General and synthetic methods., Volume 3

General and Synthetic Methods

Volume 3

A Specialist Periodical Report

General and Synthetic Methods Volume 3

A Review of the Literature Pub ished during 1978

Senior Reporter G. Pattenden, Department of Chemistry, University of Nottingham Reporters

K. Cooper, University of Nottingham A. B. Holmes, University of Cambridge D. C. Howell, Lilly Research Centre, Windlesham, Surrey M. G. Hutchings, I.C.I. Organics, Manchester R. C. F. Jones, University of Nottingham G. Kneen, Wellcome Research Laboratories, Beckenham, Kent D. W. Knight, University College, Cardiff M. Mellor, Bush Boake Allen Ltd., London S. M. Roberts, University of Salford W. J. Ross, Lilly Research Centre, Windlesham, Surrey D. J. Thompson, /.C./. Organics, Manchester S. Turner, Polytechnic of North London

The Chemical Society Burlington House, London, W I V OBN

British Library Cataloguing in Publication Data General and synthetic methods.(Chemical Society. Specialist periodical reports). VOl. 3 1. Chemistry, Organic-Synthesis I. Pattenden, Gerald 11. Series 547l.2 QD262

ISBN 0-85186-730-8 ISSN 0141-2140

Copyright @ 1980 The Chemical Society All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means -graphic, electronic, including photocopying, recording, taping or information storage and retrieval systems - without written permission from The Chemical Society

Set in Times on Linotron and printed offset by J. W. Arrowsmith Ltd., Bristol, England Made in Great Britain

In trod ucti0n

This report on General and Synthetic Methods is similar in scope and format to the previous two volumes in the series. Developments in the synthesis of saturated heterocycles, unfortunately omitted from Volume 2, are covered in this volume (Chapter 8), and a special report on ‘Photochemistry in Synthesis’ (Chapter 10) is included. There have been several high points in synthesis during 1978, but perhaps one should use this opportunity to single out the achievements of one chemist, the illustrious E. J. Corey, who during 1978 reported first total syntheses of gibberellic acid, the plant growth regulator (Chapter 7, ref. l),erythronolide B, the aglycone of the erythromycin B family of antibiotics (Chapter 9, ref. 17)’ and of N-methylmaysenine, one of the antitumoural maytensenoids (Chapter 9, ref. 23), each a major achievement in synthesis design and execution. July 1979

G. PATTENDEN

Contents

Chapter 1 Saturated and Unsaturated Acyclic Hydrocarbons By D. C. Horwell

1

1 Introduction

1

2 Saturated Hydrocarbons

2

3 Olefinic Hydrocarbons

4

4 Conjugated 1,3-Dienes

19

5 1,4-, 1 , 5 , and 1,6-Dienes

24

6 Allenic Hydrocarbons

27

7 Acetylenic Hydrocarbons

29

8 Enynes and Polyunsaturated Hydrocarbons

32

Chapter 2 Aldehydes and Ketones B y .S. M. Roberts

36

1 Preparations of Aldehydes and Ketones By Oxidation of Alcohols Thio- and Seleno-ketones Cyclic Ketones Dicarbonyl Compounds Other Preparations

36 36 37 37 39 41

2 Reactions of Aldehydes and Ketones Alkylation Aldol Reactions Reduction General Reactions

46 46 48 49 50

3 Preparations of Unsaturated Aldehydes and Ketones

54

4 Reactions of Unsaturated Aldehydes and Ketones Alkylation

60 60

vii

...

General and Synthetic Methods

Vlll

Reduction Conjugate Addition General Reactions

61 62 65

5 Protected Aldehydes and Ketones Preparation Regeneration of Aldehydes and Ketones Reactions

66 66 67 68

6 Halogeno-derivatives Preparation Reactions

71 71 72

7 Acyl, Homoenolate, Acylvinyl, and Dienolate Anion Equivalents

73

Chapter 3 Carboxylic Acids and Derivatives By D. W. Knight

75

1 Introduction

75

2 Carboxylic Acids General Synthesis Diacids Hydroxy-acids Keto-acids Unsaturated Acids Decarboxylation Protection and Deprotection

75 75 77 77 78 80 83 84

3 Lactones /3-Lactones Butyrolactones Butenolides and Tetronic Acids

85 85 86 89 93 96

-Methylenebutyrolactones Valerolactones

LY

4 Macrolides

98

5 Esters Esterification General Synthesis Diesters Hydroxy-esters Keto-esters Unsaturated Esters Thioesters and Related Compounds

100 100 101 104 106 107 109 114

6 Carboxylic Acid Amides Synthesis Reactions

117 117 120

ix

Contents

7 Amino-acids General Synthesis Unsaturated a-Amino-acids Chiral Amino-acids Protection and Deprotection

Chapter 4 Alcohols, Halogeno-compounds, and Ethers By R. C. F. Jones

122 122 124 126 128 132

1 Alcohols Preparation Carbonyl Group Reduction Allylic Alcohols Other Unsaturated Alcohols Reactions Protection 1,2-Diols

132 132 134 139 142 145 148 150

2 Halogeno-compounds Preparation Vinyl Halides Reactions

151 151 153 154

3 Ethers Preparation Reactions

155 155 155

4 Thiols and Thioethers General Preparation Reactions

157 157 157 158

5 Macrocyclic ‘Crown’ Polyethers and Related Compounds Synthesis Applications to Phase-transfer and Related Methods

158 159 159

Chapter 5 Amines, Nitriles, and Other Nitrogenco nta ining Functio naI G roups By G. Kneen

164

1 Amines Primary Amines Secondary Amines Tertiary Amines

164 164 168 169

2 Nitriles and Isocyanides

170

3 Nitro- and Nitroso-compounds

174

General and Synthetic Methods

X

4 Hydroxylamines

176

5 Hydrazines

176

6 Azo-compounds

177

7 Imines

178

8 Enamines

179

9 Azides and Diazonium Compounds

180

10 Isocyanates, Thiocyanates, and Isothiocyanates

181

11 Nitrates

182

Chapter 6 Organometallics in Synthesis Part I The Transition Elements By D. J. Thompson

183

1 Introduction

183

2 Reduction

183

3 Oxidation

186

4 Isomerization

188

5 Carbonylation

189

6 Carbon-Carbon Bond Formation Organo-copper Reagents Addition to Acetylenes and Olefins Coupling Reactions

191 191 193 194

7 Miscellaneous Organometallic-mediated Reactions

198

Part II M a i n Group Elements By M. G. Hutchings

200

1 Introduction

200

2 Group I Regiospecific Lithiation Carbonyl Equivalents A1ken yl-lithiums Metal-Lithium Exchange Miscellaneous Reactions

200 200 201 204 205 206

3 Group I1 Magnesium Zinc and Mercury

207 207 208

xi

Contents

4 Group I11 Boron Hydroboration and B-C Bond Formation Reactions of Organoboranes Reactions of Organoborates Reducing Agents Aluminium and Thallium

209 209 209 210 212 213 213

Silicon a-Metallated Silanes Hydrosilation and Fluorosilicates Miscellaneous Reagents and Reactions Tin

216 216 216 217 218 219

6 Groups V and VI Phosphorus Arsenic and Bismuth Sulphur Selenium Selenation and Oxidation a-Metallated Organoseleniurn Derivatives Miscellaneous

220 220 22 1 222 224 224 225 225

5 GroupIV

Chapter 7 Saturated Carbocyclic Ring Synthesis By K. Cooper, M. Mellor, and G. Pattenden

227

1 Introduction

227

2 Three-membered Rings General Methods Natural Cyclopropanes

227 227 23 1

3 Four-membered Rings

232

4 Five-membered Rings

234 234 239 242 242

General Methods Prostaglandins Rethrolones and Related Compounds Fused Five-membered Rings

5 Six-membered Rings Diels-Alder Cycloadditions Other Six-membered Ring Syntheses Anthracyclines and Aromatic Ring Annelation

245 245 248 252

6 Polyene Cyclizatioirs and Polycyclic Synthesis

254

7 Seven-membered Rings

258

xii

General and Synthetic Methods

8 Large Rings

26 1

9 Sgiro-ring Annelations

262

Chapter 8 Saturated Heterocyclic Ring Synthesis By W. J. Ross

265

1 Oxygen-containing Heterocycles Oxirans Dihydrof urans Pyrans Dioxolans Chromans Prostaglandin Endoperoxides, Thromboxanes, and Prostacyclins

265 265 269 270 27 1 272

2 Sulphur-containing Heterocycles Five- and Six-membered Ring Sulphur Systems Miscellaneous Sulphur Heterocycles

27 5 275 282

3 Nitrogen-containing Heterocycles Azetidines Pyrrolidines and Related Compounds Piperidines and Related Compounds Quinolines and Related Compounds Quinolizidines Tropanes Miscellaneous Nitrogen Ring Systems Triazolines Isoxazolines and Oxazines Aza-adamantanes

284 284 285 29 1 296 298 299 300 304 304 304

273

4 P-Lactams, Penicillins, Cephalosporins, and Related Compounds

Chapter 9 Strategy and Design in Synthesis By S.J. Turner

305 312

1 Introduction

312

2 General Papers

312

3 LHASA

313

4 Selected Total and Partial Syntheses Gibberellic Acid P-Lactams Lasolocid A Macrocyclic Lactones and Lactams

313 313 314 316 3 16

...

Contents

Xlll

Prostaglandins Tetrahedranes

3 18 3 19

5 Introduction and Interchange of Functional Groups Umpolung Multi -phase Systems Less Usual Elements Protecting Groups

3 19 319 321 322 322

6 The Carbon Skeleton Dianions Intramolecular Cycloadditions

323 323 323

7 Syntheses of Optically Active Materials The Use of Optically Active Starting Materials Asymmetric Syntlieses Biological Syntheses Resolution

325 325 326 327 328

Chapter 10 Photochemistry in Synthesis B y A . B. Holmes

329

1 Introduction

329

2 Ring Synthesis Cycloaddition Reactions Four-membered Rings Four-membered Rings with Subsequent Rearrangement Other Ring Sizes Ring Closure Reactions Three- and Four-membered Rings Five-membered Rings Six-membered Rings Seven-membered and Larger Rings Ring Expansion Reactions Ring Contraction Reactions Other Rearrangement Reactions

329 329 329

3 Ring Opening Reactions

35 1 351 352

Electrocyclic Reactions Norrish Type I Reactions

332 337 339 339 340 343 346 348 349 350

4 Oxidation Reactions Singlet Oxygen Remote Oxidation Other Oxidation

353 353 355 356

5 Reduction Reactions

356

General and Synthetic Methods

xiv

6 Photoelimination Reactions Decarboxylation Extrusion of Nitrogen Other Elimination Reactions

356 357 357 358

7 Photosubstitution Reactions

358

8 Photochemical Addition Reactions

358

9 Photosensitive Protecting Groups

359

Reviews on General Synthetic Methods By G. Pattenden

360

1 Introduction

360

2 Saturated and Unsaturated Hydrocarbons

360

3 Amino-acids and Peptides

360

4 P-Lactams

36 1

5 Organometallics

361

6 Carbocycies

362

7 Natural Product Synthesis

362

8 Asymmetric Synthesis

362

9 Phase Transfer Catalysis

362

10 General

362

11 Miscellaneous

363

Author I ndex

365

1 Saturated and Unsaturated Acyclic Hydrocarbons BY D. C. HORWELL

1 Introduction Volume 1 of the much heralded treatise ‘Comprehensive Organic Chemistry’ has now appeared, and has three chapters devoted to saturated hydrocarbons, olefinic hydrocarbons, dienes, polyenes, and acetylenic hydrocarbons.’ Two reviews summarize olefin synthesis via p-functionalized organosilicon with discussion of stereochemical control vis u vis the Wittig reaction. Clive has surveyed modern organoselenium ~ h e m i s t r yincluding ,~ the conversion of epoxides into olefins, inversion of olefinic geometry, selenoxide fragmentation, and the conversion of 6-hydroxyalkyl selenides into allylic alcohols and olefins. Selective reactions with diethylaluminium-2,2,6,6-tetramethylpiperidine, including stereo- and regio-selective isomerizations of substituted epoxides into allylic alcohols and their further regiospecific transformation into 1,3-dienes, are d i s c ~ s s e dWarren .~ has reviewed the use of migrating Ph2P0 and PhS groups in the synthesis of 1,3-dienes and allylic alcohols6 and modern routes to interesting sterically crowded olefins are summarized by Tidwell.’ Selective eliminations on alumina surfaces to give olefins are reviewed by Posner,8 whilst Oppolzer and Snieckus have discussed the use of the intramolecular ‘ene’ reaction in organic synthesis.’ A detailed review on the use of alkenyl-, alkynyl-, and cyanoborates as synthetic intermediates to alkynes, diynes, and enynes, and their stereochemical control of di-, tri- and tetra-substituted olefin synthesis, has appeared.” Olefin photochemistry is analysed in terms of the rearrangements and fragmentations that may occur, and some such reactions are illustrated by the industrial synthesis of Vitamin D.” Stang has reviewed the generation of unsaturated carbenes and their addition to other unsaturated moieties to give cumulenes and acetylenes.12

’ M. A. McKervey, G. H. Whitham, and G. Pattenden in ‘Comprehensive Organic Chemistry’, Vol. 1,

ti

’ *

lo

l1 l2

ed. J. F. Stoddart, Pergamon, Oxford, 1979. T. H. Chan, Accounts Chem. Res., 1977,10,442. E. W. Colvin, Chem. SOC.Rev.,1978,7, 15. D. L. J. Clive, Tetrahedron, 1978,34, 1049. H. Yamamoto and H. Nozaki, Angew. Chem. Internat. Edn., 1978, 17, 169. S. Warren, Accounts Chem. Res., 1978, 11,401. T. T. Tidwell, Tetrahedron, 1978, 34, 1855. G. H. Posner, Angew. Chem. Internat. Edn., 1978, 17,487. W. Oppolzer and V. Snieckus, Angew. Chem. Internat. Edn., 1978,17,476. G. M. L. Cragg and K. R. Koch, Chem. SOC.Rev., 1977,6,393. G. Kaupp, Angew. Chem. Internat. Edn., 1978, 17, 150. P. J. Stang, Chem. Rev., 1978, 383. 1

2

General and Synthetic Methods

Further chemistry of poly-unsaturated hydrocarbons is included in a review on the synthesis of the chiral component of insect pheromone^,^^ and applications of the retro-Diels-Alder reaction in organic synthesis have been summarized. l 4 2 Saturated Hydrocarbons

Alternative procedures to catalytic hydrogenation for the reduction of olefins to alkanes have appeared this year. A particularly smooth procedure has been the utilization of sodium hydrogen telluride as illustrated in Scheme 1.15Ashby and co-workers have studied the reduction of olefins with bis-di-isopropylaminoalane,16 and with magnesium hydride,17 both catalysed with [Cp2TiC1,]. Lithium aluminium hydride-transition-metal mixtures also reduce olefins and halides, with catalytic amounts of CoCI, and NiC1, particularly Itaconic acid is hydrogenated asymmetrically in 83.5% ( S )optical yield by benzoyl (2S,4S)-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine,*' and hydrogen transfer with cyclohexene-Pd-C-AlCI, has been shown to be effective in hydrogenating both aryl olefins and aryl alcohols to arylalkane~.,~

NaTeH+ 96%

H

Ph*CO,Me

NaTeH

88%r

PhflCO,Me

Scheme 1

Selective reductive removal of functional groups as a synthetic route to alkanes has been further developed this year. Two research groups report new mild procedures for the reduction of esters and sterically hindered alcohols to the corresponding alkanes in good yield, and without any rearrangement. Thus, tertiary steroidal acetates are reduced by Li-EtNH, or K-Bu'NH2-18-crown6,24and methane sulphonate esters by lithium triethylb~rohydride'~ (Scheme 2). Sodium in HMPA is also an effective new reagent for both the reduction of esters and the deoxygenation of alcohols to give alkanes.26Deoxygenation of ketones R. Rossi, Synthesis, 1978, 413. J. L. Ripoll, A . Rouessac, and F. Rouessac, Tetrahedron, 1978, 34, 19. l5 K. Ramasamy, S. K. Kalyanasundaram, and P. Shanmugam, Synthesis, 1978,545. l 6 E. C. Ashby and S. A. Noding, Tetrahedron Letters, 1977, 4579. " E. C. Ashby and T. Smith, J.C.S. Chem. Comm., 1978,30. '' E. C. Ashby and J. J. Lin, J. Org. Chem., 1978,43, 1263. l9 E. C. Ashby and J. J. Lin, J. Org. Chem., 1978,43, 2567. 2o E. C. Ashby and J. J. Lin, Tetrahedron Letters, 1977, 4481. 21 F. Sato, S. Sato, and M. Sato, J. Organometullic Chem., 1977,142,71. 22 K. Achiwa, Tetrahedron Letters, 1978, 1475. 23 G. A. Olah and G. K. Surya-Prakash, Synthesis, 1978, 397. 24 R. B. Boar, L. Joukhadar, J. F. McGhie, S. C. Misra, A . G. M. Barrett, D. H. R. Barton, and P. A. Prokopiou, J.C.S. Chem. Comm., 1978, 68. 25 R. W. Holden and M. G. Matturro, J. Org. Chem., 1977, 42, 2166. 26 H. Deshayes and J. P. Pete, J.C.S. Chem. Comm., 1978, 567.

l3

l4

Saturated and Unsaturated Acyclic Hydrocarbons

3

(46%)

(35%)

(65%) Reagents: i, Li-EtNH, or K-ButNH,-18-crown-6; ii, 2 LiEt,BH-THF-C,H,,

25 "C

Scheme 2

and primary alcohols may be achieved under mild conditions in good to excellent yield, by reduction of their phenylselenoacetals and selenides respectively, with triphenyltin h ~ d r i d e ; ~the ' selenoacetals are readily prepared from the aldehyde or ketone using the easily available crystalline reagent tris(phenylseleno)borane, in the presence of TFA.28In addition to this procedure, aldehydes and ketones are deoxygenated directly in good yield with triethylsilane in the presence of gaseous boron t r i f l ~ o r i d e and , ~ ~ thioketones are readily desulphurized by four equivalents of [HFe(CO),]-.30 Kornblum and his co-workers have described31 a highly efficient method for the replacement of a nitro-group by hydrogen, on treatment with the sodium salt of methyl mercaptan in an aprotic dipolar solvent at room temperature. The reduction probably proceeds via a radical anion process, and can tolerate the presence of other functionality, such as the cyano-, keto-, and ester groups (Scheme 3).

+

+

-+

MeSNa

25"CDMSO

Mesha

I \CN Me

-=& Me

Scheme 3

The photocatalytic decarboxylation of saturated carboxylic acids to alkanes has been shown to occur on T i 0 2 The direct replacement of primary 27 28

29

30

31 32

D. L. J. Clive, G. Chittattu, and C. K. Wong, J.C.S. Chem. Comm., 1978,41. D. L. J. Clive and S. M. Menchen, J.C.S. Chem. Comm., 1978,356. J. L. Fry, M. Orfanopoulos, M. G. Adlington, W. R. Dittman, jun., and S. B. Silverman, J. Org. Chem., 1978,43,375. H. Alper and H. N. Paik, J. Org. Chem., 1977,42, 3522. N. Kornblum, S. C. Carlson, and R. G. Smith, J. Amer. Chem. Soc., 1978, 100,289. B. Kraeutle and A. J. Bard, J. Amer. Chem., Sac., 1978,100, 5985.

General and Synthetic Methods

4

aliphatic amino-groups for hydrogen, termed 'hydrodeamination', takes place readily under mild conditions, on treatment with hydroxylamine-0-sulphonic acid and sodium hydroxide;33 the reaction works well even on amino-acid and dipeptide substrates. Aliphatic amines may also be used to introduce the trifluoromethyl group directly, by the novel procedure outlined in Scheme 4.34 R-NH:!

50$oo,ob

R-N=N-CF3

30$190,0R-CF3 b

Reagents: i, ONCF,-MeOH, -70 to +20 "C;ii, hexadecane or Bu'OH, hv, 25 "C

Scheme 4

3 Olefinic Hydrocarbons Several factors which influence the rate and yield of the 'ene' reaction have been identified this year. Gladysz and Yu have that the thermal ene reaction of P-pinene, which otherwise occurs only at temperatures greater than 150 "C, proceeds readily at room temperature under 40 kbar pressure (39 500 atm). For example, methyl pyruvate and P-pinene have been reported to react at 165 "C to afford the adduct (1) in 55% yield. Since (1)undergoes a rapid retro-ene reaction at this temperature, this yield is believed to represent the maximum equilibrium yield attainable. However, (1) is formed in quantitative yield at room temperature at 40 kbar pressure!

MiiFH 40 kbar

&OH

C0,Me

100%

(1)

The intramolecular ene reaction of the 1,6-enyne (2) appears to be retarded by a terminal methyl substituent, but significantly accelerated by an electronwithdrawing substituent, such as the methoxycarbonyl group.36 These observations are pertinent to the conversion (2) + (3) in a synthetic strategy to the iridoid carbon skeleton. R

a; R = C 0 2 M e r24 h, 135 "C; yield = >95% b; R = Me, 48 h, 225 "C; yield = 15% 33 34

35 36

G. A. Doldouras and J. Kollonitsch, J. Amer. Chem. SOC.,1978, 100, 341. P. Golitz and A. D e Meijere, Angew. Chem. Internat. Edn., 1977, 16, 892. J. A. Gladysz and Y. S. Yu, J.C.S. Chem. Comm., 1978, 599. B. B. Snider and T. A. Killinger, J. Org. Chem., 1978, 43, 2161.

Saturated and Unsaturated Acyclic Hydrocarbons

5

The eutectic mixture AlC1,-NaCl-KCl has been found to be a superior catalyst to A1Cl3 alone, in the Lewis acid-catalysed ene reaction of methyl acrylate with terminal olefins. Hence an 86 : 14 mixture of geometrical isomers of (4) is obtained from octene; the ester (4) is a useful intermediate in the synthesis of the sex pheromone from the Douglas Fir Tussock moth, and of its biologically active isomer.37 OMe

----+

0

0

(4)E : Z , 86:14

The olefinic ketone ( 5 ) is the major component (52%) in a mixture of four products from an apparent ene reaction of an allylic cation with isobutylene; the cation is formed by treatment of an cu,a’-dibromo-ketone with iron ~arbonyl.,~

(5)

An extensive literature has appeared this year devoted to the stereospecific and stereoselective construction of di-, tri-, and tetra-substituted double bonds. This has been largely due to advances in methodology in the use of organometallic agents as a response to the stereochemical and homologation problems encountered in the synthesis of biologically important isoprenoids, such as farnesol, squalene, and the juvenile hormones. Corey has now extended the Harvard programme for computer-assisted synthetic analysis (LHASA) to include suggested antithetical schemes to olefin target molecules. Several strategies for stereoselective olefin and polyene synthesis, which have been implemented in several test cases, are de~cribed.,~ In four papers4o43 Trost gives further details of the scope and limitations of the formation of vallylpalladium complexes and their application to stereochemical ‘allylic alkylation’ with soft nucleophiles. The use of these complexes in prenylation is demonstrated in a short stereoselective route to all-trans- farnesol from methyl geranoate. The ‘allylic alkylations’ attainable are outlined in Scheme 5. Further studies on the reaction of T-allylpalladium complexes with carbanions are reported by Hegedus and c o - w ~ r k e r s . ~ ~ 37

38 39 40

41

42

43 44

B. Akermark and A. Ljungquist, J. Org. Chem., 1978,43, 4387. R . Noyori, F. Shimizu, and Y. Hayakawa, Tetrahedron Letters, 1978, 2091. E. J. Corey and A. K. Long, J. Org. Chem., 1978,43,2208. B. M. Trost, P. E. Strege, L. Weber, T. J. Fullerton, andT. J. Dietsche, J. Amer. Chem. Soc., 1978, 100,3407. B. M. Trost, L. Weber, P. E. Strege, T. J. Fullerton, and T. J. Dietsche, J. Amer. Chem. SOC.,1978, 100,3416. B. M. Trost, L. Weber, P. Strege, T. J. Fullerton, and T. J. Dietsche, J. Arner. Chem. SOC.,1978,100, 3426. B. M. Trost and T. R. Verhoeven, J. Amer. Chem. SOC.,1978,100, 3435. L. S. Hegedus, T. Hayashi, and W. H. Darlington, J. Amer. Chern. Sac., 1978, 100,747.

General and Synthetic Methods

6

I * q -A PdCl .

W C O , R

H

2

R

Reagents: i, CH,(CO,Me), or CH,(CO,Me)SO,R; ii, PhSCH,COR; iii, CH,(CO,Me)SO,R; iv, ; vii, 'prenylation'

PhS(O)CH,CO,Me; v, RCH(CO,Me)SO,R; vi, SO, R

Scheme 5

The direct coupling of two unlike alkenyl groups, for example via vinylic cuprates and vinyl iodides, has not proved useful as a stereospecific process. However, Dang and Linstrumelle have now shown4' that stereospecific substitution (>97%) of alkenyl iodides with a variety of Grignard reagents can occur in high yield and under mild conditions, when catalysed with tetrakis(tripheny1phosphine)palladium (Scheme 6). Linstrumelle and his co-workers have

H

H

2Z,4E-undeca-2,4-diene Reagents: i, [Pd(PPh,),]; ii, EtMgX; iii, MeCECMgX; iv,

Scheme 6 4s

H. P. Dang and G. Linstrumelle, Tetrahedron Letters, 1978, 191.

7

Saturated and Unsaturated Acyclic Hydrocarbons

also extended46 the regioselective alkylation procedure of the Grignard reagent ( 6 ) ,reported last year, to reactions with epoxides. The 'normal' y-products (7) are mainly formed when no catalyst is present, but the abnormal a-products (8) are formed predominantly in the presence of 10% copper(1) iodide (Scheme 7). In contrast, the prenyl-lithium, generated from dimethylalkyltriphenyltin, gives the y-product in good yield and isomeric purity, but in the pfesence of 10% copper(1) iodide little regiospecificity is indicated in a product mixture containing 5 5 % yand 45% a-products. The new alkylating agent CfR BF3-, prepared in situ from an alkyl-lithium, copper(1) iodide, and boron trifluoride etherate, shows exclusive y-alkylation in reactions with alkyl halides.47

a;

b;

No catalyst (7):(8) 98:2 92:8

Yield YO 84 86

With 10% CUI (7):(8) Yield YO 2:98 75 1:99 86

Scheme 7

Murahashi et al. reported last year that allylic alcohols undergo direct asubstitution with copper(1) iodide and alkyl-lithium reagents in the presence of N,N-methylphenylaminotriphenylphosphonium iodide. The same group of workers have now shown that the corresponding tributylphosphonium iodide directs the substitution preferentially to the y-position, as illustrated in Scheme

8 .48 The stereochemically controlled addition of organometallic species of copper, tin, silicon, palladium, zirconium, and boron to acetylenes has been investigated as a route to di-, tri-, and tetra-substituted olefins. The carbon-metal bond thus formed is cleaved in a stereoselective manner either directly, or indirectly, via the corresponding vinyl-lithium reagents with a wide variety of electrophiles. In three 46 47

48

G. Linstrumelle, R. Lorne, and H. P. Dang, Tetrahedron Letters, 1978, 4069. K. Maruyama and Y. Yamamato, J. Amer. Chem. SOC.,1977,99, 8068. Y. Tanigawa, H. Ohta, A. Sonoda, and S. I. Murahashi, J. Amer. Chem. SOC.,1978, 100,4610.

General and Synthetic Methods

8 R'

R3

>=(

R3

,OH

___) I-IV '

R

R Z R4'C\Rs

P

R4 R

s

RZ +

Reagents: i, MeLi; ii, CuI; iii, RLi; iv, Bu,PN(Me)Ph I-

82o/'

18%

Z:E

=

0:100

Z : E = 36:64 Scheme 8

Negishi and his co-workers show how cis-addition of Me,AlClzZrCpzto terminal acetylenes provides a general route to trisubstituted olefins (9), with >98% stereoselectivity. The scheme has been readily adapted to a one-step synthesis of geraniol (10) and ethyl geranoate, from 6-methylhept-5en-l-yne (Scheme 9). Where difficulty has been encountered with palladium- or

Z49 = C02Et, CHzOH, COZH,or CHzOMe 2'' = I or D

(10) 87%

L

U

C

0

,

E

t

85% Reagents: i, Me,Al-Cl,ZrCp,; ii, BuLi-nucleophiles; v, CICO,Et, 25 "C, 1 h

iii, BuLi; iv, (CH,O),-THF,

25 "C, 3 h ;

Scheme 9

49

51

N. Okukado and E.4. Negishi, Tetrahedron Letters, 1978, 2357. D. E. Van Horn and E.-I. Negishi, J. Amer. Chem. Soc., 1978, 100, 2252. E.4. Negishi, N. Okukado, A. 0.King, D. E. Van Horn, and B. I. Spiegel, J. Amer. Chem. SOC.,1978, 100.2254.

9

Saturated and Unsaturated Acyclic Hydrocarbons

nickel-catalysed cross-coupling of alkenylaluminium, or zirconium compounds with alkenyl, aryl, or alkynyl halides, then catalytic amounts of zinc chloride can significantly increase the yield of the cross-coupled p r ~ d u c t . ~ ' that the dimethyl sulphide-copper(1) Helquist and his co-workers bromide complex with methylmagnesium bromide will add to simple terminal acetylenes in stoicheiometric amounts, or in only a small excess (10-15%); this procedure allows a more efficient means of constructing stereochemically defined methyl trisubstituted olefins found in natural isoprenoids (Scheme 10).

MeMgBr

MeCu(Me,S)MgBr,

Reagents: i, CuBr(Me,S)-Et,O,

ii, iii

-

__*

-45 "C; ii, n-C,H,,CECH;

n-HI,&

H

iii, ethylene oxide

Scheme 10

Confirmation that cis- addition of alkyl copper complexes occurs in these reactions has been obtained by studies of lanthanide-induced shift 'H n.m.r. spectra of the Corey has now introduced (3-methyl-3-methoxybut-lyny1)copper in T H F as a relatively inexpensive reagent for the generation of mixed cuprates (Gilman's reagents), which enable coupling reactions to occur in high yield with alkyl-lithium reagents.55 Trialkylboranes may also be used to convert terminal acetylenes into trisubstituted olefins stereospecifically, via the vinyl-lithium reagent generated by Normant's procedure (Scheme ll).56 The stereochemistry of the product is of

Reagents: i, EtMgX-CuBr,Me,S; ii, I,; iii, BuLi; iv, Et,B, -78 "C

Scheme 11

opposite configuration to that prepared earlier by Evans and his co-workers via the corresponding boronate esters. Alkenyldialkylboranes (11), derived from internal acetylenes, give the corresponding 2-olefin (12) in good yield on treatment with catalytic amounts of palladium diacetate at room temperature. This result is in sharp contrast to the palladium diacetate-triethylamine decomposition of alkenylboranes, derived from terminal acetylenes, which give rise to the corresponding E - ~ l e f i n s . ~ ~ A. Marfat, P. R. McGuirk, and P. Helquist, Tetrahedron Letters, 1978, 1363. P. R. McGuirk, A. Marfat, and P. Helquist, Tetrahedron Letters, 1978, 2465. 54 P. R. McGuirk, A. Marfat, and P. Helquist, Tetrahedron Letters, 1978, 2973. " E. J. Corey, D. Floyd, and B. H. Lipshutz, J. Org. Chem., 1978, 43, 3418. s6 N. J. Lahima, jun. and A. B. Levy, J. Org. Chem., 1978,43, 1279. 57 H. Yatagai, Y. Yamamoto, and K. Maruyama, J.C.S. Chem. Comm., 1978,702. 52

53

General and Synthetic Methods

10

The mono-addition of cuprates to benzenesulphonylacetylene leads to a mixture of E- and 2-adducts (13), the relative amount of each isomer being dependent on the steric bulk of the R-group in the cuprate.''

P h S 0 2 C ~ C H3 PhS02CH=CHR (13) ( E + 2 ) Reagents: i, R3,BH; ii. Pd(OAc),-cat.; iii, R,CuLi

Vinyl silanes continue to attract attention as intermediates for the stereoselective synthesis of olefins. Zweifel and Lewis now describes9 the stereoselective synthesis of both E-an/d 2-(1- halogenoalk-1-eny1)silanes (15) from alk-l-ynylsilanes, and show how they may then be processed to dialkyl-substituted vinylsilanes, alkenyl halides, and trisubstituted olefins (Scheme 12). The E-lhalogenoalkenyltrimethylsilanes are readily prepared in high isomeric purity by treatment of the dialkylhydroalumination adduct (14)with N-chlorosuccinimide,

RCGCSiMe,

1 ,

R

SiMe,

H

AlBu'2

)-.=( (14)

R

X

H

SiMe, 2-(15)

_iii R>=(SiMe, H

5R )=(SiMe,

X

H

R'

V,VI,

R>=(R ' H

5 R)=(R '

Br

H

R2

E - ( 1 5 ) X = CI,Br,orI

Reagents: i, Bu',AIH-Et,O; ii, Hal'; iii, Br,, hv; iv, R',CuLi or RLi-K'X; v, Br,; vi, NaOMe; vii, R2,CuLi Scheme 12

bromine, or iodine; the corresponding chloro- and bromo-2-isomers are obtained by the isomerization of the E-isomers. In addition to these findings, Snider has reported that nickel(acac)2-trimethylaluminium catalyses Grignard additions to alk- 1-ynylsilanes producing a mixture of vinyl organometallic compounds (16). These adducts are very reactive towards a wide range of electrophiles (Scheme 13).60 Thus, addition of the mixture of isomers (16) to excess iodine gives a 9 : 1 mixture of the vinyl iodide (17) in 71% yield, and the separated isomers serve as precursors to tri- and tetra-substituted olefins as 59

6o

V. Fiandanese, G. Marchese, and F. Naso, Tetrahedron Letters, 1978, 5131. G. Zweifel and W. Lewis, J. Org. Chem., 1978, 43, 2739. B. B. Snider, M. Karras, and R. S. E. Conn, J. Amer. Chem. SOC.,1978, 100, 4624.

11

Saturated and lJnsaturated Acyclic Hydrocarbons .

n-C,H,,

SiMe,

w

n-C6H, ,C-CSiMe,

H

MgBr(Ni)

(16)

n-C6HwSiMe3 Me

n-C6HwSiM

I

(17) (9 : 1)

Me

e

CH=CH,

(18) (85 : 15)

Reagents: i,[Ni(acac),]-Me,Al-MeMgBr;ii, I,; iii, H,C=CHBr

Scheme 13

indicated in Scheme 12. Treatment of (16) with vinyl bromide gives an 85 : 15 mixture of the 1,3-diene (18)in 48% yield, along with 15% of the corresponding dimer. Regioselective cis -hydroboration of 1 -trimethylsilylalk- 1-ynes similarly generates vinylboranes, which produce the corresponding a-trimethylsilylvinyllithium reagents on treatment with methyl-lithium. These also can be converted into trisubstituted vinylsilanes, with retention of stereochemistry.6' Chan and his co-workers have condensed a-trimethylsilyl-lithium with carbonyl compounds to give trisubstituted vinyl silanes, but the stereoselectivity is dependent on the relative sizes of the substituents on the carbonyl group.62 Disubstituted vinyl silanes, derived from terminal acetylenes, serve as useful precursors for the stereoselective preparation of vinyl halides.63 Vinyl stannanes, derived from terminal acetylenes and tri-n-butylstannane, are readily cleaved by butyl-lithium to give vinyl-lithium reagents; the latter are useful precursors to vinyl halides and they also undergo conjugate addition with cycloalkenones; the latter property has found use in a route to prostaglandin^.^^ Ashby and his co-workers have reported that the reagents MgH2-CuI and MgH2-CuOBu' reduce both internal and terminal acetylenes stereoselectively to the corresponding cis -olefins, with no trans -impurities or over-reduction to the alkanes. These new reagents, once prepared, may be superior to catalytic hydrogenation, in terms of the purity of the product and convenience of procedure.65 The addition of the reagent [Cp2Zr(H)C1] to terminal acetylenes occurs stereospecifically, leading to a vinyl zirconium complex, which in the presence of catalytic amounts of anhydrous [ N i ( a ~ a c )undergoes ~] rapid conjugate addition to a#-unsaturated ketones (Scheme 14).66 61

62 63 64 65

66

K. Uchida, K. Utimoto, and H. Nozaki, Tetrahedron, 1977, 33,2987. R. Amoroux and T. H. Chan, Tetrahedron Letters, 1978,4453. R. B. Miller and G. McGarvey, J. Org. Chem., 1978,43,4424. S . M. L. Chen, R. E. Schaub, and C. V. Gradzinskas, J. Org. Chem., 1978,43, 3450. E. C . Ashby, J. J. Lin, and A. B. Goel, J. Org. Chem., 197P, 43, 757. M. J. Loots and J. Schwartz, J. Amer. Chem. Soc., 1977, 99, 8045.

12

General and Synthetic Methods

Reagents: i, [Cp,Zr(H)CIl; ii,

, [Ni"(acac),]; iii, H,O'

Scheme 14

The use of low-valent titanium species continues to be explored in olefin synthesis. McMurray has shown6' that TiCl,-LiAlH4 is effective in the deoxygenation of epoxides to give olefins in high yield, although little stereospecificity is noted. Bromohydrins are reduced similarly, but benzylic and allylic alcohols undergo dimerization under these conditions; enol phosphates can be reduced to the corresponding olefins.68Titanium(0) may also be generated by treating TiCI, with potassium or, more safely and just as effectively, with lithium. These species are extremely useful reagents for both intra- and inter-molecular reductive coupling of carbonyl compounds, to give both cyclic and acyclic olefins respectively."' For example, 1,3-dicarbonyl compounds can be coupled to cyclop r o ~ e n e s . Coupling ~~) is most effective with two identical carbonyl compounds leading to symmetrical olefins, but the unsymmetrical coupling of aryl and diary1 ketones with other ketones can be useful in some cases. For example, the coupling of (19) with excess acetone gives (20).69The overall scheme has been used to prepare further examples of sterically crowded olefins, e.g. (21)71and (22),'* and also t o prepare the chiral olefin (23).73The Barton-Kellog double-elimination procedure has been adapted to produce the novel sterically crowded olefin (24).74

4Me,CO

____)

'

OMe

&J, '

(20) 85%

(19)

(21) 67

OMe

+

'

OMe

9o/'

(22)

J. E. McMurry, M. G. Silvestri, M. P. Fleming, T Hoz, and M. W. Grayston, J. Org. Chem., 1978,43, 3249.

S. C. Welch and M. E. Walters, J. Org. Chem., 1978, 43, 2715. J. E. McMurry, M. P. Fleming, K. L. Kees, and L. R. Krepski, J. Org. Chem., 1978, 43, 3255. 7 0 A. L. Baumstark, C. J. McCloskey, and K. E. Witt, J. Org. Chem., 1978, 43, 3609. " S. Nishida and F. Kataoka, J. Org. Chem., 1978, 43, 1612. '' D. Lenoir, Chem. Ber., 1978, 111,411. 7 3 D. Feringa and H. Wynberg, Rec. Trav. chim., 1978,97, 249. 74 R. J. Bushby and M. D. Pollard, Tetrahedron Letters, 1978, 3851. 69

13

Saturated and Unsaturated Acyclic Hydrocarbons

%+a+ 0

\

0

\

\/

/

\

\

I

x N=N

N=N

(24)

The reductive coupling of carbonyl compounds to olefins has also been effected by WCl6-LiA1H,, and by some tungsten and molybdenum c a r b o n y l ~ Further .~~ procedures for the deoxygenation of epoxides to olefins are d e ~ c r i b e d ; ~ ~ trifluoroacetyl iodide with sodium iodide77 and diphosphorus tetrai~dide’~ are particularly effective and can be used under mild conditions. Several other reductive-elimination procedures to give olefins have been developed this year. Marshall and Bierenbaum have identified a reductivedecyanation technique to give tetrasubstituted olefins. Hence, alkylation of the readily available mixture of nitriles ( 2 5 ) leads to a mixture of the (P,y)-doublebond isomers (26) which contains principally the E-isomer. Reduction of the mixture with sodium in liquid ammonia gives the isomerically pure olefin (27) in 92% overall yield (Scheme 15).79 Generally, the most highly substituted olefin is formed on reduction of the intermediate p, y-unsaturated nitriles.

Reagents: i, LDA; ii, MeI; iii, Na-NH,

Scheme 15

A fourfold excess of lithium in ethylamine is effective in reducing methanesulphonates of 2-hydroxy-nitriles to olefins, which contain only small amounts of the alkanes (Scheme 16).80 7s 76

’’ 78 79

Y. Fujiwara, R. Ishikawa, and S. Teranishi, J. O r g . Chem., 1978,43, 2477. K. Yamada, S. Goto, and Y . Hirata, J. O r g . Chem., 1978, 43, 2076. P. E. Sonnet, J. O r g . Chern., 1978, 43, 1841. H. Suzuki, T. Fuchita, A. Iwasa, and T. Mishina, Synthesis, 1978, 905. J. A. Marshall and R. Bierenbaum, J. O r g . Chem., 1977,42, 3309. J. A. Marshall and L. J. Karas, Synth. Comm., 1978, 8, 65.

14

General and Synthetic Methods

GHc&a;u"+ aHH

4

A!!!+

Bun

Bun

Bun

2 O%l

87% Reagents: i, NaBH,; ii, MeSO,Cl-pyridine; iii, Li-EtNH,

Scheme 16

Electrochemical reductive-elimination of the hydroxy- and phenylthio-groups from P-hydroxysulphides gives olefins in high yield.81 This complements the chemical route which uses 2-fluoropyridinium salts amd lithium iodide as the reagents for elimination.82 Lythgoe has shown that smooth elimination of Pacetoxy- or benzoyloxy-aryl sulphones with sodium amalgam occurs to give very high yields of E-1,2-disubstituted olefins from aldehydes (Scheme 17).83The R' .

R'

...

ArSO,l

-%/&

ArS02-(

)-OCOPh R2

RZ

Rl

Reagents: i, BuLi; ii, R'CHO; iii, PhCOCl; iv, Na-Hg-MeOH

Scheme 17

scheme works well for the syntheses of conjugated dienes and trienes, from a,& and a#, y,S- unsaturated aldehydes, respectively. A mild 'one flask' procedure, which leads to olefins in moderate to good yield, consists of treatment of a-chloro-ketones with Grignard reagents and subsequent reaction with lithium at -60 "C (Scheme 18).84 0

I1

c1 I

R'C-CHR2

OMgBr C1

-b R'R3A-CHR2

I

p

R1

Reagents: i, R3MgBr-ether, -60 "C; ii, Li, -60 "C; iii, 20 "C

Scheme 18

'' 83 84

T. Shono, Y. Matsumura, S. Kashimura, and H. Kyutoku, Tetrahedron Letters, 1978, 2807. T. Mukaiyami, Chem Letters, .1978,413. P. J. Kocienski, B. Lythgoe, and S. Ruston, J.C.S. Perkin I, 1978, 829. J. Barluenga, M. Yus, and P. Bernad, J.C.S. Chem. Comm., 1978, 847.

15

Saturated and Unsaturated Acyclic Hydrocarbons

The elimination of hydrogen chloride from primary chlorides using potassium hydroxide usually gives a mixture of olefins and alcohols; the addition of trimethylamine to the reaction, however, favours olefin formation.85 Neutral alumina appears to be an effective de-silicohalogenating agent,86 and t-butyl hydroperoxide on alumina is a powerful reagent for the oxidative elimination of and sodium hydrogen ~ e l e n i d e sThe . ~ ~chromium complex [( 7 - C5H5)Cr(N02)]288 telluride89offer mild procedures for the debromination of uic-dibrornides to give olefins. The dehydration of allylic, tertiary, and strained alcohols occurs under mild conditions with ferric chloride on silica," and borate esters of secondary alcohols readily form olefins on treatment with boron trifluoride etherate." Several other elimination procedures have been reported this year leading to 0 1 e f i n s . ~ ~ - ~S-~Alkylation-elimination from dithiocarbamates offers a stereoselective route to naturally occurring trienes." The pyrolysis of p -hydroxysulphoxides in refluxing xylene, in the presence of sodium ~ a r b o n a t eand ,~~ the oxidation of P-hydro~yselenides~~ form attractive routes to primary allylic alcohols. Terminal olefins are also available directly from reaction of chloromethyltrimethylsilane with Chan has extended his studies of the regioselective synthesis of olefins from carbonyl compounds and carbanions stabilized by silicon.99 Kaufmann and Waltermann have now shown that their procedure for the olefination of carbonyl groups with triphenylstannylmethyl-lithium may be effected in good yield, by either pyrolytic"' or acid-catalysedl'' elimination from the intermediate triphenylstannyl alcohols (28) (Scheme 19). Bestmann has described the synthesis of 1-substituted 2-11-alkenes by stereoselective Wittig OH Ph3SnCH2Li

-%Ph3SnCH2-A-R' I

R2

H2C=C

/

R1

'R2

Reagents: i, R'R2C=0, -50 "C; ii, H,O; iii, A, 75-170 "C; iv, H'-MeOH, 25 "C

Scheme 19 85

" 87 89 90

91

92 93 94

'' 96 97

9R 99 loo 101

M. Schlosser and C. Tarchini, Helv. Chim. Acta, 1977, 60, 3060. R. B. Miller and G. McGarvey, Synth. Comm., 1 9 7 7 , 7 , 4 7 5 . D . Labar, L. Helvesti, and A . Krief, Tetrahedron Letters, 1978, 1141. B. W. S. Kolthammer, P. Legzdins, and D. T. Martin, Tetrahedron Letters, 1978, 323. K. Ramasamy, S. K. Kalyanasundaram, and P. Shanmugam, Synthesis, 1978, 31 1. E. Keinan and Y. Mazut, J. Org. Chem., 1978,43, 1020. M. P. Doyle, S. B. Williams, and C. C. McOsker, Synthesis, 1977, 717. M. C. Baird and D. E. Laycock, Tetrahedron Letters, 1978, 3307. H. J. Liu, W. H. Chan, acd S. P. Lee, Chem. Letters, 1978, 923. F. Pochat, Tetrahedron Letters, 1978, 1055. T. Hayashi, A. Sakurai, and T. Oishi, Chem. Letters, 1977, 1483. J. Nokami, K. Ueta, and F. Okawara, Tetrahedron Letters, 1978, 4903. D. Labar, W. Dumont, L. Hevesi, and A . Krief, Tetrahedron Letters, 1978, 1145. A. Sekiguchi and W. Ando, Chem. Letters, 1977, 1293. P. W. K. Lau and T. H. Chan, Tetrahedron Letters, 1978, 2382. T. Kauffmann, R. Kriegesmann, and A. Woltermann, Angew. Chem. Internat. Edn., 1977,16,862. T. Kauffmann, H. Ahlers, R. Joussen, R. Kriegesmann, A . Vehrenhorst, and A . Woltermann, Tetrahedron Letters, 1978, 4399.

