Radicals in Organic Synthesis

Radicals in Organic Synthesis

Edited by Philippe Renaud and Mukund P. Sibi

@WILEY-VCH

Other Titles of Interest

D. P. Curran, N. A. Porter, B. Giese Stereochemistry of Radical Reactions Concepts, Guidelines, and Synthetic Applications 1996. XII, 280 pages with 31 figures and 2 tables. Softcover. ISBN 3-527-29409-0 H.-G. Schmalz Organic Synthesis Highlights IV 2000. XII, 364 pages with 429 figures and 4 tables. Softcover. ISBN 3-527-29916-5

F. Diederich, P. J. Stang Templated Organic Synthesis 1999. XX, 410 pages with 331 figures and 10 tables. Hardcover. ISBN 3-527-29666-2 M. Beller, C. Bolm Transition Metals for Organic Synthesis 2 Volumes 1998. LVIII, 1062 pages with 733 figures and 75 tables. Hardcover. ISBN 3-527-29501-1

Radicals in Organic Synthesis

Edited by Philippe-Renaud and Mukund P. Sibi

Weinheim * New York - Chichester Brisbane - Singapore * Toronto

Prof. Philippe Renaud Universite de Fribourg Institut de Chimie Organique Perolles CH-1700 Fribourg Switzerland

Prof. Mukund P. Sibi Department of Chemistry North Dakota State University Fargo, ND 58105 USA

This book was carefully produced. Nevertheless, editors, authors, and publisher do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

1st edition, 200 1

Library of Congress Card No.: applied for A catalogue record for this book is available from the British Library. Die Deutsche Bibliothek CIP Cataloguing-in-Publication-Data A catalogue record for this publication is available from Die Deutsche Bibliothek ~

ISBN 3-527-30160-7

(c)WILEY-VCH Verlag GmbH. D-69469 Weinheim (Federal Republic of Germany). 2001 Printed on acid-free paper. All rights reserved (including those of translation in other languages). N o part of this book may be reproduced in any form by photoprinting, microfilm, or any other means nor transmitted or translated into machine language without written permission from the publishers. Registered names, tradcmarks. etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Composition: Asco Typesetters, Hong Kong. Printing: Strauss Offsetdruck Gmbh, 69503 Morlenbach. Bookbinding: J. Schaffer GmbH & Co. KG: 67269 Griinstadt. Printed in the Federal Republic of Germany. ~

~

Foreword to Volume 1 by Bernd Giese

‘I like to sum up the present situation of radicals . . . in organic chemistry by saying that the field has been largely opened up by extensive preparatory work’. This sentence sounds up-to-date, but it was said nearly 70 years ago by Karl Ziegler at the Faraday Society Symposium on Free Radicals in 1933 [I]. Thus, 30 years after the discovery of free radicals, the way was paved for their use in organic synthesis, but another half century was to elapse before the community of organic chemists rccognized radicals as important synthetic intermediates. Nevertheless, even today, the significance of radicals in organic synthesis seems to be somehow hidden. Thus, on the plaque of the National Historic Landmarks commemorating the isolation and discovery of the first ‘free radical’ by Moses Gomberg, the last sentence says: ‘Today, organic free radicals are widely used in plastics and rubber manufacture, as well as medicine, agriculture and biochemistry.’ (Fig. 1). On this plaque organic synthesis is not mentioned explicitly. Is it implied under agriculture or medicine? These two volumes, which cover the developments of the last decade of the twentieth century, clearly show that radicals have a very broad scope in organic synthesis. The presumed correlation between high reactivity and low selectivity that prevented organic chemists from using radicals in synthesis has turned out to be wrong. A good illustration of this is the application of radical reactions in stereoselective total syntheses. The numerous examples of methods and substrates, which are collected for the first time in these volumes, will be a useful source of inspiration for organic chemists.

References [ I ] K. Ziegler, Free Rudiculs. A Generul Discussion held by the Furaduy Society. September 1933, part 1, p. 10.

VI

Foreword to Volume 1

NATIONAL HISTORIC CHEMICAL LANDMARK

THE DISCOVERY OF ORGANIC FREE RADICALS I

University of Michipn 1900

.

.! d

.

.

I

Figure 1. National Historic Landmark commemorating the isolation and discovery of the first ‘free radical’ by Moses Gomberg

Foreword to Volume 2 by Dennis P. Curran

Radical chemistry has advanced tremendously over the century since Moses Gomberg reported in 1900 on ‘Triphenylmethyl: An Instance of Trivalent Carbon’ [I]. That discovery predated electronic theory, and Gomberg wrote the triphenylmethyl radical as ‘Ph3C’, not the familiar ‘Ph3C”. Almost 30 years later, Paneth showed that alkyl radicals could exist, if only fleetingly [2]. And in a key review in 1937, Hey and Walters attributed radical mechanisms to a number of known synthetic reactions [ 31. Subsequent preparative and mechanistic studies, often on polymerizations [4], shed light on many of the most fundamental types of radical reactions, and by the mid 1970s physical organic chemists had uncovered all kinds of interesting structural and rate information about assorted types of organic radicals [ 51. All this even though, unlike the persistent trityl radical, nearly all other important organic radicals are transient (short-lived). These dramatic achievements notwithstanding, radical chemistry managed to stay out of the limelight in mainstream organic synthesis for the better part of eight decades. This is not to say that there were not things going on in the shadows. Name reactions like the Kolbe oxidation, the Hoffman-Loffler-Freytag reaction, and the Meerwein arylation were familiar to many synthetic chemists, yet these reactions were gradually displaced by other transformations and were used less and less. Functional group transformations, such as bromination with bromine or NBS, were of steady importance. But preparative radical chemistry became marginalized, and a serious natural products chemist, for example, would almost never consider using a radical reaction for something as important as forming a carbon-carbon bond. As Cheves Walling stated in a 1985 perspective [6], ‘radical chemistry remained essentially mysterious’ to the synthetic community. But before 1980, the foundations for essentially all modern synthetic radical reactions had been laid, sometimes by synthetic organic chemists but more often by physical organic chemists. Kharasch reactions (now often called atom transfer reactions) were known since the 1930s and 1940s, and tributyltin hydride was introduced in the 1960s. In the 1970s, SNAr reactions and redox chain aromatic substitutions (Minisci reactions) were already topical, and allylations with allyltributylstannane were first described. In short, there were a number of ways to generate and trap radicals on the one hand, and a number of fundamental transformations of radicals such as addition and cyclization to multiple bonds on the

VI

Foreword to Volume 2

other hand. It remained for synthetic organic chemists to put these together in useful ways. This began to happen in the early to mid 1980s. And, thanks to the solid foundation, synthetic radical chemistry blossomed with amazing speed. Giese’s reductive additions of nucleophilic radicals to alkenes convincingly showed the synthetic community that radical additions to alkenes do not have to result in polymerization [7], and Barton’s thiohydroxamates emerged as new sources of carbon (and later heteroatom) radicals [8]. Hart posited that radical reactions were under-used in natural products synthesis and made a number of pyrrolizidines in an early approach to a whole family of natural products that used a radical reaction as the heart of the strategy [9]. Keck recognized the preparative importance of radical allylations, and the procedures that he introduced have endured the test of time [ 101. Stork began to use radicals in key strategic ways to control regio- and stereoselectivity in crucial carbon-carbon bond-forming reactions [ 111, and Porter described the first radical macrocyclizations [ 121. Our short, efficient syntheses of hirsutene and related natural products by tandem radical cyclization helped to introduce the unique power of radical reactions conducted in sequence [ 131. This and other early work helped to reveal to the community at large the wealth of hidden information on radical reactions and how this information could be used. In short, by 1985 the game was afoot. Over time, the favorable features of radical chemistry - predictability, reactivity, selectivity, generality and variability -have come to be more widely recognized and have been used time and again to solve difficult synthetic problems. The overview of the last two decades of the field provided in these volumes informs and inspires, and, in so doing, ensures the continued development in this exciting and fast-paced field.

References [ l ] M. Gomberg, J. Am. Chem. Soc. 1900,22, 757. [2] F. Paneth, W. Hofeditz, Chem. Ber. 1929, 62, 1335. [3] D. H. Hey, W. A. Walters, Chem. Rev. 1937, 21, 169. [4] C. Walling, Free Radicals in Solution; John Wiley & Sons: New York, 1957. [5] J. Kochi, Free Radicals, Wiley: New York, 1973, Vol. 1 and 2. [6] C. Walling, Tetrahedron 1985, 41, 3887. [7] B. Giese, Angew. Chem. 1985, 97, 555. [8] D. H. R. Barton, S. I. Parekh, Halfa Century of Radical Chernistry; Cambridge University Press: Cambridge, 1993, pp 164. [9] D. J. Hart, Science 1984, 223, 883. 101 G. E. Keck, E. J. Enholm, J. B. Yates, M. R. Wiley, Tetrahedron 1985, 41, 4079. 111 G. Stork, Bull. Chem. Soc. Jpn. 1988, 61, 149. 121 N . A. Porter, D. R. Magnin, B. T. Wright, J. Am. Chem. SOC.1986, 108, 2787. 131 D. P. Curran, D. M. Pakiewicz, Tetrahedron 1985, 41, 3943.

Preface

Considered as a curiosity at the time of their discovery, radicals have become extremely useful reactive intermediates that can be utilized for selective organic transformations. Although radical reactions are considered by practitioners as a tool equivalent to ionic and pericyclic reactions, their use at the strategic level of planning has not yet become commonplace for many synthetic chemists. Many laboratories are still reluctant to embrace radical chemistry in day to day work. These observations and the fact that radical chemistry has reached a high degree of sophistication prompted us to serve as editors for the two volumes. We sincerely hope that these volumes will introduce the reader to the versatility of radical chemistry and allay any of the misconceptions they may have. The two monographs are the first comprehensive work in this area and the topics included are relevant and timely for modern organic synthesis. Our first goal in undertaking this work was to provide a picture of the state of the art in radical chemistry at the beginning of the 21st century. This account should help synthetic organic chemists to determine if radical chemistry can solve some of the problems they encounter in their work. In the first volume, we present the basic principles that allow a researcher to carry out radical reactions efficiently. These range from various methods to generate radicals, kinetic information, issue of stereocontrol, and polymerization techniques. In the second volume, the synthetic potential of radical chemistry is illustrated with the presentation of some of the most significant applications. These topics include unusual methodology which does not generally have ionic counterparts, total synthesis, and applications in systems relevant to biology. To our regret, because of the enormous amount of information available in the literature we had to make some choice as to the content. A second aim of this book is certainly to stimulate research in the field of synthetic radical chemistry. Indeed, even if some of the synthetic methods presented here are beautifully optimized, radical chemistry offers unique possibilities for further exploration. We are optimistic that this book will become a source of inspiration for future developments in the field. We also hope that practitioners of the art of synthetic organic chemistry, researchers ready to embark on their own careers, and students will all find these two volumes a worthy book of reference. We are very grateful to all the friends and colleagues who have contributed to this work. They have made our project of covering important synthetic aspects

VIII

Preface

of radical chemistry easy. We thank them for their contributions. Without their enthusiasm and timely submission this work would not have been possible. Finally, we would like to thank the Wiley-VCH team of editors, and in particular Dr. Peter Golitz for being the catalyst for this book and Dr. Roland Kessinger for cooperation and assistance. We thank our students and coworkers who have made working in the area of radical chemistry a very enjoyable voyage indeed. November 2000

Philippe Renaud, Fribourg Mukund Sibi, Fargo

Contents

Foreword to Volume 1 ............................................. Bernd Giese

V

Preface .............................................................

VII

List of Contributors ..........................................

XIX

1

Radical Chain Reactions ...........................................

1

1.1

Radical Initiators ................................................... Yasuyuki Kita and Masato Matsugi Introduction ........................................................ Classification of Radicals Based on Energy Supplied ............. Radical Production by Thermolysis ............................... Radical Production by Photolysis ................................. Radical Production by Radiation ................................. Radical Production by Redox System ....... Radical Initiators in Organic Synthesis . . . . . . Azo Compounds ............... ................................. Peroxides ........................................................... Organometallic Compounds ....................................... Inorganic Compounds ..................................... Summary .............. ..................................... References ......................... ..................

1

1.1.1 1.1.2 1.1.2.1 1.1.2.2 1A.2.3 1.1.2.4 1.1.3 1.1.3.1 1.1.3.2 1.1.3.3 1.1.3.4 1.1.4 1.2

1.2.1 1.2.2 1.2.3 1.2.4

Radical Chain Reactions: Organoborane Initiators ................ Hideki Yorimitsu and Koichiro Oshima Introduction ........................................................ Triethylborane-Induced Radical Reaction at Low Temperatures ...................................................... Lewis Acidic. Trialkylborane: Radical Mediator and Terminator . as well as Initiator ................................................. Triethylborane: Source of Reactive Ethyl Radical ................

1 1 1 2 2 2 3 3 5 7 9 9 10 11

11

11 16 20

X

Contents

1.2.5

Triethylborane in Aqueous Media ................................ References .........................................................

23 26

1.3

Tin. Silicon and Related Reducing Agents ......................... Chryssostomos Chatgilialoylu Introduction ..... ............................................... Reducing Agents .................................................. General Aspects of Radical Chain Reactions ..................... Hydrogen Donor Abilities of the Group 14 Hydrides ............ Basic Concepts of Carbon-Carbon Bond Formation ............. Tin Hydrides ....................................................... Stoichiometric Reactions of Tributyltin Hydride ................. Tin Hydrides Generated in situ ................................... Tin Catalysts ....................................................... Polymer-Supported Organotin Hydrides .......................... Fluorous and Water-Soluble Tin Hydrides ....................... Silicon Hydrides ................................................... Tris(trimethylsily1)silane........................................... Other Organosilanes ............................................... Comparison between Bu3SnH and (TMS)3SiH................... Related Reducing Agents ......................................... References .........................................................

28

1.3.1 1.3.2 1.3.1.1 1.3.2.2 1.3.2.3 1.3.3 1.3.3.1 1.3.3.2 1.3.3.3 1.3.3.4 1.3.3.5 1.3.4 1.3.4.1 1.3.4.2 1.3.5 1.3.6 1.4

1.4.1 1.4.2 1.4.2.1 1.4.2.2 1.4.2.3 1.4.2.4 1.4.3 1.4.3.1 1.4.3.2 1.4.3.3 1.4.4 1.5

1.5.1 1.5.2 1.5.3 1.5.4 1.5.5 1.5.6

Radical Fragmentation Reactions.................................. Ian J . Rosenstein Introduction ....................................................... Tin-Based Reagents ............................................... Allylations via Allyltributyltin .................................... Modified Allyltributyltin Reagents ............................. Cyclizations onto Allylstannanes.................................. Free Radical Vinylations and Allenylations ...................... Non-Tin Based Reagents .......................................... Sulfides, Sulfoxides and Sulfones.................................. Silane Reagents .................................................... Miscellaneous Reagents ........................................... Conclusions ........................................................ References ......................................................... Atom Transfer Reactions .......................................... Jeflrey Byers Introduction ....................................................... General Considerations ........................................... C-I Additions ..................................................... C-Br Additions .................................................... C-Cl Additions .................................................... C-SePh Additions .................................................

28 28 28 30 31 32 32 35 35 36 37 38 38 41 43 45 47 50

50 51 51 56 59 60 61 61 65 67 68 69 72 72 72 74 81 82 83

Contents

1.5.7 1.5.8

.6 .6.1 .6.2 .6.3

.6.4 .6.5 .6.6

.6.7 1.7

1.7.1 1.7.2 1.7.3 1.7.3.1 1.7.3.2 1.7.3.3 1.7.3.4 1.7.3.5 1.7.3.6 1.7.3.7 1.7.3.8

1.7.3.9

XI

C-TeR Additions .................................................. Addition of Two Heteroatoms .................................... References..........................................................

86 87 88

Xanthates and Related Derivatives as Radical Precursors......... Sumir Z . Zurd Introduction ........................................................ The Barton-McCombie Deoxygenation: Mechanism and Applications ........................................................ Synthetic Variations ............................................... Tin-Free Modifications ............................................ Degenerative Transfer of Xanthates: Mechanistic Considerations ..................................................... Synthetic Applications ............................................. Outlook and Perspectives.......................................... References..........................................................

90

Decarboxylation via O-Acyl Thiohydroxamates. . . . . William B. Motherwell and Christoph Imboden Introduction ........................................................ The Preparation of O-Acyl Thiohydroxamate Derivatives ....... Functional Group Transformations involving Radical Chain Reactions of O-Acyl Thiohydroxamates .......................... Reductive Decarboxylation to give Nor-alkanes (RC02H -+ RH) [4] ............................................... Decarboxylative Halogenation (RC02H RY; Y = C1, Br, I) [4]................................................................... Decarboxylative Rearrangement of O-Acyl Thiohydroxamates [4]................................................................... Decarboxylative Chalcogenation .................................. Decarboxylative Phosphonylation (RC02H + RPO (SPh)2) .... Decarboxylative Hydroxylation (RC02H + ROH) .............. Decarboxylative Sulfonation (RC02H + RS02Spy) [24] ........ Decarboxylative Free-Radical Chain Reactions for the Preparation of Labeled Carboxylic Acids (RC02H 4RC"02H) ............................................. Method A . Isocyanide Trapping (Scheme 23) .................... Method B . Decarboxylative Introduction of Cyanide (Scheme 24) ........ Decarboxylative Amination (RC02H + R-NH2) . Method A . The Use of Diazirine Traps .......................... Method B . Decarboxylative Nitrosation (RC02H [ R-N0]2 (Scheme 27) ...................................................... Intermolecular Carbon-Carbon Bond Formation by Addition of O-Acyl Thiohydroxamates to Alkenes ....................... Carbon-Carbon Bond-Forming Reactions of Barton Esters . involving Cyclization ............................................

90 90 94 96 98 100 104 106 109 109 110 111 111

--f

112 113 115 117 118 119 120 120 121 121 121

--f

1.7.4 1.7.5

121 123 130

XI1 1.7.6 1.7.7

Contents

Decarboxylative Radical Generation from Precursors Other than Carboxylic Acids ........................................... Conclusions ...................................................... References .......................................................

131 132 132

Use of Cobalt for Radical Initiation ............................... Juved Iqbal. Rashmi Sanylzi. Jyoti Prokusll Nundy Introduction ....................................................... Vitamin Biz-Catalyzed Radical Reactions ........................ Organocobalt-Mediated Radical Reactions ...................... References .........................................................

135

2

Single-Electron Transfer ...........................................

153

2.1

Samarium(I1) Mediated Radical Reactions ............... Gury A . Molunder Introduction .................................. Alkyl. Aryl. and Alkenyl Radical Addition Reactions ........... Pinacol and Related Coupling Reactions ......................... Ketyl Addition Reactions ................. ................. Hydrodimerization Reactions ..................................... Radical Fragmentation Reactions ................................ Miscellaneous Radical Reactions ............................. .................................................. ts ................................ ........... References ................. .................................

153

Nickel Mediated Radical Reactions ............................... Nuny Min Yoon Introduction ....................................................... The Nickel Powder-Acetic Acid Method ......................... y-Lactams .......................................................... Indolones .......................................................... B-Lactams .......................................................... Borohydride Exchange Resin-Nickel Boride (cat.) Method ...... Coupling of Alkyl Iodides with a,B-Unsaturated Compounds . . . Coupling of Alkyl Iodides with a,p.Unsaturated Esters .......... Coupling of Alkyl Iodides with a,B.Unsaturated Nitriles ........ Coupling of Alkyl Iodides with a,P-Unsaturated Ketones . . . . . . . Coupling of Homoallylic Iodide .................................. Coupling of a-Bromo Acid Derivatives with Alkenes ............ Coupling of r-Bromo Acid Derivatives with Vinyl Ether . . . . . . . . Coupling of Alkenes with a-Bromo Acid Derivatives ............ Nickel-Catalyzed Electroreductive Radical Reactions ........... Nickel-Catalyzed Kharasch Addition Reaction .................. References .........................................................

183

1.8 1.8.1 1.8.2 1.8.3

2.1.1 2.1.2 2.1.3 2.1.4 2.1.5 2.1.6 2.1.7 2.1.8

2.2 2.2.1 2.2.2 2.2.2.1 2.2.2.2 2.2.2. 2.2.3 2.2.3. 2.2.3. .1 2.2.3. .2 2.2.3. .3 2.2.3. .4 2.2.3.2 2.2.3.2.1 2.2.3.2.2 2.2.4 2.2.5

135 136 140 150

153 153 160 165 174 175 176 178 178 178

183 183 184 186 186 187 188 188 189 189 189 190 190 191 192 195 196

Contents

2.3

2.3.1 2.3.2 2.3.3 2.3.4

2.4

2.4.1 2.4.2 2.4.3 2.4.4 2.4.5

2.5

2.5.1 2.5.2 2.5.2.1 2.5.2.2 2.5.2.3 2.5.3 2.5.4 2.5.5 2.5.6

2.6 2.6.1 2.6.2 2.6.2.1 2.6.2.2 2.6.2.2.1 2.6.2.2.2 2.6.2.2.3 2.6.3 2.6.3.1

Manganese(111)-Mediated Radical Reactions ..................... Burry B. Snider Introduction ........................................................ Initiation, Termination. Solvents and Common Side Reactions ........................................................... Intermolecular Additions .......................................... Cyclizations ........................................................ References .......................................................... Cerium( IV) and Other Oxidizing Agents .......................... Torsten Linker Introduction ........................................................ Cerium(1V)-Mediated Radical Reactions ......................... Iron(II1)-Mediated Radical Reactions ............................ Copper(11)-Mediated Radical Reactions .......................... Oxidative Radical Reactions by Other Metals .................... References .......................................................... Photoinduced Electron Transfer in Radical Reactions............. Junine Cossy Introduction ................... ................................ ................................ Coupling Reactions ........... Carbon-Hydrogen Bond Dissociation ............................ Carbon-Metal Bond Dissociation ................................ Nucleophilic Addition ...................................... ...................................................... .................................... Single-Bond Fragmentations .................... Tandem Reactions ................ ........................... Acknowledgement ......................... .................... References .................................. .............. Electrochemical Generation of Radicals ........................ Huns J . Schuyer Introduction ........................................................ Electrolysis as a Synthetic Method ................................ Electrochemical C,C-Bond Formation and Functional Group Interconversion .................................................... Practice of Elcctroorganic Synthesis . . . . . . . . . . . . Electrodes and Electrolyte .. .................... Electroanalytical Investigations Prior to Preparative Scale ...................................................... ale Electrolysis ..................................... Radicals by Anodic Oxidation ................. .............. Homocoupling of Anodically Generated Radic ....

XI11 198

198 199 204 204 216 219 219 219 223 225 226 227 229 229 230 230 234 237 243 246 246 250 250 251 251

254 256 259 259

XIV

Contents

2.6.3. . 1

Anodic Decarboxylation of Carboxylic Acids (Kolbe Electrolysis) .............. ..................................... 2.6.3. .2 Anodic Homocoupling o ions. at.Complexes. Organometallics and Phenolates .................................. Heterocoupling of Radicals from Anodic Decarboxylation of 2.6.3.2 Carboxylic Acids .................................................. Stereoselectivity of Anodic Coupling Reactions .................. 2.6.3.3 2.6.3.3.1 Attempts at Enantioselective Coupling ........................... 2.6.3.3.2 Diastereoselective Coupling ................. 2.6.3.3.2.1 Facial selectivity due to a chiral auxiliary ........................ 2.6.3.3.2.2 Facial selectivity due to a stereogenic carbon atom in a-position to the radical center .................... ........................ Anodic Addition of Anions to Double nds via Radicals as 2.6.3.4 lntennediates ............. ..................................... Anodic Oxidation of Radicals .................................... 2.6.3.5 Radicals by Cathodic Reduction .................................. 2.6.4 Homo- and Heterocoupling of Cathodically Generated 2.6.4.1 Radicals ............................................................ Addition Reactions of Cathodically Generated Radicals ........ 2.6.4.2 Reduction of Cathodically Generated Radicals .................. 2.6.4.3 lndirect Electrochemical Generation of Radicals ................. 2.6.5 Indirect Electrochemical Generation of Radicals at the 2.6.5.1 Anode .............................................................. lndirect Electrochemical Generation of Radicals at the 2.6.5.2 Cathode .............................................. References ...........................................

2.7 2.7.1 2.7.1.1 2.7.1.2 2.7.1.3 2.7.2 2.7.2.1 2.7.2.2 2.7.3 2.7.3.1 2.7.3.2 2.7.4 2.7.5 2.7.5.1 2.7.5.2

The Radical-Polar Crossover Reaction ............................ John A . Murphy Concept and Discovery ............................................ The Proposal ......................... ...................... lnitial Examples ................................. Tandem Radical-Polar Crossover Experiments . . . . . . . Application to Preparation of Nitrogen Heterocycles ............ Preparation of Indolines .............. ....................... The Synthesis of (+)-Aspidospennidine .......................... Neighboring Group Participation in the Solvolysis Stage ........ Evidence for Neighboring Group Participation for Solvolysis of Secondary TTF Salts .............................................. Attempted SN2Solvolysis of Primary TTF Salts ................. C-Linked Tetrathiafulvalenium Salts ............................. Modified TTF Reagents ........................................... Polymer-Supported and Water-Soluble Derivatives .... Alternative Electron Donors Related to TTF .................... Acknowledgements .......................................... References .........................................................

259 263 265 269 269 269 269 273 274 282 283 283 285 289 289 289 290 291 298 298 298 298 301 301 301 303 305 305 308 308 310 310 312 314 314

Contents

XV

3

Synthetically Important Properties of Radicals ....................

317

3.1

Kinetics of Radical Reactions: Radical Clocks .................... Martin Newcomb What are Radical Clocks? ......................................... Types of Radical Clock Reactions ................................ Radical Clock Kinetic Studies . Concepts ........................ Radical Clock Kinetic Studies Practical Aspects ............... Assumptions in Radical Clock Studies ............................ Primary Sources of Kinetic Data .................................. Examples of Radical Clocks ....................................... Alkyl Radical Clocks .............................................. Substituted Alkyl Radical Clocks ................................. Aryl and Vinyl Radical Clocks .................................... Acyl Radical Clocks ............................................... Nitrogen-Centered Radical Clocks ................................ Oxygen-Centered Radical Clocks ................................. Conclusion ......................................................... References..........................................................

317

3.1.1 3.1.2 3.1.3 3.1.4 3.1.5 3.1.6 3.1.7 3.1.7.1 3.1.7.2 3.1.7.3 3.1.7.4 3.1.7.5 3.1.7.6 3.1.8 3.2 3.2.1 3.2.2 3.2.2.1 3.2.2.2 3.2.3 3.2.4 3.2.5

~

Calculations: a Useful Tool for Synthetic Chemists ............... Carl H . Schiesser and Melissa A . Skidmore Introduction ........................................................ Modeling Radical Cyclization Reactions ......................... Force Field Methods .............................................. Quantum Methods ................................................. Modeling Hydrogen Transfer Reactions .......................... Modeling Reaction Mechanisms .................................. Concluding Remarks .............................................. References..........................................................

317 318 319 321 324 325 326 326 329 330 331 331 332 334 335 337 331 337 337 345 349 353 356 357

3.3

Synthetic Utility of the Captodative Effect ........................ Lucien Stella and Jeremy N . Harvey

360

3.3.1 3.3.2 3.3.3 3.3.3.1 3.3.3.2 3.3.4 3.3.4.1 3.3.4.2 3.3.4.3 3.3.5 3.3.5.1 3.3.5.2 3.3.5.3

................................................... Basic Principles .................................................... Rearrangement Reactions ......................................... Via a Homolysis-Coupling Mechanism ........................... Via a Homolysis-Addition Pathway ............................... Selective Oxidation of Captodative Methylene Groups .......... Halogenation, Oxygenation and Sulfuration ...................... Dehydrodimerization and Polymerization ........................ Oxidation of Captodative Anions ................................. Radical Addition to Captodative Alkenes ........................ Intermolecular Reactions .......................................... Polymerization ..................................................... Intramolecular Reactions ..........................................

360 361 362 362 366 366 366 368 368 369 369 370 371

XVI

Contents

3.3.7 3.3.7.1 3.3.7.2 3.3.8

Radical Reactions of Aromatic Compounds with Captodative Substitution ........................................................ Cycloaddition Reactions Involving Captodative Olefins ......... [2+2] Cycloaddition ............................................... [3+2] and [4+2] Cycloadditions ................................... Conclusions ........................................................ Acknowledgement ................................................. References .........................................................

372 374 374 376 377 378 378

4

Stereoselectivity of Radical Reactions .............................

381

4.1

Stereoselectivity of Intermolecular Reaction: Acyclic Systems .... Bernd Giese Background ........................................................ Allylic Strain ....................................................... Ester-Substituted Radicals ........................................ Substituents at the Radical Center that Induce Allylic Strain .... Variation of the Radical Trap ..................................... Cram-Felkin-Anh Rules ........................................... Chiral Alkenes as Radical Traps .................................. Reference ..........................................................

381

3.3.6

4.1.1 4.1.2 4.1.2.1 4.1.2.2 4.1.2.3 4.1.3 4.1.4

4.2 4.2.1 4.2.2 4.2.2.1 4.2.2.2 4.2.2.3 4.2.2.4 4.2.3 4.2.4 4.2.4.1 4.2.4.2 4.2.5 4.2.6 4.2.7 4.2.8 4.3

4.3.1 4.3.1.1 4.3.1.2

Stereoselectivity of Radical Reactions: Cyclic Systems ........... Philippe Renaud Introduction .............. .................................... ............

.....................

Five-Membered Ri Six-Membered Rin Effect of Additives .. Conformation of

.................................

................................. ......................................... .................................

Prochiral Substituents at the Radical Center ..................... Neighboring Amide ............................. Pyramidalization of als ......................... Stereoelectronic Effects ............................................ Position of the Transition State ................................... Polycyclic Systems ................................................. References ......................................................... Chiral Auxiliaries .................................................. Ned A . Porter Background ........................................................ Radical Addition Reactions ....................................... Radical Propagation ...............................................

381 381 382 389 391 393 394 399 400 400 400 400 401 402 403 403 406 406 407 408 408 410 414 414 416 416 417 417

Contrnts

XVII

4.3.2 4.3.2.1 4.3.2.2 4.3.3 4.3.3.1 4.3.3.2 4.3.3.3

Auxiliary Groups Attached to the Unsaturated Radical Trap . . . Auxiliary on the Site Undergoing Reaction ....................... Auxiliary p to the Site Undergoing Reaction ..................... Auxiliary Groups Attached to the Radical ....................... Amide Auxiliaries .................................................. Ester Auxiliaries ................................................... Ether Auxiliaries ................................................... References ..........................................................

420 421 425 429 429 435 437 439

4.4

Lewis Acid-Mediated Diastereoselective Radical Reactions . . . . . . . Brigitte Gubin. William W. Ogilvie. Yuan Guindon Introduction ........................................................ Cyclic-Cram Model: the Endocyclic Effect ....................... Lewis Acid: Steric and Electronic Enhancements ................. Lewis Acids and Chiral Auxiliaries ............................... Conclusion ......................................................... Acknowledgement ................................................. References ..........................................................

441

4.4.1 4.4.2 4.4.3 4.4.4 4.4.5

4.5

4.5.1 4.5.2 4.5.2.1 4.5.2.2 4.5.2.3 4.5.2.4 4.5.2.5 4.5.3 4.5.3.1 4.5.3.2 4.5.3.3 4.5.4 4.5.4.1 4.5.5

441 443 452 455 458 458 459

Enantioselective Radical Reactions ................................ 461 Mukund P . Sibi and Tara R . Rheault Introduction .............. ..................................... 461 Complexation of the Radical ...................................... 462 Reductions ........................ .................. 462 Enantiosele 11ylations .............. 463 Samarium Diiodide-mediated En Additions .......................... .......................... 467 1,2-Wittig Rearrangement ................ .................... 468 Pinacol Coupling .......................................... 469 Complexation of the Trap .. ................................... 470 Conjugate Additions ............................................... 470 Imine Additions .................................................... 473 Atom Transfer Reactions .......................................... 473 Enantioselective Cyclizations ................................. .. 474 Reagent-Controlled Enantioselection ........................ .. 475 Conclusions ................................................... .. 477 References ..................................................... .. 477

5

Polymers ......................................................

..

479

5.1

Living-Radical Polymerizations. an Overview ................ ... . . Michael Georges Introduction ................................................... .. Historical Background ........................................ .. Stable Free-Radical Polymerization (SFRP) Process ........ ..

479

5.1.1 5.1.2 5.1.3

479 479 481

XVIII 5.1.4 5.1.5 5.1.6 5.1.7 5.2

5.2.1 5.2.2 5.2.3 5.2.4 5.2.5 5.2.6

Contents

Atom Transfer Radical Polymerization (ATRP) Process . . . . . . . . Reversible Addition Fragmentation Chain Transfer (RAFT) Process ............................................................. Commercial Viability of the Living-Radical Polymerization Processes ........................................................... Conclusions ........................................................ References and Notes .............................................

482

Free Radical Telomers and Polymers: Stereochemical Control ... N . A . Porter and C. L . Mero Background ........................................................ Chiral Auxiliary-Controlled Radical Additions .................. Penultimate Group Steric Effects ................................. Penultimate Group Dipolar Control .............................. Lewis Acid-Promoted Diastereoselective Copolymerizations .... Helix-Sense-Selective Radical Polymerizations ................... References .........................................................

489

Index ...............................................................

501

484 485 486 486

489 489 491 495 497 499 500

Contents

Foreword to Volume 2 ............................................. Dennis P. Curran

V

1

Radical Processes: Carbon-Carbon Bond Formation ..............

1

1.1

Novel Radical Traps ............................................... Sunggak Kim and Juo-Yung Yoon Introduction ........................................................ Carbon-Nitrogen Double Bonds .................................. Oxime Ethers ...................................................... Sulfonyl Oxime Ethers ............................................. Hydrazones ........................................................ N -Aziridinylimines ................................................. Imines .............................................................. Carbon-Oxygen Double Bonds .. .............................. Acylgermanes ..... .............................................. Acylsilanes ......................................................... Thioesters and Selenoesters ........................................ Phosgene and Oxalyl Chloride Derivatives ....................... Carbon-Carbon Double Bonds ................................... Vinylcyclopropanes ... ........................................ Methylenecyclopropanes........................................... Other Multiple Bonds .............................................

1

1.1.1 1.1.2 1.1.2.1 1.1.2.2 1.1.2.3 1.1.2.4 1.1.2.5 1.1.3 1.1.3.1 1.1.3.2 1.1.3.3 I .1.3.4 1.1.4 1.1.4.1 1.1.4.2 1.1.5 1.1.5.1 1.1.5.2 1.1.5.3 1.2

I .2.1 1.2.2

...................

..................... ................... Molecular Oxygen ................................................. References .......................................................... Radical Carbonylations Mediated by Tin. Germanium. and Silicon Reagents.................................................... Ilhyung Ryu Introduction ........................................................ Tin Hydride/CO ...................................................

1 1 2 4 6 7 10 11 12 12 12 13 15 15 16 18 18 18 19 20 22 22 23

VIII

Contents

1.2.3 1.2.4 1.2.5 1.2.6 1.2.7

Cyclizative Carbonylations ........................................ Germyl Hydride/CO .............................................. Tris(trimethylsilyl)silane/CO ...................................... All yltin/CO ........................................................ Conclusion ......................................................... References .........................................................

27 33 35 37 41 41

1.3

Isonitriles: a Useful Trap in Radical Chemistry ................... Daniele Nanni Introduction ....................................................... Radical Addition/Fragmentation Reactions: the Fate of Imidoyl Radicals .................................................. Structure and Kinetics of Radical Adducts to Isonitriles: ESR Studies on Imidoyl Radicals ...................................... Synthesis of Heterocyclic Compounds: Addition to Aromatic Isonitriles .......................................................... Synthesis of Heterocyclic Compounds: Addition to Aliphatic Isonitriles .......................................................... Miscellany ......................................................... Conclusions ........................................................ References .........................................................

44

1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6 1.3.7

1.4

1.4.1 1.4.1.1 1.4.1.2 1.4.1.3 1.4.2 1.4.2.1 1.4.2.2 1.4.2.3

1.5

1.5.1 1.5.2 1.5.3 1.5.4

Homolytic Aromatic Substitutions ................................. Arrnido Studer and Martin Bossart Intermolecular Homolytic Aromatic Substitutions ............... Aromatic Substitutions with Nucleophilic C-Radicals ........... Aromatic Substitutions with Electrophilic C- and N-centered Radicals ............................................................ Intermolecular Homolytic ips0 Substitutions ..................... Intramolecular Homolytic Aromatic Substitutions ............... Intramolecular Aromatic Substitutions with Aryl and Nucleophilic C-Radicals ........................................... Intramolecular Aromatic Substitutions with Electrophilic C-Radicals ......................................................... Intramolecular Homolytic @so Substitutions ..................... References ......................................................... Radical Reactions on Solid Support ............................... A . Gunesan Introduction ....................................................... Intramolecular Radical Cyclizations .............................. Intermolecular Radical Reactions ................................. Summary ........................................................... References .........................................................

44 45 47 48 54 57 59 59 62 62 62 66 67 68 68 72 74 76 81 81 82 86 90 90

Contents

IX

2

Radical Processes: Carbon-Heteroatom Bond Formation.........

93

2.1

Hydroxylation and Amination of Carbon-Centered Radicals...... Cyril Ollivier and Philippe Renaud Introduction ........................................................ Radical Hydroxylation ............................................ Oxygenation of Organic Halides .................................. Oxygenative Decarboxylation ..................................... Monohydroxylation of Alkenes via Organometallic Intermediates ....................................................... Oxygenation of Enolate Radicals ................................. Amination of Carbon-Centered Radical .......................... Nitrosation of Organocobalt Compounds by Nitric Oxide ....... Nitrosation with Nitrite Esters .................................... Azo Reagents ...................................................... Imines .............................................................. Azide Derivatives .................................................. N ,N-Dimethylhydrazine ......... ............................... Conclusions ........................................................ References ..........................................................

93

2.1.1 2.1.2 2.1.2.1 2.1.2.2 2.1.2.3 2.1.2.4 2.1.3 2.1.3.1 2.1.3.2 2.1.3.3 2.1.3.4 2.1.3.5 2.1.3.6 2.1.4

2.2 2.2.1 2.2.2 2.2.3 2.2.4

2.3 2.3.1 2.3.2 2.3.2.1 2.3.2.2 2.3.2.3 2.3.3 2.3.3.1

Oxidation (Hydroxylation and Acyloxylation) via C-H Bond Activation .......................................................... Tsutomu Katsuki Introduction ........................................................ C-H Hydroxylation Using Metallo-Porphyrin and -Salen Complexes as Catalysts: its Mechanism and Stereochemistry .... Kharasch-Sosnovsky Type of Allylic C-H Oxidation: its Mechanism and Stereocontrol ..................................... Conclusion ......................................................... References .......................................................... Nitroxides .......................................................... Rebecca Braslau and Marc 0. Anderson Introduction ........................................................ Nitroxides as Carbon Radical Traps in Non-Chain Synthetic Sequences .......................................................... Direct Trapping of Carbon Radicals .............................. Trapping of Carbon Radicals Following Cyclization Reactions ........................................................... Stereoselective Trapping of Prochiral Radicals with Chiral Nitroxides .......................................................... Oxidations ......................................................... Chemoselective Oxidation of Alcohols ............................

93 93 94 98 100 102 103 103 104 105 106 107 108 109 109

113 113 113 121 125 126 127 127 127 127 130 131 133 133

X

Contents Kinetic Resolutions and Desymmetrizations with Optically Active Nitroxides .................................................. Other Oxidations Mediated by Nitroxides ........................ N-Alkoxyamines as Thermally Labile Latent Radicals .......... Nitroxide-Mediated ' Living' Polymerizations .................... Miscellaneous Synthetic Applications of Nitroxides .............. References .........................................................

136 137 142 142 144 146

3

Radical Cyclizations and Rearrangements.........................

151

3.1

Unusual Cyclizations............................................... A . Srikrishna Introduction ....................................................... 3-exo Cyclization Reactions ....................................... 4-exo and 5-endo Cyclizations ..................................... 7-10 exo and endo Cyclizations ................................... References .........................................................

151

2.3.3.2 2.3.3.4 2.3.4 2.3.4.1 2.3.5

3.1.1 3.1.2 3.1.3 3.1.4 3.2

3.2.1 3.2.2 3.2.3 3.2.4 3.2.5 3.2.6 3.3

3.3.1 3.3.2 3.3.2.1 3.3.2.2 3.3.3 3.3.3.1 3.4

3.4.1 3.4.2

Radical Rearrangements of Esters ................................. David Crich Introduction ....................................................... Mechanism ......................................................... Rearrangements and their Applications in Synthesis ............. Substitution Reactions and their Applications in Synthesis ...... Fragmentations .................................................... Thiocarbonyl Esters ............................................... References ......................................................... Rearrangements of Cyclopropanes and Epoxides .................. Andreas Gansauer and Murianna Pierobon Introduction ....................................................... Ring Opening of Cyclopropanes and Epoxides in Free-Radical Chemistry .......................................................... Ring Opening of Cyclopropanes via Formation of Cyclopropylcarbinyl Radicals ..................................... Ring Opening of Epoxides via Formation of Oxiranylcarbinyl Radicals ............................................................ Opening of Epoxides via Electron Transfer from Low-Valent Metal Complexes .................................................. Titanocenes as Single-Electron Reductants for Epoxides ........ References ......................................................... 0-Stannyl Ketyl Radicals .......................................... E. J . Enholm and J . S . Cottone Introduction ....................................................... Early Work on 0-Stannyl Ketyls .................................

151 151 159 163 184

188 188 188 194 196 202 203 205 207 207 207 207 211 215 216 219 221 221 222

Contents

XI

3.4.3 3.4.4 3.4.5

Cyclization Reactions .............................................. Reactions of Tin( IV) Enolates with Electrophiles ................ Application to Triquinanes ........................................ References..........................................................

223 226 229 232

3.5

Ring Expansions ................................................... Wei Zhang Introduction ........................................................ /?-Scission of Alkoxy Radicals ..................................... Ring Expansion of Strained Systems .............................. References ..........................................................

234

Hydrogen Atom Abstraction ....................................... Laurence Feray. Nikolai Kuznetsov and Philippe Renaud Introduction ........................................................ Factors Controlling Hydrogen Atom Abstraction ................ Intramolecular Hydrogen Atom Abstraction ..................... Alkoxyl Radical .................................................... Intermolecular Hydrogen Abstraction ............................ Intramolecular Hydrogen Abstraction ............................ Aminyl Radical: Hofmann-Loffler-Freytag Reaction ............ Thiyl Radicals ..................................................... Complexed Chlorine Radicals ..................................... Alkyl Radicals ..................................................... Intermolecular Reactions .......................................... Intramolecular Reactions .......................................... Perhaloalkyl Radicals .............................................. Aryl Radicals: Protecting/Radical-TranslocatingGroups ........ Protecting/Radical-TranslocatingGroups for Alcohols .......... Protecting/Radical Translocating Groups for Amines ............ Protecting/Radical-TranslocatingGroups for Carboxylic Acids ............................................................... Miscellaneous Reactions ........................................... Alkenyl Radicals ................................................... Diastereoselectivity of Hydrogen Atom Abstraction ............. Conclusions ........................................................ References..........................................................

246

3.5.1 3.5.2 3.5.3 3.6

3.6.1 3.6.1.1 3.6.1.2 3.6.2 3.6.2.1 3.6.2.2 3.6.3 3.6.4 3.6.5 3.6.6 3.6.6.1 3.6.6.2 3.6.7 3.6.8 3.6.8.1 3.6.8.2 3.6.8.3 3.6.8.4 3.6.9 3.6.10 3.6.11

234 234 240 243

246 246 248 249 249 250 254 255 257 257 258 259 261 263 264 265 268 269 270 273 275 275

4

Radicals in Total Synthesis ........................................

279

4.1

Radical Cyclizations in Alkaloid Synthesis ........................ Dauid J . Hart Introduction ........................................................ a-Acylamino and a-Amino Radical Cyclizations ................. a-Iminoyl Radical Cyclizations .................................... N-Heterocycle Construction via Radical Cyclizations ............

279

4.1.1 4.1.2 4.1.3 4.1.4

279 279 285 289

XI1

Contents

4.1.5 4.1.6

Oxime Ethers as Radical Acceptors ............................... Concluding Remarks .............................................. Acknowledgement ................................................. References .........................................................

297 299 300 300

4.2

Synthesis of Oxacyclic Natural Products.......................... Eun Lee Introduction ....................................................... Ether-Tethered Radical Cyclizations.............................. Allylic Ether Substrates ........................................... Propargylic Ether Substrates ...................................... Homoallylic Ether Substrates ..................................... Vinylic Ether Substrates ........................................... Acetal-Tethered Radical Cyclizations......................... Allylic Acetal Substrates .......................................... Propargylic Acetal Substrates ..................................... Homoallylic Acetal Substrates .................................... Ester-Tethered Radical Cyclizations .......................... (Alkoxycarbony1)alkylRadical Intermediates .................... Acrylate and Propiolate Substrates ............................... Alkoxycarbonyl Radical Intermediates ........................... Miscellaneous Intramolecular Radical Reactions ................ Carbon-Nitrogen Multiple Bond Radical Acceptors ............ Oxacyclic Substrates ............................................... Oxy Radical Intermediates .................................. Miscellaneous Intramolecular Radical Reactions ................ Intermolecular Radical Reactions ................................. Oxacyclic Substrates ............................................... Miscellaneous Intermolecular Radical Reactions ................. References ............. ........................................

303

4.2.1 4.2.2 4.2.2.1 4.2.2.2 4.2.2.3 4.2.2.4 4.2.3 4.2.3.1 4.2.3.2 4.2.3.3 4.2.4 4.2.4.1 4.2.4.2 4.2.4.3 4.2.5 4.2.5.1 4.2.5.2 4.2.5.3 4.2.5.4 4.2.6 4.2.6.1 4.2.6.2 4.3

4.3.1 4.3.2 4.3.3 4.3.4 4.3.5 4.3.6

4.4 4.4.1

Utilization of a-Oxygenated Radicals in Synthesis ................ Alexandre J . Buckmelter and Scott D . Rjjchnovsky Introduction ....................................................... Conformation and Stereoelectronic Effects of Cyclic a-Oxygenated Radicals ............................................ Generation of &-OxygenatedRadicals and their Subsequent Reactions .......................................................... Non-Equilibrium Radical Reactions .............................. Conformational Memory of Radical Intermediates .............. Conclusions ........................................................ References ......................................................... Polycyclic Compounds via Radical Cascade Reactions............ Anne-Lise Dhimane. Louis Fensterhank. Max Malacria Introduction .......................................................

303 304 304 307 307 309 315 315 317 318 320 320 321 323 324 324 325 326 327 328 328 329 330 334 334 334 336 344 345 348 348 350 350

Contents

XI11

4.4.2 4.4.3 4.4.4 4.4.5 4.4.5.1 4.4.5.2 4.4.5.3 4.4.5.4 4.4.5.5 4.4.5.6 4.4.5.7 4.4.5.8 4.4.6

The Triquinane System ... ...................................... 6-endo-trig Cyclizations in series ........ ....................... Incorporation of Hydrogen Transfers in Cascades ............... Radical Transannular Cascades ................................... Eight-Carbon-Membered Ring Radicals .......................... Nine-Carbon-Membered Ring Radicals ...... Ten-Carbon-Membered Ring Radicals ........................... Eleven-Carbon-Membered Ring Radicals ........................ Twelve-Carbon-Membered Ring Radicals ........................ Thirteen-Carbon-Membered Ring Radicals ...................... Fourteen-Carbon-Membered Ring Radicals ...................... Seventeen-Carbon-Membered Ring Radicals ..................... Conclusion ......................................................... References..........................................................

350 358 366 366 369 373 373 374 375 375 378 379 380 381

4.5

Diradicals in Synthesis ............................................. Jonathan D . Parrish and R . Daniel Little Introduction ........................................................ Trimethylenemethane ................ ........................... Reactivity Patterns of TMM Diyls ................................ Intermolecular Cycloadditions of TMM Diyls ................... Reaction of TMM Diyls with Oxygen and Water ................ DNA Cleavage by TMM Diyls ................................... Intramolecular Cycloadditions of TMM Diyls ................... Atom Transfer via TMM Diyls ................................... Fragmentation-Cyclization of Cyclopropyl Diyls ................. Non-TMM Diradicals ............................................. Thermodynamics of Cycloaromatizations ........................ Mechanistic Studies of Bergman Cyclizations .................... Bergman Cyclizations in Organic Synthesis....................... Myers Cyclizations in Organic Synthesis.......................... Moore Cyclizations in Organic Synthesis ....... Diradicals Resulting From Other Cyclizations ................... Conclusion .......................... ............................ References..........................................................

383 383 383 384 384 385 387 387 392 392 395 396 397 400 401 402 404 405 405

5

Heteroatom-Centered Radicals ....................................

407

5.1

Nitrogen-Centered Radicals ........................................ Lucien Stella Introduction ........................................................ Basic Principles .................................................... Reactions with Saturated Aliphatic Compounds . . . . . . . . . . . . . . . . . Intramolecular Reactions .......................................... Protonated N-Centered Radicals .................................. Unprotonated N-Centered Radicals ............................... Intermolecular Reactions ..........................................

407

4.5.1 4.5.2 4.5.2.1 4.5.2.2 4.5.2.3 4.5.2.4 4.5.2.5 4.5.2.6 4.5.2.7 4.5.3 4.5.3.1 4.5.3.2 4.5.3.3 4.5.3.4 4.5.3.5 4.5.3.6 4.5.4

5.1.1 5.1.2 5.1.3 5.1.3.1 5.1.3.1.1 5.1.3.1.2 5.1.3.2

407 407 409 409 409 410 412

XIV

Contents

5.1.4 5.1.4.1 5.1.4.2 5.1.5 5.1.5.1 5.1.5.2 5.1.5.2.1 5.1.5.2.2 5.1.5.2.3 5.1.5.2.4 5.1.5.2.5 5.1.7

Reactions with Aromatic Compounds ............................ Intermolecular Reactions .......................................... Intramolecular Reactions ...................... Reactions with Olefins............................................. Intermolecular Reactions .......................................... Intramolecular Reactions .......................................... From N-Chloro-Compounds ...................................... From N-Thioaryl Compounds .................................... From N-Hydroxypyridine-2( I H)thione Compounds ............. From some other Sources ......................................... lminyl Radicals .................................................... Outlook ............................................................ References .........................................................

413 413 413 413 413 415 417 417 420 420 424 424 424

5.2

Cyclization of Alkoxyl Radicals ................................... Jens Hurtung lntroduction ....................................................... Generation of Alkoxyl Radicals .................................. Principles of 4-Penten-1-oxyl Radical Cyclizations . Stereoselectivity. Regioselectivity. and Theoretical Considerations ..................................................... Ring Closure Reactions other than 5-exo-trig Cyclizations ...... Application of Alkoxyl Radical Cyclizations in Synthesis ....... References .........................................................

427

P-Fragmentation of Alkoxyl Radicals: Synthetic Applications .... Ernest0 Sucirez lntroduction ....................................................... Synthetic Methods ............... ............................... Fragmentation of Alkoxyl Radicals Generated under Oxidative ........................................ Conditions ...... Fragmentation o hols ........................................ Fragmentation of Hemiacetals ..... ...................... Fragmentation of Carbohydrates .............. Fragmentation of Alkoxyl Radicals Generated .......................................... Conditions ...... Fragmentation o ..................................... Fragmentation of Alk dicals Generated by Addition of Carbon and Aminyl Radicals to Carbonyls ...................... Fragmentation of Alkoxyl Radicals Generated from fl,y-Epoxiradicals ............................................ Fragmentation of Hydroperoxides ................................ Fragmentation of Carbohydrates ...... ...................... Conclusion ......................................................... Acknowledgement ................................... References ........ ...............................

440

5.2.1 5.2.2 5.2.3 5.2.4 5.2.5

5.3 5.3.1 5.3.2 5.3.3 5.3.3.1 5.3.3.2 5.3.3.3 5.3.4 5.3.4.1 5.3.4.2 5.3.4.3 5.3.4.4 5.3.4.5 5.3.5

427 428 430 433 435 437

440 441 441 441 443 446 448 448 449 450 450 451 451 452 452

Contents 5.4

5.4.1 5.4.2 5.4.3 5.4.4 5.4.4.1 5.4.4.2 5.4.5 5.4.6 5.4.7 5.4.8 5.4.8.1 5.4.8.2 5.4.9

Peroxyl Radicals in Synthesis...................................... John Boukouvalas and Richard K. Haynes Introduction ........................................................ Autoxidation of Hydrocarbons .................................... Functional Group Interconversions ............................... Autoxidation of Carbonyl Compounds ........................... Oxyfunctionalization via Enols or Enolates ....................... Preparation of Cyclic Peroxides ................................... Autoxidation of Phenols ........................................... Autoxidation of Nitrogen Compounds ............................ Oxygenation of Cycloalkanols and Related Compounds ......... Peroxyl Radicals from Hydroperoxides ........................... Peroxyl Radical Cyclization ....................................... [2,3]-Peroxyl Radical Rearrangement ............................. Thiol-Oxygen-Co-Oxidation (TOCO) and Related Processes . . . . References..........................................................

XV

455 455 455 458 460 460 463 466 468 472 475 475 478 479 481

Sulfur-Centered Radicals ........................................... Michdle P . Bertrand and Carla Ferreri Introduction ........................................................ Thiols as Reducing Agents ........................................ Addition to n Bonds ............................................... Inter- and Intramolecular Additions .............................. Cyclizations Promoted by Sulfur-Centered Radicals ............. Addition to Thiocarbonyl Derivatives ............................ Processes Involving Addition and (or) Fragmentation Reactions ........................................................... Sulfonylation of Alkyl Radicals and Reversal a-Scission ......... Isomerization of Alkenes .......................................... Cascade Reactions ................................................. Homolytic Substitution at Carbon: SH2 and S H ~................ ' References..........................................................

495 495 496 497 500 501

6

Radicals in Biomaterials ...........................................

505

6.1

Modifications of Amino Acids and Peptides via Radicals . . . . . . . . . . Christopher J . Easton Introduction ........................................................ Hydrogen Atom Transfer Reactions .............................. a-Carbon-Centered Radicals ...................................... Side-Chain Radicals ............................................... Functional Group Transformations and Applications in Synthesis ........................................................... References..........................................................

505

5.5

5.5.1 5.5.2 5.5.3 5.5.3.1 5.5.3.2 5.5.3.3 5.5.4 5.5.4.1 5.5.4.2 5.5.4.3 5.5.5

6.1.1 6.1.2 6.1.2.1 6.1.2.2 6.1.3

485 485 485 486 487 491 494

505 505 506 512 514 520

XVI 6.2 6.2.1 6.2.2 6.2.3 6.2.3.1 6.2.3.2 6.2.3.3

6.3 6.3.1 6.3.2 6.3.2.1 6.3.2.2 6.3.3 6.3.3.1 6.3.3.2 6.3.3.3 6.3.4 6.3.4.1 6.3.4.2 6.3.4.4 6.3.4.5 6.3.4.6 6.3.5 6.3.5.1 6.3.5.2

Contents

Synthesis and Modifications of Amino Acids and Peptides via Diradicais .......................................................... Pablo Wessig Introduction ....................................................... Generation and Properties of Diradicals .......................... Synthetic Applications ............................................. Ketones as Diradical Precursors .................................. Imides as Diradical Precursors .................................... Azoalkanes as Diradical Precursors ............................... References ......................................................... Radicals in Carbohydrate Chemistry .............................. Akin James Pearce. Jean-Maurice Mallet and Pierre Sinay Introduction ....................................................... Intermolecular Carbon-Carbon Bond Formation ............... Synthesis of C-Glycosides ............................ Synthesis of Branched-Chain Sugars ........................ Intramolecular Carbon-Carbon Bond Formation ............... Synthesis of C-Glycosides ................. ................... Synthesis of Branched-Chain Sugars .............................. Synthesis of Functionalized Carbocycles by Cyclization of Acyclic Sugar Derivatives ......................................... Carbon-Heteroatom Bond Formation ........... ........ C-Br Bond Formation ...................................... C-N Bond Formation ............................................. C-Se Bond Formation ............................................ C-S/P Bond Formation ........................... .......... C-0 Bond Formation ..................................... Carbon-Hydrogen Bond Formation ............................. Reduction of Glycos-1-yl Radicals ......... ................ Reduction of Non-Anomeric Radicals ..... References ....... ....................................... Index ...............................................................

523 523 523 526 526 531 534 537 538 538 538 538 545 547 547 552

555 561 561 562 564 565 566 567 567 573 573 579

List of Contributors

Dr. Marc 0. Anderson Department of Chemistry and Biochemistry University of California-Santa Cruz 1156 High Street Santa Cruz, CA 95064 USA Volume 2, Chapter 2.3 Prof. Michele Bertrand Universite d’Aix Marseille 111 Faculte de St Jerbme Laboratoire Chimie Boite 562 Av. Escadrille Normandie-Niemen 13397 Marseille Cedex 20 France Volume 2, Chapter 5.5 Dr. Martin Bossart Fachbereich Chemie Universitaet Marburg Hans-Meerwein-Strasse 35032 Marburg Germany Volume 2, Chupter 1.4 Prof. John Boukouvalas Department of Chemistry Lava1 University Quebec City Quebec G 1K 7P4

Canada Volume 2, Chapter 5.4 Prof. Rebecca Braslau Department of Chemistry and Biochemistry University of California-Santa Cruz 1156 High Street Santa Cruz, CA 95064 USA Volume 2, Chapter 2.3 Dr. Alexandre J. Buckmelter Department of Chemistry University of California Irvine, CA 92697-2025 USA Volume 2, Chapter 4.3 Prof. JeRrey Byers Department of Chemistry and Biochemistry Middlebury College Middlebury, VT 05153 USA Volume 1, Chapter 1.5 Dr. Chryssostomos Chatgilialoglu 1.Co.C.E.A Area della Ricerca di Bologna CNR Via Piero Giobetti 101 401 29 Bologna Italy Volume 1, Chapter 1.3

XX

List of’Contributors

Prof. Janine Cossy Laboratoire de Chimie Organique ESPCI 10, rue Vauquelin 75231 Paris Cedex 05 France Volume 1, Chapter 2.5 Dr. J. S. Cottone Department of Chemistry University of Florida P.O. Box 117200 4000 Central Florida Blvd. Gainesville, F L 3261 1-7200 USA Volume 2, Clzupter 3.4 Prof. David Crich Department of Chemistry University of Illinois at Chicago 845 W. Taylor Street, M/C 111 Chicago, IL 60607-7061 USA Volume 2, Chupter 3.2 Prof. Dennis P. Curran Department of Chemistry University of Pittsburgh Parkman Avenue and University Avenue Pittsburgh, PA 15260 USA Dr. Anne-Lise Dhimane Universite Pierre et Marie Curie Laboratoire de Chimie Organique Tour 44-54, CP 229 4, Place Jussieu 75252 Paris Cedex 05 France Volurw 2, Chapter 4.4 Prof. Christopher Easton Research School of Chemistry Australia National University Canberra ACT 0200 Australia Volume 2, Chupter 6.1

Prof. Eric Enholm Department of Chemistry University of Florida P.O. Box 117200 4000 Central Florida Blvd. Gainesville, FL 3261 1-7200 USA Volunze 2, Chupter 3.4 Dr. Louis Fensterbank Universite Pierre et Marie Curie Laboratoire de Chimie Organique Tour 44-54, CP 229 4, Place Jussieu 75252 Paris Cedex 05 France Volume 2, Clzupter 4.4 Dr. Laurence Feray UniversitC d’Aix Marseille 111 Faculte de St Jer6me Laboratoire Chimie Boite 562 Av. Escadrille Normandie-Niemen 13397 Marseille Cedex 20 France Volume 2, Chapter 3.6 Dr. Carla Ferreri Dipartimento di Chimica Biologica Universita di Napoli “Federico 11” Via Mezzocannone 16 80134 Napoli Italy Volunze 2, Chapter 5.5 Dr. A. Ganesan University of Southampton Department of Chemistry Highfield Southampton, SO 17 1BJ UK Volume 2, Chupter 1.5 Dr. Andreas Gansauer Kekule-Institut fur Organische Chemie und Biochemie Universitat Bonn

List of Contributors

Gerhard-Domagle-Str. 1 53121 Bonn Germany Volume 2, Chapter 3.3 Dr. Michael Georges Xerox Research Center Canada Ltd 2660 Speakman Drive Mississauga, ON L5K 2L1 Canada Volume 1, Chapter 5.1 Prof. Bernd Giese Universitat Basel Institut fur Organische Chemie St. Johanns Ring 19 4056 Basel Switzerland Volunie 1, Chapter 4.1 Dr. Brigitte Guerin Institut de Recherches Cliniques de Montreal Bio-organic Chemistry Laboratory 110 Avenues des Pins Ouest Montreal, Quebec H2W 1R7 Canada Volume 1, Chupter 4.4 Prof. Yvan Guindon Institut de Recherches Cliniques de Montreal Bio-organic Chemistry Laboratory 110 Avenues des Pins Ouest Montreal, Qukbec H2W 1R7 Canada Volume I , Chupter 4.4 Prof. David J. Hart Department of Chemistry Newman and Wolfrom Laboratory The Ohio State University 100 West 18th Avenue Columbus, OH 43210-1185 USA Volume 2, Clzupter 4.1 Prof. Jens Hartung Institut fur Organische Chemie

XXI

Universitat Wiirzburg Am Hubland 97074 Wurzburg Germany Volume 2, Chapter 5.2 Dr. Jeremy N. Harvey University of Bristol School of Chemistry Cantock’s Close Bristol BS8 ITS UK Volume I , Clzupter 3.3 Prof. Richard K. Haynes Department of Chemistry The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon Hong Kong Volume 2, Cliupter 5.4 Dr. Christoph lmboden F. Hoffmann-La Roche Ltd. POAB-L, Bau 31/10] 4070 Basel Switzerland Volume I , Chapter I . 7 Prof. Javed Iqbal Department of Chemistry Indian Institute of Technology Kanpur 208 016 India Volume I , Cliupter 1.8 Prof. Tsutomu Katsuki Faculty of Science Kyushu University Hakozaki, Higashi-ku Fukuoka 812-8581 Japan Volunzc 2, Chupter 2.2 Prof. Sunggak Kim Department of Chemistry and Center for Molecular Design and Synthesis Korea Advanced lnstitute of Science and Technology

XXII

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Taejon 305-701 Korea Volume 2, Chapter 1.1

75252 Paris Cedex 05 France Volume 2, Chapter 4.4

Prof. Yasuyuki Kita Osaka University Graduate School of Pharmaceutical Sciences 1-6, Yamada-oka Suita, Osaka, 565-0871 Japan Volume 1, Chapter 1.1

Dr. Jean-Maurice Mallet Departement de Chimie Ecole Nonnale Superieure 24, rue Lhornond 75231 Paris Cedex 05 France Volume 2, Chapter 6.3

Dr. Nikolai Kuznetsov Universite de Fribourg Institut de Chimie Organique Plrolles 1700 Fribourg Switzerland Volume 2, Chapter 3.6 Prof. Eun Lee Department of Chemistry College of Natural Sciences Seoul National University Seoul 151-742 Korea Volume 2, Chapter 4.2 Prof. Torsten Linker Institute of Organic Chemistry University of Potsdam Karl-Liebknecht-Strasse 24-25 14476 Golm Germany Volume 1 Chapter 2.4 Prof. R. Daniel Little Department of Chemistry University of California Santa Barbara, CA 93 106-9510 USA Volume 2, Chapter 4.5 Prof. Max Malacria Universite Pierre et Marie Curie Laboratoire de Chimie Organique Tour 44-54, CP 229 4, Place Jussieu

Dr. Masato Matsugi Osaka University Graduate School of Pharmaceutical Sciences 1-6, Yamada-oka Suita, Osaka, 565-0871 Japan Volume I , Chapter 1.1 Dr. C. L. Mero Department of Chemistry Vanderbilt University Nashville, TN 37235 USA Volume I , Cjiapter 5.2 Prof. Gary A. Molander Department of Chemistry University of Pennsylvania 231 South 34th Street Philadelphia, PA 19104-6323 USA Volume I , Chapter 2.1 Prof. William B. Motherwell Department of Chemistry University College London Christopher Ingold Laboratories 20 Gordon Street London WClH OAJ UK Volume I , Chapter 1.7 Prof. John Murphy Department of Pure Applied Chemistry University of Strathclyde 295 Cathedral Street

List of Contributors XXIII Glasgow G1 IXL Scotland Volume 1, Chapter 2.7 Dr. Jyoti Prokash Nandy Department of Chemistry Indian Institute of Technology Kanpur 208 016 India Volume 1, Chapter 1.8 Prof. Daniele Nanni Dipartimento di Chimica Organica “A. Mangini” Universita’ di Bologna Viale Risorgimento 4 40 136 Bologna Italy Volume 2, Chapter 1.3 Prof. Martin E. Newcomb Department of Chemistry Wayne State University Detroit, MI 48202-3489 USA Volume I , Chapter 3.1 Dr. William W. Ogilvie Institut de Recherches Cliniques de Montreal Bio-organic Chemistry Laboratory 110 Avenues des Pins Ouest Montreal, Quebec H2W 1R7 Canada Volume 1, Chapter 4.4 Dr. Cyril Ollivier Universite de Fribourg Institut de Chimie Organique Perolles 1700 Fribourg Switzerland Volume 2, Chapter 2.1 Prof. Koichiro Oshima Department of Material Chemistry Graduate School of Engineering Kyoto University, Sakyo Kyoto 606-8501

Japan Volume 1, Chapter 1.2 Dr. Jonathan D. Parrish Department of Chemistry University of California Santa Barbara, CA 93 106-9510 USA Volume 2, Chapter 4.5 Dr. Alan James Pearce Departement de Chimie Ecole Normale Superieure 24, rue Lhomond 75231 Paris Cedex 05 France Volume 2, Chapter 6.3 Dr. Marianna Pierobon Institut fur Organische Chemie Albert-Ludwigs Universitat Freiburg Albertstr. 21 79 104 Freiburg Germany Volume 2, Chapter 3.3 Prof. Ned Porter Department of Chemistry Box 1822, Station B Vanderbilt University Nashville, TN 37235 USA Volume 1, Chapters 4.3 and 5.2 Prof. Philippe Renaud Universite de Fribourg Institut de Chimie Organique Perolles 1700 Fribourg Switzerland Volume 1, Chapter 4.2 Volume 2, Chapters 2.1 and 3.6 Prof. Tara R. Rheault Department of Chemistry North Dakota State University Fargo, N D 58 105 USA Volume 1, Chapter 4.5

XXlV

List of Contributors

Prof. Ian Rosenstein Department of Chemistry Hamilton College 198 College Hill Rd. Clinton, NY 13323 USA Volume 1, Chapter 1.4 Prof. Scott Rychnovsky Department of Chemistry University of California Irvine, CA 92697-2025 USA Volume 2, Chapter 4.3 Prof. Ilhyong Ryu Department of Chemistry Faculty of Arts and Sciences Osaka Prefecture University (OPU) Sakai, Osaka 599-8531 Japan Volume 2, Chapter 1.2 Dr. Rashmi Sanghi Department of Chemistry Indian lnstitute of Technology Kanpur 208 016 India Volume 1, Chapter 1.8 Prof. Hans Schafer Institute of Organic Chemistry University of Munster Corrensstrasse 40 48 149 Munster Germany Volume 1, Chapter 2.6 Prof. Carl Schiesser Department of Chemistry University of Melbourne Victoria 3052 Australia Volume 1, Chapter 3.2 Prof. Mukund P. Sibi Department of Chemistry North Dakota State University Fargo, N D 58105

USA Volume 1, Chapter 4.5 Prof. Pierre Sinay Departement de Chimie Ecole Normale Supkrieure 24, rue Lhomond 75231 Paris Cedex 05 France Volume 2, Chapter 6.3 Dr. Melissa A. Skidmore Department of Chemistry University of Melbourne Victoria 3052 Australia Volume 1, Chapter 3.2 Prof. Barry B. Snider Department of Chemistry Brandeis University Waltham, MA 02454-91 10 USA Volume 1, Chupter 2.3 Prof. A. Srikrishna Department of Organic Chemistry Indian Institute of Science Bangalore 560012 India Volume 2, Chupter 3.1 Dr. Lucien Stella Universite d’Aix Marseille I11 Faculte de St JCr6me Laboratoire Chimie Boite 562 Av. Escadrille Normandie-Niemen 13397 Marseille Cedex 20 France Volume 1, Chupter 3.3 Volume 2, Chupter 5.1 Prof. Armido Studer Fachbereich Chemie Universitaet Marburg Hans-Meerwein-Strasse 35032 Marburg

List of Contributors Germany Volume 2, Chapter 1.4 Prof. Ernest0 Suarez Instituto de Productos Naturales y Agrobiologia Carretera de La Esperanza 3 Apartado de Correos 195 38206-La Laguna, Tenerife Spain Volume 2, Chapter 5.3 Prof. Pablo Wessig Institut fur Chemie Humboldt-Universitiit zu Berlin Hessische Str. 1-2 101 15 Berlin Germany Volume 2, Chapter 6.2 Prof. Nung Min Yoon Department of Chemistry Sogang University Seoul, 121-742 Korea Volume 1, Chapter 2.2 Dr. Joo-Yong Yoon Department of Chemistry and Center for Molecular Design and Synthesis

XXV

Korea Advanced Institute of Science and Technology Taejon 305-701 Korea Volume 2, Chapter 1.1 Dr. Hideki Yorimitsu Department of Material Chemistry Graduate School of Engineering Kyoto University, Sakyo Kyoto 606-8501 Japan Volume I , Chapter 1.2 Prof. Samir Z. Zard Institut de Chimie des Substances Naturelles CNRS 9 1 198 Gif-sur-Yvette France Volume 1, Chapter 1.6 Dr. Wei Zhang Fluonous Technologies, Inc. U-PARC 970 William Pitt Way Pittsburgh, PA 15238 USA Volume 2, Chapter 3.5

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

1 Radical Chain Reactions

1.1 Radical Initiators Yusuyuki Kitu and Musuto Mutsugi

1.1.1 Introduction Organic synthesis using radical species requires efficient methods for the generation of free radicals in a convenient manner. For the production of radicals, a covalent bond has to be homolytically cleaved into two parts so that each fragment possess an electron on the atom which shared the covalent bond. Generally, the cleavage of the bond is achieved by the application of energy in the form of heat, light, or radiation; however, the use of radical initiators seems to be a good recipe from a standpoint of practical organic synthesis. In this chapter, representative radical initiators that produce radicals easily are described. These radical initiators generally require mutually conflicting properties: they should be stable at room temperature but decompose to produce radicals under mild conditions.

1.1.2 Classification of Radicals Based on Energy Supplied The following methods including redox systems are well known and widely used in the generation of radicals. First, some methods of radical generation are briefly discussed.

1.1.2.1 Radical Production by Thermolysis A covalent bond is generally cleaved to its radical fragments at temperatures higher than 800°C. Covalent bonds that can be cleaved at 20 : 1

Scheme 7. Highly stereoselective synthesis of a-linked C-glycopyranoside using V-70 [6a]

(2RS,2'RS)-Azobis(4-methoxy-2,4-dimethylvaleronitrile) ( V-70L: racemic f o r m ) V-70L is the racemic form isomer purified from V-70 (Scheme 8). Its activity as a radical initiator is higher than that of V-70 and hence an efficient initiator. V-70L is

'TN

MeoC(Me)2CH2 N'N

CH2C(Me)20Me

. ~ C N

(V-70L)

Bu3SnH t

CH2C12,25"C

RO Br

85-94% (anti : syn = >98 : 2)

R=H, COMe, COPh

Scheme 8. Highly stereoselective synthesis of carbocycles using V-70L [6e]

I.1.3 Radical Initiators in Organic Synthesis

5

commercially available as white crystals; whose melting point is 59.2-62.3 "C with a half-life of 1 h in toluene at 30 "C. It is quite stable for a few months when stored in a refrigerator.

2,2'-Azobis(2-methylpropionamidine)dihydrochluride) ( V-50) V-50 is a hydrophilic radical initiator, which has an amino function in the molecule. V-50 is commercially available as white crystals, whose melting point is 160- 169 "C with a half-life of 10 h in water at 56°C. Similar to AIBN, V-50 also requires moderate temperatures to act as an initiator (Scheme 9).

HN+ HZN

k

PhSH

eNAc +

-+::

N=N

f

(V-50) H20,60 "C

P h s x N A C (dr 65:35)

96%

Scheme 9. Radical addition reaction using V-50 in water [7b]

4,4'-Azobis(4-cyanopentunoicacid) ( V-501) V-501 is also a hydrophilic radical initiator, which has a carboxylic function in the molecule. V-50 1 is commercially available as white crystals, whose melting point is 120-123°C with a half-life of 10 h in water at 69°C. Similar to V-50, this also requires moderate temperatures to show its radical initiator properties (Scheme 10).

f

H O ~ C ( H ~ C ) ~N= N

+

f (CH~)~CO~H

(V-501) @R2

R1

X: NH2, OH

H20,75

"C

-

O

76-100%

e

R

2

R'

R' = H, Me

R2 = alkenol

Scheme 10. Radical addition reaction using V-501 in water [7b]

1.1.3.2 Peroxides Thermolysis of peroxides has been used in the study of radical reactions for a long time. On heating, peroxides produce alkoxy radicals and acyloxy radicals by the cleavage of the peroxide bond. The nature of the radicals produced is generally electrophilic, although it is dependent on the structure of the radical species. A brief description of the widely used peroxides is given below.

6

I . I Rudicul Initiutors

Benzoyl peroxide: PhC( 0)O-OC(0 ) P h Benzoyl peroxide is one of the most widely used peroxide radical initiators in organic synthesis (Scheme 11) [ 11. It appears as white crystals with melting point 105-106°C. This compound is decomposed by heat to form phenyl radical and carbon dioxide via benzoyloxy radical (Scheme 12).

@(CH2)&02H

Benzoyl peroxide

CI

CCI4 reflux

C13CA(CH2)&02H

100%

framatic acid

Scheme 11. Radical addition reaction using benzoylperoxide [ 111

-

ROC-00-COR

2RC02

R = Ph or Me RC02

.

R

'

+

CO2

R = Ph or Me

Scheme 12. Decomposition of peroxydicarbonates

Acetyl peroxide: MeC(0)O-OC(0)Me Aliphatic diacyl peroxides are generally less stable than their aromatic counterparts. Acetyl peroxide decomposes at 25 "C, so that careful handling is required to avoid dangerous explosion. These compounds are sensitive to shock, light, heat and metals. tert-Butyl perbenzoate: Ph C(0)0-OtBu tert-Butyl perbenzoate produces radicals as shown in Scheme 13 and 14 [l]. PhCO-00- f-Bu

t-BUO

.

*

-

MeCOMe

PhC02.

+

+

Me-

Scheme 13. Decomposition of tert-butyl perbenzoate

f-BUO

1.1.3 Radicul Initiators in Organic Synthesis

7

PhCO- 00-t-BU

OBZ

OTf

R-

*

1359% (0-81%ee)

Ph PhCOz-Cu(ll)

+ ~4

%u(ll)

& J

-

OBZ :

+

CU(l)

R-

R

Scheme 14. Asymmetric allylic oxidation using tert-butyl perbenzoate [ 121

di-tert-Butyl peroxide: t-BuO-Of-Bu Among the known peroxides, di-tert-butyl peroxide has a relatively stable structure. It produces methyl radical via t-butoxy radical (Scheme 15 and 16) [ 11. t-BuOOt-BU t-BUO

.

*

*

2t-BuO.

MeCOMe

+

Me.

Scheme 15. Decomposition of trrt-butyl perbenzoate

Scheme 16. Transannular radical cyclization using tert-butyl hydroperoxidc [ 131

Half-lives of the peroxides discussed so far [ 141 are given in Table 1.

1.1.3.3 Organometallic Compounds It is known that certain organometallic compounds act as radical initiators. Especially, trialkylborane analogs have been used very well as initiators in many stereo-

8

1.1 Radicul Initiators

Table 1. Commonly used radical initiators (peroxides) Initiator

Radical(s) produced

Half-life [h]

Temperature ["C]

Benzoyl peroxide (PhC00)2 Acetal peroxide

PhCOO' and Ph'

t-Butyl peroxybenzoate PhC(0)OOt-Bu Di-t-butyl peroxide (t-BuO)z

t-BuO', Me', PhCOO' and Ph' t-BuO' and Me'

7 2 8 1 20 1 218 6.4

70 90 70 85 100 125 100 130

MeCOO' and Me'

selective syntheses, because of the fact that they act effectively at -78°C. (These will be discussed in detail in Chapter 1.2) Triethylborune: Et3 B

Triethylborane acts as the initiator at -78 " C . It is particularly useful in precision stereoselective synthesis [15]. An example is shown in Scheme 17.

toluene -78 "C 85%, 85%ee

Scheme 17. Chiral Lewis acid-mediated enantioselective addition using Et3B [ 161

9-Borabicycloj3.3.I jnonane: 9-BBN

Recently Schiesser has reported the use of 9-BBN as a radical initiator. It acts as an initiator at -78 "C similarly to triethylborane (Scheme 18).

Br

9-BBN 0.05M Bu3SnH

-78"C

* -

+d+O

Scheme 18. Low-temperature free radical reduction using 9-BBN [ 171

I . I . 4 Summary

9

1.1.3.4 Inorganic Compounds Zinc chloride: ZnCIz Inorganic compounds can also act as radical initiators. Zinc chloride (ZnClz) has been used to initiate radical reactions at -78 "C.In following case (Scheme 19), zinc chloride acts as a radical initiator as well as a chelating agent.

Scheme 19. Diastereoselective allylation using ZnCl2 [ 181

Samarium iodide: SmIl Samarium iodide reacts with alkyl halides or ketones to generate radicals by electron transfer (see Volume 1, Chapter 2.1). An example is shown in Scheme 20. It is known that other transition metal compounds (Mn, Ni, Cu, Fe etc.) also act as radical initiators [ 191.

3 - I5"Smlz HMPA

HO

t-BuOH THF

86% (>150:1 )

Scheme 20. Radical cyclization induced by SmI2 [20]

1.1.4 Summary As described above, there are many kinds of radical initiators in organic synthesis. Each initiator has its individual advantages and disadvantages, and we should therefore choose the most suitable initiator according to the reaction conditions. The chemistry of radical reactions is rapidly advancing as a consequence of the discovery of the new initiators. Radical reactions at low temperatures using highly active initiators facilitate the generation of radicals at specific positions in the mole-

10

1.I Radical Initiutors

cule with excellent stereocontrol. It is likely that more practical radical initiators will be invented and applied in organic synthesis.

References [ l ] J. Fossey, D. Lefort, J. Sorba, Free Radicals in Organic Chemistry, Wiley, Masson, Paris, 1995, p. 105. [2] P. S. Engel, Chem. Rev. 1980, 80, 99. [3] H. Suginome, in Handbook of’ Organic Photochemistry and Photobiology, (Eds. P.-S. Song, W. M. Horspool), CRC, Florida, 1995, p. 824. [4] F. Minisci, Acc. Chem. Res. 1975, 8, 165. [5] A. S. Lindsay, H. Jaskey, Chem. Rev. 1957, 57, 583. [6] (a) Y. Kita, K. Gotanda, A. Sano, K. Murdta, M. Suemura, M. Matsugi, Tetrahedron Lett. 1997, 38, 8345. (b) Y. Kita, K. Gotanda, K. Murata, M. Suemura, A. Sano, T. Yamaguchi, M. Oka: M. Matsugi, Orgunic Process Reseurch & Development. 1998, 2, 250. (c) Y. Kita, A. Sano, T. Yamaguchi, M. Oka, K. Gotanda, M. Matsugi, J. Org. Chem. 1999, 64, 675. (d) K. Gotanda. M. Matsugi, M. Sucmura, C. Ohira, A. Sano, M. Oka, Y. Kita, Tetrahedron 1999,55, 10315. (c)M. Matsugi, K. Gotanda, C. Ohira, M. Suemura, A. Sano, Y. Kita, J. Org. C h m . 1999, 64, 6928. [7] (a) R. Rai, D. B. Collum, Tetrahedron Lett. 1994,35, 6221. (b) H. Yorimitsu, K. Wakabayashi, H. Shinokubo, K. Oshima, Tetrahedron Lett. 1999, 40, 519. (c) H. Yorimitsu, T. Nakamura, H. Shinokubo, K. Oshima, J. Org. Chem. 1998, 63: 8604. (d) T. Nakamura, H. Yorimitsu, H. Shinokubo, K. Oshima, Synlett 1998, 1351. [8] S. M. Culbertson, N. A. Porter, J. Am. Cliem. Soc. 2000, 122, 4032. [9] (a) P. A. Baguley, J. C. Walton, Angeiv. Cheni. In/. Ed., Enyl. 1998, 37, 3072. (b) J. Light, R. Breslow, Tetrahedron Lett. 1990, 31, 2957. 1101 E. Lee, J. W. Lim, C. H. Yoon, Y. Sung, Y. K. Kim, M. Yun, S. Kim, J. Am. Chem. Soc. 1997, 119, 8391. [ I I ] A. S. C. P. Rao, U. R. Nayac, S. Dev, Synthesis, 1975, 608. [I21 M. B. Andrus, A. B. Argade, X. Chen, M. G. Pamment, Tetrahedron Lett. 1995,36, 2945. 1131 L. Friedman, J. Am. Chem. Soc. 1964, 86, 1885. [ 141 W. B. Motherwell, D. Crich, Free Radical Chain Reactions in Organic Synthesis, Academic, London, 1992. [ 151 K. Oshima, K. Uchimoto, Journal of Synthetic Organic Chemistry Japan, 1989, 47, 40. [I61 M. Murakata, T. Jono, Y. Mizuno, 0. Hoshino, J. Am. Chem. Soc. 1997, 119, 11713. [ 171 V. T. Perchyonok, C. H. Schiesser, Tetrahedron Lett. 1998, 39, 5437. [IS] Y. Yamamoto, S. Onuki, M. Yumoto, N. Asao, J. Am. Chem. Soc. 1994, 116, 421. [ 191 (a) T. Linker, K. Hartmann, T. Sommermann, D. Scheutzow, E. Ruckdeschel, Angew. Chem. Int. Ed. Engl. 1996, 35, 1730. (b) B. Quiclet-Sire, J.-B. Saunier, S. Z. Zard, Tetrahedron Lett. 1996, 37, 1397. (c) J . 0. Metzger, R. Mahler, Angeiv. Chem. Int. Ed. Engl. 1995, 34, 902. (d) Y. Hayashi, H. Shinokubo, K. Oshima, Tetruhedron Lett. 1998, 39, 63. [20] (a) G. A. Molander, J. A. McKie, J. Org. C h m . 1995, 60, 872. (b) G. A. Molander, J. C. McWilliams, B. C. Noll, J . Am. Cliem. Soc. 1997, 119, 1265. (c) G. A . Molander, Chem. Rea. 1992, 92, 29 (d) H. B. Kagdn, J. L. Namy, Tetrahedron 1986, 42, 6573.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

1.2 Radical Chain Reactions: Organoborane Initiators Hideki Yovimitsu and Koiclzivo Oslzima

1.2.1 Introduction In general, organoboranes are very sensitive to oxidation and are normally handled under argon or nitrogen [ 11. Examples of conjugate addition of trialkylborane to a,,&unsaturated carbonyl compounds under inert atmosphere were found in the 1960s, and these reactions were initially thought to be polar [2]. However, Brown's group established in 1970 that conjugate addition of trialkylborane is a radical reaction [ 3 ] . A trace amount of oxygen in the reaction medium reacts with triAlthough the alkylborane to produce an alkyl radical as shown in Scheme 1 [4]. synthetic utility of conjugate addition had been well documented, new reaction patterns of trialkylborane via a radical process had not been discovered. In 1987, triethylborane-induced hydrostannylation of alkynes [5]had opened up new possibilities for using trialkylborane, especially Et3B, as a radical initiator in organic synthesis. Compared with other initiators such as azobis(isobutyronitri1e) (AIBN) and benzoyl peroxide (BPO), Etj B-induced radical reactions have several characteristic features. This chapter reviews the usefulness of Et3B as an excellent radical initiator [6].

Scheme 1. Gcneration of alkyl radical from trialkylborane by the action of oxygen

1.2.2 Triethylborane-Induced Radical Reaction at Low Temperatures Et3B can act as a radical initiator in the presence of a trace amount of oxygen even at -78 "C, where Et3B is decidedly superior to AIBN and BPO. Reactions at lower temperatures allow us to control stereoselectivity, to employ thermally unstable substrates and to save troubles and energy in heating.

12

1.2 Radical Chain Reactions: Organoborane Initiators

YR2 +RqnR3 R2

R3SnH(l .l ),Et3B(0.1) R'

R' CECR2

*

r. t., 15min, PhCH3

z

E SnR3

R'

R2

R3SnH

nC1~H21

H

Ph3SnH

80%

79/21

"BusSnH

40%

80/20 82/18

Yield

,yZ

HOCH2CH2

H

Ph3SnH

87%

Ph

H

Ph3SnH

75% 100/0

Me3Si

H

Ph3SnH

83%

PhaSnH

86%

"C~gHii

"C~gHii

100/0

0/100

0

Scheme 2. Et3B-induced hydrostannylation of alkynes and its applications

Et3B as a simple radical initiator was first discovered in hydrostannylation of alkynes [ 5 ] . The reactions were performed at room temperature or below in the presence of a trace amount of oxygen (Scheme 2). Hydrostannylation was applied to the synthesis of dehydroiridodiol (1) and a-methylene-y-butyrolactone (2). Et3Binduced radical addition reactions of triphenylgermane [ 71, tris(trimethylsily1)silane [8], and benzenethiol [9] to alkynes were also reported. In the case of triphenylgermane, both ( E ) - and (Z)-alkenylgermanes could be selectively obtained by changing reaction conditions (Scheme 3). Recently, it has been demonstrated [ 101 that tri-2-furylgermane (3) adds to various alkenes, including not only disubstituted alkenes but also tri- and tetrasubstituted alkenes at room temperature. Stereoselective olefination reaction was achieved by radical addition of tri-2-furylgermane to silyl enolate followed by treatment of the adduct with Me3SiOTf or with 1) KZCO3/MeOH and 2) KH (Scheme 4). Fukuyama's group illustrated [ 1 11 that 2,3-disubstituted indole 5 was prepared under mild conditions starting with 2alkenylthioanilide 4 (Scheme 5). Labile /?-lactam could be introduced at the indole 2-position. Alkyl iodides and bromides were reduced at -78 "Cwith nBu3SnH within 30 min [ 121. Alkenyl halides were also dehalogenated easily (Scheme 6). Moreover, Et3B

1.2.2 Triethylborane-Induced Radical Reaction at Low Temperatures

kGePh3+ HH R

Ph3GeH

RC!CH

*

Et3B R

H

Temp.

n-CloH21

Z

H

GePh3

E

Yield

-78°C

76%

60°C

99%

-78°C

80%

60°C

75%

EtOOC(CH2)g -78°C

64%

60°C

93%

HOCH2CHp

H

>20/1 20/1 10/1 19:1)

16

1.2 Radical Chain Reactions: Organoborane Initiators

"BusSnH

Me0

Me0

PhS COOEt

lSb 'COOEt

AIBN, benzene, reflux 3.4:1 Et3B,toluene, -78 'C

37:l

Scheme 11. Stereoselective radical cascade approach to benzo[a]quinolizidines

AIBN in boiling benzene, the radical cascade products 15a and 15b were obtained in a ratio of 3.4:l and in 36% combined yield. A similar reaction with Et3B at -78 "C in toluene afforded 15a and 15b in a ratio of 37:l in 46% yield. Recrystallization of the obtained mixture gave the pure isomer 15a (Scheme 11).

1.2.3 Lewis Acidic Triaikyiborane: Radical Mediator and Terminator as Well as Initiator Stoichiometric organoboranes are well known to undergo conjugate addition to various a$-unsaturated carbonyl compounds such as methyl vinyl ketone [2]. It was later discovered that galvinoxyl inhibited the reaction, suggesting a radical mechanism [3]. Very recently, it has been clarified [19] by spectroscopic analyses that the reaction of a$-unsaturated carbonyl compounds with Et3B under free radical conditions involves the prior formation of an 'a,P-unsaturated carbonyl compoundorganoborane' complex 16 (Scheme 12). Among many examples of conjugate addition reported, synthesis of a prostaglandin model 20 is exemplified in Scheme 13 [20]. Trialkylborane containing a ester moiety added to enone generated in situ. The second conjugate addition gave a,P-dialkylcyclopentanone20. Another exam-

R

5

Scheme 12. Mechanism of alkylation via complexed enone

1.2.3 Lewis Acidic Triulkylborane

17

0 II

t 0

0

Scheme 13. Synthesis of a prostaglandin model

ple is successive conjugate addition of alkyl radical and aldol reaction with aldehyde [21]. Subsequent addition of aldehyde instead of water to the reaction mixture resulted in aldol addition to form P-hydroxy ketone 21 (Scheme 14). Reformatsky

"Bu3B

+ 0

-[

]PhCHO

n

OB"Bu2

HO ~

~

21


Me'. Therefore, 38 was predominantly formed. Electron-deficient carbon-centered radical generated by the action of Et3B underwent homolytic aromatic substitution of 5-membered heteroaromatics [28]. The 2-position was selectively substituted to yield 2-heteroarylacetic acid derivatives (Scheme 22) Et3B is an effective tool for halogen atom transfer radical reactions (see also Chap. 1.5). Perfluoroalkyl iodide [29], a-halo nitrile and a-halo ester [30] added to alkenes and alkynes at low temperature. Not only terminal alkenes but also internal alkenes can be employed to furnish iodine atom transfer adducts (Scheme 23). Furthermore, addition of perfluoroalkyl iodide to silyl and germyl enolate provided a-perfluoroalkyl ketones [31]. The reaction would involve the elimination of a tri-

0+ N

Me

ICH(CH3)C02Et

Et3B

p

54%

QCH(CH3)COpEt Me

Scheme 22. Homolytic aromatic substitution promoted by EtJB

1.2 Radical Chain Reactions: Organohorane Initiators

22

Et3B

+

R'CH=CHR2

Rtl

hexane

R' R' CH-CH 1 R~

3.5-10 h R'

R2

MeOOC(CH2)8 "C10H21 'C~gHll

"CgHll

Rfl

Temp. ("C)

Yield ("h)

H

'c6Fi31

25

90

H

(CF3)'CFI

25

a7

-24

61

OGenPr3

+

CF31

"CgFi31

OGenPr3

Et3B

' c 6 F 1 3 d

~

"C6F13

6

02%

40

42

41

Scheme 23. Addition of perfluoroalkyl iodides to alkenes

alkylgermyl radical from the intermediate 41. Intermolecular radical addition of alkyl iodide is generally difficult. However, it was realized with satisfactory yields [32] especially in the case that trimethylsilylacetylene, ethyl propiolatc, or phenylacetylene was used (Scheme 24). Thc Sc(OTf)3 and Yb(OTf)3-promoted atom

+

R'CECH

Et3B

R'I

hexane 25 "C

R,'

R2

+

C=


c13c

eo

1MHCI 71%) 1 M NaOH 59%

50

conc. HCI 38'10

Scheme 31. Atom transfer radical addition in acidic or basic media

26

1.2 Radical Chain Reactions: Ovganohorane Initiators

a$

aq. H3P02,Et3B NaHC03 EtOH, r.t., 3 h

*

82% (81/19)

n-Pr

OCOPh n

~

B

u

o 80% ~ (66/34) ~ ~

~

~

h

Scheme 32. Radical cyclization of iodo acetals with HjPO?/base/Et3B in aqueous ethanol

References [ I ] A. Pelter, K. Smith, H . C. Brown. Borurrc Reuyents, Academic Press, London, 1988; H . C. Brown, M. Zaidlewic, E. Negishi, in Coniprehensioe Organornetullic Cl~emistry,(Eds.: G. Wilkinson, F. G. A. Stone, E. Abel), Vol. 7, Pergamon, Oxford, 1982, Chap. 45.1 to 45.1 1. 121 V. A. Sazonova, A. V. Grasimenko, N. A. Shiller, Zhur. 0hshchcG Klrirn. 1963, 33, 2042; M. F. Hawthorne, M . Reintjes, J. Am. Chem Soc. 1964, 86, 951 and 1965, 87, 4585; A. Suzuki, A. Arase, H. Matsumoto, M. Itoh, H. C. Brown, M. M. Rogic, M. W. Rathke, J. Am. Cheni. Soc. 1967, 89, 5708; H. C. Brown, M. M. Rogic, M. W. Rathke, G. W. Kabalka, J. A m Cl7em. Soc. 1967, 89, 5709. [3] G. W. Kabalka, H. C. Brown, A. Suzuki, S. Honma, A. Arase, M. Itoh, .I. A m C/xwr. SOL.. 1970, 92, 710. [4] A. G. Davis, Pure Appl. Clzern. 1974, 39, 497. 151 K. Nozaki, K. Oshima, K. Utimoto, J. AIM. C/wm. Soc. 1987, 109, 2547; K. Nozaki. K. Oshima, K. Utimoto, Bull. Client Soc. Jpri. 1987, 60, 3465. [6] Recently, it has been reported that Et,Zn/air and 9-BBN are also effective to initiate radical reactions. See, 1. Ryu, F. Araki. S. Minakata, M. Komatsu, Tetruliedron Lett. 1998, 39. 6335; V. T. Perchyonok, C. H. Schiesser, Tc~tmlrcdronLett. 1998, 39, 5437. [7] Y. Ichinose, K. Nozaki, K. Wakamatsu, K. Oshima, K. Utimoto, Tetrul7edron Lett. 1987, 28, 3709. [8] K. Miura, K. Oshima, K. Utimoto, Bull. Clrern. Soc. Jpn. 1993, 66. 2356. 191 Y. Ichinose. K. Wakamatsu, K. Nozaki. J.-L. Birbaum, K. Oshima, K. Utimoto, C h n . Lett. 1987, 1647. [lo] S. Tanaka, T. Nakamura, H. Yorimitsu, H . Shinokubo, K. Oshima, Or(/, Lett. 2000, 2 , 191 1. 1111 H. Tokuyama, T. Yamashita, M. T. Reding, Y. Kaburagi, T. Fukuyama, J. A m . Chcm. Soc. 1999. 121, 3791. [I21 K. Miura. Y. Ichinose, K . NoLaki, K. Fugami, K. Oshima, K. Utimoto, Bull. C/icr?i.Soc. Jpn. 1989, 62, 143. [I31 K. Nozaki, K. Oshima, K. Utimoto, Tetruheilrorr Left. 1988, 29, 6125 and 6127. 1141 T. Nakamura, H. Yorimitsu, H. Shinokubo, K. Oshima, Synlett 1999, 1415. [IS] K. Iseki, T. Nagai, Y. Kobayashi, Tetmhetlron Lett. 1993, 34, 2169. [I61 E. Kawashima, Y. Aoyama, T. Sekine, M . Miyahara, M. F. Radwan, E. Nakamura. M. Kainosho, Y. Kyogoku, Y. Ishido. J. Org. C/ieni. 1995, 60, 6980. 1171 P. A. Evans. T. Manangan, Tetrtrhetlron Lett. 1997. 38. 8165. [ 181 H. Ishibashi, M. Inomata, M. Ohba, M. Ikeda, Tetr.trhedrorz Lett. 1999, 40, 1149. [I91 V. Beraud, Y. Gnanou, J. C. Walton, 9 . Maillard, Ti~trcihed,onLett. 2000, 41, 1195. [20] 0 . Attanasi, G. Baccolini, L. Caglioti, G. Rosini, Guiettu 1973, 103, 31. [21] T. Mukaiyama. K. Inomata, M. Muraki, J . Am. Cliem. Soc. 1973, 95. 967. [22] K. Nozaki. K. Oshima, K. Utimoto, Tetruheilron Lett. 1988, 29, 1041.

RCjermc'rs 1

27

[23] A. L. J. Beckwith, B. P. Hay, J. Am. Chem. Soc. 1989, 111, 230 and 2674. [24] D. L. J. Clive, M. H. D. Postema, Chem. Commun. 1993, 429. [25] P. Devin, L. Fensterbank, M. Malacria, Tetruhcdron Lett. 1998, 39, 833; P. Devin, L. Fensterbank, M. Malacria, Tetruhedron Lett. 1999, 40, 5511; M. Chareyron, P. Devin, L. Fensterbank, M. Malacria, Synlett 2000, 83. [26] M. P. Bertrand, L. Feray, R. Nouguier, L. Stella, Synlert 1998, 780. [27] H. Miyabe, M. Ueda, N. Yoshida, T. Naito, Syrdett 1999, 465. [28] E. Baciocchi, E. Maraglia, Tetruhedron Lett. 1993, 34, 5015. [29] Y. Takeyama, Y. Ichinose, K. Oshima, K. Utimoto, Tetruhedron Lett. 1989. 30, 3159. [30] E. Baciocchi, E. Maraglia, Tetruhedron Lett. 1994, 35, 2763. [31] K. Miura, M. Taniguchi, K. Nozaki, K. Oshima, K. Utimoto, Tetruhedron Lett. 1990, 31, 6391. 1321 Y. Ichinose, S. Matsunaga, K . Fugami, K. Oshima, K. Utimoto, Telruhedron Lett. 1989, 30, 3155. [33] C. L. Mero, N. A. Porter, J. Am. Chem. Soc. 1999, 121, 5155. [34] H. Ikeda, H. Teranishi, N. Iwamura, H. Ishibashi, Hetc.rocyc1e.y 1997, 45, 863. [35] K. Wakabayashi, H. Yorimitsu, H. Shinokubo, K. Oshima, Ury. Lett. 2000, 2, 1899. [36] 0. Yamazaki. H. Togo, G. Nogami. M. Yokoyama, BUN. Chem. Soc. Jpn. 1997, 70; 2519; 0. Yamazaki, H. Togo, S. Matsubayashi, M. Yokoyama, Tetrahedron 1999, 55, 3735. [37] H. Yorimitsu, T. Nakamura, H. Shinokubo, K. Oshima, J. Ury. Chrm. 1998, 63, 8604; H. Yorimitsu, T. Nakamura, H. Shinokubo, K. Oshima, K. Omoto, H. Fujimoto, J. Am. Cheni. Soc. 2000, 122, 11041. [38] T. Nakamura, H. Yorimitsu, H. Shinokubo, K. Oshima, Synlrtt 1998, 1351. [39] H. Yorimitsu, H. Shinokubo, K. Oshima, Chem. Lett. 2000, 104.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

1.3 Tin, Silicon and Related Reducing Agents Chryssostomos Chatgilialoglu

1.3.1 Introduction The goal of organic synthesis is to achieve chemospecific reactions of predictable regio- and stereochemical outcomes using mild conditions. In this view, the synthetic application of free radical reactions has increased dramatically within the last quarter of the twentieth century. Indeed, synthetic strategies based on radical reactions have become popular among chemists since a wide selection of functional groups can now be used to generate carbon-centered radicals under mild conditions and a new knowledge has increased to such a level as to aid in making the necessary predictions. The purpose of this chapter is to give an overview of the most important radical chain reductions. Emphasis will be given to the different experimental methodologies for carrying out these reactions with high efficiency as well as to the synthetic potentiality of radical reactions. Several books [ 1-31 and a number of reviews [4-101 have described some specific areas in detail.

1.3.2 Reducing Agents 1.3.1.1 General Aspects of Radical Chain Reactions The reduction of a functional group by a Group 14 organometallic hydride (M = Si, Ge, Sn) is shown in Scheme 1 as an example of a chain process. Initially, R'3M' radicals are generated by some initiation process [ 111. A large number of compounds are known to decompose thermally or photolytically to generate free radicals (see Volume 1, Chapter 1.1). Generally, 5-10 mol% of initiator is added either all in one portion or by slow addition over a period of time. The most popular thermal initiator is azobisisobutyronitrile (AIBN), with a half-life of 1 h at 81 "C. Other azo compounds are used from time to time depending on the reaction conditions. Peroxides are used when the reaction requires a more reactive

1.3.2 Reducing Agents

29

initiating species. Dibenzoyl peroxide and di-tert-butyl peroxide, whose half-lives are 1 h at 91 "C and 147 " C respectively, are the most familiar to synthetic chemists. Photochemically generated radicals in chain reactions are less familiar. However, AIBN and various peroxides and ketones have been used in the presence of light to initiate radical chain reactions at room or lower temperatures. In the last few years, new developments involving initiation either by sonication or by reaction of Et3B with molecular oxygen have also been reported, the latter being more appropriate for lower temperatures (see Volume 1, Chapter 1.2). In the propagation steps, a site-specific radical R' is generated from an organic substrate by removal of the Z group. In Scheme 1 the structure [RZMR'3] represents a reactive intermediate or a transition state. The radical R' then reacts with the hydride generating the reduced product and "fresh" R'3M' radicals. The chain reactions are terminated by radical combination or disproportionation.

Initiation steps:

R'BMH

Radical Initiator

~

Propagation steps:

R'3M*

--.

Termination steps: 2 R'3M'

R'

+

R'3M'

no radical products

2R'

Scheme 1. The reaction mechanism for the radical chain removal of a functional group by organometallic hydrides (M = Si, Ge, Sn)

1.3 Tin, Silicon and Reluted Reducing Agents

30

In order to have an efficient chain process, the rate of chain-transfer steps must be higher than that of chain termination steps. The following observations: (i) the termination rate constants in liquid phase are controlled by diffusion (i.e., 10'O M-' s-'), (ii) radical concentrations in chain reactions are about 10-7-10-s M (depending on reaction conditions), and (iii) the concentration of substrates is generally in the range 0.05-0.5 M, indicate that the rate constants for the chain transfer steps must be higher than lo3 M-' s-I. If the propagation steps are fast, adventitious initiators such as traces of molecular oxygen or laboratory light are sufficient to initiate the radical chain.

1.3.2.2 Hydrogen Donor Abilities of the Group 14 Hydrides One of the propagation steps in Scheme 1 is the hydrogen abstraction from the reducing agent by a radical. In a recent review Chatgilialoglu and Newcomb reported on the reaction kinetics of silicon, germanium and tin hydrides with radicals [ 121. In Table 1 the rate constants of primary alkyl radicals with some Group 14 hydrides are reported for direct comparison. The rate constants increase along the series Et&H < Bu3GeH < (TMS)3SiH < Bu3SnH, which are in good agreement H, ,H

ph,Gl Ph

H 'R 1 R=CH3 2R=H

Ge

Ph

H H

3

Table 1. Rate constants for the reaction of primary alkyl radicals with a variety of Group 14 hydrides [ 121 Hydride

Rate constant, M-' s-' (at 80°C unless noted)

Et3SiH Ph3SiH 1 (Me3Si)2Si(H)Me (MeS)3SiH (Me3Si)3SiH 2 BuiGeH PhjGeH 3 (MeSi)iGeH Bu3SnH Ph3SnH (n-C6FI&H*CH2)3SnH

5.2 4.6 4.5 x 1.5 x 3.9 x 1.2 x 2.1 x 3.4 x 3.8 x 1.9 1.9 6.4 x 2.2 x 9.6 x

103 104 ( I I O T ) 104 105 105 106 106 105

lo6 107 (SOT) 107

lo6 107

lo6

1.3.2 Reducing Agents

31

Table 2. Rate constants (M- I s-') for the reaction of some radicals with BujSnH and (TMS)jSiH at ca. 27°C 1121

t-BuO' RCH2' R2CH' RjC' Ph' n-C,F,S' RC(0)'

2.0 x 2.4 x 1.5 x 1.9 x 7.8 x 2.0 x 4.5 x

108 10' 10' 106

lo8 108 105

1.1 x 108 3.8 x lo5 1.4 x 105 2.6 x 105 3 x 108 5.1 x 107 1.8 104

with the thermodynamic data of the Group 14 hydrides. For example, the relative rate constants of primary alkyl radicals with Et,SiH, Bu,GeH, (TMS)3SiH and Bu3SnH are 1:250:1000:6579, whereas the exothermicities of the reactions are 3.1, 9.6. 10.7 and 19.6 kcal/mol, respectively [ 121. Some rate constants for hydrogen abstraction from Bu3SnH and (TMS)&H by a variety of radicals are reported in Table 2. The rate constants decrease along the series Ph' > t-BuO' > RICFZ'> RCH2' > RC(0)'. The rate constants for the reaction of primary, secondary, and tertiary alkyl radicals with both reagents are very similar in the range of temperatures that are useful for chemical transformation in the liquid phase. This is due to the compensation of entropic and enthalpic effects through this series of alkyl radicals. For any particular radical the rate constant for (TMS)3SiH is always lower than that for BqSnH, the difference being smaller at higher regions of the kinetic scale.

1.3.2.3 Basic Concepts of Carbon-Carbon Bond Formation The initially generated carbon-centered radical R' is often designed to undergo a number of consecutive reactions prior to H-atom transfer. Care has to be taken in order to ensure that the effective rate of the consecutive radical reactions is higher than the rate of H-atom transfer. Apart from standard synthetic planning based on known rate constants (see for example Tables 1 and 2), this is usually carried out either by controlling the concentration of the reducing agent (slow addition by syringe-pump) or, in the case of intermolecular addition reactions, by adding a large excess of the radical acceptor. For example, the propagation steps for the intermolecular version are shown in Scheme 2. For a successful outcome, it is important (i) that the R'1M' radical reacts faster with RZ (the precursor of radical R') than with the alkene and (ii) that the alkyl radical reacts faster with the alkene (to form the adduct radical) than with the hydride. In other words, for a synthetically useful radical chain reaction, the intermediates must be disciplined. Therefore, in a synthetic plan one is faced with the task of considering kinetic data or substituent influence on the selectivity of radicals. The reader should note that the hydrogen donation step controls the radical

32

1.3 Tin, Silicon and Reluted Reducing Agents

R'

R'3M'

Scheme 2. Propagation steps for intermolecular carbon-carbon bond formation

sequence and that the concentration of hydride often serves as the variable by which the product distribution can be influenced.

1.3.3 Tin Hydrides Tributyltin hydride is the most popular reagent in preparative free radical chemistry. The majority of the published work deals with the use of stoichiometric quantities, although alternative approaches such as catalytic or polymer-supported procedures have been developed. Occasionally other substituted organotin hydrides have been used, Ph3SnH being the most representative.

1.3.3.1 Stoichiometric Reactions of Tributyltin Hydride The reductive removal of bromine and iodine atoms by B q S n H is straightforward. Generally, an equimolar amount or a slight excess of reducing agent is employed. A variety of solvents can be used although aromatic solvents such as benzene or toluene are the most common. The reactions are complete after a short time. Two examples are given in Eqs. ( 1 ) and (2) [16, 171. The reductive removal of chlorine atoms by Bu3SnH depends strongly on their position. Under normal conditions, the reduction of alkyl chlorides is very slow, whereas aryl or vinyl chlorides are not reduced. On the other hand, replacement of a chlorine atom by hydrogen in activated chlorides (in a-position to a carbonyl moiety) or in polychlorinated substrates is much easier. An example is shown in Eq. (3) in which the two chlorine atoms on the ring are removed, whereas the tertiary chloride resists under the same condition [18]. The method has also been successfully applied to the synthesis of deuteriumand tritium-labeled compounds by using Bu3SnD or Bu3SnT [19].

1.3.3 Tin Hydrides

33

Bu3SnH 95% EtOH

2 h, r.t.

HO

98% BrH

J,,

i,

h-AJ :\

0

PhH, 80 "C

COOBn

95%

Qcl

I

y,

Bu3SnH (2 equiv)

* AIBN, reflux PhH, 12h

\

99:l (2'R):(2'S)> 99:l

Bu3SnH reacts spontaneously at ambient temperature with acid chlorides in a non-radical process, whereas (TMS)3SiH does not. Therefore, acid chlorides can be used under free-radical conditions only with the silane.

1.3.6 Related Reducing Agents

45

The denitration of tertiary nitroalkanes by Bu3SnH is an efficient process [27]. (TMS)3SiH is not able to reduce tertiary nitroalkanes to the corresponding hydrocarbons [77]. This behavior is due to the fact that the nitroxide adducts fragment preferentially at the nitrogen-oxygen bond rather than at the carbon-nitrogen bond. Isocyanides can be reduced to the corresponding hydrocarbon by both reducing agents. The efficiency of the reduction with (TMS)3SiH is independent of the nature of the alkyl substituent and with Bu3SnH is dependent on the temperature, i.e. the yields are good in boiling toluene or benzene for secondary and tertiary isocyanides, whereas primary isocyanides can be reduced in acceptable yields only in refluxing xylene [26, 541. Thioacetals, selenoacetals and their analogs have been studied in some detail [S], and an example of reverse product stereoselectivities of the two reducing agents is shown in Eq. (38) [78]. The silicon hydride approaches from the less hindered equatorial position to give trans/cis ratios of 30/70, whereas Bu3 SnH transfers a hydrogen atom preferentially from the axial position.

t-BUA

S

se--) e

PhH,80"C* AlBN

dsea SeMRN3

t-Bu

translcis Bu3SnH (TMS)$iH

61I39 30170

1.3.6 Related Reducing Agents The rate constants for the reaction of primary alkyl radicals with a variety of germanium hydrides have recently been reported [79]. Bu3GeH reacts 2-3 times slower than (TMS)3SiH and about 20 times slower than BqSnH, whereas (TMS)3GeH is about 3 times faster than Bu3SnH at 80°C (cf. Table 1). On the other hand, the Bu3Ge' radicals have similar reactivities to the corresponding silyl and stannyl radicals. The applications of germanium hydrides in organic synthesis are very few, probably because of their elevated costs. However, (TMS)3GeH is an effective reducing agent for chlorides, bromides, iodides, phenyl selenides, thionoesters, isonitriles and tertiary nitroalkanes [80]. Roberts and coworkers reported that the low reactivity of alkyl- and/or phenylsubstituted organosilanes in the reduction processes can be ameliorated in the presence of a catalytic amount of alkanethiols [81]. The reaction mechanism is reported in Scheme 4 and shows that alkyl radicals abstract hydrogen from thiols and the resulting thiyl radical abstracts hydrogen from the silane. This procedure, termed polarity-reversal catalysis, has been applied in dehalogenation, deoxygenation and desulfurization reactions [82]. Crich and coworkers extended this concept to the

46

1.3 Tin, Silicon und Reluted Reducing Agents

+ XSH

R* XS.

+

Et3SiH

+

Et3Si*

RZ

-

+

RH

+

XSH

-

XS*

Et3SiZ

Et3Si*

+

R.

Scheme 4. Propagation steps for polarity-reversal catalysis

BusSnH/PhSeH system 1831. It was found that undesired radical rearrangements, which are sufficiently rapid to proceed in the presence of the tin hydride alone, can be suppressed in the presence of PhSeH. The facts that thiols are good H-atom donors toward alkyl radicals and that silyl radicals are among the most reactive known species for abstraction and addition reactions suggest that any class of compounds which allows the transformation of a thiyl to a silyl radical via a fast intramolecular rearrangement will potentially be a good radical-based reducing agent. The silanethiols 11 and 12 are found to have this property [84, 851. The reductions of bromides, iodides and isocyanides by thiol 12 are demonstrated to follow the expected mechanism [ 8 5 ] .

31"

Me3Si-Si-SiMe3

s,

SiMe3 Me3Si-Si-SiMe3 s\H

H

11

12

Thiols have successfully replaced Bu&H as reducing agents for the decarboxylation of acid via the acyl derivatives of N-hydroxy-2-thiopyridone(cf. Eq. 9) 1291. Barton and coworkers have introduced the use of dialkyl phosphites as reducing agents [86, 871. Dimethyl phosphite was found to reduce bromides, iodides, thionoesters and isocyanides (in good yield) in refluxing dioxane as the solvent and in the presence of large amounts of benzoyl peroxide as the radical initiator. Interestingly, the reaction cannot be initiated by AIBN in refluxing benzene (or toluene), i.e., under typical free radical chain conditions. The reaction carried out with other substituted phosphites was found to be more sluggish. These trends are typical of poor radical chain reactions (Scheme 5 ) . In fact, the (Et0)2P(O)' radical was found to be 3-4 orders of magnitude less reactive than the Et& radical toward halides 1881, whereas the rate constant for hydrogen abstraction from (Et0)2P(O)His com-

R"

+

(RO)zP(O)H

k2 t

R'H

+

(RO)zP(O)

Scheme 5. Propagation steps for dialkyl phosphites as reducing agents

References

47

parable to donation from phenyl-substituted silanes [68]. For example, values of kl = 1.0 x lo4 M-I s-’ at 25°C for n-BuBr and kz = 1.2 x lo5 M-’ SKI at 130°C for primary alkyl radicals have been reported. To overcome the scarce hydrogen donor abilities of phosphites, Barton and coworkers used benzoyl peroxide as initiator to generate phosphinoyl radicals and, more importantly, dioxane, which acts as the hydrogen donor. In fact, the reaction with thioesters proceeded in dioxane in moderate yield even without dimethyl phosphite. Radical deoxygenation of alcohols by reaction of the corresponding S-methyl dithiocarbonates with BuzP(0)H or Ph2P(O)H using various radical initiators in refluxing dioxane have also been reported [ 891. Barton and coworkers specifically introduced H3P02 or its organic salts as radicalbased reducing agents for bromides, iodides, thionoesters and isocyanides [ 87, 901. The neutralization of the acidity of hypophosphorous acid by tertiary nitrogen bases was recommended prior to the AIBN initiation of the radical reactions in dioxane. In comparison to dialkyl phosphites, the chain reactions should be somehow more efficient. Although no rate constant data is available for the two propagation steps, the fact that AIBN is able to initiate the reaction suggests that the hydrogen donation step is faster than in Scheme 5.

References [ I ] B. Giese, Radicals in Organic Synthesis: Formation oJ Carbon-Carbon Bonds, Pergamon, Oxford, 1986. [2] W. B. Motherwell, D. Crich, Free Radicul Chain Reactions in Organic Synthesis, Academic, London, 1992. [3] D. P. Curran, N. A. Porter, B. Giese, Stereochemistry cf Radical Reactions, VCH, Weinheim, 1995. [4] D. P. Curran, in Comprehensive Organic Sjdzesis, Vol. 4 , (Eds.: B. M. Trost, 1. Fleming), Pergamon, Oxford, 1991, pp 715-831. [5] W. P. Neumann, Synthesis 1987, 665. [6] D. P. Curran, Synthesis 1988, 417-439 and 489-513. [7] C. Chatgilialoglu, Acc. Chcm. Res. 1992, 25, 188. [8] C. Chatgilialoglu, C. Ferreri, T. Gimisis, Tris(trimethylsilyl).silan~~ in organic synthesis, in The Chemistry of Organic Silicon Compounds (Eds.: Z. Rappoport, Y. Apeloig), Vol. 2, Wiley, Chichester, 1997, Chap. 25, pp 1539-1579. 191 P. A. Baguley, J. C. Walton, Angcw. Chem. Int. Ed. 1998, 37, 3072. [lo] C. Chatgilialoglu, D. Crich, M. Komatsu, 1. Ryu, Chem. Ret.. 1999, 99, 1991. [ 111 C. Walling, Tetruliedron 1985, 41, 3887. [ 121 C. Chatgilialoglu, M. Newcomb, Adr. Orgunomet. Chem. 1999, 44, 67. [I61 P. G. M. Wuts, R. D’costa, W. Butler, J. Org. Chrm. 1984, 49, 2582. [I71 J. A. Aimetti, E. S. Hamanaka, D. A. Johnson, K. S. Kellogg, Tetruhedron Lett. 1979, 4631. [ 181 S. Takano. S. Nishizawa, M. Akiyama, K . Ogasaware, Synthesis 1984, 949. [ 191 For example, see: (a) K. E. Coblens, V. B. Muralidharan, B. Ganem, J. Org. Chenz. 1982, 47, 5041. (b) H. Parnes, J. Pease, J. Org. C/zem. 1979, 44, 151. [20] J. D. Buynak, M. N. Rao, H. Pajouhesh, R. Y. Chandrasekaran, K. Finn, P. de Meester, S. C. Chu, J. Org. Chem. 1985, 50, 4245. [21] K. C. Nicolaou, R. L. Magolda, W. J. Sipio, W. E. Barnette, Z. Lysenko, M. M. Joullie, J. An?. Chem. Soc. 1980, 102, 3784.

48

1.3 Tin, Silicon and Related Reducing Agents

[22] D. H. R. Barton, S. W. McCombie, J. Chem. Soc., Perkin Trans I 1975, 1574. [23] For reviews, see: D. H. R. Barton, W. B. Motherwell, Pure Appl. Chem. 1981, 53, 15. W. Hartwig, Tetrahedron 1983,39,2609. D. M. Huryn, M. Okabe, Chem. Rev. 1992,92, 1745. [24] M. J. Robins, J. S. Wilson, F. Hansske, J. Am. Chem. Soc. 1983, 105, 4059. [25] M. Oba, K. Nishiyama, Tetrahedron 1994, 59, 10193. [26] D. H. R. Barton, G. Bringmann, G. Lamotte, W. B. Motherwell, R. S. Hay Motherwell, A. E. A. Porter, J. Chem. Soc., Perkin Trans. I 1980, 2657. [27] N . Ono, A. Kaji, Synthesis 1986, 693. [28] D. Seebach, P. Knochel, Helu. Chim. Acta 1984, 67, 261. [29] D. H. R. Barton, D. Crich, W. B. Motherwell, Tetrahedron 1985, 41, 3901. (301 Representative references: (a) J. M. Merge, S. M. Roberts, Synthesis 1979, 471. (b) D. P. Curran, C.-T. Chang, J. Org. Chem. 1989, 54, 3140. (c) D. Crich, S. X. Sun, J. Org. Chem. 1996, 61, 7200. (d) P. R. Renaud, E. Lacbte, L. Quaranta, Tetrahedron Lett. 1998, 39, 2123. [31] K. Hayashi, J. Iyoda, I. Shiihara, J. Organometal. Chem. 1967, 10, 81. [32] G. L. Grady, H. G. Kuivila, J. Org. Chem. 1969, 34, 2014. [33] For a recent review, see: N. J . Lawrence, M. D. Drew, S. M. Breshell, J. Chem. Soc., Perkin Trans. I 1999, 3381. 1341 E. J. Corey, J. W. Suggs, J. Org. Chem. 1975, 40, 2554. [35] B. Giese, J. A. Gonzilez-Gomez, T. Witzel, Angew. Chem. Int. Ed. Engl. 1984, 23, 69. [36] G. Stork, P.M. Sher. J. Am. Chem. Soc. 1986, 108, 303. [37] I. Terstiege, R. E. Maleczka Jr., J. Org. Chern. 1999, 64, 342. [38] R. M. Lopez, D. S. Hays, G. C. Fu, J. Am. Chem. Soc. 1997, 119, 6949. [39] J. Tormo, D. S. Hays, G. C. Fu, J. Ory Chem. 1998, 63, 5296. [40] D. S. Hays, G. C. Fu, J. Org. Chem. 1998,63, 2796. [41] U. Gerigk, M. Gerlach, W.P. Neumann, R. Viele, V. Weintritt, Synthesis 1990, 448. [42] A. Chemin, H. Deleuze, B. Maillard, Eur. Polym. J. 1998, 34, 1395; A. Chemin, H. Deleuze, B. Maillard, J. Chem. Soc. Perkin Trans I 1999, 137. [43] G. Ruel, N. K. The, G. Dumartin, B. Delmond, M. Pereyre, J. Organomet. Chem. 1993, 444, CIS; G. Dumartin, G. Ruel, J. Kharboutli, B. Delmond, M.-F. Connil, B. Jousseaume, M. Pereyre, Synlett 1994, 952. [44] M. Gerlach, F. Jordens, H. Kuhn, W. P. Neumann, M. Peterseim, J. Org. Chem. 1991, 56, 5971. [45] C. Bokelmann, W. P. Neumann, M. Peterseim, J. Chem. Soc. Perkin Trans I 1992, 3165. [46] G. Dumartin, M. Pourcel, B. Delmond, 0. Donard, M. Pereyre, Tetrahedron Lett. 1998, 39, 4663. [47] D. P. Curran, S. Hadida, S.-Y. Kim, Z. Luo, J. Am. Chem. Soc. 1999, 121, 6607. D. P. Curran, S. Hadida, J. Am. Chem. Soc. 1996, 118, 2531. [48] J. Light, R. Breslow, Tetrahedron Left. 1990, 31, 2957. J. Light, R. Breslow, Org. Synth. 1993, 72, 199. [49] R. Rai, D. B. Collum, Tetrahedron Lett 1994, 35, 6221. [50] U. Maitra, K. D. Sarma, Tetrahedron Lett. 1994, 35, 7861. [51] J. A. Robl, Tetrahedron Lett. 1994, 35, 393-396. [52] C. Chatgilialoglu, T. Gimisis, Chem. Commun. 1998, 1249. [53] T. Gimisis, G. Ialongo, M. Zamboni, C. Chatgilialoglu, Tetrahedron Let/. 1995, 36, 6781. [54] M. Ballestri, C. Chatgilialoglu, K. B. Clark, D. Griller, B. Giese, B. Kopping, J. Org. Chem. 1991, 56, 678. [55] M. Ballestri, C. Chatgilialoglu, N. Cardi, A. Sommazzi, Tetrahedron Lett. 1992, 33, 1787. [56] B. Alcaide, A. Rodriguez-Vicente, M. A. Sierra, Tetrahedron Lett. 1998, 39, 163. [57] L. A. Paquette, D. Friedrich, E. Pinard, J. P. Williams, D. St. Laurent, B. A. Roden, J. Am. Chem. Soc. 1993, 115,4377. [58] C. Chatgilialoglu, T. Gimisis, G. P. Spada, Chern. Eur. J. 1999, 5, 2866. [59] D. Schummer, G. Hofle, Synlett 1990, 705. [60] M. Lesage, C. Chatgilialoglu, D. Griller, Tetrahedron Lett. 1989, 30, 2733. [61] D. H. R. Barton, D. 0. Jang, J. Cs. Jaszberenyi, Tetrahedron Left. 1991, 32, 7187. [62] C. Chatgilialoglu, C. Ferreri, M. Lucarini, J. Org. Chem. 1993, 58, 249. [63] C. Chatgilialoglu, C. Ferreri, Res. Chem. Zntermed. 1993, 19, 755.

References

49

[64] Bouquet, C. Loustau Cazalet, Y. Chapleur, S. Samreth, F. Bellamy, Tetrahedron Lett. 1992, 33, 1997. [65] C. Chatgilialoglu, A. Guerrini, M. Lucarini, J. Org. Chem. 1992, 57, 3405. 1661 C. Chatgilialoglu, M. Guerra, A. Guerrini, G. Seconi, K. B. Clark, D. Griller, J. KanabusKaminska, J. A. Martinho-Simoes, J. Org. Chem. 1992, 57, 2427. [67] T. Gimisis, M. Ballestri, C. Ferreri, C. Chatgilialoglu, R. Boukherroub, G. Manuel, Tetrahedron Lett. 1995, 36, 3897. [68] C. Chatgilialoglu, V. I. Timokhin, M. Ballestri, J. Org. Chem. 1998, 63, 1327. 1691 M. Oba, and K. Nishiyama, Chem. Commun. 1994, 1703. M. Oba, Y. Kawahara, R. Yamada, H. Mizuta, K. Nishiyama, J. Chem. Sac., Perkin Trans. 2 1996, 1843. [70] C. Chatgilialoglu, C. Ferreri, D. Vecchi, M. Lucarini, G. F. Pedulli, J. Organomet. Chem. 1997, 5451546,455. [71] 0. Yamazaki, H. Togo, S. Matsubayashi, M. Yokoyama, Tetrahedron Lett. 1998, 39, 1921. 0. Yamazaki, H . Togo, M. Yokoyama, J. Chem. Soc., Perkin Trans. 11999, 2891. [72] C. Chatgilialoglu, Chem. Rev. 1995, 95, 1229. [73] C. Chatgilialoglu, D. Griller, M. Lesage, J. Org. Chem. 1989, 54, 2492. [74] Y . Apeloig, and M. Nakash, J. Am. Chem. Soc. 1994, 116, 10781. [75] E. Lee, C. M. Park and J. S. Yun, J. Am. Chenz. Soc. 1995, 117, 8017. [76] E. Kawashima, S. Uchida, M. Miyahara, Y. Ishido, Tetrahedron Lett. 1997, 38, 7369. [77] M. Ballestri, C. Chatgilialoglu, M. Lucarini, G. F. Pedulli J. Org. Chem. 1992, 57, 948. [78] A. Krief, E. Badaoui, W. Dumont, Tetrahedron Lett. 1993, 34, 8517. [ 791 C. Chatgilialoglu, M. Ballestri, J. Escudie, I. Paihous, Organometallics 1999, 18, 2395. [SO] C. Chatgilialoglu, M. Ballestri, Organometallics 1995, 14, 5017. [Sl] B. P. Roberts, Chem. Soc. Rev. 1999, 28, 25. [82] S. J. Cole, J. N. Kirwan, B. P. Roberts, C. R. Willis, J. Chem. Soc., Perkin Trans. 1 1991, 103. [83] D. Crich, X.-S. Mo, J. Ovg. Chem. 1997, 62, 8624. D. Crich, J.-T. Hwang, J . Org. Chem. 1998, 63, 2765. [84] J. Daroszewski, J. Lusztyk, M. Degueil, C. Navarro, B. Maillard, J. C/7em Soc., Chem. Commun. 1991, 587. [85] M. Ballestri, C. Chatgilialoglu, G. Seconi, J. Organomet. Chem. 1991, 408, C1. [86] D. H. R. Barton, D. 0. Jang, J. Cs. Jaszberenyi, Tetrahedron Lett. 1992, 33, 231 1. [87] D. H. R. Barton, D. 0. Jang, J. Cs. Jaszberenyi, J. Org. Chem. 1993, 58, 6838. [SS] M. Anpo, R. Sutcliffe, K. U. Ingold, J. Am. Chem. Soc. 1983, 105, 3580. [89] D. 0. Jang. D. H. Cho, D. H. R. Barton, Synlett 1998, 39. D. 0. Jang, D. H. Cho, J. Kim, Synth. Commun. 1998, 28, 3559. 1901 D. H. R. Barton, D. 0. Jang, J. Cs. Jaszberenyi, Tetrahedron Lett. 1992, 33, 5709.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

1.4 Radical Fragmentation Reactions Iun J. Rosenstein

1.4.1 Introduction In 1972, Lewis and Winstein reported that the reaction of a,&-dimethylallyl phenyl sulfide (1) with thiophenol in the presence of tert-butyl hydroperoxide gave the isomeric compound y,y-dimethylallyl phenyl sulfide (3) (Scheme 1) [ I ] . It was proposed that this reaction occurred by addition of thiophenoxy radical to the terminal end of the alkene to produce radical intermediate 2. This radical then underwent p-scission with loss of the tertiary thiophenoxy group to form the rearranged alkene 3. This example represents the earliest report of a radical fragmentation reaction, a reaction that is now commonly used in organic synthesis for the allylation or vinylation of carbon-centered radicals [2]. These radical chain processes proceed by the addition of a radical to a suitably substituted ally1 or vinyl derivative (Scheme 2). The reactions rely on the facile, unimolecular B-scission of the relatively weak C-Z bond in radical intermediate A or B to form radical Z' and the allylated or vinylated product. Radical Z' may be the chain-carrying radical or it may undergo further reaction to generate a chain-carrying radical. There is a great deal of variety possible in the nature of the group Z. The pioneering, systematic mechanistic studies on this type of reaction utilized trialkyltin groups [3]. The earliest, and still most widely used, synthetic applications also involve the use of allyltins. Other Z groups have included sulfides, sulfoxides, sulfones, silanes, cobaloximes and halides. The reactions also occur with a wide variety of carbon-based radicals, from simple alkyl radicals to acyl radicals, and have been carried out in both inter- and intramolecular fashions [4]. There are three main advantages to constructing carbon-carbon bonds using radical fragmentation reactions, as opposed to standard tin hydride-based methodologies. First, once the initial radical adduct is formed, it undergoes very rapid. unimolecular decomposition to the desired product. Its lifetime is generally too short to undergo competing processes, as is often observed in tin hydride-mediated reactions. Second, in tin hydride reactions, products are formed in a reductive process, necessarily resulting in a loss of usable functionality. Third, under non-reductive conditions, radicals incapable of fragmentation have relatively long lifetimes and thus present greater opportunity for intramolecular cyclization or intermolecular

1.4.2 Tin-Based Reagents %SPh

51

(CH3)3COOH PhSH, A

1

3 /PhS*

PhS\

/

Phs*ph 2

Scheme 1

B

Scheme 2

addition. Radical fragmentation processes give products containing alkenes, which are easily manipulated to form a variety of other functional groups.

1.4.2 Tin-Based Reagents 1.4.2.1 Allylations via Allyltributyltin Allyltributyltin (5) is the most commonly used reagent for carrying out allylation reactions via a free radical fragmentation process [ 5 ] .Keck reported the first practical use of allyltributyltin for free radical allylation reactions in 1982 in the context of a synthesis of perhydrohistrionicotoxin [6]. Heating bromide 4 with allyltributyltin in the presence of AIBN as a radical initiator gave the allylated derivative 6 (Scheme 3 ) in high yield with complete control of stereochemistry. Similar transformations had proven to be very difficult by standard ionic reactions. Further investigation by Keck of the scope of allylation reactions with allyltributyltin revealed that the reaction could be carried out with numerous different types of radicals, for example simple alkyl radicals, aryl radicals and radicals x lo the oxygen atoms of ethers and esters [7]. These radicals were generated from several types of free radical precursors, such as bromides, iodides, phenylselenides,

52

1.4 Radical Fragmentation Reactions

p: S ,n -B ,u -3,

/

N-0

0

5 AIBN, A 88 %

4

6

Scheme 3

THPO-Br 7

10

OBr 8

u' 9

11

Figure 1.

xanthates, thioacylimidazoles and, in some cases, thiophenyl groups, using thermal or photochemical initiation. Also, a wide variety of functional groups, including alcohols, ethers, silyl ethers, epoxides, acetals, esters and lactones, were found to be compatible with the reaction conditions. A selection of substrates used by Keck is shown in Fig. 1. Several recent examples serve to illustrate the potential of allyltributyltin for organic synthesis (Scheme 4). Baldwin and Easton have independently shown that glycine derivatives undergo efficient allylation reactions, providing an avenue for the preparation of non-natural amino acids [8]. Subsequently, addition of glycinederived radicals to allyltributyltin was shown by Hamon to occur with stereoselectivity if the radical bears an ester chiral auxiliary [9].An alternative method for the preparation of amino acid derivatives via allylation of carbamoyloxy radicals that are incorporated into an oxazolidin-2-one ring system was reported by Kano [lo]. As part of a program directed at the synthesis of lycoctonine alkaloids, Kraus showed that bridgehead radicals undergo addition to allyltributyltin [ 1 11. Bertozzi used radical allylation to form p-C-glycosides of N-acetylglucosamine, using a phthalimide group as both an N-protecting group and as a bulky group to help direct the stereochemistry of the addition [ 121. In addition to the examples mentioned above, many others have used addition to allyltributyltin as a method for assessing the stereoselectivity of radical addition reactions (Scheme 5) [13]. Beckwith and Renaud have both demonstrated stereo-

1.4.2 Tin-Based Reagents

PhCoNHY C02CH3 Br

4---.4SnBu3 AIBN, A 63 Yo

.

L

13

14

15

16

N

Ref. 8c

0

0

Boc,

53

O

YSph

PhCHi

4---.4SnBu3

BOC, *

(Bu3Sn)*,hv, 20 "C 81 %yield

A N O

Ref. 10

PhCH:\

>99 % de 17

18

0

U

ti3.-.,

19

Ref. 11

20

.OAc

OAc AcO A c

O

d

k

Ref. 12

1O:l pa

21

22

Scheme 4

selective allylations of a-sulfinyl radicals [14, 151, while Hart and Guindon have done extensive studies of the stereoselective allylation reactions of a-carbalkoxy radicals [16, 171. The use of chiral auxiliaries for control of diastereoselectivity in allylation with allyltributyltin has been reported by Curran, Porter and Sibi, among others [ 18-20]. Porter has extended this methodology to demonstrate enantioselective allylations using chiral Lewis acid catalysts [21]. Curran and Giese provided an estimate for the rate constant for the addition of simple alkyl radicals to allyltributyltin [22]. Through several different competitive kinetic experiments, the rate of addition was found to be approximately lo4-

54

1.4 Radical Fragmentation Reactions

?-

3uBnS,-,

/

61 15 d y c l AIBN, 81 CF3

/

hv,yield "C

Oh

24:25

- +

J(S+CF3

a''-

Ref. 15a

CF3

/

:19

25

24

23

hq

OBn

@../SnBu3

LCoZC Ref. 17a -e

C02CH3

I

Ph

EtsB,0 2 , -78 "C 87 % yield 27:28 22:l

26

27

0

~

28

0

O ' N h

u

Br

CHPh2 29

30:31 >-100:1

30

31

Scheme 5

lo5 M-' s-', which is one to two orders of magnitude faster than the rate of addition of a simple alkyl radical to an unactivated alkene. The fact that the rate of addition to allyltin is faster than addition to a simple alkene is important since the allylation products themselves are simple alkenes. Allyltributyltin is a relatively electron-rich alkene and would be expected to react with electron-poor radicals at much higher rates than it reacts with simple, electron-rich alkyl radicals [23]. This has been shown to be the case qualitatively in many instances; however, detailed rate studies to confirm this point have not been reported. The differential reactivity of allyltributyltin towards electron-rich versus electronpoor radicals means that it is possible to carry out reaction sequences in which multiple carbon-carbon bonds are formed in a single transformation. The first example of such a sequence was reported by Mizuno and Otsuji [24]. They showed that reaction of alkyl iodides with electron-deficient alkenes such as 1,l-dicyano-2phenylethene 33 and allyltributyltin gives good yields of three-component coupling products 34 (Scheme 6). In this process, an electron-rich alkyl radical 35 generated either by photolysis or by AIBN-mediated initiation undergoes selective addition to the electron-deficient alkene. Addition to the alkene occurs selectively since this process is much faster than addition of the alkyl radical to allyltributyltin. However, the resulting adduct radical 36 is now electron deficient, so it adds to allyltributyltin at a rate faster than its addition to the electron-deficient alkene, resulting in overall addition of an alkyl group and an allyl group across the double bond of the alkene. Curran and Sibi have both shown that this process can be carried out

1.4.2 Tin-Bused Reagents

CH31

"wCN +

e S n B u 3

+

CN

32

AIBN, A a5 Yo

5

33

55

34 Ph I

35

33

36

&

Ph

CH3

36

5

NC

CN

34

Scheme 6

with excellent control of diastereoselectivity using chiral auxiliary-substituted acrylamides as the electron deficient olefin [25, 261. Ryu and Sonoda have extended this strategy to free radical carbonylation reactions [27]. Under low pressures of carbon monoxide an alkyl halide, such as iodooctane (37) reacts with allyltributyltin to form a ,!l,y-unsaturated ketone. The initially formed alkyl radical undergoes addition to carbon monoxide to form an acyl radical. This acyl radical then adds to allyltributyltin to form the final product (Scheme 7). It is interesting to note that the slow rate of addition of an alkyl radical to allyltributyltin allows this reaction to be carried out with much lower carbon monoxide pressures than are necessary with analogous reactions using tin hydrides as radical mediators. Ryu and Sonoda have also taken this reaction one step further, successfully intercepting the acyl radical with an electron-deficient alkene before addition to allyltributyltin [28]. In these reactions, three carbon-carbon bonds are formed and the products are ,!l-functionalized, &,&-unsaturatedketones.

