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
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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
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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
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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
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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 <15O"C are limited to weak bonds whose dissociation energies are under 30-40 kcal/mol [ 11. Azo compounds, peroxides, nitrite esters, ester of N-hydroxy-2-thiopyridoneetc. fit into this group
2
I . I Radical Initiators
31 kcallrnol
-
2 N C 3 - + NZ
(Scheme 1). Therefore azo compounds have been widely used as radical initiators in organic synthesis [2].
1.1.2.2 Radical Production by Photolysis Photolysis can be used to achieve homolytic fission. For example, azo compounds produce radicals via the unstable cis isomer by the absorption of light energy (Scheme 2) [ 3 ] .Peroxides produce alkoxy radicals and acyloxy radicals as cleavage products on absorption of light energy.
Scheme 2. Photochemical decomposition of azoalkane
1.1.2.3 Radical Production by Radiation High-energy radiation such as X-rays or prays also produce radicals (Scheme 3 ) [I]. High energy BrCCI3 radiation
-
[BrCCI3]+'
- cc13 -
Scheme 3. Radical production by radiation
1.1.2.4 Radical Production by Redox System Oxidation or reduction (redox reaction [4], Scheme 4) generate radicals by an intermolecular electron transfer. The Kolbe reaction is a representative example (Scheme 5) [5].
1.1.3 Radical Initiators in Organic Synthesis
reduction R-X
+e-
IR-XI
._
-
R.
+
3
X-
Scheme 4. Radical production by redox system
Me(CH2)4COO-
-e
-co2 -
Me(CH2)4COOm
Me(CH&.
Me(CH2)4'
-
Me(CH&Me
Scheme 5. Kolbe reaction
1.1.3 Radical Initiators in Organic Synthesis 1.1.3.1 Azo Compounds Azo compounds are widely used as radical initiators in organic synthesis [ 11. AIBN (2,2'-azobisisobutyronitrile) is the most commonly used initiator because of its high decomposition ability and stability. Azo compounds are decomposed by heat to the corresponding alkyl radicals and nitrogen [ 11. As previously described, it is known that they undergo decomposition via the cis form by absorbing light [3]. Recently, azo-type radical initiators that work below room temperature have been discovered, and are applied in the stereoselective construction of a carboncarbon bond [6]. Furthermore, it was reported that azo compounds possessing the hydrophilic functional groups act as effective initiators in aqueous media 171. Molecular design of practical water-soluble radical initiators has been performed recently [S]. In this section, the discussion is focussed on the more recent developments of representative and useful radical initiators. 2,2 '-Azobisisobutyronitrile ( A I B N ) AIBN is one of the most widely used radical initiators in organic synthesis. It is commercially available as white crystals, whose melting point is 65 "C with a halflife of 10 h in toluene at 65 "C. It is often used with trialkyltin hydrides in synthetic reactions (Scheme 6 ) [9].
2,2'-Azobis(4-metlzoxy-2,4-dimethylvaleronitrile) ( V-70) V-70 acts as a radical initiator below room temperature. So highly stereoselective carbon-carbon bond formations via radical species are achieved in neutral and mild conditions (Scheme 7). V-70 is commercially available as a mixture of meso form
4
1.1 Radical Initiators
and racemic form, whose melting point is 50-96 "C with a half-life of 10 h in toluene at 30 "C. It is quite stable for a few months when stored in a refrigerator. NC+N=N+CN
THPO',.
& j
(AIBN) Bu3SnH
t
Steps
THPOl,.
Benzene, reflux
H:
0
)"\Br
99% OEt
OEt
EtO
(+)-Cladantholide Scheme 6. Cyclization using AIBN [ 101
FH3 CH3 CH3 CH3 MeO-?-H2C+N=N+CH2tOMe CH3 CN CN CH3 (V-70) Bu3SnH
R RO O
Ro aBr
-
ACN Et20, rt
-.s:Q
68-70% R=Ac or Bz
CN
a :p = >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 <1/20
>20/1 <1/20
>10/1 <1/20
Scheme 3. Et3B-induced hydrogermylation of alkynes Et3B/02(trace)
* 3
(QH OSiMe3
*
'CCsH13 l y " C s H 1 1 Ge
cat. Me3SiOTf/CH2C12
'CSH13
e \
1) K2C03/MeOH
(major isomer)
69% (83/17)
Cdll
nC6H,3&nC5H11
2) KH/18-crown-G/HMPA
Scheme 4. Radical addition reaction of tri-2-furylgermane (Ge = (2-furyl)3Ge) / R'
K
R
'
'Bu3SnH/Et3B toluene, r. t. H
5
SAR R
Me
R' CHZOAC
YNHCb2 CH20AC Me
Yield 89%
82%
Scheme 5. Radical cyclization of 2-alkenylthioanilides
13
14
1.2 Radical Chain Reactions: Organohorane Initiators
'C10HvcH3 "Bu3SnH
I
-78 'C, 30 rnin * nC10H2+cH3H
"Bu3SnH CC12H23-OCSMe * r. t.. 5 rnin
bS
Ph
"Bu3SnH Ph
1 I
'C12H23-H
3% ph&
-ph&s]
reflux, 2 h
Ph
"Bu3SnH Et3B
00
*
toluene -78 'C, 10 min
0 7
78% E/Z=94/6
Scheme 6. Reduction of alkyl halides and dithiocarbonates
lowered the temperature at which the reduction of dithiocarbonate was performed [13]. The radical reaction of 6 showed a clear contrast between AIBN and Et3B. Treatment of 6 with nBu3SnH in the presence of Et3B at -78°C for only 10 min in toluene afforded a-benzylidene-y-butyrolactone7 in high yield whereas saturated y-lactone 8 was obtained when AIBN was employed in refluxing benzene. Tri-2furylgermane-mediated reduction of organic halides proceeded at room temperature with Et3B/Oz [ 141. Catalytic reduction by a tri-2-furylgermane/NaBH4 system was also successful (Scheme 7 ) .
Scheme 7. Reduction with tri-2-furylgermane/NaBH4/Et3 B
Stereoselective radical reactions have been actively investigated. Et3B has contributed largely toward improving stereoselectivity because one can examine at lower temperatures. Many excellent diastereoselective and enantioselective reactions were reported, and most of them will be mentioned in detail later (see Chapter 4). Some examples are shown here. Diastereoselective trifluoromethylation of chiral imide enolate with iodotrifluoromethane was performed at -78 "C to produce a-trifluoromethyl carboximide [ 151. The attack of trifluoromethyl radical to the lithium-chelated enolate 9 would proceed with C(a)-si-face preference (Scheme 8).
1.2.2 Triethylborane-Induced Radical Reaction at Low Temperatures
R ,
15
si face
'
.R'
ri
1) LDA
O T N r R 2 0 0
CF3
2) CF31, Et3B
n.
* O'fNflR' 0
R'='Pr, R2=Me
86%, 62%de (S)
R'='Pr, R2=&
67%, 86%de (S)
0..Li.o
0
9
Scheme 8. Diastereoselective trifluoromethylation of chiral imide enolates
Preparative synthesis of 2'-deo~y[2'-~H]ribonucleosides 11 with high stereoselectivity was achieved by reduction of the corresponding thionocarbonate 10 by using "Bu3Sn2H/Et3B [ 161. Stereoselectivity could not be controlled when AIBN was employed in benzene at reflux (Scheme 9). "Bu3Sn2H/Et3B
B z o ~ us
THF,-52'C
*
BzO 0 4\ 10
BzO 2H
OPh
11
U=Uracil-1-yl
Scheme 9. Diastereoselective synthesis of deuterated deoxyribonucleosides
Treatment of 12 with (Me3Si)3SiH and Et3B predominantly afrorded cyclic ethers with cis stereochemistry [17]. Construction of oxepines (n = 2) proceeded at low concentration. Additionally, the reaction at low temperature was effective to suppress decarbonylation of the intermediary acyl radical derived from acyl selenide (Scheme 10). A stereoselective radical cascade approach to benzo[a]quinolizidines using Et, B was highly effective [18]. When 14 was treated with "Bu3SnH in the presence of
(Me-SihSiH
I
13a
12 S02Ph
13b
n=O
X=Br
n=O
X=SePh Y=O
0.02 M
87% (17:l)
n=l
X=SePh Y=O
0.01 M
83% (8:l)
n=2
X=SePh Y=O
0.005M
63%(17:1)
Y=H2
0.02M
Scheme 10. Stereoselective synthesis of cyclic ethers
99%(>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
<
0
Scheme 14. Sequential radical addition-aldol reaction
type reaction mediated by Ph3SnH/Et3B provided P-hydroxyketone [22]. In the case of cyclic ketone, threo isomer was selectively obtained, which indicated the formation of boron enolate and cyclic transition state. The reaction mechanism was assumed as shown in Scheme 15. According to the recent study [19], Et3B would first coordinate to a carbonyl moiety to trap alkoxy radical. Intramolecular addition of radicals to carbonyl moieties is difficult because radical addition to a carbonyl group is reversible whereas addition to alkene is normally irreversible (Scheme 16) [23]. This is because an oxygen-centered radical is unstable and P-fragmentation of cyclopentyloxy or cyclohexyloxy radical occurs. In order to overcome the reversibility, coordination of Et3B to carbonyl group has been utilized. The EtsB-stannane-air system is highly effective for intramolecular radical addition to aldehyde [24]. Ph3SnH and Et3B were added simultaneously to aldehyde 22 in hexane. Oxidation of the crude product afforded the bicyclic ketone 26 in good yield. The directly reduced product 23 and the product 24 that was formed by the P-fragmentation of the cyclohexyloxy radical were obtained when AIBN was employed as an initiator at 80 "C (Scheme 17). Malacria's recent study has provided a new method to obtain cycloalkanols in high yield via radical cyclization to carbony1 group [25]. Treatment of 27a or 27b with nBu3SnH and excess amount of Et3B at -78 "C to 0 "C furnished methylenecyclopentanol 28a or methylenecyclohexanol 28b in good yield, respectively (Scheme 18). The cyclization of 29a in the presence of "Bu3SnH and excess amount of Et3B gave a quantitative yield of
18
1.2 Radical Chain Reactionx Organoborane Initiators
+
*
Ph3SnH Et3B/PhH
R2
"+Br
R3CH0
R1&R3
0
0
Ph
H
-(CH2)4-
RL
B
88 77
cyclohexanone
81
"CsHl3CHO
82 (erythrdtbreo=2/98)
'BUCHO
82 (erythrdtbfeo=O/lOO)
+*Rx. -
Ph3SnBr
BEt3
+
PhCHO "CBHI~CHO
r
OH
+
-
BEt3
OKBEt2 R'CHO
-j-*Rfk
R
Ph3Sn*
hEt* EtH
Ph3SnH
Scheme 15. Reformatsky type reaction of z-bromo ketone
A.-A
8
$.=
Scheme 16. Cyclization of 5-hexenyl radical and 5-oxopentyl radical
(y,\,o C02Me
Ph3SnH
C02Me
C02Me
I7
23
22
23
AIBN, benzene, 80 "C
aa
'0
H SePh
Et3B, hexane. 25 "C
+
24
25
26
trace
trace
-
73
24
11
34
-
'0 24
+
C02Me
H
1
OH 25
0 26
Scheme 17. Use of the Et3B-stannane-air system for intramolecular radical addition to aldehyde
1.2.3 Lewis Acidic Trialkylhorane
10 eq Et3B
19
20a n = l 79% 28b n=2 64%
27
30a n=l, R=H 10 eq Et3B
I $0
-78' toluene C+O':
OH 29
"Bu3SnH 10 eq Et3B toluene, r. t.
12
30b n=2, R=H
with 'Bu3SnH, -78 "C
99%
without 'Bu3SnH, 0 'C
88%
without "Bu3SnH, 0 'C
98%
30c n=l, R=Me without "Bu3SnH, 0 'C (20eq Et3B)
92%
AH
* I
85%
32
31
E=COOMe
Scheme 18. Malacria's cycloalkanol synthesis via radical addition to aldehyde
30a. Furthermore, a satisfactory yield of 30a was obtained without stannane mediator. It is crucial in this tin-free reaction that EtjB produces an ethyl radical. An ethyl radical is much more reactive than a 2-cyano-2-propyl radical derived from AIBN because no resonance stabilization exists in an ethyl radical. It is disfavored for a resonance-stabilized radical to abstract an iodine atom from alkyl iodide. However, an ethyl radical can abstract iodine reversibly to produce the corresponding alkyl radical without the help of stannanes, which is another characteristic feature of Et3B as an initiator (see the following section). They also investigated the cyclization of ketone 29c. With 1.3 equimolar amount of tin hydride, only the reduced product was formed. However, tertiary alcohol 30c was obtained in excellent yield in the absence of tin hydride. These investigations were applied to the synthesis of 2-iodomethylenecycloalkanols. The stannyl radical addition-cyclization cascade was successful in giving 2-iodomethylenecyclopentanol 32 stereoselectively after the crude vinylstannane was treated with iodine. The explanation proposed for these results was that EtjB acts as a radical quencher of the intermediary alkoxy radical to prevent the p-scission pathway. EtjB has also worked in the field of radical addition to C=N bonds. Bertrand et al. reported diastereoselective radical addition to glyoxylate imines 33 [26]. Compared with the "Bu3SnH/AlBN system, stereoselectivity of the products is higher when EtjB and no "BulSnH were employed at -40°C (Scheme 19). Naito's group demonstrated that intermolecular radical addition to glyoxylic oxime ether 35 proceeded effectively using alkyl iodide and Et3B [27]. Treatment of 35 with excess RI and EtjB afforded the corresponding adduct 36 in good yield in addition to a small amount of ethyl radical adduct 37. Both groups pointed out that EtjB acts as a radical initiator, a Lewis acid and a radical terminator as shown in Scheme 20.
20
1.2 Radical Chain Reactions: Organoborane Initiators
..
33
R=CCsH~~ A
47% 85/15
B
27% 90/10
R='Bu
A
41% 87/13
6
25% 100/0
34
Condition A: RI (0.95 eq); "Bu3SnH (1.05 eq.); AIBN; benzene; 80 'C Condition B: RI (6 eq); Et3B (3 eq.); CH2C12;-40 "C
Scheme 19. Bertrand's radical addition reaction to glyoxylate imines
g°CH2p:
RI (5 eq)
MeOZC
Et3B
I
RI
+
R*
+
NHOCH2Ph
(5 eq)
CHPCI?
* MeOzCI'R
=,.
NHOCH2Ph
+
Me02CAEt
R='Pr
65% (by-product:R=Et 17%)
R='Bu
74% (by-product:R=Et 9%)
EtzB,NOCH2Ph
37
36
MeOZCA R
O2
+t Et*
It
t
Et3B
Etl
Et3B..
*
NOCH2Ph
-f* Me02CAR
Et3B..
NOCH2Ph
II
Scheme 20. Naito's radical addition to glyoxylic oxime ether
1.2.4 Triethylborane: Source of Reactive Ethyl Radical As mentioned above, Et3B produces an ethyl radical that is reactive enough to abstract iodine atom from alkyl iodide without the help of a radical mediator such as "Bu3SnH. A carbon-iodine bond in secondary alkyl, tertiary alkyl and carbonylmethyl iodide is easily cleaved homolytically by an ethyl radical. The newly formed radical species adds to an olefinic moiety intermolecularly or intramolecularly to afford the corresponding radical species.
1.2.4 Triethylborane: Source of Reactive Ethyl Radical
+
RJIl
Et3B
R3CH0
R'&R3
~
0
0
Ph
H -(CH&
"c&l13CHO
72
cyclohexanone
77
"C&I&-lO
+
0
+
PhCHO
OH
64 (erythrdthreo=6/94)
70 (erythrdthreo=Oll 00)
'BUCHO
'Bul
21
Et3B
*t
B
u
z
+
0 38 63%
E
t
p
q
0
39 4%
Scheme 21. Reformatsky type reaction of a-iodoketone
Treatment of a-iodo ketone and aldehyde with an equimolar amount of Et3B yielded the Reformatsky type adduct in the absence of Ph3SnH (Scheme 21), unlike cr-bromo ketone as shown in Scheme 15 [22]. Ethyl radical abstracts iodine to produce carbonylmethyl radical, which would be trapped by Et3B to give the corresponding boron enolate and regenerate an ethyl radical. The boron enolate reacts with aldehyde to afford the adduct. The three-component coupling reaction of tertbutyl iodide, methyl vinyl ketone and benzaldehyde proceeded to give the corresponding adduct 38, with contamination by the ethyl radical addition product 39. The order of stability of carbon-centered radical is carbonylmethyl radical > 'Bu' > 'Pr' > Et' > 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=<
1'
1'
yield ("h)
Me3Si
Et
a4
o/ioo
COOEt Ph
'Pr 'Pr
aa
34/66 21/79
a1
~2
HZ
R2
Ri
R,' H C=C
Scheme 24. Addition of alkyl iodides to alkynes
transfer radical addition reaction of a-bromooxazolidinone imide 43 [33] proceeds smoothly not only with terminal alkenes but also 1,2-disubstituted alkenes. Addition of Lewis acid made the bromine atom transfer reaction easier (Scheme 25). 0
0
Et3B +
U 43
Sc(OTf)3
or
*
&NxO Br
u
Yb(OTf)3
Scheme 25. Sc(OTf), and Yb(OTf)3-promoted atom transfer radical addition reaction of x bromooxazolidinone imide
1.2.5 Triethylhorune in Aqueous Media
23
Scheme 26. Atom transfer radical cyclization of iodo acetal
The Et3B-induced halogen atom transfer radical cyclization reaction is a successful application. Cyclization of iodo acetal 44 afforded the tetrahydrofuran derivative 45 in almost quantitative yield (Scheme 26) [32]. Et3B also induced radical cyclization of N-allylic cc-iodoacetamide to give P-iodomethyl-y-lactam via an atom transfer process [34]. The reaction of 46 prepared from 2-prolinol proceeded smoothly within 10 min in boiling benzene in the presence of Et3B to yield ( l R , 8s)1-iodomethylpyrrolidin-3-one 47, which can be readily converted into (-)-trachelanthamidine (Scheme 27).
/I
-
O ,H
0
0 46
10 min
47
(-)-trachelanthamidine
Scheme 27. Atom transfer radical cyclization of N-allylic iodoacetamide
An intramolecular ips0 substitution reaction took place when Et3B was added to a solution of 3-iodoalkylaryldimethylstannanein refluxing benzene to migrate aryl group from tin to carbon via an atom transfer process [35]. In this case, reactive ethyl radical would play an important role in abstracting iodine from the substrate. For example, treatment of 48 with Et3B followed by addition of methylmagnesium iodide provided 3-phenylalkyltrimethylstannane49 in good yield (Scheme 28). On the other hand, AIBN could not initiate the reaction, and 48 remained unchanged.
1.2.5 Triethylborane in Aqueous Media Trialkylboranes are generally stable in alcohol and water whereas they ignite spontaneously when exposed to air. Therefore, Et3B is still active as an initiator in a protic solvent with remarkable characteristics as described above. Togo and Yokoyama demonstrated the Et3B-initiated radical reaction using water-soluble organosilanes 50-52 in ethanol or aqueous media [36]. Although aryl
1.2 Radical Chain Reactions: Organoborune Initiators
24
PhMezSn MepSn R
MeMgl THF
t Mesn
PhMe
Ph
.."
49 72%
Scheme 28. Aryl migration from tin to carbon-centered radical
bromide was hardly reduced, alkyl iodide, bromide, and aryl iodide were reduced in aqueous media. They mentioned that Et3B is superior to AIBN since AIBN could not initiate reduction with organosilanes. They also developed 1,1,2,2-tetraphenyldisilane (53), which forms stable crystals under aerobic condition, and radical reduction of alkyl bromide with 53 was examined in ethanol from the ecological and practical points of view (Scheme 29). Et3B-induced atom transfer radical cyclization of ally1 iodoacetate (54) proceeded much more smoothly in water at ambient temperature than in benzene or hexane [37].Treatment of 54 in water with Et3B at room temperature for 3 h provided piodomethyl-y-butyrolactone 55 in 67% yield. In contrast, in benzene, the desired 55 Si-H/ Et3B
'-' EtOH
Si-H
R-X
Br(CHz)5C02K
R-H
or H 2 0
A A
(Me0
0
O a S i H z 50
I
R O z K
(HOnOo2SiHZ
51
Ph4Si2H2 53
Scheme 29. Radical reduction of halides in a protic solvent with organosilanes/Et3B
1.2.5 Triethylborane in Aqueous Media
25
cat. EtsB/trace O2
*
l
b
0
55
54
30 rnl
0%
H20
30ml
67%
benzene 30rnl
0%
H20
loom1
78%
hexane
cat. Et3B/traceO2
l J o ?
*
-0
I
56
20 ml 10%
H20
benzene 100 ml 27%
H20
hexane
62 57
20 ml 33% 100 ml 69%
Scheme 30. EtnB-induced atom transfer radical cyclization in water
was not obtained at all and oligomeric products were formed. Ah initio calculation suggested that water lowers the barrier to rotation from more stable Z-rotamer to E-rotamer in a minor population that can cyclize. The powerful solvent effect of water also operated in the case of medium and large ring construction. For example, treatment of 56 with Et3B in water furnished the 9-membered lactone 57 in 69% yield. On the other hand, the reaction in benzene afforded 57 in only 27% yield. Although the exact role of water was riot clear at that stage, a hydrogen bond to carbonyl oxygen could be formed to facilitate the abstraction of iodine giving the (alkoxycarbony1)methyl radical. Hydrophobic interaction may also accelerate the cyclization (Scheme 30). Et3B also induced radical addition of halogenated compounds to alkenes and alkynes [38]. Et3B serves as an initiator in acidic and basic aqueous solutions. The reaction between BrCC13 and diallyl ether in 1 M hydrochloric acid or sodium hydroxide solution afforded 56 in 71%) or 59% yield, respectively. Moreover, the reaction took place even in concentrated hydrochloric acid (Scheme 31). A combination of phosphinic acid and a base in aqueous ethanol was effective for the radical cyclization reaction at room temperature in the presence of Et3B [39]. This method offered totally nontoxic and mild radical reaction conditions (Scheme 32). BrCCI3
+
cat. Et3B/trace0
2
Br>
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
\
(3)
59%
The importance of desulfurization and deselenation by radical processes has increased significantly in recent years. Generally, the reductive cleavage of the C-Se bond is more efficient than that of the C-S bond. Two examples are reported in Eqs. (4) and (5) [20, 21). Cleavage of the C-Se bond in acyl selenides and selenocarbonates provides a very mild method for the generation of acyl radical [lo].
$sph
Bu3SnH,AIB! N
0
N $
PhCH3,90 "C
5
0
9 95%
-8
Bu3SnH, AIBN
PhCH3,llO "C 'SePh
95%
Two important reactions were introduced by Barton's group. The radical deoxygenation of secondary alcohols via thiono esters is a selective and mild replacement of hydroxy groups by hydrogen [22-251. The deoxygenation at 2'-position of adenosine via the thionocarbamate derivative has been chosen as an example (Eq. 6) [24]. The radical deamination of primary amines can also be achieved under mild conditions via isocyanides, which are prepared easily via formylation and dehydration [26].An example is given in Eq. (7). The key steps of the reduction mechanisms are the addition of Bu3Sn' radicals to the C=S or N=C moieties to form a radical intermediate which undergoes p-scission to generate alkyl radicals. Hydrogen abstraction from the hydride gives the alkane and the Bu3Sn' radical, thus completing the cycle of this chain reaction.
34
1.3 Tin, Silicon und Related Reducing Agents
HOC(S)OPh
RO
RO
R,R = Si(i-Pr)*OSi(i-Pr)2
Bu3SnH, AlBN
*
C=N
PhH, 80 "C H
75%
&
(7)
H
89%
The denitration of tertiary nitroalkanes by Bu3SnH has proven to be an efficient synthetic methodology [27]. An example is illustrated in Eq. (8) [28]. The reaction proceeds via an intermediate nitroxide radical produced by addition of the tin radical to the oxygen atom of the nitro group followed by cleavage of the carbonnitrogen bond.
95%
Barton and coworkers have thoroughly investigated the radical chemistry of acyl derivatives of N-hydroxy-2-thiopyridone(Eq. 9) [29]. In the presence of Bu3SnH a smooth reaction takes place involving the addition of tin radicals to the thiocarbonyl moiety followed by a decarboxylation to generate R' radicals. This process provides an efficient route for reductive decarboxylation (Volume 1, Chapter 1.7).
RCOpH
O S OH
Bu3SnH t
RH
(9)
I
0
There is no doubt that Bu3SnH holds a privileged role as the reagent for reductive radical reactions. However, it should be mentioned that there are several problems associated with triorganotin reagents. The main one is the toxicity. Moreover,
1.3.3 Tin Hydrides
35
the formation of organotin compounds often makes workup and product isolation difficult, and therefore the desired products are frequently contaminated by traces of organotin compounds. Although a number of workup procedures have been proposed in order to deal with isolation problems [30], and a number of alternative approaches using tin hydrides have been developed (see below), the toxicity problems can be reduced but not eliminated.
1.3.3.2 Tin Hydrides Generated in situ In 1967 Hayashi and coworkers used polymethylhydrosiloxane (PMHS) to prepare organotin hydrides from the corresponding tin oxide derivatives (Eqs. 10 and 1 1 ) [31]. Since alkyl- or alkoxyl-substituted silanes do not react readily with reducible functional groups, it soon became clear that the use of organotin oxides for in situ preparation of tin hydrides in the presence of PMHS was a possibility [32].Several radical-based reductions have been performed to date using this approach [ 331. The performance of in situ generated tributyltin hydride has been shown in many cases to be similar to the pre-prepared one, although in some cases it was found to be less effective. ( B U ~ S ~ ) ~+O (Bu2SnO),
+
PMHS PMHS
-
-
Bu3SnH
(10)
Bu2SnH2
(11)
1.3.3.3 Tin Catalysts Tin hydrides (either pre-prepared or in situ generated) have usually been employed in stoichiometric amounts, and the products must be separated from tin-containing compounds. However, several processes using catalytic amounts of organotin species in radical reactions have been reported to date. The first of such processes was described by Corey and Suggs in 1975 [34]. They found that, in the presence of a catalytic amount of R3SnH (10 mol”/o) and a stoichiometric amount of NaBH4, bromides and iodides are dehalogenated in good yields. An example is reported in Eq. (12) and the catalytic cycle illustrated in Scheme 3. Later Giese and Stork in their studies on C-C bond formation applied this method in order to achieve low concentration of tin hydride [35, 361. More recently the development of another methodology that allows the in situ generation of catalytic amounts of tin hydride from tin halides with PMHS/KF has been reported [37].
ji:
9
Io C H 2 0 C H 3 OAc
Bu3SnCI(10 mol%) NaBH4 (2 equiv) in EtOH
-
20min/l O”C/hv
ji:
9
eCH20CH3
OAc
93%
1.3 Tin,Silicon and Related Reducing Agents
36
NaX + BH3
NaBH4
€k1:3: ~
turnover step
RH RX
radical process
Scheme 3. Catalytic cycle for the BujSnH-catalyzed reduction of alkyl iodides and bromides
Fu and co-workers have recently used tin catalysts to reduce thionocarbonates in which the turnover step is the reaction of Bu3SnOPh with PMHS (cf. Eq. 10) [38]. The same group has established Bu3SnH-catalyzed reductions of nitroalkanes to alkanes and azides to amines using PhSiH3 as the reagent for the regeneration of the tin catalyst [39, 401.
1.3.3.4 Polymer-Supported Organotin Hydrides In order to avoid contamination of the products by tin by-products as well as to simplify separation procedures some authors investigated polymer-supported organotin hydrides. Two approaches have been applied: (i) the functionalization of a polystyrene with organotin moieties [41, 421 and (ii) copolymerization of monomerbearing organotin functionalities [41, 431. The initial work of Neumann and coworkers was devoted to using polymer 4 to reduce bromides, thionocarbonates and isonitriles, and examples are shown in Eqs. (13)-(lq, respectively [44]. Apart from the simpler workup, it is worth mentioning that the polymer reagent can be regenerated for multiple use. The same group used polymer 4 as the mediator for C-C bond formation either in stoichiometric amounts of SnH moieties or in the catalytic version using NaBH4 as coreactant
WI. ?
C-C-C-C-Sn-I H2 H2 H2 H2 ,$,
Bu 4X=H 5X=CI
6
84%
1.3.3 Tin Hydrides
PhOC(S)O
37
80°C, 16h
80%
4. AlBN
Ye t-BUCHp-C-N=C
Me ~-BUCH~-$H
*
C6H6, 80°C, 47h
Me
Me
89%
On the other hand, Dumartin and coworkers prepared polymer-supported organotin hydrides in which the stannyl moieties are separated from the phenyl rings by 2-, 3-, and 4-carbon spacers and tested their reducing abilities by monitoring the reactions with haloalkanes [43]. The same group has also studied the reaction of polymer-supported tin hydrides generated in situ from the corresponding halides and NaBH4 with bromoadamantane and determined the residual tin pollution by ICP-MS [46]. Some results are reported in Table 3 together with the classical experiment using Bu3SnH/NaBH4 [46]. The tin content in ppm decreases along the entries 1 < 2 < 3, indicating that under normal conditions (entry 1) the content of tin is rather high.
1.3.3.5 Fluorous and Water-Soluble Tin Hydrides Highly fluorinated (fluorous) tin hydrides have been synthesized and studied as reagents for radical reactions by Curran's group [47]. These reagents are useful for reductive radical reactions and conducted in fluorinated solvents. An example is shown in Eq. (16). After completion, the reaction mixture was partitioned between CH2C12 and perfluoromethylcyclohexane (PFMC) by a simple liquid-liquid extraction. Catalytic procedures using fluorous tin hydride coupled with NaCNBH3 have also been developed. In this case, the reaction mixture was partitioned in threephase liquid extraction using the system water/CH2C12/PFMC.
Table 3. Reduction of 1 -bromoadamantane Entry
SnX/NaBH4"
Adamantane yield,
1
Bu,SnCI/NaBHI S/NaBH4 6/NaBH4
40 94
2 3
'Molar ratio 0.5. bAfter KF treatment.
70
%I
Tin content ppm
98000b 530 26
38
1.3 Tin, Silicon and Relutrd Reducing Agents
-
+ (n-C6F13CH2CH2)3SnH
90%
(16)
PFMC
(n-C6F13CH2CH2)3SnBr 95%
Water-soluble tin hydrides have been synthesized and studied as reducing agents for halides. The work of Breslow and coworkers is based on methoxyethoxypropyl substituents on the SnH moiety (7) in order to afford a water-soluble substrate 1481. Another procedure for the reduction of bromides in the presence of a base-soluble dialkyltin(1V) reagent (8) and NaBH4 has been carried out [49]. The use of Bu3SnH in water solubilized by a suitable detergent has also been reported for the reduction of halides [50].
7
8
1.3.4 Silicon Hydrides Tris(trimethylsilyl)silane, (TMS)3SiH, was introduced as an alternative to tin hydrides in the late 1980s 171.(TMS)3SiH has quickly proven to be a valid alternative to tin hydride for the majority of its radical chain reactions, although in some cases the two reagents can complement each other. Indeed, there is an increasing number of cases where the two reagents behave differently 181. Following the success of (TMS)3SiH, other organosilanes capable of sustaining analogous radical chain reactions have also been introduced.
1.3.4.1 Tris(trimethylsily1)silane The reductive removal of bromine and iodine atoms by (TMS)3SiH is facile, as with Bu3SnH. Again, a slight excess of silane is employed and a variety of solvents can be used. Two examples are given in Eqs. (17) and (1 8) [ 51, 521. Chlorides are also reduced reasonably well. An example is reported in Eq. (19) [53].
1.3.4 Silicon Hydrides
39
(TMS)3SiH *
0""
90%
A
H N 3
(TMS)$3iH
HN
RO *
AIBN, 80 "C PhCH3,2h
94%
0
(TMS)3SiH
*
AIBN, 80 "C
CI
OBz
OBZ
91%
Alkyl selenides are reduced by (TMS)3SiH, as expected, in view of the affinity of silyl radicals for selenium-containing substrates [54]. Equation (20) shows the phenylseleno removal from the 2'-position of a nucleoside sugar moiety [53]. 0
0
(TMS)3SiH AIBN / 80 "C
Ro@ RO
*
SePh R = TBDMS
.;":rRO
87%
Acyl chlorides and phenyl selenoesters have been reported to undergo reduction to the corresponding aldehydes and/or alkanes in the presence of (TMS)3SiH under free-radical conditions [lo]. The decrease of aldehyde formation through the primary, secondary and tertiary substituted series, under the same conditions, indicated that a decarbonylation of acyl radicals takes place. Equation (21) shows the reduc-
40
1.3 Tin,Silicon and Related Reducing Agents
tion of 1-adamantanecarbonyl chloride [ 551, whereas in Eq. (22) the phenylseleno ester afforded the decarbonylated p-lactam in good yield [56].
Q
(TMS)3SiH c
C(0)CI
AlBN I80"C
90%
(TMS)3SiH
*
AIBN / 80°C
--h O
Q
OMe
OMe 85%
The removal of the hydroxy group has been achieved from an appropriate selenocarbonate by heating with (TMS)$3H and AIBN in benzene. Equation (23) outlines a particular step in a multistep synthesis of an alkaloid [57]. OMOM
Mpe O h(O s )eC ~ c ~(~ o~ p
OMOM
(TMS)3SiH AlBN / 80°C
OMOM
NC
NC
Equation (24) has been chosen as an example of the radical deoxygenation of secondary alcohols via thiono esters [ 5 8 ] ,whereas Eq. (25) represents an example of deamination of primary amines via isocyanides [7, 541. The reaction mechanism of these reductions is similar to that described for tin hydride, i.e. attack of silyl radical on the C=S or N=C moieties to form a radical intermediate which undergoes ,&scission to form alkyl radicals. Hydrogen abstraction from the hydride gives the product and the (TMS)3Si' radical, thus completing the cycle of this chain reaction.
(TMS)3SiH
*
AIBN / 80°C :
Rd
(24)
',,
'OC(S)OPh
RO 94%
1.3.4 Silicon Hydvides OAc
41
OAc
The efficiency of these reactions coupled with the ease of purification and lack of toxicity of (TMS)3SiH and its by-products [59] have rendered this reducing agent a popular alternative to Bu3SnH in stoichiometric reactions. (TMS)3SiH has also been used as a reagent for driving the reduction of iodides and bromides through a radical mechanism with sodium borohydride, the reductant that is consumed [60]. The reduction of 1-bromonaphthalene is given as an example in Eq. (26). Br I
1.3.4.2 Other Organosilanes In Table 1 the reactivities of some organosilanes toward primary alkyl radicals are reported. The rate constants cover a range of several orders of magnitude and, therefore, the hydrogen donating abilities in organosilanes can be modulated by the substituents. Trialkylsilanes are not able to donate hydrogen atom at a sufficient rate to propagate the chain. The forced reduction of thionoesters by Et3SiH is not a common chain process [61, 621. In fact, the attack of primary alkyl radicals on Et3SiH occurs in about 60% of the cases at the SiH moiety and 40% at the ethyl groups at 130 "C [62]. Similar reactivities have been observed with other alkyl- and/or phenylsubstituted organosilanes having low hydrogen-donating abilities. Therefore these organosilanes do not to support chain reactions unless they are used at elevated temperatures and in the presence of large quantities of initiator [63]. A comparative example between PhzSiHz and (TMS)3SiH is given in Eq. (27) for the dideoxygenation of 1,6-anhydro-~-glucose[64].
PhOC(S)O
OC(S)OPh
PhzSiHz (4 equiv), AlBN (loo%), reflux toluene, 100 min, yield 46% (TMS)3SiH (2.2 equiv), AlBN (5%), reflux toluene, 30 min, yield 87%
42
1.3 Tin,Silicon and Related Reducing Agents
The reductions of organic halides, phenyl selenides, isonitriles and thionocarbonates with (TMS)ZSi(H)Meand (RS)3SiH are achieved under normal conditions [65, 661. Two examples are shown in Eqs. (28) and (29). (TMS)ZSi(H)Meis an effective reducing agent which allows the formation of the desired product to be favored because of a slower hydrogen transfer (Table I). cI
(TMS)*Si(H)Me
ip-;
-
7
W N , PhH reflux
0
0
94%
(MeS)3SiH
mNC PhH reflux* AIBN,
L3 90%
The introduction of 9,lO-disilaanthracenes as the alternative silanes for the reduction of halides and thionocarbonates has been proposed [67, 69J. Two examples are given in Eqs. (30) and (31). The rate constants for hydrogen abstraction from these substrates depend on the number of available hydrogens and can reach values as high as (TMS)3SiH (Table 1). H H
.
.
R d
*
, I
6C(S)OPh
AIBN, PhH reflux
R d
96%
aE '0 Me H
H 'Me
AIBN, PhH reflux h N H Ph
87%
Poly(phenylsi1ane)s have been used as radical-based reducing agents for organic halides [70]. The reduction of a bromide is given as an example in Eq. (32). 1,1,2,2Tetraphenyldisilane has also been introduced as a diversified radical reagent for the reduction of alkyl bromides and phenyl chalcogenides [71]. An example with 3cholestanyl phenyl selenide is given in Eq. (33).
1.3.5 Comparison hrlween BujSnH und (TMSJ3SiH
43
*
AIBN, PhH reflux
Me0
0
Me0
90%
99%
1.3.5 Comparison between Bu3SnH and (TMS)3SiH As mentioned earlier, the rate constant for the reduction of a variety of radicals with BuiSnH and (TMS)3SiH decreases along the series Ph' > t-BuO' > RfCFz' > RCH2' > RC(0)'. For any particular radical the rate constant for (TMS)3SiH is always lower than that for B u ~ S ~ the H , difference being smaller at higher regions of the kinetic scale (cf. Table 2). On the other hand, (TMS)3Si' radicals are always more reactive that Bu3Sn' radicals toward organic substrates [72]. For example, the reactivity trends for the reaction with alkyl halides (RX) are the following: (i) for a particular X group the rate constants decrease for both Bu$n' and (TMS)3Si' radicals along the series R = benzyl > tertiary alkyl > secondary alkyl > primary alkyl > aryl or vinyl, (ii) for a particular R group the rate constants decrease for both Bu3Sn' and (TMS)3Si' radicals along the series X = I > Br > C1 and (iii) although the reactivities of Bu&' and (TMS)3Si' with either RBr or RI are similar, the rate constants of chlorides with (TMS)3Si' radical are ca. 10 times higher than with Bu3Sn' radicals. Therefore, (TMS)3SiH should be the reagent of choice with chlorides [73]. Apeloig, in his paper on the reduction of gem-dichlorides, demonstrated that the different spatial shapes of Bu3SnH or (TMS)3SiH can lead to different, even reversed, product stereoselectivities (Eq. 34) [74]. In other words, there is a stronger preference for (TMS)3SiH which has a spherical and more rigid shape than Bu3SnH to transfer a hydrogen atom from the less hindered side of the ring. Following this concept, the reduction of the dichloride depicted in Eq. (35) with (TMS)3SiH at room temperature afforded the desired monochloride in high stereoselectivity, whereas the stannane gave the other epimer as the major product [75].
BuaSnH
(TMS)3SiH
1.9:l 1 : 1.3
44
1.3 Tin, Silicon and Related Reducing Agents cCI ,+"-yoyPh
Et3B, r.t. +
MeO2C-(lo&O H
Bu3SnH (TMS13SiH
83% (1 :I .6) 98% (13:l)
Ishido and coworkers have recently developed a highly diastereoselective and efficient method for the synthesis of (2'R)- or (2'S)-2'-deoxy[2'-2H]ribonucleoside derivatives starting from the corresponding bromides or thionocarbonates at 2'position [76]. Equations (36) and (37) were chosen in order to allow a comparison between (TMS)3SiH and Bu3SnH. Reduction of 9 with the two reagents, under identical experimental conditions, afforded the products in the same yield, although with (TMS)3SiH higher diastereoselectivity was observed. On the other hand, reduction of 10 showed the same results in terms of yield and diastereoselectivity, but with tin hydride lower temperatures such as -60 "C were necessary. 0
Et3B , THF, 0°C
AN
-
O
90% OR H 9 R,R = Si(CPr)20Si(i-Pr)2
(TMS)SSiH
(2'S):(2'R)= 98.5:i.3
Bu3SnH
(2'S):(2'R)= 91.8:8.2
0
H.3 A O N
Et3B , THF, 0°C
AN
O *
(37)
90% OR
br
10 R,R = Si(;-Pr)zOSi(CPr)2
OR D (TMS)3SiD/ 0°C
1 -600c
(2R):(2'S)> 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.
References [ I ] S. N . Lewis, J. J . Miller, S. Winstein, J. Org. Chem. 1972, 37, 1478 -1484. [2] For reviews, see: a) M. Ramaiah, Tetrahedron 1987, 43, 3541-3676; b) D. P. Curran, Synthesis 1988, 417-439, 489-513; c) C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, Y I , 1237-1286. For a collection of relative rate constants for B-fragmentation reactions see: P. J. Wagner, J. H. Sedon, M. J. Lindstrom, J. Am. Chem. Soc. 1978,100,2579-2580. [3] a) M. Kosugi, K. Kurino, K. Takayama, T. Migita, J. Organomet. Chem. 1973, 56, Cll-C13; b) J. Grignon, M. Pereyre, J. Organomet. Chem. 1973,61, C33-C35; c) J. Grignon, C. Servens, M. Pereyre, J. Organomet. Chem. 1975, 96, 225-235. [4] For a recent review of fragmentation processes in free radical polymerization reactions see: D. Colombani, P. Chaumont, Prog. Polym. Sci. 1996, 21, 439-503. 151 For a review of the synthesis of allyltin derivatives see: S. Jarosz, E. Kozlowska, Polish J. Chem. 1998, 72, 8 15-83 1. [6] G. E. Keck, J. B. Yates, J. Org. Chem. 1982, 47, 359-3591. [7] a) G. E. Keck, J. B. Yates, J. Am. Chem. Soc. 1982, 104, 5829-5831; b) G. E. Keck, E. J. Enholm, J. B. Yates, M. R. Wiley, Tetruhedron 1985, 41, 4079-4094. [8] a) C. J. Easton, Chem. Reu. 1997, Y7, 53--82; b) C. J. Easton, I. M. Scharfbillig, E. W. Tan, Tetrahedron Lett. 1988, ZY, 1565-1568; c) C. J. Easton, I. M. Scharfbillig, J. Ory. Chem. 1990, 55, 384-386; d) J. E. Baldwin, R. M. Adlington, C. Lowe, 1. A. O’Neil, G. L. Sanders, C. J. Schofield, J. B. Sweeney, J. Chem. Soc., Chem. Commun. 1988, 1030-1031. [9] a) D. P. G. Hamon, R. A. Massy-Westropp, P. Razzino, J. Chem. Soc., Chem. Commun. 1991, 722-724; b) D. P. G. Hamon, R. A. Massy-Westropp, P. Razzino, Tetrahedron 1995, 51, 41 83-4194. [lo] S. Kano, T. Yokomatsu, S. Shibuya, J. Org. Chem. 1989, 54, 513-515. [ I I ] G. A. Kraus, B. Andersh, Q. Su, J. Shi, Tetruhedron Lett. 1993, 34, 1741-1744. [I21 B. A. Roe, C. G. Boojamra, J. L. Griggs, C. R. Bertozzi, J. Org. Chem. 1996, 61, 64426445. [I31 For reviews on the stereoselectivity of free radical reactions see: a) M. P. Sibi, N. A. Porter, Ace. Chem. Res 1999, 32, 163-171; b) D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of Radical Reactions, VCH, Weinheim, 1996; c) W. Smadja, Svnlett 1994, 1-26; d) N . A. Porter, B. Giese, D. P. Curran, Ace. Chem. Rex 1991, 24, 296-304. [I41 A. L. J. Beckwith, R. Hersperger, J. M. White, J. Chem. Soc., Chem. Commun. 1991, 11511152. [I51 a) P. Renaud, P.-A. Carrupt, M. Gerster, K. Schenk, Tetrahedron Lett. 1994, 35, 1703-1706; b) P. Renaud, T. Bourquard, Tetrahedron Lett. 1994, 35, 1707-1710. [ 161 D. J. Hart, R. Krishnamurthy, J. Ory. Chem. 1992, 57, 4457-4470. [I71 a) Y. Guindon, G. Jung, B. Guerin, W. W. Ogilvie, Synlett 1998, 213-220; b) Y. Guindon, B. Guerin, J. Rancourt, C. Chabot, N. Mackintosh, W. W. Ogilvie, Pure Appl. Chem. 1996, 68, 89-96. [I81 N . A. Porter, I. J. Rosenstein, R. A. Breyer, J. D. Bruhnke, W.-X. Wu, A. T. McPhail, J. Am. Chem. Soc. 1992, 114, 7664-7676. 1191 J. G. Stack, D. P. Curran, S. V. Geib, J. Rebek, P. Ballester, J. Am. Chem. Soc. 1992, 114, 7007-701 8. [20] M. P. Sibi, J. Ji, Angew. Chem. Znt. Ed. Engl. 1996, 35, 190-192. [21] J. H. Wu, R. Radinov, N. A. Porter, J. Am. Chem. Soc. 1995, 117, 11029-11030. [22] D. P. Curran, P. A. van Elburg, B. Giese, S. Gilges, Tetruhedron Lctt. 1990, 31, 2861-2864.
70
1.4 Radical Fragmrntution Reactions
[23] For a discussion of the importance of polar effects in free radical addition reactions see: B. Giese, Angew. Clirm. Int. Ed. Engl. 1983, 22, 753-764. (241 K. Mizuno, M. Ikeda, S. Toda, Y. Otsuji, J. A n t Clietn. Soc. 1988, 110, 1288-1290. [25] D. P. Curran, W. Shen. J. Zhang, T. A. Heffner, J. Am. Chem. Soc. 1990, 112, 6738-6740. [26] M. P. Sibi, J. Ji, J. Or<].Clien?. 1996, 61, 6090-6091. 127) I. Ryu, H. Yamazaki, K. Kusano, A. Ogawa, N. Sonoda, J. Am. Chem. Soc. 1991, 113, 85588560. [28] I. Ryu, H. Yamazaki, A. Ogawa, N. Kambe, N. Sonoda, J. Ani. Cliem. Soc. 1993, 115, 11871189. 1291 G. E. Keck, J. B. Yates, J. Organonzet. Cliem. 1983, 248, C21bC25. RJ. [30] J. E. Baldwin, R. M. Adlington. D. J. Birch, J. A. Crawford, J. B. Sweeney, J. C ~ J ~ Sue.. Cliem. Cotnm. 1986, 1339- 1340. [31] E. Lee, S.-G. Yu: C.-U. Hur, S.-M. Yang; Tetruhedron Lett. 1988, 29; 6969-6970. [32] P. Renaud, M. Gerster, M. Ribezzo, Chiniiu, 1994, 48, 366-369. [33] D. P. Curran, B. Yoo, Tetruhedron Lett. 1992, 33, 6931-6934. [34] D. L. J. Clive, C. C. Paul, Z. Wang, J. Org. Clzem. 1997,62, 7028-7032. [35] a) B. S. Edelson, B. M. Stoltz, E. J. Corey, Tetrahedron Lett. 1999, 40, 6729-6730; b) P. Renaud, E. Lacote, L. Quaranta, Tetralzedron Lett. 1998, 39, 2123-2126; c ) D. Crich, S. Sun, J. Org. Clzem. 1996, 61, 7200-7201. [36] E. Fouquet, M. Pereyre, T. Roulet, J. Clietn. Soc.. Clietn. Commun. 1995, 2387-2388. [37] F. Ferkous, M. Degueil-Castaing, H. Deleuze, B. Maillard, Main Group Metal Chem. 1997, 20>75-80. 1381 a) D. P. Curran. Z. Luo, P. Degenkolb, Biory. & Med Cliern. Lett. 1998, 8, 2403-2408; b) I. Ryu, T. Niguma, S. Minakata, M. Komatsu, Z. Luo. D. P. Curran, Tetruhedron Lett. 1999, 40,2367-2370. [39] E. J. Enholm, M. E. Gallagher, K. M. Moran, J. S. Lombardi, J. P. Schulte, Org. Lett. 1999, I , 689-691. [40] a) G. E. Keck, E. J. Enholm, Tetruhedron Lett. 1985, 26, 331 1 -3314; b) G. E. Keck, E. N. K. Cressman, E. J. Enholm, J. Org. C h n . 1989, 54,4345-4349. 1411 S. J. Danishefsky, J. S. Panek, J. Ani. Chem. Soc. 1987, 109, 917-918. [42] J. E. Baldwin, R. M. Adlington, M. B. Mitchell, J. Robertson, Tetruhedr-on 1991, 47; 59015918. [43] a) G. A. Russell, H. Tashtoush, P. Ngoviwatchai, J. A m . Chew. Soc. 1984, 106, 4622-4623; b) G. A. Russell, P. Ngoviwatchai, Tetmlieilron Lett. 1985, 26, 4975-4978; c ) G. A. Russell, P. Ngoviwatchai, H. Tashtoush, Oryanonietullics 1988, 7, 696-702. 1441 a) J. E. Baldwin, D. R. Kelly, C. B. Ziegler, J. Cliern. Soc., (%ern. Commun. 1984, 133-134; b) J. E. Baldwin, D. R. Kelly, J. Chem. Soc., Clieni. Cowitnun. 1985, 682-684; c) G. E. Keck, D. A. Burnett, J. Org. Cliem. 1987, 52, 2958-2960; d) A. M. Gomez, J. C. Lopez, B. FraserReid, J. Clic~tn.Soc., Perkin Trans. I 1994, 1689-1695. [45] F. L. Harris, L. Weiler, Tetrahedron Lett. 1987, 28, 2941-2944. 1461 J. E. Baldwin, R. M. Adlington, A. Basak, J. Clwni. Soc., Chern. Commun. 1984, 128441285, 1471 a) M. Etheve-Quelquejeu, J.-M. Valery, Tetralzrdron Lett. 1999, 40, 4807-4810; b) S. Becouarn, S. Czernecki, J.-M. Valery, Tetralieclron Lett. 1995, 36, 873-876. [48] Y. Ueno, K. Chino, M. Okawara, Tetralzedron Lrtt. 1982, 23, 2575-2576. [49] D. E. Ward, B. F. Kaller, Tetrahcdon Lett. 1991, 32, 843-846. [50] G. E. Keck, J. H. Byers, J. Org. Cliem.1985, 50, 5442-5444. [Sl] G. E. Keck, A. M. Tafesh, J. Org. Clitv~.1989, 54, 5845-5846. [52] A. Yanagisawa, Y. Noritake, H. Yamamoto, Cheni. Lett. 1988, 1899-1902. [53] D. H. R. Barton, D. Crich, J. ChPm. Soc., Perkin Trans. I 1986, 1613-1619. [54] D. Crich, C. Chen, J.-T. Hwang, H. Yuan, A. Papadatos, R. I. Walter, J. Am. Chem. Soc. 1994, 116, 8937-8951. [ 5 5 ] B. Yoo, D. P. Curran, Bull. Korean Chenz. Soc. 1996, 17, 1009-1018. [56] F. Ponten, G. Magnusson, J. Org. Clzetn. 1996, 61, 7463-7466. 1571 S. Caddick, K. Aboutayab, R. I. West, J. Chem. Soc., Clzem. Commun. 1995, 1353-1354. [58] C. Chatgilialoglu, A. Alberti, M. Ballcstri, D. Macciantelli, D. P. Curran, Tetrahedron Lett. 1996, 37, 6391 6394.
References
71
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
89
[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.
References [ I ] P. Girard, J. L. Namy, H. B. Kagan, J. Am. Cliem. Soc., 1980, 102, 2693. [2] (a) H. B. Kagan, J.-L. Namy, Top. Organornet. Chem., 1999, 2, 155. (b) G. A. Molander, C. R. Harris, C/iem. Rev., 1996, 96, 307. (c) G. A. Molander, Ory. React., 1994, 46, 21 1. (d) D. P. Curran, T. L. Fevig, C. P. Jasperse, M. J. Totleben, Synlett, 1992, 943. (e) J. A. Soderquist, AIdrichimica Actu, 1991, 24, 15. (f) H. B. Kagan, N e w J. Chem., 1990, 14, 453. [3] G . A. Molander, L. S. Harring, J. Org. Chem., 1990, 55, 6171. [4] (a) E. Hasegawa, D. P. Curran, Tetruhedron Lett., 1993, 34, 1717. (b) R. J. Enemzrke, K. Daasbjerg, T. Skrydstrup, J. Clzem. Soc., Chem. Commun., 1999, 343. (c) M. Shabangi, M. L. Kuhlman, R. A. Flowers, 11, Org. Lett.. 1999, I , 2133. [5] (a) X. Lu, S. Ma, J. Zhu, Tetraliedron Lett., 1988, 29, 5129. (b) S. Ma, X. Lu, J. Chem. Soc., Perkin Trans. 1990, I , 2031. (c) S. Ma, X. Lu, Tetra/iedron, 1990, 46, 357. (d) S.-K. Kang, C.-H. Park, S.-G. Kim, W.-T. Oh, Bull. Korean Chem. Soc., 1991, 12, 716. (e) M. Yoshida, D. Suzuki, M. Iyoda, Cliem. Lett., 1994, 2357. [6] A. Chenede, E. Perrin, E. D. Rekai', P. Sinay, Synktt, 1994, 420. [7] (a) Z. Zhou, S. M. Bennett, Tetrahedron Lett., 1997, 38, 1153. (b) G. A. Molander, C. H. Harris, J. Ory. Cllem., 1997, 62, 7418. (c) S. M. Bennett, R. K. Biboutou, Z. Zhou, R. Pion, Tetralie(lron, 1998, 54, 4761, (d) S. M. Bennett, R. K. Biboutou, B. S. F. Salari, Tetrahedron Lett., 1998, 39, 7075. (e) H. David, C. Afonso, M. Bonin, G. Doisneau, M.-G. Guillerez, F. Guibe, Tetrulzedron Lett., 1999, 40, 8557. (81 C. R. Harris, Ph. D. Thesis, University of Colorado at Boulder, 1997. [9] D. P. Curran, R. L. Wolin, Synlett, 1991, 317. [ l o ] W. Cabri, I. Candiani, M. Colombo, L. Franzoi, A . Bcdeschi, Tetrahedron Lett., 1995, 36, 949.
References
119
[ I I ] (a) Z. Zhou, D. Larouche, S. M. Bennett, Tetrahedron, 1995,51, 11623. (b) E. J. Corey, G. Z . Zheng, Tetrahedron Lett., 1997, 38, 2045. [I21 J.-P. Dulcere, E. Dumez, R. Faure, Synlett, 1996, 391. [I31 (a) C. F. Sturino, A. G. Fallis, J. Org. Chem., 1994, 59, 6514. (b) C. F. Sturino, A. G. Fallis, J. Am. Chem. Soc., 1994, 116, 7447. [ 141 S. Fukuzawa, T. Tsuchimoto, Synlett, 1993, 803. 1151 D. P. Curran, M. J. Totleben, J. Am. Chem. Soc., 1992, 114, 6050. 116) Y. Aoyagi, T. Inariyama, Y. Arai, S. Tsuchida, Y. Matuda, H. Kobayashi, A. Ohta, T. Kurihara, S. Fujihara, Tetrahedron, 1994, 50, 13575. [I71 (a) P. de Pouilly, A. Chenede, J.-M. Mallet, P. Sinay, Tetrahedron Lett., 1992, 33, 8065. (b) A. ChenedC, E. Perrin, E. D. Rekai’, P. Sinay, Synlett, 1994, 420. [I81 (a) D. Mazeas, T. Skrydstrup, 0. Doumeix, J.-M. Beau, Angew. Chem., Int. Ed. Enyl., 1994, 33, 1383. (b) T. Skrydstrup, D. MazCas, M. Elmouchir. G. Doisneau, C. Riche. A. Chiaroni, J.-M. Beau, Chem. Eur. J., 1997, 3, 1342. 1191 S.-C. Hung, C.-H. Wong, Angeiv. Chem., Znt. Ed. Engl., 1996, 35, 2671. [20] (a) J. Aurrecoechea, A. Fernandez-Acebes, Tetrahedron Lett., 1993, 34, 549. (b) J. Aurrecoechea, A. Fernandez-Acebes, Synlett, 1996,39. (c) J. Aurrecoechea, B. Lopez, A. Fernindez, A. Arrieta, F. P. Cossio, J. Org. Chem., 1997, 62, 1125. (d) J. Aurrecoechea, A. Fernandez, J. M. Gorgojo, C. Saornil, Tetrahedron, 1999, 55, 7345. [21] L. A . Buttle, W. B. Motherwell, Tetrahedron Lett., 1994, 35, 3995. [22] M. Kunishima, K. Hioki, K. Kono, T. Sakuma, S. Tani, Chem. Phurm. Bull., 1994,42,2190. [23] D. P. Curran, T. L. Fevig, M. J. Totleben, Synlett, 1990, 773. [24] (a) J. Inanaga, 0. Ujikawa, M. Yamaguchi, Tetrahedron Lett., 1991, 32, 1737. (b) D. P. Curran, M. Totleben, J. Am. Chern. Soc., 1992, 114, 6050. [25] G. A. Molander, C. R. Harris, Tetrahedron, 1998, 54, 3321. [26] C. W. Holzapfel, D. B. G. Williams, Tetrahedron, 1995, 51, 8555. 1271 (a) X. Du, R. W. Armstrong, J. Ory. Chem., 1997, 62, 5678. (b) X. Du, R . W. Armstrong, Tetrahedron Lett., 1998, 39, 228 1. [28] (a) L. Capella, P. C. Montevecchi, Tetrahedron Lett., 1994, 35, 8445. (b) L. Capella, P. C. Montevecchi, J. Ory. Chem., 1995, 60, 7424. (c) H.-Y. Kang, M. S. Park, B.-N. Park, H. Y. Koh, Bull. Koreun Chem. Soc., 1997, 18, 1240. [29] (a) J. Souppe, L. Danon, J. L. Namy, H. B. Kagan, J. Organornet. Chem., 1983, 250, 227. (b) J. L. Namy, J. Souppe, H. B. Kagan. Tetruhedron Lett., 1983; 24; 765. [30] (a) Y. Handa, J. Inanaga, Tetrahedron Lett., 1987, 28, 5717. (b) J . S . Shiue, C.-C. Lin, J.-M. Fang, Tetruhedron Lett., 1993, 34, 335. (c) R. Nomura, T. Matsuno, T. Endo, J. Am. Chem. Soc., 1996, 118, 11666. (d) B. Hamann, J.-L. Namy, H. B. Kagan, Tetrahedron. 1996, 52, 14225. (e) T. Honda, M. Katoh, J. Chem. Soc., Chern. Comniun., 1997, 369. ( f ) L. Wang, Y. Zhang, Tetrahedron, 1998, 54, 1 1 129. (g) L. Wang, Y. Zhang, Synth. Conimun., 1998, 28, 3991. (h) N. Akane, T. Hatano, H. Kusui, Y. Nishiyama, Y. Ishsi, J. Org. Chem., 1994, 59, 7902. [31] M. Yamashit, K. Okuyama, I. Kawasaki, S. Ohta, Tetrahedron Lett., 1996, 37, 7755. [32] H. L. Pedersen, T. B. Christensen, R. J. Enemrerke, K. Daasbjerg, T. Skrydstrup, Eur. J. Org. Chem., 1999, 565. [33] T. B. Christensen, D. Riber, K. Daasbjerg, T. Skrydstrup, J. Chem. Soc., Chenz. Commun., 1999, 2051. [34] (a) N. Taniguchi, M. Uemura, Tetrahedron Lett., 1998, 39, 5385. (b) N. Taniguchi, N. Kaneta, M. Uemura, J. Org. Chem., 1996, 61, 6088. (c) N. Taniguchi, M. Uemura, Tetrahedron, 1998, 54, 12775. (351 (a) N. Miyoshi, S. Takeuchi, Y. Ohgo, Clzem. Lett., 1993, 959. (b) N . Miyoshi, S. Takeuchi, Y. Ohgo, Cliem. Lett., 1993, 2129. . h m . , 1988, 53, 2132. (b) G. A. Molander, C. Kenny, [36] (a) G. A. Molander, C. Kenny, J. O r ~ jC J. Am. Cliem. Soc., 1989, I l l , 8236. 1371 (a) J. L. Chiara, W. Cabri, S. Hanessian, Tetrahedron Lett., 1991, 32, 1125. (b) J. L. Chiara, M. Martin-Lomas, Tetruhedron Lett., 1994, 35, 2969. (c) A. Kornienko, D. I. Turner, C. H. Jaworek, M. d’Alarcao, Tetrahedron: Asymmetry, 1998. 9, 2783. (d) A. Kornienko, G. Marnera, M. d’Alarcao. Curhohydr. Rex, 1998, 310. 141. (e) M. Adinolfi, G. Barone, A. Iadonisi,
180
2.1 Samarium (II) Mediuted Radical Reactions
L. Mangoni, Tetrahedron Lett., 1998, 39, 2021. (f) J. P. Guidot, T. Le Gall, C. Mioskowski, Tetrahedron Lett., 1994, 36, 6671. [38] (a) C. Anies, A. Pancrazi, J.-Y. Lallemand, T. Prange, Tetrahedron Lett., 1994, 35, 7771. (b) C. Anies, A. Pancrazi, J.-Y. Lallemand, T. Prange, Bull. Soc. Chim. Fr., 1997, 134, 203. [39] (a) N. Taniguchi, T. Hata, M. Uemura, Angew. Chem., Int. Ed. Enyl., 1999,38, 1232. (b) A. 0. Larsen, R. A. Taylor, P. S. White, M. R. Gagne, Orgunometal/ics, 1999, 18, 5157. [40] J. Uenishi, S. Masuda, S. Wakabayashi, Tetrahedron Lett., 1991, 32, 5097. [41] M. Kawatsura, E. Kishi, M. Kito, T. Sakai, H. Shirahama, F. Matsuda, Synlett, 1997, 479. [42] (a) K. Takatori, Y. Takeuchi, Y. Sinohara, K. Yamaguchi, M. Nakamura, T. Hirosawa, T. Shimizu, M. Saito, S. Aizawa, 0. Sugiyama, Y. Ohtsuka, M. Kajiwdra, Synkdt, 1999, 975. (b) S. Arseniyadis, D. V. Yashunsky, P. R. de Freitas, M. M. Dorado, E. Toromanoff, P. Potier, Tetrahedron Lett., 1993, 34, 1 137. [43] (a) T. Kan, F. Matsuda, M. Yanagiya, H. Shirahama, Synlett, 1991, 391. (b) T. Kan, S. Hosokawa, S. Nard, M. Oikawa, S. Ito, F. Matsuda, H. Shirahama, J. Org. Chem., 1994, 59, 5532. [44] (a) H. M. R. Hoffmann, A. M. ELKhawaga, H.-H. Oehlerking, Chem. Ber., 1991, 124, 2147. (b) 0. Nowitzki, 1. Miinnich, H. Stucke, H. M. R. Hoffmann, Tetrahedron, 1996, 52, 11799. [45] T. Hanamoto, J. Inanaga, Tetruhedron Lett., 1991, 32, 3555. [46] (a) T. Imamoto, S. Nishimura, C h m . Lett., 1990, 1141. (b) F. Machrouhi, J.-L. Namy, Tetrahedron Lett., 1999, 40, 1315. [47] (a) J. Marco-Contelles, P. Gallego, M. Rodriguez-Fernindez, N. Khiar, C. Destabel, M. BernabC, A. Martinez-Grau, J. L. Chiara, J. Org. Chem., 1997, 62, 7397. (b) H. Miyabe, M. Toriedo, K. Inoue, K. Tajiri, T. Kiguchi, T. Naito, J. Org. Chem., 1998, 63, 4397. (c) H . Miyabe, S. Kanehira, K. Kume, H. Kandori, T. Naito, Tetrahedron, 1998, 54, 5883. (d) T. Kiguchi, M. Okazaki, T. Naito, Heterocycles, 1999, 51, 2711. (e) I. S. de Gracia, S. Bobo, M. D. Martin-Ortega, J. L. Chiara, Org. Lett., 1999, I , 1705. [48] E. J. Enholm, D. C. Forbes, D. P. Holub, Synth. Commun., 1990,20, 981. 1491 (a) G. A. Kraus, 0. S. James, J. Org. Chem., 1989, 54, 77. (b) G. A. Kraus, Z. Wan, Tetruhedron Lett., 1997, 38, 6509. (c) G. A. Molander, C. N. Wolfe, J. Org. Chem., 1998, 63, 9031. (b) L. Zhou, Y. Zhang, D. Shi, Tetrahedron Lett., 1998, 39, 8491. [50] Y.-S. Liu, M.-Z. Bei, Z.-H. Zhou, K. Takaki, Y. Fujiwara, Chem. Lett., 1992, 1143. 1511 A. Ogawa, N. Takami, M. Sekiguchi, I. Ryu, N. Kambe, N. Sonoda, J. Am. C/iem. Soc., 1992, 114, 8729. [52] (a) H. 0. House, Modern Synthetic Reactions, 2"d Ed., W. A. Benjamin, Menlo Park, CA, 1972. (b) I. Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley Interscience, New York, 1976. [53] (a) S. Fukuzawa, A. Nakanishi, T. Fujinami, S. Sakai, J. Chem. Soc., Chem. Commun., 1986, 624. (b) K. Otsubo, J. Inanaga, M. Yamaguchi, Tetrahedron Lett., 1986, 27, 5763. (c) S. Fukuzawa, A. Nakanishi, T. Fujinami, S. Sakai, J. Chem. Soc., Perkin Trans. I , 1988, 1669. (d) E. J. Corey, G. Z. Zheng, Tetrahedron Lett., 1997, 38, 2045. [54] (a) M. Kawatsura, F. Matsuda, H. Shirahama, J. Org. Chem., 1994, 59, 6900. (b) M. Kawatsura, K . Hosaka, F. Matsuda, H. Shirahama, Synlett, 1995, 729. (c) F. Matsuda, M. Kawatsura, K. Hosaka, H. Shirahama, Chem. Eur. J . , 1999, 5, 3252. [55] F. Matsuda, M. Kawatsura, F. Dekura, H. Shirahama, J. Chem. Soc., Perkin Trans., I , 1999, 2371. [56] K. Mikami, M. Yamaoka, Tetrahedron Lett., 1998, 39, 4501. [57] S. Fukuzawa, K. Seki, M. Tatsuzawa, K. Mutoh, J. A m . Chem. Soc., 1997, Z I Y , 1482. [58] G. A. Molander, M. Sono, Tetrdiedron, 1998, 54, 9289. [59] 0. Ujikawa, J. Inanaga, M. Yamaguchi, Tetrahedron Lett., 1989, 30, 2837. [60] (a) N. Taniguchi, M. Uemura, Tetrahedron Lett., 1997, 38, 7199. (b) C. A. Merlic, J . C. Walsh, Tetrahedron Lett., 1998, 39, 2083. [61] Y. H. Kim, H. S. Park, D. W. Kwon, Synth. Commun., 1998, 28, 4517. [62] J.-S. Shiue, M.-H. Lin, J.-M. Fang, J. Org. Chem., 1997, 62, 4643. [63] (a) J. Inanaga, J. Katsuki, 0. Ujikawa, M. Yamaguchi, Tetrahedron Lett., 1991, 32, 4921. (b) J. Inanaga, 0. Ujikawa, Y. Handa, K. Otsubo, M. Yamaguchi, J. Alloys Compd., 1993, 192, 197.
References
18 1
[64] (a) J. M. Aurrecoechea, M. Solay, Tetrahedron Lett., 1995, 36, 2501. (b) J. M. Aurrecoechea, E. Alonso, M. Solay, Tetrahedron, 1998, 54, 3833. [65] (a) K. Weinges, S. B. Schmidbauer, H. Schick, Chem. Ber., 1994, 127, 1305. (b) D. Johnston, C. M. McCusker, D. J. Procter, Tetrahedron Lett., 1999, 40, 4913. Chem. Com1661 (a) S. Fukuzawa, M. Iida, A. Nakanishi, T. Fujinami, S. Sakai, J. Chem. SOC., mun., 1987, 920. (b) E. J. Enholm, A. Trivellas, Tetrahedron Lett., 1989, 30, 1063. (c) H.-Y. Kang, H. Y. Koh, M. H. Chang, J.-T. Hwang, S. C. Shim, Bull. Korean Chem. Soc., 1994, 15, 710. [67] S. R. Angle, J. D. Rainier, J. Org. Chem., 1992, 57, 6883. [68] Y.-S. Hon, L. Lu, K.-P. Chu, Synth. Commun., 1991, 21, 1981. [69] M. Kito, T. Sakai, K. Yamada, F. Matsuda, H. Shirahama, Synlett, 1992, 158. 1701 M. Kito, T. Sakai, N. Haruta, H. Shirahama, F. Matsuda, Synlett, 1996, 1057. [71] K. Tadano, Y. Isshiki, M. Minami, S. Ogawa, J. Org. Chem., 1993, 58, 6266. [72] H. Sakai, H. Hagiward, Y. Ito, T. Hoshi, T. Suzuki, M. Ando, Tetrahedron Lett., 1999, 40, 2965. [73] (a) N. Hori, H. Matsukura, T. Nakata, Organic Lett., 1999, I , 1099. (b) N. Hori, H. Matsukura, G. Matsuo, T. Nakata, Tetrahedron Lett., 1999, 40, 2811. (c) G. Matsuo, N. Hori, T. Nakata, Tetrrrhedron Lett., 1999, 40, 8859. [74] L. G. Monovich, Y. Le Huerou, M. Ronn, G. A. Molander, J. Am. Chem. SOC.,2000,122, 52. [75] (a) J.-S. Shiue, J.-M. Fang, J. Chem. Soc., Chem. Commun., 1993, 1277. (b) S. J. F. Macdonald, K. Mills, J. E. Spooner, R. J. Upton, M. D. Dowle, J. Chem. Soc., Perkin Trans. I , 1998, 3931. [76] E. J. Enholm, A. Trivellas, Tetrahedron Lett., 1994, 35, 1627. [77] G. A. Molander, J. A. McKie, J. Org. Clzem., 1995, 60, 872. [78] S. C. Suri, K. I. Hardcastle, J. Org. Chem., 1992, 57, 6357. [79] T.-H. Chuang, J.-M. Fang, W.-T. Jianng, Y.-M. Tsdi, J. Org. Chem., 1996, 61, 1794. [80] J. J. C. Grove, C. W. Holzapfel, D. B. G. Williams, Tetrahedron Lett., 1996, 37, 5817. [81] G. A. Molander, C. Kenny, Tetrahedron Lett., 1987, 28, 4367. [82] (a) J. E. Baldwin, S. C. M. Turner, M. G. Moloney, Tetrahedron Lett., 1992, 33, 1517. (b) J. E. Baldwin, S. C. M. Turner, M. G. Moloney, Tetrahedron, 1994, 50, 9411. 1831 C. U. Dinesh, H.-U. Reissig, Angew. C/7em, Int. Ed Engl., 1999, 38, 789. 1841 (a) H . G . Schmalz, S. Siegel, J. W. Bats, Angew. Chem., Int. Ed. Engl., 1995, 34, 2383. (b) H.-G. Schmalz, S. Siegel, A. Schwarz, Tetrahedron Lett., 1996, 37, 2947. I851 0. Hoffmann, H.-G. Schmalz, Synlett, 1998, 1426. [86] M.-C. P. Yeh, F.-C. Wang, J.-J. Tu, S.-C. Chang, C.-C. Chou, J.-W. Liao, Organometal/ics, 1998, 17, 5656. 1871 (a) G. A. Molander, J. A. McKie, J. Org. Chem., 1994, 59, 3186. (b) F. A. Khan, R. Czerwonka, R. Zimmer, H.-U. Reissig, Synlett, 1997, 995. [88] R. J. Boffey, M. Santdgostino, W. G. Whittingham, J. D. Kilburn, J. Chem. Soc., Chem. Commun., 1998, 1875. [89] T. Gillmann, Tetrahedron Lett., 1993, 34, 607. 1901 (a) S. C. Shim, J.-T. Hwang, H.-Y. Kang, M. H. Chang, Tetrahedron Lett., 1990, 31, 4765. (b) J. E. Baldwin, S. C. M. Turner, M. G. Moloney, Tetrahedron, 1994, 50, 9425. [91] C. Anies, J.-Y. Lallemand, A. Pancrazi, Tetrahedron Lett., 1996, 37, 5523. [92] K. Bannai, T. Tanaka, N. Okamura, A. Hazato, S. Sugiura, K. Manabe, K. Tomimori, Y. Kato, S. Kurozumi, R. Noyori, Tetrahedron, 1990, 46, 6689. [93] J. Inanaga, Y. Handa, T. Tabuchi, K. Otsubo, M. Yamaguchi, T. Hanamoto, Tetrahedron Lett., 1991, 32, 6557. [94] T. Kikukawa, T. Hanamoto, J. Inanaga, Tetrahedron Lett., 1999, 40, 7497. 195) (a) M. Yamashita, K. Okuyama, T. Ohhara, I. Kawasaki, S. Ohta. Synlert. 1996, 547. (b) M. Yamashita, K. Okuyama, T. Ohhara, I. Kawasaki, Y. Michihiro, K. Sakamaki, S. Ito, S. Ohta, Chen?. Pharm. Bull, 1999, 47, 1439. [96] (a) S. Kanemasa, H. Yamamoto, S. Kobayashi, Tetrahedron Lett., 1996, 37, 8505. (b) L. Zhou, Y. Zhang, Tetrahedron Lett., 1997, 38, 8063. (c) A. Cabrera, R. L. Lagddec, P. Sharma, J. L. Arias, R. A. Toscano, L. Velasco, R. Gavifio, C. Alvarez, M. Salmon, J. Chem. Soc'., Perkin Trans. I , 1998, 3609.
182
2. I Samarium ( I I ) Mediated Radical Reactions
[97] (a) E. Hasegawa, M. Takahashi, T. Horaguchi, Tetrahedron Lett., 1995, 36, 5215. (b) T. Kataoka, Y. Nakamura, H. Matsumoto, T. Iwama, H. Kondo, H. Shimizu, 0. Muraoka, G. Tanabe, J. Chem. Soc., Perkin Trans. 1, 1997, 309. (c) H.-Y. Kang, W. S. Hong, S. H. Lee, K. I. Choi, H. Y. Koh, Synlett, 1997, 33. (d) D. Crich, X.-S. Mo, J. Am. Chem. Soc., 1998, 120, 8298. [98] (a) G. A. Molander, J. A. McKie, J. Ory. Chem., 1991, 56, 4112. (b) J. W. Timberlake, T. Chen, Tetrahedron Lett., 1994, 35, 6043. (c) M. Yamashita, K. Okuyama, T. Ohhara, I. Kawasaki, K. Sakai, S. Nakata, T. Kawabe, M. Kusumoto, S. Ohta, Chem. Pharm. Bull. 1995, 43, 2075. (d) T. Kirschberg, J . Mattay, J. Org. Chem., 1996, 61, 8885. (e) C. A. Merlic, J. C. Walsh, D. J. Tantillo, K. N. Houk, J. Am. Chem. Soc., 1999, 121, 3596. 1991 (a) A. Nivlet, V. Le Guen, L. Dechoux, T. Le Gall, C. Mioskowski, Tetrahedron Lett., 1998, 39, 2115. (b) P. H. Lee, J. Lee, Tetrahedron Lett., 1998, 39, 7889. [loo] (a) R. A. Batey, W. B. Motherwell, Tetrahedron Lett., 1991, 32, 6649. (b) R. A. Batey, J. D. Harling, W. B. Motherwell, Tetrahedron Lett., 1996, 52, 11421. [ I O I ] A. Haque, S. Ghosh, J. Chem. Soc., Chem. Commun., 1997, 2039. [I021 (a) G. L. Lange, C. Gottardo, Tetrahedron Lett., 1994,35, 6607. (b) G. L. Lange, A. Merica, M. Chimanikire, Tetrahedron Lett., 1997, 38, 6371. [ 1031 G. L. Lange, A. Merica, Tetrahedron Lett., 1999, 40, 7897. [I041 (a) M. Matsukawa, J. Inanage, M. Yamaguchi, Tetrahedron Lett., 1987, 28, 5877. (b) M. Murakami, M. Hayashi, Y. Ito, Appl. Organornet. Chem., 1995, 9, 385. (c) S. E. Booth, T. Benneche, K. Undheim, Tetrahedron, 1995, 51, 3665. (d) M. Kunishima, K. Hioki, K. Kono, A. Kato, S. Tani, J. Org. Chem., 1997, 62, 7542. (e) T. Honda, M. Katoh, Heterocycles, 1998, 47, 481. (f) M. Kunishima, K. Hioki, D. Nakata, S. Nogawa, S. Tani, Chem. Lett., 1999, 683. [lo51 M. D. Levin, S. J. Hamrock, P. Kaszynski, A. B. Shtarev, G. A. Levina, B. C. Noll, M. E. Ashley, R. Newmark, G . G. I. Moore, J. Michl, J. Am. Chem. Soc., 1997, 119, 12750. [I061 M. Sasaki, J. Collin, H. B. Kagan, Tetrahedron Lett., 1988, 29, 6105. [lo71 C. H. Schiesser, S.-L. Zheng, Tetrahedron Lett., 1999, 40, 5095. [I081 L. Zhou, Y. Zhang, J. Chem. Soc., Perkin Trans. 1, 1998, 2899. [I091 (a) R. Tamura, S. Susuki, N.Azuma, A. Matsumoto, F. Toda, A. Kamimura, K. Hori, Anyew. Chem., Znt. Ed. Enyl., 1994, 33, 878. (b) R. Tamura, S. Susuki, N. Azuma, A. Matsumoto, F. Toda, Y. Ishii, J. Org. Chem., 1995, 60, 6820.
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
1<(I 6%)
15
Scheme 2
11
17 (54%)
Ni/AcOH/NaOAc/2-propanol
0
Br 18
19 (60%)
186
2.2 Nickel Mediated Radical Reuctions
2.2.2.2 Indolones The intermediate carbon radical derived from haloanilide 20 is sufficiently longlived to undergo intramolecular cyclization with the aromatic ring to produce indolone 21 when heated in 2-propanol in the presence of acetic acid and nickel powder [6a]. Indolones can also be prepared by a process based on xanthate. However, this method requires a much longer period of heating (2-3 days) [6b]. In contrast, a wide variety of functional groups are compatible with reducing conditions of Ni/AcOH. For instance, ordinary halides, especially when they are attached to aromatic rings, are not affected by the reagent or react very slowly. Iodoanilide 22 gave the corresponding indolone 23 in 50% yield.
Ni/AcOH/2-propanol *
reflux, 7 h Bn 21 (70%)
Bn 20
I
Ni/AcOH/2-propanol t
reflux, 10 h
I
Bn
Bn
23 (50%)
22
2.2.2.3 j?-Lactams As shown in Scheme 2, radical 13 can be trapped by an external trap such as diphenyl diselenide to give p-lactam 14 in competition with the 5-endo cyclization leading to y-lactam 16. P-Lactams can also be prepared by introducing a fragmentation step such as P-fragmentation of sulfide [7]. Thus compound 24 is converted to p-lactam 26 in 50% yield after rapid elimination of phenylthiyl radical within 25 (Scheme 3). Under the same conditions, 27 afforded 28 in 65% yield.
CC13
P h S - p n
A0 24
Ni/AcOH/ 2-propano~
25
26 (50%)
Scheme 3
This method therefore provides a new entry into the p-lactams series which can further be functionalized at the 3- and 4-positions (p-lactam ring). The presence of the two chlorine atoms at the 3-position is especially useful. Moreover a side
2.2.3 Borohydride Exchange Resin-Nickel Boride (cat.) Method
187
26 (50%)
25 CI
Ni/AcOH/2-propanol
qyx; Bn
27
Bn 28 (65%)
chain at the 3-position can be introduced as shown by the slower reaction of dichloropropionamide 29 which led to p-lactam 30 in 60%)yield.
29
30 (60%)
2.2.3 Borohydride Exchange Resin-Nickel Boride (cat.) Method Nickel boride (Ni2B) has been utilized in many reactions mainly as a catalyst. It is usually prepared by reducing nickel salts with sodium borohydride, and it has been shown that the composition varies depending on the preparation methods [8, 91. When a catalytic amount of nickel acetate is reduced with borohydride exchange resin (BER) [ 101 in methanol, BER is covered immediately with a black precipitate of nickel boride. The BER-Ni2B (cat.) has been found to be a very convenient and selective reducing system for the reduction of nitro [ 111, halogen [ 121, and azido compounds [13]. This system has also proved to be an excellent catalyst for the semihydrogenation of alkynes to the corresponding cis-alkenes [ 141. Secondary and tertiary bromides are readily reduced by BER-Ni2B (cat.) in rates comparable with those of primary bromides. This system also converts 6-iodo-lhexene to methylcyclopentane in 38% yield. Based on this, the reduction has been suggested to proceed via radical intermediates [15]. Alkyl iodides react with a,Punsaturated esters, nitriles and ketones to give the corresponding coupling products in high yields. a-Halo acid derivatives readily couple with electron-rich alkenes via halogen atom transfer. Whereas tributyltin hydride is a homogeneous reagent, BER-Ni2B is a heterogeneous system. This makes the separation of BER-Ni2B from the reaction mixture much easier. For instance, a simple filtration is usually enough to obtain the solution of products essentially free from the insoluble reagent.
188
2.2 Nickel Mediated Radical Reactions
2.2.3.1 Coupling of Alkyl Iodides with a,P-Unsaturated Compounds The radical addition reaction of alkyl iodides with a$-unsaturated esters, nitriles and ketones (20 equiv) proceeds in moderate to excellent yields (50-95'54) using BER (3-5 equiv)-NizB (0.05-0.2 equiv) in methanol in 1-9 h at room temperature or at 65°C [15]. In this regard, BER-Ni2B (cat.) system is a good alternative to tributyltin hydride for coupling of alkyl iodides with the electron-deficient alkenes in methanol. However, the nickel system requires a large excess of a,P-unsaturated compounds (20 equiv) since the reagent readily reduces the compounds in contrast to tributyltin hydride. 2.2.3.1.1 Coupling of Alkyl Iodides with a#-Unsaturated Esters [lS]
A small amount of nickel boride (0.05 equiv) is enough to fulfill the coupling reaction at ambient temperatures with methyl crotonate 31. However, the coupling reaction with methyl acrylate 32 requires larger amounts of nickel boride (0.2 equiv) for better yields, presumably because alkyl iodides cannot compete with acrylates for the small amount of nickel boride catalyst, since the double bond of acrylates is rapidly hydrogenated even at 0 "C by this system [ 161.
0" RdOMe
31 R=CH3 32R=H
0 *I
+
RdoMe
BER MeOH (3 eq), * Ni2B (eq) 0.05 0.2
0;'"".
time (h) 9 3
85% 95%
BER (3 eq), MeOH Ni2B(eq) t i m e ( 4
&OM.
31 R = CH3
0.05 0.2
9 1
68% 42%
32R=H
0.05 0.2
20 3
45% 86%
The same tendency was also observed in the coupling reactions with m,Punsaturated nitriles and ketones. Equally good yields were observed in the couplings of alkyl iodides 33 and 34 which contain acetal or nitrile functional groups.
2.2.3 Borohydride Exclzanye Resin-Nickel Boride (cat.) Method
189
2.2.3.1.2 Coupling of Alkyl Iodides with a#-Unsaturated Nitriles 1151 Unlike the coupling with a,P-unsaturated esters, the coupling of alkyl iodides with a,P-unsaturated nitriles requires higher temperature. For instance, in the reaction with crotononitrile, only 25%) of product 36 was obtained in 12 h leaving 70%)of cyclohexyl iodide 35 unreacted at room temperature whereas an excellent yield (93%) was obtained at 65 "C. Primary iodide 37 and acetal iodide 39 also gave good yields of the corresponding coupling products 38 and 40. BER (3 eq) NizB (0.05 eq)
ACN
MeOH 35
temp 25 OC 65 OC
36 (25%) 36 (93%)
BER (3 eq)
a0EI +
BER (5 eq) Ni2B (0.2 eq) b C N
65 O C
39
40 (81Yo)
The slowness of the reaction at room temperature is probably due to the preferential adsorption and/or reduction of crotononitrile on nickel boride, which hinders the radical formation reaction of cyclohexyl iodide at room temperature. Cyclohexyl iodide is quantitatively reduced to cyclohexane by BER-Ni2B (cat.) within 1 h at room temperature in the absence of excess crotononitrile [ 12aI.
2.2.3.1.3 Coupling of Alkyl Iodides with aJ-Unsaturated Ketones 1151 Couplings of alkyl iodides with a$-unsaturated ketones also proceeds smoothly, giving good yields of products. As shown in the couplings with a,/?-unsaturated esters, unhindered a,B-unsaturared ketones such as ethyl vinyl ketone (42) and cyclopentenone (43) require a large amount of Ni2B (0.3 equiv) at 65 "C.
2.2.3.1.4 Coupling of Homoallylic Iodide [l5] The coupling of homoallylic iodide with a,/hmsaturated esters and nitriles is valuable in obtaining simple addition products with ethyl acrylate and acrylonitrile. While tributyltin hydride gives the sequential cyclization products 46 and 48 as the major products [ 171, the BER-Ni2B system yields the simple addition compounds 45
2.2 Nickel Mediated Radical Reactions
190
MeOH I(
+
R&
41 R=CH3
42R=H
BER 3
Ni2B (eq) temp ("c) 0.1 25
0.3
5
65
81% 84%
0
B
BER (5 eq), Me(I H
43
Ni2B (eq) temp ("C) 0.3 65
72%
BER (3 eq), MeOH Ni2B (eq) temp ("C) 0.1 25 72% (cisltrans = 26/74)
and 47 as the major products. This seems to happen because the reducing ability of the BER-Ni2B system is stronger than that of Bu3SnH. X
44 X = COOEt
X=CN
BER-Ni2B
45 65%
46 15%
Bu3SnH
45 0%
46 75%
BER-Ni2B
47 74%
48 10%
Bu3SnH
47 0%
48 65%
2.2.3.2 Coupling of a-Bromo Acid Derivatives with Alkenes a-Bromo acid derivatives couple not only with vinyl ethers in good yields but also with terminal alkenes in the presence of excess sodium iodide using BER-NizB, perhaps via a halogen atom transfer process [ 181.
2.2.3.2.1 Coupling of aBromo Acid Derivatives with Vinyl Ether I191 A convenient preparation of y-dialkoxy esters, amides and nitriles can be achieved from a-bromo acid derivatives and vinyl ether (10 equiv) using BER (3 equiv) and
2.2.3 Borohydride Exchange Resin-Nickel Boride (cat.) Method
191
Table 1. Reactions of ethyl a-bromopropionate with butyl vinyl ether using NiZB-BER in methanol in the presence of various alkali metal halides"
4 0 E t Br
+
BER-Ni2B(cat) MeOH
o\-
e
E
t
o./-./
95%
OMe
Entry 1
2 3 4 5 6
I 8 9
Butyl vinyl ether (eq)
Alkali metal halides (eq)
Yields ('I/.)b
20 20 20 20 20 20 20 20
none NaI ( 3 ) NaI (7) NaI (10) LiI (10) KI (10) NaBr (10) NaCl (10) Nal (10) NaI (10)
30 (55)' 68 84 95 84 71 15 50 85 95
5
10
10
"Ethyl a-bromopropionate (5.0 mmol) was reacted with butyl vinyl ether using BER (3.0 eq) and Ni(OAc)Z(0.03 eq) in MeOH at room temperature. Isolated yield. 'Ethyl a-iodopropionate was used.
Ni2B (0.03 equiv) in the presence of NaI (10 equiv) at room temperature as described below. The coupling of ethyl a-bromopropionate 49 with propenyl ether 51 gives a substantially lower yield than that of vinyl ether 50. The long alkyl chain of 52 does not affect the yield, and both a-bromoamide 53 and a-bromonitrile 54 also give excellent yields. These coupling reactions do not proceed satisfactorily in the absence of NaI as shown in Table 1. For instance, whereas x-bromopropionate and r-iodopropionate give only 30 and 55% yields of the corresponding coupling products, the yields increase dramatically to 95%)in the presence of NaI (entries 2-4). It is interesting to note that all the alkali metal halides give good effects, and NaI has been shown to be the best of them (entries 4-8).
9 0 E t Br 49
+
%o-,/" 50
BER-Ni2B(cat) MeOH
fOEt
od----./ I
OMe
95%
4 0 E t Br 49
+
b o 4 51
OMe 70%
2.2 Nickel Mediated Radical Reactions
192
52
OMe 95%
53
OMe 90%
54
I OMe 84%
2.2.3.2.2 Coupling of Alkenes with a-Bromo Acid Derivatives
Terminal alkenes and 1, 1-dialkylalkenes couple with a-bromocarboxylic acid derivatives (2.5 equiv) to give the products in moderate to excellent yields in the presence of BER-Ni2B (cat.) and 7.5 equiv of sodium iodide [20]. Interestingly, while ethyl nonanoate 57 is obtained in 60%)yield during the reaction of l-heptene 55 with ethyl bromoacetate 56 using standard conditions [BER (5.0 equiv)-NizB (0.15 equiv)], ethyl 44odononanoate 58 is obtained in 52% yield using the limited amount of reagents BER (2.5 equiv)-NizB (0.075 equiv). This clearly suggests that the reaction indeed takes place via a halogen atom transfer process. Trisubstituted alkene derivatives 60, 61, and 63 produced from methylenecyclohexane (59) are believed to be formed by rapid dehydrohalogenation of the corresponding tertiary iodides generated by a halogen atom transfer. In contrast, the coupling of norbornene with 56 also readily occurs to yield the saturated coupling product 65. While the norbornene derivatives are readily hydrogenated by BER-Ni2B (cat.) under the reaction conditions, ordinary trisubstituted alkenes are not reduced by the system 1161. NaI also sensitively affects the reaction as judged by the fact that only 3% of ethyl 3-( 1-cyclohexeny1)-propionate(60) is obtained in the absence of the NaI [20].
2.2.4 Nickel-Catalyzed Electroreductive Radical Reactions Electroreductive addition reactions of organic halides to carbon-carbon double or triple bonds have been investigated since early 1980. Nickel compounds have also been used as radical generators in electroreductive processes [211. More recently, the indirect electroreduction of 6-bromo-1 -hexene with [Ni(cyclam)12+(C104-)2(66) in
2.2.4 Nickel-Catalyzed Electroreductive Radical Reactions
+
F O E t Br
55
56
193
57 (60%)
ii 4
*
O
E I 58 (52%)
t
i +
6 6
&OEt Br
H2 80%
+ '$OEt Br
59
U
56 R=H 49 R=CH3
+
Br &NEt2
6 0 R = H 91% 61 R = CH3 51%
i
*
6""'"
59
62
63 (85%)
64
56
65 (88%)
i : BER (5 equiv) - Ni2B (0.15 equiv), Nal (7.5 equiv) ii : BER (2.5 equiv) - Ni2B (0.075 equiv), Nal (7.5 equiv)
66 : [Ni(cy~larn)]~'(CI0~-)2
67 : [Ni(CR)]2'(C104-)2
68 : [Ni(tet a)]2'(C104-)2
DMF has been demonstrated to give methylcyclopentane in 46% yield [22]. This clearly suggests that this nickel-catalyzed electroreductive cyclization proceeds via a radical pathway. [Ni(cy~lam)]~+(CI04-)2 (66), [Ni (CR)]2'(C104-)2 (67) or [Ni (tet a)I2+(C104-)2 (68) have been used as efficient catalysts in DMF in the presence of NH4C104 as a proton source [23-241. Nil species generated electro-
194
2.2 Nickel Mediated Radical Reactions
chemically rapidly abstract halogen atoms from the organic halides to generate corresponding alkyl radicals which subsequently undergo intra- or intermolecular reactions (Scheme 4). Thus indirect electroreduction of haloethers 69 and 71 led to the corresponding cyclized tetrahydrofuran derivatives 70 and 72, respectively, in good yields via 5em-trig mode [23]. On the other hand, N-allyl-a-bromoamide 73 gave the corresponding pyrrolidone 74 in DMF in the presence of 2 equiv of a hydrogen donor, diphenylphosphine, whereas N-allyl-cc-iodoamide 75 gave the iodinated pyrrolidone 76 in acetonitrile [24].
Scheme 4
y:&Ph
Ph
67
*
70 (58%)
69
68
*
71
Y
p 72 (85%)
67
*
2 eq PhPPH, DME
8 N
Ts
Ts 73
74 (78%)
67
'X N
Ts 75
O
O
Ts 76 (63%)
2.2.5 Nickel-Catalyzed Khuvusch Addition Reaction
195
It has also been shown that Ni complexes can successfully carry out intramolecular or intermolecular electroreductive addition of alkyl radicals to activated olefins. Thus bicyclic ketones 78 and 80 are conveniently prepared in good yields from 2-bromoalkyl-2-cyclohexenone 77 and 3-bromoalkyl-2-cyclohexenone 79, respectively [25]. Alkyl bromides also react with x,P-unsaturated esters and nitriles to give 1,4-addition products in moderate yields [26].
78 (70%)
77
80 (65%)
79 68 -Br
+
*
dOBn
53%
68 Ph.-,-.,Br
+
*
PhA
O
M
e
57%
68 P B ,.h -r,-.
+
k C N
*
Ph-CN
72%
2.2.5 Nickel-Catalyzed Kharasch Addition Reaction The Kharasch addition reaction of polyhaloalkanes to an alkene double bond is an important reaction of wide applicability that generates new carbon-carbon bonds and introduces synthetically useful halide substituents. This addition is catalyzed by various metal complexes including CuCl [27], RuC12(PPh3)3 [28], PdC12(PPh3)2[29], and NiC12(PPh3)2 1301. In contrast to free radical-initiated reactions, metal complex catalysis usually produces 1:1 alkene halocarbon adducts instead of polymerized products. There are many applications of this type of reaction that are of industrial importance in the preparation of fine chemicals 1271. In 1988, Ni[C6H3(CH2NMe2)22,6]C1 (81) (referred to as Ni(NCN)Cl ) was reported to be an excellent catalyst for the Kharasch addition reaction.
196
2.2 Nickel Mediated Radical Reactions
For instance, over 90%) of 1:l alkene CC14 adduct was obtained in 15 min at room temperature during the reaction of methyl methacrylate with excess Cc14 in the presence of 5 mol'l/o Ni(NCN)Cl in acetonitrile. Considering that NiCl2(PPh3)2 catalyzes the addition of polyhaloalkanes to 1-hexene in low yields only at 140°C [30], the above reaction conditions with Ni(NCN)Cl can be regarded as the mildest conditions that have ever been used in the catalytic Kharasch addition reactions. RuC12(PPh3)3is one of the most active catalysts in promoting the reaction [28], but the catalyst is active only at temperatures above 40°C [31]. Recently, Ni(NCN)Br 82 was found to be a good catalyst for the living radical polymerization which allows the synthesis of polymers with predictable molecular weights, narrow molecular weight distributions, and well-defined chain end structures [32]. While living polymerization is usually performed with near to equimolar concentrations of polyhaloalkanes and metal catalysts, Kharasch addition is typically performed under the conditions with 0.01-10 mol%) of catalysts to the polyhaloalkanes and alkene substrates. Ni" catalysts such as NiBrz(PPh3)z 83 and NiBrZ(Pn-Bu3)z 84 are also reported to be effective for living radical polymerization of methyl methacrylate as illustrated in Scheme 5 [ 3 3 ] .
81 X = CI 82 X = Br
R-Br
84
83
Nil'
-===
R - BrNi"'
--
R-CH&Br
MMA
Nil'
R-CH2tBr C02Me
-
R-CH2/
C02Me
C02Et
Nil'
BrNi"'
C02Me
0
I
R-Br : CCI3Br,
MMA -
MMA: +OM,
Scheme 5
References [ I ] (a) B. Giese, Radicals in Orgaizic SynthesiJ: Fornzation of Carhon-Carbon Bonds; Pergamon: Oxford, 1986; (b) B. Giese, Angew. Cllern. Int. Ed. Engl. 1985, 24, 553-565; (c) W. P. Neuman,
Rejerences
197
Synthesis 1987, 665-683; (d) D. P. Curran, in Comprehensive Organic Synthesis, Vol. 4 (Ed.: B. M. Trost) Pergarnon, New York, 1991, pp. 715-831. [2] (a) D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636-3638; (b) J. E. Leibner, J. Jacobus, J. Org. Chern. 1979,44,449-450; (c) D. P. Curran, C. T. Chang, J. Org. Chem. 1989. 54, 3140-3157. j3] J. Boivin, A.-M. Schiano, S. Z. Zard, Tetruhedron Lett. 1992, 33, 7849-7852. [41 J. Boivin, M. Yousfi, S. Z. Zard, Tetrahedron Lett. 1994, 35, 5629-5632. [ S ] (a) J. Cassayre, B. Quiclet-Sire, J.-B. Saunier, S. Z. Zard, Tetrahedron 1998, 54, 1029-1040; (b) J. Cassayre, S. Z. Zard, Synlett 1999, 501-503. [6] (a) J. Boibin, M. Yousfi, S. Z. Zard. Tetrahedron Lett. 1994, 35, 9553-9556; (b) J. Axon, L. Boiteau, J. Boibin, J. E. Forbes. S. Z. Zard, Tetruhedron Lett. 1994, 35, 1719-1722. [7] B. Quiclet, J.-B. Saunier, S. M. Zard, Tetrahedron Lett. 1996, 37, 1397-1400. [S] J. Ganem, 0. Osby, Chem. Rev. 1986,86, 763-780. [9] M. Khurana, A. Gogia, Org. Prep. Proced. Int. 1997, 2Y, 1-32. [ 101 BER can be prepared readily by treating a chloride form anion exchange resin (Amberite IRA 400) with aqueous NaBH4 solution. The BER thus prepared is dried in I I U L ' U ~and the borohydride content is usually 3 mmol/g of dry BER. The BER is stable for more than 6 weeks if kept under nitrogen in a refrigerator; see [ 12al. [Ill N. M. Yoon, J. Choi, Synlett 1993, 135-136. [I21 (a) N. M. Yoon, H. J. Lee, J. H. Ahn, J. Choi, J. Ory. Chem. 1994, 59, 4687-4688; (b) N. M. Yoon, J. Choi, H. J. Lee, Bull. Korean Chem. Soc. 1993, 14, 543-545. [I31 N. M. Yoon, J. Choi, Y. S. Shon, Syntlz. Comniun. 1993, 23, 3047-3053. [ 141 (a) J. Choi, N. M. Yoon, Tetrahedron Lett. 1996,37, 1057 -1060; (b) N. M. Yoon, K . B. Park, H. J. Lee, J. Choi, Terrahedron Lett. 1996, 37, 852778528, 1151 T. B. Sim, J. Choi, M. J. Joung, N. M. Yoon, J. Org. Chem. 1997,62, 2357-2361. [I61 J. Choi, N. M. Yoon. Synthesis 1996, 597-599. [ 171 J. Cekovic, R. S. Saisic, Tetruhedron Lett. 1986, 27, 5893-8596. (181 D. P. Curran, Synthesis 1988, 489-513. [I91 J. H. Ahn, D. W. Lee, M. J. Joung, K. H. Lee, N. M. Yoon, Synlett 1996, 1224-1226. [20] M. J. Joung, J. H. Ahn, D. W. Lee, N. M. Yoon, J Ory. Chem. 1998, 63, 2755-2757. [21] (a) C. Gosden, D. Pletcher, J. Oryunometal.Clwn. 1980, 186, 401-409; (b) Y.-J. Nedelec, J. Perichon, M. Troupel, Topics in Current Chemistry, 1997, 185, 141-173. [22] E. Dunach, A. P. Esteves, A. M. Freitas, J. M. Medeiros, S. Olivero, Tetruhedron Lett. 1999, 40, 8693-8696. [23] S. Ozaki, H. Matsshita, H. Ohmori, J. Chern. Soc. Cllem. Commun. 1992, 1120-1 122. [24] (a) S. Ozaki, H. Matsshita, H. Ohmori, J. Chem. Soc. Perkin Truns. I 1993, 2339- 2344; (b) S. Ozaki, H. Matsshita, M. Emoto, H. Ohmori, Chem. Phurm. Bull. 1995, 43, 32-36. [25] S. Ozaki, T. Nakanishi, M. Sugiyarna, C. Miyamoto, H. Ohmori, Chem. Pharm. Bull. 1991, 39, 31-35. 1261 S. Ozaki, H. Matsshita, H. Ohmori, J. Chem. Soc. Perkin Trans. I 1993, 649-651. 1271 D. Bellus, Pure Appl. Chem. 1985, 1827-1838. [28] H. Matsumoto, T. Nakao, Y. Nagai, Tetrahedron Lett. 1973, 5147-5150. [29] J. Ysuji, K. Sato, H. Nagashima, Chem. Lett. 1981, 1169- 1170. 1301 Y. Inoue, S. Ohno, H. Hashimoto, Chem. Lett. 1978, 367- 368. [31] D. M. Grove, G. van Koten, A. H. M. Verschuuren, J. Mol. Cutul. 1988, 45, 169-174. [32] C. Granel, Ph. Dubois, R. Jerome, Ph. Teyssie, Macromolecules 1996, 29, 8576-8582. [33] H. Uegaki, Y. Kotani, M. Kamigaito, M. Sawamoto, Mucromolecules 1998, 31, 6756-6761.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
2.3 Manganese(II1)-Mediated Radical Reactions Burry B. Snider
2.3.1 Introduction Manganese(II1)-mediated radical reactions have become a valuable method for the formation of carbon-carbon bonds over the past thirty years since the oxidative addition of acetic acid (1) to alkenes to give y-butyrolactones 6 (Scheme 1) was first reported by Heiba and Dessau [ l ] and Bush and Finkbeiner [2] in 1968. This method differs from most radical reactions in that it is carried out under oxidative, rather than reductive, conditions leading to more highly functionalized products from simple precursors. Mn(II1)-based oxidative free-radical cyclizations have been extensively developed since they were first reported in 1984-1985 [3-51 and extended to tandem, triple and quadruple cyclizations. Since these additions and cyclizations have been exhaustively reviewed recently [6-111, this chapter will present an overview with an emphasis on the recent literature. Mn(0Ac)3 AcOH reflux
0.Mn(OAc)2
-
H&
1
Go R
6
-
-Mn(OAc)*
A
*
? -
e
- M ~ ( O A C )*H2C ~
0 Mn(0Ac)n
R
0
Mn(OAc)2
5
-
$0 I R
- Mn(OAc)2
4
Scheme I
There are four steps in these reactions as exemplified in the oxidative addition of acetic acid (1) to an alkene and the oxidative cyclization of 7b (Scheme 2). The first, rate-determining step is the slow reaction of acetic acid 1 or p-keto ester 7b with Mn(OAc)3 to give Mn(II1) enolates 2 and Sb, respectively [12, 131. The rate of proton loss is proportional to the acidity of the hydrogen. Acetic acid, pK, = 25,
2.3.2 Initiation, Termination, Solvents and Common Side Reactions
199
Mn"'
0
20-50 "C 7a, R = H 7b, R = Me
.. 10
a, R = H b.R=Me
11
12a (71%) 12b (56%)
Scheme 2
forms enolate 2 at 115 "C, while 7b, pK, = 12, forms the enolate at 25 "C. However, if the proton is too acidic as with 7a, pK, = 10, the mechanism of the reaction changes as discussed below. The second step is the rapid loss of Mn(I1) from 2 and 8b to give radicals 3 and 9b, respectively. The third step involves addition of radical 3 to an alkene to give 4 or cyclization of radical 9b to give cyclohexanealkyl radical l l b . The fourth and final step is the oxidation of the radical. The Mn(II1)-carboxylate of 4 cyclizes to give 5, which undergoes reductive elimination with loss of Mn(I1) to give y-butyrolactone 6. The presence of Mn(II1) in radical 4 is crucial since Mn(II1) does not oxidize isolated primary or secondary radicals. Radical 11 instead abstracts a hydrogen from solvent or another molecule of 7b to give 10. Use of Cu(0Ac)z as a co-oxidant overcomes this problem. Although Cu(I1) is a thermodynamically weaker oxidant than Mn(III), it reacts with radicals 350 times faster than Mn(II1) does [ 141 to give a Cu(II1) intermediate that undergoes an oxidative elimination to give 56% of 12b without the intermediacy of a secondary cation [15]. The mechanism takes a different course with more acidic compounds such as 8-keto ester 7a (pK, = 10). Mn(II1) enolate 8a forms rapidly and reversibly. The rate-determining step is cyclization of the double bond to the Mn(II1) enolate of 8a with loss of Mn(I1) to give cyclohexanealkyl radical 1 la, without the intermediacy of acyclic radical 9a, which is oxidized by Cu(0Ac)z to generate 71% of 12a. Similar mechanisms are operable with very acidic 1,3-diketones; Mn(acac)3 is stable and isolable.
2.3.2 Initiation, Termination, Solvents and Common Side Reactions Initiation. In principle, any metal that is a one-electron oxidant can be used to generate a metal enolate which can undergo homolysis to generate a radical as in
200
2.3 Mungunese(III)-Mediuted Radical Reactions
the formation of 3 and 9b. Although other one-electron oxidants, most notably ceric ammonium nitrate (CAN), Fe(C104)3, and VOX3, have been employed, the majority of the work has used Mn(III), which is the only oxidant that can be used with CU(OAC)~ to generate an alkene by oxidation of the radical. CAN, which is covered elsewhere in this volume (Volume 1, Chapter 2.4), is a stronger oxidant that is very effective in the initiation step, but often leads to more complex product mixtures since cations are produced that react with solvent and nitrate. Commercially available Mn(OAc)3,2H20has been used for the majority of oxidative cyclizations. This reagent can also be prepared easily from potassium permanganate and manganous acetate in acetic acid [6]. Anhydrous Mn(OAc)3 is slightly more reactive than the dihydrate. Reaction times with the anhydrous reagent are usually somewhat shorter but the yields of products are usually comparable. Both trifluoroacetic acid and potassium or sodium acetate have been used with Mn(OAc)3. Use of trifluoroacetic acid as a co-solvent usually increases the rate of the reaction, but often decreases the yield of products. Acetate anion may accelerate enolization and act as a buffer. Narasaka introduced Mn(II1) picolinate [Mn(pic)3]in DMF as useful reagent for oxidation of P-keto acids to radicals, the oxidative cleavage of cyclopropanols to give P keto radicals, and the oxidation of nitroalkanes to cation radicals [ 161. Very different results are obtained from oxidation of P-keto acids with Mn(OAc)3 .2H20 and Mn(pic)3 [ 161. Solvent. Acetic acid is the usual solvent for Mn(OAc)3.2H20 reactions. DMSO, ethanol, methanol, dioxane, benzene, and acetonitrile can also be used, although higher reaction temperatures are required and lower yields of products are sometimes obtained [lo]. The use of ethanol can be advantageous in cyclizations to alkynes [ 171. Vinyl radicals formed by cyclization to alkynes are not readily oxidized by either Mn(II1) or Cu(I1) and will undergo undesired side reactions unless there is a good hydrogen donor available. Ethanol acts as a hydrogen donor, reducing the vinyl radical to an alkene and giving the a-hydroxyethyl radical, which is oxidized to acetaldehyde by Mn(II1). Lanthanide triflates catalyze the Mn(II1)-based oxidative cyclization of unsaturated P-keto esters in trifluoroethanol at 0 "C [ 181. Termination. Mn(OAc)3 can also be involved in the termination step as in the oxidation of 4 to give lactone 6. It rapidly oxidizes tertiary radicals to cations that lose a proton to give an alkene or react with the solvent, acetic acid, to give acetate esters. Mn(OAc)3 also oxidizes allylic radicals to allylic acetates and oxidizes cyclohexadienyl radicals, which are generated by additions to benzene rings, to cations that lose a proton to regenerate the aromatic system. On the other hand, Mn(OAc)3 oxidizes primary and secondary radicals very slowly, so that hydrogen atom abstraction from solvent or starting material becomes the predominant process as in the conversion of 11 to 10. Cu(OAc)z, which is compatible with Mn(OAc)3, oxidizes primary and secondary radicals to alkenes 350 times faster than Mn(II1) does [lo, 141. The Cu(1) that is produced in this oxidation is rapidly oxidized to Cu(1I) by Mn(II1) so that only a catalytic amount of Cu(OAc);! is needed and two equivalents of Mn(OAc)3 are still required. However, hydrogen abstraction from the solvent will occur if too little Cu(I1) is used, so these reactions are usually best carried out with one equivalent of Cu(I1). Cu(0Ac)z oxidizes secondary radicals to give primarily E-alkenes and the
2.3.2 Initiation, Termination, Solvents und Common Side Reactions
20 1
less substituted double bond (Hofmann elimination product) [ 191. This selectivity is synthetically valuable since Cu(I1) oxidation of primary and secondary radicals formed in oxidative cyclizations often gives primarily or exclusively a single regioand stereoisomer. Vinogradov and Nikishin reported that oxidation of ethyl acetoacetate with 4 equivalents of Mn(OAc)3 and excess LiCl in the presence of 1-hexene results in the formation of dichloride 13 (Scheme 3 ) [20]. Chlorination of the cc-position prevents further oxidation of the product. Unfortunately, the use of chloride is not compatible with Cu(I1); only r,a-dichlorination is observed. The combination of Mn(OAc)3 and LiCl has seen very limited use in intramolecular reactions. 4 Mn(OAc)3 LicI' [ 5 C 0 2 E t ]
0 L C 0 z E t
-
-
2-
Bu
Bu
I-hexene
13 (67%)
Scheme 3
We have found that oxidative cyclizations can be terminated by addition to nitriles to give iminyl radicals, such as 14 that is reduced to imine 15, which is hydrolyzed to ketone 16 on workup (Scheme 4) [21]. Ryu and Alper reported that radicals, such as 18 formed in the oxidative cyclization of 17, add to carbon monoxide to give acyl radicals such as 19, which are oxidized by Mn(II1) to acyl cations that react with water leading to carboxylic acids on workup as in formation of 20 (Scheme 5) [22].
Scheme 4
Mn(OAc)3 AcOH, 70 iC
E :7E
E=C02Et
Scheme 5
E 18
19
(50%)
202
2.3 Mangunese(III)-Mediated Radical Reactions
Reductive termination of the reaction sequence by hydrogen abstraction is occasionally the desired reaction. This is particularly important in converting vinyl radicals (obtained from additions to alkynes) to alkenes, since vinyl radicals are not oxidized to vinyl cations [ 171. The hydrogen can come from the solvent or from the a-hydrogen of another molecule of the a-dicarbonyl compound. Ethanol is the preferred solvent for these reactions, since it is a better hydrogen donor than acetic acid. Hydrogen transfer from ethanol gives the a-hydroxyethyl radical that is oxidized to acetaldehyde by Mn(II1) so that these reactions still require two equivalents of Mn(OAc)3. Oxidative cyclization of 21 with anhydrous Mn(OAc)3 in ethanol affords vinyl radical 22 which abstracts an a-hydrogen from ethanol affording 66% of 23 as a 2.6:1 mixture of stereoisomers (Scheme 6) [17].
-
Mn(O A C ) ~
E!
$! C02Et
\
22 Me
CH3CHO
Scheme 6
Nishino and Kurosawa have shown that radicals such as 24 that are formed by the addition of dicarbonyl compounds to alkenes can be trapped by oxygen when the reaction is run under a stream of dry air [23]. The peroxy radical 25 that is formed abstracts a hydrogen atom to give a peroxide that cyclizes to give peroxy hemiketal 26 (Scheme 7).
24
25
26 (92%)
Scheme 7
Side reactions. Oxidative cyclization of unsaturated P-dicarbonyl compounds that have two a-hydrogens will give products that still have one a-hydrogen and can be oxidized further. If the product is oxidized at a rate competitive with that of the starting material, mixtures of products will be obtained. For instance, oxidative cyclization of 27 affords 36%)of 28 and 10% of dienone 30 formed by further enolization and oxidation of 28 to radical 29 and then to dienone 30 (Scheme 8) [ 161. Competitive oxidation of the product is usually not a problem in intermolecular addition reactions because a vast excess of the oxidizable substrate, such as acetone
2.3.2 Initiation, Termination, Solvents and Common Side Reactions
&:
HC02Me
-
M ~ ( O A C )M @ e~;
Mn(OAc)3 ~
-H+ 27
\
28 (36%)
II
e:Me
30 (10%)
29
203
(
Scheme 8
or acetic acid, is usually used as solvent. Use of excess substrate is not possible in oxidative cyclizations. In some cases, the product is oxidized much more readily than the starting material so that none of the initial product is isolated. These reactions may still be synthetically useful if the products of further oxidation are monomeric. For instance, oxidative cyclization of 31 provides 78% of methyl salicylate (34) (Scheme 9) [24261. Oxidative cyclization gives radical 32; oxidation of 32 gives 33, probably as a mixture of double bond positional isomers. The unsaturated cyclic P-keto ester 33 is more acidic than 31 and is rapidly oxidized further by two equivalents of Mn(II1) to give a cyclohexadienone that tautomerizes to phenol 34. The overall reaction consumes four equivalents of Mn(OAc)3.
I",-..Me 8 .Mn(OAc)3
A H 2 31
C02MeCu(OAc)2 32
&COzMe 33
C02Me
34
(78%) Scheme 9
Further oxidation cannot occur if there are no acidic cc-hydrogens in the product. cc-Chloro substituents serve as protecting groups preventing further oxidation of the product [ 13, 27-29]. For instance, oxidative cyclization of 35 affords 82% of a 3.1:l mixture of 36 and 37 (Scheme 10) [27]. The other two stereoisomers with the octyl and vinyl groups cis are not formed. This mixture was elaborated to avenaciolide
35
Scheme 10
36 (62%) p-Cl, a-COzMe 37 (20%) a-CI, P-COzMe
avenaciolide (38)
204
2.3 Mungunese(III)-Mediuted Radical Reactions
~ on the a-chloro lactone to form the (38) by a sequence that used an S N reaction second lactone ring.
2.3.3 Intermolecular Additions Mn(OAc)? in AcOH at reflux generates the CH2C02H or .CH2C02Mn(III) radical which adds to a wide variety of alkenes, cycloalkenes and dienes to give radicals that are oxidized to generate y-butyrolactones as shown in the formation of 6 [ 1 la]. KOAc accelerates the reaction since enolization is the rate-limiting step. This sequences is not general for carboxylic acids since acetate is the ligand and preferred solvent for this reaction. Propanoic, chloroacetic and P-chloropropanoic acids have been successfully used as solvent [ 1 la]. Mn(OAc)3 in AcOH at 60°C oxidizes aldehydes RCH2CHO to RCH-CHO. These radicals add to alkenes to give radicals that abstract a hydrogen] or are oxidized to acetates or alkenes affording mixtures of limited synthetic utility [ 1la]. Similarly, Mn(OAc)3 in AcOH at 40-80 "C oxidizes acetophenone, acetone, cyclopentanone, cyclohexanone or other simple symmetrical ketones to a-keto radicals that add to alkenes leading to modest yields of coupled products [ 1 la]. Oxidative addition of more acidic P-dicarbonyl compounds to alkenes and dienes, which can be carried out in acetic acid at 2O-5O0C, are more synthetically useful [ l l a ] . Oxidation of malonic acid in AcOH containing an alkene with 4 equivalents of Mn(OAc)3 affords good to excellent yields of the bis lactone 40 (Scheme 11). The initially formed lactone 39 is more acidic than malonic acid and is therefore oxidized more rapidly than the starting material to give 40 [ l l a , 301. Lactones 41-43 are obtained in good to excellent yield by the oxidative addition of cyanoacetic acid, monoethyl malonate and monoethyl chloromalonate to alkenes (Scheme 12) [28, 311. Oxidative addition of diethyl malonate to I-heptene gives a secondary radical that abstracts a hydrogen to give 44. The unsaturated ester 45 is obtained when Cu(OAc)2 is used as a co-oxidant (Scheme 13) [32]. A more recent report indicates that the secondary radical is oxidized to an acetate if Mn(OAc)3is used as the oxidant, but that 44 is obtained selectively by slow addition of KMn04 to a solution of the reactants and Mn(0Ac)z in AcOH at 75°C [33a]. The radical
Scheme 11
2.3.3 Intermolecular Additions
C8H17k
-
+ y
x
y
205
41, X = CN,Y = H (85%) 42, X = COZEt, Y = H (74%) 43, X = COZEt, Y = CI (40%)
CEH17
Scheme 12
C5H11
C0ZEt CO2Et
M~(OAC)~ AcOH C5H11&
-
+
44
(GOzEt C02Et
Mn(OAc), Cu(OAc)z
C02Et C4H9/\\/Y
As
45
C02Et
Scheme 13
A AcO c
F
S
+
(CoZEt
Mn(OAc)3, KOAc AcOH, 95 "C
C02Et 46
47 (52%)
Scheme 14
formed by oxidation of dimethyl malonate adds to tri-0-acetyl-D-glucal (46) to give 52%) of 47 and 14% of a diastereomer (Scheme 14) [33b]. The radicals obtained by oxidative addition of P-diketones and P-keto esters to alkenes undergo oxidative cyclization to give dihydrofurans such as 48 and 49 (Scheme 15) [ l l a , 341. Enol ethers are more nucleophilic than simple alkenes and therefore react readily with the Mn(II1) enolates obtained from P-diketones and P-keto esters to give 50 and 51 in good yield (Scheme 16) [ 1 la, 351. cc-Substituted P-diketones and ,8-keto esters cannot form dihydrofurans. In these cases the intermediate radical is oxidized and reacts with a nucleophile or loses a proton as in the formation of 52 from isopropenyl acetate and ethyl 2-oxocyclohexanecarboxylate (Scheme 17) [36].
/+p
M~(OAC)~ AcOH, 45 "C
Phv 0 Scheme 15
*
Ph
x
48, X = Me (30%) 49, X = OEt (57%)
2.3 Munganese(III)-Mediuted Radical Reactions
206
(‘j
Mn(OAc)3 AcOH,6O0C
+
~
50,X=Me(26%) 51, X = OEt (53%)
0
Scheme 16
Scheme 17
2.3.4 Cyclizations More complex products are obtained from cyclizations in which the oxidizable functionality and the alkene are present in the same molecule. P-Keto esters have been used extensively for Mn(II1)-based oxidative cyclizations and react with Mn(OAc)3 at room temperature or slightly above [4, 10, 11, 151. They may be cyclic or acyclic and may be a-unsubstituted or may contain an a-alkyl or chloro substituent. Cycloalkanones are formed if the unsaturated chain is attached to the ketone. y-Lactones are formed from allylic acetoacetates [ 10, 111. Less acidic P-keto amides have recently been used for the formation of lactams or cycloalkanones [37]. Malonic esters have also been widely used and form radicals at 60-80°C. Cycloalkanes are formed if an unsaturated chain is attached to the cc-position. y-Lactones are formed from allylic malonates [ 10, 1 11. ,!?-Diketones have been used with some success for cyclizations to both alkenes and aromatic rings [ 10, 111. Other acidic carbonyl compounds such as P-keto acids, P-keto sulfoxides, P-keto sulfones, and Pnitro ketones have seen limited use [ 10, 111. We have recently found that oxidative cyclizations of unsaturated ketones can be carried out in high yield in acetic acid at 80°C if the ketone selectively enolizes to one side and the product cannot enolize [38] as in the conversion of 53 to 54 (Scheme 18).
Scheme 18
2.3.4 Cyclizutions
207
Cyclizations that form a single carbon-carbon bond can be accomplished by oxidative cyclization of unsaturated P-diketones, P-keto esters, or P-keto amides 55 that lead to cycloalkanone radicals 56 and 57, unsaturated P-diketones, P-keto esters, or malonate esters 58 that lead to cycloalkanes 59 and 60, and unsaturated esters or amides 61 that lead to lactams or lactones 62 and 63 (Scheme 19) [ 10, 371. Cyclizations of radicals stabilized by two carbonyl groups will only occur with electron-rich aromatic rings as in the conversion of 64 to 65 (Scheme 20) [39]; the initial cyclization product is acetoxylated under the reaction conditions. The addi-
ex (yx 8 0
0
-
0
Mn(OAc)3
0
+
-
55, X = C, OR, NR2
57, X = C, OR, NR2
56, X = C, OR, NR2
58, X, Y = C, OR, NR2
59, X, Y = C, OR, NR2
60, X,Y = C, OR, NR2
61, X = 0, NR Y = C, OR, NR2
62, X = 0, NR Y = C, OR, NR2
63, X = 0, NR Y = C, OR, NR2
Scheme 19
0
AcOH, rt (71%)
64
Scheme 20
2.3 Mungunese (III)- Mediated Radical Reactions
208
66a, R' = R2 = H (62%) 66b, R' = OMe, R2 = Me (65%)
67 (parvifoline)
Scheme 21
tion of radicals stabilized by only one carbonyl group to aromatic rings is more general [38] and has been used for the synthesis of 66b, which was elaborated to parvifoline (67) (Scheme 2 1) [ 401. Tandem cyclizations. More complex targets can be made with excellent stereocontrol by tandem oxidative cyclizations. These reactions can be divided into two classes depending on whether the second cyclization is to an aromatic ring or to another double bond. Oxidative cyclization of 68 with 2 equivalents of Mn(OAc)3 in MeOH at 0 ° C provides 50-60% of 69 as a single stereoisomer whose structure was established by Clemmensen reduction to give ethyl 0-methylpodocarpate (70) (Scheme 22) [4, 24, 411. ?Me
68
OMe
69, X = 0 (50-60%) 70, X = H2 (ethyl 0-methylpodocarpate)
Scheme 22
High levels of asymmetric induction can be achieved in this and other cyclizations if the ethyl ester is replaced with a phenylmenthyl ester or dimethylpyrrolidine amide [41]. The level of asymmetric induction can sometimes be improved by carrying these reactions out with Mn(OAc)3 and 0.2-1 equivalent of a lanthanide triflate in trifluoroethanol at 0 ° C [18]. Complete asymmetric induction can be achieved in modest yield by cyclization of enantiomerically pure ,!3-keto sulfoxides [42]. Tandem cyclizations can also be terminated by cyclization to an arene conjugated with a carbonyl group. Oxidative cyclization of either the E- or 2-isomer of 71 with Mn(OAc)3 in acetic acid affords 72, which undergoes slow loss of hydrogen chloride to afford 79'Yn of the desired naphthol 73 (Scheme 23) [43, 441. Similar cyclizations were used for the first syntheses of okicenone and aloesaponol I11 [45]. The utility of tandem oxidative cyclizations is clearly demonstrated in substrates in which both additions are to double bonds [lo, 11, 46, 471. Oxidative cyclization
2.3.4 Cyclizations 0
0
(pJ I”,l*Jo 0
0
OH
.
Mn(OAc)3 \
H
CI 71
209
OH
-HC’
”
H
72
73 (79%)
Scheme 23
of 74 with two equivalents of Mn(OAc)3 and Cu(0Ac)z in acetic acid at 25 “C affords 86% of bicyclo[3.2. lloctane 79 (Scheme 24). Oxidation affords a-keto radical 75, which cyclizes exclusively 6-end0 in the conformation shown to afford tertiary radical 76 with an equatorial allyl group. Chair-chair interconversion provides 77 with an axial allyl group. 5-exo-Cyclization of the 5-hexenyl radical of 77 gives 78 as a 2: 1 mixture of exo- and endo-stereoisomers. Oxidation of both stereoisomers of 78 with Cu(I1) provides 79. An unusual tandem transannular oxidative cyclization of 80 affords the tricycle 81 albeit in only 8% yield (Scheme 25) [48].
74
(86%)
75
77
C02Me
Scheme 24
Scheme 25
Triple and quadruple cyclizations. A wide variety of triple and even quadruple [49, 501 cyclizations can be carried out with multiply unsaturated 1,3-dicarbonyl compounds. Oxidative triple cyclization of 82 affords 70Y1 of 83 since the cyclopentanemethyl radical is oxidized to a double bond by Cu(I1) (Scheme 26) [47]. Similar cyclization of 84 provides 43% of 85 (Scheme 27) [49]. Oxidative cyclization
2.3 Manganese (III)-Mediated Radical Reactions
210
82
83
(70%) Scheme 26
Scheme 27
CU(OAC);! Mn(O A C ) ~
@JLOTBDPS
.. . AcOH
0
87 C02Et (47% + 11% endo)
(spongiatriol)
Scheme 28
of 86 with Mn(OAc)3 and Cu(0Ac)z in AcOH affords 47% of 87 and 1 I % of the isomer with an endocyclic double bond. Further elaboration gives furan 88, which is an intermediate in a proposed synthesis of spongiatriol (89) (Scheme 28) [49f]. Quadruple cyclizations also proceed in synthetically useful yield. Oxidative cyclization of 90a affords 31% of the unsaturated tetracycle 91a, while the methyl substituted b-keto ester 90b affords 23% of 91b (Scheme 29) [49]. Oxidative cyclization of 92 affords a mixture of unsaturated tetracycles, which are isomerized in TFA to afford 73% of 93 with the double bond in the most stable position. Further elaboration affords progesterone precursor 94 (Scheme 30) [49h]. The nitrile serves to direct the second cyclization 6-endo as would an alkyl group but can be reduc-
2.3.4 Cyclizations
21 1
x
91a, X = H (31%) C02R 91b, X = Me (23%)
90b. X = Me
Scheme 29
AcOH 0
C02Me 92
___)
ci
C02Me (73%)
94
Scheme 30
tively cleaved to remove the nitrile leading to steroid precursor 94. Oxidative quadruple cyclization of 95 provides 35% of tetracycle 96 stereospecifically [50].Further elaboration affords isosteviol (97) and beyer-l5-ene-3,19-diol (98) (Scheme 3 l ) . Application to natural product synthesis. The application of Mn(lI1)-mediated radical reactions to natural product total synthesis provides an excellent demonstration of the scope and utility of these reactions since the method must be versatile enough to deal with complex skeletons and diverse functionality. Many examples of the use of Mn(1II)-mediated radical reactions have already been presented above. Some other notable examples are described below.
2 12
2.3 Munganese(III)-Mediuted Rudicul Reactions
Oxidative addition of cyanoacetic acid to the cyclohexadienyl silyl ether 99 affords 48% of lactone 100, which already contains the complete carbon skeleton of the target paeoniflorignenin (101) (Scheme 32) [511. Mn(OAc)3 oxidizes a,P-unsaturated enones to r'-acetoxy-aJ-unsaturated enones [ 521. The intermediate cc' radical will add to an alkene either intramolecularly [53] or intermolecularly [54]. Oxidation of 4-chloropropyl-2-cyclohexenone (102) with >4 equivalents of Mn(OAc)3in benzene at 100 "C in the presence of 4-methoxy-~-methylstyreneaffords radical 103, which adds to the styrene to give 104. Cyclization of the radical onto the oxygen followed by further oxidation provides 105, which was converted to conocarpan (106) (Scheme 33) [54]. NCCHzC02H Mn(OAc),
,=(
'0~1~s rt 15 h, 48%
B z O 4 O NC..l\fo
OH II
0
99
100
101 (paeoniflorigenin)
Scheme 32
>4 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
CAN
Aco’G MeOH, 0 “C 74-94%
16
v-0
.i-----o
AcO/*OMe
+
c
Me02C
~
’M ~ O N~ O ~ ~“ “ Me02C
17a
17bCO2Me
Scheme 5. CAN-mediated radical reactions in carbohydrate chemistry
NHdSCN +
a
le
18
H
SCN MeOH, 20 “C 100%
19
H
Scheme 6. CAN-mediated radical addition by oxidation of thiocyanate l e
The cerium(1V)-mediated generation of heteroatom radicals by oxidation of anions such as azides was discovered many years ago [lo]. However, Nair et al. applied this strategy for a C-S bond-forming reaction by oxidation of ammonium thiocyanate l e only recently [ 1 I]. Addition of thiocyanate radical to indole 18 provides an intermediate radical, which is further oxidized to the cation by CAN. Loss of proton from the cationic intermediate provides the substituted arene 19 in excellent yield (Scheme 6). Finally, cerium(1V) ammonium nitrate can serve as the radical source by itself, generating NO3 radicals If by photolysis. The addition of such radicals to cycloalkynes 20 initiates an interesting tandem reaction [ 121. Transannular hydrogen atom abstraction by the vinyl radical 21 affords the intermediate 22, which undergoes a 5-ex0 cyclization to the radical 23. In the last step, the ketone 24 is formed by elimination of NO2 in moderate yield: thus, the overall sequence can be described as a self-terminating radical reaction (Scheme 7).
lf
20
24 (24%)
23
Scheme 7. CAN-mediated generation and addition of NO3 radicals If
2.4.3 Iron (III)-Mediated Radical Reactions
8 O M e H3C 25a
223
FeCI3, SO2 CH2CI2, 25 "C 95%
OMe
Me0 26a OMe OMe
FeCI3, Si02 CH2CI2, 25 "C 95% OMe
OMe
25b
26b
Scheme 8. Iron(II1)-mediated oxidative coupling of arenes 25
2.4.3 Iron(II1)-Mediated Radical Reactions Like cerium(IV), iron(II1) salts can oxidize electron-rich centers by single-electron transfer to form radicals [ 11. Early applications were developed for the oxidation of aromatic compounds, which undergo C-C bond formation to dimeric products. Because of their electronic properties, methoxy substituted arenes 25 are most reactive. Iron(II1) chloride supported on silica gel was the reagent of choice, since interand intramolecular coupling products 26 are obtained in excellent yields (Scheme 8) ~31. A similar concept was applied for the dimerization of allylic sulfones 27 [ 141. The advantage of such single-electron transfer reactions consists in the direct oxidation by FeC13 of anions, which are easily accessible by deprotonation with LDA. The dimerization proceeds with considerable regioselectivity, and the coupling products 28 are isolated in high yield (Scheme 9). More recently, the generation of radicals from malonates 29 in the presence of iron(II1) salts and following addition to alkenes 30 or cyclization was realized [ 151. Again, deprotonation facilitates the electron transfer and the reaction with a ferrocenium ion proceeds even at -78 "C. Under the reaction conditions, the intermediate benzylic radicals are readily oxidized to cations, which are trapped by the carbony1 group to afford lactones 31 in good to high yields (Scheme 10). However, the advantage of such lactonizations compared to manganese(II1)- (Volume 1, Chapter 2.3) or cerium(1V)-mediated radical reactions (see Sec. 2.4.2) is not obvious. Finally, a very interesting tandem reaction was developed by Booker-Milburn et al. [ 161. Thus, single-electron oxidation and ring opening of cyclopropyl silyl enol
2.4 Ceriurn(IV) and Other Oxidizing Agents
224
H3CyP..-/S02T01
1, LDA 2. FeCI3
CH3 27 To1 =
t
DMF, 0 "C
'0
+
84%
19
CH3
TolOaS , 28b T0l02S
,
CH3
Scheme 9. Iron(II1)-mediated dimerization of allylic sulfones 27
R*C02Et
+
C02Et 29a
4Ph 30
29b
Fe(C10&
Eto2c&o
R
DMF, 20 "C R=H 75% R=Me 91% l3:n-B~ 90% R = (CH2)3Ph 90%
31a Ph
1,2-Dimethoxyethane, -78 "C
u
64%
31b
Scheme 10. Iron(Il1)-mediated generation of radicals from malonates 29
ethers 32 by iron(II1) chloride affords radicals 33 as intermediates. The following 5-exo-trig cyclization proceeds with high stereoselectivity, and the primary radical 34 is trapped by FeC13 to the chloride 35 as final product (Scheme 11).
34
35
Scheme 11. Iron(I11)-mediated tandem reaction of cyclopropyl silyl enol ether 32
2.4.4 Copper (II)-Mediuted Radical Reactions
225
1. LDA 2. cuc12 P
h
k
P
h
Scheme 12. Copper(I1)-mediated oxidative coupling of carbonyl compounds 36
2.4.4 Copper(I1)-Mediated Radical Reactions Copper(I1) salts are efficient one-electron oxidants for the generation of radicals from lithium enolates [ 11. This concept was successfully applied for the oxidative coupling of ketones or amides 36 to afford the corresponding 1,4-dicarbonyl compounds 37 in good yield 1171. If an optically active imidazolidinone is used as chiral auxiliary, the reaction exhibits an excellent simple and induced diastereoselectivity (Scheme 12). An interesting intramolecular version of such oxidative couplings was described by Hiyama et al. 1181. Starting from acyclic amides 38, deprotonation and oxidation with Cu(0Ac)z generates diradicals, which undergo cyclization to synthetically useful p-lactams 39 (Scheme 13). However, the reactions proceed with only moderate yield and stereoselcctivity. Finally, the pioneering work of Snider et al. demonstrated that copper(I1)mediated radical reactions can be applied for an elegant tandem strategy 1191. Thus, oxidation of silyl enol ether 40 by copper(I1) triflate generates electrophilic radicals 41, which undergo a 5 - e x o - ~ i gcyclization to the intermediate 42. Oxidation to a 1. f-BuLi 2. Cu(0Ac)p * THF, -78 "C 38
4-N 3 9 b o
OMe \
OMe
R=H
40% R = Et 40% R = O M e 43% R=NBn2 77%
-
60 : 40 33 : 67 33 : 67
Scheme 13. Copper(I1)-mediated oxidative intramolecular coupling
\
OMe
226
2.4 Cerium(IV) and Other Oxidizing Agents
Cu(0Tf)z
*
CHsCN, 0 "C
H39 CH3 H3C 41
42
90%
43a
4%
Scheme 14. Copper(I1)-mediated tandem reaction of silyl enol ether 40
cation or direct attack onto the aromatic ring affords the tricyclic ketones 43 in excellent yield and good stereoselectivity (Scheme 14).
2.4.5 Oxidative Radical Reactions by Other Metals Compared to iron(III), copper(II), and especially manganese(II1) and cerium(1V) other metals have found less application for the oxidative generation of radicals [I]. An exception is cobalt(II1)-mediated radical reactions, based on the pioneering work of Iqbal et al., which was recently reviewed [20] (see also Volume 1, Chapter 1.8). Some examples of oxidative couplings of silyl enol ethers 44 in the presence of silver(1) oxide were developed [21]. However, there is no advantage over copper(I1)mediated radical reactions, since the reagent is more expensive and the 1,4-diketones 45 are isolated in only moderate yield (Scheme 15). Low-valent titanium complexes are good reducing agents and were applied in various radical reactions. In contrast, oxidative single-electron transfer processes with titanium(1V) chloride are very rare. Again, electron-rich enol ethers 46 are most reactive and are oxidized to radicals after cleavage of the silyl group, and the dimers 47 are obtained in good yields (Scheme 16) [22].
O S ~ M DMSO, ~ ~ 65 "C 44
R = Et 76% R = Ph 73%
45
0
Scheme 15. Silver(1)-mediated oxidative coupling of silyl enol ethers 44
References
227
R1 = H R2 = Me 79% R ' = H R 2 = P h 73% R', R2 = (CH2)5 78%
Scheme 16. Titanium(1V)-mediated oxidative coupling of enol ethers 46
n
k f
Me0
OMe
Scheme 17. Vanadium(V)-mediated oxidative coupling of arene 48
Finally, pentavalent vanadium complexes were employed as one-electron oxidants. The oxidative coupling of the electron-rich arene 48 in the presence of VOF3 was the key step in the total synthesis of stegnacin; however, the cyclization to the 8-membered ring 49 proceeds with only low yield (Scheme 17) [23]. In summary, oxidative radical reactions by other metals are less common than single-electron transfer to cerium(IV), iron(III), copper(Il), and especially manganese(II1) complexes. However, even for manganese(II1) acetate and cerium(1V) ammonium nitrate the synthetic potential is not completely utilized. During the next few years, many new applications should arise, which will focus on stereoselective reactions and the synthesis of complex organic molecules.
References [ I ] a) J. Iqbal, B. Bhatia, N. K. Nayyar, Chem. Rev. 1994, 94, 519-564; b) P. I. Dalko, Tetruhedron 1995, 51, 7579-7653; c) G. A. Molander, C. R. Harris, Tetruhedron 1998, 54, 3321-3354. [2] a) G. G. Melikyan, Sjvzthesis 1993, 833-850; b) B. B. Snider, Chem. Rev. 1996, 96, 339%363;c) G. G. Melikyan, Org. Reuct. 1996,49,427-675; d) T . Linker, J. Prukt. Chern. 1997,339, 488492. [3] a) V. Nair, J. Mathew, J. Prabhakaran, Chern. Soc. Rev. 1997, 127-132; b) T. Sommermann, Synlett 1999, 834. [4] a) G. A. Molander. Chern. Rev. 1992, 92, 29-68; b) K. Ruck, H. Kunz, J. Prukt. Chern. 1994, 336,470-472. [ 5 ] a) M. E. Kurz, P. Ngoviwatchai, J. Org. Chern. 1981, 46, 4672-4676; b) E. Baciocchi, D. Dell'Aira, R. Ruzziconi, Tetruheclron Lett. 1986, 27, 2763-2766.
228
2.4 Cerium(IV) and Other Oxidizing Agents
[6] A . Citterio, M. Nicolini, R. Sebastiano, M. C. Carvajal, S. Cardani, Gaz-z. Chim. Ital. 1993, 123, 189-195. [7] V. Nair, J. Mathew, J. Chem. Soc., Perkin Trans. I 1995, 187-188. [8] N. Arai, K. Narasaka, Bull. Chem. Soc. Jpn. 1997, 70, 2525-2534. [9] a) T. Linker, K. Hartmann, T. Sommermann, D. Scheutzow, E. Ruckdeschel, Angew. Chem. Int. Ed Engl. 1996, 35, 1730-1732; b) T. Linker, T. Sommermann, F. Kahlenberg, J. Am. Chem. Soc. 1997, 119, 9377-9384. [lo] a) W. S. Trahanovsky, M. D. Robbins, J. Am. Clzem. Soc. 1971, 93, 5256-5258; b) R. U. Lemieux, R. M. Ratcliffe, Can. J. Chem. 1979, 57, 1244-1251. [ 1 I ] a) V. Nair, L. G. Nair, Tetrahedron Lett. 1998,39, 4585-4586; b) V. Nair, T. G. George, L. G. Nair, S. B. Panicker, Tetrahedron Lett. 1999, 40, 1195-1 196. [ 121 U. Wille, C. Plath, Liebigs Ann./Recueil 1997, 11 1-1 19. [ 131 T. C. Jempty, L. L. Miller, Y. Mazur, J. Org. Chem. 1980, 45, 749-751. [ 141 G. Biichi, R. M. Freidinger, Tetrahedron Lett. 1985, 26, 5923-5926. 1151 a) A. Citterio, R. Sebastiano, M. Nicolini, R. Santi, Synlett 1990, 42Z43; b) U. Jahn, P. Hartmann, Chem. Commun. 1998, 209-210. (161 K. I. Booker-Milburn, D. F. Thompson, J. Chem. Soc., Perkin Trans. I 1995, 2315-2321. 1171 a) Y. Ito, T. Konoike, T. Harada, T. Saegusa, J. Am. Chem. Soc. 1977, 99, 1487-1493; b) T. Langer, M. Illich, G. Helmchen, Tetrahedron Lett. 1995, 36, 4409-4412. [IS] T. Kawabata, K. Sumi, T. Hiyama, J. Am. Chem. Soc. 1989, I l l , 6843-6845. [ 191 B. B. Snider, T. Kwon, J. Ory. Chem. 1990, 55, 4786-4788. 1201 J. Iqbal, M. Mukhopadhyay, A. K. Mandal, Synlett 1997, 876-886. 1211 Y. Ito, T. Konoike, T. Saegusa, J. Am. Chem. Soc. 1975, 97, 649-651. 1221 S. Inaba, 1. Ojima, Tetrahedron Lett. 1977, 18, 2009--2012. 1231 A. S. Kende, L. S. Liebeskind, J. Am. Chem. SOC.1976, 98, 267-268.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
2.5 Photoinduced Electron Transfer in Radical Reactions Janine Cossy
2.5.1 Introduction Electron transfer reactions have been extensively studied in chemistry [ 11 and the photochemical approach to reactions of this type has become familiar to most organic chemists [2]. Photoinduced electron transfer (PET) processes involve two neutral molecules, a donor D, an acceptor A and an electronic excitation (Scheme 1). Production of radical-ions (D'+) and (A'-) depends on the oxidation potential E"'112 (D), the reduction potential FedlI2 (A) of the starting molecules and on the electronic excitation energy Eoo, according to the Rehm-Weller equation, where the Coulombic interaction term (AEc) in polar solvents such as acetonitrile can be neglected to a first approximation [3].
+
AC(Kca1) = EoX1/2(D)- Eredlp(A)- A E o o ( K c ~ ) AEc When the PET is thermodynamically favorable (AC < 0), electron transfer proceeds at a rate close to diffusion controlled [4]. However, the fate of the radical-ion pair depends strongly on the nature of the solvent and on the rate of the reverse electron transfer to A and D in their ground state [ 5 ] . Use of polar solvents favors solvent-separated ion pairs and limits this reverse electron transfer process. Some compounds can be either donors or acceptors depending on their relative rcdox potentials such as is the case with alkenes and aromatic cyano compounds. For example, 1,4-dicyanonaphthalene (DCN) and 9,lO-dicyanoanthracene (DCA) are reducing agents in the presence of enones, ketones, alkylated arenes and alkenes, but they are oxidizing agents in the presence of amines. Furthermore, alkenes can be reducing agents in the presence of ketones and iminium salts, but oxidizing agents in the presence of DCN and DCA. We also note that amines are reducing agents in the presence of ketones, enones, esters, imides, halides and styrenes. In general, radical-anions generated by PET can be involved directly in radical reactions such as coupling reaction, reduction, intramolecular cyclization, single bond fragmentation or tandem reactions. However, for halides cleavage of the C-X bond takes place after the PET, a radical is generated and radical processes ensue. In contrast to radical-anions, radical-cations are generally not involved in radical
230
2.5 Photoinduced Electron Transfer in Radical Reactions hv
D + A
Dt
*
+
A;
-
Products
Scheme 1. General process for PET
Reduction
1 3
Fragmentation
]
Cyciization tandem reactions
Scheme 2. The different processes occurring from radical-anions and radical-cations
reactions until after their transformation to radicals, most commonly in a coupling reaction (Scheme 2). Direct coupling reactions between radical-anions and radicalcations are also possible but will not be reviewed here.
2.5.2 Coupling Reactions The transformation of a radical-cation into a radical involves processes such as carbon-hydrogen dissociation, carbon-metal bond dissociation, carbon-carbon bond dissociation (this latter process is not frequently encountered and will not be treated in this review) and nucleophilic addition.
2.5.2.1 Carbon-Hydrogen Bond Dissociation Usually, as the formation of a radical-cation from a neutral substrate is associated with an increase in its acidity, facile deprotonation can take place [6, 71. In a majority of instances, proton transfer takes place between radical-cation/radical-anion pairs, with the net result being the formation of two radicals and consequently a bimolecular coupling product (Scheme 3). This process is encountered in benzyl radical-cations, olefin radical-cations, and amine radical-cations. Several groups have studied photoreactions of dicyano-aromatic compounds with alkylbenzenes as the electron donors [8]. Efficient proton transfer from the benzylic position of the alkylbenzene radical-cation, formed by electron transfer to excited DCN, to the counter anion (DCN’-) is reported to produce a benzylic radical and
2.5.2 Coupling Reactions
AH R A Y
-
23 1
4 HA’
+
R”y
Coupling products
Scheme 3. General process for coupling reactions after a C-H bond dissociation
5 (2%)
CN 4 (17%)
CN
CN
3 (32%)
2 (38%)
Scheme 4. PET between toluene and DCN
DCN’. These two radicals, upon mutual coupling, yield products 2 , 3 and 4. A trace of bibenzyl 5 is also formed by dimerization of the benzylic radical (Scheme 4) [9]. In the presence of alkenes, an excited ketone can become a sufficiently strongly oxidizing agent to abstract an electron from an alkene, leading to a radical-ion pair. A typical example of a ketone-olefin reaction which proceeds via PET and proton transfer to produce coupling products is shown in Scheme 5 [lo]. Even more than in the case of aromatic cyano compounds, carbonyl compounds such as enones [ 1 11, ketones [ 121 or imides [ 131 usually act as electron-accepting partners in the presence of amines. Alkenes or alkylarenes are also accepting partners in the presence of amines [14]. The coupling products are derived from an initial electron transfer followed by hydrogen atom transfer. Depending on the nature of the amine, either a CH (Scheme 5 , eq 1) or an NH bond (Scheme 6, eq 2) intervene in the hydrogen atom transfer. Until recently the intermolecular photoreduction of ketones by amines has not provided much synthetic utility. In general, coupling of the radicals formed by PET and proton transfer produces a mixture of a-amino alcohols, diamines and/or
2.5 Photoinduced Electron Transfer in Radical Reactions
232
&
hv
0
6
(45%)
HO
I
0
*
> 400 nm Benzene
7
9
OH%K !8
(20%)
H
Scheme 5. PET between a ketone and an olefin
A
+
-
R~R~NH
hv
A:
+ R~R~NH;
I coupling products
A
+
R~R~N-,
+ -
hv
HA’ +
A:
R3
coupling products
+
+I HA’
+
eq 1
-
R~RIN
+.
R W N ~ R3 eq 2 R2R1N
A = enone, ketone, imide
’
7
R3
Scheme 6. PET between an amine and an acceptor
pinacols [ 141. More interestingly, the amino and the carbonyl groups can belong to the same molecule without disturbing the charge transfer process and produce intramolecular coupling products via a biradical intermediate. Depending on the structure of the starting aminoketone, a-aminocyclopropanols, hydroxyazetidines or a-aminocyclopentanones, as well as azalactones, can be obtained in high yields (Scheme 7) [ 151. The direct photocyclization of another interesting acceptor-donor pair, the amine-enone, has been reported [ 161. Intramolecular single-electron transfer from the amine donor to the cyclohexenone excited state results in the formation of a zwitterionic biradical. a-Deprotonation and coupling of the intermediate biradical 16” leads to spiro N-heterobicyclic systems of type 17 (Scheme 8). The same process has been observed by irradiating phthalimides that are Nsubstituted with alkylamines. In particular, the photochemical cyclization of w-
2.5.2 Coupling Reactions
Ph 10
hv, 313 nrn
HO
HO
benzene 95%
Ph
PhH
H
233
[ref 15 c-e]
13 R
9 HohN*Ph
k
hv, 313 nm ether 50%
11
- u - H8-ph [ref 15 f-i]
14
R2
R2
hv, 313 nrn
HO ph&&.
R’
J !R &in
[ref 15 I-rn]
0
0
30-50%
12
0
0
* R
ether
15
Scheme 7. Intramolecular photoreduction of ketones by amines
b,.v>Mp: :sj 4-& 2
MeCN
R’”N
R”’-N k2
16
k2
A2
k2
16‘
16“
17
MP’ = Hanovia rnedium-pressure mercury lamp
Scheme 8. Intramolecular PET between an enone and an amine
anilinoalkylphthalimides 18 offers interesting synthetic potential (Scheme 9) [ 13a, 171. Intramolecular coupling reactions between acceptor-donor styrene-amine pairs have been intensively studied. For example, direct irradiation of an aminoethylstilbene involves an electron transfer from the ground state of the amine to the singlet state of the styrene. Following electron transfer, an N-H transfer to either C-a or C-p of the styrene double bond takes place and a biradical intermediate is formed which produces the cyclized product (Scheme 10) [IS]. Further investigations on the acceptor-donor arene-amine system have been made. Direct irradiation of 9-(~-anilinoalkyl)phenanthrenes give spirocyclic pyrrolidine derivatives by NH addition to the phenanthrene C(9)-C(10) bond [ 191.
2.5 Photoinduced Electron Transfer in Radical Reactions
234
Scheme 9. Intramolecular coupling in N-(w-anilinoalky1)phthalimides
d:H &:. CH3 hv,HP*
70%
/
20
CH3
/'
=H+ ,Ph
1 .f
Ph
21 HP* = High-pressure mercury lamp Scheme 10. Intramolecular coupling in an (aminoethy1)stilbene
It is worthy of note that the photoreduction of [60]fullerene by tertiary amines, such as triethylamine, results in the formation of a coupling product. This product is likely to be formed by a PET-proton transfer mechanism [20].
2.5.2.2 Carbon-Metal Bond Dissociation Fragmentation of the C-M bonds of Group 4A organometallic radical-cations usually generates carbon-centered radicals which add to the reduced form of the acceptor to give coupling products [21] (Scheme 11). Carbon-silicon bond heterolysis of the radical-cation from trimethylsilylsubstituted ethers, thioethers, and amines, generated by PET to 'DCA, produces the corresponding methylene radical, which ultimately combines with reduced DCA' to yield coupling products (Scheme 12) [22].
2.5.2 Coupling Reactions A
hv
RMR'
+
A;
R-AH
-
+.
RMR'
+
1
M = Si, Ge, Sn, Pb H+
235
R-A-
R * + 'MR'
+
AT
Scheme 11. Dissociation of C-metal bonds
hv, MeCN
1L> 290 nrn 22
CN
X = S,O, N
DCA
23
t
0-90% DCA;
+
22t
DCA'
*
+
'CHzXR
Scheme 12. Dissociation of a C-Si bond and coupling
0
60-
+ Et2NCH2SiMe3
hv' " " ,
MeOH
R 25
24
3046%
+. +
Et2NCH2SiMe3
I
26
Scheme 13. Dissociation of the C-Si bond in an cc-silylmethylamine
Dissociation of the C-Si bond from a-silylmethylamine radical-cations formed by PET to a triplet excited enone takes place in alcoholic solvent and produces a 'free a-amino-radical' which adds to the p-ketyl radical to give a conjugate addition product (Scheme 13) [23].The C-Si bond cleavage has been exploited extensively in such reactions for synthetic purposes [24]. The synthetic potential of the C-Si bond cleavage from allyl- and benzylsilane radical-cations produced by photoreaction of electron-deficient iminium salts has been extensively investigated [25].When a benzylsilane or allylsilane is irradiated in the presence of an iminium salt such as 27, a one-electron oxidation of the silane to the excited iminium salt produces a radical/radical-cation pair. Subsequent C-Si bond dissociation from the silane radical-cation by the loss of T M S leads to an
236
2.5 Photoinduced Electron Transfer in Rudical Reactions
- Gph
f.
clod-
@ph+
RCH2SiMe3
I
CH3 27 R = Allyl, Benzyl
+ RCH2SiMe3
hv MeOH
I
CH3 271
40-80%
whR 27'
I
I
RCH2' '++SiMe3
CH3 28
MeOH
1
MeOSiMe3
Scheme 14. PET between iminium salts and alkylsilanes
allyl/benzyl radical which, upon coupling with the ct-amino-radical27', provides 28. Nucleophilic-assisted elimination of TMS+ is suggested as the key factor in these reactions (Scheme 14).
2.5.2.3 Nucleophilic Addition Nucleophilic addition to organic radical-cations is one of the most common pathways to produce radicals. Irradiation of a wide variety of N-(2-alkenyl)- and N (3-alkeny1)phthalimides and N-alkenylphthalimides [26] with a remote alkenyl double bond [27] afford new 5-, 6- and medium-size ring systems. Irradiation in methanol-acetonitrile triggers intramolecular electron transfer from the olefin double bond to the excited phthalimide carbonyl group. Because of the highly nucleophilic character of methanol, the olefin radical-cation can be trapped. The derived radical combines with the radical-anion to yield coupling products (Scheme 15). Although the imine group resembles the carbonyl group to some extent, their
1
75% 29 Ph
-
30
c
x
y
y
p
MeOH
h OMe
0
HP* = High-pressure mercury lamp
Scheme 15. PET in N-(2-alkenyl)phthalimides involving nucleophilic addition of MeOH to the olefin radical-cation
2.5.3 Reduction
,,
n
237
hv, MP*
31 MP' = Medium-pressure mercury lamp Scheme 16. PET between an iminium salt and an olefin promoted by nucleophilic addition of
MeOH to the olefin radical-cation
photochemistry differs quite remarkably. This applies even more to iminium salts, because of their powerful electron-acceptor properties. Therefore, PET is even possible with simple alkenes or electron-rich aromatic compounds. One typical example is shown in Scheme 16 [28]. As in the case of phthalimide photochemistry, here the products arise from the initially formed radical/radical-cation pair (after PET) by attack of methanol on the charged alkene fragment followed by radical coupling. Other alkenes with oxidation potentials less than 2.6 eV behave similarly [28a, 291. In contrast to radical-cations, radical-anions can be involved directly in radical reactions such as reductions, single bond fragmentations, cyclizations or tandem reactions.
2.5.3 Reduction In aqueous media, the coupling of radical-anions can be avoided. In water, it was found that reduction of ketones by amines proceeded rapidly to form a secondary alcohol rather than a pinacol (Scheme 17) [30, 311. Alcohols are also obtained when solvated electrons are produced by irradiation. For example, y-radiolysis of ketones in 2-propanol gives the corresponding alcohols [ 321.
e, 32
+
Et3N
hv
H20
+
Et3N
?
6 33
Scheme 17. Photoreduction of cyclohexanone by triethylamine
2.5 Photoinduced Electron Transfer in Radical Reactions
238
2.5.4 Cyclization The addition of radicals, generated by photoelectron transfer, to an unsaturated functional group has received the most attention. The fate of the intermediate radical does not depend strongly on the method used to produce it. An interesting example of a photoreductive reaction of w-unsaturated ketones in the presence of hexamethylphosphoric triamide (HMPA, neat) or triethylamine (Et3N) in acetonitrile has been reported [33]. The thus formed 6, &-unsaturatedketyl radicals exhibit the same behavior as o-unsaturated radicals [34] and they cyclize to produce cyclopentanols and cyclohexanols. A typical example is provided in Scheme 18. The reaction proceeds by electron donation from excited HMPA to the ground state of the ketone or by reduction of the excited ketone by the ground state of Et3N. Good yields and stereoselectivity are observed under these mild reaction conditions. From a preparative point of view, it was found that the procedure using Et3N tolerates various substituents such as carbonitriles, esters, ethers, alkenes, and alkynes. Compared to other chemical reductions, or electroreduction, the photoreduction offers the advantage of being carried out under mild and homogeneous conditions with few problems of reproducibility and constitutes a complementary and advantageous approach to cyclic compounds. For this reason, the photoreductive cyclization has been applied successfully to the synthesis of cyclopentanoids [35], alkaloids [ 361, iridoids [37] and furofuranic systems [38]. o-Unsaturated aldehydes, which are more readily reduced than ketones, can also be used as precursors to cyclopentanols and cyclohexanols [39]. The synthetic utility of this process was exemplified by an improved synthesis of isocarbacyclin [40]. The photoreduction by DCA'- of cr, P-unsaturated ketones or esters tethered to activated olefins proceeds with efficient diastereoselective cyclization to give substituted carbocycles [41] (Scheme 19). The photooxidation of w-unsaturated cr-alkylsilylamines by the singlet excited state of DCN proceeds with selective desilylation to generate cc-amino radicals from a-alkylsilylamine radical-cation. Cyclization of the cc-amino radicals leads to substituted pyrrolidines and piperidines [42] (Scheme 20). The reduction of halides by organotin hydrides via radical intermediates has continued to find applications since its discovery in the 1960s [43]. Another method
C02Me
C02Me
?OpMe
HMPA EtSN/CH&N
EO2Me
35
36
87%
3%
56%
4%
34
Scheme 18. Cyclization of w-unsaturated ketyl radicals
2.5.5 Single-Bond Frugmentutions
239
hv, 405 nm
DCA, Ph3P OEt
37
90%
37’
38 translcis = 8511 5
Scheme 19. Photoreduction of a, P-unsaturated esters tethered to activated olefins
40
(n = 1, 2; R’ = H, alkyl; R2 = alkyl)
Scheme 20. Photooxidation and cyclization of w-unsaturated a-alkylsilylamines
for conducting radical reductions involves treatment of halide compounds with electron donors. The photochemistry of aryl halides is dominated by the SRNIreaction, which involves electron transfer from a carbanion to the aryl halide. As this reaction has been extensively reviewed it will not be reported here [44].Radicals are formed efficiently when alkyl halides are irradiated in the presence of donors such as alkenes, amines or arenes [45]. For example, when a halide is irradiated in the presence of a tertiary amine at 254 nm, an amine-halide exciplex is formed which leads to a radical R’ and a halide anion (Scheme 21, eq 1). The radicals generated from halides can also be trapped efficiently by an internal n-bond to produce cyclized products [46] (Scheme 21, eq 2). This reaction was used to synthesize precursors of antifungal compounds [47].
2.5.5 Single-Bond Fragmentations Arenesulfonyl derivatives are frequently employed in organic synthesis to activate hydroxy groups for nucleophilic substitution reactions or to protect primary and secondary amines. The PET cleavage of tosyl groups is closely related to reductions
240
2.5 Photoinduced Electron Trans@ in Radical Reactions
QoT-
-
nm
;;;vh
CH3CN
41 X= Br, I
eq2 42
90-94%
Scheme 21. Photoreduction of halides and photocyclization of unsaturated halides
by metals in liquid ammonia [48], sodium naphthalenide [49] or by electroreduction [50].From a preparative point of view, the photolysis of tosylates and sulfonamides in the presence of a donor provides an efficient way to regenerate cleanly and with high yield the corresponding alcohols or amines (Scheme 22, eq 1). This deprotection method was applied efficiently to the regeneration of hydroxy groups from the corresponding sulfonates in sugars (Scheme 22, eq 2) [51]. Furthermore, the PET process can be made catalytic in electron donor when small quantities of sodium P-naphtholate and a large excess of sodium borohydride are used. Under these conditions, dialkylamines can be regenerated almost quantitatively from their tosylamides [52]. While most of the work related to PET reactions has been focussed on the formation of C-C bonds, the cleavage of C-0 and C-C bonds has also received attention. Until recently, satisfactory conditions for preparative photodeoxygenation
+
ArS02-XR
hv Donor
-
HXR
Solvent
[ ArS02-XR]
-
'
-
recjuctant
-
1
MeOH NaBH4
eq 1
ArS02- + ' X R
X = 0, N; Donor = 2-(4,8-dimethylnaphthyl)propionicacid
Xb0 Xh '" hv, 350 nm Donor
"A
Tso 43
*
MeCN HPN-NH~ 65%
"A
Ho44
Scheme 22. Photolysis of tosylates and sulfonamides in the presence of an electron donor
2.5.5 Single-Bond Fragmentations
241
of carboxylic esters were still unknown because of their highly negative reduction potential. It was later recognized that the irradiation of esters in the presence of HMPA and water can produce alkanes in good yield [53]. The mechanism for the process, shown in Scheme 23, indicates an electron transfer between excited HMPA and the carboxylic ester in its ground state with formation of a radical-ion pair [54]. It was proposed that, at least for acetates, the presence of water is essential to allow protonation of the radical-anion and to prevent the reverse electron transfer to regenerate HMPA and ester in their ground states. Subsequently, dissociation of the protonated radical leads to the alkyl radical and the carboxylic acid. Finally, abstraction of a hydrogen from HMPA leads to the deoxygenated compound R 2 H (Scheme 23, eq 1). Deoxygenation of alcohols through photolysis of their carboxylic esters and especially their acetates is a general process that has been of particular interest in the production of deoxysugars (Scheme 23, eq 2) [ 5 5 ] and in the synthesis of trichodermol [56]. In the case of perfluoro esters, expulsion of a fluoride anion is preferred to C-0 bond cleavage (Scheme 23, eq 3) [57]. When an cc-monoalkoxy ketone is irradiated in the presence of Et3N, cleavage of the CEO bond is observed. One synthetic application of such cleavages is the removal of an ally1 group from the anomeric position of a carbohydrate (Scheme 24) [581.
