defined which enable thiazoles with chiral substituents at C-2 to be synthesized by a modified Hantzsch procedure without racemization (Scheme 31).'O0 H,NHNHcO~BUt (i) KHC03.-15 "C Et0,C (iii) (ii) BrCH2COC02Et (CF,CO),O, base c C%NHC0213d S R R Scheme 31 2-Arylbenzothiazoles have been prepared in one pot from 2-aminothiophenol by reaction with sodium hydride (4 moles) and an aromatic nitrile"' and by reaction with an aryl iodide and carbon monoxide in the presence of a palladium(0) catalyst. lo' Benzothiazoles have also been produced in good yield by photochemical ring contraction of dihydrobenzothiazine-3-carboxylic acids: an example is shown in Scheme 32.1°3 OH OH hv>320nrn Me Me Scheme 32 8 Isoxazoles, isothiazoles, isoselenazoles, and fused analogues The acylation of oxime dianions, already known as a method for the preparation of 5-arylisoxazoles, has now been applied to the preparation of 5-alkylisoxazoles.Both N-methoxy-N-alkylamides and aliphatic carboqlic esters have been used as the acylating agents. Most of the preparations reported started from either acetone oxime or cyclohexanone oxime; an example of a preparation from acetone oxime is shown in Scheme 33.1°4 1 /"" PhJol\N Scheme 33 The diplar cycloaddition of trimethylstannyl- acetylenes 45 to nitrile oxides gives 4-trimethyl- stannylisoxazoles, with the exception of et hynyltrime t hylstannane which gives 5- trimet hyl- ~tannylisoxazoles.'~~ The regiochemistry is consistent with the predictions of FMO theory.A route to 3-vinylisoxazole which is based on a dipolar cycloaddition and retro Diels-Alder reaction sequence is outlined in Scheme 34.1°6 3-Bromoisoxazoles can be prepared by dipolar cycloaddition of bromonitrile oxide to alkynes and it has now been shown that even unactivated alkynes will give isoxazoles in acceptable yield, but with little regioselectivity, if the reaction is carried out in the presence of potassium fluoride dihydrate. *07 A pH below 5 is maintained during the reaction and this seems to be necessary for the cycloaddition to take place. The cyclization of ortho-substituted aromatic azides provides a useful route to several fused five- membered heterocycles. The reaction has now been Gilchrist: Synthesis of aromatic heterocycles 345Me3Sn+R 45 quant.I= Scheme 34 1-Alkylimidazoles were prepared in moderate yield by an analogous method from the corresponding alkylamines. Several other new or improved procedures for the preparation of specifically substituted imidazoles have been described. An improved route to imidazole-2-carboxaldehyde is shown in Scheme 37 and similar procedures were used to prepare imidazole-2-carboxylic acid and its ethyl ester in good yield.'12 NH NH c l p O M e + H 2 N Y o M e -c'+#"r"Me CI OMe CI OMe HCOzH 1- used for the preparation of thieno[3,2-~]-isothiazole (Scheme 35);lo8 several other fused isothiazoles were synthesized in a similar way. Scheme 37 ( L O H Two methods for the preparation of 1,4-disubstituted imidazoles are illustrated in S S for the synthesis of 4-alkylimidazoles. A new (Me3S02S 80% N3 &o - ds -ms Scheme 38;1137114 both procedures can also be used procedure related to the second method of Scheme Scheme 35 38 has been described for the preparation of 2-aminoimidazoles; this involves the condensation of a-haloketones with N-acetylguanidine.' l5 New routes to 6-fluorobenzisothiazoles109 and to benzisoselenazolesll' are shown in Scheme 36; the radical cyclization leading to benzisoselenazoles is R' R '.claimed to be an effective alternative to existing R' 8) +o + Ts-NC - J;) ~ ~ 3 v h a t methods for the preparation of this ring system. H Ts R2 (i) SOCi2 (ii) NH3 1 Scheme 38 0 .tE C I A C I Scheme 36 9 Imidazoles and benzimidazoles 0 Ph xk Ph NH~OAC Ph H 0 An improved procedure for the synthesis of imidazole from glyoxal, formaldehyde, and ph+co2Et + Fo 88% *Et02C H ammonium chloride has been described.'" The pH 0 of the reaction medium is 0-1 and this is an essential feature of the procedure.Scheme 39 346 Contemporary Oeanic SynthesisIsocyanides are useful for the preparation of several types of imidazole unsubstituted at C-2 and a new example is shown in Scheme 39.116 New routes to imidazoles from mesoionic 1,3-oxazolium- 5-01ates"~ and from vicinal tricarbonyl compounds' l8 are also illustrated. The latter method represents the first use of vicinal tricarbonyl compounds for the preparation of imidazoles; ethyl imidazole-5-carboxylates with propyl or phenyl groups at C-2 and C-5 were isolated in good yield. Two unusual procedures for the preparation of arylimidazoles, shown in Scheme 40, involve a hetero Cope rearrangement"' and the substitution of arylnitromethanes.120 PhvNR3 R' NOH CI R2 ' Ph )* -t )=NR3 c4:&0H SiMe3 * WNHN c4F+ph H 0 MeNHNH2 195% pNc4FQ Ph N Me Fk E t g H Et2Nx r F NMeJ F NEf2 F reg."" kN Me Scheme 41 Ph,,NHR3 ( i ) Na2Sf14, NaHC03 (ii) NH,NH2 * CF3CF21 + 46 9- Ar? Scheme 40 The palladium-catalysed carbonylation of aryl iodides as a route to 2-arylbenzothiazoles was described in Section 7; an analogous method has been used to prepare 2-arylbenzimidazoles from o- phenylenediamine.121 Several new syntheses