16

General and Synthetic Methods

reactions.102Non-cyclic phosphonates [e.g.MeO,CCH,PO(OEt),] lead mainly to trans- olefins in the Wadsworth-Emmons reaction with aldehydes. Steric constraints allow reactions of certain five-membered cyclic phosphonates with aldehydes to form c i ~ - o l e f i n s . ' ~ ~ Mild eliminations of uic-diols to olefins, related to the Corey-Winter and Tipson-Cohen procedures, are outlined in Scheme 20.104*'05 These methods are particularly suitable with sensitive substrates such as carbohydrates and nucleosides. (ref. 104)

H

O

n

B

R

O

p

B

--+ OH OH

ii. iii

H

o

n -

B (ref. 105)

OAc

(e.g. B = adenyl) Reagents: i, MeI-toluene, 100 "C; ii, 2e-, MeOH-OSN-NaOAc, 25 "C; iii, NaOMe

Scheme 20

The Shapiro reaction of tosylhydrazones with base has now been extended as a route to a wider variety of functionalized olefins. Thus, treatment of tosylhydrazones, which contain only a tertiary a-hydrogen, with lithium isopropylamide, can now yield trisubstituted olefins. lo6 The yields are only moderate, but the procedure is convenient. Regiospecifically generated tosylhydrazone dianions may be trapped with aldehydes and ketones to give, on neutralization, P-hydroxytosylhydrazones; further treatment with alkyl-lithium reagents yields allylic and homoallylic alcohols. lo' These procedures are exemplified in Scheme 21. NNHTs

NNHTs

(1.0: 1.1) Reagents: i, LDA-TMEDA; ii, 2RLi-THF, -50 "C; iii, EtCHO; iv, RLi

Scheme 21 lo'

H. J. Bestmann, I. Kantardjiew, P. Rosel, W. Strandsky, and 0.Vostrowsky, Chem. Ber., 1978,111, 248.

'03 104

'06

lo'

E. Breuer and D. M. Bannet, Tetrahedron, 1978,34, 997. S. Hanessian, A. Bargiotti, and M. LaRue, Tetrahedron Letters, 1978, 737. R. Mengel and J. M. Seifert, Tetrahedron Lercers, 1977, 4203. K. J. Kolonko and R. H. Shapiro, J. Org. Chem., 1978, 43, 1404. M. F. Lipton and R. H. Shapiro, J. Org. Chem., 1978, 43, 1409.

17

Saturated and Unsaturated Acyclic Hydrocarbons

Bond and his co-workers have demonstrated1osthat vinyl-lithium reagents may be prepared from benzenesulphonylhydrazones. These reagents react with a variety of electrophiles providing routes to allylic alcohols, olefins, and other unsaturated functions, as outlined in Scheme 22.

CO, H Ac6H1

3

Reagents: i, 2BuLi, -78 "C; ii, 0 "C, 15 min; iii, RCOR'; iv, RCH,Br; v, CO,; vi, HCONMe,; vii, Br+; viii, Sic1

Scheme 22 t

-

Raucher views vinyl phenyl selenide as a CH=CH synthon, on the basis of its reaction with alkyl-lithium reagents under strictly controlled conditions. Trapping of the resulting a-lithioalkyl phenyl selenide with electrophiles, followed by oxidative elimination of phenylselenenic acid, offers a route to disubstituted olefins (Scheme 23).lo9 CHZ=CHSePh

Li I RCH2CHSePh

111

H

\

C=C

+

\ H

H

E

R

H

>=(

E

=

Ii

E I RCHzCHSePh

D, Me, PhSe, PhCH(OH), or SiMe3

Reagents: i, RLi; ii, E'; iii, [O]

Scheme 23

The reaction of halogenomethylvinylsulphones with sulphinate anions, termed the Michael-induced Ramberg-Backlund olefin synthesis, represents an intereslo*

lo9

R.Chamberlin, J. E. Stemke, and F. T. Bond, J. Org. Chem., 1978,43, 147. S. Raucher and G. A. Koolpe, J. Org. Chem., 1978, 43, 4252.

A.

18

General and Synthetic Methods

ting new concept in olefin and polyene synthesis (Scheme 24)."' The reaction appears to be useful, as illustrated by the 48% yield of the diene (30) (2 : 1,E :Z ) , by reaction of (29) with sodium phenylsulphinate. The stepwise repetition of this scheme may provide a route to polyenes with extension of the chain by four carbon atoms at a time! 0 2

x V s V - N U

Nu

=

nucleophile

1

Scheme 24

a-Halogenosulphoximines have been subjected to the Ramberg-Backlund rearrangement. Benzylic a -bromo-N- ( p-tolylsulphony1)sulphoximines react with methanolic potassium hydroxide to give 2-olefins as the major product, whereas a-chlorodialkylsulphoximinesgive largely the E-olefins.lll Benzeneseleninic acid and anhydride appear to be attractive alternatives to selenium dioxide as dehydrogenation agents of steroidal ketones (31)'l 2 and amides (32).'13 Potassium fencholate as the base, and fenchone as hydrice acceptor, is an effective mixture for deprotonation-elimination of acidic C-H bonds, e.g. (33) to (34) in 90% ~ i e 1 d . I ' ~

a 1-+oal

0

(31)

a/ -oal

0

H

(32) \

0

(33) 'I1 'I2

H

--m \

\

0

(34)

T. B. R. A. Chen, J. J. Burger, and E. R. de Waard, Tetrahedron Letters, 1977,4527 C. R. Johnson and H. G. Corkins, J. Org. Chem., 1978,43,4140. D. H. R. Barton, D. J. Lester, and S. V. Ley, J.C.S. Chem. Comm., 1978, 130. T. G. Back, J.C.S. Chem. Comm., 1978, 278. M. T. Reetz and F. Eibach, Angew. Chem. Internat. Edn., 1978, 17, 278.

19

Saturated and Unsaturated Acyclic Hydrocarbons

Preparative-scale olefin metathesis of hept-3-ene, to give a mixture of hexene (14’/0), heptene (38%), and octene (20%), is described by Sammes and

’’

Matlin, using the tungsten hexachloride-lithium aluminium hydride reagent.’ Other synthetic applications of the olefin metathesis reaction have also been reported”6-’18 and reviewed.’” Several striking transpositions of double bonds have been reported this year. The 1,3-rearrangement of the allylic alcohol (35) is effected by treatment with p-NO,C,H,SeCN and PBun3followed by oxidation with hydrogen peroxide. The resultant transposed allylic alcohol (36) is obtained in excellent yield.”’ A

R

1(3.

(35)

E +RL O-SeAr

R

(36)

rearrangement of the double bond of ally1 ethers with catalytic amounts of a cationic iridium complex gives the corresponding trans-propenyl ether (37) in extremely high yield (>95%) and stereoselectivity (>97%).’” A remarkable isomerization of the remote double bond in (38), catalysed by rhodium chloride trihydrate, leads to the substituted phenol (39).’” RZ R’&OMe

R2

[1r(~od)(PMePh~)~]PF, b

R

’

A

O

M

e

4 Conjugated 1,3-Dienes

Several novel conjugated 1.3-dienes, which have substituents that are able to be transformed into other functionalities, or react in the Diels-Alder reaction, have been prepared this year. An E,Z-mixture of the highly substituted 1,3-diene (41)

11’ ‘18

‘I9 12’

12’

S. A. Matlin and P. G. Sammes, J.C.S. Perkin I, 1978, 624. W. B. Hughes, Ann. New York Acad. Sci., 1977, 295,271. M.Leionte, J. L. Bilhou, and J. M. Basset, J.C.S. Chem. Comm., 1978, 341. P.Krausz, F. Gamier, and J. E. Dubois, J. Organometallic Chem., 1978, 146, 125. T. J. Katz, Adv. Organometallic Chem., 1977, 16, 283. D. J. Clive, G. Chittattu, N. J. Curtis, and S. M. Menchen, J.C.S. Chem. Comm., 1978,770. D. Baudry, M. Ephritikhine, and H. Felkin, J.C.S. Chem. Comm., 1978, 694. P.Grieco and N. Marinovic, Tetrahedron Letters, 1978, 2545.

20

General and Synthetic Methods

is available from methoxypropadiene (40) (Scheme 25);'23the dienes are readily hydrolysed to LY -alkylidene-ketones.

Reagents: i, BuLi; ii, R'R2CO; iii, methanesulphinylation; iv, [RCuBr],MgX,LiBr-THF

Scheme 25

The functionalized 1,3-diene (43) has been synthesized by Claisen rearrangement of the allenic ortho-ester (42).'24These diene esters are useful intermediates for the conversion of allenic alcohols into myrcene derivatives such as ( )ipsenol and ipsdienol. The Cope rearrangement of the allene (44) offers a general route to a mixture of the ( E + 2)-1,3-dienones (45) in good yield.'25

*

R'

Me

R2

0 (44)

(45)

Julia has described a mild base-catalysed elimination of phenylsulphenate anion from (46) to give an E,Z-mixture of the 1,3-diene tagetone (47).lZ6Also reported is a simple route to the thermally unstable keten bisthioacetal(48) from 124

12'

H. Kleijn, H. Westmijze, and P. Vermeer, Tetrahedron Letters, 1978, 1133. M. Betrand and J . Viala, Tetrahedron Letters, 1978, 2575. A. Doutheau, G. Balme, M. Malacria, and J. Gore, Tetrahedron Letters, 1978, 1803. E. Guittet and S. Julia, Tetrahedron Letters, 1978, 1155.

Saturated and Unsaturated Acyclic Hydrocarbons

21

OSN-NaOH, 1 h 50%

'kSPh

Me

SPh

commercially available 1,3-di~hlorobut-2-ene.'~~ A new synthesis of both 1- and 2-phenylthiobuta-1,3-diene, (49)and (50)respectively, is given by Warren and his co-workers.1282-Trimethylsilylbuta-1,3-diene(51)has now been prepared in The 2-trimethylsilyl group shows little two steps from 1,4-di~hlorobut-2-yne.'~~ directing effect in the Diels-Alder reaction, in common with the previously reported 1-trimethylsilylbuta-1,3-diene. The unstable 2-methoxycarbonylbuta1,3-diene (52) is now readily accessible from the stable precursor 3-methoxycar-

Rx R2

R2

PhS

(rR1

R'

SPh (49)e.g. R'

=

Pr', R2 = Ph or Me

Me,Si

L

(50) e.g.

R1 = Ph, R2 = Me,R3 = H

Me0,C

R (51)

(52) R =

H,Ph,or alkyl

bonyl-2,5-dihydr0thiophen.~~'This diene only participates well in the DielsAlder reaction with electron-deficient dienophiles. 1,2-Dimethylenecycloalkanes (54;IZ = 4,5 , 6, or 10) can be obtained from the corresponding cyclic ketones (53) by conventional but practical c h e m i ~ t r y . ' ~ ~

12'

lZ8

lZ9 13'

V. Ratovelomanana and S. Julia, Synth. Comm., 1978, 8, 87. P. Blatcher, J. I. Grayson, and S. Warren, J.C.S. Chem. Comm., 1978, 657. D. G. Batt and B. Ganem, Tetrahedron Letters, 1978, 3323. J. M. Mclntosh and R. A. Sieler, J. Org. Chem., 1978, 43, 4431. J. W. van Straten, J. J. van Norden, T. A. M. van Schaik, G. Th. Franke, W. H. deWolf, and F. Bickelhaupt, Rec. Trav. chim., 1978, 97, 105.

22

General and Synthetic Methods

The readily available E-ethylidene-7-butyrolactone (55) may serve as precursor for the synthesis of 2-methoxycarbonyl-l,3-dienes(56).'32The procedure (Scheme 26) involves ring opening of the lactone with potassium or sodium selenoate, and thus extends Liotta and Smith's synthesis of u-olefinic esters described last year.

( 5 5 ) e.g.

R

=

Me

(56)

Reagents: i, PhSeM (M = K or Na); ii, CH,N,; iii, MeC0,H; iv, 40-50 "C

Scheme 26

1,l-Difunctionalized 1,3-dienes [e.g. ( 5 8 ) ] are easily obtained by treatment of lithiated alkoxy- or thioalkoxy-dienes (57) with a variety of e1e~trophiles.l~~ The anions from 3,6-dihydrobenzoic esters are readily alkylated to provide a general route to difunctionalized cyclohexa- 1,3-dienes (59).134 H HzC=C-HC=C

/

H

. .. %

\XR (57) X

=

0 or S

\XR

/o

(58) E d iii, iv

Me0,C

.>o =

Me, SMe, or CH(Me)OH

Me0,C

Reagents: i, BuLi; ii, E'; iii, LDA, -78 "C;iv, RX

A technique that now enables the synthesis of a variety of unstable 1,3-diaryl1,3-dienes under mild conditions is the dehydrative decarboxylation of phydroxycarboxylic acids (61) with dimethylformamide dimethylacetal. The Econfiguration of the starting a,@-unsaturatedketone (60) is unaffected during the reaction sequence, as illustrated in Scheme 27.135 Catalytic amounts of

Scheme 27 132

133 134

13'

T. R. Hoye and A. J. Caruso, Tetrahedron Letters, 1978,461 1. R. H. Everhardus, R. Grafing, and L. Brandsma, Rec. Truv. chim., 1978,97,69. R. K. Boeckman, jun., M. Ramaiah, and J. B. Medwid, Tetrahedron Letters, 1978,4485. J. Mulzer, U. Kiihl, and G. Briintrup, Tetrahedron Letters, 1978, 2953.

Saturated and Unsaturated Acyclic Hydrocarbons

23

magnesium bromide appear to favour the a-regiospecific addition of l-trimethylsilylalkyl carbanions to aldehydes and ketones to give the alkoxide (62) as the major product. Quenching of (62) with acetyl or thionyl chloride gives the 1,3-diene (63) after distillation (Scheme 28).136

Reagents: i, Bu'Li; ii, MgBr2-R1R2CO; iii, MeCOCl; iv, A

Scheme 28

A new site-selective dehydration can convert allylic alcohols (64) and (66) into the dienes (65) and (67) respectively, using 2,4-dinitrobenzenesulphenylchloride in trieth~lamine.'~'The intermediate selenenate ester presumably undergoes [2,3] sigmatropic rearrangement to the ally1 selenoxide, which then fragments to the diene. Palladium diacetate-triphenylphosphine appears to be an effective catalyst for the elimination of acetic acid or phenol from allylic acetates or phenyl ethers respectively, leading to 1,3-dienes in high yield.'38

An interesting application of the retro-Diels-Alder reaction is provided Rouessac and Haslouin in a new synthesis of the 1,3-diene (*)-ipsenol (70) (Scheme 29).139Protection of the double bond of itaconic anhydride is achieved by formation of the cyclopentadiene adduct (68). Further synthetic elaboration gives (63)which affords (*)-ipsenol in quantitative yield on thermolysis at 450 "C. Negishi finds that the palladium-catalysed coupling reaction of E- 1alkenylzirconium derivatives (71)with alkenyl halides gives 1,3-dienes with high regio- and stereo-selectivity. Furthermore, the conditions will tolerate functionality in the molecule, such as THP ether^.'^' In this respect, the procedure may offer a wider scope of application than the corresponding organoalanes derived from acetylenes. 'Head-to-tail' unsymmetrical 1,3-dienes (73) are obtained in excellent yield on dimerization of even sterically crowded terminal and internal acetylenes, via the vinyl mercurial derivatives (72).14' Other diene syntheses of interest are the P. W. K. Lau and T. H. Chan, Tetrahedron Letters, 1978, 2383. H. J. Reich, I. L. Reich, and S. Wollowitz, J. Amer. Chem. SOC.,1978, 100, 5981. 13* J. Tsuji, T. Yamakawa, M. Kaito, and T. Mandai, Tetrahedron Letters, 1978, 2075. 139 J. Haslouin and F. Rouessac, Bull. SOC.chim. France, 1977, 1242. '41 N. Okukado, D. E. Van Horn, W. L. Klima, and E.-I. Negishi, Tetrahedron Letters, 1978, 1027 14' R. C. Larock and B. Riefling, J. Org. Chem., 1978,43, 1468. 136

137

24

General and Synthetic Methods

(70) Reagents: i,

; ii, NaBH,; iii, Bu',AlH, -80 "C; iv, Bu'MgBr; v, C,H,NHCrO,Cl-CH2Cl,,

0 "C;

80 "C; vii, A, 450 "C

vi, cH,6Ph,-C,H6,

Scheme 29 THP-OCH2

)=( H

H

+)=(H

ZrCp2C1

H

77%

H

H

(71)

Me H

HgCl But

(72)

Me

(73)

preparation of optically active 1,4-dialkylbuta-1,3-dienesfrom coupling of the vinyl aluminium derivatives of chiral acetylenes*42and the short stereoselective syntheses of 1-substituted (E,E)-and (E,Z)-deca-2,4-dienyl derivatives reported by Rickards and Weiler.'43 5 1,4-, 1,5-, and 1,6-Dienes

The lead tetra-acetate-induced fragmentation of the dichlorocyclopropane (74) produces the Z-1,4-diene (75) in high yield.'44 Modification of this scheme provides intermediates to a wide variety of natural products. For example, transformation of (75)into the enyne (76) offers a route to crepynoic acid (77) in 2 1O/O overall yield. Catalysis of the ene reaction of methyl propiolate with citronellyl acetate by aluminium chloride leads to the 1,4-diene ester (78) in 5 5 % yield, as a 1: 1 mixture of diastereomers. This diene is transformed efficiently into the 1,6-diene (79), a component of the female sex pheromone of the California Red S~a1e.I~' 143 144

145

G. Giacomelli, L. Lardicci, C. Bertacci, and A. M. Caporusso, Tetrahedron, 1978, 34, 2015. G. Rickards and L. Weiler, J. Org. Chem., 1978, 43, 3607. T. L. McDonald, Tetrahedron Letters, 1978,4201. B. B. Snider and D. Rodini, Tetrahedron Letters, 1978, 1399.

mi

Saturated and Unsaturated Acyclic Hydrocarbons

25

C1

c1

1

5 steps

Acetylenes are converted into terminal E-(1,4-dienes) in a regio- and stereoselective manner by a new process which involves the palladium-catalysed cross-coupling of their alkenylpentafluorosilicate derivatives [i.e.(SO)] with allylic

OAc

+ E-CO,Me

__.+

*IC',

Reagents: i, HSiC1,-H,PtCI,;

'

Y C0,Me O

A

c

ii, KF-H,O; iii, CH=CHCH,Cl-Pd(OAc),

chlorides. The procedure can tolerate the presence of functional groups such as esters, and in this respect is more useful than hydroalumination in natural product synthesis. '41 The stabilization of vinyl cuprates by dimethyl sulphide offers a means for their regioselective cross-coupling with allylic substrates, to give 1,4-diene~.l~~ 146

'41

J. I. Yoshida, K. Tamao, M. Takahashi, and M. Kumada, TetrahedronLetters, 1978, 2161. G. L. van Mourik and H. J. J. Pabon, Tetrahedron Letters, 1978, 2705.

26

General and Synthetic Methods

In two papers, with wide ranging synthetic implications, Normant has shown how the conjugate opening of unsaturated epoxides by vinylic and allylic organocopper reagents gives rise to 1,4- and 1,5-dienols, r e ~ p e c t i v e l y . ' The ~ ~ , overall ~~~ scheme appears to have general applicability to the synthesis of insect sex pheromones, as illustrated by a stereoselective route to the pheromone of Phtorimaea opercallella (81) (Scheme 30).149 (n-c5H1

l)2cuLi

i ,n-C,H,

I

CuLi

+2A40

n-C5H O -H lii-v

Reagents: i, 2 H C E C H ; ii, NCS-Me$;

iii, CuCH,CO,Et; iv, LiAlH,; v, AcCl

Scheme 30

The lithium borates exhibit the highest regioselective 'head-to-tail' coupling amongst a number of boron 'ate' complexes of allylic halides, to give the corresponding 1,5-dienes in good yield."' Non-regiospecific Wurtz coupling of allylic halides, to the mixture of 1,5-dienes, may now be brought about by catalytic amounts of chromium(Ir), using an electrochemical cell to regenerate the low-valent chromium species.151Hence, this method may be adaptable to a continuous industrial process. Elaboration of the C,,-cyclopropane unit (83), generated by 'head-to-tail' cross-linking of the C, allene carbene (82) and isoprene, has been investigated by the Nottingham group as a novel entry into m o n o t e r p e n e ~For . ~ ~example, ~ the action of strong base on (82) gives (84),which in turn is transformed into the irregular terpenoid structure (85) on treatment with methanolic hydrochloric acid; the reduction of (82) with sodium in liquid ammonia gives the 1,5-diene dihydromyrcene (86) as the major product in 50% yield (Scheme 31).153

(86) Reagents: i, K0Bu'-DMSO; ii, MeOH-H';

iii, Na-NH,

Scheme 31 149

I5O

15'

C. Cahiez, A. Alexakis, and J. F. Normant, Synthesis, 1978, 528. C. Cahiez, A. Alexakis, and J. F. Normant, Tetrahedron Letters, 1978, 2027. Y. Yamamoto and K. Maruyama, J. Amer. Chem. Soc., 1978,100, 6282. J. Wellmann and E. Steckhan, Synthesis, 1978, 901. L. Crombie, P. J. Maddocks, and G. Pattenden, Tetrahedron Letters, 1978, 3479. L. Crombie, P. J. Maddocks, and G. Pattenden, Tetrahedron Letters, 1978, 3483.

27

Saturated and Unsaturated Acyclic Hydrocarbons

Julia has describedlS4 the con jugate addition of isoprenoid vinyl-lithiums to isoprenoid keten dithioacetals, providing a simple route to mono- and sesquiterpenes with 1,5-diene unsaturation. The method is illustrated by the synthesis of (E)-lanced (87) (Scheme 32).

kyi"

___* ii, iii

__*

57%

5 3O h

(MeS),CH

HOH,C

(87)

SMe Reagents: i,

SMe

; ii,

CuC1,-CuO-Me,CO;

iii, LiAlH,

Scheme 32

6 Allenic Hydrocarbons The transformation of non-aromatic ketones into their corresponding terminal allenes has proven to be a difficult process. Posner has now shown that the sulphoxides (88), derived from condensation of a ketone with lithium diethylphenylsulphinylmethylphosphinate, undergo re-giospecific a-alkylation; the terminal allenes are then readily formed by base-catalysed elimination from the alkylated product (89), with no formation of the corresponding acetylenes (Scheme 33). 1 5 5 Chan also describes conditions whereby aldehydes and ketones can be condensed with vinyl carbanions a- to silicon, to give terminal allenes or ally1 chlorides. 156

+ -

Reagents: i, LiCH

/

PO(OEt),

'SOPh

; ii,

LDA-MeI; iii.

; iv, NH,Cl

Li

Scheme 33 155

B. Cazes and S. Julia, Tetrahedron Letters, 1978,4065. G. H. Posner, P. W. Tang, and J. P. Mallamo, Tetrahedron Letters, 1978, 3995. T. H. Chan, W. Mychajlowskij, B. S. Ong, and D. N. Harpp, J. Org. Chem., 1978, 43, 1526.

28

General and Synthetic Methods

The propargyl-allene rearrangement has been further explored as a method for the regiospecific preparation of alkylated allenes. Pasto has indicated that the rate of addition of Grignard reagents to propargyl bromides is tremendously accelerated in the presence of catalytic amounts of certain transition-metal halides, such as ferric chloride. The resulting allenic products are uncontaminated with acetylenic In addition to these findings, the regiospecific addition of dialkylcuprates and alkylalkenylcuprates to propargyl chloride^,'^^ tosylates,160 triflates,16' chiral sulphonates,162 c a r b a r n a t e ~ ' (to ~ ~ give chiral allenes), and a m i n e ~ has l ~ ~been further developed this year as a route to the corresponding functionalized alkylated allenes. The addition of boranes to acetylenes also generates functionalized allenes. Organoboration of the alkynylstannanes (90) offers a general route to the interesting functionalized allene (91), which shows promise as a precursor to other allenes, by selective reaction of either the carbon-tin or carbon-boron bonds (Scheme 34).165Midland has described procedures for the conversion of /SnMe,

R I2B Me,SnC-CR2

(90)

+

R',B

&

\ /

R'

Me,Sn

4

C=C \

\

/C=C=C

R' BR',

\ /

R3

R2

/

/

Me,Sn

C

\

R2

(91) Reagents: i, THF or hexane, 0 " C ; ii, Me,SnC=CR3, 80-120

"C

Scheme 34

propargyl acetates into either alkylated allenes or acetylenes by addition of alkylboranes to the lithium propargylates.166 Furthermore, Zweifel shows how the lithio-propargylorganoboron intermediate (92) can add to a$-unsaturated aldehydes, which may give either homopropargyl (93) or a-allenic (94) alcohols, by strict temperature control during the addition sequence (Scheme 35).167 Catecholborane can be used to reduce conjugated acetylenic ketone tosylhydrazones ( 9 9 , with regiospecific double-bond migration, to afford the allenes (96) in fair to good yield.'68 Diethylformamide acetals appear to be excellent reagents for the smooth conversion of propargyl alcohols into the tertiary allenic amides (97).'" Propargyl alcohols are also readily transformed into the corIs*

163

165

D. J. Pasto, R. H. Shults, J. A . McRath, and A . Waterhouse, J. Org. Chem., 1978, 43, 1382. D. J. Pasto, S. K. Chou, A . Waterhouse, R. H. Shults, and G. F. Hennion, J. Org. Chem., 1978,43, 1385. D. J. Pasto, S. K. Chou, E. Fritzen, R. H. Shults, A . Waterhouse, and G. F. Hennion, J. Org. Chem., 1978,43, 1389. L. A. van Dijck, P. Vermeer, H. Westmijze, and H. Kleijn, Rec. Truu. chim., 1978, 97, 56. R. A . Amos and J. A. Katzenellenbogen, J. Org. Chem., 1978, 43, 555. G. Tadema, R. H. Everhardus, H. Westmijze, and P. Vermeer, Tetrahedron Letters, 1978, 3935. W. H. Pirkle and C. W. Boeder, J. Org. Chem., 1978, 43, 1950. A . Claesson and C. Sahlberg, Tetrahedron Letters, 1978, 1319. B. Wrackmeyer and R. Zentgraf, J.C.S. Chem. Comm., 1978,402. M. M. Midland, J. Org. Chem., 1977, 42, 2650. G. Zweifel, S. J. Backlund, and T. Leung, J. Amer. Chem. SOC., 1978, 100, 5561. G. W. Kabalka, R. J. Newton, jun., and J. H. Chandler, J.C.S. Chem. Comm., 1978, 726. K. A. Parker and J. J. Petraitis, Tetrahedron Letters, 1977, 4561.

29

Saturated and Unsaturated Acyclic Hydrocarbons

(93)

ClCH,C=CLi

[Li(R3BCECCH2C1)] (92)

C= R

Reagents: i, R,B, -90 "C; ii, prop-2-enal, -78 "C; iii, NaOH-H,O,; iv, warm to 25 "C

Scheme 35

NNHTs

II

MeCrC-CPh

% MeCH=C=CHPh

(95)

(96)

responding allene with the reagent l-ethyl-2-fluoro-4,6-dimethylpyridinium tetrafluoroborate. 1 7 0 A convenient procedure for the conversion of terminal olefins into terminal allenes by a hydroalumination procedure has been reported. 17' Protection of the allenic group, by formation of its Diels-Alder adduct with furan, enables otherwise incompatible chemical modification of the a-allenic substituents to be performed. Thermal regeneration of the allenic moiety at 450-5 10 "C completes the synthesis of novel substituted allenes, such as the hitherto unknown a-allenic o x i m e ~ . ' ~ ~ 7 Acetylenic Hydrocarbons

Two groups of workers have reported a new synthesis of the acetylenic linkage from carboxylic acid esters. The key step is the reductive elimination of the enol phosphate of a P-keto-sulphone with sodium amalgam or sodium in liquid ammonia. The novelty of this procedure is that it is eminently suitable to the synthesis of some important classes of acetylenes, such as dialkylacetylenes and T. Mukaiyami and K. Kawata, Chem. Letters, 1978, 785. F. Sato, K. Oguro, and M. Sato, Chem. Letters, 1978, 805. 172 M. Bertrand, J. L. Gras, and B. S. Galledou, Tetrahedron Letters, 1978, 2873. ''O

17'

General and Synthetic Methods

30

conjugated enynes. For example, the ester (98) is transformed into the unsymmetrical dialkylacetylene (99) in 55% overall yield,’73 and the dienyne (101) is obtained in 69% yield from the enol phosphate (Scheme 36).

y + OCO” -L

SO,Ph

(98)

bii

0

\/

1

SO, Ph

(101) Reagents: i, base; ii, base-(EtO),POCI; iii, Na-Hg or Na-NH,

Scheme 36

Prolonged reaction of the Wittig reagent chloromethylenetriphenylphosphorane (102) with aromatic aldehydes, in the presence of excess potassium t-butoxide, allows a ‘one pot’ procedure to the corresponding arylacetylenes (103).’752-Arylacetylenic ethers are now available by coupling l-ethoxy2-iodoacetylene with the aryl copper(1) ~ p e c i e s . ” ~However, Negishi now that direct coupling of aryl halides with acetylenic zinc compounds (104), catalysed by palladium, is more convenient and higher yielding than utilizing the aryl Grignard or copper reagents. This new coupling procedure may find use in the synthesis of naturally occurring arylacetylenes, such as freelingyne and junipal. The acetylenic zinc compound (105) has been used to prepare the 173 174

17’ 176

177

P. A. Bartlett, F. R. Green, and E. H. Rose, J. Amer. Chem. SOC.,1978, 100, 4852. B. Lythgoe and I. Waterhouse, Tetrahedron Letters, 1978, 2625. S. Miyano, Y. Izumi, and H. Hashimoto, J.C.S. Chem. Comm., 1978,446. W . Verboom, H. Westmijze, H. J. T. Bose, and P. Vermeer, Tetrahedron Letters, 1978, 1441. A. 0. King and E.-I. Negishi, J. Org. Chem., 1978, 43, 358.

31

Saturated and Unsaturated Acyclic Hydrocarbons

hitherto unknown perfluoroacetylenic ethers (106),178and an improved procedure for the formation of bis(pentafluoropheny1)acetylene (107), by coupling of pentafllrorophenylcopper and tetrabromoethylene, has been described. 79

+ ArCHO

Ph3P=CHC1

--+ ArC_CH (103)

(102)

RCsCZnCl (104) R

+ ArX + RCECAr =

F,CC_CZnCl

H, alkyl, or aryl, X

-b

I or Br

+ F3CC=COCF*CF2CF3 (106)

(105)

C6F5Br

=

C6F5Cu -+ C ~ F S C E C C ~ F S ( 107)

The treatment of propargyl alcohol derivatives with alkylating agents usually gives a mixture of acetylenes and allenes (see Section 6). By crowding the 1-position with the bulky trimethylsilyl group, the 3-acetate group in (108) may be displaced directly by an organocuprate with no allene formation. The synthetic utility of this interesting steric effect to give the substituted acetylenes (109) in high yield is illustrated in Scheme 37.lgo OH

I

HC=CCHC5Hl

OAc i-iii d

I

5 Me3SiC=CCHC5Hl1

Me3SiC~CCHC5Hl (108)

R I

(109)

Reagents: i, 2BuLi; ii, Me3SiC1;iii, Ac,O; iv, R,CuLi

Scheme 37

Terminal acetylenes can be alkylated to give chain-lengthened internal acetylenes in good yield, either by the rapid addition of trialkylalanes in the presence of nickel(I1) catalysts181or by electrochemical addition of organoboranes.182 Hydroalumination may be used in a convenient conversion of terminal olefins into the corresponding acetylene^.'^^ An improved procedure for the synthesis of cyclo-octyne from cyclo-octene by a bromination-dehydrobromination sequence has been r e p 0 ~ t e d . l ~ ~ Conditions have been described where both vinyl sulphides and vinyl sulphoxides may serve as acetylene equivalents. Thus the ‘super-base’ potassium 3aminopropylamine (KAPA), reacts readily with the internal vinyl sulphide (110) at room temperature, to produce the corresponding terminal acetylene (11 l).lg5 17’ 179

la3 la4

’”

S. Trofimenko, R. W. Johnson, and J. K. Doty, J. Org. Chem., 1978,43,43. R. G. Gastinger, E. F. Tokas, and M. D. Rausch, J. Org. Chem., 1978,43, 159. R. S. Brinkmeyer and T. L. McDonald, J.C.S. Chem. Comm., 1978, 876. G. Giacomelli 2nd L. Lardicci, Tetrahedron Letters, 1978, 2831. Y. Takahashi, M. Tokuda, and A. Suzuki, Chem. Letters, 1977,999. F. Sato, H. Kodarna, and M. Sato, Chem. Letters, 1978, 789. L. Brandsma and H. D. Verkruijsse, Synthesis, 1978, 290. C. A. Brown, J. Org. Chem., 1978, 43, 3083.

32

General and Synthetic Methods

(111)

The reaction involves elimination followed by rapid isomerization. Phenylvinyl sulphoxide (112) serves as a convenient alternative to acetylene gas in the Diels-Alder reaction. The in situ thermal extrusion of phenylsulphenic acid under the reaction conditions gives the adducts [e.g. (113)] in excellent yield.lg6 0

8 Enynes and Polyunsaturated Hydrocarbons A useful application of the oxy-Cope rearrangement has been used to produce conjugated enynes [e.g. (114) + (115)]. The enyne (115) is an intermediate in a synthesis of the sex pheromone of the Pine Sawfly Neodiprion le~ontei.'~'Potassium t-butoxide in liquid ammonia has been found to be the preferred base to produce high yields of the conjugated 1-alkylthio- or 1-arylthiobut-3-en-1-ynes (117).lg8Elimination of thiols from the acetylenic disulphides (116) under these conditions completely suppresses the competing formation of cumulene or diene-sulphides.

RSCH2CZCCH2SR -+ RSCrCCH=CHZ (116)

(117)

Two molar equivalents of homopropargylating agents, such as (11 S), couple in excellent yield with the cuprates (119) derived from terminal acetylenes, provided that hexamethylphosphoramide and trimethyl phosphite are present in the reaction medium. The coupled products (120) serve as useful precursors to insect pheromones. 189 lS6

lS7

lS8

lS9

L. A. Paquette, R. E. Moerck, B. Harirchian, and P. D. Magnus, J. Amer. Chem. SOC.,1978,100, 1597. P. Place, M. L. Roumestant, and J. Gore, J. Org. Chem., 1978, 43, 1001. R. H. Everhardus and L. Brandsma, Synthesis, 1978,359. H. Westmijze, H. Kleijn, and P. Vermeer, Tetrahedron Letters, 1978, 3125.

Saturated and Unsaturated Acyclic Hydrocarbons

<

Me

H \ / [Et/c=c\CH2CH2~

Me3SiC=CCH2CHzI (118) +

c=c

(119)

Et Me Et

1

33

MgBr,LiBr. CuEt

70% THF-HMPA-P(OMe),

\

,c=c

1

/

H

\CH,CH, \

Et

/

/

c=c

\

CH2CH2CGCSiMe3

(120)

Methods of alkylating terminal acetylenes to give internal acetylenes have been described above (see Section 7). A new technique, which is particularly applicable to the synthesis of polyacetylenes, is the use of diazabicycloundecane to promote the copper(1) halide-catalysed coupling of ally1 or propargyl derivatives with terminal acetylenes. This procedure is iilustrated by the formation of a Cll diacetylene fragment (121) which is an intermediate in a route to eicosatetraynoic acid. 190 The silyl-protected Grignard reagent (122) couples with cyclo-octatetraene dibromide to give the expected E,Z,Z,E-polyenynes, which on photolysis isomerize to the all-E-isomer. The parent polyenyne (123) may then be regenerated on treatment with aqueous base.191 Me(CHJ4C~CH2I

8219/, + Me(CH2)&=CCH2CrCCH20H (121)

Reagents: i, HCrCCH,OH-DBU-CuI

R3Si(C=C),MgBr

d

R3Si(C~C),(CH=CH)4(C=C),SiR3

ti. iii

H(CrC),(CH=CH)4(CZC),H

Reagents: i, cyclo-octatetraene dibromide; ii, h v ; iii, aqueous base

A novel scheme to Vitamin D3derivatives has been reported by Okamura and his c o - w o r k e r ~ . 'The ~ ~ key step in the sequence is the coupling of the cuprate (124) with the acetylene (125), to produce a 1 : 1 mixture of the vinylallenes (127a) and (127b) in 37% yield, after removal of the acetate protecting group. Thermolysis of (127a) gives a 52% yield of the trienol (126a) as the major product. Unfortunately, the C-1 epimer (127b) gives only 11%of the biologically active Vitamin D3analogue (126b), in a mixture of isomeric trienes (Scheme 38). 190

19' '91

K. Eiter, F. Lieb, H. Disselnkotter, and H. Oediger, Annalen, 1978, 658. S. J. Harris and 0. R. M. Walton, Tetrahedron, 1978, 34, 1037. M. L. Hammond, A. Mouriiio, and,W. H. Okamura, J. Amer. Chem. SOC.,1978, 100,4907.

34

General and Synthetic Methods

(124)

, 1 1 1

(126) a; R' b; R'

= =

H, R2 = OH OH, R2 = H

Reagents: i, - 7 8 ° C 5 h; ii, Bu,&F; iii, A

Scheme 38

Functionalization of the terminal double bond of polyisoprenoids is achieved by regioselective addition of benzenesulphenyl chloride followed by baseinduced elimination of hydrogen chloride; thus treatment of the benzyl ether (128) of E,E-farnesol gives the sulphide (129) in 48% yield.'93 Trienes and (OCHZPh

Reagents: i, PhSCI, -78 "C; ii, Et,N-DMF

polyenes, which are formed by the Wittig coupling of a,&unsaturated ylides and a,P-unsaturated aldehydes invariably contain large amounts of the products of 2-olefination. Clough and Pattenden have now shown that the corresponding reactions with phosphine oxide anions (Horner variation) lead to largely Eolefination in favourable [e.g. (130) +- (131)]. 193 194

Y. Masaki, K. Hashimoto, and K. Kaji, Tetrahedron Letters, 1978, 5123. J. M. Clough and G. Pattenden, Tetrahedron Letters, 1978, 4159.

Saturated and Unsaturated Acyclic Hydrocarbons

POPh,

(130)

35

Aldehydes and Ketones BY S. M. ROBERTS

1 Preparations of Aldehydes and Ketones By Oxidation of Alcohols.-Barium manganate is readily available and stable, and has been recommended for the oxidation of primary and secondary alcohols to aldehydes and ketones respectively.' Chromic acid adsorbed on to silica gel2 and the recyclable poly[vinyl(pyridinium chromate)13 effect the same changes, while acid-stable primary and secondary alcohols are oxidized rapidly using potassium dichromate, sulphuric acid, methylene chloride, and a phase-transfer ~ a t a l y s tBenzeneseleninic .~ anhydride is an alternative reagent for the oxidation of alcohols under essentially neutral conditions.' Trityl tetrafluoroborate oxidizes secondary alcohols to ketones: primary, secondary diols are selectively oxidized at the secondary position by this reagent.6 p-0x0-bis(chlorotripheny1bismuth)is a mild reagent for the oxidation of alcohols, and is particularly suitable for the oxidation of the hydroxy-group in allylic alcohols.' Dichlorodicyanobenzoquinone (DDQ) with periodic acid in HCI-benzene has also been used for the latter purpose.8 Further information has appeared concerning the oxidation of primary, secondary, and benzylic alcohols (including hindered and bicyclic cases) using dimethyl sulphoxide (DMSO) 'activated' by various electrophiles.' Among previously unreported 'activators' for this system, oxalyl chloride'" is generally effective. Primary and secondary alcohols activated by the pyridinium salt (1)

I Me

Ts

(1) 1 2

3 4 5

6

7 8 Y

10

H. Firouzabadi and E. Ghaderi, Tetrahedron Letters, 1978, 839. E. Santaniello, F. Ponti, and A. Manzocchi, Synthesis, 1978, 534. J. M. J. Frkchet, J. Warnock, and M. J. Farrall, J. Org. Chem., 1978, 43, 2618. D. Pletcher and S. J. D. Tait, Tetrahedron Letters, 1978, 1601. D. H. R. Barton, A. G. Brewster, R. A. H. F. Hui, D. J. Lester, S. V. Ley, and T. G. Back, J.C.S. Chern. Comm., 1978,952. M. E. Jung and R. W. Brown, Tetrahedron Letters, 1978, 2771. D. H. R. Barton, J. P. Kitchin, and W. B. Motherwell, J.C.S. Chem. Comm., 197d, 1099. S. Cacchi, F. LaTorre, and G. Paolucci, Synthesis, 1978, 848. S. L. Huang, K. Ornura, and D. Swern, Synthesis, 1978,297; K. Omura and D. Swern, Tetrahedron, 1978,34, 1651. A. J. Mancuso, S. L. Huang, and D. Swern, J. Org. Chem., 1978,43, 2480.

36

37

Aldehydes and Ketones

react with DMSO to give the corresponding aldehydes and ketones in good yields. l 1

Thio- and Seleno-ketones.-A new regiospecific synthesis of a-thioketones has been described (Scheme l ) . I 2 Note that desulphurization of a-phenylthioketones can be achieved by treatment of these ketones with zinc and chlorotrimethyl~ilane.'~ Methyl 2-nitrophenyl disulphide is a convenient reagent for bis-a-sulphenylation of ketones.14

HySEt % RCH(0H)CSEt It CH,

RCOCH(Me)SEt

CH2

Reagents: i, Bu"Li; ii, RCHO; iii, TsOH-toluene, A

Scheme 1

The established routes to organo-selenoketones have been reviewed. l 5 New methods of preparation of these important synthetic intermediates include the oxidation of alkenes, e.g. using diphenyl diselenide, bromine, and hexabutyldistannoxane (Scheme 2).l6 For terminal alkenes alternative procedures involve the intermediate formation of the corresponding bromoselenide or ethoxyselenide; the former species is converted into a phenyl selenomethyl ketone using silver hexafluorophosphate in DMSO followed by reaction with triethylamine. l 7 @-Phenylselenoketonesprotected as the trimethylsilyl enol ether are available by reaction of an a@-unsaturatedketone with phenyl trimethylsilyl selenide.'* OSnBun3

1

R1&HCH(R2)SePh -+ R'COCH(R2)SePh Reagents: i, (PhSe),-Br,-(Bu",Sn),O

Scheme 2

Cyclic Ketones.-A simple method for the preparation of cyclobutanone from phenylthiocyclopropane and formaldehyde applicable to large-scale (30 g) runs has been described." The conversion of unsymmetrical cyclic ketones into aa-spiroalkyl-cyclobutanones through oxaspiropentanes has been extended so that both diastereomers are now available (Scheme 3)." The synthetic utility of these cyclo-

l2 13

l4 l5 l6

l9

*"

K. Hojo and T. Mukaiyama, Chern. Letters, 1978, 369. M. Braun, Tetrahedron Letters, 1978, 3695. S . Kurozumi and T. Toru, Synth. Comm., 1977, 7,427. Y. Nagao, K. Kaneko, K. Kawabata, and E. Fujita, Tetrahedron Letters, 1978, 5021. D. L. J. Clive, Tetrahedron, 1978, 34, 1049. I. Kuwajima and M. Shimizu, Tetrahedron Letters, 1978, 1277. S . Raucher, Tetrahedron Letters, 1978,2261; T. Takahashi, H. Nagashima, and J. Tsuji, ibid., p. 799. D. Liotta, P. B. Paty, J. Johnston, and G . Zima, Tetrahedron Letters, 1978, 5091. B. M. Trost and W. C. Vladuchick, Synthesis, 1978, 821. B. M. Trost and P. H. Scudder, J. Amer. Chem. Soc., 1977,99, 7601.

38

General and Synthetic Methods

I Reagents: i, LiC,H,SPh,;

87%

ii, NaSePh; iii, m-CIC,H,CO,H-pyridine;

13 O/o

iv, Li' or H'

Scheme 3

butanone derivatives has been exemplified by a novel chain-extension procedure involving a Grob fragmentation (Scheme 4).21

Reagents: i, LiC,H,SPh,;

ii, H'; iii, M e 0

Scheme 4

Two new methods for one-carbon atom homologation of a cyclic ketone have been described (Scheme 5).22

6 Reagents: i, Bu"Li; ii, N,CH,CO,R; iii, Na-NH,

Scheme 5 "

B. M. Trost, M. J. Bogdanowicz, W. J. Frazee, and T. N. Salzmann, J. Amer. Chem. Soc., 1978,100, 5512.

22

H. Taguchi, H . Yamamoto, and N. Nozaki, Bull. Chem. SOC. Japan, 1 9 7 7 , 5 0 , 1 5 9 2 ;S . W. Baldwin and N. G . Landmesser, Synth. Comm., 1 9 7 8 , 8 , 413.