1
HO’& Ho\PA+NHMe
HMPA’
hv, 254 nm t
HMPA-H2 0
65% 46
hv, 254 nm RFCF~CO~R
+
HMPA-H20
RFCFHCO~R +
75%
RFCH~CO~R eq 3 12%
Scheme 23. Photolysis of esters in the presence of HMPA-H20
242
2.5 Photoinduced Electron Transfer in Radical Reactions
H2Nq ; H 2
Wacker
RO 47 0 -
48
98% H2Nq
H
Ro
49
2
I
hv, 254 nm EtsN, CH3CN
H2N
.
OH
Scheme 24. Ally1 deprotection via the photoreduction of a derived hydroxy ketone
The cleavage of strained heterocyclic rings can also be achieved by PET (Scheme 25). Cleavage of the epoxide ring of an a-epoxy ketone leads to a y-hydroxy ketone [59]. Although the exact mechanism of the epoxide ring opening from intermediate 50' has not yet been determined, a PET process is involved. The C - 0 bond cleavage is similar to the reductive cleavage of the same bond by metals in liquid ammonia [60], Bu3SnH [61], cathodic reduction [62] or SmI2 [63]. Oxanorbornanones, which possess a strained oxabridge, can be cleaved under PET conditions [59, 641. This reaction was applied to the synthesis of erianolin precursors [47] and bisabolangelone [65], as well as a new class of disaccharide mimics [66]. The PET-induced ring opening of oxygenated strained rings can be extended to cyclopropanes and cyclobutanes. One of the first examples of a PET-induced cyclobutane cleavage was reported in 1990 [67]. Irradiation of ketone 54 in the presence of triethylamine results in the formation of spiro compound 55 (Scheme 26) [68]. A PET mechanism was postulated for this reaction, since the cleavage of the cyclobutane is not observed in the absence of triethylamine. Similarly, various cyclobutyl ketones have been cleaved under PET conditions in the presence of triethylamine [69].
Scheme 25. Cleavage of C - 0 bonds in r-oxygenated ketones
2.5.6 Tandem Reactions
hv,254nrn Et3N CH&N 40 - 80%
54
1
0I
243
A 55
t
?-
Scheme 26. Cleavage of a C -C bond in an a-cyclobutyl ketone
This photofragmentation method has been extended to the cleavage of the cyclopropyl moiety of cyclopropyl ketones [70, 711. Irradiation of bicyclo[4.1.O]heptanone 56 at 254 nm in acetonitrile in the presence of Et3N led to cyclohexanone 60 according to Scheme 27 [71]. When bicyclo[3.1 .O]hexanone and bicyclo[4.1.O]heptanone are substituted by electron-withdrawing groups a t C(p),a ring-expanded product is formed. Similarly, the irradiation of bicyclo[5.1.O]octanone 58 and bicyclo[6.1.O]nonanone 59 in the presence of EtiN led to ring-expanded products (Scheme 27). The preferred regioselectivity of ring opening (exo versus endo) depends on the substitution pattern of the bicycloalkanones and on their ring size [71, 72, 731. Cleavage of the cyclopropane ring of a chiral bicyclo[4.1.O]heptanone has been used as a key step in the synthesis of the antifungal agent, (+)-ptilocaulin [74].
2.5.6 Tandem Reactions The radical intermediate produced by the PET cleavage of bicyclo[n. 1.O]alkanones can be trapped intramolecularly by an olefin as shown by the formation of bicyclic ketone 66 from bicycloalkanone 65 [70, 721 (Scheme 28). The linear triquinane skeleton is easily accessible from methyl S-oxotricyclo[5.4.0.0]2.6undecan-1-carboxylate 67 [64]. Photoreduction of 67 affords ringexpanded intermediate 67” which cyclizes to the linearly fused triquinane 68 (Scheme 29, eq 1). An extension of this reaction to the heterocyclic angular tricyclic compound 70 has also been achieved starting from keto lactone 69 (Scheme 29, eq 2) [751. Compound 74 was obtained when N,N-dimethylaniline and furanone 72 were irradiated in the presence of the Michler’s ketone 73. These compounds are formed by tandem radical addition-cyclization. The a-amino alkyl radical 71’, produced by
2.5 Photoinduced Electron Transfer in Radical Reactions
244
8 b? 56
57
“ZMe
-
hv, 254 nm
Et3N CH3CN
60
60% hv, 254 nrn
Et3N CH3CN 65% hv, 254 nrn
Et3N * CH3CN
e -b 62 (61Yo)
58
63 (trace)
hv, 254 nrn c
Et3N 59
CH~CN 55%
64
Scheme 27. Photoreduction of cyclopropyl ketones
hv, 254 nrn
Et3N 65
CH3CN 70%
t 0-
65’
0-
65“
Scheme 28. Ring opening and cyclization
a PET process involving the excited Michler’s ketone 73, adds to 72 affording radical 74/, which yields intermediate 74” after intramolecular addition to the electron-rich aromatic ring. Mechanistic studies show that aromatization of radical 74” occurs by transfer of a hydrogen atom to furanone 72 (Scheme 30) [76].
2.5.6 Tandem Reactions
a
hv, 254 nm
Et3N CH3CN 26%
E 67
245
EH 68
t
- 0\
't 67'
67"
67"'
hv, 254 nm
CH3CN R 69
70
Scheme 29. Ring expansion-cyclization \
hv, 254 nm CH3CN,acetone
/
6 71
0
4 '"/OR*
72
&N'
+
'N
H%
0 .'"OR*
73
74"
Scheme 30. Tandem addition-cyclization reaction of an aromatic amine
Reactions involving PET processes are usually chemo-, regio-, and diastereoselective. For this reason, numerous synthetic developments have appeared during the last twenty years. For example, in the field of photodegradable protective groups, PET-induced cleavage has been used for the regeneration of alcohols and amines. Transformation of alcohols into alkanes, via photoreduction of the corresponding acetates and triflates, is easily carried out in HMPA, because of the re-
246
2.5 Photoinduced Electron Transfer in Radical Reactions
ducing character of the reaction mixture under UV irradiation. At present, and in spite of the interest in these reactions, the photoreduction of ketones by tertiary amines is probably one of the most useful processes from a synthetic point of view. Natural products, carbocyclic and heterocyclic compounds can be easily prepared from unsaturated ketones and PET processes cannot be neglected in synthetic schemes. The mild conditions and the high selectivity of these reactions make them very attractive for the formation of radicals and for further synthetic applications.
Acknowledgement Prof. J. M. Marshall is acknowledged for his particular assistance in the preparation of the manuscript.
References [ l ] a) M. A. Fox, M. Chanon, Photoinduced Electron Transfer, Elsevier, Amsterdam, 1988. b) M. Julliard, M. Chanon, Chem. Rev. 1983, 83, 425. [2] a) J. Mattay, Synthesis 1989, 233. b) J. Cossy, Bull. Soc. Chim. Fr. 1994, 131, 344. c) L. Eberson, Electron Transjer Reactions in Organic Chemistry; Springer-Verlag Berlin, 1987. d) G. Pandey in Molecular and Supramolecular Photochemistry, Vol. 1 (Eds.: V. Ramamurthy, K. S. Schanze), M. Dekker, New York, 1997. e) S. Hintz, A. Heidbreder, J. Mattay in Topics in Current Chemistry, Electron Trunsfer 11, Vol. 117 (Ed.: J. Mattay), Springer-Verlag, Berlin, 1996, 77. f ) J. Cossy, J. P. Pete in Advances in Electron Transfer Chemistry, Vol. 5 (Ed.: P. S. Mariano), Jai Press, 1996, 141. [3] D. Rehm, A. Weller, Isr. J. Chem. 1970, 8, 259. 141 A. Weller, J. Phys. Chem. Neue FoIge 1982, 130, 89. [5] a) J. Mattay, Angew. Chem. Int. Ed. Engl. 1987, 26, 825. b) M. A. Fox in Adv. Photochem., Vol. 13 (Eds.: D. H. Volman G. S. Hammond, K . Gollnick), Wiley, New York, 1986, 237. [6] a) X.-M. Zhang, F. G. Bordwell, J. Am. Chem. Soc. 1994, 116, 904. b) X.-M. Zhang, F. G. Bordwell, J. Am. Chem. Soc. 1994, 116,4251. c) J. P. Dinnicenzo, T. E. Banach, J. Am. Chem. Soc. 1989, I l l , 8646. [7] A. M. D. P. Nicholas, D. R. Arnold, Can. J. Chem. 1982, 60, 2165. [8] a) F. D. Lewis, Acc. Chem. Res. 1986, 19, 401. b) D. R. Arnold, P. C. Wong, A. J. Maroulis, T. S. Cameron, Pure Appl. Chem. 1980, 52, 2609. c) A. Albini, E. Fasani, M. Mella, Top. Curr. Chem. 1993, 168, 143. d) J. Santamaria, R. Jroundi, J. Rigaudy, Tetrahedron Lett. 1989, 30, 4617. [9] a) A. Albini, S. Spreti, Tetrahedron 1984, 40,2975. b) A. Albini, E. Fasani, A. Sulpizio, J. Am. Chem. Soc. 1984, 106, 3562. [ 101 J. Mattay, J. Gersdorf, K. Buchkremer Chem. Ber. 1987, 12, 307. [Ill U.-C. Yoon, J.-U. Kim, E. Hasegawa, P. S. Mariano, J. Am. Chem. SOC.1987, I O Y , 4421. [I21 a) S. G. Cohen, A. Parola, G. H. Parsons, Chem. Rev. 1973, 73, 141. b) J . D. Simon, K. S. Peters, J. Am. Chem. Soc. 1983, 105, 4875. [I31 a) J. D. Coyle, G. L. Newport, Tetrahedron Lett. 1977, 899. b) H. J. Roth, D. Schwartz, B. Hundeshagen, Arch. Pharm. 1976, 309, 48.
References
247
[I41 a) P. J. Wagner, R. J. Truman, A. E. Puchalski, R. Wake, J. Am. Chem. Soc. 1986, 108, 7727. b) P. J. Wagner, B. S. Park in Organic Photochemistry, Vol. 11 (Ed.: A. Padwa), M. Dekker, New York, 1991, 227. [IS] a) H. J. Roth, M. H. El Raie, Tetrahedron Lett. 1970, 2445. b) H. J. Roth, M. H. El Raie, Arch. Pharm. 1972, 305, 209. c) J. Cossy, M. Guha, unpublished results. d) A. Abdul-Baki, F. Rotter, T. Schrauth, J. L. Roth, Arch. Pharm. 1978, 3II, 341. e) G. A. Kraus, L. Chen, Tetrahedron Lett. 1991,32, 7151. f ) K. L. Allworth, A. A. El-Hamamy, M. M. Hesabi, J. Hill, J. Chem. Soc., Perkin Trans I 1980, 1671. g) M. M. Hesabi, J. Hill, A. A. El-Hamamy, J. Chem. Soc., Perkin Trans I 1980, 2371. h) E. H. Gold, J. Am. Chem. Soc. 1971, 93, 2793. i) R. A. Clasen, S. Searles Jr, J. Chem. Soc., Chem. Commun. 1966, 289. j) P. J. Wagner, B. Scheve J. Am. Chem. Soc. 1976, 99, 1858. k) T. Hasegawa, K. Miyata, T. Ogawa, N. Yoshihara, M. Yoshioka, J. Chem. Soc., Chem. Commun. 1985, 363.1) T. Hasegawa, T. Ogawa, K. Miyata, A. Karakizawa, M. Komiyama, K. Nishizawa, M. Yoshioka, J. Chem. Soc., Perkin Trans I 1990, 90 1. 116) a) W. Xu, Y. T. Jeon, E. Hasegawa, U.-C. Yoon, P. S. Mariano, J. Am. Chem. Soc. 1989, 111, 406. b) U.-C. Yoon, P. S. Mariano, Ace. Chem. Res. 1992, 25, 233. c) W. Xu, X.-M. Zhang, P. S. Mariano, J. Am. Chem. Soc. 1991, lI3, 8863. d) W. Xu, P. S. Mariano, J. Am. Chem. Soc. 1991, 113, 1431. [17] a) H. J. Roth, D. Schwartz, B. Hundeshagen, Arch. Pharm. 1976, 309, 48. b) M. Machida, H. Takechi, Y. Kanaoka, Chem. Pharm. Bull. 1982, 30, 1579. c) M. Machida, H. Takechi, Y. Kanaoka, Heterocycles 1977, 7, 273. [IS] a) F. D. Lewis, G. D. Reddy, S. Schneider, M. Gahr, J. Am. Chem. Soc. 1989, IZI, 6465. b) F. D. Lewis, G. D. Reddy, Tetrahedron Lett. 1990, 31, 5293. c) F. D. Lewis, G. D. Reddy, S. Schneider, M. Gahr, J. Am. Chem. Soc. 1991, 113, 3498. d) F. D. Lewis, D. M. Bassani, G. D. Reddy, J. Org. Chem. 1993,58, 6390. [I91 a) A. Sugimoto, R. Sumida, N. Tamai, H. Inoue, Y. Otsuji, Bull. Chem. Soc. Jpn. 1981, 54, 3500. b) A. Sugimoto, S. Yoneda, J. Chem. Soc., Chem. Commun. 1982, 376. c) A. Sugimoto, K. Sumi, K. Urakawa, M. Ikemura, S. Sakamoto, S. Yoneda, Y. Otsuji, Bull. Chem. Soc. Jpn. 1983, 56, 31 18. [20] G. E. Lawson, A. Kitaygorodskiy, B. Ma, C. E. Bunker, Y.-P. Sun, J. Chem. Soc., Chem. Commun. 1995, 2225. [21] Y. Otsuji, Bull. Chem. Soc. Jpn. 1993, 3747. [22] a) E. Hasegawa, M. A. Brumfield, P. S. Mariano, U.-C. Yoon, J. Org. Chem. 1988, 33, 5435. [23] a) E. Hasegawa, W. Xu, P. S. Mariano, U.-C. Yoon, J.-U. Kim, J. Am. Chem. Soc. 1988, 110, 8099. b) X.-M. Zhang, P. S. Mariano, J. Org. Chem. 1991, 56, 1655. [24] a) W. Xu, X.-M. Zhang, P. S. Mariano, J. Am. Chem. Soc. 1991, 113, 8863. b) S. K. Khim, P. S. Mariano, Tetrahedron Lett. 1994,35, 999. c) Y. S. Jung, P. S. Mariano, Tetrahedron Lett. 1993,34, 461 1. [25] P. S. Mariano, Ace. Chem. Res. 1983, 16, 130. [26] a) K. Maruyama, Y. Kubo, M. Machida, K. Oda, Y. Kanaoko, K. Fukuyama, J. Org. Chem. 1978, 43, 2303. b) M. Machida, K. Oda, K. Maruyama, Y. Kubo, Heterocycles 1998, 14, 779. c) K. Maruyama, Y. Kubo, J. Org. Chem. 1981, 46, 3612. [27] K. Maruyama, Y. Kubo, J. Am. Chem. Soc. 1978, 100, 7772. [28] a) P. S. Mariano, J. L. Stavinoha, G. Pepe, E. F. Meyer Jr, J. Am. Chem. Soc. 1978, 100, 71 14. b) J. L. Stavinoha, P. S. Mariano, J. Am. Chem. Soc. 1981, 103, 3136. c) U.-C. Yoon, S. L. Quillen, P. S. Mariano, R. Swanson, J. L. Stavinoha, E. Bay, J. Am. Chem. Soc. 1983, 105, 1204. d) U.-C. Yoon, S. L. Quillen, P. S. Mariano, Tetrahedron Lett. 1982,23, 919. [29] P. S. Mariano, J. Stavinoha, E. Bay, Tetrahedron 1981, 37, 3385. [30] S. G. Cohen, A. Parola, G. H. Parsons, Chem. Rev. 1973, 73, 141. [31] S. G. Cohen, N. M. Stein, J. Am. Chem. Soc. 1971, 93, 6542. [32] a) E. Alipour, J. C. Micheau, N. Paillous, A. Lattes, J. Mathieu, Tetrahedron Lett. 1976, 2833. b) E. Alipour, D. Vidril, J. C. Micheau, M. Paillous, A. Lattes, L. Gilles, Tetrahedron 1983, 39, 2807. [33] a) D. Belotti, J. Cossy, J. P. Pete, C. Portella, Tetrahedron Lett. 1985, 26, 4591. b) D. Belotti, J. Cossy, J. P. Pete, C. Portella, J. Org. Chem. 1986, 51, 4196.
248
2.5 Photoinduced Electron Transfir in Radical Reactions
1341 B. Giese in Radicals in OrGjanic Synthesis: Formation of' Carbon-Carbon bonds, Pergamon, 1986. [35] a) D. Belotti, J. Cossy, J . P. Pete, Tetrahedron Lett. 1987,28, 4547. b) J. Cossy, D. Belotti, J. P. Pete, Tetrahedron 1990, 46, 1859. 1361 a) J. Cossy, D. Belotti, Tetrahedron Lett. 1988, 29, 61 13. b) J. Cossy, D. Belotti, C. Leblanc, J. Org. Chem. 1993, 58, 2351. c) J. Cossy, C. Leblanc, Tetrahedron Lett. 1991, 32, 3051. 1371 J. Cossy, Tetrahedron Lett. 1989, 30, 41 13. 1381 A. P. Brunetiire, M. Leclaire, S. Bhatnagar, J. Y. Lallemand, J. Cossy, Tetrahedron Lett. 1989, 30, 341. 1391 J. Cossy, J. P. Pete, C. Portella, Tetrahedron Lett. 1989, 30, 7361. [40] K . Bannai, T. Tanaka, N. Okamura, A. Hazato, S. Sugiura, K. Manabe, K. Tominori, Y. Kato, S. Kurozumi, R. Noyori, Tetrahedron 1990, 46, 6689. 1411 a) G. Pdndey, S. Hajra, M. K. Ghorai, K. R. Kumar, J. Am. Chem. Soc. 1997, 119, 8777. b) G. Pandey, S. Hajra, M. K. Ghorai, J. Ory. Clzem. 1997, 62, 5966. c) G. Pandey, M. K. Ghorai, S. Hajrd Tetrahedron Lett. 1998, 37, 1831. 1421 a) G. Pandey, G. Kumaraswamy, U. T. Bhalerao, Tetrahedron Lett. 1989, 30, 6059. 1431 H. G. Kuivila, Acc. Chem. Rex 1968, I , 299. 1441 L. M. Tobert in Organic Photochemistry, Vol. 6 (Ed.: A. Padwa), M. Dekker, New York, 1983. [45] R. A. Beecraft, R. S. Davidson, D. Goodwin, Tetrahedron Lett. 1983, 24, 5673. 1461 J. Cossy, J.-L. Ranaivosata, V. Bellosta, Tetrahedron Lett. 1994, 35, 8161. 1471 a) J. Cossy, J.-L. Ranaivosata, V. Bellosta, Tetrahedron Lett. 1994, 35, 1205. b) J. Cossy, J.-L. Ranaivosata, V. Bellosta, Tetrakedron Lett. 1995, 36, 2067. 1481 a) D. B. Denney, B. Golstein. J. Org. Chern. 1956, 21, 479. b) T. Cuvigny, M. LarchevCque, J. Organornet. Chem. 1974, 64, 315. 1491 a) L. Horner, R. J. Singer, Cliem. Ber. 1968,101, 3329. b) W. D. Classon, S. Ji, S. Schulenberg, J. Am. Chem. Soc. 1970, 92, 650. 1501 a) P. T. Cottrell, C. K. Mann, J. Am. Cliem. Soc. 1971, 93, 3579. b) V. G. Mairanovsky, Angeiv. Clzem. Int. Ed. Engl. 1976, IS, 281. I511 A. Nishida, T. Hamada, 0. Yonemitsu, J. Org. Chem. 1988, 53, 3386. 1521 J. F. Art, J. P. Kestemont, J. Ph. Soumillon, Tetrahedron Lett. 1991, 32, 1425. 1531 H. Deshayes, J. P. Pete, C. Portella, D. Scholler, J. Clzem. Soc., Clzem. Comniun. 1975, 439. [54] a) H. Deshayes, J. P. Pete, C. Portella, Tetrahedron Lett. 1976, 2019. b) C. Portella, H. Deshayes, J. P. Pete, D. Scholler. Tetruliedron 1984, 40, 3635. [55] a) J. P. Pete, C. Portella, C. Monneret, J. C. Florent, Q. Khuong-Huu, Synthesis 1977, 774. b) P. M. Collins, V. R. Munasinghe, J. Chern. Soc., Chem. Conzmun. 1977, 927. c) J. P. Pete, C. Portella, D. Scholler, J. Photochem. 1984, 27, 128. d) A. Klausener, J. Runsink, H. D. Scharf, Liebigs Ann. Chern. 1984, 783. e) J. Dornhagen, A. Klausener, J. Runsink, H. D. Scharf, Ann. Cheni. 1985, 1838. f) J. Dornhagen, H. D. Scharf, J. Carbohydrate C'hem. 1986,5, 115.
1561 W. C. Still, M.-Y. Tsai, J. Am. Chern. Soc. 1980, 102, 3654. 1571 a) C. Portella, J. P. Pete, Tetrahedron Lett. 1985, 26, 21 1. b) C. Portella, M. Iznaden, Tetrulzedron 1989, 45, 6467. 1581 J. Liining, U. Moller, N. Debski, P. Welzel, Tetrahedron Lett. 1993, 34, 5871. 1591 J. Cossy, P. Aclinou, V. Bellosta, N. Furet, J. Baranne-Lafont, D. Sparfel, C. Souchaud, Tetrahedron Lett. 1991, 32, 1315. 1601 a) D. Caine in Organic Reactions (Ed.: W. G . Dauben), John Wiley. New York, 1976. b) J. D. McChesney, T. N. Thompson, J. Org. Cliem. 1985, 50, 3473. 1611 E. Hasegawa, K . Ishiyama, T. Kato, T. Horaguchi, T. Shimizu, J. Org. Chem. 1992, 57, 5352. 1621 E. L. Shapiro, M. J. Gentles, J. Ory. Chem. 1981, 46, 5017. 1631 G . A. Molander, G. Hahn, J. Org. Clzem. 1986, 51, 1135. [64] J. Cossy, J.-L. Ranaivosata, V. Bellosta, J. Ancerewicz, R. Ferritto, P. Vogel, J. Org. Chem. 1995, 60, 8351. 1651 J. Cossy, V. Bellosta, unpublished results. 1661 R. Ferritto, P. Vogel, Tetrahedron Lett. 1995, 36, 3517. [67] E. W. Bischof, J. Mattay, Tetrahedron Lett. 1990, 31, 7137.
References 681 691 701 711 721 731 741 751 761
249
J. Mattay, A. Banning, E. W. Bischof, A. Heibreder, J. Runsink, Chern. Ber. 1992, 125, 2119. G. Pandey, A. T. Rao, P. I. Dalvi, P. Kumar, Tetrahedron 1994, 50, 3835. T. Kirschberg, J. Mattay, Tetrahedron Lett. 1994, 35, 7217. J. Cossy, N. Furet, Tetrahedron Lett. 1993, 34, 8107. J. Cossy. N. Furet, S. Bouzbouz, Tetrahedron 1995, 51, 11751. J. Cossy, S. Bouzbouz, Tetrahedron Lett. 1997, 38, 1931. J. Cossy, S. Bouzbouz, Tetrahedron Lett. 1996, 37, 5091. S. Le Blanc-Piva, 0. Piva, J. P. Pete, unpublished results. S. Bertrand, N. Hoffmann, J. P. Pete, V. Bulach Chern. Commun. 1999, 2291.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
2.6 Electrochemical Generation of Radicals Hans J. Schafer
2.6.1 Introduction Organic synthesis relies on efficient and selective C,C-bond-forming reactions and functional group interconversions. Electrolysis can contribute to these requirements by activation of substrates via electron transfer. The first important electrochemical reaction for C,C-bond formation was discovered by H. Kolbe in 1849, when he electrolysed carboxylates and obtained dimers of their alkyl groups [ 11. This reaction turned out to be a unique, versatile and simple method to generate radicals by anodic decarboxylation. 150 years after its discovery, this reaction is still intensively and constantly employed in creative ways for organic synthesis [2].In 1942 F. Fichter comprehensively summarized electroorganic syntheses known at that time [ 31. In the 1960s, electroorganic synthesis advanced strongly, especially in the field of cathodic reduction by the contributions of H. Lund and M. M. Baizer. The development of a technical electrosynthesis for adipodinitrile by M. M. Baizer [4], a process that is performed today on a scale larger than 300 000 t/y, gave an extra impetus to this advancement. Today there is a broad repertoire of selective C,C-bond-forming reactions and functional group interconversions available for organic synthesis, which is summarized in several books and reviews [ 5 ] . An electrode is inexpensive when compared with most chemical reagents. It is immobile, and thus causes less environmental and solubility problems than most chemical oxidants and reductants. It can change the polarity of reagents by oxidation or reduction (‘Redox-Umpolung’) and in this way can shorten synthetic sequences. Controlled potential electrolysis allows the selective conversion of one out of several electrophores in a molecule. A technical scale-up causes in most cases lesser problems than the scale-up of a chemical reaction. These advantages and the wide choice of conversions have made electrolysis today at least for those that take the small effort to assemble an electrolysis cell and connect it to a d.c. power supply to an attractive alternative and supplement for chemical synthetic mcthods. ~
~
2.6.2 Electrolysis as a Synthetic Method
251
2.6.2 Electrolysis as a Synthetic Method 2.6.2.1 Electrochemical C,C-Bond Formation and Functional Group Interconversion The electrode is best suited for C,C-bond-forming reactions that occur via reactive intermediates. These are accessible from charged or neutral substrates by electron transfer (Scheme 1). At the anode, anions can be oxidized to radicals (la), neutral substrates to radical cations that can either lose a proton or react with a nucleophile to form a radical (1b), and the radicals can be further oxidized to carbocations (lc). At the cathode, the mirror image reactions occur. Carbocations formed either by dissociation (Id) or by protonation of a C=X double bond are reduced to radicals (Id), neutral substrates are reduced to radical anions that can expel a leaving group or can be protonated to a radical (le,f), and the radicals can be further reduced to anions (Ig). Pathways (la) and (Id) are the most frequent routes employed for the electrochemical generation of radicals. The radicals can be used in homocoupling, heterocoupling and addition reactions. In some cases these reactions have to compete with further oxidation or reduction of the radicals (see Sections 2.6.3.5 and 2.6.4.3). Electrogenerated radical ions (lb), (le), (If), cations (Ic) and anions (lg) have been very efficiently used in electroorganic synthesis, e.g. for cathodic hydrodimerization, anodic dehydrodimerization, anodic substitution, cathodic cleavage or ring closure reactions [2, 5, 61. These conversions are not treated in this review. In functional group interconversions (FGI), where the oxidation number of the substrate is changed, the electrode is the reagent of choice. Thereby mostly charged
Cathode
Anode -H+
(la)
RH
(Ib)
RH
(lc)
Re
H+
-e
-e +
R-
RH'
R-
-H+,
(Id)
RX
-X
-
+X-
R+
R*
R-
I
FT
+e
R
X = leaving group
Scheme 1. Reactive intermediates for C,C-bond formation generated at the anode and cathode
252
2.6 Electrochemical Generation of Radicals
(2a)
R-H
-
-2e, -2H+, +HNu
(2b)
HtX-H
-
-
R-NU
+2e, +2H+, -HNu -2e, -2Hf
-
+2e, +2H+
HX#XH
-2e, -2H+, +2HX +2e, +2H+, -2HX -2e, -2Hf
-
,ttX
*
Scheme 2. Functional group interconversions at the anode (lcft to right) and at the cathode (right to left). (2a) Anodic substitution and cathodic cleavage. (2b) Anodic dehydrogenation ( X is almost always a heteroatom) and cathodic hydrogenation [X is a heteroatom or a carbon atom (CRz)]. (2c) Anodic addition and cathodic elimination; (2d) Anodic cleavage
intermediates are electrogenerated that react with protons or heteroatom nucleophiles. FGIs at the anode (left to right) and the cathode (right to left) are shown in Scheme 2. They are anodic substitution and cathodic cleavage (2a), anodic dehydrogenation and cathodic hydrogenation (2b), anodic addition and cathodic elimination (2c) and anodic cleavage (2d). Besides advantages outlined in the introduction, the reagent electrode also has some disadvantages that limit its use. The necessary conductivity of the supporting electrolyte makes preparative scale electrolyses below -50 "C difficult because of the increased resistance of the electrolyte. Sometimes the electrode surface becomes deactivated by insulating films (passivation, see Section 2.6.2.4). However, the most serious drawback is the lack of experience with the method, which makes the potential user rather take a chemical oxidant or reductant from the shelf. Therefore, the practice of electroorganic synthesis, which involves electrodes, electrolyte, electroanalytical investigation of the substrate and preparative scale electrolysis will be addressed briefly in the next section.
2.6.2.2 Practice of Electroorganic Synthesis 2.6.2.2.1 Electrodes and Electrolyte
Electrons are delivered (cathode) or accepted (anode) by the electrode. At electrodes with a small area (<0.1 cm2) the electrolysis can be conducted on a microscale. From the current/voltage curves obtained, valuable information can be obtained with regard to the reaction conditions for carrying out preparative scale electrolysis. The electrolysis is conducted in a cell, which is equipped with three electrodes:
2.6.2 Electrolysis as a Synthetic Method
253
working-, auxiliary- and reference electrode and in some cases a diaphragm to separate anolyte and catholyte. Additionally, a current source (potentiostat or a rectifier which can be regulated), a high ohmic voltmeter to measure the potential between working and reference electrode, and an electronic coulometer to determine the current consumption are necessary. For reductions in protic media the cathode must have a sufficient overvoltage against proton discharge to suppress competing hydrogen evolution. Suitable materials for the cathode are mercury, lead, tin and graphite. At metals with a low hydrogen overvoltage such as platinum or nickel, catalytic hydrogenation with cathodically generated hydrogen can occur. In aprotic solvents the hydrogen overvoltage of the cathode has no significance. The anode materials: platinum, glassy carbon, graphite and lead dioxide are fairly universally applicable. Copper, silver, nickel or iron, however, can only be used in alkaline electrolytes or at low oxidation potentials. As reference electrodes, unpolarizable electrodes have to be used. These are the saturated calomel electrode [sce, Hg/HgCll, 0.25 V vs the normal hydrogen electrode (nhe)], the Ag/AgCl-electrode [in sat. aqueous KCl 0.197 V vs nhe; in sat. LiCl in EtOH 0.143 V vs nhe], the Ag/Ag+-electrode [Ag/O.Ol M AgNO3 in acetonitrile, 0.503 V vs nhe] or the Marple electrode [Hg(Cd)/CdCll . H20 in dimethyl formamide, -0.487 V vs nhe]. The reference electrode is connected via a salt bridge (Luggin capillary) with the electrolyte. The orifice of the capillary should be at a distance of about 0.5 mm from the working electrode. The electrolyte consisting of solvent and supporting electrolyte must dissolve the substrate sufficiently, supply the necessary conductance and be stable towards reduction or oxidation. The stability of the electrolyte can be expressed by the decomposition potential (potential at which the current density for oxidation or reduction of the solvent reaches about 10 pA cmP2 for analytical experiments or 10 mA crn-l, respectively, for preparative scale electrolysis). The decomposition potential quotes the potential within which the electrolyte can be used without decomposition (Table 1). Methanol is the solvent of choice for the majority of electrolyses, whenever its nucleophilicity and acidity does not interfere with the desired electrochemical conversion. The fairly low anodic decomposition potential at platinum can be shifted anodically by 0.8 V when graphite or glassy carbon is used as anode material. When aprotic, non-nucleophilic solvents in anodic conversions are needed, acetonitrile and dichloromethane are the best choice. Addition of small amounts of CF3C02H and (CF3CO)zO increases the stability of radical cations in dichloromethane. For cathodic reductions under aprotic conditions, dimethylformamide and tetrahydrofuran are suitable. They are fairly inert chemically and exhibit a very negative decomposition potential. As supporting electrolytes, salts are used that dissociate also in less polar solvents. Suitable anions are tetrafluoroborate, hexafluorophosphate, tosylate and perchlorate. The last one, however, should be avoided for safety reasons in preparative scale electrolyses. For reductions, bromides or iodides can be used. As cations, lithium and tetralkylammonium ions (Et4N' = TEA', Bu4N+ = TBA+) have proved to be very versatile.
254
2.6 Electrochemical Generation of Radicals
Table la. Anodic decomposition potentials of selected solvent/supporting electrolytes [7] Solvent
Decomposition potential ( V )
Supporting electrolyte
Electrode
Methanol Methanol Acetonitrile Dichloromethane Dimethylformamide Tetrahydrofuran
1.1 [a] 1.9 [a] 3.0 [b] 3.3 [b] 1.5 [a] 1.8 [d]
NaC104 NaC104 TBAP TBAPF6 TBAP LiC104
Pt glassy carbon Pt Pt Pt Pt
[a] us. sce; [b] us. Ag/AgCl; [c] (C4H,),NC104; [d] us. Ag/Ag+.
Table lb. Cathodic decomposition potentials for selected solvent/supporting electrolytes [7] Solvent
Decomposition potential
Supporting electrolyte
Electrode
Methanol Acetonitrile Dichloromethane Dimethylformamide Tetrahydro furan
-2.2 -2.6 -1.7 -2.7 -3.6
TBAP TBAP TBAP TBAP LiC104
Hg Pt Pt Pt Pt
[a] [a] [a] [a] [b]
[a] us. sce; [b] us. Ag/Agi
2.6.2.2.2 Electroanalytical Investigations Prior to Preparative Scale Electrolysis
Cyclovoltammetry (cv) is a simple method that provides useful information about an electrochemical conversion [8]. This is illustrated by the cv of 9,lO-diphenylanthracene (1) (Fig. 1 and Eq. 1).
-1e +1 e
/
/
/
C6H5
1 '+
1. -e 1'+
2
.+
k z d
2++
2.6.2 Electrolysis as CI Synthetic Method
255
2 . 0 ~ 1 ~ ~ 1.5x1U5 1.ox1u5
-1 .5x1U5 1.o
1.1
1.2
1.3
1.4
1.5
1.6
E [VI
I
1.o
.
I
1.1
1
1
1.2
1
1
1.3
.
I
1.4
~
I
1.5
.
'
1
1.6
E [VI Figure 1. (a) Cyclovoltammogram of 5 . 9,10-diphenylanthracene (1) in 0.1 M TBAP acetonitrile. Working electrode: platinum. Reference electrode: Ag/AgCl. (b) As (a) but with addition of 0.2 M 2,6-lutidine
256
2.6 Electrochemical Generation of Radicals
With a potentiostat the potential at the working electrode is linearly increased from 1.0 to 1.6 V and then decreased back to 0 V. In the first interval 1 is oxidized to the radical cation 1" with a peak potential of Ep.a= 1.38 V. 1" is stable in this solvent and is reduced in the reverse scan back to 1 at Ep,c= 1.32 V. The ratio of the current for reduction and oxidation ip,c:ip.a = 1 indicates the stability of the radical cation. All of l+',that is formed by oxidation of 1 is reduced back to 1. This behavior is termed chemically reversible. Upon addition of 2,6-lutidine, the radical cation 1" reacts with the nucleophile to afford 2+', which is further oxidized to a dication, which yields the dication 2*' with 2,6-lutidine. This can be seen in the decrease of ip,c:ip,a and an increase of ip,. due to the transition from an le- to a 2eoxidation. From the variation of the ratio ip.c:ip,a with the scan rate, the reaction rate of the radical cation with the nucleophile can be determined [9]. This can also be achieved by digital simulation of the cyclovoltammogram, whereby the currentpotential dependence is calculated from the diffusion coefficients, the rate constants for electron transfer and chemical reactions of substrate and intermediates at the electrode/electrolyte interface [lo]. With fast cyclovoltammetry [ 111 scan rates of up to lo6 VS-' can be achieved and the kinetics of very short-lived intermediates thus resolved. With reference compounds, from which the number of electrons n that are transferred is known, e.g. ferrocene with n = 1, n for an unknown compound can be approximately calculated from the peak current in the cyclovoltammogram. New and EP+peaks in the cyclovoltammogram can be compared with the values of possible electroactive products. From cyclovoltammetry of 10-20 mg of substrate, valuable information can be obtained prior to preparative scale electrolysis on the best suited electrolyte and electrode, the oxidation or reduction potential of the substrate, the reactivity of the intermediate, the number of electrons n transferred and possible products. More information on the mechanism and kinetics of the reactive intermediates can be gained from a variety of sophisticated electroanalytical techniques [ 121.
2.6.2.2.3 Preparative-Scale Electrolysis In preparative laboratory scale electrolysis, in general between 1 and 100 mmol of substrate is converted. For that purpose the undivided or divided cell shown in Figs. 2 and 3, respectively, are suitable. Most anodic oxidations in protic solvents can be performed in an undivided cell, because at the cathode the protons of the electrolyte are discharged. Most cathodic reductions, however, need a divided cell. Anolyte and catholyte are separated by a diaphragm, e.g. a G4 glass frit, a porous ceramic plate or an ion exchange membrane. In some cases the diaphragm can be replaced by a dissolving anode [13]. As current source, rectifiers with an a.c. voltage regulator or power supplies with current (galvanostat) or potential control (potentiostat) are used. The current consumption is measured with an electronic coulometer. For larger scale conversions, the circulation cell [2b], the capillary gap cell [ 14a] and the 'Swiss roll' cell [ 14b] are available. All three cells work at low cell voltage
2.6.2 Electrolysis as a Synthetic Method
257
a
;, I, Figure 2. Undivided thermostatted beaker type cell: (a) teflon stopper, (b) graphite electrode with current feeder (steel rod), (c) platinum foil electrode supported on a teflon frame with current feeder (steel rod)
even in moderately conducting electrolytes because of a very narrow electrode gap. The latter two also allow for fast conversions at low current density because of their large electrode surface. For performing a preparative electrolysis the following procedure is recommended: (a) At first a current/voltage curve from the electrolyte is taken. High currents below the decomposition potential point to electroactive impurities in the electrolyte. These can often be removed by purging with nitrogen to remove oxygen or by preelectrolysis close to the decomposition potential.
258
2.6 Elrctrochemicul Generation of Radicals
b
d
. / c
-
b
l
a
Figure 3. Divided thermostatted beaker type cell: (a) mercury pool cathode with current feeder (platinum wire sealed in glass rod), (b) diaphragm, (c) platinum foil anode, (d) Luggin capillary to reference electrode
(b) After addition of the substrate a second current/voltage curve is recorded. Because of the high substrate concentration and a voltage drop due to ohmic resistance, this is generally quite different from that obtained by cyclovoltammetry. If no distinct potential step can be detected, the potential is adjusted to such a value that the current for electrolyte decomposition is less than 10% of the substrate current. If the current drops significantly in a second recording of the current/voltage curve, passivation is indicated. The unwanted passivation can in most cases be eliminated or suppressed by periodic reversal of the electrode polarity during electrolysis or by exchange of the electrode or the electrolyte. (c) During the electrolysis the conversion is followed by coulometry, thin layer or gas chromatography, and further current/voltage curves. (d) Workup follows the general procedures applied in chemical reactions.
2.6.3 Radicals by Anodic Oxidation
259
2.6.3 Radicals by Anodic Oxidation 2.6.3.1 Homocoupling of Anodically Generated Radicals 2.6.3.1.1 Anodic Decarboxylation of Carboxylic Acids (Kolbe Electrolysis) Anodic decarboxylation is a powerful method that generates radicals in a simple procedure for synthetic use. The radicals can be used in homocoupling, heterocoupling (Section 2.6.3.2) and addition reactions (Section 2.6.3.4). The large amount of literature in relation to anodic decarboxylation is covered in a number of reviews [2a, 15, 161 and chapters in books [2b, 17, 181. High current densities (>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
4
2-Nitrobutane
25% NaOH
3,4-dimethyl-3,4dini trohexane
70%
54
5
EtzO
R-R
54-600/;1
55
6
MeOH, KOH
R-R
24-82%1
56
I
THF; LiC104
(Ph-CEC),
35%
51
tetracarboxylates by first reductive dimerization at the cathode and subsequently mediated dimerization of the enolates at the anode [60]. In one rare example, in which a useful product is obtained simultaneously at the working electrode and the counterelectrode (coupled or paired electrosynthesis), diethyl malonate dimerizes at the anode to give tetraethyl ethanetetracarboxylate; at the same time ethyl acrylate couples at the cathode to give diethyl adipate in yields of over 90% in each case 1611. Furthermore, anions of nitroaliphatic compounds are coupled to give vicinal dinitroalkanes (Table 4, entry 4). Grignard compounds (Table 4, entry 5) and borates (Table 4, entry 6) couple to give alkanes, alkyne anions to give dialkynes (Table 4, entry 7), sulfamides to give azoalkanes 1621, and dialkylamides to give tetraalkylhydrazines [ 631. The anodic oxidation of a-sulfonyl carbanions is shown to involve a coupling reaction between the electrogenerated radical and the parent anionic species. The relevance of this mechanism to transition metal oxidations of a-sulfonyl carbanions has been investigated 1641. Phenols are coupled mostly in alkaline media by anodic oxidation of the phenolates to phenoxy radicals [65]. However, coupling in neutral or acidic media by way of phenoxy radical cations and phenoxonium cations as intermediates is also
2.6.3 Radicals by Anodic Oxidation
265
known. To generate the phenolate ion, bases such as alkali hydroxides, Et4NOH or 2,6-lutidine is used. The anodically generated phenoxy radicals react by carboncarbon and carbon-oxygen coupling to dimers, which can be also further oxidized. This frequently leads to product mixtures that are synthetically not very useful. Blocking of the 2-, 4-, or 6-position makes the coupling reaction more selective. Phenols with unsubstituted para-position usually form para, para-coupling products as the major dimer (Table 5, entries 1 and 2). If the 4-position is blocked, ortho, ortho-coupling is the main reaction (Table 5 , entries 3-8). The dimerization of the tetrahydroisoquinoline, shown in Table 5 , entry 3, yields only one of three possible diastereomers. This outcome is best explained as a result of a surface reaction on the graphite electrode, at which only molecules of identical configuration couple.
2.6.3.2 Heterocoupling of Radicals from Anodic Decarboxylation of Carboxylic Acids Heterocoupling (cross coupling) of two different carboxylates (= mixed Kolbe electrolysis) is a method for synthesizing unsymmetrical compounds (Eq. 5 ) . However, as the intermediate radicals combine statistically: the mixed coupling product is always accompanied by two symmetrical dimers as major side-products.
-
R'-R'
+
2 ~ l - 1 3+ ~R ~ - R ~
To make this coupling more attractive for synthesis, the less costly acid is used in excess. This way the number of major products is lowered to two, which facilitates the isolation of the mixed dimer. Furthermore, the more costly acid is incorporated to a large extent into the mixed dimer. The chain length of the two acids should be chosen in such a way that the symmetrical dimer formed in excess can be separated from the cross-coupling product either by distillation or crystallization. Problems due to passivation that lead to an increase of the cell voltage or due to competing oxidation of the radicals to carbocations (non-Kolbe electrolysis) are often less pronounced in mixed coupling. Despite the disadvantage that at least one symmetrical dimer is formed as a major side-product, mixed Kolbe electrolysis has turned out to be a powerful synthetic method. It enables the efficient synthesis of rare fatty acids, pheromones, chiral building blocks or non-proteinogenic amino acids. Selected examples of a large number of compounds that have been synthesized are given below either in Table 6 or in formulas; for further examples see [2]. Heterocoupling has been used for the extension of the carbon chain in fatty acids [83]. The method has recently been applied to the synthesis of pheromones [16]. For example, muscalure (24) has been synthesized in 80% yield [84, 851. Furthermore, the antagonist of muscalure: ( Z ) - l l-heneicosene [ 861, looplure (25) [87], brevicomin
266
2.6 Electrochemical Generation of Radicals W W
I-
19
00
W
m
r0
W
2 m
0
W m
m
m
++ 8
I
0
0,
8
8
0
0
e,
-x
c a c
3
9 ... .*
Q
N
cd
N
9
N
m
2.6.3 Radicals by Anodic Oxidution
3
%!
'
rn
W
4
r-
6
267
268
2.6 Electroclzemicul Generation of Radicals
Table 6. Selected examples of mixed Kolbe electrolysis of carboxylic acids
R I COOH
R*COOH
Yield
Ref.
RI-R~
MeOOC(CH2)4COOH H3C(CH2),COOH n = 2,4,8,12 H3C(CH2)7CH(CH3)CH2COOH Me00C(CH2)2COOH C H ~ ( C H ~ ) ~ C H = C H ( C H Z ) ~ C O MeOOC(CH&COOH OH EtOOC(CH2)gCOOH Br(CH2)loCOOH (E)-C2H5CH=CHCH2COOH MeOOC(CH2)3COOH COOH C~HIICOOH I C~HIICOOH MeOOC(CH2)7COOH
12-48?0 35% 35% 54% 59% 69% 54?" 49%
75 16 77 78 46 79
Ac+Ac H OAc CH~OAC
Yqo
G C O O H
O
7OYo 5 1Y n (Z)-CH3(CH2)7CH=CH(CH2)7COOH46%
79
AcO(CH~)~COOH CII HziCOOH Br(CH2)loCOOH
30% 33% 32%
80, 81
C7Hi sCOOH
40%
80, 81
ROOC(CHz),COOH R=Me, Et; n = 4-7
10-43'%
82
Y
COOH
HOOC
C7HlsCOOH CI3 H27COOH
OMe
&J O X 0
COOH
(26) [88], disparlure (27) [89], optically active 28 (a Trogoderma pheromone) [90], and pheromones with a diene or triene structure, such as 29 [91] (the arrows indicate the coupling position) have been prepared. In addition, alkyne carboxylic esters with different chain lcngths can be obtained [92], which can be hydrogenated at will to either ( E ) - or (Z)-pheromones. Furthermore, useful intermediates for the syn-
2.6.3 Radicals by Anodic Oxidution
24
25
48%
269
26
62%
27
28 52%
thesis of dicarbaanalogs of cystine peptides have been prepared from L-glutamate [93], and chiral building blocks from enantiomerically pure P-hydroxybutyric acid derivatives [94]. A heterocoupling reaction has been applied in the course of the synthesis of (*)nephromopsinic acid [95] and for the preparation of 3-alkylsubstituted indoles [96].
2.6.3.3 Stereoselectivity of Anodic Coupling Reactions 2.6.3.3.1 Attempts at Enantioselective Coupling Enantioenriched carboxylates with a non-racemic stereogenic center in the CIposition totally lose their optical activity in heterocoupling [21, 221. This result indicates that in anodic decarboxylation either a free radical or a radical that undergoes fast desorption-adsorption at the anode is involved. 2.6.3.3.2 Diastereoselective Coupling 2.6.3.3.2.1 Facial selectivity due to a chiral auxiliary
Carboxylates with different non-racemic chiral auxiliaries have been anodically decarboxylated to explore the face-selective hetero- and homocoupling of the intermediate radicals. 2-Substituted malonamides were subjected to heterocoupling with served as different coacids. In the acids 30a-c, (2R,SR)-2,5-dimethylpyrrolidine chiral amido group. Heterocoupling with the coacids 31-35 led to the amides 36a-g with different diastereomeric excess (Eq. 6), Table 71 [97].
2.6 Electrochemical Generation of Radicals
270
30
31-35
a: R’ = CH2C6H5 b: R’ = C(CH& C: R’ = C(CH3)2C2H5
(2R)-36a-g
(2S)-36a-g
31 : R2 = C4H9 32: R2 =C6H13 33: R2 = C H ~ B U 34: R2 = CH(C3H7)z 35: R2 = C(CH&COOEt
Table 7. Diastereoselective heterocoupling to 36. 36
R’
R’
Yield (x)
2 R/2S
38 32
1.7:l 1.5:1
36 39 69
2.9:l 4.7:1 4.5:1 3.3:l
42
551
37
5.6:l 13.4:1
40
13
Side-products besides 36 were compounds arising from hydrogen abstraction and further oxidation of the radical to a carbocation. This was especially pronounced in the case of 36i, where these compounds became the major products. As a-amido radicals assume the Z-conformation preferentially [98, 991, the prostereogenic carbon in the intermediate radical 37 originating from 30 is differently shielded by the methyl groups of the (2R,SR)-2,5-dimethylpyrrolidine auxiliary. So the coradicals produced from the coacids 31-35 will approach preferentially from the re-face rather than from the si-face for steric reasons. The increasing diastereoselectivity with growing size of R ’ and R 2 points to an increasing portion of the Z-conformer 37 and a growing steric hindrance for the si-approach. Replacement of the methyl group by the methoxymethyl group in the auxiliary of 30b in the coelectrolysis with 33 leads to the coupling product 38 in a similar yield and diastereoselectivity to that with 30b [ 1001. The energy profile for the heterocoupling of the radicals from 30b and 33 has been modeled with the semiempirical method PM3 (BIRADICAL LET GNORM = 0.001 EF). The reaction pathways to the diastereomers 2R-and 2s-36d show a flat maximum at about 270 pm. The energy maximum leading to the major (2R)-diastereomer is calculated to be 0.34 kcal/mol lower than that leading to the minor (2s)-diastereomer [ 1001.
2.6.3 Radicals by Anodic Oxidation
271
i
R2 *
Me0
37
38 R = tBuCH2, 38% yield, 67% de R = cyclohexyl, 27% yield, 35% de R = cyclopropyl, 45% yield, 26% de
With oxazolidine auxiliaries the diastereomeric heterocoupling products 39 and 40 are obtained in 33% yield (46Y0de) and 20% yield (45% de) respectively 1971. The oxazolidinone 41 as auxiliary leads to a maximum diastereoselectivity of only 9‘Yo
PI.
39
40
41
2,1O-Camphorsultam, a frequently used chiral auxiliary in diastereoselective syntheses [ 1011, has also been applied in radical reactions 1991. Heterocoupling reactions with 42,43, and the coacids 33 and 35, afforded the products 44-48 (Eq. 7). The results demonstrate that the diastereoselectivity strongly increases with the steric bulk of the 2-substituent in the malonates 42 and 43, namely 79.5% de with R ’ = tBu and 41.3% de with R ‘ = iPr. With increasing bulk of the substituents in the coacid, hydrogen abstraction of the auxiliary substituted radical becomes a major competing reaction leading to 47 and 48.
R’
42 tBu 43 iPr
R2
yield tBuCH2 51% 45 tBu C(CH&COOEt 9% 46 iPr C(CH3)2COOEt 14% R’ 44 tBu
de
60% 80%
R’ yield 47 tBu 44% 48 iPr 34%
(7)
41%
With menthol and its derivatives, the competing hydrogen abstraction is decreased. With the acids 49-52 and the coacid 33, yields ranging from 22 to 69% and 5 to 65Y0 de are obtained (Eq. 8).
2.6 Electrochemical Generation o j Radicals
212
1
1
55-59
49-54
R'
R2
H H Ph Ph
53
/Pr Bu /Pr Bu Bu
54
Ph
Ph
49 50 51 52
Bu
55
56 57 58 59
R'
R2
de (%)
/Pr Bu /Pr
H
5
Bu
H Ph Ph
Bu
Bu
10 38 65 27
In the homocoupling of 49-52, ratios of diastereomers from 1.17:2.0:0.81 to 7.03:2.00:<0.1 were found [ 1001. For the heterocoupling of 52 and 54 with the coacids 33 and 35, respectively, the temperature dependence (- 15 to 53 "C) of the diastereoselectivity has been determined. The yields in heterocoupling products ranged from 9 to 79%, the diastereoselectivity from 2.24: l to 14.6:l . Side-products were formed by hydrogen abstraction of the ester-substituted radical (3-69%) and with the acid 54, the methylether 60 originating from the cation that is formed by further oxidation of the intermediate benzyl radical (19-330/1).
I
With both acids 52 and 54 and the coacid 33, the diastereoselectivity is temperature independent. This means that the rate difference for the diastereofacial coupling of the intermediate ester radical is fully entropy controlled. In the corresponding heterocoupling with the radical from the coacid 35, the diastereoselectivity is controlled by activation enthalpy and entropy [ 1021. The configurations of the heterocoupling products point to the following preferred conformers of the intermediate radicals. Namely, 37 originating from 30, 61 from 42 and 43, 62 from 52, 63 leading to 39 and 64 produced from the malonate bound to 41. This is in agreement with the preferred conformers of these radicals deduced from the results of diastereoselective atom transfer in radical chain reactions [ 1011. In 64 the oxazolidinone carbonyl group points toward the radical center, which results in very low diastereofacial shielding. The diastereoselectivity generally increases with
2.6.3 Radicals by Anodic Oxidation
213
increasing size of the group R ' in the auxiliary-substituted radical and the size of the coradical.
H 61
Ph
62
63
64
2.6.3.3.2.2 Facial selectivity due to a stereogenic carbon atom in a-position to the radical center Facial selectivity induced by a stereogenic carbon atom in a-position to the radical center has been probed with acyclic and cyclic radicals [103]. In the first cases, 2substituted malonates 65-68 served as precursors for the prochiral radicals; these were coupled in moderate yields with coradicals formed from acetic acid and the acids 34 and 35 (Eq. 9). R3.
~w~~~ J
E2 Ri?COOMe
R3C00;
5'
-
R
.
+
(-0065-68
R' R' 65 Ph Me 66 Bu Me 67 Me OMe 68 Ph OMe
-e,-coz
g2
,+COOMe
H
k3
major
R1
R'YCooMe R3 minor
69-75 R'
R2
Me Me Me Me 73 BU Ph 74 Me OEt 75 Ph OMe 69 Ph 70 Ph 71 Bu 72 Bu
R3
CH(C3H7)z C(CH3)2COOEt Me C(CH3)2COOEt C(CH3)zCOOEt C(CH3)2COOEt C(CH3)2COOEt
dr
yield
1.30:l 1.67:l 2.02:l 6.01:l 2.16:l 1.40:l 1.96:l
34% 31% 37% 31% 33% 32% 30%
(9)
The conformation of the intermediate radical originating from the malonate is controlled by allylic strain [ 101b, 1041. The diastereoselectivity increases with the difference in size of R ' and R 2 and the size of the coradical R3. Anodic decarboxylation of the 2-carboxy-butyrolactones76-78 with acetic acid and the coacids 34 and 35 affords the butyrolactones 79-86 in moderate yields and diastereoselectivities up to 94% de (Eq. 10). In these cases a conformationally rigid intermediate radical is generated from 76-78. The facial selectivity is increased compared to the radicals from 65-68 as one side is shielded by R ' and the other by hydrogen. The face selectivity increases slightly from R ' iPr to R ' = Ph and strongly with R ' = tBu.
214
2.6 Electrochemical Generation of Radicals .COOH
R3COOH R2
-H+, -e-,
R2
76 77 78
R’ Ph /Pr
-cop*
R2
Me Me mu H
79 80
81 82 83 84 85
86
R’ Ph
R2 Me Ph Me Ph Me Pr Me IPr Me /Pr Me mu H mu H
R~ R2 trans (major) R3 CH3 CH(C3H7)2 C(CH3)2COOEt CH3 CH(C3H7)2 C(CH3)2COOEt CH3 C(CH&COOEt
COOH
R2 cis (minor) translcis 1.32:l 1.35:l 2.10:1 1.01:1 1.24:l 1.7211 1.76:l 15.5:l
yield
43% 33% 34% 41% 36% 35% 40% 33%
2.6.3.4 Anodic Addition of Anions to Double Bonds via Radicals as Intermediates If anions R- are oxidized in the presence of olefins, additive dimers 87 and substituted monomers 89 are obtained (Eq. (1 l), Table 8, and [ la]). The products can be rationalized by the following pathway: the radical R obtained by a le- oxidation from the anion R- adds to the alkene to give the primary adduct 88, which dimerizes to give the additive dimer 87 with regiospecific head-to-head connection of the two olefins, or couples with R to give the additive monomer 89. If the substituent Y in the olefin can stabilize a carbenium ion, 88 is oxidized to the cation 90, which reacts intra- or intermolecularly with nucleophiles to give 91 or 92.
R-R
90
Y
91
92
Satisfactory to good yields of adducts have been found for styrenes (Eq. (1 l), = phenyl), conjugated dienes (Y = vinyl), enamines (Y = NRz), and enol ethers
2.6.3 Radicals by Anodic Oxidution
275
(Y = alkoxy), particularly if they are unsubstituted at the carbon atom in P-position to Y. Non-activated alkenes react less satisfactorily. In the oxidation of anionic 1,3-dicarbonyl compounds (Table 8, entries 1-8) at potentials between 0.6 and 1.4 V (sce) and in the presence of butadiene, only the additive dimer 87 is obtained; in the presence of ethyl vinyl ether only the disubstituted monomers 91 or 92 arise, but with styrene both types of products 87 and 91 are formed. This result indicates that the primary adduct 88 is oxidized fast between 0.6 to 1.4 V to the carbenium ion in the case of an ethoxymethyl radical (Y = OEt) and slowly in the case of an ally1 radical (Y = vinyl). In an electroinitiated radical addition, an olefin and oxygen can be added simultaneously to the 1,3-dicarbonyl compound (Eq. (12) and Table 8, entry 5) [ 1071.
bPh 0 -0'
Also other anions, such as the 2-nitropropanate anion, Grignard reagents, and borates, can be added to olefins (Table 8, entries 9-1 1). If carboxylates are subjected to Kolbe electrolysis in the presence of olefins, the generated radicals add to the double bonds to afford mainly additive dimers (Table 8, entries 12-20). In vicinal disubstituted styrenes, upon addition of the Kolbe radical Me02CCH2', the yields of adducts decrease with increasing size of the P-substituent: H = 42%, Me 27941,Et = 11%, iPr = 5'%, tBu = 2% [ 1251. The ratio of additive dimer 87 (Eq. 11) to monomer 89 can be changed to some extent by the current density i. Upon electrolysis of trifluoroacetate in MeCN-HzO-(Pt) in an undivided cell in the presence of electron-deficient olefins, additive dimers and additive monomers are obtained. The selectivity can be controlled by current density, temperature and the substitution pattern of the olefin [ 1261. Trifluoromethylation of various aromatic compounds with -M substituents has been achieved in satisfactory yield via electrolysis of pyridinium trifluoroacetate in acetonitrile [ 1271. Electrolysis of a methanol solution of methyl oxalate with ethylene under pressure yielded 70-90% of the dimethyl esters of succinic, adipic, suberic, and sebacic acids. Decrease in the ethylene pressure or increase in the current density led to a decrease in the proportion of higher esters in the product mixture [ 1281. The influence of mechanism and kinetic data on yields and selectivities in addition reactions of anodically generated radicals to olefins has been calculated and the predictions tested in preparative electrolyses [ 1291. Good yields can be obtained with non-activated alkenes when the reaction is conducted intramolecularly. P-Allyloxy- and /?-allylaminopropionates cyclize in a mixed Kolbe electrolysis (5-rxo-trig cyclization) by way of an intramolecular addi-
(MeOOC)zCH2
2
4
ho
ho
MeOOCCCHzCOMe
1
3
Radical precursor
Entry
CHz=CHPh,
CH*=CHPh
0 2
CH?=CHOEt
CH*=CHOEt
CH2=CHOEt
Olefin
Conditions
Product
MeCN, Et4NOTs
EtOH. EtONa
MeOH, MeONa, Pt
MeOH, MeONa, Pt
0
E
t
e
OH
bPh phd
b
0
M
MeOOC U
O
OEt
MeOOC
Anions of 1,3-dicavbonyl compounds
Table 8. Addition of anodically generated radicals to alkenes
79%
85Yo
37%
36Yo
Yield
107
107
105
105
Ref.
CH?=CHR R = Bu,C H ~ O A C
CHr=CHPh
CH3COCH2COOEt
PhCHlCH(COOMe)2
PhCOCH2NO2
(CH3)2CHN02
8b
8c
9a
9b
i
x
R-H R = hexyl TMS, Ph
R' = propyl, pentyl, t-Bu R2 = H,Me
R
Butadiene
(MeOOC)*CH2
8a
CH2=CHPh
(MeOOC)2CH2
7
MeOH, MeONa, Pt
HOAC, B u ~ N B F ~ Mn(OAc)z, 60°C C-anode
Other anions
KOAc/HOAc, 0.25 eq. Mn(OAc)2 C-anode
HOAc/EtOAc NaOAc (0.1 eq.) Mn(OAc)z, C-anode
MeOH, MeONa, Pt
MeOH, MeONa, Pt
MeOH, MeONa
'- w 0
P
P
W
R' R
O
e
COOEt
M
b N-0
M
e
R
O O E t R
-o' +
h
C
s
COOEt
\(MeOOC)2CHCH2CH=CHCH2]2 + isomers
M e o a P h Me0
MeOOC,
k O O M e MeOC
p
43%
46%
4OYo
67Yo
112
105
105
108
2
N
MeCN, H20, Pt MeCN, H20, NaOH
Butadiene
CH2=CHnPr
CH2=C(Me)CHO
CH~=CHOAC
Dimethyl fumarate
MeOOC(CH2)4COOH
F3CCOOH
CHjCOOH
F3CCOOH
CH3COOH
16
17
18
19
20
MeCN, H2O
MeCN, NaOH, Pt
MeOH, Pt
MeOH, Pt
CHz=CHPh
MeOOCCH2 COOH
15
MeOH, Pt
MeOH. Pt
CH2=CH2
CH2=CHOEt
MeOH, Pt
Butadiene
MeOOCCH2COOH
EtOOCCOOH
14
13
12
Carboxylates
MeOH, MeONa, C
Butadiene
11
Et20, LiC104, Pt
CH2=CHPh
n Bu Mg Br
10
Conditions
Olefin
Radical precursor
Entry
Table 8 (continued)
38%) 47%"
[ MeOOC(CH2)zCH(Ph)]2 [M ~ O O C ( C H ~ ) I C H = C H C H ~ ) ~
[CHMeCOOMe]2
[CF~CH~CH(OAC)]~
[CH3CH2C(Me)(CHO)]2
[CF3CH2CH(nPr)]2
80%
122
121
120 SOY"
24%
1 I9
118
115
117
116
115
114
113
Ref.
40%
MeOOC(CH2)5CH=CH(CH2)5COOMe 47%
35%
92-95%
4%
66%)
14%
5"O
29%
Yield
[ MeOOC(CH2)2CH(OEt)]2
MeOOC(CH2)12COOMe MeOOC(CH2)l IoCOOMe
(EtOOCCH2CH=CHCH2)2 + isomers EtOOCCH2CH=CHCH2COOEt
(CsHI , C H ~ C H = C H C H ~ ) ~ C~HIICH~CH=CHCH~C~HI~ C6H I CH2CH=CHCH20Me + isomers
Product
a 2
$7
2
B
6' s
9 s
E
3F;.
B
5
9
$
W
N 4
2.6.3 Radicals by Anodic Oxidation m
2
I
6
8 \0
d N
\
o
z-a
N N
279
280
2.6 Electrochemical Generution of Rudiculs
tion and a subsequent heterocoupling of the exocyclic radical to form 3-substituted tetrahydrofurans and pyrrolidines (Table 7, entries 21 and 22). This intermolecular addition has been used to synthesize a precursor of prostaglandin PGF2, (Eq. 13)] [130] and a branched carbohydrate (ratio of diastereomers1.8:l) (Eq. 14) [131].
a
b
R: CH3(CH2)7, 54%,a:b 3.0:l R: PhMezSiCHz,38%,a:b 4.3:l
CH3COzH
A AcO'" c o
~
o
~
0
2-2 COP, H -2 H+, -2 e-* MeOH, Pt
(14)
50%
The extension of the cyclization from tetrahydrofurans and pyrrolidines to carbocycles led to a sharp decrease in the yield of the cyclized product [ 1331. This is due to the slower cyclization rate of 5-hexenyl radicals compared to 5-(3-oxahexenyl) radicals [ 134, 1351, which favors the competing bimolecular coupling to the acyclic product. Three measures help to increase the yield in these cyclizations. The geminal dialkyl effect, namely the introduction of two methyl groups into the 3-position of the 5-hexenyl radical, increases the cyclization rate of the 5-hexenyl radical [134, 1351 and results in a higher portion of cyclization product via the radical intermediate 93 11331. cyclization R = H: 21% R = CH3: 32% R
R
93
The current density controls the concentration of radicals at the electrode surface. This concentration, depending on the rate constants of the follow-up reactions of the radicals, is lo3 to lo6 times higher than in homogeneous reactions. A low current density favors the monomolecular cyclization against the bimolecular coupling to an acyclic product. A decrease in the current density by a factor of 30 increased the proportion of cyclized product tenfold (Eq. 15) [ 1331.
2.6.3 Radicals by Anodic Oxidation
95
R
281
96
u 97
R3
-H+, -e, -C02
R1
R2
R3
yield (?Lo)
CN
CH3
(CH2)4C02CH3
75
C02Et
CH3
(CH2)&02CH3
76
CN
H
(CH2)4C02CH3
71
COCH3
H
CH3
71
The electrophilicity of the double bond also influences the addition rate of the mostly nucleophilic radical. With vinylic electron-attracting groups the carbocycle yield could be increased to more than 70% (Eq. 16) [ 1331. A radical tandem cyclization, consisting of two radical carbocyclizations and a heterocoupling reaction, has been achieved by electrolysis of unsaturated carboxylic acids with different coacids. This provides a short synthetic sequence to tricyclic products, e.g. triquinanes, whereby the carboxylic acids are accessible in only a few steps (Eq. 17) [132]. The selectivity for the formation of the tricyclic, bicyclic and monocyclic product could be predicted by applying a mathematical simulation based on the proposed mechanism.
282
2.6 Electrochemical Generation of’ Radicals
1 . LDA 2. I(CH2)3COONa(85%)
3. C4H7MgBr OEt 4. H+ (74%)
5eq.CH3CO2H-e, -C02
@ @ @ ~
42% (2 diast. 2.7:l)
~
15%
8%
Radical cyclization of this type can also be obtained as part of radical chain reactions [ 134, 1351, often in an even wider scope. The anodically initiated cyclization, however, has certain advantages. It avoids tin hydride, which is mostly used as a coreagent in chemical radical chain cyclizations. The toxicity of tin organics in these reactions make them less attractive for the synthesis of pharmaceuticals. In chemical radical chain reactions, which involve in most cases an addition and an atom transfer reaction, one C,C- and one C,H- or C,X-bond is being formed, while in anodic addition followed by heterocoupling, two C,C-bonds are being formed, where the second one is established simply and in wide variety by the appropriate choice of the coacid.
2.6.3.5 Anodic Oxidation of Radicals Radicals generated by oxidation of anions can be further oxidized to carbocations. The selectivity of the radical reaction compared with carbocation reaction is determined by the rate of the radical reaction and the rate of the radical oxidation, the latter being related to the oxidation potential of the radical [ 1361. Oxidation potentials for radicals have been determined by photomodulation voltammetry to be in the range of -1.03 V (vs sce) for the N,N-dimethylaminomethylradical, -0.24 V for methoxymethyl, 0.09 V for tbutyl, 0.35 V for diphenylmethyl, 0.73 V for benzyl, <0.99 V for ethyl and <2.49 V for methyl [137]. In anodic addition of anions to double bonds it has been found that, depending on the oxidation potential of the adduct radical, either radical- or carbocation-derived products are obtained (Section 2.6.3.4). In anodic decarboxylation, products arising from radicals (Kolbe electrolysis) or from carbocations (non-Kolbe electrolysis) are formed. The radical pathway is favored by a high current density, a smooth anode surface (platinum, glassy carbon), an acidic electrolyte (only partial neutralization of the acid) and hydrogen or electron-withdrawing substituents in the x-position of the carboxylic acid. The carbocationic route is supported by a low current density, a rough electrode surface (graphite), additives (e.g. perchlorate anion, Cu2+) and electron-donating sub-
2.6.4 Radicals by Cathodic Reduction
283
stituents in the @-position.From product ratios and ionization potentials of the intermediate radicals, it was concluded that radicals with ionization potentials above 8 eV lead preferentially to coupling products, while those with ionization potentials below 8 eV are further oxidized to carbenium ions [ 1381. Non-Kolbe electrolysis has found many synthetic applications, as with its aid the carboxyl group in an acid can be replaced by a hydroxy, alkoxy, or amino group or a double bond. Furthermore, a Wagner-Meerwein rearrangement or P-cleavage of the alkyl group in the acid can be induced [2]. Radicals are frequent intermediates in anodic coupling, substitution or addition of neutral compounds via radical cations [ 1391. In these conversions the radical cation is either deprotonated to a radical or reacts with a nucleophile to a distonic radical cation [ 1401. In most cases, however, the intermediate radical is further oxidized to a cation that undergoes deprotonation (elimination) or solvolysis. Stable nitroxyl radicals can be oxidized to N-oxo-ammonium salts that are selective oxidants for alcohols and other substrates [ 1411. Their redox potentials have been modeled by AM 1-SM2 calculations [ 1421.
2.6.4 Radicals by Cathodic Reduction 2.6.4.1 Homo- and Heterocoupling of Cathodically Generated Radicals Radicals can be generated by cathodic reduction from carbocations, protonated C=X bonds, and the reduction of halides or onium salts. The reduction potentials of carbocations range from 1.87 V (vs nhe) for NCCH(4-CN-C6H4)+, 0.97 V for the benzylcation, 0.33 V for the teut-butyl cation, and 0.0 V for the methoxymethylcation to -0.88 V for EtZN=CHCH3+ [ 1431. Stable cations as tropylium salts [ 1441, cyclopropenylium salts [ 1451, alkylpyridinium salts (Eq. 18) [146], and pyrylium salts [147] have been dimerized at the cathode and radicals are proposed as intermediates.
+3
Me-N,
air
/
Pb-cathode, +e*
H20-cosolvent 90% M
e
h
m
M
M
e
-
N
m-M
e
e
The cathodic dimerization of aromatic aldehydes and ketones in slightly acidic medium via ketyls or hydroxymethyl radicals is a powerful method for the preparation of pinacols in good to excellent yields, e.g. 98 [ 148a1, 99 [ 148bl or 100 [ 148~1. Correspondingly, the heteroanologous azomethines, pyrimidines, quinazolines and immoniuni ions can be hydrodimerized, presumably also via radicals [ 1491.
284
2.6 Electrochemical Generution of Radicals
98 (71%)
99 (87%)
101 (95%)
102 (91 %)
Electrohydrocyclization of bis-imines provides a short access to piperazines, e.g. 101 [ 1501. Heterocoupling between acetaldehyde and methyl acrylate in slightly acidic medium affords 102 in high yield, and probably involves a hydroxymethyl radical as intermediate, which adds to the acrylate [151]. The large number of synthetically useful intermolecular hydrodimerizations and intramolecular cyclizations of activated olefins to complex carbon skeletons involves in most cases radical anions as key intermediates [ 1521. In the cathodic reduction of substrates with appropriate leaving groups X, these groups can be replaced by hydrogen in a reaction which is termed 'cathodic cleavage'. A mechanism is assumed involving the reduction of the substrate to a radical anion that dissociates into a radical and X-, sometimes both reactions occur in a single step (dissociative electron transfer) [153]. The radical is further reduced to an anion that is subsequently protonated (Eq. 19). R-X
R - X ' X
R.
L!%+
R-
H+,
RH
(19)
When RX is easily reduced, as in the case of ally1 iodides and benzyl bromides, the competing further reduction of the intermediate radical is suppressed and radical reactions such as dimerization, addition to double bonds and aromatic compounds or reaction with anions can be favored. The radical pathway can be also promoted by catalysis with reduced forms of vitamin B12, cobaloximes or nickel complexes. These react with the alkyl halide by oxidative addition and release the alkyl radical by homolytic cleavage. The reduction of a-substituted benzylbromides at the least negative reduction potential affords dibenzyl compounds, possibly via intermediate benzyl radicals (Eq. 20) [154].
X = CI: 93 % mesold/= 1 : 1 X = Br: 69 % mesoldl = 5 : 1 X = Si(CH3)3: 72 YOmeso/d/= 1.2 : 1
2.6.4 Radicals by Cathodic Reduction
285
The dimerization of ethylene halohydrins to 1,4-butanediol is of technical interest and has been optimized by controlled-potential electrolysis, voltammetry and laser photoemission studies [ 1551. In the case of a-alkoxy, -halo or -thioalkylsulfones cyclic voltammetry has provided strong evidence that free radicals are intermediates in the cathodic cleavage [156]. In the cathodic cleavage of sulfonium ions intermediate radicals have been identified by cyclovoltammetry, ESR and by spin trapping [157]. Radicals R that are generated by indirect reduction of alkylhalides RX with aromatic radical anions A-' can couple with these radical anions to R A P , which are protonated to alkylhydroaromatics RAH. The coupling rates are nearly diffusion controlled and are barely influenced by the structure of A- and R [ 1581. In the SRN1 reaction a nucleophilic substitution involving a radical chain reaction is induced at an aromatic compound by an electrochemical, chemical or photochemical electron transfer (Eq. 21).
Nu-: enolate, thiolate, CN-, (Et0)2PO-, NH2-
The rate constants for the single steps of the chain reaction, namely the coupling of radical with nucleophile, the electron transfer to the aromatic compound and the dissociation of the radical anion have been determined by electroanalytical techniques, and its scope by way of cathodic induction has been demonstrated [159]. The reaction has been extended to substrates other than aromatics. For example, perfluoroalkylation of purine and pyrimidine bases can be achieved by cathodic initiation [ 1601.
2.6.4.2 Addition Reactions of Cathodically Generated Radicals Radicals generated at the cathode by either direct or indirect reduction (see also Section 2.6.5.2) have been added to alkenes, aromatic compounds, pyridinium salts, nitriles, alkynes, carbon and metals. The cathodic cyclization of 5-enones leads regio- and stereoselectively to cyclopentanols (Eqs. 22, 23) [ 1611. The reduction of the non-conjugated dienone affords in a tandem reaction a bicyclic alcohol (Eq. 24) [162]. C-rod, +e
MeOH, Et4NOTs
98%
*
"""P ,$
2.6 Electrochemical Generation of Radicals
286
+e, C-rod, Et4NOTs MeOH/dioxane 69%
0
Hg/Pt-Cathode +e, DMF
54%
H
+e
-OPO(OE&
58 Yo
Enol phosphates can be reduced to vinyl radicals, which cyclize in a tandem reaction to cyclopropanes (Eq. 25) [163]. 4-Arylketones can be cyclized in good yield at a tin cathode in Et4NOTsliPrOH. The reaction is stereoselective with the preferential formation of the product in which hydrogen and hydroxy group on the vicinal carbon are cis to each other. The cathodic cyclization proved to be superior as compared to the use of chemical reducing agents. The process is assumed to occur by cyclization of an initially formed ketyl. The stereochemistry is explained by repulsion of the negative charge on oxygen and the n-system of the aromatic ring (Eq. 26) [164]. Esters that are normally difficult to reduce can be readily cyclized - possibly via magnesium salts of ketyls in a 5-exo-trig-cyclization (Eq. 27) [ 1651.
& C02Me
a . HO
2.6.4 Rudicals by Cathodic Reduction
287
R': H, Ph, 4-CH3-Ph, 4-MeO-Ph, 4-CI-Ph R2: H, Ph
In situ-generated acylphosphonium salts can be reduced to the corresponding ketyls, which cyclize to a-substituted cyclopentanones (Eq. 28) [ 1661. Aryl radicals that are generated by cathodic reduction of aryl halides have been added to phenols [ 1671. With aromatic radical anions as mediators, the follow-up reduction of aryl radicals can be suppressed, which enables the cathodic addition of 4-chlorobenzonitrile via an aryl radical to styrene in SOYOyield [ 1681. Aryl radicals generated from aryl halides by cathodic reduction at mercury can cyclize onto an adjacent benzene ring. In this respect 5-(2-halophenyl)-l-(4-fluorophenyl)tetrazole has been cyclized to 7-Auorotetrazolo[ 1,5-f]phenanthridine in high yield using an undivided cell, a mild steel cathode and a sacrificial magnesium anode (Eq. 29) [169]. N-N +e, steel-cathode+ CHBCN, 90 %
:I;::: /
F
F
OH +e, Hg-cathode 1 M H2S04 55 %
+
+e, Hg-cathode 1 M H2S04 71 %
H
13
H
1
Oxoalkyl-pyridinium salts can be converted in a one-pot reaction to quinolizidine and indolizidine derivatives (Eq. 30) [ 1701. From the comparison of the reduction
288
2.6 Electrochemical Generation of Radicals
potential of the pyridinium ring and the carbonyl group comes evidence that the protonated or hydrogen-bonded carbonyl group is reduced to a hydroxymethyl radical that undergoes a reversible addition to the C=N bond of the pyridinium ring. This conclusion follows from the thermodynamically controlled ratio of the diastereomers. The initially formed dihyropyridine is reduced to the tetrahydropyridine product after protonation. Ketonitriles can also serve as substrates in reductive cyclization. The reaction is assumed to occur via the formation of a ketyl, leading by a second electron transfer and two protons to an a-hydroxyimine, that hydrolyzes to a ketol (Eq. 32) [152a, 1711.
aCN
+e, Sn-cathode iPrOH 2Yo
76%
68%
nBybl
nBu
C-cathode, DMF
(34) nBu
(CF&CHOH, R4NC104 60%
31%
With cobaloxime as a mediator, bromoalkynes can be cyclized in good yield at zinc electrodes to E,Z-alkenes (Eq. 33) [ 1721. Similar cyclizations of 5-alkynyl halides can be achieved with nickel(I1) complexes [173]. The direct reduction of haloalkynes has been examined with regard to the influence of reduction potential, proton donor and the electrode on the yield (Eq. 34) [174]. Substituted phenyl radicals that are generated by electroreduction of substituted phenyl diazonium ions at glassy carbon and highly orderd pyrolytic graphite (HOPG) react with the electrode. Voltammetry, XPS, Raman and IR reflection absorption spectroscopy, Auger and Rutherford backscattering spectroscopy allowed characterization of the overlayer and an estimate of the surface coverage [175, 1761. Electrogenerated radicals can also react with other active electrode materials. Reduction of ally1 bromide at a tin cathode, or ethyl bromide at lead arords the corresponding organometallic tin or lead compounds in 75% or 90% yield, respectively [ 1771. The anodic oxidation of ethyl magnesium bromide also generates ethyl radicals that can be trapped at a lead anode. This reaction is the basis of the NALCO process, which until recently has been used to produce tetraethyllead in a technical scale [ 1781.
2.6.5 Indirect Electrochemical Generation o j Radicals
289
2.6.4.3 Reduction of Cathodically Generated Radicals Radicals that are formed by reduction at the cathode can be further reduced to anions, and the reactivity of the intermediate radical is thus shifted to that of a base or nucleophile. This is especially the case in the cathodic cleavage of the R-X bond, where the intermediate radical in most cases is further reduced to an anion R - , which is protonated, resulting in a replacement of X by hydrogen. In a number of cases the competing reduction can be suppressed by an indirect electrolysis, where the use of a mediator can shift the reduction potential to less negative values and also move the radical further apart from the cathode to a region with a lower concentration of reductant (see also Section 2.6.5.2). The competition between radical reaction and reduction depends on their relative rates, the latter being determined by the reduction potential of the radical. The reduction potentials of photochemically generated benzyl and substituted alkyl radicals have been determined by voltammetry [ 1791. From the competition between coupling and reduction in the reaction of aromatic radical anions with radicals, the reduction potentials of benzyl, ally], sterically hindered alkyl, and acyl radicals have been determined [ 180, 1811.
2.6.5 Indirect Electrochemical Generation of Radicals Indirect electrochemical reactions combine a heterogeneous with a homogeneous electron transfer. The redox reagent (mediator) thereby oxidizes or reduces the substrate and is subsequently regenerated to the active form at the electrode. The chemo- and stereoselectivity of the mediator can profitably be used in the electrochemical conversion. Disadvantages of direct electrolysis such as deactivation of the electrode surface (passivation) or slow heterogeneous electron transfer, which leads to unwanted overpotentials, can be avoided. The sometimes undesired high concentration of electrogenerated intermediates at the electrode surface in direct electrolysis can be decreased by using a mediator, whereby reactions first order in intermediate can be favored. On the other hand the choice of the mediator and of the reaction conditions needs very careful optimization to allow high turnovers. The subject has been thoroughly reviewed for mediated chemical and enzymatic reactions [ 1821841.
2.6.5.1 Indirect Electrochemical Generation of Radicals at the Anode Alcohols can be oxidized to carboxylic acids at the nickel hydroxide electrode. Here, nickel hydroxide acts as an immobile mediator at the surface of a nickel net anode. It is oxidized at a low potential to nickel(II1) oxide hydroxide, which abstracts a hydrogen from the hydroxymethyl group to generate a hydroxymethyl radical, which is then further oxidized. The nickel(I1) hydroxide thereby formed is reoxidized without going into solution. The electrode is selective for primary alco-
290
2.6 Electrochemical Generution of Radicals
hols and oxidizes amines faster than alcohols. The application of this modified anode to a number of substrates has been reviewed [185]. Manganese(II1) can oxidize carbonyl compounds and nitroalkanes to carboxymethyl and nitromethyl radicals [ 1861. With Mn(II1) as mediator, a tandem reaction consisting of an intermolecular radical addition followed by an intramolecular electrophilic aromatic substitution can be accomplished [ 186, 1871. Further Mn(111)mediated anodic additions of 1,3-dicarbonyl and 1-keto-3-nitroalkyl compounds to alkenes and alkynes are reported in [110, 111, 1881. Sorbic acid precursors have been obtained in larger scale and high current efficiency by a Mn(II1)-mediated oxidation of acetic acid-acetic anhydride in the presence of butadiene [189]. Also the nitromethylation of benzene can be performed in 78% yield with Mn(II1) as electrocatalyst [ 1901. A N03' radical, generated by oxidation of a nitrate anion, can induce the 1,4-addition of aldehydes to activated olefins. NO3' abstracts a hydrogen from the aldehyde to form an acyl radical, which undergoes addition to the olefin to afford a 1,4-diketone in 34-58% yield [191].
2.6.5.2 Indirect Electrochemical Generation of Radicals at the Cathode In the Fenton reaction, hydroxy radicals are generated by reduction of hydrogen peroxide with ferrous ion, which is oxidized to ferric ion. By way of cathodic regeneration, Fe2+can be used as mediator in the radical hydroxylation of benzene to afford phenols in good yield [ 192, 1931. Fenton's reagent has been generated in situ by simultaneous reduction of oxygen and ferric ion on a carbon felt cathode. The hydroxy radicals are intended to be used for remediation of water containing toxic organic pollutants through their conversion into biodegradable products or through their mineralization into water and carbon dioxide. 2,4-dichlorophenoxyacetic acid (2,4-D) as a model compound could be mineralized this way to more than 95% [194]. The impact of new cell technologies on the use of hydrogen peroxide in indirect electrolyses was discussed recently [ 1951. By using hydroxylamine instead of hydrogen peroxide it is possible to do an amination of benzene or toluene by indirect cathodic reduction with the redox pairs Cu2+/Cu+ and V4+/V3+[ 1961. In the presence of 1,3-butadiene diaminooctadienes and diaminododecatrienes are obtained by reductive amination [ 1971. Transition metal complexes are increasingly being applied as redox catalysts in indirect electrolyses. Co(II1) complexes, e.g. vitamin B I Z ,are cathodically reduced to Co(1) complexes, which react with an alkyl halide in an oxidative addition to give the alkylcobalt(II1) complexes. These then undergo reductive elimination at a more negative potential regenerating the Co(1) system. The reaction has been efficiently used in reductive alkylation and acylation of Michael acceptors [ 198, 1991. The intermediate cobalt complexes and the alkyl radicals have been identified by cyclovoltammetry, controlled potential electrolysis and scavengers [200, 2011. Cathodic radical tandem cyclizations starting from bromoenynes and bromodienes to bicyclic five-membered ring compounds have been mediated by vitamin B12 or Ni(cyclam)(ClO4)2 [202]. Radical migrations have been achieved by reduction of suitably substituted alkylbromides with vitamin Bl2 or cobaloximes [203]. Nickel(1)
References
29 1
complexes, generated by reduction of nickel(I1) complexes, e.g. nickel(sa1en) complexes, undergo oxidative addition with alkylhalides to nickel(II1) complexes that cleave in a reductive elimination to alkyl radicals which couple and disproportionate [204], or add intermolecularly to activated double bonds [205] and intramolecularly to non-activated alkenes [206]. A comprehensive compilation of radical processes initiated by electron transfer at the electrode or by chemical redox reagents, that lead to transition metal complexes, has been provided by D. Astruc [207].
References [ I ] H. Kolbe, Ann. 1849; 69: 257 and 1860, 113, 125; J. Prakt. Chem. 1874, 10, 89 and 1875, 11, 24. [2] (a) H. J. Schafer, Top. Curr. Chem. 1990, 152, 91. (b) H. J. Schafcr in Comprehensiue Organic Synthesis (Ed.: B. M Trost, I. Fleming), Pergamon, 1991, Vol. 3, p. 633. [3 ] F. Fichter, Organische Elektrochemie, Steinkopf, Dresden 1942. [4] (a) M. M. Baizer, J. Electrochern. Soc. 1964, 111, 215. (b) D. E. Danly, C. R. Campbell in Technique of’Electroorganic Synthesis (Ed.: A. Weissberger), Wilcy, 1982, Part III, p. 283. 151 A. P. Tomilov, M. Y. Fioshin, Russ. Chem. Rev. 1963,32, 30; L. Eberson, H. J. Schafer, Top. Curr. Chem. 1971, 21, 1; A. J. Fry, Synthetic Organic Electrochemistry, Harper and Row, New York. 1972; F. Beck, Elektroorganiscke Chemie, Verlag Chemie, Weinheim, 1974; N. L. Weinberg, Technique of Electroorganic Synthesis, Purt I, II, in Techniques of Chemistry (Eds.: A. Weissberger, B. W. Rossiter), Vol. 5 , Wiley-Interscience, New York, 1974; M. Rifi, F. H. Covitz, Introduction to Orgunic Electrochemistry, Dekker, New York, 1974; S. D. Ross, M. Finkelstein, E. J. Rudd, Anodic Oxidation, Academic Press, New York, 1975; H. J. Schafer, Angew. Chem. 1981, 93, 978; Angew: Chem. Int. Ed. Engl. 1981, 20, 911; S. Torii, Electroorgunic Synthesis, Verlag Chemie, Weinheim, 1985; T. Shono, Electroorganic Chenzistry us a Tool in Organic Synthesis, Springer, New York, 1984; H. J. Schafer, Kontukte, Darmstadt, 1987, 17, 37; Organic Electrochemistry (Eds.: H. Lund, M. M. Baizer), 3. ed., Dekker 1991; T. Shono, Electroorganic Synthesis, Academic Press, 1991; J. Volke, F. Liska, Electrochemistry in Organic Synthesis, Springer, 1994. [6] Radical cations: H. J. Schafer in Organic Electrochemistry (Eds.: H. Lund, M. M. Baizer), 3. ed. Dekker, 1991, p. 949; Radical anions: R. D. Little, M. K. Schwaebe, Top. Curr. Chem. 1997, 1.
[7] (a) H. Lund in Organic Electrochemistry (Eds.: H. Lund, M. M. Baizer), 3. ed. Dekker, 1991, Chapter 6; (b) H. J. Schafer, Kontukte, Darmstadt, 1987, 17. [8] J. Heinze, Angew. Chen?. 1984, 96, 823; Angew. Chem. Int. Ed. Engl. 1984, 23, 831. 191 R. S. Nicholson, 1. Shain, Anal. Chem. 1964, 36, 706. [ 101 D. K. Smith, W. E. Strohben, D. H. Evans, J. Electroanal. Chem. 1990, 288, 111; Programs for digital simulation of cyclovoltammograms are commercially available, eg. Digibib (BAS). [ 1 I ] Fast cyclic voltammetry: C. Amatore, E. Maisonhaute, G. Simonneau, Electrochen?. Comrnun. 2000, 2 , 81; C. P. Andrieux, P. Hapiot, J. M. Saveant, Chem. Rev. 1990, 90, 723. [ 121 0. Hammerich, M. F. Nielsen in Orgunic Electrochemistry (Eds.: H. Lund, 0. Hammerich), Dekker, 2001, Chapter 2; Laboratory Techniques in Electroanalytical Chemistry (Eds.: P. T. Kissinger, W. R. Heinemann), Dekker, 1996. 1131 G. Silvestri, Actu Chern. Scand. 1991, 45, 987. A. K. Datta, P. A. Maron, C. J. H. King, J. H. Wagenknecht, J. Appl. Electrochem. 1998, 28, 569. J. Y. Nedelec, J. Perichon, M. Troupel, Top. Curr. Chem. 1997, 185, 141. [I41 (a) F. Beck, J. Appl. Electrochem. 1972, 2, 59. (b) P. Seiler, P. M. Robertson, Chimia 1982, 36. 305.
292
2.6 Electrochemical Generation of Radicals
[ I S ] G. E. Svadkoskaya, S. A. Voitkevich, Russ. Chenz. Reu. 1961, 29, 161. [ 161 H. J. Schafer, Chem. Phys. Lipids. 1979, 24, 321. [ 171 S. Torii in Electroorganic Syntheses, Part I , VCH-Publishers, Deerfield Beach, 1985, p. 5 I . [IS] Organic Electrockemistry (Eds.: H. Lund, 0. Hammerich), Dekker, 2001, Chapters 14, 23. [ 191 L. Eberson in Chemistry ojcarboxylic acids and esters (Ed.: S. Patai), Interscience, 1969, p. 58. [20] (a) L. Eberson, Electrochim. Acta 1967, 12, 1473. (b) L. Eberson, S. Granse, B. Olofsson, Acta Chem. Scand. 1968,22, 2462. (c) L. Eberson, Acta Chem. Scand. 1963, 17, 2004. 1211 L. Eberson, G. Ryde-Petterson, Actu Chenz. Scand. 1973, 27, 1159. [22] L. Eberson, K. Nyberg, R. Servin, Acta Chern. Scand. 1976, B30, 906. [23] G. E. Hawkes, J. H. P. Utley, G. B. Yates, J. Chem. Soc., Perkin Trans 11 1976, 1709. [24] J. H. P. Utley, G. B. Yates, J. Chem. Soc., Perkin Trans. I/ 1978, 395. [25] N. L. Weinberg, H. R. Weinberg, Chern. Ret.. 1968, 68, 449. [26] H. J . Schafer in Organic Electrochemistry (Eds.: H. Lund, 0. Hammerich) 41h ed. Dekker, 2001, Chapter 23. [27] B. C. L. Weedon, Adu. Org. Chern. 1963, 1, 1 . [28] L. Eberson, Acta Chem. Scund. 1959, 13, 40. [29] J. Haufe, F. Beck, Chem. Ing. Tech. 1970, 42, 170. [30] F. L. M. Pattison, J. B. Stothers, H. G. Woolford, J. Amer. Chem. Soc. 1956, 78, 2255. [31] F. Fichter, S. Lurie, Helu. Chim. Acta. 1933, 16, 885. [32] A. Weiper-Idelmann, M. aus dem Kahmen, H. J. Schafer, M. Gockeln, Acta Chem. Scand. 1998, 52, 672. (331 R. F. Garwood, N . ud Din, C. J . Scott, B. C. L. Weedon, J. Chem. Soc., Perkin Trans. I 1973, 2714. [34] G. Nuding, F. Vogtle, K. Danielmeier, E. Steckhan, Synthesis 1996, 71. [35] J . Hiebl, M. Blanka, A. Guttmann, H. Kollmann, K. Leitner, G. Mayrhofer, F. Rovenszky, K. Winkler, Tetrahedron 1998, 54, 2059. [36] G. Stork, A. Meisels, J. E. Davies, J. Am. Chem. Soc. 1963, 85, 3419. [37] N. Rabjohn, G. W. Flash, J. Org. Chem. 1981, 46, 4082. [38] S. Kobayashi, Jap. Patent 7686401; Chem. Ahstr. 1977, 86, 120766b. [39] K. Kimura, S. Horie, I. Minato, Y. Odaria, Chem. Lett. 1973, 1209; see also: T. D. Binns, R. Brettle, G. B. Cox, J. Chem Soc. [London] C 1968, 584. [40] L. B. Rodewald, M. C. Lewis, Tetrahedron 1972, 27, 5273. [41] D. Degner, Top. Curr. Chem. 1988, 148, 1. [42] L. Eberson, Acta Chern. Scand. 1959, 13, 40; L. Eberson, B. Sandberg, Acta Chem. Scand. 1966, 20, 739; L. Eberson, Acta Chem. Scand. 1960, 14, 641. [43] H. Quast, J. Christ, Liebigs Ann. Chem. 1984, 1180. [44] G. Cauquis, B. Haemmerle, Bull. Soc. Chim. Fr. 1970, 183. [45] M. Harenbrock, PhD thesis, University of Munster (FRG), 1994. [46] J. Knolle, PhD thesis, University of Munster (FRG), 1976. [47] J. E. Baldwin, J. Chem. Soc., Chenz. Commun. 1976, 734. [48] M. Huhtasaari, H. J. Schafer, H. Luftmann, Acta Chem. Scand. 1983, B37, 537. [49] H. G. Thomas, M. Streukens. H. Peek, Tetrahedron Lett. 1978, 45. [50] R. Hertwig, Master thesis, University of Munster (FRG), 1983. [51] F. Adickes, W. Brunnert, 0. Lucker, J. Prakt. Chem. 1931, 130, 163. [52] S. Kato, G. Dryhurst, J. Electroanal. Chem. 1977, 79, 391. 1531 H. G. Thomas, U. Wellen, J. Simons, G. Raabe, Synthesis 1993, 11 13. [54] (a) C. T. Bahner, Ind. Eng. Chem. 1952, 44, 317; U. S. Patent 1949, 2,485,803; Chem. Abstr. 1950, 44, 2876b. (b) H. J. Schafer, Chern. Ing. Tech. 1969, 41, 179. [ 5 5 ] J. L. Morgat, H. Pallaud, C. R. Acad. Sci. 1965, 260, 574, 5579. [56] G. Schlegel, H. J. Schafer, Chern. Ber. 1984, 117, 1400. [57] R. Bauer, H. Wendt, J. Electroanal. Chem. 1977, 80, 395. [58] T. Okubo, S. Tsutsumi, Bull. Soc. Jpn. 1964, 378, 1794. 1591 M. N. Elinson, S. K. Feducovich, T. L. Lizunova, G. I. Nikishin in Nouel Trend.?in Electroorganic Synthesis (Ed.: S. Torii), Kodansha, Tokyo, 1995, p. 47; M. N. Elinson, S. K. Feducovich, S. G . Bushuev, A. A. Zakharenkov, D. V. Pashchenko, G . I. Nikishin, MendeleeuComnzun. 1998, 15; M. N. Elinson, S. K. Feducovich, S. G. Bushuev. D. V. Pashchenko, G. I.
References
293
Nikishin, Ru.w Chern. Bull. 1998, 47, 1133; M. N. Elinson, S. K. Feducovich, A. A. Zakharenkov, G. I. Nikishin, Mendeleeu-Commun. 1999, 20. [60] G. I. Nikishin, M. N. Elinson, S. K. Feducovich, B. 1. Ugrak, Y. T. Struchkov, S. V. Lindemann, Tetrahedron Lett. 1992, 3223. [61] (a) H. G. Thomas, E. Lux, Tetrahedron Lett. 1972, 965. (b) M. M. Baizer, R. C. Hallcher, J. Electrochem. Soc. 1976, 123, 809. [62] R . Bauer, H. Wendt, Angew Chem. 1978, 90, 390; Angew. Chem. Int. Ed. Engl. 1978, 17, 370. [63] R. Bauer, H. Wendt, Angeiv. Chem. 1978, 90, 214; Angeiv. Chem. In[. Ed. Engl. 1978, 17, 202. [64] C . Amatore, T. el Moustafid, C . Rolando, A. Thiebault, J.-N. Verpeaux, Tetrahedron 1991, 47, 777. [65] (a) H. Lund in The Chemistry o f t h e Hydroxyl Group (Ed.: S. Patai), Vol. I , Wiley, New York, 1971, Chap. 5. (b) A. Ronlan in Encyclopedia of Electrochemistry of the Elements (Eds.: A. J. Bard, H. Lund), Vol. 11, Dekker, New York, 1978, p. 242. [66] K. Sasaki, S. Nanao, A. Kunai, Denki Kayaku 1977,45, 130; Chem. Ahstr. 1977,87, 134212. [67] H. J. Schafer, Top. Curr. Chem. 1987, 142, 100, there p. 116. [68] S. Torii, A,-L. Dhimane, Y. Araki, T. Inokuchi, Tetrahedron Lett. 1989, 39, 2105. [69] J. M. Bobbitt, I. Noguchi, H. Yagi, K. H. Weisgraber, J. Amer. Chem. Soc. 1971, 93, 3551; J. M. Bobbitt, I. Noguchi, H. Yagi, K. H. Weisgraber, J. Ory. Chem. 1976, 41, 845. [70] K . M. Johnston, Tetrahedron Lett. 1967, 837. (711 L. L. Miller, R. F. Stewart, J. P. Gillespie, V. Ramachandran, Y. H. So, F. R. Stermitz, J. Org. Chem. 1978, 43, 1580. [72] A. Rieker, H. P. Schneider, E. Streich in Recent Aduances in Electrooryar~icSynthesis (Ed.: S. Torii), Kodansha, Elsevier, Amsterdam, 1987, p. 57. [73] M. Iguchi, A. Nishiyama, Y. Terada, S. Yamamura, Chem. Lett. 1978, 451. [74] F. J. Vermillion, Jr., I. A. Pearl, J. Electrochem. Soc. 1964, I l l , 1392. [75] W. S. Greaves, R. P. Linstead, B. H. Shephard, S. L. S. Thomas, B. C. L. Weedon, J. Chem. Soc. 1950, 3326. [76] R. P. Linstead, J. C. Lunt, B. C. L. Weedon, J. Chem. Soc. 1950, 3331. [77] D. G. Bounds, R. P. Linstead, B. C. L. Weedon, J. C h m . Suc. 1954, 3326. [78] Y. Suhura, S. Miyazaki, Bull. Cheni. Soc. Jpn. 1969, 42, 3022. [79] M. Harenbrock, A. Matzeit, H. J. Schafer, Liehigs Ann. 1996, 55. [SO] A. Weiper, H. J. Schafer, Anyew. Chem. 1990, 102, 228; Anyew. Chem. Int. Ed. Engl. 1990, 29, 195. (811 A. Weiper, PhD thesis, University of Munster, 1990. [82] K. Schierle, J. Hopke, M.-L. Niedt, W. Boland, E. Steckhan, Tetrahedron Lett. 1996, 37, 8715. [83] Ref. [2b],p. 644. [84] A. K. Yadav, P. Tissot, Helc Clzini. Acta. 1984, 67, 1698. [85] G. W. Gribble, J. K. Sanstead, J. W. Sullivan, J. Chem. Suc., Chem. Commun. 1973, 735. [86] W. Seidel, PhD thesis, University of Munster, 1980. [87] W. Seidel, J. Knolle, H. J. Schafer, Chem. Ber. 1977, 110, 3544. [88] J. Knolle, H. J. Schafer, Angeltx. Chem. 1975, 87, 777; Angeiv. Chem. Int. Ed. Engl. 1975, 14, 758. [89] H. Klunenberg, H. J. Schafer, Angew. Chem. 1978, 90, 48; Angew. Chem. Int. Ed. Engl. 1978, 17, 47. 1901 U. Jensen, H. J. Schafer, Chem. Ber. 1981, 114, 292. [91] H. J. Bestmann, K. Roth, K. Michaelis, 0. Vostrowsky, H. J. Schafer, R. Michaelis, Liebigs Ann. Chem. 1987, 417. [92] W. Seidel, H. J. Schafer, Chem. Ber. 1980, 113, 3898. 1931 H. F. Nutt, H. G. Strachan, D. F. Veber, F. W. Holly, J. Org. Chem. 1980, 45, 3078. 1941 D. Seebach, P. Renaud, Helv. Chim. Acta. 1985, 68, 2342. [95] A. Forster, J. Fitremann, P. Renaud, Tetruhedron Lett. 1998, 39, 7097. [96] A. K. Jadav, A. Singh, L. Prakash, hdiun. J. Chem. Section B, 1998, 37, 1274. [97] B. Klotz-Berendes, H. J. Schafer, Angeiv. Chem. 1995, 107, 218; Angew. Chem. Int. Ed. Engl. 1995, 34, 189; B. Klotz-Berendes, PhD thesis, University of Miinster (FRG), 1994.
294
2.6 Electrochemical Generation of Radicals
[98] W. Straub, E. Roduner, H. Fischer, J. Phys. Chem. 1987, 91, 4379. [99] N. A. Porter, B. Giese, D. P. Curran, Ace. Chem. Res. 1991, 24, 296. [ 1001 M. Letzel, PhD thesis. University of Munster (FRG), 1997. [ I O I ] W. Oppolzer, Pure Appl. Chem. 1990, 62, 1241; D. P. Curran, W. Shen, J. Zhang, T. S. Heffner, J. Am. Chem. Soc. 1990, 112, 6738. [I021 P. Q. Nguyen, PhD thesis, University of Munster (FRG), 2001. [I031 M. Hauck, PhD thesis, University of Munster (FRG), 1996. 11041 W. Smadja, Synlett 1994, 1. [ 1051 H. Schafer, A. A1 Azrak, Chem. Ber. 1972, 10.5, 2398. [I061 S. Torii, K. Uneyama, T. Onishi, Y. Fujita, M. Ishiguro, T, Nishida, Europ. Patent; Chem. Ahstr. 1982, 96, 181142. [I071 J. Yoshida, K. Sakaguchi, S. Isoe, J. Org. Chem. 1988, 53, 2525; J. Yoshida, K. Sakuguchi, S. Nakatani, S. Isoe in Recent Aduances in Electroorganic Synthesis (Ed.: S. Torii), Elsevier, Amsterdam, 1985, p. 85; J. Yoshida, K. Sakaguchi, S. Isoe, Tetrahedron Lett. 1986,27, 6075; J. Yoshida, K. Sakaguchi, S. Isoe, K. Hirotsu, Tetrahedron Lett. 1987, 28, 667. [I081 T. Chiba, M. Okimoto, H. Nagai, Y. Takata, J. Org. Chem. 1979, 44, 3519. [I091 R. Shundo, I. Nishiguchi, Y. Matsubara, T. Hirashima, Tetrahedron 1991, 47, 831. [I 101 F. Bergamini, A. Citterio, N. Gatti, M. Nicolini, R. Santi, R. Sebastiano, J. Chem. Research ( S ) , 1993, 364. [ 11 I ] R. Warsinsky, E. Steckhan, J. Chern. Soc. Perkin Trans I , 1994, 2027. [ 1121 H. Schiifer, Habilitation thesis, University of Gottingen (FRG), 1970. [ 1131 H. Schiifer, H. Kuntzel, Tetrahedron Lett. 1970, 333. [I141 H. Schafer, D. Koch, Angew. Chem. 1972, 84, 32; Angew. Chem. lnt. Ed. Engl. 1972, 11, 48. [ I 151 H. Schafer, R. Pistorius, Angeiv. Chem. 1972, 81, 893; Angew. Chem. Int. Ed. Engl. 1972, 11, 841. [ 1161 Y. B. Vasilev, L. S. Kanevskii, K. G. Karapetyan, E. P. Kovsman, A. M. Skundin, G. A. Tarkhanov, G. N. Freidlin, Elektrokhimiya 1978, 14, 770; Chem. Ahstr. 1978, 89, 119649. 11171 H. Schafer, L. Stork, unpublished results, 1977. [ 1181 M. Y. Fioshin, L. A. Salmin, L. A. Mirkind, A. G. Kornienko, Zh. Ohshch. Khim. 1965, 10, 594; Chetn. Ahstr. 1966, 64, 1949d. [I191 C. J . Brookes, P. L. Coe, D. M. Owen, A. E. Pedler, J. C. Tatlow, J. Chem. Soc., Chem. Commun. 1974, 323. [I201 M. Chkir, D. Lelandais, J. Chem. Soc., Chem. Commun. 1971, 1369; Additive monomers: ref. [121], [122]; K. G. Karapetyan, A. A. Bezzubov, L. S. Kanevskii, A. M. Skundin, Y. B. Vasilev, Elektrokhimiya 1976, 12, 1623; Chem. Abstr. 1977, 86, 62705. [I211 R. N. Renaud, P. J. Champagne, M. Savard, Can. J. Chem. 1979,57, 2617. [122] P. J. Champagne, R. N. Renaud, Can. J. Chern. 1980,58, 1101. [I231 M. Huhtasaari, H. J. Schafer, L. Becking, Angew. Chem. 1984, 96, 995; Angew. Chem. lnt. Ed. Enyl. 1984, 23, 980. [ 1241 L. Feldhues, H. J. Schafer, Tetrahedron Lett. 1988, 29, 2797. [125] R. Pistorius, PhD thesis, University of Gottingen (FRG), 1974. [I261 K. Uneyama, Tetrahedron 1991, 47, 555. [ 1271 C. Depecker, H. Marzouk, S. Trevin, J. Devynck, New J. Clzenz. 1999, 23, 739. [128] Y. B. Vasilev, V. S. Bagotsky, E. P. Kovsman, V. A. Grinberg, L. S. Kanevskii, V. H. Polischyuk, Elektrochirn. Actu 1982, 27, 919. [I291 H. Wendt, V. Plzak, J. Ekefroanal. Chem. 1983, 154, 13, 29. [I301 L. Feldhues, H. J. Schafer, Tetrahedron Lett. 1988, 29, 2801; J . Weiguny, H. J. Schiifer, Liehigs Ann. Chern. 1994, 225, 235. [I311 T. Lubbers, PhD thesis, University of Munster (FRG), 1991. [I321 A. Matzeit, H. J. Schafer, C. Amatore, Synthesis 1995, 1432. [I331 G. Dralle, PhD thesis, University of Munster (FRG), 1990. [I341 (a) B. Giese, B. Kopping, T. Gobel, J. Dickhaut, G. Thoma, K. J. Kulicke, F. Trach, Org. React. 1996, 48, 301. (b) Radicul Reaction Rates in Liquids (Ed.: H. Fischer), Vols. 1I 13u-e, Latidolt-Biirnstein, Springer, Berlin, 1983- 1985. [ 1351 D. P. Curran in Comprehensive Organic Synthesis (Ed.: B. M. Trost), Vol. 4, Pergamon Press, Oxford, 1991, p. 715.
References
295
[ 1361 L. Eberson, Electron Transfer Reactions in Organic Chemistry, Springer, Berlin, 1987. 11371 (a) D. D. M. Wayner, A. Houmann, Acta Chem. S c a d 1998,42, 377 (b) D. D. M. Wayner, V. D. Parker, Ace. Chem. Res. 1993, 26, 292. (c) M. S. Workentin, D. D. M. Wayner, Res. Chem. Intermediates 1993, 19, 177. [I381 L. Eberson, Actu Chem. Scand. 1963, 17, 2004. [I391 H. J. Schifer, in Organic Electrochemistry (H. Lund, M. M. Baizer ed.), Dekker, 1991, Chapter 23. [ 1401 M. Schmittel, A. Burghart, Angew. Chem. 1997,109,2659;Angew. Chem. Int. Ed. Engl. 1997, 36. 2550. [ 1411 ( a jA. E. J. de Nooy, A. C. Besemer, H. v. Bekkum, Synthesis 1996, 1153. (b) K. Schnatbaum, H. J. Schafer, Synthesis 1999, 5, 864-872. [I421 S. D. Rychnovsky, R. Vaidyanathan, T. Beauchamp, R. Lin, P. J. Farmer, J. Org. Chem. 1999, 64, 6745. [ 1431 T. Linker, M. Schmittel, Radikale und Radikalionen in der Organischen Synthese, WileyVCH, 1998, Table 9.1, p. 375. [I441 J. M. Leal, T. Teherani, A. J. Bard, J. Electroanal. Chem. 1978, 91, 275. [I451 R. Breslow, W. Bahdry, W. Reinmuth, J. Am. Chem. Soc. 1961, 83, 1763. [I461 D. Degner, Top. Cur. Chem. 1988, 148, there p. 46; L. N. Nekrasov, H. Almualla, T. M. Khomchenko, Y. D. Smirnov, A. P. Tomilov, Russ. J. Electrochem. 1994, 30, 66. [ 1471 D. Farcasiu, A. T. Balaban, U. L. Bologa, Heterocycles 1994, 37, 1165. [I481 R. E. Sioda, B. Terem, J. H. P. Utley, B. C. L. Weedon, J. Chem. Soc., Perkin Trans. I , 1976, 561; T. Nonaka, M. Asai, Bull. Soc. Chem. Soc. Jpn. 1978, 51, 2976; C. Maurice, B. Schoellhorn, 1. Canet, G. Mousset, C. Mousty, J. Guilbot; D. Plusquellec, Europ. J. Org. Chem. 2000, 813; F. Beck, Elektroorganische Cliemie, VCH, 1974, p. 217. [ 1491 F. Beck, Elektroorganische Chemie, VCH, 1974, p. 220. [ 1501 T. Shono, N. Kise, E. Shirakawa, H. Matsumoto, E. Okazaki, J. Org. Chem. 1991, 56, 3063. [I511 A. P. Tomilov, B. L. Klyuev, V. D. Nechepurnoi, Zh. Org. Khim. 1975, 11, 1984; Chem. Ahstr. 1976, 84, 23698; A. Froling, Rec. Trav. Cliirn. Pays-Bas 1974, 93, 47. [I521 (a) R. D. Little, M. K. Schwaebe, Top. Curr. Chem. 1997, 185, 1 . (b) A. J. Fry, R. D. Little, J. Leonetti, J. Org. Chem. 1994, 59, 5017. [ I531 J.-M. Saveant, Arc. Chem. Res. 1993, 26, 455. [154] J. M. Porter, P. F. Fry, A. J. Fry, J. Org. Chem. 1996, 61, 3191. I1551 V. A. Kurmaz, A. G. Krivenko, A. P. Tomilov, V. V. Turygin, A. V. Kudenko, N. N . Shaloshova, A. S. Kotkin, Russ. J. Electrochem. 2000, 36, 308. [156] C. Amatore, M. Bayachou, F. Boutejengout, J. N . Verpeaux, Bull. Soc. Chim. France 1993, 130, 371. [ 1571 A. Ghanimi, J. Simonet, New J. Chem. 1997,21, 257; J. Q. Chambers, P. H. Maupin 11, C. S. Liao, J. Electroanal. Chem. 1978, 239. [ 1581 S. U. Pedersen, T. Lund, Acta Chem. Scand. 1991, 45, 397; T. Lund, K. Daasbjerg, M. Pop, I. Fussing, H. Lund, S. U. Pedersen, Acta Chem. Scand. 1998, 52, 657; S. U. Pedersen, T. Lund, Acta Chem. Scand. 1991,45, 397. [I591 J.-M. Saveant, Tetrahedron 1994, 50, 10117; J.-M. Saveant, Arc. Chem. Res. 1980, 13, 323; F. J. Bunnett, Arc. Chem. Res. 1978, 11, 413. [160] M. Medebielle, J. Pinson, J. M. Saveant, Tetrahedron Lett. 1992, 33, 7351; M. A. Oturan, J. Pinson, J. M. Saveant, M. Medebielle, J. Org. Chem. 1996, 61, 1331. [I611 T . Shono, I. Nishiguchi. H. Ohmizu, M. Mitani, J. Am. Chem. Soc. 1978, 100; 545. [ 1621 E. Kariv-Miller, H. Madea, F. Lombardo, J. Org. Chem. 1989, 54, 4022. [I631 P. G. Gassman, C.-J. Lee, Synth. Commun. 1994, 24, 1465; P. G. Gassman, C. Lee, J. Am. Chem. Soc. 1989, 111, 739. [I641 N . Kise, T. Suzumoto, T. Shono, J. Ory. C'henz. 1994, 59, 1407. [ 1651 S. Kashimura, Y. Murai, M. Ishifune, Acta Chem. Scand. 1999, 53, 949. [I661 H. Maeda, T. Maki, H. Ohmori, Chem. Lett. 1995, 249. [ 1671 C. Combellas, H. Marzouk, C. Seeba, A. Thiebault, Synthesis 1993, 788. [I681 Z . Chami, M. Gareil, J. Pinson, J. M. Saveant, A. Thiebault, Tetrahedron Lett. 1988, 29, 639. [I691 S. Donnelly, J. Grimshaw, J. Trocha-Grimshaw, Electrochim. Acta 1996, 41, 489; J. Chem. Soc., Chem. Commun. 1994, 2 171.
296
2.6 Electrochemical Generation of Radicals
[I701 (a) R. Gorny, H. J. Schafer, R. Frohlich, Angew. Chem. 1995, 107, 2188; Angetv. Chem. Int. Ed. Engl. 1995, 34, 2007. (b) J. Heimann, PhD thesis, University of Miinster (FRG), 2001. [171] T. Shono, N. Kise, T. Fujimoto, N. Tominaga, H. Morita, J. Org. Chem. 1992, 57, 7175. [I721 T. Inokuchi, H. Kawafuchi, S. Torii, J. Org. Chem. 1991, 56, 5945; T. Inokuchi, in: Novel Trends in electrooryunic synthesis (Ed.: S. Torii), Kodansha, Tokyo, 1995, p. 223; see also: J.-Y. Nedelec, J. Perichon, M Troupel, Top. Curr. Chem. 1997, 185, 141. [173] (a) S. Mitoh, H. Ohmori, S. Ozaki, Tetruhedron Lett. 1995, 36, 8799. (b) M. Ihara, A. Katsuma, F. Setsu, Y . Tokunaga, K. Fukumoto, J. Org. Chem. 1996, 61, 677. [ 1741 R.-I. Shao, J. A. Cleary, D. M. La Perriere, D. G. Peters, J. Org. Chem. 1983, 48, 3289; R.-I. Shao, D. G. Peters, J. Org. Chem. 1987, 52, 652. [I751 M. Delamar, R. Hitmi, J. Pinson, J. M. Saveant, J. Am. Chem. Soc. 1992, 114, 5883; P. Allanggue, M. Delamar, B. Desbat, 0. Fagebaume, R. Hitmi, J. Pinson, J. M. Saveant, J. Anz. Chem. Soc. 1997, 119, 201. [I761 Y. C. Liu, R. L. McCreery, J. Am.Chern. Soc. 1995, 117, 11254. I Electrochem. . Soc. 1972, 119, 1474: M. Fleischmann, D. Pletcher, C. J. Vance, [I771 H. Ulery, . J. Electrounul. Chem. 1971, 29, 325. [I781 US Pat. 3,007,858 (Nalco Chemical Co.), 1959; Chem. Abstr. 1962, 56, 4526h. 11791 P. H. Milne, D. D. Wayner, D. P. DeCosta, J. A. Pincock, Can. J. Chem. 1992, 70, 121 and earlier literature there; V. Benderskii, A. G. Krivenko, Russ. Chem. Rev. 1990, 59, 1; C. P. Andrieux, I. Gallardo, J. M. Saveant, J. Am. C h i . Soc. 1989, 111, 1620. [180] R. Fuhlendorff, D. Occhialini, S. U. Pedersen, H. Lund, Actu Chem. Scund. 1989, 43, 803; D. Occhialini, S. U. Pedersen, H. Lund, Actu Chem. Scund. 1990, 44, 715; D. Occhialini, J. S. Kristensen, K. Daasbjerg, H. Lund, Acta Chem. Scund. 1992, 46, 474. [181] D. Occhialini, K. Daasbjerg, H. Lund, Actu Chem. Scand. 1993, 47, 1100. 11821 E. Steckhan, Top. Curr. Chem 1987, 142, 1. [183] E. Steckhan, Top. Curr. Chem. 1994, 170, 83. [184] J. M. Saveant, M. G. Severin, A. A. Isse, J. Electrounul. Chem. 1995, 399, 157. [I851 H. Schafer, Top. Curr. Chem. 1987, 142, 100. [186] B. B. Snider, Chem. Rev. 1996, 96, 339. [I871 R. Shundo, I. Nishiguchi, Y. Matsubara, T. Hirashima, Chem. Lett. 1991, 235; For related mediated tandem cyclizations see also: B. B. Snider, B. A. Mc Carthy, Symp. Ser. ACS 1994, 557, 84; Chem. Ahstr. 1994, 122, 11 7324. [I881 R. Shundo, I. Nishiguchi, Y. Matsubara, T. Hirashima, Tetrahedron 1991, 47, 831 [189] J. P. Coleman, R. C. Hallcher, D. E. McMackins, T. E. Rogers, J. H. Wagenknecht, Tetruhedron 1991, 47, 809. [190] A. J. Bellamy, Actu Chem. Scund. 1979, B 33, 208. [191] T. Shono, T. Soejima, K. Takigawa, Y. Yamaguchi, H. Maekawa, S. Kashimura, Tetruhedron Lett. 1994, 35, 4161. [I921 E. Steckhan, J. Wellmann, Anyeit,. Chem. 1976, 88, 306; Angew. Chem. Int. Ed. Enyl. 1976, 15, 294. [193] J. Wellmann, E. Steckhan, Clzem. Ber. 1977, 110, 3561. [ 1941 M. A. Oturan, J. Appl. Electrochc~m.2000, 30, 475. [ 1951 D. Pletcher, Actu Chem. Scund. 1999, 53, 745. [I961 R. Tomat, A. Rigo, J. Electroanal. Chem. Interfuciul Electrochem. 1977, 75, 629; ibid. 1975, 63, 329; ibid 1974, 57, 363. [197] T. Chibata, Y. Takata, BUN. Chern. Soc. Jpn. 1978, 51, 1418. [I981 R. Scheffold, G. Rytz, L. Walder in Modern Synthetic Methods, (Ed.: R. Scheffold), Vol. 3, 1983, 355. [ 1991 R. Scheffold, Chimiu 1985, 39, 203. [200] K. S. Alleman, D. G. Peters, J. Electrounal. Chem. 1998, 451, 121. [201] A. Gennaro, E. Vianello, A. A. Isse, J. Electrounul. Chem. 1998, 444, 241. [202] A. Katsumata, K. Takasu, M . Ihara, Heterocycles 1999, 51, 733. [203] (a) Y. Hisaeda, J. Synth. Org. Chem. Jup. 1996, 54, 859. (b) T. Inokuchi, M. Tsuji, H. Kawafuchi, S. Torii, J. Org. Chem. 1991, 56, 5945. [204] (a) C. Gosden, K. P. Healy, D. Pletcher, J. Chenz. Soc., Dalton Trans. 1978, 972. (b) M. S. Mubarak, D. G. Peters, J. E/ectroanal.Chem. 1995, 388, 195.
References
297
[205] (a) C. Gosden, D. Pletcher, J. Organomet. Chem. 1980, 186, 401. (b) S. Ozaki, H. Matsushita, H. Ohmori, J. Chern. Soc. Perkin Trans 1993, 649, 206. [206] (a) S. Mitoh, H. Ohmori, S. Ozaki, Tetrahedron Lett. 1995, 36, 8799. (b) S. Ozaki, H. Matsushita, H. Ohmori, J. Chem. Soc. Chem. Commun. 1992, 1120: (c) M. Ihara, A. Katsumata, F. Setsu, Y. Tokunaga, K. Fukumoto, J. Org. Chem. 1996, 61, 677. (d) E. Dunach, A. P. Esteves, A. M. Freitas, M. J. Medeiros, S. Olivero, Tetrahedron Lett. 1999, 40, 8693. [207] D. Astruc, Electron Transfer and Radical Processes in Transition Metal Chemistry, VCH, Weinheim, 1995.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
2.7 The Radical-Polar Crossover Reaction John A. Murphy
2.7.1 Concept and Discovery 2.7.1.1 The Proposal This review focusses on an extension to radical methodology, discovered in 1993 [ 11, namely the Radical-Polar Crossover Reaction. This reaction, which allows a novel splicing of radical and ionic reactions in one pot, arose from the concept outlined below (Scheme 1). An easily oxidized sulfide would undergo electron transfer to an appropriate electrophile, generating a radical-cation/radical-anionpair. Fragmentation of the radical-anion would afford an organic radical R’. This radical would either directly recombine with the radical-cation or undergo further reaction before recombination to afford a sulfonium salt. The radical chemistry would then be complete, and the sulfonium salt could undergo further transformation (substitution is shown, but other reaction types are also possible) in situ, liberating a molecule of sulfide in the final step. The substitution step could occur by unimolecular (ionic) or bimolecular (non-ionic) mechanisms, and so this part of the scheme is labeled as the ‘polar’ chemistry. The term ‘radical-polar crossover’ arises since the scheme involves a transition from radical to polar chemistry. The polar chemistry and radical chemistry have to be orthogonal for the scheme to be realized as a one-pot method, but this would be an attractive aim since the transformation would then provide a cycle which was catalytic in sulfide.
2.7.1.2 Initial Examples Many easily oxidized organic sulfides exist, but, of these, tetrathiafulvalene [2] (TTF) has been more extensively researched than most, because of interest in the electrical properties of its salts. Its oxidation potential makes it a reasonable electron donor [ 3 ] .Arenediazonium salts were chosen as the partner reagents since their electron-accepting properties had been well explored [4, 51. Furthermore, reaction of TTF with diazonium salts had recently been discussed in the Russian literature [6], but this reported only the formation of the radical-cation, TTF+’. We were keen
2.7.I Concept and Discovery
Step 7
Step 3
-[
+ Ar2S
R-X
+.
R' + Ar2S
X
+
Step 4
R'-SAr2
R-X
] -.+
-d
+'
Ar2S
-
recombination
-
polar substitution
X
+-
+ Ar2S
R'-$Ar2
*
I
R-X
*
+
299
X
X-
Ar2S
Scheme 1. Radical-polar crossover proposal
to investigate the fate of the diazonium substrate, and so initial experiments were performed in which TTF [ 1) was reacted with diazonium salts la-c in undried acetone at room temperature (Scheme 2). Immediate effervescence occurred, and alcohols 3b and 3c were isolated. No alcohol was isolated from reaction of la, but this substrate afforded instead the tetrathiafulvalenium salt 2a, which was present as a mixture of diastereoisomers, indicating that the sulfonium sulfur must have tetrahedral geometry, as expected. This result established that 'recombination' between the carbon radical and the radical cation, TTF+', had formed a C-S bond rather than a C-C bond (C-C bonded products are also produced, but in very low yields;
a0kR
TTF, Acetone, H 20
+N2
R'
- N2
- TT ';
BF4
-
QR R'
BF4
la, R = R' = H l b , R = H, R ' = Me l c , R = R' = Me
3b, R = H, R ' = Me, X = O H 3c, R = R' = Me, X = OH
2a-c
spin density distribution in TTF" I
J
Scheme 2. Mechanism of the radical-polar crossover reaction
300
2.7 The Radical-Polar Crossover Reaction
see Chapter 3 for further discussion). This was our anticipation in the light of computational results from Zahradnik et al. [7] who had shown that the spin density would be greatest on the sulfur of TTF+’. Repeating the experiment with l b , but quenching the reaction by addition of diethyl ether as soon as the effervescence had subsided, afforded the tetrathiafulvalenium salt 2b; this compound was then subjected to solvolysis in undried deuteroacetone and afforded the corresponding alcohol 3b, consistent with its intermediacy in the reaction. The basic mechanism of the reaction can thus be represented by Scheme 2. Aryl radicals are formed following electron transfer to the diazonium cation and subsequent loss of dinitrogen. Rapid cyclization is followed by formation of the sulfonium salt 2b, and a facile solvolysis occurs to afford the alcohol 3b. Since the tertiary alcohol 3c was formed from substrate lc, a similar pathway may have been followed, but the direct oxidation of the tertiary radical by electron transfer to a diazonium cation cannot yet be ruled out. The resistance of the primary salt to solvolysis is a classic hallmark of an SN1 reaction. (A refinement for the mechanism of the solvolysis step will be presented in Section 2.7.3.1 of this review, backed by very recent results). The loss of TTF in situ from 2b and 2c means that the radical-polar proposal had been realized! TTF has since been shown to behave catalytically, but its turnover number is very limited, and it appears that it is slowly destroyed in side-reactions. Nucleophiles other than water can participate in the termination step. Thus methanol affords methyl ethers 3, X = OMe, and acetonitrile affords nitrilium salts which are hydrolyzed to the corresponding amides 3, X = NHAc. The nitrilium salts can also be trapped in cycloaddition reactions [8]. An alternative mechanism featuring aryl cation intermediates, rather than aryl radicals, (the ‘aryl cation proposal’, Scheme 3) was considered shortly after the discovery of the reaction. This would invoke a completely non-radical mechanism to explain the observations. Loss of dinitrogen from an arenediazonium salt would afford an aryl cation which then cyclizes to cation 4; this could be (reversibly) intercepted by TTF acting as a nucleophile to give rise to salts 2, solvolysis of which would afford alcohols 3. However, this proposal can be dismissed. Firstly, these
Scheme 3. The aryl cation proposal
2.7.2 Application to Preparation of Nitrogen Heterocycles
301
q \SPh
6
Scheme 4. Radical-polar crossover reaction of an allyl sulfide
diazonium salts do not decompose into their cations at an appreciable rate at room temperature in acetone, as witnessed by NMR experiments. If the 'aryl cation mechanism' were correct, then the sulfide would simply be present to trap the cations 4 following cyclization. Therefore sulfides other than TTF would be capable of performing the reaction. However, when the arenediazonium salt l b was treated separately with TTF and with dimethyl sulfide, no reaction occurred [9] in the dimethyl sulfide reaction, but immediate effervescence was seen for the TTF reaction, clearly establishing the special nature of TTF. Moreover, when the allyl sulfide substrate 5 was reacted with TTF, (Scheme 4) the product 6 was isolated together with diphenyl disulfide 7 - the products expected from a radical cyclization.
2.7.1.3 Tandem Radical-Polar Crossover Experiments A key question concerned the kinetics of the R'/TTF+' combination process. Whereas the aryl radical cyclizations described above occurred efficiently, slower cyclizations might be prevented due to premature trapping. Two substrates 8 and 14, which could undergo tandem cyclization reactions [ 1b], provided information on this (Scheme 5). The alkene-containing substrate 8 afforded a mixture of monocyclized and bicyclized products 11 and 13. The cyclization of intermediate radical 9 and the recombination reaction of 9 with TTF+' occurred at comparable rates under the conditions used. This provided a warning that slower radical cyclizations would not be successful, and focussed attention on applying the chemistry to rapid radical cyclizations. The related substrate 14, which would feature two successive rapid cyclizations (of aryl and vinyl radicals respectively), intriguingly afforded the benzofuran 15. The cyclopropane formation may occur either by radical cyclization or during solvolysis of the derived TTF salt 16.
2.7.2 Application to Preparation of Nitrogen Heterocycles 2.7.2.1 Preparation of Indolines The reaction has been extended to the formation to indolines. Here the N-protecting group proved to be of great importance. For carboxamides, N-acetyl substrates 17
302
2.7 The Radical-Polar Crossover Reaction
J
14
J
11,X=OH
115
10)
12, X = TTFfBF413, X = OH
16
Scheme 5. Cascade processes
underwent successful cyclization (Scheme 6 ) , whereas N-benzoyl derivatives showed the expected complications [lo]. Thus 18 cyclized to form products 19 i 21. Cyclization of aryl radical 22 could lead to cyclohexadienyl radicals 23 and/or 24, which may equilibrate through a neophyl rearrangement. Fragmentation of 24 would afford carbamoyl radical 25, which was then oxidized and decarboxylated to the observed amine 21. The intermediacy of 26 was not established, and direct oxidation of the carbamoyl radical to the corresponding cation cannot be ruled out. However, direct decarbonylation of 25 is not a likely alternative route to 21 [ 111. Of the three products, the indoline 19 was the most surprising, since it had been reported [ 121 that aryl radical 22, formed by reduction of the precursor aryl bromide with tributyltin radicals, underwent exclusive cyclization to afford 20, with no indoline formation. However, repeating the tin experiment with the bromide demonstrated that indoline was indeed produced [13] along with 20. Hence the partition between cyclizations onto the aryl ring and onto the alkene is essentially identical regardless of how the radical is generated. Only one example of N,N-dialkyl diazonium salt was studied, but it provided key information on the mechanism of the solvolysis step in the radical-polar crossover scheme [lo]. Thus, the N-ally1 substrate 27 was reacted in moist acetone and afforded the primary alcohol 28. Since previous primary substrates, for example la, had afforded tetrathiafulvalenium salts 2a which did not undergo solvolysis, this showed that the N-ally1 group was important in exerting a neighboring group effect, assisting the solvolysis of salt 29 via delocalized cation 30. Since ortho-alkoxy
2.7.2 Application to Preparation of Nitrogen Heterocycles
w
303
22
27
28
29 X = N-ally1 2aX=O
30
Scheme 6. Formation of indolines showing the central role of the protecting group
groups and ortho-amido groups could not effect solvolysis, then a strong electron donor like an amine was a requirement for solvolysis at primary carbon. Selective solvolysis of the intermediate 30 to afford an indoline product is not surprising, since the breaking cyclopropane bond 'a' overlaps more efficiently than bond 'b' with the n-system, giving its rupture a kinetic advantage.
2.7.2.2 The Synthesis of ( f )-Aspidospermidine Having prepared simple indolines using the radical-polar crossover reaction, more complex targets were undertaken (Scheme 7). Diazonium salt 31 reacted very stereoselectively to afford 33 [ 101. The ring-junction was cis as expected, but the bonus was that the alcohol 33 was detected and isolated as a single diastereoisomer. This
304
2.7 The Radical-Polar Crossover Reaction Aspidosperrnidine
I
Ac 31
- &-Q& Ac
35
Ac H
32
33
'NH2
: 36
dt \
H
I
!
37x=o 38 X = NMs 39X=NSO*Ph
H H
34
40X=O 41 X = NMs 42 X = NS02Ph
Scheme 7. Formation of polycyclic products using intramolecular terminations for the first time
suggested that either TTFf' trapped the radical 32 stereoselectively and/or that water trapped the subsequent cation selectively. (As this point will be taken up in more detail in Section 2.7.3.1, discussion is deferred until then.) This result suggested that the reaction might be useful in the synthesis of complex alkaloids of the Aspidosperma family such as aspidospermidine 34. To probe this, model compounds were prepared and subjected to the reaction. Firstly, formation of the ABE ring system was modeled [ 141. Diazotization of the amine 35 and reaction of the resulting diazonium salt afforded the spirocyclic product 36 in an acceptable 57% yield from the amine. This marked the first example where the radical-polar crossover reaction was terminated in an intramolecular manner. Modeling the ABCE tetracycle also worked well in preparing products 40 + 42. Importantly, the relative stereochemistry of 42, and by implication that of the other tetracycles, was verified by X-ray crystal structure analysis 1151. To complete the synthesis, it would be necessary to incorporate the second nitrogen of aspidospermidine 34 and to build the D ring of the alkaloid. The first of these issues was addressed by the diazonium salt 43 (Scheme 8). Cyclization in dry acetonitrile afforded a nitrilium salt which was hydrated to afford the amide 44. Oxidative cleavage of the alkene afforded an aldehyde which underwent spontaneous cyclization to yield 45 - for the first time, the skeleton of the ABCE ring system had been assembled using the radical-polar crossover reaction [ 161. However, it was not immediately apparent how this product could lead to a total synthesis of the alkaloid, since selective functionalization would be required to introduce the D ring and the ethyl side-chain. A slight change in strategy was needed. Accordingly, the related diazonium salt 46 was treated with TTF, but in moist acetone, to afford the corresponding alcohol 47, which was oxidized to the ketone; aldol condensation incorporated an ethylidene side-chain, which would later become the ethyl sidechain of aspidospermidine 34, and this led to completion of the synthesis [ 171. This
2.7.3 Neighboring Group Participution in the Solvolysis Stage
3bnF - &-&
305
0
4nctionalisation needed here
CH3CN
H
Ms 43
H
MS
MS
44
45
F3COCHN
F3COCHN
&
t
M SH
MS
acetone, H20
46
MS
47
40
F3COCHN
(ii)
H
Ms 49
Ms
Ms (v)
R' = COCF3 R'= H
Scheme 8. Completion of the Synthesis of aspidospermidine. Reagents and conditions: (i) PCC, SiOz, DCM, 18 h, 82%); (ii) TMSCI, Et3N, DMF, S OT, 48 h; TiC14, paraldehyde, DCM, -78°C 0.5 h, then r.t. 48 h, 51%; (iii) NaBH4, CeC13. 7H20, MeOH, O T , 100%; (iv) DEAD, PPhzMe, THF, 0 ° C + r.t. 99%; (v) NaBH4, EtOH, 60"C, 82'X; (vi) K2CO3, dry THF, 80%; (vii) Pd(OAc)z, Et,N, PPh3, dryCH3CN, reflux, 370/0; (viii) 10% Pt / C, 4Opsi, EtOH, 5 days, 58%; (ix) Red-Al, toluene, I00 "C, 84%.
was the first, and at the time of writing, the only natural product synthesis so far completed using the radical-polar crossover methodology.
2.7.3 Neighboring Group Participation in the Solvolysis Stage 2.7.3.1 Evidence for Neighboring Group Participation for Solvolysis of Secondary TTF Salts During the above synthesis, the diazonium salt 46 had led to 47 as the sole isolated product. The predicted intermediate tetrathiafulvalenium salt from this reaction, 50,
306
2.7 The Radical-Polar Crossover Reaction
yHCOCF3
yHCOCF3
nr
I
I
Ms 51
"
MS
FsCOCHN,
52
F3COCHN
H H20
MS
Ms 50
54
MS
47
Scheme 9. Neighboring group participation by the aryl ring
should lead to carbocation 51, and it seemed remarkable that this cation should not undergo rearrangement to potentially more stable cations, for example 52 and 53. This suggested that the intermediate carbocation, 51, was not behaving normally, and led us to the conclusion that the aromatic ring must be involved in neighboring group participation, perhaps forming a delocalized and more stable carbocation 54 (Scheme 9). To investigate, the cyclohexyl substrate 55 was treated with T T F in acetone [ 181 (Scheme 10). The aim of this experiment was to prepare an aliphatic radical (the cyclohexyl radical) not linked to an aromatic ring, and observe its behavior under radical-polar crossover conditions. The cyclohexyl radical, which was prepared by a radical substitution reaction at sulfur [ 191, was trapped by TTF+', but the resulting salt 56 proved stable to solvolysis under our standard conditions. This implied that the aromatic ring in 50 and in other secondary tetrathiafulvalenium salts such as 2b played a crucial role in assisting the solvolysis. To ensure that the radical substitution at sulfur was not interfering with the solvolysis of 56, diazonium salt 58 was treated with TTF. This should produce the radical 57, which is the intermediate previously seen in the radical-polar crossover reaction of l b . The products isolated from reaction of 58 were dihydrobenzothiophene 60 as well as the alcohol 3b, showing that radical 57 behaved in exactly the same way, whether it was generated from l b or from 58. A series of related diazonium salts was next prepared to probe the neighboring group participation [ 181. Thus 59 led to alcohol 61; removing the electron-donating oxygen from the neighboring group as in 62, led, via the sulfonium salt 63, to alcohol 64, whereas substrate 65 led to the tetrathiafulvalenium salt 66, which was not solvolyzed. The demarcation for solvolysis is thus quite sharp - when the
2.7.3 Neighboring Group Participution in the Solvolysis Stage
301
OMe
55
-
56
59
BF4 62
65
61
63, X = TTF' BF464, X = OH
66
Scheme 10. Establishing the requirements for successful solvolysis
neighboring group features an arene with one extra donating group, as for 63, solvolysis is seen, and when the neighboring aryl ring is less electron-rich than this, as in 66, the tetrathiafulvalenium salt does not solvolyze. The requirements for anchimeric assistance are noticeably different at primary and secondary carbon, presumably reflecting the diEerentia1 build-up of positive charge at the carbon in the two transition states. For the solvolysis of a primary tetrathiafulvalenium salt, for example 29, the neighboring group requires to be more strongly electron-donating than for a secondary salt. This study helps to explain why no rearrangement is seen in the solvolysis of TTF salt 50. The solvolysis is assisted by the aromatic ring via the delocalized cation 54. The formation of the delocalized cation may prevent rearrangement and should also protect one face of
308
2.7 The Radical-Polar Crossover Reuction
Scheme 11. An oxygen atom provides anchimeric assistance
the cyclohexyl ring from attack. The apparent absolute requirement for anchimeric assistance implied that products 13 and 15 may arise from participation by groups other than an aromatic ring, namely the ether oxygen or the styryl alkene bond. This led us to probe the behavior of the diazonium salt 67, featuring a neighboring silyloxy group (Scheme 11). When subjected to the reaction, this afforded the bicyclic ether product 68, confirming that neighboring group participation had occurred.
2.7.3.2 Attempted S NSolvolysis ~ of Primary TTF Salts We now return to the attempts to solvolyze primary S-coupled TTF salts. Reasoning that the solvolysis might be triggered in an sN2 manner with more powerful nucleophiles, the salt 2a was treated with sodium azide [20]. Although TTF was produced, this did not result from a simple substitution reaction, as the other product was the Z-alkene 69. This can be rationalized as resulting from attack by azide at the peripheral alkene bond followed by fragmentation of the heterocycle; however it is not clear why only the Z-isomer is detected. No other product was isolated from this reaction, but, to rationalize the formation of TTF, the thioketenedithioacetal70 was proposed as an intermediate. Fragmentation of the azide adduct could occur by either of two possible pathways, as shown in Scheme 12. When malonate anion [20] was used as nucleophile, surprisingly, the internal alkene of 71 was attacked; subsequent elimination afforded 72. When the salt 2a was treated with an oxygen nucleophile, hydroxide anion [20], then elimination occurred to yield the alkyne 73. It is clear from these reactions that sN2 solvolysis of primary TTF salts is not easy; the only successful example of solvolysis (i.e. of 29) is unimolecular and requires neighboring group assistance.
2.7.4 C-Linked Tetrathiafulvalenium Salts All of the TTF salts discussed so far have featured linkage to the TTF unit via sulfur. However, salts linked through carbon of TTF have also been observed [21] (Scheme 13). These were the major products isolated when the diazonium salts 74a-
2.7.4Tetruthed Tetruthiujulvulenium Salts
309
Scheme 12. Reaction of nucleophiles with a primary TTF salt
c were treated with TTF. These salts were prepared to observe whether hydrogen atom transfer could be effected prior to coupling with TTF+'. Here, the aryl radicals are partly intercepted prior to hydrogen atom abstraction, and afford the corresponding S-coupled TTF salts 75. Following hydrogen atom abstraction, the Ccoupled salts 76 were obtained. These compounds are easily observed in the NMR spectrum, where the downfield shift of the dithiolium protons are diagnostic. It is not clear why coupling to carbon occurs in these cases. Our working hypothesis is that the transition state 77 leading to coupling at sulfur should feature positive charge build-up on two adjacent carbons, i.e. the carbonyl carbon and the carbon bonding to sulfur. This would retard this reaction by electrostatic effects. On the other hand, during C-coupling, the developing positive charge of the dithiolium ring may be well isolated from the carbonyl carbon. In the more complex substrate 78, reaction led to the lactone 82. This arose from the electrophilic radical 79 undergoing rapid cyclization and the product radical 80
310
2.7 The Radical-Polar CrpPolar Craction
+- -
TTF
BF4
Me
-
74a, R = R' = H 74b, R = Me, R' = H 74c, R = R' = Me
,./ +.
Me
JN f$
75
H
BF4
*
Me
aNls4 H
S 76
&/s
s
Et02C C02Et 78
+*
TTF
79
80
BF4
-
*
- TTF Et02C
C02Et 81
82
Scheme 13. Reactions of electrophilic radicals with TTF+'
being oxidized to a cation before trapping by the amide oxygen. The product imidate cation 81 is then hydrolyzed.
2.7.5 Modified TTF Reagents 2.7.5.1 Polymer-Supported and Water-Soluble Derivatives One of the primary motivations for developing new reagents and new uses for reagents is that they will prove useful in the preparation of human medicines. The
2.7.5 Modified TTF Reagents
3 11
NaH, DMA
CI
84
83
85
87
86
+.
0
88
Scheme 14. Polymer-supported and water-soluble derivatives of TTF
requirement to replace organotin reagents as the principal reagents in radical chemistry is well recognized, because of their toxicity and because of the longstanding problem of separation of tin by-products from reaction products [22]. To provide for easier separations with the radical-polar crossover reaction, both watersoluble and polymer-supported TTF reagents have been made and tested. Polymersupported TTF derivatives 84 were prepared [23] by coupling the TTF-alcohol83 to a polymer derived from styrene-chloromethylstyrene-divinylbenzene(scheme 14). Both macroporous and gel-type polymers were prepared, with the latter working more successfully. The polymer is removed by filtration at the end of the reaction. This results in polymer bearing oxidized TTF, which can be regenerated using sodium borohydride for re-use. Three cycles have been effected with minimal decrease in activity of the polymer. In general, the polymer-supported TTF behaved like solution-phase TTF itself. If the radical-polar crossover reaction were to be used on a large scale, it would be best to conduct it on the diazonium salt generated in situ. Arenediazonium tetrafluoroborates are soluble in acetone, but less soluble in water, whereas the chloride salts are readily soluble in water. The water-soluble TTF 87 was prepared [24] by reacting the alcohol 85 with the sultone 86. The product was able to effect the radical-polar crossover reaction either in water with the diazonium chlorides or in acetone/water 1:1 with the tetrafluoroborates. Product purification was extremely simple by extracting the desired reaction product into organic solvent. It is a little surprising that the reaction works in water in view of the findings of Shine [25]and Parker [26], who had elegantly shown that sulfur radical-cations derived from thianthrene 88 are readily trapped by water in a complex reaction which affords thianthrene as well as its sulfoxide. If this process occurred rapidly with TTF+’, it could completely inhibit the radical-polar crossover reaction. Whereas we had pre-
312
2.7 The Radical-Polar Crossouer Reaction
viously been successful in carrying out such reactions in undried acetone, the concentrations of water involved under those conditions are very low by comparison with those present when carrying out the reaction in pure water or acetone/water 1:1.
2.7.5.2 Alternative Electron Donors Related to TTF TTF adds a new dimension to the reactions of radicals, and yet there is great scope for the development of alternative and better reagents. Reagents with a greater reducing potential would react with a wider range of substrates; modulation of the kinetics of combination of carbon radical with sulfur radical-cation would allow slower radical cyclizations to proceed under these conditions, while greater catalytic turnover numbers would improve the efficiency of the reaction. At the outset, it must be stated that the very widely available tetrathiotetrathiafulvalenes89 (Scheme 15)
89
90
91
92
R'
R"
l a , R" = H 1b, R" = Me
Scheme 15. Reactions of diazadithiafulvalenes
R"
94a, R" = H, R' = Me, R = C02Me. 70% 94b, R" = H, R' = Ph, R = C02Me, 69% 9 4 ~R" , = H, R' = Et, R,R = (CH=CH)z 39% 94d, R" = H, R' = Me, R,R = (CH=CH)? 22%
2.7.5 Mod$ed TTF Reagents
3 13
are weaker reducing agents than TTF itself, and have not proved reactive under our conditions. However, two possible leads towards second-generation electron donors have been followed. The first was to use the extended conjugated system 91 as a more powerful reducing agent than TTF. In converting to the radical-cation 92, two rings of 91 undergo aromatization, whereas, in the static representation of TTF+' 90, only the dithiolium ring has gained aromaticity. This should provide a greater driving force for conversion of 91 to the radical-cation. This molecule has been prepared [27], but in our hands [28] it is so easily oxidized that it is impractical as a normal reagent. The alternative lead features derivatives of TTF in which one or more sulfur atoms have been replaced by nitrogen. In particular, the diazadithia derivatives 93a and 93 are of interest, since attachment of a bulky group to nitrogen could retard the rate of coupling of their radical-cations to carbon radicals. These are excellent reducing agents, and it has been shown that even the tetraester [29] (93a, R = C02Me, R' = Me) is a stronger reducing agent than TTF. Firstly it was necessary to demonstrate that coupling to the radical-cations of 93a would occur via sulfur. Reaction of the diazonium salts la and l b with diazadithiafulvalenes 93a afforded the formamides 94 [30]. These products may arise by further reaction of the expected intermediates 95. Cleavage of the fulvalene nucleus may be driven by the enhanced ability of nitrogen to stabilize positive charge. The resulting ketiminium salt 96 is attacked by water, resulting ultimately in the observed product and the carbene 98, which can dimerize to reform 93. As detailed below, extension of the chemistry to more complex substrates gave parallel results. To investigate whether the radical cations of the diazadithiafulvalenes would undergo coupling with carbon radicals at a different rate than TTF+', comparative experiments were performed with the ally1 sulfide 99. This led to the products 100 and 101 as for TTF (Scheme 16). However the yield of the bicyclic product was higher for the diaza compounds, indicating a slow-down in the kinetics of the recombination reaction. Although this is likely to be a fairly small change, it is clear that the modulation of kinetics in this way may be useful with radical-polar crossover reactions to permit slower cyclizations to occur before recombination. In summary, the tetrathiafulvalene-mediated radical-polar crossover reaction has been developed extensively since its discovery in 1993, and has now been applied in
qo\ \
+
BF4 N2
fSph
0
-
fsPh-PhS
TTF
__r
or
93a, R=COzMe, R=Me
0
99
Scheme 16. Comparison of TTF with diazadithiafulvalenes
0 101
3 14
2.7 The Radical-Polar Crossover Reuction
natural product synthesis. The study of improved electron donors with greater reducing capability, with modified crossover kinetics and with higher catalytic turnover number is still in its infancy, and this is one of the many aspects of this new type of reaction which is likely to be developed in the near future.
Acknowledgements The discovery and development of the radical-polar crossover reaction is due to the enthusiasm, skill and hard work of the students and research associates who have worked on this project and whose names are cited in the references. I also thank the EPSRC both for funding and for providing high resolution mass spectra for this project, and SmithKline Beecham, in particular Dr. Norman Lewis, for constant support of this work.
References [ I ] (a) J. A. Murphy, C. Lampard, N. Lewis, J. Chem. Soc., Chem. Commun., 1993, 295-297. For previous reviews, see (b) J. A. Murphy, R. J. Fletcher, C. Lampard, N. Lewis, J. Chem. Soc., Perkin Truns I, 1995, 623-633. (c) N. Bashir, B. Patro, J. A. Murphy, in Advunces in Free Rudicul Cheniistry Vol. 2, Ed. S. Z. Zard, JAI Press, USA, 1999, pp. 123 -150. [2] A. E. Underhill, J. Mat. C%em.,1992, 2, 1 - 1 1 . M. R. Bryce, J. Mut. Chem., 1995, 15, 14811496. M. B. Nielsen, S. B. Nielsen, J. Becher, Chem. Commun., 1998, 475-476. [3] J.-M. Fabre, J. Garin, S. Uriel, Tetruhedron, 1992, 48, 3983-3990. [4] D. S. Wulfman in The Chemistry of’Dici,-onium und Diazo Groups, ed. S. Patai, J. Wiley and Sons, USA, 1978, pp. 247-313. [5] For reactions of diazonium salts with electron donors, see for example: A. L. J. Beckwith, G. F. Meijs, J. Ory. Chrm., 1987, 52, 1922-1930. A. N. Abeywickrema, A. L. J. Beckwith, J. Ory. Chem., 1987, 52, 2568-2571. A. N. Abeywickrema, A. L. J. Beckwith, J. Am. Chern. Soc., 1986, 108, 8227-8229. A. L. J. Beckwith, R. A. Jackson, R . W. Longmore, Aust. J. Chem., 1992, 45, 857-863. T. Cohen, A. G. Dietz, Jr., J. R. Miser, J. Ory. Chem., 1977, 42, 20532058. F. Trondlin, C. Ruchardt, chem. Brr. 1977, 110, 2494-2505. F. W. Wassmundt, R. P. Pedemonte, J. Ory. Chem.: 1995, 60, 4991-4994. [6] V. E. Kampar, V. Bumbure, V. R. Kokars, 0. Ya. Neiland, Zh. Obshch. Khim., 1980, 50, 2057-2061 (translation J. Gen. Chem. U.S.S.R., 1980, 50, 1663-1666). V. R. Kokars, V. E. Kampar, 0. Ya. Neiland, Zh. Ory. Khim., 1983, 19, 1224-1228 (translation J. Ory. Chem. U.S.S.R., 1983, 19, 1092-1095). [7] R. Zahradnik, P. Carsky, S. Hunig, G . Kieslich, D. Scheutzov, Znt. J. Surfur Chenz. C, 1971, 6 , 109. [8] A. R. Knowles and J. A. Murphy, unpublished results. [9] N. Bashir, 0. Callaghan, J. A. Murphy, T. Ravishanker, S. J. Roome, Tetrahedron Lett., 1977. 38, 6255-6258. [lo] J. A. Murphy, C. Lampard, F. Rasheed, N. Lewis, M. B. Hursthouse, D. E. Hibbs, Tetruhedron Lett., 1994, 35, 8675-8679. [ I I ] G. B. Gill, G. Patenden, S. J. Reynolds, J. Chem. Soc., Perkin Trrrns 1, 1994, 369-378.
References
3 15
[12] H. Togo, 0. Kikuchi, Tetrahedron Lett., 1988, 29, 4133-4134. H. Togo, 0. Kikuchi, Heterocycles, 1989, 28, 373-378. [13] J. A. Murphy, F. Rasheed, S. Gastaldi, T. Ravishanker, N. Lewis, J. Chem. Soc., Perkin Trans I , 1997, 1549-1558. [I41 J. A. Murphy, N. Lewis, F. Rasheed, S. J. Roome, J. Chem. Soc., Chem. Commun., 1996, 737738. J. A. Murphy, F. Rasheed, S. J. Roome, K. A. Scott, N. Lewis, J. Chem. Soc., Perkin Trans I , 1998, 2331 -2340. [ 151 R. J. Fletcher, D. E. Hibbs, M. Hursthouse, C. Lampard, J. A. Murphy, S. J. Roome, J. Chem. Soc., Cheni. Commun., 1996, 739-740. R . Fletcher, M. Kizil, C. Lampard, J. A. Murphy, S. J. Roome, J. Chem. Soc., Perkin Trans 1, 1998, 2341L2351. [16] J. A . Murphy, M. Kizil, C. Lampard, Tetrahedron Lett., 1996, 37, 251 1-2514. [I71 0. Callaghan, C. Lampard, A. R. Kennedy, J. A. Murphy, Tetrahedron Lett., 1999, 40, 161164. 0. Callaghan, C. Lampard. A. R. Kennedy, J. A. Murphy, J. Chem. Soc., Perkin Trans I , 1999, 995--1001. 1181 N. Bashir, J. A. Murphy, Chem. Conzmun. 2000, 627-628. [I91 J. A. Kampmeier, T. R. Evans, J. Am. Cheni. Soc., 1966, 88, 4096-4097. A. L. J. Beckwith, S. A. M. Duggan, J. Chem. Soc., Perkin Truns 2, 1994, 1509-1518. B. A. Smart, C. H. Schiesser, J. Chem. Soc., Perkin Trans2, 1994, 2269-2270. C. H. Schiesser, M. L. Styles, L. M. Wild, J. Chem. Soc., Pevkin Trans2, 1996, 2257-2262. D. Crich, Q. Yao, J. Org. Chem., 1996, 61, 3566-3570. D. Crich, X. Hao, J. Org. Cheni., 1997, 62, 5982-5988. [20] 0. Callaghan, X. Franck, J. A. Murphy, Chem. Commun. 1997, 1923-1924. 0. Callaghan, X. Franck, J. A. Murphy, Chem. Commun. 2000,319. B. Patro and J. A. Murphy, unpublished results. [21] J. A. Murphy, M. J. Begley, S. J. Roome, Tetrahedron Lett., 1994, 35, 8679-8683. J. A. Murphy, S. J . Roome, J. Chem. Soc., Perkin Trans I , 1995, 1349-1358. [22] J. E. Leibner, J. Jacobus, J. Org. Chern., 1979, 44, 449-450; D. H. R. Barton, R. S. HayMotherwell, W. B. Motherwell, J. Chern. Soc., Perkin Trans I, 1981, 2363-2367. D. P. Curran, C.-T. Chang, J. Org. Chem., 1989, 54, 3140-3157. P. Renaud, E. Lacote, L. Quarantd, Tetrahedron Lett., 1998, 39, 2123--2126. D. L. J. Clive, W. Yang, J. Org. C/iem., 1995, 60, 26072609. J. Light, R. Breslow, Tetrahedron Lett., 1990, 31, 2957 -2958. E. Vedejs, S. M. Duncan, A. R. Haight, J. Org. Chem., 1993, 58, 3046-3050. R. Rai, D. B. Collum, Tetrahedron Lett., 1994, 35, 6221L6224. E. J . Corey, J. W. Suggs, J. Org. Chem., 1975, 40, 2554-2555. J. Junggebauer, W. P. Neumann, Tetruhedron, 1997, 53, 1301-1310. [23] B. Patro, M. Merrett, J. A. Murphy, D. C. Sherrington, M. G. J. T. Morrison, Tetrahedron Lett., 1999, 40, 7857-7860. 1241 B. Patro, M. C. Merrett, S. D. Makin, J. A. Murphy, K. E. B. Parkes, Tetrahedron Lrtt., 2000, 41,42 1-424. [25] A. J. Bard, A. Ledwith, H. J. Shine, Adu. Phys. Org. Chem., 1976, 13, 155-278. H. J. Shine in The Chemistry of the Sulphoniurn Group, Eds: C. J. M. Stirling, S. Patai, Wiley, USA, 1981, pp. 523-570. [26] 0. Hammerich, V. D. Parker, Adc. Phys. Org. Chem., 1984, 20, 55-189. [27] M. Sato, M. V. Lakshmikantham, M. P. Cava, A . F. Garito, J. Or<+ Chem., 1978, 43, 2084. [28] S. R. Graham and J. A. Murphy, unpublished results. [29] G. V. Tormos, M. G. Bakker, P. Wang, M. V. Lakshmikantham, M. P. Cava and R. M. Metzger, J. Am. Chem. Soc., 1995, 117, 8528-8535. F. G. Bordwell and A. V Satish, J. Am. Chem. Soc., 1991, 113, 985-990. [30] T. Koizumi. N. Bashir and J. A. Murphy, Tetrahedron Lett., 1997,38, 7635-7638. T. Koizumi, N. Bashir, A. R. Kennedy and J. A. Murphy, J. Chcm Soc., Perkin Trans I, 1999, 3637-3643.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
3 Synthetically Important Properties of Radicals 3.1 Kinetics of Radical Reactions: Radical Clocks Murtin Newcomb
3.1.1 What are Radical Clocks? The term ‘radical clock’ is used to describe a unimolecular radical reaction that is kinetically calibrated and, thus, can be applied in a competition study to ‘time’ a particular radical reaction of interest [ 11. Such kinetic information is necessary for mechanistic studies where a radical might be formed as a transient. It is also important for synthetic applications because most radical-based methods involve chain reactions that commonly have several competing reaction steps; with absolute kinetic values available, one can calculate the concentrations of reagents necessary for a high-yield synthetic conversion. Because lifetimes of simple radicals are usually in the microsecond range, direct kinetic measurements require sophisticated instrumentation. Radical clocks provide an inexpensive alternative for kinetic studies because the rate constants for the competing reactions are determined from the product mixtures present at the end of the reaction, usually with common organic laboratory instruments. Any kinetically calibrated radical reaction could serve to time another radical reaction, but unimolecular clock reactions provide important experimental advantages. Because the clock reaction is a first-order process, the kinetics of the ‘timing’ reaction will not be affected by changes in concentration of any agent. Moreover, the rate constants for simple alkyl radical clocks are quite insensitive to solvent. In addition, because the unimolecular clock reaction converts one radical into another, one avoids an additional reagent for the competing reaction. The unimolecular design also results in a disadvantage of the radical clock approach in that the range of kinetics studied with a particular clock is more limited than it would be if a secondorder reaction was used for timing; for that reason, one wishes to have a large collection of calibrated clocks at one’s disposal. This chapter contains a brief description of the background and methods of radical clock studies and examples of clocks. A wide range of calibrated clock reactions exists for many types of radicals, and the examples are only representative.
3 18
3.1 Kinetics of Radical Reactions: Radical Clocks
3.1.2 Types of Radical Clock Reactions Figure 1 shows the types of unimolecular reactions that are most often used as clocks, illustrated with some common examples. Fragmentation reactions such as that of the tert-butoxyl radical are not commonly employed in alkyl radical clocks, but the cyclic equivalents of fragmentations, ring-opening reactions, are quite common. Homolytic cyclization reactions, such as shown for the 5-hexenyl radical, are among the most familiar radical clock reactions. Radical rearrangements, which have the net result of a group migration, generally occur by initial cyclizations followed by ring openings. The fastest radical clock reactions are fragmentations and ring openings of strained small-ring radicals. Entropy effects in these reactions are a major factor, resulting in the large rate constants. For example, both the fragmentation of the tert-butoxyl radical [2] and the ring opening of the cyclopropylcarbinyl radical [ 3 ] shown in Fig. 1 have log A terms of about 13, which corresponds to A S % 0 at ambient temperature. One might think that the ca. 30 kcal/mol strain energies in the small cycloalkanes are the major driving forces in the ring openings, but the inherent exothermicities of these reactions are not nearly as large as this because a pi-bond is created at the expense of a sigma-bond. The result is that the archetypal reaction of this group, ring opening of the cyclopropylcarbinyl radical to the 3butenyl radical shown in Fig. 1, is exothermic by only about 5 kcal/mol [4]. Of course, both the fragmentation and ring-opening reactions will be accelerated when the overall exothermicities of the reactions are increased, either by increasing the strain in the precursor radical or by addition of substituents that give highly stabilized radical products. Radical cyclizations usually comprise the central portions of radical clock scales. Cyclizations that produce low-strain five- and six-membered rings are exothermic, but the entropy demand in the transition states for these cyclizations results in reactions that are considerably slower than ring openings. Increasing the exo-
-
Figure 1. Typical radical clock reactions
3. I .3 Radical Clock Kinetic Studies
-
Concepts
3 19
thermicities of the reactions by incorporation of radical-stabilizing groups at the incipient radical center eventually results in cyclization reactions that are about as fast as some ring-opening reactions. For example, addition of two phenyl groups at C6 of the 5-hexenyl radical in Fig. 1, such that the 5-ex0 cyclization gives a diphenylalkyl radical product, results in a reaction approximately as fast as the ring opening of the cyclopropylcarbinyl radical at ambient temperature (see below). The entropy penalty for obtaining the transition states for cyclizations is reduced as the ring size decreases, and 3-exo cyclizations giving cyclopropylcarbinyl radicals have only low entropy demand [4, 51. However, the reactions are endothermic unless the radical product contains strong stabilizing groups, and simple 3-exo or 4-exo cyclizations usually cannot be employed as radical clocks. These reactions are incorporated into radical clocks in the form of rearrangements that have the appearance of group migrations. The example in Fig. 1 involves an initial 3-exo cyclization that is followed by a ring opening to complete the rearrangement sequence. Radical rearrangement reactions usually provide the slower radical clocks in kinetic scales. The initial cyclizations (usually 3-exo) are much slower than the ring openings, but the rate constants for the clock reaction are not necessarily equal to those for the cyclizations. If the cyclic radical intermediate partitions back to the initial radical in addition to proceeding to the product radical, the rate constant for rearrangement will be smaller than that for cyclization. When the entire rearrangement process is calibrated, a partitioning of the intermediate radical has no practical consequence in terms of the kinetics of the clock. However, significant partitioning of the intermediate is a signal that the overall conversion is not highly exothermic, and this raises the possibility that the clock reaction can be reversible under the conditions of the study. A reversible clock reaction can provide useful kinetic information, but studies with such systems require multiple reactions with a range of concentrations of reagents as discussed below.