of benzimidazoles being methoxy and other electron releasing groups at specific positions in the benzene ring have been d e s ~ r i b e d . ' ~ ~ - l ~ ~ 10 Pyrazoles and indazoles Two new methods of preparation of 4-fluoro- pyrazoles are illustrated in Scheme 41.125,126 3-( Fluoroalkyl)pyrazoles have also been prepared from a variety of fluorinated precursors by cyclization with hydrazine.The fluorinated iodoalkanes 46127 and 4712* and 2-(trifluoroacety1)ketones such as 4?312' are suitable starting materials (Scheme 42). The enaminoketone 27 (shown in Scheme 16) also reacts with hydrazine to give 4-trifluoroacetyl-3-trifluoromethylpyrazole in high yield.54 A route to tetrasubstituted pyrazoles is provided by the reaction of the salts 49 (which are generated from a-chloroazoalkanes and aluminium chloride) with monosubstituted alkynes (Scheme 43).130 47 ( X = F,CI; n =2,4,6,8) ($3 48 Scheme 42 d N c F3 R N H $"iJ H R2 R' 1.2-Me 1 *2jMe R' Scheme 43 Disubstituted alkynes also react with the salts but give pentasubstituted pyrazolium salts.A simple procedure for the preparation of a variety of substituted indazoles is illustrated by the synthesis Gilchrist: Synthesis of aromatic heterocycles 347of 4-methylindazole shown in Scheme 44; the diazo compound 50 is probably an intermediate in the r e a ~ t i 0 n . l ~ ~ In a method analogous to that used for the preparation of indoles from 2-nitrostyrenes and illustrated in Scheme 23, 2-nitrobenzaldimines have been catalytically reduced to 2H-indazoles. This is the first example of a transition metal catalysed synthesis of a 2H-indaz0le.~' KOBU' b"" - N=NSBU' 50 Scheme 44 11 Thiadiazoles 3-Aryl-1,2-5-thiadiazoles are produced in good yield when chloroketoximes 51 are heated with tetrasulfur tetranitride (S4N4) in dioxan (Scheme 45).132 a,a-Dibromoacetophenone derivatives have also been used in related syntheses.133 3,4-Disubstituted- 1,2,5-thiadiazoles have also been prepared in moderate yield from alkyl aryl ketoximes and S4N4.134 * dAr N, 0N S 51 Scheme 45 The ring contraction of pyrimidinethiones 52 to the 1,2,4-thiadiazoles 53 (Scheme 46) is analogous to a previously reported preparation of thiazoles from 52 in which phenacyl halides were used as co-reagents.'". R' 52 R2 53 Scheme 46 12 Piazoles and tetrazoles 3,5-Dichloro-2H-1,4-oxazin-2-ones, which are readily prepared from aldehyde cyanohydrins and oxalyl chloride, can be converted into 1,2,3-triazoles by sequential reaction with diazoalkanes and alcohols (Scheme 47).136 Analogous reactions with sodium azide give the corresponding tetrazoles.Another new route to 1,2,3-triazoles is also illustrated in Scheme 47; this involves an unusual diazo transfer reaction. 137 "'d Scheme 47 Several new or improved methods have been reported for the preparation of tetrazoles. The preparation of 5-substituted tetrazoles from nitriles and trimethylsilyl azide is improved either by adding an equimolar amount of trimethylaluminium (which may simply act as a Lewis acid)13' or by using two moles of trimethylsilyl azide with a catalytic amount of dimethyltin oxide [the active reagent in this case probably being Me2Sn(OSiMe3)N3].'39 Secondary amides can be activated by reaction with triflic anhydride and the resulting imidates are then converted into 1,5-disubstituted tetrazoles in a one- pot rea~ti0n.l~' Analogous routes have been described from secondary thioamides, tin(1v) chloride, and trimethylsilyl azide14' and, more directly, by the reaction of aryl ketones with an excess of sodium azide in the presence of tin(1v) chloride (Scheme 48).'42 For example, 1,5-diphenyltetrazole was prepared from benzophenone in 93% yield by this method.A one- pot synthesis of 5-halo-1-phenyltetrazoles has been achieved from phenyl isocyanide, sodium azide, and the appropriate N-halosuccinimide in the presence of a phase transfer catalyst. This is analogous to the known synthesis from isocyanide dihalides but avoids the need to isolate these reactive halides.'43 Scheme 48 r F N 3 ] % R )=NAr -R.(N,N N-! N3 Ar R 348 Contemporary Organic Synthesis13 Pyrones, coumarins, and chromones The first examples have been reported of the synthesis of a-pyrones by the cycloaddition of trialkylsilylketenes to d i e n e ~ ' ~ ~ and the ring system has also been produced by the cycloaddition of ketenes to a-oxoketene~.'~' These methods are exemplified in Scheme 49.Other new methods of forming this ring system include the aluminium chloride catalysed cyclization of carboxylic acid chlorides RCH,COCl, which leads to the formation of the pyrones 54 from three moles of the acid chloride'46 and the conjugate addition of Meldrum's acid derivatives to but-3-yn-2-0ne.I~~ Me ButMe2sib.