Aldehydes and Ketones

39

The triphenyl- 1-phenythiovinyl phosphonium salt (2) has been prepared and utilized to prepare cyclopentanone derivatives (Scheme 6).23

CH,=C-6Ph31-

+

I

SPh

(2) Reagents: i, MeCOCH,CH(CO,Et),-NaH; ii, CF,CO,H

Scheme 6

A new procedure for the synthesis of large-ring a,@-ynones involves the intramolecular acylation of readily accessible w-trimethylsilylethynyl-alkanoyl chlorides. 24 Dicarbonyl Compounds.-Phase-transfer catalysis allows potassium permanganate oxidation of lipophilic non-terminal alkynes to 1,2-diones to be a~hieved.'~ Se-Acylmethylselenocarboxylatesare available by reaction of potassium selenocarboxylates and a-bromo-ketones. t-Pentoxide readily extrudes the selenium to provide 1,3-diones [equation (l)].'"Cyclopentane-1,3-dione is now R'COSeK

+ BrCH2COR2

-KBr b

R'COSeCH2COR2

K°C5H11b

R'COCH2COR2 (1)

available from norbornene in three steps and 70°/0 yield.274-Ylidenebutenolides rearrange to the corresponding cyclopentene- 1,3-diones in high yield on treatment with methoxide ion as illustrated in equation (2).28A method for the

0

preparation of 2,2-dialkylcyclopentane-1,3-diones involves the intramolecular using oxidative coupling of dilithium enolates of 3,3-dialkylpentane-2,4-diones copper(I1) triflu~roacetate,~'and an equally facile route to 2-acylcyclohexane1,3-diones has been disclosed [equation (3)].30 23

A. T. Hewson, Tetrahedron Letters, 1978, 3267.

K. Utimoto, M. Tanaka, M. Kitai, and H. Nozaki, Tetrahedron Letters, 1978, 2301. D. G. Lee and V. S. Chang, Synthesis, 1978, 462. 26 H. Ishihara and Y. Hirabayashi, Chem. Letters, 1978, 1007. " C. Lick and K . Schank, Chem. Ber., 1978,111, 2461. 28 D. R. Gedge and G. Pattenden, J.C.S. Chem. Comm., 1978,880. 29 Y . Kobayashi, T. Taguchi, and T. Morikawa, Tetrahedron Letters, 1978, 3555. 30 A . A . Arhrem, F. A. Lakhvich, S. I. Budai, T. S. Khebnicova, and I. I. Petrusevich, Synthesis, 1978, 925. 24

25

General and Synthetic Methods

40

R’COCI

+ 0

bzl

o

CSH5N,

b

R

z

RZ

I

(3)

R’c1&R2

___* *‘‘I3

R2

COR’

Acyl derivatives of Meldrum’s acid (3) are readily prepared and undergo alcoholysis to give P-keto-esters [equation (4)].31Two new procedures for the

preparation of y-keto-aldehydes have appeared: one involves the acylation of LY -silyloxyallylsilanes (Scheme 7),32 while the second involves the use of -OSiRi,

i,ii

iii, iv

-SIR’,

--+ R3CO(CH2),CH0

OSiR‘,

R” = alkyl or vinyl

Reagents: i, Bu’Li; ii, ClSiR’,; iii, R3COCl-TiCI,; iv, H,O

Scheme 7

tris(pheny1thio)methyl-lithium as a formyl anion equivalent in conjugate addition reactions (Scheme 8).33 R’

I

a OCHCH(R’)CH2COR2

(PhS)3CLi+ R’CH=CHCOR2 + (PhS)3CCHCH2COR2 Reagents: i, CrC1,; ii, Cl+-Ag’-H,O

Scheme 8

Skipped alkynes yield 1,4-diones on treatment with mercuric oxide and perchloric acid in aqueous d i ~ x a nA. ~base-catalysed ~ oxy-Cope rearrangement procedure provides a convenient pathway to partially protected unsymmetrical 1,6-diones [equation (5)].35 H

O

R ZX

R4

KH

,

R ~1 C Z R 3~

~ (5)

R2X

R4

X=OorS 31

32 33 34

3s

Y. Oikawa, K. Sugano, and 0. Yonemitsu, J. Org. Chem., 1978,43,2087. A. Hosomi, H. Hashimoto, and H. Sakurai, J. Org. Chem., 1978,43, 2551. T. Cohen and S. M. Nolan, Tetrahedron Letters, 1978, 3533. W. J. Gender, J.-C. Petitpierre, and J. W. Dean, J. Org. Chem., 1978, 43, 4081. D. A. Evans, D. J. Baillargeon, and J. V. Nelson, J. Amer. Chem. Soc., 1978, 100, 2242.

Aldehydes and Ketones

41

Other Preparations.-Carboxylic acids have been converted into aldehydes through di-isobutylaluminium hydride reduction of 3-a~ylthiazolidine~~ or 2-thiazoline-2-thiol ester37 intermediates. Bis(triphenylphosphine)copper(I) tetrahydroborate, (Ph3P)2CuBH4,shows promise as a new reagent for the reduction of acid chlorides to aldehydes.38 The same conversion can be accomplished using sodium borohydride in a mixture of acetonitrile and hexamethylphosphoramide containing a cadmium(@ chloride-dimethylformamide Organotin compounds readily undergo palladium-catalysed coupling with acid chlorides [equation ( 6 ) ] : this process has distinct advantages over similar traditional methods; e.g. an aldehyde moiety is unaffected in the new method.40 R'COCl

+ R24Sn

[PhCH,Pd(PPh,),Cl] b

R'COR2

+ R23SnCI

The transformation of acid chlorides into hydroxymethyl ketones can be achieved in good yield under mild conditions using tris(trimethylsily10xy)ethylene.~~aHydroxy-carboxylic acids, readily available from carboxylic acids, are decarbonylated at room temperature on treatment with a benzoxazolium salt and triethylamine to give ketones in good yields [equation (7)].42

R IRZC ( O H ) C 0 2 H

+ Et

I

o N $ C i

'

0

+ 2 Et,N

-

Et

R'R'CO

+ CO +

(7)

+ Et,&HCl- + Et3&HBF4Polymer-supported tetracarbonylhydridoferrate converts an alkyl bromide or iodide into the corresponding aldehyde in excellent yield.43 The acylation of a-lithiated trimethylsilyl esters R'CH(Li)CO,SiMe, can be achieved using the mixed anhydride system R2COOC0,Et to give the corresponding ketone R'CH2COR2 after hydrolysis and d e c a r b ~ x y l a t i o nAlkyl .~~ (but not vinyl) Grignard reagents are cleanly acylated using the mixed anhydride Alternatively ' Grignard reagents system RCOOP(0)Ph2 (R = alkyl or a r ~ l ) . ~ R'MgBr can be converted into ketones R'COR2 using pentacarbonyliron followed by alkyl iodide R21.46 36

37

38

39 40 4'

42 43 44

45 46

T . Izawa and T. Mukaiyama, Chem. Letters, 1977, 1443. Y. Nagao, K. Kawabata, and E. Fujita, J.C.S. Chem. Comm., 1978, 330. G. W. J. Fleet, C. J. Fuller, and P. J. C. Harding, Tetrahedron Letters, 1978, 1437; T. N. Sorrel1 and R. J. Spillane, ibid., p. 2473. R. A. W. Johnstone and R. P. Telford, J.C.S. Chem. Comm., 1978,354. D. Milstein and J. K. Stille, J. Amer. Chem. SOC.,1978, 100, 3636. A. Wissner, Tetrahedron Letters, 1978, 2749. T. Mukaiyama and Y. Echigo, Chem. Letters, 1978,49. G . Cainelli, F. Manescalchi, A. Umani-Ronchi, and M. Panunzio, J. Org. Chem., 1978, 43, 1598. R. Couffignal and J.-L. Moreau, Tetrahedron Letters, 1978, 3713. A. S. Kende, D. Scholz, and J. Schneider, Synth. Comm., 1978,8, 59. M. Yamashita and R. Suemitsu, Tetrahedron Letters, 1978, 761.

42

General and Synthetic Methods

A new type of catalyst, a cobalt carbonyl complex, has been found for low-temperature (uiz. 50 "C) homogeneous hydroformylation of a l k e n e ~ . ~ ' Nafion-H (a superacidic perfluorinated resin sulphonic acid) impregnated with mercury is recommended as a catalyst for the hydration of alkynes R ' C z C R 2 (R' = I4 or aryl, R2 = H, alkyl, or aryl) to form ketones R'CH2COR2.48Two mild methods for the hydrolysis of vinyl halides to ketones have been described: one utilizes BF3,Et20 and mercury(I1) acetate in acetic acid and the second mercury(r1) acetate in trifluoroacetic acid.49 A new facile conversion of sulphoxides into aldehydes involves an initial Pummerer reaction with trifluoroacetic acid and subsequent hydrolysis (Scheme 9)?O RCH2SOPh i ,RCH(OCOCF3)SPh R

=

RCHO

alkyl or aryl

Reagents: i, (CF,CO),O; ii, NaHCO, (or CuCl, or HgCI,)-H,O-MeCN

Scheme 9

A novel procedure for the homologation of aldehydes involves a phase-transfer catalysed Wittig reaction using the phosphonium salt MeSCH2PPh3C1-, and mercury(I1) chloride catalysed hydrolysis of the resultant vinyl ~ulphide.~' Alternatively, the pkusphonate (Et0)2P(0)CH20CH2CH20Me can be employed to achieve the same goal giving an acid-sensitive enol ether on reaction with an aldehyde or ketone.52 Phenyl alkyl ketones may be prepared by the reaction sequence depicted in Scheme OSiMe3

I

OSiMe3

PhCHO -b PhCHP(O)(OEt),

4 Ph(!P(O)(OEt), I R

PhCOR

Reagents: i, Me,SiY(O)(OEt),; ii, RX-base; iii, O H

Scheme 10

a-Hydroxysulphides are now readily available from alkenes, and they are susceptible to oxidative cleavage forming an aldehyde-acetoxysulphide: the overall result is the conversion of an alkene into a mono-protected dialdehyde Both cis- and trans-1,2-diols are cleaved to dialdeydes by iodine (Scheme 1l).54 triacetate and iodine(1) A. Matsuda, S. Shin, J. Nakayama, K. Bando, and K. Muraka, Bull. Chem. SOC.Japan, 1978, 51, 3016. 48 G. A. Olah and D. Meidar, Synthesis, 1978, 671. 49 S. F. Martin and T. Chou, Tetrahedron Letters, 1978, 1943. '"H. Sugihara, R. Tanikaga, and A. Kaji, Synthesis, 1978, 881. 5 1 C. Botteghi, G. Caccia, and S . Gladiali, Chimica e Industria, 1977, 839. '* A. F. Kluge, Tetrahedron Letters, 1978, 3629. 53 T. Hata, A. Hashizume, M. Nakajima, and M. Sekine, Tetrahedron Letters, 1978, 363. 54 B. M. Trost, M. Ochiai, and P. G. McDougal, J. Amer. Chem. Soc., 1978, 100, 7103. '' R. C. Cambie, D. Chambers, P. S. Rutledge, and P. D. Woodgate, J.C.S. Perkin I, 1978, 1483.

47

43

Aldehydes and Ketones

Reagents: i, Pb(OAc),-PhSSPh-CF,CO,H; ii, base; iii, Pb(OAc),-pyridine-MeC0,H

Scheme 11

Doleschall has provided a satisfactory method for the conversion of a primary amine containing a primary aikyl group into an aldehyde (Scheme 12).56 Ph

I

N

Pr"NH2

Ph NI

SMe

A

Pr"N< N"

I

Ph

EtCH-N=( NH-NCO2Et I

N" I

I

Ph

C0,Et

SMe

7

Ph

I

Ph Ph I N

SMe Reagents: i, B r < , ~ ~ ~Br--Et,N; ii, EtO,CN=NCO,Et; iii, H30' NS"

I

Ph

Scheme 12

n-Hexylamine can be transformed into hexanal by the procedure outlined in equation (8) (R' = C5Hll,R2 = H): secondary alkylamines give ketones using this meth~dology.~' R'CM(R2)NHR3

R'CH(R2)N(CI)R3 -02

R'C(R2)=NR3 H', R'COR2

(8)

Treatment of t-alkyl nitriles with alkali metals gives imine salts which on hydrolysis furnish ketones. The method is well suited to the synthesis of highly hindered symmetric ketones [equation (9)].'" R'

I

R2-C-CN I R3

R'

R'

I

--%R2-&-C-C-R2 l 3 II

I

R'

%+

R N- R3

G . Doleschall, Tetrahedron Letters, 1978, 2131. F. E. Scully, jun. and R. C. Davis, J. Org. Chem., 1978,43, 1467. '' J.-P. Mazaleyrat, Canad. J. Chem., 1978,56, 2731. 56

"

I (R2-C ) 2 C0 I R3

(9)

General and Synthetic Methods

44

Nitroalkanes (R'R2CHN02)give the carbonyl compounds (R'R2CO) on reaction of singlet oxygen with the corresponding nitronate Vacuum pyrolysis of sodium (or lithium) salts of 1-acyl-2-p-tosylhydrazines realizes a simple method for the preparation of aldehydes and represents a modification of the McFadyen-Stevens procedure that is applicable to basesensitive aldehydes [equation ( a-Bromoselenides can be obtained quantitatively from vinyl selenides: now it has been demonstrated that anhydrous dimethyl sulphoxide will transform these halogenoselenides into aldehydes [equation (11)].61

M+

RCONHNSO, O

M

RCHO

e

R'

R'

MseR3 HBr

--+

RZ

H

\

/ R2

+

N,

+

Me R' Me,SO

CHCH(Br)SeR3 --+

\CHCHO

(11)

R2/

A full paper has appeared on the use of UF, for the regiospecific oxidative cleavage of alkyl methyl ethers. Oxonium ions are formed as intermediates and these species can be trapped with the appropriate dithiol to give 1,2-dithiolans or 1,3-dithi01ans.~~ 2-Substituted benzothiazoles are available from 2-aminothiophenol and the appropriate carboxylic acid63or by metallation and subsequent alkylation of the parent molecule. These benzothiazole derivatives provide aldehydes on methylation, sodium borohydride reduction, and h y d r ~ l y s i sReaction .~~ of 2-lithiobenzothiazole with ketones and subsequent dehydration yields 2-vinylbenzothiazoles which can be transformed into alkenyl carboxaldehydes or alkenyl alkyl ketones as desired.65 2-Vinylbenzothiazoles are alkylated a- to the heterocyclic ring. Moreover, 2-vinylbenzothiazoles act as Michael acceptors towards organolithium and organocuprate species so that two appendages may be attached to the cycloalkenyl unit prior to removal of the benzothiazole group (Scheme 13).66 Two new methods for the 1,2-transposition of a carbonyl group both involve the formation of a arenesulphonylhydrazone derivative. One method proceeds uia a vinyl sulphide,' while the second involves a vinyl silane (Scheme 14).68 Direct acylation of sodium or potassium methanenitronate using the appropriate N-acylimidazole allows the preparation of a variety of a - n i t r o - k e t ~ n e s . ~ ~ Acylation of the dianion (4) derived from ethyl hippurate leads to a-aminomethyl ketones (as the hydrochloride salts) after acid hydrolysis [equation (1a].'" 59

6' 62 63 64 65

66 67

7o

J. R. Williams, L. R. Unger,'and R. H. Moore, J. Org. Chem., 1978, 43, 1271.

M. Nair and H. Shechter, J.C.S. Chem. Comm., 1978,793. W. Dumont, M. Sevrin, and A. Krief, Tetrahedron Letters, 1978, 183. G. A. Olah and J . Welch, J. Amer. Chem. SOC., 1978, 100, 5396. D. L. Boger, J. Org. Chem., 1978, 43, 2296. E. J. Corey and D. L. Boger, Tetrahedron Letters, 1978, 13. E. J. Corey and D. L. Boger, Tetrahedron Letters, 1978, 5. E. J. Corey and D. L. Boger, Tetrahedron Letters, 1978, 9. S . Kano, T. Yokomatsu, T. Ono, S. Hibino, and S . Shibuya, J.C.S. Chem. Comm., 1978,414. W. E. Fristad, T. R. Bailey, and L. A. Paquette, J. Org. Chem., 1978, 43, 1620. D. C. Baker and S. R . Putt, Synthesis, 1978, 478. D. A. Evans and P. J. Sidebottom, J.C.S. Chem. Comm., 1978, 753.

Aldehydes and Ketones

45

lvii

Me

SO3F-

b i i i , ix

l v i i i . iv

M e C 0 c R 3

MeAR3 Reagents: i, P,O,-MeS0,H; ii, R'X; iii, MeS0,F; iv, NaBH,; v, Ag'-H,O; vii, P,O, or MeS0,H etc.; viii, MeLi; ix, CH,=CHCH,Br

vi, R2COCH,R3;

Scheme 13

Reagents: i, ArSO,NHNH,-H'; ii, Bu"Li; iii, Me,SiCl; iv, m-CIC,H,CO,H; v, LiAlH,; vi, CrO,; vii, MeSSMe; viii, HgC1,-H,O-MeCN

Scheme 14 COR

PhCONHCH,CO,Et

% PhCORCHC0,Et

(RCo)zo b

I kc,

PhCONHCHCO2Et

(4)

RCOCH2NH3+Cl-

(12)

46

General and Synthetic Methods

Ketones are converted into thioketones using the dimer of p-methoxyphenylthionophosphine sulphide (5).71 Thermal decomposition of the readily prepared triphenylphosphorylidene hydrazone of a ketone in the presence of elemental sulphur is recommended for the synthesis of highly hindered thioketone~.~’

iMeQ2 Reactions of Aldehydes and Ketones Alky1ation.-Potassium enolates of aldehydes can be prepared by reaction of the aldehyde with potassium hydride in tetrahydrofuran. Reaction of these enolates with activated primary bromides (ally1 or benzyl) and methyl iodide gives rise to C-alkylated products exclusively: secondary alkyl iodides afford mixtures of Cand 0-alkylated Powdered sodium hydroxide suspended in benzene containing tetra-n-butylammonium iodide is an effective system for alkylation of isobutyraldehyde and also P - k e t o - e ~ t e r s . ~ ~ a-t-Alkylation of aldehydes and ketones can be accomplished by treatment of the corresponding trimethylsilyl enol ether with t-alkyl chloride in the presence of titanium(1v) chloride or zinc(I1) ~ h l o r i d e . ’Note ~ that sodium (or potassium) hydride with chlorotrimethylsilane in dioxan represents a new way of preparing trimethylsilyl enol ethers from Intramolecular alkylation of w-bromo-enolates is a useful synthetic route to substituted cyclohexanones (Scheme 15); with some limitations it is also applicable to the synthesis of cycloheptanone derivative^.^^

R’

=

R2

=

Me; R’

=

Ph, R2 = Handothers

Reagents: i, Pr’,NLi; ii, HMPA

Scheme 15

Potassium amyloxide in dimethoxyethane has been recommended as the base for simple monoalkylation of c y ~ l o p e n t a n o n e Polyalkylation .~~ of acyclic and cyclic ketones can be minimized by reaction of the appropriate alkyl iodide and 71

72

73 74 75

76 77

’*

B. S. Pedersen, S. Scheibye, N. H. Nilsson, S . - 0 . Lawesson, Bull. SOC.chim. beiges, 1978, 87, 223. P. de Mayo, G . L. R. Petrasiunas, and A . C. Weedon, Tetrahedron Letters, 1978,4621. P. Groenewegen, H. Kallenberg, and A. van der Gen, Tetrahedron Letters, 1978,491. V. G . Purohit and R. Subramanian, Chem. and Znd., 1978, 731. M. T. Reetz and W. F. Maier, Angew. Chem. Znternat. Edn., 1978, 17,48. P. F. Hudrlik and J. M. Takacs, J. Org. Chem., 1978, 43, 3861. H. 0. House, W. V. Phillips, T. S. B. Sayer, and C.-C. Yau, J. Org. Chem., 1978,43,700. H. N. Edwards, A. F. Wycpalek, N. C. Corbin, and J. D. McChesney, Synth. Comm., 1978,8,563.

Aldehydes and Ketones

47

O n the other hand the lithium enolate in the presence of triethan~laminoborate.'~ per-a-methylation of ketones can be accomplished using potassium hydride and methyl iodide." Mixtures of mono- and di-alkylated products are obtained when cyclohexanone and acetophenone are methylated using aqueous formaldehyde and carbon monoxide with rhodium(II1) chloride acting as catalyst." Alkylation of 1,5-dimethoxycyclohexa- 1,4-diene is a convenient process for the obtention of 2-alkyl- and 2-alkenyl-cyclohexane-l,3-diones[equation (13)].82

R = primary alkyl

Nucleophilic a-alkylation of a ketone can be effected by its preliminary conversion into the corresponding vinylsilane, which is susceptible to nucleophilic addition. Restoration of the carbonyl function is achieved via the intermediacy of a sulphine (Scheme 16).83 . ...

R'COCH2R2

3 R'C(SiMe3)=CHR2 -%R'C-CH(R2)R3 --%R'COCH(R2)R3 II It

S

0 R'

= aryl,

R2 = H or alkyl, R3 = Bun o r But

Reagents: i, ArSO,NHNH,; ii, Bu"Li; iii, Me,SiCI; iv, R3Li; v, SO,;

VI,

hv

Scheme 16

Remarkably high optical yields (84--98%) are achieved in asymmetric induction employing anions of enamines made from chiral arnines (Scheme 17).84

R'

=

Pr' or But, R2 = H o r Ph, R3 = Me, Pr", o r ally1

Reagents: i, Pr',NLi; ii, R3X; iii, H,O+

Scheme 17 M. W. Rathke and A. Lindert, Synth. Comm., 1978,8, 9. ' O A. A. Millard and M. W. Rathke, J. Org. Chem., 1978,43, 1834. Y. Watanabe, Y. Shimizu, K. Takatsuki, and Y. Takegarni, Chem. Letters, 1978, 215. a2 E. Piers and J. R. Grierson, J. Org. Chem., 1977, 42, 3755. 83 M. van der Leij and B. Zwanenburg, Tetrahedron Letters, 1978, 3383. " S. Hashimoto and K. Koga, Tetrahedron Letters, 1978, 573. '9

48

General cnd Synthetic Methods

Chiral imines of acyclic ketones have been metallated and alkylated also. A pronounced excess of one enantiomer (generally 250%) is only obtained on ~ thermal isomerization of the intermediate l i t h i o - e n a m i n e ~ . ~Asymmetric syntheses of a-substituted ketones (and acids) (optical yields 44--74%) have also been achieved by metallation, alkylation, and further reaction of chiral N , N disubstituted amides.86

Aldol Reactions.-A

new highly effective aldol synthesis employs an aluminium enolate derived regiospecifically from the appropriate a-halogeno-ketone using zinc and dialkylaluminium chloride (Scheme 18).87 R2

R2

R'CO&R3

I

--bR'C=C

=

R'COC(R2)(R3)C(OH)R4R5

I

'R3 OAlEt,

Br R'

/

Ph o r alkyl, R2 = R3 = H o r alkyl, R4 = Ph or alkyl, R5 = H or alkyl

Reagents: i, Zn-Et2A1C1; ii, R4CORS

Scheme 18

P-Ketoalkyltrimethylsilanes (6) can be employed to produce two types of aldols regiospecifically depending on whether enolate formation is arranged to precede or to occur simultaneously with desilylation (Scheme 19).88 R'CHCOCH2R2

I

*

R'CHCOCH2R2

I

5R'CH2COCHR2

SiMe3

CH(0H)

I

1

CH(OH)R3

(6)

R3 R'

=

alkyl, R2 = H or alkyl, R3 = aryl o r alkyl

Reagents: i, Pr',NLi; ii, R3CHO; iii, H'; iv, BF3,0Et,

Scheme 19

Buse and Heathcock have extended their work on the stereochemistry of aldol formation. They find that condensation of the aldehyde (7) with the enolate (8) gives only two of the four possible diastereomers [equation (14)].89 The first PhCH(h4e)CHO (7)

+

Me

Me

Me

A. I. Meyers and D. R. Williams, J. Org. Chem., 1978, 43, 3245. M. Larcheveque, E. Ignatova, and T. Cuvigny, Tetrahedron Letters, 1978, 3961. '' K . Maruoka, S . Hashimoto, Y .Kitagawa, H. Yamamoto, and H. Nozaki, J. Amer. Chem. SOC.,1977, 99, 7705. 8 R I. Kuwajima, T. Inoue, and T. Sato, Tetrahedron Letters, 1978, 4887. 89 C. T. Buse and C. H. Heathcock, J. Amer. Chem. Soc., 1977,99, 8109.

85

86

Aldehydes and Ketones

49

examples of regiospecific and enantioselective aldol reactions have been disclosed: enantiomeric excesses of 3 1-62% are recorded (Scheme 20).90 j

H N

R'COMe

NJJ

R'

=

R3

=

m

alkyl, R2

OH I

e

H

% R'COCH2CR3

=

H or alkyl

CH,OMe

Reagents: i, P

H

I N"

; ii, Bu"Li; iii, R2COR3;iv, Me,SiCI; v, H,O, or '0,

2

Scheme 20

Reduction.+- (3'- Methyl-2'- butyl)-9-borabicyclo[ 3,3,1]n0nane~~ and the 9borabicyclo[3,3, llnonane-pyridine complex92are mild chemoselective reducing agents for aldehydes. Tri-n-butyltin hydride on dried silica gel reduces aldehydes rapidly and unhindered ketones relatively slowly yielding the corresponding alcohols in high yields.93Sodium borohydride adsorbed on to alumina94 and the zirconium borohydride (9)9sreduce aldehydes and ketones to alcohols in aprotic (C5HS)2Zr(Cl)BH4 (9)

media. The complex reducing agent formed from sodium hydride, sodium t-amyloxide, and nickel(I1) acetate reduces ketones and a-substituted aldehydes cleanly when used in conjunction with magnesium Hydridomagnesium alkoxides and dialkylaminomagnesium hydrides reduce cyclic ketones in high yield; the corresponding methylmagnesium compounds are efficient methylating agents. The steric bulk of the reagents can be geared so that delivery of the hydride or methyl moiety takes place from the least hindered face with very high s e l e ~ t i v i t y . ~ ~ Most alkynones are reduced to the corresponding R-alkynols with high (6282%) enantiomeric excess using a complex formed from lithium aluminium hydride and the amino-alcohol The asymmetric reduction of ketones by borohydride in the presence of quaternary ammonium derivatives of (2S,3S)1,4-diaminobutane-2,3-diolhas been described.99 When lithium aluminium 9" 91

92 93 94

95

96

97

90

99

H. Eichenauer, E. Friedrich, W. Lutz, and D. Enders, Angew. Chem. Internat. Edn., 1978,17,206. M. M. Midland and A. Tramontano, J. Org. Chem., 1978,43, 1470. H. C. Brown and S. U. Kulkarni, J. Org. Chem., 1977,42,4169. N. Y . M. Fung, P. de Mayo, J. H. Schauble, and A. C. Weedon, J. Org. Chem., 1978,43,3977. E. Santaniello, F. Ponti, and A. Manzocchi, Synthesis, 1978, 891. T. N. Sorrell, Tetrahedron Letters, 1978, 4985. J. J. Brunet, L. Mordenti, and P. Caubere, J. Org. Chem., 1978,43,4804. E. C. Ashby, J. J. Lin, and A . B. Goel, J. Org. Chem., 1978,43,1560,1564; E. C. Ashby and G . F. Willard, ibid., p. 4094. R. S. Brinkmeyer and V. M. Kapoor, J. Amer. Chem. Soc., 1977,99,8339. C. Innis and G. Lamaty, Nouv. J. Chem., 1977, 1, 503.

50

General and Synthetic Methods Me I

hiPh

Me,N

OH

hydride is used in association with (S)-2- (N-substituted aminomethy1)pyrrolidines (11)[readily obtained from (S)-proline] optically active alcohols having the (§)-configuration are formed in 13-92% optical purity."' Similarly, optically active alcohols are produced in good optical yields on treating aromatic and aliphatic aldehydes with alkyl-lithium using (2S,2'S)-2-hydroxymethyl-1-[( 1methylpyrrolidin-2-yl)methyl]pyrrolidine as the chiral ligand.'"

(11)

Further work has been published concerning the use of N-methylephedrinium saltslo2 and other chiral ammonium in the phase-transfer catalysed borohydride reduction of prochiral ketones. Sodium borohydride reductions of aralkyl ketones in the presence of bovine serum albumin gave enantiomeric excesses of 20-80% in the product alcoh o l ~ . ~ ~ ~ Alkyl and aryl trifluoromethyl ketones are reduced to the corresponding alcohols in good chemical and high optical yield (optical purity 60->99%) by actively fermenting yeast.los Similarly, reduction of simple P-keto-sulphides, P-keto-sulphoxides, and P-keto-sulphones by fermenting yeast proceeds readily, and affords good yields of the corresponding optically active secondary alcohols; e.g. l-(benzylthio)propan-2-onegives optically pure ( S ) -1- benzylthiopropan-201.'O6

Ketones and aryl aldehydes (which should not contain electron-withdrawing substituents) are converted directly and rapidly into hydrocarbons by the action of gaseous boron trifluoride and triethylsilane in methylene ~hloride.'"~

General Reactions.-A 'forgotten' carbonyl reaction, namely halogenoacylation of aliphatic ketones and aliphatic a$-unsaturated and aromatic aldehydes has been reinvestigated [equation (131. lo* R'COR* + M ~ C O C '"% ~ R*C(C~)(R~)OCOM~ 100

'"' 'OS

lo6 107

(15)

M. Asami, H. Ohno, S. Kobayashi, and T. Mukaiyama, Bull. Chem. SOC.Japan, 1978, 51, 1869. T. Mukaiyama, K. Soai, and S. Kobayashi, Chem. Letters, 1978, 219. J . Mass6 and E. Parayre, Bull. SOC.chim. France, 1978, 395. S. Colonna and R. Fornasier, J.C.S. Perkin I, 1978, 371. T. Sugimoto, Y. Matsumura, S. Tanimoto, and M. Okano, J.C.S. Chem. Comm., 1978, 926. M. Bucciarelli, A. Forni, I. Moretti, and G. Torre, J.C.S. Chem. Comm., 1978,456. R. L. Crumbie, B. S. Deol, J. E. Nemorin, and D. D. Ridley, Austral. J. Chem., 1978, 31, 1965. J. L. Fry, M. Orfanopoulous, M. G. Adlington, W. R. Dittman, jun., and S. B. Silverman, J. Org. Chem., 1978,43,374. M. Neuenschwander, P. Bigler, K. Christen, R. Iseli, R. Kyburz, and H. Muhle, Helu. Chim. Acta, 1978, 61, 2047; see also P. Bigler, S. Schonholzer, and M. Neuenschwander, ibid., p. 2059.

Aldehydes and Ketones

51

A novel zinc-promoted coupling of three components, namely alkyl halides, activated alkenes, and carbonyl compounds, is characterized by remarkable simplicity and high yield [equation ( 16)].'09 R'

R'X+ R2CH=C(R3)Y+ R4COR'

R'

= alkyl, R2, R3 = H

3

'CHC(Y)(R3)C(OH)R4R' / R2

(16)

or Me, R4 = alkyl or aryl, R5= alkyl or H, X = Br or I, Y = CN or CO2h4e

Die thyl trime thylsilyloxycarbonylmethanep hosp honate' l o and diethyl carboxymethanephosphonate"' are the preferred reagents for the two-carbon homologation of aldehydes and ketones to give a,P-unsaturated carboxylic acids, while 2,2-difluoro-1-tosylvinyl-lithium is a novel effective reagent for the preparation of a-keto-acids from carbonyl compounds (Scheme 21).l12 a-Methoxyaliphatic acids have been prepared from aliphatic aldehydes and chloroform using CF2=C(Li)OTs -b R2C(OH)C(OTs)=CF2

CF3CH20Ts

R2CHCOC02H +

Y

ivsiii

R2 C=C(0Ts)COZH

Reagents: Pr',NLi; ii, R,CO; iii, H,O'; iv, OH-

Scheme 2 1

sodium hydride as catalyst: the yield for this conversion is generally in the range 51-63% (Scheme 22).'13 RCHO + CHCI3 % RCH(OMe)C02H Reagents: i, NaH; ii, NaOH-MeOH

Scheme 2 2

The carbonyl group in aldehydes and ketones has been replaced by the 2-aminoethylidene group through a Wittig r e a ~ t i 0 n . lA ' ~simple method for the synthesis of nitroalkanes from aliphatic aldehydes is described in Scheme 23."' RCHO + CH3N02

RCHCH2N02 6RCH(OAc)CH2N02

I

*

RCH2CH2N02

0Reagents: i, KOH (cat.); ii, H'-Ac,O;

iii, NaBH,

Scheme 2 3 lo' 'lo

'I2

'I5

T. Shono, I. Nishiguchi, and M. Sasaki, J. Arner. Chern. Soc., 1978, 100, 4314. L. Lombard0 and R. J. K. Taylor, Synthesis, 1978, 131; Synth. Comm., 1978,8,463. P. Coutrot, M. Snoussi, and P. Savignac, Synthesis, 1978, 133. K. Tanaka, T. Nakai, and N. Ishikawa, Tetrahedron Letters, 1978, 4809. E. L. Compere, jun. and A. Shockravi, J. Org. Chern., 1978, 43, 2702. A. Marxer and T. Leutert, Helv. Chim. Acta, 1978, 61,1708. R. H. Wollenberg and S. J. Miller, Tetrahedron Letters, 1978, 3219.

52

General and Synthetic Methods

Carbonyl olefination (R'R2C0 -+ R'R2=CH2) can be accomplished using triphenylstannylmethyl-lithium, Ph3SnCH2Li,'l 6 or the systems CH212-ZnMe3AI or CH2Br2-Zn-TiCI4.' l 7 The same overall transformation can be accomplished through the intermediate formation of the corresponding P-hydroxysulphide [R'R2C(OH)CH2SPh]followed by electrochemical reduction.' Tetrasubstituted alkenes and terminal allenes are available from the reaction of ketones and 1-1ithio-1-trimethylsilylethene using the procedures described in Scheme 24.'19 Reductive coupling of carbonyl compounds to furnish alkenes [R'COR2 -+R'C(R2)=C(R2)R'] using active titanium metal'20 or lowvalency tungsten as the catalyst121has been explored further. The former method has been employed to cross-couple dicyclopropyl ketone to some aliphatic ketones. 122 R'COR2 + Me3SiC(Li)=CH2 --+

R 'H C H z R ' , R2

R'R2C(OH)C(SiMe3)=CH2

R'

iii

>C=CH,

R k C H z R 3 R2 SiMe,

Br

R'

= R2 = alkyl,

RZ

R3 = Me or Bun

Reagents: i, MeCOCI-AgCN; ii, R',CuM; iii, BrCN-AlCI,; iv, SOC1,; v, F-

Scheme 24

Chloromethyltriphenylphosphoniumiodide (12) is easy to prepare and effects chloromethylenation of aldehydes and ketones [equation (17)l."' R' CH2CII+Ph3P --+ P h 3 k H 2 C I i (12)

base

Ph3hCHC1

R1CoR2 b

>cCHCI RZ

(17)

Enolizable aldehydes are easily converted into vinyl chlorides in good yields on treatment with 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (13) in the presence of tetraethylammonium chloride and triethylamine [equation ( 18)]."4 Et

'I6

'I7 'I8 'I9

120

12'

Et

T. Kauffmann, R. Kriegesmann, and A. Woltermann, Angew. Chem. Internat. Edn., 1977,16,862. K. Takai, Y. Hotta, K. Oshima, and H. Nozaki, Tetrahedron Letters, 1978, 2417. T. Shono, Y. Matsumura, S. Kashimura, and H. Kyutoku, Tetrahedron Letters, 1978, 2807. R. Amouroux andT. H. Chan, Tetrahedron Letters, 1978,4453; T. H. Chan, W. Mychajlowskij, B. S. Ong, and D. N. Harpp, J. Org. Chem., 1978, 43, 1526. J . E. McMurry, M. P. Fleming, K. L. Kees, and L. R. Krepski, J. Org. Chem., 1978,43, 3255. Y. Fujiwara, R. Ishikawa, F. Akiyama, and S. Teranishi, J. Org. Chem., 1978, 43, 2477. S. Nishida and F. Kataoka, J. Org. Chem., 1978, 43, 1612. S. Miyano, Y. Izumi, and H. Hashimoto, J.C.S. Chem. Comm., 1978, 446. Y. Echigo and T. Mukaiyama, Chem. Letters, 1978, 465.

53

Aldehydes and Ketones

Glycols are formed, often in a highly stereoselective fashion, when an aldehyde is irradiated in the presence of Me8Sn3[equation (19].'25 R ~ H Ohv, Me8Sn3

b

RCH(OH)CH(OH)R

(19)

Reaction of an aliphatic or aromatic aldehyde (RCHO) with sodium hydrogen selenide and an amine hydrochloride, followed by a sodium borohydride reduction, yields symmetrical diselenides (RCH2SeCH2R).126 The aminimide (14) has been used as a means of effecting a mild, one-pot conversion of aryl and alkyl aldehydes into the corresponding nit rile^.'^' HN-&Me2CH2CH20H

(14)

While the full scope of the reaction has yet to be defined, it seems that aldehydes having seven or more carbon atoms and an alkyl substituent at the 6-position undergo acid-catalysed cyclization to tetrahydropyran derivatives in high yields as exemplified in equation (20)."'

When cyclohexanones are treated with diphenyl disulphide and sodium methoxide, aromatization accompanies sulphenylation if not more than one alkyl group is present in the a-position of the ketone [equation (21)].129

0:: '"'OR' OH

0

__* PhSSPh NaOMe

RZ I

I

R3

RJ

R'

= R2 = R3= alkyl

or H

Ketones are oxidatively cleaved in 87-96'/0 yield using potassium superoxide (KO,) and a phase-transfer ~ata1yst.l~'The oxidative cleavage of a-ketols, R'COC(OH)R2R3, has been found to proceed smoothly with alkaline hydrogen peroxide in aqueous methanol, affording high yields of ketones R2COR3 and carboxylic acids R1C02H.131Oxidation of enolizable ketones to a-nitratoketones can be achieved using thallium(II1) nitrate in a~etonitri1e.l~~ Certain a$-epoxy-ketones (the requirements for a successful reaction are not clear) cyclize on reaction with hydrazine to form cyclopentene carbinols [equation (22)1.'~~ L26

12' 129 130 13'

132 133

C. Grugel, W. P. Neumann, J. Sauer, and P. Seifert, Tetrahedron Letters, 1978, 2847. J. W. Lewicki, W. H. H. Gunther, and J. Y. C. Chu, J. Org. Chem., 1978, 43,2672. I. Ikeda, Y. Machii, and M. Okahara, Synthesis, 1978, 301. J. G . D. Schulz and A. Onopchenko, J. Org. Chem., 1 9 7 8 , 4 3 , 3 3 9 . B. M. Trost and J. H. Rigby, Tetrahedron Letters, 1978, 1667. M. Lissel and E. V. Dehmlow, Tetrahedron Letters, 1978, 3689. Y. Ogata, Y. Sawaki, and M. Shiroyama, J. Org. Chem., 1977, 42, 4061. A. McKillop, D . W. Young, M. Edwards, R. P. Hug, and E. C . Taylor, J. Org. Chem., 1978,43,3773. G. Stork and P. G. Willard, J. Amer. Chem. SOC.,1977, 99, 7067.

General and Synthetic Methods

54

R3 NH2NH2 I__+

R4

R2,

0

R' = R2 = alkyl or cycloalkyl, R3 = R4 = Me or H

Diazocarbonyl compounds react rapidly and efficiently with nitriles in the presence of Lewis acids such as aluminium chloride and boron trifluoride to form oxazoles in high yield [equation (23)].i.34A cyclic a-diazo-ketone has been observed to give oxiren as an intermediate on photon-induced elimination of nitrogen. ' 3 5 R2

R ' C O C ( R ~ ) = N+~R'CN

Lay: R'

R'

= aryl

or alkyl, R' = H or aryl, R3 = alkyl or aryl

3 Preparations of Unsaturated Aldehydes and Ketones One-carbon homologation of a ketone to an a#-unsaturated aldehyde can be accomplished by formation of the requisite enol ether using methoxymethylenetriphenylphosphorane (Scheme 25).136Alternatively, the lithioenaminophosphonate (15) can be used to effect the same conversion [equation (24].137

Reagents: i, Ph,P=CHOMe; ii,

lo2; iii,

Ph,P

Scheme 25

Finally, conversion of a ketone into the corresponding a-selenoalkyl-lithium and subsequent reaction with alkylene oxide and Jones oxidation results in homologation to furnish an a#-unsaturated ketone (Scheme 26).138

135 13'

I" "13

T. Ibada and R. Sato, Chern. Letters, 1978, 1129; M. P. Doyle, M. Oppenhuizen, R.C. Elliott, and M. R. Boelkins, Tetrahedron Letters, 1978, 2247. U. Timm, K.-P. Zeller, and H. Meier, Chem. Bcr., 1978, 111, 1549. G. Rousseau, P. LePerchec, and J. M. Conia, Synthesis, 1978, 67. A. I . Meyers, K. Tomioka, and M. P. Fleming, J. Org. Chem., 1978, 43, 3788. M . Sevrin and A. Krief, Tetrahedron Letters, 1978, 187.

Aldehydes and Ketones

55

R1COR2 -+ R1R2C(Li)SeR3& R1R2C(SeR3)CH2CH(OH)R4 0 Reagents: i, /R4

; ii,

R'R2C=CHCOR4

[O]

Scheme 26

Cycloalkyl and aralkyl ketones have been modified to include an adjacent alkylidene unit by the intermediate formation and alkylation of an enaminoketone [equation (25)].139 RiCOCH2R2

Me2NCHIOMe)2

+ R'COC(R2)=CHNMe2

R3Li

+ R1COC(R2)=CHR3 (25)

Dehydrogenation of steroidal ketones to give the a,@-unsaturatedspecies can be accomplished efficiently using benzeneseleninic anhydride. 140 Ketone to enone conversion can also be attained by hydride-ion abstraction from the corresponding trialkylsilyl enol ether [equation (26)].141 PhC+

H O

---%---

A

R1C=CHCH2R3 3 RIC-CH-CHR3

I

I

OSiR23

R1COCH=CHR3

(26)

OSiR23

Corey has described the conversion of ketones R2COCH2R3 into a,@unsaturated aldehydes or a,@-unsaturatedketones via benzothiazole derivatives (Scheme 13).65 The reaction of trialkylalkynyl borate salts with benzeneselenyl chloride followed by selective oxidation constitutes a new synthetic pathway from alkynes to acyclic a,@-unsaturatedketones. The latter method is especially useful for the preparation of unsymmetrical acyclic enones (Scheme 27).142

A

R'~B-c=c-cH,R~ Li

l2

+

R1COCH=CHR2

BF=( Se CH2R2

R'

li

i

d-R1COCH(SePh)CH2R2

Reagents: i, PhSeCI; ii, Me,NO-H20; iii, H 2 0 2 Scheme 27

2-Phenylthioallyl alcohols are readily prepared and rearrange in acid to give a-phenylthioethyl ketones which, on oxidation and elimination, yield vinyl

14'

R. F. Abdulla and K. H. Fuhr, J. Org. Chem., 1978, 43,4248. D. H. R. Barton, D. J. Lester, and S. V. Ley, J.C.S. Chem. Comm., 1978, 130. M. E. Jung, Y.-G. Pan, M. W. Rathke, D. F. Sullivan, and R. P. Woodbury, J. Org. Chem., 1977,42, 3961. J. Hooz and R. D. Mortimer, Cunad. J. Chem., 1978, 56, 2786.

56

General and Synthetic Methods

ketones [equation (27)]: through a similar reaction sequence 2-phenylthioallenyl alcohols furnish 2.4-dienones. 143 RCHO

+ H2C=C(Li)SPh

RCOCH=CH2

t

_+

RCH(OH)C(SPh)=CH2

I"'

[ol'A RCOCH(SPh)CH3

(27)

Acyclic y-epoxy-sulphones have been converted into cyclobutenones (Scheme 28)144while cyclic P-epoxy-sulphones have been used for the synthesis of a$-disubstituted cyclopentenones (Scheme

0

/ \

PhSO,CH(CH,),CH-CHZ

t i , iii

1 ,PhSO,

I R'

R'

R'

n=lor2 Reagents: i, MeMgI; ii, CrO,; iii, NEt,

Scheme 28

Reagents: i, PhLi; ii, MeI; iii, [ O ] ;iv, DBU

Scheme 29

Substituted allenic ethers are easily obtainable and furnish pure trans-conjugated ketones on mild acid hydrolysis (Scheme 30).146 RIKOMe

C

II

-

C

II

,

-

RIKOMe

,,

I, I I

R'

c

Reagents: i, Bu"Li; ii, R'X; iii, H'

Scheme 30

Nakai has extended his work on [3,3] sigmatropic rearrangements of allylic thioncarbamates to include the synthesis of unsaturated ketones (Scheme 3 1).147 143 144

'41

14'

R. C. Cookson and P. J. Parsons, J.C.S. Chem. Cornm., 1978, 821, 822. B. Corbel, J. M. Decesare, and T. Durst, Cunud. J. Chem., 1978, 56, 505 P. C. Conrad and P. L. Fuchs, J. Amer. Chem. SOC., 1978, 100, 346. J. C. Clinet and G. Linstrumelle, Tetrahedron Letters, 1978, 1137. T. Nakai, T. Mimura, and T. Kurokawa, Tetrahedron Letters, 1978, 2895.

Aldehydes and Ketones

57

R', R2, R3= H or alkyl, R4= M e or Bu" Reagents: i, H2C=C(Li)R3; ii, Me,NCSCl; iii, Pr',NLi; iv, MeSSMe; v, R41; vi, HgO-BF,-H20 Scheme 31

a-Methylenation of cyclic ketones is elegantly performed using s-trioxan and N-methylanilinium trifluoroacetate.14* The same reagents can be used to effect The two carbonyl groups the conversion of methyl ketones into vinyl in the enyne (16) accelerate the ene reaction to the extent that the unsaturated ketone (17) is formed smoothly at 90 "C [equation (28)]."O 0

0

A new facile route to functionalized cyclopentenones involves metallation of ethyl p-( 1-pyrrolidinyl)acrylate to give the lithium derivative (18)and subsequent reaction with a,@-unsaturatedcarbonyl compounds (Scheme 32).151Substituted

R ',N

A H

C0,Et

R'2N)=(Li H C02Et

R

R2

Ph, COPh, or N(CH2),, R3 = Ph, But, or OEt

vH

H Reagents: i, Bu'Li; ii,

=

Ii

R',N

(18)

R2

-

~

0

~

~

3

Scheme 32

cyclopentenones are also available on acid treatment of adducts formed from dichlorocarbene and various sulpholene derivatives [equation (29)]15*or by annulation of the five-membered ring to cyclic and acyclic ketones [equation (3O)]. '' 14*

'41 15"

15'

J.-L. Gras, Tetrahedron Letters, 1978, 21 11. J.-L. Gras, Tetrahedron Letters, 1978, 2955. B. B. Snider and T. A. Killinger, J. Org. Chem., 1978, 43, 2161. R. R. Schmidt and J. Talbiersky, Angew. Chem. Internat. Edn., 1978,17,204. Y. Gaoni, Tetrahedron Letters, 1978, 3277. T. Hiyama, M. Shinoda, and H. Nozaki, Tetrahedron Letters, 1978, 771.