3.1.3 Radical Clock Kinetic Studies - Concepts Radical clock experiments involve indirect kinetic determinations [6]. The concept is illustrated in Scheme 1 where the clock reaction is the 5-hexenyl radical (1) cyclization to the cyclopentylmethyl radical (2). Radical 1 is produced in the presence of an excess of trapping agent X-Y, and cyclization of 1 to 2 competes with radical trapping that gives acyclic product 3. The cyclic radical 2 also will react with X-Y, giving product 4. At the end of the reaction, the yields of products 3 and 4 can be determined by a simple technique such as NMR spectroscopy or GC. If trapping of radical 3 is fast enough such that the cyclization of 1 to 2 is effectively irreversible and if the concentration of trapping agent was great enough such that it was effectively constant throughout the reaction, i.e. pseudo-first-order conditions, the second-order rate constant for the trapping reaction ( k ~can ) be calculated readily. Under pseudo-first-order conditions for trapping agent X-Y, the ratio of the rate
3.1 Kinetics of Radical Reactions: Radical Clocks
320
1
X-Y
J 3
2
kT
x-yI 4
Scheme 1. Competing processes in a typical radical clock study
laws for the competing reactions reduces to Eq. (1) where U is the unrearranged product, R is the rearranged product, kT is the second-order rate constant for the trapping reaction, kR is the first-order rate constant for the rearrangement, and [X-Y] is the concentration of trapping agent. The rate constant of interest can be obtained from a single experiment, but a more precise value would usually be found by conducting a series of reactions at varying concentrations of the trapping agent; in the latter approach, a plot of U/R versus [X-Y] has a slope of kT/kR. The relative rate laws for more complex competition kinetic studies, including those in which one or two reactions are conducted under second-order conditions, have been collected [6].
Typically, one attempts to avoid complex situations by experimental design, but one complicating case often cannot be avoided, namely that involving a reversible unimolecular clock reaction. One should be especially concerned about this possibility when a radical clock is being calibrated. The relative rate law for this case is described by Eq. (2) where the rate constants are those shown in Scheme 2. The noteworthy features of this situation are the following. A single experiment will not provide an accurate rate constant, and a series of studies with varying concentrations of trapping agent must be performed. As in the irreversible case in Eq. (l), the relative rate constants (kTl/kR) are obtained from the slope of a plot of U/R versus the concentration of X-Y. Note that one does not need to know the rate constant for trapping the rearranged radical ( k ~ 2 )nor the rate constant for the reverse reaction (k-R) to obtain a value for the rate constant of interest, kR or k ~ l . However, if either k ~ 2or k-R is known, then it is possible to obtain the other value
Scheme 2. Competing proceses with a reversible radical clock
3.1.4 Radical Cluck Kinetic Studies - Practical Aspects
321
/
0.0
I
I
I
1
I
0.1
0.2
0.3
0.4
0.5
IX-YI (MI
Figure 2. Idealized results for a reversible clock reaction
because division of the intercept of Eq. (2) by the slope gives the relative rate constants (k-~/kT*).
Figure 2 shows an idealized set of data for a radical clock study in which the clock reaction is reversible. The positive intercept is the indication of reversibility in the clock reaction. In this case, the rate constant for the forward reaction ( k ~is) . slope of the line from twice as great as that for the reverse reaction ( k - ~ )The multiple experiments, shown as a solid line, will give an accurate ratio of rate constants; ( k ~ l / k=~5) M-' in this example. If a single experiment had been conducted at 0.2 M concentration of trapping agent, however, a line with an assumed intercept of zero would result in a considerable kinetic error. The result, shown as a ) M-I. dashed line in Fig. 2, gives an apparent value of ( k ~ l / k=~7.5
3.1.4 Radical Clock Kinetic Studies - Practical Aspects The examples of clock reactions in Fig. 1 are well known and are the fundamental reactions in many radical-based synthetic conversions. In synthesis, one attempts to maximize the yield of the reaction and minimize the amounts of reagents employed. Clock experiments can be conducted in a manner similar to that used for synthetic reactions up to a point, but there are some differences in the design of the reactions. The most important difference is that all of the trapping agent must be present at the beginning of the reaction and not added continually throughout the reaction. In addition, the most accurate information is provided when the clock reaction is only about 50% efficient. Finally, the reagents for reaction with the clocks should be present in sufficiently large excesses, >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 (8:92) CN >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 <95:5 respectively (Scheme 4). Experimentally, these ratios are 92:8 and 89:ll [13]. Many other examples are presented. Jaime and coworkers utilised a modified version of the HS method, based on the MM3 molecular mechanics protocol, to examine the effect of steric control during 6-ex0 cyclization in radicals derived from acyclic sugars and observed a pleasing correlation between calculated and experimentally determined data [ 14al. Takahashi and coworkers utilized the HS model to examine the tandem ring closure of 30 prior to experimental work, and noted that both epimers of 30 are predicted to provide primarily epimeric trans-31, which, in turn, are predicted to afford almost exclusively the epimeric mixture of 32 with the required trans-anti-trans (B/C/D) relative stereochemistry [ 14b]. To their delight, iodide 33 affords the desired bicyclic system 34 in 93% yield upon treatment with Bu3SnH (Scheme 5) [ 14bl. Myers also found that the HS model provided accurate predictions of the regioand stereochemical outcomes of ring closures aimed at the synthesis of cembranoid natural products [ 151. Calculations for the cyclization of macrocyclic radicals 35
OTBDMS
33
OTBDMS
34
Scheme 5. Predicted (above) and observed (below) tandem cyclization of 30/33
344
3.2 Calculations: a Useful Tool for Synthetic Chemists Me .Me
Me
\
Me predicted major product
35
Me
Me
Me
37 predicted major product
predicted major product
36
Me
Me
. d (
Me Me
Me
38
Me MB
39
40
Scheme 6. Predicted (above) and observed (below) tandem cyclization of macrocyclic radicals 35 and 36
and 36 proved to be in excellent agreement with experiment (Scheme 6). For example, isomeric radicals 35, 36 are both predicted to afford the same product radical 37 with greater than 90% efficiency. By comparison, photolysis of radical precursor 38 affords a mixture of tricyclic alkenes 39, 40 as the only identifiable products of reaction [ 151. Several other examples are provided. The reader is referred to numerous other examples in which these modeling methods have been employed with great success [16]. While these examples, and those provided above, demonstrate the versatility of both the BS and HS modeling methods and provide examples of strong performance, the reader should be aware that examples exist in which these methods perform poorly. Most notably, these are cases where considerable electronic influences exist in the radicals and transition states in question or where conformational factors lead to modeling difficulties. One early example involves the 6-methylenecyclodecyl radical (41) which was incorrectly predicted by the BS model to cyclize to afford the trans-decalinylmethyl radical 43 (Scheme 7) [17]. Other examples include systems expected to be influenced by the anomeric effect, as in the case of allyloxytetrahydropyranyl radicals [ 181. Force field modeling has also been applied to intramolecular homolytic substitution reactions at selenium. Schiesser and coworkers modeled the steric requirements for the formation of five- six- and seven- membered rings as well as the stereo-
3.2.2 Modeling Radical Cyclization Reactions
H 41
345
H
43
42
AEs(cis) - AE,(trans) = -5.9 kJ.rnol-’ AE*(cis) - AE*(trans) = 7.5
Scheme 7. Calculated and experimental data for the cyclization of the 6-methylenecyclodecyl radical 41
44:n=1 45: n = 2 46: n = 3
2.39A 2.33A AEsa n=1 n=2 n=3
49.0 57.7 86.6
AEs (trans) - AEs (cis) = 1.3 kJ.rnol-’ (R = t-Bu)
Scheme 8. Calculated and experimental data for the cyclization of some w-(alky1seleno)alkyl radicals 44-47
chemistry during the ring closure of several o-( tert-buty1seleno)alkyl radicals 44-47 (Scheme 8) [19]. The model used was essentially an adaptation of the BS model, in which the geometry of the transition state for homolytic substitution at selenium determined by ab initio molecular orbital calculations was incorporated [20]. The modeling was able to predict correctly the order of reactivity of radicals 44-46 toward ring closure at selenium (viz. 44 = 45 >> 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
<. H
O
f
Br
49 - s-trans (Elel = 0)
1 AE* =15.9
0
50
1 AE* = 20.1 *.
I
Bu3SnH 80%
7>. $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.
References
359
[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
11o"C, 48h 86% *
CN Me 129
CN Me 131a
CN Me 1.4
131b
Scheme 23. Intramolecular Diels-Alder reaction of 2-cyano-l-aza-l,3-butadiene
3.3.8 Conclusions It is by now a well-recognized fact that radical reactions can be efficient and selective, even for complicated substrates bearing multiple functional groups, and that they are thereby complementary to ionic processes. Many factors, including steric, polar, stereoelectronic, thermochemical, and so forth, can influence the selectivity (chemo-, regio-, diastereo-) of such reactions, and the captodative effect has an important role in this respect. The examples collected together in this Chapter are designed to show that the captodative effect affects all the elementary processes undergone by radicals, namely (i) homolysis, and its reverse, coupling; (ii) homolytic substitution S H ~corresponding , to atom- or group-transfer; (iii) addition to multiple bonds, and its reverse, /?-cleavage; and (iv) electron transfer. Basically, any reaction involving radicals, or with a radicaloid transition state, can have its selectivity and efficiency affected by captodative substitution. Although the effect is small, even a change of a few kcal mol-' in the activation energy of a given pathway can have a tremendous effect on selectivity. The present survey has
378
3.3 Synthetic Utility of the Cuptodative E f e c t
tried to give as broad a survey as possible of examples of this, but it is clearly far from complete, so that the captodative effect is of significance in a far wider range of synthetic contexts, as well as in other areas such as biochemistry or materials, which have not been discussed here.
Acknowledgement Dedicated to Prof. H. G. Viehe, in grateful recognition for his inspiration and support.
References [ I ] a) J. March, Advanced Organic Chemistry, Reuctions, Mechanisms, and Structure, 4th edn., Wiley, New York, 1992, Chap. 9; b) T. H. Lowry, K. S. Richardson, Mechanism and Theory in Organic Chemistry, 3rd edn., Harper & Row, New York, 1987, Chap. 2. [2] I. Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley, New York. 1976. [3] H. G. Viehe, Z. Janousek, R. Merenyi, L. Stella, Acc. Chem. Res. 1985, 18, 917 -932. [4] a) L. Stella, Z. Janousek, R. Merenyi, H . G. Viehe, Angeiv. Chem. 1978, 90, 741 -742; Anyrw. Chem. Int. Ed. Engl. 1978, 17, 691-692; b) F. Huys, R. MerCnyi, Z. Janousek, L. Stella, H. G. Viehe, Angenv. Chem. 1979, 91, 650-651: Angel?. Chem. Int. Ed. Engl. 1979, 18, 615-616. [5] M. J. S. Dewar, J. Am. Chem. Soc. 1952, 74, 3353-3354. [6] a) A. T. Balaban, Rev. Roum. Chim. 1971, 16, 725-737; b) R. W. Baldock, P. Hudson, A. R. Katritzky, F. Soti, J. Chem. Soc. Perkin Trans. 1 1974, 1422-1427. [7] H. G. Viehe, R. Merknyi, L. Stella, Z. Janousek, Angerv. Cliem. 1979, 91, 982-997; Anyew. Chem. Int. Ed Engl. 1979, 18, 917-932. [8] H. G. Viehe, Z. Janousek, R. Merenyi Eds, Suhstituent E’ecst in Radicul Chemistry, NATO AS1 Series C, Vol. 189, Reidel, Dordrecht, 1986. 191 R. Sustmann, H. G. Korth, Adv. Phys. Org. Chem. 1990, 26, 131-178. [lo] a) M. Karelson, A. R. Katritzky, M. C. Zerner, J. Ory. Chem. 1991,56, 134-137; b) D. D. M. Wayner, B. A. Sim, J. J. Dannenberg, J. Ory. Cliem. 1991, 56, 4853-4858; c) G. Leroy, M. Sana, C. Wilante, J. Mol. Strucf. (Theochem) 1991, 234, 303-328; d) D. J. Pasto, J. Ory. Clzem. 1992, 57, 1139-1 145; e) G. Leroy, J.-P. Dewispelaere, H. Benkadour, D. Riffi Temsamani, C. Wilante, Bull. Soc. Chim. Bely. 1994, 103, 367-378; f ) D. Yu, A. Rauk, D. A. Armstrong, J. Am. Chem. Soc. 1995, 117, 1789-1796; g) B. S. Jursic, J. W. Timberlake, P. S. Engel, Tetruhedron Lett. 1996, 37, 6473-6474; h) R. Arnaud, N. Bugaud, V. Vetere, V. Barone, J. An?. Chrm. Soc. 1998,120, 5733-5740; i) A. Rank, D. Yu, J. Taylor, G. V. Shustov, D. A. Block, D. A. Armstrong, Biochemistry 1999, 38, 9089-9096. [ 111 a) F. G. Bordwell, T. Gallager, X. Zhang, J. Am. Chetn. Soc. 1991, 113, 3495-3497; b) F. G. Bordwell, X.-M. Zhang, M. S. Alnajjar, J. Am. Chem. Soc. 1992, 114, 7623-7629; c) A. L. J. Beckwith, S. Brumby, C. L. L. Chai, J. Chem. Soc. Perkin Trans. 2 1992, 2117-2121; d) F. G. Bordwell, G. Z. Ji, X. Zhang, J . Phgs. Chem. 1992, 89, 1623-1630; e) K. B. Clark, D. D. M. Wayner, S. H. Demirdji, T. H. Koch, J. Am. Chem. Soc. 1993, 115, 2447-2453; f ) A. R. Katritzky, P. A. Shipkova, M. Qi, D. A. Nichols, R. D. Burton, C. L. Watson, J. R. Eyler, T. Tamm, M. Karelson, M. C. Zerner, J. A m . Chem. Soc. 1996, 118, 11905-1 191 I ; g) J. J. Brocks, H.-D. Beckhaus, A. L. J. Beckwith, C. Ruchardt, J. Org. Chem. 1998, 63,1935-1943. [I21 F. G. Bordwell, X.-M. Zhang, Ace. Chem. Rrs. 1993, 26, 510-517.
References
379
[13] M. J. Bausch, C. Guadalupe-Fasano, B. M. Peterson, J. Am. Chem. Soc. 1991, 113, 83848388. [I41 H. Birkhofer, H.-D. Beckhaus, C. Riichardt, in ref. [8], pp 199-218. [I51 F. M. Welle, H.-D. Beckhaus, C. Riichardt, J. Org. Chem. 1997,62, 552-558. [I61 R. Schulze, H.-D. Beckhaus, C. Riichardt, Chem. Ber. 1993, 126, 1031-1038. [17] a) H. G. Viehe, R. Merenyi, Z. Janousek, Pure Appl. Chem. 1988, 60, 1635-1644; b) H. G. Viehe, Z.Janousek, R. Merenyi, in Free Radicals in Synthesis and Biology, F. Minisci, Ed., NATO AS1 Series C, Vol. 260, Kluwer: Dordrecht, 1989, pp 1-26; c) L. Stella, in ref. [8], pp 361-370. [IS] Z. Janousek, F. Huys, L. Rene, M. Masquelier, L. Stella, R. Merknyi, H. G. Viehe, Angew. Chem. 1979, Yl, 651-652; Angew. Chem. Int. Ed. Enyl. 1979, 18,616-617. [19] Fr. Pat. 1548390 (1969) Bayer. Chem. Ahstr. 1971, 74, 3625w. [20] M. Rover-Kevers, L. Vertommen, F. Huys, R. Merenyi, L. Stella, Z. Janousek, H. G. Viehe, Angew. Chem. 1981, 93, 1091-1092; Anyew. Chem. In/. Ed. Engl. 1981,20, 1023-1024. [21] W. D. Ollis, M. Rey, I. 0. Sutherland, J. Chem. Soc. Perkin Trans I , 1983, 1009-1027. [22] I. E. Marko, in Comprehensive Organic Synthesis, Vol. 3, (Eds.: B. M. Trost and I. Fleming), Pergamon, Oxford, 1991, Chap. 3.10 pp 913-974. [23] J. A. Marshall, in Comprehensive Organic Synthesis, Vol. 3, (Eds.: B. M. Trost and I. Fleming), Pergamon, Oxford, 1991, Chap. 3.11 pp 975-1014. [24] A. Padwa, W. Dent, H. Nimmesgern, M. K. Venkatrdmanan, G. S. K. Wong, Chem. Ber. 1986, 119, 813-828. [25] a) A. De Mesmaeker, L. Vertommen, R. Merenyi, H. G. Viehe, Tetrahedron Lett. 1982, 23, 69-72; b) R. Merenyi, A. De Mesmaeker, H. G. Viehe, Tetrahedron Lett. 1983,24, 2765-2769. [26] X. Creary, M. E. Mehrshiekh-Mohammadi, J. Org. Chem. 1986, 51, 2664-2668. [27] M. Newcomb, A. G. Glenn, J. Am. Chem. Soc. 1989,111, 275-277. [28] J. H. Udding, H. Hiemstra, M. N. A. van Zanden, W. N. Speckamp, Tetrahedron Lett. 1991, 32, 3123-3126. [29] J. H. Udding, C. (Kees) J. M. Tuijp, H. Hiemstra, W. N. Speckamp, J. Chem. Soc. Perkin Trans. 2, 1992, 857-858. [30] H. Ishibashi, N. Uemura, H. Nakatdni, M. Okazaki, T. Sato, N. Nakamura, M. Ikeda, J. Ory. Chem. 1993,58,2360-2368. [31] S. D. Burke, K. W. Jung, Tetrahedron Lett. 1994, 35, 5837-5840. 1321 Y. Yamamoto, S. Onuki, M. Yumoto, N. Asao, J. Am. Chem. Soc. 1994, 116,421-422. 1331 J.-Y. Ortholand, N. Vicart, A. Greiner, J. Org. Chem. 1995, 60, 1880-1884. [34] A. I. Meyers, F. X. Tavares, J. Org. Chem. 1996, 61, 8207-8215. [ 3 5 ] U. Schmidt, J. HBusler, E. Ohler, H. Poisel, Fortschr. Chem. Org. Naturst. 1979, 37, 251-327. [36] E. V. Brown, Synthesis 1975, 358-375. [37] F. Dutron-Woitrin, R. Merenyi, H. G. Viehe, Synthesis 1985, 79-80. [38] H. Naarmann, M. Beaujean, R. Merenyi, H. G. Viehe, Polym. Bull. 1980, 2, 363-372 and 417-425. [39] H. Tanaka, Trends Polym. Sci. 1993, 1, 361-365. [40] G. A. Russell, G. Kaupp, J. Am. Chem. Soc. 1969, Yl, 3851-3859. [41] a) K. Deuchert, U. Herstenstein, S. Hunig, Synthesis 1973, 777-779; b) D. Grierson, M. Urrea, H.-P. Husson, J. Chem. Soc., Chem. Commun. 1983, 891-893. [42] a) J. Chauffaille, E. Hebert, Z. Welvart, J. Chem. Soc., Perkin Trans. 2, 1982, 1645-1648; b) C. E. Barry 111, R. B. Bates, W. A. Beavers, Fernando, A. Camou, Bernard Gordon 111, H. F.-J. Hsu, N. S. Mills, C. A . Ogle, T. J. Siahaan, K . Suvannachut, S. R. Taylor, J. J. White, K. M. Yager, Synlett 1991, 207-212. [43] R. Sustmann, W. Miiller, S. Mignani, Z. Janousek, H. G. Viehe, New J. C h m . 1989, 13, 557563. [44] a) S. Mignani, M. Beaujean, Z. Janousek, R. Merenyi, H. G. Viehe, Tetrahedron 1981, 37, 111-115; b) S. Mignani, R. Merenyi, Z. Janousek, H. G. Viehe, Tetrahedron 1985, 41, 769773; c) S. Mignani, Z. Janousek, R. Merenyi, H. G. Viehe, Tetrahedron Lett. 1984, 25, 15711574; d) S. Mignani, Z. Janousek, R. Merenyi, H. G. Viehe, Bull. Soc. Chim. Fr. 1985, 12671274; M. Beaujean, S. Mignani, Z. Janousek, R. Merenyi, H. G. Viehe, M. Kirch, J. M. Lehn, Tetrahedron 1984, 40, 4395-4400.
380
3.3 Synthetic Utility of the Cuptodutive Efect
[45] Z. Janousek, S. Piettre, F. Gorissen-Hervens, H. G. Viehe, J. Organomet. Chem. 1983, 250, 197-202. [46] A. L. J. Beckwith, Chem. Sue. Rev. 1993, 143-151. (471 J. R. Axon, A. L. J. Beckwith, J. Chem. Soc., Chem. Commun. 1995, 549-550. [48] J. Penelle, H. K. Hall. Jr., A. B. Padias, ‘Captodative Olefins’, in The Polymeric Materials Encyclopaedia: Synthesis, Properties, and Applications, J. C. Salamone, (Ed.), CRC Press, Boca Raton, 1996, Vol. 2, pp 918-926. [49] S.-U. Park, S.-K. Chung, M. Newcomb, J. Am. Chem. Soc. 1986,108,240-244. (SO] G. F. Meijs, A. L. J. Beckwith, J. Am. Chem. Soc. 1986, 108, 5890-5893. [51] a) J. E. Baldwin, J. Chem Sor., Chem. Cummun. 1976, 734-736; b) J. E. Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman, R. C. Thomas, J. Chem. Soc., Chem. Commun. 1976, 736-738; c) J. E. Baldwin, L. 1. Kruse, J. Chem. Suc., Chem Commun. 1977, 233-235; J. E. Baldwin, M. J. Lusch, Tetrahedron, 1982, 38, 2939-2947. [52] K. Ogura, N. Sumitani, A. Kayano, H. Iguchi, M. Fujita, Chem. Lett. 1992, 1487-1488. [53] a) K. Goodall, A. F. Parsons, J. Chem. Soc. Perkin Trans. 1 1994, 3257-3259; b) S. R. Baker, A. F. Parsons, M. Wilson, Tetrahedron Lett. 1998, 39, 2815-2818. [54] a) L. Colombo, M. Di Giacomo, G. Papeo, 0. Carugo, C. Scolastico, L. Manzoni, Tetrahedron Lett. 1994, 35, 4031-4034; b) L. Colombo, M. Di Giacomo, L. Belvisi, L. Manzoni, C. Scolastico, A. Salimbeni, Gazz. Chim. It. 1996, 126, 543-554. [55] C.-C. Yang, J.-M. Fang, J. Chem. Soc. Perkin Trans. 1 1995, 879-887. [56] E. Lee, C. Lee, J. S. Tae, H. S. Whang, K. S. Li, Tetrahedron Lett. 1993, 34, 2343-2346. [57] K. D. Gunderman, E. Rohrl, Liebigs Ann. Chem. 1974, 1661-1670. [58] Ch. De Cock, S. Piettre, F. Lahousse, Z. Janousek, R. Merenyi, H. G. Viehe, Tetrahedron, 1985, 41,4183-4193. [59] R. M. Moriarty, C. R. Romain, I. L. Karle, J. Karle, J. Am. Chem. Soc. 1965, 87, 3251-3253. 1601 W. Flitsch, H. G. Kneip, Liebigs Ann. Chem. 1985, 9, 1895- 1903. [61] G. Ksander, G. Bold, R. Lattmann, C. Lehmann, T. Frueh, Y. B. Xiang, K. Inomata, H. P. Buser, J. Scheiber, E. Zass, A. Eschenmoser, Helu. Chim. Acta 1987, 70, 1 1 15-1 172. [62] G. Coppe-Motte, A. Borghese, Z. Janousek, R. Merenyi, H. G. Viehe, in ref. [8/,371-374. [63] A. De Meijere, H. Wenck, F. Seyed-Mahdavi, H. G. Viehe, V. Gallez, Tetrahedron 1986, 42. 1291-1 297. 1641 A. Alder, D. Bellus, J. Am. Chem. Soc. 1983, 105, 6712-6714. [65j a) D. Dopp, J. Walter in ref. [8], pp 375-378; b) D. Dopp, J. Walter, S. Holz, in ref. [8], vv 379-381. [66] L. Stella in ref. [8], pp 361-370. 1671 M. J. S. Dewar, S. Olivella, J. P. Stewart, J. Am. Chem. Soc. 1986, 108, 5771-5779. [68] a) J. L. Boucher, L. Stella, Tetrahedron Lett. 1985, 26, 5041-5044; b) J. L. Boucher, I. De Riggi, L. Stella, J. Org. Chem. 1997, 62, 6077-6019. [69] a) M. Ten, F. W. Fowler, J. Ory. Chem. 1990, 55, 5646-5653; b) N. J. Sisti, E. Zeller, D. S. Grierson, F. W. Fowler, J. Org. Chem. 1997, 62, 2093-2097; c) I. A. Motorina, F. W. Fowler, D. S. Grierson, J. Org. Chem. 1997, 62, 2098-2105.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
4 Stereoselectivity of Radical Reactions 4.1 Stereoselectivity of Intermolecular Reaction: Acyclic Systems Bernd Giese
4.1.1 Background Until the end of the 1980s it was believed that the high reactivity and flexibility of acyclic radicals prevent stereoselective reactions. This opinion changed in 1991 when the review of Porter, Giese, and Curran appeared [ 11. In the middle of the 1990s, it became obvious that in most cases acyclic radicals follow the same rules of stereoselectivity as non-radicals [2]. This chapter describes diastereoselective, substrate-controlled reactions of acyclic radicals. The chemistry of cyclic radicals, the influence of chiral auxiliaries and of Lewis acids as well as enantioselective radical reactions are reviewed in Chapters 4.2-4.5. Actually, radicals are suitable intermediates for an understanding of stereoselectivity because (a) their conformation can be determined by ESR spectroscopy, and (b) the transition states of synthetically relevant radical reactions are very early on the reaction coordinate. The present chapter makes use of these features.
4.1.2 Allylic Strain The concept of allylic strain (A-strain) is based on conformations of Z-alkenes (1) where allylic alkyl groups adopt preferred conformations in which the smallest substituent (in most cases an H atom) points in the direction of the vicinal alkene substituent R 3 [3].
.., \ ,c=c..
R’
‘1.
,,d
R ‘3 /c\H R*
M 1
2
382
4.1 Stereoselectivity of Intermolecular Reaction: Acyclic Systems
Hart [4] and Giese [ 5 ]have recognized that the concept of A-strain can be applied to ester-substituted radicals. Thus, radical 2 reacts stereoselectively because the 'upper' side of the semioccupied p-orbital in 2 is shielded to a larger extent (L: large substituent) than the 'lower' side (M: medium-sized substituent).
4.1.2.1 Ester-Substituted Radicals A typical example for stereoselective reactions of acyclic radicals occurs during the reaction of alkene 3 with tBuHgCl/NaBH4. The reactions proceed by addition of a tert-butyl radical to 3 and subsequent stereoselective H atom abstraction by radical 4 that leads to 5 as main product (Scheme 1). The surprisingly high diastereoselectivity was rationalized by ESR spectroscopy and quantum chemical calculations (Figs. 1 and 2). The /?-coupling constant (706 Gauss) of radical 6, which is analogous to radical 4, shows that a preferred conformation 6A is adopted, in which the dihedral angle 8 between the B-C,H bond and the singly occupied p-orbital is small [6]. Quantum chemical calculations demonstrated that the change of this dihedral angle increases the strain by up to 7 kcal/mol (Fig. 2), so that conformer 6A has a relatively deep minimum conformation that should be attacked anti to the bulky tert-butyl group. An additional methyl group at the radical center gives rise to two minimum conformations as shown for radical 7 in which 7A is about 1.5 kcal/mol lower in energy than 7B (Scheme 2). In these conformations the large tert-butyl group is far from both substituents at the radical center, and the dihedral angle between the C,H and C,CO;!Me bonds in the A-strain conformer 7A is small (Scheme 2). This is in agreement with a /?-coupling constant of 4.8 Gauss in the ESR spectrum of 7 which demonstrates that the angle between the singly occupied radical orbital and the C,H bond of the stereogenic center is between 80 and 90". Furthermore, the 13Ccoupling constant of 29.5 Gauss in the achiral enolate radical 7' provides the sp2 hybridization of the radical carbon atom (Fig. 3). In reactions with Bu3SnH as H-donor, radical 7 yielded mainly 8a (Scheme 3). This could be the product of anti attack at radical 7A. Quantum chemical calcu-
diastereoselectivity 25:l
Scheme 1
4.1.2 Allylic Strain tBu
I
ESR
,C02R
H-C-C.
Coupling constants (Gauss)
g-Factor
H6
H6'
2.0035
1.54
0.36
Ha
383
HP
20.40 7.60
Figure 1. ESR spectrum of radical 6
E (kcal mol-') 8 6
4 2 6A 0 240
0 180
120
60
0
-60
-120
Figure 2. Quantum chemical calculations of the rotation barrier of radical 6
lations of the six possible routes of attack at 7A and 7B are in accord with this discussion. The transition state energies in Fig. 4 demonstrate that the less strained conformer 7A leads to the lowest transition state and that the attack anti to the tertbutyl group is the energetically favored pathway. As a result, the qualitative order of the ground state energies remains unchanged
384
4.1 Stereoselectivity of Intermolecular Reaction: Acyclic Systems tBu
49" 8Le@k2Me Me
Energy (kcal mol-l)
iev18: 97"
12"
16"
C02Me
tBu
7A
78
0.0
1.5
=
Scheme 2
H3C \*
H 3 C y ,C-C02Me
l3
C-C02Me
/
tBu-CHp
H3C
I
Me 7'
7
Coupling constants (Gauss) Radical 7
Hp(CH)
Hp(CH3)
4.8
21.9
7'
13c
21.4
29.5
Figure 3. ESR coupling constants of radicals 7 and 7' tB_u
t Bu
tBu Bu3SnH
+ -
C02Me
8a
7
8b C02Me
C02Me 25 : 1 anti syn
attack \tB:
Fattack 2
Me &?Me
Me 7A
Scheme 3
78
4.1.2 Allylic Strain 67"tBu 76" C02Me 62"Me&H Me i 39" : 63" 530 HSiH3
HSiH3 320 96" itBu
960
7a
7f
Energy =o.o (kcal mol-')
4.0
HSiH3 540: 60"
385
63" Me
H 34"
3.0
72"
59"
58"
HSiH3
85" H 49"
83"
44" HSiH3
7d
7b
7c
2.7
3.6
5.2
Figure 4. Transition state energies of the H-abstraction by radical 7
in the transition states (Fig. 5). This seems to be typical for these radical reactions and offers a simple prediction of the stereoselectivity. The stereoselectivities of ester-substituted radicals 9a-f show that with tertiary radicals 9a-c the anti products 10 are always formed predominantly. In secondary radicals 9d-f the selectivity is lower and can even lead to a loss of selectivity with the substituent L=Ph (Scheme 4) [6, 71. Interestingly, a polar substituent at the stereogenic center increases dramatically the stereoselectivity. Already in 1990, Guindon had suggested that because of dipole-dipole interactions a polar substituent at the stereogenic center of an enolate radical should increase the dihedral angle between the P-C,H and the a-C,CO*R bond [8]. This suggestion could be proved by quantum chemical calculations and ESR measurements [9]. Thus, comparison of radicals 12 and 13 demonstrates that the dihedral angle in the A-strain conformer increases from 5" to 35" if the methyl group in 12A is substituted by the methoxy group in 13A. Therefore, the phenyl group shields the syn face in 13A more effectively than in 12A. In addition, the energy difference between the conformers increases from 0.5 kcal/mol (12A compared to 12B) to 2.4 kcal/mol (13A compared to 13B) so that 13B is less important for the stereoselectivity than 12B (Scheme 5). As a consequence, the selectivity increases from 2:l (1Oc:llc) to 32:l (15d:16d). Several examples show high stereoselectivities for P-methoxy-substituted radicals (Table 1).
386
4.1 Stereoselectivity of Intermolecular Reaction: Acyclic Systems SiH3
SiH3
7A
7B
Figure 5. Ground state and transition state conformations of radical 7
i Bu3SnH 20°C C02Me
C02Me
9
CO2Me
10
a : R=Me
L=tBu
25
R=Me
L=tBu
11
1
(20°C)
49
1
(-78°C)
b : R = Me
L = (Me3Si)3Si 16
1
(20°C)
c : R=Me
L=Ph
2
:
1
(-78°C)
d: R=H
L=tBu
7
:
1
(-78"C, Bu3SnD)
e: R=H
L=PhMe2Si
9
:
1
(-78"C, Bu3SnD)
f: R=H
L=Ph
1
:
1.4 (-78"C, Bu3SnD)
Scheme 4
:
4.1.2 Allylic Strain
387
Ph 12A
128
Energy ~ 0 . 0 (kcal mol-')
0.5
Ph
Ph 13A
138
Energy -0.0 (kcal mol-')
2.4
Scheme 5
M
e
0
7
7 Bu3SnH M e
C02Me
O
+
Y
M
C02Me
14
15
e
O
y
C02Me 16
Table 1. Diastereoselectivity of radicals 14
L 1516
a
b
C
d
e
Me 3: 1
iPr 8: 1
CC6HII
Ph 32: 1
tBu 20: 1
11:l
As already demonstrated, tertiary radicals are more selective than secondary radicals. In general, when the bulk of a substituent R at the radical center is decreased, the stereoselectivity decreases. Thus, when a neopentyl (R = CHztBu) is replaced by a nonyl (R = C9Hlg) group in radical 17, the stereoselectivity of the H-abstraction decreases from 19:l (17a) to 5:l (17c), and the secondary radical 17d is less selective than tertiary radicals (Scheme 6) [ 101. This decrease of the stereoselectivity shows the influence of A1,2-straineffects. If the size of the group R at the radical center becomes smaller, the repulsion between R and the large substituent L at the stereogenic center decreases. As a consequence, the dihedral angle between these groups is reduced and the shielding of the syn face becomes less effective. This will be demonstrated by radicals 7 and 20. In tertiary radical 7A the P-tert-butyl substituent and the /I-H atom are on opposite faces of the
388
4.1 Stereoselectivityof Intermolecular Reaction: Acyclic Systems
TBDPSO
TBDPSO
-yR 20°C Bu3SnH
/y+ &R
C02Me
C02Me
17
602Me 19
18
a : R=CH2tBu b : R = CH2CCeH11 C
TBDPSQ
R = CH2CaH17
d: R=H
19
:
1
7
.
1
5
.
1
4
.
1
Scheme 6
a-ester plane. Thus, the bulky P substituent is far from both c( substituents and shields effectively the syn face. In contrast, P-tert-butyl and P-H are on the same side of the wester plane in secondary radical 20, because of the modest repulsion between the bulky P-substituent and the a-H atom.
Me
7A
20
anti : syn = 49 : 1
anti:syn=7:1
(Bu3SnH, -78°C)
(Bu3SnD, -78°C)
As a consequence, the tert-butyl group shields the syn face of tertiary radical 7A more effectively than that of secondary radical 20, and 7A reacts with a 49: 1, but 20 only with a 7:l anti:syn stereoselectivity. In cases where the tertiary radical yields products with a low anti:syn selectivity (for example 12A), the corresponding secondary radical 21 can even reverse the direction of the stereoselectivity [ 111.
Me
111" 12A
Preferred conformation
-
Me
21
Preferred conformation
anti : syn = 2 : 1
anti : syn = 1 : 1.4
(Bu3SnH, -78°C)
(Bu3SnD,-78%)
4.1.2 Allylic Strain tgu
tBu
tBu
M e 0 2 C yR Bu3SnH* M e 0 2 C y R C02Me
+ Me02C-R
C02Me
C02Me
23
22
389
24
a : R=Me
27
:
1
b: R=Et
17
:
1
d : R = iPr
e: R=H Scheme 7
There are exceptions to the rule that the stereoselectivity should increase with more bulky a substituents. Thus, H-abstraction reactions by radical 22 gave the II surprising result that replacing CH3 (22a) by CH2CH3 (22b), and C H Z - C C ~ H(22c) the selectivity decreases from 27: 1 via 17:1 to the inverted ratio of 1:3, respectively (Scheme 7). Nevertheless, the tertiary radical 22a is more selective than the secondary radical 22e. This effect can be explained by a preferred conformer 25. Following the A'.3strain effect, one of the H-atoms of the prostereogenic center points into the direction of the ester group and substituent R' should be anti to the bulky tert-butyl group. Thus, the shielding effect of the tert-butyl group is reduced because R' shields the opposite face. With R' = C C ~ H I(22c), I this can even give rise to a reversal of the stereoselectivity. In agreement with this model the isopropyl substituted radical 22d reacts with higher selectivity again, because the two methyl groups in conformer 26 are on opposite faces of the radical. This explanation could be proved by quantum chemical calculations [ 121.
25
26
4.1.2.2 Substituents at the Radical Center that Induce Allylic Strain In order to induce preferred conformations by A-strain effects, the substituent at the radical center should be in conjugation with the radical p-orbital, branched at the a-C atom and preferentially planar in structure.
390
4.1 Stereoselectivity of Intermolecular Reaction: Acyclic Systems
This has been successfully tested by Curran [13], Renaud [14], and Giese [5, 10, 151. The results in Table 2 demonstrate that disubstituted sp2 hybridized carbon and nitrogen functions induce stereoselectivity that can be explained by the Astrain model. On the other hand, linear ( X = CN, C1) or tetrahedral substituents ( X = Me, Me3Si, Me3Sn, S02Ph) induce only negligible selectivities in radical 27. The completely different situation of linear substituents X can be demonstrated by ab initio calculations. For X = CN, the A-strain conformation 30 is no longer favored compared to conformer 31, and the attack from both sides leads to transition states 32 and 33 that are of equal energy. With oxygen functions X at the radical center of 27 the stereoselectivity can even be reversed [lo]. Thus, radical 34
27
2a
29
Table 2. Influence of x-substituent Y on the diastereoselectivity of the reaction of 27 with Bu&H(D)
x
Y
R
28:29
OTBDPS
COMe C02Me Ph 0
CH2tBu CH2tBu Me H
>30:1 19:l 10:l 9:l"
N W
Bn
0 NO?
CHzfBu Et
"At 80°C.
6: 1 30:1
4.1.2 Allylic Strain
kCN ;-I
Me
391
SiHB
H&eMe&CN
H 19"
Me
79"
Me
tBu
CN
H
tBu
H
tBu
SiH3
30 Energy 1.2 (kcal rnol-')
31
32
33
= 0.0
0.1
= 0.0
TBDPSQ
TBDPSO
T
TBDPSQ
r 'y++
RSH
OTTMS
34
TTMS = (Me3Si)$3
OTTMS 35
OTTMS 36
1 :4
Scheme 8
yields the syn isomer 36 as major product (Scheme 8). This effect will be explained in Section 4.2.3.
4.1.2.3 Variation of the Radical Trap Although systematic studies have been performed only with H- or D-donors, other radical traps seem to follow the same trends as those discussed in Section 4.1.2. Some examples are shown in Tables 3 and 4 [ 7d, 13a, 161. It is not surprising that the degree of stereoselectivity depends upon the reagent; nevertheless the direction of the stereoselectivity of radicals 37 and 40 remains the same with Bu$n-D, Bu$%-CH2CH=CH2, Me(CN)zC-SePh, and Me(CN)2C-I. But it is conceivable that the stereoselectivity could invert in certain cases because during H- or D-abstraction reactions a very small substituent is transferred in fast reaction steps, so that early transition states are reached. Thus, radical 43 reverses the stereoselectivity if a D-abstraction is compared to an allylation reaction (Scheme 9). But the stereoselectivity in both reactions is very low [7d].
4. I Stereoselectivity of Intermolecular Reaction: Acyclic Systems
392
Bu3SnY
R
-78°C
W
C02Me
+
Y
C02Me
37
C02Me
38
39
Table 3. Diastereoselective H-abstraction and allylation reaction of radical 37 L
Stereoselectivity 38:39
R
tBu PhMezSi Ph Ph
Me Me Me OMe
BulSn-D
Bu~S~-CH~CH=CH~
7: 1 9: 1 1:1.4 4: 1
16:l 4.5: 1 1:2.8 17:l
YH
Me(CN12C
Me(CN)2C
x-Y
Me(CN)2C
m
y
+
60-80°C
Ph
Ph
40
Ph
41
42
Table 4. Diastereoselective reactions of radical 4 with different radical traps ~
x-Y
41:42
BuJSn-D Me(CN)zC-SePh Me(CN)2C-I
4: 1 4: 1 6: 1
OH
43
OH
OH
Reagent H - / \ / y + Toluene C02Et -78°C
E02Et 44 1.4 : 1 1 : 1.5
Scheme 9
C02Et 45 (Bu3Sn-D) (Bu3Sn-CH2CH=CH2)
4.1.3 Cram-Felkin-Anh Rules
393
4.1.3 Cram-Felkin-Anh Rules Ab initio calculations of Giese [I71 and Houk [18] have demonstrated that the geometry of the H-abstraction reaction by a-oxyalkyl radicals 46 resembles that of a nucleophilic addition to a carbonyl group 47. "
H*
"
"
H-
HSiH3
"
\
\*
Y - O46R
104r
ysR
y C =47 O
135'
Thus, the newly formed C,H bond at the radical center of 48 is tetrahedral in the transition state, and it is already bound slightly in the ground state as one can conclude from the a ("C) ESR coupling of 61.9 Gauss (Fig. 6).
r
61.9 Gauss
1
MeiJ3C-OSiMe3
d144' l
Me
48
a (13C) : 61.9 Gauss
H,,..CAiPr Me$%OSi(SiMe3)3
I
Ph
49
a (13C) : 61.4 Gauss
Figure 6. ESR spectrum of radical 48
This similarity of transition state geometries of a-oxyalkyl radicals and carbonyl groups suggests that the Felkin-Anh rule should be applicable also in radical chemistry. This is actually the case. The transition state 50A of chiral radical 50 is about 1.5 kcal/mol lower in energy than 50B. HSiH3
63" 41"
65" Me 48" ;
60"
Ph
50A
HSiH3 50B
394
4. I Stereoselectivity of Intermolecular Reaction: Acyclic Systems
Ph 49 Ig = 7.7 Gauss
(Me3Si)3Si
Figure 7. ESR spectrum of radical 49
Again, the radical is already bent in the ground state (Fig. 7). In accord with these calculations and ESR measurements, radical 51 leads predominantly to 52a (Scheme 10). OR Me Ph 51
3 HSi(SiMe3)3 0°C , ,M+
OR
+
My-,,
Ph 52a
Ph 75 : 25
52b
R = Si(SiMe3)3
Scheme 10
It is interesting to see that the classical experiments of Cram with ketone 53a-c and LiAlH4 have a radical counterpart with (Me3Si)3SiH as reagent, which leads to oxyalkyl radicals 56 as intermediates (Scheme 11). The Felkin-Anh rule can also be applied to the formation of C,C bonds as Curran and Giese have shown starting from bromide 57 as radical precursor (Scheme 12). In summary, one can say that the Felkin-Anh rule is applicable to oxyalkyl radicals but the asymmetric induction is in most cases only moderate.
4.1.4 Chiral Alkenes as Radical Traps This Section is focussed on substrate-induced diastereoselectivity in reaction between achiral radicals and chiral, acyclic alkenes. The influence of chiral auxiliaries
4.1.4 Chiral Alkenes as Radical Traps
395
OH
0
53
54
55
Cram
anti-Cram
*E l OSi(SiMe3)3
53 (Me3Si)3SiH
54' + 55'
H S; : ;H
fBuON=NOfBu
b : iPr
12.6:1
C : tBu
5.3:1
Scheme 11
-
QAc
-SnBu3
/
f
B
.
+
&B ,uf
80°C AlBN
t B U y v \ \
Me
7 Br
58a
Me
4:l
58b
Me
57
-
OAc
@CN
Bu3SnH/80"C AlBN
CN + B t U+
tBu+ Me
59a
CN Me
4:l
59a
Scheme 12
will be described in Chapter 4.3 and the enantioselective trapping of achiral radicals is a topic of Chapter 4.5. Acyclic alkenes with a stereogenic substituent at the carbon atom undergoing attack can react stereoselectively with radicals. Thus, the addition of R',generated by sonolysis of RI in the presence of Zn/Cu, to alkene 60 yields products 61a and 61b. With increase of the bulk in the radical trap and the radical R',the amount of product 61b increases. If both substituents are tert-butyl groups, then the reaction yields only one diastereomer (Table 5) [19]. This 1,2-stereoinduction (60 4 61b) is surprising because alkene 60 adopts the A',3-strain conformation 60A. Therefore, according to the reactions of ester sub-
4. I Stereoselectivity of Intermolecular Reaction: Acyclic Systems
396
61a
60
61b
Table 5. Diastereoselectivity of the radical addition of R-I to alkene 60 L
R
61a:61b
Yield (%)
tBu
tBu iPr Ph Et Me tBu tBu
<1:99 3197 1496 5050
35 50 75 20 50 45 61
iPr Et
62:38 14:86 30:70
stituted radicals, addition anti to the shielding group L should give 61a as main product. But ab initio calculations have shown that Felkin-Anh transition state 60B which leads to 61b is of lowest energy.
C(CN)2 Me/--
I
-
61b
L
60A
preferred ground state
transition state from 60B
The reason for this unexpected stereochemistry is that the tetrahedral attack of the radical is shielded by the methyl- and the L substituents in the A-strain conformation to such a degree that a reaction after rotation to a conformation where hydrogen is the shielding substituent is energetically favored. Thus, the main product is formed from the less stable but more reactive conformer. This is a case, described by the Curtin-Hammett principle, where the transition states and not the ground states govern the stereoselectivity of the reaction [20]. If both L and R are tert-butyl groups, ab initio calculations show that the FelkinAnh transition state 62B is much lower in energy than 62A. Only with the small methyl radical does alkene 60 react via its A1>3-strain conformer 63A, which has a slightly lower energy than the Felkin-Anh conformer 63B.
4.1.4 Chiral Alkenes as Radical Traps
397
Energy
\ 60A
*
I
Reaction coordinate
Figure 8. Transition states for the addition of R. to alkene 60.
tBu;
61a
-
H &(CN)z . Me j’ tBu’
Energy (kcal rnol-’)
=
C(CN)z H
-
-
61b
tBu
62A
628
8.6
0.0
Me
63A
Energy = 0.0 (kcal rnol-’)
63B 0.3
Interestingly, the silyloxy-substituted alkene 64 yields predominantly 65a, but the 1,2-induction is relatively low (Scheme 13). According to X-ray analysis alkene 64 adopts conformation 64A. The face anti to the bulky siloxy group is open for a tetrahedral attack of radical R,and 66A is the transition state of lowest energy.
398
4.1 Stereoselectivity of Intermolecular Reaction: Acyclic Systems
9 R-1
TBDPSOTCN
~
TBDPSOTCN
Zn / Cu ((((
CN
=
20°C
64
+
TBDPSO
=
CN 65a
R = tBu
CN 65b
8 5 : 15
(67%)
~ B u67133
(41%)
Scheme 13
R;
Me 91"
,,
C(CN)2
TBDPSO H A i W ) z
TBDPSO
64A
-
65a
66A
Both alkenes 67 and 68, synthesized from L-glyceraldehyde react to give predominantly product 69b. Whereas the E-alkene 67 in most cases shows only moderate stereoselectivity, 1,2-~tereoinductionfor Z-alkene 68 is high (Table 6). The reaction of E-alkene 67 could occur via Felkin-Anh transition state 70 whereas an A-strain transition state 71 might explain the 1,2-stereoinduction with Z-alkene 68 [21].
67
.C02R
X-H
+
___)
AlBN ~ ~ ~ c o 2 0 - 8 0 0 C
.C02R
69a
69b
68
Table 6. Diastereoselectivity of the radical addition to alkenes 67 and 68 X-H
Alkene
69a:69b
Yield ("/o)
(Me3Si)3Si-H PhlHSi-H BuiSn-H c C ~ HI/Bu,SnH I PhzHSi-H 1/Bu3SnH
67 67 67 67 68 68
2:98 30:70 30:70 40:60 9:91 6:94
95 69 93 65 75 82
References
Felkin-Anhtransition state
399
A-strain transition state
References [ l ] N. A. Porter, B. Giese, D. P. Curran, Acc. Chem. Res. 1991, 24, 296. [2] D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of Radical Reactions VCH, Weinheim 1996. [3] R. W. Hoffmann, Chem. Rev. 1989,89, 1841. [4] (a) D. J. Hart, H.-C. Huang, R. Krishnamurthy, T. Schwartz, J. Am. Chem. Soc. 1989, 111, 7507; (b) D. J. Hart, R. Krishnamurthy, Synlett 1991, 412. [5] B. Giese, M. Bulliard, H.-G. Zeitz, Synlett 1991, 425. 161 B. Giese, W. Damm, F. Wetterich, H.-G. Zeitz, Tetrahedron Lett. 1992, 33, 1863. [7] (a) D. J. Hart, H.-C Huang, Tetrahedron Lett. 1985, 26, 3749; (b) Y. Guindon, J.-F. LaVallee, L. Boisvert, C. Charbot, D. Delorme, C. Yoakim, D. Hall, R. Lemieux, B. Simmoneau, Tetrahedron Lett. 1991, 32, 27; (c) B. Kopping, C. Chatgilialoglu, M. Zehnder, B. Giese, J. Org. Chem. 1992,57, 3994; (d) D. J. Hart, R. Krishnamurthy, J. Org. Chem. 1992,57, 4457. [8] Y. Guindon, C. Yoakim, R. Lemieux, L. Boisvert, D. Delorme, J.-F. Lavallee, Tetrahedron Lett. 1990, 31, 2845. [9] B. Giese, W. Damm, F. Wetterich, H.-G. Zeitz, J. Rancourt, Y. Guindon, Tetrahedron Lett. 1993,34, 5885. [lo] B. Giese, M. Bulliard, J. Dickhaut, R. Halbach, C. Hassler, U. Hoffmann, B. Hinzen, M. Senn, Synlett 1995, 116. [ 1 I ] B. Giese, W. Damm, R. Batra, Chemtructs-Organic Chemistry 1994, 7, 355. [ 121 B. Giese, W. Damm, T. Witzel, H.-G. Zeitz, Tetrahedron Lett. 1993, 34, 7053. [I31 (a) D. P. Curran, G. Thoma, J. Am. Chem. Soc. 1992, 114, 4436; (b) D. P. Curran, A. C. Abraham, Tetrahedron 1993, 49, 4821; (c) D. P. Curran, P. S. Krishnamoorthy, Tetrahedron 1993, 49, 4841. [I41 (a) P. Renaud, P. Bjorup, P.; Carrupt, P.-A,; Schenk, K.; Schubert, S. Synlett 1992, 211.; (b) Schubert, S.; Renaud, P.; Carrupt, P.-A,; Schenk, K. Helv. Chim. Acta 1993, 76, 2473. [15] (a) B. Giese, M. Bulliard, H.-G. Zeitz, Synlett 1991, 425; (b) W. Damm, U. Hoffmann, L. Macko, M. Neuburger, M. Zehnder, B. Giese, Tetrahedron 1994, 50, 7029. [I61 K. A. Durkin, D. C. Liotta, J. Rancourt, J.-F. Lavallee, L. Boisvert, Y. Guindon, J. Am. Chem. Soc. 1992, 114, 4912. [I71 W. Damm, J. Dickhaut, F. Wetterich, B. Giese, Tetrahedron Lett. 1993, 34, 431. [I81 J. E. Eksterowicz, K. N. Houk, Tetrahedron Lett. 1993, 34, 427. 1191 B. Giese, W. Damm, M. Roth, M. Zehnder, Synlett 1992, 441. [20] M. Roth, W. Damm, B. Giese, Tetrahedron Lett. 1996, 37, 351. [21] (a) W. Smadja, M. Zahouily, M. Malacria, Tetrahedron Lett. 1992,33, 551 1; (b) T. Morikawa, Y. Washio, M. Shiro, T. Taguchi, Chem. Lett. 1993, 249.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
4.2 Stereoselectivity of Radical Reactions: Cyclic Systems Philippe Renuud
4.2.1 Introduction Cyclic radicals are very often involved in the key step of a reaction sequence. They are particularly useful since the stereochemical outcome of their reactions can be easily predicted and in some cases directed. Selected examples from the recent literature have been chosen in order to illustrate the different factors governing the stereochemical outcome. The importance of steric effects, conformational effects, neighboring prochiral centers, pyramidalization, stereoelectronic effects and position of the transition states will be discussed based on examples of synthetic importance.
4.2.2 The anti Rule Cyclic radicals can only exist in a reduced number of conformations relative to acyclic ones. Therefore, prediction of the stereochemistry is simplified. As nicely documented in two excellent review articles [ l , 21, the anti rule could be applied with great success to many cases of cyclic radicals: reactions occur preferentially in unti fashion to the substituents present in the cyclic moiety. This simple model is based on minimization of steric interactions in the transition state and is particularly efficient when the conformation of the radical intermediate is known.
4.2.2.1 Four-Membered Rings Excellent stereocontrol is observed in reactions of four-membered rings. For instance, methyl a-allylpenicillinate 1,l-dioxide is formed as a single isomer via radical allylation (Scheme 1, Eq. 1.1) [3]. Interestingly, the p-isomer was obtained when a gem-dibromide was used as radical precursor (Scheme 1, Eq. 1.2). In this approach, the stereochemistry is established during the reduction of the intermedi-
4.2.2 The anti Rule
H
Ho
0
401
CH2=CHCH2SnBu3 AIBN, 80 "C *
Br,HJ 0 COOMe
(1.1)
93% COOMe
Scheme 1
ate a-allyl-a-bromolactam. The stereochemistry of all radical reactions depicted in Scheme 1 is in accordance with the anti rule (model 1).
4.2.2.2 Five-Membered Rings Excellent stereocontrol is usually observed in 5-membered ring systems. For instance, the allylation of the 2-bromolactone depicted in Scheme 2 (Eq. 2.1) gave the trans compound as a single isomer [4].The ionic allylation of the dianion of the corresponding lactone gave an 88:12 translcis mixture of isomers. The high anti selectivity in five-membered rings has been utilized during the synthesis of (-t)botryodiplodin [ 5 ] . The key step of this approach is depicted in Scheme 2 (Eq. 2.2). Cyclization of a gem-dibromide gave a cyclic 3-bromofuran as a mixture of isomers. Reduction of this intermediate with a bulky silane afforded the desired all-cis tetrahydrofuran with good stereocontrol. Interestingly, direct preparation of the final
CH2=CHCH2SnBu3
Qo CbzHN'
*
AIBN,8O0C 82%
Br
(2.1)
CbzHN'
Bu3SnH Et3B. 02,-78OC
[
EtO
ofH
1
(TMS)3SiH Et36, 0 2 , -78 "C
(2.2)
62% overall yield cisltrans 88: 12
Scheme 2
EtO
402
4.2 Stereoselectivity of Radical Reactions: Cyclic Systems EtO
t-BuNC
r/'
0
o-(OEt
Bu3SnCI, NaBH3CN t-BuOH, reflux
71% (one diastereorner)
, .
TBDMSO-'
TBDMSO
-
-
Q
TBDMS~
(3.1)
CN
EtopCOOH
0
PhMezSiCH2COOH
o-(OEt
-e
(3.2) 30% dr81:19
AcO
Acd
SiMezPh
Scheme 3
product by radical cyclization of the corresponding monobromide produced a mixture of four diastereoisomers. The diastereoselectivity is particularly high when fused systems with bent structures are involved. For example, Stork has developed a highly diastereoselective approach to prostaglandins based on a fused cyclopentyl radical intermediate (Scheme 3, Eq. 3.1) [ 6 ] .This approach has been extended to a radical-radical coupling reaction by Schiifer based on a mixed Kolbe electrolysis (Scheme 3, Eq. 3.2) [7]. The stereoselectivity of this reaction (transleis 81:19) is still remarkably good for a highly exergonic radical coupling reaction occurring through an early transition state.
4.2.2.3 Six-Membered Rings Six-membered ring radicals have been investigated in detail because of their importance in carbohydrate chemistry [2]. Model systems have been examined to clarify the different effects involved in the stereochemical control [S]. With psubstituted cyclohexyl radicals, the anti rule is still valid. The level of anti attack is usually higher when the p-substituent is axial rather than equatorial. The stereoselectivity is modulated by 1,3-diaxial interactions favoring the equatorial attack and torsional effects favoring the axial attack (Scheme 4, radicals 2 and 3). As a consequence, small reagents tend to favor axial selectivity and large reagents equatorial selectivity. For example the reductive alkylation of enamines provides an excellent level of cis stereoselectivity. This has been rationalized by transition state 4 where the sulfonylmethyl group occupies an axial position to minimize allylic strain with the N,N-dialkylamino moiety (Scheme 4, Eq. 4.1) [9].
4.2.3 Conjormation of Cyclic Compounds
anti (e)
trap
antilsyn
@CN
79:21
*CN 2
>95:5
t SYn (a)
6. H
t-Bu
@CN
syn(e)
3
403
t
*CN
923 87:13
anti (a)
I
anti
Scheme 4
4.2.2.4 Effect of Additives When the substituents in the ring are not large enough, only moderate stereocontrol is obtained. By using additives capable of binding to the substituent in a covalent or non-covalent way, it is possible to reach a very high level of stereoselectivity. Two such cases are depicted in Scheme 5. In the first one (Eq. 5.1), the very bulky and oxophilic Lewis acid MAD [ = methylaluminum di(2,6-di(tert-butyl)-4-methylphenoxide)] was used to complex the oxygen atom of the sulfinyl group [lo]. In the second example (Eq. 5.2), a free hydroxyl group was allowed to react with the same MAD to form an aluminum alkoxide prior to carrying out the radical allylation [ I I]. The reaction is then essentially occurring in an unti mode (antilsyn 99:l). It is of interest to mention that bulky silyl protecting groups do not provide such a high level of stereocontrol.
4.2.3 Conformation of Cyclic Compounds As expected, the conformation of the cyclic compounds has a strong influence on the stereochemical outcome of radical reactions [ 121. Nagano has reported an illustrative example of this effect during his study aimed at the synthesis of mag-
404
4.2 Stereoselectivity of Radical Reactions: Cyclic Systems
0I
6 S e P h
CH2=CHCH2SnBu3 AIBN, 80 "C Lewis acid
0I
(si+
(5.1)
no Lewis acid: 63%, translcis 82:18 1.1 eq. MAD: 8O%, translcis 99:l
,,,,,1 OH
CH2=C(COOMe)CH2SnBu3 AIBN, sun lamp, 10 "C additive
MeOOC ,1111
)=
(5.2)
OH no Lewis acid: 66%, translcis 5446 1.1 eq. MAD: 69%, translcis 99:l
Scheme 5
ydardienediol. The cyclization-trapping reaction of the trans-cyclohexene derivative is completely stereoselective (Scheme 6, Eq. 6.1) [13]. A similar reaction with a cisconfigured cyclohexene afforded a mixture of isomers (Eq. 6.2) [14]. The strong effect of a very remote substituent could be explained by examining the conformation of the transient cyclic radicals 5 (Eq. 6.1) and 6 (Eq. 6.2). The two intermediate radicals are in inverted chair conformations. Radical 5 reacts then exclusively in an anti mode because the nearest substituent is axial; radical 6 gives rise to a mixture of diastereomers because the adjacent substituent is equatorial. Conformational effects have also been invoked to explain some inverted temperature dependence of radical reactions. Liining has examined the stereoselectivity of the radical addition of N-bromophthalimide to cyclohexene (Scheme 7) [ 151. Higher trans selectivities were observed at elevated temperatures. The existence of two radical conformers in equilibrium explains this outcome. At low temperature, the reaction occurs exclusively through the most stable equatorial conformer 7; however, this conformer does not react with very high selectivity. The pathway via the less stable axial conformer 8 becomes accessible at higher temperature and is highly anti selective. Recently, it has been shown by Rychnovsky that slow conformational interconversion can be an important factor in the reaction of simple 2-tetrahydropyranyl radicals [ 161. These non-equilibrium radical reactions provide a strategy for the
4.2.3 Conformation of Cyclic Compounds
nph CH2=CH2COOMe BuaSnCI, NaBH3CN AIBN. 80 "C
M
e
O
C
n Ph
(6.1)
F
63%, dr >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:<20 (TCP = tetrachlorophthalirnide)
Scheme 14
Bertozzi has reported a very elegant approach to CI- and p-C glycosides of Nacetylglucosamine via tin-mediated radical allylation (Scheme 14) [38]. The stereochemical outcome of the reaction was essentially controlled by the anomeric effect when the N-acetyl derivative was used (alp 1O:l). However, by using a large amino protecting group such as TCP (= tetrachlorophthalimide), the stereochemical outcome could be reversed and the p-isomer was predominant. This clearly demonstrates that even if anomeric effects are playing a major role in controlling the stereochemical outcome at the anomeric position, proper choice of protecting groups still allows reversion to steric control (anti rule).
4.2.7 Position of the Transition State The contribution of the transition state position is usually not discussed as a main factor in controlling the stereochemistry of a radical reaction. However, its importance was recently raised in several publications. Moreover, the reactivity-selectivity principle proposed by Giese to rationalize the influence of the radical trap on the stereochemical outcome of 2-substituted cyclopentyl radicals [ 391 could also be considered as an influence of the transition state position (Scheme 15): in early transition states (reactive olefins such as fumarodinitrile) the reagent is far away from the radical center and the face discrimination is low. With less reactive olefins such as styrene, a later transition state is occurring and the product stability starts to influence the stereochemical outcome. Therefore, the most stable trans disubstituted cyclopentanes are produced with a higher degree of stereocontrol. This effect starts to be even more important when the kinetic and thermodynamic products of a reaction are different diastereoisomers. Three examples of this type R1
R2
NaBH4
\O~%
t
Scheme 15
R’ CN H H H
R2
CN CN COOMe Ph
trans /cis
60:40 77:23 88:12
9O:lO
4.2.7 Position of the Transition State
41 I
cis
trans
M-H = cyclohexane: transkis 8 9 : l l M-H = c-CeHlIHg-H: transkis 3:97 Scheme 16
RSnBu3, AIBN, 80 OC Ph
X = P-ToIS, CI
trans
cis
R = D, transkis 4.6:l R = CH2=CHCH2,trandcis 1:l
0
0
0
0
PrK O
Pr K O
Pr K O
Pr K O
mo
i
early TS
m0*
late TS
7
+2.2 kcallrnol
I
MHf 0 kcal/mol
Scheme 17
are depicted in Schemes 16-18. For instance, Metzger reported that trapping of the disubstituted succinyl radical with cyclohexylmercuric hydride afforded the kinetic cis product with good diastereoselectivity (Scheme 16) [23]. When cyclohexane (a bad hydrogen donor relative to mercuric halide) was used, the reaction was proceeding through a much later transition state and the thermodynamic trans compound was formed preferentially. Beckwith has examined the reaction of 3-acyloxytetrahydropyran-2-yl radical [34b].The reduction with tin hydride occurs via an early transition state and affords the trans compound with good stereocontrol (Scheme 17). Interestingly, the allylation reaction is not stereoselective. This was attributed to a much later transition state favoring the formation of the most stable cis compound (according to calculations, the trans isomer bearing the acyloxy group in the axial position is less stable by 2.2 kcal/mol than the cis isomer). Finally, the stereoselectivity of the alkylation of dioxolanyl radicals was studied. Interestingly, the reactions became more selective when the reactivity of the radical trap was enhanced (Scheme 18) [40]. This is clearly contrary to the reactivityselectivity principle and is best explained by the position of the transition state.
412
4.2 Stereoselectivity of Radical Reactions: Cyclic Systems
R'
R2
trandcis
H C6H13 H COOMe COOMe COOMe
10:1 15:l 23:l
I
+2.1 kcallmol
0 kcallmol
AIBN, 80 "C
I (18.2)
R
R
R = H, translcis 2:l R = Me, translcis 7:l Scheme 18
MeOOC
MeOOC Bu3SnH, AIBN, 80 "C
(19.1)
OSiPh2Me
H Z
Bu3SnH,AIBN, 80 "C
(19.2)
0
Scheme 19
4.2.7 Position of the Transition State
41 3
Indeed, early transition states favor the kinetic trans compound (reactive radical trap such as dimethyl fumarate). When later transition states are involved (octene case), the stability of the final products starts to influence the stereochemical outcome, and since the cis product is more stable than the trans, the diastereoselectivity of the process becomes lower. The same interpretation could also be used to rationalize the results depicted in equation 18.2 [41a]. Indeed, the allylation reaction is occurring via a relatively late transition state. Therefore, when R = H the stereoselectivity is low because the cis final product is more stable than the trans. When R = Me, the cis and trans products have almost the same stability, therefore the influence of the transition state position on the stereochemical outcome vanishes and the diastereoselectivity is higher.
Bu3SnH, AIBN, 80 "C *
(0o&%'OOBn
(& o 0
I H
OBn
(20.1)
0
0
Ph3SnH Et& 0 2 , -20"C (20.2)
I
f-BU
\
(TMS)3SiH AIBN, 100°C
(20.3)
X = Br, 46%
Y
f-BU
Sn-H
Scheme 20
4 14
4.2 Stereoselectivity of Radical Reactions: Cyclic Systems
4.2.8 Polycyclic Systems Radical cyclization reactions have proven to be a very efficient approach for polycyclic natural product synthesis. In many cases, the last step involves a reduction of a cyclic radical with formation of a new stereogenic center. Very good stereochemical control has been achieved with such polycyclic radicals. For example, Beckwith has reported a highly stereoselective formation of a quinolizidine ring (Scheme 19, Eq. 19.1) [41b]. This process is the key reaction in a four-step synthesis of epilupinine and the stereochemical outcome results from a stereoselective axial reduction by tin hydride of a bicyclic radical. In a related process, Tsai has prepared silylated hydroxyquinolizidine by radical cyclization to an acylsilane followed by a radical-Brook rearrangement (Scheme 19, Eq. 19.2) [42]. Rigby has developed a fully stereoselective formation of the tetracyclic core of erysotrine [43]. A similar reaction was used later by Schultz as key step for the synthesis of (+)-lycorine (Scheme 20, Eq. 20.1) [44]. The last stereogenic center is established during the axial reduction of the tetracyclic radical by tin hydride. Very interestingly, Hallberg has been able to control the stereochemical outcome in tricyclic systems. For instance, tin hydride favors the formation of the trans ring junction (axial reduction of the most stable conformer) (Scheme 20, Eq. 20.2) whereas the bulky (TMS)3SiH prefers equatorial reduction of a less stable conformation to avoid destabilizing diaxial interactions (Scheme 20, Eq. 20.3) [45].
References [ I ] B. Giese, Angew. Chem. Znt. Ed. Engl. 1989, 28, 969-1146. [2] D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of Radical Reactions; VCH: Weinheim, 1995. [3] S. Hanessian, M. Alpegiani, Tetrahedron 1989, 45, 941-950. [4] S. Hanessian, B. Vanasse, H. Yang, M. Alpegiani, Can. J. Chem. 1993, 71, 1407-1411. [5] F. Villar, 0. Andrey, P. Renaud, Tetrahedron Lett. 1999, 40, 3375-3378. [6] G. Stork, P. M. Sher, H.-L. Chen, J. Am. Chem. Soc. 1986, 108, 6384-6385. [7] J. Weiguny, H. J. Schafer, Liebigs Ann. Chem. 1994, 235-242. [8] W. Damm, B. Giese, J. Hartung, T. Hasskerl, K. N. Houk, 0. Huter, H. Zipse, J. Am. Chem. Soc. 1992,114,4067-4079. [9] P. Renaud, S. Schubert, Angew. Chem. Int. Ed. Engl. 1990, 29, 433-434. [ 101 P. Renaud, N . Moufid, L. H. Kuo, D. P. Curran, J. Org. Chem. 1994,59, 3547 -3552. [ I l l N. Moufid, P. Renaud, Helu. Chim. Acta 1995, 78, 1001-1005. [I21 D. Horton, W. Priebe, M. L. Sznaidman, J. Org. Chem. 1993, 58, 1821-1826. [13] H. Nagano, K. Yamada, N. Hazeki, Y. Mori, T. Hirano, Bull. Chem. Soc. Jpn. 1992, 65, 2421 -2426. [I41 H. Nagano, Y. Seko, K. Nakai, J. Chem. Soc. Perkin Truns. I 1991, 1291-1295. [I51 A. Kirsch, U. Luning, 0. Kriiger, J. Prakt. Chem. 1999, 341, 649-656. [16] A. J. Buckmelter, J. P. Powers, S. D. Rychnovsky, J. Am. Chem. Soc. 1998, 120, 5589-5590. [I71 L. Colombo, M. Digiacomo, G. Papeo, 0. Carugo, C. Scolastico, L. Manzoni, Tetrahedron Lett. 1994, 35, 403 1-4034.
References
41 5
[IS] B. Giese, M. Hoch, C. Lamberth, Tetrahedron Lett. 1988, 29, 1375-1378. [ 191 B. Giese, W. Damm, T. Witzel, H. G. Zeitz, Tetrahedron Lett. 1993, 34, 7053-7056. [20] M. Bulliard, M. Zehnder, B. Giese, Helu. Chim. Acta 1991, 74, 1600-1607. [21] N. Ono, Y. Yoshida, K. Tani, S. Okamoto, F. Sato, Tetrahedron Lett. 1993, 34, 6427-6430. 122) H. Urabe, K. Kobayashi, F. Sato, J. Cham. Soc.. Chem. Commun. 1995, 1043-1044. [23] J. 0. Metzger, K. Schwarzkopf, W. Saak, S. Pohl, Chem. Ber. 1994, 127, 1069-1073. [24] J . R. Axon, A. L. J . Beckwith, J. Chem. Soc., Chem. Commun. 1995, 549-550. [25] D. Seebach, B. Lamatsch, R. Amstutz, A. K. Beck, M. Dobler, M. Egli, R. Fitzi, M. Gautschi, B. Herradon, P. C. Hidber, J. J. Irwin, R. Locher, M. Maestro, T. Maetzge, A. Mourino, E. Pfammatter, D. A. Plattner, C. Schickli, W. B. Schweizer, P. Seiler, G. Stucky, W. Petter, J. Escalante, E. Juaristi, D. Quintana, C. Miravitlles, E. Molins, Helu. Chim. Acta 1992, 75, 9 13-935. [26] T. W. Badran, C. J. Easton, E. Horn, K. Kociuba, B. L. May, D. M. Schliebs, E. R. T. Tiekink, Tetrahedron: Asymmetry 1993, 4, 197-200. [27] D. Crich, S. Natarajan, J. Org. Chem. 1995, 60, 6237-6241. 1281 C. L. L. Chai, A. R. King, J. Chem. SOC.Perkin Trans. I 1999, 1173-1182. [29] H. M. Walborsky, Tetrahedron 1981, 37, 1625-1651. [30] M. Gerster, P. Renaud, Angew. Chem. Int. Ed 1996, 35, 2396-2399. [31] M. Gerster, P. Renaud, Synthesis 1997, 1261-1267. [32] D. L. J. Clive, X. He, M. H. D. Postema, M. J. Mashimbye, J. Org. Chem. 1999, 64, 43974410. [33] D. H. R. Barton, W. Hartwig, W. B. Motherwell, J. Chem. Soc., Chem. Commun. 1982, 447448. H.-G. Korth, R. Sustmann, J. Dupuis, B. Giese, J. Chem. SOC.Perkin Trans. 2 1986, 1453-1459. [34] (a) A. L. J. Beckwith, P. J. Duggan, Tetrahedron 1998, 54, 4623-4632. (b) A. L. J. Beckwith, P. J. Duggan, Tetrahedron 1998, 54, 6919-6928. [35] B. Giese, J. Dupuis, M. Nix, Organic Synthesis 1987, 65, 236-242. [36] B. Giese, Pure Appl. Chem. 1988, 60, 1655-1658. [37] C. Ollivier, P. Renaud, J. Am. Chem. Soc. 2000, 122, 6496-6497. [38] B. A. Roe, C. G. Boojamra, J. L. Griggs, C. R. Bertozzi, J. Org. Chem. 1996, 61, 6442-6445. [39] B. Giese, K. Heuck, H. Lenhardt, U. Luning, Cizen?. Ber. 1984, 117, 2132-2139. [40] S. Abazi, L. Parra Rapado, P. Renaud, manuscript in preparation. [41] (a) A. L. J. Beckwith, C. L. L. Chai, Tetrahedron 1993, 49, 7871 -7882. (b) A. L. J. Beckwith, S. W. Weswood, Tetrahedron 1989, 45, 5269-5282. [42] Y. M. Tsai, H. C. Nieh, J. S. Pan, D. D. Hsiao, Chem. Commun. 1996, 2469-2470. [43] J. H. Rigby, M. Qabar, J. Am. Chew. Soc. 1991.113, 8975-8976. [44] A. G. Schultz, M. A. Holoboski, M. S. Smyth, J. Am. Chem. Soc. 1996, 118, 6210-6219. [45] L. Ripa, A. Hallberg, J. Ory. Chem. 1998, 63, 84-91.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
4.3 Chiral Auxiliaries Ned A. Porter
4.3.1 Background The control of the configuration of new stereogenic centers formed in free-radical transformations is now well established. For purposes of discussion, strategies used to control new stereogenic centers have been divided into categories according to whether the stereo-controlling element is subsequently removed from the product of reaction or rather is retained in the product [ 11. If a stereochemistry-controlling substructure is subsequently removed from the product, it is designated a ‘chiral auxiliary’ and the reaction is said to be under chiral-auxiliary control. If the stereocontrolling element is retained in the product, the reaction is said to be ‘substrate-controlled’. A final definition, ‘reagent-controlled’ indicates a reaction in which the stereochemistry-controlling element is not attached to the molecule or radical from which the new stereogenic center is formed. These definitions were developed for important non-radical synthetic reactions such as transformations of enolates, concerted cycloadditions, and allylic epoxidations, but they apply equally well to radical transformations. Indeed, examples of each of these strategies have been observed in free-radical transformations. A general analysis of a radical reacting with a radical trap is described in Eqs. (1) and (2) [2]. In Eq. (1) a prostereogenic radical is shown to react with a radical trap, ‘C’, to give a product with a new stereogenic center. In the transformation described in Eq. (2), it is the reaction of radical ‘C’ with a trap having prostereogenic faces that gives a product with a new stereogenic center. Most of the examples that use ‘chiral auxiliaries’ in radical transformations involve radical addition reactions, and the trap shown in Eq. (2) involves an addition reaction to an unsaturated substructure. Chiral-auxiliary control in radical addition reactions is presented in a general format in Eqs. ( 3 ) , (4) and (5). In these equations, a* or d* represents a resident group which has a stereogenic center that controls the configuration of the new center formed in the transformation. In Eq. ( 3 ) , the resident stereogenic center resides on the radical. In Eq. (4), the resident center is attached to the radical trap at the site of unsaturation undergoing reaction, while in Eq. ( 5 ) , the center resides on the unsaturated radical trap at a site remote from the unsaturated center undergo-
4.3.I Background
417
b
ing addition. If a* or d* are good stereocontrol elements, subsequent reaction of the group to remove the auxiliary and generate the group designated by ‘e’ provides a product with controlled configuration of the new stereogenic center.
4.3.1.1 Radical Addition Reactions The addition of carbon radicals to carbon-carbon double bonds is, perhaps, the single most important radical transformation [ 31. This reaction is discussed elsewhere in this volume, but, because of the importance of addition reactions in the development of the use of chiral auxiliaries, a few background comments are made here. Typical carbon radicals are nucleophilic and undergo reaction more readily with electron-deficient than with electron-rich compounds. For alkene addition reactions, therefore, substitution of electron-withdrawing groups on the alkene increases the rate of radical addition relative to the unsubstituted parent compound. Groups attached to the alkene at the center undergoing radical attack, X in Eq. (6), influence the rate of addition by both polar and steric effects [ 3 ] .Thus, electronwithdrawing groups at X promote the addition of carbon radicals while large bulky groups in that position retard the rate of addition. On the other hand, groups remote from the site of radical attack influence the rate of radical addition mostly by polar effects. Thus, Z groups such as -CN, -COOR, and -COR promote the addition of
4 18
4.3 Chiral Auxiliaries
carbon radicals to the olefin and the size of the remote substituent is understandably of limited importance.
Activation of an alkene to enable addition of carbon radicals may be achieved by complexation of the alkene undergoing addition to an electron-deficient species such as a Lewis acid. This strategy has been used extensively in the activation of dienophiles towards cycloadditions, and the reasons for its efficacy in both cycloaddition and radical addition have the same roots. In a Diels-Alder reaction [4]with ‘normal’ electron demand, the dominant frontier orbital interaction is between the HOMO of the diene and the LUMO of the dienophile. Complexation of a Lewis acid to the dienophile lowers its LUMO and magnifies the important frontier MO interaction. For addition of nucleophilic radicals to an alkene, the dominant interaction is between the SOMO of the radical and the LUMO of the olefin. Complexation of a Lewis acid to the alkene lowers its LUMO and magnifies the SOMO-LUMO interaction [3a]. Thus, one expects that the rate of addition of carbon radicals to alkenes should be dependent on the presence of Lewis acid if that alkene is capable of complexation to Lewis acid. The important processes for such a reaction are shown in Eqs. (7)-(9).
Lewis Acid = M0
In the reactions described in Eqs. (7)-(9), the unactivated alkene adds the radical with some rate constant, ko, while the alkene complexed to a Lewis acid, adds the radical with some rate constant k,. For a maximum effect of Lewis acid on the reaction, k, should be much greater than ko and the equilibrium constant K should be
4.3.I Background
4 19
very large. Should both of these conditions be met, Lewis acid will have a dramatic kinetic effect on the addition process relative to other reactions that the radical may undergo. Another point to be made in Lewis acid-promoted additions is that for most systems of the type shown in Eqs. (7)-(9), there will be a ‘background’ reaction of addition that is independent of Lewis acid. In the special case in which a Lewis acidpromoted reaction occurs stereoselectively while the background reaction does not, it is essential that the rate and equilibrium constants for the system are such that the ‘background’ reaction is minimized, since this reaction will degrade the overall stereocontrol of the transformation.
4.3.1.2 Radical Propagation A host of different propagation sequences have been used to examine the efficacy of chiral auxiliaries in radical transformations. A few of the more common sequences are outlined here with particular advantages and disadvantages associated with each indicated. Among the most common propagation sequences used is the reaction of alkyl halides or selenides with trialkyltin hydride [3a]. This reaction has been used extensively in the examination of stereoselection in reactions such as those outlined in Eqs. (4) and (5). As an example, shown in Eq. (lo), is the tinhydridemediated addition of an alkyl radical to an alkene radical trap. This sequence is usually efficient and leads to moderate to good yields of addition product, but a drawback of the approach is that a large excess of alkene is frequently required in the reaction. Tin hydride can usually be replaced by commercially available tristrimethylsilylsilane, thus avoiding the use of toxic reagents [ 51.
RX
+
d*
a*
H
b
>=(
+
Bu3SnH
-
* d*CH,R< .;a
b
+
Bu3SnX
Allylstdnnanes and allylsilanes have also been used in propagation sequences to assess chiral auxiliary groups. Ally1 transfer reactions involving these reagents have been particularly helpful in assessing the effect of auxiliaries attached directly to a reacting radical (see Eqs. 3 and 11). An addition reaction that is coupled to allyl transfer from stannane or silane with the stereochemistry being set in the addition to the transfer agent is shown in Eq. (1 I). For the stannane reaction, transfer occurs by a simple addition-fragmentation of the allyl group, trialkyltin radical being readily formed by p fragmentation of the adduct (Eq. 12). Atom transfer reactions have proven to be particularly useful in radical transformations, and these reactions have been used to examine the efficacy of chiral auxiliaries. Atom transfer addition, sometimes called the Kharasch-Curran reaction, has been the focus of extensive investigation in recent years [6]. This transformation results in the addition of R-X to a carbon-carbon double bond. Although respectable yields are possible with certain R-X/alkene combinations. recent studies have provided insight into some of the limitations of intermolecular atom transfer
420
4.3 Chiral Auxiliaries
M = Sn or Si
R
T S H a*
~
I
R
'
~
reactions and how these limitations might be overcome. A general illustration of the use of an atom transfer sequence is shown Eqs. (13) and (14).
Ally1 silanes undergo atom transfer reactions, which result in the transfer of an allyl group. Although the overall transformation achieved is similar to that of an allyl stannane, the mechanism of allyl transfer from the stannane and silane is strikingly different [7]. Radicals bearing a p-silyl group do not undergo significant p fragmentation at normal temperatures, unlike the reaction of analogous stannanes shown in Eq. (12) [ 5 ] . The sequence with allyl silanes proceeds by an atom transfer of X from R-X to the intermediate radical followed by elimination of silyl-X in a non-radical process (see Eq. 15).
Ry + R',Si-X
a
4.3.2 Auxiliary Groups Attached to the Unsaturated Radical Trap Alkenes bearing an auxiliary group have been used as radical traps in addition reactions as described generally in Eqs. (4) and (5). Although radical addition reactions have low energy barriers, the critical feature that determines whether selectivity occurs in a given reaction is the relative energy of the diastereomeric transition
4.3.2 Auxiliury Groups Attached to the Unsaturated Radical Trap
421
states leading to products having opposite configurations. Thus, if diastereomeric transition states differ by 1.5 to 2.0 kcal/mol, significant stereoselectivity will occur in a reaction even though the magnitude of both barriers is less than 10 kcal/mol. This simple fact lies at the heart of all stereoselective transformations; one only needs to find a few kcal/mol difference between competing transition states to achieve a selective outcome. Free radicals may undergo addition to activated alkenes with rate constants on the order of 103-107 M-'s-' but steric effects may still impose one to two orders of magnitude difference in the rates of addition at diastereotopic faces of the alkene, kR vs. ks. The relationship between transition state enthalpies and entropies and the rate constants for addition is shown in Eq. (16), in which the subscripts R and S indicate the enthalpies and entropies of activation of the transition states leading to the R and S products respectively. In-
kR kS
=
AHJ-AH~ -
RT
AS: - A S $ R
4.3.2.1 Auxiliary on the Site Undergoing Reaction The addition of carbon radicals to carbon-carbon double bonds is generally exothermic, and transition states are early for such transformations, resembling the reactants. Factors that control the ground state conformation of a reacting alkene may also affect the energies of transition states of reactions deriving from the alkene. Strategies for promoting selective reactions from alkenes bearing an auxiliary group have therefore focussed on reactions in which the auxiliary ground state conformation confers a differential facial steric shielding of the alkene diastereotopic faces. Many strategies to achieve this goal have been attempted, but most of the successful approaches rely on the use of carboxamides or carboximides bearing a resident chiral group attached directly to the alkene carbon undergoing addition. Carboxamides and imides attached to alkenes have possible conformations as shown in Eq. (17). The preferred conformation of tertiary carboxamides substituted with small (S) and large (L) groups on the amide nitrogen is the 2,2 arrangement shown in Eq. (17) (for purposes of discussion the priorities are assumed to be L > S). This conformational preference is due to steric strain introduced by conjugation of the carboxamide and alkene that brings substituents on the amide nitrogen into the same plane as groups substituted on the alkene carbons. Given that the preferred 2, 2 conformation brings the small group attached to nitrogen close to the a carbon on the alkene, judicious substitution of a resident chiral center on 'S' would presumably maximize the potential for selectivity in reactions at C-a.
422
4.3 Chiral Auxiliaries
2
1 Figure 1. Single-crystal structures for 1 and 2
The first examples of control of stereochemistry in free-radical addition to alkene radical traps utilized 2,5-dimethylpyrrolidine carboxamides as the chiral auxiliary [8]. In this approach, the C, symmetry of the pyrrolidine reduces the conformational options for the cQ-unsaturated carboxamide. Thus, the preferred 2 conformation for carboxamides of 2,5-dimethylpyrrolidine is shown in Fig. 1 (structure 1). Single-crystal X-ray analysis of several dimethylpyrrolidine carboxamides, including 1 and 2, have been carried out, and these structures support the notion that the preferred ground state conformation for these carboxamides is as shown [9]. The X-ray structures for 1 and 2 are shown in Fig. 1.
1
2
Factors that influence the ground state conformation of 1 are also important in the transition state for addition of a radical at the carbon bearing the carboxamide. For 1, the proximal methyl of the pyrrolidine protects the back face of the alkene, and addition occurs predominantly from the front, or Si,face. Figure 2 shows the relative rates of addition of cyclohexyl radical to 1 and 2 at 22 "C [9]. The proximal methyl group on 1 reduces the rate of cyclohexyl radical addition to the R e face of the alkene by a factor of 20 at room temperature, relative to addition to the model alkene 2. Addition to the Si face of 1 occurs some 30% faster than addition to the
4.3.2 Auxiliary Groups Attached to the Unsaturated Radical Trap
H
C02Me
H
C02Me
423
0 Q*C02Me
''
p ' & (0C 0 2 M e
*Satistically corrected
Figure 2. Relative rates for the addition of cyclohexyl radical to 1 and 2
model compound. The selectivity observed for the addition at room temperature is the ratio of rate constants, ksi/ka, = 1.28/0.05 or 25/1. It is noteworthy that the favored addition to 1 is actually 1.28 times faster than addition to 2. Analysis of the X-Ray structures shows that 2 is essentially planar in the carboxamide-a#unsaturated alkene substructure while 1 is somewhat distorted from planarity because of the interaction of the proximal methyl on the pyrrolidine with the hydrogen on the c( carbon. Deviation from planarity presumably reduces conjugation and destabilizes the alkene. There is a significant temperature dependence on the selectivity observed for addition of cyclohexyl to 1. Reactions carried out at -78 "C proceed with selectivities > 100/1. Analysis of product selectivity as a function of temperature provides a means of determining the extent to which enthalpy and entropy differences in the transition state are responsible for the selectivities measured [lo]. Thus, by application of Eq. (16) it is generally concluded that transition state enthalpy differences are the major source of differential transition state free energies. The C2-symmetric carboxamide strategy has been used in several radical transformations, and good to excellent stereoselectivities have been observed. Much of this work has been previously reviewed. Most of the applications are extensions of the fundamental idea that ground state carboxamide conformations can be translated to transition state selectivities, given an early transition state for an addition reaction. Improvements in selectivity and practical utility of the auxiliary group can be made by variations on the C, symmetry theme. Thus, Giese and collaborators have prepared substituted pyrrolidines from carbohydrate precursors that can be readily removed after use as an auxiliary [ 1 11. This solves a significant problem associated with use of the parent dimethylpyrrolidine, very vigorous reactions generally being required for auxiliary removal. In the C2 symmetry strategy, the conformation of the carbonyl carbon-amide
424
4.3 C h i d Auxiliaries
nitrogen bond is removed from consideration by the symmetry of the amide group (see structure 1 and Eq. 17). Other strategies for positioning a resident stereogenic center in a position analogous to that found in 1 have been advanced. Oppolzer's camphorsultam, which is commercially available in both enantiomers and is easily removed after use, has been employed extensively in ionic and thermal cycloaddition reactions and this auxiliary has been used extensively in radical reactions. Curran, who pioneered this work, has suggested that in imides derived from camphorsultam, dipole-dipole interactions control the C(0)-N rotamer population as shown in 3 [ 121. In this preferred conformation, the in-plane S-0 dipole is opposed to the carbonyl dipole, as shown.
E. E
3
Experiments have recently been reported that utilize Oppolzer's sultam as an auxiliary group attached to an unsaturated oxime undergoing radical addition [ 13171. As suggested by the studies on the camphorsultam derivative of glyoxylic acid, 4, it is expected that the sterically more stable E,Z planar conformation between the cdrbonyl group and the oxime ether group would be favored. If the ground state conformation is translated to an early transition state, the radical addition to the Re face would be favored. This discrimination is presumably due to steric interactions with the axial oxygen of the sulfonyl group, which effectively prevent addition to the Si face. Thus, reaction of 4 with i-PrI at -78 "C in a reaction mediated by tributyltin hydride gives the addition product 5 in good to excellent yields with selectivities in excess of 95:5 [17]. The configuration of the product hydroxylamine is consistent with a transition state for its formation represented by structure 6. In this preferred transition state, the radical can avoid the 'axial' sultam oxygen that protects the top face of the oxime from addition. This axial oxygen serves essentially the same role as does one of the methyl substituents of 2,5-dimethylpyrrolidine (see structure 7). Indeed, the two groups (sultam oxygen and pyrrolidine methyl) occupy identical positions relative to the center undergoing addition. The radical addition to 4 has been used as a basis for the synthesis of amino acids. Thus, the isopropyl radical adduct 5 has been converted to the amino acid 8 by reductive removal of the benzyloxy group of the major diastereomer R-5 by treatment with Mo(C0)6. Subsequent removal of the sultam auxiliary by standard hydrolysis afforded the enantiomerically pure D-valine without any loss of stereochemical purity. A variety of alkyl radicals were employed in the addition reaction, which gave the alkylated products with excellent diastereoselectivity, allowing access to a wide range of enantiomerically pure natural and unnatural amino acids. Even in the absence of Bu3SnH, treatment of 4 with alkyl iodide and Et3B at 20 "C gave the C-alkylated products with moderate diastereoselectivities. The use of
4.3.2 Auxiliary Groups Attached to the Unsuturuted Radical Trap
425
EtzZn instead of Et3B as a radical initiator was also effective for the radical reaction. In these tin-free reactions, the mechanism of propagation is proposed to be a process in which boron or zinc Lewis acids complex to the oxime, promoting addition. Once addition of a radical to the complexed oxime occurs, fragmentation of the Et3B or EtzZn complex generates an ethyl radical that propagates the chain.
4
5
I
R.
6
5
7
FI-
8
9
4.3.2.2 Auxiliary p to the Site Undergoing Reaction Control of the configuration of the alkene center remote from an auxiliary group presents a challenge. For auxiliary groups such as the dimethylpyrrolidine amide the remote carbon of the alkene is ‘beyond the reach’ of the auxiliary. Thus, addition of cyclohexyl radical to 10 proceeds without regioselectivity, and stereoselectivity is only observed for the products formed by addition to the end of the alkene bearing the auxiliary group [8]. Different strategies have been developed to solve this problem. Curran and his collaborators have developed auxiliaries based upon Rebek’s imide, shown in the unsymmetrical alkene 11 [ 18, 191. Addition of tert-butyl radical to 11 proceeds with good regio- and stereoselectivity. Thus, addition occurs at 0 ° C with 97:3 regioselectivity, preferential addition being on the carbomethoxy-bearing carbon, The major regioisomers are formed as an 88:9 mixture of diastereomers. The major diastereomer formed results from addition to the top face of the alkene, as shown in structure 11.
426
4.3 Chiral Auxiliaries
0.03
0.47
10 0 ~ c 6 H 11
0.25
0.25
";'q353
CH30 Y O z M e 0
H3C
/
11
Oxazolidinones have proven to be extremely useful auxiliary groups in a variety of synthetic reaction types. Thus, the Evans auxiliaries are useful in the control of configuration in enolate alkylations and concerted cycloadditions, to name a few of the more important applications. Sibi and his collaborators at North Dakota State University have pioneered the use of these auxiliary groups in radical transformations mediated by Lewis acids [21-24]. Consider the general conformational questions that arise in a carboximide, such as 12, derived from an oxazolidinone (Eq. 18). The conformer 12 is disfavored by steric factors while 13 and 14 have similar steric demands. In the absence of any chelating Lewis acid, one expects that 13 would be of lower energy than 14 because of the opposed dipoles of the anti carbonyls in this conformation.
\
R2
12
U
13
14
Conformation 14, in fact, has parallel carbonyl dipoles that destabilize this arrangement. In the presence of Lewis acids, however, this conformation can serve as
4.3.2 Auxiliary Groups Attached to the Unsaturated Radical Trap
427
Scheme 1
an excellent bidentate chelator, and the Lewis acid complex of 12 fixes the orientation about the carbonyl carbon-imide nitrogen bond (Eq. 19).
Lewis acid = Mo
The diphenyl oxazolidinone, 15, in combination with Lewis acids provides a general solution for diastereoselective reactions. Sibi has prepared the diphenyloxazolidinone in three steps from the methyl ester of serine (the hydrochloride) as shown in Scheme 1 [23, 241. The overall yield for the sequence is 60%, and both enantiomers are available from commercially available starting materials. The oxazolidinone itself is now commercially available. Steric factors slow the rate of intermolecular addition of radicals to non-terminal alkenes such as 1, 2 and 10-12. In the absence of a Lewis acid additive, radical additions to the cinnamate 16 or the crotonate 17 are inefficient at -78 "C because radical reduction is faster than radical addition [21, 22, 251. The reaction is also nonselective in the absence of Lewis acid. When stoichiometric amounts of Lewis acids are added to the reaction of isopropyl radical with 16, however, both the yield and the diastereoselectivity increase significantly. Thus, Yb(OTf)3 gives a product yield of 90% in a ratio of 18a/19a of 45: 1. This record diastereoselectivity in radical addition is comparable to or better than that obtained under ionic conditions. Use of catalytic Yb(OTf)3 (10 mole/) gives only a slight reduction in selectivity. Addition to the crotonate 17 promoted by Yb(OTf)3 gives a product ratio of 18b/ 19b of 25: 1. A model consistent with the products obtained is shown in structure 20. The radical attacks the alkene from the face opposite the bulky diphenylmethyl oxazolidinone substituent. The bulk of the diphenylmethyl group is critically important in determining the selectivities obtained. Replacement of this bulky substituent on the auxiliary by a smaller benzyl group leads to a substantial reduction of selectivity observed.
428
4.3 Chiral Auxiliaries 0
0
-78 "C Ph 16R=Ph 17R=Me
Ph 18
Ph 19
yield, % 18 : 19
a R = P h Yb(OTf)3 b R = M e Yb(OTf)3
>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
><%'
+
9
T(%) Yb(OTf)3 (equiv) 0 none 0 Yb(OTf)3 (1) (-)-8-PhMen -5 Yb(0Tf)s (1) (-)-8-PhMen -5 Yb(OTf)3 (0.2) R'
:
o
R
[44]
l
10
yield, % 9 43 5 79 7 77 38 71 26
: 10
: I* : I* : 1 : 1
* enol form observed
Scheme 13. Lewis acid-promoted diastereoselective intra- or intermolecular radical addition using a$-unsaturated esters bearing chiral auxiliaries
ester (Scheme 13) [42]. Nishida and collaborators found that Lewis acid had to be present in order for the reaction to proceed at 0 "C or lower. In their intramolecular version of this reaction, a bulky aluminum reagent was effectively employed to achieve higher diastereoselectivity (model V, Scheme 13) [43]. (-)-8-Phenylmenthol was also used by Yang et al. in an Mn"'-based oxidative radical cyclization reaction catalyzed by Ln(OTf)3 (lanthanide triflate) [44]. With the achiral substrate (R' = Me), the cyclization reaction was very slow in
458
4.4 Lewis Acid-Mediuted DiustereoselectiveRadical Reactions
CF3CH20H at 0 ° C in the absence of Lewis acid (Scheme 13). However, in the presence of Yb(OTf)3 the cyclization proceeded faster and gave higher yield and selectivity. The radical cyclization of (-)-8-phenylmenthyl ester afforded 77% of trans cyclized products with excellent diastereoselectivity. Interestingly, a similar ratio and yield were obtained when a catalytic amount (0.2 equivalent) of Yb(OTf)3 was used. To account for the increase in diastereoselectivity, Yang’s group proposed that the p-keto ester chelation to Yb(OTf)3 would lock the two carbonyls in a syn orientation, allowing the (-)-8-phenylmenthyl group to mask the si-face of the radical and thus restrict cyclization to the opposite face in order to favor compound 9 (transition state W ).
4.4.5 Conclusion These selected examples show the importance of Lewis acid in diastereoselective radical reactions. Complexation with Lewis acid, in an endocyclic manner or by using extremely bulky metal complexes such as MABR or MAD, reduces the conformational flexibility of intermediate radicals resulting in an improved facial bias. Lewis acid has been shown to effectively enhance facial selectivity by making a temporary ring CI to the radical, thus mimicking the exocyclic effect. Radical reactions involving chiral auxiliaries have also benefited from the use of Lewis acid. In the design of radical processes involving Lewis acids, all of the possible pathways and equilibria as well as the relative reactivity of species present in a reaction mixture must be considered. Within a given reaction mixture, products can be formed via uncomplexed mono- or bidentate pathways, and the complexes formed may be monomeric or polymeric. In stereoselective reactions, it is important to consider pathways leading not just to major products but also to minor products. Small changes in the efficiency of minor product formation can have a significant impact on product ratios. Although viewed with skepticism ten years ago, the use of Lewis acid to influence stereoselective radical processes is now well established. However, considerable work remains to be done in this area of research. While the perception of complexity in diastereoselective radical reactions involving Lewis acids has in the end proven valid, the richness of the resulting chemistry has been delightfully rewarding.
Acknowledgement We would like to thank Ms. LaVonne Dlouhy for her assistance in the preparation of this chapter.
References
459
References [ I ] For reviews see: (a) N. A. Porter, B. Giese, D. P. Curran, Acc. Chem. Rex 1991,24, 296-301. (b) D. P. Curran, N. A. Porter, B. Giese in Stereochemistry of Radical Reactions - Concepts, Guidelines and Synthetic Applications, VCH: New York, 1996. (c) P. Renaud, M. Gerster, Anger{,. Chem. Int. Ed. 1998, 37, 2562-2579. (d) M. P. Sibi, N. A. Porter, Ace. Chem. Res. 1Y99,32, 163-171. [2] Y. Guindon, J.-F. LavallCe, M. Llinas-Brunet, G. Horner, J. Rancourt, J. Am. Chem. Soc. 1991, 113, 9701-9702. [3] Y. Guindon, J. Rancourt, J. Org. Chem. 1998, 63, 6554-6565. [4] Y. Guindon, B. Guerin, C. Chabot, N. Mackintosh, W. W. Ogilvie, Synlett 1995, 5, 449451. [5] Y. Guindon, B. Guerin, J. Rancourt, C. Chabot, N. Mackintosh, W. W. Ogilvie, Pure Appl. Chem. 1996, I , 89-96. .161. B. GuCrin, C. Chabot, N. Mackintosh, W. W. Ogilvie, Y. Guindon, Can. J. Chem. 2000, 78, 852-867. 171 . _Y. Guindon, B. Guerin, C. Chabot, W. W. Ogilvie, J. Am. Chem. Soc. 1996, 118, 1252812535. [S] C . L. Mero, N. A. Porter, J. Am. Chem. Soc. 1999, 121, 5155. [9] H. Nagano, Y. Kuno, Y. Omori, M. Iguchi, J. Chem. Soc., Perkin Trans. 11995, 389-394. [ l o ] M. Gerster, L. Audergon, N. Moufid, P. Renaud, Tetrahedron Lett. 1996, 37, 6335-6338. [ I I ] P. Renaud, L. Andrau, K. Schenk, Synlett 1999, 9, 1462-1464. [I21 P. Renaud, M. Gerster, J. Am. Chem. Soc. 1995, 117, 6607-6608. [ 131 Na2C03 was used to trap the HCI formed upon mixing the Lewis acid with the free alcohol. [ 141 B. Giese, B. Carboni, T. Gobel, R. Muhn, F. Wetterich, Tetrahedron Lett. 1992, 33, 2673. 1151 K. S. Feldman, H. M. Berven, P. H. Weinreb, J. Am. Chem. Soc. 1993, 115, 11364. [I61 M. Gerster, K. Schenk, P. Renaud, Angew. Chem. Int. Ed. Engl. 1996, 35, 2396-2399. [17] G. A. Molander, C . R. Harris, Chem. Rev. 1996, 96, 307. [IS] M. Kawatsura, K. Hosaka, F. Matsuda, H. Shirahama, Synlett 1995, 7, 729-732. [I91 M. Kawatsura, F. Matsuda, H. Shirahama, J. Org. Chem. 1994, 59, 6900-6901. [20] M. Kawatsura, F. Dekura, H. Shirahama, F. Matsuda, Synlett 1996, 4 , 373-376. [21] G. A. Molander, C. Kenny, J. Am. Chem. Soc. 1989, I l l , 8236-8246. [22] M. Newcomb, D. P. Curran, Acc. Chem. Res. 1988, 21, 206. [23] (a) A. L. J. Beckwith, C . H. Schiesser, Tetrahedron Lett. 1985, 41, 3925. (b) D. C. Spellmeyer, K. N. Houk, J. Org. Chem. 1987,52,959. [24] H. Nagano, Y. Azuma, Chem. Lett. 1996, 845-846. [25] H. Urabe, K. Yamashita, K. Suzuki, K. Kobayashi, F. Sato, J. Org. Chem. 1995, 60, 35763577. [26] H. Nagano, S. Toi, T. Yajima, Synlett 1999, I , 53-54. [27] K. Maruoko, T. Itoh, H. Yamamoto, J. Am. Chem. Soc. 1985,107, 4573. [28] P. Renaud, N. Moufid, L. H. Kuo, D. P. Curran, J. Ory. Chem. 1994, 59, 3547-3552. [29] H. Urabe, K . Kobayashi, F. Sato, J. Chem. Soc., Chem. Commun. 1995, 1043-1044. [30] N. Moufid, P. Renaud, C. Hassler, B. Giese, Helv. Chim. Acta 1995, 78, 1006-1012. [31] Y. Guindon, C. Yoakim, V. Gorys, W. W. Ogilvie, D. Delorme, J. Renaud, G. Robinson, J.-F. Lavallee, A. Slassi, G. Jung, J. Rancourt, J. Org. Chem. 1994, 59, 1166-1 178. [32] Y. Guindon, A.-M. Faucher, E. Bourque, V. Caron, G. Jung, S. R. Landry, J. Org. Chem. 1997, 62, 9276-9283. [33] Y. Guindon, Z. Liu, G. Jung, J. Am. Chem. Soc. 1997,119, 9289-9290. [34] Selected examples: (a) D. Crich, J. W. Davies, Tetrahedron Lett. 1987, 28, 4205. (b) N. A. Porter, D. M. Scott, B. Lacher, B. Giese, H. G. Zeitz, H. J. Lindner, J. Am. Chem. Soc. 1989, 111, 8311. (c) B. Giese, U. Hoffmann, M. Roth, A. Velt, C. Wyss, M. Zehnder, H. Zipse, Tetrahedron Lett. 1993, 34, 2445-2448. (d) D. P. Curran, H. Qi, S. J. Geib, N. C. DeMello, J. Am. Chem. Soc. 1994, 116, 3131. (e) N. A. Porter, R. L. Carter, C . L. Mero, M. G. Roepel, D. P. Curran, Tetrahedron 1996, 52, 4181 and references cited therein. Use of Lewis acid with
460
4.4 Lewis Acid-Mediated Diustereoselective Radical Reactions
chiral auxiliaries. (f) M. P. Sibi, C. P. Jasperse, J. Ji, J. Am. Chem. SOC. 1995, 117, 1077910780. (g) M. P. Sibi, J. Ji, Angew. Chetn., Int. Ed. Engl. 1997, 36, 274-275. (h) B. DelouvriC, L. Fensterbank, E. Lac6te, M. Malacria, J. Am. Chem. SOC.1999, 121, 11395-1 1401. [35] Y. Yamamoto, S. Onuki, M. Yumoto, N. Asdo, J. Am. Chem. SOC.1994, 116,421-422. [36] M. P. Sibi, J. Ji, Angew. Chem. Int. Ed. Engl. 1996, 35, 190-192. [37] M. P. Sibi, J. Ji, J. Org. Chem. 1996, 61, 6090-6091. [38] C. L. Mero, N. A. Porter, J. Org. Chem. 2000, 65, 775. [39] J. K. Whitesell, Chem. Rev. 1992, 92, 953. [40] N. A. Porter, B. Gicse, D. P. Curran, Ace. Chem. Rex 1991, 24, 296 and references cited therein. [41] (a) W. Oppolzer, M. Kurth, D. Reichlin, C. Chapuis, M. Mohnhaupt, F. Moffatt, Heluetica Chem. Acta 1981, 64, 2801. (b) R. J. Loncharich, T. R. Schwartz, K. N. Houk, J. Am. Chem. SOC.1987, 109, 14 and references cited therein. [42] M. Nishida, A. Nishida, N. Kawahara, J. Org. Chem. 1996, 61, 3574-3575. [43] M. Nishida, E. Ueyama, H. Hayashi, Y. Ohtake, Y. Yamaura, E. Yanaginuma, 0. Yone1994,116, 6455-6456. mitsu, A. Nishida, N. Kawahara, J. Am. Chem. SOC. 1999, 121, 5579-5580. [44] D. Yang, X.-Y. Ye, S. Gu, M. Xu, J. Am. Chem. SOC.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
4.5 Enantioselective Radical Reactions Mukund P. Sibi and Tam R. Rheault
4.5.1 Introduction While diastereoselective radical reactions have been investigated over the last two decades [ 11, only over the last 5 years have the first practical examples of enantioselective radical reactions emerged. Spanning this time, the previous notion that radical reactions could not be performed with reasonable levels of enantiocontrol has been disproven many times over. In fact, enantioselective radical chemistry has been shown to proceed via three primary routes. The first involves the formation of a temporary association of the radical intermediate with a chiral adduct (Scheme la). This is the case when the substrate is complexed with a chiral Lewis acid prior to the reaction such that trapping of the chiral-complexed radical intermediate proceeds through a diastereomeric transition state, providing facial selectivity for the transformation. Second, a temporary chiral association can also be formed with the radical acceptor, such that the radical will approach one face of the chiral acceptor with selectivity (Scheme lb). Third, a chiral reagent can be used to perform an asymmetric transformation (Scheme 1c). Optimally, the chiral reagent’s byproduct after the reaction has taken place can be regenerated into its reactive form thus allowing this route to proceed catalytically. In instances where a chiral Lewis acid complex is used in order to impart stereocontrol, several issues are at hand:
(1) complexation of the chiral Lewis acid with the substrate; this can be accomplished through appropriate arrangement of Lewis basic donor sites on the substrate to form either a chelate with the Lewis acid or a single point coordination through the use of a monodentate Lewis acid; in addition, 71-complexation can occur with olefin-containing substrates (2) Matching of Lewis acid strength with substrate reactivity; possibility of Lewis acid enhancement of reactivity ( 3 ) careful choice of chiral ligand such that facial selectivity can be controlled (4) in order to allow for the possibility of using substoichiometric amount of the catalyst, dissociation of the chiral Lewis acid from the substrate after the reaction has taken place is desirable; the product should ideally be less reactive towards the chiral Lewis acid than the starting material
462
4.5 Enantioselective Radical Reactions
-
RX + ML;
-
[RX-ML;]
[(Re)-ML,*]+ Acceptor
-
Product* + ML;
(la)
MLn' = Chiral Lewis Acid Acceptor
+
ML;
-
Substrate + Reagent*
[Acceptor-ML;]
-
+
Re
-
[Substrate-Reagent*]*
Byproduct*
-
Product*+ ML,*
-
Product*
+ Byproduct*
(1b) (Ic)
Reagent'
Scheme 1
By incorporating all of the issues outlined above, researchers have met the challenge of performing highly enantioselective free-radical reactions with great success. Sibi and Porter have recently summarized this progress in a comprehensive review [2]. Since its publication many more new and exciting examples of enantioselective radical chemistry have been reported. The previous examples as well as the most recent will be covered comprehensively in the following section.
4.5.2 Complexation of the Radical 4.5.2.1 Reductions Radical reductions typically involve a hydrogen atom transfer from a suitable donor (organotin or silicon hydride) to an acceptor, commonly a radical intermediate generated ci to a carbonyl. In cases where enantiomerically pure products are desired, a chiral Lewis acid is employed in order to coordinate to the Lewis basic carbonyl oxygen(s) and provide facial bias for the ensuing hydrogen atom transfer. This concept has proven successful for the enantioselective reduction sequence shown in Eq. (1) [3]. H
l a R = CH20Me 1b R = CH20Et l c R = CH20Bn ldR=Me
(S)-2
A prochiral radical intermediate is generated from a-methoxymethyl-a-iododihydrocoumarin (la) which is coordinated via the carbonyl oxygen to the chiral Lewis acid/ligand combination of MgI2 and 2. Enantiomeric excesses of up to 62% and yields of 88% have been obtained in this enantioselective reduction using tributyltin
4.5.2 Complexation of the Radical
463
hydride as the hydrogen atom source. The degree of asymmetric induction was found to be dependent on several factors including the hydrogen atom source (triphenyltin hydride decreased the enantioselectivity from 62% to 39%), reaction temperature (increasing temperatures markedly decreased the selectivity) and substrate concentration. Several other amine and imine chiral ligands and multiple Lewis acids including Mg(C104)2, TiC14, ZnI2, AlC13 and Eu(tfc)j were screened without success. In order to better rationalize the stereoselectivity obtained in these reactions, reductions of other similar substrates were examined using the conditions optimized for l a [4]. It was found that reduction of substrates l a through l c all provided similar levels of enantioselectivity (-60% ee) and good yields. On the other hand, reaction using Id only provided 30% ee. The absence of a second donor oxygen in Id indicates that this extra Lewis basic moiety is needed in order to form a chelate with the chiral Lewis acid complex and provide a more rigid chiral environment for the asymmetric hydrogen atom transfer. A somewhat different approach towards enantioselective reductions c( to a carbony1 involved a radical conjugate addition to a-methylene-y-butyrolactone followed by stereoselective hydrogen atom transfer as shown in Eq. (2) [ 5 ] . Bul, Bu3SnH, Et3B, toluene -78 "C - RT
4
* o
CI-At
47% yield 28% ee
In this example, a relatively strong chiral Lewis acid 5 is employed in order to activate the a,p-unsaturated ester 4 and promote nucleophilic radical additions to the p position. It is noted that the Lewis acid presumably coordinates the oxygen lone pair on the carbonyl from the side opposite the ring oxygen [6], and thus chirality is imparted by the atropisomeric BINOL ligand. Low levels of asymmetric induction were observed.
4.5.2.2 Enantioselective Allylations Radical allylations have proven to be a successful route for enantioselective carbon-carbon constructions. Typically, in arrangements where the radical intermediate is complexed to a chiral Lewis acid, one can envision either monocoordinate or multidentate binding of the chiral Lewis acid complex to the substrate. This interaction is dependent on both the substrate (number of donor atoms available) and the Lewis acid's binding capabilities. Highly successful examples of both such scenarios have been realized. Conjugate radical addition to Lewis acid-activated acceptors followed by trapping with allyltributyltin has been demonstrated as a viable strategy towards
464
4.5 Enuntioselective Radical Reactions
enantioselective allylations. Oxazolidinone acrylates 7 are good templates for the formation of bidentate chelates with chiral bisoxazoline ligand (9)/Lewis acid complexes. Equation (3) shows that good selectivities (up to 90% ee) result using Zn(0Tf)z as a Lewis acid and when R is large (t-butyl) [7, 81. The configuration of the product 8 can be rationalized using a model (10) similar to that used for DielsAlder reactions where the zinc metal possesses a tetrahedral geometry with two bidentate donors: the oxazolidinone substrate and the ligand [9]. One face of the prochiral radical is shielded by one of the phenyl groups on the ligand and the s-cis conformation is favored as a result of steric interactions within the template. This allows the allylstannane to selectively approach the unhindered face of the radical.
0
Zn(OTf)z, RX
0
0
0
0
u
CH2C12, Et,B/Oz -78 "C
7
8
9 Yield % ee %
RI t-Bu c-hex
92 62
(3)
90 68
10
A similar type of allylation has been performed by generating the CI radical directly from the corresponding halide l l , also using an oxazolidinone substrate and a chiral zinc Lewis acid (Eq. 4)[S]. Enantioselectivities in this latter case are slightly lower (76% ee) than those obtained in the addition and trapping experiments, but the trend showing that larger R groups provide increased levels of selectivity still holds true. 0
Zn(OTf)2,RX
0
RI Br
11
CHzC12, Et3B/02, -78 "C 12
t-Bu c-hex ethyl methyl
ee% 76 64 53 46
(4)
4.5.2 Complexation of the Radical
465
The intermediate a-amide radical generally prefers an s-cis orientation 13, minimizing allylic strain. However, when R is small, allylic strain is decreased and the strans conformation 14 is more accessible (Eq. 5). The lower selectivity generally observed with the a-bromide substrates is presumably due to the fact that the a-halo amide carbonyl is not as good a donor as the a,P-unsaturated amide carbonyl and that this may be adversely affecting interactions with the chiral Lewis acid. No selectivity was observed using these conditions when R = H.
P' CON
13
14
15
16
Interestingly, changing the radical trap from allylstannane to allylsilane increased the enantioselectivity of these allylations from 76% ee to 900/0 ee (Eq. 6 ) [lo]. The by-product in the allylstannane reactions is tin halide, which is itself a Lewis acid which can promote achiral allylations. In addition, it was observed that a simple change in Lewis acid reversed the sense of stereoinduction.
RI
LA
t-Bu Zn(OTf), t-Bu Mglp
Yield %
88 86
ee% 90 (R) 68(S)
Chiral bisoxazolines were also used in the formation of a-substituted y-lactams (Eq. 7) [ I l l . Selectivity is controlled by the bidentate coordination of the chiral Lewis acid to the lactam carbonyl and the pyridine moiety. The combination of Zn(0Tf)z and ligand 19 proved to be the most effective combination, allowing for selectivities of up to >99% ee to be reached at -78 "C with 2 equivalents of chiral Lewis acid. Warming to -20 "C only decreased the enantioselectivity to 95?4 ee. Conversely, the use of substoichiometric amounts of chiral Lewis acid (20 mol%) substantially decreased the enantiomeric excess to 81% at -20 "C. A trans octahedral model (21) is proposed to account for the sense of stereoinduction.
466
4.5 Enantioselective Radical Reactions e S i M e 3
Br-(":."
Lewis acid CHzCIz, EtsB/Oz
17
Ligand
LA (eq.)
Temp. "C
18
Yield %
ee%
-20
54 42 94
59 (S) >99 (S) 84 (S) 75 (s) 95 (S)
-20
69
81 (S)
9 19
Zn(OTf)z(l.O) Zn(OTf)z(2.0)
-78 -78
19
MgBrz(1.0)
-78
20
-78
19
Zn(OTf)z(l.O) Zn(OTf),(2.0)
19
Zn(OTf)z(0.2)
70 83
21
L * = Ligand19
OTf
The combination of aluminum Lewis acids and chiral diols has allowed for modest enantioselectivities in similar reactions using a-iodopropionate oxazolidinone substrates as in Eq. (8) [ 121. The 4,4-gem-dimethyl substituent on the oxazolidinone (22) favors the s-cis conformation for the intermediate radical. Enantioselectivities of 32 and 34% and yields above 90%) were obtained for allylations with R = H and R = Me respectively. R &SnBu3
O
?
, I Q
R Yield Yo ee% Me 93 32 34(R) (R)
MeAl-TADDOLate
(8)
EtSB/02, -78"C
22
23
Radical reactions are also valuable strategies for the formation of quaternary carbon-based centers. An enantioselective variant of this has recently come to light utilizing aluminum as a Lewis acid complexed to chiral BINOL ligand 26 in the allylation of a-iodolactones 24 (Eq. 9, Table I ) [13]. Table 1. Enantioselective allylations - effect of additives Entry
Substrate
Chiral LA (eq)
Additive
Yield (oh)
ee ('XI)
Config
1 2 3 4 5
24a 24a 24a 24b 24c
1 .o
none EtzO EtzO EtzO EtzO
12 84 81 85
27 81 80 82 91
R R R R R
1 .o
0.2 1 .o 1.o
16
4.5.2 Complexation of the Radical
p../SnBu3
-
CHzCIz, Me3AI Et3B/02 24a: R = Me 24b: R = CH20Me 24c: R = CH20Bn
& 0
0
g; \ /
\
-78 "C
25
/
467
SiPh3
SiPh3
26
(9)
27
Me-?;''] *
28
OEtP
This work illustrates an asymmetric transformation using a single donor atom complexed to a single-point binding chiral Lewis acid. It was established that diethyl ether as an additive in these reactions dramatically increases product enantioselectivities (compare entries 1 and 2, Table 1). Catalytic reactions were also demonstrated (entry 3 ) with no appreciable loss of selectivity. A proposed model for how diethyl ether functions to enhance selectivity in the enantioselective formation of these quaternary chiral centers is shown in 27. Similar allylations using Lewis acids generated from aluminum reagents and chiral sulfonamides were also performed [ 141. These allylations were carried out on substrates 24b and 24c with either AIMe3 or AI'Bu3 and chiral ligand 28. Enantioselectivities for allylations under these conditions were poorer than those reported using ligand 26, reaching a maximum of only 54% ee.
4.5.2.3 Samarium Diiodide-mediated Enantioselective Radical Additions Recently, enantioselective additions of samarium diiodide-generated ketyl radicals to olefins have been demonstrated [15]. As illustrated in Eq. (lo), the reductive coupling of acetophenone with methyl acrylate (31a) in the presence of chiral phosphine ligand 29 (R-BINAPO) gives somewhat low yields (mostly under 50%) but moderate to good levels of enantioselectivity (60-70% ee) for the y-butyrolactone products 34. Since samarium diiodide is only a one electron donor, two equivalents of the metal are required in order for the reaction to proceed. The first electron donated from the samarium produces a chiral ketyl radical 30 which undergoes enantioselective addition to the acrylate according to the chelated transition state shown in 32. The second electron donation then provides a chiral samarium enolate intermediate 33 that can potentially undergo stereoselective proton transfer in the formation of a second chiral center.
468
4.5 Enantioselective Radical Reactions
Me0 Smlp
0 t
Ph
31a R = H 31b R = Me
30
Me
32 29 *L,Sm"',
Smlp c
ph&OMe
33
O'SmlllL,'
]
cyclization
H+
Ph 34
ee (major)
R Yield % cistrans Me 93 66:34 H
89 67
90
Chiral samarium (11) complexes have also been applied towards the hydrodimerization of acrylic acid amides [ 161. Such reactions involve the ligandcontrolled dimerization of conjugated ketyl radicals in the enantioselective formation of 3,4-tvans-disubstituted adipamides (Eq. l l). Yields were mainly low, often under 40% and enantiocontrol was modest with selectivities ranging from around 50-85% ee. A nine-membered chelated transition state 37 is used to rationalize the stereoselectivity of the dimerization where the ligand-bound conjugated ketyl radicals are oriented cis to each other on the metal assuming an octahedral geometry. Bn2N
L O .
Bn
70 % yield 71 % ee
NBnP
37
4.5.2.4 1,2-Wittig Rearrangement An interesting example of chemistry involving a radical dissociation-recombination mechanism is the 1,2-Wittig rearrangement [17]. The general scheme for the Wittig rearrangement is shown in Eq. (12).
4.5.2 Complexation of the Radical
469
The enantioselective variant employs a bisoxazoline ligand (39) which coordinates the lithium in a similar fashion to other known asymmetric lithiation protocols (Eq. 13) [18].
Ph-0-
Ph
'
Ph
t-BuLi, Et20, -78 "C t
HO
-7
38
Ph
40
eqs t-BuLi
-4
\
I
eqs 38
2 2 2
(S)-39
Yield Yo ee Yo 94 86 81
1 0.1 0.05
62 60 54
It was observed that when 2.0 equivalents of BuLi were introduced, yields of the desired product (S)-40 reached a maximum of 94% while maintaining moderate levels of enantioselectivity (approximately 62% ee). The use of substoichiometric amounts of chiral ligand did not have a significant effect on either the selectivity or yield. It was postulated that the second equivalent of t-BuLi was needed in order to facilitate dissociation of initial Li-ligand complex resulting in a t-BuLi dimer which coordinates the substrate. This process serves to regenerate the active chiral catalyst species and allow for this reaction to proceed with substoichiometric amounts of ligand.
4.5.2.5 Pinacol Coupling Pinacol coupling reactions also involve radical-radical recombinations; thus, enantiocontrol in these reactions remains a daunting problem. Initially it was found that addition of TMEDA as an additive increased the solubility of TiC12, thus increasing the conversion of the aldehyde to diol product [ 191. It was hypothesized that addition of an optically active amine would not only help to solubilize the Lewis acid, but also offer enantiocontrol in the coupling. When chiral diamines such as 41 were added, modest levels of enantioselectivity were achieved (Eq. 14).
mNMe2 u""NMe2
0 PhKH
'
OH P h q p h
41 THF, 25 "C,8 h
-k
OH
p h L P h OH
(S,S)-42
43 ~
TiCI2 1 .o
2.0
Amine eq. Yield 42 %(ee Yo) Yield 43 YO 34 (41) 3 2.0 82 (40) 6 4.0
470
4.5 Enantioselective Radical Reactions
4.5.3 Complexation of the Trap 4.5.3.1 Conjugate Additions Success in diastereoselective Lewis acid-mediated conjugate radical additions using chiral oxazolidinones led Sibi and Porter to evaluate enantioselective variants. Based on previous work from their laboratories as well as information in the literature (control of the s-cis vs s-trans rotamer of the enoate), they surmised that a bidentate Lewis acid in combination with an achiral oxazolidinone template and a chiral ligand would be a good starting point to probe enantioselective conjugate radical additions (Scheme 2).
44
45
46
47
Scheme 2
Chiral bisoxazoline ligands were initially chosen for these experiments. It was found (Eq. 15) that simple bisoxazoline ligands 49 derived from amino acids led to good yields but moderate selectivities of products 50 when catalytic amounts of chiral Lewis acid were used (67% ee with 20 mol% of the catalyst and 86% chemical yield) [20]. 0
0
0
U
Mgl2, i-Pr-I, Bu3SnH Et3B/02, CH2CI2, -78 O C '
'h 0NuP
u
48
50
i-Bu
49
eq. 49
yield YO ee%
-i-6U
1 .o
88
82
0.5
86
79
0.2
86
67
0.05
57
40
4.5.3 Complexation of the Trap
471
Table 2. Enantioselective conjugate additions Lewis acid (moW)
Entry
Yield (“XI)
T (“C)
a?(“h)
er ~
1 2 3 4
I00 30 30 30
-78 -78 -20 25
28: I 66: 1 39: 1 28: 1
93 97 95 93
88 91 93 87
After some modifications to the bisoxazoline ligand, a practical and efficient route was developed by Sibi for catalytic enantioselective conjugate radical additions [21]. These included changing the bite angle of the ligand by adding a cyclopropane functionality at the methylene bridge and making the ligand more rigid by incorporating an aminoindanol framework instead of phenyl glycinol in the formation of the ligand [22]. Equation (16) (Table 2) illustrates how the new cyclopropyl bisoxazoline ligand 52 improved these asymmetric conjugate radical additions. 0
0
ANk,, 0 U 51
i-Prl, Bu3SnH, Mg12 Et,B/O,,
* o
Ph + 0
Ph
u
CH~CIZ, -78 OC
53
54
R. 55
An octahedral model (55) is proposed and is consistent with the observed absolute stereochemistry of the product. In the case of the amino indanol-derived ligands, the ligand-MgI2-substrate complex adopts an octahedral geometry where the two iodides have a cis orientation and the more Lewis-basic carbonyl oxygen is trans to the iodide [23]. The ring constraint and the larger bite angle in 52 provides for optimal face shielding in the radical addition and thus accounts for the high levels of enantioselectivity. Attack of the radical on the least hindered re-face of the substrate accounts for the observed absolute stereochemistry of the product (4S,5R-52 gave R product).
472
4.5 Enantioselectiue Radical Reactions
The effect of varying the achiral template on enantioselective conjugate additions was also studied (Eq. 17) [24]. N-Acylpyrazoles, templates capable of forming 5membered chelates with a two-point binding Lewis acid have been evaluated in conjugate radical additions. Addition of iso-propyl radical to 56 using a chiral Lewis acid prepared from Zn(OTf)2 and 52 gave 57 with moderate enantioselectivity (51% ee). In comparison, isopropyl radical addition to 51, an oxazolidinonederived substrate, using Zn(0Tf)z and 52 gave product of opposite configuration (84% yield, 51%)ee). Model 58, a trans octahedral model, accounts for the product configuration. These experiments demonstrate that achiral templates are thus convenient handles for the formation of products of opposite configuration.
H
3
C
LPh a
CH3
i-Prl, Bu3SnH, Et3B/02
H
3
C
Zn(OTf)2/52
a=Ph CH3
56
57 58
L * = Ligand52
CH3 Ph
76 % yield 51 Yo ee
Previously, every example of enantioselective conjugate radical additions featured asymmetric induction through the application of bidentate bisoxazoline chiral Lewis acids. A recent report, however, illustrates the utility of a new type of chiral bisoxazoline ligand known as DBFOX-Ph (59), which features a furan-containing bridge that offers tridentate chelation of the Lewis acid for asymmetric conjugate radical additions [25].
Ph
Ph
59 - (R, R)-DBFOWPh
After screening no less than two dozen Lewis acids in the iso-propyl radical addition to 51, it was concluded that Mg(C104)2 offered the highest levels of enantioselectivity (75% ee) and yield (100%). Other Lewis acids screened that produced yields reaching a maximum of only 20-30'%) included NiC12, MgI2, ZnCl2, Zn(ClO4)z and Zn(0Tf)z. Interestingly, it was observed that both enantioselectivities and yields were moderately increased with decreasing counterion nucleophilicity: Mg(0Tf)z < Mg(BF4)2 < Mg(SbF6)z < Mg(C104)2.
473
4.5.3 Complexation of the Trap Table 3. Enantioselective radical addition to 60 Entry
Lewis acid
Solvent
Yield
('%I)
ee (9'0)
Config
10
R R R R R R
24 2 52 13 10
4.5.3.2 Imine Additions Diastereoselective radical additions to glyoxylic oxime ethers are well established; however, only one recent report describes attempted enantioselective additions using chiral Lewis acids [26]. It was found that bisoxazoline ligand 9 provided the best results as illustrated in Eq. (18) and Table 3.
The highest selectivity for this set of experiments was observed using MgBrz as a Lewis acid (entry 4). Yields were generally high, again optimized using MgBrz (entries 4-6). A model for the facial selectivity of the radical addition is shown in 62 where one phenyl ring from the chiral ligand shields the si face of 60 leaving the re face exposed for the radical to approach.
4.5.3.3 Atom Transfer Reactions Recently, results describing an attempted enantioselective Kharasch reaction were reported (Eq. 19) [27].
414
4.5 Enantioselective Radical Reactions
Using conditions optimized for diastereoselective atom transfer additions, enantioselective reactions of 63 with 1-octene in the presence of either Zn(0Tf)z or Sc(OTf)3 and chiral ligand 9 were attempted. This reaction with Zn(0Tf)z as a Lewis acid proved very inefficient, offering yields of less than 15%. The selectivity was not determined. Reaction with Sc(OTf)3 proved more promising, with conversions around 64%; enantioselectivities were low however, reaching only 10% ee. It is presumed that coordination of the Sc(OTf)3 with the chiral ligand 9 functions to deactivate the metal such that it is no longer strong enough of a Lewis acid to bind the oxazolidinone substrate. Reaction mainly occurs though the uncomplexed Sc(OTf)3 resulting in racemic products. Previously, examples of chiral Lewis acid coordination of either the radical or radical acceptor involved coordination to Lewis basic sites, typically oxygen or nitrogen. However, certain transition metals are also capable of coordination to alkenes and, if complexed to a chiral ligand, can also afford chiral addition products. This has been illustrated in the enantioselective atom transfer additions of alkane and arene-sulfonyl chlorides and bromotrichloromethanes to olefins using chiral ruthenium complexes. These reactions are thought to follow a radical redox chain process detailed in Eq. (20). I/ R-X + 65a R = ArS02, X = CI 65b R = CCI3, X = Br
;Ru-
L* 66 L = (-)-DIOP
69
x/ ,Ru-.R L*
/Ph
x/
P h q y - '
67
70a R = ArS02 X = CI 70b R = CCI3 X = Br
68
66
The initial ruthenium(I1) catalyst 66 abstracts a halogen (either chlorine or bromine) from the substrate forming a ruthenium(II1) species 67. This is followed by p i complexation (68), radical addition (69) and halogen atom transfer to form the desired product (70). Starting from 65a, enantioselectivities of the resulting product 70a ranged from 20 to 40% ee with excellent chemical yields [28]. Reactions with a slightly different substrate bromotrichloromethane (65b) provided 70b in 32% ee, and a poor yield of 26% [29].
4.5.4 Enantioselective Cyclizations Few examples have been reported demonstrating enantioselective cyclization methodology. One known example, however, is similar to the diastereoselective cyclization which uses a menthol-derived chiral auxiliary and a bulky aluminum Lewis acid to impart selective cyclization [ 301. The enantioselective variant simply
4.5.4 Enantioselective Cyclizations
475
utilizes substrate 71 in conjunction with a bulky chiral BINOL-derived aluminum Lewis acid 72 (Eq. 21) [31]. Once again the steric bulk of the chiral aluminum Lewis acid complex favors the s-trans rotamer of the acceptor olefin. Facial selectivity of the radical addition can then be controlled by the chiral Lewis acid. The highest selectivity (48% ee) was achieved with 4 equivalents of chiral Lewis acid providing a yield of 63Y0. Bu3SnH, Et3B CH2Cl2, -78 "C, dry air
71 R = cyclohexyl 63 % yield
43% ee
72
4.5.4.1 Reagent-Controlled Enantioselection Occasionally, enantioselective reactions are possible where a prochiral substrate is allowed to react with a chiral reagent such that the diastereomeric transition state provides facial bias for the pending transformation. As previously stated, this is most beneficial when the chiral reagent can be recycled back into a useful form after the reaction has taken place. One area that has been well studied is the use of chiral tin hydride reagents for enantioselective hydrogen atom transfers. Early investigations into chiral tin hydride reagents looked into the transfer of chirality via a chiral tin center [32, 331. These tin hydrides, however, were prone to racemization, and as a result chiral carbon-based ligands were studied. The helical chirality of the binaphthyl group has been taken advantage of in the design of chiral tin reagents. An example of an enantioselective reduction using chiral tin hydride 75 is shown in Eq. (22) [34]. Low enantiomeric excesses of reduced products (41% ee) and low yields (often under 50%) as well as difficulty in synthesizing the chiral tin hydride reagents all serve to diminish the utility of these types of enantioselective reductions thus far. Replacing the methyl group in 75 with a t-butyl group offers a slight increase in enantioselectivity to 52% ee [35].
Ph B r h P h
xMe
+
0
74
Et3B, -78 "C *
Ph' 4 P h 0
75
(22)
76
Recently, a number of chiral tin reagents were surveyed and significant improvements in the levels of asymmetric induction and chemical yield were achieved.
416
4.5 Enantioselective Radical Reactions
& &
menPh2SnH
Me2N
77 men = men2PhSnH
\
A
78
/
W N M e . \
-
Sn(H)men2 80
79
tin Subst. yield % ee %
R &%OEt
81a 81b 81c 81d
-
Sn(H)men2
0 R=Me R=Et R = cyclopentyl R = f-BU
(S)
77
81b
51
42
78
81b
78
70 (S)
79
81b
79
52 (S)
80
81b
68
72 (s)
80
81c
75
96 (s)
Utilizing the menthol-derived chiral tin reagents 77-80 in conjunction with bulky Lewis acids such as zirconocene dichloride or a manganese-salen complex, selective reductions of esters (81a-d) offered excellent levels of selectivity up to 96Yn ee in a 75% yield (for reduction of 81c) [36]. Chiral stannane 80 offered the most consistent high levels of enantioselectivity for reduction of all substrates, ranging from 62% ee to above 90% ee in many cases with a bulky Lewis acid additive. Additional examples of reagent-based enantioselection involve the enantioselective hydrogen atom abstraction by chiral amine-boryl [ 371 or silanethiyl radicals [38], radical hydrosilation of prochiral alkenes mediated by chiral thiol catalysts [39], and reductive carboxyalkylation of electron-rich alkenes also using chiral thiol catalysts [40]. Each of these examples is based upon polarity reversal catalysis. Several excellent reviews are available for further information [41]. Typically, these reactions performed using polarity reversal conditions suffer from inconsistent levels of product enantioselectivity; often small changes in reaction conditions prove to be detrimental to the resultant selectivity of the transformation. There are, however, a few noteworthy examples where good levels of enantioselectivity are observed. The first involves the use of chiral amine-boryl radicals for enantioselective hydrogen atom abstraction in the kinetic resolution of carbonyl-containing substrates. f-BuO'
+
fast
R*BH2-NMe2R
t-BuOH +
82
R*bH-NMe2R
83
A:x -
+
fast
i-Pr02C
J;x
i-Pr02C
i-Pr02Cc. R*BH-NMe2R
I
R*BH2-NMe2R 82
+
(b)
LPrO2C
83 racemic - 84
85
86
(231
References
477
Enantioselective hydrogen atom abstraction by chiral amine boryl radical 83 allows for kinetic resolution of racemic ester 84. In the specific example illustrated in Eq. (23), the enantioselectivity of the residual enantiomer of the substrate reached 74% (R,R).It is postulated that a transition state as shown in 86 could account for the asymmetric hydrogen atom abstraction. Reasonable levels of enantioselectivity are also observed for the chiral hydrosilation of alkenes using optically active thiol catalysts. Several catalysts were screened, and it was found that the sugar-derived catalyst 89 provided optimal levels of selectivity at a loading of only 5 mol% (Eq. 24).
a.
+
1 a0
di-tert-butyl hyponitrite (5 %) Ph3SiH
Dioxane, 60" C
87 5 mol Yo *
*
p h 3 s i a o 88
Ph3Si AC c& fH :
90
89
Yield
ee
72%
50%
4.5.5 Conclusions In closing, it has been proven that radical chemistry can indeed be performed enantioselectively. In fact in certain systems they even rival results obtained using well-established ionic chemistry while still reaping the benefits of radical reactions including mild reaction conditions and water tolerance in most cases. This short review of current enantioselective methods for carbon-carbon bond construction, however, shows that there remains quite a range of chemistry to be discovered in this still emerging field.
References [ 11 For leading monographs describing diastereoselective radical chemistry see: (a) B. Giese, Radicals in Organic Synthesis. Formation of Carbon-Carbon Bond, Pergamon, Oxford, 1986. (b) D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of Radical Reactions, VCH, Weinheim, 1995. For key reviews on diastereoselective radical reactions see: (a) B. Giese, Angew. Chem., Int. Ed. Engl. 1989, 28, 969. (b) N. A. Porter, B. Giese, D. P. Curran, Ace. Chern. Res. 1991,24, 296-301. (c) W. Smadja, Synlett 1994, 1-26. (d) A. L. Beckwith, J. Chem. SOC.Rev. 1993, 143. For an excellent recent review on Lewis acid-mediated radical reactions see: P. Renaud, M. Gerster, Angew. Cheni. Int. Ed. Engl. 1998, 37, 2562-2579.
418
4.5 Enantioselective Radical Reactions M. P. Sibi, N. A. Porter, Ace. Chem. Res. 1999, 32, 163-171. M. Murakata, H. Tsutsui, 0. Hoshino, J. Chem. Soc., Chem. Commun. 1995, 481-482. M. Murakata, H. Tsutsui, N. Takeuchi, 0. Hoshino, Tetrahedron 1999, 55, 10295-10304. H. Urdbe, K. Yamashita, K. Suzuki, K. Kobayashi, F. Sato, J. Org. Chem. 1995, 60, 35763577. S . Shambayati, S . L. Schreiber, Comprehensive Organic Synthesis; B. M. Trost, Ed.; Pergamon: Oxford, 1991, Vol. 1, p 283. J. H. Wu, R. Radinov, N. A. Porter, J. Am. Chem. SOC.1995, 117, 11029-11030. J. H. Wu, G. Zhang, N. A. Porter, Tetrahedron Lett. 1997, 38, 2067-2070. (a) E. J. Corey, K. Ishihara, Tetrahedron Lett. 1992, 33, 6807-6810. (b) D. A. Evans, S. J. Miller, T. Lectka, J. Am. Chem. Soc. 1993, 115, 6460-6461. N. A. Porter, J. H. Wu, G. Zhang, A. D. Reed, J. Org. Chem. 1997,62, 6702-6703. N. A. Porter, H. Feng, I. K. Kavrakova, Tetrahedron Lett. 1999, 40, 6713-6716. A.-R. Fhal, P. Renaud, Tetrahedron Lett. 1997, 38, 2661-2664. M. Murakdta, T. Jono, Y. Mizuno, 0. Hoshino, J. Am. Chem. SOC.1997, 119, 11713-11714. M. Murakata, T. Jono, 0. Hoshino, Tetrahedron: Asymmetry 1998, 9, 2087-2092. K. Mikami, M. Yamaoka, Tetrahedron Lett. 1998, 39, 4501-4504. T. Kikukawa, T. Hanamoto, J. Inanaga, Tetrahedron Lett. 1999, 40, 7497-7500. K. Tomooka, K. Yamamoto, T. Nakai, Angew. Chem. Int. Ed. Engl. 1999,38, 3741-3743. (a) P. Beak, A. Basu, D. J . Gallagher, Y. S . Park, S. Thayumanavan, Ace. Chem. Res. 1996, 29, 552-560; (b) D. Hoppe, T. Hense, Angew. Chem. 1997, 97, 2376-2410. S. Matsubara, Y. Hashimoto, T. Okano, K. Utimoto, Synlett 1999, 9, 1411-1412. 1996, 118, 9200-9201. M. P. Sibi, J. Ji, J. H. Wu, S. Gurtler, N. A. Porter, J. Am. Chem. SOC. M. P. Sibi, J. Ji, J. Org. Chem. 1997, 62, 3800-3801. I. W. Davies, L. Gerena, L. Castonguay, C. H. Senanayake, R. D. Larsen, T. R. Verhoeven, P. J. Reider, J. Chem. Soc., Chem. Commun. 1996, 1753-1754. For work on octahedral cis-models using iron Lewis acids see: E. J. Corey, N. Imai, H.-Y. Zhang, J. Am. Chem. Soc. 1991, 113, 728-~729.For an octahedral model using Mg Lewis acid see: G. Desimoni, G. Faitd, P. P. Righetti, Tetrahedron Lett. 1996, 37, 3027-3030. M. P. Sibi, J. J. Shay, J. Ji, Tetrahedron Lett. 1997, 38, 5955-5958. U. Iserloh, D. P. Curran, S. Kanemasa, Tetrahedron: Asymmetry 1999, 10, 2417-2428. H. Miyabe, C. Ushiro, M. Ueda, K. Yamakawa, T. Naito, J. Org. Chem. 2000, 65, 176-185. C. Mero, N . A. Porter, J. Am. Chem. Soc. 1999, 121, 5155-5160. M. Kameyama, N. Kamigata, M. Kobayashi, J. Org. Chem. 1987, 52, 3312-3316. S. Murai, R. Sugise, N. Sonoda, Angew. Chem. Int. Ed. Engl. 1981, 20, 475-476. M. Nishida, H. Hayashi, 0. Yonemitsu. Synlett 1995, 1045-1046. M. Nishida, H. Hayashi, A. Nishida, N. Kawahara, J. Chem. Soc., Chem. Commun. 1996, 579-580. For the synthesis of compounds chiral at tin see: (a) H. Mokhtar-Jamai, M. Gielen, Bull. Chem. Soc. Belg. 1975, 84, 197-202. (b) J. Vigeron, J. Jacquet, Tetrahedron, 1976, 32, 939. (c) M. Gielen, Y. Tondeur, J. Organomet. Chem. 1979, 169, 265-281. For a recent example using reagents chiral at the tin center see: K. Schwarzkopf, M. Blumenstein, A. Hayen, J. 0. Metzger, Eur. J. Org. ChLm 1998, 177-181. D. Nanni, D. P. Curran, Tetrahedron: Asymmetry 1996, 7, 2417-2422. M. Blumenstein, K. Schwarzkopf, J. 0. Metzger, Angew,. Chem. Int. Ed. Engl. 1997, 36, 235236. D. Dakternieks, K. Dunn, T. Perchyonok, C. H. Schiesser, Chem. Commun. 1999, 1665-1666. H . 6 . Dang, V. Diart, B. P. Roberts, J. Chem. Soc., Perkin Trans. 1 1994, 1033-1040. H.-S. Dang, B. P, Roberts, Tetrahedron Lett. 1995, 36, 3731-3734. (a) M. B. Haque, B. P. Roberts, Tetrahedron Lett. 1996,37,9123-9126. (b) M. B. Haque, B. P. Roberts, D. Tocher, J. Chem. Soc., Perkin Trans. 1 1998, 2881-2889. H.-S. Dang, K.-M. Kim, B. P. Roberts, J. Chem. Soc., Chem. Commun. 1998, 1413-1414. B. P. Roberts, Chem. Soc. Rev. 1999, 28, 25-35.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
5 Polymers
5.1 Living-Radical Polymerizations, an Overview Michael Georges
5.1.1 Introduction Of all the various types of polymerization processes that are available to the synthetic chemist, the free-radical polymerization process is probably the most popular. It is easy to perform, requires minimal purification of monomers, can be performed under a wide variety of conditions and is economical. However, dead polymers form throughout the course of the polymerization resulting in not only poor control over molecular weights but also an inability to make polymers with complex architectures. To overcome these limitations, one can imagine trying to manipulate the free-radical process to behave in a living manner. This chapter focusses on the progress made in the last few years in the area of living-radical polymerizations [I]. The intent is to give a general overview of the main living-radical polymerizations, with a discussion at the end on the feasibility of commercializing these processes. Detailed technical reviews of the iniferter [ 131 and atom transfer radical polymerization [40] processes have been published. One on the nitroxide-mediated radical polymerization process is in preparation and will be published shortly.
5.1.2 Historical Background Like other ‘overnight’ discoveries, the present success of living-radical polymerization is built on the work of pioneers in the field who laid the groundwork for what was to come. The first indication that a terminated polymer prepared by a freeradical polymerization could chain extend was reported by Braun [2]in 198 1. Thus, a purified oligomeric methyl methacrylate, terminated with a primary radical from 1,1,2,2-tetraphenyl-I,2-diphenoxyethane, grew to a higher molecular weight when heated in the presence of more methyl methyacrylate. The beginnings of a livingradical polymerization process were defined. Living-radical polymerizations are essentially conventional radical polymerizations performed in the presence of some species that react reversibly with the
5. I Living-Radical Polymerizations, an Overview
480
I.
P,.
+
T
+
Pn-T
Monomer
P,.
+
T
Pn
M
P .,
+
T
3
Pm-T
Scheme 1. General reaction scheme for living-radical polymerizations
propagating chains. The general chemistry of a living-radical polymerization process is illustrated in Scheme 1. After initiation, a propagating radical chain (P,,') will either add monomer (M) and continue to grow, or react with a reversible capping species, T, to form a dormant chain (P,-T). At any given time most of the polymer chains are in the dormant form and the concentration of the active chains is so low (lop6 M ) that the probability of two chains colliding with each other and terminating is dramatically reduced. Although some termination continues to occur throughout the course of the polymerization [ 31, the amount decreases progressively as the polymerization proceeds, since termination by coupling generally involves at least one very short chain [4]. At high conversions (>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<
HO*SH
C02Et 2b,3p,4a-41
77% 2p,3a,4a-40
y..oOTBDMS +
anti-39
OQ,tiOTBDMS 8217
2p,3 (r,4p41
C02Et 2b33a,4a-41
Scheme 17. Stereocontrol in the Bachi reaction
new method of temporary sulfur connection entailing linking of the CHZCOzMe moiety to the chiral iso-propenyl anchor, intramolecular connection to the pyrroline ring, and eventual disconnection from the anchor by a sequential reductive double elimination (Scheme 18) [ 231. SEt
k:: EtSH
y /
-
c .
QoH BOC' C02t-Bu
(4,s'LC02Me
BOC'
C02t-Bu
43
Scheme 18. The Bachi synthesis of kainic acid
1.3.6 Miscelluny
57
It is worth noting that the same kind of reactions can be carried out by tinradical-mediated ring closure of analogous isothiocyanates (e.y., 33, 37, 39, NC = NCS) [22b,c]. In this case, the intermediate a-thio-substituted imidoyl radical is generated by addition of a stannyl radical to the sulfur atom of the isothiocyanate. Although it had been known for a few decades, this way to imidoyl radicals had found very little application in organic synthesis. Bachi's work was the first example of synthesis of heterocyclic compounds by radical addition to isothiocyanates, showing the way to further possible applications [9].
1.3.6 Miscellany There are a few other interesting radical reactions with isonitriles that could not find a place in the above categories but are worth mentioning. Among them, the first is Barton's method for carboxyl group labelling [24]. In one of his studies on radical generation from esters of N-hydroxy-2-thiopyridone, Barton discovered that decomposition of thiohydroxamic ester 44 in the presence of an isonitrile furnished adduct 45 through the addition of radical R to the isonitrile and trapping of the resulting imidoyl radical by the starting ester. Since 45 can be easily hydrolyzed to the corresponding carboxylic acid 46 and the starting compound 44 is readily accessible from the same derivative 46, the overall process can serve as a method to incorporate 13C in the carboxylic acid simply by using an isotopically enriched isonitrile (Scheme 19). This method can be useful for the labelling of the carboxyl group in prostaglandins and the side-chain carboxyls of peptides.
O
S
---
Y
R ..
R'-N=C.
4
p
45
46 (C =
13C)
t Scheme 19. The Barton reaction for carboxyl group labelling
I
58
1.3 Isonitriles: a Useful Trap in Radical Chemistry
'b9 '' &
PO PO
hv
OP TeAr
+
CN
hea;
PO
PO
-
o p% 'o
48TeAr
47
%
Scheme 20. Isonitriles in the radical synthesis of 1 -acyl glycoside derivatives
Another very recent application of radical addition to isonitriles is the radical-mediated imidoylation of telluroglycosides 47 [25].These compounds were found to react with isonitriles under photothermal conditions to give l-telluroimidoglycosides 48 through an atom transfer radical reaction (Scheme 20). Products 48 can be further transformed into imidic esters and I-acyl glycosides, a class of derivatives that are part of important biologically active compounds. Finally, a novel three-component radical cascade reaction involving isonitriles has just been published [6]. In this paper, aromatic disulfides, alkynes, and isonitriles have been reported to react under photolytic conditions to afford p-arylthiosubstituted acrylamides 49 or acrylonitriles 50 in fair yields as mixtures of the E and Z geometric isomers (Scheme 21). The procedure entails addition of a sulfanyl radical to the alkyne followed by attack of the resulting vinyl radical on the isonitrile. A fast reaction, for example, scavenging by a nitro-derivative (route a) or pfragmentation (route b), is necessary in order to trap the final imidoyl radical, since addition of vinyl radicals to isonitriles seems to be a reversible process. The reaction provides very easy access to potentially useful poly-functionalized alkenes through a very selective tandem addition sequence. The stereochemistry of the tandem reaction is of significance. The lower or even inverted preference for either geometrical isomer observed in this case with respect to that encountered in related hydrogen abstraction reactions by the same vinyl radicals was explained in terms of transition state interactions in the addition step to the isonitrile and/or isomerization of the final imidoyl radical. The latter possi-
Scheme 21. Synthesis of poly-functionalized alkenes through a three-component radical cascade reaction with isonitriles
References
59
51
Scheme 22. Structure of B,y-unsaturated imidoyl radicals
bility was studied by semi-empirical methods. The results of these calculations, the first theoretical study performed on these radicals, clearly confirm that both the structure and spin distribution of imidoyl radicals strongly depend on the substitution at the radical center. In the case of P,y-unsaturated imidoyls 51, the possibility of conjugation gives the intermediate a quasi-linear arrangement (170.5") of the N=C-C moiety and a maximum spin density on the C, atom (0.40) instead of the expected C, carbon (0.28) (Scheme 22). Calculation of the rotation barrier around the Cp-C, bond confirmed that rotation of the carbon-carbon double bond can efficiently compete with /?-fragmentation leading to the final alkene, thus altering the expected stereochemistry.
1.3.7 Conclusions All of the above reactions have thoroughly proved that isonitriles, rather than being a mere curiosity in the field of organic chemistry, are exceptionally versatile intermediates for useful transformations. This had already been proved by the usual 'non-radical' studies, but was definitely confirmed by the great deal of work on their use as radical traps that has flourished in recent years and is expected to continue in the future. Cyclizations, annulations, and other cascade reactions with imidoyl radicals, their radical adducts, have proven to be not an academic pastime but instead a useful tool for the synthesis of heterocyclic compounds and other interesting derivatives, even with high stereocontrol. Furthermore, the geminal radical acceptor/radical donor properties of isonitriles, a feature shared with carbon monoxide only, place them in a very distinct class of radicophiles, whose potentialities have unquestionably not been fully exploited yet. It is to be hoped that the next years could keep the promises isonitriles have made to a more and more demanding organic synthesis.
References [ I ] For a general review on isonitrile chemistry see: (a) P. Hoffmann, D. Marquarding, H. Kliimann, 1. Ugi, Isonitriles, in The Chemistry oj the Cyano Group (Eds. S. Patai and Z.
60
1.3 Isonitriles: a Usejul Trap in Radical Chemistry
Rappoport), Wiley, London, 1970, Chap. 15; (b) I. Ugi, Isonitrile Chemistry, Academic, New York, 1979; (c) R. Grashey, Synthesis of’ Pseudohalides, Nitriles and Related Compounds, in Comprehensive Organic Synthesis (Eds. B. M. Trost and I. Fleming), Vol. 6, Pergamon, Oxford, 1991, Chap. 1.8.2; (d) W. Kantlehner, Synthesis of Iminium Salts, Orthoesters and Related Compounds, ihid., Vol. 6, Chap. 2.7.2.1.1; (e) R. Bishop, Ritter-type Reactions, ibid., Vol. 6, Chap. 1.9.4.2; ( f ) I. Ugi, S. Lohberger, R. Karl, The Passerini and Ugi Reactions, ibid., Vol. 2, Chap. 4.6; for multicomponent reactions with isonitriles see: A Domling, I. Ugi, Angew. Chem. Int. Ed. 2000, 39, 3 I68 and references therein. [2] This terminology was first introduced by Curran et al. in 1991: D. P. Curran. H. Liu, J. Am. Chem. Soc. 1991, 113, 2127. [3] D. H. Shaw, H. 0. Pritchard, Can. J. Chem. 1967, 45, 2749. A free-radical chain mechanism for the isonitrile-nitrile rearrangement in solution was definitely claimed by Ruchardt in 1983: M. Meier, C. Ruchardt, Tetrahedron Lett. 1983, 24, 4671. Radical addition to isonitriles had been previously claimed by Shono: T. Shono, M. Kimura, Y. Ito, K. Nishida, R. Oda, Bull. Chem. Soc. Jpn. 1964, 37, 635. [4] T. Saegusa, S. Kobayashi, I. Yoshihiko, N. Yasuda, J. Am. Chem. Soc. 1968, 90, 4182. [5] (a) T. Saegusa, S. Kobayashi, I. Yoshihiko, J. Org. Chem. 1970, 35, 21 18; (b) R. E. Banks, R. N. Haszeldine, C. W. Stephens, Tetrahedron Lett. 1972, 3699; (c) L. A. Singer, S. S. Kim, Tetrahedron Lett. 1974, 861; (d) P. M. Blum, B. P. Roberts, J. Chem. Soc., Chem. Commim. 1976, 535; (e) S. S. Kim, Tetrahedron Lett. 1977, 2741; ( f ) P. M. Blum. B. P. Roberts, J. Chem. Soc., Perkin Trans. 2 1978, 1313; (g) D. H. R. Barton, G. Bringmann, W. B. Motherwell, J. Chem. Soc., Perkin Trans. I 1980, 2665; (h) G. Stork, P. M. Sher, J. Am. Chem. Soc. 1983, 105, 6765. [6] R. Leardini, D. Nanni, G. Zanardi, J. Org. Chem. 2000, 65, 2763. [7] An analogous deamination method was worked out by Ruchardt through generation of imidoyl radicals by halogen abstraction from imidoyl chlorides: T. Wirth, C. Ruchardt, Clzinzia 1988, 42, 230. [8] (a) D. H. R. Barton, G. Bringmann, G. Lamotte, W. B. Motherwell, R. S. Hay Motherwell, A. E. A. Porter, J. Chem. Soc., Perkin Trans. 1 1980, 2657; (b) Z. J. Witczak, Tetrahedron Lett. 1986, 27, 155; (c) M. D. Bachi, D. Denenmark, J. Org. C h m . 1990, 55, 3442. [9] R. Leardini, D. Nanni, P. Pareschi, A. Tundo, G. Zanardi, J. Ory. Chenz. 1997, 62, 8394. L. Benati, R. Leardini, M. Minozzi, D. Nanni, P. Spagnolo, G. Zanardi, J. Ory. Chem. 2000, 65, 8669. [ 101 D. Nanni, P. Pareschi, A. Tundo, Tetrahedron Lett. 1996, 37, 9337. [ I l l W. C. Danen, C. T. West, J. Am. Chem. Soc. 1973, 95, 6872. [12] D. Griller, J. W. Cooper, K. U. Ingold, J. Am. Chem. Soc. 1975, 97, 4269. [13] V. Diart, B. P. Roberts, J. Cliem. Soc., Perkin Trans. 2 1992, 1761. [ 141 P. Pareschi, “Imidoyl Radicals: Spectroscopic Properties, Reactivity, and Use in the Synthesis of’ Heterocyclic Conzpounds”, PhD Thesis, University of Bologna, Italy, 1996, Chap. 1, in collaboration with J. C. Walton, University of St. Andrews, UK. 1151 (a) R. Leardini, G. F. Pedulli, A. Tundo, G. Zanardi, J. Chem. Soc., Chem. Commun. 1984, 1320; (b) R. Leardini, A. Tundo, G. Zanardi, G. F. Pedulli, Synthesis 1985, 107; (c) R. Leardini, D. Nanni, G. F. Pedulli, A. Tundo, G. Zanardi, J. Chem. Soc., Perkin Trans. I 1986, 1591; (d) R. Leardini, D. Nanni, A. Tundo, G. Zanardi, Gazz. Chim. Ital. 1989, 119, 637; (e) R. Leardini, D. Nanni, A. Tundo, G. Zanardi, J. Chem. Soc., Clzem. Commun. 1989, 757; ( f ) M. D. Bachi, D. Denenmark, J. Am. Chem. Soc. 1989, 111, 1886; (g) R. Leardini, D. Nanni, M. Santori, G. Zanardi, Tetrahedron 1992, 48, 3961; (h) S. Guidotti, R. Leardini, D. Nanni, P. Pareschi, G. Zanardi, Tetrahedron let^ 1995, 36, 451; (i) R. Leardini, H. McNab, D. Nanni, Tetrahedron 1995, 51, 12143; (j) Y. Dan-oh, H. Matta, J. Uemura, H. Watanabe, K. Uneyama, Bull. Cliem. Soc. Jpn. 1995, 68, 1497. [I61 (a) D. P. Curran, H. Liu, J. Am. Clzem. Soc. 1992, 114, 5863; (b) D. P. Curran, J. Sisko, P. E. Yeske, H. Liu, Pure Appl. Clzem. 1993, 65, 11 53; (c) D. P. Curran, S.-B. KO, H. Josien, Angew. Chem. Int. Ed. 1995, 34, 2683; (d) I. Ryu, N . Sonoda, D. P. Curran, Cl7em. Rev. 1996, 96, 177; (e) D. P. Curran, H. Liu, H. Josien, S.-B. KO, Tetrahetlron 1996, 52, 11385; (f) H. Josien, D. P. Curran, Tetralzedron 1997, 53, 8881; (g) H. Josien, D. Bom, D. P. Curran, Y.-H. Zheng, T.-C.
References
61
Chou, Bioory. Med. Chem. Lett. 1997, 7, 3189; (h) H. Josien, S.-B. KO, D. Bom, D. P. Curran, Chem. Eur. J. 1998, 4 , 67. [ 171 D. Nanni, P. Pareschi, C. Rizzoli, P. Sgarabotto, A. Tundo, Tetrahedron 1995, 51, 9045. [ 181 C. M. Camaggi, R. Leardini, D. Nanni, G . Zanardi, Tetrahedron 1998, 54, 5587. [19] (a) T. Fukuyama, X. Chen, G . Peng, J. Am. Chem. Soc. 1994, 116, 3127; (b) Y. Kobayashi, T. Fukuyama, J. Heterocyclic Chem. 1998, 35, 1043. [20] H. Tokuyama, T. Yamashita, M. T. Reding, Y. Kaburagi, T. Fukuyama, J. Am. Chem. Soc. 1999, 121, 3791. [21] J. D. Rainier, A. R. Kennedy, E. Chase, Tetrahedron Lett. 1999, 40, 6325. [22] (a) M. D. Bachi, A. Balanov, N. Bar-Ner, J. Ory. Chem. 1994, 59, 7752; (b) M. D. Bachi, A. Melman, J. Ory. Chem. 1995, 60, 6242; (c) M. D. Bachi, A. Melman, Synlett 1996, 60; (d) M. D. Bachi, N. Bar-Ner, A. Melman, J. Org. Chem. 1996, 61, 7116; (e) M. D. Bachi, A. Melman, J. Org. Chem. 1997, 62, 1896; (f) M. D. Bachi, A. Melman, Pure Appl. Chem. 1998, 70, 259. [23] A particularly convenient procedure for the enantioselective total synthesis of (-)-a-kainic acid also employed tin-radical-mediated cyclization of an alkenyl monothioformimide (See Ref. 22e). [24] D. H. R . Barton, N. Ozbalik, B. Vacher, Tetrahedron 1988, 44, 3501. [25] S. Yamago, I. Miyazoe, R. Goto, J.-I. Yoshida, Tetruhedron Lett. 1999, 40, 2347.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
1.4 Homolytic Aromatic Substitutions Arrnido Studer and Martin Bossart
Radical arylations can either be performed by S R N reactions ~ or by homolytic aromatic substitutions. The SRN1 type reactions have recently been reviewed [ 11 and will not be included in the present article. Because of space limitations this review will focus on examples mostly from the recent literature. Especially for the older literature, we refer to several good review articles on homolytic aromatic substitutions which appeared in the 1960s, 1970s and 1980s [2].