=0 + H OSiMe3 ButMe2Si do examples of this type of preparation make use of phosphonium ylides, Ph,P=CRCO,Et, to produce the second An efficient synthesis of the coumarin 56 from the benzyl ether of salicyladehyde is illustrated in Scheme 7,8-Dimethoxycoumarin has been prepared in good overall yield from 2,3,4-trimethoxybenzaldehyde by condensation with Meldrum's acid, cyclization, and decarboxylat ion.OH 56 Scheme 50 2-Substituted chromones are formed in high yield from alkynones 57 (R' = t-butyldimethylsilyl) by 6-endo cyclization (Scheme 51); anhydrous conditions are essential, otherwise products of 5-ao cyclization are also isolated.155 In the absence of a proton source the a o cyclization is reversible and the products come only from the endo process. A related synthesis has been described in which the intermediates 57 (R' = H) are produced in situ from 2-iodophenols and alkynes by palladium-catalysed * Ph Me Me 0 excess I btene Me 0 Ph u o Me carbonylation.lS6 0 MeAOAO II 0 II Scheme 49 0 R' a R2 KF. 18-crown4 57 Scheme 51 4-Methylcoumarin has been produced from phenol and acetic anhydride in up to 75% yield by passing the vapours over a zeolite catalyst at 380 0C.148 A new palladium-catalysed route to 4-methylcoumarin from the ester 55 has also been de~cribed.'~' Coumarins are most often formed from salicylaldehyde derivatives; several new The cyclization of N , N-dialkylsalicylylacetamides 58 in acidic or basic conditions is known to give 4-hydroxycoumarins, but when triflic anhydride is used as the cyclizing agent the products are 2-diallqdaminochromones 59. lS7 A one-pot synthesis of flavonols in water from 2-hydroxyacetophenone derivatives and benzaldehyde has been described.lS8 54 55 58 59 Gilchrist: Synthesis of aromatic heterocycles 34914 Pyridines The electrocyclic ring closure of 2-azatrienes, produced in situ from iminophosphoranes and a,/?-unsaturated aldehydes or ketones, provides a good method for the preparation of a variety of substituted pyridines.Molina and his co-workers have developed this as a synthetic method and have reviewed the use of iminophosphoranes in the preparation of pyridines and other nitrogen heterocycles. lS9 Two examples of the synthesis of monocyclic pyridines by this method are given in Scheme 52;’607161 the second, by Katritzky and his colleagues, illustrates a new way of producing unsaturated iminophosphoranes by using benzotriazole as a leaving group.(Bt = l-benzotriazolyl) C02Et * R+N*pph3 NaH R 7 N = p p h 3 Bt Ph IPhTPh Rb Ph Scheme 52 Because of the stability of the ring system, pyridines are often the final end products of complex reaction sequences. Three such processes, in which the reaction pathway is not obvious, are shown in Scheme 53. The discoverers of the first reaction have suggested that the initial steps are the reduction of the nitro to a nitroso group and a [3,3]-sigmatropic rearrangement;162 the second may involve the Diels-Alder cycloaddition of phenylacetylene to a 1,2-oxazinium cation.163 The third1@ seems likely to be initiated by activation by the electrophile of the acetal which is then cleaved by nucleophilic attack of the nitrile.4-Pyridones 60 have been isolated in moderate to good yield from the reductive cleavage of isoxazoles 61 by molybdenum he~acarbony1.l~~ A one stage synthesis of 4-amino-2,6-diethylpyridine from the corresponding 4-pyrone 62 has been achieved using tosyl isocyanate and ammonia.166 60 EtO xyPh 61 62 SnC12.2H&, heat 31% rn QPh (i) F3E.OEtz (ii) PhCSH 67Vo * Ph QPh (i) MeSiOMs (ii) F3E.0Et2. MeCN Me Me Scheme 53 15 Quinolines and isoquinolines Some new examples of the construction of quinolines by cyclization of aniline derivatives with a free ortho position are shown in Scheme 54. The reaction of Schiff bases of aromatic aldehydes with alkenes or alkynes is formally a Diels-Alder reaction, although there is evidence for a stepwise mechani~m.’~~ The enaminone 63, which is prepared H 63 64 MeN * Ph H 0 X/ pONk H Ph Ph H 65 Scheme 54 350 Contemporary Organic Synthesisfrom compound 27 (shown in Scheme 16) and aniline, is converted into the quinoline 64 in high yield by titanium( IV) chloride.54 A similar exchange of an aromatic for an aliphatic amino group is used to construct the precursors for 2-arylquinolin-4-ones 65.168 Two cyclization processes in which a carbon- nitrogen bond is formed are shown in Scheme 55.169.170 VHAr YHAr hv.HBF4 ~ X X Ph Scheme 55 2-Trifluoromethylaniline has been shown to react with lithium enolates derived from methyl ketones to give 4-fluoroquinolines in moderate yield (Scheme 56).17'. 172 The Pfitzinger quinoline synthesis (in which the ring system is constructed from isatin and a ketone) has been shown to go with fewer side-reactions when performed in an acidic medium.173 Two procedures for constructing functionalized 4-quinolones are illustrated in Scheme 57.1749 175 Other methods reported include the ruthenium-catalysed reductive cyclization of 2-nitro~halcones'~~ and a route from 2-iodoanilines, alkynes, and carbon monoxide analogous to that used for chromones (Section 13).156 A convenient new route to 3-substituted isoquinolines has been described starting from benzocyclobutenols and nitriles (Scheme 58)177 and the ring system has also been produced by cyclization of divinylcarbodiimides, as illustrated. 