General and Synthetic Methods

58

0

RR% '2

S -

R'

0 2

R'

= R2 = R3 = H

or alkyl

R'COCH2R2 + LiCC12CH=CH2 --+R'C(OH)CH2R2

I

H',

CC12CH=CH2

"b

(30)

R2

R', R2 = alkyl or cycloalkyl

Tetra-t-butylcyclopentadienonehas been prepared.'54 The ether (19) is smoothly formed by a Birch reduction: metallation followed by addition of alkyl halide gives, after hydrolysis, cyclohexenones (Scheme 33).155

R = alkenyl or aralkyl Reagents: i, Bu"Li; ii, RBr

Scheme 33

Oxidative cationic cyclization using pyridinium chlorochromate (PCC) as both the oxidant and the acid catalyst constitutes an effective method for the preparation of a,P-disubstituted a,P-unsaturated cyclohexenones from alk-5-enols [equation (31)].'56 OH R ' f i R2

"0 0

PCC.,

R2

R' = alkyl or H, R2 = alkyl or aryl Various alk-2-ynones have been prepared, albeit in modest yield in some cases, by direct reaction of a lithium acetylide and an e ~ t e r , ' ~while ' allenyl ketones are now available from propargyl alcohols by the procedure outlined in Scheme 34. ''' G. Maier and S. Pfriem, Angew. Chem. Internat. Edn., 1978, 17, 551 J. Amupitan and J. K. Sutheriand, J.C.S. Chem. Comm., 1978, 852. "'E. J. Corey and D. L. Boger, Tetrahedron Letters, 1978, 2461. 15' H. Hauptmann and M. Mader, Synthesis, 1978,307. J. M. Reuter and R. G. Salomon, Tetrahedron Letters, 1978, 3199. 154

155

59

Aldehydes and Ketones

--+

R'

PhCOC(R')=C< RZ

R'=H, Ph, or alkyl, R2 = R3 = H or alkyl Reagents: i, PhCOCHN,-Rh(OAc),; ii, Et,N-Me,SiCI; iii, H'; iv, 10,

Scheme 34

Addition of sodium derivatives of allyl alcohols to phenylthioacetylene furnishes adducts which on oxidation and pyrolysis undergo Claisen rearrangement and elimination of benzenesulphenic acid to yield 2,4-dienals (Scheme 35).159Similarly, primary and secondary allyl alcohols add to alIenyl phenyl

RZ

R'

=

H or alkyl, R2

R'

=

I: $#

-

H

R'

H, Me, or CI, R3 = H or Me

Reagents: i, PhSC-CH; ii, m-CIC,H,CO,H; iii, ZnCO,

Scheme 35

sulphoxides to form enol ethers that undergo rearrangement and elimination to give 2,4-dienones [equation (32)]. I6O R 2 QOPh

R'

R.i

h C 4 S 0 P h + H 0 K R 6--&

R2

R3

R4

R5

O N " " R" R5

-R'5++4 ZnCO,

R1

0

R' = R2 = R3= R5 = R 6 = H or Me, R 4 = H , alkyl or Ph R. C . Cookson and R. Gopalan, J.C.S. Chem. Comm., 1978,924. R. C. Cookson and R. Gopalan, J.C.S. Chem. Comm., 1978, 608.

R5

R3

R6

(32)

60

General and Synthetic Methods

A new efficient synthesis of polyunsaturated ketones via an oxy-Cope rearrangement is exemplified in equation (33) by the preparation of geranylacetone (20).16' The conversion of aliphatic and aromatic aldehydes and cyclic ketones

M Me

-

e

4

+

-

-

Me

Me

(33)

Me

into conjugated dienals can be accomplished using 4-ethoxybutadienyl-lithium [equation (34)].16' R'COR' + LiCH=CHCH=CHOEt

--+R'C(OH)CH=CHCH=CHOEt

I

R2 (34)

4 Reactions of Unsaturated Aldehydes and Ketones Alky1ation.-a-Alkylation of some cyclohex-2-enone derivatives has been achieved through formation of the corresponding epoxy-ketone followed by reaction of the latter with a cuprate reagent and then an alkylating agent (Scheme 36).163A n alternative strategy involves conversion of the enone into the corresponding a-bromo-acetal (76--84%), followed by halogen-metal exchange, alkylation, and hydrolysis (51--84%) (Scheme 37),"'

Reagents: i, Me,CuLi; ii, MeI; iii, Hi

Scheme 36 Ih' 162

16'

Y . Fujita, T. Onishi, and T. Nishida, Synthesis, 1978, 934. R. H. Wollenberg, Tetrahedron Letters, 1978, 717. R. P. Szajewski, J. Org. Chem., 1978, 43, 1819. M. A. Guaciaro, P. M. Wovkulich, and A. B. Smith, Tetrahedron Letters, 1978, 4661

61

Aldehydes and Ketones

R = alkyl Reagents: i, Br,-CCl,; ii, base; iii, H', (CH,OH),; iv, Bu"Li; v, RI; vi, H'

Scheme 37

Preliminary studies indicate that for @-alkoxy-a,@-unsaturatedcarbonyl compounds, y-alkylation of the corresponding dienolate will only occur when the latter contains an exocyclic double bond [e.g. equation (35)].16' A general method OLi

0

R' = H or Me, R2 = alkyl for preferential y-alkylation of a,@-unsaturatedketones has been disclosed. This new procedure involves the temporary incorporation of a y-arylsulphonyl substituent into the a,@-unsaturated ketone as a regioselective control element (Scheme 38).166 M e 0 c r y H 2 ) n

i,ii

~

iii,iv

MeocQH21n

CH2 SOzPh

~

Meo Meo R

S0,Ph

R

n = 2 or 3; R = Me (72-88%

y-alkylation) or CH2CH=CH2 (55-68%

y-alkylation)

Reagents: i, NBS; ii, PhS0,Na; iii, NaH; iv, RX; v, Zn-HOAc or Li-NH, or LiCuMe,; vi, H'

Scheme 38

Reduction.-Selective hydrogenation of a,@-unsaturatedaldehydes to the corresponding unsaturated alcohols has been accomplished using a catalytic amount A. B. Smith and R. M. Scarborough, jun., Tetrahedron Letters, 1978, 4193. P. T. Lansbury and R. W. Erwin, Tetrahedron Letters, 1978, 2675.

General and Synthetic Methods

62

of the iridium complex [HIrCl,(Me,SO),] in propan-2-01 .167 Lanthanide (particularly samarium and cerium) complexes greatly increase the selectivity of the reduction to allylic alcohols by borohydride ion,168while the opposite effect, uir. reduction of the alkene bond, can be promoted by addition of the cryptand (21).169 A stoicheiometric quantity of lithium bronze (Li,4NH3) is sufficient to ' ~ ~range of effect high-yield conjugate reduction of various c y c l o h e ~ e n o n e s . A a$-unsaturated aldehydes and cyclic and acyclic a$-unsaturated ketones have been reduced to the saturated carbonyl compounds (81-91°/0) using formic acid and trialkylamine in the presence of palladi~rn.'~' Solutions of Na[HFe2(CO),] and acetic acid in THF reduce the olefinic bond in a$-unsaturated carbonyl compounds in high yield.172

Conjugate Addition.-Acetals and aldehydes as well as alcohols add to a-enones Reactions of the formyl carbanion on photolysis as illustrated in Scheme 39.173

0

R' = Pr or CH20H, R2 = H, (CH2),0H or CH2C02Me Reagents: i, hv, R'


; ii, hv, MeCHQ; iii,

hv, RZCH,OH

Scheme 39 B. R. James and R. H. Morris, J.C.S. Chem. Comm., 1978,929. J.-L. Luche, J. Amer. Chem. SOC.,1978, 100, 2226. 169 A. Loupy and J. Seyden-Penne, Tetrahedron Letters, 1978, 2571. 170 R. H . Mueller and J. G. Gillick, J. Org. Chem., 1978, 43,4647. 17' N. A. Cortese and R. F. Heck, J. Org. Chem., 1978, 43, 3985. '71 J. P. Collman, R. G. Finke, P. L. Matlock, R. Wahren, R. G. Komoto, and J. I. Bauman, J. Amer. Chem. SOC.,1978, 100, 1119. 173 B. Fraser-Reid, R. C. Anderson, D. R. Hicks, and D. L. Walker, Canad. J. Chem., 1977,55, 3978, '67

3986.

Aldehydes and Ketones

63

equivalents LiCH(SR)SOR with cyclic a,@-unsaturated ketones have been examined: lY4-additionis preferred when R is a small group (e.g. methyl) and an a-unsubstituted cyclopentenone is the Cyclohexenone is attacked by LiCH(SeR)C02Me at -78 "C to give the 1,2-adduct under kinetic control: isomerization to the more stable 1,4-adduct can be accomplished by raising the reaction temperature and/or by adding HMPA as a C O - S O ~ V Net ~ ~ ~1,4."~ addition of acetate to cyclic and acyclic ketones has been achieved in high yield (generally 70-98%) using magnesium monoethyl malonate (22) and decarboxylaaing the first-formed. a d d ~ c t . It ' ~has ~ been shown that intramolecular Michael addition within 3,4-disubstituted cyclohexenones (23), readily available by a previously reported synthesis, constitutes a useful stereospecific route to angularly substituted ~is-hydrindane-2~5-diones (24).177 Asymmetric induction in the Michael reaction of nitromethane and chalcone is greatly enhanced (1 + 20%) by replacing, as the catalyst, a chiral amine by an aminium fluoride salt in an aprotic

EtO

i$, 0'

(22)

Et0,CO

RY (23)

p

0

OQ

R

0

(24)

Addition of organocuprate reagents to a,@-enones is solvent dependent:179 indeed the addition is retarded by the inclusion of HMPA in the reaction medium to the extent that halide-ion displacement occurs preferentially.'" Coppercatalysed conjugate addition of the magnesio-acetal (25) to cyclic enones is the key step in a new cyclopentene annelation procedure [equation (36)].'8'

Similarly, copper derivatives of hydrazones add in Michael fashion to cyclic enones to give products that are susceptible to further modification (Scheme 40).182Good yields of lY4-additionproducts are obtained on addition of the chiral cuprate reagents (26) to unsaturated esters, aldehydes, and ketones: the asymmetric induction, however, is < 1O/O. Prolinol has a more pronounced effect in that R-3-methylcyclohexanone is produced in 15.5% optical yield on reaction of 174

17'

177

'71 179

'"

K. Ogura, M. Yamashita, and G. Tsuchihashi, Tetrahedron Letters, 1978, 1303. J. Lucchetti and A . Krief, Tetrahedron Letters, 1978, 2697. J . E. McMurray, W. A . Andrus, and J. H. Musser, Synth. Comm., 1978, 53. G. Stork, D. F. Taber, and M. Marx, Terrahedron Letters, 1978, 2445. S. Colonna, H. Hiernstra, and H. Wynberg, J.C.S. Chem. Comm., 1978, 238. H. 0. House and J. M. Wilkins, J. Org. Chem., 1978,43, 2443. H. 0. House and T. V. Lee, J. Org. Chem., 1978,43,4369. A. Marfat and P. Helquist, Tetrahedron Letters, 1978,4217. E. J . Corey and D. L. Boger, Tetrahedron Letters, 1978,4597. A.-T. Hansson, M. T. Rahman, and C. Ullenius, Acta Chem. Scand., 1978, B32,483.

General and Synthetic Methods

64 C0,Et

0

8 li,

ii

Reagents: i, PhSLiCu[CH,C(Me)NNMe,]; ii, CuCI,; iii, NaOH then NaOAc-Ac,O; iv, NaH; v, H'-Me,CHOH; vi, LiAlH, then H,O'; vii, LiCH,P(O)(OMe),; viii, MeLi then H30'

Scheme 40

the 'reagent' (27) with c y c l ~ h e x e n o n e .Polyalkylmagnesiocuprates '~~ of the type (28) add 1,4 with transfer of the group R (which can be t-butyl) to enones which can be hindered.'"

L'Lu

(26)

'

'Y

IH

I

R4MeCu3(MgBr)* Me

(27)

(28)

A catalyst prepared from [Ni(acac),] and di-isobutylaluminium hydride catalyses the conjugate addition of alkenylzirconium complexes to a$-enones: the same catalyst also promotes 1,4-addition of alanes to cyclic a#-unsaturated enones.18' Trimethylstannyl-lithium (Me3SnLi) adds to cyclic enones in the 1,2 sense initially, but this adduct rapidly isomerizes to the 1,4-system: on the other hand trimethylsilyl-lithium (Me,SiLi) reacts with cyclohex-2-enone to give directly and exclusively the product of 1,4-addition.lS8 Treatment of Me3SnLi with PhSCu affords PhS(Me3Sn)CuLi, a new reagent which efficiently transforms P-iodoenones into p- trimethylstannyl-a,p-enones,a new class of organotin derivatives. 189

'"

'89

F. Ghozland, J.-L. Luche, and P. Crabbt, Bull. SUC.chim. belges, 1978, 87, 369. F. Leyendecker, J. Drouin, and J. M. Conia, Nuuv. J. Chem., 1978, 2, 267, 271. M. J. Loots and J. Schwartz, J. Amer. Chem. Suc., 1977, 99, 8045. R. T. Hansen, D. B. Carr, and J . Schwartz, J. Amer. Chem. SOC.,1978, 100, 2244. W. C. Still and A. Mitra, Tetrahedron Letters, 1978, 2659. E. Piers and H. E. Morton, J.C.S. Chem. Comm., 1978, 1033.

65

Aldehydes and Ketones

Though less reactive towards nucleophiles and dienes than the corresponding unsubstituted compounds it has been shown that a-alkoxy-a,@-unsaturated ketones will undergo conjugate addition and Diels-Alder reactions. 190 General Reactions.-a$-Unsaturated aldehydes, ketones, and esters are efficiently transformed into the corresponding cyclopropanes by a sulphonemediated cyclization reaction (Scheme 41).19' a#-Unsaturated ketones have been shown to react with trimethysilylmethylene-sulphurane(Me,SiCH=SMe2) to give silylcyclopropyl ketone^.'^' R'CH=CHCOR2 PhS0,-FR2 R' R'

=H

-%PhSCH(R1)CH2CH(OH)R2

1

4

or Ph, R2 = H ; R'

vi

PhSO2CH(R1)CH2CH(OTs)R2

= H,

R2 = Me; R'

= Me(CH2)5,R2 = OEt;

R', R2 = -(cH2)3Reagents: i, PhSNa; ii, NaBH,; iii, HOAc; iv, K,CO,-MeOH; v, TsCI-pyridine; vi, Pr',NLi

Scheme 4 1

It had been established previously that a$-enones can be transformed into epoxy-oximes in high yield: now it has been shown that the latter species yield potentially useful y-hydroxy-a-nitroalkenes on peracid oxidation [equation (37)1.'93

R'

= R2 = Me

or H

4-Alkenylcyclohex-2-enonesgive rise to 4-alkylphenols on rhodium(II1) chloride-catalysed double-bond migration: similarly the corresponding unsaturated imines can be transformed into substituted aniline derivative^.'^^ Photocycloaddition of cyclohexene to the bicyclic ketone (29) gives the cisanti-trans-adduct with high stereo~electivity,'~~ while on irradiation 2-fluoro-

(29) '91 19' 19' 193

lg4

J. Quick and R. Jenkins, J. Org. Chem., 1978, 43, 2275. Y.-H. Chang, and H. W. Pinnick, J. Org. Chem., 1978, 43, 373. F. Cooke, P. Magnus, and G . L. Bundy, J.C.S. Chem. Comm., 1978,714. T. Takarnoto, Y. Ikeda, Y. Tachirnori, A. Seta, and R. Sudoh, J.C.S. Chem. Comm., 1978,350. P. A. Grieco and N. Marinovic, Tetrahedron Letters, 1978, 2545. Y. Tobe, T. Hoshino, Y. Kawakami, Y. Sakai, K. Kirnura, and Y. Odaira, J. Org. Chem., 1978,43, 4334.

66

General and Synthetic Methods

cyclohexenone and 2-methylpropene were found to combine predominantly in the unexpected 'head-to-head' fashion. '91 a'-Hydroxylation or a'-acetoxylation of a,P-unsaturated ketones can be accomplished by treatment of the corresponding trimethylsilyl dienol ether with rn-chloroperoxybenzoic acid followed by desilylation under the appropriate conditions. 197 Lithium phenyl selenolate, LiSePh, is sufficiently nucleophilic to add in conjugate [ 1,5]-fashion to monoactivated cyclopropyl ketones, nitriles ,and 5 Protected Aldehydes and Ketones

Prepa. ation.-Dimethylsilyl enol ethers of aldehydes and ketones may be prepared by irradiating the carbonyl compounds in the presence of dodecamethylcyclohexasilane (Me2%),. 199 Highly stereoselective formylatioii of (2)-en01silyl ethers has been achieved on treatment of acyclic ketones with ethyl triinethylsilylacetate and tetrabutylammonium fluoride; on the other hand lithiation of pentan-3-one with lithium 2,2,6,6-tetramethylpiperidide followed by chlorotrimethylsilane gave mainly (84%) the (E)-enol silyl ether.," In bicyclic systems containing enones in a six-membered ring the double bond has a strong tendency to shift to the P,y-position on acetalization with a strong acid catalyst. To prevent this shift, a stabilizing substituent must be introduced into the a-position. In systems containing cyclopentenones the double bond does not tend to migrate on acetalization, and even on introducing stabilizing groups in the y-position only partial migration is effected.'"' Rare-earth chlorides, particularly erbium(II1) chloride and ytterbium(Ii1) chloride, are efficient catalysts for the acetalization of aliphatic and aromatic aldehydes.202A convenient synthesis of monoacetals of a-diones involves two simple reactions from the readily available a-keto-amides (30) (Scheme 42) .,03 a-(Phenylthio)a!kylboron EtOCOC0,Et

-&

EtOCOCONEt,

-% R'COCONEt,

f R 'CGOR' 0'

0

U

R'

= alkyl,

&

(30)

R'CCONEt, 0' 0

U

R2 = alkyl o r aryl

Reagents: i, Et,NH; ii, R'MgX; iii, (CH,OH),-H';

iv, R'Li

Scheme 42

compounds are efficiently and selectively cleaved by N-chlorosuccinimide (NCS) in basic methanol to yield monothioacetals or (on using excess NCS) acetals 196

'97 '98 19'

"" 201

202 203

M. L. Greenlee, E. L. Fritzen, .iun., and J. S. Swenton, J. Org. Chem., 1978, 43, 4512. G. M. Rubottom and J. M. Gruber, J. Org. Chem., 1978, 43, 1599. A. B. Smith and R. M. Scarborough, jun., Tetrahedron Letters, 1978, 1649. W. Ando and M. Ikeno, Chem. Letters, 1978, 609. E. Nakamura, K. Hashimoto, and 1. Kuwajima, Tetrahedron Letters, 1978, 2079. D. Becker, N. C. Brodsky, and J. Kalo, J. Org. Chem., 1978,43,2557. J.-L. Luche and A. L. Gemal, J.C.S. Chem. Comm., 1978, 976. T. Cuvigny, M. Larcheveque, and H. Normant, Synthesis, 1978, 857.

Aldehydes and Ketones

67

(Scheme 43).204A very simple method for the preparation of cyclopropanone dithioacetals in almost quantitative yield has been reported (Scheme 44).205

Reagents: i, NCS-MeOH-Et,N;

ii, excess NCS-MeOH-Et,N

Scheme 43

R' R'R2C=CHCH0

1 ,R'R2C(SPh)CH2CH(SPh)2-5

g i p h SPh

Reagents: i, PhSH-HCI; ii, LDA-TMEDA

Scheme 44

A new two-step procedure for the preparation of cyanohydrins from ketones is particularly useful for the synthesis of highly hindered cyanohydrins [equation (38)].206Note that potassium cyanide and trimethylsilyl chloride can be used in place of trimethylsilyl cyanide in the above reaction.207

Regeneration of Aldehydes and Ketones.-a$-Unsaturated acetals but not p,y-unsaturded acetals are hydrolysed by oxalic acid in 95% aqueous methanol at room temperature: P, y-unsaturated acetals give the corresponding ketones, generally with little or no isomerization of the double bond, using 80% aqueous acetic acid at room Hydrolysis on wet silica gel is a convenient procedure for regenerating carbonyl compounds from the corresponding a ~ e t a l s , ~while ' ~ it has been shown that dethioacetalization can be accomplished using isoamyl nitrite."" Ketoximes are converted into the corresponding ketones using two molar equivalents of pyridinium chlorochromate." ' Parent aldehydes (including aliphatic) and ketones can be regenerated from aryl hydrazones using benzeneseleninic anhydride212 or hydrogen peroxide and potassium carbonate.*13 A. Mendoza and D. S. Matteson, J.C.S. Chem. Comm., 1978, 357; J. Organometallic Chem., 1978, 156, 149. 2os T. Cohen and W. M. Daniewski, Tetrahedron Letters, 1978, 2991. '06 P. G. Gassman and J. J. Talley, Tetrahedron Letters, 1978, 3773. 2117 J. K. Rasmussen and S. M. Heilmann, Synthesis, 1978, 219. 208 J. H. Babler, N. C. Malek, and M. J. Coghlan, J. Org. Chem., 1978, 43, 1821. *(I9 F. Huet, A. Lechevallier, M. Pellet, and J. M. Conia, Synthesis, 1978, 63. 210 K. Fuji, K. Ichikawa, and E. Fujita, Tetrahedron Letters, 1978, 3561. "' J. R. Maloney, R. E. Lyle, J. E. Saavedra, and G. G. Lyle, Synthesis, 1978, 212. 2 1 2 D. H. R. Barton, D. J. Lester, and S . V. Ley, J.C.S. Chem. Comm., 1978, 276. 2 1 3 J. Jirieny, D. M. Orere, and C. B. Reese, Synthesis, 1978, 919. "I4

68

General and Synthetic Methods

Tosyl hydrazones can be hydrolysed using copper(I1) sulphate in methanol.214 @-(Trimethylsily1)-ketones may be converted into a,@-unsaturatedketones by bromination and desilylbromination: since silyl-lithium reagents add to the @-position of a$-unsaturated enoneslS8 protection of the enone system can be effected in this manner.215 Reactions.-Various cyclohexenyl trimethylsilyl ethers react with a combination of 2,3-dichloro-5,6-dicyanoquinone(DDQ) 'and bis(trimethylsi1yl)acetamide (BSA) to give the corresponding cyclohexenone [equation (39)]: cyclopentenyl and cycloheptenyl analogues give lower yields.2'6 A combination of palladium(I1) acetate and p-benzoquinone will effect the same dehydr~silylation.~"

p-Cyano-silylenol ethers are now available in high yield from the corresponding enone (Scheme 45), and the cyano- and the enol ether moieties have been further modified by standard methodology.218

Reagents: i, Et,AlCN-Me,SiCl;

ii, PhSCl

Scheme 45

The phosphonates (3 1) react with aldehydes and ketones to give 2-azadienes which form metallo-enamines on reaction with butyl-lithium; trapping of these metallo-enamines occurred with a high degree of regioselectivity (Scheme 46).219

(EtO),P(O)CHN=CHPh

I

R'

a R z>-(R' R'

L) RZS (R"

N=CHPh

R1

Bun

Fi<

R'XCOR' R1

Ph

(311

R'

=

H , alkyl, or aryl, R2 = alkyl, R3= H or Me, R4 = Me or CH2CH=CH2

Reagents: i, Bu"Li; ii, R1COR2;iii, R4X; iv. H,O'

Scheme 46 214 215 *16 217

'Ix 219

0. Attanasi and S. Gasperoni, Gazzetta, 1978, 108, 137. D. J. Ager and I. Fleming, J.C.S. Chem. Comm., 1978, 176. I. Ryu, S. Murai, Y. Hatayama, and N. Sonoda, Tetrahedron Letters, 1978, 3455 Y. Ito, T. Hirao, and T. Saegusa, J. Org. Chem., 1978, 43, 1011. M. Samson and M. Vandewalle, Synth. Comm., 1978, 8, 231. S. F. Martin and G. W. Phillips, J. Org. Chem., 1978, 43, 3792.

R4

69

Aldehydes and Ketones

Acetals react with 1,2-bis(trimethylsilyloxy)cyclobut-1-ene in the presence of stannic chloride through two successive reactions, uiz. an aldol and a ring cleavage reaction, to give the silyl enol ether of a y-keto-ester; the overall reaction [equation (40)] represents a new, single-pot method for the reductive succinoylation of a ketone function.220Acetals of aliphatic and aromatic aldehydes can be converted into carboxylic acids without recourse to hydrolysis using N-bromosuccinimide (NBS) followed by treatment with zinc [equation (4 l)]."' Extending their work with allylsilanes, Hosomi and Sakurai now report the regiospecific prenylation of acetals [equation (42)] and carbonyl compounds.222

Me3SiCMe2CH=CH2

+ R'CH(OR2)2 --+ Me2C=CHCH2CHR1 I OR2

(42)

1 -Lithiophenylthiocyclopropaneshave been prepared by reductive lithiation of readily available2" cyclopropane dithioacetals using lithium n a ~ h t h a l e n i d e . ~ ~ ~ Selenoacetals R'C(R2)(SePh)2are reduced to the corresponding hydrocarbon R'CH2R2 using 2-3 equivalents of triphenyltin h ~ d r i d e . ~ ~ ~ Primary or secondary a-ketols are available from alkyl methyl ketones through the intermediacy of lithiated imines or oximes respectively (Scheme 47).225It has .

R'CHOH I COMe

...

R'CH2CMe c- R'CH2COMe

II

4

R'CH2CMe

I/

N

N R ~ 'OH

1-iii

R'CH2

I

COCH20H Reagents: i, LiNR2,; ii, 0,; iii, H 3 0 f

Scheme 47

been firmly established that lithiation followed by alkylation of ketimines gives only syn and only axial (in cyclohexanone) alkylation products.226 Lithioenamines can be generated regiospecifically from a$-unsaturated imines, and 220 221

222 223

224 225 22h

E. Nakamura, K. Hashirnoto, and I. Kuwajima, J. Org. Chem., 1977, 42, 4166. L. C. Anderson and H. W. Pinnick, J. Org. Chem., 1978, 43, 3417. A. Hosomi and H. Sakurai, Tetrahedron Letters, 1978, 2589. T. Cohen, W. M. Daniewski, and R. B. Weisenfeld, Tetrahedron Letters, 1978, 4665. D . L. J. Clive, G. Chittattu, and C. K. Wong, J.C.S. Chem. Comm., 1978, 41. T. Cuvigny, G. Valette, M. Larcheveque, and H. Normant, J. Organometallic Chem., 1978,155,147. R. R. Fraser, J. Banville, and K. L. Dhawan, J. Amer. Chem. SOC., 1978, 100, 7999.

General a n d Synthetic Methods

70

they react readily with alkyl halides (Scheme 48): this constitutes a new method for reductive a-alkylation of an e n ~ n e . ' ~ ~

R'

= R2 = alkyl

or cycloaikyl

Reagents: i, Bu'OK; ii, But Li; iii, R'I(Br); iv, H 2 0 t

Scheme 48

Selenium dioxide,228 a triethylamine-sulphur dioxide complex,229 diphosphorus t e t r a i ~ d i d e , ~and ~ " various phosphonvl halides and imidazolesZ3' have been recommended for dehydrating aldoximes to form nitriles. Sodium borohydride in acetic acid is a convenient new system for the reductive while reduction of deoxygenation of carbonyl tosylhydrazones [equation (43)],232 a$-alkynyl tosylhydrazones using catechol-borane provides a useful route to allenes [equation (44)].233 N-NHTs

N-NHTs

II

IH], R'CH=C=CHR~

R'C=C-C-R~

(44)

Metallated tosylhydrazones react with aldehydes and ketones to afford P-hydroxytosylhydrazones in good to excellent yield. Further reaction with organolithium reagent gives the corresponding homoallylic alcohol (Scheme 49).234 N-NHTs

II

R'CH2-C-CH2R2

*

N-NHTs

II

K'CH2C-CHR2

--% R'CH=CH \

HOC(R3)R4

CHR~

/

HOC(R3)R4 Reagents.

I,

2 x R5Li; i i , R3COR4; iii, excess R'Li

Scheme 49 227 22R 22y

230

231 212

*" 274

P. A. Wender and M. A. Eissenstat, J. Amer. Chem. SOC.,1978, 100, 292. G. Sosnovsky and J. A. Krogh, Synthesis, 1978, 703. G. A. Olah and Y. D. Vonkar, Synthesis, 1978, 702. H. Suzuki, T. Fuchita, A. Iwasa, and T. Mishina, Synthesis, 1978, 90.5. G. Sosnovsky and M. Konieczny, Z . Naturforsch., 1978, 33b, 1033. R. 0. Hutchins and N. R. Natale, J. O r g . Chem., 1978, 43, 2299. G. W. Kabalka, R. J. Newton, J. H. Chandler, and D. T. C. Yang, J.C.S. Chem. Comm., 1978, 726. M. F. Lipton and R . H. Shapiro, J. Org. Chem., 1978, 43, 1409.

Aldehydes and Ketones

71

A repertoire of reactions involving metallated dimethylhydrazones has been reported in a full paper by Corey and Enders. Electrophiles such as saturated and a$-unsaturated carbsnyl compounds and oxirans react satisfactorily to effect regiospecific C-C bond formation in the a-position to the masked carbonyl Regiospecific acylation of ketones to afford 1,3-diones can also be accomplished through the intermediacy of metallated dim ethyl hydra zone^.^^^ Oxidation of 1,2-diphenyl- or 1,2-di-isopropyl-hydrazine with benzeceseleninic acid or anhydride gives the corresponding azo-compound. Treatment of monosubstituted aryl hydrazines with the same reagents gives rise to aryl phenyl selenides and a r e n e ~ .Phenyl* ~ ~ and p-nitrophenyl-hydrazone derivatives of a number of aldehydes have been shown to give the corresponding acyl azo-compounds in good yield on treatment with benzeneseleninic anhydride: tosyl hydrazones and oximes give the parent aldehyde under the same reaction conditions, while hydroxylamines furnish nitroso-compounds.212

6 Halogens-derivatives Preparation.-Fluorination of diazo-ketones with trifliloro(fluoro-oxy)methane produces mainly a mixture of a,a-difluoro-ketones and a-fluoro-a-trifluorome thoxy - ke tones. 238 Pyridine hydrochloride in pyridine is a mild reagent for the nucleophilic cleavage of a conjugated (but not necessarily strained) cyclopropyl ring furnishing P-chloromethyl ketones.239Photo-oxidation of mono- and di-substituted alkenes in the presence of iron(II1) chloride affords a-chloro-ketones whereas tri- and tetra-substituted alkenes suffer cleavage to form dichloro-ketones [equations (45)and (46)].240 R'CH=CHR~

O,, hw, FeCI,-C,H5N

+ R'COCH(CI)R~+ R'CH(CI)COR~ (45) Me

Me 02.hv, FeCI,-C,H,N

Photo-catalytic bromination of epoxides derived from terminal alkenes results in the formation of ketones brominated exclusively on the less substituted a-carbon atom [equation (47)].241 5,5-Dibromo-2,2-dimethyl-4,6-dioxo-1,3dioxan (32) has been shown to monobrominate saturated aldehydes and ketones 0 / \

RCH-CH, 235 236

237 23g 239 240 241

+Br2 hv, RCOCH2Br+HBr

E. J. Corey and D. Enders, Chem. Ber., 1978, 111, 1362. D. Enders and P. Weuster, Tetrahedron Letters, 1978, 2853. T. G. Back, J.C.S. Chem. Comm., 1978,278. J . Leroy and C. Wakselman, J.C.S. Perkin I, 1978, 1224. N. DiBello, L. Pellacani, and P. A. Tardella, Synthesis, 1978, 227. E. Murayama, A. Kohda, and T. Sato, Chem. Letters, 1978, 161. V. Calo, L. Lopez, and D. S. Valentino, Synthesis, 1978, 139.

(47)

General and Synthetic Methods

72

in excellent yield; moreover the a '-carbon atom of a$-unsaturated ketones is brominated with high selectivity using this reagent.242 A new facile synthesis of a-iodo-ketones involves oxidation of alkenes using silver chromate and iodine [equation (48)],243while thallium(II1) acetate and iodine are effective for the conversion of enol acetates into a - i o d o - k e t o n e ~ . ~ ~ ~

-

Ag2Cr0,-12

R'CH=CHR~

R'COCHIR~

(48)

R1 = Ph or alkyl, R2 = alkyl or H

a-Fluoro and a-chloro-a#-unsaturated aldehydes are available by a new two-stage, two-carbon atom homologation of ketones as shown in Scheme ~

1

~

... ..

L!0.., R~ ~ C2 ( R ~ ) C X = C F1II.l1 ~

I

,R'C(R~)CX=CFH -% I

OH

R'R~C=C(X)CHO

OH

R'

= alkyl

or aryl, R2 = alkyl or H, X = F or C1

Reagents: i, F,C=CXLi; ii, H,O+; iii, LiAlH,; iv, H2S04

Scheme 50

Reactive aldehydes can be homologated to a-chloro-a$-unsaturated ketones using diethyl trichloromethanephosphonate and the procedure exemplified in Scheme 5 1.246 Cl,CP(O)(OEt),

% PhCH=C(Cl)COBu'

Reagents: i, Bu"Li; ii, Bu'COCI; iii, PhCHO

Scheme 51

Reactions.-Lithium di-isopropylamide can effect facile reduction of a-halogeno- (and a-alkoxy-) ketones at a rate comparable to the rate of e n 0 1 i z a t i o n . ~ ~ ~ A convenient one-pot synthesis of alkenes involves reaction of a-chloroketones with Grignard reagents and lithium [equation (49)].248 Dehydro242 243 244

245

246 247 24K

R. Bloch, Synthesis, 1978, 140. G. Cardillo and M. Shirnizu, J. Org. Chem., 1977, 42, 4268. R. C. Carnbie, R. C . Hayward, J. L. Jurlina, P. S. Rutledge, and P. D. Woodgate, J.C.S. Perkin I, 1978,126. R. Sauvetre, D. Masure, C. Chuit, and J. F. Norrnant, Synthesis, 1978, 128; D. Masure, C. Chuit, R. Sauvetre, and J. F. Norrnant, ibid., p . 458. J. Villieras, P. Perriot, and J. F. Norrnant, Synthesis, 1978, 29. C . Kowalski, X. Creary, A. J. Rollin, and M. C. Burke, J. Org. Chem., 1978, 43, 2601. J. Barluenga, M. Yus, and P. Bernad, J.C.S. Chem. Comm., 1978, 847.

Aldehydes and Ketones

73

bromination of a-bromo-aldehydes can be realized using dimethylhydrazine through the formation of the corresponding, readily hydrolysed a#-unsaturated dimethyl hydrazone.249 H

R'

R1COCH(CI)R2+ R3MgBr

d

R'R3C(OMgBr)CH(CI)R2%

>='R Z R"

(49)

Titanium(II1) chloride and HCl provide a means of reduction of cup-dibromoketones to the corresponding a-chloro-compounds [equation (50)].250a,a'Dibromo-ketones are reduced to a-acetoxy-ketones by ultrasonically dispersed mercury in acetic acid.25' A wide variety of dienes react with a,&'-dibromoketones in the presence of a zinc-silver couple252or an iron ~ a r b o n y l in * ~the ~ [3 + 4 -+ 71 sense to give cyclohept-4-enones [equation (51)].

R'

0

R3

0

R'

R4

7 Acyl, Homoenolate, Acylvinyl, and Dienolate Anion Equivalents Reference has been made to various f ~ r m y l , ~acy1,26353 ~ , ~ ' and acylviny1153*162*164 anion equivalents in the above text. The lithiated enol ether (33) is a masked equivalent of the enolate of acetaldewhile ethyl dithioacetate has been used as an equivalent to the dianion -

-

(34) are readily CH2-C=0.255 The anions of 2-substituted-l,3-benzodithioles prepared and are useful acyl carbanion equivalents.256 N,N-Diethylaminoacetonitrile anion, Et2NCHCN, has been used as a latent formaldehyde anion.257 Acetals of /3-diphenylphosphinoyl-ketones(35) (available by five different routes) act as equivalents of homoenolate anions [CH(R')CH(R2)COR3] on Lim OEt

01'FR ' s

(33) 249

251

252

253 254

255

256

"'

(34)

Ph2P(0)CH@')CH(R2)C 'Ol $0

(35)

L. Duhamel and J.-Y. Valnot, Compt. rend., 1978, 286, C, 47. D. Bright-Angrand and B. Muckensturm, J. Chem. Research, 1977, S274. A. J. Fry, and D. Herr, Tetrahedron Letters, 1978, 1721. T. Sato and R. Noyori, Bull. Chem. SOC.Japan, 1978, 51, 2745. H. Takaya, S. Makino, Y. Hayakawa, and R. Noyori, J. Amer. Chem. SOC.,1978,100, 1765. R. H. Wollenberg, K. F. Albizati, and R. Peries, J. Amer. Chem. SOC.,1977, 99, 7365; R. H. Wollenberg, Tetrahedron Letters, 1978, 717. A. I. Meyers, T. A. Tait, and D. L. Lomins, Tetrahedron Letters, 1978,4657. S. Ncube, A. Pelter, K. Smith, P. Blatcher, and S. Warren, Tetrahedron Letters, 1978, 2345, 2349. G. Stork, A. A. Ozorio, and A. Y. W. Leong, Tetrahedron Letters, 1978, 5175.

General and Synthetic Methods

74

(36)

utilizing the Wittig-Horner reaction.258The readily prepared p-nitro-acetals (36) have been used as equivalents for P-acylvinyl anions (CH=CHCOR).2591Bromo-2-ethoxycyclopropyl-lithiumis the synthetic equivalent of the 2-lithiopropenal moiety (Scheme 52).2604-Nitrobut-1 -ene forms the dianion (37) which

Reagents: i, BuLi; ii, C,H,,CHO; ii, EtOH-K,CO,; iv, H,Ot

Scheme 52

undergoes electrophilic attack at the 2- and 4-positions. In so doing it behaves like equivalent that reacts with a crotonaldehyde enolate (CK,CH=CH-CHO) electrophiles at the y-position preferentially.261The phenylselenopentenone (38) is a new divinyl ketone equivalent.262

-NO,

Liz (37)

25u

259

261

262

0

(38)

A. Bell, A. H. Davidson, C. Earnshaw, H. K. Norrish, and S. Warren, J.C.S. Chem. Comm., 1978, 988. P. Bakuzis, M. L. F. Bakuzis, and T. F. Weingartner, Tetrahedron Letters, 1978, 2371. T. Hiyama, A. Kanakura, H. Yamamoto, and H. Nozaki, Tetrahedron Letters, 1978, 3047, 3051. D . Seebach, R. Henning, and F. Lehr, Angew. Chem. Internat. Edn., 1978, 17, 458; cf. ref. 162. S. Danishefsky and C. F. Yan, Synth. Comm., 1978, 8, 211.

3 Carboxylic Acids and Derivatives BY D. W. KNIGHT

1 Introduction The Report this year shows some changes. The section on pyrones and coumarins has been omitted, and a new section on the synthesis of thioesters and related compounds is included. Cross references in the Report refer to the corresponding chapters in earlier volumes, i.e. (1, 236) refers to reference 236 in Chapter 3 of Volume l,la ( 2 , 2 3 6 ) to Chapter 3 of Volume 2,1b and ( 3 , 2 3 6 ) to the present chapter.

2 Carboxyiic Acids General Synthesis.-Trialkylboranes can be converted into carboxylic acids by treatment with the dianion of phenoxyacetic acid (cfi 3, 16), the ability of the phenoxy substituent to act as a leaving group being crucial to the method (Scheme l).’Limitations are the low yields when ‘R’ is large and the waste of two ‘R’ groups; these problems can be overcome by using B-alkyl-9BBN derivatives.

Scheme 1

Some studies3 on Meyer’s route to chiral carboxylic.acids (1, 1; 2, 10) have revealed that stereoselectivity in the deprotonation of chiral oxazolines is very dependent on the particular base-solvent combination used. A further route to chiral acids is by alkylation (with primary halides) and subsequent hydrolysis of the bis-anionic species (1) derived from acid anhydrides and I - e ~ h e d r i n e . ~ Chemical yields are in the range 50--70%, while optical yields are around 75%. A full report has appeared’ on the general approach to chiral acids by the Michael addition of Grignard reagents to oxazepinedione derivatives ( 2 ) , also derived from I-ephedrine. Optical yields of 80--99% have been claimed (2, 11;3 , 27). ( a ) D. W. Knight, in ‘General and Synthetic Methods’, ed. G. Pattenden (Specialist Periodical Reports), The Chemical Society, London, 1977, Vol. 1, p. 11 1; ( h ) ibid.,1978, Vol. 2, p. 67. S. Hara, K. Kishirnura, and A. Suzuki, Tetrahedron Letters, 1978, 2891. M. A. Hoobler, D. E. Bergbreiter, and M. Newcornb, J. Amer. Chem. SOC.,1978,100,8182; A. I. Meyers, E. S. Snyder, and J. J. H. Ackerman, ibid., p. 8186. M. Larcheveque, E. Ignatova, and T. Cuvigny, Tetrahedron Letters, 1978, 3961. T. Mukaiyarna, T. Takeda, and F. Fujirnoto, Bull. Chem. SOC.Japan, 1978,51, 3368.

75

General and Synthetic Methods

76

A study of the addition of dilithium carboxylates to acyclic enones under conditions of kinetic control has revealed that the reaction is irreversible and that the intrinsic preference for [1,2] addition may be completely changed to [1,4] when large groups are present on the acid or adjacent to the ketone group.6 The acid-catalysed decomposition of a-hydroperoxy-ketones to acids and ketones has been studied in detail; in some cases, yields of acids can be e ~ c e l l e n t . ~ 1,3-Dioxolans can be converted into the corresponding carboxylic acids by oxidative bromination followed by reduction with zinc under various conditions (Scheme 2).8Readily available tetra-n-butylammonium permanganate (3) prom-

Scheme 2

ises to be a valuable alternative to potassium permanganate and other reagents for general oxidations.' Used in pyridine solution, the reagent can be used to oxidize aromatic aldehydes, benzyl alcohol, and p-nitrotoluene to the corresponding benzoic acids in all but quantitative yield. It is to be hoped that further reports on the reagent's scope and limitations will appear soon. Dimethyl polyethylene glycol mixtures can be used in place of crown ethers in the potassium permanganate oxidation of terminal alkenes to carboxylic acids under phasetransfer conditions (2,6).1° Bis-(~3-methylallyl)nickelcomplexes [e.g. (4)] undergo insertion of carbon dioxide in the presence of phosphines to give carboxylates [e.g (S)]."

(3)

(4)

(5)

' J . Mulzer, G . Hartz, U. Kiihl, and G. Briintrup, Tetrahedron Letters, 1978, 2949. Y . Sawaki and Y. Ogata, J. Amer. Chem. Soc., 1978, 100, 856.

' L. C. Anderson and H. W. Pinnick, J. Org. Chem., 1978, 43, 3417. ' T. Sala and M. V. Sargent, J.C.S. Chem. Cotnm., 1978, 253. l1

D. G . Lee and V. S. Chang, J. Org. Chem., 1978,43, 1532. P. W. Jolly, S. Stobbe, G. Wilke, R. Goddard, C. Kriiger, J. C. Sekutowski, and Y.-H. Tsay, Angew. Chem. Internat. Edn., 1978, 17. 124.

77

Carboxylic Acids and Derivatives

Acid chlorides can be prepared under essentially neutral conditions (cyclic acetals unaffected) by treating t-butyldimethylsilyl esters with oxalyl chloride in DMF. Diacids.-Diols (other than 1,2-diols) can be carbonylated to give diacids using the system C0-HF-SbF5.l3 Cyclic ketones are efficiently cleaved to diacids using potassium superoxide under phase-transfer conditions with methyltri-n-octylammonium chloride as ~ata1yst.l~ Under the influence of a ruthenium catalyst, carbon tetrachloride adds across the olefinic bond of o-unsaturated esters to give w-trichloromethyl derivatives which, on hydrolysis, afford P-chloro-a,w-diacids. l 5 Hydroxy-acids.-Adam's group16 has reported the preparation and some reactions of bis-anions (6) and (7) derived from phenoxy- and benzyloxy-acetic acids, (cf.3 , 2 ) as well as the bis-anion (8), derived from diphenoxyacetic acid (cf. 2, 226). The bis-anions are generated under 'traditional' conditions (LDA-THF, -78 "C), but their chemistry has yet to be fully defined. The trianionic species (9) OLi PhCH ,OYCO2Li

PhoYco2Li Li

Li

' ,&hp PhoXCo2Li Li

PhO

OLi OLi

can be generated from mandelic acid (3 equivs. LDA), but unfortunately with alkyl halides only modest yields of a-substituted derivatives have been obtained so far.17Aliphatic a-methoxy-acids (11)can be prepared in 50-60% yield by the addition of an aldehyde (10) in chloroform solution to sodium hydride in THF, followed by base hydrolysis."

Following last year's report (2,26) of the specific synthesis of erythro-3hydroxy-2-methylcarboxylic acids, Buse and Heathcocklghave now developed a route to the corresponding threo-isomers by coupling aldehydes to allylic halides in the presence of chromium(i1) chloride followed by ozonolysis (Scheme 3). As in the previous study, use of an optically pure aldehyde [e.g. (12)] leads to only two of the four possible diastereoisomers. A. Wissner and C. V. Grudzinskas, J. Org Chem., 1978, 43,3972. N. Yoneda, Y. Takahashi, Y . Sakai, and A. Suzuki, Chem. Letters, 1978, 1151. l4 M. Lissel and E. V. Dehmlow, Tetrahedron Letters, 1978, 3689. T. Nakano, H. Arai, H. Matsumoto, and Y . Nagai, Org. Prep. Proced. Internut., 1978, 10, 5 5 . l 6 W. Adam, L. A. Encarnacion, and H.-H. Fick, Synthesis, 1978, 828; W. Adam and H.-H. Fick, J. Org. Chem., 1978, 43,772. " M. Newcomb and D. E. Bergbreiter, J. Org. Chem., 1978, 43,3963. E. L.Compere, jun., and A. Shockravi, J. O r g . Chem., 1978, 43,2702. l Y C.T. Buse and C. H. Heathcock, Tetrahedron Letters, 1978, 1685. l3

General and Synthetic Methods

78

f3-Hydroxy-a-phenylthio-acids and their methyl esters can be prepared by condensations between carbonyls and the bis-anionic species (13) from phenylthioacetic acid or the monoanion (14) from methyl phenylthioacetate*' respectively. Yields are often excellent although the bis-anion (13) is less reactive, failing to condense with 2-methylcyclohexanone or acetophenone. With enones, (13) undergoes [1,2] addition; by contrast the monanion (14) adds in a Michael fashion. Li

Li

PhSAC02Li

PhSAC02Me

(13)

(14)

Keto-acids.-A new method for the synthesis of a-keto-acids uses 2,2-difluoro1-tosyloxyvinyl-lithium as a key intermediate (Scheme 4).21Although yields are

very high, the final hydrolytic conditions may limit its application somewhat. The acyl anion equivalent (16), generated by the addition of alkyl-lithiums to sulphines (15), can, among other uses, b s employed to prepare a-keto-acids by carboxylation and desulphurization (Scheme 5).22

(16) Scheme 5 2o 21

22

S. Yarnagiwa, N. Hoshi, H. Sato, H. Kosugi, and H. Uda, J.C.S. Perkin Z, 1978, 214. K. Tanaka, T. Nakai, and N. Ishikawa, Tetrahedron Lerters, 1978, 4809. G. E. Veenstra and B. Zwanenburg, Tetrahedron, 1978, 34, 1585.