1.4.1 Intermolecular Homolytic Aromatic Substitutions 1.4.1.1 Aromatic Substitutions with Nucleophilic C-Radicals The reaction of a nucleophilic alkyl radical R' with benzene affords the o-complex 1, a fairly stable cyclohexadienyl radical, which under oxidizing conditions leads to cation 2 (Scheme 1). Depending on the stability of the attacking radical, the formation of 1 is a reversible process. Deprotonation eventually affords the homolytic aromatic substitution product 3. If the reaction is performed under non-oxidizing conditions, cyclohexadienyl radical 1 can dimerize (+ 4),disproportionate to form cyclohexadiene 5 and the arene 3, or further react by other pathways [3]. Along with these side reactions, there are additional problems associated with these processes. A major limitation is the slow initial reaction of the alkyl radical with benzene derivatives. For example, the rate of a-complex formation for the reaction of the butyl radical with benzene is 3.8 x lo2 M p l spl a t 79°C [4]. This is far below the rate of an efficient radical reaction. Other possible side reactions of the alkyl radicals, such as rearrangement, dimerization, disproportionation, halogen as well as hydrogen abstraction can therefore compete with the addition to benzene. Furthermore, the reactivity of the homolytic aromatic substitution product 3 toward alkyl radical addition is only slightly diminished as compared to the reactivity of the starting benzene. Overalkylation is a serious problem. The homolytic aromatic substitution with differently substituted benzene derivatives has been carefully studied by various groups [2]. Generally, the regioselectivity of the alkyl radical
1.4.1 Intermolecular Homolytic Aromatic Substitutions
1
2
Scheme 1. Homolytic aromatic substitution
-
63
3
a general scheme
addition to substituted benzene derivatives is low [ 5 ] . High selectivities were only obtained in the reactions of nucleophilic radicals with benzene derivatives bearing electron-withdrawing substituents. For example, the reaction of methyl benzoate with the adamantyl radical gave the para product with rather high regioselectivity (ortho:meta:para= 0:5:95) [6]. Similar results were obtained in the reaction with heteroarenes, such as thiophene, furan, and thiazole, where the homolytic aromatic substitution occurred regioselectively, but in low yields [7]. Recently, a base promoted homolytic aromatic substitution of electron-deficient arenes was developed in the Russell laboratory. Alkylmercury halides [8] or alkyl halides [9] were reacted with arenes in the presence of 1,4-diazabicyclo[2,2,2]octane (DABCO) to afford the corresponding alkylation products (Scheme 2). The following mechanism was suggested for these interesting reactions. The nucleophilic radical generated from the alkyl or alkylmercury halide adds to the electron-deficient arene to give radical 6. Deprotonation with DABCO then affords radical anion 7, which is oxidized by the starting halide or the mercury compound to give the homolytic aromatic substitution product 8. In the case of the mercury halides, the radical anion (RHgX'-), generated in the oxidation of 7, fragments to elemental mercury, the chain-propagating radical R and X-. A similar chain transfer also occurs if alkyl halides are used instead of the toxic alkylmercury compounds [9]. However, these processes only work well if nucleophilic radicals such as tert-butyl radicals are used together with activated, electron-poor benzene derivatives. In summary, the intermolecular homolytic aromatic substitution of benzene derivatives with nucleophilic C-radicals is not a synthetically useful reaction and is only efficient in a few limited cases.
R
R.
PhZ
R
H
Q
DABCO
Q
Z
Z
6
7
R-HgX (Or R-X)
R ~
+
- Hg(O) - x-
Scheme 2. Base-promoted homolytic aromatic substitution
Z
8
Re
64
1.4 Homolytic Aromatic Substitutions X
X
(R = Me, Bu, sBu, tBu)
X
Me'
Bu'
sBu'
tBu'
CN COMe CI H Me OMe
12.5 3.6
20.3 5.6 1 0.3 0.1
259.0 55.6 1 0.3 0.02
1890 144 11.1 1 0.15 0.005
2.4 1 0.5 0.3
Scheme 3. Relative rates for the alkylation of protonated para-substituted pyridines with methyl-, butyl-, sec-butyl- and tert-butyl radicals
More important is the radical alkylation of protonated heteroaromatic compounds, the so-called Minisci reaction [2e, 2g, 101. Protonated heteroarenes are electron-deficient substrates, which react with nucleophilic radicals with high regioselectivity to yield the corresponding homolytic aromatic substitution products. In the case of para-substituted pyridine derivatives, the substitution process is very clean, and the reaction occurs with complete regioselectivity at the 2-position. The rate of radical addition to the protonated heteroarene correlates with the nucleophilicity of the attacking radical. Thus, tert-butyl radical addition to 4-cyanopyridine in an acidic medium is about 70 times faster than the analogous process with the primary butyl radical [ l l ] . On the other hand, electrophilic radicals, such as 'CH2C02H, 'CH2CN and 'CH2N02 do not react with protonated pyridines. Furthermore, the reactivity toward aromatic substitution depends on the electrophilicity of the arene moiety. The highest rates were observed for the addition to the electron-poor 4-cyanopyridium salts (Scheme 3). Similar reactions with the 4-methoxy derivative are up to 3.5 x lo5 times slower [ I 1, 121. In a non-acidic medium, homolytic aromatic substitutions of pyridines with nucleophilic radicals occur with low regioselectivity and generally in low yields, being very similar to the reactions with substituted benzene derivatives as discussed above. These reactivity trends clearly show that polar effects are involved in these radical substitution reactions. The transition state is thought to include a charge transfer (+ 9) from the radical (electron donor) to the pyridinium ion (electron acceptor) [13]. Frontier Molecular Orbital Theory (FMO) [14] has been applied to explain the reactivity differences which have been observed upon varying the substituents at the pyridinium ion and upon altering the nucleophilicity of the attacking radical. Moreover, FMO can be used to explain the regioselectivities obtained in these homolytic aromatic substitutions. The LUMO of the substituted pyridinium cation
1.4.1 Intermolecular Homolytic Aromatic Substitutions
65
has the highest coefficients at the carbon atoms 2 and 4 [ 151. The dominant interaction of the radical addition is between the SOMO of the nucleophilic radical and the LUMO of the protonated heteroarene. Since the 4-position is blocked in the para-substituted systems discussed above, addition occurs regioselectively at the 2-position.
[.+@I
x
+
77% (H20) 29% (benzene)
4 H 9
R3
0 / ' +
23% (H20) 71Yo (benzene)
10 (with Bu')
/(-k H+
R'
1l a (1.5%, R' = Et, R' = R3 = H) 11b (21.5%, R' = Et, R' = R3 = H) 1I C (41.5%0, R' = R3 = Et, R' = H) 1 Id (26.5%0, R' = R' = Et, R3 = H) 1 le (9%, R' = R' = R3 = Et)
For the unsubstituted pyridinium cation, reaction at the 2- and at the 4-position is predicted according to the theory. Indeed, reaction of protonated pyridine with the tert-butyl radical at low conversions (<30%) afforded selectively the ortho- and para-substituted derivatives without any alkylation at the meta position [ 161. It turned out that the ortho-para ratio is highly solvent dependent. If the reaction is conducted in H20, the para product is formed as the major compound (see 10, ortho:para = 23:77). The same reaction in benzene afforded mainly the ortho compound (ortho:para = 71:29). The reversal of the selectivity can be explained by assuming a reversible initial radical addition, especially if the reaction is conducted in H20 [16]. Similar results were obtained for the reaction with the tetrahydrofuryl radical [16]. The alkylations are generally stopped at low conversions. Since the alkylated pyridinium cations are only slightly less electrophilic than the starting pyridinium cations, overalkylation competes at higher conversion. For example, ethylation of the pyridinium cation at 100'30 conversion afforded a mixture of mono-, double- and tri-ethylated pyridinium salts (+ lla-e) [ 171. The Minisci reaction has successfully been applied for the alkylation of various heteroarenes, i. e. lepidine, pyrazine, quinoline and quinoxaline [2e, 2g, 101. Organic compounds such as alkanes, alkenes, carboxylic acids, esters, amides, amines, alcohols, ethers, aldehydes, ketones, halides etc. have been successfully used as radical precursors in the Minisci reaction. A good overview of the different methods which have been applied to generate the alkyl radicals in these processes is summarized in [lob]. Acyl-, carbamoyl- and alkoxycarbonyl radicals have been shown to add to protonated heteroarenes with high efficiency [2, 101. The regioselectivity of these reactions is very similar to the regioselectivities obtained in the analogous alkylations discussed above. In contrast to the Friedel-Crafts acylation, where the acylated product is highly deactivated toward further acylation, the acylated heteroarenes are more reactive towards a second radical acylation. This is because of the higher electrophilicity of the protonated heteroarene after initial acylation. To suppress
66
1.4 Homolytic Aromatic Substitutions
the second acylation, the reactions can be performed in an HzO/organic biphasic reaction medium, where the product due to its higher lipophilicity is continuously extracted into the organic phase and is therefore prevented from further acylation [18, 191. High yields of the monoacylated product can be obtained using this modified procedure.
1.4.1.2 Aromatic Substitutions with Electrophilic C- and N-centered Radicals The first examples of homolytic aromatic substitutions with electrophilic C-radicals were published by Heiba et al. in the late 1960s. Toluene was reacted with acetic acid in the presence of either lead tetraacetate [20a] or manganese(II1) acetate (Mn(OAc)3) [20b] to afford the regioisomers of tolylacetic acid along with various side products. After initial oxidation of the acetic acid to a carboxymethyl radical ('CHZCO~H), the arene can react via intermolecular homolytic aromatic substitution to form the corresponding arylated acetic acids (see Scheme 1, R = CH2C02H, ox. = Mn(OAc)3 or Pb(OAc)4). Later, acetone was shown to be oxidized by Mn(OAc)3 to the corresponding electrophilic C-radical, which in turn can react in a homolytic substitution with toluene to afford 1-p-tolylpropan-2-one [21]. Similar reactions were later more carefully studied by Kurz [22]. He showed that the reaction outcome depends on the nucleophilicity of the arene. In contrast to the reactions with nucleophilic C-radicals, better results were obtained with electron-rich arenes. Thus, anisole gave 740/0 of the corresponding arylated acetone derivative, whereas the analogous reaction with chlorobenzene afforded the product in only 25% yield. The alkylated arenes were always obtained as regioisomeric mixtures. Nitromethylation of arenes can also be conducted under similar conditions [23]. In general, the 'electrophilic' homolytic aromatic substitution using Mn(OAc)3 as an oxidant can be performed with methylene derivatives bearing acidifying, electron withdrawing substituents. It is obvious that dialkyl malonates have been used as radical precursors in these processes [24a]. For example, the transformation of indole 12 to 13, comprising an intermolecular followed by an intramolecular aromatic malonylation is depicted in Scheme 4 [25a]. Cerium (IV) ammonium nitrate (CAN) has also been successfully applied as the oxidant in the aromatic malonylation [24b]. Recently, Minisci reported the use of Pb(OAc)4 to generate alkyl radicals from alkanoic acids (RC02H), which were then allowed to react with maleic anhydride to afford the corresponding electrophilic C-radicals 14. These radicals then further reacted with various arenes to yield after oxidation a-arylated-P-alkylated maleic anhydride derivatives 15 as a diastereoisomeric mixture [25b]. More recently, Baciocchi [26a] and Byers [26b] showed that cc-iodo esters, a-iodo malonates and a-iodo carbonitriles can be used as radical precursors in the aromatic substitution of various heteroarenes. The perfluoroalkylation of arenes is also possible using the same method [27]. Homolytic aromatic amination with electrophilic dialkyl aminyl radical cations is a valuable method for the preparation of aniline derivatives [2e, 1OaI. The radical cations (R2HN+') are generally prepared from the corresponding N-chloroamines
I . 4. I Intermolecular Homolytic Aromatic Substitutions
67
(83%) 13 (R = C02Me)
12
RCOzH
+
no
0
0
- 2-f Aryl-H
Pb(OAc)4
0
0 14
0
0
x
.
0
0
0
15
Scheme 4. Mn(OAc)3- and Pb(OAc)d-mediated aromatic substitutions
in acidic medium using catalytic amounts of a metal salt (Fe2+,Ti3+,Cu+ and Cr2+ salts). The reaction works best for electron-rich arenes such as phenols and phenyl ethers. In the amination of monosubstituted benzene derivatives, a mixture of the ortho and para isomer is formed, with the para compound as the main product. For further information on this reaction, we refer to two good review articles [2a, lOa].
1.4.1.3 Intermolecular Homolytic ips0 Substitutions Intermolecular homolytic @so substitution reactions have not received much attention and are not of synthetic importance [28]. They only occur if several criteria are fulfilled: generally, the attacking radical has to be nucleophilic. Furthermore, the reactions are only efficient for electron-poor arenes, and an additional important issue is the ability of the group to be replaced to act as a leaving group. Often, radical attack at an unsubstituted position competes with the @so attack or is even the exclusive reaction pathway. For example, reaction of thiophene 16 with the nucleophilic adamantyl radical afforded the ips0 product 18 in 45% yield, whereas the analogous reaction with the methyl radical gave selectively the homolytic aromatic substitution product 17 (35'1/0, Scheme 5) [28]. In the case of the nucleophilic 1-adamantyl radical, the regioselectivity of the attack is controlled by polar effects, whereas for the methyl radical, where polar effects are less important, the stability of the intermediate o-complex is responsible for the regioselectivity of the attack [28]. A similar change in the reaction outcome upon changing the attacking radical (1-adamantyl versus methyl radical) was observed in the reaction with 1,3,5trinitrobenzene [29]. Alkyldenitration by the 1-adamantyl radical in para-substituted nitrobenzenes (p-X-C6H4-N02) is an efficient process only for electron-poor arenes. Thus, while for anisole ( X = OMe), benzene ( X = H) and toluene ( X = Me) derivatives no ips0 products were observed, the analogous reaction with nitrobenzenes bearing electron withdrawing substituents ( X = NO2, CN, S02R, COzR, COMe, CHO) afforded the corresponding alkyldenitration products in 45-60%, yield 1301. The effect of the
68
1.4 Homolytic Aromatic Substitutions
o
s
N k
X
+
Ad'
19
(X = NOz, SOZPh, SOPh, COMe)
-
Q d A &
N
20 (60-95%) (Ad = adamantyl)
Scheme 5. Intermolecular ips0 substitutions
leaving group on the ips0 substitution was studied by the reaction of l-adamantyl radical with differently substituted benzothiazole derivatives 19 to give heteroarene 20 (Scheme 5) [31]. Best results were obtained for the alkyldenitration ( X = NO2, 95%). It turned out that phenylsulfonyl, phenylsulfinyl and acyl radicals are good leaving groups in these ips0 substitutions as well ( X = S02Ph, 80%; X = SOPh, 80%; X = COMe, 60%). Halogenides [32], the methylsulfanyl and the methoxy group were not efficiently replaced by the adamantyl group. More recently, the ips0 substitution with the phenylsulfonyl radical as a leaving group was applied for the preparation of various stannylated heterocycles (stannyldesulfonylation) [ 331.
1.4.2 Intramolecular Homolytic Aromatic Substitutions 1.4.2.1 Intramolecular Aromatic Substitutions with Aryl and Nucleophilic C-Radicals The first example of an intramolecular homolytic aromatic substitution was published by Pschorr more than a century ago [34]. Biaryls were prepared by intramolecular homolytic substitution of arenes by aryl radicals which were generated by treatment of arenediazonium salts with copper(1) ions (Pschorr reaction). Later it has been shown that similar reactions can be conducted under basic conditions or by photochemical or thermal decomposition of the diazonium salts [35]. Electrochemical reduction [36], titanium (111) ions [37], Fe(I1)-salts [38], tetrathiafulvalene [39] and iodine anion [40] have also been used to generate aryl radicals from the corresponding diazonium salts in the preparation of biaryls [41]. The application of the Pschorr and related reactions in synthetic organic chemistry has previously been reviewed [35]. To illustrate the potential of this method, a modified Pschorr reaction, which was used in the synthesis of tylocrebrine, is shown in Scheme 6 [40, 421. In 1988, Narasimhan [43] and Togo [44] independently reported that biaryls can
1.4.2 Intramolecular Homolytic Aromatic Substitutions
Me0
69
Me0
OMe
OMe tylocrebrine
Scheme 6. Intramolecular radical biaryl synthesis for the preparation of tylocrebrine
be prepared by intramolecular homolytic aromatic substitution starting from aryl bromides using tributyltin hydride. In a series of papers, various groups showed the potential of this method for C(sp2)-C(sp2) bond formation in biaryl synthesis [45]. The reaction has been successfully applied to the synthesis of the following natural products: various amaryllidaceae alkaloids [46], glaucine [47], cryptopleurine [48] and an anticancer benzo[clphenanthridine alkaloid [49]. These reactions involve initial halogen abstraction by Bu3Sn’ to afford an aryl radical, followed by an intramolecular addition of the aryl radical onto an arene to give a stable cyclohexadienyl radical which is then oxidized (!) to the product. This oxidation has to occur under reducing tin hydride conditions. In our eyes, the most reasonable mechanism for the oxidation under those conditions was suggested by Bowman [50].According to the Bowman pseudo-SRN 1 mechanism, cyclohexadienyl radical 23 generated by cyclization of aryl radical 22 onto the arene reacts with Bu3SnH in an ionic process to form Bu3Sn+, HI and radical anion 24 (Scheme 7). Single-electron transfer (SET) from the intermediate radical anion 24 to the starting halide 21 gives the desired biaryl 25 and a new radical anion, which as in ‘normal’ SRNI type reactions [ l ] rapidly loses X- to afford aryl radical 22 (compare also Scheme 2). It has been shown in several examples that intramolecular attack of the aryl radical can also occur at the @so position to yield cyclohexadienyl radical 26, which subsequently rearranges to radical 23 [50]. Bu3SnH-mediated intramolecular arylations of various heteroarenes such as substituted pyrroles, indoles, pyridones and imidazoles have also been reported [ 5 11. In addition, aryl bromides, chlorides and iodides have been used as substrates in electrochemically induced radical biaryl synthesis [ 521. Curran introduced [4+ 1] annulations incorporating aromatic substitution reactions with vinyl radicals for the synthesis of the core structure of various camptothecin derivatives [53]. The vinyl radicals have been generated from alkynes by radical addition reactions [53, 541. For example, aryl radical 27, generated from the corresponding iodide or bromide, was allowed to react with phenyl isonitrile to afford imidoyl radical 28, which further reacts in a 5-exo-dig process to vinyl radical 29 (Scheme 8) [53a,b].The vinyl radical 29 then reacts in a 1,6-~yclizationfollowed by oxidation to the tetracycle 30. There is some evidence [55] that the homolytic aromatic substitution can also occur via initial ipso attack to afford spiro radical 31, followed by opening of this cyclo-
70
1.4 Homolytic Aromatic Substitutions
/"
26
\
Bu3Sn'
22
21
23
1 25
21
Bu3SnH
24
Scheme 7. Pseudo SRN1 mechanism
27
29
28
31
32
30
Scheme 8. [4+ 11 Annulation reaction comprising a homolytic aromatic substitution
hexadienyl radical to an iminyl radical 32, reclosure, and finally oxidation. Similar annulation reactions have been studied by Nanni, Tundo and Zanardi [54]. Furthermore, iminyl radicals, which are supposed to be intermediates in the annulations discussed above (see 32), have been directly generated from the corresponding oximes [56] or hydrazones [57]and applied in the intramolecular homolytic aromatic substitution. The intramolecular radical alkylation of arenes [ 581 and heteroarenes [59-62] was investigated by various research groups. As for the aryl radicals, the alkyl radicals used in these reactions are generally generated from the
1.4.2 Intramolecular Homolytic Aromatic Substitutions
71
corresponding bromides or iodides using Bu3 SnH. Bowman has carefully studied the intramolecular radical alkylation of differently substituted imidazoles and pyrroles [59].As for the analogous intermolecular processes, good results were obtained for imidazoles bearing electron-withdrawing substituents such as the formyl or the methoxycarbonyl group. Along with the activation of the heteroarene toward radical addition, these substituents further increase the regioselectivity of the homolytic substitution. For imidazoles bearing the activating formyl group at the 4-position (see 33) radical addition occurs selectively at the 5-position. It turned out that the reaction works well for the formation of 5-, 6-, and 7-membered rings. If the formyl substituent is located at the 5-position, reaction occurs selectively at the 2-position. Similar reactivity trends were observed in the pyrrole series. Indoles have also been transformed to the corresponding tricyclic systems using the same method [ 601.
Me3Si
33 (n = 0,1,2)
34
35
36
An intramolecular version of the Minisci reaction using Bu3SnH to generate the radicals from the corresponding iodides was also reported [61]. For example, radical 34 gave the corresponding [6, 51 bicylic pyridinium salt in 65'% yield. In analogy, the homologous 16, 61 as well as the [6, 71 bicyclic pyridinium salt were obtained in high yields. Very recently, triazoles have been successfully used as radical acceptors in the intramolecular homolytic aromatic substitution. The primary radical 35, derived from the corresponding bromide, underwent clean cyclization to form the corresponding tetracycle [62]. Acyl radicals were also shown to undergo intramolecular homolytic aromatic substitution (see 36) [ 631. Furthermore, electrochemical [64], photochemical [65] and iodine transfer methods [66] have been successfully used for the generation of alkyl radicals in homolytic aromatic substitutions. Moreover, nucleophilic cc-oxyalkyl radicals, prepared from the corresponding aldehydes by treatment with either samarium diiodide [67] or stannyl radicals [68],were reacted with arenes to afford the homolytic substitution products. In a series of papers, Zard showed the potential of xanthates as alkyl radical precursors in homolytic aromatic substitutions. For example, the transformation of xanthate 37 to the indole derivative 38 is depicted in Scheme 9 [69]. Secondary alkyl radicals 40, generated by intermolecular addition of the pura-toluenesulfonyl radical (sodium para-toluenesulfinate/Cu(OAc)2) to the double bond in various pent-4-enyl benzene derivatives 39, were shown to cyclize to afford after oxidation the corresponding tetrahydronaphthalene derivatives 41 [ 701. Mn(OAc)3-mediated cascade reactions comprising intramolecular homolytic aromatic substitutions with primary and secondary alkyl radicals are well known [71]. In these processes, the alkyl radicals are generated by intramolecular or intermolecular addition of an electrophilic radical to
72
1.4 Homolytic Aromatic Substitutions AcO
EtOCSSlauroyl peroxide
*
CICGH~, A ..
H
H 37
39
38 (54%)
40
(R’ = H, Me, CI, Br, OMe, CN; R2 = Me, iPr, )
42
41 (53-98%)
43
44 (83%)
Scheme 9. Homolytic aromatic substitution with alkyl radicals
an alkene. The alkyl radicals then cyclize under oxidizing conditions to afford the homolytic aromatic substitution products. If the cyclization is too slow, oxidation of the intermediate alkyl radical to the corresponding cation can precede the cyclization. In Scheme 9, an application of this method is presented. The reaction of pketo ester 42 with Mn(OAc)3 in acetic acid provided the tricyclic ketone 44 as a single diastereoisomer in high yield [72]. The reaction occurred via intermediate radical 43.
1.4.2.2 Intramolecular Aromatic Substitutions with Electrophilic C-Radicals Compared to the intramolecular aromatic alkylation with nucleophilic radicals, the analogous process with electrophilic radicals is far less common. Citterio carefully studied the Mn(OAc)3-mediated intramolecular homolytic aromatic substitution of various dialkyl malonates [71, 731. He showed that the reaction is well suited for the formation of 5- (see 45), 6- (see 46) and 7-membered benzanellated rings (see 47). For cyclizations forming a 6-membered ring, high yields were obtained in the alkylation of electron-rich as well as electron-poor arenes. However, the formation of the 7-membered ring occurred only with electron-rich arenes. Cerium(1V) ammo-
1.4.2 Intramolecular Homolytic Aromatic Substitutions
xqma
Q
C02Et
Et02C
Et02C C02Et
45 (39%)
EtOzC
(X = H, OMe, NOz, NHCOMe)
73
COZEt
47 (70%)
46 (80-88%)
nium nitrate [74] and iron(II1) perchlorate [75] have also been used as oxidants in similar reactions. As already presented in Scheme 4, cascade reactions comprising an intermolecular followed by an intramolecular aromatic malonylation can be performed using the Mn(OAc)3-mediated oxidative aromatic alkylation [25a]. Recently, Chuang reported the use of allylsulfonyl group as a precursor for the generation of electrophilic radicals for the homolytic alkylation of various arenes and indole derivatives [ 761. For example, reaction of the benzenesulfonyl radical with sulfone 48 leads to the corresponding secondary radical, which after P-fragmentation and Sol-extrusion affords the electrophilic radical 49 (Scheme 10). Intramolecular homolytic substitution eventually gives tetrahydronaphthalene 50 (92%). Beckwith showed that the N-(o-bromopheny1)amide 51 can be transformed into the corresponding oxindole 54 (70%) at high temperatures using Bu3SnH via tandem radical translocation of the initially formed aryl radical 52 to form 53 with subsequent intramolecular homolytic substitution [ 771. The nucleophilic a-aminomethyl radical 55 reacted in a tandem addition/homolytic aromatic substitution reaction via radical 56 to tetrahydroquinoline 57 [78]. Radical 55 can either be prepared by oxida-
48 (R = COZiPr)
51
50
49
I
55
54
53
52
I
CN 56
q I
CN 57
Scheme 10. Intramolecular aromatic alkylation with electrophilic C-radicals
74
1.4 Homolytic Aromatic Substitutions
58
59
60
Scheme 11. Neophyl rearrangement
tive decarboxylation (+ 87% of 57) from the corresponding acid or by hydrogen abstraction from NJV-dimethylaniline (+ 50% of 57).
1.4.2.3 Intramolecular Homolytic ips0 Substitutions Since the pioneering work of Urry and Kharasch on the neophyl rearrangement [79], numerous reports on radical aryl migration reactions have appeared [80]. The neophyl rearrangement, the 1,2-phenyl migration of the neophyl radical 58 to form the tertiary radical 60, probably via spirocyclohexadienyl radical 59, has been carefully studied by various groups (Scheme 11) [SO]. Despite these efforts, the postulated intermediate 59 could not be identified so far [Sl]. Kinetic data for the 1,2-phenyl transfer of radical 58 have been determined [82]. The slow neophyl rearrangement ( k = 762 s-' at 25"C, [82]) is nowadays used as a radical clock [83]. For further information on the neophyl and neophyl-type rearrangements, the reader is referred to the previously reported review articles on these processes [SO, 841. The 1,3-aryl migration from carbon to C-centered radicals has not been observed so far. Probably the transition state of this reaction is too strained. Regarding the same aspect, the corresponding 1,4- and 1,5-aryl shifts should occur more readily. Indeed, the first report on a 1,4-aryl migration between two carbon atoms appeared as early as 1956 [SS], and other studies followed. However, in most cases the 1,4aryl migration is only a side reaction. The corresponding intramolecular homolytic arylation is the main reaction pathway (see Section 1.4.2.1). Nevertheless, there are some reports on synthetically useful processes involving 1,4-aryl migrations between two carbon atoms [86]. Recently, the radical 1,5-aryl migration from carbon to carbon has been reported for the preparation of various biaryls [87]. Compared to the radical aryl migration between two carbon atoms, the corresponding aryl transfers from nitrogen to C-centered radicals are less common. There are only a few reports on those reactions in the literature [88]. The 1,2- [89], 1,4- [90] and 1,5radical aryl migration [91] from oxygen to carbon has also been observed. However, as for the nitrogen case, the aryl migration from oxygen to C-radicals is not of synthetic importance. The reverse process, namely the aryl migration from carbon to alkoxyl radicals is also known [92]. In contrast to the neophyl rearrangement discussed above, the analogous 1,2-radical aryl migration between silicon and carbon does not occur [93]. However, Wilt showed that the 1,4- as well as the 1,5phenyl migration from silicon to carbon is a rather efficient process [94]. Furthermore, he proved that the radical aryl migration between carbon and silicon is reversible in the systems studied. Similar conclusions have been drawn by Sakurai and
1.4.2 fntrumoleculur Homolytic Aromatic Substitutions
qn
Me3Si Me3Sisi'o
)J ,-l,..
I
1)BusSnH 1)BusSnH AlBN benzene benzene 2)MeLi *
64
i
*L SiMe3
v
62 (70%) (u:/=10:1)
61
b"'
OH
75
1) BuaSnH AlBN benzene 2) MeLi (71Yo)
p /
65
63
1) Ph3SnH AlBN xylene (64%)
OBr 66
Scheme 12. Stereoselective 1,5 phenyl migration from silicon to secondary C-radicals and radical biaryl synthesis
Hosomi, who looked at the 1,Sphenyl migration from carbon to silyl radicals [95]. Recently, Studer investigated the stereoselective 1J-aryl migration from silicon to secondary C-centered radicals [96]. The 1,5-phenyl migration worked well for diphenyl(trimethylsily1)silyl ethers. For instance, the transformation of iodide 61 to the corresponding aryl migration product 62 is depicted in Scheme 12. Cyclohexadienyl radical 63, with the methyl substituents in pseudo equatorial position, was suggested as an intermediate in the formation of the major isomer. Later, it was shown that functionalized aryl groups can also be transferred using the same method [97]. Furthermore, the analogous 1,4-aryl migration from Si to secondary C-radicals worked even better [97]. Recently, it was shown that the radical aryl migration from silicon to carbon can be used for the preparation of biaryls [98]. Thus, transformation of bromide 64 under radical conditions, followed by desilylation, afforded biaryl 65 in 7 1% yield. The same product can be obtained by aryl migration from phosphorus (see 66) to the appropriate aryl radical [99]. To the best of our knowledge, this is the only report of a radical aryl migration between a phosphorus and a carbon atom. The 1,4-aryl migration from sulfur in sulfonamides to C-centered radicals was first investigated by Speckamp in the 1970s [loo]. Iodides of type 67 were reacted with Bu3SnH under radical conditions to afford the corresponding arylated products 69 (Scheme 13). In these processes, the initially formed primary alkyl radical reacts at the ips0 position to form cyclohexadienyl radical 68. Rearomatization followed by reduction and SO2 extrusion finally leads to amine 69. Electron-poor as well as electron-rich arenes can be transferred by that method. As a side-product, the homolytic substitution product 70 deriving from initial ortho attack is formed.
76
1.4 Homolytic Aromatic Substitutions
69
68
70
67
71 (X = NMe or 0)
72
K
73
0 0
‘3
OH
Aryl’u i 74
50-76% *
:
LAryl 75 ( d r = 9-13 : 1)
(Aryl = Ph, 4-FPh, 4-MeOPh, 2-thieny1,5-Me2N-naphthyl)
Scheme 13. Radical aryl migrations from sulfur to carbon
Later, Motherwell developed a new biaryl synthesis using 1,4- as well as 1,5-aryl migrations from sulfur to aryl radicals [ 1011. Easily available arenesulfonates as well as arenesulfonamides were used as starting materials in these reactions (+ 72). As in the Speckamp studies with primary alkyl radicals, the aryl radicals 71 were shown to also react by ortho attack to afford the side product 73. However, by judicious choice of the migrating aryl group, it is possible to completely suppress the ortho attack [ 1021. Recently, Studer used the radical aryl migration from sulfur in sulfonates to secondary C-radicals for the stereoselective C(sp2)-C(sp3)bond formation [ 1031. Various aryl groups were transferred with high selectivities and in high yields as shown for the transformation of arylsulfonates 73 to the corresponding alcohols 74. Further C(sp2)-C(sp3)bond-forming processes using radical @so substitutions not comprising aryl migrations were developed by Caddick [ 1041 and Bowman [ 1051. Sulfone-substituted imidazoles and indoles were shown to easily undergo intramolecular ips0 substitution with primary alkyl radicals with expulsion of the sulfonyl moiety. To close this chapter, we can state that the large number of recent articles on intramolecular homolytic ips0 substitutions clearly document the importance of these processes in the field of aromatic substitutions. However, despite these efforts, a great deal of qualitative and quantitative work remains to be done, especially in the area of stereoselective radical aryl migration reactions.
References
77
References [ I ] R. A. Rossi, A. B. Pierini, A. N. Santiago in Organic Reactions, Vol. 54 (Ed.: L. A. Paquette), John Wiley & Sons, Inc., New York, 1999, p. 1. [2] a) G. H. Williams, Homolytic Aromatic Substitution, Pergamon: Oxford, 1960; b) D. H. Hey in Advances in Free Radical Chemistry, Vol. 2 (Ed.: G. H. Williams), Logos: London, 1967, p. 47; c) M. J. Perkins in Free Radicals, Vol. 2 (Ed.: J. K. Kochi), John Wiley & Sons: New York, 1973, p. 231; d) M. Tiecco in Free Radical Reactions, (Ed.: W. A. Waters), Butterworths: London, 1975, p. 25; e) F. Minisci in Topics in Current Chemistry, Vol. 62, SpringerVerlag: Berlin, 1976, p. 1; f ) M. Tiecco, L. Testaferri in Reactive Intermediates, Vol. 3 (Ed.: R. A. Abramovitch), Plenum: New York, 1983, p. 61; g) F. Minisci, E. Vismara, F. Fontana, Heterocycles 1989, 28, 489. [3] These side products have been observed in the radical alkylation of anthracene: A. L. J. Beckwith, W. A. Waters, J. Chem. Soc. 1957, 1001. [4] A. Citterio, F. Minisci, 0. Porta, G. Sesana, J. Am. Chem. Soc. 1977, 99, 7960. [ 5 ] See discussion in reference 2f, p. 72. [6] L. Testaferri, M. Tiecco, P. Spagnolo, P. Zanirato, G. Martelli, J. Chem. Soc. Perkin Trans. 2, 1976, 662. 171 J. Hutton, W. A. Waters, J. Chem. Soc. 1965, 4253; U. Rudqvist, K. Torssell, Acta Chem. Scand. 1971, 25, 2183; M. Baule, G. Vernin, H. J. M. Dou, J. Metzger, Bull. Soc. Chim. Fr. 1971, 2083; M. Janda, J. Srogl, I. Stibor, M. Nemec, P. Vopatrna, Tetrahedron Lett. 1973, 637. [8] G. A. Russell, P. Chen, B. H. Kim, R. Rajaratnam, J. Am. Chem. Soc. 1997,119,8795;B. H. Kim, Y. S. Lee, D. B. Lee, I. Jeon, Y. M. Jun, W. Baik, G. A. Russell, J. Chem. Res. Synop. 1998, 826. [9] C. Wang, G. A. Russell, W. S. Trahanovsky, J. Ory. Chem. 1998, 63, 9956. [ 101 a) F. Minisci, Synthesis 1973, 1; b) F. Minisci, F. Fontana, E. Vismara, J. Heterocyclic Chem. 1990, 27, 79. [ I l l A. Citterio, F. Minisci, V. Franchi, J. Org. Chem. 1980, 45, 4752. [ 121 F. Minisci, R. Mondelli, G. P. Gardini, 0. Porta, Tetrahedron 1972, 28, 2403. [I31 F. Minisci, R. Galli, V. Malatesta, T. Caronna, Tetrahedron 1970, 26, 4083; A. Clerici, F. Minisci, 0. Porta, Tetrahedron 1974, 30, 4201. [14] I. Fleming, Frontier Orbitals and Organic Chemical Reactions, John Wiley & Sons: Chichester, 1976. [ 151 G. Klopman, J. Am. Chem. Soc. 1968, YO, 223. [16] F. Minisci, E. Vismara, F. Fontana, G. Morini, M. Serravelle, C. Giordano, J. Org. Chem. 1987, 52, 730. [17] F. Minisci, R. Bernardi, F. Bertini, R. Galli, M. Perchinummo, Tetrahedron 1971, 27, 3575. [IS] G. Heinisch, G. Lotsch, Heterocycles 1987, 26, 731. [ 191 See for example in the alkoxycarbonylation: Y. Houminer, E. W. Southwick, D. L. Williams, J. Heterocylic Chem. 1986,23, 497. [20] a) E. I. Heiba, R. M. Dessau, W. J. Koehl, Jr. J. Am. Chem. Soc. 1968, 90, 1082; b) E. I. Heiba, R. M. Dessau, W. J. Koehl, Jr. J. Am. Chem. Soc. 1969, 91, 138. See also: E. I. Heiba, R. M. Dessau, J. Am. Chem. Soc. 1971, 93, 995. [21] M. G. Vinogradov, S. P. Verenchikov, T. M. Fedorova, G. I. Nikishin, J. Org. Chem. (USSR) 1975, 11, 937. 1221 M. E. Kurz, V. Baru, P.-N. Nguyen, J. Org. Chem. 1984, 49, 1603. [23] M. E. Kurz, T.-Y. R. Chen, J. Org. Chem. 1978. 43, 239. [24] a) A. Citterio, R. Santi, T. Fiorani, S. Strologo, J. Org. Chem. 1989,54,2703; I.-S. Cho, J. M. Muchowski, Synthesis 1991, 567; D. R. Artis, I.-S. Cho, J. M. Muchowski, Can. J. Chen7. 1992, 70, 1838; E. Baciocchi, E. Muraglia, J. Org. Chem. 1993, 58, 7610; b) E. Baciocchi, D. Dell’Aira, R. Ruzziconi, Tetrahedron Lett. 1986, 27, 2763. See also: L. M. Weinstock, E. Corley, N. L. Abramson, A. 0. King, S. Karady, Heterocycles 1988, 27, 2627.
78
1.4 Homolytic Aromatic Substitution3
[25] a) C.-P. Chuang, S.-F. Wang, Heterocycles 1996, 43, 2215; S.-F. Wang, C.-P. Chuang, Heterocycles 1997, 45, 347. b) S. Araneo, R. Arrigoni, H.-R. Bjarsvik, F. Fontana, F. Minisci, F. Recupero, Tetrahedron Lett. 1996, 37, 7425. [26] a) E. Baciocchi, E. Muraglia, C. Sleiter, J. Org. Chem. 1992, 57, 6817; E. Baciocchi, E. Muraglia, Tetrahedron Lett. 1993, 34, 501 5; E. Baciocchi, E. Muraglia, C. Villani, Synlett 1994, 821; b) J. H. Byers, J. E. Campbell, F. H. Knapp, J. G. Thissell, Tetrahedron Lett. 1999,40, 2677. [27] A. Bravo, H.-R. Biarsvik, F. Fontana, L. Liguori, A. Mele, F. Minisci, J. Org. Chem. 1997, 62, 7128 and references cited therein. [28] M. Tiecco, Acc. Chem. Res. 1980, 13, 51; M. Tiecco, Pure Appl. Chem. 1981, 53, 239. [29] L. Testaferri, M. Tiecco, M. Tingoli, J. Chem. Soc. Perkin Trans. 2 1979, 469. [30] L. Testaferri, M. Tiecco, M. Tingoli, M. Fiorentino, L. Troisi, J. Chem. Soc. Chem. Comm. 1978, 93. [31] M. Fiorentino, L. Testaferri, M. Tiecco, L. Troisi, J. Chem. Soc. Chem. Commun. 1977, 316. [32] Halogens as leaving groups: J. G. Traynham, Chem. Rev. 1979, 79, 323. [33] K. Aboutayab, S. Caddick, K. Jenkins, S. Joshi, S. Kahn, Tetrahedron 1996, 52, 11329. [34] R. Pschorr, Ber. Dtsch. Chem. Ges. 1896, 29, 496. [35] R. A. Abramovitch in Aduances in Free Radical Chemistry, Vol. 2 (Ed.: G. H. Williams), Logos Press: London, 1966, p. 87; M. Sainsbury, Tetrahedron 1980, 36, 3327. [36] R. M. Elofson, F. F. Gadallah, J. Orq. Chem. 1971, 36, 1769. [37] T. Coronna, F. Ferrario, S. Servi, Tetrahedron Lett. 1979, 657. [38] F. W. Wassmundt, W. F. Kiesman, J. Org. Chem. 1995, 60, 196. [39] C. Lampard, J. A. Murphy, F. Rasheed, N. Lewis, M. B. Hursthouse, D. E. Hibbs, Tetrahedron Lett. 1994, 35, 8615. [40] B. Chauncy, E. Gellert, Aust. J. Chem. 1969, 22, 993. [41] For further methods to decompose diazonium salts to aryl radicals: C. Galli, Chem. Rev. 1988, 88, 765. [42] E. Gellert, T. R. Govindachari, M. V. Lakshmikantham, I. S. Ragade, R. Rudzats, N. Viswanathan, J. Chem. Soc. 1962, 1008; B. Chauncy, E. Gellert, K. N. Trivedi Aust. J. Chem. 1969, 22, 427. 1431 N. S. Narasimhan, I. S. Aidhen, Tetrahedron Lett. 1988, 29, 2987. [44] H. Togo, 0 . Kikuchi, Tetrahedron Lett. 1988, 29, 4133. [45] J. C. Estevez, M. C. Villaverde, R. J. Estevez, L. Castedo, Tetrahedron 1993, 49, 2783; J. C. Estevez, M. C. Villaverde, R. J. Estevez, L. Castedo, Tetruhedron 1995, 51, 4075; 0 . Tsuge, T. Hatta, H. Tsuchiyama, Chem. Lett. 1998, 155; K. Orito, S. Uchiito, Y. Satoh, T. Tatsuzawa, R. Harada, M. Tokuda, Org. Lett. 2000, 2, 307. [46] A. M. Rosa, A. M. Lobo, P. S. Branco, S. Prabhakar, M. Sa-da-Costa, Tetruhedron 1997, 53, 299. [47] J. C. Estevez, M. C. Villaverde, R. J. Estevez, L. Castedo, Tetrahedron 1994, 50, 2107; D. L. Comins, P. M. Thakker, M. F. Baevsky, M. M. Badawi, Tetrahedron 1997, 53, 16327. [48] H. Suzuki, S. Aoyagi, C. Kibayashi, Tetrahedron Lett. 1995, 36, 935. [49] T. Nakanishi, M. Suzuki, A. Mashiba, K. Ishikawa, T. Yokotsuka, J. Org. Chem. 1998, 63, 4235. [50] W. R. Bowman, H. Heaney, B. M. Jordan, Tetrahedron 1991, 47, 10119. See also: A. M. Rosa, A. M. Lobo, P. S. Branco, S. Prabhakar, A. M. D. L. Pereira, Tetrahedron 1997, 53, 269. [ S l ] G. A. Kraus, H. Kim, Synth. Commun. 1993, 23, 55; F. Suzuki, T. Kuroda, J. Heterocyclic Chem. 1993, 30, 811; Y. Antonio, M. E. De La Cruz, E. Galeazzi, A. Guzman, B. L. Bray, R. Greenhouse, L. J. Kurz, D. A. Lustig, M. L. Maddox, J. M. Muchowski, Can. J. Chem. 1994, 72, 15; D. L. Comins, H. Hong, G. Jianhua, Tetrahedron Lett. 1994, 35, 5331; T. C. T. Ho, K. Jones, Tetrahedron 1997, 53, 8287. [52] S. Donnelly, J. Grimshaw, J. Trocha-Grimshaw, J. Chem. Soc. Chem. Commun. 1994, 2171 and references cited therein. [53] a) D. P. Curran, H. Liu, J. Am. Chem. Soc. 1992, 114, 5863; b) D. P. Curran, H. Liu, H. Josien, S.-B. KO, Tetrahedron 1996, 52, 11385; c) H . Josien, S.-B. KO, D. Bom, D. P. Curran, Chem. Eur. J. 1998, 4, 67 and references cited therein.
References
79
[54] D. Nanni, P. Pareschi, C. Rizzoli, P. Sgarabotto, A. Tundo, Tetrahedron 1995, 51, 9045 and references cited therein. R. Leardini, D. Nanni, P. Pareschi, A. Tundo, G. Zanardi, J. Org. Chem. 1997,62, 8394; C. M. Camaggi, R. Leardini, D. Nanni, G. Zanardi, Tetrahedron 1998, 54, 5587; D. Nanni, G. Calestani, R. Leardini, G. Zanardi, Eur. J. Org. Chem. 2000, 707. 1551 D. Nanni, P. Pareschi, A. Tundo, Tetrahedron Lett. 1996, 37, 9337. [56] H. Sakuragi, S.4. Ishikawa, T. Nishimura, M. Yoshida, N. Inamoto, K. Tokumaru, Bull. Chem. Soc. Jpn. 1976, 49, 1949; A. R. Forrester, M. Gill. J. S. Sadd, R. H. Thomson, J. Chem. Sor. Perkin Trans. 1 1979, 612. [57] H. McNab, J. Chem. Soc. Perkin Trans. 1 1984, 377. [58] H. Ishibashi, N. Nakamura, K. Ito, S. Kitayama, M. Ikedd, Heterocycles 1990, 31, 1781. 1591 F. Aldabbagh, W. R. Bowman, E. Mann, A. M. Z. Slawin, Tetrahedron 1999, 55, 81 1 1 . (601 C. J. Moody, C. L. Norton, J. Chem. Soc. Perkin Trans. I1997, 2639. [61] J. A. Murphy, M. S. Sherburn, Tetrahedron 1991, 47,4077. (621 J. Marco-Contelles, M. Rodriguez-Fernindez, Tetrahedron Lett. 2000, 41, 381. [63] L. D. Miranda, R. Cruz-Almanza, M. Pavon, E. Aha, J. M. Muchowski, Tetrahedron Lett. 1999, 40, 7153. See also: M. K.-H. Doll, J. Org. Chem. 1999, 64, 1372. 1641 S. Ozaki, S. Mitoh, H. Ohmori, Chem. Pharm. Bull. 1996, 44, 2020. 1651 E. L. Ruchkina, A. J. Blake, M. Mascal, Tetrahedron Lett. 1999, 40, 8443. [66] D. R. Artis, I.-S. Cho, S. Jaime-Figueroa, J. M. Muchowski, J. Ory. Chem. 1994, 59, 2456. [67] H.-G. Schmalz, S. Siegel, J. W. Bats, Anyew. Chem. 1995, 107, 2597; Angew. Chem. Int. Ed. Engl. 1995, 34, 2383. [68] T. Sugawara, B. A. Otter, T. Ueda, Tetrahedron Lett. 1988, 29, 75. [69] T. Kaoudi, B. Quiclet-Sire, S. Seguin, S. Z. Zdrd, Angew. Chem. 2000, 112, 747; Angew. Chem. Int. Ed. 2000, 39, 731 and references cited therein. [70] S.-F. Wang, C.-P. Chuang, J.-H. Lee, S.-T. Liu, Tetrahedron 1999, 55, 2273. [71] B. B. Snider, Chem. Rev. 1996, 96, 339. [72] R. Mohan, S. A. Kates, M. Dombroski, B. B. Snider, Tetrahedron Lett. 1987, 28, 845. [73] A. Citterio, D. Fancelli, C. Finzi, L. Pesce, R. Santi, J. Org. Chem. 1989, 54, 2713. See also: A. Citterio, R. Sebastiano, M. Nicolini, Tetrahedron 1993, 49, 7743; J . L. Garcia Rudno, A. Rumbero, Tetrahedron: Asymmetry 1999, 10, 4427. [74] A. Citterio, L. Pesce, R. Sebastiano, R. Santi, Synthesis 1990, 142. [75] A. Citterio, A. Cerati, R. Sebastiano, C. Finzi, R. Santi, Tetrahedron Lett. 1989, 30, 1289. [76] S.-F- Wang, C.-P. Chudng, W.-H. Lee, Tetrahedron 1999, 55, 6109. [77] A. L. J. Beckwith, J. M. D. Storey, J. Chem. Sor. Chem. Commun. 1995, 977. [78] S. Araneo, F. Fontana, F. Minisci, F. Recupero, A. Serri, Tetrahedron Lett. 1995, 36, 4307. See also: S. Bertrand, N. Hoffmann, J.-P. Pete, V. Bulach, Chem. Commun. 1999, 2291. [79] W. H. Urry, M. S. Kharasch, J. Am. Chem. Soc. 1944, 66, 1438. [80] A. L. J. Beckwith, K. U. Ingold in Rearrangements in Ground and Excited States, (Ed.: P. de Mayo), Academic Press: New York, 1980, p. 170; R. Kh. Freidlina, A. B. Terent’ev in Advances in Free Radical Chemistry, Vol. 6 (Ed.: G. H. Williams), Heyden & Son: London, 1980, p. 32. [81] A. Effio, D. Griller, K. U. Ingold, J. C. Scaiano, S. J. Sheng, J. Am. Chem. Soc. 1980, 102, 6063. 1821 D. A. Lindsay, J. Lusztyk, K. U. Ingold, J. Am. Chen7. Soc. 1984, 106, 7087. See also: R. Leardini, D. Nanni, G. F. Pedulli, A. Tundo, G. Zanardi, E. Foresti, P. Palmieri, J. Am. Chem. Soc. 1989, I l l , 1723. [83] D. Griller, K. U. Ingold; Acc. Cliem. Res. 1980, 13, 317; M. Newcomb, Tetrahedron 1993, 49, 1151. [84] For some newer examples see: A. N. Abeywickrema, A. L. J. Beckwith, S. Gerba, J. Ory. Cliem. 1987, 52, 4072; H. Ishibashi, K. Ohata, M. Niihara, T. Sato, M. Ikeda, J. Chem. Soc. Perkin Trans. 12000, 547. [85] S. Winstein, R. Heck, S. Lapporte, R. Baird, Experientia 1956, 12, 138. 1861 L. Benati, L. Capella, P. C. Montevecchi, P. Spagnolo, J. Org. Chem. 1994, 59, 2818; P. C. Montevecchi, M. L. Navacchia, J. Org. Chem. 1998, 63, 537; H. Amii, S. Kondo, K . Uneyama, Cliem. Commun. 1998, 1845.
1.4 Homolytic Aromatic Substitutions L. Giraud, E. Lac6te, P. Renaud, Helv. Chim. Acta 1997, 80, 2148;B. Alcaide, A. RodriguezVicente, Tetrahedron Lett. 1998, 39, 6589. D.H. Hey, T. M. Moynehan, J. Chem. Soc. 1959,1563;L. Benati, P. Spagnolo, A. Tundo, G. Zanardi, J. Chem. Soc. Chem. Commun. 1979, 141;J. Grimshaw, R. J. Haslett, J. Chem. Soc. Perkin Trans. I 1980, 657;E. Lee, H. S. Whang, C. K. Chung, Tetrahedron Lett. 1995, 36, 913. A. Ohno, N. Kito, Y. Ohnishi, Bull. Chem. Soc. Jpn. 1971, 41, 467; J. I. Cadogan, J. B. Husband, H. McNab, J. Chem. Soc. Perkin Trans. 2 1983, 697. M. D. Bachi, E. Bosch, J. Org, Chem. 1989,54, 1234;E.Lee, C. Lee, J. S. Tae, H. S. Whang, K. S. Li, Tetrahedron Lett. 1993, 34, 2343;A. M. Rosa, A. M. Lobo, P. S. Branco, S. Prabhakdr, Tetrahedron 1997, 53, 285;D.Crich, J.-T. Hwang, J. Org. Chem. 1998, 63, 2765. R. Leardini, H. McNab, D. Nanni, Tetrahedron 1995, 51, 12143. H.Wieland, Ber. Dtsch. Chem. Ges. 1911, 44, 2550; J. W. Wilt, D. D. Oathoudt, J. Org. Chern. 1958, 23, 218; W. H. Starnes Jr., J. Am. Chem. Soc. 1963, 85, 3708; R. L. Donkers, J. Tse, M. S. Workentin, Chem. Commun. 1999, 135. For a 1,2-aryl migration from carbon to nitrogen see: S. Kim, J. Y. Do, J. Chem. Soc. Chem. Commun. 1995, 1607. J. W. Wilt. 0. Kolewe, J. F. Kraemer, J. Am. Chem. Soc. 1969, 91, 2624. J. W. Wilt, W. K. Chwang, C. F. Dockus, N. M. Tomiuk, J. Am. Chem. Soc. 1978, 100,
5534. H. Sakurai, A. Hosomi, J. Am. Chem. Soc. 1970, 92, 7507. A. Studer, M.Bossart, H. Steen, Tetrahedron Lett. 1998,39, 8829. S. Amrein, M. Bossart, T. Vasella, A. Studer, J. Org. Chem. 2000, 65, 4281. A. Studer, M. Bossart, T. Vasella, Org. Lett. 2000,2, 985. D.L. Y.Clive, S. Kang, Tetrahedron Lett. 2000, 41, 1315. R. Loven, W. N. Speckamp, Tetrahedron Lett. 1972, 1567; H. J. Kohler, W. N. Speckamp, J. Chem. Soc. Chem. Commun. 1980, 142 and references cited therein. W. B. Motherwell. A. M. K. Pennell. J. Chem. Soc. Chem. Commun. 1991. 877: M. L. E.N. ' da Mata, W. B. Motherwell, F. Ujjainwalla, Tetrahedron Lett. 1997, 38, 137;M. L. E.N. da Mata, W. B. Motherwell, F. Ujjainwalla, Tetrahedron Lett. 1997, 38, 141. J E. Bonfand, L. Forslund, W. B. Motherwell, S. Vazquez, Synlett 2000, 475. [I031 A. Studer, M. Bossart, Chem. Commun. 1998,2127. [I041 S. Caddick, K. Aboutayab, R. West, Synlett 1993, 231; S. Caddick, C. L. Shering, S. N. Wadman, Tetrahedron 2000, 56, 465. [I051 F. A.Aldabbagh, W. R. Bowman, Tetrahedron 1999, 55, 4109.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
1.5 Radical Reactions on Solid Support A . Gunesun
1.5.1 Introduction The concept of performing organic synthesis with a substrate immobilized on an insoluble matrix was pioneered by Merrifield (for peptides) and Letsinger (for oligonucleotides) in the early 1960s. These oligomer syntheses involve only carbonheteroatom bond formation and the repetition of a small cycle of operations (monomer activation, coupling, and deprotection). Reactions can be driven to completion by a large excess of reagents, with workup accomplished by simple filtration. Although there were early attempts [ l ] to extend the principle to nonoligomeric small molecules, this was largely regarded as an intellectual curiosity until the birth of combinatorial chemistry [2] in the last decade. Since then, a variety of carbon-carbon bond-forming reactions have been adapted to solid-phase conditions, and the period 1990-1999 has been reviewed [ 3 ] . While there is nothing fundamentally different about solid-phase reactions compared to traditional solution-phase chemistry, it is useful to be aware of the method’s idiosyncrasies. The solvent choice is crucial, in order to swell the solid phase (usually 1%) crosslinked polystyrene) and enable free diffusion of reagents. Even in the swollen gel phase, the kinetics of solid-phase reactions are often slower than their solution-phase counterparts, and there are differences in rate between one type of resin and another. The extent of solvation can also change during the course of the reaction [4]. Since radical reactions often involve a complex series of elementary steps, there may be contexts where such rate deceleration is advantageous. A second unique feature is the loading of polymeric resins, typically < 1 mmol/g of beads, thus effectively placing an upper limit for the maximum concentration attainable for solid-phase reactions. This enforced dilution can be useful for radical reactions, although gel-phase polymer chains do exhibit significant freedom of motion and the conditions certainly do not approach ‘infinite dilution’. A further variable is the spacer length between the substrate and the matrix. Many reactions, including Merrifield’s original peptide synthesis, were done with the substrate attached directly to polystyrene, while in other cases it is beneficial to include a ‘linker’ [5] between the two. The linker can profoundly influence chain mobility as well as the polymer microenvironment where the reaction is taking place. As will be seen, linkers are
82
1.5 Radical Reactions on Solid Support
often used for solid-phase radical reactions, although the reasons for selecting a particular linker are seldom described.
1.5.2 Intramolecular Radical Cyclizations The first carbon-carbon bond-forming radical reactions reported on solid phase were aryl radical 5-ex0 cyclizations, which have ample solution-phase precedents [6]. Routledge et al. [7] investigated the formation of dihydrobenzofuran 1 from an aryl halide precursor (Scheme 1). With polystyrene, more than 1 equivalent of AIBN was required, while the reaction was complete within 20 h using 6 mol% of AIBN on TentaGel resin (which has a polyethylene spacer between the polystyrene and the site of compound attachment). Addition of t-butanol helped prevent an alternative p-elimination pathway. An attempt to force the latter was made with thiyl linker 2, but only trace amounts of the p-elimination product 3 were formed. Also investigated were the cyclizations of iodides 4, in which the cyclization of an alkyl radical to an acetylene is approximately lo4 times slower than the aryl radical cyclization to a double bond. A direct comparison of the same reaction on solution phase was attempted, but yields could not be determined for the latter because of contamination by tin residues. This illustrates one advantage of solid-phase radical reactions mediated by tributyltin hydride, namely the ease of product purification. Similar cyclizations were reported by Du and Armstrong [8], who used SmI2 for radical generation from aryl iodides such as 5 loaded on polystyrene-Rink resin
1) 4.7 equiv Bu3SnH,AlBN t-BuOH, toluene, 100 "C 2) NaOMe, MeOH, r i 24 h
0
Br
NH2 >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 <7% hydrogen atom transfer from the polymer matrix. Electron-withdrawing groups at the 2-position of the allylstannane were also found to improve the reaction yield, as in the formation of 28. The majority of solid-phase radical reactions have involved organotin reagents. Zhu and Ganesan investigated [ 181 the conjugate addition of radicals photochemically generated from Barton esters. Acrylic acid was immobilized as the ester 29 (Scheme 7) using the Wang linker on both polystyrene and TentaGel resins, followed by conjugate addition and cleavage to provide acids 30. Also noteworthy, as
-
v
1) 10 equiv Bu3Sn 3-4 equiv AIBN
benzene, reflux 14 h 0r
/Q
k
Br
2
HO& R i R2 27, 5 examples 58-76%
2)TFA
26
0
similar conditions C02Me
H *
R1
O W R2 C02Me
28, R1 = R2 = Me, 95%
Scheme 6 . Intermolecular allylations by Sibi and Chandramouli [ 171
1.5.3 Intermolecular Radical Reactions
87
1) 10equiv R
0
b 29
S hv, CH2CI2, 4 h 2) 75% TFA/CH,CI,,
H
90 min *
O
V
R
SPY 30, 5 examples 32-94%
37, 36%
Scheme 7. Intermolecular conjugate additions by Zhu and Ganesan [ 181
in the tin-mediated reactions, is the ability to use large excesses of reagent without problems in product isolation. The yields with polystyrene resin were similar to solution-phase results with methyl acrylate, while TentaGel resin gave consistently lower yields, suggesting interference from the polyether spacer. When acrylic acid was immobilized as the amide on polystyrene-Rink resin, yields were also lower, which is consistent with the lower solution-phase yields with acrylamide compared to methyl acrylate. An interesting cascade reaction was observed with the Barton ester 31 of cyclopent-2-enylacetic acid. Radical generation and addition to the acrylate resin results in electrophilic acyl-substituted radical 32, which can undergo
88
1.5 Radical Reactions on Solid Support 1) 3 equiv RHgCI, 8 equiv NaBH4 CH2Cl2/H20,90 rnin 2) 20% TFA/CH2Cl2, 30 rnin
r% rL4
0""
38
q
R
,,
R = I-Pr, t-Bu, c-C6H, 49-60%
1) 6 equiv TsBr 6 equiv AlBN toluene, 65-70 "C, 16-22 h 2) 95% TFA, 90 rnin *
39
O
HN-AC
'AC
0
0
H
TS
94% (alkene) and 93%
Scheme 8. Intermolecular alkene additions [ 19, 201
chain transfer to produce 33 (after cleavage and esterification). The major pathway is intramolecular 5-ex0 cyclization to bicycle 34. Chain transfer yields 35, or being nucleophilic, radical 34 can add to a second acrylate chain to give 36 and ultimately 37 upon chain transfer. The major product 37 requires the crosslinking of two polymer chains and shows that site isolation is not significant. Another conjugate addition, to the dehydroalanine derivative 38 on solid-phase, was reported by Yim et al. [ 191. Radical generation using t-butyl iodide and tributyltin hydride afforded only 8% of the desired product, while better results were obtained with organomercurials (Scheme 8). The intermolecular addition of tosyl radicals to unactivated alkene and alkyne 39 has also been reported [20], and the reaction was found to be quite sensitive to solvent. Optimum results were obtained in toluene, although the scope is difficult to gauge with only two examples disclosed. Naito's group has published several solid-phase applications of intermolecular additions to oxime ethers. Alkyl radicals, generated by the low-temperature method of tributyltin hydride and triethylborane, reacted with immobilized glyoxylic oxime ether 40 (Scheme 9) to give amino acid derivatives [21]. In a later paper [22], the glyoxylate was attached to Oppolzer's camphorsultam chiral auxiliary and immobilized as oxime 41. The product 42a of ethyl addition occurred with >95% diastereoselectivity using both triethylborane and diethylzinc as radical initiators. This was better than the analogous solution-phase reaction, suggesting that the immobilized oxime is less reactive. The addition of isopropyl and cyclohexyl radicals by atom transfer from the corresponding iodide to give 42b,c was also demonstrated. In these cases, the product was contaminated by the competing addition of initiating ethyl radical, and this was avoided by using a large excess of the alkyl iodide. The Naito group has also prepared pyrrolidines [23] on solid phase by a combination of intermolecular radical addition to alkene 43 (Scheme 10) followed by intramolecular oxime ether cyclization to yield 44. These reactions proceeded sluggishly with triethylborane at room temperature, while the analogous solution-phase process was kinetically much faster. Radical additions to the phenylsulfonyl oxime ether 45 were reported by Jeon et al. [24]. Yields were better with primary and secondary alkyl iodides, and the tandem cyclization sequence with iodide 46 to afford bicyclic 47 was also accomplished, albeit in modest yield.
89
1.5.3 Intermolecular Radical Reactions 1) 7 eauiv RI 2 equiv Bu,SnH, 1 equiv Et,B CHzCI2, rt 1 h 2) 25% TFNCHCI,, 30 min
0
LNoBn
HN-OBn 7 examples, 28-78%
40
1) for R= Et, 5 equiv Et,B or Et,Zn CHzCI,, -78 “C or for R = i-Pr/cCsHIl, Rl/toluene (4:1, v/v) 10 equiv Et,B or Et,Zn, 0 “C 2) TFNCHzCI, (1:5, V/V)
41
O,N
c
42a R = Et, 74% (Et,B) or 67% (Et,Zn), >95% de 42b R = i-Pr, 69% (Et,B) or 53% (Et,Zn), 92% de 42c R = c-C6H11,58% (Et3B) or 41% (Et,Zn), 90% de
Scheme 9. Intermolecular oxime ether additions by Miyabe et al. [21, 221 0
LNOBn
1) RH, 13 equiv Et3B toluene, 80 “C, 1 h 2) 20% TFNCH2C12
HO z
HN-OBn 43
44a R = Bu3Sn,64% 44b R = (Me,Si),Si, 50%
;do/‘-,~\yco,”’ SQPh
\
1) 3 equiv RI, 3 equiv Me3Sn-SnMe, hv, benzene, 24 h 2) 1N HCI/Et,O, MeOH/CH,CI,, 48 h c
45
similar conditions, 45
46 47, 24%
EtOpI?
Scheme 10. Intermolecular oxime ether additions by Miyabe et al. and Jeon et al. [23, 241
90
1.5 Radical Reactions on Solid Support
1.5.4 Summary Intramolecular or intermolecular carbon-carbon bond-forming radical reactions on solid phase were uncharted territory until very recently, and the early work has focussed on establishing their feasibility. Many of the examples feature 5-ex0 cyclizations of a radical onto an alkene or alkyne, perhaps reflecting the popularity of this transformation in solution phase, while intermolecular reactions are less well explored. In the beginning, there was some concern about benzylic hydrogen abstraction from the polystyrene matrix, but this has largely proven to be unfounded, and in fact the Wang linker (also containing benzylic hydrogens) is most commonly used. From a practical point of view, this is beneficial as these resins are the cheapest and are available with a high loading. Nevertheless, compared to solutionphase reactions, large amounts of radical initiator and propagator are typically employed. The slower solid-phase kinetics also appears tolerant of high concentrations of tin hydride without premature reduction, although in some cases portionwise addition gave superior results. Finally, the solid-phase does offer obvious advantages in terms of reaction workup. Overall, the inescapable conclusion is that there are no inherent difficulties in carrying out radical reactions on solid phase, and more sophisticated examples can be anticipated. A major challenge for future workers will be the development of efficient and robust radical reactions on solid phase that are sufficiently reliable for the preparation of combinatorial libraries.
References [ l ] (a) C. C. Leznoff, Chem. Soc. Rev. 1974,3,65-85. (b) C. C. Leznoff, Ace. Chem. Res. 1978, 11, 327-333. (c) C. C. Leznoff, Can. J. Chem. 2000, 78, 167-183. (d) H. I. Crowley, H. Rapoport, Acc. Chem. Res. 1976, 9, 135-144. [2] For representative monographs, see: (a) N. K. Terrett, Comhinatorial Chemistry, OUP, Oxford, 1998. (b) B. A. Bunin, The Combinutorial Index, Academic, San Diego, 1998. [3] (a) B. A. Lorsbach, M. J. Kurth, Chem. Rev. 1999, 99, 1549-1581. (b) R. E. Sammelson, M. J. Kurth, Chern. Rea. 2001, 101, 137-202. [4] For example, see: (a) B. Yan, Comb. Chem. High-Throughput Screening 1998, I , 215-229. (b) B. Yan, Ace. Chem. Res. 1998,31, 621-630. [ 5 ] For reviews, see: (a) I . W. James, Tetrahedron 1999, 55, 4855-4946. (b) F. Guillier, D. Orain, M . Bradley, Chem. Rev. 2000, 100, 2091-2157. [6] For a review, see: B. K. Banik, Curr. Org. Chem. 1999, 3, 469-496. [7] A. Routledge, C. Abell, S. Balasubramanian, Synlett 1997, 61-62. [8] X . Du, R. W. Armstrong, J. Org. Chem. 1997, 62, 5678-5679. [9] X. Du, R. W. Armstrong, Tetrahedron Lett. 1998, 39, 2281-2284. [lo] For a review, see: S. Wendeborn, A. De Mesmaeker, W. K. D. Brill, S. Berteina, Ace. Chem. Res. 2000, 33, 215-224. [ 111 S. Berteina, A. De Mesmaeker, Tetrahedron Lett. 1998, 39, 5759-5762. [12] S. Berteina, S. Wendeborn, A. De Mesmaeker, Synlett 1998, 1231-1233. [I31 S. Berteina, A. De Mesmaeker, S. Wendeborn, Syn/t.fr 1999, 1121-1123.
References
91
[I41 G. Jia, H. Iida, J. W. Lown, Synlett 2000, 603-606. [I51 Y. Watanabe, S. Ishikawa, G. Takao, T. Toru, Tetrahedron Lett. 1999, 40, 3411-3414. [I61 K. C. Nicolaou, A. J. Roecker, J. A. Pfefferkorn, G.-J. Cao, J. Am. Chem. SOC.2000, 122. 2966-2967. [ 171 M. P. Sibi, S. V. Chandramouli, Tetrahedron Lett. 1997. 38, 8929-8932. [I81 X. Zhu, A. Ganesan, J. Comb. Chem. 1999, 1 , 157-162. [ 191 A.-M. Yim, Y. Vidal, P. Viallefont, J. Martinez, Tetrahedron Lett. 1999, 40, 4535-4538. [20] S. Caddick, D. Hamza, S. N. Wadman, Tetrahedron Lett. 1999, 40, 7285-7288. [21] H. Miyabe, Y. Fujishima, T. Naito, J. Org. Chem. 1999, 64, 2174-2175. [22] H. Miyabe, C. Konishi, T. Naito, Org. Lett. 2000, 2, 1443-1445. [23] H. Miyabe, H. Tanaka, T. Naito, Tetruhedron Lett. 1999, 40, 8387-8390. [24] G.-H. Jeon, J.-Y. Yoon, S. Kim, S. S. Kim, Synlett 2000, 128 -130.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
2 Radical Processes: Carbon-Heteroatom Bond Formation 2.1 Hydroxylation and Amination of CarbonCentered Radicals Cyril Ollivier and Philippe Renaud
2.1.1 Introduction Radical reactions are widely used for carbon-carbon bond formations. This has led to highly efficient novel synthetic methods that can be used in natural product synthesis as well as preparation of fine chemicals. Many of these processes involve a reductive final step (see for instance Volume 1, Chapter 1.3). Alternative methods that allow functionalization of carbon-centered radicals are highly desired. In this chapter, we will focus on oxygenation and amination reactions.
2.1.2 Radical Hydroxylation The formation of a carbon-oxygen bond from a carbon-centered radical can be performed by reaction with molecular oxygen and with nitroxides. These two processes are fast and lead, after a reductive step, to hydroxylated compounds (Scheme 1). The rate constants of these two reactions are high [l, 21. However, by keeping the concentration of the oxygenating agent low, cascade reactions involving intramolecular formation of C-C bonds followed by C - 0 bond formation are feasible. In this review, we will cover the preparative aspects of the hydroxylation reaction. Catalytic hydroxylation via C-H bond activation (Volume 2, Chapter, 2.2) and reactions of peroxyl radicals (Volume 2, Chapter 5.4) are covered in separate chapters and are not included here. Chemistry involving nitroxides will be limited to the most practical hydroxylation processes since a chapter is dedicated to this chemistry (Volume 2, Chapter 2.3). The oxygenation of organometallic compounds (Li, Mg, Al, Cd, Zn and Sm) involves in some cases radical intermediates [3] but will not be treated in this review excepted when the organometallic compound is produced by a radical cyclization process.
94
2.1 Hydroxylation and Amination of Curbon-Centered Radicals
Alkyl radicals : k(02) > lo9 M-' s-l [11
Alkyl radicals : k(R2NO) = 10' M-' s-l [21
Scheme 1
2.1.2.1 Oxygenation of Organic Halides Tin-mediated oxygenations
Nakamura has reported the first efficient and useful procedure for the conversion of halides to alcohols [4].The transformation is accomplished by treatment of the halide with molecular oxygen and tin hydride at low temperature. Final reductive treatment with NaBH4 ensures complete reduction of the hydroperoxide to the alcohol. The procedure is efficient with activated alkyl bromides and alkyl iodides (Scheme 2, Eq. 2.1). It tolerates a wide range of functional groups and constitutes a powerful
Bu3SnHor/and NaBH4
v"
*
I
-C-OH
I
1) Bu3SnH (2.5 equiv) air, 0-20 "C
52:48
2) NaBH4
(2.1)
81Yo
moMe Bu3SnCI (5 mol%)
O2 AlBN (1.5(1equiv) mol%)
*
NaBH3CN (2 equiv) tBuOH, 60 "C 83%
Scheme 2
&OMe
(2.2)
95
2.1.2 Radical Hydroxylation H3Cn;CH3
1) toluene, Bu3SnH,60 AIBN, "C, 3airh
H3c",
H
*
AcO
:
2) Ac20, pyridine 82%
OAc
AcO
3
C
r
+
.
fJAc
AcO 2: 1
.
H OAc
3 (3.1)
OAc
H
TBSO/,~:J TBSO . OTBs
toluene, 60 "C, 3 h ph
(3.2)
82%, dr 53:28:12:7
Scheme 3
synthetic strategy for tandem intramolecular radical cyclization/oxygenation. A catalytic version using Bu3SnC1 ( 5 mol'%) and stoichiometric NaBH3CN under aerobic sonochemical conditions was also reported [ 51. The ultrasound irradiation plays a key role in both radical initiation and formation of the tin hydride reagent [6]. Interestingly, oxygenative cyclizations are possible and high yielding (Scheme 2, Eq. 2.2). Prandi slightly modified the procedure and used it for the oxygenation of 2-desoxy-2-iodohexapyranosideswith molecular oxygen. Iodosugars that fail to react under Nakamura's conditions were placed in toluene and treated with the classical tin hydride system (Bu3SnH/AIBN/SO "C) under aerobic conditions to give the epimeric C(2)-alcohols in high yield and low-to-moderate selectivity (Scheme 3, Eq. 3.1). The use of rigid structures such as 1,6-anhydroglucopyranoseor protection of the adjacent alcohols with tert-butyldimethylsilyl groups allows one to control to some extend the stereochemical outcome of the reaction [7]. Oxygenative cyclizations were also performed under these conditions (Scheme 3, Eq. 3.2) [S]. Similar radical cyclization/oxygenations were used for the synthesis of anomeric spironucleosides [9] and trans bicyclic ketones [ 101. Yoshida reported the oxygenative conjugate addition of perfluoroalkyl radicals to styrene derivatives (Scheme 4) [ 1 I]. The reaction is photochemically initiated and used hexabutyldistannane as radical chain mediator and as reducing agent for the intermediate peroxide.
( B U ~ S(2.2 ~ ) equiv) ~ cF3(cF2)31 + /'Ph 3 equiv
Scheme 4
Benzene, 02,hv
88%
OH
*
cF3(cF2)3aph
2. I Hydroxylution and Amination of' Curbon-Centered Radicals
96
PhpSb
I
OX0
OH
3OTyMe
PhpSbSbPh2, PhH* hv, > 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
N
*
500 mW laser
96% U
Scheme 21
106
2. I Hydroxylation and Amination of Carbon-Centered Radicals
hv, 95% 1) B(OH), (87%) 2) ACPO(90Yo)
Ac - N H
‘“‘0
Scheme 22
Intramolecular alkyl and aryl radical additions onto the azo group were investigated by Beckwith and Warkentin [66]. Alkyl radicals cyclize preferentially in a 5-exo mode. Aryl radicals prefer the 6-endo pathway, but exceptions have been reported by Zardini and Leardini [67].A rare 5-endo cyclization of aryl radicals was observed with highly reactive azo acceptors and used for the synthesis of indazole derivatives (Scheme 23) (681. r
1
Scheme 23
2.1.3.4 Imines Intramolecular additions of carbon-centered radicals to the N-terminus of imines are reported. Frey studied the mechanism of the interconversion of L-M-lysine to L-P-lysine catalyzed by lysine 2,3-aminomutase [69]. They proved the feasibility of a radical mechanism involving a 3-exo cyclization of a primary radical to the N=C bond followed by ring opening to the most stable radical by performing the reaction under tin hydride conditions (Scheme 24). This overall process corresponds to a 1,2imino shift. The nature of the substituents on the imine function influences the preferred cyclization mode (radical attack on the N - vs C-terminus) [70-731. In most cases, mixtures of 5-exo and 6-end0 cyclizations are observed, limiting the synthetic utility
2.1.3 Amination of Carbon-Centered Radical
Bu3SnH Ph
AlBN 62%
J ., Ph
N C02Me
-
107
Me Ph VN ACOOMe
Scheme 24
of this type of processes. However, ketimines derived from benzophenone react exclusively at the N-atom for steric and thermodynamic reasons. Takano used this approach for the preparation of indolines as depicted in Scheme 25. Ryu developed a nitrogen-philic cyclization of acyl radicals onto N=C bond [74]. In this reaction, a polar component favors the selective reaction at the N-atom. This fully regioselective reaction led to an efficient synthesis of 2-pyrrolidinones (4+ 1 annulation, Scheme 26, Eq. 26.1) and piperidinones (5+1 annulation, Eq. 26.2). Me0 Bu3SnH,AlBN 59 Yo
Me0
*
Me0m
N
Ph
y
P
h Ph
Scheme 25
YN-SePh
CO (70 atm) Bu&nH, V-40, 110 "C
(26.1)
71Yo
CO (70 atm) BusSnH, V-40, 110 "C Me0
49%
Me0
Scheme 26
2.1.3.5 Azide Derivatives Intermolecular processes
Thermal decomposition of sulfonyl azides produces variable amounts of alkylazides presumably through a radical mechanism [75,761 .The first preparative and attractive tin-free procedure for the azidation of radicals was recently reported. Secondary and tertiary alkyl iodides and dithiocabonates are easily transformed into the corresponding azides by reaction with ethanesulfonylazide in the presence of dilauryl peroxide (DLP) as radical initiator (Scheme 27, Eq. 27.2). Interestingly, this
108
2. I Hydroxylation and Amination of' Carbon-Centered Radicals R
. + N=h=N-SOpEt -
DLP (10 rnol%L
~o~~
benzene, reflux
-
R-N3
+ SO2 + Et '
1 9;;1:>0]
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.
References
II1
[37] C. L. Hill, G. M. Whitesides, J. Am. Chem. Soc. 1974, 93, 870. (381 K. E. Harding, T. H. Marman, D.-H. Nam, Tetrahedron 1988,44, 5605 and references therein. [39] (a) T. Okamoto, S. Oka, Tetrahedron Lett. 1981, 22, 2191. (b) T. Okamoto, S. Oka, J. Org. Chem. 1984, 49, 1589. 1401 A. R. Howell, G. Pattenden, J. Chem. Sac., Chem. Commun. 1990, 103. 1411 S. Isayama, Bull. Chem. Soc. Jpn. 1990, 63, 1305. [42] S. Inoki, K. Kato, S. Isayama, T. Mukaiyama, Chem. Lett. 1990, 1869. [43] P. Magnus, A. H. Payne, L. Hobson, Tetrahedron Lett. 2000, 41, 2077. [44] E. Nakamura, Y. Imanishi, D. Machii, J. Org. Chem 1994, 59, 8178. [45] F. A. Chowdhury, H. Nishino, K. Kurosawa, Tetrahedron Lett. 1998, 39, 7931 and references therein. T. Ohshima, M. Sodeoka, M. Shibasaki, Tetrahedron Lett. 1993, 34, 8509. [46] V. Nair, L. G. Nair, J. Mathew, Tetrahedron Lett. 1998, 39, 2801. [47] J. Cossy, D. Belotti, V. Bellosta, D. Brocca, Tetrahedron Lett. 1994, 35, 6089 and references therein. [48] U. Jahn, J. Org. Chem. 1998, 63, 7130. [49] M. A. Naylor, A. W. Anderson, J. Org. Chem. 1953, 18, 115. [50] T. Okamoto, S. Oka, J. Chem. Soc., Chem. Commun. 1984, 289. [51] V. F. Patel, G. Pattenden, Tetrahedron Lett. 1987, 28, 1451. [52] A. Ghosez, T. Gobel, B. Giese, Chem. Ber. 1988, 121, 1807. A. Veit, B. Giese, Synlett 1990, 166. [53] D. H. R. Barton, J. M. Beaton, L. E. Geller, M. M. Pechet, J. Am. Chem. Soc. 1960,82, 2640. D. H. R. Barton, J. M. Beaton, L. E. Geller, M. M. Pechet, J. Am. Chem. Soc. 1961, 83, 4076. For review, see : D. H. R. Barton, Pure Appl. Chem. 1968, 16, 1. [54] M. P. Bertrand, J.-M. Surzur, Bull. Soc. Chin?. Fr. 1973, 2393. 1551 R. D. Rieke, N. A. Moore, J. Org. Chem. 1972, 37, 413. 1561 M. Kizil, J. A. Murphy, Tetrahedron 1997, 53, 16847. [57] P. Girard, N. Guillot, W. B. Motherwell, R. S. Hay-Motherwell, P. Potier, Tetrahedron 1999, 55, 3573. [58] K. Alder, F. Pascher, A. Schmitz, Ber 1943, 76, 27. L. Horner, W. Naumann, Annulen, 1954, 81, 587. [59] R. Huisgen, H. Pohl, Chem. Ber. 1960, 93, 527. [60] A. Shah, M. V. George, Tetrahedron 1971,27, 1291. [61] B. D. Baigrie, J. I. G. Cadogan, J. T. Sharp, J. Chem. Soc. Perkin Trans. 1 1975, 1065. 1621 M. Gorgenyi, T. Kortvelyesi, L. Seres, J. Chem. Soc. Faraday Trans. 1993, 89, 447. [63] H. Wamhoff, K. Wald, Chem. Ber. 1977, 110, 1699. [64] F. Risi, A.-M. Alstanei, E. Volanschi, M. Carles, L. Pizzala, J.-P. Aycard, Eur. J. Org. Chem. 2000, 617. [65] D. H. R. Barton, J. Cs. Jaszberenyi, E. A. Theodorakis, J. H. Reibenspies, J. Am. Chem. Soc. 1993, 115, 8050. [66] A. L. J. Beckwith, S. Wang, J. Warkentin, J. Am. Chem. Soc. 1987, 109, 5289. S. F. Wang, L. Mathew, J. Warkentin, J. Am. Cliem. Soc. 1988, 110, 7235. 1671 R. Leardini, M. Lucarini, A. Nanni, D. Nanni, G. F. Pedulli, A. Tundo, G. Zanardi, J. Org. Chem. 1993, 58, 2419. [68] C . P. A. Kunka, J. Warkentin, Can. J. Chem. 1990, 68, 575. [69] 0. Han, P. A. Frey, J. Am. Chem. Soc. 1990, 112, 8982. [70] W. R. Bowman, P. T. Stephenson, N. K. Terrett, A. R. Young, Tetrahedron 1995, 51, 7959. [71] S. Takano, M. Suzuki, A. Kijima, K. Ogasawara, Chem. Lett. 1990, 315. M. T. Tomaszewski, J. Warkentin, Tetrahedron Lett. 1992, 33, 2123. M. T. Tomaszewski, J. Warkentin, J. Chem. Soc., Chem. Commun. 1993, 966. 1721 S. Takano, M. Suzuki, K. Ogasawara, Heterocycles 1994, 37, 149. M. Gioanola, R. Leardini, D. Nanni, P. Pareschi. G. Zanardi, Tetrakedron 1995, 51, 2039. C. K. McClure, A. J. Kiessling, J. S. Link, Tetrahedron 1998, 54, 7121. [73] M. Departure, J. Diewok, J. Grimaldi, J. Hatem, Eur. J. Org. Chem. 2000, 275. [74] I. Ryu, K . Matsu, S. Minakata, M. Komatsu, J. Am. Chem. Soc. 1998, 120, 5838. [75] R. A. Abramovitch, W. D. Holcomb, J. Chem. Soc., Chem. Commun. 1969, 1298. 1761 D. S. Breslow, M. F. Sloan, N. R. Newburg, W. B. Renfrow, J. Org. Cheni. 1969, 91, 2273.
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--
-
a
+
o
+
HX
I OH
Scheme 13. Oxidation of primary and secondary alcohols by oxoammonium salts
134
2.3 Nitroxides
+++ Q + Q basic or mildly acidic conditions
n
HX +
I
0
OH
0
II
O
x-
strongly acidic Scheme 14. pH-dependent
disproportionation of nitroxides to oxoammonium salts and
hydroxylamines
hensive review covering the literature up to 1995 was published by van Bekkum et al. [31]. The use of optically pure nitroxides to effect kinetic resolution of racemic alcohols or desymmetrization of meso alcohols has also been developed. Oxoammonium salts can be generated from nitroxides by oxidation, or by disproportionation under acidic conditions approximately at or below pH = 2. Under mildly acidic or basic conditions (above pH = 3), oxoammonium species react with the corresponding hydroxylamines to regenerate nitroxides in a syn proportionation reaction (Scheme 14). The ease of oxoammonium formation can be measured by cyclic voltammetery; the lower the oxidation potential of the nitroxide, the more effective the nitroxide is at mediating alcohol oxidation [32]. If the nitroxide is to be used in a catalytic fashion, the oxoammonium species must be stable under the reaction conditions. Predominately piperidinyl nitroxides have proven to be effective oxidants. The mechanism of alcohol oxidation and thus the selectivity of the oxidation reaction is dependent on the pH of the reaction conditions. Note in Scheme 13 that upon oxidation of an alcohol to a carbonyl compound, an equivalent of acid is formed, making the reaction conditions more acidic as the reaction proceeds. In addition, use of a peracid as the stoichiometric oxidant results in the generation of a carboxylic acid as the by-product, which further acidifies the reaction mixture at longer reaction times. Thus in some cases the reaction mechanism and hence the selectivity may change as the reaction proceeds. For a more thorough discussion of the mechanism and details of these reactions, the review by van Bekkum is suggested. A simplified overview will be presented here. Oxidation under strongly acidic conditions will be examined first. Treatment of nitroxides with strong acids such as toluenesulfonic acid or perchloric acid facilitates disproportionation to form one oxoammonium salt in situ for every two equivalents of starting nitroxide. Under strongly acidic conditions, secondary alcohols are efficiently oxidized to ketones, whereas primary alcohols are much slower to react [33].The reaction mechanism [31] is most likely that shown in Scheme 15. A kinetic isotope effect ( k ~ / =k 3.1) ~ supports deprotonation of the alpha hydrogen as the rate limiting step [34]. The use of an additional oxidant such as bleach (NaOCI) or hypobromous acid (HOBr) or hypochlorous acid (HOCl) generated in situ from bromide or chloride ion [35] can facilitate the reaction by rapidly reforming the oxoammonium species under the reaction conditions. This allows the nitroxide to be utilized in catalytic amounts. Recently, Bobbitt [36] has
2.3.3 Oxidations
135
Scheme 15. Postulated mechanism for oxoammonium oxidation of alcohols under strongly acidic conditions
I 0
NHAc
NHAc
I
II
OH
0.5 eq.
0.5 eq.
NHAc
II 0 ClO, air-stable yellow salt
Scheme 16. Preparation of an air-stable, stoichiometric oxoammonium salt
developed a pre-formed, stable, non-hygroscopic, stoichiometric oxoammonium salt using a combination of perchloric acid and bleach as oxidizing agents (Scheme 16). Under mildly acidic or basic conditions, primary alcohols are oxidized much more rapidly than secondary alcohols. A variety of stoichiometric oxidants and additives have been utilized. A very popular set of conditions is that developed by Anelli 1371, which utilizes bleach as the stoichiometric oxidant, and requires only 0.01 equivalents of the nitroxide. The addition of bromide ion under biphasic conditions (dichloromethane and sodium bicarbonate buffer, pH = 9.5) provides the aldehyde product in high yield in minutes at 0°C. Secondary alcohols can also be oxidized using longer reaction times. Addition of a phase transfer reagent results in oxidation to the carboxylic acid. Use of 1,4- or 1,5-diols gives lactones via a cyclic hemiacetal intermediate 1381 (Scheme 17). The conditions are mild enough that the preparation of optically pure a-amino aldehydes and cc-amino acids by oxidation can proceed without epimerization 1391. A few recent developments published after the van Bekkum review include the use of alternative oxidants including bis(acetoxy)iodobenzene [40], N-chlorosuccinimide 1411, and anodic oxidation 1421. Use of sodium chlorite (NaC102) as the stoichiometric oxidant with catalytic TEMPO and catalytic bleach provides oxidation of primary alcohols to carboxylic acids in high yields, and minimizes competing chlorination observed when bleach is used in excess 1431. A silica-supported TEMPO derivative provides convenient oxidation under the Anelli conditions in the form of an easily removed, recyclable nitroxide catalyst [44]. The favored mechanism for oxidation under basic or mildly acidic conditions is shown in Scheme 18, and involves an intramolecular deprotonation in
136
2.3 Nitroxides
0.01 eq.
fT I
TS-N
-OH
0
wOH 0.1 eq. KBr
-OH
2.4 eq. NaOCl CH2C12/H20 pH = 9.5
85%
Scheme 17. Oxidation of a 1,5-diol to give a lactone
Scheme 18. Postulated mechanism for oxoammonium oxidation of primary alcohols under basic or mildly acidic conditions
an oxa-Cope fragmentation. Semmelhack [45] has measured a kinetic isotope effect of kH/kD = 1.8 in support of this mechanism. The faster reaction of primary compared with secondary alcohols is attributed to the slower addition of the more hindered secondary substrates to the oxoammonium species [31]. A strong sign that a new methodology is genuinely useful is adoption of that technique by others. There are numerous examples of nitroxide-mediated alcohol oxidation in synthesis, both in cases which take advantage of the mild conditions and chemoselectivity of the reaction [46] and in examples in which the simple protocol and inexpensive reagents make it attractive [47].
2.3.3.2 Kinetic Resolutions and Desymmetrizations with Optically Active Nitroxides The use of optically active nitroxides [48] as oxidants affords the opportunity to carry out kinetic resolution with racemic substrates and desymmetrization with meso substrates. In kinetic resolution, both the % ee of the product and the conversion are important in evaluation of the efficacy of the process. Thus the selectivity value S is used to combine both % ee and conversion into a measure of overall effectiveness ( S = In[(1 - C)(1 - ee)]/ln[(1 - C)(1 ee)]),where C is the fractional conversion and ee is the fractional enantiomeric excess [49]. The selectivities achieved to date have been modest. Table 1 summarizes the results of kinetic resolution using optically active nitroxides by a number of different groups. The only very promising result is a report of excellent enantioselectivity in the kinetic resolution of
+
2.3.3 Oxidations
1 O2
0
137
0
Scheme 19. Oxidation by an acyl nitroxide involving hydrogen abstraction at a benzylic position
secondary alcohols using a TEMPO-modified electrode in the presence of an equivalent of (-)-sparteine [52]. However, Schafer was unable to replicate these results, and found instead that (-)-sparteine was oxidized faster than the alcohol substrates under the reaction conditions [53]. Using an axially chiral nitroxide, Rychnovsky obtained moderate selectivity ( S = 3.9-7.1) [54], and was thus motivated to prepare a number of other optically active nitroxides; however, many of them were ineffective at mediating alcohol oxidation [35, 571. In the case of the pinene-derived acyl nitroxide 31 [50], as well as the phthalimideN-oxyl radical 32 [56], the mechanism of the oxidation involves hydrogen abstraction by the reactive acyl nitroxide [58] (or phthalimidyl nitroxide), followed by trapping of the resulting carbon radical with either a second equivalent of nitroxide or by molecular oxygen (Scheme 19). Table 2 summarizes the results of oxidative desymmetrization using optically active nitroxides.
2.3.3.4 Other Oxidations Mediated by Nitroxides The reagent potassium nitrosodisulfonate (33), known as Fremy's salt, was first prepared in 1845. Its use as a chemoselective oxidizing agent has been reviewed extensively by Zimmer [59a] and Parker [59b] and will only be mentioned briefly here. While it is most widely known for its use in the oxidation of various heteroatom-substituted aromatic compounds to quinones [59], it has also been used in the selective oxidation of benzylic alcohols to ketones [60] and the oxidation of a-amino and ol-hydroxy acids to a-keto acids [61]. The mechanism of the oxidation of phenols to benzoquinones with Fremy's salt is fairly well understood [59a], and the kinetics of this reaction have been studied recently [62]. Fremy's radical abstracts the phenolic hydrogen atom to generate a resonance-stabilized phenoxy radical intermediate (Scheme 20). Trapping of the carbon radical with another equivalent of Fremy's salt, followed by elimination of the aminosulfonate group gives the ortho or para benzoquinone products, depending on the ring substitution.
138
2.3 Nitroxides
*
09
m
r-
0,
c 0 .in e,
c
3
s
g
W
m
0
*
s m
m
W m
e,
g
a, e ,
2
N
% v,
z 0
0
Y
9
e,
0
2
."-c.'
-
x
0
m 0
I
8
2.3.3 Oxidations
$
W
I
m
@J
P 0
I
m 0
W W I
s al
$ r-
I
c.( W
139
140
2.3 Nitroxides
141
2.3.3 Oxidations
k
I
R
(R=OR, alkyl)
- NH,
k
R 0.N S03K
0 (R=H, OH)
Scheme 20. General mechanism for the oxidation of phenols to benzoquinones with Fremy’s salt
Many aromatic systems have been oxidized by Fremy’s salt, including phenols, naphthols, anilines, quinolines, indoles, carbazoles, and polyaromatic systems. The review articles by Zimmer and Parker can be consulted for specific examples. Slight modifications of the mechanism presented in Scheme 20 explain the oxidation of most of these classes of compounds [63]. Oxidations by Fremy’s salt and related nitroxides have been used in the total synthesis of several biologically active compounds [64]. Recent examples can be found in the syntheses of the antitumor antibiotic streptonigrone (34), the antitumor agent EO-9 (354, the anti-rheumatic agent epoxyquinomicin B (36), and the antineoplastic agent makaluvamine C (37) (Scheme 21) [65].
M HZN
e
H2N0 /
3OH Me
\
bN&
0
Me
OH
OMe
OMe streptonigrone (34)
epoxyquinornicin B (36)
EO-9 (35)
makaluvamine C (37)
Scheme 21. Synthetic targets recently prepared utilizing oxidation by Fremy’s salt
142
2.3 Nitroxides
A few miscellaneous oxidations using oxoammonium salts generated from TEMPO or substituted TEMPO analogs have been reported in the literature. These include the electrochemical oxidation of thiols to disulfides by a TEMPO-modified felt electrode [66], the electrochemical oxidation of amines to imines or nitriles [67], the cleavage of benzyl ethers by a single electron transfer mechanism with an oxoammonium bromide salt [68], and the dibromination of propargyl acetates by catalytic oxoammonium tribromide generated from a nitroxide and bromine 1691.
2.3.4 N-Alkoxyamines as Thermally Labile Latent Radicals 2.3.4.1 Nitroxide-Mediated ‘Living’ Polymerizations ‘Living’ free-radical polymerizations [ 701 offer excellent control over both polydispersity and molecular weight, and are thus attractive for the controlled design of advanced materials. As Chapter 5.1 in Volume 1 of this series details this subject in depth, only a short treatment will be offered here. Nitroxide-mediated ‘living’ polymerizations [711 have become attractive because of the wide tolerance of functional groups, the simplicity of the polymerization procedure, and the lack of metal impurities in the final polymer. TEMPO and other thermally stable nitroxides have been used for the controlled polymerization of styrenes with excellent results; however, they are less effective in preparing controlled polymers of other monomer classes. We have recently introduced an N-alkoxyamine, nick-named the ‘Braslau/ Vladimir initiator’, which effects the polymerization of styrenes, acrylates, acrylamides, acrylonitriles [72] and dienes [73] with good control over both molecular weight and polydispersity (Scheme 22). The success of nitroxides at mediating freeradical polymerization stems from the reversible trapping of the reactive radical chain end by the nitroxide to form an N-alkoxyamine dormant species. The pre-
R = Ar, C02R, CONR2, CN
Y
Ph .NAiPr
4Ph
BraslaulVladimir Initiator
R 4
120 “C
Ph
R
,I
I
J
dormant intermediate
Scheme 22. ‘Living’ nitroxide mediated polymerization with the ‘Braslau/Vladimir initiator’
2.3.4 N-Alkoxyamines as Thermally Labile Latent Radicals
143
ponderance of dormant species at any time in the polymerization mixture severely restricts the amount of early termination events (dimerization or disproportionation), as the concentration of transient free carbon radical species is extremely low. This leads to excellent polydispersities, as all of the polymer chains grow with similar rates, and are repeatedly ‘capped’ by the nitroxide moiety. The ‘living’ character of the growing polymer chains can be further utilized in the preparation of block copolymers. Although the reversible ‘capping’ of the reactive radical chain ends minimizes carbon radical self encounters, occasionally two carbon radicals do find each other and react in a chain-terminating event. This results in the build-up of free nitroxide in the polymerization mixture [74]. The success of TEMPO and other related nitroxides in controlled styrene polymerizations is a result of a styrene autoinitiation process which slowly generates carbon free radicals at the high polymerization temperature, typically at or above 120 “C. These carbon radicals scavenge any excess concentration of TEMPO that have built up by termination processes. When TEMPO is used to polymerize other monomers, no autoinitiation occurs, and thus the concentration of nitroxide climbs over time, eventually preventing chain elongation because of the fast rate of nitroxide trapping of carbon radicals compared to the relatively slow rate of carbon radical addition to the olefin monomer. This is manifested in incomplete consumption of olefin monomer, and consequently poor control over molecular weight. Nitroxide 38 is unusual in that it contains a hydrogen atom on the carbon a to the nitroxide nitrogen. Normally, these types of nitroxides are unstable, as they disproportionate to form hydroxylamine and nitrone (Scheme 23) [75]. However a number of isolable a-hydrogen nitroxides have been developed [76] which are kinetically stable at room temperature. In these cases, the substituents are sterically hindered enough to restrict rotation about the acarbon nitrogen bond (Scheme 24). The a-carbon hydrogen bond lies approximately in the nodal plane of the three-electron nitroxide N-0 n bond, preventing disproportionation [76b, 771. Upon heating, rotation occurs and the nitroxides decompose by disproportionation. This is the situation for nitroxide 38 as well as nitroxide 39, known as SG-1, another excellent mediator for living polymerizations [78]. At the temperature of the polymerization process, these nitroxides can exist in isolation from other nitroxides, acting as reversible caps for the growing polymer chain. However, when a small amount of chain termination occurs, the free nitroxide concentration increases, and disproportionation occurs to remove the excess nitroxide. Thus the existence of an a-hydrogen induces a self-scavenging mode: inhibition of chain growth by build-up of the nitroxide concentration is avoided. The use of the reversible N-alkoxyamine fragmentation - coupling sequence, a ‘degenerate’ radical reaction [79], has been extended by Studer to the synthesis
Scheme 23. Disproportionation of nitroxides bearing @-hydrogens
144
2.3 Nitroxides
Scheme 24. Mode of decomposition of cc-hydrogen nitroxides at elevated temperatures.
Ph
70% (2.511 CLIP) 40
41
42
43
Scheme 25. Radical cyclization by degenerate nitroxide trapping using an N-alkoxyamine
of small molecules [80]. Thermolysis of an N-alkoxyamine bearing a tethered olefin generates a radical which can undergo 5-exo or 6-ex0 radical cyclization with net transfer of the N-alkoxyamine group (Scheme 25). For example, when N-alkoxyamine 40 is heated to 130°C, an equilibrium is established between the starting material and the stabilized carbon radical intermediate 41. Cyclization followed by nitroxide trapping forms product 43. The final nitroxide trapping step is irreversible, as homolysis of the C - 0 bond of the product would generate the unstable primary radical 42. The reaction sequence is facilitated by factors which lower the dissociation energy of the C - 0 bond of the N-alkoxyamine starting material. These factors include the presence of a radical-stabilizing group such as an aromatic ring, ester or nitrile adjacent to the nascent radical center, the choice of solvent, and the nitroxide structure. A very polar solvent system consisting of tert-butanol and 10% camphorsulfonic acid was beneficial, presumably because of enhanced stabilization of the polar free nitroxide intermediate compared to the relatively nonpolar N-alkoxyamine.
2.3.5 Miscellaneous Synthetic Applications of Nitroxides In most of the examples described in this chapter, nitroxides have been added as reagents to mediate or catalyze organic reactions. In the following example, Corey
2.3.5 Miscellaneous Synthetic Applications of Nitroxides
145
(203 pa)
44
46
45
48
47
Scheme 26. Synthesis of a hindered amine through a transient nitroxide intermediate
developed a synthesis of hindered optically active amines that generates and traps nitroxides in situ [81]. Menthone-derived alkyl hydrazine 44 was oxidized to the corresponding diazene intermediate, which fragments with loss of dinitrogen to form radical 45 (Scheme 26). This reacts with nitroso-t-octane to give nitroxide 46, which is trapped by a second equivalent of carbon radical to yield N-alkoxyamine product 47. Reductive cleavage of the N-alkoxyamine yielded the desired optically active amine 48 in high diastereoselectivity. In Magnus' studies of P-azidonation of triisopropylsilyl (TIPS) enol ethers, it was found that addition of TEMPO had a profound effect on the reaction pathway [82]. When TIPS protected enol ether 49 was allowed to react with PhIO and TMSN3 in the absence of TEMPO, compound 51 was obtained as the major product; however, in the presence of catalytic TEMPO, compound 53 was obtained (Scheme 27). The formation of product 51 is postulated to occur via conjugate addition of azide anion to an enonium cation intermediate 50, whereas compound 53 is proposed to form via the formation of azide radical, which adds to the silyl enol ether double bond to form intermediate 52.
,
1.2 eq. PhlO 2.4eq.TMS-N;
?TIPS
1 81 +OTIPS
N3-
50
N3
51
84% TIPSO,, N3
\ L
49
-0 ,%O
1.5 eq. PhlO
2 eq. TMS-Ns cat. TEMPO
TMSO-!-N3
/TEMPO
N3
91% sinale diast. I
52
TMSO-/-OTEMP Ph
53 +
'N3
Scheme 27. Effect of catalytic TEMPO to the mechanism of addition of trimethylsilyl azide to a TIPS enol ether
146
2.3 Nitroxides r
1
PhO, /,CG0
54
55
56
Scheme 28. Diaddition of TEMPO to ketenes
A novel use of nitroxides in synthesis involves the addition of TEMPO to ketenes [83]. Tidwell carried out ah initio computational studies to predict that the addition of nitroxides to the carbonyl carbon of ketene would be exothermic. This was then verified experimentally by the reaction of TEMPO with various ketenes to give diaddition products. For example, ketene 54 was allowed to react with TEMPO to give product 56 (Scheme 28). The intermediacy of radical 55, suggesting initial nitroxide addition to the carbonyl carbon, is supported by the isolation of alternative products derived from the trapping of molecular oxygen at the a position.
References [ l ] H. Fischer, J. Am. Chem. Soc. 1986, 108, 3925-3927. [2] D. Griller, K. U. Ingold, Acc. Chem. Res. 1976, 8, 13-19. [3] (a) V. W. Bowry, K. U. Ingold, J. Am. Clzem. Soc. 1992, 114, 4992-4996. (b) J. Chateauneuf, J. Lusztyk, K. U. Ingold, J. Org. Chem. 1988, 53, 1629-1632. (c) I. W. C. E. Arends, P. Mulder, K. B. Clark, D. D. M. Wayner, J. Phys. Chem. 1995, 99, 8182-8189. [4] (a) T. J. Stone, T. Buckmann, P. L. Nordio, H. M. McConnell, Proc. Natl. Acad. Sci. U.S.A., 1964,54, 1010-1017. (b) J. F. W. Keana, Chem. Reu. 1978, 78, 37-65. (c) J. F. W. Keana, Spin Labeling in Pharmacology; Academic: New York, 1984; pp. 1-85. (d) N. Kocherginsky, H. M. Swartz, Nitroxide Spin Labels: Reactions in Biology and Chemistry, CRC: New York, 1995. (e) L. B. Volodarsky, Imidazoline Nitroxides, Volume II: Applications, CRC: Boca Raton, Florida, 1988. [5] (a) E. G. Janzen, Acc. Chem. Res. 1971, 4 , 31-40. (b) M. J. Perkins, Adu. Phys. Org. Chem. 1980, 17, 1-64. (c) E. Breuer, H. G. Aurich, A. Nielsen, Nitrones, Nitronates and Nitroxides, John Wiley: New York, 1989; pp. 321-328, pp. 374-378. (d) C. Lagercrantz, J. Phys. Chem. 1971, 75, 3466-3475. [6] (a) K. Fegy, D. Luneau, T. Ohm, C. Paulsen, P. Rey, Angew. Chem. Int. Ed. Engl. 1998, 37, 1270-1273. (b) M. M. Matsushita, A. Izuoka, T. Sugawara, T. Kobayashi, N. Wada, N. Takeda, M. Ishikawa, J. Am. Chem. Soc. 1997, 119, 4369-4379. (c) F. M. Romero, R. Ziessel, M. Bonnet, Y. Pontillon, E. Ressouche, J. Schweizer, B. Delley, A. Grand, C. Paulsen, J. Am. Chem. Soc. 2000,122, 1298-1309. [7] (a) L. B. Volodarsky, V. A. Reznikov, V. I. Ovcharenko, Synthetic Chemistry of Stable Nitroxides, CRC: Boca Raton, Florida, 1994. (b) L. B. Volodarsky, Imidazoline Nitroxides, Volume I: Synthesis and Properties, CRC: Boca Raton, Florida, 1988. [8] (a) K. S. Root, C. L. Hill, L. M. Lawrence, G. M. Whitesides, J. Am. Chem. Soc. 1989, I l l , 5405-5412. (b) V. D. Sholle. V. A. Golubev, E. G. Rozantsev. Dokl. Akad. Nauk. SSSR. 1971. 200, 137. (c)'Chem.Abstr. 1972, 76, 25049e. (d) T. N. Nagashima, D. P. Curran, Synlett 1996, 330-332.
References
141
[9] V. A. Golubev, E. V. Kobylyanskii, J. Org. Chem. USSR 1972, 8, 2657-2662. [lo] (a) G. B. Gill, G. Pattenden, G. A. Roan, Tetrahedron Lett. 1996, 37, 9369-9372. (b) J. L. Gage, B. P. Branchaud, Tetrahedron Lett. 1997,38, 7007-7010. [ I ll A. R. Howell, G. Pattenden, J. Chem. Soc., Chem. Commun. 1990, 103-104. [I21 G. Pattenden, Chem. Soc. Rev. 1988, 17, 361-382. [ 131 G. B. Gill, G. Pattenden, S. J. Reynolds, Tetrahedron Lett. 1989, 30, 3229-3232. [ 141 C. Ollivier, R. Chuard, P. Renaud, Synlett 1999, 807-809. [ 151 R. Braslau, S. Garber, unpublished results from this laboratory. [16] C. L. Hill, G. M. Whitesides, J. Am. Chem. Soc. 1974, 96, 870-876. [17] Synthesis of (+)-lactacystin: (a) S. H. Kang, H.-S. Jun, J.-H. Youn, Synlett 1998, 1045-1046. (b) S. H. Kang, H.-S. Jun, J. Chem. Soc., Chem. Commun. 1998, 1929-1930. Synthesis of(+)furanomycin: S. H. Kang, S. B. Lee, J. Chem. Soc., Chem. Commun. 1998, 761-762. [I81 (a) R. J. Kinney, W. D. Jones, R. G. Bergman, J. Am. Chem. SOC.1978, 100, 7902-7915. (b) A. G . M. Barrett, B. C. B. Bezuidenhoudt, L. M. Melcher, J. Org. Chem. 1990, 55, 51965197. (c) A. G. M. Barrett, L. M. Melcher, B. C. B. Bezuidenhoudt, Carbohydrate Res. 1992, 232,259-272. (d) A. G. M. Barrett, D. J. Rys, J. Chem. Soc., Chem. Commun. 1994, 837-838. (e) A. G. Schultz. M. Dai, F. S. Tham, X. Zhang. Tetrahedron Lett. 1998, 39, 6663-6666. (f) A. G. Schultz, X. Zhang, J. Chem. Soc., Chem. Commun. 2000, 399-400. [I91 (a) D. L. Boger, J. A. McKie, J. Org. Chem. 1995, 60, 1271-1275. (b) D. L. Boger, J. A. McKie, H. Cai, B. Cacciari, P. G. Baraldi, J. Org. Chem. 1996, 61, 1710-1729. (c) D. L. Boger, R. M. Garbaccio, Q. Jin, J. Org. Chem. 1997, 62, 8875-8891. [20] M. Lucarini, E. Marchesi, G. F. Pedulli, C. Chatgilialoglu, J. Org. Chem. 1998, 63, 16871693. M. Tercel, M. A. Gieseg, W. A. Denny, W. R. Wilson, J. Org. Chem. 1999, 64, 5946-5953. P. A. Baguley, J. C. Walton. Angew. Chem. Int. Ed. Engl. 1998, 37, 3072-3082. B. C. Gilbert, W. Kalz, C. I. Lindsay, P. T. McGrail, A. F. Parsons, D. T. E. Whittaker, Tetrahedron Lett. 1999, 40, 6095-6098. For a series of reviews on tandem reactions, see: Chem. Rev. 1996, 96, issue 1. U. Jahn, M. Miiller, S. Ausieker, J. Am. Chem. SOC.2000, 122, 5212-5213. For oxidation of enolates to r-carbonyl radicals and trapping with TEMPO, see: U. Jahn, J. Org. Chem. 1998, 63, 7130-7131. R. Braslau, L. C. Burrill, L. K. Mahal, T. Wedeking, Angew. Chem. Int. Ed. Eng. Engl. 1997, 36, 237-238. (a) R. Braslau, H. Kuhn, L. C. Burrill, K. Lanham, C. J. Stenland, Tetrahedron Lett. 1996, 37, 7933-7936. (b) R. Braslau, L. C. Burrill, V. Chaplinski, R. Howden, P. W. Papa, Tetrahedron: Asymmetry 1997, 8, 3209-3212. R. S. Puts, D. Y. Sogah, Macromolecules 1996, 29, 3323-3325. (b) N. Benfaremo, M. Steenbock, M. Klapper, K. Miillen,V. Enkelmann, K. Cabrera, Liebigs Ann. 1996, 1413-1415. (c) J. Einhorn, C. Einhorn, F. Ratajczak, I. Gautier-Luneau, J.-L. Pierre, J. Org. Chem. 1997, 62,9385-9388. R. Braslau, N. Naik, H. Zipse, J. Am. Chem. Soc. 2000, 122, 8421-8434. (a) J. M. Bobbitt, M. C. L. Flores, Heterocycles 1988, 27, 509-533. (b) V. A. Golubev, Y. N. Kozlov, A. N. Petrov, A. P. Purmal, Bioact. Spin Labels, Ed. R. I. Zhdanov: Springer, Germany, 1992; pp. 119-140. A. E. J. de Nooy, A. C. Besemer, H. van Bekkum, Synthesis 1996, 1153-1174. S. D. Rychnovsky, R. Vaidyanathan, T. Beauchamp, R. Lin, P. J. Farmer, J. Org. Chem. 1999, 64, 6745-6749. (a) J. A. Cella, J. A. Kelley, E. F. Kenehan, J. Org. Chem. 1975,40, 1860-1862. (b) B. Ganem J. Org. Chem. 1975, 40, 1998-2000. (c) Z. K. Ma, J. M. Bobbitt, J. Org. Chem. 1991, 56, 6110-6114. (d) M. G. Banwell, V. S. Bridges, J. R. Dupuche, S. L. Richards, J. M. Walter, J. Org. Chem. 1994, 59, 6338-6343. V. A. Golubev, V. N. Borislavskii, A. L. Aleksandrov, Bull. Acad. Sci. USSR. Diu.Chem. Sci. 1977, 1874-1894. S. D. Rychnovsky, R. Vaidyanathan, J. Org. Chem. 1999, 64, 310-312. J. M. Bobbitt, J. Org. Chem. 1998, 63, 9367-9374. P. L. Anelli, C. Biffi, F. Montanari, S. Quici, J. Org. Chem. 1987, 52, 2559-2563.
148
2.3 Nitroxides
1381 P. L. Anelli, S. Banfi, F. Montanari, S. Quici, J. Org. Chem. 1989, 54, 2970-2972. [39] M. R. Leanna, T. J. Sowin, H. E. Morton, Tetrahedron Lett. 1992, 33, 5029-5032. [40] A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli, J. Org. Chem. 1997, 62, 6974-6977. [41] J. Einhorn, C. Einhorn, F. Ratdjczak, J. L. Pierre, J. Org. Chem. 1996, 61, 7452-7454. 1421 (a) K. Schnatbaum, H. J. Schafer, Synthesis 1999, 864-872. (b) Y. Kashiwagi, F. Kurashima, J. Anzai, T. Osa, Heterocycles 1999, 51, 1945-1948. [43] M. Z. Zhao, J. Li, E. Mano, Z. G. Song, D. M. Tschaen, E. J. J. Grabowski, P. J. Reider, J. Org. Chem. 1999, 64, 2564-2566. [44] C. Bolm, T. Fey, J. Chem. Soc., Chem. Commun. 1999, 1795-1796. [45] M. F. Semmelhack, C. R. Schmid, D. A. Cortes, Tetrahedron Lett. 1986,27, 11 19-1 122. [46] (a) J. Jurczak, D. Gryko, E. Kobrzycka, H. Gruza, P. Prokopowicz, Tetrahedron 1998, 54, 6051-6064. (b) J. B. Epp, T. S. Widlanski, J. Org. Chem. 1999,64, 293-295. (c) Z. G. J. Song, M. Z. Zhao, R. Desmond, P. Devine, D. M. Tschaen, R. Tillyer, L. Frey, R. Heid, F. Xu, B. Foster, J. Li, R. Reamer, R. Volante, E. J. J. Grabowski, U. H. Dolling, P. J. Reider, S. Okada, Y. Kato, E. Mano, J. Org. Chem. 1999, 64, 9658-9667. [47] C. Comesse, 0. Piva, Tetrahedron: Asymmetry 1999, 10, 1061-1067. [48] N. Naik, R. Braslau, Tetrahedron 1998, 54, 667-696. [49] H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249-330. [50] (a) C. Berti, M. J. Perkins, Angew. Chem. fnt. Ed. Engl. 1979, 18, 864-865. (b) M. J. Perkins, C. Berti, D. J. Brooks, L. Grierson, J. A . M. Grimes, T. C. Jenkins, S. L. Smith, Pure Appl. Chem. 1990, 62, 195-200. [51] Z. K. Ma, Q. T. Huang, J. M. Bobbitt, J. Org. Chem. 1993, 58, 4837-4843. [52] Y. Kashiwagi, Y. Yanagisawa, F. Kurashima, J. Anzai, T. Osa, J. M. Bobbitt, J. Chem. Soc., Chem. Commun. 1996, 2745-2746. [53] E. M. Belgsir, H. J. Schafer, J. Chem. Soc., Chem. Comniun. 1999, 435-436. [54] S. D. Rychnovsky, T. L. McLernon, H. Rajapakse, J. Org. Chem. 1996, 61, 1194-1 195. [55] (a) Y. Kashiwagi, F. Kurashima, C. Kikuchi, J. Anzai, T. Osa, J. M. Bobbitt, J. Chem. Soc., Chem. Commun. 1999, 1983-1984. (b) Y. Kashiwagi, F. Kurashima, C. Kikuchi, J. Anzai, T. Osa, J. M. Bobbitt, Tetrahedron Lett. 1999, 40, 6469-6472. [56] (a) C. Einhorn, J. Einhorn, C. Marcadal-Abbadi, J. L. Pierre, J. Org. Chem. 1999, 64, 45424546. (b) Y. Ishii, T. Iwahama, S. Sakaguchi, K. Nakayama, Y. Nishiyama, J. Org. Chem. 1996, 61, 4520-4526. (c) Y. Yoshino, Y. Hayashi, T. Iwahama, S. Sakaguchi, Y. Ishii, J. Org. Chem. 1997,62, 6810-6813. [57] S. D. Rychnovsky, T. Beauchamp, R. Vaidyanathan, T. Kwan, J. Org. Chem. 1998,63, 63636374. [58] R. Braslau, J. R. Axon, B. Lee, Org. Lett. 2000, 2, 1399-1401. (591 (a) H. Zimmer, D. C. Lankin, S. W. Horgan, Chem. Rev. 1971, 71, 229-246. (b) K. A. Parker, D.-S. Su in Encyclopedia of Reagentsfor Organic Synthesis, Vol6 (Ed.: L. A. Paquette), John Wiley, New York, 1995, pp. 4271-4274. 1601 J. Morey, A. Dzielenziak, J. M. Saa, Chem. Lett. 1985, 263-264. 1611 (a) A. Garcia-Raso, P. M. Deya, J. M. Saa, J. Org. Chem. 1986, 51, 4285-4287. (b) B. Kawle, M. T. Rao, M. Adinarayana, Indian J. Chem. 1996, 35A, 667-670. (c) B. Kawle, M. T. Rao, M. Adinarayana, Indian J. Chem. 1994, 33A, 1021--1023. [62] B. Kawle, M. Adinarayana, Indian J. Chem. 1994, 33A, 124-127. [63] Recently insight was gained in the mechanism of oxidizing indolines to 5-hydroxyindoles with Fremy’s salt: B. Giethlen, J. M. Schaus, Tetrahedron Lett. 1997, 49, 8483-8486. [64] Dudfield, P. J. in Comprehensiue Organic Synthesis (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, pp. 345-356. [65] (a) D. L. Boger, K. C. Cassidy, S. Nakahara, J. Am. Chem. Soc. 1993, 115, 10733-10741. (b) M. Kinugawa, Y. Masuda, H. Arai, H. Nishikawa, T. Ogasa, S. Tomioka, M. Kasai, Synthesis, 1996, 633-636. (c) N. Matsumoto, H. Iinuma, T. Sawa, T. Takeuchi, Bioorg. Med, Chem. Lett., 1998, 8, 2945-2948. (d) G. A. Kraus, Selvakumar, N. J. Org. Clzem. 1998, 63, 9846-9849. [66] Y. Kashiwagi, A. Ohsawa, T. Osa, Z . Ma, J. M. Bobbitt, Chem. Lett. 1991, 581-584. [67] M. F. Semmelhack, C. R. Schmid, J. Am. Chem. Soc. 1983, 105, 6732-6734.
References
149
168) T. Miyazawa, T. Endo, Tetrahedron Lett. 1986, 29, 3395-3398. [69] T. Inokuchi, S. Matsumoto, M. Tsuji, S. Torii, J. Org. Chem. 1992, 57, 5023-5027. [70] M. Szwarc, J. Polym. Sci. Part A: Polym. Chrm. 1998, 36, R9-RI5. [71] (a) D. H. Solomon, E. Rizzardo, P. Cacioli, U.S. Pat. 4581429; Chem. Abstr. 1985, 102, 221335q. (b) M. K. Georges, R. P. N. Veregin, P. M. Kazmaier, G. K. Hamer, Macromolecules 1993, 26, 2987-2988. (c) C. J. Hawker, G. G. Barclay, A. Orellana, J. Dao, W. Devonport, Macromolecules 1996, 29, 5245-5254. (d) S. 0. Hammouch, J. M. Catala, Macromol. Rapid Commun. 1996, 17, 149-154. (e) T. Fukuda, T. Terauchi, A. Goto, K. Ohno, Y. Tsujii, T. Miyamoto, S. Kobatake, B. Yamada, Macromolecules 1996,29, 6393-6398. [72] D. Benoit, V. Chaplinski, R. Braslau, C. J. Hawker, J. Am. Chem. Soc. 1999, 121, 3904-3920. [73] D. Benoit, E. Harth, P. Fox, R. M. Waymouth, C. J. Hawker, Macromolecules 2000, 33, 363370. [74] M. Steenboc, M. Klapper, K. Mullen, C. Bauer, M. Hubrich, Macromolecules 1998, 31, 52235228. [75] (a) D. F. Bowman, T. Gillan, K. U. Ingold, J. Am. Chem. Soc. 1971, 93, 6555-6561. (b) J. Martine-Hombrouck, A. Rassat, Tetrahedron 1974, 30, 433-436. [76] (a) V. A. Reznikov, L. B. Volodarsky, Tetrahedron Lett. 1994, 35, 2239-2240. (b) V. A. Reznikov, I. A. Gutorov, Y. v . Gatilov, T. v . Rybdlova, L. B. Volodarsky, Russ. Chem. Bull. 1996,45, 384-392. (c) M. Iwamura, N. Inamoto, Bull. Chem. Soc. Jpn. 1970,43, 860-863. [77] H. B. Stegmann, F.-M. Schaber, P. Schuler, K. Scheffler, May Res. Chem. 1989,27, 887-891. [78] (a) S. Grimaldi, J. P. Finet, F. Le Moigne, A. Zeghdaoui, P. Tordo, D. Benoit, M. Fontanille, Y. Gnanou, Macromolecules 2000, 33, 1141- 1147. (b) D. Benoit, S. Grimaldi, J. P. Finet, P. Tordo, M. Fontanilk, Y. Gnanou, Polym. Prepr. 1997, 38, 729. (c) D. Benoit, S. Grimaldi, J. P. Finet, P. Tordo, M. Fontanille, Y. Gnanou, ACS Symposium Series 685; K. Matyjaszewski, Ed.; American Chemical Society: Washington, DC, 1998; p. 225. [79] B. Quiclet-Sire, S. Z. Zard, Pure Appl. Chem. 1997, 69, 645-650. [80] A. Studer, Anyew. Chem. Int. Ed. Engl. 2000, 39, 1108-1 111. [81] (a) E. J. Corey, A. W. Gross, Tetrahedron Lett. 1984, 25, 491-494. (b) E. J. Corey, A. W. Gross, J. Ory. Chem. 1985, 50, 5391-5393. [82] (a) P. Magnus, M. B. Roe, C. Hulme, J. Chem. Soc., Chem. Commun. 1995, 263-265. (b) P. Magnus, M. B. Roe, Tetrahedron Lett. 1996, 37, 303-306. (c) P. Magnus, J. Lacour, P. A. Evans, M. B. Roe, C. Hulme, J. Am. Chem. Soc. 1996, 118, 3406-3418. [83] (a) J. Carter, M. H. Fenwick, W.-W. Huang, V. V. Popik, T. T. Tidwell. Can. J. Chem. 1999, 77, 806-809. (b) A. D. Allen, B. Cheng, M. H. Fenwick, W.-W. Huang, S. Missiha, D. Tahmassebi, T. T. Tidwell, Ory. Lett. 1999, I , 693-696. (c) W.-W. Huang, H. Henry-Riyad, T. T. Tidwell, J. Am. Chem. Soc. 1999, 121, 3939-3943.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
3 Radical Cyclizations and Rearrangements 3.1 Unusual Cyclizations A. Srikrishna
3.1.1 Introduction The use of radical-mediated reactions in organic synthesis has dramatically increased in the last two decades [l]. At the beginning of the 1980s, the place of radical reactions in organic synthesis was limited to a few functional group transformations. However, during the past two decades, radical carbon-carbon bond forming reactions, particularly intramolecular addition of a carbon-centered radical to a double or triple bond leading to cyclic compounds, i.e. radical cyclization reactions, have grown in importance to reach the present status where they are routinely considered at the strategy level planning of complex target molecules. By far the most frequently used radical cyclizations in organic synthesis involve the formation of five-membered rings (Eq. 1) via kinetically favorable 5-exo trig or dig cyclizations and to some extent the formation of six membered rings [ 11. Earlier, the radical cyclization reactions were considered not to be suitable for the generation of either small rings (3- and 4-membered) or medium-sized rings (7- to 12-membered). However, during the last decade a significant number of reports of such reactions have appeared. This chapter reviews the radical cyclization reactions leading to the formation of small and medium-sized rings. However, radical reactions involving either oxidative conditions such as cobalt- manganese- and copper-mediated reactions etc., or reductive conditions such as samarium iodide-mediated reactions etc. are not included.
3.1.2 3-exo Cyclization Reactions The formation of a three-membered ring by 3-exo trig cyclization of a 3-butenyl radical, even though kinetically allowed, is highly unfavorable because the opening
152
3.I Unusual Cyclizations
of the cyclopropylmethyl radical to a 3-butenyl radical is much faster than the cyclization. Hence, 3-exo cyclizations are generally followed by opening of the resulting cyclopropane, which can result in an overall 1,2-vinyl shift (Eq. 2), depending on the stability of the initial and final radicals, commonly referred to as a homoallylhomoallyl radical rearrangement [2]. Because of the facile opening of cyclopropylmethyl radicals, radical chemistry was successfully employed to cleave cyclopropane compounds in a regio- and stereospecific manner [3]. Although numerous examples have been reported in the literature of 1,2-vinyl shifts proceeding via cyclopropylmethyl radical intermediates, it has rarely been possible to obtain cyclopropane products from acyclic precursors because the equilibrium lies too heavily towards the open-chain radicals. Cyclized products can be anticipated only in systems where a large proportion of the ring strain is already present in the initial radical, for example bridged systems, or if the cyclized radicals are stabilized by substituents such as aryl and carbonyl groups. Only very few reports were present in the literature prior to 1990 on the formation of a cyclopropane via a 3-exo trig cyclization under standard radical reaction conditions. The most efficient among them was the generation of nortricyclene from a norbornene system [4]. Kuivila and coworkers reported the formation of a 1:l mixture of norbornene and nortricylene by the reduction of bromide or chloride (Eq. 3) by tributyltin hydride either bicyclo[2.2.l]hept-5-en-2-y1 (Bu3SnH) in the presence of azobisisobutyronitrile (AIBN).
x
(1 :1)
(X = CI or Br)
In 1990, Ingold and coworkers [5] discovered that the reaction of 4-phenylbut-3enyl iodide 1 with BqSnH in the presence of di-revt-butylhyponitrile as the radical initiator generates a 1:8.8 mixture of 3-exo trig cyclized product 2 and the uncyclized reduction product 3. The presence of the phenyl group on the olefin stabilized the cyclized radical to some extent, but not strongly enough to drive the equilibrium toward the cyclized radical.
\
-1 1
ph
Bu3SnH di-t-butylhyponitrile *
pPh+ \ Ph 2 (1 :8.8) 3
Almost at the same time, we discovered [6]a very efficient formation of a cyclopropane ring via 3-exo trig radical cyclization reactions of bicycle[ 2.2.2loct-5-en-2yl and bicyclo[3.2.l]oct-6-en-2-yl bromides 4 and 5. The bromides 4 and 5, obtained from carvone via a common bicyclo[2.2.2]octene precursor, on treatment with
3.1.2 3-ex0 Cyclization Reactions
153
Bu3 SnH and AIBN furnished exclusively the tricyclic compound 6 via 3-ex0 trig radical cyclization. Because of the presence of a radical-stabilizing group, such as an aryl or arylethynyl group on the olefin, the equilibrium was completely shifted to the cyclized form. The electrophilicity of the olefin was increased enough for it to act as a very good internal radicophile. It is worth noting that even the presence of a large excess (20 equivalents) of an external radicophile, such as acrylonitrile, in the medium could not prevent the 3-exo trig cyclization. However, either the absence of a radical-stabilizing group on the olefin (e.g. 7a) or a slight increase in the steric bulk of the aryl group (for example replacing phenyl with 2-methylphenyl 7b) changed the course of the reaction. Cyclopropane formation was not observed and only the simple reduction products 8 were obtained. Because of steric crowding, the olefin and the aryl groups lie orthogonal to each other, thereby losing the coplanarity of the olefin and the aromatic rings and resulting in the loss of the electrophilic nature of the olefin.
AR 0
R = phenyl
~
Br
65-95%
R =4-rnethylphenyl R = 2-phenylethynyl R = 2-naphthyl
4
6
0
Br
Iy
B%JH 70-90%
Me 5
*
J!$ 6
&
B%r* 55-70%
Br&R 7
R
R = phenyl R = 4-rnethylphenyl R = 4-rnethoxyphenyl R = 2-rnethoxyphenyl R = 2-naphthyl
R
a.R=H b. R = 2methylphenyl c. R = 1 maphthyl
8
Dowd and Zhang [ 71, during their investigations on radical-mediated ring expansions employing vinyl bromides, observed the formation of cyclopropanes. Reaction of the vinyl bromides 9 and 13 with Bu3SnH and AIBN furnished the cyclopropane-annulated products 11 and 14 in addition to the simple reduction products 12 and 15, respectively. Formation of the cyclopropanes 11 and 14 was explained via 5-exo trig addition of the initial vinyl radical to the carbonyl group followed by oxy radical-initiated regiospecific opening of the cyclobutane ring in 10 and finally 3-ex0 trig cyclization of the resulting cycloheptenone radicals. It is interesting to note that the corresponding cycloheptenones via the hydrogen abstraction of the penultimate radical were not observed, and only products due to either cyclopropane formation or simple reduction were formed.
154
3. I Unusual Cyclizations
13
14
15
Utilization of vinyl radical for the generation of cyclopropanes was also explored by Gravel and coworkers [8]. Reaction of the bicyclic vinyl bromides 16 with BqSnH and AIBN underwent an initial 5-exo trig cyclization followed by a 3-ex# trig cyclization furnishing the tetracyclic compounds 17. As expected, the presence of a radical-stabilizing group such as phenyl on the olefin retarded the second cyclization and resulted in the formation of significant amount of the tricyclic compound 18. On the contrary, the vinyl halides 19 underwent 5-exo trig cyclization but failed to undergo the second 3-exo trig cyclizations and resulted in only the tricyclic compounds 20. From molecular mechanics calculations it was established that the molecular rigidity, such as the distance and the corresponding angle between the radical center and the olefin, plays an important role in these cyclizations.
16
R
R H OTBDMS Ph
R
17 100% 100% 39%
18
R
45%
k-@
(CWn
(CWn
R
R
19
20
n = 1 or2; R = H or Me; X = I or Br
The importance of the rigidity in the 3-exo trig cyclization was also observed by Luh and Weng [9] in their study of the tandem radical cyclizations of the vinyl bromides 21 and 22. Reaction of the ally1 ethers 21 with Bu3SnH and AIBN re-
3.1.2 3-ex0 Cyclization Reactions
155
sulted in the formation of the 3-oxabicyclo[3.1.O]hexanes23 via the initial 5-exo-trig cyclization followed by 3-exo trig addition of the resulting radical to the diene system, whereas the introduction of flexibility, by increasing one more carbon atom in the ether side chain as in 22, led to the 3-oxabicyclo[4.3.0]nonanesystem 24 via a 6-ex0 trig and 5-exo trig tandem radical cyclization sequence. SiMe2R'
J
SiMe2R' BunSnH
R 21
I
R = Me; Ph; C6HI3; R' = Me or Ph
SiMePPh
23 (SiMepPh
Bu3SnH AlBN 65%
0 22
24
Addition of a radical to a diene system to efficiently generate cyclopropanes was also exploited by Malacria and Journet [ 101. Reaction of the vinyl bromides 25-27 with Bu3SnH and AIBN generated the vinylcyclopropanes 28-30 via the 5-ex0 dig5-exo (or 6-exo) trig-3-exo trig tandem radical cyclization sequence. The dibromide 27, in addition, also furnished the cyclopropane cleaved product 31. 1
E E
BuaSnH AlBN
1 Bu3SnH AlBN X = OCHpCHpO
-a?
25% 92%
26
27
28
E E
29
30 (1 1%)
31 (33%)
156
3.1 Unusual Cyclizations
We have made an interesting observation with norbornene systems [ 1I]. Reaction of the bromide 32a with Bu3SnH and AIBN led to the homoallyl-homoallyl radical rearrangement product 34a exclusively, whereas the corresponding ketal 32b generated a 5:l mixture of the rearrangement product 34b and the 3-exo trig cyclization product 35b. In contrast, the corresponding anti and syn alcohols 36a and 36b reacted differently. The anti alcohol 36a furnished exclusively the rearrangement product 37a, whereas the syn alcohol 36b furnished predominantly the 3-exo trig cyclization product 38b. The origin of these differences is yet to be understood.
32
33
ps
a.X=O b. X = OCHpCHpO Bu3SnH AIBN
34
35
34 : 35 98%
72%
1 :0 5 :1
P w+ p
s
~
Br
Ph
Ph
36 a. X = 0H;Y = H b. X = H:Y = OH
X
37 80% 0Yo
Ph
38 0% 86%
Application of the homoallyl-homoallyl radical rearrangement for the construction of novel polycyclic frameworks in natural product synthesis has received significant attention [ 121. During their synthetic approaches towards the atiserene natural products via homoallyl-homoallyl radical rearrangements, Ihara and coworkers [ 131 investigated the radical cyclization of the vinyl bromide 39. Reaction of the bromide 39 with Bu3SnH and AIBN furnished the tricyclic compound 40 via a tandem S e x 0 trig 3-exo trig radical cyclization sequence, whereas the same reaction without the phenyl group on the olefin led to the formation of the bicyclo[2.2.2] and [3.2.1] octane systems via an initial 5-exo trig cyclization followed by the homoallyl-homoallyl rearrangement of the resulting radical. ~
M6’’ MeOOC
39
35% Ph
COOMe Me
40
Rapid elimination of an atom or a group at the ,&position of the radical, such as bromide or thiophenyl, to suppress the opening of the cyclopropylmethyl radical
3.1.2 3-ex0 Cyclization Reactions
157
to acyclic radicals, was developed as an alternative strategy for the generation of vinylcyclopropanes via 3-exo trig cyclization of radicals. Cekovic and coworkers [14] demonstrated the application of this strategy employing the esters 41. Thus, thermal decarboxylation of the esters 41 in refluxing toluene furnished the vinylcyclopropanes 42 via 3-exo trig cyclization of the initial radical followed by elimination of the thiophenyl group. In a similar manner, Gravel and Denis [ 151 employed the same strategy in a tandem sequence. Photolysis of the vinyl iodides 43 in the presence of a catalytic amount of hexabutylditin furnished the vinylcyclopropanes 45 via an initial 5-ex0 trig cyclization followed by a 3-ex0 trig cyclization of the resulting radical 44 and elimination of the thiophenyl group. The homologue 46 furnished the vinylcyclopropane 47 along with the divinyl compound 48 obtained via a 1,5-radical transposition followed by a Sex0 trig cyclization and elimination of the thiophenyl group. S
R R'
R R ' H PhCH2 Me PhCH:, H n-Cloi21
41
,SPh
yield 32% 25% 30%
42
vrU Y5 X
__t
44
45
43
X = C(COOMe)2; R = H 50% X = C(COOMe)2; R = Me 41% ( 1 O : l ) X = NTs; R = H 54%
K 52%
MeOOC COOMe 46
MeOOC COOMe MeOOC COOMe 47
(4:5)
48
Recently, Saicic and coworkers [ 161 extended this methodology in combination with a radical annulation sequence. Photolysis of the esters 49 in the presence of dimethyl acetylenedicarboxylate generated the bicyclo[3.1.O]hex-2-enes 50. Intermolecular addition of the initial radical to the acetylenedicarboxylate followed by 5exo trig cyclization of the resulting acyclic radical 51 led to the radical 52, which on 3-exo trig cyclization and elimination of the thiophenyl group furnished the products 50.
158
3. I Unusual Cyclizations
,is 4
R' R"
MeOOC
hv
MeOOC
R
COOMe
R
PhS O O - F 49
I
4
/
50
R H Me ally1 H
R, R,, R' R"
MeOOC
MeOOCqph
c'
~
MeOOC $Ph
MeOOC
H
R' H H H H Me
R" H H H Me Me
yield 52% 35% 22% 40%
23%
R
51
52
Recently, Malacria and coworkers [ 171 described a tandem reaction sequence for the construction of a propellane-based system comprising of four radical cyclization reactions. Thus, reaction of the bromide 53 with Bu3SnH and AIBN furnished the tetracyclic compound 54 as only one stereoisomer via a sequential 5-exo dig-5-exo trig-3-exo trig-5-exo dig radical cyclization reactions. Protection of the terminal acetylene groups in the starting material with trimethylsilyl groups as in 55 led to further events. Reaction of the bromide 55 with Bu3SnH and AIBN furnished the bi- and pentacyclic compounds 56 and 57. The radical 58, obtained as described above, underwent a 1,6-radical translocation to generate the silylmethyl radical 59, which on 6-end0 trig cyclization followed by an unprecedented elimination of ptrimethylsilyl radical from the resulting radical 60 led to the formation of the pentacyclic compound 57 in 65% yield.
4
=sioq
BunSnH AiBN
/
35% Br 53
iMs
54
551
-
-Si / 58
t
I
TMS
56(24%)
57(65%)
-
-Si /
-Si
59
60
3.1.3 4-ex0 and 5-endo Cyclizations
159
3.1.3 4-exo and 5-endo Cyclizations Cyclizations of pent-4-enyl radicals are very interesting, because neither the 4-ex0 trig nor the 5-endo trig cyclizations are considered favorable (Eq. 4). The 4-ex0 cyclizations are unfavorable because of the strain and rapid opening of the cyclobutylmethyl radical to pent-4-enyl radical, whereas the 5-endo trig cyclization is disfavored based on Baldwin's rules of ring closures [ 181. As in the case of 3-ex0 cyclizations, neither the 4-exo nor 5-endo radical cyclization reactions were reported in the literature prior to 1988.
U-
5-endo
4-eXO
(4)
Balasubramanian and Gopalsamy [ 191, during their investigations on the synthesis of benzofuranochromans, encountered perhaps the first examples of 5-end0 trig radical cyclization reactions. Generation of the aryl radical from the aryl chromenyl ethers 61 with Bu3SnH and AIBN under standard radical cyclization conditions in 0.02 M benzene furnished the benzofurochromenes 62 via a 5-endo trig cyclization.
61
62
R=R'=H R = OMe; R'R' = -CH=CH-CH=CHR = CI; R'R' = -CH=CH-CH=CH-
82%
90% 88%
The first example of a 4-exo-trig radical cyclization reaction was reported by Araki and coworkers [20] in 1989 during their investigations on the synthesis of higher sugars from lower sugars. Slow addition of a benzene solution of Bu3SnH/AIBN to a refluxing solution of the allofuranose derived iodide 63 in benzene furnished the oxetane 64 via a 4-ex0 trig radical cyclization with 100% diastereoselectivity.
#Aho
B;r;;Fcxo
P
EtOOC
71Yo
THPo 63
O
f
THPo O 64
f
In 1990, Newcomb and coworkers [21] described the 4-exo trig radical cyclization of the bromonitrile 65. Reaction of the bromonitrile 65 with an in situ generated
160
3.1 Unusual Cyclizations
catalytic Bu3SnH (Bu3SnC1 and NaCNBH3) and AIBN furnished a 1:l mixture of the uncyclized reduction product 67 and the 4-ex0 trig radical cyclization product cyclobutane 66. It was observed that the electrophilic nature of the olefin (due to nitrile) as well as the presence of a quaternary carbon atom (gem dialkyl effect) in the chain were essential for the 4-ex0 cyclization to take place.
65
66
(1 : 1)
67
Jung and coworkers [22] have systematically investigated the 4-ex0 trig cyclizations employing 6-bromohex-2-enoates 68 as substrates to generate the cyclobutanes 69. The gem dialkyl effect was further established as 4-ex0 cyclization was not observed in the absence of a quaternary carbon in the chain, and resulted in only the uncyclized reduction products 70. Theoretical calculations further supported this observation. The presence of a dialkyl group on the intervening carbons reduces the activation energy of the 4-ex0 trig cyclization by 2-5 kcal/mol. Qualitatively it was explained as rotamer effect, i.e. higher population of the reactive rotamer or the selective destabilization of ground state rotamer. The 4-ex0 trig cyclization was found to be efficient when the reaction was carried out employing a slow addition (syringe pump) technique. It was interesting to note that the dialkoxy group has a tremendous effect when compared to the dialkyl effect. However cyclic ketals generated an interesting anomaly. The presence of a six-membered ketal predominantly generated the 4-exo trig-cyclized product 69 even when the reaction was carried out using the normal procedure, whereas the presence of a five-membered ketal generated significant amount of simple reduction product 70 (similar to gem dialkyl compound). Perhaps the small ring angle of the dioxalane, compared to that of a dioxane ring or the free alkoxy groups, might increase the angle between the radical-bearing carbon and the electrophilic double bond.
68
69
R,R H Me OEt OCH2CH20 OCHzCH2CH20 COOEt
70
Ratio of 69 and 70 slow addition normal reaction 0 : 100 88 : 12 25 : 75 100 : 0 75 : 25 25 :75 97 : 3 70 : 30
3.1.3 4-ex0 and 5-endo Cyclizations
161
A significant amount of research work was carried out using a-amidyl radicals to compare the 4-exo with the 5-endo trig radical cyclization reactions, particularly to develop a radical cyclization-based strategy to p-lactams. Belletire and coworkers [23] reported the efficient formation of p-lactams via the 4-exo trig cyclization of bromo enamides 71. Reaction of the bromo enamides 71 with Bu3SnH and AIBN employing slow addition technique led to the formation of the trans p-lactams 72 with excellent stereoselectivity. The efficiency of the 4-ex0 trig cyclization was obviously due to the presence of two phenyl groups on the terminal carbon of the olefin making it a strong radicophile. AlBN
R R' Me C6Hll Et C6Hll Et t-Bu Et Me
0
71
yield 69% 72 70% 58% 40% (+ 60% simple reduction)
This was further supported by the investigations of Ikeda and coworkers [24] with substrates 73 containing the phenyl group on the internal carbon of the olefin. Reaction of either the enamides 73 or the bisthiophenyl enamides 74 with Bu3SnH and AIBN furnished only the 5-endo trig radical cyclization products 75 and 76 along with varying amounts of uncyclized reduction products 77 and 78, and 4-exo trig cyclization was completely suppressed. This reaction was further extended to an efficient synthesis of the alkaloid (*)-cotinine by replacing the phenyl group with a 3-pyridyl group in 73. Bu3SnH Ph'Nfl Me I
Ph L N i : h SPh I
Me 74
Me I
0
'Oy'Ph' Me
75 X,Y = CI,H 17% X,Y = I,H 47% X = Y = S P h 70%
73
R
* Ph0
AlBN
77 18% 12%
-
Bu3SnH AlBN R yield Ph 92% Bn 46% Me 53%
I
Me 76
Me 78
Ishibashi, Ikeda and coworkers [25] further investigated the effect of different substituents on the olefin. With alkyl substituents on the olefin, e.g. 79-81, only the 5-endo trig cyclized products 82-84 along with uncyclized reduction products 85437 were formed, and 4-ex0 trig cyclized products were not formed. It is interesting to note that the chloro enamide 80 produced more of the 5-endo trig cyclized product
162
3.1 Unusuul Cyclizutions
83 than the 5-exo trig cyclized product 88, which is in line with the general observation that the a-acyl radicals are poor substrates toward 5-ex0 trig cyclizations. The importance of the carbonyl group in the chain was established through the attempted cyclization of the N-acetyl compound 81b, which resulted in only the uncyclized reduction product 87b. The presence of a benzo-fused cyclohexene, e.g. 89, led to variable amounts of 4-exo trig cyclized product 90 along with the 5-endo product 91 and uncyclized reduction product 92. It is interesting to note that no 4-exo cyclized product was formed from the corresponding cycloheptene analogue 93, and furnished only the 5-endo trig cyclized product 94 and the uncyclized reducMe
H Me
Bu3SnH
79
R=H R = Me R = Ph
80
Me
82 63% 73% (a:P6:l) 75% (.:P 2:3)
85 8%
83 (58%)
88 (14%)
aNL:ph AlBN* miPh SPh
Bu3SnH
+
R = Me;X = 0 R = Ac; X = H2
89
k
k
k 81
R H Me Ph
90 50% 29%
84 59% 0%
91 40%
87 6% 65%
92 32% 12%
76%
94 (41O h )
95 (20%)
86 (15%)
3.1.4 7-10 ex0 and endo Cyclizations
163
tion product 95. This was explained by considering the conformation of final radical where the p-orbital of the radical carbon lies orthogonal to the aromatic system and hence the aryl group does not stabilize the final radical sufficiently to induce the 4-exo cyclization. Further investigations on the influence of the substituents on the terminal carbon of the olefin were reported by Ikeda and coworkers [26] employing the bromo enamides 96 as substrates. These studies revealed that two thiophenyl groups on the terminal olefinic carbon accelerate the 4-exo trig cyclization to synthetically useful levels. Subsequently, these reactions were applied in the total syntheses of the plactam antibiotics PS-5 and thienamycins first in racemic form and later in optically active forms, employing a-phenylethylamine as the chiral auxiliary.
%AR,,. yR,, Bu3SnH AlBN
$$R,,
N.R*
N-R*
0 96
R H H H H OAc OAc
R * = P M B or (S)-1-phenylethyl
+
+
0
0 97 R' Ph Ph SPh SPh SPh SPh
R" H SPh SPh
H H SPh
'R'
N.R'
0
98 4-ex0 5-endO 15% 16% 56%
99 reduction 41%
80% 74% 39% 64%
14%
Recently, Clark and Peacock [27] explored the application of amidyl radical cyclization for the construction of p-lactams. Reaction of the 0-benzoylhydroxamic acids 100 with Bu3SnH and AIBN employing a slow addition technique furnished the 4-exo trig cyclized product 101, the uncyclized reduction product amide 102 and the benzoyloxy group migration product 103. Ph
L oA loo
-
o
o,N.
R
Ph
Ph
Bu3SnH AlBN
R Me Bn Bu ally1
yield
ratio
:1
R
101
101 1102 1103 70% 1 :1.8: 1 82% 3 : 1 : o 28% 1.4 : 1 : 1 50% 1
O
+
LHN-Ro 102
103
11
3.1.4 7-10 exo and endo Cyclizations The radical cyclization methodology was relatively under-explored for the synthesis of medium ring compounds compared to that of five- and six-membered and large ring compounds [28, 291. Construction of seven-membered rings employing radical
164
3.I Unusual Cyclizations
methodology was achieved both by exo and endo modes of cyclization, whereas the eight-, nine- and ten-membered rings were assembled mainly via the endo cyclization. Bachi and coworkers [30] reported in 1983 one of the early examples of 7-end0 radical cyclization, encountered during their explorations toward the construction of fused p-lactams. Reaction of the chloro lactams 104 with Bu3SnH and AIBN generated a mixture of the 7-end0 trig cyclized product 105 and the uncyclized reduction product 106, and interestingly the products derived from 6-ex0 radical cyclization were not formed. Changing the ally1 ether to propargyl ether 107 produced a 1:2 mixture of the 7-endo dig cyclized product 108 and the reduction product 109. The rigidity of the four-membered ring might have forced the confor-
Go] 0
Bu3SnH
*
A’BN
0
b C l
R
104
,;”.+ofiol ’I
R H Coot-BU
107
R
R
105 34% 47%
108
106 31% 22%
(1 :2)
110
111 (70%)
113
116 (8%)
109
112 (30%)
115 (21%)
114 (54%)
. Bu3SnH AIBN
+
Me
117
X Y H OPh H OAc OBn H
118 65% 55% 60%
119 0% 10% 5yo
3.1.4 7-10 exo and endo Cyclizations
165
mation of the intermediate radical to facilitate the endo cyclization. Quite expectedly, introduction of a phenyl or ester group at the terminal carbon of olefin (or acetylene) changed the course and proceeded via the 6-ex0 mode of cyclization. In a similar manner, Beckwith and Boate [31] have demonstrated the 7-end0 trig cyclization of the /?-lactam 110 to efficiently generate the cycloheptane-fused /?-lactam 111 along with the uncyclized reduction product 112. Supporting the logic of rigidity for favorable 7-end0 cyclization, almost at the same time Hart and coworkers [32] demonstrated that replacement of the four-membered ring by a five-membered ring as in 113 made the 64x0 cyclization dominate over 7-endo cyclization to furnish the cyclized products 114 and 115 and the uncyclized reduction product 116. Subsequently, Bose and coworkers demonstrated that the presence of two sp2 carbons in the chain, e.g. 117, suppressed the 7-end0 cyclization and resulted in the generation of the /?-lactam-fused tetrahydroisoquinolines 118 via 6-ex0 trig cyclization as the major products. Satoh and coworkers [34] reported the 7-endo Michael-type cyclization of the selenoenones 120 to generate the bicyclic ketones 121 along with the uncyclized reduction products 122.
I
120 SePh
n=l n=2
122 24% 11%
121 52% 76%
An intramolecular Michael-type 7-end0 radical cyclization was reported by Kobayashi and coworkers [ 351 employing a trifluoromethyl substituted olefin as the internal radicophile. Thus, reaction of the iodide 123 with Bu3SnH and AIBN furnished the 7-end0 trig cyclized product 124 in 80% yield along with a minor amount of 6-ex0 trig cyclized product 125.
, 123
"YL
124 (80%)
125 (6%)
Boger and Mathvink [36] explored the 7-exo trig cyclization of acyl radicals using selenoesters as precursors. Reaction of the selenoesters 126 and 128 with Bu3SnH and AIBN furnished exclusively the benzocycloheptanones 127 and 129, respectively. Crich and coworkers [37] investigated the influence of oxygen substituents at various carbons on the 7-end0 trig cyclization of 6-heptenoyl radicals. Presence of one or two oxygen substituents at C-5 favored the 7-end0 trig radical cyclizations along with simple reduction (130 + 131 132), and the competitive 6-ex0 cycliza-
+
166
3.1 Unusual Cyclizations
tion was not observed, whereas the presence of either an oxygen substituent at C-3 or any substituent at the terminal carbon of the olefin increased substantially the efficiency of the 6-ex0 cyclization, 136 from 133, and 138 from 137. A mixed effect was observed when oxygen substituents were present at both the C-3 and C-5 positions (139 4 140 + 141).
-
..
X=H 74% X = COOMe 92% 126
127
d '-..
-Q BuaSnH
SePh COOMe
AlBN 71%
COOMe
128
130
129
X
X
131 32% 27%
X = -0CHzCH20X = H, OEt
132 55% 35%
134 X = -0CH2CH2012% X = H, OSiPh2f-Bu 11%
133
P S eP h
135 10% 9Yo
136 72% 41 yo
Bu3SnH AlBN
.SPh
'4
. BuaSnH AlBN
OTBDMS 139
(-'
+
OTBDMS
140 (24%)
Oi'X;"(3:1) OTBDMS
(-0
141 (72%)
3.1.4 7-10 exo and endo Cyclizations
167
The methodology was also extended for the synthesis of cyclic ethers [38]. Reaction of the selenoester 142 with Bu3SnH and AIBN furnished a mixture of 7-end0 and 6-ex0 cyclized products 143 and 144. Interestingly the selenoester 145 furnished the 7-endo trig cyclized product 146 and the perhydrobenzofuran 147 obtained via decarbonylation of the initial radical followed by a 5-ex0 trig cyclization. Once again the presence of two sp2 carbons in the chain, e.g. benzannulated system 148, completely retarded the 7-endo mode and only 6-ex0 cyclization was observed leading to the formation of ketones 149.
142
145
143 (25%)
146 (25%) BusSnH AIBN
148
*
X=O 52% X=S 66% X=NHAc 44%
144 (12%)
147 (32%)
dMe 149
Crich and Batty [39] further extended the studies with cis and trans 4,5-dioxygensubstituted (as acetonide) hept-6-enoyl radicals and found that in the trans isomer 154 the 7-endo mode was suppressed when compared to that in the cis isomer 150 for conformational reasons. It was further extended to a tandem 7-end0 trig - 5-exo dig radical cyclization sequence starting from the selenoester 158 to generate the perhydroazulenes 159. Evans and Roseman [40] explored the 7-exo trig acyl radical cyclization for the generation of cyclic ethers 161 and 162 starting from the selenoesters 160. The efficiency and the diastereoselectivity of these reactions were found to increase when tristrimethylsilylsilane was used instead of Bu3SnH. The generality of this reaction was further established with the corresponding vinylsulfones (instead of acrylates) and also with the corresponding vinyl bromides (instead of selenoesters). Pattenden et al. [41] extended the utility of acyl radicals for the generation of aketenyl radicals. Reaction of the selenoester 163 with Bu3SnH and AIBN generated the benzocycloheptadienone 164 via the acyl radical 165 and 7-endo trig cyclization of the acyl radical 167. Attempted generation of the corresponding 8-membered ring system 169 from the cyclopropyl selenoester 168 via cleavage of the cyclopropylacyl radical, however failed and generated only a 1:l mixture of the products due to the simple reduction and cyclopropane cleavage 170. In contrast, reaction of the sele-
168
Ra :++"1;:;
3.1 Unusual Cyclizations
JSePh
& H B :
R
OX0
OX0 150
R=H R=Me
151 7%
18%
OX0
OX0
152
153
42% 43%
51% 21%
J=d+++(J SePh
O
O
f
f
O
155 (44%)
154
SePh
f
O
156 (1 9%)
f
157 (10%)
(-&
.
four isomers
QI
Bus45% ,
158
(20:13:8:4)
159O X 0
OX0
flSePh . Oh -/.OOMe
(TMgi3siH
160
COOMe 161
R
Me Ph i-Pr
Bu3SnH yield (ratio) 70% (111)
48% (1911)
COOMe 162
(TMS)3SiH yield (ratio)
89% (19:l) 80% (1 9:1) 90% (19:l)
noester 171 with Bu3SnH and AIBN cleanly furnished the 8-end0 trig cyclized product 172, a trans-fused 8-3 system. Perhaps the absence of sp2 carbons in the chain also might have played a crucial role in facilitating the %-end0trig radical cyclization. Shishido and coworkers [42] have employed a highly stereoselective 7-endo trig radical cyclization reaction for the construction of a key intermediate 174 in their synthesis of a pseudoguanolide (+)-confertin starting from the selenoester 173. Araki and coworkers [20] during their approaches to higher sugars discovered an efficient 7-ex0 trig cyclization. Reaction of the allofuranose derivatives bromoacrylates 175 with Bu3SnH and AIBN furnished the bicyclic product 176 via 7-end0 radical cyclization in a stereoselective manner.
3.1.4 7-10 exo and endo Cyclizations
164
a 165
166
t
167
H
SePh
% (f
+ I
169
168 SePh
Bu3SnH AlBN
~e 170
80-95% R = H;OH;OMOM
171
-
) :&*% B J
-
0
169
172
85% 173
174
OH
Br
Bu3SnH
yo O
175
P AlBN
f
MeOOC@p R
176 R = H, 82% (three diastereomers 6:l:l) R = Me, 61% (one isomer) + 13% reduction product
Hart and Ghosh [43] have explored the 7-ex0 aryl and vinyl radical cyclizations for the construction of polycyclic systems as part of their tandem cycloadditionradical cyclization strategies for polycycles. Treatment of the bromides 177-179 with Bu3SnH and AIBN furnished the tetra- and pentacyclic compounds 180-182 via stereoselective 7-ex0 trig cyclizations. Jones and coworkers [44] reported the formation of minor amounts of dihydrobenzazepinone 184 via a 7-ex0 trig cyclization of the aryl halides 183, along with a significant amount of the uncyclized reduction product 185.
170
3. I Unusual Cyclizations
179
182
+ 25% reduction product
183 R = Me; X = I R = Bn: X = Br
184
185
13% 25%
49%
60%
Ikeda and coworkers 1451 reported the formation of the dihydrobenzazepinones 187 via 7-end0 trig cyclization of the dichloroacetamides 186 in excellent yield with an excess of Bu&H and a catalytic amount of AIBN. The presence of two aryl groups on the olefin obviously facilitated the 7-end0 trig cyclization. Further they have discovered that the presence of an allyl group as in 188, generated a mixture of the 7-exo trig and 8-end0 trig radical cyclized products 189 and 190. It was found that the ratio of the 7-ex0 and 8-end0 products 189 and 190 depends on the radical substrate. For example, a dichloroamide generates exclusively the 7-ex0 product 189 and the bisthiophenyl group exclusively furnishes the 8-endo product 190. Ghatak and coworkers 146-491 investigated the aryl radical cyclizations for the construction of benzo-fused seven- to nine-membered rings. To begin with, they have investigated 1461 the 7-endo trig cyclization of the aryl bromides 191 containing an ex0 methylene group. Reaction of the bromides 191 with Bu&H and AIBN furnished a 1:9 mixture of the uncyclized reduction products 193 and 7-end0 trig cyclized products 192, from which 42-67% of the cyclized products 192 were isolated as a mixture (1:l to 2:3) of diastereomers. To avoid the formation of stereoisomers, the cyclohexane moiety was shifted to 4,5 position. Accordingly, reaction of the allyl alcohols 194 with Bu3SnH and AIBN furnished the 7-end0 trig cyclized
3.1.4 7-10 exo and endo Cyclizations Dh
C < I*
R. ,R
R=Me R R= =H H
*& A
Bu3SnH AlBN N
83% 43% 43%
186
dx:
187
R n
Bu3SnH AlBN
188
Me
X Y CI CI SPhSPh CI H CI Me CI Ph
189 49%
-
38% 58% 23%
171
+
190
-
47% 44% 36% 63%
q - $ Y
Me 0
0
+wy 0
Me/
189
190
R i
R'
Jy R'
193 (1OYO)
BunSnH
194
HO
,-.I/---
R = H or Me; R' = H 195 (55-65%) R = H or Me: R ' = OMe
R' 196 (10%)
products 195 in 55-65'30 yield. It is worth noting the absence of 6-ex0 trig cyclized products. Subsequently, the second methodology was successfully extended for the construction of 8- and 9-membered rings [47, 481. Thus, reaction of the bromides 197 and 200 with BuiSnH and AIBN smoothly underwent %end0 trig cyclization to furnish the tricyclic compounds 198 and 201, along with varying amounts of uncyclized reduction products 199 and 202, respectively. It is worth noting that products due to 7-ex0 trig cyclization were not observed, providing the first experimental support for the theoretical prediction [50]that oct-7-enyl radicals should undergo exclusive 8-end0 trig cyclization. Similarly, reaction of the bromoalcohols 203 and 206 with BuiSnH and AIBN furnished the 9-end0 trig cyclized products 204 and 207 along with the uncyclized reduced products 205 and 208, respectively. Recently, they have discovered [49] that the efficiency of these cyclizations was dependent on the temperature of the reaction also. Reaction of the bromo alcohols 209 and 212 with Bu3SnH and AIBN in refluxing xylene produced the tricyclic compounds 210 and 213 containing a bridgehead methyl group, respectively.
\ g Qo . gr
112
3. I Unusuul Cyclizations
H
Bu3SnH AlBN
+
85-90%
R
R
R' 197
R' 198
199
% R &
. Bu3SnH AlBN
R' 200
+
90-95% R' R=R'=H R = Me, R' = H R = Me, R' = OMe
1
R' 201 (60-65%)
202
. Bu3SnH AlBN
t
80% = Me, R' = R" = H = COOMe; R',R" = H,OMe
: & . R"
203
@ +
% & Bu3SnH R
R'
204
(3: 1)
205
AlBN 95%
R'
1
206
R=R'=H R = Me; R ' = H or OMe
R'
\
/
R'
207
-
(1 : 1 )
208
BusSnH AlBN
\
94%
n -
O H 212
213
(1:l)
214
3.1.4 7-10 ex0 and endo Cyclizations
173
Chattopadhyay and coworkers [ 511 extended this strategy for the construction of glucose-derived benzoxocine ring ethers. Thus, reaction of the bromoethers 215, obtained from glucose, with Bu3SnH and AIBN furnished the tetracyclic compounds 216 via 8-endo trig radical cyclization in 50-60% yield.
Br 215
R = H or OMe
216
Rawal and coworkers [52] explored the 6-ex0 and 7-endo cyclizations of alkoxymethyl selenides 217 to generate the 6- and 7-membered cyclic ethers 218 and 219 along with varying amounts of uncyclized reduction product 220.
217 normal reaction slow addition
218 69% 92%
219 8.5% 6.4%
220 22% 1.6%
Addition of aryl radical to oximes was explored by Jenkins and coworkers [53]. Reaction of the oxime ethers 221 with Bu3SnH and AIBN using slow addition techniques furnished the tricyclic alkoxyamines 222 via 7-exo trig radical cyclization along with the uncyclized reduction product 223.
221
R Me 'BU
222 49% 47%
223 29% 36%
Parsons and coworkers [54] explored the possibility of a 10-endo dig cyclization for the construction of germacranes. Reaction of the vinyl bromide 224 with Bu3SnH and AIBN furnished uncyclized reduction product 226 as the major prod-
174
3. I Unusual Cyclizations
uct along with 14% of the 10-endo dig cyclized product 225, which contains the desmethylperiplanone carbon framework.
225 (14%)
224
226
(58%)
Recently, Duffault [55]en route to the beticolin and cebetin group of compounds, investigated aryl radical cyclizations for the construction of bridged compounds. Reaction of the iodoenones 227 with Bu3SnH and AIBN underwent a preferential 7-endo (or exo) trig cyclization to furnish the bicyclo[3.2.2]nonanes 228 as major products along with minor amounts of 6-ex0 trig cyclized products bicyclo[3.3.1]nonanes 229 and 0-10% of uncyclized reduction compounds 230. The presence of a methyl group at the cc-position of the enone as in 231 furnished, as expected, exclusively the 7-endo radical cyclized product 232.
Rwx*
R'
+ R' R j p
R'
x
o
X 228
227
X 229
R-R'
X
yield
CH=CH-CH=CH CH=CH-CH=CH CH=CH-S CH=CH-S CH=CH-0
H,H
98%
0
77%
H,H 0 0
81%
72% 56%
+7-,9 R'
x
o
230
ratio
93:7:0 78:12:10 9O:lO:O
73:27:0 65251 0
- qM:
H; : ;B
86%
0 231
0
0 232
Lee and coworkers [56] explored the 8-endo trig cyclization of a-acyl radicals. Reaction of the bromoacetates 233 with Bu3SnH and AIBN generated the eightmembered lactones 234 via 8-endo trig cyclization along with varying amounts of the uncyclized reduction products 235. The presence of a trimethylsilyl group on the internal carbon of the olefin facilitated the 8-endo trig cyclization. It was further extended to a tandem sequence. Thus, 8-endo trig radical cyclization followed by 5exo trig cyclization of the bromoacetates 236 and 239 furnished the bicyclic lactones 238 and 240, respectively, as the major products along with a minor amount of the 8-endo trig cyclized product 237. It is interesting to note that the initial radical underwent a facile 8-endo trig cyclization in preference to the 5-exo trig cyclization.
3.1.4 7-10 exo and endo Cyclizations
Br R=H R=Me R =TMS
233
235
38% 38%
31 % 18% 32%
54%
237 (31%)
236
239
234
O
r Br
175
238 (53%)
240
0
Lee and coworkers [57]also employed a tandem 5-exo trig 7-endo trig cyclization to assemble a key intermediate in their synthesis of (+)-cladantholide. Reaction of the bromoacetal241 with Bu3SnH and AIBN underwent a very clean tandem 5exo trig and 7-endo trig radical cyclization sequence to furnish the hydroazulene system 242 with excellent stereochemical control. It is worth noting the difference in reactivity of the bromoacetal 241 and the bromoacetate 239. An a-acyl radical cyclization was employed [58] for the synthesis of a key intermediate 244 in their synthesis of (-)-clavukerin A and (-)-hydroxyguaienes. Reaction of the bromoacetate 243, derived from limonene, with Bu3SnH and AIBN employing slow addition technique furnished, exclusively, the 8-endo trig cyclized product 244 in a stereoselective manner. ~
AlBN
68% 243
0 244
0
--
(-)-clavukerin-A (-)- hydroxyguaiene
3.1 Unusual Cyclizations
116
Colombo and coworkers [59] have reported the 7-endo trig cyclization of the iodide 245 to generate the bicyclic compound 246. The reaction with tristrimethylsilylsilane proceeded with almost equal efficiency to that with Bu3 SnH but with slightly improved stereoselectivity. Interestingly, the reaction proceeded smoothly under slow addition conditions when Bu3SnH was used, whereas it gave a complex mixture under the same conditions when tristrimethylsilylsilane was used.