17' Isoquinoline has been prepared (55%) from phthalaldehyde by reaction with the iminophosphorane (EtO)2POCH(Li)N=PPh3.179 6- Scheme 58 Scheme 56 CN &Ar &Ar CH(OMe), ' NHAc ' NHAc 1 H+ 0 QyJAr H 0 0 NPh -PhNCO I -PhBPO 0 Scheme 57 Gilchrist: Synthesis of aromatic heterocycles heat EtO- c NAc 66 0 &NHMe - 2.2 BuLi R2 CN OEt 0 (i) RCOCOR (ii) Me3SiC1, NaI 0 R* Scheme 59 The product of acetylation of 2-cyanophenyl- acetonitrile has been identified as the isocoumarin 66.'" This compound reacts with a variety of 35 1nucleophiles to give isoquinolines or isoquinolones. An example of this reaction, and of other recent methods for the preparation of isoquinolones, are shown in Scheme 59.1817'82 16 Pyrimidines and quinazolines A cycloaddition-cycloreversion sequence has been described for the preparation of pyrimidine diesters (Scheme 6O).ls3 Two other methods in which amidines are used to construct the ring system are also illustrated.1269 lS4 The pyrimidine 67 and related bis(methy1thio)pyrimidines have been prepared in good yield from aliphatic ketones, methyl thiocyanate, and triflic anhydride.lS5 4-Dimethylaminopyrimidines 68 are formed by thermal cyclization of the iminium salts 69.lS6 The ring system has also been produced by ring expansion of imidazolinones. lS7 CO2Et I + F NMeJ F NEt2 F qLPh The pyridinium salts 70, which are produced in situ from aldehydes, thionyl chloride, and pyridine, are proving to be useful electrophilic components in heterocyclic synthesis. An example is their reaction with 2-aminobenzylamine to give tetrahydroquinazoline salts 71 in high yield."' These compounds can then be oxidized to quinazolines. Two other recent methods for the preparation of quinazolines are outlined in Scheme 6 1 .1 8 ~ ~ ~ 0 70 71 9' NHC6HdCI-4 NCS Scheme 61 17 Pyrazines, cinnolines, and triazines A new cycloaddition-cycloreversion method for the construction of pyrazines has been explored with compound 72 as a precursor. This reacted readily with enamines at low temperature; for example, the fused pyrazine 73 was isolated in high yield from a reaction with pyrrolidinocyclohexene.191 N y J o Ph 72 73 Scheme 60 67 68 69 Some new routes to cinnoline l-oxides from aromatic nitro compounds have been described; an example, shown in Scheme 62, provides a route to the previously unknown l-oxides of cinnoline- 4-carboxylic New routes to 4-amino~innolines'~~ and to l-methylcinnolinium are also illustrated in Scheme 62.The (N-cyanoimino)thiazolidine 74 reacts with secondary amines to give the 1,3,5-triazines 75 in good yield.'96 A synthesis of 5-trifluoromethyl- 1,2,4-triazines 76 has been described from the hydrazones 77, aldehydes, and ammonia. 197 352 Contemporary Organic SynthesisHo+N, Ho’r_N, 0- NaOCl CO2H I I 0- 0 2 , 0 “c I 85% Scheme 62 CH(OMe), 74 75 oq R’ NNH2 76 77 18 References 1 T.L. Gilchrist, Contemp. 0%. Synth., 1994, 1, 205. 2 J.A. Marshall and W.J. DuBay, J. 0%. Chem., 1993, 3 J.A. 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ISSN:1350-4894    

DOI:10.1039/CO9950200337

出版商:RSC    

年代:1995

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Nitro and related compounds GRAEME ROBERTSON Glaxo Group Research, Biomolecular Structure, Second Floor; Chemistry Building, Building 2, Stevenage, He@ordshire, UK Reviewing the literature published between December 1993 and May 1995 1 2 2,l 2.2 2.3 2.4 3 4 5 6 Introduction Nitro compounds Aryl nitro compounds Alkyl nitro compounds %-Substituted nitro compounds x, /I-Unsaturated nitro compounds Nitrate esters Nitramines Nitroso compounds References 1 Introduction This review covers not only the recent advances in the synthesis of nitro compounds and related derivatives, but also indicates the main current areas of interest in the properties of such compounds, both chemically and biologically. 2 Nitro compounds A review of the most expedient reactions and conversions of aliphatic and aromatic nitro compounds for organic synthesis has recently been published.’ 2.1 Aryl nitro compounds Primary anilines can be oxidized to the corresponding nitro compounds under very mild conditions using oxone (potassium peroxymono- sulfate) in 5 to 20% aqueous acetone, buffered with sodium bicarbonate.2 A mixture of sodium nitrate and TMSCl has been developed as a convenient method for the in situ generation of nitryl chloride.In combination with complexation with a Lewis acid, such as aluminium trichloride, this forms a convenient system for the nitration of aryl rings (Scheme l).3 Nitryl chloride was previously prepared by either the oxidation of nitrosyl chloride, or by the reaction of chlorosulfonic acid with nitric acid. However, both these earlier methods are rather inconvenient and also potentially dangerous.The utilization of the reaction of TMSCl with sodium nitrate for the in situ generation of nitryl chloride is therefore a distinct improvement. 5: * 0 TMSCI. NaN03, AICb, CCl,, 0 “c 6247% Scheme 1 Aromatic compounds can be nitrated with HN03 under mild non-corrosive conditions, by co- treatment with an activated mixture of a metal nitrate modified silicate and TFAA in CH2C12. Polynitration can also occur depending both on the nature of the substrate and the conditions empl~yed.