37

Scheme 7

5

38

56

1.4 Radical Fragmentation Reactions

1.4.2.2 Modified Allyltributyltin Reagents A wide variety of derivatives of allyltributyltin have been prepared and used for free radical allylation reactions. The successful reagents differ from the parent allyltributyltin either by having a group substituted at the 2-position of the allyl system or by replacement of one or more of the butyl substituents on the tin. Simple substitution of the tributyl groups for trimethyl or triphenyl groups are fairly commonplace. There do not seem to be great differences in reactivity toward radical addition between allyltins bearing different alkyl groups. The choice of which alkyl group to use depends largely on synthetic availability. Safety is also a concern as allyltrimethyltin derivatives have much higher vapor pressures than their heavier counterparts. In his initial studies of the scope of free radical allylation of carbon-centered radicals, Keck investigated the use of allyltributyltin reagents with a methyl group substituted at either the 2-position or the 3-position of the alkene [7b]. He found that when a methyl group is substituted at the 2-position, that is with methallyltributyltin (42), methallylation reactions proceeded smoothly with yields approaching or exceeding those of the parent allyltributyltin. No adducts were formed, however, when the 3-methylated compound 45 was used [7b, 291. Instead, the products of reduction of the alkyl radical were isolated (Scheme 8). Keck presumed that this was due to hydrogen abstraction by the alkyl radical from the allylic methyl group. This process competes with addition, since the rate of addition is retarded by the steric effect of the methyl group. He was able to trap out butadiene, the expected byproduct of this reaction, to support his conclusion. While allylation reactions are unsuccessful for most 3-substituted allylstannanes, the reaction with certain radicals has given the desired allylation products [3b, 8c]. Baldwin experimented with substitution at the 1-position [30]. He found that both 1,l -dialkyl- and 1-alkoxy-substituted allyltributyltin reagents 47 and 48 underwent rearrangement when heated with AIBN to form the more stable 3-substituted compound (Scheme 9). Baldwin also reported in this study several examples of allyltrialkyltins with substitution at the 2-position (Fig. 2). Substitution at the 2-

oBr +

AIBN, A

A S n B u 3 42

41

+ *SnBua Ph r B 44

Scheme 8

43

(t-BUO)*, 140 "C 78 Yo

Ph

O

72 %

r

P

OQC"3+ Ph Ph

45

46

1.4.2 Tin-Bused Reagents a S n B u 3 X Y

AlBN 110°C

47 X = Y = C H 3 48 X = H, Y = OCH20CH3

57

Y 49 X = Y = C H 3 50 X = H, Y = OCH20CH3

Scheme 9

C02Et &SnBu3 51

CONH'BU &SnBu3 52

OAc &SnBu3

CN &SnBu3

53

54

Figure 2.

position with either an ethyl ester group or a tert-butylamide gave allyltin reagents 51 and 52, which successfully allylated alkyl radicals while 2-acetoxy compound 53 did not. Compounds 51 and 52 are excellent substrates for allylation of simple alkyl radicals since their electron-withdrawing groups should increase the rate of addition. The failure of the 2-acetoxy compound to react properly with alkyl radicals reflects the electron-donating nature of the substituent. In a later paper, Baldwin also reported the synthesis and successful use of 2-cyano compound 54 [Sd]. Several allyltin reagents have been synthesized bearing heteroatoms at C-2. Baldwin showed that 2-chloroallyltributyltin reacts with a glycine-derived radical to form allylation products with moderate yields [8d]. Lee synthesized (2-trimethylsilylallyl)triphenyltin and showed that, at least in one example, it reacts with alkyl radicals at higher rates and with better yields compared to the parent allyltriphenyltin [31]. Renaud carried out a more extensive study of this effect [32]. His studies confirmed that (2-trimethylsilylallyl)tributyltin (56) reacts faster with carbon-centered radicals than the parent compound, allyltributyltin (5), and that the effect occurs for electronrich and electron-poor radicals. Renaud proposed that the rate enhancement is due to stabilization by the silicon of partial charges, which develop in the transition states of the addition reactions. The relative reactivity of the 2-trimethylsilyl derivative 56 and methallyltributyltin (42) was also compared. The silylated compound reacted faster with electron-rich radicals but more slowly with electron-poor radicals. These results are also explained by electronic effects. Renaud was able to demonstrate that the radical adducts such as 57 resulting from addition to the 2-trimethylsilyl compound could be protodesilylated or converted into hydroxymethylketones in good yields (Scheme 10). Finally, Curran prepared the 2trimethylstannyl-substituted reagent 61 and showed that it reacts well with a variety of carbon-centered radicals (Scheme 11) [33]. The vinyl stannane products of these reactions also have ready functionalization for further manipulation. A reagent closely related to the 2-trimethylsilyl derivative discussed above is the 2-(trimethylsily1)methyl compound 64 utilized by Clive (Scheme 12) [34]. This

58

1.4 Radical Fragmentation Reactions

R-CI

-k

7 AlBN R

& sSiMe3 n~u3

J

~

~

63 /o' 55

56

57 77%

R = PhS02CH2

59

Scheme 10

05'. '

60

%Me3 &SnMe3

AlBN hv 72 %

61

62

Scheme 11

SiMe3

@ -@ dBr &.SnBu3

64 86 hv%

63

Bu~NF 74 %

/

65

"H

/

66

Scheme 12

compound reacts very efficiently with electrophilic radicals but not as well with more electron-rich radicals. This effect can again be explained on the basis of the polar nature of the transition states. With one of the radical adducts, Clive was able to demonstrate that the allylic trimethylsilyl group could be converted to an anion for subsequent reaction. One of the major drawbacks of carrying out allylation reactions with allyltributyltin is that the tin by-products of the reactions are often difficult to remove. Many methodologies have been reported for removing the tin by-products, but these are not always convenient or satisfactory 1351. Several groups have made modifications in the trialkyl group of allyltrialkylstannanes in an effort to develop reagents with by-products that can be removed by simple experimental procedures. One general approach is to use a highly polar group in place of the non-polar butyl groups. For example, Fouquet synthesized a series of allylstannanes (67) with varying substituents at the 2-position bearing the ally1 group as the only alkyl group

1.4.2 Tin-Based Reagents

67

59

E = H, CI, Ph, CN, C02Et X = CI, Br, I

Figure 3.

on the tin (Fig. 3) [36]. Two of these were shown to undergo reaction with carboncentered radicals in good yields. In this case, the tin by-products were separable by flash chromatography. Similarly, Maillard reported that reagents 68 and 69 containing a polar polyether chain in place of one of the butyl groups of allyltributyltin also give good yields of radical adducts with by-products that can be separated chromatographically [ 371. A related approach has been reported by Curran, who devised allyltin reagents containing highly fluorinated trialkyl groups [38]. Reactions of these fluorinated reagents are comparable to those of the parent allylstannanes and the by-products can be removed by extraction into fluorous solvents. Most recently, Enholm reported the synthesis of a polymer-supported allyltin reagent which gives by-products that are insoluble in cold methanol [39]. One final interesting variation on allyltributyltin is the pentadienyltributyltin compound 70. Kraus was the first to investigate free radical addition reactions with this substrate and found that the reaction of bromide 19 with compound 70 gave the pentadienyl substituted adduct 71 in moderate yield (Scheme 13) [ 1 I].

SnBu3

'

&Br

19

AlBN 48 yo

70

71

Scheme 13

1.4.2.3 Cyclizations onto Allylstannanes Intramolecular reactions involving cyclization onto an allylstannane work in much the same fashion as their intermolecular counterparts. For example, Keck carried out the cyclization of compound 72 as a late step in the synthesis of the pyrrolizidine alkaloid skeleton, although the yield was not particularly good (Scheme 14) [40]. In an interesting variation, Danishefsky carried out the cyclization of compound 74 substituted with an acetoxy group on the same carbon as the tributyltin group [41]. This compound cyclized to give an enol acetate (75), which was further

60

1.4 Radical Fragmentation Reactions

72

73

cH30q p CH30

Bu3SnH

YSePhAlBN 65 %

AcO

*

c H 3 0 v N CH3O

SnBu3

OAc 75

74

Scheme 14

manipulated to form the natural product 3-demethoxyerythratidinone. Baldwin also showed that one could form 10 to 15-membered rings by macrocyclization of suitably substituted allylstannanes 1421.

1.4.2.4 Free Radical Vinylations and Allenylations Russell was the first to describe the reaction of vinyl stannanes with alkyl radicals 1431. He found that alkyl radicals, generated from the corresponding alkyl halides or alkyl mercuric halides, add regioselectively to the tin-substituted carbon of pstannyl styrenes and acrylates (Scheme 15). The resulting radicals undergo rapid pscission with loss of tributyltin radical to form vinylated products. In most cases, the E-isomer of the olefin is formed with excellent control of stereochemistry. Baldwin, Keck and Fraser-Reid have each applied this reaction to the synthesis of natural products [44].Weiler has reported an intramolecular version of this reaction [45].These vinylation reactions require an electron-withdrawing group at the alkene carbon /3 to the tin in order to direct addition of the incoming radical to the proper center. Baldwin has explored the chemistry of propargylstannanes and found that they serve as allene transfer agents 1461. For example, when amino acid derived iodide 80

+

Bu3SnmY 76 Y = Ph 77 Y = C02Et

Scheme 15

-

R

hY Bu3Sn

R

%

+

Y 78 Y = Ph 79 Y = C02Et

*SnBu3

I . 4.3 Non- Tin Based Reagents

61

0 BnOL .l NHCbz 80

+

AIBN 80 "C 60 %

/SnPh3

81

82

Scheme 16

was refluxed in benzene with four equivalents of triphenylprop-2-ynylstannane(81) and a catalytic amount of AIBN, the allenylated product 82 was formed in 60% yield (Scheme 16). An excess of the propargyltin reagent is necessary because it isomerizes to the more stable allenylstannane under the reaction conditions. This reaction has also been used by Valery and Czernecki in the synthesis of allenylated nucleoside analogs [47].

1.4.3 Non-Tin Based Reagents 1.4.3.1 Sulfides, Sulfoxides and Sulfones In 1982, Ueno reported the first uses of allylic sulfur compounds for carrying out the allylation of a carbon-centered radical [48]. The reactions detailed are cyclization reactions in which an aryl radical adds to an allylic sulfide to form either an indole or benzofuran product (Scheme 17). Tin, in the form of tributyltin hydride, was used to carry the radical chain. With low concentrations of tin hydride, yields of the desired products as high as 96% were observed. A more recent set of examples of cyclizations onto allylic sulfides was reported by Ward in 1991 [49]. Driven by the inability to substitute allyltin compounds at the 3-position, Keck examined intermolecular addition reactions of allyl sulfides [50]. He was able to show that 3-methyl- and 3,3-dimethyl-substituted allyl phenyl sulfides 86 and 88 undergo reaction with alkyl halides and alkyl phenyl selenides in the presence of hexabutylditin to form good yields of the allylation products (Scheme 18). These

Bu3SnH

H 83 Scheme 17

AIBN, 80 "C 96 %

H

84

I . 4 Radical Fragmentation Reactions

62

85

74 %

88

89

Scheme 18

reactions occurred without significant rearrangement of the allyl sulfide reagent. Keck later successfully used a 3-substituted allylic sulfone in the synthesis of the natural product (+)-pseudomonic acid C [ 5 11. Yamamoto also prepared several allylic sulfides with substitution at the 3-position, for example the acetoxymethyl compound 91, and showed that they react efficiently with allylic bromides when photolyzed with hexabutylditin [52]. This was in contrast to the reactions of allylic bromides with allylstannane reagents which did not give the desired allylated products. Barton and Crich reported the first examples of the uses of 2-substituted allylic sulfur compounds [53]. Their initial experiments with additions of simple alkyl radicals to allyl sulfides, sulfoxides and sulfones were relatively unsuccessful. This failure was largely due to the fact that the nucleophilic alkyl radicals, which were generated by photolysis of the corresponding Barton ester, underwent addition to a second equivalent of Barton ester faster than they added to the allyl transfer agent. Reactions were much more successful with the electron-deficient acrylate reagent 93 (Fig. 4). Crich was later able to show that this same reagent underwent addition reactions with an acyl radical derived from an acyl phenyl telluride [54]. Two additional allylic sulfide reagents bearing substituents at C-2 are the bromo substituted compound 94 and the acetoxymethyl compound 95 (Fig. 4). The 2-

93

Figure 4.

94

95

1.4.3 Non-Tin Bused Reugents

96 Z=PhS02 97 Z=PhSO 98 Z = P h S

62% 87% 55 Yo

63

99

Scheme 19

bromo compound was synthesized by Yo0 and Curran and was shown to react with alkyl halides in the presence of hexabutylditin to give moderate to good yields of vinyl bromide products [55].The product vinyl bromides were then used in vinyl radical cyclization reactions to form carbocyclic products. The use of the 2-acetoxysubstituted allylic sulfide 95, along with the corresponding sulfone and several other previously known sulfides and sulfones, was reported by Magnusson in reactions of carbohydrate-derived radicals [56]. Russell’s studies of vinylation reactions using vinylstannanes also examined similar reactions of vinyl sulfides, sulfoxides and sulfones [43a]. For example, isopropyl radical, generated from isopropyl mercuric chloride, adds to the non-sulfursubstituted alkene carbon of compounds 96, 97 and 98 to form the vinylated product 99 (Scheme 19). Recently, Caddick applied an intramolecular version of this process using alkyl halides and sulfides or sulfoxides in the presence of tributyltin hydride to the synthesis of indole derivatives [57]. All of the reactions of sulfur-substituted allyl and vinyl compounds detailed so far provide alternatives to the more traditional allyl and vinylstannane reagents. However, they still require the use of a heavy metal (tin in all but one case) to propagate the radical chain process. Unfortunately, because of their high toxicity and because of the difficulties in removing tin by-products, methods utilizing tin reagents are incompatible with the commercial synthesis of compounds for pharmaceutical use. The real power in using non-tin-based reagents, then, lies in the development of methodologies which do not require the use of any tin compounds. Tin-free methodologies have been pursued in recent years for carrying out several types of free radical transformations, including fragmentation processes. In the simplest application of this concept, Chatgilialoglu and Curran carried out allylation reactions with allyl phenyl sulfones in the presence of tris(trimethylsily1)silane [%I. These reactions are analogous to the tin-mediated reactions previously discussed; however, tris(trimethylsily1)silane is used instead of tributyltin hydride or hexabutylditin for propagating the radical chain. The yields in these reactions ranged from moderate to good. Zard showed that one can carry out allylation reactions of alkyl radicals using allyl ethyl sulfone 100 as the allylating agent [59]. The alkyl radicals can be generated from the corresponding iodide or dithiocarbonate or from the corresponding allyl alkyl sulfone. Using the iodide reaction as an example, the radical chain process begins with addition of an isobutyrylnitrile radical, generated from AIBN, adding to ally1 ethyl sulfone 100 (Scheme 20). This liberates an ethyl sulfonyl radical. This ethyl sulfonyl radical may add to allyl ethyl sulfone in a degenerate pro-

64 In-

1.4 Radical Fragmentation Reuctions

-

+

In-

+

*S02Et

+

*S02Et

-

SO2 + Et-

100

-

Eta

+

R-l

R.

+

e S 0 2 E t

R*

+

Et-l

-

R -

100

Scheme 20

cess, which reforms the ethyl sulfonyl radical, or it may extrude SO2 to form an ethyl radical. The ethyl radical then exchanges iodine with the alkyl iodide, forming the alkyl radical, which can add to allyl ethyl sulfone to form the desired product and regenerate the chain-carrying ethyl sulfonyl radical, Addition of the ethyl radical to allyl ethyl sulfone is slow, so it does not compete effectively with the iodine transfer reaction. Zard was able to demonstrate that the reaction gives good yields with a wide variety of substrates. Zard has also extended this general idea to vinylation reactions using appropriately substituted ethyl vinyl sulfones [60]. Several other groups have reported related sulfonyl radical-catalyzed, tin-free cyclization reactions [61]. Another approach to carrying out tin-free radical fragmentation processes, developed by Fuchs, utilizes trifluoromethyl sulfone, or triflone, derivatives. Fuchs first reported examples of free radical alkynylation reactions using acetylenic triflone 102 [62]. What is most remarkable about these reactions is that the radicals being alkynylated are formed from the cleavage of C-H bonds; standard radical precursors are not required. For example, when tetrahydrofuran is mixed with triflone 102 at room temperature, alkynylation occurs a to the ether oxygen in 92% yield (Scheme 21). In this case, the radical chain process is most likely initiated by traces of peroxides in the THF. Similarly, unactivated alkanes such as cyclohexane will react with triflone 102 in good yield (83% for cyclohexane) when heated with a catalytic amount of AIBN. These reactions are successful because of the highly electrophilic nature of the trifluoromethyl radical. The reaction starts with addition of an initiator radical to the sulfonyl-substituted carbon of the alkyne. The resulting vinyl radical then fragments with loss of trifluoromethylsulfonyl radical, which loses SO2 to form a trifluoromethyl radical. This highly electrophilic radical will not add to the electron-

0

+

101

Scheme 21

CF3S02-C-C-Ph 102

92 Yo

-

fiCEC-Ph 103

1.4.3 Non-Tin Bused Reagents

In*

+

-

CF3S02-C:C-Ph

65

In

>-\Ph

CF3SO2

102 In

>-\Ph

CF3SO2

-

In-C32-Ph

0. +

CFSS02-CEC-Ph

+ CF3SOp

-

SO2

+

CF3*

-

102

6 C E C - P h

+

CF3SOp

103

Scheme 22

deficient alkyne. Instead, its only available course of action is to abstract a hydrogen atom from an available substrate. Hydrogen abstraction from a carbon atom a to an ether oxygen is especially favorable for electronic reasons, and so this occurs preferentially for a substrate such as THF. The alkyl radical thus produced adds to triflone 102 and the resulting adduct fragments with loss of trifluoromethylsulfonyl radical to form the alkynylated product (Scheme 22). Fuchs has examined a number of additional alkynes. One in particular, silylsubstituted triflone 104, may prove most useful, as it provides silylated alkyne products upon reaction with suitable substrates [62c]. In general, attempts to functionalize triflones with other groups at the alkyne carbon or at propargylic positions were unsuccessful. Triflones with more remote functionality, including bisacetylenes, gave useful reagents. Fuchs' triflone methodology can also be extended to vinylation and allylation reactions (Scheme 23) [63, 641.

1.4.3.2 Silane Reagents Allyltrialkylsilanes can serve as ally1 transfer agents for carbon-centered radicals under tin-free reaction conditions. An early example, published by Saito in 1985, involves the allylation of the uracil derivative 111 under photolytic conditions with allyltrimethylsilane 112 (Scheme 24) [65]. No comment was made regarding the mechanism of this process, but it is presumably radical in nature. In 1994, Hirao

66

1.4 Radical Fragmerztation Reactions AIBN, 65 "C 94 Yo

104

101

105

o+

AIBN, 65 "C

Ph *SO2CF3

101

94 Yo

106

107

109

110

O+ 108

Scheme 23 0

0

Me

Me

111

112

113

114

112

115

Scheme 24

showed that benzyl radicals, generated by oxidation of benzyl silanes, are also allylated by several different allylsilanes [66]. In a related oxidative process, Hwu used allyltrialkylsilanes for the allylation of ketones and P-dicarbonyl compounds such as 114 in the presence of ceric ammonium nitrate (CAN) or manganese(II1) acetate [67]. Hirao and Hwu both proposed mechanisms that are technically not radical fragmentation processes but instead involve a radical addition followed by oxidation of the initial adduct to a p-silyl carbocation which then undergoes ionic elimination. Guindon investigated diastereoselective allylation reactions of alkyl halides and phenyl selenides using allylsilanes [68]. For example, substrate 116 is allylated by allyltrimethylsilane in the presence of magnesium bromide diethyl etherate using triethylborane as an initiator (Scheme 25). No tin is required in these reactions.

1.4.3 Non- Tin Bused Reagents OMe

+

k,-.C , 02Me

MgBr2.0 Et2 e S i M e 3

I 116

0

Et36, 0 2 , -78 "C 87 Yo antisyn >100:1

-% C02Me

112

117

0

0

tB"/yANK0 + /-.4SiMe3 Br 118

67

Et36, Zn(OTf),, 0 2 , -78 L*"C 88 Yo 90 % ee

c

0

t B u y N ' 0

U

112

119

Scheme 25

Guindon demonstrated that this reaction is not technically a fragmentation reaction either. Instead the reaction occurs by an atom transfer process. The atom transfer product undergoes an ionic elimination to form the final allylated product, 117. Similarly, Porter has used allyltrimethylsilane to carry out enantioselective allylation reactions in the presence of Lewis acids and chiral ligands, L" [69]. Chatgilialoglu and Curran synthesized a variety of allyl tris(trimethylsily1)silanes bearing substituents at the 2-position (Scheme 26) [70]. These allylsilanes underwent reaction with alkyl halides when heated with a radical initiator to give very good yields of allylated products. The reactions were relatively sensitive to electronic effects; electrophilic radicals reacted well only with electron-rich allyl silanes and vice versa. One potential drawback of this methodology is that the reactions reported were all carried out at 80 "C or above, suggesting that relatively high temperatures are necessary for efficient reaction.

60

120

ASi(TMS)3

121 122 E=CH3 123 E = C I

124 E = C N 125 E=CO*Et

Scheme 26

1.4.3.3 Miscellaneous Reagents In 1979, Johnson reported the first reactions of cobaloximes with carbon-centered radicals (Scheme 27) [71].These reactions provide the allylated products in generally

68

1.4 Rudical Fragmentation Reactions

126

CBrCI3

127

+

128

yCo(dmgH)2pyr *

126

129

c’3c7? 130

Scheme 27

clean reactions. However, yields were not specified. Unlike allylstannane reagents, substitution at the 3-position of the allyl cobaloxime is tolerated without rearrangement. All of the radicals reported in Johnson’s studies were halomethyl radicals. Gaudemer reported similar reactions with a variety of different radicals [72]. In a very simple system, Singleton showed that allyl and vinyl halides can undergo reaction with alkyl radicals in the presence of hexabutylditin to form the allylated or vinylated products (Scheme 28) [ 731. Since most allylstannanes, sulfides, sulfones and silanes are ultimately synthesized from the corresponding allyl halides, this methodology circumvents one or more synthetic steps. Successful reactions were reported with a variety of alkyl radicals using either allyl chlorides or vinyl bromides. Yields were generally good to excellent. 0 Oy-BI

+

60

131

132

aBr +

41

133

134

Scheme 28

1.4.4 Conclusions Free radical fragmentation reactions provide a convenient method for the construction of carbon-carbon bonds. A wide variety of reagents are available for carrying out allylation, vinylation and alkynylation reactions of numerous types of

References

69

carbon-centered radicals. The current focus on the development of tin-free methodologies for carrying out radical fragmentation reactions will make them of increasing importance for the synthesis of biologically important molecules.

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1591 a) B. Quiclet-Sire, S. Z. Zard, J. Am. Chem. SOC.1996, 118, 1209-1210; b) F. Le Guyader, B. Quiclet-Sire, S. Seguin, S. Z. Zard, J. Am. Chem. Soc. 1997, 119, 7410-7411; c ) B. Sire, S. Seguin, S. 2. Zard, Angew. Chem. Int. Ed. Engl. 1998, 37, 2864-2866. [60] F. Bertrand, B. Quiclet-Sire, S. Z. Zard, Angew. Chem. 1nt. Ed. Engl. 1999, 38, 1943-1946. [61] a) S. Caddick, C. L. Shering, S. N. Wadman, Tetrahedron Lett. 1997, 38, 6249-6250; b) I. W. Harvey, E. D. Phillips, G. H. Whithman, Tetrahedron 1997, 53, 6493-6508; c ) R. Nouguier, S. Gastaldi, D. Stien, M. Bertrand, P. Renaud, Tetrahedron Lett. 1999, 40, 3371-3374. 1621 a) J. Gong, P. L. Fuchs, J. Am. Chem. SOC.1996, 118, 4486-4487; b) J. S. Xiang, P. L. Fuchs, Tetrahedron Lett. 1996, 37, 5269-5272; c ) J. Xiang, W. Jiang, P. L. Fuchs, Tetrahedron Lett. 1997, 38, 6635-6638. [63] a) J. Xiang, P. L. Fuchs, J. Am. Chem. Soc. 1996, 118, 11986-1 1987; b) J. Xiang, W. Jiang, J. Gong, P. L. Fuchs, J. Am. Chem. Soc. 1997, 119, 4123-4129. [64] J. Xiang, J. Evarts, A. Rivkin, D. P. Curran, P. L. Fuchs, Tetrahedron Lett. 1998, 39, 41634166. [65] I. Saito, H. Ikehira, T. Matsuura, Tetrahedron Lett. 1985,26, 1993-1994. 1661 T. Hirao, T, Fujii, Y. Ohshiro, Tetrahedroiz Lett. 1994, 35, 8005-8008. [67] a) J. R. Hwu, C. N. Chen, S.-S. Shiao, J. Org. Chem. 1995, 60, 856-862; b) J. R. Hwu, K. Y. King, I.-F. Wu, G. H. Hakimelahi, Tetrahedron Lett. 1998, 3Y, 3721-3724. [68] Y. Guindon, B. GuCrin, C. Chabot, W. Ogilvie, J. Am. Chem. SOC.1996, 118, 12528-12535. [69] N. A. Porter, J. H. Wu, G. Zhang, A. D. Reed, J. Org. Chem. 1997, 62, 6702-6703. 1701 a) C. Chatgilialoglu, M. Ballestri, D. Vecchi, D. P. Curran, Tetrahedron Lett. 1996, 37, 63836386; b) C. Chatgilialoglu, C. Ferreri, M. Ballestri, D. P. Curran, Tetrahedron Lett. 1996, 37, 638776390, [71] a) A. Bury, C. J. Cooksey, T. Funabiki, B. D. Gupta, M. D. Johnson, J. Chem. SOC., Perkin Trans. 2, 1979, 1050-1057; b) M. D. Johnson, Acc. Chem. Res. 1983,16, 343-349. 1721 A. Gaudemer, K. Nguyen-Van-Duong, N. Shahkarami, S. S. Achi, M. Frostin-Rio, D. Pujol, Tetrahedron 1985, 41,4095-4106. [73] C. C. Huval, D. A. Singleton, Tetrahedron Lett. 1993, 34, 3041-3042.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

1.5 Atom Transfer Reactions Jeffrey Byers

1.5.1 Introduction Atom transfer reactions encompass a broad range of radical addition reactions in which C-heteroatom or heteroatom-heteroatom bonds are added across alkenes, alkynes, or other multiply bonded functionality. Atom transfer processes were first proposed [ 11 to account for the low degree of polymerization of polystyrene in CC14 [2]. The paper generally recognized as the first report of an atom transfer radical addition reaction involving carbon-carbon bond formation and yielding a monomeric product was that of Kharasch et al., in which CCl4 was shown to add to 1-octene in the presence of catalytic radical initiators [ 3 ] . Shortly thereafter, ethyl bromoacetate was shown to add to 1-octene upon thermolysis, with diacetyl peroxide as a radical initiator [4]. The mechanism originally proposed for this process and shown in Scheme 1 remains as the generally accepted mechanism for most atom transfer additions. Step 1 involves initiation. The chain-propagating steps 2 and 3 , which provide for addition to olefin and atom transfer, respectively, allow for a radical chain process. More recently, reactions involving transfer of halogens (I, Br, or C1) and aryl chalcogens (SePh, TePh) have been developed. Atom transfer reactions offer synthetic advantages relative to more commonly employed tin hydride-based radical processes because of the fact that the radical-olefin addition step is also an intimate component of the productive radical chain. Thus, slower olefin addition steps are not as deleterious to productive radical processes as in tin hydride-mediated chemistry, where simple reduction is observed in cases where addition to olefin is too slow. Atom transfer additions (where the atom transferred is not H) are also inherently non-reductive, yielding more highly functionalized products, thus facilitating subsequent radical and non-radical transformations.

1.5.2 General Considerations General considerations will be covered in the context of C-C bond-forming reactions, although the mechanistic generalities also apply to those reactions involv-

1.5.2 General Considerations

73

Scheme 1. The general mechanism for atom transfer addition [4]

ing addition of two heteroatom-based functionalities. A successful atom transfer reaction requires a suitably weak bond between C and the heteroatom or group being transferred in order to facilitate initiation. Initiation can occur thermally in the presence of initiators such as AIBN, less commonly the BEt3/02 system [ 5 ] ,or photochemically, depending on the substrate and the specifics of the radical chain. The light sources for photolyses in much of the earlier literature were sunlamps. Unfortunately, sunlamps are no longer commercially available in the U.S., and researchers need to use other UV light sources such as commercially available, albeit more costly, medium pressure Hanovia lamps. Radical-olefin reaction steps in atom transfer additions are typically subject to the same steric and electronic constraints observed in tin hydride-mediated reactions. The general pattern of steric deceleration arising from alkyl substituents on the radical species or olefin have been observed and quantified in atom transfer reactions [6, 71. Precursors yielding electrophilic radicals, such as malonate or malononitrile radicals, add preferentially to electron-rich olefins. Alkyl radicals and heteroatom-stabilized radicals are nucleophilic and offer preferential reactivity with electron-deficient olefins. In contrast to reductive C-C bond formation via tin hydride cycles, where the rate of radical addition to the olefin must be faster than the rate of hydrogen abstraction from the tin hydride, the C-C bond-forming step in atom transfer reactions is a discrete step in the productive radical chain. Thus, atom transfer reactions give greater latitude to the synthetic chemist in this regard in that they can be used for reactions involving slower olefin addition steps. The olefin addition step must only be faster than radical-radical or radical-solvent reactions. Most successful atom transfer processes are exothermic. This usually requires that the C-heteroatom bond formed in the product is stronger than that broken in the initial reactant. The rate at which the new C-centered radical abstracts the transferred group to complete the radical chain must also be kept in mind, and this step is quite fast in most successful atom transfer addition reactions. The fast rate of atom transfer and the diminished reactivity of the product relative to the reactants minimize potential olefin oligomerization. Included in Table 1 are rate constants for homolytic substitution reactions by alkyl radicals on a variety of alkyl halides and chalcogenides of relevance to atom

74

1.5 Atom Transfer Reactions

Table 1. Rate constants for homolytic substitution reactions Radical

Halide/chalcogenide

Temp ("C)

k (M-ls-')

(CH3)3CI (CH313CBr (CH313CCI ICMe(C02Et)2 ICH2C02Et BrCMe(C02Et)2 BrCH2C02Et PhTeCHzC02Et PhSeCHzCOzEt PhSeCMe(CO2Et)z PhSeCMe(CN)z PhSCMe(CN)2

50 50 50 50 50 50 50 50 50 50 50 25

3 x 106 4.6 103 6 x lo2 1.8 x 109 2.6 x 107 1.0 x 106 7 x 104 2.3 107 1 105 s x 105 8 x 106 2.3 x 105

Reference

transfer reactions. These have been excerpted from a much more extensive list of rate constants for homolytic substitution reactions in a recent review by Schiesser [8]. From this data, one can see why alkyl iodides are generally more reactive than bromides, which in turn are more reactive than chlorides in atom transfer reactions. Likewise, phenyl tellurides are more reactive than phenyl selenides. In general, the rates of atom transfer to alkyl radicals from organoiodides are comparable to those from organotellurides. Comparable rates of atom transfer are also observed for bromides and phenyl selenides. Chlorides are not as useful in atom transfer addition reactions because of their comparatively slow rates of atom transfer, and atom transfer reactions of phenyl sulfides are not commonly observed.

1.5.3 C-I Additions Organoiodides are the most reactive precursors for atom transfer addition reactions, and thus have been the object of the most extensive study. Some examples of early successes in I-transfer radical addition reactions are shown in Scheme 2. The first examples of I-transfer radical addition reactions involved the addition of perfluoroalkyl iodides to olefins [ 121. Subsequently, I-transfer addition reactions appeared sporadically in the literature from time to time, but first became the object of significant study in the course of Curran's synthesis of capnellene [ 131. Tin hydride cyclization of the organoiodide precursor was found to proceed through the intermediacy of a vinyl iodide, which underwent subsequent reduction to form capnellene. This cyclization could be halted at the vinyl iodide by using a non-reducing stannane Me3SnSnMe3. Subsequent model studies with hexynyl iodides demonstrated that excellent yields of atom transfer cyclization products could be obtained

1.5.3 C-I Additions

75

30 rnin Bu3SnSnBu3 hv/benzene

>go% 15/1 E/Z

46%

~ 4 1

~ 4 1

Bu3SnSnBu3hdbenzene

Scheme 2. Examples of the hexenyl radical cyclization accompanied by I-transfer

upon sunlamp photolyses in the presence of 10% Bu3SnSnBu3. These processes are exothermic since a C-C G bond is formed at the expense of a C-C TL bond, and a product with a stronger C-I bond is generated. The effectiveness of the I-transfer method is further demonstrated by the modest success of the corresponding isomerization cyclization of a hexenyl iodide, a reaction which is virtually thermoneutral [14]. While the Bu3SnSnBu3 is probably involved in the initiation step through the formation of tributylstannyl radicals, its more critical role is to scavenge 12, which acts as a radical chain suppressant [ 151. The use of greater quantities of Bu3SnSnBu3 diminishes product yields by removing I atoms from the productive radical chain. The use of organostannanes in general has come under increasing scrutiny in recent years, because of the high cost and toxicity of these reagents. The additional challenges faced in the removal of trialkyltin halides are also well documented [ 161. As a result, some of the more recently published I-transfer reactions, several of which are illustrated in this chapter, have been developed to succeed in the absence of stannane reagents. Some examples of more elaborate radical cyclizations accompanied by I-transfer are illustrated in Scheme 3 . The cyclization of alkyl radicals onto propargyl esters has been demonstrated in synthesis of a-methylene butyrolactones [ 171. This procedure uses thermolysis in the presence of benzoyl peroxide in order to induce initiation, and appears to progress in the absence of a distannane reagent. Attempts to carry out the cyclization under tin hydride conditions led to uncyclized, reduced substrate. A series of more complex radical cyclizations involving both I-transfer and unimolecular H-transfer have recently been reported. In these reactions, the radical initially formed by I-abstraction underwent 5-ex0 cyclization to generate a vinyl radical. This radical, in turn, abstracted H from silicon in an intramolecular

76

1.5 Atom Transfer Reactions

0 t-BU

U

Scheme 3. Further radical cyclization accompanied by I-transfer

(Unimolecular Chain Transfer = UMCT) process. The silicon radical thus formed propagates the radical chain via I-abstraction [ 181. Intermolecular atom transfer reactions of simple alkyl iodides to acetylenes bearing electron-withdrawing substituents have been observed [ 151 and are exemplified in Scheme 4. Yields were relatively poor when primary iodides are employed, but improved when secondary or tertiary iodides were added. Electron-withdrawing activating groups are needed on the acetylene in order to accentuate the polar effects and hence increase the initial rate of radical attack. This is done at the cost, however, of diminishing the rate of subsequent iodine transfer to the betterstabilized radical.

+I

+I

+

+

p,,, 111

Bu3SnSnBu3 * hdbenzene *

. 1?fs02ph83s6 83%

>150:1 U

E

/ \

Scheme 4. Intermolecular I-transfer addition

Most of the useful iodine transfer radical reactions arise from the addition of alkyl iodides, which have been activated by one or more adjacent carbonyl or nitrile substituents, to unactivated olefins. This both labilizes the initial iodide, facilitating chain initiation, and helps ensure that the atom transfer step is exothermic. The requisite iodides are typically synthesized by deprotonation with LDA or NaH, followed by iodination with 12 or N-iodosuccinimide. Cyclization of an iodoester yields primarily lactone product, proceeding through the intermediacy of the Itransfer products as shown in Scheme 5 [19]. Reactions in which a-iodoesters cyclized with alkynes also proved efficient. Similar ketones yielded less synthetically useful mixtures of cyclopentyl and cyclohexyl (arising from 6-endo transition states) products. It had been assumed for some time that the radicals derived from a-iodocarbonyl compounds would be electrophilic in character. More recently, however, rate studies

I . 5.3 C- I Additions

c y t - B u Me3SnSnMe3 \

t

di-f-butyl pyridine hvlbenzene

c : B U + cis

+ trans

p C 0 2 f - B ] I cis

- o&‘

+ trans

77

I191

H 74%

Scheme 5. Cyclization of an a-iodoester

have indicated that radicals alpha to carbonyls and nitriles are actually ambiphilic in character [20]. This property is illustrated in the successful addition of a-iodoacetates to alkynes bearing both donor and acceptor substituents [21]. Iodine transfer addition to allyltrimethylsilane provides a more environmentally friendly alternative to allyltributylstannane. In these allylations, which are exemplified in Scheme 6, the initially formed I-transfer product undergoes spontaneous loss of TMSI to generate the observed allylation product. Guindon has shown that allylation of the Lewis acid complexes of P-alkoxy esters in this manner can lead to products with high anti stereoselectivity [22]. It is also believed that the presence of Lewis acids enhances the electrophilicity of the radical. Allylations of this type can also prove successful when Br-transfer or PhSe-transfer reactions are employed.

Scheme 6. Stereoselective atom-transfer allylation with allyltrimethylsilane

Intermolecular addition reactions of iodomalonates have also proven successful, but are typically limited to addition reactions with monosubstituted or 1 , l disubstituted olefins [7]. Curran has also demonstrated that iodomalonates can cyclize with ease [ 191. The iodomalonate shown in Scheme 7 generated a 9: 1 ratio of 5-e.xo:6-endo cyclized products upon photolysis for as little as 10 min. This predominate 5-exo regiochemistry is in contrast to the classic studies of Julia [23] in which well-stabilized radicals arising from homolyses of C-H bonds were shown to equilibrate in the course of the hexenyl radical cyclization, leading to formation of the thermodynamically favored 6-endo cyclization product. Apparently the rate of iodine transfer in Curran’s iodomalonates is much too fast to allow for equilibra-

78

1.5 Atom Transfer Reactions C02Me

Meo2CeMe 1. Bu3SnSnBudhv

+

H3C

@ "

* Me02Ck

2. DBU

p

h [7]

CH3

Me3SnSnMe3 hv 10-30 min 9: 1

Scheme 7. Addition reactions of iodomalonates

tion of cyclized radicals through reversible ring closure, leading to the observed products of kinetic control. Iodine transfer reactions offer enhanced opportunities for lactone formation as illustrated in Scheme 8. The attempted cyclization of allyl iodoacetate under tin hydride conditions has been reported to yield only uncyclized allyl acetate [24]. Standard atom transfer conditions generated the desired butyrolactone in poor yield, in addition to isolable quantities of cyclic dimer and trimer lactones. This effect is mostly due to the high barrier to rotation around the CO-0 bond exhibited by esters, as well as the high energy of the E ester rotamer required for cyclization relative to the lower energy Z ester rotamer. For methyl formate and methyl acetate, the E rotamers have been shown experimentally to be 4.8 and 8.5 kcal/mol higher in energy than the corresponding 2 rotamers, respectively, with a 10-15 kcal/ mol barrier to rotation [25]. At low concentrations (0.03-0.003 M) of allyl iodoacetate and higher temperature photolysis (80 "C), the cyclized butyrolactone can be

Z rotamer

E rotamer

0

Bu3SnSnBu3/hv

-OL'

-4

0.03 M

0 ~

41% [24]

80 OC, benzene *

0 ~

O

Bu3SnSnBu3/hv 80 C OC, benzene H ~

O x O c ! +

0.5 M

Scheme 8. I-transfer cyclizations yielding lactones

51% 1271

1.5.3 C-I Additions

79

obtained in 41% isolated yield. A similar strategy will also allow N-allyl-N-methyl iodoacetamide to cyclize in 87% yield [24]. An explanation for this effect is as follows. When iodine is abstracted, the radical is formed only in the Z rotamer, and is topologically prohibited from cyclizing. Thus only reduced product is generated under tin hydride conditions, and the only atom transfer products that can be generated under non-reducing conditions are oligomeric in nature. At elevated temperatures, bond rotation is rapid enough for radical cyclizations, which require a sufficient population of the E rotamer. This reaction is also prone to a substantial solvent effect. When the reaction is carried out at 25°C and significantly higher concentration (0.1 M) in water with Et3B/Oz as an initiator, the yield improves to 67% [26]. The authors speculate that water might decrease the barrier to rotation between the E and Z rotamers. These conditions have also been used for formation of 9-18 membered ring lactones, but can be limited by solubility issues. The successful cyclization of a similar ally1 iodomalonate at 0.5 M and 40-50 "C has been observed in benzene [27]. The reasons for the success of this reaction at such high concentrations are not known. Iodomalononitriles are the most reactive reagents for I-transfer addition reactions. Unlike iodomalonates, iodomalononitriles add to 1,2 di- and tri-substituted olefins in synthetically useful yields [28]. Addition procedures typically involve combining the nitrile with an excess of the olefin and heating to reflux in CHC13 or benzene. Iodomalononitriles do not require distannane additives in order to undergo I-transfer addition reactions, in contrast to other iodides, and distannane addition actually suppresses the reaction. A conclusion which can be drawn from this observation is that the 12 generated in the course of iodomalononitrile addition reactions does not suppress the radical chains, and may even be a critical component of the productive chains. Several possible mechanisms have been proposed to account for this observation [28]. High stereoselectivities have been observed in the addition reactions of iodomalononitriles to E-alkenes. Syn stereochemistry predominates in the products, and the highest stereoselectivity is observed when there is a significant difference in the steric bulk between the two alkene substituents [29], as shown in Scheme 9. A model invoking minimization of A-strain has been proposed to account for this stereoselectivity. Ally1 and propargyl iodomalonates and propargyl iodomalononitriles have been used in a variety of annulation processes, illustrated in Scheme 10. Propargyl iodomalonate adds to 2-ethylbutene to generate a radical suitably disposed for immediate cyclization, with subsequent I-transfer to give the annulated product in 77% yield [7]. Propargyl iodomalononitrile, when heated with 1-hexene in benzene generated the addition adduct in 95% yield. This, in turn can undergo I-transfer cycli-

Ncx7N+ H & A R

"'GR + "'+ CN

600C CHC13 ~

CH3

!

CH3

Scheme 9. Stereoselectivity in iodomalononitrile addition reactions

syn:anti 75:25, R= i-Pr 98:2, R = t-Bu

[29]

80

1.5 Atom Tvansjer Reactions

$,

E t ~ E t 13;3SnSnBu3

+

C02Me

Me02C

[71

Et C02Me 77%4.4:1 E:Z

1

+

fBu

I

NC

0~~ & I "I.

A,5 h

Bu3SnSnBu3

benzene

NC CN

CN

Bu P81

hv

NC CN 78% 2.6:1 E:Z

95%

Scheme 10. I-transfer annulation reactions

zation under standard distannane conditions to generate the vinyl iodide [28]. Somewhat remarkably, atom transfer from the iodomalononitrile is so rapid that it occurs faster than cyclization to an alkyne to form a vinyl radical. Reaction sequences involving halogen transfer, followed by non-radical interception of the alkyl iodide or bromide formed can allow for the trapping of products arising from less exothermic or even endothermic atom transfer additions and are exemplified in Scheme 11. Yoon [30] and Curran [31] have demonstrated that the a-halo ethers formed upon addition to vinyl ethers can be trapped with alcohols, leading to formation of acetals. Substitution reactions on the heteroaromatics pyrrole and indole have been carried out through a sequence of steps involving I- or Br-

BrCH2C02Et + P O B u

Br Et02CH2,-,koBj

NEt3

-

OMe Et02CH2,-,kOBU

95% [311

hv Na25203

ICH2C02Et +

0 N

BU4N+Brpropylene oxide MTBE/hv

+ 20 atrn CO

K

~

hv hexane EtoH *

Me02C

L;

Me02C

lHRBu3;;SnBuL

90% [32]

1

c

~

~

C6Hj3%]

-

p H R N E t 3 C02Me

boEt 72% [33]

C6H13

0

pHR 43% [34]

C02Me

Scheme 11. Halogen transfer addition products trapped by nucleophilic species

1.5.4 C-Br Additions

81

transfer addition followed by HI or HBr elimination to regenerate aromaticity [ 321. This process also demonstrates the use of Na2S2O3 as a reductant to suppress I2 generation, thus eliminating the need for a distannane reagent. Ryu and Sonoda have shown that the acyl iodides obtained from I-transfer addition to CO can be trapped with alcohols or amines, yielding esters, lactones or amides [33]. This process also does not appear to require distannanes. In an interesting variation on the Curran allyl iodomalonate annulations, Flynn has shown that this compound can add to protected allyl amines to generate an atom transfer product which undergoes cyclization to generate a pyrrolidine upon treatment with NEt3 in a one-pot procedure [34].

1.5.4 C-Br Additions Although bromine transfer reactions were among the earliest examples of atom transfer additions, C-C bond-forming reactions involving Br-transfer have not been as heavily developed as the analogous I-transfer processes. These reactions are generally slower than the analogous I-transfer process, but have advantages in some situations. Bromides are generally more readily available, less costly, and more amenable to long-term storage than the corresponding iodides. Simple alkyl bromides are not labile enough to react in atom transfer radical processes, but addition reactions of bromotrichloromethane comprise some of the earliest examples of atom transfer addition [35]. Boldt has studied the addition reactions of bromomalononitrile extensively. This reagent adds quite readily to mono-, di-, and tri-substituted alkenes upon photolysis (Scheme 12) [36]. The product thus formed can undergo

NEt3

"6 H'"

Scheme 12. Bromine transfer radical addition reactions

'"'H

[361

82

1.5 Atom Transfer Reactions

subsequent cyclizations to generate dicyanocyclopropanes or butyrolactones. In one of the more interesting examples of this reaction, it has been demonstrated that bromomalononitrile adds cleanly to allenes to generate allylic bromides (Scheme 12) [37]. The ability of bromomalononitrile to transfer Br to a stabilized allylic radical further illustrates the high reactivity of malononitrile-based atom transfer reagents. Giese has demonstrated successful Br-transfer additions to enol ethers with bromomalonates in the presence of BugSnH. The a-bromo ethers thus generated underwent spontaneous loss of HBr to regenerate enol ether functionality (Scheme 12) [38].

1.5.5 C-Cl Additions While C-C bond-forming processes involving C1 transfer from polyhalomethanes comprise the earliest observed class of atom transfer reactions, they are typically unsuccessful when performed on olefins prone to polymerization [40]. As a result, there are only a modest number of examples of C1 atom transfers in other typical organic systems because of their slow rate relative to other radical processes. An example of a successful reaction of this type is illustrated in the addition of CC14 to germacrene, illustrated in Scheme 13 [41].

Scheme 13. Addition of CC14

Addition of metal catalysts, most commonly CuCl and FeC12, can allow for clean formation of 1:l adducts. A large number of other metals and salts have been shown to catalyze reactions of this type. A mechanism for processes of this type [42], whose certain aspects have been called into question [43], is as shown in Scheme 14. In this variation on the typical atom transfer process, it is proposed that the CuCl abstracts a C1 atom to form the trichloromethyl radical, which adds to the olefin. The subsequently formed radical, instead of abstracting C1 from CC14, a slow process, reacts with CuC12 to complete the atom transfer addition. Reactions of this general type have been extensively used in cyclizations to generate lactones [44] and lactams (Scheme 15). Lactam-forming reactions involving metal-catalyzed C1 transfer have played a key role in total syntheses of a variety of natural products, including pyrrolizidine alkaloids (Scheme 15) [45]. Slough has demonstrated that the kinetic product arising from a (Ph3P)2RuCl catalyzed C1-

1.5.6 C-SePh Additions

cc14 +

CUCI

- c13c* +

83

CUClp

Scheme 14. Mechanism for metal-catalyzed chlorine transfer additions

n

ji?

CUCI

0

n

0

0

Scheme 15. Metal-catalyzed chlorine transfer cyclizations

transfer cyclization can epimerize through Cl atom abstraction to generate the more stable stereoisomer (Scheme 15) [46].

1.5.6 C-SePh Additions Carbon-carbon bond forming radical reactions of phenyl selenides have also provided a wealth of synthetically useful methodology. Phenylselenomalonates [47] and malononitriles (Scheme 16) [48] can be added to olefins upon photolysis or thermolysis in the presence of AIBN. Phenylselenomalononitriles are the more reactive of the two, as expected, based on the I-transfer evidence. For example, phenylselenomalonates will not add to styrene [47]. This is presumably because of the inability of the stable benzylic radical formed upon malonate radical addition to carry out the atom transfer step with another phenylselenomalonate. The phenylselenoma-

84

1.5 Atom Transfer Reactions hv

Et02C

95% [47]

Et02CYCozEt SePh + 0

SePh

uC6H13

0

0

0

hv

benzene

i

- N V O E t

w

N

,

SePh

+

E

t

86% (491

"-SePh

0 h P e S, ,k,

O

pC,jH13

h benzene v

72% [50]

&c6H13

SePh MeO2EU/

80-85 atm CO hv

-

Meo2cms 58% [51]

Scheme 16. Phenyl selenide transfer radical addition reactions

lononitriles, on the other hand, are better able to transfer their phenylseleno substituent to the benzylic radical, and are thus reactive with styrene. Phenylselenomalonate derivatives have also been shown to undergo hexenyl radical cyclizations (Scheme 16) [49]. Phenylseleno precursors to ambiphilic radicals such as ethyl phenylselenoacetate and phenylselenoacetone can also be added effectively, albeit much more sluggishly (Scheme 16) [50].Methyl phenylselenoacetate can also add to alkenes to form an alkyl radical which traps CO at high pressures prior the PhSe transfer (Scheme 16) [51]. The acyl selenides thus obtained do not undergo subsequent atom-transfer radical additions, but are valuable intermediates for a variety of other radical processes. Geminal diphosphonates bearing an a-phenylseleno substituent have also been added to olefins [52]. A major advantage of phenyl selenide transfer reactions over their halogen counterparts lies in the greater ionic stability of the organoselenide compounds formed. Iodine transfer radical addition reactions of iodomalonates and iodomalononitriles to enol ethers or enamines typically fail. Non-radical processes involving nucleophilic attack of the electron-rich olefin on the electrophilic iodine appears to be the source of this failure [48]. Apparently, the phenylseleno group in the analogous selenides is not nearly as electrophilic. Also, the cc-iodo ethers and amines which would be formed in these reactions are too labile to isolate, in contrast to the corresponding phenyl selenides. Thus, phenylselenide transfer addition reactions to these electron-rich olefins succeed, as shown in Scheme 17 [47, 481. High stereoselectivity in the addition of phenylselenomalononitriles to heteroatom-substituted olefins has been observed. Primarily anti products are observed, with stereoselectivity arising from a Felkin-Anh type transition state [48]. Higher diastereoselectivity (40:1) has been observed in the addition of this reagent to phenylmentholderived enol ethers [53].

1.5.6 C-SePh Additions

-

Me02CyC02M; SePh

NC

SPh

uoAc

Me02C

hv

Me02C

85

SePh

64% [471

-Ncqlhph AlBN 80 OC

73% [48]

CH3

anti:syn 9O:lO

[531

84%

Scheme 17. Phenyl selenide transfer addition to heteroatom-substituted olefins

The ionic stability of phenyl selenides can also be advantageous in the choice of addition reagents. Reagents serving as precursors to heteroatom-stabilized radicals are more accessible because of the poorer leaving group ability of the phenylseleno substituent, as shown in Scheme 18. Phenylseleno precursors to cuptodative radicals have been shown to be ambiphilic in nature, with successful additions to electronrich as well as electron-deficient olefins [54]. The stable precursor to a highly nucleophilic radical, 2-phenylseleno- 1,3-dithiane has been shown to add to electrondeficient olefins [ 5 5 ] .

SePh

u~

Me02C

OMe SePh 51Yo(R = C02Me) 52% (R = C6H13) [541

Scheme 18. Phenyl selenide transfer addition of heteroatom-stabilized radicals

In some situations, the slower rate of phenyl selenide transfer can lead to advantages over other faster atom transfer additions. This is particularly useful when a relatively slow rearrangement step is desired prior to atom transfer. In a synthesis of a precursor to the all-cis Corey lactone, Renaud has shown that radical addition is followed by rearrangement prior to PhSe-transfer (Scheme 19) [56].Products arising from unrearranged olefin addition were observed when the reaction was attempted using BrCC13.

86

1.5 Atom Transfer Reactions C02Me I

.';? -

hv Me02CYC02Me SePh +

0

73%

[56]

SePh 0

Scheme 19. Phenyl selenide transfer addition in synthesis of Corey lactone

Phenyl selenide transfer radical addition reactions can be limited by the lack of reactivity observed in some precursors. Simple alkyl phenyl selenides do not undergo inter- or intramolecular radical additions to olefins. Phenylselenotrichloromethane will add to olefins upon photolysis, and the products formed can be elaborated into a$-unsaturated carboxylic acids (Scheme 20) [ 571. Benzyl phenylselenides have been observed to undergo atom transfer cyclization (Scheme 20) [%I.

Scheme 20. Phenyl selenide transfer reactions of alkyl selenides

1.5.7 C-TeR Additions Carbon-carbon bond formation via radical RTe transfer has been only modestly studied up to this point. Nonetheless, reactions of this type hold synthetic potential, in that they provide for high rates of atom transfer, and hence high radical lability, roughly comparable to that observed in iodides, yet maintain some of the ionic stability more characteristic of the chalcogens. Organotellurides do have the drawback of sometimes being quite light sensitive, again in parallel with the behavior observed in iodides. Some examples of this class of reaction are illustrated in Scheme 21. lsopropyl phenyl telluride adds to a variety of alkynes in less than 1 h upon treatment with catalytic AIBN in refluxing benzene [59]. Use of aryl tellurides does not appear to be critical, as evidenced by the nearly comparable success observed in addition reactions of n-BuTet-Bu. Simple alkenyl and alkynyl phenyl tellurides have also been shown to undergo cyclization upon photolysis [60]. Several acyl aryl tellurides have been shown to undergo ArTe transfer radical cyclization in

1.5.8 Addition of Two Heteroatoms

ynSnBu3

87

WPh

HO

68% [SO]

Scheme 21. Carbon-carbon bond formation via phenyl telluride transfer

outstanding yields (86-96%) upon photolysis [61], in contrast to the acyl selenides, which are not known to undergo PhSe transfer additions. Aryl tellurides are also useful precursors to heteroatom-stabilized radicals, as was also the case with phenyl selenides. Vinyl glycosides have been synthesized upon atom transfer addition of aryl telluroglycosides to alkynes [62]. While radical carbonylation of alkyl telluride bonds has not proven successful, telluroglycosides have been successfully added to isonitriles under atom transfer conditions [63].

1.5.8 Addition of Two Heteroatoms Most atom transfer radical reactions involving the addition of two heteroatoms fall into two general categories - dichalcogen additions and sulfonations. There are many synthetically useful reactions involving disulfide additions, as well as examples involving net addition of PhSSePh, and these will be covered in a later chapter in this series dealing with sulfur-centered radicals. The addition of PhSeSePh to alkynes has been observed under thermal [64] and photochemical [65]conditions, leading to predominately E products, as shown in Scheme 22. A variety of atom transfer radical reactions involving addition of halo, phenylseleno, and phenylthio sulfonates have been developed. In these reactions, it is believed that the sulfonyl radical attacks the olefin, and the halogen or arylchalcogen

Ph

=

PhSeSePh

ph*

SePh

. , / 170 O C

PhSe

Scheme 22. Radical addition of diphenyl diselenide

70% [64]

88

1.5 Atom Transfer Reactions

undergoes the subsequent atom transfer. Reactions of this type have been reviewed relatively recently [66], and will also be covered in the chapter on sulfur-centered radicals (Volume 2, Chapter 6.4).

References [ I ] F. R. Mayo, J. Am. Chem. Soc. 1943,65, 2324. [2] (a) H. Suess, K. Pilch, H. Rudorfer, Z. Phys. Chem. 1937, A1879, 361. (b) H. Suess, A. Springer, Z. Phys. Chem. 1937, A181, 81. [3] M. S. Kharasch, E. V. Jenson, W. H. Urry, Science 1945, 102, 128. [4] M. S. Kharasch, P. S. Skell, P. Fisher, J. Am. Chem. Soc. 1948, 70, 1055. [5] Y. Ichinose, S. Matsunaga, K. Fugami, K. Oshima, K. Utimoto, Tetrahedron Lett. 1989, 30, 3155. [6] G. J. Gleicher, B. Mahiou, A. J. Aretakis, J. Org. Chem. 1989, 54, 308. [7] D. P. Curran, M.-H. Chen, E. Spletzer, C. M. Seong, C.-T. Chang, J. Am. Chem. Soc. 1989, 111, 8872. [8] C. H. Schiesser, L. M. Wild, Tetrahedron 1996, 52, 13265. [9] M. Newcomb, R. M. Sanchez, J. Kaplan, J. Am. Chem. Soc. 1987, 109, 1195. [lo] D. P. Curran, E. Bosch, J. Kaplan, M. Newcomb, J. Org. Chem. 1989, 54, 1826. [ 1I ] D. P. Curran, A. A. Martin-Esker, S.-B. KO, M. Newcomb, J. Org. Chem. 1993, 58, 4691. [12] N. 0. Brace, J. Org. Chem. 1966, 31, 2879. [I31 (a) D. P. Curran, M.-H. Chen, Tetrahedron Lett. 1985, 26, 4991. (b) D. P. Curran, M.-H. Chen, D. Kim, J. Am. Chem. Soc. 1986,108, 2489. [ 141 D. P. Curran, D. Kim, Tetrahedron Lett. 1986, 27, 5821. [I51 D. P. Curran in Free Radicals in Synthesis and Biology (Ed.: F. Minisci), Kluwer, Dordrecht, 1989, pp. 37-51. [16] P. Renaud, E. Lacote, L. Quaranta, Tetrahedron Lett. 1998, 39, 2123, and references therein. [ 171 G. Haaima, M. J. Lynch, A. Routledge, R. T. Weavers, Tetrahedron 1993, 49, 4229. [l8] A. Martinez-Grau, D. P. Curran, J. Org. Chem. 1995, 60, 8332. [I91 D. P. Curran, C.-T. Chang, J. Org. Chem. 1989, 54, 3140. [20] (a) B. Giese, J. He, W. Mehl, Chem. Ber. 1988, 121, 2063. (b) I. Beranek and H. Fischer in Free Radicals in Synthesis and Biology (Ed.: F. Minisci), Kluwer, Dordrecht, 1989, pp. 303315. [21] D. P. Curran, D. Kim, C. Ziegler, Tetrahedron 1991, 47, 6189. [22] Y. Guindon, B. Guerin, C. Chabot, W. Ogilvie, J. Am. Chem. Soc. 1996, 118, 12528. [23] M. Julia, Acc. Chem. Rex 1971, 4, 386. [24] (a) D. P. Curran, J. Tamine, J. Org. Chem. 1991, 56, 2746. (b) F. Barth, C. 0-Yang, Tetrahedron Lett. 1990, 31, 1121. [25] (a) C. E. Blom and H. H. Gunthard, Chem. Phys. Lett. 1981,84, 267. (b) K. B. Wiberg, K. E. Laidig, J. Am. Chem. Soc. 1987, 109, 5935. [26] H. Yorimitsu, T. Nakamura, H. Shinokubo, K. Oshima, J. Org. Chem. 1998, 63, 8604. [27] J. H. Byers, E. A. Shaughnessy, T. N. Mackie, Heterocycles 1998, 48, 2071. [28] (a) D. P. Curran, C. M. Seong, J. Am. Chem. Soc. 1990, 112, 9401. (b) D. P. Curran, C. M. Seona. Tetrahedron 1992. 48. 21 57. [29] G. Tlhbma, D. P. Curran, S.’V. Geib, B. Giese, W. Damm, F. Wetterich, J. Am. Chem. SOC. 1993. 115. 8585. [30] (a) J.’H. Ahn, D. W. Lee, M. J. Joung, K. H. Lee, N. M. Yoon, Synlett 1996, 1224. (b) M. J. Joung, J. H. Ahn, D. W. Lee, N. M. Yoon, J. Org. Chem. 1998,63, 2755. [31] D. P. Curran, S.-B. KO, Tetrahedron Lett. 1998, 39, 6629. [32] J. H. Byers, J. E. Campbell, F. H. Knapp, J. G. Thissell, Tetrahedron Lett. 1999, 40, 2677.

References

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[33] (a) K. Nagahara, I. Ryu: M. Komatsu, N. Sonoda, J. Am. Chem. Soc. 1997, 114, 5465. (b) S. Kreimerman, I. Ryu, S. Minakate, M. Komatsu, Org. Lett. 2000, 2, 389. (c) I. Ryu, K. Nagahara, N. Kambe, N. Sonoda, S. Kreimerman, M. Komatsu, Chem. Commun. 1998, 1953. [34] D. L. Flynn, D. L. Zabrowski, J. Org. Chem., 1990,55, 3673. [35] (a) M. S. Kharasch, H. N. Friedlander, J. Org. Chem. 1949, 14, 239. (b) M. S. Kharasch, M. Sage, J. Org. Chem. 1949, 14, 537. [36] (a) P. Boldt, L. Schulz. J. Etzemuller, Chem. Ber. 1967, 100, 1281. (b) P. Boldt, W. Thielecke, J. Etzemuller, Chem. Ber. 1969, 102, 4157. (c) P. Boldt, L. Schulz, Tetrahedron Lett. 1967, 4351.

137) H. M. Bartels, P. Boldt, Liebigs Ann. Chem. 1981, 40. [39] B. Giese, H. Horler, M. Leising, Chem. Ber. 1986, 119, 444. [40] F. Minisci, Acc. Chem. Rex 1975, 165. [41] T. W. Sam: J. K. Sutherland, J. Chem. Soc., Chem. Commun. 1971, 970. [42] (a) M. Asscher, D. Vofsi, J. Chem. Soc. 1963, 1887. (b) M. Asscher, D. Vofsi, J. Chem. Soc. 1963, 3921. [43] P. Martin, E. Steiner, J. Streith, T. Winkler, D. Bellus, Tetrahedron 1985, 41, 4057. [44j S. Takano, S. Nishizawa, M. Akiyama, K Ogasawara, Synthesis 1984, 949. [45] Y. Hirai, A. Hagiwara, T. Terada, T. Yamazaki, Chem. Lett. 1987, 2417. [46] (a) M. A. Rachita, G. A. Slough, Tetrahedron Left. 1993, 34, 6821. (b) G. A. Slough, Tetrahedron Lett. 1993, 34, 6825. [47] (a) J. H. Byers, G. C. Lane, Tetruhedron Lett. 1990, 31, 5697. (b) J. H. Byers, G. C. Lane, J. Ory. Chem. 1993, 58, 3355. [48] (a) D. P. Curran, G. Thoma, J. Am. Chem. Soc. 1992, 114, 4436. (b) D. P. Curran, E. Eichenberger, M. Collis, M. G. Roepel, G. Thoma, J. Am. Chem. Soc. 1994, 116,4279. [49] J. H. Byers, T. G. Gleason, K. S. Knight, Chem. Cornmun. 1991, 354. [SO] J. H. Byers. B. C. Harper, Tetrahedron Lett. 1992, 33, 6953. [ S l ] 1. Ryu, H. Muraoka, N. Kambe, M. Komatsu, N. Sonoda, J. Org. Chem. 1996, 61, 6396. [52j J. H. Byers, J. G. Thissell, M. A. Thomas, Tetrahedron Lett. 1995, 36, 6403. [53] D. P. Curran, S. J. Geib, L. H. Kuo, Tetrahedron Lett. 1994, 35, 6235. [54] P. Renaud, S. Abazi, Synthesis 1996, 253. [55\ J. H. Byers, C. C. Whitehead, M. E. Duff, Tetrahedron Lett. 1996, 37, 2743. [56] P. Renaud, J.-P. Vionnet, J. Org. Chem. 1993, 58, 5895. 1571 T. G. Back, K. Minksztym, Chem. Commun. 1997, 1759. [58] I. Sugimoto, S. Shuto, A. Matsuda, J. Org. Chem. 1999, 64, 7153. [59] L.-B. Han, K.-I. Ishihara, N. Kambe, A. Ogawa, I. Ryu, N. Sonoda, J. Am. Chem. Soc. 1992, 114, 7591. 1601 L. Engman, V. Gupta, Chem. Commun. 1995, 2515. [61] (a) C. Chen, D. Crich, A. Papadatos, J. Am. Chem. Soc. 1992, 114, 8313. (b) D. Crich, C. Chen, J.-T. Hwang, H. Yuan, A. Papadatos, R. I. Walter, J. Am. Chem. Soc. 1994, 116, 8937. [62] S. Yamago, H. Miyazoe, J.-I. Yoshida, Tetrahedron Lett. 1999, 40, 2343. [63] S. Yamago, H. Miyazoe, R. Goto, J.-I. Yoshida. Tetrahedron Lett. 1999, 40, 2347. [64] A. Ogawa, N. Takami, M. Sekiguchi, H. Yokoyama, Chem. Lett. 1991, 2241. 1651 A. Ogawa, H. Yokoyama, K. Yokoyama, T. Masawaki, N. Kambe, N. Sonoda, J. Org. Chem. 1991, 56, 5721. [661 M. P. Bertrand, Org. Prep. and Proc. Int. 1994, 26, 257.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

1.6 Xanthates and Related Derivatives as Radical Precursors Samir Z. Zurd

1.6.1 Introduction Xanthates (or dithiocarbonates) and related thiocarbonyl derivatives made their entry into synthetic radical chemistry in the early 1970s through the pioneering work of Barton and McCombie [la]. Indeed, it would not be an exaggeration to say that the Barton-McCombie reaction represents a major milestone in the application of radical processes to synthetic problems: spectacular deoxygenations could be performed, especially on complex carbohydrates, which were - and still are to a large extent totally beyond the reach of known ionic and organometallic methods. More generally, the homolytic cleavage of the C - 0 bond in the xanthate group (Scheme 1, path A) constitutes an exceptionally powerful tool for producing radicals from alcohols, and a large number of C-C bond-forming processes can be implemented using this approach. A more recent development concerns the generation and capture of free radicals by the reversible scission of the C-S bond (Scheme 1, path B). This latter route is at the heart of the degenerative transfer of the xanthate group, a versatile process that also allows a wide variety of synthetically useful, mostly tin-free, transformations. Both of these modes of radical generation will be discussed in this chapter, with emphasis placed on more recent developments. ~

1.6.2 The Barton-McCombie Deoxygenation: Mechanism and Applications The mechanistic basis of the Barton-McCombie [ 1, 21 reaction is outlined in Scheme 2. Tributylstannyl radicals add rapidly und reversibly to the thiocarbonyl group of the xanthate to give an intermediate (2),which undergoes irreversible fragmentation into radical R' and S-tributylstannyl dithiocarbonate (3). Hydrogen abstraction from the stannane finally delivers the alkane, RH, and tributylstannyl radicals to propagate the chain. The main driving force is the conversion of a C-S 7r-bond into

I . 6.2 The Barton-McComhie Deoxygenation: Mechanism and Applications

91

Scheme 1. Pathways for radical generation from xanthates

1

/

2

,'Slow

/"SnBu3

1-cos

Bu3Sn'

Bu3SnSMe

SSnBu3

+

Me'

R-H

+

4

Scheme 2. Mechanism of the Barton-McCombie deoxygenation

the much stronger C - 0 n-bond. The co-product 3 may be observed by "'Sn NMR below -2O"C, but above this temperature it is rapidly converted into sulfide 4 by extrusion of carbon oxysulfide [ 3 ] . The starting xanthate 1 is easily obtained by treatment of the requisite alcohol with base (e.g. NaOH, KOH, NaH, KH, or BuLi), carbon disulfide, and methyl iodide, normally in this order, but variations have been reported where all the ingredients are mixed in the presence of a phase transfer catalyst [4]. Thus, the overall transformation is a deoxygenation of the initial alcohol ROH into the corresponding alkane RH. Other thiocarbonyl derivatives are also suitable as substrates for the deoxygenation: thiocarbonyl imidazolides [ 11, 0-aryldithiocarbonates [ 5 ] ,or even certain thiocarbamates [6]. These derivatives are often easier to introduce than a xanthate, but are more expensive. The choice of the methyl group on the sulfide sulfur of the xanthate is important: rupture of the C-S bond in 2 to give a methyl radical is a difficult process and fragmentation therefore proceeds as desired, on the side of the oxygen. In practice, the Barton-McCombie deoxygenation is best suited for secondary alcohols. Xanthates of tertiary alcohols are generally unstable, decomposing more or less readily into an alkene through the Chugaev elimination; however, in the case of tertiary alcohols where for some reason the Chugaev elimination is sufficiently slow at room temperature to allow handling of the xanthate (one case is bridgehead tertiary alcohols), the deoxygenation works beautifully [7]. It is generally advantageous in

92

1.6 Xanthates and Related Derivatives as Radical Precursors

these cases to initiate the chain reaction at low temperature using for example the combination of triethylborane and oxygen as the initiating system. With primary alcohols, the problem is the greater cost of forming a primary carbon radical from intermediate 2 [8]. In these cases, higher temperatures are usually required since the collapse of 2 is a unimolecular process with a large positive entropy term; its rate is therefore especially sensitive to a rise in temperature. In addition, the competition between the release of a methyl radical by cleavage of the C-S bond and a primary radical by scission of the C-0 bond is no longer totally biased towards the latter process. It is therefore often better, in the case of primary alcohols, to use other thiocarbonyl derivatives (thiocarbonyl imidazolides or 0aryldithiocarbonates). Their advantage over xanthates in the case of primary alcohols is that the fragmentation can normally only occur on the side of the oxygen. Alcohols are ubiquitous in natural products or as intermediates in organic synthesis, and the Barton-McCombie deoxygenation has been applied hundreds of times on all kinds of molecules, and several reviews have already appeared [l]. Three examples, illustrating its tremendous synthetic potential, are set out in Scheme 3; they represent a deoxygenation of secondary thiocarbonyl imidazolide [9], a low-temperature reduction of a tertiary xanthate [7] and, finally, deoxygenation of a primary 0-trichlorophenyl thiocarbonate [5a]. Like stannane-based radical chemistry in general, the process is tolerant of many of the functional groups en-

CI Bu3SnH (AIBN) 91O/O

0Y

toluene reflux

Scheme 3. Some examples of deoxygenation

1.6.2 The Barton-McCombie Deoxygenation: Mechanism and Applications S

'SnBu3

MeSKO'R

SSnBu3

MeS H

H

-

S,SnBu3

HSnBu3

H&O*R H

S

SSnBu3

A O ,~ MeS&O,R HSnBu3

93

Bu3SnSMz

-

HKO,R 5

-

Scheme 4. Side reactions in the Barton-McCombie deoxygenation: an example of methyl ether formation

countered in modern organic synthesis and can be applied with success to quite complex structures, late in a synthetic scheme. The slow step in the deoxygenation process is the collapse of the radical adduct 2. Under certain circumstances, this intermediate may be intercepted by the stannane, causing the formation of unwanted side-products arising mostly from further reactions of the thioformate 5 [2, 101. The various possibilities are depicted in Scheme 4, which also includes an example of formation of a methyl ether as a co-product in the reaction of a xanthate with tributylstannane [lob]. The yield is variable, depending strongly on the exact reaction conditions. Another potential complication arises from the reaction of radical R' with the starting xanthate (Scheme 5). This leads to a dithiocarbonate (6) by a chain reaction

Benzene *

reflux (lauroyl peroxide)

Scheme 5. 0- to S-Radical chain rearrangement of xanthates

70% (a$,ca 1:l)

94

1.6 Xanthates and Related Derivatives us Radical Precursors

that parallels that with stannyl radicals. Indeed such compounds have been occasionally observed as side products [ 111. It is worth while pointing out that the mobility on silica gel of dithiocarbonates (6) is often very close to that of the starting xanthate and its presence goes unnoticed. In the absence of the stannane and under appropriate conditions, namely a concentrated medium and using a peroxide as initiator, this radical chain rearrangement of the xanthate group becomes a synthetically useful means for exchanging a c-0 bond for a c-S bond, as illustrated by the example in the same Scheme [12a]. A mechanistically similar 0- to S-rearrangement has recently been used to generate iminyl radicals from oxime xanthates; their capture leads to highly functionalized nitrogen heterocycles [ 12bl.

1.6.3 Synthetic Variations The carbon radical generated by cleavage of the C-0 bond can be captured by internal or (but less commonly) external olefins, or incorporated into various cascade sequences. For instance, the simple 5-exo-addition to an alkyne displayed in Scheme 6 was used to build the last ring of the kaurene skeleton of the potent antiHIV agent neotripteriforin [ 13al. The kaurene structure may in turn be converted into a bicyclo[2.2.2] system, found for example in atisirene, by a double homoallylic rearrangement illustrated by the second transformation in the same Scheme [ 13bl. The Barton-McCombie process for radical generation has also been extensively used for elaborating highly oxygenated structures by manipulating carbohydrates, where hydroxy functions are present in great abundance [ 1, 141. Ring opening of a cyclopropane can be made to precede a ring-closure step as in the elegant approach to spiro systems devised by Motherwell and co-workers [ 151 and displayed in Scheme 7. Since the introduction of the cyclopropane ring via the

Bu3SnH (AIBN) *

toluene reflux

K Bu3SnH (AIBN) toluene * reflux MOMO

67%

MOMO

via MOMO

Scheme 6. Examples of deoxygenative radical cyclizations

1.6.3 Synthetic Vuriutions

95

Bu3SnH (AIBN) Me Me

benzene reflux

Me

Me Me

'

ISiMe3 79%

Scheme 7. Deoxygenative radical cascade for the stereoselective construction of spiro structures

Simmons-Smith reaction is directed by the hydroxy function, the configuration at the spiro junction may be controlled at will by selecting the appropriate epimer of the starting allylic alcohol. Another nice cascade, one of many based on the Barton-McCombie reaction, is depicted in Scheme 8 [ 161; it involves addition to an aldehyde, 1,3-stannyl shift from carbon to oxygen, and cyclization to give a diquinane derivative. Application of the deoxygenation process to p-hydroxysulfides or phydroxysulfones results in the clean formation of trans-olefins through pelimination of a thiyl or sulfonyl radical [17]. This mild, radical version of the Julia olefin synthesis, initially described by Lythgoe and Waterhouse [ 17a], has been applied by two groups in the total synthesis of (+)-pseudomonic acid C. The transformation shown in Scheme 9 is taken from the synthesis by Williams and coworkers [ 17bl. One interesting modification concerns the capture of intermediate 2 by an internal olefin. Such a reaction, as the one outlined in Scheme 10, was originally designed by Bachi and Bosch [18] as a clear-cut proof for the mechanism of the Barton-McCombie reaction. It beautifully and unambiguously demonstrated that

benzene reflux

MeSA-;)

I 0.-

'SnBu3 ~

H-SnBu3

uu3anu

Scheme 8. Synthesis of diquinanes via a 1,3-stannyl shift

96

1.6 Xunthutes and Related Derivutives as Radical Precursors OBn

OBn ,0SiPh2f-Bu

>OSiPh2f-Bu Bu3SnH (AIBN)

*

MeAOAOBn

MehOAOBn

Scheme 9. Synthesis of alkenes from P-hydroxysulfones

Ph

BusSnH benzene reflux

Scheme 10. Capture of the initial radical adduct in the Barton-McCombie deoxygenation

the major pathway indeed involved attack on the thiocarbonyl group and not on the sulfide sulfur, as an earlier esr study seemed to indicate [19]. Synthetically, this variation allows a convenient access to thiolactones following mild hydrolysis of the tetrahedral intermediate. Lactones may in principle be obtained if the olefinic trap is placed on the oxygen side of the xanthate. The more complex sequence in Scheme 11, discovered serendipitously, illustrates the construction of such a lactone starting with an aryl thiocarbonate [20]. It also involves the transfer of the aryl group in the penultimate step.

1.6.4 Tin-Free Modifications The toxicity of organotin derivatives and the difficulty in removing tin residues has spurred considerable efforts to devise catalytic systems or, preferably, completely tinfree processes for conducting radical reactions. The use of poly(methylhydrosi1oxane) in conjunction with a small amount of hexabutylditin oxide, a combination of reagents initially proposed by Grady and Kuivila [21a], has recently been applied to Barton-McCombie type dcoxygenations [21b]. Several silanes have been examined

1.6.4 Tin-Free ModiJications

97

,'-'SnBu3

Bu3SnH(AIBN) benzene, reflux

0 0 -\

.

CONH;!

0 49%

OR0

0

H

Scheme 11. Synthesis of lactones by interception of the radical adduct

as replacements for triorganostannanes; the most promising are the arylsilanes [ 221 and especially tris(trimethylsily1)silane [23]. The radical chemistry of these reagents is described in detail elsewhere in this book (Volume 1, Chapter 1.3); nevertheless, the highly efficient deoxygenation of the thiocarbamate in Scheme 12 [8] provides a neat demonstration of the considerable synthetic potential of silicon hydrides. Another practical tin-free reducing agent for the Barton-McCombie deoxygenation is hypophosphorous acid and its salts. The utility of this reagent as a cheap and ecologically acceptable replacement for triorganostannanes was demonstrated by

i ~ r > T ( o ~ ~ ~ ~ (Me3Si)3SiH (AIBN) *

0, iPr0,Si-O OKNHPh iPr S

benzene reflux

97%

iprOSi-O iPr

0

dioxane

BuO

80°C 0

0

92%

Scheme 12. Deoxygenations using tris(trimethylsily1)silane and hypophosphorous acid as reducing agents

1.6 Xanthates and Related Derivatives as Radical Precursors

98

Lauroyl peroxide (stoichiometric) 2-propanol reflux

OMe

90% SMe

n CN

CN

0 @ o

~

Benzoyl peroxide (stoichiometric) ~ ~ PhCl reflux

~

3

91Yo(41% conversion)

Scheme 13. Radical generation from xanthates using stoichiometric amounts of peroxide

Barton and his students [24] and, more recently, by other groups [25]. The second transformation in Scheme 12 illustrates the conversion of a tartrate-derived thiocarbonate into a malate using hypophosphorous acid [26]. Phosphine-borane complexes have also been proposed as convenient hydrogen atom donors for the deoxygenation [271. Efficient deoxygenations can be accomplished by adding lauroyl peroxide gradually to a refluxing solution of the xanthate in isopropanol [12]. Stoichiometric amounts of the peroxide are required since the process is not a chain. Lauroyl peroxide is quite cheap and safe to handle. The solvent is the actual hydrogen atom donor, as shown by the transformation in Scheme 13. It is interesting that a reduction is performed using an oxidant! The possibility of using stoichiometric amounts of peroxide to generate radicals from xanthates and related derivatives is further illustrated by the second transformation in Scheme 13, an example taken from the pioneering study of Minisci and his colleagues [28].

1.6.5 Degenerative Transfer of Xanthates: Mechanistic Considerations A completely different way of employing xanthates is to exploit the possibility of cleaving the C-S bond of the sulfide according to path B in Scheme 1. This allows the conception of a degenerative transfer of the xanthate group, delineated in Scheme 14 [29]. Thus, following a chemical or photochemical initiation step, radical R' arising from rupture of the C-S bond reacts rapidly with the starting xanthate to

1.6.5 Degenerative Transfer of Xanthates: Mechanistic Considerations

O,Et

1

99

Initiation

Scheme 14. Degenerative radical chain transfer of a xanthate group

give adduct 7. This radical cannot easily undergo p-scission of the C-0 bond, which in this case would lead to a high-energy ethyl radical. The easier cleavage of the C-S bond returns the system to its original state, i.e. back to R’ and the starting xanthate. This back and forth addition-fragmentation process occurs rapidly and continuously, but it is degenerate and no change is observed macroscopically. The constant regeneration of R’ means that its effective lifetime in the medium is increased, allowing it to partake in various radical processes, even ones with relatively slow kinetics. For example, addition to an olefin leads to adduct 8; this is followed by a rapid reversible addition-fragmentation sequence to give finally a new xanthate (9) and radical R’, which propagates the chain. The ethyl group on the oxygen may be replaced by another group, as long as its corresponding radical is of comparable but preferably lower stability compared to R’. For most applications a primary substituent is sufficient (methyl, ethyl, neopentyl “neoPn”, etc.). It is useful, before proceeding to the synthetic applications, to make some general comments on the properties of this system. No heavy and/or toxic metals are involved and the starting materials are cheap and readily available. A wide variety of radicals such as alkyl, acyl, alkoxycarbonyl, alkoxythiocarbonyl, and even tincentered radicals may be generated and captured. Furthermore, the end product is also a xanthate that can be used as a starting point for another radical sequence or modified further using the immensely rich chemistry of sulfur. However, looked at from a different angle, this fact constitutes at the same time a limitation since the reversibility of the xanthate group transfer means that the last two propagating steps represent an equilibrium that must be biased in the forward direction by making R’ more stable than the adduct radical 8. This point is crucial and has to be kept constantly in mind when designing a synthetic sequence, especially when dealing with intermolecular additions. Experimentally, the procedure is quite

1.6 Xanthates and Related Derivatives as Radical Precursors

100

simple: mere heating of the xanthate and trap in a suitable solvent (benzene, cyclohexane, dichloroethane, toluene, chlorobenzene etc.) under an inert atmosphere and in the presence of a catalytic amount of an appropriate initiator (dibenzoyl or dilauroyl peroxide, di-t-butyl peroxide etc., depending on the reaction temperature, which is usually the boiling point of the solvent; AIBN is not generally suitable since it gives rise to isobutyronitryl radicals that are too stable to efficiently trigger the process). Photochemical initiation (visible or UV, depending on the type of xanthate) may also be employed. Another practical advantage, of some importance when operating on a large scale, is that the reactions can be run in a quite concentrated medium, typically 0.5-2 M, and sometimes even without solvent.

1.6.6 Synthetic Applications The xanthate transfer may be used to perform otherwise sluggish cyclizations, as illustrated by the two comparative experiments shown in Scheme 15 involving a difficult 6-end0 ring closure [30]. In a pioneering study of this p-lactam system, Bachi and coworkers were able to accomplish the cyclization with reasonable efficiency (500/0)using tributylstannane but only under high dilution conditions (0.003 M) [30a]. Displacement of the chloride with commercially available potassium 0ethylxanthate and heating of the resulting xanthate (10) in cyclohexane (0.25 M) with a small amount of lauroyl peroxide gave the cyclized product in good yield, despite the nearly 100-fold higher concentration [30b]. Another interesting application of the xanthate technology is the construction of an oxocane by a direct 8-

+&) Benzene

50y0 SvOEt cyclohexane 0.25M 74%

t-BuOpC

65% t-BuOpC EtO 10 SCSOEt f-Butylbenzene SCSOEt 150-160°C (di- t-butyl peroxide)

79:21 68%

H

Scheme 15. 6-Endo- and 8-endo- ring closures using xanthate transfer

1.6.6 Synthetic Applications

101

Me02C C02Me

OK

S

I

EtO

G

Lauroyl peroxide

Copt-BU

+P-

lsopropanol A

89% (a:P3:1)

0

0

MATRINE

Scheme 16. Reductive cyclization of a xanthate mediated by lauroyl peroxide in 2-propanol

endo-cyclization (the second example in the same scheme) [31]. The aldehyde sideproduct arises from an intracyclic 1$hydrogen atom translocation within the cyclized radical, followed by /?-scission and xanthate transfer. The xanthate group may be reduced away using any of the methods described above for the Barton-McCombie reaction. The lauroyl peroxide/isopropanol system appears to be especially useful in this respect [ 32al. This is demonstrated by the transformation in Scheme 16, a key step in the synthesis of (*)-matrine [32b]. Thus, upon heating in refluxing isopropanol with portion-wise addition of a stoichiometric amount of lauroyl peroxide, the double cyclization is followed by the reductive removal of the xanthate group. The reaction gives a 3: 1 mixture of isomers, the minor having the relative stereochemistry of do-matrine. In some cases, it is possible to use cyclohexane as the hydrogen atom source in a chain process. This is illustrated by the efficient synthesis of tetra-0-acetyl-2-deoxyD-glucose pictured in Scheme 17 [33]. The intermediate radical 11 arising from the 1,2-shift of the acetoxy group is not stabilized, yet it is electrophilic in character because of the inductive electron-withdrawing effect of the adjacent acetates. Because of matching polarity characteristics, the rate of the otherwise essentially thermoneutral hydrogen abstraction from the cyclohexane solvent becomes sufficiently rapid to sustain the chain reaction. Unstabilized secondary radicals flanked by fluorine atoms are also capable of undergoing reduction with cyclohexane [33]. AcO

AcO AcOAcO OAc

OAc cyclohexyl-S

0' A AcOc AcO 90%

O

h 4

OAc

U

x 0-neoPn

--

1'

AcO AcO* AcO A AcO c

O

11

W OAc

Scheme 17. Synthesis of 2-deoxy-sugars by hydrogen atom transfer from cyclohexane

1.6 Xanthates and Related Derivatives as Radical Precursors

102

cyclohexane reflux (lauroyl peroxide)

80%

O ~ AcNH C 0 2 E t

k

I

C02Et I

Bn/

S

Y=s

Etd FOOMe

H,N y C O O M e 5

FS

EtO

*

cyclohexane reflux (lauroyl peroxide)

Norbornene t-BuOOt-Bu (cat.) benzene 150°C (sealed tube)

74%

NHC02Me

SCSOEt 69% (endo:exo 81 :19)

Scheme 18. Intermolecular additions to unactivated olefins

The most important synthetic asset of the xanthate transfer methodology lies in its ability to induce carbon-carbon bond formation by intermolecular addition to unactiuated olefins. Again, this is possible because the initial radical has a comparatively long lifetime in the medium. Unhindered, terminal olefins are the best substrates, but other types of olefins (especially strained or lacking allylic hydrogens) may be made to react in some cases. Three examples of additions are collected in Scheme 18. The first involves formation and capture of a trifluoroacetonyl radical, a species hitherto only studied by mass spectrometry but never employed in synthesis [ 34aI. This reaction represents a convenient route to various, otherwise inaccessible, trifluoromethyl ketones. In the second example a tetrazolylmethyl radical, also a previously unused intermediate, is intercepted by a latent ally1 glycine [34b]. The amino acid moiety may be part of the xanthate partner as highlighted by the last example [ 34~1. The intermolecular addition represents a simple, convergent way of bringing together various functional groups, which can then be made to react in a more traditional ionic manner. The first transformation in Scheme 19 illustrates the synthesis of a cyclopropylpiperidine by addition of the cyclopropyl methyl ketone unit to a protected allylamine [35a]. Reductive removal of the xanthate followed by deprotection of the amine and borohydride reduction of the imine intermediate gives a good yield of the cis-piperidine derivative. The second sequence represents a convenient approach to the CD ring system of steroids [35b]. It hinges on the expedient

1.6.6 Synthetic Applications

103

Ph J-NHBOC

NHBoc %SLOEt 0

(Lauroyl peroxide) CICH2CH2CI reflux

'Ys OEt

/

1) Bu3SnH, Benzene 2) Trifluoroacetic acid 3) NaBH4I MeOH

55% &Ph

(Et0)pOP

/

89%

S

Et02CASKOEt (Lauroyl peroxide) ClCH2CH2Cl reflux

EtOCSS Et02C

1) pTSA, acetone 2) K2C03/ 18-Crown-6 toluene 80°C

EtOCSS,,,,& 49% C02Et

Scheme 19. Synthesis of piperidines and cyclohexenes

assembly of the required elements for an intramolecular Wittig-Horner reaction, which, interestingly, occurs on only one of the two ketones to give the isomer with the xanthate group in the pseudo-equatorial orientation. Other combinations of ring systems may be accessed by this route simply by modifying the size of the ring in the olefinic partner. Xanthates may be used to generate acyl (R-C'=O), alkoxycarbonyl (RO-C'=O), and related radicals. Addition of these species to olefins leads to ketones, esters, or lactones [l].Under suitable conditions, they may be made to extrude carbon monoxide or carbon dioxide respectively, providing the corresponding alkyl radicals. As expected, the rate of such fragmentation depends greatly on the stability of the alkyl radical produced, being greater the more stable the alkyl radical. The loss of carbon monoxide from an acyl radical, a reaction first described by Barton and his collaborators in 1962 [36a], was exploited in a recent synthesis of a new class of antiinflammatory steroids outlined in Scheme 20 [36b]. S-Acyl xanthates are lemon yellow in color and their radical reactions may be conveniently triggered by visible light.

1.6 Xanthates and Related Derivatives as Radical Precursors

104

(visible) toluene reflux

0

I

F

I

(chain reaction)

-co

Scheme 20. Synthesis of an anti-inflammatory steroid

1.6.7 Outlook and Perspectives The products of the xanthate transfer reactions being themselves xanthates, a second radical step may be envisaged. This possibility may be exploited for the synthesis of several important aromatic derivatives such as oxindoles, indolines, tetralones, dihydroisoquinolinones, etc. [37]. The two examples in Scheme 21 give an idea of

C02f-Bu peroxide Lauroyl

F &

-

(stoich.) peroxide (cat.) CICH2CH2CI reflux

81 Yo S02Me

CICH2CH2CI reflux

Lauroyl peroxide (stoich.)

EtOCSS

*

Br

Lauroyl peroxide (cat.) cyclohexane reflux

Br 77% NC

Scheme 21. Synthesis of indolines and tetralones

CICH2CH2CI Br reflux SCSOEt

N 79y0 S02Me

0

Jql /J

56% NC

105

1.6.7 Outlook and Perspectives

(m+l)--IY

S

t

R

(initiator)

w

S SO ' Et

Scheme 22. Formation of block polymers using xanthates

the potential of this approach. The ring closure onto the aromatic ring is not a chain process, a stoichiometric amount of the peroxide being needed for the aromatization step. In some cases, even a seven-membered ring could be constructed by a similar approach [ 37eI. Living polymerization is another rapidly developing area where the degenerative transfer of xanthates and related derivatives (e.g. dithioesters, dithiocarbamates, trithiocarbonates) is having a significant impact [38] (see also Volume 1, Chapter 5.1). The conception, outlined in Scheme 22, simply makes use of the fact that a polymerization performed using an appropriate xanthate gives a polymer capped by a xanthate group. This polymer may then be made to undergo a second polymerization sequence involving another monomer. This process, which may of course be repeated, provides interesting, and hitherto not easily accessible, block polymers. Moreover, since the radical exchange of the xanthate group is usually faster than the addition of a monomer, the chains grow throughout the polymerization process, causing a considerable narrowing of the molecular weight distribution (polydispersity). Finally, the principle of degeneracy may be used to replace the xanthate group with an allyl or a vinyl substituent without the need for a stannane-based reagent [39]. This conception, hingeing on the ability of alkylsulfonyl radicals to extrude sulfur dioxide, is delineated in Scheme 23. Thus, an ethylsulfonyl radical produced

yS02-Et

Scheme 23. Mechanism of the allylation of xanthates with allyl sulfones

106

1.6 Xanthates and Related Derivatives as Radical Precursors

. (AIBN) heptane, reflux

S

CI P h C O N 3 S EtO

"

heptanel chlorobenzene reflux (peroxide)

-

I

R = H, 74% R = Me, 69%

PhCON *Cl 76%

CI

Scheme 24. Examples of allylation and vinylation of xanthates

from allyl ethyl sulfone following an initiation step can, in principle, add to the thiocarbonyl group of the xanthate, but this step (path A) is highly reversible, because of the weakness of the S-S bond. Its reaction with another molecule of ethyl allyl sulfone is totally degenerate (path B). The only alternative is extrusion of sulfur dioxide to give a highly reactive ethyl radical, which is capable of triggering the desired chain reaction (path C). The same mechanistic picture prevails with vinylation reactions. Examples of allylation [39a] and vinylation [39b] are shown in Scheme 24. The dichlorovinylation is especially interesting since the products are immediate precursors of alkynes via the Corey-Fuchs reaction. The process is also applicable to aliphatic iodides, exchange of iodine replacing the exchange of xanthate in the mechanistic manifold in Scheme 22 [39b,c]. Xanthates and their relatives may justifiably be considered as major precursors of a wide variety of radicals. The highly radicophilic thiocarbonyl group and the possibility of two distinct modes of fragmentation, summarized in Scheme 1 for the case of a xanthate, allow numerous useful combinations. The foregoing, brief overview of their radical chemistry gives only a glimpse of their vast and exceptional potential for synthesis, a potential that is far from being completely explored and exploited.

References [ I ] (a) D. H. R. Barton, S. W. McCombie, J. Chem. Soc. Perkin Trans. 1. 1975, 1574-1585; (b) D. H. R. Barton, Half' a Century of Free Radical Chemistry, Cambridge University Press, Cambridge, 1993; ( c )W. Hartwig, Tetrahedron 1983, 39,2609-2645; (d) D. Crich, L. Quintero, Chem. Reo. 1989, 89, 1413-1432; (e) D. H. R. Barton, J. A. Ferreira, J. Cs. Jaszberenyi, in Preparatioe Curhohydrate Chemistry; S. Hanessian, Ed., Marcel Dekker, New York, 1997, 15-172.

Rejerences

101

[2] D. H. R. Barton, D. Crich, A. Lobberding, S. Z. Zard J. Chem. Soc., Chem. Commun. 1985, 646-647; Tetrahedron 1986,42, 2329-2338. [3] D. H. R. Barton, D. 0. Jang, J. Cs. Jaszberenyi, Tetrahedron Lett. 1990, 31, 3991-3994. [4] (a) I. Degani, R. Fochi, V. Regondi, Synthesis 1979, 178-181; (b) P. di Cesare, B. Gross, Synthesis 1980, 714-715. [5] (a) D. H. R. Barton, P. Blundell, J. Dorchak, D. 0. Jang, J. Cs. Jaszberenyi, Tetrahedron 1991,47, 8969-8984; (b) M. J. Robbins, J. S. Wilson, J. Am. Chem. Soc. 1981, 103, 932-933; M. J. Robbins, J. S. Wilson, F. Hansske, J. Am. Chem. SOC.1983, /05, 4059-4065. [6] M. Oba, K. Nishiyama, Tetrahedron 1994, 50, 10193-10200. [7] D. H. R. Barton, S. I. Parekh, and C.-L. Tse, Tetrahedron Lett. 1993, 34, 2733-2736. [8] D. H. R. Barton, W. B. Motherwell, A. Stange, Synthesis 1981, 743-745. [9] E. J. Corey, A. K. Ghosh, Tetrahedron Lett. 1988,29, 320553206, [lo] (a) K. C. Nicolau, M. Sato, E. A. Theodorakis, N. D. Miller, J. Chem. Soc., Chem. Commun. 1995, 1583-1585; (b) C. S. Bensasson, J. Cornforth, M.-H. Du, J. R. Hanson, J. Chem. Soc., Chem. Commun. 1997, 1509-1510. [ 1 I ] (a) J. Marco-Contelles, P. Ruiz-Fernandez, B. Sanchez, J. Org. Chem. 1993, 58, 2894-2898; (b) D. Crich, A. L. J. Beckwith, C. Chen, Yao, Q., I. G. E. Davison, R. W. Longmore, C. Anaya de Parodi, L. Quintero-Cortes, J. Sandoval-Ramirez, B. Sanchez, J. Am. Chem. Soc. 1995, 117, 48757-8768; (c) V. H. Rawdi, R. C. Newton, V. Krishnamurthy, J. Org. Chem. 1990, 55, 5181L5183. [ 121 (a) B. Quiclet-Sire, B., S. Z. Zard, Tetrahedron Lett. 1998,39, 9435-9438; (b) F. Gagosz, S. Z. Zard, Synlett 1999, 1978-1980. [13] (a) E. J. Corey, K. Liu, J. Am. Chem. Soc. 1997, 119, 9929-9930; (b) M. Toyota, T. Wada, K. Fukumoto, M. Ihara, J. Am. Chem. Soc. 1998, 120,4916-4925. [I41 T. V. RajanBabu, Acc. Chem. Rex 1991,24, 139-145. [ 151 R. A. Batey, J. D. Harling, W. B. Motherwell, Tetrahedron 1992, 48, 8031-8052. [I61 S.-Y. Chang, Y.-F. Shao, S.-F. Chu, G.-T. Fan, Y.-M. Tsai, Org. Lett. 1999, I , 945-948. [I71 (a) B. Lythgoe, 1. Waterhouse, Tetrahedron Lett. 1977,/8,4223-4226; (b) D. R. Williams, J. L. Moore, M. Yamada, J. Org. Chem. 1986, 51, 3916-3918; (c) J. C. Barrish, H. L. Lee, T. Mitt, G. Pizzolato, E. G. Baggliolini, M. R. Uskokovic J. Org. Chem. 1988, 53, 4282-4295. [I81 M. D. Bachi, E. Bosch, J. Chem. Soc., Perkin Trans. I . 1988, 1517-1519; M. D. Bachi, E. Bosch, D. Denenmark, D. Girsh, J. Org. Chem. 1992, 57, 6803-6810. 1191 A. L. J. Beckwith, P. J. Barker, J. Chem. Soc., Chem. Cornmun. 1984, 683-684. [20] H. Hotodd, M. Daigo, T. Takatsu, A. Muramatsu, M. Kaneko, Heterocycles 2000, 52, 133136. [21] (a) G. L. Grady, H. G. Kuivila, J. Org. Chem. 1969, 34, 2014-2016; (b) R. M Lopez, D. S. Hays, G. C. Fu, J. Am. Chem. Soc. 1997, 119, 6949-6950. [22] D. H. R. Barton, D. 0. Jang, J. Cs. Jaszberenyi, Tetrahedron Lett. 1990, 31, 4681-4684. [23] C. Chatgilialoglu, Chem. Rev. 1995, 95, 1229-1251; Acc. Chem. Res. 1992,25, 188-194. [24] D. H. R. Barton, D. 0. Jang, J. Cs. Jaszberenyi, Tetrahedron Lett. 1992, 33, 5709-5712; J. Org. Chem. 1993, 58, 6838-6842. [25] S. R. Graham, J. A. Murphy, D. Coates, Tetrahedron Lett. 1999, 40, 2415-2416; C. Gonzdiez Martin, J. A. Murphy, C. R. Smith, Tetrahedron Lett. 2000, 41, 1833-1836; H. Yorimitsu, H. Shinokubo, K. Oshima, Chem. Lett., 2000, 104-105. [26] D. 0. Jang, S. H. Song, Tetrahedron Lett. 2000, 41, 247-248. (271 D. H. R. Barton, M. Jacob, Tetrahedron Lett. 1998, 39, 1331-1334. [28] F. Coppa, F. Fontana, F. Minisci, G. Pianese, P. Tortoreto, L. Zhao, Tetrahedron Lett. 1992, 33,687-690. [29] S. Z. Zard, Angew. Chem. Int. Ed. Eng. 1997,36, 672-685; Angew. Chem. 1997, 109, 724-737; B. Quiclet-Sire, S. Z. Zard, Phosphorus. Sulfur and Siliron 1999, 1.53-154, 137-154; B. QuicletSire, S. Z. Zard, J. Chin. Chem. Soc. 1999, 46, 139-145. [30] (a) M. D. Bachi, A. De Mesmaeker, N. Stevenart-De Mesmaeker, Tetrahedron Lett. 1987, 28, 2637-2640; (b) L. Boiteau, J. Boivin, B. Quiclet-Sire, J.-B. Saunier, S. Z. Zard, Tetrahedron 1998, 54, 2087~~ 2098. [31] J. H. Udding, J. P. M. Giesselink, H. Hiemstra, W. N. Speckamp, J. Org. Chem. 1994, 59, 667 1-6682.

108

1.6 Xanthates and Related Derivatives as Radical Precursors

[32] (a) Liard, A,; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996, 37, 5877-5880; (b) L. Boiteau, J. Boivin, J., A. Liard, B. Quiclet-Sire, S. Z. Zard, Angew. Chem. Int. Ed. Engl. 1998, 37, 1128-1131; Angew. Chem. 1998,110, 1197-1199. [33] B. Quiclet-Sire, S. Z. Zard, J. Am. Chem. Soc. 1996, 118, 9190-9191; for a related reaction starting from iodides, see: J. Boivin, B. Quiclet-Sire, L. Ramos, S. Z. Zard, J. Chem. Soc., Chem. Commun. 1997, 353-354. [34] (a) M.-P. Denied, B. Quiclet-Sire, S. Z . Zard, J. Chem. Soc., Chem. Commun. 1996, 25112512; (b) T. Biadatti, B. Quiclet-Sire, J.-B. Saunier, S. Z. Zard, Tetrahedron Lett. 1998, 39, 1922; (c) J. H. Udding, H. Hiemstra, W. N. Speckamp, J. Org. Chem. 1994, 59, 3721-3725. [ 3 5 ] (a) J. Boivin, J. Pothier, S. 2 . Zard, Tetrahedron Lett. 1999, 40, 3701-3704; (b) N. Cholleton, I. Gillaizeau-Gauthier, Y. Six, S. Z. Zard, Chem. Commun. 2000, 535-536. [36] (a) D. H. R. Barton, M. V. George, M. Tomoeda, J. Chem. Soc. 1962, 1967-1974; (b) QuicletSire, B.; Zard, S. Z. Tetrahedron Lett. 1998, 39, 1073-1074. [37] (a) J. Axon, L. Boiteau, J. Boivin, J. E. Forbes, S. Z. Zard, Tetrahedron Lett. 1994, 35, 17191722; (b) A. Liard, B. Quiclet-Sire, R. N. Saicic, S. Z. Zard, Tetrahedron Lett. 1997,38, 17591762; (c) T.-M. Ly, B. Quiclet-Sire, B. Sortais, S . Z. Zdrd, Tetruhedron Lett. 1999, 40, 25332536; (d) N. Cholleton, S. Z. Zard, Tetrahedron Lett. 1998, 3Y, 7295-7298; (e) T. Kaoudi, B. Quiclet-Sire, S. Seguin, S. Z. Zard, Angew. Chem. Int. Ed. Engl. 2000, 39, 731-733. [38] D. Charmot, P. Corpart, D. Michelet, S. Z. Zard, T. Biadatti, WO 9858874 Priority June23, 1997 (to Rhodia Chimie). This polymerization process has been named MADIX (for MAcromolecular Design via Interchange of Xanthate); a mechanistically similar system using dithioesters was concomittantly developed by CSIRO chemists and termed RAFT: J. Chiefari, Y. K. Chong, F. Ercole, J. Kristina, J. Jeffrey, T. P. T. Le, R. T. A. Mayadunne, G. F. Meijs, G. Moad, C. L. Moad, E. Rizzardo, S. H. Thang Macromolecules 1998, 31, 5559-5561. [39] (a) B. Quiclet-Sire, S. Seguin, S. Z. Zard, Angew. Chem. Znt. Ed. Engl. 1998, 37, 2864-2866; Angew. Chem. 1998, 110, 3056-3058; (b) F. Bertrand, B. Quiclet-Sire, S. Z. Zard, Anyew. Cliem. Int. Ed. Engl. 1999, 38, 1943-1946; Angew. Chem. 1999, I l l , 2135-2138; (c) F. Le Guyader, B. Quiclet-Sire, S . Seguin, S. Z. Zard, J. Am. Chem. Soc. 1997, 119, 7410-7411.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

1.7 Decarboxylation via 0-Acyl Thiohydroxamates William B. Motherwell und Christoph Imboden

1.7.1 Introduction The invention or discovery of a highly efficient free-radical chain reaction in an ideal world requires that each collision between a neutral free radical and the reagent or substrate in the propagation sequence is an effective one, especially since radical-radical combination and disproportionation reactions can occur at diffusioncontrolled rates. The introduction of 0-acyl thiohydroxamates (mixed anhydrides of carboxylic acids with thiohydroxamic acids) by the Barton group in 1983 [ I ] has provided one of the mildest and most convenient and versatile sources of carbon-centered radicals which fulfill the above criteria, and can hence, in Sir Derek’s own words, be described as ‘disciplined’. Since their preparation from carboxylic acids is extremely straightforward, and since they have demonstrated a rapacious radicophilicity in a wide variety of very useful transformations, it is no surprise that these derivatives are commonly named either as Barton esters or by the acronym PTOC (pyridine thiocarbonyl) esters. The ongoing development of this chemistry has been summarized over the years in several useful reviews [2], and some of the tried and tested experimental procedures have also been collated [ 31. The basic propagation sequence for the simplest possible reaction involving a reagent X-Y, where X is a thiophilic radical, and featuring the most commonly used class of 0-acyl thiohydroxamate derived from the readily available salt of the cyclic thiohydroxamic acid, N-hydroxypyridine-2-thione(2-mercaptopyridineN-oxide) is shown in Scheme 1. Some idea of the extraordinary range of chaincarrying radicals for simple functional group transformations can be gained from examination of typical reagents X-Y. Examination of the various steps in the above sequence provides considerable insight. From a thermodynamic standpoint several factors are important. In the first instance, the conceptual link between acylthiohydroxamate chemistry and the elegant Barton-McCombie reductive deoxygenation of xanthates and similar thiocarbonyl derivatives is immediately apparent, inasmuch as the reaction involves formation of the strong carbonyl bond at the expense of a weak thiocarbonyl moiety. The enhancement of the aromatic character which occurs when the pyridine nucleus

110

1.7 Decarboxylution via 0-Acyl Thiohydroxamates x-Y

x-Y

mBu3Sn-H

PhS-P(SPh)p

R3CS-H

PhS-Sb(SPh)p

C13C-halogen

R'SOZ-CN

R'S-SR' (Se, Te)

Ph3CS-NO

I

S'

4 I

R-Y

+

x.

x-Y

?J'

R.

?

Y-x

chain carrier

Scheme 1. The propagation sequence for reactions of 0-acyl thiohydroxamates

is released also provides a second driving force for reaction to occur. Finally, the release of carbon dioxide during the reaction certainly makes a favorable entropic contribution. From a preparative viewpoint, reaction conditions are also influenced by the nature of the alkyl group R in carboxy radicals, RC02'. Carbon-centered radicals, R', are readily generated from primary, secondary and tertiary alkyl and cycloalkyl groups. If R is an aromatic group, however, the corresponding arylcarboxy radicals do not lose carbon dioxide at less than 100°C. In contrast to oxidative methods such as Kolbe electrolysis, however, further oxidation of carboncentered radicals to carbocations is not problematic in the reactions of Barton esters.

1.7.2 The Preparation of 0-Acyl Thiohydroxamate Derivatives The most straightforward method for 0-acyl thiohydroxamate formation consists of reacting the commercially available sodium salt of 2-mercaptopyridine-N-oxide (1) with the corresponding acid chloride, which is best prepared using the traditional dimethylformamide-catalyzed reaction with oxalyl chloride [4]. Activation of the carboxylic acid with dicyclohexylcarbodiimide works well for primary carboxylic acids but leads to the problematic formation of N-acyl ureas with more hindered systems [4]. Condensation of the free thionohydroxamic acid with the mixed anhydride formed from the acid and isobutyl chloroformate in the presence of Nmethylmorpholine has proven to be the most useful method for studies using amino acids [ 5 ] . The most recent addition to the armory of methods based on activation of the acid is also derived from peptide chemistry and is based on the beneficial effect which uronium salts have shown in hindered peptide couplings. Thus, S-( l-oxido-2pyridiny1)-1,1,3,3-tetramethylthiouroniurn hexafluorophosphate (2) (HOTT) is a stable crystalline solid which is readily prepared by combining the parent thiohydroxamic acid with the salt 3. Subsequent esterification of even hindered carboxylic acids can then be achieved simply by combining HOTT with the carboxylic acid, a tertiary amine, and a catalytic amount of DMAP in tetrahydrofuran [6]. The strat-

1.7.3 Functional Group Transformations involving Radical Chain Reactions

coc12

Me2N

-0 PF&

OH 4

2

O

0

11 I

N-Cy

0

H

RCOCl DMAP (cat.)

0-

05

Scheme 2. Preparation of 0-acyl thiohydroxamates based on 2-mercaptopyridine-N-oxide

egy of activating the thiohydroxamic acid rather than the carboxylic acid has also been employed for in situ generation of 0-acyl thiohydroxamates using the cyclic carbonate salt 4 which is prepared from 2-mercaptopyridine-Noxide with phosgene. Finally the corresponding disulfide 5 has also been used in conjunction with tributylphosphine and the carboxylic acid [7]. The above methods can be summarized as illustrated in Scheme 2.

1.7.3 Functional Group Transformations involving Radical Chain Reactions of 0-Acyl Thiohydroxamates 1.7.3.1 Reductive Decarboxylation to give Nor-alkanes (RC02H -+ RH) [4] Hydrogen atom donors such as non-nucleophilic tertiary thiols or tri-n-butyltin hydride are extremely efficient traps for the capture of the alkyl radical R' derived from 0-acyl thiohydroxamates, thus providing a very efficient method for reductive decarboxylation (Scheme 3). In practical terms, the use of the mercaptan is preferred since the tertiary alkyl pyridyl disulfide can be easily removed during work up by a simple acid extraction. The reaction has been successfully applied to a very wide range of complex substrates [8] possessing primary, secondary, or tertiary aliphatic carboxylic acids, and reactions at room temperature or below require only photolysis from a simple tungsten lamp and often involve in situ 0-acyl thiohydroxamate derivatization.

1 12

I . 7 Decarhoxylation via 0 - A c y l Thiohydroxarnates

R

Scheme 3. Reductive decarboxylation of 0-acyl thiohydroxamates

Some selected transformations, all of which feature the use of a mercaptan, are shown in Scheme 4.

A (62%) [4]

A (82%) [4]

A (94%) [9]

hv (96%) [5]

Scheme 4. Some examples of reductive decarboxylation (Z = COzH

+

Z = H)

1.7.3.2 Decarboxylative Halogenation (RC02H 4RY; Y = C1, Br, I) [4] An excellent alternative to the classical Hunsdiecker reaction and its variants, which totally avoids the use of heavy metal salts and potent electrophilic reagents, consists of the simple photolysis or thermolysis of Barton esters in refluxing bromotrichloromethane for the bromides or tetrachloromethane for the chlorides [4]. The analogous decarboxylative iodination can also be achieved using iodoform as the reagent in a benzene/cyclohexene solvent system (Scheme 5). For the cases of vinylic and aromatic acids, where the usual problems of chain efficiency are encountered, the addition of azobisisobutyronitrile (AIBN) is also required [ 101. Nevertheless, since this method can operate on both electron-rich and electron-poor aromatic systems, and moreover does not suffer from the competitive electrophilic aromatic bromination found with electron rich aromatics under normal Hunsdiecker conditions, this route to synthetically useful aryl iodides and bromides should find widespread application.

1.7.3 Functional Group Transformations involving Radical Chain Reactions

1 13

R

Scheme 5. Decarboxylative halogenation

This protocol has been successfully applied to primary, secondary and tertiary aliphatic carboxylic acids encompassing a wide range of functionality. Some illustrative examples are shown below in Scheme 6 and include the sensitive derivative 6 [ 1 11 (where all classical Hunsdiecker variants were unsuccessful) and the fragile a-halooxetane 7 reported by the Fleet group [ 121.

f

9 5

NH

0

F3C' Z = C02H

-

Z = Br (50%)[13]

o,,,,,

H

Z = C02H

Y(-p 0"'

H

-

Z = Br (90%) [ l l ]

MeO,

Z

7

Z = C02Na+

-

M

e

O

a

Z

MeO'

Z = CI (18%) [12]

Z = CO2H

-

Z = Br (62%) [lo]

Scheme 6. Decarboxylative halogenation via 0-acyl thiohydroxamates

1.7.3.3 Decarboxylative Rearrangement of 0-Acyl Thiohydroxamates [4] In terms of generation and manipulation of 0-acyl thiohydroxamates it is important to recognize that, in the absence of any other reagents, decarboxylative rearrangement to alkyl-2-pyridyl sulfides can occur (Scheme 7). This is the simplest free-radical reaction of Barton esters and is of preparative utility in its own right. A series of crossover experiments demonstrated that the only mechanism which oper-

1 14

1.7 Decurboxylution via 0-Acyl Thiohydroxarnutes

Scheme 7. Decarboxylative rearrangement of 0-acylthiohydroxamates

ates under photochemical conditions is the chain process, while under thermal conditions competing cage recombinations can also occur [ 141. The product alkyl-2-pyridyl sulfides are of synthetic interest by virtue of their ability to form a chelated lithio anion for reaction with carbon electrophiles. Subsequent removal of the sulfide can then be achieved using either nickel boride or tri-n-butyl stannane [4] (Scheme 8). n-BuLi

E+

Reduction +

HZC,

E"R

Li-( R

R

Scheme 8. Reactions of alkyl-2-pyridyl sulfides [4]

The decarboxylative rearrangement of a considerable variety of 0-acyl thiohydroxamates has been an ongoing interest within the Barton group and has led to a 'tuneable' series of alkyl radical triggers which can be preselected to require either a normal tungsten lamp or a medium-pressure mercury lamp for activation [14, 151. The reaction conditions for decarboxylative rearrangement of some representative derivatives are shown in Scheme 9. The decarboxylative rearrangement of 0-acyl thiohydroxamates is thus a very convenient method for the preparation of useful alkyl-2-pyridyl sulfides and functions well irrespective of the nature, primary, secondary, or tertiary of the intermediate alkyl radical. Some representative examples are collected in Scheme 10. The congeneric 0-acyl esters of N-hydroxypyridine-2-selenone can also be prepared since the corresponding selenohydroxamic acid is readily available by treatment of 2-bromopyridine-N-oxide with sodium borohydride and selenium. As shown in Scheme 11, this variant of the decarboxylative rearrangement, when followed by ozonolysis and subsequent selenoxide elimination, provided a useful route to optically pure L-vinylglycine from a protected glutamic acid derivative [ 161.

S

O Y R O

Thermal 110 "C Photochemical W

X=Ph Thermal 110 "C Photochemical w

S

X=Me Thermal 110 "C Photochemical Hg (medium)

0

0 O K R 0 Thermal stable to 130 "C Photochemical Hg (medium)

Thermal stable to 130 "C Photochemical Hg (medium)

Scheme 9. Photochemical and thermal rearrangement of 0-acyl thiohydroxamates

AcO"" G OAc L A c

(77%) [4]

(72%) [14]

Scheme 10. Decarboxylative rearrangement of 0-acyl thiohydroxamates to alkyl-2-pyridyl sulfides

1.7.3.4 Decarboxylative Chalcogenation The reactions of disulfides, diselenides or ditellurides with 0-acylthiohydroxamates provide an efficient method for the synthesis of unsymmetrical thio-, seleno-, and telluroethers respectively (Scheme 12). In this instance, low-temperature tungsten lamp photolysis is the best preparative method since competing decarboxylative rearrangement to alkyl pyridyl sulfides is problematic under thermal conditions [ 171. In addition to the wide variety of primary, secondary and tertiary alkyl aryl sulfides, selenides and tellurides which can be prepared by this method, the Barton group also developed concise syntheses of two of the most important selenoamino acids, L-selenomethionine and L-selenocystine using this approach [ 181 (Scheme 13). The use of crystalline dicyanogen triselenide for introduction of the selenocyanate moiety is also very useful.

1 16

1.7 Decarhoxylation via 0-Acyl Thiohydroxamates

0 . g

(i), (ii), (iii)

PhnOKN

H

C02Me

H

0

'y'"oAc~

key: (i)

A , 0 NMe U

(ii)

0

(iii) hv

Se

OH (iv) 03;(v) 6 N HCI, heat

Scheme 11. Synthesis of ~-vinylglycinevia the alkyl-2-pyridyl selenide [ 161

R'-x-x-R' t

S

hv X = S, Se, Te R' = alkyl, aryl

R' -x- R'

Scheme 12. Decarboxylative chalcogenation

H

R = t-BU

Z = CHzCOzH

R = PhCH2

Z = C02H

R = PhCH2

Z = C02H

-

Z = SeMe (78%) Z = SeCH2Ph (64%)

-

Z = SeCN (73%)

Scheme 13. Preparation of unsymmetrical selenides from 0-acyl thiohydroxamates

1.7.3 Functional Group Transformations involving Radical Chain Reactions

1 17

1.7.3.5 Decarboxylative Phosphonylation (RC02H + RPO (SPhh) The specific replacement of a carboxylic acid in a biologically active molecule by a phosphonic acid moiety is a useful reaction for substrate modification. This can be accomplished very simply by the reaction sequence shown in Scheme 14.

Scheme 14. Preparation of S,S-diphenyldithiophosphonatesusing tris(pheny1thio)phosphorus[ 191

The key element is the free-radical chain reaction of an acylthiohydroxamate with tris (pheny1thio)phosphorus which involves the phenylthio radical as the chain carrier and trapping of the liberated alkyl radical at the phosphorus center. This first-formed product is not isolated but undergoes reaction with the disulfide by-product to give a pentavalent intermediate, which, on hydrolysis, affords the (dipheny1thio)phosphate [ 191. The method works reasonably well for primary acids (60-70% yields) but is somewhat less efficient for secondary and tertiary carboxylic acid derivatives. The 0-acyl thiohydroxamates from N-hydroxypyridine-2-thione have also been employed in this sequence. Subsequently, in a simple and conceptually elegant alternative, elemental white phosphorus (P4) was shown to be a very effective trap for the carbon-centered radicals generated via photolysis of the corresponding Barton PTOC esters in tetrahydrofuran [20]. Oxidation of the resultant products of this reaction either with aqueous hydrogen peroxide or even more unusually hydrogen peroxide followed by sulfur dioxide afforded phosphonic acids in very good yields. The conversion of linoleic acid shown in Scheme 15, which does not result in any attack at the sensitive skipped diene unit, provides ample testimony to the power of this method.

0,OH -"'OH 82%

Scheme 15. Preparation of phosphonic acids using white phosphorus [20]

118

1.7 Decarboxylution via 0-Acyl Thiohydroxamates

1.7.3.6 Decarboxylative Hydroxylation (RC02H t ROH) The above transformation is a particularly useful one which would require several steps by conventional methodology. Two distinctly different methods, both of which depend on the free-radical chain reactions of Barton esters, have however been developed. The first of these to be discussed, although chronologically the second to be developed, involves reaction of an acyl thiohydroxamate with tris(pheny1thio)antimony, and the chain sequence effectively parallels that outlined for the phosphorus congener above [21] (Scheme 16). In this instance, the first-formed alkyl bis(pheny1thio)antimony derivative is very air sensitive, and undergoes oxygen insertion into the carbon-antimony bond. The resultant peroxy intermediate then rearranges rapidly to the pentavalent derivative, from which the alcohol can be released on hydrolysis. The specific example shown below in Scheme 17 is indicative of the power of this transformation, although it must be admitted that the method requires very pure, thiophenol-free antimony reagent. From a mechanistic standpoint, however, the first method to be developed [22, 41 is of more interest and relied very simply on available kinetic data, which indicated that the capture of an alkyl radical by molecular oxygen is some ten thousand times faster than the competitive hydrogen atom abstraction from a thiol. Thus, the simple passage of triplet oxygen through a solution of the 0-acylthiohydroxamate and a non-nucleophilic mercaptan such as tert-butanethiol leads to excellent yields of hydroperoxides (Scheme 18). Whilst these primary products can of course be iso-

II

S

H20

ROH

R.O.Sb,

,SPh SPh

Scheme 16. Decarboxylative hydroxylation using tris(pheny1thio)antimony [21]

g,, (82%)

"'CO2Me

Scheme 17. Decarboxylative hydroxylation 1211

"'C02Me

1.7.3 Functional Group Transformations involving Radical Chain Reactions

R

H

1 19

R >O R'

xOH

R

Scheme 18. Decarboxylative hydroxylation using triplet oxygen and a mercaptan

lated if desired, it is often more convenient to carry out a subsequent in situ conversion either to the nor-alcohol by reduction with trimethyl phosphite or dimethyl sulfide or, through reaction with p-toluenesulfonyl chloride and pyridine, to the corresponding carbonyl compound. Subsequent studies using the same concept established that tungsten lamp irradiation of the Barton esters based on N-hydroxy2-thiazolinethione under air or oxygen at room temperature in the presence of tertdodecanethiol followed by reductive work up with triphenylphosphine was the most practical solution [23]. Some examples are shown in Scheme 19.

,>_z

ZH

Ph

Z = C02H

-

Z = OH (82%) (Me0)3P work up

AcO"''

Z = ketone (62%) (TsCI, py work up)

z = CO2H

-

Z = OH (69%) (Me0)3P work up

Z = nor aldehyde (56%) (TsCI, py work up)

Scheme 19. Examples of decarboxylative hydroxylation using triplet oxygen and a mercaptan

1.7.3.7 Decarboxylative Sulfonation (RC02H -+ RS02Spy) [24] Although sulfur dioxide is not as efficient in capturing alkyl radicals as oxygen, it can, when used in a sufficiently large excess, act as a kinetically favorable trap in the same manner as oxygen without competition from the simple decarboxylative rearrangement. From an experimental standpoint, sufficiently high concentrations of sulfur dioxide can be obtained by using a mixture of dichloromethane and liquid sulfur dioxide at -10°C with photolysis from a simple tungsten lamp (Scheme 20) [24]. Some representative yields are illustrated in Scheme 21.

120

I . 7 Decarboxylation via 0-Acyl Thiohydroxumates

S

-10°C

Scheme 20. Decarboxylative sulfonation [ 241

Scheme 21. Some examples of decarboxylative sulfonylation [24]

R SO2 NR'2

Scheme 22. Preparation of unsymmetrical sulfones and sulfonamides

The Barton Group has also devised useful methods for the elaboration of these adducts into either unsymmetrical sulfones or sulfonamides as indicated in Scheme 22.

1.7.3.8 Decarboxylative Free-Radical Chain Reactions for the Preparation of Labeled Carboxylic Acids (RC02H --+ RC"02H) Method A. Isocyanide Trapping (Scheme 23)

In similar fashion to the decarboxylative sulfonylation described above, the trapping of the intermediate alkyl radical by an electron-withdrawing isocyanide is a kinetically favorable process, and hydrolysis of the resultant adduct can then lead to the structure of the original carboxylic acid, thereby providing a method for the preparation of labeled carboxylic acids as indicated [25].A disadvantage of this

1.7.3 Functional Group Transformations involving Radical Chain Reactions

12I

Scheme 23. lsocyanide trapping of alkyl radical from 0-acyl thiohydroxamates [25]

approach however is that the sufficiently radicophilic isonitriles are also easily polymerized.

Method B. Decarboxylative Introduction of Cyanide (Scheme 24) The replacement of a carboxylic acid group by nitrile functionality can also be used for the preparation of labeled compounds, and conditions for alkaline hydrolysis which did not lead to conjugation in skipped dienes like linoleic acid were developed by the Barton group. In this case, the free-radical chain sequence is straightforward, with the methanesulfonyl (or p-toluenesulfonyl) radical acting as the chain carrier [26]. This methodology also represents an interesting way for the preparation of nitriles without the necessity for amide formation followed by dehydration.

Scheme 24. Decarboxylative introduction of cyanide [26]

1.7.3.9 Decarboxylative Amination (RC02H

+ R-NH2)

Method A. The Use of Diazirine Traps The search for a nitrogen-centered radical trap for the radicals produced from 0-acyl thiohydroxamates was initially thwarted by competing ionic reactions but eventually culminated in the introduction of 3-bromo or 3-(trifluoromethyl)-3phenyl diazirine as extremely effective reagents [27]. In contrast to almost all of the other reactions of Barton esters described in this chapter, however, the reaction sequence does not involve a chain process. Thus, as outlined in Scheme 25, capture of the alkyl radical by the diazirine is followed by dimerization and subsequent loss of nitrogen to give the product imine from which the desired amide or amine is easily liberated by mild hydrolysis. Some typical yields are shown in the Scheme 26.

Method B. Decarboxylative Nitrosation (RC02H

+ [R-N0]2)

(Scheme 27)

In contrast to the diazirine method outlined above, the reaction of 0-acyl thiohydroxamates with trityl thionitrite proceeds via the standard chain mechanism with the tritylthiyl radical as chain carrier, and, as in the case of the Barton nitrite pho-

122

I . 7 Decarhoxylation via O-Acyl Thiohydroxamates Ph

X

X

Ph XPh X

x x

N-N-N-N% R

d 0

Ph

X=Br R-NKph H

1

X=CFs

RNH2

Scheme 25. Diazirine trapping of alkyl radicals from O-acyl thiohydroxamates [27]

B z Z = C02H

-

Z = NHCOPh (74%) Z = C02H

-

Z = NHCOPh (71%)

Scheme 26. Representative examples of decarboxylative amination using diazirine traps [27]

tolysis, the initial isolable products of the reaction are the nitroso dimers, even in spite of the fact that nitroso monomers are very efficient radical traps [28]. As a consequence, this approach is limited to primary and secondary carboxylic acids, since tertiary nitroso compounds do not dimerize. From a synthetic standpoint, although yields are moderate (50-60%), the value of the reaction lies in the variety of useful functional group transformations which can subsequently be performed on the product nitroso dimers as indicated in Scheme 28.

Scheme 27. Decarboxylative nitrosation of U-acyl thiohydroxamates [28]

Z = C02H

-

Pt02

Z = [NO12 (55%)

Z = NH2 (75%)

H2

*

3 iHr N ' O H

Z = C02H

-

Z = [NO12 (62%)

oxime (100%) A

Scheme 28. Product evolution from decarboxylative nitrosation

1.7.4 Intermolecular Carbon-Carbon Bond Formation by Addition of 0-Acyl Thiohydroxamates to Alkenes The photochemical or thermally induced reaction of 0-acyl thiohydroxamates produces nucleophilic alkyl radicals, which can, of course, add to electron-deficient alkenes. The efficient generation of a chain process however then requires that the resultant radical can effectively capture the sulfur atom of the Barton ester, thereby incorporating the pyridyl sulfide moiety into the resultant adduct and producing the alkyl radical as the chain carrier as shown in Scheme 29. In practice, since the decarboxylative rearrangement to alkyl pyridyl sulfides is the competing reaction, electron-withdrawing terminal alkenes have proven to be the most efficient traps [29]. Addition to electron-deficient alkynes is however only moderately effective. The Barton group have studied this facet of 0-acyl thiohydroxamate chemistry in considerable detail over the years, and some examples of the extensive range of richly functionalized adducts which can be produced are collected in Scheme 30.

R Y s p y Z

+

C02

+

R'

ORYO Z = C02Me, CN, NO2, S02Ph, OPO(OEt)2

Scheme 29. Propagation sequence for the trapping of alkyl radicals from U-acyl thiohydroxamates by electron-deficient alkenes

Substrate

Alkene

Adduct

fo2H

BOCHN ..-sH C02CH2Ph

',.

C02Me

f

FCO2Me

,,,,HSPY C02CH2Ph

BOCHN

(62%) [30]

h

Q-..,. @SO2Ph

Ph Ph>S02ph

SPY

(75%) [32]

Ph>C02H Ph

0

-

,OEt P, OEt

&

OTBDPS

0 (0Et)zOP (70%) [35]

OTBDPS

Scheme 30. Free radical chain reactions of 0-acyl thiohydroxamates with alkenes

1.7.4 Intermolecular Carbon-Carbon Bond Formation

125

The power of this methodology becomes fully apparent however on further synthetic manipulation of the geminally functionalized pyridyl sulfide adducts, with two ‘general reactions’ being reductive removal of the sulfide by Raney nickel, nickel boride or tri-n-butyltin hydride, or controlled oxidation to the sulfoxide and subsequent thermal syn elimination (Scheme 31). The 2-S-pyridyl sulfones are particularly versatile intermediates, and the chemistry of this geminally functionalized unit was considerably expanded by the Barton group to the range of useful reactions shown below in Scheme 32 [32]. The chemistry of these trapped sulfide adducts also provided no less than three distinct solutions to the problem of the homologation of carboxylic acids, thereby providing a mild radical alternative to the classical Arndt-Eistert reaction. Thus, as shown in Scheme 33, the CI nitrosulfides obtained using nitroethylene as the alkene trap could be converted by oxidation to carboxylic acids or ‘hydrolyzed’ to aldehydes using aqueous titanium trichloride [29, 3 I]. At a later stage, since nitroethylene itself is difficult to produce on a large scale, a second procedure using the adducts derived from phenyl vinyl sulfone was developed. This involved oxidation to the sulfoxide followed by Pummerer rearrangement with trifluoroacetic anhydride and finally mild alkaline hydrolysis (Scheme 34) [321.

Scheme 31. Oxidation and reduction of alkyl-2-S-pyridyl sulfide adducts

* NaHTe

RASO,Ph

R“CO~H

Scheme 32. Elaboration of adducts from addition of 0-acyl thiohydroxamates to phenyl vinyl sulfone [33]

126

1.7 Decarboxylation via 0-Acyl Thiohydroxamates

Scheme 33. Oxidation and hydrolysis of a-nitrosulfide adducts [29, 311

'0

(i) P

R kS02Ph F3COCO

I

Rr\C02H

(ii)(CF3CO)20*

\

Scheme 34. Homologation of carboxylic acids via phenyl vinyl sulfone adducts [32]

A final solution to the homologation problem involves the geminally disubstituted terminal alkene trap shown in Scheme 35, which is already at the correct oxidation level for alkaline hydrolysis to the desired acid [36]. In similar fashion, ethyl a-trifluoroacetoxy acrylate was shown to be the most effective alkene for the homologation of carboxylic acids to a-keto carboxylic acids [37]. The overall sequence is illustrated for the preparation of 2-oxoadipic acid in Scheme 36 and the methodology was also successfully applied in carbohydrate chemistry [38]. In general terms, save for the powerfully electron-withdrawing nitroalkenes, the use of a 1,2-disubstituted alkene requires 'double activation' in order to be a preparatively useful reaction. On some occasions the pyridyl sulfide adducts can be isolated from these reactions, whilst in other cases spontaneous elimination of 2-mercaptopyridine occurs. The overall trends for these alkenes [29, 39, 401 are collected in

0 II

R

Lo"?

S

O' P-OMe 'OMe

+

A

S02Ph

V

\\ ,OMe

--- Ryo;--;oMe SPY

Scheme 35. Homologation of carboxylic acids using a-phenylsulfonyl enol phosphate traps [ 361

1.7.4 Intermolecular Curbon-Curbon Bond Formation

127

DCC (88%) OCOCF3 OCOCF3 Aco2Et_

Me0~

c

o

2

,

,

H

O

W

O

SPY

hv, 0 "C

H

0

(94%)

(83%) overall

Scheme 36. Homologation of carboxylic acids to cc-ketocarboxylicacids [37]

Scheme 37. Thus simple methods are available for alkylation of p-quinones 1391 and maleic anhydride 1291, whilst, inter aliu, hydrolysis of the adducts from 1,1dichloro-2,2-difluoroethene with aqueous silver nitrate T H F provides homologated a,a-difluoroalkane-carboxylicacids 1401.

"XiPY F

F

I

R

NC

[401

Scheme 37. The trapping of alkyl radicals from 0-acyl thiohydroxamates using 1,2-disubstituted alkenes

128

1.7 Decarboxylation via 0-Acyl Thiohydroxamates

The use of a protonated heterocyclic base as the radical trap has also proven to be a very useful extension of 0-acyl thiohydroxamate chemistry and is typically carried out by photolysis of the Barton ester in a dichloromethane solution containing the camphorsulfonate salt of the heterocycle [41]. Two examples of this approach are shown in Scheme 38. The intermolecular addition of 0-acyl thiohydroxamates to alkenes with concomitant displacement of a chain-carrying vinyl radical (i.e. the addition elimination strategy) [ 3 1, 421 is also a very useful carbon-carbon bond-forming reaction as shown in Scheme 39. However, a necessary prerequisite for an efficient chain sequence is the incorporation of an electron withdrawing group at the central carbon atom of the allylic unit. When these criteria are fulfilled, good yields can be obtained for the addition of the usefully functionalized three-carbon units (Scheme 40). ~

C02Me

9

Ad Qco2Me

\

(81Yo)

NHCOPh

(60%) Scheme 38. The use of protonated heterocyclic bases as alkene traps for alkyl radicals from 0-acyl

thiohydroxamates [41]

S Z = C02Et, R = S'Bu (carboethoxyallylation) Z=NOz, R=Ph Scheme 39. Distal addition elimination procedures using 0-acyl thiohydroxamates [ 3 1, 321

I . 7.4 Intermolecular Curbon-Curbon Bond Formation

I

0-

I

OAc

(77%)

Scheme 40. Distal addition-elimination adducts from 0-acyl thiohydroxamates [ 3 1, 321

129

130

1.7 Decarboxylation via 0 - A c y l Thiohpdroxarnates

1.7.5 Carbon-Carbon Bond-Forming Reactions of Barton Esters involving Cyclization Although 0-acyl thiohydroxamate-mediated reactions leading to cyclic products can be readily envisaged, they have not thus far been extensively used. Some representative examples involving both simple cyclizations [29, 43, 441 and more complex multiple addition cyclization sequences 1451 are collected in Scheme 41.