.
Bu3SnH AlBN or Coo'BU (TMS)3SiH AcHN 41-42% yield 88-95% stereoselectivity
b S 0N
AcHN
245
0
COO'Bu
246
Gibson and coworkers [60] have used a similar methodology employing aryl iodides 247 for the generation of the conformationally restricted amino acid derivatives benzofused 7- to 9-membered rings 248. Bu3SnH AlBN
Pedrosa and coworkers [61] have investigated the 6-ex0 and 7-endo modes of cyclization of the 8-aminomenthol derived acrylamides 249 to lactams 250 and 251. As expected, the presence of a methyl group at the terminal carbon of the olefin suppressed the 7-endo mode, whereas the presence of a methyl group at the aposition of the enone moiety increased the efficiency of the 7-endo trig cyclization.
d 249
R H H Me
R' H Me H
yield 88% 93% 99%
6-exo:7-endo 65:35 1OO:O 1337
250
251
Sinay and coworkers [62] have used a combination of temporary silicon connection and 9-endo trig radical cyclization for linking two sugar molecules. Reaction of the silyl ether 252 with Bu3SnH and AIBN employing the slow addition technique generated the 9-endo trig radical cyclization product 253, which on hydrolysis with HF to remove the silicon connection generated one major and two minor diastereomers of the bissugar 254, a key synthon for the biologically active heparin pentasaccharide mimetics.
3.1.4 7-10 exo and endo Cyclizations
phz:\
Ph-0 M o\'
Ph-0 ' " X S e P h
Me@.
O, O-SiMe;!
BuaSnH MeO% Me0
0-
Me0 Me0
AIBN
OMe
0
HF
OMe 253
252
177
OH Me0 Me0 OMe
254 four diastereomers (70: 16 : 14 : 1)
Recently, Curran and Liu [63] encountered an interesting 7-ex0 dig cyclization reaction during their attempts to use cyclopropanes as rddicophiles. Reaction of the bromodinitrile 255 with an excess of Bu3SnH and AIBN resulted in the formation of the eight-membered enaminonitrile 257, whose formation was explained by initial 7-ex0 dig cyclization of the radical onto one of the nitriles followed by Bu3SnHmediated cleavage of the cyclopropyl imine 256. BuSSn
L
255
-
256
J
257
Kim and Kim [64] reported a C-glycosylation reaction employing an efficient 7exo dig cyclization as the key step. The 7-ex0 dig cyclization of the propargyl ether 258, derived from a sugar, furnished efficiently the bicyclic allyl ethers 259. Cleavage of the allyl ether moiety in 259 and further manipulations led to showdomycin and a pyrazine C-glycoside. It is worth noting that the efficiency of the 7-ex0 dig cyclization reaction was very poor in the absence of either a methyl or TMS group on the acetylene. = R
k7 . SePh
Bu3SnH AIBN
R = H low yield R=Me 93% R=TMS 82%
258
259
Naito and coworkers [65]have reported the synthesis of hexahydroazepine part of balanol employing a radical addition of an aldehyde to an oxime ether. Treatment of the aldehyde 260 with Bu3SnH and AIBN furnished a 1:2 mixture of cis and trans amino alcohols 261 via a 7-ex0 trig radical cyclization reaction. The effi-
178
3.1 Unusual Cyclizations
ciency of the reaction was found to increase to 70% when the amount of AIBN was increased to one equivalent.
I
cBz
cBz
260
261
Aryl radical cyclizations using enamides as radical receptors have been reported for the construction of a variety of polyhydroazepins. Rigby and Qaber [66] reported the 7-endo trig radical cyclization of the aryl bromide 262 to generate the tetracyclic compound 263.
C Q Y J+
0
a)
Bu3SnH AIBN
p: \
-
65%
(Cy = cyclohexyl)
262
/
263
Castedo, Dominguez and coworkers 1671 carried out the cyclization of the Nformyl enamines 264. The 7-endo trig radical cyclization of the enamines 264 with Bu3SnH and AIBN using slow addition technique proceeded with excellent stereoselectivity to generate only the trans isomer of the tetracyclic system 265. CHO
,CHO
M e O K & $
' I
Me0
Bu3SnH AlBN
% ;oM e
' R3 R4
264
~
Me0 R'-R4 = H 85% R4 R',R2 = OCH20; R 3 = R 4 = H 76% R2,R3= OCH20; R' = R4 = H 40% 265 R3,R4 = OCH20; R' = R2 = H 65%
The methodology has been extended [68] to the total synthesis of the alkaloid lennoxanine 267 starting from the enamide 266. Subsequently an alternative methodology was also developed for lennoxanine 267 based on a 1O-endo dig cyclization. The 1O-endo dig radical cyclization of the TMS-protected acetylene 268 generated the tricyclic compound 269, which was further cyclized and transformed into lennoxanine 267. The 10-endo dig radical cyclization reaction (268 + 269) with free acetylene was found to generate an E,Z mixture of olefins.
3.1.4 7-10 exo andendo Cyclizations Bu3SnH AlBN
< = & M e =
266
OMe
\
?%Me
..
179
/
0
61Yo
267
\
OMe
1. KO t-Bu
Bu3SnH
Me
268
269
Bowman and coworkers [69] have reported the addition of a carbon-centered radical to heteroaromatic systems substituted with a carbonyl group, followed by spontaneous oxidation to generate the cycloheptane-fused heteroaromatic compounds. Reaction of the bromides 270-272 with Bu3SnH and AIBN furnished the 7-exo trig cyclized products 273-275 along with the uncyclized reduction products 276-277. The carbonyl group directs the radicals to add in a Michael-type fashion.
270
273 (14%)
Cd -@ COCH3
COCH3
271
+
274 (54%)
276 (8%)
COCH3
Ld
277 (18%)
Bu3SnH
272
CHO
40%
CHO 275
Recently, Nadin and Harrison [70] made a similar observation with pyridones, employing a rare example of a pyridine radical. Reaction of the 3-bromopyridine derivative 278 with Bu3SnH and AIBN furnished the 7-ex0 trig cyclized product 279 along with 10% of uncyclized reduction product. It is worth noting that the same reaction failed under the Heck conditions.
w3 rNYAN
180
3.1 Unusual Cyclizations
\
' Br
sB ? -)u@H
- - -
OBn
AlBN 50%
OBn
278
+
279 10% simple reduction
Atom transfer radical methodology was also explored in the 7-end0 cyclizations. Curran and Chang [71]have investigated the cyclization of a-iodoesters. Photolysis of the a-iodo ester and a-iodo malonates 280 in the presence of hexabutyldistannane generated a mixture of the 6-exu and 7-endu trig radical cyclized iodides 281 and 282. Quite expectedly, the presence of a methyl group on the internal carbon of the olefin (283) shifted the reaction to 7-endo mode exclusively. The product underwent spontaneous cyclization to furnish the lactone 284.
COOMe
R&
(Bu3Sn)~,hv",
283
R=H 58% R=COOMe 80%
Q0
284
Kilburn et al. [72] have investigated the atom transfer 7-endo and 8-endu trig cyclization reactions of the methylene cyclopropanes 285 to generate the bicyclic compounds 286, and found that the efficiency of the reaction increased when a trimethylsilyl group was present on the cyclopropane. I COOEt COOEt
$--J 285
acooEt COOEt
(Bu3Sn)Z, hv, 80
n 1
R H
1 TMS 2 TMS
yield 57%
86% 31%
"c *
286
Crich and coworkers [ 731 investigated a tellurium atom transfer radical cyclization. Thus, photolysis of the acyl telluride 287 in benzene at 80 "C underwent 7-exo
3.1.4 7-10 exo and endo Cyclizations
181
and 8-endo atom transfer radical cyclization reactions to furnish a 1:3.7 mixture of the cycloheptanone 289 and cyclooctanone 288.
0 YTeAr hv, 80 OC
t
>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.
References [ 11 B. Giese, Radicals in organic synthesis: Formation ojcarbon-carbon bond, Pergamon, Oxford, 1986; A. L. J. Beckwith, Tetrahedron, 1981, 37, 3073; B. Giese, Angew. Chem., Int. Ed. Engl., 1983, 22, 753; D. J. Hart, Science, 1984, 223, 883; B. Giese, Angew. Chem., Int. Ed. Engl., 1985, 24, 553; M. Ramaiah, Tetrahedron, 1987, 43, 3541; A. Srikrishna, Cum Sci,, 1987, 56, 392; D. P. Curran, Synthesis, 1988, 41 7 and 489; G. Pattenden, Chem. SOC.Rev., 1988, 17, 361; C. P. Jasperse, D. P. Curran and T. L. Fevig, Chem. Rev., 1991, 91, 1237; N. A. Porter, B. Giese and D. P. Curran, Acc. Chem. Rex, 1991, 24, 296; D. P. Curran, Synlett, 1991, 63; B. Giese, B. Kopping, T. Gobel, J. Dickhaut, G. Thoma, K. J. Kulicke and F. Trach in Organic Reactions, Ed., L. A. Paquette, John Wiley and Sons, Inc., 1996, 48, pp 301-855; D. P. Curran in Comprehensive Organic Synthesis, Ed., B. M. Trost, Pergamon, Oxford, 1991. Vol. 4, pp 715-831. [2] M. Newcomb, A . G. Glenn, W. G. Williams, J. Org. Chem., 1989, 54, 2675; M. Newcomb, A. G. Glenn, J. Am. Chem. Soc., 1989, I l l , 275; M. Newcomb, S.-U. Park, J. Am. Chem. Soc., 1986, 108, 4132; D. D. Tanner, J. J. Chen, C. Luelo, P. M. Peters, J. Am. Chem. Soc., 1992, 114, 713. [3] D. L. J. Clive, S. Daigneault, J. Chem. Soc., Chem. Commun., 1989, 332; D. L. J. Clive, S. Daigneault, J. Org. Chem., 1991, 56, 3801. [4] C . R. Warner, R. J. Strunk, H. G. Kuivila, J. Org. Chem., 1966, 31, 3381; L. K. Montgomery, J. W. Matt, J. Am. Chem. SOC., 1967,89, 934; T. A. Halgren, M. E. H. Howden, M. E. Medof, J. D. Roberts, J. Am. Clzcm. Soc., 1967, 89, 3051; T. A. Halgren, J. L. Fiekins, T. A. Fujimoto, H. H. Suzukawa, J. D. Roberts, Proc. Nut. Acad. Sci., USA, 1971, 68, 3216; D. Griller, K. U. Ingold, Acc. Chem. Res., 1980, 13, 317; P. C. Wong, D. Griller, J. Org. Chem., 1981, 46, 2327.
References
185
[5] V. M. Bowry, J. Lusztyk, K. U. Ingold, J. Chem. Soc., Chem. Commun., 1990, 923; J. Masnovi, E. G. Samsel, R. M. Bullock, J. Chem. Soc., Chenz. Commun., 1989, 1044. [6] A. Srikrishna, G. V. R. Sharma, P. Hemamalini, J. Chem. Soc., Chenz. Commun., 1990, 1681; A. Srikrishna, P. Hemamalini, G. V. R. Sharma, J. Org. Chem.: 1993, 58, 2509; A. Srikrishna, G. V. R. Sharma, J. Chem. Soc., Perkin Trans. I , 1997, 177; A. Srikrishna, S. Danieldoss, J. Org. Chem., 1997, 62, 7863. [7] W. Zhang, P. Dowd, Tetrahedron Lett., 1992, 33, 7307. [8] R. C. Denis, J. Rancourt, E. Ghiro, F. Boutonnet, D. Gravel, Tetrahedron Lett., 1993, 34, 2091. [9] W.-W. Weng, T.-Y. Luh, J. Ory. Chem., 1993, 58, 5574. [lo] M. Journet, M. Malacria, J. Org. Chem., 1994, 59, 718. [ 1 I ] A. Srikrishna, R. Viswajanani, T. J. Reddy, D. Vijaykumar, P. P. Kumar, J. Org. Chem., 1997, 62. 5232. [ 121 K. Kaliappan, G. S. R. Subba Rao, J. Chem. Soc., Chem. Commun., 1996,2331; K. Kaliappan, G. S. R. Subba Rao, J. Chem. Soc., Perkin Trans. I , 1997, 3393. [13] M. Toyota, M. Yokota, M. Ihara, Tetruhedron Lett., 1999, 40, 1551. [14] R. N. Saicic, Z. Cekovic, Tetrahedron, 1992, 48, 8975; Z. Cekovic, R. N. Saicic, Tetrahedron Lett., 1990, 31, 6085. [ 151 R. C. Denis, D. Gravel, Tetrahedron Lett., 1994, 35, 4531, 1 Z. Ferjancic, R. N. Saicic, Z. Cekovic, Tetrahedron Lett., 1997, 38, 4165. 1 P. Devin, L. Fensterbank, M. Malacria, J. Org. Chem., 1998, 63, 6764. 1 J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734. 1 A. Gopalsamy, K. K. Balasubramanian, J. Chem. Soc., Chem. Commun., 1988, 28. 1 Y. Araki, T. Endo, Y. Arai, M. Tanji, Y. Ishido, Tetrahedron Lett., 1989, 30, 2829. ' S.-U. Park, T. R. Varick, M. Newcomb, Tetrahedron Lett., 1990, 31, 2975; K. Ogura, N. Sumitani, A. Kayano, H. Iguchi, M. Fujita, Chem. Lett., 1992, 1487. M. E. Jung, I. D. Trifunovich, N. Lensen, Tetrahedron Lett., 1992, 33, 6719; M. E. Jung, R. Marquez, Tetrahedron Lett., 1997; 38, 6521; M. E. Jung. J. Gervay, J. Am. Chem. Soc., 1991,113, 224; M. E. Jung, R. Marquez, K. N. Houk, Tetrahedron Lett., 1999,40,2661;M. E. Jung, Synlett, 1999, 843. S. L. Fremont, J. L. Belletire, D. M. Ho, Tetrahedron Lett., 1991, 32, 2335. T. Sato, N. Machigashira, H. Ishibashi, M. Ikeda, Heterocycles, 1992, 33, 139; T. Sato, H. Chono, H. Ishibashi, M. Ikeda, J. Chem. Soc., Perkin Trans. I , 1995, 11 15. H. Ishibashi, N. Nakamura, T. Sato, M. Takeuchi, M. Ikeda, Tetrahedron Lett., 1991, 32, 1725; T. Sato, N. Nakamura, K. Ikeda, H. Ishibashi, M. Ikeda, J. Chem. Soc., Perkin Trans. I , 1992, 2399; M. Ikeda, S. Ohtani, T. Yamamoto, T. Sato, H. Ishibashi, J. Chem. Soc., Perkin Trans. I , 1998, 1763; See also, S. R. Baker, K. I. Burton, A. F. Parsons, J.-F. Pons, M. Wilson, J. Chem. Soc., Perkin Trans. I , 1999, 427. H. Ishibashi, C. Kameoka, A. Yoshikawa, R. Ueda, K. Kodama, T. Sato, M. Ikeda, Synlett, 1993, 649; H. Ishibashi, C. Kameoka, T. Sato, M. Ikeda, Synlett, 1994, 445; H. Ishibashi, K. Kodama, C. Kameoka, H. Kawanami, M. Ikeda, Synlett, 1995, 912; H. Ishibashi, C. Kameoka, H. Iriyama, K. Kodama, T. Sato, M. Ikeda, J. Ory. Chem., 1995, 60, 1276; H. Ishibashi, C. Kameoka, K. Kodama, M. Ikeda, Tetrahedron, 1996, 52, 489; H. Ishibashi, K. Kodama, C. Kameoka, H. Kawanami, M. Ikeda, Tetrahedron, 1996,52, 13867. A. J. Clark, J. L. Peacock, Tetrahedron Lett., 1998, 39, 1265; A. J. Clark, R. P. Filik, J. P. Peacock, G. H. Thomas, Synlett, 1999, 441. For an excellent review on the construction of 7- to 9-membered rings by radical cyclization methodology, see: L. Yet, Tetrahedron, 1999, 55, 9349. For copper-mediated construction of 8 and 9 membered lactones see, F. 0. H. Pirrung, H. Hiemstra, W. N. Speckamp, B. Kaptein, H. E. Schoemaker, Synthesis, 1995, 453. M. D. Bachi, F. Frolow, C. Hoornaert, J. Org. Chem., 1983, 48, 1841. A. L. J. Beckwith, D. R. Boate, Tetrahedron Lett.; 1985,26, 1761. D. A . Burnett, J.-K. Choi, D. J. Hart, Y.-M. Tsai, J. Am. Chem. Soc., 1984, 106, 8201. B. K. Banik, G. V. Subbaraju, M. S. Manhas, A. K. Bose, Tetrahedron Lett., 1996, 37, 1363. T. Satoh, M. Itoh, K. Yamakawa, Chem. Lett., 1987, 1949. T. Morikawa, T. Nishiwaki, Y. Kobayashi, Tetrahedron Lett., 1989, 30, 2407.
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.P
+
A i - 7 8
-
A
r
Ar = 4-MeOC6H4
7
Free ions SSlP
Scheme 2. Mechanism for the rearrangement and decomposition of Barton ester 6
3.2.2 Mechanism
Ph $ ? h p
M 2 OPO(OEt)2
191
2’ OPO(0Et)z 9
observed -
OPO(0Et)z
Scheme 3. Giese’s CIDNP experiment
again the linearity of a plot of rate constants for the formation of 7 and 8 against solvent polarity [ E ~ ( 3 0 )which ], indicates no change in the rate-determining step over a wide range of solvents. To date it has not been possible to observe directly radical cations in any of the p(acy1oxy)alkylmigrations studied by the time-resolved laser flash photolysis method [2]. It now appears that this is best interpreted in terms of a very rapid collapse of the initial contact ion pairs to the product radicals before any equilibration with solvent-separated ion pairs and free ions occurs. The more rapid collapse is of course in line with the more reactive nature of carboxylate ions as opposed to phosphate ions. The close similarities between the activation entropies of the carboxylate and phosphate migrations also point to reactions in which the rate-determining steps are closely related. Good indirect evidence for radical cation formation as the key step in the fragmentation of a model nucleotide C4’ radical (9) was obtained by the groups of Giese and Rist, who observed a CIDNP signal in the enol ether product 10 (Scheme 3 ) [lo]. Direct observation of enol ether type radical cations such as are expected to be important in the fragmentation of nucleotide C4’ radicals is not possible by the time-resolved laser flash photolysis technique owing to the lack of a suitable chromophore. However, it has recently been demonstrated that if such an LFP experiment is conducted in the presence of a triarylamine then any diffusively free enol ether radical cations oxidize the amine to the corresponding highly colored aminium radical cation. In this manner the overall rate constant for fragmentation and cage escape may be determined (Scheme 4) [ 111. Direct evidence for the formation of a radical cation 12 on cleavage of a radiolytically generated a,a-dimethoxy-p-acetoxyethylradical 11 was obtained by SchulteFrohlinde and coworkers by ESR spectroscopy (Scheme 5 ) [12]. Thus, taken together the ensemble of evidence is now persuasive that the p(phosphat0xy)alkyl migrations occur by a rate-determining fragmentation into a contact radical cation/anion pair followed by extremely rapid collapse to the product radical. It seems very likely that the analogous mechanism also operates for the P-(acy1oxy)alkyl rearrangement although direct evidence for the contact ion pair is necessarily harder to come by because of the more rapid collapse. On the whole it seems appropriate to write a general mechanism (Scheme 6) and to interpret different outcomes in terms of the effects of substituents and solvents on the equilibria between contact and solvent-separated ion pairs and free ions.
192
3.2 Radical Rearrangemetits of Esters
9 X 1o6 S-l (acetonitrile) k23
+
Ar3Nf
Ar3N
t-BU
)== Me0
t-Bu
F
Me0
Scheme 4. Detection of enol ether radical cations via aminium radical cations
Me0
k20
11
-
-
Me0
106 s-1
Me0
H20, H+
)"
OAc
12
ESR observable
Scheme 5. Observation of a radical cation by ESR spectroscopy
L
J
CIP
SSlP
i 0'
x:o
4-.
R Rearranged Products
Free ions
1 -
R/= Fragmentation Products
X = CR; P(OR)2, NO, SOR
Scheme 6. General mechanistic scheme
This general mechanistic scheme readily explains a number of experimental observations. For instance it is very clear why such ester shifts only ever take place between vicinal carbons [ 11, as it is only this arrangement that permits the formation of an alkene radical cation as intermediate. Intermolecular ester shifts are excluded for the same reason. Rearrangements of o-(acy1oxy)aryl radicals (Scheme 7) [ 13, 141 and their vinyl counterparts would require the intermediacy of very high energy benzyne radical cations, as such no examples are known. Failed migrations between two secondary radicals (Scheme 8) may now be seen as being due not so
3.2.2 Mechunism
193
Scheme 7. o-(Acy1oxy)arylradicals do not rearrange
AcO@
&
l7
H
l7
H
AcO
Scheme 8. Failure of the acetoxy group to migrate between two secondary radicals
%HI7
AcO
dP , i OAc
59%
Scheme 9. Stereoselective migration of an acetoxy group along one face of a steroid
Scheme 10. Efficient contraction of a seven-membered lactone by a formal 1,2-shift
much to a lack of a thermodynamic driving force as to insufficient stabilization of any radical cation to permit the initial fragmentation to take place [15, 161. Seemingly stereospecific migrations along one face of a rigid system (Scheme 9) [15, 161 as well as other highly diastereoselective migrations in less rigid acyclic systems [8] are now readily appreciated to be consequences of the structure of the contact ion pair and collapse before any equilibration with the solvent-separated ion pair. Acceleration of the migrations of chelating esters in the presence of Lewis acids [ 171 is also readily understood in terms of stabilization of the ion pair, as is the accelerating effect of polar solvents [ 1-31. The exclusive 1,2-shift nature of the contraction of six- seven- and eight-membered lactones (Scheme 10) [5] is easily appreciated to be a consequence of the enforced s-cis conformation of the lactone and recollapse of the contact ion pair before rotation about the CH2-COz- bond. Similarly the predominant 1,2-nature of several
194
3.2 Radical Reurrungements o j Esters
Ph k75 = 2.5 x 10‘ s-l
Scheme 11. Typical formal 2,3-shift of a carboxylate group
17
Bu3SnH, AIBN,
k75
= 1.6 x 1O6 s - ~ AcO
76% 1,2-shift
Pr
Pr
Scheme 12. Predominant 1,2-shift of a carboxylate
phosphatoxy [8, 9, 181 and nitroxy [19] alkyl shifts may be understood in terms of the initial conformation of the ester and very rapid collapse before any reorganization. Much more difficult to understand are the predominantly 2,3-shifts usually seen with standard s-trans-carboxylates, from which conformation it would seem that the 1,2-shift is also possible (Scheme 11) [20, 211. This latter situation is rendered all the more obscure by the existence of examples of standard s-trans esters which rearrange predominantly by the 1,2-shift (Scheme 12) [22, 231. We can only suggest that these apparent contradictions are the result of subtle conformational effects in the initial radical, which predispose the contact ion pair toward collapse in one direction. Scrambling or partial scrambling, as opposed to greater than 50% inversion, of the two oxygens of an ester of course arises from loosening of the contact ion pair and, indeed, stabilizing substituents are usually present in such cases [24]. Extensive computational studies have been carried out on the P-(acy1oxy)alkyl and p-( phosphatoxy)alkyl rearrangements by Radom and coworkers and by Zipse. These calculations in general support the possibility of concerted rearrangements taking place via 5-center-5-electron and 3-center-3-electron cyclic transition states [25, 261. However, before such computations can be used as an aid in distinguishing between reaction pathways, it will be necessary for theoretical chemists to circumvent the present difficulties in calculating the radical ionic fragmentations.
3.2.3 Rearrangements and their Applications in Synthesis The true synthetic potential of the acyloxy rearrangement was realized by Giese and coworkers with their application of the method in carbohydrates. In these re-
3.2.3 Rearrangements and their Applications in Synthesis
195
Bu3SnH,AIBN,
AcO
Bu3SnH, AIBN,
AcO* AcO
+
C6H6, A
A c ? A O A c AcO
Br
65%
BzO
BzO BuSSnH, AIBN,
Bseph BzO OBz
P O B z BzO 75%
C6H6,A
Scheme 13. Rearrangements in carbohydrates AcO A
c
TTMSS, AIBN, C6H6, A
OAc O
~
ACOB,
-
k75 = 5.4 x 1O3 s-l
70%
OAc
Scheme 14. Carbohydrate rearrangement with tris(trimethylsi1yl)silane
A $ O q AcOS
C6H12, dilauroyl peroxide*
K O S
A E o y 96%
OAc
Scheme 15. Rearrangement employing Zard’s xanthate methodology
arrangements a 2-0-carboxylate ester migrates to an anomeric radical with the formation of a 2-deoxy sugar of considerable added value (Scheme 13) [21, 27-29]. The reaction is typically conducted with tributylstannane but is equally valid with tris(trimethylsily1)silane when less of the reduction product is observed (Scheme 14) [30]. Another interesting variant was introduced by Zard, who used anomeric xanthates as radical precursors and cyclohexane as both solvent and source of hydrogen atoms (Scheme 15) [31]. Not surprisingly in view of the rate constants for these rearrangements, the migration may be completely suppressed by working with tributylstannane and a catalytic quantity of diphenyl diselenide when a 1-deoxy sugar is formed [32]. The thermodynamic driving force for the above carbohydrate-based rearrangements is derived from the formation of the strong anomeric C-0 bond. This effect
196
3.2 Radical Rearrangements of Esters
TBDMsowu TBDMSOB"
nMSS, C6H6, A
t
OPiv
TBDMSO
k8,,= 7.0 x
TBDMSO OPiv
104 S-1
86%, a l p = 4011
Scheme 16. Migration away from the anomeric center in nucleosides
66%
Scheme 17. Rearrangement coupled with allylation
is, however, relatively easily reversed by small changes to the stability of the anomeric radical and/or the putative anomeric C-0 bond. Thus, replacement of the ring oxygen by a sulfur atom shuts down the migration [21]. Similarly, migration toward a tertiary 'anomeric' radical at the glucose C-5 position has so far not been observed [211. With nucleosides, the extra stabilization of the anomeric radical or the weakening of the anomeric C-0 bond is such that migration away from the anomeric center is observed (Scheme 16) [33-351. In the carbohydrate and nucleoside series the acyloxy shift has been coupled with radical allylation using allyltributylstannane to give rearranged allylated products (Scheme 17) [36, 371. Like acetoxy groups, phosphatoxy groups migrate from the 2-position of sugars to anomeric radicals and, in doing so, generate very labile 2-deoxyglycosyl phosphates. If the reaction is conducted in benzene at reflux, elimination ensues very rapidly and the isolated product is the glycal [8, 381. Under photolytic conditions at room temperature, the 2-deoxyglycosyl phosphates were shown to be formed rapidly (Scheme 18) and, although not isolable, to have half-lives long enough to permit their use as in situ glycosylating agents (Scheme 19) [39, 401.
3.2.4 Substitution Reactions and their Applications in Synthesis Radicals substituted with a leaving group in the /I-position may in principle undergo ips0 or cine substitution (Scheme 20), and both overall processes are known. Zipse has suggested on the basis of computational work that both the ips0 and cine processes might take place via open-shell concerted mechanisms [26, 411.
3.2.4 Substitution Reactions and their Applications in Synthesis
Bu3SnH,AIBN, A,.. Ac&o * AcO C6H6, hu kz7 = 1.O x 1O5 s-'
197
+ (PhO)zP,\o
50%
50%
Scheme IS. Photolytically induced carbohydrate-based phosphatoxy migrations BnO
i:o% AAcO ~
BuSSnH, ACT% AIBN, AcO
-
(Ph0)2F;;OB'
~
OMe
THF,h u
(pho) p / O
Mg(CIO& cat.
0
"'bBr BzO OPO(0Ph)zTHF,hu
Bzo@OPO(OPh)z BzO
~
I
$
I
72%, a l p = 4.511
-
Z
O
~
~
BzO 6O%, a/p = 1/l
Scheme 19. Carbohydrate-based phosphatoxy migrations coupled with glycosylation reactions
dN" Nu-
'
'
ips0
Nu-
'
'
cine
Nu
R
~
BnO
H W N TN B
Bu3SnH,AIBN,
&
R'
Scheme 20. ips0 and cine Substitutions
However, the evidence increasingly points to the substitution reactions as simply being an adjunct of the general scheme for radical rearrangement and as taking place via nucleophilic capture of one or other of the radical cation/anion pairs or of the free-radical cation. Early studies on such substitution reactions were carried out by the group of Norman, who studied the action of hydroxyl radicals generated with the TiC13/ H202 couple on P-methoxyethyl acetate by ESR spectroscopy. A more detailed
>
~
~
3.2 Radical Rearrangements of' Esters
198
Me0 Me0
OAc +H+
Me0
v --HOAc 13
+H20
pH 4 . 8
Lf'
14
-H+
Me0
OH
v 15
Scheme 21. Acid-catalyzed substitution of radical 13 in water
study was later conducted by the Schulte-Frohlinde group using pulsed radiolysis, in which it was revealed that the nature of the product radical is a function of pH. Thus it was demonstrated that presumed intermediate radical cation (14) was quenched by water above pH 1.8 to give a 3/7 mixture of the ips0 (15) and cine (16) substituted radicals, whereas below pH 1.8 only the thermodynamically more stable cine radical was observed (Scheme 21) [42, 431. Schulte-Frohlinde and coworkers also observed that the more highly substituted 2-acetoxy-1-methoxy- 1-propyl and the 1-acetoxy-2-methoxy-2-propyl radicals underwent solvolysis by water more rapidly than the lower homolog (13) in Scheme 21. This again is indicative of a dissociative rather than a 'Zipse-like' associative phenomenon [43]. In the case of the more stable ESR-observable 1,l-dimethoxyethene radical cation (17), Schulte-Frohlinde and coworkers were able to determine rate constants for addition of water and of diphosphate (Scheme 22) [44]. Rate constants for the addition of various nucleophiles to substituted styrene radical cations have been determined by the Johnston group, using a time-resolved LFP method [45, 461. With nucleophiles such as azide, bromide and chloride the additions are extremely rapid ( 109-10'0 M-' s-'), unless the radical cation is stabilized by strongly electrondonating groups, when a loss of several orders of magnitude is observed. As might be expected methanol is a much poorer nucleophile and attacks a given radical cation some 2 or 3 orders of magnitude more slowly than does chloride. Working with a DNA C4', model radical precursor (18) in the presence of allyl alcohol as nucleophile Giese and his coworkers obtained two regioisomeric sets (20) and (21) of diastereomeric tetrahydrofurans. The products are best explained as arising from nucleophilic attack on the radical cation (19) by the allyl alcohol, followed by radical cyclization (Scheme 23) [47].
Me0 \OH Me0
OH-
*
HO
MeO*' Me0
k = 4.2x 1O9 M-' s-'
Me0
HP042-, OH-
F l7
*
Me0
k = 0.9 x lo6 M-' s-'
Scheme 22. Reaction of nucleophiles with radical cation 17
9
0' P\ - -0 MeO+.' Me0
3.2.4 Substitution Reactions and their Applications in Synthesis
?yjT
PO
199
+
p\yjT +
S
' O 0 w T
0"'
<
20,30%
21,10%
I/
3%
Scheme 23. Capture of a nucleotide-derived 3',4' radical cation by allyl alcohol with predominant retention of configuration
The very high degree of retention of configuration at the 3' site in the major product prompted Zipse to propose a double inversion mechanism for the direct substitution. In this hypothesis the urea carbonyl of the thymine group expels the phosphate with inversion leading to a bicyclic framework. This is then opened, again with inversion, by the allyl alcohol [41]. Such a double inversion process cannot be operative in a system (22) in which the thymine ring is replaced by a simple phenyl group and which nevertheless undergoes substitution predominantly with retention (Scheme 24) [48]. The obvious implication is that all processes take place by a dissociative mechanism and that the steric bulk of the substituent is sufficient to provide facial selectivity. Two regioisomeric p-( phosphatoxy)alkyl radicals (23) and (24), generated from Barton esters in the presence of tert-butyl thiol and allyl alcohol, gave a single pair of diastereomeric tetrahydrofurans (26) in excellent yield. This result is most readily interpreted in terms of the highly regioselective quenching of a common radical cation (25) with formation of the more stable benzylic radical (Scheme 25) [49].
OTBDMS
phf&o
o ,
hu, MeOH,
PhpqOTBDMS
.-
P h w O T B D M S
-
Bu3SnH
t-Bu
( W Z F ; ,
0
0 22 Ph
OTBDMS
OTBDMS ph
OTBDMSph
OMe
34%
OMe
28%
OTBDMS
5%
13%
8%
Scheme 24. Capture of a sterically biased, phosphate-derived radical cation with predominant retention of configuration
200
3.2 Radical Rearrangements of Esters
& O H/
t-BUSH
1
2
Ph
26
/\
24
Scheme 25. Two regioisomeric /Iphosphatoxy)alkyl -( radicals give one set of stereoisomeric tetrahydrofurans via common radical cation
The hallmark of a concerted process is stereoselectivity. Crich and Gastaldi investigated the cine substitution reaction with the diastereomeric probes 27 and 28 and found partial (i.e. incomplete) scrambling in the products 29 and 30 (Scheme 26) [50].This result is best interpreted in terms of the evolving general mechanistic picture and stereoselective capture of the two diastereomeric contact or solventseparated ion pairs by the nucleophile. The possibility remains, however, of a concerted mechanism in which the nucleophile does not distinguish between the two lobes of the singly occupied p-orbital in the initial radical. The above intermolecular processes, while interesting and instructive, are of relatively limited scope because the high concentration of nucleophiles required limits them to readily available, volatile alcohols. Intramolecular processes therefore hold more promise. In an early ESR study of the interaction of hydroxyl radicals with 4-pentenol, Davies and Gilbert observed the predominant formation of the 2-tetrahydrofuranylmethyl radical. It was thought that this chemistry could best be attributed to cyclization of the alcohol onto the alkene radical cation, but the possibility of the hydroxyl radical adding to the alkene to give a 1,5-dihydroxy-
4.511
29
30 1.711
Scheme 26. Diastereoselectivity in the cine substitution of b-(phosphatoxy)alkyl radicals
3.2.4 Substitution Reactions and their Applications in Synthesis
201
Scheme 27. Intramolecular hydrogen atom abstractionlcine substitution sequence for the formation of tetrahydrofurans
2-pentanyl radical followed by a 'Zipse-like' displacement was not excluded [51]. A preparative sequence to tetrahydrofurans has been developed in which the oxygen atom serves a double purpose, first as an alkoxy radical (31) generating the p(phosphatoxy)alkyl radical (32) by 1,5-hydrogen atom abstraction, and second as the nucleophile (Scheme 27) [49, 521. The most telling observation here is the higher yield obtained for displacement of diethylphosphate on the more hindered system 34 as opposed to the unsubstituted 33, which strongly suggests a dissociative process going via a radical cation (Scheme 28).
Ph% 90%
Scheme 28. Effects of substituents on yield in the hydrogen atom abstractionlcine substitution process
202
3.2 Radical Rearrangements of Esters
35 85%
43
37
36 I
25
1
16
38 1
16
Scheme 29. Tandem cine substitution/radical cyclization process for the formation of pyrrolizidines
The use of intramolecular nitrogen nucleophiles in such schemes holds much promise for the formation of nitrogenous heterocycles. This is especially the case when a second radical ring closure may be built in tandem-wise (Scheme 29) [53]. The stereochemistry of the two major products (35)and (36) here is best explained by transition states for the radical cyclization which put the phenyl ring on the exosurface of the developing bicyclic system. trans-Selectivity in cyclization of benzyl radicals is standard [54] and provides the major product (35).
3.2.5 Fragmentations To recapitulate, it is now clear that the predominant reaction of p-( phosphatoxy)alkyl and P-(acy1oxy)alkylradicals is radical ionic fragmentation to give contact ion pairs consisting of alkene radical cations and phosphate and/or carboxylate anions (Scheme 6). The different types of reaction observed overall result from the recollapse and/or capture of the ion pairs. The widely differing products observed as substrate and conditions are varied may be interpreted in terms of shifting equilibria between contact and solvent-separated ion pairs and free ions. Radical ionic fragmentation is therefore the single most important reaction of p-( phosphatoxy)alkyl and ,!l-(acyloxy)alkyl radicals. Aside from the synthetic aspects discussed here these radical ionic fragmentations are of considerable importance in the cleavage of DNA and RNA by hydrogen abstracting species such as hydroxyl radicals and several antitumor antibiotics. Rate constants for the fragmentation of /I-(acyloxy)alkyl, /I(phosphatoxy)alkyl and D-(su1fonatoxy)alkylradicals in water were determined by Schulte-Frohlinde and coworkers using their pulsed radiolysis/time-resolved conductimetry method [ 1, 551. Further radical ionic fragmentation rate constants have been provided by the Giese group [ l , 561.
3.2.6 Thiocarbonyl Esters
xo
\\-. R
203
. xo. +
=
Scheme 30. Pure radical fragmentation R
R
R
R = lo, 2",3" alkyl
Scheme 31. Radical fragmentation followed by decarboxylation
Scheme 32. Radical fragmentation/decarboxylation of p-lactones
Examples of pure radical fragmentation (Scheme 30) are extremely rare, presumably because the radical ionic fragmentation is so much more facile. In order to achieve such a radical fragmentation Barton and coworkers implemented a system (Scheme 31) in which the newly formed double bond leads to aromatization, so providing an extra driving force for elimination [57]. Further examples were provided by Crich and Mo, who took advantage of the strain inherent in a p-lactone to drive the fragmentation (Scheme 32) [58, 591.
3.2.6 Thiocarbonyl Esters The chemistry of p-(thiocarbony1oxy)alkyl radicals stands in complete contrast to that of the (acy1oxy)alkyl radicals, with elimination, while not the rule, being the norm [ I ] . The difference between the acyloxy and thiocarbonyloxy series is likely a consequence of the much weaker thiocarbonyl bond and the related higher stability of sulfur-centered radicals. The method has been developed in combination with the Barton deoxygenation method (Volume 1, Chapter 1.6) as a means of converting a vicinal diol, via the dixanthate, into an alkene (Scheme 33) [60-621. Tributyltin hydride has been the reagent of choice for this reaction but it may also be conducted with the triethylsilane/benzoyl peroxide couple [ 631 and, doubtless, tris(trimethylsily1)silane.
3.2 Radical Rearrangements of Esters
204
Bu3SnH, AIBN, 60% MeSCSO,
'-cnsobo Bu3SnH,AIBN,
,
Me0
C6H6,A
M% 'o e0
*
\
,
62%
\
Scheme 33. Alkene formation from vicinal dixanthates
Bu3SnH,AIBN,
OMe
39%
Ph
Scheme 34. Ring closure of P-(thiobenzoy1oxy)alkyl radicals
MeSCSO
H;CSMe
y>-
Bu3SnH, AIBN, *
MeSCSO
0
\?Oh
" \
Scheme 35. Ring closure of a y-dixanthate
I
OCS2Me
32%
47% SCOSMe
Scheme 36. Migration of a y-dixanthate
Thiobenzoate esters, while closely related to xanthates, can take part in cyclization reactions rather than eliminations (Scheme 34) [64]. Fortuitously, xanthates are much easier to prepare. Again unlike the acyloxy group, thiocarbonyl esters interact with y - as well as 8radicals, and again this reactivity may be attributed to the weakness and reactivity of the thiocarbonyl bond. According to the conditions of temperature and concentration of the chain-propagating stannane, the intermediate ring-closed radical may be trapped (Scheme 35) [65] or may undergo fragmentation to yield rearranged products (Scheme 36) [66-681. Related processes are also known for &(thiocarbonyloxy)alkyl radicals [ 691.
References
205
References [ I ] A. L. J. Beckwith, D. Crich, P. J. Duggan, Q. Yao, Chem. Rev. 1997, 97, 3273. [2] S.-Y. Choi, D. Crich, J. H. Horner, X. Huang, M. Newcomb, P. 0. Whitted, Tetrahedron 1999,59, 3317. [3] M. Newcomb, J. H. Horner, P. 0. Whitted, D. Crich, X. Huang, Q. Yao, H. Zipse, J. Am. Chem. Soc. 1999, 121, 10685. [4] P. 0. Whitted, J. H. Horner, M. Newcomb, X. Huang, D. Crich, Org. Lett. 1999, I , 153. [5] D. Crich, X. Huang, A. L. J. Beckwith, J. Org. Chem. 1999, 64, 1762. [6] M. Sprecher, Chemtracts: Org. Chem. 1994, 7, 115. [7] L. R. C. Barclay, D. Griller, K. U. Ingold, J. Am. Chem. Soc. 1982, 104, 4399. [8] D. Crich, Q. Yao, G. F. Filzen, J. Am. Chem. Soc. 1995, 117, 11455. (91 D. Crich, Q. Yao, Tetrahedron Lett. 1993, 34, 5677. [ l o ] A. Gugger, R. Batra, P. Rzadek, G. Rist, B. Giese, J. Am. Chem. Soc. 1997, 119, 8740. [ I l l M. Newcomb, N. Miranda, X. Huang, D. Crich, J. Am. Chem. SOC.2000,122, 6128. [I21 G. Behrens, E. Bothe, G. Koltzenberg, D. Schulte-Frohlinde, J. Chem. Soc., Perkin Trans. 2 1980, 883. 1131 W. T. Evanochko, P. Shevlin, J. Org. Chem. 1979, 44, 4426. [I41 F. Shahidi, T. T. Tidwell, Can. J. Chem. 1982, 60, 1092. [ 151 S. Julia, R. Lorne, C. R. Acad. Sci. Fr. Ser. C 1971, 273, 174. [I61 S. Julia, R. Lorne, Tetrahedron 1986, 42, 5011. [I71 E. Lacote, P. Renaud, Angeiv. Chem. In/. Ed. Enyl. 1998, 37, 2259. [IS] D. Crich, Q. Yao, J. Am. Chem. Soc. 1994, 116, 2631. (191 D. Crich, G. F. Filzen, J. Org. Chem. 1995, 60, 4834. 1201 A. L. J. Beckwith, C. B. Thomas, J. Chem. Soc., Perkin Trans. 2 1973, 861. 1211 H.-G. Korth, R. Sustmann, K. S. Groninger, M. Leisung, B. Giese, J. Org. Chem. 1988, 53, 4364. 1221 A. L. J. Beckwith, P. J. Duggan, J. Chem. Soc., Perkin Trans. 2 1992, 1177. [23] P. Kocovsky, I. Stary, F. Turecek, Tetrahedron Lett. 1986, 27, 1513. [24] A. L. J. Beckwith, P. J. Duggan, J. Chem. Soc., Perkin Trans. 2 1993, 1673. 1251 S. Saebo, A. L. J. Beckwith, L. Radom, J. Am. Chem. SOC.1984, 106, 5119. 1261 H. Zipse, Arc. Chem. Res. 1999, 32, 571. 1271 B. Giese, K . S. Groninger, T. Witzel, H.-G. Korth, R. Sustmann, Angew. Chem. Int. Ed. Engl. 1987, 26, 233. I281 B. Giese, S. Gilges, K. S. Groninger, C. Lamberth, T. Witzel, Liebigs Ann. Chem. 1988, 615. 1291 B. Giese, K. S. Groninger, Org. Synth. 1990, 69, 66. [30] B. Giese, B. Kopping, Tetrahedron Lett. 1989, 30, 681. 131) B. Quiclet-Sire, S. Z. Zard, J. Am. Chenz. Soc. 1996, 118, 9190. 1321 D. Crich, Q. Yao, J. Ory. Chem. 1995, 60, 84. 133) Y. Itoh, K. Haraguchi, H. Tanaka, K. Matsumoto, K. T. Nakamura, T. Miyasaka, Tetrahedron Lett. 1995, 36, 3867. 1341 T. Gimisis, G. Ialongo, C. Chatgilialoglu, Tetrahedron 1998, 54, 573. [35] T. Gimisis, G . lalongo, M. Zamboni, C. Chatgilialoglu, Tetrahedron Lett. 1995, 36, 6781. [36] B. Giese, J. Dupuis, K. Groninger, T. Haskerl, M. Nix, T. Witzel, in H. G. Viehe, Z. Janousek, R. Merenyi (Eds.): Suhstituent Efft,cts in Radical Chemistry, Reidel, Dordrecht 1986, p. 283. [37] B. Giese, Silicon, Germanium, Tin, and Lead Cnzpds 1986, 9, 99. 1381 D. Crich, Q. Yao, J. Am. Chem. Soc. 1993, 115, 1165. (391 A. Koch, C. Lamberth, F. Wetterich, B. Giese, J. Org. Clzem. 1993, 58, 1083. [40] A. Koch, B. Giese, Helv. Chim. Acta 1993, 76, 1687. 1411 H. Zipse, Angew. Chem. In/. Ed. EngI. 1994, 33, 1985. 1421 B. C. Gilbert, J. P. Larkin, R. 0. C. Norman, J. Chem. Soc., Perkin Trans. 2 1972, 794. [43] G. Behrens, G. Koltzenberg, D. Schulte-Frohlinde, Z. Natuvforsch. 1982, 37c, 1205. [44] G. Behrens, E. Bothe, G. Koltzenburg, D. Schulte-Frohlinde, J. Chem. Soc., Perkin Trans 2 1981, 143. [45] L. J. Johnston, N. P. Schepp, Purr and Appl. Chem. 1995, 67, 71.
206
3.2 Radical Rearrangements of Esters
1461 L. J. Johnston, N. P. Schepp, J. Am. Chem. Soc. 1993, 115, 6564. [47] B. Giese, X. Beyrich-Graf, J. Burger, C. Kesselheim, M. Senn, T. Schafer, Angew. Chem. Int. Ed. Enyl. 1993, 32, 1742. [48] S. Peukert, B. Giese, Tetrahedron Lett. 1996, 37, 4365. [49] D. Crich, X. Huang, M. Newcomb, J. Org. Chem. 2000, 65, 523. [50] D. Crich, S. Gastaldi, Tetrahedron Lett. 1998, 39, 9377. Perkin Trans. 2 1984, 1809. [51] M. J. Davies, B. C. Gilbert, J. Chem. SOC., [52] D. Crich, X. Huang, M. Newcomb, Org. Lett. 1999, I , 225. [53] D. Crich, X. Huang, M. Newcomb, unpubished work. [54] C. Walling, A. Cioffari, J. Am. Chem. Soc. 1972, 94, 6064. [55] G. Koltzenburg, G. Behrens, D. Schulte-Frohlinde, J. Am. Chem. Soc. 1982, 104, 7311. 1561 S. N. Muller, R. Batra, M. Senn, B. Giese, M. Kisel, 0. Shadyro, J. Am. Chem. Soc. 1997, 119, 2796. [57] D. H. R. Barton, H. A. Dowlatshahi, W. B. Motherwell, D. Villemin, J. Chem. SOC., Chem. Commun. 1980, 732. [SS] D. Crich, X.-S. Mo, J. Org. Chem. 1997, 62, 8624. [59] D. Crich, X.-S. Mo, J. Am. Cliem. Soc. 1998, 120, 8298. 1601 A. G. M. Barrett, D. H. R. Barton, R. Bielski, J. Chem. Soc., Perkin Truns. I 1979, 2378. [61] T. Hayashi, T. Iwaoka, N. Takeda, E. Ohki, Chem. Pharm. Bull. 1978,26, 1786. [62] C. Chu, V. S. Bhadti, B. Doboszewski, Z. P. Gu, Y. Kosugi, K. C. Pullaiah, P. Van Roey, J. Org. Chem. 1989, 54, 2217. [63] D. H. R. Barton, D. 0. Jang, J. C. Jaszberenyi, Tetrahedron Lett. 1991, 32, 7187. [64] D. H. R. Barton, S. W. McCombie, J. Chem. Soc., Perkin Trans. I 1975, 1574. [65] P. A. M. Herdewijn, A. Van Aerschot, L. Jie, E. Esmans, J. Feneau-Dupont, J.-P. Declerq, J. Chem. Soc., Perkin Trans. I 1991, 1729. [66] D. Crich, A. L. J. Beckwith, C. Chen, Q. Yao, I. G. E. Davison, R. W. Longmore, C. Anaya de Parrodi, L. Quintero-Cortes, J. Sandoval-Ramirez, J. Am. Chem. Soc. 1995, 117, 8757. [67] C. J. France, I. M. McFarlane, C. G. Newton, P. Pitchen, D. H. R. Barton, Tetrahedron 1991, 47, 6381. [68] P. Boquel, C. L. Cazalet, Y. Chapleur, S. Samreth, F. Bellamy, Tetrahedron Lett. 1992, 33, 1997. [69] A. V. R. Rao, K. A. Reddy, M. K. Gurjar, A. C. Kunwar, J. Chem. Soc., Chem. Commun. 1988, 1273.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
3.3 Rearrangements of Cyclopropanes and Epoxides Andreas Gunsuuer and Marianna Pierobon
3.3.1 Introduction Three-membered rings are useful intermediates in organic synthesis that can be transformed into a number of valuable products. The thermodynamic driving force for these reactions is the release of ring strain during ring opening. Because of their ease of preparation, cyclopropanes [ 11 and epoxides [2] have received special attention in this context. The purpose of this article is to describe ring-opening reactions of these two types of three-membered rings in radical reactions. Both reactions of free radicals and reactions of metal-bound radicals will be treated.
3.3.2 Ring Opening of Cyclopropanes and Epoxides in Free-Radical Chemistry 3.3.2.1 Ring Opening of Cyclopropanes via Formation of Cyclopropylcarbinyl Radicals Butenyl cyclizations are in principle fast reactions proceeding in a 3-ex0 mode. The rate constant for this type of cyclization is usually in the range of lo4 - 6 x lo6 SKI. Still, the preparative usefulness of this transformation has remained rather limited because the ring opening of the product cyclopropyl carbinyl radical is usually much faster ( k = lo8 - lo9 s-') as shown in Scheme 1 [3]. Consequently synthetic chemists have made use of this efficient ring opening of a radical intermediate in a number of elegant applications. In this chapter, ring-opening reactions followed by inter- and intramolecular C-C bond-forming or -breaking steps will be described. Simple reductive ring openings will not be dealt with here. Feldman [4] and Oshima [5] have independently reported reactions of vinylcyclopropanes in the presence of olefins to obtain vinyl cyclopentanes as the first
208
3.3 Rearrangements of Cyclopropcmes and Epoxides
L
k<3x104S-1
'?
k = 5.6 x
- A. k = 8.9 x
A.
l o 6 s-'
- A.
l o 8 s-' t
+
%-
Scheme 1
yR /+
PhS
R
"\ x,
-. PhS
*
.
PhS-.-TfR
PhS- - - O R
/ PhS
PhS
R
Scheme 2
examples of intermolecular C-C bond-forming reactions after cyclopropane opening. In this manner, an intermolecular [3+2] bond construction strategy as shown in Scheme 2 was realized. The initial step is the addition of a thiophenyl radical to the double bond. After fast ring opening of the cyclopropylcarbinyl radical, the critical event is the addition of the resulting radical to the olefin. If this intermolecular reaction is slow, trapping by a second equivalent of the thiophenyl radical leads to the formation of an undesired by-product. Only activated olefins, e.g. qP-unsaturated carbonyl compounds, enolethers, and enolacetates, are good radical acceptors in these reactions. The olefins have to be used in five- to tenfold excess. The overall transformation is completed by elimination of the thiophenyl radical. Thus, diphenyl disulfide, the source of thiophenyl radicals, can in principle be employed in substoichiometric amounts. The diastereoselectivity of vinylcyclopentane formation is difficult to control, and mixtures of diastereomers are often obtained. A highly stereoselective example is shown in Scheme 3.
3.3.2 Ring Opening of Cyclopvopanes and Epoxides in Free-Radical Chemistry
209
fiC02Me C02Me 71%
single diastereorner
Scheme 3
+%iBu Ph2S2, AlBN
*
&O/Bu
81Yo, ds = 56 : 44
+/
Ph02S
\
PhS *
OiBu
-PhS*
%h Ph02S
Eph /
I'
PhOpS
PhOnS* O i B u OiBu
Scheme 4
The concept of ring opening of cyclopropylcarbinyl radicals has been extended to substituted methylenecyclopropanes. As shown in Scheme 4, the crucial step in the reaction sequence is the regioselective addition of a substituted thiyl radical. After opening of the cyclopropane ring, the resulting radical adds to the olefin. Subsequent cyclization and reductive regeneration of the thiyl radical with concomitant liberation of the methylenecyclopentane product complete this transformation [6]. It should be noted that to a small extent the diastereoselectivity of the overall process depends on the substituents of the thiyl radical. An attractive feature of this method is the ability to use simple alkenes without acceptor groups, e.g. limonene, as coupling partners. Besides, only stoichiometric quantities of the olefin have to be employed. The synthesis of vinylcyclohexanones through fragmentation of oxygensubstituted vinyl cyclopropanes has also been reported (Scheme 5) [7]. After addition of the thiophenyl radical to the olefin, benzophenone is extruded to yield an unsaturated enol radical. The reaction sequence is completed as described above for the [3+2] annulation. Besides the intermolecular versions of this [ 3+2] annulation, intramolecular reactions are also possible. The first example of this transformation was reported by Oshima as early as 1988 in a synthesis of vinyl cylopentenes [8]. More recently this methodology was applied to the preparation of bicyclo[3.3.0]lactams and lactones
3.3 Rearrangements of Cyclopropanes and Epoxides
2 10
pS02Ph PhS
42% S02Ph
d s = 2.7:l Scheme 5
1:l
Scheme 6 S Bu3SnH AlBN
79% SiMe3 SiMe3
Scheme 7
and their [3.2.1]analogs, depending on the mode of cyclization, as shown in Scheme 6 ~91. An efficient system for the construction of spirocyclic quartenary centers based on cyclopropane opening is described in Scheme 7 [lo]. Samarium diiodide has also proven to be a useful reagent for this type of transformation with cyclopropyl ketones [ 111. In this case a ketyl radical is generated adjacent to the cyclopropane ring. Ring opening takes place as readily as with simple cyclopropyl carbinyl radicals. Initial studies toward the syntheses of natural products using the [3+2] strategy have been described. An approach to a key intermediate in the synthesis of (-t-)rocglamide is shown in Scheme 8 [12]. Tricyclic [5.5.n] ring systems have been obtained from bicyclic vinylcyclopropanes (Scheme 8) [ 131.
3.3.2 Ring Opening of Cyclopropanes and Epoxides in Free-Radical Chemistry
6.5
21 1
2.5
Scheme 8
3.3.2.2 Ring Opening of Epoxides via Formation of Oxiranylcarbinyl Radicals Similar to the reactions of cyclopropanes, epoxides are ring opened if a radical is generated at a carbon atom adjacent to the oxirane. The fragmentation of these oxiranylcarbinyl radicals is even faster than that observed for cyclopropylcarbinyl radicals. Early studies established a lower limit for the rate constant of epoxide opening of 1O'O s-' by an elegant competition experiment between epoxide and cyclopropane opening [ 141. Later direct measurement has delivered values in the range of 4 x 1O'O s-l for this rate constant [15]. Although it was initially assumed that the oxygen-centered radical formed after epoxide opening does not cyclize in the reverse reaction, synthetic studies demonstrated this assumption to be wrong [ 161. The rate constants for the cyclization of allyloxy radicals have been determined to be in the range of 2 x lo9 s-' (Scheme 9) [17]. Oxiranylcarbinyl radicals can also react by cleavage of the C-C bond. Even though both modes of ring opening have been observed, the reactions arising from carbon oxygen bond cleavage seem to be more widely applied in organic synthesis.
&/
k = 2 x logs-'
Scheme 9
~
@-
212
3.3 Rearrangements of Cyclopropanes and Epoxides S
LJ
Bu3SnH,
AIBN,
f
-
f 53%
& 14%
translcis from trans and cis
from cis only
Scheme 10
This cleavage will therefore be discussed first. Several substrates have proven useful for the generation of the pivotal oxiranylcarbinyl radicals. ‘Sharpless epoxides’ are valuable starting materials for radical precursors [ 181. After formation of the oxygen-centered radical, reactions typical for radicals are observed. With a suitably positioned double bond, cyclization occurs as shown in Scheme 10 [ 191. It is interesting that the cis-disubstituted carbon-centered radical can react further to yield a bicyclo[2.2.1] system. If cyclizations are impossible, the highly reactive oxygen-centered radical can either react through hydrogen atom abstraction or induce a skeletal rearrangement. The former transformation allows for an efficient formation of bicyclic systems containing a hydroxy group [20, 211. The crucial step after epoxide opening is constituted by hydrogen atom abstraction to give the enol radical. Addition of this intermediate to the double bond formed during C-0 bond cleavage as outlined in Scheme 11 completes the overall transformation. Fragmentation reactions have been observed in systems similar to the one shown in Scheme 12. The radical-stabilizing ester substituent seems necessary to efficiently obtain the cyclodecane or cyclodecene systems, respectively [22a,b]. A system without ester groups has been described, but isolated yields were lower [22c]. With iodoepoxides as starting materials, interesting ring enlargement reactions have been reported. After iodine abstraction by a tributyltin radical and epoxide
s
Bu3SnH OH
-
C 5 O z M e OH
69%, ds = 2.7 : 1
Scheme I 1
3.3.2 Ring Opening of Cyclopropanes and Epoxides in Free-Radical Chemistry
21 3
m+
C02Me Bu3SnH, AlBN *
0 40%
0 22%
Scheme 12
opening, the resulting radical fragments to yield a species containing an a,Punsaturated carbonyl group and a carbon-centered radical. This intermediate cyclizes in the exo mode or is reduced by the stannane [23]. In analogy to the opening of vinylcyclopropanes the opening of vinyl epoxides by addition of thiophenyl radicals has been described. The method has been studied in some detail with spiro epoxides as shown in Scheme 13 [24]. The regioselectivity of the fragmentation of the oxygen-centered radical is influenced by the stability of the forming radical. The cyclobutane ring is thus opened to yield the higher substituted radical and an a$-unsaturated ketone. An extension of this methodology has been developed for epoxides containing an adjacent enol acetate and reaction sequences similar to the one described in Scheme 1 1 are reported [21]. An attractive feature of the overall transformation is the retention of the enol acetate moiety in the product that allows for further synthetic elaboration. It has been demonstrated that epoxide opening can also be initiated by the intramolecular addition of ketyl radicals formed by electron transfer from SmI2. For an example proceeding with excellent diastereoselectivity see Scheme 14 [25].
>30:1
60% Scheme 13
< 2%
2 14
3.3 Rearrangements of Cyclopropanes and Epoxides
ds > 200 : 1 Scheme 14
&
Ph
"w
@C02Me Ph& hv, AlBN
+
"v
k02Me
*
C02Me
36%
20%
Scheme 15
2 Sm12
Ph&Bt'
6HMPA *
75%
Ph/\l/ OSml2
-A Ph
OH
Scheme 16
S
Scheme 17
It should be noted that C-C bond scission in epoxides can be obtained if the radical formed is stabilized by aryl or vinyl substituents [26, 271. In this manner tetrahydofurans can be obtained as shown in Scheme 15 [28] in reactions employing samarium diiodide as electron transfer reagent for radical generation [ 291. A synthesis of cyclopropanols exploiting C-C bond cleavage has been reported with @-haloepoxides as starting materials (Scheme 16). The diradical formed by reduction of the bromide and by direct epoxide opening via electron transfer (see below) has been postulated as the crucial intermediate [30]. A combination of the opening of cyclopropanes and epoxides has been developed as outlined in Scheme 17. An intriguing mechanistic analysis has also been carried out demonstrating the reversibilty of epoxide opening [31]. This reaction has also been utilized in the preparation of prostaglandin derivatives [ 321.
3.3.3 Opening of Epoxides via Electron Transfer
215
3.3.3 Opening of Epoxides via Electron Transfer from Low-Valent Metal Complexes Another possibility to generate radicals is constituted by electron transfer from low valent metal complexes to epoxides. The general idea of this type of transformation has been outlined by Nugent and RajanBabu as shown in Scheme 18 [33].
Scheme 18
A o-complex of an epoxide with a low-valent transition metal possessing an unpaired electron in a d-orbital of n-symmetry constitutes the decisive intermediate in their reasoning. This species can be regarded as an electronic analogue of the cyclopropylcarbinyl radical. Thus, epoxide opening by breaking of one of the C-0 bonds is expected to be a fast reaction. Epoxides can be reduced under Birch conditions by solvated electrons [34] and by arene radical anions [35] without the presence of low-valent metal complexes. In both cases p-lithiumoxy organolithium compounds are formed after further reduction with a second equivalent of the electron transfer reagent. These species are stable enough to be trapped by electrophiles at low temperatures. They do not show the typical reactivity patterns of radicals. Thus, these transformations will not be dealt with here in detail. Chromium(I1) reagents have been used for the deoxygenation of styrene oxide and cyclohexene oxide [36]. The first step of this transformation is thought to be epoxide opening via electron transfer yielding a p-chromiumoxy radical that is trapped by a second equivalent of chromium(I1). Elimination of a chromium 0x0 species completes the reaction as shown in Scheme 19. Similar results were obtained with samarium diiodide. The presence of psamariumoxy radicals is supported by the isolation of mixtures of ( E ) - and ( Z ) -
OCrC'2
a
OCrCI2 CrC12
Scheme 19
-0
+
-
C~CI~
(CrCI2)20
216
3.3 Rearrangements of Cyclopropanes and Epoxides
olefins from cis- or trans-disubstituted epoxides [ 371. The P-samariumoxy radicals seem to have sufficient lifetimes to rotate around the C-C bond before being trapped by the second equivalent of SmI2.
3.3.3.1 Titanocenes as Single-Electron Reductants for Epoxides Although both samarium(I1) and chromium(I1) reagents yield radicals from epoxides, the typical reactivity of these intermediates in C-C bond-forming reactions and hydrogen atom abstractions has not been exploited. The use of titanocene(II1) reagents with their increased steric demand and reduced electron transfer ability has led to the realization of exactly these transformations. Nugent and RajanBabu have demonstrated that epoxides can be opened by titanocene(II1) chloride with high regioselectivity to yield the higher substituted radicals [33]. These radicals can be reduced by hydrogen atom donors, e.g. 1,6cyclohexadiene or tert-butyl thiol to yield the corresponding alcohols. The method has been applied to the synthesis of sensitive and functionalized molecules as depicted in Scheme 20 [33c]. With 'Sharpless epoxides', 1,2- or 1,3-diols can be obtained with high regioselectivity by proper choice of the protecting group [33d, 381.
bTiCp2CI 1) 1,4-C,jH8 2) H+ 55%
T r o w o"'OMe T r
OH
Scheme 20
The P-titanoxy radicals formed after epoxide opening can also add to a$unsaturated esters. The resulting enol radicals are reduced by a second equivalent of the titanocene reagent to yield titanium enolates. After aqueous workup the corresponding hydroxy esters or lactones are obtained. This method allows easy access to b-lactones in a one-step procedure from epoxides (Scheme 21) [33b].
0
Scheme 21
3.3.3 Opening of Epoxides via Electron Transfer
217
( endo/exo)
Scheme 22
2 CpnTiCl
&
Et02C Et02C
OTiCp2Cl TiCp2Cl
H
12
Et02C OTiCp2CI H
H 52%
Scheme 23
Arguably one of the synthetically most important applications of radical chemistry are 5-exo cyclization reactions [39]. Suitably substituted unsaturated epoxides are good substrates for these transformations as shown in Scheme 22. After reductive opening of the epoxide the resulting titanocene-bound radical adds to the double bond to yield a primary radical. Trapping with a second equivalent of titanocene(II1) chloride results in the formation of an organotitanium compound. After protic workup the corresponding hydrocarbon is isolated. Addition of iodine instead of protic workup results in the formation of an iodo titanocene alkoxide that cyclizes to yield a tetrahydrofuran (Scheme 23) [33a]. A general disadvantage of the reactions depicted so far is the need to use at least stoichiometric amounts of titanocene(II1) reagents. This is especially unattractive when complex ligands [40] are to be used to investigate reagent-controlled reactions. Catalytic transformations circumventing this problem have been realized by protonation of titanium oxygen and carbon Iionds in the presence of 2,4,6-collidine hydrochloride and a stoichiometric reducing agent, usually zinc or manganese. The reaction conditions for the reductive opening in the presence of 5 mol% titanocene dichloride are depicted in Scheme 24 [41]. The crucial aspect for catalytic turnover is the stability of radicals, epoxides, and the titanium(II1) reagent under buffered protic conditions. C-C bond-forming reactions have also been realized using the same concept. In these cases, both titanium-oxygen bonds (addition to a$-unsaturated esters) or a titanium-oxygen
218
3.3 Rearrangements of Cyclopropunes and Epoxides
5 moth Cp2TiClp
P
h2 g
*
Mn, 2,4,6-C0ll*HCI 88%
Scheme 24
5 mol% Cp2TiC12 Zn, 2,4,6-Coll*HCI 66%
H
Scheme 25
Ph 1
2
10 mol% 2, Zn
EtOA
O
E
t
3
6
+
1,4-C6H8, Collidine'HCI
74%, 94% ee COptBu
(ico2tBu
1 0 m o 1 ~ 0 2 , ~*n 1,4-CsH~, Collidine*HCI
HbJ 72%, 82% ee
Scheme 26
and a titanium-carbon bond (cyclization reaction) have to be protonated. An example of cyclization is shown in Scheme 25. Recently this methodology was expanded to the enantioselective opening of meso-epoxides with chiral, enantiomerically pure titanocene complexes as demonstrated in Scheme 26 [42]. Complexes 1 and 2 emerged as the best catalysts giving the highest enantioselectivity in the reductive opening of epoxide 3 in the presence of 1,4-cyclohexadiene. When cyclopentene oxide was opened by 2 in the presence of tert-butyl acrylate the corresponding hydroxyester was isolated with reasonable enantioselectivity and high diastereoselectivity as shown in Scheme 26. The catalyst did therefore not only induce enantioselectivity in epoxide opening but also con-
References
219
trolled the diastereoselectivity of the C-C bond formation to a higher extent than CpzTiCl2 (translcis = 86:14).
References [ l ] (a) For a comprehensive coverage of the recent literature see: A. de Meijere (Ed.), Methods
Org. Chem. (Houben- Weyl) 4'h ed., 1997, Vol. E 17a,b. For recent reviews on enantioselective cyclopropanations see: (b) A. Pfaltz in Comprehensive Asymmetric Catalysis (Eds. E. N . Jacobsen, A. Pfaltz, H. Yamamoto), Springer, 1999, Vol. 2, pp 513-538. (c) K. M. Lydon, M. A. McKervey in Comprehensive Asymmetric Catalysis (Eds. E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, 1999, Vol. 2, pp 539-580. (d) A. B. Charette, H. Lebel in Comprehensive Asymmetric Catalysis (Eds. E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, 1999, Vol. 2, pp 581-606. [2] For recent reviews on the generation of epoxides see: (a) A. S. Rao in Comprehensive Organic Synthesis (Ed. B. M. Trost), Pergamon, 1991, Vol. 7, pp 357-387. (b) B. Meunier, Chem. Rev. 1992, 92, 1411. (c) A. Gansauer, Angew. Chem. 1997, 109, 2701; Angew. Chem. Int. Ed. Engl. 1997, 36, 2591. For recent reviews on enantioselective epoxidations see: (d) T. Katsuki in Comprehensive Asymmetric Catalysis (Eds. E. N. Jacobsen, A. Pfdtz, H. Yamamoto), Springer, 1999, Vol. 2, pp 513-538. (e) E. N. Jacobsen, M. H. Wu in Comprehensive Asymmetric Catulysis (Eds. E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, 1999, Vol. 2, pp 649-678. (f) V. K. Aggarwal in Comprehensive Asymmetric Catalysis (Eds. E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, 1999, Vol. 2, pp 679-696. [3] (a) M. Cashing, M. Pereyre, M. Ratier, P. M. Blum, A. G. Davies, J. Chem. Soc., Perkin Truns. 2 1979, 287. (b) A. L. J. Beckwith, G. Moad, J. Chem. Soc., Perkin Truns. 2 1980, 1473. (c) M. Newcomb, A. G. Glenn, J. Am. Chem. Soc. 1989, I l l , 275. (d) M. Newcomb, A. G. Glenn, W. G. Williams, J. Org. Chem. 1989, 54, 2675. (e) D. C. Nonhebel, Chem. Soc. Rev. 1993, 22, 347. (41 (a) K. S. Feldman, A. L. Romanelli, R. E. Ruckle Jr., R. F. Miller, J. Am. Chem. SOC.1988, 110, 3300. (b) K. S. Feldman, A. L. Romanelli, R. E. Ruckle Jr., G. Jean, J. Org. Chem. 1992, 57, 100. (c) K. S. Feldman, K. Schildknegt, J. Org. Chem. 1994, 59, 1129. [5] K. Miura, K. Fugami, K. Oshima, K. Utimoto, Tetrahedron Lett. 1988,29, 5135. [6] (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) D. A. Singleton, K. M. Church, M. J. Lucero, Tetrahedron Lett. 1990, 31, 5551. (d) C. C. Huval, D. A. Singleton, J. Org. Chem. 1994, 59, 2020. [7] K . S. Feldman, A. K. K. Vong, Tetrahedron Lett. 1990, 31, 823. [8] K . Miura, K. Fugami, K. Oshima, K. Utimoto, Tetrahedron Lett. 1988, 29, 1543. [9] M. P. Bertrand, R. Nouguier, A. Archavlis, A. Carrikre, Synlett 1994, 736. [lo] (a) J. D. Harling, W. B. Motherwell, J. Chem. Soc., Chem. Commun. 1988, 1380. (b) R. A. Batey, J. D. Harling, W. B. Motherwell, Tetrahedron 1992, 48, 8031. (c) W. B. Motherwell, Aldrichimica Acta 1992, 25, 71. 111) R. A. Batey, W. B. Motherwell, Tetrahedron Lett. 1991, 32, 6211. [ 121 K. S. Feldman, C. J. Burns, J. Org. Chem. 1991, 56, 4601. [13] M. E. Jung, H. L. Rayle, J. Org. Chem. 1997, 62, 4601. [14] K . W. Krosley, G. J. Gleicher, J. Phys. Org. Chem. 1993, 6, 228. [ 151 V. Krishnamurthy, V. H. Rawal, J. Org. Chem. 1997, 62, 1572. [I61 (a) H. Suginome, J. B. Wang, J. Chem. Soc., Chem. Commun. 1990, 1629. (b) 1'. Galatsis, S. D. Millan, Tetruhedron Lett. 1991, 32, 7493. [I71 F. E. Ziegler, A. K. Petersen, J. Org. Chem. 1995, 60, 2666. [ 181 (a) R. A. Johnson, K. B. Sharpless in Catalytic Asymmetric Synthesis (Ed.: I. Ojima), VCH, 1993, pp 103-158. (b) T. Katsuki, V. S. Martin in Organic Reactions (Ed. L. A. Paquette), Wiley, 1996, Vol. 48, pp. 1-300.
220
3.3 Rearrangements of Cyclopropanes and Epoxides
[ 191 (a) A. Johns, J. A. Murphy, Tetruhedron Lett. 1988, 29, 837. (b) R. C. Gash, F. MacCorquodale, J. C. Walton, Tetrahedron 1989, 45, 5531. [20] V. H. Rawal, R. C. Newton, V. Krishnamurthy, J. Org. Chem. 1990, 55, 5181. [21] V. H. Rawal, V. Krishnamurthy, Tetrahedron Lett. 1992, 33, 3439. [22] (a) W. R. Bowman, B. A. Marples, N. A . Zaidi, Tetrahedron Lett. 1989, 30, 3343. (b) D. A. Corser, B. A . Marples, R. K. Dart, Synlett 1992, 987. (c) D. H. R. Barton, R. S. H. Motherwell, W. B. Motherwell, J. Chem. Soc., Prrkin Trans. 1 1981, 2363. [23] P. Galatsis, S. D. Millan, T. Faber, J. Org. Cheni. 1993, 58, 1215. [24] S. Kim, S. Lee, Tetrahedron Lett. 1991,32, 6575. [25] G. A. Molander, S. R. Shakya, J. Org. Chern. 1996, 61, 5885. [26] E. Stogryn, M. H. Gianni, Tetruhedron Lett. 1970, 3025. [27] J. A. Murphy, C. W. Patterson, Tetrahedron Lett. 1993, 34, 867. [28] K. S. Feldman, T. E. Fisher, Tetrahedron 1989, 45, 2969. [29] E. Hasegawa, M. Takahashi, T. Horaguchi, Tetrahedron Lett. 1995, 36, 5215. [30] H. S. Park, S. H. Chung, Y. H. Kim, Synlett 1998, 1073. [31] F. E. Ziegler, A. K. Petersen, J. Org. Chem. 1994, 59, 2707. [32] F. E. Ziegler, A. K. Petersen, Tetrahedron Lett. 1996, 37, 809. [33] (a) W. A. Nugent, T. V. RajanBabu, J. Am. Chem. Soc. 1988,110, 8561. (b) T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1989,111,4525. (c) T. V. RajanBabu, W. A. Nugent, M. S. Beattie, J. Am. Chem. Soc. 1990, 112, 6408. (d) T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116, 986. [34] (a) A. J. Birch, J. Proc. Roy. Soc. N. S. W. 1950, 83, 245. (b) R. A. Benkeser, A. Rappa, L. A. Wolsieffer, J. Org. Chem. 1986, 51, 3391. [35] (a) E. Bartmann, Anyew. C/zem. 1986, Y8, 629; Angeio. Chem. Int. Ed. Engl. 1986, 25, 855. (b) T. Cohen, I.-H. Jeong, B. Mudryk, M. Bhupathy, M. M. A. Awad, J. Ory. Chern. 1990,55, 1528. (c) A. Bachki, F. Foubelo, M. Yus, Tetrahedron; Asymmetry 1995, 6 , 1907. (d) A. Bachki, F. Foubelo, M. Yus, Tetrahedron: Asymmetry 1996, 7 , 2997. [36] J. K. Kochi, D. M. Singleton, L. J. Andrews, Tetrahedron 1968, 24, 3503. [37] M. Matsukawa, T. Tabuchi, J. Inanaga, M. Yamaguchi, Chem. Lett. 1987, 2101. [38] J . S. Yadav, T. Shekharam, V. R. Gadgil, J. Chem. Soc., Chem. Cornmun. 1990, 843. [39] B. Giese, B. Kopping, T. Gobel, J. Dickaut, G. Thoma, K. J. Kulicke, F. Trach in Oryunic Reactions (Ed. L. A. Paquette), Wiley, 1996, Vol. 48, pp. 301-856. [40] (a) R. L. Halterman, Chem. Reu. 1992, 92, 965. (b) R. L. Halterman in Metullocenes (Eds. A. Togni, R. L. Halterman), Wiley-VCH, 1998, Vol. I , pp. 455--544. [41] (a) A. Gansauer, M. Pierobon, H. Bluhm, Angeiv. Chem. 1998, 110, 107; Angew. Chenz. Int. Ed. Engl. 1998, 37, 101. (b) A. Gansauer, H. Bluhm, J. Cl7em. Soc., Chem. Commun. 1998, 2143. (c) A. Gansauer, H. Bluhm. M. Pierobon, J. Am. Chem. Soc. 1998, 120, 12849. [42] (a) A. Gansauer, T. Lauterbach, H. Bluhm, M. Noltemeyer, Anyew. Chem. 1999, 111, 3112; Angew. Chem. Int. Ed. Engl. 1999, 38, 2909. (b) A. Gansauer, H. Bluhm, M. Pierobon, M. Keller, manuscript submitted.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
3.4 0-Stannyl Ketyl Radicals E. J. Enholm and J. S. Cottone
3.4.1 Introduction Only recently have 0-stannyl ketyl radical anions emerged as useful synthetic intermediates. Previously, ketyl intermediates have been formed by partial reduction or one-electron transfer to a ketone or aldehyde by photochemical, electrochemical, and metal-mediated methods [I]. Metal-associated ketyl radical anions have also undergone a variety of free-radical reactions [ 1, 21. The 0-tributylstannyl ketyls discussed in this chapter are produced under neutral free-radical conditions by reaction of carbonyl functional group 1 (R' or R 2 = H or alkyl) with tributyltin radical and AIBN as an initiator. These provide an adjacent, delocalized radicalanion species spanning a carbon-oxygen bond with a tin counterion, as shown in Scheme 1 [3-61. Two resonance structures, 2 and 3, account for the charge distribution; however, structure 2 is a more significant contributor than 3 because of the positioning of anionic character on the more electronegative oxygen atom. Reactions herein significantly differ from most standard nBu3SnH-mediated radical transformations that employ a variety of well-known precursors for carboncentered radicals, including halides, thioacyl moieties, olefins, selenides and sulfides. Most of these potentially useful precursors are sacrificed and lost during the radical reaction and are not available for subsequent manipulations [7]. However, 0stannyl ketyl intermediates conserve the carbonyl oxygen for further functionalization. A delocalized 0-stannyl radical anion can also be generated from the reaction of an N,P-unsaturated ketone or aldehyde with tributyltin hydride and radical initiator AIBN [3,4, 5a, 5b]. Thus, a,B-unsaturated carbonyl compound 4 (R' or R2 = H or alkyl), can be reacted with nBu3SnH under standard free-radical conditions to give allylic 0-stannyl ketyl species (5 c) 6), shown in Scheme 2. After hydrogen atom transfer to the /3-position of 6, a synthetically useful tin(1V) enolate is produced [5b, 5d, 5g]. Allylic 0-stannyl ketyls have both one- (radical) and two-electron (anionic) sites for reactivity. These reactions can proceed in a sequential manner - a rdpidlyevolving methodology in organic synthesis [2, 5, 81. If the one-electron reactivity in 6 is used with a radicophile, then the tin enolate or two-electron reactivity can be used in reactions with suitable electrophiles (E+). Note that the carbonyl species,
222
3.4 0-Stannyl Ketyl Radicals
1
8OoC,PhH
L
3 minor
major
Scheme 1. 0-Stannyl ketyl intermediates
r
6 i
6+
Scheme 2. Allylic 0-stannyl ketyl intermediates
obtained after electrophilic quenching of the tin enolate, can undergo further synthetic manipulation. This direct and neutral radical method to prepare tin(1V) enolates is seldom applied in synthetic procedures. This mild methodology is in marked contrast to the strongly reductive conditions of a dissolving metal reaction of an enone or trapping a basic lithium enolate with Bu3SnC1 [3]. The following series of allylic and 0-stannyl ketyl reactions is intended to provide insight into the reactivity and potential of these interesting synthetic intermediates. Various cyclizations, strained ring scissions, and electrophile trapping reactions will be demonstrated on diverse substrates such as ketones, aldehydes, enones and aketocyclopropanes. All of the chemistry described herein utilizes mild and neutral reaction conditions to accomplish a wide range of synthetic transformations.
3.4.2 Early Work on 0-Stannyl Ketyls 0-Stannyl ketyls have been proposed as intermediates for almost 30 years. Much of the early work came from the laboratories of Davies [9a], Pereyre [ 3 , 9b, 9c] and Beckwith [6a, 101 and provided a framework for a modern understanding of 0stannyl ketyls. These seminal studies were often focussed on mechanistic aspects of tin ketyls in a-cyclopropyl- and a-epoxy-ketone ring openings. In one of the first carbonyl-alkene cyclizations, it was determined that the tributyltin radical added to a ketone in a somewhat sluggish manner and that excess amounts of tin hydride were needed to drive the reaction to completion [6a]. It was also understood that a ketyl radical anion is more stable than a simple carbon-centered radical, likely attributed to more effective delocalization. Ketyl reactive intermediates are now being utilized in new strained-ring cleavage-recyclization sequences (see below) and are
3.4.3 Cyclization Reactions
223
responsible for useful cyclopentane annulations. Early studies also showed that the 0-stannyl ketyl, perhaps best described by the major resonance contributor 3 (Scheme l), is nucleophilic and prefers electrophilic substrates for reactivity.
3.4.3 Cyclization Reactions Reactions involving 0-stannyl ketyl intermediates have been categorized into two main classes: 0-stannyl ketyl cyclizations and electrophilic trapping of tin(1V) enolates. It should also be noted that both reactions can take place in a tandem sequence with the same precursor substrate. Simple cyclization reactions are mediated by a homolytic chain mechanism with a 5-exo-trig closure (Scheme 3). Addition of a tributyltin radical to the enone carbonyl in 7 (EWG = electron-withdrawing group) produces allylic 0-stannyl ketyl intermediate 8. A subsequent 5-exo-trig ring closure is then possible by addition to the activated olefin, producing the carboncentered free radical intermediate 9. Transfer of hydrogen atom from tributyltin hydride then renders 10 and tributyltin radical which repeats the process. It is noteworthy that prior to workup, intermediate 10 contains a useful tin enolate functionality. Enolate 10 can now readily react with D20 or bromine or can be employed as a scaffold for subsequent synthetic manipulations [sa]. After workup, the tin by-products in this study and others can be easily removed with I2 and DBU [Ill. These cyclization reactions can be conveniently catagorized into simple 5-hexenyl1-oxy cyclizations, annulation reactions, and tandem cyclizations. The 5-hexenyl-loxy cyclizations afford 2-substituted cyclopentanols, as shown in Scheme 4 [4a]. This reaction is readily distinguished by the use of a bifunctional acyclic precursor 12, which, when transformed into the corresponding ketyl intermediate, yielded
n
4
i/
A 0
Bu3SnH
5-exo-trig
.
8oAdENPhi
EWG
7
BuSt!16+
8
EWG = electron withdrawing group, i.e. C 0 2 R , CN
BUS; 6+
9
10
Scheme 3. Mechanism of a n 0-stannyl ketyl-alkene cyclization
11
224
3.4 0-Stannyl Ketyl Radicals
EWG = electron withdrawing group Example:
Scheme 4. 5-Hexenyl-I-oxy cyclizations
substituted monocyclic product 13, where the trans-diastereomer was slightly favored. Olefins activated by esters, nitriles and phenyl substituents all functioned well. Annulation reactions are possible when a precursor monocyclic substrate contains an activated alkene in a tether [4a].As demonstrated in Scheme 5, an ester was employed to activate the olefin appended to cycloalkanone 17. Upon generation of the 0-stannyl ketyl with tributyltin hydride, the carbon-centered radical attacks the electron-poor P-position on the activated alkene. The corresponding cyclized adduct 18 is a bicyclic skeleton with a bridgehead hydroxyl group. An example of this reaction shows cyclopentanone 19 undergoing cyclization to diquinane 20 and tricycle 21 (76:24) in 69% yield. The presence of reasonable amounts of the minor, yet readily isolable, syn-diastereomers in the reaction indicated that the reaction may not be reversible.
+ n = 1,2
17
SEWG nH =
18
EWG = electron withdrawing group
F!
Example:
C02Me
,Bu3SnH '
& 19
*
PhH, AIBN, 80°C H 20
Scheme 5. Annulations with an alkene tether
H 21
76 24,69%
0’
p
3.4.3 Cyclization Reactions
225
t
EWG 22
EWG = C02Me, 55 % EWG = Ph. 75 %
23
Separated n
EWG 24
A EWG‘
U
EWG = Ph, monocyclized product only
25
Fused
I
EWG 26
EWG
EWG = C02Me, 54 % EWG = Ph, carbonyl reduction
27
Scheme 6. Tandem radical reactions
More interesting reactions are possible when the carbonyl-alkene cyclizations are applied in a tandem reaction sequence [4b]. The three precursor motifs of ‘spiro’, ‘separated’, and ‘fused’ ring systems 22, 24 and 26, respectively, were each constructed; however, not all cyclized readily (Scheme 6). In each reaction the intermediate alkene bearing the EWG, which both receives the radical and transfers the radical in the last cyclization, was activated for addition from the 0-stannyl ketyl. With the appropriate placement of the alkene tether in the starting substrate, complex ring structures can be synthesized in a one-pot procedure. Even though the primary focus of these studies was on the success of the tandem radical cyclizations, in most cases only a few of the possible stereoisomers formed, suggesting some selectivity within the reaction mechanism [7, 12-16]. When subjected to treatment with nBu3SnH, aldehyde 22 gave successful results, yielding the expected spiro-[4.4]-ring system 23. The ‘spiro’ ring skeleton 23 was produced in 55% yield as four diastereomers in a ratio of 6:2:2:1. No mono-cyclized products, resulting from the first closure only, were observed. Conversely, efforts to synthesize a ‘separated’ bicyclic structure 25 failed, resulting in only a monocyclized cyclopentanol. The contrast between the ‘spiro’ and ‘separated’ cases can best be differentiated by their intermediate carbon-centered radical species [4b]. Lastly, construction of the ‘fused’ ring system 27 was also possible. Precursor 26 was reacted with tributyltin hydride under normal radical conditions, producing the fused bicyclic ring system 27 in 52% yield as a 1:1 diastereomeric ratio of separable isomers. This reaction was more sensitive, depending strongly on the activating capacity of
226
3.4 0-Stannyl Ketyl Radicals
the appended electron-withdrawing group. The a,P-unsaturated ester was better at promoting the initial cyclization. Moreover, it stabilized the monocyclized radical intermediate in the second cyclization in a manner superior to an appended phenyl group. 0-Stannyl ketyl-induced tandem cyclizations are effective; however, the reaction depends markedly on the structure of the starting substrate and the activating group. By simply varying (1) the types of alkene appendages, (2) their relative tether and distance, and ( 3 ) the activating function on the alkene, a potentially useful tandem cyclization method is possible with 0-stannyl ketyls.
3.4.4 Reactions of Tin(IV) Enolates with Electrophiles As discussed above, tin(1V) enolates are readily formed from a$-unsaturated ketones and aldehydes. The common free-radical protocol of AIBN and benzene at 80°C can be applied to enones to generate the tin enolate in situ (Scheme 2). Moreover, the use of a-ketocyclopropanes as precursors is equally effective, as shown in Scheme 7 [5i]. This protocol takes advantage of the inherent strain of the cyclopropane ring in 28 that is released via the cyclopropylcarbinyl radical when the 0-stannyl ketyl 29 forms. These reactions provide a very mild alternative to metal enolate formation. Depending on the regiochemistry of ring scission, 30 or 31 can be formed and subsequent enolate chemistry is now possible. Note that the radical is now separated from the anion, allowing truly independent reactivity of both radical and anion species. The tin(1V) enolate can be quenched with a variety of electrophiles to form new carbon-carbon bonds, including carbonyl addition (aldol-type) reactions, alkylations and conjugate additions of tin(1V) enolates. Tin(1V) enolates react readily with aldehydes in both intra- and intermolecular aldol-type reactions [Sj].The best conditions for the intermolecular aldol condensation reaction were to initially generate the tin enolate by reacting the desired enone with tributyltin hydride and then
28 (R1, R2 = alkyl, H)
29
30
Scheme 7. z-Ketocyclopropanes as ti@)
31
enolate precursors
3.4.4 Reactions of Tin(IV) Enolates with Electrophiles
227
lntermolcular Aldol
& 6 *&-.-.Q 6+
SnBu3
Bu3SnH, AlBN ~
benzaldehyde-
PhH, 80°C
34 73 Yo, 6:l
33
32
erythrohhreo
pTsOH
35 92 Yo, 82:l E:Z Intramolecular Aldol
6+
8~6- 0'
Bu3SnHtA1BN, PhH, 80°C
H3C b-CHO
36
H3C
SnBu3
- , ,*
CHO
37
O%Hs HO
38 81 %, 5011
Scheme 8. Tin(1V) enolates and the aldol reaction
subsequently to quench the reactive species with an aldehyde at low temperatures (Scheme 8). The aldol diastereomeric ratios ranged from 1:l to 6:l (20:l with aketocyclopropanes), favoring the erythro-diastereoisomer. Treatment of the aldol products with p-TsOH readily afforded dehydration products. The intramolecular variant of these aldol reactions was studied using 2-cyclohexenone precursors with aldehyde tethers, as shown in Scheme 8. The benefit of this sequence is that it provides an intramolecular aldol from an enone under neutral and non-basic freeradical conditions. The intramolecular aldol reaction was much more successful, providing yields as high as 81% with high diastereoselectivity unlike the intermolecular aldol. For instance, bicyclic alcohol 38 was formed in 81% yield (50:l). It is also interesting that the alcohol has a sterically more hindered endo orientation, confirmed by X-ray diffraction [5b]. Once an allylic O-stannyl ketyl forms at the cyclohexanone site, hydrogen atom abstraction from tributyltin hydride at the pposition leaves the a-position available for the tin(1V) enolate to act as a nucleophile and attack the aldehyde in an intramolecular fashion. Therefore, free radicals are not involved in the carbon-carbon bond-forming step: rather it proceeds via a two-electron reaction [Sj]. Alkylation reactions via the tin(1V) enolate intermediate were also achieved with a protocol analogous to the above-mentioned aldol reaction (Scheme 9). By preforming the tin(1V) enolate under neutral free radical conditions, subsequent reactions with alkyl halides formed a-alkylated ketone products. This radical reaction
228
3.4 0-Stunnyl Ketyl Radiculs
1
40
39
76%
Scheme 9. Alkyl halide addition to tin(1V) enolates
is in direct contrast to the way in which an a,P-unsaturated ketone classically undergoes additions in a free radical reaction with an alkyl halide [7]. The normal attack of the alkyl radical occurs at the P-position of an enone in a 1,4-manner as it does with essentially all one- and two-electron donors. However, as Scheme 9 shows, the tin(1V) enolate is prepared first and the alkyl halide is only added after the tin hydride has reduced the enone. Careful stoichiometry and the order of reagent addition govern this reaction because of the higher reactivity of the tributyltin radical with alkyl halides versus the enone [ 171. When alkyl halides were initially studied, yields of the alkylated product were low to modest. However, the addition of HMPA (hexamethylphosphoramide) was key to activation of the tin-oxygen bond, thus enhancing the nucleophilicity of the tin enolate [18]. The high coordination ability of HMPA allows it to act as a Lewis base and increase the polarity of the tin(1V) enolate (Scheme 10). Alkylation of the enolate was greatly facilitated by this additive. Conjugate addition-dimerization reactions were also successfully accomplished within the tin(1V) enolate methodology, albeit in modest yields. Activated alkenes using two enone precursors formed conjugate addition products (Scheme 10). These conjugate additions with enone Michael acceptors provide a regiocontrolled route to bicyclic products. Because the enolate forms on the alkene side of the ketone, the reaction outcome can be predicted with some confidence. One of the more commonly used organotin reagents in both free-radical reactions and Lewis acid-mediated reactions is allyltributyltin [3, 71. This reagent permits the construction of new carbon-carbon bonds from free radical precursors such as alkyl halides; however, reactions with a-ketocyclopropanes were poorly understood. Tin(1V) enolates generated from a-ketocyclopropane 44 and allyltributyltin undergo both radical allylation and electrophilic quench as shown in Scheme 11, forming 0stannyl ketyl 45 with allyltributyltin and subsequent scission of the cyclopropane
6
Bu3SnH,
ti+/ [O=P(NMed31n BUSS: 0 s - 2-cyclohexenone
PhH, 8OoC,HMPA 41
42
Scheme 10. Tin(1V) enolates and conjugate additions
43
41
3.4.5 Application to Triquinanes ”
Bu3Sn ‘ 0 6
Bu3SnR, AlBN
R’
h
R’
PhH,80°C * R = allyl
44
Bu3SnR, AlBN *
AA-
R’
k. 46
E+ * b E+ = R-X, H20
/
\
R
Bu3Sn‘ 0 6
45
& Bu3Sn ‘68 ’
R
47
’
k
48
Example:
-CO2Et Bu3SnR, AlBN *
49
229
PhH, 8OoC R = allyl
H20
O”
50
94 %
Scheme 11. 3-Ketocyclopropane precursors and allylstannane reagents
constructs intermediate 46 [5i]. This radical anion intermediate provides an unparalleled dual reactivity in synthesis, allowing for independent transformations with both electrophiles and radicophiles. The radical species in intermediate 46, separated from the enolate by a methylene unit, can undergo allyl transfer from allyltributyltin to prepare a new carbon-carbon bond. The reaction sequence provides one of the only non-basic and non-nucleophilic alternatives to well-known l,4additions of organocuprates to enones. The remaining tin enolate 47 can then be quenched with various electrophiles to fully exploit carbon-carbon bond formation. Note that in the example reaction of 49 + 50 the opening of the cyclopropane ring is governed by the ester substituent which stabilizes the intermediate radical species, and very selectively affords only regio- and stereoisomer 50 in 940/0 yield. Overall, these new trialkyltin-associated radical anion intermediates allow entry into the rapidly developing manifold of one- and two-electron reactions.
3.4.5 Application to Triquinanes As demonstrated above, tandem radical anion cyclizations via formation of two or more consecutive rings from one initial radical anion species have potential to become a useful method to generate sophisticated carbon skeletons [7]. Although not as fully exploited as cation tandem reactions, this general methodology could lend itself to the synthesis of complex natural products formed by various tandem methods such as linear- and angular-fused triquinanes [ 121, steroids [ 131, milbemycin [14], prostaglandins [15] and other ring constructs [7, 161.
230
3.4 O-Stannyl Ketyl Radicals
Linear-fused triquinane:
-
Bu3SnH, AlBN
0 PhH, 8OoC
6+6Bu3Sn0
51
-
c
Bu3Sn0
52
54
53
55
Angular-fused triquinane:
-
Bu3SnH, AlBN
0 PhH, 8OoC 56
-
6+ Bu3Sn0
Bu3Sn0
57
59
58
60
Scheme 12. O-Stannyl ketyl approachs to triquinane skeletons
Triquinanes rank among the most important natural carbon frameworks [ 12, 191. Angular- and linear-fused carbon skeletons possess three five-membered rings which share one or two carbon-carbon bonds, respectively. Natural products from a wide array of biological sources produce these compounds with a considerable range of functionality. A new radical anion tandem process to prepare two triquinane skeletons, linear and angular, was initiated by the radical anion of strained ring systems 51 and 56 respectively, as shown in Scheme 12. The O-stannyl ketyl intermediates 52 and 57 trigger a strained ring-opening-closing cascade. Intermediates 53 and 58, differ only in the placement of alkene appendages on a similar diquinane foundation, leading to new synthetic sequences that allow for the synthesis of either linearand angular-fused triquinane skeletons. As shown in Scheme 12, bond ‘a’ is cleaved in preference to bond ‘b’ in the ring opening. Because of favored overlap in the ketyl C-0 bond in 52 and 57, the capture of the generated radical by the suitably tethered olefin affords linear triquinane 55 or angular triquinane framework 60, respectively [5e, 5f, 5h].
3.4.5 Application to Triguinanes
1. PDC, CH2C12
H+, reflux H
23 1
*
2. Dibal. -78 OC
2.THF, MgBrH
62
61
1 63
64
H
H
65
66
Scheme 13. Synthesis of an angular triquinane via U-stannyl ketyls
The actual synthesis of an angular triquinane skeleton using this technology is shown in Scheme 13. The unsaturated tether was appended by addition of ally1 Grignard to the oxidized alcohol of 62. Once the a-ketocyclopropane 63 was properly functionalized, implementation of the tandem radical anion scission/cyclization cascade could commence. Treatment with Bu3SnH furnished the angular triquinane skeleton 65 in 93‘1/0yield. High stereochemical control was realized in the 5-exo-trig radical cyclization where the endo:exo stereoselectivity for the methyl was found to be >57: 1. A Beckwith chair-like intermediate 64 supported the stereochemistry of the endo-methyl in 65 [20]. Diketone 66 was obtained by direct oxidation with PCC providing a single diastereomer of the triquinane in 78% yield. The entire synthetic sequence is very efficient, producing triquinane 66 in 46Y0 overall yield from 61. A linear triquinane skeleton was also constructed using a related methodology, as shown in Scheme 14. A cyclopropane ring was first installed in commercial diquinane 67 using a two-step method of monoiodination, followed by treatment with DBU [21]. The dehydrohalogenation constructed the symmetrical tricyclodione 68 in a 52% overall yield. Next, reaction with the Grignard reagent of 4-bromo-lbutene gave 69 as the sole stereoisomer, which was isolated in 64% yield. Cleavage of the ‘b’ bond in 69 by treatment with Bu3SnH afforded linear triquinane 71 in 83% yield as the only isolable product. Some measure of stereochemical control was realized in the 5-exo-trig radical cyclization where the endo:exo stereoselectivity ratio, determined by capillary GC, was >4:1. As in the angular triquinane, a Beckwith chair-like intermediate 70 readily explained the stereochemistry of the endo-methyl in 71 [20]. Collectively, these examples illustrate the applicability of tandem O-stannyl ketyl cyclizations via a-ketocyclopropane. O-Stannyl ketyls are
232
3.4 0-Stannyl Ketyl Radicals
1.12, HgC12, CH2C12
+o-fJ= Me
2. DBU, CH&N
0M gTHF, B r v0
Me 68
67
Me 69 Me
Bu3SnH,AlBN *
0
PhH, 8OoC L
Me
‘OH J
70
Me 71
Scheme 14. Synthesis of a linear triquinane via 0-stannyl ketyls
viable intermediates for the construction of polycyclic structures in a tandem fashion. Although 0-stannyl ketyl radical anions are intermediates only recently developed for synthetic applications, they already provide ready access to carbonylalkene cyclizations, ring scissions, and tin(1V) enolates. Unlike standard radical reactions, these transformations provide an alcohol or ketone after workup that can be further synthetically manipulated. Finally, the intermediates can be applied to natural product skeletons such as the triquinanes.
References [ I ] a) J. Cossy, D. Belotti, J. P. Pete, Tetrahedron Lett. 1987, 4547; (b) T. Shono, S . Kashimura, Y. Mori, T. Hayashi, T. Soejima, Y. Yamaguchi, J. Org. Chem. 1989, 54, 6002; (c) T. Shono, N. Kise, T. Suzumoto, T. Morimoto, J. Am. Chem. Soc. 1986, 108,4676; (d) J. E. Swartz, T. J. Mahachi, E. Kariv-Miller, J. Am. Chern. Soc. 1988, 110, 3622; (e) E. Kariv-Miller, H. Maeda, F. Lombardo, J. Org. Chem. 1989, 54, 4022; (f) R. D. Little, D. P. Fox, L. V. Hijfte, R. Dannecker, G. Sowell, R. L. Wolin, R. L. Moens, M. M. Baizer, J. Org. Chem. 1988, 53, 2287; (g) G. A. Molander in The Chemistry vfthe Metal-Curhon Bond (Ed. J . Wiley & Sons), New York, 1989, Vol. 5, Chapter 8, pp. 319-396; (h) G. A. Molander, Chem. Rev. 1992, 92, 29. [2] (a) N. Hirota in Radical Ions (Ed.,Wiley Interscience), New York, 1968, pp. 35-85; (b) G. A. Russell in Radical Ions (Ed., Wiley Interscience), New York, 1968, pp. 87-150; (c) A. R. Forrester, J. M. Hay, R. H. Thompson in Organic Chemistry ofstable Free Radicals (Academic), New York, 1968, pp. 82-90. [3] M. Pereyre, J.-P. Quintard, A. Rahm in Tin in Organic Synthesis (Butterworths), Boston, 1987. [4] (a) E. J. Enholm, G. Prasdd, Tetrahedron Lett. 1989, 4939; (b) E. J. Enholm, J. A . Burroff, Tetrahedron Lett. 1992, 1835. [5] (a) E. J. Enholm, K. S. Kinter, J. Am. Chem. SOC.1991, l I 3 , 7784; (b) E. J. Enholm, Y. Xie, K. A. Abboud, J. Org. Chem. 1995, 60, 1112; (c) E. J. Enholm, K. S. Kinter, J. Org. Chern. 1995, 60, 4850; (d) E. J. Enholm, P. E. Whitley, Tetrahedron Lett. 1996, 37, 559; (e) E. J. Enholm, Z. J. Jia, Tetrahedron Lett. 1996, 37, 1177; (f) E. J. Enholm, Z. J. Jia, Tetrnhedrvn
References
233
Lett. 1995,36, 6819; (g) E. J. Enholm, P. E. Whitley, Tetrahedron Lett. 1995,36,9157; (h) E. J. Enholm, Z. J. Jia, J. Chem. Soc., Chem. Commun. 1996, 1567; (i) E. J. Enholm, Z. J. Jia, J. Org. Chem. 1997, 62, 174; (j) E. J. Enholm, P. E. Whitley, Y.-P. Xie, J. Org. Chem. 1996, 61, 5384; (k) E. J. Enholm, A. Trivellas, Tetrahedron Lett. 1994, 1627. 161 (a) A. L. J. Beckwith, D. H. Roberts, J. Am. Chern. Soc. 1986, 108, 5893; (b) T. Sugawara, B. A. Otter, T. Ueda, Tetrahedron Lett. 1988, 75; (c) V. Rawal, V. Krishnamurthy, A. Fabre, Tetrahedron Lett. 1993, 2899; (d) D. D. Tanner, G. E. Diaz, A. Potter, J. Org. Chem. 1985, 50, 2149. (71 (a) B. Giese in Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds (Pergamon), New York, 1986; (b) M. Ramaiah, Tetrahedron 1987, 43, 3541; (c) D. P. Curran, Synthesis 1988, 417, 489; (d) D. J. Hart, Science 1984, 223, 883; (e) W. B. Motherwell, D. Crich in Free Radical Chain Reactions in Organic Synthesis (Academic), New York, 1992; (f) C. Thebtaranonth, Y. Thebtaranonth, Tetrahedron 1990, 46, 1385; (g) C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91, 1237. [8] (a) Y. H. Kim, I. S. Lee, Heteroatorn Chem. 1992, 3, 509; (b) R. A. Batey, W. B. Motherwell, Tetrahedron Lett. 1991, 32, 6211; (c) G. A. Molander, J. A. McKie, J. Org. Chem. 1991, 56, 41 12; (d) T. Kirschberg, J. Mattay, J. Org. Chem. 1996, 61, 8885; (e) T. Kirschberg, J. Mattay, Tetrahedron Lett. 1994, 35, 7217; (f) K . Takai, K. Nitta, 0. Fujimura, K. Utimoto, J. Ory. Chem. 1989, 54, 4732; (8) D. P. Curran, T. L. Fevig, M. J. Totleben, Synlett 1990, 733; (h) G. A. Molander, L. S. Harring, J. Org. Chem. 1990, 55, 6171; (i) G. A. Molander, C. Kenny, J. Org. Chem. 1991, 56, 1439; (j) D. P. Curran, T. L. Fevig, C. P. Jasperse, M. J. Totleben, Synlett 1992, 943; (k) M. J. Totleben, D. P. Curran, P. Wipf, J. Org. Chem. 1992, 57, 1740; (1) D. P. Curran, M. J. Totleben, J. Am. Chem. Soc. 1992,114, 6050; (m) G. A. Molander, J. A. McKie, J. Org. Chem. 1992, 57, 3132. [9] (a) A. G. Davies, M.-W. Tse, J. Orgunornet. Chem. 1978, 155, 25; (b) A. G. Davies, J.-Y. Godet, B. Muggleton, M. Pereyre, J. Chem. Soc., Chem. Commun. 1976, 813; (c) A. G. Davies, B. Muggleton, J.-Y. Godet, M. Pereyre, J.-C. Pommier, J. Chem. Soc. Perkin Trans. 2. 1976, 1719. [lo] A. L. J. Beckwith, G. Moad, J. Chem. Soc. Perkin Trans. I 1980, 1473. [ l I ] D. P. Curran, C. Chang, J. Org. Chem. 1989, 54, 3140. [12] (a) D. P. Curran, J. Sisko, P. E. Yeske, H. Liu, Pure Appl. Chem. 1993, 65, 1153, and references therein; (b) D. P. Curran, D. M. Rakiewicz, J. Am. Chem. Soc. 1985, 107, 1448. [I31 G. Stork, R. Mook, J. Am. Chem. Soc. 1983, 105, 3270. [14] P. J. Parsons, P. A. Willis, S. C. Eyley, J. Chem. Soc., Chem. Conzmun. 1988, 283. [15] G. Stork, P. M. Sher, H. L. Chen, J. Am. Chem. Soc. 1986, 108, 6384. [16] (a) J. D. Winkler, V. Sridar, J. Am. Chem. Soc. 1986, 108, 1708; (b) A. L. J. Beckwith, D. H. Roberts, C. H. Schiesser, A. Wallner, Tetrahedron Lett. 1985, 3349; (c) M. Julia, F. Le Goffic, L. Katz, Bull Soc. Chim. Fr. 1964, 1122; (d) A. G. Angoh, D. L. J. Clive, J. Chem. Soc., Chem. Commun. 1985, 980; (e) H. Pak, I. I. Canalda, B. J. Fraser-Reid, J. Org. Chern. 1990, 55, 3009; (F) D. L. Clive, J. Pure Appl. Chem. 1988, 60, 1645. [ 171 K. U. Ingold, J. Lusztyk, J. C. Scaiano, J. Am. Chenz. Soc. 1984, 106, 343. [I81 (a) I. Shibata, T. Suzuki, A. Baba, H. Matsuda, J. Chem. Soc., Chem. Commun. 1988, 882; (b) A. Baba, M. Yasuda, K. Yano, I. Shibata, H. Matsuda, J. Chem. Soc. Perkin Trans. 1 1990, 3205; (c) M. Yasuda, T. Oh-hata, I. Shibata, A. Baba, H. Matsuda, J. Chem. Soc. Perkin Trans. 11993, 859. [19] L. A. Paquette, A. M. Doherty in “Polyquinane Chemistry” in Reactivity and Structure Concepts in Organic Chemistry Vol. 26, (Springer-Verlag), New York, 1987; (b) T. Hudlicky, F. Rulin, T. C. Lovelace, J. W. Reed in Studies in Natural Products Chemistry (Eds. Atta-urRahman), Elsevier, Amsterdam, 1989, Vol. 3, pp. 3-72. [20] (a) A. L. J. Beckwith, Tetrahedron 1981, 37, 3073; (b) A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985, 41, 3925. [211 (a) J. Barluenga, J. M. Martinez-Gallo, C. Najera, M. Yus, Synthesis 1986, 678; (b) R. Gleiter, G. Jahne, G. Muller, M. Nixdorf, H. Irngartinger, Helu. Chim. Acta 1986, 63, 71.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
3.5 Ring Expansions Wei Zhang
3.5.1 Introduction Ring-expansion reactions are important tools in organic syntheses which take advantage of existing ring structures and avoid the unfavorable entropic factors associated with other approaches in the construction of medium and large rings. The utility of these reactions has been demonstrated by the development of various ionic methods over the years [ 11. Recent advances in radical chemistry, which opened broad avenues to five- and six-membered rings by radical cyclizations, also offered attractive routes to standard, medium-sized and even large rings via radical ring expansions [2]. Progress in this area is exemplified by the development of (i) the Dowd-Beckwith ring expansion of ketones via alkoxy radicals, and (ii) ring expansion of various strained systems. This chapter reviews the basic concepts and synthetic applications of these two general methodologies.
3.5.2 /?-Scission of Alkoxy Radicals The Dowd-Beckwith ring expansion utilizes the ‘side-chain incorporation’ method for ketone ring enlargement (Scheme 1). This reaction is believed to go through a two-step sequence: exo-cyclization of initial side chain radical onto the carbonyl group followed by 8-scission of the intermediate alkoxy radical to regenerate the ketone moiety. The fragmentation of the central carbon-carbon bond is facilitated by the Y group which activates the carbonyl and stabilizes the ring-expanded radical. Ring expansions of one-, three- and four-carbon have been achieved but the two-carbon fails because the rate of 4-ex0 cyclization is too slow to compete with the direct reduction of the initial radical. One-carbon ring expansion was first observed by Barton and then by Tadd [3], but its synthetic potential was not fully explored until Dowd and Beckwith’s concurrent work on /?-keto esters (Scheme 2) [4]. Radical precursors, readily prepared by alkylation of 8-keto esters derived from the Dieckmann condensation, undergo
3.5.2 p-Scission of Alkoxy Radicals
235
Scheme 1. Side-chain-incorporated free-radical ring expansion
Bu,SnH (1.1 eq) AlBN (cat)
&&Me
w
PhH, 80 "C
WCooMe n = 0-2: 71-75%
Scheme 2. One-carbon ring expansion of /I-keto esters
Bu3SnH (1.1 eq) AlBN (cat)
&EOMe
PhH, 80 "C
-
&COOMe
[71
X = CHP: 39% X = N H : 84%
Scheme 3. One-carbon ring expansion of benzannulated ketones
+ L COOMe Bu3SnH "2.,
I
\
@+
(1.2 eq)* 0
:rje;OO"
AlBN (cat) TBSO
TBSO
97% (1:l)
Scheme 4. One-carbon ring expansion and subsequent cyclization
ring expansion upon treatment with tributyltin hydride and catalytic amounts of AIBN in refluxing benzene. In many cases, a small amount of direct reduction product is observed as a result of competitive reduction of the initial radical. Straightforward one-carbon ring expansion of P-keto esters has attracted a relatively large amount of attention. The scope of this reaction was quickly extended to expansions of large rings [ 5 ] ,heterocyclic [6] and benzannulated ketone [7]systems (Scheme 3 ) . The development of tandem free-radical reactions offers synthetic chemists the opportunity to combine the one-carbon ring expansion reaction with other radical transformations such as cyclization [8a] and addition [8b] in the construction of ring-expanded bicyclics (Scheme 4).
236
3.5 Ring Expansions
92%
lubiminol
MeOOC
I
\
II
- -f-,-, Bu?SnH (1.2ea) ,k,-..$
EtOOc H
PhMe, 110 "C
H 86 %
manicol
Scheme 5. One-carbon ring expansion in natural product synthesis
One-carbon ring expansion was also found to be useful in the construction of ring skeletons of natural products such as lubiminol [9a], manicol [9b] and fusicoplagin D [9c] (Scheme 5). In addition to one-carbon ring expansion, the Dowd-Beckwith reaction has been successfully applied to three- and four-carbon ring expansions (Scheme 6) [4, 101. Because of the slower cyclization rate associated with a longer side chain, the
-
0
Bu3SnH AlBN (cat) (1.1 eq)
+
Q)m
[4b1
PhH, 80 "C
COOR
R = Me, n = 1, m = 1:
69%
R = Et, n = 1, rn = 2: R = Et, n = 2 , rn = 1: R = Et, n = 2 , m = 2 :
36% 75% 71%
22% 37% 12% 25%
0
COOMe
AlBN (cat) PhH, 80 "C
COOMe
COOMe n=l: n = 2:
14% 21Yo
75% 58%
0 Bu3SnH (cat) SnBu3
AlBN (cat) PhH. 80 "C
I
SnBu3
Scheme 6. Three- and four-carbon ring expansions
89%
3.5.2 p-Scission of Alkoxy Radicals
237
x=o Bu3SnH(1.1 eq) AlBN (cat), hv
62%
*
b R
R = OSiEt,, X = CHz: 51% R = COOEt, X = CHZ: 22% R = H. X = NTs: 29%
Scheme 7. Tandem ring expansion-ring closures
amount of direct reduction product increases in this series. The reaction prefers a low concentration or syringe pump addition of tributyltin hydride for a better yield. Another potential challenge that needs to be taken into consideration is the 1,5-hydrogen atom transfer which, in many cases, interrupts the ring expansion process by relocating the initial radical center to an undesired position [ 1 11. A ring expansion-reclosure reaction sequence has been devised to prepare ring expanded bicyclic molecules (Scheme 7) [ 121. One of the best examples for three-carbon ring expansion is the total synthesis of DL- and (R)-muscone starting from a cyclododecanone derivative [5, 131. A good yield of ring expansion product is obtained by the use of selenide as the radical precursor (Scheme 8). Generation of alkoxy radicals is not restrtricted to carbon-centered radical additions to a carbonyl group. Additions of oxygen- and nitrogen-centered radicals to carbonyl groups have also been used to initiate ring expansions in the synthesis of ring-expanded lactones and lactams (Scheme 9) [ 141. Because of the toxicity and purification problems associated with tributytin hydride reactions, many ring expansions have been attempted under tin-free conditions. These include the use of reagents such as (Me3Si)3SiH [ 15a], Et3B/Oz [15b] and SmI2 [ 1Sc], the photoinduced electronic transfer (PET) process [ 15d], photolysis of thiohydroxamic esters or organocobalt complexes [ 15e], and electroreductions of P-keto esters [ 15f].
SePh
Bu3SnH
COOMe
+ +
t
AlBN (cat) PhH, 80 “C 82%
Scheme 8. Synthesis of (R)-muscone
~ 3 1
(R)-rnuscone
238
3.5 Ring Expansions
rn = 1: 52% rn = 2: 76%
+
Bu3SnH AlBN (cat) PhH, 80 "C
a),, [14b]
COOEt
COOEt
rn = 1: m=2:
68% 92%
23% 5%
Scheme 9. Synthesis of ring-expanded lactones and lactams
The discovery of fused-cyclobutanone ring expansions is another milestone in the development of the Dowd-Beckwith ring expansion [ 161. In this series, release of ring strain drives the ring expansion process. Of the two possible ring opening pathways for the cyclobutyloxy radical, endo-cyclic cyclobutyl bond cleavage to give a ring-expanded radical has always been found to be favorable [ 171. Numerous ring expansions have been explored by taking advantage of cyclobutanones which are readily available from [2+2] cycloaddition of ketenes (Scheme 10) [ 181. Alkoxy radicals for ring expansion can be generated from alcohols by oxidative methods such as hypohalite thermolysis/photolysis [ 19a] and lead tetraacetate oxidation [19b], or peroxide reduction [lsc]. The recent development of the hypervalent organoiodine reagent (diacetoxyiodo)benzene (DIB) provides another way for efficient generation of alkoxy radicals (Scheme 11) [ 19d]. Additional oxidative methods to prepare cyclopropyloxy radicals include reaction of tertiary cyclopropanols or their silyl ether derivatives with various reagents such as manganese(II1) tris( pyridine-2-carboxylate) [Mn(pic)3] [20a], Fe(II1) salts [20b], and vanadyl acetylacetate [ ~ O C ](Scheme 12). The Carbon-oxygen bond fragmentation of a,/?-epoxyalkyl radicals provides another way to generate alkoxy radicals for ring expansions (Scheme 13) [21].
AlBN (cat) PhH, 80 "C
0 m = 1: 80% rn = 2: 60%
Scheme 10. Ring expansion of fused cyclobutanones
3.5.2 p-Scission of Alkoxy Radicals
-
H J 0$
97%
PAo
Pb(OAc), (1.2 eq)
SnBUs
PhH,80"C
* Et
Et
87%
Scheme 11. Ring expansion reactions of tertiary alcohols
HO
Bu3SnH (1.5 eq)
WaI
DMF, 0 "C
Scheme 12. Ring expansion of tertiary cyclopropanol and silyl ether derivative
PhSSPh (0.3 eq) &OTBS
AlBN (0.4 eq), hv PhH, 80 "C
SPh
n = 1: 85%
n Scheme 13. Ring expansion of alkoxy radicals generated from epoxides
= 2:
87%
239
240
3.5 Ring Expansions
3.5.3 Ring Expansion of Strained Systems Small-ring radical opening is a facile process. This process has been incorporated in the 'zero bridge cleavage' of strained bicycles for one- and two-carbon ring expansions (Scheme 14). Ring expansions of cyclopropyloxy and cyclobutyloxy radicals have been discussed in the previous section. This section focuses on cyclopropylcarbinyl, a,&epoxyalkyl and cyclobutylcarbinyl radicals.
n=1,2
Scheme 14. Ring expansion of strained bicycles
The selective cleavage of the endo-carbon bond of fused-cyclopropylcarbinyl radicals to yield one-carbon expanded rings is kinetically preferred. If the fused cyclopropane already exists in the starting material, ring expansion can be achieved by zero bridge cleavage of appropriate radical precursors (Scheme 15) [22]. If a strained bicyclic ring is not present in the radical precursor, cyclization of a carbon radical to form either a cyclopropane [7a, 23a] or a larger ring fused to a cyclopropane [23b] can initiate the subsequent ring expansion (Scheme 16). If ring opening of a fused-cyclopropylcarbinyl radical cleaves the exo-carbon bond instead of the endo-carbon bond as described above, cyclopropane ring expansion can be achieved by reacting the ring-opened radical with an appropriately positioned radical acceptor (Scheme 17) [24]. The ring opening of epoxyalkyl radicals, unlike that of cyclopropanecarbinyl radicals, usually proceeds with cleavage of the exo-cyclic carbon-oxygen bond of the epoxides. However, a substituent group that stabilizes the radical produced by
wc5H11
HO ' 'j
HO
Bu3SnH 3.72 M (neat)
AlBN (cat), 90 "C *
0:
54%
Bu3SnH (2.5 eq) AlBN (cat) PhH, 80 "C
Q N NH
*
Q - a::, Bu3Sn'
NH
Scheme 15. Ring expansions of fused cyclopropanes
56%
241
3.5.3 Ring Expansion of Strained Systems EtOOC
EtOOC 10 h addition
AlBN (cat)
I
I
I
I
PhH. 80 "C
68%
'--
PhH.80"C
OH
\O
91 %
/
+Br
B5Ghnaddition H (1 eq) AlBN (cat) PhMe, 110 "C
Me,Si
M~,s, Me,Si
n = 1: 67% n = 2 : 41%
Scheme 16. Formation and sequential ring expansion of cyclopropylcarbinyl radicals
s Bu,SnH (1.2 eq)
COOMe
AlBN (cat) PhH, 80 "C
*
P
C
O
O
M
e
-
m
C
O
O
M
e
30%
Scheme 17. Two-carbon ring expansion of cyclopropane
r
2,
AlBN (cat) PhH,80"C
n = 1: 62% n = 2: 58%
Scheme 18. Ring expansion of epoxides
cleavage of the endo-cyclic carbon-carbon bond can change the ring opening pathway to offer ring expanded cyclic ethers (Scheme 18) [25]. Fused cyclopropyl ketyls, which undergo ring expansion, can be produced by the reduction of fused cyclopropyl ketones. For example, tin hydride [26a], SmIz [26b],
242
3.5 Ring Expansions
0 H
LJ
BuaSnH (1.6 eq) AlBN (cat) PhH, 80 "C
*
85%
60%
10%
Scheme 19. Ring expansion of cyclopropyl ketones
and the photoinduced electronic transfer (PET) processes [26c] have led to the formation of one-carbon ring-expanded ketones (Scheme 19). One of the important methods in the construction of five-membered rings is [3+2] radical cycloaddition. This reaction is initiated by radical-induced opening of a three-membered ring followed by addition of ethylene to create a new radical and subsequent cyclization onto a double bond (Scheme 20). Addition of the initial ring-opened radical to the double bond can be carried out either inter- or intramolecularly [27]. Cyclobutylcarbinyl and cyclopropylcarbinyl radicals share some common chemical properties. Many ring expansion protocols developed for the three-membered ring systems can be adapted for the four-membered ring systems (Scheme 21) [28], especially in the synthesis of natural products such as guaiane alisomol [28f], pentalenene [28g] and dictamnol [28h]. Fused-four-membered ring starting materials are often available through [2+2] cycloadditions.
OBU
vCooMe COOMe
PhSH (0.4 eq) * 60 "C
COOMe
MeOOC
~7a1
COOMe
MeOOC 77%
Scheme 20. Ring expansion via [3+2] cycloaddition
References
243
80%
P 0
0
0w COOMe
COOMe
PhH, 80 "C hv, 96 h
-
e0 "
Lo
&Me
COOMe
P 0-
COOMe
-0
HO
26%
@
PhH.80"C AlBN Bu3SnH (cat)* LO 'H
HO 92%
H
[28f]
guaiane alisrnol
Scheme 21. Ring expansion of cyclobutylcarbinyl radicals
Br H
Bu3SnH(1.5 eq) AlBN (cat) PhH, 80 "C
n = 1 or 2: 86% Scheme 22. Ring expansion of fused methylenecyclobutanes
Ring expansions of methylenecyclobutanes through a cyclization-fragmentation sequence is similar to previously discussed ring expansion of cyclobutanones (see Scheme 10) [16]. Compared to its ketone counterpart, the alkene system gives higher yields of ring expansion products (Scheme 22) [29].
References [ I ] M. Hesse, Ring Enlargement in Organic Chemistry, VCH, Weinheim, 1991; C. D. Gutsche, D. Redmore, Carbocyclic Ring Expansion Reactions, Academic, New York, 1968. [2] For a review, see: P. Dowd, W. Zhang, Chem. Rev. 1993, 93, 2091; see also L. Yet, Tetrahedron, 1999, 55, 9349.
244
3.5 Ring Expansions
[3] H. Reimann, A. S. Capomaggi, T. Straws, E. P. Oliveto, D. H. R. Barton, J. Am. Chem. Soc. 1961, 83, 4481; M. Barbier, D. H. R. Barton, M. Devys, R. S. Topgi, J. Chem. Soc., Chem. Commun. 1984, 743. M. Okabe, T. Osawa, M. Tada, Tetrahedron Lett. 1981,22, 1899. [4] (a) P. Dowd, S.-C. Choi, J. Am. Chem. Soc. 1987, 109, 3493; (b) P. Dowd, S.-C. Choi, Tetrahedron, 1989,45, 77; (c) A. L. J. Beckwith, D. M. O’Shea, S. Gerba, S. W. Westwood, J. Chem. Soc., Chem. Commun. 1987,666; (d) A. L. J. Beckwith, D. M. O’Shea, S. W. Westwood, J. Am. Chern. Soc. 1988, 110, 2565. [5] P. Dowd, S.-C. Choi, Tetrahedron 1992, 48, 4773. [6] P. Dowd, S.-C. Choi, Tetrahedron 1991, 47, 4847. [7] (a) B. Z. Zheng, P. Dowd, Tetrahedron Lett. 1993, 48, 7709; (b) W. R. Bowman, P. J. Westlake, Tetrahedron 1992, 48, 4027. [8] (a) H. Nemoto, M. Shiraki, N . Yamada, N. Raku, K. Fukumoto, Tetrahedron 1996, 52, 13339; (b) B. Yoo, D. P. Curran, J. H. Kim, S. H. Kim, K. Y. Bull. Korean Chem. Soc. 1997, 18, 793; (c) D. L. Boger, R. J. Mathvink, J. Org. Chem. 1990, 55, 5442. [9] (a) M. T. Crimmins, Z. Wang, L. A. McKerlie, J. Am. Chem. Soc. 1998, 120, 1747; (b) M. G. Banwell, J. M. Cameron, Tetrahedron Lett. 1996, 37, 525; (c) G. Mehta, N. Krishnamurthy, S. R. Karra, J. Am. Chem. SOC. 1991, 113, 5765. [lo] (a) P. Dowd, S.-C. Choi, J. Am. Chem. Soc. 1987, 109, 6548; (b) J. E. Baldwin, R. M. Adlington, J. Robertson, Tetrahedron 1989, 45, 909; (c) J. E. Baldwin, R. M. Adlington, R. Singh, Tetrahedron 1992, 48, 3385. [ 111 C. Wang, X. Gu, M. S. Yu, D. P. Curran, Tetrahedron 1998, 54, 8355. 1121 A. Nishida, H. Takahashi, H. Takeda, N. Tekada, 0. Yonemitsu, J. Am. Chem. Sor. 1990, 112, 902. [13] D. S. Wang, C. H. Zhou, D. Q. Wang, Chin. Chem. Lett. 1992,3,235. [I41 (a) H. Suginome, S. Yamada, Tetrahedron 1987, 43, 3371; (b) S. Kim, G. H. Joe, J. Y. Do, J. Am. Chem. Soc. 1993, 115, 3328. 1151 (a) C. Chatgilialoglu, V. I. Timokhin, M. Ballestri, J. Org. Chem. 1998, 63, 1327; (b) P. Devin, L. Fensterbank, M. Malacria, Tetrahedron Lett. 1999, 40, 551 1; (c) E. Hasegawa, T. Kitazume, K. Suzuki, E. Tosaka, Tetrahedron Lett. 1998, 39, 4059; (d) E. Hasegawa, Y. Tamura, E. Tosaka, J. Chem. Soc., Chem. Commun. 1997, 1895; (e) R. Matovic, Z. Cekovic, Gazz. Chim. Ital. 1997, 127, 483; Y. Murakami, Y. Hisaeda, T. Ohno, Y. Matsuda, Chem. Lett. 1988, 621; T. Inokuchi, M. Tsuji, H. Kawafuchi, S. Torii, J. Org. Chem. 1991, 56, 5945; (f) T. Shono, N. Kise, N. Uematsu, S. Morimoto, E. Okazaki, J. Org. Chem. 1990, 55, 5037. [I61 P. Dowd, W. Zhang, J. Am. Chem. Soc. 1991, 113, 9875; P. Dowd, W. Zhang, J. Org. Chem. 1992, 52, 7163. [17] S. Wilsey, P. Dowd, K. N. Houk, J. Org. Chem. 1999, 64, 8801. 1181 W. Zhang, P. Dowd, Tetrahedron Lett. 1992,33, 3285; W. Zhang, P. Dowd, Tetrahedron 1993, 49, 1965; W. Zhang, Y. Hua, S. J. Geib, G. Hoge, P. Dowd, Tetrahedron 1994, 50, 12579; P. Dowd, W. Zhang, K. Mahmood, Tetrahedron 1995,51, 39; P. Dowd, W. Zhang, S. J. Geib, Tetrahedron 1995, 51, 3435; W. Zhang, P. Dowd, Tetrahedron Lett. 1996, 37, 957; W. Zhang, R. Gorny, P. Dowd, Synth. Commun. 1999,2Y, 2903. [ 191 (a) R. N. Saicic Tetrahedron Lett. 1997, 38, 295, (b) G. H. Posner, K. S. Webb, E. Asirvatham, S.-s. Jew, A. Degl’lnnocenti, J. Am. Chem. Soc. 1988, 110, 4754; (c) C. E. Mowbray, G. Pattenden, Tetrahedron Lett. 1993, 34, 127; (d) A. Boto, C. Betancor, T. Prange, E. Suarez, J. Org. Chem. 1994, 59, 4393. [20] (a) N. Iwasawa, M. Funahashi, S. Hayakawa, T. Ikeno, K. Narasaka, Bull. Chem. Sor. Jpn. 1999, 72, 85; (b) A. J. Highton, T. N. Majid, N. S. Simpkins, Synlett 1999, 237; K. I. BookerMilburn, A. Baraker, W. Brailsford, B. Cox, T. E. Mansley, Tetrahedron 1998,54, 15321; K. I. Booker-Milburn, D. F. Thompson, J. Chem. Soc., Perkin Trans. I 1995, 2315. (c) M. Kirihara, M. Ichinose, S. Takizawa, T. Momose, Chem. Commun. 1998, 1691; 1211 (a) S. Kim, S. Lee Tetrahedron Lett. 1991, 32, 6575; (b) A. Nishida, Y.4. Kakimot, Y. Ogasawara, N. Kawahara, M. Nishida, H. Takayanagi, Tetrahedron 1997, 53, 5519; P. Galatsis, S. D. Millan, T. Faber, J. Org. Chenz. 1993, 58, 1215; W. R. Bowman, B. A. Marples, N. A. Zaidi, Tetrahedron Lett. 1989, 25, 3343; M. Afzal; J. C. Walton, J. Chem. Soc., Perkin Trans. 2 1999, 937.
References
245
[22] (a) F. E. Ziegler, A. K. Petersen, Tetrahedron Lett. 1996, 37, 809; (b) D. P. Curran, W. Liu, Synlett 1999, 117; (C) E. J. Kantorowski, S. W. E. Eisenberg, W. H. Fink, M. Kurth, J. Org. Chem. 1999, 64, 570; P. H. Lee, B. Lee, J. Lee, S. K. Park, Tetrahedron Lett. 1999, 40, 3427; H. Venkatesan, M. M. Greenberg, J. Org. Chem. 1994, 59, 3514. [23] (a) G. Neef, E. Eckle, A. Muller-Fahrnow, Tetruhedron 1993, 49, 833; (b) K. G. Pike, C . Destable, M. Anson, J. D. Kilburn, Tetrahedron Lett. 1998, 39, 5877. [24] R. A. Batey, J. D. Harling, W. B. Motherwell, Tetrahedron 1992, 48, 8031. [25] (a) D. A. Corser, B. A. Marples; R. K. Dart Synlett 1992, 987; (b) J. A. Murphy, C. W. Patterson, Tetrahedron Lett. 1993, 34, 867. [26] (a) B. C. Maiti, S. Lahiri Tetrahedron 1998, 54, 91 11; E. J. Enholm, Z. J. Jia, J. Org. Chem. 1997, 62, 174; (b) P. H. Lee, J. Lee, Tetrahedron Lett. 1998, 3Y, 7889; (c) J. Cossy, S. BouzBouz, Tetrahedron Lett. 1997, 38, 1931. [27] (a) K. Miura, K . Fugami, K. Oshima, K. Utimoto, Tetrahedron Lett. 1988,29, 5135; (b) K. S. Feldman, A. L. Romanelli, R. E. Ruckler, Jr., R. F. MillerJ. Am. Chem. SOC.1988, 110, 3300; K. S. Feldman, H. M. Berven, A. L. Romanelli, J. Org. Chem. 1993, 58, 6851; K. S. Feldman, K. Schildknegt, J. Org. Chem. 1994, 59, 1129; K. S. Feldman, T. E. Fisher Tetrahedron 1989, 45, 2969; C. C . Huval, D. A. Singleton, J. Org. Chem. 1994, 59, 2020, S. Handa, G. Pattenden, W.-S. Li, J. Chem. Soc., Chem. Commun. 1998: 31 1. [28] (a) M. T. Crimmins, C. M. Dudek, A. W.-H. Tetrahedron Lett. 1992, 33, 181; (b) J. Mattdy, A. Banning, E. W. Bischof, A. Heidbreder, J. Runsink, Chem. Ber. 1992, 125, 2119; (c) M. T. Crimmins, S. Huang, L. E. Guise-Zawacki, Tetrahedron Lett. 1996,37, 6519; (d) F. E. Ziegler, Z.4. Zheng, J. Org. Chem. 1990, 55, 1416; (e) G. L. Lange, C. Gottardo, Tetrahedron Lett. 1990, 31, 5985; (f) G. L. Lange, C. Gottardo, Tetrahedron Lett. 1994, 35, 8513; (g) G. L. Lange, C. Gottardo, J. Org. Chem. 1995, 60, 2183; (h) G. L. Lange, A. Merica, M. Chimanikire, Tetrahedron Lett. 1997, 38, 6371; (i) G. L. Lange, A. Merica, Tetruhedron Lett. 1999, 40, 7897. [29] W. Zhang, P. Dowd, Tetrahedron Lett. 1995, 36, 8539.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
3.6 Hydrogen Atom Abstraction Laurence Feray, Nikolai Kuznetsou and Philippe Renaud
3.6.1 Introduction Radical reactions represent a very valuable tool for organic synthesis. For instance, they have been applied for the formation of carbon-carbon bonds under mild conditions. Indeed, many functional groups that are incompatible with ionic processes are tolerated in radical reactions. A second aspect contributing to the development of radical reactions is the possibility to carry out rearrangements that are specific and have no classical counterparts. Among these rearrangements, hydrogen atom abstractions from C-H bonds are particularly attractive for the functionalization of positions considered as unreactive under classical conditions [ 1, 21. In this chapter, we will concentrate on the synthetic application of inter- and intramolecular hydrogen atom abstraction from C-H bonds by heteroatom- and carbon-centered radicals. Because of the abundant literature in this field, we will present a subjective selection of reactions with high synthetic potential. Carbon-hydrogen bond activation mediated by transition metals is described in another part of this book (Chapter 2.2, Volume 2). Photochemical processes involving photoelectron transfers and Norrish/Yang type I1 reactions are discussed elsewhere in this book (Chapter 2.5, Volume 1; Chapter 6.2, Volume 2). Because of space limitation, hydrogen atom abstractions by halogen atoms (radical halogenation) will not be presented in this review with the exception of hydrogen abstraction by complexed chlorine atoms.
3.6.1.1 Factors Controlling Hydrogen Atom Abstraction The efficiency of hydrogen atom abstraction is influenced by many different factors making its rationalization difficult. For instance, thermodynamic, polar, stereoelectronic, and geometric effects all play a role. In the first place, exothennicity of the abstraction step is a precondition. Therefore, knowledge of bond dissociation energies is crucial for planning hydrogen atom abstraction. A few characteristic values are shown in Table 1.
3.6. I Introduction
247
Table 1. Selected bond dissociation energies (BDEs) (from [ 31 unless otherwise indicated) X-H
BDE [ Kcal/mol]
X--H
BDE [Kcal/mol]
CH30-H (CH3)3CO-H CH3NH-H CH3S-H CH3CONH-H CH2=CH-H C6H5-H CF3-H CF3CF2-H CH3-H CH3CH2-H (CH3)2CH-H (CH3)3C-H Cyclohexyl-H Cyclopropyl-H CH2=CHCH2-H
104.4 105.1 103 88 107" -:I08 110.2 106 103.1 105 98 95 92 95.5 106.3 86.6
c6H~cH2-H HCCCH2-H CH30CH2-H Tetrahydrofuran-2-yl-H (CH3)2NCH>-H CH3CO-H NCCH2-H CH3COCH2-H C6H5COOCH2-H C6H5S02CH2-H CF3S02CH2-H C13C-H (CH3)3SiCH*-H HO(CH3)zC-H (PhCO)[N(CH3)2]CH-H (PhCO)(CH,O)CH-H
87.9 90 93 92 84d 86 93 98.3 100.2 99 103' 95.8 99.2 91 72' 8Ic
"From [4]; 'From [5], 'From [6],dFrom [7]
Interestingly, besides experimental values [ 81, progress realized in the calculation of complex systems by the use of density functional theory (DFT) allows to determine, with excellent accuracy, the BDE of almost any system of interest [9, 101. Simple enthalpic considerations show that efficient hydrogen atom transfers are possible when the initial radicals are alkoxyl, aminyl, aryl and vinyl radicals. Alkyl radicals can be used when stabilized radicals are generated during the hydrogen transfer step. Mostly, primary and perfluoroalkyl radicals were successfully used. The regiochemistry of intermolecular hydrogen atom abstraction is often determined by thermochemical factors: all other things being equal, the weakest C-H bond undergoes H-abstraction. However, polar factors also play an important role in the outcome, often reflecting a subtle interplay of polar and thermochemical effects [ 111. For example, reaction of y-butyrolactone with the tert-butoxyl radical is confined to the position adjacent to the ether oxygen (Scheme 1, Eq. 1.1) [12]. This result is in agreement with the thermochemistry and also with the polar effects since the tert-butoxyl radical is electrophilic. On the other hand, reaction with the nucleophilic aminyl-boryl radical proceeds exclusively at the position adjacent to the carbonyl group (Scheme 1 , Eq. 1.2) [13]. Recently, polar effects have been incorporated into a more general theory taking repulsive forces into consideration [ 141. Stereoelectronic effects also have a strong influence on the rate of hydrogen transfer. For example, the cleavage by the tert-butoxyl radical of an axial C-H bond is 14 times faster than one of an equatorial C-H bond (Scheme 1) [15, 161. This is rationalized by interactions between the axial lone pair at oxygen and the bond being broken.
248
3.6 Hydrogen Atom Abstraction
oQ
+
-
t-BuO.
0. (1.1)
0
0
n
Me3N+ BHThx Thx = thexyl = 1,1,2-trimethylpropyl
H
kabst (rel.)
Me
14 : 1
H
transition state stabilized by stereoelectronic effects
Scheme 1. Polar and stereoelectronic effects in hydrogen abstractions
3.6.1.2 Intramolecular Hydrogen Atom Abstraction In intramolecular hydrogen abstraction, geometric factors dominate, and the thermochemical factors usually only determine the feasibility of the transfer but not its regioselectivity [ 171. Efficient 1,4-, 1,5-, 1,6- and 1,7-hydrogen atom transfer (= H T ) have been observed but the 1,5-process is by far the most common reaction (for theoretical treatment of 1,2- to 1J-hydrogen transfers, see [IS]; for 1,4-hydrogen transfer, see [ 191; for competition between 1,5-, 1,6- and 1,7-hydrogen transfer, see [20]). Houk has demonstrated that the preference for 1,5-hydrogen transfer results from more favorable entropy of activation of the six membered transition state and not from the enthalpy of activation [21, 221. The calculated transition state for a 1,Shydrogen atom abstraction in butoxyl radical is depicted in Scheme 2. It resembles a five membered ring having an envelope shape like that of cyclopentane, but with one long bond (2.5 A) between the carbon bearing the hydrogen atom and the oxygen of the alkoxyl radical. The 0-C-H bond is reasonably close to linear (153") and far away from the 109" expected for chair-like transition states resembling a cyclohexane ring. Ah initio calculations have confirmed the structure of this transition state.
Scheme 2. Transition state for a 1,Shydrogen transfer by an alkoxyl radical
3.6.2 Alkoxyl Rudicul
249
3.6.2 Alkoxyl Radical Alkoxyl radicals can be generated via a wide variety of methods from the corresponding alcohols (oxidative processes), by homolytic cleavage of 0-X bonds ( X = halogen, SR, SeR), by decomposition of peroxides and by photolysis or pyrolysis of nitrites. They are particularly powerful for hydrogen atom abstraction relative to any other types of radicals. Because of their electrophilic character, they are extremely potent for removing hydrogen atom at oxygen- and nitrogensubstituted carbon atoms as well as unactivated alkane C-H bonds. For example, at 20 "C, the tert-butoxyl radical abstracts hydrogen from cyclopentane with a rate constant of 3.4 x lo5 M-I S K I and from tert-butyl methyl ether with a rate of 2.4 x 105 M-1 s-1 [15, 23-25].
3.6.2.1 Intermolecular Hydrogen Abstraction tert-Butoxyl radicals have been widely used to initiate radical chain reactions involving a hydrogen abstraction step. Pioneering studies concerning the addition of radicals generated from ethers, acetals, esters, aldehydes and amines have been reviewed by Walling [26] and Abell [27]. Fraser-Reid further developed this reaction by using di-tert-butylhyponitrite (DTBH = t-BuO-N=N-Ot-Bu) as radical initiator [28].This initiator has a lifetime of 29 min at 65 "C and is more convenient than di(tert-buty1)peroxide as a radical initiator. Oxycarbinyl radicals generated from alcohols, acetals and aldehydes add cleanly to enones in intermolecular (Scheme 3,
(3.1) DTBH, CH3CN
'"OEt
77%
DTBH = di(tertbuty1)hyponitrite
benzil, O2
hv
hv
P h q P h 0
ph
'
2
0 phKO,o'
Scheme 3. Intermolecular hydrogen abstractions by alkoxyl radicals
250
3.6 Hydrogen Atom Abstraction
Eq. 3.1) and intramolecular mode. Selective oxidation of ethers to esters by irradiation in the presence of benzil and oxygen was reported by Set0 1291. By this procedure, a tricyclic y-lactone is prepared from the corresponding fused tetrahydrofuran as shown in Scheme 3, Eq. (3.2). The mechanism presumably involves a hydrogen abstraction by an acylperoxyl radical.
3.6.2.2 Intramolecular Hydrogen Abstraction Followed by C-X bond formation (remote functionalization). Remote intramolecular free radical functionalization via hydrogen abstraction from alkoxyl radicals has attracted tremendous interest since the pioneering work of Arigoni [ 301, WallingPadwa 1311, Barton 132, 331 and Heusler [34]. A review by Majetich in 1995 summarizes the results in this field 1351. Lead tetraacetate is an efficient reagent for the generation of radicals from alcohols 136, 371. This reagent was used to convert hainanolidol into harringtonolide (Scheme 4, Eq. 4.1) 1381. Very often, lead tetraacetate is used together with iodine. This procedure proved to be very efficient for tetrahydrofuran derivatives. A typical example is shown in Scheme 4 (Eq. 4.2) 1391. Isolation of intermediate iodohydrins is possible by using short reaction times and limited quantities of the reagents, but yields remain usually modest [40]. A procedure for lactone formation has been developed by using excess Pb(OAc)4/Iz followed by Jones oxidation of the intermediate iodoethers or acetals (Scheme 4, Eq. 4.3). However, in this case also, the yields are typically below 50% [41]. Suarez has demonstrated that (diacetoxyiod0)benzene (= DIB) in the presence of iodine is a convenient reagent for remote functionalization 1421. Over-oxidation to lactols and/or iodoethers does not arise with this reagent and only iodoalcohols, tetrahydrofurans (1,5-hydrogen transfer) or tetrahydropyrans (1,6-hydrogen transfer) are formed. In a typical example, 26-hydroxyfurostane is converted to the corresponding tetrahydropyran in excellent yield via a 1,6-hydrogen atom transfer (Scheme 5 , Eq. 5.1) [42, 431. More recently, Paquette applied this reaction for a key step in the total synthesis of (+)-epoxydictymene (Scheme 5 , Eq. 5.2) [44]. Further applications for the synthesis of dispiroketals [45] and anomeric spironucleosides were also reported [46]. The regioselectivity of the hydrogen transfer has been studied by Burke during the synthesis of nagilactone F 1471. Mercuric acetate-iodine is a useful alternative to the DIB-iodine system. For instance, it has been used for a cascade reaction starting from a steroidal hemiacetal such as depicted in Scheme 6 (Eq. 6.1) [48]. Under an oxygen atmosphere, the initial alkoxyl radical fragments to give a secondary alkyl radical that reacts with oxygen to give a peroxyl and finally an alkoxyl radical. Abstraction of a hydrogen atom (1,5-hydrogen transfer) affords a bicyclic furan possessing the same A and A’ rings as limonin. The complete regioselectivity of the 1$hydrogen transfer is remarkable. The use of mercuric oxide-iodine has also been reported [49] and used as a key step in an avermectin A,, synthesis 1501 (Eq. 6.2). Recently, Bols has developed a procedure for selective deprotection of benzyl ethers and formation of acetals based on hypoiodite chemistry [51]. The use of N iodosuccinimide (NIS) proved to be superior to DIB-iodine in many cases and
25 1
3.6.2 Alkoxyl Radical
HO
Pb(OAc)d,
12,
hv
(4.2)
t
67%
1) Pb(OAc)4, 12, hv
(4.3)
t
2) Jones
0
0
45%
-(ACO)~P~.
(Ac0)~Pb-o
&
bJ
1,5-HT_
09.
+ (Ac0)sPb
0
o
u Pb(0Ac)3 - Pb(OAc)2 - AcOH
X
_Jones
9
-
I
) further ox.
X = I or OAc
O
3
lodohydrin
Scheme 4. Lead tetraacetate-mediated remote functionalization
A
Me HO'*'' Qe '"'H
hv, DIB, 50°C l2
.
H
OAc
95%
-
Me"'' MeQ
(5.2) H
OAc
Scheme 5. (Diacetoxyiod0)benzene-iodine-mediated formation of pyran and furan derivatives
252
3.6 Hydrogen Atom Abstruction CBH17
Scheme 6. Mercuric acetate/oxide-iodine-promoted reactions cascade involving regioselective 1,5and 1,6-hydrogen transfers
fl OH OBn OBn
Yh
Ph
-
NIS (2.5 eq), hv 64y0
OBn OBn
OBn OBn
Scheme 7. Benzilidene formation with an acyclic ribitol derivative by use of NIS
the reaction was applied to cyclic and acyclic sugar derivatives. A typical example involving formation of a benzilidene acetal from an acyclic ribitol derivative is depicted in Scheme 7. Pasto has reported the generation of alkoxyl radical by the photo-induced homolytic dissociation of alkyl 4-nitrobenzenesulfenate [ 521. Cekovic has examined the photolytically induced decomposition of benzenesulfenates in the presence of hexabutylditin [ 531. This reaction allows selective introduction of a phenylthio group at the &position via a 1,5-hydrogen transfer. The overall reaction is an 0 to C transfer of a phenylthio group. This reaction has been applied for the synthesis of acetyl scopine starting from (N-ethoxycarbony1)nortropine benzenesulfenate (Scheme 8) [54]. The sulfenate esters are stable compounds and are easily prepared by reaction of alcohols with PhSCl/Et3N. Followed by C-C bond formation. Cekovic reported sequential reactions involving generation of alkoxyl radicals from hypochlorites and nitrite esters followed by
3.6.2 Alkoxyl Radical EtOOq
EtOOq
253
EtOOq
-
(1,5-HT)
p
h
s
q
45% OH acetylscopine precursor
"SPh
Scheme 8. Synthesis of acetyl scopine via free-radical phenylthio group transfer
53%
dr 55:45
0,; -
(2S,5R)-2-methyl-5-hexanolide U
1,5-HT + u H co -.I'J.H ',,,
ox.
'%,
lactone
Scheme 9. Lactone synthesis by 8-carbonylation of alcohols under oxidative conditions
'SPh
CH2=CHCOOMe
Et02C
+ BusSnH, hv 33%
Scheme 10. Remote 8-alkylation of alcohols
1,5-hydrogen transfer and 5-ex0 or 6-ex0 cyclizations [55]. Because of oxidation processes competing with the formation of the carbon-carbon bond, yields were not high. More recently, Ryu has described an efficient carbon-carbon bond-forming reaction under oxidative conditions. This process allows the 8-carbonylation of saturated alcohols and is based on a 1,5-hydrogen transfer from alkoxyl radicals. This procedure was successfully applied for the synthesis of carpenter bee pheromone from optically pure (R)-(-)-2-hexanol (Scheme 9) [56]. Several procedures for remote alkylation at the &carbon of alcohols have been reported. For instance, Cekovic has shown that photolysis of alkyl nitrites and/or benzenesulfenates in the presence of Bu3SnH and olefinic radical traps such as acrylate esters afforded the alkylated product in moderate yields (Scheme 10) [57, 581. Intramolecular carbon-carbon bond formation is more efficient as demonstrated by Kim and Rawal, who reported the radical-induced fragmentation of epoxides followed by hydrogen abstraction and cyclization (Scheme 1 1). Kim's approach
254
3.6 Hydrogen Atom Abstraction
(1,5-HT) (5-exo-trig)
(11.1)
h
67%
OH
cat. ( B U ~ S ~hv) ~ ,
(11.2)
75%
OH
Scheme 11. Radical-induced epoxide fragmentation followed by H-abstraction and 5-ex0 cyclization
(Eq. l l . l ) , starting with an epoxy ketone, only requires a catalytic amount of tin hydride since the tin radical is regenerated at the end of the chain process by a fragmentation [59].Rawal’s procedure (Eq. 11.2) is based on an iodine atom transfer [60].
3.6.3 Aminyl Radical: Hofmann-Loffler-Freytag Reaction The Hofmann-Loffler-Freytag reaction involves a 1,5-hydrogen transfer to a nitrogen atom. This reaction has been reviewed [61-631, and a recent update is available [35] (see also Chapter 5.1, Volume 2). Its mechanism has been investigated [64], and the formation of an aminium radical has been postulated (Scheme 12). The strong
1) t-BuOCI, 90% (12.1) 2) hv, H2SO4 3) NaOH
}
H
dr 1:l
Me02C
&
HN
1) Br2, NaOH 2) hv, H2S04 96%
Scheme 12. The classical Hofmann-Loffler-Freytag reaction
(12.2)
255
3.6.3 Aminyl Radical: Hofmann-Lofler-Frey fag Reaction
Z = NO2, PO(OR)*, CN
& u
Y
AcO
“
Pb(OAc)4, 12, hv*
(13.2)
h17
100%
AcO
H .LHZ .. .-
H
Z = PO(OBn)2
Scheme 13. Suarez modification of the Hofmann-Loffler-Freytag reaction
acidic conditions required by the Hofmann-Loffler-Freytag reaction considerably limit its synthetic utility. Nevertheless, some interesting transformations have been accomplished by this procedure and some typical examples are shown in Scheme 12. For instance, L-leucine is converted into cis- and trans-4-methyl-~-prolinein good yield (Eq. 12.1) [65]. Rassat applied the Hofmann-Loffler-Freytag reaction for the key step of the synthesis of 1,3,5,7-tetramethyl-2,6-diazaadamantane-2,6-dioxide (Eq. 12.2) [66]. Suarez developed neutral conditions for the Hofmann-Loffler-Freytag reaction using a similar approach to the hypoiodite reaction described in Section 3.6.2.2. In this procedure, N-iodoamides are generated in situ by reaction of the corresponding amine derivative with iodine in the presence of lead tetraacetate or DIB as oxidizing agent. Nitroamines (Z = NOz) [67], phosphoramidates [Z= PO(OR)2 and PO(OEt)*] [68] and cyanamides (Z= CN) [69] have been used (Scheme 13, Eq. 13.1). A typical example is presented in Eq. (13.2). 1) Bu3SnD (0.3 eq), AlBN 2) TsCI, Py Bu3Sn + A , , ,
*
N3
Bu3Sn
“SnBu,
92%
JN -3
Bu3Sn
1 ) Bu3SnH,AlBN 2) TsCI, Py 53%
(14.2)
Scheme 14. Alkyl azides as radical precursors for the Hofinann-Liilffer-Freytag reaction
256
3.6 Hydrogen Atom Abstraction
Recently, Kim has reported a modified Hofmann-Loffler-Freytag reaction under reducing conditions [70].Treatment of alkyl azides with B q S n H afforded N tributylstannyl radicals. These radicals proved to be more reactive than ordinary aminyl radicals towards hydrogen atom abstraction presumably because of their higher nucleophilicity. Two examples are shown in Scheme 14. In the first one (Eq. 14.l), the 1,5-hydrogen abstraction is followed by fragmentation of the tributylstannyl radical. The second reaction (Eq. 14.2) combines a 1,5-hydrogen abstraction followed by a cyclization-fragmentation process leading to a furan derivative. These two reactions require only a catalytic amount of tin hydride.
3.6.4 Thiyl Radicals Thiols are excellent reducing agents as illustrated by their low bond dissociation energy (see Table 1). Consequently, thiyl radicals are usually not suitable for hydrogen atom abstraction, except when weak C-H bonds are involved in the process. Roberts used the concept of polarity-reversal catalysis [711 to achieve highly efficient radical-chain intermolecular addition and cyclization of unsaturated aldehydes [72], acetals and thioacetals (Scheme 15) [73].For instance, the unsaturated acetal depicted in Eq. (15.1) gave the cyclopentane derivative in excellent yield when treated with dilauroyl peroxide (DLP) as initiator and 5 mol% of tri-tert-butoxysilanethiol as polarity transfer catalyst. The electrophilic thiyl radical efficiently abstracts the acetal H-atom because of matching polarity. After 5-exo-trig cyclization, the alkyl radical is reduced by the thiol, thus regenerating the initial thiyl radical. In the absence of thiol, no trace of cyclized product is isolated, presumably because of the lack of regioselectivity of the hydrogen atom abstraction when a nucleophilic alkyl radical is involved.
\v?
DLP (10 rnol%), 80°C (f43~0)~SiSH (5 mol%)
Me02C C02Me
(15.1)
97%
C02Me
Scheme 15. Radical-chain cyclization of unsaturated acetals using polarity reversal catalysis
3.6.6 Alkyl Radicals
257
3.6.5 Complexed Chlorine Radicals Hydrogen atom abstractions by halogen atom (radical halogenation) have been reviewed elsewhere [74-761. In this review, we will concentrate on hydrogen abstraction by complexed chlorine atom. This approach, pioneered by Breslow [77], proved to be highly efficient for regioselective remote functionalization of steroids such as cholestan-3a-01 and linear alkanols. The strategy of this process is to complex the chlorine radical to an iodoaryl template attached by an ester bond to the hydroxy function of the substrate. The chain reaction is propagated by dichloro( phenyl)-A3iodane (PhIC12). The hydrogen abstraction by the complexed chlorine atom is highly regioselective and efficient as demonstrated with cholestan-3a-01 (Scheme 16) [78, 791. When the reaction is run in the presence of tetrabromomethane or thiocyanogen [ (SCN)z],the corresponding bromide or thiocyanate is isolated.
. radical trap
radical trap
(SCN)p
Yield X CI >go% 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 <4 : 96 87 : 13 88 : 12
Scheme 39. Translocation of alkenyl radicals followed by 5-exo-trig cyclization
3.6.9 Alkenyl Radicals
271
A systematic study for the system depicted in Eq. (39.1) has demonstrated that rate constants k1.5 for 1,5-hydrogen transfers are between 5 x 10’ sP1 (X,Y = Me,H) and > 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.
References [ I ] A. L. J. Beckwith, K. U. Ingold In Rearrangements in the Ground and ,!%cited States; P. de Mayo, Ed.; Academic: New York, 1980; Vol. I ; pp 161. [2] G. A. Russell In Free Radicals; J. K. Kochi, Ed.; Wiley-Interscience: New York, 1973; Vol. 1; pp 275. [3] Handbook Oj'Chemistry and Physics; CRC: Boca Raton, 1986. [4] F. G. Bordwell, J. A. Harrelson, X. Zhang J. Org. Chem 1991, 56, 4448-4450. 151 F. G. Bordwell, D. L. Singer, A. V. SatishJ. Am. Chem. Soc. 1993, 115, 9790-9795. [6] F. G. Bordwell, J. A. Harrelson Can. J. Chem. 1990, 68, 1714-1718. [7] F. G. Bordwell. T.-Y. Lynch J. Am. Chem. Soc. 1989, 111, 6558-7562. [8] NIST Standard Reference Database (http://webhook.nist.gov/chemi.stry/). [9] M. D. Bartberger, W. R. Dolbier, J. Lusztyk, K. U. Ingold Tetrahedron 1997, 53, 9857-9880. [lo] A. B. Shtarev, F. Tian, W. R. Dolbier, B. E. Smart J. Am. Chem. Soc. 1999, 121, 7335-7341. [ 1I ] J. M. Tedder Angew. Chem. 1982, 94,433-442. [I21 A. L. J. Beckwith, A. A. Zavitsas J. Am. Chem. SOC.1995, 117, 607-614.
276 [ 131 [I41 [ 151 [I61 [I71
3.6 Hydrogen Atom Abstraction
P. Kaushal, P. L. H. Mok, B. P. Roberts J. Chem. Soc. Perkin Trans. 2 1990, 1663-1670. A. A. Zavitsas, C. Chatgilialoglu J. Am. Chem. Soc. 1995, 117, 10645-10654. V. Malatesta, K. U. Ingold J. Am. Chem. Soc. 1981, 103, 609-614. A. L. J. Beckwith, C. J. EastonJ. Am. Chem. Soc. 1981, 103, 615-619. D. Denenmark, P. Hoffmann, T. Winkler, A. Waldner, A. De Mesmaeker Synlett 1991,621624. (181 B. Viskolcz, G. Lendvay, T. Kortvelyesi, L. Seres J. Am. Chem. Soc. 1996, 118, 3006-3009. [19] M. Gulea, J. M. Lopez-Romero, L. Fensterbank, M. Malacria Org. Lett. 2000, 2, 2591-2594. [20] D. Denenmark, T. Winkler, A. Waldner, A. De Mesmeaker Tetrahedron Lett. 1992, 33, 3613-3616. [21] A. E. Dorigo, K. N. Houk J. Am. Chem. Soc. 1987, 10Y,2195-2197. [22] A. E. Dorigo, M. A. McCarrick, R. J. Loncharich, K. N. Houk J. Am. Chem. Soc. 1990, 112, 7508-7514. [23] S. K. Wong J. Am. Chem. Soc. 1979, 101, 1235-1239. [24] W. K. Busfield, I. D. Grice, I. D. Jenkins J. Chem. Soc. Perkin Trans. 2 1994, 1079-1086. [25] V. Malatesta, J. C. Scaiano J. Org. Cheni. 1982, 47, 1455-1459. [26] C. Walling, E. S . Huyser Org. Reactions 1963, 13, 91-149. [27] P. I. Abell In Free Radicals; J. K. Kochi, Ed.; Wiley-Interscience: New York, 1973; Vol. 2; PP 63. [28] B. V. Rao, J. Chan, N. Moskowitz, B. Fraser-Reid Bull. Soc. Chim. Fr. 1993, 130, 428-432. [29] H. Seto, K. Yoshida, S. Yoshida, T. Shimizu, H. Seki, M. Hoshino Tetrahedron Lett. 1996, 37,4179-4182. [30] G. Cainelli, M. L. Mihailovic, D. Arigoni, 0. Jeger Helo. Chim. Acta 1959, 1124-1 127. 1311 C. Walling, A. Padwa J. Am. Chem. Soc. 1961,83, 2207-2208. [32] D. H. R. Barton, J. M. Beaton, L. E. Geller, M. M. Pechet J. Am. Chem. Soc. 1961, 83, 4076-4083. [33] D. H. R. Barton Pure Appl. Chem. 1960, 16, 1-15. [34] K. Heusler, J. Kalvoda Angew. Chem. 1964, 12, 518-531. [3S] G. Majetich Tetruhedron 1995, 51, 7095-7129. [36] M. L. Mihailovic, Z. Cekovic Synthesis 1970, 5, 209-224. [37] M. P. Bertrand, J. M. Surzur, M. Boyer. M. L. Mihailovic Tetrahedron 1979, 35, 1365-1372. [38] B. Frey, A. P. Wells, D. H. Rogers, L. N. ManderJ. Am. Chem. Soc. 1998, 120, 1914-1915. [39] P. Ceccherelli, M. Curini, M. C. Marcotullio J. Org. Chem. 1986, 51, 1505-1509. [40] P. Bogan, R. E. Gall Aust. J. Chem. 1979, 32, 2323-2326. [41] P. M. Burden, H. T. A. Cheung, T. H. Ai, T. R. Watson J. Chem. Soc. Perkin Trans. I 1983, 2669-2674. [42] J. I. Concepcion, C. G. Francisco, R. Hernindez, J. A. Salazar, E. Suirez Tetrahedron Lett. 1984,25, 1953-1956. [43] C. G. Francisco, R. Freire, R. Hernandez, M. C. Medina, E. Suirez Tetrahedron Lett. 1983, 24. 4621 -4624. [44] L.’A. Paquette, L. Q. Sun, D. Friedrich, P. B. Savage J. Am. Chem. Soc. 1997, I I Y , 84388450. [45] R. L. Dorta, A. Martin, J. A. Salazar, E. Suarez, T. Prange J. Org. Chem. 1998, 63, 22512261. [46] C. Chatgilialoglu, T. Gimisis, G. P. Spada Chem. Eur. J. 1999, 5, 2866-2876. [47] S. D. Burke, M. E. Kort, S. M. S. Strickland, H. M. Organ, L. A. Silks Tetrahedron Lett. 1994,35, 1503-1506. [48] A. Boto, R. Freire, R. Hernandez, E. Suirez, M. S. Rodriguez J. Ory. Chem. 1997, 62, 2975298 1. [49] 1. T. Kay, E. G. Williams Tetrahedron Lett. 1983, 24, 5915-5918. [50] S. J. Danishefsky, D. M. Armistead, F. E. Wincott, H. G. Selnick, R. Hungate J. Am. Chern. Soc. 1989, 111, 2967-2980. [Sl] J. Madsen, C. Viuf, M. Bols Chem. Eur. J. 2000, 6, 1140-1146. [52] D. J. Pasto, F. Cottard Tetrahedron Lett. 1994, 35, 4303-4306. [53] G. Petrovic, R. N . Saicic, Z. Cekovic Tetrahedron Lett. 1997, 38. 7107-71 10. [54] G. Petrovic, R. N. Saicic, Z. Cekovic Sjmlett 1999, 635-637.