Carboxylic Acids and Derivatives

79

Ethyl dithioacetate is the starting material for a general synthesis of y-hydroxya-keto-acids outlined in Scheme 6.23The dithioacetate thus acts as a synthon of the dianion (17).

Reagents: i, LDA; ii, RCHO; iii, EtOCH=CH,; iv, EtMgl; v, CO,

Scheme 6

Various benzyl chlorides undergo double carbonylation on treatment with octacarbonyldicobalt under phase-transfer conditions {generation of [Co(CO),]-) to give arylpyruvic acids in moderate yields.24 on the synthetic utility of Corey and Enders have published full metallated dimethylhydrazones, including the preparation of lactones and &hydroxy-P-keto-acids, by condensations between carbonyls and the dianion derived from the dimethylhydrazone of methyl acetoacetate. P-Acylacrylic acids afford a-aryl- y-keto-acids under Friedel-Crafts conditions.26The enolate of the (2R,3S)-oxazepinedione (18), simply prepared from methyl hydrogen malonate and l-ephedrine hydrochloride, undergoes smooth Michael additions to enones to give, after hydrolysis and decarboxylation, 5-oxocarboxylic acids of high optical Thus, cyclopent-2-en-l-one is converted into the keto-acid (19), while addition of (18) to l-phenylbut-2-en-lone leads to (20) (cf. 2, 11; 3,4,5 ) .

23 24

25

26

27

A. I. Meyers, T. A. Tait, and D. L. Comins, Tetrahedron Letters, 1978,4657. H. des Abbayes and A . Buloup, J.C.S. Chem. Comm., 1978, 1090. E. J. Corey and D. Enders, Chem. Ber., 1978, 111, 1337, 1362. J. C. Cankvet and Y. Graff, Bull. SOC.chim. France, 1978, 278. T. Mukaiyama, Y. Hirako, and T. Takeda, Chem. Letters, 1978, 461.

General and Synthetic Methods

80

Unsaturated Acids.-The phosphonate (21) is a useful reagent for the direct elaboration of a,@-unsaturated acids from aldehydes and ketones, the silyl ester group being hydrolysed during work-up;28 the phosphonate also reacts specifically with an aldehyde in the presence of an unprotected ketone. Further work2' has shown that there is no need t o 'protect' the ester function in such phosphonates as the dianionic phosphonate species (22) can be generated directly and this reacts normally with carbonyls, although again coupling to aldehydes is much faster than to ketones. In similar vein, a-chloro-a,@-unsaturatedacids can be prepared using the phosphonate dianion (23).30

-

0

II

( E t O), P

0

,

CO Si M e

(21)

I1

(Eto),P

-

(22)

CO 2-

0

CI

II A

(EtO),P

C0,-

(23)

The generation of vinyl-lithium species from 2,4,6-tri-isopropylbenzenesulphonyl hydrazones is a method which should find considerable application.31 Of relevance to this section is the reaction with carbon dioxide to give substituted acrylic acids (Scheme 7). Given a choice, the least substituted double bond is formed, e.g. ( 2 4 )+ ( 2 5 ) .

Ar =

Scheme 7

A novel route to labelled a,@-unsaturated acids is the Doebner reaction between aldehydes and [0,O'-2H2]malonic acid which gives the expected acid with deuterium at the a - p ~ s i t i o n Condensation .~~ with a,@-unsaturated aldehydes leads t o dienoic acids labelled at both the a- and the y-positions. The enolate of crotonic acid is known to react with electrophiles predominantly at the y-position. However, it has now been that the initial product is 28

29

30 3' 32 33

L. Lombardo and R. J. K. Taylor, Synthesis, 1978, 131. L. Lombardo and R. J. K. Taylor, Synrh. Comm., 1978, 8, 463; P. Coutrot, M. Snoussi, and P. Savignac, Synthesis, 1978, 133. P. Savignac, M. Snoussi, and P. Coutrot, Synth. Comm., 1978, 8, 19. A. R. Chamberlin, J. E. Stemke, and F. T. Bond, J. Org. Chem., 1978,43, 147. J. A. Elvidge, J . R. Jones, R. B. Mane, and M. Saljoughian, J.C.S. Perkin I, 1978, 1191. I. Casinos and R. Mestres, J.C.S. Perkin I, 1978, 1651.

81

Carboxylic Acids and Derivatiiyes

from reaction at the a-position, [i.e. (26) by addition of a ketone], which on warming with strong base gives the usually observed product (27). At ca. 0 "C, crotonic acid and 3,3-dimethylacrylic acid enolates undergo Michael addition to enones to give unsaturated keto-acids of type (28). R'

R'

OH

,.yf.-

OH

R Z X ~ c o z H

CO,H (27)

(26)

(28)

An alternative method for the classical Knoevenagel-type preparation of cinnamic acids has been reported; this came to light during a study of the Cinnamic acid bromine-induced decarboxylat ion of substituted cinnamic derivatives can also be prepared by the palladium-catalysed coupling of methyl acrylate with electron-rich aryl iodides;35similarly 5 -arylpenta-2,4-dienoic acids (29) can be synthesized from penta-2,4-dienoic acid and bromo-aryls. A Stobbetype condensation between aromatic aldehydes and methyl propylidenemalonate leads to the E,E-unsaturated acids (30), probably via a 8-lactone intermediate.36 *-,CC)H ,

A

,

~

C

O ,

M

e

CO,H

(29)

(30)

A preliminary report has appeared on a new, potentially general method for the preparation of y,S-unsaturated acids based on a Claisen rearrangement (Scheme 8).37

vo> i,ii

,~

~

o

iii-v

~ ,

o

~

R

PhSe Reagents: i, PhSeBr; ii, HO-R

R; iii, Oxidize; iv, A; v, saponify

Scheme 8

Oxidative ring cleavage of dichloronorcarenol (31) with lead(1v) acetate affords the 2-unsaturated acid (.32),a potentially valuable synthetic intermediate, as illustrated by its use in the synthesis of crepenynic acid (33).38 [1,3]-Dipolar addition of diphenyl phosphorazidate [(PhO),P(O)N,] to enamines derived from alkyl arlyl ketones gives intermediates of type (34) which readily rearrange with loss of nitrogen to give the amidine derivatives (35); these, on hydrolysis (potassium hydroxide in refluxing ethylene glycol) afford a-aryl34

C. A. Kingsbury and G. Max, J. Org. Chem., 1978, 43, 3131.

'' B. A. Patel, J. E. Dickerson, and R. I;. Heck, J. Org. Chem., 1978,43,5018;C . B. Ziegler, jun., and 36

37 38

R. F. Heck, ibid., p. 2941 and following papers. S. Rebuffat, M. Giraud, and D. Molho, Bull. SOC.chim. France, 1978, 457. M. Petrzilka, Helv. Chim. Acta, 1978, 61, 2286. T. L. Macdonald, Tetrahedron Letters, 1978, 4201.

82

General and Synthetic Methods

alkanoic acids3’ Arylacetic acids can be degraded oxidatively to the corresponding benzoic acids by alkaline sodium hyp~chlorite.~’ Meyer’s group has published a full report on the displacement of o-methoxygroups from o -methoxyaryl-oxazolines (36) by nucleophiles. Hydrolysis under acidic conditions (or with hot aqueous alkali, after quaternization) completes this route to ortho-substituted benzoic acids.41Overall yields are generally high if a suitable metal counterion is used, although, disappointingly, a number of organometallic species failed to react (e.g. allyl-lithium, acetate and acetone enolates, dithians); it seems that the nucleophile must first form a complex with the oxazoline, and that the carbanion must not be greatly delocalized. Oxazolines (37) derived from o-fluorobenzoic acid undergo much the same type of displacement rea~tion.~’ Sequential displacement of the two fluorines in the 2,6-difluoroderivative by different nucleophiles is also possible. A further, contrasting application of this complexing ability is the direct metallation (MeLi) of the oxazoline obtainable from isonicotinic acid to give the 0-lithium derivatives (38).43The co-ordinating properties of the oxazoline ring are clearly strong enough to compete with the usually observed addition of alkyl-lithiums to the pyridine ring.

z’ 41 42

47

T. Shioiri and N. Kawai, J. Org. Chem., 1978, 43, 2936. F. Kaberia and B. Vickery, J.C.S. Chem. Comm., 1978, 459. A. I. Meyers, R. Gabel, and E. D. Mihelich, J. Org. Chem., 1978, 43, 1372. A. I. Meyers and B. E. Williams, Tetrahedron Letters, 1978, 223. A. I. Meyers and R. A. Gabel, Tetrahedron Letters, 1978, 227.

83

Carboxylic Acids and Derivatives

The dianionic species (39) can be generated directly from 2,4-dimethyl-3furoic acid (LDA-THF, -78 “C) and behaves as a good nucleophile in some trial reactions.44 Various routes to pyridylpropiolic acids (40) have been investigated;45 pyrolysis of the appropriate phosphorane was found to be the most expeditious method.

Decarboxy1ation.-Krapcho’s has published details of a systematic study of the decarboxylation of geminal diesters and P-keto-esters by the widely used wet dimethyl sulphoxide-salt method. Although optimum conditions are obviously substrate dependent, the system DMSO-H20-LiC1 is often the best choice. When a similar decarboxylation of geminal diesters is carried out in hexamethylphosphoramide at ca. 155 “C in the presence of diphenyl disulphide, a-phenylthioesters are generated in yields usually less than 60% .47 An attractive alternative for the reduction of carboxylic acid functions to methyl groups is by condensation with benzene- 1,2-dithiol followed by borohydride reduction and desulphurization using sodium in ammonia (Scheme 9).48

0”” +RCO,H

SH

.. ...

A

11, 111

‘

RCH,

s BF4-

Reagents: i, HBF, or BF,; ii, NaBH,; iii, Na-NH,

Scheme 9

Sodium salts of a-thio-acids [e.g. (4l)]can be decarboxylated oxidatively to give the less thermodynamically stable isomer of the enol thioether product [e.g. (42)] by using N-chlorosuccinimide in d i m e t h ~ x y e t h a n e(cf. ~ ~2,49). The rate of C0,Na Ar

Ar

(41)

(42)

decarboxylation of sodium salts of carboxylic acids in general is increased by between 13 and 500 times by the addition of 18-cr0wn-6.~~ a-Hydroxy-p-ketocarboxylates can be decarboxylated oxidatively to a-diketones by mercury(I1) 44 45 46

47 48 49

50

M. Tada and T. Takahashi, Chem. Letters, 1978, 275. W. N. Lok and A. D. Ward, Austral. J. Chem., 1978, 31,617. A . P. Krapcho, J. F. Weimaster, J. M. Eldridge, E. G. E. Jahngen, jun., A. J. Lovey, and W. P. Stephens, J. Org. Chem., 1978, 43, 138. M. Asaoka, K. Miyake, and H. Takei, Bull. Chem. SOC.Japan, 1978,51,3008. I. Degani and R. Fochi, J.C.S. Perkin I, 1978, 1133. B. M. Trost, M. J. Crimmin, and D . Butler, J. Org. Chem., 1978, 43, 4549. D. H. Hunter, M. Harnity, V. Patel, and R. A. Perry, Canad. J. Chem., 1978,56, 104.

General and Synthetic Methods

84

salts; the broad generality of this method has not been i n ~ e s t i g a t e dp-Nitro.~~ phenyl N-acyl-a-amino-acid esters can be decarboxylated oxidatively by reaction with rn-chloroperoxybenzoic acid in mildly basic dioxan. Yields are generally good; typical of this method is the conversion of Z-Ala-ONp to the N-acetylcarbamate (43).s2

"""Y 0 (43)

Protection and Deprotection.-In an extension of alcohol protection methodology, the preparation and cleavage of methylthiomethyl (MTM) esters has been d e ~ c r i b e dThey . ~ ~ are obtained from carboxylic acids and chloromethyl methyl sulphide in hot benzene in the presence of sodium iodide and 18-crown-6, and may be saponified by treatment with mercury(I1) chloride in refluxing, wet acetonitrile. It is possible to form an MTM ester in the presence of a tetrahydropyranyl ether and to remove the latter without affecting the MTM group. One problem could be the susceptibility of the MTM group to oxidative hydrolysis by air, so care is needed in their storage. Carboxylic acid groups in the sensitive gibberellins can be protected by the photosensitive p-methoxyphenacyl group.s4 2-Halogenoethyl esters can easily be cleaved with sodium hydrogen ~ e l e n i d e , ~ ~ and allyl ester groups can be removed specifically by reaction with lithium dimethylcuprate, to give the lithium salt of the acid, methylcopper, and but-lene.s6 Trimethylsilyl iodide, already established as a useful reagent for the dealkylation of esters, is best prepared in situ owing to its extreme sensitivity to hydrolysis. Unfortunately, existing conditions for this involve elevated temperatures (ca. 110 "C), and so the reagent selectivity is lost (t-butyl and benzyl groups are removed much more rapidly than methyl or ethyl groups) (1,47; 2,59,60).A new procedure for its preparation which avoids this problem is by reaction between allyltrimethylsilane and iodine.57A disadvantage of this method is the removal of the other reaction product, highly electrophilic allyl iodide. An even better solution is to prepare Me3SiI from (44), itself available from benzene, trimethylsilyl chloride, and lithium. On a small scale, yields with a range of esters are essentially quantitative and a wide variety of reaction times (15 m + 78 h) at SiMe,

0 SiMe,

(44) L. M. Sayre and F. R. Jensen, J. Org. Chem., 1978, 43, 4700. G . Lucente, F. Pinnen, and G. Zanotti, Tetrahedron Letters, 1978, 3155. s3 L. G. Wade, jun., J. M. Gerdes, and R. P. Wirth, Tetrahedron Letters, 1978, 731. s4 E. P. Serebryakov, L. M. Suslova, and V. F. Kucherov, Tetrahedron, 1978, 34,345. 55 T. L. H o , Synth. Comm., 1978, 8 , 301. '' T. L. Ho, Synth. Comm., 1978, 8 , 1.5. " M. E. Jung and T. A. Blumenkopf, Tetrahedron Letters, 1978, 36.57. "

52

Carboxylic Acids and Derivatives

85

room temperature is required, presumably allowing for specific saponifications of mixed polyesters. An alternative to this is to use mixtures of trimethylsilyl chloride and sodium iodide.” Good yields are obtained except for isopropyl esters (37%), and seemingly trimethylsilyl iodide is not an intermediate in the reaction. The cleavage of esters can be achieved at ambient temperatures by using a mixture of aluminium tribromide and ethanethi~l;~’ yields are generally excellent. A similar reaction with lactones (45) leads to w-ethylthiocarboxylic

(46)

(45)

An alternative method for the cleavage of p-nitrobenzyl esters is to use sodium sulphide.60Aromatic polymethyl esters can be mono-demethylated by heating in neat 1,l-dimethylhydrazine.61 The most exposed group is attacked; thus trimethyl 1,3,4-benzenetricarboxylateis converted into dimethyl 4-carboxyphthalate in 73% yield.

3 Lactones P-Lactones.-The enolate of phenoxyacetic acid (3, 16) affords, on reaction with aldehydes, the expected P-hydroxy-acids which can be dehydrated with benuseful prezenesulphonic acid to give 3-substituted-2-phenoxypropiolactones, cursors of phenyl enol ethers.62p-Lactones can also be prepared by the therHydroxymolysis of tri-n-butylstannyl derivatives of P-hydro~y-esters.~~ palladation of olefins has been shown to occur in a trans manner, as reaction of [cis-l,2-*H2]ethylene followed by carbonylation (known to proceed with retention of configuration) gives only the trans-substituted p-lactone (47).64 A series of dichloro-P-lactones (48) have been prepared from substituted benzaldehydes and dichloroketen ; yields are higher with electron-deficient aldehydes.6s Unsaturated p-lactones of type (49) have been obtained by a [ 2 +~ 2771 addition reaction between isopropylideneketen and k e t e d 6 (cJ 1, 50).

(47) 58 59 60 61 62

63 64

65 66

(48)

(49)

T. Morita, Y. Okamoto, and H. Sakurai, J.C.S. Chem. Comm., 1978, 874. M. Node, K. Nishida, M. Sai, and E. Fujita, Tetrahedron Letters, 1978, 5211. S. R. Lammert, A. I. Ellis, R. R. Chauvette, and S. Kukolja, J. O r g . Chem., 1978, 43, 1243. S. Kasina and J. Nematollahi, Tetrahedron Letters, 1978, 1403. W. Adam and H.-H. Fick, J. O r g . Chem., 1978, 43, 4574; cf. D. J. Humphreys and C. E. Newall, J.C.S. Perkin I, 1978, 33. P. Didier and J.-C. Pommier, J. Organometallic Chem., 1978, 150, 203. J. K. Stille and R. Divakaruni, J. Amer. Chem. SOC., 1978, 100, 1303. H. 0. Krabbenhoft, J. Org. Chem., 1978, 43, 1305. G . J. Baxter, R. F. C. Brown, F. W. Eastwood, B. M. Gatehouse, and M. C. Nesbit, Austral. J. Chem., 1978,31, 1757.

86

General and Synthetic Methods

Butyroiactones.-A simple method for the direct conversion of protected butyrolactols into the corresponding butyrolactones is by oxidation with m-chloroperoxybenzoic acid in the presence of a catalytic amount of boron trifluoride e t h e ~ a t e Yields . ~ ~ are usually high but, disappointingly, the method fails with 8-lactols. Unsaturated amide (50) can be converted into the substituted butyrolactone (5 1) by treatment with phenyl selenenyl chloride.68 The generality of this reaction remains to be established. 2-Chloro-4-alkylbutyrolactones ( 5 2 ; X = H or C1) can be formed from di- or tri-chloroacetic acid respectively and alk-1-enes in the presence of dichlorotris(triphenylphosphine)ruthenium(~~).~~ X

(50)

(51)

(52)

A full report has been published7" on the preparation of optically pure 4-.tosylmethylbutyrolactone (53), and iis enantiomer from the appropriate glutamic acid, both enantiomers of which are commercially available. The elaboration of chiral 4-substituted butyrolactones from (53) relies upon the specific displacement of the tosyl group by lithium dialkylcuprates (2,70). The cyclization of 2-en-4-ynoic acids to 4-ylidenebutenolides using sodium bicarbonate has been known for some time. It has now been shown that 4-ylidenebutyrolactones (55) can be prepared from 4-ynoic acids (54) on heating with a catalytic amount of mercury(I1) oxide7* (cf. 3,117). Irradiation of the 2,3-epoxycyclohexa-l,4-dione( 5 6 ) in acetone leads to the formation of the lactone (57) in 38% yield.72Adducts similar to (57) but with anthracene as the diene component can be made to undergo a retro-Diels-Alder reaction to give y- ylidenebutenolides, although yields are very low.

+YR2 Hao HgO,

TsO

R"

0

(55)

(54)

(53)

R l w R '

CO, H

CHO

(56) h7 68 hY

70 7' 72

(57) E : Z = 3:l

P. A. Grieco, T. Oguri, and Y. Yokoyama, Tetrahedron Letters, 1978,419. D. L. J. Clive, C . K. Wong, W. A. Kiel, and S . M. Menchen, J.C.S. Chem. Comm., 1978,379. H. Matsumoto, T. Nakano, K. Ohkawa, and Y. Nagai, Chem. Letters, 1978, 363. U. Ravid, R. M. Silverstein, and L. R. Smith, Tetrahedron, 1978, 34, 1449. M. Yamamoto, J.C.S. Chem. Comm., 1978, 649. T. Kitarnura, T. Imagawa, and M. Kawanisi, Tetrahedron Letters, 1978, 3443; T. Kitamura, Y. Kawakima, T. Imagawa, and M. Kawanisi, ibid., p. 4297.

87

Carboxylic Acids and Derivatives

Butyrolactones can be obtained from carbonyls and the P-lithiopropionate (SS), derived from P-bromopropionic acid by sequential treatment with n-butyllithium and lithium n a ~ h t h a l e n i d e .Although ~~ yields are generally less than 50%, the method could find use as a simple route to spirolactones. The spirolactone (59),a potential precursor of the trichothecane antibiotic verrucarin A, has been obtained by a Diels-Alder reaction using a-methylenesuccinic anhydride as ene component followed by borohydride reduction to the l a ~ t o n eSpirolactone .~~ (60) can be prepared in low yield by a thallium(II1) trifluoroacetate oxidation of 3-(3,4-dimethoxyphenyl)propionic In a similar reaction, the carboxylate (61) can be cyclized to spirolactone (62) on treatment with N-bromosuccinimide at -20 "C, whereas at +10 "C the major product is the lactone (63) having the reverse stereo~hemistry.~~

0

Further work by Schlessinger's on approaches to vernolepin has revealed that t-butyl dilithioacetoacetate is a preferable reagent to dilithioacetate for the stereoselective synthesis of fused butyrolactones, originally developed by Danishefsky, from a-hydroxy-epoxides. The greater stereoselectivity of this reagent allows the preparation of pure cis-fused lactones from trans-a-hydroxyepoxides (Scheme 10).

y-y0"-rn"-+yJJo **

0

OH

C0,Bu'

OH

Scheme 10

A route to the potential prostaglandin precursor (64) has as its key step a regioselective [27r + 27r] addition reaction between cyclopent-2-en- 1-one and 73 74 75

76

77

D. Caine and A. S. Frobese, Tetrahedron Letters, 1978, 883. B. B. Snider and S. G. Amin, Synth. Comm., 1978,8, 117. E. C. Taylor, J. G. Andrade, G. J. H. Rall, and A. McKillop, J. Org. Chem., 1978, 43, 3632. D. Berney and K. Schuh, Helv. Chim. Acta, 1978,61, 1399. G. R. Kieczykowski, M. R. Roberts, and R. H. Schlessinger, J. Org. Chem., 1978,43, 788.

88

General and Synthetic Methods

ethyl P,P-diethoxyacrylate (Scheme 1l).78 The related cis-fused lactone (65)has been obtained optically pure in 15% overall yield from cis-cyclohex-2-ene-l,4d i 0 1 ~(cf. ~ 2, SO). The citraconate ester (66), prepared from citraconic anhydride and sorbyl alcohol, affords the fused lactone (67) upon intramolecular DielsAlder reaction.80 The other product from the initial esterification step, arising by attack at the 2-carbonyl of the anhydride, does not undergo cyclization.

C0,Et

Scheme 11

Acid-catalysed cyclization of the terpenoid a-phenylsulphonyl carboxylic acid (68)with pure sulphuric acid gives the cis-lactone (69) in 75% yield. Other acid catalysts give mixtures of (69) and its truns-isomer.81 Treatment of 4-alkyloxycinnamic acids with thallium(II1) trifluoroacetate and trifluoroacetic acid results in the very rapid formation of bis-lactones (70) in yields varying between 12 and 5 4 ’ / 0 . ~ ~There is good evidence for a mechanism involving a one-electron oxidation of the acid followed by dimerization of the radical cation so produced.

(68)

(69)

(70)

Some further studies on the preparation of antileukaemic lignans, e.g. steganone, podorhizon, etc., have appeared. A simple ‘one-pot’ route to these involves a Michael addition reaction between aryl dithians and 78

79 ’(’

81

82 83

M. Van Audenhove, D. Termont, D. D e Keukeleire, M. Vandewalle, and M. Claeys, Tetrahedron Letters, 1978, 2057. S. Terashima, M. Nara, and S.-I. Yamada, Tetrahedron Letters, 1978, 1487. J. D. White, B. G . Sheldon, B. A. Solheim, and J. Clardy, Tetrahedron Letters, 1978, 5189. K. Uneyama, M. Kuyama, and S. Torii, Bull. Chem. SOC. Japan, 1978,51,2108; c f T. R. Hoye and M. J. Kurth, J. Org. Chem., 1978, 43, 3693. E. C. Taylor, J. G . Andrade, G . J. H. Rall, and A. McKillop, Tetrahedron Letters, 1978, 3623. F. E. Ziegler and J. A. Schwartz, J. Org. Chem., 1978, 43, 985.

89

Carboxylic Acids and Derivatives

but-2-en-4-olide followed by trapping of the resulting enolate with benzyl halides (Scheme 12). An alternative to this method is the coupling of aryl aldehydes with enolates of 3-benzylbutyrolactones generated from the parent lactone using lithium he~amethyldisilylamide,~~ rather than the ubiquitous lithium di-isopropylamide. Finally, a Japanese group has developed an interesting route to optically active 2,3-disubstituted butyrolactones of this type, starting from optically pure 4-benzyloxymethylbutyrolactone,85based o n the chiral induction effects of the 4-substituent which is subsequently removed.

Ar

Scheme 12

Butenolides and Tetronic Acids.-An alternative method for the preparation of but-2-en-4-olide itself, in 62-71% yield, from furan employs a mixture of bromine, acetic acid, acetic anhydride, and sodium acetate.86 A general route to 3-substituted butenolides (72), which could have considerable potential, is the cyclization of phosphonium salts (7 l ) , simply by treatment with triethylamine in methylene ~hloride.~’ The salts are easily obtained from a-bromo-ketones and bromoacetic acid and, in the examples quoted in this preliminary study, overall yields are high except when 2-bromocyclohexanone was used as the ketonic component (cf. 3, 133). The 3-substituted butenolide group present in naturally occurring cardenolides can be built up from an a-methylthioketone residue by a Reformatsky reaction, followed by acid- and base-catalysed rearrangements.88

Some chiral allene carboxylic acids have been cyclized to 4-substituted butenolides with little racemization by heating with acid catalysts.892-Acyloxy-5methylfurans (73) rearrange to give the 4-disubstituted butenolides (74), in yields 84

85

86 87 88

89

E. Brown, J.-P. Robin, and R. Dhal, J.C.S. Chem. Comm., 1978,556; cf. E. Brown and J.-P.Robin, Tetrahedron Letters, 1978, 3613. K. Tomioka, H. Mizuguchi, and K. Koga, Tetrahedron Letters, 1978, 4687. R. M. Boden, Synthesis, 1978, 143. S. F. Krauser and A. C. Watterson, jun., J. Org. Chem., 1978, 43, 3400. E. Yoshii, T. Oribe, K. Tumura, and T. Koizumi, J. O r g . Chem., 1978,43, 3946. S. Musierowicz and A. E. Wroblewski, Tetrahedron, 1978, 34, 461.

General and Synthetic Methods

90

(74)

(73)

of 40-65%, on treatment with boron trifluoride at room temperature” (cf.3,99, 100). A general route to substituted butenolides has as its key intermediate the dianionic species (75) obtained from P-bromoacrylic acids using n-butyllithium.’’ Yields are lowered to 40-60% by the occurrence of a competing elimination reaction to give acetylenic carboxylates (cf.3, 73). Dimethyl y-bromoalkylidene malonates can be cyclized to butenolides of type (76) simply by thermal elimination of methyl bromide in boiling xylene.’* A

RZ simple method for the elaboration of 2-methoxycarbonylbut-2-en-4-olide from butyrolactone has been reported (Scheme 13).93The product has considerable C0,Me

0 Reagents: i, NaH; ii, CO(OMe),; iii, PhSS0,Ph; iv, m-CIC6H,C03H, 0 “C

Scheme 13

synthetic potential both as a Michael acceptor and as an electron-deficient ene component of Diels-Alder reactions. (&)-Lichensterinate(77) has been prepared in three steps (58% yield) from methyl a-ketopalmitate by a magnesium bromide-catalysed condensation with 1-diethylaminopropyne followed by allylic bromination and bicarbonate-induced lact~nization’~ (cf. 2, 101).

90 91

92

93 94

G. A. Kraus and B. Roth, J. Org. Chem., 1978, 43, 2072. D. Caine and A. S. Frobese, Tetrahedron Letters, 1978, 5167. R. VerhC, N. De Kimpe, L. D e Buych, D. Courtheyn, and N. Scharnp, Bull. Soc. chim. belges, 1978, 87, 215. M. 5. Quesada and R. H. Schlessinger, J. Org. Chem., 1978,43, 346. S. I. Pennanen, Heterocycles, 1978, 9, 1047.

Carboxylic Acids and Derivatives

91

An interesting photochemical rearrangement of 4-aryl-2,4-diphenylbutenolides gives the 3-arylbutenolides (78) as major prod~cts,’~ while 2,3diphenylbutenolides of type (79) can be obtained from the condensation of P-keto-ester enolates and diphenylcyclopropanone.96 Condensation with 2ethoxycarbonyl cycloalkanones gives rise to spiro-butenolides, while reaction with dimethyl malonate affords a 4-methoxycarbonylmethylidene butenolide. Ph

Ar

(79)

(78)

on the preparation of 3-chloroLarock’s group has published a full butenolides from propargylic alcohols by sequential mercuration (HgC12) and carbonylation (CO, Li,PdCl,) (1,74). Although the mercuration step is not very efficient, carbonylation proceeds in very good yields. A preliminary report has appeared of a related method for the preparation of 4-hydroxybutenolides (80) by a cobalt carbonyl-catalysed carbonylation of terminal acetylenes, under basic phase-transfer conditions.’* Yields for the three examples quoted are 18,44, and 68%. During studies aimed at the total synthesis of some natural products, it has been found that the 2-ethoxyfuran (81)undergoes acid-catalysed rearrangement to the fused butenolide (82).99Further use of the acid-catalysed rearrangement of

2-alkoxyfurans has been made in a general, two-step route to 4-alkylidenebutenolides (Scheme 14).’0° Overall yields for the five examples reported are in the range 44-81% (cf. 3,901.

Reagents: i, Bu‘Li; ii, R’COR’; iii, p-TsOH-aq. THF

Scheme 14 95 y6

97

9y loo

A. Padwa, T. Brookhart, D. Dehm, and G. Wubbels, J. Amer. Chem. Soc., 1978, 100, 8247. V. Veprek-Bilinsky, K. Narasimhan, and A. S. Dreiding, Helu. Chim. Actu, 1978, 61, 3018. R. C. Larock, B. Riefling, and C. A. Fellows, J. Org. Chem., 1978, 43, 131. H. Alper, J. K. Currie, and H. des Abbayes, J.C.S. Chem. Zornm., 1978,311. P. A. Jacobi and T. Craig, J. Arner. Chem. SOC., 1978,100, 7748. G. A. Kraus and H. Sugimoto, J.C.S. Chem. Comm., 1978, 30.

92

General and Synthetic Methods

The phthalisoimidiurn salt (83), readily available from phthalic anhydride, reacts with Knoevenagel-type enolates to give the ylidene-phthalides (84). The related isoimidium perchlorate ( 8 5 ) ,on deprotonation with triethylamine, affords the butenolide (86) which with aromatic aldehydes and carbon disulphide forms the 'ene'-type adducts (87) and (88) respectively. lo'

ArCHO

Ph

c10,(85) (88)

4-Substituted tetronic acids (89) can be obtained by condensation between the magnesium complex of ethyl hydrogen malonate and a-acetoxy-acid chlorides, followed by acid-catalysed lactonization in the presence of an alcohol (Scheme 15).lo* The fungal metabolite derivative methyl (E)-O-methylmulticolanate (90)

Scheme 15

(89)

can be easily prepared by a Wittig reaction between the appropriate maleic anhydride and methoxycarbonylmethylenetriphenylphosphorane.lo3 The vinyllithium species (91), obtained from the parent p -aminoacrylate using t-butyllithium at -1OO"C, condenses with ketones and esters to give the butenolide derivatives (92) in around 50% yieldlo4 (cf. 2, 105; 3, 91). lo'

lo'

'03 '04

G. V. Boyd and R. L. Monteil, J.C.S. Perkin I, 1978, 1338; A. R. Bayder and G. V. Boyd, ibid., p. 1360. P. Pollet and S. Gelin, Tetrahedron, 1978, 34, 1453. M. J. Begley, D. R. Gedge, and G. Pattenden, J.C.S. Chem. Comm., 1978, 60. R. R. Schmidt and J. Talbiersky, Angew. Chem. Internat. Edn., 1978, 17,204.

Carboxylic Acids and Derivatives

93

c,

R'),O R2

L A , C0,Et

(91)

(90)

(92)

2-Acetyltetronic acid derivatives (94) are formed during base-catalysed rearrangement of 4-ethoxycarbonyl-3(2H)-furanones (93). lo' 3-(Arylmethylene)furandiones (95) can be obtained in fair yield from tetronic acid itself (for which an improved preparation has been found) by condensation with aromatic aldehydes (three equivalents!) in the presence of concentrated hydrochloric acid. lo6 Butyrolactones are transformed into their 2-keto analogues upon dye-sensitized photo-oxygenation of their readily available 2-dimethylaminomethylene derivatives, the overall yield for the two steps, with model compounds, being about 60%. lo7

R

(93)

(95)

(94)

a-Methylenebutyro1actones.-In spite of all the many and varied methods which have been developed for the synthesis of a-methylenebutyrolactones, a Belgian group'08 has recently recommended the use of the Minato-Horibe procedure (ca. 1967) for the introduction of an a-methylene group into butyrolactones on the grounds of its reliability if not its brevity. Nevertheless, attractive new approaches to this series of compounds continue to be developed. One of these, outlined in Scheme 16, is based on the generation of vinyl-lithium species from arylsulphonylhydrazones (cJ the Shapiro reaction). Overall yields are between 40 and 60%, and this 'one-pot' procedure appears to be both simple and gene~a1.I'~ Li ,NHSO,Ar . ..

. ...

d 1, I I

bR R'

Reagents: i, Bu"Li; ii, R'COR2; iii, -70 to -3 "C;iv, CO,; v, CF,C02H

Scheme 16 '05

Io6

lo'

B. Chantegrel and S. Gelin, J. Heterocyclic Chem., 1978, 15, 327. H. Zimmer, W. W. Hillstrom, J . C. Schmidt, P. D. Seemuth, and R. Vogeli, J. O r g . Chem., 1978,43, 1541. H. H. Wasserman and J. L. Ives, J. Org. Chem., 1978, 43, 3238. P. Kok, P. D e Clercq, and M. Vandewalle, Bull. SOC.chim. belges, 1978, 87, 617. R. M. Adlington and A. G . M. Barrett, J.C.S. Chem. Comm., 1978, 1071.

94

General and Synthetic Methods

The dianionic derivative (96), obtained from methallyl alcohol using mixtures of potassium t-butoxide and n-butyl-lithium as base, has been utilized in another general route to a-methylenebutyrolactones following condensation with carbonyls and manganese dioxide oxidation (Scheme 17).'l0 Although the yields

(96)

Scheme 17

obtained in the initial step are rather low, the simplicity of both the starting material and the method could make this a worthwhile alternative route. a-Trimethylsilylvinylmagnesiumbromide, in the presence of copper(1) iodide, condenses with epoxides to give 3-trimethylsilylbut-3-en-1-ols which on conversion into the 1-bromo-derivative afford a-methylenebutyrolactones directly upon treatment with nickel carbonyl (Scheme 18).ll1

a-Methylenation of lactones (and esters) can be achieved by a 'deacylative condensation' procedure. This consists of a condensation between, for example, the enolate of 2-acetylbutyrolactone (97) and formaldehyde, followed by thermal rearrangement of the resulting alkoxide (98) to unsaturated lactone (99) and acetate ions112(cf. 3, 2, 17). Substituted a-methylenebutyrolactones have been obtained, generally in very good yield, by electrolysis of the corresponding a-carboxy-a-phenylthiomethylbutyrolactones. l1

The thiocarbonate enolate (100) is a useful reagent for the preparation of a-alkylidenebutyrolactones by condensation with aldehydes followed by elimination.'14 Similarly, the very reactive dianion (101) derived from a-mercaptobutyrolactone has been used in a 'one-pot' procedure for the elaboration of

'I2

'I3 114

R. M. Carlson, Tetrahedron Letters, 1978, 111. I. Matsuda, Chem. Letters, 1978, 773. Y. Ueno, H. Setoi, and M. Okawara, Tetrahedron Letters, 1978, 3753. S. Torii, T. Okamoto, and T. Oida, J. Org. Chem., 1978, 43, 2294. K . Tanaka, N. Yamagishi, H. Uneme, R. Tanikaga, and A. Kaji, Chem. Letters, 1978, 197.

95

Carboxylic Acids and Derivatives

a-dialkylidene-butyrolactones by condensation with ketones. '15 The phosphonate (102) is another precursor of such compounds, although in this case the delocalized anion is rather unreactive, necessitating the use of rather high temperatures (170 "C)to obtain the desired reaction."6 0

Simple mercury(I1)-catalysed cyclization of pent-4-ynoic acid gives y-methylenebutyrolactone (cf.3, 71), the enolate of which, on condensation with aldehydes followed by mesylation and base-induced elimination, affords a-alkylidene derivatives in moderate yields (Scheme 19).lI7This method has been used to prepare deoxyobtusilactone, a relative of some naturally occurring cytotoxic lactones.

Reagents: i, LDA; ii, RCHO; iii, MsCl; iv, D B U

Scheme 19

The dianion from a-phenylselenopropionic acid has been utilized to prepare both trans- and cis-fused a-methylenebutyrolactones.' l8 Coupling with cyclohexane-1,2-epoxide leads to mainly the trans-isomer (trans :cis = 12 : 1) whereas alkylation with 3-bromocyclohexene followed by either acid-induced cyclization or iodolactonization gives only the cis-isomer (Scheme 20). cis-Fused a-methylenebutyrolactones can also be prepared by Lewis acid-catalysed condensation of cyclic ketones with Meldrum's acid followed by lactonization

@h: -&em

--

H

H

c0,-

H Scheme 20 'I6

'"

K. Tanaka, U. Uneme, N. Yamagishi, N. Ono, and A. Kaji, Chem. Letters, 1978, 653. T. Minami, M. Matsumoto, H. Suganuma, a n d T . Agawa, J. Org. Chem., 1978, 43, 2149. R. A. Amos and J. A. Katzenellenbogen, J. Org. Chem., 1978,43, 560. N. Petragnani and H. M. C. Ferraz, Synrhesis, 1978,476.

96

General and Synthetic Methods

with mineral acid; as yet, yields are rather sporadic in quality"' (cf. 1, 97). A further route is by cycloaddition of methylchloroketen to cyclic olefins followed by Baeyer-Villiger oxidation and base elimination120(cf. 1,95). Following model studies reported in 1976 (1,92), it is satisfying to read that a total synthesis of (*)-confertin has been achieved by a nickel(0)-induced cyclization of (103) to fused lactone (104).'*l A total synthesis of optically active canadensolide (105) has been reported, starting from diacetone glucose. During the synthesis, considerable difficulties were encountered, especially in the final steps aimed at introduction of the a-methylene substituent.'22

(1 04)

(103)

(105)

Valero1actones.-Chiral mevalonolactone has been obtained from optically active a-arylsulphinyl acetates in ca. 17% optical yield. l Z 3 The sulphoxides were prepared from the corresponding sulphides by selective oxidation with a variety of micro-organisms. A general route to both cis- and trans-fused valerolactones has as key step a photochemical [277 + 27r] cycloaddition of olefins to furanone (106) (Scheme 21).124The precise geometry of the final lactone depends upon the subsequent steps used. Overall yields are in the order of 60--80%, and the method can also be applied to the elaboration of both non-fused and spiro-valerolactones.

o +Q

W

0

H

O

H

H Reagents: i, h v ; ii, m-CIC,H,CO,H; iii, MeOH-H,O; iv, NaBH,-Pr'OH, vi, retro-Aldol (H'-MeOH, A); vii, NaBH,

A; v, H + ;

Scheme 21 E. Campaigne and J. C. Beckmann, Synthesis, 1978, 385. A. Hassner, H . W. Pinnick, and J. M. Ansell, J. O r g . Chem., 1978, 43, 1774. M. F. Semmelhack, A. Yamashita, J. C. Tomesch, and K. Hirotsu, J. Amer. Chem. SOC., 1978, 100, 5565. R. C. Anderson and B. Fraser-Reid, Tetrahedron Letters, 1978, 3233. E. Abushanab, D. Reed, F. Suzuki, and C. J. Sih, Tetrahedron Letters, 1978, 3415. S. W. Baldwin and M. T. Crimmins, Tetrahedron Letters, 1978, 4197.

Carboxylic Acids and Derivatives

97

During efforts towards the preparation of prostaglandin^,'^^ optimum conditions for selective bridgehead migration have been established in the BaeyerVilliger conversion of bicyclo[2,2,l]heptan-2-ones (107) into lactones (108). 3,5-Dinitroperoxybenzoicacid, a stable crystalline solid, may in some cases be preferable to peroxytrifluoroacetic acid for Baeyer-Villiger oxidation, as well as for olefin epoxidation. 126 Various molybdenum peroxo-complexes catalyse the conversion of cyclic ketones into lactones by hydrogen p e r 0 ~ i d e . l ~ ~ R'

R'

(107)

(108)

Unsaturated valerolactones (109) can be prepared in good yield from a-(nbutylthiomethy1ene)cyclohexanones by reaction with acetate enolates, followed by desulphurization and addition of an organolithium reagent (Scheme 22).128

R5, \

+ iii Q R

&R@co2Et

SBu"

R3

0

(109)

Reagents: i,

Ti /

.. OEt ,ii, Hg"; iii, 2 eqivs. R3Li

Scheme 22

Cyclohexanol derivatives (1 10) can be transformed into unsaturated lactones of type (111)by heating with s-trioxan in mixtures of sulphuric and acetic acids.129

-@ J

02H $;(

(110)

(111)

The preparation of a-methylenevalerolactones by carbonylation of 5-hydroxy- 1ynes, recently described by Norton et al. (1,94), has been found to be effective only when the alcohol and ethynyl groups are rigidly held in a cis-config~ration.'~~ 125

126

129

13'

Z. Grudzinski, S. M. Roberts, C . Howard, and R. F. Newton, J.C.S. Perkin I, 1978, 1182. W. H. Rastetter, T. J . Richard, and M. D. Lewis, J. Org. Chem., 1978, 43, 3163. S. E. Jacobson, R. Tang, and F. Mares, J.C.S. Chem. Comm., 1978, 888. A. J. G. M. Peterse, Ae. de Groot, P. M. Van Leeuwen, N. H. G. Penners, and B. H. Koning, Rec. Trav. chim., 1978, 97, 124. T. Fujita, S. Watanabe, K. Suga, R. Yanagi, and F. Tsukagoshi, J. Org. Chem., 1978,43, 1248. T. F. Murray, V. Varma, and J. R. Norton, J. Org. Chem., 1978, 43, 353.

98

General and Synthetic Methods

For example, pent-4-yn-1-01 failed to give any more than traces of a-methylenevalerolactone itself. A photoannelation procedure for the elaboration of a-methylenevalerolactones, which is reported to give good yields, is shown in Scheme 23. 13' OH

C0,Me Reagents: i, h v ; ii, LiAIH,; iii, MnO,

Scheme 23

A general route to 6-substituted valerolactones (112) is by condensation between aldehydes and the dianion derived from butynoic acid followed by hydrogenation using Lindlar's During the synthesis of some steroid derivatives, use has been made of an intramolecular Wadsworth-Emmonds procedure to construct an unsaturated valerolactone group (I14) from phosphonate (113)'33 (cf. 3,87). A new preparation of (k)-pestalotin (115) has as its pivotal step a Lewis acid-catalysed condensation between 2-benzyloxyhexanol and diketen.134 P-Ethylenic valerolactones (116) can be obtained from the corresponding 6-allenic acids by treatment with methanolic boron trifl~oride'~' (cf. 3, 89). 0

0

R

4 Macrolides

A new route to macrolides containing an aromatic ring is by cyclization of 2-(phenylthiornethy1)benzoic acid derivatives (Scheme 24).136The reaction is 131

132 133 134

13'

13'

S. W. Baldwin, M. T. Crimmins, and V. I . Cheek, Synthesis, 1978, 210. H. H. Meyer, Annalen, 1978,327. G . R. Weihe and T. C. McMorris, J. Org. Chem., 1978, 43, 3942. T. Izawa and T. Mukaiyama, Chem. Letters, 1978, 409. J. Grimaldi, Compt. rend., 1978, 286, C, 593. T. Takahashi, K. Kasuga, and J. Tsuji, Tetrahedron Letters, 1978, 4917.

Carboxylic Acids and Derivatives

99

I

SPh

SPh

Scheme 24

carried out in THF at 40°C under moderately dilute conditions (ca. 1mM substrate in 45 ml THF) using the potassium salt of hexamethyldisilazane as base. Yields are around 70% for 14- and 15-membered rings but the reaction fails with a 12-membered substrate. However, this problem can be overcome by replacing the iodoalkane side-chain with the corresponding allylic chloride; O-methyllasiodiplodin has been prepared by this method. The same principle has been used to obtain macrolides from o-iodoalkyl phenylthioa~etates;'~~ yields compare favourably with those of other methods. Two novel, potentially general, rearrangement procedures have been reported for the synthesis of phoracantholide J (117). The first employs an internal acetal formation followed by a Claisen r e a ~ r a n g e m e n twhile , ~ ~ ~the alternative involves a 'Keten-Claisen' rearrangement (Scheme 25).139

c1 Reagents: i, PhSeBr; ii,

>C=O

c1'

Scheme 25

Alternatives to the established 'double activation' method for the lactonization of o-hydroxy-acids via 2-pyridyl thioesters are use of the more reactive 4-(2amino-6-methy1)pyrimidylanalogues14oor mixtures of 2-chloro-6-methyl-l,3diphenylpyridinium tetrafluoroborate, 2,6-dimethylpyridine, and benzyltriethylammonium chloride in refluxing 1,2-dichloroethane. 14' 137 13* 139 140

14'

T. Takahashi, S: Hashiguchi, K. Kasuga, and 3. Tsuji, J. Amer. Chem. SOC.,1978, 100,7424. M. Petrzilka, Helu. Chim. Actu, 1978,61, 3075. R. Malherbe and D. Bellus, Helu. Chim. Actu, 1978, 61, 3096. J. S. Ninitz and R. H. Wollenberg, Tetrahedron Letters, 1978, 3523. K. Narasaka, K . Maruyama, and T. Mukaiyarna, Chem. Letters, 1978, 885.

