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SYNTHESIS of [B]-ANNELATED PYRROLES VIA an ACYLATION APPROACH Eric D

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SYNTHESIS of [B]-ANNELATED PYRROLES VIA an ACYLATION APPROACH Eric D ADVANCES IN NITROGEN HETEROCYCLES Volume 3 • 1998 This Page Intentionally Left Blank ADVANCES IN NITROGEN HETEROCYCLES Editor: CHRISTOPHER J. MOODY School of Chemistry University of Exeter Exeter, England VOLUME3 • 1998 JAI PRESS INC. Stamford, Connecticut London, England Copyright 0 1998 by JAI PRESS INC. 100 Prospect Street Stamford, Connecticut 06904 JAI PRESS LTD. 38 Tavistock Street Covent Garden London WC2E 7PB England All rights reserved. No part of this publication may be reproduced, stored on a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, filming, recording, or otherwise, without prior permission in writing from the publisher. ISBN: 0-7623-0209-7 Manufactured in the United States of America CONTENTS LIST OF CONTRIBUTORS vii PREFACE Christopher J. Moody THE ACTIVATION AND MANIPULATION OF PYRROLES BY PENTAAMMINEOSMIUM(II) L. Mark Hodges and W. Dean Harman SYNTHESIS OF [b]-ANNELATED PYRROLES VIA AN ACYLATION APPROACH Eric D. Edstrom 45 APPLICATIONS OF IMINIUM CATION CHEMISTRY TO ACTIVATED INDOLES David StClair Black 85 APPLICATION OF NITROGEN YLIDE CYCLIZATIONS FOR ORGANIC SYNTHESIS L. Scott Beall and Albert Padwa 117 SYNTHESIS OF KAINOIDS AND KAINOID ANALOGUES Mark E. Wood and Andrew M. Fryer 159 INDEX 219 This Page Intentionally Left Blank LIST OF CONTRIBUTORS L. Scott Beall Department of Chemistry Emory University Atlanta, Georgia David 5tClair Black School of Chemistry University of New South Wales Kensington, Australia Eric D. Edstrom Department of Chemistry University of Montana Missoula, Montana Andrew M. Fryer The Dyson Perrins Laboratory Oxford, England W. Dean Harman Department of Chemistry University of Virginia Charlottesville, Virginia L. Mark Hodges Department of Chemistry State University of New York at Buffalo Buffalo, New York Albert Padwa Department of Chemistry Emory University Atlanta, Georgia Mark E. Wood School of Chemistry University of Exeter Exeter, England vii This Page Intentionally Left Blank PREFACE Heterocyclic molecules account for over half of all known organic compounds. A large proportion of these heterocyclic compounds contain nitrogen; indeed many classes of important natural products, as well as a majority of synthetic drugs, dyes, etc. are based on nitrogen heterocy- cles. Advances in Nitrogen Heterocycles reflects the importance of this area, by providing up-to-date accounts of key research. Volume 3 of the Series contains articles on a range of topics in heterocyclic chemistry. Harman and Hodges describe their work on the activation and manipulation of pyrroles by the formation of osmium(II) complexes. Edstrom addresses the synthesis of annelated pyrroles using acylation reactions, and Black discusses his work on the applications of iminium ion chemistry in the functionalization of activated indoles. Padwa and Beall discuss their work on nitrogen ylide cyclizations in the synthesis of a range of heterocycles, and finally Wood and Fryer describe work on the synthesis of kainoids, a family of highly biologically active nitrogen heterocycles. x PREFACE We hope that these accounts from acknowledged experts will provide the reader with an interesting and informative look at an important area of organic chemistry. Christopher J. Moody Series Editor THE ACTIVATION AND MANIPULATION OF PYRROLES BY PE NTAAMMI N EOSMI U M(I I) L. Mark Hodges and W. Dean Harman Abstract ................................ 2 I~ Introduction .............................. 2 II. Synthesis and Reactivity of rl2-Pyrrole Complexes .......... 7 A. Protonation and Isomerization .................. 8 B. Electrophilic Additions ..................... 12 C. Nucleophilic Addition to Pyrrolium Complexes ........ 17 D. 1,3-Dipolar Cycloadditions ................... 20 Ill. Ligand Decomplexation ....................... 29 A. Aromatic 1H-Pyrroles ..................... 29 B. 3-Pyrroline and Cycloadduct Complexes ........... 30 C. 2-Pyrroline Complexes ..................... 33 IV. Synthesis and Utility of 13-Vinylpyrrole and Tetrahydroindole Complexes .................... 34 A. Synthesis of 13-Vinylpyrrole Complexes ............ 34 Advances in Nitrogen Heterocycles Volume 3, pages 1--44. Copyright 9 1998 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0209-7 L. MARK HODGES and W. DEAN HARMAN B. Linkage Isomerization of 13-Vinylpyrrole Complexes ..... 36 C. Diels-Alder Reactions and the Synthesis of Indoles ..... 37 Acknowledgments ......................... 41 List of Abbreviations ........................ 42 References and Notes ........................ 