(82%) 1291

Me0

OMe

% o &BUSH,heat

*

(60%) [43]

THF

(52%) [44]

Scheme 41. Reactions of 0-acyl thiohydroxamates involving cyclization

I . 7.6 Decurboxylative Radical Generation

13 1

1.7.6 Decarboxylative Radical Generation from Precursors Other than Carboxylic Acids Although the vast majority of publications involving Barton esters have involved the generation of carbon-centered radicals from carboxylic acids, the O-acylthiohydroxamate decarboxylative protocol has also been extended to other substrates. Thus, as shown by the example in Scheme 42, sequential treatment of the trimethylsilyl ethers of a variety of tertiary alcohols with oxalyl chloride and the parent thionohydroxamic acid furnishes mixed ‘oxalate esters’ which undergo reductive deoxygenation on subsequent reaction with a tertiary thiol in refluxing benzene [46]. The selectivity of this method for tertiary alcohols arises as a consequence of the relativity slow rates of decarboxylation of primary and secondary alkoxycarbonyl radicals.

-

X=OSiMe3 (80%) Y=CH3

X = CH3 Y=H

Scheme 42. Free radical deoxygenation of tertiary alcohols [46]

As anticipated, by analogy with the chemistry of Barton esters, the same mixed oxalate esters can be used to prepare tertiary alkyl chlorides, simply by refluxing in carbon tetrachloride [47], and also for the creation of quaternary carbon centers through selection of either a Michael acceptor [46] or 2-(carboethoxy) ally1 trrtbutyl sulfide [46] as the radicophile. Derivatives based around the use of 2-mercaptopyridine- N-oxide have also featured in decarboxylative methods for the generation of nitrogen-centered radicals. Thus, the generation of aminyl radicals by tungsten lamp photolysis of the mixed anhydrides of carbamic acids with the parent thiohydroxamic acid provided the basis for the elegant studies by Newcomb [48] as exemplified by the cyclization shown in Scheme 43. An even more complex fragmentation reaction, which provides a mild and very useful source of iminyl radicals, was developed by Zard and Boivin using the Bar-

132

1.7 Decarboxylation via 0-Acyl Thiohydroxarnates H n-?"

qrn

H n-Bu CH3COzH

\

R3SH

*

H

(60%)

Scheme 43. Decarboxylative generation of aminyl radicals [48]

Scheme 44. Decarboxylative generation of iminyl radicals [49]

ton esters prepared from 0-carboxymethyl derivatives of oximes [49]. As shown in Scheme 44, these can be subsequently captured by intramolecular cyclization using group transfer chemistry.

1.7.7 Conclusions The foregoing chapter has hopefully demonstrated that the chemistry of Barton esters provides a very disciplined source of carbon-centered radicals. The host of mild, high-yielding and very useful functional group transformations and carboncarbon bond-forming reactions which have been developed all testify to the power of the radicophilic thiocarbonyl group for the generation and sustenance of highly efficient chain reactions. These facets, when combined with the neutral reaction conditions and functional group tolerance exhibited, should certainly encourage the practitioner of organic synthesis to select the carboxylic acid group as his precursor for carbon-centered radical generation.

References [ l ] D. H. R. Barton, D. Crich, W. B. Motherwell, J. Chem. Soc., Chem. Commun. 1983, 939. [2] D. H. R. Barton, W. B. Motherwell, Heterocycles 1984, 21, 1; D. Crich, Aldrichimicu Actu 1987, 20, 35; D. H. R. Barton, S. Z. Zard, Pure Appl. Chem. 1986, 58, 675; D. Crich, L. Quintero, Chem. Rev. 1989, 89, 1413; D. H. R. Barton, Tetrahedron 1992, 48, 2529; D. H. R. Barton, Pure Appl. Chem. 1994, 66, 1943.

References

133

[3] D. Crich, W. B. Motherwell, Free Radical Chain Reactions in Organic Synthesis, Academic Press, 1992, Harcourt Brace Jovanovich, London. [4] D. H. R. Barton, D. Crich, W. B. Motherwell, Tetrahedron 1985, 41, 3901. [5] D. H. R. Barton, Y. Herve, P. Potier, J. Thierry, J. Chem. Soc., Chem. Commun. 1984, 1298; D. H. R. Barton, Y. Herve, P. Potier, J. Thierry, Tetrahedron 1988, 44, 5479. [6] P. Garner, J. T. Anderson, S. Dey, J. Org. Chem. 1998, 63, 5732. [7] D. H. R. Barton, M. Samadi, Tetrahedron 1992, 48, 7083. [8] For additional examples of this transformation see inter a h : - J. C. Braeckman, D. Daloze, M. Kaisin, B. Moussiaux, Tetrahedron 1985, 41, 4603; 0. Campopiano, R. D. Little, J. L. Petersen, J. Am. Chem. Soc. 1985, 107, 3721: A. Otterbach, H. Musso, Anyew. Chem. Int. Ed. Enyl. 1987, 26, 554; J. D. Winkler , V. Sridar, J. Am. Chem. Soc. 1986, 108, 1708; J. D. Winkler, J. P. Hey, P. G. Williard, J. Am. Chem. Sac. 1986, 108, 6425; J. D. Winkler, K. F. Heuegar, P. G. Wiliard, J. Am. Chem. Soc. 1987,10Y, 2850; Z. Hell, L. Toke, Synth. Commun. 1996,26, 2127. [9] E. W. Della, J. Tsanaktsidis, Aus. J. Chem. 1986, 39, 2061. [ l o ] E. Vogel, T. Schieb, W. H. Schulz, K. Schmidt, H. Schmickler, J. Lex, Angew, Chem. Int. Ed. Enyl. 1986,25, 723; D. H. R. Barton, B. Lacher, S. Z. Zard, Tetrahedron Lett. 1985,26, 5939; D. H. R. Barton, B. Lacher, S. Z. Zard, Tetrahedron 1987, 43, 4321. [ 111 J. Zhu, A. J. H. Klunder, B. Zwanenburg, Tetrahedron Lett. 1993, 34, 3335. [12] G. W. J. Fleet, J. C. Son, J. M Peach, T. A. Hamor, Tetruhedron Lett. 1988, 29, 1449. [13] T. F. Herpin, W. B. Motherwell, J.-M. Weibel, J. Chem. Soc., Chem. Commun. 1997, 923. [ 141 D. H. R. Barton, D. Crich, P. Potier, Tetrahedron Lett. 1985, 26, 5943. [15] D. H. R. Barton, C. Tachdjian, Tetrahedron 1992, 48, 7091; D. H. R. Barton, P. Blundell, J. Sc. Jaszberenyi, J. Am. Chem. Soc. 1991, 113, 6937; D. H. R. Barton, P. Blundell, J. Cs. Jaszberenyi, Tetrahedron 1992, 48, 7121; D. H. R. Barton, J. Cs. Jaszberenyi, K. Tang, Tetrahedron Lett. 1993, 34, 3381: D. H. R. Barton, C-Yu Chern, C. Tachdjian, Heterocycles 1994, 37, 793. [I61 D. H. R. Barton, D. Crich, Y. Herve, P. Potier, J. Thierry, Tetrahedron 1985, 41, 4347. [17] D. H. R. Barton, D. Bridon, S. Z. Zard, Tetrahedron Lett. 1984, 25, 5777; D. H. R. Barton, D. Bridon, S. Z. Zard, Heterocycles 1987,25, 449. [18] D. H. R. Barton, D. Bridon, Y. Herve, P. Potier, J. Thierry, S. Z. Zard, Tetrahedron 1986, 42, 4983. [19] D. H. R. Barton, D. Bridon, S. Z. Zard, Tetrahedron Lett. 1986, 27, 4309. [20] D. H. R. Barton, J. Zhu, J. Am. Chem. Soc., 1993, 115, 2071; D. H. R. Barton, R. A. V. Embse, Tetrahedron 1998, 54, 12475. [21] D. H. R. Barton, D. Bridon, S. Z. Zard, Tetrahedron 1989, 45, 2615; D. H. R. Barton, D. Bridon, S. Z. Zard, J. Chem. Soc., Chem. Commun. 1985, 1066; D. H. R. Barton, N. Ozbalik, M. Schmitt, Tetrahedron Lett. 1989, 30, 3263. [22] D. H. R. Barton, D. Crich, W. B. Motherwell, J. Chem. Soc., Chem. Commun. 1984, 242. [23] D. H. R. Barton, S. D. Gero, P. Holliday, B. Quick-Sire, S. Z. Zard, Tetrahedron 1998, 54, 6751. [24] D. H. R. Barton, B. Lacher, B. Misterkiewicz, S. Z. Zard, Tetrahedron 1988, 44, 1153. Trapping of alkyl radicals from 0-acyl thiohydroxamates with sulfur followed by borohydride reduction also provides a convenient synthesis of thiols, viz. D. H. R. Barton, E. Castagnino, J. Cs. Jaszberenyi, Tetrahedron Lett. 1994, 35, 6057. [25] D. H. R. Barton, N. Ozbalik, B. Vacher, Tetrahedron 1988, 44, 3501. [26] D. H. R. Barton, J. Cs. Jaszberenyi, E. A. Theodorakis, Tetrahedron Lett. 1991, 32, 3321; D. H. R. Barton, J. Cs. Jaszberenyi, E. A. Theodorakis, Tetrahedron 1992, 48, 2613. [27] D. H. R. Barton, J. Cs. Jaszberenyi, E. A. Theodorakis, J. Am. Chem. Soc. 1992, 114, 5904; D. H. R. Barton, J. Cs. Jaszberenyi, E. A. Theodorakis, J. H. Reibenspies, J. Am. Chem. Soc. 1993, 115, 8050. [28] P. Girard, N. Guillot, W. B. Motherwell, P. Potier, J. Chem. Soc., Chem. Commun. 1995, 2385; P. Girard, N . Guillot, W. B. Motherwell, R. S. Hay-Motherwell, P. Potier, Tetrahedron 1999, 55, 3573. [29] D. H. R. Barton, D. Crich, G. Kretzschmar, J. Chem. Soc. Perkin Trans. 1 1986, 39; For a useful overview see D. H. R. Barton, C-Y. Chern, J. Cs. Jaszberenyi, Aust. J. Chem. 1995, 48,

134

1.7 Decarboxylation via 0-Acyl Thiohydroxamates

407; For related 1,2 disubstituted alkenes see also D. H. R. Barton, C-Y. Chern, J. Cs. Jaszberenyi, Tetrahedron Lett. 1992, 33, 7299. [30] D. H. R. Barton, Y. Herve, P. Potier, J. Thierry, Tetrahedron 1987, 43, 4297. 1311 D. H. R. Barton, H. Togo, S. Z. Zard, Tetrahedron 1985, 41, 5507. [32] D. H. R. Barton, H. Togo and S. Z. Zard, Tetrahedron Lett. 1985,26, 6349; D. H. R. Barton, J. Boivin, J. Sarma, E. da Silva, S. Z. Zard, Tetrahedron Lett. 1989, 4237; D. H. R. Barton, J. Boivin, E. Crepon, J. Sarma, H. Togo, S. Z. Zard, Tetrahedron 1991, 47, 7091. [33] D. H. R. Barton, B. Lacher, S. Z. Zard, Tetrahedron 1986, 42, 2325. [34] D. H. R. Barton, W. Liu, Tetrahedron Lett. 1997, 38, 2431; D. H. R. Barton, W. Liu, Tetrahedron 1997, 53, 12067. [35] D. H. R. Barton, S. D. Gero, B. Quiclet-Sire, M. Samadi, Tetrahedron Lett. 1989, 30, 4969; D. H. R. Barton, S. D. Gero, B. Quiclet-Sire, M. Samadi, J. Chem. Soc., Chem. Commun. 1988, 1372; D. H. R. Barton, S. D. Gero, B. Quiclet-Sire, M. Samadi, J. Chem. Soc., Chem. Commun. 1989, 1000; D. H. R. Barton, S. D. GCro, B. Quiclet-Sire, M. Samadi, J. Chem. Soc. Perkin. Trans. 1 1991, 981; D. H. R. Barton, A. Gateau-Olesker, S. D. Gero, B. Lacher, C. Tachdjian, S. Z. Zard, Tetrahedron 1993, 49, 4589; D. H. R. Barton, J. Cleophax, A. Gateau-Olesker. S. D. Gero, C. Tachdjian, Tetrahedron 1993,49, 8381; D. H. R. Barton, S. D. Gero, B. Quiclet-Sire, M. Samadi, Tetrahedron; Asymmetry 1994, 5, 2123; D. H. R. Barton, S. D. Gero, G. Negron, B. Quiclet-Sire. M. Samadi, C. Vincent, Nucleosides and Nucleotides 1995, 14, 1619. [36] D. H. R. Barton, C. Y. Chern, J. Cs. Jaszberenyi, S. Z. Zard, Tetrahedron Lett. 1991,32, 3309. [37] D. H. R. Barton, C.-Y. Chern, J. Cs. Jaszberenyi, Tetrahedron Lett. 1992, 35, 5017; D. H. R. Barton, C.-Y. Chern, J. Cs. Jaszberenyi, Tetrahedron 1995, 51, 1867. For alternative uses of this alkene trap see D. H. R. Barton, C-Y. Chern, J. Cs. Jaszberenyi, T. Shinada, Tetrahedron Lett. 1993, 34, 6505. [38] D. H. R. Barton, J. Cs. Jaszberenyi, W. Liu, T. Shinada, Tetrahedron 1996, 52, 2717; D. H. R. Barton, W. Liu, Tetrahedron Lett. 1997, 38, 367. [39] D. H. R. Barton, D. Bridon, S. Z. Zard, Tetrahedron 1987, 43, 5307; D. H. R. Barton, W. Sas, Tetrahedron 1990, 46, 3419. [40] T. Okano, N. Takakura, Y. Nakano, A . Okajima, S. Eguchi, Tetrahedron 1995, 51, 1903. [41] D. H. R. Barton, B. Garcia, H. Togo, S. Z. Zard, Tetrahedron Lett. 1986, 27, 1327; E. Castagnino, S. Corsano, D. H. R. Barton, S. Z. Zard, Tetrahedron Lett. 1986, 27, 6337. [42] D. H. R. Barton, D. Crich, J. Chem. Soc. Perkin Trans. I 1986, 1613. [43] S. A. Ahmad-Junan, A. J. Walkington, D. A. Whiting, J. Chem. Soc., Chem. Conzmun. 1989, 1613. [44] F. E. Ziegler, Y. Wang, Tetrahedron Lett. 1996, 37, 6299. [45] D. H. R. Barton, E. da Silva, S. Z. Zard, J. Chem. Soc., Chem. Commun. 1998, 285. [46] D. H. R. Barton, D. Crich, J. Chem. Soc. Perkin Trans. I 1986, 1603. [47] D. Crich, S. M. Fortt, Synthesis 1987, 35. [48] M. Newcomb, S. U. Park, J. Kaplan, D. J. Marquardt, Tetrahedron Lett. 1985, 26, 5651; M. Newcomb, T. B. Deeb, J. Am. Chem. Soc. 1987, 109, 3163. [49] J. Boivin, E. Fouquet, A.-M. Schiano, S. Z. Zard, Tetrahedron 1994, 50, 1769.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

1.8 Use of Cobalt for Radical Initiation Javed Iqbal, Rashmi Sanghi, Jyoti Prokash Nandy

1.8.1 Introduction The formation of a carbon-carbon bond via free-radical-mediated reactions has emerged as a powerful tool in the domain of synthetic organic chemistry. This development is due to the concerted efforts from the groups of Julia, Walling, Ingold and Beckwith, whose pioneering studies have elicited enormous interest in the area of synthesis using free radicals. Consequently these efforts have culminated in adding a new dimension to the repertoire of synthetic methodology. There are several protocols available for free-radical reactions: however, the transition metalpromoted radical reactions offer a useful alternative to stannane and other main group metal-based radical chemistry. The advantage of the former method over the latter is that these reactions are usually terminated with the introduction of functionality into the product. Among the various transition metals that are known to mediate the generation of a carbon-centered radical, cobalt-initiated radical formation has shown exceptional versatility in carbon-carbon and carbon-heteroatom bond formation. The cobalt-mediated radicals can be generated by a reductive process where the metal acts as a reductant and the carbon-centered radicals can be generated by an electron transfer from the cobalt complex to the radical precursor. The free radicals formed by this process may react with the cobalt complex and exist as an organocobalt complex (Scheme 1). The thermal and photochemical lability of the carbon-cobalt bond make the organocobalt complex an attractive precursor to carbon-centered free radicals which are formed by the homolysis of this bond (Scheme 1). As described earlier carbon-centered radicals can be efficiently generated by homolysis of an alkylcobalt(II1) species. This species can be synthesized by a reductive process from an alkyl halide and a nucleophilic Co(1) reagent [l-61. This chapter describes the recent advances in cobalt-initiated carbon-centered free radicals (generated via a reductive process) in organic synthesis. The cobalt-mediated free-radical reactions generated via this protocol can be broadly divided into the following two categories.

136

1.8 Use of Cobalt for Radical Initiation

X-

Scheme 1. Cobalt-mediated generation of radicals by a reductive process

1.8.2 Vitamin B12-Catalyzed Radical Reactions Vitamin Bl2-promoted radical reactions have found widespread application in organic synthesis mainly because of the pioneering work of Scheffold and coworkers. Vitamin BI2 can be reduced chemically (Zn-NH4Cl) or electrochemically (-0.8 V) to afford Cob(1)alamin ( B I ~ ~which ) , can be converted to the corresponding alkyl analog on reaction with various alkyl halides [7, 81. The ability of Vitamin B12 and its analog to form alkylcobalt derivatives in combination with the ease of homolysis of the carbon-cobalt bonds in these molecules has led to the development of novel synthetic routes to various natural products. Vitamin B12 is used in catalytic quantities and is an efficient catalyst in electroorganic synthesis since it acts as a mediator in the transfer of electrons from a cathode to electrophilic organic substrates. The two useful Bl2-catalyzed reactions are the reductive p-elimination and the conjugate addition of R-X to activated olefins. The B12-catalyzedcyclization by electrolysis at - 1.4 to - 1.6 V in the presence of 5 mol% hydroxocobalamin hydrochloride (electrocatalysis EC) of a,P-unsaturated ketones 1 and 4 bearing a bromo side chain occurs in excellent yields. The cyclization is dependent upon the number of carbon atoms present in the side chain, and the reaction usually proceeds via 5-exo-trig or 6-endo-trig arrangement to give 2 and 5 respectively (Scheme 2). 2-(Bromoethy1)propargylic ethers 7 undergo facile 5-exo-dig cyclization to yield precursors for CI- and a-methylene lactones 8 (Scheme 3). The consecutive addition of alkyl halide to activated olefins by photoelectrocatalysis (PEC) of hydroxocobalamin hydrochloride allows the construction of extended carbon chains as shown for the synthesis of pheromone queen substance 9. The mild conditions of the B12/PEC reaction are suited for the addition of primary alkyl halides 10 containing a potential leaving group. This is illustrated in the synthesis of endo- and exo-brevicomin (11) (Scheme 4). The synthesis of C-glycosides may be achieved by B12-catalyzed C-C bond for(13) can be premation. Thus, 3-(2,3,4,6-tetra-O-acetyl-a-~-glucosyl)propionitrile pared from acetobromoglucose (12) by reduction with Zn in DMF in the presence of acrylonitrile and 3 mol% hydroxocobalamin hydrochloride. Similarly, the ribofuranosyl derivative 15 can be prepared from the corresponding acetobromofuranose 14 (Scheme 5).

1.8.2 Vitamin Biz-Catalyzed Radical Reactions

4 n=3 n=4 n=5

5 95% 70%

137

6 90% 10%

Scheme 2. Vitamin Blpxitalyzed cyclization by electrocatalysis (EC)

8a

7a SiMe3

7b

8b

Scheme 3. Vitamin Blr-catalyzed cyclization in the presence of zinc

Interestingly, acid anhydride 16 reacts under B12/PEC conditions with an a$unsaturated carbonyl compound to give the corresponding 1,4-addition product 17 which may be converted to the cyclopentanone 18 (Scheme 6) [9]. The BI*-catalyzed electrolysis of acetoxy bromo acetal 19a in DMF at -1.0 V afforded the diastereomeric acetal 20 as a product of a cyclization-elimination sequence. Starting from a chiral cyclopentene bromoacetal (19b) and 1-octyn-3-one, a prostaglandin Fzr precursor (21) containing all the structural features from C6 to C ~ with O 8 R , 11 R, and 12R chirality, is obtained by the one-step formation of two carbon-carbon bonds in the BI2-catalyzed radical cyclization addition sequence (Scheme 7) [ 101.

1.8 Use of Cobalt f o r Radical Initiation

138

Br

OAc

L

15%

O

A

I

C

1. NaOHIMeOH 2. PBra

0 Br

+ e C 0 2 E t

9 (E:Z =7:1)

+ H 11 exo-Brevicornin

10

Scheme 4. Vitamin Biz-catalyzed addition of alkyl halides by PEC

AcO,

AcO.

F C N 35-40%

Br

AcO

12

I

CN

13

I

I I AcO OAc

55%

AcO OAc 14

15

Scheme 5. Vitamin Biz-catalyzed addition of bromosugars to acrylonitrile

A

c

O

~

BldPEC O 55%c q

16

H

0

&

OAc NaOMe

17

&"-%-'OAc la

Scheme 6. Vitamin Biz-catalyzed addition of anhydride to r,p-unsaturated carbonyl compound by PEC

1.8.2 Vitumin Biz-Catalyzed Radical Reactions

07 0

139

0-(OEt

0'

612 )r

Zn-NH&I-EtOH

Br

AcO""

73%

19a

20

YE'

612

t

Zn-NH4CI-EtOH

TBDMSO"'

73%

19b

0

21

R1 = OEt, R2 = H 26% R1 = H, R2 = OEt 21%

Scheme 7. Vitamin Biz-catalyzed intramolecular cyclization

,p-Br

+

B,~/PEC

_INHCoCH3

0

COOCH3

0

72%

22

COOCH3

23

Scheme 8. Vitamin Blr-catalyzed photochemical 1,4-hydroaddition of alkyl halides

Similarly, the 2-amino ester 23 can be synthesized by Blz-catalyzed photoelectrochemical 1,4-hydroaddition of alkyl halide 22 [ 1 11 or carboxylic anhydrides to 2-acetamidoacrylate (Scheme 8). A recent study has demonstrated a reductive vitamin B 12-catalyzed transformation of some tetrachloroalkanols to cyclopropane alkanols [12]. In studies directed towards forskolin, Pattenden et al. have observed dichotomous reactivity in stannane- and cobalt-mediated radical cyclization. In one instance, it was shown that the radical cyclization of the bromoacetal 24 initiated by Bu3Sn' (BusSnH, AIBN) led to predominantly (95%) the equatorial-oriented sidechain isomer 25a, whereas use of catalytic vitamin B12 (MeOH, LiC104, - 1.9 V, 24 h) produced (70%) almost entirely the corresponding axial epimer 25b (Scheme 9) [ 131.

-1.9 v

AIBN

25a

24

25b

Scheme 9. Dichotomous reactivity in stannane and cobalt-mediated radical cyclization

1.8 Use of Cobalt f o r Rudicul Initiation

140

1.8.3 Organocobalt-Mediated Radical Reactions Organo-cobalt complexes are excellent precursors to carbon-centered radicals. A facile homolytic cleavage (thermal or photochemical) of a range of alkyl and acyl cobalt complexes and the addition of the resulting carbon-centered radical to a carbon-carbon double bond can be carried out by cobalt-mediated radical reactions. The required organocobalt reagents can be prepared by single-electron transfer from a nucleophilic Co' reagent to the alkyl or acyl halides. Johnson and coworkers have demonstrated that the ally1 organocobaloximes 26 undergo an SH2' displacement with a trichloromethyl radical to give 27 [ 14-17]. Cyclopropane 29 can be synthesized from homoallylic cobaloximes 28 and a suitable radical precursor by an intramolecular homolytic displacement at the a-carbon (Scheme 10). Similarly, fused and spiro cyclopropane systems 31 and 33 can also be synthesized by the reaction of appropriate cycloalkenyl cobaloximes 30 and 32 with free radical precursors such as toluenesulfonyl iodide (Scheme 11). The thermal and photochemical reactions of hexenyl cobaloximes 34 with a large excess of CC14 gives mainly the pentachloroheptane 35 (path A). On the other hand, the photochemical reactions in the presence of low concentration of CC14 gives mainly the cyclopentyl methyl chloride 36a through homolysis of the C-Co bond followed by cyclization of the hexenyl radical and chlorine atom abstraction (path B). However,

R

,+&/-.. Co(drngH)zL

+

A or hv

BrCCI3

+ BrCo(drngH)pL

c13c

26

27

&Co(drngH)2L

+

BrCC13

A Or hv

[C'3cLC~(drngH)zL

28

29

Scheme 10. S H ~reaction ' using nucleophilic Co(1) reagent

wCo(dmgH)aL

a

. ArS021 hv

S02Ar 30a

31a

32

eCo(drngH)2L

+

", S09Ar 31b

hv 30b

33

Scheme 11. Organocobalt-mediated intramolecular cyclopropanation using toluenesulfonyl iodide

1.8.3 Organocobalt-MediatedRadical Reactions

R

CI

hv or A

CI

R LC~(dm~H),L

Path C

k4(excess)

35

141

Path A R = H hv

34 CC14(low)

!

36b R = H or Me

Path 0

36a

Scheme 12. Intramolecular homolytic displacement of cobalt by attack of a secondary radical center

the thermal reaction in the presence of a low concentration of CC14 gives a higher yield of trichloroethyl cyclopentane 36b through attack of a trichloromethyl radical at the terminal unsaturated carbon followed by the intramolecular homolytic displacement of cobalt by attack of the secondary radical center on the a-carbon (path C) (Scheme 12) [17]. In their pioneering studies, Pattenden and coworkers have synthesized a variety of organocobalt compounds using salen and salophen ligands and have exploited the weakness of the C-Co bond to generate a carbon-centered radical which undergoes a new carbon-carbon bond formation to give a product radical [18-351. The latter carbon-centered radical can be trapped with Co" to give a carbon-cobalt bond which can be manipulated to introduce functionality (i.e C=C and -OH) into the product. This process is termed as a cobalt group transfer reaction and is formally related to atom transfer reactions because of the nature of the transformation that they effect; however the mechanistic pathways for these differ considerably. They have demonstrated the wide applicability of this new cobalt-initiated cyclization- trap functional group interconversion strategy for the synthesis of a very wide range of OH-substituted aromatic and heterocyclic molecules. Reaction between the Co(1) species derived from Co(II1) salen or Co(I1) salophen and (O-allyl) or (O-but-3-enyl) iodophenols 37 lead to an isolable cobalt complex 38 which can be converted into substituted benzofurans 38a-e upon treatment with a variety of reagents (Scheme 13) [19]. The carbon-cobalt bond in 38 can be replaced with iodine (38a), oxygen atom (38b), cyano group (38c) and with SPh group (38d) to afford a variety of functional benzofurans. Interestingly the radical cyclization of acetal 40 in the presence of cobaloxime leads to the cis-ring-fused alkyl-cobalt complex 41 which can be converted in a preparative manner to 42a,b following 1,2-elimination and hydrolysis/oxidation. Similarly the lactone 43 can be obtained from 40 following insertion of molecular oxygen and hydrolysis/oxidation protocol (Scheme 14). These reactions are believed to proceed via a reductive process to give an organocobalt complex 37a, which undergoes an intramolecular cyclization of the radical 37b generated by homolytic cleavage of C-Co bond (Scheme 15).

1.8 Use of Cobalt for Radical Initiation

142

I hv/N

39d

BrCo(Salen)PPh3 1% Na-Hg, rt, dark

38

39a

z l 0 It-BuNC heat

~ o o c o ( s a l e n )

45%

=o in

39e

39c

OH

39b

Scheme 13. Cobalt-salen-mediated synthesis of substituted benzofurans

1

cobaloxime

Ot-Bu 1. elimination

1. elimination

4

0 H 42a

O E ~ 2. BF3-mCPBA

2.BF3-mCPBA

R1 = Me; R2 = H

H 41

I

R1= H; R2 = Ot-BU

1. Odhv 2. NaBH4 3. BFymCPBA

43

Scheme 14. Cobaloxime-mediated synthesis of fused y-lactones

H 42b

1.8.3 Organocobalt-Mediated Radical Reactions

37

37a

37b

143

38

Scheme 15. Mechanism of cobalt-mediated intramolecular radical cyclization

COlll(salophen)

38

+

-

R

hv

0

4555%

46 R = C02Et or Ph or CN

Scheme 16. Intermolecular addition of organocobalt complexes to alkenes

The intermolecular addition reactions between organocobalt reagents 44 and 38 and a variety of deactivated C=C bonds led to new alkene products 45 and 46 respectively which resulted from radical addition to the C=C bonds followed by ‘dehydro-cobaltation’ from the presumed [20] organocobalt intermediates (Scheme 16). One of the significant developments in this area has been due to the excellent work by Pattenden and coworkers who have prepared a range of acylcobalt salophen compounds, precursors to the corresponding acyl radicals. Irradiation of deaerated, refluxing solutions of the acylcobalt salophens 47 in methylene dichloride, in the presence of deactivated C=C bonds, similar to the reactions with alkylcobalt compounds, led to good yields of the corresponding highly functionalized alkene products 48 and 49 resulting from the familiar homolysis (to RCo) addition-elimination (dehydrocobaltation) sequence (Scheme 17) [23, 241. In another significant development, Branchaud and coworkers have discovered an alkyl equivalent to the Heck reaction via a novel cobalt-mediated radical-olefin coupling involving alkyl bromides 50a-d and styrene leading to the synthesis of 51a-d [36-451. This protocol is useful for the synthesis of functional styrene derivatives, which are obtained by the addition-elimination sequence of the organocobalt intermediates (Scheme 18). They have also achieved a novel cobaloxime-mediated radical alkyl-heteroaromatic cross-coupling, replacing a C-H in the protonated heteroaromatic with C-alkyl via anaerobic visible-light photolysis of 95% ethanol solutions of primary and secondary alkyl cobaloximes 52a-e and pyridinium, quinolinium, 4-methylpyridinium, benzothiazolium p-toluenesulfonates leading to alkyl-substituted heteroaromatic derivatives 53a-e respectively (Scheme 19).

1.8 Use of Cohaltfor Radical Initiation

144

+

@C02Et

hv

&COZEt

47a

48a

&[Co]

+

@Ph

hv

&Ph

47b

48b

A C o l

hv

47c

49

Scheme 17. Addition of acylcobalt salophen to alkenes. Synthesis of functionalized alkenes by dehydrocobaltation process

@Ph

HOe

*

P

h

51a 80%

@Ph

@Ph

-

E

t o w P 0 51b 85%

h

E

t o OEt

h

50c

w

P

51c 86%

Ph

@Ph*

OBz 50d

OBz

HO

OH OBz 51d 79%

Scheme 18. Cobalt-mediated radical olefin couplings. Synthesis of functionalized styrene derivatives

145

1.8.3 Organocobalt-Mediuted Radical Reactions R 1. hv, 24 h 95% EtOH t

2. Neutralize 60-70%

t

I

Ts- H

53b

?

1. hv, 24 h 95% EtOH

R-Co"'(dmgH)pPy +

53a

2. Neutralize 60-70%

a+a R

52b

53c

53d

6

1. hv, 24 h 95% EtOH t

2. Neutralize

R

60-70%

53e

Scheme 19. Cobaloxime-mediated radical alkyl-heteroaromatic cross-coupling

They have recently demonstrated that radical alkyl-styryl coupling can be catalyzed by in situ generated cobaloxime in the presence of zinc [44]. A variety of alkyl bromides can be coupled with styrene provided that (a) the concentration of styrene is high, (b) there is a low catalyst concentration (pyridine dimethylglyoxime CoC12) to avoid premature B-H elimination, and (c) there is low (50-100 mM) concentration of alkyl bromide. A mechanism has been proposed for the catalytic process using Co"(dmgH)z-Py during the coupling of alkyl bromide with styrene. In another elegant study, Branchaud and coworkers have demonstrated an efficient cross-coupling between alkyl cobaloximes 54 and nitroalkyl anions 55 to give nitroalkanes 56 (Scheme 20). The alkyl-cobalt addition-elimination (cobalt group transfer) sequence has been used by Baldwin and Li during the enantiospecific synthesis of (-)-a-kainic acid (58a) and (-)-a-allokainic acid (58b). These reactions proceed via the carbon-centered

+

+

R

R1

Yield,%

H

H

85%

H

CZH5

83%

CH3

H

58%

CH3

C2H5

62%

Scheme 20. Cross-coupling between alkyl cobaloximes and nitro alkyl anions

146

1.8 Use of Cobalt for Radical Initiation

-

/"iP 'h

co'

-OR BnO

57

?N-CO.Ph

'fN-CO2Ph \

BnO

'OR 58a 50%

(-)-a-Kainic acid

BnO

OR 58b 30%

(-)-a-allokainic acid

Scheme 21. Synthesis of precursors to (-)-a-kainic acid and (-)-a-allokainic acid by cobalt group transfer protocol

radicals which are generated from the corresponding organocobalt (111) intermediate formed by a reductive process using 57 as the substrate (Scheme 21) [45-481. In a similar manner, these researchers have also synthesized [48] a C-8 side-chain analog 60 of domoic acid using a cobalt-mediated cyclization-elimination sequence on the iodide 59 (Scheme 22). They extended this methodology to an enantiospecific total synthesis of acromelic acid A 64, a potent neurotoxin obtained from poisonous mushrooms [46]. The cornerstone of their synthetic strategy was a cobalt-mediated radical cyclization of the substrate 61 which was prepared from the epoxy alcohol in optically pure form. Treatment of 61 with cobalt(1) afforded 62, which was converted to the natural product 64 via pyridone 63 using routine functional group manipulation (Scheme 23). Pattenden and coworkers have shown that unsaturated carbamylcobalt salophens 65a-c undergo homolytic cleavage producing carbamyl radicals, which then undergo cyclization, accompanied by trapping (with Co" or TEMPO) or dehydrocobaltation leading to functionalized 8-, y- and S-lactams 66a-g (Scheme 24) [25]. The key intermediate 66h for the synthesis of (f)-Thienamycin has been prepared by heating a solution of carbamylcobalt salophen 65d in toluene (Scheme 25) [26]. Epoxy olefins 67a-b can be converted to cycloalkanols 69a-b respectively on treatment with cobalt(1) dimethylglyoxime using a sunlamp. These reactions proceed via the cyclization of the intermediate p-hydroxycobaloximes 68a-b, which are produced by a nucleophilic opening of epoxides with cobalt(1) (Scheme 26) [27, 281. Pattenden and coworkers have developed a cascade cobalt group transfer reaction by effecting consecutive cobalt-mediated radical cyclizations in a controlled

Scheme 22. Cobalt-mediated synthesis of C-8 side-chain analog of domoic acid

1.8.3 Organocobalt-Mediated Radical Reactions

-

BnO-OH

co'

0 64%

OBn I

61

1. H30+

t

HN*NH

4

2. N H ~ O A C H

o

BnO/

I

Meo BnO

64 Acromelic acid A

62 E:Z = 1:3

63

Scheme 23. Cobalt-mediated synthesis of acromelic acid

Co(salophen) I

-N,n-Bu OACo(salophen)

65a

Toluene

1

66a

TEfWO heat

n-Bu

66b 71%

, , A . ~ ,

n-Bu

O A O

+

a do -

TEMPO L N , n - B u

CH2C12

Toluene

OACo(salophen)

A-Bu

23%

+

'Yn - '-O ~u

65b

66d

Toluene c

heat

n-Pr

65c

N O n-Bu

'

62%

6 6 59% ~

'OACo(salophen)

147

66f 51 %

Scheme 24. Synthesis of lactam via carbamyl cobalt salophen complexes

669 7%

66e

148

K 0

1.8 Use of Cobalt f o r Radical Initiation

Ph

Wl) -

G O , P h

Toluene

),,PO,Ph *

KNVPh 65d

heat

0

N-Ph

66h 55%

Thienamycin

Scheme 25. Synthesis of precursor to Thienamycin via carbonyl cobalt salophen complex

67a

68a

69a 94%

67b

68b

69b 86%

Scheme 26. Intramolecular cyclization of epoxy olefin-mediated by cobalt(1) dimethyl glyoxime

manner, allowing trapping and interception of the organocobalt intermediates leading to functionalized mono- and bicyclic systems [ 351. Treatment of a mixture of diastereomers of 70a with cobaloxime resulted in exclusive 5-exo-trig cyclization leading to tetrahydrofuranyl methyl cobaloxime 71a (Scheme 27). The latter, on ir-

70a

71a

72a 71%

70b

71b

72b 65%

Scheme 27. Synthesis of fused ylactones by a cascade cobalt group transfer protocol

1.8.3 Organocobalt-Mediated Radical Reactions

149

"'lop

Me0

70a

73d 56%

71c

&

Me0

Me0 73a 72%

73b 62%

M e O A O w 73C 67%

Scheme 28. Cobalt-mediated tandem cyclization and radical trapping

radiation with an ultraviolet sunlamp, was then found to undergo a second equally smooth, 6-exo-trig cyclization, which was accompanied by dehydrocobaltation producing the trans-ring-fused bicycle 72a in high yields. A similar treatment of vinyl iodide 70b led to the formation of the intermediate cobalt salophen 71b which on irradiation gave the corresponding bicyclic product 72b. The tandem cyclization and radical trapping of substrate 70c which incorporates only monosubstituted carbon-to-carbon double bonds first led to the corresponding furan cobaloxime 71c; however, the latter on irradiation underwent exclusive 7-endo-trig cyclization to give the bicyclic product 73a in good overall yield. Hydrolysis and in situ oxidation of 73a in the presence of Jones reagent gave the bicyclic lactones. When a solution of cobaloxime 71c was irradiated in the presence of triplet oxygen, the only product isolated was the aldehyde 73b, which is presumably formed by oxidative elimination involving a peroxycobalt intermediate. Irradiation of 71c in the presence of tetramethylpiperidine oxide led to the substituted hydroxylamine 73c. Similarly, irradiation of cobaloximes 71c in the presence of styrene led to the product 73d resulting from tandem 5-exo-7-endocyclization with in situ product radical trapping by styrene terminating in dehydrocobaltation (Scheme 28). The mechanism for the radical addition-elimination, promoted by alkyl- or acylcobalt reagent can be explained by Michael addition followed by dehydrocobaltation (Scheme 29).

A

RI'

'[Co]

or hv

R

addition

R

*

EWG

Scheme 29. Mechanism of radical addition-elimination protocol for alkyl or acyl cobalt reagents

150

1.8 Use of Cobalt for Radical Initiation

References [ I ] J. Iqbal, B. Bhatia, N. K. Nayyar, Chem. Rev. 1994, 94, 519. [2] D. Dodd, M. D. Johnson, Organomet. Chem. Rev. 1973, 52, 1. [3] J. M. Patt, P. Craig, J. Adu. Organomet. Chem. 1973, I / , 331. [4] R. Scheffold, Mod. Synth. Methods 1981, 3, 362. [ 5 ] G. N. Schranger, E. Deutsch, J. Am. Chem. Soc. 1969, 91, 3341. [6] R. H. Abeles, D. Dolphin, Ace. Chem. Res. 1976, 9, 114. [7] R. Scheffold, G. Rytz, L. Walder, Vitamin B I Zand related Co-complexes as catalyst in organic synthesis in modern synthetic methods, R. Scheffold, Ed., J. Wiley: New York, 1983, Vol. 3, p 355. [8] R. Scheffold, S. Abrecht, R. Orlinski, R. Hans-Rudolf, P. Stamouli, 0. Tinembdrt, L. Walder, C. Weymuth, Pure Appl. Chem. 1987, 59, 363. [9] R. Scheffold, R. Orlinski, J. Am. Chem. Soc. 1983, 105, 7200. [ 101 S. Busato, 0. Tinembart, Z. Zhang, R. Scheffold, Tetrahedron 1990, 46, 3 155. [ 111 R. Orlinski, T. Stankiewicz, Tetrahedron Lett. 1988, 29, 1601. [ 121 Z. Petrovic, Z. Bugarcic, L. Marjanovic, S. Konstantinovic, J. Mol. Cat. 1999, 142, 393. [13] M. J. Begley, H. Bhandal, J. H. Hutchinson, G. Pattenden, Tetrahedron Lett. 1987, 28, 1317. [I41 A. Bury, C. J. Cooksey, T. Funabiki, B. D. Gupta, M. D. Johnson, J. Chem. Soc. Perkin Trans. I 1979, 1050. [15] A. Bury, S. T. Corker, M. D. Johnson, J Chem. Soc., Perkin Trans. 1 1982, 645. [16] A. Bury, M. D. Johnson, J. Chem. Soc., Chem. Commun. 1980, 498. [I71 M. D. Johnson, Acc. Chem. Res. 1983, 16, 343. [18] H. Bhandal, G. Pattenden, J. J. Russel, Tetrahedron Lett. 1986, 27, 2299. [19] V. F. Patel, G. Pattenden, J. J. Russel, Tetruhedron Lett. 1986, 27, 2303. [20] V. F. Patel, G. Pattenden, J. Chem. Soc., Chem. Commun. 1987, 871. [21] H. Bhandal, G. Pattenden J. Chem. Soc., Chem. Commun. 1988, 1110. [22] G. Pattenden, Chem. Soc. Rev. 1988, 17, 361. [23] D. J. Coveney, V. F. Patel, G. Pattenden, Tetrahedron Lett. 1987, 28, 5949. [24] V. F. Patel, G. Pattenden, Tetrahedron Lett. 1988,29, 707. [25] G. B. Gill, G. Pattenden, S. J. Reynolds, Tetrahedron Lett. 1989, 30, 3229. [26] R. Howell, G. Pattenden, S. J. Reynolds, J. Chem. Soc., Chem. Commun. 1990, 103. 1271 D. C. Harrowven, G. Pattenden, Tetrahedron Lett, 1991, 32, 243. [28] G. Pattenden, S. J. Reynolds, Tetrahedron Lett. 1991, 32, 259. [29] H. Vandal, V. F. Patel, G. Pattenden, J. J. Russel, J. Chem. Soc. Perkin Trans. I 1990, 2691. 1301 V. F. Patel, G. Pattenden, J. Chem. Soc. Perkin Trans. I 1990. 2703 [3l] H. Bhandal, A. R. Howell, V. F. Patel, G. Pattenden, J. Chem. Soc. Perkin Trans. 1 1990, 2709. [32] R. Howell, G. Pattenden, J. Chem. Soc., Perkin Trans. 1 1990, 2715. [33] D. J. Coveney, V. F. Patel, G. Pattenden, D. M. Thompson, J. Chem. Soc. Perkin Trans. / 1990, 2721. [34] V. F. Patel, G. Pattenden, D. M. Thompson, J. Chem. Soc., Perkin Trans. I 1990, 2729. [35] A. Ali, D. C. Harrowven, G. Pattenden, Tetrahedron Lett. 1992, 33, 2851. [36] B. P. Branchaud, M. S. Meier, M. N. Malekzadeh, J. Ory. Chem. 1987, 52, 212. [37] B. P. Branchaud, M. S. Meier, Y. Choi, Tetrahedron Lett. 1988, 29, 167. [38] B. P. Branchdud, M. S. Meier, Tetrahedron Lett. 1988, 29, 3191. [39] B. P. Branchaud, Y. L. Choi, Tetrahedron Lett. 1988,29, 6037. [40] B. P. Branchaud, Y. L. Choi. J. Org. Chem. 1988, 53, 4638. [41] B. P. Branchaud, G-X. Yu, Tetrahedron Lett. 1988, 29, 6545. [42] B. P. Branchaud, M. S. Meier, J. Org. Chem. 1989, 54, 1322.

References 431 441 451 46) 471 481

B. P. Branchaud, G-X. Yu, Tetrahedron Lett. 1991, 32, 3639. B. P. Branchaud, W. D. Detlefsen, Tetrahedron Lett. 1991, 32, 6273. J. E. Baldwin, C-S. Li, J. Chem. Soc., Chern. Comrnun. 1987, 166. J. E. Baldwin, C. S. Li, J. Chem. Soc., Chern. Commun. 1988, 261. J. E. Baldwin, M. G. Moloney, A. F. Pearsons, Tetrahedron 1990, 46, 1263. J. E. Baldwin, M. G. Moloney, A. F. Pearsons, Tetrahedron 1991, 47, 155.

151

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

2 Single-Electron Transfer

2.1 Samarium(I1) Mediated Radical Reactions Gary A. Molunder

2.1.1 Introduction The seminal report on samarium(I1) iodide by Kagan and coworkers [ I ] outlined numerous applications for this remarkable reducing agent. Although most of the reactions in that initial offering involved what can best be described as two-electron processes, an alert and receptive community quickly recognized the extraordinary versatility of this reagent [2]. The ensuing years have witnessed an explosion of activity wherein the chemistry of SmI2 has been extensively explored. Of particular note has been the application of SmI2 to radical chemistry. The recognition that SmI2 can complement other reducing agents such as n-Bu3SnH, CrC12, Na/NH3(1), and Zn(Hg) in the mediation of radical reactions has inspired much research in this important area of chemistry. The present contribution attempts to focus on those radical processes in which Sm12 provides unique advantages over more traditional reductants. Because of the prodigious number of publications describing the use of SmI2 in promoting radical reactions, a comprehensive review is not possible. However, an attempt has been made to highlight those processes deemed synthetically among the most valuable or unique.

2.1.2 Alkyl, Aryl, and Alkenyl Radical Addition Reactions The persistence of carbon-centered radicals is based on many factors. In a reductive medium, wherein the radicals are generated from halides or related substrates, one of the most important elements is the rate at which the radical is further reduced (kredn) (Eq. 1). Thus there is an inherent competition between the desired radical process (krad) leading to radical product P and kredn [3]. In elegant mechanistic studies, the details of electron transfer and the relative rate constants for the reduction of primary alkyl radicals by SmI2 have been determined [4]. In THF/ HMPA, for example, the rate constant for the reduction of a primary alkyl radical

2.1 Sammium(I1) Mediated Radical Reactions

154

is 6 x lo6 M-' s-' . This rate factor sets an inherent limit on the types of radical processes that can be carried out in the presence of Sm12. kredn

Sml2

RX

Bimolecular radical reactions are particularly limited under reducing conditions because they do not benefit from the rate enhancements associated with intramolecularity. Consequently, few useful intermolecular alkyl radical reactions promoted by SmI2 have been reported. One class of alkyl radicals that persist long enough to react intermolecularly with alkenes and alkynes are polyhaloalkyl radicals [ 5 ] . Catalytic SmI2 can be utilized to promote the addition of fluoroalkyl iodides and chlorodifluoromethylbenzene across alkynes, providing a mixture of diastereomers [ 5d,e]. A single-electron transfer chain mechanism is postulated for this and the reductive reaction of perhaloalkanes with alkenes (Eq. 2) [ 5 ] . In the only other intermolecular reaction of synthetic interest, C-disaccharides have been prepared via an intermolecular coupling reaction of anomeric radicals and unsaturated carbohydrate derivatives (Eq. 3) [6]. BrCCI3 cat. Smlz

*FAC

Br * C 1 3 C A O 8A c

DMF, 90 'C, 24 h 71%

Ph"'~

~

,

+H

g "'OMe "'OBn p PhH, h60 Sm12 HMPA* "C ph"' 0 (0.'' +'\'OMe

~o

OBn

"'OBn '"OH OBn

OBn 41%

OBn

(3) Of decidedly greater versatility are intramolecular alkyl radical reactions with various acceptors. For example, several research groups have investigated alkyl radical addition reactions to activated (electron-deficient) alkenes [7]. The SmI2promoted conjugate addition reaction is extremely general, and allows one to avoid many of the limitations of tin hydride-promoted radical reactions as well as intramolecular conjugate additions via organometallics [7b]. Thus, in contrast to these other methods, three- [7e], five-, and six-membered rings that incorporate a wide range of structural motifs can all be generated [7b], and higher diastereoselectivities can often be achieved as well (Eqs. 4-6). C02f-BU HO,,,. @02t-Bu

.

-

0 2

Sm12 *

THF, MeOH, HMPA -78 'C to 0 'C, 6 h 91%

Ho"*,.@ .~

0 2

(4)

2.1.2 Alkyl, Aryl, and Alkenyl Radical Addition Reactions

155

Smla, cat. Nil2 -78 "C, to rt

(5)

U

85%

0

&

OMe

Sm12, cat. Nil2 c

THF, t-BuOH -78 "C, to rt 88%

I

The initial radical addition reactions can also be sequenced with a second, nucleophilic reaction. Thus radical conjugate addition and subsequent reduction leads to an enolate. Enolates thus generated can undergo a variety of reactions [8] including aldol reactions [9], Claisen condensations, intramolecular Michael reactions, and intermolecular Tischenko redox processes (Eqs. 7, 8).

EtO

a

Sm12, cat. Nila

cyclohexanone * THF, 0°C 76%

0

(7)

C02Et

1. Sm12,THF, DMPU 2. Ph(CH2)2CHO

ph

0 -

Ph

6

81%

A series of substrates has been investigated that pits 5-exo cyclization versus 6-endo cyclization. Interestingly, even though electronic effects might be considered to favor the latter, the 5-ex0 product predominates [lo]. Yields in these cases are quite good (70-80'!4), but regioselectivities are less than 4:l (Eq. 9). I THF, -18 TMG, Smlp "C H 2

0

* * o + Rq f major

R

R

(9)

minor

Relatively few alkenes that do not possess some type of activating group react with SmIz-generated alkyl radicals. Alkenes adorned with allylic heterosubstituents have been employed in this capacity [7a]. The heterosubstituents serve to lower the LUMO of the alkene, making it a better radical acceptor. In these systems elimination occurs subsequent to the initial radical addition (Eq. 10).

156

2. I Sumariutn( I I ) Mediuted Radical Reactions

Hotl,.&

Sml2

OH

-

>

c

.

.

THF, MeOH, HMPA -78 ' C to 0 'C, 3 h 51Yo

Other activated systems, specifically activated alkynes and hydrazones, have been employed as radical acceptors for alkyl radicals generated from alkyl halides and SmI2 [ 1 I]. Radical addition reactions to activated alkynes appear to be more capricious than the reactions with activated alkenes, and thus are perhaps more limited in scope. Additionally, mixtures of diastereomers inevitably result from such systems (Eq. 11) [ 121. Diphenylhydrazones were shown to react approximately 200 times faster than the analogous alkenes in 5-ex# additions as determined in a series of studies by Fallis and Sturino [ 131. Reasonable diastereoselectivities were exhibited in these processes (Eq. 12).

Sml2

THF, DMPU, f-BuOH rt, 2 h 84%

Smlp

Ph2N,N I1

H

U

j

Br - p

(2.4: 1 E : Z )

- Ph2NHNNi-Pr

r THF, HMPA -10 ' C 70%, 10 : 1 ds

Most SmI2-promoted alkyl radical cyclizations onto unactivated alkenes occur with rates that are too slow to be synthetically useful [3, 4a]. One strategy to improve the cyclization event is to employ substrates with more persistent radicals, i.e., those that are less rapidly reduced to the corresponding organometallic under the reaction conditions. Tertiary halides constitute one such class of substrates. Unfortunately, the rate of cyclization of the highly hindered tertiary radical is also depressed, and thus this method is of limited value [2d]. Radical precursors incorporating intervening heteroatoms are known to cyclize at enhanced rates (for 5-exo cyclization, kcyc= 5 x lo6 s-I). Such heteroatomic substrates can be utilized under reductive conditions with satisfactory results. This approach has facilitated the synthesis of a variety of heterocycles with good to excellent yields [ 3 , 4a, 141. In one such example, haloacetals were cyclized and subsequently converted to the corresponding lactones (Eq. 13). Additionally, sequential reactions based upon this process have also been realized [ 151. In one such cascade, radical cyclization ultimately leads to an organosamarium species that is trapped by an electrophilic isocyanide. The resulting iminoylsamarium reagent is ultimately trapped by acetophenone, leading to the observed product (Eq. 14).

2.1.2 Alkyl, Aryl, and Alkenyl Radical Addition Reactions

157

1. Sm12 THF, HMPA, f-BuOH c

+

1. Sm12

CEN-Xy

(14) 2. acetophenone 62%

'

0

N.

XY

Cyclization of an alkyl radical onto an unactivated alkyne has been utilized as one key step in the synthesis of (&)-oxerine. The reaction proceeds to provide the desired bicyclic intermediate in excellent yield (Eq. 15) [ 161. OBn

OBn Sm12 THF, HMPA * N -78 'C, 30 min 86%

q

Among the most useful applications of alkyl radical cyclization reactions employing SmI2 as an initiator are those in which C-glycosides are generated. Pioneered by Sinay [ 171 and extensively developed by Skrydstrup and Beau [ 181, the method provides a rapid and efficient entrte to functionalized C-glycosides. The choice of glycosyl precursor is critical for the success of the process. Among the more useful substrates are glycosyl pyridyl sulfones (Eq. 16) [ 181 and glycosyl phosphates (Eq. 17) 1191.

1. Sm12, THF 2. TBAF, THF

3. cat. PdlC, H2 4. Ac20, pyr 48%

63%

In the same sense that a-alkoxy radicals derived from carbohydrates can be generated and utilized in intramolecular addition reactions, a-amino radicals can be employed by the reduction of N-(a-benzotriazoly1alkyl)alkenylaminesin syntheses of amino-substituted carbocycles and C-substituted pyrrolidines [20]. In the carbocycle synthesis, o-unsaturated aldehydes are condensed with benzotriazole and secondary amines to provide (a-benzotriazoly1alkyl)alkenylamines (Scheme 1). These intermediates rapidly ionize in solution to the corresponding iminium ions

2. I Samarium(II) Mediated Radical Reactions

158

YCHO

Bn2NH *

r

1

L

J

66%, 19 : 1 ds

Scheme 1. Generation of cc-amino radicals from benzotriazole derivatives

and benzotriazolyl anion. The iminium ions thus obtained can be reduced in situ by SmI2, affording a radical poised for cyclization. Electron deficient alkenes are required for efficient cyclization, and although both 5-ex0 and 6-ex0 cyclizations are synthetically feasible, only the 5-ex0 products could be generated with high diastereoselectivities [ ~ O C ] .Employing unsaturated amines in a related process affords pyrrolidines [2Od]. Yields for the construction of the heterocycles are modest to good, but diastereoselectivities are typically quite low (Eq. 18). Me0

W

C02Et

?

C

H

O

Smlz

Me0

* H

%

Me

OMe 72%, 7.3: 1 ds

Ditluoroalkyl radicals have also been generated by SmI2 and utilized in cyclization processes [21].A variety of alkenes, alkynes, and oxime ethers have been utilized as radical acceptors, providing facile entry to a host of substituted difluorocyclopentanes (Eq. 19). ,NOBn

d

BrF2C MeOZC

Me02C

Sm12 THF, DMPU, rt 71Yo

MeOZC&NHOBn MeOZC

Aryl- and alkenyl radicals are relatively resistant to reduction by SmI2 1221, providing them with a longer lifetime under reductive conditions. Several individual studies have been carried out describing various aspects of aryl radical cyclization

2.1.2 Alkyl, Aryl, and Alkenyl Radical Addition Reactions

159

reactions promoted by SmI2 [3, 23, 241. The rate constant of 5-ex0cyclization of aryl radicals has been measured to be as high as 4 x lo9 s-' [23] making such cyclizations particularly attractive using this method. Oxygen- and nitrogenheterocycles have been created in addition to carbocycles, and alkenes and alkynes alike serve as suitable acceptors for these radicals (Eqs. 20, 21). Sm12

d

o

-

HMPA, THF, CH t-BUOH 3CN rt, 6 h

a:\,\

89% Smlp

\

THF, HMPA, rt

55%

Many of these studies incorporate reaction cascades, wherein the aryl radical initially created cyclizes, and the resulting radical is further reduced to afford an organosamarium intermediate. This nucleophile can be trapped by a number of electrophiles, further enhancing the value of the sequential method (Scheme 2) [2b, 3, 23, 251. i-Pi

55%

0 THF, HMPA *

bNEtf

&Et*

76%

65% 65%

82%

Scheme 2. Sequential radical reactions promoted by SmIz

160

2. I Samarium ( I I ) Mediated Radical Reactions

Alternatively, a radical cyclization/reduction can be followed by a p-elimination, resulting in the synthesis of unsaturated ring systems [24a]. This process has been a key structural component utilized to access 3a,8a-dihydrofuro[2,3-b]benzofurans, of the aflatoxins (Eq. 22) [26].

a’ 0~

O

rt, 2 A h

~

0

0

76%

In an interesting development for combinatorial chemistry, SmIz-promoted radical cyclizations have been adapted for use on solid support 1271.The procedures developed have some inherent advantages over n-BqSnH-mediated reactions and sometimes even to the corresponding solution phase SmIz-promoted reactions. Unfortunately, they still appear to lack the consistency necessary for general use in the synthesis of chemical libraries. The chemistry of alkenyl radicals generated by reaction of SmIz with alkenyl halides is much less well developed, and at this point in time appears to be of modest synthetic utility 1281.

2.1.3 Pinacol and Related Coupling Reactions The pinacol coupling reaction, traditionally carried out with active metals such as sodium, magnesium, or aluminum, can also be accomplished with SmI2 1291. Since the initial contribution describing intermolecular pinacolization reactions, several variants have been described [30]. Although many of these papers outline adaptations of the reaction in which additives and catalytic methods have been introduced to improve the reactivity and the economics of the reaction, few of these have adequately addressed the lack of stereoselectivity typically observed in these processes [30a, 311. A fascinating paper has been conveyed by Daasbjerg and Skrydstrup 1321 that not only begins to address the stereochemical issue but at the same time also sheds light on mechanistic details of the process. On the basis of their studies of ligand effects on SmI2-promoted pinacol syntheses, the authors conclude that intermolecular coupling between aromatic aldehydes most likely occurs via diradical coupling. In intermolecular coupling reactions between alkyl aldehydes, either ketyl radical addition to the carbonyl substrate or reduction of a ketyl to a dianion and subsequent carbonyl addition can be invoked. lntramolecular pinacol coupling presumably occurs by the addition of one ketyl radical to the unreduced carbonyl. Skrydstrup has continued his studies in this vein, designing ferrocene-based chelating hosts that would bind to two Sm(II1) metal ions 133). Substantial increases in the yield of the pinacol products were observed, and diastereoselectivities were greatly enhanced as well.

2.1.3 Pinacol and Related Coupling Reactions

161

Normally, reasonably high diastereoselectivity for the erythro isomer is observed in the pinacolic coupling of aryl aldehydes, and thus enantiomerically pure threo isomers are difficult to access by this method. Uemura and coworkers have, however, discovered that the coupling of planar chiral organometallic aldehydes leads to threo-diols in high yields [34], often as single diastereomers (Eqs. 23, 24).

&

Sm12

G

THF, -78 "C 92%

Q

Ho

Q

From a synthetic standpoint the intermolecular pinacolic coupling reaction is limited because only homocoupling reactions are generally practical. Cross-coupling reactions mediated by SmI2 are restricted to specialized, matched partners [35]. Thus a-dicarbonyl compounds can be heterocoupled with aldehydes, providing facile entry to 2,3-dihydroxy ketones. Although selectivities vary, in some cases the diastereoselectivity of the process can be quite high (Eq. 25). 0

+

+Ph

OH 0

Sml2

phP.../CHO

THF, HMPA * P rt 66%

0

h

w

P h "0H

By contrast, the intramolecular version of the reaction is considerably more useful, and a wide range of substrates have been successfully coupled. The first reasonably general survey of SmI2-promoted intramolecular pinacolic coupling reactions [36] made it clear that dialdehydes, keto aldehydes, and diketones were all suitable partners for the intramolecular coupling reaction. For each class, selectivity is high for cis-l,2-diols. Polycarbonyl substrates cyclize with excellent diastereoselectivity, albeit in modest yield (Eq. 26). Dialdehyde substrates ultimately derived from carbohydrate precursors provide access to highly functionalized carbocycles (Eq. 27) [37]. The utility of SmIz-promoted intramolecular pinacolic coupling reactions of dialdehydes was nicely demonstrated in the key step of one synthesis of the natural product forskolin (Eq. 28) [38].

46%

162

2.1 Sumurium ( I I ) Mediuted Rudicul Reactions OBn

OBn BnO,, f C O H

Sm12 L C H O BnO OTlPS ~

THF, -78 'C, 0.5 h * >To%, >20 : 1 dS

BnO-OH OTlPS

*

CHo

THF, t-BuOH -78 'C to rt, 2 h

OH

In analogy to intermolecular pinacolic coupling reactions, organometallic dialdehydes have served as precursors for the intramolecular version of the reaction, affording cyclic 1,2-diols [39]. Both arene chromium tricarbonyl (Eq. 29) and ferrocene complexes (Eq. 30) afford excellent yields of the desired products.

OHC

THF, -78 "C FeCp

Keto aldehydes from classes similar to those described above also undergo successful pinacolic coupling. Thus /I-keto ester and P-keto amide substrates cyclize with excellent diastereoselectivity (Eq. 3 1) [36], and cyclizations utilizing carbohydrate-like precursors have also been described (Eq. 32) [37a,e, 401. Similarly, keto aldehydes derived from the arene chromium tricarbonyl platform cyclize in high yields and with excellent diastereochemical control [39a]. Stereochemical control through hydroxyl-directed chelation has been described as well (Eq. 33) [41]. These types of SmIz-promoted intramolecular pinacolic coupling reaction of keto aldehydes have also served as key step in approaches to natural products including taxanes (Eqs. 34, 35) [42] and the grayanotoxins (Eq. 36) [43].

2.1.3 Pinacol and Related Coupling Reactions

163

Sm12 BnO

CHo

THF, t-BuOH

OBn

(33)

THF, MeOH, HMPA OHC

rt

66%

CHO

43%

H ,J02Me 0

THF, heat

C ,.HO

Smlz

THF, MeOH -25 "C 91Yo

*

(34) H

ti0 : OH

(35)

Far fewer examples of intramolecular diketone coupling have been presented, perhaps because such a process is inherently more difficult [36]. Nevertheless, some spectacular successes have been reported (441, leading to unusual, highly strained structural motifs that would be difficult to access by any other means (Eqs. 37, 38).

In addition to the various dicarbonyl coupling reactions previously described, SmI2 also promotes the cross-coupling of carbonyl substrates with oximes [45] and aldimines [46]. Intermolecular examples have been reported, but mixtures of diastereomers result unless the ketone is sterically biased (Eq. 39). Much more useful

2.1 Samarium ( I I ) Mediated Radical Reactions

164

are the intramolecular versions of this reaction [13b, 471, which have mimicked the dicarbonyl couplings in the sense that carbohydrates have often served as the ultimate source of the substrates. Both ketones and aldehydes have been utilized as starting materials. Curiously, cyclization leads to the construction of trans amino alcohols (Eqs. 40, 41). Six- [47a,d] and even seven-membered rings have been constructed in this manner [47b], but yields and/or selectivities tend to be lower for these systems. Intramolecular coupling between ketones and imines have also been performed and lead to enantiomerically pure amino alcohols when using the appropriately functionalized planar chiral mono-Cr(CO)3 complexes of biaryls (Eq. 42) [39a]. SmlP

NHOBn

+ CH2=NOBn

t.BU&o

THF, HMPA, f-BuOH rt 57%, 94 : 6 d$ -NOBn

t-Bu

(39)

Sm12

BOCN

bo

"0H

THF, f-BuOH -78 "C 70%, 9 : 1 ds

(40)

' 0 " ' U

Various protocols have been developed for the dimerization of imines, providing high yields of the desired 1,2-diamines [46, 481. Unfortunately, diastereoselectivities are quite low in these cases. By contrast, the intramolecular coupling reaction of the Cr(CO)3-biaryl complexes [ 39a) and dimeric ferrocenyl complexes [ 39b] proceed with generally high stereoselectivities (Eq. 43). MeN,

WFeC p

Sm12 MeN~

,

THF, -78 "C F 59%,~95 : 5: d c

4""

MeHN,,, me^^ ~

(43)

O"FeCp

The coupling of ketones with nitriles has been studied in some detail [36b, 491. Using this method, five-membered ring a-hydroxy ketones can be created with ease

2.1.4 Ketyl Addition Reuctions

165

in high yields (Eq. 44), but six-membered rings are typically accessed in moderate to low yields. These SmI2-promoted reactions provide a viable alternative to Zn, electrochemical, and photochemical protocols for the same or similar transformations. Sm12

(44)

C N THF, t-BuOH hv. 0-10 "C.2 h 93%

Finally, isocyanates have been dimerized to form oxamides in good yields with SmI2 in THFiHMPA [50],and amides can be coupled with a combination of SmIz and Sm(0) to afford vicinal diaminoalkenes [51].

2.1.4 Ketyl Addition Reactions By far the most useful and highly utilized radical reactions promoted by SmI2 are couplings between ketyls and alkenes or alkynes. The selectivity that can be achieved in these transformations, combined with the versatility of the method for the construction of diverse targets, makes it an extremely attractive means to form carbon-carbon bonds. The utility of SmIz-generated ketyl radicals in selective organic synthesis can be ascribed in part to their persistence. Thus ketyl radical anions have been postulated to form reversibly in the presence of SmI2 [9]. With the possible exception of aromatic carbonyls, the radical anions are not further reduced under the reaction conditions to the corresponding dianions. In addition, ketyls are not particularly prone to quenching by hydrogen atom abstraction from the solvent, from disproportionation, or related processes [52]. Several contributions have appeared in which intermolecular reductive couplings between ketones or aldehydes and electron-deficient alkenes have been described [30h, 531. Reactions of aldehydes and ketones with unsaturated esters result in the formation of lactones. Diastereoselectivities are normally modest in these cases, but can be quite high for certain substitution patterns (Eq. 45).

71%, 20 1 d s

Chelation control has been utilized as one means to effect high diastereoselectivity in the intermolecular ketyl coupling reactions [54]. Examples of both 1,2- and I ,3-relative asymmetric induction have been rcported, and exceptional levels of stereoinduction were observed in both systems (Eqs. 46, 47). In a similar capacity,

2.1 Samarium ( I I ) Mediated Radical Reactions

166

urethanes have also served as stereocontrol elements in intermolecular coupling reactions (Eq. 48) [ 5 5 ] .

&

+

eo

Sm12

THF,MeOH,O"C 71%, 91 : 9 ds *

Smlp +

HO HO

P C N 0 "C 85%

87%, 94 : 6 ds

A single attempt has been made to induce asymmetry in the intermolecular cross coupling reaction by employing a chiral ligand for the samarium ketyl [56]. Utilizing 2,2'-bis(diphenylphosphinyl)-l , 1'-binaphthyl (BINAPO) as a chiral ligand, a modest start has been made to develop an enantioselective process. However, in the examples reported to date the method is plagued by low yields and/or moderate stereoselectivities. Better success has been achieved in asymmetric induction by utilizing chiral auxiliaries on the acceptors [ 571. Among the diverse auxiliaries tested, N-methylephedrine proved to provide the highest ee's of the desired lactone products (Eq. 49). O

C

H

O +

do.

0

Ph

Sm12

N M ~THF, ~ t-BuOH -78 "C to rt 74%, 97% ee

Intermolecular ketyl alkene coupling reactions have been incorporated into a cascade that ultimately affords medium sized rings [ 581. Specifically, chloroalkyl ketones react with acrylates, whereupon chloroalkyl lactones are formed in situ. Photolysis of these intermediates in the presence of excess SmIz initiates an intramolecular nucleophilic acyl substitution reaction between the halide and the lactone, creating the medium-sized ring (Eq. 50).

Numerous activated alkenes outside of the acrylates and acrylonitriles have

2.1.4 Ketyl Addition Reactions

167

served as acceptors for ketyls generated by SmI2 [59]. Conjugated alkenes, enol acetates, silyl enol ethers, alkenylsilanes, and allylic acetates are all effective traps for the ketone ketyl radical anions thus generated (Eq. 51). Sm12 * THF, HMPA rt, 5 min 93%

Ph

&TMS Ph

Some diversity among the carbonyl components of the reaction has also been examined in the intermolecular reactions. For example, two groups have reported that the reaction of Cr(C0)3-complexed aryl aldehydes and ketones with u,Punsaturated esters leads to diastereomerically pure lactones, with radical coupling directed anti to the metal tricarbonyl center (Eq. 52) [60].

a

CHO

(co)~c~'

Sm12 +

OMe

(52)

FC02Me THF, t-BuOH rt, 5 min (CO),Cr' 83%

OMe

Isocyanates and isothiocyanates have also been coupled with various acrylates, providing the corresponding amides or thioamides in good yields (Eq. 53) [61]. EtN=C=S

+

Sm12 +CO2~t THF, t-BuOH, HMPA -78 'C, 3 rnin 81%

* R

H

N

GC02Et

(53)

Few examples of what might be described as an intermolecular coupling reaction on inactivated alkenes has appeared [62]. Thus ketyl radicals generated from aromatic aldehydes and ketones underwent intermolecular addition to the para position of another aldehyde. Cross-coupling reactions are not feasible in these systems and typically yields are quite low. Intermolecular coupling of ketyls with alkynes has proven successful in some instances [63]. Using this protocol, allylic alcohols are typically generated in good yields, but often as a mixture of E / Z isomers (Eq. 54). Additionally, some type of activation of the triple bond is necessary. In particular alkynyloxiranes have proven to be very useful substrates for the generation of to 2,3-pentadiene-1,5-diols (Eq. 55) [64]. Acceptors such as 1-octyne provide low yields of the desired products. OAc Ph

Sm12 *

THF, HMPA, f-BuOH rt, 5 min 90%

/OAc Ph

(54)

168

2. I Samarium ( I I ) Mediated Radical Reactions

67%. 4.5 : 1 dS

Not surprisingly, intramolecular ketyl alkene coupling reactions are much more common than the preceding bimolecular examples. The diversity of structures that can be obtained utilizing these procedures is impressive, and, as will be described, the method has been employed for the construction of a wide array of natural products. As was the case for the intermolecular coupling reactions, activated alkenes and alkynes constitute one important class of acceptors for the ketyl radical anions. Notably, even highly strained four-membered rings can be accessed via a 4-ex0 cyclization process (Eq. 56) [6S]. Bno+CHO h C 0 2 E t

Srnl2 THF, HMPA * 10 'C, 1 h 60%

*co2Et

Most published studies have addressed the synthesis of five- and six-membered rings, and have demonstrated that both of these ring systems can be accessed with relative ease [66]. a,P-Unsaturated esters and nitriles are the most commonly used acceptors. Quinone methides have also been used as vinylogous acceptors for the ketyls, generating aryl-substituted cyclopentanes and cyclohexanes [67]. In most cases, the hydroxy group generated from the ketyl and the acceptor normally are positioned trans to one another on the newly formed ring, but this is subject to some substrate dependence (Eq. 57). Seven- and eleven-membered rings have also been synthesized via the intramolecular coupling reaction, but yields are modest [66a].

A number of bridgehead bicyclic alcohols have been constructed in this manner [68], again attesting to the ability to access structures with considerable built-in strain (Eq. 58).

-& rco2 Sm12

0

THF, HMPA, t-BuOH

80%

HO

H

C02Me

2. I . 4 Ketyl Addition Reactions

169

A high degree of stereoselectivity can be achieved in chelation-controlled reactions, utilizing hydroxy groups as stereodirectors (Eq. 59) [69]. Studies have revealed that non-chelation-controlled processes may also proceed with enhanced selectivities, and this led to the synthesis of the cis-decalin skeleton of vinigrol (Eq. 60) [70]. OH

Samarium(I1) iodide-promoted reductive coupling reactions have served as the key step in approaches to several classes of natural products, including the insect sex attractants (-)-anastrephin and (-)-epianastrephin [71] and (+)-cyclomyltaylan5a-01 (Eq. 61) [72]. An elegant, iterative approach to the synthesis of trans-fused polytetrahydrofurans, -tetrahydropyans, and -0xepanes has also been communicated (Eq. 62) [73]. The ketyl/olefin coupling reaction has also been employed as the key step in an enantioselective synthesis of (-)-steganone, in which an eightmembered ring is created (Eq. 63) [74]. Sml2 w

CHO

THF, t-BuOH, HMPA -78 "C, 10 rnin 52%, 2.4 : 1 ds :02Et

' O b C H O H

w 0

Sml2 THF, MeOH

H

rt

84%

Y O

Y O Sm12 THF, HMPA, t-BuOH 0 'C 73%

-

2. I Samarium (11) Mediated Rudical Reactions

170

Nitrogen heterocycles can be accessed by the same reductive cyclization strategy [75].Modest yields of the desired products are obtained in these reactions (Eq. 64), which serve as intermediates in the synthesis of human neutrophil elastase inhibitors. ,C02Et

IfConEt CbzNJ

CHo

u

Sm12 THF, HMPA, MeO; 0 "C, 90 min

CbrN>OH

53%

A sequential process wherein the enolate generated in the initial ketyl addition is trapped by carbonyl electrophiles has been reported [76].The examples reported to date have utilized enals derived from carbohydrate precursors. Although diastereoselectivities vary depending on the substrate, high levels can be achieved in some cases (Eq. 65).

OTBDMS

(65)

Although unactivated alkenes have not been employed as acceptors in intermolecular coupling reactions mediated by SmI2, the persistence of these ketyls does allow less activated alkenes to serve as acceptors in intramolecular processes. A thorough study has been carried out in which the stereochemical outcome of 5-ex0 and 6-ex0 processes has been delineated [77].It is generally the case that the diastereoselectivities of SmIz-promoted reactions are higher than those of other reductant-based methods, as well as those of electrochemically and photochemically induced reductive couplings. Both the sense and magnitude of diastereoselection is quite readily predicted on the basis of chair-like transition structures normally associated with radical cyclization reactions. This method has been applied to diverse systems, including bridged bicyclic enones [78],acyl silanes [79],and unsaturated aldehydes derived from carbohydrates (Eq. 66) [80].

BIlo~,,.~cHo BnO

Sm12

THF, HMPA 76%

- b BnO,. ..

..$,OH

BnO

Chelation has been invoked as an additional stereocontrol element in ketyl olefin coupling reactions [36b, 811. Both P-keto esters and /3-keto amides can serve as centers of chelation, leading to the assembly of functionalized ring systems with excellent selectivity (Eq. 67).

2.1.4 Ketyl Addition Rructions

171

Sm12 c

THF, t-BuOH -78 ' C 87%

Samarium(I1) iodide-promoted radical cyclizations have also played a key role in the total synthesis of (-)-grayanotoxin I11 [43b]. Among the methods utilized for the synthesis of this molecule was an intramolecular ketyl olefin coupling reaction generating a bridged bicyclic ring system (Eq. 68). '

H

THF, HMPA OH

86%

Oxygen [77] and nitrogen heterocycles [82] can be prepared utilizing 5-exo and 6-ex0 ketyl radical cyclization reactions as well. Although both have limitations in terms of substitution patterns that can be accessed, yields, and diastereoselectivities, in some cases the transformations are quite impressive (Eq. 69).

'

THF, HMPA, t-BuOH 76%

P-Jo

The intramolecular coupling of ketyls with aromatic systems has been briefly studied, and appears reasonably effective (Eq. 70) [62, 831. Of perhaps greater interest are the intramolecular coupling reactions to ($-arene)Cr(C0)3 complexes [84]. Such couplings have great potential for the enantiocontrolled syntheses of polycyclic systems (Eq. 71). Of note in this process is a demethoxylation leading to rearomatization of the organometallic system. The chemistry has been extended to ketimines, in which case a 2:l mixture of diastereomeric products results [85]. Interestingly, a highly unusual 5-endo-trig cyclization has been observed in these systems (Eq. 72). It has been proposed that the initial cyclization, providing the highly stabilized benzylic radical, is reversible, with the second electron transfer step driving the reaction [84a].

Sm12 THF, HMPA, t-BUOH rt, 4 h 91Yo

OH

172

2.1 Samarium(II) Mediated Radical Reactions

Sm12

k

0

.Y

e

, OMe Cr(C0)3

* THF, HMPA, t-BuOH -78 "C to rt 68%

OMe Cr(C0)3

Smlp

, OMe Cr(c0)3

THF, HMPA, t-BuOH -78 'C to rt 66%

OMe C~(CO),

Other organometallic complexes have served as alkene acceptors for ketyls generated by SmI2. Thus (v4-diene)Fe(CO)3complexes have been employed in ketyl cyclizations [ 861, leading to stereocontrolled syntheses of cyclopentanols and cyclohexanols (Eq. 73).

Most unusually, 8-endo cyclizations can be carried out with extraordinary efficiency when mediated by SmI2 [83, 871. Although the scope and limitations of the method have not been studied in detail, it is clear that some type of activation of the alkene is necessary to achieve reasonable yields of the desired products (Eq. 74). Ph Ph

THF,HMPA, SmlP f-BuOH* HOQ

(74)

787'0, 1 : 1 ds

Ketyls generated by the reaction of SmI2 with aldehydes and ketones have been incorporated into numerous sequential processes in which a radical reaction is involved. Sequential radical processes, radical cyclization/carbonyl additions, radical cyclization/substitution reactions, nucleophilic acyl substitution/radical cyclizations, cyclization/elimination processes, and others have all been realized. Because these types of reactions have been extensively reviewed [2b, 251, further details will not be given here. Needless to say, new sequential processes based on SmI2promoted ketyl/olefin coupling reactions are still being developed (Eq. 75) [88]. Sm12

69,

THF, HMPA, t-BuOH 0 "C 79%

(75)

2.1.4 Ketyl Addition Reactions

173

Although many cyclization reactions onto alkenes have been recorded, few examples incorporating allenes as acceptors have been reported [89]. For the substrates investigated, stereoelectronic control provides high selectivities for 5-ex0 and 6-rxo cyclization products (Eq. 76).

M

e

O

b CHo

THF,82% f-BuOH

OH

In addition to alkenes and allenes, alkynes have also served as acceptors in a variety of ketyl cyclization reactions [36b, 83, 901. Activated alkynes in general appear to work most favorably in the 5-ex0 and 6-ex0 cyclization processes, permitting the synthesis of carbocycles as well as oxygen and nitrogen heterocycles in reasonable yields, albeit as mixtures of diastereomers (Eqs. 77-79). HO C02Et

A

..,,!

Sm12 THF, MeOH 51Yo

SiMea

-

b C 0 2 E t

Sm12

oy 0

THF, HMPA, f-BuOHD 64%

0

Sm12

/COTBDMS THF, HMPA, f-BuOH OHC 70%

/ /

N

h

HO

(79) OTBDMS

An intramolecular ketyl/alkyne coupling method has been employed in a synthetic approach to erigerol [91], wherein a reasonably complex tricyclic system was created in high yield (Eq. 80), and in the synthesis of isocarbacyclin (Eq. 81) [92]. Finally, the analogous 8-end0 cyclization process has also been applied with some success [83], creating functionalized cyclooctenols in modest yield (Eq. 82).

THF, f-BuOH 90%

Sm12 TBDMSO'

*

n-C5H11 THF, f-BuOH -70 "C, 0.5 h TBDMSO" OH 71%, 9 : 1 ds

n-C5H11

OH

2.1 Samarium ( I I ) Mediated Radical Reactions

174 Me02C\

MeO&

2.1.5 Hydrodimerization Reactions Conjugated, electron-deficient alkenes can be reductively coupled in the presence of SmI2, providing hydrodimerized products virtually instantaneously in excellent yields [93]. Both inter- and intramolecular versions of the reaction have been established, the latter leading to the construction of 3- and 6-membered rings (Eq. 83). Alkynes also take part in the reaction, albeit in modest yields. Sm12

THF, MeOH, HMPA rt 80%, 7 : 1 ds

Me02C

-

k’-co2M

Some success has been achieved in conferring enantioselectivity into the hydrodimerization process [94], but the method as it exists does not appear to be general and furthermore requires huge excesses of expensive reagents (Eq. 84). N(Bn);!

Srn12, (4-BINOL

0 -78 “C, 4 h 70%, 71% ee

In an interesting adaptation of this chemistry, cyclopropanes serve as ‘pseudo’ alkenes, resulting in homologous hydrodimerizations [95]. Yields in these cases can be quite high, but the process is rarely stereocontrolled (Eq. 85).

Several sequential intermolecular hydrodimerization/intramolecular condensation reactions have been reported [30f, 961. Yields and diastereoselectivities in these processes can be quite high, and the products possess an array of useful functionality (Eqs. 86, 87).

2.1.6 Radical Fragmentation Reactions

175

C02Et

()@=LN 0

'

Sml2 P

THF, rt

79%

2.1.6 Radical Fragmentation Reactions a-Heterosubstituted carbonyls and related substrates can be rapidly cleaved under reductive conditions. For many of the intermediates in these reactions, in particular cc,P-epoxy ketyls and other strained systems resembling cyclopropyl carbinyl radicals, bond cleavage undoubtedly occurs at the radical stage [97]. This chemistry has been reviewed [2c] and will not be discussed further. Related to the epoxy ketones are cyclopropyl ketones, whose ketyls can also fragment under reductive conditions afforded by SmI2 [98]. Ring expansions have been developed based upon these observations [99], and yields and selectivities can be high when the cleavage is stereoelectronically favored (Eqs. 88, 89). As shown by the results depicted in Eq. (88), the ring expansion can be accompanied by pelimination of appropriately situated leaving groups.

Sm12 THF, MeOH 85% COZB~

C02Bn

A further extension of the cyclopropyl fragmentation method involves entrapment of the initially formed radical by a suitable radical acceptor [ 1001. This radical cascade has facilitated the efficient synthesis of spirocyclic ketones (Eq. 90).

176

2.1 Sumurium(II) Mediated Rudicul ReuctionJ

Ph

.

Sm12

S

I IV1.3

Other strained carbonyl systems also undergo reductive cleavage, resulting in ring-expanded products [ 1011. Thus several diverse bridged bicyclic ketones are readily cleaved to provide high yields of the corresponding medium sized ring products (Eq. 91).

Smlp

THF, HMPA, t-BuOH rt, 2 min 78%

Finally, SmI2-induced reduction of strained alkyl halides has also resulted in cleavage of carbon-carbon bonds [102]. The method has been utilized as the key step in the synthesis of dictamnol (Eq. 92). Further development of the method has led to an approach to the aromadendrane carbon skeleton [ 1031 by a radical fragmentation/3-exo cyclization process (Eq. 93).

c

H O H H

(92)

(,.I(

I

73%

*

THF, DMPU 73% C02Et

(93) LC02Et

2.1.7 Miscellaneous Radical Reactions Samarium(I1) iodide has been utilized quite extensively as a reducing agent to create aryl or alkenyl radicals that are used in a variety of atom transfer reactions [ 1041. Both intra- and intermolecular atom transfer reactions have been observed. Al-

2.1.7 Miscellaneous Radical Reactions

177

though there are some exceptions [ 1051, in nearly all reported cases the ultimate and key reactivity of the systems after atom transfer is anionic in character, and thus they will not be discussed further. Acyl radicals can be generated by the interaction of SmI2 with acyl halides [ 1061. For those substrates wherein decarbonylation is slow and cyclization is fast, cyclopropanols can be created in reasonable yields (Eq. 94).

In an interesting transformation, ketyls have been demonstrated to undergo an intramolecular S"2 reaction on benzylseleno ethers, generating seleno hemiacetals [ 1071. Carbohydrate derived precursors have been utilized to create several selenopyranoses (Eq. 95). OBn OBn

Sm12

B n S e a C H O OBn

t

THF, HMPA 50%

.0,:ln

Brio''

OBn

(95)

Aromatic nitriles have been coupled with nitro groups in the presence of SmI2, providing a unique synthesis of amidines [ 1081. The intramolecular version of the reaction provides an excellent synthesis of 2-aminoquinolines (Eq. 96).

Finally, chiral nitroxyl radicals can be synthesized by the intramolecular coupling of enones with nitro compounds under reductive conditions [ 1091. Thus reaction of appropriately substituted nitro enones with SmI2, followed by a quench with reactive acyl chloride electrophiles, provides a-asymmetric nitroxide radicals in excellent yields (Eq. 97). 0 Sm12 &2

THF,-50"C =

F3C F3c@cocl

ArKO

(97)

178

2. I Samarium(II) Mediated Radical Reactions

2.1.8 Conclusions An attempt has been made in this brief survey to convey the message that SmI2 may be applied to all manner of radical reactions, with reactivities and selectivities matching or exceeding those of other reagents. Unique transformations are possible, allowing one to generate structures that would otherwise be very difficult to synthesize. The scope and breadth of samarium(I1) iodide's utility in this arena is truly breathtaking, with many more diverse applications most assuredly yet to come.

Acknowledgements The author thanks his coworkers who are listed in the references below for their many important contributions to this area of chemistry, and the National Institutes of Health for their continuing support of this research effort. I am grateful to Dr. Anne Courtney for her extraordinarily thorough critique of the manuscript.

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Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

2.2 Nickel Mediated Radical Reactions Nung Min Yoon

2.2.1 Introduction The tributyltin hydride-mediated carbon-carbon bond formation via radical addition and cyclization of alkyl halides with alkenes has often been a choice for construction of various organic molecules [ 11. However, the requirement for hightemperature initiators or photo initiation and the difficulties associated with purification of the products from tributyltin halides tend to limit the widespread use of these methods, despite the efforts to make the methods easier [lc, 21. Recently, nickel-mediated radical additions and cyclizations have been introduced as promising alternatives to the tributyltin hydride methods. These are the nickel powderacetic acid method for cyclization of haloamides to y-lactams, p-lactams and indolones, the borohydride exchange resin-nickel boride method for radical addition, nickel-catalyzed electroreductive cyclization and nickel-catalyzed Kharasch addition of polyhalo compounds.

2.2.2 The Nickel Powder-Acetic Acid Method The use of nickel powder in combination with acetic acid was first introduced in 1992 by Zard and coworkers [3]. It has been proven that powdered nickel in the presence of an organic acid such as acetic acid works as a very mild reducing agent capable of cleaving an oxime ester into a carboxylate anion and an iminyl radical. The key feature of this system is that the produced iminyl radical 2 is sufficiently long-lived to undergo useful radical reactions. This property was applied in a practical procedure for inverting the 13-methyl group in 17-ketosteroids [3]. Thus 17acetoxime 1 was converted to 13-epi-ketone 3 in 59% yield (Scheme 1). This system was also found to be capable of reducing certain halogenated derivatives to form carbon-centered radicals, which can also be captured in various

184

2.2 Nickel Mediated Radical Reactions

& &tioAc Ni/AcOH/octane* reflux

AcO

\

1\

AcO

3 (59%)

1 e-

L

Scheme 1

ways. New syntheses of y-lactams, indolones, and p-lactams have been successively investigated.

2.2.2.1 y-Lactams

A variety of y-lactams are prepared by 5-ex0 or 5-end0 cyclization of a-haloamides depending on the substrate [4, 51. Dimethylbromoacetanilide 4 reacted smoothly with nickel powder-acetic acid in 2-propanol to give the bromolactam 5 in 68% yield together with debrominated lactam 6 (23%). However, when 2-propanol was replaced by cyclohexane, a poorer hydrogen donor, bromide 5 was the sole product (85%).

4

5 (85%)

6

Transfer of a phenylseleno group can be accomplished simply by adding an excess (3 equiv) of diphenyl diselenide. Trichloroacetamide 7 was converted into bicyclic lactam 8 in 91%)yield. On the other hand dimethylbromoacetamide 9 gave the corresponding Kharasch addition product 10 in 58% yield. The yield of 10 increased to 78% in the presence of 3 equiv of bromotrichloromethane, a bromine transfer reagent. N-Alkenyltrichloroacetamidesgive y-lactams by h n d o cyclization in competition with 4-ex0 cyclization as shown in Scheme 2. In the presence of 2 equiv of diphenyl diselenide, trichloroacetamide 11 afforded p-lactam 14 in 39% yield along

2.2.2 The Nickel Powder-Acetic Acid Method

oc1

Ph”Nk;l

185

Ni/AcOH/3 eq of PhSeSeP: -8ISePh

phA&L1

7

8 (91%)

Ni/AcOH/2-Propanol 3 eq of BrCCI3

P h n N v

0 9

-

-4iBr

phn&

10 (78%)

with y-lactam 16 (16%). In the absence of the trap, only y-lactam 17 was isolated in 54% yield. This unusual cyclization occurs even when it is disfavored by the presence of substituents on the terminus of the double bond as in 11 [5a].Recently, in a short synthesis of y-lycorane, trichloroamide 18 gave the unsaturated amide 19 whereas Bu3SnH and AIBN afforded the corresponding saturated amide [5b]. SePh 2-propanol

Bn’ 11

12

0 14 (39%)

13

14 Mn(OAc)3

I::

benzene 110 "C, 36 h

-

PhOMe

CI

102

CI 103

'1 X C I 104

\GI 105

(25%)

106 (conocarpan)

Scheme 33

Oxidation of alkynyl ketone 107 with Mn(OAc)3 in 9:l EtOH/AcOH at reflux affords the cc-keto radical which undergoes 5-ex0 cyclization to give the vinyl radical, which abstracts a hydrogen from EtOH to afford 62% of tricycle 108. Protodesilylation and reduction completes a synthesis of gymnomitrol (109) (Scheme 34) [55]. Oxidative cyclization has been used in two approaches to the unusual sesquiterpene upial. Oxidation of diketone 110 with Mn(OAc)3 and Cu(0Ac)z in AcOH at 25°C for 3 h affords the cc-keto radical, which cyclizes to give a radical that is oxidized by Cu(0Ac)z to give 88Yn of 112 as a mixture of four isomers all of which can be converted to upial (113) (Scheme 35) [56]. Oxidative cyclization of monomethyl malonate 114 affords 68% of lactone 115, which was elaborated to epiupial (116); a similar sequence failed in the upial series with the methyl groups cis (Scheme 36) [57]. Oxidative cyclization of 117 with Mn(OAc)3 in AcOH gives 61% of 118 which was elaborated to dihydropallascensin D (119) (Scheme 37) [58]. Oxidative cycliza-

2.3.4 Cyclizations

Mn(OAc)3 9.1 EtOH/AcOH 90 "C, 22 h

107

SiMe3 108 (62%)

SiMe3

109 (gyrnnornitrol)

Scheme 34

0 H2c%

Mn(OAc)3 CU(OAC)~ AcOH 25 "C 2 h

P?

*

0

*cHo

110

112 (88%)

113 (upial)

Scheme 35

C02Me

Mn(OAc)3 AcOH 70 "C 2 h

-

eM C02Me

-

115 (68%)

114

116 (epi-upial)

Scheme 36

AcOH, Mn(OAc)3 25 *"C, 3 h

117

Scheme 37

go

Me02C

C02Me

118 (61%)

119 (dihydropaIIescensin D)

2 13

2 14

2.3 Munyanese(III) -Mediated Radical Reactions HO

(100%)

(N-methyl-A'*-isokoumidine)

Scheme 38

tion of the highly functionalized P-keto ester 120 affords 121 quantitatively, which was converted to N-methyl-A'8-isokoumidine(122) (Scheme 38) [59]. It is noteworthy that the tertiary amine is not oxidized, presumably since it is present as the ammonium salt in AcOH. Tandem oxidative cyclization of a-chloromalonate ester with Mn(OAc)3 and Cu(0Ac)z in EtOH at reflux affords 65% of lactone 124, analogously to the conversion of 35 to 36 and 37 [60]. Further elaboration yields estafiatin (125) (Scheme 39). Oxidation of 126 with Mn(OAc)3 and Cu(0Ac)z in AcOH at 50°C results in hydrolysis to the ene dione, which is oxidized to the a-keto radical. Tandem cyclization and oxidation of the cyclopentanemethyl radical by Cu(I1) affords 70-80% of 127, which was converted to tricycloillincinone (128) (Scheme 40) [61]. Oxidative cyclization of phenylmenthyl P-keto ester 129 with Mn(OAc)3 and Yb(OTf)3 in trifluoroethanol at -5 "C provides 77% of 130 as a 38:1 mixture of diastereomers.

Mn(O A C ) ~ CU(OAC)~

THPO~~~~

w

EtOH 80°C,3h 123

124 (65%)

0

b

125 (estafiatin)

0

Scheme 39

H2C*7f-BuPhpSiO

Y 1 2 6

Scheme 40

Mn(OAc)3 CU(OAC)~ AcOH 50 "C, 3 h

p- p

H2C

d

127 (70-80%)

H2C

128 (tricycloillicinone)

2.3.4 Cyclizutions

&e H3C

I

,

215

2 Mn(OAc)3 1 Yb(OTf)3 CF3CH20H

0 Ph

OAO

y

130

131 (-)-triptonide

(77%,38:l de)

Scheme 41

.

AcOH, 23 "C, 24 h

0 C02Et

132

C02Et

133 (58%)

(norlabdane oxide)

Scheme 42

Further elaboration gives (-)-triptonide (131) (Scheme 41) [ 181. Tandem oxidative cyclization of 132 with Mn(OAc)3 and Cu(0Ac)z in AcOH at 25 "C provides 58% of 133, which was elaborated to norlabdane oxide (134) (Scheme 42) [49g] Mn(OAc)3 and Mn(pic)3 can be used to oxidatively cleave cyclopropanols to /?-keto radicals [16] and cyclobutanols to y-keto radicals [62]. Oxidation of 135 with Mn(pic)3 in DMF containing Bu3SnH at 0 ° C affords P-keto radical 136 which undergoes a 5-exo cyclization. The resulting radical is reduced by Bu3SnH to give 76% of 137, which is >90% isomerically pure. Further reactions yield 10isothiocyanatoguaia-6-ene (138) (Scheme 43) [ 16f]. Mn(pic)3 oxidizes cyclobutanol 139 in DMF at 100 "C to y-keto radical 140. 5-Exo cyclization affords vinyl radical 141 which is reduced to afford 58% of a-methylenecyclopentanone 142, which was

DMF, 0 "C

%:.

SCN i OTH P 135

Scheme 43

136

137

138

(76%) (10-isothiocyanatoguaia-6-ene)

2.3 Mungunese (III)-Mediated Rudical Reactions

2 16

N

Ill

0

139

140

141

N 0

142 (58%)

I C02Me 143 144 (silphiperfol-6-ene) (methyl cantabradienate)

Scheme 44

converted to silphiperfol-6-ene (143) and methyl cantabradienate (144) (Scheme 44) [61b]. Since the initial discovery of the Mn(II1)-mediated addition of acetic acid to alkene to give y-lactones in the late 1960s, these radical additions and cyclizations have been developed into a broadly applicable synthetic method for producing highly functionalized compounds. Although further development is needed, the scope, limitations and mechanism of these reactions is sufficiently well understood that they can be used predictably and reliably in organic synthesis.

References E. I. Heiba, R. M. Dessau, W. J. Koehl Jr., J. Am. Chem. Soc. 1968, 90, 5905-5906. J. B. Bush Jr., H. Finkbeiner, J. Am. Chem. Soc. 1968, 90, 5903-5905. E. J. Corey, M.-C. Kang, J. Am. Chem. Soc. 1984, 106, 5384-5385. B. B. Snider, R. M. Mohan, S. A. Kates, J. Org. Clienz. 1985, 50, 3659-3661. A. B. Ernst, W. E. Fristad, Tetrahedron Lett. 1985, 26, 3761-3764. W. J. de Klein, in Organic Synthesis bj>Oxidution with Metul Compounds, (Eds: W. J. Mijs, C. R. H. de Jonge), Plenum, New York, 1986, pp 261-314. Sh. 0. Badanyan, G. G . Melikyan, D. A. Mkrtchyan, Russ. Chem. Rev. 1989, 58, 286-296; Uspekhi Khimii 1989, 58, 475-495. G. G. Melikyan, Synthesis, 1993, 833-850. J. Iqbal, B. Bhatia, N. K. Nayyar, Clzcm. Rev. 1994, 94, 519-564. B. B. Snider, Chem. Rev. 1996, 96, 339-363. (a) G. G. Melikyan, Organic Reactions 1997, 49, 427-675. (b) G. G. Melikyan, Aldrichimicu Acta 1998, 31, 50-64. W. E. Fristad, J. R. Peterson, A. B. Ernst, G. B. Urbi, Tetrahedron, 1986, 42, 3429-3442. B. B. Snider, J. J. Patricia, S. A. Kates, J. Org. Chem. 1988, 53, 2137-2143. (a) E. I. Heiba, R. M. Dessau, J. Am. Clieni. Soc 1971, 93, 524-527. (b) E. I . Heiba, R. M. 1972, 94, 2888-2889. Dessau, J. Am. Chem. SOC. S. A. Kates, M. A. Dombroski, B. B. Snider, J. Org. Chem. 1990, 55, 2427-2436. (a) K. Narasaka, N. Miyoshi, K . Iwakurd, T. Okauchi, C/wm. Lett. 1989, 2169-2172. (b) K. Narasaka, K . Iwakura, T. Okauchi, Clzem. Lett. 1991,423-426. (c) N. Iwasawa, S. Hayakawa, K. Isobe, K. Narasaka, Clzem. Leit. 1991, 1193-1196. (d) N. Iwasawa, S. Hayakawa, M. Funahashi, K. Isobe, K. Narasaka, Bull. Chem. Soc. Jpn. 1993, 66, 819-827. (e) N. Iwasawa, M. Funahashi, S. Hayakawa, K. Nardsdka, Chem. Lett. 1993, 545-548. (f) N. Iwasawa,

References

2 17

M. Funahashi, M.; S. Hayakawa, T. Ikeno and K. Narasaka, Bull. Chem. Soc. Jpn. 1999, 72, 85-97. [I71 B. B. Snider, J. E. Merritt, M. A. Domboski, B. 0. Buckman, J. Org. Chem. 1991, 56, 55445553. [IS] (a) D. Yang, X.-Y. Ye, M. Xu, K.-W. Pang, N. Zou, R. M. Lechter, J. Org. Chem. 1998, 63, 6446-6447. (b) D. Yang, X.-Y. Ye, S. Gu, M Xu, J. Am. Chem. Soc. 1999, 121, 5579-5580. (b) D. Yang, X.-Y. Ye, M. Xu, K.-W. Pang, K.-K. Cheung, J. Am. Chem. Soc. 2000, 122, 1658-1663. (d) D. Yang, X.-Y. Ye, M. Xu, J. Org. Chem. 2000, 65, 2208-2217. [I91 B. B. Snider, T. Kwon, J. Org. Chem. 1990, 55, 1965-1968. [20] (a) M. G.Vinogradov, V. I. Dolinko, G. I. Nikishin, Bull. Acad. Sci. USSR. Ser. Chem. 1984, 1884- 1887; Izo. Akad. Nauk SSSR., Ser. Khim. 1984, 2065-2068. (b) M. G.Vinogradov, V. I. Dolinko, G. I. Nikishin, Bull. Acud. Sci. USSR. Ser. Chem. 1984, 334--341; Izu. Akud. Nauk SSSR., Ser. Khim. 1984, 375-383. [21] B. B. Snider, B. 0. Buckman, J. Org. Chem. 1992,57, 322-326. [22] I. Ryu, H. Alper, J. Am. Chem. Soc. 1993, 115, 7543-7544. [23] (a) H.Nishino, S. Tategami, T. Yamada, J. D. Korp, K. Kurosawa, Bull. Chem. Soc. Jpn. 1991, 64, 1800-1809. (b) C.-Y. Qian, H. Nishino, K. Kurosawa, Bull. Chem. Soc. Jpn. 1991, 64, 3557-3564. (c) T.Yamada, Y. Iwara, H. Nishino, K. Kurosawa, J. Chem. Soc., Perkin Trans. I 1993, 609-616. (d) V.-N. Nguyen, H. Nishino, K. Kurosawa, Heterocycles 1998, 48. 465-480. (e) L. Lamarque, A. Meou, P. Brun, Can. J. Chem. 2000, 78, 128-132. [24] R. Mohan, S. A. Kates, M. A. Dombroski, B. B. Snider, Tetrahedron Lett. 1987,28, 845-848. [25] J. R. Peterson, R. S. Egler, D. B. Horsley, T. J. Winter, Tetrahedron Lett. 1987, 28, 610961 12. (261 B. B. Snider, J. J. Patricia, J. Org. Cherz. 1989, 54, 38-46. [27] B. 9. Snider, B. A . McCarthy, Tetrahedron 1993, 49, 9447-9452. [28] (a) E. J. Corey, A. W. Gross, Tetruhedron Lett. 1985, 26, 4291-4294. (b) L. Lamarque, A. Miou, P. Brun, Tetruhedron 1998, 54, 6497-6506. [29] N.Fujimoto, H.Nishino, K. Kurosawa, Bull Chem. Soc. Jpn. 1986; 59, 3161-3168. [30] N. Ito, H.Nishino, K. Kurosawa, Bull Chem. Soc. Jpn. 1983, 56, 3527-3528. [31] W. E. Fristad, J. R. Peterson, A. B. Ernst, J. Ory. Chem. 1985, 50, 3143-3148. (321 G. I. Nikishin, M. G. Vinogradov, T. M. Fedorova, J. Chem. Soc., Chem. Commun. 1973, 693-694. [33] (a) T. Linker, B. Kersten, U. Linker, K. Peters, E.-M. Peters, H. G. von Schnering, Svnkett 1996,468-470. (b) T. Linker, T. Sommermann, F. Kahlenberg, J. Am. Chem. Soc. 1997, 119, 9377-9384. [34] E. I. Heiba, R. M. Dessau, J. Org. Chem. 1974, 39, 3456-3459. [35] J. M. Mellor, S. Mohammed, Tetrahedron 1993, 49, 7557-7566. [36] E.J. Corey, A. Ghosh, Tetruhedron Lett. 1987, 28, 175-178. [37] (a) J. Cossy, C. Leblanc, Tetrahedron Lett. 1989, 30, 4531-4534. (b) J. Cossy, A. Bouzide, C. Leblanc, Synlett 1993, 202-204. (c) R. Galeazzi, S. G. Mobbili, M. Orena, Tetrahedron 1996,52, 1069-1084. (d) A. D’Annibale, A. Pesce, S. Resta, C. Trogolo, Tetrahedron 1997, 53, 13129-13138. (e) D. T. Davies, N. Kapur, A. F. Parsons, Tetrahedron Lett. 1998, 39, 43974400. (f) H.Ishibashi, A. Toyao, Y. Takeda, Synlett 1999, 1468-1470. (g) F. A. Chowdhury, H. Nishino, K. Kurosawa, Heterocycl. Commun. 1999, 5, Ill-112. (h) A. D’Annibale, D. Nanni, C. Trogolo, F. Umani, Org. Lett. 2000,2, 401-402. [38] (a) 9 . A. M. Cole, L. Han, 9. B. Snider, J. Org. Chem. 1996, 51, 7832-7847. (b) J. L.Garcia Ruano, A. Rumbero, Tetrahedron: Asymmetry 1999, 10, 442774436, [39] (a) J. F. Jaime, R. W. Rickards, J. Chem Soc., Perkin Trans. 1. 1996, 2603-2613. (b) J . F. Jaime, R. W. Rickards, J. Chem Soc., Perkin Tran.7. I . 1997, 3613-3621. [40] D. R. Bhowmik, R. V. Venkateswaran, Terruhedron Lett. 1999, 40, 7431-7433. [41] Q.Zhang, R. M. Mohan, L. Cook, S. Kazanis, D. Peisach, B. M. Foxman, B. B. Snider, J. Org. Chem. 1993, 58, 7640-765 1. [42] B. B. Snider, 9 . Y.-F. Wan, 9 . 0 . Buckman, 9 . M. Foxman, J. Org. Chem. 1991,56, 328-334. [43] B. B. Snider, R. M. Mohan, S. A. Kates, Tetrahedron Lett. 1987, 28, 841-844. 1441 B. B. Snider, Q. Zhang, M. A. Dombroski, J. Org. Chem. 1992, 57, 4195-4205. [45] B. B. Snider, Q. Zhang, J. Org. Chem. 1993. 58, 3185-3187.

2 18

2.3 Manganese (III)-Mediated Radical Reactions B. B. Snider, M. A. Dombroski, J. Org. Chem. 1987,52, 5487-5489. M. A. Dombroski, S. A. Kates, B. B. Snider, J. Am. Chem. Soc. 1990, 112, 2759-2767. P. Jones, G. Pattenden, Synlett 1997, 398-400. (a) P. A. Zoretic, X. Weng, M . L. Caspar, D. G. Davis, Tetrahedron Lett. 1991, 32, 4819.4822. (b) P. A. Zoretic, Z. Shen, M. Wang, A. A. Riberio, Tetrahedron Lett. 1995, 36, 2925+ 2928. (c) P. A. Zoretic, Y. Zhang, A. A. Riberio, Tetrahedron Lett. 1995, 36, 2929-2932. (d) P. A. Zoretic, M. Wang, Y. Zhang, Z. Shen, A. A. Riberio, J. Org. Chem. 1996, 61, 1806.1813. (e) P. A. Zoretic, Z. Chen, Y. Zhang, A. A. Riberio, Tetrahedron Lett. 1996, 37, 79097912. ( f ) P. A. Zoretic, Y. Zhang, H. Fang, A. A. Riberio, G. Dubay, J. Org. Clzem. 1998, 63, 1162-1 167. (g) P. A. Zoretic, H. Fang, A. A. Riberio, J. Ory. Chem. 1998, 63, 4779-4785. (h) P. A. Zoretic, H. Fang, A. A. Riberio, J. Ory. Chem. 1998, 63, 7213-7217. B. B. Snider, J. Y. Kiselgof, B. M. Foxman, J. Org. Chem. 1998, 63, 7945-7952. E. J. Corey, Y. J. Wu, J. Am. Chem. Soc. 1993, 115, 8871-8872. A. S. Demir, A. Jeganathan, Synthesis 1992, 235-247. B. B. Snider, E. Y. Kiselgof, Tetrahedron 1996, 52, 6073-6084. B. B. Snider, L. Han, C. Xie, J. Org. Chem. 1997, 62, 6978-6984. S. V. O’Neil, C. A. Quickley, B. B. Snider, J. Ory. Chem. 1997, 62, 1970-1975. B. B. Snider, S. V. O’Neil, Tetrahedron 1995, 51, 12983-12994. L. A. Paquette, A. G. Schaefer, J. P. Springer, Tetrahedron 1987, 43, 5567-5582. (a) J. D. White. T. C. Somers, K. M. Yager, Tetrahedron Lett. 1990, 31> 59-62. (b) J. D. White, S. C. Jeffrey, Synleti 1995, 831-832. Z. Liu, F. Xu, Tetrahedron Lett. 1989. 30. 3457-3460. E. Lee, J. W. Lin, C. H. Yoon, Y.-s. Sung, Y. K. Kim, M. Yun, S. Kim, J. Am. Chem. Soc. 1997, 119, 8391-8392. T. R. R. Pettus, X.-T. Chen, S. J. Danishefsky, J. A m . Chem. Soc. 1998, 120, 12684-12685. (a) B. B. Snider, N. H. Vo, B. M. Foxman, J. Ory. Chem. 1993,58, 7228-7237. (b) N. H. Vo, B. B. Snider, J. Ory. Chem. 1994, 59, 5419-5423.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

2.4 Cerium(1V) and Other Oxidizing Agents Torsten Linker

2.4.1 Introduction The metal-mediated generation of radicals by single-electron transfer is of current interest in organic chemistry [ 11. The advantage over traditional methods of radical generation is the oxidative or reductive termination of the non-chain reactions with the introduction of functionality into the products. Many synthetic applications were developed for oxidative processes, where manganese(II1) acetate has received most attention (Volume 1, Chapter 2.3) [2]. However, other metals in high oxidation states were applied as oxidizing agents, and especially cerium(1V) became more and more attractive for radical C-C bond formations very recently [3]. A broad variety of CH-acidic compounds 1 may serve as precursors for the oxidative metalmediated generation of radicals (Scheme 1). Thus, a single-electron transfer from the enol form 2 to the metal in a high oxidation state affords radical cations 3 (pathway A), which undergo fast deprotonation to the radicals 4. Alternatively, the reactions proceed in the ligand sphere of the metal via enolates 5, and an inner sphere electron transfer generates the radicals 4 without cationic intermediates 3 (pathway B).

2.4.2 Cerium(1V)-Mediated Radical Reactions Among the various cerium(1V) complexes, cerium(1V) ammonium nitrate (CAN) is the most important oxidant in organic synthesis, since it is sufficiently stable in different solvents and is commercially available. Besides its propensity of introducing and removing protecting groups via single-electron transfer or Lewis acid catalysis [4], CAN serves as a convenient reagent for the generation of radicals from CHacidic substrates (Sec. 2.4.1) [3]. Because of the comparable oxidation potential of CAN (+1.61 V vs NHE) and manganese(II1) acetate (t1.54 V vs NHE), both oneelectron oxidants exhibit a similar reactivity pattern. However, the advantage of cerium(1V) ammonium nitrate consists in the milder reaction conditions, which allow the generation of radicals in methanol or acetonitrile at lower temperatures.

220

2.4 Cerium(IV) and Other Oxidizing Agents

R' = alkyl, aryl, COR, COzR, CN, NO2 R2 = alkyl, aryl, OH, OR

Scheme I . Mechanism of the oxidative metal-mediated radical generation

Early applications of CAN in C-C bond-forming reactions were developed for the radical addition of enolizable compounds 1 to arenes 6 (Scheme 2) [ 5 ] .The intermediate cyclohexadienyl radicals are oxidized to cations by CAN and afford the substitution products 7 after deprotonation. The same concept was used for radical cyclizations [6]. However, the disadvantages of such reactions are the moderate yields or regioselectivities. More recently, cerium(1V)-mediated radical reactions were extended to additions to alkenes [ 3 ] .One of the many examples from the pioneering work of Nair et al. is the addition of dimedone l c to the cyclohexene derivative 8 [7]. In the first step, adduct radicals 9 are formed, which are rapidly oxidized to the cation 10 by CAN. Intramolecular trapping of this intermediate by the carbonyl group affords after deprotonation the dihydrofuran 11 in excellent yield (Scheme 3 ) .

la

H3CN02

lb

6a

+

53%

7a

OR

CAN MeOH, 20 C ''

6b

R = H 55% R = M e 99%

7b 0 : m :

P

57 : 19 : 24

a

CAN * MeOH,25"C Et02C COZEt 82% Et02C"C02Et

Scheme 2. CAN-mediated radical additions of CH-acidic compounds 1 to arenes 6

2.4.2 Cerium (I V )-Mediated Radical Reactions

22 1

0

A. +k)

CAN

H3C H3C l c

MeOH, 5 "C

Ph

8

Ph

11 (98%)

Scheme 3. CAN-mediated radical reaction of dimedone l c

The advantage of mild reaction conditions is obvious, if enolates are oxidized at low temperatures in methanol. Thus, Narasaka et al. demonstrated that cerium(1V) ammonium nitrate smoothly generates radicals 12 after deprotonation of nitro compounds Id [8]. The electrophilic radicals can be added to electron-rich double bonds like silyl enol ethers 13. Ketones 14 are formed as intermediates, which after elimination of HN02 under the basic reaction conditions afford enones 15 in high yields as final products (Scheme 4). Very recently, cerium(1V)-mediated C-C bond formations were applied for the first time in carbohydrate chemistry [9]. Again, radicals are generated from malonates l a at low temperatures, and even sensitive glycals 16 are stable under such conditions. The regioselectivity of the additions is controlled by favorable orbital interactions and the adduct radicals are oxidized to cations, which are trapped by the solvent or CAN to afford the carbohydrate C-analogs 17 in good yields (Scheme 5). This methodology can be extended to various glycals 16, and the reactions exhibit high stereoselectivities.

1. KOH, MeOH, 20 "C 2. CAN, MeOH, -78 "C

ph-

*

ptp./-vN02

Id

4 ° yR? e 3*

12

P

h

x

:

0

-HN02 *

ph7R

R = Ph R = n-Pr R = (CH2)zPh

99% 81% 78%

Scheme 4. CAN-mediated radical reaction of nitro compound Id

0

222

2.4 Cerium(IV) and Other Oxidizing Agents

-0

250 mA cm-2) and high carboxylate concentrations favor radical coupling, which is due to a high radical concentration at the anode surface. There is no need for potential control (discharge potentials for carboxylates are in the range of 2.1-2.8 V vs nhe [19]) as long as the current density exceeds 10 mA cmP2. A weakly acidic electrolyte is preferable, which is achieved by neutralizing the electrolyte to an extent of 2 to 10% by an alkali metal hydroxide or alkoxide. This allows the use of an undivided cell, because hydrogen discharge, which continuously regenerates carboxylate that is consumed at the anode, is the exclusive cathode reaction. The endpoint of the electrolysis is indicated by the change of the electrolyte to an alkaline pH. Additives can strongly influence the coupling. Foreign anions should be excluded, because they disturb the necessary formation of a carboxylate film at the anode. Their unfavorable effect increases with the charge of the anion. Foreign cations that can form oxide layers or promote radical oxidation (Fe2+, Co2+, Cu2+, Mn2+) lower the coupling yield. Alkali and alkylammonium ions have no negative effect. Methanol is the solvent of choice, but acetonitrile can also be used if some water is added. Smooth platinum as foil or net is most universally applicable as anode material, but glassy carbon and hard graphite have also been successfully used. The nature of the cathode material is non-critical. For substrates with double or triple bonds, however, a platinum cathode should be avoided, as an unwanted cathodic hydrogenation can occur. In this case, a steel cathode should be used instead. In summary, the following experimental conditions should be used for a successful dimerization of carboxylic acids. An undivided beaker type cell (Fig. 2) is used, equipped with a smooth platinum anode and a platinum, steel or nickel cathode at a close distance; a current density of 0.25 A cmP2 or higher should be provided by a regulated power supply; a slightly acidic or neutral electrolyte, preferably methanol as solvent and a cooling device to maintain temperatures between 10 and 45°C should be employed. With this simple procedure and equipment, yields of coupling product as high as 90% can be obtained, provided the intermediate radical is not easily further oxidized. Electron transfer from the carboxylate to the anode leads with simultaneous bond breaking to the alkyl radical and carbon dioxide or to a very short-lived acyloxy

2.6 Electrochemical Generation of Radicals

260

radical that rapidly decarboxylates [20]. The anodic oxidation of a single carboxylate affords homocoupling products (Eq. 2). Despite the high discharge potential for carboxylates, a fair number of substituents are tolerated. ?l

R~-C-CO~-

-e

-c02

R2

R’ R’ R3#R3 R2 R2

R’, R2, R3 : H, Alkyl, Arylalkyl R’, R2 = H, R3 : C02Me, (CH2),X (X = COR, COpR, n>l X = OAc, NHAc, Hal, n>4)

The stereochemistry of the products and the regioselectivity of the coupling reaction indicates that adsorption of saturated alkyl radicals is relatively unimportant [20]. Carboxylates which are chiral and non-racemic at the a-position totally lose their optical activity in mixed heterocoupling [21, 221. This racemization indicates either a free radical as intermediate or its fast desorption-adsorption at the anode. These findings are further supported by the decarboxylation of 3 and 4, which both form the same 1:2: 1 mixture of truns,truns-, cis,trans- and cis,cis-coupled dimer, whilst 5-7 show a slight diastereoselectivity [23, 24). The latter could be due to some adsorption caused by the phenyl group or double bond andfor by a more effective facial shielding of the radicals (see Chapter 3.3).

3

4

Polar substituents can be handled without protection because nonpolar radicals are involved as reactive intermediates. This saves steps for protection and deprotection that are necessary when substrates with such substituents are submitted to reactions where strong bases, nucleophiles and electrophiles are involved. Together with the availability of a wide variety of carboxylic acids, this method of homocoupling is a unique and attractive method for the construction of symmetrical compounds. A great number of homocoupling reactions have been tabulated in refs. [2, 25, 261. Table 2 and molecular structures 8-17 show some selected examples. In general, only the substituent in the a-position is critical for the yield of the coupling product. Electron-donating groups (more than one alkyl group, phenyl, vinyl, halo or amino substituents) more or less shift the reaction toward products that originate from carbenium ions formed by further oxidation of the radical (see Section 2.6.3.5). Electron-attracting groups (cyano, ester or carbonyl substituents) or hydrogen, on the other hand, favor radical dimerization.

2.6.3 Radicals by Anodic Oxidation

261

40% (MeOH, Pt)

I 81%

62% (Pyr., H 2 0 , Et3N)

-50%

CO2H AcO"' 8 [361

12 [40]

9 [371

10 [38]

13 [43]

11 [39]

14 [44]

CH20Ac AcOi

,OAc

1

OAc 52%

15 [32]

0

AcO\.oAc

17 [451

OAc

OAc

CH~OAC 16 [45]

The coupling of carboxylic acids has been profitably used in natural product synthesis. Kolbe electrolysis of 8 is part of a (+)-a-onocerin synthesis [36], the electrolysis of 9 afforded a dimer with two quaternary carbon atoms [37], and 2,6,10,15,19,23-hexamethyltetracontane has been synthesized from 10 [38]. Cyclopropylcdrboxylic acids, e.g. 11 [39] and 12 [40], could be coupled to bicyclopropyl compounds; others led to allylic compounds via ring opening of an intermediate carbenium ion. The dimerization of half-esters of diacids is also of industrial interest: because in this way l,n-diesters are easily accessible [41]. Efficient syntheses of substituted succinic acids have been developed in the past [42]; a more recent application is the coupling of 13 as part of a semibullvalene synthesis [43]. While ketocarboxylic acids can be dimerized satisfactorily (Table 2), the corresponding aldehydes couple poorly. However, good yields can be obtained in these cases when the acetals, e.g. 14 [44], are electrolyzed instead. Hydroxy- and amino-carboxylic acids can be dimerized in moderate to good yields when the substituents are not in the CI- or P-position and when they are additionally protected against oxidation by acylation. Methyl hydrogen azelate has been coupled to the l,o-Cls-diester, which has been converted by acyloin condensation, deoxygenation and 1,4-addition of a methyl

2.6 Electrochemical Generation of Radicals

262

Table 2. Examples of homocoupling of carboxylic acids Carboxylic acid

Yield (“h)

Reference

60 -90 45-95 67 73-83 45-70 75 75 70 56 61 80

27 27 28 29 30 31 32 32 32 32 32

15-79

33

30

34

38

35

-

~~

H3C(CH2),C02H, n = 5-15 R02C(CH2),C02H, n = 4-16 (CH3)2CH-CH(C02Et)COzH AcO(CHz),C02H, n = 3-5 F(CHz),C02H, n = 4-10 EtCO(CH2)4COzH (Z)-CH3(CH2)7CH=CH(CH2)7C02H(Oleic acid) (Z)-CH3(CH2)7CH-CH (CH2)I 1 CO2H (Erucic acid)

CH~(CH~)~CH(OH)(CH~)IOC~~H CF3(CFz)7C02H CH302C(CH2)7C02H Rz: ,,octyl, R’: , MeiBu, iPr

R1&COzH

R3: H

R2

H3~~2~QCozH

group to homomuscone (15) [32]. C-Disaccharides 16 and 17, which are potential glucosidase inhibitors, are accessible in a few steps [45]. 3-Alkenoic acids 18 dimerize to a mixture of three 1,5-dienes 20a-c (Eq. 3); the dimers arise by l,l’-, 1,3’- and 3,3/-coupling of the intermediate allyl radical 19 [46]. When the 3-position of the allyl radical is increasingly sterically shielded, the proportion of 3-coupling decreases. The relative amount of the 1,l’-dimer can thus vary from 52 to 76% (Table 3). The configuration of non-terminal double bonds is retained to a high degree (-90%) [46]. \ R

20a

cop-

R

18

-e

-cop

R

‘ 7 :

e

31g

20b

3,

*\‘up

(3)

20c

,-

With 6-alkenoic acids 21, the intermediate radical 22 partially cyclizes to a cyclopentylmethyl radical 23 in a 5-exo-trig cyclization (Eq. 4) (see also Section

2.6.3 Radicals by Anodic Oxidation

263

Table 3. Kolbe dimerization of 3-alkenoic acids 1461 Product ratio (?YO)

Carboxylic acid [a]

Yield

1,l'

1,3/

3,3'

CH3 (CH2)7-C H=CH-CH2 -C02 (CH~)~-CH-CHTCH-CH~-CO~(CHI)~-C-CH=CH-CH~-CO~-

52 59 60

39 41 40

9

C (

60

40

-

45%

65

-

36

42%

76

24

-

H2CO2-

-

-

6IYo 79%) 15%

29'Yo

[a] 0.1 5-0.4 M in methanol, 8-50'%1neutralization with Et3N, undivided cell, platinum electrodes, 400-800 mA cm-2.

2.6.3.4) [47, 481. Z-4-Enoic acids partially isomerize to E-configured products. Results from methyl- and deuterium- labelled carboxylic acids support an isomerization by way of a reversible ring closure to cyclopropylcarbinyl radicals. The double bonds of Z-n-enoic acids with n 3 5 fully retain their configuration [48]. CH2=CH-(CH2)4C02-

21

CH*=CH-(CH2)842%

40%

-

CH~=CH-(CH~)S-CH~.

-e, -C02

CH-CHp

/

12/ 0

CH2=CH-(CH2)5

I

37%

@H2.

J. p

2

-

c

(4)

23 H

2

a

21%

2.6.3.1.2 Anodic Homocoupling of Anions, at-Complexes, Organometallics and Phenolates

In addition to the carboxylates, other anions can be dimerized at the anode, presumably via radicals. Anionic or enolized 1,3-dicarbonyl compounds and heteroanalogs of CH-acids couple in satisfactory yields (Table 4, entries 1-3). With some substrates, the yield is substantially improved with iodide as supporting electrolyte; an indirect electrolysis probably takes place here with iodine as electrocatalyst [58]. Mediated oxidations with NaBr, NaI of doubly activated methylene compounds CH2XY ( X = COzMe, CN, Y = C02Me) can be used to synthesize cyclopropane derivatives [59]. Electrolysis of methylene malonates in the presence of sodium iodide in an undivided cell results in 50-70% yield of stereoisomeric cyclobutane-

264

2.6 Electrochemical Generation of Radicals

Table 4. Selected Examples of Coupling of Anodically Generated Radicals from Carbanions Entry

Carbanion or precursor

Conditions

Product

Yield

Ref.

1

EtCH(COOEt),

EtONa, MeCN

[(EtOOC)2EtC]*

55%

49

2

CH(COOEt)3

NaOH, H20 acetone, EtOH

[(EtOOC)3C]*

50%

50 51

69'%

52

92%)

53

Me

Me

I

3

Me OyJie

0

Q

3a

CH(COMe)3

Et3N, MeCN Sfold excess, such that pseudo-first order conditions are maintained; clock experiments can be conducted with stoichiometric

322

3.1 Kinetics of Radical Reactions: Radical Clocks

heat

Propagation R-X

+

.SnBu3

R *

R'.

+ H-SnBu,

-

-

R

)-CN

-

+

X-SnBu3

R'*

R'-H

+

.SnBu3

Figure 3. Initiation and propagation steps in the tin hydride method

amounts of trapping agents, or even limiting amounts of trapping agents, but the analysis is simplified when pseudo-first-order conditions are maintained. The most convenient radical clock studies are based on radical chain reactions because these processes usually have high conversions with small amounts of initiation. Two general types of radical chain processes have been extensively employed in clock studies, the tin hydride method and the PTOC-thiol method. The initiation and propagation steps in the chain sequence of the tin hydride method are shown in Fig. 3. The radical source is an alkyl halide or pseudo-halide. A tin-centered (or silicon-centered) radical abstracts halogen to give the clock radical, R'.The bimolecular reaction competing with the unimolecular clock reaction is hydrogen atom transfer from Bu3SnH, 'tin hydride', or the relatively reactive silane (Me3Si)3SiH, tris-(trimethylsily1)silane or 'tris'. The rearranged radical, R'., also reacts with the tin hydride. The tin- or silicon-centered radicals produced in the competing H-atom transfer reactions rapidly abstract halogen or pseudo-halogen from the precursor such that the chain reaction is propagated. Figure 3 shows the simple case of a clock reaction competing with hydrogen atom transfer from tin hydride. If one wished to determine, for example, the rate of addition of a primary alkyl radical to an activated alkene such as an acrylate, then the reaction could be run at low concentrations of tin hydride such that both the radical clock and its rearrangement product reacted predominantly with the alkene. The products of the acrylate addition reaction are deactivated with respect to addition to another acrylate molecule, and one could control concentrations such that these adducts reacted primarily with the tin hydride (Scheme 3). In this case, then, one would analyze for the acrylate addition products of the unrearranged and rearranged radicals. Tin hydride reaction sequences are usually initiated by thermal decomposition of azo-bis-isobutyrylnitrile (AIBN), which has a decomposition half-life of about 1 h at 80 "C. Although other initiators can be used at different temperatures, AIBN is

3.1.4 Radical Clock Kinetic Studies

~

Practical Aspects

323

Scheme 3. Additional propagation steps in a radical clock study

convenient for reactions conducted at temperatures as low as 5OoC, and it can be used at high temperatures (>lOO"C) when it is added portion-wise to a reaction mixture. At low (sub-ambient) temperatures, photochemical cleavage of AIBN is possible, or one can employ the Et3B/oxygen initiation method [7]. If one of the reactions in a radical chain sequence is too slow to compete effectively with radical-radical reactions, the chain will collapse. Slow reactions of simple silanes such as Et3SiH with alkyl radicals precludes their use in the tin hydride method. Although quite reactive with alkyl radicals, thiols and selenols fail in the tin hydride method because the thiyl and selenyl radicals do not react rapidly with organic halide precursors. Nonetheless, it is possible to use thiols and selenols in tin hydride sequences when a Group 14 hydride is used as a sacrificial reducing agent. The thiyl or selenyl radical reacts with the silane or stannane rapidly, and the silicon- or tin-centered radical thus formed reacts rapidly with the organic halide [8]. In practice, benzeneselenol in catalytic amounts has been used in radical clock studies where Bu3SnH served as the sacrificial reductant [9]. The fundamental steps in the PTOC-thiol method are illustrated in Fig. 4 [lo]. The radical source is one of Barton's PTOC esters or a related thiohydroxamic acid derivative [ 11, 121; these are made from the corresponding carboxylic acids. The acyloxyl radicals produced in the initiation step rapidly decarboxylate to give the radical of interest. This radical reacts with a hydrogen atom donor, a thiol in this

Initiation

Propagation

RCO2.

R

+

C02

Figure 4. Initiation and propagation steps in the PTOC-thiol method

324

3.1 Kinetics of' Radical Reactions: Radical Clocks

example, to give the trapped product and a thiyl radical. The thiyl radical adds to the thiono group of the precursor to give another acyloxyl radical. As with the tin hydride method, competing radical rearrangement and addition steps can be incorporated in the propagation sequence. The thiono group is highly reactive with a wide range of radical types, and, therefore, thiols and selenols can be used as competing H-atom transfer agents as well as stannanes. The thione moiety is also photochemically labile, and PTOC esters are cleaved even by visible light irradiation. This feature requires that one handle the precursors with care, shielding them from laboratory light, but it also provides a simple method for radical chain initiation. Following thermal equilibration of the reaction mixture, one simply irradiates the mixture with visible light to initiate the chain reaction sequence. Because no extraneous radical initiators are present, all radical reactions cease when the PTOC ester is depleted, and by-products due to, for example, radical chain hydrostannation are avoided. PTOC esters are also thermally unstable, and kinetic studies using these precursors can not be performed above 50-60 "C.

3.1.5 Assumptions in Radical Clock Studies By the nature of the study, one often is required to make assumptions about the kinetics of clock reactions. The most important are (1) that one radical is an appropriate model for another and (2) that solvent effects for radical reactions can be approximated or ignored. The assumption that one radical is an appropriate model for another is most sound when one is using a clock to calibrate a bimolecular reaction and the local environment of the clock is similar to that of the radical of interest. For example, the rate constant found for reaction of the 5-hexenyl radical with a specific trapping agent should be a good approximation of the rate constant for reaction of another primary alkyl radical, especially one without substituents at C3. For most synthetic applications, the small errors in rate constants from this assumption will be unimportant. The assumption that solvent effects on radical kinetics can be estimated is precarious in some cases. Fortunately, for alkyl radical clocks that give simple alkyl radical products, i.e. neither the reactant nor product contains polar substituents at the radical center, the kinetics have been shown to be insensitive to solvent polarity effects [13, 141. This will not be the case, however, for alkyl radical clocks that involve additions to polarized groups such as an ci,jl-unsaturated carbonyl, nor for the reverse reactions, fragmentations of radical clocks that contain readily polarized groups such as esters. The transition states for the reactions are polarized, and rate constants increase with increasing solvent polarity [ 14, 151. Solvent polarity effects also are present in fragmentations of oxygen-centered radicals where increasing polarity accelerates the reactions. In decarbonylations of acyl radicals, the transition states are less polarized than the ground states, and rate constants decrease with increasing solvent polarity.

3.1.6 Primury Sources of Kinetic Dutu

325

3.1.6 Primary Sources of Kinetic Data The evolution of kinetic scales has been highly dependent on radical clock and, more generally, indirect competition kinetic studies [6]. These types of studies provide ratios of rate constants as discussed above. One can build an extensive series of relative rate constants for unimolecular clocks and bimolecular reactions, and the relative rate constants often are determined with very good to excellent precision. At some point, however, absolute rate constants are necessary to provide real values for the entire kinetic scale. These absolute kinetic values are the major source of error in the kinetics, but the absolute values are becoming more precise and, one certainly hopes, more accurate as increasingly refined techniques are introduced and multiple methods are applied in studies of specific reactions. Early radical kinetic values involved ESR methods, typically with continuous irradiation [16]. Much of the work had to be performed at low temperatures, and the resulting kinetic values at ambient temperatures could contain large errors. A modern variant of ESR spectroscopy removes the low-temperature requirement for relatively slow radical reactions and provides more precise data at ambient temperatures. The technique involves time-resolved ESR studies using pulsed photolyses with continuous monitoring. It can be applied not only when the radicals of interest are formed ‘instantly’ in the photochemical reaction but also when they are produced during the observing period from reaction of a first-formed transient [2]. The advent of laser flash photolysis (LFP) methods permitted kinetic studies of radicals at ambient temperatures with both increased precision and accuracy relative to those obtained by steady-state ESR methods. In a seminal study, Ingold’s group reported the rate constants for reactions of ‘tin hydride’ (Bu3SnH) with alkyl radicals [17]. The experiments involved monitoring the signal from the Bu3Sn’ radical which has a weak UV absorbance. This report provided the ‘workhorse’ kinetic values for alkyl radical reactions, and most alkyl radical clocks are calibrated relative to these second-order rate constants. Two other LFP-measured sets of secondorder rate constants for alkyl radical reactions are noteworthy. One consists of rate constants for reactions of alkyl radicals with thiophenol [18],and the other involves rate constants for couplings of alkyl radicals with nitroxyl radicals [ 191. Both trappings by PhSH and couplings with nitroxyl radicals are considerably faster than radical reactions with Bu3SnH. The availability of radical clocks that are a-substituted carbon-centered radicals or heteroatom-centered radicals is limited, however. Several experimental difficulties have limited progress in measurements of absolute rate constants for these types of radicals. One problem is the lack of precision for low-temperature ESR studies, and another has been a limited number of reactions available for production of radicals in LFP studies. A third fundamental problem affects the types of LFP studies described above for Bu3SnH; specifically, the UV absorbance of the tin-centered radical is weak, and its signal can be obscured by absorbances of other species. Alternative LFP-based approaches for measuring radical kinetics exist, and these are providing the absolute kinetic data for some of the presently evolving kinetic

326

3.1 Kinetics of Radical Reactions: Radical Clocks

scales. One method involves using a probe substrate that reacts with the radical of interest to give a readily detected product. The probe reaction can be either a bimolecular reaction or a unimolecular process. Following direct kinetic calibration of the probe reactions, one can determine bimolecular kinetics either directly by LFP methods or indirectly by competition kinetics. When the probe reaction being calibrated is a unimolecular process, one measures the rate constant of a radical clock directly for the initial absolute kinetic values, and, thus, the method is inverted in approach from that used for alkyl radical kinetics. LFP studies of unimolecular process give more precise data than those of bimolecular processes, and the approach typically starts with inherently good kinetic data. The synthetic efforts necessary for production of appropriate radical precursors are a drawback to this method, but it is, nonetheless, useful for establishing absolute kinetics for some classes of radicals where little kinetic information was available, such as nitrogen-centered radicals discussed later.