100

General and Synthetic Methods

A preliminary report has been published on a stereoselective approach to medium-sized ketolactones involving an alumina-catalysed cyclization of epoxydihydropyrans followed by addition of singlet oxygen and thermal decomposition of the resulting dioxetan (Scheme 26).'42Previous studies (1,134, 135) have been extended to a synthesis of keto-thiola~tones.'~~ H

H

Reagents: i, Basic alumina (Grade I), hexane; ii, Ac,O-pyridine; iii, ' 0 ,

Scheme 26

The use of classical reactions in an intramolecular fashion continues to be a fruitful approach to large rings. A further route to the ten-membered diplodialides is by an internal Reformatsky reaction of ~-formyl-bromoacetates'44while another total synthesis of vermiculin employs an intramolecular WadsworthEmmonds r e a ~ t i 0 n . Large I ~ ~ rings containing a number of lactonic bonds have been prepared by a photochemical [ 2 7 ~+ 27r] addition between w,w'-dicinn a m a t e ~A . ~group ~ ~ of papers'47 on approaches to the cytochalasan carbon skeleton by intramolecular Diels-Alder reactions is well worth reading. 5 Esters

Esterificati0n.-Carboxylic acids can be esterified under virtually neutral conditions using two equivalents of alcohol and either N,N-dimethylphosphoramidic dichloride [Me,NP(O)Cl,] or commercially available phenyl dichlorophosphate as dehydrating Yields are typically above 80% ; the method can be used to prepare t-butyl esters. N,N-Dicyclohexylcarbodi-imidehas often been used as a coupling reagent in ester and amide formation although its efficiency is sometimes lowered by side reactions (e.g. anhydride formation). These can be eliminated simply by the addition of 3-10 mole% of 4-dimethylamino~ y r i d i n e (cf. ' ~ ~2, 303). A full report has appeared o n the use of 2-fluoro-1,3,5trinitrobenzene (FTNB) as a condensing agent for the conversion of acids into 142 143 144

145 I46 147

14n 149

R. K. Boeckman, jun., K. J . Bruza, and G. R. Heinrich, J. Amer. Chem. Suc., 1978, 100, 7101. H. C. Araiyo and J . R. Mahajan, Synthesis, 1978, 228. J . Tsuji andT. Mandai, Tetrahedron Lerters, 1978,1817; cf. J . Yoshida, K. Tamao, M. Takahashi, and M. Kumada, ibid., p. 2161; J . Tsuji, T. Yamakawa, and T. Mandai, ibid., p . 565. K. F. Burri, R. A. Cardone, W. Y. Chen, and P . Rosen, J. Amer. Chem. Suc., 1978, 100, 7069. J. A. Ors and R. Srinivasan, J.C.S. Chem. Comm., 1978, 400. G . Stork, Y .Nakahara, Y. Nakahara, and W. J. Greenlee, J. Amer. Chem. Suc., 1978,100,7775; S . J. Bailey, E. J . Thomas, W. B. Turner, and J. A. J. Jarvis, J.C.S. Chem. Comm., 1978,474; C . Owens and R. A. Raphael, J.C.S. Perkin I, 1978, 1504; T. Schmidlin and C. Tamm, Helv. Chim. Actu, 1978, 61, 2096. H. Liu, W. H. Chan, and S . P . Lee, Tetrahedron Letters, 1978, 4461. B. Neises and W. Steglich, Angew. Chem. Znternat. Edn., 1978, 17, 522; G. Hofle, W. Steglich, and H. Vorbruggen, ibid., p. 569; A. Hassner and V. Alexanian, Tetrahedruii Letters, 1978, 4475; A Hassner, L. R. Krepski, and V. Alexanian, Tetrahedron, 1978, 34, 2069.

Carbox ylic Acids and Derivatives

101

esters, thioesters, and amides."" Yields are generally good but tend to be lower when either substrate is bulky. An alternative brew for the esterification of carboxylic acids (alkyl halide-DBU-benzene) seems to be very general, giving excellent yields for a wide range of ester types.'" The 'Nafion-H' superacid-catalysed preparation of esters from equal amounts of acid and alcohol is best carried out in a special reactor designed to allow only brief exposure (5-7 s ) of the reactants to the catalyst, usually at 125°C.'52 An improved synthesis of pentamethoxyphosphorane has been d e ~ e l o p e d . " ~ This reagent is useful for the preparation of methyl esters under neutral conditions as well as for the permethylation of various other substrates, e.g. phenols and phthalimides. The Rydon reagent methyltriphenoxyphosphonium trifluoromethanesulphonate could find use as a mild esterifying reagent'54 while a brief, 'one-pot' esterification procedure uses the adduct of dimethylformamide and oxalyl chloride to activate the carboxylic acid group.15sThe latter method can also be used to prepare acid chlorides and amides. Polymer-bound yneamine groups are also useful for the activation of acid groups in the preparation of phenyl esters, anhydrides, and amides.15' This method has been subjected to only a preliminary investigation, so the yields reported have not been optimized. A mild, high-yielding method for the esterification of sensitive cephalosporanic acids proceeds via the 3-nitro-2-pyridinethioester and subsequent reaction with alcohols (cf. 2, 162). The intermediate, activated esters are obtained using 3-nitro-2-pyridinesulphenyl chloride and triphenylpho~phine.'~' Amino-alcohols can be esterified by acyl chlorides in mixtures of acetonitrile and benzene.'58 Reaction between sodium pyruvate and alkyl halides in DMSO, at 50 "C for 3-5 h, provides pyruvate esters in good ~ie1d.I'~ Various t-butyl peroxy-esters have been prepared from t-butyl hydroperoxide with N,N-carbonyldi-imidazoleas transfer reagent. 160 General Synthesis.-Alkyl silyl ethers, upon irradiation with N-bromosuccinimide in carbon tetrachloride at 0 "C, are converted into the corresponding alkyl alkanoates (Scheme 27).I6l Mixed esters can be formed, often in good yield, R-OSiMe,

+

1

OAR

R-0

Scheme 27 1 so

152 153 154

Is' 15h

Is' '51

15'

K. Inomata, H. Kinoshita, H. Fukuda, K. Tanabe, and H. Kotake, Bull. Chem. Soc. Japan, 1978,51, 1866. N. Ono, T. Yamada, T. Saito, K. Tanaka, and A. Kaji, Bull. Chem. Soc., Japan, 1978, 51, 2401. G. A. Olah, T. Keumi, and D. Meidar, Synthesis, 1978, 929. D. B. Denny, R. Melis, and A. D. Pendse, J. Org. Chem., 1978, 43, 4672. E. S. Lewis, B. J. Walker, and L. M. Ziurys, J.C.S. Chem. Comm., 1978,424. P. A. Stadler, Helv. Chim. Acta, 1978, 61, 1675. J. A. Moore and J. J. Kennedy, J.C.S. Chem. Comm., 1978, 1079. R. Matsueda, Chem. Letters, 1978, 979. T. Y. Luh and Y. H. Chong, Synth. Comm., 1978, 8, 327. P. J . Boyle and J. F. W. Keana, Org. Prep. Proced. Internat., 1978, 10, 101. M. J. Bourgeois, C. Filliatre, R. Lalande, B. Maillard, and J. J . Villenave, Tetrahedron Letters, 1978, 3355. H. W. Pinnick and N. H. Lajis, J. Org. Chem., 1978, 43, 371.

102

General and Synthetic Methods

by performing the reaction between a silyl ether and an aldehyde; thus decanal and ethyl trimethylsilyl ether give ethyl decanoate in 83% yield. Clearly, substrates containing olefinic bonds cannot be used in the reaction. In the presence of various rhodium catalysts, terminal epoxides (118) can also be dimerized to give esters (1 19) in ca. 40% yield. Mixtures of two epoxides tend to give mainly the ‘crossed’ products. 16*

(1 18)

(119)

Model have established that the pyridyl amide (120; R’ = Ph or Et) is a useful acyl transfer reagent, as on reaction with alkoxides or metal amides, esters (121; R2 = OCH2Ph) and amides (121; R2 = NEt,) respectively are produced in good yields.

Trialkylboranes transfer an alkyl group to ethyl acrylate or methacrylate in a Michael sense under electrolytic conditions to give saturated esters in 5 1-94% ~ i e 1 d s . lSimple ~~ Grignard reagents can be converted directly into esters in 70-80% yield by sequential treatment with pentacarbonyliron and an alcohol saturated with iodine; the presumed intermediates are acyltetracarbonylferAn aprotic deamination of primary amines with isoamyl nitrite in the presence of a carboxylic acid also leads directly to esters.166 Esters are obtained from aldehydes by treatment with alcoholic potassium or lithium alkoxides and ozone at -78 0C.167While the method has obvious limitations, it looks sufficiently expedient to be of use with suitable substrates. The ozonolysis of olefins leads directly to esters when the reaction is carried out in the presence of an alcohol and anhydrous hydrogen chloride’68or boron trifluoride in methanol. 169 Addition of Grignard reagents to ‘spiro-activated’ cyclopropanes (122) gives mainly the trans-product ( 123).170Highly substituted (P,P or a,P) a#unsaturated esters, often inert to conventional Gilman reagents, can be subjected 162

J. Blum, B. Zinger, D. Milstein, and 0. Buchman, J. Org. Chem., 1978, 43, 2961. A. I. Meyers and D. L. Comins, Tetrahedron Letters, 1978, 5179. Y. Takahashi, K. Yuasa, M. Tokuda, M. Itoh, and A. Suzuki, Bull. Chem. SOC.Japan, 1978,51,339. 16.5 M. Yamashita and R. Suemitsu, Tetrahedron Letters, 1978, 1477. 166 R. M. Jackobson, Synth. Conim., 1978, 8, 33. 167 P. Sundararaman, E. C. Walker, and C. Djerassi, Tetrahedron Letters, 1978, 1627. 168 J. Neumeister, H. Keul, M. P. Saxena, and K. Griesbaum, Angew. Chem. Znternat. Edn., 1978, 17, 939. 169 J.-L. Sebedio and R. G. Ackman, Canad. J. Chem., 1978,56. 2480. I70 T. Livinghouseand R. V. Stevens, J.C.S. Chem. Cornm., 1978, 754; J. Amer. Chem. SOC.,1978,100, 6479. I63

164

Carbonylic Acids and Derivatives

103

to Michael additions with the novel cuprate (124); yields in this preliminary study are around 50%.I7l The complex also undergoes smooth addition to a,@unsaturated acids; for example, crotonic acid gives 3-methylheptanoic acid in 8 1% yield when treated with (124).

t-Butyl groups can be introduced into the a-position of esters in moderate to good yield, by converting the unsubstituted ester into its trimethylsilyl enolate and treating this with t-butyl chloride in refluxing methylene chloride containing small amounts of zinc chloride. a-1-(Adamantyl) esters can be prepared ~imi1arly.l~~ a-Halogeno-esters are generated in 75--95'/0 yields by halogenation of ester enolates with carbon tetra halide^.'^^ A simple scheme has been developed for the preparation of a-fluoro-a-halogenoacetates from afluoroacetates. 174 The addition of singlet oxygen to ester trimethylsilyl enolates has provided some examples of a-hydroperoxy-esters in good yield. '71 Thallium(1) cyanide is a suitable reagent for the conversion of chloroformates into cyan of or mate^."^ p-Aryl-/3-hydroxypropionates are transformed into the corresponding pfluoro-derivatives in very high yield by silylation, followed by reaction with phenyltetrafluor~phosphorane.'~~ P-Trimethylstannyl esters are available by conjugate addition of trimethylstannylsodium to a,@-unsaturatedesters. 178 Iodolactonization of y,S- or &&-unsaturatedacids [e.g. (1291 under thermodynamic control leads predominantly to the more stable trans-lactcme (126), which retains its stereochemistry on methanolysis to provide a highly stereoselective route to epoxy-esters [e.g. ( 127)].17' 0

(1 25) 171

(126)

(127)

Y. Yamamoto and K. Maruyama, J. Amer. Chem. SOC.,1978, 100, 3240. M. T. Reetz and K. Schwellnus, Tetrahedron Letters, 1978, 1455. 173 R. T. Arnold and S. T. Kulenovic, J. Org. Chem., 1978,43,3687; cf. Y. Ogata andT. Sugimoto, ibid., p. 3684. 174 E. Elkik and M. Imbeaux-Oudotte, Tetrahedron Letters, 1978, 3793. W. Adam and J. del Fierro, J. Org. Chem., 1978,43, 1159. '76 E. C . Taylor, J. G. Andrade, K. C . John, and A. McKillop, J. Org. Chem., 1978,43, 2280. A . I. Ayi, R. Condom, P. C. Maria, T. N. Wade, and R. Guedj, Tetrahedron Letters, 1978, 4507. H. G. Kuivila and G. H. Lein, jun., J. Org. Chem., 1978, 43, 750. 179 P. A . Bartlett and J. Myerson, J. Amer. Chem. SOC.,1978, 100, 3950.

General and Synthetic Methods

104

Diestem-Mild, non-hydrolytic, two-phase conditions using solid sodium (or potassium) carbonate and tetra-alkylammonium chlorides or crown ethers as transfer reagents have been shown to be applicable to the alkylation of Knoevenagel-type substrates.180Such conditions are useful for a number of other condensations involving carbanions, e.g. the Darzens glycidic ester reaction. A novel route to ally1 malonates from alkenes in which the overall position of the double bond is retained begins with an ene reaction between the olefin and hexafluorothioacetone (generated in situ from its dimer) followed by addition of diazomalonate to generate a sulphonium ylide (Scheme 28).lS1This undergoes a [2,3] sigmatropic rearrangement, and the sequence is completed by desulphurization. The moderate overall yields are offset by the difficulties in obtaining such compounds in other ways.

Reagents: i, 2,2,4,4-tetra(trifluoromethyl)-1,3-dithietan-KF-DMF; ii, dimethyl diazornalonate-CuSO,, 110 "C;iii, Na/Hg-MeOH-Na,HPO,

Scheme 28

Malonate enolates condense with the nitroenamine (128) leading to unsaturated keto-diesters (129).'81 A direct C-acylation of Knoevenagel-type substrates by carboxylic acids is possible in the presence of phosphorocyanidate (130).183 0 (Et0),PCN I1

(128)

(129)

(130)

Enolates derived from monoalkylated malonates can be dimerized by electrochemical methods; unfortunately the yields decrease with increase in the size of the alkyl ~ u b s t i t u e n t Cerium(1v) .~~~ salts can also be used for this type of coupling, but only with a limited number of Treatment of malonate

'"' lE2

M. Fedoryfiski, K. Wojciechowski, Z . Matacz, and M. Makosza, J. Org. Chem., 1978,43, 4682. B. B. Snider and L. Fuzesi, Tetrahedron Letters, 1978,877. T.Severin and I. Ipach, Chem. Ber., 1978,111,692. T. Shioiri and Y. Hamada, J. Org. Chem., 1978,43, 3631. H. G.Thomas, M. Streukens, and R. Peek, Tetrahedron Letters, 1978,45. N.G . Galakatos, J . E. H. Hancock, 0. M. Morgan, M. R. Roberts, and J. K. Wallace, Synthesis,

1978,472.

105

Carboxylic Acids and Derivatives

enolates with dimethyl- (or diphenyl-) bromosulphonium bromide leads, by contrast, to reductive dimerization.lR6 Electrochemical reduction of bis-a-bromo-esters (131) leads to cyclic 1,2diesters (132).'" Yields are reasonable when based on the amounts of starting materials recovered.

Among many other uses, the ambifunctional electrophile (133) can be condensed with succinate enolates to give the triester (134).'88 C0,Et Me,N,p,NMe* CO2Et

(-.lo,-

+ Me2N+Co2Et

C02Et

(133)

(134)

The Claisen rearrangement of benzyl vinyl ethers is not usually possible, so it is interesting to find that an ortho-Claisen rearrangement of ethyl mandelate Presumably this is due to the stabilizderivatives can be effected (Scheme 29).189 ing influence of the ethoxycarbonyl group in the intermediate (135). Yields are in the range 20-80%, and the reaction can also be performed with 3-indolylglycolic esters.

R'

R'

CO,R~ R3

Scheme 29 N. Furukawa, T. Inoue, T. Aida, T. Akasaka, and S. Oae, Phosphorus, Sulfur Relat. Elements, 1978, 4, 15. 18'

189

S. Satoh, M. Itoh, and M. Tokuda, J.C.S. Chem., Comm., 1978, 481. R. Gompper and R. Sobotta, Angew. Chem. Internat. Edn., 1978, 17, 760. S. Raucher and A . S.-T. Lui, J. Amer. Chem. SOC.,1978, 100, 4902.

106

General and Synthetic Methods

Excess m-chloroperoxybenzoic acid is capable of cleaving the trimethylsilyl enol ether of cyclohexanone to give adipic acid e ~ t e r s . ' ~ '

Hydroxy-esters.-Enolates derived from esters as well as those from lactones and ketones can be oxidized to the corresponding a-hydroxy-derivatives by the crystalline complex [Mo05,pyridine,HMPA].19' Typically, yields are in the range 5 6-8 5 '/o. A mild 'acidic equivalent' of the condensation of acetate enolates with aldehydes to give 6-hydroxy-esters has been developed. This consists of a zinc chloride-catalysed cycloaddition reaction between the aldehyde and a keten acetal followed by acid-catalysed hydrolysis (Scheme 30).192 The method works R1

OMe

4R

'R ~ Z OBM0e M e

RZC02Me

>-( R2

OMe

OH

R3

Reagents: i, R3CHO-ZnCI,; ii, H,O-TsOH

Scheme 30

especially well with simple alkanals which often give low yields in a Reformatsky reaction (cf. 1,185). Very preliminary results have been reported on what appears to be a very practical, possibly general route to highly substituted P-hydroxyesters by a three-component condensation reaction, illustrated in Scheme 3 1.193

I

r

( 57 */o )

Scheme 31

Asymmetric reduction of methyl acetoacetate to methyl-3-hydroxybutyratecan be achieved in optical yields of up to 90% by hydrogenation over Raney nickel modified by mixtures of tartaric acid and sodium A Reformatsky reaction between a-bromo-esters and a - and P-dialkylaminoketones gives y- and 6-dialkylamino-P-hydroxy-esters, the latter mainly as the erythro-isomers; yields are ~ariab1e.l~' a-Diazo-P-hydroxy-ester derivatives are available by condensations between aldehydes and enolates of d i a z ~ a c e t a t e s ' ~ ~ (cf. 1, 182).

19'

G. M. Rubottom, J. M. Gruber, R. K. Boeckman, jun., M. Ramaiah, and J. B. Medwid, Tetrahedron Letters, 1978, 4603. E. Vedejs, D. A. Engler, and J. E. Telschow, J. Org. Chem., 1978, 43, 188. R. W. Aben and H. W. Scheeren, Synthesis, 1978, 400. T. Shono, I. Nishiguchi, and M. Sasaki, J. Amer. Chem. Soc., 1978, 100, 4314. T. Harada and Y . Izumi, Chem. Letters, 1978, 1195. M. Lucas and J.-P. GuettC, J. Chem. Research ( S ) , 1978, 214; Tetrahedron,1978, 34, 1675, 1681,

196

E. Wenkert, P. Ceccherelli, and R. A. Fugiel, J. Org. Chem., 1978, 43, 3982.

19')

19'

193 194

1685.

107

Carboxylic Acids and Derivatives

Keto-esters.-A further application of enolates of methyl methylthiomethyl sulphoxide is as alkoxycarbonyl anion equivalents in the conversion of nitriles into a-keto-esters (Scheme 32).19' The intermediate enamino-sulphoxides can also be converted into S-methyl a-keto-thioesters or a-keto-amines. Bis-asulphenylation of esters can be achieved using the novel reagent methyl 2nitrophenyl disulphide; the thioacetals thus obtained may be transformed into the corresponding dimethyl acetals by treatment with thallium(II1) nitrate. 19' aKeto-esters are available from a-amino-esters by sequential N-chlorination and dehydrochlorination to give the a-imino-derivative, followed by h y d r o l y ~ i s(cf. '~~ 2, 278). a-Phenylazo-derivatives of cyclic 6-keto-esters undergo ring cleavage with sodium borohydride to give phenylhydrazones of w-hydroxy-a-ketoesters.200 Methoxyacetylenes are converted into a-keto-esters in good yields simply by oxidation with potassium chlorate and osmium tetroxide.201

Scheme 32

An excellent general method for the elaboration of P-keto-esters is by acylation of readily available Meldrum's acid with acid chlorides, followed by alcoholysis (Scheme 33).202Typically, overall yields are above 70% and the scheme is applicable to a complete range of alcohols. It is good to see a new recipe which does not involve expensive, esoteric reagents and which can be used on a large scale.

0 Reagents: i, R'COC1-pyridine-CHzClz; ii, R'OH, A

Scheme 33

A 1968 patent report has been developed into a practical synthesis of P-ketoesters by Lewis acid-catalysed condensations of alkyl nitriles with acetoacetates and subsequent acid hydrolysis (Scheme 34).2"3A new three-step procedure for the alkoxycarbonylation of cyclic ketones consists of an addition of

19* 199

201

'02

203

K. Ogura, N. Katoh, I. Yoshimura, and G. Tsuchihashi, Tetrahedron Letters, 1978, 375. Y. Nagao, K. Kaneko, K. Kawabata, and E. Fujita, Tetrahedron Letters, 1978, 5021. H. Poise], Chem. Ber., 1978, 111,3136. A. P. Kozikowski and W. C. Floyd, Tetrahedron Letters, 1978, 19. L. Bassignani, A. Brandt, V. Caciagli, and L. Re, J. Org. Chem., 1978, 43, 4245. Y. Oikawa, K. Sugano, and 0. Yonemitsu, J. Org. Chem., 1978,43, 2087. i3.Singh and G. Y. Lesher, Synthesis, 1978, 829.

General and Synthetic Methods

108

Reagents: i, SnCI,; ii, HCl-H,O

Scheme 34

dichlorocarbene to the silyl enol ether derived from the ketone to give (136) which on electrolysis gives keto-esters (137) in yields of between 39 and 97'/0.~O~ Electrolytic ring expansion of cyclic ketones by one carbon is possible by a cathodic addition of ethyl trichloroacetate; however, yields of the p -chloroketo-ester products (138) are only H & C 2i-$'

CI

-

CO, R iH2c9,0

C0,Et

OSiMe, (136)

d*

iH,C)"

(137)

(138)

A general route to y-keto-esters is by monoalkylation and monosulphenylation of bis-1,3-dithian (139) (Scheme 35).206Some y-keto-esters have been formed

(139) Reagents: i, Bu"Li; ii, R'X; iii, MeSSMe; iv, HgCI,-HgO(or CaC0,)-R20H-H20

Scheme 35

unexpectedly by addition of 1,l -dimethoxyethylene to oxyallyl species generated from a,a'-dibromo-ketones and copper (Scheme 36).*07Ester enolates, particularly those derived from t-butyl esters, react with lactones to give cyclic hemiacetals [e.g. (140) from valerolactone] in very good yields.208

I'

--v

K-+---( Scheme 36

204 'OS

*06 '07

'OR

S . Torii, T. Okamoto, and N. Ueno, J.C.S. Chem. Comm., 1978, 293. F. Karrenbrock and H. J. Schafer, Tetrahedron Letters, 1978, 1521. W. D. Woessner and P. S. Solera, Synth. Cornm., 1978, 8, 279. A. P. Cowling and J. Mann, J.C.S. Chem. Comm., 1978, 1006. A. J. Duggan, M. A. Adams, P. J. Brynes, and J. Meinwald, Tetrahedron Letters, 1978, 4323; A. J. Duggan, M. A. Adams, and J. Meinwald, ibid.,p. 4327.

Carboxylic Acids and Derivatives

109 (fH..

R'

W

(140) R'

=H

O R2

or OR3

The magnesium enolate of ethyl hydrogen rnalonate has been found to add in a conjugative manner to enones (141) to provide a 'one-pot' method for the elaboration of 8-keto-esters ( 142).209 0

0

0

(141)

(142)

Stetter and his co-workers have extended their investigations of the thiazolium salt-catalysed condensation of aldehydes with activated olefins (cfi 1, 191) to include a synthesis of dioxo-esters (Scheme 37).*" Although yields are not always

Scheme 37

spectacular, the simplicity and generality of the method make it an attractive route to such compounds. Methods for the preparation of the potentially useful 1,3-dithianyl-P-keto-esters(143) and (144) have been reported.21'

(143)

Unsaturated Esters.-A simple, stereoselective route to terpenoid esters, i.e. ( E )- 3 -methylalk-2-enoates, is by zirconium-catalysed carboalumination of terminal acetylenes, illustrated in Scheme 38 for the preparation of ethyl geranoate in 78% isolated yield.*12In common with related vinylcuprates, the 209 21"

211

212

J. E. McMurray, W. A. Andrus, and J. H. Musser, Synth. Comm., 1978, 8, 5 3 . H. Stetter, W. Bas e, and K. Wiemann, Chem. Ber., 1978,111,431;H. Stetter and J. Nienhaus, ibid., p. 2825. E. C . Taylor and J. L. LaMattina, J. Org. Chem., 1978, 43, 1200. N. Okukado and E. Negishi, Tetrahedron Letters, 1978, 2357.

110

General and Synthetic Methods

L+ -&[

\

Reagents: i, Me,Al-Cl,ZrCp,,

U

N

M

e

,

]

U

C

0

2

E

t

25 "C, 2 h; ii, ClCO,Et, 25 "C, 1 h

Scheme 38

intermediate alkenylaluminiun species react well with other one-carbon electrophiles either as shown or by prior conversion to an 'ate' complex by the addition of n-butyl-lithium. A stereoselective route to a$-unsaturated esters involves a condensation of the enolate of methyl a-phenylselenyl acetate with carbonyls followed by separation of the resulting diastereoisomeric mixture of 6-hydroxyselenides and antielimination using thionyl chloride or phosphorus oxychloride in the presence of trieth~larnine.~ The ' ~ same method can be used to prepare isomerically pure a-alkylidene-lactones. The a-selenylacetate enolate adds [ 1,2] to cyclohexenone at -78 "C in THF but this preference may be reversed almost completely by the addition of hexamethylphosphoramide or by warming the reaction mixture to room temperature. Allylic thiocarbamates (145) are available from ketones by sequential condensation with vinyl-lithium species and dimethylthiocarbamoyl chloride followed by a [3,3] sigmatropic rearrangement. It has now been shown that these can be used as precursors to a$-unsaturated esters by bis-sulphenylation and mercury(1x)promoted hydrolysis (Scheme 39).214 Only the E-isomers are produced when the final product (146) is unsubstituted (k.e. R2 = R3 = H) or carries an a-methyl R3

R"

A

-& . R'*CONMe,

R',+SCONMe2

RZ

R',&-ozEt

R Z SMeSMe

R2

(145)

(146)

Reagents: i, 2 equivs. LDA-MeSSMe; ii, Hg"-EtOH

Scheme 39

group (i.e. R2 = H, R3 = Me) although mixtures of both E- and 2-isomers are formed when the product is P,P-disubstituted. A potentially useful conversion of ketones into a$-unsaturated esters, involing the addition of one carbon atom, is by a Wittig reaction using methoxymethyltriphenylphosphorane followed by oxidation with singlet oxygen (Scheme 40).215 Overall yields vary between 30 and

;). i

+

>j

4 .

-

3 ..

;>ooH

OMe

&'>

C0,Me

OMe

. ii, '02-C6H6; iii, AcC1-pyridine

Scheme 40 213

J. Lucchetti and A. Krief, Tetrahedron Letters, 1978, 2693, 2697. T. Nakai, T. Mimura, and T. Kurokawa, Tetrahedron Letters, 1978, 2895. G. Rousseau, P. Le Perchec, and J. M. Conia, Synthesis, 1978, 67.

i

Carboxylic Acids and Derivatives

111

90%. A novel route to substituted a,P-unsaturated esters, which has been very briefly tested,216is a radical chain reaction between gem-dinitro-compounds and enolates of a-sulphonyl esters and subsequent elimination using sodium sulphide. The anion (147), a synthon of methyl a-lithioacrylate, has been prepared but unfortunately, owing to its chelated structure, it is rather unreactive and viable yields have been obtained only in reactions with primary allylic halides217(cf. 3, 112). Sensitive enol pyruvates (149) can be obtained in ca. 30% yield from the corresponding methyl a-hydroxypropionate derivatives (148) by sequential enolate formation, addition of phenylselenenyl bromide, and oxidative elimination using hydrogen peroxide.*l* \

N”

.Li,

’U

0

RO o M (147)

e

A C0,Me (148)

- - + ROKCO,Me (149)

The enolate of t-butyl a-chloro-a-trimethylsilylacetate condenses with carbonyls to give a-chloro-a,P-unsaturatedesters in up to 50% yield.*19 An alternative, ‘one-pot’ route to this class of compound (Scheme 41) uses diethyl trichloromethylphosphonate as starting material; yields are reported to be between 70 and 85 .220 0

I1

Ci3CP(OEt),

R y C 0 2 E t

--%

ci

Reagents: i, Bu“Li; ii, CIC0,Et; iii, RCHO

Scheme 41

During studies aimed at a total synthesis of the verrucarins (cf.3,74), Trost and Rigby have briefly outlined an interesting new approach to y-hydroxy-a,& unsaturated esters (Scheme 42).221Ethyl P-nitropropionate serves as a useful R 1 e C O z R 2+ R 1 3 C 0 2 R ’ & . .. R 1 q C O , R z

PhS

SPh

PhS i i , iii

HO Reagents: i, m-ClC6H,C0,H, - 15 “C; ii, (MeO),P-CH,Cl,,

reflux; iii, DBU-MeOH, reflux

Scheme 42

’I8

*”

N. Ono, €2. Tamura, J. Hayami, and A. Kaji, Tetrahedron Letters, 1978, 763. L.-C. Yu and P. Helquist, Tetrahedron Letters, 1978, 3423. N. Ikota and B. Ganem, J. Org. Chem., 1978,43, 1607. T. H. Chan and M. Moreland, Tetrahedron Letters, 1978, 515. J. Villieras, P. Perriot, and J. F. Normant, Synthesis, 1978, 31. B. M. Trost and J. H. Rigby, J. Org. Chem., 1978, 43, 2938.

112

General and Synthetic Methods

P-acyl vinyl anion equivalent (cf. 3, 217) in its condensations with aldehydes, using di-isopropylamine as base in unpurified dimethylformamide, and with enones to which it adds in a Michael fashion (Scheme 43).222P-Amino-acyanoacrylates can be prepared by condensing a-bromo-a-cyanoacetates with thioamide~.~~~ 0

5 2 O/O

5 8 O/O

Reagents: i, Hexanal-Pr',NH-DMF-DMSO, 20 "C, 24 h; ii, cyclopent-2-en-1-one-ButOK-THF, -20 "C then add MeOH, 20 "C, 16 h

Scheme 43

Two r e p ~ r t have ~ ~ appeared ~ ~ * ~on~ the ~ synthesis and utility of ethyl 2diethylphosphonatoacrylate (150). The compound undergoes smooth Michael addition of various nucleophiles, and the resulting enolates react with aldehydes in refluxing THF in a Wadsworth-Emmonds manner, to provide disubstituted C0,Et AP(OEt),

II

C0,Et

5[ N d J ( O E t ) 2 ] 5

'+ C0,Et

R

0 (15 0 ) N = ketone and ester enolates, A S

Scheme 44

a,P-unsaturated esters (Scheme 44). Substituted vinylphosphonates (1 5 l), obtained by an aldol condensation between methyl diethylphosphonatoacetate and aldehydes, react with a-mercaptoaldehydes t o give dihydrothiophens (152), which can readily be converted into butadienes (153) by sequential oxidation and pyrolysis.226 C0,Me

In a series of full papers, Trost et al. have described recent developments in the use of .rr-allylpalladium complexes as electrophilic components in carbon-carbon 222 223

224

"' 226

P. Bakuzis, M. L. F. Bakuzis, and T. F. Weingartner, Tetrahedron Letten, 1978, 2371. H. Singh and C. S. Gandhi, Synth. Comm., 1978, 8,469;J. Chem. Research ( S ) , 1978, 407. W.A. Kleschick and C. H. Heathcock, J. Org. Chem., 1978, 43, 1256. M. F.Sernrnelhack, J. C. Tornesch, M. Czarny, and S. Boettger, J. Org. Chem., 1978, 43,1259. J. M. McIntosh and R. A. Sieler, Canad. J. Chem., 1978,56,226.

Carboxylic Acids and Derivatives

113

bond-forming reactions227 (cf, 2, 152, 189, 201). Only doubly stabilized carbanions, i.e. 'soft' nucleophiles, can be used in this type of coupling reaction, but this is not a serious drawback in terms of limiting the generality of the method as the initial products can be specifically degraded in a variety of ways (Scheme 45). -C02Me /

W C O , M e

PhSCHCOR

RIyCO,Me

J

S0,R2

-CO,Me /

Scheme 45

In a most interesting paper, another group led by Trost has described a stereoselective route to unsaturated esters from a$-epoxy-ketones by spiroannelation followed by Grob-type trans-coplanar fragmentation. The overall idea is outlined for one example in Scheme 46.228

+

+

;)" i 0

iii, i v

b

H O T C O , M e


+

Reagents: i,

pSPh2 ii, LiBF,-C6H6; iii, Separate isomers (prep. g.1.c.);iv, NaOMe Scheme 46

227

22R

B. M. Trost, P. E. Strege, L. Weber, T. J. Fullerton, and T. J. Dietsche, J. Amer. Chem. Soc., 1978, 100, 3407, 3416, 3426; B. M. Trost and T. R. Verhoeven, J. Amer. Chem. SOC.,1978, 100, 3435. B. M. Trost, M. J. Bogdanowicz, W. J. Frazee, andT. N. Salzrnann, J. Amer. Chem. SOC., 1978,100, 5512.

General and Synthetic Methods

114

Substituted, terpenoid 3,7-dienoic acid esters, and presumably other 3,7dienoates, can be obtained by consecutive ortho-Claisen and Cope rearrangements of 2,5-dienols (Scheme 47).229In the example shown, the starting dienols were obtained from mesityl oxide.

Scheme 47

The ring opening of lactones by sodium phenyl selenoate leading to ounsaturated esters, which was reported last year (2,205), has been applied to a synthesis of 1-substituted 2-methoxycarbonylbuta-1,3-dienesfrom a-alkylidene-butyrola~tones;~~~ yields overall are around 40-50%. The ability of copper(1) counter-ions to induce carbanions to undergo Michael additions or SN2’displacements has been further exemplified in a preparation of 3,4-dienoic esters (155) from propargylic bromides (154) and the lithium enolate of ethyl acetate in the presence of 0.2 or more equivalents of cuprous iodide.231 Although the yields are not outstanding, isolation of the allene is often easy as it is the only volatile product. A similar preparation of 6-allenic-a$-unsaturated esters using a vinylogous copper enolate was only successful when 3,3-dimethylacrylates were used. Conjugation of the double bonds of the resulting product, using sodium ethoxide, gave mainly the 2E,4Z-dienoate. Substituted 2,5-dimethoxyacetophenonescan be oxidized directly to quinone acetic acid esters (156) by using a modification of Taylor and McKillop’s original procedure for the oxidation of acetophenones to phenyl acetates by thallium(II1) nitrate.232 The product is usually contaminated with small amounts of the a-methoxy-derivative (cf.3, 75).

Thioesters and Related Compounds.-A new general route to thio- and selenoesters employs the versatile ‘push-pull’ acetylene (157) as an acyl group transfer reagent.233Reaction with carboxylic acids (which may contain unprotected OH, NH2, or SH groups) affords enol esters (158) which give thio- or seleno-esters on 229 230 23’

232

233

Y. Fujita, T. Onishi, and T. Nishida, Synthesis, 1978, 5 3 2 . T. R. Hoye and A. J. Caruso, Tetrahedron Letters, 1978, 4611. R. A. Amos and J. A. Katzenellenbogen, J. Org. Chem., 1978, 43, 5 5 5 . K. Maruyama and T. Kozaku, Bull. Chem. SOC.Japan, 1978,51, 3586. H.-J. Gais and T. Lied, A n g e w . Chem. Internat. Edn., 1978, 17,267.

Carboxylic Acids and Derivatives

115

treatment with a large range of alkali-metal salts of thiols or selenols (Scheme 48) (cf.3, 254). Overall yields for this ‘one-pot’ sequence are very high. Thioesters

(157)

(158)

X = S or Se M = Li or Na

Scheme 48

can also be prepared from acid chlorides and the alkylthiocopper complex (159), obtained by reaction of bis(tripheny1phosphine)methylcopper with alkylthi~ls.’~~ This high-yielding approach seems to be generally applicable; in addition, complex (159) catalyses transesterification reactions between thioesters and thiols. One of the few methods available for the direct conversion of esters into phenyl thioesters uses either boron thiophenoxide (from thiophenol and comThe latter reagent gives mercially available B2S3) or aluminium thi~phenoxide.~~’ very high yields of thioesters rapidly at 25 “C but is sufficiently reactive also to give P-(pheny1thio)-thioesterswhen added to a,P-unsaturated esters. By contrast the much less reactive boron analogue reacts only at the ester group although overnight reflux in xylene is usually necessary to effect the displacement. One other limitation is that P-keto-esters are inert whereas y-keto-esters are converted into the corresponding thioester thioacetals. A preliminary has appeared on a method for the preparation of phenyl thioesters from alkyl halides, with the addition of one carbon atom, by reaction with sulphoxide enolate (160). The initial product (161) is then C-silylated (LDA then Me3SiC1) and this, on warming, undergoes a silicon Pummerer rearrangement to give the thioester (162). Carboxylic acids can be directly converted into phenyl seleno- (or thio-)

esters by treatment with phenyl seleno- (or thio-) cyanates in the presence of tri-n-b~tylphosphine.~~’ S-t-Butyl 6-keto-thioesters can be obtained by the conjugate addition of the trimethylsilyl enolate of S-t-butyl thioacetate to enones in the presence of tetra-n-butylammonium This methodology forms part of a neat total synthesis of the macrolide jasmine keto-lactone. 234 235 236 237 238

M. Kubota and A. Yamamoto, Bull. Chem. SOC.Japan, 1978,51, 3622. T. Cohen and R. E. Gapinski, Tetrahedron Letters, 1978, 4319. K. M. More and J. Wemple, J. Org. Chem., 1978, 43, 2713. P. A. Grieco, Y. Yokoyama, and E. Williams, J. Org. Chem., 1978, 43, 1283. H. Gerlach and P. Kiinzler, Helu. Chim. Acra, 1978,61, 2503.

General and Synthetic Methods

116

Methyl selenoesters can be synthesized directly from alkyl esters or lactones using dimethylaluminium methylselenolate, simply prepared from trimethylaluminium and selenium.239Very good yields can be obtained, and the reagent also reacts with epoxides to give 2-methylselen-1-01s and delivers a methylseleno-group in a Michael fashion to cyclohexenone. Phenyl orthothioesters can be easily degraded to the corresponding phenyl thioesters by reaction with silver t e t r a f l u ~ r o b o r a t e . ~ ~ ~ Unsaturated thio- and seleno-esters of type (163) are available from ally1 alkyl sulphides or selenides by reaction with dichloroketen and rearrangement as described earlier.’39Homologues (165) of aryl thioesters are available via the dipole-stabilized intermediate (164); so far the reaction has only been reported for 2,4,6-trie th ylphen yl t hioesters. 2 4 1

(163) X = 0, S, or Se

(164)

(165)

Bis(acy1thio)alkanes (166) can be prepared from thioacids and tertiary amine~.~~~ A simple, general route to dithioesters (168) is by the addition of Grignard reagents to phenyl isothiocyanate and ‘hydrolysis’of the intermediate imine (167) 0

by hydrogen sulphide in a ~ e t o n i t r i l e Methyl . ~ ~ ~ a-0x0-dithiocarboxylates are formed by reaction between phenacyl halides, elemental sulphur, and methyl iodide in the presence of a tertiary amine.244A simple route to 1,1-dithio-oxalate esters carrying different alkyl groups is by successive alkylation of the dipotassium salt of the parent acid, first with an alkyl iodide in water (reaction with sulphur), then cation exchange to the half-ester, sodium salt and reaction with a different alkyl iodide in hexamethylpho~phoramide.~~~ General methods for the prephave also aration of y,&unsaturated d i t h i o a ~ i d sand ~ ~bis(thioa~y1)sulphides~~~ ~ been described. 239 240

241 242

243 244

24s 246

247

A. P. Kozikowski and A. Ames, J. Org. Chem., 1978, 43, 2735. R. A. J. Smith and G. S. Keng, Tetrahedron Letters, 1978, 675. D. B. Reitz, P. Beak, R. F. Farney, and L. S. Helmick, J. Amer. Chem. Soc., 1978, 100, 5428. L. Sternson, J. Org. Chem., 1978, 43,4532. P. Gosselin, S. Masson, and A. Thuillier, Tetrahedron Letters, 1978, 2715, 2717. R. Mayer, H. Viola, and B. Hopf, Z. Chem., 1978, 18, 90. J. Voss and H. Giinther, Synthesis, 1978, 849. M. Schoufs, J. Meijer, P. Vermeer, and L. Brandsma, Synthesis, 1978,439. S. Kato, K. Sugino, M. Mizuta, and T. Katada, Angew. Chem. Znternat. Edn., 1978, 17, 675.

Carboxylic Acids and Derivatives

117

In contrast to a report which appeared last year (2,42), electron-rich S-alkylthioesters can be oxidized (03 or RuOJ to mixed sulphonic acid-carboxylic acid anhydrides.248 Of relevance to this section is the preparation of some new heterocyclic from thiocarbonyl transfer reagents, analogous to 1,l‘-thiocarbonyldi-imidazole, an N-silylated heterocycle and thiophosgene; some of these derivatives show considerably more reactivity than the currently used The dimer of p-methoxyphenylthionophosphine(169) has been found to be a very useful reagent for the conversion of amides into thioamides2” as well as for preparing thionesters from esters and dithioesters from t h i ~ e s t e r s . ~The ’ ~ usual

method for the preparation of thioamides (base-catalysed addition of H2S to nitriles) can, in common with many other reactions, be carried out under phase-transfer conditions.252a$?-Unsaturatedthioamides undergo efficient [ 1,4] additions of organolithium (or magnesium) compounds providing a simple method for the homologation of t h i o a m i d e ~ . ~It’ ~is significant that even the carbanion derived from 2-methyl- 1,3-dithian, normally very reluctant to add in a [1,4] fashion, can be utilized in this reaction. Further homologues are obtained by trapping the intermediate thioenolate with reactive electrophiles (e.g. ally1 bromide).

6 Carboxylic Acid Amides Synthesis.-The so-called ‘push-pull’ acetylenes [e.g. (157)], already mentioned in connection with thioester can also be utilized as acyl transfer reagents in a general method for the formation of amide bonds between carboxylic acids and amines (Scheme 49).254The overall, ‘one-pot’ sequence gives excellent yields and appears to be very simple to perform. The isolable intermediates are usually clean and crystalline, and when it is used in dipeptide syntheses little racemization occurs. As mentioned earlier, the carboxylic acid component may contain unprotected alcohol, amino-, and mercapto-groups. 248 249 250

2s 1 252 253 254

M. J. Sousa Lob0 and H. J. Chaves de Neves, Tetrahedron Letters, 1978, 2171. C . Larsen, K. Steliou, and D. N. Harpp, J. Org. Chem., 1978, 43, 337. S. Scheibye, B. S. Pedersen, and S.-0. Lawesson, Bull. SOC.chim. belges, 1978,87,229;H. Fritz, P. Hug, S.-0. Lawesson, E. Logeniann, B. S. Pedersen, H. Sauter, S. Scheibye, and T. Winkler, ibid., p. 525. B. S. Pedersen, S. Scheibye, K. Clausen, and S.-0. Lawesson, Bull. SOC.chim. belges, 1978,87,293. L. Cassar, S. Panossian, and C. Giordano, Synthesis, 1978, 917. Y. Tamaru, T. Harada, H. Iwamoto, and Z. Yoshida, J. Amer. Chem. Soc., 1978, 100, 5221. M. Neuenschwander, U. Lienhard, H. P. Fahrni, and B. Hurni, Chimia (Switz.),1978,32,212,214; Helv. Chim. Acta, 1978, 61, 2428; U. Lienhard, H.-P. Fahrni, and M. Neuenschwander, ibid., p. 1609; H.-J. Gais, Angew. Chem. Internat. Edn., 1978, 17, 597.

General and Synthetic Methods

118

-R

Scheme 49

A promising alternative to this is to treat a carboxylic acid with catecholborane and then an amine.255Furthermore, this method can also be applied to the preparation of macrocyclic lactams from w-amino-acids, although yields, as yet, are rather low. A preliminary report has appeared on the use of the phospholen (170), obtainable from 2,3-dimethylbuta-1,3-dieneand MePCl,, for the formaYields are typically above 80% with tion of amide bonds in peptide little racemization. Other reagents for effectingthis type of coupling reaction are t-butyl isocyanide in the presence of zinc chloride2” and the l-hydroxybenzotriazole derivative ( 171)25s(cf. BOP reagent; 2, 300); the corresponding sulphonate derivative has also been reported to be useful in this

The DCC peptide coupling method can be improved both in terms of yield and suppression of racemization by the addition of Lewis acids, especially zinc chloride.260 A promising pilot study on the use of polymer-bound carboniccarboxylic anhydride functions for the preparation of amides has been reported.261It has been suggested in two reports that peptide bond formation is more rapid when soluble polymers are used, specifically a,w-diaminopolyethylene glycol (‘amino PEG’)262and chloromethylated poly~tyrene.’~~ 255

25’

258

259

26” 261

262 263

D. B. Collum, S. Chen, and B. Ganem, J. Org. Chem., 1978,43,4393. E. Vilkas, M. Vilkas, and J. Sainton, Tetrahedron Letters, 1978, 2933. H. Aigner and D. Marquarding, Tetrahedron Letters, 1978, 3325. V. Dourtoglou, J.-C. Ziegler, and B. Gross, Tetrahedron Letters, 1978, 1269. M. Itoh, H. Nojirna, J. Notani, D . Hagiwara, and K. Takai, Bull. Chem. SOC.Japan, 1978, 51,3320. H.-D. Jakuhke, C. Klessen, E. Berger, and K . Neubert, Tetrahedron Letters, 1978, 1497. G. E. Martin, M. B. Shambhu, S . R. Shakhshir, and G. A. Digenis, J. Org. Chem., 1978, 43,4571. M. Mutter, Tetrahedron Letters, 1978, 2839, 2843. M. Narita, Bull. Chem. SOC.Japan, 1978, 51, 1477.