~ Dinitrogen pentoxide in liquid sulfur dioxide has been developed as a new nitration system with wide potential for the nitration of aromatic systems, including deactivated rings (Scheme 2).5 The resulting aryl nitro compounds are formed with similar substitution patterns to those observed in ‘traditional’ nitrations with HNO,/H,SO,.0- I C0,Me C0,Me C0,Me Scheme 2 Some heteroaromatic rings, such as pyridines and quinolines, can also be nitrated with this system, but others such as pyrimidines, pyrroles, imidazoles, or indoles are not nitrated under these conditions6 The replacement of a t-butyl group by a nitro group in electrophilic substitution reactions is typically complicated by concomitant side-reactions. The replacement of a t-butyl group via @so- electrophilic substitution of t-butylarenes is, however, possible for activated aryl rings where the initial a-complex has increased stabilization.’ For example, biaryl compounds of the type 1 undergo clean @so-nitration, whilst the less substituted analogues 2 undergo simultaneous nitration at the position ortho to the anisole group (Scheme 3).The orientation of electrophilic substitution, including nitration, of benzaldehydes can be changed selectively by the prior conversion of the aldehyde group into the corresponding O-ethyloxy- oxime. Thus, whilst nitration of benzaldehyde gives a mixture of the ortho- and meta-isomers, treatment of the corresponding 0-alkyl oxime with nitric acid Robertson: Nitro and related compounds 357Scheme 3 OMe OM8 1 fum'ng HN03 ?Me 1 ?Me OMe OMe 2 in sulfuric acid gives selectively the meta-isomer in high yield.' substituted phenols has been developed. Thus, para- substituted phenols are readily ortho-nitrated at room temperature by treatment with sodium nitrate in a 2-phase aqueous/organic system, in the presence of HC1 and a catalytic amount of acetic anhydride.This protocol has been applied to the nitration of biaryl compounds, such as 3 (Scheme An efficient two-phase nitration of para- 4).9 NO, 3 Scheme 4 Nitrogen dioxide, in the presence of ozone, is a good nitrating agent for aromatic systems. The active nitration reagent is probably in situ generated dinitrogen pentoxide. This novel nitration method has become known as the 'kyodai-nitration' and is suitable for the nitration of nonactivated and even deactivated aromatic compounds into the corresponding mono- or poly-nitro derivatives in good to excellent yields. Even acid-sensitive aromatic compounds, such as benzaldehyde acetals, can be nitrated under neutral conditions via this ozone-mediated reaction of the aromatic compound with nitrogen dioxide by carrying out the reaction in the presence of magnesium oxide." However, the reaction is limited to cyclic acetals and provides a mixture of isomeric nitro compounds in which the para- and ortho-isomers predominate (Scheme 5).The related acylal is also nitrated under these conditions, but in contrast gives mostly the ortho- and rneta-isomers. 0-, J$?+ !T 0 4 : 2 : 1 O " @ " O 3 @ Scheme 5 The regioselectivity of the kyodai-nitration process differs from that of conventional nitration such that, for example, substrates bearing an electron-withdrawing group are preferentially nitrated in the ortho-position. Thus alkyl aryl ketones react smoothly with nitrogen dioxide at low temperatures in the presence of ozone to give ortho- and meta-nitro derivatives, with a limited preference, of up to 4:1, for the ortho-analogue." Controlled mononitration is also possible using modified conditions with nitrogen dioxide and ozone in the presence of methanesulfonic acid as catalyst; for example, polychlorinated benzenes undergo selective mononitration with this system.12 an effective method for the nitration of various benzoic acid derivatives (and the corresponding nitriles), yielding predominantly the meta-i~omer.'~ Benzamide, however, is not nitrated but rather undergoes loss of the nitrogen to afford benzoic acid and its nitrated derivatives, whilst N,N- dialkylbenzamides are nitrated to mixtures of all three regioisomeric nitro compounds.Finally, the kyodai-nitration process of ozone- mediated nitration of aromatic compounds has also been studied as an environmentally cleaner alternative to conventional nitration mixtures.I4 Hydroquinone ethers react with nitrogen dioxide in dichloromethane to give either the nitrated product or the product of oxidative dealkylation. The competition between these two processes can be controlled by the solvent polarity and added nitrate. Thus, with acetonitrile as solvent chemoselective nitration occurs, whilst in non-polar solvents, such as hexane, only oxidative dealkylation is observed.'' Ozone-mediated nitrogen dioxide nitration is also 358 Contemporary Organic SynthesisMichael condensation reactions involving p-nitrobenzyl sulfones containing carbonyl or cyano substituents ortho to the methylsulfonyl group and electrophilic olefins or alkynes as the acceptor moiety provide a facile and efficient route to substituted 2-nitronaphthalene derivatives.’6 New synthetic routes to tetranitrotoluenes have been reported, including the previously unknown 2,3,4,S-tetranitrotol~ene.’