References
277
[55] Z. Cekovic, D. Ilijev Tetrahedron Lett. 1988, 29, 1441-1444. [56] S. Tsunoi, I. Ryu, T. Okuda, M. Tanaka, M. Komatsu, N. SonodaJ. Am. Chem. Soc. 1998, 120, 8692-8701. [57] G. Petrovic, Z. Cekovic Tetrahedron Lett. 1997, 38, 627-630. [58] G. Petrovic, Z. Cekovic Tetrahedron 1999, 55, 1377-1390. [59] S. Kim, J.-S. K o h J . Chem. Soc., Chem. Commun. 1992, 1377-1378. [60] V. H. Rawal, S. Iwasa Tetrahedron Lett. 1992, 33, 468774690, [61] M. E. Wolff Chem. Rev. 1963, 63, 55-64. 1621 R. S. Neale Synthesis 1971, 1-15. [63] P. Mackiewicz, R. Furstoss Tetrahedron 1978, 34, 3241-3260. [64] E. J. Corey, W. R. Hertler J. Am. Chem. Soc. 1960, 82, 1657-1668. [65] S. L. Titouani, J.-P. Lavergne, P. Viallefont, R. Jacquier Tetrahedron 1980, 36, 2961-2965. [66] R. Chiarelli, A. Rassat Bull. SOC.Chim. Fr. 1993, 130, 299-303. 1671 P. De Armas, C. G. Francisco, R. Hernandez, J. A. Salazar, E. Suarez J. Chem. Soc. Perkin Trans. I 1988, 3255-3265. [68] C. Betancor, J. I. Conceptibn, R. Hernandez, J. A. Salazar, E. SuarezJ. Urg. Chem. 1983, 48, 4430-4432. [69] R. Carrau, R. Hernandez, E. Suarez, C. Betancor J. Chem. Soc. Perkin Trans I 1987, 937T 943. [70] S. Kim, K. M. Yeon, K. S. Yoon Tetrahedron Lett. 1997, 38, 3919-3922. [71] B. P. Roberts Chem. Soc. Rev. 1999,28, 25-35. [72] H.-S. Dang, B. P. Roberts J. Chem. Soc. Perkin Trans. 1 1998, 67-75. [73] H.-S. Dang, B. P. Roberts Tetrahedron Lett. 1999, 40, 8929-8933. [74] C. Walling Free Radicals in Solution; Wiley: New York, 1957; Vol. ch. 8. [75] J. M. Tedder, J. C. Walton in Free Radical Chemistry; G. H. Williams, Ed.; Heyden: Philadelphia, 1980; Vol. 6. [76] L. Somsak, R. J. Ferrier Ado, Carbohydr. Chem. Biochem. 1991, 49, 37-92. [77] R. Breslow Chemtracts Org. Chem. 1988, I , 333-348. [78] D. Wiedenfeld, R. Breslow J. Am. Chem. Soc. 1991, 113, 8977-8978. [79] D. Wiedenfeld J. Chem. Soc. Perkin Trans. I 1997, 339-347. [SO] B. Quiclet-Sire, S. Z. Zard Tetrahedron Lett. 1998, 39, 9435-9438. [81] P. A. Baguley, G. Binmore, A. Milne, J. C. Walton Chem. Commun. 1996, 2199-2200. [82] A. Studer, S. Amrein Angew?. Chem. Int. Ed. 2000, 39. [83] T. Yoshimitsu, M. Tsunoda, H. Nagaoka Chem. Commun. 1999, 1745-1746. [84] P. C. Van Dort, P. L. Fuchs J. Ory. Chem. 1997, 62, 7142-7147. [85] L. Fensterbank, A. L. Dhimane, S. H. Wu, E. Lacote, S. Bogen, M. Malacria Tetrahedron 1996, 52, 11405-1 1420. [86] A. Gross, L. Fensterbank, S. Bogen, R. Thouvenot, M. Malacria Tetrahedron 1997, 53, 13797- 1 38 10. [87] B. Delouvrie, E. Lacote, L. Fensterbank, M. Malacria Tetrahedron Lett. 1999, 40: 35653568. [88] M. Masnyk Tetrahedron Lett. 1997, 38, 879-882. [89] L. Boiteau, J. Boivin, B. Quicletsire, J. B. Saunier, S. Z. Zard Tetrahedron 1998, 54, 20872098. [90] A. De Mesmaeker, A. Waldner, P. Hoffmann, T. Winkler Synlett 1994, 330-332. 1911 A. De Mesmaeker, A. Waldner, P. Hoffmann, P. Hug, T. Winkler Synlett 1992, 285-290. [92j D. Crich, S. Sun, J. Brunckova J. Ory. Chem. 1996, 61, 605-615. 1931 J. Brunckova, D. Crich, Q. W. Yao Tetrahedron Lett. 1994, 35, 6619-6622. (941 J. Brunckova, D. Crich Tetrahedron 1995, 51, 11945-1 1952. [95] T. Sugimura, S. Goto, K. Koguro, T. Futagawa, S. Misaki, Y. Morimoto, N. Yasuoka, A. Tai Tetrrihedron Lett. 1993, 34, 505-508. [96] T. Sugimura, A. Tai, K. Koguro Tetrahedron 1994, 50, 11647-1 1658. [97] J. Boivin, E. Da Silva, G. Ourisson, S. Z. Zard Tetrahedron Lett. 1990, 31, 2501-2504. [98] J. D. Winkler, V. Sridar, L. Rubo, J. P. Hey, N. Haddad J. Urg. Chem. 1989, 54, 3004-3006. 1991 J. D. Winkler, B. C. Hong Tetrahedron Lett. 1995, 36, 683-686. [ 1001 W. R. Dolbier Chem. Reo. 1996, 96, 1557 -1584.
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
<
-
OH 61
60
62
1
n-Bu3SnH PhH, A o & A'BN R
& o
2 steps
X = H (+)-1 -deoxylycorine (66) X = OH ent-lycorine
\
I /
n-Bu3SnH
i
H N 0 65 (50%)
\ : ( I 12a H
o
1 2 ~
/ 63 R = Bn (53%)
2 steps
S
Scheme 7. Schultz synthesis of (+)-l-deoxylycorine [41]
tion substrate 62. The highlight of the synthesis of 62 was a highly diastereoselective reductive alkylation of 60 to afford 61 in 96% yield. Free-radical cyclization of 62 provided 63 in 53% yield with complete control of stereochemistry at C12b and C I ~ ~ . Schultz suggested that attack of the initially formed aryl radical on the p-face of the enamide is likely due to a combination of steric factors and better orbital overlap between the reacting centers than observed in a-face attack. The cyclization event is followed by reduction of the resulting a-acylamino radical from the p-face, resulting in formation of the thermodynamically more stable product at C I ~Conversion ~ . of 63 to N-hydroxy-2-thiopyridone ester 64 was followed by a Barton-type radical induced epoxide fragmentation to give 65 in 50% yield. The synthesis was completed in two steps. It is likely that this route could be modified to afford lycoranoids that are more richly oxygenated in the C-ring. This synthesis is truly elegant in that it incorporates new methodology into a very direct route to alkaloid targets to which efficient routes have long been sought. Other groups have reported free-radical approaches to lycoranoids less richly decorated than 66. For example, Rigby has reported a short synthesis of a-lycorane (67) via an aryl radical-enamide cyclization that constructs the C I ~ ~ - C I bond ~ I , [42]. Padwa focused on the same bond construction via an aryl radical-dihydroindole cyclization in his synthesis of anhydrolycorin-7-one (68) [43]. Both Zard [44] and Cossy [45] have reported syntheses of y-lycorane (69) that involve initial construction of the N - C I ~bond ~ via cyclization of nitrogen-centered radicals. Both ap-
4.1.4 N-Heterocycle Construction via Radical Cyclizations
29 1
proaches also involve construction of the C12a-CI2b bond via radical cyclizations. Zard constructs this bond via an alkyl radical-arene cyclization used in tandem with N-C1zc bond construction. Cossy constructs this bond by addition of an aryl radical to a CI2b-cI double bond.
69
67 a-lycorane
anhydrolycorin-7-one
y-lycorane
Danishefsky and Panek have reported a synthesis of an erythrina alkaloid that revolves around a cyclization-fragmentation sequence to establish the B-ring while Thus, p-amino selenide 70 retaining useful functionality in the A-ring (Eq. 21) [46]. (10 steps from N-Boc-3,4-dimethyoxy-2-phenethylamine) was treated with TBTH to give enol acetate 71 in 65% yield. A simple oxidation sequence completed the synthesis of 3-demethoxyerythratidinone. The chemistry shown in Eq. (21) uses a p-amino selenide as a radical precursor. ,!I-Amido radical cyclizations in which P-amido selenides served as the radical precursors have also been reported. One example has been described within the context of an approach to the ABC-ring system of manzamine A [47].Another appears in an efficient synthesis of indolizidine 72, a component of castoreum derived from the Canadian beaver scent gland (Eq. 22) [48].It is notable that allylic strain plays a role in the latter free-radical cyclization, as the fury1 residue undoubtedly occupies an axial site on the incipient tetrahydropiperidone ring.
-
n-Bu3SnH
2 steps
Meo% Me0
64%
0 3-demethoxyerythratidinone
OAc 71 (65%)
70
-
Ph3SnH 83%
Me0
op - p2 3 steps
0
0
Kuehne has reported remarkably efficient syntheses of several vinca alkaloids via /I-amino radical cyclizations in which the radicals were derived from selenides
292
4. I Radical Cyclizations in Alkaloid Synthesis
SePh toluene, A H
C02Me
@ 2:1
\
SePh
-*L
\
H
C02Me
7[ 1. x / B r 2. PhSeCH2CH0
H
C02Me
r
& y \
74 (70%)
76 (56%)
B
\
H
H
C02Me
C02Me
75 X = SePh (77-80%)
n-Bu3SnH
(*)-y-vincadifformine (68%)
2:1 ,%./
H
I
C02Me
(*)-vincadifforrnine
Scheme 8. Kuehne synthesis of vinca alkaloids [49]
(Scheme 8) [49]. Treatment of indoloazepine 73 with 2-phenylselenenylbutanalgave 74 as a 2:l mixture of stereoisomers. Alkylation of the perhydroindole nitrogen, followed by treatment of the resulting 75 with TBTH, gave vincadifformine in excellent yield. The final step in this synthesis involves a free-radical cyclizationreduction sequence, and illustrates that tin-mediated selenide bond homolysis competes favorably with radical generation from a vinylic bromide. Azepine 73 was also converted to 76, and a similar 6-endo free radical cyclization afforded a 2:l mixture of $-vincadifformine and its Czo-epimer in 68% yield. /3-Amino radicals derived from /3-amino sulfides have been used in syntheses of several Amaryllidaceae alkaloids including (*)-montanine, ( f )-coccinine and ( f)-pancracine [50]. Another efficient synthesis of 3-demethoxyerythratidinone has been reported by the Zard group (Eq. 23) [51].Trichloracetamide 77 was prepared in 3 steps from the monoketal of cyclohexan-1,4-dione. Treatment of 77 with excess nickel in acetic acid gave 78 in 49%)yield. An N-acyliminium ion cyclization converted 78 to 79, and the synthesis was then completed via a 2-step sequence. This nickel-mediated cyclization-oxidation chemistry has also been used in model studies directed toward (+)-mesembrine [52]. TBTH-mediated cyclization of a dichloroacetamide has been used to prepare the amaryllidaceae alkaloid (+)-mesembranol (Eq. 24) [ 53].4-Benyzyloxycyclohexanone was converted to cyclization substrate 80 in 6 steps. Free-radical cyclization of 80 gave 81 in 51% yield and two additional steps were required to reach mesembranol. A variation of this route provided the structurally related alkaloid (*)-elwesine. Strategically related syntheses of (-)-mesembrine, (+)-sceletium A-4, (+)tortuosamine and (+)-N-fonnyltortuasamine have also been reported [54]. These syntheses involve free-radical cyclization methodology introduced by Stork [ 551 and post-cyclization introduction of nitrogen.
4.1.4 N-Heterocycle Construction via Radical Cyclizations
J‘N ‘ ~CCI~
77
293
M~O-
NaOAc i-PrOH
78 (49%)
s
U
3-demethoxyerythratidinone
BnO”’
HO”‘ Me
80
H he mesembranol
81 (51%)
The theme of enamides as radical acceptors continues with the Zard synthesis of (&)-matrine outlined in Scheme 9 [56]. This brilliant synthesis begins with the coupling of xanthate 82 (1 equivalent) with N-allylamide 83 (3 equivalents), mediated by a small amount of lauroyl peroxide. This reaction provided a 30% yield of 84 along with a 3:l mixture of 85 and 86, respectively, in 18% yield. Treatment of the mixture of 85 and 86 with lauroyl peroxide in the presence of isopropyl alcohol afforded a mixture of 87 and 88 in 65% yield. Identical treatment of 83 also gave 87 and 88 as a 3:l mixture in 89% yield. Stereoisomer 87 was then converted to (&)matrine in high yield via a 4-step sequence. In this synthesis, the conversion of 82 + 83 to 85 + 86 involves an intermolecular free-radical xanthate-transfer addition, followed by two radical-enamide cyclization reactions. The stereochemical partitioning between 85 and 86 occurs in the first cyclization which establishes C5-C6 stereochemistry. The rest of the stereochemistry is a natural outgrowth of this 3: 1 partitioning. Two other syntheses that involve enamides as radical acceptors are shown in Eqs. (25) and (26). Clive has reported syntheses of the ACE inhibitors A-58365 [57] and A-58365B [58]. The latter synthesis involved preparation of enamide 89 via a short reaction sequence, followed by a triphenyltin hydride-initiated addition-
60MeIn;t? 60Me60Me FN.~
0 H be (-)-rnesernbrine
N’ \
I k
Me
(+)-sceletiurn A-4
Me
N’ \
R = H (+)-tortuosarnine R = CHO (+)-N-forrnyltortuosarnine
294
4. I Radical Cyclizations in Alkaloid Synthesis MeOZC
CO2Me
O O
X ~ N ~ c o p ' B u lauroyl peroxide
+
*
o
benzene
0 lauroylperoxide i-PrOH
a5 + a6 (18%; 3:i)
C
4J a2
84 X = SC(S)OEt (30%) a7 + 88 (89%;3:1)
86 X = SC(S)OEt
lauroyl
P E ~aa x~= H (65%) C +
Copt-BU
& &4 steps
EtOAS
83
7
0
(+)-matrine
lauroyl peroxide I-PrOH
M :e
COptBu
x =sc(s)oa C a5 a7 x = H (65%)
Scheme 9. Zard synthesis of (?)-matrine [56]
cyclization reaction to give 90 (Eq. 25). Protodestannylation of 90 gave 91 which was converted to the target structure in 3 steps. Ikeda has reported syntheses of (+)tetrahydropalmatine (Eq. 26) [59], (i)-saulatine [59], (*)-chilenine [60] and (?)lennoxamine [ 601 via radical cyclizations in which an amidoketene-S,S-acetal serves as a radical acceptor [59]. The key step in the synthesis of (f)-tetrahydropalmatine was the cyclization of 92 [from (PhS)zCHCHO, 2,3-dimethyoxybenzylamineand 3,4-dimethyoxyphenylacetylchloride] to give 93. It is notable that enamides related to 92, but lacking the gem-disulfide, fail to cyclize - an illustration of the effect of olefin substitution pattern on cyclization rate.
111
90 X=SnPha 91 X = H (62%)
A-58365B
toluene, A ACN
(26) OMe
OMe 92
OMe
93 (67%)
OMe
(+)-tetrahydropalmitine
4.1.4 N-Heterocycle Construction viu Radical Cyclizations
295
A convergent approach to the corynanthe-type alkaloid geissoschizine is shown in Eq. (27) [61].Vinyl iodide 95 was assembled in four steps from tryptamine, (Z)-1bromo-2-iodo-2-butene, and diester 94. Free-radical cyclization of 95 gave E-olefin 96 in 33%)yield along with its Z-isomer (17%) and interesting by-product 97 (32%). Geissoschizine was prepared from 96 in two steps. Whereas the free-radical cyclization step of this synthesis is problematic from the standpoint of yield, it has some interesting features. The stereochemical course of the cyclization to 96 at C3 and C15 is most likely a consequence of minimization of allylic strain in a cyclization transition state wherein the C3 substituent occupies an equatorial site on the tetrahydro-P-carboline. The formation of both olefin geometrical isomers illustrates the general principle that vinylic radicals undergo isomerization faster than cyclization. In fact, it is surprising that the E-isomer predominates, albeit only by a margin of 2: 1, in this cyclization. Finally, the formation of 97 illustrates that the C Z - C ~bonds of indoles will behave as radical acceptors. One might have expected the rate of addition of the radical derived from 95 to the alkylidene malonate to be far greater than the rate of addition to the indole, yet considerable amounts of 97 is formed. This may be a result of the C3 substituent preferring an axial site on the P-carboline because of allylic strain, and perhaps the nitrogen substituent also preferring an axial site for similar reasons. The Ziegler group has described a creative approach to mitomycin derivatives and the related alkaloid FR-900482 that involves use of indoles as radical acceptors (Eq. 28) [62]. The key step involves cyclization of aziridinyl bromide 98 to 99 which was carried on to (+)-desmethoxymitomycin A. This reaction surely illustrates the unusual bond constructions that can be accomplished using free-radical chemistry. Interesting approaches to other indole alkaloid substructures have been reported as illustrated in Eqs. (29) [63] and (30) [64]. The former was developed in an approach to lysergic acid while the later is a model study for the synthesis of aspidosperma alkaloids. Neither of these interesting approaches has been brought to fruition. A synthesis of carbazomycin that involves an aryl radical cyclization for construction of the C3-C3a bond of an indole has also been described [65]. This section concludes with syntheses of pumilliotoxin 251D [66] (a frog toxin) and isooxyskytanthine [67] reported by the Cossy group and described in Eqs. (31) and (32). The pumilliotoxin 251D synthesis began with the preparation of cyclization substrate 100 in 7 steps from L-proline. Free-radical cyclization of 100 gave 101 in 40% yield along with 35% of the compound resulting from reduction prior to cyclization. Mercuric acetate-mediated hydration of the double bond and three subsequent steps completed the synthesis. The synthesis of isooxyskytanthine began Irradiawith preparation of 102 in two steps from 4-methyl-cyclohexan-1,3-dione. tion of an acetonitrile solution of 102 in the presence of triethylamine gave 103 in 46% yield. This cyclization presumably involves addition of a ketyl-like radical to the alkyne. The synthesis was completed in a straightforward manner. Similar methodology was also used to prepare (+)-acthidine, a component of an ant defense secretion that has been reported to attract cats.
296
4. I Radical Cyclizations in Alkaloid Synthesis
yj, n-Bu3SnH
toluene, Et3B rt
Boc
I
Me02C
\ 19
\
C02Me Me
95
Me02C
X Me
96 R = Boc X = C02Me (33%) geissoschizine R = H X = CHO
steps
(27)
+
*
Me
+ A19,20 isomer (17%)
C02Me M e o A C 0 2 M e 94
Me
Meow 0
Br 2.mBu3SnH
M~
OMe
N-Boc
N-H
99 (55%)
98
(+)-desmethoxymitomycinA
Boc MeO&H q;H
H 0 2 C pN,Me
n-Bu3SnH,AlBN
UiJ
toluene, A 74%
1
Ac
AC
lysergic acid H
QJ;5 & &/ 1. (Me3Si)3SiH AIBN. 60 "C*
S02Me
QC02H I
2. H20 83%
Me02S
-+ , 7 steps
0&l3'
H
H
H H aspidospermine
4 steps HJ
~
n-~u3~n_~ AIBN PhH,A
(30)
(31)
0 Me
101 (40%) + 35% reduction
100
L-proline
-& -
f@ CH3CN Et3N
p,,,qN-Me Me
0 102
hv
NhMe 2steps
Me
0
103 (46%)
@N.Me Me
(k)-isooxyskytanthine
pumilliotoxin 251D
@N Me (f)-actinidine
(32)
4.1.5 Oxime Ethers as Radical Acceptors
297
4.1.5 Oxime Ethers as Radical Acceptors Free-radical cyclizations in which oxime ethers behave as free-radical acceptors were first noted in the 1980s [68], and a good review of the field has been published [69]. This methodology has seen use in the field of alkaloid synthesis, and the aforementioned review nicely presents many of these accomplishments. This chapter will be restricted to studies directed toward what the author considers to be targets of reasonable structural complexity. Keck has reported a short, enantioselective synthesis of lycoricidine as outlined in Scheme 10 [70]. The synthesis began with the acetonide of D-gulonolactone (104). This material was converted in 6 steps to oxime ether 105. Irradiation of 105 with thiophenol in toluene gave a 90% yield of 106, resulting from addition of a thiophenoxy radical to the alkyne and cyclization of the resulting vinyl radical onto the oxime ether. It is notable that tri-n-butylstannyl radicals failed to mediate this addition-cyclization sequence. The synthesis of lycoricidine was completed from 106 in two steps. Keck also reported that the enantiomer of lycoricidine could be prepared in a similar manner starting from D-lyxose [71], and also described a modification of this route that provided (+)-narciclasine [70]. The Keck group used a slightly different approach in a synthesis of (+)-7deoxypancratistatin (Scheme 11) [72]. Once again 104 served as the starting material. A 3-step sequence provided 107, and an additional 6 steps afforded hydrazone-oxime ether 108. Treatment of this substrate with triphenyltin hydride gave tandem-cyclization product 110 in 78% yield. The first cyclization involves powerful methodology introduced by Kim in which a free radical adds to a hydraOH
104
OH
105
106 (90%)
1. Srn12,THF 2. CF&OzH
OH
$
0
,,,.OH ' "'OH
OH PLyxose
-
OH
?#:: o \
NH
OH 0 (+)-narciclasine
Scheme 10. Keck synthesis of lycoricidine [70]
NH
o \ 0 lycoricidine
298
4.I Radical Cyclizations in Alkaloid Synthesis
p:< - a--r"
OH
e
OTBS
2.Y
o \
NH
\
0 L O
0 (+)-pancratistatin
NHOBn
OTBS
NOBn
\
0 L O
110 (78%)
109
Scheme 11. Keck synthesis of (+)-pancratistatin [72]
zone, followed by a series of fragmentations that afford styrene, nitrogen and a new free radical [73]. In this specific case, this results in the conversion of 108 to 109, which then cyclizes to afford 110. The synthesis of (+)-7-deoxypancratistatin was completed in 4 steps from 110. A tandem free-radical cyclization involving an oxime ether radical acceptor played a key role in the development of the Parker group synthesis of (+)-morphine (Eq. 33) [74]. In model studies, treatment of 111 with TBTH gave a mixture of Cg isomers 112 in combined 71% yield. Although this specific cyclization was eventually abandoned in favor of other tactics, this tandem radical cyclization strategy eventually afforded an efficient route to morphine (Scheme 12) [75]. Thus, alcohol 113 (prepared in 7 steps from m-methoxy-P-phenethylamine) and phenol 114 were coupled to provide 115. Free-radical cyclization of 115 gave 116 in 35% yield via a cyclization-cyclization-fragmentationsequence. Reduction of sulfonamide 116 with lithium in ammonia provided 117 in a process that appears to involve cyclization of a nitrogen-centered radical. A Swern oxidation then provided dihydrocodeinone, which had previously been converted to morphine.
HO.
A
n-Bu3SnH AlBN
140°C-
o:,,$y,, 9
"'NHOMe HO"
111
112 (40%)
+ Cg-isorner (30%)
morphine
4.1.6 Concluding Remarks Me,
,Ts
-
299
NMeTs
2 steps
+
H o d TBSO 113
h p s +:M ;
HO
Br 114
115
1
117 (85%)
Dihydrocodeinone(83%)
n-Bu3SnH AlBN 135 "C
116 (35%)
Scheme 12. Parker synthesis of morphine [74]
4.1.6 Concluding Remarks This chapter has attempted to present a thorough overview of alkaloid syntheses in which free-radical cyclizations have played a pivotal role. It is not meant to be a comprehensive review, but focusses on syntheses in which nitrogen plays a clear role in the cyclization process, either as an attenuator of radical reactivity (Sections 4.1.2 and 4.1.3), a tether (Section 4.1.4), or a radical acceptor (Section 4.1.5). Several other notable alkaloids syntheses have been reported in which carbocyclizations play the pivotal role and introduction of nitrogen is secondary, for example Sha's syntheses of (-)-dendrobine [76] and (+)-paniculatine [77], and Clive's synthesis of (2)-fredericamycin [78]. Syntheses in which nitrogen-centered radicals play a critical role are also known, such as the Zard synthesis of (-)-dendrobine [79]. My apologies to these authors for not elaborating on their fine contributions, to authors who have nicely used intermolecular radical addition reactions in alkaloid synthesis, and to others whose contributions may have escaped my attention. Me?
(-)-dendrobine
(+)-paniculatine
(+)-fredericarnycin
300
4. I Radical Cyclizations in Alkaloid Synthesis
Finally, it is my hope that this chapter illustrates that attempts to use free-radical cyclization reactions in alkaloid synthesis have led to the development of interesting chemistry and the pursuit of some creative and, sometimes, very direct approaches to complex natural products.
Acknowledgement I dedicate this chapter to the memory of Arthur G. Schultz. I thank my students for their many contributions and the National Institutes of Health and National Science Foundation for financial support of our research in the area of free-radical chemistry.
References [ l ] D. J. Hart, Y.-M. Tsai, J. Org. Chem. 1982, 47, 4403. [2] D. A. Burnett, J.-K. Choi, D. J. Hart, Y.-M. Tsai, J. Am. Chem. Soc. 1984, 106, 8201. [3] D. J. Hart, Y.-M. Tsai, J. Am. Chem. Soc. 1982, 104, 1430. [4] D. J. Hart, Science 1984, 223, 883. [ 5 ] E. I. Heiba, R. M. Dessau, J. Am. Chem. Soc. 1967, 89, 3772. [6] M. D. Bachi, C. Hoornaert, Tetrahedron Lett. 1981, 22, 2693. [7] D. J. Hart, Y.-M. Tsai, J. Am. Chem. Soc. 1984, 106, 8209. [8] J. M. Dener, D. J. Hart, Tetruhedron 1988, 44, 7031. [9] J.-K. Choi, D. J. Hart, Tetrahedron 1985, 41, 3959. [lo] a) S. Kano, Y . Yuasa, K. Asami, S. Shibuya, Chem. Lett. 1986, 735. b) S. Kano, Y. Yuasa, S. Shibuya, Heterocycles 1988, 27, 253. [I I] P. Renaud, L. Giraud, Synthesis 1996, 913. [12] D. L. J. Clive, V. S. C. Yeh, Tetrahedron Lett. 1998, 39, 4789. [I31 E. J. Corey, M. M. Mehrotra, Tetrahedron Lett. 1988, 29, 57. [I41 W.-J. Koot, R. van Ginkel. M. Kranenburg. H. Hiemstra, S. Louwrier, M. J. Moolenaar, W. N. Speckamp, Tetrahedron Lett. 1991, 32, 401. [I51 J. M. Dener, D. J. Hart, S. Ramesh J. Ory. Chem. 1988, 53, 6022. [I61 a) D. Kuzmich, W. C. Wu, C.-C. Ha, C . S . Lee, S. Ramesh, S. Atarashi, J.-K. Choi, D. J. Hart, J. Am. Chem. SOC.1994, 116, 6943. b) S. Atarashi, J.-K. Choi, D.-C. Ha, D. J. Hart, D. Kuzmich, C . 4 . Lee, S. Ramesh, S. C. Wu, J. Am. Chem. Soc. 1997, 119, 6226. [17] a) 2. Sheikh, R. Steel, A. S. Tasker, A. P. Johnson, J. Cliem. Soc., Chem. Commun. 1994, 763. b) J. K . Dutton, R. W. Steel, A. S. Tasker, V. Popsavin, A. P. Johnson, J. Chem. Soc., Chem. Commun. 1994, 165. [IS] T. Fukuyama, G. Gang, J. Am. Chem. Soc. 1996, 118, 7426. [I91 A. Madin, C. J. O’Donnell, T. Oh, D. W. Old, L. E. Overman, M. J. Sharp, Angew. Chem., Int. Ed. Engl. 1999, 38, 2934. [20] N. J. Newcombe, F. Ya, R. J . Vijn, H. Hiemstra, W. N. Speckamp, J. Chem. Soc., Chem. Commun. 1994, 161. [21] K. Jones, J. Wilkinson, J. Chem. Soc., Cheni. Commun. 1992, 1167. [22] G. Stork, R. Mah, Heterocycles 1989, 28, 723.
References
30 1
[23] F.-T. Chiu, J. W. Ullrich, P. S. Mariano, J. Org. Chem. 1984, 49, 228. [24] G. Dai-Ho, P. S. Mariano, J. Org. Chem. 1987, 52, 704. [25] Y. S. Jung, W. H. Swartz, W. Xu, P. S. Mariano, N. J. Green, A. G. Schultz, J. Org. Chem. 1992,57, 6037. (261 Y. S. Jung, P. S. Mariano, Tetrahedron Lett. 1993, 34, 461 1. 1271 S. E. Hoegy, P. S. Mariano, Tetrahedron Lett. 1994, 35, 8319. [28] a) D. P. Curran, H. Liu, J. Am. Chem. Soc. 1992, 114, 5863. b) D. P. Curran, H. Liu, H. Josien, S.-B. KO, Tetrahedron 52, 11385. [29] D. P. Curran, S.-B. KO, H. Josien, Angew. Chem. Int. Ed. Engl. 1995, 34, 2683. [30] H. Josien, D. P. Curran, Tetruhedron 1997, 53, 8881. [31] S. Kobayashi, G. Peng, T. Fukuyama, Tetrahedron Lett. 1999, 40, 1519. [32] Y. Kogayashi, T. Fukuyama, J. Heterocyclic Chem. 1998, 35, 1043. [33] M. T. Reding, T. Fukuyama, Org. Lett. 1999, I , 973. [34] R. J. Sundberg, R. J. Cherney, J. Org. Chem. 1990, 55, 6028. [3S] M. D. Bachi, A. Melman, Pure Appl. Chem. 1998, 70, 259. [36] a) T. V. Rajanbabu, Acc. Chem. Rex 1991, 24, 139. b) D. J. Hart, K. Kanai, J. Am. Chem. Soc. 1983, 105, 1255. c) P. M. Esch, H. Hiemstra, R. F. de Boer, W. N. Speckamp, Tetrahedron 1992, 48, 4659. [37] J. E. Baldwin, M. G. Moloney, A. F. Parsons, Tetrahedron 1990, 46, 7263. 1381 J. E. Baldwin, C.-S. Li, J. Chem. Soc., Chem. Commun. 1987, 166. [39] J. E. Baldwin, C.-S. Li, J. Chem. Soc., Chem. Commun. 1988, 261. [40] J. Cossy, M. Cases, D. G. Pardo, Synlett 1998, 507. [41] A. G. Schultz, M. A. Holoboski, M. S. Smyth, J. Am. Chem. Soc. 1993, 115, 7904. [42] J. H. Rigby, M. E. Mateo, Tetrahedron 1996, 52, 10569. [43] A. Padwa, M. Dimitroff, A. G. Waterson, T. Wu, J. Org. Chem. 1998, 63, 3986. [44] X. Hoang-Cong, B. Quiclet-Sire, S. Z. Zard, Tetrahedron Lett. 1999, 41, 2125. [4S] J. Cossy, L. Tresnard, D. G. Pardo, Tetrahedron Lett. 1999, 40, 1125. [46] S. J. Danishefsky, J. S. Panek J. Am. Chem. Soc. 1987, 109, 917. [47] D. J. Hart, J. McKinney, Tetrahedron Lett. 1989, 30, 261 1. [48] D. L. J. Clive, R. J. Bergstra, J. Org. Chem. 1991, 56, 4976. 1491 M. E. Kuehne, T. Wang, P. J. Seaton, J. Org. Chem. 1996, 61, 6001. [50] M. lshizaki, K. Kurihara, E. Tanazawa, 0. Hoshino, J. Chem. Soc., Perkin Trans. 1 1993, 101. [51] J . Cassayre, B. Quiclet-Sire, J.-B. Saunier, S. Z. Zard, Tetrahedron Lett. 1998, 39, 8995. [52] J. Cassayre, B. Quiclet-Sire, J.-B. Saunier, S. Z. Zard, Tetrahedron 1998, 54, 1029. (53) H. Ishibashi, T. S. So, K. Okochi, T. Sato, N. Nakamura, H. Nakatani, M. Ikeda, J. Org. Chem. 1991, 56, 95. [54] 0. Yamada, K. Ogasawara, Tetrahedron Lett. 1998, 39, 7747. [ 5 5 ] G. Stork, R. Mook Jr., J. Am. Chem. Soc. 1983, 105, 3720. (561 Boiteau, J. Boivin, A. Liard, B. Quiclet-Sire, S. Z. Zard, Angew. Chem. Int. Ed. Engl. 1998,37, 1128. [57] D. L. J. Clive, D. M. Coltart, Tetrahedron Lett. 1998, 39, 2519. [58] D. L. J. Clive, Y. Zhou, D. Pires de Lima, J. Chem. Soc., Chem. Commun. 1996, 1463. [59] H. Ishibashi, H. Kawanami, H. Nakagawa, M. Ikeda, J. Chem. Soc., Perkin Trans 1 1997, 2291. 1601 a) H. Ishibashi, H. Kawanami, M. Ikeda, J. Chem. Soc., Perkin Trans. 1 1997, 817. b) H. Ishibashi, H. Kawanami, H. Iriyama, M. Ikeda, Tetruhedron Lett. 1995, 36, 6733. [61] H. Takayama, F. Watanabe, M. Kitajima, N. Aimi, Tetrahedron Lett. 1997, 38, 5307. [62] a) F. E. Ziegler, M. Y . Berlin, Tetrahedron Lett. 1998, 39, 2455. (b) F. E. Ziegler, M. Belema, J. Org. Chem. 1997, 62, 1083. [63] (a) Y. Ozlu, D. E. Cladingboel, P. J. Parsons, Synlett 1993, 357. b) Y. Ozlu, D. E. Cladingboel, P. J. Parsons, Tetrahedron 1994, 50, 2183. [64] M. Kizil, B. Patro, 0. Callaghan, J. A. Murphy. M. B. Hursthouse, D. Hibbs, J. Org. Chem. 1999,64, 7856. [6S] D. L. J. Clive, N. Etkin, T. Joseph, J. W. Lown, J. Org. Chem. 1993, 58, 2442. (661 J. Cossy, M. Cases, D. G. Pardo, Bull. Chim. Soc. Fr. 1997, 141. [67] J. Cossy, D. Belotti, C. Leblanc, J. Org. Chem. 1993, 58, 2351.
302
4.1 Radical Cyclizations in Alkaloid Synthesis
(681 a) E. J. Corey, S. G. Pyne, Tetrahedron Lett. 1983,24, 2821. b) D. J. Hart, F. L. Seely, J. Am. Chem. Soc. 1988, 110, 1631. c) P. A. Bartlett, K. L. McLaren, P. C. Ting, J. Am. Chem. Soc. 1988, 110, 1633. [69] A. B. Fallis, I. M. Brinza, Tetrahedron 1997, 53, 175443. [70] G. E. Keck, T. T. Wager, J. F. D. Rodriquez, J. Am. Chem. SOC.1999, 121, 5176. [71] G. E. Keck, T. T. Wager, J. Org. Chem. 1996, 61, 8366. [72] G. E. Keck, T. T. Wager, S. F. McHardy, J. Org. Chem. 1998, 63, 9164. 1991, 113, 9882. [73] S. Kim, I. S. Kee, S. Lee, J. Am. Chem. SOC. [74] a) K. A. Parker, D. M. Spero, K. C. Inman, Tetrahedron Lett. 1986,27, 2833. b) K. A. Parker, D. M . Spero, J. Van Epp, J. Org. Chem. 1988, 53, 4628. [75] K. A. Parker, D. Fokas, J. Am. Chem. Soc. 1992, 114, 9688. [76] C.-K. Sha, R.-T. Chiu, C.-F. Yang, N.-T. Yao, W.-H. Tseng, F.-L. Liao, S.-L. Wang, J. Am. Chem. SOC. 1997, 119, 4130. [77] C.-K. Sha, F.-K. Lee, C.-J. Chang, J. Am. Chem. Soc. 1999, 121, 9875. [78] D. L. J. Clive, Y. Tao, A. Khodabocus, Y.-J. Wu, A. G. Angoh, S. M. Bennett, C. N. Boddy, L. Bordeleau, D. Kellner, G. Kleiner, D. S. Middleton, C. J. Nichols, S. R. Richardson, P. G. Vernon, J. Am. Chem. Soc. 1994, 116, 11275. [79] J. Cassayre, S. Z. Zard, J. Am. Chem. Soc. 1999, 121, 6072.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
4.2 Synthesis of Oxacyclic Natural Products Eun Lee
4.2.1 Introduction A large number of oxacyclic compounds are accessible via radical cyclization reactions involving oxygen-tethered substrates. Substitution of oxygen for C-3 of 5hexenyl radicals is known to accelerate cyclization [ 11, and cyclization reactions of p-oxy carbon radicals of the type A and B serve well for preparation of cyclic ethers (Scheme 1). Allylic and propargylic ether substrates are easily prepared and cyclization reactions show enhanced regioselectivity. Another type of cyclic etherforming reactions involves a-oxy carbon radicals of the type C, for which consideration of electronic modification is deemed necessary. The type D radical cyclization reactions feature vinylic ether substrates with unique electronic and conformational constraints effecting useful stereochemical control. Many examples of cyclic acetal-forming reactions employ radicals of the type E and F, generated from allylic acetals of high accessibility. The type G propargylic and the type H homoallylic acetal radical reactions are also encountered frequently. For preparation of lactones, the type I radicals play the most important role. Cyclization reactions of these (alkoxycarbony1)alkyl radicals exhibit interesting regioselectivity stemming from conformational constraints. Acrylate moieties serve as intramolecular radical acceptors in lactone-forming reactions, and the type J radicals may be used in macrolide synthesis. Alkoxycarbonyl radicals of the type K are also useful in lactone synthesis. In addition, many cyclic ethers and acetals may serve as intermediates for the eventual preparation of lactonic natural products. Carbon-nitrogen multiple bonds serve as intramolecular radical acceptors for oxacycle synthesis. Many oxacyclic natural products are synthesized via carbocycleforming radical reactions of oxacyclic substrates. Oxygen-centered radicals play an important role in oxacycle synthesis, which frequently involves initial hydrogen abstraction and subsequent displacement reactions. Many different kinds of intermolecular radical reactions are also of considerable practical value in the synthesis of a plethora of oxacyclic natural products.
304
4.2 Synthesis of Oxacyclic Natural Products
K
J
I
Scheme 1. Radical cyclization reactions for oxacycle preparation
4.2.2 Ether-Tethered Radical Cyclizations 4.2.2.1 Allylic Ether Substrates Reaction of the bromohydrin 1 under the standard radical generating conditions gave the 5-exo-trig cyclization product 2, which was identified as dihydrosesamin [2] (Scheme 2). Stereochemical features in the major product 2 may be explained by consideration of the standard Beckwith-Houk model [ 3 ] . The intermediate 1 was prepared from NBS-promoted dimerization of the corresponding cinnamyl alcohol, for which stereochemical assignment is irrelevant. Similar strategies were employed for the synthesis of marmelo oxides [4]. An elegant modification involves the synthesis of (+)-samin (5) by Wirth [ 5 ] . In this synthesis (Scheme 3), the selenium compound 3 was prepared from the corresponding cinnamyl ether, a chiral sele-
cat. Bu3SnH AlBN
t
Benzene (0.02 M) Reflux, 10 h 80 Yo
Scheme 2. Synthesis of dihydrosesamin
WJ CD''>' 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, ,<..,
OH 7 (-)-TalarornycinA
Scheme 4. Total synthesis of talaromycin A
306
4.2 Synthesis of Oxacyclic Natural Products 0
0
8 1) 2.0 eq. Bu3SnH Toluene(0.001 M), 0 OC, 2 h 0.1 eq. Et3B (15 min Intervals) 2) 25 eq. KF, MeOH 60%
~
HO-
H
g-/ ~'H x 1-0
HO
OH
n
U
R=
0
hL(CH2)&H(CH3)2 10 (+)-Tunicamycin V
(Epimeric product: 8 %)
Scheme 5. Total synthesis of tunicamycin V
cat. AlBN
OAc 11
OAc 12
Scheme 6. Synthesis of the hexahydrobenzofuran subunit of avermectins
Meon Me
: C : ~ T S
HO 13
Bu3SnH Me0 AlBN Benzene (0.035 M) 13OoC,35h (Sealed tube) 35 Yo
/
HO 14
Scheme 7. Morphine synthesis via aryl radical cyclization
15 Morphine
4.2.2 Ether-Tethered Radical Cyclizations
307
4.2.2.2 Propargylic Ether Substrates Propargylic ethers are frequently used as intramolecular radical acceptors. In the synthesis of (-)-avenaciolide (18) [ 161, the D-glucose-derived propargyl ether 16 underwent efficient radical cyclization to provide the intermediate 17 (Scheme 8). Synthesis of paulownin (21) was accomplished starting from the propargyl ether 19, which was prepared from the corresponding cinnamate ester [ 171 (Scheme 9). Further examples include (-)-sporothriolide [ 181, samin [ 191, methylenolactocin [20], and frullanolide [21]. Paeonilactone B (24) synthesis is interesting as it involves SmIz-mediated cascade radical cyclizations of a methylenecyclopropane derivative 22 [22] (Scheme 10). Silicon-tethered radical cyclization is also useful, as highlighted by Malacria’s synthesis of epi-illudol (27) [23]. The (bromomethy1)dimethylsilyl ether of the major isomer of the cyclic alcohol 25 underwent 5-exo-dig/4-(n-exo)exo-trig/6-exo-trig tandem radical cyclizations affording the tricyclic intermediate Bu3SnH Oe’ MeS2C0
0
/ / 16
cat, A ~ B N* Benzene Reflux, 6 h 80 %
n-c8H178:Me
---*
0
17
18 (-)-Avenaciolide
Scheme 8. Synthesis of avenaciolide
Bu3SnH cat. AlBN 0 19
Benzene (0.02 M) Reflux, 4 h 82 %
21 Paulownin
20
Scheme 9. Total synthesis of paulownin
2.2 HMPA, eq. Sm12 f-BuOH
+H
____
% H
t
dp, 22
THF, 0 OC (Slow addition) 63 % 23 (10:1 Favored)
Scheme 10. Synthesis of paeonilactone B
0 24 Paeonilactone B
308
4.2 Synthesis of Oxacyclic Natural Products 1) BrCH2SiMe2CI DMAP, Et 3N, DCM 2) Bu3SnH, AlBN Benzene, Reflux *
*
3) H202, KHC03 KF, MeOH-THF 47 Yo
OTBS
OH
OTBS
25 (3:lMixture)
27 epi-llludol
26
Scheme 11. Total synthesis of epi-illudol
26 after Tamao oxidation (Scheme 1 1). (Phenylethyny1)dimethylsilylether moieties were used in the stereospecific synthesis of C-glycosides via intramolecular radical cyclization reactions by Stork [ 241. The hexahydrobenzofuran subunit of avermectins was synthesized from a propargylic ether precursor containing a bromopropenyl ether unit [25].
4.2.2.3 Homoallylic Ether Substrates In the cyclization reactions of homoallylic ethers and higher homologs, alkoxymethyl radicals play a prominent role [26]. Substrates like 28 supply more useful carboncentered radicals enjoying captodative stabilization, and trans-2,3-disubstituted tetrahydropyrans were prepared stereoselectively with judicious modification of the double bond in the substrate [27] (Scheme 12). The same radical species from the substrate 30 was reported to give the oxocane 31 via the xanthate transfer 8-end0 cyclization, from which lauthisan (32) was obtained [28] (Scheme 13).
SiPh2f-Bu
Y O"&~-B~ S P h
1.14 eq. Bu3SnH 0.3 ea. AlBN Benzene (0.02 M)
(Slow Reflux, addition) 27 h *
SiPh2t-Bu
Qi02t-B~ 29
82 Yo
28
Scheme 12. Synthesis of unti-2,3-disubstituted tetrahydropyrans 0.1 eq. ( ~ - B U O ) ~ Ph-t-Bu (0.1 M) 150°C, 1.5 h * C O W
36%
30
31 (56:44)
Scheme 13. Synthesis of lauthisan
32 Lauthisan
4.2.2 Ether-Tethered Radical Cyclizations
309
AIBN Benzene *
33
(Slow addition) 62 Yo
H 34
Scheme 14. Rotenoid synthesis via aryl radical cyclization
An efficient 6-ex0 cyclization was observed for the aryl radical generated from the iodide 33 to yield the core structure 34 of rotenoids [29] (Scheme 14).
4.2.2.4 Vinylic Ether Substrates An early example of vinyl ether radical acceptors is found in curvulol (38) and albidin (39) synthesis from the precursor 35 [30] (Scheme 15). Araki reported radical cyclization reactions of the P-alkoxyacrylates obtained from carbohydrates [31]. Results from reactions of the P-alkoxyacrylates 40 and 42 derived from simple secondary alcohols are more interesting, as Lee found that the cis-2,5disubstituted tetrahydrofuran 41 and the cis-2,6-disubstituted tetrahydropyran 43 were obtained stereoselectively [32] (Scheme 16). Hydrolysis of 43 afforded (cis-6methyltetrahydropyran-2-y1)acetic acid, which is a component of civet. This cis selectivity was maintained in the reactions of substrates with extra substituents in forming C-furanosides [ 3 3 ] . (2R, 3S)-3-Phenylcholestan-2-01was found to be a moderately effective chiral auxiliary in these reactions [34]. In Lee's synthesis of 3Z-dactomelyne (48) [ 351, the trichloromethyl-homologated precursor 44 from D-tartrate was converted into 45 and the pivotal bicyclic intermediate 47 was obtained stereoselectively from the dibromo substrate 46 (Scheme 17). Synthesis of (-)-trans-kumausyne (51) was accomplished via the P-alkoxyacrylate 49 obtained from D-xylose [36] (Scheme 18), and a formal synthesis of (-)-kumausallene (55)
Me0
Me0
38 Curvulol k
c j $0cA
39 Albidin
2.0 0.02eq. eq.Bu3SnH AlBN *
Me0
35
Benzene (0.01 M) Reflux, 30 min
. c Me0
36 61 /o'
Scheme 15. Synthesis of curvulol and albidin
o
h
37 26 %
o
3 10
4.2 Synthesis o j Oxacyclic Natural Products 1.2 eq. Bu3SnH 0.25 eq. AlBN
P
~
C
0
2
E
t
o I+CO".
Benzene (0.03 M) Reflux, 6 h
H
(Syringe pump, 5 h)
40 n=l 42 n=2
41 98 % 43 96 %
Scheme 16. Stereoselective radical cyclization of P-alkoxyacrylates
1.1 eq. (cHex)&H 0.2 eq. AIBN Benzene (0.02 M) +
; ; T . P h Me02C+o
I
Reflux
H
(Syringe pump, 10 h) 67 /o'
44
,-,,4, 0
46
Br
Br
H
Me02C
1.3 eq. Bu3SnH 0.2 eq. AlBN Benzene (0.02 M) TBDPSO
CI
45
(Monochloride: p 17 O h , a 11 %)
-
C02Me
Reflux (Syringe pump, 5 h) 75 Yo
"'Br
47 t
Scheme 17. Total synthesis of dactomelyne
AcO,
Br 51 (-)-trans-Kumausyne
4 1.4 eq. Bu3SnH 0.1 Benzene eq. AIBN (0.02 M)
MeO$
Meoe Reflux, L 4c h o * 2Et.,C02Et
H
49
(Syringe pump, 3 h) 86 %
Scheme 18. Total synthesis of trans-kumausyne
50
4.2.2 Ether-Tethered Radical Cyclizations
311
55 (-)-Kumausallene
I
9 H
M e 0 2 C ~ ~ +C02Me s e p h PhSe
Me02C’””
2.5 eq. Bu3SnH 0.25 eq. AlBN Benzene (0.02 M)
,.
53
*
Reflux, 5 h (Syringe pump, 4 h) 73 Yo
H 52
C02Me
(1O:l)
Meo2c~..,,,,C02Me 54
Scheme 19. Formal synthesis of kumausallene
i Breco2M 3 Me02C
2.4 eq. Bu3SnH 0.2 Benzene eq. AlBN (0.025 M)
Me02C&C02Me
t
Me02C*o
i H
Br
Reflux, 5 h (Syringe pump, 4 h)
0
H
56
58 6 %
C02Me 57 66%
Scheme 20. Formation of (tetrahydrofurany1)tetrahydrofurans
was claimed as the major product 53 from the reaction of the bis(P-alkoxyacrylate) precursor 52 was converted to a known intermediate in the racemic synthesis [37] (Scheme 19). A C2-symmetric (tetrahydrofurany1)tetrahydrofuran 57 was mainly obtained from another biso-alkoxyacrylate) substrate 56 [38] (Scheme 20). In the presence of Lewis acids (EtZAlCl), cis-2,7-disubstituted oxepanes are accessible via radical cyclization of P-alkoxyacrylates [39]. A more recent example of 7-ex0 cyclizations is found in Tachibana’s partial synthesis of ciguatoxin [40], as the fused oxepane 60 was obtained from the precursor 59 in good yield (Scheme 21). The scope of the reaction was expanded considerably by Lee, who reported stereoselective synthesis of (+)-methyl nonactate by converting the P-alkoxymethacrylate precursor 61 into the benzyl ether 62 of methyl nonactate with high threo selectivity [41] (Scheme 22). Use of aldehyde substrates for radical cyclization of P-alkoxyacrylates presents opportunities for construction of fused oxacyclic systems. Under the tributylstan-
4.2 Synthesis of Oxacyclic Naturul Products
312
Toluene (0.01 M) 80 OC 85 % OMOM
59
60
OMOM
Scheme 21. Partial synthesis of ciguatoxin
COPMe OBn
-
1.3 eq. (TMS)$3iH 1.5 eq. EtBB
e
Toluene -20 OC, 30 min 90 %
61 I
C
0
2
M
e
OBn 62 (threo: >25:1 favored))
Scheme 22. Synthesis of methyl nonactate
1.3 eq. Bu3SnH 0.25 eq. AlBN
O&C02Et
H
0 Benzene(O.03 M) Reflux, 8 h
63
"'OH 64
91 O h (4654)
1) Bu3SnH, cat. AlBN
-
"ZEt
67
Benzene Reflux, 7 h
2) AqO, Pyridine cat. DMAP 91 Yo
H 65
t
&LCOZE H 66
Scheme 23. Fused oxacyclic systems via radical cyclization of p-alkoxyacrylates
nane conditions, the aldehyde 63 yielded a mixture of the trans hydroxy ester 64 and the cis lactone 65 in good yield (421 (Scheme 23). The second aldehyde 66 was prepared from the cis lactone 65, and it reacted under the same conditions to give a single product isolated as the acetate 67. Little stereoelectronic control is apparent for these reactions, and the selectivity obtained in the second cyclization may be attributed to substrate-specific steric control. More recently, Nakata reported that these aldehydes reacted under samarium iodide conditions to yield only trans hydroxy esters, paving the way for efficient synthesis of trans-fused poly(tetrahydropyran) and poly(oxepane) systems [43]. Photosensitized electron transfer cyclization of these aldehydes was also reported for C-furanoside synthesis initiated by visible light [44].
4.2.2 Ether-Tethered Radical Cyclizations
3 13
(TMS)3SiH Et3B *
BnOJSePh O+COzMe
Toluene 0 2 , -78OC 92 Yo
68
C02Me
BnO
69 (32:lFavored)
Scheme 24. Total synthesis of kumausallene
Bu3SnH 0.1 eq.AIBN
0
Benzene
0 %
0 *
Reflux, 5 h (Slow addition) 59 %
70
0
g
~
n
~
. u- - 3+
:q 72 Longianone
71
Scheme 25. Synthesis of longianone
(TMS)3SiH, Et3B p
yh o
s i e S02Ph OBn
L
~
&o
8 Benzene, 1 1 ;. p Yo ~ 02,~
73
OPMB S02Ph
OBn 74
Scheme 26. Vinylogous sulfonate cyclization
Acyl radical cyclization of P-alkoxyacrylates provides five-, six-, and sevenmembered oxacyclic ketones with high stereoselectivity [45]. In a key step in the synthesis of (-)-kumausallene (55) by Evans, the tetrahydrofuran-3-one 69 was obtained stereoselectively from the acyl selenide 68 [46] (Scheme 24). With modifications in the substrate, spiro ethers are accessible via radical cyclization reactions. For example, the spirocycle 71 was efficiently prepared from the tetronate ether 70 in the longianone (72) synthesis [47] (Scheme 25). Vinylogous sulfonates are valuable radical acceptors for the stereoselective synthesis of cyclic ethers [48]. Evans used the Z-vinylogous sulfonate 73 for preparation of the intermediate 74, which will be used in the synthesis of mucocin [49] (Scheme 26). More recently, an intermediate in the synthesis of garsubellin A was prepared via E-vinylogous sulfonate radical cyclization by Nicolaou [ 501. There are a number of examples of 6-end0 radical cyclization of vinylic ether substrates. For example, Thomas reported synthesis of the tetrahydropyran fragment 76 of bryostatin 1 via radical cyclization reaction of the a-alkoxyacrylate 75, capitalizing on the higher activity of Z-vinyl radicals [51] (Scheme 27). In the syn-
314
M~o~c
4.2 Synthesis of Oxacyclic Natural Products
~
~
Bu3SnH
~ C02Me
~
~
AlBN
Benzene Reflux
OTBS
OTBS 76 68%
75
OTBS 77 17%
Scheme 27. Synthesis of the tetrahydropyran fragment of bryostatin 1
OMe
OMe
Me0
Me0 hn (W lamp) 1.5 eq. t-BUSH THF (0.022 M) Reflux
L.$
79 Dehydroisorotenone
78
Scheme 28. Rotenoid synthesis via aryloxymethyl radical cyclization
OMe
&
83 Trimethylpeltogynol
t
Me0
1.I eq. BuaSnH
OMe
Z0&OMe
0.05 eq. AlBN *
M
e
m0 q
0
0
l
Benzene Reflux, 15 h (Slow addition, 1 h)
80
/
/
0
H 0
81 48 %
0
tio
82 1 2 %
Scheme 29. Synthesis of trimethylpeltogynol
thesis of dehydroisorotenone (79), the product formation may be explained by 6endo cyclization of the aryloxymethyl radical generated from the precursor 78, abstraction of the pyridylthio moiety, and thermal elimination [52](Scheme 28). A key intermediate 81 for the trimethylpeltogynol (83) synthesis was prepared from the aryl iodide 80 via 6-end0 radical cyclization [53](Scheme 29).
4.2.3 Acetal-Tethered Radical Cyclizations
3 15
4.2.3 Acetal-Tethered Radical Cyclizations 4.2.3.1 Allylic Acetal Substrates Early examples of radical cyclization by Ueno [54] and Stork [55] involve preparation of cyclic acetals. (-)-Isoavenaciolide [56], (+)-eldanolide [57], and angular triquinane systems [ 581 were synthesized following the 'bromoacetal' strategy. In the synthesis of (-)-taxusin (86) [59] (the enantiomer of natural (+)-taxusin), Holton employed the same strategy for the conversion of 84 into 85, thus introducing a crucial quaternary stereogenic center (Scheme 30). Highly efficient 5-ex0, 7-endo
@
%inH
P
Benzene Reflux, 3 h
OMe
@~~~lOAc
-___
Acd
85
98 Yo
86 (-)-Taxusin
Scheme 30. Total synthesis of taxusin
tandem radical cyclizations of the bromoacetal 87 yielded the hydroazulenic intermediate 88 in the total synthesis of (+)-cladantholide (89) reported by Lee [60] (Scheme 31). Formation of an extra carbon-carbon bond is possible via intermolecular trapping of the cyclic radical produced. Stork used the a-silyl enone 91 in the radical cyclization of 90 to produce the cyclic acetal92, which is an intermediate in the prostaglandin synthesis [61] (Scheme 32). Keck used a P-stannyl enone for the same transformation under non-reducing conditions [62]. Acrylonitrile was used in the synthesis of C-glycosyl derivatives [63]. A synthesis of magydardienediol (95) employed methyl acrylate as the intermolecular radical trapping agent in the reaction from 93 to 94 [64] (Scheme 33). More recently, Renaud reported examples of diastereoselective radical cyclization of bromoacetals controlled by the acetal configuration [65] (Scheme 34).
THPO"..
& :
H j
O F B r
0.2 1.5 eq. AlBN BusSnH
Benzene (0.025 M) *
Reflux, 6 h (Syringe pump, 5 h) 99%
OEt 87
Scheme 31. Total synthesis of cladantholide
THPO"..
qQ - ':
.-
>
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
[22] R. J. Boffey, M. Santagostino, W. G. Whittingham, J. D. Kilburn, Chem. Commun. 1998, 1875. [23] M. R. Elliott, A.-L. Dhimane, M. Malacria, J. Am. Chem. Soc. 1997, 119, 3427. [24] G. Stork, H. S. Suh, G. Kim, J. Am. Chem. Soc. 1991,113, 7054. 1251 P. J. Parsons, P. Willis, S. C. Eyley, Tetrahedron 1992, 48, 9461. 1261 S. Kim, P. L. Fuchs, J. Am. Chem. Soc. 1991,113,9864; V. H. Rawal, S. P. Singh, C. Dufour, C. Michoud, J. Org. Chem. 1993, 58, 7718. [27] S. D. Burke, J. Rancourt, J. Am. Chem. Soc. 1991, 113, 2335. [28] J. H. Udding, J. P. M. Giesselink, H. Hiemstra, W. N. Speckamp, J. Ory. Chem. 1994, 59, 6671. [29] S. A. Ahmad-Junan, P. C. Amos, D. A. Whiting, J. Chem. Soc., Perkin Trans. 1 1992, 539. [30] S. Tennant, D. Wege, J. Chem. Soc., Perkin Trans. 1 1989, 2089. [31] Y. Araki, T. Endo, Y. Arai, M. Tanji, Y. Ishido, Tetrahedron Lett. 1989, 30, 2829. [32] E. Lee, J. S. Tae, C. Lee, C. M. Park, Tetrahedron Lett. 1993, 34, 4831. [33] E. Lee, C. M. Park, J. Chem. Soc., Chem. Comrnun. 1994, 293. [34] E. Lee, J.-W. Jeong, Y. Yu, Tetrahedron Lett. 1997, 38, 7765. [35] E. Lee, C. M. Park, J. S. Yun, J. Am. Chem. Soc. 1995, 117, 8017. [36] E. Lee, S.-K. Yoo. Y.-S. Cho: H.-S. Cheon, Y. H. Chong, Tetrahedron Lett. 1997, 38, 7757. [37] E. Lee, S.-K. Yoo, H. Choo, H. Y. Song, Tetrahedron Lett. 1998, 39, 317. (381 E. Lee, H. Y. Song, H. J. Kim, J. Chem. Soc., Perkin Trans. 11999, 3395. [39] Y. Yuasa, W. Sato, S. Shibuya, Synth. Commun. 1997, 27, 573. [40] M. Sasaki, T. Noguchi, K. Tachibana, Tetrahedron Lett. 1999, 40, 1337. [41] E. Lee, S. J. Choi, Org. Lett. 1999, I , 1127. [42] E. Lee, J. S. Tae, Y. H. Chong, Y. C. Park, M. Yun, S. Kim, Tetrahedron Lett. 1994,35, 129. [43] N. Hori, H. Matsukura, G. Matsuo, T. Nakata, Tetrahedron Lett. 1999, 40, 2811; N. Hori, 13. Matsukura, T. Nakata, Org. Lett. 1999, I , 1099. [44] G . Pandey, S. Hajra, M. K. Ghorai, K. R. Kumar, J. Org. Chem. 1997, 62, 5966. [45] P. A. Evans, J. D. Roseman, Tetrahedron Lett. 1995, 36, 31; P. A. Evans, J. D. Roseman, J. Ory. Chem. 1996,61,2252; P. A. Evans, J. D. Roseman, L. T. Garber, J. Org. Chem. 1996, 61, 4880. [46] P. A. Evans, V. S. Murthy, J. D. Roseman, A. L. Rheingold, Angew. Chem. Int. Ed. Enyl. 1999,38, 3 175. [47] P. G. Steel, Chem. Commun. 1999, 2257. [48] P. A. Evans, T. Manangan, Tetrahedron Lett. 1997, 38, 8165. [49] P. A. Evans, J. D. Roseman, Tetrahedron Lett. 1997, 38, 5249. [50] K. C. Nicolaou, J. A. Pfefferkorn, S. Kim, H. X. Wei, J. Am. Chem. Soc. 1999, 121,4724. 1511 S. P. Munt, E. J. Thomas, J. Chem. Soc., Chem. Commun. 1989, 480. [52] S. A. Ahmad-Junan, A. J. Walkington, D. A. Whiting, J. Chem. Soc., Perkin Trans. 1 1992, 2313. 1531 S. A. Ahmad-Junan, D. A. Whiting, J. Chem. Soc., Perkin Trans. 1 1990, 418. [54] Y. Ueno, K. Chino, M. Watanabe, 0. Moriya, M. Okawara, J. Am. Chem. Soc. 1982, 104, 5564. 1.551 G. Stork, R. Mook, Jr., S. A. Biller, S. D. Rychnovsky, J. Am. Chem. Soc. 1983, 105, 3741. [56] C . E. McDonald, R. W. Dugger, Tetrahedron Lett. 1988, 29, 2413; A. G. H. Wee, Tetrahedron 1990, 46, 5065. 1571 J. S. Yadav, V. R. Gadgil, J. Chem. SOC.,Chem. Commun. 1989, 1824. [58] J. S. Yadav, T. K. Praveen Kumar, V. R. Gadgil, Tetrahedron Lett. 1992, 33, 3687. [59] R. A. Holton, R. R. Juo, H. B. Kim, A. D. Williams, S. Harusawa, R. E. Lowenthal, S. Yogai, J. Am. Chem. SOC.1988, 110, 6558. [60] 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. 1611 G. Stork, P. M. Sher, H.-L. Chen, J. Am. Chem. Soc. 1986, 108, 6384. [62] G. E. Keck, D. A. Burnett, J. Org. Chem. 1987, 52, 2958. [63] J. C. Lopez, B. Fraser-Reid, J. Am. Chem. Soc. 1989, 111, 3450. [64] H. Nagano, Y. Seko, K. Nakai, J. Chem. Soc., Perkin Trans. 1 1991, 1291. 1651 F. Villar, P. Renaud, Tetrahedron Lett. 1998, 39, 8655.
332
4.2 Synthesis of Oxacyclic Natural Products
[66] J. D. White, H. Shin, Tetrahedron Lett. 1997, 38, 1141. [67] R. A. Alonso, G. D. Vite, R. E. McDevitt, B. Fraser-Reid, J. Org. Chem. 1992, 57, 573. [68] S. R. Graham, J. A. Murphy, A. R. Kennedy, J. Chem. Soc., Perkin Trans. I 1999, 3071. [69] 0. Moriya, M. Okawara, Y. Ueno, Chem. Lett. 1984, 1437. [70] A. De Mesmaeker, P. Hoffmann, B. Ernst, P. Hug, T. Winkler, Tetrahedron Lett. 1989, 30, 6311; A. De Mesmaeker, P. Hoffmann, B. Ernst, Tetrahedron Lett. 1988, 29, 6585. [71] C. P. Sloan, J. C. Cuevas, C. Quesnelle, V. Snieckus, Tetrahedron Lett. 1988,29, 4685. [72] G. Stork, R. Mook, Jr., J. Am. Chem. Soc. 1983, 105, 3720. [73] A. Srikrishna, K. Krishnan, Tetrahedron Lett. 1988, 29, 4995. [74] A. Srikrishna, S. Nagaraju, S. Venkateswarlu, Tetrahedron Lett. 1994, 35, 429. [751 R. McCague, R. G. Pritchard, R. J. Stoodley, D. S. Willamson, Chem. Commun. 1998, 2691. [76] G. Stork, M. E. Krafft, S. A. Biller, Tetrahedron Lett. 1987, 28, 1035. [77] M. Ihara, K. Yasui, N. Taniguchi, K. Fukumoto, J. Chem. Soc., Perkin Trans. I 1990, 1469. [78] A. V. Rama Rao, G. V. M. Sharma, M. N. Bhanu, Tetrahedron Lett. 1992, 33, 3907. [79] J. D. White, C. S. Nylund, N. J. Green, Tetrahedron Lett. 1997, 38, 7329. [80] M. Ihard, A. Katsumata, K. Fukumoto, J. Chem. Soc., Perkin Trans. I 1997, 991. [Sl] M. Kim, K. Kawada, R. S. Gross, D. S. Watt, J. Org. Chem. 1990, 55, 504. 1821 S. Hatakeyama, N. Ochi, H. Numata, S. Takano, J. Chem. Soc., Chem. Commun. 1988, 1202. 1831 H. Nagaoka, K. Shibuya, Y. Yamada, Tetrahedron Lett. 1993, 34, 1501. [84] D. P. Curran, J. Tamine, J. Org. Chem. 1991, 56, 2746. [SS] T. G. Back, P. L. Gladstone, M. Parvez, J. Org. Chem. 1996, 61, 3806. [86] S. Hanessian, R. Di Fabio, J.-F. Marcoux, M. Prud’homme, J. Org. Chem. 1990, 55, 3436. [87] J. L. Belletire, N. 0. Mahmoodi, Tetrahedron Lett. 1989, 30, 4363. [88] E. Lee, C. H. Yoon, T. H. Lee, J. Am. Chem. Soc. 1992, 114, 10981. [89] 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. [901 E. Lee, C. H. Yoon, Tetrahedron Lett. 1996, 37, 5929. [91] F. 0. H. Pirrung, H. Hiemstra, W. N . Speckamp, B. Kaptein, H. E. Schoemaker, Synthesis 1995, 458. [92] G. A. Russell, C. Li, Tetrahedron Lett. 1996, 37, 2557. j931 E. J. Corey, M. Kang, J. Am. Chem. Soc. 1984, 106, 5384. [94] B. B. Snider, B. A. McCarthy, Tetrahedron 1993, 49, 9447. [95j 0. Hamelin, J. Depres, A. E. Greene, J. Am. Chem. Soc. 1996, 118, 9992. [96] E. Lee, C. U. Hur, Y. C. Jeong, Y. H. Rhee, M. H. Chang, J. Chem. Soc., Chem. Commun. 1991, 1314. [97] N. A. Porter, V. H.-T. Chang, J. Am. Chem. Soc. 1987. 109, 4976. [98] J. E. Baldwin, R. M. Adlington, M. B. Mitchell, J. Robertson, Tetrahedron 1991, 47, 5901. [99] J. E. Baldwin, R. M. Adlington, S. H. Ramcharitar, Tetrahedron 1992, 48, 3413. [loo] S. D. Mawson, R. T. Weavers, Tetrahedron 1995, 51, 11257. [loll A. L. J. Beckwith, P. E. Pigou, J. Chem Soc., Chem. Commun. 1986, 85. [I021 S. A. Hitchcock, G. Pattenden, Tetrahedron Lett. 1990, 31, 3641. [I031 A. K. Singh, R. K. Bakshi, E. J. Corey, J. Am. Chem. Soc. 1987, 109, 6187. [lo41 R. N. Saicic, S. Z. Zard, Chem. Commun. 1996, 1631. [ 1051 B. Noya, R. Alonso, Tetrahedron Lett. 1997, 38, 2745. [I061 G. E. Keck, T. T. Wager, S. F. McHardy, J. Org. Chem. 1998, 63, 9164. [I071 J. Zhang, D. L. J. Clive, J. Org. Chem. 1999, 64, 1754. [IOS] R. A. Alonso, C. S. Burgey, B. Venkatesward Rao, G. D. Vite, R. Vollerthun, M. A. Zottola, B. Fraser-Reid, J. Am. Chem. Soc. 1993, 115, 6666. [I091 G. Buchi, H. Wuest, J. Org. Chem. 1979, 44, 546. [ 1101 D. C. Harrowven, M. C. Lucas, P. D. Howes, Tetrahedron Lett. 1999, 40, 4443. [ I 1 I ] T. Honda, M. Satoh, Y. Kobayashi, J. Chem. Soc., Perkin Trans. I 1992, 1557. [1121 K . Takao, H. Ochiai, K. Yoshida, T. Hashizuka, H. Koshimura, K. Tadano, S. Ogawa, J. Org. Chem. 1995, 60, 8179. [ I 131 M. Ladlow, G. Pattenden, J. Chem. Soc., Perkin Trans. I 1988, 1107. [ I 141 K. Tadano, Y. Isshiki, M. Minami, S. Ogawa, J. Org. Chem. 1993, 58, 6266. [ I 151 G. Pattenden, L. Roberts, Tetrahedron Lett. 1996, 37, 4191.
References
333
[I161 J. Hartung, M. Hiller, P. Schmidt, Chem. Eur. J. 1996, 2, 1014. [ 1171 R. L. Dorta, C. G. Francisco, R. Freire, E. Suirez, Tetrahedron Lett. 1988, 29, 5429. [I181 L. A. Paquette, L.-Q. Sun, D. Friedrich, P. B. Savage, J. Am. Chem. Soc. 1997, 119, 8438. [ 1191 S. J. Danishefsky, D. M. Armistead, F. E. Wincott, H. G. Selnick, R. Hungate, J. Am. Chem. Soc. 1989, 1I I , 2967. [I201 S. L. Schreiber, J. Am. Chem. Soc. 1980, 102, 6163. [121] H. Suginome, S. Yamada, Chem. Lett. 1988, 245. [I221 P. de Armas, C. G. Francisco, E. Suarez, Tetrahedron Lett. 1993, 34, 7331. [I231 P. Dowd, S. Choi, Tetrahedron 1991, 47, 4847; A. Nishida, H. Takahashi, H. Takeda, N . Takada, 0. Yonemitsu, J. Am. Chem. Soc. 1990, 112, 902. [I241 G. A. Kraus, P. J. Thomas, M. D. Schwinden, Tetrahedron Lett. 1990, 31, 1819. [ 1251 K. C. Nicolaou, C.-K. Hwang, M. E. Duggan, K. Bal Reddy, B. E. Marron, D. G. McGarry, J. Am. Chem. SOC. 1986, 108, 6800. [ 1261 K. C. Nicolaou, D. G. McGarry, P. K. Somers, C. A. Veale, G. T. Furst, J. Am. Chem. Soc. 1987, 109, 2504. [I271 K. C. Nicolaou, F. P. J. T. Rutjes, E. A. Theodorakis, J. Tiebes, M. Sato, E. Untersteller, J. Am. Chem. Soc. 1995, 117, 10252. [128] M. Inoue, M, Sasaki, K. Tachibana, J. Org. Chem. 1999, 64, 9416. [ 1291 R. M. Adlington, J. E. Baldwin, A. Basak, R. P. Kozyrod, J. Chem. Soc., Chem. Commun. 1983, 944; B. Giese, J. Dupuis, Angew. Chem. fnt. Ed. Engl. 1983, 22, 622; H.-D. Junker, N. Phung, W.-D. Fessner, Tetrahedron Lett. 1999, 40, 7063. [130] H. Kessler, V. Wittmann, M. Kock, M. Kottenhahn, Angew. Chem. fnt. Ed. Engl. 1992, 31, 902. [131] D. H. R. Barton, M. Ramesh, J. Am. Chem. Soc. 1990, 112, 891. [132] G. E. Keck, A. M. Tafesh, J. Org. Chem. 1989,54, 5845. (1331 E. J. Corey, Y.-J. Wu, J. Am. Chem. SOC.1993, 115, 8871. [I341 S. Fukuzawa, K. Seki, M. Tatsuzawa, K. Mutoh, J. Am. Chem. Soc. 1997, I f Y , 1482.
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%<*OA~
AcO
AcO H
Scheme 7. Synthesis of p-disaccharides by radical anomeric inversion.
p: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
349
[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
(2,6-dimethylbenzene)-sulfinyl chloride CH2C1;?, i-PrzNEt,PhSSPh -50°C to rt
Ni, AcOH, i-PrOH
Ph
wMi
Ph*
t-Bucoou
Reactant
Table 8. Homolytic cyclizations of iminyl radical precursors
86
75
73
82
60
93 81
Yield (x)
[771
Ref
424
5. I Nitrogen-Centered Radicals
group. Many examples of N-centered radical formation by intramolecular addition of a C-centered radical onto a carbon-nitrogen n system of oxime ether, hydrazone, imine and nitrile acceptors have been reported [4].A limited number of additions to azides and azo acceptors have also appeared [4]. The fragmentation reaction of aziridinylmethyl radical has been used recently to generate allylaminyl radical, which participates in cascade reactions [70]. The selected transformations shown in Table 7 are illustrative of the scope of these reactions. 5.1.5.2.5 Iminyl Radicals
Iminyl radicals are particularly useful for the construction of nitrogen heterocycles, since the cyclization products are functionally disposed for further elaboration into a variety of useful systems. Zard and coworkers have pioneered the development of methodology for the generation and cyclization of iminyl radicals (Table 8) [ 5 , 711. Iminyl radicals cyclize one order of magnitude more rapidly than the related neutral aminyl radicals but react less rapidly than the aminyl radicals with hydrogen atom transfer trapping agents, and one would predict that iminyl radicals formed in chain reaction sequences could prove to be as versatile as carbon radicals [78].
5.1.6 Outlook Remarkable progress has been achieved for the comprehension of the reactivity of N-centered radicals. For a long time, electrophilic aminium cation radicals have proven more attractive for synthetic applications than nucleophilic neutral aminyl radicals. However, conditions for protonation have often been severe. The use of Lewis acids as activating agents or catalysts instead of protic acids is now a proven alternative method which could offer considerable advantages in general organic synthesis and particularly in asymmetric synthesis. Further investigation of the broad and hot topic of catalytic enantioselective radical reactions should enhance the range of possible applications of N-centered radical reactions. Such species are significant because of their potential for use in the development of enantioselective routes to increasingly complex nitrogen atom-containing skeletons.
References [ I ] S. F. Nelsen, in Free Rudiculs (Ed.: J. K. Kochi), Wiley, New York, 1973, Chap. 21, pp 527-593. [2] Y. L. Chow, in Recictice Intermediuter, Vol. I , (Ed. R. A . Abramovitch), Plenum. New York, 1980, Chap. 3, pp 151-262. [3] B. J. Maxwell , J. Tsanaktsidis, in N-Centered Rudiculs, (Ed.: Z. B. Alfasi), Wiley, Chichcster, 1998, Chap. 22, pp 665-684. [4] A. G. Fallis, 1. M. Brinza, Tetruhedron 1997, 53, 17543-17594.
References
425
[5] S. Z. Zard, Synlett 1996, 1148-1154. [6] J. L. Esker, M. Newcomb, in Advances in Heterocyclic Chemistry, Vol. 58, (Ed.: A. R. Katritzky), Academic, San Diego, 1993, pp 1-45. [7] L. Stella, Angew. Chem. 1983, 95, 368-380; Angew. Chem., Int. Ed. Engl. 1983,22, 337-350. [8] J.-M. Surzur, in Reactiue Intermediates, Vol. 2, (Ed. R. A. Abramovitch), Plenum, New York, 1982, Chap. 3 , pp 121-295. [9] W. C. Danen, F. A. Neugebauer, Angew. Chem. 1975, 87, 823-829; Angew. Chem., Int. Ed. Engl. 1975,14, 783-789. 101 F. Minisci, Acc. Chem. Res. 1975, 8, 165-171. 1 I ] K. Heusler, Heterocycles 1975, 3, 1035-1064. 121 F. Minisci, Synthesis 1973, 1-24. 131 R. S. Neale, Synthesis 1971, 1-15. 141 0. M. Musa, J. H. Horner, H. Shahin, M. Newcomb, J. Am. Chem. Soc. 1996, 118, 38623868. C. Chatgiglialoglu, K. U. Ingold, J. C. Scaiano, J. Am. Chem. Soc. 1981, 103, 7739-7742. J. C. Scaiano, J. Am. Chem. Soc. 1980, 102, 5399-5400. M. Newcomb, 0. M. Musa, F. N. Martinez, J. H. Horner, J. Am. Chem. Soc. 1997, 119, 4569-4511. A. L. J. Beckwith, C. H. Schiesser, Tetrahedron Lett. 1985, 26, 373-376. J. Hartung, F. J. Gallou, J. Org. Chem. 1995, 60, 6706-6716. M. C. R. Symons, Tetrahedron 1973,29, 615-619. M. E. Wolff, Chem. Rev. 1963, 63, 55-64. E. J. Corey, W. R. Hertler, J. Am. Chem. Soc. 1960,82, 1657-1668. (a) R. M. Dupeyre, A. Rassat, Tetrahedron Lett 1973, 2699-2701. (b) M. Kimura, Y. Ban, Synthesis, 1976, 201-202. J. F. Kerwin, M. E. Wolff, F. F. Owings, B. B. Lewis, B. Blank, A. Magnani, C. Karash, V. Georgian, J. Org. Chem. 1962,27, 3628-3639. D. H. R. Barton, A. L. J. Beckwith, A. Gossen, J. Chem. Soc. 1965, 181-190. R. Carrau, R. Hernandez, E. Suarez, C. Betancor, J. Chem. Soc., Perkin Trans 1 1987, 937943. G. 1. Nikishin, E. Troyansky, M. I. Lazareva, Tetrahedron Lett. 1985, 26, 1877-1878. a) F. Minisci, G. P. Gardini, F. Bertini, Can. J. Chem. 1970, 48, 544-545. b) J. Spanswick, K. U. Ingold, ibid. 1970,48, 546-553 and 554-560. N. C. Deno, R. Fishbein, J. C. Wyckoffd, J. Am. Chem. Soc. 1971, 93, 2065-2066. F. Minisci, R. Galli, Chim. Ind. (Milan) 1967, 49, 947-948. F. Minisci, R. Galli, Tetrahedron Lett. 1966, 2531-2533. M. Newcomb, M. U. Kumar, Tetrahedron Lett. 1990, 31, 1675- 1678. J.-M. Surzur, L. Stella, P. Tordo, Tetrahedron Lett. 1970, 3107-3108. W. R. Bowman, D. N. Clark, R. J. Marmon, Tetrahedron Lett. 1991,32, 6441-6444. B. J. Maxwell, B. J. Smith, J. Tsanaktsidis, J. Chem. Soc., Perkin Trans. 2 2000, 425-431. W. R. Bowman, D. N. Clark, R. J. Marmon, Tetrahedron 1994, SO, 1295-1310. C. Ha, 0. M. Musa, F. N. Martinez, M. Newcomb, J. Org. Chem. 1997, 62, 2104-2710. J. H. Horner, 0. M. Musa, A. Bouvier, M. Newcomb, J. Am. Chem. Soc. 1998, 120, 77387748. W. R. Bowman, M. J. Broadhurst, D. R. Coghlan, K. A. Lewis, Tetrahedron Lett. 1997, 35, 6301-6304. J.-M. Surzur, L. Stella, P. Tordo, Bull. Soc. Chim. Fr. 1970, 115-127. J.-L. Stein, L. Stella, J.-M. Surzur, Tetrahedron Lett. 1980, 21, 287-288. J.-L. Bougeois, L. Stella, J.-M. Surzur, Tetrahedron Lett. 1981,22, 61-64. L. Stella, B. Raynier, J.-M. Surzur, Tetrahedron Lett. 1977, 2721-2724. M. Hemmerling, A. Sjoholm, P. Somfai, Tetrahedron; Asymmetry 1999, 10, 4091-4094. H. Senboku. H. Hasegawa, K. Orito, M. Tokuda, Heterocycles, 1999, 50, 333-340. P. Mackiewicz, R. Furstoss, B. Waegell, R. Cote, J. Lessard, J. Org. Chem. 1978, 43, 37463750. J. Lessard, R. Cote, P. Mackiewicz, R. Furstoss, B. Waegell, J. Org. Chem. 1978, 43, 37503756.
426
5.1 Nitrogen-Centered Radicals
[48] J.-M. Surzur, L. Stella, Tetrahedron Lett. 1974, 2191-2194. [49] D. Boate, C. Fontaine, E. Guittet, L. Stella, Tetrahedron, 1993, 49, 8397-8406. [50] H. Senboku, Y. Kajizuka, H. Hasegawa, H. Fujita, H. Suginome, K. Orito, M. Tokuda, ihid, 1999, 55, 6465-6474. [51] A. L. J. Beckwith, B. J. Maxwell, J. Tsanaktsidis, Aust. J. Chem. 1991, 44, 1809-1812. [52] W. R. Bowman, D. N. Clark, R. J. Marmon, Tetrahedron Lett. 1992, 33, 4993-4994. [53] W. R. Bowman, D. N. Clark, R. J. Marmon, Tetrahechn 1994, 50, 1275-1294. [54] J. L. Esker, M. Newcomb, Tetrahedron Lett. 1993, 34, 6877-6880. 1551 M. Newcomb, K. A. Weber, J. Org. Chem. 1991,56, 1309-1313. [56] M. Newcomb, D. J. Marquardt, T. M. Deeb, Tetrahedron 1990, 46, 2329-2344. [57] M. Newcomb, C. Ha, Tetrahedron Lett. 1991, 32, 6493-6496. [58] M. Newcomb, J. L. Esker, Tetrahedron Lett. 1991,32, 1035-1038. [59] C. J. Michejda, D. H. Campbell, D. H. Sieh, S. R. Koepke in Organic Free Radicals, (Ed. W. A. Pryor), Am. Chem. SOC.,Washington, D.C., 1978, Chap. 18, pp 292-308. [60] R. A. Perry, S. C. Chen, B. C. Menon, K. Hanaya, Y. L. Chow, Can. J. Chem. 1976, 54, 2385-2401. [61] Y. L. Chow, R. A. Perry, Can. J. Chem. 1985, 63, 2203-2210. [62] M. Tokuda, Y. Yamada, T. Takagi, H. Suginome, Tetrahedron 1987,43,281-296. [63] a) A.-C. Callier, B. Quiclet-Sire, S. Z. Zard, Tetrahedron Lett. 1994, 35, 6109-6112; b) J. Boivin, A,-C. Callier-Dublanchet, B. Quiclet-Sire, A. M. Schiano, S. Z. Zard, Tetrahedron, 1995,51, 65 17-6528. 1641 a) A. J. Clark, J. L. Peacock, Tetrahedron Lett. 1998, 39, 1265-1268; b) A. J. Clark, J. L. Peacock, ibid. 1998, 39, 6029-6032; c) A. J. Clark, R. P. Filik, J. L. Peacock, G. H. Thomas, Synlett 1999,441-443; d) A. J. Clark, R. J. Deeth, C. J. Samuel, H. Wongtap, ibid. 1999, 444446. [65] X. Lin, D. Stien, S. M. Weinreb, Tetrahedron Lett. 2000, 41, 2333-2337. [66] C. J. Albissetti, D. D. Coffman, F. W. Hoover, E. L. Jenner, W. E. Mochel, J. Am. Chem. Soc. 1959,81, 1489-1494. [67] F. Minisci, R. Galli, V. Malatesta, T. Caronna, Tetrahedron 1970, 26, 4083-4091. [68] J. Aube, B. Giilgeze, X. Peng, Bioorg. Med. Chem. Lett. 1994, 4, 2461-2464. [69] X. Hoang-Cong, B. Quiclet-Sire, S. Z. Zard, Tetrahedron Lett. 1999, 40, 2125-2126. [70] D. De Smaele, P. Bogaert, N. De Kimpe, Tetrahedron Lett. 1998, 39, 9797-9800. [71] F. Gagosz, S. Z. Zard, Synlett. 1999, 1978-1980. [72] J. Boivin, E. Fouquet, S. Z. Zard, Tetrahedron Lett. 1990, 31, 85-88. [73] J. Boivin, E. Fouquet, S. Z. Zard, Tetrnhedron Lett. 1990, 31, 3345-3348. [74] J. Boivin, A.-M. Schiano, S. Z. Zard, H. Zhang, Tetrahedron Lett. 1999, 40, 4531-4534. [75] L. El Kaim, C. Meyer, J. Org. Chem. 1996, 61, 1556-1557. [76] X. Lin, D. Stien, S. M. Weinreb, Org. Lett. 1999, 1 , 637-639. [77] K. Uchiyama. Y. Hayashi, K. Narasaka, Tetrahedron 1999, 55, 8915-8930. [78] 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.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
5.2 Cyclization of Alkoxyl Radicals Jens Hartung
5.2.1 Introduction Alkoxyl radicals R-0’ are short-lived reactive intermediates which exhibit electrophilic properties in hydrogen abstractions and addition reactions to C-C double bonds [ 11. The basic structural unit of an alkoxyl radical includes a monovalent oxygen atom which is attached to an alkyl group. This definition distinguishes alkoxyl radicals from other oxygen-centered radicals such as the hydroxyl [2], aryloxyl [3], peroxyl [4], and alkoxycarbonyloxyl radicals [ 51, which will not be treated in this chapter. The chemistry of alkoxyl radicals is of extreme significance, for instance in the oxidative breakdown of hydrocarbons in the earth’s atmosphere [6]. Further, substituted cyclopentyloxyl radical 2 is probably a key intermediate in the biosynthesis of the human hormone prostacycline (PGI2) (3) from endoperoxide PGH2 (1) and the enzyme PGI-synthase. Intermediate 2 is trapped intramolecularly by addition to the olefinic double bond in the proximate side chain to afford, in subsequent transformations, eicosanoid 3 (Scheme 1) [ 71. In addition to their significance as structural and functional units in hormones [7], cyclic ethers are frequently found in natural products [8], pharmaceuticals [9], ionophores [lo], fragrances [ l l ] , solvents [12], reagents [13], or building blocks in organic synthesis [ 141. Several stereoselective syntheses of these target compounds have been accomplished which proceed via addition of an oxygen nucleophile to an activated olefinic double bond [ 151. Cyclizations of electrophilic alkoxyl radicals to C-C double bonds, however, provide a new alternative access to cyclic ethers which takes profit from the mild and neutral reaction conditions of free-radical reactions compared to their ionic counterparts [16]. In principle, any cyclic ether should be accessible from 0-radical cyclizations. However, the high reactivity of alkoxyl radicals with respect to competitive p-C-C cleavages (kp z lo6 - lo7 s-I) and C-H hydrogen abstractions ( k z~ lo6 - lo7 s-’) [I71 restricts the number of synthetically useful processes to fast intramolecular addition reactions. At the moment, 5exo-trig (formation of 2-substituted tetrahydrofurans) and 6-endo-trig ring closures (synthesis of tetrahydropyrans) constitute the majority of known alkoxyl radical cyclizations. This chapter reviews fundamentals and applications of alkoxyl radical chemistry in the stereoselective synthesis of tetrahydrofurans and includes a few selected examples of tetrahydropyran syntheses.
428
5.2 Cyclization of Alkoxyl Radicals
r"
9.
R'
TnLR2
PGI-Synthase*
r"
LR Of'
R' R2
- PGI-Synthase +
O,,,,
9
OH
-ielvProtein-S
R' = (CH2)3COOH R2 = (CH2)4CH3
-re'"-
Protein-S
1
OH
HO
OH
2
= PGI-Synthase
Scheme 1. Proposed formation of prostacycline PGIz (3) from endoperoxide 1 via alkoxyl radical cyclization [7]
5.2.2 Generation of Alkoxyl Radicals Alkoxyl radicals are accessible from four different types of precursors, which differ in the origin of the oxygen atom which is finally converted into the radical center, whether or not 0-radicals originate from sources which are only accessible in situ or are generated in carbon radical rearrangements (Scheme 2). Thus, alcohols can be converted into chemically moderately stable esters with a weak oxygen-nitrogen [ 18, 191, oxygen-sulfur [20, 211, or oxygen-chlorine bond [22]. These compounds serve as alkoxyl radical precursors in photochemically or thermally induced radical reactions (type I precursors). In type I1 0-radical precursors, the radical oxygen atom is introduced into the alkyl residue by a separate nucleophilic substitution [23-271, by an insertion of an 0 2 molecule (for example autoxidation) [28], or by a cycloaddition of a diene with singlet oxygen [29]. Photochemically, thermally or electron transfer-induced radical reactions have been observed with this group of radical precursors. A third group of alkoxyl radical sources can be generated in situ from the reagent combination of an alcohol and a strong oxidant such as Pb(OAc)4 [30], Ag~S20s[31], (NH4)2[Ce(N03)6][32], or Iz/PhIO/hv [33] (type I11 precursors). Since competitive oxidation reactions of functional groups, for example C-C double bonds, generally interfere with the 0-radical generation step, the use of type I11 precursors in cyclization reactions of alkenoxyl radicals is limited [34]. Strained oxygen-containing carbon radicals R", which efficiently rearrange to afford 0radicals R-O', are grouped as type IV alkoxyl radical precursors. For example, homolytic ether cleavage of epoxymethylene radicals affords allyloxyl radicals which have been used in syntheses [35]. The choice of an appropriate alkoxyl radical precursor for a given mechanistic or synthetic task generally is guided by the chemical nature of the alkyl substituent in R-0' since not all precursors allow a similar efficient access to n-, sec-, or tert-
5.2.2 Generation of Alkoxyl Radicals
429
Generation of Alkoxyl Radicals R-O-Y
-
AT or hv
+
R-O*
Y*
Type I Precursors
R-O-H
R-0-Y
*\-
X-Y
H-X
Type II Precursors
Examples
x-
yb
y-0-
Examples R-O-NO R-O-CI R-O-SPh
'-'
R-O-Y
R-X
O,R 4
t-BuO-OH (Y = OH) 302
Type 111 Precursors
R-O-H
n -R-O-Y X-Y
Examples for X-Y Pb(0Ac)r [Y = Pb(OAc)3] l2/PhlO/hv (Y = I)
H-X
Type IV Precursors
Example
d3 CH2* Scheme 2. Classification of alkoxyl radical precursors. Ar = p-ClC6H4
alkoxyl radicals (361.A further issue is related to the chemical compatibility of functional groups in the radical precursor and reagents which are applied in the radical generation step. For instance, oxidations of alkenols not only afford alkenoxyl radicals, but also cyclized products from ionic side reactions [34]. Therefore, photochemically or thermally initiated radical chain reactions, which frequently avoid combinations, dimerizations, or disproportionations of radicals due to low stationary concentrations of free radicals [ 371, have become increasingly popular for studying clear-cut alkoxyl radical selectivities in cyclization reactions. Especially non-peroxide type I1 O-radical precursors have been used for this purpose. These compounds, for instance N-alkoxy-4-( p-chlorophenyl)thiazole-2(3H)-thione4, are readily available from a variety of different procedures in synthetically useful amounts [25-271. A few derivatives thereof, which generally have good shelf life, have already been studied by X-ray diffraction [27, 381.
430
5.2 Cyclization of Alkoxyl Radicals
5.2.3 Principles of 4-Penten-1-oxyl Radical Cyclizations Stereoselectivity, Regioselectivity, and Theoretical Considerations The 4-penten- 1-oxyl radical ( 5 ) has been generated from the corresponding nitrite [ 39, 401, hydroperoxide [41], peroxycobaloxime [42], benzene 0-sulfenate [20],para-nitrobenzene 0-sulfenate [21], or N-alkoxypyridine-2( 1H)-thione [ 16, 431. Reaction of radical 5 with Bu3SnH (co = 0.44 M ) affords a 98:2 mixture of 2methyltetrahydrofuran (8) and tetrahydropyran (lo), besides 4-penten-1-01 (9) (Scheme 3) [16]. The cyclization 5 + 6 proceeds under kinetic control. The ratio of cyclized versus non-cyclized products is dependent on the concentration of the hydrogen donor. Application of the radical clock technique (competition kinetics) [44]allows a measurement of the rate constant of the 5-exo-trig [k5-exo = (4 f 2) x lo8 sP1] and of the 6-endo-trig cyclization [k6-endo = (8 f 4) x lo6 sP1] [16]. According to quantum mechanical calculations ( U H F method including post-HartreeFock corrections and density-functional methods), the geometry of the lowest energy transition structure of the 5-exo-trig cyclization is reminiscent of a flattened envelope conformer of tetrahydrofuran (Scheme 3, bottom left) [45]. The distance between the radical center and C-4 is 1.907 A in the UHF/6-31G*-calculated geometry and points to an early transition state on the reaction coordinate. The computed angle of attack of the radical center at C-4 is 104.6'. The transition structure of 6-endo attack (Scheme 3, bottom right) is significantly higher in energy
H H 8 (52%)
9 (31Yo)
0 10 (1%)
Transition Structures [45]
5-exo-trig
6-endo-trig
Scheme 3. Reactions (top) and transition structures (bottom) of 4-penten-I -0xy1 radical cyclizations. Quoted yields refer to c,(Bu,SnH) = 0.44 M. Shaded balls denote atoms and positions which are important in regiocontrol (6-endo-trig-reaction of 5 ) or in 5-exo-trig stereocontrol in substituted 4penten-I-oxyl-radicals (for example 12, Scheme 4, or 19 and 22, Scheme 5) [16, 45, 461
5.2.3 Principles of 4-Penten-l-oxyl Radical Cyclizations
43 1
(for example, UHF/6-31G*: AAH:.yo-endo = -9.70 kJ mol-I), which is in accord with the experimental findings [AAG:xo-endo= -9.50 kJ mol-' (7' = 298 K)]. In the course of the 6-endo-attack of the radical center at the C-C double bond (UHF/ 6-31 G*-calculated transition structure: d 0 - c ~= 1.925 A ), hydrogen 4-H, which has moved in an early stage of the addition reaction toward the oxygen atom, passes in between the vicinal hydrogens at C-3 and C-5 (shaded balls) to afford the tetrahydropyryl radical 7. This change causes additional torsional strain which is reflected in a lower kh-end,) value. 1-, 2-, and 3-substituted 4-penten-l-oxyl radicals have been generated from the corresponding N-alkoxypyridine-2( 1H)-thiones [ 16, 461, N-alkoxythiazole-2(3H)thiones [27], pentenyl benzene-O-sulfenates [ 16, 471, or pentenyl nitrites [39] in photochemically or thermally induced radical reactions. For instance, photolysis of thiazolethione 11 (c, = 0.05 M ) with long wavelength UV light (1= 350 nm) affords alkoxyl radical 12 via homolytic cleavage of the weak N-0 bond. Intermediate 12 rearranges to carbon-centered radicals 14 and 15, which are both trapped by Bu3SnH (c, = 0.18 M) to furnish 2-methyl-4-phenyl tetrahydrofuran (16) (cisltrans 88:12) in 50% yield (57% according to G C analysis), as well as 2-phenyl tetrahydropyran (17) (2%, G C analysis) and 2-phenyl-4-penten-1-01 (not shown in Scheme 4, 4%, GC). Propagation of the chain reaction is achieved by addition of a tributylstannyl radical to the thiocarbonyl group of 11, which affords thiazole 18 (56% yield) and a second molecule of alkoxyl radical 12. 2-Phenyl-4-penten-1-01 is formed by direct hydrogen transfer from the tin hydride prior to cyclization of radical 12. In principle, formation of alcohol should be avoided by reducing concentration of the hydrogen donor. In practice, Bu3SnH concentrations below c, = 0.05 M are not recommended for this purpose, since formation of carbonyl compounds (for example 2-phenyl-4-pentenal) from cyclic thiohydroxamic acid O-esters is observed at very low hydrogen donor concentrations. These side-products, however, are often harder to separate from cyclic ethers than corresponding alkenols in preparative scale reactions [ 16, 461. 1-, 2-, and 3-substituted 4-pentenoxyl radicals such as intermediates 12, 19, and 22 undergo diastereoselective irreversible 5-exo-trig cyclizations to afford in the given examples after hydrogen trapping by Bu3SnH disubstituted tetrahydrofurans 16,20, and 23 (Schemes 4 and 5 ) [ 16, 46,481. Tetrahydropyrans, for instance 17, 21, and 24, are generally formed in minor amounts. Substituent effects in stereoselective 4-penten- 1-oxyl radical cyclization can be summarized as follows: 1-, or 3-substituted 4-penten- 1-oxyl radicals afford 2,5-truns-, or 2,3-transdisubstituted tetrahydrofurans. The observed stereoselectivity increases with increasing steric size, for example in the series CH3 < C2H5 < CH(CH3)2 < C(CH3)3 < mesityl for 1-substituted radicals. Cyclization of 2-substituted 4-penten- 1-oxyl radicals leads to 2,4-cis-disubstituted tetrahydrofurans. The cis-stereoselectivity improves in going from CH3 to C6H5 to C(CH3)3.
Results from competition kinetics indicate that major diastereomers in stereoselective 5-exo-trig cyclizations are formed in elementary reactions which are by a factor of -1.5-3 faster than the reference reaction 5 6 (Scheme 3). Likewise, --+
5.2 Cyclization of Alkoxyl Radicals
432
13
12
Bu3Sn 18(56%)
v 17 (GC: 2%)
Ar
..
Ar ,
+
\\ - 0 0
I
*yo\ + ' O15 P h
Ph 16 (50%, GC: 57%) cisltrans 88:12
Scheme 4. Mechanism for the synthesis of cyclic ethers 16-17 from thiazolethione 11. Ar = p-ClC6H4 [27]
19
20 (82%)
21 (2%)
cisltrans 15:85
22
23 (72%) cisltrans 2:98
24 (7%)
Scheme 5. Stereoselective cyclization of substituted 4-penten-1-oxyl radicals 19 and 22 [ 16, 461
5.2.4 Ring Closure Reactions other than 5-exo-trig Cyclizations
433
minor diastereomers are obtained from cyclizations which are by the same factor slower than the reference reaction 5 + 6. The stereoselectivity pattern of alkenoxyl radical cyclizations is rationalized if the lowest energy transition structure (5-exotrig) of the parent radical 5 is taken as a model for its alkyl-substituted derivatives (Scheme 3, bottom left). Substituents larger than hydrogen should preferentially be located in pseudo-equatorial positions (shaded balls) and give rise to the observed major products in O-radical cyclizations. This description is reminiscent of the Beckwith-Houk model for selectivities in 5-hexen-l-yl radical cyclizations [49-5 11, although the rate constants of O-radical ring closures are three orders of magnitude higher than those of their non-fluorinated carbon-analogs [ 521. Exceptions to these general guidelines are observed in ring closure reactions of the l-phenyl-4-penten-l-oxylradical and its para-substituted derivatives, which provide both diastereomeric 5-exo-trig cyclization products in equal amounts [36, 481. Stereo- and regioselectivities of alkoxyl radical cyclizations may be improved by lowering the reaction temperature. Thus, the selectivity for the formation of trans-2isopropyl-5-methyl tetrahydrofuran from N-( 14sopropyl-4-penten- 1 -0xy)pyridine2( 1H)-thione increases from cisltrans 40:60 to 25:75 if the reaction temperature is changed from 140 "C to 15 "C. Likewise, the ratio of 2-isopropyl-5-methyl tetrahydrofuran (5-exo-trig) to 2-isopropyl tetrahydropyran (6-endo-trig) increases from 94:6 to 98:2 in the same temperature range. Solvent effects in the photochemical reaction of N-(2-phenyl-4-penten-l-oxy)pyridine-2( 1H)-thione and Bu3SnH have been studied [36]. Neither the use of tert-butyl benzene, chlorobenzene, bromobenzene, anisole, cyclohexane, tetrahydrofuran, nor ethanol leads to a significant change in yields and selectivities for the formation of 2-methyl-4-phenyl tetrahydrofuran (16) (50-70%, &/trans 88: 12), 2-phenyl tetrahydropyran (17) (1-3%, exolendo 96:4), and 2-phenyl-4-penten- 1-01 (4-9%) compared to benzene as standard solvent (see Scheme 4). Cyclizations of 5-alkyl-substituted 4-penten-1 -oxyl radicals are faster and frequently more selective than those of terminal unsubstituted derivatives [48, 531. This finding is in accord with the electrophilic nature of alkoxyl radicals in addition reaction to C-C double bonds. 5-Alkyl- or 5-phenyl-substituted 4-pentenoxyl radicals, such as intermediates 25 or 26, were generated from a number of different sources. For example, alkyl nitrites [39], N-alkoxypyridine-2( 1H)-thiones [46], and N-alkoxy-( p-chlorophenyl)thiazole-2(3H)-thiones[ 541 in photochemically induced reactions, and N-alkoxyphthalimides [55] or type IV radical precursors [53] in thermally initiated reactions have been applied for this purpose (Scheme 6).
5.2.4 Ring Closure Reactions other than 5-exo-trig Cy clizations 5-exo-, 6-endo-, and 6-exo-trig alkoxyl radical cyclizations have also been investigated. 4-Alkyl-, or 4-phenyl-substituted 4-penten- 1-oxyl radicals 27 were generated
434
5.2 Cyclization of Alkoxyl Radicals
96%
25
95% cisltrans 33:67
63%
22%
major trans Scheme 6. Cyclization of 5-substituted 4-penten-I-oxyl radicals 25-26 [46, 531
from the corresponding N-alkoxypyridine-2(1H)-thiones [ 16, 461 and N-alkoxy-( p chlorophenyl)thiazole-2(3H)-thiones[36] in the presence of hydrogen or deuterium donors. Tetrahydrofurans 28 were obtained as well as tetrahydropyrans 29. The yields of tetrahydropyrans 29a-c varied from 16% (R = CH3) to 31% [R = C(CH3)3] to 89%)(R = C6H5). The ratio of 6-endo- to 5-exo-cyclized product is determined by the substituent at position 4 and increases in the sequence CH3 < C(CH3)3 < C6H5 from 1892 to 9 5 5 (Scheme 7) [36]. These selectivities should originate from a combination of steric and polar effects. Trapping of cyclized tetrahydropyryl radicals by Bu3SnH proceeds stereoselectively and affords trans-tetrahydropyrans 29a and 29b as major products. Only a few examples of tetrahydropyran syntheses from 6-exo-trig cyclizations have been reported. Photolysis of alkyl nitrate 30 and Bu3SnH affords bicyclic tetrahydropyran 31 in 68% yield (Scheme 8) [56]. Furthermore, tributylstannanemediated 0-radical reaction starting from epoxymethylene bromide 32 leads to 2,5-cis-configured tetrahydropyran 33 [53]. Compounds which originate from a S-hydrogen abstraction as primary step in simple or more complex sequential transformations, for instance cyclopentanol 34, usually account for the majority of
27 27-29
R
28
R‘
28 cisltrans Yield
[“lo]
29
29 28:29 cisltrans Yield [“lo] exolendo
a
CH3
CH3
-
73
a:92
16
82:18
b
C(CH&
CH3
50150
12
37:63
31
37:63
C
C6H5
H
-
5
-
a9
5195
Scheme 7. Formation of tetrahydropyrans 29 from 6-endo-trig cyclizations [36]
5.2.5 Application of Alkoxyl Radical Cyclizations in Synthesis
30
32
435
31
33 (27%) cisltrans 91:9
34 (32%)
Scheme 8. Synthesis of substituted tetrahydropyrans 31 and 33 via 6-exo-trig ring closures [53,561
reaction products in these or other attempted 6-exo-trig alkoxyl radical cyclizations
PI.
Several benzo-fused tetrahydropyrans have been prepared either from arylpropanhydroperoxides in the presence of iron(I1) and copper(I1) salts, from the corresponding arylpropanol either by oxidation with FeS208, or in a photochemical reaction with iodine and mercury(I1) oxide (type I11 radical precursors). These reactions are considered to proceed via alkoxyl radical intermediates which add to the aromatic part of the molecule. Subsequent C- or 0-migration in spirocyclized intermediates affords substituted chromanes. However, ionic cyclizations may significantly interfere with the key step of the C-0 bond formation [57-591.
5.2.5 Application of Alkoxyl Radical Cyclizations in Synthesis For synthetic purposes cyclized radicals are preferentially trapped by chlorine [ 161, bromine [ 601, or iodine atom donors [ 541 to provide P-functionalized tetrahydrofurans, for instance halides 35-37 (Scheme 9), which serve as building blocks for subsequent ionic or free-radical reactions. This radical version of the classical halogen cyclization (Bartlett reaction [61]) is particularly useful if functionalized tetrahydrofurans can be obtained from terminal alkyl- or aryl-substituted alkenols. If these compounds are reacted for example with iodine or with N-bromosuccinimide, tetrahydropyrans are formed from ionic cyclofunctionalizations [ 621. If, however, the corresponding alkenols are converted into a thiohydroxamic acid 0-ester, subsequent photoreactions with either Cl-CC13, or Br-CC13 [63], ILC(CH3)(COZEt)z [64], or I - C ~ F Yefficiently leads to functionalized tetrahydrofurans, for example 35-37, via the alkoxyl radical pathway [54]. This method has been extended to prepare muscarine alkaloids, constituents
5.2 Cyclization of Alkoxyl Radicals
436
CI-cc13
.CCI3
CI
96% 35 cisltrans 30:70
I
Br
36 cisltrans <2:>98
37 cisltrans 29:71
Scheme 9. Stereoselective synthesis of P-halogen-substituted tetrahydrofurans 35-37 [ 16, 541
of the fly agaric Amanitu muscariu [60]. Photoreaction of 1,2-unti-configured N alkoxythiazolethione 38 and BrCC13 stereoselectively afford trisubstituted tetrahydrofurans 40 (3,5-cis/3,5-trans 67:33) in 82% yield as well as thiazole 39. The transition state model 42 explains the observed stereoselectivity for the formation of product 40. Both substituents should be located in pseudo-equatorial positions and should therefore direct the formation of the C-0 bond to the (Re)-face of the olefinic double bond in alkenoxyl radical 42 (Scheme 10). Tetrahydrofuran 3,5-cis-40
XLs
L
Br hv / 20 "C
BrCCI3
Iy$-s,CC13 N
+
*\r.'
BzOO
BzO"" 38
39 (77%)
40 (82%) 3,5-cid3,5-trans 67:33 1 2 steps
Proposed Major Transition Structure for 5-exo-trig-Cyclization
PMe3B; U
Hd' 41 ~~
42
(2R,3S,5S)-(+)allo -Muscarine
Scheme 10. Stereoselective synthesis of (2R,3S,5S)-(+)-allo-muscarine 41 [60]
References
437
Br
hv 120 “C
‘x“,
BrCCI3
* I”
u
BzO‘
BzO
70-75%
44 (80%) 3,5-cis/3,5-trans 50:50
43
Proposed Major Transition Structures for 5-exo-trig-Cyclization
BzO 45
k y
BzO
Scheme 11. Photoreaction of 1,2-syn-configured pyridinethione 43 and BrCC13 [60]
was converted in a two-step synthesis into (+)-do-muscarine (41). The efficiency of ring closures of /3-0x0-substituted 4-penten- 1-oxyl radicals is highly dependent on the nature of the substituents at oxygen. Whereas acceptor groups (benzoyl, trifluoroacetyl) afford cyclized trisubstituted tetrahydrofurans in excellent yields, a tert-butyldimethylsilyl substituent mainly leads to P 4 - C cleavage [60]. The 1,2-syn-configured radical 45 does not cyclize stereoselectively. Both diastereomeric bromomethyl-substituted tetrahydrofurans 3,5-trans-44 and 3,5-cis-44 are obtained in equal amounts from the photoreaction of pyridinethione 43 and BrCC13 (Scheme 11). This observation is explained by the transition state model for intermediate 45, where the methyl and the benzoyloxy substituent should both compete for pseudo-equatorial, energetically more favorable positions to afford conformationally flexible intermediate 45.
References [ l ] a) M. J. Jones, G. Moad, E. Rizzardo, D. H. Solomon, J. Org. Chem. 1989, 54, 1607-1611; b) A. L. J. Beckwith, K. U. Ingold in Rearrangements in Ground and Excited States Vol. 1 (Ed.: P. de Mayo), Academic, New York, 1980, pp. 203-205. [2] F. J. Comes, Anyew Chem. 1994, 106, 1900-1910; Angeiv. Chon., Int. Ed. Engl. 1994, 33, 18 16-1826. 131 D. H. R. Barton, S. I. Parekh, H d f a Century qfFree Radical Chemistry, Cambridge University, Cambridge, 1993. [4] a) N. A. Porter, Alkylhydroperoxides in Organic Peroxides (Ed.: W. Ando), Wiley, Chichester, 1992, pp. 102-156; b) N. A. Porter, M. 0. Funk, D. Gilmore, R. Isaac, J. Nixon, J. Am. Chem. Soc. 1976, 6000-6005; c) A. L. J. Beckwith, R. D. Wagner, J. Chem. Soc., Chem. Comrnun. 1980, 485-486. [ S ] a) M. Newcomb, M. U. Kumar, J. Boivin, E. Crepon, S. Z. Zard, Tetrahedron Lett. 1991, 32, 45-48; b) A. L. J. Beckwith, I. G. E. Davison, Tetrahedron Lett. 1991, 32, 49-52.
438
5.2 Cyclization of Alkoxyl Radicals
161 R. P. Wayne, Chemistry of Atmospheres, 2nd edn., Oxford University, 1991. [7] a) W. Herz, R. C. Ligon, J. A. Turner, J. F. Blount, J. Org. Chem. 1977, 42, 1885-1895; b) V. Ullrich, R. Brugger, Angew. Chem. 1994, 106, 1987-1996; Angew. Chem., Int. Ed. Engl. 1994, 33, 1911-1919. [8] a) W. Francke, J. Bartels, S. Krohn, S. Schulz, E. Baader, J. Tengo, D. Schneider, Pure Appl. Chem. 1989, 61, 539-542; b) C. H. Eugster, Naturwissenschafen 1968, 55, 305-313; c) G. W. Gribble, Acc. Chem. Res. 1998, 31, 141-152; d) M. Cueto, J. Darias, Tetrahedron 1996, 52, 5899-5906; e) L. T. Burka, L. J. Felice, S. W. Jackson, Phytochemistry 1981, 20, 647-652; f ) S. Matsunaga, T. Wakimoto, N. Fusetani, J. Org. Chem. 1997, 62, 2640-2642; g) T. Martin, M. A. S o h , J. M. Betancort, V. S. Martin, J. Org. Chem. 1997, 62, 1570-1571. [9] A. K. Saksena, V. M. Girijavallabhan, R. G. Lovey, R. E. Pike, H. Wang, A. K. Ganguly, B. Morgan, A. Zaks, M. S. Puar, Tetrahedron Lett. 1995, 36, 1787-1790; P. Angeli, F. Cantalamessa, R. Cavagna, R. Conti, M. De Amici, C. De Micheli, A. Gamba, B. Marucci, J. Med. Chem. 1997,40, 1099-1103; H. Naito, E. Kawahara, K. Maruta, M. Maeda, S. Sasaki, J. Org. Chem. 1995, 60, 4419-4427. [lo] H. Tsukube, K. Takagi, T. Higashiyama, T. Iwachido, N. Hayama, Inorg. Chem. 1994, 33, 298442987; L. F. Lindloy, Coord. Chem. Rev. 1996, 148, 349 -368. [ 111 A. F. Barrero, J. Altarejos, E. J. Alvarez-Manzaneda, J. M. Ramos, S. Salido, Tetrahedron 1993, 49, 9525-9534. [ 121 C. Reichardt, Solvent and Solvent Effects in Organic Chemistry, 2nd edn., VCH, Weinheim, 1995. [13] D. C. Harrowven, R. F. Dainty, Tetrahedron Lett. 1997, 38, 7123-7124. [14] D. E. Shaw, G. Fenton, D. W. Knight, J. Chem. SOC.,Chem. Commun. 1994, 2447-2448; M. D. Lord, J. T. Negri, L. A. Paquette, J. Org. Chem. 1995, 60, 191-195; C. Paolucci, C. Mazzini, A. Fava, J. Org. Chem. 1995, 60, 169-175; U. Koert, M. Stein, K. Harms, Angecv. Chem. 1994, 106, 1238-1240, Angew. Chem., Int. Ed. Engl. 1994,33, 1180-1182. [ 151 J.-C. Harmange, B. Figadere, Tetrahedron: Asymmetry 1993, 4, 171 1 - 1754. [16] J. Hartung, F. Gallou, J. Org. Chem. 1995, 60, 6706-6716. [17] J. A. Howard, J. C. Scaiano, Kinetische Daten ljon Rudikalreuktionen in Losung Oxyl, Peroxyl und verwandte Radikale in Landolt-Bornstein, Zuhleniverte und Funktionen aus Naturwissenschaft und Technik, New Series, Vol. 13, Part D, Springer, Berlin 1984. [18] D. H. R. Barton, J. M. Beaton, L. E. Geller, M. M. Pechet, J. Am. Chem. SOC.1960,82,2640264 1. [19] a) M. J. Begley, R. J. Fletcher, J. A. Murphy, M. S. Sherburn, J. Chem. Soc., Chem. Commun. 1993, 1723-1725; b) C. G. Francisco, E. I. Leon, P. Moreno, E. Suarez, Tetrahedron: Asymmetry 1998, 9, 2975-2978. [20] A. L. J. Beckwith, B. P. Hay, G. M. Williams, J. Chem. Soc., Chem. Commun. 1989, 1202-1203. [21] D. J. Pasto, F. Cottard, Tetrahedron Lett. 1994, 35, 4303-4306. [22] a) C. Walling, Bull. SOC.Chim. Fr. 1968, 1609-1615; b) C. Walling, R. T. Clark, J. Am. Chem. SOC.1974, 96, 4530-4534. [23] A. L. J. Beckwith, B. P. Hay, J. Org. Chem. 1989, 54, 4330-4334. [24] J. Hartung, Synlett 1996, 1206-1209. [25] J. Hartung, M. Schwarz, Synlett 1997, 848-850. J. Hartung, M. Schwarz, Synlett 1997, 1 1 16. [26] J. Hartung, R. Kneuer, M. Schwarz, 1. Svoboda, H. FueB, Eur. J. Org. Chem. 1999,97-106. [27] J. Hartung, M. Schwarz, I. Svoboda, H. FueB, M.-T. Duarte, Eur. J. Ory. Chem. 1999, 12751290. [28] E. Hagel, H. Krapf, P. Margaretha, S. Munke, J. Pospisil, Methoden Org. Chem. (HoubenWeyl) 4th edn. 1952-, Vol. E13/2, pp. 59-175. [29] a) J. A. Turner, W. Herz, J. Org. Chem. 1977,42, 1895 -1900; b) J. A. Turner, W. Herz, J. Org. Chem. 1977, 42, 1900-1904. [30] a) V. M. Micovic, R. 1. Mamuzic, D. Jeremic, M. Lj. Mihailovic, Tetrahedron 1964, 20, 22792287; b) J.-M. Surzur, M.-P. Bertrand, Bull. SOC.Chim. Fr. 1973, 1861-1867. [31] A. Clerici, F. Minisci, K. Ogawa, J.-M. Surzur, Tetrahedron Lett. 1978, 1149-1 152. [32] T.-L. Ho, CeriumlIV) O~uidationsof Organic Compounds in Organic Synthesis by Oxidation with Metal Conzpounds (Eds.: W. J. Mijs, C. R. H. I. De Jonge), Plenum, New York, 1986, pp. 569-63 1. -
References
439
[33] a) J. L. Courtneidge, J. Lusztyk, D. Page, Tetrahedron Lett. 1994, 35, 1003-1006; b) A. Boto, C. Betancor, T. Prange, E. Suarez, J. Org. Chem. 1994, 59, 4393-4401. [34] J.-M. Surzur in Reactive Intermediates (Ed.: R. A. Abramovitch), Plenum, New York, 1982, Vol. 2. 159-163. [35] D. H.’R. Barton, R. S. H. Motherwell, W. B. Motherwell, J. Chem. Soc., Perkin. Trans. I, 1981.2363-2367. [36] J. Hartung, Eur. J. Org. Chem. 2001, 619-632. 1371 B. Giese: Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon, Oxford, 1986. [38] J. Hartung, M. Hiller, M. Schwarz, I. Svoboda, H. Fuess, Liebigs Ann. 1996, 2091-2097. [39] J.-M. Surzur, M.-P. Bertrand, R. Nougier, Tetrahedron Lett. 1969, 4197-4200. [40] R. D. Rieke, N. A. Moore, J. Org. Chem. 1972,37,413-418. [41] B. C. Gilbert, R. G. G. Holmes, H. A. H. Laue, R. 0. C. Normann, J. Chem. Soc., Perkin Trans. 2 1976, 1047-1052. [42] J. Hartung, B. Giese, Chem. Ber. 1991, 124, 387-390. [43] A. L. J. Beckwith, B. P. Hay, J. Am. Chem. Soc. 1988, 110, 4415-4416. [44] D. Griller, K. U. Ingold, Acc. Chem. Res. 1980, 13, 317-323. [45] J. Hartung, R. Stowasser, D. Vitt, G. Bringmann, Angew. Chem. 1996, 108, 3056-3059, Angew. Chem., Int. Ed. Engl. 1996,35, 2820-2823. [46] J. Hartung, M. Hiller, P. Schmidt, Chem. Eur. J. 1996,2, 1014-1023. [47] Y. Guindon, R. C. Denis, Tetrahedron Lett. 1998, 39, 339-342. [48] J. Hartung, M. Hiller, P. Schmidt, Liebigs Ann. 1996, 1425-1436. [49] A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985, 41, 3925-3941. [50] D. C. Spellmeyer, K. N. Houk, J. Org. Chem. 1987,52, 959-974. [51] B. Giese, N. Porter, D. P. Curran, Stereochemistry of Radical Reactions, VCH, Weinheim, 1995. [52] B. Giese, B. Kopping, T. Gobel, J. Dickhaut, G. Thoma, K. J. Kulicke, F. Trach, Org. React. 1996, 48, 301-856. 1531 A. Johns, J. A. Murphy, Tetrahedron Lett. 1988,29, 837-840. [54] J. Hartung, R. Kneuer, P. Schmidt, K. Spehar, I. Svoboda, H. Fuess, Eur. J. Org. Chem.,
submitted for publication. I551 S. Kim, T. A. Lee, Y. Song, Synlett 1998, 471-473. [56] S. Kim, K. H. Kim, J. R. Cho, Tetrahedron Lett. 1997, 38, 3915-3918. [57] A. Goosen, C. W. McCleland, F. C. Rinaldi, J. Chem. Soc., Perkin Trans. 2, 1993, 279-281. (581 A. Goosen, C. F. Marais, C. W. McCleland, F. C. Rinaldi, J. Chem. Soc., Perkin Trans. 2, 1995, 1227-1236. 1591 H. Togo, T. Takahito, Y. Hoshima, K. Yamaguchi, M. Yokoyama, J. Chem. Soc., Perkin Trans. I 1997, 787-793. [60] J. Hartung, R. Kneuer, Eur. J. Org. Chem. 2000, 1677-1683. [61] P. A. Bartlett, Asymmetric Synthesis 1984, 3, 411-453. [62] P. Schmidt, Diploma Thesis, Universitiit Wurzburg, 1997. [63] D. H. R. Barton, D. Crich, W. B. Motherwell, Tetrahedron 1985, 41, 3901-3924. [64] D. P. Curran, E. Bosch, J. Kaplan, M. Newcomb, J. Org. Chem. 1989, 54, 1826-1831.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
5.3 P-Fragmentation of Alkoxyl Radicals: Synthetic Applications Ernesto Suurez and Maria S. Rodriguez
5.3.1 Introduction The /?-fragmentation reaction is the reversible homolytic cleavage of a C-C bond a,P to an alkoxyl radical (I) which gives rise to a carbon radical and a C-0 double bond (11) (Scheme 1) [ 11. The equilibrium is strongly displaced to the fragmented Cradical (11). This is especially more pronounced in cyclopentane or smaller ring systems, or in a-substituted systems (R = alkyl, allyl, aryl) where the radical could be stabilized. For the cyclopentyloxyl radical, the equilibrium constant k,-/k, is approximately 2000, while it is only 10 for the cyclohexanyloxyl radical [2]. The formation of the final products 111 and IV is strongly influenced not only by the equilibrium constant but also by kl and k2, and the reaction can be best interpreted by using the Curtin-Hammett kinetic principle (31. In some cases when the reagent used reacts much faster with alkoxyl radicals than with carbon radicals (kl >> kz), the reverse cyclization reaction is possible and alkyl radicals can add intramolecularly to aldehydes or ketones generating alkoxyl radicals despite the unfavorable equilibrium [4]. The regioselectivity of the fragmentation is not always apparent. In most cases the more stable radical is formed, but the different constants of equilibrium must be taken into account. A study of the fragmentation of 9-decalinoxyl radicals realized by Beckwith et al. is a good example of this [ 5 ] . Rearrangement at 0°C of 9decalinyl hypobromite gives 6-bromocyclodecanone, whereas 2-(4-bromobutyl)cyclohexanone is obtained at 8 1 "C. The increase in temperature displaces the equilibrium to the formation of an a priori less stable primary radical. The effect of alkyl substituents and ring size on the regioselectivity of the alkoxyl radical fragmentation has recently been evaluated by computational methods [6]. The importance of the activation energy and the energy of the reaction has been examined for a variety of cyclic and acyclic alkoxyl radicals.
5.3.3 Fvaymentution of' Alkoxyl Radicals Generated under Oxidative Conditions
111
II
I
44 1
IV
Scheme 1. Fragmentation of Alkoxyl Radicals.
5.3.2 Synthetic Methods Because of the high energy of the O-H bond (1 19 kcal mol-') even greater than that of the C-H bond (104.8 kcal mol-') alkoxyl radicals are not generally prepared from alcohols. However, several indirect preparative methods are available: (a) decomposition of alkyl hydroperoxides [7], alkyl peroxides [8], and (alky1peroxy)cobaloximes [9], (b) photolysis of alkyl nitrites [lo], N-alkoxypyridine-2( 1 H ) thiones [ 1I], and N-(alkoxy)-4-arylthiazole-2(3H)-thiones[ 121, (c) oxidation of alcohols by heavy metal salts [ 131, (d) thermal or photochemical decomposition of hypohalogenites [ 141 and O-alkylarylsulfenates [ 151, (e) reduction of nitrate esters [ 161, O-alkylarylsulfenates [ 171, N-alkoxyphthalimides [ 181, and phenyl Nalkoxybenzenecarbimidoselenoates[ 191, (f) addition of C-radicals [ 1b, 20a] and N radicals [21] to ketones, and (g) rearrangement of /?,y-epoxyradicals [ lc, 20b]. The methods that have been used most frequently in the /?-fragmentation reaction may be broadly classified into two types: oxidative and reductive methods. ~
~
5.3.3 Fragmentation of Alkoxyl Radicals Generated under Oxidative Conditions Two methodologies are widely used: the research group of Suginome (Hokkaido University) generates the alkoxyl radicals by irradiation of the hypoiodites prepared in situ by the reaction of alcohols with excess of mercury(l1) oxide and iodine, with a 100-W high pressure mercury lamp through a Pyrex filter [22].In La Laguna, we have introduced the use of hypervalent iodine compounds, especially (diacetoxyiod0)benzene (DIB), and iodine to generate the hypoiodites [23a]. The /?-fragmentation reaction proceeds by irradiation with visible light or thermally with temperatures between 0 and 45 "C [23b].
5.3.3.1 Fragmentation of Alcohols Probably the most interesting synthetic application of this reaction is the preparation of medium-sized and macrocyclic ketones by ring expansion involving a selec-
442
5.3 p-Fragmentation of Alkoxyl Radicals: Synthetic Applications
& J I
:&
":*,
AcO'"
I
HO
AcO
d'
&sH (4)
H
H
&
(5)
HO
dp
0
OH
0
& 0'0
I
(6)
Scheme 2. Fragmentation of Alcohols. DIB = (diacetoxyiodo)benzene; Ch indicates the rest of a cholestane molecule.
tive scission of a ring fusion bond starting from a bicyclic tertiary alcohol. Suginome et al. have demonstrated the utility of this reaction by synthesizing a variety of compounds [24], including natural products such as: ($-)-caryophyllene [25] and (*)-muscone [26]. This is illustrated in Scheme 2 with the key step of the synthesis of (*)-muscone (Eq. 1). Also notable is the great deal of effort devoted by these authors to the study of the /?-fragmentation of cyclobutanoxyl and cyclobutenoxyl radicals and their application to the synthesis of, among others, phthalides, [27] phthalide lignans [28] and (*)-himachalene [29]. In general, two-carbon ring ex-
5.3.3 Fragmentation of Alkoxyl Radicals Generated under Oxidative Conditions
443
pansion reactions are observed as indicated (Eq. 2) [30]. One-carbon ring-expanded unsaturated ketones can be obtained by treatment of 1-[(trimethylsilyl)oxy] bicyclo[n.l.0]alkanes, where n can take values 1, 2, 3 or 8 with iron trichloride. This reaction seems to proceed through an alkoxyl radical fragmentation [311. A C-radical originated by a P-fragmentation is able to participate in cascade reactions. For example, a double p-fragmentation reaction has been described (Eq. 3) [32]. The alkoxyl radical initially formed underwent a tandem P-fragmentationcyclopropylcarbinyl rearrangement reaction to afford an eleven-membered cyclic ketone. Another example is the polycycle construction via cascade radical fragmentation-transannulation-cyclizationprocess from the work of Pattenden and Mowbray, presented in (Eq. 4). The tricyclic core unit found in the natural product laurenene is prepared by treatment of a bicyclic dienol with DIB/I2 [ 3 3 ] . The Cradical also reacts with molecular oxygen and the resulting peroxy radical intermediate adds intramolecularly to olefins as shown in (Eq. 5). The stereoselectivity observed in the formation of the 1,2-dioxolane group is noteworthy and could be attributed to steric hindrance within the steroidal framework [34]. The intramolecular addition of a peroxy radical intermediate to a suitably positioned carbonyl compound to give a P-peroxylactone is illustrated in a steroidal model as shown in (Eq. 6) WI.
5.3.3.2 Fragmentation of Hemiacetals The P-fragmentation of alkoxyl radicals generated from oxabicyclic hemiacetals of the [n.rn.O] type is an attractive method for the synthesis of medium-sized and macrolactones by ring expansion reactions (Eq. 7 [36] and Eq. 8 [37], Scheme 3). Moreover, spirolactones can be prepared by fragmentation of other types of oxand 6-oxabicyclo[3.2.I]abicyclic hemiacetals such as 2-oxabicyclo[2.2.2]octan-l-ol octan-5-01 (Eqs. 9, 10) [36b]. The excision of the keto bridge present in tricycle[ 5.3.1.12,6]dodecan-l1-one taken from the work of Cha et al. on synthetic studies of taxol deserves special mention. Highly functionalized derivatives of bicycle[ 5.3. llundecane are obtained using the DIB/I2 system (Eq. 11) [38]. The fragmentation of a related derivative of oxabicyclo[3.3.l]nonan-9-one is used by the same authors as a key step in the synthesis of cis-2,8-disubstituted oxocanes (Eq. 12) [39]. When the alkoxyl radical is generated from hemiacetals formed by interaction of a hydroxy aldehyde, the /?-fragmentation reaction gives iodoformates. There are several examples in the literature where the DIB/I2 system has been used to fragment 5-membered hemiacetals of this type. Some of them are outlined in Scheme 4, including Stork’s introduction of angular methyl groups via radical cyclization (Eq. 13) [40], the synthesis of (+)-cyclophellitol of Ziegler et al. [41], and Danishefsky’s synthesis of the C28442 segment of rapamycin (Eq. 14) [42] and myrocin C [43]. The reaction has also been applied to fragment 6-membered hemiacetals as indicated in the last two examples of Scheme 4. An interesting variation is developed in Rigby’s recent total synthesis of (+)-estradiol: adding cupric acetate as an electron-transfer agent leads to oxidative elimination of the intermediate C-radical
444
5.3 /I-Fragmentation of Alkoxyl Radicals: Synthetic Applications
(8 DIB/lp
OH
n = 1,2
(7)
HgOIlz
n = 1,2 rn = 1,2,7
@
HO
DIB/lp Y
84%
DIB/Ip 77%
DIBI12 77%
t - B u P h z S0i O J s o H
DIBIIp ___)
80-85%
Scheme 3. Fragmentation of Ketol-Hemiacetals. DIB = (diacetoxyiodo)benzene; Ch indicates the rest of a cholestane molecule.
to give an olefin (Eq. 15) [44]. A double a-fragmentation has been envisioned by Suginome et al. during the synthesis of (f)-sesamin (Eq. 16) [45]. A new ring expansion route to olefinic lactones was developed by Nagao et al. to the C-radical When readily eliminating groups (PhS-, Bu3Sn-) are present center, an additional fragmentation occurs to give stereospecifically unsaturated medium-ring lactones in good yields (Eq. 17, Scheme 5) [46]. A short synthesis of (+)-8-deoxyvernolepin by 1,4-fragmentation of a y-hydroxy stannane using DIB/Iz as the key step has been described by our laboratory. The reaction proceeded with complete regioselectivity to give in one single step the most important structural featurcs of this compound and other vernolepin congeners, the S-valerolactone cisfused to ring B moiety and the angular vinyl group (Eq. 18) [47].
5.3.3 Fragmentation of Alkoxyl Radicals Generated under Oxidative Conditions
445
HO
(13)
( i /I G OCOHOSiMe2f-Bu \ r O B n
DIB/I$C u"
0"'
70%
HOCO'"
~
,-,
/i
HO
HOCO
no\
Scheme 4. Frigmentation of Aldol-Hemiacetals. DIB = (diacetoxyiodo)benzene.
a-Bu3Sn P-Bu3Sn
(14)
(6-alkene, 86% (4-alkene, 50%
Scheme 5. Fragmentation of y-Hydroxy Stannanes. DIB
=
(diacetoxyiodo)benzene.
446
5.3 p-Fragmentation of Alkoxyl Radicals: Synthetic Applications
)W
55%-
I H
COPH R = PhS02CH2
Scheme 6. Fragmentation-Peroxidation of Hemiacetals. DIB = (diacetoxyiod0)benzene; Ch indicates the rest of a cholestane molecule.
Interestingly, a cascade alkoxyl radical fragmentation-peroxidation-hydrogen abstraction reaction occurs in some cases when a hemiacetal is treated with DIB/I2 under oxygen pressure. This reaction may have interesting applications in synthetic organic chemistry. We have used it in a one-step synthesis of A and A‘ rings of the tetranortriterpene limonene and related compounds (Eq. 19, Scheme 6) [48]. The system DIB/I* may be compatible with very sensitive molecules. In fact, the steroidal peroxyhemiacetal shown in the Scheme 6 is transformed into a very unstable iodoperoxylactone which cyclized spontaneously into a 1,2-dioxolane derivative. It is noteworthy that despite the fact that the P-fragmentation sequence occurs through a radical process, total stereoselectivity was observed for the resulting dioxolanes (Eq. 20) [49].
5.3.3.3 Fragmentation of Carbohydrates As a logical extension of this hemiacetal fragmentation, we became particularly interested in the reaction of anomeric alkoxyl radicals from carbohydrates (Scheme 7). The formation of the alkoxyl radical and its fragmentation reaction proceeded smoothly in high yields using DIB/Iz at room temperature. The anomeric carbon is transformed into a formate group and the sugar is degraded to a lower member of the aldose series of carbohydrates. Some features of the procedure are remarkable: the mild reaction condition compatible with the protecting groups widely used in carbohydrate chemistry and also the fact that the reaction outcome does not depend on C-2 configuration or ring size. Using an electron donor as protecting group at C-2 (e.g. ether, isopropylidene), oxidation of the C-radical to an oxycarbenium ion intermediate is favored. This ion is trapped by an acetate anion from the medium to account for the obtained acetyl alkyl acetals (Eq. 21) [50].Nevertheless, electronwithdrawing groups at C-2 (e.g. ester, carbonate) decrease the electron density at this position, avoiding the oxidation and allowing the competitive trapping of the C-radical by an iodine atom. For instance, the carbonate shown in Scheme 7 gives
5.3.3 Fragmentation of Alkoxyl Radicals Generated under Oxidative Conditions
-
x ' b O H
HOCO
447
OAc
DIBIIz
OX0 t-BuMepSiO
WoH d o -
-
K 0
"A cOO ~b ~ O ~
H
DlBllz 88%
ACO
N,
Ph 10112 ___)
A
c
HOCO
5
O
GC=N
HOCO
OAc
H O C 0 8 ~ ~ ~ O B n
86%
Bnd
OBn
PhlOll, __t
72%
DIB112
+ow.* OSit-BuMe,
70%
Scheme 7. Fragmentation of Carbohydrates under Oxidative Conditions. DIB = (diacetoxyiod0)benzene.
an a-iodoalkyl carbonate which may be interesting as a four-carbon chiral intermediate (Eq. 22) [51]. A new method for the synthesis of nitriles by fragmentation of 2-deoxy-2-azides is described in (Eq. 23) [52]. This protocol can also be applied to non-carbohydrate P-hydroxy azides. The oxycarbenium ion can be trapped intramolecularly by suitably positioned alcohols or amine derivatives to give cyclic carbohydrates with one less carbon. The
448
5.3 /I-Fragmentation of Alkoxyl Radicals: Synthetic Applications
ring size obtained is only dependent on the position of the free alcohol, and the reaction may be interesting for preparing specific furanose or pyranose forms of aldotetroses and aldopentoses which are sometimes difficult to achieve by other methods (Eq. 24) [53]. The oxycarbenium trapping reaction by carbamate or phosphoramidate groups is particularly interesting since pyrrolidine and piperidine derivatives structurally related to the so-called azasuyars are obtained in high yields (Eq. 25) [ 541. Aldopyranosuronic and aldofuranosuronic acid lactones (so-called pseudolactones) can be easily accessible using this methodology. The reaction of the corresponding uronic acid with DIB/I2 gives the mentioned lactones that are chiral intermediates in the synthesis of polyhydroxylated five- and six-membered carbocycles (Eq. 26) [55].
5.3.4 Fragmentation of Alkoxyl Radicals Generated under Reductive Conditions The alkoxyl radical may be generated either directly by reduction of appropriate derivatives of alcohols or hemiacetals with tin hydrides [16-191 or iron(I1) compounds [7], or indirectly by intramolecular addition of C- [lb, 20a] and N-radicals [21] to carbonyl compounds or by rearrangement of P,y-epoxyradicals [ lc, 20bl.
5.3.4.1 Fragmentation of Alcohols Since the discovery of Binkley and Koholic, nitrate esters have been used as sources of alkoxyl radicals by treatment with either tributyltin hydride/AIBN or photolysis [16]. These authors described the conversion of the nitrate ester derivative of Dallose into the inverted alcohol by a radical p-fragmentation-recyclization reaction as shown (Eq. 27, Scheme 8) [ 16e,f].
e
COOEt
Bu3SnH/AIBN b
@/a= 10.5:l
OX0
Scheme 8. Fragmentation of Nitrate Esters.
5.3.4 Frugmentation of Alkoxyl Radicals Generated under Reductive Conditions
449
An example of a tandem fragmentation-cyclization reaction is Murphy’s tributyltin hydride-induced cleavage of nitrate esters derived from L-(+)-tartrate [ 16al. The initially formed alkoxyl radical suffers a rapid P-fragmentation to form a dioxolanyl radical which undergoes stereoselective cyclization to form a [ 5,5]-fused dioxolane (Eq. 28).
5.3.4.2 Fragmentation of Alkoxyl Radicals Generated by Addition of Carbon and Aminyl Radicals to Carbonyls The finding by Fraser-Reid and Tsang that C-radicals readily add to suitably positioned aldehydes and ketones opened a new field of research in radical cyclization chemistry [4a-c]. One particular use of this methodology is the ring expansion reaction developed by Dowd and Choi [lb, 561. The alkoxyl radical generated from addition of a primary C-radical to the ketone carbonyl undergoes fragmentation to yield a cyclic ketone with one-, three- or four-carbon increments (Eq. 29, Scheme 9). No rearrangement occurs when the tether is two carbons long, and only the product of direct reduction of the halogen is obtained. The starting substrates are readily prepared by facile alkylation of a Dieckmann P-keto ester and the expanded ketones are obtained in good yields. Concurrently the group of Beckwith reported an analogous series of rearrangements starting from the iodomethyl and (selenopheny1)methyl derivatives of cyclic P-keto esters [57].Baldwin et al. described a related
&se~3Snti/AlBN~
89%
SnBu,
Bu,SnH/AIBN 64%
Et0&
Bu,SnH/AIBN 93-96% EtOZC
n=1.2 Scheme 9. Fragmentation of Alkoxyl Radicals Generated by Addition of Carbon and Aminyl
Radicals to Carbonyls.
450
5.3 a-Fragmentation of Alkoxyl Radicals: Synthetic Applications
process of ring expansion of cis- and trans-a-alkylated-P-stannylcyclohexanones to provide efficient routes to E- and Z-cyclononenones and cyclodecenones. The geometry of the alkene is controlled by the cis-trans stereochemistry of the precursor (Eq. 30) [58]. Another interesting example of the formation of alkoxyl radicals by addition of C-radicals to carbonyls has been reported by Nishida et al. (Eq. 31) 1591. The key steps of the proposed mechanism are two consecutive four- and one-carbon ring expansions promoted by alkoxyl radical fragmentations. A new intramolecular addition of aminyl radicals to carbonyl groups as a method to promote a ring expansion reaction leading to lactams has been described by Kim et al. In this reaction, the aminyl radicals are generated from azides which are tethered to the a-position of cyclic ketones by a two- or three-carbon chain. The addition of this N-radical to the carbonyl group generates an alkoxyl radical which is responsible for the ring expansion reaction (Eq. 32) [21a].
5.3.4.3 Fragmentation of Alkoxyl Radicals Generated from p,y-Epoxyradicals Two representative examples are provided in Scheme 10. The allyloxyl radical is generated, in the first step, by a C-radical-induced epoxide fragmentation [20b]. A ring expansion reaction occurs subsequently to give the ten-membered enedione system (Eq. 33) [60].Nishida et al. show in the second example (Eq. 34) [61] another interesting case of a double ring expansion reaction induced by alkoxyl radicals similar to the one previously reported by the same authors (Eq. 31) [59].
/OC(S)lrn
w 0 0 U
OSiMe2f-Bu Bu3SnH/AIBN 59%
-
(34)
U
Scheme 10. Fragmentation of Alkoxyl Radicals Generated by Rearrangement of B,y-Epoxyradicals.
5.3.4.4 Fragmentation of Hydroperoxides Schreiber et al. have reported the iron(II)/copper(II)-mediated fragmentation of a-alkoxy hydroperoxides as a route to unsaturated macrolides. The ferrous ion promoted the alkoxyl radical formation, and the C-radical in the presence of the
5.3.5 Conclusion
45 1
Scheme 11. Fragmentation of Alkoxyl Radicals Generated by Reduction of Hydroperoxides.
cupric ion gave rise to an olefin with high regio- and stereoselectivity. This methodology has been used by these authors in the synthesis of (f)-recifeiolide (Eq. 35, Scheme 11) [7].
5.3.4.5 Fragmentation of Carbohydrates The fragmentation reaction of anomeric alkoxyl radicals generated by reaction of the alcohols with DIB/Iz shown in Scheme 7 can also be realized under reductive conditions. Treatment of anomeric nitrate esters (Eq. 36) [62] or N-phthalimido glycosides (Eq. 37) [63] with an excess of tributyltin hydride/AIBN gave the corresponding erythritol derivatives in excellent yield (Scheme 12). Although anomeric nitrate esters, in some cases, have proved to be unstable, N-phthalimido glycosides are stable and can easily be prepared by reaction of the corresponding alcohol with N-hydroxyphthalimide under Mitsunobu conditions [64].
I
R = COH, H
Scheme 12. Fragmentation of Carbohydrates under Reductive Conditions.
5.3.5 Conclusion The results described herein demonstrate that the /?-fragmentation reaction of alkoxyl radicals generated under oxidative or reductive conditions is well suited for the synthesis of medium-sized and macro ketones and lactones. The system hyper-
452
5.3 /I-Fragmentation of Alkoxyl Radicals: Synthetic Applications
valent iodine compound and iodine is a very mild and versatile reagent for the generation of alkoxyl radicals from alcohols. The reaction seems especially valuable in the promotion of unique transformations in the carbohydrate field. The fragmentation of anomeric alkoxyl radicals formed from simple derivatives of alcohols under reductive conditions offers interesting new perspectives.
Acknowledgement We would like to thank all those who have participated in the work realized in this group at La Laguna whose names appear in the references below. Financial support from the Direccion General de Investigacibn Cientifica y Tecnica (Programme no. PB96-1416) is gratefully acknowledged.
References [ I ] Reviews on alkoxyl radicals: a) P. Brun, B. Waegell in Reactive Intermediates, Vol. 3 (Ed.: R. A. Abramovitch), Plenum, New York, 1983, pp. 367-426; b) P. Dowd, W. Zhang, Chem. Rev. 1993, 93, 2091-2115; c) A. Nishida, M. Nishida, Rev. Heteroatom Chem. 1997, 16, 28731 I ; d) T. Muraki, H. Togo, M. Yokoyama, ibid. 1997, 17, 213-243; e) M. Ramaiah, Tetrahedron 1987, 43, 3541-3676. For brief mentions in more general reviews see: f ) D. P. Curran, Radical Cyclizations and Sequential Rudical Reaction in Comprehensive Organic Synthesis (Eds.: B. M. Trost, I. Fleming), Vol. 4, Pergamon, Oxford, 1991, pp 715-831; g) C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91, 1237-1286. [2] A. L. J. Beckwith, B. P. Hay, J. Am. Chem. Soc. 1989, 111, 230-234; A. L. J. Beckwith, R. Kazlauskas, M. R. Syner-Lyons, J. Org. Chem. 1983, 48, 4718-4722. [3] J. I. Seeman, Chem. Rev. 1983, 83, 83-134. (41 a) B. Fraser-Reid, G. D. Vite, B.-W. A. Yeung, R. Tsang, Tetrahedron Lett. 1988, 29, 16451648; b) R. Tsang, B. Fraser-Reid, J. Am. Chem. SOC.1986, 108, 2116-2117 and 1986, 108, 8102-8104; c) R. Tsang, J. K. Dickson, Jr., H. Pak, R. Walton, B. Fraser-Reid, ibid. 1987, 109, 3484-3486; d) A. L. J. Beckwith, B. P. Hay, ibid. 1989, 111, 2674-2681. [5] A. L. J. Beckwith, R. Kazlauskas, M. R. Syner-Lyons, J. Org. Chem. 1983, 48, 4718-4722. [6] S. Wilsey, P. Dowd, K. N. Houk, J. Org. Chem. 1999, 64, 8801-8811. [7] S. L. Schreiber, J. Am. Chem. Soc. 1980, 102, 6163-6165; S. L. Schreiber, B. H u h , W.-F. Liew, Tetrahedron 1986, 42, 2945-2950. [8] S. Matsugo, I. Saito in Organic Peroxides (Ed.: W. Ando), Wiley, Chichester, 1992, pp. 157194. [9] J. Hartung, B. Giese, Chem. Ber. 1991, 124, 387-390. [lo] D. H. R. Barton, J. M. Beaton, L. E. Geller, M. M. Pechet, J. Am. Chem. Soc. 1961,83, 40764083. [ l l ] A. L. J. Beckwith, B. P. Hay, J. Am. Chem. Soc. 1988, 110, 4415-4416; B. P. Hay, A. L. J. Beckwith, J. Org. Chem. 1989, 54, 4330-4334; J. Hartung, M. Hiller, P. Schmidt, Chem. Eur. J. 1996,2, 1014-1023. [12] J. Hartung, M. Schwarz, I. Svoboda, H. Fuess, M. T. Duarte, Eur. J. Ory. Chem. 1999, 12751290.
References
453
1131 M. Lj. Mihailovic, R. E. Partch in Selective Organic Transformations, Vol. 2 (Ed.: B. Thyagarajan), Wiley-Interscience, New York, 1972, pp. 97-182; M. P. Doyle, L. J. Zuidema, T. R. Bade, J. Org. Chem. 1975, 40, 1454-1456. [I41 K. Heusler, J. Kalvoda, Angew. Chem. 1964, 76, 518; Angew. Chem. Int. Ed. Engl. 1964, 3, 525-538; J. Kalvoda, K. Heusler, Synthesis 1971, 501-526; K. Heusler, J. Kalvoda in Organic Reactions in Steroid Chemistry, Vol. 2 (Eds.: J. Freid, J. A. Edward), van Nostran Reinhold, New York, 1971, pp. 237-287. [15] D. J. Pasto, G. L’Hermine, J. Org. Chem. 1990, 55, 5815-5816; D. J. Pasto, G. L’Hermine, Tetrahedron 1993, 49, 3259-3272; D. J. Pasto, F. Cottard, Tetrahedron Lett. 1994, 35, 43034306. [I61 a) A. S. Batsanov, M. J. Begley, R. J. Fletcher, J. A. Murphy, M. S. Sherburn, J. Chem. Soc., Perkin Trans. I 1995, 1281-1294; b) N. Hussain, D. 0. Morgan, C. R. White, J. A. Murphy, Tetrahedron Lett. 1994, 35, 5069-5072; c) G. D. Vite, B. Fraser-Reid, Synth. Commun. 1988, 18, 1339-1342; d) J. C. Lopez, R. Alonso, B. Fraser-Reid, J. Am. Chem. Soc. 1989, 111,64716473; e) R. W. Binkley, D. J. Koholic, J. Org. Chem. 1979, 44, 2047-2048; f ) R. W. Binkley, D. J. Koholic, J. Carhohydr. Chem. 1984,3, 85-106; g) C. J. Easton, A. J. Ivory, C. A. Smith, J. Chem. Soc., Perkin Trans. 2 1997, 503-507. [I71 A. L. J. Beckwith, B. P. Hay, G. M. Williams, J. Chem. Soc., Chem. Commun. 1989, 12021203. [18] K. Okada, K. Okamoto, M. Oda, J. Am. Chem. Soc. 1988, 110, 8736-8738; K. Okada, K. Okamoto, M. Oda, J. Chem. Soc., Chem. Comnmn. 1989, 1636-1637; D. H. R. Barton, P. Blundell, J. C. Jaszberenyi, Tetrahedron Lett. 1989, 30, 2341-2344; S. Kim, T. A. Lee, Y. Song, Synlett 1998, 471-472. [19] S. Kim, T. A. Lee, Synlett 1997, 950-952. [20] a) W. R. Bowman, P. J. Westlake, Tetrahedron 1992, 48,4027-4038; b) D. H. R. Barton, R. S. Hay-Motherwell, W. B. Motherwell, J. Chem. Soc., Perkin Trans. I 1981, 2363 -2367; A. Johns, J. A. Murphy, M. S. Sherburn, Tetrahedron 1989, 45, 7835-7858; P. Galatsis, S. D. Millan, T. Faber, J. Org. Chem. 1993, 58, 1215-1220. [21] a) S. Kim, G. H. Joe, J. Y. Do, J. Am. Chem. Soc. 1993, 115, 3328-3329; b) S. Kim, K. S. Yoon, S. S. Kim, H. S. Seo, Tetrahedron 1995, 51, 8437-8446; c) L. Benati, D. Nanni, C. Sangiorgi, P. Spagnolo, J. Org. Chem. 1999, 64, 7836-7841. [22] M. Akhtar, D. H. R. Barton, J , Am. Chem. Soc. 1964, 86, 1528-1536; H. Suginome, S. Yamada, J. Org. Chem. 1984,4Y, 3753-3762. [23] a) For spectroscopic evidence in the formation of alkyl hypoiodites under our conditions see: J. L. Courtneidge, J. Lusztyk, D. Page, Tetrahedron Lett. 1994>35, 1003-1006; b) J. I. Concepcion, C. G. Francisco, R. Hernandez, J. A. Salazar, E. Suarez, Tetrahedron Lett. 1984,25, 1953- 1956. 1241 H. Suginome in Handbook of Organic Photochemistry and Photohiology: Photochemistry of Alkyl Hypohalites, (Eds.: W. H. Horspool, P.-S. Song,), CRC, London, 1995, pp. 1229-1253. [25] H. Suginome, T, Kondoh, C. Gogonea, V. Singh, H. Goto, E. Osawa, J. Chem. Soc., Perkin Trans. I 1995, 69-8 1. [26] H. Suginome, S. Yamada, Tetrahedron Lett. 1987,28, 3963-3966. [27] K. Kobayashi, M. Itoh, A. Sasaki, H. Suginome, Tetrahedron 1991, 47, 5437-5452. [28] K. Kobayashi, Y. Kanno, S. Seko, H. Suginome, J. Chem. Soc., Perkin Trans. I 1992, 31 1131 17. [29] H, Suginome, Y . Nakayama, Tetruhedron 1994, 50, 7771-7782. [30] K. Kobayashi, A. Konishi, M. Itoh, H. Suginome, J. Chem. Soc., Perkin Trans. 1 1993, 825829. [31] Y. Ito, S. Fujii, T. Saegusa, J . Org. Chem. 1976, 41, 2073-2074; Y. Ito, T. Sugaya, M. Nakatsuka, T. Saegusa, J. Am. Chenz. SOC. 1977, YY, 8366-8367; K. 1. Booker-Milburn, Synlett 1992, 809-810. [32] A. Boto, C. Betancor, E. Suirez, Tetrahedron Lett. 1994, 35, 5509-5512. [33] C. E. Mowbray, G. Pattenden, Tetrahedron Lett. 1993, 34, 127-130. [34] A. Boto, C. Betancor, T. Prange, E. Suarez, J. Org. Chem. 1994, 59, 4393-4401. [35] A. Boto, R. Hernandez, E. Suarez, C. Betancor, M. S. Rodriguez, J. Org. Chem. 1995, 60, 8209-8217.
454
5.3 /3-Fragmentation of Alkoxyl Radicals: Synthetic Applications
[36] a) R. Freire, J. J. Marrero, M. S. Rodriguez, E. Suarez, Tetrahedron Lett. 1986, 27, 383 386; b) M. T. Arencibia, R. Freire, A. Perales, M. S. Rodriguez, E. Suarez, J. Chem. Soc., Perkin Trans I 1991, 3349-3360; see also: M. Kaino, Y. Naruse, K. Ishihara, H. Yamamoto, J. Org. Chem. 1990; 55, 5814-5815. [37] H. Suginome, S. Yamada, Tetrahedron 1987, 43, 3371-3386; H. Suginome, S. Yamada, Chem. Lett. 1988, 245-248. [38] J. Lee, J. Oh, S.-j. Jin, J.-R. Choi, J. L. Atwood, J. K. Cha, J. Org. Chem. 1994, 59, 69556964. [39] H. Kim, C. Ziani-Cherif, J. Oh, J. K. Cha, J. Org. Chem. 1995, 60, 792-793. [40] G. Stork, R. Mah, Tetrahedron Lett. 1989, 30, 3609-3612. [41] F. E. Ziegler, Y. Wang, J. Org. Chem. 1998, 63, 7920-7930; see also: J. Oh, Tetrahedron Lett. 1997, 38, 3249-3250; G. Mehta, N . Mohal, Tetrahedron Lett. 1999, 40, 5791-5794. [42] C. M. Hayward, M. J. Fisher, D. Yohannes, S. J. Danishefsky, Tetrahedron Lett. 1993, 34, 3989-3992. [43] M. Y. Chu-Moyer, S. J. Danishefsky, J. Am. Chem. Soc. 1992, 114, 8333-8334. (441 J. H. Rigby, N. C. Warshakoon, A. J. Payen, J. Am. Chem. Soc. 1999, 121, 8237-8245. [45] K . Orito, K. Yorita, H. Suginome, Tetrahedron Lett. 1991, 32, 5999-6002. [46] M. Ochiai, S. Iwaki, T. Ukita, Y. Nagao, Chem. Lett. 1987, 133-136; see also: G. H. Posner, E. Asirvatham, K. S. Webb, S.-s. Jew, Tetrahedron Lett. 1987, 28, 5071-5074. [47] C. G. Francisco, R. Freire, M. S. Rodriguez, E. Suirez, Tetrahedron Lett. 1987, 28, 33973400; R. Hernandez, M. S. Rodriguez, S. M. Velazquez, E. Suarez, J. Org. Chem. 1994, 59, 6395-6403. [48] A. Boto, R. Freire, R. Hernandez, E. Suarez, M. S. Rodriguez, J. Org. Chem. 1997, 62, 2975298 1. [49] A. Boto, R. Hernandez, S. M. Velazquez, E. Suarez, T. PrangC, J. Org. Chem. 1998,63,46974705. [50] P. de Armas, C. G. Francisco, E. Suarez, Angew. Client 1992, 104, 746; Angew. Chem., Int. Ed. EngL 1992.31,772-774; see also: J. Inanaga, Y. Sugimoto, Y. Yokoyama, T. Hanamoto, Tetrahedron Lett. 1992,33, 8109-81 12; M. Adinolfi, G. Barone, A. Iadonisi, Synlett 1999, 6566. [51] C. G. Francisco, C. GonAez, E. Suarez, J. Org. Chem. 1998, 63, 8092-8093. [52] R. Hernandez, E. de Leon, P. Moreno, E. Suarez, J. Org. Chem. 1997, 62, 897448975, [53] P. de Armas, C. G. Francisco, E. Suirez, J. Am. Chem. Soc. 1993, 115, 8865-8866. [54] C. G. Francisco, R. Freire, C. Gonzalez, E. Suarez, Tetrahedron: Asymmetry 1997, 8, 19711974. [55] C. G. Francisco, C. Gonzdez, E. Suarez, J. Org. Chem. 1998, 63, 2099-2109. [56] P. Dowd, S.-C. Choi, Tetrahedron 1989, 45, 77-90. [57] A. L. J. Beckwith, D. M. O’Shea, S. W. Westwood, J. Am. Chem. Soc. 1988, 110, 2565-2575. I581 J. E. Baldwin, R. M. Adlington, J. Robertson, Tetrahedron 1989, 45, 909-922. [59] A. Nishida, H. Takahashi, H. Takeda, N. Takada, 0. Yonemitsu, J. Am. Chem. Soc. 1990, 112, 902-904. [60] V. H. Rawal, H. M. Zhong, Tetruhedron Lett. 1993, 34, 5197-5200. [61] A. Nishida, Y.-I. Kakimoto, Y. Ogasawara, N. Kawahara, M. Nishida, H. Takayanagi. Tetrahedron Lett. 1997, 38, 5519-5522. [62] C. G. Francisco, E. I. Leon, P. Moreno, E. Suarez, Tetrahedron: Asymmetry 1998, 9, 29752978. [63] A. Martin, M. S. Rodriguez, E. Suarez, Tetrahedron Lett. 1999, 40, 7525-7528. [64] E. Grochowski, J. Jurczak, Synthesis 1976, 682-684.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
5.4 Peroxyl Radicals in Synthesis John Boukouvalus and Richard K. Huynes
5.4.1 Introduction This chapter covers organic compounds prepared via intermediates which are alkyl peroxyl radicals (ROO') generated either by addition of ground state (triplet) oxygen to carbon-centered radicals, or by hydrogen atom abstraction from the corresponding hydroperoxides (ROOH). While some earlier work is briefly mentioned, the focus is primarily on new developments, published over the past decade or so. The emphasis is heavily on synthetic applications rather than physical, biological and environmental aspects of peroxyl radical chemistry. A book exclusively devoted to the latter topics has recently been published [l]. Some preparatively relevant pathways involving peroxyl radicals have been previously discussed in the context of reviews on the oxidation of organic molecules [2-41 and the synthesis of organic peroxides [5-8]. The present survey is clearly distinguished in scope; it is intended to cover a more diverse array of peroxyl radical pathways and to highlight recent applications in the field of natural product synthesis. The aim is to alert not only the peroxide specialist, but also the synthetic chemist in general, since the first-formed peroxidic products can be used as relay intermediates in the synthesis of nonperoxidic compounds.
5.4.2 Autoxidation of Hydrocarbons The oxidation of hydrocarbons and other organic molecules with oxygen or air is usually referred to as autoxidation [4, 7a, 91. This entirely atom-economical process (Eq. 1, Scheme 1) is ca. 18-24 kcal/mol exothermic and irreversible at temperatures below 250°C. Although the initiation step (Eq. 2) is not well understood [2, lo], it is clear that a chain radical process is involved, with addition of molecular oxygen to R as the initial propagation step (Eq. 3 ) . At oxygen pressures above 100 mm Hg, the reaction of R' with 0 2 proceeds with rate constants approaching the diffusioncontrol limit [7a, 9a]. The second propagation step involves hydrogen atom abstrac-
456
5.4 Peroxyl Radicals in Synthesis RH
Initiation:
Propagation:
Termination:
I
+
0 2
In.
+
R.
+ 0 2
ROOH
RH
R
fast
ROO.
2R00
-
+
RH
- ZZ
slow
(1)
+
ROO-
-1
path B 2R0
+
(2)
(3)
ROOH
+
R-
(4)
-
path A
ROOOOR
InH
ROH + RO.H R = 1" or 2" alkyl
+
0 2
(5)
R = t-alkyl
O2
(Non-termination)
Scheme 1
tion from RH by the peroxyl radical to generate R (Eq. 4). This step is slower and rate determining for the propagation sequence; the rate constant strongly depends on the strength of the C-H bond to be broken. As a consequence, only substrates with m-activating groups (e.g. an Ar, vinyl or OR) undergo autoxidation at preparatively useful rates. Because ROO' is strongly stabilized by resonance (BDE of ROO-H is ca. 88-89 kcal/mol) [ 111, reasonable selectivity is often observed for the weakest C-H bond(s) available for abstraction [7a]. Termination of the chain process occurs via combination of two peroxyl radicals to form unstable tetroxides (Eq. 5) [7a, llc]. Primary and secondary alkyl tetroxides readily decompose to alcohols, aldehydes (RO-H) and oxygen (path A, Scheme 1). On the other hand, tertiary peroxyl radicals decay much more slowly since the corresponding tetroxides collapse primarily to alkoxy radicals, which can continue the chain process (path B). Of considerable practical importance is the concentration of substrate. Even fairly reactive compounds do not autoxidize readily at sub-millimolar concentrations [7a].The rate of initiation is also crucial in promoting autoxidation. Although many autoxidation reactions are auto-initiated, the use of initiators such as di-tertbutyl peroxyoxalate (DBPO) [ 12a1 or di-tert-butyl hyponitrite (DTBN) [ 12b] can be beneficial. DBPO and DTBN are convenient sources of tert-butoxyl radicals in the temperature ranges of 20-60 and 20-90 "C, respectively (Scheme 2). They are especially effective when used in conjunction with an excess of tert-butyl hydroperoxide (TBHP), whose role is to trap product peroxyl radicals as hydroperoxides, thereby preventing side-reactions [ 13a,c]. In contrast to auto-initiated autoxidation, the autoxidation of simple alkenes (e.g. 1-methylcyclohexene, Scheme 2) by the DBPOTBHP procedure is of comparable preparative value to the widely used singlet oxygen route [ 13a,b]. While the autoxidation of hydrocarbons is of paramount importance to the industrial synthesis of several bulk chemicals [2b, 141 including phenol (Scheme 3) [ 14a1, it is rarely used as a preparative method in the laboratory [7a]. Nonetheless, autoxidation reactions can provide a highly atom-economical means for elaborating densely functionalized structures, as illustrated by the concise synthesis of the naturally occurring antifungal peroxide rugosal A (Scheme 4) [ 15al.