3.1.7 Examples of Radical Clocks 3.1.7.1 Alkyl Radical Clocks Some primary alkyl radical clocks are collected in Table 1. These examples demonstrate the wide range of kinetics that can be studied with radical clocks, but other classes of clocks are not nearly as well developed. Radical 1-1 was calibrated by kinetic ESR methods [2], and radical 1-9 was calibrated directly by LFP [3]. All of the others [3, 17, 20-281 were calibrated by indirect methods. Most alkyl radical clocks with rate constants smaller than 1 x lo7 s-' at ambient temperatures are ultimately calibrated against LFP-determined Bu3SnH trapping kinetics [ 17, 291; this includes cases where the second-order competition studies were performed with tris-(trimethylsilyl)silane, (Me3Si)3SiH, because rate constants for alkyl radical reactions with the silane were determined via clocks that were calibrated against tin hydride [30]. The rate constants for radical 1-10 depend on multiple methods, those for 1-11 depend on nitroxyl trapping kinetics, and those for 1-12 and 1-13 depend on PhSH and PhSeH trapping kinetics. Rate constants for reactions of PhSH with alkyl radicals were determined by LFP [18], and these values were incorporated into the kinetic values for PhSeH via clock studies [ 3 11. A more recent calibration of PhSeH trapping kinetics involved competition kinetic studies with a series of fast radical clocks whose rate constants for cyclization were measured directly by LFP [3]. This work resulted in an adjustment of the PhSeH trapping kinetics and also those for reaction of PhSH with a primary alkyl radical, and, accordingly, the rate constants for the fast radical clocks must be adjusted. Arrhenius functions for all of the reactions shown in Table 1 have been determined or estimated, but those listed are for illustrative purposes and are among the more secure. The large log A values for ring openings of 1-11 and 1-13 and for rearrangement of 1-1 via initial 3-exo cyclization are typical for these types of re-

3.1.7 Examples of Radical Clocks

321

Table 1. Primary alkyl radical clocks Entry

k2,, (s-I)

Clock reaction

1-1

3 x 102

1-2

4

1-3

d' --/

14

1-5

1-6

& -wax/ -y

1-7

1-8

f

-

'

0

3

.

12.7 - 13.810

Ref.

2

103

20

5 x 103

21

2 x 105

22

2.3 x 105

9.3 - 5.010

17

x 106

23

5 x 106

24

9 x 106

25

5

107

10.17 - 3.4918

3

6.7 x 107

13.04 - 6.9910

3

4

1-9

Arrhenius function

Ph

1-10

1-11

4.-.d

A

-*

4 x 109

26

328

3. I Kinetics of Radical Reactions: Radical Clock3

Table 1 (continued) Entry

Clock reaction

k20 (s-')

Ix

1-12

1-13

Ph"*'

Arrhenius function

21

1010

1.5 x 10"

Ref.

13.1

- 2.58/8

28

actions, showing little entropy demand in the transition states. The 5-ex0 cyclizations of 1-5 and 1-9 have considerably smaller frequency factors because of the organization required to obtain the transition states; again, these log A values are typical. In fact, one can use these log A values (i.e. 13 for a cyclopropylcarbinyl ring opening or 3-ex0 cyclization and 9.5 for a 5-ex0 cyclization) and a rate constant at one temperature to estimate a rate constant at another temperature. Many of the primary alkyl radical clocks have secondary and tertiary counterparts. The rate constants for these clocks usually are somewhat smaller than those for the corresponding primary clocks as shown in a examples in Fig. 5 where rate constants in units of sP1 for reactions at 20 or 25 "C are given for 5 [ 17, 24, 321, 6 [3, 26, 331, 7 [ 3 ] ,and 8 [14].One might imagine that the reduction in rate constants is due to increased stability of a secondary or tertiary alkyl radical in comparison to a primary alkyl radical, but radical stability probably has less to do with the changes in rate constants than steric and entropy effects in many cases. For example, the rate constants for the two series of radical clocks 7 and 8 have been measured directly by LFP with good precision. For the series 7, the activation energies for 5-ex0 cyclizations are progressively smaller for the l o , 2" and 3" radicals, but decreasing

Ph

5: R, R' = H, Me 10:2 x lo5 20:1 lo5 3": 1 lo5

6: R, R' = H, Me 1": 7 x lo7 2": 4 x lo7 3": 2 x lo7

7 : R, R' = H, Me 10:3.7 x lo7 2": 2.2 x lo7 3":i.i x107

F'h Ph

\

8: R, R' = H, Me 10:3.9 1o8 20: 1.5 lo8 30:0.9~10~

Figure 5. Secondary and tertiary alkyl radical clocks and their rate constants for rearrangements at 20 "C in units of s-l

329

3.1.7 Examples of Radical Clocks Table 2. Rate constants in s-' for cyclizations of substituted 5-hexenyl radicals at 20°C X

Ph

2-1

H CH3 OCH3 CO2Et C(O)NEt2 CN

2x 1 2x 2x 1x

105 105

2-2

2-3

1 x 105 1 x 105

4 2x 4 5 2x

105

105 105

1 x 104

Ph

107 107 107 107 107

Ph

2-4 2 I 6x 3 I x 2x

107 107 lo7 105 104

105

log A terms for the sequence (i.e. increasingly negative entropies of activation) more than offset the decreasing enthalpic barriers [3]. In the case of ring openings of radicals 8, the reduction in the rate constant for the secondary radical in comparison to the primary radical is due to an entropic effect; the further reduction in the rate constant for the tertiary radical is enthalpic in origin, but it is ascribed to a steric effect, an unavoidable eclipsing interaction in the transition state for ring opening [ 141.

3.1.7.2 Substituted Alkyl Radical Clocks Limited examples of substituted alkyl radical clocks are available. Fortunately, some calibrated clocks that are available have rate constants in the middle ranges for radical reactions and should be useful in a number of applications. Examples of clocks based on the 5-exo cyclization of the 5-hexenyl radical are shown in Table 2. The data for the series of radicals 2-1 and 2-2 [17, 32, 34, 351 are from indirect studies, whereas the data for radicals 2-3 and 2-4 [3, 35-38] are from direct LFP studies. The striking feature in these values is the apparent absence of electronic effects on the kinetics as deduced from the consistent values found for secondary radicals in the series 2-1 and 2-3. The dramatic reduction in rate constants for the tertiary radical counterparts that contain the conjugating ester, amide and nitrile groups must, therefore, be due to steric effects. It is likely that these groups enforce planarity at the radical center, and the radicals suffer a considerable energy penalty for pyramidalization that would relieve steric compression in the transition states for cyclization. Phenyl-substituted radical clocks (Fig. 6) display definite enthalpy effects that one expects for strong radical-stabilizing groups. The result is that unimolecular clock reactions are orders of magnitude less rapid than their non-substituted counterparts as evidenced in the rate constants at ambient temperatures for 5-ex0 cyclization of radical 9 [39] and ring openings of radicals 10 [4, 401, 11 [4], and 12 [41]. Note that

330

3.1 Kinetics of Radical Reactions: Radical Clocks

-

6.1

6

P h 10

p h v P h

10~s-l L

.

Ph

5.4x 106s-1

3 x 108 s-'

-Ph Ph

12

Figure 6. Phenyl-substituted radical clocks and their rate constants for reactions at 20 "C

ring openings of 10 and 11 are reversible, and the cyclic forms are thermodynamically favored; nonetheless, these radicals can be used as clocks, provided that the multiple concentration studies are performed as described earlier. In the ring opening of radical 12, the effects of the two phenyl groups cancel, and the rate constant is comparable to that of the unsubstituted parent, the cyclopropylcarbinyl radical.

3.1.7.3 Aryl and Vinyl Radical Clocks The availability of radical clocks for sp2-hybridized carbon systems has been limited by the high reactivity of phenyl and vinyl radicals and by the lack of appropriate methods for preparation of these radicals for direct kinetic studies. Competition kinetic studies have given relative rate constants for some radical clocks in this group, but absolute rate constants for the radical-trapping reactions used in the competitions are not generally available. In that regard, one should note that reported rate constants for reactions of Bu3SnH with the phenyl and 2,2-dimethylvinyl radicals [29] were later vitiated when it was found that these radicals had not been produced cleanly. A more recent determination of the rate constant for reaction of an aryl radical with BqSnH at ambient temperature is available, viz. kT = 7.8 x 10' M-'s-' [421. If one assumes that this kinetic value can be used for any aryl radical reacting with tin hydride, then the rate constants for cyclization of the aryl radical clocks shown below can be calculated from the reported relative Arrhenius functions [29]. Specifically, radicals 13 and 14 cyclize with rate constants of 5 x lo8 S K ' and

3.1.7 Examples of Radicul Clocks

33 1

8 x lo9 SKI,respectively, at 25°C. For the vinyl radical clock 15, the ratio of rate constants for cyclization and Bu3SnH trapping is kc/ka = 0.9 M at 80 "C [43].

13

14

15

3.1.7.4 Acyl Radical Clocks Several acyl radical clocks have been calibrated, and these are collected in a recent excellent review of the general subject [44]. Examples of the two types of unimolecular clock reactions, decarbonylations and cyclizations, are shown in Fig. 7, with rate constants for reactions at ambient temperature. Decarbonylations of acyl radicals, as shown for radical 16 [45], and the related decarboxylations of alkoxycarbonyl radicals such as 17 [2] have log A terms of about 13 for cases where alkyl radical products are formed [46, 471. The decarbonylation reactions involve a reduction in charge separation in the transition states, and the kinetics are sensitive to solvent polarity with decreases in rates as polarity increases [45]. Cyclization reactions, such as that shown for radical 18, are complicated. The 5-ex0 products shown are the predominant first-formed products, but they further rearrange to the thermodynamically favored 6-end0 products by addition of the radical center to the carbonyl group to give a cyclopropyloxyl radical followed by ring opening [48].

3.1.7.5 Nitrogen-Centered Radical Clocks Nitrogen-centered radicals have been applied in synthetic conversions infrequently, in part because convenient sources of nitrogen-centered radicals have not been readily available until recently [49, 501. Nitrogen-centered radical conversions are

16

17

18

Figure 7. Acyl radical clocks and their rate constants for reactions at 20°C

332

3.1 Kinetics of Radical Reactions: Radical Clocks

attractive in some cases because of the generally mild conditions of radical reactions. Furthermore, several types of electrophilic nitrogen-centered radicals are available which complement the nucleophilic polar reactivity of nitrogen, and electrophilic nitrogen-centered radicals are considerably more reactive than nucleophilic nitrogen radicals. Nitrogen-radical kinetic scales are not well developed, but progress has been made recently. Figure 8 contains a collection of cyclization reactions, most of which were calibrated by indirect kinetics using H-atom transfer trapping. The original works cited below contain the kinetics for the bimolecular H-atom transfer trapping reactions as well as those for the fast-reacting clocks that gave benzylic or diphenylalkyl radical products and were calibrated directly by LFP. Amidyl radicals 19-21 are quite reactive [51]. The rate constant for the iminyl radical clock 25 is estimated from results with the terminal diphenyl-substituted analog [ 521. Cyclization of the aminyl radical 22 is slow and reversible [53], and the kinetics of related cyclizations and P-fragmentations were measured directly by LFP [ 541. Protonation of the dialkylaminyl radicals gives dialkylaminium cation radicals such as 24 that react much more rapidly [55], and Lewis acid complexes of aminyl radicals such as 23 are intermediate in reactivity [56]. Clocks such as 23 and 24 are in equilibrium with the neutral aminyl radicals, and the concentrations of the protonated or complexed forms are necessary if one is to use these clocks; equilibrium constants for protonations and Lewis acid complexations in some solvents were determined in the initial kinetic calibration studies.

3.1.7.6 Oxygen-Centered Radical Clocks Because of their high reactivity, alkoxyl radicals (especially the tert-butoxyl radical) are important for generating other radicals by hydrogen atom abstraction. Alkoxyl radicals are also important in other synthetic applications, as intermediates in a number of rearrangement reactions and as first-formed radical intermediates that fragment to give desired product radicals. Despite the interest in alkoxyl radicals, kinetic studies for establishing clock reactions are difficult because the high reactivity results in multiple reaction pathways; i.e. hydrogen atom abstractions and additions to solvent molecules compete with the fragmentations. Rate constants for some alkoxyl radical fragmentations are shown in Fig. 9. The tert-butoxyl radical (26) fragmentation to acetone and the methyl radical has been studied for years, but the rate constant shown below is from a very recent work that employed time-resolved ESR methods [2]. The cumyloxyl radical (27) fragmentation was studied directly by LFP methods, taking advantage of the IR and UV absorbances of this radical [57]. The rate constants for the reversible ring opening of the cyclopentyloxyl radical (28) were determined by competition kinetics [58], and one should note that the kinetic values are at 80 "C. Alkoxyl radical cleavages have log A terms of about 13 as expected for fragmentation reactions. Increasing alkyl substitution, such that the product alkyl radicals are increasingly more stable, results in considerable kinetic accelerations [ 591. One should note that the kinetics of alkoxyl radical fragmentations arc sensitive to

3.1.7 Examples of Radical Clocks

9 O

333

R

C 19

OYR

O

O Y R

L 20

R

21

9

L-

2 x lo4 s - ~ L

1 x lo4 s - ~

22

R, ,BF3

23

25

Figure 8. Nitrogen-centered radical clocks and their rate constants for rearrangements at 20 "C

334

3.1 Kinetics of Radical Reactions: Radical Clocks

26

27

8 - L. 5 x 1O8 s-' (80 "C)

9

-

105 s-l (80 oc)

28

Figure 9. Alkoxyl radical clocks and their rate constants for reactions

solvent polarity, increasing as the polarity increases, and solvent effects were among the major points of interest in the cited studies of radicals 26 and 27. The rate constants for the examples shown here are for reactions in benzene.

3.1.8 Conclusion This brief overview was intended to introduce the concepts of the radical clock method with a relatively limited number of examples. Extensive tables of radical kinetics exist, and many reactions can be used as clocks. In regard to the kinetic values available, however, one should appreciate that determinations of radical kinetics tend to involve a series of increasingly precise and accurate approximations. For that reason, more recently determined rate constants usually were selected for this overview. When using radical clocks, one is well advised to search a reference in the forward direction for improved kinetic values, especially those involving recalibrations of absolute rate constants. Many points of interest related to radical clocks were not covered in this overview. A recent extensive compilation of the kinetics of reactions of Group 14 hydrides (silanes, germanes, stannanes) with radicals is available [60], and this work contains the current 'best values' for use with results from many competition studies. Radical anion clocks [61] and radical cation clocks [62] are just starting to emerge at the time of this writing. Computational studies of radical reactions have progressed to the point that kinetics of cyclopropylcarbinyl radical ring-opening reactions can be well estimated [63], and computational results for alkyl radical reactions which do not have polarized transition states should be increasingly important in the near future.

References

335

References [ 11 D. Griller, K. U. Ingold, Arc. Chem. Res. 1980, 13, 317-323. [2] M. Weber, H. Fischer, J. Am. Chem. Soc. 1999, 121, 7381-7388. [3] M. Newcomb, S. Y. Choi, J. H. Horner, J. Org. Chem. 1999,64, 1225-1231. [4] T. A. Halgren, J. D. Roberts, J. H. Horner, F. N. Martinez, C. Tronche, M. Newcomb, J. Am. Chem. Soc. 2000, 122, 2988-2994. [5] E. Furxhi, J. H. Horner, M. Newcomb, J. Org. Chem. 1999, 64, 4064-4068. (61 M. Newcomb, Tetrahedron 1993, 49, 1151-1176. 171 K. Nozaki, K. Oshima, K. Utimoto, J. Am. Chem. Soc. 1987,109, 2547-2549. [8] R. P. Allen, B. P. Roberts, C. R. Willis, J. Chem. Soc., Chem. Commun. 1989, 1387-1388. [9] D. Crich, X. Y. Jiao, Q. W. Yao, J. S. Harwood, J. Org. Chem. 1996, 61, 2368-2373. [lo] M. Newcomb, A. G. Glenn, J. Am. Chem. Soc. 1989, 111, 275-277. 1111 D. H. R. Barton, D. Crich, W. B. Motherwell, Tetrahedron 1985, 41, 3901-3924. [I21 D. Crich, L. Quintero, Chem. Rev. 1989, 89, 1413-1432. 1131 A. L. J. Beckwith, V. W. Bowry, K. U. Ingold, J. Am. Chem. Soc. 1992, 114, 4983-4992. [I41 J. H. Horner, N. Tanakd, M. Newcomb, J. Am. Chem. Soc. 1998, 120, 10379-10390. [I51 M. Newcomb, J. H. Horner, C. J. Emanuel, J. Am. Chem. Soc. 1997,119, 7147-7148. [I61 D. Griller, K. U. Ingold, Acc. Chem. Res. 1980, 13, 193. [17] C. Chatgilialoglu, K. U. Ingold, J. C. Scaiano, J. Am. Chem. Soc. 1981, 103, 7739-7742. I181 J. A. Franz, B. A. Bushaw, M. S. Alnajjar, J. Am. Chem. Soc. 1989, 111, 268-275. [I91 J. Chateauneuf, J. Lusztyk, K. U. Ingold, J. Org. Chem. 1988, 53, 1629-1632. [20] A. Effio, D. Griller, K. U. Ingold, A. L. J. Beckwith, A. K. Serelis, J. Am. Chem. Soc. 1980, 102, 1734-1736. [21] a) J. C. Walton, J. Chem. Soc., Perkin Trans. 2 1989, 173-177; b) A. L. J. Beckwith, G. Moad, ibid. 1980, 1083-1092; c ) K. U. Ingold, B. Maillard, J. C. Walton, ibid. 1981, 970-974. [22] a) D. A. Lindsay, J. Lusztyk, K. U. Ingold, J. Am. Chem. Soc. 1984, 106, 7087-7093; b) J. A. Hawari, S. Davis, P. S. Engel, B. C. Gilbert, ibid. 1985, 107, 4721-4724. [23] M. Newcomb, A. G. Glenn, W. G. Williams, J. Org. Chem. 1989, 54, 2675. [24] A. L. J. Beckwith, C. J. Easton, T. Lawrence, A. K. Serelis, Aust. J. Chem. 1983, 36, 545-556. [25] A. L. J. Beckwith, S. A. Glover, Aust. J. Chem. 1987, 40, 157--173. [26] V. W. Bowry, J. Lusztyk, K. U. Ingold, J. Am. Chem. Soc. 1991, 113, 5687-5698. [27] S. Y. Choi, M. Newcomb, Tetrahedron 1995, 51, 657-664. [28] a) M. Newcomb, C. C. Johnson, M. B. Manek, T. R. Varick, J. Am. Chem. Soc. 1992, 114, 10915-10921; b) M. Newcomb, S.-Y. Choi, P. H. Toy, Can. J. Chem. 1999, 77, 1123-1135. [29] L. J. Johnston, J. Lusztyk, D. D. M. Wayner, A. N. Abeywickreyma, A. L. J. Beckwith, J. C. Scaiano, K. U. Ingold, J. Am. Chem. SOC.1985,107,4594-4596. [30] C. Chatgilialoglu, J. Dickhaut, B. Giese, J. Org. Chem. 1991, 56, 6399-6403. [31] M. Newcomb, T. R. Varick, C. Ha, M. B. Manek, X. Yue, J. Am. Chem. Soc. 1992, 114, 81 58-8163. [32] C. Tronche, F. N. Martinez, J. H. Horner, M. Newcomb, M. Senn, B. Giese, Tetrahedron Lett. 1996, 37, 5845-5848. [33] P. S. Engel, S. L. He, J. T. Banks, K. U. Ingold, J. Lusztyk, J. Org. Chem. 1997, 62, 12101214. [34] M. Newcomb, M. A. Filipkowski, C. C. Johnson, Tetrahedron Lett. 1995, 36, 3643-3646. [35] 0. M. Musa, S. Y . Choi, J. H. Horner, M. Newcomb, J. Org. Chem. 1998, 63, 786-793. 1361 C. C. Johnson, J. H. Horner, C. Tronche, M. Newcomb, J. Am. Chem. SOC.1995, 117, 16841687. [37] M. Newcomb, J. H. Horner, M. A. Filipkowski, C. Ha, S. U. Park, J. Am. Chem. Soc. 1995, 117, 3674-3684. 1381 C. F. Tronche, PhD thesis, Wayne State University (USA), 1996. [39] J. A. Franz, N. K. Suleman, M. S. Alnajjar, J. Org. Chem. 1986, 51, 19-25. [40] A. L. J. Beckwith, V. W. Bowry, J. Am. Chem. Soc. 1994, 116, 2710-2716. [41] R. Hollis, L. Hughes, V. W. Bowry, K. U. Ingold, J. Org. Chem. 1992, 57, 4284-4287.

336

3.1 Kinetics of Radical Reactions: Radical Clocks S. J. Garden, D. V. Avila, A. L. J. Beckwith, V. W. Bowry, K. U. Ingold, J. Lusztyk, J. Org. Chem. 1996, 61, 805-809. A. L. J. Beckwith, D. M. O’Shea, Tetrahedron Lett. 1986,27, 4525-4528. H. Chatgilialoglu, D. Crich, M. Komatsu, I. Ryu, Chem. Rev. 1999, 99, 1991-2069. Y. P. Tsentalovich, H. Fischer, J. Chem. Soc., Perkin Trans. 2 1994, 729-733. C. Chatgilialoglu, C. Ferreri, M. Lucarini, P. Pedrielli, G. F. Pedulli, OrganometaNics 1995, 14, 2672-2676. P. A. Simakov, F. N. Martinez, J. H. Horner, M. Newcomb, J. Org. Chem. 1998, 63, 12261232. C. Chatgilialoglu, C. Ferreri, M. Lucarini, A. Venturini, A. A. Zavitsas, Chem. Eur. J. 1997,3, 376-387. J. L. Esker, M. Newcomb in Advances in Heterocyclic Chemistry, Vol. 58 (Ed.: A. R. Katritzky), Academic, San Diego: 1993, pp. 1-45. A. G. Fallis, I. M. Brinza, Tetrahedron 1997, 53, 17543-17594. J. H. Horner, 0. M. Musa, A. Bouvier, M. Newcomb, J. Am. Chem. Soc. 1998, 120, 77387748. M. H. Le Tadic-Biadatti, A. C. Callier-Dublanchet, J. H. Horner, B. Quiclet-Sire, S. Z. Zard, M. Newcomb, J. Org. Chem. 1997, 62, 559-563. 0. M. Musa, J. H. Horner, H. Shahin, M. Newcomb, J. Am. Chem. Soc. 1996, 118, 38623868. M. Newcomb, 0. M. Musa, F. N. Martinez, J. H. Horner, J. Am. Chem. Soc. 1997, 119, 4569-4577. J. H. Horner, F. N. Martinez, 0. M. Musa, M. Newcomb, H. E. Shahin, J. Am. Chem. Soc. 1995, 117, 11124-11133. C . Ha, 0. M. Musa, F. N. Martinez, M. Newcomb, J. Org. Chem. 1997, 62, 2704-2710. D. V. Avila, C. E. Brown, K. U. Ingold, J. Lusztyk, J. Am. Chem. Soc. 1993, 115, 466-470. A. L. J. Beckwith, B. P. Hay, J. Am. Chem. Soc. 1989, I l l , 230-234. T. Nakamura, W. K. Busfield, I. D. Jenkins, E. Rizzardo, S. H. Thang, S. Suyama, J. Org. Chem. 2000, 65, 16-23. C . Chatgilialoglu, M. Newcomb, Adu. Organometal. Chem. 1999, 44, 67-1 12. J. M. Tanko, J. P. Phillips, J. Am. Chem. Soc. 1999, 121, 6078-6079. N. P. Schepp, D. Shukla, H. Sarker, N. L. Bauld, L. J. Johnston, J. Am. Chem. Soc. 1997, 119; 10325- 10334. a) F. N. Martinez, H. B. Schlegel, M. Newcomb, J. Org. Chem. 1996, 61, 8547-8550; b) F. N. Martinez, H. B. Schlegel, M. Newcomb, J. Org. Chem. 1998, 63, 3618-3623; c) D. M. Smith, A. Nicolaides, B. T. Golding, L. Radom, J. Am. Chrm. Soc. 1998, 120, 10223-10233.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

3.2 Calculations: a Useful Tool for Synthetic Chemists Curl H. Schiesser and Melissa A . Skidmore

3.2.1 Introduction Not so long ago, free-radical reactions were considered to give rise only to intractable tars or polymers [ 11. Over the past few decades, considerable effort from numerous research groups has led to a solid understanding of the factors which govern the reactivity and regio- and stereochemistry of radical addition reactions [ 1, 21. Undoubtedly, free-radical processes, in particular homolytic addition reactions, are now firmly entrenched in the armory available to the synthetic organic chemist. As is clearly demonstrated in other chapters of this compilation, numerous elegant and impressive syntheses based on free-radical methodology have arisen as a direct result of our increased understanding of these processes. Computational chemistry has played, and continues to play, a crucial role in this story. The purpose of this chapter is to provide a cross-section of information about the application of computational techniques to free-radical chemistry. It is deliberately not intended to be comprehensive, but rather, through examples, intended to provide useful information about what is attainable through the use of modern computational techniques. Specific attention to modeling intramolecular homolytic additions, substitutions and hydrogen transfer chemistry is given as well as insight into recent important mechanistic questions.

3.2.2 Modeling Radical Cyclization Reactions 3.2.2.1 Force Field Methods By far the greatest impact that free-radical chemistry has had on organic synthetic methodology is in the area of ring construction [ l , 21. The ability to construct complex carbocyclic and heterocyclic frameworks through intramolecular rearrangement has revolutionized synthetic thinking. It is hard to believe that the prototypical freeradical cyclization reaction, the ring closure of the 5-hexenyl radical 1 (Scheme I ) ,

338

3.2 Calculations: a Useful Tool for Synthetic Chemists

1*

1 1

6-endo

4

1

2

Scheme 1. Ring closure of the 5-hexenyl radical 1

was only reported in 1963 [ 3 ] . It took, however, another twenty years to fully appreciate the factors which control the preference for Sex0 cyclization in this species; computational chemistry was instrumental in this understanding. At around about the time of the early Apollo space missions, several suggestions about the origin of the regiochemistry of the ring closure of 1 were circulating among the free-radical community. For example, Julia argued that the transition state 2 for 6-end0 ring closure is destabilized over that for the 5-exo mode by unfavorable non-bonded interactions between the pseudo-axial hydrogen at C-2 and the syn-hydrogen at C-6, which do not occur in the 5-exo structure [4]. At around about the same time, Beckwith suggested that 'the strain engendered in accommodating the mandatory disposition of reacting centers within the transition complex for 1,6-ring closure outweighs those steric and thermochemical factors expected to favor the formation of the more stable possible product' [ 5 ] . In an attempt to gain insight into the factors which govern these reactions, Bischof explored the modes of ring closure of several a-alkenyl radicals through the use of MIND0/3 semi-empirical molecular orbital theory [6]. It is clear that this first attempt to use computational techniques to provide a definitive answer to the exo/ endu problem was an unmitigated failure. Not only did MIND0/3 fail to even provide an accurate ball-park estimate of the activation energies for these reactions, it predicted that both modes of cyclization have the same energy barrier (67 kJ mol-'), some 39 and 26 kJ mol-' higher than the experimental values for the exo and endo reaction respectively [7]. If the Beckwith hypothesis [5] were accurate, then it seemed reasonable that a modeling method based on strain energies may well provide the answer to this vexing problem. Transition states 3, 4 for the exu and endo modes of cyclization of 1 were optimized using MNDO [7]. It is interesting to note that MNDO (as did MIND0/3) overestimates the activation energies for these reactions, but predicts a slight (2.1 kJ mol-') preference for the ex0 mode [7]. More importantly, these calculations provided the geometric details of the intimate array of reacting centers, which were subsequently incorporated into the MM2 (molecular mechanics) method. These dimensions, as well as those for the 6-heptenyl and 7-octenyl systems, are

339

3.2.2 Modeling Radical Cyclization Reactions

Table 1. Dimensions" of the intimate array of reacting centers in the ex0 and endo transition states ( 5 , 6) for the cyclization of w-alkenyl radicals ~~

n

1 2 3 a

6

5 YI

r2

0

0

r2

m

2.20 2.20 2.20

1.388 1.392 1.393

104.0 101.0 99.0

2.20 2.20 2.25

1.392 1.387 1.389

98.0 100 0 106.0

Distances in

A, angles in degrees.

5

6

listed in Table 1. It is noteworthy that there is little distance variation in these structures; however, the attack angle (0) is more sensitive to ring size. When the dimensions of the arrays of reacting centers were incorporated (fixed) into model transition states which were then optimized by MM2, remarkable agreement between calculated values of AE, (the strain energy component of the activation energy) and experimentally determined activation energies ( A E i )were observed for a large cross-section of radical species (1, 7-17) (Table 2) [7, 81. This result provides strong support for the stereo-electronic hypothesis of Beckwith [ 5 ] . It would appear, therefore, that the major factor responsible for determining the mode of ring closure in o-alkenyl radicals is the strain engendered in the transition states involved during homolytic addition. Spellmeyer and Houk provided a valuable alternative 'flexible' force-field method in which transition state parameters were developed from ah initio data on simple

8

7

10

11

14

15

9

12

16

13

17

340

3.2 Calculations: a Useful Tool for Synthetic Chemists

Table 2. Calculated transition structure strain energies (A Es)a,b and experimental datab for the ring closures of selected w-alkenyl radicals (1, 7-17) Radical

Beckwith-Schiesser AEs (ex.) AE, (endo)

Spellmeyer-Houk AE5 (exo) AE, (endo)

Experimental AEi ( e m ) AEI (endo)

1 7 8 9 10 11 12 13 14 15 16 17

31.3 38.1 62.7 40.6 25.1 25.5 28.5 25.1 18.8 7.5 21.3 9.6

28.5' 18.0 46.4 34.7 16.7

34.3 43.5 41.0 31.3 30.5

28.5' 33.0 nd 35.6 22.6 21.3 23.0 17.2 15.5 13.0 nd 13.0

43.1 45.2 54.4 39.7 40.6 38.5 34.7 46.4 26.4 25.5 23.8 23.4

-

-

-

-

-

-

-

-

-

-

-

-

-

-

35.6 36.8 40.2 33.5 nd nd -

nd nd nd nd 24.7

"Energies in kJ.mol-'. Data taken from references 4 and 6. 'The SH model has been developed to reproduce the experimental value of AI? for the exo mode of cyclization of 1. nd: not determined.

intermolecular addition reactions [9]. While the data provided by the SpellmeyerHouk (SH) model are qualitatively similar to those provided by the BeckwithSchiesser (BS) model, there are quantitative differences (Table 2), which arise primarily because of differences in the treatment of the array of reacting centers and conformational differences [9]. In general, the SH model would appear to provide more accurate quantitative data, while the BS model is simpler to implement [9]. Both methods reliably reproduce the differences in AE,(exo) - AE,(endo) and hence the regiochemical preference for ring closure, as well as stereochemical trends (Table 3). Molecular modeling of intramolecular homolytic additions was recently Table 3. Calculated transition structure strain energies (A Es)aib and experimental datab for the ring closures of selected substituted o-alkenyl radicals (18-13) Radical

Beckwith-Schiesser AEs (cis) AEs (trans)

Spellmeyer-Houk AE, (cis) AEb(trans)

Experimental AEI (cis) Al? (trans)

18

30.5 30.5 25.5 33.1 37.7 35.6

26.4 23.4 23.8 28.5

29.3 21.8 25.5 23.8

-

-

-

-

29.0 27.2 25.1 32.2 35.1 36.4

19

20 21 22 23

31.4 26.4 32.2 25.9 40.6 34.3

"Energies in kJ.mol-'. bData taken from references 4-6. nd: not determined.

31.8 25.5 26.8 27.6 37.7 23.0

3.2.2 Modeling Radical Cyclization Reactions

5-hexenyl radical (5-exo)

341

5-hexenyl radical (6-endo)

3-methyl-5-hexenyl radical (5-eXO)

4-methyl-5-hexenyl radical (5-eX0)

Figure 1. Beckwith-Schiesser Model calculated transition states for the ring-closure of the 5-hexenyl radical 1, and some substituted systems 20, 21. Note the preferred pseudo-equatorial disposition of substituents in the two lower examples

22

23

streamlined with the incorporation of the SH model into the commercially available MacroModel modeling package [lo]. Both models have been used extensively to model a large cross-section of intramolecular homolytic addition reactions. Not only can regio- and stereochemical trends be modeled accurately, but the ratealtering effects of substitution are also well reproduced (Table 2). Some calculated transition structures are displayed in Fig. 1. Beckwith and coworkers reported that the BS model accurately predicts the isomeric outcome during the tandem (cascade) cyclization of radical 24 (Scheme 2) [ 111. Note the exclusive formation of the cis-ring fusion in the initial cyclization

3.2 Calculations: a Useful Tool for Synthetic Chemists

342

H

Z4

AEs = 13.8 kJ.mol-I (AE,(trans) = 20.5)

Scheme 2. The tandem cyclization of the trienyl radical 24

25

26

27 AESa

n

R

ex0 (26)

1 1 1 2 2 2

H COOt-Bu f-Bu H COOt-BU t-BU

46.4 39.7 26.8 54.8 45.2 40.2

endo (27)

114.6 110.0 101.3 70.7 60.7 54.0

Scheme 3. Force field (BS) predictions of regioselectivity during the ring closure of some substituted cyclobutyl radicals

step. Pigou utilized the BS model in order to determine the likelihood of cyclization and selectivity during the ring closure in some substituted cyclobutyl radicals 25 (Scheme 3) [ 121. While high selectivity as well as Thorpe-Ingold rate enhancement was predicted, this route proved not to be synthetically viable due to other competing rearrangement processes [ 121. Houk and coworkers investigated the diastereofacial selectivity in radical additions of substituted cyclohexyl radicals to alkenes [13]. In this work, the force field developed by Spellmeyer and Houk was applied to intermolecular homolytic addition with success and demonstrated the added versatility of the HS model over the BS procedure which is limited to intramolecular systems. Extraordinarily accurate predictions of diastereoselectivity were made. For example, acrylonitrile is predicted to react with the 4-tert-butyl-2-methylcyclohexylradical 28 to afford the products

3.2.2 Modeling Radical Cyclization Reactions

'

'

28

343

29

R = H: cidfrans = 21:79 (expt: 21 :79) Me 5:95 (1139)

Scheme 4. Diastereoselectivity during additions of some substituted cyclohexyl radicals to alkenes

29 in a 79:21 trans;cis ratio; experimentally this ratio was determined to be 79:21 [ 131. Trans;cis selectivity during additions to crotononitrile and fumaronitrile were predicted to be >95:5 and > 46) and the lack of stereoselectivity during the cyclization of 47 to afford an equal mixture of the cis and trans isomers of 2,5-dimethylselenophene 48 [ 191.

3.2.2.2 Quantum Methods The advent of faster, more powerful computing facilities over the past five years has seen the increased use of ab initio and other molecular orbital techniques applied to more complex problems, including radical cyclization reactions.

346

3.2 Calculations: a Useful Tool for Synthetic Chemists

-

O Y . -0

&

MOMOI'..

- _ _ _ .

H

49 - s-cis (Ere,= 47.3)

H

. $1 1* A0 * MOMOla. : H

52

1

53

51

-ejj l

o

5-ex0

=0

54

AE* = 72.8 55

56

Scheme 9. Calculated and experimental data for the ring closure of 49 and related experimental data. Energies are in kJ mol-'

Lee and coworkers recently explored the competition between 5-exo and 8-endo ring closure in some (alkoxycarbony1)methyl radicals [21]. Among the numerous examples given are calculations relating to the ring-closure of 49 (Scheme 9). ROMP2/3-21 G//ROHF/3-21G calculations predict that the s-trans form of 49 is more stable than the s-cis form by some 47 kJ mol-I. In turn, 49-s-trans is predicted to cyclize in 8-endo fashion with a barrier of about 20 kJ mol-' via transition state 53 to afford 55; subsequent 5-ex0 ring closure produces 56. By comparison, the s-cis form of 49 is calculated to ring-close in 5-exo mode with a barrier of about 16 kJ mol-'. The authors conclude that 49 preferentially affords products arising from 8-endo cyclization because of a strong conformational preference for the s-trans form of 49 (211. It is interesting to note that both force field methods are unable to correctly predict the outcome in this and several other similar cases. The ROMP2/ 3-21G//ROHF/3-2 1G calculations are in excellent qualitative agreement with the experimental observation that bromide 50 affords the tricyclic lactone 51 in good yield upon treatment with Bu3SnH [21]. Corminboeuf, Renaud and Schiesser explored the applicability of various quantum methods to the diastereoselective radical cyclization of several bromoacetals during the Ueno-Stork reaction (Scheme 10) 1221. It is interesting to note the performance of the various methods. All of the methods employed correctly predict the anomeric affect (transition states 61, 62 were calculated to lie some 20 kJ mol-' above 59, 60) and the observed cis stereochemistry [23]. However, only a handful of

3.2.2 Modeling Radical Cyclization Reactions

57

347

58

61

6d ~

AE*( trans) AES(cis)a

cishrans (-78")

~1

~2

Calcd.

Exat

UHF/AMl UHF/PM3 UHF/3-21G UHF/6-311G" MP2/6-311G*' UHF/6-311G'*//UHF/AM1[6-311G"Ib UHF/6-311G**//UHF/PM3[6-311G"] B3LYP/3-21G//B3LYP/3-21G[6-311G "1 UHF/6-31lG"//B3LYP/3-21G[6-311G '*I

H

H

2.9 2.5 1.9 5.7 3.5 7.6 6.8 1.7 5.9

86:14 83: 17 75:25 97:3 9O:lO 99: 1 98:2 74:26 97:3

98:2

UHN6-311G" UHF/6-31lG"//UHF/AMl[6-311 G"] UHF/6-311G"//UHF/PM3[6-311G"] UHF/6-311G"//B3LYP/3-21 G[6-311G " 1

Me

Me

1.6 0.5 3.2 3.7

75:25 60:40 87:13 91:9

77:23

UHF/6-311G" UHF/6-311G'*//UHF/AM1[6-311G'*]

H

n-Pr

5.4 6.6 5.9 5.7

96:4 98:2 97:3 97:3

92:8

UHF/6-311G'*//UHF/PM3[6-311G"] UHF/6-311G"//B3LYP/3-21 G[6-311G '*I

akJ.mol-l. bTransition state distance fixed at that calculated using UHF16-311G'* remaining structure optimized using UHF/AMl ; single point energy determined using UHF/6-311G"

Scheme 10. Calculated and experimental data for the diastereoselective ring closures of bromoacetals 58

procedures accurately predict the magnitude of this effect (Scheme 10). The data displayed in Scheme 10 suggest that the UHF/6-311G** procedure is the most consistent in providing accurate stereochemical predictions in these examples, but that single-point calculations based on lower-level optimized geometries can provide good qualitative estimations [22]. In this last example, in an attempt to provide a definitive answer to controversial questions surrounding the reversibility of aminyl radical ring-closures, Tsanaktsidis

348

3.2 Calculations: a Useful Tool f o r Synthetic Chemists

0

AE*(expt.)a 63 64

1

AH*(calcd.)a

ex0

endo

ex0

endo

33.9 10.9 26.3

51.9 18.8 36.4

31.0 8.4 23.4

49.0 16.3 33.5

64

1

akJ.mol-l

5-eXO Cyclization rate constants / s-'

63 64

1

Temp I "C

Calcd.

80 30 80

2.3x lo9 8.2x lo6

7.8

104

exo:endo

Exot.

Calcd.

Expt.

2.5x 104 (45 2)x 10' 1.5x lo6

1oo:o

1oo:o

98:2 98:2

98:2 98:2

Scheme 11. High-level ab initio and experimental data for the cyclization of the N-methyl-4pentenylaminyl, 4-pentenyloxyl and 5-hexenyl radicals 63, 64,1

and coworkers examined the cyclization of the N-methylpent-4-enylaminyl, pent-4en-1-oxyl and the 5-hexenyl radicals 63, 64, 1 and concluded that all three radicals cyclize irreversibly [24]. Earlier calculations reported by Newcomb and coworkers provided a more thermoneutral perspective on this ring closure [25]. Somewhat surprisingly, this study represents the first time that the ring closure of the 5-hexenyl radical 1 has been seriously revisited using molecular orbital techniques since the MNDO work of Beckwith and Schiesser [4]. CBS-RAD(B3LYP,B3LYP) calculations provide energy barriers, rate constants and regioselectivities in excellent agreement with experiment for the ring closure of all three systems 63, 64, 1 (Scheme 11). These calculations should be viewed as a time stamp, representing the cutting edge of molecular modeling technology toward the end of the twentieth century, requiring in excess of 15 h of CPU time on a newly commissioned NEC SX-4 supercomputer for the CCSD(T) component of the energy calculation for 63 and 14 Gbytes of temporary storage for the CBS component [24]. It is interesting to compare these results for 63 with those of an earlier study in which UMP2/6-3 1G*//UHF/6-3 1G* calculations predict that the 5-ex# mode of cyclization of 63 has an energy barrier of 60 kJ mol- l , is preferred over the analogous 6-end0 process by 27 kJ mol-' and that this reaction is highly exothermic (62 kJ mol-') [26].

3.2.3 Modeling Hydrogen Transfer Reactions

349

d R3SnBr

&--,---

Br

Scheme 12. Prototypical stannane-mediated ring closure reaction

3.2.3 Modeling Hydrogen Transfer Reactions Both quantum mechanical and force field-based methods have been employed in the attempt to model hydrogen transfer reactions. In free-radical chemistry, by far the most significant hydrogen transfer process involves the reaction between a carbon-centered radical and a chain-carrying reagent such as tributyltin hydride [ 11. Indeed, stannanes have largely dominated the class of reagents used to effect hydrogen transfer because of favorable rate constants ( k ~for ) the hydrogen transfer step itself [27] coupled with excellent rate constants for subsequent reaction with a wide cross-section of radical precursor ( k x ) [I]; the prototypical chain process is illustrated in Scheme 12. The synthetic utility of stannane-based reagents is discussed in other chapters of this compilation. While several workers have examined more general types of hydrogen transfer reactions by computational techniques, this chapter will focus on the modeling of hydrogen transfers of synthetic utility, in particular the ability of various modeling methods to accurately predict the stereochemical outcome of freeradical reductions. This story begins with the work of Chatgilialoglu and Zavitsas, who reported an elegant empirical method for the estimation of the reactivity of various classes of hydride toward hydrogen abstraction by several classes of alkyl radical [28]. The E* (ee-star) method provides remarkable agreement with experiment. For example, E* provides activation energies of 13.4, 16.3, 30.5 and 7.1 kJ mol-I for the reactions of MqSnH with methyl, ethyl, benzyl and phenyl radicals respectively [ 2 8 ] . These values are in excellent agreement with available experimental data (viz. 13.4, 15.5, 23.5, 7.1 kJ mol-I) [27]. It is interesting to note that Roberts had earlier reported an extended form of the Evans-Polanyi equation for predicting activation energies for a large cross-section of hydrogen transfer reactions to within k2.0 kJ mol-' with a correlation coefficient of 0.988 [29]. The role of polar effects operating in the tran-

350

3.2 Calculations: a Useful Tool for Synthetic Chemists

65

66

67

ME*(68 - 67)a R

R'

H t-Bu H CH3 CH3 CH3 CH2C02H f-BU

expt.

calcd.

3.2 0.7 5.7 6.1

4.4 0.8 5.7 3.2

68

67:68 (80 "C) expt.

3:l 1.3:l 7: 1 8:l

calcd.

4.51 1.3:l 7:1 3:1

akJ.mol-l

Scheme 13. Calculated and experimental diastereoselectivity data for the reduction of several radicals 66 derived from bromo-l,3-dioxolan-4-ones 65

sition states in question was also quantitatively described [29], although Roberts' interpretation has been questioned by Zavitsas and is somewhat controversial [28]. While the E* method has distinct computational advantages over other molecular orbital methods, it does suffer from two main drawbacks. E* is unable to provide geometries of reacting species and transition states involved in the reactions of interest, nor is it able to accommodate novel reagents and substrates because empirical bond strength data are required for the reacting species [28]. In order to address these issues, Beckwith and Zavitsas explored the use of the AM 1 semiempirical technique to model the reactivities and diastereoselectivities during hydrogen transfer from Bu3SnH to a series of radicals 66 derived from 1,3-dioxolan-4-ones 65 and related oxygen heterocycles (Scheme 13) [30]. It would appear that AM1 is capable of providing reliable predictions of not only the stereochemistry of the preferred diastereoisomer, but also the magnitude of the observed diastereoselectivities. During the course of this work, AM1 transition state geometries for hydrogen atom transfer were determined; Sn-HTs and C-HTS distances are predicted to be about 1.70 and 1.72 8, respcctively for all transition states, providing overall Sn-C transition state separations of about 3.42 8, [30]. It would also appear that these transition states prefer to adopt collinear arrangements of attacking and leaving radicals [30]. In addition, the authors report that AM1 overestimates slightly the activation energy for the delivery of hydrogen atom from Bu3SnH to ethyl radical (21.8 vs 16.0 l-2.5) [30], but conclude that the method provides reliable differences in activation energy for the systems in their study and that AM1 calculations might give reasonable results in calculations of activation energy in more complex systems ~301. More recently, work in our laboratories has been directed toward the development of enantioselective free-radical processes and reliable methods for modeling

3.2.3 Modeling Hydrogen Transfer Reactions

35 1

Figure 2. MP2/DZP calculated transition state geometries for the delivery of hydrogen atom from trimethylstannane to methyl radical. (UHF/DZP date in parentheses) [AM1 data In square brackets]

the outcomes of free-radical reductions by chiral, non-racemic stannanes [ 3 1-33]. To this end we modeled the transition states for the delivery of hydrogen atom from several types of stannanes to a variety of alkyl radicals [34]. Ab initio techniques provided overall Sn-C distances of about 3.50 A, slightly longer than analogous calculations by AM1 [30, 341. This separation was shown to be largely unaffected by either the level of theory employed, the substituents attached to tin, or the nature of the carbon-centered radical involved [ 341. The exact position of the hydrogen atom undergoing translocation was, however, dependent on the method employed, with UHF methods providing 'later' transition states than methods which included electron correlation, which, in turn, were calculated to be later than AM 1 estimates (Fig. 2) [34]. With this information in hand, it seemed reasonable to attempt to use force field methods to model the transition states of more complex, chiral systems. To that end, transition states for the delivery of hydrogen atom from stannanes 69-71 derived from cholic acid to the 2,2,3-trimethyl-3-pentyl radical 72 (which was chosen as the prototypical prochiral alkyl radical) were modeled in a similar manner to that published for intramolecular free-radical addition reactions (Beckwith-Schiesser model) and that for intramolecular homolytic substitution at selenium [32]. The array of reacting centers in each transition state 73-75 was fixed at the geometry of the transition state determined by ab initio (MP2/DZP) molecular orbital calculations for the attack of methyl radical at trimethyltin hydride (viz. TS,,-H= 1.81 A; YC-H = 1.69 A; H s n - ~ - C= 180") [33]. The remainder of each structure 73-75 was optimized using molecular mechanics (MM2) in the usual way. In all, three transition state conformations were considered for each mode of attack (re or s i ) in structures 73-75 (Scheme 14). In general, the force field method described overestimates experimentally determined enantioselectivities (Scheme 15), and the development of a 'flexible' model is now being considered [33]. More recently, the use of the AM 1 method in predicting enantioselectivities during stannane reductions has also been examined [33]. In preliminary work, Schiesser and coworkers found that the AM1 molecular orbital method is capable of correctly predicting the preferred stereochemistry, as well as the stereo-enhancing effect of Lewis acids, during the delivery of hydrogen atom from a series of chiral non-

352

3.2 Calculations: a Useful Tool for Synthetic Chemists

69

cho;

'*O"

70

Me

73 chol = 24-nor-5 P-cholan- 3 -yl 74 chol = 24-nor-5 P-cholan- 7 -yl 75 chol = 24-nor-5 P-cholan- 12 -yl

Stannane

MES(re- sqa

69a 69P 70a 7OP 71a 71D

1.13 -0.56 -1.39 -0.56 -1.26 -4.95

%ee (-78") 67 58 71 58 69 95

akJ.mol-l

Scheme 14. Calculated enantioselectivity data for reactions of the 2,2,3-trimethyl-3-pentyl radical 72 with stannanes 69-71 derived from cholic acid

R Br

Ph+OEt 0

70

~

-78 "C /toluene

(R = Me, Et, t-Bu)

R H ph%OEt

0 4 - 14 %ee

Scheme 15. Reduction of several cc-bromoesters with 3m- or 3/~'-dimethylstannyl-24-norcholestane 70

racemic stannanes 76-80 to several prochiral radicals [ 3 3 ] .While the method is able to accurately predict the magnitude of observed ees in only a limited number of cases, the differences in energy involved were found to be too subtle for AM1 to provide accurate estimates. Indeed, the examples provided in Scheme 16 testify to AM 1's consistency in overestimating the levels of enantioselectivity observed experimentally. It is satisfying, however, that AM 1 correctly predicts the dominant isomer in each case, providing confidence in the method's qualitative predictive abilities [ 3 3 ] .

3.2.4 Modeling Reaction Mechanisms

353

menPh2SnH 76

77 Me2N

Sn(men)2H

I

I

menMe2SnH

men3SnH 78

79

G : O,

80

H '0.(

-78 7 7"Co rI 8Lewis 0 AcidPh+\'