119

Carboxylic Acids and Derivativzs

Amino-esters such as (172) can be cleanly cyclized to give benzodiazepinones (173) by treatment with sodium methylsulphinylmethide; the generality of this reaction has yet to be explored.264In a notable paper, a group led by Corey has described the first total synthesis of a maytansenoid, (&)-N-methylmaysenine, a crucial feature of which is a new set of conditions for the ring-closure step [i.e. (174) + (175)]. This lactamization was achieved by prior conversion into the C0,Et

0

H

H

Me

I

A ,NH r

Me

,

(174)

A COzH

--+ % < h

(175)

tetra-n-butylammonium salt, which was slowly added to excess mesitylenesulphony1 chloride and di-isopropylamine in benzene, to give ca. 65% of the m a c r o ~ y c l eRapoport .~~~ et al. have reported a route to some naturally occurring ansapeptides, 14-membered cyclopeptide alkaloids containing two lactam bonds,266whereas a group of French workers have had some trouble in preparing such 14-membered rings, although they have been successful in obtaining some related model 15, 17-, and 18-membered m a c r o l a c t a r n ~ . ~ ~ ~ The amazing ‘zip’ reaction for the ring expansion of N-polyamino-lactams (2, 156) has been further investigated and used for the preparation of a 53membered polyaminolactam in very high yield!268 A new, mild method for acyl exchange in amides involves conversion to the imidoyl chloride, reduction to the imine [LiAl (OBu‘),H], and acylation with an acid 2-Phenylaziridine is a useful reagent for the preparation of a-halogeno-Nphenacylacetamides directly from a-halogenoacetic a-Mercapto-amides (17’7) can be obtained by reaction between primary amines and the thialactone (176).271Nitriles may be transformed into N-alkyl-amides under basic conditions 264 265

266 267

26M

260 270

”’

J. K. Chakrabarti, T. A. Hicks, T. M. Hotten, and D . E. Tupper, J.C.S. Perkin I, 1978, 937. E. J. Corey, L. 0. Weigel, D. Floyd, and M. G. Bock, J. Amer. Chem. Soc., 1978, 100, 2916. J . C. Lagarias, R. A. Houghten, and H. Rapoport, J. Amer. Chem. Soc., 1978, 100,8202. F. Rocchiccioli, F.-X. Jarreau, and M. Pais, Tetrahedron, 1978, 34, 2911, 2917. A. Guggisberg, B. Dabrowski, U. Kramer, C. Heidelberger, M. Hesse, and H. Schmid, Heio, Chim. Acta, 1978,61, 1039; A. Guggisberg, U. Kramer, C. Heidelberger, R. Charubala, E. Stephanou, M. Hesse, and H. Schmid, ibid., p. 1050; U. Kramer, A. Guggisberg, M. Hesse, and H. Schmid, ibid., p. 1342; Angew. Chem. Internat. Edn., 1978, 17, 200. S. Karady, J. S. Amato, L. M. Weinstock, and M. Sletzinger, Tetrahedron Letters, 1978,403. D. St.C. Black and J. E. Doyle, Austral. J. Chem., 1978, 31, 2313. Y. A. Davidovich, L. A. Pavlova, and S. V. Rogozhin, Zhur. org. Khim., 1978,14, 664.

General and Synthetic Methods

120

R

+

~

~ ~ R4NH, R 3 + R3$NHR4 SH 0

(176)

(177)

' o R2

+ R~CO,R~

by heating with potassium hydroxide in t-butyl alcohol followed by the addition of an alkyl iodide.272With primary iodides, yields are in the range 52-96%, although much lower yields are obtained when secondary iodides are used. Carbonium ions, generated by electrochemical oxidation of hydrocarbons in acetonitrile, are trapped by the solvent to give nitrilium species which in turn can be trapped by a cationic exchange resin. Hydrolysis of the resin complex with aqueous sodium hydroxide results in an overall acetamidation of the hydrocarbon (Scheme 50).273Condensations between p-substituted benzaldehydes and 0

Reagents: i, Cationic exchange resin; ii, NaOH-H,O

Scheme 50

phenylacetonitriles in hexamethylphosphoramide containing the sodium salt of a,a-dimethylbenzyl hydroperoxide give a-benzoyl acetamides (178) in 40-50% yields.274N,N-Diacetylamines (179), very useful as acetyl transfer reagents, can be obtained from primary amines by reaction with acetic anhydride containing magnesium and copper(I1) acetate.275

R'

Reactions.-Enolates of dialkylamides undergo both C- and 0-silylation when treated with trialkylsilyl chlorides although a preference for the latter is observed when either reactant is On heating, 0 --+ C migration of the silyl group occurs. The same workers have also described the generation and isolation of 272

273 274

*'' '''

S. Linke, Synthesis, 1978, 303. A. Bewick, J. M. Mellor, and B. S. Pons, J.C.S. Chem. Comm., 1978, 7 3 8 . K. Takahashi, K. Yamada, and H. Iida, Bull. Chem. SOC.Japan, 1978,51,3389. H. J. Meyer, C. Nolde, I. Thornsen, and S . - 0 . Lawesson, Bull. SOC.chim. belges, 1978, 87, 621. R. P. Woodbury and M. W. Rathke, J. Org. Chem., 1978, 43, 881.

121

Carboxylic Acids and Derivatives

enolate (180) derived from N,N-dimethyl-2-trimethyl~ilylacetamide.~~~ This reacts with aldehydes or ketones to give good yields of a,P-unsaturated arnide~,”~ and with N,N-dimethylamides whep P-keto-amides are obtained, after hydrolysis, again in good yields (Scheme 51).278On treatment of (180) with epoxides, 4-silyloxy-amides are obtained uia a C + 0 silyl migration277(cf. 2,253-255). OLi

Scheme 5 1

The regioselectivity of reaction of the enolates derived from a,P-unsaturated amides (181) and (182) has been investigated.279With a variety of electrophiles, overall yields of products are in the range 30-80%, reaction occurring mainly at the a-position when lithium is the counterion; however, when copper is the counterion, a distinct tendency for y-attack is observed, especially with dicuprates (i.e. R’ = H). A useful feature of the latter mode of reaction is the almost exclusive production of 2-isomers, presumably due to chelation between the metal ion and the amino-group. Dianions [e.g. (183)] from P-keto-amides react cleanly with a range of electrophiles at the y-position, as expected.280The use of (183) overcomes Some problems found in similar condensations of dianions derived from 0-keto-esters, which tend to undergo self-condensations, particularly during attempted polyketide syntheses when rather unreactive electrophiles (e.g. monoanion of acetoacetaldehyde) are used.

( 181)

R’= H or Pr’, R2 = Me or Pr’

(182)

(183)

ortho-Metallation of benzamides to give (184) has been shown to be a very useful method for the preparation of tri- and tetra-substituted benzene derivatives.281By contrast, ‘sterically protected’ N,N-dimethylamides can be metallated at the N-methyl position using s-butyl-lithium to give carbanions (185) and (186) 0

R’ (184) 277

278 279

280

(185)

(186)

R. P. Woodbury and M. W. Rathke, J. Org. Chem., 1978, 43, 1947. R. P. Woodbury and M. W. Rathke, Tetrahedron Letters, 1978, 709. J. A. Oakleaf, M. T. Thomas, A. Wu, and V. Snieckus, Tetrahedron Letters, 1978, 1645. J. S. Hubbard and T. M. Harris, Tetrahedron Letters, 1978, 4601. S. 0. de Silva, J. N . Reed, and V. Snieckus, Tetrahedron Letters, 1978, 5099, 5103, 5107.

122

General and Synthetic Methods

(probably cis to the carbonyl, as shown) which react well with primary halogenoalkanes, aldehydes, and ketones282(cf. 2,250). The utility of these reactions as a general route to secondary amines is rather limited by the resistance of the amide bond to hydrolysis, especially in the case of products from (185). This problem can be overcome by using the carbamate (187), derivatives of which are cleaved by lithium aluminium hydride in hot d i ~ x a n . ~N-Benzylbenzamide ’~ can be metallated by lithium di-isopropylamide; the dianion (188) which results

(187)

(188)

undergoes clean reactions with e l e c t r ~ p h i l e s .N-Allylamides ~~~ can also be metallated by LDA to give bis-anionic species, which react exclusively at the y-position with primary alkyl iodides giving predominantly cis-enamides, in very high yields (Scheme 52).285 0

0

H

RZ Scheme 52

N-Methyl groups in amides may be monochlorinated by irradiation in the on the Birch reduction of benzamides presence of chlorine.286Some have revealed reactant-reagent ratios that are preferable to those previously recorded in the literature. 7 Amino-acids

General Synthesis.-The alkylation of enolates of Schiff’s bases derived from glycine originally described by Stork et al. is a valuable homologation method (1,221; 2,256-258) but not without some drawbacks, such as the instability of some of the Schiff’s bases and the need to use a strong base under anhydrous conditions at low temperatures (usually LDA-THF, -78 “C) to generate the enolate. These difficulties can be largely overcome by using the Schiff’s base derived from benzophenone and glycine ethyl ester and by employing phasetransfer conditions for the alkylation step.288Yields are slightly lower than in the 282 283

284 285

286

”’ 288

R. Schlecker, D. Seebach, and W. Lubosch, Helv, Chim. Acta, 1978,61, 512. D . Seebach and T. Hassel, Angew. Chem. Internat. Edn., 1978,17,274; Helv. Chim. Acta, 1978,61, 2237. A. N. Tischler and M. H. Tischler, Tetrahedron Letters, 1978, 3 . A. N. Tischler and M. H. Tischler, Tetrahedron Letters, 1978, 3407. H. Reimlinger, F. Billiau, and R. MerCnyi, Chem. Ber., 1978, 111, 1619. L. Dickson, C. A. Matuszak, and A. H. Qazi, J. Org. Chem., 1978,43, 1007. M. J. O’Donnell, J. M. Boniece, and S. E. Earp, Tetrahedron Letters, 1978, 2641.

Carboxylic Acids and Derivatives

123

original method; also, the concentration of the aqueous sodium hydroxide used as base can be no higher than 10% or else the glycine ester group is hydrolysed, which means that one equivalent of the phase-transfer ‘catalyst’ has to be used. Further investigation^^^^ have revealed that by using the Schiff’s base from benzophenone and a-aminoacetonitrile up to 50% aqueous sodium hydroxide may be used together with only a catalytic amount of the phase-transfer reagent. Acid hydrolysis provides the substituted glycine in very good overall yield (80-95%). A further application of Stork’s original method is in the preparation of a-halogenomethyl-alanines from enolates of alanine Schiff’sbases and various polyhalogen~methanes.~~~ Some alternative but related methods for the homologation of glycine have also been developed. Bis(dipheny1phosphino)glycine methyl ester yields an enolate (189), when treated with potassium t-butoxide, which can be cleanly monoalkylated with, for example, benzyl The phosphorus group is removed by acid hydrolysis. The oxazolin-5-ones (190), derived from N-benzoyl-a-aminoacids and acetic anhydride, can be readily alkylated in the 4-position; hydrolysis gives a,a-disubstituted N-benz~yl-a-amino-acids.~~~ Ph, P \N n C 0 , M e /

Ph,P

P h q N r R 0 0

A variation of the Ugi reaction, which may have general application, is the preparation of N-benzyl-a-isopropylglycine amides from benzamide, isobutyraldehyde, an isocyanide and carbon dioxide (50 atm).293 The complex (191) derived from acetonitrile undergoes nucleophilic attack by cyanide ions to provide alanine, after reduction, hydrolysis, and decarboxyla t i ~ nin, a~ procedure ~ ~ which may find use as a method €or preparing a-aminoacids labelled at the carboxy-group. A variety of a-amino-acids have been

obtained in 24-88 YOyields by electrochemical reductive ammination of a-ketoacids in aqueous ammonia containing ammonium Imines and iminium salts of a-keto-esters can be reduced to a-amino-acid esters by Hantzsch’s ester (a 1,4-dihydr0pyridine),~~~ while oximes (or o-benzyloximes) of a-keto289 290

291 292

293 294

295

296

M. J. O’Donnell and T. M. Eckrich, Tetrahedron Letters, 1978, 4625. P. Bey and J. P. Vevert, Tetrahedron Letters, 1978, 1215. P. W. Lednor, W. Beck, H. G. Fick, and H. Zippel, Chem. Ber., 1978,111,615. R. Lohmar and W. Steglich, Angew. Chem. Znternat. Edn., 1978, 17, 450. E. Haslinger, Monatsh., 1978,109, 749. I. I. Creaser, S. F. Dyke, A. M. Sargeson, and P. A. Tucker, J.C.S. Chem. Comm., 1978, 289; J. Springbord, R. J. Geue, A. M. Sargeson, D. Taylor, and M. R. Snow, ibid., p. 647. E. A. Jeffery and A. Meisters, Austral. J. Chem., 1978, 31, 73; E. A. Jeffery, 0.Johansen, and A. Meisters, ihid., p. 79. U. K. Pandit, M. J. de Nie-Sarink, A. M. van der Burg, J. B. Steevens, and R. F. M. van Dokkum, Rec. Trau. chim., 1978, 97, 149.

General and Synthetic Methods

124

esters are reduced to the corresponding N-hydroxy- (or N-benzy1oxy)-a-aminoacid esters by the complex of borane and ~ y r i d i n e . ~ ~ ~ The synthesis of N-acyl-a-chloroglycine and its use in the preparation of other a-substituted glycines has been described.298N-Acylhemiaminals, prepared from glyoxylic acid and amides, carbamates, or ureas, can be converted into N-acyl-aarylglycines by reaction with aromatic hydrocarbons in sulphuric acid.299The same type of hemiaminals may be converted into N-acyl- y-keto-a-amino-acids by reactions with 1,3-dicarbonyl compounds again in the presence of concentrated sulphuric acid.300 P-Hydroxy-a-amino-acids are available by reduction and hydrolysis of the corresponding P-keto-esters, obtained from methyl isocyanoacetate and acyl halides via oxazole-4-carboxylate intermediate^.^'^ A synthesis of L- y-amino-Phydroxybutyric acid has been reported in which the key step is a dehydration of L-a-hydroxysuccinamic acid to the corresponding y-cyano-acid, presumably via a y - i r n i n o b ~ t y r o l a c t o n e .This ~ ~ ~ could prove to be a general route to P- and y-cyano-carboxylic acids. a,@-Diamino-acids can be prepared from cyclic N-acetylamines by electrochemical a-methoxylation followed by ring opening under Strecker A short route to 8-aminolaevulinic acid is by reaction between succinic anhydride and the dianion derived from ethyl N-benzoylhippurate followed by acid hydrolysis (Scheme 53).304 Coupling with acyclic anhydrides leads to a-amino-ketones. I

PhCOh

Li

Reagents: i, Succinic anhydride; ii, HCI-H,O, A

Scheme 53

Unsaturated a-Amino-acids.-A general route to a-vinyl-a-amino-acids is based upon Stork’s approach to substituted glycines (see ref. 288 etc.) and uses the enolate of the Schiff’s base formally derived from benzaldehyde and methyl a-Vinylglycine itself cannot be prepared by a-aminocrotonate (Scheme 54).30s this method as addition of water to the intermediate anion gives pure ( E )starting material. a-Vinylalanine has been obtained in good yields by a somewhat different approach from the enolate of alanine methyl ester and truns-phenyl-2J. D. M. Herscheid and H. C. J. Ottenheijm, Tetrahedron Letters, 1978, 5143. D. Matthies, Synthesis, 1978, 53. 2yq A. Schouteeten, Y. Christidis, and G . Mattioda, Bull. Soc. chim. France, 1978, 248. 300 D. Ben-Ishai, J. Altman, Z . Bernstein, and N. Peled, Tetrahedron, 1978, 34, 467. 301 M. Kirihata, H. Tokumori, I. Ichimoto, and H. Ueda, J. Agric. Chem. SOC.Japan, 1978,52, 271. T. Yoneta, S. Shibahara, S . Fukatsu, and S . Seki, Bull. Chem. SOC.Japan, 1978, 51, 3296. 303 K. Warning, M. Mitzlaff, and H. Jensen, Annalen, 1978, 1707, 1713. ‘04 D. A. Evans and P. J. Sidebottom, J C . S . Chem. Comm., 1978,753. lo5W. J. Greenlee, D. Taub, and A. A. Patchett, Tetrahedron Letters, 1978, 3999.

2y7

2y8

’(”

Carboxylic Acids and Derivatives

125 R

i,ii

N=CHPh

R

y C O , M e N=CHPh

--+

~

C O NH2

,

H

Reagents: i, LiN(SiMe,),; ii, RX

Scheme 54

chlorovinyl sulphone (Scheme 55).306An alternative method (cf. 2, 283) for the dehydration of threonine and serine is to treat the respective N-protected amino-acid esters with diethyl azodicarboxylate and triphenylphosphine in THF.307 NR'R2

+OLi OMe

NR'R' +

C1*S02Ph

WHO,

-+

qCoZMe NR'R,

S02Ph

Scheme 55

Cycloalk- 1-enylglycines, useful in some penicillin syntheses, are available from N-formylcycloalkylideneglycinates, themselves prepared from methyl isocyanoacetate and cycloalkanones (Scheme 56).308a-Alkylated homologues (193) of cycloalk- 1-enyl-glycines may be obtained from the enolate of the unsaturated isocyano-esters (192).309

KOH

OHCNH

C0,Me

HCI

OHCNH

CO2H

Scheme 56

306 307

B. W. Metcalf and E. Bonilavri, J.C.S. Chem. Comm., 1978, 914. H. Wojciechowska, R. Pawiowicz, R. Andruszkiewicz, and J. Grzybowska, Tetrahedron Letters, 1978,4063.

3n8 309

M. Suzuki, K. Nunami, and N. Yoneda, J.C.S. Chem. Comm., 1978, 270. K. Nunami, M. Suzuki, and N. Yoneda, Synthesis, 1978,840.

General and Synthetic Melhods

126

Following last year's reports (2, 287, 288) of the first preparations of an a-ethynyl a-amino-acid, Casara and Metcalf have developed an efficient general route to such compounds by alkylation of the dianion derivable from the readily available urethane (194).310The dianion also adds [1,4] to methyl acrylate to provide, after deprotection, a-etkynylglutamic acid. /

SiMe,

(194)

a-Aminoacrylates, predominantly as the (E)-isomers, have been prepared by using a variation of the Ugi reaction from methyl isocyanoacetate, an aldehyde, and a secondary amine. Yields are between 40 and 50% . 3 1 1 A Japanese group has reported a general method for the synthesis of a,@-unsaturated-a,@-diaminoacids from a-aminoacrylates [ e . g (1991, derived from ethyl pyruvate and benzyl carbamate, by N-bromination and halogen displacement with azide followed by a [1,3] azide shift and reduction (Scheme 57).312

Chiral Amino-acids.-A full report has been published313 on a synthesis of D-amino-acids which has as its key intermediate the optically active enolate (196),derived from glycine t-butyl ester and (lS, 2S, SS)-2-hydroxypinan-3-one. Alkylation and hydrolysis gives homologues of glycine in around 70% chemical aad optical yield. Related to this work is the alkylation of 2-imidazolin-5-one enolates (197), obtained from ( S ) -1-phenylethylamine which leads to dialkylated glycine derivatives in chemical yields of between 60 and 90%, and optical yields often in excess of 95'/0.~'~In both cases, the original chiral component can be recovered virtually optically pure. Thiol addition to dehydroalanyl prolineamides [ e . g (198)] gives D-cysteinyl peptides in high optical yields.315The presence of the chiral amido-group is essential ;virtually no stereoselectivity is observed when it is replaced by an ester or alcohol group. P. Casara and B. W. Metcalf, Tetrahedron Letters, 1978, 1581. M. Suzuki, K. Nunami, T. Moriya, K. Matsumoto, and N. Yoneda, J. Org. Chem., 1978, 43,4933. 3 1 2 C. Shin, K. Watanabe, H. Ohmatsu, and J. Yoshimura, Tetrahedron Letters, 1978, 4535. 3 1 3 T. Oguri, N. Kawai, T. Shioiri, and S. Yamada, Chem. and Pharm. Bull. (Japan),1978, 26, 803. 3 14 U. Schollkopf, H. H. Hausberg, I. Hoppe, M. Segal, and U. Reiter, Angew. Chem. Znternat. Edn., 1978, 17, 117. 3 1 5 E. Ohler, E. Prantz, and U. Schmidt, Chem. Ber., 1978, 111, 1058. 310 311

Carboxylic Acids and Derivatives

127

Enantiomeric enrichment of a-amino-acids can be achieved by quenching the enolates of the corresponding Schiff’s base methyl esters with (2R,3R)-diacyltartaric The (S): (R) ratio in the product varies from 55 :45 up to 81 : 19. Some further reports on the ‘asymmetric transammination’ procedure have appeared (1,238). Thus, hydrogenolysis of the chiral hydrazones derived from N-amino-l-ephedrine and methyl pyruvate or methyl phenyl glyoxylate leads to (R)-alanine and (R)-phenylglycine respectively, both in ca. 37% optical yields, together with /-ephedrine, the optical purity of which is only slightly reduced.317 The optical yields from this type of reaction when ethyl-(R)-a-phenylglycine is used as chiral component have been found to be very solvent and temperature dependent; variations in the latter parameter can even lead to a change in the configuration of the final P- Amino-acids of around 20% enantiomeric enrichment have been obtained by coupling optically pure Schiff’s bases with Reformatsky When the latter reagents contain 1-menthyl ester groups, enrichments of only 2-5% are observed with racemic Schiff’s bases. Cram and his co-workers have reviewed in full their latest work on the use of host-guest complexes for the total optical resolution of amines and a-amino-ester salts. This important method can be used with both liquid-solid systems (host chemically bound to silica) and liquid-liquid systems, when the host is contained in the mobile phase and a racemic mixture of the guest is adsorbed on to the stationary A neat trick for the resolution of a-amino-acids is to mix solutions of the racemic acid and rucemic ephedrine and then seed the mixture with a pure diastereoisomer. In this way, only two of the four possible diastereoisomers crystallize out, in turn.321 The preparation of optically pure a-amino-acids by asymmetric hydrogenation of their a,P-unsaturated derivatives catalysed by chiral rhodium(1) diphosphine complexes continues to be actively pursued. In an outstanding paper, Fryzuk and Bosnich have described the preparation and use of the rhodium(1) complex of (R)-1,2- bis(dipheny1phosphino)propane (‘R-prophos’) which catalyses the reduction of (2)-N-acylaminoacrylic acids to (S)-a-amino-acids in ca. 90% 31d 317 318

319

320

321

L. Duhamel and J.-C. Plaquevent, J. Amer. Chem. SOC.,1978,100, 7415. H. Takahashi, H. Noguchi, K. Tomita, and H. Otornasu, J. Pharm. SOC.Japan, 1978,98,618. K. Harada and Y. Kataoka, Chem. Letters, 1978, 791; Tetrahedron Letters, 1978, 2103. M. Furukawa, T. Okawara, Y. Noguchi, and Y. Terawaki, Chern. andPharm. Bull. (Japan), 1978, 26, 260. E. P. Kyba, J. M. Timko, L. J. Kaplan, F. de Jong, G . W. Gokel, and D. J. Cram, J. Amer. Chem. Soc., 1978,100,4555; L. R. Sousa, G. D . Y. Sogah, D. H. Hoffmzn, and D. J. Cram, ibid.,p. 4569; S. C. Peacock, L. A. Domeier, F. C. A. Gaeta, R. C. Helgeson, J. M. Timko, andD. J. Cram, ibid.,p. 8190; J. M. Timko, R. C. Helgeson, and D. J. Cram, ibid.,p. 2828. C.-H. Wong and K.-T. Wang, Tetrahedron Letters, 1978, 3813.

General and Synthetic Methods

128

optical yield.322The chiral ligand was initially synthesized from (S)-lactic acid, but once obtained it can be used to 'breed' further quantities of itself by catalysing the hydrogenation of the enol acetate of ethyl pyruvate to (S)-ethyl 0-acetyl lactate (Scheme 58). Similarly, 'S-prophos' can be prepared from (R)-lactic acid and used both to generate larger quantities of itself, and to catalyse the formation of (R)-a-amino-acids (cf.2,291).

'R-prophos' Reagents: i, 'R-prophos'-H,; ii, LiAIH,; iii, TsCI; iv, LiPPh2

Scheme 58

Other diphosphino-complexes of rhodium(1) include those derived from (1R,2R)-bis(methylamino)cyclohe~ane,~~~ D - g h ~ o S e ,and ~ ~ ~~-1,6-anhydroglucose;325all are capable of catalysing the hydrogenation of N"-acetamidoacrylic acids to a-amino-acids in optical yields of between 70 and 90%. A preliminary study on the use of protein-diphosphinerhodium(1) complexes has been carried out, but here optical yields of only 40% have been realized so far.326An insoluble polymer-bound Rh'-DIOP catalyst has also been developed.327Studies of the hydrogenation of some ( E ) - and (2)-N"-acylaminocinnamic acids in the presence of Rh'-DIOP suggest that some ( E )+ ( 2 )isomerization occurs prior to hydrogen addition.328 The hydrogenation of P-acetamidoacrylates has also been achieved under similar conditions to give P-amino-acid derivatives of ca. 5 5 '/o optical An example of chiral induction at two adjacent carbon atoms is the hydrogenation of dimethyl (Z)-2-acetamido-3-methylfumarate,in the presence of a chiral cationic pyrrolidine-phosphine Rh' complex, which leads to (2R,3R)-P-methylaspartic acid of about 5 5 % enantiomeric enrichment.330Studies of the mode of action of the aforementioned catalyst have been carried and a flexible synthesis of functionalized chelating diphosphines has been Protection and Deprotection.-An improved method for the formation of benzyl esters of a-amino-acids is first to protect the amino function as an enamine salt 322 323

324 325 326

327

328

329 330 331

332

M. D. Fryzuk and B. Bosnich, J. Amer. Chem. SOC.,1978, 100, 5491. K. Hanaki, K. Kashiwabara, and J. Fujita, Chem. Letters, 1978, 489. W. R. Cullen and Y . Sugi, Tetrahedron Letters, 1978, 1635. G. Descotes, D. Lafont, and D. Sinou, J. Organometallic Chem., 1978, 150, C14. M. E. Wilson and G. M. Whitesides, J. Amer. Chem. SOC., 1978, 100, 306. N. Takaishi, H. Imai, C. A. Bertelo, and J. K. Stille, J. Amer. Chem. SOC.,1978,100,264; T. Masuda and J. K. Stille, ibid., p. 268. C. Detellier, G. Gelbard, and H. B. Kagan, J. Amer. Chem. SOC.,1978,100,7556;K. E. Koenig and W. S. Knowles, J. Amer. Chem. SOC.,1978, 100, 7561; R. Glaser, S. Geresh, M. Twaik, and N. L. Benoiton, Tetrahedron, 1978, 34, 3617. K. Achiwa and T. Soga, Tetrahedron Letters, 1978, 1119. K. Achiwa, Tetrahedron Letters, 1978, 2583. K. Achiwa, Y. Ohga, Y. Iitaka, and H. Saito, Tetrahedron Letters, 1978,4683; J . M. Brown and P. A. Chaloner, J.C.S. Chem. Comm., 1978, 321. M. E. Wilson, R. G. Nuzzo, and G. M. Whitesides, J. Amer. Chem. SOC.,1978,100, 2269.

Carboxylic Acids and Derivatives

129

(using ethyl acetoacetate and tetramethylguanidine in DMF) followed, without isolation, by the addition of a benzyl halide.333Work-up using cold methanolic HCl gives hydrochlorides of a-amino-acid benzyl esters in 62-100% yield with no detectable racemization. N-Protected amino-acids can easily be converted into their diphenylmethyl esters by treatment with tri(diphenylmethy1) phosphate and a small amount of trifluoroacetic acid in refluxing methylene Penta-amminecobalt(II1) complexes can be employed to protect carboxylic acid functions during peptide synthesis using the HOBT-DCC coupling method.335The complexes are stable to conditions under which N-BOC groups are removed and may themselves be removed under mild reducing conditions (Na2S-NaHC03). N-BOC a-amino-acids can be esterified with methanol or ethanol using boron trifluoride etherate as catalyst; in this way large-scale esterifications using diazomethane are avoided. Yields are usually excellent, with little racemization A simple method for the esterification of aminoacids with polyethyleneglycol has been reported337 (cf. 2, 262), as have the preparation and deprotection of a-amino-acid t - b u t y l t h i o e ~ t e r s , ~ ~ ~ A number of papers have appeared on the use of the fluoren-9-ylmethoxycarbony1 (FMOC) group (199) as an amine protecting group in peptide Its extreme lability to cyclic secondary amines avoids the need continually to expose substrates to strong acids during a peptide synthesis. In addition, FMOC groups are essentially inert to tertiary amines during brief exposure. A problem with this approach is the separation of the dibenzofulvene, produced on deprotection. This can be overcome by using polymer-bound piperazine which forms an adduct with the fulvene and is simply removed by filtration.340 An alternative to the BOC group for protection of an amino-group is the 1-(1-adamanty1)-1-methylethoxycarbonyl (Adpoc) moiety (200). It is stable to hydrogenolysis and is removed about one thousand times faster than N"-BOC groups on treatment with 3% aqueous trifluoroacetic

Oxazoline derivatives (201) have also been reported to be useful as N"protecting groups. Stable to aqueous, ethanolic sodium hydroxide and to liquid 333 334

33s

336

33'

338 339

340 341

J. A . Maclaren, Austral. J. Chem., 1978, 31, 1865. L. Lapatsanis, Tetrahedron Letters, 1978, 4697. S. S. Isied and C. G. Kuehn, J. Amer. Chem. SOC., 1978, 100,6752. T. Yamada, N. Isono, A. Inui, T. Miyazawa, S. Kuwata, and H. Watanabe, Bull. Chem. SOC.Japan, 1978, 51, 1897. C. S. Pande and J. D. Glass, Tetrahedron Letters, 1978, 4745. U.Schmidt and F.Steindl, Synthesis, 1978, 544. E.Atherton, H.Fox,D.Harkiss, C.J. Logan, R. C. Sheppard, and B. J. Williams, J.C.S. Chem. Comm., 1978,537; E.Atherton, H.Fox,D.Harkiss, and R. C . Sheppard, ibid., p. 539; L. A. Carpino and J. Meienhofer, Internat. J. Peptide Protein Res., 1978,11, 246. L. A. Carpino, J. R. Williams, and A. Lopusinski, J.C.S. Chem. Comm. 1978,450. H. Kalbacher and W. Voelter, Angew. Chem. Internat. Edn., 1978, 17, 944.

130

General and Synthetic Methods

HF, they can be removed by h y d r o g e n ~ l y s i s A . ~ ~method ~ for the masking of terminal amino-groups during peptide synthesis is to convert the C-terminally protected peptide [e.g. (202)]into the corresponding hydantoin derivative (203) using N,N'-carbonyldi-imidazole; the reaction occurs without r a ~ e m i z a t i o nA .~~~ report has appeared on the use of various substituted phenylsulphenyl groups for N"-protection of a - a m i n o - a ~ i d s . ~ ~ ~ 0

R2

R'

n

V

A general synthesis of e n d chloroformates (204) from bis(keto)-mercurals and phosgene has been developed.345This now allows the preparation of less baselabile analogues of the vinyloxycarbonyl (VOC) amino protecting group,

WOK,, (204)

reported last year (2,307).In an extension of acid protection methodology (cfi2, 141, 298), the P-(trimethylsily1)ethoxycarbonyl function has been applied to amino-group Removal is by reaction with fluoride ions (from Et4N'F-) to give gaseous products (CO,, CH2=CH2, and Me3SiF);unfortunately the group is also labile to trifluoroacetic acid. Esters of p-hydroxybenzyloxycarbonyl groups are more stable than the corresponding N" -benzyloxycarbonyl moieties to trifluoroacetic They may be cleaved using weak alkali, the reaction proceeding via ester hydrolysis and [ 1,6] elimination. Some isopropenyl carbonates (205),analogues of isopropenyl acetate, have been prepared and found to react smoothly with amino-groups to give the N-alkoxy- or N-aryloxy-carbonyl derivatives (206).348 A promising variant of the

(205)

+

R2R3NH

L

RL

halogenoalkoxycarbonyl function for the protection of amino-groups in cu-aminoacids is the 2,2,2-trichloro-t-butoxycarbonyl(TCBOC) moiety, introduced by 342

343 344 34s

34h 347 348

M. Kanaoka, and Y. Kurata, Chem. and Pharm. Bull. (Japan), 1978,26,660. F. Esser and 0. Roos, Angew. Chern. Internat. Edn., 1978, 17,467. H. Ito, K. Ogawa, T. Iida, and I. Ichikizaki, Chem. and Pharm. Bull. (Japan), 1978, 26, 296. R. A. Olofson, B. A. Bauman, and D. J. Wancowicz, J. Org. Chem., 1978,43,752. L.A. Carpino, J.-H. Tsao, H. Ringsdorf, E. Fell, and G. Hettrich, J.C.S. Chem. Comm., 1978,358. G . Le Corre, E. Guibt-Jampel, and M. Wakselman, Tetrahedron, 1978, 34, 3105. Y. Tamura, J. Haruta, S. Okuyama, and Y. Kita, Tetrahedron Letters, 1978, 3737.

Carboxylic Acids and Derivatives

131

means of the corresponding readily available chloroformate derivative under Schotten-Baumann conditions.349The derivatives are usually highly crystalline and are stable both to conditions basic enough to hydrolyse methyl esters and sufficiently acidic to remove t-butyl ester groups. They themselves can be cleaved by lithium cobalt(1) phthalocyanin or zinc in acetic acid. N"-ethoxythiocarbonyl (Etc) derivatives of a-amino-acids are best prepared from bis(ethoxythiocarbonyl)sulphide, itself obtained from carbon disulphide and ethyl c h l o r ~ f o r m a t e . ~Further ~" progress towards peptide synthesis in aqueous solution has been made by utilizing 2-triaryl- (or alkaryl-)phosphonioethoxycarbonyl (Poec) groups as amino function protectors. The Poec derivatives are liable to mildly basic conditions and peptide bond formation is effected using a water-soluble carbodi-imide and HOBT.35' p-Nitrophenyl esters of some a-amino-acids have been hydrolysed under mild conditions using poly-(N"-methacryloyl-L-histidine)or N"-pivaloyl-L-histidine as catalysts; the preparation of these materials is 2-Mercaptopyridine has been shown to be an extremely efficient reagent for the specific removal of N"-o-nitrophenylsulphenyl (NPS) groups.353(cf.1, 275). Not surprisingly, cyclohexa-1,4-diene has been found to be an excellent source of hydrogen for the removal of hydrogenolizable protecting groups using 10% Pd/C (cf. 1, 276; 2, 309). The hydrolysis of N"-acyl- and N"-phenylas acetyl-a-amino-acid derivatives by benzylpenicillinacylase, isolated from an E. coli species, has been

34 9 350 35 I 352

353 354

35s

H. Eckert, M. Listl, and I. Ugi, Angew. Chem. Internat. Edn., 1978, 17, 361. G. Barany, B. W. Fulpius, and T. P. King, J. Org. Chem., 1978, 43, 2930. H. Kunz, Angew. Chem. Internat. Edn., 1978, 17, 67. Y. Okarnoto, J. Chem. SOC. Jap. Chem. Ind. Chem.. 1978,870;cf. Y. Ihara, J.C.S. Chem. Comm., 1978,984. A. Tun-Kyi, Helu. Chim. Acta, 1978, 61, 1086. A.M.Felix, E. P. Heirner, T. J. Larnbros, C. Tzougraki, and J. Meienhofer, J. O r g . Chem., 1978,43, 4194. D. Rossi, A. Romeo, and G. Lucente, J. Org. Chem., 1978, 43, 2576.

4 Alcohols, Halogeno-compounds, and Ethers BY R. C. F. JONES

1 Alcohols Preparation.-A simple route to alcohols is the chain extension of chloroalcohols by reaction of their Grignard derivatives with alkyl halides. The requirement for protection (and subsequent deprotection) of the hydroxy-group during this sequence has been shown' to be unnecessary if the chloro-magnesium alcoholate is formed initially (Scheme 1). Cl(CH2),0H

-%

ClMg(CH2),0MgCl

5R2(CH2),0H

Reagents: i, R'MgCI; ii, Mg; iii, R2X; iv, H,O'

Scheme 1

Primary alcohols are available in good yields from terminal alkenes uia the organopentafluorosilicate adducts (1) and a novel oxidative carbon-silicon bond cleavage using peracid (Scheme 2).2This latter reaction is very medium-dependent; DMF was found to be the solvent of choice.

.

RCH=CH2

Reagents: i, HSiCI,-H,PtCI,;

-

..

K2[RCH2CH2SiF5] (1)

RCH2CH20H

ii, KF; iii, rn-ClC,H,CO,H

Scheme 2

A 'one-pot' synthesis of unsymmetrical tertiary alcohols from the N-methylaminopyridine amides (2) by successive addition of two metallo-nucleophiles (Grignard reagents or organolithiums) has been developed (Scheme 3).3Substitution of LiAIH, for the second organometallic reagent leads to secondary alcohols. Two related reports have appeared of new alcohol preparations involving synthetic equivalents of the 'umpolung' species (3). One approach utilizes aalkoxystannanes (4),readily available from carbonyl compounds (Scheme 4),to generate a-alkoxy-organolithiums which will react with e l e ~ t r o p h i l e s In . ~ the

'

G. Cahiez, A. Alexakis, and J. F. Normant, Tetrahedron Letters, 1978, 3013. K. Tamao, T. Kakui, and M. Kumada, J. Amer. Chem. Soc., 1978,100,2268 A. I. Meyers and D. L. Comins, Tetrahedron Letters, 1978, 5179. W. C. Still, J. Amer. Chem. Soc., 1978, 100, 1481.

132

Alcohols, Halogeno-compounds, and Ethers

N

NMe

133

NMe

NMe

O N l - I M e

+ R'RZR3CO-M+

+ R'R2R3COH

Reagents: i, R2M; ii, R3M; iii, H,O

Scheme 3

RCHOH (3)

second report deprotonation of 2,4,6-tri-isopropylbenzoates (which have a sterically protected carbonyl group) is used to form a- acyloxy-organolithiums (5) . ..

RCHO

',I1

... .

+ RCH(OR')SIIBU~ (4)

RCH(OR')R*

"I,'"

Reagents: i, Bu,SnLi; ii, R'X; iii, BuLi; iv, R2X

Scheme 4

that can be treated with electrophiles in similar fashion (Scheme 5).5 If the presence of the excess base needed to prepare (5) is undesirable, quenching to the stannane (6),and regeneration of (5) with stoicheiometric methyl-lithium when required, is an alternative. ArCO,CH,Me

oo...L i

Arc,

.. ...

I 0-CHMe

'I, 111

--+

MeCH(0H)R

ArCOOCH(SnBu,)Me

(6)

Reagents: i, Bu"Li-TMEDA; ii, RX; iii, LiAIH,; iv, Bu,SnCl; v, MeLi

Scheme 5

The known carbonylation of trialkylboranes in the presence of LiA1H(OMe)3 can now be used as part of a mild route to dialkylcarbinols if the initial adducts, P. Beak, M. Baillargeon, and L. G. Carter, J. Org. Chem., 1978,43,4255.

134

General and Synthetic Methods

presumably (7), are treated with acid to effect migration of a second alkyl group (Scheme 6).6This 'one-pot' procedure is an attractive alternative to earlier routes from trialkylboranes using acyl carbanion equivalents. Full details are now available' of the converson of trialkylboranes into tertiary alcohols via the alkenyltrialkylborate adducts (8) (Scheme 7). R3B

Li[R2BCH(R)OAl(OMe)3] 171

'l"ii

R2CHOH

Reagents: i, LiAIH(OMe),-CO; ii, HX; iii, H,O,-OH

Scheme 6

Reagents: i, CH,=C(OMe)Li; ii, R'X; iii, H,O,-OH

; iv,

HCI

Scheme 7

Carbonyl Group Reduction. Carboxylic acids, as their 2-thiazoline-2-thiol esters (9), can be reduced to primary alcohols with sodium borohydride in a reaction easily monitored by following the disappearance of the y e l l o ~colour of (9).8

Rcos<s) N

(9)

Sodium borohydride adsorbed on alumina is a new reagent combination for the reduction of aldehydes and ketones to alcohols in aprotic solvents such as ether.' Cyanoborohydride anion, [BH3CN]-, supported on an anion-exchange resin containing quaternary ammonium groups has been found in preliminary results1o to be a successful and convenient reagent for, inter alia, the reduction of enones to allylic alcohols. Ease of work-up and retention of cyanide by the resin are obvious advantages. Carbonyl compounds can also be reduced to alcohols by tributyltin hydride in a cyclohexane-silica gel slurry; aldehydes are selectively reduced in the presence of ketones and products are obtained by simple elution from the silica." Adsorption, and consequent polarization, of the carbonyl group by the silica seems to be important in the mechanism of this mild, non-basic, process. A new borohydride derivative soluble in benzene is the bis(cyc1opentadieny1)chlorotetrahydroboratozirconium compound (10).It has a reactivity similar to that of sodium borohydride and can thus be used to reduce non-polar

' J . L. Hubbard and H . C. Brown, Synthesis, 1978, 676. A. B. Levy, S. J. Schwartz, N. Wilson, and B. Christie, J. Organornetallic Chern., 1978, 156, 123.

' Y. Nagao, K. Kawabata, and E. Fujita, J.C.S. Chem. Cornrn., 1978, 330. lo

"

E. Santaniello, F. Ponti, and A. Manzocchi, Synthesis, 1978, 891. R. 0 . Hutchins, N. R. Natale, and I. M. Taffer, J.C.S. Chem. Cornrn., 1978, 1088. N. Y. M. Fung, P. de Mayo, J. H. Schauble, and A. C. Weedon, J. Org. Chem., 1978,43,3977.

Alcohols, Halogeno-compounds, and Ethers

135

aldehydes and ketones not soluble in the alcoholic media used with NaBH4.I2The adduct (11) is a stable form of thexylborane whilst still remaining an active reducing agent.13The reduction of aldehydes and ketones at rates comparable to those found for thexylborane itself has been reported; adjustment of the amine component of (11)to give a graded series of reactivities should be possible. Cp,Zr(C1)BH4

HBH,,NEt,Ph

(10)

(11)

Optimum conditions for the reduction of saturated ketones by the complex reducing agent formed from sodium hydride, sodium t-amylate, and Ni” acetate (NiCRA) have been delineated.14 Reoxidation of the secondary alcohol products is ‘dramatically postponed’ by the addition of alkali- or alkaline-earth-metal salts, and catalytic ketone reductions are achieved with NiCRA-MgBr2 mixtures. Full details of the reducing properties of various complex metal hydrides (12) of copper, formed by reaction of LiAlH, with appropriate lithium methylcuprates [equation (l)],have been published;” for example enones are reduced pre;(n

+ 1)LiAIH4 -k Li,CuMe,+l -+ Li,CuH,+l + $(n + 1)LiAlH2Me2

(1)

(12)

ferentially 1,2 (to allylic dcohols) by Li4CuH, but 1,4 by Li2CuH3, and 4-tbutylcyclohexanone is reduced predominantly from the axial side (as is the case with LiAlHJ. The full investigation of reductions with active magnesium hydride, and the THF-soluble alkoxymagnesium hydrides (13)prepared from it, has been revealed16 this year. Aldehydes are reduced in the presence of many other functional groups, and ketones are also reduced. The stereochemistry of reduction of substituted cyclohexanones with (13)” and the dialkylamino-magnesium hydrides ( 14)18has been examined, and the observed selectivity for equatorial attack (to give axial alcohols) is found to depend on the steric requirements of the alkoxy (or dialkylamino) groups and the degree of association of the hydrides in solution. KOMgH

R2NMgH

(13)

(14)

The use of B-alkyl-9-BBN compounds, especially (15), as mild and very chemoselective reducing agents for aldehydes (Scheme 8), even in the presence of ketones, has been explored” and the variation in reducing ability with different B-alkyl groups examined.” The cyclic transition state (16) is consistent with an increase in rate both with increase in substitution p- to boron and when the B-C-C-H unit can adopt a planar arrangement. This system has also been l3

l4 l5

l6 ”

’’ l9

T. N. Sorrell, 7etrahedron Letters, 1978, 4985. A. Pelter, D. J. Ryder, and J. H. Sheppard, Tetrahedron Letters, 1978, 4715. J. J. Brunet, L. Mordenti, and P. Caubere, J. Org. Chem., 1978,43,4804. E. C. Ashby, J. J. Lin, and A. B. Goel, J. Org. Chem., 1978,43, 183. E. C. Ashby, J. J. Lin, and A. B. Goel, J. Org. Chem., 1978, 43, 1557. E. C. Ashby, J. J. Lin, and A . B. Goel, J. Org. Chem., 1978,43, 1560. E. C. Ashby, J. J. Lin, and A . B. Goel, J. Org. Chem., 1978, 43, 1564. M. M. Midland and A. Tramontano, J. Org. Chem., 1978,43, 1470. M. M. Midland, A. Tramontano, and S. A . Zderic, J. Organometallic Chem., 1978, 156, 203

136

General and Synthetic Methods

Scheme 8

shown to reduce a#-unsaturated aldehydes selectively to the allylic alcohols with no conjugate r e d u ~ t i o n . 'Some ~ other new reagents for the conversion of conjugated carbonyls into allylic alcohols include the diborane-methyl sulphide complexYz1 sodium borohydride in the presence of rare-earth halides,22and an iridium complex (17) in propan-2-01 as solvent.z3 In the latter case a transfer hydrogenation, with the propan-2-01 as donor, is involved.