5.4.2 Autoxidution of Hydrocarbons
f:?
t-B~O-OC-CO-OB~-t DPBO
A
DTBN
(40% conversion)
+
2C02
1124
(20 "C in benzene) = 24.5 h
t1/2
(45 "C in benzene) = ca. 0.7 h
t1/2
*
2t-BuO'
t112
A
t-BUO-N=N-OBu-t
0 2 , DBPO, PhH, 30 "C,TBHP 24 h
-
457
2t-B~Om + N2
[12bI
(45 "C in isooctane) = 7 h
& gH+ OOH
&OH
+
(37%)
[134
(24%)
(36%)
Scheme 2
90-120 "C 5- 7 bar
+
Me2CO
'Hock cleavage'
Scheme 3 [ 14a]
40 "C, 3 h*
F
c
H
OOH 2
o
N MeOH H 2 c s N H 2 ~ ~ H o 50%
OH Rugosal A
Scheme 4 [ 15a]
Key to the success of this sequence is undoubtedly the ease of formation of the bis-allylic carbon-centered radical 3 (BDE of C-H is about 76 kcal/mol) from diene 1. The transformation of 3 to hydroperoxide 2 proceeds by sequential oxygenation and peroxyl radical cyclization-oxygen entrapment (Scheme 4). The overall cascade accomplishes the formation of three C-0 bonds and three stereocenters in a single
458
5.4 Peroxyl Radicals in Synthesis
operation and with complete regio- and stereocontrol. The autoxidation of several related sesquiterpenes has been reported [ 15b,c].
5.4.3 Functional Group Interconversions The generation of specific carbon radicals from appropriately functionalized precursors, followed by capture with molecular oxygen, provides a potentially general route to regiodefined peroxyl radicals (Eq. 6). Unlike autoxidation, this approach is useful when R is not stabilized and therefore difficult to obtain by hydrogen abstraction from R-H.
Barton has devised such a pathway for converting carboxylic acids to hydroperoxides via N-hydroxypyridine-2-thioneesters [ 16a,b] (Scheme 5). The yields of hydroperoxides are 45-899'0 [ 161. Reduction of the crude products with trimethyl phosphite (rt) or dimethyl sulfide (80 "C) readily provides the corresponding alcohols. On the other hand, tosylation and ensuing Kornblum-De La Mare type fragmentation [17] leads to carbonyl compounds [16b] (Scheme 5). Organoboranes readily react with'molecular oxygen in T H F at low temperatures to form peroxyboranes via peroxyl radicals. There is ample evidence that these reactions proceed via peroxyl radicals by the mechanism shown in Scheme 6 [ 181. Depending on the organoborane concentration, the initially formed peroxyboranes undergo further oxygenation to give diperoxyboranes (5 + 6), or an intermolecular redox reaction to produce alkoxyboranes (5 47). Subsequent perhydrolysis provides the corresponding hydroperoxides or alcohols as major products. While alcohols are produced with high efficiency, only two of the three alkyl groups on the 02
1) Q-OH
Ph
2) hv, 0 2 , &BUSH
Ph
*from 4
Scheme 5 [ 16b]
5.4.3 Functional Group Interconversions
0 2
* (R00)2BR ROOBRp 5 (0.01-0.05 M) 6
R3B (0.5 M )
(\>
+
H202
H202 H0-
2ROBR2 7
1) BH3, THF, 0
-
2ROOH
+
459
ROH
3ROH
50 "C
2) 0 2 , aq. H202, MeOH - 7 8 "C, l h
(10 gram scale)
Scheme 6 [ 181
Et2BH
R'
R'
E B E t 3
-& 1) Et2Zn
R2
H O O 2)ZnBr2 R'
,ZnBr,
02,
.
PFH - *J
-780c
R2
R'
, 58-85%
Scheme 7 [ 19b]
boron are used in the formation of hydroperoxides (Scheme 6). This limitation can be overcome by using alkyldichloroborane etherates, which undergo clean autoxidation at - 18 "C to give primary and secondary hydroperoxides in yields of 8494%, as determined by iodometric titration [ 181. More recently, Knochel reported the conversion of organoboranes to hydroperoxides via organozinc compounds [19] (Scheme 7). The latter undergo facile autoxidation at -78 "C in perfluorohexane (PFH), which dissolves higher quantities of oxygen than traditional solvents such as ether and THF. Functionalized hydroperoxides such as HOO(CH2)60TIPS, as well as alcohols (through reductive workup), have been prepared by this method. Although it has not been stated how the oxidation may proceed [ 191, earlier observations on organozinc compounds suggest that peroxyl radicals may be involved [Sb]. Several primary and secondary amines have been converted to hydroperoxides through N-sulfonylhydrazines [20] (Scheme 8). The mechanism of the oxidation step has been discussed [20]. 1) TsCl
2) Base 3) ONH2
-
CI*(CH2),yNH2 Ts
I
77% EtOWEtOH 02,12 "C
Scheme 8 [20]
460
5.4 Peroxyl Radicals in Synthesis
5.4.4 Autoxidation of Carbonyl Compounds 5.4.4.1 Oxyfunctionalization via Enols or Enolates The autoxidation of carbonyl compounds can be performed under a variety of conditions, the choice of which depends on the substrate and the desired product. Metalcatalyzed autoxidation proceeds via intermediate enols to generate a-hydroperoxides or other products resulting from hydroperoxide decomposition [21-23]. Autoxidation under basic conditions also requires generation of an enol or enolate [ 3 ] ;under photochemical or protic conditions, tautomerism of the carbonyl compound to an enol may be observed prior to autoxidation [24-251. Both on the basis of detection of enol radicals as discrete intermediates in certain cases [24] and on kinetic studies [26], these reactions proceed via a chain reaction involving peroxyl radicals, whose rate-determining step is formation of the corresponding enol or enolate [21-241. For a neutral enol, the individual steps may be formalized as depicted in Scheme 9 ( R ” 0 H = enol; R ” 0 ’ = enol radical; R”’O0’ = a-keto peroxyl radical; R”’O0H = a-keto hydroperoxide):
R’OO.
R’OOH
Scheme 9
Neutral enols can be preformed by photochemical enolization of carbonyl compounds. The enols in the presence of oxygen are then rapidly converted into hydroperoxides under thermal conditions (Scheme 10) [24, 271. Enols have also been generated as isolable intermediates in the ’1,4’-hydrogenation of steroidal enones. Under neutral conditions, the enols are readily autoxidized to hydroperoxides, which can be reduced to the corresponding alcohols (Scheme 11) [281.
Scheme 10 [24]
5.4.4 Autoxidation of Curbonyl Compounds
HO"
461
2) (Et0)3P
EtOH 20 "C
H0''
Scheme 11 1281
Scheme 12 1291
50%, R = Me 80%, R = Ph
Scheme 13 1301
Isolable enols have also been produced by methanolysis of enol trifluoroacetates. Such enols rapidly undergo autoxidation at room temperature in non-polar solvents (benzene, dichloromethane or chloroform) to give hydroperoxides in high yields (Scheme 12) [29]. A fourth, more recent method for generating enols via Hock cleavage of allylic hydroperoxides is discussed in Section 5.4.4.2. It follows that any carbonyl compound which undergoes facile enolization is prone to spontaneous autoxidation. Thus, P,y-unsaturated ketones [6b, 301 and cyclic 1,3-diketones [311 readily autoxidize under neutral conditions as illustrated by the examples in Scheme 13 [30, 311. Although enols may be involved in these reactions, direct C-H abstraction is also feasible [30]. aJ'-Unsaturated carbonyl compounds are usually less reactive toward molecular oxygen than their P,y-unsaturated counterparts [32]. A general procedure for the autoxidation of a,B-unsaturated ketones lacking a'-hydrogens entails stirring at
462
I'
5.4 Peroxyl Radicals in Synthesis
I
AIBN 60 "C, 15 h
J
66%
Scheme 14 (331
60 "C under oxygen in the presence of tert-butyl hydroperoxide and AIBN as initiator. The resulting y-hydroperoxides were reduced to the corresponding alcohols as shown by the example in Scheme 14 [33]. It has been suggested that autoxidation proceeds via direct abstraction of the y-hydrogen atom of the enone [33]. The autoxidation of carbonyl compounds under basic conditions has found numerous applications in organic synthesis; this topic has been reviewed [3]. In general, base-induced reactions become synthetically useful when enolate formation is regiochemically defined. Such enolates are generated either by deprotonation of the carbonyl compound with a base [3] or via conjugate addition of organometallics to a,B-unsaturated carbonyl compounds [ 341. The resulting a-hydroperoxides are usually unstable [8b, 351, and only a few have been isolated in pure form [35]. In most cases they are reduced in situ to the corresponding alcohols [3] or decomposed to give other products depending upon the nature of the substrate and the reaction conditions [25, 34, 361. An especially noteworthy development is Shioiri's catalytic enantioselective autoxidation process which allows a-hydroxyketones to be obtained (after in situ reduction of the hydroperoxides) in high yields and reasonable optical purity (Scheme 15) [37]. In a study on the synthesis of the antibiotic SF 2315B, the core structure of the natural product was assembled in stereocontrolled fashion by TBAF-induced autoxidation of a quinone (cf. 8 4 9, Scheme 16), thereby forming three stereocenters and three C-0 bonds in a single operation [38]. A reaction cascade involving sequential oxygenation of an enol radical, cyclization and cleavage of the resultant endoperoxide accounts for this transformation [ 381.
P(OW3 PhMe / aq. NaOH
02,
5% mol Cat.
Me0
79%ee 95% yield
Cat.
Scheme 15 [37]
5.4.4 Autoxidation of' Curhonyl Compounds
463
TBSO, 02,
TBAF
+
*
THF, - 78 "C
+ rt HO
HO
TBSO,
HO
0
29%
TBSO,
HO
HO
0
24%
TBSO,
0
HO
0.
Scheme 16 [38]
5.4.4.2 Preparation of Cyclic Peroxides With the increasing frequency of isolation of cyclic peroxides from natural sources [ 391 and the demonstrable antiparasitic and many other biological properties possessed by both the natural products and their analogs, there is currently considerable interest in the synthesis of such compounds [5]. In particular, the opportunity of exploiting the facile conversion of enols or enolates into peroxyl radicals and then inducing cyclization of the peroxyl radical (or hydroperoxide) by addition to a distal carbonyl group is apparent. In an early example, spontaneous autoxidation of the Knoevenagel product of syncarpic acid and isobutyraldehyde cleanly provided the plant growth regulator G3 isolated from Eucalyptus grandis (Scheme 17) [40]. A closely related autoxidationcyclization has been reported more recently for Knoevenagel adducts derived from cyclohexane-1,3-dione (Scheme 17) [41].
WI
0 80%
OH SPh Na104 H20,MeOH *
Scheme 17
OH G3
464
5.4 Peroxyl Radicals in Synthesis
02,
PhH
7 days
80% 0
peroxide
Scheme 18 [42]
Alpinolide peroxide, a secoguaiane-type sesquiterpenoid from Alpinia juponica, has been prepared with complete stereocontrol by autoxidation of a p,y-butenolide (Scheme 18) [42]. Conceivably, tautomerization of the butenolide to 2-furanol may occur prior to oxygenation. The biogenesis of alpinolide peroxide appears to proceed by a similar pathway [42]. Mesityl oxide is oxygenated under irradiation in methanol in the presence of copper(I1) sulfate to give a peroxy acetal via photoenolization and stabilization of the s-cis conformation of dienol by Cu(I1); the intermediate peroxyhemiacetal undergoes exchange with the solvent to generate the peroxyacetal (Scheme 19) [43]. Closely related reactions have been used in the preparation of natural products [44], e.g. (+)-isoacetylsaturejol (Scheme 20) [44b] and several unnatural antimalarial compounds exemplified by the para-nitrophenyl peroxyacetal shown below (Scheme 20) [45]. A dramatic recent application of the enol autoxidation-peroxide cyclization technology has been the preparation of the Chinese peroxidic antimalarial artemisinin (qinghaosu, QHS) from dihydroartemisinic (dihydroqinghao) acid (DHQA) [46-481. Based on a proposal relating to biosynthesis of QHS from artemisinic (qinghao) acid [48], the latter was reduced to DHQA, which was converted by reaction with singlet oxygen primarily into a tertiary allylic hydroperoxide. This, without isolation, was treated with catalytic Cu(I1) triflate to generate QHS in 29% overall yield from DHQA (Scheme 21) [46]. While it was initially assumed that the peroxyl radical derived from the allylic hydroperoxide was involved in this reaction, an examination of the reaction by using the hydroperoxide of the methyl ester of artemisinic acid demonstrated that
Scheme 19 [43]
5.4.4 Autoxidution
1) CuSO4, 02, hv (350 CH2CI2-MeOH nm)
rQ
2) H30'
of Curbonyl Compounds
,OH
?
465
"W 52%
(+)-lsoacetylsaturejol 0 02,
hv (350 nrn)
% 0-0 OMe
-
cuso4 ~0~ CH2C12-MeOH
[451
NO2
Scheme 20
0 2 ,MeCN MB, hv
HOOT 9 CU(OTf)2 air
OH CH2C12-MeCN
OH
\<<
DHQA
~
0
\\\
0
QHS
0
0 29% overall
Scheme 21 (461
9
u .
&OMe
4 O M e 0
0
I OHC
4
4 O M e
0 1
0
9
N2
HO"' OMe 0
0
0
Artemisitene
Scheme 22 [47-481
the Lewis acidic Cu(I1) catalyst induced Hock cleavage of the allylic hydroperoxide to generate, not the expected ketoaldehyde, but rather a simple enol, which was isolated and characterized by NMR spectroscopy (Scheme 22) [47-481. The enol under oxygen in the presence of Cu(I1) is rapidly converted into an equilibrating
466
5.4 Peroxyl Radicals in Synthesis
n
79%: electrochemical initiation 66%; AlBN initiation
I OH
Scheme 23 [ 5 1]
mixture of the hydroperoxide and peroxy hemiacetal; treatment of this mixture with tosic acid generated artemisitene, another peroxide which occurs in A . annua (Scheme 22) [47-481. Under nitrogen, direct closure to the aldol is followed by retroaldolization to a ketoaldehyde. The ketoaldehyde is unaffected by exposure to oxygen in the presence of Cu(I1). Related autoxidation reactions involving the hydroperoxide of dihydroartemisinic acid leading to artemisinin but using trifluoroacetic acid instead of Cu(I1) were reported independently by Roth and Acton [49]. The generation of enols by Hock cleavage is significant from both synthetic and biosynthetic viewpoints; other examples have been noted [48, 501. Carbon radicals generated by the addition of enol radicals derived from 1,3dicarbonyl compounds to alkenes are efficiently trapped by oxygen in a chain reaction leading to hemiperacetals [ 511. The process is illustrated by the electrochemical or AIBN-initiated reaction of 2-methyl- 1,3-~yclopentanedionewith styrene and oxygen in acetonitrile, which provides the thermodynamically favored all-cis bicyclic peroxide in good yield (Scheme 23) [51]. A complementary process, which succeeds with a wide range of enolizable substrates, makes use of transition metals for the generation of enol radicals (Scheme 24) [52]. Although Mn(II1) acetate is commonly used, the combination of Mn(I1) and Mn(II1) acetates is usually more effective [52f]. The hemiperacetal products can be readily transformed to trisubstituted furans by heating under reflux in acetonitrile in the presence of perchloric acid, as illustrated by the examples in Scheme 24 [53]. This process involves aryl migration to the adjacent oxygen atom with rupture of the 0-0 bond [53].
5.4.5 Autoxidation of Phenols Substituted phenols, such as 2,6-di-tert-butyl-p-cresol, readily inhibit autoxidation reactions through formation of the corresponding phenoxyl radicals (ArO') [ 541. The latter may undergo either oxygenation to give ketohydroperoxides by a chain
5.4.5 Autoxidatiori of Phenols
467
,x + RCOCH2X
or air, Mn(OAc)3
0 2
Ar
AcOH, rt
Ar
0-0 OH
X = COR', COOR', CN, CONR'R", SOR', S02R', PO(OMe)2
* EtoocKl +
Ph
Ph
P
N Bn
t
Ph
-
4
2
0-0 OH
air, Mn(OAc)3 AcOH, 23 "C, 12 h
[52h]
O.0
84% OH
HC104
MeCN, A 15rnin
:hhq:'Bn
Ph
Me
93%, R = Me 90%, R = OMe 57%, R = NH2
[531
Scheme 24
PhH, O2rt, 3h*
&OH
&
Scheme 25 [56]
I
t
Scheme 26 [57]
process in which the phenoxyl radical is captured at the ortho or para position by molecular oxygen or coupling to biphenyls or aromatic ethers [54, 551. Oxygenation to ketohydroperoxides may occur spontaneously or in the presence of bases or metals [6d], especially Co(I1) complexes [55]. Among the few substrates that undergo spontaneous autoxidation are 1-alkyl-2-naphthols, which are converted to 1-hydroperoxynaphthalen-2( 1H)-ones in highly regioselective fashion, as illustrated below (Scheme 25) [56]. Recently, an interesting spontaneous autoxidation of a cyclopropyl phenol to a 1,2-dioxolane (Scheme 26) was reported by Creary [57]. The proposed pathway in-
468
5.4 Peroxyl Radicals in Synthesis -
HO OOH and I or
Scheme 27 [58]
volves rearrangement of the initially formed phenoxyl radical to a carbon-centered radical, oxygen entrapment and conjugate addition of the resulting peroxyl radical to the dienone [57].The same dioxolane was formed upon TBAF-deprotection of the TBS ether of the starting phenol [57]. Although the autoxidation of phenols has not found many applications in the laboratory, it has long been exploited by industrial chemists for the production of hydrogen peroxide. In an ingenious process, which is still widely used today, a 2alkylanthraquinol is autoxidized to the corresponding anthraquinone and hydrogen peroxide. The anthraquinone is then hydrogenated back to anthraquinol so that the net outcome is: HZ 0 2 -+ H202 (Scheme 27) [ 5 8 ] .
+
5.4.6 Autoxidation of Nitrogen Compounds It is well known that many classes of nitrogen compounds, including imines, enamines and hydrazones of the type RR'C=X-NHR2 ( X = CR3 or N ) , 9aminoanthracenes and 2,3-disubstituted indoles, autoxidize spontaneously at room temperature to give hydroperoxides via peroxyl radicals [6c, 81. An early but pertinent example is the 100-g scale autoxidation of 2-methyl-3-phenyl-3,4,5,6tetrahydropyridine in cyclohexane (Cy) to provide the corresponding hydroperoxide in excellent yield (Scheme 28) [59].
air, Cy rt, 20 h
98%
Scheme 28 [59]
5.4.6 Autoxidotion o j Nitrogen Compounds
i-PrCHO
+
H2NAr
469
air, hexane
25-30 "C
Scheme 29 [60]
"&"
air acetone-d6
,N-N 10 (R = Me)
- 20 "C, 3 h - 80%
+"Ph p h N=N A O O H 11
02,
PhH
-22 "C, 1-3 h 48%
0-0 12
Scheme 30 [61]
5-Aryl or heteroaryl 1,2,4-trioxanes have been prepared in variable yields from amines and aldehydes by autoxidation of the in situ-formed imine and reaction of the resulting hydroperoxide with excess aldehyde (Scheme 29) [60]. This one-pot sequence provides the 1,2,4-trioxanes as diastereomeric mixtures with the cis-isomer predominating [60b]. Low-temperature autoxidation of 3,4-dihydro-2H-pyrazoles (e.g. 10, R = Me) provides unstable cc-azo hydroperoxides (Scheme 30) [61a,b]; 3,4-dihydro-2Hpyrazoles that are inert towards autoxidation (cf. 10, R = Ph) can be converted to hydroperoxides by reaction with singlet oxygen (photooxygenation) at 0-5 "C [61b]. cc-Azo hydroperoxides readily decompose at room temperature to P-keto radicals which can be entrapped with oxygen to furnish 3-hydroxy-l,2-dioxolanes(e.g. 11 + 12, Scheme 30) [61c]. The preparation and thermal decomposition of several ether, silyl ether and ester derivatives of 3-hydroxy- 1,2-dioxolanes have been reported [621. Hydroperoxides obtained by autoxidation of 2,3-disubstituted indoles have long been known to undergo facile rearrangement to ketoamides, presumably via thermal decomposition of 1,2-dioxetane intermediates (Scheme 31) [8, 631. When the autoxidation is carried out under basic conditions (t-BuOKIDMF), the initially formed ketoamides undergo intramolecular aldol-type condensation to give quinolinones in a preparatively useful process known as Winterfeldt oxidation [64].
470
5.4 Peroxyl Radicals in Synthesis
Scheme 31 [63]
O2 or air
/
R 13a, 13b, R = H COOEt
Path a
0 1Path b & decarboxylation
\
H 79% from 13a
N
O
H 72% from 13b
Scheme 32 [65]
The versatility of this methodology is illustrated by Husson’s regiocontrolled synthesis of pyrrolo[3,4-b]quinolin-9-ones (path A) and pyrrolo[2,3-c]quinolin-4-ones (path B) from 1,2,4,5-tetrahydro-/?-carbolines 13a and 13b (Scheme 32) [65]. Another interesting recent development from Husson’s laboratory is the autoxidation of tetrahydrocarbazol- 1-one under Winterfeldt’s conditions. This reaction did not produce the expected lactam 14 but imide 15 instead (Scheme 33) [66]. In situ autoxidation of the initially formed lactam 14 (or its 2-hydroxypyrrole tautomer) to a hydroperoxide and subsequent Kornblum-De La Mare type fragmentation [ 171 accounts for this unprecedented transformation (Scheme 33) [66]. A remarkable seven-step reaction cascade, involving autoxidation of a transient 2-aminofuran [67], was recently employed by Nicolaou for installing the maleic anhydride moiety of the architecturally unique natural products CP-263,114 and CP-225,917 (cf. 16 + 17, Scheme 34) [68]. The proposed pathway to maleic anhydride (Scheme 35) [67]entails b-elimination of the epoxide (A 4 B), 5-exo-dig cyclization of alkoxide B to give the unprecedented imino compound C, tautomerization to 2-aminofuran (C D), oxygena---f
5.4.6 Autoxidation of Nitrogen Compounds 02
0
14
(3 bar)
rt, 5 days
50%
15
1
0 Base
0
Scheme 33 [66]
Me0 OMe
“RI
3) H ~ O + air
16
(k)-CP-263,114
Scheme 34 [68]
Scheme 35 1671
I
17
(k)-CP-225,917
47 1
472
5.4 Peroxyl Radicals in Synthesis
tion, tautomerization (E F), peroxide fragmentation and eventual hydrolysis of the imino butenolide to maleic anhydride (G + H). --f
5.4.7 Oxygenation of Cycloalkanols and Related Compounds The propensity of cyclopropanols to undergo free-radical opening reactions triggered by facile hydrogen abstraction from the hydroxyl group has been recognized for some time [69]. This propensity manifests itself in the reaction of cyclopropanone cyanohydrins with oxygen in acetonitrile at 50°C in the presence or absence of silver nitrate to provide 1,2-dioxolan-3-ones @-peroxy lactones) (Scheme 36) [70]. Evidence for a radical chain mechanism was secured by the addition of 2,6di-tert-butyl-para-cresol (0.1 equiv), which resulted in full recovery of the starting material, even in the presence of silver nitrate [70]. The cyanohydrin was also recovered intact after heating in acetonitrile under nitrogen [ 701. Likewise, non-functionalized cyclopropanols readily undergo autoxidation to give 1,2-dioxolan-3-0ls and/or keto hydroperoxides in high yields (Scheme 37) [711.
02,MeCN 50 "C, 12 h 52% 61% (AgN03)
I ph&cNPh
PhfiCN
0.
Scheme 36 1701
Scheme 37 171]
Ph
0
-
t
N C, ,2', . - fhP Ph00. 0
5.4.7 Oxygenation of Cycloalkanols and Related Compounds
CH2N2
R=H ( 19, 20, R = Me (81% from 18)
473
0
Scheme 38 [72]
An effective method for inducing fragmentation-oxygenation of bicyclic alcohols and lactols that do not readily autoxidize has been reported by SuareL [72-741. Typically, the alkoxyl radical is generated by photolysis in the presence of an excess of (diacet0xyiodo)benzene (DIB) and iodine under oxygen (or air). Ensuing fragmentation and oxygenation leads to a peroxyl radical which may add to the carbony1 group to form a cyclic peroxide, as illustrated by the transformation of lactol 18 to P-peroxy lactone acid 19 (Scheme 38) [72].Treatment of the product mixture with diazomethane provides the ester 20 in 81% overall yield [72]. Other reagents, including lead tetraacetate (LTA) or HgO, can be used instead of DIB, although the latter is usually more effective [72-741. In all cases an excess of the reagent must be used (typically 1.5 equiv for DIB) since a chain reaction involving abstraction of the hydrogen atom from hydroxyl cannot be maintained by the peroxyl radical. A complcrnentary pathway involves addition of the peroxyl radical to a double bond to generate a carbon radical, which is eventually trapped by oxygen or iodine [73]. Thus, alcohol 21 is converted to diastereomeric iodides 22 (Scheme 39) "731. On treatment with silica gel, the iodides undergo facile p-elimination to afford a single 1,2-dioxane product (23) [73]. A distinctly different reaction cascade leading to tetrahydrofurans is illustrated in Scheme 40 [74]. It was proposed that these reactions proceed by iodine-mediated deoxygenation of the peroxyl radical to an slkoxyl radical, which undergoes intramolecular C-H abstraction to form a /?-keto radical [74]. Elimination of an M hydrogen atom generates an enone, which is ultimately captured intramolecularly by conjugate hydroxyl addition to give a tetrahydrofuran (Scheme 40). Several other tetrahydrofurans have been obtained from steroidal precursors in completely diastereoselective fashion [ 741. The preparative value of this chemistry was demonstrated by an expedient synthesis of the A-A' bicyclic unit of the natural product limonin (Scheme 41) [74].
474
5.4 Peroxyl Radicals in Synthesis %Hi7
dP OH
DIB,
12,
hv
Si02
+
-HI
(2 atm) Cy, 40-45 "C 1.75 h 0 2
'
t
22
23 50% (from 21)
?at@ 0
Scheme 39 [73]
DIB,
12,
h t
O2 (3.5 atm) Cy, 40 "C, 1 h
Ph 49% 0 -H, ill,4-addition
O@ Ph
0
Scheme 40 [74]
56%
Scheme 41 [ 741
I
Lirnonin
I
5.4.8 Peroxyl Radicals from Hydroperoxides
475
5.4.8 Peroxyl Radicals from Hydroperoxides 5.4.8.1 Peroxyl Radical Cyclization On a per hydrogen basis, tert-butoxyl radicals abstract hydrogen 200-1000 times faster from a hydroperoxyl than an allylic methylene or methyl [75]. Consequently, specific peroxyl radicals are accessible on treatment of unsaturated hydroperoxides with a convenient source of tert-butoxyl radicals such as DBPO [ 12a] or DTBN [12b] (see also Section 5.4.2). This strategy was first employed by Porter to study peroxyl radical cyclization pathways as models for prostaglandin biosynthesis [7a, 751. A typical example is the conversion of hydroperoxide 24 to 1,2-dioxane 25 (Scheme 42) [75]. The process is initiated by abstraction of the hydroperoxyl hydrogen by the tert-butoxyl radical to generate peroxyl radical A. Intramolecular addition to the alkene, followed by oxygenation of the resulting carbon radical B, leads to a new peroxyl radical C, which maintains the chain process by generating radical A (Scheme 42). The low yield of 25 (23%) can be attributed to termination reactions involving dimerization of C to an unstable tetroxide (see Section 5.4.2). DBPO
02,
t-BuO.
(
23%
1 . 3
y
A
-
PhH, rt,48h
24
-
&
”
W
B
25
t O
(24
+ A)
’
C
Scheme 42 [75]
Several 1,2-dioxolanes [7, 75-76] and polycyclic peroxides [7, 771 have been obtained in modest yields from unsaturated hydroperoxides by peroxyl radical cyclization-oxygenation pathways under initiation with DBPO or DTBN (cf. Scheme 43) [76a, 771. In general, there is a strong bias for exo cyclization [7a, 75b], although an exception has been noted [78]. Moreover, when there is a choice, the 5-exo-trig mode is preferred over the 6-exo-trig [76c]. In 1994, Corey reported a new reagent, obtained by reaction of SmI2 in T H F with oxygen [79], which is particularly effective for inducing cyclization of alkenyl hydroperoxides (Scheme 44) [79, 801. It was proposed that this reagent, presumably ‘I2SmOOSmI2’, may produce IZSmO’ as the initiating species [79]. A short synthesis of the antimalarial peroxide yingzhaosu C, which allowed the relative stereochemistry of the natural product to be assigned as cis, has been achieved by means of tandem peroxyl radical cyclization-oxygen entrapment
476
5.4 Peroxyl Radicals in Synthesis 02,
DBPO 1764
PhH, rt,19 h * 20% OOH
02,
0-0
DTBN
PhH, 30 "C, 48-72 h ca. 50% conversion
-
0-0
0-0
OOH [771
Scheme 43
OOH
02,"12Sm00Sm12" PhH-THF, 23 "C, 15 h *
W
O
O
H
70% Scheme 44 1791
Initiator
27b Initiator / Dtn time DBPO, 7 h DBPO, TBHP, 4.5 h
Yield (Yo)of 27
1
91%
nuI f
PPh3, PhH, 5-10 "C, 1h
epi-Yingzhaosu C
0-0
94% ---a,
OH
Yingzhaosu C
Scheme 45 [ 8 11
(Scheme 45) [81]. After probing several initiators, it was found that a combination of DBPO (0.5 equiv) and tert-butyl hydroperoxide (TBHP; 10 equiv) is remarkably effective for inducing cyclization of hydroperoxide 26 to diastereomeric 1,2-dioxanes 27a and 27b (811. More recently, Nojima utilized the DBPO-TBHP procedure for making 1,2,4trioxanes and trioxepanes from unsaturated hydroperoxy acetals (cf. Scheme 46) [ 821. The preparation of 1,2,4-trioxepanes is especially noteworthy since sevenmembered cyclic peroxides have not been previously obtained by such pathways. An appealing cycloperoxyhalogenation route to 1,3-dioxolanes from alk-3-enyl hydroperoxides was reported some time ago by Blooodworth [83]. Reactions with bromine, iodine or N-bromosuccinimide (NBS) proceed primarily by ionic pathways and tend to be stereoselective. However, the use of N-iodosuccinimide (NIS) leads to diastereomeric mixtures, suggesting that in this case the reaction proceeds
5.4.8 Peroxyl Radicals from Hydroperoxides
477
54%, n = 1 31%, n = 2
Scheme 46 [82] F
E
t
NIS, CH2C12
OOH
?Et
00
t
+
.
mEt 0-0
Initiation
OOH
F OOH E
*
rt, 0.5-3 h ca. 50%
:>
-
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<'""W C O O M e
+
MeO"
Plakortin
-
COOMe
ent-Chondrillin
Scheme 50 [89]
5.4.9 Thiol-Oxygen-Co-Oxidation (TOCO) and Related Processes Beckwith pioneered the use of a Thiol-Oxygen-Co-Oxidation (TOCO) process for the transformation of 1,4-dienes and 1,3,6-trienes to 1,2-dioxolanes [90]. As illustrated by the example in Scheme 51 [90a], this process involves phenylthio radical addition to the least substituted double bond, oxygen entrapment, peroxyl radical cyclization, oxygen entrapment and hydrogen atom transfer from the thiol. In accord with the Beckwith-Houk transition state model [91, 921, cyclization provides preferentially the cis-3,5-disubstituted 1,2-dioxolanes. Recently, Bachi applied the TOCO process to the synthesis of new antimalarial analogs of yingzhaosu A [93]. An example is shown in Scheme 52 [93a].
d
dH
PhS
0-0
-
PhSH
t
4'
PhS
PhS+
0-0
Scheme 51 [90a]
480
5.4 Peroxyl Radicals in Synthesis
y /
02, PhSH, DBPO
9
P
h
S
T
Ph& CH $32 P
h
S
T
c
0-5 "C, 2 h
PhH, heptane, rt, 24 OOH
I
54% OH
overall
Scheme 52 [93a]
AcOH, 0 2 , PhSH 19 h, rt *
bSPh OH
75%
Scheme 53 I951 02,
4Ph
Ph&
(or Ph2Se2)
AIBN,MeCN,O"C
PhS-1
PhSAPh
PhS-
W *
P
0-0 63%
-PhS
.
h
-1
0-0
Ph
02
t -0-0
Scheme 54 [97a, 981
An interesting variant is provided by the addition of phenylthio radicals to a y,dunsaturated carbonyl compound in acetic acid in the presence of oxygen, wherein the resulting peroxyl radical or hydroperoxide is trapped by carbonyl group to provide a cyclic hemiperacetal [94, 951. In the example below, a single stereoisomer is obtained (Scheme 53) [94]. These reactions may be accelerated through electrochemical generation of the phenylthio radical. Under electrolytic conditions, alkenylsilanes are converted to ct-phenylthio carbonyl compounds in good yields [96]. Feldman has developed a new version of the TOCO process [97-981 that incorporates a cyclopropylcarbinyl-homoallyl rearrangement, as illustrated by the example in Scheme 54 [97a]. The stereochemical outcome of cyclization can be
References
48 1
modulated by the appropriate substitution. Thus, alkyl and aryl groups confer cisselectivity whereas certain electron-withdrawing groups such as COOCH(CF3)2 provide preferentially the trans product [99]. This methodology was utilized in conjunction with peroxide reduction as a stereocontrolled pathway to allylic 1,3-diols [98]. The single-electron reductant SmI2 was found to be especially effective for this purpose [loo]. An application of this chemistry to the synthesis of a naturally occurring 1,3,5-triol has been reported [98, 1001.
References [ I ] Pero.wyl Radicals (Ed.: Z . B. Alfassi), Wiley, Chichester, 1997. [2] (a) J. Fossey, D. Lefort, J. Sobra, Free Radicals in Organic Chemistry, Wiley, Chichester, 1995, Chapter 16. (b) Chapter 24 in ref 2a. [3] A. B. Jones in Comprehensive Organic Synthesis (Eds: B. M. Trost, I. Fleming), Vol. 7 (Ed.: S. V. Ley), Pergamon Press, Oxford, 1991, pp 151-191. A. B. Jones in Encyclopedia of Reagents,for Organic Synthesis (Ed.-in-Chief: L. A. Paquette), Wiley, Chichester, 1995, Vol. 6, pp. 3832-3836. [4] N. A. Porter, Acc. Chem. Rex 1986, 19, 262. [5] K. J. McCullough, Contemp. Org. Synth. 1995,2, 225. 161 (a) H. Kropf, S. Munke in Methoden der Organischen Chernie (Houben-Weyl): Band E l 3 ‘Organische Peroxo-Verbindungen’, Georg Thieme, Stuttgart, 1988, pp. 59-70. (b) H. Kropf, S. Munke, pp. 64-70 in ref. 6a. (c) H. Kropf, S. Munke, pp. 121-126 in ref. 6a. (d) J. Pospisil, pp. 126-134 in ref. 6a. [7] (a) N. A. Porter in Organic Peroxides (Ed.: W. Ando), Wiley, Chichester, 1992, Chapter 2. (b) E. L. Clennan, C. S. Foote in ref. 7a, Chapter 6. [8] (a) A. G. Davies, Organic Peroxides, Butterworths, London, 1961, Chapter 1. (b) R . Hiatt in Organic Peroxides (Ed.: D. Swern), Wiley-Interscience, New York, 1971, Vol. 11, Chapter 1. [9] (a) Z. B. Alfassi in ref. I , Chapter 1. (b) R. Lesclaux in ref. I , Chapter 6. (c) Z . B. Alfassi, R. E. Huie, P. Neta in ref. I , Chapter 9. (d) A. Howard in ref. 1, Chapter 10. [lo] P. D. Bartlett, R. Banavali, J. Org. Chem 1991, 56, 6043. [ 1 I ] (a) Chapter 8 in ref. 2a. (b) S. W. Benson, N. Cohen in ref. 1, Chapter 4. (c) C. von Sonntag, H.-P. Schuchmann, in ref. I , Chapter 8. [ 121 (a) J. Boukouvalas in Encyclopedia qf Reagents f b r Organic Synthesis (Ed.-in-Chief: L. A. Paquette), Wiley, Chichester, 1995, Vol. 3, pp 1621-1623. (b) J. Boukouvalas in Encycloprdia of Reagents f b r Orgunic Synthesis (Ed.-in-Chief: L. A. Paquette), Wiley, Chichester, 1995, Vol. 3, pp 1610-1612. [I31 (a) J. L. Courtneidge, M. Bush, J. Chem. Soc., Perkin Trans. I 1992, 1531. (b) J. L. Courtneidge, M. Bush, L . 3 . Loh, J. Chem. Soc., Perkin Trans. I 1992, 1539. (c) N. A. Porter, K. A. Mills, R. L. Carter, J. Am. Chem. Soc. 1994, 116, 6690. [I41 (a) W. Jordan, H. van Barneveld, 0. Gerlich, M. Kleine-Boymann, J. Ullrich in Ullmunn’s Encyclopedia of Industrial Chemistry, 5th Edition, VCH, Weinheim, 1991, Vol. A19, pp 299312. (b) J. W. Frost, K. M. Draths, Chem. in Britain 1995, 31, 206. [I51 (a) Y . Hashidoko, S. Tahara, J. Mizutani, J. Chem. Soc., Perkin Truns. I 1991, 21 I . (b) Y. Hashidoko, S. Tahara, J. Mizutani, J. Chem. Soc., Chem. Commun. 1991, 1185. (c) H. Morita, N. Tomioka, Y . Iitaka, H. Itokawa, Chem. Pharm. Bull. 1988, 36, 2989. [I61 (a) D. H. R. Barton, D. Crich, W. B. Motherwell, J. Chem. Soc., Chem. Commun. 1984, 242. (b) D. H. R. Barton, D. Crich, W. B. Motherwell, Tetrahedron 1985, 41, 3901. (c) A. J. Bloodworth, D. Crich, T. Melvin, J. Chem. Soc., Chem. Commun. 1987, 786.
482
5.4 Peroxyl Radicals in Synthesis
[I71 N. Kornblum, H. E. De La Mare, J. Am. Cheni. Soc. 1951, 73, 880. [ 181 H. C. Brown, M. M. Midland, Tetrahedron 1987, 43, 4059 and cited refs. [ 191 I. Klement, P. Knochel, Synlett 1995, 11 13. I. Klement, H. Lutjens, P. Knochel, Tetrahedron 1997,53, 9135. [20] L. Collazo, F. S. Gusiec, Jr., W.-X. Hu, A. Muiioz, D. Wei, M. Alvarado, J. Org. Chem. 1993, 58, 6169. [21] H. C. Volger, W. Brackman, J. W. F. M. Lemmers, Rec. Trav. Chim. Pays-Bus 1965, 84, 1203; W. Brackman, C. J. Gaasbeek, P. J. Smit, Rec. Trau. Chim. Pays-Bas 1966, 85, 437; V. Van Rheenen, Tetrahedron Lett. 1969, 985; L. M. Sayre, S.-J. Jin, J. Org. Chem. 1984, 49, 3498; S.-J. Jin, P. K. Arora, L. M. Sayre, J. Org. Cheni. 1990, 55, 3011. [22] H. J. den Hertog, E. C. Kooijman, J. Cutal. 1966, 6, 357; E. T. Denisov, V. D. Kimissarov, D. I. Metelitsa, Discuss. Furaduy Soc. 1968, 127; V. D. Komissarov, E. T. Denisov, Kinet. Kntal. 1969, 10, 513 (CA 71:74613); Y. Kamiya, M. Kotake, Bull. Chem. Soc. Jap. 1973, 46, 2780; J. Lubach, W. Drenth, Recl. Trau. Chim. Pays-Bas 1973, 92,403; A. N . Grechkin; R. A. Kuramshin, E. Y. Safonova, L. S. Mukhtarova, S. K. Latypov, A. V. Ilyasov, Chem. Phys. Lipids 1993,66, 199; H. B. Dunford, Quim. Nova 1993,16, 350 (CA 120:24994). [23] G. Midgley, C. B. Thomas, J. Chem. Soc., Perkin Trans. 2 1987, 1103. [24] H. Goerner, J. Leitich, 0. E. Polansky, W. Riemer, U. Ritter-Thomas, B. Schlamann, Monutsh. Cheni. 1980, 111, 309. [25] T. Ishikawa, K. Hino, T. Yoneda, M. Murota, K. Yamaguchi, T. Watanabe, J. Org. Chem. 1999, 64, 5691. 1968, 127; V. D. [26] E. T. Denisov, V. D. Kimissarov, D. I. Metelitsa, Discuss. Faruduy SOC. Komissarov, E. T. Denisov, Kinet. Kutal. 1969, 10, 513 (CA 71:74613). L. Barhacs, J. Kaizer, G. Speier, J. Org. Chem. 2000, 65, 3449. [27] B. J. Ramey, P. D. Gardner, J. Am. Chem. Soc. 1967,89, 3949. [28] P. R. Enslin, Tetrahedron 1971, 27, 1909. [29] J. W. Jaroszewski, M. G. Ettlinger, J. Org. Chem. 1988, 53, 4635. [30] A. B. Smith 111, J. Kingery-Wood, T. L. Leenay, E. G. Nolen, T. Sunuzaka, J. Am. Chem. SOC. 1992, 114, 1438. [311 H. Brederick, G. Bauer, Liebigs Ann. C‘hem. 1970, 739, 117. [32] For an exception, see: R. V. Venkateswaran, P. Goswami, Tetrahedron Lett. 1977, 1943. [33] M. R. Sabol, C. Wiglesworth, D. S. Watt, Synth. Commun. 1988, 18, 1. [34] S. P. Modi, J. 0. Gardner, A. Milowsky, M. Wierzba, L. Forgione, P. Mazur, A . J. Solo, W. L. Duax, Z. Galdecki, P. Grochulski, Z. Wawrzak, J. Org. Chem., 1989 54, 2317. [35] See for example: W. Adam, 0. Cuerto, J. Org. Chem., 1977 42, 38; J. D. Druliner, F. W. Hobbs, W. C. Seibel, J. Ory. Chem., 1988 53, 700. [36] D. V. Rao, F. A. Stuber, H. Ulrich, J. Org. Chem. 1979, 44, 456. W. Sucrow, Chem. Ber. 1967, 100, 259. F. G. Bordwell, A. C. Knipe, J. Am. Chem. SOC.1971, 93, 3416. L. A. Paquette, S. Borrelly, J. Org. Chem. 1995, 60, 6912. [37] M. Masui, A. Ando, T. Shioiri, Tetrahedron Lett. 1988, 29, 2835. [38] K. Kim, Y. Guo, G. A. Sulikowski, J. Org. Chem. 1995, 60, 6866. [39] D. A. Casteel, Nut. Prod. Rep. 1992, 9, 289. D. A. Casteel, Nut. Prod. Rep. 1999, 16, 55. [40] M. L. Bolte, W. D. Crow, S. Yoshida, Aust. J. Chem. 1982, 35, 1421 and cited refs. [41] K. Fuchs, L. A. Paquette, J. Org. Chem. 1994, 59, 528. [42] H. Itokawa, H. Morita, K. Osawa, K. Watanabe, Y. Iitaka, Chem. Pharm. Bull. 1987, 35, 2849. [43] T. Sato, K. Tamura, K. Maruyama, 0. Ogawa, T. Imamura, J. Chem. Soc., Perkin Trans. 1 1976, 779. [44] (a) B. V. Snider, Z. Shi, J. An?. Chem. Soc. 1992, 114, 1790. (b) B. V. Snider, S. V. O’Neill, Synth. Commun. 1995, 25, 1085. [45] G. H. Posner, H. O’Dowd, P. Ploypradith, J. N. Cumming, S. Xie, T. A. Shapiro, J. Med. Chem. 1998, 41, 2164. [46] R. K. Haynes, S. C. Vonwiller, J. Chem. Soc., Chem. Commun. 1990, 451. [47] S. C. Vonwiller, J. A. Warner, S. T. Mann, R. K. Haynes, J. Am. Chem. Soc. 1995, 117, 11098. [48] R. K. Haynes, S. C. Vonwiller, ACC.Chem. Res. 1997, 30, 73.
References
483
1491 R. J. Roth, N. Acton, J. Nut. Prod. 1989, 52, 118. N. Acton, R. J. Roth, J. Org. Chem., 1992, 57. 3610. [50] R.’K. Haynes, S. C. Vonwiller: J. Clien~.Soc., Cheni. Commun. 1990, 449. 1511 J. Yoshida, S. Nakatdni, K. Sakaguchi, S. Isoe, J. Org. Chern. 1989, 54, 3383. [52] (a) S. Tatcgami, T. Yamada, H. Nishino, J. D. Korp, K. Kurosawa, Tetrahedron Lett. 1990, 31, 6371. (b) H. Nishino, S. Tategami, T. Yamada, J. D. Korp, K. Kurosawa, Bull. Chem. Soc. Jpn. 1991, 64, 1800. (c) C.-Y. Qian, H. Nishino, K. Kurosawa, Bull. Chem. Soc. Jpn. 1991, 64, 3557. (d) C.-Y. Qian, T. Yamada, H. Nishino, K. Kurosawa, Bull. Chem. Soc. Jpn. 1992,65, 1371. (e) C.-Y. Qian, H. Nishino, K. Kurosawa, J. Heterocycl. Chem. 1993, 30, 209. ( f ) T. Yamada, Y. Iwahara, H. Nishino, K. Kurosawa. J. Chem. Soc., Perkin Trans. 1 1993, 609. (8)V.-H. Nguyen, H. Nishino, K. Kurosawa, Tetrahedron Lett. 1996,37,4949. (h) V.-H. Nguyen, H. Nishino, K. Kurosawa, Heterocycles 1998, 48, 465. [53] C.-Y. Qian, J. Hirose, H. Nishino, K. Kurosawa, J. Heterocycl. C/iem. 1994, 31, 1219. [54] (a) P. D. McDonald, G. A. Hamilton in Oxidation in Organic Chemistry (Ed.: W. S. Trahanovsky), Part B, Academic Press, New York, 1973, Chapter 11. (b) Chapter 7 in ref. 8b. (c) G. Scott in Atmospheric Oxidation and Antioxidants (Ed.: G. Scott), Elsevier, Amsterdam, 1993, Chapter 8. [55] A. Nishinaga, H. Iwasaki, T. Shimizu, Y. Toyoda, T. Matsuura, J. Urg. Chem. 1986,SJ, 2257. [56] J. Carnduff, D. G. Leppard, J. Chem. Soc., Perkin Trans. 1 1976, 2570. [57] X. Creary, A. Wolf, K . Miller, Org. Lett. 1999, I , 1615. [ 5 8 ] G. Goor, W. Kunkel, 0. Weiberg in Ullmann’s Encyclopedia of Industrial Chemistry, 5th Edition, VCH, Weinheim, 1989, Vol. A13, pp 443-466. [59] R. F. Parcell, F. P. Hauck, Jr., J. Org. Chem. 1963, 28, 3468. [60] (a) H. Yamamoto, M. Akutagawa, H. Aoyama, Y. Omote, J. C/iem. Soc., Perkin Trans. 1 1980, 2300. (b) H. Yamamoto, M. Hirayama, M. Akutagawa, T. Nishio, C. Kashima, Y. Omote, Bull. Chem. Soc. Jpn. 1988,61, 2678. (c) H. Nakamura, T. Goto, Bull. Chem. Soc. Jpn. 1988, 61, 3776. [61] (a) A. L. Baumstark, M. Dotrong, P. C. Vasquez, Tetrahedron Lett. 1987,28, 1963. (b) A. L. Baumstark, P. C. Vasquez, J. Heterocycl. Chem. 1991, 28, 113. (c) A. L. Baumstark, P. C. Vasquez, J. Org. Chem. 1992, 57, 393. [62] A. L. Baumstark, P. C. Vasquez, Y.-X. Chen, J. Org. Chem. 1994, 59, 6692. [63] B. Witkop, J. B. Patrick, J. Am. Chem. Soc. 1951, 73, 2196. [64] E. Winterfeldt, Liebigs Ann. 1971, 745, 23. [65] J.-F. Carniaux, C. Kan-Fan, J. Royer, H.-P. Husson, Synlett 1999, 563; J.-F. Carniaux, C. Kan-Fan, J. Royer, H.-P. Husson, Tetrahedron Lett. 1997, 38, 2997. [66] C. Tratrat, S. Giorgi-Renault, H.-P. Husson, Synlett 1998, 1071. [67] K. C. Nicolaou, P. S. Baran, R. Jautelat, Y. He, K. C. Fong, H.-S. Choi, W. H. Yoon, Y.-L. Zhong, Angew. Chem. Int. Ed. 1999, 38, 549. [68] K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, H.-S. Choi, H. Yoon, Y. He, K. C. Fong, Angew. Chem. Int. Ed. 1999,38, 1669; K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, K. C. Fong, Y. He, H. Yoon, H.-S. Choi, Angew. Chem. Int. Ed. 1999, 38, 1676. [69] S. E. Schaafsma, H. Steinberg, T. J. DeBoer, Reel. Trau. Chim. Pays-Bas 1966, 85, 70; D. H. Gibson, C. H. De Puy, Chem. Rev. 1974, 74, 605. [70] A. Ohu, T. Yokoyama, T. Harada, Tetrahedron Lett. 1983, 24, 4699. 1711 (a) M. P. Ceccherelli, M. Curini, R. Coccia, M. Diamantini, J. Chem. Soc., Perkin Trans. 1 1984, 1693. (b) E. Scheller, P. Mathies, W. Petter, B. Frei, Helc. Chim. Acta 1984, 67, 1748. [72] A. Boto, R. Hernindez, E. Suirez, C. Betancor, M. S. Rodriguez, J. Org. Chem. 1995, 60, 8209 (correction: J. Org. Chem. 1996, 61, 9635). [73] A. Boto, C. Betancor, T. Prange, E. Suarez, J. Org. Chem. 1994, 5Y, 4393. [74] A. Boto, R. Freire, R. Hernandez, E. Suirez, M. S. Rodriguez, J. Org. Chem. 1997, 62, 2975. [75] (a) M. 0. Funk, R. Isaac, N. A. Porter, J. Am. Chem. Soc. 1975, Y7, 1281. (b) N. A. Porter, M. 0. Funk, D. Gilmore, R. Isaac, J. Nixon, J. Am. Chem. Soc. 1976, 98, 6000. [76] (a) H. A. J. Carless, R. J. Batten, Tetrahedron Lett. 1982.23, 4735. (b) H. A. J. Carless, R. J. Batten, J. Chem. Soc., Perkin Trans. 1 1987, 1999. (c) A. J. Bloodworth, R. J. Curtis, N. Mistry, J. Chem. Soc., Chem. Commun. 1989, 954. (d) A. J. Bloodworth, M. D. Spencer, Tetrahedron Lett. 1990, 31, 5513.
484
5.4 Peroxyl Radicals in Synthesis
[77] A. N. Roe, A. T. McPhail, N. A. Porter, J. Am. Chem. Soc. 1983, 105, 1199. [78] C. H. Schiesser, H. Wu, Aust. J. Chem. 1993, 46, 1437. [79] E. J. Corey, Z. Wang, Tetrahedron Lett. 1994, 35, 539. [80] S. Fielder, D. D. Rowan, M. S. Sherburn, Synlett 1996, 349; S. Fielder, D. D. Rowan, M. S. Sherburn, Tetrahedron 1998, 54, 12907. [81] J. Boukouvalas, R. Pouliot, Y. FrCchette, Tetrahedron Lett. 1995, 36, 4167. [82] Y. Ushigoe, A. Masuyama, M. Nojima, K. J. McCullough, Tetrahedron Lett. 1997,38, 8753. [83] A. J . Bloodworth, R. J. Curtis, J. Chem. Soc., Chem. Commun. 1989, 173. [84] Y. Ushigoe, Y. Kano, M. Nojima, J. Chem. Soc., Perkin Trans. I 1997, 5. [85] J. Boukouvalas, M. Trudeau, manuscript in preparation; M. Trudeau, M.Sc. Thesis (No. 17503), 1999, Lava1 University. [86] (a) N. A. Porter, J. Sullivan Wujek, J. Org. Chem. 1987, 52, 5085. (b) N. A. Porter, J. K. Kaplan, P. H. Dussault, J. Am. Chem. Soc. 1990, 112, 1266. (c) S. L. Boyd, R. J. Boyd, Z . Shi, L. R. C. Barclay, N. A. Porter, J. Am. Chem. Soc. 1993, 115, 687. (d) N. A. Porter, K. A. Mills, S. E. Caldwell, G. R. Dubay, J. Am. Chem. SOC.1994, 116, 6697. (e) J. R. Lowe, N. A. Porter, J. Am. Chem. SOC.1997, 119, 11534. [87] A. L. J. Beckwith, A. G. Davies, I. G. E. Davidson, A. Maccoll, M. H. Mruzek, J. Chem. Soc., Perkin Trans. 2 1989, 815. [88] H.-S. Dang, A. G. Davies, I. G. E. Davison, C. H. Schiesser, J. Org. Chem. 1990, 55, 1432. [89] P. H. Dussault, K. R. Woller, J. Am. Chem. SOC.1997, 119, 3824. [90] (a) A. L. J. Beckwith, R. D. Wagner, J. Am. Chem. Soc. 1979, 101, 7099. (b) A. L. J. Beckwith, R. D. Wagner, J. Chem. SOC.,Chem. Commun. 1980,485. (c) P. J. Barker, A. L. J. Beckwith, Y. Fung, Tetrahedron Lett. 1983, 24, 97. [91] A. L. J. Beckwith, C. H. Schiesser, Tetrahedron Lett. 1985, 26, 373; Beckwith, A. L. J.; Schiesser, C.H. Tetrahedron 1985, 41, 3925; D. C. Spellmeyer, K. N. Houk, J. Org. Chem. 1987, 52, 959. [92] D. P. Curran, N. A. Porter, B. Giese, Stereocheniisrry of Radical Reactions, VCH, Weinheim, 1996, Chapter 2. [93] (a) M. D. Bachi, E. E. Korshin, Synlett 1998, 122. (b) M. D. Bachi, E. E. Korshin, P. Ploypradith, J. N. Cumming, s. Xie, s. Xie, T. A. Shapiro, G. H. Posner, Bioorg. Med, Lett. 1998, 8, 903. (c) M. D. Bachi, E. E. Korshin, R. Hoos, A . M. Szpilman, J. Heterocycl. Chem. 2000, 37, 639. [94] J. Yoshida, S. Nakatani, S. Isoe, Tetrahedron Lett. 1990, 31, 2425. [95] R. Hernandez, S. M. Velazquez, E. Suirez, Tetrahedron Lett. 1996, 37, 6409; A. Boto, R. Hernandez, S. M. Velazquez, E. Suirez, T. PrangC, J. Org. Chem. 1998, 63, 4697. [96] S. Nakatani, J. Yoshida, S. Isoe, Tetrahedron 1993, 49, 2011. [97] (a) K. S. Feldman, R. E. Simpson, M. Parvez, J. Am. Chem. SOC.1986, 108, 1328. (b) K. S. Feldman, R. E. Simpson, J. Am. Chem. SOC.1989, 111, 4878. [98] K. S. Feldman, Synletr 1995, 217. [99] K. S. Feldman, C. M. Kraebel, J. Org. Cheni. 1992, 57, 4574; C. K. Weinreb, D. Hartsough, K. S. Feldman, Tetrahedron Lett. 1995,36, 6859. [ 1001 K. S. Feldman, R. E. Simpson, Tetrahedron Lett. 1989, 30, 6985.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
5.5 Sulfur-Centered Radicals Michde P. Bertrand and Carla Ferreri
5.5.1 Introduction The chemistry of sulfur-centered radicals has grown exponentially over the last century [ 11. Sulfur-centered paramagnetic species are important in different fields, such as atmosphere [2], polymer [3], and biological chemistry [4], and their structural characteristics have been reviewed [ 51. This chapter is concerned with organic synthesis. Among the different types of sulfur-centered radicals, the most interesting species for synthetic chemists are thiyl (RS') and sulfonyl radicals (RS02'). Excellent reviews [5a, 6-81 have been published on the subject, and the reader is invited to consult these in order to have a deeper understanding of any topic, and for complete coverage. Because of space constraints, this survey includes only the most representative examples of thiyl and sulfonyl radical reactivity, taking into account the recent literature. The leaving group ability of both thiyl and sulfonyl radicals, which is one of their most important features, will be treated elsewhere in this book (see Volume 1, Chapter 1.4).
5.5.2 Thiols as Reducing Agents Thiols are good hydrogen donors toward carbon-centered radicals (Eq. 1); the relatively low dissociation energy of the sulfur-hydrogen bond [Do(MeS-H) = 87.4 & 0.7 and Do(PhS-H) = 78.9 & 1.4 kcal mol-'1 [9] is one important reason for this property.
This event, called 'repair reaction', occurs in biological systems where glutathione plays a major role by quenching the carbon-centered radicals derived from biomolecules [4,lo].
486 R-SH
5.5 Sulfur-Centered Radicals
+
In'
R-S'
R-S' + (Et0)sP R-S-i(OEt)3 R-SH
+
R'
+
In-H
R-S-;(OEt),
+ S=P(OEt)3
*
R'
-
R-S'
+
R-H
Scheme 1. Desulfuration of thiols in the presence of phosphites
In organic synthesis, thiols can function as stoichiometric reducing agents, provided that thiyl radical is able to propagate the chain reaction. This is indeed not the case, since thiyl radicals have little propensity to abstract atoms or to remove groups of atoms 16-71. The desulfuration of thiols in the presence of phosphine or phosphites [ 1 11 (Scheme 1) and Barton's decarboxylation of acids via thiocarbonyl derivatives [ 121 are the only examples. The radical reduction of alkyl halides and xanthates to the corresponding hydrocarbons by trialkylsilanes, which are poor radical-based reducing agents because of their low hydrogen-donating ability, becomes efficient in the presence of a catalytic amount of alkanethiols. According to the concept introduced by Roberts 1131, the thiols act as polarity-reversal catalysts. This principle may be applied to promote the overall abstraction of electron-rich hydrogen by nucleophilic alkyl radicals from silicon in simple triorganosilanes, through the catalytic cycle shown in Eqs. (2)-(4). +
XSH
XS'
+
RSSiH
R'
+
R3SiH
R'
w
*
RH
+
XS'
XSH
+
R3Si'
(3)
RH
+
R3Si'
(4)
(2)
This concept turned out to be useful for a variety of transformations, including reductions, epimerizations [ 141, hydrosilylations of alkenes, hydrostannations of alkynes [I 51 and carbon-carbon bond formation [ 131. As an example, thiols catalyze the cyclization of acyl radicals [ 16a] and masked acyl radicals [ 16b]; these reactions have no preparative value in the absence of thiols because the nucleophilic radicals resulting from the cyclization step are not able to abstract efficiently a hydrogen atom from the starting material, whereas thiyl radicals can (Scheme 2).
5.5.3 Addition to n Bonds The most useful synthetic applications of thiyl and sulfonyl radicals are based on their ability to add to carbon-carbon multiple bonds. As precursors of thiyl radi-
5.5.3 Addition to 7~ Bonds
487
Scheme 2. Thiol-catalyzed cyclization of masked acyl radicals
cals, thiols and disulfides are used in most cases, whereas common precursors of sulfonyl radicals include sulfonyl halides, sulfonyl cyanides, sulfonyl thiocyanates, and selenosulfonates. The oxidation of sulfinate anions offers an alternative pathway [6-81. The generation of the corresponding radicals can easily be initiated by the thermal decomposition of peroxides or azo compounds or by UV irradiation or radiolysis. In some cases boranes have been utilized as initiators [ 171. Transition metal complexes are also efficient. This includes both reductive and oxidative routes, for instance, the Ru(I1)-mediated addition of phenylselenotosylate to electron-rich olefins [18] (Eq. 5 ) and the Mn(II1)-catalyzed synthesis of vinyl sulfides ~ 9 (Eq. 1 6).
-JrA
+
Mn(OAc)3 2 H20 RSH
Ar *
AcOH, reflux, 2' 78 - 98%
*
SR
(€/Z = 6-9/4-1)
5.5.3.1 Inter- and Intramolecular Additions Scheme 3 represents the propagation of the chain process in intermolecular additions. Both thiyl and sulfonyl radicals are electrophilic species, so that they add faster to electron-rich double bonds [20]. However, this property is frequently masked by the reversibility of the addition step [21]. The chain transfer step competes with the reversal P-fragmentation, the rate of which depends strongly on the stabilization of radical 1. Many recent syntheses take advantage of the rapid fragmentation of P-sulfenyl and P-sulfonyl radicals (the reader is referred to Chapter 1.4 in Volume 1 and
488
Y'
5.5 Suljur-Centered Radicals
+
G'&
Y A G
+
Y-x
-
X Y
d
G
+Y'
1 For thiyl radicals:
Y = RS; X = H
For sulfonyl radicals:Y = RSO2; X = CI, Br, I, SePh, CN, SCN
Scheme 3. Intermolecular addition to carbon-carbon double bonds
Chapter 1.1 in Volume 2). The a-elimination of thiyl or sulfonyl radicals will be further considered in Section 5.5.4. The addition of thiols and sulfonyl derivatives to unsaturated compounds under radical conditions represents a mild method to prepare sulfides and sulfones in high yield and with anti-Markovnikov orientation [8-91. Recent examples have been reported in carbohydrate chemistry. Thioacetic acid and thiols react with exocyclic glycals 2 [22a] and with allyl a- and P-glycosides 3 [22b] to give sulfur functionalized derivatives to be used as intermediates for the synthesis of biologically active compounds. OR
OAc
'SAC
'SR
3
Similarly, unnatural amino acids can be quantitatively obtained from allyl derivatives of natural amino acids. An example is given in Eq. (7), i.e., a-allylglycines react with methanethiol in dioxane/water or methanol/water as the solvent [23]. Under these conditions, the addition of thiyl radical competes with hydrogenabstraction at the C-2 position of the amino acid; a small amount of racemization is found in the addition product. COOH h N H 2 (S)-allylglycine 76% e.e.
CH&H AlBN (l-lO%)99%
COOH H 3 C S d N H 2
(7) (S)-thioalkylglycine 73% e.e.
The addition of thiyl radicals can be performed in the presence of oxygen, the process being known as cooxidation. This is an attractive method to generate peroxy radicals through the capture of the P-sulfenyl radical, and it can be electrochemically initiated. As shown in Scheme 4, the products are a-( pheny1thio)aldehydes starting from either alkenyl sulfides or alkynes [24];P-hydroxysulfoxides can also be prepared [25] (Eq. 8).
5.5.3 Addition to
PhSH
R
- e-
PhS
E
PhSH P h S R e s p h
7c
Bonds
489
PhS R d s p h
R+Sph PhS
0
'OH
R+H PhS
t -
oO'
P h S PhSH
'+SPh PhS
.$-SPh PhS
Jo2
Scheme 4. Electroinitiated cooxidation of alkenyl sulfides and alkynes
Similarly, thioselenation of olefins can be achieved with the diphenyl disulfide/ diphenyl diselenide binary system [26] (Eq. 9). The radical chain addition of disulfides to olefins is quite inefficient because of the competition of p-elimination with the attack of the P-thioalkyl radical on the disulfide; diphenyl diselenide is a far better radical trap. As shown in Eq. (lo), the reaction has been extended to thiotelluration. With the exception of norbornene and vinylcyclopropanes, for which the addition step is followed by the fast opening of the three-membered ring, thiotelluration does not proceed with olefins. In contrast, the thiotelluration of acetylenes is highly efficient.
n46H13E
+
(PhS)2
+
hv (>300nrn)
n46Hi3
(PhSe)p 45 "C, 35 h* 74%
84%
PhSe*SPh
(f/Z = 73/27)
(u2= 14/86)
A great variety of sulfones are available from the addition of RS02X to alkenes, alkynes, and allenes [6, 8, 18, 27-30] (Eqs. 11-16). In the case of cyclic alkenes, the addition is highly stereoselective in favor of the trans adduct (Eq. 11). ArS02CN, hv 72%, ref. 28a
S02Ar CN
Ar = tolyl
These reactions can be carried out under solid-phase conditions [29]. The adducts
490
5.5 Sulfur-Centered Radicals
are generally further transformed via base-promoted elimination or oxidation [ 301, as shown in Eqs. (12)-(14).
TsSCN
Ts+s~~
+
Et3N
TS
ref. 28c
PhSeS02Ar
+ Me3SiG
-
AIBN (cat) Me3Si) _ i S 4 A r Benzene 8OoC-96h PhSe 94%
(€:Z=3.8 : 1)
83%
-
1)MCPBA
-
S :02Ar
2) H20 88%, ref. 27d
89%, ref. 27e
The addition of arylsulfinates mediated by Ce(1V) leads directly to vinyl sulfones, since the intermediate alkyl radical undergoes oxidative elimination under these conditions [30b] (Eq. 15).
86Y0, ref. 30b
Many total syntheses take advantage of the temporary introduction of a sulfide or a sulfone group. As illustrated in Scheme 5 , an allenyl sulfone is a key intermediate in the synthesis of brassinolide reported by Back [31a]. It is obtained through sequential addition of TsSePh, base-promoted migration of the double bond, and oxidative elimination of the phenyl selenide. The addition of EtSH to the
+,,,,p ii//tT. OH
1) TsSePh, 06%
R=
'"'
2) Et3N - A, 86%
R
SePh
,,
@
Scheme 5. Back's synthesis of brassinolide
f-BuOOH 03 Yo
R
1 ,
R
i-Pr2CuLi-SMe2
y g , MeoH
other isomers + "',,,&
OMe
OH
R
53 %
1
Ts
56 YO
5.5.3 Addition to n Bonds
491
0hv, C5H12
I
R R = allyl
- R'
50%
R' = H, 40% R' = allyl, 55%
Scheme 6. Cyclization of pent-4-enylthiyl radical
vinyl cyclopropyl moiety of casbene and subsequent oxidative elimination of the resulting sulfide has been applied to the preparation of cembrenes [31b]. The additions of thiyl radical to alkenes and alkynes can also occur intramolecularly, thus leading to sulfur heterocycles. This subject has been explored by Surzur's group [32-331. Based on steric and stereoelectronic factors, the BaldwinBeckwith rules [34] predict the 5-exo ring closure as the favored pathway. Scheme 6 shows that the pent-4-enylthiyl radical, generated from the allyl sulfide, yields both five- and six-membered rings, in the ratio of 1:19. The predominance of the larger cycle, in contrast with the above-mentioned rules, is due to the reversibility of the reaction. The product distribution reflects a thermodynamic control. Cephams have been prepared via a biomimetic pathway, i.e. the iron(II1)promoted cyclization of thiyl radical, as exemplified in Eq. (16) [35].
Several examples of intramolecular addition of &unsaturated sulfonyl radicals have also been reported [36]. In agreement with Baldwin's rule and notwithstanding the reversibility of the cyclization step, the 5-exo mode is preferred when the reaction is catalyzed by copper salts, since in this case the carbon-centered radical is trapped through a fast atom transfer reaction [36b].
5.5.3.2 Cyclizations Promoted by Sulfur-Centered Radicals The addition of thiyl and sulfonyl radicals, either in stoichiometric or in catalytic amounts, is used as the first step of tandem processes which have been widely applied to prepare carbocyclic compounds. The catalytic procedure will be further described in Section 5.5.4.3 during the discussion of cascade processes involving fragmentation reactions. The mechanism of the stoichiometric procedure, which can involve thiols, disulfides, or any sulfonyl radical precursor, is represented in Scheme 7. It consists of (i) the initial addition step, (ii) the cyclization with formation of the final radical species, and (iii) the quenching of the final radical to give the product.
\v xv
492
5.5 Sulfur-Centered Radicals
(i)
+x*
Et02C C02Et
Et02C C02Et
X-Y
I
Et02C C02Et X-Y
(iv)
I
(iii)
X-Y
ref.
Conditions
T "C
Yield
cis/trans
EtSH TsBr
37a 38a
PhSSPh, hv hv
80 20
92% 90%
611 1311
Scheme 7. Cyclizations of diallylmalonates promoted by sulfur-centered radicals
The ideal substrates for these reactions are 1,6-dienes [37-381, for example (Scheme 7), dimethyl diallylmalonate is easily transformed into cyclopentane derivatives, as a mixture of cis and trans isomers. The methodology also applies to analogous enynes [39-401, diynes [41], or eneallenes [42].The radical acceptor in the cyclization step can even be an imino group [43a-c], or a nitrile [43d]. It is worth pointing out that the correct choice of the precursor together with the appropriate concentration of the reactants is essential for avoiding the competitive 1,2-addition. For example the cyclization of the enyne, shown in Eq. (17) [39a], is performed with an equimolar amount of thiophenol slowly added to the refluxing mixture of AIBN and substrate, so that the 5-exo cyclization of the intermediate vinyl radical is followed by ring expansion, before the final quenching by thiophenol occurs. SPh
+
PhSH
AIBN / 80°C 70%
Thiyl- as well as sulfonyl radical-mediated cyclizations have been reviewed previously [6-8, 441. One of the interesting features in these reactions is their chemoselectivity [45]; totally selective functionalizations of dissymmetrical substrates have been performed. The origin of the chemoselectivity has been a subject of polemics [46]. It is obvious that the rate of the /I-fragmentation reaction, which is the reversal of the initial addition step and which competes with the cyclization, is a determining factor in these reactions. The synthesis of natural products has been accomplished by this strategy; examples are shown in Eqs. (1 8), (1 9). The key step used by Keck and Wager in the total synthesis of ent-lycoricidine [43a] relies on the addition of phenylthiyl radical to the
5.5.3 Addition to 71 Bonds
493
triple bond of a suitable precursor followed by cyclization onto a pendant oxime moiety, hydrogen abstraction from thiophenol, and nucleophilic addition to the carbonyl group. The synthesis of bromalysin [37c] is based on the cyclization of the appropriate 1,6-diene via the addition of t-BUS' to the electron-rich double bond.
Bachi has extended this strategy to the synthesis of naturally occurring endoperoxides with antimalarial activity via the thiol-oxygen cooxidation of dienes [47] (Scheme 8); the reaction involves the formation of a peroxy radical 4, which adds intramolecularly to the double bond to give the endoperoxide function required in the final product. Another significant example of tandem reaction is given by the synthesis of substituted (alky1thio)pyrrolines or pyroglutamates as shown in Scheme 9 starting from a syn-substituted alkenoyl ester [49]. It consists of the addition of thiyl radicals to the isocyanide function, followed by a 5-exo-trig cyclization of the imidoyl radical to the double bond. Tandem procedures have recently been described for alkynyl azides in a simple reaction with an equimolar amount of the appropriate thiol in the presence of AIBN as initiator, to afford cyclic compounds in good yields. The authors previously used vinyl azides for simple addition procedure [49a] and have extended this reaction to tandem procedures. Scheme 10 describes an example with thiophenol and alkynyl
PhSHvo', BzOOBz
[
PhSflx
-
Px] 1
PhS
Scheme 8. Bachi's synthesis of antimalarial endoperoxides
494
5.5 Sulfur-Centered Radicals
X
EtSH
OSiTBDMS
i
T
N
EtS
D MS
B
COzEt
1
J X i T BEtSH DMS
N
EtS
C02Et
Scheme 9. Synthesis of (alky1thio)pyrrolines
PhSH
+
P
h
F
N=N=N PhS
p
AlBN
80°C 5
Ph
PhS
Ph
PhS
'I
Ph
@-Ng / 85% yield
Scheme 10. Synthesis of indoles from o-alkynyl aryl azides
azide 5, in which the indole 6 was the sole product. It is formed through the cyclization of the 2-sulfanylvinyl radical onto the azide moiety, followed by nitrogen loss from the triazenyl radical intermediate and H-abstraction by the derived aminyl radical [49b]. Finally, it is worth noting that the generation of sulfonyl radicals through the oxidation of sulfinate anions has allowed these tandem reactions to be extended to cyclizations onto aromatics which need an oxidative termination [50](Eq. 20).
TsNa, Cu(OAc)2 (3 equiv.) 80% aq. HCOOH, 90°C E = C02i-Pr
E
E
88%
E
E
5.5.3.3 Addition to Thiocarbonyl Derivatives In addition to the reduction of thiohydroxamates, already mentioned in Section 5.5.2, Barton and his coworkers have developed routes to nitriles [51b], sulfones,
5.5.4 Processes Involving Addition and ( o r ) Fragmentution Reactions
495
Scheme 11. Addition of sulfonyl radicals to C=S bonds
and sulfonamides [ 5 la] which are based on the reactivity of thiocarbonyl derivatives toward sulfonyl radicals (Scheme 1 I). The decarboxylation process generates an alkyl radical which reacts with sulfur dioxide to form an alkanesulfonyl radical which subsequently adds to the C=S bond. The sulfonylation of alkyl radicals will be further considered in Section 5.5.4.
5.5.4 Processes Involving Addition and (or) Fragmentation Reactions 5.5.4.1 Sulfonylation of Alkyl Radicals and Reversal a-Scission The addition of alkyl radicals to sulfur dioxide is reversible [52] (Eq. 21). The rate of the reversal a-scission depends on the stabilization of the alkyl radical [5a, 8d, 521; the rate constant for the loss of sulfur dioxide from PhCH2S02' exceeds 2 x 10' s-l at 295 K [52a]. R'
+
SO2
=======
(211
RSO;
The sulfonylation of alkyl radicals plays an important role in the copolymerization of olefins with sulfur dioxide [53a]. In a recent study, Shevlin [53b] has shown that the cyclooligomerization of diallyl malonate could be controlled by the addition of a chain transfer agent such as PhSH (Eq. 22).
=+phsQ202Et LZCQOZEt CH2SOz
Et02C
+
C02Et
CH2
CH2-X
(22)
X = H, S02H
Conversely, numerous applications of a-scission reactions have been oriented towards the synthesis of fluorinated compounds [54]. As an example, the photochemically induced homolysis of the thio- and selenoesters of triflic acid has been
496
5.5 Sulfur-Centered Radicals
used recently to prepare trifluoromethyl sulfides and selenides [54a] (Eqs. 23, 24). The propagation of the reaction involves homolytic substitution at sulfur or selenium. The Cu(I1)-mediated addition of trifluoromethanesulfinate to enol esters affords cr-trifluoromethyl ketones [54d] (Eq. 25). 0,
,?
/s-R + so2
RS-SR hv, CH2C12 reflux* 74% (R = n- Oct)
CFfS-STR
0 0 “ S .Ph cF3/ ‘Se
cF3
PhSe-SePh
CFgSe\Ph + “2
hv, CH2C12reflux58%
moAc CF3S02Na/f-Bu00H I
II
-
Cu(OS02CF3)2/CH3CN, 20 “C
I
flo I
~
C
F
~
66%
Ethyl or trifluoromethyl radicals generated from the corresponding sulfonyl radicals are able to abstract iodine or hydrogen atoms or add to thiocarbonyl derivatives, and in so doing to play the role of chain carrier [see Volume 1, Chapter 1.61. Their involvement in cascade processes will be exemplified in Section 5.5.4.3.
5.5.4.2 Isomerization of Alkenes The observation that thiyl radicals are able to isomerize alkenes was first made by Walling et al. many years ago [55] and, now the addition-elimination sequence of the phenylthiyl radicals is an established methodology in fine chemical synthesis [56]. It has been utilized as key step in the synthesis of biologically active compounds, such as (-)-gloeosporone [57a], (+)-hitachimycin [57b] and other naturally occurring macrolides [5b], as well as for preparing non-natural isomers of phospholipids [58]. The isomerization mechanism, shown in Scheme 12, is based on the fragmentation of the P-thioalkyl radical represented by 7 and 8, formed upon addition of thiyl radicals to the double bond, which affords the two geometrical isomers of the starting alkene in an E/Z ratio determined by their thermodynamic stability [59]. SPh PhS’
Z +
Y
W
-z
H
G
80”
Y
SPh
z
\=\
H
Y 7
8
Scheme 12. Mechanism of thiyl radical-mediated isomerization of alkenes
+
PhS‘
5.5.4 Processes Involving Addition and (or) Fragmentation Reactions
491
A recent example is given by the synthesis of 5H-furanones, achieved through a radical-polar crossover sequence, containing the isomerization as the radical step [60] (Eq. 26).
[
OH
Me02C
hv, reflux
I
OH
C02Me
1
Me02C,
Me026
L
benzene, 66%
It is worth pointing out that isomerization processes can affect the course of other radical reactions, such as the addition of thiyl radical to triple bonds. Post-isomerization is in some cases the most evident explanation for the E/Z isomeric ratios observed in the products [61].
5.5.4.3 Cascade Reactions The synthesis of carbocyclic compounds from acyclic precursors can be accomplished by a sequence of radical reactions, where thiyl radicals act as catalysts. As an example, the generation of homoallyl radicals through the addition of phenylthiyl radical to the double bonds of vinyl cyclopropanes results in the multi-step synthesis of cyclopentanoids [62]. The mechanism is shown in Scheme 13. Feldman and coworkers have demonstrated that the success of this strategy is based on the coupling of vinyl cyclopropanes with the electronically complementary functionalized alkenes. A judicious choice of substituents R and X accelerates the rate limiting step (c). This strategy has been elegantly applied to the construction of rocaglamid skeleton [62g] (Eq. 27). Numerous analogous reactions have been carried out [63-651. The chemistry of dienyl cyclopropanes has been investigated by Oshima [64] (Eq. 28). Singleton [65] has shown that methylene cyclopentanes are obtained in good
PhS’
phS*R \b
.
R
Scheme 13. Feldman’s synthesis of cyclopentanoids
498
5.5 Sulfur-Centered Radicals
yields from methylene cyclopropanes via a closely related protocol (Eq. 29). The synthesis of bicyclic compounds starting from alkenyl epoxides [ 661 involves similar steps.
Ph&
AIBN
hv, PhH, 40°C, 94% *
PhSH
aTM
.
60"C, PhH, 80%
4
Me02C Me02C
BU2S2 +
hv,77%*
Me02C Me02C
Simple to highly sophisticated combinations of elementary steps involving thiyl or sulfonyl radicals as stoichiometric reagents have been devised. Most of them benefit from the ready fragmentation of P-sulfenyl and P-sulfonyl radicals. Whitham and Padwa 1671 have reported the first examples involving tosyl radical in the construction of fused ring systems through sequential addition/cyclization/Pfragmentation. This strategy has been applied to the synthesis of kainic acids. Bertrand and coworkers [68a] have proposed a formal route based on the addition of tosyl radical to a dissymmetrical diene (Scheme 14). The tosylmethyl group is a potential precursor for the second carboxylic function of kainic acids. This has subsequently been verified [68b] in a closely related protocol involving first the rearrangement of the corresponding allylic sulfide and then oxidation of the resulting sulfide.
Scheme 14. Synthesis of kainic acids based on the rearrangement of an ally1 sulfone
5.5.4 Processes Involving Addition and (or) Fragmentation Reactions
499
The same type of methodology involving a radical isomerization has been applied by Caddick [69] to the preparation of fused [1,2-a]indoles; the reaction is limited to 5- and 6-membered ring fused skeletons (Eq. 30). TsSePh (0.25 equiv.) t
AIBN, PhH, 80 "C n = 1 : 89% n = 2 : 84%
The P-fragmentation can be used as one of the cascade steps in processes which do not start from the addition of a sulfur-centered radical. Rearrangements of sulfur compounds, catalyzed by tributylstannyl radical, which lead to 3vinyldihydrothiophene or dihydrothiopyran derivatives, have been developed [ 701. The mechanism is shown in Scheme 15: the cyclic P-thioalkyl radical 9, produced in two steps, fragments, thus producing the thiyl radical 10, which cyclizes in a 5- or 6endo fashion onto the stannylated double bond; subsequent elimination leads to the final heterocyclic compound.
ssEwG p-fragmen.
SnBu3
11
-
h
Scheme 15. Derivatives of dihydrothiophenes and dihydrothiopyrans through cascade processes involving endo-trig cyclizations of thiyl radicals
The a-scission of ethylsulfonyl radicals, forming ethyl radicals, which are able to abstract atoms or groups of atoms, has found interesting applications in allylation and vinylation reactions [71]. The choice of ethylsulfonyl radical as leaving group in 5-exo ring closure has led to a synthesis of (+)-botryodiplodin [72]. When the intermediate a-alkoxycarbonyl radical is generated by the classical tin methodology, the cyclization, which is slowed down by the rotation around the (C0)O-C bond, is disfavored compared to the direct reduction by tin hydride. In the cascade process involving iodine atom transfer to ethyl radical, the cyclization suffers no competitive pathway (Scheme 16). A sequence involving the same elementary steps but in a different order has been designed by Chuang [73] to prepare fused aromatic compounds. Examples of domino reactions, where an ally1 sulfide moiety is introduced purposely in order to induce the P-fragmentation of a radical intermediate, are numerous [74]. One
500
5.5 Sulfur-Centered Rudiculs
.-q-u"
1) LDA
(Bu3Sn)P h," I
PhH,80"C
63y0 ESOP -Et-lnkEt'
2) CSA, -100 "C
-"
-7
trans :cis = 60:40
EtS02'
(OF0
7 trans :cis = 18:82
4
COY0
-'-
1
2 steps
1
Scheme 16. Synthesis of (+)-botryodiplodin
example, which is illustrated in the enantioselective synthesis of a-kainic acid [ 74a], relies on the addition of tributylstannyl radical to thioformamide 11 (Eq. 31). SEt
-<,dMs --.f -
1) Bu3SnH
7 steps
S Boc
2) B u ~ N F 73%
11
YBoc
a-kainic acid
Coat-BU
A sequence consisting of three steps, i.e. radical cyclization/fragmentation/ electrocyclization, recently reported by Parsons [75],allows for the construction of a fused ring system in one synthetic operation starting from an appropriately substituted furan.
5.5.5 Homolytic Substitution at Carbon: S Hand ~ SH~' S H and ~ S H ~reactions ' have been devised to prepare sulfides or sulfones. The former ones are limited to highly strained carbocyclic compounds [6d-e, 761. The latter ones are more common, and various vinylic or allylic derivatives including stannanes and cobaloximes are known to react with sulfur-centered radicals [77].A representative example is shown in Eq. (32), where the three-membered ring in 1Hcyclopropabenzene opens upon attack by various thiyl radicals to give the corresponding ortho-substituted toluenes.
hv, 24-67%
SR
References
501
References [ 11 For the very first studies see: a) T. Posner, Ber. Deut. Chem. Ges. 1905, 38, 646-657; b) M. S. Kharash, A. A. T. Reed, F. R. Mayo, Chem. Ind. (London) 1938, 57, 752. [2] S. P. Urbanski, P. H. Wine in S-Centered Radicals (Ed.: Z. B. Alfassi), Wiley, New York, 1999, Chap. 4. [3] For recent applications to living radical polymerization see: a) V. Percec, B. Barboiu, H.-J. Kim, J. Am. Chem. Soc. 1998, 120, 305-316; b) M. vandersluis, B. Barboiu, N. Pesa, V. Percec, Macromolecules 1998, 31, 9409-9412. [4] a) C. Chatgilialoglu, K.-D. Asmus, (Eds), Sulfur-centred Reactive Intermediates in Chemistry and Biology, Plenum, New York, 1990; b) P. Wardman in S-Centered Radicals (Ed.: Z. B. Alfassi), Wiley, New York, 1999, Chap. 10. [5] a) C. Chatgilialoglu in The Chemistry of Sulfones and Sulfoxides: Sulfonyl Radicals (Eds.: S. Patai, Z . Rappoport and C. J. M. Stirling), Wiley, New York, 1988, Chap. 25; b) C. Chatgilialoglu, M. Guerra in Supplement S: The Chemistry of’ Sulphur-Containing Functional Groups (Eds: S. Patai, Z. Rappoport), Wiley, New York, 1993, Chap. 8; c) D. A. Armstrong, D. M. Chipman in S-Centered Radicals (Ed.: Z. B. Alfassi), Wiley, New York, 1999, Chap. 1. [6] For previous general reviews see: a) J. L. Kice in Free Radicals, Vol. 2 (Ed.: J. K. Kochi), Wiley, New York, 1973, Chap. 24; b) E. Block, Reactions of Organosulfur Compounds, Academic, New York, 1978; c) F. W. Stacey, J. F. Harris, Org. Reactions 1963, 13, 150-376; d) D. Crich in Organosulfur Chemistry: Synthetic Aspects (Ed.: P. Page), Academic, London, 1995, Chap. 2; e) C. Chatgilialoglu, M. P. Bertrand, C. Ferreri in S-Centered Radicals (Ed.: Z. B. Alfassi), Wiley, New York, 1999, Chap. 11. [7] For reviews concerning thiyl radicals see: a) K. Griesbaum, Angew. Chem. Int. Ed. Engl. 1970, 9, 273; b) R. M. Kellogg in Methods in Free Radical Chemistry (Ed.: E. S. Huyser), Dekker, New York, 1969. [8] For reviews concerning sulfonyl radicals see: a) K. Schank in The Chemistry of Sulfones and Sulfoxides: Synthesis of Open-chain Sulfones (Eds.: S. Patai, Z. Rappoport and C. J. M. Stirling), Wiley, New York, 1988, Chap. 7; b) J. 0. Metzger in Methoden der Organischen Chemie (Houben-Weyl), Vol. 1 (Eds.: M. Regitz and B. Giese), Thieme, Stuttgart, 1989, pp. 476-485; c) N. S. Simpkins, Sulphones in Organic Synthesis, Pergamon, 1993; d) M. P. Bertrand, Org. Prep. Proc. Int. 1994, 26, 257-290. [9] D. A. Armstrong, D. M. Chipman in S-Centered Radicals (Ed.: Z. B. Alfassi), Wiley, New York, 1999, Chap. 1. [lo] a) C. Schoeneich in Methods in Enzyinology 1991, 251, 45-55; b) P. Wardman, C. vonSonntag ibid. 1991, 251, 31-45. [ 111 a) F. W. Hoffmann, R. J. Ess, T. C. Simmons, R. S. Hanzel, J. Am. Chern. Soc. 1956, 78, 6414; b) C. Walling, R. Raboniwitz, ibid. 1959, 81, 1243-1249. [12] a) D. Crich, W. B. Motherwell in Free Radical Chain Reactions in Organic Synthesis, Academic, 1992; b) D. Crich, L. Quintero, Chem. Rev. 1989,89, 1413-1432 and references therein. [13] a) For a review see: B. P. Roberts, Chem. Soc. Rev. 1999,28, 25%35and references therein. For an application to the reduction of electron deficient bromides see: b) M. Amoli, M. S. Workentin, D. D. M. Wayner, Tetrahedron Lett. 1995,36, 3997-4000. [ 141 H.-S. Dang, B. P. Roberts, Tetrahedron Lett. 1999, 40, 4271-4274. [ 151 J.-C. Meurice, M. Vallier, M. Ratier, J.-G. Duboudin, M. Petraud, J. Orgunornet. Chem. 1997, 542, 67-73. [I61 a) H . 4 . Dang, B. P. Roberts, Tetrahedron Lett. 1999, 40, 8929-8933; b) H.-S. Dang, M. R. J. Elsegood, K.-M. Kim, B. P. Roberts, J. Chem. Soc., Perkin Trans. 1 1999, 2061-2068. [17] a) Y. Masuda, M. Hoshi, Y. Nonokawa, A. Arase, J. Chen?. Soc., Chem. Commun. 1991, 1444-1445; b) Y. Ichinose, K. Wakamatsu, K. Nozaki, J.-L. Birbaum, K. Oshima, K. Utimoto, Chem. Lett. 1987, 1647-1650; c) Y. Ichinose, K. Oshima, K. Utimoto, ibid. 1988, 14371440. [ 181 D. H. R. Barton, M. A. Csiba, Jasberenyi, Tetrahedron Lett. 1994, 35, 2869-2872. [ 191 V.-H. Nguyen, H. Nishino, S. Kajikawa, K. Kurosawa, Tetrahedron 1998, 54, 11445-1 1460.
502
5.5 Sulfur-Centered Radicals
[20] a) D. J. McPhee, M. Campredon, M. Lesage, D. Griller, J. Am. Chem. Soc. 1989, 111, 75637567; b) 0. Ito, M. Matsuda, ibid. 1979,101, 5732-5735; c) M. Nakamiura, 0. Ito, M. Matsuda, hid. 1980, 102, 698-701; d) Y. Takahara, M. Iino, M. Matsuda, Bull. Chem. Soc. Jpn. 1976, 49,2268-2271; e) A. S. Gozdz, P. Maslak, J. Org. Chem. 1991,56,2179-2189; f ) C. M. M. da Silva CorrZa, M. D. Fleming, M. A. Oliveira, E. M. Garrido, J. Chem. Soc., Perkin Trans. 2 1994, 1993-2000; g) C. M. M. da Silva Corria, M. D. Fleming, ibid. 1987, 103-107. [21] a) C. Walling, W. Helmreich, J. Am. Chem. Soc. 1959, 81, 1144-1148; b) G. M. Bristow, F. S. Dainton, J. Proc. Roy. Soc. (London) 1955, A229, 509-524 and 525-536; c) M. Asscher, D. Vofsi, J. Chem. Soc. 1964, 4962; d) J. Sinnreich, M. Asscher, J. Chem. Soc., Perkin Trans. 1 1971, 1543-1545. [22] a) J. Gervay, T. M. Flaherty, D. Holmes, Tetrahedron, 1997, 53, 16355-16364; b) P. B. van Seeventer, J. A. L. M. vanDorst, J. F. Siemerink, J. P. Kamerling, J. F. G. Vliegenthart, Carbohydrate Res. 1997, 300, 369-373. [23] Q. B. Brozterman, B. Kaptein, J. Kamphuis, H. E. Schoemaker, J. Org. Chem. 1992, 57, 6286-6294 and references therein. [24] J. Yoshida, S. Nakatani, S. Isoe, J. Org. Chem. 1993, 58, 4855-4865. [25] a) S. Iriuchijima, K. Maniwa, T. Sakakibara, G-I. Tsuchihashi, J. Org. Chem. 1974, 39, 11701171; b) X. Wang, Z. Ni, X. Liu, A. Hollis, H. Banks, A. Rodriguez and A. Padwa, ibid. 1993, 58. 5377-5385. [26] a) A. Ogawa, R. Obayashi, H. h e , Y. Tsuboi, N. Sonoda, T. Hirao, J. Org. Chem. 1998, 63, 881--884; b) A. Ogawa, I. Ikuko, R. Obayashi, K. Umezu, T. Hirao, ibid. 1999, 64, 86-92 and references therein. [27] a) D. C. Craig, G. L. Edwards, C. A. Muldoon, Synlett 1997, 1318-1320; b) J. R. Bull, N. S. Desmond-Smith, S. J. Heggie, R. Hunter, F.-C. Tien, ibid. 1998, 900-902; c) M. Yoshimatsu, M. Hayashi, G. Tanabe, 0. Muraoka, Tetrahedron Lett. 1996,37,4161-4164; d) T. G. Back, S. Collins, R. G. Kerr, J. Org. Chem. 1983,48, 3077-3084; e) T. G. Back, E. K. Y. Lai, K. R. Muralidharan, ibid. 1990, 55, 4595-4602. [28] a) J.-M. Fang, M.-Y. Chen, M.-C. Cheng, G.-H. Lee, Y. Wang, S.-M. Peng, J. Chem. Res. ( S ) 1989, 272-273; b) M. C. M. de C. Alpoim, A. D. Morris, W. B. Motherwell, D. M. O’Shea, Tetrahedron Lett. 1988, 29, 4173-4176; c) G. C. Wolf, J. Org. Chem. 1974, 39, 34543455. [29] S. Caddick, D. Hamza, S. N. Wadman, Tetrahedron Lett. 1999, 40, 7285-7288. [30] a) N. Narasaka, T. Mochizuki, S. Hayakawa, Chem. Lett. 1994, 1705-1708; b) T. Mochizuki, S. Hayakawa, N. Narasaka, Bull. Chem. Soc. Jpn. 1996, 69, 2317-2325; c) N. Kamigata, K. Udodaira, T. Shimizu, J. Chem. Soc., Perkin Trans. 1 1997, 783-786. [31] a) T. G. Back, K. Brunner, M. Vijaya Krishna, E. K. Y. Lai, Can. J. Chem. 1989, 67, 10321037; G. Pattenden, A. J. Smithies, Synlett 1992, 577-578. [32] For a review of the early work see: J. M. Surzur in Reactive Intermediates (Ed.: R. A. Abramovitch), Plenum, New York, 1982, Chap. 3. [33] a) G. Bastien, J.-M. Surzur, Bull. Sue. Chim. Fr.II 1979, 601-605; b) G. Bastien, M. P. Crozet, E. Flesia, J.-M. Surzur, ibid. 1979, 606-613. [34] a) J. E. Baldwin, J. Chem. Soc., Chem. Commun. 1976, 734-736; b) A. L. J. Beckwith, C. H. Schiesser, Tetrahedron 1985, 41, 3925-3941. [35] W. Cabri, D. Borghi, E. Arlandini, P. Sbraletta, A. Bedeschi, Tetrahedron 1993, 49, 68376848. [36] a) M. D. Johnson, S. Derenne, J. Organomet. Chem. 1985, 286, C47-50; b) P. N. Culshaw, J. C. Walton, J. Chem. Soc., Perkin Trans. 2 1991, 1201-1208. [37] a) M. E. Kuehne, R. E. Damon, J. Org. Chem. 1977, 42, 1825-1832; b) H. Yorimitsu, K. Wakabayashi, H . Shinokubo, K. Oshima, Tetrahedron Lett. 1999, 40, 519-522; c) D. C. Harrowen, M. C. Lucas, P. D. Howes, ibid. 1999, 40, 4443-4444. [38] a) 1. De Riggi, J.-M. Surzur, M. P. Bertrand, A. Archavlis, R. Faure, Tetrahedron 1990, 46, 5285-5294; b) M. P. Bertrand, I. De Riggi, C. Lesueur, S. Gastaldi, R. Nouguier, C. Jaime, A. Virgili, J. Org. Chem. 1995, 60, 6040-6045; c) M. P. Bertrand, C. Lesueur, R. Nouguier, Carhohydr. Lett. 1995, I , 393-398; d) M. P. Bertrand, S. Gastaldi, R. Nouguier, Synlett 1997, 1420-1422; e) M. P. Bertrand, S. Gastaldi, R. Nouguier, Tetrahedron 1998, 54, 12829-12840; f ) C.-P. Chuang, ibid. 1991, 47, 5425-5436; g) C.-P. Chuang, S.-F. Wang, Synth. Commun.
References
503
1995, 25, 3549; h) C. Wang, G. Russell, J. Org. Chem. 1999, 64, 2066-2099; h) A. J. Blake, A. J. Highton, T. N. Majid, N. S. Simpkins, Org. Lett. 1999, 1, 1787-1789. [39] a) C. A. Broka, D. E. C. Reichert, Tetrahedron Lett. 1987, 28, 1503-1506; b) P. M. J. Jung, J. Dauvergne, A. Burger, J.-F. Biellmann, ibid. 1997, 38, 5877-5880. [40] a) J. E. Brumwell, N. S. Simpkins, N. K. Terrett, Tetrahedron 1994, 50, 13533-13552; b) B. Alcaide, I. M. Rodriguez-Campos, J. Rodriguez-Lopez, A. Rodriguez-Vicente, J. Org. Chem. 1999,64, 5377-5387. [41] S. Caddick, C. L. Shering, S. N. Wadman, J. Chem. Soc., Clzem. Commun. 1997, 171-172. [42] a) F. El-Gueddari, J. R. Grimaldi, J. M. Hatem, Tetrahedron Lett. 1995, 36, 6685-6688; b) M. Depature, D. Siri, J. Grimaldi, J. Hatem, R. Faure, ibid. 1999, 40, 4547-4550. [43] a) G. E. Keck, T. T. Wager, J. Org. Chem. 1996, 61, 8366-8367; b) 0. Miyata, K. Muroya, J. Koide, T. Naito, Synlett 1998, 271-272; c) L. El Kaim, A. Gacon, A. Perroux, Tetrahedron Lett. 1998, 39, 371-374; d) P. C. Montevecchi, M. L. Navacchia, P. Spagnolo, Tetrahedron 1998,54, 8207-8216. [44] T. Naito, Heterocycles 1999, 50, 505-541. [45] I. De Riggi, S. Gastaldi, J.-M. Surzur, M. P. Bertrand, A. Virgili J. Org. Chem. 1992, 57, 6118-6125. [46] C. Wang, G. A. Russell, J. Org. Chem. 1999, 64, 2346-2352. [47] M. D. Bachi, E. D. Korshin, Synlett 1998, 122-124. 1481 a) M. D. Bachi, A. Melman, J. Org. Chem. 1995,60, 6242-6244; b) M. D. Bachi, N. Bar-Ner, A. Melman, ibid. 1996, 61, 71 16-7124. [49] a) P. C. Montevecchi, M. L. Navacchia. P. Spagnolo, J. Org. Chem. 1997, 62, 5846-5848; b) P. C. Montevecchi, M. L. Navacchia, P. Spagnolo, Tetrahedron Lett. 1997, 38, 79137916. [50] a) C.-P. Chuang, S.-F. Wang, Synlett 1995, 763-764; b) S.-F. Wang, C.-P. Chuang, J.-H. Lee, S.-T. Liu, Tetrahedron 1999, 55, 2273-2288. [51] a) D. H. R. Barton, B. Lacher, B. Misterkiewics, S. Zard, Tetrahedron 1988, 44, 1153-1158; b) D. H. R. Barton, J. C. Jaszberenyi, E. A. Theodorakis, Tetrahedron Lett. 1991, 32, 33213324; c) See also [ 121 and references therein. [52] a) C. Chatgilialoglu, L. Lunazzi, K. U. Ingold, J. Org. Chem. 1983, 48, 3588-3589; b) C. Chatgilialoglu, ibid. 1986, 51, 2871 -2873. [53] a) K. J. Ivin, J. B. Rose, Adu. Macromol. Chem. 1968, I, 335-406; b) J.-Y. Tsai, P. B. Shevlin, J. Org. Chem. 1998,63, 3230-3234. [54] a) T. Billard, N. Roques, B. R. Langlois, J. Org. Chem. 1999, 64, 3813-3820; b) B.-N. Huang, J.-T. Liu, W.-Y. Huang, J. Chem. Soc., Perkin Tran.s. 1 1994, 101-104; c) B. R. Langlois, E. Laurent, N. Roidot, Tetrahedron Lett. 1992,33, 1291-1294; d) Q.-Y. Chen, Z.-T. Li, J. Org. Chem. 1993, 58, 2599-2604. [55] C. Walling, W. Helmreich, J. Am. Chem. Soc. 1959, 81, 1144-1148. [56] For a review see: P. E. Sonnet, Tetrahedron, 1980, 36, 557-604. [57] a) N. R. Curtis, A. B. Holmes, M. G. Looney, L. N. D. Pearson, G. C. Slim, Tetrahedron Lett. 1991,32, 537-540; b) A. B. Smith 111, T. A. Tano, N. Chida, G. A. Sulikowski, J. Org. Chem. 1990, 55, 1136-1138. [58] C. Chatgilialoglu, C. Ferreri, M. Ballestri, Q. G. Mulazzani, L. Landi, J. Am. Chem. Soc. 2000,122,4593-4601. [59] For a recent study see: C. Chatgilialoglu, M. Ballestri, C. Ferreri, D. Vecchi, J. Org. Chem. 1995, 60. 3826-3831. 1601 D. C. Harrowen, J. C. Hannam, Tetrahedron, 1999, 55, 9341-9346. [61] For a discussion see: C. Chatgilialoglu, C. Ferreri in Supplement C2: The Chemistry of Triple Bonded Functional Groups, (Ed: S. Patai), Wiley, New York, 1994, Chap. 16. [62] a) K. S. Feldman, A. L. Romanelli, R. E. Ruckle Jr., R. F. Miller, J. Am. Chem. Soc. 1988, 110, 3300-3302; b) K. S. Feldman, H. M. Berven, P. H. Weinreb, ibid. 1993, 115, 1136411369; c) K. S. Feldman, R. E. Simpson, ibid. 1989, I l l , 4878-4886; d) K. S. Feldman, C. M. Kraebel, J. Org. Chem. 1992,57, 4574-4576; e) K. S. Feldman, A. L. Romanelli, R. E. Ruckle Jr., G. Jean, ibid. 1992, 57, 100-1 10; f ) K. S. Feldman, H. M. Berven, A. L. Romanelli, M. Parvez, ibid. 1993, 58, 6851-6856; g) K. S. Feldman, C. J. Burns, ibid. 1991, 56, 46014602; h) K. S. Feldman, K. Schildknegt, ibid. 1994, 59, 1129-1 134.
504
5.5 Suljiir-Centered Radicals
[63] a) M. P. Bertrand, R. Nouguier, A. Archavlis, A. Carrikre, Synlett 1994, 736-738; b) Z. Cekovic, R. Saicic, Tetrahedron Lett. 1990, 31, 6085-6088; c) C.-P. Chuang, S.-S. Hu, R.-R. Wu, Synth. Commun. 1992,22, 467-476. 1641 a) K. Miura, K. Fugami, K. Oshima, K. Utimoto, Tefruhedron Lett. 1988, 29, 1543-1546; b) K. Miura, K. Fugami, K. Oshima, K. Utimoto, Tetrahedron Lett. 1988, 29, 5135-5138. [65] a) D. A. Singleton, K. M. Church, J. Org. Chem. 1990, 55, 4780-4782; b) C. C. Huval, D. A. Singleton, ibid. 1994, 59, 2020-2024; c) D. A. Singleton, C. C. Huval, K. M. Church, E. S. Priestley, Tetrahedron Lett. 1991, 32, 5765-5768; d) C. C. Huval, K . M. Church, D. A. Singleton, Synlett 1994, 273-274. [66] V. H. Rawal, V. Krishnamurthy, Tetrahedron Lett. 1992, 33, 3439-3442. [67] a) T. A. K. Smith, G. H. Whitham, J. Chem. Soc., Chem. Commun. 1985,897-898; b) T. A. K. Smith, G. H. Whitham, J. Chem. Soc., Perkin Trans. 1 1989, 313-317 and 319-325; c) A. Padwa, W. H. Bullock, A. D. Dyszlewski, J. Org. Chem. 1990, 55, 955-964; d) I. W. Harvey and G. H. Whitham, J. Chem. Soc., Perkin Trans. 1 1993, 185-190 and 191-196. [68] a) M. P. Bertrand, S. Gastaldi, R. Nouguier, Tetrahedron Lett. 1996, 37, 1229-1232; b) 0. Miyata, Y. Ozawa, I. Ninomiya, T. Naito, Synlett 1997, 275-276. See also [48b]. [69] a) S. Caddick, C. L. Shering, S. N. Wadman, Tetrahedron Lett. 1997,38, 6249-6250. For other reactions leading to annulated-heteroaromatics through @so-substitution see: b) F. Aldabbagh, W. R. Bowman, Tetrahedron 1999, 55, 4109-4122; c) S. Caddick, K. Aboutayab, R. I. West, J. Chcm. Soc., Perkin Trans. I 1996, 675-682 and references therein. [70] M. Journet, A. Rouillard, D. Cai, R. D. Larsen, J. Org. Chem. 1997, 62, 8630-8631. [71] a) B. Quiclet-Sire, S. Zard, J. Am. Chem. Soc. 1996, 118, 1209-1210; b) F. Le Guyader, B. Quiclet-Sire, S. Seguin, S. Z. Zard, ibid. 1997, 119, 7410-7411; c) B. Sire, S. Seguin, S. Z. Zard, Angew. Chem., Int. Ed. Engl. 1998, 37, 2864-2866; d) F. Bertrand, B. Quiclet-Sire, S. Z. Zard, hid. 1999, 38, 1943-1946. [72] R. Nouguier, S. Gastaldi, D. Stien, M. P. Bertrand, P. Renaud, Tetruhedron Lett. 1999, 40, 3371-3374. [73] S.-F. Wang, C.-P. Chuang, W.-H. Lee, Tetruhedron 1999, 55, 61 18-6109. [74] a) M. Bachi, A. Melman, J. Org. Chem. 1997, 62, 1896-1898; b) L. A. Paquette, S. Usui, Tetrahedron Lett. 1999, 40, 3499-3502. [75] A. Demircan, P. J. Parsons, Synlett 1998, 1215-1216. [76] a) C. L. L. Chai, D. Christen, B. Halton, R. Neidlein, M. A. E. Starr, Aust. J. Chem. 1995, 48, 577-591; b) K. Mlinaric-Majerski, Z. Majerski, B. Rakvin, Z. Veksli, J. Org. Chem. 1989, 54, 545-548; c) P. F. McGarry, L. J. Johnston, J. C. Scaiano, ibid. 1989, 54, 6133-6135. [77] a) G. A. Russell, P. Ngoviwatchai in Sulfur-Centered Reactive Intermediates in Chemistry and Biology (Eds.: C. Chatgilialoglu and K.-D. Asmus), Plenum, New York, 1990, pp 291-301 and references therein; b) N . Kamigata, K. Ishii, T. Ohtsuka, H. Matsuyama, Bull. Chem. Soc. Jpn 1991, 64, 3479-3481; c ) S. Roy, I. Das, K. Bhanuprakash, B. D. Gupta, Tetrahedron 1994, 50, 1847- 1858.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
6 Radicals in Biomaterials 6.1 Modifications of Amino Acids and Peptides via Radicals Christopher J. Easton
6.1.1 Introduction Non-proteinogenic amino acids and their peptides and other derivatives are important components of biological systems and attractive targets for synthesis [ 11 because of the diverse range of physiological and pharmaceutical activities that they display. The proteinogenic amino acids are commonly used as starting materials for such syntheses because they are often the natural precursors of the non-proteinogenic amino acids and they are generally readily available in enantiopure form. Traditionally the transformations have been carried out mostly using ionic reactions, but radical processes are increasingly being used [2, 31, with the realization that they can be accomplished in good yield and with a high degree of regio- and stereocontrol. The purpose of this chapter is to briefly overview the methods for these synthetic radical transformations. Aspects of the underlying mechanistic studies and their biological ramifications have been reviewed elsewhere [4, 51.
6.1.2 Hydrogen Atom Transfer Reactions Free-radical reactions are particularly useful where they allow transformations that are not possible using ionic methods. In this regard, hydrogen transfer processes are of special interest, because they can be used ?ither to introduce a functional group or to form a carbon-carbon bond, by directly substituting for hydrogen, at a position which need not be activated by adjacent functional groups. There are no directly analogous cationic processes, and, while the anionic counterparts have been used to good effect [ 6 ] ,they require strong bases and suffer other limitations, and the regioselectivity of proton transfer is typically quite different from that of hydrogen atom transfer.
506
6.1 ModiJications of Amino Acids and Peptides via Radicals
6.1.2.1 a-Carbon-Centered Radicals Most intermolecular hydrogen atom transfer reactions of amino acids and peptides afford x-carbon-centered radicals, partly as a result of the stability of these species. There is extensive delocalization of the unpaired spin density in radicals of this type through the resonance effects of the electron-releasing amino or amido substituent and the electron-withdrawing carboxy group [7], and, as a consequence, the acentered radicals of uncharged glycine and N-acetylglycine are calculated to be more stable than methyl radical by 102 and 91 kJ mol-', respectively [8]. Polar effects are also likely to be important in these hydrogen transfer processes, and the resonance electron-donating and -withdrawing groups can delocalize charge as well as spin density to lower the energy of the reaction transition states [9]. Early synthetic procedures exploiting hydrogen atom transfer reactions to give acarbon-centered radicals were reported by Elad and coworkers [ 101. Using a variety of hydrogen-abstracting species, including tert-butoxy radical and triplet ketones, they generated a-carbon-centered radicals of glycine derivatives which underwent addition and coupling reactions (Scheme 1). When generated in the absence of an alkylating agent, the glycyl radicals reacted to give dimers [ 10, 111. Other hydrogen transfer reactions of glycine derivatives have been used to introduce functional groups at the a-position. For example, reactions with bromine or N-bromosuccinimide, tert-butyl perbenzoate in the presence of a copper catalyst, and tert-butyl hydroperoxide and formate, have been used to produce a-bromo-, benzoyloxy- and carboxy-substituted glycine derivatives, respectively (Scheme 2) [ 12- 141. -CONH-CH-CO-
I
-CONH-CH-CO-
.
R' (from RH)
-CONH-CH-CO-
~
-CONH-CH-CO-
R I -CONH-CH-CO-
-CONH-CH-CO-
I--\
I--\
RH = M e O V M e , F-Me. R' = H, Me, Et, Bu, n-C6HI3
Scheme 1
MeC02H
6.1.2 Hydrogen Atom Transfer Reactions
J
\
\
507
cop-
OCOPh I -CONH-CH-CO-
I -CONH-CH-CO-
Scheme 2
Glycine residues in cyclic dipeptides (diketopiperazines) may be brominated, and it is possible to selectively functionalize only one in a symmetric diketopiperazine [ 151. These bromides are useful for the synthesis of asymmetric diketopiperazines. In order to obtain bromoglycine derivatives for use in stereocontrolled synthesis, chiral auxiliaries have been attached to the amino and carboxy groups of glycine before bromination. For example, the bromides 1-4 have been prepared in this manner [ 16-19]. They were obtained as various mixtures of diastereomers, but this stereochemistry is not particularly important as their reactions mostly involve intermediates that are planar at the a-carbon.
Br
-GH~SO~NH-AH-CO~E~ 0 4
The susceptibility of glycine derivatives toward hydrogen atom transfer depends on the nature of the amino and carboxy protecting groups, and the more marked effects can be exploited in regioselective modification of peptides. Whereas either an amido substituent or the free base form of an amino group will stabilize a radical formed at an adjacent carbon, dative stabilization does not occur with a protonated or quaternized amino group, and the corresponding radical is therefore much less stable and much less easily formed [2, 31. Accordingly, on photolysis with di-tertbutyl peroxide, triglycine 5 afforded approximately equal quantities of the crosslinked species 6 and 7, and there was no indication of reaction of the N-terminal glycine residue [20]. It is also apparent from these results that the radical 8 forms in preference to the regioisomer 9. There are few reports of radical reactions at the c(-
508
6.1 Modijications of Amino Acids and Peptides via Radicals
position of either free amino acids or N-terminal amino acids in peptides, since the basic conditions required to maintain an amino group in the nonprotonated form are generally incompatible with radical processes.
+
NH3-CH2-CONH-CH2-CONH-CH-CO2-
+
NH3-CHz-CONH-CH2-CONH-CH-COz-
5
I
6
+
NH3-CHz-CONH-CH2-CONH-CH-CO28
.
7
+
.
NH,-CH2-CONH-CH-CONH-CH2-C029
With N-acylated and sulfonylated glycine derivatives, the ease of glycyl radical formation correlates directly with the resonance electron-donating ability of the amido or sulfonamido group, as measured by the relative rates of reaction of amino acid derivatives with N-bromosuccinimide (Table 1) [8]. This is reflected in reactions of the dipeptide derivatives 10a and lla. Whereas N-benzoylglycylglycine methyl ester 10a affords only the bromide 10b from reaction of the N-terminal amino acid residue, the triflamide lla gives only the C-terminal bromide llb. Imides have also been exploited as protected amino groups which are less activating than amido substituents, as illustrated by the reaction of N-phthaloylglycylglycinemethyl ester Table 1. Relative rates of reaction of glycine derivatives with N-bromosuccinimide
RNH-CH2-C02Me
C6HsCO ChFsCO CH3CO CFiCO PhSOz CF3SOz
NBS
1.0 0.25 1.2 0.05 0.6 <0.005
Br I RNH-CH-C02Me
6.1.2 Hydrogen Atom Transfer Reactions
509
12a to give only the bromide 12b [21] and the regioselective reaction of the diketopiperazine 13a to give the sulfide 13b after treatment with N-bromosuccinimide and then p-chlorothiophenol [22]. The effect of an imido group compared to an amide derives from a combination of steric and electronic factors. R
9
I
BzNH-CH-CONH-CH2-C02Me 10
CF&O2NH-CH2-C0NH-CH-CO2Me a:R=H b: R = Br c: R = OMe
11
a:R=H b: R = Br c: R = OMe
?
R'
PhthN-CH2-CONH-CH-C02Me 12
O+NM ,e Ac,N,,-!+o
a:R=H b: R = Br c: R = OMe
a: R'= H b: R'= SPh-pCI
13
The discussion above is focussed on reactions of glycine derivatives. The reactions of other amino acids are affected by similar factors. They also tend to proceed via a-carbon-centered radicals and often give products analogous to those obtained from reactions of the corresponding glycine derivatives, as shown through the synthesis of the dimer 14 by treatment of the corresponding pyroglutamate monomer with di-tert-butyl peroxide [23]. a-Functionalization is also common, as illustrated by autoxidation of the cyclic dipeptide 15a to give the hydroperoxides 15b and 15c [24]. In other cases, the amino acid side chain alters the course of reaction. For example, whereas N-benzoylglycine methyl ester reacts with nickel peroxide to give benzamide from cleavage of the a-C-N bond, identical treatment of N-benzoylalanine methyl ester gives the dehydroalanine derivative 16 [ 251. Presumably these processes involve the corresponding a-carbon-centered radicals, but reaction of the alanine derivative is diverted because of the abstractable hydrogen at the P-position. Derivatives of many other amino acids in addition to glycine react to give a-brominated products, but, with only a few notable exceptions [ 17, 261, the instability of these compounds limits their accessibility and utility in synthesis. h
SH2
MeOCO 14
BzNH-C-C02Me 15
16
a: R' = R~ = H b: R' = OOH, R2 = H c: R' = R2 = OOH
With peptides containing more than one type of amino acid residue, the possibility of selective reaction exists. Under these circumstances glycine residues show
510
6.1 ModiJications of'tlmino Acids and Peptides via Radicals
Table 2. Relative rates of reaction of amino acid derivatives with N-bromosuccinimide H I BzNH-CR-C02Me
H Me i-Pr t-Bu
NBS
Br I BzNH-CR-C02Me
1.o 0.33 0.04 <0.004
particular reactivity in hydrogen atom transfer reactions to give the corresponding a-carbon-centered radicals. The earliest synthetic applications of this selectivity were developed by Elad and coworkers [lo],who reported, for example, a 60:l selectivity for alkylation of glycine residues in synthetic polypeptides containing alanine and glycine, and a 4:l selectivity in peptides comprising proline and glycine. They also selectively alkylated glycine residues in lysozyme, collagen, gelatin and ribonuclease. More recently, Koch et al. [14] selectively carboxylated glycine residues in gelatin, using tert-butyl hydroperoxide and formate. The selectivity for hydrogen atom abstraction from glycine residues in small peptides and other simple amino acid derivatives correlates with the ability of the product a-carbon-centered radicals to adopt planar conformations where there is maximum stabilization [S, 271. This is reflected in the relative rates of reaction of amino acid derivatives with N-bromosuccinimide, which decrease as unfavorable non-bonding interactions involving the side chains in the corresponding intermediate radicals become more severe (Table 2 and Fig. 1). In proteins and other polypeptides, the selectivity is likely to be enhanced by the tendency for glycine residues to be exposed on the outer surfaces of the three-dimensional structures. It is also likely that the reactivity of a glycine residue may be facilitated through a stereoelectronic effect, i.e. its distortion to improve overlap of the developing semioccupied p-orbital with adjacent 71-orbitals [28]. The selective halogenation of glycine residues in peptides is demonstrated by the bromination of the derivatives of valylglycine 17a, glycylvaline 18a, and the cyclic dipeptide 19a to give only the corresponding bromides 17b, 18b and 19b [29, 301. This selectivity can be exploited in combination with the other effects discussed
Figure 1. Non-bonding interactions associated with planar conformations of amino acid radicals
6.1.2 Hydrogen Atom Transfer Reactions
51 1
above. Accordingly the tripeptide 20a reacts with N-bromosuccinimide to give only the bromide 20b because of the effect of the phthaloyl group to reduce the reactivity of the N-terminal amino acid residue and the relatively low reactivity of valine residues [21]. The extent of the phthaloyl group effect is generally sufficient to overcome the selectivity for reaction of glycine residues, as illustrated by the regioselective reaction of the aspartate residue of the dipeptide 21 on treatment with nickel peroxide, to give the dehydropeptide 22 [25].
i-Fjr
R
?
j-Fjr
BzNH-CH-CONH-CH-C02Me
I
BzNH-CH-CONH-CH-C02Me
17
18
19
a:R=H b: R = Br
20
MeOCO,
CH2C02Me I
PhthN-CH2-CONH-CH-C02Me
H
S’
PhthN-CH2-CONH-C-C02Me
21
22
Amino acids and their peptide derivatives can also give a-carbon-centered radicals by electron transfer from the free or protected amino group, followed by proton loss, and in methanol the reactions tend to give a-methoxylated amino acid derivatives. The regioselectivity of reactions of this type in peptides is determined by the preferred site of electron transfer. For example, the derivatives of valylglycine 23a and prolylglycine 24a afford the corresponding methoxides 23b and 24b [31], presumably as a result of the relative ease of electron transfer from amides compared to carbamates. In some cases it is difficult to distinguish between the electron transfer and hydrogen atom abstraction mechanisms, although sometimes the regioselectivity of these processes is complementary. Whereas bromination of the dipeptide 10a followed by reaction with methanol gave the N-terminal methoxyglycine derivative 1Oc [21], anodic oxidation of the same material in methanol gave the product 25 from reaction of the C-terminal glycine [31]. R
RI j-7, BocNH-CH-CONH-CH-C0,Me
23
a: R = H b: R = OMe
I
CONH-CH-C0,Me Boc
24
?Me BzNH-CH2-CONH-CH-C02Me 25
5 12
6.I ModiJcations of Amino Acids and Peptides via Radicals
6.1.2.2 Side-Chain Radicals While most intermolecular hydrogen atom transfer reactions of amino acid derivatives afford a-carbon-centered radicals, side-chain radicals can form when either they are the more stable or factors other than radical stability determine the outcome of the hydrogen abstraction. Side-chain halogenation of amino acids occurs on photolysis with chlorine in sulfuric acid, as illustrated by the reactions of alanine 26a and lysine 27a to give the chlorides 26b and 27b, respectively [ 3 2 ] . The regioselectivity of these reactions can be attributed to the inability of a protonated amino group to stabilize an adjacent radical through resonance and the inductive effect of the electron-withdrawing carboxy and protonated amino groups to disfavor a nearby hydrogen transfer that involves a charged transition state and formation of an electron-deficient center at the site of hydrogen abstraction.
26
a:R=H b: R = CI
27
The opposing deactivating inductive and activating resonance effects of a carboxy group towards hydrogen abstraction from an adjacent carbon and similar effects of amino and amido groups can be exploited to avoid reactions of amino acid derivatives at the a-position. While the valine and sarcosine derivatives 28a and 29a react with N-bromosuccinimide to give the corresponding bromides 28b and 29b as the primary products, they react with sulfuryl chloride to give mainly the chlorides 28c and 29c [ 3 3 ] . With little carbon-hydrogen bond homolysis in the transition state for hydrogen transfer in the chlorination, the regioselectivity is controlled by the inductive electron-withdrawing effects of the amido and carboxy groups, acting to retard attack at the a-carbon by electrophilic radicals involved in the hydrogen abstraction. Bromination involves more extensive carbon-hydrogen bond homolysis in the reaction transition state, and the regioselectivity of reaction is therefore more dependent on the stability of the product radical. Me,CR2JvIe BzNH-&-C02Me 28
BzN-CHR1C02Me I CH& a: RI= R~ = H b: R’ = Br, R2 = H C : R’ = H, R2 = CI
29
As discussed above, with N-acylated and sulfonylated amino acid derivatives, the ease of a-carbon-centered radical formation depends on the resonance electron-
6.1.2 Hydrogen Atom Transfer Reactions
5 13
donating ability of the amido or sulfonamido group. This is inversely proportional to the magnitude of the inductive deactivating effect of the substituent. When the resonance effect is sufficiently weak, reaction at the cc-position is no longer preferred, and, instead, hydrogen transfer occurs to give the most stable side-chain radical, as indicated by the reactions of the triflamides 30a and 31a with N-bromosuccinimide to give the bromides 30b and 31b [8]. Similar regioselectivity is seen in reactions of the phthalimides 32a-34a to give the bromides 32b-34b, because the imido group is a relatively poor resonance electron donor and steric effects disfavor hydrogen transfer from the a-position of these reactants [9, 211. Ph,CH-R
I
CF3S02NH-CH-C02Me
CF3S02NH-CH-C02Me
30
31
PhYCH-R PhthN-CH-C02Me
32
PhXCH,R
I
I
PhthN-CH-C02Me
PhthN-CH-CONH-t-Bu
33
34
a:R=H b: R = Br
The side-chain reactivity depends on the nature of the carboxy group, being five times greater for the amide 34a than for the ester 33a [34]. This reflects neighboring group effects that appear to be significant in radical processes which involve polar transition states. The steric effects of the phthalimido substituent in reactions of the amino acid derivatives 32a-34a result from its proximity to the carboxy group. Alone, on the side chain of an amino acid derivative, a phthalimido substituent activates an adjacent position towards hydrogen transfer, as indicated in the reactions of the ornithine and lysine derivatives 35a and 35b to give the bromides 35c and 35d, respectively [8]. Similar regioselectivity is observed on direct anodic oxidation of the ornithine and lysine derivatives 36a and 36b to give the corresponding methoxides 36c and 36d [35]. PhthN.CHcR
I y2)" PhthN-CH-C02Me
35 a: n =2, R = H b: n = 3, R = H c: n = 2, R = Br d: n = 3, R = Br
MeOCONH,CH.-R
I y 2 ' "
MeOCONH-CH-C02Me 36 a:n=2,R=H b: n = 3, R = H c: n = 2, R = OMe d: n = 3 . R = OMe
Where functionalization is required adjacent to the site of direct bromination, it is sometimes possible to move the halide through hydrogen bromide elimination
514
6.I Mod8cations of Amino Acids and Peptides via Radicals Me,C5CH2
32
AgNO3
I
PhthN-CH-C02Me
HBr
hv
Me,CiCH2Br
I
PhthN-CH-COpMe
37
Scheme 3
followed by radical addition, as illustrated in Scheme 3 for the synthesis of the ybromovaline derivative 37 [ 361. The bromine migration is a logical consequence of the reaction mechanisms. Geometrical constraints associated with intramolecular hydrogen transfer reactions can also be exploited to accomplish side chain reactions of amino acid derivatives, in some cases via radicals that would not be formed through intermolecular processes. Photolytic reactions of N-phthaloyl and N-halo amino acid derivatives have been used in this manner [8, 371. For example, the chloroamides 38 and 40 reacted to give the corresponding alkyl chlorides 39 and 41.In these reactions, the regioselectivity of chlorination is determined by the preference for intramolecular 1$hydrogen atom transfer. Me
CH2CI
I CH2
FH2
YH2 Acty-CH-C02Me
FH2 AcN-CH-C02Me
I
I
Me I CH2 I PhthN-CH-CON-t-BU
38
I
I
A
CI
CH2CI I CH2 I PhthN-CH-CON-t-Bu
CI
39
40
H 41
6.1.3 Functional Group Transformations and Applications in Synthesis The principal objective of the hydrogen transfer reactions is to introduce functional groups that, together with others already present in amino acid derivatives and peptides, are suitable for use in synthesis. Halogenated glycine derivatives have been alkylated and arylated with, for example, Grignard reagents, alkyl nitronates, higher order cuprates and trimethylsilyl enol ethers [ 12, 29, 30, 381. In the cases of the bromides 1-4 and 17b-l9b,varying degrees of asymmetric induction have been observed. With the peptide derivatives 17b-l9b,the valine residue serves as a chiral auxiliary and has the advantages that it is cheap, readily available in either enantiomeric form, and easily recovered, after reaction, to be recycled. The cyclic dipeptide 19b is particularly useful because of the closely controlled spatial relationship of the chiral centers [30].
6.1.3 Functional Group Transformations and Applications in Synthesis
5 15
I
I
COP-t-Bu
Cop-t-Bu
Scheme 4
Side-chain brominated amino acid derivatives have been exploited in stereocontrolled syntheses of dehydro, cyclopropyl and hydroxy amino acids [ 39-41]. The biochemical hydroxylation of amino acids often involves radical oxidation, where the regioselectivity is analogous to that of bromination. Consequently bromination followed by hydrolysis provides a convenient method for synthesis of the natural products [41]. Alternatively, dimethyldioxirane has been used for the direct synthesis of y-hydroxyleucine derivatives through oxygen atom insertion into the yC-H bond [42]. Many of the synthetic applications of halogenated amino acid derivatives involve ionic reactions, but radical processes have also been developed. Halogenated glycine derivatives have been treated with tin deuterides, allylstannanes and hexabutylditin to give the corresponding deuterated, allylated and cross-linked glycine derivatives [ 11, 18, 29, 30, 43-47]. The stereoselectivity of such reactions of chiral halides is often low, but the bromides 4 and 19b afford the deuteride 42 in 90% diastereomeric excess [44] and the allylated product 43 as the sole diastereomer [30]. Zinc chloride has been used to increase the diastereoselectivity of allyl group transfer [45]. Reactions of 1- and 3-alkyl-substituted allylstannanes with bromoglycine derivatives are not complicated by competing eliminations, which often limit the utility of other allyl transfer processes [46]. 2-Methyl p-(tributylstanny1)acrylate has also been used to alkylate bromoglycine derivatives through a radical additionelimination reaction sequence [47], while tin hydrides have been used to promote inter- and intramolecular addition reactions of halogenated glycine derivatives with alkenes [48], as illustrated in Scheme 4. Such reactions are not restricted to halogenated glycine derivatives and a-alkoxy- and benzoyloxy-glycine derivatives, and analogous sulfides and xanthates have also been used as sources of glycyl radicals for these purposes [49]. Glycyl radicals have also been produced through treatment of pyridyl glycyl sulfides with samarium iodide [50].
C(Me2)Ph
dA
~*8~OCO-CH-NHC02-f-B~
M i
D
42
CH,CH=CH, 43
Where a-functionalized amino acid derivatives are unstable or inaccessible and the corresponding a-centered radicals are therefore difficult to obtain directly, remote
5 16
6.1 Modifications of Amino Acids and Peptides via Radicals
Scheme 5
p\ D G Bu3SnH (cat.)
0
44
0
'YHz Copt-Bu
Copt-Bu
+Bu3Sny P
S
O 44
n
B
'YHz COzt-BU
u
,
-
q -q SnBu3
0
44
copt-Bu
0
COpf-Bu SnBu3
Scheme 7
functional groups may be used instead to access the desired radicals through hydrogen atom transfer [51]. This is illustrated in Schemes 5 and 6 with alanine derivatives where, for example, the corresponding a-brominated amino acid derivatives would be prone to elimination and therefore unsuitable for use. Synthesis of bicyclic Blactams has also been reported (Scheme 7) [52]. Side-chain halogenated amino acid derivatives are reduced, deuterated, allylated and alkylated with stannanes and related reagents in free-radical processes [53]. Other side-chain functional groups may also be manipulated to produce amino acid radicals [8, 54-58], and, in particular, Barton decarboxylation of aspartate and glutamate derivatives has been applied in this manner (Scheme 8) [55]. Related procedures have been developed to generate amino acid radicals by dehydroxylation of hydroxy amino acid derivatives [56]. Hydroxy amino acid derivatives may also be converted to nitrate esters, from which the corresponding alkoxy radi-
6.1.3 Functional Group Transformations and Applications in Synthesis
CO,H (7Hz)n -CONH-CH-CO-
5 17
HO-N i-BuOCOCI
(7Hz)n -CONH-CH-CO-
jnY / 1
(7Hdn -CONH-CH-CO-
Bu3SnH /RZC=CRZ
Me I (7H2)n -CONH-CH-CO-
t-BUSH
FH2'
($Wdn
c _ _
-CONH-CH-COCCI,X
CHZ
\;oco-c-cx
S-f-BU HZ
n=Oorl
-CONH-~H-CO-
HzC, FH2
X = CI, Br, I
(?HA" -CONH-CH-CO-
Scheme 8
cals are generated by photolysis or treatment with stannanes [57]. Generally the alkoxy radicals give carbon-centered amino acid radicals by p-scission, but, in solvents such as water, 1,2-hydrogen transfer is a competing process [ 5 ] . Radicals analogous to those formed through decarboxylation of aspartate and glutamate derivatives may also be produced from cysteine and methionine residues, as shown in Scheme 9 [8]. Homolytic substitution of the disulfide moiety of cystine derivatives is also common [8, 581, but a detailed discussion of these processes and the oxidative coupling reactions that occur with tyrosine and hydroxyphenylglycine derivatives [59] is beyond the scope of this review. As described above for a-carbon-centered radicals, where it is not feasible to access a side-chain amino acid radical by direct manipulation of a functional group, radical translocation may be employed instead, as illustrated in Scheme 10 [60]. Regiocontrol may be achieved by exploiting product radical stability and the preferred geometry of intramolecular hydrogen atom transfer. Radicals are also produced by manipulation of the a-carboxy and amino groups. The former usually results in decarboxylation, with the products no longer being uamino acids [611. Aminyl radicals have been generated from sulfenamide precursors and exploited in cyclization reactions, as illustrated in Scheme 11 [62]. Radical additions to imines [63], oximes [64], isothiocyanates [65] and isocyanides [66] of M -
5 18
6.1 Modifications of Amino Acids and Peptides via Radicals
SH
FH2 (7H2)n -CONH-CH-CO-
?Me Me1 n=O
7H2 ('72)n -CONH-CH-CO-
SOMe Na104
FH2
___)
(7Wn
-CONH-CH-CO-
(t-BuO)p, hv
Me I (7H2)n -CONH-CH-CO-
c -
cc/
n=Oorl yH2CI (7Wn -CONH-CH-CO-
1
FH2' (7H2)" -CONH-CH-CO-
iPhH
FHpPh (7Wn
-CONH-CH-CO-
Scheme 9
Scheme 10
amino acids have also been reported, and the product radicals have been exploited in cyclization and rearrangement reactions, as illustrated in Scheme 12 [63]. Many other radical addition reactions of dehydro amino acid derivatives have been reported [60, 67-69]. While they are far too numerous to describe individually, it is generally true that they conform to the well-established guidelines for such processes [70].The selected examples [68, 691 shown in Schemes 13 and 14 illustrate some of the scope of the methodology.
6.1.3 Functional Group Transformations and Applications in Synthesis
5 19
Bu3SnH "SPh
A
HiC02Me
&,C02Me
Scheme 11
Bu3Sn'
C02Et I PhCH=N-C-Me I CH2Br
C02Et I PhCH=N-C-Me I
-
C02Et
Ph6H-N
CH;
,C02Et PhCH=N-CH2-Cy Me
kMe
I
Bu3SnH
,C02Et PhCH=N-CH,-C; Me
Scheme 12
-
SH2 CF3CONH"'C02Me
RMgX NaBH,
CH2R I CF3CONH'CH'C02Me
Scheme 13
f-Buln,.(
x-fo ,c I"
BZ
RX
x-fo
t-Buln*.( N.CH
\
*cH2
Bu3SnH-
B:
CH2R
X = 0 or NMe
Scheme 14
In summary, the processes outlined above illustrate ways in which amino acids and their derivatives have been modified using free radicals. Our understanding of these reactions now allows the methodology to be applied in new systems with predictable results, and more numerous and sophisticated applications can therefore be expected.
520
6.1 ModiJcations o j Amino Acids and Peptides via Radicals
References [ I ] See, for example: R. M. Williams, Synthesis of Optically Active cc-Amino Acids (Eds.: J. E. Baldwin, P. E. Magnus), Organic Chemistry Series, Vol. 7, Pergamon Press, Oxford, 1989; R. 0. Duthaler, Tetrahedron 1994, 50, 1539; R. M. Williams, Adv. Asymmetric Synth. 1995, I , 45. [2] For reviews see: C. J. Easton, Chem. Rev. 1997, 97, 53; C. J. Easton, in Advances in Detailed Reaction Mechanisms (Ed.: J. M. Coxon), Vol. I , JAI Press, London, 1991, Chap. 3. [3] For a review see: P. Renaud, L. Giraud, Synthesis 1996, 913. [4] For a review see: W. M. Garrison, Chem. Rev. 1987, 87, 381. [ 5 ] For a review see: M. Davies, R. Dean, Radical-Mediated Protein Oxidation: From Chemistry to Medicine, Oxford University Press, Oxford, 1998. [6] For a review see: D. Seebach, A. K. Beck, A. Studer, in Modern Synthetic Methods (Eds.: B. Ernst, C. Leumann), Vol. 7, VCH, Weinheim, 1995, Chap. 1. [7] See, for example: H. G. Viehe, R. Merenyi, L. Stella, Z. Janousek, Angew. Chem., Znt. Ed. Engl. 1979, 18, 917; R. Schulze, H.-D. Beckhaus, C. Ruchardt, Chem. Ber. 1993, 126, 1031; F. G. Bordwell, X.-M. Zhang, M. S. Alnajjar, J. Am. Chem. Soc. 1992, 114, 7623. [8] B. Clark, A. K. Croft, C. J. Easton, N. L. Fryer, K. Kociuba, L. Radom, C. M. Ward, unpublished observations. [9] C. J. Easton, C. A. Hutton, G. Rositano, E. W. Tan, J. Org. Chem. 1991, 56, 5614. [lo] J. Sperling, D. Elad, J. Am. Chem. Soc. 1971, 93, 3839; M. Schwarzberg, J. Sperling, D. Elad, J. Am. Chem. Soc. 1973, 95, 6418. [l I ] V. A. Burgess, C. J. Easton, M. P. Hay, P. J. Steel, Aust. J. Chem. 1988, 41, 701. [12] Z. Lidert, S. Gronowitz, Synthesis 1980, 322; R. Kober, K. Papadopoulos, W. Miltz, D. Enders, W. Steglich, H. Reuter, H. Puff, Tetrahedron 1985, 41, 1693. [I31 C. J. Easton, K. Kociuba, S. C. Peters, J. Chem. Soc., Chem. Commun. 1991, 1475. [I41 P. Wheelan, W. M. Kirsch, T. H. Koch, J. Ory. Chem. 1989, 54, 4360; S. D. Copley, E. Frank, W. M. Kirsch, T. H. Koch, Anal. Biochem. 1992, 201, 152. [I51 R. M. Williams, R. W. Armstrong, L. K. Maruyama, J.-S. Dung, 0. P. Anderson, J. Am. Chem. Soc. 1985, 107, 3246; T. W. Badran, C. J. Easton, Aust. J. Chem. 1990, 43, 1455. 1161 P. J. Sinclair, D. Zhai, J. Reibenspies, R. M. Williams, J. Am. Chem. Soc. 1986, 108. 1103. [ 171 J. Zimmermann, D. Seebach, Helv. Chim. Acta 1987, 70, 1104. 1181 P. Ermert, J. Meyer, C. Stucki, J. Schneebeli, J.-P. Obrecht, Tetrahedron Lett. 1988. 29, 1265; D. P. G. Hamon, R. A. Massy-Westropp, P. Razzino, Tetrahedron 1993, 49, 6419. [ 191 A. K. McFarlane, G. Thomas. A. Whiting, Tetrahedron Lett. 1993, 34, 2379. [20] C . J. Easton, J. B. Kelly, C. M. Ward, J. Chem. Res. ( S ) 1997, 470. [21] C. J. Easton, E. W. Tan, M. P. Hay, J. Clzem. Soc., Chem. Commun. 1989, 385. [22] T. W. Badran, C. L. L. Chai, C. J. Easton, J. B. Harper, D. M. Page, Aust. J. Chem. 1995, 48, 1379. [23] N. Obata, K. Niimura, J. Chem. Soc., Cheni. Commun. 1977, 238. [24] J. Hausler, R. Jahn, U. Schmidt, Chem. Ber. 1978, 111, 361. [25] C. J. Easton, S. K. Eichinger, M. J. Pitt, J. Chem. Soc., Chem. Commun. 1992, 1295; C. J. Easton, S. K. Eichinger, M. J. Pitt, Tetrahedron 1997, 53, 5609. [26] J. Yoshimura, H. Nakamura, K. Matsunari, Bull. Chem. Soc. Jpn. 1975, 48, 605; A. L. J. Beckwith, S. G. Pyne, B. Dikic, C. L. L. Chai, P. A . Gordon, B. W. Skelton, M. J. Tozer, A. H. White, Aust. J. Chem. 1993, 46, 1425. [27] C. J. Easton, M. P. Hay, J. Chem. Soc., Chem. Commun. 1986, 55; V. A. Burgess, C. J. Easton, M. P. Hay, J. Am. Chem. Soc. 1989, 111, 1047. [28] A. Rauk, D. A. Armstrong, J. Am. Chem. Soc. 2000, 122, 4185. [29] C. J. Easton, I. M. Scharfbillig, E. W. Tan, Tetrahedron Lett. 1988, 29, 1565. [30] T. W. Badran, C. J. Easton, E. Horn, K . Kociuba, B. L. May, D. M. Schliebs, E. R. T. Tiekink, Tetrahedron: Asymmetry 1993, 4, 197. 1311 A. Papadopoulos, J. Heyer, K.-D. Ginzel, E. Steckhan, Chem. Ber. 1989, 122, 2159; A. Papadopoulos, B. Lewall, E. Steckhan, K.-D. Ginzel, F. Knoch, M. Nieger, Tetrahedron 1991, 47, 563.
References
521
[32] J. Kollonitsch, A. Rosegay, G. Doldouras, J. Am. Chem. Soc. 1964, 86, 1857; Y. Fujita, 1965,87, 2030; J. Kollonitsch, A. N . Scott, G. A. J. Kollonitsch, €3. Witkop, J. Am. Chem. SOC. Doldouras, J. Am. Chem. SOC.1966, 88, 3624. [33] C. J. Easton, M. P. Hay, S. G. Love, J. Chem. Soc., Perkin Trans. 1, 1988,265; N . J. Bowman, M. P. Hay, S. G. Love, C. J. Easton, J. Chem. Soc., Perkin Trans. I 1988, 259. [34] C. J. Easton, M. C. Merrett, J. Am. Chem. SOC. 1996, 118, 3035. [35] T. Shono, Y. Matsumura, K. Inoue, J. Org. Chem. 1983, 48, 1388; T. Shono, Y. Matsumura, K. Tsubata, K. Uchida, J. Org. Chem. 1986, 51, 2590. [36] C. J. Easton, M. C. Merrett, Tetrahedron 1997, 53, 1151. [37] A. G. Griesbeck, H. Mauder, Angew. Chem., Int. Ed. Engl. 1992, 31, 73. [38] See, for example: T. Bretschneider, W. Miltz, P. Miinster, W. Steglich, Tetrahedron 1988, 44, 5403; M. E. Lloris, M. Moreno-Mafias, Tetrahedron Lett. 1993, 34, 7119; C. J. Easton, P. D. Roselt, E. R. T. Tiekink, Tetrahedron 1995, 51, 7809; G. Trojandt, K. Polborn, W. Steglich, M. Schmidt, H. Noth, Tetrahedron Lett. 1995, 36, 857. [39] C. J. Easton, C. A. Hutton, P. D. Roselt, E. R. T. Tiekink, Aust. J. Chem. 1991, 44, 687. [40] C. J. Easton, E. W. Tan, C. M. Ward, Aust. J. Chem. 1992, 45, 395; C. J. Easton, N. L. Fryer, A. J. Ivory, E. R. T. Tiekink, J. Chem. Soc., Perkin Trans. 1 1997, 3725. [41] C. J. Easton, C. A. Hutton, E. W. Tan, E. R. T. Tiekink, Tetrahedron Lett. 1990, 31, 7059; C. J. Easton, C. A. Hutton, P. D. Roselt, E. R. T. Tiekink, Tetrahedron 1994: 50, 7327; A. V. Rama Rao, T. K. Chakraborty, K. L. Reddy, A. S. Rao, Tetrahedron Lett. 1994, 35, 5043; C. J. Easton, C. A. Hutton, M. C. Merrett, E. R. T. Tiekink, Tetrahedron 1996, 52, 7025. [42] M. Mezzetti, E. Mincione, R. Saladino, J. Chem. Soc., Chem. Commun. 1997, 1063; R. Saladino, M. Mezzetti, E. Mincione, I. Torrini, M. P. Paradisi, G. Mastropietro, J. Org. Chem. 1999, 64, 8468. [43] R. M. Williams, D. Zhai, P. J. Sinclair, J. Org. Chem. 1986, 51, 5021; S. E. Ramer, H. Cheng, M. M. Palcic, J. C. Vederas, J. Am. Chem. SOC. 1988, 110, 8526. [44] D. P. G. Hamon, R. A. Massy-Westropp, P. Razzino, Tetrahedron 1995, 51, 4183. [45] Y. Yamamoto, S. Onuki, M. Yumoto, N . Asao, J. Am. Chem. SOC. 1994, 116,421. [46] C. J. Easton, I. M. Scharfbillig, J. Org. Chem. 1990, 55, 384. [47] J. E. Baldwin, R. M. Adlington, C. Lowe, I. A. O’Neil, G. L. Sanders, C. J. Schofield, J. B. Sweeney, J. Chem. Soc., Chem. Commun. 1988, 1030. [48] See, for example: C. L. L. Chai, D. M. Page, Tetrahedron Lett. 1993, 34, 4373; J. H. Udding, C. J. M. Tuijp, H. Hiemstra, W. N. Speckamp, J. Chem. Soc., Perkin Trans 2 1992, 857; J. H. Udding, C. J. M. Tuijp, H. Hiemstra, W. N. Speckamp, Tetrahedron 1994, 50, 1907; M. D. Bachi, C. Hoornaert, Tetrahedron Lett. 1981, 22, 2689; M. D. Bachi, C. Hoornaert, Tetrahedron Lett. 1982,23, 2505. [49] See, for example: P. M. Esch, H. Hiemstra, R. F. de Boer, W. N . Speckamp, Tetrahedron 1992, 48, 4659; C. J. Easton, S. C. Peters, Tetrahedron Lett. 1992, 33, 5581; G. Apitz, M. Jager, S. Jaroch, M. Kratzel, L. Schaffeler, W. Steglich, Tetrahedron 1993, 49, 8223; J. H. Udding, H. Hiemstra, W. N. Speckamp, J. Org. Chem. 1994, 59, 3721; C. J. Easton, S. C. Peters, Phos. Sulf: Sil. 1999, 150-151, 157. [SO] M. Ricci, L. Madariaga, T. Skrydstrup, Angew. Chem., Int. Ed. Engl. 2000, 39, 242. [51] J. E. Baldwin, D. Brown, P. H. Scudder, M. E. Wood, Tetrahedron Lett. 1995, 36, 2105; J. Rancourt, V. Gorys, E. Jolicoeur, Tetrahedron Left. 1998, 39, 5339; L. Giraud, P. Renaud, J. Org. Chem. 1998, 63, 91 62. [52] E. Bosch, M. D. Bachi, J. Org. Chem. 1993, 58, 5581. [53] See, for example: C. J. Easton, N . G. Findlay, J. Labelled Compounds and Radiopharmaceutica1.s 1985, 22, 667; D. H . R. Barton, Y. Herve, P. Potier, J. Thierry, Tetrahedron 1987, 43, 4297; M. Bruncko, D. Crich, R. Samy, J. Org. Chem. 1994, 59, 5543; J. E. Baldwin, R. M. Adlington, D. G. Marquess, A. R. Pitt, M. J. Porter, A. T. Russell, Tetrahedron 1996, 52, 2537; A. Avenoza, C. Cativiela, M. A. Fernandez-Recio, J. M. Peregrina, Tetrahedron: Asymmetry 1996, 7, 721. [54] V. A. Burgess, C. J. Easton, Aust. J. Chem. 1988, 41, 1063; M. J. Crossley, C. W. Tansey, Aust. J. Chem. 1992, 45: 479; J. H. Udding, J. P. M. Giesselink, H. Hiemstra, W. N. SpeckChim. Belg. 1994, 103, 329. amp, Bull. SOC.
522
6.1 Mod$cations of Amino Acids and Peptides via Radicals
15.51 See, for example: D. H. R. Barton, Y. He&, 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; J. E. Baldwin, M. G. Moloney, M, North, Tetrahedron 1989, 45, 6309; D. H. R. Barton, S. D. Gero, B. Quiclet-Sire, M. Samadi, J. Chem. Soc., Perkin Trans. I 1991, 981; D. H. R. Barton, S. D. GCro, B. Quiclet-Sire, M. Samadi, Tetrahedron 1992, 48, 1627; D. H. R. Barton, D. Crich, Y. Herve, P. Potier, J. Thierry, Tetrahedron 1985, 41, 4347; D. H. R. Barton, D. Bridon, Y. Herve, P. Potier, J. Thierry, S. Z. Zdrd, Tetrahedron 1986, 42, 4983. 1561 R. M. Valerio, P. F. Alewood, R. B. Johns, Synthesis 1988, 786. [57] C. J. Easton, A. J. Ivory, C. A. Smith, J. Chem. Soc., Perkin Trans. 2 1997, 503. [581 C. J. Easton, S. C. Peters, Aust. J. Chem. 1994, 47, 859. For reviews see: A. V. Rama Rao, M. K. Gurjar, K. L. Reddy, A. S. Rao, Chem. Rev. 1995, 95, 2135; K. C. Nicolau, C. N. C. Boddy, S. Brase, N. Winssinger, Angew. Chem., Znt. Ed. Engl. 1999, 38, 2097. J. R. Axon, A. L. J. Beckwith, J. Chem. Soc., Chem. Commun. 1995, 549. See, for example: A. Stojanovic, P. Renaud, Synlett 1997, 181; A. Stojanovic, P. Renaud, K. Schenk, Helv. Chirn. Acra 1998, 81, 268. W. R. Bowman, M. J. Broadhurst, D. R. Coghlan, K. A. Lewis, Tetrahedron Lett. 1997, 35, 6301. D. D. Tanner, P. M. Rahimi, J. Org. Chem. 1979, 44, 1674; P. Dowd, S.-C. Choi, J. Am. Chem. Soc. 1987, 109, 3493; S.-C. Choi, P. Dowd, J. Am. Chem. Soc. 1989, 111, 2313; P. Dowd, S.-C. Choi, Tetrahedron 1989,45, 77; 0.Han, P. A. Frey, J. Am. Chem. Soc. 1990,112, 8982. H. Miyabe, C. Ushiro, M. Ueda, K. Yamakawa, T. Naito, J. Org. Chem. 2000, 65, 176. M. D. Bachi, D. Denenmark, J. Org. Chem. 1990, 55, 3442. M. D. Bachi, A. Balanov, N. Bar-Ner, J. Org. Chem. 1994,59,7752;M. D. Bachi, A. Melman, J. Org. Chem. 1995, 60, 6242. See, for example: C. L. L. Chai, A. R. King, Tetrahedron Lett. 1995, 36, 4295; S. E. Gibson, N. Guillo, M. J. Tozer, J. Chem. Soc.,. Chem. Commun. 1997, 637; S. R. Baker, A. F. Parsons, M. Wilson, Tetrahedron Lett. 1998, 39, 2815. D. Crich, J. W. Davies, G. Negron, L. Quintero, J. Chem. Res. (S) 1988, 140. A. L. J. Beckwith, C. L. L. Chai, J. Chem. Soc., Chem. Commun. 1990, 1087. B. Gicse, Angew. Chem., Int. Ed. Engl. 1983, 22, 753.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
6.2 Synthesis and Modifications of Amino Acids and Peptides via Diradicals Pablo Wessig
6.2.1 Introduction Peptides and proteins represent, apart from the nucleic acids, the most important class of compounds governing the basic biochemical principles in nature. During the last hundred years the synthesis of natural and unnatural amino acids as well as peptide synthesis has experienced a breathtaking development. The interest in this process has grown as the knowledge about the relationship between the structure of peptides and proteins and their physiological effects has increased. Nowadays the chemist may refer to a variety of synthetic methods to prepare enantiomerically enriched or pure a-amino acids (for an overview see [ 11). Nevertheless, the need for amino acids with a very special substitution pattern often reveals the limits of the established methods. Consequently, the development of new synthetic routes to CIamino acids (and, naturally, also to p-amino acids, which have enjoyed increased attention over the last years) is playing an important role in the current chemical research. This chapter reviews the application of a special part of radical chemistry in the synthesis and modification of amino acids and peptides, namely reactions that proceed via diradicals.
6.2.2 Generation and Properties of Diradicals At the beginning of this section the crucial difference between radicals and diradicals needs to be discussed. Whereas the former has only one spin state, the latter may exist in two distinct spin states, the singlet and the triplet state. The following discussion is limited to diradicals that are formally derived from a-bond homolysis and are not concerned with broken (twisted) 7c-bonds. Singlet diradicals may be rationalized as molecules with a more or less stretched single bond. Therefore, it is not surprising that they exhibit very short lifetimes. Recently, the lifetimes of singlet diradicals formed during the Norrish-Yang reaction of aliphatic ketones (1,4-diradicals) were determined. They amount to only
524
6.2 Synthesis and Modijications of Amino Acids and Peptides via Diradicals
400-700 femtoseconds [2]. It is expected that the lifetimes increase by some orders of magnitude with increasing distance between the radical centers, but it is also very likely that the lifetimes remain below 1 ns for 1,n-diradicals ( n 5 6 ) . During the lifetime of a singlet diradical, rotations around bonds are scarcely possible. Consequently, one conspicuous feature of singlet diradicals is the conservation of the reactant’s stereochemical information. Triplet diradicals, however, because of their spin state, cannot cyclize directly but have to undergo an Intersystem Crossing (ISC) first. The resulting lifetimes are more than six orders of magnitude longer than those of singlet diradicals. Typical values are 30-100 ns, but extreme cases with 1 ns or 1000 ns are also known [3].Thus, extensive conformational changes are possible, and the stereochemical information of reactants (preferred conformations, configuration at the future radical centers) are lost in most cases. It follows that the discernible feature of triplet diradicals is the diustereoselective ring closure as a result of conformational equilibration at this stage. A detailed discussion of the factors influencing the crossing from triplet to singlet diradicals would go beyond the scope of this chapter [4]. Nonetheless, it should be noted that different ISC rates of different triplet diradical conformers may be responsible for product stereoselectivity in some cases [5]. The different chemical behavior of excited molecules in the singlet and the triplet state led to the concept of ‘spinisomers’, a phenomenon introduced to the chemical literature by Turro [6] and Quinkert. [7]. The preparative routes to diradicals differ substantially from those to monoradicals. Naturally, the generation of singlet diradicals from molecules with two reaction centers using typical methods of monoradical chemistry may be discussed. But this is not meant to be a subject of this chapter. All the methods described below have in common that a closed-shell molecule is converted into an open-shell molecule (diradical). Such a process requires at least 60-90 kcal/mol, and it is difficult to raise this energy by thermal activation. Thus, it is no wonder that photochemical methods play a large part. Though the emission wavelength of the commonly used UV light sources (above all mercury arc lamps, but also lasers) correspond with energies that exceed the typical values of C-C and C-H bond energies, it is in most cases impossible to break these bonds directly by a u-g* excitation [it is only thanks to this circumstance that life is possible on our planet, despite the fact that the shortest wavelength of sunlight (300 nm) corresponds to an energy of 95 kcal/mol]. In contrast to 7c-7c* excitation, n-n* excitation of functional groups X=Y bearing one or two hetero atoms is a very valuable entry for generating diradicals. This is because of the distinct spin separation in the n-n* excited state as a consequence of the perpendicular arrangement of the corresponding molecular orbitals. The resulting singly occupied and highly localized n-orbital may result in an abstraction of a hydrogen atom from another position within the molecule or a cleavage of an adjacent single bond and thus lead to the formation of diradicals. In this chapter we will deal with two classes of substances, which are of great importance as diradical precursors and are used in the preparation of amino acids: the carbonyl compounds (A) and the azo compounds (B). Scheme 1 depicts the corresponding reaction course. The former process is called Norrish-Yang reaction and has been reviewed in some excellent articles [8]. It should be noted that not all carbonyl compounds
6.2.2 Generation and Properties of Diradicals
U.
525
>C-BH
A
Scheme 1. Carbonyl and Azo compounds as diradical precursors
undergo this reaction. In the case of carboxylic acids, esters, amides, carbonates, urethanes and ureas, the conjugation between the neighboring heteroatoms and the carbonyl group causes crucial changes in the molecular orbital scheme, especially an increase of the n-z* gap. Therefore these functional groups have large excitation energies compared with the n-z* band of aldehydes and ketones and consequently they are of less importance in photochemical transformations. On the other hand, there are only few examples in which aldehydes have been used as reactants in the Norrish-Yang reaction. Most probably, the very low C-H bond energy in the formyl group is the reason. Looking at ketones, the question of spin state is fundamental, as noted above. Aliphatic ketones and a-keto esters mainly react from the singlet state even though they undergo ISC to the triplet state to some extent. Bearing in mind the special peculiarities of the two spin states, it is worth mentioning that a distinct state may be forced using triplet sensitizers or triplet quenchers [9]. Aromatic ketones are characterized by strong spin-orbit coupling because the S1 and the T2 state are nearly degenerate. Their ISC rates are therefore very fast (-10" s-'), and they react entirely from the triplet state. The application of the Norrish-Yang reaction of ketones to the synthesis of amino acids and peptides will be described in Section 6.2.3.1. Interestingly, imides possess a photochemical behavior that is very similar to that of ketones. Especially, phthalimides behave like phenyl ketones with respect to some of their photophysical properties. Despite many similarities there are at least three important differences. First, phthalimides are more prone to photoelectron transfer (PET) processes than ketones. This property was very successfully applied in the synthesis of a variety of amino acid derivatives (see Section 6.2.3.2). Second, the cyclization of imides often affords 0,N-acetals as primary products, and this obviously has some consequences for the stability and the follow-up reactions of these products. Third, in contrast to aryl ketones, phthalimides are not quantitatively converted into the triplet state, and thus they may react both from the singlet and the triplet excited state. As shown in Scheme 1, cyclic azoalkanes are also suitable as diradical precursors. The driving force for the cleavage is an overlap of the singly occupied n orbital in
526
6.2 Synthesis and ModiJications of’ Amino Acids and Peptides via Diradicals
the excited state with the a*-orbital of the breaking bond. Looking at the reaction pathway of the cleavage, a surface touching occurs, i.e. the energies of the SI and So states become very similar with increasing length of the breaking bond. Therefore, it is very likely that the fragments recombine in the solvent cage (‘internal return’), reforming the starting material. This process is the reason for the almost always low product quantum yields of nitrogen extrusion from cyclic azoalkanes. Nevertheless, it is an elegant way to prepare small rings and was applied in the synthesis of aminocyclopropane carboxylic acids (see Section 6.2.3.3).
6.2.3 Synthetic Applications 6.2.3.1 Ketones as Diradical Precursors The Norrish-Yang reaction of ketones was applied to the synthesis of amino acids for the first time by Henning and coworkers [lo]. They started from glycine derivatives 1 bearing a photochemically active P-benzoylethyl side chain. Upon irra~ nm), the excited benzoyl group abstracts a hydrogen atom from diation ( 1 1 2~ 300 the glycine methylene group giving the triplet biradical 2. The latter cyclizes after ISC to 3-hydroxyprolines 3 (Scheme 2 ) . Remarkably, the ring closure proceeds with very high diastereoselectivity. Only the 2,3-cis products were obtained in aprotic solvents, which indicated the importance of an intramolecular hydrogen bond. About ten years later this interesting method was developed into an enantioselective synthesis using Cz-symmetric pyrrolidine derivatives as chiral auxiliaries. Thus, irradiation of the amide 4 gave exclusively the proline amide 5 (Scheme 2 ) [ 111. High diastereoselectivity may be achieved not only by asymmetric induction by a chiral amide auxiliary but also by introduction of a chiral center into the side-chain. Starting with the cheap aspartic acid 6, a synthetic route to enantiomerically pure 5carboxy prolines 8 was developed (Scheme 2 ) [ 121. The concept of intramolecular alkylation of N-substituted amino acid derivatives via 1,5-diradicals also turned out to be an excellent system for studying the different stereochemical course of ‘spinisomers’ as discussed in Section 6.2.2. Thus, the aketoester 9, which contains an alanine moiety, was prepared, In contrast to aryl ketones, a-ketoesters are not completely converted into the triplet state after photochemical excitation. Upon addition of either a triplet quencher (naphthalene) or a triplet sensitizer (benzophenone), each of the two spin states may be forced (Scheme 3 , Table 1). The chiral center at the &position with respect to the keto carbonyl group raises the question whether a memory effect of chirality may be observed during the cyclization. The results summarized in Table 1 amply demonstrate the specific properties of ‘spinisomeric’ biradicals. In the presence of naphthalene, which probably acts not only as a triplet quencher but also as a singlet sensitizer, the chiral information of the reactant 9 is almost entirely conserved in the helical diradical 10 because of its very short lifetime. In contrast, the addition of benzophenone results in almost complete racemization, and also the cisltrans selectivity is
l3 R
O
R
1
6.2.3 Synthetic Applications
60;.
X R ==AOR', c y l NR'R"
ISC
__t
R
O
o
2
4
527
3
5 (70%, dr > 20:l) Ph hv
ROOC''"
-
I
C'COOBn Ts 7
6
ROOC'"'
do:ooBn r Ts
8 R = Me: 65%, ee > 98% R = mu:57%. ee > 98%
Scheme 2. Photochemical preparation of prolines
r 0 MeOOCIJ/.\?