0

ME*(si- re)" Stannane 77

R

Lewis Acid

Me

none BF3 B(OMe), none BF3 none BF3

f-BU

80

Me ~~

~~~~

~

%ee (-78")

calcd.

expt.

calcd.b

0.8 2.8 8.9 3.5 13.0 1.1 6.7

0.8 2.6 n.d. n.d. n.d. n.d. n.d.

0 28 98 46 100 44 98

expt. 2 32 n.d. 6 10 n.d. 68c

~

akJ.mol'l. bCalculated assuming log(NM-'s-'), - log(NM-'s-'), = -0.5, which is estimated from experimental data CDeterminedfor Jacobsen's catalyst as Lewis acid. n.d. = not determined

Scheme 16. Calculated and experimental enantioselectivity data for the reactions of several x-bromoesters with chiral, non-racemic stannanes 77, 80

3.2.4 Modeling Reaction Mechanisms The ability to provide quality data relating to the intimate details of reaction mechanisms is of critical importance to their understanding. While experimental studies have the potential of providing significant mechanistic insight into a multitude of chemical reactions, the fine detail able to be provided by quality quantum computational data is unrivalled; in no other way can the geometry and electronic structure of transition states and unstable hypervalent intermediates along reaction pathways be understood. Computational chemistry has been employed from time to time in order to obtain

3.2 Calculations: a Useful Tool f o r Synthetic Chemists

354

a fuller picture of the intimate details of free-radical reactions. The aim of this section of this work is to provide examples of how computational chemistry can be used to unravel the mystique surrounding several classes of free-radical reaction. Through the use of three examples, we hope to provide the reader with confidence in the use of computational methods. These examples focus on three diverse questions, namely the mechanism of free-radical homolytic substitution reactions, the details of ‘polarity reversal catalysis’, and the P-phosphatoxylkyl radical rearrangement reaction. Until recently, several questions surrounding the mechanism of free-radical homolytic substitution reactions at higher heteroatoms were hotly debated topics [ 351. For example, despite the numerous reports of 1,n-transfers of stannyl and silyl groups, we are aware of only one example in which chalcogen is involved in intramolecular homolytic group transfer and are unaware of any examples involving halogen atoms in rearrangements of this type [35].Why should Group IV heteroatoms undergo readily intramolecular homolytic group transfer reactions while there are so few reports for chalcogen- or halogen-containing systems? The answer to this question almost certainly rests with the intimate details of the homolytic substitution step itself. In order to gain insight into this question, Schiesser and coworkers, over a number of years, have investigated the details of inter- and intramolecular free-radical attack at several main-group higher heteroatoms using ab initio molecular orbital theory [36-401. This work has led to the conclusion that there are distinct periodic trends across the main-group higher heteroatoms (Scheme 17). Homolytic substi-

[

ii

R ......

E = S,Se R’

+

/

RIEL

1 E =Te

L

t-

1,

._..

RER’

+

i

R-Te-L I

R’

i

Scheme 17. Calculated periodic trends associated with intermolecular homolytic substitution at main-group higher heteroatoms

3.2.4 Modeling Reaction Mechunisms

t-

x--,-+c?

1 v

X

X

355

likelihood

SiR3 /a GeR3 /a SnR3 /a PRP /Xb SR X SeR X TeR /Xb CI X Br X 1 % aFrontside mechanism. bTranslocation possible via hypervalent intermediate

Scheme 18. Ah initio predictions of the likelihood intramolecular translocations involving maingroup higher heteroatoms

tution at halogen is predicted to prefer a collinear arrangement of attacking and leaving groups [35, 361. Indeed, deviations from co-linearity lead to marked increases in activation energy, which explains why there are no examples of 1,nhalogen atom transfer reactions [35, 391. Analogous reactions involving sulfur and selenium are predicted to mostly involve smooth (collinear) transition states, while reactions involving tellurium are calculated to involve [9-Te-3] hypervalent intermediates. Once again, deviation from co-linearity is predicted to result in marked increases in energy barrier to translocation [39]. On the other hand, homolytic attack at silicon, germanium and tin is predicted to proceed either via backside attack through a collinear transition state, or via frontside attack, a mechanism not available to the chalcogens and halogens (Scheme 17), while attack at phosphorus, as expected [35], results in the formation of stable phosphoranyl radical species [40]. These computational data provide an elegant explanation for why Group IV heteroatoms are observed to readily become involved in intramolecular homolytic translocation chemistry (Scheme 18) [35]. It is interesting to note that this work made extensive use of pseudo-potential basis sets together with high levels of electron correlation correction and that most density functional methods explored modeled poorly the intimate details of homolytic substitution reactions [33, 36dl. In the second example, Skidmore examined extensively the mechanism of 'polarity reversal catalysis' as described by Roberts [41] (Scheme 19) and concluded that the key step (step 2, Scheme 19) in the proposed mechanism, namely the transfer of hydrogen atom from a trialkylsilane to a thiyl radical, is severely endothermic [42].At the highest level of theory used in this study (CCSD(T)/6-31 lG**// MP2/6-31 lG**), the reaction of Me3SiH with methylthiyl radical (MeS') is calculated to be endothermic by 30.8 kJ mol-' and to have an associated energy barrier of 41.9 kJ mol-' leading to an approximate equilibrium constant of 1.3 x lop4 at 80°C, in all likelihood too small to sustain the radical chain [42]. By way of comparison, the analogous reaction involving silane (SiH4) is calculated at the CCSD(T)/aug-cc-pVDZ//MP2/aug-cc-pVDZ + AZPE level of theory to be endo-

356

3.2 Calculations: a Useful Tool for Synthetic Chemists Me3SiX A

I Me3SiH

CH3S'

+

H-SiMe3

___+ +----

CH3SH +'SiMe3

AH = 30.8 kJ.mol"

Scheme 19. CCSD(T)/6-31 1G**//MP2/6-3 1 1G** calculated energies associated with the prototypical "'polarity reversal catalysis' mechanism

thermic by 19.4 kJ mo1-I and to have an associated energy barrier of 28.1 kJ mol-' leading to an approximate equilibrium constant of 1.4 x lop3 at 80"C, a value which verges on chain sustainability [42]. These computational data have distinct significance and may require that the synthetically useful chemistry developed by Roberts be mechanistically re-examined. In the last example, Newcomb, Crich and Zipse examined the mechanism of the P-phosphatoxyalkyl rearrangement by ab initio molecular orbital theory [43]. B3LYP/6-31 l+G(d,p)//B3LYP/6-31G(d) AZPE calculations predict a 12.1 kJ mol-' preference for [ 1,2] homolytic migration of the phosphatoxy group in the 1,l -dimethyl-2-(dimethyIphosphatoxy)ethyl radical 81, via transition state 82, over the analogous [3,2] migration pathway via transition state 83, to afford the 2,2dimethyl-2-(dimethylphosphatoxy)ethyl radical 84 (Scheme 20) [43]. The authors also examined possible competing /I-scission pathways and concluded that they are not competitive with migration. They also suggest that elimination products observed in some experiments are possible due to solvent effects, as the transition states for both rearrangement and homolytic elimination are calculated to be significantly polar in nature [43].

+

3.2.5 Concluding Remarks In this chapter we have attempted to provide an overview of the application of computational chemistry to free-radical reactions of synthetic utility. We hope that the reader will be encouraged to add various modeling techniques to their chemical

References

357

+-

1

1

AE = 56.5

-

AE = -53.6 kJ.mol-'

Me0 MeO.b=O

AE = -41.4

84

Scheme 20. B3LYP/6-3 1 1 +G(d,p)//B3LYP/6-3 1G(d) + AZPE calculated energy barriers (kJ mol-') for the [ 431 and [ 1,5] migration modes for the 1,1-dimethyl-2-(dimethyIphosphatoxy)ethyl radical 81

arsenal. Indeed, as we enter the new millennium, and as computer technology becomes increasingly more powerful, levels of modeling sophistication will undoubtedly improve, providing the synthetic practitioner with ever-increasing levels of predictive ability. Who knows what a similar compilation will contain in another twenty, fifty or even one hundred years.

References [ 11 (a) B. Giese, Radicals in Organic Synthesis: Formation of' Carbon-Carbon Bonds, 1986, Pergamon, Oxford. (b) M. Regitz, B. Giese, Radicale, Houben- Weyl Methoden der Oryanischen Chemie, 1989, Vol E IYa, Georg Thieme, Stuttgart. [2] (a) A. L. J. Beckwith, K. U. Ingold, in Rearrangements in Ground and Excited States, 1980, Vol. I , p. 161; de Mayo, P. (Ed.), Academic Press, New York. (b) A. L. J. Beckwith, Tetrahedron, 1981, 37, 3073. (c) M. Ramaiah, Tetrahedron; 1987, 43, 3541. (d) D. P. Curran, Synthesis, 1988, 417. (e) D. P. Curran, Synthesis, 1988, 489. (f) N. A. Porter, B. Giese, D. P. Curran, Acc. Chem. Rex, 1991,24, 296. (g) W. R. Bowman, in Organic Reaction Mechanisms, 1992, Chapt. 3, p. 73; Knipe, A. C.; Watts, W. E. (Eds.) Wiley, New York. (h) W. B. Motherwell, D. Crich, Free Radical Chain Reactions in Organic Synthesis, 1992, Academic Press, San Diego. (i) A. L. J. Beckwith, Chem. Soc. Rev., 1993, 143. (j) B. Giese, B. Kopping, T. Gobel, J. Dickhaut, G. Thoma, K. J. Kulicke, F. Trach, Org. React., 1996, 48, 301. (k) H. Fischer, NATO ASI Ser., Ser. 3, 1997,27, 63. (1) D. Boger, Isr. J. Chem., 1997,37, 119. (m) W. R. Dolbier, Jr., Top. Curr. Chem, 1997, 192, 97. (n) L. Yet, Tetrahedron, 1999, 55, 9349. 131 R. C. Lamb, P. W. Ayers, M. K . Toney, J. Am. Chem. Soc., 1963,85, 3483. [4] M. Julia, M. Maumy, Bull. Soc. Chim. Fr., 1968, 1603.

358

3.2 Calculations: a Useful Tool f o r Synthetic Chemists (a) D. L. Struble, A. L. J. Beckwith, G. E. Cream, Tetrahedron Lett., 1968, 3701. (b) A. L. J. Beckwith, G. E. Cream, D. L. Struble, Aust. J. Chem., 1972, 25, 1081. (c) also see: A. L. J. Beckwith, Tetrahedron, 1981, 37, 3703. (a) P. Bischof, Helu. Chim. Acta, 1980, 63, 1434. (b) P. Bischof, Croat. Chem. Actu, 1980, 53, 51. (a) A. L. J. Beckwith, C. H. Schiesser, Tetrahedron Lett., 1985, 26, 373. (b) A. L. J. Beckwith, C. H. Schiesser, Tetrahedron, 1985, 41, 3925. (a) A. L. J. Beckwith, M. D. Cliff, C. H. Schiesser, Tetrahedron, 1992, 48, 4641. (b) C . H. Schiesser, PhD thesis, The Australian National University, 1986. D. C. Spellmeyer, K. N. Houk, J. Org. Chem., 1987, 52, 959. MacroModel: F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp, M. Lipton, C. Caufield, G. Chang, T. Hendrickson, W. C. Still, J. Comput. Chem, 1990,II, 440. A. L. J. Beckwith, D. H. Roberts, C. H. Schiesser, A. Wallner, Tetrahedron Lett., 1985, 3349. P. E. Pigou, J. Org. Chem., 1989, 54, 4943. W. Damm, B. Giese, J. Hartung, T. Hasskerl, K. N. Houk, 0. Huter, H. Zipse, J. Am. Chem. Soc., 1992, 114, 4067. (a) X. Sanchez-Ruiz, C. Jaime, J. Marco-Contelles, J. Mol. Struct., 1998, 471, 209. (b) T. Takahashi, S. Tomida, Y. Takamoto, H. Yamada, J. Org. Chem. 1997, 62, 1912. A. G. Myers, K. R. Condroski, J. Am. Chem. Soc., 1995, 117, 3057. Selected examples: (a) K. N. Houk, M. N. Paddon-Row, N. G. Rondan, Y-D Wu, F. K. Brown, D. C. Spellmeyer, J. T. Metz, Y. Li, R. J. Loncharich, Science, 1986, 231, 1108 and references cited therein. (b) D. A. Singleton, K. M. Church, M. J. Lucero, Tetruhedron Lett., 1990, 31, 5551. (c) C. Gennari, G. Poli, C. Scolastico, M. Vassallo, Tetrahedron: Asymmetry, 1991, 2, 793. (d) J. L. Broeker, K. N. Houk, J. Org. Chem., 1991, 56, 3651. (e) A. L. J. Beckwith, J. Zimmermann. J. Org. Chem. 1991, 56: 5791. (f) L. Belvisi, C. Gennari. G. Poli. C. Scolastico, B. Salom, M. Vassallo, Tetrahedron, 1992, 48, 3945. (8)J. E. Eksterowicz, K. N. Houk, Chem. Rev., 1993, 93, 2439 and references cited therein. (h) L. Belvisi, C. Gennari, G. Poli, C. Scolastico, B. Salom, Tetrahedron: Asymmetry, 1993, 4, 273. (i) D. E. Ward, Y. Gai, B. F. Kaller, J. Ory. Chem., 1995, 60, 7830. (j) D. P. Curran, C-H. Lin, N. DeMello, J. Junggebauer, J. Am. Chem. Soc., 1998, 120, 342. A. L. J. Beckwith, V. W. Bowry, C. H. Schiesser, Tetrahedron, 1991, 47, 121. A. L. J. Beckwith, D. M. Page, Tetrahedron, 1999, 55: 3245. L. J. Benjamin, C. H. Schiesser, K. Sutej, Tetrahedron, 1993, 49, 2557. J. E. Lyons, C. H. Schiesser, J. Organornet. Chem., 1992, 437, 165. E. Lee, C. H. Yoon, T. H. Lee, S. Y. Kim, T. J. Ha, Y.-S. Sung, S.-H. Park, S. Lee, J. Am. Chem. Soc., 1998, 120, 7469. 0. Corminboeuf, C. H. Schiesser, P. Renaud, Chimiu, 1999, 53, 397. (Abstract 24 of the Second Swiss COST Chemistry Symposium, October 15 1999, Basel Switzerland) F. Villar, P. Renaud, Tetrahedron Lett., 1998, 39, 8655. B. J. Maxwell, B. J. Smith, J. Tsanaktsidis, J. Chem. Soc. Perkin Trans. 2, 2000, 425. M. Newcomb, 0. M. Musa, F. N. Martinez, J. H. Horner, J. Am. Chem. Soc., 1997, 119, 4569. B. J. Maxwell, C. H. Schiesser; B. A. Smart, J. Tsanaktsidis, J. Chem. Soc. Perkin Trans. 2, 1994, 2385. C . Chatgiliaioglu, M. Newcomb, Adu. Orgunomet. Clicwz., 1999, 44, 67, and references cited therein. A. A. Zavitsas, C. Chatgilialoglu, J. Am. Chem. Soc., 1995, 117, 10645. B. P. Roberts, A. J. Steel, J. Chem. Soc. Perkin Trans. 2, 1994, 2155. A. L. J. Beckwith, A. A. Zavitsas, J. Am. Chem. Soc., 1995, 117, 607. D. Dakternieks, K. Dunn, V. T. Perchyonok, C. H. Schiesser, Chem. Cornmun, 1999, 1665. C. H. Schiesser, M. A. Skidmore, Phosphorus Sulfur Silicon Relat. Elem., 1999, 150-151, 177. C . H. Schiesser, Presented at the 1 l t h Royal Australian Chemical Institute National Convention (1 1RACIC), Australian National University, February 2000, Canberra, ACT, Australia. D. Dakternieks, D. J. Henry, C. H. Schiesser, J. Chem. Soc. Perkin Trans. 2, 1997, 1665. C. H. Schiesser, L. M. Wild, Tetrahedron, 1996, 53, 13256.

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[36] (a) B. A. Smart, C. H. Schiesser, J. Chem. Soc. Perkin Trans. 2., 1994, 2269. (b) C. H. Schiesser, B. A. Smart, T.-A. Tran, Tetrahedron, 1995. 51, 3327. (c) C. H. Schiesser, B. A. Smart, Tetrahedron, 1995, 51, 6051. (d) C. H. Schiesser, B. A. Smart, J. Comput. Chem. 1995, 16, 1055. [37] (a) C. H. Schiesser, M. A. Skidmore, Chem. Commun., 1996, 1419. (b) C. H. Schiesser, M. A. Skidmore, J. Organomet. Chem., 1998, 552, 145. [38] (a) C. H. Schiesser, M. L. Styles, L. M. Wild, J. Chem. Soc. Perkin Trans 2., 1996, 2257. (b) C. H. Schiesser, M. L. Styles, J. Chem. Soc. Perkin Trans. 2., 1997, 2335. (c) S. M. Horvat, C. H, Schiesser, L. M. Wild, Organometallics, 2000, 19, 1239. [39] (a) C. H. Schiesser, L. M. Wild, J. Ory. Chem., 1998, 63, 670. (b) C. H. Schiesser, L. M. Wild, J. Org. Chem., 1999, 64, I 1 31. [40] C. H. Schiesser, L. M. Wild, Aust. J. Chem., 1995, 48, 175. [41] B. P. Roberts, Chem. Soc. Rev., 1999, 28, 25, and references cited therein. [42] (a) C. H. Schiesser, M. A. Skidmore, J. Chem. Soc. Perkin Trans. 2, 1998, 2329. (b) M. A. Skidmore, Ph.D thesis, The University of Melbourne, 2000. [43] (a) M. Newcomb, J. H, Horner, P. 0. Whitted, D. Crich, X. Huang, Q. Yau, H. Zipse, J. Am. Chem. Soc., 1999, 121, 10685. (b) See also the related study: H. Zipse. J. Am. Chem. Soc., 1997, 119, 2889.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

3.3 Synthetic Utility of the Captodative Effect Lucien Stella and Jeremy N. Harvey

3.3.1 Introduction Substituent effects, whether of electronic or steric origin, have a major influence on the efficiency and selectivity of chemical reactions - heterolytic, homolytic, and concerted. The quantitative study of these effects has often relied on linear free energy relationships, and has led to much valuable information on reaction mechanisms [ 11. In organic chemistry, substituents affect the strength of o (C-H, C-C, C-X . . .) and n (C=C, C=O . . .) bonds, thus influencing the reactivity of the corresponding molecules. Free radicals are stabilized both by electron-withdrawing substituents (‘captors’ such as carbonyl, cyano, nitro . . .) and by electron-releasing ones (‘donors’ such as dialkylamino, alkyloxy, alkylthio . . .). This is readily explained by frontier molecular orbital (FMO) theory [2]. For ‘captors’ such as the carbonyl group, because energetically close-lying orbitals mix most, the main interaction of the radical singly-occupied MO (SOMO) is with the adjacent n” LUMO of the carbonyl group. This lowers the energy of the SOMO, making the radical electrophilic. For a ‘donor’, such as the amino group, the main interaction is with the non-bonding nitrogen lone pair, thus raising the energy of the SOMO and making the radical nucleophilic. From these descriptions, it can be seen that a second substituent on a radical center will have a weukened effect if it is of the same polarity as the first one, but a strengthened effect if it is of opposite polarity. It is this fact which leads to the cuptodutiue eflect, that is the stabilization of cuptodative radicals 1, bearing simultaneous captor and donor substituents. In turn, this means that compounds such as 2 and 3 tend to react by radical pathways [3], via radical abstraction (C-X homolysis of 2) or radical addition (to the n system of 3).

2

1

3

proradical

captodative radical

radicophiIe

Although the precise quantitative importance of the captodative effect is still being debated, it has been shown to exist by many experiments, and, as a guiding

3.3.2 Basic Principles

361

principle in synthesis, it is frequently used to rationalize or predict the efficiency or the selectivity of reactions.

3.3.2 Basic Principles The concept of the captodative effect was first put forward more than 20 years ago to explain experimental observations in the field of organic synthesis [4]. Similar concepts had been put forward on the basis of theoretical considerations [5] or of physical organic chemistry [6]. The main synthetic observations leading to the concept of radical stabilization [7] were of the remarkable radicophilic behavior of ‘captodative’ alkenes 3 [4a], and of the tendency toward radical reactivity (‘proradical-like’ behavior) of dichloromethylene compounds with captodative substitution [4b]. Because of the obvious analogy to the rules governing substituent effects in carbanions and carbocations, the concept was very simple to understand and very general in scope. This explains its considerable impact over the last 20 years within the organic chemistry community, leading to much experimental and theoretical work [8]. Implicit in the concept of the captodative effect is the fact that far from always being additive, as is often assumed in radical chemistry, substituent effects can be either synergistic or antagonistic, depending on the nature of the substituents. Along with other aspects related to the theory, the spectroscopic investigation and the physical chemistry of the captodative effect were reviewed in 1990 in the excellent critical survey by Sustmann and Korth [9]. Since then, some of the controversial points have been resolved by improved theoretical [ 101 and experimental [ 1 I] work. For example, measurement of acid constants PKHAand carbanion oxidation potentials in DMSO solution, as perfected in Bordwell’s group [ 121, provides reliable C-H bond energies. For compound 4, which is captodative via conjugation through the anthracene z system, the bond energy is found to be 2 kcal mol-’ weaker than would be expected by adding the two substituent effects, demonstrating a synergistic radical stabilization [ 131.

CN

In another example, Riichardt has reviewed the factors influencing C-C bond energies [ 141. This analysis led to the recognition of captodative synergistic stabilizations of respectively 10.8 and 6.7 kcal mol-’ for the ct-amino-ct-methylcarbonyl radical 5 [ 151 and the alanine-derived radical 6 [ 161. In synthesis, the captodative effect can be used to weaken g- and n-bonds thus creating a bias towards radical-like reactivity and enhancing selectivity. Reactions

362

5

3.3 Synthetic Utility of the Captodutive Effect CO-R

C02Et

NMe2

MeqNMe2

Me--(*

6

such as isomerization, coupling, substitution, addition to multiple bonds, and cycloaddition can thus be affected. Several reviews covering various aspects of these synthetic applications are already available [3, 7, 171. The aim of the present contribution is to summarize the main results, grouped by reaction type, including recent examples, and thereby to illustrate the usefulness of the captodative effect as a guiding principle in organic synthesis.

3.3.3 Rearrangement Reactions 3.3.3.1 Via a Homolysis-Coupling Mechanism The iminium chlorides 7, bearing an electron-withdrawing 'captor' group X, undergo a 1,3 C1-atom rearrangement between the captodative and a-hydrogen positions (Scheme 1). This reaction is enabled by the captodative weakening towards homolysis of the C-Cl bond in 7, and it is found to be fastest for the strongest 'captor' groups X. When X is an iminium group, the reaction is spontaneous even at -6O"C, whereas with the trichloromethyl group it occurs only upon heating to 60-100°C. When X is not electron-withdrawing, the reaction does not occur. The rearrangement has significant synthetic utility; for example, diaminoalkyne 9 and dithiooxamide 10 both lead upon chlorination to the iminium chloride 11 which spontaneously rearranges into 12 (Scheme 2). Cyclization and loss of two equivalents of methyl chloride lead to trichloroimidazole 14 in high yield [ 181. Perchlorination of dimethylamino-acetonitrile also forms 14 via the same intermediate

7

'N-C-X

- I -

'N-~--x

Scheme 1. Rearrangement of amide chlorides substituted by electron-withdrawing groups

3.3.3 Rearrangement Reactions

\

363

/

\

9

\ N-YC -C

N

15

Scheme 2. Syntheses of trichloroimidazoles via 1,3 C1-atom rearrangement

13 [ 191. The 1,3-dichlorinated compounds 8 are bis-electrophilic synthons of great use in heterocyclic chemistry [4b, 201. Radical mechanisms are also known to be involved in 1,2-rearrangement reactions, such as the R' alkyl group migration leading from ammonium ylids 16 to tertiary amines 19 (Scheme 3). Whilst the possible ion pair intermediate 17 is destabilized by the electron-withdrawing carbonyl group, the radical pair 18 is favored by the captodative stabilization of one of the radicals. The reaction was shown to occur via the homolytic mechanism involving 18 in elegant experiments by Ollis et al. [21]. It is consistent with the migratory ability of different R' groups, the observation of a CIDNP signal, and the formation of diphenylethane by dimerization when R' is the benzyl radical. This mechanism is general and also occurs frequently in the synthetically important Stevens [22] and Wittig [23] rearrangements.

r

1

17

18a

18b

Scheme 3. Ylidic rearrangement via radical pair intermediates

3.3 Synthetic Utility of the Captodative EfSect

364 NC

I

Ar NC

I

"'0

20

22

23

21

Scheme 4. Cyclodimerization of an azomethine ylide behaving as a 1,3 diradical

NC

CN 24c

X

J

25 E, (cis-trans)

24t E, (trans-cis)

CO-OMe

31,7

31,7

CI

28,2

29,4

Ph

27,O

26,9

PhS

26,9

26,9

Me0

24,l

24,l

Scheme 5. Cis-trans isomerization of tetrasubstituted cyclopropanes

A biradical analogous to the radicals discussed here was suggested by Padwa [24] to explain why the 1,3-dipole 20 did not lead to the expected intramolecular cycloadduct 21 (Scheme 4). The dipole 20 reacts instead like 1,3-diradical22, undergoing self-reaction to give the head-to-head dimer 23. Many studies of substituent effects on radical stabilization involved C-C homolysis reactions leading to rather similar diradicals. Cis-trans isomerization of tetrasubstituted cyclopropanes 24 (Scheme 5) is found to occur fastest when the intermediate diradical 25 is stabilized by captodative substitution [25], with better 'donors' yielding faster reactions. Likewise, the isomerization of methylenecyclopropanes 26 to give 28 (Scheme 6) is also fastest when the diradical-like transition state 27 is stabilized by captodative substitution [26]. The rearrangement of vinylcyclopropanes 29 to cyclopentenes 30 (Scheme 7) is another example [ 17bl. Thus, cyclopentenes with captodative substitution on carbon number 4 are obtained upon heating to 120 " C , whereas unsubstituted derivatives require heating to 340-390 "C. This example is related to the rearrangement of cyclopropylmethyl radicals 32 to give homoallylic systems 33 (Scheme 8). The parent reaction is very fast (k25 = 1.0 x lo8 s-') [27], so that cyclopropylmethyl radical 32a is kinetically stable only below - 140 "C. Captodative substitution has a remarkable stabilizing effect: the radicals 32b-e are kinetically stable up to room temperature [ 17al. This observation is related to the use of the captodative effect to carry out radical cyclization reactions which are otherwise not kinetically favored (cf: Sec. 3.3.5.3).

3.3.3 Rearrangement Reactions

365

Et02c)yEto2c '

X

26

1'

27

'

X

krel

H S02Me SOMe F C02Et Me SMe OMe

1,oo

\

1,17 1,22 1,42 1,63 1 ,a9 3,a3 435

-

.

x

28

.

Scheme 6. Kearrangement of tetrasubstituted methylene cyclopropanes

.. 29

30

R

R'

X

Y

Temperature ("C)

H

H

H

H

H

H

340-390

H

OMe

220-250

H

H

H

NMe2

180-200

Me

Me C02Me

C02Me

180

Me

Me

C02Me

120

SMe

Scheme 7. Rearrangement of vinyl cyclopropanes to cyclopentenes

31

32

33

X

Y

Z

32 stable until

a

H

H

H

-140°C

b

Et2N

CN

C02Me

+20°C

c

Et2N

C02Me C02Me

+2O0C

d

Bus

CN

C02Me

+2O0C

e

BUS

C02Me C02Me

+20°C

Scheme 8. Rearrangement of substituted cyclopropylmethyl radicals

366

3.3 Synthetic Utility of the Cuptodutive EfSrct

3.3.3.2 Via a Homolysis-Addition Pathway Work in the group of Speckamp has shown that C-Cl bonds in a captodative position are weak enough to lead to radical chain cyclization reactions by chlorine atom transfer [28]. Chlorine atom transfer from 34 to the catalyst, Cu'C1bipyridine, leads to radical 35 which then undergoes 5-exo intramolecular addition to form the proline derivative 36 (Eq. 1). The captodative substitution is necessary for this radical process; in the absence of an electron-withdrawing substituent, a cationic reaction leading to a piperidine occurs instead [29]. Et

Et

Et

G N Z O Z M e acetone 1

36

35

34

(four diastereoisorners)

In a similar process, the a-chloro-a-thioacetamide 37 leads to the pyrrolizidines 38 and 39 upon chlorine atom-transfer cyclization initiated by catalytic ruthenium chloride (Eq. 2). The high efficiency of this method, which was applied to alkaloid synthesis, was attributed to the captodative effect [30].

cN/'

RuCh, (PPh3)3

GSMe 0 67%

37

*

H

W

S

-CI M

0 38 (94)

e

+

M e:&

(2) 0 39 (6)

Phenylthio radicals add to the alkyne 40 to yield, after 1,5 intramolecular hydrogen transfer, the captodative a-alkoxyester 41, which cyclizes in good yield to the 2,3-disubstituted tetrahydrofurans 42 and 43 [311.

3.3.4 Selective Oxidation of Captodative Methylene Groups 3.3.4.1 Halogenation, Oxygenation and Sulfuration Halogenation in captodative position is efficient and selective. For example, NBS bromination of the chiral glycine compound 44 gives a quantitative yield (as a 1:l diastereoisomeric mixture) of 45 [32].

3.3.4 Selective Oxidution of Captodative Methylene Groups

367

(4) 0

0

0

44

45

0 R= H Me CHPCO~H

46a b C

47a

0 quantitative

‘‘R 96%

b 95% C

92%

Scheme 9. Selective bromination of 1.3-dioxolan-4-ones

Similar conditions convert the 1,3-dioxolan-4-0nes 46a-c regioselectively to a single diastereoisomer of 47a-c (Scheme 9) [33]. Oxidation of 4-carboxyoxazolines and thiazolines 48 (Eq. 5 ) can be performed efficiently using a modified version of the Kharasch-Sosnovsky reaction (CuCl, CuBrZ, and t-butyl perbenzoate). The conditions are compatible with a broad range of substituents in position 2, and the reaction has been applied in the total synthesis of several biologically active oxazole or thiazole compounds 51. Captodative substitution is essential, since removing the 4-carboalkoxy substituent, which stabilizes the intermediate 49,prevents the reaction from occurring [34]. CuBr C~(0Ac)p *

c

~

PhC03t-BU ~ M ~

48 X = O , S

49

50

51

(5)

Piperazine dione (52) reacts selectively with oxygen to yield bis-hydroperoxides 53 P51.

0

0

52

53

368

3.3 Synthetic Utility of the Cuptodative Effect

Elemental sulfur and morpholine, reagents of the Willgerodt-Kindler reaction [ 361, react at room temperature with captodative methylene compounds to form thioamides with an electron-withdrawing substituent. For example, cr-morpholinoketone 54 leads to thioamide 55 [37].

(“T

o d

S8,rnorpholine, DMF, 20°C

0

(7)

52%

54

55

3.3.4.2 Dehydrodimerization and Polymerization Dehydrodimers 58 can be obtained essentially quantitatively from captodative methylene compounds 56 upon oxidation (Scheme 10). For example, methyl crmethoxyacetate (c = COzMe, d = OMe) leads to the dimer of the captodative radical 57 in 91‘% yield upon reaction with t-butyl peroxide [38]. This reaction can be extended, under certain conditions, to yield polymers with interesting properties [ 391. Oxidative polymerization of methyl methoxyacetate, methoxyacetonitrile or methylthioacetonitrile occurs under photochemical or thermal (130 “C) conditions in the presence of t-butyl peroxide or 1,2-bis(t-butylperoxy)ethaneto yield 59. Under the same conditions, aromatic compounds such as phenylacetonitrile or diphenylmethane do not yield polymers. Molecular weights reaching several thousand can be achieved in good yield (-70%) [39].

c = OMe, SMe

d = CN, C02Me

Scheme 10. Dimerization and polymerisation of captodative methylene compounds

3.3.4.3 Oxidation of Captodative Anions Indigo (62) is made from indoxyl (60) upon treatment with captodative radical 61 [40].

0 2

d”d.1-W O

H

oxygen H 60

H 61

H

O 62

in base, via the

3.3.5 Radical Addition to Captodative Alkenes

64

63 1) BuLi *

2)

I

369

mui

wu

yield = 80%

I

65

CN 66

Scheme 11. Nucleophilic substitution of t-butyl iodide by captodative anions

The delocalized benzylic or allylic captodative carbanions derived from 63 or 65 react with normal electrophiles, but also, surprisingly, with tertiary alkyl halides, to give, for example, 64 and 66 in good yield (Scheme 11) [41]. The mechanism is thought to involve single-electron transfer and recombination of the stabilized radicals formed [42].

3.3.5 Radical Addition to Captodative Alkenes 3.3.5.1 Intermolecular Reactions Photoelectron, UV and I3C NMR spectroscopy, as well as MNDO calculations all predict a reduced HOMO-LUMO gap for alkenes with captodative substitution, and an enhanced reactivity of the carbon [43]. This explains their radicophilic behavior and their high reactivity in cycloaddition processes, the diradicaloid transition states of which are stabilized when the mechanism is asynchronous (cJ Sec. 3.3.7). Captodative alkenes 67 can be dialkylated, for example, by addition of isobutyronitrile radical derived from thermal decomposition of AIBN under the same conditions as those which lead to polymerization of other acrylic alkenes. For example, cc-morpholino-acrylonitrile (67, c = CN, d = N(CH2CH2)20) leads to 69, in 71% yield (Scheme 12) [4a]. With a-t-butylthio-acrylonitrile (67, c = CN, d = SC(CH3)3), the same process leads to 70 in 88%) yield [7]. The adduct radical 68 is highly stabilized, and is in equilibrium with dimer 70. The reaction is quite general, and has been applied to other captodative alkenes (c = CN, COR, C02R and d = NR2, OR, SR) together with various sorts of radical partners, derived from alkanes, alcohols, thiols, thioethers, amines, amides, ketones, aldehydes, acetals and thioacetals [44, 451. Chiral dioxolanone 71 and oxazolidinone 72 alkenes, which can be readily prepared from lactic acid or alanine, respectively, undergo diastereoselective radical

370

3.3 Synthetic Utility of the Cuptodutive Effect

R-H+

==(C

-[y]

R f

c

y - R d

69

d 67

68

d d

R

Scheme 12. Radical additions to captodative alkenes

AcO

~

Bu3SnCl H02C

72a

73

74

NH2

75

Scheme 13. Synthesis of a-D-glycosyl-(R)-alanine

addition. These processes lead to new enantioselective syntheses of cx-amino and ahydroxy acids [46]. As illustrated by the preparation of a-D-glucosyl-(R)-alanine75, the method is simple and efficient (Scheme 13). Alkene 72a is treated with iodide 73, sodium cyanoborohydride, and tributyltin chloride in t-butanol to give exclusively the diastereoisomer 74 (88%) arising from addition of the glucosyl radical on its cx-face followed hydrogen-atom transfer to the intermediate oxazolidinonyl radical anti to the bulky t-butyl group [47].

3.3.5.2 Polymerization Homopolymers and copolymers derived from captodative olefins have been synthesized for various purposes, and the main interest resides in their polyfunctional nature. Two points are worth mentioning: first, polymerizations occurring without added initiator have been observed for some captodative olefins, and second, disproportionation of low-molecular-weight captodative radicals is a very uncommon reaction. As a consequence, the termination process during the polymerization of captodative olefins occurs mainly by recombination. By using captodative mono-

3.3.5 Rudical Addition to Captodative Alkenes

371

Jy- d. 76

77

Y

a H H

CN

H OMe

10-6 k c , S1(50°C)

0,60

165

1,45

249

E, , kcallmol (25-75°C)

6,85

5,81

6,56

5,12

X

b H

d CN

C

OMe

Scheme 14. Cyclization of 6-substituted hex-5-enyl radicals

mers, one can generate structure-dependent polymer properties. Many applications have been considered up to now [48].

3.3.5.3 Intramolecular Reactions Rate constants and activation energies for cyclization of substituted hexenyl radicals 76 have been measured (Scheme 14) [49]. The highest rates (275- and 415-fold acceleration for 76b and 76d, respectively) can mostly be attributed to enhanced interaction of the radical SOMO and the double bond LUMO. The activation energies show however that the transition state for 76d has a small extra stabilization compared to that for 76b. Nucleophilic radical 79, derived from bromide 78, is expected to add intramolecularly to the electrophilic double bond to yield cc-acyl radical 80, but it can also add to the radicophilic alkene group to yield captodative species 81 (Scheme 15). The observed ratio of final products 82 and 83 is 1:1.4, indicating a slight preference for the captodative double bond [ 501.

Br 78 L

81

Scheme 15. Competing 5-exo-trig-cyclizations

83 (1.4)

3.3 Synthetic Utility of the Cuptodutive Effect

372

Bu3SnH AlBN 85

84

N

’

I4

Bn

c

o

AlBN

LuzMe

I

Bn 87

86

z

+o NHAc 88

B

U

(Me3Si)$3iH AlBN

48%

-

70%

GCozBu NHAc 89

42% de>95%

Scheme 16. Homolytic cyclizations controlled by the captodative effect

Captodative substitution can also drive radical cyclization processes in a direction opposite to that predicted by the usual selectivity rules [51] by affecting the stability of the radical produced (Scheme 16). For example, Bu3SnH/AIBN treatment of iodide 84 under dilute conditions leads to the cyclobutane 85 via 4-exo-trig cyclization [ 521. The dehydroalanine 86 yields pyroglutamate 87 via 5-endo-trig addition [ 5 3 ] .Another example is the greatly enhanced rate of 7-endo-trig cyclization in the conversion of iodide 88 to bicyclic lactam 89 [54]. The substrates 90-93 (Scheme 17) all have two double bonds in the same relative position to the incipient radical center. One of these double bonds is captodative (-CN, -NMePh), with the other bearing an electron-withdrawing (CN or COzMe) or -releasing (PhCH20, PhS) group, or a phenyl substituent. In each case, cyclization is seen to favor, in some cases exclusively, formation of the captodative radical [551. Radical treatment of bromide 98 leads to a diastereoisomeric mixture of cyclohexenes 102 (Scheme 18). The mechanism presumably involves 4-exo-trig cyclization to radical 100 then ring-opening and final 6-exo-trig addition [55].

3.3.6 Radical Reactions of Aromatic Compounds with Captodative Substitution To date, 1,3 (or 1,5) captodative substitution of aromatics has not been the focus of many synthetic applications. A lone example (Scheme 19) of great promise, how-

373

3.3.6 Radical Reactions of Aromatic Compounds with Cuptodutive Substitution

RI = H R1 = NMePh R2 = NMePh R2 = H

Bu3SnH AlBN PhH, 80°C

-

@-Br

Ph r / :

63

37

54

46

12

88

94

h

95

91 PhSr /

z

h

96

92

T

60

l +

82%

90

40

z

h

Br 97

93

Scheme 17. Chemoselective cyclizations directed by the captodative effect

8Meph

Bu3SnH, AlBN PhH, 80”C, 6h T

M Br : h

57% *

1

98

NMePh 99

100

101

Scheme 18. Cascade reaction involving 4-exo-trig cyclization

3.3 Synthetic Utility of the Cuptodative EfSect

314

-xql.../&

x7QJ

X

\

x q 0-l l Y

Br

Y

Y 106

\

104

'9 0-

O *'H

Y

Y

103

107

105

108

a

X H

Y H

85%

2Yo

b

CHO

H

49%

c

H CHO

OMe OMe

21Yo

34% 53%

0%

90%

d

Scheme 19. Homolytic rearrangement via a cyclohexadienyl captodative radical

ever, is the clean and efficient conversion of 3-bromopropyl vanillyl ether 103d into 3-aryl-1-propanol 108d in high yield (90%) and under standard conditions (AIBN, Bu3SnH) [ 561. The mechanism involves favorable 5-em-trig @so intramolecular attack by 104 to form the captodative spiro hexadienyl radical 106. This is the only pathway followed starting from 103d, whereas for the other substrates 103a-c, where the radical 106 is not captodative, competitive reduction of 104 to form 105 is also observed.

3.3.7 Cycloaddition Reactions Involving Captodative Olefins 3.3.7.1 [2+2] Cycloaddition Several captodative alkenes have been found to dimerize spontaneously and quantitatively at room temperature via reversible formation of a bis-captodative 1,4 diradical (Scheme 20). This occurs, for example, with a-alkylthioacrylonitriles 109 [ 571, with a-alkylselenoacrylonitriles 110 [58], with protoanemonin 111 [59], and with cyanopyrrolin 112 [60]. Eschenmoser et al. used the reverse thermal fragmentation reaction of cyclobutane 113 to generate captodative alkene 114 [61].

MeCN NHz113

CN 114

(9)

315

3.3.7 Cyclouddition Reuctions Involving Cuptodative Olefins

2o"c_ -

==(sR CN 109

+-&

[

c

$N

_

120°C

SR

CN

q0+crm

Go 0 -

SeR 110

111

0

112

NH

CN

Scheme 20. [2+2] cyclodimerization of captodative alkenes

Captodative alkenes also react well with other alkenes in [2+2] cycloaddition reactions. For example, trifluorochloroethylene 115 reacts more efficiently with a-alkythioacrylonitrile 116 than with acrylonitrile [ 5 8 ] .

115

116

Allenes also react with captodative alkenes to form 3-methylene cyclobutanes regioselectively. For example, 116 reacts with allene to give 117 upon heating at 140°C for two days [62]. Captodative allenes can even react at room temperature with captodative olefins; as an illustration, a-methoxycyanoallene 118 adds to 116 to form 119 in 41% yield [62].

C , N H&=C=C,

CN 41%

smu

OMe 118

116

119

sm

376

3.3 Synthetic Utility of the Cuptodative Effect

Bicyclopropylidene 121 forms a [2+2] cycloadduct with a-methoxyacrylonitrile 120. Captodative methylene cyclopropane 123 undergoes dimerization at 60 "C [63]. 180°C +

4days

CN 120

%Me CN

121

122 59% SPh

A

123

124

The bis-alkenes 125a-b undergo intramolecular [2+2] cycloaddition, the efficiency of which is dependent upon the magnitude of the captodative effect (Scheme 21) [64]. With 125a, 4 days at 140°C are required for full conversion, against 5 min at 140 "C (or 3 days at 40 "C) for captodative 125b.

L

125a X = Me 125b X = SMe 125b X = SMe

140°C, 4 days 14OoC,5 min 40°C, 3 days

_I

126a 75% 126b 91% 126b 90%

Scheme 21. Intramolecular [2+2] cycloaddition of a captodative alkene

3.3.7.2 [3+2] and [4 +2] Cycloadditions Captodative alkenes are also good dipolarophiles 1651 and dienophiles 1661. The corresponding [3+2] and [4+2] cycloaddition reactions seem to be concerted, as usual, so that diradicals are not directly involved as such. However, the mechanism may be rather asynchronous, with the transition state having pronounced diradicaloid character, and thereby being stabilized by the captodative effect 1671. This can explain the higher dienophilic character of a-methylthioacrylonitrile 127 compared to acrylonitrile, despite the unfavorable steric effect (Scheme 22) [68]. 128 and 129, also Captodative dienes, such as the 2-cyano-l-aza-l,3-butadienes undergo hetero Diels-Alder reactions, both inter- and intramolecularly (Scheme 23). Reactivity and regio- and stereo-selectivity in these processes have been accounted for in terms of a concerted asynchronous mechanism involving a diradicaloid transition state [69]. The intramolecular cases illustrated here have been shown to be successful for the preparation of indolizidine 130 and quinolizidine 131 ring systems.

3.3.8 Conclusions

r'l-

377

I

CN 54/46

I SMe 80:20

127

CN

Scheme 22. Diels-Alder reactivity of a-methylthioacrylonitrile compared to acrylonitrile

98:2

1-0

O

405

EtO

OEt

CHz=CHpCN BusSnCI, NaBH3CN AIBN, 80 "C

NC-

b

NC.-/+,,,

*

,.,OMEM

+

+.,,,-OMEM

69%

OEt

(6.2)

EtO

EtO

2 : l

P

I

P

h

'

T

O

M

OEt

OEt

5

6

E

M

Scheme 6

LIDhI

T

trandcis

7 low selectivity

I

8 high selectivity

Pht = phthaloyl

control of the stereochemistry (Scheme 8). For example, radical additions to acrylonitrile at low temperature gave preferentially the cis or the trans isomer depending on the radical precursor used. This clearly indicates that the rate of reaction competes with the rate of chair-chair interconversion (9 to 10) of the radical intermediate. Finally, excellent 1,4-asymrnetric induction has been observed by Colombo in a 7,5-fused bicyclic radical and the selectivity has been rationalized by confonnational analysis of the intermediate radical (Scheme 9) [ 171.

4.2 Stereoselectivity of Radical Reactions: Cyclic Systems

406

Bn trans/cis 62:38

Mee; G."

or

+

Me

trans

Cis

trans/cis 4:96

Scheme 8

I '-d$COOt-Bu

AIBN, (TMS)3SiH 80 "C

~

~

0

0

t

-

B

~

42%, dr >97:3 NHAc

NHAc

Scheme 9

4.2.4 Exocyclic Substituents In many cases, substituents not bound to a stereogenic center can strongly influence the stereochemistry of a radical process. Two different types of effect will be discussed here: the presence of a prochiral substituent at the radical center of enolate radicals and the presence of an amide moiety next to the radical center.

4.2.4.1 Prochiral Substituents at the Radical Center Giese has investigated this effect in detail and applied it for highly stereoselective synthesis of C-disaccharides [ 18, 191. For instance, the radical conjugate addition

4.2.4 Exocyclic Substituents

407

t-Bul, Bu3SnH AIBN, hv, 20 "C 97%, dr >98:2 ',,

Scheme 10

depicted in Scheme 10 leads exclusively to the trans isomer [20]. This indicates that the final H-abstraction from tin hydride occurs syn to the neighboring methyl group. This was explained by a preferred conformation in which the tert-butyl group is turned away from the methyl substituent at the cyclic radical. This conformation is controlled by minimization of allylic l13-strain. Similar situations are reported in the literature [21-231.

4.2.4.2 Neighboring Amides Beckwith has reported an astonishing inversion of selectivity during the radical conjugate addition to methyleneoxazolidinone when the nitrogen protecting group was changed from a benzyloxycarbonyl to a benzoyl group [24]. With this latter group, the surprising formation of the trans isomer was observed indicating that the final reduction step by tin hydride was occurring syn to the bulky tert-butyl group (Scheme 11). This effect was not rationalized in the original articles but fits nicely into the model developed by Seebach for enolate alkylation [25].The radical intermediate exists in the conformation depicted in model 11, the benzoyl group controls the conformation of the exo tert-butylmethyl group and preferential attack then occurs according to the arrow. Related effects have been reported with other radicals derived from cyclic amino acid derivatives [26-281.

Scheme I1

408

4.2 Stereoselectivity of Radical Reactions: Cyclic Systems 1) 2,2'-dithiobis(pyridineN-oxide), Bu3P 2) CHP=CHS02Ph, hv, 10 "C

35%, dr 86:14

CIBupSnH, 110 "C 88% Pmb = para-methoxybenzyl

I

Bn&V%%BupCI

Brio 0 mb

I

Scheme 12

4.2.5 Pyramidalization of Radicals Cyclopropyl radicals are pyramidalized (sigma radicals) and known to isomerize relatively slowly depending on the substitution. This has of course obvious consequences for the stereochemical outcome of their reactions. This point has been reviewed separately and will not be discussed here [29]. Simple alkyl radicals are nearly planar or, when they are pyramidalized, they possess negligible inversion barrier. However, under some special circumstances, this pyramidalization can lead to a surprising stereochemical outcome in total disagreement with the anti rule presented above. This effect was identified first when chelated radicals were examined [30]. This observation was then extended to 1,3-dioxolanyl and oxiranyl radicals [31]. In Scheme 12, a typical example of a syn reaction is depicted (Scheme 12, Eq. 12.1). The carboxylic acid was converted to the Barton ester. Radical addition to phenyl vinyl sulfone occurred preferentially syn to the very bulky tert-butyl group. This is best explained by the existence of a pyramidalized radical intermediate 12. The pyramidalization is caused by the very strong steric interactions between

4.2.6 Stereoelectronic Effects

409

the tert-butyl and the methyl groups. Since this reaction most likely occurs via an early transition state, the interaction of the radical trap with the tert-butyl group is less important than the interaction with the methyl group. A related example has been reported by Clive during the synthesis of D-myo-inositol derivatives (Scheme 12, Eq. 12.2) [32]. Reduction of a polyoxygenated cyclohexanone derivative with CIBuZSnH was the only method to give exclusively the equatorial alcohol presumably via the pyramidalized ketyl radical 13.

4.2.6 Stereoelectronic Effects Stereoelectronic effects play a major role in reactions at the anomeric center of carbohydrate radicals. However, they are general and not limited to sugar derivatives. Two main effects have been identified: the anomeric effect (Scheme 13, 14) and the quasi-homo-anomeric effect (= P-oxygen effect) (Scheme 13, 15) [33, 341. Giese has developed an efficient and stereoselective approach to C-glycosides based on this effect [35, 361. More recently, a highly stereoselective preparation of an aanomeric azide was reported (Scheme 13, Eq. 13.1). These compounds are valuable intermediates for the synthesis of N-linked glycoconjugates [37]. The stereochemical outcome of this reaction is fully controlled by the anomeric effect (model 16). Crich has developed a completely stereoselective access to P-mannosides. The stereochemistry is controlled during the decarboxylation step as described in Scheme 13 (Eq. 13.2) and can be rationalized by additive anomeric and quasi-homo-anomeric effects (model 17).

t

14 anorneric effect (n-sorno)

t

15 quasi-homo-anornericeffect = p-oxygen effect ( s o m o d )

(13.1)

A%* A%&%+ AcoOMe

Scheme 13

1

16

N3

17

AcoOMe

i

410

4.2 Stereoselectivity of Radical Reactions: Cyclic Systems

R2N= NHAc: 71%, alp 1O:l R2N= NTCP: 77%, alp 1:90 >90

45: 1 25: 1

20

High selectivities are obtained with several lanthanide and pre-lanthanide Lewis acids (Ho, Lu, Yb, Y, Eu, Er, for example). Chelating Lewis acids capable of binding both substrate carbonyls consistently showed better selectivities than Lewis acids limited to a monodentate complex. Substoichiometric Lewis acid provided only reduced selectivities and yields. For example, stoichiometric Yb(0Tf ) 3 promotes addition of isopropyl to crotonates with selectivity of 25:l (90% yield) while this Lewis acid present in 0.1 equivalents gives product with selectivity of 16:1 (88% yield). A variety of solvents and solvent mixtures were examined, and for most Lewis acids a 4: 1 mixture of dich1oromethane:THF proved effective. The diphenylmethyl oxazolidinone proves to be effective in promoting selective additions of radicals to unsymmetrical fumarates 21 [25]. Thus, addition of isopropyl radical to 16 proceeds regioselectively, addition to the carboethoxyl side of the alkene being favored in the absence of Lewis acid; 22/23 = 11:l. Diastereoselectivity for formation of 17 in the absence of Lewis acid was poor, about 1.6:l. Several lanthanide and prelanthanide Lewis acids used stoichiometrically improve 0 O

0 N &C02Et

u,, "rPh Ph 21

0

i-Pr-I

Bu3SnH Lewis Acid -78 "C

O u

0

0

i-Pr

N uC02Et t

+

0

'-4

OKN+C02Et i-Pr

,

"rPh Ph

'FPh Ph

22

23

yield % none >go 90 Y(OTf)3 Yb(0Tf)S >go 90 Er(OTf),

22

22/23

i.6:i 21:l 1O:l 3311

11:l 1OO:l 8O:l >100:1

4.3.3 Auxiliary Groups Attached to the Radical

429

both regioselectivity and diastereoselectivity. Selectivity improves in some cases with excess Lewis acid while substoichiometric amounts result in a significant degradation of diastereoselectivity. This is undoubtedly due to the 'background' reaction that occurs without added Lewis acid. In the case of cinnamates and crotonates, this background reaction is slow at -78 "C while the fumarate derivatives gave a higher background reactivity.

4.3.3 Auxiliary Groups Attached to the Radical The idea that resident chiral centers must be fixed in space relative to the center undergoing reaction coupled with a reactant-like transition state applies for both components of radical-molecule reactions. The strategies that have been useful for the development of chiral auxiliary groups for radical reactions appear to be general, applying for auxiliaries attached to either a radical trap or a radical. Thus, auxiliary groups that have proved to be useful in controlling the configuration of stereogenic centers when attached to a radical trap are also useful when attached to a radical undergoing addition.

4.3.3.1 Amide Auxiliaries Radicals substituted a to the amide linkage, 24, have been used in several studies to control stereochemistry in radical transformations, while radicals substituted a to esters, 25, and ethers, 26, have been used on a few occasions. Resonance structures for each of these radicals (A and B) can be written as shown in 24-26, with stabilization resulting from delocalization of the odd electron into the adjacent functional group. This resonance delocalization also restricts the geometry of these radicals, maximum delocalization being obtained when overlap between the radical and adjacent group is highest.

24A

248

25A

258

.. 26A

+. 26B

430

4.3 Chiral Auxiliaries

radical

Dirnethylpyrrolidine

Oxazolidinone

alkene

Oxazolidine

Oppolzer Sultarn

Figure 3. Amide auxiliaries with a-radical

Radicals substituted a to amides present conformational issues similar to those of amides substituted on carbon-carbon double bonds. Thus, control of the configuration about the carbonyl carbon-radical bond and the carbonyl-nitrogen bond is critical to the success of potential auxiliary groups. For radical centers substituted by a carboxamide, alkyl group, and hydrogen, the conformation about the radicalcarbonyl bond is 2, the small carbonyl oxygen and large alkyl substituent being cis. This is essentially the same conformation as is observed when amides are substituted on a carbon-carbon double bond (see Eq. (17) and the comparison in Fig. 3 ) . Several strategies have been used to control the conformation about the carbonyl-nitrogen bond of carboxamide radicals, and several of these approaches shown in carboxamides or carboximides have all proved to be useful auxiliaries for controlling the configuration of new stereogenic centers formed from prostereogenic radicals. Dimethylpyrrolidine and its analogs are efficient stereocontrol elements, since the C2 axis of the pyrrolidine makes the conformation about the carbonyl-nitrogen bond irrelevant. In radicals such as 27, both conformations provide essentially the same stereochemical environment for the radical center. An example of the use of dimethylpyrrolidine, is shown in Fig. 4. In this transformation, a tert-butyl PTOC ester is reacted with the acryloyl carboxamide of dimethylpyrrolidine and the addition product is isolated in excellent yield and selectivity. The propagation sequence involves addition of a tert-butyl radical to the acrylamide, trapping of the adduct radical, 27, by the PTOC ester, and decarboxylation of the pivaloyl carboxy radical. This transformation may be initiated thermally or photochemically, and photoinitiation at reduced temperatures gives product with higher diastereoselectivity. A

4.3.3 Auxiliary Groups Attached to the Radical

43 1

27

f-BU

Figure 4. Addition-trapping sequence for the dimethylpyrrolidine carboxamide of acrylic acid

6: 1 mixture of diastereomers is obtained at room temperature and the product that is favored is the one shown in Fig. 4 [26]. Radicals such as 27 add to alkenes and abstract halogen from bromotrichloromethane selectively [27]. In each case, selectivities in excess of 1O:l are obtained and the observed product is as predicted based upon the proposed structure of the radical. The proximal methyl of the dimethylpyrrolidine protects one face of the radical from reaction. Carboxamides of oxazolidines have been used to control configuration in the reactions of a substituted radicals [28]. The preferred conformation of the radical is proposed to be as shown in 28, with the gem-dimethyl of the oxazolidine oriented Z to the carboxamide carbonyl. The oxazolidine carboxamides are readily prepared from aminoalcohols that are, in turn, available from amino acids. The 2 conformation about the carbonyl-nitrogen bond of 28 is apparently enforced by the gemdimethyl group, which is larger than the CH-R attached to the other a carbon of the oxazolidine. The larger gem-dimethyl carbon prefers to be Z to the smaller 0 of the carbonyl functional group. The radical 28 reacts with alkenes, PTOC esters, and allylstannane with good selectivity. The oxazolidine with R1 = t-Bu is particularly effective as an auxiliary group. Thus, the radical 28 having R = (C6Hll)CHz and R1 = t-Bu reacts with allytributylstannane with a selectivity greater the 20:l at 80°C, and its reaction with PTOC esters gives a 60:l mixture of thiopyridyl ester products at room temperature.

432

4.3 Chiral Auxiliaries

27

28

Rosenstein and Tynan have used the oxazolidine auxiliary to control the configuration of radicals substituted by both a carboxamide and an acyl group [29]. The transformation, shown in Fig. 5, gives good yields and selectivity for reactions carried out over a wide range of temperatures. Selectivity is substantially lower for transformations in which the oxazolidine auxiliaries are derived from valinol and phenylalaninol. The configuration of the major product diastereomer has not been rigorously established but a transition state similar to that proposed for simple amide radicals bearing the oxazolidine amide has been proposed and seems reasonable (see Fig. 5). Oxazolidinones have proven to be useful auxiliaries in reactions of radicals substituted a to carboxiimides bearing this group. The use of this auxiliary requires a Lewis acid to control the conformation of the oxazolidinone relative to the reactive radical center, and the complexation of the Lewis acid to the radical makes thc radical very electrophilic, promoting reactions to unactivated olefins. The equilibrium between radical and Lewis acid is shown for structures 29A and B. The con-

-r ("C)

yield

diastereomer ratio

80 25 0 -78

>go% >90% >go%

13:l 24:l 32:1

80%

>100:1

Figure 5. Transformations of electron-deficient oxazolidine radicals

4.3.3 Auxiliary Groups Attached to the Radical

433

formers of the radical are essentially the same as those described in Eqs. (18) and (19) for oxazolidinone auxiliaries attached to alkene radical traps. The preferred conformation about the carbonyl-radical bond is Z , and the Lewis acid fixes the Z conformation about the carbonyl-nitrogen bond. The equilibrium described in Eq. (20) is for the prostereogenic radical, but a similar equilibrium applies to the radical precursor. The kinetics and thermodynamics of the equilibria of the Lewis acid and radical precursor as well as that of the radical intermediate will be critical in determining the selectivity of reactions involving radicals such as 29, and the determination of such equilibria provides significant hurdles. Reactions of such radicals have proven to be highly stereoselective, greatly expanding the utility of carboxamide radicals [24, 30, 311.

Lewis acid = M0

29A

298

The new diphenylalanine-derived oxazolidinone, 15, is particularly effective when used as an auxiliary on radical 29. The auxiliary can be used in a propagation sequence that involves radical addition followed by trapping of the addition radical with allylstannane or allylsilanes, Eq. (21). Excellent yield and diastereoselectivity are observed if the reaction is carried out in the presence of Lewis acids such as magnesium bromide or lanthanide triflates at -78 "C. The reaction promoted by magnesium bromide, for example, provides a diastereomer mixture in excess of 1OO:l with a yield of 85%. Sc, Yb, Y, La, or Sm triflates provide similar results in reactions usually carried out in ether.

u, 'r Ph

+

R-X

Lewis Acid

Ph

The Lewis acids not only affect product distribution but also promote the otherwise sluggish low-temperature reaction. An alternative sequence that involves the same intermediate starts from the bromide precursor 30. In the absence of Lewis acid the reaction is nonselective, giving a product diastereomer ratio of only 1:1.8. With excess MgI2 or MgBr2, the product ratio is in excess of 1OO:l under otherwise similar reaction conditions. Even at 25 "C, reactions of 30 carried out in the presence of 2 equivalents of MgBr2 gave products in a ratio of 30: 1. A model (31) ac-

434

4.3 Chiral Auxiliaries

counts for the observed selectivity. Minimization of A',3 strain confines the radical intermediate 31 to an s-cis conformation and the oxazolidinone 4-substituent provides shielding of the diastereotopic faces. Any radical trap therefore reacts on the face of the radical as shown in 31.

30

31

Oxazolidinones used in conjunction with Lewis acids promote radical atom transfer sequences with inactivated alkenes, and these reactions proceed with good to excellent selectivity [32]. In the absence of Lewis acid, poor conversion was seen. Several common Lewis acids (e.g. MgBr2, Zn(OTf)Z, and La(OTf)3), which are effective promoters of the ally1 transfer reaction described in Eq. (22), failed to improve conversion significantly. Sc(0Tf )3 performed moderately well with the 1O bromide while Yb(OTf)3 gave excellent yields of product. With terminal alkenes, the reactions were rapid and efficient; complete conversion was seen within 15 min at room temperature. Internal alkenes were slower to react, but near quantitative yields were possible with cis alkenes in reactions promoted by Yb(OTf)3. 1,2-Dichloroethane (DCE) appears to be a particularly good solvent for these transformations.

Diastereoselectivity for the atom transfer sequence was studied by employing chiral oxazolidinone auxiliaries with 1-hexene and the oxazolidinone imide derived from a-bromopropionic acid, as described in Eq. (23). The results of these studies are reported in Table 1. The major product formed has the R configuration, consistent with model 31. Diastereoselectivity was good to excellent for either R = i-Pr or benzyl. Presumably the auxiliary with R = CH(Ph)2 would give even better selectivities in these transformations.

4.3.3 Auxiliary Groups Attached to the Radical

435

Table 1. Auxiliary-controlled atom transfer additions

R

Solvent

T ["CI

Conversion

RIS

i-Pr i-Pr i-Pr Bn i-Pr

1,2-DCE I,2-DCE Ether Ether Ether

25 25 25 25 0

1OO'X, 85'Yn >90'%1 >90% 44Y"

82: 18 93:7 95:5 964 964

All reactions with 1 eq Sc(OTf)3, 5 eq alkene, 0.5 eq Et,B/02. 1,2-DCE = 1,2-dichloroethane

N-acyl radicals bearing oxazolidinone groups have recently been used in addition reactions with unactivated alkenes, vinyl ethers, and silyl enol ethers [33]. The reactions proceed in good yield for most systems studied (Eq. 24). Thus, reaction of the selenide 32 having R = H with several vinyl ethers or silyl enol ethers gives product in greater than 70% yield. For example, the tin hydride-mediated reaction of the selenide with the TBS ether of propiophenone gave the product 33 in 80% yield in a diastereomer ratio of 30: 1. Attempts to utilize chiral oxazolidinones with Lewis acid promoters (magnesium bromide etherate) failed in reactions of selenide 32 (R = Bn) with the same silyl vinyl ether. The corresponding xanthate gave products with significant diastereoselectivity but in poor yield.

32

33

X = SePh or SCS(0Et)

4.3.3.2 Ester Auxiliaries Several studies have focussed on the use of chiral esters as auxiliary groups in radical transformations. Perhaps the most comprehensive survey of auxiliary groups was reported by Snider and collaborators in their pioneering examination of Mn(II1)-promoted radical cyclization reactions of /? keto amides and esters [34]. The selectivities obtained in cyclization generally mirror those observed in intermolecular addition reactions. These examples again illustrate that the models developed for intermolecular radical reactions can apparently be applied successfully to intramolecular additions (cyclizations). Selectivity for the conversion of 34 to 35

436

4.3 Chiral Auxiliaries

Y b(OTf),

0

0 Figure 6. Synthesis of (+)-triptophenolide using 8-phenylmenthol as auxiliary

is greater than lO:l, while the same transformation for the radical bearing the 2,5dimethylpyrrolidine occurs with a somewhat higher selectivity. Nevertheless, the 8phenylmenthol of 34 is readily available and can be removed under relatively mild conditions. This makes this auxiliary particularly useful in radical transformations, and it has been used extensively in cyclization reactions [35, 361. Several other ester auxiliaries have been studied, but the 8-phenylmenthol appears to be the best of those examined.

35

34

A recently reported synthesis of (+)-triptophenolide illustrates the utility of this auxiliary in radical reactions [37].The key step in the synthesis, outlined in Fig. 6, is a lanthanide triflate-promoted oxidative radical cyclization of an 8-phenylmenthyl keto ester mediated by Mn(OAc)3. The product of the radical cyclization is formed in excellent yield and selectivity in the presence of ytterbium triflate. The Lewis acid presumably locks the keto ester in a syn orientation. The configuration of the transformation can be understood based upon a transition state arrangement as shown in 36.

a

4.3.3 Auxiliary Groups Attached to the Radical

437

4.3.3.3 Ether Auxiliaries Significant control of stereochemical configuration may be obtained when radicals with chiral auxiliaries attached through an ether linkage are trapped. Garner et al. have used carbohydrates as a basis for auxiliary groups [38]. These workers have examined the addition reactions of radicals bearing acetal-based auxiliary groups derived from carbohydrates. In particular, a 'pseudo-enantiomeric' auxiliary derived from L-rhamnose was examined in addition reactions to activated alkenes such as methyl acrylate. Radical 37 adds to methyl acrylate in good yield with a selectivity of 11:1 at -78°C. The addition of 37 to more reactive radical traps such as 2-nitropropene gives product with lower selectivity, however, 5:l at -78 "C. Garner suggests that the reason for poorer selectivity of 37 in reactions with the more reactive alkene is that an earlier transition state makes substituents at the C-6 position less effective as a stereoscreening element. In support of this notion, a 6-tert-butyltetrahydropyransubstituted radical provides selectivities of 35: 1 in reactions with 2-nitropropene carried out at -78°C. A model for the early transition state in reactions with 2nitropropene is presented in Fig. 7 [39].

Figure 7. Model for addition of radical to 2-nitropropene

The carbohydrate-based ether auxiliaries have been used to develop a radicalbased asymmetric aldol reaction. Glycoside radicals such as 37 are generated from Barton ester precursors 39 [40], and the addition of these radicals to 2-nitropropene gives a thiopyridyl adduct 40 that can be converted to an aldol product [41]. The yield for the conversion is moderate to good and the diastereoselectivity ranges from 5:l to 8:1, depending on R and temperature.

438

4.3 Chiral Auxiliaries

An iterative approach to polyols has also been developed, based upon glycoside auxiliary groups and radical chemistry [42]. The general strategy involving serial reactions generating aldol products is shown in Eqs. (25) and (26). Reaction of the Barton ester (R* is a glycoside auxiliary group) with ethyl trifluoroacetyl acrylate followed by hydrolysis to give 41 and reduction of the ketoester provides a substrate that can be converted in another iterative sequence to generate another alcohol with control of configuration of the new stereogenic center. The sequence provides keto ester in 80-90% yield after radical addition and in situ hydrolysis. New innovations incorporated in the sequences shown in Eqs. (25) and (26) are an improved method for Barton ester formation by the use of a thiouronium derivative of Barton's reagent 42 [41] and new auxiliary groups 43 bearing a tertiary C-6 substituent, which can be prepared in either enantiomeric form. These new auxiliaries give product as a mixture of diastereomers in a ratio of 7:l to 1O:l. The fact that both enantiomers of 43 are available permits one to 'dial in' the configuration of each stereogenic center produced in a complex product.

NaBH,

41

9-

42

R*O

OH

iterate a and b

RuC02Et

+

OBn

43

R'O R'O RdC02Et

(26)

References

439

References [ I ] For monographs describing general concepts in stereoselective reactions, see: (a) D. A. Evans, In Asymmetric Synthesis, J. D. Morrison, Ed., Academic, Orlando, 1984, p. 2. (b) C. H. Heathcock, In Asymmetric SyntheJis, J. D. Morrison, Ed., Academic, Orlando, 1984, p. 1 1 1. (c) K. A. Lutomski, A. I. Meyers, Asymmetric Synthesis, J. D. Morrison, Ed., Academic, Orlando, 1984, p. 213. For general reviews of stereoselective free radical reactions, see (d) D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of Radical Reactions, VCH, Weinheim, 1995. (e) B. Giese, Angew. Chem., Int. Ed. Engl. 1989, 28, 969. (f) N. A. Porter, B. Giese, D. P. Curran, Ace. Chem. Res. 1991, 24, 296-301. (g) W. Smadja, Synlett 1994, 1-26. 121 M. P. Sibi, N. A. Porter, Acc. Chem. Res. 1999, 32, 163-171. 131 (a) B. Giese, Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon, New York, 1986. (b) C. Walling, Free Radicals in Solution, John Wiley and Sons, New York, 1957. (c) J. K. Kochi, Free Radicals, John Wiley and Sons, New York, 1973. (d) “C-Radikale” In Houben-Weyl Methods of Organic Chemistry, Vol. E 19; M. Regitz and B. Giese, Ed.; Georg Thieme Verlag: Stuttgart, 1989 [4] For example, see D. A. Evans, J. A. Murray, Matt, P. V., R. D. Norcross, S. J. Miller, Angew. Chem., Int. Ed. Engl. 1995, 34, 798. [5] C. Chatgilialoglu, Chem. Rev. 1995, 95, 1229-1251. [6] C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91, 1237. [7] Y. Guindon, B. Guerin, C. Chabot, W. Ogilvie, J. Am. Chem. Soc. 1996, 118, 12528-12535. (b) Y. Guindon, B. Guerin, J. Rancourt, C. Chabot, N. Mackintosh, W. Ogilvie, Pure Appl. Chem. 1996,68,89-96. (c) N. A. Porter, J. H. Wu, G. Zhang, A. D. Reed, J. Org. Chem. 1997, 62, 6702-6703. [8] (a) N. A. Porter, B. Lacher, V. H. Chang, D. R. Magnin, J. Am. Chem. Soc. 1989, 111, 8309. (b) N. A. Porter, D. M. Scott, B. Lacher, B. Giese, H.-G. Zeitz, H. J. Lindner. J. Am. Chem. Soc. 1989, 111, 831 1. For a discussion of 2,5-dimethylpyrrolidine as a chiral auxiliary, see (c) J. K. Whitesell, Chem. Rev. 1989, 89, 1581, and (d) J. K. Whitesell, Ace. Chem. Res. 1985, 18, 280. 191 N. A. Porter, W.-X. Wu, A. T. McPhail, Tetruhedron Lett. 1991, 32, 707. [lo] D. M. Scott, A. T. McPhail, N. A. Porter, Tetrahedron Lett. 1990, 31, 1679. [ 1 I ] A. Veit, R. Lenz, M. E. Seiler, M. Neuburger, B. Giese, Helv. Chim. Acta 1993, 76, 441. [I21 D. P. Curran, W. Shen, J. Zhang, T. A. Heffner, J. Am. Chem. Soc. 1990, 112, 6738. [I31 H. Miyabe, C. Ushiro, T. Naito, Chem. Commun. 1997, 1789-1796. (141 H. Miyabe, N. Yoshioka, C. Ushiro, M. Ueda, T. Naito, J. Chem. Soc. Perkin Trans. 1, 1998, 3659-3660. 1151 H. Miyabe, M. Ueda, N. Yoshioka, T. Naito, Synlett 1999, 466-467. [I61 H. Miyabe, Y. Fujishima, T. Naito, J. Org. Chem. 1999, 64, 2174-2175. [I71 H. Miyabe, C. Ushiro, M. Ueda, K. Yamakawa. T. Naito, J. Org. Chem. 2000, 65, 176-185. [I81 J. G. Stack, D. P. Curran, J. Rebek, P. J. Ballester, J. Am. Chem. Soc. 1991, 113, 5918. [I91 J. G. Stack, D. P. Curran, S. V. Geib, J. Rebek, P. J. Ballester, J. Am. Chem. Soc. 1992, 114, 7007. [20] D. A. Evans, J. A. Murray, P. V. Matt, R. D. Norcross, S. J. Miller, Angew. Chem., Int. Ed. Engl. 1995, 34, 798. [21] M. P. Sibi, C. P. Jasperse, J. Ji, J. Am. Chem. Soc. 1995, 117, 10779-10780. [22] For an application in synthesis, see M. P. Sibi, J. Ji, Angew. Chrm., Inl. Ed. Engl. 1997, 36, 274-275. [23] M. P. Sibi, P. K. Deshpande, A. J. La Loggia, J. W. Christensen, Tetrahedron Lett. 1995, 36, 8961. [24] M. P. Sibi, Aldrichirnica Acta, 1999, 32, 93-103. [25] M. P. Sibi, J. Ji, J. B. Sausker, C. P. Jasperse, J. Am. Chem. SOC.1999, 121, 7517-7526. [26] (a) B. Giese, M. Zehnder, M. Roth, H.-G. Zeitz, J. Am. Chem. SOC.1990, 112, 6741. (b) N. A. Porter, E. Swann, J. Nally, A. T. McPhail, J. Am. Chem. Soc. 1990, 112, 6740.

440

4.3 Chiral Auxiliaries

[27] N . A. Porter, R. Breyer, E. Swann, J. Nally, J. Pradhan, T. Allen, A. T. McPhail, J. Am. Chem. Soc. 1991, 113, 7002. [28] (a) N. A. Porter, J. D. Bruhnke, W.-X. Wu, I. J. Rosenstein, R. A. Breyer, J. Am. Chem. Soc. 1991, 113, 7788. (b) N. A. Porter, I. J. Rosenstein, R. A. Breyer, J. D. Bruhnke, W.-X. WU, A. T. McPhail, J. Am. Chem. Soc. 1992, 114, 7664. [29] I. J. Rosenstein, T. A. Tynan, Tetrahedron Lett. 1998, 39, 8429-8432. [30] M. P. Sibi, J. Ji, J. Org. Chem. 1996, 61, 6090-6091. [31] M. P. Sibi, J. Ji, Angew. Chem., Znt. Ed. Engl. 1996, 35, 190-191. [32] N. A. Porter, C. R. Mero, J. Am. Chem. Soc., 1999, 121, 5155-5160. [33] G. E. Keck, M. C. Grier, Synlett, 1999, 1657-1659. [34] A. Zhang, R. M. Mohan, L. Cook, S. Kazanis, D. Peisach, B. Foxman, B. B. Snider, J. Org. Chem. 1993, 58, 7640. [35] M.-Y. Chen, J.-M. Fang, Y.-M. Tsai, R.-L. Yeh, J. Chem. Soc., Chem. Commun. 1991, 1603. [36] S. D. Mandolesi, L. C. Koll, A. B. Chopra, J. C. Podesta, J. Organomet. Chem. 1998, 555, 151-1 59. (371 D. Yang, X.-Y. Ye, M. Xu, J. Org. Chem. 2000,65, 2208-2217. [38] P. P. Garner, P. B. Cox, S. J. Klippenstein, J. Am. Chem. Soc. 1995, 117, 4183. [39] P. P. Garner, J. T. Anderson, Tetrahedron Lett. 1997, 38, 664776650, [40] P. P. Garner, J. T. Anderson, S. Dey, W. J. Youngs, K. Galat, J. Org. Chem. 1998, 63, 57325733. [41] P. P. Garner, R. Leslei, J. T. Anderson, J. Org. Chem. 1996, 61, 6754-6755. [42] P. P. Garner, J. T. Anderson, Org. Lett. 1999, 1, 1057-1059.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

4.4 Lewis Acid-Mediated Diastereoselective Radical Reactions Brigitte GuPrin, William W Ogiluie, Yuan Guindon

4.4.1 Introduction The formation of new stereogenic centers using chemical intermediates such as free radicals, carbanions, or carbocations can be influenced by many factors such as solvents, electronic effects, the electrophilicity or nucleophilicity of reagents, and the presence of Lewis acid. Of course, the intrinsic reactivity of the intermediate used will also affect the outcome of the reaction. Still, the general principles governing the induction of diastereoselectivity remain the same for all of the above-mentioned species. Inhibited by a perceived complexity, the study of diastereoselective processes involving free radicals did not begin until the late 1980s. Studies involving the stereoselectivity of radical reactions under the influence of Lewis acid soon followed. This chapter will review the effect of Lewis acid on the diastereoselectivity of substratecontrolled radical reactions. Reactions involving chiral Lewis acids and chiral hydrogen donors (reagent control) will be reviewed in another chapter [Volume 1, Chapter 4.51. High ratios in favor of a single isomer are difficult to achieve in kineticallycontrolled diastereoselective reactions involving acyclic molecules. Often, the flexibility of these molecules can allow for several transition states with similar energy, resulting in low levels of stereocontrol. Circumventing this conformational flexibility can be accomplished by the creation of temporary rings. Alternatively, the steric and/or electronic effects associated with the stereogenic center on the molecule can be optimized in order to favor a single transition state. Lewis acid could be useful in both of these approaches. Lewis acid complexation with Lewis basic sites can decrease the rotational degrees of freedom of acyclic intermediate species, thus enhancing the difference in energy between competing transition states. Lewis acids can also influence a reaction by modulating the electronic and/or steric fdctors of functionalities adjacent to the chemical transformation site. The nature of the free radical and the reagent involved will affect whether or not a diastereoselective reaction can benefit kinetically from the presence of Lewis acid. To be efficient, Lewis acid has to influence the SOMO of a free radical and con-

442

4.4 Lewis Acid-Mediated Diustereoselective Radical Reactions

tribute to a decrease in the energy gap between the SOMO and the LUMO (or HOMO) of the incoming reagent. Varying amounts of Lewis acid can be used in a reaction. A catalytic amount of Lewis acid can be used when rate enhancement is predicted and substrate complexation is rapid. In this case, product decomplexation must also be rapid for an efficient turnover of the reaction. Stoichiometric amounts of Lewis acid are required when there is little kinetic benefit for the reaction pathways involving complexation and when the equilibria between complexed and uncomplexed species are not favorable. Because substrates bearing more than one basic site can interact in different ways with Lewis acid, the formation of more than one complex in such processes should be taken into consideration. For example, both monodentate and bidentate complexes can be formed with the same substrate, which leads to the assumption that three pathways could be found competing in the same reaction (Scheme 1): (1) the

OR2 0 Ri+OMe

(X = Br)

N 2 : 2 r 2 : E t h \ non-chelate

monodentate

Me-' X . 2

MgBr2.0Et2 bidentateR2

bidentate

Ri 3

HSnBu3

1

B

1

1

OR2

OR2

R 1 - f CMe oZMe

R ' - f CMe ozMe

5 anti

5 anti

1 OR2

a

Me

R 1 - f CMe oZMe 5 anti

Scheme 1 . Chelation-controlled radical reduction of substituted a-bromo-P-alkoxy esters [ 31

4.4.2 Cyclic-Cram Model: the Endocyclic Effect

443

non-complexed, (2) the monodentate, and (3) the chelated. Given this assumption, the earlier arguments could then be elaborated upon. Does one of these pathways have a kinetic bias? And if the rate enhancement does not favor the desired pathway, is it possible to force the reaction through that pathway via preorganization of stable complexes? Are the complexes monomeric or polymeric? Little is known about the structure and reactivity of different complexes involving a Lewis acid. Clearly, such knowledge will lead to a better understanding of many chemical reactions. The use of a Cram-chelate intermediate in the presence of bidentate Lewis acid is a powerful approach to imbedding a free radical in a temporary monocyclic or polycyclic ring. Such a cyclic intermediate may react intra- or intermolecularly, depending on the substrate or reagent being used. This is one of the approaches that will be reviewed in this chapter. A second use of Lewis acid is as an enhancer of steric and electronic effects. Another popular approach involves using Lewis acid to immobilize and diminish the rotational freedom of chiral auxiliaries. In this approach, the presence of stereogenic groups on the ring (chiral auxiliaries) favors the attack of one radical face over the other.

4.4.2 Cyclic-Cram Model: the Endocyclic Effect Diastereoselective processes involving Lewis acid in free-radical reactions of acyclic molecules began to be explored in the last decade [ 11. Our group has been particularly interested in the reactivity of radicals flanked by both an ester and a stereogenic center in hydrogen transfer, allylation, and atom or group transfer reactions. These radicals can be obtained via the homolytic cleavage of a halide or phenylselenide. As shown in Scheme 2, hydrogen transfer reactions of cc-iodo-P-alkoxy esters in the absence of Lewis acid give excellent selectivity favoring the unti isomer (>25:1 R’=Ph, R2=Me, X=I) [2]. This stereochemical outcome is best rationalized by transition state A (Scheme l), which takes into account allylic 1,3-strain, dipoledipole repulsion, and hyperconjugative stabilization and results in a bottom-face attack by the tin hydride. Based on the above model, it was hypothesized that bidentate Lewis acid could reverse facial selectivity by promoting the intermediacy of transition state C (Scheme 1). The reduction of the tertiary iodide with Bu3SnH in the presence of MgBrz.OEt2 indeed afforded the syn product with excellent diastereoselectivity (>25:1) and good yield (Scheme 2) [2]. Tertiary bromides gave similar results but required both an initiator and an excess of MgBrz-OEtz [3]. A key feature of these reactions is the formation of a chelate that reduces the conformational space of the radical. We have used the expression ‘endocyclic effect’ to describe the high syn diastereoselectivity achieved when a radical is imbedded in such a temporary ring. The unti iodide, anti bromide, and anti phenylselenide substrates were transformed into their corresponding ally1 derivatives with excellent selectivity and yield when MgBrz-OEtz and allyltributylstannane were present (Scheme 2) [4]. The anti

4.4 Lewis Acid-Mediated Diastereoselective Radical Reactions

444 oMe

-

Bu3SnH, solvent,

OMe 0

Ph+OMe Me X

Ph+OMe T ( "c), MgBr20Et2 Me anti Et3B

X

Solvent

T ( "C)

I

toluene

-78

I

CH2C12 -50

Br

CH2C12

-78

+P

h v O M e Me SYn

: svn

MaBr~oEt:,

Yield

anti

none 0.25equiv

90% 91 %

>25 : 1 1 : >25

5equiv

70%

1

anti

X

R2

Yield

Me

I

H

80%

Me

Br

H

78%

Me

SePh

H

90%

Me

I

Me

76%

TBS

I

H

90%

Me

H

I

69%

R'

OMe 0

:

28

121 121 [31

: syn

38

:

19

:

1 1 65 : 1 >I00 : 1 1 : 8 5 : I

Scheme 2. Chelation-controlled radical reduction and allylation of cc-halo- and a-phenylseleno-Palkoxy esters

isomer was formed preferentially from these substrates in ratios of 38:1, 19:1, and 65:1, respectively. Under the same conditions, the tertiary iodide gave a > 100:1 ratio in favor of the anti product. Since asymmetric quaternary centers are difficult to form, these reactions clearly have interesting synthetic utility. The presence of the bidentate chelate in allylation reactions was supported by I3CNMR studies with the anti halide and phenylselenide substrates in the presence of MgBr2-OEt2 [5]. The introduction of a bulky protecting group such as tertbutyldimethylsilyl ether (TBS) on the hydroxyl function led to the syn allylated product (Scheme 2) [4]and was thus shown to prevent chelation of the bidentate Lewis acid in favor of monodentate complex formation. I3C NMR studies with TBS ether in the presence of MgBrz-OEtz validated this finding [ 5 ] . The possibility of monodentate species complicates the analysis of chelationcontrolled radical reactions. Monodentate complexation leads to transition states such as B (Scheme 1) that, in terms of stereoselectivity, behave similarly to uncomplexed radicals. Lewis acid complexation with the ester function has the potential to lower the energy of the transition state, particularly when the incoming reagent is electrophilic (e.g. allyltrimethylsilane), thus enhancing the reactivity of such radicals relative to uncomplexed species. Because radical reactions can occur

4.4.2 Cyclic-Cram Model: the Endocyclic Effect

445

more rapidly than complexation equilibria, the presence of monodentate species in such reactions cannot be ignored. Remaining to be determined is whether or not the monodentate and bidentate species participate competitively in the establishment of the final product distribution resulting from radical reactions. Competition experiments have shed light on the relative rates of the monodentate and bidentate pathways in reactions involving different reagents. The OTBS derivative is a valuable substrate in such experiments because it reacts in only the monodentate complex form. By contrast, the OMe derivative can theoretically react as both monodentate and bidentate complexes in the presence of Lewis acid, although 13C NMR analysis has indicated a preference for the bidentate chelate in the preorganized complex with this substrate. In allylation reactions of secondary iodide substrates, silyloxy and methoxy derivatives reacted with comparable speed [ 6 ] ,suggesting that the monodentate and bidentate complexes had reacted at similar rates. Conversely, within the tertiary bromide series, the silyloxy substrate reacted eight times faster than the methoxy derivative in hydrogen transfer reactions [ 3 ] . This result suggested that the monodentate complex had reacted faster than the bidentate. However, the consistent attacks that occurred on the same face of the radical in the allylation and reduction reactions implied that the bidentate complex formations had been stable and the exchange rates between the mono- and bidentate species had been slow. Normally, the configuration of a halide precursor has no impact on the outcome of a free-radical reaction, but ratios for chelation-controlled allylations varied significantly depending upon the stereochemistry of the iodides (precursors to the same radical) (Scheme 2) [4].Not only did the syn iodide give the lower ratio, but it also gave the smaller chemical shift of the carbonyl signal in the presence of MgBrz'OEtz, as compared to the anti iodide (4.8versus 7.5 ppm) [ 5 ] . These results indicate that the syn iodide forms a less stable bidentate chelate, presumably because of steric interactions, and that the monodentate species originating from the syn iodide participates competitively in the establishment of the final product distribution. Scheme 3 shows the effect of Lewis acid on atom transfer reactions. Since Lewis acid complexation can increase the electron-withdrawing nature of a group involved in a complex, it should also increase the rate of addition of alkenes onto a-carbonyl radicals. Both our group [7] and Porter's group [8] have improved the scope of

+

P h T 0 O M CHzCIz, e Ph+OMe OMe -78"C,. Et3B l ~

h

q

i

M

e

3 % O M e I:p

/

x

CHzCIz, -78"C, MgBr2.OEt X = I, Br, PhSe

2

l

k

MgBrz.OEt2 (equiv) none, X = I MgBr2,OEtz (1)

1 yield, % 39 67-87

anti : SYn

1

.

'42

Scheme 3. Chelation-controlled atom transfer free-radical addition [7]

5 1

446

4.4 Lewis Acid-Mediated Diastereoselective Radical Reactions

atom transfer reactions by exploiting this hypothesis (see below). The addition of MgBr2.0Etz was shown to greatly improve the yield of reactions with allyltrimethylsilane and a-halo or phenylseleno substrates [ 71. In these reactions, the presence of the chelate accounted for the high anti diastereoselectivity achieved and was also found to improve the overall rate and yield of the process. Porter’s results for atom transfer addition reactions will be presented and discussed later on in this chapter. Several research groups have shown how the endocyclic effect can be capitalized upon to increase diastereoselectivity in bidentate complexes. Nagano and his collaborators found that the allylation of diethyl-2-bromo-3-(tert-butyldimethylsiloxy)succinate was nonselective in the absence of Lewis acid (Scheme 4) [9]. However, a good level of stereocontrol favoring the syn product was achieved when the substrate was allylated in the presence of 1.1 equivalents of La(fod)3. To account for the stereochemical outcome, this group proposed transition state E involving a 7-membered ring formed by chelation with the two ester functions, A tertbutyldimethylsilyl group on the hydroxyl function was employed to disfavor the formation of a 5- or 6-membered ring chelate. Renaud et al. reported highly stereoselective radical allylations of /3-hydroxyesters (Scheme 4) [ 101. An excellent level of diastereoselectivity was achieved with ethyl-3hydroxy-2-phenylselenylbutyratein the presence of 1.1 equivalents of AlMe3. Transition state F, involving a 6-membered ring chelate, was proposed to explain the anti selectivity. A low ratio was obtained for this substrate in the absence of AlMe3. The same group showed that a similar strategy can be used in an intramolecular sense leading to cyclopentene derivatives (Scheme 4) 1111. In the absence of Lewis acid, the reaction gave the desired cyclized products in good yield but with low stereoselectivity. A slight preference for the trans isomer was observed independently from the synlanti stereochemistry of the radical precursor. In this series, treating the /3-hydroxyesters with 1.1 equivalents of MeAl(0Ph)z (methylaluminium diphenoxide) gave better results. The yield of cyclization was over 70%, and the reaction was highly cis selective. Trialkoxyaluminum chelate G (Scheme 4) was suggested to rationalize this result. Renaud’s group also designed two model systems for studying the effect of Lewis acid on the stereoselectivity of 1,2-dioxy radical-mediated reactions. In the first model, a 1,5-hydrogen atom abstraction reaction was successful in generating the desired alkoxy substituted radical (Scheme 5) [12]. Like and unlike products were obtained in the same quantity in the absence of Lewis acid. The presence of Lewis acid was shown to be essential for achieving selectivity. Chelated alkoxyaluminum transition state H accounted for the excellent ratio of 20: 1 in favor of the chelationcontrolled isomer (like) achieved with Et2A1C1/Na2CO3 [ 131. The formation of the unlike diastereoisomer was best explained by a Felkin-Ahn-type transition state 1141. In the second model, the 1,2-dioxy radical was generated from vinylcyclopropane using the highly efficient ring opening reaction of cyclopropylmethyl radicals [ 151. High diastereoselectivity was achieved only when the tandem ring opening and reduction substrates were pre-treated with 1.1 equivalents of Me3Al (Scheme 5) [ 161. The formation of the major like product was best rationalized by an ‘anti Cram

4.4.2 Cyclic-Cram Model: the Endocyclic EfSect OTBS

+SnBu3

Et0zCyCozE~H2r&,

OTBS

AIBN', j v EtOzC%

T ( "C), L a ( f ~ d ) ~

Br

t

C02Et

447

OTBS +E

-*

t O z C T E t

SYn

anti

191 La(fod)3 none 1.1 equiv

OEt

OH Me?C0zEt

+SnBu3 P AIBN, hv CH2C12,

OH Me+C02Et

+

-*

10 "C, AIMe3

SePh

t

syn : anti

T ( "C) Yield reflux 57% 3 63%

1.1 : 1 11 : 1

M

SYn

OH e T

E

t

anti

[I 01 Yield AIMe3 98% none 1.1 equiv 97%

OH

anti : syn 1.7 : 1 20 : 1

OH 0

Bu3SnH

OH

0

P

CHzC12, AIBN, hv 10 "C, MeAI(OPh)z

t

OPh

G

trans

[I 11

(Chelation Control)

MeAI(0Ph)Z (equiv) none MeAI(0Ph)z (1.1)

yield, % cis : trans

90 70-72

1 49

. :

2 1

Scheme 4. Chelation-controlled radical allylation and cyclization of P-hydroxyesters: the endocyclic effect

cyclic model', which accounted for the tin hydride attack coming from the more crowded face syn to the tert-butyl group (transition state I ) . Also accounted for was the critical steric interaction between the two vicinal alkyl groups as well as the importance of the pyramidalization of the radical center. Another class of chelation-controlled reactions involves SmI2, which has been used to mediate inter- and intramolecular ketone-olefin couplings [ 171. Matsuda and collaborators showed that coupling erytlzro-P-hydroxyketone with acrylonitrile led exclusively to the anti diol under SmI2 reductive conditions [ 181. Chelation control model J in Scheme 6 was proposed to account for the sense of diastereoselectivity. In this model, chelation of the Smlz to both the P-hydroxy and the

448

4.4 Lewis Acid-Mediated Diastereoselectiue Radical Reactions

Lewis acid, C6H6 t

1

OMe like (Chelation Control)

1' 7t

r

0' Et q o : A I C Me E t BusSnH

Lewis acid (equiv) none EtZAICI, Na2C03(1.1)

OMe unlike (Felkin-Anh) like : unlike

H-transfer (yield, %) 36 (75) 13(83)

>1 OH

[I 21

1

:

l

20

:

1

OH

K O P M P 1) AIMe3, BusSnD, CH2C12 AIBN, hv tBu L O P M P + tBu+OPMP tBU 2)TFA unlike T like t Bu (Chelation Control) Me BusSnH-,. like : unlike AIMe3 (equiv) yield, % Al: opMpMe none 87 1 : l AIMe3 (1.1) 77 >20 : 1 Bu3Sn I ~

f!-L./

9

J,-~'

Scheme 5. Chelation-controlled reduction of 1,2-dioxy-substituted radicals

t

Ph> O H ] -

Ph%o

OH Me

Me*C02Me t

P

h

A

s

M 0

e

Et02C /

0

e Srnlz, MeOH THF. 0 ° C 74% yield

0 O E

t

Me

HO-Smlll

Me

K Me&C02Me

:'::,

~

99 : 1

t ~

[

88% yield Srn"'

~

-

~Me, HO u . . "o C02Et "e

I""'

C02Et 200 : 1

Scheme 6. Chelation-controlled radical reactions of ketones with samarium iodide

E

]

4.4.2 Cyclic-Cram Model: the Endocyclic Eflect

449

carbonyl groups, followed by the transfer of a single electron from the samarium to the carbonyl, resulted in a 6-membered cyclic ketyl radical. The approach of the acrylonitrile in the chelated transition state, having occurred opposite to the axial methyl group, had led to the observed anti diol. Another example presented by this group involved the reduction of (f )-3hydroxy-5-phenyl-2-pentanonewith SmI2 in the presence of ethyl crotonate to afford syn-y-lactone in excellent yield and diastereoselectivity at three contiguous stereocenters (Scheme 6) [19, 201. Cram cyclic model K was used to explain the selectivity in the formation of the first new stereogenic center. Subsequent coordination of the ethyl crotonate ester group to the Sm"' was responsible for the facial selectivity during the formation of the second center [20]. Molander et al. reported an intramolecular version of the above reductive coupling reaction promoted by SmI2 (Scheme 6) [21]. In this study, cyclization of ethyl 6-carbethoxy-6-methyl-7-oxo-2-octenoate in the presence of SmI2 gave polysubstituted cyclopentane derivatives as a 200: 1 mixture of diastereoisomers. The group proposed that the Sm"' chelation had produced a cyclic ketyl intermediate, which had then cyclized irreversibly to the olefin [22] via a chair-like transition state [23] such as in L (Scheme 6). Few examples of chelation-controlled allylation reactions involving bicyclic chelates can be found in literature. Nagano and Azuma have shown that the allylation of a dialkoxy-substituted radical adjacent to a dimethyl acetal proceeds, in the presence of MgBrz-OEtz (2.5 equivalents), with excellent stereocontrol independent of the synlanti stereochemistry of the radical precursor (Scheme 7) [24]. To best explain the high anti ratio obtained, they proposed bicyclic transition state M in which the allylstannane attacks from the side of the pyramidalized radical chelate. Surprisingly, when the same reaction was conducted at a lower temperature (0 "C), poor selectivity was observed. No explanation was proposed to account for this decrease. It should be noted that the allylation gave no selectivity in the absence of Lewis acid. Our group performed a similar allylation study with a-iodo esters bearing a tetrahydrofuran (THF) or a tetrahydropyran (THP) ring adjacent to the radical [5].The results indicated a low anti preference in the reaction of the THF substrate in the presence of MgBr2.OEtz (3 equivalents). In contrast, substrates bearing a THP ring gave excellent diastereoselectivity under chelation controlled conditions (Scheme 7). The bicyclic intermediate chelate with two 6-membered rings was clearly more efficient than the bicyclic intermediate with 5- and 6-membered rings in inducing anti diastereoselectivity. A potential rationale for the difference in selectivity between the THF and T H P substrates is illustrated in Scheme 7. For the T H F compound, the bicyclic intermediate formation may have been impaired by the development of eclipsing interactions between the C - 0 bond and a Mg-Br bond in the cis bicyclo complex. An additional eclipsing interaction was postulated to have taken place between the C-I and Mg-Br (or Mg-OEt2) bonds when the geometry of the magnesium was either square pyramidal or trigonal bipyramidal. Such interaction implied that the preexisting mixture could have contained monodentate complexes or uncomplexed substrates. In support of this argument was the observation that less than one

450

4.4 Lewis Acid-Mediated Diastereoselectiue Radical Reactions

$0

+SnBu3

e like

MgBrZ.OEt2, T ( "C)

OMe

+ M -e'

hv O-OMe

CHzC12, Ae l ;, Br

$0

OMe

/

unlike

(Chelation Control) MgBrp.OEt2 (equiv) T ( "C) 25 MgBr2.0Et2 (2.5) 25 (2.5) 0

n 1

yield, % anti : syn 91 5 : l

2

84

A -

'Mg;-0

/ i Br

18

:

1

-

MgBrz.OEt:

'OEtl

OMe

yield, % like : unlike 52 1 : 1.1 70 52 : 1 nd 4.2 : 1

OMe

I

Scheme 7. Chelation-controlled allylation: bicyclic chelates

equivalent (0.88 equivalent, as opposed to 0.3 equivalent without the substrate) of Mg" was found in the allylation reaction mixture [ 5 ] . By contrast, less steric interaction appeared in the bicyclic complex with the THP substrate. Pre-equilibration seems to have favored the formation of a chelated intermediate, a conclusion that was supported by the high level of selectivity obtained in this series and by the amount of Mg" (1.85 equivalents) found in solution [ 5 ] . With the exception of the chelation-controlled reduction of the 1,2-dioxysubstituted radical (Scheme 5) and the radical reactions of ketones with SmI2, most of the radicals illustrated so far were generated from the homolytic cleavage of a carbon-halide or carbon-selenide bond. Radicals can also be generated by other chemical means, such as by the addition of radicals to an a$-unsaturated ester as Sat0 and Nagano have shown (Scheme 8).

4.4.2 Cyclic-Cram Model: the Endocyclic EfSect

45 1

t OH

1) Et2AICI toluene, -78

HSnBu3 [Buw;AIEt]-

':

E t T c 0 2 t B u 2 ) Bu3SnH, Et3B Bul 79 % yield

N

Et

E

yield, (%)

syn : anti

31 79

2.3 7

HSnBu3 OMe

I)BusSnH, Et3B iprl * 2) La(fod), CH2C1210 "C 90 % yield

Br

-0

(fad)] phTco2 [261

do~t Me

iPr syn : anti

0

Bu3SnH, Et3B CH2CI2, 0 "C

1 l

1'

phyC02Me

\

: :

OMe

Pri Pht,..' L

OMe

~ 5 1

Bu

OtBu

Lewis acid (equiv) none Et2AICI (1.1)

P h ~ C 0 2 E t

OH t TC02tBu

Bu3SnH

11 : 1

'

OMe

[31 +

syn : anti 6 : l

Scheme 8. Chelation-controlled radical addition reactions

Sat0 determined that the use of Lewis acid was advantageous for tandem radical addition/reduction reactions in terms of both yield and selectivity [25].As shown in Scheme 8, Lewis acid promoted the addition of the butyl radical to the a,Punsaturated ester, which in turn led to the formation of chelated transition state N. The improved selectivity was likely the result of a tighter complexation between the hydroxyl and carbonyl functions of the substrate and the aluminum atom. Nagano and collaborators used the same strategy with y-methoxy-a-methylenecarboxylic esters [26]. The use of La(fod)3 delivered a very good ratio of anti isomer in that reaction involving 1,3-asymmetric induction and a 7-membered cyclic transition state, illustrated by 0 in Scheme 8. To support the intermediacy of free radicals in chelation-controlled reactions, our group compared the level of diastereoselectivity in tandem radical addition/ reduction reactions with that of reactions involving the homolytic cleavage of a halide (Scheme 8) [3]. The stereochemical outcome in this series was the same regardless of the manner in which the radical was generated. Other examples involving tandem intra- or intermolecular addition/reduction reactions will be presented and discussed later in this chapter.

452

4.4 Lewis Acid-Mediated Diastereoselective Radical Reactions

4.4.3 Lewis Acid: Steric and Electronic Enhancements The diastereoselectivity of kinetically-controlled reactions is dictated by the difference in energy between transition states. In some reactions, the formation of one diastereoisomer is disfavored because the orientation of a large proximal group impedes the approach of the reagent to the radical, thus increasing the energy of the transition state. Increasing the size of the proximal group, via a temporary complexation with Lewis acid, can further increase the difference in energy between transition states by making the attack even more difficult. Of course, the electronwithdrawing effect of the Lewis acid also increases the electrophilicity of the functionality to which the Lewis acid is being complexed. Renaud and Curran demonstrated the validity of this approach. They reported that the very bulky and oxophilic methylaluminum diphenoxide (MABR) [27] was quite compatible with allylation reactions involving cyclic a-sulfinyl radicals and provided an exceptional level of stereocontrol when used stoichiometrically (Scheme 9) [28]. The simple model (Q) proposed to account for the enhancement of stereoselectivity in the presence of Lewis acid was based on a steric effect. The allylation reaction proceeded with poor selectivity when conducted in the absence of MABR. Sat0 et al. used the above strategy to reverse facial selection during radical addition to a-methylenebutyrolactones [29]. In the absence of Lewis acid, the y-substituted lactone was butylated and reduced with BuI and Bu3SnH, respectively, to give a cisa,y-disubstituted lactone in high selectivity (Scheme 9). The presence of the bulky methylaluminum diphenoxide ((TMP0)2AlCl)reversed the cis selectivity to give the trans isomer as the major product. In this complexation, the approach of the tin hydride reagent was impeded on the bottom face of the lactone as seen in transition state R, and the delivery of the hydrogen radical occurred on the face bearing the lactone substituent. Lewis acid complexation also improved noticeably the yield of this reaction. Another example of this strategy involved the deuteration of an a-oxy-substituted benzylic radical [30], wherein the remarkable shielding effect of the aluminum diphenoxide group (MAD) was responsible for the high selectivity observed (Scheme 9). In the transition state proposed (S), the radical adopts a conformation that minimizes allylic 1,3-strain. Recently, we showed that the facial discrimination of a radical could be enhanced significantly by linking together substituents of the stereogenic center responsible for the induction of diastereoselectivity [3I]. While the hydrogen transfer reaction of the acyclic substrate gave little diastereoselectivity (Scheme lo), the tetrahydrofuran derivative gave a 12:l ratio favoring the anti product. Embedding the methoxy and ethyl groups in a ring presumably forced the rotation of the hydrogen toward the top face of the radical, which prevented the Bu3SnH attack from occurring on that face. Syn product formation was thus reduced. We have used the term ‘exocyclic effect’ to describe the impact of such a cycle a to a radical. The result obtained for the T H F substrate inspired us to design strategies implicating the formation of cyclic derivatives. Of particular interest were compounds

4.4.3 Lewis Acid: Steric and Electronic Enhancements

ArO,

453

,OAr

9'

MABR (equiv) yield, % trans : cis none 63 4.6 : 1 MABR(l.l) 57 70 : 1 Ar = 4-bromo-2,6-di-fert-butylphenyl

?

I z L S n B u !

0

Bul, Bu3SnH, Et3B (TMP0)2AICI * toluene, -50 "C Pti:

OA""'\BU

~

B

U [29]

p ~ . ' trans

CiS

pn.5-

O

+

$

: trans : I : 1.5

(TMP0)zAICI (equiv) yield, % cis none 44 9 (TMP0)2AICI (1.1) 90 1 TMP = 2,4,64rimethylphenyl

" SePh

r

1

~

~

~

*"

~

2) BzCI, pyridine 4-DMAP DSnBu3

,

~ D

+

~

?

unlike

, D

o

o

[30] c

~

like

1' MAD (equiv) none MAD (1.1)

0 (Ar0)2Al' S

~

1

yield, % unlike : like 75 1.4 : 1 75 13 : 1

Ar = 2,6-di(tert-butyl)-4-rnethylphenyl

Scheme 9. Lewis acid as a steric enhancer

possessing an additional heteroatom in an CI o r p position to a first heteroatom responsible for the transfer of stereogenic information. Based on the use of benzylidene and isopropylidene protecting groups [ 321, these strategies were very successful but imposed additional steps of protection and purification prior to the hydrogen transfer reaction, as well as subsequent deprotection. In situ derivatization of p-amino alcohols was consequently employed to minimize the number of steps required in the above strategy [ 3 3 ] .Scheme 10 shows that the addition of MezBBr was effective both in creating an in situ boronate cycle with the amino alcohol prior to the hydrogen transfer reaction and in increasing conse-

454

4.4 Lewis Acid-Mediated Diastereoselective Radical Reactions \0

W

O

\O

0 E

Me I

tB

'

~ +OEt~

89 % yield

\o

0

+

~

~

0

d ~O

anti : syn

Me

1.5

:

Me I

OEt

Me

Ph

0

M~ Seph

Ph

toluene

W

-78 "C,EW 73% yield

Me

:

B

u

Me

-

Boc,

1) MezBBr, iPr2NEt B o c N ~ . B \ O

oMet SePh B u 2) CH2C12, Et3B, 0°CBu3SnH

0 t

1

\ /

-

O

anti : syn 40

Boc, NH OH 0

Me

1

OAO

w O t B ; u 3 S n H .

w

:

Ph

OAO

OEt

.

anti : syn 12

t"

1

qoEt Bu3SnH, toluene -30 OC,Et$ 90 % yield

~E Me

NH OH 0 W

) c r O t B u

O

Me exocyclic radical MezBBr none 1.1 equiv

Boc,

NH OH 0

MgBr2.OEt2

BOC,

)crofBu Mk SePh

CHZCI2, Et3B,Bu3SnH 0°C * 57% yield

''P

,Mg" NH OH W

O

t

B

Me endocyclic radical

f

B

u

[331

Me

88% 90%

-

Boc,

u

anti : syn 1.4 : 1 24 : 1

Yield

NH OH 0 W

O

t

B

u

[331

Me anti : syn 1 : 24

Scheme 10. The exocyclic effect: Lewis acid complexation to enhance stereoselectivity

quently the diastereoselectivity in favor of the anti product. By contrast, the use of MgBr2.OEt2 favored the formation of a bidentate complex with the ester and led to the syn product via the endocyclic effect [33]. These results demonstrated that the end product could be pre-determined with a judicious choice of Lewis acid.

4.4.4 Lewis Acids and Chiral Auxiliaries

455

4.4.4 Lewis Acids and Chiral Auxiliaries Numerous research groups have shown that chiral auxiliaries can be used in freeradical reactions for the generation of new stereogenic centers [34]. Sibi and Yamamoto have used oxazolidinone chiral auxiliaries in the presence of bidentate Lewis acid to create bicyclic intermediates and control the outcome of reactions (Scheme 11). In the latter example, chelation with Lewis acid (ZnC12-OEt2 [35] and MgBrz-OEtz [36]) was done to lock the two carbonyls present on the molecule into a cis-oid conformation and to force the alkyl group on the planar radical to

P i

Pti MgBr2.0Et2(equiv) yield, % S : R 93 1 :1.8 MgBr2.0Et2(2) 94 >loo: 1

/-

u 0

MeLp../SnBu3

0

0

A N b

0

1

u,

Etl, &SnBu3t CH2C12, Et3B, -78 "C MgBr2.0Et2

0

OAN%t

u

k P h Ph MgBr2.OEtz (equiv) yield, % S : none 90 1 : MgBrZ.OEtz(2) 93 >loo:

;-'Ph Ph

R I 1

Scheme 11. Acyclic stereocontrol in radical reactions: Lewis acid and chiral auxiliaries

456

4.4 Lewis Acid-Mediated Diastereoselective Radical Reactions Bn

1 .O equiv Sc(OTf)3 *&N%

Br

' 0&

[8]

R : S = 11.5:l

Scheme 12. Lewis acid and chiral auxiliary oxazolidinones. Atom transfer radical addition and radical polymerization reactions

be oriented as transition states T and U of Scheme 11 indicate. Intramolecular steric interaction was thus minimized. Allylstannane addition took place from the face opposite the bulky oxazolidinone substituent, and products were obtained with good to excellent levels of stereocontrol considering their conformationally restricted nature. The allylation reactions were not selective in the absence of Lewis acid because of the presence of trans-oid conformations and the conformational flexibility of the radical center. A similar approach was used for the tandem radical addition/allylation of N-propenoyloxazolidinone [ 371. This reaction proceeded with a high level of diastereoselectivity in the Lewis acid-mediated process (Scheme 11). Porter and Mero showed that stereochemical control in atom transfer addition can also be obtained by the use of chiral benzyl oxazolidinone with 1-hexene in the presence of Lewis acid [8]. Excellent diastereoselective control was achieved in the presence of Sc(OTf)3, and the expected R configuration was observed as the major product formed (Scheme 12). One important application of Lewis acid to asymmetric radical reactions is in the control of tacticity in free radical polymerizations. Recently, Porter [ 381 showed that Sc(0Tf )3 modulates the polymerization of oxazolidinone acrylamides to produce highly isotactic copolymers (Scheme 12). The same study described homopolymerizations in which the mlr dyad ratio was dependent on the reaction temperature. 8-Phenylmenthylalcohol has been widely employed as a chiral auxiliary in diastereoselective reactions [ 391. Essential to achieving good diastereoselectivity in radical additions are proper rotamer distributions with respect to the O=C-C=C bond and successful shielding of the alkene n-face. The conformation of the acrylate in this scenario exists as an equilibrium mixture of s-cis and s-trans isomers [40]. Reports indicate that the acrylate can be fixed in the s-trans conformation in the presence of Lewis acid [41]. The addition of BF3.OEt2 was shown to promote 1,4-addition of the stannyl radical through an s-trans conformation, giving the optically active (R)-P-stannyl

4.4.4 Lewis Acids and Chirul Auxiliaries 0

toluene, Bu3SnH

457

Bu 3Sn

R 1 4 O R 2

QoR2

R' ( R )

BF3.OEt2

R' R2 T("C) BF3.OEt2(equiv) yield, % R : S CH2=CHCHzCH2 Me 0 none 0 - . PhCH2CH2 (-)-8-PhMen -25 BF3.0Et2 (4) 78 19 : 1

s-cis

s-trans Re

+

I U

O

P

h

M

e

Et3B, -78 "C toluene, BusSnH n

MAD(equiv) none MAD (1.8)

~ o R , C F 3 C HMYb(OTf)3,HzO z~ (OO AHC ,TCC) ) ~2O .~H

(R) COsPhMen

yield, % R : S 92 2 : I 79 24 : 1

OR'q

>80'%) it does appear that termination increases, as indicated by an increase in dead chains, but this is a qualitative observation and needs to be studied in more detail. In the case of the nitroxide-mediated polymerization some of the termination may be caused by the nitroxide itself [ 5 ] . Under appropriate conditions, typically elevated temperatures, the dormant species reacts to generate a propagating radical chain and the species T. The reversible terminating species T then competes with monomer to add to the propagating chain. Narrow polydispersity resins are obtained when the equilibrium between the active and dormant chains is fast. The persistent radical effect ensures that a steady concentration of active radicals exist to enable the polymerization to proceed at an acceptable rate [6]. The work of Braun was followed by that of Otsu et al., [7] who in 1982 introduced the use of iniferters (initiator-transfer agent-terminator) to control radical polymerizations. Using tetraethylthiuram disulfide to generate dithiocarbamate radicals as reversible terminating agents, Otsu and his group were able to show for the first time that free-radical propagating polymer chains could be made to grow in a linear fashion with time. This behavior, readily evident in the case of the anionic polymerization process, had now been demonstrated to be possible in a free-radical polymerization system. Limitations to the use of iniferters to define a truly livingradical polymerization system were reported by Turner [8], Tardi [9] and Otsu [lo]. In 1984, Rizzardo and Solomon [ I l l demonstrated that acrylate and methacrylate oligomers could be prepared by the reversible addition of nitroxides to propagating radical chains. Yields were low, but the demonstration that nitroxides could react in a reversible manner with a free-radical propagating chain was important. In 1993, Georges and his group at Xerox opened up the field of living radical polymerization by demonstrating that polystyrene, in the presence of the nitroxide TEMPO, could be prepared in high yield with polydispersities (1.25) narrower than what was considered theoretically possible at the time [ 121. The critical decision in the success of this work was to start with styrene as the monomer, as

5.1.3 Stable Free-Radical Polymerization ( S F R P ) Process

48 1

opposed to acrylates or methacrylates, which would probably have led to failure. The feasibility of a living-radical polymerization process was demonstrated. Four major systems now exist for performing living-radical polymerizations; IP, iniferter polymerization [ 131, SFRP, stable free-radical polymerization, ATRP, atom transfer radical polymerization and RAFT, reversible addition fragmentation chain transfer polymerization. The reversible capping reagents in the four systems are thiocarbamates, nitroxides, halogen/metal complexes and (thiocarbony1)sulfanyl compounds, respectively. All four processes can be applied to a wide range of monomers and produce homopolymers as well as, random, gradient and block copolymers, to different degrees of purity. The focus in the remainder of the chapter will be on SFRP, ATRP and RAFT.

5.1.3 Stable Free-Radical Polymerization (SFRP) Process The chemistry for the SFRP process is illustrated in Scheme 1, where T is a stable nitroxide. Most of the earliest work focussed on TEMPO, a commercially available nitroxide. Polymerizations are typically performed at temperatures between 1 15 "C and 135 "C under a blanket of an inert gas. They can be initiated with any number of azo ( e g , 2,2'-azobisisobutyronitrile,AIBN) and peroxy (e.g., benzyl peroxide, BPO) initiators [12], as well as alkoxyamines [11, 141. Initial reactions for styrene were slow, typically taking about 70 h to go to 85% conversions. The polymerization could be sped up significantly by the addition of reagents such as camphorsulfonic acid, CSA [ 151, or 2-fluoro- 1-methylpyridinium p-toluenesulfonate, FMPTS [ 161. A series of electron spin resonance experiments showed that increases in the rates of polymerization are directly correlated with decreases in free nitroxide levels, and free nitroxide levels decrease with increases in either CSA or FMPTS. This led to the conclusion that the rate of polymerization is controlled by the free nitroxide level in the reaction mixture. Any process that decreases the nitroxide levels will lead to an increase in rates of polymerization. Thus, in the case of styrene, autopolymerization plays an important role in enabling the polymerization to proceed by providing free radicals that consume some of the excess nitroxide that is generated as a result of a small amount of premature termination. This interpretation is in contrast to another in which the rate of polymerization is believed to be dominated by thermal initiation [ 171. A thorough kinetic analysis and a lively debate concerning these positions have been presented [18, 191. Monomers that cannot be polymerized by other conventional living-radical polymerization methods can be polymerized by the SFRP process. Examples include chloromethylstyrene and water-soluble monomers such as p-toluenesulfonate, sodium salt. While most of the earlier work in the SFRP process was performed under bulk conditions, some solution polymerizations, as well as dispersion polymerizations [20] have been performed. Recent focus has shifted to the more commercially compatible emulsion and mini-emulsion processes with good success [211. While styrene and its derivatives polymerized very well under SFRP conditions, acrylate polymerizations proved to be a problem. Although styrene/acrylate ran-

482

5.1 Living-Radical Polymerizations, an Overview

dom copolymers, with up to 50% acrylate, could easily be prepared, as the amount of acrylate increased above that amount the polymerization became increasingly sluggish. Homopolymerization of acrylates typically went to 5%- 10% conversions and then stopped. The problem was eventually traced to the fact that since acrylates do not exhibit the same amount of autopolymerization as styrene there is no mechanism to get rid of the free nitroxide that slowly builds up due to the small amount of termination inherent in these polymerizations. The free nitroxide level eventually builds up to the point where it inhibits the polymerization [22]. Interestingly, reagents such as CSA and FMPTS, so effective at increasing the rate of polymerization of styrene, were ineffective with acrylates. However, two solutions to the problem have been found. One solution makes uses of enediols, which react with the excess free nitroxide to give the corresponding hydroxyamine [23]. The second makes use of acyclic a-hydrogen-bearing nitroxides that appear to have just the right amount of instability associated with them to allow the free nitroxide concentrations to be maintained at levels that allow the polymerization to proceed ~41. Further expanding the list of monomers that can be polymerized by the SFRP process, the polymerization of 1,3-dienes has been reported in the synthesis of block copolymers [25]and, more recently, homopolymers [26]. Reported limitations of the SFRP process include the high temperatures required to enable the polymerization to proceed at reasonable rates and the limited range of monomers that can be used. As outlined above, this latter concern has been addressed and should no longer be considered an issue. Using this new synthetic polymerization tool, different classes of materials, previously inaccessible by a free-radical polymerization process have been reported. These materials include block copolymers [27] as well as hyperbranched and dendritic [28] structures.

5.1.4 Atom Transfer Radical Polymerization (ATRP) Process Scheme 2 illustrates the chemistry of the ATRP process. The mechanism, illustrated with copper as the metal, involves a metal halide/ ligand complex [Cu(l)XL,] that undergoes a one-electron oxidation with an alkyl halide (RX) to form a radical species (R)that can add monomer. The radical species is an initiator radical at the beginning of the polymerization and subsequently becomes the active polymer chain (P,l'). The initial metal halide/ligand complex adds a halide atom to give a higher oxidation state metal halide/ligand complex [XCu(2)X2Ly],which at any time can react in the reverse manner to terminate the propagating chain with a halide atom. The first example of this type of living-radical polymerization was reported by Sawamoto, who used a ruthenium metal complex in association with methylaluminum bis(2,6-di-tert-butylphenoxide), as an accelerator, to polymerize methyl

5.1.4 Atom Transfer Radical Polymerization ( A T R P ) Process RX +Cu(l)XLY

P"X

+ CU(l)XLy

-

-

R*

+

483

CU(II)X~L~

IM P,

+

CU(II)X2LY

c3 M

Scheme 2. The ATRP process

methacrylate 1291. Sawamoto referred to the polymerization as a transition metalcatalyzed polymerization. The polymerizations were typically performed at 80 "C but the reaction times were long, in the order of 60 to 80 h. Further improvements to this system have been made, in particular, extending it to other monomers [30]. This result was quickly followed by a similar polymerization also based on the Kharasch addition reaction [311. Referred to as atom transfer radical polymerization, ATRP, the polymerization involved the use of Cu complexes with various nitrogen-based bidentate ligands [ 321. Typical ATRP polymerizations are performed in the bulk at temperatures between 90 "C and 130 "C, although good results are also obtained in non-polar solvents. Some oxygen is tolerated in this system [33]. The nature of the bidentate ligand can have a dramatic effect on the outcome of the polymerization. Thus, a more electron-donating ligand will increase the rate of polymerization while polydispersity tends to increase with less soluble metal/ligand complexes. Increasing the length of the aliphatic chain on the ligand increases the solubility of the metal complex [34]. The ATRP polymerization appears to be sensitive to acids in that they tend to deactivate the metallo-organic catalyst. A recent study has shown that small amounts of acid, such as benzoic acid, tend to speed up the polymerization, but higher levels poison the catalyst [35].Other metals that can be used are Ni 1361, Fe [37] and Pd 1381. Percec et al. reported a modified version of the ATRP polymerization in which sulfonyl chlorides are used as initiators in combination with either ruthenium or copper complexes [39]. A comprehensive review of the ATRP process, up to 1998, has been recently published 1401. Some of the limitations of the ATRP system, such as the use of toxic halide species as initiators and the sensitivity of the metal halides to air and/or moisture are being addressed. Jerbme and Teyssie reported on the use of an alternative ATRP process in which a classical initiator, such as AIBN, rather than an alkyl halide, is used in the presence of FeC13 and triphenylphosphine to initiate the ATRP process 1411. This followed work by Matyjaszewski who similarly used AIBN but with CuBrz rather than CuBr 1421. Work has also been reported on the immobilization of the Cu catalyst on various silica and crosslinked polystyrene supports, although more work is required in this area 1431. A comprehensive paper on the role of initiator efficiency and its control in the ATRP process has been published [44].

484

5.I Living-Radical Polymerizations, an Overview

The ATRP process has been successfully used with styrene, acrylate and methacrylate monomers, although each monomer requires a slightly different set of conditions to be successfully polymerized.

5.1.5 Reversible Addition Fragmentation Chain Transfer (RAFT) Process The chemistry for RAFT is illustrated in Scheme 3. The RAFT process is the newest of the living-radical processes and is reported not to have the limitations of the two previously described systems [45]. It is essentially a degenerative transfer process in which a polymer chain (P,'), initiated with an azo or peroxy initiator, reacts with a (thiocarbony1)sulfanyl compound, S=C(Z)-S-R, to release R', an alkyl radical which can go on to initiate another polymer chain. Another propagating chain (Pm') can subsequently react with P,-S-C(Z)=S to release P,' which can go on to add more monomer. This cycle then repeats itself to produce polymer. For the RAFT process to be effective Z must activate the C=S functionality toward radical addition to ensure high transfer constants while R should give a stabilized radical that can still initiate polymerization. RAFT is effective with a wide range of monomers, but distinguishes itself from SFRP and ATRP in that it can polymerize carboxylic acid-containing monomers such as methacrylic acid [46]. The polymerizations are performed at temperatures of 100°C or less with typical polydispersities in the 1.1-1.25 range under either bulk, solution or emulsion conditions. Initially formed homopolymers can readily be chain extended or transformed into block copolymers by reaction with a second monomer [47]. Two concerns with the RAFT process are that the polymers tend to have an odor and often are reddish in color.

s-Pn

S

Pn.

+

R

+

Z

,C,SOR

Monomer

I

===

-

,C,S,R

z .

s-Pn

====

I

z ,GS +

Pm

s-Pn I

Scheme 3. Reaction scheme for RAFT

I

S

R-

5.1.6 Commercial Viability of the Living-Radical Polymerization Processes

485

5.1.6 Commercial Viability of the Living-Radical Polymerization Processes The success of the living-radical polymerization field will be defined on the basis of the commercialization of any of these processes [48]. It is believed that the strength of the living-radical polymerization systems lies in their ability to make polymers of novel architecture, for example, block copolymers. However, very little work has been done to look at the properties of materials prepared by these processes. It remains to be seen whether block copolymers, prepared by living-radical polymerization processes, have any performance advantages over random copolymers prepared by conventional free-radical polymerization. In contrast to anionic polymerization, some termination of the propagating chains is inevitable in all of these living-radical polymerization processes. The ability to maintain livingness is probably the single largest issue with these processes, since their main application will be to prepare specialty materials, such as block copolymers, the purity of which will depend on the degree of livingness of the polymer chains. Unfortunately, at present there is no analytical method readily available to allow a quantitative analysis of the dead chains. Polydispersity, it should be noted, is a poor indicator of the degree of livingness of a polymeric mixture. Narrow polydispersity does not guarantee that all the polymer chains are living, while, on the other hand, broad polydispersity does not necessarily mean that there is a significant amount of dead chains. In addition, at present, there appear to be limitations to the molecular weights that can be obtained while still maintaining livingness. Thus, the synthesis of polymers with molecular weights of about 100 K or less are feasible, but anything above that is questionable. More work needs to be performed in this area to better define the molecular weight limits in each process. Conversion is also an issue in that it is very difficult to go to conversions above 80% in bulk primarily because of the high viscosity of the reaction medium. Miniemulsions can readily be taken to 99.5% conversion, and this has been accomplished in the SFRP and RAFT processes, but it is still an open question as to how living the system is at these high conversions. All systems report the ability to perform the polymerizations in solution, but certainly in the case of SFRP broader polydispersities result, probably due to chain transfer to solvent. The cost of a material is a major factor in any decision to move ahead with commercialization. Any added reagent or extra process step that is required in any of these processes will inevitably add to the cost of the material. In the case of the SFRP process, the cost of the nitroxides is variable from relatively inexpensive (1215 $/kg) for hydroxyTEMP0 to very expensive (hundreds of dollars per kilogram) for custom-synthesized nitroxides. The use of an expensive nitroxide does not preclude the use of SFRP, but restricts it to high-value-added applications. Also, the amount of nitroxide that will be used will vary according to the molecular weight of the polymer that is desired. For the ATRP process, the cost of the ligands associated with the metals can be costly, so judicious choice of ligands will be necessary if the polymer is to be used in

486

5.1 Living-Radical Polymerizations, an Overview

a high-volume application where cost is an important factor. Any process required to remove metal contaminants or an undesired color will add to the cost of the materials and will have to be considered. An added process step to reduce the color or odor of a RAFT-produced polymer may also have to be taken into account. Finally, it should be noted that almost no work has yet been performed on scaling up these polymerizations. While no major issues are anticipated there is still considerable work to be done to transfer these processes from the laboratory to manufacturing readiness.

5.1.7 Conclusions A lot of progress has been made in the area of living-radical polymerization processes in the last 7 years or so, especially with respect to understanding the chemistry and demonstrating how it can be applied to many new and different classes of materials. There are still many questions to be answered and issues to be resolved as highlighted in this article. However, the main thing the living-radical polymerization processes have going for them are the many talented and creative scientists worldwide working in this area. This alone bodes well for the future of these processes.

References and Notes [ I ] The term living-radical polymerizations will be used in this paper to describe the polymerization of interest as opposed to the term controlled polymerization since all polymerization are controlled, even conventional polymerizations. [2] (a) A. Bledski, D. Braun, Makromol. Chem. 1981, 182, 1047. (b) D. Braun, Macromol. Symp. 1996, I l l , 63. [3] For a review on the inevitability of termination in these living-radical polymerization systems see: K. Matyjaszewski, S. Gaynor, D. Greszta, D. Mardare, T. Shigemoto, J. Phy. Org. Chem. 1996, 8, 306. [4] P. A . Clay, R. G. Gilbert, Macromolecules 1995, 28, 552. [ 5 ] (a) A. Gridenev, Macromolecules 1997, 30, 7651. (b) H. Malz, H. Komber, D. Voigt, J. Pionteck, Macromol. Chem. Phys. 1998, 199, 583. [6] (a) H. Fischer, Macromolecules, 1997, 30, 5666. (b) T. Kothe, S. Marque, R. Martschke, M. Popov, H. Fischer, Chem. Soc., Perkin Trans. 1998, 2, 1553. [7] (a) T. Otsu, M. Yoshida, Makromol. Chem., Rapid Commun. 1982, 3, 127. (b) T. Otsu, M. Yoshida, T. Tazaki, Makromol. Chem., Rapid Commun. 1982, 3, 133. (c) For a review see G. Clouet, Rev. Macromol. Chem. Phys 1991, C31, 31 1. [8] R. S. Turner, R. W. Blevins, Macromolecules 1990. 23, 1856. [9] P. Lambrinos, M. Tardi, A. Polton, P. Sigwalt, Eur. Polym. J . 1990, 26, 1125. [ 101 K. Endo, K. Murata, T. Otsu, Macromolecules 1992, 25, 5554. [ 111 (a) D. H. Solomon, E. Rizzardo, P. Cacioli, European Patent 1985, 135280. (b) E. Rizzardo, Chem. Aust. 1987, 54, 32.

References

487

[12] (a) M. K. Georges, R. P. N . Veregin, P. M. Kazmaier, G. K. Hamer, Macromolecules, 1993, 26, 2987. (b) M. K. Georges, R. P. N. Veregin, P. M. Kazmaier, G. K. Hamer, Trends in Polymer Science, 1994, 2, 66. [ 131 A very extensive review on iniferter chemistry has been written. T. Otsu, A. Matsumoto, Ado. Polym. Sci., 1998, 136, 75C. (141 J.Hawker, J. Am. Chem. Soc. 1994,116, 11314. [15] (a) M. K. Georges, R. P. N. Veregin, P. M. Kazmaier, G. K. Hamer, Macromolecules 1994, 27, 7228. (b) R. P. N. Veregin, P. G. Odell, L. M. Michalak, M. K. Georges, Macromolecules 1996,29, 4161. [I61 (a) P. G. Odell, R. P. N. Veregin, L. M. Michalak, D. Brousmiche, M. K. Georges, Macromolecules 1995, 28, 8453. (b) P. G. Odell, R. P. N. Veregin, L. M. Michalak, M . K. Georges, Macromolecules 1997, 30, 2232. [I71 D. A. Shipp, K. Matyjaszewski, Macromolecules 1999, 32(9), 2948 and references cited therein. 1181 (a) T. Fukuda, T. Terauchi, Chem. Lett. 1996, 293. (b) T. Fukuda, T. Terauchi, A. Goto, Y. Tsujii, T. Miyamoto, S. Lobatkae, B. Yamada, Macromolecules 1996,29, 6393. (c) R. P. N. Veregin, P. Kazmaier, P. G. Odell, M. K. Georges, Chem. Lett. 1997,467. (d) M. K. Georges, R. P. N. Veregin, K. Daimon, ACS Symposium Series 685 (Am. Chem. Soc.) 1998, 170. (e) T. Fukuda, A. Goto, K. Ohno, Y. Tsujii, ACS Symposium Series 685 (Am. Chem. Soc.) 1998, 180. [19] T. Fukuda, A. Goto, K. Ohno, Macromol. Rapid Commun. 2000, 21, 151 and references cited therein. [20] (a) M. Holderle, M. Bumert, R. Miilhaupt, Macromolecules 1997,30, 3420. (b) L. I. Gabaston, R. A. Jackson, S. P. Armes, Macromolecules 1998, 31, 2883. [21] (a) S. A. F. Bon, M. Bosveld, B. Klumperman, A. L. German, Macromolecules 1997, 30, 324. (b) C. Marestin, C. Noel, A. Guyot, J. Claverie, Macromolecules 1998, 31, 4041. (c) T. Prodpran, V. L. Dimonie, E. D. Sudol, El-Aasser, (Am. Chem. Soc. Div. Polym. Chem.), Polym. Mat. Sci. Eng. 1999, 80, 534. (d) Y. G. Durant (Am. Chem. Soc. Div. Polym. Chem.), Polym. Mat. Sci. Eng. 1999, 80, 538. (e) P. J. MacLeod, B. Keoshkerian, P. G. Odell, M. K. Georges, (Am. Chem. Soc. Div. Polym. Chem.), Polym. Mat. Sci. Eng. 1999, 80, 539. [22] P. G. Odell, N. A. Listigovers, M. Quinlan, M. K. Georges, ACS Symp. Ser.713, (Am. Chem. Soc.) 1998, 80. [23] B. Keoshkerian, M. K. Georges, M. Quinlan, R. P. N. Veregin, B. Goodbrand, Macromolecules 1998, 31, 1559. [24] (a) D. Benoit, S. Grimaldi, J. P. Finet, P. Tordo, M. Fontanille, Y. Gnanou, ACS Symposium Series 685, (Am. Chem. Soc.) 1998 225. (b) D. Benoit, V. Chaplinski, R. Braslau, C. J. Hawker, J. Am. Chem. Soc. 1999, 121, 3904. [25] M. K. Georges, G. K. Hamer, N. A. Listigovers, Macromolecules 1998, 31, 9087. [26] D. Benoit, E. Harth, P. Fox, R. M. Waymouth, C. J . Hawker, Macromolecules 2000, 33, 363. [27] There are numerous examples of the synthesis of block copolymers. These are some of the earlier references. (a) M. K. Georges, R. P. N. Veregin, P. K. Kazmaier, G. K. Hamer, Polym. Prep. 1994, 35(2), 582. (b) M. K. Georges, R. P. N. Veregin, G. K. Hamer, P. K. Kazmaier, Macromol. Symp. 1994, 88, 89. (c) E. Yoshida, T. Ishizone, A. Hirano, S. Nakahama, T. Takata, T. Endo, Macromolecules 1994,27, 31 19. (d) C. J. Hawker, J. Am. Chem. Soc. 1994, 116, 11314. (e) T. Fukuda, T. Terauchi, A. Goto, Y. Tsujii, T. Miyamoto, Y. Shimizu, Macromolecules 1996, 29, 3050. [28] (a) C. J. Hawker, Trends Polym. Sci. 1996, 4 , 183. (b) M. R Leduc, W. Hayes, J. M. J. Frechet, J. Polym. Sci., Polym. Chem. 1998, 36, 1. (c) C. J. Hawker, E. E. Malmstrom, J. M. J. Frechet, M. R. Leduc, R. B. Grubbs, G. G. Barclay, ACS Symposium Series 685 (Am. Chem. Soc.) 1998, 433. [29] M. Kato, M. Kamigaito, M. Sawamoto, T. Higashimura, Macromolecules 1995, 28, 1721. [30] M. Sawamoto, M. Kamigaito, Polym. Prep. (Am. Chem. Soc. Diu. Polym. Chem.) 1997, 38, 740. [31] M. S. Kharasch, E. V. Jenson, W. H. Urry, Science 1945, 102, 128. [32] J. S. Wang, K. Matyjaszewski, J. Am. Chem. Soc. 1995, 117, 5614.

488

5.1 Lizjing-Radical Polymerizations, an Ooeruiew

[33] K. Matyjaszewski, S. Coca, S. G. Gaynor, M. Wei, B. E. Woodworth, Macromolecules 1998, 31, 5967. 1341 T. E. Patten, T. Xia, K. Abernathy, K. Matyjaszewski, Science 1996,272, 866. [35] D. M. Haddelton, A. M. Heming, D. Kukuji, D. J. Duncalf, A. J. Shooter, Macromolecules 1998,31, 2016. [36] (a) C. Granel, P. Dubois, R. Jerbme, P. Teyssie, Macromolecules 1996, 29, 8576. (b) H. Uegaki, Y. Kotani, M. Kamigaito, M. Sawamoto, Macromolecules 1997, 30, 2249. [37] (a) T. Ando, M. Kamigaito, M. Sawamoto, Macromolecules 1997, 30, 4507. (b) K. Matyjaszewski, M. Wei, J. Xia, N. E. McDermott, Macromolecules 1997, 30, 8161. [38] P. Lecomte, I. Drapier, P. Dubois, TeyssiC, R. JCrbme, Macromolecules 1997, 30, 7631. 1391 (a) V. Percec, B. Barboiu, Macromolecules 1995, 28, 7970. (b) V. Percec, B. Barboiu, A. Neumann, J. C. Ronda, M. Zhao, Macromolecules 1996, 29, 3665. (c) V. Percec, B. Barboiu, M. van der Sluis, Macromolecules 1998, 31, 4053. (401 T. E. Patten, K. Matyjaszewski, Adu. Muter. 1998, 10, 901. (411 G. Moineau, P. Dubois, R. Jtrbme, T. Senninger, P. TeyssiC, Macromolecule, 1998, 31, 542. [42] J. Xia, K. Matyjaszewski, Macromolecules 1997, 30, 7692. 1431 G. Kickelbick, H. J. Paik, K. Matyjaszewski, Macromolecules 1999, 32, 2941. 1441 K. Matyjaszewski, J. L. Wang, T. Grimaund, D. A. Shipp, Macromolecules 1998, 31, 1527. [45] J. Chiefari, Y. K. Chong, F. Ercole, J. Krstina, J. Jeffery, T. P. T. Le, R. T. A. Mayadunne, G. F. Meijs, C. L. Moad, G. Moad, E. Rizzardo, S. H. Thang, Macromolecules 1998, 31, 5555. [46] D. G. Hawthorne, G. Moad, E. Rizzardo, S. H. Thang, Macromolecules, 1999, 32, 5457. [47] R. T. A. Mayadunne, E. Rizzardo, J. Chiefari, J. Krstina, G. Moad, A. Postma, S. H. Thang, Macromolecules 2000, 33, 243. [48] These are some thoughts and notes that came out of a symposium, ‘Commercialization of Controlled Polymer Synthesis’, San Francisco, 1999, organized by The Knowledge Foundation.

Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001

5.2 Free Radical Telomers and Polymers: Stereochemical Control N. A . Porter and C. L. Mero

5.2.1 Background The control of the configuration of new stereogenic centers formed in free-radical transformations is now well established. The formation of carbon-carbon bonds by adding a radical to an alkene has the potential to generate new stereocenters. A suitably substituted radical and alkene can create two new stereocenters in a single addition (Fig. I), but, because radicals have planar geometries or rapidly interconverting pyramidal configurations, racemic mixtures of products are formed. When the radical or alkene is substituted with a chiral group, non-racemic mixtures of diastereomers are possible. In the past five to ten years, significant progress has been made in designing and utilizing appropriate chiral groups to control selectivity in free-radical transformations. Specifically, amide-based chiral auxiliaries have been the most widely studied and successful of the auxiliaries. Using these auxiliaries in synthetic transformations is the topic of another chapter in this volume, and the focus here is the use of these strategies in the stereocontrolled formation of telomers and polymers. The reader is referred to Chapter 4.3 (Volume 1) for a detailed discussion of chiral auxiliaries in free-radical transformations.

5.2.2 Chiral Auxiliary-Controlled Radical Additions The general framework for consideration of stereochemistry in radical telomerization or polymerization is described in Fig. 1. For vinyl polymers, a new stereogenic center is formed in every addition reaction, and controlling configuration at each center might be exercised from a chiral substituent on the ultimate group or by the stereogenic center located in the polymer chain backbone, for example, at the penultimate or penpenultimate centers. In this chapter we will consider the control of configuration in polymers and telomers by chiral auxiliaries on the vinyl monomer. Acrylamides equipped with chiral auxiliaries give good to excellent selectivities in

490

5.2 Free Radical Telomers and Polymers: Stereochemical Control

Telomerization

benzene 80 "C

1 a-c Polymerization

AlBN benzene 80 "C

derived from (S)-valinol

derived from (S)-tert-leucinol

derived from Oppolzer's sultam

Figure 1. Allyl transfer telomerizations vs polymerizations

allyl transfer telomerizations (Fig. 1, where n = 1). Since each monomer is equipped with a chiral auxiliary group, the configuration of each center formed in the addition reaction will be controlled by that auxiliary. One expects, therefore, that highly isotactic polymers should result from polymerization of monomers bearing these auxiliary groups. Polymerizations of these monomers, however, show surprising results (Table 1). While all three monomers, la-c, gave isotactic polymers, acrylamide la gave much greater selectivity in the polymerizations than the allyl transfer reactions while lc showed much poorer selectivity. An additional element of stereocontrol must be operating, and one possible source of control is the previously added (penultimate) group (Fig. 2). A discussion of the use of oxazolidines as auxiliary groups to control polymer stereochemistry has been previously published [ 11. The influence of penultimate groups on stereochemistry has been cited to explain slight deviations from the expected stereorandom configurations in polymerizations of monosubstituted and 1,l -disubstituted vinyl monomers [2]. For example, the

Table 1. Allyl transfer vs polymerization selectivities

Allyl transfer Polymerization

la

lb

lc

18:22 96:4

96:4 96:4

92% 64136

5.2.3 Penultimate Group Steric Effects R

R

&*

R

i d -

7-n

penpenultimate group

penultimate group

& /*

R

R

R

*

*

*

491

R

ultimate group

m

r

Figure 2. Generation of stereogenic centers in vinyl polymerization

polymerization of styrene shows a slight preference for racemic ( r ) dyad formation, see Fig. 2 for definitions of r and m. For nearly all monosubstituted vinyl monomers, however, this effect is quite small (r:m usually no greater than 55:45). In contrast, 1,l -disubstituted monomers such as methyl methacrylate (MMA) produce markedly syndiotactic polymers (approximately 75% r dyads in bulk polymerization at 50°C) [3]. This selectivity is thought to arise from repulsion between the amethyl group on the radical and the same methyl group on the incoming monomer.

5.2.3 Penultimate Group Steric Effects Acrylamide 1 was synthesized [4] and telomerized with four different alkyl iodides and allyltributylstannane (Fig. 3). GC and HPLC were used to determine selectivities in the n = 1 (2 and 3) and n = 2 products (4-7). For the n = 1 products, both diastereomers separated in all cases. However, for the n = 2 products, only the neopentyl-derived telomers (4a-7a) would separate by GC for all four diastereomers; in all of the other telomer mixtures, two of the four diastereomers co-eluted or incompletely separated. The results are summarized in Table 2. Analysis of the distribution of 4a-7a shows a definite preference for erythro arrangements in addition to the stereocontrol provided by the auxiliary; compare n = 1 selectivity (Table 3) with selectivity in n = 2 telomers (Fig. 4). The temperature dependence of selectivity was studied and A(AH)$ and A(AS)' were obtained. As expected, selectivity was greater at lower temperatures. Eyring plots for the three selectivities (addition of the second monomer to the n = 1 radical, ally1 transfer

492

5.2 Free Radical Telomers and Polymers: Stereochemical Control

for a =Rneopentyl b = cyclohexyl c = methyl d = t-butyl

7 1

cox n = 1 products

R&

R& 2

cox cox n = 2 products (major)

\

3

cox cox

R&

R

h

4

(9s)

n = 2 products (minor)

cox cox . . -R

cox cox R

\

erythro pair

A

threo pair

Figure 3. n = 2 Telomer products

Table 2. n = 1 and n = 2 stereoselectivities

R

2

3

4

Neopentyl c-C6H II c-C~H I (bis amides)

80 78.4 na

20 21.6 na

83.7 82.5 77.6

R

2

3

Methyl t-B~tyl

79.6 61.4

20.4 32.6

telomers 5 and 6 co-elute bstereochemistry unknown, listed in order of elution 'incomplete separation of peaks

6

5

1.8

8.4 6.4" 10.3 n

83.5 8.6

7

=2

6.4 3.8"

2.6

6.2 10.1 9.5

telomersb 10.1 84.8'

2.8

5.2.3 Penultimate Group Steric Efsects

493

n = 2 (major)

91Yo

// \ n = 2 (minor)

9Yo

xoc

cox

xoc.

cox . 6a

Figure 4. n = 2 Stereoselectivities

to the major n = 2 radical, and allyl transfer to the minor n = 2 radical) provide A(AH)' and A(AS)' from the slope and intercept. For the addition of the second monomer to the n = 1 radical (generation of the first stereocenter), stereochemistry is enthalpy controlled with little contribution from entropy (Fig. 5). This agrees with previous temperature studies of radical reactions with chiral auxiliarysubstituted alkenes [ 5 ] . For the allyl trapping reactions leading to the n = 2 products, the entropic term contributes to A(AG)i, and in both cases, entropy favors erythro arrangements. A series of telomerizations were performed in which the auxiliaries were varied in an attempt to determine which factors influence the penultimate effect. Bulky auxiliary groups analogous to those shown in Fig. 3 were used, and mixed auxiliary telomerizations were performed in which methyl acrylate was co-telomerized with the acrylimides. In cases where auxiliaries were sterically bulky and especially when

n = 1 telomers

A(AH)* = -7.4 f 0.4 kJ mol-' A(AS)* = -0.9 1.3 J K-' mol-'

*

Figure 5. A ( A H ) $and A(AS)$

5.2 Free Radical Telomers and Polymers: Stereochemical Control

494

both were substituted in the 5-position, erythro preference for n = 2 products was seen. For less sterically demanding auxiliaries, threo biases were noted. These results allow the formulation of a working hypothesis based on the precedents in methyl methacrylate polymerizations. Four reasonable conformations of the radical 8, leading to the major n = 2 telomers, are presented in Fig. 6. The important features of this hypothesis are: The orientation of the radical orbital relative to the growing chain is controlled by allylic strain and 1,3-steric interactions. This is supported by evidence from EPR studies on similar radicals [6]. Attack of the next monomer (or ally1 stannane) comes from the bottom face of the radical since the top face is blocked by the penultimate group. Transition states for radical addition derived from conformations 8A and 8D are favored energetically relative to 8B and 8C because of 1,3-steric interactions between auxiliaries (8C) or between the auxiliary and growing chain (8B). The difference between threo and erythro penultimate effects rests with the relative energies of conformations 8A and 8D and, more importantly, the transition states leading from these conformations. Transition states deriving from 8A are favored

threo

8A

8C

11

11

x, oc ,

A

x

2 0

8

erythro

J..ycox2 R

R W

i

H!

2

x,oc

x,oc 8B

Figure 6. Radical conformers

X

8D

5.2.4 Penultimate Group Dipolar Control

495

in situations where the penultimate auxiliary lacks steric bulk. In this case, the growing chain (CHzR) is the bulkier group and placed anti to the radical center. Formation of threo n = 2 products is enhanced. Conformation 8D favors situations where the penultimate auxiliary (COX,) possesses more steric bulk; in the case of oxazolidine auxiliaries, substituents in the 5 position appear to have significant influence. In these cases, erythro bias is seen. These arguments apply only to acrylates. With methacrylates, steric interactions may lead to pyramidalized radicals, and other effects will then control polymer and telomer tacticity. Indeed, large bulky substituent groups can be used to control polymer tacticity in methacrylate polymerizations. Trityl methacrylate, for example, gives highly isotactic polymers under free-radical conditions. These polymerizations are thought to give helical polymer structures; it seems likely that product thermodynamic effects may be important in determining polymer structure. Stereoregular polymerization of methacrylates has been recently reviewed.

5.2.4 Penultimate Group Dipolar Control High threo selectivity in allyl transfer reactions giving n = 2 telomers has been observed using achiral oxazolidone acrylamides (Fig. 7). Selectivities as high as 93:7 in favor of threo products were obtained in pentane. Selectivity also appeared to depend on solvent polarity with higher selectivities in solvents of lesser polarity [7]. The H = 2 telomers from the allyl transfer reaction of cyclododecyl iodide and ally1 stannane can be crystallized, and the X-ray crystal structure of the threo product

cox cox f

0 "C, Et3B

H

2

*

3 C 1 2 \L 10a - threo

cox cox H23Cl2*

End View

Figure 7. Oxazolidinone acrylimide n = 2 telomers

Side View

10b - etythro

5.2 Free Radical Telorners and Polymers: Stereochemical Control

496

Table 3. Tho-selective n = 2 telomerizations 10a:lOb

Solvent

Threo:Erythro Pentanea Toluene Benzene CH2C12 CH2C12/CH3CN ( I : 1) ~

93:7 88:12 84:16 78:22 72:28 ~

All reactions: 1.2 eq. stannane, 2.4 equiv iodide a run as suspension

shows the likely source of the high selectivities. Carbonyls on adjacent auxiliaries align such that unfavorable dipolar interactions are minimized, i.e., the carbonyls align anti with respect to each other. The oxazolidinone rings are nearly parallel (within 18") and the distance between carbonyls is just under 3.5 A. In addition, ' H NMR signals of the two chiral methine protons show a strong downfield shift consistent with the antiparallel orientation of carbonyls, supporting the assumption that the solution state conformation is similar to the solid state. It is worth noting that this threo selectivity is predicted by the theory developed in Section 5.2.3, except that in this case dipolar rather than steric interactions determine the radical conformation. Dipolar interaction between adjacent S=O groups could also contribute to the abnormally low n = 2 selectivities seen in telomerizations of l c (Oppolzer's sultam acrylamide) noted at the beginning of the chapter. To test this hypothesis, achiral sultam 11 was synthesized and its selectivity studied. Stereochemistry was determined by isolation of the major n = 2 diastereomer and converting them to the methyl esters. As with 9, sultam acrylamide 11 demonstrated threo selectivity, although not as great as that seen with 9. Reactions performed in different solvents showed the same dependence on solvent polarity-less polar solvents giving greater selectivities. Both 9 and 11 show significant temperature dependence. Eyring plots of both sets of data show that, for 9, enthalpy differences appear to drive the selectivity toward threo products with little entropic contribution. For 11, enthalpy still favors threo arrangements, but, unlike 9, it has a noticeable entropic component, and it favors erythro arrangements.

dN2

\

threo

04 11

0

erythro

0

5.2.5 Lewis Acid-Promoted Diastereoselective Copolymerizations

491

5.2.5 Lewis Acid-Promoted Diastereoselective Copolymerizations Lewis acids have long been used in both polymerizations and copolymerizations to enhance the reactivities of monomers. The addition of ZnCl2, alkyl aluminum compounds, or boron halides has been shown to increase both the rate and degree of polymerization of monomers such as acrylonitrile and methyl methacrylate [8]. The use of Lewis acids to enhance electrophilicity of acrylate monomers has also been exploited to enhance alternation in copolymerizations with electron-rich alkenes such as isobutylene [9]. Systems that would never produce alternating copolymers can be induced to do so with as little as 0.1 equivalents of an appropriate Lewis acid. This section focusses on efforts to utilize Lewis acids to both alter reactivity and control stereochemistry in copolymerizations. The copolymerizations of 2-methyl-1-propene (isobutylene) and acrylamides 13a-f were studied in Lewis acid-promoted copolymerizations (Fig. 8). Although 13a-f can be homopolymerized in the presence of Lewis acids, poor conversions are obtained except with 13a. Presumably, complexation renders the radical and monomer too electron-deficient to react efficiently. This effect, however, should enhance the reactivity of the complexed radical toward more electron-rich alkenes and has been observed to increase the alternating character of copolymers of isobutylene and methyl acrylate [9]. Isobutylene also is an ideal choice for a comonomer as it does not homopolymerize by radical pathways, and the analysis of the copolymer’s tacticity is not complicated by additional stereocenters as would be the case with monosubstituted vinyl comonomers. The resulting copolymer from polymerizations of isobutylene and 13a precipitated from methanol or ethyl acetate to give a white powder, which was partially soluble in CHC13 and CH2C12, completely soluble in DMSO and DMF, and insoluble in all other common organic solvents and all aqueous solutions. Gel permeation chromatography analysis of 14a relative to polystyrene standards gave an average molecular mass of 380000. Analysis of the degree of alternation was per-

0’ 13 a-f

a b c d e f

R=H R=CH3 R = i-propyl R = benzyl R=phenyl R = rnethylcyclohexyl