42 ABSTRACT In contrast to 1"11- and rlS-pyrrole complexes, which generally react either at the nitrogen or at the s-positions, rl2-coordination of pyrrole by osmium(II)pentaam- mine activates the pyrrole ring toward regioselective protonation and electrophilic addition at the ~-position. Depending on the reaction conditions, the resulting products are either 1H-pyrrole or 3H-pyrrolium complexes, the latter of which are several orders of magnitude less acidic than their uncomplexed counterparts and resist rearomatization, rl2-Pyrrole complexes also undergo a dipolarcycloaddition reaction with certain electrophiles to generate a wide variety of 7-azanorbornene complexes. In most cases, the metal can be removed from the products by oxidation or heating to generate functionalized pyrroles, azanorbornanes, or pyrrolizinines. A series of I]-vinylpyrrole complexes can be synthesized via initial electrophilic addition to the pyrrole ring. These vinylpyrrole complexes readily undergo a Diels-Alder cycloaddition reaction with electron-deficient olefins to give func- tionalized 5,6,7,7a-tetrahydroindole complexes. These complexes, which are sta- ble to isomerization, can be decomplexed and oxidized with DDQ to generate highly substituted indoles in moderate to good yields. I. INTRODUCTION The pyrrole nucleus is an integral part of many natural products, being found in chlorophylls, bile pigments, porphyrins, antibiotics, and poly- mer systems. Given that all of the carbons in the pyrrole ring are unsaturated, pyrroles represent valuable synthetic precursors to other aromatic heterocycles, cyclic alkaloids, and other biologically active compounds. Unfortunately, the synthetic utility of pyrroles is severely limited by its aromaticity. For example, pyrroles tend to undergo addition and substitution at the ~x-positions instead of the more biologically relevant 13-positions, as well as polymerization in the presence of elec- trophiles. ~ Indeed, most pyrroles are synthesized from ring closure of appropriately substituted acyclic precursors. Common examples include the Knorr and Paal-Knorr pyrrole syntheses. ~'2 Three primary methods are available to synthesize l-substituted pyrroles from a pyrrolic precur- sor: 3 (a) placement of a removable electron-withdrawing group at the ~-position, which directs electrophilic addition to the t-position on the Osmium Activation of Pyrroles opposite side of the ring; (b) isomerization of an t~-substituted pyrrole to the corresponding I]-substituted isomer; and (c) placement of a bulky substituent on the nitrogen to direct electrophilic addition away from the ~-position. Pyrrole has also been utilized to some extent as a diene in Diels-Alder reactions to give functionalized 7-azabicylo[2.2.1 ]heptenes and 7-azabi- cyclo[2.2.1]heptadienes. 4 While the synthetic utility of this reaction is limited by the aromatic stability of the pyrrole ring, the use of Lewis acids, electron-withdrawing groups on the pyrrole, alkyne dienophiles, and high pressures have allowed pyrroles to be employed in the synthesis of several azanorbomane targets. 4 Activation of the pyrrole ring toward regioselective and chemoselec- tive functionalization can be achieved by coordination of the heterocycle to a transition metal. Depending on such factors as the electronic nature of the metal center and the type of binding, the reactivity of pyrroles can be drastically altered. While rlS-pyrrole complexes are generally unsta- ble, rlS-pyrrolyl complexes are more robust, especially when electron- donating or alkyl groups are present: These complexes typically undergo N-protonation or alkylation as a result of the high electron density present on the nitrogen. When the metal center is electron deficient, however, nucleophilic attack can be achieved at the t~-position of the pyrrole ring. As reported by Zakrzewski, iodination of the Rem(PPh3)2(H)2(rlLpyrro - lyl) complex 1 followed by addition of an alkyllithium results in alkyla- tion of the pyrrole at C-2 to give 3 (Figure 1).5 Recently, DuBois and co-workers have reported complexes of the formula RuIX(PPh3)z(X)(rl5- pyrrolyl) (4), which undergo nucleophilic attack at C-2 with a wider selection of nucleophiles including alkyllithiums, amides, certain Grig- nard reagents, and the lithium salt of propionitrile (Figure 1).6 Alkylation or protonation of these adducts (5) results in the formation of ~lS-pyrrole complexes, which are easily decomplexed to produce the free pyrroles. In a separate report, nucleophilic attack of an osmium(II) ~lS-pen- tamethylpyrrole complex with either hydride or methoxide ion gives a dearomatized rl4-complex. 7 Gladysz has reported a protonation study of the chiral N-bound rhenium (Cp)(NO)(PPh3)(rll-pyrrolyl) complex 6 (Figure 2). 8 Protona- tion of 6 with either triflic acid or HBF4oEt20 initially gives the metal- stabilized N-bound 2H-pyrrolium complex 9, which isomerizes to give the carbon-bound 2H-pyrrolium complex 10. Electrophilic
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