~ The methods employed include the peroxydisulfuric acid oxidation of trinitrotoluenes, and the hypophosphorus acid reduction of diazonium salts derived from tetranitrotoluenes.complex mixture of polynitrated products. A significantly improved met hod for the selective nitration of chrysazin to 4,s-dinitrochrysazin has been reported involving the addition of boric acid to the nitration mixture.’* Typically, direct nitrations of chrysazin 4 give a 5 II 4 0 4 The nitration of toluene with n-propyl nitrate can be catalysed by the zeolite H-ZSM-5.The reaction proceeds in a regioselective manner to give the ortho-isomer preferentially.” The regioselectivity of the reaction can be controlled by the Si/Al ratio of the catalyst with high ratios, preferably 1000: 1, favouring the formation of the ortho-isomer. 2.2 Alkyl nitro compounds Alkenes react with nitrosyl chloride, generated in situ from TMSCl and sodium nitrite, to give or-chloro nitro compounds.20 The Henry reaction of nitroalkanes with aldehydes, leading to 2-nitroalkanols, can be catalysed by potassium-exchanged layered zirconium phosphate, Zr(KOP03)2, as a base catalyst.21 The reaction occurs under mild conditions at ambient temperature and without solvent.This protocol offers potential improvements over the ‘classical’ methods of preparation of 2-nitroalkanols, which often give poorer yields. However, the required zirconium catalyst must be prepared by titration of a zirconium phosphate. Asymmetric Henry reactions can be effected by the use of (S)-2,2’-dihydroxy- 1,l ’-binaphthyl in the presence of a lanthanum salt such as L ~ ( A c ~ ) ~ and LiCl as catalyst.22 Excellent chemical yields and high optical yields of 90% e.e. are obtained with this protocol. Henry reactions can also be promoted by ion-exchange resins such as Amberlyst-A21. These reaction conditions for the nitroaldol condensation are suitable for compounds containing acid-sensitive groups such as THP-protecting groups (Scheme 6).23 0 Scheme 6 23 a-Substituted nitro compounds Reactions of aldehydes with trichloronitromethane in the presence of tin(I1) chloride yield dichloronitro alcohols via a novel Reformatsky-type reaction (Scheme 7).24 Aliphatic aldehydes react more efficiently and give higher yields than aryl aldehydes.0- - I CI o=N;ta + 0- R “ (i) SnC12, Et@, 0 “C (ii) acidic work-up I M HCI 5342% I 0’ OH Scheme 7 a-Keto nitro compounds can be synthesized from the corresponding carbonyl compound by reaction in a two-phase system of the nitration mixture in CHC13 at - 10 to + 10 oC.25 The utilization of a two- phase system avoids the formation of furoxanes as by-products and facilitates the work-up procedure. Oxidative cross-coupling reactions of alkylated derivatives of activated CH compounds, such as malonic esters, acetylacetates, cyanoacetates, and some ketones, with nitroalkanes promoted by silver nitrate or iodine lead to the formation of the corresponding nitroalkylated products.26 This reaction is of particular value for systems where the Kornblum reaction fails.Reduction of benzofuroxan derivatives with iron sulfate in aqueous DMSO, or with thiophenol in the presence of a catalytic amount of an Fe2+ or Fe3+ salt, has been shown to provide o-nitroanilines in high yield (Scheme 8).27 0- z Scheme 8 Oxidations of or-amino esters with the HOF- MeCN complex (prepared by bubbling Robertson: Nitro and related compounds 359fluorine gas through aqueous acetonitrile), provides a new route to a-nitro acids under mild conditions.2s Moreover, although the HOF.MeCN complex can oxidize aromatic rings and especially activated systems, the rapid reaction times for its reaction with amino groups allow their selective oxidation in the presence of aromatic rings. regioselectively at the most substituted carbon to give the corresponding a-nitro triisopropylsilyl enol ether via treatment with tetra-n-butylammonium nitrate and TFAA at 0 "C (Scheme 9).2y Triisopropyl silyl enol ethers are nitrated o, Si pr', o,~i~r'3 Scheme 9 Vicinal-dinitro compounds containing a nitrodioxane sub-unit can be obtained by the SRNl reaction between either open-chain gem-chloronitro derivatives as substrates and an anion from nitrodiozane as the nucleophile and vice versa with the gem-chloronitrodioxane as the substrate. The former protocol is the more efficient as the reaction conditions are more readily tailored to the participating reagent^.^' Functionalized nitro compounds such as the chiral P-nitrohydrazone 5 which can provide ready access to a variety of other functionalized systems (Scheme 10) are readily prepared via the non-catalysed Michael-type addition of formaldehyde SAMP hydrazone to nitro ole fin^.