Figure 8. Diastereoselective copolymerization

14 a-f

498

5.2 Free Radical Telomers and Polymers: Stereochemical Control

formed by 'H NMR at 95 "C in DMSO-d6. Of the Lewis acids studied, only scandium trifluoromethanesulfonate gave alternating, 1:1 copolymers. Lewis acids such as MgI2, MgBr2, and Yb(OTf)3, which all give good yields in allyl transfer reactions with oxazolidinone acrylamides [lo], either showed poor alternating characteristics (excess of acrylamide units) or no reaction at all. Scandium triflate also promotes copolymerization of 13b-f with isobutylene. Although the oxazolidinone auxiliaries can be removed under very mild conditions from small organic molecules, all attempts to derivatize 14a-e failed at the hydrolysis step - only completely insoluble material was recovered regardless of the method of hydrolysis. Attempts to derivatize the oxazolidinones by reduction followed by acetylation also failed. Determination of tacticity was performed by ' H or I3C NMR analysis of the co-polymers. The geminal CH3 groups of the oxazolidinone co-polymers gave both ' H and I3C signals from which dyad stereochemistry could be determined. Three separate signals were seen in both the ' H spectra and I3C spectra. Just as in the copolymer of methyl acrylate with isobutylene [9a], the meso signals were the most upfield and downfield, while the racemic dyad signals were the middle of the three. COSY spectra confirmed coupling between the rn dyad peaks, and HMQC experiments confirmed assignments of the gem-CH3 m and r dyad signals in the I3C spectra. Polymer 14a exhibits gem-CH3 signals in both the ' H and I3C spectra in an almost 1:2:1 ratio expected in an predominantly atactic polymer. Polymers 14b-e show a preponderance of meso dyad signals. With these assignments, the m:r ratios were determined as well as selectivity at each step of the polymerization (Table 4). As expected, auxiliaries with larger shielding groups (benzyl and phenyl) have higher selectivities than the smaller alkyl shielding groups (methyl and isopropyl). Still, in all four cases, selectivities were quite high. The copolymerization of 13a with isobutylene in the presence of a Lewis acid and ligand 14g was chosen to study enantioselective copolymerizations. A variety of Lewis acids were assayed in combination with ligand 14g to determine if alternating 1:l copolymers could be synthesized. Sc(OTf)3, which performs well in the absence of ligand, does not effectively promote copolymerizations in the presence of 14g. Only with large excesses of Zn(0Tf)z and ligand could 1:l copolymers be obtained. Not surprisingly, this combination of substrate and chiral Lewis acid has proved to be the most effective for generating enantioselectivity in allyl transfer reactions [ 111. Selectivity was 68:32 in the best cases in favor of rn dyads (80% selectivity at each step), somewhat lower than the typical enantiomeric excesses seen in allyl transfer

Table 4. Co-polymer tacticities for 14b-e

R

eq. LA

ni:r

selectivity

CH3 i-Pr Phenyl Benzyl

2.5 2.0 2.5 2.0

80:20 90: 10 >95:5 >95:5

1O:l 20: 1 >30: 1 >30: 1

All reactions at -40 "C with EtjB/Oz initiation. Sc(OTf), catalyst, excess isobutylene used.

5.2.6 Helix-Sense-Selective Radical Polymerizations

499

reactions (93% selectivity under identical reaction conditions). This low selectivity can be explained in part by the presence of background copolymerization that can occur when only Zn(0Tf)z is present. In the ally1 transfer reactions, conversion does not occur without the presence of both Zn(0Tf)z and ligand 14.

5.2.6 Helix-Sense-Selective Radical Polymerizations Optically active polymers can be prepared by free-radical additions that give polymers whose chirality is the result of an excess of one single-screw sense. Most polymers will not maintain a helix screw conformation in solution unless the chain backbone is rigid or the polymer side-chains are very large and prevent conformational relaxation. Polymers derived from trityl and related methacrylates have this apparent capacity, i.e. they display excess helical content in solution. Comprehensive reviews of helix-sense-selectiveanionic polymerizations have appeared [ 121, and in this section, we highlight some of the recent developments in this field related to radical polymerizations of these highly hindered methacrylates. Yamamoto and collaborators have pioneered efforts to prepare polymers of methacrylates containing very bulky ester substructures. For the most part, the approaches reported involve anionic polymerization utilizing chiral amines and alkyl lithium initiators. Polymers prepared in this way are highly helical and have many useful properties, including their use in chiral chromatography. The benzosuberyl methacrylate, 15, gives a highly isotactic helical polymer by free-radical polymerization [ 131. Excess helicity may be obtained when mentholderived thiols are used as chain transfer agents, these thiols presumably selecting one helical form for reaction over the other [ 141. Success in selecting one helical form of these highly hindered polymers has also been achieved by the use of the chiral cobalt(I1) complex 16. Polymerization of 15 initiated by AIBN in chloroform/pyridine at 60 "C in the presence of 16 gave a polymer with greater than 99% m m triad; the polymerization has a strong preference for isotactic diads [ 151. Estimates in these polymerizations are about 25-30% excess helical content. The mechanism of chiral induction is not obvious. Differential binding interactions of the right- and left-hand growing helical chains with the chiral complex are proposed, thus biasing the propagation rates for the different helices. These results are indeed intriguing, and high control of dispersity, tacticity, and helicity in radical

15

500

5.2 Free Radical Telomers and Polymers: Stereochemical Control

polymerizations is today a reality, albeit one in which mechanistic understanding and important applications remain to be revealed.

References [ I ] See, for example, (a) D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of Radical Reactions, VCH, Weinheim, 1995, Chapter 5. (b) N. A. Porter, T. R. Allen, R. A. Breyer, J. Am. Chem. Soc. 1992, 114, 7676. [2] P. Pino, U. W. Suter, Polymer 1976, 17, 977. [3] For a review of stereochemistry in MMA polymerizations, see: K. Hatada, T. Kitayama, K. Ute, Proy. Polym. Sci. 1988, 13, 189. [4] N. A. Porter, I. J. Rosenstein, R. A. Breyer, J. D. Bruhnke, W. Wu, A. T. McPhail, J. Am. Chem. SOC.1992, 114, 7664. [5] N. A. Porter, B. Giese, D. P. Curran, Acc. Chem. Rex 1991, 24, 296. [6] A. Matsumoto, B. Giese, Macromolecules, 1996,29, 3758. For earlier ESR studies, see (b) H. J. Fisher, Z. Koll, Polym. 1965, 206, 131. (c) M. Kamachi, M. Kohno, D. J. Liaw, S. Katsuki, Polym. J. 1978, 10, 69. [7] R. Radinov, C. L. Mero, A. T. McPhail, N. A. Porter, Tetrahedron Lett. 1995, 36, 8183. [8] For a review, see J. Barton, E. Borsig, Complexes in Free Radical Polymerization, Elsevier: Amsterdam, 1988. p 148. [9] (a) I. Kunz, N. F. Chamberlain, F. J. Stehling, J. Poly. Sci. A . 1978, 16, 1747. (b) Z. Florjanczyk, W. Kuran, N. Langwald, J. Sitkowska, Makromol. Chem. 1982, 183, 1081. (c) Z. Florjanczyk, W. Kuran, S. Pasynkiewicz, N. Langwald, Makromol. Chem. 1978, 179, 287. (d) G. Y. Wu, Y. C. Qi, G. J. Lu, Y. K . Wei, Polymer Bulletin. 1989, 22, 393. (e) Z. Florjanczyk, W. Kurdn, N. Langwald, J. Sitkowska, Makromol. Chem. 1983, 184, 2457. 101 M. P. Sibi, J. Ji, Angew. Chem. Int. Ed. Engl. 1996, 35, 190. 111 J. H. Wu, R. Radinov, N. A. Porter, J. Am. Chem. Soc. 1995, 117, 11029. 121 Y. Yamamoto, T. Nakano, Chem. Rev., 1994, 94, 349. 131 T. Nakano, M. Mori, Y. Yamamoto, Mucromolecules, 1993, 26, 867. 141 T. Nakano,Y. Shilkisai, Y. Yamamoto, Polym. J., 1996, 28, 51. 151 T. Nakano, Y. Yamamoto, Macromolecules, 1999, 32, 2391.

Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

1 Radical Processes: Carbon-Carbon Bond Formation 1.1 Novel Radical Traps Sungyak Kim and Joo- Yony Yoon

1.1.1 Introduction Free-radical addition to multiple bonds is recognized as a powerful means for carbon-carbon bond-forming reactions and can be divided into intramolecular addition and intermolecular addition [ 11. As compared with the synthetic usefulness of intramolecular addition, that of intermolecular addition is rather limited because of the relatively slow rate, the limited availability of radical precursors, and several competing side reactions. To provide efficient intermolecular carbon-carbon bond formation when planning syntheses, highly efficient radical traps are required and two approaches involving additions to activated olefins and fragmentation reactions are generally useful. Most studies involve reactions of carbon-centered radicals with alkenes and alkynes as radical traps. Heteroatom radical traps such as carbonyl groups, imines, and nitriles have received much less attention. Since radical reactions involving carbon-centered radicals and C=C bonds lead to the loss of the two participating functional groups, one of the advantages in radical reactions using heteroatom radical traps is to retain synthetically useful functionality for further manipulations. This chapter deals with recent advances in efficient radical traps and also includes newly developed radical acceptors for both intramolecular and intermolecular addition. Special attention will be given to the synthetic importance of newly developed heteroatom radical traps, particularly carbon-nitrogen double bonds.

1.1.2 Carbon-Nitrogen Double Bonds The addition of alkyl radicals onto C=N bonds such as imines, oximes, and hydrazones has been studied extensively during the last 10 years. According to the kinetic data (Fig. 1) 12, 31, additions of alkyl radicals onto C=N bonds are much faster than additions onto C=C bonds, and the cyclization step is irreversible, indicating that C=N bonds are much better radical acceptors than C=C bonds. It is noteworthy

2

I . 1 Novel Radical Traps

X = Bn = OBn = NMe2

n=l

n=2

6.2 X 1O6 4.2 x lo7 7.6 x lo7

6.7 x 105 2.9 X lo6 3.1 X lo6

Figure 1. Kinetic data of additions of alkyl radicals

that a hydrazone group is slightly better than an oxime group as a radical acceptor. Therefore, the efficiency of C=N bonds as radical traps can be anticipated based on the kinetic data. Since an amino group is one of the most important functional groups in organic chemistry and is found in many natural products, the radical reactions using C=N bonds as radical traps have attracted a great deal of recent attention among organic chemists and have proved to be of synthetic importance in natural product synthesis [41.

1.1.2.1 Oxime Ethers Oxime ethers are the first of three different types of C=N bonds to be used as radical acceptors. After the cyclization of an alkyl radical onto the oxime ether using zinctrimethylchlorosilane was first reported by Corey in 1983 [ 5 ] , n-tributyltin hydridemediated radical cyclization onto oxime ethers has been successfully applied to the conversion of carbohydrate derivatives to carbocycles (Scheme 1) [6]. Parker employed the oxime ether as the radical trap in the synthesis of the morphine skeleton

84% N,OBn P~O&

4 BnO

Scheme 1

'

NHOBn

+OBn

O B OBn

n

n-Bu3SnH A'BN

B

n

O

Bnd

NHOBn

4..%sOBn-+ BnO/''''.Q ..00Bn [6] OBn Bnd 93% (62:38)

OBn

1.1.2 Curbon-Nitrogen Double Bonds

BnoT.,,,oB HO

n-Bu3SnH AlBN

P

BnO"'

"'OBn OBn

3

NHOMe

PI

BnO''"

OBn 68% (translcis = 111.4)

I

Boc

Boc

Sm12 I HMPA n-Bu3SnH1 AlBN

Sm12 / HMPA R = H

53% (translcis = 6.6/1) 58% (translcis = 1.5/1)

73% (translcis = 18/1)

n-Bu3SnHIAIBN R =Me 68% (trans/cis> 180/1)

2

BnO,N\

C02Me

B a S n B u 3

[12]

n-Bu3SnH AlBN C02Me 90%

Scheme 2

[7]. Similarly, in the synthesis of (+)-7-deoxypancratistatin, a 6-ex0 cyclization of a benzylic radical onto the oxime ether was employed as a key step [S]. An important variation of these reactions is the free-radical cyclization of the oxime ethers with aldehydes and ketones as radical precursors (Scheme 2). The n-Bu3Sn radical adds to the carbonyl group, generating the ketyl radical, which then adds to the oxime ether to produce the nitrogen radical which is quenched by n-Bu3SnH. The newly found radical cyclization provides a synthetically useful method for the construction of cyclic amino alcohols widely found in biologically active natural products such as amino sugars and amino cyclitols [9].This approach was also extended to the synthesis of (-)-balanol, a potent inhibitor of protein kinase C enzymes [ 101 and the diastereoselective synthesis of p-amino alcohols [ 111. A vinyl radical was also utilized as a starting point in radical cyclization (Scheme 2). Terminal alkynes undergo hydrostannylation to generate vinyl stannyl radicals that add readily to oxime ethers [12]. This approach was further utilized to prepare carbocycles from carbohydrates [ 131. Intermolecular reaction of an aldoxime as a radical trap was first reported by Citterio (Scheme 3) [ 141. When di-t-butyl peroxide is decomposed thermally in

4

I . I Novel Radical Traps

61Yo

0I

+

CHpN-OBn

-

Bu,SnO OSnBu, Ph*Ph Ph Ph -PhAPh

- eNHoB [15]

-

76%

OSnBu,

Bu3Sn.

+

Ph,CO

1

Et-I

+ Et 70%

Scheme 3

cyclohexane or 1,4-dioxane in the presence of an aldoxime, the corresponding ketoximes are isolated. The introduction of electron-withdrawing groups such as an acetyl and a methyl ester on the aldoxime improves the yield considerably. Thus, this procedure has several limitations and can only be utilized in the functionalization of unactivated C-H bonds. The effectiveness of O-benzylformaldoxime as a radical trap in intermolecular addition of alkyl radicals was also examined [ 151. To obviate the problem of the direct reduction of the initially formed alkyl radical under the standard cyclization conditions (n-Bu3SnH/AIBN), benzopinacolate 1 is used to generate tributyltin radical and benzophenone upon heating. This new intermolecular addition reaction is quite general for alkyl and aryl radicals. Recently, the application of formaldoxime as a radical trap to nucleosides has provided dimeric nucleosides [ 161. The reaction was further extended to the aldoximes by performing the reaction in the presence of boron trifluoride etherate using triethylborane as a radical initiator [ 171. Highly diastereoselective radical addition to the Oppolzer’s camphor sultam derivative of glyoxylic oxime ether was also achieved, providing a convenient method for preparing a variety of enantiomerically pure M amino acids [ 181. This approach was extended to triethylborane-induced solid-phase radical reactions [ 191.

1.1.2.2 Sulfonyl Oxime Ethers Despite the synthetic importance of acylation reactions in organic synthesis [20], a successful free-radical-mediated acylation reaction is not presently available. Re-

1.1.2 Curbon-Nitrogen Double Bonds

5

2a : R~ = H

2b : R2 = Me Scheme 4

cently, sulfonyl oxime ethers have been developed as carbonyl equivalent radical traps for an indirect radical acylation approach [21]. This novel acylation approach involves the additions of alkyl radicals to C=N bonds and subsequent fast and irreversible p-exclusion of phenylsulfonyl radicals to afford oxime ethers 3 which can be readily converted into carbonyl compounds 4 (Scheme 4). The presence of a phenylsulfonyl group is essential for the success of this approach. The electronwithdrawing phenylsulfonyl group on the iminyl carbon lowers the energy of LUMO of the radical trap thereby increasing the rate of the addition reaction. In contrast, a phenylthio-substituted oxime ether is not effective in radical additions because of its electron-donating nature. Approximate rate constants for intermolecular additions of alkyl radicals to phenylsulfonyl oxime ethers 2 have been determined to be k , = 9.6 x los M-l SKIat 25 "C for 2a and k, = 7.3 x lo4 M-' s-] at 60 "C for 2b, indicating that the additions are fast and highly efficient processes [22]. Thus, the addition of an alkyl radical to 2a is much faster than a radical allylation reaction. This reaction works well with primary, secondary, and sterically hindered tertiary alkyl iodides. Furthermore, the efficiency of this acylation approach is shown in the cyclization-acylation sequence, which cannot be achieved by conventional methods (Scheme 5).

HgHoEi

_t

H g "H 0 "

'FN-OBn R

R = H 88% cktrans = 1 :6 R = Me 78% cistrans = 1:6

Scheme 5

[21]

1.I Novel Radical Traps

6

6

5

R-I

+ 5

-

N,OBn

(Me3Sn)2 THF hv

RKC02Me

aq. HCHO H+

~ 3 1

Scheme 6

This free-radical acylation approach is extended for the synthesis of cc-keto esters and ketones using phenylsulfonyl methoxycarbonyl oxime ether 5 [23] and bismethanesulfonyl oxime ether 6, respectively (Scheme 6) [24]. 5 is more reactive and effective than 2b. For instance, radical reaction of tert-butyl iodide with 5 gave tert-butyl oxime ester in 65% yield, whereas the use of 2b gave the corresponding tert-butyl oxime ether in 15% yield. In free-radical-mediated ketone synthesis via a sequential radical acylation approach, 6 is used as a carbonyl equivalent geminal radical acceptor. This method works well with primary alkyl iodides but somewhat less efficiently with secondary iodides and can be applied to prepare unsymmetrical acyclic ketones as well as cyclic ketones. It is noteworthy that stable allylic and benzylic radicals react smoothly with 6. The free-radical acylation approaches appear to be highly useful for the synthesis of a variety of carbonyl compounds and have great synthetic potential because the present methods succeed in complex molecules under mild conditions, where more conventional methods would be inappropriate.

1.1.2.3 Hydrazones In contrast to oxime ethers, hydrazones have received much less attention in radical chemistry. N-Aziridinylimines was first introduced in the radical literature in 1991 [25]. Hydrazones are slightly better radical acceptors than oxime ethers and the radical cyclizations of hydrazones are highly efficient [26]. Among hydrazones, an N,N-diphenylhydrazone is the most widely used radical trap. The N,N-

1.1.2 Carbon-Nitrogen Double Bonds

R

R n = 1 n-Bu3SnH

(80°C) (-42°C)

n=2

Sml, Sml2

n=1 n=2

Smlz Smlz

(21 "C) (21 "C)

(-42°C)

NHNMe,

R

7

NHNMe,

cis:trans (95%) 2:l 7:l 3:l

(88%) (63%)

cis:trans 25:l (63%) 251 (62%)

Scheme 7

diphenylhydrazones are more reactive than N,N-dimethylhydrazones and can be readily cleaved to generate an amino group. The radical cyclization of hydrazones can be effectively used in the synthesis of amino-substituted cyclopentanes and cyclohexanes [27]. In the radical reaction of bromohydrazones with Smlz-HMPA, the cisltrans ratio of the cyclic products depends to some extent on the reaction temperature. Reductive cyclization of ketohydrazones provides much better stereoselectivities, yielding a 25:l mixture of cis and trans cyclic hydrazino alcohols (Scheme 7) [28]. Furthermore, cyclic p-amino alcohols having considerable current interest can be readily prepared by use of the hydrazones as radical traps.

1.1.2.4 N-Aziridinylimines Since 5-endo ring closure is a disfavored process, the formation of five-membered ring radicals by radical cyclizations is not generally possible. To solve this problem, radical cyclization of N-aziridinylimines was studied and these have been found to be the most ideal radical trap to provide ready access to five- and six-membered ring radicals. Based on the Eschenmoser reaction [29], the present approach comprises three steps: cyclization, the opening of a cyclopropane ring, and consecutive p-fragmentations (Scheme 8). The radical cyclization reactions are clean, giving high yields of the cyclized products. It is of interest that the N-aziridinylimine can be used as a radical precursor, which involves the intermolecular addition of n-Bu3Sn radical to the Naziridinylimino group to generate the wBu3Sn-substituted carbon-centered radical. One of the most exciting results is obtained by the radical cyclization of Naziridinylimine in the presence of an activated olefin such as acrylonitrile or methyl acrylate. This example shows the formation of two consecutive carbon-carbon bonds indicated by solid lines (Scheme 9). This unprecedented approach is unique

8

1.1 Novel Radical Traps

Scheme 8

I

I

A=2-phenyl N-aziridinyl

EWG=CN (86%) = C02Me (87%)

Scheme 9

Scheme 10

and has great synthetic potential, particularly for the construction of quaternary carbon centers. Tandem radical cyclization approaches normally involve the formation of alternating carbon-carbon bonds, in which alkenes and other multiple bonds serve as vicinal radical acceptor and donor equivalents (Scheme 10). Conventional transition metal-mediated and anionic tandem cyclizations also show similar vicinal reactivity. Thus, the contrasting formation of consecutive geminal carbon-carbon bonds is an unusual and new type of bond-forming strategy. Although only a few examples have been reported for the consecutive carboncarbon bond formation approach in cyclization reactions [ 301, N-aziridinylimines are ideally suited for the construction of quaternary carbon centers. Based on the consecutive carbon-carbon bond formation approach, several sesquiterpenes (Fig. 2) have been synthesized. In order to demonstrate how to execute the synthesis using the consecutive carbon-carbon bond formation approach, the synthesis of m-zizaene is discussed [ 3 11.

1.1.2 Carbon-Nitrogen Double Bonds

modhephene

zizaene

cedrene

9

pentalelene

Figure 2. Sesquiterpenes

X

A = 2-phenyl N-aziridinyl

Zizaene

Figure 3. Radical cyclization of N-aziridinylimines

According to the retrosynthetic analysis based on the radical cyclization of Naziridinylimines, of the four bonds at the quaternary carbon center of the ring junction, disconnection of two bonds should be possible (Fig. 3). In this approach, the carbonyl carbon would be converted into the quaternary carbon center by tandem radical cyclizations. Thus, two of the four carboncarbon bonds can be formed to construct the quaternary carbon center in a consecutive manner. Although several routes are available, approaches a and b are promising for the synthesis of DL-zizaene. In approach a, we would expect difficulties in maintaining cis-stereochemistry of the two substituents and in forming the N-aziridinylimine selectively with a 1,3-dicarbonyI or P,y-unsaturated ketone group in the molecule. Thus, approach b seems to be more attractive than approach a since the intermediate should be readily accessible. In addition, it is expected that the radical cyclization would provide the correct stereochemistry at the ring junction required in the synthesis of DL-zizaene. The high stereoselectivity in the radical cyclization of key intermediate 7 can be anticipated. As shown in Scheme 11, conformation 8b would be disfavored because of steric interaction, as compared with 8a. Thus, intermediate 9, the more stable product having the equatorial substituent, could be produced. Radical cyclization of 7 with n-BqSnH/AIBN in refluxing benzene under high dilution conditions provided a 1:5 mixture of a- and p-isomer of 10 in 67% yield. As predicted, the correct trans-fused product 10 was obtained from cyclopentenone by a six-step sequence in an overall 30% yield [ 3 11. This consecutive carbon-carbon bond formation approach was further applied for the synthesis of DL-modhephene [32], DL-cedrene [33], and DL-pentalelene [34]. Recently Keck successfully completed the total synthesis of (+)-7-deoxypancratistatin using a radical cyclization of N-aziridinylimine as a key step [35].The formation of two carbon-carbon bonds in a consecutive manner through radical cyclization of N-aziridinylimine is indicated by solid lines as shown in Scheme 12.

10

1.1 Novel Radical Traps

Zizaene 10 (67%) ~(:p=1:5

9

Scheme 11

-

0

0 (+)-7-Deoxypancratistatin

Scheme 12

N-Aziridinylimines have been introduced as geminal radical acceptor and donor equivalents for the first time, thereby allowing the consecutive carbon-carbon bond formation. This approach allows not only the versatility of synthetic routes during planning but also very impressive and efficient construction of quaternary carbon centers, thereby providing highly efficient routes for the synthesis of various natural products of high molecular complexity.

1.1.2.5 Imines As expected from kinetic data [2, 31, imines as radical traps are somewhat less efficient than oxime ethers and hydrazones. An intramolecular radical addition onto

1.1.3 Carbon-Oxygen Double Bonds

11

Meoq~

Me0

Me0 Ar 11

+

[36] Me0 “ “ \ O m

Ar 12 (56%)

LAr 13 (10%)

Scheme 13

14

AlBN

Scheme 14

an imine bond was first used as a key step in the synthesis of the cryptostyline alkaloids [36]. Radical cyclization of aryl bromide 11 under the standard cyclization conditions gave isoquinoline 12 as a major product along with a small amount of dihydroindole 13, resulting from a 6-end0 and 5-exo ring closure, respectively. The competition between the 5-ex0 and 6-end0 ring closures has been extensively investigated and is dependent on the imine substituents and reaction conditions (Scheme 13) [37]. Thus, this type of radical cyclization has limited use because of poor selectivities associated with 5-ex0 versus 6-end0 cyclizations. An elegant variation of this cyclization is based on the use of the polar nature of an acyl radical instead of an alkyl radical. The use of the polarized acyl radical is expected to increase the selectivity by matching with the polar nature of the imine acceptor. This idea has been demonstrated by the radical carbonylation and cyclization approach. When the reaction of 3-bromopropylimine 14 with carbon monoxide is carried out in refluxing benzene under 80 atm in the presence of n-Bu3SnH and AIBN, acyl radical 15 undergoes cyclization at the nitrogen atom selectively, yielding the desired 2-pyrrolidinone 16 in 81% yield (Scheme 14) [38].

1.1.3 Carbon-Oxygen Double Bonds Additions of alkyl radicals onto carbonyl groups are reversible and energetically unfavorable because of strong 71 bond strengths of carbonyl bonds. Fragmentation reactions of oxy radicals are faster than additions to carbonyl groups. Thus, it is anticipated that carbonyl derivatives cannot be used as efficient radical traps. Only several carbonyl derivatives are effective to some extent in radical cyclizations. The intermolecular addition of alkyl radicals to carboxylic acid derivatives represents a radical acylation reaction in which carboxylic acid derivatives are required to be

12

1.1 Novel Radical Traps

efficient radical traps. However, the use of carboxylic acid derivatives as radical traps is uncommon, and only several reports have appeared to date [39, 401.

1.1.3.1 Acylgermanes The most interesting example is the use of an acylgermane as a radical trap in intramolecular radical acylation [41]. Addition of an alkyl radical onto the acylgermane and rapid fragmentation of the resulting a-germylalkoxy radical provides a cycloalkanone and a germyl radical. Since the germyl radical propagates the radical chain by abstraction or addition, this reaction occurs by a unimolecular chain transfer process. Acylgermanes are excellent radical traps in intramolecular radical acylation reactions and are used as synthetic equivalents of carbonyl radical traps (Scheme 15). However, the use of acylgennanes as radical traps in intermolecular reactions has not been reported.

1.1.3.2 Acylsilanes Acylsilanes, as well as the corresponding acylgermanes, are excellent radical traps in intramolecular cyclizations. The difference between these acyl derivatives is that acylsilanes give cycloalkanols [42], whereas acylgermanes give cycloalkanones (Scheme 15). The a-silylalkoxy radical undergoes formal radical Brook rearrangement to afford the a-silyloxy-substituted radical, which abstracts a hydrogen from the tin hydride rather than eliminates a silyl radical. This approach appears to be useful for the synthesis of cyclopentanols and cyclohexanols under radical conditions.

1.1.3.3 Thioesters and Selenoesters Most studies have been directed toward the use of selenoesters and thioesters as radical precursors to generate acyl radicals in radical cyclizations [43]. However, selenoesters and thioesters as radical traps have not been well studied [4Oa]. Since the cyclization step is much slower than direct reduction by n-Bu3SnH, the use of (n-Bu3Sn), is required. Intramolecular cyclization of thioester 17 furnished cyclo-

&3

I

Scheme 15

-

n-Bu3SnH AlBN

'0

MR3

6

?SiR3 M = Si

?SIR3

1.1.3 Curbon-Oxygen Double Bonds

18 (85%)

13

19 (14%)

Scheme 16

PhO(CH2)41

HCOSPh (n-Bu3Sn),, hv CH3COSePh (~-Bu~SII)~, hv

9

PhO(CH2)4-C-H 15%

9

+ PhO(CH2)4-C-SPh

6%

9

PhO(CH2)4-C-CH3 18%

[211

Scheme 17

pentanone 18 in high yield along with a small amount of the direct reduction product 19 (Scheme 16). Selenoesters are more effective than thioesters in trapping alkyl radicals. However, intermolecular acylation reactions using selenoesters and thioesters as radical traps are inefficient. Thus, radical reaction of 4-phenoxybutyl iodide with formyl thioester gives a mixture of an aldehyde and a thioester in low yield (Scheme 17). A similar result is obtained with acetyl selenoester. The fundamental problems associated with very strong 7c bond strength of carbonyl groups can not be easily solved for successful radical acylation.

1.1.3.4 Phosgene and Oxalyl Chloride Derivatives Since Kharasch reported radical-mediated carboxylation of saturated hydrocarbons with phosgene as a radical trap in the 1940s [39], no successful radical acylation and carboxylation reactions have appeared. In intermolecular radical acetylations, biacetyl was used as a radical trap (Scheme 18) [44]. The addition of an alkyl radical to the carbonyl carbon of biacetyl gives the methyl ketone along with an acetyl radical. S-Phenyl chlorothioformate was used as a radical trap in the radical-mediated carboxylation approach (Scheme 18) [40b]. Among several carbonyl derivatives including phosgene and bis(thiopheny1) carbonate, S-phenyl chlorothioformate gives the best result and works with primary, secondary, and tertiary alkyl iodides. In addition to the desired thioester, a small amount of the corresponding sulfide is isolated as a by-product.

14

I.1 Novel Radical Traps

32-70% R-I

+

0

0

(n-Bu3Sn), hv

*

RKSPh 44-56%

5940%

Scheme 18

Methyl oxalyl chloride was also employed as a radical trap for the same purpose (Scheme 18) [~OC]. Radical reaction of an alkyl iodide with methyl oxalyl chloride in the presence of hexabutylditin under photochemically initiated conditions affords an acid chloride along with a small amount of the corresponding methyl ester. Sequential radical reaction involving cyclization and carboxylation can be performed using methyl oxalyl chloride. cc,p-Unsaturated acyl radicals are useful precursors to a-ketenyl radical intermediates which take part in a variety of synthetically useful ring-forming reactions [45]. In these approaches, ketenes are utilized as novel radical traps in the radical cyclization. This approach was applied for the synthesis of DL-modhephene (Scheme 19) [46]. The propellane 23 is produced from the thioester 20 following

23 Scheme 19

dkModhephene

1.1.4 Curbon-Curbon Double Bonds

15

formation of the a,P-unsaturated acyl radical intermediate, which takes part in a 5-ex0 transannulation via its a-ketenyl radical 21, leading to 22. The intermediate 22 then undergoes 5-exo cyclization onto the ketene to give 23. Interestingly, the reaction of an alkyl radical with carbon monoxide as a C1 radical synthon has been extensively studied in recent years [47]. The efficient trapping of CO by a variety of alkyl radicals in a radical chain has been demonstrated since 1990 but is discussed separately in this book (Volume 2, Chapter 1.2).

1.1.4 Carbon-Carbon Double Bonds The addition of an alkyl radical onto C=C bonds is energetically favorable and is very widely utilized in radical reactions. Although C=C bonds are normally used as radical traps in radical cyclizations, they are not very suitable in intermolecular radical reactions because of the relatively slow rate and the presence of several competing side reactions. The efficiency of most intermolecular additions is much below the synthetically useful level, with several exceptions such as allylations and additions to activated C=C bonds. Radical allylations have been extensively studied and proved to be useful for the selective introduction of ally1 groups into organic molecules under mild conditions [48]. The efficiency of allylating agents as radical traps depends very much on matching the reactivity of the allylating agent with that of the radical. Thus, electrophilic radicals add smoothly to electron-rich allylating agents, whereas nucleophilic radicals add to electron-poor allylating agents. This notion is generally applied to other alkenyl radical traps. Since radical allylations together with vinylations will be discussed separately in this book (Volume 1, Chapter 1.4), only vinyl cyclopropanes and methylene cyclopropanes as radical traps are discussed here.

1.I -4.1 Vinylcyclopropanes Feldman and Oshima have independently developed intermolecular [ 3+2] ring expansion strategies for the synthesis of functionalized cyclopentanes using vinylcyclopropanes as radical traps [49]. The phenylthio radical-induced ring opening leads to homoallylic radical 24, which can be trapped by an activated alkene or alkyne. Cyclization of the resulting radical 25 then leads to vinyl cyclopentane 26 along with regeneration of phenylthio radical (Scheme 20). To facilitate the ring opening of vinylcyclopropanes, the presence of activating groups in the cyclopropane ring is needed. This approach was applied to the preparation of not only [5.5.n]tricyclic ring compounds [50]but also 1,2-dioxolane compounds using oxygen as a radical trap (Scheme 21) [51]. An intramolecular version of this approach was applied to the preparation of the cyclopenta[b]benzofuran system of the antileukemic natural product DL-Rocaglamide [52].

I . 1 Novel Radical Traps

16

2 24

$Xil

.x

Y

PhS

R2

R'

25

26

Scheme 20

0

H I

H

k

68% 02

(PhSe)2,hv

[511

t

AlBN

64%

/Q

0 (PhS)2, hv, AlBN TMS

"@. k

TMS

94% (one isomer)

Scheme 21

1.1.4.2 Methylenecyclopropanes Singleton has developed an intermolecular [3+2] addition strategy for the synthesis of functionalized cyclopentane rings using strained methylenecyclopropanes as radical traps (Scheme 22) [53]. The success of methylenecyclopropane 27 with electron-rich and unactivated alkenes arises from the ready formation of the highly stable electrophilic radicals 28b. Thus, this reaction works well with equimolar amounts of unactivated and electron-rich alkenes but does not work with electronpoor alkenes. The reagent 29 and 30 are prepared by the structural modification of 27. Furthermore, [ 3+2] methylenecyclopentane annulations of electron-poor alkenes can be carried out with unactivated methylenecyclopropane 31 and 32 [54].

1.1.4 Curbon-Curbon Double Bonds

28a

27

17

28b

Wbl

-

-

&B~

E

0-i-Bu

E

-c

$O-i-Bu

&O-i-Bu E

E

74% E = C02Me

R=H,Me 30

29

31

32

Scheme 22

Methylenecyclopropane derivatives have been used as radical traps in radical cyclizations. This approach involves the 5-exo cyclization of a (methylenecyclopropyl) propyl radical 33, followed by the opening of the resulting cyclopylmethyl radical 34 to give cyclohexyl radical 35 [55].Radical cyclizations of methylenecyclopropane derivatives give a variety of cyclic compounds including spirocyclic and tricyclic compounds (Scheme 2 3 ) .

33

34

35

[551

I

i i) i) T (TMS)$iH ~ C/I DMAP / AlBN*

(& LNH +

53%

Scheme 23

4%

18

I . I Novel Radical Traps

1.1.5 Other Multiple Bonds 1.1.5.1 Alkyl Azides An azido group is known to be susceptible to n-Bu3Sn radical and is utilized as a precursor of n-Bu3Sn-substituted aminyl radical. The azido group was first employed as a radical trap in radical cyclization and this reaction is useful for the synthesis of N-heterocycles (Scheme 24) [56]. Because of the high reactivity of the azido group toward n-Bu3Sn radical, only the iodo group can be utilized as a radical precursor under the standard radical conditions. However, the azido group is relatively inert toward tris(trimethylsily1)silyl radical, extending its synthetic utility as a radical trap. Thus, bromo, xanthate, and carbonyl groups can be utilized as radical precursors. Murphy has demonstrated the synthetic utility of the azido group as a radical trap in his approach toward the synthesis of aspidospermidine and related alkaloids (Scheme 25) [57]. Furthermore, it is noteworthy that azido groups can be used as radical precursors rather than as radical traps when aldehydes and ketones are utilized as radical traps [58].

Y

5 E

(TMS)3SiH or n-Bu3SnH

X _.

AlBN

I

N3

N3

6

E

E

TsCl/ Py

E

[56]

NJ TS’

X = Br, I E = C02Me

Scheme 24

(TMS),SiH AlBN

Me02S

*

N3

Scheme 25

1.1S.2 Diazirines The problem of the transfer of a primary amino group to an alkyl radical is solved by employing diazirines as radical traps [59] (for a review on radical aminations, see Volume 2, Chapter 2.1). This involves the addition of carbon radicals onto the N=N bond of diazirine 36 to form the adduct radical 37 which dimerizes to the tetraazo intermediate 38. This compound then undergoes a rearrangement with the loss of N2 to furnish imine 39, which can be easily hydrolyzed to the desired amine (Scheme 26). Due to the high reactivity of diazirine derivatives, alkyl radicals are generated from the corresponding thiohydroxamates via visible-light irradia-

1.1.5 Other Multiple Bonds

I

19

1

::x!,-

R'

N-N-N-N'

R

R

X

R'

R"

38

37 Scheme 26

tion and from the corresponding organotellurides via radical exchange. Thus, this approach allows the amination of a carboxylic acid and an alcohol function.

1.15 3 Molecular Oxygen Carbon-centered radical oxygenation with molecular oxygen is a well-known reaction and was originally applied to the biosynthesis of prostaglandins [60] (for a review on radical oxygenations, see Volume 2, Chapter 2.1). A striking synergetic action of molecular oxygen and a tin hydride at low temperatures (0-20 "C) effects an efficient conversion of an organic halide to the corresponding alcohol under neutral and mild conditions [61]. In addition, the aerobic conversion of halides to alcohols can be applied to oxidative radical cyclizations to provide cyclized alcohols (Scheme 27) [62].

0 2

R' = (CH2)4CO*CH3

OH dry air

R-I

Qy".;

n-Bu3SnH_ AIBN, 0 2 toluene

-

R-OH

aHqH

toluene 15-20 O C

F21

+

OH

72% (94:6)

Scheme 27

OH

20

1.I Novel Rudicul Trups

References [ l ] D. P. Curran in Comprehensive Organic Synthesis, Vol 4 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, pp. 715-831. [2] S. Kim, J. H. Cheong, K. S. Yoon, Tetrahedron Lett. 1995,36, 6069; S. Kim, K. S. Yoon, Y. S. Kim, Tetrahedron 1997, 38, 73; S. Kim, Y. Kim, K. S. Yoon, Tetrahedron Lett. 1997, 38, 2487. [3] A. G. Fallis, I. M. Brinza, Tetrahedron 1997, 53, 17543. [4] U. Koert, Angew. Chem. Int. Ed. Engl. 1996, 35, 405. [ 5 ] E. J. Corey; S. G. Pyne, Tetrahedron Lett. 1983, 24, 2821. [6] P. A. Bartlett, K. L. McLaren, P. C . Ting, J. Am. Chem. Soc. 1988, 110, 1633; J. MarcoContelles, C. Pozuelo, M. L. Jimeno, L. Martinez, A. Martinez-Grau, J. Org. Chem. 1992, 57, 2625. [7] K. A. Parker, D. M. Spero, J. Van Epp, J. Org. Chem. 1988, 53, 4628. [S] G. E. Keck, S. F. McHardy, J. A. Murry, J. Am. Chem. Soc. 1995, 117, 7289. 191 T. Kiguchi, K. Tajiri, I. Ninomiya, T. Naito, H. Hiramatsu, Tetrahedron Lett. 1995, 36, 253; T, Naito, K. Tajiri, T. Harimoto, I. Ninomiya, T. Kiguchi, Tetrahedron Lett. 1994, 35, 2205. [lo] H. Miyabe, M. Torieda, T. Kiguchi, T. Naito, Synlett 1997, 580; H. Miyabe, M. Torieda, K. Inoue, K. Tajiri, T. Kiguchi, T. Naito, J. Org. Chem. 1998, 63, 4397. [ l l ] J. Tormo, D. S. Hays, G. C. Fu, J. Org. Chem. 1998, 63, 201. 1121 E. J. Enholm, J. A. Burroff, L. M. Jaramillo, Tetrahedron Lett. 1990, 31, 3727. [I31 J. Marco-Contelles, C. Destabel, J. L. Chiara, M. Bernabe, J. Org. Chem. 1996, 61, 1354. [ 141 A. Citterio, L. Filippini, Synthesis 1986, 473. [I51 D. J. Hart, F. L. Seely, J. Am. Chem. Soc. 1988, 110, 1631. [I61 B. Bhat, E. E. Swayze, P. Wheeler, S. Dimock, M. Perbost, T. Sanghvi, J. Org. Chem. 1996, 61, 8186. 1171 H. Miyabe, R. Shibata, C. Ushiro, T. Naito, Tetrahedron Lett. 1998, 39, 631. [IS] H. Miyabe, C. Ushiro, T. Naito, Chem. Commun. 1997, 1789. [191 H. Miyabe, Y. Fujishima, T. Naito, J. Org. Chem. 1999, 64, 2174. [20] B. T. O’Neill in Comprehensive Organic Synthesis, Vol I (Eds.: B. M. Trost, 1. Fleming), Pergamon, Oxford, 1991, pp. 397-458. [21] S. Kim, I. Y. Lee, J.-Y. Yoon, D. H. Oh, J. Am. Chem. Soc. 1996, 118, 5138. [22] S. Kim, I. Y. Lee, Tetrahedron Lett. 1998, 39, 1587. [23] S. Kim, J.-Y. Yoon, I. Y. Lee, Synlett 1997, 475. [24] S. Kim, J.-Y. Yoon, J. Am. Chem. Soc. 1997, 119, 5982. [25] S. Kim, I. S. Kee, S. Lee, J. Am. Chem. Soc. 1991, 113, 9882. [26] J. W. Grissom, D. Klingberg, D. Huang, B. J. Skittery, J. Org. Chem. 1997, 62, 603. [27] C. F. Sturino, A. G. Fallis, J. Org. Chem. 1994, 59, 6514 and ref [3]. [28] C. F. Sturino, A. G. Fallis, J. Am. Chem. Soc. 1994, 116, 7447. [29] A. Eschenmoser, Hdv. Chim. Acta 1968, 51, 1461; D. Felix, R. K. Muller, U. Horn, R. Joos, J. Schreiber, A. Eschenmoser, Helv. Chim. Acta 1972, 55, 1276. [30] a) D. P. Curran, H. Liu, J. Am. Chem. Soc. 1992, 114, 5863; b) Y.-M. Tsai, K.-H. Tang, W.-T. Jiaang, Tetrahedron Lett. 1993, 34, 1303; c) M. Nagai, J. Lazor, C. S. Wilcox, J. Org. Chem. 1990, 55, 3440. [31] S. Kim, C . H. Cheong, Synlett 1997, 947. [32] H.-Y. Lee, D. Kim, S. Kim, Chem. Conimun. 1996, 1539. [33] H.-Y. Lee, S. Lee, D. Kim, B. K. Kim, J. S. Bahn, S. Kim, Tetrahedron Lett. 1998, 39, 7713. [34] S. Kim, J. H. Cheong, J. Yoo, Synlett 1998, 981. [35] G. E. Keck, T. T. Wager, S. F. McHardy, J. Org. Chem. 1998, 63, 9164. [36] S. Takano, M. Suzuki, A. Kijima, K. Oasawara, Chem. Lett. 1990, 315. [37] a) M. J . Tomaszewski, J. Warkentin, Tetrahedron Lett. 1992, 33, 2123; b) S. Takano, M. Suzuki, A. Kijima, K. Oasawara, Heterocycles 1994, 37, 149; c) W. R. Bowman, P. T. Stephenson, N. K. Terrett, Young, A. R. Tetrahedron Lett. 1994,35, 6369; d) M. Gioanola, R. Leardini, D. Nanni, P. Pareschi, G. Zanardi, Tetrahedron 1995, 51, 2039. [38] I. Ryu, K. Matsu, S. Minakata, M. Komatsu, J. Am. Chem. Soc. 1998, 120, 5838.

References

21

[39] H. C. Brown, M. S. Kharasch, J. Am. Chem. Soc. 1942, 64, 329 and 1942, 64, 333. [40] a) S. Kim, S. Y. Jon, Chem. Commun. 1996, 1335; b) S. Kim, S. Y. Jon, Chem. Commun. 1998, 815; c) S. Kim, S. Y. Jon, Tetrahedron Lett. 1998, 39, 7317. [41] D. P. Curran, H. Liu, J. Org. Chem. 1991, 56, 3463; D. P. Curran, M. Palovich, Synlett 1992, 631; D. P. Curran, U. Diederichsen, M. Palovich, J. Am. Chem. Soc. 1997, 119, 4797. [42] a) Y.-M. Tsai, C.-D. Cherng, Tetrahedron Lett. 1991, 32, 3515; b) D. P. Curran, W. T. Jiaang, M. Palovich, Y. M. Tsai, Synlett 1993, 403; c) Y.-M. Tsai, S. Y. Chang, J. Chem. Soc.. Chem. Commun. 1995, 981 and ref [30b]. 1431 D. L. Boger, R. J. Mathvink, J. Org. Chem. 1988, 53, 3377 and 1992, 57, 1429; D. L. Boger, 1990, 112, 4003 and 1990, 112, 4008; J. H. Penn, F. Liu, R. J. Mathvink, J. Am. Chem. SOC. J. Org. Chem. 1994, 59, 2608. [44] W. G. Bentrude, K. R. Darnall, J. Am. Chem. Soc. 1968, 90, 3588. [45] a) B. D. Boeck, N . Herbert, G. Pattenden, Tetruhedron Lett. 1998, 39, 6971; b) N. M. Harrington-Frost, G. Pattenden, Synlett 1999, 1917. [46] B. D. Boeck, G. Pattenden, Tetrahedron Lett. 1998, 39, 6975. [47] I. Ryu, N. Sonoda, Angew. Chem. Int. Ed. Engl. 1996, 35, 1050; I. Ryu, N. Sonoda, D. P. Curran, Chem. Rev. 1996, 96, 177. [48] G. E. Keck, E. J. Enholm, J. B. Yates, M. R. Wiley, Tetruhedran 1985, 41, 4079; C. Chatgilialoglu, C. Ferreri, M. Ballestri, D. P. Curran, Tetrahedron Lett. 1996, 37, 6387; F. L. Guyader, B. Quiclet-Sire, S. Seguin, S. Z. Zard, J. Am. Chem. SOL.1997, 119, 7410. [49] a) K. S. Feldman, A. L. Romanelli, R. E. Ruckle, R. F. Miller, J. Am. Chem. SOC.1988, 110, 3300; b) K. Miura, K. Fugami, K. Oshima, K. Utimoto, Tetrahedron Lett. 1988,29, 5135. 1501 M. E. Jung, H. L. Rayle, J. Org. Chem. 1997, 62, 4601. [51] K. S. Feldman, R. E. Simpson, J. Am. Chem. Soc. 1989, I l l , 4878. [52] K. S. Feldman, C. J. Burns, J. Org. Clzem. 1991, 56, 4601. [53] a) D. A. Singleton, K. M. Church, J. Org. Chem. 1990, 55, 4780; b) D. A. Singleton, C. C. Huval, K. M. Church, E. S. Priestley, Tetrahedron Lett. 1991, 32, 5765; c) C. C. Huval, D. A. Singleton, J. Org. Chem. 1994, 59, 2020. [54] C. C. Huval, K. M. Church, D. A. Singleton, Synlett 1994, 273. [55] a) M. Santagostino, J. D. Kilburn, Tetrahedron Lett. 1994, 35, 8863; b) M. Santagostino, J. D. Kilburn, Tetrahedron Lett. 1995, 36, 1365. [56] S. Kim, G. H. Joe, J. Y. Do, J. Am. Chem. Soc. 1994, 116, 5521. 1571 M. Kizil, J. A. Murphy, J. Chem. Soc., Chem. Commun. 1995, 1409. [58] S. Kim, G. H. Joe, J. Y. Do, J. Am. Chem. Soc. 1993,115, 3328. 1591 D. H. R. Barton. J. C. Jaszberenyi, E. A. Theodorakis, J. Am. Chem. Soc. 1992, 114, 5904; D. H. R. Barton, J. C. Jaszberenyi, E. A. Theodorakis, J. H. Reibenspies, J. Am. Chem. Soc. 1993. 115, 8050. 1601 N. A. Porter, M. 0. Funk, J. Org. Chem. 1975, 40, 3614; E. J. Corey, K. Shimoji, C. Shih, J. Am. Chem. Soc. 1984, 106. 6425; D. E. O’Connor, E. D. Mihelich, M. C. Coleman, J. Am. Chem. Soc. 1984, 106, 3577. [61] E. Nakamura, T. Inubushi, S. Aoki, D. Machii, J. Am. Chem. Soc. 1991, 113, 8980. [62] S. Mayer, J. Prandi, Tetrahedron Lett. 1996, 37, 3117.

Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

1.2 Radical Carbonylations Mediated by Tin, Germanium, and Silicon Reagents Ilhyong Ryu

1.2.1 Introduction The discovery that carbon radicals react with carbon monoxide dates from a report in 1939 by Faltings who observed the formation of acetone when a mixture of ethane and CO was irradiated with UV light [ 11. Pioneering work in this area was carried out by chemists at DuPont in the 1950s who were looking mainly at new polymer synthesis based on the use of ethylene and carbon monoxide as cheap feedstocks [2]. They observed that (i) polyketones were formed when peroxides were used as initiators, and (ii) even using gas mixtures under extremely high pressures and rich in carbon monoxide (>lo00 atm, ethylene/CO = 3/7), no evidence of consecutive CO trapping was observed in the obtained polymer structures. This suggests that the carbonylation of acyl radicals was particularly difficult. This polymerization chemistry served as a stimulus to others who prepared simple carbonyl compounds using radical carbonylations in the 1950s. However, up to the end of the 1980s, radical carbonylation chemistry largely failed to attract the attention of mainstream organic chemists. Research in the mid-1980s [3] broke ground for the renaissance of radical carbonylation chemistry that began in 1990 [4, 51. These efforts, which were mainly pursued by ourselves and a few other groups, clearly eradicated many of the prejudices surrounding this promising carbonylation method by virtue of the discovery of a multitude of useful synthetic reactions and kinetic data. It is now clear that radical carbonylations represent a powerful method for the preparation of a variety of carbonyl compounds [6]. This chapter will focus on applications of radical carbonylations that have been published during the past decade, with a special emphasis on tin, germanium, and silicon mediated systems. Accordingly, all radical carbonylations treated in this chapter are radical chain processes. One-electron reduction and oxidation systems, as well as atom transfer carbonylations, can also participate in radical carbonylation systems, but, because of space limitations, these methods will not be covered here. Irrespective of the reagents used for individual carbonylation reactions, the principle is simple (Scheme 1). The radical is generated from the requisite precursor, carbonylation is effected, and an appropriate trapping reagent traps the resulting acyl radical. Needless to say, the chemistry of radical carbonylations cannot be

1.2.2 Tin HydridelCO

23

substrates (radical precursors)

products:

Scheme 1. Basic concept of radical carbonylations

considered without knowledge of the chemistry of acyl radicals. Experts in this field [7] have recently published a review of the chemistry of acyl radicals. Readers are advised to consult this comprehensive review to have a complete understanding of the chemistry discussed here.

1.2.2 Tin Hydride/CO In 1990 Ryu and Sonoda reported the first efficient trapping of alkyl radicals by CO leading to the synthesis of aldehydes where alkyl bromides were used as the substrates and tributyltin hydride was used as a mediator for trapping the acyl radicals [S]. This work is the first breakthrough, which opened up the frozen gates of the long-forgotten chemistry. Scheme 2 illustrates an example of this formylation for the case of a primary alkyl radical. In general, a radical formylation reaction mediated by tin hydride requires high CO concentrations relative to tin hydride and also high dilution, which serves to compete with premature quenching of an alkyl radical by H-abstraction. A high CO concentration is also effective in competing with the course of the decarbonylation, and this is understandable from the wellknown fact that acyl radical generated from acyl selenide suffers from decarbonylation [9]. In the first equation of Scheme 3 , decarbonylation results from tin hydride-mediated reduction of an acyl selenide [lo]. However, decarbonylation pathway is not always a problem, since a rapid event such as 5-ex0 cyclization onto the styryl C-C double bond can overwhelm the decarbonylation course (Scheme 3, the second equation) [ 10, 111.

24

I .2 Radical Carbonylations Mediated by Tin, Germanium, and Silicon Reagents AlBN (10 mol%), C&3

+ CO

rB-

+

*

Bu3SnH

70 atm, 80 "C, 2 h

0.02 M 0.05 M

'-I

co . 0

*-

I 0

9Yo 20%

84% 66%

Scheme 2. Radical formylation using tributyltin hydride AIBN,

vSePh +

Bu3SnH

1OO"C, 2 h

*

0

0.02 M

60%

p

h

v

S

e

P

h +

BusSnH

AIBN, C6H6 I

100°C, 2 h

n

0.02 M

36%

U

- co

1

phrapid

&Ph 90%

not observed

Scheme 3. Important and unimportant decarbonylation reactions

Basic kinetic data surrounding the formylation scheme are now available [ 12, 131. Among the kinetic data, Ryu and coworkers measured rate constants for the addition of a primary alkyl radical to carbon monoxide, which were calibrated by an indirect method employing established kinetic data for the 5-exo mode of cycliza-

1.2.2 Tin HydridelCO

I

Ph

1

product (B)

products (A)

I

a

25

P

25 "C

p;

+

p'

k = 2.4 x 105s-1 k = 4.5 X 105s-1 Ref. 14 I

[CO] = [CO],

x (pressure)

[CO],

= 0.0084 M (60%) Ref. 15

Scheme 4. A plan to measure rate constants for the addition of a primary alkyl radical to CO

tion as a radical clock. The 'decarbonylation-free' cyclization system shown in Scheme 3 was used for the kinetic study to avoid the inherent complex numerical treatment. Scheme 4 summarizes a plan to estimate the approximate rate constant for the addition of primary alkyl radical to carbon monoxide. Rate constants for CO trapping of a primary radical were calculated from the experimental k/kco values with known values of k [ 141 and with postulated CO concentrations [ 151. Consequently, the calculated rate constant for addition of the radical to CO at 80°C is 6.3 x lo5 sK1MK' [lo]. It should be noted that the rate constants for the addition of methyl radical and cyclohexyl radical to CO were measured by Bakac and Goldman to be 2.0 x lo5 s-I M-I ('n 1 water, 25°C) [I61 and 1.2 x lo5 sK1M-' (in cyclohexane, 50 "C) [ 171, respectively. A variety of carbonyl compounds can be prepared, using tin hydride as a radical mediator. Table 1 illustrates examples of radical formylation of several organic halides. The reaction can be applied to aromatic formylation [I81 but not to stable radicals such as allyl, benzyl, alkoxymethyl, a-cyanoalkyl, and a-acylalkyl radicals.

26

1.2 Radical Carbonylations Mediated by Tin,Germanium, and Silicon Reagents

Table 1. Tin hydride-mediated radical carbonylations: Part 1

Run 1

Substrates

Reagents"

CO, Bu3SnH

Products

Yield ("A)

H-

Reference

I0

8

80

8

0

2

CO, Bu3SnH

3

CO, Bu3SnH

4

CO, Bu3SnH

68

18

5

CO, Bu3SnH

85

18

6

CO, Bu3SnH

71

19

59

22

46

22

36

22

40

22

7

CO, BulSnH @CN

8

CO, Bu3SnH @COOMe

T 0 COOMe

9

CO, Bu3SnH RCN

&

10

11

CN

CO, Bu3SnH @COMe CO, Bu3SnH @Ph

12

0

&

CO, Bu3SnH

"AIBN was used as a radical initiator in each reaction.

Ph

I . 2.3 Cyclizative Curhonylutions

27

As shown in the sixth example, 5-exo cyclization precedes carbonylation, thus giving aldehyde having a five-membered ring [ 191. The acyl radical has a nucleophilic character in terms of rapid rates of addition to electron-deficient alkenes. The rate of addition of an acyl radical to acrylonitrile was measured by Fischer and co-workers to be 5 x lo5 M-' s-' [20]. Using radical cascade reactions, carbon monoxide can be introduced directly into the carbonyl group of ketones. Indeed, the tin hydride-mediated radical coupling reaction of alkyl halides, CO, and electron-deficient alkenes permits the synthesis of unsymmetrical ketones. The scope of the alkenes in this transformation is similar to that of the acyl selenide/alkene/tin hydride system [21, 111 but covers a wider range of aliphatic (primary, secondary, tertiary), aromatic, and vinylic halides [22].Although it is not classified as an electron-deficient alkene, styrene can also be used. Table 1 summarizes some examples. To compete with the addition of the initial alkyl radical to the alkene and minimize premature quenching by radical mediators, a set of higher CO pressure and dilution conditions were used. In the case of the tin hydridemediated reaction, a three- to four-fold excess of alkene was generally used to suppress quenching of the acyl radical by tin hydride. One of the drawbacks of tin-mediated radical reactions is the tedious workup procedure involved in separating tin compounds from the products after the reaction. If one would like to examine parallel synthesis, which treats a number of reactions at the same time, the tedious workup does not allow for the isolation of a large number of compounds in a short period of time. Very recently, however, Curran and Hadida invented fluorous tin hydride [23].This has a distinct advantage over conventional tributyltin hydride: the use of fluorous/aqueous biphasic workup or fluorous reverse phase silica for purification [24] can circumvent the tedious workup. In a collaborative effort with the Curran group, Ryu and coworkers examined radical carbonylation using a fluorous tin hydride, with a special emphasis on the hydroxymethylation (formylation and in situ reduction) of organic halides using a catalytic quantity of a fluorous tin hydride and sodium cyanoborohydride as a reducing reagent [19]. Two-methylene spaced fluorous tin hydride was used for the formylation, and it was found that hydrogen donation ability is higher than tributyltin hydride (251. Thus, it is necessary to tune reaction conditions in the direction of higher dilution and higher pressures so as to compensate for the enhanced hydrogen donating ability of fluorous tin hydride. Importantly, this fluorous reagent, as is always the case for the related fluorous reactions [24], permits concise purification by a three-phase (aqueous/organic/fluorous) extractive workup and, as a result, the recovered fluorous tin hydride can be used repeatedly. Three examples of hydroxymethylation of adamantyl bromides are given in Scheme 5.

1.2.3 Cyclizative Carbonylations Radical carbonylations of 4-alkenyl halides are distinguished from those of other alkenyl halides, since an acyl radical resulting from a 4-alkenyl radical and CO is ready to undergo rapid 5-exo cyclization to form 3-oxocyclopentylcarbinyl radical.

28

1.2 Radical Carbonylations Mediated by Tin,Germanium, and Silicon Reagents

AlBN

+

80 atm, 90 OC, PhCFdt-BuOH 77%

(C~FI~CH~CH~)~S~H recovered from fluorous layer

81%

79%

Scheme 5. Hydroxymethylation of RX using a catalytic amount of a fluorous tin hydride

This radical can be quenched by tin hydride, but still is able to undergo tandem C-C bond-forming reactions if a rationally designed system follows. However, as summarized in Scheme 6, tandem sequences have to overcome the problem of isomerization to the thermodynamically more stable six-membered radical [26]. Table 2 lists several examples of cyclopentanone synthesis based on a 4+1 radical annulation process. The first example shown in Table 2 demonstrates that the 4-hexenyl radical/CO system faces this isomerization problem, which is difficult to suppress [27, 26al. Of course, some substituents, such as phenyl and alkoxycarbonyl groups, are effective in hindering such an isomerization process from 5 to 6 (runs 2, 3,4) [27].

- --

COor C=C

1

6 6 Bu3SnH

tandem reactions

v3s:H

&

Scheme 6. Possible reaction pathways in the 4-pentenyl radical/CO system

1.2.3 Cyclizutive Curbonylutions

29

Table 2. Tin hydride-mediated radical carbonylations: Part 2 Run

Substrates

Reagents"

1

2

CO, Bu3SnH

Br

E

t

o

W

B

r

CO, Bu3SnH

0

3

Br

Ph

Products

8-9.""

CO, Bu3SnH

Yield (YO)

Reference

43,21

21

60

21

62

21

40 ( E / Z = 213)

21

15, 53

21

&Ph

CO, Bu3SnH

4

&Ph

CO, Bu3SnH

5

CO, Bu3SnH

6

I

P C N

I

+CN

CO, Bu3SnH

---.?Ca-.

b 11 (cislfrans= 38/62)

44

28

40 (43/57)

28

8

CO, Bu3SnH

9

CO, Bu3SnH

29

10

CO, BujSnH

29

E = C02Me

"AIBN was used as a radical initiator in each reaction. 'Tsunoi, S.; Ryu, I.; Fukushima, H.; Tanaka, M.; Komatsu, M.; Sonoda, N . Synleft 1995, 1249.

30

1.2 Radical Carbonylations Mediated by Tin, Germanium, and Silicon Reagents

These are good substrates for obtaining cyclopentanone derivatives in good yields, whereas the resulting radicals are too stable to undergo the second carbonylation. In a system where the first carbonylative cyclization yields a primary radical, there is a good chance for the radical to undergo second carbonylation. Thus, using 90 atm of CO pressure, 4-keto aldehydes are formed in reasonable yields (runs 7, 8 in Table 2) [28]. Curran and Ryu jointly reported some tandem radical carbonylation reactions using Curran’s cyclopentadienyl system as an acceptor/precursor template [29].Two examples, (runs 9 and lo), which led to a tetracycle and tricycle respectively, are given in Table 2. In the first example, five consecutive C-C bondforming reactions (involving two carbonylation steps) took place successfully, leading to a tetracycle as a major product. In the second example, a tricyclic compound was obtained in good yield and excellent selectivity. The system contains an equilibration of E and Z unsaturated acyl radicals, with the latter undergoing cyclization, leading to a tetracycle, and cleavage to provide the malonyl type radical via a round trip. Chatgialialoglu and coworkers applied carbonylative cyclization to a unique synthesis of polyketones from 1,4-&-polybutadiene and CO [30]. This polymer contains a unit each of cyclopentanone and cyclohexanone as well as an unreacted olefin unit. Carbonylative 6-endo cyclization which leads to a selective formation of cyclohexanones is also possible using 4-pentenyl radical precursors having a substituent at the 4-position [31]. Scheme 7 illustrates such an example. Unlike the 4-alkenyl/CO system, the following two cyclization systems, based on C-N double bonds, are completely selective and favor a five-membered ring (Scheme 8). Fallis and Brinza who used a diphenylhydrazone derivative as an acyl radical trap [32] reported the first example in this series. As shown in the first two examples in Table 3 , radical carbonylation gave 2-hydrazinocyclopentanones in good yields. Ryu, Komatsu and coworkers reported acyl radical cyclization onto N-C double bond, which proceeds exclusively in a 542x0 manner to give pyrrolidinones in good yield (runs 3-5) [33]. For an aromatic substrate, it is necessary to use a ketimine rather than an aldimine, since aromatic radical abstracts an imine hy-

70% Scheme 7. Synthesis of a cyclohexanone by selective 6-endo cyclization

1.2.3 Cyclizutive Carhonylutions

31

Scheme 8. Two types of selective 5-ex0 cyclization onto N-C double bonds

/

+

CO

+

Bu3SnH

0.02 M

* h 80atm,llOoC,4

27%

1,5-H shift I

V-40

,$,s N

/

0

76%

Scheme 9. Carbonylative cyclization of an aromatic radical onto an N-C double bond

drogen, which leads to a fragmentation reaction (Scheme 9). The nitrogen-philic cyclization can be extended successfully to include 6-ex0 (run S ) , 7-ex0, and even 4exo cyclization. Scheme 10 illustrates the synthesis of a p-lactam by stannylcarbonylation of an azaenyne via a rare 4-ex0 type of radical cyclization [34]. Using Stille coupling conditions, each stereoisomer was successfully converted to an arylated product with retention of configuration. Stannylcarbonylation is also possible for 1,6-dienes [35]and vinylcyclopropanes [36]. However, in terms of the selectivity and product yields, the reaction using azaenynes is better. The next four examples shown in Table 3 demonstrate that tin hydride-mediated ~ reradical carbonylation can be efficiently combined with intramolecular S H type action of acyl radicals at sulfur, providing good yields of y-thiolactones [37].The ability of the tert-butyl radical as an S H 2 type leaving group is inferior to that of the benzyl radical [ 381. Nevertheless, the tert-butyl radical in this case has an advantage over the benzyl radical, since the starting benzylthiobutyl radical suffers an unde-

32

1.2 Radical Carbonylations Mediated by Tin, Germanium, and Silicon Reagents

Table 3. Tin hydride-mediated radical carbonylations: Part 3 Run

Substrates

Reagents"

1

CO, Bu3SnH

Products

Yield

Ph2NHN

75 (l/l)

32

81

33

65

33

49

33

14

37

86

31

60

31

78

37

61 ( E = CN) 62 ( E = CHO)

39

81

40

("/a)

Reference

U

2

3

CO, Bu3SnH

0B r,-,-,-N ./

CO, Bu3SnH

Ph2NHN&

04

4

C0'Bu3SnH

T&

5

6

CO, Bu3SnH

s 4

U

7

8

c

f-BUS

9

10

CO, Bu3SnH

sb .

q+' (E = CN, CHO)

E

11

CO, Bu3SnH

a0

"AIBN was used as a radical initiator in each reaction.

1.2.4 Germyl HydrideJCO

33

CO,AIBN, C6H6 A

N

/

+

*

Bu3SnH

90 atm, 90 "C, 8 h

70% (E/Z=32/68) Scheme 10. P-Lactam synthesis by stannylcarbonylation

sirable 1,5-H shift. An approximate rate constant of an acyl radical cyclization to extrude tert-butyl radical was determined to be 7.5 x lo3 s-' at 25 "C [37]. Recently, Miranda and coworkers reported that tin hydride-mediated radical carbonylation can be applied to include the synthesis of ketones fused with heterocyclic rings, such as pyrroles and indoles. In the example given in run 10, an acyl radical attack at aromatic carbon and in situ oxidation leads to an indole-fused cyclopentanone in good yield [39]. On the other hand, an example shown in run 11 makes use of a methanesulfonyl group as a leaving radical [40]. When a related substrate which does not contain a sulfonyl substituent was used, a simple radical formylation took place.

1.2.4 Germyl Hydride/CO To the best of our knowledge, only two reports describe radical carbonylation using germyl hydrides as the mediator. Germyl hydrides are quite expensive compared with tin and silicon hydrides, and this may limit their use as radical mediators. Kahne and Gupta reported the radical hydroxymethylation (formylation and in situ reduction) of organic halides using a catalytic amount of triphenylgermyl hydride in the presence of sodium cyanoborohydride as a reducing agent (Scheme 11) [41]. Hydroxymethylation of a sugar substrate proceeds stereoselectively (20: 1) to give the equatorial isomer. As has already been shown in Scheme 5 , it is obvious that a tin reagent can be used for a similar transformation to convert organic halides to the corresponding one-carbon homologated alcohols. Another example was reported by Ryu and coworkers, who examined the use of tributylgermyl hydride for cyclizative double carbonylation reactions (Scheme 6)

34

1.2 Radical Carbonylutions Mediated by Tin, Germanium, and Silicon Reagents

+ CO + NaBH3CN

10 rnol% Ph3GeH,AlBN 95 atrn, 105 OC,12 h *

+ CO + NaBH3CN

BzO

"""0

10 mol% Ph3GeH,AlBN 95 atrn, 105 OC, 12 h CrjHs-THF (5011)

Bzo OMe

37% (eq/ax= 2011)

Scheme 11. Hydroxymethylation using a catalytic amount of triphenylgermane

[28]. What they planned was to encourage the 5-ex0 cyclized radical to add to a second molecule of CO by discouraging premature quenching of the key radical, by employing a slower mediator than tris(trimethylsily1)silane. Contrary to their expectation, the yield of the desired keto aldehyde was dramatically decreased, and instead they discovered serendipitously the unusual formation of a bicyclic lactone (Scheme 12). This lactone corresponds to a product obtained via a 5-end0 cyclization of an acyl radical. However, two observations speak against such a rare 5-end0 cyclization pathway: (i) high dilution does not necessarily favor the formation of the

0.01 M

BunSnH

40% (43157)

4%

(42158)

Scheme 12. Tributylgermane-mediated double carbonylation of 5-iodo-1-heptene

I .2.5 Tris (trimethylsilyl)silane/CO

35

lactone and (ii) when 4-pentenyl bromide was used instead of iodide, lactone formation was completely suppressed. It was proposed that iodine atom transfer carbonylation would be permitted by a slow mediator system involving tributylgermyl hydride, and the resulting acyl iodide cyclizes spontaneously to give a lactone precursor. The concept of atom transfer carbonylation is now being established with many useful examples which will be reviewed elsewhere [42].

1.2.5 Tris(trimethylsilyl)silane/CO The typical triorganylsilanes are inert to radical reactions because their Si-H bonds are too strong to sustain a radical chain [43]. However, some reactive silanes, such as tris(trimethylsilyl)silane, (TMS)3SiH, are useful reagents which can be used to replace toxic tin reagents [44]. Kinetic studies by Chatgilialoglu and coworkers show that the ability of (TMS)3SiH for delivering hydrogen to alkyl radicals is rather modest compared with that of tin hydride [44]. During radical carbonylations, however, the use of silicon hydrides should be carefully treated on a case-bycase basis. For example, the reagent is not necessarily suited to formylation reactions leading to aldehydes or carbonylation of substrates having a C-C unsaturation, since the silane can cause undesirable hydrosilylation of these functionalities which can lower the yield of the desired products. Furthermore, care should be taken in regards to secondary ionic reactions of the product, which are induced by reactive ionic by-products, i.e. silicon halides. Ryu, Sonoda and coworkers reported that tris(trimethylsily1)silane is a useful mediator for a three-component coupling reaction [45]. Table 4 summarizes examples of radical carbonylations mediated by (TMS)3SiH. The first example shows a three-component coupling reaction in which hexyl iodide, CO, and acrylonitrile combine to form a P-cyano ketone. The CO addition step is in competition with the addition to the alkene and the hydrogen abstraction from radical mediator. Thus, it is anticipated that a set of less efficient hydrogen donors, such as (TMS)3SiH, and the use of a smaller excess amount of an alkene is most favorable. Indeed, the reaction can be carried out at only 20-30 atm of CO pressure, substantially below the 80-90 atm which is used for carbonylative acyl radical reactions which are mediated by tin hydride, and a nearly stoichiometric amount (1.2 equiv) of acrylonitrile is sufficient. Some other examples, which include vinyl radical carbonylation, are also shown in Table 4. Ryu, Sonoda and coworkers have investigated the macrocyclization of acyl radicals generated by the carbonylation of alkyl radicals which employ (TMS)3SiH as chain carrier [46]. Ring sizes from 10 and upwards could be successfully synthesized by [n+ 11 type annulation. Competing macrocyclizations of the initial alkyl radical do not appear to be a problem in this work when a combination of high dilution and 30 atm of CO pressure was used. It is interesting to note that Ikariya and Kishimoto recently investigated (TMS)3SiH-mediated radical carbonylation using supercritical carbon dioxide as a

36

1.2 Radical Carbonylations Mediated by Tin, Germanium, and Silicon Reagents

Table 4. (TMS)$iH-mediated radical carbonylations Run 1

Substrates

Reagents"

Products

Yield

CO, (TMS)3SiH

1-

P C N

2

I

P C N

3

CO, (TMS)jSiH

1-

Reference

70

45

67

45

CN

0

CO, (TMS),SiH

("/n)

/

0

CN

AH 67

45

69

45

45

45

68

46

70

46

36

46

P C H O

0

CO, (TMS)3SiH PCOOMe

'

I

d

O

M

e

0

CO, (TMS)3SiH

5

@COMe

EtO

0

6

===.p-l

CO, (TMS)3SiH

0

7

oL

CO, (TMS)3SiH

9 0 8

CO, (TMS)jSiH

85 48 (cisltrans = 66/34)

(TMS)3Si

10

&-+4,5A

C02Me

CO, (TMS)$3H (TMS)3Si

"AIBN was used as a radical initiator in each reaction.

C02Me

56 48 (cisltrans = 66/34)

1.2.6 AllyltinJCO

37

reaction medium [47]. They found that using 310 atm (partial CO pressure: 50 atm) of supercritical carbon dioxide the three-component coupling reaction comprised of n-octyl iodide, CO and acrylonitrile gave the unsymmetrical ketone in 90% isolated yield. The yield is dependent on the pressure of supercritical carbon dioxide, and at lower pressure the product yield decreased. They speculated that the excellent solubility of CO in s c C 0 ~at high total pressures accounts for the excellent yield. A further variant on the radical carbonylation/acyl radical cyclization theme involves the silylcarbonylation of 1,5-hexadienes [48]. Here, the sequence is initiated by the addition of a tris(trimethylsily1)silyl radical to the least substituted terminus of the diene. Carbonylation and acyl radical cyclization then ensues in the normal way. It should be noted that this type of carbonylation cannot be achieved with tin hydride, since the carbonylation rate is not sufficient to capture P-tin-attached alkyl radical, which quickly reverts to tin radical and the 1,5-diene.

1.2.6 Allyltin/CO Allyltin compounds behave as excellent ‘unimolecular chain transfer’ (UMCT) reagents [49] which serve as radical acceptors and sources of tin mediators [50]. Since acyl radicals are nucleophilic radicals, the addition reaction to allyltin, which is regarded as an electron rich alkene, is not a rapid process. Ryu, Sonoda, and coworkers found that unsaturated ketones can be synthesized by a three-component coupling reaction, comprised of alkyl halides, CO, and allyltin reagents [5 11. Because of the slow direct addition of alkyl radicals to allyltin compounds [50b], radical carbonylations with allyltin can be conducted at relatively low CO pressures, and high substrate concentrations (0.1-0.05 M) were used to ensure the chain length. The second example in Table 5 shows the cyclization-carbonylation-allylation sequence, in which 5-hexenyl radical cyclization precedes CO trapping. Because of the nucleophilic nature of acyl radicals, in a mixed alkene system comprised of an electron deficient alkene and allyltin, they favor the electron deficient alkene first and the resulting product radical, which have an electrophilic character, and then smoothly add to allyltributyltin. This four-component coupling reaction provides a powerful radical cascade approach leading to P-functionalized 8,eunsaturated ketones, which are not readily accessible by other methods [52]. Recent progress in allyltin-mediated radical carbonylation reactions include the use of fluorous allyltin reagents for a four-component coupling reaction [53].Propylene-spaced fluorous allyltin and methallyltin [ 541 proved particularly useful as reagents for four-component coupling reactions, where alkyl halides, CO, alkenes and allyltin are combined in the given sequence. In the example in Scheme 13, after the reaction, BTF (benzotrifluoride) was removed by vacuum evaporation and the resulting oil was chromatographed on fluorous reverse-phase silica gel (FRPS) [ 5 5 ] , which is ideal for the separation of products from tin compounds. The fluorous allyltin reagents were reproduced quantitatively by treatment of the tin residue with

38

1.2 Radical Carbonylations Mediated by Tin, Germanium, and Silicon Reagents

Table 5. Allyltin-mediated radical carbonylations Run

Substrates

Reagentsa

Products

co

Yield (uh)

Reference

70

51

66

51

65

b

70

52

70 ( E / Z = 90/10)

52

67

52

60

52

70

46b

*SnBu3

co y S n B u 3

co y S n B u 3

co F C H O *SnBu3 I

co F C N -SnBu3

co pCO2Me y S n B u 3

-

O

Y

M

e

co FCO~CHCH~ *SnBu3

I

co FCO2Me

y S n B u 3

co *SnBu3

"In each reaction, AIBN was used as a radical initiator. bRyu, I.; Yamazaki, H.; Sonoda, N. unpublished.

1.2.6 AllyltinlCO

39

Scheme 13. Separation of the fluorous reagent and product by fluorous reverse-phase silica (FRPS)

an ether solution of ally1 and methallyl magnesium bromides, which were subsequently reused. Carbonylation of fluorous compounds was also tested with the use of conventional tributyltin reagents. In this case the fluorous product is isolated from the fluorous media and conventional tin compounds are isolated from organic media. Unfortunately, the carbonylation of perfluoroalkyl radicals was unsuccessful, probably because of the very rapid reaction of these electrophilic radicals with allyltributyltin [56]. However, 2-( perfluoroalky1)ethyl radical can be used for this radical carbonylation. In this case, FRPS separation again works well for the preparation of the product from tin compounds. The final example shown in Table 5 shows that allyltin-mediated radical carbonylation can be successfully applied to macrocyclization, as in the case of tris(trimethylsily1)silane [46b]. Recent work has shown that the AIBN/allyltin system serves as an efficient radical initiator system which can be used as an alternative for light-induced atom transfer carbonylation [42b, 571. The radical carbonylation of an alkyl iodide in the presence of Kim's sulfonyl oxime ethers [58, 59, 601 provides a new type of multicomponent coupling reaction where plural radical C1 synthons are consecutively combined [61]. In the transformation, allyltin was used to serve as a trap of benzenesulfonyl radical which converts sulfonyl radical to a tin radical, thus creating a chain. Scheme 14 illustrates such an example, where the product was easily dehydroxylated to give the corresponding tricarbonyl compound on treatment with zinc/AcOH. The radical acylation reaction by Kim's sulfonyl oxime ethers can be conducted under irradiation with the addition of hexamethylditin. This is an alternative path for achieving a similar transformation without the use of photolysis equipment. Scheme 15 illustrates several examples where carbon monoxide and Kim's sulfonyl oxime ethers are successfully combined to create new tandem radical reaction sequences [61].

40

1.2 Radical Carbonylations Mediated by Tin, Germanium, and Silicon Reagents

Scheme 14. Use of allyltin as a trap for the benzenesulfonyl radical and a chain carrier

Scheme 15. Synthesis of singly and doubly acylated oxime ethers by radical cascade reactions

References

41

1.2.7 Conclusion It is clear that radical carbonylations, which are mediated by tin, germanium, and silicon reagents, are powerful tools for the synthesis of carbonyl compounds. The significance of this method derives from the fact that the initially generated radical adds to CO to form another radical (an acyl radical) that can then react with unsaturated species, such as alkenes, creating yet another new radical. The final products are obtained by quenching this radical with these Group XIV reagents to create a chain. This type of tandem strategy has now been expanded to include additions to carbon-heteroatom multiple bonds such as N-C double bonds irrespective of whether an intramolecular or an intermolecular trap is employed. Despite the tremendous recent progress in this area, there is a little doubt that many opportunities remain and that many exciting findings will be reported in the coming years.

References [ l ] K. Faltings, Ller. 1939, 72B, 1207. [2] (a) D. D. Coffman, P. S. Pinkney, W. H. Wall, H. S. Young, J. Am. Chem. Soc. 1952, 74, 3391. (b) M. M. Brubaker, D. D. Coffman, H. H. Hoehn, J. Am. Chem. Soc. 1952, 74, 1509. [3] (a) Giese, B. Radicals in Organic Synthesis: Formation of’ Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986. (b) Curran, D. P. Synthesis, 1988, 417 (part I); 489 (part 2). (c) Motherwell, W. B.; Crich, D. Free Radicul Chain Reactions in Organic Synthesis, Academic, London, 1992. (d) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237. (e) Beckwith, A. L. J.; Crich, D.; Duggan, P. J.; Yao, Q. Chem. Rev. 1997, 97, 3273. (f) Fallis, A. G.; Branza, I. M. Tetrahedron 1997, 53, 17543. (g) Curran, D. P.; Porter, N. A,; Giese, B. Stereochemistry of’Free Rudical Reactions, VCH; Weinheim, 1996. (h) Sibi, M. P.; Porter, N. A. Acc. Chem. Rcx, 1999, 32, 163. (i) Baguley, P. A,; Walton, J. C. Anyew. Chem. Int. Ed. 1998, 37, 3072. 141 Rhy, I.; Sonoda, N. Angew. Chem. Int. Ed. Engl 1996, 35, 1050. [ S ] Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177. 161 For a review on synthesis of carbonyl compounds by radical reactions, see: I. Ryu, M. Komatsu, in Modern Carbonyl Chemistry, J. Otera (Ed.), Wiley-VCH, Weinheim, 2000, pp 93- 129. [7] C. Chatgilialoglu, D. Crich, M. Komatsu, I. Ryu, Chem. Rev. 1999, 99, 1991. [S] 1. Ryu, K. Kusano, A. Ogawa, N. Kambe, N. Sonoda, J. Am. Chem. Soc. 1990, 112, 1295. 191 (a) J. Pfenninger, C. Henberger, W. Graf, Helv. Chim. Acta 1980, 63, 2328. (b) J. Pfenninger, W. Graf, Helv. Chim. Acta 1980, 63, 1562. [lo] K. Nagahara, I. Ryu, N. Kambe, M. Komatsu, N. Sonoda, J. Org. Chem. 1995, 60, 7384. [ l l ] C . E. Schwartz, D. P. Curran, J. Am. Chem. Soc. 1990, 112, 9272. [I21 C. E. Brown, A. G. Neville, D. M. Rayner, K. U. Ingold, J. Lusztyk, Aust. J. Client 1995, 48, 363. [ 131 C. Chatgilialoglu, C. Ferreri, M. Lucarini, P. Pedrielli, G. F. Pedulli, Organometallics 1995, 14, 2672. [I41 A. L. J. Beckwith, C. J. Easton, T. Lawrence, A. K. Serelis, Aust. J. Chem. 1983, 36, 545. [IS] P. G. T. Fogg, W. Gerrard, Solubility qf’ Gases in Liquids, Wiley, New York, 1991, p. 274.

42

1.2 Rudicul Curbonylutions Mediuted by Tin, Germanium, and Silicon Reagents

[I61 (a) A. Bakac, J. H. Espenson, J. Chem. Soc., Chem. Commun. 1991, 1497. (b) A. Bakac, J. H. Espenson, V. G. Young, Jr., Inorg. Chem. 1992,31, 4959. [I71 W. T. Boese, A. S. Goldman, Tetrahedron Lett. 1992, 33, 2119. [ 181 I. Ryu, K. Kusano, N. Masumi, H. Yamazaki, A. Ogawa, N. Sonoda, Tetrahedron Lett. 1990, 31, 6887. (191 I. Ryu, T. Niguma, S. Minakata, M. Komatsu, S. Hadida, D. P. Curran, Tetrahedron Lett. 1997,38, 7883. [20] F. Jent. H. Paul, E. Roduner, M. Heming, H. Fischer, Int. J. Chem. Kinet. 1986, 18, 1113. [21] D. L. Boger, R. J. Mathvink, J. Org. Chem. 1989, 54, 1777. [22] I. Ryu, K. Kusano, H. Yamazaki, N. Sonoda, J. Org. Chem. 1991,56, 5003. [23] D. P. Curran, S. Hadida, J. Am. Chem. Soc. 1996, 118, 2531. [24] D. P. Curran, Angew. Chem. Int. Ed. 1998, 37, 1174. [25] J. H. Homer, F. N. Martinez, M. Newcomb, S. Hadida, D. P. Curran, Tetrahedron Lett. 1997, 38, 2783. (261 (a) C. Chatgilialoglu, C. Ferreri, M. Luarini, A. Venturini, A. A. Zavitsas, Chem. Eur. J. 1997, 3, 376. (b) C. Wang, X. Gu, M. S. Yu, D. P. Curran, Tetrahedron, 1998, 54, 8355. (c) I. Ryu, H. Fukushima, T. Okuda, K. Matsu, N. Kambe, N. Sonoda, M. Komatsu, Synlett 1997, 1265. [27] I. Ryu, K. Kusano, M. Hasegawa, N. Kambe, N. Sonoda, J. Chem. Soc., Chem. Commun. 1991, 1018. [28] S. Tsunoi, I. Ryu, S. Yamasaki, H. Fukushima, M. Tanaka, M. Komatsu, N. Sonoda, J. Am. Chem. Soc. 1996, 118, 10670. [29] D. P. Curran, J. Sisko, A. Balog, N. Sonoda, K. Nagahara, I. Ryu, J. Chem. Soc., Perkin Trans 1 1998, 1591. [30] (a) C. Chatgilialoglu, C. Ferreri, A. Sommazzi, J. Am. Chem. Soc. 1996, 118, 7223. (b) A. Sommazzi, N. Cardi, F. Garbassi, C. Chatgilialoglu, U.S. Patent 5;369.187 (1994). [31] I. Ryu, T. Kawamura, F. Araki, M. Komatsu, unpublished. [32] I. M. Brinza, A. G. Fallis, J. Org. Chem. 1996, 61, 3580. [33] I. Ryu, K. Matsu, S. Minakata, M. Komatsu, J. Am. Chem. Soc. 1998, 120, 5838. [34] I. Ryu, H. Miyazato, H. Kuriyama, M. Komatsu, unpublished. [35] I. Ryu, A. Kurihara, H. Muraoka, S. Tsunoi, N. Kambe, N. Sonoda, J. Ory. Chem. 1994. 59, 7570. [36] S. Tsunoi, I. Ryu, H. Muraoka, M. Tanaka, M. Komatsu, N. Sonoda, Tetrahedron Lett. 1996, 37, 6729. [37] I. Ryu, T. Okuda, K. Nagahara, N. Kambe, M. Komatsu, N. Sonoda, J. Org. Chem. 1997,62, 7550. [38] J. A. Frdnz, D. H. Roberts, K. F. Ferris, J. Org. Chem. 1987, 52, 2256. [39] L. D. Miranda, R. Cruz-Almanza, M. Pavon, J . M. Muchowski, Tetrahedron Lett. 1999, 40, 7153. [40] L. D. Mirdnda, R. Cruz-Almanza, A. Alvarez-Garcia, J. M. Muchowski, Tetrahedron Lett. 2000,41, 3035. [41] V. Gupta, D. Kahne, Tetrahedron Lett. 1993, 34, 591. (421 (a) K. Nagahara, I. Ryu, M. Komatsu, N. Sonoda, J. Am. Chem. Soc. 1997. 119, 5465. (b) I. Ryu, K. Nagahara, N. Kambe, N. Sonoda, S. Kreimerman, M. Komatsu, Chem. Commun. 1998, 1953. (c) I. Ryu, Chem. Soc. Reu. 2001, 30. [43] C. Chatgilialoglu, Arc. Chenz. Res. 1992, 25, 188. 1441 (a) C. Chatgilialoglu, Chem. Rev. 1995, 95, 1229-1251. (b) C. Chatgilialoglu, C. Ferreri, T. Gimisis, The Chemistry c?f Organic Silicon Compounds, Vol 2; S. Rappoport, Y, Apeloig, (Eds.); Wiley: London, 1998; Chapter 25; pp 1539-1579. [45] I. Ryu, M. Hasegawa, A. Kurihara, A. Ogawa, S. Tsunoi, N. Sonoda, Synlett 1993, 143. [46] (a) I. Ryu, K. Nagahara, H. Yamazaki, S. Tsunoi, N. Sonoda, Synlett 1994, 643. (b) K. Nagahara, I. Ryu, H. Yamazaki, N. Kambe, M. Komatsu, N. Sonoda, A. Baba, Tetrahedron 1997, 53, 14615. [47] Y. Kishimoto, T. Ikariya, J. Ory. Chem. 2000, 65, 7656. [48] 1. Ryu, K. Nagahara, A. Kurihara, M. Komatsu, N. Sonoda, J. Organomet. Chem. 1997, 548, 105. [49] D. P. Curran, J. Xu, E. Lazzarini, J. C k m . Soc., Perkin Trans. I, 1995, 3049.

Refereiz ces

43

1501 (a) G. Keck, E. J. Enholm, J. B. Yates, M. R. Wiley, Tetrahedron 1985, 41, 4079. (b) D. P. Curran, P. A. van Elburg, B. Giese, S. Gilges, Tetrahedron Lett. 1990, 31, 2861. 1511 I. Ryu, H. Yamazaki, K. Kusano, A. Ogawa, N. Sonoda, J. Am. Chein. Soc. 1991,113,8558. 1521 I. Ryu, H. Yamazaki, A. Ogawa, N. Kambe, N. Sonoda, J. Am. Chem. Soc. 1993, 115, 1187. [53] I. Ryu, T. Niguma, S. Minakata, M. Komatsu, Z. Luo, D. P. Curran, Tetrahedron Lett. 1999, 40, 2361. 1541 D. P. Curran, Z. Luo, P. Degenkolb, Bioorg. Med. Chem. Lett. 1998, 8, 2403. 1551 (a) D. P. Curran, S. Hadida, M. He, J. Org. Chem. 1997, 62, 6714. (b) S. Kainz, Z. Luo, D. P. Curran, W. Leitner, Synthesis 1998, 1425. 1561 I. Ryu, S. Kreimerman, T. Niguma, S. Minakata, M. Komatsu, Z. Luo, D. P. Curran, Tetrahedron Lett. 2001, 42, 947. [57] S. Kreimerman, I.Ryu, S. Minakata, M. Komatsu, Org. Lett. 2000, 2, 389. 1.581 S. Kim, I.Y. Lee, J.-Y. Yoon, D. H. Oh, J. Am. Chem. Soc. 1996, 118, 5138. 1591 S. Kim, J.-Y. Yoon, J. Am. Chem. Soc. 1997, 119, 5982. 1601 S. Kim, J.-Y. Yoon, I. Y. Lee, Synlett 1997, 475. 1611 I. Ryu, H. Kuriyama, S. Minakata, M. Komatsu, J.-Y. Yoon, S. Kim, J. Am. Chem. Soc. 1999, 121, 12190.

Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

1.3 Isonitriles: a Useful Trap in Radical Chemistry Daniele Nanni

1.3.1 Introduction Isonitriles are a unique class of organic compounds, as they are the only stable derivatives (apart from carbon monoxide) containing formally a bivalent carbon. Their discovery by Lieke, Gautier, and Hofmann dates back more than 130 years, but up to the 1960s only a relatively small number of studies concerning their chemistry had been reported [ I ] . This was probably because of the virtual absence of convenient, generally applicable synthetic methods, as well as their very penetrating, unpleasant smell. The two classical isonitrile syntheses remained for a long time the ‘carbylamine reaction’ and the ‘alkylation method’. The former [ l a ] involves the reaction of a primary amine with chloroform and a strong base and entails addition of a dichlorocarbene to the amino group, followed by elimination of hydrogen chloride. Due to the strong odor of the resulting isonitrile, this method was usually recommended for qualitative detection of primary amines. The ‘alkylation’ route [ la,c] requires treatment of metal cyanides with alkylating agents such as halogen compounds or dialkyl sulfates; since the cyanide ion is an ambident nucleophile, the reaction yields mixtures of nitrile and isonitrile derivatives. However, a marked preference for the latter is observed in the presence of heavy metal cyanides (especially silver), which gives rise to isocyanide-transition metal complexes that are then transformed into the desired isonitriles by treatment with potassium cyanide. In general, these two reactions are definitely not suitable for the preparation of appreciable quantities of pure isonitriles: indeed, they have been largely replaced by the more widely applicable ‘dehydration method’ [ lc,d,f]. This was first discovered by Hagedorn in 1956 and entails transformation of primary amines into formamides, followed by dehydration either with phosgene (or its precursors) and triethylamine, or phosphorus oxychloride and di-iso-propylamine [ 1f]. The chemistry of isonitriles, now readily accessible by this very general method, has thus flourished in the last four decades, not only proving that these compounds are not merely a curiosity in the field of organic chemistry, but also indicating that they possess an outstanding versatility. Noteworthy synthetic procedures, all of them involving attack of electrophilic species (e.g., carbenium and iminium ions) on the

1.3.2 Radical AdditionlFragmentation Reactions: the Fate of Imidoyl Radicals

45

Scheme 1. Resonance in isonitrile structure

nucleophilic carbon of the isonitrile, include Ritter-type processes [ le] and the Passerini and Ugi reactions [ If]. The latter are remarkable one-pot, multi-component reactions that easily afford, usually in high yields and often in a stereoselective way, a wide range of functionalized carboxamides, lactams, amino acids, and peptides. As anticipated, the structure of isonitriles can be described in terms of a divalent carbon atom, but, in valence bond terms, a full description of the isonitrile moiety requires the two resonance structures 1 and 2 (Scheme 1). Physical properties indicate that the dipolar contribution (1) is the major one and this structure actually accounts for the nucleophilic behavior of the terminal carbon of isonitriles. However, in terms of radical chemistry, the more interesting form is the divalent one (2). This clearly shows that the isonitrile group does not behave toward radical species like a vicinal radical acceptor/radical donor synthon, that is, like an usual unsaturated bond. It instead reacts like a gerninal acceptor/donor synthon [2], where an incoming radical attacks the same carbon atom that will be the new radical center in the resulting imidoyl intermediate 3 (Scheme 1). Actually, isonitriles can serve as very efficient radical traps and this chapter reviews the structural, mechanistic, and synthetic studies carried out in this field, with outstanding results, in the last three decades.

1.3.2 Radical Addition/Fragmentation Reactions: the Fate of Imidoyl Radicals The first examples of radical addition to isonitriles were reported in the sixties. In 1967 Shaw [ 3 ] observed the isonitrile-nitrile isomerization of methyl and ethyl isonitrile when heated in the presence of catalytic amounts of di-tert-butyl peroxide (DTBP). Although the concerted isonitrile-nitrile thermal (or photochemical) isomerization had been well known for many years [ le], he suggested a radical chain mechanism, based on thermodynamic and kinetic data, involving addition of methyl radicals to isonitrile 2. This is followed by p-scission of the resulting radical adduct, imidoyl radical 3: the fragmentation gives rise to an alkyl radical, the chainpropagating species, that is finally responsible for the complete conversion of the starting isonitrile into cyano compound 4 (Scheme 2). The feasibility of a radical attack on the carbon atom of isonitriles was then who studied the reaction of tributyltin hydride with alkyl claimed by Saegusa [4], isonitriles. Formation of alkane and tributyltin cyanide, together with the need for a

46 DTBP

1.3 Isonitriles: a Useful Trap in Radical Chemistry

- A

Me.

2 R-N=C-Me (R = Me, Et)

T N=C-Me

Scheme 2. DTBP-mediated isomerization of alkyl isonitriles

Bu3SnH /In.

\Bu3SnH R-N=C-SnBu,

R.

Bu3SnCN Scheme 3. Radical chain reaction of isonitriles with tributyltin hydride

radical initiator (AIBN), supported a radical chain mechanism entailing addition of tin radicals to the isonitrile (Scheme 3). From 1970 to 1980, several papers reported the addition of carbon [5c,e,f,h], oxygen [5b-d,f], sulfur [5a,d,f],silicon [5d,f], phosphorus [5d,f], and tin [5g] radicals to isonitriles. Interestingly, the fate of the intermediate imidoyl radical depends upon the nature of both the attacking radical and the R alkyl group of the isonitrile. Normally, (reactions were usually carried out with tert-butyl isonitrile) addition of oxygen- or sulfur-centered radicals gives an imidoyl ( 5 ) that suffers P-fragmentation of the 0 - Y or S-Y bond of the attacking radical to give isocyanates or isothiocyanates (6),respectively (Scheme 4, path a). On the other hand, carbon, tin, and silicon radicals produce nitriles 7 through /&fragmentation of the N-R bond of the isonitrile (Scheme 4, path b). However, this behavior is not completely general, since fragmentation of likewise substituted imidoyls 5 can follow two competitive pathways depending on the stability of the released radical (R or Y ) . For instance, addition of methylsulfanyl radicals to tert-butyl isonitrile does not afford tert-butyl isothiocyanate (6, R = tertBu, X = S) but instead methyl thiocyanate (7, XY = SMe), due to preferential formation of the more stable tert-butyl radical [5f]. Such reactions have a noteworthy synthetic potential: they were used as an effi-

1.3.3 Structure and Kinetics of' Radical Adducts to Isonitriles

R-N=C: 2

+ .XY

-

a

47

R-N=C=X

v

6 (X = 0, S )

R-N=C-XY 5

'L -R-

N=C-XY

7 (XY = R3Sn, R'3Si, R'3C)

Scheme 4. Fragmentation pathways of imidoyl radicals

cient, easy way to introduce a cyano group into a molecule [5h, 61 or, by prior conversion of an amino group into the isonitrile moiety, as a useful deamination method [5g, 71. It should be noted that imidoyl radicals 5, when generated by other routes, could undergo an additional fragmentation reaction, that is, an a-scission with release of the XY radical. This process was observed with a-(tributy1tin)thio [8], M (arylsulfanyl) [9], and ce(triphenylmethy1)imidoyl radicals [lo], generated by either radical addition to isothiocyanates or hydrogen abstraction from the corresponding imines. When imidoyl radicals are produced from isonitriles, this behavior would result in a reversibility of the radical addition process. Actually, evidence has been reported that formation of imidoyl 5 from 2 seems to be reversible, at least with particularly stable XY radicals [6]; this could definitely be an important detail that should be taken into account in designing a synthetic project involving isonitriles.

1.3.3 Structure and Kinetics of Radical Adducts to Isonitriles: ESR Studies on Imidoyl Radicals The first study on the structure of imidoyl radicals dates back to 1973 [ 111, when Danen described the ESR spectra of the radicals obtained by irradiation of cyclopropane solutions of some aldimines and di-tert-butyl peroxide. On the basis of the low g-values (2.0016) and the P-hydrogen hyperfine splittings, the authors claimed that imidoyls are 0-radicals with a non-linear arrangement about the N=C-C bond. The facile abstraction of the aldiminic hydrogen, and hence the remarkable stabilization of imidoyl radicals, was explained by the intervention of the mesomeric forms 3a and 3b (Scheme 5 ) , in which the unpaired electron is stabilized by interaction with the lone pair on nitrogen. The low a N values exhibited by imidoyls (1.20-1.85 G) could be accounted for through a spin polarization mechanism that induces negative spin density at the nitrogen, somewhat balancing the positive spin density resulting from resonance effect. In subsequent papers [5d,f], Roberts used isonitriles as the source of various r-heteroatom-substituted imidoyl radicals and calculated some rate constants for both the radical addition steps and the /?-fragmentation processes (Scheme 4, routes

1.3 Isonitriles: a Useful Trap in Radical Chemistry

48 R\

..

*

N=C, 3a

Rl

-

R,

z

N=C,

R1

3b

Scheme 5. Resonance in imidoyl radical structure

a and b). Using INDO calculations, he also predicted for the unsubstituted imidoyl (R = R ' = H) a trans configuration that is in reasonable agreement with the observed low aN values. Furthermore, the a( I3C,) and aNvalues were found to depend upon the nature of R ' : in particular, the more electronegative R ' is, the greater a(13C,)and the N=C-C angle are. At the same time, the ability of R ' to stabilize negative charge on C , enhances positive spin density on nitrogen and hence the magnitude of aN. With R ' = SiEt3, the low electronegativity of silicon leads to quite a low a( 13Ca)value (29.8 G), whereas the ability of the silyl group to stabilize an adjacent negative charge gives rise to relatively large nitrogen hyperfine splittings (8.6 G). This particular imidoyl radical appears close to linear at C , , similar to what was proposed for isoelectronic a-(trialkylsily1)vinylradicals [ 121. More recently, analogous studies were carried out on the addition of electrophilic radicals to methyl and tert-butyl isonitrile [ 131. 1, l-Bis(alkoxycarbony1)alkyl-and tris(ethoxycarbony1)methyl radicals were found to add to the (nucleophilic) carbon atom of isonitriles more rapidly than simple (nucleophilic) alkyl radicals, and the addition to isonitriles is faster than that of the same radicals to ethene. This is a result of charge transfer interactions in the transition state and proves once again the importance of polar effects in many radical reactions. The resulting imidoyl radicals are strongly bent at C,, and the extent of bending increases with the number of electron-withdrawing groups attached to Cp, as expected from the previous studies [5f].The authors suggested that polar effects should be definitely taken into account in planning useful radical procedures with isonitriles: substituent effects that increase both the nucleophilicity of the isonitrile and the electrophilicity of the attacking species might provide a proper basis for successful synthetic developments. As far as the structure of imidoyl radicals is concerned, it is worth noting that their geometry and the degree of delocalization of the unpaired electron seem to depend on both the a-group and the nitrogen substituent, particularly when this is an aromatic ring [ 141. Moreover, semiempirical calculations showed that the imidoyl radical center can change its hybridization and geometry, provided it is bonded to a group that allows delocalization of the spin density, for example, a carboncarbon double bond [61.

1.3.4 Synthesis of Heterocyclic Compounds: Addition to Aromatic Isonitriles Imidoyl radicals are in principle very attractive intermediates for the synthesis of N-heterocycles. Actually, during the great upsurge of synthetic work carried out

1.3.4 Synthesis of Heterocyclic Compounds: Addition to Aromatic Isonitriles

8

9

10

13

12

11

49

Scheme 6. The Curran annulation for cyclopenta-fused quinolines

through radical reactions in the 1970s and, especially, the 1980s, they had been effectively employed in the construction of several heterocyclic compounds. However, in all cases they had been generated from imines or imidoyl derivatives as precursors [ 151. Only since 1991 has generation of imidoyl radicals from isonitriles been successfully employed in the synthesis of heterocycles. In his pioneering work [2], Curran carried out several reactions using aryl isonitriles 8 and alkyn-5-yl radicals 9, generated from the corresponding iodides. The reactions, the first examples of [4+1] radical annulations, afforded cyclopenta-fused quinolines 12 and 13 (in 36-70% yields) through addition of 9 to the isonitrile, 5-exo-dig-cyclization of the resulting imidoyl 10 onto the carbon-carbon triple bond, and final ring closure of vinyl radical 11 (Scheme 6). The rearranged product 13 was explained in terms of competitive 6- and 5-membered ring closures of the vinyl radical, as previously suggested for analogous annulations involving imidoyl radicals and alkynes [ 154. The cyclopenta-fused quinoline moiety is one of the main structural features of the antitumor agents of the camptothecin family (14, Fig. l), a group of molecules that has recently moved to the forefront of research in the treatment of solid tumors by chemotherapy. Starting from key intermediates containing the pyridone (D) and lactone (E) rings, the cascade radical reaction shown in Scheme 6 has been an outstanding breakthrough for the synthesis of (20s)-camptothecin (14a) and a wide series of approved drugs (topotecan and irinotecan) and drug candidates [ 161. The stereochemical requirements for the synthesis were fulfilled starting from enantiomerically pure alkynes 16, whereas the regiocontrol was achieved, when necessary (the [4+ 11 annulation can afford mixtures of quinoline derivatives, see Scheme 6), using ortho-(trimethylsily1)-substitutedarylisonitriles 15 (Scheme 7). In conclusion, the authors set up an asymmetric, regioselective, and widely applicable protocol that allowed the synthesis of more than fifty different compounds, proving once more the broad scope and functional-group tolerance of radical reactions. Analogous reactions leading to heterocyclic compounds were carried out in the same years by Tundo and coworkers by reacting aromatic isonitriles with alkyl and sulfanyl radicals bearing a cyano-substituted side-chain. In the first example [ 171,

50

1.3 Isonitriles: a Useful Trap in Radical Chemistry

Camptothecin a: R7-R” = H 9-Arninocarnptothecin(9-AC) b: R7, R’O, R” = H; R9 = NHz TopotecanTM(TPT) c: R7, R’’ = H; Rg = CHzNMe2; R’O = OH lrinotecanTM(CPT-11) d: R9, R” = H; R7 = Et; RIO = O C O N > N s GI-147211C

e: R9 = H; R’O-R’l = OCH2CH20; R7 = H2C-N

n

N-Me

U

Figure 1. Camptothecin derivatives synthesized by the Curran method

R9

15

0

16

Scheme 7. Reagents and conditions of Curran annulation for Camptothecin derivatives

the alkyl radical was generated in a three-component system comprising, besides the isonitrile, azo-bis-iso-butyronitrile (AIBN) and phenylacetylene. Decomposition of AIBN gives 2-cyanoprop-2-yl radical 17, which adds to the terminal carbon of the alkyne to give vinyl radical 18; addition of 18 to the isonitrile affords imidoyl radical 19, whose tandem cyclization leads to the quinoxaline derivative 20 (Scheme 8). This was the first trimolecular version of the radical addition, tandem cyclization strategy. The reaction also yielded small amounts of products derived from direct attack of radical 17 on the isonitrile and subsequent addition of the resulting imidoyl to phenylacetylene; however, compared to the route shown in Scheme 8, this was a very negligible competing process. The same overall results were obtained in more usual two-component reactions carried out through generation of the cyano-substituted alkyl radical by photolysis of the corresponding iodide [18]. In these papers the authors also showed that, in the absence of good oxidizing agents, isonitriles can be involved in the oxidation step of the cyclohexadienyl radical precursor of the final aromatic compound 20. At this stage it is not clear whether 8 is transformed into imidoyl 21 through a direct

1.3.4 Synthesis of Heterocyclic Compounds: Addition to Aromatic Isonitriles

17

51

Ph

18

19

Scheme 8. The Tundo three-component annulation for cyclopenta-fused quinoxalines H-atom-abstraction

Scheme 9. Isonitriles as aromatizing agents of cyclohexadienyl radicals

hydrogen abstraction, a mechanism that is the disproportionation analog of a radical-radical reaction, or a two-step reaction entailing an electron-transfer step (Scheme 9, routes a and b, respectively). However, the intermediacy of imidoyl 21 was clearly demonstrated, since it gave rise to competing [4+2] and [3+2] annulations with phenylacetylene to give the two isomeric quinolines 22 and 23, a route that is typical of annulation involving imidoyl radicals (see Scheme 6) [15c]. Analogous [4+ 11 annulations were also obtained starting from isonitriles and pcyano-substituted sulfanyl radicals, generated either by hydrogen abstraction from aliphatic thiols or (more profitably) through photolysis of aromatic disulfides [ 181. The reactions afforded thieno- (24) and benzothienoquinoxalines (25), respectively (Scheme 10). It is worth noting that, unlike the analogous reactions with alkynes, all of these annulations involving the cyano group always led to a unique quinoxaline derivative, since the final iminyl radical cyclizes onto the aromatic ring of the isonitrile in an exclusive 1,6-fashion.

52

1.3 Isonitriles: a Usejul Trap in Radical Chemistry

24

..-

25

Scheme 10. [4+ 11 Annulations with isonitriles and sulfanyl radicals

Aromatic isonitriles, particularly ortho-alkenyl-substituted aryl isonitriles, were also successfully employed by Fukuyama in the synthesis of indole derivatives [ 191. Cyclization of compounds 26 was accomplished with tin radicals, and 6-membered ring closure did not significantly compete except in one case (R = n-Bu) where, on the other hand, this problem was interestingly alleviated by using the Z-alkene instead of the E-analog (Scheme 11). The reaction products are the N-unprotected 2-stannylindoles 27, which are available for further manipulation through the Stille palladium-mediated coupling with aromatic or unsaturated halides or triflates. Since a very wide variety of functional groups are known to tolerate both radical and palladium-mediated reactions, this synthesis was an interesting innovation for the construction of 3- or 2,3-substituted indoles. It was effectively employed in the approach to some key intermediates for the total syntheses of indole alkaloids [19b] (Scheme 12).

1 Bu3SnH

H

3uBnS$-J( H d

:

H1 N

27

Scheme 11. The Fukuyama synthesis of indole derivatives

1.3.4 Synthesis of Heterocyclic Compounds: Addition to Aromatic Isonitriles

53

===3

NHZ COZMe

0

OBn

MeOZC

OBn

Discorhabdin A

c$,

\

COZMe BOC

H

Vincadifformine

Scheme 12. Ketrosynthetic approach to indole alkaloids through the Fukuyama method

dTMs - a rTMS

Bu3SnH

dTMY

initiation

/

NC 28

RSH

initiation

SnBu3

Bu3SnH

~ ~ 0 '

29

dyRs

H

30 RS)/-TMS

/

H 31

32

Scheme 13. The Rainier synthesis of indole derivatives

Very recently, a variant of this methodology was developed by the same author through tin-radical-mediated cyclization of ortho-alkenyl-substituted thioanilides [20]. Moreover, Rainier et al. demonstrated that a very efficient synthesis of indoles can be carried out also with ortho-alkynyl-substituted aryl isonitriles, provided that a TMS group is linked to the alkyne moiety [21] (Scheme 13). With this substrate (28) the ring closure can be conveniently accomplished with either stannyl or sulfanyl radicals with no concomitant formation of the sixmembered-cyclization quinoline product, which is present instead, or is predominantly formed, in all of the reaction mixtures obtained with group other than TMS. At the same time, both radical precursors, that is, stannane and thiol, can serve as nucleophiles for the intermediate indolenines 29 and 31, which are trapped to give the final substituted indoles 30 and 32 with high efficiency.

54

1.3 Isonitriles: a Useful Trap in Radical Chemistry

1.3.5 Synthesis of Heterocyclic Compounds: Addition to Aliphatic Isonitriles In 1970 Saegusa paved the way for applications based on radical addition of thiols to isonitriles. Unexpectedly, for more than twenty years, no synthetic work followed his observations. Chemists had to wait for the 1990s to witness the development of synthetic methods based on Saegusa’s work. The pioneer in this field was Bachi, who exploited the potentialities of this reaction for the synthesis of 5-membered nitrogen heterocycles starting from aliphatic isonitriles bearing a suitable unsaturated side chain [22]. The first results were obtained with the alkenyl-substituted isonitriles 33, easily accessible from glycine imines. Treatment of 33 with benzenethiol or an alkanethiol in the presence of AIBN gave high yields of the cis- and trans-pyrroline derivatives 35, according to Scheme 14 [22a]. Slower cyclizations (R’ # H) were more conveniently carried out with an alkanethiol. The reaction of 33 (R’ = R 2 = R 3 = H) with mercaptoethanol afforded instead a mixture of cisand trans-pyroglutamates 36. Fragmentation of imidoyl radical 34 to isothiocyanate was sometimes a competing process, especially when R’ # H and the scission yields a fairly stable radical (e.g., R 5 = CH2COZMe); in those cases, control over the two competing reactions was gained by adequate temperature adjustment. Analogous cyclizations were performed on the silylated alkynyl isonitriles 37 (R’ = TBDPS or TBDMS), which required higher temperatures (Scheme 15), and allylsulfides 38, which underwent an interesting cyclization-isomerization process mediated by catalytic amounts of sulfanyl radicals (Scheme 16). Very little or no diastereoselectivity was observed in the formation of pyrrolines 35, whereas somewhat better results were obtained with pyroglutamate 36 (R4 = tert-Bu), which was formed in a 1:2.5 cisltruns ratio. An efficient stereocontrol of the key cyclization step was however achieved with suitably designed starting materials bearing a bulky OTBDMS group vicinal to the site of radical addition [22b]. Cyclization of the syn-isonitrile 39 with either ethanethiol or mer-

R2

R5SH

:‘“$I- “8’ “3’ ‘’ld’ R3

~5.53~

R’

initiation

CN

C02R4 R5SAN

C02R4

C O ~ R ~

34

33

+

R3

R5S

R5S

R3

R5S

C O ~ R ~ cis-35

C O ~ R ~

trans-35

initiation

33

cis-36

trans-36

Scheme 14. The Bachi synthesis of pyrrolines and pyroglutamates with alkenyl isonitriles

1.3.5 Synthesis of Heterocyclic Compounds: Addition to Aliphatic Isonitriles

55

R3SH F

O

"

R'\ CNAC02R2

37 HO*SH

O

d

C02R2 l

Scheme 15. The Bachi synthesis of pyrrolines and pyroglutamates with alkynyl isonitriles SPh

SPh I

P

h

S

T

PhS

C N*C02Et *

38

PhSH + AlBN

Scheme 16. Sulfanyl-radical-catalyzed cyclization-isomerisation of (isocyano)allylsulfides

captoethanol proceeded in high yields and excellent stereocontrol, giving pyrroline 40 and pyroglutamate 41 as pure diastereoisomers (Scheme 17). A slightly lower

diastereoselectivity was observed starting from the corresponding anti-isonitrile. This methodology was used as the key cyclization step in the stereo- and enantioselective synthesis of (*)- and (-)-a-kainic acid 43, the prototype of a group of neuroexcitatory amino acids that are important substrates in physiological and pharmacological studies of the central nervous system [22c-f]. One of the major obstacles in the synthesis of kainic acid is the establishment of the 3,4-cisstereochemistry. This was overcome by using on the pyrroline intermediate 42 a

56

1.3 Isonitriles: u Useful Trup in Radical Chemistry

2p,3D,4a-40

syn-39

O e O T B D M S HN
90%

1

Br\c:

20-25 equiv Bu3SnH 5 mol% AlBN toluene 70-80 "C 4 examples, 63-80%

4

R2

Scheme 1. Aryl halide cyclizations by Routledge et al. [7]

-

83

1.5.2 Intramolecular Radical Cyclizations

1) 40 equiv HMPA 10 equiv Smlz 2) THF 20%'TFAJCH&I, rtlh

Me0

H

~

63% "

OMe 1) 40 equiv HMPA 20 equiv 3-pentanone 10 equiv Sml2 THF,TFNCH2C12 rt2 h ,02c& *

0

6

Scheme 2. Aryl iodide cyclizations by Du and Armstrong [8, 91

(Scheme 2). These mild, room temperature conditions do not require any special precautions such as degassing, although HMPA was found to be necessary for the reaction. Switching to a TentaGel-type resin allowed polymer swelling in aqueous solvents, enabling Sm(II1) impurities in the beads to be removed by saturated NaHC03 prior to resin cleavage. In a later paper [9], the anionic capture of the intermediary Sm(II1) species by electrophiles was studied. For example, substrate 6 on TentaGel-Wang resin was treated with HMPA and 3-pentanone followed by addition of SmI2 to give the product of anionic capture in moderate yield. The reaction was unsuccessful when the carboxylic acid was immobilized on polystyreneRink resin as an amide, possibly because of quenching of the anion by the amide proton. While the 33% yield obtained with TentaGel-Wang compares favorably with the 40% in solution phase, the authors conclude that these reactions are highly substrate-dependent and perhaps inappropriate for generation of libraries. A series of aryl radical cyclizations were reported by a group at Novartis [lo], and some of these processes were also compared with bond formation by Pd-mediated Heck cyclization of the same substrates. The tributyltin hydride-mediated reaction of iodo alkenes 7 (Scheme 3), immobilized on polystyrene resin through a linker, gave dihydrobenzofurans 8 [ l I]. It was also possible to perform a tandem cyclization using allyltributyltin to give the allylated product 9, although the yields were less satisfactory. The radical cyclization onto enol ethers was demonstrated [ 121 by the conversion of 10 to 11. For best results, the tributyltin hydride and AIBN were added portionwise every 5-8 h. The impressive 95% yield was in fact higher than that for the solid-phase Heck cyclization of 10. Similarly, cyclization of anilide 12 afforded the phenanthridine 13. In an effort to prepare more highly functionalized small molecules, the Novartis group studied [ 131 the radical cyclization of cyclohexenediols, immobilized by a ketal linkage on polystyrene (Scheme 4). Although the reaction of 14 gave the de-

N

84

1.5 Radical Reuctions on Solid Support

Me

7 , R = H. Me, Ph

1) 3 equiv Bu3SnH 0.6 equiv AlBN benzene, reflux 46 h 2) NaOMe. MeOH/dioxane, rt 24 h

1) 15 equiv Bu3Sn1.5 equiv AlBN benzene, reflux 46 h 2) NaOMe, MeOH/dioxane, rt 24 h

Ho-Q€j

Ho-Ql$?

a, 95-97%

9, 10.78%

1) (6 x 0.5) equiv Bu3SnH (6 x 0.1) equiv AlBN benzene, reflux 48 h 2) 25% TFA/CHzCIz c

8 L

o

P

X

O

.

&

)

,

10, R = Me, OMe

,

R 0

H2N 11, 95%

0

1) (9 x 1.8) equiv Bu3SnH (9 x 1 5) equiv AlBN

q p

2) benzene, NaOMe. MeOHldioxane reflux

HO

/N

\

12

13

Scheme 3. Aryl iodide cyclizations by the Novartis group [ 1 I , 121

sired dihydrobenzofuran 15, the noncyclized product of direct reduction 16 was also isolated, while allylamine 17 afforded a similar mixture of cyclized 18 and reduced 19. A related cyclization was recently reported by Jia et al. [ 141 with allylamine 20 immobilized on polystyrene-Wang resin. The reaction was monitored by acetylation and cleavage to yield 21, as a mixture of free and Boc-protected amines. This solidphase synthesis of seco-CBI (21, R = H), related to the pharmacophore of the C C 1065 and duocarmycin class of cyclopropylindole antitumor antibiotics, has potential for the preparation of analogue libraries, and an example of further transformation of resin-bound 21 to a polyamide was presented. A solid-phase route to y-butyrolactones was reported by Watanabe et a]. [15]. A series of bromoacetals 22 (Scheme 5) linked to polystyrene were cyclized to the

85

1.5.2 Intramolecular Radical Cyclizations

0,,,in CI Cl

1) ((9 x 0.5) + 10) 1) equiv Bu3SnH ((9 x 0.1) + (2 x 0.5)) 0 5))equiv AlBN benzene, reflux 80 h 2) 5% TFNCHZCIZ HO"'

HO

OH 14

15, X = CI. 20%; X = H, 51%

H0 ,*.. HO'"

OH 16, 20%

1) (6 x 0.5) equiv Bu3SnH (6 x 0.1) equiv AlBN benzene, reflux 48 h

CI

+

AcO'"' AcO

18, 52%

Bu

19, 40%

1) 1.3 equiv Bu3SnH cat. AlBN benzene, reflux 8 h 2) AcCI, DlEA 3) 95% TFA

H

OBn

21, R = H. 46%; R = BOC,28%

Scheme 4. Aryl and vinyl iodide cyclizations by Berteina et al. and Jia et al. [ 13, 141

1) 5 equiv Bu3SnH 0.5 equiv AlBN R,

benzene. reflux 18 h 2) 2 equiv Jones reagent

91

&L:

B r l rt,o 3h t b 0 *

Q-o-O-0

23,6 examples 47-93%

22 4 equiv Bu3SnH 1.3 equiv AlBN toluene, 90 "C, 4 h

-%

36% (overall from 2-allylaniline, including the two previous steps)

24

0 ;

25

Scheme 5. Intramolecular cyclizations by Watanabe et al. [ 151 and Nicolaou et al. [ 161

86

1.5 Radical Reactions on Solid Support

corresponding acetals 23, which were then oxidatively cleaved from the support using Jones reagent. The final example in this section features radical generation from a selenide rather than a halide. Furthermore, the radical reaction itself results in a cyclizing cleavage from the resin, instead of requiring a separate step for compound release. Nicolaou et al. report [ 161 the tributyltin hydride-mediated reaction of polymer-bound selenide 24 to furnish indoline 25 by a 6-endo cyclization. The overall efficiency of the 3-step process (indoline formation on solid-phase, acylation of the indoline, and cyclizing cleavage) is nevertheless modest for this and the four other examples given.

1.5.3 Intermolecular Radical Reactions The carbon-carbon bond-forming steps in the previous section are facilitated by the tremendous entropic acceleration of intramolecular reactions. In that respect, it would seem that intermolecular reactions offer a more stringent test of the feasibility of solid-phase radical reactions. The first example, reported by Sibi and Chandramouli [ 171, featured the allylation of polymer-bound alkyl radicals generated from a-bromo esters 26 (Scheme 6) to give y,&unsaturated acids 27. Large excesses of allylstannane and AIBN were required for good yields, while radical initiation at room temperature using EtjB/Oz was less successful. The yields were comparable with those for solution-phase reactions, while reduction of 26 with tributyltin deuteride gave 93% deuterium incorporation, implying 24h 40-60%

*

0 2

40-60%

?A:Me

OX0

OX0

Scheme 5

Antimony-mediated oxygenation

Barrett has developed a procedure for the oxygenation of alkyl iodides mediated by antimony derivatives. Irradiation of a solution containing an alkyl iodide and stoichiometric amount of tetraphenyldistibine afforded an air-sensitive alkyl(dipheny1)stibine via a chain radical process. Oxidation of this derivative with air delivered the alcohol in moderate yield (Scheme 5 ) [12]. Cobalt-catalyzed radical oxygenation

The generation of radicals from halides via organocobalt derivatives is a wellestablished method that has been applied in many radical processes (see Volume 1, Chapter 1.8) [ 131. In pioneering work, Pattenden has achieved oxidative free-radical cyclizations by means of nucleophilic cobalt(1) reagents. Irradiation with a 450 W Hg lamp of the intermediate organocobalt(II1) derivatives in the presence of oxygen gave stable alkyl peroxycobalt complexes that can be reduced with sodium borohydride to afford the corresponding alcohols (Scheme 6) [14, 151. Prandi has improved the previous oxygenation conditions by using only a catalytic amount of cobalt in the presence of two equivalents of sodium borohydride. Radical cyclization/oxygenation has been applied to the syntheses of biologically important carbofuranosides from iodohexenyl carbohydrates (Scheme 7) [ 161.

Co(lll) OEt

60%

"'0

Co(111)OO hv 0 2 53%

Scheme 6

()""'&OEt ""0

2.1.2 Radical Hydroxjdution OH B n O * , , , bI BnO

OBn

Co(lll) 3% + NaBH4(2 equiv) NaOH, air, EtOH 69%

BnO

O ,H

+

BnO,,,,b

97

BnO,,,,p

OBn

BnO

OBn

12:l

Scheme 7

Triethylborane-promoted oxygenation

Treatment of a-iodocarboxylic acid derivatives with two equivalents of triethylborane under oxygen atmosphere gives the corresponding a-hydroxy acid derivatives [ 171. This method is based on an iodine atom transfer from the ethyl radical (generated by the reaction of triethylborane and oxygen) with the a-iodocarbonyl compound. Interestingly, no hydroperoxide was detected at the end of the reaction. This indicates that triethylborane is acting as radical initiator, chain transfer reagent and reducing agent for the intermediate alkylperoxyborane. It offers several advantages over classical ionic substitution reactions: no elimination product is observed, tertiary iodides are efficiently converted to alcohols (Scheme 8, Eq. 8.1), and this onestep procedure is compatible with substrates sensitive to nucleophiles. Only moderate stereocontrol is observed in this hydroxylation procedure (Scheme 8, Eq. 8.2). This tendency has been observed for all reactions involving oxygen as radical trap.

@

EtaB (2 0 2equiv) * 82%

Et3B (2 0 2equiv) * 98%, dr 60:40

(8.1)

0

N $& ,

(8.2)

SO2 0

Scheme 8

Hydroxylation with TEMPO

Radical oxygenation can be performed by reaction with nitroxides to give alkoxylamines that are easily reduced to the corresponding alcohols by classical methods. The high reactivity of the nitroxides toward carbon-centered radicals make it a valuable alternative to oxygen for hydroxylation processes. Efficient and simple oxygenation procedures using 2,2,6,6-tetramethylpiperidin- 1oxyl (TEMPO) are reported [18-211. Tin hydride, ditin and silanes have been suc-

2. I Hydroxylation and Amination of Carbon-Centered Radicals

98

&

OBn

I

R 2R02 0

,OR'

OBn IR' = OTMP

A

@NBoc

TEMPO, (TMS)3SiH, hv

&NBoc

(9.2)

84% OMe

OMe

Scheme 9

cessfully applied as chain transfer reagents for these processes. Barrett used this reaction for the synthesis of sucrose octaacetate (Scheme 9, Eq. 9.1) [19]. lnterestingly, the primary iodide used in this reaction sequence is refractory towards S N ~ displacement by oxygen-centered nucleophiles. Boger used an oxygenative cyclization as key step in the synthesis of analogs of CC-1065 and duocarmycin (Scheme 9. Eq. 9.2) [21]. It is however important to note that these reactions require a large excess of TEMPO (up to 6 equivalents) and of tin hydride or silanes, presumably because of direct reaction of stannyl or silyl radicals with TEMPO. A wide range of organometallic species react rapidly with TEMPO. Two typical examples involving organosamarium derivatives [22] and organocobalt complexes [13] are shown in Scheme 10.

2.1.2.2 Oxygenative Decarboxylation The conversion of carboxylic acids into alcohols with one less carbon atom is an important synthetic transformation. Such decarboxylative hydroxylations have proven to be difficult to accomplish by classical ionic methods. Electrochemical decarboxylation (Hofer-Moest reaction) [ 2 3 ] has been applied successfully to different types of carboxylic acids such as amino acids (Scheme 11, Eq. 11.1) [24]. This reaction proceeds through an intermediate radical that is further oxidized to a carbenium ion and trapped by the solvent. The efficiency of the second oxidation step (the formation of the carbenium ion) depends on the ionization potential of the in-

2.1.2 Radical Hydvoxylation

SrnL

OTMP

Ts

Ts

99

Scheme 10

-e, AcOH COOMe

O cA‘ ;*

87%

OAc

?’ ‘ , ,

H

0 Me

COOMe

OAc

I

X

(11.1)

1) tert-dodecanethiol 0 2 , hv 2) Ph3P

(1 1.2)

57 %

S

75%

(xX == o H0 - N bS Me

Scheme 11

termediate radical and is high only when tertiary alkyl radicals and heteroatom substituted radicals are involved. An alternative and more general method was reported by Barton [25, 261. Irradiation of esters of N-hydroxy-2-thiazolinethione under air or oxygen at room temperature in the presence of tert-dodecanethiol affords the corresponding nor-alcohols after a reductive treatment with triphenylphosphine (Scheme 11, Eq. 11.2) [26]. Procedures involving the formation of intermediate organoarsines, organostibines, and organobismuth derivatives were also reported but are synthetically less attractive [27].Hydroxylative decarboxylation of carboxylic acids was also performed by Pattenden via formation of acylcobalt derivatives and homolysis of the C-Co bond followed by decarbonylation. This

100

2.1 Hydroxylation and Amination

of

Carbon-Centered Radicals

method is limited to systems giving fast decarbonylation such as phenylacetic acid PI.

2.1.2.3 Monohydroxylation of Alkenes via Organometallic Intermediates Studies on prostaglandin biosynthesis in the early 1970s have shown that molecular oxygen is incorporated into polyunsaturated lipids. It was shown that autoxidation of polyunsaturated species leads to peroxyl radical intermediates that can undergo p-scission, H-atom abstraction, and allylic rearrangement or/and cyclization. Beckwith looked into the oxygenation of dienes initiated by phenylthiyl radicals [29]. The idea was extended by Feldman to vinylcyclopropane derivatives [30]. The chemical conversion of C ~ polyunsaturated O fatty acid into prostaglandin backbone developed by Corey represents a pertinent and elegant illustration of the previous studies [31]. This chemistry is presented in Volume 2, Chapters 5.3 and 5.4. Therefore, we have limited our account to hydroxylation of double bonds by conversion to organometallic intermediates. Via hydrobora t ion

Generation of alkyl radicals from trialkylboranes initiated by molecular oxygen was reported and investigated by Brown (see Volume I , Chapter 1.2) [32]. In the presence of a controlled quantity of oxygen (1.5 mol 0 2 per mol R3B), the three alkyl groups on the boron are rapidly and quantitatively converted into the corresponding alcohols. Mixed organoboranes prepared via hydroboration of alkenes with 9BBN, thexylborane or disiamylborane are also successfully converted into alcohols [33, 341. Recently, we have shown that p-alkylcatecholboranes, obtained by hydroboration of alkenes with catecholborane catalyzed by N,N-dimethylacetamide, react cleanly and efficiently with TEMPO to give alkyl radicals that can be trapped by a second equivalent of TEMPO. The resulting alkoxyamines are reduced with Zn/ AcOH to the corresponding alcohol 1351. A typical example involving the hydroboration of (+)-2-carene followed by radical-mediated ring opening of the cyclopropane ring is described in Scheme 12.

h '8

Catecholborane Me2NCOMe (cat.))

zn

R=OTMP

82%C R = H

Scheme 12

2.1.2 Radical Hydroxylation

101

Via alkoxymercuration

Treatment of alkylmercuric halides, easily obtained by alkoxymercuration, by metal hydrides such as sodium borohydride constitutes a mild and convenient way to generate alkyl radicals [36]. When the reaction is run in the presence of oxygen, alcohols are obtained in good yield. Interestingly, molecular oxygen is highly reactive toward alkyl radicals but relatively inert toward organomercuric compounds and borohydride ions. An example of the conversion of alkenes to P-alkoxyalcohols by alkoxymercuration followed by treatment with sodium borohydride and oxygen is depicted in Scheme 13 [37, 381.

79 %

60:40

i

Scheme 13

Via hydrocohaltation and other cobalt- and manganese-catalyzed reactions

The first example of olefin hydrocobaltation and its subsequent oxygenation was reported by Okamoto [39]. Later, Pattenden studied the hydrocobaltation of 1,3dienes and found that they led exclusively to 1,4-addition. Under aerobic condition, tertiary peroxycobaloximes are produced. After reductive treatment, tertiary allylic alcohols are obtained (Scheme 14, Eq. 14.1). Interestingly, reactions with TEMPO afford primary alkoxyamines and after reductive treatment primary allylic alcohols (Scheme 14, Eq. 14.2). This change in regioselectivity may be attributed to steric effects [40]. Isayama has reported an elegant procedure for the hydration of alkenes with molecular oxygen and triethylsilane catalyzed by a cobalt(I1) complex followed by a reductive treatment with NaZS203 [41]. The reaction is efficient with terminal alkenes and a,P-unsaturated esters. The radical nature of this reaction is ques-

1) 0 2 (35Yo)

*==%

2) NaBH4 (40%)

1) TEMPO (55 Yo) 2) Zn (60 %)

Scheme 14

OH

102

2. I Hydroxylation and Amination

of

Carbon-Centered Radicals

tionable. An even more efficient procedure for the conversion of a,P-unsaturated esters to a-hydroxyesters was reported by the same research group. Excellent conversions and yields are obtained with phenylsilane and oxygen under catalysis by bis(dipivaloylmethanato)manganese(II) [42]. The regioselectivity is dependent on the nature of the substituents in the P-position. Generally, the hydroxyl group is introduced in the cc-position except with P-diphenyl substrates that orient the hydroxylation in P-position. A radical mechanism was postulated to account for this regioselectivity. Magnus presented an elegant application of this transformation in the final step of the (f)-11,12-demethoxylahadinineB synthesis (Scheme 15) [43].

Scheme 15

Hydroxystannylution

Nakamura reported that the ultrasound-promoted reaction of tin hydride with alkenes in the presence of air results in the addition of stannyl and hydroxyl groups across the double bond (hydroxystannylation) (Scheme 16). This procedure is the first example of the conversion of alkenes to hydroxylated organotin compounds

WI. R-

70%

Ph3SnH (3 equiv) AIBN, air, ))) *

OH RL S n P h 3

69%

71Yo

Scheme 16

2.1.2.4 Oxygenation of Enolate Radicals Formation of enolate radicals by oxidation with transition metals of the enol and enolate forms of 1,3-dicarbonyl compound is well documented (Volume 1, Chap-

2.1.3 Amination of Carbon-Centered Radical

OH

1) LDA 2) Fe (Ill),TEMPO

*

ACooEt 90%, anti/ syn 2.8:l

~ C O O E t

OTMP 84%

Fe(III)=

Q F &

103

I

Zn,AcOH

PFC

E C O O E t

OH Scheme 17

ters 2.3 and 2.4). When the reactions are performed under an oxygen atmosphere, peroxyl radicals are generated and have served as intermediates for further transformations [45-471. We will focus here on a simple hydroxylation process of enolate radicals generated from ester enolates via SET oxidation. Ferrocenium ion was used as the oxidizing agent, and the radical intermediate was trapped with TEMPO [48].In a second step, the alkoxylamine was reduced with zinc to the corresponding a-hydroxyester. The hydroxylation of ethyl 3-hydroxybutyrate gave the ethyl 2,3-dihydroxybutyrate with moderate stereocontrol (Scheme 17).

2.1.3 Amination of Carbon-Centered Radical Despite the fact that nitrosation of cyclohexane is a classical textbook example of an industrial radical reaction [49], only a few procedures for the amination of carboncentered radicals have been reported. However, some valuable radical alternatives to classical amination processes have been developed and will be described here.

2.1.3.1 Nitrosation of Organocobalt Compounds by Nitric Oxide Because of its free-radical character, nitric oxide (NO) can act as an efficient radical trap. The first example of carbon-nitrogen bond formation using NO as a radical trap was reported by Okamoto [50]and was catalyzed by a cobalt complex. Later, Pattenden extended this reaction to organocobalt species. Photolytic homolysis of an alkyl-cobalt(II1) bond in the presence of nitric oxide affords a nitroso compound that tautomerizes to the corresponding oxime [51]. Giese described an elegant preparation of an acetylated mannosamine from the 2-bromoglucopyranose via conversion to the corresponding cobaloxime and photolysis in the presence of nitric

104

2. I Hydroxylation and Amination of Carbon-Centered Radicals ’) NaCo(dmgH)py

~

OMe 2) NO, hv

AcO

AcO

Br

OMe NOH

. HP,PdIC

Scheme 18

oxide [ 521. Catalytic hydrogenation and acetylation affords the desired mannosamide (Scheme 18).

2.1.3.2 Nitrosation with Nitrite Esters The Barton nitrite ester photolysis is undeniably one of the most popular and useful reactions in radical chemistry for the functionalization of remote and inactivated positions within steroids (Scheme 19). Photolysis of nitrite esters gives nitric oxide and an alkoxyl radical that abstracts an ideally positioned hydrogen atom (1$hydrogen atom abstraction). The resulting alkyl radical reacts with nitric oxide in a solvent ‘cage’ to afford the nitroso-alcohol derivative that is finally isolated as an oxime [53]. Related cyclizations of alkoxyl radicals have been reported by Surzur: photolysis of y,balkenyl nitrite esters leads to alkoxyl radicals that undergo subsequent tandem 5-exo cyclization followed by NO-trapping [54, 551.

-

NO

AcOd

AcO+ H

ON0

- @ + NO

AcO

C8H17

AcO

H OH

80% Scheme 19

OH

2.1.3 Amination of Carbon-Centered Radical

105

Scheme 20

A conversion of alkyl halides to oxime derivatives was proposed by Murphy [56]. Irradiation of iodides or activated bromides in the presence of isoamyl nitrite and hexabutylditin afforded the corresponding oxime. Interestingly, this reaction is suitable for cyclization-nitrosation cascade reactions (Scheme 20). Motherwell and Potier have been interested in the reactivity of thionitrite esters as a potential surrogate of nitric oxide toward carbon-centered radicals. Tertiary thionitrite esters react with Barton esters to give after decarboxylation the corresponding oximes or the nitroso-dimers in moderate yield [57].

2.1.3.3 Azo Reagents A radical mechanism is at least partially responsible for the reaction of alkenes with azodicarboxylates [ 58-60]. Addition of phenyl and methyl radicals to dialkyl azodicarboxylates was investigated from a mechanistic point of view [61, 621. Wamhoff reported the thermal and photochemical addition of ethers to 4-aryl-l,2,4-triazoline3,5-dione [63]. Aycard further developed this reaction and reported the photo(Scheme 2 1) addition of ethers and polyethers to 4-methyl-l,2,4-triazoline-3,5-dione [64]. A radical chain mechanism involving hydrogen abstraction in the a-position of the ether oxygen atom followed by addition to the azo moiety leading to an urazolyl radical was proposed. Barton used 3-(trifluoromethyl)-3-phenyldiazirineas a radical aminating agent [65]. Alkyl radicals, generated from Barton esters or organotellurides, add to the diazirine present in large excess (20 equivalents). After dimerization of the radical adducts and nitrogen extrusion, imines were isolated. Hydrolysis with boric acid followed by acetylation afforded the corresponding acetamides (Scheme 22).

0

N 4 0-0

.>

( 0U

N0]

EtS02N3 (5 equiv) t

DLP, PhCI, 100 "C N3

DLP = dilauroyl peroxide

80%, exo/endo 74:26

EtS02N3(5 equiv)

AcO

SCSOEt

(27.2)

t

DLP, PhCI, 100 "C 74%

N3

Scheme 27

reaction can be combined with an iodine atom transfer mediated carbon-carbon bond formation in a one-pot procedure (Scheme 27, Eq. 27.1) [77]. Magnus reported the direct a- and 8-azido functionalization of triisopropylsilyl enol ethers using trimethylsilylazide and iodosylbenzene. In this mechanistically complex reaction sequence, it is believed that azidation of a carbon centered radical is occurring [78]. Intramolecular processes

Kim developed a new entry into N-heterocycles by radical cyclizations onto alkyl azides. Iodides, bromides and thionocarbonates (Scheme 28, Eq. 28.1) are suitable radical precursors. 5-Exo cyclizations afford 3,3-triazenyl radicals that lose N2 to furnish an aminyl radical [79]. Following this work, Kilburn has applied this strategy to the formation of spiro-heterocycles from methylenecyclopropanes [ 801. Finally, this reaction was applied as a key step in a very elegant cascade synthesis of aspidospermidine developed by Murphy (Scheme 28, Eq. 28.2) [81].

2.1.3.6 N,N-Dimethylhydrazine Reaction of 8-naphthol with N,N-dimethylhydrazine under oxygen atmosphere and tungsten lamp irradiation leads via a radical process to the formation of l-amino-2binaphthol in high yield (Scheme 29) [82]. This unique example of C-N bond for-

References

109

-6 a

S

(TMS)3SiH, AlBN

-N2*

benzene reflux

N3

-a

COOEt

N' '\N

COOEt TsCI, pyridine (28.1) H 60%

db !J

Ts

*&

(TMS)3SiH,AlBN benzene, 80 "C 95%

S02Me

(28.2)

!J

S02Me

Scheme 28

moH

1) Me2NNH2 NaOMe, hv, O2

2) ACzO, PY

90%

Scheme 29

mation via an SH2 process is however of limited scope since it does not work with other phenols.

2.1.4 Conclusions A number of procedures for the hydroxylation and amination of radicals are reported. They offer attractive alternatives to the classical ionic processes. Extremely mild reaction conditions characterize most of these radical procedures. They offer promising perspectives for the synthesis of natural products and other complex polyfunctionalized molecules.

References [ I ] Rate constants for the reaction of radicals with oxygen have been measured. Resonancestabilized and nonstabilized radicals react at rate constant > l o 9 M-' s-' (trrt-butyl 4.9 x

110

2.1 Hydroxylution and Amination of Carbon-Centered Rudicals

109 M-' s - I . , benzyl 2.4 x lo9 M-' S K I, cyclohexadienyl 1.6 x lo9 M-I s-' ). B. Maillard, K. U. Ingold, J. C. Scaiano, J. Am. Chem. Soc. 1983, 105, 5095. [2] J. Chateauneuf, J. Lusztyk, K. U. Ingold, J. Org. Chem. 1988, 53, 1629. V. W. Bowry, K. U. Ingold, J. Am. Chem. Soc. 1992, 114,4992. I. W. C. E. Arends, P. Mulder, K. B. Clark, D. D. M. Wayner, J. Phys. Chem. 1995, 99, 8182. [3] Leading references: F. Chemla, J. Normant, Tetrahedron Lett. 1995, 36, 3157. I. Klement, P. Knochel, Synlett 1995, 11 13. [4] E. Nakamura, T. Inubushi, S. Aoki, D. Machii, J. Am. Chem. Soc. 1991, 113, 8980. [5] E. Nakamura, D. Machii, T. Inubushi, J. Am. Chem. Soc. 1989, 111, 6849. E. Nakamura, T. Inubushi, D. Machii, J. Org. Chem. 1994, 59, 8178. [6] M. Sawamura, Y. Kawagushi, K. Sato, E. Nakamura, Chem. Lett. 1997, 705. M. Sawamura, Y . Kawagushi, E. Nakamura, Synlett 1997, 801. [7] S. Moutel, J. Prandi, Tetrahedron Lett. 1994, 35, 8163. [8] S. Mayer, J. Prandi, Tetrahedron Lett. 1996, 37, 3117. [9] A. Kittaka, Y. Tsubaki, H. Tanaka, K. T. Nakamura, T. Miyasaka, Nucleosides & Nucleotides 1996, 15, 97. [lo] T. Takahashi, S. Tomida, T. Doi, Synlett 1999, 644. i l l ] M. Yoshida, M. Ohkoshi, N. Aoki, Y. Ohnuma, M. Iyoda, Tetrahedron Lett. 1999, 40, 5731. [I21 A. G. M. Barrett, L. M. Melcher, J. Am. Chetn. Soc. 1991, 113, 8177. [13] G. Pattenden, Chem. Soc. Rev. 1988, 17, 361. [14] C. Bied-Charreton, A. Gaudemer, J. Organomet. Chem. 1977, 124, 299. C . Giannotti, C. Fontaine, B. Septe, J. Organomet. Chem. 1974, 71, 107. [IS] H. Bhandal, G. Pattenden, J. J. Russel, Tetrahedron Lett. 1986, 27, 2299. V. F. Patel, G. Pattenden, Tetrahedron Lett. 1987, 28, 1451. V. F . Patel, G. Pattenden, J. Chem. Soc. Perkin Trans. 1 1990, 2703. [I61 T. Bamhaoud, J. Prandi, Chem. Commun. 1996, 1229. J . Desire, J. Prandi, Tetruhedron Lett. 1997,38, 6189. [17] N. Kihara, C. Ollivier, P. Renaud, Org. Lett. 1999, 1, 1419. [18] R. J. Kinney, W. D. Jones, R. G. Bergman, J. Am. Chem. Soc. 1978,100, 7902. (191 A. G. M. Barrett, B. C. B. Bezuidenhoudt, L. M. Melcher, J. Org. Chem. 1990, 55, 5196. 1201 A. G. M. Barrett, D. J. Rys, J. Chem. Soc., Chem. Commun. 1994, 837. [21] D. L. Boger, J. A. McKie, J. Org. Chem. 1995, 60, 1271. [22] T. Nagashima, D. P. Curran, Synlett 1996, 330. [23] P. Renaud, D. Seebach, Anyew. Chem. Int. Ed. Engl. 1986, 25, 843. 1241 D. Seebach, G. Stucky, P. Renaud, Chimia 1988, 42, 176. [25] D. H. R. Barton, D. Crich, W. B. Motherwell, J. Chem. Soc., Chem. Commun. 1984, 242. [26] D. H. R. Barton, S. D. GCro, P. Holliday, B. Quiclet-Sire, S. Z. Zard, Tetrahedron 1998, 54, 675 1. 1271 D. H. R. Barton, D. Bridon, S. Z. Zard, J. Clzenz. Soc., Clzem. Cotnmun. 1985, 1066. D. H. R. Barton, D. Bridon, S. Z. Zard, Tetrahedron 1989, 45, 2615. [28] V. F. Patel, G. Pattenden, Tetrahedron Lett. 1988, 29, 707. [29] A. L. J. Beckwith, R. D. Wagner, J. Chem. Soc., Chem. Commun. 1980,485. 1301 K. S. Feldman, R. E. Simpson, M. Parvez, J. Am. Chem. Soc. 1986, 108, 1328. K. S. Feldman, Synlett 1995, 217. [31] E. J . Corey, K. Shimoji, C. Shih, J. Am. Chem. Soc. 1984, 106, 6425. E. J. Corey, C. Shih, N.-Y. Shih, K. Shimoji, Tetrahedron Lett. 1984, 25, 5013. E. J. Corey, Z. Wang, Tetrahedron Lett. 1994, 35, 539. [32] Reviews: H. C. Brown, M. M. Midland, Angew. Chem. Int. Ed. 1972, 11, 692. A. Ghosez, B. Giese, H. Zipse, in Houben-Weyl, 4'h ed., (Eds. M. Regitz, B. Giese), Vol. E19a, p 753. [33] S. B. Mirviss, J. Am. Chem. Soc. 1961, 83, 3051. S. B. Mirviss, J. Org. Chem. 1967, 32, 1713. [34] H. C. Brown, M. M. Midland, G. W. Kabalka, J. Am. Chem. Soc. 1971, 93, 1024. H. C. Brown, M. M. Midland, G. W. Kabalka, Tetrahedron 1986, 42, 5523. 1351 C. Ollivier, R. Chuard, P. Renaud, Synlett 1999, 807. 1361 Review: J. 0. Metzger, in Houhen- Weyl, 41h ed., (Eds. M. Regitz, B. Giese), Vol. E19a, p 147.

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112

2.1 Hydroxylation and Amination of Carbon-Centered Radicals

[77] C. Ollivier, P. Renaud, J. Am. Chem. SOC.2000, 122, 6496. [78] P. Magnus, J. Lacour, P. A. Evans, M. B. Roe, C. Hulme, J. Am. Chem. Soc. 1996, 118, 3406. [79] S. Kim, G . H. Joe, J. Y. Do, J. Am. Chem. SOC.1994,116, 5521. [80] M. Santagostino, J. D. Kilburn, Tetrahedron Lett. 1995, 36, 1365. [81] M. Kizil, B. Patro, 0. Callaghan, J. A. Murphy, M. B. Hursthouse, D. Hibbs, J. Org. Chem. 1999, 64, 7856. [82] D. H. R. Barton, S. Le Greneur, W. B. Motherwell, Tetruhedron Lett. 1983, 24, 1601.

Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

2.2 Oxidation (Hydroxylation and Acyloxylation) via C-H Bond Activation Tsutomu Katsuki

2.2.1 Introduction Like the oxidation of olefins, the oxidation of C-H bonds is a useful reaction for the functionalization of organic molecules. However, in contrast with the former reaction, of which many stereocontrolled examples have been developed, only a limited number of examples of the latter reaction have been reported. This is mainly because of the high stability of the C-H bond relative to that of the olefinic double bond: the energy level of an occupied o-orbital is generally much lower than that of an occupied 71-orbital, and most of chiral electrophilic oxidants that stereoselectively react with a n-bond cannot oxidize a C-H bond. Despite this, concerted stereospecific C-H hydroxylation is possible with some highly electrophilic oxidants such as dioxirane and p-nitroperoxybenzoic acid [ 11. Another important C-H oxidation is the reaction via radical intermediates generated by hydrogen atom abstraction or by one-electron and subsequent proton transfers. The stereochemistry of this stepwise C-H oxidation is affected by the stereochemistry in hydrogen atom abstraction and oxygen rebound steps and by the behavior of the radical intermediate. In this chapter, catalytic and enantioselective C-H oxidation reactions of this type are highlighted [2].

2.2.2 C-H Hydroxylation Using Metallo-Porphyrin and -Salen Complexes as Catalysts: its Mechanism and Stereochemistry Cytochrome P-450s carrying an iron-porphyrin complex at their active sites are representative oxidizing enzymes that catalyze the oxidation of C-H and C=C bonds. To reproduce these stereoselective biological reactions in a flask, various chiral metalloporphyrin complexes have been prepared as model compounds of the active site of P-450 [3] and used as catalysts for C-H and C=C oxidation in the

1 14

2.2 Oxidation (Hydroxylation and Acyloxylation) via C-H Bond Activation Terminal oxidant

C-OH

C-H

Scheme 1. C-H hydroxylation catalyzed by metalloporphyrin complexes

presence of terminal oxidants such as iodosylbenzene (Scheme 1). In these reactions, electrophilic metal-oxo complexes 1 are considered to be the active species [4]. In 1976, Groves et al. proposed for P-450 catalyzed hydroxylation of alkanes the ‘oxygen rebound mechanism’: the iron-oxo species abstracts a hydrogen atom to give an alkyl radical which subsequently displaces hydroxy group from the iron atom (Scheme 2) [ 5 ] . On the other hand, Newcomb et al. proposed a cationic pathway for P-450 catalyzed C-H hydroxylation, based on experiments using various radical probes [6]. The results suggest that no intermediate is formed during the reactions. Recently Collman et al. proposed that alkane makes a complex with 0x0 species and oxygen transfer occurs in a stereospecific manner [7]. Although the mechanism of hydroxylation of C-H bonds by P-450 is surrounded by controversy [8], it is very likely that hydroxylation of activated C-H bonds catalyzed by synthetic metalloporphyrin complexes proceeds through radical intermediates. Groves examined the hydroxylation of optically active mono-deuterated ethylbenzene using optically active vaulted iron-porphyrin complex 2 as the catalyst and disclosed that k D / k H was 6.4 and enantiotopic selectivity in the hydrogen atom D k ~ / xkk [ ~ p r o - R ~ / k [ p r o - ~ ~= 92:s). Howabstraction step was 84% ee ( ~ R H / ~ S = ever, this enantiotopic selectivity is not directly reflected in the enantiomeric excess (77% ee) of the product (Scheme 3) [9]. These results indicate that hydrogen atom abstraction is the rate-determining step and that the reaction is not concerted but stepwise, and are well compatible with the oxygen rebound mechanism. Discrepancy between the enantiotopic selectivity and the enantiomeric excess is rationalized

hydrogen atom abstraction

rebound

Scheme 2. Oxygen rebound mechanism for C-H oxidation

2.2.2 C-H Hydroxylation Using Metallo-Porphyrin

HOJD

Me (R)

DJOH Me

HJoH

(s)

Me (S)

115

H0-J-H Me (R)

(77% ee) kinetic isotopic effect: kH/ kD = 6.4 FeP* = chiral iron-porphyrin complex 2 enantiotopic selectivity: kRH/ ksD = 92 / 8 enantiomeric excess of alcohol= [S(D) + S(H)]-[R(H)+ R(H)]

Scheme 3. Kinetic isotopic effect and radical decay in benzylic oxidation using 2 as the catalyst

by considering that the decay of (R)-and (S)-radical intermediates kept in the cave of the chiral vaulted ligand occurs at different rates ( k R D ( S ) > k R D ( R ) ) (Scheme 4). Because of the unfavorable steric interaction, the minor (S)-radical intermediate is more readily released from the chiral cave. Hydroxylation of ethylbenzene traces the same reaction pathway (Scheme 4, Ar = Ph) and the radical decay improves the enantiomeric excess of the resulting alcohols up to 40% ee, though the enantiotopic selectivity in hydrogen atom abstraction is modest (2:l) [9b]. Hydroxylation of tetralin gives 1-hydroxytetralin of 76% ee, though the enantiotopic selectivity has not been determined [ 9b]. Quite recently Che et al. reported benzylic hydroxylation using chiral ruthenium complex 3 which carried Halterman’s D4-porphyrin ligand bearing a well-crafted chiral cavity [lo]. Dioxoruthenium complex 3a reacts with ethylbenzene to give phenethyl alcohol of 45% ee in a stoichiometric manner. This reaction also includes a hydrogen atom abstraction by an ‘Ru=O’ intermediate giving a radical inter) mediate. This was supported by the primary kinetic isotope effect ( k ~ / kof~ 8.9 (313 K) observed for this reaction and by a linear dual-parameter Hammet correlation between log kre,[krel= k(4-substituted ethylbenzene)/k(ethylbenzene)] and the aJ., and.:a Both electron-donating and -withdrawing substituents promote the reaction. It is noteworthy that the catalytic hydroxylation of ethylbenzene using complex 3b as catalyst and 2,6-dichloropyridine N-oxide as terminal oxidant shows a better enantioselectivity (72% ee) than the stoichiometric reaction using 3a. Hy-

1 16

2.2 Oxidation (Hydroxylation and Acyloxylution) via C-H Bond Activation

ArCH2CH3

-

*-

+

PhlO

33% ee

major radical intermediate

,

minor radical intermediate

(Ar = Ph) ~ W R )

radical decay

kRD(y 1

radical rebound step

J HO H (major enantiomer)

40% ee (Ar = Ph)

HO H (minor enantiomer)

Scheme 4. Selective radical decay in the oxidation of alkylarene with 2

2 (The chiral bridge at the bottom was omitted for clarity.)

droxylation of acyclic alkylarenes proceeds with good enantioselectivity, while that of cyclic substrates only with modest selectivity (Table 1). The enantiotopic selectivity in the hydrogen atom abstraction has not been determined, but the reactions are also considered to involve enantioselective collapse of the benzylic radical intermediates, which enhances the enantioselectivity of the reactions, because the substrates fit to the chiral cavity are expected to undergo smooth oxygen rebound (see also Scheme 4). Although the first-formed alcohols are partly oxidized to the corresponding ketones during the reactions, efficient kinetic resolution has not been observed in this process.

2.2.2 C-H Hydroxylution Using Metullo-Porphyrin

1 17

Table 1. Asymmetric benzylic oxidation using complexes 3 as the catalysts Substrate

Product

3a (stoichiometric)

3b (catalytic)

Alcohol

Alcohol

Ketone

Ketone

Yield (“YO) % ee Yield (0%) Yield (“/I) % ee Yield (“A))

45

33

8.1

12

4.8

55

26

9.1

65

4.8

48

9

25

35

12

18.4

41

18

24

25

12

16.8

\ 3a: X = Y = 0 3b: X = CO. Y = EtOH

In 1986, Kochi et al. reported that (salen)manganese(III) complex 4 having a structure similar to metalloporphyrin also catalyzed C-H hydroxylation via a radical intermediate. In this reaction, 4 is oxidized to the corresponding 0x0 Mn( V ) species, which abstracts hydrogen atom to give the radical intermediate [ 111. Subsequent to this study, Jacobsen et al. reported kinetic resolution of racemic benzocyclic epoxides using chiral (sa1en)manganese complex 5 as the catalyst [ 121. Assuming the formation of radical intermediates, the reaction proceeds stereospecifically for stereoelectronic reasons. Axial benzylic hydrogen atom cis to epoxide is preferentially

1 18

2.2 Oxidation (Hydroxylation and Acyloxylation) via C-H Bond Activation

abstracted and oxygen rebound occurs to give an axial alcohol. This was supported by the results that anti-epoxide 6 bearing an axial benzylic hydrogen atom was oxidized to give syn-epoxy alcohol, while the diastereomeric cis-epoxide 7 was not under the same conditions (Scheme 5 ) . Efficiency of kinetic resolution (krel) is only modest except for the oxidation of epoxide 8.

n

4

Katsuki and coworkers examined enantiotopic selective hydroxylation of prochiral substrates with chiral (sa1en)manganese complexes as catalysts [ 131. This reaction also proceeds via a radical intermediate [13a]. The kinetic isotopic effect ( k ~ / =k 4.6) ~ observed in the hydroxylation of ethylbenzene with complex l l b supports the idea that hydrogen atom abstraction is the rate-determining step [ 13b]. In the reaction using chiral (sa1en)manganese complexes which have no chiral cavity, radical decay should occur less selectively and should deteriorate the enantioselectivity of hydroxylation. A solvent of intense viscosity constitutes a strong

qo 5

NaOCl V

I

k,d

4.8

3.5

2.6

Scheme 5. Kinetic resolution of benzocyclic epoxides with complex 5

28

1 19

2.2.2 C-H Hydroxylution Using Metallo-Porphyrin