COOMe
Me
Ts
0
0
Ts
10
9
MeOOc OH P
i
Ho COOMe +
@e
@e
COOEt
COOEt I
I
Ts
Ts
lla
llb
Scheme 3. Memory effect of chirality on photocyclization of a-ketoesters
lost [ 131. The latter result suggests that the preferred formation of the cis isomer in the singlet case is a reflection of reactant conformation rather than an intramolecular hydrogen bond similar to those discussed for the diradical 2. Prolines play an important role in that they often can be found in /3-turn sub-
528
6.2 Synthesis and ModiJications of Amino Acids and Peptides via Diradicals
Table 1. Selectivities of the photocyclization of alanine derivative 9 [ 131 Conditions
er (lla )
er ( l l b )
(11 a):(1 1b)
Overall yield ['rh]
hvlnaphthalene (1 M) hvlbenzophenone (1 M)/Ar
24: 1 1.4: 1
16:l 1.4: 1
5.7:l 0.8: 1
41 10
structures of peptides and proteins. A similar influence on peptide conformation can be achieved using azetidine-2-carboxylic acids, and therefore it is not surprising that a photochemical route to these amino acids was also developed. It seems reasonable to apply the above-described synthesis of prolines by shortening the side-chain bound at the N-atom of the glycine moiety by one methylene group. Surprisingly, this approach was unsuccessful [ 141. The apparently insignificant change in the molecular structure gave rise to a considerable change in the conformation of the intermediate diradical with the result that only a back-transfer of the hydrogen atom or Norrish-Type I1 cleavage was observed. The synthetic aim was achieved via an alternative route starting with the commercially available aminodiol 12. In several steps the three functional groups in 12 were selectively converted, yielding the ketone 13. Upon irradiation, the excited benzoyl group abstracted a hydrogen atom from the N-methyl group and the 1,4-diradical 14 was formed. The latter cyclized highly stereoselectively and with good yields to the azetidine 15. Notably, the Norrish-Type I1 cleavage, which almost always competes with cyclization, was not observed. Protection of the tertiary hydroxyl group, deprotection and oxidation of the primary hydroxyl group and cleavage of the Z-group finally afforded the (2R)-azetidine-2-carboxylic acid 16. A similar route starting with D-serine provided the enantiomer of 16 (Scheme 4) [ 141. The successful synthesis of amino acids by intramolecular alkylation of Nsubstituted natural amino acids via diradicals brought up the question whether this concept may be applied to peptides. The ability to influence peptide conformation
1 16
ISC
15 (71%, dr> 20:l)
Scheme 4. Preparation of azetidine-2-carboxylic acids
6.2.3 Synthetic Applicaations
529
by irradiation of a peptide bearing a photolabile N-substituent seems fascinating. Scheme 5 shows the most important results in this area of research. Dipeptides 17 are analogs of 1, 4 and 9 in which the tosyl group is replaced by a Z-Gly moiety. Surprisingly, no 1,6-hydrogen transfer from the C-terminal amino acid of the peptide took place, but the d-lactams 18 and 19, as a result of a 1,7-hydrogen transfer, were formed regioselectively. This selectivity was explained by the higher stability of 1,6-diradicals compared with that of the 1,5-diradicals and proven by ab initio calculations. Furthermore, only the cis-configured products with respect to the newly formed C-C bond were observed, which emphasizes once more the importance of hydrogen bonding during the cyclization. The asymmetric induction by the chiral center of the C-terminal amino acid is moderate, however. Shortening of the N-sidechain led to a dipeptide 20 with a slight increase of the asymmetric induction together with a decrease of the total yield but without changes in the regioselectivity and the simple diastereoselectivity. Besides the three aspects of regio-, diastereoselectivity and asymmetric induction, a fourth one is added if both amino acids are substituted in the a-position. Irradiation of the N-phenacyl Ala-Val-derivatives 23 and 26 resulted in hydrogen atom abstraction from the chiral center in the N terminal amino acid portion of the dipeptide. Bearing in mind the behavior of the triplet sensitized compound 9, one might expect a near complete racemization of Ala part. Consequently, 23 and 26 would be expected to provide the same product ratio. Surprisingly, the opposite is the case. A distinct memory effect is observed and the outcome depends on which enantiomer of Ala is incorporated into the peptide. Thus, the L-Ala-L-Val derivative 23 yields the opposite ratio of 2425 as compared to the D-Ala-L-Val-derivative 26. Obviously, a hindered rotation in the intermediate diradical is responsible for the observed memory effect (Scheme 5) [ 151. In addition to the incorporation of unnatural amino acids into peptides, the utilization of peptide mimetics is a well-established method to influence the conformation of peptides. Since the pioneering work of Nagai and Sat0 [16], highly substituted bicyclic lactams have gained significance and a number of alternative synthetic routes to these compounds have been developed. Very recently, a straightforward photochemical synthesis via a diradical intermediate was published. Starting with L-P-benzoyl alanine 27, which is easily accessible from aspartic acid, the dipeptides 28 were prepared by protection with several carbamate protecting groups and subsequent coupling with L-proline esters. Upon irradiation, the dipeptides 28 underwent a fully stereoselective cyclization to the bicyclic turned dipeptides (B TD ) 29 in good yields (Scheme 6) [17]. The protecting groups in the bicyclic lactams 29 were orthogonal with respect to their deprotection, and thus they meet the requirements for their use in peptide synthesis. Another group followed a similar approach and investigated the photochemical behavior of some dipeptides consisting of the L-P-benzoyl alanine and N-substituted glycines. The irradiation of the iminodiacetic acid derivative 30 provided the 6lactam 31 in good yields and with an excellent diastereoselectivity. If sarcosine is used instead of iminodiacetic acid, the cyclization proceeds with lower regioselectivity [18]. Obviously, only reactants with cyclic residues such as 28 or symmetrically substituted compounds such as 30 ensure a highly selective cyclization (Scheme 6).
530
6.2 Synthesis and ModiJications of Amino Acids and Peptides via Diradicals
Ph HOIl*.
hv N-COOMe
ZHN/\[(
-.+
HO
ZHN"'\(;?NyCOOMe+
ZHN Ph'~NyCOOMe
i
O
O
R 17
R
HO,.,
Q,
Pr 20
21
R
19
35% 22% 8% 8%
Ph
510/, hv ZHNit-. 0
O
18 a , R = H 35% b, R = Me 48% c, R = rPr 59% d, R = Bn 63%
OH Ph,,. COOMe + z H N h y C O O M e
iPr
Pr
10.1
22
hv BocHN
50%
0
Pr
Ph,,,OH BocHN*N+OOBn
23
+
BocHN
Pr COOBn
0
Sr
hv
35%
rPr
24
25
8 : 1 (from 23) 1 : 10 (from 26)
26
Scheme 5. Photochemical behavior of N-w-benzoylalkyl substituted dipeptides
Though only few examples of the preparation of p-lactams via diradicals have been reported, these efforts should be discussed briefly because of the enormous biological and pharmaceutical interest in these compounds. Nearly twenty years ago Aoyama and coworkers investigated the photochemical behavior of a-ketoamides 32. It was shown that the observed range of products remarkably depends on the substituents and solvents used during photolysis. A thorough discussion of the complex reaction course would go beyond the scope of this chapter, and therefore only the most important facts will be mentioned. The a-ketoamides 32 firstly form the diradicals 33, which should exist, at least partially, in the singlet state. In contrast to the examples presented hitherto, the appearance of a zwitterionic intermediate 36 was unambiguously proven. It may be formed either directly from the singlet diradical33 or by an addition of the Norrish-Type-I1 products 34 and 35 and cyclizes to the p-lactams 37. It seems that this ring closure is limited to radical-
6.2.3 Synthetic Applications
531
2 steps
27
29 (56-60%)
28
hv
Ho&COOMe
31 (75%, dr > 9713) Scheme 6. d-lactams by photocyclization of dipeptides
stabilizing substituents (CHZPh) if performed in solution, whereas less stabilizing substituents preferably afford oxazolidin-4-ones [ 19aI. Interestingly, the product ratio can be substantially altered in favor of p-lactams if amides 32 are irradiated as inclusion complexes with desoxycholic acid or cyclodextrin (Scheme 7, Table 2) [ 19b,c].
6.2.3.2 Imides as Diradical Precursors The following section will deal solely with phthalimides, because only these imides were applied to the preparation and modification of amino acids. It was mentioned in Section 6.2.2 that phthalimides differ in some respects from aryl ketones despite
32
33
37
Scheme 7. Cyclization of r-ketoamides to /I-lactams
34
35
36
532
6.2 Synthesis und Modijications of Amino Acids and Peptides via Dirudiculs
Table 2. /I-Lactams by photocyclization of a-ketoamides (* inclusion complex with desoxycholic acid)
R'
R2
Yield 37 ['YO]
Me Ph Me Me Me
CH2Ph CH2Ph H Me (CH2)3
94 100 42* 14* 52*
their apparently similar photophysical properties. It is very likely that many of these differences arise from the fact that the radicals A and the radical anions B formed by hydrogen or electron transfer onto the triplet excited phthalimide are more stable than the corresponding species derived from aryl ketones (C and D), even though the triplet energies are very close (Fig. 1). Ah initio calculations predict that A is more stable than C by about 7 kcal/mol [20]. This stabilization of the products and consequently the increased exoergonicity enables reactions which were unknown from ketones. Thus, upon irradiation of N-phthaloyl amino acids, a photodecarboxylation takes place which is initiated by a hydrogen abstraction from the carboxyl group [21]. Some years later, this method was developed further by Griesbeck to a very straightforward synthesis of a-monodeuterated primary amines starting with N-phthaloyl a-amino acids [22]. To the same group a very versatile cyclization method is owed, which is based on the irradiation of the potassium salts of N-phthaloyl amino acids in an acetone/water mixture. Under these special conditions no simple decarboxylation occurs if the carboxyl group is in the &position (or in more remote positions with respect to the excited carbonyl group) but the resulting diradicals preferably cyclize. In this way both small-sized rings such as pyrrolizidine 39 [23] as well as macrocycles such as 42 and 44 may be obtained [24]. The latter results are particularly remarkable because there is obviously no dependence of the cyclization yield on the ring size. On the other hand, it was shown that the cation plays a fundamental role in this reaction.
OH
C
00
D
Figure 1
533
6.2.3 Synthetic Applications
COOMe hv/K2C03
/
0 @'-fcoIetone
~
@
COOMe H+/ROH
@
0
/ HO ,
0
39
38
41
COOMe
/
6OOH
40
42 (26-68%)
acetone / H,O HNI\/
$In 43
I
COOH
n=1,10 44 (71-80%)
Scheme 8. Synthesis of bicyclic lactams by remote photodecarboxylation
If potassium is replaced by other metals or by ammonium cations only poor cyclization yields were observed [23], which suggests the importance of complexation effects. In Scheme 8 some particularly interesting examples are summarized. Another fascinating photochemical modification of phthaloyl amino acids utilizes two reactions of the primarily formed diradicals that have rarely been observed in the ketone photochemistry: the radical disproportionation and the photoelimination. As a consequence of this process, P,y-unsaturated amino acid derivatives are accessible, which are very interesting as peptide building blocks as well as versatile synthons. As shown in Scheme 9, the yields of the unsaturated compounds 46 strongly depend on whether the P-carbon atom bears one or two substituents. Whereas the valine and isoleucine derivatives 45b,c afforded the desired products in good yields, the method is ineffective from a synthetic point of view if amino butyric acid or norvaline is used (45a,d) [25].From dehydrovaline 45b the methyl analog of the antitumor agent acivicin (47) was prepared via few steps [26]. The photoelimination seems to be more generally applicable. Thus, compounds 48, prepared from L-methionine or L-homoserine and bearing a leaving group in the y-position provided the unsaturated product 49 in good yield. Deprotection of 49 affords vinylglycine 50, a amino acid which is of considerable interest for the synthesis of pharmaceutically active compounds [27]. The applications of phthalimides hitherto presented have one feature in common: an analogous behavior of aryl ketones is rarely observed. In the last part of this
534
6.2 Synthesis and ModiJications of Amino Acids and Peptides via Diradicals 0
R’
R2
OH R’
R2 Me
0
0 47
45a R’ = R~ = H 45b R’ =Me, R 2 = H 45cR’=Et,R2=H 45d R’ = H, R2 = Me
46a 20% 46b 85% 4 6 75% ~ 46d 15%
48 X = SOMe, CI, Br
49 (69-85%)
Scheme 9. Preparation of p,y-unsaturated amino acids
50 (88%)
. .
section cyclization reactions are to be presented, which formally resemble the reactions in Section 6.2.3.1, though PET processes often play an important role. The y-hydrogen abstraction affords bicyclic azetidines 52 whose structural peculiarity is that they are 0,N-acetals. Therefore it is not surprising that they undergo an immediate ring expansion yielding the benzazepinediones 53 [25, 281. If the residue R bears hydrogen atoms in P-position, a second photochemical hydrogen transfer takes place and the resultant 1,4-diradical cleaves in most cases giving the 6-unsubstituted benzazepinedione 53d [25, 291, though a cyclization was observed in one case [30]. It should be noted that the reaction from the S-substituted cysteine derivatives 51f only proceeds in the presence of the triplet quencher piperylene whereas otherwise the annulated products 54 are formed. The reason seems to be the different behavior of the radical anion/radical cation pair formed by an initial PET from the sulfur atom. In the singlet case, a rapid reverse electron transfer occurs and products are only formed from the homolytic y-hydrogen transfer. In contrast to that the triplet ion pair persists some time and a proton migration from the kinetically more acidic remote CH-position may take place [29]. If only 6-CH’s are available as in the case of the phthaloyl tert-leucine ester 55, the expected pyrrolizidine 56 is formed in excellent yield (Scheme 10) [31]. The examples presented in this section have elucidated the variety of photochemical reactions of phthaloyl amino acid derivatives. Therefore only a selection of the most interesting methods could be discussed.
6.2.3.3 Azoalkanes as Diradical Precursors In this last section the preparation of aminocyclopropane carboxylic acid derivatives by nitrogen extrusion from cyclic azoalkanes will be discussed. These amino
6.2.3 Synthetic Applications
535
0
51a R = H 51b R = Me 51c R = 3,4-(OCMe20)Ph 51d R = Et 51e R = CH(Me2) 51f R = SCHR‘R” *)
52
53a (60%) 53b (60%) 53c ‘(100%) 53d (R = H) 60% from 51d. 67%‘from 51e,95% from 51f
*) irradiation in the presence of piperylene.
I
R’!
hv COOMe
0
54 (48-95%0)
I
COOMe
COOMe PhH
0
55
0
56 (95%)
Scheme 10. Cyclizations of phthaloyl amino acid derivatives
acids are particularly valuable because they constitute a unique form of “conformationally constrained” amino acid which has been found in nature. Subsequently, several groups have been dealing with their preparation and investigation of their biological properties and peptides containing them. It must be pointed out that there are only few synthetic applications of the above mentioned approach and that alternative ionic routes exist, which are superior to diradical methods in most cases. Nevertheless, some interesting enantioselective syntheses were published and therefore a treatment of this subject seems to be justified. The syntheses always starts with a 1,3-dipolar addition of diazomethane to dehydroamino acid derivatives. Naturally, the aim was the preparation of enantiomerically pure amino acids and in this regard two concepts were pursued (preparation of racemic aminocyclopropane carboxylic acids as well as the preparation of the parent compound will not be discussed here). Barnabe and coworkers used L-proline as chiral auxiliary which was built in a diketopiperazine moiety [32]. Thus, 3-alkylidene pyrrolo[ 1,2-a]pyrazine1,6diones 57 were treated with diazomethane and gave the spiropyrazolines 58 highly stereoselectively. Upon irradiation, nitrogen extrusion takes place and the spirocyclopropanes 60 were obtained via intermediate 1,3-diradicals 59. Finally, the amino acids 61 were formed after acid hydrolysis (Scheme 11). The stereoselectivity of the ring contraction from 58 to 60 may originate either from an asymmetric induction at the diradical stage or from a memory effect due to the short lifetime of the 1,3-diradicals. In the latter case the chiral information at the C-3 atom of the pyrazoline 58 would be conserved. Although the authors have not discussed this aspect it seems very likely that the memory effect is responsible for the stereo-
536
6.2 Synthesis and ModiJicutions of Amino Acids and Peptides via Diradicals
57
58
59
R’ = Ph, Me,Et, i P r R2 = Ac, BOC
61
K
0
60
K
0
0
COOMe 61
63
0
62
64
65
Scheme 11. Preparation of aminocyclopropane carboxylic acids
selectivity particularly since it was irradiated in the absence of a triplet sensitizer and thus singlet 1,3-diradicals are formed. The second chirality source used in the synthesis of aminocyclopropane carboxylic acids was D-glyceraldehyde acetonide, which after Wittig-Horner-Emmons reaction provided the alkenes 61. Treatment with diazomethane and subsequent irradiation at low temperatures afforded the cyclopropanes 62, which were converted into several other derivatives by modification of the side chain (Scheme 11). Notably, the best results were obtained by irradiating in the presence of benzophenone as triplet sensitizer [ 33, 341. Following a similar synthetic procedure allocoronamic acid 65 was prepared, which is one of the amino acids that can be processed by plant tissues and promises the possibility to control the enzymatic processes underlying plant growth and fruit ripening [35].
References [ I ] a) R. W. Williams, Aldrichimica Acta 1992, 25, 1 1 . b) R. 0. Duthaler, Tetrahedron 1994, 50, 1539. [2] S. Feyter, E. Diau, A. Zewail, Angew. Chem., Int. Ed. Engl. 2000, 39, 260. [3] L. J. Johnston, J. C. Scaiano, Cliem. Rev. 1989, 89, 521. [4] a) L. Salem, C. Rowland, Angeiv. Chem., Int. Ed. Engl. 1972, 11, 92. b) A. G . Griesbeck, H. Mauder. S. Stadtmuller, Acc. Chenz. Res. 1994, 27, 70. [5] J. C. Scaiano; Tetrahedron 1982, 38, 819. [6] N. J. Turro, Chem. Eng. News 1967, 45, 84. [7] G . Quinkert, Angeiv. Chem. Int. Ed. Engl. 1975, 14, 790. [8] a) P. J. Wagner, Ace. Chem. Res. 1971, 4, 168. B) P. J. Wagner, Topics Curr. Chem. 1976, 66, I . c) P. J. Wagner, Acc. Chem. Res. 1989, 22, 83. D) P. J. Wagner, B. Park in A. Padwa (ed.), Organic Photochem., Marcel Dekker Inc., New York, 1991, 227. e) P. J. Wagner, in W. M. Horspool and P . 3 . Song (eds.), CRC Handbook of Organic Photochemistry and Photobiology, CRC, Boca Raton, 1995, 449. [9] R. S. Davidson, D. Goodwin, Ph. Fornier de Violet, Tetrahedron Lett. 1981,22, 2485. [lo] a) H. Haber, H. Buchholz, R. Sukale, H.-G. Henning, J. Prakt. Chem. 1985, 327, 51. b) K. Walther, U. Kranz, H.-G. Henning, J. Prakt. Chem. 1987, 329, 859. [ 1I] P. Wessig, P. Wettstein, B. Giese, M. Neuburger, M. Zehnder, Helu. Chim. Acta, 1994, 77, 829. 1121 A. Steiner, P. Wessig, K. Polborn, Helv. Chim. Acta 1996, 79, 1843. [13] B. Giese, P. Wettstein, C. Stahelin, F. Barbosa, M. Neuburger, M. Zehnder, P. Wessig, Angew. Chem. Int. Ed. Enyl. 1999,38, 2586. [I41 P. Wessig, J. Schwarz, Helv. Chim. Acta 1998, 81, 1803. [I51 a) C. Wyss, R. Batra, C. Lehmann, S. Sauer, B. Giese, Arzyew. Chem. 1996, 108, 2660. b) S. Sauer, C. Stahelin, C. Wyss, B. Giese, Chimia 1997, 51, 23. c) S. Sauer, A. Schumacher, F. Barbosa, B. Giese, Tetrahedron Lett. 1998, 39, 3685. [16] a) U. Nagai, K. Sato, Tetrahedron Lett. 1985, 26, 647. b) K. Sato, U. Nagai, J. Chem. Soc. Perkin Trans. I 1986, 1231. [ I71 P. Wessig, Tetrahedron Lett. 1999, 40, 5987. [18] A. G. Griesbeck, H. Heckroth, H. Schmickler, Tetrahedron Lett. 1999, 40, 3137. [19] a) H. Aoyama, M. Sakamoto, K . Kuwabara, K. Yoshida, Y. Omote, J. Am. Chem. Soc. 1983, 105, 1958. b) H. Aoyama, K. Miyazaki, M. Sakamoto, Y. Omote, J. Chem. Soc. 1983, 333. c) H. Aoyama, K. Miyazaki, M. Sakamoto, Y. Omote, Tetrahedron 1987, 43, 1513. [20] P. Wessig, unpublished results. [21] Y. Sato, H. Nakai, T. Mizoguchi, M. Kawanishi, Y. Hatanaka, Y. Kanaoka, Chem. Pharm. Bull. 1982, 30, 1263. [22] A. G. Griesbeck, A. Henz, Synlett 1994, 931. 1231 A. G. Griesbeck, A. Henz, K. Peters, E.-M. Peters, H.-G. v. Schnering, Angew. Chem. 1995, 107, 498. [24] A. G. Griesbeck, A. Henz, W. Kramer, J. Lex, F. Nerowski, M. Olgemoller, K. Peters, E.-M. Peters, Helv. Chim. Acta 1997, 80, 912. [25] A. G. Griesbeck, H. Mauder, I. Muller, Clzem. Ber. 1992, 125, 2467. 1261 A. G. Griesbeck, J . Hirt, K. Peters, E.-M. Peters, H.-G. v. Schnering, Liebigs Ann. 1995, 619. [27] A. G. Griesbeck, J. Hirt, Liebigs Ann. 1995, 1957. [28] A. G. Griesbeck, A. Henz, J. Hirt, V. Ptatschek, T. Engel, D. Loffler, F. W. Schneider; Tetrahedron 1994, 50, 70 1. [29] A. G. Griesbeck, J. Hirt, K. Peters, E. Peters, H.-G. v. Schnering, Chem. Eur. J. 1996,2, 1388. [30] A. G. Griesbeck, EPA Newsletters 1998, 62, 3. [31] A. G. Griesbeck, H. Mauder, Angeiv. Chem. 1992, 104, 97. [32] C . Alcaraz, D. Fernandez, P. de Frutos, J. L. Marco, M. BarnabC, Tetruhedron 1994,50, 12443. [33] J. M. JimCnez, J. Rifk, R. M. Ortufio, Tetrahedron: Asymmetry 1995, 6 , 1849. [34] J. M. Jimenez, R. M. Ortufio, Tetrahedron 1996, 7, 3203. [35] C. Cativiela, M. D. Diaz-de-villegas, A. I. Jimenez, Tetrahedron: Asymmetry 1995, 6 , 177.
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
6.3 Radicals in Carbohydrate Chemistry Alan James Pearce, Jean-Maurice Mallet and Pierre Sinay
6.3.1 Introduction Radical methods are of central importance in organic synthesis [ 11. These reactions are performed under mild and neutral conditions, which usually avoids competing ionic side reactions. Carbon-centered radicals are compatible with a range of functional groups (e.g. aliphatic alcohols, amines, ketones, esters) and also show high chemoselectivity under carefully controlled reaction conditions. Furthermore, reactions involving loss of stereochemistry at the non-radical center are not problematic, and hence radical methods are emerging as a powerful synthetic tool in the field of carbohydrate chemistry. In this article we provide a broad overview of the application of radical methods in carbohydrate chemistry, including typical examples classified by the type of bond formed. The factors controlling the stereoselectivity of inter- and intramolecular C-C bond formation are now well understood and have been exploited in the synthesis of C-glycosides [2]. Intramolecular C-C bond formation using carbohydratebased chiral templates also provides a powerful route to branched-chain sugars [ 3 ] and carbocycles [4]. Finally, we include synthetically useful processes involving key carbon-heteroatom and C-H bond formation.
6.3.2 Intermolecular Carbon-Carbon Bond Formation 6.3.2.1 Synthesis of C-Glycosides A powerful strategy for the formation of C-glycosides is the intermolecular addition of an anomeric radical to n-systems [2]. Anomeric pyranosyl radicals are readily generated by a variety of standard methods and are nucleophilic in character because of interaction of the SOMO with the non-bonding electron pair of the adjacent ring oxygen. Anomeric radicals therefore undergo addition to n-systems when the high-lying SOMO can interact with a low-lying LUMO as in electron-deficient
woBz
6.3.2 Intermoleculur Curbon-Curbon Bond Formation A
C
O
G
OBz
AcO& AcO AcO
AcO
a:P97:3
4 t
539
BzO'
I"
2 t a
a:p >95:5
AcO
Scheme 1. Stereoselectivity of anomeric radical addition to C=C (ratios indicated for acrylonitrile) is controlled by conformational and stereoelectronic factors [ 1 11
alkenes. Anomeric pyranosyl radicals are therefore synthetically useful glycosyl donors [5] in an addition mode, and furthermore they react with predictable stereoselectivity, leading preferentially to a-C-glycosides. For example, the peracylated glucopyranos-1 -yl and mannopyranos- 1-yl radicals undergo stereoselective addition to a variety of standard electron-defient alkenes including acrylonitrile [6], fumarodinitrile [7], acrylate esters [8], dimethyl maleate [9] and methylene maleate [ 101 with high a-selectivity. Giese rationalized this behavior in terms of the radical conformation and stereoelectronic effects [ 111. Electron spin resonance studies [ 121 indicate that at room temperature the glucopyranosyl- 1-yl radical adopts a B2,5 conformation 1, while the mannopyranos-1-yl radical adopts a 4C1 conformation 2 (Scheme 1). These conformations are preferred because of the conjugative stabilizing interaction between the SOMO and the coperiplanar a*-LUMO of the p-C-0 bond [ 131. Pseudo-equatorial attack on the boat conformation of glucopyranosyl-lyl radical 1 or a-attack from the opposite face to the axial C-2 substituent in the chair conformation of mannopyranos-1 -yl radical 2 maintains these conjugative stabilizing interactions and leads to the observed a-C-glycosides. Anomeric furanosyl radicals may also undergo highly stereoselective additions to alkenes, which can similarly be rationalized by conformational-stereoelectronic arguments [2b]. Thus, arabinofuranos-1-yl radical 3 adopts a 2 E conformation and adds to acrylonitrile with excellent a-selectivity. In constrast, poor selectivity was observed in the addition of peracetylated arabinopyranos- 1-yl radicals to acrylonitrile, apparently because of conformational equilibrium between the 4C1 4 and B0.3 5 forms, in which both conformers allow conjugative stabilizing interactions between the SOMO and a*-LUMO of the p-C-0 bond. The general synthetic utility of the intermolecular addition of glycosyl-1-yl radical donors to electron-deficient alkenes for the synthesis of C-glycosides has been
6.3 Radiculs in Carbohydrate Chemistry
540
...,,,ti + OAc
,,,B
AcO
%OH
OAc 2. 1. Ac~O. BuSSnH, Py AIBN, 80°C *
0
‘OAC
5
AcO
6
0
‘QAc 8
3,Ac;0,
7
AcOoi. b C H r <
(81%)
py
-
~
’-
9
Scheme 2. Preparation of C-disaccharides by intermolecular addition of glycos-1 -yl radicals to C=C
reviewed [2]. Standard C=C-based radical traps such as a,P-unsaturated carbonyl compounds are of particular use. More elaborate traps have been exploited by Giese [ 141 in the preparation of C-disaccharides, which are non-hydrolyzable disaccharide mimetics with potential applications as tools in glycobiology. Addition of the glucos-l-yl radical, generated by the tin method [15] from glucosyl bromide 5 , to the exocyclic double bond of a-methylene lactone 6 [ 14a] or 7 [ 14b] provides direct access to the a-( 1 2)-linked C-disaccharides 8 and 9 respectively (Scheme 2) with high diastereoselectivities. A wide variety of a-linked C-disaccharides have also been prepared by Vogel [16] by glucos-l-yl radical addition to radical traps based on the bicyclic a-methylene lactone 10. Kessler [17] prepared a range of C-glycosyl amino acids, which are important building blocks for the preparation of C-glycopeptides [ 181, by intermolecular addition of glycos-l-yl radicals to dehydroalanine derivatives such as 11. High Eselectivity in the addition process, but only moderate diastereoselectivity for the H-abstraction at the amino acid center, was observed (Scheme 3 ) . Beckwith [ 191 similarly prepared C-glucosyl and C-galactosyl amino acids with improved overall diastereoselectivity by glycos- 1-yl radical addition to the chiral methyleneoxazolidinone 12. Fessner [20] showed that C-glycosyl phosphonates such as 13 are available from the addition of glycosyl-l-yl radicals to vinyl phosphonate 14. Hart [21] also demonstrated that the glucosyl-1-yl radical, generated from glucosyl bromide 5 by thermolysis of bis(trimethylstannyl)benzopinacolate,was trapped by 0benzylformaldoxime 15, ----f
6.3.2 Intermolecular Curbon-Curbon Bond Formation
54 1
OAc OAc OAc OAc AcO
(3:lS:R)
AcO% NHBoc Br 11
C02Bn
OAc OAc
AcO
I
Cbz NH2
12
,OAc AcO& AcO
C 1 3 C -0 p
0 JT-OEt - OEt
Bu3SnH, hv
(44%)
*
14
(>98:2a:P) P,-OEt OEt
13 Bu3Sn0 OSnBu3 PhZC-CPhz
=NOBn Br
5
(45%)
N(Ac)OBn 15
Scheme 3. Preparation of C-glycopyranosides by intermolecular addition of glycos- 1 -yl radicals to
c=c
Stereoselective addition of ribofuranosyl radicals to a,P-unsaturated carbonyl compounds was exploited by Araki [22] in the formal synthesis of the antiobiotic Showdomycin 16 (Scheme 4). Barton [23] provided a more direct synthesis of 16 by addition of the ribofuranosyl radical, generated using the sugar telluride 17, to maleimide. Ribofuranosyl radicals also undergo addition to z-systems of electrondeficient aromatics such as 18, which provides a direct route to C-nucleosides [24]. Addition of glycosyl radical donors to allyltributyltin was introduced by Keck [25] and provides a general method for the preparation of C-ally1 glycosides, for example 19, avoiding the inherent problem of competitive reduction encountered in tin hydride-mediated intermolecular additions (Scheme 5). The C-ally1 glycosides of N-acetylneuraminic acid 20 [26]and N-phtalimidoglucosamine 21 [27] have been prepared by this method and are important targets for the design of C-linked glycopeptide mimetics. The reaction is also extended to branched derivatives such as methallyltributyltin 22 [28] and 23 [ lo], although substitution at the terminal position of allyltributyltin in not tolerated. Giese [ 10a] showed that allylation of glu-
6.3 Rudiculs in Curbohydrute Chemistry
542
eOc(s)sM: -
OBz
‘OnMe
.
.
Bu3SnH, (62%)AlBN
C02Me
‘COzMe
.
i
H d
OH
16
/
A
\
17
(An=pMeOC6H4)
. . U Bnd
bBn
- ‘,)Jk ~ 2 S
(46%)
. Bnd
18
. bBn
(a:P73:27)
Scheme 4. Preparation of C-glycofuranosides by intermolecular addition of glycofuranos-1-yl radicals to C=C
cosy1 bromide 5 with the allyltin reagent 23 was biomimic of the enzymatic aldol reactions reactions between phosphoenol pyruvate and carbohydrates. Glycosyl radical donors similarly undergo stereoselective allylation with allylic sulfides and sulfones [29]. Glycos-1-yl radicals may undergo dimerization in the absence of an intermolecular trap. Thus, photolysis of glycosyl phenylsulfones [ 301 or irradiation of pyranosyl bromides or selenides [31] in the presence of hexamethylditin affords glycosyl dimers in low yield (24-32%). Beau [32] reported a more efficient variant of this process by SmIz-induced dimerization of glycosyl 2-pyridylsulfones such as 24 (Scheme 6). Vasella [33] has also shown that glycosyl radicals derived from 1-Cnitroglycosyl halides undergo additions to weakly basic carbanions by an SRN1 mechanism. Thus, irradiation of the l-C-nitromannosyl bromide 25 with the lithium salt of 26 afforded the glycosyl dimer 27 in good yield. C-Glycosides are also prepared by the coupling of exocyclic carbohydrate-based radical donors with electron-deficient alkenes. Addition of the exocyclic radical derived from iodide 28 to the enone 29 led to the C-disaccharide 30 [34]. Motherwell [ 351 has shown that difluoromethylene-linked C-glycosides may be prepared by intermolecular additions of radicals derived from exocyclic difluorosulfides or sele-
6.3.2 Intermolecular Curbon-Curbon Bond Formation
+
&SnBu3
543
AlBN
~
(79%)
19
II A
cAcHN o
~
c
o
2
M + e &SnBu3
(92%) AlBN
OAc
*
A
c
O
M
c
o
2
M
e
AcHN OAc 20
A c O ~
+
AcAcO o-Br
AlBN &Snb
ACOY AAcO c
O
L
(71%) . ,
NHPhth
NHPhth 21 (a:Pl:lO)
C02Et Br 5
+
A S n B u s
23
1. AlBN 2. O3
AcO
(70%) C02Et
Scheme 5. Preparation of C-ally1 glycosides by intermolecular addition to ally1 tin reagents
nides. For example, allylation of difluoroalkyl sulfide 31 proceeded smoothly, and difluoroalkyl selenide 32 undergoes diastereoselective addition to the chiral oxazolidinone 33 to afford the yem-difluoromethylene-linked glycosyl serine analog 34 (Scheme 7). C-Glycosides are also available from the coupling of carbohydrate-based radical acceptors at C-1 with radical donors (Scheme 8). Motherwell [35]has developed this complementary strategy for the synthesis of difluoromethylene-linked C-glycosides. Thus, the difluoroalkyl sulfide 31 was prepared by the intermolecular addition of
544
6.3 Radicals in Carbohydrate Chemistry
(aa:ap:PP1.5:3.0:1.O)
24
25
27
26
Scheme 6. Dimerization of glycos-l -yl radicals
OAc
1. BusSnH, Cy-N=N-Cy BnO””
0
“‘OBn OBn 20
ACON-, b C AcO ~~
H
2
d
i
A
c
<
‘bAC
‘OAc
29
30
33
34 (4:l trans:cis)
31
32
Scheme 7. Preparation of C-glycosides via intermolecular addition of exocyclic carbohydrate radical donors to C=C
6.3.2 Intermolecular Curbon-Carbon Bond Formution
545
O[Si]
Y
F
[silo"'
"'o[s~] O[Si]
PhSH,AIBN
~
(79%)
[Si]=TMS
O[Si]
35
+
Bp,\oMe Bu3SnH, AlBN
BZO"'
37
31
"'OAc OAc
(25%)
"OAc OAc
36
v
38
OTr
AcO"' 0
MeOH, hv (60%)
40
+ AcO'"' O w0 o
H
39 (73a$)
Scheme 8. Preparation of C-glycosides via intermolecular addition of radicals to unsaturated carbohydrate acceptors
thiophenol to the exocyclic difluoroenol ether 35, and addition of the primary radical derived from glucosyl bromide 36 to acceptor 37 gave the C-disaccharide 38. Fraser-Reid [ 361 has prepared C-glycosides 39 by the photochemically induced addition of methanol to the endocyclic enone 40.
6.3.2.2 Synthesis of Branched-Chain Sugars A major strategy for the preparation of branched-chain sugars is the intermolecular addition of non-anomeric, carbohydrate-based nucleophilic radical donors to n-systems [ 31. The stereoselectivity of the radical addition to electron-deficient alkenes such as acrylonitrile is sterically controlled by the substituents adjacent to the radical center [ 111, and unless both substituents are axial, equatorial attack is usually favored. In situ reduction of the unprotected organomercury salt 41 afforded the C-2-based radical donor, which added to fumarodinitrile to give the C-2 branched sugar 42 with high equatorial stereoselectivity [37]. Giese [ 141 prepared C-disaccharides 43 and 44 by the addition of the C-4- or C-6-based radical donors to the a-methylene lactone 6, respectively (Scheme 9). Photolysis of the alkyl coba-
546
6.3 Radicals in Carbohydrate Chemistry
P.::?
OH
BusSnH (40%)
D
NC
HO"'
OH
OH
42
41
GH
OBz
1. Bu3SnH, AlBN 2. ACPO
"OBZ
"
OBZ
0
*
(35%)
43
6
1. Bu3SnH, AlBN 2. ACZO
*
6
AcO""Ir(,,,..>OMe OAc
(54%)
"'OAc OAc
''"OAc OAc
44
EtOH, hv
ljPh
(85%) "OAc OAc 46
0
TBDMSO"
4,
1
F3C0C0~c0zEt 49
50
52
1. hv, 0°C 2. NaHC03 3.Dowex (HI)
Hov ',,OH
HO"'
OH 51
53
Scheme 9. Preparation of branched-chain sugars by intermolecular addition of glycosyl radical donors to olefins
6.3.3 Intrarnoleculur Curbon-Carbon Bond Formation
547
loxime 45 afforded the C-6-based radical donor, which was trapped by styrene to give the branched-chain product 46 by a radical equivalent to the Heck coupling [38]. Barton [39] showed that radicals generated by the photolysis of N-hydroxy-2thiopyridone uronic esters reacted stereoselectively with electron-deficient alkenes, leading to highly functionalized chain-elongated pentafuranosides, hexapyranosides and pentafuranosyl-nucleosides through the C-4, C-5 and C-4’ radicals, respectively. Thus, addition of the radical generated by photolysis of 47 to a vinyl phosphonate allowed preparation of the isostere of AZT-5’ monophosphate 48. Barton ester-based chemistry was also applied to generate the open-chain radical donor 49, which undewent stereoselective intermolecular addition to the electron-deficient alkene 50 in the preparation of the seven-carbon sugar DAH 51 [40].The free-radical allylation process developed by Keck provides a general method for the preparation of allyl branched sugars [25, 28, 411. Irradiation of L-lyxose derivative 52 in the presence of allyltributyltin gave the C-4 allyl adduct 53, which was transformed into Pseudomonic acid C [42]. A second generation synthesis of Pseudomonic acid C utilized an analogous radical allylation process by addition to a vinylic sulfone [43]. Branched-chain sugars are also prepared by the coupling of carbohydrdte-based radical acceptors with radical donors. As discussed previously, the C-2 exocyclic radical acceptors of a-methylene lactones 6 and 7 and bicyclic a-methylene lactone 10 have been exploited by Giese [ 141 and Vogel [ 161, respectively, for the preparation of C-disaccharides. Chapleur [44] has reported conjugate radical additions to other chiral enone acceptors. The electrophilic radical generated by the tin method from chloroacrylonitrile adds to the more electron-rich terminal position of the exo54 to give the chain-extended cyclic double bond in 6-deoxyhex-5-eno-pyranoside product 55 [45] (Scheme 10). Electrophilic carbon radicals similarly undergo addition to 4/,5’-unsaturated uracilnucleotides [46]. Fraser-Reid [47] has prepared C-2and C-4-branched sugars by the photochemically induced addition of methanol to the endocyclic enone acceptors 56 and 57, respectively. The use of endocylic enone levoglucosenone 29 as a suitable acceptor for the preparation of C-disaccharides [34] has been discussed. Radical conjugate addition to enolone 58 occurred with equatorial selectivity and radical migration of the 0-2 benzoyl to 0 - 3 [48]. Trifluoromethyl radical addition to the open-chain ketene thiacetal 59 provides a convenient route to 2-C-trifluoromethyl derivative 60 [49].
6.3.3 Intramolecular Carbon-Carbon Bond Formation 6.3.3.1 Synthesis of C-Glycosides In addition to intermolecular reactions, C-glycosides can also be prepared by intramolecular addition of a glycos-1-yl radical donor onto an acceptor group tethered to a suitable hydroxyl or amino group of the sugar. Radical cyclizations such as the 5-exo-trig process are usually very rapid, and therefore, unlike the intermolecular addition, intramolecular radical additions do not require activation of the alkene
548
6.3 Radicals in Carbohydrate Chemistry
CICH2CN, Bu3SnH AcO
““0Ac OAc
*
(57%)
“ AcO ‘ b ; O MOAc e “‘OAc 55
54
OH
OH
MeOH, Ph2C0, hv t
(66%)
56
OTr CO,.+OMe I I
MeOH, Ph2C0, hv t
(65%)
57
w
OBz
OBz 0Me
OBz P O
M
(24%)
e
+
‘
W
M
e
D
(83%)
t-BU“‘
”‘OBz
t-Bu‘”’
0
OBz
0 (4:l)
58
n CF31, SO2, HC02Na D
NaHC03, pyr OH
59
(75%)
60
Scheme 10. Preparation of branched-chain sugars by radical addition to unsaturated carbohydratebased acceptors
acceptor with electron-withdrawing substituents. De Mesmaeker [50]showed that glycos-1-yl radicals undergo stereospecific tin hydride-induced 5-exo-cyclization onto C-2 hydroxyl-linked allylic and propargylic acceptors to give the geometrically required cis-ring fusion only (Scheme 11). The configuration at C-2 is therefore transferred to the anomeric center, providing a powerful strategy for the stereo-
6.3.3 Intramolecular Carhon-Carbon Bond Formation OBn
549
p::;$
OBn
vsy
Bu3SnH , AlBN (95%) e or hv, -78°C (88%)
BnO'"
(1:1)
BnO"'
OBn
OBn
61
62
OBn
OBn Bu3SnH, AlBN
BnO"'
or hv, -30°C (90%)
BnO+
6Bn
OBn 64
63 OBn
OBn
65
"\
66 OBn
OBn OMe
BnO"
BnO"' OBn 67
-
BnO"
OBn
"'OMe OBn 68
Scheme 11. Stereoselective formation of C-glycosides by intramolecular C--C bond formation
specific formation of cc- or p-C-glycosides. Thus, the 2-0-allyl-I -selenoglucoside 61 afforded the cc-C-glycosides 62, and the 2-O-allyl-I -selenomannoside 63 afforded the /3-C-glycosides 64 [50b]. Careful control of reaction conditions is required in the formation of a-C-glycosides in order to avoid competing epimerization at C-5 due to intramolecular 1,5-hydrogen abstraction of the intermediate cc-cyclized radical. The SmI2-promoted 5-exo-radical cyclization of perbenzylated 2-O-allyl- 1-phenylsulfonylglucoside 65 has been reported by Sinay [5 11. The analogous tributyltin hydride-induced radical cyclization of 2-N-allyl- 1-selenogalactoside 66 and glucosides are also known [52]. De Mesmaeker [53] developed a temporary acetal-linked variant that could be cleaved after cyclization, as illustrated by conversion of 67 to cc-C-glycoside 68.
550
6.3 Radicals in Carbohydrate Chemistry
0-Si,
0-Si
I
OMe
VSePh
MeO"'
'"'OMe
0, Si-Ph
1. Bu3SnH, AlBN
2. TBAF (73%)
MeO"'
"'OMe
(E:Z>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.'<'OMe
)To S 175
(20%)
(50%)
167
+
)To
o~''''oMe
p
0
0
176 (31%)
177 (41%)
Scheme 29. Radical reactions of carbohydrates involving C-P or C-S bond formation
566
6.3 Radicals in Carbohydrate Chemistry
[ 1 121 performed model studies on radical-induced DNA cleavage based on the addition of benzothiol radicals to unsaturated sugar nucleotide fragments. Finally, the rearrangement of 3,4-O-thionocarbonate 175 under radical conditions led to a mixture of thiol carbonates 176 and 177, and deprotection of 176 provided a novel route to a thio sugar present in the calicheamicin antitumor antibiotics [ 1131.
6.3.4.6 C - 0 Bond Formation The formation of an alkoxy radical or excited state at a suitable position on an aglycone chain can induce H-abstraction from C-1 leading to C-0 bond formation. Useful synthetic approaches to spirocycles based on this approach have largely been pioneered by Descotes [2d]. Thus, irradiation of hydroxylalkyl glycoside 178 in the presence of iodine and mercury(I1) oxide gave spiroorthoester 179 [ 1141 (Scheme 30). This reaction is equally applicable to c(- and P-2-deoxy glycosides [ 1151. The analogous formation of chiral spiroacetals by irradiation of C-glycosides in the presence of (diacetoxyiodo)benzene and iodine has also been reported [ 1161. Thus, the n-propanol C-glycoside 180 gave the 1,6-djoxaspir0[4,5]decanes181 and 182,
HgO, hv,lp AcO
0 179
% +~ : :BBnO BnO 180
BnO 182 (17%)
181 (51%)
RO 7
Ro%
v 183
BnO
184 (30%)
Phl(OAc)z, hv,lp
186
Scheme 30. Synthesis of spirocycles via generation of alkoxy radicals
+
Ro%
185 (22%)
6.3.5 Curbon-Hydrogen Bond Formation
a'
hv
---+
Norrish II
567
A
AcO
AAcO c
AcO o
~
o
~ hv R
+
AAcOc
O AcO
0
W
0
187 (R=H) 188 (R=(O)
OAc
I
n
AcO (70%)
190
AcO
/
Y O A c 0 189
Scheme 31. Application of the Norrish I1 process to the oxidation of carbohydrates
while the n-butanol C-glycoside 183 afforded the 1,7-dioxaspiro[5,5]undecanes 184 and 185. This approach has also been applied to the synthesis of anomeric spironucleotides such as 186 [ 1171. The intramolecular abstraction of a hydrogen atom from the y-carbon of a photoexcited carbonyl group is called the Norrish I1 process (Scheme 31). This reaction has been applied to the oxidation of the anomeric carbon by irradiation of 2-0x0 propyl glycoside 187 [ 1181 or glycosyl pyruvic esters 188 [ 1191. Binkley [ 1 191 similarly prepared the kojic acid diacetate 189 by photochemically induced oxidation of the glucosyl pyruvic ester 190.
6.3.5 Carbon-Hydrogen Bond Formation Most radical reactions involve H-abstraction as the chain terminating process and hence C-H bond formation. However, here we discuss only processes leading to direct C-H/C-D bond formation and with synthetically useful applications in the carbohydrate field.
6.3.5.1 Reduction of Glycos-1-yl Radicals Synthesis of I ,S-anhydro-hexitols The a-glucosyl bromide 5 undergoes rapid and highly stereoselective reduction with Bu3SnD leading to retention of configuration at the anomeric center [ 1201. In con-
568
6.3 Radicals in Carbohydrate Chemistry
Bu3SnD, 20 minhv,
%' : :A AcO
.
% o:A : AcO
AcO Br
Bu3SnD, 1 5 h hv
AcO
AcO
5
CI
AcO 191
AcO
AcO /OAc
Bu3SnH, AlBN (75%)
AcO
CI
*
AcO AcO 192
Scheme 32. Preparation of 1,5-anhydro-hexitoIs by reduction of glycosyl halides
trast, P-glucosyl chloride 191 undergoes stereoselective deuteration more slowly and with inversion of configuration (Scheme 32). These results reflect the preference for the axial attack of glycosyl-l-yl radicals as discussed above. David [ 1211 reported the preparation of a series of 1,5-anhydro-hexitols such as 192 by reduction of glycosy1 chlorides with Bu3SnH.
Stereoselective synthesis of P-O/C-ylycosides The preference for axial delivery of a hydrogen atom to a glycosyl-l-yl radical has been especially useful for the stereoselective formation of P - 0 - and C-glycosides. Crich [ 1221 for example has developed a general method for the preparation of 2-deoxy-P-O-glucosides based on the Barton decarboxylation of O-acyl thiohydroxamates of heptulosonic acids (Scheme 33). Thus, photolysis of the Barton ester 193 in the presence of tert-dodecyl mercaptan gave the 2-deoxy-P-~-glucoside194 with high stereoselectivity. Crich [ 122d] also applied the same strategy for the preparation of p-mannopyranosides such as 195. Similarly, Kahne [ 1231 used the stereoselective radical reduction of hemithio ortho esters to prepare P-glycosides such as disaccharide 196. Kishi [124] reduced monothioketal 197 with BujSnH to afford exlusively a P-Cglycoside en route to the C-disaccharide 198 (Scheme 34). Crich [125] reported a general alkylation-decarboxylation strategy for the synthesis of 2-deoxy-P-Cglycosides. Thus, sequential treatment of sulfone 199 with lithium naphthalenide and benzyl bromide followed by ester saponification and radical reductive decarboxylation gave the P-C-glycoside 200. Vasella [ 1261 reported a similar alkylationreductive denitration strategy for the preparation of /I-C-glycosides; alkylation of 1-C-nitrosyl compound 201 with paraformaldehyde and acetylation gave /I-C-glycoside 202 after radical denitration with BujSnH. Reductive dehalogenation of the
6.3.5 Curbon-Hydrogen Bond Formation
569
BnOT RSH, hv (40%)
BnO
( p a 1O:l) 193
A ~ AcO
i
S
o
~
o
S
194
,
. N ~ RSH, hv
(67%)
AcO
AcO (p:a>25:1)
AcO& AcO
BnO
7
OMe
195
OMe
Bn07
n
AcOAco-OAc AcO AcO
@:a >10:1)
AcO
196
Scheme 33. Preparation of P-O-glycosides by reduction of anomeric radicals
chloride 203 afforded 2-deoxy-N-acetylneuraminic acid derivative 204 exclusively [ 1271. Radical translocution Radical translocation has already been discussed in the context of unwanted epimerizations during radical cyclizations [ 501. Radical translocation also has useful applications such as spirocycle formation (Section 6.3.4.6: C-0 bond formation). A particularly interesting application of radical translocation is the preparation of P-mannosides by radical-induced anomerization of a-mannosides using PRT (protecting and radical translocating) groups (Schtme 35). Curran [ 1281 showed that 3-0acyl-a-methyl-D-mannoside 205 underwent a 1,6-intramolecular hydrogen transfer reaction on treatment with Bu3SnH to afford the desired P-mannoside 206, although in only moderate yield. Poor regioselectivity in the hydrogen abstraction afforded the isomeric gluco derivative 207 via competing 1,5-hydrogen transfer. Crich [ 1291 has developed a related strategy based on 1,Shydrogen transfer [ 1301, and photolysis of the a-mannoside 208 with dropwise addition of Bu3SnH/AIBN led to a 3:l mixture of p-209 and a-mannoside 210 without detrimental side re-
510
6.3 Radicals in Carbohydrate Chemistry
do
1. Bu3SnH, AlBN (91%) 2. steps
BnO BnO BnO
OBn
HHO
O
M
* OH
Brio SPh
OHOMe 198
197
1. LiNapth; BnBr 2. KOH; H
q+ +
SOzPh
3.
CI-
C02Me
4. RSH, hv, (92%)
Ph
-
200
199
1. (CHzO)", KzCO3; AcpO 2. Bu3SnH, AlBN (95%) t
Boi:*N BnO oz
.:i0* BnO
OBn 201
OAc
202
Bu3SnH,AlBN
AcO AcHN
OBn
COzMe OAc
(82%)
*
A
AcHN c
203
O
W COZMe
OAc 204
Scheme 34. Preparation of P-C-glycosides by reduction of anomeric radicals
actions. These reactions are presently limited by the inefficiency of the intramolecular hydrogen transfer step, and the full potential of this elegant strategy is still to be realized. Synthesis of 2-deoxy-sugars
The thermodynamically driven 1,2-migration of an acyloxy group generated in glycos-1-yl radicals is well known [131]. Giese [132], for example, showed that reduction of acetylated or benzoylated glycosyl halides or selenides at low concentrations affords 2-deoxy-sugars. This rearrangement is cis-selective and generally applicable to both furanose and pyranose substrates (Scheme 36). The analogous 1,2-migration of a phosphate group is also known [ 1331 and has been applied to the synthesis of glycosyl donors, which were converted to 2'-deoxy-disaccharides such as 211 [134].
6.3.5 Carbon-Hydrogen Bond Formation 1. Bu3Sn. 2. intramolecular H-abstractioL
Br
&H
511
o-Y, Bu3SnE
OR (a-manno)
H (p-manno)
Bu3SnH, AIBN, Dowex (H +)
(3:l)
209
210
Scheme 35. Application of radical translocation to the synthesis of P-mannosides by anomerization
of a-mannosides OAc
OAc Bu3SnH, AlBN (70%)
AcO
*
OAc
BzoW."'SePh .
Bzd
Bu3SnH, AIBN
.
bBz
M 3 -& 0
-k
AcO9 . , ' O A C OAc
(75%)
BZO
Bu3SnH, AIBN t
2
(79%)
Scheme 36. Preparation of 2-deoxysugars by reduction of glycos-2-yl radicals generated in situ by
the 1,2-acyloxy or phosphate rearrangement glycos-1-yl radicals
572
6.3 Radicals in Carbohydrate Chemistry
1. Bu3SnH, AlBN (60%) 2. Amberlite IR-120 (H+)
*
O f l 0
H
7-20
:
HOo
Of-
212
~
AcO ~ O
~
C
OH
213
NO2 NCPh2 A
OH y
0
NCPh2
Bu3SnH,AlBN E t
2
Aco%C02Et AcO AcO 214
Bno
Bu3SnH,AlBN (70%)
BnO"'
(a$ -1:l)
Bno
Bu3SnH,AlBN Bno+i02Et
BnO'"
(90%)
BnO"' 216
BzO
OC(S)lm
1. Ph3SnH, AlBN (70%) 2. stem
BzO BZO 217
218
OMe
1. Bu3SnH, AlBN 2. steps
MeS(S)CO"
*
TBDMSNKo 0 219
Scheme 37. Preparation of C-glycosides by reduction of exocyclic radicals
OMe
References
573
6.3.5.2 Reduction of Non-Anomeric Radicals Synthesis of deoxy-sugars
The preparation of simple deoxy-sugars by reductive radical methods such as deoxygenation of thiocarbonyl derivatives of alcohols is now considered a routine operation [ 1351 and is therefore not discussed here. Photochemical chemical reduction of halides, for example the photolysis of primary iodides for the preparation of 6-deoxy sugars, is also described elsewhere [136]. A novel approach to the synthesis of 2’-deoxy-p-disaccharides using p-directing N-formylglucosamine donors, which were subsequently deaminated by radical reduction of intermediate isonitriles, is however particularly noteworthy [ 1371. Synthesis of C-glycosides
Reduction of radicals generated on C-glycosyl chains and deprotection often represent the final steps in the synthesis of C-glycosides (Scheme 37). Martin [138], for example, reported that radical denitration of the nitroaldol condensation product 212 led to the p-( 1 + 6) linked C-disaccharide 213. A similar nitroaldol denitration strategy was exploited in the synthesis of the C-glycosyl amino acid 214 [ 1391. Interestingly, radical denitration of the cc-nitro C-glycoside 215 led to extensive anomerization (via formation of the radical at C-l), whilst the p-nitro C-glycoside 216 underwent smooth denitration with retention of configuration [ 1401. Beau utilized the radical deoxygenation of a thiocarbonyl derivative 217 during the preparations of methyl cc-C-mannobioside 218 [ 1411 and the C-glycoside Tn antigen analog 219 [142].
References [ I ] (a) B. Giese, Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, (Ed.: J. E. Baldwin), Pergamon, Oxford, 1986; (b) D. P. Curran, Synthesis 1988, 41 7-439; Synthesis 1988,489-513. [2] (a) H. Togo, W. He, Y. Waki, M. Yokoyama, Synlett 1998, 700-717; (b) B. Giese, H.-G. Zeitz, C-Glycosyl Compounds from Free Radical Reactions, in Preparative Carbohydrate Chemistry (Ed.: S. Hanessian), Marcel Dekker, 1997, Chap 23; (c) M. H. D. Postema, Tetrahedron 1992, 48, 8545-8599; (d) G. Descotes, J. Carhohydr. Chem. 1988, 7, 1-20; (e) D. E. Levy, C. Tang, The Chemistry qf C-Glycosides, Pergamon, Exeter, 1995. (31 Y. Chapleur, F. Chretien, Methods for Synthesis of Branched-Chain Sugars, in Preparative Carbohydrate Chemistrlv (Ed.: S. Hanessian), Marcel Dekker, 1997, pp. 219-225. [4] T. V. RajanBabu, Functionalized Curhocyclic Derivatives from Curbohydrates: Free Radical and Orgunometallic Methodss, in Preparative Carbohydrate Chemistry (Ed.: S. Hanessian), Marcel Dekkcr, 1997, Chap 25. [ S ] J.-M. Beau, T. Gallagher, Top. Curr. Chem. 1997, 187, 1-54. [6] B. Giese, J. Dupuis, Angew. Chem. 1983, 95, 633; Angcw. Chem. Int. Ed. Engl. 1983,22, 622623. [7] B. Giese, J. Dupuis, M. Leising, M. Nix, H. J. Lindler, Curhohydr. Res. 1987, 171, 329-341.
514
6.3 Rudicals in Curbohydrute Chemistry
[8] R. M. Adlington, J. E. Baldwin, A. Basak, R. P. Kozyrod, J. Chem. Soc., Chem. Commun. 1983, 944-945. [9] Y. Araki, T. Endo, M. Tanji, J. Nagasawa, Y. Ishido, Tetrahedron Lett. 1987,28, 5853-5856. [lo] (a) B. Giese, T. Linker, R. Muhn, Tetrahedron 1989, 45, 935-940; (b) S. Abel, T. Linker, B. Giese, Synlett 1991, 171-172. [ 111 (a) B. Giese, Angew. Chem. 1989, 101, 993; Angew. Chem. Int. Ed. Engl. 1989,28, 969-980: (b) B. Giese, J. Dupuis, K. Groninger, T. Hasskerl, M. Nix, T. Witzel, Orbital Effects in Carbohydrate Chemistry, in Substituent Effects in Radical Chemistry (Ed.: H. G. Viehe), D. Reidel Publishing Co., 1986, pp. 283-296. 1121 H.-G. Korth, R. Sustmann, J. Dupuis, B. Giese, J. Chem. Soc., Perkin Trans. 2 1986, 14531459. [13] J. Dupuis, B. Giese, D. Ruegge, H. Fischer, H.-G. Korth, R. Sustmann, Angew. Chem. 1984, 96, 887; Angew. Chem. lnt. Ed. Engl. 1984,23, 896-898. [I41 (a) B. Giese, T. Witzel, Angew. Chem. 1986, 98, 459; Angew. Chem. Int. Ed. Engl. 1986, 25, 450-451; (b) B. Giese, M. Hoch, C. Lamberth, R. R. Schmidt, Tetrahedron Lett. 1988, 29, 1375-1378. 1151 B. Giese, J. A. Gonzilez-Gomez, T. Witzel, Angew. Chem. 1984, 96, 51; Angew. Chem. Int. Ed. Engl. 1984, 23, 69-70. [16] (a) R. M. Bimwala, P. Vogel, Tetrahedron Lett. 1991,32, 1429-1432; see also (b) R. Ferritto, P. Vogel, Synlett 1996, 281-282; (c) R. M. Bimwala, P. Vogel, J. Org. Chem. 1992, 57, 20762083. [I71 H. Kessler, V. Wittman, M. Kock, M. Kottenhahn, Angew. Chem. 1992, 104, 874; Angew. Chem. Int. Ed. Enql. 1992, 31, 902-904. [18] K. Michael, V. Wittman, W. Konig, J. Sandow, H. Kessler, Int. J. Pept. Protein Res. 1996, 48, 59. [19] J. R. Axon, A. L. J. Beckwith, J. Chem. Soc., Chem. Commun. 1995, 549-550. [20] H.-D. Junker, W.-D. Fessner, Tetrahedron Lett. 1998, 39, 269-272. [21] D. J. Hart, F. L. Seely, J. Am. Chem. Soc. 1988, 110, 1631-1632. [22] Y. Araki, T. Endo, M. Tanji, J. Nagasawa, Y. Ishido, Tetrahedron Lett. 1988, 29, 351-354. [23] D. H. R. Barton, M. Ramesh, J. Am. Chem. Soc. 1990, 112, 891-892. [24] (a) H. Togo, S. Ishigami, M. Fuji, T. Ikuma, M. Yokoyama, J. Chem. Soc., Perkin Trclns. I 1994, 2931-2942; for related examples see (b) W. He, H. Togo, Y. Waki, M. Yokoyama, J. Chem. Soc., Perkin Trans. I 1998, 2425-2433; (c) W. He, H. Togo, M. Yokoyama, Tetrahedron Lett. 1997, 38, 5541-5544. [25] G. E. Keck, J. B. Yates, J. Am. Chem. Soc. 1982, 104, 5829-5831. [26] (a) H. Paulsen, P. Matschulat, Liebigs Ann. Chem. 1991, 487-495; (b) J. 0. Nagy, M. D. Bednarski, Tetrahedron Lett. 1991, 32, 3953-3956. [27] B. A. Roe, C. G. Boojamra, J. L. Griggs, C. R. Bertozzi, J. Org. Chem. 1996, 61, 6442-6445. [28] G. E. Keck, E. J. Enholm, J. B. Yates, M. R. Wiley, Tetrahedron 1985, 41, 4079-4094. [29] F. Ponten, G. Magnusson, J. Org. Chem. 1996, 61, 7463. [30] (a) P. M. Collins, B. R. Whitton, J. Chem. Soc., Perkin Trans. 1 1974, 1069-1075; (b) P. M. Collins. B. R. Whitton. Carbohvdr. Rex 1974. 36. 293-301. [31] B. Giese, B. Ruckert, K. S. Groninger, R. Muhn, H. J. Lindner, Liebigs Ann. Chem. 1988, 997-1000. [32] G. Doisneau, J.-M. Beau, Tetrahedron Lett. 1998, 39, 3477-3480. [33] B. Aebischer, R. Meuwly, A. Vasella, Helv. Chim. Acta 1984, 67, 2236-2241. [34] Z. J. Witczak, R. Chhabra, J. Chojnacki, Tetrahedron Lett. 1997, 38, 2215-2218. [35] (a) W. B. Motherwell, B. C. Ross, M. J. Tozer, Synlett 1989, 68-70; (b) T. F. Herpin, W. B. Motherwell, J.-M. Weibel, J. Chem. Soc., Chem. Commun. 1997, 923-924. [36] D. L. Walker, B. Fraser-Reid, J. Chem. Soc., Chem. Commun. 1974, 319-320. [37] B. Giese, K. Groninger, Tetrahedron Lett. 1984, 25, 2743-2746. [38] B. P. Branchaud, M. S. Meier, Y. Choi, Tetrahedron Lett. 1988, 29, 167-170. [39] (a) D. H. R. Barton, S. D. Gero, B. Quinclet-Sire, M. Samadi, Tetrahedron 1992, 48, 16271636; (b) D. H. R. Barton, S. D. GCro, B. Quinclet-Sire, M. Samadi, Tetrahedron:Asymmetry 1994,5, 2123-2136. [40] D. H. R. Barton, W. Liu, Tetrahedron Lett. 1997, 38, 367-370.
References
575
[41] (a) R. J. Ferrier, C.-K. Lee, T. A. Wood, J. Chem. Soc., Chem. Commun. 1991, 690-691; (b) D. Mootoo, P. Wilson, V. Jammalamadaka, J. Carbohydr. Chem. 1994, 13, 841; (c) K. S. Groninger, K. F. Jager, B. Giese, Liehigs Ann. Chem. 1987, 731-732. [42] G. E. Keck, D. F. Kachensky, E. J. Enholm, J. Org. Chem. 1985, SO, 4317-4325. [43] G. E. Keck, A. M. Tafesh, J. Org. Chem. 1989,54, 5845-5846. [44] P. Mayon, M. N. Euvrard, N. Moufid, Y. Chapleur, J. Chem. Soc., Chem. Commun. 1994, 399-401. [45] See p. 64 in [la]. [46] K. Haraguchi, H. Tanaka, T. Miyasaka, Tetrahedron Lett. 1990, 31, 227-230. [47] B. Fraser-Reid, N. L. Holder, M. B. Yunker, J. Chem. Soc., Chem. Commun. 1972, 12861287. [48] B. Giese, T. Witzel, Tetrahedron Lett. 1987, 28, 2571-2574. [49] G. Foulard, T. Brigaud, C. Portella, J. Org. Chem. 1997, 62, 9107-9113. [50] (a) A. De Mesmaeker, P. Hoffmann, B. Ernst, P. Hug, T. Winkler, Tetrahedron Lett. 1989, 30, 6307-6310; (b) A. De Mesmaeker, A. Waldner, P. Hoffmann, T. Mindt, P. Hug, T. Winkler, Synlett 1990, 687-690; (c)A. De Mesmaeker, A. Waldner, P. Hoffmann, P. Hug, T. Winkler, Synlett 1992, 285-290. 1511 P. de Pouilly, A. ChCnede, J.-M. Mallet, P. Sinay, Tetrahedron Lett. 1992, 33, 8065-8068. 1521 S. Czernecki, E. Ayadi, J. Xie, Tetrahedron Lett. 1996, 37, 9193-9194. 1531 A. De Mesmaeker, P. Hoffmann, B. Ernst, P. Hug, T. Winkler, Tetrahedron Lett. 1989, 30, 6311-6314. [54] G. Stork, H. S. Suh, G. Kim, J. Am. Chem. Soc. 1991,113, 705447056, [55] (a) Y. C. Xin, J.-M. Mallet, P. Sinay, J. Chem. Soc., Chem. Commun. 1993, 864-865; (b) G. Rubinstenn, J.-M. Mallet, P. Sinay, Tetrahedron Lett. 1998, 39, 3697-3700; (c) A. Mallet, J.-M. Mallet, P. Sinay, Tetrahedron; Asymmetry 1994, 5, 2593-2608; (d) E. D. Rekai', G. Rubinstenn, J.-M. Mallet, P. Sinay, Synlett 1998, 831-834. [56] B. Vauzeilles, D. Cravo, J.-M. Mallet, P. Sinay, Synlett 1993. 522-524. [57] G. Rubinstenn, J. Esnault, J.-M. Mallet, P. Sinay, Tetrahedron:Asymmetry 1997,8, 1327-1336. [58] A. Chenede, E. Perrin, E. D. Rekai', P. Sinay, Synlett 1994, 420-422. [59] (a) D. Mazeas, T. Skrydstrup, 0. Doumeix, J.-M. Beau, Angew. Chem. 1994, 206, 1457; Angew. Chem. Znt. Ed. Engl. 1994, 33, 1383-1386; (b) T. Skrydstrup, D. Mazeas, M. Elmouchir, G. Doisneau, C. Riche, A. Chiaroni, J.-M. Beau, Chem. Eur. J. 1997,3, 1342-1356. [60] (a) A. De Mesmaeker, P. Hoffmann, B. Ernst, Tetrahedron Lett. 1988, 29, 6585-6588; (b) A. De Mesmaeker, P. Hoffmann, B. Ernst, Tetrahedron Lett. 1989, 30, 57-60; (c) C. Lesueur, R. Nouguier, M. P. Bertrand, P. Hoffmann, A. De Mesmaeker, Tetrahedron 1994, SO, 53695380. [61] (a) Y. Chapleur, N. Moufid, J. Chem. Soc., Chem. Commun. 1989, 39-40; (b) R. J. Ferrier, P. M. Petersen, M. A. Taylor, J. Chem. Soc., Chem. Commun. 1989, 1247-1248; (c) N. Moufid, Y. Chapleur, P. Mayon, J. Chem. Soc., Perkin Trans. 1 1992, 991-998; (d) N. Moufid, Y. Chapleur, P. Mayon, J. Chem. Soc., Perkin Trans. I 1992, 999-1007. [62] V. Pedretti, J.-M. Mallet, P. Sinay, Carbohydr. Res. 1993, 244, 247. [63] P. Mayon, Y. Chapleur, Tetrahedron Lett. 1994, 35,3703-3706. [64] J. C. Lopez, A. M. Gomez, B. Fraser-Reid, J. Org. Chem. 1995, 60, 3871-3878. [65] A. M. Gomez, J. C. Lopez, B. Fraser-Reid, J. Org. Chem. 1995, 60, 3859-3870. [66] A. De Mesmaeker, P. Hoffmann, T. Winkler, A. Waldner, Synlett 1990, 201-204. [67] C. Audin, J.-M. Lancelin, J.-M. Beau, Tetrahedron Lett. 1988, 29, 3691-3694. [68] M. E. Jung, S. W. T. Choe, Tetrahedron Lett. 1993, 34, 6247-6250. [69] T. Skrydstrup, 0. Jarreton, D. Mazeas, D. Urban, J.-M. Beau, Chem. Eur. J. 1998, 4 , 655671. [70] J.-C. Wu, Z. Xi, C. Gioeli, J. Chattopadhyaya, Tetrahedron 1991, 47, 2237-2254. [71] S. Shuto, M. Kanazaki, S. Ichikawa, N. Minakawa, A. Matsuda, J. Ory. Chem. 1998, 63, 746-754. [72] A. M. Horneman, I. Lundt, I. Sstofte, Synlett 1995, 918-920. [73] (a) B. Fraser-Reid, R. Tsang, in Strategies and Tactics in Organic Synthesis (Ed.: T. Lindberg), Academic, New York, 1989, 2, 123-162; (b) K. J. Henry, Jr., B. Fraser-Reid, J. Org. Chem. 1994,59, 5128-5129.
516
6.3 Radicals in Carbohydrate Chemistry
[74] R. A. Alonso, G. D. Vite, R. E. McDevitt, B. Fraser-Reid, J. Org. Chem. 1992, 57, 573-584. [75] J. Marco-Contelles, C. Alhambra, A. Martinez-Grau, Synlett 1998, 693-699. [76] B.-W. A. Yeung, J. L. Marco-Contelles, B. Fraser-Reid, J. Chem. Soc., Chem. Commun. 1989, 1160-1162. [77] J. K. Dickson, Jr., R. Tsang, J. M. Llera, B. Fraser-Reid, J. Org. Chem. 1989,54, 5350-5356. [78] S. Hanessian, Total Synthesis of’ Natural Products: The Chiron Approach, Pergamon, New York, 1983. [79] R. J. Ferrier, S. Middleton, Chem. Rev. 1993, 93, 2779-2831. [80] C. S. Wilcox, L. M. Thomasco, J. Org. Chem. 1985, 50, 546-547. [81] T. V. RajanBabu, Ace. Chem. Res. 1991,24, 139-145. [82] C. S. Wilcox, J. J. Gaudino, J. Am. Chem. Soc. 1986, 108, 3102-3104. [83] T. V. RajanBabu, T. Fukunaga, G. S. Reddy, J. Am. Chem. Soc. 1989, 111, 1759. [84] P. A. Bartlett, K. L. McLaren, P. C. Ting, J. Am. Chem. Soc. 1988, 110, 1633-1634. [85] N. S. Simpkins, S. Stokes, A. J. Whittle, J. Chem. Soc., Perkin Trans. 1 1992, 2471. [86] S. Hanessian, R. Leger, J. Am. Chem. Soc. 1992, 114, 3115-3117. [87] (a) E. J. Enholm, A. Trivellas, J. Am. Chem. Soc. 1989, 111, 6463-6465; (b) E. J. Enholm, H. Satici, A. Trivellas, J. Org. Chem. 1989, 54, 5841-5843. [88] (a) A. Bioron, P. Zillig, D. Faber, B. Giese, J. Org. Chem. 1998, 63, 5877-5882; (b) S. Bobo, I. S. de Gracia, J. L. Chiara, Synlett 1999, 1551-1554 and references cited therein. [89] E. Untersteller, B. Fritz, Y. Bleriot, P. Sinay, C. R. Acad. Sci. Paris, t.2, Serie II c 1999, 429433. [90] H. Redlich, W. Sudau, A. K. Szardenings, R. Vollerthun, Carbohydr. Res. 1992, 226, 57-78. [91] J. Marco-Contelles, L. Martinez, A. Martinez-Grau, C. Pozuelo, M. L. Jimeno, Tetrahedron Lett. 1991, 32, 6437; J. Org. Chem. 1992, 57, 2625. [92] E. Maudru, G. Singh, R. H. Wightman, J. Chem. Soc., Chem. Commun. 1998, 1505-1506. [93] A. M. Gomez, G. 0. Danelon, S. Valverde, J. C. Lopez, J. Org. Clzem. 1998, 63, 9626-9627. [94] J. P. Guidot, T. Le Gall, C. Mioskowski, Tetrahedron Lett. 1994,35, 6671-6672; see also J. L. Chiard, M. Martin-Lomas, Tetrahedron Lett. 1994, 35, 2969-2972. [95] L. Somsik, R. J. Ferrier, Adu. Curb. Chem. Biochem. 1991, 49, 37-92. [96] R. J. Ferrier, R. H. Furneaux, J. Chem. Soc., Chem. Commun. 1977, 332-333. [97] T. Chiba, P. Sinay, Curbohydr. Res. 1986, 151, 379-389. [98] M. D. Smith, D. D. Long, A. Martin, N. Campbell, Y. Bleriot, G. W. J. Fleet, Synlett 1999, 1151-1153. [99] (a) F. W. Lichtenthaler, P. Jarglis, Angew. Chem. 1982, 94, 643; Angew. Cllem. Znt. Ed. Engl. 1982,21, 625; (b) J.-P. Praly, L. Brand, G. Descotes, L. Toupet, Tetrahedron 1989, 45, 41414152. [ 1001 F. Chretien, M. Khaldi, Y. Chapleur, Synth. Commun. 1990, 20, 1589-1596. [ 1011 S. Hanessian, N. R. Plessas, J. Org. Chem. 1969, 34, 1035-1044. [lo21 R. J. Ferrier, R. H. Furneaux, Aust. J. Chem. 1980,33, 1025-1036. [lo31 N. J. Newcombe, M. F. Mahon, K. C. Molloy, D. Alker, T. Gallagher, J. Am. Chem. Soc. 1993, 115, 6430-6431. [I041 R. A. Alonso, C. S. Burgey, B. V. Rao, G. D. Vite, R. Vollerthun, M. A. Zottola, B. FraserReid, J. Am. Clzenz. Soc. 1993. 115. 6666-6672. [I051 (a) A. V. Veit, B. Giese, Synlett 1990, 166; (b) A. Ghosez, T. Gobel, B. Giese, Chem. Ber. 1988. 121. 1807. [ 1061 (a) F. Santoyo-Gonzilez, F. G. Calvo-Flores, P. Garcia-Mendoza, F. Hernandez-Mateo, J. Isac-Garcia, R. Robles-Diaz, J. Org. Clzem. 1993, 58, 6122-6125; (b) S. Czernecki, D. Randriamandimby, Tetrahedron Lett. 1993, 34, 791 5-7916. [lo71 Z. J. Witczak, S. Czernecki, Adu. Carb. Chern. Biochem. 1998, 53, 143-199. [ 1081 F. Santoyo-Gonzalez, F. G. Calvo-Flores, F. Hernandez-Mateo, P. Garcia-Mendoza, J. IsacGarcia, D. PCrez-Alvarez, Synlett 1994, 454-456. [I091 R. L. Whistler, C.-C. Wang, S. Inokawa, J. Org. Chem. 1968, 33, 2495-2497. [ 1 101 J. Kovensky, M. McNeil, P. Sinay, J. Org. Chem. 1999, 64, 6202-6205. [ l l l ] K. Igarashi, T. Honma, J. Org. Chem. 1970, 35, 606-610. [ I 121 B. Giese, J. Burger, T. W. Kang, C. Kesselheim, T. Wittmer, J. Am. Chem. Soc. 1992, 114, 7322-7324.
References
577
[ 1 131 K. V. Laak, H.-D. Scharf, Tetrahedron Lett. 1989, 30, 4505-4506. [ 1 141 (a) J.-P. Praly, G. Descotes, Tetrahedron Lett. 1982,23, 849-852; (b) J.-P. Praly, G. Descotes, M.-F. Grenier-Loustalot, F. Metras, Carbohyclv. Res. 1984, 128, 21-35. [ 1151 G. Descotes, H. ldmoumaz, J.-P. Praly, Carbohydr. Rex 1984, 128, 341-344. [ 1161 (a) A. Martin, J. A. Salazar, E. Suarez, Tetrahedron Lett. 1995, 36, 4489-4492; (b) D. L. Dorta, A. Martin, J. A. Salazar, E. Suarez, T. Prange, Tetrahedron Lett. 1996, 37, 60216024; (c) A. Martin, J. A. Salazar, E. Suarez, J. Org. Chem. 1996, 61, 3999-4006. [ 1 171 C. Chatgilialoglu, T. Gimisis, G. P. Spada, Chem. Eur. J. 1999, 5, 2866-2876. [I181 C. Bernasconi, L. Cottier, G. Descotes, M. F. Grenier, F. Metras, Nouu. J. Chem. 1978,2, 79. (1191 R. W. Binkley, J. Org. Chem. 1977, 42, 1216-1221. [120] (a) J.-P. Praly, Tetrahedron Lett. 1983, 24, 3075S3078; (b) B. Giese, J. Dupuis, Tetrahedron Lett. 1984,25, 1349-1352. [121] J. Auge, S. David, Carbohydr. Res. 1977, 59, 255-257. [122] (a) D. Crich, T. J. Ritchie, J. Chem. Soc., Chem. Commun. 1988, 1461-1463; (b) D. Crich, T. J. Ritchie, J. Chem. Soc., Perkin Trans. 1 1990, 945-954; (c) D. Crich, F. Hermann, Tetrahedron Lett. 1993, 34, 3385-3388; (d) D. Crich, J.-T. Hwang, H. Yuan, J. Org. Chem. 1996,61, 6189-6198. [I231 D. Kahne, D. Yang, J. J. Lim, R. Miller, E. Paguaga, J. Am. Chem. SOC.1988, 110, 8716-87 17. [124] Y. Wang, S. A. Babirad, Y. Kishi, J. Org. Chem. 1992, 57, 468-481. [I251 D. Crich, L. B. L. Lim, Tetrahedron Lett. 1990, 31, 1897-1900. [I261 F. Baumberger, A. Vasella, Helv. Chim. Acta 1983, 66, 2210-2222. [I271 (a) C . R. Petrie 111, M. Sharma, 0. D. Simmons, W. Korytnyk, Carbohydr. Rex 1989, 186, 326-334; (b) W. Schmid, R. Christian, E. Zbiral, Tetrahedron Lett. 1988, 29, 3643-3646. [I281 N. Yamazaki, E. Eichenberger, D. P. Curran, Tetrahedron Lett. 1994, 35, 6623--6626. [I291 D. Crich, S. Sun, J. Brunckova, J. Org. Chem. 1996, 61, 605-615. [ 1301 J. Brunckova, D. Crich, Q. Yao, Tetrahedron Lett. 1994, 35, 6619-6622. [I311 A. L. J. Beckwith, D. Crich, P. J. Duggan, Q. Yao, Chem. Rev. 1997, 97, 3273-3312. 11321 (a) B. Giese, K. S. Groninger, T. Witzel, H.-G. Korth, R. Sustmann, Angew. Chem. 1987, 99, 246; Angew. Chem. Int. Ed. Engl. 1987,26, 233-234; (b) B. Giese, S. Gilges, K. S. Groninger, C . Lamberth, T. Witzel, Liebigs Ann. Chem. 1988, 615-617; (c) H. G. Korth, R. Sustmann, K. S. Groninger, M. Leisung, B. Geise, J. Org. Chem. 1988, 53, 4364-4369. 11331 (a) A. Koch, B. Giese, Helv. Chim. Acta 1993, 76, 1687-1701; (b) D. Crich Q. J. Yao, J. Am. Chem. SOC.1993, 115, 1165. 11341 A. Koch, C. Lamberth, F. Wetterich, B. Giese, J. Org. Chem. 1993, 58, 1083-1089. [I351 D. H. R. Barton, J. A. Ferreira, J. C. Jaszberenyi, Free Radical Deoxygenation of Thiocarbonyl Derivutives of Alcohol, in Preparative Carbohydrate Chemistry (Ed.: S. Hanessian), Marcel Dekker, 1997, Chap 8. 11361 R. W. Binkley, Adt. Curb. Chem. Biochem. 1981, 38, 105-193. 11371 M. Trumtel, P. Tavecchia, A. Veyrieres, P. Sinay, Carbohydr. Rex 1989, 191, 29-52. 11381 0. R. Martin, W. Lai, J. Org. Chem. 1990, 55, 5188-5190. [ 1391 L. Petrus, J. N. BeMiller, Carbohydr. Res. 1992, 230, 197. [I401 M. Brakta, P. Lhoste, D. Sinou, J. Banoub, Carbohydr. Res. 1990, 203, 148-155. [I411 0.Jarreton, T. Skrydstrup, J.-M. Beau, J. Chem. Soc., Chem. Commun. 1996, 1661-1662. [142] D. Urban, T. Skrydstrup, J.-M. Beau, J. Chem. Soc., Chem. Commun. 1998, 955-956.
Radicals inb Organic Synthesis Edited by Philippe-Renaud and Mukund P. Sibi copyright@WILEY-VCH Verlag GmbH. D-69469 Weinheim 2001
Index
A-strain (see allylic strain) 434 ab initio calculation 25, 339,345, 35 1,354, 356, 390, 393, 396 Acceptors 229,232, 233, 240 1,2-Acetoxyshift 101 N-Acetylglucosamine 52 Acetyl peroxide 6 Acromelic acid A 146 Acrylates 480,482, 484 Acrylamides 489,491,493,495 Activation energy 364, 37 1 Acyclic a-hydrogen-bearing nitroxide 482 Acyl cobalt 143 Acyl radical 55, 84-87,99, 103, 143, 331, 435 - formation 84-87 Acyl selenide 15, 84 Acyl telluride 86 S-Acyl xanthate 103 N-Acyl pyrazole 472 0-Acylthiohydroxamate 109, 110, 11 1, 112, 113, 114, 115, 116, 117, 118, 119, 120, 122, 123, 126, 127, 129 - addition to alkene 122 - addition to alkyne 123 - addition to protonated heteroaromatics 127 - carbon-heteroatombond formation 112 - cyclization I29 - decarboxylation 111 - formation of nor- alcohol 1 18 - formation of aldehyde 119, 126 - formation of nor-alkane 111
formation of alkyl-2-pyridyl sulfide 113, 123 - formation of nor-hydroperoxide 118 - formation of S-pyridyl alkylthiosulphonate 120 - preparative method 110 - selenocyanation 115 - with ally1 thioether 129 -with diselenide 114 - with disulphide 114 - with ditellurides 114 - with tris (phenylthio) antimony 118 - with tris (phenylthio) phosphorus 117 Acyloxyl radical 323 Addition reactions 369, 370, 371, 445,446, 450-452,456 - diastereoselective 370 - intramolecular 37 1 - intermolecular 369 Additive effects 403 Alcohol 118,237,240,241 Aldehyde 119, 126,238 Aldol reaction 17, 437 Alkaloid synthesis 366 Alkenes 191, 192, 394 - captodative 369, 374, 376 - chiral, as acceptors 394 - 1,l-dialkyl 191 - norbornene 191, I92 - terminal 191 Alkenylgermane 12 2-Alkenylthioanilide 12 Alkoxycarbonyl radicals 99, 103 -
502
Index
Alkoxyl radical 19, 157, 332 Alkoxythiocarbonyl radicals 99 Alkyl iodides - cyclohexyl iodide 188, 189, 190 - homoallylic iodide 189 - iodoacetal 188, 189 - iodonitrile 188 - octyl iodide 188 , 189, 190 Alkyl-2-pyridyl sulfides, by decarboxylative rearrangement 1 13, 123 Alkynylation 64 a-Alkylseleno-acrylonitrile 374 a-Alkylthio-acrylonitriles 374, 375 Allene 375 Allenylation 60 (-)-a-Allokainic acid 145 Allyl cobaloximes 67-68 Allyl ethyl sulfone 63-64 Allyl halides 68 Allyl sulfides 61-63 Allyl sulfoxides 62, 63 Allyl sulfones 62, 63, 106 Allyl transfer 491,495,498 Allylation 51-59, 61-68, 77, 106, 391,400,
401,409,443-446,449,450,452,456, 463 diastereoselective 52, 53,55,66, 77 - enantioselective 53, 67,463 - polar effects 54, 57 - rate constant for 53-54 Allylic strain (see A-strain) 38 I , 385, 389, 395,402,407,434,443,452,494 - substituents that will induce 389 Allylic 1,3-strain 443,452 Allylic sulfone 223 Allylsilanes 419, 433,465 Allylstannanes 419,43 1,433 Allyltributyltin (allyltributyl stannane) 51-57,59, 77,443, 491 - 2-acetoxy 57 - 2-chloro- 57 -2-cyano- 57 - derivatives 56-59 - polymer-supported 59 - 2-methyl- 56 - 2-trimethylsilyl- 57 -
- 2-(trimethylsilyl)methyl-
57 Allyltrimethyl silane 65-67, 77, 444,446 Allyl tris(trimethylsi1yl)silane 67 Alternating polymer 497,498 Ambiphilic radicals 77, 84,85 Amide chlorides 362 Amidyl radical 332 Amine 229,230,231,232,234,237,239, 240,245 Amine-boryl radicals 476 Amines, from carboxylic acids 12 1 Amino acids 52,60, 1 15,407,424,431 a-Amino acids 370 Amino alcohols 164 a-Amino-a-methyl carbonyl radical 361 a-Amino radicals 157 Aminyl radicals 122, 131, 332, 347,348 - generation 122, 131 Ammonium ylids 363 (-)-Anastrephin 169 Anion oxidation 36 1, 368 Anodic addition 274, 278, 280 - enolates 274 - intramolecular 280 - organometallics 278 - carboxylates 278 Anomeric effect 344, 409ff - quasi-homo 409 Anomeric radicals 154 Aqueous media 23 Arndt-Eistert reaction 125 Aromatic substitution 21 3-Aryl- 1-propanol 374 Aryl cation proposal 300 Aryl chalcogen 72, 83-87 Aryl radicals 159 0-Aryldithiocarbonates 91, 92 Aspidospermidine 303 Asymmetric induction 165, 405 - 1,2- 165 - 1,3- 165 - 1,4- 405 Atom or group transfer reactions 21, 22, 23, 24, 67, 72-73, 74, 76, 80-83, 141, 146, 176, 191, 192, 366,419,443,445,456, 473
Index Atom Transfer Radical Polymerization 479, 482,483,485 ATRP see atom transfer radical polymerization Auxiliaries see chiral auxiliaries Avenaciolide 203 Azidation 409 Azide 409 Azobis(isobutyronitri1e) (AIBN) 3, 11, 14, 15, 16, 17, 19, 23,24, 73, 83, 85, 322, 481,483 - initiation 48 I , 483 4,4’-Azobis(4-~yanopentanoic acid) (V-501) 4
503
Bond dissociation energies 361 Borohydride exchange resin (BER) 187 Boron enolate 17, 21 a-Bromo oxazolidinone 22 9-Borobicyclo[3.3.llnonane (9-BBN) 6,26 Boron trifluoride 353 Botryodiplodin 401 Brevicomin 136, 265 Bridgehead radical 52 Bromo acetal 137 a-Bromo ester 191 Bromine transfer 74,77, 80-82 Bromotrichloromethane 8 1, 85, 185 Bromomalononitrile 8 1, 82 2,2’-Azobis(4-methoxy-2,4-dimethylN-Bromophthalimide 404 valeronitrile) (V-70) 3 N-Bromosuccinimide 366 (2RS,2’RS)-Azobis(4-methoxy-2,4-dimethylBrook rearrangement 414 valeronitrile) (V-70L) 3 3-Bromo-propyl-vanillyl ether 374 2,2’-Azobis(2-methylpropionamidine) Bu,SnH (see tributyltin hydride) 183, 185, dihydrochloride (V-50) 4 190,443,452 Azomethine ylid 364 3-Butenyl radical 327 tert-Butoxyl radical 318, 332 Barton Esters. see 0-Acylthiohydroxamates tert-Butyl hydroperoxide 50 62, 109,438 4-~ert-Butyl-2-methylcyclohexyl radicals Barton’s hydroxy thiopyridone 34 342 Barton-McCombie reaction 90, 91, 92, 93, tert-Butyl perbenzoate 6, 367 94,95,96,97, 101, 109 tert-Butyl peroxide 7, 368 Barton’s PTOC ester 323, 324 a-tert-Butylthio-acrylonitrile 369 Benzenethiol 12 Butyrolactone 78, 8 1, 82, 198, 204 Benzeneselenol 323,326 - formation 78, 81, 82 Benzo[a]quinolizidine 15 Benzofurans 61, 141 Camphorsulfonic acid 48 1,482 Benzosuberyl methacrylate 499 Captodative alkene 369, 374, 376 Benzoyl peroxide 6, 11,75,76,48 1 Captodative aromatic compound 372 - initiation Captodative radical 85 Beyer-15-ene-3,19-diol 21 1 a-Carbalkoxy radicals 53 BER-Ni2B(cat.) 187-192 Carbamoyl radical 302 - reductions 187 Carbanion oxidation potential 36 1 Bicyclic 449,450,455 Cprbanions 289 Bicyclopropylidene 376 Carbamoyloxy radical 52 Bidentate chelation (also see complex) 464 Carbocation 282 BINAPO 467 Carbocycle 157, 159, 161, 173 BINOL 463,466,468,475 Carbon monoxide 55 Biradical 232, 233 Carbonylation 55 Bisoxazolines 464,465,469,470,473 Carbonylation of radical 201 Block copolymers 482, 484, 485 Carbohydrate 90, 94, 221
504
Index
Carbohydrate-based 437 Carbohydrate C-analog 22 1 4-Carboxy-oxazoline 367 4-Carboxy-thiazoline 367 Carboxylic acids, anodic decarboxylation 259 Cascade reactions 373 Catalytic turnover 298, 312, 314 Cathodic addition, intramolecular 285 Cathodic cyclization 285 C-C Bond formation 32, 219-221, 223-227 Cerium(1V) ammonium nitrate (CAN) 66, 219-222 Cerium(1V)-mediated radical reactions 219-222 CH-acidic compounds 219-222,224-225 Chelate 443-446, 449-45 1 Chelation 426 Chelation-control 165, 169, 444,445,446, 447,450,45 1 Chiral alkenes as acceptors 394 Chiral auxiliary 52, 53, 55, 84, 85, 166, 208, 369,416,420,421,424,426,427, 429,431,432,435,436,437,443,455, 456, 457, 458,459,489,489, 490, 493, 495,496,498 - acetal-based 437 - alkenes bearing 420 - carbohydrate-based 437 - carboxamides 421 -ester 435 -ether 437 -imides 421 - N-methylephedrine 166 - radicals bearing 429 - Oppolzer’s camphorsultam 424, 496 - oxazolidines 43 1 - oxazolidinone 369,426, 427,432,455, 456,490,495,498 - 8-phenylmenthol 84, 85,208,436,456, 457 - sulfinyl auxiliaries 208 Chiral dioxolanone 369 Chiral glycine compounds 366 Chiral ligands 67, 166, 174,437,462,463, 464,465,466,467,468,469,470,472,
473,474,475 - BINOL 174,463,466,468,475
BINAPO 166,437 bisoxazolines 464,465,469,470,473 -DBFOX/Ph 472 - diamines 462,469 -DIOP 474 - Sulfonamides 467 -TADDOL 466 Chiral stannanes 35 1 Chiral tin hydride 475 Chlorination 201,362 Chlorine atom transfer 74, 82, 83, 366 a-Chloro-a-thioacetamide 366 Chloromethylstyrene 48 1 Chlorotrifluoroethylene 375 Cholic acid 351, 352 Chromium tricarbonyl complexes 162, 164, 167, 171 Chugaev elimination 9 1 CINDP 363 Cob(I)alamin (B,2d) 136 Cobaloxime 141, 145 Cobalt group transfer reactions 141, 146 Cobalt-initiated radical reactions 135 Combinatorial chemistry 160 Competition experiments 445 Complex 442-446,449,450,454,458,464 - bidentate (see chelate) 442-445, 454 - monodentate 442-445, 449 Concerted asynchronous mechanism 376 Conformation 403 Conjugate addition 11, 16, 17, 154, 235, 463,470 Conocarpan 2 12 Conversion 485 Copolymers 105, 370 Copolymerization 497,498 Copper (I) chloride 82 Copper(I1) acetate 225-226 Copper(l1)-mediatedradical reaction 225-226 Corey-Fuchs reaction 106 Corey lactone 85 Coupling 223,402 - intermolecular-223
-
-
Index - intramolecular 223 - oxidative 226, 227
Coupling reaction 229,230, 232, 233, 234, 236 -arene 233 - fullerene 234 - phenanthrene 233 -pinacol 237 Cram cyclic model 446, 447, 449 Cram-chelate 443 Cross-coupling 143 C-S bond formation 222 Cu(OAc), 198, 199, 200 - oxidation of radicals to alkenes by 200 Cumyloxyl radical 332 Cuprous chloride-bipyridine 366 Curtin-Hammett principle 396 2-Cyano-1-aza- 1,3-butadienes 376, 377 Cyanopyrrolin 374,375 Cyclization 75,77, 100, 136, 148, 149, 184, 193,206, 208-216, 220, 222, 223, 224, 225,229, 232, 233, 237, 238, 239, 243, 244,245, 262,275,278,280,281,286, 30 1, 3 19, 326, 328, 329, 343, 346,372, 373,374,446,449,457,458,474 - antifungal 239 - cyclohexanol 238 - cyclopentanoid 238 - cyclopentanols 238 - diastereoselective 208-216 - 5-endo 184,372 - 6-endo 100, 136,209,339,348 - 7-endo 149,372 - 8-endo- 100,346 - 3-exo-319, 326, 328 - 4-exo-184, 3 19,372,373 -5-exo 75, 77, 136, 148, 149, 184, 193, 209,212,215,222,224,225,262, 275, 278,280, 286, 319, 328, 329,338, 346, 348,366, 371,373,374 - 5-exo-trig-ips0 374 - 6-exo 149,343,346,348, 372,373 -iridoid 238 - isocarbacyclin 238 - piperidine 238 - pyrrolidine 238
505
- quadruple 209-2 1 1
stereoselective 301 -tandem 208,281,301 - triple 209-2 11 Cyclization of - a-haloamides 184, 185, 186,I93 - haloethers 193 Cyclization reactions 137, 337, 339, 340, 34 I , 342, 343, 344,345, 346,348,366, 373,402 - (alkoxycarbony1)methylradicals 346 - atom transfer 366 - chemoselective 373 - cyclobutyl radicals 342 - diastereoselectivity 342, 343, 344 - 6-heptenyl radical 339, 340 - 5-hexenyl radical 337,338, 339, 340, 341,348 - homolytic substitution 344, 345 - macrocyclization 344 - tandem reactions 342, 343, 344 - 6-methylenecyclodecy1radical 344, 345 - N-methylpent-4-enylaminyl radical 348 - 7-octenyl radical 339,340 - pent-4-en- 1-oxyl radical 348 - substituted radicals 339, 340, 341 - Thorpe-Ingold effect 342 - Ueno-Stork reaction 346,402 -vitamin B,, as reagent 137 Cycloaddition reactions 374, 376, 377 -[2+2] 374 -[3+2] 376 -[4+2] 376 Cycloalkanol 17 Cyclobutane 242,372, 374 Cyclobutylcarbinylradical 327 Cyclodimerization 364,375 Cyclohexadienyl radical 374 Cyclohexanes, synthesis 102-103 Cyclohexyl radical 402 (+)-Cyclomyltaylan-5a-ol 169 Cyclopentenes 364, 365 Cyclopentylmethyl radical 3 19 Cyclopentyloxylradical 332 Cyclopropane 242,243 Cyclopropane opening 94 -
506
Index
Cyclopropanes cis-trans isomerizations 364 Cyclopropylcarbinyl radical 175, 3 18, 3 19, 327,330 Cyclopropylmethyl radicals 364, 365 Cyclovoltammetry 254 DBFOXPh 472 Deamination 33,40 DCA 229,234,238 DCN 229,230,23 1,238 Decarbonylation 39, 33 I Decarboxylation 34, 1 1 1, 130,402,409 - Kolbe electrolysis 402 Decarboxylative 112, 113, 117, 118, 119, 121, 123 - amination 121 - halogenation 1 12 - hydroxylation 1 18 - iodination 1 12 - Nor-halide formation 1I2 - nitrosation 12 1 - phosphonylation 117 -rearrangement 113, 119, 123 - sulfonation 1 19 Degenerative chain transfer 99 Dehydro -cobatlation 143 Dehydroiridodiol 12 3-Demethoxyerythratidinone 60 Dendrimers 482 Denitration 34 Density functional 355 Deoxygenation 33,40, 41,45, 90, 13 1 - of tertiary alcohols vin mixed oxalate esters of thionohydroxamic acid 131 2’-Deo~y[2’-~H]ribonucleoside 15 Deselenization 33, 39 Desoxy-sugars 101 Desulfurization 33,45, 124 Dexanthylation 101 Diacetyl peroxide 72 Dialkylaminium cation radical 332 Dialkylaminyl radical 332 Dialkylphosphites 46 y-Dialkoxy acid derivatives 190 Diamines 462,469 Diastereoselective allylations 77
Diastereoselective atom transfer additions 79,84 Diastereoselective cyclizations 208-2 16 Diastereoselective heterocoupling 269, 273 Diastereoselective radical reaction 44 1,458 - intermolecular 443,447,451,457 - intramolecular 443,446,447,449,456, 457 - kinetically-controlled 441,452 Diastereoselectivity 342, 343, 344 - allylic strain 402,407 - 1 &asymmetric induction 405 - conformation 403 - cyclic radicals 400 ff - exocyclic substituents - 4-membered ring 400 - 5-membered ring 401 - 6-membered ring 402 - polycyclic systems 413ff - reactivity-selectivity principle 4 1Off -torsional effects 402 -transition state position 410 Diastereotopic faces 421 Diazadithiafulvalenes 3 13 Diazonium salts 299-3 15 - -chlorides 3 11 gem-Dibromide 400,401 Dictamnol 176 1,3-Dienes 482 Diethylzinc 26,425 Dihydrobenzofurans 2 12 Dihydrofurans 205 Dihydropallascensin D 2 12, 2 13 Dihydroisoquinolones, synthesis 104 Diketone 163, 205 - Coupling I63 a,a-Dimethylallyl phenyl sulfide 50 y,y-Dimethylallyl phenyl sulfide 50 Dimethylamino-acetonitrile 362 2,5-Dimethylpyrrolidine 422, 425,430 3-Dimethylstannyl-24-nor-5~-cholane 352 7-Dimethylstannyl-24-nor-5~-cholane 352 12-Dimethylstannyl-24-nor-5~-cholane 352 Diphenyl diselenide 87, 184, 185 Diphenylmethyl oxazolidinone 427 threo-Diols 161
Index DIOP 474 1,3-Dioxolan-4-ones 367 1,3-Dipoles 364 Dipolar interaction-496 Dipole-dipole interactions 385,424 Dipole-dipole repulsion 443 Dipolarophiles 376 Diquinane 95 1,3-Diradical 364 Diradical coupling 160 Diradicaloid transition state 369, 376 C-Disaccharide 262,406 9,lO-Disilaanthracenes 42 Dispersion polymerization 481 Dissociation 230, 234, 235 - allylsilane 235 - benzylsilane 235 - silane 235 - silylmethylamine 235 Di-tert-butyl peroxide 100 Dithiocarbamates 105 Dithioesters 105 Dithiooxamide 362 Donor 229,232,233 Electroanalysis 254 Electrochemistry, Kobe electrolysis 402 Electrode 256 Electrolysis 251, 256, 258 - cells 251, 256, 258 - preparative scale 256 Electrolyte 252, 253 Electron transfer 298 Electronic effect 329,44 1,443 - on kinetics 329 Electronic enhancement 452 Electron-withdrawing effect 445,452 Electrophile 298 Electrophilic radicals 73, 76, 221 P-Elimination 160 Electroreductive reaction 193 Emulsion polymerization 48 1,484 Enamine 402 Enantioselectivity 35 I , 352, 353 Enantioselective radical reactions 46 1, 462, 463,470,473,474,475,476,477
507
allylations 463 atom-transfer 473 - conjugate additions 463, 470 - cyclizations 474 -hydrogen atom abstraction 476 - hydrosilation 477 - imine additions 473 - reductions 462, 475 Endocyclic effect 443,446,454,458 Enediols 482 Enone 229,235 Enthalpy effects on kinetics 329 Entropy effects on kinetics 328 (-)-Epianastrephin 169 Epilupidine 414 Epoxides 146 - Co(1) nucleophilic opening 146 Erigerol 173 ESR 325,332,382,393 -kinetic method 325 - steady state 325 - time-resolved 325, 332 Estafiatin 214 Ester 229, 239, 241 Ester-substituted radicals 382, 395 Ether 234 Ethyl radical 19, 20, 21 Ethyl vinyl sulfones 64 Exocyclic substituents 406 Exocyclic effect 452, 458 Eyring plots 49 1, 496 -
Facial selectivity 443,449, 458 Felkin-Anh 84, 393, 396, 398, 446 - model 393,396,398 - transition state 84 Ferrocene complexes 162, 164 Ferrocenium ion 223 2-Fluoro- 1-methylpyridinium p-toulenesulfonate 48 I , 482 Fluorous extraction 59 Force field methods 337, 338, 339, 340, 341,342,344,345,351 - Beckwith-Schiesser model 340, 341, 342, 344,345,35 1 - MacroModel 341
508
Index
-MM2 338,339 -MM3 343 - Molecular mechanics 338 - Spellmeyer-Houk model 339,340 Forskolin 139, 161 Fragmentation 17, 186,237,239,240,241, 242,242,243 - arenesulfonyl 239 - carbohydrate 24 1 - cyclopropyl ketone 243 - deoxysugar 24 1 - disaccharide 242 - epoxyketone 242 - erianolin 242 - organometallic 234 - oxanorbornanone 242 - perfluoroester 241 - ptilocaulin 243 - tosylate 240 - trichodermol 24 1 Frontier molecular orbital theory 360 Functional group interconversion 25 1 Galvinoxyl 16 Geminal diphosphonates 84 Germanium hydride 45 Germyl enolate 2 1 Glycal 221 Glycosides 52 C-Glycoside 136, 157,409 Glycoside radical 437 a-D-Glycosyl-(R)-alanine 370 Glyoxylate imine 19 Glyoxylic oxime ether 19 Grayanotoxins 162, 171 Gymnomitrol 212,213 Halide 229,238,239, 240 a-Haloamides 184, 185, 186, 191, 193 - N-alkenyltrichloroacetamide 184 - N-allyl-a-bromoamide 193 - a-bromoamide 191 - dimethylbromoacetanilide 184 - trichloroacetamide 184, 185 - haloanilide 184, 186 Haloethers 193
Halogen atom transfer 80, 191, 192 Halogen reduction 33,38, 42,45 Halogenation 366 Heck reaction 143 Helical polymer 499 Heterocoupling 265,268,269,273 - carboxylic acids 265,268 - Diastereoselective 269, 273 Heterocycles 1.56, 159, 170, 173 Hexamethyl distannane 74, 77, 78 Hexabutyldistannane 75-76, 78, 80, 87 5-Hexenyl radical 319, 327, 337, 338, 339, 340,341,348 HMPA 238,24 1,245 HOMO 442 Homocoupling 259,263,264,266,284 - carboxylic acids 259 - cathodic 284 - cathodic: aldehydes, ketones, imines 284 - cathodic halides 284 - enolates 263 - organometallics 264 - phenolates 264, 266 Homologation of carboxylic acids via 0-Acylthiohydroxamate 125 Homolytic addition 337, 340, 341, 342 Homolytic substitution 73, 74, 357 Homopolymers 370 Hunsdicker reaction 112 Hydrodimerization reactions 174 Hydrogen atom abstraction 30, 56, 382, 476 1,5-Hydrogen atom abstraction 446 IS-Hydrogen atom shift 101 Hydrogen donor 30,441 Hydrogen transfer reactions 349, 350, 35 I , 352,353 - diastereoselectivity 350 - 1,3-dioxolan-4-onyl radical 350 -E' 349,350 -ee-star 349 - enantioselectivity 3.51, 352, 353 - Lewis acid 35 I , 353 Hydrogen transfer see also reduction 443, 445,452,453 Hydrosilation 477
Index
509
Hydrostannylation 11 P-Hydroxyketone 17 Hydroxocobalamin 136 a-Hydroxy acids 370 Hydroxyquinolizidine 414 P-Hydroxy sulfides 95 j3-Hydroxy sulfones 95 Hyperconjugativestabilization 443 Hypophosphorous acid 47,97
ips0 substitution 23 Iron (11) chloride 82 Iron(II1) chloride 223-224 Iron(II1)-mediatedradical reaction 223-224 Isocyanates 167 Isosteviol 2 1 1 Isotactic polymer 490,495,499 10-Isothiocyanatoguaia-6-ene 215 Isothiocyanates 167
Imide 23 1,232,236 Imine additions 473 Iminium 229,235,236,237 Iminium chlorides 362 Iminyl radical 94, 131, 183, 332 - generation 131 Indigo 368 Indirect anodic oxidation 289, 290 - mediator: manganese(II1) 290 - mediator: nickel(II1)oxidehydroxide 289 Indirect cathodic reduction 290, 29 1 - Fenton reaction 290 - mediators: nickel (cyclam), nickel (salen) 290,291 - mediator: vitamin B,, 290 Indole 12,61, 80 Indolines 104, 301 - synthesis 104 Indolizidines 376 Indolones 186 Iniferter Polymerization 479,480 a-Iodoester 77 Initiation 28 Initiators see radical initiators Inner sphere electron transfer 219-220 In situ derivatization 453 Intermolecular 99, 102, 223 - coupling 223 - radical addition 99, 102 Intramolecular coupling 223 Iodine transfer 74-8 I , 83-84 Iodoform - in decarboxylativehalogenation 1 12 Iodomalonate 77-80, 84 Iodomalononitrile 79, 80, 84 IP see iniferter polymerization
Julia olefin synthesis 95 (-)-a-Kainic acid 145 Kaurene 94 a-Ketocarboxylic acids by homologation of carboxylic acids 127 Ketone 201,206,229,231,237,238,242 - from radical addition to nitriles 201 - oxidation to a-keto radicals 206 P-Keto esters 205, 206 P-Keto sulfoxides 206,208 Ketone-olefin coupling 447 Ketyl radical 165, 166, 168, 170, 171, 172, 173,235,238,408,449,467 - 4-ex0 cyclization 168 - 5-endo cyclizations 171 - 5-exo cyclization 170, 173 - 6-ex0 cyclization 170, 173 - 8-end0 cyclizations 172, 173 - enantioselective process 166 Kharasch reaction 195, 196,473,483 - nickel catalysts 196 Kharasch-Curran reaction 419 Kharasch-Sosnovsky reaction 367 Kinetic probe substrates 326 Kinetic resolution 476 Kolbe electrolysis 259, 261, 265, 275, 282, 402 Lactam 82-84, 146 - formation 82-84
P-Lactam 12, 100, 184, 186, 187 y-Lactam 23, 184, 185 y-Lactone 12, 14, 24 Lactic acid 369 Lactone 165, 167
510
Index
Laser flash photolysis (LFP) 325 Lauroyl peroxide 98, 100, 101 Lewis Acid 16, 19, 22,67, 77, 214, 322, 351, 353,403,418,425,432,433, 441 -446,449,451,452,454-459,462, 463,464,465,469,470,472, 473, 474, 497,498 - aluminum 403 -AICI, 463 -AlMe, 446 -BEt, 16 - BF,*OEt, 456 - Bidentate 442-446,451,455,458 - Catalytic amount 442,458 - Chiral 441,443,455,456,498 - Et,AICI 446,452 - La(fod), 446,45 1 - lanthanide triflates 433 -Ln(OTf), 457 - MABR 452,458 - MAD 403,452.458 - MeAI(OPh), 446 -Me,BBr 453 - MgBr, 77,433,442-447,449-451,454, 455,473 - Mg(C10,), 472 - MgI, 433,462, 465,470 - Monodentate 442-445,449 - Ru(I1) 474 - Sc(OTf), 22,456,474,498 - SmI, 447,449,450 - TiCI, 469 - (TMPO),AICI 452 - Yb(OTf), 22,214,427,434,458 - ZnCI,*OEt, 455 - Zn(OTf), 434,464,465,472 Ligand effects 160 Living-radical polymerization 105, 196, 479 LUMO 418,442 Lycoctonine 52 Lycorine 414
Manganese (111) acetate 66 Matrine 101 Medium and large ring 25, 166,446, 449 - 5-Membered ring 446,449 - 6-Membered ring 446,449 - 7-Membered ring 446 Mesodyad 498 a-Methoxy-acetonitrile 368 a-Methoxy-acrylonitrile 376 a-Methoxy-cyanoallene 375 Methyl acrylate 493 Methyl cantabradienate 2 16 3-Methylene-cyclobutanes 375 Methylene-cyclopropanes 364, 365, 376 N-Methyl-A-18-isokoumidine 2 14 Methyl methacrylate 479,480,484, 49 1,497 Methyl a-methoxy acetate 368 a-Methylthio-acetonitrile 368 a-Methylthio-acrylonitrile 376, 377 Methyl vinyl ketone 16, 21 Michler’s ketone 243 Mini-emulsion 48 1 Mn(OAc), based radical reactions 56, 198-218, 385 - initiation 199 - intermolecular reactions 204-206 - mechanism 198 - side reactions 202 - solvents 200 - termination 200 - methallylation 56 - methallyltributyltin 56 - P-methoxy-substituted radicals 385 Mn(picolinate), 200, 2 15 MNDO calculations 369 Molecular mechanics 338 Molecular weight 485 Monodentate binding see also complex 467 a-Morpholino-acrylonitrile 360, 369 a-Morpholino-ketone 368 Monomer 489
Macrocyclization 60 Magnesium bromide diethyl etherate 66 Malonate 221, 223
N-Centered radical 33 1 Narrow polydispersity resins 480, 485 Natural product synthesis 21 1, 261
Index Neighbouring group participation 305 - by N-ally1 group 302
Neophyl radical 327 Neotripteriforin 94 Nickel catalysts for Kharasch reaction 196 - Ni(NCN)Cl 196 - Ni(NCN)Br 196 - NiBr,(PPh,), 196 - NiBr,(Pn-Bu,), 196 Nickel catalysts for electroreductive reaction 193 - [Ni(cyclam)]*'(ClO,-), 193, 194 - [Ni (CR)]2'(CI0,p), 193, 194 - [Ni (tet a)]z'(C10,p)2 193, 194 Nickel boride (Ni,B) 187 Nickel powder-acetic acid 183-187 Nitriles, from carboxylic acids 121 Nitrilium salts 300 Nitro compound 221 Nitrogen heterocycles 301 Nitroxide 480, 48 1,485 Nitroxyl radicals 177 NMR studies 444 NO, radical 222 Nor alkanes 111 Norlabdane oxide 215 Nucleophilic addition 236, 237 Nucleophilic radicals 73, 85,417 Nucleoside analogs 6 1 Octahedral geometry 465,468,471,472 Okicenone 208 Organocobalt complexes 135, 140, 143, 146 - acyl complexes 140, 143 - alkyl complexes 140 - cross-coupling 143 - intermolecular additions 143 - radical cyclizations 141, 146 Olefin 230,239,243 Olefination 12 a-Onocerin 26 1 Oppolzer's camphorsultam 424 Optically active polymer 499 Organometallics, synthesis 288 Oxamides 165
511
Oxazolidines 43 1 Oxazolidinone auxiliary 490, 495, 498 Oxazolidinone 407,426,432,464,466, 470,474,495 Oxepanes 169 Oxepine 15 (+)-Oxerine 157 Oxidative polymerization 368 Oxidation potential 2 I9 Oxidative coupling 226, 227 Oxidative radical reaction 2 19-228 Oxime ester 183 Oxindoles, synthesis 104 Oxocanes 100 a-Oxyalkyl radicals 393 P-Oxygen effect 409 Oxygenation 366 Paeoniflorigenin 2 12 Parvifoline 208 Penicillinate 400 Pentadienyltributyltin 59 Perfluoroalkyl iodide 2 1 Perfluoromethylcyclohexane 37 Perhydrohistrionicotoxin 5 1 Peroxide 94,98, 100, 105,202 - from radicals 202 Persistent radical effect 480 Phenanthrene 233 8-PhenyImenthol208,436 Phenylselenoacetone 84 a-Phenylseleno ester 84 Phenylseleno transfer 74, 77, 83-85 Phenylselenomalonate 83-85 Phenylselenomalononitrile 83-84 Phenylselenotrichloromethane 86 Phenyltelluro transfer 74, 85, 86 Pheromones 265 Phosphatoxyalkyl radical rearrangement 356 Phosphine-borane complex 98 Phosphinic acid 25 Phosphonic acids, from carboxylic acid 117 Photoelectro catalysis 136 Photoelectron transfer (PET) 229, 230, 231, 233, 234, 236, 237,239, 240, 241, 242,
512
Index
243,245,246 Photolysis 2 Photoreduction 231, 234, 238, 239, 240, 242,243,244,245 Phthalimide 232, 233, 236,237 pi complexation 474 Pinacol coupling 160, 161, 163, 164, 165, 469 - aldimines 163 -amides 165 - diastereoselectivity 161 - diketone coupling 163 - intermolecularreaction 16 I - isocyanates 165 - nitriles 164 -oximes 163 - SmI, 160 Piperazine dione 367 Piperidines, synthesis 102 pKa 361 Podocarpic acid 208 Polar effects 417 Polarity reversal catalysis 45, 355, 356, 476 Polydispersity 480,484,485 polyhaloalkyl radicals 154 Polymer 105,482,484,485 -block 482,484 -random 485 Polymerization 72, 368,369, 370,456,479, 480,48 1,482,483,484,485,486 - atom transfer 479,482, 483,485 - dispersion 48 1 - emulsion 48 1,484 -homo 482 - iniferter 479, 480 - living-radical 479 - micro-emulsion 48 1 - reversible addition fragmentation 480, 484,485 - stable free-radical 480,48 1,482,485, 486 Polymethylhydrosiloxanes (PMHS) 35,96 Poly(pheny1silane)s 42 Polystyrene support 36 Polytetrahydrofurans I69 Proline derivatives 366
Propargyl iodomalonate 79, 80 Propargyl iodomalononitrile 79, 80 Propargylstannanes 60 Prostaglandin 16 Prostereogenic radicals 430,433 Protoanemonin 374 (+)-Pseudomonicacid C 62,95 PTOC Esters. see 0-Acylthiohydroxamates 109,430 Pyramidalization 408, 447 Pyridine-2-thione-N-oxide 111 Pyroglutamate 372 Pyrrolizidines 366 Pyrrole 80 Pyrrolidines 157 Pyrrolidizidine 59
Quadruple cyclizations 209-21I Quantum chemical calculations 25, 339, 345, 351, 354, 356,382, 389. 390,393, 396 - ab initio 25, 339,345, 351, 354, 356, 390, 393,396 Quantum methods - 3-21G 346 - 6-31 l+G(d,p) 356,357 - 6-31 1G** 347,355 - 6-31G(d) 356, 357 -6-31G* 348 - ab initio 339,345,351, 354, 356 - AM1 347,350,351,352, - aug-cc-pVDZ 355 - B3LYP 347,348,356,357 -CBS-RAD 348 -CCSD(T) 348 - density functional 355 -DZP 351 -MIND0/3 338 - MNDO 338,348 - MP2 346,348,355 -PM3 347 - semi-empirical 338, 350 - UHF 346,347,348 Quaternary center 444, 466 Quinolizidine 376,414
Index Radiation 2 Radical 19, 20, 21,52, 55, 73, 75, 76, 84-87, 94, 95, 99, 102, 103, 131, 143, 154, 157, 159, 165, 168, 170, 171, 172, 173, 175, 177, 183, 201, 219, 220, 221, 222,223,224,235, 238, 273, 280, 282, 289, 318, 319, 323, 325, 327, 330, 331, 332, 337, 338, 339, 340, 341, 348, 374, 402,408,410,411,417,435,441-459, 467,476 - acyl 55, 84-87,99, 103, 143, 331,435 - acyloxyl 323 - alkoxycarbonyl 99, 103 - alkoxyl 19, 157, 332 - alkoxythiocarbonyl 99 - ambiphilic 77, 84, 85 -amidyl 332 - amine-boryl 476 -aminyl 332 - anodic oxidation 282 - ~ y l 159 - 3-butenyl 327 - tert-butoxyl 318, 332 - captodative 85 - a-carbalkoxyl 302 - carbmoyloxy 52 - carbonylation 201 - cathodic reduction 289 - cation 219, 220 - cumyloxyl 332 - cyclic 400ff - cyclization 220, 222, 223, 224 - cyclobutylcarbinyl 327 - cyclohexadienyl 374 - cyclohexyl 402 - cyclopentyl 410 - cyclopentylmethyl 3 I9 - cyclopentyloxyl 332 - cyclopropyl 408 - cyclopropylcarbinyl 175, 3 18, 3 19, 327, 330 - cyclopropylmethyl 446 - dialkylaminium 332 - dialkylaminyl 332 - dialkoxy-substituted 449 - dimerization-223,227
513
dioxolanyl 408, 41 1 dioxy 446,450 - electrophilic 73, 76, 221 - ester-substituted 382, 295 -ethyl 19, 20, 21 - 5-hexenyl 319,327,337,338,339,340, 341,348 - iminyl 94, 131, 183,332 - ketyl 165, 168, 170, 171, 172, 173, 235, 238,408,449,467 - N-centered 33 I -neophyl 327 - nitroxyl 177, 325 -NO, 222 - nucleophilic 73, 85,417 - oxiranyl 408 - a-oxy-substituted benzylic 452 -phenyl 330 - polycyclic 413ff - polyhaloalkyl I54 - prochiral 273 - stannyl 19 - succinyl 410 - a-sulfinyl 452 - tetrahydropyranyl 410 - tetrazolylmethyl 102 - thiyl 95 - tributyltin 325 - trifluoroacetonyl 102 - vinyl 75,330 Radical acceptors 156, 158, 166, 167, 173 - acrylates 166 - acrylonitriles 166 - alkenes 158, 167 - alkenylsilanes 167 - alkynes 156, 158, 173 - allenes 173 - allylic acetates 167 - enol acetates 167 - hydrazones 156 - oxime ethers 158 - silyl enol ethers 167 Radical addition 4 16,417 Radical-anion 298 Radical atom transfer see atom transfer Radical-cation 219, 220, 298 -
514
Index
Radical chain reactions 28 Radical clock, definition 317 Radical cyclizations 137, 141, 146,220, 223-225 Radical dimerization 223-227 Radical fragmentation reactions see allylation 175 - 3-exo cyclization 176 Radical initiators 3-9 - acetyl peroxide 6 - 2,2’-azobisisobutyronitrile(AIBN) 3, 1 1, 14, 15, 16, 17, 19, 23, 24, 73, 83, 85,322, 481,483 - 4,4’-azobis(4-~yanopentanoic acid) (V-501) 4 -
2,2’-azobis(4-methoxy-2,4-dimethylvaleronitrile) (V-70) 3
- (2RS,2’RS)-azobis(4-methoxy-2,4-
dimethylvaleronitrile) (V-70L) 3 2,2’-azobis(2-methylpropionamidine) dihydrochloride (V-50) 4 - benzoyl peroxide 6 - 9-borabicyclo[3.3. llnonane (9-BBN) 8, 26 - t-butyl perbenzoate 6 - di-t-butyl peroxide 7 - samarium iodide 9 - triethyl borane (Et,B) 8 - zinc chloride 9 Radical-ion 229, 230, 234, 235, 236, 237, 238,241 Radical pair 363 Radical-polar crossover reactions 298-3 15 Radical recombinations 468,469 Radical trap see acceptors) Radicophilic alkenes 361, 369, 37 1 RAFT see reversible addition fragmentation chain transfer Rate constants 30,41,45, 53, 153, 159, 364,365,371 Reaction cascades 159, 166 Reaction mechanisms 353 - homolytic substitution 354, 355 - polarity reversal catalysis 355, 356 - translocation reactions 354, 355 - j3-phosphatoxyalkyl radicals 356 -
Reactivity-selectivity principle 410ff Reagent-controlled 416 Rearrangement, 0-to S- 94 Rearrangement, radical Brook 414 Rearrangement reactions - -1,2- 363 - - 1,3-C1 atom 362 - ylidic 363 Recombination (radical /radical-cation) 299 Radical substitution at sulfur 306 Redox system 2 Reducing agents 28, 30,45 - Bu,GeH 30,45 - Bu,SnH 30, 32, 35, 43 -Et,SiH 30 -Ph,SnH 30 - (TMS),SiH 30,43 - other organosilanes 41 Reduction 462,475 - alkenyl halide 12, 23 - alkyl halide 12, 24 - dithiocarbonate 14 Reduction see hydrogen transfer 443,445, 446,449-45 1 Reductive decarboxylation 11 1 Reference electrode 253 Reformatsky type reaction 17, 21 Regiochemistry 338, 340, 341 Regioselectivity 366, 367 Reversible Addition Fragmentation Chain Transfer 480,484,485 Reversible radical reaction 3 19 Ring expansion 175 Ruthenium chloride 366 Salen ligand 141 Salicylate ester 203 Salophen ligand 141 Samarium(I1) iodide (SmIJ 9, 153, 154, 155, 176,467 - atom-transfer reactions 176 - catalytic 154 - 6-end0 cyclization 155 - 5-exo cyclization 155, 156 - conjugate addition 154 -enolate 155
Index p-Scission 50, 60 Selective oxidation 367 Selenides, from carboxylic acids 1 15 Selenium 344 Self terminating radical reaction 222 SFRP see stable free radical polymerization Silanes 96,355, 356 Silphiperfol-6-ene 2 16 Silver(1)-mediatedradical reaction 226 Silyl enol ether 221, 22.5-227 Silyl enolate 12,21 Simmons-Smith reaction 95 Single-electron transfer 140, 154, 219, 223, 226-227, 369 Spiro systems 94 Sodium Iodide 191, 192 Solvent effect 25 Solvolysis 300-308 - of secondary TTF salts 305 - of primary TTF salts 308 SOMO 418,441,442 Spongiatriol 2 10 S,,1 reaction 285 Stable Free Radical Polymerization 480, 481,482,485,486 Stannanes 350,351,352,353 P-Stannylacrylates 60 P-Stannylstyrenes 60 Stannyl radical 19 1,3-Stannyl shift 95 (-)-Steganone 169 Stereochemistry 340, 341, 344 Stereoelectroniceffects 409ff Stereoelectroniceffects, anomeric effect 409ff Stereoelectroniceffects, quasi-homoanomeric effect 409 Stereoelectroniceffects, P-oxygen effect 409 Stereo-electronichypothesis 339 1,2-Stereoinduction 395, 398 Stereoselectivecyclization 303 Stereoselectivity 381, 382, 385, 388, 390, 391,393 - acyclic systems 38 1 - ester-substitutedradicals 382
515
- H-atom abstraction 382
P-methoxy-substituted radicals 385 a-oxyalkyl radicals 393 -reversal of 388, 390 - variation of the radical trap 391 Steric effect 328,417,421,424,426,441, 443,4.52 - on kinetics 328 Steric enhancement 452 Stevens 363 Stilbene 233, 234 Strain energy 338, 339, 340 Styrene 233,481,484 Substrate-controlled 416, 441 Sulfides, from carboxylic acids 115 a-sulfinyl radicals 53 Sulfone synthesis 120 Sulfonamide 240,467 Sulfonamide synthesis 120 Sulfonyl radicals 95, 105 Sulfur dioxide extrusion 105 Sulfoxide 403 Sulfuration 366 -
TADDOL 466 Tandem cyclization 208, 281, 301 Tandem reaction 222-225, 229,237,243 - bicycloalkanone 243 -furanone 244 - spirocylic 233 - triquinane 243 Taxanes 162 Tellurides 62, 115 TEMPO 146,480,481 Termination 304, 485 - intramolecular 304 Tertiary alkyl halides 369 Tetrahedral geometry 464 Tetrahydrofuran 40 1 Tetrahydropyrans 169 a-Tetralones, synthesis 10 Tetraphenyldisilane 24,42 Tetrathiafulvalene 298-3 15 - derivatives, polymer-supported 3 10 - derivatives, water-soluble 3 10 - derivatives, tetrathio 3 12
516
Index
Tetrathiafulvalenium salt - C-linked 308 - S-linked 299-3 13 Tetrazolylmethyl radical 102 Thermolysis 1 Thianthrene 3 11 (+)-Thienamycin 146 Thioamide 368 (Thiocarbony1)sulfanyl compound 480 Thiocarbamate 9 1,97 Thiocarbonyl imidazolide 9 1,92 Thioformate 93 Thiolactone 96 Thiol 45 Thiophenol 50,325 Thiophenoxy radical 50 Thiyl radical 95 Tin-free methodologies 19, 63-68, 96 Titanium(1V)-mediatedradical reaction 226-227 p-Toluenesulfonate, sodium salt 48 1 Torsional effect 402 Trachelanthamidine 23 Transition metal catalyzed polymerization 483 Transition state 324,441, 443, 444, 446, 447,449,452,458 Trialkylsilanes 41 Tributyltin hydride see Bu,SnH 30, 32, 35, 43, 75, 81, 82, 139, 322, 325, 326, 330, 343,350,419,424 - catalytic 35 - comparison with (TMS),SiH 43 -fluorous 37 - in situ generated 35 - polymer-supported 36 - stereoselectivity 43 - stoichiometric reaction 32 - water-soluble 37, 38 Tributyltin radical 325 Trichloroimidazole 362, 363 Tricycloillicinone 2 14 Triethyl silane 323 Triethylamine 237, 238, 242 Triethylboraneloxygen 11, 66,73, 77, 79, 92,323
Trifluoroacetonyl radicals 102 Trifluoromethylation 14 Trifluoromethyl sulfones (triflones) 64-65 Trifurylgermane 12, 14 Trimethylsilane 355 (2-Trimethylsilylally1)triphenyltin 57 Trimethyltin hydride 349 Triphenylgermane 12 Triphenylprop-2-ynylstannane 6 1 Triphenyltin hydride 30 Triple cyclizations 209-21 1 Triptonide 215 (+)-Triptophenolide 436 Tris(trimethylsilyl)silane 12, 15,30, 38, 63, 97,322,326,394,419 - comparison with Bu,SnH 43 - stereoselectivity 43 Trithiocarbonates 105 Ueno-Stork reaction 346,402 Unimolecular chain transfer 76 Unimolecular clock 3 17, 320 a$-Unsaturated acid derivatives 188, 195 Upial 212, 213 Vanadium(V)-mediated radical reaction 227 Vinigrol 169 Vinylation 50, 60, 63-65, 106 Vinyl bromides 63 Vinylcyclopropanes 364, 365 Vinyl halides 68 Vinyl radical 75, 330 Vinylstannanes 57 Vinyl sulfides 63 Vinyl sulfoxides 63 Vinyl sulfones 63, 106 Vitamin B,, 136 - radical cyclization 137 Water 23, 24 Willgerodt-Kindler reaction 368 1,2-Wittig rearrangement 468 Wittig 363 Wittig-Homer reaction 103 Working electrode 253
Index Xanthate 90-108,435 -synthesis 91, 100
Zinc chloride 9 Zero-point energy 355
517
Radicals in Organic Synthesis Edited by Philippe Renaud and Mukund P. Sibi
copyright OWILEY-VCH Verlag GmbH, 2001
Index
acetals 315 -hydrogen abstraction 271 acetoxyfukinanolide 32 1 acetylation I3 acetylene dicarboxylate 157 N-acetylglucosamine 541 N-acetylglycine 506 N-acetylneuraminic acid 54 1 acivicine 533 acrylamide 87 acrylic acid 87 acrylonitrile 27, 35, 37 actinidine 295 acyl germanes 12 acyl iodides 35 acyl radicals see radical, acyl acyl selenides 23 acyl silanes 12 acyl tellurides 180 acylation 4ff, 13 acyloxy migration 189, 191 , 196, 342, 570 acyloxylation 1 13 aflatoxin B, 3 17 alanine 268, 509, 5 16 albidin 309 alcohols - 6-carbonylation 253 -oxidation 133, 136, 264, 441 - protectinghadical-translocatinggroups 264 meso-alcohols 134 aldehydes 23ff aldol reaction 226
aldoximes 3 , 4 alkaloids 1 1, 18, 279ff, 52, 69 alkenes, isomerization 496 alkenylation 263 P-alkoxyacrylates 309ff N-alkoxyamines 127, I42 N-(alkoxy)-4-arylthiazole-2(3H)-thiones 44 1 S-alkoxycarbonyl 323 a-alkoxy hydroperoxides 450 a-alkoxylithium species 336 alkoxymercuration 101 N-alkoxyphthalimides 441 N-alkoxypyridine-2(IH)-thiones 430,43 1, 44 1 N-alkoxythiazole-2(3H)-thiones 43 1 alkyl nitrites, photolysis 441 alkylation 228 alkylmercury halides see organomercurials alkynylation 263 allenes 259, 378 alliacolide 325 allocoronamic acid 536 allofuranose 168 allosamizoline 559 allylation 5 , 15,228, 263, 553, 86 allylic hydroperoxides 46 1 allylic oxidation, asymmetric 121 allylic strain 283 allylstannanes 37ff, 86, 228, 547, 553 allyltributyltin see allylstannanes alpinolide peroxide 464 Airiuryllidaceae alkaloids 292
580
Index
amination 19,67, 93, 103ff, 407 - azides 107 - azodicarboxylate 105 - diazirines 105 - N,N-dimethylhydrazine 108 -imines 106 - nitric esters 103 - nitric oxide 103 - nitrosation 103ff -olefins 415 amines, metallation 267 amines, protecting/radical-translocating groups 265 amino acids 4,98, 176, 268, 505ff -1ysine 106 - diradicals 523 -hydrogen abstraction 506 a-amino acids 122 - N-phthaloyl 532 P-amino acids 266 amino alcohols 3 , 7 amino sugars 3 aminocyclopropane carboxylic acid 534 2-aminofuran, autoxidation 470 aminyl radicals see radical, aminyl anastrephin 325 anhydrolycorin-7-one 290 anisole 66 annulation 15ff, 28,35,70, 357 - [3+2] 208, 209, 5 I - [4+1] 49 - [4+2] 51 anodic oxidation - lysine 513 - ornithine 5 13 anomeric effect 335 anomeric radicals 195, 196, 260, 334, 538 antimony 96 antitumor antibiotics 202 aphidicolin 390 aplysin 325 armillol 374 aromatic substitution 62ff artemisinic acid 464 aryl sulfones, elimination 259, 269 arylsulfonates 75
aspidosperma alkaloids 287, 295 aspidospermidine 18 asymmetric induction, remote 366 atom transfer 180, 320,435 - carbonylation 35 -chlorine 415,417 - iodine 35,97, 108, 254,322 - light induced 39 -telluride 58 atractyligenin 323 autoxidation 455ff, 468 - 2-aminofuran 470 - P,y-butenolides 464 - carbonyl compounds 460 - cyclopropanols 472 - 3,4-dihydro-2H-pyrazoles 469 - enamines 468 - enantioselective 462 - hydrazones 468 -hydrocarbons 455 -imines 468 - nitrogen compounds 468 -phenols 466 avenaciolide 307, 320 avermectin 305, 327, 308 azasugars 448 azepins 178 azetidine-2-carboxylic acid 528 azetidines 534 azidation 107ff, 145 azides 107,447,450, 493, 564 -alkyl 18, 108 - ethanesulfonyl- 107 - trimethylsilyl 108 2-azido-2-deoxyselenoglycosides564 azidoselenation 562 aziridinyl bromide 295 N-aziridinylimines 7ff, 324 azoalkanes 526 azodicarboxylate 105, 384 balanol 177 Baldwin’s rules 159, 491 Barton VI Barton decarboxylation 57, 99, 157, 260, 338,345,346,486,568
Index aspartate 516 glutamate 516 Barton-McCombie reaction 203, 258, 558 Barton esters 18, 57, 86, 92,99, 105, 189, 209,237,328,345,420,435,458,547 Barton, nitric ester photolysis 104 Beckwith-Houk model 304 benzazepinediones 534 benzene 62 benzilidene acetals 252 benzo[c]phenanthridine 69 benzofulvene 404 benzofuranochromans 159 benzopinacolate 4 benzothiazole 68 N-benzoylglycine 509 N-benzoylglycylglycine 508 0-benzoylhydroxamic 163 Bergman cyclization 396, 397ff beticolin 174 biacetyl 13 biaryls 68, 74,75 bicyclo[3.2. Ilnonanes 174 bicyclo[3.2.2]nonanes 174 bis(oxazo1ine) 122, 123 bis(trimethylstanny1)benzopinacolate 540 bleach 134 block coplymers 143 bond dissociation energies 246 - calculations 247 boranes 487 boron trifluoride 4 botryodiplodin 499 branched-chain sugars 545,552 brassinolide 490 bromalysin 493 bromination 56 I bromine 133 bromoacetals 84, 3 15 orrho-bromobenzyl ethers 264 a-bromoesters 86 bromoglycine 507 (bromomethyl)dimethylsilyI ether 305, 307, 353 bromomethyldimethylsilyl propargyl ether 374 -
-
581
(ortho-bromophenyl)dimethylsilylgroup 264 N-bromosuccinimide 506, 509, 5 12 bromotrichloromethane 435 Brook rearrangement, radical 12 bryostatin 3 13 building blocks, carbohydrates 555 tert-butyl hydroperoxide 456 tert-butyl isocyanide 554 tert-butyl isonitrile 48 tert-butyl perbenzoate 506 y-butyrolactone 84, 3 16 calculations, bond dissociation energies 247 calicheamicin 387, 397, 566 camptothecin 49,69, 286, 350 captodative stabilization 562 carbocycles 2, 3 - from sugar 555 carbohydrates 2, 3, 538 - fragmentation 446, 45 1 P-carboline 295 carbon monoxide 11, 15, 22ff, 44 carbonyl compounds, autoxidation 460 carbonylation 22ff -kinetic 24 carboxylation 13, 14 - Kharasch 13 carboxylic acids, protecting/radicaltranslocating groups 268 caryophyllene 373,442 cascade reactions 5 , 8, 927, 28, 30,41, 87, 130, 155, 158, 181, 182,225, 235, 350ff, 424,443,457,497 catharanthine 287 cebetin 174 cedrene 9 N-centered radical 407ff cephams 491 cerium (IV) 490 - ammonium nitrate 66, 72, 428 C-H activation 113 C-H hydroxylation, desymmetric 120 chilenine 294 chiral auxiliary 271, 318, 329, 364
582
Index
- acetals 316 - a-phenylethylamine 163
N-chloramine 352 chlorine radicals 257 N-chloroamine 66, 409,413 N-chlorocarboxamide 41 0 N-chlorosuccinimide 135 cholestan-311-01 257 ent-chondrillin 478 C-H oxidation 113 - allylic 121 chromium (11) 215 ciguatoxin 3 1 1, 328 cine substitution 196, 200 cladantholide 175, 3 15, 350 clavukerin 175, 320 cobaloxime 103 cobalt 96, 101 cobalt(sa1ophen) 128 coccinine 292 combinatorial chemistry 81 o-complexes 62, 67 conanine 409 conformation, a-oxygenated radicals 334 conformational interconversion 345 conjugate addition 228 consecutive reactions see cascade reactions cooxidation 479, 488 copper (I), catalyzed cyclization 320 copper (11) 359 copper 121,417,435 coriolin 350, 390 corynanthe alkaloids 295 cotinine 161 CP-225,9 17 470 CP-263,114 470 cryptopleurine 69 cryptostyline 1 1 Curran VI curvulol 309 cyanoborohydride 33 cyanohydrin acetonides 342 cyclic ethers 167 cyclization 151, 207 - 5-endo 159, 161,274 - 6-endo 359,86
-8-endo
320
- 3-ex0 106, 151
-4-exo
159
- 5-exo 82, 88,90 - 7-10 ex0 and endo 163 - alkaloid synthesis 279ff
alkoxyl radicals 427ff nitrogen radical 415 - oxacycle preparation 304 - oxygenative 95 - peroxyl radical 475 - silicon-tethered 305 - 0-stannyl ketyl 223 cycloalkenes 12 1 cycloaromatization 395 cyclobutane 160 cyclobutanone 238 cycloheptenone 153 cyclohexadiene 62, 21 8,259, 379, 398 cyclohexane 561 cyclohexanones 30 cyclohexenediols 83 cyclopentene 122 cyclophellitol 443 cyclopropanes 152,207ff, 535 - methylene- 108 cyclopropanols 238 cyclopropanols, autoxidation 472 cyclopropanone cyanohydrins 412 cyclopropyl ketones 210,222,226,23 1, 24 I cytochrome P-450 1 13 -
-
dactomelyne 309 decarbonyl ati on 23 decarboxylation see also Barton decarboxylation) 98 - amino acids 98 - electrochemical 98 - Hofer-Moest reaction 98 - oxidative 73 - oxygenative 98 decyanation 337,344 dehydroalanine 50, 88, 540 dehydrohastanecine 28 1 dehydroisorotenone 3 14
Index demercuration, oxidative 129 dernethoxyahadinine B 102 3-demethoxyerythratidinone 29 1 dendrobine 299 denitration 68,568,573 density functional theory 247 2-deoxy sugars 195,570 6-deoxy sugars 573 deoxygenation see Barton-McCombie reaction deoxyisoamijiol 305 deoxylycorine 289 deoxypancratistatin 2,9, 10, 297,298, 324 deoxypodorhizon 320 8-deoxyvernolepin 444 2-deoxy-P-D-glucoside 568 2-deoxy-P-glycosides 34 desrnethoxymitomycin A 295 desulfuration 486 desulfurization 328 desymmetrization 120, 134, 136 (diacetoxyiod0)benzene 135, 238,250,255, 373,410,428,441,473,564 gem-dialkyl effect see Thorpe-Ingold effect diazenes 384,387,390, 391, 393, 394 diazirines 18, 19, 105 diazonium salt 68, 266, 269 di-tert-butyl hyponitrite 249, 456 di-tert-butyl peroxyoxalate 456 2,6-dichloropyridine N-oxide I 15 dictamnol 242 Diels-Alder 377 diene 155,492 - oxygenation 100 dienyl cyclopropanes 497 diethylketomalonate 384 diethylzinc 88 gem-difluoroalkenes 565 dihydroagarofuran 3 16, 325 dihydrobenzazepinones 170 dihydrobenzofuran 84 dihydrosesamin 304 dihydroxyheliotridane 273,28 1 diketopiperazines 507 dilauroyl peroxide 256,258 dimaganese decacarbonyl 130
dirnerization, glycos- 1-yl radicals 542 dirnethyldioxirane 515 N,N-dimethylhydrazine 108 dioxetane 469 dioxolanes 15,475 dipeptides, irradiation 529 diphenyl diselenide 195, 489, 564 diphenyl disulfide 208, 489 diquinanes 23 1,353 1,l-dimethylindan 120 diradicals 383ff, 523 - 1,4-didehydrobenzene 396 - precursors, azoalkanes 534 - precursors, imides 53 1 - precursors, ketones 526 -triplet 524 C-disaccharides 540 discorhabdin A 287 dispiroketals 250 disproportionation 533 disulfides 58 diterpenes 361 diylophiles - azodicarboxylate 384 - diazenes 384 - diethylketomalonate 384 -imines 384 - thioketones 384 DNA cleavage 387,396 DNA 202 domino reaction see cascade reactions duocarmycin 84, 130 electrochemistry 98 - oxidation 133
Hofer-Moest reaction 98 electrophilic radicals, 48 elimination 156 - phenylthiyl 157 0-elimination - sulfones 357 - thiophenyl radical 355 enamides 161 - radical acceptor 293 enamines 178 - autoxidation 468 -
583
584
Index
enaminonitriles 177 enantioselective reactions 131, 2 18 enantioselectivity 116 enantiotopic selectivity 1 14, 115, 116 endoperoxides 493 eneallenes 492 enediynes 400 enol acetates 208 enol ethers 83, 208 enol radicals 460 - oxygenation 462 enolate radical, oxygenation 102 enolate, oxidation 103 enyne-allene cyclization 396 enynes 492 enzymes 113 epialboatrin 3 16 epibatidine 266, 282 epidevinylantirhine 3 18 epilupine 285 epoxides 117, 118,21Iff, 428 meso-epoxides, enantioselective opening 218 epoxy ketones 222 epoxydictymene 250,326 P,y-epoxy radicals, fragmentation 450 P,y-epoxy radicals, rearrangement 441 eremantholide 325 erythrina alkaloids 291 Eschenmoser reaction 7 estafiatin 32 1, 350 estradiol 443 ethyl camphorate 122 ethylbenzene 1 14, 1 18 evodone 317 exaltolide 327 ferrocenium ion 103, I30 fluorous allyltin 37 formylation 23ff, 33 N-formyltortuosarnine 292 fragmentation 202ff - carbohydrates 446,45 1 - P,y-epoxiradicals 450 - hemiacetals 443 - y-hydroxystannane 444
Kornblum-De La Mare 458 j3-sulfenyl radicals 487,498, 487 - P-sulfonyl radicals 498 - sulfoxides 274 P-fragmentation 7, 11,46, 128, 161, 163, 234,530,53 1 - alkoxyl radicals 440ff fragmentation-oxygenation 473 fredericamycin 299 Fremy’s salt 137 frullanolide 307 furans 63 furanomycin 129,324 fusicoplagin D 236 -
gadain 321 garsubellin A 3 13 geissoschizine 295 gelsemine 283, 3 18 germanes 322 germyl hydride 33ff Giese VI gloeosporone 496 glucuronic acid, bromination 562 glucoside, 1-phenylsulfonyl 549 glutathione 485 glycine 268,506, 528 - halogenation 5 10 C-glycosides 538ff, 547ff C-glycosylation 177 glyoxylates 4 glyoxylic oxime 88 Gomberg V Grignard reagents 128 guaiane alisomol 242 hainanolidol 250 ortho-halobenzoyl 265 halogenation 4 12 Hammet correlation 1 15 harringtonine 285 harringtonolide 250 Hart VI hastanecine 28 1 heliotridine 28 1 hemiacetals 443
Index heparin 176 herbicidine glycoside 562 heterocycles 48, 202 meso-heterocycles 120 N-heterocycles 18, 289ff hexabutylditin 105 1,5-hexadienes 37 hexytols 568 himachalene 442 hirsutene 389 historical background V hitachimycin 496 Hock cleavage 461,465,466 Hofer-Moest reaction 98 Hofmann-Loffler-Freytag reaction 409, 254ff homogynolide B 3 I7 homolytic substitution 62ff, 500 homoserine 533 hydrazine 145 - oxidation 131 hydrazones, N,N-dimethylhydrazone 7 hydrazones 6ff, 30 - autoxidation 468 - N-aziridinylimine 7ff - N,N-diphenylhydrazone 6 hydrindane 361,362 hydrindanone 181 hydroboration 100 - oxidation 129 hydrocarbons, autoxidation 455 hydrocobaltation 101, 128 hydrogen abstraction 115, 120, 121, 124, 158, 212, 237, 246ff, 343, 355, 357, 366, 392,407,409,434,462,473,505ff, 553, 566,73,569 - diradical 529 - rate constants 271 - alkoxyl radical 249 - diastereoselectivity 273 - intramolecular 248 hydrogen atom transfer see hydrogen abstraction hydrogen peroxide, production 468 hydroperoxides 121, 430, 450, 458 hydrosilylation 486
585
hydrostannation 3,486 hydroxamic acids 420 3-hydroxy- 1,2-dioxanes 469 a-hydroxyesters 102 hydroxyguaienes 175 hydroxylation 93ff, 1 13 - benzylic 1 15 hydroxymethylation 33 N-hydroxypyridine-2(1H)thione 420 hydroxystannylation 102 P-hydroxysulfoxides 488 hydroxytetralin 1 15 N-hydroxy-2-thiopyridoneesters see Barton esters hypervalent iodine compounds 238,441 hypnophilin 350, 390 hypobromous acid 134 hypochlorite 133, 134 hypochlorous acid 252 hypohalogenites 441 hypoiodite 250 - irradiation 441 hypophosphite 3 I6 epi-illudol 307, 374 imidazoles 69, 7 I imines 7ff, 10,30,54, 106, 324,384 - autoxidation 468 imino shift 106 indanomycin 340 indoles 52, 53,69, 71, 286 indolines 86 initiators 39 - Braslau-Vladimir 142 - diethylzinc 88 - di-tert-butylhyponitrite 249 inositol 561 intersystem crossing 524 N-iodoamide 4 10 N-iodoamides 255 ortho-iodoanilides 268 ortho-iodobenzyl ethers 264 a-iodo carbonitriles 66 iodocyclization 477 iodoepoxides 212 a-iodo esters 66
586
Index
iodoethers 250 iodohydrins 326 a-iodo malonates 66 N-iodosuccinimide 250 N-iodosuccinimide 476 iodosylbenzene 108, 114 ion pairs -contact 191 - solvent-separated 191 ionic fragmentation 202 ipomeamarone 260 ips0 substitution 196, 67ff irinotecan 49 iron (11) 435 iron (111) 238, 372,491 - perchlorate 72 - trichloride 443 iron-oxo species 114 iron-porphyrin 114 isoacetylsaturejol 464 isocyanates 46 isocyanides 493 isoleucine 533 isonitriles 44ff, 69 - aromatic 48ff isooxyskytanthine 295 isoretronecanol 280 isospongiadiol 360 isothiocyanate 46,47, 54, 57 isotope effect 115, 134, 189, 120 kainic acid 55,287,498, 500 karahana 325 Keck VI ketenes 14, 15, 146 ketene-S,S-acetals 294 a-keto esters 6 P-keto ester 72, 359 - ring expansion 234 ketones 23ff -synthesis 6 - macrocyclic 441 - medium-sized 441 ketoximes 4 Kharasch V - carboxylation 13
-phosgene 13 Kharasch-Sosnovsky reaction 121 kinetic resolution 117, 136 kinetic see rate constants kumausallene 313 trans-kumausyne 309
lactacystin 129 P-lactams 272 lactones 34, 180, 323 - bicyclic 174 - contraction 193 - medium-sized 443 &lactones 216 y-lactones 250, 320 laser flash photolysis 189 latent radicals, N-alkoxyamines 142 laurenene 443 lauthisan 308, 328 lead dioxide 131 lead tetraacetate 250, 255,428, 473, 66 lennoxamine 294, 178 lepidine 65 Lewis acids 4, 193,269,408 -boron trifluoride 4 - copper 417 libraries 90 limonene 209 limonin 473 linker 81 2-lithiotetrahydropyran 336 lithium I-(dimethy1amino)naphthalenide (LDMAN) 336 lithium di-tert-butylbiphenylide (LiDBB) 337 lithium naphthalenide (LN) 340 living polymerization 142 longifolene 260 low-valent metals 215 lubiminol 236 a-lycorane 290 y-lycorane 290 lycorane alkaloids 289 lycoricidine 297 lysine 106,5 13
Index macrocyclization 35, 39, 362 macrodithionolides 327 macrolactones 443 macrolides 450 magydardienediol 3 I5 malonates 66 manganese (111) 329,359,466 - acetate 66,7 1,72 - tris(pyridine-2-carboxylate) 238 manganese (11) 101 manicol 236 P-mannopyranosides 338 mannosamine 103 manzamine A 291 mappicine 286 matrine 293 medium rings 151, 163 memory of chirality 345, 527, 535 mercuric acetate 250 mercuric oxide 250, 566 Merrifield 81 mesembranol 292 mesembrine 292 methallyltributyltin 541 methionine 533 4-methoxy- 1-ethylbenzene 120 methyl elenolate 3 19 methyl nonactate 3 1 1 methyl oxalyl chloride 14 a-methylene-y-butyrolactones 3 16 methylenecyclobutanes 243 methylenecyclopentanes 497 methylenecyclopropanes 16ff, 209, 307. 383,498 a-methylene lactones 547 methylenolactocin 307, 322 N-methylephedrine 329 milbemycin 229 Minisci reaction 64, 65,71 modhephene 9, 14,370 montanine 292 Moore cyclization 396,402ff morphine 2, 298, 305 muscarine 435 muscone 442 Myers cyclization 396,401ff
nagilactone F 250 narciclasine 297 Nishiyama’s ligand 123 nitrate esters 434, 441,448,45 1 nitrite esters 252, 430 - photolysis 104 nitriles 46 - radical acceptors 324 nitrobenzenes 67 4-nitrobenzenesulfenate 252 nitrogen compounds, autoxidation 468 nitrogen extrusion 535 nitrogen heterocycles 424 nitrosation 103 nitrosoamines 420 nitroso-tert-octane 145 nitrous oxide 562 nitroxides 93, 97, 127 - C,-symmetric 132 - camphoxyl 132 -chiral 131 - oxidations mediated by 133 - steroidal doxy1 norbonene 152 Norrish-Type I1 528,530,567 Norrish-Yang reaction 523,524 norsecurinine 266 nortricyclene 152 nortropine 252 nucleosides 4, 196 Oppolzer’s camphor sultam 4 Oppolzer’s camphorsultam 88 organoboranes 100, 128,458 organocobalt 237,96 - hydroxylation 128 organocuprates 127 organomercurials 63, 88, 101 - oxidation 129 organosamarium 127, 267 organotitanium 127 organozinc 127 ornithine 5 13 oxa-Cope fragmentation 136 3-oxabicyclo[3.l.0]hexanes 155 oxacyclic natural products 303ff
587
588
Index
oxalyl chloride 13ff oxaziridines 420 oxazolidin-4-ones 53 1 oxazolidinones 268 oxazoline 122 oxepanes 311 oxetanes 159 oxidation 113 - C-H bonds 113 oxidative radical cyclization 19 oxime ethers 2ff, 88, 173, 177, 297, 324,
559 sulfonyl 4ff, 39 oximes 2ff, 493,562 - aldoximes 3 , 4 - ketoximes 4 oxindoles 73, 269, 284 oxoammonium salts 134 oxy radicals see radical, alkoxyl oxygen 19,93,94, 133, 146,250,455, 458,480 a-oxygenated radicals 334 P-oxygen effect 336 oxygen rebound mechanism 114 oxygenation 19,93ff, 472 -
paeoniflorigenin 329 paeonilactone B 307 palitaxel 390 pancracine 292 paniculatine 299 Passerini reaction 45 pentalenene 9, 242 peptides 57,505ff - diradicals 523 -hydrogen abstraction 506 peracids 133 perchloric acid 135 perfluoroalkylation 66 perhydroazulenes 167 perhydroazulenone 18 1 periplanone 174 peroxides -cyclic 463 -1auryl 107 peroxy esters 121
peroxyboranes 458 peroxycobaloxime 430 peroxyl radicals 455ff persistant radicals 127 PGI-synthase 427 phenols, autoxidation 466 S-phenyl chlorothioformate 13 phenyl ketones 525 phenyl migration 74 phenyl N-alkoxybenzenecarbimidoselenoate 44 I phenylacetylene 5 1 a-phenylethylamine 163 phenylsulfones, anomeric 340 phenylsulfonyl oximes 88 a-(pheny1thio)aldehydes 488 phenylthio group transfer 252 phorbol 391 phosgene 13ff phosphines, radical addition 565 photochemical transformation 525 photocyclization 285, 527 photodecarboxylation 532 photoelimination 533 photoinduced electron transfer 242 photooxygenation 469 phthalimides 525, 531 N-phthalimido glycosides 45 1
N-phthaloylglycylglycine 508 picrasin B 3 19 pinacol coupling 559 piperidines 41 2 piperidinones I07 plakortin 478 polar effects 48, 247 polarity-reversal catalysis 256,486 polycyclization 36 1 polyhydroxylated carbocycles 448 polyketones 22, 30 polymer-bound selenides 86 polyquinanes 350 polystyrene 8 1 porphyrin 113ff -iron 114 potassium nitrodisulfonate 137 prochiral radicals 132
Index product purification 82 prolines 527 propellanes 23, 158 prostacyclines 427 prostaglandins 19,57, 100, 214, 229,315 protectinghdical-translocating groups 263ff protoemetinol 3 18 protoilludanes 374 protoilludanols 368 Pschorr reaction 68 pseudomonic acid C 328,547 pumilliotoxin 25 ID 295 pyrazines 65 pyridine 64 pyridine[bis(oxazoline)] 123 pyridinium cations 64, 65 pyridones 49,69,179 2-pyridylsulfones 542 pyroglutamates 54, 55, 509 pyrroles 69, 71 pyrrolidines 88, 409 meso-pyrrolidine 120 pyrrolidinones 11 , 30, 107 pyrrolines 54,55 pyrrolizidines 273, 280 qinghao 464 quasi-homo-anomeric 335 quaternary carbon centers 8, 9, 3 18 quinolines 49, 65 quinolinones 469 quinoxaline 65 radical anions 22 1 radical cations 191 - aminium 408 radical translocation see hydrogen abstraction radical traps, nitroxides 127 radical -acyl 11, 12, 14, 15,23ff, 25,68, 165, 167, 174,486 - a-acylamino 279 - acylperoxyl 250 - I-adamantvl , 67 -
589
alkoxycarbonyl 323 (alkoxycarbony1)methyl 320 - alkoxyl 11, 104, 121, 201,234, 238, 250, 326, 427ff, 440ff - ally1 121 - allyloxy 450, 21 1 -amidyl 408 - aminium 254, 407 - a-amino 279,282 - I -amidoalkyl 265,272 - I-aminoalkyl 272 - a-aminomethyl 73 - aminyl 18,66,254,407, 450,5 17 -aryl 82 -azide 145 - aziridinylmethyl 424 - benzenesulfonyl 73 - benzoyloxy 358 -benzyl 33 - 3-butenyl 152 - tert-butoxyl 249, 456 - tert-butyl 31 - conformation 344 - conformational memory 345 - cyclobutenoxyl 442 - cyclobutylcarbinyl 242 - cyclobutyloxy 238, 207ff, 240, 442 - cyclohexadienyl 50,62, 69, 74 - cyclooct-4-enyl 368 - cyclooctanyl 37 1 - cyclooctenyl 373 - cyclopropylcarbinyl 226, 240, 242 - cyclopropylmethyl 152, 17 - cyclopropyloxy 240 - dialkylaminyl 407 - 1,3-dioxolan-3-yl 189 -diyls 383 - epoxyalkyl 240 - ethylsulfonyl 499 - glucosyl 335,540 - glycyl 506, 5 15 - 4-hexenyl 28 - homoallyl 152, 156 - hydroxyl 197,202 - imidoyl 45ff, 493,69 - a-iminoyl 285ff -
590
Index
- iminyl 424,70 - ketenyl 371 - a-ketenyl 14 -
ketyl 3, 210, 213, 221ff
- mannopyranosyl 335 - methanesulfonyl 33 -neophyl 74 - oxiranylcarbinyl -0xy 153 - a-oxyalkyl 7 1 - 4-penten-1-0xy1 430 - 4-pentenyl 30 - perfluoroalkyl 39,95, 261 - perhaloalkyl 261 - peroxyl 455ff - phenoxyl 466 - phenyl 213 - phenylsulfinyl 68 - phenylsulfonyl 5, 68 - phenylthiyl 15,479,496 - P-(phosphatoxy)alkyl 189 - phosphoranyl 189 - pyranosyl 539 - nbofuranosyl 541 - p-silyl 354 - silylmethyl 158 - stannyl 53 - 0-stannyl ketyl 22 1ff - sulfanyl 53,58 - sulfonyl 39,269,273,485ff - sulfur-centered 485ff - tetrahydrofuryl 65 - tetrahydropyran-2-yl 259 - 2-tetrahydropyranyl 334, 344 - P-(thiocarbony1oxy)alkyl 203 - &(thiocarbonyloxy)aIkyl 204 - thiophenyl 208 - thiyl 209, 255, 485ff - toluenesulfonyl 7 I , 88 - trichloromethyl 262, 270 - trifluoromethyl 263,496 - triphenylmethyl V - tris(trimethylsilyl)silyl 18, 37 - a,P-unsaturated acyl 14 - vinyl 35,58, 154 rapamycin 264,443
rate constants 2 carbonylation 25 - hydrazones 2 -imines 2 - isonitriles 47 rearrangement lSSff, 207ff - I ,2-acyloxy migration 570 - cyclopropylcarbinyl 443 - 1 ,2-imino shift 106 -neophyl 74 - P-(nitroxyalkyl) 188 - [2,3]-peroxyl radical 478 - 6-(phosphatoxy)alkyl 188 recifeiolide 327, 45 1 redox processes 417 reductive lithiation 336 remote asymmetric induction 366 remote functionalization 257 repair reaction 485 reserpine 305 retrosynthetic analysis 9 rhizoxin 318 ring expansion 153, 234ff, 441,443,444, 450 - cyclobutanone 238 - cyclopropane 241 - Dowd-Beckwith 234 - epoxides 241 - four carbons 236 -lactams 237 - lactones 237 - one carbon 236 - three carbons 236 -two carbons 442 ring-opening reactions 207 Rink resin 82 Ritter reaction 45 rocaglamide 15,210 rotenoids 309 rugosal A 456 ruthenium 115 -
salen 113ff manganese complex 1 17, 1 18
-
Index samarium iodide 3, 7,71, 82, 130, 210, 213, 214, 215,266,289, 307, 312,515, 542,55 1,559 - reaction with oxygen 475 samin 304,307 sarcosine 5 I2 saulatine 294 sceletium 292 a-scission 47,495,499 0-scission see 0-fragmentation selenocarbonates 323 selenoesters 12ff, 165, 167 selenoglucoside 549 serine 528 sesamin 444 sesquiterpenes 9 - autoxidation 458 -cedrene 9 - modhephene 9, 14 - pentalenene 9 - zizaene 9, 10 SET, oxidation 103 showdomycin 177,328 silicon tether 176 silyl enol ethers 14.5 single electron tranfer 69, 142 singlet oxygen 469 small rings 151 solid support 8 1ff solid-phase reactions 8 Iff solvent effects 193 spin labels 127 spin traps 127 spiro 225 spironucleosides 250, 27 1 spongian-16-one 325, 362 sporothriolide 307 statine 282 stereoelectronic effects 117, 247, 539 - a-oxygenated radicals 334 stereoselectivity 131 steroids 104,229, 360, 362, 364, 380,409, 443 Stork VI stylopine 285 Suarez reagent see (diacet0xyiodo)benzene
591
substitution reactions 196ff sulfenate esters 252 sulfenates 430,441 sulfinate anions, oxidation 487 sulfones 4ff, 33,73 - elimination 273 - 2-pyridyl 542 sulfonyl oxime ethers 4ff sulfonylation, alkyl radicals 495 sulfoxides 274 - fragmentation 259 sulfur dioxide 495 sulfur-centered radicals 485ff sulfuryl chloride 5 12 sultam 411 supercritical carbon dioxide 35, 37 swainsonine 282 tabersonine 287 talaromycin 305 tandem cyclizations see cascade reactions taxusin 315 tellurides 19, 105 telluroglycosides 58 TEMPO 97, 100, 101, 103, 127 temporary silicon connection see silicon tether TentaGel resin 82, 83, 87 terreic acid 402 tethers - acetals 552 - silicon 305, 550 - silyl ethers 552 - vinylsilyl 555 - dimethylketals 551 - ketals 551 tetrabromomethane 257 tetracycles 30 tetrahydrofurane-3-one 3 13 tetrahydrofurans 201,2 14,21 7,250, 427ff meso-tetrahydrofurans 120 tetrahydroisoquinolines 165 tetrahydropalmatine 294 tetrahydropyrans 250,427ff - trans-2,3-disubstituted 308 tetrahydroquinolines 41 3
592
Index
tetralin I15 tetraphenyldistibine 96 tetrathiafulvalene 269 tetrazenes 420 tetrodotoxin 324, 562 tetroxides 456, 475 thermochemical factors 247 thiazoles 63, 43 1 thiazolethiones 432 thienoquinoxalines 5 1 thioanilides 53 thiocarbazones 420 thiocarbonyl esters 203ff thiocyanogen 257 thioesters I2ff thiohydroxamate esters see Barton esters thioketones 384 thiol-oxygen-co-oxidation (TOCO) 479 thiols 53, 54 thiolactones 3 1, 5 1,485 thiophene 63 thioselenation 489 thiotelluration 489 thioxothiazolyloxycarbonyl 420 Thorpe-Ingold effect 160 three-membered rings 207ff tin enolates 221, 223, 226 - alkylation 228 - conjugate addition 228 tin hydride 23ff titanium (111) 216 - trichloride 420 titanocenes 2 16ff - enantiomerically pure 2 18 topotecan 49 tortuosarnine 292 transannular cyclizations 260, 366ff translocation, see hydrogen abstraction triazoles 71 tricycles 30 triethylborane 4, 88, 97, 259 a-trifluoromethyl ketones 496 trifluoromethyl sulfones 262 trifluorornethanesulfinate 496 trimethylenemethane 383ff trimethylpeltogynol 3 14
N-(trimethylsily1methyl)amines 285 triplet diradicals 386 triplet sensitizers 526 triquinanes 229ff, 273, 350ff, 370 tris(oxazo1ine)amine 123 tris(trimethylsilyl)silane 35ff tsugicoline 374 tunicamycin 305, 339 tylocrebrine 68 tyrosine 517
Ueno-Stork reaction 315 Ugi reaction 45 unimolecular chain transfer 37 upial 319
6-valerolactone 444 valine 512 vanadyl acetylacetate 238 vernolepin 444 vinblastine 287 vinca alkaloids 29 1 vincadifformamine 286, 292 vincristine 287 vinyl epoxides 213 vinyl phosphonates 547 vinyl shift 152 vinyl sulfones 167 vinylcyclohexanones 209 vinylcyclopentanes 208 vinylcyclopropane lsff, 31, 155, 157,207, 376,392,497 vinylglycine 533 C-vinylthymidine 305
Walling V Wang linkers 86 Wang resin 83 Winterfeldt oxidation 469
xanthates 71 group transfer 323
-
xylopinine 285 yingzhaosu A 477,479 yingzhaosu C 475 ynone 377
zearalenone 322 zinc chloride 515 zipper strategy 352 zizaene 9, 10 zwitterions 387