^' dN II R 0- 5 N C T y + = o R 0- O y y + = o R 0- 2.4 a, B-Unsaturated nitro compounds The relevant literature on the synthetic routes to, and the reactions of, nitroalkenes up to 1993, with a special emphasis on the recent literature, has been reviewed by Perekalin and his co-authors in their in- depth monograph.32 This book should serve as an excellent source of information on the chemical transformations of nitroalkenes.Alkenes can be nitrated in a regioselective manner to give the corresponding a, P-unsaturated nitroalkenes by sonication in a sealed tube at 25-73 "C of a CHC13 solution of the alkene, containing excess sodium nitrite and the cerium salt Ce(NH4)2(N03)6.33 The reaction occurs via the addition of a NO; radical to the least substituted carbon atom; thus mono-substituted alkyl or aryl alkenes are nitrated exclusively on the vinylic carbon. An improved asymmetric nitroolefination reaction of a-alkyl-y-lactones and h-lactones utilizes modified nitroenamines, such as 6, as the nitro-transfer reagent. In these addition reactions zinc enolates were found to have enhanced reactivity over their lithium counterparts (Scheme ll).34 High enantiomeric excesses are reported and presumably arise from chelation control in the transition state.35 TBDMS, oJJ + @No2 LD4 Z n C l p 6 THF.-78 "C 1 0 O-r""' 95% (myo e.e) Scheme 11 A new one-pot procedure for the conversion of a-nitrocyclic ketones into a, P-unsaturated nitro olefins involves the NaBH4 reduction of the ketone, followed by successive acetylation, and dehydroacetylation with basic alumina and DMAP (Scheme 12).36 NaBH,, THF. 0 "C Ac,O. DMAP, CH2Ch. A 5540% I Scheme 10 Scheme 12 360 Contemporary Organic Synthesisa, @-Unsaturated oximes can be converted into allylic nitrates via their reaction with sodium nitrite in acetic The reaction can occur either with retention or rearrangement of the carbon skeleton, depending on the substrate.For example, carvone oxime 7 undergoes nitration without skeletal rearrangement (Scheme 13), whilst car-2-en-4-one oxime 8 is nitrated with concomitant skeletal rearrangement to the cyclopentene 9. 7 Ha. fi ‘OH NaN02, AcOH o.&-(!f H-- - -H * =ti 45% I I 0‘ I OAc H. &/“OH 0 9 Scheme 13 3 Nitrate esters Nitrate esters can be prepared in moderate to high yields from the corresponding alkyl tosylates by treatment with sodium nitrate at 110-135 “C in a sealed tube using a two-phase benzene/water system, in the presence of tetrabutylammonium nitrate as catalyst.” primary and secondary alcohols into the corresponding nitrate esters is their treatment with zinc nitrate in the presence of DCC (Scheme 14).39 Tertiary alcohols are unreactive under these conditions.A mild and selective method for the conversion of Zn(NO&, DCC. MeCN 3944% vields at R-OH Scheme 14 Catalytic amounts of ceric ammonium nitrate, either alone or in the presence of excess nitrate ion, react smoothly with epoxides under mild conditions to produce the corresponding p-nitrato alcohols (Scheme 15) through the intermediacy of an epoxonium radical cation which undergoes nucleophilic attack by the nitrate anion.40 This procedure avoids the harsher and strongly acidic conditions previously used for the formation of P-nitrato alcohols from epoxides using nitric acid. OH - c l ~ o . N “ o c, CAN, Bu4N+N03-. MeCN 80 “c. *96% I 0- Scheme 15 4 Nitramines Secondary amines (diaryl, dialkyl, and aryl akyl) are converted into the corresponding nitramines by reaction with ethereal Grignard reagents (to give the corresponding RNR’ MgBr), followed by treatment with BuON02 in benzene or hexane (Scheme 16).41 HN’ (i) EtBr, Mg(m), Et@, benzene (ii) acidic work-up 4&77% I o=NtNO I Scheme 16 1 0- The influence of the type of substituent on the ring nitrogen on the nitration of azetidines by dinitrogen pentoxide (N205) has been investigated and was found to play a critical role in determining the chemistry of the system.42 Thus for N-alkyl or ethoxycarbonyl substituted derivatives, 1,3-nitramine-nitrate products are formed by a novel ring-opening nitration reaction analogous to that established for aziridine~.~~ In contrast, azetidines bearing N-acyl substituents (acetyl, butyryl, or carbamyl) undergo preferential nitrolysis of the exocyclic substituent to form N-nitroazetidines whilst azetidines bearing strongly electron- withdrawing groups, such as picryl, are inert to attack by N205.The different reactivity of azetidines compared with aziridines can be rationalized in terms of the reduced ring strain of the four- membered ring series. Cyclocondensation of urea, guanidine, or 3,4-diaminofurazan with formaldehyde and potassium sulfamate, followed by nitration, leads to the formation of the heterocyclic nitramines 10, 11, or 12 re~pectively.~~ 10 11 12 A molecular orbital study of the effects of electron correlation of the N-N bond of nitramines has revealed a considerable lengthening of both the N-N02 bond as compared to the N-NH2 bond and Robertson: Nitro and related compounds 361of C-C bonds, which can be attributed to the antibonding character of the N-N02 bond in the LUMO."' The results also suggest the importance of the N-N02 bond in the impact sensitivity of crystalline nitramines. The thermal decomposition of nitramines has been studied and found to show first-order reaction kinetics with the triggering mechanism believed to be homolysis of the N-N02 bond, in agreement with the above theoretical studiesM 5 Nitroso compounds A review of the reactions of nitroso compounds has recently been published.' The significant developments and changes in the chemistry and biochemistry of nitrosamines and other N-nitroso compounds over the last twelve years, with a particular emphasis on the implications of endogenous nitrosation in living cells, has been reviewed as part of the ACS Symposium Series.47 The methods for analysis of N-nitroso compounds, with particular reference to human biomonitoring, have also been reviewed as part of the same series.