Table 2. Asymmetric benzylic oxidation with optically active (salen)manganese(III) complexes as CatdlyStS Entry

Substrate

Product

Catalyst

Time

Solvent Yield (viscosity) (YO)

1.5 h

CH,CN

Y'n

~~

1

9

ee Yield of k,, ketone ("/") ~

~

18

39

4.5

2.6

17

50

4.3

2.9

(0.341)

OH 2

9

1.5 h

3

9

10 min

2

53

0.2

9 10 lla lla llb

1.5 h 1.5 h 10 min 20 h 10 min

7

61 9 84 90 83

2.3 0.3

trace

llb

20 h

87

11

I)H

Me0

9

1 4.8 25 1.8

4.2 1.o

10

trace

Me0

9: Ar = Ph; R,R= -(CHz)4l l a : Ar = 4-(t-BuPhzSi)C6H4;R,R= Ph l l b : Ar = 4-(t-BuPhzSi)CGH4;R,R= -(CH2)4-

C ~ H S C I 13

10

solvent cage, and the use of such a solvent suppresses random radical decay to some extent, resulting in the improvement of enantioselectivity (Table 2, entries 1, 2, and 4). To directly reflect the enantiotopic selectivity in hydrogen atom abstraction in the ee of the resulting alcohol, the radical decay must be suppressed efficiently. To solve this problem, complex 11 in which the manganese ion is covered by the t-butyldiphenylsilyl group introduced into the phenyl substituent was synthesized [ 13bl. Good ees (84 and 83%) observed at the initial stage of the oxidation of 1,l-

2.2 Oxidation (Hydroxylation and Acyloxylation) via C-H Bond Activation

120

OH 12a (2 mol%), PhlO

-30 "C, CBHSCI 90% ee, 60%

13

OH

89% ee, 41%

OH 12b (2 mol%), PhlO

NCOpPh

NCOpPh -25 "C, CH3CN

88% ee, 78%

12a: R,R = -(CH2).,12b: R,R = Ph

OH NCOpPh

NCOpPh

82% ee, 57%

Scheme 6. Desymmetrization of meso-heterocycles

dimethylindan (entry 6) and 4-methoxy-1-ethylbenzene(entry 8) indicate that the hydrogen atom abstraction proceeds with high enantiotopic selectivity and the radical decay is suppressed efficiently. Since the alcohols are further oxidized to the corresponding ketone with modest enantiomer differentiation (krel= 1.8-5.0), ees of the alcohols increase as the reactions proceed (entries 6-9). The problem of radical decay is avoided in the desymmetric C-H hydroxylation of meso-heterocycles such as meso-tetrahydrofurans because the intermediary radical species is not prochiral but chiral. Therefore, the enantiotopic selectivity in hydrogen atom abstraction is considered to be directly reflected in the ee of the product in this type of reaction [ 141.Actually, complex 12a, which has no group covering the manganese ion shows high enantioselectivity (up to 90% ee) in the desymmetrization of meso-tetrahydrofurans (Scheme 6). The small kinetic isotopic effect ( k ~ / =k 2~. 3 ) observed in the oxidation of 13 and 7,7,9,9-d4-13, however, might indicate that these reactions do not start with hydrogen atom abstraction but with one-electron transfer from lone-pair electrons to 0x0 species and subsequent proton abstraction, though both reaction paths involve a common radical intermediate [ 151. Oxidation of meso-pyrrolidine derivatives also proceeds with high enantioselectivity [ 161. Murahashi et al. reported desymmetrization of prochiral 2(t-butyldimethylsi1oxy)indan (up to 70% ee) using Mn-salen catalyst of Jacobsen type [ 171. These results indicate that appropriate (salen)manganese(III) complexes exert high asymmetric catalysis for not only face- but also topos-selective reactions.

2.2.3 Khavush-Sosnovsky Type of Allylic C-H Oxidation

121

2.2.3 Kharasch-Sosnovsky Type of Allylic C-H Oxidation: its Mechanism and Stereocontrol In 1958, Kharasch et al. reported that treatment of olefins with peroxy ester in the presence of copper(1) salts provides the acyloxylated product(s) at the allylic carbon(s) [ 181. A combination of alkyl hydroperoxide (or hydrogen peroxide) and carboxylic acid can be used in place of peroxy ester. In this reaction, copper(1) salt reductively cleaves the 0-0 bond of the peroxide to generate an alkoxy (or hydroxy) radical and a copper(I1) carboxylate (Scheme 7). The alkoxy (or hydroxy) radical abstracts allylic hydrogen atom to give an allyl radical. The allyl radical then combines with the copper(11) species and the resulting allyl copper(II1) species undergoes reductive elimination to yield allyl ester, regenerating copper(1) salt. To make this reaction valuable for organic synthesis, its regio- and stereo-chemistries must be controlled. If an olefin has multiple substituents, hydrogen atom abstraction occurs to give thermodynamically more stable radical intermediate(s): for example, two radical intermediates are generated by hydrogen atom abstraction at the two allylic methylene carbons in the oxidation of 1-methylcyclopentene but no hydrogen atom abstraction from its methyl group is observed (see Scheme 11) [ 19a,d]. Regiochemistry in the coordination step of allyl radical is mainly dictated by a steric factor: sterically less hindered terminal carbon of allyl radical preferentially combines with copper ion. The reaction of 1-alkene, for example, gives 3acetoxy-1-alkene as a major product, because the radical intermediate coordinates with copper ion mainly at the C-1 carbon, and the resulting copper(II1) species undergoes S~2’-likerearrangement (Scheme 8) [20]. Regiochemistry in the reaction of dialkyl-substituted olefins is low. Except for the hydrogen atom abstraction step, the other steps in the Kharasch-Sosnovsky reaction occur in the coordination sphere of the copper ion. Therefore, the stereochemistry of the reaction should be controlled if the copper ion carries well-crafted optically active ligand(s). In order to avoid a regiochemical problem in hydrogen atom abstraction, most studies of this asymmetric allylic oxidation have been examined with cycloalkenes as substrates which impose no regiochemical problem. RCOO-OR’ or

R’OOH + RC02H

]

cu(l)

*OR’ + RCOO-Cu(l1)

CH,=CHCH,OCOR

RCOO-Cu(l1)

Scheme 7. Mechanism of Kharasch-Sosnovsky reaction

122

2.2 Oxidation (Hydroxylation and Acyloxylation) via C-H Bond Activation

R=Et(90%) >90

:

~ 1 0

Scheme 8. Kharasch-Sosnovsky reaction of terminal olefins

Q

1) TBHP, Cu(ll)-(@-ethyl camphorate

*

2) NaOH

[a]-10.1"

Scheme 9. The first example of an asymmetric Kharasch-Sosnovsky reaction

f-BuOOCOPh, PhCOzH

*

cI>.COPh

cat. Cu(OAc)&u (0) C6H6,2O0

65% ee

Jyo2H Scheme 10. Asymmetric Kharasch-Sosnovsky reaction using a-aminoacid as a chiral auxiliary

In 1965, Denny et al. for the first time reported a catalytic asymmetric KharaschSosnovsky reaction by using Cu(I1)-(@)-ethylcamphorate as a catalyst, though enantioselectivity was low (Scheme 9) [21]. A quarter of a century later, natural or synthetic amino acids were introduced as chiral auxiliaries and much improved enantioselectivity (up to 65% ee) was achieved (Scheme 10) [22]. Although no detailed information on the structures of these copper complexes has been obtained, the observed non-linear relationship between the ee of the chiral auxiliary and the ee of the product suggests that the copper-amino acid complex is not monomeric but instead is oligomeric (at least dimeric) species [22e]. In 1995, three different chiral oxazoline derivatives were introduced as chiral ligands which remarkably improved enantioselectivity in allylic oxidation [ 191. Pfaltz et al. reported that copper(1)-bis(oxazo1ine)(15) complex show good to high enantioselectivity (up to 84% ee at -20 "C) in the oxidation of cyclopentene (Scheme 11) [ 19al. Enantioselectivity is dependent on the solvent used, and acetonitrile gives

2.2.3 Kharash-Sosnovsky Type of Allylic C-H Oxidation

c)

Cu complex, PhC020f-Bu

123

..,,102CPh

\-I

Cu(I)-15,CH3CN,-20 "C Cu(l)-17, CH3CN, -20 "C Cu(ll)-18, acetone, 0 "C Cu(ll)-18, acetone, -20 "C

84% ee, 61% 81% ee, 49% 83% ee, 81% 93% ee, 30%

h+aoBz+ Q OBz

PhCOpOf-BU * CU(I)OTf-1 5 acetone, 0 "C 70-85%

42% ee

37% ee

OBZ

73% ee

(50 : 42 : 8)

15

17

Ph 18

Scheme 11. Asymmetric Kharasch-Sosnovsky reaction using bis- or tris(oxazo1ine) as a chiral auxiliary

the best results. As presupposed from the reaction mechanism, regioselectivity of the reaction of substituted cyclopentene was modest (see above): oxidation of 1methylcyclopentene gave a mixture of three regioisomers in the ratio of 50:42:8 resulting from hydrogen atom abstraction at the two allylic methylene groups. They also reported that pyridine[bis(oxazoline)] ligand 16 (Nishiyama's ligand) is as effective as bis(oxazo1ine) ligand 15. Andrus et al. independently reported that the copper(1) complex-bearing ligand 17 is as effective a catalyst (81% ee) under similar reaction conditions as the Cu(1)-15 complex [ 19bl. Kawasaki and Katsuki reported that tris(oxazo1ine)amine 18 was also an efficient chiral ligand [ 19c,d]. Different from bis(oxazo1ine) complexes, however, its copper(I1) complex was catalytically more reactive than the corresponding copper(1) complex, though enantioselection by these two complexes is almost equal. For the reaction using Cu(I1)-18 as the

124

2.2 Oxidation (Hydroxylution and Acyloxylution) via C-H Bond Activation Cu catalyst, PhC020f-Bu

-0

.~~IIOBZ

Cu(l)-15: CH3CN, 7 "C, 15days 77% ee, 64%lga C~(l)-17:CHSCN, -20 "C 80% ee, 4 3 ~ ~ " ~ 72y0 ee, 4Y01gd Cu(ll)-18: acetone, -20 "C C~(l)-15,PhCO2Of-BU CH3CN, 7 "C, 14days

-0

.-SOIOB~

82% ee. 4 4 ~ ' ' ~

Scheme 12. Other examples of the Asymmetric Kharash-Sosnovsky reaction

y----86% ee, 81Yo

N

Ph

N

19

Ph

Scheme 13. Asymmetric allylic oxidation using 19 as the chiral auxiliary

catalyst, acetone is the solvent of choice. Contamination by water adversely affects enantioselectivity and the reaction showed 83% ee at 0 "C and 93% ee at -20 " C in the presence of molecular sieves, though lowering reaction temperature reduces the reaction rate. The reaction with other cycloalkenes also proceeds with good enantioselectivity (Scheme 12). On the other hand, DattaGupta and Singh reported that oxidation of cycloalkenes is effected by using the copper(1) complex bearing a modified Nishiyama ligand 19 as the catalyst (Scheme 13) [23]. The reactions of cyclohexene and cyclooctene in the presence of molecular sieves proceeds with high enantioselectivity of 86 and 81% ee, while that of cyclopentene proceeds with moderate selectivity of 54% ee [23b]. Upon hydrogen atom abstraction, some racemic olefins such as cis-3,4dialkylcyclopentenes give a Mzeso-intermediate which may be selectively converted into the corresponding chiral benzoate (Scheme 14) [24]. Actually, oxidation of racemic acetonide 20 provided the desired ally1 benzoate 21 with 80% ee but, because of poor regioselectivity in the hydrogen abstraction step, it also produced the undesired side products 22 and 23 (Scheme 15).

125

2.2.4 Conclusion R Cu(I)-L' or Cu(II)-L'

*

PhCOzOf-Bu

[J-I ]

l-J,,oBz

cuL'(oBz~

optically active

Scheme 14. Asymmetrization of racemic olefins by the Kharasch-Sosnovsky reaction

Cu(l)[or Cu(II)]L'

+

f-BuOOCOPh

r

-

t-BuO*

+

Cu(ll)[or Cu(III)]L'(OCOPh)

-

RO % R

H

.'

v

ROR%

H 21

I

RO=

A

BzO

+ 20

and its enantiomer OBz 23

(Absolute configuration of 22 and 23 has not been determined.) Cu(l)-15 (CH3CN); 46%, 21 (74% ee) : 22 (30% ee) : 23 (52% ee) = 4.4 : 1.2 : 1 Cu(ll)-18 (acetone); 78%, 21 (80% ee) : 22 (12% ee) : 23 (42% ee) = 6.0 : 5.9 : 1

Scheme 15. Asymmetrization of a racemic cyclopentene derivative

2.2.4 Conclusion Recent development of asymmetric C-H hydroxylation was discussed in this chapter. Although the discussions were limited to C-H hydroxylation at active methylene via a radical intermediate, it was demonstrated that efficient differentiation of enantiotopic hydrogen atoms could be achieved by using a well-crafted molecular catalyst as discussed in Section 2.2.2. This may open a gateway to enantioselective C-H hydroxylation at non-activated methylene. On the other hand, studies of asymmetric Kharasch-Sosnovsky reaction proved that transform of a topos-selective issue to the face-selective one by generating an ally1 radical intermediate is another useful approach to asymmetric C-H hydroxylation.

126

2.2 Oxidation (Hydroxylution and Acyloxylution) via C-H Bond Activation

References [ I ] a) R. W. Murray, R. Jeyaraman, L. Mohan, J. Am. Chem. Soc. 1986, 108, 2470-2472; b) W. Adam, R. Curci, L. D’Accolti, A. Dinoi, C. Fusco, F. Gasparini, R. Kluge, R. Paredes, M. Schulz, A. K. Smerz, L. A. Veloza, S. Weinkotz, R. Winde, Chem. Eur. J. 1997, 3, 105-109; c) “Comprehensive organic synthesis”, (Ed: B. M. Trost), Pergamon, Oxford (l99l), Vol. 7. [2] For other examples of C-H oxidation, see: a) A. E. Shilov, G. B. Shul’pin, Chem. Rev. 1997, 97, 2879-2932; b) Y. Moro-oka, M. Akita, Cutalysis Today 1998, 41, 327-338. c) T. Naota, H. Takaya, S.-I. Murahashi, Chem. Rev. 1998, 98, 2599-2660. [3] J. P. Collman, X. Zhang, V. L. Lee, E. S. Uffelman, J. I. Brauman, Science 1993, 261, 14041411. [4] J. T. Groves, T. E. Nemo, R. S. Myers, J. Am. Chem. Soc. 1979, 101, 1032-1033. [ 5 ] J. T. Groves, G. A. McClusky, J. Am. Chem. Soc. 1976, 98, 859-861. [6] K. E. Liu, C. C. Johnson, M. Necomb, S. J. Lippard, J. Am. Chem. Soc. 1993, 115, 939-947; b) P. H. Toy, M. Newcomb, P. F. Hollenberg, J. Am. Chem. Soc. 1998, 120, 7719-7729. [7] J. P. Collman, A. S. Chien, T. A. Eberspacher, J. I. Brauman, J. Am. Chem. Soc. 1998, 120, 425-426. [8] a) S. Shapiro, J. U. Piper, E. Caspi, J. Am. Chem. SOC. 1982, 104, 2301-2305; b) S. Shaik, M. Filatov, D. Schroder, H. Schwalz, Chem. Eur. J . 1998, 4 , 193-199. [9] a) J. T. Groves, P. Viski, J. Am. Chem. Soc. 1989, I l l , 8537-8538; b) J. T. Groves, P. Viski, J. Org. Chem. 1990,55, 3628-3634. [lo] R. Zhang, W.-Y. Yu, T.-S. Lai, C.-M. Che, Chem. Commun. 1999, 1791-1792. [ 1 I ] K. Srinivasan, P. Michaud, J. K. Kochi. J. Am. Chem. Soc. 1986, 108, 2309-2320. [I21 J. F. Larrow, E. N. Jacobsen,J. Am. Chem. Soc. 1994, 116, 12129-12130. [I31 a) K. Hamachi, R. Irie, T. Katsuki, Tetrahedron Lett. 1996, 37, 4979-4982; b) T. Hamada, R. hie, J. Mihara, K. Hamachi, T. Katsuki, Tetruhedron 1998, 54, 10017-10028. [I41 a) A. Miyafuji, T. Katsuki, Synlett 1997, 836-838; b) A. Miyafuji, T. Katsuki, Tetrahedron 1998, 54, 10339-10348. [I51 T. Nishida, A. Miyafuji, Y. N. Ito, T. Katsuki, Tetrahedron Lett. 2000, 41, 7053-7058. [16] a) T. Punniyamurthy, A. Miyafuji, T. Katsuki, Tetrahedron Lett. 1998, 39, 8295-8298; b) T. Punniyamurthy, T. Katsuki, Tetrahedron 1999, 55, 9439-9454. [I71 N. Komiya, S. Noji, S.-I. Murahashi, Tetrahedron Lett. 1998, 39, 7921-7924. [I81 D. J. Rawlinson, G. Sosnovsky, Synthesis 1972, 1-28. (191 a) A. S. Gokhale, A. B. E. Minidis, A. Pfaltz, Tetrahedron Lett. 1995, 36, 1831-1845; b) M. B. Andrus, A. B. Argade, X. Chen, M. G. Pamment, Tetruhedron Lett. 1995, 36, 2945-2948; c ) K. Kawasaki, S. Tsumurd, T. Katsuki, Synlett 1995, 1245-1246; d) K. Kawasaki, T. Katsuki, Tetrahedrvn 1997, 53, 6337-6350; e) M. B. Andrus, X. Chen, Tetrahedron 1997, 53, 16229- 16240. [20] A. L. Beckwith, A. A. Zavitsaa, J. Am. Chem. Soc. 1986, 108, 8230-8234. [21] D. B. Denny, R. Napier, A. Cammarata, J. Org. Chem. 1965, 30, 3151-3152. [22] a) J. Muzart, J. Mol. Cutul. 1991, 64, 381-384; b) A. Levina, J. Muzart, Tetrahedron: Asymmetry 1995, 6, 147-156; c) M. J. Sordergen, P. G. Anderson, Tetrahedron Lett. 1996, 42, 7557-7580; d) M. T. Rispense, C. Zondervan, B. L. Feringa, Tetrahedron: Asymmetry 1995, 6, 661-664; e) C . Zondervan, B. L. Feringa, Tetrahedron: Asymmetry 1996, 7, 1895-1898. [23] a) A. DattaGupta, V. K. Singh, Tetrahedron Lett. 1996, 37, 2633-2636; b) G. Sekar, A. DattaGupta, V. K. Singh, J. Org. Chem. 1998, 63, 2921-2967. [24] Y. Kohmura, T. Katsuki, Synlett 1999, 1231-1234.

Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

2.3 Nitroxides Rebecca Braslau and Marc 0. Anderson

2.3.1 Introduction Nitroxides are persistent free radicals [ 11 which can often be isolated and handled as kinetically stable species. Nitroxides react rapidly with carbon free-radical intermediates [2]with well-characterized rate constants [ 3 ] ,and can thus be used as kinetic and mechanistic probes, as well as to trap carbon radicals in synthetic processes. They are easily oxidized or reduced, and thus have a rich redox chemistry that has been utilized for a variety of oxidations. As nitroxides have an unpaired electron, they are paramagnetic and thus ESR active, making them valuable as ‘spin labels’ for biomolecules [4]and as ‘spin traps’ for transient radicals [5].In addition, nitroxides have been developed as organic ferromagnetic materials [6].The synthesis of nitroxides has been reviewed in 1994 [7]. This review will focus on the synthetic applications of nitroxides.

2.3.2 Nitroxides as Carbon Radical Traps in Non-Chain Synthetic Sequences 2.3.2.1 Direct Trapping of Carbon Radicals The use of nitroxides as traps for carbon-centered radicals in organic chemistry is widespread; a number of examples are presented in this section. Synthetically, nitroxides are useful as traps as the resulting N-alkoxyamine products can be cleaved to yield alcohols, providing functionality for further structural elaboration. Several classes of organometallic species react with nitroxides to provide Nalkoxyamine products. Most commonly used is the commercially available nitroxide 2,2,6,6-tetrarnethyl-l-piperidinyloxy (TEMPO, 1). This has been demonstrated for numerous species including: R-Li, R-MgBr, R-TiX3, R-ZrX, R-CuCN-Li, RZn-I, R-Cu-CN-ZnI, and R-SmI2 [8]. These reactions generally require two equiv-

128

2.3 Nitroxides

Scheme 1. Cobalt-mediated radical cyclization followed by functionalization by trapping with TEMPO

alents of TEMPO, and are thought to proceed through a mechanism where the first equivalent of TEMPO attacks the metal atom in a formal s H 2 step to generate a carbon radical. This radical is subsequently trapped by a second equivalent of TEMPO to give the N-alkoxyamine. A less common reaction pathway involves addition of an organometallic, such as a Grignard reagent, to the oxygen atom of an oxidized nitroxide, the oxoammonium salt, to give the N-alkoxyamine product [9]. The conversion of organocobalt species to N-alkoxyamine products with TEMPO has been demonstrated, and serves as a useful second step for reactions such as cobalt-mediated cationic cyclizations [lo], hydrocobaltation reactions [ 1 11, and cobalt-mediated free-radical cyclization reactions [ 121. An example of the latter can be seen in Pattenden's synthesis of /I-lactams using cobalt(sa1ophen) complexes [13]. Acyl cobalt species 2 was photolyzed to give the isolable 4-exo-trig radical cyclization product 3 (Scheme 1). Subsequent thermal reaction with TEMPO (1) in refluxing toluene gave N-alkoxyamine 4 which was cleaved by catalytic hydrogenolysis to yield the corresponding hydroxy methyl B-lactam 5 . A recent example demonstrates that organoboranes can serve as useful precursors to carbon radicals that can then be trapped by nitroxides [ 141. For example, (+)-2carene (6) was hydroborated with catecholborane and then allowed to react with two equivalents of TEMPO to produce the N-alkoxyamine 8 (Scheme 2). The first equivalent of TEMPO attacks the organoborane intermediate 7 in an overall S H ~ fashion, which probably involves the intermediacy of a boron 'ate'-like radical species. The resulting cyclopropylcarbinyl intermediate rearranges to a homoallylic

d

(+)-carene 6

-

2 eq. TEMPO

* Y 7

63%

Zn/AcOH 82%

(two steps) I

8

6:a. I

9

Scheme 2. Hydroboration followed by TEMPO-mediated radical generation and trapping

2.3.2 Nitroxides as Carbon Radical Traps in Non-Chain Synthetic Sequences

129

1 eq.TEMP0

PhH 40 “C 21%

24%

Scheme 3. Generation and trapping of alkyl radicals from an organoborane

radical, which is then trapped by a second equivalent of TEMPO. Reductive cleavage of the N-alkoxyamine yields alcohol 9. This overall process could serve as an alternative to traditional hydroboration/oxidation sequences using H202/ NaOH. Instead of using two equivalents of nitroxide, formation of the carbon radical is possible by addition of tert-butoxy radical, conveniently generated from di-tevt-butylhyponitrite (Scheme 3) [ 151. The use of TEMPO to effect oxidative demercuration was originally demonstrated by Whitesides [16], and is attractive because it gives a functional handle for further structural elaboration. This technique was invoked by Kang in the syntheses of (+)-lactacystin and (+)-furanomycin [ 171. For example, alkene 10 was subjected to mercurioamidation conditions to afford the cyclized organomercury intermediate 11 (Scheme 4). Treatment with lithium borohydride in the presence of TEMPO forms the unstable organomercury hydride. This fragments to release the primary carbon radical, which is trapped by TEMPO to yield the masked alcohol product 12, an intermediate in the synthesis of the neurotropic factor (+)-lactacystin. Another interesting use of TEMPO has been in ‘free-radical substitution’ of alkyl halides. In this reaction, halides react with tributyltin hydride and TEMPO to yield N-alkoxyamine ‘substitution’ products [ 181. This reaction is especially attractive in cases where anionic nucleophiles are sterically prevented from carrying out substitution reactions. An example of this can be seen in Barrett’s synthesis of sucrose [ 18b], in which a stereoselective iodoetherification reaction was used to produce neopentyl alkyl iodide 13 (Scheme 5). Free radical ‘substitution’ mediated by tributyltin hydride and TEMPO yielded N-alkoxyamine 14. The mechanism [ 191 involves TEMPO abstraction of hydrogen from tributyltin hydride [20]; the stannyl radical then abstracts iodide from the substrate, and a second equivalent of TEMPO traps the resulting carbon radical.

10

11

Scheme 4. Use of TEMPO in oxidative demercuration

12

130

2.3 Nitvoxides

TEMPO OTEMP

BnO'"

BnO"'

OBn

OBn 14

13

Scheme 5. 'Free-radical substitution' of an alkyl iodide in Barrett's synthesis of sucrose

2.3.2.2 Trapping of Carbon Radicals Following Cyclization Reactions TEMPO has also been utilized as a functionalizable trap in radical cyclization reactions. Bergman demonstrated the use of alkenyl iodides with tributyltin hydride and TEMPO to produce cyclized N-alkoxyamine products [ 18aI. This methodology has been used as a key step in the synthesis of several novel analogs of the CC-1065 and duocarmycin antitumor antibiotics [ 19, 211. In an example from Boger's laboratory, aryl iodide 15 was cyclized and trapped with TEMPO to give N-alkoxyamine product 16 (Scheme 6). This was further elaborated to N-BOC-iso-CBI (17), an analog of the DNA alkylation promoting subunit found in CC-1065 and duocarmycin. MOM0

OTEMP

3 eq. TEMPO

-

94%

BOC 15

0

BOC 16

BOC 17

Scheme 6. Tin hydride-mediated radical cyclization followed by trapping with TEMPO

Recent examples of 'tin-free' radical cyclization reactions [22] using TEMPO as a trap have been effected using samarium(I1) iodide or manganese complexes (Scheme 7). For example, Curran found that aryl iodide 18 gave N-alkoxyamine product 19 upon treatment with samarium(I1) iodide and TEMPO [Sd]. In another example, Gilbert used dimanganese decacarbonyl to mediate the radical cyclization of 20 followed by trapping with TEMPO to give N-alkoxyamine product 21 [23]. The emergence of tandem/'domino' reactions has been an exciting development in organic synthesis [24]. A recent example of a tandem anionic/oxidative radical cyclization sequence terminated by trapping with TEMPO was demonstrated by Jahn [25]. In this sequence, lithium amide 23 was added to enone 22 to give the conjugate addition intermediate 24, which was then oxidized by ferrocenium cation in an SET process to give a-carbonyl radical 25 (Scheme 8). This radical intermediate rearranged to give the 5-exo-trig cyclization product which was subsequently trapped by TEMPO to give 26.

2.3.2 Nitroxides as Carbon Radical Traps in Non-Chain Synthetic Sequences

":; '7

TEMPO

72%

Ts I 18

*

&single 19

(I

131

Mnz(COh0 TEMPO

20

diasterorner

i s

K O T E M P

21

Scheme 7. Samarium(l1) iodide and dimanganese decacarbonyl-mediated cyclizations followed by trapping with TEMPO

,g

Of-BU

)/

Ph

TEMPO 22

23

Of-BU

PI

TEMPO

fp > ,;.

NR

N R

24

25

R 26

68% (5.8:la$)

Scheme 8. Tandem anionic/oxidative reaction sequence followed by trapping with TEMPO

2.3.2.3 Stereoselective Trapping of Prochiral Radicals with Chiral Nitroxides Prochiral carbon radicals have enantiotopic faces: reaction with chiral nitroxides can result in two possible diastereomeric products (Scheme 9). Our laboratory has been investigating the ability of chirdl nitroxides to differentiate between the two enantiotopic faces of a transient prochiral carbon radical. In many of the examples, the prochiral radical is generated by the lead dioxide oxidation of a secondary benzylic hydrazine. Early work utilized a camphor-derived nitroxide 27, which was coupled to a secondary benzylic prochiral carbon radical with low but reproducible stereoselectivity (Scheme 10) [ 261. The stereoselectivity jumped dramatically upon moving to a conformationally rigid nitroxide in the form of the steroid doxy1 radical

Scheme 9. Reaction of a chiral nitroxide with the enantiotopic faces of a prochiral radical

132

2.3 Nitroxides

m tol, -78°C

81 Yo

1.4:lds

I

*-

27

1.7:lds

39%

,3.5:1- 10.811ds

Scheme 10. Stereoselective coupling of prochiral carbon radicals with camphor and steroid-derived nitroxides

28. However, the N-alkoxyamine products of the steroidal doxyl substrate displayed dynamic NMR spectra, making the analysis of the coupling reactions challenging. Thus other chiral nitroxides were developed to probe the stereoselective coupling reaction. Two conformationally rigid doxyl nitroxides prepared from camphene, camphoxyl nitroxides 29, were synthesized and coupled to several prochiral carbon radicals. In this series, the results were disappointing; very low diastereoselectivities were obtained (Scheme 11) [27]. The Cz-symmetric nitroxide 30 [28] is an excellent choice for this stereochemical study, as the two faces of the three-electron N - 0 z-bond of the nitroxide are enantiotopic, simplifying the possibilities to only two possible modes of attack in the key coupling reaction. Generation of a range of prochiral carbon radicals was examined under a variety of conditions, with diastereoselectivities ranging from 1.1:1 to as high as 5.2:l at room temperature. By varying the substituents on the prochiral radical, it was found that sterics make a significant contribution to the selectivity; however, there is a small but real electronic component. A particularly interesting result from this study is the dependence of the stereoselectivity on solvent viscosity. The very viscous solvent ethylene glycol results in fairly low diastereoselectivity (2.1:1 ds), whereas non-viscous diethyl ether as the solvent results in relatively high selectivity (5.2:l ds) (Scheme 12). This result provides evidence for an encounter complex in the coupling reaction of a nitroxide with a transient carbon radical, despite the lack of a clear transition state by ab initio calculations [29].

+ N $ 29

0

[

*

22-95%

+,:&c

1.1:l4 ex. - 1.6:lds

N R

6

R = M~ R = S-BU

O R

Scheme 11. Coupling of prochiral carbon radicals with camphoxyl nitroxides

2.3.3 Oxidations

133

Pb02 rt vary solvent Solvent Et20 toluene f-BuOH ethylene glycol

ds

Viscosity(cp)

0.233 0.590 3.897 19.9

5.2:l 4.7:l 3.9:l 2.1:l

Scheme 12. Effect of solvent viscosity on the stereoselectivity of coupling of a Cz-symmetric nitroxide with a prochiral carbon radical

2.3.3 Oxidations Nitroxide-mediated oxidation based on oxoammonium salts is a very common application of nitroxides in organic synthesis. In addition to a variety of alcohol oxidations, applications using oxoammonium species as one-electron oxidants have been utilized with a number of different substrates [30].

2.3.3.1 Chemoselective Oxidation of Alcohols Oxidation of primary and secondary alcohols by oxoammonium salts derived from nitroxides has become very popular because of the very mild and chemoselective reaction conditions available (Scheme 13). The stoichiometric oxidant can often be an inexpensive reagent, such as hypochlorite (bleach), 0 2 with a metal catalyst, electrochemical anodic oxidation, peracid, or bromine. The oxoammonium salt can be either pre-formed and used stoichiometrically or generated catalytically from the nitroxide in situ. The mechanism of the reactions is pH dependent: strongly acidic conditions chemoselectively oxidize secondary alcohols with accelerated rates over primary alcohols, whereas basic or mildly acidic conditions provide chemoselective oxidation of primary alcohols in the presence of secondary alcohols. A compre-

a II

O x-

+

R HO--63%

287

Ar = 4-fluorophenyl

288

(3.7: 1)

289

Oshima and coworkers [74] discovered a triethylborane-mediated atom transfer 9-endo and 12-endo trig cyclization of the acyl iodides 290 to generate the 9- and 12membered lactones 291. It was observed that use of water as the solvent, instead of benzene, significantly increased the efficiency of the reaction.

Et3B (0.1 equiv)

290

n solvent yield 1 benzene 27% 1 water 69% 2 benzene 22% 2 water 84%

I

291

Pattenden and coworkers [75] have reported tandem sequences involving the 9and 10-endo trig followed by 5- and 6-radical cyclizations. Treatment of the iodide 292 with Bu3SnH and AIBN furnished a 3:2 mixture of the trans and cis decalones 294 via the initial 10-endo trig cyclization followed by 6-ex0 trig cyclization of the resulting radical 293. It is interesting to note that no 5-ex0 trig cyclization leading to perhydroazulenone was observed. The origin of the formation of two diastereomers was explained on the basis of the two possible conformations of the intermediate radical 293. Relocation of the double bond in the precursor altered the course of the reaction. Radical cyclization reaction of the iodide 295 furnished a 1:1 mixture of the trans-tetralone 294 and perhydroazulenone 297 via the initial 10-endo trig cyclization followed by competitive 5-ex0 and 6-ex0 cyclization of the resulting radical 296. However, the sequence was not successful with the corresponding 1 1-endo system. Radical cyclization reaction of the iodide 298 failed to generate the products derived from the initial 1 1-endo cyclization, instead generated the ketone 299 via a tandem 5-ex0 trig - 6-end0 trig radical cyclization sequence. In contrast, the reaction was successful with the lower homolog 300. Radical cyclization reaction of the iodide 300 furnished the hydrindanone 301 via the initial 9-endo trig cyclization

182

3.1 Unusual Cyclizations

followed by 5-ex0 trig cyclization. The eight-membered system also proceeded in the same manner but resulted in the formation of cyclooctenone 303. Formation of cyclooctenone 303 was explained by the initial 8-endo trig cyclization to furnish the trans cyclooctenone radical 304, which underwent a reversible 5-ex0 trig cyclization to generate the cis olefin in cyclooctenone 303 via the bicyclic radical 305.

-

q

Bu3SnH AlBN

0

72%

I

292

L

295

293

I 1

296

294 trans:cis 3 : 2

294

298

(1 : 1)

H 297

299

. Bu3SnH AlBN 50%

300

($2 301

0

G' ;", 0 -

+ 50% starting

1 9 302 '0

40%

material

30&&

18-endo

q - G Q

f-

5-eXO

304

0

305

0

Further investigations led to the formation of tricyclic compounds [76]. Radical cyclization reaction of the iodide 306 furnished the tricyclic ketone 308, via a 13endo trig cyclization followed by a tandem 5-exo trig - 5-exo trig cyclization of the intermediate radical 307. However, the lower homolog failed to generate the tricyclic ketone 309 by a similar sequence, and instead furnished the enone 311. Interestingly, instead of the 12-endo trig cyclization, the initial radical underwent a 3-exo trig cyclization followed by a 5-exo trig cyclization.

3. 4 7-10 exo and endo Cyclizations

Bu3SnH AlBN

183

flo

55%

306

307

308 0

310

309

311

+ 23% starting material

The tandem cyclization sequence was also carried out using the acryl amides and esters [77]. The iodoamide 312 (X=NH) underwent a sequential 10-endo trig cyclization followed by a 5-exo cyclization to furnish stereoselectively the trans 7-5 lactam 313 (X=NH), whereas the corresponding ester 312 (X=O) furnished a 1:l mixture of the trans 7-5 and 6-6 systems 313 (X=O) and 314 (X=O) via the initial 10-endo trig cyclization followed by competitive 5-ex0 and 6-endo trig cyclizations. The amide and esters 315 underwent a 12-end0 trig cyclization followed by a 642x0 trig cyclization to furnish the 8-6 systems 316, whose stereochemistry was found to depend on the E,Z stereochemistry of the starting material 315.

Bu3SnH AlBN

I

W

312

dJ dX +

x H;

H 31 4

313

NH 45% 0 37%

JxBu3SnH AlBN

I

315

X = N H 45% X = O 61%

0%

37%

& H

316

The tandem radical cyclization sequence was further extended to the taxane framework by Pattenden and coworkers [78]. Radical cyclization reaction of the iodobisenone 317 furnished a 3:l mixture of the tricyclic dione 319, containing the taxane carbon framework, via a 12-endo trig cyclization followed by a 64x0 trig cyclization sequence, along with the 12-endo trig cyclized product 320 and the uncyclized reduction product 318. The methodology was also carried out with the corresponding acetylenic compound 321 to furnish a 6: 1 mixture of the dione 323 in 45560% yield. However, further explorations revealed that the strategy is substrate dependent as several similar systems failed to undergo the tandem sequence to provide taxoids.

184

3.I Unusual Cyclizations

& oko 317

0

318 (28%)

.

321

0

319 (29%, P:CX3:l)

BuSSnH AlBN

4-

322 (17%)

O@

320 (30%)

H0

323 (49%, P:CL6:l)

From the foregoing discussion it is clear that, during the last decade, the radical cyclization reactions have grown in importance and established their suitability for the construction of both small rings and medium rings in addition to the conventional five- and six-membered rings.

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186

3.1 Unusual Cyclizations

[36] D. L. Boger, R. J. Mathvink, J. Org. Chem., 1988, 53, 3377. [37] D. Crich, S. M. Fortt, Tetrahedron, 1989, 45, 6581; D. Crich, K. A. Eustace, T. J. Ritchie, Heterocycles, 1989, 28, 67. [38] D. Crich, S. M. Fortt, Tetrahedron Lett., 1988, 29, 2585; D. Crich, K. A. Eustace, S. M. Fortt, T. J. Ritchie, Tetrahedron, 1990, 46, 2135. 1391 D. Batty, D. Crich, Tetrahedron Lett., 1992,33, 875; D. Batty, D. Crich, J. Chem. Soc., Perkin Trans. I , 1992, 3193. [40] P. A. Evans, J. D. Roseman, J. Org. Chem., 1996, 61, 2252; P. A. Evans, T. Manangan, Tetrahedron Lett., 1997, 38, 8165; Y. Yuasa, W. Sato, S. Shibuya, Synth. Commun., 1997, 27, 573. [41] B. D. Boeck, N. Herbert, G. Pattenden, Tetrahedron Lett., 1998, 39, 6971. [42] M. Ohtsuka, Y. Takekawa, K. Shishido, Tetrahedron Lett., 1998, 39, 5803. [43] T. Ghosh, H. Hart, J. Org. Chem., 1989, 54, 5073; T. Ghosh, H. Hart, J. Org. Chem., 1988, 53, 2396. 1441 A. J. Clark, K. Jones, C. McCarthy, J. M. D. Storey, Tetrahedron Lett., 1991, 32, 2829. [45] T. Sato, S. Ishida, H. Ishibashi, M. Ikeda, J. Chem. Soc., Perkin Trans. I , 1991, 353. 1461 A. K. Ghosh, K. Ghosh, S. Pal, U. R. Ghatak, J. Chem. Soc., Chem. Commun., 1993, 809; A. K. Ghosh, J. K. Mukhopadhyay, U. R. Ghatak, J. Chem. Soc., Perkin Trans. I , 1997, 2747. [47] K. Ghosh, A. K. Ghosh, U. R. Ghatak, J. Chem. Soc., Chem. Commun., 1994, 629. [48] K. Ghosh, U. R. Ghatak, Tetrahedron Lett., 1995, 36, 4897. [49] J . K. Mukhopadhyaya, S. Pal, U. R. Ghatak, Indian J. Chem. 1999,38B, 264. [SO] A. L. J. Beckwith, C. H. Schiesser, Tetrahedron, 1985, 41, 3925. [51] P. Chattopadhyay, M. Mukherjee, S. Ghosh, J. Chem. Soc., Chem. Commun., 1997, 2139. [52] V. H. Rawal, S. P. Singh, C. Dufour, C. Michoud, J. Org. Chem., 1993, 58, 7718. [53] S. E. Booth, P. R. Jenkins, C. J. Swain, J . B. Sweeney, J. Chem. Soc., Perkin Trans. I , 1994, 3499; S. E. Booth, P. R. Jenkins, C. J. Swain, J. Chem. Soc., Chem. Commun., 1991, 1248. [54] D. Jonas, Y. Ozlu, P. J. Parsons, Synlett, 1995, 255. [55] J.-M. Duffault, Synlett, 1998, 33. [56] E. Lee, C. H. Yoon, T. H. Lee, J. Am. Chem. Soc., 1992, 114, 10981; E. Lee, C. H. Yoon, T. H. Lee, S. Y. Kim, T. J. Ha, Y.-S. Sung, S.-H. Park, S. Lee, J. Am. Chem. Soc., 1998, 120, 7469. [57] E. Lee, J. W. Lim, C. H. Yoon, Y.-S. Sung, Y. K. Kim, M. Yun, S. Kim, J. Am. Chem. Soc., 1997, 119, 8391. I581 E. Lee, C. H. Yoon, Tetrahedron Lett., 1996, 37, 5929. [59] L. Colombo, M. D. Giacomo, G. Papeo, 0. Carugo, C. Scolastico, L. Manzoni, Tetrahedron Lett., 1994, 35, 403 1. [60] S. E. Gibson (nie Thomas), N. Guillo, M. J. Tozer, J. Chem. Soc., Chem. Commun., 1997, 637. [61] C. Andres, J. P. Duque-Soladana, J. M. Iglesias, R. Pedrosa, Tetrahedron Lett., 1999, 40: 2421. [62] A. Helmboldt, J.-M. Mallet, M. Petitou, P. Sinay, Bull. Soc. Chim. Fr., 1997, 134, 1057. [63] D. P. Curran, W. Liu, Synlett, 1999, 117. [64] G. Kim, H. S. Kim, Tetrahedron Lett., 2000, 41, 225. 1651 T. Naito, K. Tajiri, T. Harimoto, I. Ninomiya, T. Kiguchi, Tetrahedron Lett., 1994, 35, 2205; H. Miyabe, M. Torieda, K. Inoue, K. Tajiri, T. Kiguchi, T. Naito, J. Org. Chem., 1998, 63, 4391. [66] J. H. Rigby, M. N. Qabar, J. Org. Chem., 1993, 58, 4473; see also, J. Cassayre, S. Z. Zdrd, Synlett, 1999, 501. [67] J. Fidalgo, L. Castedo, D. Dominguez, Tetrahedron Lett., 1993, 34, 7317; M. M. Cid, D. Dominguez, L. Castedo, E. M. Vazquez-Lopez, Tetrahedron, 1999, 55, 5599. [68] C. Lamas, C. Saa, L. Castedo, D. Dominguez, Tetrahedron Lett., 1992, 33, 5653; G. Rodriguez, M. M. Cid, C. Saa, L. Castedo, D. Dominguez, J. Ory. Chem., 1996, 61, 2780. [69] F. Aldabbagh, W. R. Bowman, E. Mann, Tetrahedron Lett., 1997, 38, 7937. [70] A. Nadin, T. Harrison, Tetrahedron Lett., 1999, 40, 4073. [71] D. P. Curran, C.-T. Chang, J. Ory. Chem., 1989, 54, 3140. [72] C. Destabel, J. D. Kilburn, J. Knight, Tetrahedron, 1994, 50, 11289.

References

187

[73] D. Crich, C. Chen, J.-T. Hwang, H. Yuan, A. Papadatos, R. I. Walter, J. Am. Chem. Soc., 1994, 116, 8937. [74] H. Yorimitsu, T. Nakamura, H. Shinokubo, K. Oshima, J. Org. Chem., 1998, 63, 8604. [75] G. Pattenden, A. J. Smithies, D. S. Walter, Tetrahedron Lett., 1994, 35, 2413. [76] M. J. Begley, G. Pattenden, A. J. Smithies, D. S. Walter, Tetrahedron Lett., 1994, 35, 2417; G. Pattenden, A. J. Smithies, D. Tapolcjay, D. S. Walter, J. Chem. Soc., Perkin Trans. 1, 1996, 7. [77] A. J. Blake, G. J. Hollingworth, G. Pattenden, Synlett, 1996, 643. [78] S. A. Hitchcock, G. Pattenden, Tetrahedron Lett., 1992, 33, 4843; S. A. Hitchcock, S. J. Houldsworth, G. Pattenden, D. C. Pryde, N. M. Thomson, A. J. Blake, J. Chem. Soc., Perkin Trans. I , 1998, 3181.

Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

3.2 Radical Rearrangements of Esters David Cvich

3.2.1 Introduction Long considered inert toward radicals, esters are now known to have a rich and interesting spectrum of free-radical chemistry. The purpose of this chapter is to highlight this reactivity and its applications, real and potential, in synthetic organic chemistry. Application and mechanism are intimately linked and it is therefore necessary to begin by placing the very broad spectrum of reactivity within as comprehensive a mechanistic framework as possible, which should provide a solid basis for further rational development of the area. The subject was comprehensively reviewed in 1997 [ I] and the reader is referred to that article for a detailed discussion of the early development of the field as well as for a complete listing of kinetic parameters available at the time. In the meantime, however, there have been major developments, particularly with regard to mechanism, and a brief recapitulation is needed in order that they may be fully appreciated. Kinetic parameters that have appeared since 1997 are to be found in articles by Crich and Newcomb [2-41; illustrative rate constants are given, whenever available, in the Schemes below.

3.2.2 Mechanism The mechanism of the p-( phosphatoxy)alkyl and /I-(acy1oxy)alkyl rearrangements and their less well known but closely related cousins, the /?-(su1fatoxy)alkyland pnitroxyalkyl rearrangements, has long presented a conundrum to workers in the field [ 11. Instances of reactions proceeding via pure 2,3-shifts [ I ] and pure 1,2-shifts [5] are known as are apparent mixed mechanisms, leading to the suggestion [ 11 that 5-center-5-electron and 3-center-3-electron concerted pathways both exist, with the precise selection for a particular example being a function of substituent effects and solvent. However, the possibility that all rearrangements occurred via a rapid radical ionic fragmentation, to give an alkene radical cation and a carboxylate or phosphate counter ion followed by rapid recombination, advocated by Sprecher [6],

3.2.2 Mechanism

189

was never ruled out. Indeed, the only pathway to be conclusively excluded was that of a stepwise ring closure, giving a 1,3-dioxolan-2-yl radical in the case of the acyloxy shift or a cyclic phosphoranyl radical in the case of the phosphate migration, followed by ring opening [7-91. Very strong evidence has, however, now begun to emerge for the p-( phosphatoxy)alkyl rearrangement and, by extrapolation, the acyloxy migration and their cousins that the whole range of chemistry observed is due to a radical ionic fragmentation, the differences being due to the extent of partitioning between contact ion pairs, solvent separated ion pairs, and diffusively free radical ions and ions [3, 41. Evidence for the contact ion pair mechanism is drawn from time resolved laser flash photolytic studies of two /I-(phosphatoxy)alkyl radicals. In the first of these [3], 355-nm flash photolysis of Barton ester 1 gave, instantaneously, the p-( phosphatoxy)alkyl radical 2 which underwent rearrangement to the benzyl radical 3 (A,,, 320 nm) and elimination to the allyl radical 4 (A,,, 354 nm), which were formed with the same rate constants within experimental error. When the experiment was repeated with d14 1 there was no change in the overall rate constant, for a given solvent, but the ratio of radicals 3 and 4 was altered in favor of 3. This indicates that there is no KIE on the rate-determining step but one for the product-forming step for allyl radical 4. When the photolysis was conducted in acetonitrile/water mixtures a further absorbance (Ama, 390 nm) was observed to grow in rapidly and, on the basis of a spectrum of the authentic species, this signal was assigned to the diffusively free radical cation 5 . Photolyses of 1 were conducted in solvents ranging in polarity from benzene to 67/33 water/acetonitrile and the rate constants, be they for the formation of 3 and 4 in most solvents or for that of 5 in aqueous acetonitrile, were plotted against the E ~ ( 3 0solvent ) polarity scale. The high linear dependence of rate constant on solvent polarity observed strongly suggests that there is no change in the nature of the rate-determining step across the whole range of solvents. It then follows that the different spectrum of product radicals observed in different solvents must be a function of partitioning after the rate-determining step. This notion is further supported by examination of the Arrhenius parameters across the range of solvents, which reveals the change in rate constant to be due to a lowering of the activation energy with increased solvent polarity and not to a change in the preexponential factor. The picture that therefore emerges is one in which the rate-determining step under all conditions is the fragmentation of the initial radical (2) into a contact ion pair. This contact ion pair either collapses to generate the rearranged benzylic radical 3 or undergoes proton transfer, with a KIE of 3-4, to generate the allylic radical 4. In more polar solvents partition of the contact ion pair with a solventseparated ion pair and, eventually, free ions is possible, which enables observation of the radical cation 5 (Scheme 1). A second, closely related experiment was conducted with the Barton ester 6 [4]. Here, the results were cleaner owing to the stronger C-H bonds, which effectively eliminated the deprotonation pathway and the formation of any allyl radicals. Moreover, as expected, because of the electron-donating effect of the para-methoxy group the diffusively free radical cation 8 could now be observed even in pure acetonitrile (Scheme 2). However, the telling feature of this series of experiments was

190

3.2 Radical Rearrangements of Esters

PhO\ OPh o. P z o

hv

PhO\ ,OPh o/Pzo P h y : h

S

-

PhO\ ,OPh -o. P e g [Phx:h

CIP

2

1: R = CH2Ph l-di4: R = CHzPh-+

-

PhO\ ,OPh Pzo

-p h x h p h SSlP

i

Scheme 1. Mechanism for the rearrangement and decomposition of Barton ester 1

EtO\ ,OEt o.Pzo

Ar

hv

A -

0

O - N 2

EtO\ ,OEt o/Pzo

A r x f

EtO\ ,OEt -o. P z o

Ar

7

s

CIP

6

EtO, ,OEt -o.PzO EtO\ ,OEt -o.Pgo% Br 58% SCN 64%

complexed chlorine atom

Scheme 16. Remote functionalization by a complexed chlorine atom

3.6.6 Alkyl Radicals For thermodynamic reason (see Table 1 for bond dissociation energies), alkyl radicals are less prone to abstract hydrogen atoms than alkenyl and aryl radicals. However, some efficient reactions based on alkyl radicals are known.

258

3.6 Hydrogen Atom Abstraction

3.6.6.1 Intermolecular Reactions Addition of carbon radicals to carbon-carbon double bonds is an important reaction that can be carried out under hydrogen transfer conditions [27]. Peroxides are usually used as radical precursors and an application of this chemistry is presented in Scheme 3 (Eq. 3.1). More recently, reduction of alkyl radical by C-H hydrogen donor has been examined in order to find an environmentally friendly alternative to tin hydride. Zard has reported a simple and cheap alternative to tin hydride for Barton-McCombie deoxygenation reactions [SO].Heating of xanthates derived from carbohydrates in 2-propanol in the presence of dilauroyl peroxide affords the deoxygenated products in good yields (Scheme 17, Eq. 17.1). 2-Propanol functions as

DLP (1.3 eq) i-PrOH, reflux

(17.1)

90%

S

$ie

SiMe2t-Bu OMe (1.5 eq)

(17.2)

AIBN, hexane

82%

SiMepf-Bu G

OMe i e

R'-H

CMex

i I

rearrangement or radical addition

t-BuMe2S'i-X

,OMe

t-BuMe2Si.

OMe

R-X

Scheme 17. Reduction of alkyl radical with C-H hydrogen donors

3.6.6 Alkyl Radicals

OHCD

O

M

e

259

. Et3B,air

THF, rt 42% (dr 91:9)

0"'

OH

Scheme 18. Et3B-promoted preparation of tetrahydrofuran-2-methanol derivatives from THF

a reducing agent. The process is not a chain reaction, and equimolar amounts of initiator are required. Walton and Studer have developed other approaches based on cyclohexadiene derivatives [ 8 1, 821. Studer's approach uses a silylated cyclohexadiene that can efficiently replace tin hydride for many radical reactions such as reductive dehalogenation, deoxygenation, and deselanylation reactions. Alkyl radicals are easily reduced by the cyclohexadiene and the cyclohexadienyl radical rearomatizes with formation of a silyl radical which is able to propagate the chain. Since the rate of hydrogen transfer is relatively low (10 times slower than TMS3SiH), this procedure is particularly suitable for conjugate additions, cyclizations and other radical rearrangements [82]. A cyclization reaction based on this procedure is presented in Scheme 17 (Eq. 17.2). Ethyl radical, obtained from the reaction of triethylborane with air, has been used to generate the tetrahydropyran-2-yl radical. Reaction with aldehydes afforded the corresponding alcohols with good stereoselectivity (Scheme 18) 1831.

3.6.6.2 Intramolecular Reactions Alkyl radicals have been used to abstract hydrogen atom from C-H bonds at secondary carbon centers. For instance, Fuchs has developed a self-immolative elimination of aryl sulfones [84]. The ortho-silylated sulfone gives upon treatment with tin hydride and AIBN a primary alkyl radical that abstracts a hydrogen atom in a 1,7-mode to give a /3-sulfonylated radical (Scheme 19, Eq. 19.1). Fragmentation delivers the corresponding alkene in 88% yield. During radical cascade reactions, Malacria has observed that primary alkyl radicals abstract allylic and alkyl hydrogen efficiently when the conformation is favorable [85, 861. Recently, the same group has reported a fragmentation of a sulfoxide leading to an allene after a radical 1,5-hydrogen transfer starting from a secondary alkyl radical (Eq. 19.2) 1871. Masnyk has used a hydrogen abstraction under iodine atom transfer conditions [88] (for a related reaction, see 1891). Reaction of an a-iodo sulfone with benzoyl peroxide furnishes the &-iodidevia a 1,5-hydrogen transfer in 83% yield (Scheme 19, Eq. 19.3). Most of the reported hydrogen abstractions promoted by alkyl radicals are concerned with the formation of stabilized 1-alkoxyalkyl radicals. For instance, De Mesmaeker has observed epimerization in glycopyranosidic radicals due to 1,5-

260

3.6 Hydrogen Atom Abstraction

Bu3SnH, AIBN, 80°C 88% rSiMep Br

.-SiMe2

- Ph

(1,7-HT) (19.1)

?-

Me3Si Eo\s+.Tol

-

(TMS)3SiH, AIBN

(- PhSO*)

*

TolH, reflux 61%

+OMe

I Ph02S

(19.2) +OMe

I

(BZO)~,100°C*

d

PhOZS

(19.3)

83%

Scheme 19. Activation of C-H bond at secondary carbon atom with alkyl radicals

hydrogen transfers and has shown that conformational effects govern the ease of hydrogen transfer [90, 911. Crich has developed a practical method for the inversion of a- to P-mannopyranoside based on a 1$hydrogen shift [92-941. Interestingly, this process was only possible with alkyl radicals, presumably because of a favorable conformational effect. In this method, the hydroxy group at C-2 is transformed into a bromoacetal and treated with tin hydride and AIBN at room temperature. 1,5-Hydrogen transfer and reduction of the anomeric radical from the less hindered a-face gave the inverted P-mannoside in 30% yield (Scheme 20, Eq. 20.1). The reaction has been used to epimerize a disaccharide [92]. Generation of a 1alkoxyalkyl radical via 1,5-hydrogen shift is the key step in Sugimura’s synthesis of (+)-ipomeamarone [95, 961. Treatment of the primary organomercury compound with sodium borohydride furnishes an intermediate primary alkyl radical that abstracts a hydrogen atom from the 1,3-dioxane ring (1,5-hydrogen transfer). The resulting radical is trapped with complete stereocontrol with acrylonitrile. The product is converted into (+)-ipomeamarone in four steps [96] (Scheme 20, Eq. 20.2). Transannular reactions represent an interesting family of hydrogen transfer processes that can be applied for highly selective and efficient remote functionalization. For instance, Zard reported 8-functionalization in the longifolene series via Barton decarboxylation of isolongifolic acid (Scheme 21, Eq. 21.1) [97].A spectacular regioand stereoselective remote hydroxylation of bicyclic ketone is reported by Winkler

3.6.7 Perhuloulkyl Rudiculs M

e

Bu3SnH, AIBN, hv, rt

BnO

(1 5 H T )

30% OMe

Y

-

C Br

Ph5°*H

I

OMe

fl """HCJOAC

NaBH4

H

Y ""'f'f

H,C=CHCN

""'

26 1

*

,/'

(20.2)

U

(+)-ipomeamarone

Scheme 20. Generation of 1 -alkoxyalkyl radicals via 1 $hydrogen transfer

@

(21.1)

PhH, 8O"C, hv

80%

Scheme 21. Transannular hydrogen shifts

[98, 991. The reaction takes advantage of a Barton reductive decarboxylation in the presence of tert-butanethiol and air (Scheme 21, Eq. 21.2).

3.6.7 Perhaloalkyl Radicals The electrophilic character of perhaloalkyl radicals (and in particular perfluoroalkyl radicals) makes them particularly attractive for hydrogen atom abstraction [ 1001. Indeed, their reactivity resembles that of alkoxyl radicals, and rates of hydrogen atom abstraction from C-H bonds are much higher than those of the corresponding hydrocarbon radicals [ 1011. Their electrophilic character facilitates abstraction at

262

3.6 Hydrogen Atom Abstraction

Scheme 22. Formation of tetrahydrofuranyl ethers under mild radical conditions

0

C4Fg1, t-BuOOH AcOH, 80°C > 80%

Scheme 23. Iodination of alkanes with perfluoroalkyl iodides.

carbon-bearing heteroatoms such as nitrogen and oxygen. For example, a convenient synthesis of tetrahydrofuranyl ethers from alcohols has been reported [ 1021. A wide spectrum of alcohols and phenols are transformed to the corresponding 2-THP ethers by treatment with CrC12 and CC14 in T H F under nearly neutral conditions and room temperature (Scheme 22). The mechanism involves the formation of the transient trichloromethyl radical, which abstracts a hydrogen atom at position 2 of tetrahydrofuran. Minisci has reported an interesting iodination reaction involving perfluoroalkyl iodides [103]. For instance, cyclohexane is cleanly iodinated when treated with perfluorobutyl iodide in acetic acid with tert-butylhydroperoxide as initiator (Scheme 23). The key step is the hydrogen atom abstraction by the perfluorobutyl radical. In a series of papers, Fuchs has reported allylation [ 1041, alkenylation [ 105, 1061 and alkynylation [107-1101 of C-H bonds. All these processes are based on the radical @-fragmentation of triflones liberating a trifluroromethyl radical suitable for hydrogen atom abstraction (Scheme 24). The regioselectivity of the hydrogen abstraction has been examined and is governed by polar and thermodynamic effects as shown in Scheme 24 [ 1071. An example of allylation is depicted in Scheme 25 (Eq. 25.1). In this reaction, dioxane is used as solvent [ 1041. The alkenylation reactions (Eqs. 25.2 and 25.3) are run under similar conditions [ 1051. Very interestingly, these reactions are stereospecific and the geometry of the initial triflone is preserved during the process. Finally, the alkynylation of adamantane is performed in acetonitrile (Eq. 25.4) [ 1101. The reaction occurs exclusively at the bridgehead position.

3.6.8 Aryl Radicals: ProtectingJRadical-TranslocatinyGroups . I I I

-C-C-SO2-CF3

-

\C=d / \

+

263

SO2 + CF3.

Scheme 24. Generation of trifluoromethyl radicals from triflones and regioselectivity in hydrogen abstraction C02Et

AIBN, dioxane

&so2cF3

reflux 77%

CFsSO:!

I

’=(Ph

*

AIBN, THF reflux

Ph

%Br

(25.2) Ph z/E 67:l

Z

cF3s02

(25.1)

AIBN, c-hexane

(25.3)

t

reflux Br

93%

E

E/Z 38:l

+ TIPS-SO2CF3

AIBN, CH3CNreflux

&

(25.4)

TIPS

50%

Scheme 25. Fuchs allylation, alkenylation and alkynylation with ally1 and vinyl triflones

3.6.8 Aryl Radicals: ProtectinglRadical-Translocating Groups Following pioneering work of Curran [ 1111 and De Mesmaeker [ 17, 201 on hydrogen atom transfer to aryl radicals, an intense research activity has focussed on the development of protecting/radical-translocating groups (= PRT groups) [ 1 121. This strategy allows remote functionalization of alcohols, amines and amides and has led to unique synthetic applications.

264

3.6 Hydrogen Atom Abstraction

3.6.8.1 Protecting/Radical-Translocating Groups for Alcohols The generation of 1-alkoxyalkyl radicals is not an easy task because of the instability of most radical precursors that might be used. Therefore, a hydrogen atom transfer process has been studied. Initial experiments have concentrated on orthobromo- or ortho-iodobenzyl ethers [ 17, 11 11. A typical example is shown in Scheme 26. The outho-iodobenzyl group meets the requirements for combined protecting/ radical-translocating group. It is easy to introduce, it functions as a typical alcoholprotecting group before the radical reaction, and finally, it selectively generates a radical adjacent to the oxygen atom via a 1,5-hydrogen transfer process [ 1 1 I].

-6

Bu3SnH, AlBN

,,'"\

56%

C02Me

transkis 2.5:l

Scheme 26. Generation of 1-alkoxyalkyl radicals with the ortho-iodobenzyl PRT group

A side reaction is frequently observed with benzyl PRT groups: indeed, fragmentation of the radical intermediates afforded an aldehyde or ketone together with a stabilized benzyl radical [ 171. After some tuning of the PRT group, Curran has developed an original procedure for selective oxidation of alcohols under reductive conditions by using the ortho-bromotrityl PRT group (Scheme 27) [ 1131. For the generation of 1-alkoxyalkyl radicals, Curran has introduced the use of the (ortho-bromopheny1)dimethylsilyl group [ 1 141. Treatment of the silyl ether with tin hydride afforded the desired radical via 1,5-hydrogen atom transfer. However, competing 1,6- and 1,7-hydrogen transfers are observed. This reaction has been used for selective deuteration at C-42 of the immunosuppressant rapamycin (Scheme 28, Eq. 28.1). Interestingly, with a-mannopyranosides, the 1,6-hydrogen transfer becomes the major process and the reaction was used to invert CI- to pmannopyranosides [ 1151. The best results were obtained with the (2-bromo-4,5difluoropheny1)dimethylsilyl group (Eq. 28.2). This reaction is related to the one depicted in Scheme 20 (Eq. 20.1).

Ph

BusSnH, AlBN

Scheme 27. Selective oxidation of alcohols under reductive conditions

Ph

3.6.8 Aryl Radicals: ProtectinglRadical-Translocating Groups

Raz

1) (o-BrPh)Me,SiCI 2) Bu,SnD, AlBN (28.1)

3)AcOH

H rapamycin

D

\ I

SiMe2(3,4-F2Ph)

BuSSnH, AlBN F

265

(28.2)

68%

0

58 : 42

SiMe2(3,4-F2Ph)

R = 1-naphthyl

Scheme 28. ortho-(Bromoaryldimethylsilyl) protective/radical-translocating groups

OMe

Scheme 29. Selective b-functionalization of ortho-bromo-para-methoxyphenyl group

The ortho-bromo-para-methoxyphenyl group has been used for efficient generation of radicals in the P-position to an oxygen atom [ 1121. This unique reactivity is of very high synthetic interest, particularly when tertiary radicals are generated (>80% efficiency for the 1,6-hydrogen transfer). An example of a radical cyclization is depicted in Scheme 29. Deprotection of the para-methoxyphenyl ether is possible under standard oxidative conditions with ceric ammonium nitrate.

3.6.8.2 Protecting/Radical Translocating Groups for Amines N-Benzoyl PRT groups. Snieckus and Curran have reported the first application of ortho-halobenzoyl groups to generate 1-amidoalkyl radicals [ 1 161. From this initial work, it was already apparent that a major problem of this approach was the control of the rotamer population of the benzamide (Scheme 30, Eq. 30.1). Indeed, conformer interconversion is slower than the lifetimes of the transient aryl radicals in solution. Therefore, the control of the conformation of the radical precursor is a prerequisite for high yields. Equation (30.1) illustrates this point: when R = cyclohexyl, a very modest 27% yield is obtained reflecting the population of the anti conformer (antilsyn 33:67) at equilibrium. As expected, the symmetrical compound gave much higher yield (82%). An attempt to control the synlanti conformation by using a bulky R group (R = tert-butyl) was only partially successful. Indeed, a high level of the desired 1,5-hydrogen transfer was observed but the resulting radicals gave no trace of the desired cyclization product. Instead, a product of aromatic substitution was isolated [ 116, 1171. Good yields were obtained with symmetrical amides as shown in Eqs. (30.2) and (30.3) for intra- and intermolecular reactions.

266

3.6 Hydrogen Atom Abstraction

0 Bu3SnH, AlBN

(30.1)

PhH, reflux

COOEt

R=c-C~H 1 ~ R = (CH2)4CH=CHCOOEt

27% 82%

SYn

Bu3SnH,AlBN

(30.2)

PhH, reflux

0

67%

CHz=CHCOOMe Bu3SnH,AlBN

*

Br

PhH, reflux 68-91 %

fN I R

R

q

0

(30.3)

MeooC+YN7 R R R,R = H,H; Me,Me; CH2CH2

Scheme 30. Generation of 1-amidoalkyl radical from ortho-halobenzamides

ebo yN/

CH2=CHCOOMe NH2

BuaSnH,AIBN, PhH, reflux 41%

HOOC&COOH

80%

(31.l)

3-aminoadipicacid

Scheme 31. Synthetic application of the benzoyl promoted generation of 1-amidoalkyl radicals

3.6.8 Aryl Radicals: ProtectingJRadical-TranslocatingGroups

267

Scheme 32. Amide oxidation via 1,5-hydrogen transfer toward the synthesis of (-)-norsecurinine

Snieckus applied the intermolecular version of this reaction for a highly stereoselective synthesis of p-amino acids (Scheme 31, Eq. 31.1) [118]. Ikeda used an intramolecular regioselective reaction to synthesize the core of ( f)-epibatidine (Eq. 31.2) [119]. Weinreb has developed a method for amide oxidation taking advantage of a 1,5-hydrogen abstraction starting from an ortho substituted benzamide [ 1201. The radical is generated from the diazonium salt in the presence of a catalytic amount of cuprous chloride. A typical example designed toward the synthesis of (-)norsecurinine is shown in Scheme 32. N-Benzyl PRT groups. An obvious solution to the conformation problem discussed above is the use of ortho-halobenzyl PRT groups instead of the benzoyl derivatives [ 1171. Ito [ 1211 and Undheim [ 1221 have demonstrated the synthetic potential of this approach. Under classical tin hydride conditions, excellent yields for the alkylation of amines have been obtained as shown in Scheme 33 (Eq. 33.1) [ 1221. Starting from a chiral 1,3-oxazolidine, a novel approach for the functionalization of aminoalcohols has been reported [ 1231. When samarium iodide was used for such reactions, the formation of an organosamarium intermediate at the a-N position was achieved. This corresponds to the metallation of an amine under nonbasic conditions. Subsequent reaction of the organosamarium species with electrophiles such as ketones [121, 124, 1251 (Eq. 33.2) and isocyanides [121, 1241 has been reported.

0 N

I

CH2=C(Me)COOMe Bu3SnH, AlBN

*

N uCOOMe

(33.1)

PhH, reflux 95%

Scheme 33. Generation of 1-aminoalkyl radical with an ortho-iodobenzyl PRT group

268

3.6 Hydrogen Atom Abstraction 1) Bu3SnH. ACCN

(34.1)

PMB

75% trandcis 10:l

Me

Bu3SnH,AIBN t-BuPhH, reflux53%

(34.2) Me

Me

CN

Scheme 34. Generation of 1-amidoalkyl radical with an ortho-bromobenzyl PRT groups

Similar results have been obtained for the formation of 1-amidoalkyl radicals starting from N-ortho-halobenzyl amides. For instance, the synthesis of y-lactam from glycine derivatives was reported (Scheme 34, Eq. 34.1) [126]. A new route to spirooxindole based on 1,5-hydrogen transfer followed by cyclization onto an activated indole was recently published (Eq. 34.2) [ 1271. 1,3-Oxazolidinones. Oxazolidinones prepared from a-hydroxy acids and 2bromobenzaldehyde have been used to protect the amino group of amino acids and to generate 1 -amidoalkyl radicals. Interestingly, by using chiral cc-hydroxy acid derivatives such as lactic acid, it was possible to develop a PRT group that also acts as a chiral auxiliary. This strategy was applied to the preparation of nonproteinogenic amino acids by diastereoselective alkylation of glycine and alanine derivatives (Scheme 35) [ 1281.

CH2=C(COOMe)CH; AIBN, PhH, reflux

85%

4

MeOOC

dr 72:28

Scheme 35. Stereoselective alkylation of a glycine derivative mediated by a protective/radicaltranslocating chiral auxiliary

3.6.8.3 Protecting/Radical-TranslocatingGroups for Carboxylic Acids The ortho-iodoanilide group proved to be broadly useful for the generation and subsequent reaction of radicals adjacent to carboxyl groups. The conformational feature of N-methyl-N-ortho-iodophenylpropanamide has been examined, and it was found that it exists almost predominantly in the E conformation required for

3.6.8 Aryl Rudicals: ProtectinglRudical-TranslocatingGroups

269

(5-exo-trig) (36.1)

exo/endo 1:1

OH 0 CH2=CHCH2SnBu3

(36.2)

AIBN, hv 64%

Scheme 36. Generation of radicals adjacent to a carboxyl group from ortho-iodoanilides

the hydrogen transfer step. The efficacy of the 1,5-hydrogen transfer is astonishing (k1,5 > 5 x 10' s-I). It was shown that, even with a high concentration of tin hydride (0.2 M), over 93% of hydrogen transfer was observed. This strategy was applied with excellent results for cascade reactions as depicted in Scheme 36 (Eq. 36.1) [ 1291 and also for stereoselective alkylation of 3-hydroxy alkanoic acids (Eq. 36.2) [130]. A related approach, where the aryl radicals are generated by electron transfer from tetrathiafulvalene to arenediazonium salts, has been reported [ 1311. Beckwith used a similar radical translocation followed by aromatic substitution to prepare oxindole derivatives [ 1321.

3.6.8.4 Miscellaneous Reactions 1,5-Hydrogen transfer by aryl radicals has been used to generate 1-alkoxysubstituted radicals in the presence of Lewis acids (Scheme 37) [133]. Classical methods for the generation of such radicals were not compatible with Lewis acids because of the instability of the radical precursors. Simpkins has presented an attractive method for the elimination of aryl sulfones [ 1341. ortho-Bromophenyl sulfones gave alkenes via a 1,5-hydrogen transfer followed by fragmentation of a sulfonyl radical according to Scheme 38. The scope and

Scheme 37. Generation of I-alkoxyalkyl radical in the presence of a Lewis acid

210

3.6 Hydrogen Atom Abstraction

Bu3SnH, AlBN

OBz

/o. (1,5-HT) (- PhSOp)

02s

PhH, reflux ++H 42% BzO Ph

OBz

Scheme 38. Radical elimination of ortho-bromophenyl sulfones

limitations of this method have not been examined but a related reaction involving sulfoxides has been more deeply investigated (see Section 3.6.10, Scheme 46).

3.6.9 Alkenyl Radicals Heiba and Dessau have described how vinyl radicals, generated by the addition of trichloromethyl radicals to terminal alkynes such as heptyne, readily undergo internal 1,5-hydrogen shift followed by a 5-exo-trig cyclization [ 1351. Curran has further developed the chemistry of alkenyl radicals. He has demonstrated that intramolecular hydrogen abstraction from alkenyl radicals furnishes hexenyl radicals that cyclize to cyclopentane derivatives [ 11 11. In this process, the radical is first generated on the alkene that is destined to become the acceptor for the subsequent cyclization (Scheme 39). Low concentrations of tin hydride are necessary to favor the hydrogen abstraction step and the cyclization reaction. The Stork catalytic method (Bu3SnC1, NaBH3CN in tert-butanol [ 1361) proved to be particularly simple and efficient for these reactions.

MeOOC COOMe

B ~ ~10smolyo ~ c MeOOC ~

COOMe

MeOOC COOMe

NaBH3CN t-BuOH, reflux Y X,Y = H,H: 72% X,Y = Me,Me: 73% X,Y = OTBS,H: 87%

X

Y lo7 ssl (X,Y = S(CH2)3S) [136]. Hydrogen abstraction from a Consequently, methyl group (X,Y = H,H) does not occur readily (k1.5 < lo5 SKI). highly efficient hydrogen transfer-cyclization processes are possible only when stabilized intermediate radicals are generated. Abstraction a to an oxygen atom. Formation of a bicyclic system starting from a free alcohol is depicted in Scheme 40 (Eq. 40.1) [136]. Malacria has recently reported the preparation of enantiomerically pure 1,2,3-triols via an unusual 1,4hydrogen atom abstraction followed by a highly diastereoselective trapping of the resultant alkoxy substituted radical with acrylonitrile (Eq. 40.2) [ 191. In this particular case, intramolecular reaction with the alkenyl group (3-exo-trig or 4-endo-trig cyclization) is not feasible; therefore, reaction with an external radical trap is fdvored.

woH -

BuaSnCl 10 mol% H $ , (40.1)

f-BuOH, NaBH3CN reflux 45%

-

0

1) Bu~NF 2) AcOH,HpO

Si,

(40.2)

85%

Scheme 40. Generation and cyclization of l-alkoxyalkyl radicals

Abstraction at acetal centers. Simpkins used a hydrogen atom abstraction from tetrahydrofuranyl and tetrahydropyranyl acetals for the preparation of spiroketals (Scheme 41, Eq. 41.1)] [137]. Malacria has inserted this process in a cascade reaction leading to functionalized cyclopentanone (Eq. 41.2) [ 1381. Bertrand and Crich applied this reaction for the preparation of optically active cyclopentane derivative under chiral auxiliary control (Eq. 41.3) [139]. The synthesis of anomeric spironucleosides was reported independently by Chatgilialoglu [46] and Kittaka [ 1401. In the example reported in Eq. (41.4), the gem-dibromovinyl derivative was treated with hexabutyldistannane to afford the desired spiro derivatives. This kind of reac-

272

3.6 Hydrogen Atom Abstraction

(41.1)

(41-2)

Bu3SnCl 10 mol% NaBH3CN CBuOH. reflux

*

&

: : : t o $ ',,,

PdCI&H3CN)z

acetone

+

:;zzzco

(41.3)

95% ee

(41.4)

Scheme 41. Generation and cyclization of radicals at acetal centers

tion is particularly interesting since it works under non-reductive conditions and allows the formation of cyclopentene derivatives [46]. Abstraction a to a nitrogen atom. A nice example of cascade radical reactions involving 1,6-hydrogen abstraction a to nitrogen atom has been reported by Bachi during the synthesis of bicyclic p-lactams [ 1411. The reaction involves the addition of a tributyltin radical onto a terminal alkyne providing a vinyl radical that undergoes a 1,6-hydrogen transfer. The resulting radical then cyclizes in a 7-end0 mode to give, after p-elimination, the desired bicyclic p-lactam (Scheme 42, Eq 42.1).

a'], O

'

I C02Me

Bu3SnH,

DBU

(42.1)

PhH, reflux C02Me

then PhSH, rt 64%

C02Me

dihydroxyheliotridane

Scheme 42. Generation and cyclization of 1 -amido- and I-aminoalkyl radicals

3.6. I0 Diastereoselectivity of Hydrogen Atom Abstraction

213

Robertson has shown that treatment of N-(3-bromo-3-buteny1)pyrrolidine derivatives with tributyltin hydride and AIBN leads to pyrrolizidine derivatives [ 1421. This reaction was used for the synthesis of dihydroxyheliotridane (Eq. 42.2). Abstraction at the allylic position. Abstraction of an allylic hydrogen atom followed by a radical cyclization sequence has been applied to the synthesis of fused pyrrolizidine rings (Scheme 43) [ 143, 1441. c

\-

PhH, reflux 1

60-85%

uE rJ 63% MeOH

H dr 4:l

MeUUC;\

HO

Scheme 43. Generation and cyclization of allylic radicals

Generation of non-stabilized alkyl radicals. Malacria has developed several new cascade reactions taking advantage of selective hydrogen atom abstractions by alkenyl radicals [ 1451. Recently, he achieved the preparation of a linear triquinane from an acyclic precursor. The last steps of the reaction sequence are a hydrogen abstraction by a vinyl radical at the P-position of the sulfone followed by the elimination of a sulfonyl radical, affording the final product in 50% yield (Scheme 44) [146].

Scheme 44. Triquinane synthesis involving the generation of an alkyl radical from an alkenyl radical via 1 $hydrogen transfer

3.6.10 Diastereoselectivity of Hydrogen Atom Abstraction Surprisingly, the stereochemistry of hydrogen atom abstraction has not been investigated in a systematic way. However, the analogy of the transition states of cyclization reactions and those of hydrogen atom abstractions lead us to speculate that stereoselective hydrogen transfers could be achieved. Malacria has reported an example of a totally diastereoselective 1$hydrogen atom abstraction (Scheme 45)

274

3.6 Hydrogen Atom Abstraction

SiMe3

1) Bu3SnH, AlBN 2) MeLi

(45.1)

69%

SiMe3

/ \

”

SiMe3

SiMea

favored

S02Ph

disfavored

1) Bu3SnH, AlBN 2) Tamao

(1,5-HT)

69% / \

\ ‘ /Si

$.

3

(s-endo-trig) /Si \ 0

____t

\

L

S02Ph

S02Ph

(-PhS02*) (Tamao)

____)

S02Ph

d$

-

(45.2)

HO

Scheme 45. Diastereoselective hydrogen atom abstraction by an alkenyl radical

[147]. In the process described in Eq. (45.1), the stereochemistry of four new stereogenic centers is controlled. The relative stereochemistry of the two first centers is established during the hydrogen atom abstraction and rationalized by steric interactions between one of the diastereotopic methyl groups and the non-reacting isopropyl residue. The two other centers are controlled during an unusual 5-endo cyclization and during the final reduction step. An application of this reaction for the synthesis of polysubstituted cyclopentenol derivatives is presented in Eq. (45.2). The last step of the reaction sequence is the elimination of a phenylsulfonyl radical that propagates the chain reaction. The radical fragmentation of sulfoxide has recently been reported. Besides the obvious advantage of running sulfoxide elimination at room temperature, the reaction proved to be very efficient for the preparation of optically active 4-substituted cyclohexenes starting from enantiopure ortho-bromophenyl sulfoxides (Scheme 46) [ 1481. The enantioselectivity of the elimination process is controlled by the diastereoselectivity of the hydrogen atom abstraction and is rationalized by minimization of steric interactions between the sulfoxide oxygen atom and the cyclohexane ring.

References

275

Bu3SnH, AlBN

hv, 10 "C

70% 80% ee

major

minor

Scheme 46. Enantioselective preparation of 4-substituted cyclohexenes by radical fragmentation of sulfoxides

3.6.11 Conclusions Translocation of radicals has been shown to be a remarkably powerful means of introducing functionality at unactivated sites. The diversity of the examples presented in this chapter proves the generality and usefulness of hydrogen atom abstraction. Based on simple rules, it is possible to plan radical translocation and to incorporate them into useful synthetic strategy.

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3.6 Hydrogen Atom Abstraction

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278

3.6 Hydrogen Atom Abstraction

IlOl] A. B. Shtarev, W. R. Dolbier, B. E. Smart J. Am. Chem. Soc. 1999, 121, 2110-2114. [ 1021 R. Baati, A. Valleix, C. Mioskowski, D. K. Barma, J. R. Falck Org. Lett. 2000, 2, 485 -487. [ 1031 F. Minisci, F. Fontana, F. Recupero, A. Bravo, E. Pagano, C. Rinaldi, M. di Luca, F. Grossi, 1999, 121, 7760G7765. H. R. Bjorsvik J. Am. Chem. SOC. 11041 J. Xiang, J. Evarts, A. Rivkin, D. P. Curran, P. L. Fuchs Tetrahedron Lett. 1998, 39, 41634166. 1997, 119, 4123-4129. 11051 J. Xiang, W. L. Jiang, J. C. Gong, P. L. Fuchs J. Am. Chem. SOC. 11061 J. Xiang, P. L. Fuchs J. Am. Chem. Soc. 1996, 118, 11986-11987. [I071 J. C. Gong, P. L. Fuchs J. Am. Chem. Soc. 1996, 118,4486-4487. [ 1081 J. C. Gong, P. L. Fuchs Tetrahedron Lett. 1997, 38, 787-790. [ 1091 J . S. Xiang, P. L. Fuchs Tetrahedron Lett. 1996,37, 5269-5272. [ 1101 J. Xiang, W. Jiang, P. L. Fuchs Tetrahedron Lett. 1997, 38, 6635-6638. I11 I ] D. P. Curran, D. Kim, H. T. Liu, W. Shen J. Am. Chem. SOC. 1988,110, 5900-5902. 11121 D. P. Curran, J. Y. Xu J. Am. Chem. SOC.1996, 118, 3142-3147. [113] D. P. Curran, H. Yu Synthesis 1992, 123-127. 11 141 D. P. Curran, K. V. Somayajula, H. Yu Tetrahedron Lett. 1992, 33, 2295-2298. [ 1 151 N. Yamazaki, E. Eichenberger, D. P. Curran Tetrahedron Lett. 1994,35, 6623-6626. [ 1161 V. Snieckus, J.-C. Cuevas, C. P. Sloan, H. Liu, D. P. Curran J. Am. Chem. SOC. 1990, 112, 896-898. [ 1171 D. P. Curran, L. Hongtao J. Chem. SOC.Perkin Trans 1 1994, 1377-1393. I1181 F. Beaulieu, J. Arora, U. Veith, N. J. Taylor, B. J. Chapell, V. Snieckus J. Am. Chem. SOC. 1996, 118, 8727-8728. [119] M. Ikeda, Y. Kugo, Y. Kondo, T. Yamazaki, T. Sat0 J. Chem. Soc. Perkin Trans. 1 1997, 3339-3344. [ 1201 S. M. Weinreb J. Heterocyclic Chem. 1996, 33, 1437. [ 1211 M. Murakami, M. Hayashi, Y. Ito J. Org. Chem. 1992, 57, 793-794. 11221 L. Williams, S. E. Booth, K. Undheim Tetrahedron 1994, 50, 13697-13708. [ 1231 R. Gosdin, A. M. Norrish, M. E. Wood Tetrahedron Lett. 1999, 40, 6673-6676. 11241 M. Murakami, M. Hayashi, Y. Ito Appl. Organometal. Chem. 1995, 9, 385-397. 11251 S. E. Booth, T. Benneche, K. Undheim Tetrahedron 1995, 51, 3665-3674. [ 1261 J. Rancourt, V. Gorys, E. Jolicoeur Tetrahedron Lett. 1998, 39, 5339-5342. 11271 S. T. Hilton, C. T. Tim, G. Pljevaljcic, K. Jones Org. Lett. 2000, 2, in press. 11281 L. Giraud, P. Renaud J. Org. Chem. 1998,63,9162-9163. (1291 D. P. Curran, H. S. Yu, H. T. Liu Tetrahedron 1994, 50, 7343-7366. [130] D. P. Curran, A. C. Abraham Tetrahedron 1993, 49, 4821-4840. 11311 J. A. Murphy, S. J. Roome J. Chem. SOC. Perkin Trans. 1 1995, 1349-1358. Chem. Commun. 1995, 977-978. [132] A. L. J. Beckwith, J. M. D. Storey J. Chem. SOC., 1995, 117, 6607-6608. [133] P. Renaud, M. Gerster J. Am. Chem. SOC. [ 1341 C. D. S. Brown, A. P. Dishington, 0. Shiskin, N. S. Simpkins Synlett 1995, 943-944. 1967, 89, 3772-3777. 11351 E. I. Heiba, R. M. Dessau J. Am. Chem. SOC. 11361 D. P. Curran, W. Shen J. Am. Chem. Soc. 1993, I15, 6051-6059. 11371 C. D. S. Brown, N. S. Simpkins, K. Clinch Tetrahedron Lett. 1993,34, 131-132. [138] S. Bogen, M. Journet, M. Malacria Synlett 1994, 958-960. (1391 M. P. Bertrand, D. Crich, R. Nouguier, R. Samy, D. Stien J. Org. Chem. 1996, 61, 35883589. 11401 A. Kittaka, T. Asakura, T. Kuze, H. Tanaka, N. Yamada, K. T. Nakamurd, T. Miyasaka J. Org. Chem. 1999,64, 7081-7093. 11411 E. Bosch, M. D. Bachi J. Org. Chem. 1993, 58, 5581-5582. 11421 J. Robertson, M. A. Peplow, J. Pillai Tetrahedron Lett. 1996, 37, 5825-5828. [I431 D. C. Lathbury, P. J. Parsons, I. Pinto J. Chem. Soc., Chem. Commun. 1988, 81-82. 11441 A. D. Borthwick, S. Caddick, P. J. Parsons Tetrahedron 1992, 48, 10655-10666. 11451 S. Bogen, L. Fensterbank, M. Malacria J. Ory. Chem. 1999, 64, 819-825. [ 1461 P. Devin, L. Fensterbank, M. Malacria J. Org. Chem. 1998, 63, 6764-6765. [147] S. Bogen, M. Gulea, L. Fensterbank, M. Malacria J. Ory. Chem. 1999, 64, 4920-4925. [ 1481 C. Imboden, F. Villar, P. Renaud Org. Lett. 1999, I , 873--875.

Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

4 Radicals in Total Synthesis 4.1 Radical Cyclizations in Alkaloid Synthesis David J. Hart

4.1.1 Introduction Over twenty years ago, my research group became interested in free-radical cyclization chemistry because we were impressed with the efficiency of a 5-hexenyl radical cyclization which we used to prove the stereochemistry of a product derived from an N-acyliminium ion cyclization [ 1, 21. A survey of the literature suggested that, at that time, free-radical cyclizations had been well developed for the preparation of carbocyclic materials, but the use of such reactions in heterocycle synthesis was not well developed. As one can see from the wealth of information that appears in Radicals in Organic Synthesis, we were clearly mistaken in our judgement of the state of the field relative to carbocycles. Nonetheless, it was this point of view that prompted us to pursue a research program designed to develop free radical cyclization reactions for use in alkaloid synthesis. Since the onset of our program [3, 41, this field has expanded enormously. This chapter will review progress in the area with certain limitations. The major focus will be on intramolecular carbon-carbon bond-forming reactions, and the chapter will be organized largely according to the type of free radical cyclization featured in the synthesis. Intermolecular free-radical reactions and cyclizations involving carbon-heteroatom bond-forming reactions will be mentioned only in passing. Although emphasis will be placed on free radical cyclization chemistry, additional details will be described in an attempt to provide the reader with an overview of each synthesis. Whereas we recognize that the inherent value of a synthesis may lie in the methodology, there is no question that chemists judge syntheses in part by their length, and this information will therefore be provided in most instances. Finally, the focus will be on completed syntheses, and only a few model studies will be presented.

4.1.2 a-Acylamino and a-Amino Radical Cyclizations Our own efforts began with failure. Inspired by the radical addition-atom transfercyclization-fragmentation sequence reported by Heiba (Eq. 1) [ 51, we attempted the

280

4.1 Radical Cyclizcltions in Alkaloid Synthesis

same chemistry using pyrrolidine 1 and pyrrolidinone 2 as substrates (Eq. 2). We had hoped that these reactions might provide pyrrolizidines of type 3 that could be further transformed into simple pyrrolizidine alkaloids. Both of these reactions, however, gave intractable materials. To better test the free-radical cyclization portion of this plan, we decided to develop a site-selective method for generation of the type of a-acylamino radical intermediate we had hoped to generate from 2. This was accomplished by tri-n-butyltin hydride (TBTH) mediated homolysis of a carbonsulfur bond [ 3 ] ,methodology independently developed by Bachi for use in the field of p-lactam synthesis [6].Radicals generated in this manner did undergo cyclization to provide nitrogen heterocycles [ 3 ] .For example, 4 cyclized to a mixture of 5 and 6 (Eq. 3 ) . Several aspects of this cyclization are notable. For example, the stereochemistry at C1 is in accord with expectations based on related hydrocarbons [7], but the regioselectivity of the cyclization is much lower than that observed for the related 5-hexenyl radical. In addition, the stereochemistry at is that expected from approach of the olefin to the radical from the least hindered face of the pyrrolidinone ring. This observation follows long-established principles in organic synthesis and will be seen on a number of occasions throughout this chapter.

cc14

1. cyclization

+

(t-BU0)p

*

2. fragmentation

A

24%

‘LQ

GOMe

X 3 X=HPorO

1 mBu3SnH

2

Me

*

0

OMe

H :

+

@OM.

PhH, A

0 4

0 5 (28%)

0 6 (31%)

In spite of the low regioselectivity observed in Eq. ( 3 ) , we were able to develop a number of pyrrolizidine alkaloid syntheses through rational modifications of the cyclization substrate. Our first examples of pyrrolizidine alkaloid syntheses are outlined in Scheme 1 [7]. Imide 7 was prepared from succinimide and 3-butyn-1-01 in 6 steps. Reduction of 7 followed by hydroxy-thiophenoxy exchange gave cyclization substrate 8. Treatment of 8 with TBTH gave a 71% isolated yield of pyrrolizidinone 9, which was converted to isoretronecanol in 4 steps. The radical cyclization step also gave small amounts of the C1 isomer of 9, reduction product 10 (5%), and

281

4.1.2 u-Acylamino and a-Amino Radical Cyclizations

&

AcO

*h&

n-Bu3SnH

PhH, AlBN A

0

0

7

0

8 X=SPh 10 X = H

y:q

9 (71%)

0 11

I

steps

HO-

t-BUOpC

J

5 steps

____)

PhH, AlBN

0 12

0

A

13 (81%)

(*)-isoretronecanol

Scheme 1. Synthesis of isoretronecanol [7]

endo-cyclization product 11 (4%). The stereochemistry of the endo-cyclization product was informative and suggests that the endo-cyclization proceeds via a transition state in which the piperidine ring is born in a chair conformation. A slightly shorter synthesis involved the 4-step preparation of 12 from succinimide, acrolein and the appropriate phosphorane, radical cyclization to give 13 (8 l%), and completion of the synthesis in an additional 5 steps. It is notable that although this route still suffered from production of stereoisomers at C1 (9:l ratio), reduction of the initially formed radical and endo-cyclization were not observed. Whereas the aforementioned syntheses are too long, given the simplicity of the targets, they were informative in terms of developing a fundamental understanding of this cyclization process. More efficient syntheses of more complex pyrrolizidine alkaloids followed as shown in Scheme 2. It is clear that the olefin component of the cyclizations used to prepare isoretronecanol were not good hydroxymethyl group equivalents. Use of a vinylsilane as the radical acceptor provided a better solution to this problem as illustrated by a synthesis of (-)-dihydroxyheliotridane, abbreviated in Eq. (4) [8]. Cyclization substrate 14 was prepared from malic acid and 3butyn-1-01 via a longest linear sequence of 6 steps. Cyclization of 14 provided 15 in 63% yield after separation from the usual side products. Tamao-Fleming oxidation of 15 followed by reduction of the lactam completed this rather short and direct synthesis. Alkynes were also shown to be useful within the context of pyrrolizidine alkaloid synthesis [9, lo]. For example 16 was prepared in 6 steps from the same starting materials used to prepare 14. Fret radical cyclization gave 17 as a 4:l mixture of olefin geometrical isomers in 71% yield. Protodesilylation (17 418) and lactam reduction provided (-)-dehydrohastanecine (Eq. 5). Pyrrolizidinone 17 was also converted to (-)-hastanecine and (+)-heliotridine (see below) via 7-step reaction sequences. Finally, allenes were investigated as cyclization substrates, resulting in a short synthesis of (+)-heliotridine (Eq. 6) [8]. Mitsunobu coupling of (S)-3acetoxysuccinimide with 2,3-butadien-l-01 gave imide 19. Conversion of the imide to selenide 20 was followed by radical cyclization to give crystalline endocyclic

282

4. I Radical Cyclizations in Alkaloid Synthesis

-

PhMepSiL5

n-Bu3SnH

PhMe2Si-:m$'

1. HBFpEt20&-% 0 8:(

0 15 (81%)

A

14

M e 3 S i Y : q

0

(-)-dihydroxyheliotridane

n-Bu3SnH

PhH, AlBN A

16 PhS02H

LiAIH4 (90%)

0 (-)-dehydrohastanecine

c

17 R = Me3Si (71%) 18 R = H (81%)

'cNP h S g

0 19

*

2. LiAIH4 (78%)

PhH, AlBN

0

0

20

-Hou

n-Bu3SnH

1. SeOP (28%)

PhH,AIBN A

2. LiAIH4(53%)

0 21

(+)-heliotridine

Scheme 2. Syntheses of oxygenated and unsaturated pyrrolizidine alkaloids [S, 91

olefin 21 in 40% yield along with 11% of 18 and 17% of the C7a isomer of 21. It is notable that use of the sulfide analog of 20 failed, as tri-n-butyltin radicals added to the allene faster than they reacted with the sulfide. The synthesis of (+)-heliotridine was completed by selenium dioxide oxidation of 21 followed by reduction of the resulting lactam. Although this synthesis suffers from a low yield in the oxidation step, it is one of the most direct routes to pyrrolizidine alkaloids reported to date. This approach also provides access to the less complex pyrrolizidine alkaloid supinidine [2]. A nice review of a-amino radical chemistry has been published [ 111, and this methodology has played a key role in the synthesis of other alkaloids and nitrogencontaining natural products (Scheme 3). For example, Clive used an a-acylamino radical cyclization of 22 (9 steps from pyroglutamic acid) as the key step in a synthesis of the frog toxin epibatidine (Eq. 7) [ 121. Corey used a radical-alkyne cyclization in an imaginative synthesis of biotin (Eq. 8) [13]. The radical cyclization precursor 23 was prepared in 8 steps from the methyl ester of cystine hydrochloride. Speckamp and Hiemstra reported a synthesis of the biologically important y-amino acid statine in which a silicon-tether was used in conjunction with an a-acylamino radical cyclization to control stereochemistry (Eq. 9) [ 141. My research group has extended the radical-alkyne cyclization chemistry to the synthesis of (-)-swainsonine (Eq. 10) [ 151. Free-radical cyclization precursors 24 were prepared from the appropriate tartarimide and 5-phenyl-4-butyn- 1-01. Radical cyclization gave a mixture of isomeric olefins 25 in 80-85% yield. Ozonolysis followed by a sodium borohydride reduction gave 26. Whereas this synthesis got off to an excellent start, an additional 9 steps were required to accomplish inversion of stereochemistry at C1 and reach the target.

4.1.2 a-Acylamino and a-Amino Radical Cyclizations

283

CI

9 steps H'

*

CO2H

ph3 Boc'

Ph

22

n-Bu3SnH toluene 110°C B 76%

0

4 steps w

h

(-)-epibatidine

0

0

-

H NK N rCH2Ph

4 steps

H-NAN--H

Hy$c-. S 40% + 8% of 6-membered ring

23

,O

?

-

n-Bu3SnH

D

O

AlBN

PhS CH2Ph

M

(7)

B &

e

A

y O CH2Ph

(8) '*'"-C02H (+)-biotin

-

75%

:

C02H

(9)

OH (3S,4S)-statine

[8steps from malic acid] Ph

-

n-BuBSnH utsOAc

0 24 (X = PhS or PhSe)

AlBN A

2 steps

9 steps

74%

0 25 (8045%)

0 26

(-)-swainsonine

Scheme 3. a-Acylamino radical cyclizations

The most complex application of this methodology to a problem in alkaloid synthesis is that of gelsemine shown in Scheme 4 [16]. Treatment of free radical cyclization precursor 27 (12 steps from commercially available materials) with TBTH gave 31 in 64% yield. The stereochemical outcome at C16 indicates that this 5-hexenyl radical cyclization takes place from boat-like conformation 30 rather than chair-like conformation 29. This is likely due to A ' , 3strain present in 29. It is also notable that the presence of an electron-withdrawing group on the olefin terminus was critical to the success of this cyclization. For example, radical precursors related to 27, in which the radical acceptor was merely a vinyl group, gave only reduction product upon treatment with TBTH. This illustrates that, as expected, the rate of addition of cc-acylamino radicals to olefins increases with electron deficiency of the olefin. In this case, using an electron-deficient olefin overcame an unfavorable conformational equilibrium. In other words, in the absence of the carboethoxy group, bimolecular reduction of the lower energy 28 is faster than unimolecular cyclization of the higher energy 30. A minor product from the reaction of 27 with TBTH is 32, the product of a radical translocation-cyclization process that appears to occur from conformation 28. It is notable that sulfide 33 gave none of this

284

4. I Rudicul Cyclizations in Alkaloid Synthesis OBn

n-Bu3SnH

Me

g+:

COpEt

CO2Et 29

28

27 R = Bn (12 steps) 33 R = M e

Ac:T: Ac

.

(OBn

f OR

-

li

OBn

5 steps

I

COpEt

CO2Et 31 R = B n 34 R = M e

Ph phOMe

30

I

n-Bu3SnH H

8 steps

tEtOpC g ;

-

M

e

Me

X = 0 21-oxogelsemine X = H2 gelsemine

32

ph

Scheme 4. Hart total synthesis of (i)-gelsemine [ I 61

translocation product, and afforded 34 in 87% yield. A free radical cyclization was also used to construct the oxindole substructure of gelsemine. A 5-step sequence was used to prepare 35 from 31. Treatment of 35 with TBTH gave oxindole 36 in 42% yield. Other products obtained from this reaction included the C7 epimer of 36 (9%), and the oxindole epimeric to 36 at both C.7 and C7 (7%). The synthesis of 21oxogelsemine was completed using a 7-step sequence, and 21 -0xoge1semine has been converted to gelsemine in a single step. From the standpoint of efficiency, this synthesis is comparable to three other syntheses of gelsemine [17, 18, 191, but falls short of a synthesis that uses N-acyliminium ion chemistry to construct the C5-C16 bond [ 201. The oxindole construction mentioned above is a variation of an oxindole synthesis developed by Jones. An application of this method to the synthesis of horsfiline is outlined in Eq. (11) [21]. It is notable that whereas the cyclization of 37 is quite efficient, attempts to cyclize amide 38 gave only reduction of the aryl bromide. This is a common problem in radical cyclizations involving secondary amides as the E-geometry of the amide precludes cyclization. This general problem was first

4.1.3 a-Iminoyl Radical Cyclizations

285

addressed by Stork and Mook [22] and will be seen on several occasions throughout the rest of this chapter. M e O a ; p - C b z mBuZSnH M I

R

e

O

/

a

Np-cbzNp 3 steps

0

AlBN A

M

*

SEM

e

0

Me

0

0

H

70% 37 R = SEM (8 steps from ethyl KCbz-glycinate) 38 R = H

(11)

(f)-horsfiline

At the same time that the Hart group was developing a-acylamino radical chemistry, the Mariano group was independently developing a-amino radical chemistry for use in alkaloid synthesis. Initial studies involved the development of an approach to the harringtonine alkaloids via photocyclization of { [ (trimethylsilyl)methyl]allyl}imminium perchlorates, reactions proceeding via diradical coupling of allylic and aamino free radicals [23]. This methodology was also applied to total syntheses of the protoberberine alkaloids xylopinine (Eq. 12) and stylopine [24]. Later studies from the Mariano group resulted in a new method of a-amino and a-acylamino freeradical generation via sensitized irradiation of N-(trimethylsilylmethy1)aminesand N-(trimethylsilylmethy1)amides [25]. This methodology has been used in model studies directed toward yohimbe alkaloids [26] and has been applied to a synthesis of epilupinine (Eq. 13) [ 271.

Me0

C104

Me0

(12)

OMe OMe

OMe

OMe

[7steps from 3,4-dimethoxybenzyl alcohol]

4.1.3 a-Iminoyl Radical Cyclizations There has been an explosion in the development of a-iminoyl radical cyclizations over the past decade, and a number of applications have appeared in the field of alkaloid total synthesis. Perhaps the most outstanding use of this chemistry is the

286

4. I Radical Cyclizations in Alkaloid Synthesis 0

PhN=C

9 steps PhH, 70 "C

MeaSi 39

'

0 40

I

camptothecin (63% from 39)

Scheme 5. Curran synthesis of camptothecin [29]

Curran group synthesis of the cancer chemotherapy candidate camptothecin [28]. Curran's second-generation synthesis is outlined in Scheme 5 [29]. The synthesis begins with an efficient 9-step synthesis of iodo alkyne 39. Absolute stereochemistry was established using a Sharpless asymmetric dihydroxylation of a vinyl ether. Irradiation of 39 in the presence of hexamethylditin and phenylisonitrile gives camptothecin in 63%)yield. This brilliant last step proceeds via initial generation of vinylic radical 40, addition to the isonitrile to generate iminoyl radical 41, cyclization to vinyl radical 42, and a cyclization-oxidation sequence to provide the natural product. This methodology has been used to prepare a number of camptothecin analogs as well as the structurally related alkaloid (S)-mappicine (Eq. 14) [30]. An asymmetric hydroxylation reaction using Davis's reagent was used to establish the absolute stereochemistry of mappicine.

- &&ME PhN=C

Y C O 2 M e

0

8 steps

Br OH

''

Me

(14)

HO. (S)-mappicine (38%)

The Fukuyama group has developed a versatile indole synthesis that relies on cyclization of iminoyl radicals generated by addition of tri-n-butylstannyl radicals to isonitriles. For example isonitrile 43 [4 steps from N-(o-iodophenyl)formamide] was converted to 44 in 71% overall yield as shown in Eq. (15) [31]. This reaction takes place via an iminoyl radical cyclization followed by tautomerization of the resulting imine. Indole 44 was a key intermediate in a synthesis of vincadifform-

4.1.3 a-Iminoyl Radical Cyclizations

287

amine. A notable feature of this method is that it provides indoles with a tin substituent at Cz that serves as an excellent handle for further elaboration of the indole. This method has also been applied to a synthesis of the structurally related aspidosperma alkaloid (-)-tabersonine [31], and model studies directed toward the marine natural product discorhabdin A [32]. A variation of this indole synthesis, actually involving an a-amino radical cyclization, has been used to prepare 45, an intermediate in a synthesis of the iboga alkaloid catharanthine (Eq. 16) [33], a precursor of the clinically important alkaloids vinblastine and vincristine. Note the use of hypophosphorous acid in place of TBTH as a mediator of this reaction. Although not involving iminoyl radicals, the Sundberg synthesis of catharanthine analog 47 from 3-iodoindole 46 should be mentioned (Eq. 17) [34]. This cyclization involves con-

coAc - doAc = @ (15)

AIBN, n-Bu3SnH MeCN 80 "C

43

75%

NIS BoCzO

OAc

c

X R=SnBus X = H R=l X=H

H

C02Me Vincadifformine

R = I X = B o c (44) OAc

I

45

SOpPh

46

40-50%

Catharanthine

S02Ph

47

struction of an 8-membered ring via a radical addition to a vinylic sulfone in a respectable 70% yield. The neuroexcitatory amino acid a-kainic acid, a popular testing ground for new pyrrolidine syntheses, has been prepared by a number of routes that involve freeradical cyclization reactions. Bachi has reported two approaches that involve iminoyl radical cyclizations. One enantioselective route is described in Scheme 6 [35]. Isonitrile 48 was prepared in 4 steps from 4-bromo-3-methyl-2-butenal dimethyl acetal, the key reaction being an enantioselective addition of tert-butyl a-isocyanoacetate to an aldehyde mediated by Hiyashi's catalyst. Treatment of 48 with a catalytic

288

4.1 Radical Cyclizations in Alkaloid Synthesis

SEt

J

EtSH

+-fOTBS

AlBN SEt 49

48

50 (77%) 10 steps

SEt I

OTBS H COptBu Boc 51

1. n-Bu3SnH toluene, A

7 steps

I

J,

...-COpH

2. n-BudNF

Boc 52 (73%)

H (-)-a-kainic acid

Scheme 6. Bachi syntheses of (-)-x-kainic acid [ 3 5 ]

amount of ethyl mercaptan in the presence of a free-radical initiator gave thioimidate 50 in 77% yield. This transformation proceeds by addition of an ethanethiyl radical to the isonitrile, cyclization of the resulting iminoyl radical, and p-elimination of ethanethiyl radical, which continues the chain reaction. The stereochemistry at C4 presumably is the result of cyclization via conformation 49. Allylic strain is minimized in 49 relative to the conformation-derived rotation around the C3-C4 bond. The role of allylic strain in determining the stereochemical course of free radical cyclizations has been noted above [ 141 and elsewhere [9, 361. The conversion of 50 to (-)-(a)-kainic acid is lengthy (10 steps), but proceeds in good overall yield. A slightly shorter variation of this synthesis involved cyclization of thioformamide 51 to pyrrolidine 52 via an intermediate a-acylamino radical. Two other groups have reported syntheses of a-kainic acid that revolve around free-radical cyclizations. Although they do not involve a-iminoyl or a-amino radicals, they illustrate interesting methodology and are presented here for the sake of continuity. Baldwin focussed on construction of the C3-C4 bond, an approach that establishes two stereogenic centers in the free radical cyclization (Eq. 18) [37]. Iodide 53 was prepared from L-serine in 10 steps. Cyclization was mediated using cobaloxime(1) in methanol to afford a 400/0 yield of 54 along with other minor products. Whereas stereochemistry at C3 was clean, a 1.7:1 mixture was obtained at C4. The major isomer had the required configuration at C4 and was carried on to (-)-a-kainic acid in 6 steps and the minor stereoisomer was converted to (-)aallokainic acid [38].The notable feature of this synthesis is retention of functionality that results from using a cobalt-mediated cyclization. Note that use of TBTH terminates with reduction. Application of this strategy to acromelic acid is outlined in Eq. (19) [39]. Cyclization of substrate 55 afforded 56 in 64% yield, along with 11%

4.1.4 N-Heterocycle Construction via Radical Cyclizations

289

of its C4-epimer. The synthesis of acromelic acid was then completed via a reaction sequence that revolves around adjustment of oxidation states at several carbons.

H2N HO

-'

-

-

- $ ~ < c o 2 t B ~ o ( l )MeOH

h-0

0

53

1 . .

..-cOptBU

.~-C02H

6 steps

'QCO2H

J-0

H

0 54 (40%) + isomers

(-)-a-kainic acid H02C

0' , ....- COzH

16 steps b

MeOH H

55

57 (55%)

56 (64%) + 11% of C4-epimer

59

acromelic acid

(-)-a-kainic acid

Cossy has reported a synthesis of cc-kainic acid that establishes the stereogenic centers on a preformed pyrrolidine ring (Eq. 20) [40].Thus, ketone 57 was prepared from L-pyroglutamic acid in 11 steps. Samarium iodide-mediated cyclization of 57 gave 58 as a mixture of stereoisomers at the carbinol carbon. Dehydration gave 59, and a 6-step sequence, starting with oxidative cleavage of the double bond, provided cc-kainic acid. One notable aspect of this synthesis is the use of an enamide as a free-radical acceptor in the key cyclization. This process has been used in a number of alkaloid syntheses as will be seen in the next section.

4.1.4 N-Heterocycle Construction via Radical Cyclizations This section will describe selected alkaloid syntheses in which a nitrogen heterocycle is constructed using a free-radical cyclization, but radicals adjacent to nitrogen are not involved in the ring-forming reaction. The lycorane family of alkaloids have been popular targets for such methodology. The Schultz group synthesis of (+)-1deoxylycorine (66), described in Scheme 7, currently stands as the crowning achievement in this area [41]. The synthesis began with the preparation of cycliza-

290

Me0

4.1 Radical Cyclizations in Alkaloid Synthesis

0

Me0


' O 2 Dihydrosesamin (7:lFavored)

4.2.2 Ether-Tethered Radical Cyclizations

305

,OTBS 1.3 eq. Ph3SnH 0.4 eq. AlBN Toluene 90 OC, 1 h

64 Yo

O (D

_-_

O 4

(S:a=1:2)

Scheme 3. Total synthesis of samin

nium triflate reagent, and 2,3-butadien-l-o1 with a diastereomeric ratio of 16:1, establishing the crucial benzylic stereogenic center. Silicon-containing cyclic ethers are formed with relative ease via radical cyclization of (bromomethy1)dimethylsilyl ether substrates. The strategy was introduced by Stork [6], and used by Koreeda [7] and others for stereoselective introduction of hydroxymethyl groups at the allylic and homoallylic positions via 5-ex0 or 6-end0 radical cyclizations. Crimmins applied this reaction for the synthesis of (-)-talaomycin A (7) [8] (Scheme 4). Additional examples include 14-deoxyisoamijiol [9] and an intermediate used in Woodward's reserpine synthesis [lo].Diphenylvinylsilyl ether moieties are useful radical acceptors, and intramolecular vinyl transfer reaction was employed for preparation of 4'a-C-vinylthymidine, a potent antiviral nucleoside [ l l ] . A spectacular example of silicon-tethered radical cyclizations is found in the (+)-tunicamycin V (10) synthesis by Myers [12]. Two sugar units are joined in the 0-silyl hemiselenoacetal substrate 8 for stereoselective 7-endo-trig radical cyclization (Scheme 5). Alkenyl and aryl radicals are also useful for expedient synthesis of oxacyclic natural products. For example, the hexahydrobenzofuran subunit 12 for avermectin synthesis was obtained from the bromopropenyl ether 11 [13] (Scheme 6). A formal synthesis of morphine (15) was reported by Parker utilizing tandem radical cyclizations initiated by the aryl radical from the bromoaryl ether 13 [ 141 (Scheme 7). A closely related example for the morphine skeleton synthesis also employed aryl radical cyclization [ 151.

1) BrCH2SiMe2CI Et3N, DMF 2 ) Bu3SnH,AlBN

OT 0 :

OH

6

Benzene, Reflux t 3) 30 % H202 MeOH, Na2C03 78 %

H0, ,

H i

Hi

OEt

88

0 89 (+)-Cladantholide

3 16

4.2 Synthesis of Oxacyclic Natural Products

+

1) 7.0 eq. SiMe3

0

91

0.1 eq. Bu3SnCI

2.0 eq. NaBH3CN hn (254 nm), THF, r.t. 10 h

0

H

*

2) 140 OC, neat 3) Pd(OAc)z, MeCN, r.t. 58 Yo

TBSO

90

TBSO

L

92

0

Scheme 32. Synthesis of prostaglandin Fza

O r B r

25 eq. CH2CHC02Me 0.3 eq. Bu3SnCI 7.0 eq. NaBH3CN * 0.5 eq. AlBN f-BUOH, 80 OC 56%

OEt

OEt

95 Magydardienediol

94

93

(4:lFavored)

Scheme 33. Formal synthesis of magydardienediol

Ph

Br

1) HCI, THF

~o~of-z *

96

0

88 %

2) PCC, Alp03 57 Yo

97

o

q

98 (>99% ee)

(9:lFavored) Scheme 34. Diastereoselective radical cyclization of bromoacetals

Enantiomerically pure samples of P-vinyl-;,-butyrolactone (98) were prepared starting from the diastereomerically pure bromoacetal96 (obtained by separation of the 1:1 mixture of products from the corresponding vinyl ether, 1,2-butadiene-4-01, and NBS) via purification of the major cyclization product 97. The bromoacetal obtained from 1-ethoxypropene was used in an approach to the dihydroagarofuran framework [66]. Bridged pyranosides were synthesized from cyclic iodoacetals [67]. Bicyclic acetals may be prepared with relative ease: epialboatrin (100) was synthesized via a successful hypophosphite-mediated radical cyclization of the cyclic bromohydrin 99 [68] (Scheme 35). In one of the early examples reported by Ueno, bromoacetals obtained from butoxyallene, allylic alcohols, and NBS underwent efficient radical cyclization reactions providing easy access to a-methylene-ybutyrolactones after Jones oxidation [ 691.

4.2.3 Acetul-Tethered Radical Cyclizations

3 17

10 eq. 1-EPHP 0.2 eq. AlBN Benzene (0.09 M) HO Reflux, 4 h

TBSO & B y

77 Yo

99

100 Epialboatrin (6.7:l) 101 Alboatrin

1-EPHP = 1-Ethylpiperidhiurn hypophosphite

Scheme 35. Synthesis of epialboatrin

0

0

cat. AlBN

0 Me0

Benzene Reflux

102

'

0 103

74 Yo

Me0 104 Aflatoxin B1

Scheme 36. Formal synthesis of aflatoxin B,

Halogenoacetals generating the type F radicals were used by De Mesmaeker in the synthesis of C-glycosides and C-2 branched pyranosides [70]. Easy access to furobenzofurans was provided as shown in the conversion of the aryl bromide 102 into the product 103 in a formal synthesis of aflatoxin B1 (104) by Snieckus [71] (Scheme 36).

4.2.3.2 Propargylic Acetal Substrates The butenolide synthesis by Stork [72] is an early example of the use of propargylic acetals. Srikrishna reported syntheses of a large number of natural products, which employed propargyl acetal intermediates: examples include evodone (107) [73] (Scheme 37) and homogynolide B (110) [74] (Scheme 38). Radical cyclizations leading to the construction of almost stereopure quaternary carbon stereogenic centers were reported using glucose-derived vinylogous esters such as 111. The stereochemical outcome in forming the product 113 is determined solely by the acetal configuration of the propargyl acetal 112 [75] (Scheme 39). 1.2 eq. Bu3SnH cat. AlBN *

OMe 105

Benzene Reflux, 90 min

&

/

OMe 106

cat. pTsOH Benzene * r.t. 15 min

& 107 Evodone

45 Yo(Two steps) Scheme 37. Synthesis of evodone

3 18

4.2 Synthesis of Oxacyclic Natural Products

cwJ 0

0.1 5 eq. Bu3SnCI NaBH3CN cat.AlBN

-cqy$

t-BUOH Reflux, 90 min

108

-

H

76 Yo

110 Homogynolide B

109

Scheme 38. Synthesis of homogynolide B

AcO"

Toluene (0.07 M) Reflux, 1 h

AcO"' OAc 112

111

AcO"'

(Crystal.)

""0Ac OAc 113

Scheme 39. Construction of stereopure quaternary carbon centers

4.2.3.3 Homoallylic Acetal Substrates The homoallylic acetal radical cyclization product reported by Stork [ 551 was later used in the construction of a significant portion of the gelsemine structure [76]. Further examples for homoallylic acetal cyclization exhibiting useful stereoselectivity include the (-)-protoemetino1 synthesis by Fukumoto [77] and the rhizoxin partial syntheses by Rama Rao [78] and White [79]. In the synthesis of (+)-12bepidevinylantirhine (117) [SO] (Scheme 40), Ihara adopted low-temperature conditions for radical cyclization of the chiral unsaturated ester 114 in the presence of MAD. The lactone 116 in high diastereomeric excess was obtained from the cycli-

EtO-+O,

1.5 eq. Bu3SnH 1.05 eq. Et3B Eto-+o\ *

B'J{ RO2C

1.05 eq. MAD Toluene -40 OC, 1.5 h

u , :

1) 10 % HC104 TH F 20 OC, 12 h

0-0,

2) Ag2CO3-CeliL Benzene C02R Reflux, 1 h

115

u .

\

C02R

116

38 % (>98% de)

Scheme 40. Total synthesis of 12b-epidevinylantirhine

H O. 117 (+)-I 2b-Epidevinylantirhine

&

3 19

4.2.3 Acetal-Tethered Radical Cyclizations &A

OBz

70 %

____ 5 H

118

HO,,

OMe

H

: H

119

H

0

0

120 (+)-Picrasin B

Scheme 41. Total synthesis of picrasin B

CHO Me02C

T O ' Me02C 124 (-)-Methyl elenolate

4 TBDPSO,

M~O~C/\\/\]

1) 1.2 eq. Bu3SnH,0.05 eq. AlBN Benzene, Reflux, 1 h; +' 0.4 eq. pTsOH, Reflux, 1 h

~ ~ 0 ~ ~ 2) " 46 - %f aq. ~HF-MeOH (1:3) OMe 121

M

~

~

~

c

\ o

*

58 %

122

(4:l)

123

Scheme 42. Total synthesis of methyl elenolate

\!

3.0 eq. Sm12 THF-HMPA (211) * 25 OC, 30 rnin

OCHO &OCHO 125 (2:l Mixture)

---*

76 % 126

127 (+)-Upial

Scheme 43. Total synthesis of upial

zation product 115. The (+)-picrash B (120) synthesis by Watt [81] (Scheme 41) also features conversion of the homoallylic acetal 118 to the product 119. The bromoacetal 121 derived from a P-alkoxyacrylate precursor was used in the enantioselective synthesis of (-)-methyl elenolate (124) [82] (Scheme 42). In the total synthesis of (+)-upial (127) [83] (Scheme 43), the cyclic acetal 126 was obtained from the diformate 125 via SmIz-induced cyclization.

320

4.2 Synthesis of Oxacyclic Natural Products

4.2.4 Ester-Tethered Radical Cyclizations 4.2.4.1 (Alkoxycarbony1)alkyl Radical Intermediates The rate of 5-exo cyclization of (alkoxycarbony1)methyl radicals is low, and the atom transfer strategy was used for the formation of lactones from allylic esters [ 84, 851. However, direct synthesis of substituted y-lactones is feasible [86], and deoxypodorhizon (129) was obtained from the cr-bromopropionate substrate 128 [87] (Scheme 44). It was then found by Lee that 8-endo cyclization is the intrinsically favored process in the reaction of (alkoxycarbony1)methyl radicals [88], and the transformation of the bromoacetate 130 into the tricyclic heptanolactone 131 testifies to the complete dominance of 8-endo cyclization over the 5-exo alternative [89] (Scheme 45). This particular regiochemical preference originates from the conformational bias favoring Z-ester arrangements, and it was used profitably in the synthesis of (-)-clavukerin A (134) [90] (Scheme 46). The 8-endo preference was further demonstrated in the Cu(1)-catalyzed cyclization of di- and trichloroacetates [91] and the cyclization reactions initiated by the addition of tert-butyl radicals to acrylates [92]. y-Lactone synthesis is more common in the oxidative processes involving Mn(II1) as exemplified by the synthesis of polycyclic y-lactones from allylic malonates by Corey [93]. Oxidative radical cyclization of chloromalonate species is especially useful, and the examples include the avenaciolide synthesis [94] and the

Me0 Reflux 40 % 129 Deoxypodorhizon (Epirneric product: 10 %)

128

Scheme 44. Synthesis of deoxypodorhizon

MOMOls.

& ; HQ

O)("Br

1.5 eq. Bu3SnH 0.2 eq. AlBN Benzene (0.025 M)

-

Reflux, 5 h (Syringe pump, 4 h) 80 Yo

MOMOl,.

131

130

Scheme 45. 8-Endo/S-exotandem radical cyclizations of bromoacetates

&

32 1

4.2.4 Ester-Tethered Radical Cyclizations

* o

0.05 1.2 eq. eq.Bu3SnH AlBN

@

Benzene (0.025 M) __*

* 0

Reflux, 5 h 6 8% (Syringe pump, 4 h)

~ r'-o f)

'. 134 (-)-ClavukerinA

133

132

Scheme 46. Total synthesis of clavukerin A

2.0 eq. M ~ ( O A C ) ~ . ~ H ~ O 1.O eq. CU(OAC)~.H~O THPOl,, EtOH, Reflux, 3 h 65 %

TH POI,..

---

0 136 (33 Favored)

0 135

0 137 (-)-Estafiatin

Scheme 47. Total synthesis of estafiatin 1) HCCCHzOH pTsOH, Benzene Reflux, 30 h *

138

2) 2.5 eq. Mn(OAc)3 EtOH, 20 OC, 2.5 h 61 %

% 3'.

O 00

139

140 9-Acetoxyfukinanolide

Scheme 48. Total synthesis of 9-acetoxyfukinanolide

(-)-estafiatin (137) synthesis via 5-exo,7-endo tandem cyclizations reported by Lee [60] (Scheme 47). In the synthesis of 9-acetoxyfukinanolide (140), the propargyl ester derived from the precursor 138 underwent successful cyclization to yield the lactone 139 [95] (Scheme 48). A retroaldol-aldol sequence on the hydroxy lactone derivative resulted in the epimerization at the quaternary diastereogenic center leading to the natural configuration. The allylic propiolate 141 reacted with tributylstannane to produce the Z-a-stannylmethylene-y-butyrolactone142, which served as an intermediate in the stereoselective synthesis of gadain (143) [96] (Scheme 49).

4.2.4.2 Acrylate and Propiolate Substrates Radical-mediated macrolide synthesis is feasible as shown by Porter in the conversion of the w-iodoalkyl acrylate 144 to the macrolide 145 [97] (Scheme 50). Unsat-

322

4.2 Synthesis of Oxacyclic Natural Products

1.2 eq. Bu3SnH 0.1 eq. AlBN

141

Benzenef0.04M) Reflux (Syringe pump, 3 h) 35 Yo

143 Gadain

142

Scheme 49. Synthesis of gadain

0

0

144

0

145

-

47 56 Yo

146 19 %

Scheme 50. Macrolide synthesis by free radical cyclization

147

148

149 (-)-Methylenolactocin

Scheme 51. Synthesis of methylenolactocin

urated macrolides are accessible by reaction of a-(stannylmethy1)acrylates and propiolates as reported by Baldwin [98, 991. In the synthesis of (-)-methylenolactocin (149) [ 1001 (Scheme 51), Weavers utilized direct formation of the a-iodomethyleney-butyrolactone 148 from the propiolate 147 via atom transfer cyclization. Alkenoyloxymethyl iodides and selenides were converted into lactones upon treatment with tributylstannane or tributylgermane [ 1011. In the (-)-zearalenone (152) synthesis reported by Pattenden [ 1021 (Scheme 52), the ester tether is a bystander in the radical macrocyclization.

q3!resiH

Me0

4.2.4 Ester-Tethered Radical Cyclizations

* Meo*---

323

HO

80 'C, 8 h (Syringe pump)

0

0

55 %

150 Br

151

152 (-)-Zearalenone

Scheme 52. Zearalenone synthesis via allylic radical cyclization

4.2.4.3 Alkoxycarbonyl Radical Intermediates Alkoxycarbonyl radical cyclization leads to direct formation of lactones. For example, the lactone 154 was obtained from the selenocarbonate 153 in Corey's synthesis of atractyligenin (155) [ 1031 (Scheme 53). S-Alkoxycarbonyl xanthates are also viable precursors for alkoxycarbonyl radicals; the lactone 157 was prepared from the xanthate 156 via group transfer radical cyclization en route to methylenolactocin (149) [ 1041 (Scheme 54).

1.5 eq. BusSnH 0.03 eq. AlBN Benzene (0.01 M)

-

153

Reflux, 12 h (Slow addition) 73 %

U

155 Atractyligenin

Scheme 53. Total synthesis of atractyligenin

OCbt-Bu

hv (500 W lamp) Toluene *

Reflux, 5.5 h 156

157 149 Methylenolactocin 63 % (From the alcohol)

Scheme 54. Cyclization of S-alkoxycarbonyl xanthates

324

4.2 Synthesis of Oxacyclic Natural Products

4.2.5 Miscellaneous Intramolecular Radical Reactions 4.2.5.1 Carbon-Nitrogen Multiple Bond Radical Acceptors Oxime ethers and imines are viable intramolecular radical acceptors. Advanced precursors of (-)-tetrodotoxin were prepared via radical cyclization reactions using oxime ethers as radical acceptors [ 1051. In the synthesis of (+)-7-deoxypancratistatin (160) [lo61 (Scheme 5 5 ) , the intermediate 159 was prepared via tandem radical cyclizations of the precursor 158 possessing an N-aziridinylimine and an 0-benzyloxime moiety. Direct formation of lactones is possible as shown in the reaction of the (2,2dipheny1hydrazono)acetate 161, which afforded the hydrazino lactone 162 along with the epimer 163. (+)-Furanomycin (164) was synthesized from 162 [lo71 (Scheme 56). Normally, use of nitrile radical acceptors is limited to cyclopentanone synthesis, but the rigidity of the 1,6-anhydro scaffolding in the bromide 166 enabled radical cyclization to give the tricyclic ketone 167, which comprises the entire skeletal framework of tetrodotoxin [lo81 (Scheme 57).

OTBS

158

4

Ph3SnH

OH

OTBS

Benzene Reflux

(

78 O h

'

/

NH

0 160 (+)-7-Deoxypancratistatin

Ph

Scheme 55. Total synthesis o f 7-deoxypancratistatin

164 (+)-Furanomycin

! I

PhSe"'"

Q:zINPh2

HO'" 161

Ph3SnH AlBN

Toluene Reflux (Slow addition)

Scheme 56. Total synthesis of furanomycin

H NHNPh2

r

H0"

H NHNPh2

0

HO"' 162

42 Yo

163

37%

4.2.5 Miscellaneous Intvamoleculav Radical Reactions 1.O eq. NBS 0.07 eq. (PhC02)2 Br, CC14 (0.04 M) hv (Heat lamp), 1 h; NC

ro “ P O A C NHAc AcO 165

Repeat

81 Yo

-

1.25 eq. Bu3SnH 0.05 eq. AlBN

-

O

F

325

O

A

C

P O A C Xylenes, 155 OC, 1 h AcO NHAc (Slow addition, 20 min) AcO NHAc 77 Yo 166 167

Scheme 57. Synthesis of the tetrodotoxin carbocyclic core

4.2.5.2 Oxacyclic Substrates A number of oxacyclic natural products were synthesized via carbocycle-forming radical reaction of oxacyclic intermediates. An early example is the synthesis of (-)dihydroagarofuran (170) by Buchi [ 1091 (Scheme 58). The bridgehead chloride 168 obtained from the corresponding hydroxy ketone was amenable to radical cyclization, and the tricyclic ether 169 was duly obtained. The aplysin synthesis [ 1101 provides another example, and (-)-karahana ether (173) was synthesized via radical cyclization of the substrate 171 [ l 111 (Scheme 59). Lactonic natural products (+)eremantholide A [ 1 121, alliacolide [ 1 131, and (-)-anastrephin [ 1 141 were prepared via a variety of carbocycle-forming radical cyclization reactions. In the total synthesis of spongian-16-one (176) [115] (Scheme 60), the butenolide moiety in the substrate 174 served as the final radical acceptor for three consecutive 6-endo-trig cyclizations.

B--Qq

1.25 eq. Bu3SnH 0.03 eq. AlBN

Cyclohexane hv (W lamp) (0.27 M) t Reflux, 1 h 72 %

MeaSi

I 0 Me3Si 169 (4:l)

168

5

Scheme 58. Total synthesis of dihydroagarofuran

1.2 eq. BusSnH 0.1 Benzene(0.03M) eq.AIBN

SiMe3 OCSlm

___

170 (-)-Dihydroagarofuran

&

Reflux, 5.5 h (Slow addition, 4 h)

75 Yo

171

Scheme 59. Synthesis of karahana ether

SiMe3 172 (1:l)

173 (-)-Karahana ether

326

4.2 Synthesis of Oxacyclic Natural Products

@!

BusSnH cat. AlBN Benzene Reflux, 8 h (Syringe pump) 65 Yo

SePh

175

174

176 Spongian-16-one

Scheme 60. Total synthesis of spongian-16-one

4.2.5.3 Oxy Radical Intermediates Formation of oxacycles via intramolecular radical addition reactions of oxygencentered radicals under oxidative and reductive conditions is known [ 1161 (see also Chapter 5.2, Volume 2). However, cyclic ether formation via intramolecular displacement reaction of iodohydrins obtained by hydrogen abstraction of oxy radicals has been more widely used, as exemplified in the reports by Suarez [117]. The usefulness of this reaction was amply demonstrated by Paquette in the synthesis of (+)-epoxydictymene (179) [118] (Scheme 61), in which the strained trans-

. .

hv, 50 OC 95 0x3

Scheme 61. Total synthesis of epoxydictymene

H

A

PvO-

.+

2.0 eq. HgO 2.0 eq. 12

i

OMe

pvo4 c

hv (275 W lamp) OPV 6 Pv

CCII, r.t. 1.5 h CC14, 53 Yo

180 182 Avermectin A,,

Scheme 62. Total synthesis of avermectin A,,

4.2.5 Miscellaneous Intramolecular Radical Reactions

30 % H202 AcOH * 99 % (57 % conv.) 183

a

327

CU(OAC)~ FeS04

MeOH 96 % OOH 184 (Mixture of stereoisomers)

*

185 Recifeiolide

Scheme 63. Synthesis of recifeiolide

oxabicyclo[3.3.0]octane system in 178 was efficiently constructed from the hydroxy precursor 177. In the total synthesis of avermectin A,, (182) [119] (Scheme 62), Danishefsky successfully assembled the spiroketal moiety 181 from the alcohol 180 under similar conditions. P-Fragmentation of oxy radicals may be profitably employed in oxacycle synthesis. Schreiber converted the keto alcohol 183 into recifeiolide 185 via P-fragmentation of the oxy radical obtained from the alkoxy hydroperoxide 184 [120] (Scheme 63). Exaltolide was prepared from a keto alcohol precursor by Suginome under modified conditions [ 1211. Tandem P-fragmentation-cyclization reactions of carbohydrates were reported by Suarez to give cyclic ketoses [ 1221. Intramolecular reactions of carbon-centered radicals and carbonyl groups generate oxy radicals, which undergo 8-fragmentation and further rearrangements [ 1231.

4.2.5.4 Miscellaneous Intramolecular Radical Reactions An approach to aflatoxins using type I1 photocyclization reactions was reported by Kraus, in which dihydrobenzofuranols were obtained from aryl alkyl ketones via 175-hydrogenabstraction [ 1241. An interesting reaction reported by Nicolaou involves preparation of the fused poly(oxacyc1e) systems employing electron transfer reaction of macrodithionolides as shown by the eventual synthesis of 188 from 186 [ 1251 (Scheme 64).

E %

2.2 eq. Na-naph THF, -78 oc; *

ex. Mel,

H

S 186

H

-

-78 2 5 % 80 %

SMe

2.2 eq. AgBF4 ex. Et3SiH *

0 MeSO H

DCM,25OC 9 5%

187

Scheme 64. Macrodithionolide cyclization via electron transfer

H0 H 188

328

4.2 Synthesis of Oxacyclic Natural Products

4.2.6 Intermolecular Radical Reactions 4.2.6.1 Oxacyclic Substrates Stereoselective hydrogen transfer reactions on oxacyclic radical intermediates are useful as shown in the synthesis of lauthisan (32) [126]. A key step in the total synthesis of brevetoxin B by Nicolaou [127] (Scheme 65) features conversion of the hydroxy dithioketal 189 into the oxocene system 190 via cyclic hemithioketal formation and stereoselective radical-mediated desulfurization. More recently, Tachibana employed the same reaction sequence in the partial synthesis of ciguatoxin [128]. C-Glycopyranosides may be obtained from glycopyranosyl halides via intermolecular addition of glycopyranosyl radicals [ 1291. In a more useful example, the a-aminoacrylate 192 was used as the radical acceptor for preparation of C-glycosyl amino acids 193 and 194 [130] (Scheme 66). In a concise synthesis of showdomycin (197), Barton utilized the ‘trigger’ reaction of the N-hydroxy-2-thiopyridonederivative and the exceptional radicophilicity of tellurides in concocting the conditions for the conversion from the anisyl telluride 195 to the intermediate 196 after oxidative elimination [ 1311 (Scheme 67). In Keck’s synthesis of (+)-pseudomonic acid C (201), the intermediate 200 was prepared via stereocontrolled intermolecular addition of the radical generated from the iodide 198 to the allylic sulfone 199 [132] (Scheme 68).

OTPS

OTPS

Scheme 65. Total synthesis of brevetoxin B

329

4.2.6 Intermolecular Radical Reactions

Acoq Aco9 +Br

yC02Bn

2 0 eAIBN cat q BusSnH

..\y-C02Bn

*

AcO

"OAc OAc

N H B ~ ~Toluene (01 M) 60 OC

lg2

191

,,oAtHBoc

AcO OAc

61 %

HBOC

AcO OAc

(381)

193

194

2.0 eq.

Scheme 66. a-Aminoacrylates as radical acceptors 1) 5.0 eq. Maleimide

HO P

h

@

s

195

n

H

*

hv (W lamp), DCM 5 OC, 10 min; Repeat with 0.25 eq. 2) Oxidation-Elimination

--

Hd

i

b H

i

197 Showdomycin 196

62 Yo

Scheme 67. Synthesis of showdomycin

OH

201 (+)-Pseudomonicacid C

4

1 .O eq.

74 %

Scheme 68. Total synthesis of pseudomonic acid C

4.2.6.2 Miscellaneous Intermolecular Radical Reactions An early intermediate (203) in the synthesis of paeoniflorigenin (204) by Corey was prepared from the silyl enol ether 202 and cyanoacetic acid under the Mn(II1)mediated radical addition conditions [ 1331 (Scheme 69). Highly enantioselective synthesis of y-lactones was reported by Fukuzawa [ 1341 (Scheme 70). The crotonate 205 derived from N-methylephedrine reacted with pentanal in the presence of SmI2 to yield the lactone 206 suggesting chelation control by samarium in the ketyl addition step.

330

4.2 Synthesis of Oxacyclic Natural Products

Scheme 69. Total synthesis of paeoniflorigenin 2.0 eq. Srnlplt-BuOH THF, -78 OC,1 h -78OC

205

LMe2 5 7 %

- r.t.5 h

*

206 (cidtrans=97:3) (96 Yo e.e.)

Scheme 70. Chiral y-butyrolactone synthesis mediated by SmI2

References [ l ] For mechanistic discussions and many early examples of radical reactions in the synthesis of oxacyclic and other natural products, see: C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91, 1237. [2] G. Maiti, S. Adhikari, S. C. Roy, J. Chem. Soc., Perkin Trans. 1 1995, 927. [3] A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985,41, 3925; D. C. Spellmeyer, K. N. Houk, J. Org. Chem. 1987, 52, 959. For more discussions on stereocontrol in radical reactions, see D. P. Curran, N. A. Porter, B. Giese, Stereochemistry ofRadical Reactions, VCH, New York, 1996. [4] A. Srikrishna, K. Krishnan, J. Org. Chem. 1989, 54, 3981. [5] T. Wirth, K. J. Kulicke, G. Fragale, J. Org. Chem. 1996, 61, 2686. [6] G. Stork, M. J. Sofia, J. Am. Chem. Soc. 1986,108, 6826. 1986, 108, 8098. (71 M. Koreeda, 1. A. George, J. Am. Chem. SOC. [8] M. T. Crimmins, R . O'Mahony, J. Org. Chem. 1989,54, 1157. [9] G. Majetich, J. S. Song, C. Ringold, G. A. Nemeth, Tetrahedron Lett. 1990, 31, 2239. [lo] A. M. Gomez, J. C. Lopez, B. Fraser-Reid, J. Org. Chem. 1995, 60, 3859. [ I l l 1. Sugimoto, S. Shuto, A. Matsuda, J. Org. Chem. 1999, 64, 7153. [12] A. G. Myers, D. Y. Gin, D. H. Rogers, J. Am. Chem. Soc. 1994, 116,4697. [13] S. Hanessian, P. Beaulieu, D. Dube, Tetrahedron Lett. 1986, 27, 5071. [I41 K. A. Parker, D. Fokas, J. Am. Chem. Soc. 1992, 114, 9688. [ 151 G. Butora, T. Hudlicky, S. P. Fearnley, A. G. Gum, M. R. Stabile, K. Abboud, Tetrahedron Lett. 1996, 37, 8155. (161 G. V. M. Sharma, S. R. Vepachedu, Tetrahedron Lett. 1990, 31, 4931. [17] S. C. Roy, S. Adhikari, Tetrahedron 1993, 49, 8415. [18] G. V. M. Sharma, K. Krishnudu, Tetrahedron Lett. 1995, 36, 2661. 1191 G. Maiti, S. Adhikari, S. C. Roy, Tetrahedron Lett. 1994, 35, 6731. [20] G. Maiti, S. C. Roy, J. Chem. Soc., Perkin Trans. 1 1996, 403. 1211 D. L. J. Clive, A. C. Joussef, J. Ory. Chem. 1990, 55, 1096.

References

331

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4.2 Synthesis of Oxacyclic Natural Products

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Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

4.3 Utilization of a-Oxygenated Radicals in Synthesis Alexandre J. Buckmelter and Scott D. Rychnovsky

4.3.1 Introduction @-Oxygenated radical intermediates play an important role in modern synthetic chemistry and the stereochemistry of radical reactions is an area of considerable interest. These intermediates are important in a number of stereoselective transformations, including the radical-mediated syntheses of C-glycosides, 2-deoxyP-glycosides, spironucleosides, and axial (2-tetrahydropyrany1)lithium and 1glycosyllithium reagents. Substituted 2-tetrahydropyranyl radicals exhibit anisotropic interactions between the radical center and the adjacent oxygen atom which dictate the stereochemical outcome of these radical reactions. In general, xoxygenated radicals are rapidly equilibrating intermediates, but recent advances have shown that non-equilibrium radical reactions are now possible as a result of the inherent conformational memory present in the radical intermediate. This chapter will focus on the conformations of a-oxygenated (anomeric) radicals in cyclic ethers, the stereoselectivities associated with their reactions, and the applications of these important synthetic intermediates.

4.3.2 Conformation and Stereoelectronic Effects of Cyclic a-Oxygenated Radicals Stereoelectronic effects dominate in the reactivities of simple 2-tetrahydropyranyl radicals [I]. In these ring systems, anomeric radicals are best characterized as an equilibrating mixture of pseudoaxial and pseudoequatorial radicals, which tend to be slightly pyramidalized because of the presence of the a-oxygen atom. Moreover, 2-tetrahydropyranyl radicals prefer to be axial in order to maximize overlap with the lone pair of the ring ether oxygen; ab initio calculations predict the axial radical to be >2 kcal/mol more stable than the equatorial radical [2]. In terms of molecular orbital theory, the stabilization between the axial oxygen lone pair and the singly occupied molecular p-orbital (SOMO) of an axial carbon-

4.3.2 Conformation and Stereoelectronic Effects

335

b stabilized axial radical

destabilized equatorial radical

Scheme 1. Axial and equatorial HF/6-3 lG* minima for the 2-methyl-2-tetrahydropyranyl radical

PI based radical is a manifestation of the generalized anomeric effect [3], sometimes referred to as conjugative electron delocalization. Thus an axial a-oxygenated radical is significantly stabilized, in contrast to an equatorial anomeric radical, which is destabilized because of its orthogonal alignment with the neighboring oxygen lone pair (Scheme 1). The conformations of various carbohydrate radical intermediates have been examined extensively by electron spin resonance (ESR) [4]. In contrast to the slightly pyramidalized radicals of simple 2-tetrahydropyrans, anomeric carbohydrate radicals tend to adopt a nearly planar conformation due to increased electronegative substitution on the pyran ring. In the case of the anomeric glucosyl radical, stereoelectronic effects alone are enough to induce a conformational change from the ground state 4C1 chair into a twist B ~ , boat J conformation upon generation of the anomeric radical. ESR also predicts mannopyranosyl radicals to exist in a 4C1 conformation and galactopyranosyl derivatives to exist in a 4H half-chair (Scheme 2) [41. The conformations of these pyranose radicals can be rationalized by (1) a conjugative electron delocalization between the pyran oxygen and the SOMO of the carbon-based radical, and (2) a stabilizing ‘P-oxygen effect’ between the SOMO and the a*-LUMO of the coplanar ,8-C-OR bond. The combination of these two factors has also been called a ‘quasi-homo-anomeric’ stabilizing effect. Recent studies

Glucosyl

Mannosyl

Galactosyl

Scheme 2. Conformations of various carbohydrate radicals as determined by ESR

336

4.3 Utilization of a-Oxygenated Radicals in Synthesis

have suggested this effect to be significant [ 5 ] , although firm quantitative evidence for the existence of a ‘P-oxygen effect’ has not yet been forthcoming [6]. In contrast to tetrahydropyranyl and carbohydrate anomeric radicals, the corresponding radical structures in tetrahydrofuranyl and medium-sized rings are not well documented, although in certain instances, they can exhibit stereoselective reactivities (see below).

4.3.3 Generation of a-Oxygenated Radicals and their Subsequent Reactions Reductive lithiations of substituted tetrahydropyrans are often highly stereoselective reactions as a direct consequence of the anomeric radical intermediates involved. The mechanism involves one-electron reduction of a thiophenyl ether (or an equivalent reactive functional group) to generate an axial anomeric radical that is reduced by a second electron to form an axial a-alkoxylithium species, which can then be alkylated or protonated. Thus the high selectivities observed in reductive lithiations are a direct reflection of the axial preference for a-oxygenated radicals. Cohen has shown that 2-( pheny1thio)tetrahydropyrans are effective precursors to 2-lithiotetrahydropyrans, and that for conformationally restricted rings the axial 2lithiotetrahydropyran is the kinetic .product (Scheme 3) [7]. Treating a mixture of thiophenyl ethers with lithium 1-(dimethylamino)naphthalenide (LDMAN) at -78°C in THF initially generates a mixture of anomeric radicals which rapidly equilibrates to the more stable axial radical. Subsequent reduction gives a configurationally stable axial a-alkoxylithium [8], which is then alkylated with benzaldehyde to give 95:5 selectivity for the axially trapped product.

L

mixture of diastereomers

J

most stable radical

I

PhCHO

phL>

/i

LDMAN

Scheme 3. A stereoselective reductive lithiation

78% yield

95 : 5

4.3.3 Generation of a-Oxygenated Radicals and their Subsequent Reactions Li/NH3

[

i-Pr

,-.I

I '

-78°C

i-Pr

1

337

i-Pr

6

I

ii

L

52:48 dr R = /J-C~HI~

\

t

-

B

u

~

t

-

B

u

]

~

+

y 6 3 ; syn-l,3-diol acetonide

LiDBB Scheme 4. Stereoselectivity is governed by the conformation of the anomeric radical

Rychnovsky has employed highly stereoselective reductive decyanations of cyanohydrin acetonides in the synthesis of syn-1,3-diols [9, 101. In the reduction of a 52:48 mixture of cyanohydrin acetonides by lithium in ammonia at -78"C, the stereochemistry of the reduction is set during the rapid and non-selective electron transfer to the intermediate axial radical, which generates the configurationally stable axial alkyllithium. Subsequent protonation from the axial direction gives the syn-1,3-diol acetonide with >100:1 stereoselectivity (Scheme 4). The same syn1,3 stereochemistry results from reductive lithiation employing lithium di-tertbutylbiphenylide (LiDBB) in THF at -78 "C followed by axial protonation. The presence of an a-oxygen atom makes anomeric radicals nucleophilic species. As such, these radicals readily react with electron-deficient olefins or hydrogen atom donors. Giese has demonstrated a diastereoselective one-pot synthesis of axial Cglycopyranosides starting from a-D-glycopyranosyl bromides [ 1 11. Exposure of an r-bromo glucopyranoside to trialkyltin radicals readily effects homolytic cleavage to afford the anomeric glucosyl radical, which adopts the boat conformation shown in Scheme 2. The radical then adds to acrylonitrile from the more sterically hindered p-face to generate the axial C-glucopyranoside (Scheme 5). Analogous results were observed in the synthesis of axial C-galacto- and C-mannopyranosides [ 1 11. Consistent with the concept of a single preferentially stabilized anomeric radical configuration, it is noteworthy that the a:p ratio of the products is independent of the geometry of the radical precursor. Both a-bromo and P-phenylseleno tetraacetyl

@CN

-

a to p

ether, Bu3SnH 35 "C, hv 2:89-- : { : ' I

72%

CN

Scheme 5. C-Glucopyranoside synthesis via anomeric radical addition to acrylonitrile

338

4.3 Utilization of a-Oxygenated Radicals in Synthesis

CN

Scheme 6. Product ratios are independent of radical-precursor configuration

glucosides give the same ratio of products when separately exposed to trialkyltin radicals (Scheme 6) [ 11-13]. A slight decrease in a:P selectivity is observed when the reaction is carried out at higher temperature (compare to Scheme 5) [3]. The P-0-mannopyranoside linkage is traditionally one of the most challenging anomeric linkages to form in carbohydrate chemistry. One popular solution to this problem has been to generate an equatorial radical and allow it to isomerize to its more stable axial position prior to quenching. Kahne has generated alkoxy-substituted anomeric radicals using hemithio orthoesters as precursors, which generate P-pyranosides upon hydrogen radical quenching [ 141. The glucosyl, mannosyl, and 2-deoxyglucosyl hemithio orthoesters gave p:a selectivities of 12:1, 18:1, and 6:1, respectively, all in >81% yield. The method also allows for the construction of P-linked disaccharides (Scheme 7) with high p:a selectivity. These results suggest that the anomeric radical, rather than the anomeric alkoxy group, prefers to be axial to maximize overlap with the lone pair of the neighboring oxygen atom. Crich has also taken advantage of the driving force for anomeric radical inversion in the formation ofp-mannopyranosides [ 15, 161. In this case, an intramolecular 1$hydrogen atom abstraction generates an equatorial anomeric radical from an a-mannopyranoside, which rapidly inverts to the more stable axial radical. The observed P-mannopyranoside results after trapping by an external hydrogen atom source and cleavage of the acetal (Scheme 8). Crich has reported another example of anomeric radical inversion which involves a Barton reductive decarboxylation [ 171 of mannoulosonic acid glycosides to generate P-mannopyranosides (Scheme 9) [ 161. Photolysis of the intermediate 0-acyl thiohydroxamate in the presence of t-BUSH cleanly affords the requisite p-anomer. Using a related anomeric radical inversion concept, Curran has synthesized pmannopyranosides from their corresponding a-epimers via an intramolecular 1,6-

SC H3

n-Bu3SnH, AIBN, toluene, 30 "C, 4 h

-

Bt++-ioBnO

H

75% yield

A%10:1

H

OAc

4.3.3 Generation of a-Oxygenated Radicals and their Subsequent Reactions M

e

K

Bu&H

Ph'C'O.

AIBN, then Hf hv *

n.gH *B'

339

PhVj+/ BnO

H ACO

Acb

AcO

25% yield

A AcO c o o a

OMe

I

OMe

Scheme 8. 1,5-Radical translocation/inversion in the synthesis of P-disaccharides CI1.

+ NEt3, CHPCI~

E*co*H Me0

2. &BUSH, hv

OMe

75% yield

2:soMe Me0

H P:a>25:1

Scheme 9. Barton decarboxylation/radical inversion in the synthesis of P-mannosides

F

R = 1-naphthyl

F

p-manno

a-gluco ratio

Scheme 10. Anomeric radical inversion via radical translocation

hydrogen atom abstraction followed by an intermolecular hydrogen transfer (Scheme 10) [18]. One limitation of this method is the formation of the a-gluco epimer (arising from 1,5-radical translocation), but interestingly the authors note that the 1,6-hydrogen transfer in this particular system is slightly preferred over 1,5transfer. As the key step in the total synthesis of (+)-tunicamycin V, Myers employed a stereoselective free-radical cyclization onto an enol ether [ 191. Favorable hydrogen bonding between the C-3' hydroxyl and the glucosamine residue leads to the observed C-5' stereochemistry (7.51) upon radical addition to the enol ether. The crucial p-glycoside linkage is then established upon H-atom trapping of the axial anomeric radical, forming the observed product in 60'% yield after cleavage of the siloxane linker (Scheme 11).

340

4.3 Utilization of u-Oxygenated Radicals in Synthesis 0

60% yield

1 . Bu3SnH, Et3B toluene, 0 "C 2. KF.2H20, MeOH

\

0

7.5:l

HO

OH

stereoselectivity

Scheme 11. Intramolecular anomeric radical cyclization onto an enol ether

Beau and Sinay have developed an efficient synthesis of 2-deoxy-P-glycosides based on anomeric phenylsulfone alkylation followed by in situ reductive lithiation with lithium naphthalenide (LN). The p-C-glycoside product is established after protic quench of the intermediate axial alkyllithium (Scheme 12) [20]. In his enantioselective total synthesis of the antibiotic ionophore X- 14547A (indanomycin), Boeckman was one of the first to employ a stereoselective reductive lithiation in a natural product synthesis [21]. Both alkyl substituents on the tetrahydropyran ring function to effectively lock the ring into a defined conformation.

-lRgoCIOLi 1 r

S02Ph

ii.CH20

RO

RO

LN'THF -78°C

1

I e-, Lit

R =TBS

LN

57% overall 40:l b t o a

Scheme 12. Alkylation/reductive lithiation of an anomeric phenylsulfone

1

4.3.3 Generation of a-Oxygenated Radicals and their Subsequent Reactions

'',,,, p

s

p

h

THF, LiDBB -78 "C

MOMO

-

< % p* :3 :H LC i- ] - J

341

then PPTS

MOMO

,,pTc - .",;., axial a-alkoxylithiurn

*>, -!I

~

H'"

H02C

MOMO

- -~

H .z

42% overall yield

lndanornycin

Scheme 13. Reductive lithiation in the total synthesis of indanomycin

Treatment with LiDBB generates a single axial alkyllithium reagent via the axial radical, which adds effectively in a 1,2-fashion to the a,P-unsaturated ketone (Scheme 13). Reductive lithiations of 4-phenylthio-l,3-dioxanesprovide efficient entries into 4-lithio-l,3-dioxanes, which are useful synthons for syn- or anti-l,3-diols [22]. An application of reductive lithiation in the partial synthesis of the polyene macrolide antibiotic lienomycin is shown in Scheme 14 [9]. Treating an equatorial thiophenyl ether with LiDBB initially forms the equatorial anomeric radical, which immediately isomerizes to its more stable axial position. Subsequent reduction generates a configurationally stable axial a-alkoxylithium, which is alkylated with ethylene oxide. After functional group interconversion, the alkylation sequence is repeated

L

J

axial a-alkoxylithium

Segment of lienornycin

Scheme 14. Reductive lithiation in the synthesis of anti-l,3-diols

I,

342

4.3 Utilization of a-Oxygenated Radicals in Synthesis CN

CN

LiNEt2,THF DMPU

70% yield

\

69% yield

Roflamycoin

Scheme 15. Reductive decyanation/debenzylation in the total synthesis of roflamycoin

with the same axial a-alkoxylithium to form a skipped polyol degradation product of lienomycin. An alkylation/reductive decyanation method was developed for the efficient synthesis of syn-l,3-diols [9, lo]. Cyanohydrin acetonides are rapidly deprotonated by amide bases and alkylated with suitably reactive electrophiles to yield diastereomerically pure coupled products. Subsequent exposure to Li/NH3 affords exclusively syn-1,3-diol acetonides (see above). Although the alkylation itself is stereoselective, it is noteworthy that the 1,3-syn stereochemistry is ultimately set in the reductive decyanation by virtue of the anomeric axial radical intermediate. This methodology was effectively applied in the total synthesis of the polyene macrolide roflamycoin (Scheme 15) [23]. Noteworthy is the formation of the entire protected polyol segment of roflamycoin by treatment of a late-stage intermediate with Li/ NH3 to effect a simultaneous decyanation/debenzylation. Tetrahydrofurans are known to be less conformationally rigid than their 6membered ring counterparts, and hence anomeric effects in these systems also tend to be less pronounced. In the reactions of 2-tetrahydrofuranyl radicals, stereoselectivities tend to be dictated by steric rather than electronic effects [13]. With respect to C- 1’ nucleoside radicals, both Tanaka and Chatgilialoglu have independently reported methods for forming these species via 1,2-acyloxy migration and

4.3.3 Generation of a-Oxygenated Radicals and their Subsequent Reactions

343

B u 3 S n e (5equiv) Bu3SnSnBu3(1 equiv)

~

hv, benzene, rt, 4 h

R = -Si(i-Pr)2-O-Si(i-Pr)2-

66%

6%

R=Ac

75%

5%

Scheme 16. 1,2-Acyloxy migration in the formation of cc-oxygenated nucleoside radicals

1,5-translocation. These a-oxygenated radicals are only slightly pyramidalized, and stereoselectivity in their nucleophilic additions is believed to be governed by minimization of unfavorable steric interactions between the 2’-substituent, the base, and the radical acceptor. Scheme 16 shows a representative example of nucleoside radical formation via 1,2-acyloxy migration [24], in which face-selective migration of the pivaloyl group from C-I’ to C-2’ generates the a-oxygenated radical. In this system, inversion of the C-1 ’ radical center is observed followed by nucleophilic addition to allyltributyltin, generating the observed product along with a small amount of the addition product arising from unmigrated pivalate. A conceptually related 1,2-acyloxy rearrangement has also been utilized in the syntheses of 2-deoxy-a-glucosides [25]. Another successful strategy has involved an intramolecular 1$hydrogen atom abstraction followed by a 5-end0 radical cyclization (Scheme 17) [26]. Rychnovsky has systematically examined 5-, 6-, 7-, and 8-membered a-oxygenated radicals as intermediates in reductive decyanations and the diastereoselectivities associated with their reactions (Scheme 18) [27]. In each case, reductive decyanation with lithium in ammonia proceeds in good yield, but the selectivity varies from >20:1 in the case of the 2,6-disubstituted tetrahydropyran to 1:l in the case of the 2,5-disubstituted tetrahydrofuran. The observed stereoselectivities in these anomeric radical reductions correlate with the conformational rigidity of the parent ring systems.

TBDMSO

Bu3SnH (2 equiv) AlBN (0.5 equiv)

-

benzene, reflux, 3 h

77%

Scheme 17. Intramolecular 1 $radical migration/cyclization to form spironucleosides

344

4.3 Utilization of a-Oxygenated Radicals in Synthesis cisltrans ratio n

Li, NH3

n

1:1

n

Li, NH3 *

>20 : 1

1.1 : 1

11.5: 1

Scheme 18. Stereoselectivities of 5-, 6-, 7-, and 8-membered anomeric radical reductions

4.3.4 Non-Equilibrium Radical Reactions In general, free radicals are rapidly equilibrating intermediates, which makes stereoselective radical reactions extremely challenging. In ring systems that have little or no conformational bias, reactive radical intermediates can racemize either by a conformational interconversion (i.e., ring flip) or by a simple radical inversion. For simple 2-tetrahydropyranyl radicals, the barrier to radical inversion has been estimated to be < 1 kcal/mol, while the barrier to ring inversion is -10 kcal/mol. Therefore, if conformational interconversion is slow relative to reaction of the radical intermediate, then non-equilibrium radical reactions are possible. Recently it has been shown that reduction of 2-tetrahydropyranyl radicals can be competitive with conformational interconversions, which allows for a new strategy for the control of stereochemistry in radical reactions [28]. Scheme 19 depicts an experimental test for the detection of non-equilibrium radical reactions. At issue was whether there would be a complete equilibration of the radical intermediates (2ax and 2eq) under the reaction conditions. Each diastereomeric cyanohydrin (lax or leq) was subjected separately to various reductive decyanation conditions and the product ratios (3ax:3eq)were determined. It was found that each

4.3.5 Conformational Memory of Radical Intermediates

conditions

1 1 Me&H

e-,H+

~

345

Me@H

CN 1ax

3ax

2ax

Entry

Substrate

1

1ax

2

1eq

3

1 ax

4

1eq

Conditions Li/NH3 (-78 "C)

Ratio (3ax:3eq) 66 : 34

4 :96 LiDBB (-78 " C )

66 : 34

5 :95

Scheme 19. Non-equilibrium radical reactions in reductive decyanations

diastereomeric cyanohydrin afforded a different ratio of 3ax:3eq after reduction with LiDBB or Li/NH3. These findings suggest that radical reduction is competitive with a conformational interconversion. Radical reduction was also shown to be competitive with ring inversion under classical radical-forming conditions (Scheme 20) [28]. Photolysis of thiohydroxamate ester 4ax at -78 "C generates initially the intermediate radical 2ax after Barton decarboxylation [17]. At low thiol concentration (entry 1, 0.1 M t-BUSH), 2ax completely equilibrates to give a mixture of 2ax and 2eq, leading to the observed 3ax:3eq ratio. However, at high thiol concentration (entry 3, 1.0 M t-BUSH), the selectivity is increased to attain non-equilibrium product ratios of 3ax:3eq (compare with entries 1 and 3, Scheme 19). Importantly, when acrylonitrile is present as a radical acceptor, one observes diastereoselective C-C bond formation by nonequilibrium radical processes (Scheme 20).

4.3.5 Conformational Memory of Radical Intermediates Recently it has been discovered that %-oxygenatedradicals can possess 'memory of chirality' [29] based solely upon the conformation of the radical precursor. In an

346

4.3 Utilization of a-Oxygenated Radicals in Synthesis

Me$H

0 0

hv, conditions -78 "C

-

Me$H

+

M

e

b

B

H

n

H

3ax

3eq

4ax Entry

Conditions

Ratio (3ax:3eq)

1

0.1 M f-BUSH

18 : 82

2

0.5 M f-BUSH

54 : 46

3

1 .O M f-BuSH

63 : 37

Bn

A

w

w I

YN3 v 4ax

'CN (1.O M) Bu3SnH (0.15 M) * hv, f-BuSH -78 "C

Me

I

CN

+

M

CN

I

I

62 :38 ratio

I

I e

w

B

n

H

1

Scheme 20. Non-equilibrium radical reactions in Barton decarboxylations

overall transformation which resembles Seebach's self-regenerating stereocenter concept [ 301, 2-tetrahydropyranyl radicals with defined conformations can be generated from optically active precursors and trapped to give optically active products with retention of stereochemistry. In this process, the anomeric radical intermediate is able to relay chirality to the reduced product via the inherent 'memory' present in the pyramidalized radical intermediate. Conformational memory in the reductive decyanation of optically active cyanohydrins [31] is shown in Scheme 21. In order to obtain optically active products by this process, reduction of the initially-formed radical intermediate must be faster than any other racemizing process such as ring inversion. Typically in these reductions, the products possess only modest enantiomeric excesses (entries 1 and 2), but if high concentrations of lithium in ammonia are used, then the reduced products can be obtained in up to 90% ee (entry 3). Conformational memory is also observed in Barton radical decarboxylations of optically active tetrahydropyrans [ 3 11. Photolysis of thiohydroxamate esters derived from optically pure tetrahydropyrans in the presence of various hydrogen atom

4.3.5 Conformational Memory of Radical Intermediates

347

CN >97% ee

1

1

I

I

e-, H+

7

e-, H+

7'

Entry

Conditions

Yoee of 7

1

Li (0.8 M)/NH3, -78 "C

30% ee

2

LiDBB (0.63 M), -78 "C

40% ee

3

Li (6.4 M)/NH3, -78 "C

90% ee

Scheme 21. Conformational memory in reductive decyanations

donors affords the reduced products. By judicious selection of H-atom donor and careful control of its concentration, optically active products can be produced in up to 86% ee; some representative examples are shown in Scheme 22. It was found that better hydrogen atom donors gave products with higher enantiomeric excesses, with the overall trend in H-atom reducing ability decreasing in the series: PhSeH >

DMAP

HO'

Bn CO2H

1

,!,J

ii. hv, toluene, -78 "C L

H-atomdonor+

-Bn H

J

ca. 95% ee

7

Yoee of 7

Entry

H-atom donor (conc.)

Yield

1

Bu3SnH(1 .O M)

42

0

2

&BUSH (1 .O M)

23

26

3

t-BuSH (0.05 M)

30

2

4

PhSH (1 .O M)

50

86

5

PhSH (0.05 M)

58

23

6

PhSeH (0.05M)

16

32

Scheme 22. Conformational memory in Barton decarboxylations

348

4.3 Utilization of a-Oxygenated Radicals in Synthesis

ring-flip

>98% ee

b- 1

n

J

one diastereorner 42% ee, 71 O h yield

Scheme 23. Conformational memory in intramolecular cyclizations to make spiro compounds

PhSH > t-BUSH > Bu3SnH, consistent with rates of H-atom transfer reported by Newcomb [33]. Conformational memory has also been demonstrated in intramolecular cyclizations to form spiro compounds [32]. In the event, treatment of an optically active cyanohydrin with LiDBB in T H F at -78°C for 10 min affords a high yield of a single diastereomeric cis-spiroether in 42% ee (Scheme 23). The cyclization proceeds most likely via an equatorial a-alkoxylithium, which arises from ring inversion of the kinetic axial alkyllithium intermediate [34].

4.3.6 Conclusions The control of anomeric stereochemistry continues to fuel the investigation into the synthetic utility of a-oxygenated radical intermediates. Moreover, it has proven to be a valuable tool in organic synthesis, especially in the stereoselective synthesis of various substituted tetrahydropyrans, syn-l,3-dioxanes, and carbohydrate derivatives. The recent discovery of non-equilibrium radical reactions and conformationinduced self-regeneration of stereocenters should provide new opportunities in the ever-expanding field of a-oxygenated radical chemistry.

References [ I ] (a) V. Malatesta, R. D. McKelvey, B. W. Babcock, K. U. Ingold, J. Org. Chem. 1979, 44, 1872-1873. (b) A. R. Gregory, V. Malatesta, J. Org. Chem. 1980, 45, 122-125. [2] S. D. Rychnovsky, J. P. Powers, T. J. LePage, J. Am. Chem. Soc. 1992, 114, 8375-8384. [3] B. Giese, J. Dupuis, Tetruhedron Lett. 1984, 25, 1349-1352. [4] (a) J. Dupuis, B. Giese, D. Riiegge, H. Fischer, H.-G. Korth, R. Sustmann, Anyeiv. Chem. In/. Ed. Eng/. 1984,23, 896-898. (b) H. G. Korth, R . Sustmann, J. Dupuis, B. Giese, J. Chenz. Soc. Perkin Truns 2 1986, 1453-1459. (c) H.-G. Korth, R. Sustmann, K. S. Groninger, T. Witzel, B. Giese, J. Chern. Soc. Perkin Trans. 2 1986, 1461-1464. (d) H.-G. Korth, R. Sustmann, B. Giese, B. Riickert, K. S. Groninger, Chem. Ber. 1990, 123, 1891-1898. [ 5 ] A. L. J. Beckwith, P. J. Duggan, Tetruhedron 1998, 54, 4623-4632.

References

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[6] D. Crich, A. L. J. Beckwith, C. Chen, Q. Yao, I. G. E. Davison, R. W. Longmore, C. A. de Parrodi, L. Quintero-Cortes, J. Sandoval-Ramirez, J. Am. Chem. SOC.1995, I 1 7, 8757-8768. [7] (a) T. Cohen, J. R. Matz, J. Am. Chem. Soc. 1980, 102, 6900-6903. (b) T. Cohen, M. T. Lin, J. Am. Chem. Soc. 1984, 106, 1130-1131. ( c ) T. Cohen, M. Bhupathy, Ace. Chem. Rex 1989, 22, 152Ll61. [8] W. C. Still, C. Sreekumar, J. Am. Chem. Soc. 1980, 102, 1201-1202. [9] S. D. Rychnovsky, J. Org. Chem. 1989, 54, 4982-4984. [lo] (a) S. D. Rychnovsky, S. Zeller, D. J. Skalitzky, G. Griesgraber, J. Org. Chem. 1990, 55, 5550-5551. (b) S. D. Rychnovsky, G. Griesgraber, J. Org. Chem. 1992,57, 1559-1563. [ 1 I] B. Giese, J. Dupuis, Angew. Chem. Int. Ed. Engl. 1983, 22, 622. [I21 J. Dupuis, B. Giese, D. Ruegge, H. Fischer, H.-G. Korth, R. Sustmann, Angew. Chem. Int. Ed. Engl. 1984,23, 896-898. [13] B. Giese, Angeiv. Chem. Int. Ed, Engl. 1989, 28, 969-980. [I41 D. Kahne, D. Yang, J. J. Lim, R. Miller, E. Paguaga, J. Am. Chem. SOC.1988, 110, 87168717. [I51 (a) J. Brunckova, D. Crich, Q. Yao, Tetrahedron Lett. 1994, 35, 6619-6622. (b) D. Crich, S. Sun, J. Brunckova, J. Org. Chem. 1996, 61, 605-615. [I61 D. Crich, J.-T. Hwang, H. Yuan, J. Org. Chem. 1996, 61, 6189-6198. [I71 D. H. R. Barton, D. Crich, W. B. Motherwell, Tetruhedron 1985, 41, 3901-3924. [ 181 N. Yamazaki, E. Eichenberger, D. P. Curran, Tetrahedron Lett. 1994, 35, 6623-6626. [I91 A. G. Myers, D. Y. Gin, D. H. Rogers, J. Am. Clzem. Soc. 1993, 115, 2036-2038. [20] (a) J.-M. Beau, P. Sinay, Tetrahedron Lett. 1985, 26, 6185-6188. (b) J.-M. Beau, P. Sinay, Tetrahedron Lett. 1985,26, 6189-6192. [21] R. K. Boeckman, E. J. Enholm, D. M. Demko, A. B. Charette, J. Org. Chem. 1986,51,47434745. [22] S. D. Rychnovsky, A. J. Buckmelter, V. H. Dahanukar, D. J. Skalitzky, J. Org. Chem. 1999, 64, 6849-6860. [23] S. D. Rychnovsky, U. R. Khire, G. Yang, J. Am. Chem. Soc. 1997, 119, 2058-2059. [24] (a) Y. Itoh, K. Haraguchi, H. Tanaka, K. Matsumoto, K. T. Nakamura, T. Miyasaka, Tetrahedron Lett. 1995, 36, 3867-3870. (b) T. Gimisis, G. Ialongo, M. Zamboni, C. Chatgilialoglu, Tetrahedron Lett. 1995, 36, 678 1-6784. [25] H.-G. Korth, R. Sustmann, K. S. Groninger, M. Leisung, B. Giese, J. Ory. Chem. 1988, 53, 4364-4369 and references therein. [26] (a) T. Gimisis, C. Chatgilialoglu, J. Org. Chern. 1996, 61, 1908-1909. (b) A. Kittaka, H. Tanaka, N. Yamada, T. Miyasaka, Tetruhedron Lett. 1996, 37, 2801-2804. (c) A. Kittaka, H. Tanaka, N. Yamada, H. Kato, T. Miyasaka, Nucleosides Nucleotides 1997, 16, 1423-1426. (d) C. Chatgilialoglu, T. Gimisis, G. P. Spada, Chem. Eur. J. 1999,5,2866-2876. (e) A. Kittaka, T. Asakura, T. Kuze, H. Tanaka, N. Yamada, K. T. Nakamura, T. Miyasaka, J. Org. Chem. 1999,64, 708 1-7093. [27] S. D. Rychnovsky, V. H. Dahanukar, J. Org. Chem. 1996,61, 7648-7649. [28] A. J. Buckmelter, J. P. Powers, S. D. Rychnovsky, J. Am. Chem. Soc. 1998, 120, 5589-5590. [29] (a) K. Fuji, T. Kawabata, Chem. Eur. J. 1998, 4 , 373-376. (b) S. Sauer, A. Schumacher, F. Barbosa, B. Giese, Tetrahedron Lett. 1998, 39, 3685-3688. (c) H. G . Schmalz, C. B. de Koning, D. Bernicke, S. Siegel, A. Pfletschinger, Angew. Chem. Int. Ed. 1999, 38, 1620-1623. (d) E. Vedejs, S. C. Fields, R. Hayashi, S. R. Hitchcock, D. R. Powell, M. R. Schrimpf, J. Am. Chem. Soc. 1999, 121, 2460-2470. (e) B. Giese, P. Wettstein, C. Stahelin, F. Barbosa, M. Neuburger, M. Zehnder, P. Wessig, Angew. Chem. Int. Ed. Engl. 1999, 38, 2586-2587. [30] D. Seebach, A. R. Sting, M. Hoffmann, Anyew. Chem. Int. Ed. Enyl. 1996, 35, 2708-2748. [31] A. J. Buckmelter, A. I. Kim, S. D. Rychnovsky, J. Am. Chrm. Soc. 2000, 122, 9386-9390. [ 3 2 ] S. D. Rychnovsky, T. Hata, A. I. Kim, A. J. Buckmelter, Org. Lett. 2001, 3, 0000. [33] (a) C. Ha, J. H. Horner, M. Newcomb, T. R. Varick, B. R. Arnold, J. LusLtyk, J. Org. Chem. 1993, 58, 1194-8. (b) M. Newcomb, S.-Y. Choi, J. 11. Horner, J. Org. Chem. 1999, 64, 12251231. 1341 Equilibration experiments suggest that the equatorial r-alkoxylithium species is thermodynamically more stable: see reference 22.

Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

4.4 Polycyclic Compounds via Radical Cascade Reactions Anne-Lise Dhimane, Louis Fensterbank, Max Malacvia

4.4.1 Introduction Because a radical cyclization gives birth to a new radical species that can also engage in a new radical cyclization and so on, a great number of synthetic sequences involving radical cyclizations in cascades have been devised. This principle was initially worked out on tandem radical cyclizations relying on a templating ring. Landmarks in this concept include for instance the total synthesis of hirsutene by Curran [l], and a more elaborated version relying on the use of samarium(I1) chemistry and leading to an advanced precursor of hypnophilin and coriolin (Scheme 1) [2]. Besides 5-exo-trig cyclizations, other ring closures have been implemented in these tandem reactions. Thus, Lee proposed a total synthesis of (+)-cladantholide and (-)-estafiatin, the key step consisting in a 5-exo-trig, 7-endo-trig sequence from an adequately functionalized precursor (Scheme 2) [3]. Intermolecular events can also intervene in spectacular radical cascades. Curran used isonitriles as versatile partners for the preparation of cyclopentaquinolines. This was applied to the synthesis of the antitumor agent (20s)-camptothecin (Scheme 3) [4]. In all these cases, we dealt with precursors bearing a ring, which generally serves as a template or as a radical acceptor. Many excellent reviews and book chapters have covered radical tandem reactions [5]. Herein, we will focus on two distinct approaches to radical cascades. The chapter will be devoted to the construction of polycyclic structures (at least 3 rings). We will deal with two distinct approaches: the first one focussing on the use of acyclic precursors, the second one based on transannular processes.

4.4.2 The Triquinane System As pointed out by Curran: ‘Polyquinanes . . . are especially suited for construction by radical methods because 5-ex0 cyclizations are often rapid’ [6]. Concomitant to

4.4.2 The Triquinane System

hypnophilin

Scheme 1

Q H I

0 (+)-cladanthiolide Scheme 2

cyclopentaquinolines

Me3SnSnMe3, hv, 70°C 0

63%

Scheme 3

-0

Et'"' HO (S)-camptothecin

0

351

352

4.4 Polycyclic Compounds via Radical Cascade Reactions

Strategy A

Strategy B

Scheme 4

the development of tandem reactions leading to triquinane frameworks, a more ambitious triple cyclization strategy has also been envisaged. Two distinct strategies (A and B, see Scheme 4) have been discerned. The first example of the ‘zipper’ strategy A was reported by Beckwith in 1985 [7]. The reaction of tributylgermane, a very slow hydrogen donor, with bromo precursor 1 afforded a complex mixture of compounds including the four triquinanes 2 in 45% yield and in a 3:2: 1.5:1 ratio (Scheme 5). Although the efficiency of this process is acceptable, the lack of stereoselectivity is a major issue. Moreover, no useful functionalization on tricyclic compounds 2 allows for further transformations. The behavior of the aza analog of I , N-chloramine 3, was also investigated. Four diastereomers of the azatriquinane 4 were isolated in a very good yield. However, in contrast to the previous case, a major diastereomer, the cis-syn-cis 4Maj is present. This diastereoselectivity originates during the second cyclization step from a pseudochair transition state placing the 1, 2, 3 substituents respectively in equatorial, axial, and equatorial positions. BusGeH, 45% 1

Scheme 5

2, 4 dias.

4.4.2 The Triquinune System

353

AH

5

6.60%

Scheme 6

Interestingly, Snider showed that a related zipper triple cyclization from 5 gave the fused 6.5.5 tricyclic compound 6 as a single diastereomer (Scheme 6). Consistent with other studies, the initial 6-exo-trig cyclization is completely diastereoselective. The subsequent 5-exo-trig cyclization minimizes the steric interactions by positioning the ally1 and methylene groups cis to each other and trans to the axial ester group. Inspired by the computer program from Barone, Curran examined approach B from vinyl iodide 7 [6]. A complex mixture of compounds was obtained from which four diastereomers of triquinanes 8 were detected (Scheme 7). In order to improve the stereoselectivity of the reaction, Marco-Contelles examined the behavior of the 4,9-dioxa precursor 9 under radical conditions [ 101. In this case, the initial radical is generated by the terminal addition of the stannyl radical onto the alkyne moiety. This approach proved rewarding since only two diastereomeric tricyclic derivatives 10 were isolated in a 1:3 ratio. No determination of the relative chemistry was achieved though. By rigidifying the system with the introduction of a carbonyl moiety and using a bulkier vinyl radical as in precursors lla,b, the cascade is now completely diastereoselective [ 1 11. We proposed another strategy to alleviate the stereochemical issue by appending an alkyne moiety as the central unsaturation (precursor 13) [ 121. After a 5-exo-dig, 5-exo-trig tandem, the resulting homoallyl radical 14 undergoes a major 3-exo-trig cyclization to yield a particularly stable allylic radical. After reduction, cyclopropyl adduct 15 was isolated, and no triquinane adduct was observed in this reaction. Finally, Spino, intent on developing a polyenyne cyclization method using a catalytic amount of metal hydride, focussed on ynones 16 to direct the initial attack by the metal radical [13]. Following a diquinane formation, a Michael-oriented 6endo-trig, p-elimination sequence of the metal radical produced the expected 5-6-5 adduct 17 as a 2:2:2:1 mixture of diastereomers (Scheme 8). Best results were obtained with germanium hydride, although oligomers were also formed, resulting in an over-consumption of hydride. Formation of linear triquinanes, originating from a final 5-exo-trig, was not detected in these reactions. A third strategy was proposed by Saicic [ 141 and us [ 151 in order to functionalize more elaborate triquinane frameworks. The key step is a radical [3+2] condensation between a homoallylic radical and a Michael acceptor such as acrylonitrile. Using the bromomethyldimethylsilyl (BMDMS) ether of a propargyl alcohol (precursor 18) as an efficient trigger for radical cascades [ 151, we initially prepared diquinane 19 in 51'h overall yield as a single diastereomer after Tamao oxidation. Consistent

4.4 Polycyclic Compounds via Radical Cascade Reactions

3 54

Ph3SnH, AlBN

q?

-4p 8

7

0-0

Ph3SnH, Et3B

h\I 9

-

f

O * Ph3Sn

0-0

10, 39% 2 dias, 1 : 3

Bu3SnH, AlBN *

0 TMeS S

M

e

jR

lla,R=H l l b , R = Me

12a, 26% 12b, 19%

L

13, E = C02Me

14

15,48%

Scheme 7

'63

Bu3GeH,ACCN

16

40%

*

QH 17

Scheme 8

with previous findings, the initial steps consist of a completely diastereoselective 5exo-dig, 5-exo-trig sequence. The resulting homoallylic radical 20 readily engages in the [3+2] cycloaddition, placing the cyano group on the convex face of the incipient tricyclic skeleton. Finally, a diastereoselective reduction of the p-silyl radical 21 occurs, with no further trapping with acrylonitrile. Four C-C bonds have been created chemo-, regio-, and stereoselectively, as well as two contiguous quaternary

4.4.2 The Triquirlane System

355

1. Ph3SnH,AlBN

l o eq. //'CN

2. Tamao ox.

C ~ H ~

*

51 yo

O%ir\Br I' 18

5-exo-dig, 5-exo-trig

""CN [3+21

-(j

PhS X

22

22 eq.//"\crq hv, 150W PhH, 70°C

gCN 1 gcN] c

46%

23,

2 dias, 3.7 : 1

X=

Phs

Scheme 9

centers in the overall process. The initial 1,3-asymrnetric induction directed the creation of the four new stereogenic centers (Scheme 9). Similarly, through a sequence forming four carbon-carbon bonds, Saicic was able to assemble the all-carbon triquinane 23 from acyclic precursor 22 with good diastereoselectivity [ 141. No tin derivative is necessary, since a final p-elimination of the thiophenyl radical propagates the radical chain. Clearly, there was no reason to stop at p-silyl radical 21. An access to linear and angular triquinanes 24 and 27 was open by adding a new 5-ex0 cyclization from intermediate radicals 25 and 28. This just required us to work with substrates 26 and 29 bearing three unsaturations (Scheme 10). However, our initial attempts were thwarted by hydrogen transfer reactions [15, 161. To overcome this problem, we prepared a new generation of precursors

4.4 Polycyclic Compounds via Radical Cascade Reactions

356

'

24

25

26

R2

' 28

29

Scheme 10

bearing a quaternary (gem-dimethyl) propargylic position, as in 30, and we checked its behavior under radical conditions without acrylonitrile. The cyclization of 30 furnished two adducts 31 and 32-TMS in a good overall yield (Scheme 11). After a 5-exo-dig, 5-exo-trig tandem, the homoallyl radical 33 was reduced to produce 31. It can also undergo a 3-exo-trig cyclization, followed by a 5-exo-dig cyclization,

1. Bu3SnH ,1111

S .,i Br ,S-i

\

30

5-exo-dig, 5-exo-trig

Scheme 11

,S-i

I 31,24%

32,65%

p-elimination

4.4.2 The Triquinane System

-c

.. ,si-

BusSnH

I

30

351

I

I

36,54%

32,24%

a-CN : P-CN, 80 : 20

Scheme 12

which constitutes the driving force of this radical cyclopropanation. Interestingly, the resulting vinyl radical 34 is protected from any intermolecular reduction because of the surrounding steric bulk, and it engages in a 1,6-H transfer with the neighboring TMS group to create an a-silyl radical. This radical cyclizes in a 6-endo-trig manner. Once again, the tertiary radical 35 is highly protected from any reduction. The only way out is an unprecedented p-elimination of a trimethylsilyl group. The good news from this reaction was the efficient trapping of the p-silyl radical, which is necessary to construct the last carbocycle. The more worrying news was the 3-exo-trig cyclization from 33, since, in order to assemble the triquinane framework, we need to involve this nucleophilic radical in a [3+2] addition. This implies a competition between an intermolecular addition step and an intramolecular 3-exo-trig ring closure. Work by Cekovic suggested that the [3+2] annulation should prevail [ 181, and indeed, adding ten equiv. of acrylonitrile proved rewarding. Pentacyclic derivatives 36 could be isolated in 54% yield, accompanied by the cyclopropyl adduct 32 (Scheme 12). Starting from the dissociation of AIBN, an 11 elementary step process is involved in the construction of these triquinanes. Six carbon-carbon bonds are formed, as well as four new stereogenic centers. Only an incomplete stereocontrol during the [3+2] annulation is responsible for the formation of the minor P-CN epimer of 36. Finally, we sought to obtain the triquinane framework without any supplementary ring. We focussed on an approach ending with a favorable 1,5-H transfer from vinyl radical of type 34 and followed by the p-elimination of a suitable leaving group, thus avoiding any telomerization of the final radical species. We prepared sulfoxide 37 and sulfone 39 because of the reported very fast p-elimination [ 191 of the arylsulfinyl and arylsulfonyl groups (Scheme 13). Both substrates allowed the synthesis of vinyltriquinane 38, with a diastereoselectivity consistent with previous findings. The difference of yield between the cyclization from 37 or 39 simply reflects the poorer ability of the sulfinyl radical to propagate the radical chain. In conclusion, it is now possible to assemble highly functionalized linear triquinanes from acyclic precursors with high diastereocontrol. The sequence mixing intramolecular cyclizations and a [3+2] radical annulation appears as the strategy of choice. To probe its versatility, this strategy will have to materialize into total syntheses of natural products.

358

/Si,

’

4.4 Polycyclic Compounds via Radical Cascade Reactions

37,X = SOPh 39,X= S02Ph

38,22%,a-CN : P-CN, 85 15 50%, a-CN : B-CN, 90 10

r

Scheme 13

4.4.3 6-endo-trig Cyclizations in Series Although most attention has focussed on a cationic mechanism in the oxidative cyclization of squalene [20]. Breslow was concerned with the possibility that nature utilizes a free-radical pathway [21]. and studied the addition of benzoyloxy radical to truns, trans-farnesyl acetate [ 221. The benzoyloxy radicals generated by CuClcatalyzed thermal decomposition and copper(I1) benzoate was added to provide a termination mechanism. Excluding any intervention of a carbocationic process, Breslow obtained a trans-decalin compound (20-30% yield) bearing an exomethylene moiety. As pointed out by Breslow, despite a ‘limited biochemical interest’, this work evidenced ‘a new synthetic reaction of considerable potential’. An application shortly followed with the first example of a triple cyclization by Julia [23]. Triene isomers 40 were treated by benzoylperoxide in benzene and afforded after saponification alcohol 41 in 12% yield as a single diastereomer (relative stereochemistry confirmed by an X-ray analysis) with a similar trans-decalin system (A and B rings, Scheme 14).

Scheme 14

4.4.3 6-endo-trig Cyclizations in Series

359

C02Me

i$TH

\si’O &H2CQMe

-Si

I ‘0

44

I

H 45

Scheme 15

In this context, Scheffold [24] wanted to determine the factors favorable for conducting polycyclizations from terpenoid substrates. Whereas the cyclization of bromoacetal 42 led only to 5-ex0 products, the silyl ether 43 underwent an initial 6-end0 cyclization, consistent with Wilt’s [25] and Nishiyama’s [26] previous findings on a-silyl radicals, and which allowed a subsequent 5-ex0 step to occur. Logically, radical cyclization of triene 44 could afford 28% of tricyclic derivative 45, which corresponds to the most stable tricyclic system (Scheme 15). The development, by Snider, of intramolecular cyclizations of unsaturated P-keto esters with Mn(II1) and Cu(I1) has been the source of numerous and spectacular cascades [27]. Intrigued by the potential of this chemistry as a biomimetic approach to polycyclic systems, Zoretic [28] reported the tetracyclization of precursor 46 to provide tetracyclohexyl derivative 47, in which seven asymmetric centers have been established with complete stereocontrol (Scheme 16). This remarkable sequence deserves several comments. The regioselectivity (6-endo-trig) and diastereoselectivity of the initial cyclization is consistent with Snider’s seminal studies; notably the ester group adopts an axial position to minimize unfavorable dipole/dipole interactions with the ketone. The two subsequent 6-endo-trig cyclizations that can be rationalized by a slower 5-ex0 mode of cyclization involving a bond formation sandwiched

Scheme 16

360

4.4 Polycyclic Compounds via Radical Cuscude Reactions

between two quaternary centers establish trans-decalin systems. As in carbocationic cascades, an all-chair conformation in the transition state was advanced. The last step involves a 6-exo-trig cyclization, and a final oxidation of the radical installs an exo-methylene moiety. Based on a similar triene precursor, the triple cyclization yielded advanced precursors for the total synthesis of furanoditerpenes, such as D,Lisospongiadiol. However, this chemistry cannot be directly extended to genuine steroid since substrate 47 possesses an extra methyl group at C8. This issue will be solved as shown below. Further inquiries by the Zoretic group focused on the introduction of a cyano group instead of a methyl group at a pro C-8 angular position. It was anticipated that the intervention of an electrophilic radical intermediate in the cascade should decrease the overall energy of the process and result in higher yield. Moreover, the cyano group should allow additional chemistry in order to prepare steroids. This turned out to be judicious since precursor 48 gave 60% of tricyclization (49), which corresponds to an increase of 20% yield compared to the analog possessing a C-8 methyl group (Scheme 17). The complete diastereoselectivity is in agreement with the above discussion. Tetracyclization of 50 gave only one diastereomer of cyano derivative 51. Then, a few steps including a stereoselective reduction of the nitrile afforded an androstane homosteroid. A mixture of D-ring double-bond isomers of 53 was isolated in 61% yield after a tetracyclization process from 52 involving four 6-endo-trig cyclizations. The chlo-

Scheme 17

4.4.3 6-endo-trig Cyclizations in Series

361

p 0 ClCh2Et

53

Scheme 18

ride on 52 was required to introduce geminal hydrogens at C4. After several steps, homosteroid 54, a precursor of Sa-pregnane, was prepared (Scheme 18). Snider was interested in the synthesis of tetracyclic diterpenes. For that purpose, he examined the radical cyclization of tetraene precursor 55 to give highly valuable intermediate 56 for the total synthesis of isosteviol and beyer-l5-ene-3,19-diol (Scheme 19). After the initial 6-endo-trig cyclization, a subsequent 8-endo-trig cyclization involving the unsubstituted ene partner was responsible for the erosion of the yield [33]. Acyl radicals as pioneered by Boger have served as efficient triggers for 6-end0 cascades and have been mainly exploited by the Pattenden group for polycyclization reactions. While a 6-endo-trig, 6-exo-trig sequence from 57 gave hydrindane 58 as four diastereomers, a unique truns-hydrindane 60 was obtained from a double 6endo cyclization, suggesting the versatility of this strategy (Scheme 20). Parameters for conducting efficient triple 6-endo cyclizations have been examined by Pattenden. Notably, he wanted to determine the importance of the methyl group

0' O%CX

55

isosteviol

Scheme 19

YH" C02Et

Ho

56

beyer-15-ene-3,lg-diol

362

4.4 Polycyclic Compounds via Radical Cascade Reactions

Bu3SnH, AlBN 71%

-@ 0

58, 71%

4 dias.

1 dias.

Scheme 20

substitution (positions C-5, C-9 and C-13) on the various double bonds of the precursors in view of controlling the regio- and the diastereoselectivity of the cascade [36]. This is illustrated in Scheme 21. Preliminary experiments with precursors 61 and 63 indeed showed that adding a methyl at C-9 was important for imposing the second 6-endo-trig cyclization. However, this result was not so sensitive with substrates 65, 68 and 71. In the three cases, a significant amount of competitive 5em-trig cyclization took place, giving rise to products 67, 70 and 73. With trimethylated precursor 71, the yield of triple 6-endo-trig adducts 72 reached 55%, which is sufficiently satisfactory for envisaging further synthetic applications. The diastereoselectivity of the cascade is total in terms of ring junction (trans decalins) and is consistent with the all-chair transition state. Only the final reduction of the tertiary radical creates two diastereomers. Applications included a related triple cyclization from lactone 74, which opened a route to spongian-16-one [37] and an approach to azasteroids involving an enamine double bond (75) as a final radical acceptor (Scheme 22) [38]. Moreover, spectacular tetracyclizations from acyclic 76 and 77 have also been accomplished to provide the corresponding all-trans tetracyclic ketones [36], both of them consisting of ring D methyl epimers (Scheme 23). Pattenden also proposed a novel type of cascade for the steroid skeleton construction [39]. Starting from the relatively elaborated precursor 78, that notably bears a cyclopropyl ring, a double 6-endo-trig creates cis-hydrindane 80 (Scheme 24). As expected, the resulting a-cyclopropyl radical rearranges to provide a methylene radical that readily engages into a 9-endo-trig macrocyclization step. The resulting a-carbomethoxy radical 81 then undergoes a diastereoselective transannular radical cyclization, setting a cis ring junction, followed by a diastereoselective stannane reduction to provide tetracycle 79. Not only does this cascade greatly extend the palette of molecular processes for running cascades, notably with the incorporation of a transannular step, which will be developed in detail in Section 4.4.5, but it also gives birth to an unusual all-cis steroid ring system.

4.4.3 6-endo-trig Cyclizations in Series

AlBN PhSe

61

BU3SnH’-

/

PhSe

0

AlBN Bu3SnH,

‘-..

*

G F % 8 0

0

63

64, 60%

Scheme 21

0

@: H

BusSnH, AlBN

+

53% SePh

74

0 spongian-16-one

Ac

-

Bu3SnH, AlBN 45% AePh

75

Scheme 22

363

364

4.4 Polycyclic Compounds via Radical Cascade Reactions

Bu3SnH, AlBN

SePh

O H

76

.

I

SePh

77

Scheme 23

C02Me

Bu3SnH, AlBN I

SePh

78

2 x 6-endo-trig, ring opening

transannular

t

9-endetrig

*

0

81

Scheme 24

On this subject, eventually, Demuth has recently reported the shortest biomimetic synthesis of steroidal skeletons in enantiopure form [40]. Using the photoinduced electron transfer (PET) technology, he examined the behavior of diastereomeric (E,E,E)-geranylgeranylmethyl 82 and 86 bearing a (-)-menthone-based chiral auxiliary. Irradiation of 82 provided the two diastereomers 83 and 84 in a 1:7 ratio, and in 10% yield (Scheme 25). The all-trans chair approach from the a-face (82-a+') appears much more favorable than that from the p-face because of steric interactions with the chiral auxiliary. Enantiopure C- 17-substituted steroid 85 was

4.4.3 6-endo-trig Cyclizations in Series

'I"'

"5

$-( 0

111..

111..

365

366

4.4 Polycyclic Compounds via Radical Cascade Reactions

cleanly delivered from the chiral auxiliary. The stereochemical outcome of this sequence is impressive: eight stereogenic centers are established, and ‘only 2 out of 256 possible isomers are formed’, which represents an outstanding example of remote asymmetric induction. Similarly, the PET route from the epimer 86 furnished ent-85.

4.4.4 Incorporation of Hydrogen Transfers in Cascades Although radical hydrogen transfers are most often undesired side-reactions, they can also be highly valuable processes to be incorporated into cascades. Curran has described a class of functional groups that play a dual role of Protection and Radical Translocation (‘PRT’) and which have been useful as triggers for tandem reactions [41]. Recently, we have reported a radical cascade based on hydrogen transfers and which allows the diastereoselective constructions of highly strained bicyclo[3.1.l]heptanes [42]. Thus, when silyl ether 87 was submitted to radical cyclization conditions, a single diastereomer of 88 was obtained after treatment with methyllithium in 85% yield. Clearly, this reaction, which consumes the two acetylenic moieties to create three carbon-carbon bonds and three new stereogenic centers in a bridged bicyclic structure, involves a novel type of cascade. After an initial 5-exo-dig cyclization, the resulting vinyl radical 89 undergoes a 1,6-H transfer at the expense of an entropically and statistically more favorable 1,5-H transfer on the iso-propyl group. Stabilized propargyl radical 90 then follows a completely diastereoselective 6-endo-trig cyclization from the p-face. This leads presumably to cyclohexyl radical 9lpeq bearing the acetylenic chain in a pseudo-equatorial position on the less occupied a-face. However, no stannane reduction (syn to a tert-butyl or an iso-propyl group) or a 4-exo-dig cyclization orienting the tert-butyl group in an axial position seems possible. Rather, equilibration to 9lpax now places the acetylenic partner in a particularly favorable pseudo-axial position for a further 4exo-dig cyclization that achieves the construction of the bridged bicyclic framework. The reversibility of the formation of a-cyclobutyl radicals is well established. Deuterium labeling, however, shows that an additional 1,6-H transfer from the vinyl radical 92 occurs to give stabilized a-silyl radical 93, as proved by the exclusive formation of 88D when using tributyltin deuteride (Scheme 26). This constituted to the best of our knowledge the first example of an unfavorable cyclization process, a 4-exo-dig ring closure, driven by a hydrogen transfer.

4.4.5 Radical Transannular Cascades Transannular cyclizations are an important class of radical reactions that are nowadays frequently used as a key step in the synthesis of polycyclic natural product

4.4.5 Radical Transannular Cascades

87

88, 85%

87 5-exo-dig

‘Si

1,6-H transfer

\

89

6-endo-trig

\

90

?

4-exo-dig

Si /

91pax

-

92

Bu3SnH(D) t

MeLi

1,6-H transfer

’-

H(D) BuBSnH: 88 (85%) BuiSnD : 88D (71%) pseudeboat, attack from the p face

\ /

no cyclization, or reduction (R = H)

\

\ /

\

9Opax

Scheme 26

91pax

367

368

4.4 Polycyclic Compounds via Radical Cascade Reactions

+4]+

(PhC00)2 RH, or ( f - B u 0 ) ~

94

95

30-70%

R = CONHt-Bu, PO(OEt)2,CCI3, COOMe, COCH3

Scheme 27

skeletons. The pionnering research of Dowbenko and Friedman in 1964 in the field of radical transannular cyclizations has focussed on the behavior of a cyclooct-4enyl radical to produce the cis-bicyclo[3.3.0]octaneframework 95. The observed stereoselectivity probably results from the proposed equatorially substituted chairtransition state 94, which clearly shows the adequacy of the 5-exo/S-endo transannular process in establishing the relative configurations of the three stereogenic centers (Scheme 27) [43]. Many studies have investigated how to reach efficiently, from a monocyclic precursor, bicyclic systems as such [3.3.0] octanes, [4.3.0] nonanes, [4.4.0] and [S.3.0] decanes, [6.3.0] undecanes and so on [44]. A few applications dealt with bicyclic or tricyclic precursors, thus opening access to tricyclic or tetracyclic structures, but with a unique radical cyclization. For instance, in 1984, in the course of research on new aromachemicals, Van der Linde investigated the radical-induced addition of acetaldehyde to the caryophyllene bicyclic skeleton 96. The initially generated Smethylene cyclooctanyl radical 97 cyclized following a transannular S-exo/6-exo pathway, thus producing a mixture of four isomeric methylketones possessing the protoilludane tricyclic framework (Scheme 28) [4Sa]. One decade later, Demuth showed that irradiation in an anionic micellar medium of trans-caryophyllene 96 in the presence of an electron acceptor produced, via the formation of the radicalcation 99, a mixture of protoilludanols 100. This constituted a photochemically triggered biomimetic-type terpene cyclization via a single-electron transfer (Scheme 28) [4Sb]. On the other hand, in the last ten years, many groups have explored different elegant radical cascade strategies implying one or more transannular cyclization(s) to reach polycyclic frameworks of natural products [43]. From the literature, we can highlight four distinct strategies aiming at the construction of tricyclic or tetracyclic frameworks, based on cascade radical combinations of (C) intra one (or two) transannular processes, (D) transannular - intra processes, (E ) macrocyclization two transannular processes, (F ) two (or three) transannular processes inside a macrocycle (illustration of each strategy is shown on Scheme 29). Herein, we will focus on these cascade strategies, and rank them according to the size of the macrocycle involved in the first radical transannulation. We will particularly describe the regio- and stereoselectivity of the radical processes and the type of polycyclic system obtained. ~

~

4.4.5 Radical Transannular Cascades

-

CH3CHO (f-BU0)p

125°C

96

b)

369

98, 54% four diastereomers

1-cyanonaphtalene

96

t

MeCN / HzO, hv, 20h 99

100, 27% three diastereomers

Scheme 28

intra -

Strategy C

transannular

(PI

transannular -

Strategy D

intra

\

Strategy E

.+a ‘=u QP macrocyclization transannular*

completely Strategy F transannular

Scheme 29

4.4.5.1 Eight-Carbon-Membered Ring Radicals Following strategy C, Winkler proposed a suitably substituted cycloocta-l,5diene 101, which led selectively to the cis-anti-cis tricyclic derivative 103, thus opening a novel synthesis of linearly fused triquinanes (Scheme 30). The cyano ester renders the initial 5-ex0 cyclization of radical 102 reversible, and then serves as a stereocontrol element for the (5-exo/5-endo) transannular process of the intermediate cis[6.3.0]bicycloundecenyl radical. In this reaction, a single stereocenter in the starting macrocycle has been translated into four contiguous stereogenic ones. Another tri-

4.4 Polycyclic Compounds via Radical Cascade Reactions

370

102

101

'

103, 45% two diastereomers

104, 15% two diastereomers Scheme 30

cyclic product 104, possessing a gymnomitrane framework, was produced, originating from the attack of the cyano ester-stabilized radical 102 on the distal olefin, followed by transannulation [46]. While studying the stereochemical outcome of the cyclization of an o-iodo substituted link in disubstituted cyclooctadienic precursors, Winkler reported that the trans-disubstituted cyclooctadiene 105 led to the formation of a 1:l mixture of cisanti-cis and cis-syn-cis triquinanes 107 in 28% global yield and, as major products, trans- and cis-bicyclo[6.3.0]undecenes108 (Scheme 3 1). This example reveals a complete lack of stereocontrol during the first 5-ex0 cyclization from radical 106; an exactly 1: 1 trans, cis junction stereoselectivity is obtained [47]. Access to another class of natural triquinane sesquiterpenes, ( f)-modhephene and (f)-epi-modhephene, was targeted following strategy D. Indeed, the [3.3.3]propellane skeleton 111 was efficiently assembled by Curran from the Barton thiohydroxamate 109. The generated 5-methylene cyclooctanyl radical 110 engages in a (5-exo/5-exo)transannular-5-exo-trig cyclization tandem (Scheme 32). The resulting radical then adds to the starting compound 109, which, without any tin reagent, efficiently propagates the radical chain to yield 111. The modest selectivity can be

OH

PH

-

Bu3SnH, AIBN, I 105

Scheme 31

benzene, hv

106

'

107, 28% 108, 42% two diastereomers (111) two diastereomers (trans/& : 5/1)

4.4.5 Radical Transannular Cascades

toluene

3 11

*

reflux, 8h

109

110

-

111,63% (two Me-a diastereomers I two Me-p diastereomers = 2.7 11)

S

I d

major TS-A

4

a minor TS-B

Me-a: modhephene Me-p: epi-modhephene

Scheme 32

explained through the observation of the proposed stereochemical models. An unfavorable interaction between the methyl group and the (exo)methylene group in transition state B favors TS-A (precursor of modhephene), at the expense of TS-B (precursor of epi-modhephene) [48]. Recently, Pattenden, following the same D strategy, has developed the use of aketenyl cyclooctanyl radical 114 toward a new and concise formal synthesis of modhephene (Scheme 33). The a$-unsaturated seleno ester 112, treated under usual Bu3SnH-AIBN conditions, generates the corresponding a$-unsaturated acyl radical 113, which transannularly cyclizes via its mesomeric radical counterpart 114. The resulting tertiary radical undergoes a 5-exo-dig cyclization onto the ketene central carbon giving rise to a final enoxy radical, which is reduced to provide the tricyclic ketone 115 [49].

Q

SCH2CH2CrjH41-o

112

\

Scheme 33

BU3SnH, AlBN

benzene reflux

/”

115,59%

372

4.4 Polycyclic Compounds via Radical Cascade Reactions

F -

36 :a-Me I p-Me = 1/1) \

1& Bn

9

BnON)

-hl

L

p-fragmentationt

6-(x-exo)exo

117

118

119

Scheme 34

The challenge of synthesizing angular triquinane ring systems based on transannular processes was also checked and won. Pattenden designed a cascade strategy involving a series of radical cyclization-fragmentation-transannulation-cyclization processes from cyclobutanone oxime 116 (Scheme 34) [50].Thus, vinyl radical 117, created in the presence of Chatgilialoglu's reagent, cyclized onto the oxime moiety following a 6-(n-exo)-exo-trig pathway to give the aminyl radical 118. Subsequent /?-fragmentation provided a double ring expansion to the 5-exo-methylene cyclooctanyl radical 119, precursor of a (5-exo/5-exo) transannular 5-exo cyclization cascade which belongs to the D class (see Scheme 34). The expected triquinane oxime 120 was isolated as the major product and as a 1:l mixture of a- and pmethyl diastereomers. The efficiency of the bicyclo[3.3.0]octanone formation by Fe(II1)-mediated ring expansion-transannular cyclization reactions of cyclopropyl ethers incited BookerMilburn to study the possibility of broadening this 'without tin' radical methodology to obtain the angular triquinane framework, here again following the D strategy. Oxidative treatment of cyclopropyl ether 121 with ferric nitrate and cyclohexadiene in D M F gave the 3-oxocyclooctenyl radical 122, which underwent a (5-exo/5-endo) transannular cyclization furnishing a bicyclic a-ketyl radical (Scheme 35) [ 5 I]. This electrophilic radical then slowly cyclized onto the non-activated terminal double bond to furnish the expected tricyclic ketone 123 with modest yield. The major isolated ketone is the bicyclic one 124. Conducting the same procedure

Meg f

Fe(N03)3

+

*

1,4-~yclohexadiene DMF, rt to 60°C 121

Scheme 35

122

123,10%

124, 39%

4.4.5 Radical Transannular Cascades

373

on the phenyl-substituted alkene precursor, with a view to stabilizing the final radical, gave no triquinane at all. These findings could be ascribed to the reduction of the intermediate a-keto radical, with the Fe(1I) formed in situ, into an enoate anion which would then be unable to undergo cyclization. In the area of stereodefined sesquiterpenic triquinane construction, radical cascades involving one transannular cyclization from cyclooctanyl or cyclooctenyl radicals proved to be very efficient and reliable strategies.

4.4.5.2 Nine-Carbon-Membered Ring Radicals Surprisingly few examples in this category of nine-membered ring radicals are devoted to the synthesis of polycyclic frameworks through a radical cascade involving transannular closures. We have previously mentioned the capacity of the caryophyllene radical to cyclize transannularly (Scheme 28), but this example of a unique radical cyclization step was not applied in cascade strategies [45]. Nevertheless, Pattenden was interested in a new synthetic approach (strategy C, Scheme 29) to steroidal ring systems, and constructed a sequential five-carboncarbon-bond-forming cascade. The behavior of cyclopropyl-substituted trienoneselenylester 78 under radical conditions was described in Section 4.4.3 (Scheme 24). After a 6-endo/6-endo tandem cyclization and an a-cyclopropyl radical opening, a Michael-directed 9-end0 macrocyclization occurred. The cyclonon-5-enyl radical 81 thus generated followed the planned (5-exo/6-endo)-transannularclosure to yield the steroidal skeleton 79 [39].

4.4.5.3 Ten-Carbon-Membered Ring Radicals Ten-membered ring radicals have been studied extensively to reach cis- or trunsdecalins and hydroazulenes, but the construction of polycycles was only envisaged by Pattenden. Thus, starting from the judiciously substituted exo-methylene [4.4.O]bicyclodecanol 125 in presence of (diacetoxyiod0)benzene and iodine, the alkoxy radical 126 is created and P-fragments to form cyclodecanyl radical 127, which is well oriented to undergo a (5-exo/7-exo) transannulation-5-exo-trig cyclization cascade (strategy D) to provide a unique elaborated angularly fused 7,5,5tricyclic derivative 128 (Scheme 36) [52].

125

Scheme 36

126

127

128,58% (81% based on recovered material)

374

4.4 Polycyclic Compounds via Radical Cascade Reactions

4.4.5.4 Eleven-Carbon-Membered Ring Radicals Using the biosynthesis of humulene as a model, we have carried out a biomimetic synthesis of a natural sesquiterpene from a conveniently substituted cyloundecadienyne via a double transannular radical cascade (strategy F ) . As a first target, we chose an angularly fused protoilludane 4,6,5-tricyclic framework which possesses a bis-allylic diol, an entity easily prepared through a one-pot radical cyclizationTamao oxidation from a bromomethyldimethylsilyl propargyl ether [ 151. We prepared the required monocyclic precursor 129 as a mixture of diastereomers. Under classical Bu3SnH-AIBN conditions followed by Tamao oxidation and a subsequent desilylation, the natural product was obtained in good overall yield (Scheme 37) [53]. The initial a-silyl radical 130 cyclizes in a regioselective 5-exo-dig manner. The generated vinyl radical 131 undergoes a challenging 4-(n-exo)-exo-trig transannular closure to 132, followed by a (6-exo/5-endo) process serving as a driving force, to build the tetracycle 133 as a unique diastereomer. A similar strategy is now being developed to prepare natural protoilludanes incorporating this intriguing em-methylene cyclobutane e.g. tsugicolines, armillol, In parallel, the triquinane sesquiterpenic skeleton can also be considered as etc. [54]. a potential target following the same retrosynthetic strategy. This would require an I 1. Bu3SnH,AIBN, benzene, reflux

-

2. Tamao oxidation 3. n-BudNF, THF

OTBDMS

47%

I

1

H’ pmao 0 ;

6-exo-trigI 5-endo trig 4-(n-exo)-exo-trigI 9-(n-endobendetria

OTBDMS

Scheme 37

132

4.4.5 Radical Transannular Cascades

375

eleven-membered ring with three adequately placed unsaturations as a precursor. This would constitute a new route to linear or angular triquinanes.

4.4.5.5 Twelve-Carbon-Membered Ring Radicals Among the very few reported possibilities offered by transannular cycle contraction of cyclododecenyl radicals to construct 93-, 8,6- or 7,7-bicyclic systems, the radical tandem approach to the taxanes planned by Pattenden, from the substituted A-ring precursor 134, introduces a new conceptual strategy, described as E in Scheme 29. First, a 12-endo-dig macrocyclization involving alkyl radical 135 occurs easily on the triple bond of the ynone moiety. The produced vinyl radical (major conformer is transannular manner to presented) 136 cyclizes in a 6-(7c-endo)-exo/8-(nI-exo)-endo assemble the unusual tricyclo[9.3.1.O3>*]pentadecaneframework 137 as a 6:1 ratio of diastereomers (Scheme 38) [55]. This example should not have appeared in this review, because a templating ring is already present; nevertheless, it conveniently permits the introduction of Pattenden’s macrocyclization tandem transannulation strategy E.

\\

AlBN

0 . 1

R

0 134a (R = I)

L

-

135

major 136

137,43% (P-H / a-H = 6/1)

+

134b (R = H), 17%

Scheme 38

4.4.5.6 Thirteen-Carbon-Membered Ring Radicals Pattenden next studied the behavior of cyclotridecadienyl or -trienyl radicals to obtain various tricyclic systems relying on his above-described strategy. First, he designed the iodotrienone 138 to prepare 6,6,5-tricyclic framework 141, via a 13-endo macrocyclization - a (5-exo/lO-endo) followed by a (6-exo/6-endo) transannular closure. Under the Bu3SnH-AIBN protocol, a unique saturated ketone was isolated. It proved to be the unexpected cis-anti-trans 5,7,5-tricyclic ketone 142 (Scheme 39). The sequence begins with a Michael-oriented 13-endo macrocyclization to furnish the a-oxo-cyclotridecadienyl radical 139. The first transannular process generates the predicted oxo-cyclodecenyl radical 140, which, however, prefers the (5-exo/7-endo) mode of cyclization to yield the isolated ketone 142 ~61. In the same paper, two unrewarding results are interesting. An iodo-unde-

376

4.4 Polycyclic Compounds via Radical Cascade Reactions

1

5-ex0

-f-?a

13-endo

\

0

-

V

I O

“y-

]

0 139

Hfp

140

141

Scheme 39

catrienone and -heptadecatetraenone were tested aiming at the synthesis of the linear triquinane and steroid skeleton respectively. Both led only to the corresponding macrocyclization product. Complete MM2 calculations are consistent with the outcomes of the three experimental results [56b]. The use of vinylcyclopropanes was tried experimentally as an alternative functionality to the electron-deficient alkene radical acceptors generally described in the radical macrocyclizations. This choice was directed by the idea that the release of strain produced by the radical-induced cyclopropane opening will favor irreversibility of the macrocyclization, and that the one additional carbon will feature novel tandem transannular possibilities. Thus, as an initial endeavor, the treatment of vinylcyclopropylketone 143 with (TMS)3SiH-AIBN, afforded, in good yield, a 2:l mixture of 6,5,6- and 5,6,6-tricyclic ketones 147 and 148 respectively (Scheme 40). The 12-endo-trig macrocyclization-cyclopropyl opening sequence originates from homoallylic radical 144 and leads to oxocyclotridecadienyl radical 145. This radical gives birth to cyclononenyl radical 146 in a (6-exo/9-endo) transannular manner. Then two competitive 5-ex0 transannular processes have led to the isolated ketones 147 and 148, with lack of regioselectivity [57]. Also belonging to strategy E (Scheme 29) was the interesting exploration of radical-mediated transannular Diels-Alder (DA) reactions. Thus, the adequately

0

(TMS)SSiH *

I

AlBN benzene

143

(J 3

65%

0

-

12-endo-=

-

J ..

144

145

Scheme 40

(2/1)

1

146

4

i

148

4.4.5 Radical Transannular Cascades

377

H

/r*

\

transannular tandem

L

150

151

Scheme 41

functionalized precursor 149, bearing a ynone and a diene moieties, was exposed to radical conditions and led to the isolation of the cis-syn-cis 6,6,5-tricyclicketone 152 in modest yield, but as a unique diastereomer (Scheme 41). After the 13-endo Michael-activated closure, it seems, based on the low conversion to 152, that the vinyl radical 150 is reduced to 151 and then follows a thermal Diels-Alder rather than a radical tandem transannular pathway [ 581. Other attempts to promote radical DA reactions were pursued, notably to open an entry into steroidal structures. An interesting case is the radical cyclization of ynone 153 in order to prepare tetracyclic ketone 155 through a 13-endo-dig macrocyclization-radical tandem transannular DA cascade. The unique resulting tetracyclic compound 158, displays a completely different structure with two contiguous quaternary sp3 carbons and two conjugated enone moieties (Scheme 42),

Bu3SnH AlBN benzene 40%

‘ Ov- A 15s

..

1

*

H 158

-& $y(!

\ (5-eXO/ 6-exo)

13-endo

[@

6-(K-endo)- ex0 / 8-(~-exo)-exo

-

1

154

- \.

*

r‘.

156

O‘ - ’

Scheme 42

fragment.

155

‘0

157

0

378

4.4 Polycyclic Compounds via Radical Cascade Reactions

and results from an elaborate cascade. Vinyl radical 154 undergoes a transannular 6-(~-endo)-exocyclization rather than the planned 6-(7~-exo)-exoone, to create the bis-allylic radical 156, which fragments to form a new bis-allylic radical 157. A final (5-exo/6-exo)transannular cyclization assembles the tetracyclic structure [ 581. Thus, the radical Diels-Alder stratagem has not yet proved its feasibility. Nevertheless, new routes to polycycles have been devised.

4.4.5.7 Fourteen-Carbon-Membered Ring Radicals The elegant first total synthesis of natural 7,8-epoxy-4-basmen-6-one proposed by Myers in 1993 has highlighted, as a key step, the first example of a tandem transannular cyclization. The choice of generating cyclotetratrienyl radical 160, as key intermediate, was first guided by biomimetic considerations, as in the abovementioned total synthesis of epi-illudol. Moreover, the orientation of iso-propyl and methyl substituents was chosen to set the stereocenters of the natural framework, and the allene was incorporated as radical acceptor in order to favor the second transannulation leading to a strained eight-membered ring (Scheme 43). Thus, ester

/

159

163

PhSH, AlBN

I

hexane, hv, 93%

I

r

L

Scheme 43

164

I 160

161

162

t

4.4.5 Radical Transannular Cascades

319

159 was photolyzed in presence of N-methylcarbazole and 1,4-cyclohexadiene and led to the hoped-for radical 160. This one reacts in a (5-exolll-endo) first transannulation on the 2-olefin to give radical 161 via a chair-like conformer with an equatorially oriented iso-propyl substituent. Then P-H radical 161 undergoes a second transannular process (5-exo/S-endo)to construct the tricyclic skeleton. The resulting delocalized allylic radical 162 is reduced to produce a 2: 1 mixture of three allylic stereoisomers: two epimers 163 and the desired cyclopentenic precursor of the natural product 164. A subsequent irradiation in the presence of thiophenol solves this lack of selectivity by transforming almost quantitatively the mixture into the desired single isomer 164 [59].

4.4.5.8 Seventeen-Carbon-Membered Ring Radicals The seventeen-carbon envelope would constitute the appropriate precursor of the steroid framework, considering a judiciously unsaturated macrocycle to manage a triple transannular cascade (strategy D). Following these considerations, Pattenden first attempted the tandem transannnular cyclizations under oxidative conditions [manganese(III) acetate], on 2,Zand E,E-cycloheptadecadienones 165. The expected cascade was thwarted by a competitive 1,5-transannular hydrogen abstraction, shown on structure 166, which occurs exclusively after the first (6-eso/l3-endo) transannular process (Scheme 44). Thus, transposition of the allylic alcohol, oxidation to a carbocation and acetic acid quench of the resulting radical led to the disappointing bicyclic compound 167 [60]. This issue was addressed with cycloheptadecadienone 168, which bears an olefin at the hydrogen shift position. The ketoester-substituted radical 169 is involved in a (6-exo/l3-endo), (5-exo/lO-endo) tandem and yields tricyclic skeleton 170, albeit in low yield (Scheme 45) [60]. The last but not least example is the first case of a triple transannular radical cyclization. Phenylselenocycloheptadecatriene171, submitted to reductive Bu3 SnHAIBN conditions, furnishes an a-cyano radical that undergoes a first transannular (5-exoll4-endo) to deliver cyclotetradecadienyl radical 172. Then, competitive pro-

w

AcOH

0

165aZ,Z 165b €,€

E = C02Me

\

\

0

/

0

Scheme 44

166

167a44% 167b 37%

380

4.4 Polycyclic Compounds via Radical Cascade Reactions

- @

M~(OAC)~*~H~O CU(OAC)~H~O AcOH E = COZMe

168

0 170, 8%

Scheme 45 CN NC SePh Bu3SnH AlBN

TBDPSO

- & TBDPSO

173, 4%

171

I

1) Bu3Sn' 2) (5-exol14-endo)

(6-exoll 0-endo)/ (6-exol6-endo)

[a H'

TBDPSO

172

TBDPSO 174

\

main products

1,5-H transfer

TBDPSO 175

Scheme 46

cesses appear. Main products 174 and 175 result from direct reduction and 1,5-H transfer respectively (Scheme 46). Nevertheless, a single tetracyclic steroid product 173 possessing a cis CD-ring junction was isolated in 4% yield. This finding proves the feasibility of the triple cyclization strategy. However, the next investigators will have to elaborate judiciously modified precursors in order to suppress the undesirable 1,5-H transfer [61].

4.4.6 Conclusion In this account, we have described the synthesis of polycyclic compounds by radical cascade reactions. Most of the contributions have appeared during the last decade,

References

38 1

suggesting an increasing interest of the organic community. The distinct approaches we have discerned have proved to be elegant and efficient, including several applications in the field of natural product total synthesis. No doubt the cascade strategy will now be envisioned as a priority for the synthesis of theoretically or biologically relevant molecules.

References [ I ] D. P. Curran, D. M. Rakiewicz, Tetruhedron 1985, 41, 3943-3958. [2] T. L. Fevig, R. L. Elliott, D. P. Curran, J. Am. Chem. Soc. 1998, 120, 5064-5067. [ 3 ] E. Lee, J. W. Lim, C. H. Yoon, Y.-s. Sung, Y. K . Kim, J. Am. Chem. Soc. 1997, 119, 83918392. [4] a) D. P. Curran, S. B. KO, H. Josien, Angew. Chem. In/. Ed, Engl. 1995, 34, 2683-2684. b) D. P. Curran, H. Liu, H. Josien, S. B. KO, Tetruhedron 1996, 52, 11385-1 1404. [S] a) T.-L. Ho In Wiley: New York, 1992; pp 398-420. b) C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91, 123771286, c) R. A. Bunce, Tetrahedron 1995, 51, 13103-13159. [6] D. P. Curran, S. Sun, Aust. J. Chem. 1995, 48, 261-267. 171 A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985, 41, 3925-3941. [8] D. Boate, C. Fontaine, E. Guittet, L. Stella, Tetrahedron 1993, 49, 8397-8406. [9] M. A. Dombroski, S. A. Kates, B. B. Snider, J. Am. Chem. Soc. 1990, 112, 2759-2767. [ 101 J. Marco-Contelles, Synth. Conzmun. 1997, 3163-3170. [I11 M. Yamamoto, A. Furusawa, S. Isawa, Bull. Chrm. Soc. Jpn. 1992, 65, 1550-1555. [I21 M. Journet, M. Malacria, J. Org. Chem. 1994, 59, 718-719. [ 131 C. Spino, N. Barriault, J. Org. Chem. 1999, 64, 5292-5298. [I41 R. N. Saicic, Z. Cekovic, Tetruhedron Lett. 1994, 35, 7845-7848. [I51 a) M. Journet, M. Malacria, J. Org. Chem. 1992, 57, 3085-3093. b) review : L. Fensterbank, M. Malacria, S. M. Sieburth, Synthesis 1997, 813-854. [I61 S. Bogen, P. Devin, L. Fensterbank, M. Journet, E. L a d e , M. Malacria, Recent Res. Devel. Org. Chem. 1997, I , 385-395. [ 171 P. Devin, L. Fensterbank, M. Malacria, J. Org. Chem. 1998, 63, 6764-6765. [ 181 R. N. Saicic, Z. Cekovic, Tetrahedron 1992, 48, 8975-8992. [ 191 C. Chatgilialoglu In The Chemistry ofSulphones and Sulphoxides; S. Patai; Z. Rappoport and C. J. M. Stirling, Ed.; John Wiley: New York, 1988; pp 1081-1087. [20] I. Abe, M. Rohmer, G. D. Prestwich, Chem. Rev. 1993, 93, 2189-2206. [21] R. Breslow, E. Barrett, E. Mohacsi, Tetruhedron Lett. 1962, 3 , 1207-1211. [22] R. Breslow, S. S. O h , J. T. Groves, Tetrahedron Lett. 1968, 9, 1837-1840. [23] J. Y. Lallemand, M. Julia, D. Mansuy, Tetrahedron Lett. 1973, 14, 4461-4464. 1241 E. R. Lee, I. Lakomy, R. Scheffold, H d v . Chim. Actu 1991, 74: 146-162. [25] J. W. Wilt, Tetrahedron 1985, 41, 3979-4000. [26] H. Nishiyama, T. Kitajima, M. Matsumoto, K. Itoh, J. Ory. Chem. 1984, 49, 2298-2300. [27] G. G. Melikyan, Org. Reuct. (N. Y. ) 1997, 49, 427-700. [28] P. A. Zoretic, X. Weng, M. L. Caspar, Tetrahedron Lett. 1991, 32, 4819-4822. [29] a) P. A. Zoretic, M. Wang, Y. Zhang, Z. Shen, J. Org. Chem. 1996, 61, 1806-1813. b) P. A. Zoretic, Y. Zhang, H. Fang, A. A. Ribeiro, G. Dubay, J. Org. Chem. 1998, 63, 1162-1167. [30] P. A. Zoretic, Y. Zhang, A. A. Ribeiro, Tetrahedron Lett. 1996, 37, 1751-1754. [31] P. A. Zoretic, Z. Chen, Y. Zhang, Tetrahedron Lett. 1996, 37, 7909-7912. [32] P. A. Zoretic, H. Fang, A. A. Ribeiro, J. Org. Chem. 1998, 63, 7213-7217. [33] B. B. Snider, J. Y. Kiselgof, B. M. Foxman, J. Org. Chem. 1998, 63, 7945-7952. [34] a) D. L. Boger, R. J. Mathvink, J. Am. Chem. Soc. 1990, 1 / 2 , 4003-4008. b) review: C. Chatgilialoglu, D. Crich, M. Komatsu, I. Ryu, Chem. Rev. 1999, 99, 1991-2069.

382

4.4 Polycyclic Compounds via Radical Cascade Reactions

1351 L. Chen, G. B. Gill, G. Pattenden, Tetrahedron Lett. 1994, 35, 2593-2596. [36] A. Batsanov, L. Chen, G. B. Gill, G. Pattenden, J. Chem. Soc., Perkin Trans. 1 1996, 45-55. 1371 G. Pattenden, L. Roberts, A. J. Blake, J. Chem. Soc., Perkin Trans. 1 1998, 863-868. 1381 P. Double, G. Pattenden, J. Chem. Soc., Perkin Trans. 1 1998, 2005-2007. Chem. Commun. 1998, 311-312. 1391 S. Handa, G. Pattenden, W.-S. Li, J. Chem. SOC., 1401 C. Heinemann, M. Demuth, J. Am. Chem. SOC. 1999,121,4894-4895. 1411 a) D. P. Curran, D. Kim, H. T. Liu, W. Shen, J. Am. Chem. Soc. 1988, 110, 5900-5902. b) C. E. Schwartz, D. P. Curran, J. Am. Chem. SOC.1990, 112, 9272-9284. 1421 a) S. Bogen, L. Fensterbank, M. Malacria, J. Am. Chem. SOC.1997, 119, 503775038, b) S. Bogen, L. Fensterbank, M. Malacria, J. Org. Chem. 1999, 64, 819-825. 1964, [43] a) R. Dowbenko, Tetrahedron 1964, 20, 1843--1858.b) L. Friedman, J. Am. Chem. SOC. 86, 1885-1886. 1441 S. Handa, G. Pattenden, Contemp. Org. Synth. 1997, 196-214. 1451 a) L. M. van der Linde, A. J. A. van der Weerdt, Tetrahedron Lett. 1984, 25, 1201-1204. b) U. Hoffmann, Y. Gao, B. Pandey, S. Klinge, K.-D. Warzecha, C. Kriiger, H. D. Roth, M. Demuth, J. Am. Chem. Soc. 1993, 115, 10358-10359. [46] J. D. Winkler, V. Sridar, J. Am. Chem. SOC.1986, 108, 1708-1709. 1471 J. D. Winkler, V. Sridar, Tetrahedron Lett. 1988, 29, 6219-6222. 1481 D. P. Curran, W. Shen, Tetrahedron 1993, 49, 755-770. 1491 B. De Boeck, G. Pattenden, Tetrahedron Lett. 1998, 39, 6975-6978. [50] G. J. Hollingworth, G. Pattenden, D. J. Schulz, Aust. J. Chem. 1995, 48, 381-399. 1511 K. I. Booker-Milburn, R. F. Dainty, Tetrahedron Lett. 1998, 39, 5097-5100. 1521 C. E. Mowbray, G. Pattenden, Tetrahedron Lett. 1993, 34, 127-130. 1.531 M. Rychlet Elliott, A. Dhimane, M. Malacria, J. Am. Chem. Soc. 1997, 119, 3427-3428. 1541 M. Rychlet Elliott, A. Dhimane, L. Hamon, M. Malacria, Eur. J. Org. Chem. 2000, 155-163. 1551 a) S. A. Hitchcock, G. Pattenden, Tetrahedron Lett. 1992, 33, 4843-4846. b) S. J. Houldsworth, G. Pattenden, D. C. Pryde, N. M. Thomson, J. Chem. Soc., Perkin Trans. 1 1997, 1091-1093. c) S. A. Hitchcock, S. J. Houldsworth, G. Pattenden, D. C. Pryde, N. M. Thomson, A. J. Blake, ibid. 1998, 3181-3206. 1561 a) M. J. Begley, G. Pattenden, A. J. Smithies, D. S. Walter, Tetrahedron Lett. 1994, 35, 24172420. b) M. J. Begley, G. Pattenden, A. J. Smithies, D. Tapolczay, D. S. Walter, J. Chem. Soc., Perkin Trans. 1 1996, 21-29. 1571 G. Pattenden, P. Wiedenau, Tetrahedron Lett. 1997, 38, 3647-3650. [SS] P. Jones, W.-S. Li, G. Pattenden, N. M. Thomson, Tetrahedron Lett. 1997, 38, 9069-9072. 1591 a) A. G. Myers, K. R. Condroski J. Am. Chem. Soc. 1993, 115, 7926-7927. b) A. G. Myers, 1995, 117, 3057-3083. K. R. Condroski J. Am. Chem. SOC. 1601 P. Jones, G. Pattenden, Synlett 1997, 398-400. 1611 U. Jahn, D. P. Curran, Tetrahedron Lett. 1995, 36, 8921-8924.

Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

4.5 Diradicals in Synthesis Jonathan D. Punish and R. Daniel Little

4.5.1 Introduction In the preface to Diradicals, Borden writes: ‘It seems almost as hard to define what diradicals are as it is to study these reactive intermediates [l].’ Salem and Roland described a diradical as ‘an atom or molecule in which two electrons occupy two degenerate or nearly degenerate molecular orbitals [2].’ A few examples befitting this description include the conjugated non-Kekuli hydrocarbons trimethylenemethane (TMM, l), tetramethyleneethane (TME, 2), and meta-quinodimethane 3, as well as the nonconjugated 1,3- and 1,4-diradicals (diyls) trimethylene (4) and tetramethylene (5), and the now very familiar benzene 1,4-diyl 6 (Fig. 1). A variety of methods are used to generate and study diyls including, to name a few, the thermal or photochemically promoted extrusion of nitrogen from a pyrazoline, the Norrish type I photochemically initiated extrusion of carbon monoxide from a cyclic ketone, and the Bergman cyclization of enediynes [3-51. In this chapter we focus upon the synthetic utility of diradicals, paying particular attention to the work of others as well as research originating from our laboratory.

4.5.2 Trimethylenemethane Trimethylenemethane (TMM, 1) has been of interest to scientists with varied interests and expertise since the late 1940s [6]. It exists at low temperatures as both a singlet and a triplet species, the latter being its ground state. Its chemistry is characterized by dimerization, a triplet-derived process, and intramolecular cyclization of the singlet to form methylenecyclopropane. Attempts to intercept TMM (1) in cycloaddition processes have not led to synthetically useful chemistry. On the other hand, various organometallic analogs, 7 being the most notable, have emerged as exceptionally useful synthons for TMM in cycloaddition chemistry (Fig. 2) [7]. This chemistry has been beautifully described elsewhere and is not discussed in this chapter [8].

384

4.5 Divadicals in Synthesis

TM M

TME

1

2

3

.A.

0 .

5

6

4

Figure 1. Examples of diradicals

8

7

Figure 2. Organometallic and cyclopenta-TMM diradicals

4.5.2.1 Reactivity Patterns of TMM Diyls In contrast to the parent hydrocarbon, cyclopenta-TMMs of general structure 8 (Fig. 2) have proven very useful in a number of contexts that call for their use in organic synthesis. There exist five fundamentally different reactivity patterns that characterize their chemistry (Scheme I). With the exception of dimerization [9], each is discussed in the sections that follow. The other reactions include cycloaddition (19 20 21) [lo], atom transfer-cyclization (9 to 11) [ 111, fragmentation-cyclization (12 + 15 and/or 16) [12], and interception of a dipolar diyl 17 with water and/or alcohols [ 131.

+

--f

4.5.2.2 Intermolecular Cycloadditions of TMM Diyls Intevmoleculuv cycloaddition provides an indication of the range of diylophiles that are capable of intercepting TMM diyls (Scheme 2) [ IOa]. Since nearly all of the diyls that have been examined have been electron rich, it is not surprising that the most effective trapping agents (diylophiles) are electron deficient. These preferences could presumably be reversed by constructing electron-poor diyls. This would allow electron-rich diylophiles to be used. At this point we note that diyls add across carboncarbon double and triple bonds (e.g., dimethylacetylene dicarboxylate) [ 141 and to allenes (e.g. 20) [ 151 as well as across nitrogen-nitrogen double bonds (e.g., dimethyl azodicarboxylate). The diyl can also be intercepted by thioketones (PhZC=S) and by imines (PhN=CHPh) [14]. The Lewis acid promoted depolymerizaton of paraformaldehyde in the presence of diazene 19, as well as the reaction of the unsubstituted diyl 24 with diethylketomalonate, provide striking examples of the high

4.5.2 Trimethylenemethane

QJ

385

-9 Q

Q 10

11

-& -

L

14

13

12

G

1 G 15

17

16

18

Scheme 1. Reactivity patterns for TMM diyls

level of regioselectivity that can be observed in several cases involving cycloaddition to a carbonyl unit. The following equations illustrate that when followed by the application of any of several fragmentation processes, intermolecular cycloaddition provides a simple means of synthesizing the bicyclo [5.3.0], [6.3.0], and [7.3.0] ring systems (Scheme 3) 1161.

4.5.2.3 Reaction of TMM Diyls with Oxygen and Water Two additional examples of intermolecular processes further illustrate the diversity of TMM-diyl chemistry (Scheme 4). Each serves as an indicator of the nature of

386

4.5 Diradicals in Synthesis

21

22

23

25

24

Scheme 2. Examples of intermolecular cycloaddition of T M M diyls

28

26

19

29

75 "C, 8 h

C02CH3

b) NH,CI/H20

(94%)

C02CH3 30

@ C02CH3

H3

31

Scheme 3. Cycloaddition-fragmentation of TMM diyls en route to jn.3.01 ring systems

the species being intercepted. The first, illustrated by the conversion of diazene 32 to cyclopentenol 33, is a reaction with molecular oxygen [ 17, 181. The chemistry is diagnostic of the intervention of a triplet diradical. The second transformation occurs in an aqueous or semi-aqueous environment. Under these conditions, the intermediate 17 reacts with water (and/or an alcohol) to form an alcohol (35/36) [13]. This is not a reaction that is characteristic of the involvement of a diradical; rather, a dipolar intermediate 17 is implicated. The reactive species displays prop-

4.5.2 Trimethylenemethane

R

;I"

03. -. CHiCN " ~

reflux (75%)

*

381

I?

vr7H40CH3-p // "t

"

R)

so 17

Scheme 4. Reactions of TMM diyls with oxygen and water

erties that are best described as being those of a hybrid between diradical and zwitterion canonical forms. As illustrated by the preferential formation of 35, the regiochemical course of these reactions can be understood by postulating that polarization places the negative portion of the dipole on the exocyclic carbon and an ally1 cation on the ring, as is illustrated by 17.

4.5.2.4 DNA Cleavage by TMM Diyls A dipolar diyl could be responsible for the chemistry that is observed when diazene 38 is irradiated in the presence of plasmid DNA. Like calicheamicin and related systems, the intermediate formed from 38 binds to AT-rich regions and cuts DNA [19]. In principle, either a diyl or the dipolar species 37 could be responsible for cleavage (Fig. 3 ) . Any of several possibilities exist, including pre-reaction of a diyl with oxygen to form a more reactive oxygen-centered radical that could initiate the cleavage event via hydrogen atom abstraction. Alternatively, the dipolar intermediate 37 could engage in an Ez-like process involving abstraction of a proton from C ~ ofI the sugar-phosphate backbone, leading to elimination of the C31 or C ~ I phosphate units.

4.5.2.5 Intramolecular Cycloadditions of TMM Diyls As illustrated, intramolecular cycloaddition can provide access to a variety of different structures. Focus has been upon the linear and bridged systems 40 and 43 (Fig. 4). Access to either can be achieved through a judicious choice of the substituent, R, that is appended to the diylophile. Diazenes 44a and 44b (entries 1 and 2, Scheme 5) illustrate that as the size of the alkyl substituent appended to the diylophile increases, so does the ratio of bridged

388

4.5 Diradicals in Synthesis OP

0

Me

0

37

n Me O 38

Figure 3. DNA cleavage by TMM diyls

40, linear

41

R

39

42

43, bridged

Figure 4. Bridged and linearly fused ring systems

to linear cycloadduct [20]. Notice also that one can easily switch between the two regioisomers simply by changing the electronic characteristics of R (cf. entries 1 and 2 with entries 3-5). When it is an electron withdrawing group (entries 3-9, the linearly fused adduct is preferred. Of the many examples that illustrate the ability to easily select between the two forms, we highlight that of methyl ketone 47a and the corresponding dimethyl ketal 47b (Scheme 6). While the ketone 47a preferentially affords linear cycloadduct 48, the dimethyl ketal 47b leads to the bridged adduct 49 with high selectivity. A useful

4.5.2 Tvimethylenemethane

389

CH3CN, reflux t

44 a-e

45 a-e

46 a-e

yield (YO)

entry

diazene

1

44a

CH20H

90

1.2 : 1

2

44b

C(OCH&CH3

82

16:l

3

44c

CHO

93

1 :7

4

44d

COCH3

98

1 : 7.3

44e

C02CH3

88

1 :19

5

R

bridged : linear

Scheme 5. Substituent influence on bridged/linear product ratios

THF, reflux

48

[a] THF, reflux [b] NH4CI, H20/acetone R = C(OMe)&H3 47a, R = COCH3 47b, R=C(OMe)2CH3

16:l bridgedhinear (70% overall)

“OMe 49

Scheme 6. Selective formation of bridged or linearly fused ring systems

rule of thumb is that intramolecular diyl trapping reactions selectively afford linear cycloadducts from the singlet state of the diyl when an electron-withdrawing group is appended to either carbon of the diylophile; selective formation of bridged cycloadducts occurs from the triplet state of the diyl when a large alkyl group is appended to the internal carbon of the diylophile. The first application of intramolecular cycloaddition to the construction of natural products was to a total synthesis of hirsutene (52) [21]. Initially, an electronwithdrawing group was appended to the diylophile in order to assure the selective

390

4.5 Diradicals in Synthesis

c-(,

CH3CN, reflux

-

I\

(76%,5 : 1 cis-antihis-syn)

*,

&&

hirsutene 52

H

54

53

HO hu, 6 "C MeOH (84%)

55

OH coriolin

H i OH

57

6

56

0

OH hypnophilin 58

Scheme 7. Intramolecular cycloaddition approaches toward natural product synthesis

formation of the linearly fused skeleton 51. Ultimately, it was learned that linear fusion is preferred even when the diylophile is unsubstituted [22]. As the equations show, this discovery proved advantageous in the development of a streamlined synthesis of hirsutene (52) and in the total synthesis of both of the antitumor antibiotics coriolin (57) and hypnophilin (58) (Scheme 7) [23, 241. The ability to access bridged-ring systems is exemplified by the efficient conversion of diazene 59 to cycloadduct 60. It is noteworthy that the conversion can routinely be carried out on a 20 g scale [25]. This chemistry was explored in conjunction with the development of a route to a paclitaxel analog (61) (Scheme 8), and is currently being examined as a key step in the development of a synthesis of aphidicolin [26]. It is possible to predict both the relative and the absolute stereochemical outcome of diyl trapping reactions [27] (Scheme 9). The preferred stereochemical outcome

4.5.2 Trimethylenemethane

391

20 gram scale

59

60

61

Scheme 8. D i y l trapping toward taxane ring systems

[a] t

* .

J

L

63

fi 1

* fixed absolute configuration CHBCN, reflux

%

4

62

84% de

65

/ diastereorneric

I

4

E

hu, CH&N, 7 "C 93% de

H i OP 64

H i OP 66 OSiZ

67

* fixed absolute configuration

68

69

C = Me,Bu-t

Scheme 9. Stereoselectivity in intramolecular cycloadditions

corresponds to a model wherein the substituents that are located on the tether assume pseudoequatorial orientations in transition state structures of the variety portrayed by 63 and 68. These guidelines are applicable when the length of the tether linking diyl to diylophile corresponds to three or four. An example of the latter is found in the conversion of 67 to 69, a possible precursor to the phorbol esters [28]. In this instance (and with 62), the absolute configuration of the stereogenic centers marked with an asterisk were fixed early in the synthetic scheme that led to diazene 67.

392

4.5 Diradicals in Synthesis

70

Figure 5. Diazene with unsubstituted tether

Interestingly, if substituents are absent from the tether, as in 70 (Fig. 5), stereoselection is entirely eroded [29].Thus, the preference substituents express for occupying pseudoequatorial orientations substantially biases the stereochemical outcome.

4.5.2.6 Atom Transfer via TMM Diyls Unlike their non-delocalized (hard) mono- and diradical counterparts, TMM diyls are delocalized (soft) and might not, therefore, be expected to be as reactive. One might reasonably wonder, for example, whether they are sufficiently reactive to engage in hydrogen abstraction (atom transfer) in a manner that is common for many monoradicals and for apdiradicals of the benzene 1,6diyl variety [ 111. There are a great many solvents that are compatible with the existence of TMM diyls and the chemistry with which they typically engage. Cycloaddition reactions, for example, have been conducted in THF, 2-methyl-THF, toluene, benzene, acetonitrile, ethanol, methanol, ethylene glycol, n-octane, etc. In no instance have products been isolated that are indicative of hydrogen atom abstraction by the diyl. Nevertheless, these diyls do engage in atom transfer. Intramolecular transfer of a remotely positioned hydrogen atom to the exocyclic carbon of diyl72, for example, leads to a new diradical73. Subsequent formation of a C-C bond provides a novel and direct route to several bicyclic systems [30].The transformation of diazene 71 to the tricyclic adduct 74 illustrates the overall process and serves to highlight its utility as a route to natural products (Scheme 10). Key to achieving successful transfer is the choice of the radical stabilizing groups, X and Z of 75, that are positioned at the site of the atom being transferred (Fig. 6). Push-pull units that lead to a captodative radical (e.g. 71 shown in Scheme 10, and 75, X = OH, Z = C02Me, n = 1, 73-83%) work most effectively. Two electron withdrawing groups are satisfactory (75, X = Z = CN, n = 2, 53%) while two electron-donating groups are not (X = Z = OMe, n = 1). A useful rule of thumb is that transfer will occur when the C-H bond dissociation energy is less than or equal to 90 kcal/mol.

4.5.2.7 Fragmentation-Cyclization of Cyclopropyl Diyls The cyclopropylcarbinyl radical is one of the most thoroughly studied of all radicals [ 3 11. The thermally initiated rearrangement of vinylcyclopropanes has also been

4.5.2 Trimethylenemethane

L

71

393

\

72

I

toluene, reflux

(70%)

I

ar

OR

C02Me

OMe

74

73 Scheme 10. Example of atom transfer cyclization

z x

75

H

76

Figure 6. Schematic representation of atom transfer cyclization

examined in great detail. When these subunits are combined with a TMM diradical, the unique vinylcyclopropyl diyl 77 results. Its fragmentation could lead to a distonic diyl 78 that is characterized by the presence of two remotely tethered allylic radicals. Subsequent sigma bond formation can occur in two ways, one leading to the [6.3.0] ring system 79, the other to the alternative [4.3.0] adduct 80 (Scheme 11) [121. A few examples are illustrated by the chemistry of diazenes 81a,b (Scheme 12). As illustrated, the preference seems to be for the formation of [4.3.0] adducts. The simple methyl ester 83 is an exception as it leads to a slightly greater than 2:1 preference for the [6.3.0] product 84. The reasons for these observations are being explored as is the notion of how best to selectively form one or other of the structural isomers.

394

4.5 Diradicals in Synthesis

77

78 80

Scheme 11. Diyl fragmentation of cyclopropyl rings towards [6.3.0] and [4.3.0] ring systems

-

reflux (1 -2 mM) 81a, R = CHOMe 81b, R = C(C02Me)2

82a, R = CHOMe(58-62%) 82b, R = C(C02Me)2(83%)

PhH (1-2 m u ) C02Me

reflux Me02C (64%)

83

(24-26%)

84

C02Me

85

Scheme 12. Examples of cyclopropyl ring opening by TMM diyls

As indicated earlier, heterocyclic systems can be synthesized via intermolecular cycloaddition of a diyl to a carbon-heteroatom z-bond (e.g., 19 to 22 and 23 to 25). Certain intramolecular processes also lead to heterocycles. For example, diazenes 86 and 91 are smoothly converted to the bicyclic furans, 90 and 92, in 87 and 70% yield respectively (Scheme 13) [ 14b]. These reactions are formally intramolecular cycloadditions to the carbonyl 7c bond. A similar involvement of a carbonyl unit is available to the cyclopropyl aldehyde and ketone, 93a and 93b, potentially providing a route to 96. Given the ncharacter of cyclopropyl bonds, one might consider such a process as a vinylogous analog of that displayed by 86 and 91. In fact, neither of the cyclopropyl diazenes affords a heterocyclic product 96; each is efficiently converted to the corresponding [6.3.0] adduct 97a and 97b (Scheme 14) [ 121.

4.5.3 Non-TMM Diradicals

395

CDC13, 50 "C

m

R 0

0.

I

87 86 chromatography

90

88

89

THF, reflux; SiO (70%) A

L

N'

N 92

91

Scheme 13. Intramolecular diyl additions to carbon-heteroatom bonds

I -

93a, R=H 93b, R=CH3

L

L

94

95

96

97a, R = H, 79-84% 97b, R = CH3, 80-84%

R

Scheme 14. Diyl fragmentation of cyclopropyl aldehydes and ketones

4.5.3 Non-TMM Diradicals Of course, diradicals enjoy a rich and varied history in other settings as well. In the remainder of this chapter, we focus upon the chemistry of three major classes of diyls (6, 98, 99), formed from cycloaromatizations (Fig. 7). Each has attracted

396

4.5 Diradicals in Synthesis

Figure 7. Examples of non-TMM diradicals formed by cycloaromatization

widespread interest particularly in relation to their role in DNA cleavage processes [32].

4.5.3.1 Thermodynamics of Cycloaromatizations Bergman and coworkers initially studied the cyclization of enediynes more than two decades ago [5, 331. The parent compound of these systems, (Z)-hex-3-ene-1,5-diyne (100) cyclizes at elevated temperatures to afford the 1,4-didehydrobenzene diradical 6 (Fig. 8). The cyclization of enyne-allenes was first reported by Myers and coworkers in the late 1980s [34]. These reactions are energetically favorable and often proceed at ambient temperature. The parent (Z)-1,2,4-heptatrien-6-yne (101) cyclizes to afford a,3-didehydrotoluene 98 with a half-life of 30 min at 75 "C (Fig. 9). An analogous cyclization of enyne-ketenes to produce phenolic diradicals like 99 was first reported by Moore and coworkers [35] (Fig. 10). It is interesting to compare the thermochemistry for the formation of these diyls and to note, in particular, the predicted exothermicity of cyclization ( A H in figures 8-10) for both the enynylketene 102 as well as the enynylallene 101. This contrasts

t1/230 s at 200 "C

100

6

Figure 8. Cyclization of enediyne 100

t1/2 = 30 min, 75 "C AH = -1 5 kcal/mol *

101

Figure 9. Cyclization of enyne-allene 101

b. 98

4.5.3 Non-TMM Dirudicals

397

6.

-

AH = -1 2 kcal/rnol

99

102

Figure 10. Cyclization of enyne-ketene 102

markedly with the endothermicity that is associated with the Bergman cyclization of endiyne 100, and correlates well with the differing temperatures that are required to affect each of the transformations. The diyls resulting from these cycloaromatizations can be quenched with a variety of donors (e.g., 1,4-cyclohexadiene [ 1,4-CHD], CC14, CBr4) or intercepted by a radical acceptor (e.g., alkenes).

4.5.3.2 Mechanistic Studies of Bergman Cyclizations Because of the DNA-cleaving ability and antitumor properties of such naturally occurring diyl precursors as calicheamicin, there has been a great deal of study directed toward the mechanism of diyl formation [32]. The rate of diradical formation has been found to depend on many factors, including: (1) the distance between the two alkyne subunits; (2) concentration of the trapping agent; (3) substituent effects; and (4) the difference in strain energy between the enediyne and the cyclization transition state. Nicolaou and coworkers found that the reactivity of a group of cyclic enediynes 103 (n = 1-7) toward diyl formation depended greatly upon the ring size [36]. For example, they found that 103, with a ring size of 10 ( H = 1) and cd distance of 3.25 A, cyclized with a half-life of 18 h at 37"C, while the larger ring sizes (n 2 2) were stable toward cyclization at 25°C (Fig. 11). Nicolaou concluded from this study and earlier published work that the distance between the two acetylenic ends of the enediyne subunit should be roughly 3.2-3.3 A to permit a reasonable rate of cyclization. This effect of distance upon rate has recently been explored in another manner. Thus, Buchwald and coworkers showed that chelation of a diphosphine enediyne 105 with palladium or platinum salts dramatically accelerated the rate of cycliza-

103

104

Figure 11. Bergman cyclization of cyclic enediynes

398

4.5 Diradicals in Synthesis

axPPh2 KPPh2 additive

-

1,4-CHD, A

\\

105

PPh2

PPh2

106

cddistance Tmi, ("C)

additive

__

4.1

243

PdC12

3.3

61

PtCI*

3.3

81

HSC12

3.4

n. r.

Scheme 15. Bergman cyclization of diphosphines in the presence of metal salts

tion, while mercury salts retarded the reaction (Scheme 15) [37]. Using differential scanning calorimetry, the authors were able to determine the minimum temperatures required for cyclization. Magnus and coworkers have concluded that the cyclization rate of enediynes depends on the strain energy of the transition state leading to the diyl (Scheme 16) [38]. They examined bicyclic systems 107 and 108, comparing their rates of cyclization and discovered that despite similar cd distances, substrate 107 cyclizes much faster. By performing calculations on a model system 111, they concluded that the greater strain energy of product 109 retards the rate of cyclization relative to 110. This work was carried out under the assumption that the transition state is product-like. Semmelhack and coworkers found that the rate of cyclization depended markedly upon the concentration of the trapping agent employed in the reaction [39]. Using 10-membered cyclic enediyne 112, they discovered that the rate dramatically increased with increasing amounts of 1,4-~yclohexadiene(Scheme 17). This suggests

'"'a 1,4-CHD, A

0

-

109 (n = 0) 110 (n = 1)

? TBSO A 7

compound n 107 0 108 1

rcd I

(4SEmodel(kcalhol)

3.37 3.39

19.6 15.1

k, 5-1 (T, oc) 2.08 x (124) . . 1.07 x 10'4 (71)

Scheme 16. Enediyne cyclization of strained ring systems

111 (model)

4.5.3 Non-TMM Diradicals

399

1,4-CHD solvent, 84 "C 112

113

conc. of 1,4-CHD (M) 0.00 0.25 0.50 10.5

solvent C6D6 C&j C6D6 neat

f112 (h)

129 39 24 10.5

Scheme 17. Rate dependence on trapping agent concentration

I

'R 114,115

116 compound

R

R t1/2(h)

114

OH 4.5

115

H

24

Scheme 18. Substitution effect on the rate of enediyne cyclization

117

118 R T ("C) f112 (min)

71

16

TES 71

H

104

Scheme 19. Effect of silylation on rate of enediyne cyclization

that the initial cyclization may be reversible in this instance, and that radical quenching is associated with the rate determining step. Substituents can also have a large effect on cyclization rates. Work by Semmelhack and coworkers showed that substituents placed near the acetylenic ends of the enediyne structure can markedly alter the reaction rates [39b, 401. For example, inclusion of a hydroxyl group at the propargylic position markedly increases the rate of cyclization for 114 relative to the unsubstituted system 115 (Scheme 18). Recent work by Nantz and coworkers found that silylation of alcohol 117 significantly prolongs the reaction time needed for cyclization (Scheme 19) [41].

400

4.5 Diradicals in Synthesis

4.5.3.3 Bergman Cyclizations in Organic Synthesis Despite the many reports of the DNA-cleaving ability of enediynes and related species, there has not been nearly as much exploration of the utility of these diradicals in organic synthesis. The diradicals that are formed as a result of Bergman cyclizations can be quenched or allowed to react with a radical acceptor in either an intra- or intermolecular fashion [42]. For example, Grissom and coworkers found that diradicals 120a-c formed from the cyclization of 119a-c can be intercepted by an internal olefin radical acceptor to afford dihydrobenzindene derivatives 121a-c in good to high yields (Scheme 20) [43]. Margoritis and Kim have used a tandem Ireland/Claisen rearrangement followed by Bergman cyclization to access highly functionalized tetrahydronaphthalene products 124 and 125 (Scheme 21) [44]. Another example from Grissom has both radicals formed from enediyne 126 tethered to two olefinic radical acceptors (Scheme 22). The resulting tricyclic product, 127, was isolated as a 1:l mixture of diastereomers in excellent yield [45].

1,4-CHD

120a-c

121a-c

119a, R’ = H, CH20H, CH20TBS 119b, R2 = H, CH3, C02Me, CH20H, CH20TBS 1 1 9 ~R3 , = H, CH3

Scheme 20. Intramolecular diyl interception with a tethered alkene

I

122

OTlPS

123

124,125

124, R = H, ratio of C-2 epimers 3:1, 50% yield 125, R = SPh, ratio of C-1 epimers 7 : 1, 45% yield

Scheme 21. Bergman cyclization toward functionalized tetrahydronaphthalene products

4.5.3 Non- T M M Diradicals

H

Me02C%

1,4-CHD PhCI, 230 "C

Meo23

-

(98'70)

Me02C

/

Me02C

126

H

127 ( 1:1 mixture of diastereomers)

Scheme 22. Tandem diyl interception by two tethered olefins

major path

/

\\

129

40 1

H

/

hydrogen abstraction

130

@O

.

minor path 132 Scheme 23. Myers cyclizaton toward naphthalenic ring systems

133

402

4.5 Diradicals in Synthesis

4.5.3.5 Moore Cyclizations in Organic Synthesis 4-Alkynylcyclobutenones can also serve as diradical precursors [ 35c,d]. Those of general structure 135, for example, undergo conrotatory electrocyclic ring opening when heated; the OG group rotates outward to afford the enynylketene 136. These materials cyclize rapidly to afford either the six- and/or the five-membered ring diyl, 139 and 137, respectively (Scheme 24). Formation of the latter is competitive when the substituent appended to the terminal carbon of the alkyne is radical stabilizing. Migration of the G-group completes the process, one culminating in the production 1,3-dione 138. of either a benzoquinone 140 or the 2-alkylidenecyclopentene-

"Toz B

OG 135

G*A B

A*z B

OG

0

137

OG

138

0'

136

fast

0

OG 139

140

Scheme 24. Moore cyclization of enyne-ketenes

A substantial amount of fundamental investigation has served to place this chemistry on a firm footing, sufficiently so that it can be applied to the synthesis of natural products. Its role in the synthesis of terreic acid (143)is portrayed in Scheme 25 [47].

t-BuO

OH

reflux

t-BuO

(2) TFA

0 141

142

Scheme 25. Synthesis of terreic acid via Moore cyclization

HO

0 terreic acid (143)

4.5.3 Non-TMM Diradicals

403

BuLi/lHF

OH Me0 144

145

146

147

Scheme 26. Synthesis of dihydrobenzophenanthridine-9,12-dioIsvia Moore cyclization

This type of cyclization has also seen extensive use toward quickly accessing complex multi-ring systems. In recent work by Moore, alkyne 144 was lithiated and added to dimethyl squarate (145). The resulting cyclobutenone 146 was refiuxed at 132 "C in chlorobenzene to produce benzophenanthridine derivative 147 in a good yields (Scheme 26) [48]. In another example from Moore, cyclobutenone 148, rearranges to give enyneketene 149, The resulting diradical was intercepted by a tethered alkyne, which in turn led to spirocycle 153 (Scheme 27) [49].

-

OMe

Me0 OMe R'

R' 149

148

150

I

153

152

Scheme 27. Synthesis of spirocyclic oxiranes via Moore cyclization

151

404

4.5 Diradicals in Synthesis

4.5.3.6 Diradicals Resulting From Other Cyclizations A novel radical cyclization of ketimine-enynes has recently been reported by Wang and coworkers [50].The diradical intermediates were synthesized en route to quinolines 156, 157 and benzocarbazoles 160-163 (Scheme 28).

Ph

Ph

155

156, R = H, 66% 157, R = Pr, 58%

154

1 R 4

Ph

Ph

159

158

160, R = f-Bu, 98% 161, R = SiMe3, 89% 162, R = Ph, 91% 163, R = Pr, 33%

Scheme 28. Enyne-ketenimine cyclizations toward quinolines and benzcarbazoles

Schmittel and coworkers have recently discovered that enyne-allenes can also produce substituted fulvenes when the alkyne terminus is substituted with bulky groups such as phenyl, tert-butyl and trimethylsilyl [ 5 11. For example, enyne-allene 164 when heated in the presence of 1,4-CHD afforded benzofulvene 166 in good yields (Scheme 29).

1,4CHD

*

toluene 80 "C (60 Yo)

164

165

Scheme 29. Fulvenes from Schmittel cyclization of enyne-allenes

166

References

405

4.5.4 Conclusion We hope to have given the reader a sense of the breadth and scope of diradical chemistry and a feel for the role it plays in organic synthesis. We also hope to have piqued the interest of those who have not made use of these fascinating intermediates so that they might consider using them to meet their own challenges.

References [ I ] W. T. Borden in Diradicals. (Ed. W. T. Borden), Wiley, New York, 1982, p. 1. 121 L. Salem and C . Rowland, Angew. Chem., Int. Ed. Engl. 1972, 11, 92-1 1 1 . (31 V. Von Auken, K. L. Rinehart, J. Am. Chem. Soc. 1962,84, 3736-3743. [4] a) P. Dowd, J. Am. Chem. Soc. 1970, 92, 1066-1068. b) N. Turro, Modern Molecular Photochemistry, 1st ed., Benjamin/Cummings, Menlo Park, 1978, Chapter 13. [ 5 ] R. G. Bergman, Acc. Chem. Rex 1973, 6 , 25- 31. [6] a) P. Dowd, Acc. Chem. Res. 1972, 5, 242-248. b) F. Weiss, Q. Rev. Chem. Soc. 1970,24, 278309. c) H. C . Longuet-Higgins, J. Chem. Phys. 1950, 18, 265-274. d) W. Moffitt, Trans. Faraduy Soc. 1949, 45, 373-385. e) P. Dowd, J. A m . Chem. Soc. 1966, 88, 2587-2590. f ) R. J. Baseman, D. W. Pratt, M. Chow, P. Dowd, J. Am. Chem. Soc. 1976, 98, 5726-5727. g) J. A. Berson, R. J. Bushby, J. M. McBride, M. Tremelling, J. Am. Chem. Soc. 1971, 93, 1544-1546. [7] B. M. Trost, Angeiv. Chem., Int. Ed. Engl. 1986, 25, 1-20. [8] D. M. T. Chan, in Comprehensive Organic Synthesis, (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991; Vol. 5 , Chapter 3.2. [9] J. A. Berson, M. S. Platz, J. Am. Chem. Soc. 1976, 98, 6743-6744. [ l o ] (a) J. A. Berson in Dirudicals, (Ed.: W. T. Borden), Wiley, New York, 1982; Chapter 4. (b) C . F. Billera, R. D. Little, Tetrahedron Lett. 1988, 29, 571 1-5714. (c) A. Allan, G. L. Carroll, R. D. Little, Eur. J. Org. Chem. 1998, 1, 1-12. [ 1 I ] C. F. Billera, R. D. Little, J. Am. Chem. Soc. 1994, 116, 5487-5488. [ 121 G. L. Carroll. R. D. Little, Tetrahedron Lett. 1998, 39, 1893-1 896. [I31 R. D. Little, L. M. Brown, M. R. Masjedizadeh, J. Am. Chem. Soc. 1992, 114, 3071-3075. [I41 a) R. D. Little, H. Bode, K. J. Stone, 0. Wallquist, R. Dannecker, J. Org. Chem. 1985, 50, 2400-2401. b) R. D. Little, K. D. Moeller, Tetrahedron Lett. 1985, 26, 3417-3420. [I51 R. D. Little, X. D. Lin, Tetrahedron Lett. 1997, 38, 15-18. (161 R. D. Little, J. A. Leonetti, T. Gross, J. Ory. Chem. 1996, 61, 1787-1793. [ 171 R. D. Little, L. Lisonski-Dang, M. G. Venegas, C. Medic, Tetrahidron Lett. 1983, 24, 44994502. [ 181 R. D. Little, M. R. Masjedizadeh, I. Dannecker-Doerig, J. Org. Chem. 1990, 55, 2742-2752. [I91 a) R. D. Little, T. M. Bregant, J. Groppe, J. Am. Cliem. Soc. 1994, 116, 3635-3636. b) H. P. Spielman, P. A. Fagan, T. M. Bregant, R. D. Little, D. E. Wemmer, Nucl. Acids Res. 1995,23, 1576- 1583. [20] R. D. Little, M. R. Masjedizadeh, K. D. Moeller, I. Dannecker-Doerig, Synlett 1992, 107-113. (211 a) R. D. Little, G. W. Muller, J. Am. Client Soc. 1979, 101, 7129-7130. b) R. D. Little, G. W. Muller, M. G. Venegas, G. L. Carroll, A. Bukhari, L. Patton, K. Stone, Tetrahedron 1981, 37, 4371-4383. [22] R. D. Little, R. G. Higby, K. D. Moeller, J. Ory. Clzem. 1983, 48, 3139-3140. [23] R. D. Little, L. Van Hijfte, .I. Org. Chem. 1985, 50, 3940-3942. 1241 R. D. Little, L. Van Hijfte, J. L. Petersen, K. D. Moeller, J. Org. Chem. 1987, 52, 4647-4661. [25] R. D. Little, M. M. Ott, J. Org. Clzem. 1997, 62, 1610-1616. (261 R. D. Little, V. V. Villalon, unpublished result.

406

4.5 Diradicals in Synthesis

[27] a) R. D. Little, K. J. Stone, J. Am. Chem. Soc. 1983, 105, 6976-6978. b) R. D. Little, K. J. Stone, J. Am. Chem Soc. 1985, 50, 3940-3942. [28] R. D. Little, J. I. McLoughlin, R. Brahma, 0. Campopiano, Tetrahedron Lett. 1990, 31, 13771380. [29] R. D. Little, 0. Campopiano, J. L. Petersen, J. Am. Chem. Soc. 1985, 107, 3721-3722. [30] a) A. Allan, PhD thesis, University of California - Santa Barbara (USA), 1999. b) G. L. Carroll, PhD thesis, University of California - Santa Barbara (USA), 2000. c) M. Schwaebe, PhD thesis, University of California - Santa Barbara (USA), 1996. [31] M. Newcomb, Tetrahedron 1993, 49, 1151-1176. [32] a) K. C. Nicolaou, W.-M. Dau, Angew. Chem., Znt. Ed. Engl. 1991, 30, 138771416, see also: b) M. E. Maier, Synlett 1995, 13-26. c) C. A. Townsend, J. J. DeVoss, J. J. Hangeland, J. Am. Chem. Soc. 1990, 112, 4554-4556. c) M. Chatterjee, K. D. Cramer, C. A. Townsend, J. Am. Chem. Soc. 1994, 116, 8819-8820. [33] a) R. G. Bergman, R. R. Jones, J. Am. Chem. Soc. 1972,94,660-661 b) R. G. Bergman, C. B. Mallon, T. P. Lockhart, J. Am. Chem. Soc. 1980, 102, 5976-5978. c) T. P Lockhart, P. B. Comita, R. G. Bergman, J. Am. Chem. Soc. 1981, 103, 4082-4090. d) T. P. Lockhart, R. G. Bergman, J. Am. Chem. Soc. 1981, 103, 4091-4096. [34] a) A. G. Myers, P. J. Proteau, J. Am. Chem. Soc. 1989,111, 1146-1 147. b) A. G. Myers, E. Y. Kuo, N. S. Finney, J. Am. Chem. Soc. 1989,111, 8057-8059. c) A. G. Myers, P. S. Dragovich, J. Am. Chem. Soc. 1989, 111, 9130-9132. d) A. G. Myers, N. S. Finney, J. Am. Chem. Soc. 1992, 114, 10986-10987. [35] a) H. W. Moore, L. D. Foland, J. 0. Karllson, S. T. Perri, R. Schwabe, S. L. Xu, S. Patil, J. Am. Chem. Soc. 1989, 111,975-989. see also: b) I. Saito, S. Maekawa, S. Isoe, K. Kakatani, Tetrahedron Lett. 1994, 35, 605-608. For reviews see: c) H. W. Moore, B. R. Yerxa, Chemtracts 1992,273. d) H. W. Moore, B. R. Yerxa, Advances in Strain in Organic Chemistry, Vol4. (Ed.; B. Halton), JAI, Greenwich, 1995, pp 81-162. [36] K. C. Nicolaou, G. Zuccarello, Y. Ogawa, E. J. Schweiger, T. Kumazawa, J. Am. Chem. Soc. 1988, 110, 4866-4868. [37] a) S. L. Buchwald, B. P. Warner, S. P. Millar, R. D. Broene, Science 1995, 269, 814-816. See also: b) J. M. Zaleski, N. L. Coalter, T. E. Concolino, W. E. Streib, C. G. Hughes, A. L. Rheingold, J. Am. Chem. Soc. 2000, 122, 3112-3117. [38] P. Magnus, P. Carter, J. Elliott, R. Lewis, J. Harling, T. Pitterna, W. E. Bauta, S. Fortt, J. Am. Chem. Soc. 1992,114,2544-2559. [39] a) M. F. Semmelhack, T. Neu, F. Foubelo, Tetrahedron Lett. 1992, 33, 3277-3280. b) M. F. Semmelhack, T. Neu, F. Foubello, J. Org. Chem. 1994, 59, 5038-5047. [40] See also: D. L. Boger, J. Zhou, J. Org. Chem. 1993, 53, 3018-3024. [41] M. H. Nantz, J. D. Spence, D. K. Moss, J. Org. Chem. 1999,64,4339-4343. [42] For two excellent reviews, see: a) J. W. Grissom, G. U. Gunawardene, D. Klingberg, D. Huang, Tetrahedron 1996,52, 6453-6518. b) K. K. Wang, Chem. Rev. 1996, 96, 207-222. [43] a) J. W. Grissom, T. L. Calkins, Tetrahedrom Lett. 1992, 33, 2315-2318. b) J. W. Grissom, T. L. Calkins, M. Egan, J. Am. Chem. Soc. 1993, 115, 11744-11752. [44] P. A. Magriotis, K. D. Kim, J. Am. Chem. Soc. 1993, 115, 2972-2973. [45] a) J. W. Grissom, T. L. Calkins, H. A. McMillen, Y. Jiang, J. Org. Chem. 1994, 59, 58335835. (b) J. W. Grissom, D. Klingberg, D. Huang, B. J. Slattery, J. Org. Chem. 1997,62,603-626. [46] J. W. Grissom, D. Huang, J. Org. Chem. 1994,59, 5114-5116. [47] H. W. Moore, A. Enhsen, K. Karabeles, J. M. Heerding, J. Org. Chem. 1990, 55, 1177-1185. [48] a) H. W. Moore, A. R. Hergueta, J. Org. Chem. 1999, 64, 5979-5983. b) H. W. Moore, Y. Xiong, J. Org. Chem. 1996, 61, 9168-9177. [49] a) H. W. Moore, M. Taing, S. L. Xu, J. Org. Chem. 1991, 56, 6104-6109. See also: b) H. W. Moore, H. Xia, Y . Xiong, J. Org. Chem. 1995, 60, 6460-6467. [SO] a) K. K. Wang, C. Shi, J. Org. Chem. 1998,63, 3517-3520. b) K. K. Wang, C. Shi, Q. Zhang, J. Org. Chem. 1998,64, 925-932. [51] a) M. Schmittel, M. Strittmatter, Tetrahedron 1998, 54, 13751-13760; For other examples, see: b) M. Schmittel, M. Strittmatter, S. Kiau, Tetrahedron Lett. 1995, 36, 4975-4978. c) M. Schmittel, M. Strittmatter, S. Kiau, Angew. Chem., Znt. Ed. Engl. 1996, 35, 1843-1845. d) M. Schmittel, M. Strittmatter, K. Vollman, S. Kiau, Tetrahedron Lett. 1996; 37, 999-1002.

Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi

copyright OWILEY-VCH Verlag GmbH, 2001

5 Heteroatom-Centered Radicals 5.1 Nitrogen-Centered Radicals Lucien Stella

5.1.1 Introduction A wide variety of useful organic transformations involve N-centered radicals. Two of the most characteristic inter- and intramolecular reactions of N-centered radicals are selective hydrogen abstraction and amination of unsaturated substrates (olefinic or aromatic). Hydrogen abstraction is a reaction in which an alkane C-H (T bond is cleaved. The resulting C-centered radical generally combines with a halogen atom donor, in a chain mechanism, to form a carbon-halogen bond. Aminations of olefinic or aromatic substrates are reactions in which N-centered radicals add to the system of a carbon-carbon double bond to form a carbon-nitrogen bond and a Ccentered radical, which is generally removed by atom or group transfer reaction in a chain mechanism. Both these types of intramolecular reaction are particularly useful for heterocyclic synthesis. A comprehensive review of N-centered radical reactions appeared in 1973 [ 11, and the aminium radical chemistry has also been thoroughly reviewed in 1980 [2]. Other reviews, some dealing with specific sub-areas, have been published throughout the last thirty years [3-131. It is the aim of this report to survey the more important developments in the area of synthetic applications and to summarize how a practicing organic chemist can expand the classical repertoire of synthetic methods by using N-centered radical reactions. No attempt has been made to present an exhaustive review of the literature, but, rather, a few specific examples without excessive details are discussed to demonstrate the key features.

5.1.2 Basic Principles Aminyl radicals are less reactive than carbon radicals, which in turn are less reactive than alkoxy radicals. For dialkylaminyl radicals, the reduction rate constant with tributyltin hydride ( k %~5 x lo5 M-' s-' ) [I41is about ten times lower than for primary alkyl radicals [15] and a thousand times lower than for alkoxy radicals [ 161.

408

5.1 Nitrogen-Centered Radicals

This reactivity pattern follows the X-H bond dissociation energies. Even though nitrogen is more electronegative than carbon, it forms weaker bonds to hydrogen. Similarly, for dialkylaminyl radical, the addition rate constants of 5-exo-trig cyclization is lower (k, z lo4 s-l) [17] than for primary alkyl (k, = lo6 sC1)[18] and for alkoxy radicals (k, z 5 x lo* sC1)[ 191, and this reactivity pattern follows the X-C bond dissociation energies. The carbon-nitrogen single bond is weaker than the corresponding carbon-carbon bond. This is because electronic repulsion between bonded electron pairs and lone pairs is greater than repulsion between bonded electron pairs and other bonded electron pairs. Thus, the types of reactions favored by amino radicals depend to a significant degree upon the extent with which the lone electron pair is associated with a proton, with a Lewis acid, or with an electron-withdrawing group. Clearly, aminium radical cations 2 (Scheme l), metal-complexed aminyl radicals 3, amidyl radicals 4, sulfonamidyl radicals 5 and cyanamidyl radicals 6 are electrophilic in nature. On the other hand, dialkylaminyl radicals 1 have been shown to display nucleophilic character [ 141. In any case, greater synthetic utility has been observed by increasing the electrophilic character of N-centered radicals. The precise control of reaction conditions (particularly the presence of Br~nstedor Lewis acids) and the nature of the substituent on the nitrogen atom are thus very important in determining which type of intermediate is generated and consequently which efficiency and which selectivity should be expected. Aminyl free radicals 1 are unique in that the central nitrogen atom possesses both an unpaired electron and a lone pair of electrons. The available evidence is in support of a 71 electronic ground state for a variety of alkylaminyl, arylaminyl, acylaminyl and aminium radicals [9]. The greater acidity of the dimethylaminium cation radical of type 2 (pK, z 7.0), compared to dimethylammonium ion Me2NH2+ (pK, z 10.7) is a result of a greater amount of s character in the sp2 lone pair orbital of the aminyl radical compared to the more basic sp3 lone pair orbital of the amine. The pK, of the conjugate acid of phenylaminyl radical is also 7.0. Yet, the methaniminyl radical 7 has its unpaired electron in a 2p orbital on nitrogen with both p hydrogens equivalent [20]. Iminyl radicals are in fact just slightly less reactive than alkyl radicals [5]. There is another point which deserves consideration in the context of synthetic efficiency: The reaction of an N-centered radical species with another organic molecule (saturated or unsaturated) always produces another free radical, primarily a C-centered radical, which will undergo further reactions. In order to make a reaction preparatively useful, this sequence of events has to be interrupted by trapping a

5.1.3 Reactions with Saturated Aliphatic Compounds

409

newly produced free-radical center in an appropriate way. The necessity for the presence of radical-trapping agents dictates the choice of the reaction conditions used in the formation of the starting species. Nearly all radicals formed by addition or fragmentation reactions will be removed from the radical pool to give non-radical products by redox or atom transfer reactions.

5.1.3 Reactions with Saturated Aliphatic Compounds 5.1.3.1 Intramolecular Reactions 5.1.3.1.1 Protonated N-Centered Radicals The oldest synthetic reaction which involves N-centered radical intermediates is the so-called Hofmann-Loffler reaction [211. When N-haloalkylamines 8 are heated or photolyzed in strongly acidic solution, pyrrolidines 12 are isolated upon basic workup (Scheme 2). Ferrous salts can also promote the reaction [22]. This reaction is a simple and useful synthetic procedure accepted to be a chain reaction involving intramolecular 1$hydrogen abstraction by aminium radicals 9. The synthetic importance of the reaction lies in the fact that the substitution, which is brought about at the 6 carbon atom, may be very difficult to obtain by other chemical methods. This selective attack is due to the necessity for a six-membered cyclic transition state. Only in exceptional cases can a seven-atom cyclic transition state be induced by various electronic as well as conformational driving forces [23]. Cyclic as well as aliphatic N-chloroamines undergo the reaction. Intramolecular Habstraction by aminium radical centers exhibit the preferential order of abstraction 3" > 2" > 1" hydrogens if the steric and electronic effects for competing processes are not too different. Thus, for example, the N-chloroamine 8 when R = Me and R' = nBu yields N-butyl-2-methylpyrrolidine 12 exclusively, without a trace of the alternative pyrrolidine [22]. It is noteworthy that, under irradiation, allylic chlorination does not occur appreciably in the cyclization of N-chloro-20cc-methylamino-4pregnen-3-one 13, the corresponding conanine derivative 14 being the only isolated product (Scheme 3 ) . Although pyrrolidines could formally be produced by attack at three other positions, steric constraints in the steroid system only allow abstraction from the methyl group at position 18.

Scheme 2. The radical chain mechanism of the Hofmann-Loffler reaction

5. I Nitrogen-Centered Radicals

4 10

1) TFA, hv (87%) t

2) KOH, MeOH (76%)

0

66% 13

14

Scheme 3. Synthesis of conanine derivative by the Hofmann-Loeffler reaction [24]

The scope of the reaction has been reviewed 1211. Its success requires a high degree of protonation of the N-chlorodialkylamine (pKa z 0.4) in the reaction mixture. Trifluoroacetic acid or 4 N sulfuric in acetic acid were employed as solvents. 5.1.3.1.2 Unprotonated N-Centered Radicals

Photolysis of N-iodoamides 15 ( X = I) gives y-lactones via iminolactone intermediates 17 [25] (Scheme 4). N-Bromocarboxamides 15 ( X = Br) can be rearranged in inert solvents to 4-bromocarboxamides 16 under weak UV irradiation. Brief heating of the crude product 16 effects their cyclization to 2-iminotetrahydrofuran hydrobromide 17. This simple, two-step method is a convenient entry to the 4substituted y-lactones 18 which hydrolysis of 17 affords. N-Chlorocarboxamide 15 ( X = C1) can also be photolytically rearranged, but the resulting 4-chloroamides are far less readily cyclized than the bromo analogs. N-acyl-N-chlorocarboxamides (N-chlorimides, 15 with R = Ac) have also been rearranged and the products are hydrolyzed in 10Y0 sulfuric acid to lactones. Closely related to the N-haloamide reactions are those of the N-nitrosocarboxamides (15 with X = NO), whose photolysis in a hydrocarbon solvent selectively places the oxime group at the C-4 of N-alkyl groups (R in 15) in moderate yield (-40%), but fails to yield oximes by nitrosation of long-chain N-acyl groups. Photolysis of 8,12-epoxylabdanyl cyanamide 19 in the presence of iodine and diacetoxyiodobenzene (DIB) leads to neutral cyanamidyl radical, which undergoes intramolecular hydrogen abstraction to produce N-cyano- 12,15-epimino compound 20 in 91% yield (Scheme 5). From N-tert-butyl-N-haloalkane-sulfonamides 21, products halogenated on the third carbon atom from the sulfonyl group 22 are

..

15

R=t-Bu R=t-Bu

16

R'=Me R'=Me

X=Br X=CI

17 71Yo

69'/o

Scheme 4. Synthesis of 4-substituted y-lactones by photolysis of N-haloamides [ 131

18

5.1.3 Reactions with Saturated Aliphatic Compounds

qpN 12 1

NH

c-C6H12 hv, 12, DIB

* 40 rnin, 20 "C

41 1

@ 91Yo

19

20

Scheme 5. Intramolecular functionalization of N-cyanamidyl radical [26]

x,

50%

Nt-Bu

f"A0,

YHt-Bu

hv, 25 "C, N2

solvent

21

xTsoz t-Bu

22

x = CI

C6H6

X = Br

CCll

79% 60%

60%

24

Scheme 6. Synthesis of cyclopropanes or 7-sultams from N-halosulfonamides [ 131

R

f )

Na2S208I CuCI,

HY

HzO, 90 "C, 5h

S0,Me

25

(-H+)

94% 39% conversion

Scheme 7. Oxidative rearrangement of N-alkylmethane-sulfonamide 1271

afforded. Of particular interest is the conversion of 22 to cyclic compounds on treatment with bases: either a cyclopropane 23 or a sultam 24 can be obtained depending upon the deprotonation conditions (Scheme 6). These photolytic reactions undoubtedly proceed via a radical chain analogous to that shown in Scheme 2 for N-chloroamines, except, of course, that the radical species are unprotonated. A similar mechanism is also involved in cyclization of Nalkylmethane sulfonamides 25 by oxidation with NazS2O8 in the presence of cupric ions (Scheme 7). In contrast, aminyl radicals complexed to metal ions, such as neutral aminyl radicals, do not undergo Hofmann-Loffler reaction. The Hofmann-Loffler reaction is unable to compete with intramolecular aromatic amination, with intramolecular addition to olefins, and with intermolecular addition to dienes [7].

412

5.I Nitrogencentered Radicals

Table 1. Selective monohalogenation of saturated aliphatic compounds using N-haloamines Reagent

Product distribution (YO)

i-PrzN-Cl

CH3-CH2-CH2-CH2-CH3

Me2N-CI

CH3-CH2-CH2-CH2-CI

74

4

5

22

89

6

0

i-PrzN-CI

CH3-CH2-CH2-CH2-CH2-CH2-OH

i-PrzN-CI

CH3-CH2-CH2-CH2-CH2-CH2-O-CH3

6

9

8

0

9

2

2

2

0

0

0

0

0

0

CH3-CH2-CH2-CH2-CH2-CH2-O-CO-CH3

i-PrZN-CI

4

x

5

1

0

1

0

0

CH3-CH2-CH2-CH2-CH2-CO-O-CH3

i-PrlN-Cl

7

9

0

3

0

0

Experimental conditions: Iron (11) sulfate heptahydrate, conc. sulfuric acid, 15 min [ 121.

5.1.3.2 Intermolecular Reactions In the absence of a 6 hydrogen in the side-chain, the aminium cation radical may undergo intermolecular H abstraction if there is suitable substrate. The halogenation reaction of alkyl derivatives by N-haloamines under strongly acidic conditions is a radical-chain process which was originally studied by Minisci and later by Ingold and Den0 [12]. Generally the reaction is carried out by photolytic or metal-ioncatalyzed decompositions of N-haloamines in sulfuric or trifluoroacetic acids in the presence of the substrate. Selected examples of such oxidations of straight-chain aliphatic compounds are listed in Table 1. The remarkable monohalogenation and w-1 selectivities in these reactions have been attributed to polar, steric, and conformational effects. The yields of monohalogenated derivatives, based on converted (60-80%) substrate, are generally quantitative. Comparison of these selectivities with a number of oxidations using bromine, chlorine or tert-butoxy radical chain carriers shows that aminium radical-mediated oxidation is far superior to others for synthetic, indeed industrial, applications [28]. The high selectivity and clean monooxidation displayed by the aminium radical chain process has been referred as an 'enzyme-mimetic reaction' [29]. An alternative cyclization pathway in azacyclic synthesis is provided by the (w- 1) chlorination of hexylamine derivatives: the efficient syntheses of 2-methyl piperidines 26 are significant complements to Hofmann-Loffler cyclization of N chlorohexylamines in which 2-ethylpyrrolidines were obtained (Scheme 8). Neutral

CH3(CHz),NHR

+

MezNCI

1) H2S04, FeS04 5-36 "C, 15 min * 2) HO-, HZO

QCHs

70-80% 26

Scheme 8. Synthesis of 2-methyl piperidines by selective chlorination of hexylamines [30]

5.1.5 Reactions with Olefins

413

or metal-complexed aminyl radicals are not useful hydrogen-abstracting agents, since they seem to abstract only activated hydrogens intermolecularly, e.g. from benzyl or ally1 groups, and from thiols, tributyltin hydride and various solvents [7].

5.1.4 Reactions with Aromatic Compounds 5.1.4.1 Intermolecular Reactions N-Chloroamines, hydroxylamine and hydroxylamine-O-sulfonic acid have been used for direct homolytic aromatic aminations, but only N-chloroamines are useful from the synthetic point of view. The reaction is carried out in strongly acidic medium. An aminium cation radical is generated by a redox reaction using iron(I1) sulfate. The use of a redox system has particular advantages with respect to the thermal, photochemical, or AlC13-catalyzed reactions; it permits the reaction to be carried out in a short time, with complete or partial elimination of electrophilic chlorination reactions with activated substrates. Benzene is not subject to electrophilic chlorination under the conditions employed (conc. sulfuric acid or mixture of sulfuric and acetic acids, room temperature, within 5 to 10 min). In this case, the amination yields reach 80% with N-chlorodimethylamine and decrease with increasing bulk of alkyl groups. With benzene derivatives having activating substituents with ortho,paru-orientation, principally the amino and hydroxy groups, the main difficulties are competitive chlorination and sulfonation. These latter can be limited by working with a high concentration of reducing metal salts and a low concentration of N-chloroamine, which is slowly added to the reaction mixture. The reaction of phenol with N-chloropiperidine results in 87% yield of amination products; the para isomer is always present in larger amounts (91%). The most representative results are given in Table 2.

5.1.4.2 Intramolecular Reactions Homolytic intramolecular amination allows the synthesis of tetrahydroquinoline 28 from the 3-phenyl-propylamine 27 (n = 2). The yield of indoline 30 is lower because the aminium cation radical 29 generated from N-chloro-2-phenethylamine27 (n = 1 ) undergoes an easy p-scission reaction to form the benzyl radical (Scheme 9).

5.1.5 Reactions with Olefins 5.1.5.1 Intermolecular Reactions The sluggishness of the addition of neutral dialkylaminyl radicals to olefins, as well as their strong tendency towards non-selective abstraction of hydrogen, seemed to

414

5.1 Nitrogen-Centered Radicals

Table 2. Homolytic amination of aromatic compounds with protonated N-chloroamines N-Chloroamine

Isomers Yn

Yield %,

/L=5N-c’

o-amino ( 9 ) p-amino (91)

87

EN-CI

o-amino ( 9 ) p-amino (91)

65

c=sN-c’

p-amino

98

Me2N-CI

5-amino

89

Qlp

Me2N-CI

5-amino

86

Br I

MeZN-CI

5-amino (92)

97

Me2 N-CI

4-amino (92)

74

Me2N-CI

2-amino

98

4’-amino

86

Me2N-CI

4’-amino

90

MezN-Cl

3-amino (5) 4-amino (95)

96

Aromatic substrate

OCH,

H

qp 0

Experimental conditions: Iron (11) sulfate heptahydrate, sulfuric acid/water, 15-60 min [ 121.

rule out reactions that could be of preparative value. Generally, they dimerize to hydrazines and disproportionate to Schiff bases and amines [7]. In contrast, the protonated radicals add efficiently to many types of unsaturated hydrocarbons in preference to abstracting allylic or benzylic hydrogen atoms. The aminium radical

5.1.5 Reactions with Ole$ns P

H

d

n

FeSO4-H2SO4

n=2

CI/”R 27

415

a

81%

28 R

Scheme 9. Synthesis of tetrahydroquinoline and indoline [31]

addition proceeds via a radical-chain sequence, in acidic media, at 30°C or lower temperature and usually in less than 1 h. The reaction of N-chloroamines results in synthetically meaningful yields of 1: 1 adducts with conjugated olefins and with moderately deactivated olefins (Table 3). However, with allenes, acetylenes, simple alkenes, and a fortiori with electron-rich alkenes, electrophilic chlorination competes effectively, therefore reducing the yield of radical adducts. Olefins conjugated with electron-withdrawing groups (CN, COR, CO2R . . .) do not react owing to the strong electrophilic character of aminium cation radical. More extensive work with aminyl radicals produced from redox reactions of N chloroamines with metal ions has been reported for the amination of olefins in aqueous methanol [lo]. The use of a mild and functionally tolerant non-acidic medium in many cases prevents electrophilic chlorination of the double bond. The complexation of aminyl radicals induces a reactivity for addition similar to that of protonated species. Moreover, the C-Cl bond formation results from a rapid transfer of a chlorine atom bonded to the metal (‘ligand transfer’) in a redox chain process where the chain carrier is the metallic salt. A significant difference in stereochemistry occurs in the addition of protonated and complexed aminyl radicals to cyclohexene. Thus, addition of N-chloropiperidine in acidic media gives a mixture of cis and trans products, whereas in non-acidic solvents mainly the cis isomer (80%) is obtained. This stereoselectivity was explained by coordination of the unprotonated radical by the metal salt, which of course is not expected with the protonated species [ lo]. The mild reaction conditions used to produce aminium cation radical from N-hydroxypyridine-2-thione carbamate precursors are compatible with many reagents. Additions to acid-sensitive enol ethers give p-amino ethers in good yield. When ally1 group is present on nitrogen, a cyclization reaction follows the addition, and pyrrolidines are formed (Scheme 10).

5.1 S.2 Intramolecular Reactions The applications of nitrogen radical cyclization to heterocyclic synthesis have received the most attention. Two excellent review articles have documented this topic and compiled the numerous target molecules that have been synthesized [4, 61. We have selected some representative examples to describe the prominent features and

416

5.1 Nitrogen-Centered Radicals

Table 3. Homolytic amination of olefinic compounds with protonated N-chloroamines Olefinic substrate

N-Chloroamine

Initiator

12-Bu2N-Cl

none

42

EtZN-Cl

none

22

n-Bu2N-CI

hv

15

Yield (%)

Time (min) Adduct

60

n-Bu2N

c-1

68

CI

44

n-Bu,N&

EtzN-CI

none

YO

45

EtlN-Cl

hv

48

82

hv

12

92

hv

240

88

hv

270

71

Lz7N-c1

c=s/N-c'

mN-cl

mNJBr

EtzN-Cl

hv

20

65

Et2N-CI

hv

35

83

mN-cl

hv

12

EtZN-CI

50

hv

CI

88

G-/S&OEt

EtzN-CN

Experimental conditions: 4M sulfuric acid in acetic acid, at 30°C, under nitrogen [13].

84

5.1.5 Reactions with Olefins

417

Scheme 10. Addition-cyclization reaction of aminium cation radical to enol ether [32]

k5, = 5.0 * 1

kj, = 1.7 0.2

o4 s-l

n-Bu.

lo4 s-'

31

32

Scheme 11. Kinetic data of the 5-exo cyclization of 31 and the reverse reaction

to open the future prospects. Neutral aminyl radicals such as 31 cyclize slowly [ 171, and reopening of the carbon radical 32 has a similar rate constant. Depending on the experimental conditions, hydrogen transfer to radical 31 can compete with its cyclization [33, 341, and, similarly, rapid atom transfer [35] or intramolecular addition reaction [36] involving the radical 32 can prevent its reopening (Scheme 11). Increasing the electrophilicity at nitrogen accelerates ring closure and thereby shifts the equilibrium toward the cyclized radical. This can be done either by protonation (which increases the rate of cyclization of 31 to 4 x lo7 sS1 at 2.5") [37], by complexation to a metal center (for example, MgBrz increases the rate of cyclization 6.2-fold) [37], or by electron-withdrawing substitution, as for N-butyl-4-pentenamidyl radicals (2 x lo9 sS1 at 20°C) [38] or aminyl radicals derived from a-amino esters [39]. 5.1.5.2.1 From N-Chloro-Compounds The N-chloro-compounds were the first to be employed as radical cyclization precursors in the synthesis of pyrrolidines and piperidines, as well as fused and bridged heterocyclic skeletons [7].Aminyl and amidyl radicals were thus generated and used in intramolecular additions. Higher yields and selectivities are obtained with the metal-complexed species. Some selected examples are reported in Table 4. Generally, a typical radical chain mechanism is involved (with chlorine atom transfer from N-chloro-compound). In the particular case of copper-complexed aminyl radical cyclization, a redox chain process operates (with fast chlorine ligand transfer from cupric chloride) 5.1.5.2.2 From N-Thioaryl Compounds Beckwith [51] and Bowman [34] have developed the use of sulfenamides as precursors for aminyl and amidyl radicals. Bowman [36, 52, 531 and Newcomb [54] have applied the protocols to the synthesis of a range of nitrogen heterocycles. The best examples are given in Table 5.

n-Pr

CI

I

CI

CI'N'Me

4

R' Q,-Me

CI

$

59

Bu3SnH, AIBN, PhMe, 11 1 "C

CI

92 (80:20)

[431

[421

[411

[331 [401 [401

Ref

[451

[441

phyN-M

81 (1OO:O) 79 (9:91)

55

62 (4357) 66 (1OO:O) 81 (1OO:O)

Yield% (ratio)

93 (93:7)

Ph-I

Product(s)

TiClI, BF3, CH2Clz -78 "C

TiCII, AcOH, H20, 0°C

CuC1, CUClz, AcOH, H20, -10°C R 1 = Me, R 2 = H R 1 = H, R2 = M e

TiCI,, AcOH, HzO, -5 "C

MeOH, hv, 5°C FeS04,4M HzS04, AcOH, 25 "C TiC13, AcOH, H20, -5 "C

0,

n-Pr

Conditions

Reactant

Table 4. Homolytic cyclizations of N-chloroalkenylamines

5.1.5 Reactions M?th OleJins

m m "

woo

w w

Y u

0

419

420

5. I Nitroyen-Centered Radicals

Table 5. Homolytic cyclizations of N-alkenyl-arenesulfenamides

Reactant

&

Conditions

Product(s)

Ratio

Yield (%I)

Ref

90

1361

75:25

95

1541

63:37 74.26

82 87

[39I

Bu,SnH, AIBN, THF, 66°C

N

SPh

Bu3SnH, AIBN, C6H6, 65 "C 0 SPh

Bu3SnH, AMBN, PhMe, 11 1 "C R ' = Me, R2 = Me R ' = Bn, R 2 = t-Bu

fN i H+COzRZ

dl

5.1.52.3 From N-Hydroxypyridine-2(ZH)thione Compounds The N-hydroxypyridine-2(IH)thione derivatives (PTOC carbamates and PTOC imidates) permit facile generation of neutral, protonated, Lewis acid-complexed aminyl radicals and amidyl radicals. For cyclization reactions, the PTOC protocol was comparable or superior in yield to those involving N-chloro or N-thioaryl compounds. The thioxothiazolyloxycarbonyl (TTOC) carbamates containing a primary amine group would appear to be the most useful precursors now available for generating monoalkylaminium cation radicals [ 551. Some representative examples are collected in Table 6. 51.5.2.4 From some other Sources Other methods, among which thermolysis or photolysis of tetrazene [59], photolysis of nitrosoarnines in acidic solution [60], photolysis of nitrosoamides in neutral medium [61], anodic oxidation of lithium amides [62], tributylstannane-mediated homolysis of O-benzoyl hydroxamic derivatives [63,64],and spontaneous homolysis of a transient hydroxamic acid sulfinate ester [ 651 could have specific advantages. The redox reaction of hydroxylamine with titanium trichloride in aqueous acidic solution results in the formation of the simplest protonated aminyl radical [66]; similarly, oxaziridines react with various metals, notably iron and copper, to generate a nitrogen-centered radical/oxygen-centered anion pair [ 67, 681. The development of thiocarbazone derivatives by Zard [ 5 , 691 has provided complementary useful method able to sustain, under favorable conditions, a chain reaction where stannyl radicals act simply as initiators and allow transfer of a sulfur-containing

PTOC

0

PTOC

PTOC

cr-

Reactant

MeCN, CHz(COlH)2, t-BUSH, hv, 25 "C

MeCN, AcOH, hv, 25 "C

MeCN, AcOH, hv, 25 "C

MeCN, AcOH, hv, 25 "C

MeCN, AcOH, t-BUSH, hv, 25 "C MeCN, AcOH, hv, 25 "C CH2C12, BF3-OEt2, hv, -78 "C

Conditions

Table 6. Homolytic cyclization of N-PTOC and N-TTOC-alkenylamines

R = SPY R = SPV

N H

60:40

63.37

66:33 71:29 66:33

Ratio

n-Bspy

Product(s)

78

94

95

82

96

60 90 70

Yield ("h) Ref

N

P

BrCCli, hv

Conditions

Ar= 3,4,5-trirnethoxyphenyI

Ar

-3

Ph

Bn

BuiSnH, AIBN, C6H6, 80 "C

Bu3SnH, PhMe, 11 1 "C azobis(cyc1ohexanecarbonitrile)

C U ( C H ~ C N ) ~ PTHF, F ~ , 66°C

t-BuSOC1, (PhS)2, i-Pr2NEt CH2C12, -50°C to rt

THF, HMPA, LiC104, -10°C anodic oxidation (Pt)

m N N o

Reactant

Table 7. Some original examples of N-centered radical cyclizations

\

H

0

Bn

0

(&

Rxt3 R'

)?$?O r

Ar

P h,

Me

y

J)

PhS

MePih f

H

Product(s)

49-63

63 (40/60)

72 (ee 2 95%)

74

52

89

Yield% (ratio)

[701

[68]

Ref

w

g

+

Bu3SnH, AIBN C - C ~ H ,81 ~ ,"C

idem

Bu3SnH, AIBN, C-CgH12, 81 "c methyl acrylate ( 5 eq)

Conditions

PNh

MeS

S

R

Product(s)

Ph

NaH, dioxane, 50°C cyclohexa-l,4-diene

OH



-

Propagation

0

I

i : i mixtureof diastereoisomers

0-0

0

yE: 00. H-N> 0

Scheme 47 [83]

by a free-radical mechanism (Scheme 47) [83]. The proposed sequence involves: (a) peroxyl radical cyclization, (b) transfer of an iodine atom from NIS to the resulting carbon radical (first propagation step), and (c) hydrogen atom abstraction by the succinimide radical from the hydroperoxide (second propagation step). Recently, Nojima reported that NIS-induced iodocyclization of unsaturated hydroperoxy acetals can occur by the 6 - e m or 7-end0 mode to give isomeric 1,2,4-trioxanes and/ or 1,2,4-trioxepanes depending on the substrate and reaction conditions [84]. Ample experimental evidence suggests that trioxanes are obtained by a radical chain process, whereas trioxepanes are produced by an ionic pathway [84]. The iodocyclization of an unprotected P-hydroperoxyalcohol (28 29, Scheme 48) was the key step in a recent, highly efficient total synthesis of the structurally unprecedented antimalarial peroxide yingzhaosu A (Scheme 48) [85].Cyclization of 28 proceeded with complete chemo-, regio- and stereoselectivity to give iodide 29, which was not purified but directly dehalogenated to furnish more than a gram of advanced intermediate 30 (63%)yield from 28). The striking chemoselectivity reflects the weakness of ROO-H in comparison to RO-H (BDE = 89 and 103 kcal/mol respectively). The observed diastereoselectivity in both iodocyclization and dehalogenation is due to the strong steric bias for attack from the convex face of their common bicyclic radical intermediate. ---f

5.4 Peroxyl Rudiculs in Synthesis

418 H

O

Z

NIS, PhH * Ho&

n-Bu3SnH * H

rt, 14 h

28

29

O

Et3B, CH2C12 -78 “C, 3 h

I

X

30

Yingzhaosu A

OH

Scheme 48 [85]

5.4.8.2 [2,3]-Peroxyl Radical Rearrangement There is considerable evidence that the rearrangement of allylic hydroperoxides proceeds by abstraction of hydroperoxyl hydrogen to produce a peroxyl radical which undergoes [2,3]-rearrangement through a tight radical cage (Scheme 49) [86871. Hydrogen abstraction from another hydroperoxide propagates the reaction and produces the rearranged product. The process is usually accelerated by radical initiators or light [86a, 87, 881. DTBN is typically used for reactions run at 20-40°C [ 12b, 86e, 871, and AIBN is used at higher temperatures [86e, 881. The rearrangement is highly stereoselective. For example, the conversion of 31 to 34, where R’= (CH&COOMe and R 2 = n-C7H15, occurs with 97% chiral transmission at 22°C [86b].

31

32

J

33

34

Scheme 49 [49]

Dussault has reported a remarkable example of stereocontrolled peroxyl radical rearrangement (cf. 35 + 36) in the context of his asymmetric total synthesis of the marine natural product plakortin and its C6-epimer, ent-chondrillin (Scheme 50) [89]. A systematic study of initiators and reaction conditions revealed that the yield of rearranged products can be substantially improved by using DTBN in conjunction with an excess of TBHP [89]. Equilibration of 35 under these conditions provided a 1:1.2 mixture of 35 and 36, which were obtained as single diastereoisomers after separation on silica gel in yields of 29 and 3694, respectively. The synthesis of ent-chondrillin allowed the assignment of absolute stereochemistry to the natural product chondrillin [89].

5.4.9 Thiol-Oxygen-Co-Oxidation(TOCO) and Related Processes OH n-Cl6H33

DTBN, TBHP PhH, 60 "C, 20 h

OTlPS OOH

OH

*

:

*

Me0

OTlPS

n-Cl6H33

(35/36 1 : 1.2)

35

479

36

0-0

HOO

n m c 1 6 H 3 3 s

n-Cl6H3 98% R = mu:57%. ee > 98%

Scheme 2. Photochemical preparation of prolines

r 0 MeOOCIJ/.\?20:1)

OH

' \ 69

70

OBn

OBn 1. Bu3SnH, AlBN 2. TBAF

BnO"" OBn 71

(83%)

BnO"' OBn 72

Scheme 12. Stereospecific synthesis of C-styryl glycosides using temporary silicon tethering

Stork [54] refined this strategy by using a temporary silicon tether for the stereospecific synthesis of styryl C-glycosides (Scheme 12). The C-3 hydroxyl-tethered selenoglucoside 69 afforded the P-C-glucoside 70 and the C-2 hydroxyl-tethered selenoglucoside 71 gave the a-C-glucoside 72 after desilylation. Sinay [ 551 adapted this approach to the stereoselective synthesis of Cdisaccharides by tethering together a glycosyl radical donor and an exocyclic methylene monosaccharide acceptor as a dimethylsilaketal. 8-Endo or 9-endo cyclization leads efficiently to C-disaccharides after cleavage of the silaketal tether, provided that the correct pair of hydroxyl groups are used for tethering [55a]. Fine tuning of the stereoselectivity is therefore possible with this approach because of the availability of an array of hydroxyl groups present in the monosaccharide acceptor. Thus, tethering of selenoglucoside 73 and radical acceptor 74 gave the so-called 6,2' adduct 75, which underwent stereoselective 9-endo-trig cyclization to afford methyl a-C-maltoside 76 after deprotection (Scheme 13).

6.3.3 Intramolecular Carbon-Carbon Bond Formation

(40yo)

H -rHO

HO

BnO

HO 76

1. BusSnH, AlBN 2. HF, THF

J.

"" %o : :BBnO

~

55 1

BnO

OMe

OMe

Scheme 13. Synthesis of methyl u-C-maltoside 76 via temporary silaketal tethering

In contrast, the corresponding 3,2' adduct underwent non-stereoselective 8-endotrig cyclization. However, in the case of the 3,2' adduct 77, stereoselective 8-endotrig cyclization led to formation of the methyl P-C-lactoside 78 after deprotection (Scheme 14). Sinay has also reported similar coupling strategies using other temporary tethers including dimethylketals [ 561 and ketals derived from para-methoxybenzyl ethers [55d]. Also noteworthy is the use of a temporary phosphoramidic connection for the synthesis of N-acetylglucosamine containing C-disaccharides [ 571. An important development in the preparation of C-disaccharides was the use of SmIZ/HMPA by Sinay [58]in which the anomeric radical is generated by SET to a glycosyl phenyl sulfone such as 79 (Scheme 15). Beau [59] has reported a similar approach to methyl

,OBn

77 1. BusSnH, AlBN 2. TBAF

(45yo)

OH OH

B

n

J.

O

M

steps HO0-Me

HO

OH

4

BnO

HO

78

Scheme 14. Synthesis of methyl a-C-lactoside 78 via temporary silaketal tethering [ 55b]

OBn

OMe

552

6.3 Rudicals in Curhohydrute Chemistry

1 Smlz, HMPA

"OBn BnO

(41%)

"OBn

"OH

BnO

BnO

79

OMe 21 Sml,,THF steps

~

(48%)

BnO'

A

c

O

AcO'

T

"*'s "OAc

"OAc

OAc

AcO

BnO /

\

81

80

Scheme 15. Preparation of C-disaccharides via SmIz-induced radical cyclization using silicon tethering

C-isomaltoside 80 using glycosyl pyridyl sulfone 81 which avoids the use of cosolvents such as HMPA. This method is also generally applicable to the synthesis of 1,2-cis-C-glycosides.

6.3.3.2 Synthesis of Branched-Chain Sugars The preparation of branched-chain sugars by intramolecular C-C bond formation is based on the tether approach. The radical donor may either be generated on a tether and cyclize onto an unsaturated sugar acceptor or, alternatively, the radical donor can be generated on the sugar template which cyclizes onto a tethered radical acceptor. De Mesmaeker [60] and others [61] have shown that alkyl and vinyl radicals generated to the glycosidic oxygen atom in a glycosidic chain of hex-2-enopyranosides undergo 5-exo-trig cyclization to form cis-fused furanopyrans (Scheme 16). Selective cleavage of the bicyclic acetal 82 afforded the C-2 branched-chain sugar 83 [60a]. Addition of tributyltin radicals to alkyne 84 generated a vinyl radical which cyclized to form stannane 85, which could be destannylated or oxidatively cleaved to ketone 86 [61d]. Chapleur [61c] demonstrated that acetal-tethered radicals similarly undergo 5-exo-trig cyclization onto 2,3-unsaturated sugars to form C-2 branched-chain derivatives such as 87. When the same acetal tethering is attached to the C-4 hydroxyl of a 2,3-unsaturated sugar such as 88, the C-3 branched-chain derivative 89 was obtained [61a]. Sinay [62] used a temporary silyl ether tether attached to the C-3 hydroxyl of the 4,5-unsaturated sugar 90 to achieve stereoselective C-4 hydroxymethylation after oxidative cleavage of the tether. Chapleur [63] has reported that a-silyl radicals derived from allylic silylethers may also undergo 6endo cyclizations in conformationally biased cases. Radical cyclization onto an unsaturated sugar template results in a carbohydrate-

6.3.3 Intramolecular Carbon-Carbon Bond Formution

82

83

b,~'"],

OAc

553

OAc

OAc

AcO"' 84

85

86

87 OTr

OTr

Bu3SnH, AlBN

I\/I

(85%)

EtO

88

EtO 89

OBn

pBn

OBn Bu3SnH

Br

""OBn

H202, Na2C03

"

,si-O

' \

\

8

0

~

~

(71%)

* HO

OH

90

Scheme 16. Synthesis of branched-chain sugars by intramolecular tethered radical addition to unsaturated carbohydrates

based radical which may subsequently undergo H-abstraction (as above) or further inter- or intramolecular radical additions (so-called serial radical reactions). Ferrier [61b] showed that truns-2,3 doubly chain-branched sugars were formed by intramolecular cyclization of C- 1 or C-4 hydroxyl-tethered radicals onto 2,3-unsaturated templates followed by intermolecular radical addition. Thus, the glycal-derived bromide 91 underwent cyclization-allylation when treated with allyltributyltin/ AIBN to give the C-3 allyl-branched 92, and the iodoacetal 93 similarly afforded the C-2 allyl-branched 94 (Scheme 17). A novel approach to the synthesis of C-2-

6.3 Radicals in Carbohydrate Chemistry

554

OAc

b''';]

OAc

+

&SnBu3

AlBN

*

(56%)

AcO""

AcO""

I1

91

g2

OBz

OBZ

+

&SnBu3

b.*,\OEt

Zl

AlBN (84%)

%

*

\

0"

1-i

EtO

EtO

94

93

'CN

(87%)

OEt 96

95 C02Et C02Et

1. Bu3SnCI, NaBH3CN 2. H202, KF, KHC03

$7

/K

O

(75%)

-

CHO

steps

'

Me02C BOAc

HO 98

Me02C

OMe 99

97

Scheme 17. Preparation of branched-chain sugars via serial radical reactions initiated by tethered radical addition to unsaturated sugars

branched C-glycosides was reported by Fraser-Reid [64] based on the intramolecular addition of C-3 hydroxyl (acetal or silyl ether)-tethered radicals to glycals generating intermediate glycos-1-yl radicals which were trapped by electron-deficient alkenes, allyltin derivatives or tert-butyl isocyanide. The stereochemistry at C-2 is controlled by C-3 because of the requirement for cis-ring formation, and the stereochemistry at C-1 is dependent on the interplay of steric effects (directing attack trans to the C-2 branch) and the electronic preference for a-attack of glycos-1-yl radicals. Thus, the glucal derivative 95 underwent (matched) cyclization-intermolecular trapping with acrylonitrile to afford the a-C-glycoside 96. An alternative cyclization-intramolecular trapping was exploited by Fraser-Reid [65] for the synthesis of Woodward's reserpine intermediate 97. The substrate 98 underwent

6.3.3 Intramolecular Curbon-Curbon Bond Formation

555

5-exo-trig cyclization onto the 2,3-double bond to generate the C-2 radical, which underwent smooth 6-exo-trig cyclization onto the off-template C-7 double bond to afford the highly functionalized cyclohexane skeleton of 99. Branched-chain sugars can alternatively be prepared by cyclization of sugar template-based radical donors onto a tethered radical acceptor. De Mesmaeker [60b, 661 and Beau [67] showed that O-linked vinylic iodo compounds such as 100 or 101 underwent smooth 5- or 6-exo-trig cyclizations to afford the C-2-branched sugars 102 and 103, respectively (Scheme 18). The corresponding propargylic glycoside also undergoes the analogous 5-exo-dig cyclization. A stereospecific synthesis of the 1,2-cis C-2 formyl derivative 104 by a radical formyl transfer process from the cr-glucoside 105 was reported by Jung [68]. A similar process was developed by Beau [69] for the preparation of the 1,2-trans C-2 formyl derivative 106, an intermediate for the preparation of C-mannobioside. Formyl transfer from the correctly disposed C-3-OH in 107 is driven by the formation of a stable benzyl radical. Intramolecular cyclizations of sugar-based radicals onto O-linked acceptors has also been applied to the synthesis of C-2’- and C-3’-branched chain nucleosides [70]. It is noteworthy that 5-exo-trig cyclization at the p-face of arabino derivative 108 is diastereospecific, whereas 5-exo-trig cyclization at the a-face is only diastereoselective. An interesting approach to C-4’-branched chain nucleosides using an intramolecular radical cyclization onto an O-linked vinylsilicon tether has also recently been reported [71]. Sugar template-based radicals also undergo intramolecular addition onto Clinked acceptors, providing access to branched-chain sugars including bicyclic derivatives. Giese [41c] showed that the glucosyl iodide 109 underwent 5-exo-trig cyclization on treatment with Bu3SnH to give the bicyclic dideoxysugar 110, a cyclization which is believed to occur via the B2.5 conformation 111 (Scheme 19). The highly functionalized cyclopentane 112 was prepared via 5-exo-trig cyclization of the unsaturated aldonolactone 113 [72]. The conversion of carbohydrates to carbocycles by radical cyclization routes has largely been pioneered by Fraser-Reid [73]. The on-template radical at C-2 generated from iodide 114 undergoes cyclization onto the pendant electron-deficient acceptor to afford the [2.2.1] bicyclic system 115 that was cleaved to give the cyclopentane 116 [74]. A similar strategy led to the cyclohexane 117 by cleavage of the [2.2.2] bicyclic system 118. Non-template radical cyclizations in which both the radical donor and acceptor are attached to a sugar unit by pendant carbon chains provides a powerful strategy for synthesis of fused carbocycles [75]. The key step in Fraser-Reid’s [76] preparation of Collum’s intermediate 119 for the synthesis of phyllanthocin was achieved by Bu3SnHpromoted cyclization of the iodoaldehyde 120. Finally, Fraser-Reid [ 771 prepared the diquinane 121 by a serial radical cyclization of the unsaturated iodide 122.

6.3.3.3 Synthesis of Functionalized Carbocycles by Cyclization of Acyclic Sugar Derivatives Carbohydrates are an immensly important natural source of building blocks for the preparation of enantiomerically pure and highly oxygenated derivatives [78]. A

556

6.3 Radicals in Carbohydrate Chemistry

p:::;?

OAc

OAc

'ruizpl,

B u ~(880/) S ~AlBN H,

*

(-1:l)

AcO"'

AcO""

OAc

OAc

102

100

OAc

'e,:;:;?

OAc BusSnH, AlBN *

(60%)

AcO"'

(-1:l)

AcO'"

OAc

OAc

101

103

wHn

OBn

OBn

BuaSnH, AlBN

(84%)

BnO"'

""CHO

BnO"'

6Bn

OBn 104

105

OBn

D:e

BnO"'

OBn B u ~ S ~ AlBN H, (63%)

OYCHO Ph 107

i-i

PhSe

4+

?

D=

BnO"'

OBn

106

(79%)

108

(92%)

0

*

S ' SSePh

..

..

O G ,

Scheme 18. Preparation of branched-chain sugars by intramolecular addition of sugar-based radicals to 0-tethered acceptors

6.3.3 Intramolecular Carbon-Carbon Bond Formation

OAc

557

OAc

(exo:endo 93)

111

109

Bu3SnH,AIBN AcO

*

110

BH3.SMe2

AcO&

(want)

0

H

Br

qoH

HOJ'".

(88%) HO

OH

112

Bu3SnH, AlBN t

(97%)

b&:ozEt

1. CSA, MeOH 2. Ac20. DMAPb

/

(88%)

OMe

AcO 114

%H(OMe)z

115

116

COZEt

OAc

steps

TBDMSO

t

(82%)

BnO"'

BnO

.

.,COpEt

SAS

U

OBn

117

118

119

120

P h q O

o%oMe

Bu3SnH,AlBN (80%)

NC

0

I 122

121

Scheme 19. Preparation of bicyclic ring systems by intramolecular addition of carbohydrate-based radicals onto Clinked acceptors

558

"

6.3 Radicals in Carbohydrate Chemistry

O

~

-. ..

0 2

1. NBS, Ph3P O 2.DlBAl 3. Ph3P=CHC02Et 4. BzCl

B

z

O

hC02Et

* 123

I

Bu3SnH, AlBN

(89%)

126

Brio* BnO'" BnO

C02Me

OBn

1. Bu3SnH (85%) 2. PhMgBr; AcOH; 03;NaBH4 3. H2s Pd(0H)2/C

*

HO T

o HO

J

O

H

OH 127

Scheme 20. Preparation of cyclopentanes via 5-exo cyclization of primary radicals

powerful illustration of this is the conversion of carbohydrates into functionalized carbocycles [4, 791; protection of a monosaccharide, then ring opening and functionalization to position the radical donor and acceptor, is followed by cyclization. The 5-exo-cyclization of hex-5-enyl radicals is particularly rapid and provides a synthetically useful route to cyclopentanes. Thus, Wilcox [80] prepared a series of unsaturated bromo esters such as 123, which underwent smooth cyclization to cyclopentanes 124 and 125 on generation of the primary radical (C-1) by treatment with BqSnH/AIBN. The stereoselectivity is rationalized in terms of Beckwith's chair-like transition state model 126 [81] in which substituents at C-2 and C-4 preferentially adopt pseudoequatorial positions leading to the major product 124 with exo orientation of the ester group (Scheme 20). Wilcox [82] also synthesized carba-D-fructofuranose 127 using this methodology. RajanBabu [ 8 1, 831 developed a versatile approach to cyclopentanes via the cyclization of secondary radicals generated by Barton-type deoxygenation of pyranose-derived imidazole carbothiolates such as 128 (Scheme 21). Higher stereoselectivity is achieved using the benzylidene constrained radical 129 leading exclusively to the 1,5-truns product 130. The stereo-

6.3.3 Intramolecular Carbon-Carbon Bond Formation

Bnb F=

BnO"'

OBn

1

OC(S)lm

BunSnH,AIBN

BnO-;

559

-CH20Bn

OBn

"'OBn

128

(+ 26% minor isomers)

OC(S)lm Ph'"

"OBn OBn

(Y=H,OMe)

129

B n o OC(S)OPh b N o M e

BnO"'

"'OBn OBn 131

130

Bu3SnH,AIBN-

OBn ;"i"Me BnO""

+ "'OBn

OBn 132 (62%)

OBn 'z,,,gNHOMe BnO"'

"'OBn 6Bn

133 (38%)

Scheme 21. Preparation of cyclopentanes via 5-exo cyclization of secondary radicals

selectivity of these reactions has been discussed in detail [Sl]. It is noteworthy that unactivated olefins as well as electron-rich enol ethers were suitable radical traps in these reactions. Bartlett [84] also showed that oxime ethers were suitable radical acceptors in 5-exo-cyclizations, and the glucose-derived oxime ether 131 afforded the cyclopentanes 132 and 133 in high yield and with stereoselectivity similar to that observed with the corresponding enol ether cyclizations. Simpkins [ 851 reported an analogous radical cyclization of a glucosamine-derived oxime ether for the preparation of allosamizoline. Radically induced coupling of two n-systems provides a powerful synthetic route to cyclopentanes (Scheme 22). Hanessian [86] showed that addition of a trimethyltin radical to the terminal olefin in the 1,6-diene 134 initiated C=C to C=C coupling, resulting in carbocyclization to afford the cyclopentane 135, which underwent oxidative destannylation with CAN. Intramolecular radical coupling between aldehydes and electron-deficient alkenes has been developed by Enholm [87].These and related couplings [88] are based on the generation of ketyl radicals using the one-electron reducing agent SmI2. Thus, reductive cyclization of 136 with SmI2 proceeded with high stereoselectivity to give the syn product 137. Intramolecular pinacol couplings between two carbonyl components are also well known [88], and Sinay [89] reported the synthesis of calditol 138 based on the key SmIf-induced cyclization of

560

6.3 Radicals in Carbohydrate Chemistry SnMe3

BzO,,,,

Me3SnCI, NaCNBH3

BzOL , c. o z M e

(52%)

OBz

*

"X

BzO

OBz COzMe

134

135

TBDM I

136

137

bo OBn

B n O ~ O l ~ . OBn

BnO 139

bBn

HO .

1. SmlZ 2. step-

hu 138

140

Scheme 22. Preparation of highly functionalized cyclopentanes via radical coupling of two n-systems

1,5-dicarbonyl compound 139. Similarly, intramolecular radical couplings between carbonyl groups and oxime ethers have been reported, as in the preparation of trehazolamine 140 from the D-glucose [88]. The cyclization of hex-6-enyl radicals proceeds much more slowly than that of hex-5-enyl radicals, and consequently reduction or 1,5-hydrogen abstraction may occur before cyclization. Preparations of cyclohexanes by 6-exo-cyclization of hex6-enyl radicals have nevertheless been reported by Redlich [90], although the success of the reaction is very sensitive to steric and stereochemical features of the substrate. Thus, while the D-allo-iodide 141 underwent smooth cyclization to cyclohexane 142 in excellent yield, the D-gulo-iodide 143 gave the carbaseptanose 144 by an unusual 7-endo-trig cyclization (Scheme 23). Enol ethers and oximes can also act as radical acceptors in analogous 6-exo-cyclizationsreported by Marco-Contelles

6.3.4 Carbon-Heteroatom Bond Formation

BusSnH, AlBN

*

" ' ~ ; A c

(87%)

561

Aeon 0W O A C

%O 142

141

Bu3SnH, AlBN (81%)

+

6OQ

o x o 144

143

MOM0

x$

Bu3SnH, (49%) AlBN *

OMOM 145

MOMO"'

kMoM o+ 146

Scheme 23. Preparation of highly functionalized cyclohexanes (142 and 146) by 6-ex0 radical cyclization

[91]. Singh and Wightman [92] recently reported the preparation of carbasugars by 6-exo-dig cyclization of hex-6-ynyl radicals derived from iodides such as 145. Radically induced coupling of two 71-systems also provides a synthetically useful route to cyclohexanes. The 6-endo-trig cyclization of the vinyl radical generated by Bu& radical addition to the carbohydrate alkyne 147 provided a novel route to carbasugar 148 [93]. The intramolecular pinacol coupling of 1,6-dicarbonyl compounds such as 149 provides a direct synthesis of the inositol 150 [94] (Scheme 24).

6.3.4 Carbon-Heteroatom Bond Formation 6.3.4.1 C-Br Bond Formation Methods for the regioselective radical-mediated bromination of carbohydrates have been reviewed by Somsak and Ferrier [95]. Photobromination of hexuronic acid derivatives with non-activating anomeric substituents leads preferentially to formation of the C-5 brominated product via the stabilized captodative radical at C-5.

562

6.3 Radicals in Carbohydrate Chemistry

SnBu3 steps (71%)

* IZQOAc AcO

147

BnO,,,

148

Smlp

(56%)

BnO

OAc

BnO,,,. (+22% minor isomers)

BnO

OBn

OBn

149

150

Scheme 24. Preparation of highly functionalized cyclohexanes by radical coupling of two n-systems

Thus, irradiation of anhydro-L-gulonate 151 with NBS provided the bromide intermediate 152, which was transformed into L-ascorbic acid 153 [96] (Scheme 25). Sinay [97] exploited this Ferrier photobromination in the preparation of L-iduronic acid derivative 154 by a radical epimerization of the D-glucuronic acid derivative 155. Fleet [98] recently reported a related radical bromination of C-glycosyl esters such as 156 en route to the preparation of a-amino acids. The presence of electronwithdrawing groups (halogens, cyano groups) at C-1 may activate the anomeric center to bromination because of captodative stabilization of the glycosyl radical [99]. The presence of keto functions or oxime ethers at C-2 of 175-anhydrohexitols such as 157 also activates the proanomeric center toward radical bromination [99a]. A synthetically useful procedure [ 1001 for the regioselective cleavage of benzylidene acetals [loll such as 158 is probably initiated by radical bromination at the benzylidene acetal center and leads selectively to the C-4-benzoylated 6-brominated product 159. Ferrier [ 1021 showed that 176-anhydropyranoses may undergo regioselective photobromination at C-6. This observation was exploited by Gallagher [ 1031 during the synthesis of herbicidin glycoside 160 and by Fraser-Reid [ 1041 during the preparation of a precursor 161 to the carbocyclic core of tetrodotoxin (Scheme 26).

6.3.4.2 C-N Bond Formation Giese [ 1051 reported that carbohydrate-based cobaloximes undergo photolysis to generate radicals, which are trapped by nitrous oxide to afford oximes. Thus, mannosylbromide 162 gave oxime 163 via the readily prepared mannosylcobaloxime 164, whilst mannosamine 165 was prepared by a similar strategy from the 2bromopyranoside 166 (Scheme 27). The radical azidoselenation described below also leads to C-N formation with concomitant C-Se formation.

563

6.3.4 Carbon-Heteroatom Bond Formation

C02Me A c AcO

O

C02Me ~ ~ 0 % AcO Br OAc

NBS, hv (47%)

M

+ -

OAc 151

1. Hg(OAc)2,AcOH 2. NaOMe; HCI

HO

152

155

153

154

NaN3

*

[Si] = TBDMS

(87%)

OlSi]

O[Si]

O[Si]

156

-*

BzO& BZO

hv

BBZO

z

O

~

~

~

0 157

158

159

Scheme 25. Synthetic applications of the radical bromination of carbohydrates

0

0

160

BL, Bra hv

OAC

Bu3SnH, AlBN *

(81%) NC@ AcO NHAc

OAc

(77%)

o

W

O

AcO NHAc 161

Scheme 26. Radical bromination in the synthesis of natural products

A

c

564

6.3 Radicals in Carbohydrate Chemistry

1. NaCo(dmgH)zpy ACO 2. NO, hv OMe (60%) * AAcO c

At:o* AcO

Br

HP, PdlC, A c ~ O O

W OMe NOH

166

(76%) 165

Scheme 27. Preparation of oximes by radical methods

6.3.4.4 C-Se Bond Formation The azidoselenation of glycals with (diacetoxyiodo)benzene, sodium azide and diphenyl diselenide is a powerful method for the preparation of phenyl 2-azido2-deoxyselenoglycosides [ 1061. Furthermore, this method is complementary to the ionic azidoselenation which leads to 2-Se-phenyl-2-deoxyselenoglycosylazides [107]. In situ oxidation of the azide ion generates an electrophilic azide radical, which adds to C-2 of the electron-rich double bond of glycals, affording a stabilized anomeric radical, which undergoes a-selective trapping to afford the a-selenoglycosides observed. Thus, radical azidoselenation of tri-0-acetyl-~-glucal167 gave the a-selenoglycosides 168, whilst tri-0-acetyl-D-galactal 169 gave exclusively the agalacto isomer 170 (Scheme 28). The presence of a strong oxidant limits this reagent combination to substrates containing compatible (non-oxidatively cleavable) protecting groups such as acetates, although other reagent combinations are available

OAc

OAc

rg

Phl(OAc)z, (PhSe)z, NaN3

(3:2ga1acto:gluco)

(88Yo)

AcO"'

AcO""

OAc

OAc

167

168

OAc

9

OAc

Phl(OAc)2,(PhSe)2,NaN3

AcO

OAc

(70%)

*

169

Scheme 28. Radical azidoselenation of glycals

AcO OAc 170

6.3.4 Carbon-Heteroatom Bond Formation

565

in these cases [ 1071. It is noteworthy that under suitable radical conditions, rapid 8elimination of vicinal azidophenylselenides can occur to regenerate the glycal [ 1081.

6.3.4.5 C-S/P Bond Formation The formation of C-P bonds by the radical addition of phosphines to exocyclic carbohydrate alkenes was originally reported by Whistler [ 1091, who demonstrated that irradiation of alkene 171 in the presence of phenylphosphine afforded the phosphine oxide 172 (Scheme 29). Sinay [ 1101 prepared the gem-difluoro-Cgalactofuranoside 173 by phosphonyl radical addition to gem-difluoroalkene 174 during studies related to the preparation of potential inhibitors of the enzyme UDPgalactofuranose mutase. The formation of C-S bonds by thiol radical additions to unsaturated sugars has also been reported, such as the addition of thiolacetic acid to glycal 167 [ 11 11. Giese

y.302

1. PhPHz, hv

2. air (75%)

HO

v.,sa12

HPh(0)P e

"'0

HO 172

171

173

174

OAc

L O - O H

oAc

OAc

AcO"' OAc

Bu3SnH, AIBN-

0" D.'