# The oxaziridinium tetrafluoroborate 13, derived from dihydroisoquinoline, acts as an oxygen transfer reagent for the conversion of primary alkylamines into the corresponding nitroso compounds.49 Anilines, however, are converted into nitro compounds and tertiary amines form N-oxides, whilst secondary amines and imines are converted into the corresponding nitrones.13 N-Alkyl and N-aryl indoles react with N- nitrosodiphenylamine, in the presence of catalytic amounts of trichloroacetic acid, to give the corresponding 3-nitroso derivatives in good yields.50 In contrast, under identical conditions, N-H indoles (and N-OH indoles) give the corresponding 3-oximes (3-isonitroso compounds).anisoles are possible with the electrophilic nitrosonium cation NO', with NO'BF; as the preferred nitrosonium salt (Scheme 17).5' Reactions occur under mild conditions in which the more conventional procedure, based on nitrite neutralization with strong acid, is ineffective. The reactivity patterns for NO + aromatic nitrosations differ from previously established electrophilic aromatic nitrosation. This is ascribed to the rate- limiting deprotonation of the reversibly formed Wheland intermediate, which for aromatic nitration with NO? occurs with no deuterium isotope effect. nitrosoisoureas, such as N-aryl-N-nitrosoureas allows the facile conversion of indolines, N- alkylanilines, and related compounds into their N- Direct nitrosations of aromatic hydrocarbons and Transnitrosation by NO-carrying 0- o Scheme 17 nitroso derivative^.^^ The transnitrosation reactions are accelerated by electron-releasing groups on the acceptor molecules. The reaction is thought to proceed via thermal decomposition of the N- nitrosourea to form NO and a ureidyl radical, followed by formation of the NO-carrying agent, a 0-ni t rososiourea intermediate, and subsequent nitrosation of the substrate aniline or urea.containing a covalent N-N bond. A theoretical study of the reaction 2HNO+(HNO)* has been carried out to try to gain an insight into this dimerization process. Calculations for the reaction energy of formation of the truns-isomer have predicted a value of between - 16.4 and - 17.2 kcal mol-' and an equilibrium constant for the association to the trans-dimer of Kp = 259 atm, indicating that the dimer should be observable in the gas-pha~e.~~ There has been significant recent interest in N- nitrosopeptides as potential carcinogenic agents, especially since N-nitrosopeptides can potentially arise naturally from in vivo reactions of the parent peptide.This emphasis has prompted an investigation of the nitrosation of amino acid and peptide derivatives. Thus, although the esters of N- protected or-amino acids and peptides readily yield stable N-nitroso products, the parent acids have been rather more elusive. However, N-acylamino acids and peptides are nitrosated readily by reaction with excess N2O4 in CH2C12, and the resulting N- acyl-N-nitrosoamino acids and peptides can be easily isolated (Scheme 18).54 The resulting N-nitroso- acylamino acids and polynitrosoacylpeptides are readily hydrolyzed with cleavage occurring preferentially at the C-terminus.Many C-nitroso compounds form stable dimers O*N U I Ac,N?foH 0 U + I Scheme 18 A range of novel S-nitroso analogues of penicillamine dipeptides has been prepared as potential slow-release agents for NO in v~vo.'~ The optimum conditions for the preparation of a key compound in this area, N-acetyl-S-nitroso- penicillamine (SNAP), have been determined as sodium nitrite in an acidic media, such as AcOH. 362 Contemporary Organic SynthesisThis procedure is highly effective, in contrast to a range of alternative conditions.The similar nitrosations of penicillamine dipeptides under these conditions give the corresponding bis-thionitroso compounds (Scheme 19). “02. M H I Scheme 19 The addition, reduction, and oxidation reactions of nitrosobenzenes have been reviewed, with a special emphasis on the reactions of nitroso- benzenes with nitrogen nucleophiles.’6 6 References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 P. dalla Croce, Semin. Org. Synth., Summer Sch. ‘A. Corbella’, 1992, 163. (Chem. Abstr., 1995, 122, 186553). K.S. Webb and V. Seneviratne, Tetrahedron Lett., 1995, 36, 2377. G.A. Olah, P. Ramaiah, G. Sandford, A. Orlinkov, and G.K.S. Prakash, Synthesis, 1994,468. B.M. Silva Gigante Carvalheiro, P. Laszio, A.Cornelis, and M.J. Vidal de Oliveira Baptista Marcel0 Curto, WO 94-PT1 940225 (Chem. Abstr., 1994,121,280377). J.M. Bakke and I. Hegbom,Acta Chem. Scand., 1994, 48, 181. J.M. Bakke, I. Hegbom, E. Oevreeide, and K. Aaby, Actu Chem. Scand., 1994,48, 1001. T. Yamato, H. Kamimura, K. Nodo, and M. Tashiro, J. Chem. Res. (S), 1994,424. H. Goda, H. Ihara, C. Hirayama, and M. Sato, Tetrahedron Lett., 1994,35, 1565. P. 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ISSN:1350-4894    

DOI:10.1039/CO9950200357

出版商:RSC    

年代:1995

数据来源: RSC