HIrClZ,(Me2S0)3 / \

(17)

In a recent review of asymmetric synthesis the stereoselective reduction of carbonyl groups to alcohols by hydrogenation or hydrosilylation using chiral catalysts, and by the use of chiral modified metal hydrides, is The best optical yields in ketone reductions are obtained using enzymes and further applications have been publishedz5 of a method based on horse liver alcohol dehydrogenase (HLAD) that permits the production of gram quantities of enantiomerically pure (S)-alcohols with the use of only very small quantities of enzyme, and of the coenzyme NAD'. The oxidized coenzyme is continually reduced (and hence recycled) in situ by HLAD with ethanol as hydrogen donor [equation (2)]. The chiral 1,4-dihydropyridine (18), a model for the reduction coenzyme NADH, has been used in attempted biomimetic asymmetric reduction;z6for example it will reduce (19) to (20) in 50% chemical yield and 27% en an tiomer excess.

RWCO NADH MeCHO " 22

23 24 25

26

R'R~CHOH NAD' EtOH

E. Mincione, J. Org. Chem., 1978,43, 1829. J.-L. Luche, J. Amer. Chem. Soc., 1978, 100, 2226. B. R. James and R. H. Morris, J.C.S. Chem. Comm., 1978,929. D. Valentine and J. W. Scott, Synthesis, 1978, 329. T. A. Van Osselaer, G. L. Lemiere, E. M. Merckx, J. A. Lepoivre, and F. C. Alderweireldt, Bull. SOC. chim. belges, 1978, 87, 799. H. J. van Ramesdonk, J. W. Verhoeven, U. K. Pandit, and T. J. de Boer, Rec. Truo. chim., 1978,97, 195.

137

Alcohols, Halogeno-compounds, and Ethers

PhCOC02Me -+ PhCH(OH)C02Me

M e 3 c - k y 0 0 M r

Some attention has been given this year to attempts at asymmetric reductions of aryl alkyl ketones in chiral environments. Among the systems tried have been borohydride, or the NADH model (21), in the presence of sodium cholate mice1les2'*** (enantiomeric excess in the products very low, 0-2%) or of bovine serum albumin,28s29 a biological carrier protein, where the optical yields were better [up to 47% enantiomer excess with (21) as reducing agent, or 2O--8O% with NaBH4] and the aqueous protein solution could be re-used. The configuration of the predominant aryl carbinol enantiomer obtained using NaBH4 was often different to that found using (21).

0

CONH,

Phenyl alkyl ketones are reduced by sterically hindered chiral organoaluminium compounds (22) (Scheme 9).30The predominant enantiomer and extent of asymmetric induction observed (0-57% enantiomer excess) was found to depend on the reaction conditions and the structure of the alkyl group on aluminium. RCH(Me)CH2CI

% [RCH(Me)CH2I3B PhCH(0H)R'

[RCH(Me)CH2I3Al

+ CH2=C(Me)R

Reagents: i, Mg, ii, BF,-Et,O; iii, Et,AI; iv, R'COPh

Scheme 9

Full details have been published3' of the reduction of aryl alkyl ketones with a chiral hydride reagent prepared from the diamine (23), available from (S)proline, and LiAlH4 (Scheme 10). Enantiomeric excesses of (S)-carbinols in the range 50-92% are reported. The related chiral pyrrolidine ligand (24) has been 27

28

29

30 31

T. Sugimoto, Y. Matsumura, T. Imanishi, S. Tanimoto, and M. Okano, Tetrahedron Letters, 1978, 343 1. N. Baba, Y. Matsumura, and T. Sugimoto, Tetrahedron Letters, 1978, 4281. T. Sugimoto, Y . Matsumura, S. Tanimoto, and M. Okano, J.C.S. Chem. Comm., 1978, 926. G. Giacomelli, R. Menicagli, A. M. Caporusso, and L. Lardicci, J. O r g Chem., 1978, 43, 1790. M. Asami, H. Ohno, S. Kobayashi, and T. Mukaiyama, Bull. Chem. SOC.Japan, 1978, 51, 1869.

138

General and Synthetic Methods

\ .H

I.iAIH,

HNPh (23) Scheme 10

prepared and used in the asymmetric addition of organolithiums to aldehydes A later [equation (3)] to yield dialkylcarbinols of 11-72% optical 2R'Li

+ R2CH0 (24), R'CH(OH)R2

(3)

i n ~ e s t i g a t i o nof~ the ~ effects of solvent and temperature on this reaction led to optimization of the conditions for addition of butyl-lithium to benzaldehyde such that product of 95 '30optical purity was obtained in dimethoxymethane-dimethyl ether mixtures at -123 "C.The reaction is suggested to occur via a complex ( 2 5 ) between the alkyl-lithium and the lithium salt of (24). This lithium salt has also

Li (25)

been used in the reaction of dialkylmagnesiums with benzaldehyde [equation (4)]34to produce (R)-phenylcarbinols with optical purities of 36--88%. PhCHO

+ R2Mg

Li''24'-b

PhCH(0H)R

(4)

A kinetic investigation3' of the phase-transfer (PT) borohydride reduction of acetophenone in a water-dichloromethane system catalysed by the ephedrinium salts (26) has concluded that the optimum value of n is 8. Another investigation of the asymmetric induction in such PT borohydride reductions of phenyl alkyl ketones has found the best catalyst of those examined to be benzylquinium chloride (27),36which gave a carbinol from pivalophenone with enantiomeric excess of 32%, believed to be the best value so far obtained with a chiral ammonium salt. The results suggest that efficient asymmetric reduction requires a conformationally rigid catalyst with a hydroxy-group /3- to the 'onium' function. A further study in this area has compared the results from borohydride reductions using PT catalysts (26) with those from electroreduction employing (26) as a chiral supporting ele~trolyte.~'Interestingly the configurations of the 32

33 34 35

36

37

T. Mukaiyama, K. Soai, and S. Kobayashi, Chem. Letters, 1978, 219. K. Soai and T. Mukaiyama, Chem. Letters, 1978, 491. T. Sato, K. Soai, K. Suzuki, and T. Mukaiyama, Chem. Letters, 1978, 601. J . MassC and E. Parayre, Bull. SOC.chim. France II, 1978, 395. S. Colonna and R. Fornasier, J.C.S. Perkin I, 1978, 371. L. Horner and W. Brich, Annalen, 1978,710.

Alcohols, Halogeno-compounds, and Ethers

139

predominant enantiomers obtained from the two methods are usually opposite, suggesting that the transition states are very different. Some pinacolic products are formed along with carbinols in the electroreduction, and chiral crown ethers as electrolytes were to produce less asymmetric induction than the quaternary salts. AllylJc Alcohols. The direct allylic oxidation of alkenes by selenium dioxide has been discussed in a review of modern organoselenium chemistry.39 The use of selenium dioxide in pyridine4" allows oxidation of allylic positions to be performed in the presence of acid-labile groups (acetals, THP ethers) that are normally at least partially cleaved by Se02. An efficient synthesis of allylic alcohols from vinyl bromides via the corresponding vinyl-lithiums and reaction with carbonyl compounds (Scheme 11) R2

R'

.

Me,CH

R3

+ Me2C=CH2 + LiBr +

Br

R2

R'

R3

Li

iiY R2 ~3

R'

M C(OH)R4RS

Reagents: i, 2Bu'Li; ii, ROCOR'; iii, H,O

Scheme 11

has been reported.41 Any possibility that the alkyl bromide produced in the lithium-halogen exchange using an alkyl-lithium may compete with added electrophile for the vinyl-lithium is avoided by employing a second mole of alkyl-lithium to remove this bromide. Total retention of alkene geometry was observed in this sequence. The known stereospecific zirconium-catalysed carboalumination of alkynes has been utilized to produce allylic alcohols by conversion of the alkenyl alane adducts into the 'ate' complexes (28) and subsequent reaction with formaldehyde in a stereoselective process (Scheme 12).42Allylic methyl ethers are also available by quenching (28) with chloromethyl methyl ether. 38

39 O'

42

L. Homer and W. Brich, Chem. Ber., 1978, 111, 574. D. L. J. Clive, Tetrahedron, 1978, 34, 1049. F. Camps, J. Coll, and A. Parente, Synthesis, 1978, 215. H. Neumann and D. Seebach, Chem. Ber., 1978,111,2785. N. Okukado and E. Negishi, Tetrahedron Letters, 1978, 2357.

General and Synthetic Methods

140

R R RCrCH

ly

H

>=(

Me

AlBuMe, Li'

MH CH,OH

Me

>

R

(28)

Me Reagents: i, Me,Al-Cp,ZrCI,;

H

>=(

CH,OMe

ii, BuLi; iii, (CH,O), ; iv, CICH,OMe

Scheme 12

An article on the use of diphenylphosphinoyl and phenylthio as migrating groups in organic synthesis has reviewed the construction of allyl phenyl thioethers, and hence of allyl A new sequence developed by the same allows the conversion of allyldiphenylphosphine oxides (29),prepared with or without diphenylphosphinoyl migration, into allyl alcohols (Scheme 13). The adducts of aldehydes with the carbanion derived from (29) undergo regiospecific reductive elimination of the phosphinoyl group, possibly through a transition state such as (30). 0

II

Ph,P.y-.R1

A

R2

R'

R2 Ph,P

Reagents: i, BuLi; ii, R3CHO; iii, H'; iv, R2COCH2R'; v, R4CHO; vi, LiAlH,

Scheme 13

A stereospecific synthesis of trans- terminal allylic alcohols, suitable for application in isoprenoid work, has been Addition of phenylsulphenyl 43 44

45

S. Warren, Accounts Chem. Res., 1978, 11,401. R. R. Arndt and S. Warren, Tetrahedron Letters, 1978, 4089. Y. Masaki, K. Hashimoto, and K. Kaji, Tetrahedron Letters, 1978, 4539.

141

Alcohols, Halogeno-compounds, and Ethers

chloride to the alkenes (31)gives P-chloro-phenylthioethers; elimination, either directly (of HC1) or indirectly (of H,O from the derived P-hydroxy-phenylthioethers), leads to allyl thioethers that can be converted after oxidation into allyl alcohols (Scheme 14) via the known sulphoxide-sulphenate equilibrium in the presence of a sulphenate trap.

,

v,vi

CH,OH

Rx PhS

Reagents: i, PhSCl; ii, SiO,; iii, H'; iv, DMF, 60 "C,or Et,N; v, NaIO,; vi, (MeO),P-MeOH Scheme 14

Pyrolysis of a-alkyl-P-hydroxy-phenylsulphoxides(32) can be made to produce allylic alcohols [equation (5)], avoiding elimination towards the hydroxy-group, when performed in refluxing xylene containing suspended sodium ~ a r b o n a t e . ~ ~ OH

OH

I

(32)

The related oxidation-elimination of P -hydroxyselenides also leads regiospecifically to allyl alcohols, and two new methods have appeared utilizing this reaction. The addition of an alkene to a mixture of phenylseleninic acid (PhSe02H)and diphenyl diselenide yields, presumably via electrophilic addition of PhSeOH formed in situ, the adduct (33) that is directly oxidized and eliminated in a 'one-pot' route to allyl alcohols (Scheme 15).47 The oxidation used in this sequence employed t-butyl hydroperoxide, a new general procedure for elimination of phenylselenyl moieties. Another group of workers has developed the OH I R'R2CH(!X(OH)R4Rs -$ R'R2C=CCR4Rs I I R3 R3 SePh

R'R2CHC=CR4RS

I R3

(33) Reagents: i, 'PhSeOH'; ii, Bu'OOH

Scheme 15 46

47

J. Nokarni, K. Ueta, and R. Okawara, Tetrahedron Letters, 1978,4903. T. Hori and K. B. Sharpless, J. Org. Chem., 1978, 43, 1689.

General and Synthetic Methods

142

t-butyl hydroperoxide-alumina system for the same purpose48 and applied it to the synthesis of primary allylic alcohols from aldehydes uia their diselenoacetals (Scheme 16)49in an extension of their earlier work. R1CH2CH(SeR)2-% R’CH2CH(SeR!CH20H

5R1CH=CHCH20H

Reagents: i, BuLi; ii, H,CO (gaseous); iii, Bu‘00H-AI20,

Scheme 16

Other Unsaturated Alcohols. y,S- Unsaturated (homoallylic) alcohols may be made by homologation of ally1 alcohols with allylic transposition using a new methods0 that involves [2,3] sigmatropic rearrangement of an a-allyloxyorganolithium (34) (Scheme 17); some comments on the observed stereochemistry have been made.

Reagents: i, KH-Bu,SnCH,I; ii, BuLi

Scheme 17

The ylide ( 3 3 , prepared from base treatment of the methylenetriphenylphosphorane-isobutene oxide adduct, has been showns1 to react with steroidal aldehydes to give the (E)-homoallylic alcohol stereoselectively [equation (6)], especially at low temperatures. Ph$-CHCH,CMe,O-

+ RCHO

+

(6)

(35)

The known addition of organo-copper species to alkynes has been confirmed as occurring in a cis The adducts (36) react sluggishly with epoxides, but a recent reports3 indicates that if a I-lithioalkyne is added the (presumed) mixed cuprate formed adds smoothly to the less substituted carbon of epoxides to provide a highly regio- and stereo-selective ‘one-pot’ route to homoallylic alcohols (Scheme 18). a-Lithio-selenides (37), available from ketones, also add to epoxides (Scheme 19).54The y-hydroxyselenides so produced can be converted into homoallylic alcohols regiospecifical1.y via elimination from the corresponding selenonium 48 4q

” ” s2 s3 s4

D. Labar, L. Hevesi, W. Dumont, and A. Krief, Tetrahedron Letters, 1978, 1141. D. Labar, W. Dumont, L. Hevesi, and A. Krief, Tetrahedron Letters, 1978, 1145. W. C. Still and A. Mitra, J. Amer. Chem. Soc., 1978, 100,1927. W. G. Salmond, M. A. Barta, and J. L. Havens. J. Org. Chem., 1978, 43, 790. P. R. McGuirk, A. Marfat, and P. Helquist, Tetrahedron Letters, 1978, 2973. P. R. McGuirk, A. Marfat, and P.Helquist, Tetrahedron Letters, 1978, 2465. M. Sevrin and A. Krief, Tetrahedron Letters, 1978, 187.

143

Alcohols, Halogeno-compounds, and Ethers

. ..

R'MgBr

R'

Cu(Me2S)MgBr2

)=/

P.

iii--v

+

R*o~

R4

R2

(36) 0 / \

Reagents: i, CuBr(Me,S); ii, R2C_CH; iii, LiCzCPr; iv, R'CH-CHR4;

R3

v, NH4Cl

Scheme 18

R'CH2COR2

a

R'CH2

-%RSe-&-CH2CH(OH)R3 I R2

J,iv,v

R'CH=C(R2)CH2CH(OH)R3

(37) 0

Reagents: i, 2RSeH-ZnCI,; ii, BuLi; iii, R3C/H->H,;

iv, MeI; v, base, e.g. Bu'OK-DMSO

Scheme 19

salts, thus making (37) synthetically equivalent to a vinyl anion. Selenoxide elimination was unsatisfactory in this instance as it gave both allylic and homoallylic products. An alternative route to y-hydroxyselenides from enones is shown in Scheme 20. R'CH~ R1CH2C(R2)=CHCOR4

% RSe -A-CH2C(OH)R3R4 I

R2 Reagents: i, RSeH-piperidine; ii, R3MgX

Scheme 20

A different strategy to the above 'vinyl anion'-epoxide approaches to homoallylic alcohols involves allyl anion (or equivalent) additions to carbonyl groups. A new method for the addition of allyl silanes to aldehydes and ketones (Scheme 21)

Reagents: i, R'COR2-Bu4&F(catalytic); ii, HCl-MeOH

Scheme 21

is mediated by a catalytic quantity of tetra-n-butylammonium fluoride,55 i.e. fluoride ion cleavage of the C-Si bond. This is a mild neutral alternative to the published procedure using Lewis acids. The known addition of allyl boronic esters 55

A. Hosomi, A. Shirahata, and H. Sakurai, Tetrahdron Letters, 1978, 3043.

General and Synthetic Methods

144

to aldehydes has recently been modifieds6 by use of the chiral boronates (38) to give optically active homoallylic alcohols (Scheme 22) with good enantiomeric excess, usually 65-80%.

I

Ph

R'

Reagents: i, B(CH2CR2=CH2),; ii, R'CHO; iii, N(CH,CH,OH),

Scheme 22

The syn-dianions (39) of tosylhydrazones have also been reported to act as ally1 anion equivalent^.^^ They add to carbonyl compounds to yield P-oxy-adducts that, on treatment with excess alkyl-lithium, give rise to homoallylic alcohols (Scheme 23).

, N Ts

,NHTs R

L

R

2

&CR

3 ~ 4 0 -

RZ

j1i.i"

Reagents: i, 2BuLi; ii, R3COR4;iii, MeLi; iv, H 2 0

R2

Scheme 23

The product of treatment of metallated propargyl chloride with trialkylboranes at -78 "C (Scheme 24) has been shown to lead to homopropargyl alcohols (40) if treated directly at low temperature with aldehyde^.^' However, warming to room temperature before addition of the aldehyde, again at -78 'C, yields exclusively a-allenic alcohols (41). 56

"

'*

T. Herold and R. W. Hoffmann, Angew. Chem. Internat. Edn., 1978, 17, 768. M. F. Lipton and R. H. Shapiro, J. Org. Chem., 1978,43, 1409. G. Zweifel, S. J. Backlund, andT. Leung, J. Amer. Chem. Soc., 1978, 100, 5561.

145

Alcohols, Halogeno-compounds, and Ethers

ClCH2CrCLi + R:B

ii,iiy

Li[R:BCzCCH,CI]

R' CrCCH2CH(OH)R2 (40)

qiijii

R' )=C=CH, R'CHOH

(411 Reagents: i, -78 "C; ii, R*CHO, -78 "C; iii, H202-OH-; iv, -78 "C to room temperature

Scheme 24

The reactions of unsymmetrical allylic Grignard reagents such as (42) with epoxides have recently been s t ~ d i e d . 'The ~ products are S,E- unsaturated alcohols, and normally the reaction occurs at the 'internal' ( y - ) carbon of the ally1 system to give (43) (Scheme 25), but the addition of Cur iodide reverses this regioselectivity to give the a-product (44).

. 'f

OH

R'

R' (43) 0 Reagents: i, R'CHGCHR2;

(42)

(44)

0 / \ ii, R'CH-----CHR2-CuI

Scheme 25

A C-alkylation procedure for alkynols has been published6' which avoids the need to protect the hydroxy function [equation (7)] and serves therefore as a convenient route to many substituted alkynols (and, by reduction, to alkenols). I

HC=C-(C),

I

1

-C-OH

I

2LiNH2-RX

I I

1 1

RC=C-(C),-C-OH

(7)

Reactions.-A new method for the determination of absolute configuration in chiral secondary alcohols is based on the changes in chemical shifts observed in their 13Cn.m.r. spectra on glycoside formation.61Characteristic shift changes for the glycosidic carbon of the sugar, and for C-a and C-p of the alcohol, have been summarized as rules. Measurement of lanthanide-induced shifts for the CF3 resonance in the 19F n.m.r. spectra of a-methoxy-a-trifluoromethylphenylacetate (MTPA) esters of secondary alcohols has been reported6, as an 59

6o 61

62

G. Linstrumelle, R. Lorne, and H. P. Dang, Tetrahedron Letters, 1978, 4069. J. Flahaut and P. Miginiac, Helv. Chim. Acta, 1978, 61, 2275. S . Seo, Y. Tomita, K. Tori, and Y. Yoshimura, J. Amer. Chem. SOC.,1978,100, 3331. E. M. Merckx, A. J. Van der Wal, J. A. Lepoivre, and F. C. Alderweireldt, Bull. SOC.chim. belges, 1978,87,21; A. J. Van der Wal, E. M. Merckx, G. L. Lernikre, T. A. Van Osselaer, J. A. Lepoivre, and F. C. Alderweireldt, ibid., p. 545.

General and Synthetic Methods

146

improvement over the known ' H n.m.r. method for determining both absolute configuration and enantiomeric purity of the alcohols; resolution of the signals is much better. Lithium triethylborohydride has been shown to be an excellent reagent for the rapid reduction of alcohol tosylates to alkanes, even in hindrred cases.63 A comparative study on cyclohexyl tosylate marked out this reagent or the 9-BBN derivative (45) as the reagents of choice, but LiEt3BH is more readily available.

Primary alcohols can be reduced to alkanes by treatment of the derived selenides with tin hydrides (Scheme 26).64Two new methods for deoxygenation RCH20H 4RCH2SePh % RCH3 Reagents: i, PhSeCN-Bu,P; ii, Ph,SnH

Scheme 26

of sterically hindered alcohols involve radical processes, and are the lithiumdiethylamine reduction of their acetate and the sodium-ammonia reduction of N,N-dimethylsulphamoyl derivatives (Scheme 27).66 A convenient R'R2CHOH Reagents: i, NaH-Me,NSO,CI,

R1R2CHOSO2NMe2% R'R2CH2

or ( a )SO,CI,, (6) Me,NH; ii, Na-NH,

Scheme 27

reductive cleavage of benzylic (or benzhydrilic) and their ethers,68 has been reported and involves catalysed hydrogen transfer from cyclohexene [equation (S)]. ArCR'R20R3

Pd-AICI, cyclohexene

' AI-CHR'R~+ R"OH

Full details are now available69of Overman's procedures for [1,3] transposition of ally1 alcohols using the mercuric salt-catalysed [3,3] sigmatropic rearrangement of their dimethyl carbamate derivatives (Scheme 28). The evidence suggests a cyclic intermediate (46),such that the reaction may be termed as 'cyclization induced'. This sequence is rather limited in scope if employed as a preparative method for contra-thermodynamic isomerization of the allylic S. Krishnamurthy, J. Organometallic Chem., 1978, 156, 171. D. L. J. Clive, G. Chittattu, and C. K. Wong, J.C.S. Chem. Comm., 1978, 41. R. B. Boar, L. Joukhadar, J. F. McGhie, S. C. Misra, A. G. M. Barrett, D. H. R. Barton, and P. A. Prokopiou, J.C.S. Chem. Comm., 1978, 68. 66 T. Tsuchiya, I. Watanabe, M. Yoshida, F. Nakamura, T. Usui, M. Kitamura, and S. Umezawa, Tetrahedron Letters, 1978, 3365. " G. A. Olah and G. K. S. Prakash, Synthesis, 1978, 397. G . A. Olah, G. K. S. Prakash, and S. C. Narang, Synthesis, 1978, 825. 69 L. E. Overman, C. B. Campbell, and F. M. Knoll, J. Amer. Chem. SOC.,1978, 100,4822.

63

64

147

Alcohols, Halogeno-compounds, and Ethers

Scheme 28

system. Another recent report does, however, provide a mild method for such contra-thermodynamic [1,3] transpositions of primary allylic alcohols (Scheme 29)70uia the spontaneous [2,3] sigmatropic rearrangement of allylic selenoxides to selenenates followed by in situ selenenate hydrolysis (cf.the allylic sulphoxidesulphenate equilibrium). RCH=CHCH20H 4 RCH=CHCH2SeAr % RCH(OH)CH=CH2

Reagents: i, ArSeCN-Bu,P; ii, H202-H20

Scheme 29

The oxy-Cope [3,3] rearrangement of ally1 vinyl carbinols [e.g. (47) + (48)] is often complicated by the alternative pericyclic process of ‘retro-ene’ cleavage [(47) -+ (49)]. In contrast, the alkali-metal salts of these 1,5-dienols have been r e p r t e d to show marked rate enhancements of the [3,3] sigmatropic process, and this is the basis of a new route to 1,6-dicarbonyl compounds (Scheme 30).71

(X = OMe or SPh) Scheme 30

Another recently developed way to enhance the selectivity for oxy-Cope rearrangement (relative to cleavage) involves the use of N-methylpyrrolidone (NMP) as solvent for the thermolysis.’* Slight rate accelerations are observed, yields of 7” 71

72

D. L. J. Clive, G. Chittattu, N. J. Curtis, and S. M. Mechen, J.C.S. Chem. Comm., 1978, 770. D. A. Evans, D. J. Baillargeon, and J. V. Nelson, J. Amer. Chem. Soc., 1978, 100 2242. Y. Fujita, T. Onishi, and T. Nishida, ( a ) Synthesis, 1978,612; ( b )J.C.S. Chem. Comm., 1978,972; ( c ) Synrhesis, 1978, 934.

General and Synthetic Methods

148

rearrangement product are increased, and the E : Z ratio in the newly formed C-C double bond is improved. This technique has been applied to synthesis in the polyisoprenoid area [e.g. (50) --* (51)].72'

(51)

(50)

A new, high-yield version of the ester Claisen rearrangement involves selenoxide elimination in generation of the required keten-acetal system (Scheme 3 1).73Two other new applications of the Claisen rearrangement (to prepare 2 , 4 - d i e n a l ~or~ ~die none^^^ from ally1 alcohols) are outlined in Scheme 32.

PhSe'

7'

Reagents: i, PhSeBr; ii, CH,=C(Me)CH,OH-PriNH; iii, NaIO,; iv, heat

Scheme 31

R4

R'

H iji,

RR:+R,

RZ

R5WR 0

R2

R7

R2

Reagents: i, PhSCECH-NaH; ii, m-ClC6H,C0,H; iii, ZnCO,-distil; iv, RSR6C=C=C(SPh)R7-NaH

Scheme 32

Protection.-A phase-transfer method for methoxymethylation of phenols has been which avoids the need for preformation of phenolate salts and the use of anhydrous conditions. The usual reagent for methoxymethylation of 73 74 75 76

M. Petrzilka, Helv. Chim. Acta, 1978, 61,2286. R. C. Cookson and R. Gopalan, J.C.S. Chem. Comm., 1978,924. R. C. Cookson and R. Gopalan, J.C.S. Chem. Comm., 1978,608. F. R. van Heerden, J. J. van Zyl, G. J. H. Rall, E. V. Brandt, and D. G. Roux, Tetrahedron Letters, 1978,661.

Alcohols, Halogeno-compounds, and Ethers

149

alcohols, chloromethyl methyl ether, is often contaminated commercially with the carcinogenic bis(chloromethy1) ether, so that the recent appearance7' of an alternative, iodomethyl methyl ether, is welcome. It can be prepared in high yield, with no bis-halogeno-ether contamination, as shown in equation (9), and is (Me0)*CH2+ Me3SiI + MeOSiMe3 + ICH20Me

(9)

more reactive than the chloro-compound in methoxymethylations. The conditions required to remove methoxymethyl protection from hydroxy-groups can be too vigorous for some acid-sensitive functionalities whereas the newly developed t-butoxymethyl ethers (Scheme 33)78can also act as alcohol protecting groups and are cleaved with aqueous TFA at room temperature, conditions to which methoxymethyl ethers are stable. They do, however, survive some other acid treatments to allow selective removal of other acid-labile groups in their presence. Bu'OMe

Bu'OCH2CI % ROCH20Bu'

ROH

Reagents: i, NCS; ii, ROH-Et,N; iii, TFA aq., room temperature

Scheme 33

Full details have now a p p e a ~ e d ' of ~ the general method for formation of methylthiomethyl (MTM) ethers from alcohols by treatment with DMSO in acetic anhydride containing acetic acid. These authors also report their mild cleavage method of methyl iodide in moist acetone; the use of volatile reagents is advantageous as it allows easier product isolation than the previous Ag' and Hg2+ procedures. A recent study has developed the synthesis of 2-tetrahydrothienyl (THT) ethers (52) and their application to alcohol protection." The reagent used for their introduction is the stable crystalline thioacetal ester (53) which reacts smoothly with primary and secondary alcohols (Scheme 34). The THT ethers can

Reagents: i, S02C12;ii, Et,N; iii, Ph2CHC0,H-Et,N; iv, ROH-TsOH

Scheme 34

be cleaved by aqueous Hg2+under conditions that do not affect tetrahydrofurfury1 (THF) and MTM ethers; an alternative Ag'-based cleavage procedure leaves tetrahydropyranyl (THP), 2-methoxyethoxymethyl (MEM), and t-butyldimethylsilyl (TBDMS) ethers intact. Conversely, refluxing methanol removes THF and THP groups in the presence of THT ethers. An interesting 'extra' in this 77 78

79

M. E. Jung, M. A. Mazurek, and R. M. Lim, Synthesis, 1978, 588. H. W. Pinnick and N.H. Lajis, J. Org. Chem., 1978, 43, 3964. P. M. Pojer and S. J. Angyal, Austral. J. Chem., 1978, 31, 1031. C. G. Kruse, E. K. Poels, F. L. Jonkers, and A. van der Gen, J. Org. Chem., 1978,43, 3548.

150

General and Synthetic Methods

report is that the acetal esters (54)can be used in the synthesis of THF and THP ethers.

(54)n

=0

or 1

A new preparation" of trimethylsilyl ethers from alcohols employs bis(trimethylsilyl) ether, often regarded as 'inert', in the presence of pyridinium tosylate; these conditions are mildly acidic, in contrast to the more usual basic silylation media. t-Butyldimethysilyl perchlorate has been prepared [equation (lo)] and is a more reactive reagent than the corresponding silyl chloride for the Bu'Me2SiH + Ph3CC104 -+ Bu'Me2SiOC103+ Ph3CH

(10)

synthesis of TBDMS ethers from alcohols.82The related bis-(t-buty1)methylsilyl perchlorate was made in the same way, and the ethers derived from it were found to be far more stable to acid conditions than TBDMS or THP ethers. 1,2-Diols-The osmium tetroxide-catalysed uic-hydroxylation of alkenes to provide cis- 1,2-diols, using t-butyl hydroperoxide in a basic medium (tetraethylammonium hydroxide) to recycle Osvl to Osvl", itself an advance over earlier methods, has been further improved by eliminating the need for strongly basic conditions. It has been reporteds3 that tetraethylammonium hydroxide may be replaced by the corresponding acetate if the solvent is simply changed from t-butyl alcohol to acetone, and that base-sensitive groups such as esters can survive the new conditions. High stereoselectivity €or the d,l product diastereomer has been found in the photochemically induced pinacol-type coupling of aldehydes by tristannanes (Scheme 35).84The stannadioxolans (55) produced may be worked-up with acetyl chloride (or trimethylsilyl chloride) to give derivatives of 1,2-diols.

H

R.

(Me3Sn)$3nEtz + 2RCHO

hv

H

H

H

R.

R

MeCOCl

H

b

w

R

____*

__+

0,

Sn' Et 2

0

OAc OAc

(55) Scheme 35

Baker's yeast is reported8' to reduce asymmetrically the a-keto-phosphates (56), easily prepared from the readily available a-halogeno-ketones; reductive removal of the phosphate function (Scheme 36) yields diols with a wide range of

83 84

8s

H. W. Pinnick, B. S. Bal, and N. H. Lajis, Tetrahedron Letters, 1978, 4261. T. J. Barton and C. R. Tully, J. Org. Chem., 1978, 43, 3649. K. Akashi, R. E. Palermo, and K. B. Sharpless, J. Org. Chem., 1978,43, 2063. C. Grugel, W. P. Neumann, J. Sauer, and P. Seifert, Tetrahedron Letters, 1978, 2847. A. Pondaven-Raphalen and G . Sturtz, Bull. SOC.chim. France II, 1978, 215.

15 1

Alcohols, Halogeno-compounds, and Ethers

t o

0 X,& X= halogen

+

OH

(RIO),PAR

3

H

AR

O

(56)

Reagents: i, baker's yeast; ii, LiAlH,

Scheme 36

optical purities depending on the substituents. An efficient synthesis of enantiomeric pairs of 1,2-diols from an optically active a-hydroxy-acid has been published (e.g. Scheme 37).86

CO,H HO+H CH ,Ph

i-y \

C0,H TsO+H

LHo$' H OH

CH,Ph

CO,Et HO+H CH,Ph

Reagents: i, PhCH,OH-H';

R

CH,Ph

--%

"$. HO

H

CH,Ph

ii, TsCl; iii, debenzylation; iv, RLi (excess); v, EtOH-H'

Scheme 37

2 Halogeno-compounds Preparation.-Primary alcohols react only sluggishly with dimethyl phosphoramidic dichloride (57) at room temperature, but they have been shown8' to be transformed to the chlorides in excellent yields in 1,2-dimethoxyethane under reflux. Tertiary alcohols are dehydrated, however, and secondary cases produce mixtures. 0

II

Me2NPCI2

(57)

Trimethylsilyl iodide is known to convert alcohols into iodides but is very sensitive to hydrolysis, so some new mild methods have been developed" for the in situ generation of this reagent under neutral conditions. The reaction of allyltrimethylsilane and iodine does generate Me3SiI, but the ally1 iodide byproduct is not compatible with the presence of nucleophilic groups. A better solution is to use the bisallylic silane (58) and iodine (Scheme 38), where the other product is benzene.88 Trimethylsilyl bromide, although much less electrophilic "

*'

S. Terashima, M. Hayashi, C. C. Tseng, and K. Koga, Tetrahedron Letters, 1978, 1763. H.-J. Lin, W. H. Chan, and S. P. Lee. Chem. Letters, 1978, 923. M. E. Jung and T. A. Blumenkopf, Tetrahedron Letters, 1978, 3657.

152

General and Synthetic Methods

0

Li-Me3SiCI

M e 3 S io S i M e 3

-%

0

+ 2Me3SiI

(58)

Scheme 38

than the iodide (for example, it does not cause ester or ether dealkylation under mild conditions), has been shown to convert alcohols into their bromides [equation (1l)],with predominant inversion at carbon.89 Me3SiBr+ ROH -+ RBr + Me3SiOH

(1 1)

N- Alkyltrifluoromethanesulphonimides(59) are reported to give alkyl iodides in synthetically useful yields on treatment with KI in HMPA as ~olvent.’~ RN(S02CF3h (59)

S- Alkylation of allyl dithiocarbamates (60) leads eventually to allyl iodides in excellent yields (Scheme 39),91with precipitation of salt (61) probably displacing the equilibria. The iodides, which are sentive to light and heat, may be converted into the allyl chlorides by exchange with lithium chloride in DMF.

SMe

(61)

Scheme 39

‘Anti-Markovnikoff’ hydrohalogenation of alkenes can be achieved by reaction of the organopentafluorosilicate adducts (62) with cupric halides,92 molecular halogens,93or N- brorno~uccinimide,~~ to produce chlorides or bromides (Scheme 40). In a related sequence, a new method for conversion of the tetra-alkylaluminate adducts (63), from titanium-catalysed hydroalumination of alkenes, into chlorides and bromides involves treatment with the Cull halides (Scheme 41).94The low cost and ready availability of cupric halides are advantages of this procedure over the same authors’ earlier use of N- halogenosuccinimides. 89 90 91

92 y3

94

M. E. Jung and G. L. Hatfield, Tetrahedron Letters, 1978, 4483. R. S. Glass and R. J. Swedo, J. Org. Chem., 1978, 43, 2291. A. Sakurai, T. Hayashi, I. Hori, Y. Jindo, and T. Oishi, Synthesis, 1978, 370. J. Yoshida, K. Tamao, A. Kurita, and M. Kumada, Tetrahedron Letters, 1978, 1809. K. Tamao, J. Yoshida, M. Takahashi, H. Yamamoto, T. Kakui, H. Matsumoto, A. Kurita, and M. Kumada, J. Amer. Chem. SOC., 1978,100,290. F. Sato, Y. Mori, and M. Sato, Chern. Letters, 1978, 833.

153

Alcohols, Halogeno-compounds, and Ethers RCH=CH2 -% K2[RCH2CH2SiF5]--%RCH2CH2X (62) Reagents: i, HSiC1,-H,PtCl,;

ii, KF; iii, CuX,, X,, or NBS

Scheme 40

RCHzCH2

LiAIH,-TiCI,

b

LiA1(CH2CH2R)4

CUX,

RCH2CH2X

(63) Scheme 41

Vinyl Halides. A recently reported method for the production of vinyl flaorides from alkenes employs the reaction with N-bromoacetamide in the presence of HF, as an equivalent to electrophilic addition of the unstable BrF, and subsequent elimination of HBr (Scheme 42).95

Reagents: i, MeCONHBr-HF; ii, KOH

Scheme 42

1,2-Dialkylvinyl bromides have been prepared stereoselectively from 1bromo-1-alkynes by hydroboration with dialkylboranes as shown in Scheme 43.96

BrCrCR'

+ RiBH

Br -+

RiB

-

R Z PbI(OAc), Br

>=(

H

R'

R2

>=(

H

Scheme 43

Full details are now available of another versatile and highly stereoselective synthesis of vinyl bromides and chlorides from alkynes (Scheme 44).97 Conversion into either the cis- or trans-vinyl silanes is followed by trans-addition of halogen and then base-mediated trans-elimination of halogenotrimethylsilane; the overall result from vinyl silane is replacement of trimethylsilyl by halide with double-bond inversion. The enol tautomer of enolizable aldehydes has been found to react with the 2-chloro-3-ethylbenzoxazolium salt (64) and to lead, in the presence of tetraethylammonium chloride, to vinyl chlorides in good yield (Scheme 45),9*an extension of the technique developed earlier for the alcohol to chloride conversion. 95

96

"

''

L. Eckes and M. Hanack, Synthesis, 1978, 217. Y. Masuda, A. Arase, and A. Suzuki, Chem. Letters, 1978,665. R. B. Miller and G. McGarvey, J. Org. Chem., 1978, 43,4424. Y. Echigo and T. Mukaiyama, Chem. Letters, 1978, 465.

General and Synthetic Methods

154 R

SiMe,

M 'H H

v,vi

R

H

R

X

H

H

- H'M 'X

i-Y R'CECH y i i i

R

H

H

SiMe,

)+

%>=(

Reagents: i, MeLi; ii, Me,SiCI; iii, BuiAlH; iv, H,SO,; v, X,; vi, NaOMe-MeOH; vii, HSiCIMe,-H,PtCl,; viii, MeMgBr

Scheme 44

Scheme 45

A general method for the conversion of vinyl bromides into iodides, with retention of geometry, is mediated by a Ni" bromide-zinc reagent.99 Reactions.-The use of NaBH4 in polar aprotic solvents as a convenient and effective source of riucleophilic hydrogen for the reduction of alkyl halides (and tosylates) to alkanes has been reported in fullloothis year. This reagent is selective and does not affect other functional groups such as ester or nitrile (contrast LiAIH4). Sodium trimethoxyborohydride is an alternative, especially for reduction in the presence of alkene functions; this report also includes details of a 'one-pot' sequence from alcohols via the iodides to alkanes (Scheme 46).loo ROH

RI % RH

Reagents: i, Mei'(OPh),i; ii, NaBH,-HMPA

Scheme 46

The efficiency of halide to alkane reductions with the less selective LiA1H4can be improved by addition of either stoicheiometric or catalytic quantities of some 99 loo

K. Takagi, N. Hayama, and S. Inokawa, Chem. Letters, 1978, 1435, R. 0.Hutchins, D. Kandasamy, F. Dux, C. A. Maryanoff, D. Rotstein, B. Goldsmith, W. Burgoyne, F. Cistone, J. Dalessandro, and J. Puglis, J. Org. Chem., 1978, 43, 2259.

Alcohols, Halogeno-compounds, and Ethers

155

transition-metal halides, especially Ni" chloride. lo' Reagents mentioned earlier in this Report that reduce halides include Li4C~Hs,1sMgH2,I6 and resinsupported cyanoborohydride," and another new reagent is the vanadium complex (65).lo2 Two report^^^^,'^^ have appeared in which it has been demonstrated that the polymeric insolubilized HMPA derivative (66) acts as a good catalyst for reactions between two liquid phases (i. e. liquid-solid-liquid triphase catalysis) such as the treatment of organic bromides with aqueous metal chlorides and iodides (for halide interconversion) or other nucleophiles. In contrast to the 'onium' ions and crown compounds, (66) is a more efficient catalyst than its soluble equivalent (67);lo3it can also be used with 18-crown-6 as an additional catalyst for solid-liquid phase transfer in the same reactions (i.e. a solid-liquid-solid triphase mode).lo4

(65)

(67)

(66)

The oxidative displacement of iodine from iodides by reaction with m-chloroperbenzoic acid has been discussed in two recent publications. 105~106Good yields of alcohols, 1 o s ~ 1 0 6or their methyl ethers,Io6 could be obtained in primary cases; mixtures resulted from secondary iodides.

3 Ethers Preparation.-Routes to primary alkyl methyl ethers from iodides,lo6 and to allylic methyl ethers from a l k ~ n e s , ~have * been mentioned elsewhere in this Report. An efficient new route for the reductive cleavage of acetals to methyl ethers involves sodium cyanoborohydride in acid [equation (12; a)].1o7The same type of process can also be performed on the acetals of aliphatic aldehydes and ketones using what is believed to be a Tiospecies [equation (12; b)].'08 R'CH(OR2)*A R1CH20R2

(12)

( a ) R2 = Me, Reagent: i, NaBH,CN-HCl(g)-MeOH ( b ) Reagent: i, TiCI4-2LiAIH4

Reactions.-Dialkyl ethers may be cleaved to the two alkyl bromides [equation (1 3)] by aqueous HBr under phase-transfer Aryl alkyl ethers react + R10R2+ 2HBr(aq.) BU3PC16H33BrR'Br + R2Br+ H 2 0 (13)

,

E. C. Ashby and J. J. Lin, J. Org. Chem., 1978,43, 1263. R. J. Kinney, W. D. Jones, and R. C. Bergman, J. Amer. Chem. SOC.,1978,100, 7902. lo3 M. Tomoi, M. Ikeda, and H. Kakiuchi, Tetrahedron Letters, 1978, 3757. '04 S. L. Regen, A. Nigam, and J. J. Besse, Tetrahedron Letters, 1978, 2757. H. J. Reich and S. L. Peake, J. Amer. Chem. SOC.,1978, 100, 4888. lo6 R. C. Cambie, B. G. Lindsay, P. S. Rutledge, and P. D. Woodgate, J.C.S. Chem. Comm., 1978,919. lo' D. A. Horne and A. Jordan, Tetrahedron Letters, 1978, 1357. H. Ishikawa and T. Mukaiyama, Bull. Chem. SOC.Japan, 1978, 51, 2059. lo9 D. Landini, F. Montanari, and F. Rolla, Synthesis, 1978, 771.

156

General and Synthetic Methods

under these conditions, but give the phenol and alkyl bromide; they can also be dealkylated by a trimethylsilyl chloride-sodium iodide combination (Scheme 47)."O ArOR

+;H20 RI + ArOSiMe3 % ArOH +&(Me3Si)20

Reagents: i, Me,SiCI-NaI; ii, H,O

Scheme 47

A new reagent in the ether cleavage area is 9-bromo-9-BBN (68) [equation (14)].'" Tertiary alkyl groups on the ethers are converted into their bromides more readily than secondary or primary groups. R'ORZ

+

Br-B(D-+ (68)

R'Br -I- R Z O - B a

(14)

Full details are now available of the oxidative cleavage of ethers by uranium hexafluoride.'12 An interesting new mild method of oxidative removal of p methoxybenzyl ethers (used as alcohol protecting groups) employs as an electrontransfer reagent the stable cation radical (69),'13 used either stoicheiometrically or in catalytic quantities, and regenerated electrochemically during the reaction (Scheme 48). ROCH2Ar+ (4-BrC6H4)&

$

( ~ - B T C ~ H+~[ROCH2Ar]+' )~N

11HZO

(69)

ROH + ArCHO + H+

ROCHAr ,-I

(69)

ROCHAr + H 3 0 C

Ar = 4-methoxyphenyl Scheme 48

The contribution of ether rearrangements, such as the Claisen and Wittig processes, to asymmetric synthesis has been reviewed.24 A new type of Claisen rearrangement of ally1 ethers is illustrated in Scheme 49;'14 the presumed 1,3-dipolar intermediates (70) arise from addition of the ether oxygen to dichloroketen prepared in situ. RZ

r

Scheme 49 'lo

"' '13

'I4

T. Morita, Y. Okamoto, and H. Sakurai, J.C.S. Chem. Comm., 1978, 874. M. V. Bhatt, J. Organometallic Chem., 1978, 156, 221. G. A. Olah and J. Welch, J. Amer. Chem. SOC., 1978, 100, 5396. W. Schmidt and E. Steckhan, Angew. Chem. Internat. Edn., 1978,17, 673. R. Malherbe and D. Bellus, Helv. Chim. Acra, 1978,61, 3096.

Alcohols, Halogeno-compounds, and Ethers

157

4 Thiols and Thioethers

General.-Attention this year has been focused on thioethers rather than thiols, and this is reflected in the content of this section. In an updating of an earlier review, some recent developments in synthetic organosulphur chemistry since 1970 have been surveyed."' Preparation.-It has recently been shown that the reaction of lithium triethylborohydride with elemental sulphur in THF in the correct proportions [equation (15)] produces a solution believed to contain lithium sulphide, and which reacts with alkyl halides RX to give the dialkyl sulphides R2S in high yields.' l6 Commercially available Li2S is insoluble in THF, so the triethylborane produced here must play a role. S + 2LiEt3BH

-B

Li2S + 2Et3B + H2

(15)

Another route to symmetrical dialkyl sulphides, from alkyl methyl sulphides and the corresponding alkyl halides by demethylation of the intermediate sulphonium salts with halide ions, has been disclosed (Scheme 50).'17 In the same MeSCH2R + RCH2Br

5

[(RCH2)2SMeBr-1 -+ (RCH2)2S

Scheme 50

report unsymmetrical methyl (or ethyl) alkyl thioethers were shown to be available from alkyl halides or sulphonium salts by reaction with excess methyl (or ethyl) sulphide (Scheme 51). Both of these sequences use non-basic reaction conditions. R1R2CHBr

2 [R1R2CHiMe2Br-]

-+ R'R2CHSMe

Scheme 51

Once again the reduction of sulphoxides to sulphides has received attention. Two publications, '18*119 one a full account of an earlier communication,l" have appeared on the application of phosphorus pentasulphide as a mild and cheap solution to this problem. The driving force for this deoxygenation is presumably formation of the strong P-0 bond, and this is the basis also of the use of the triphenylphosphine-iodine complex.'2o A more effective method than this latter combination involves tris(dimethy1amino)phosphine and iodine;'*' the byproduct here, HMPA, is water soluble and hence easily removed. Sodium iodide is added with both of these reagent systems and has a marked catalytic effect. Other new reducing agents reported this year include hexamethyldisilthiane '15 'I6

'" 11*

L. Field, Synthesis, 1978, 713. J. A. Gladysz, V. K. Wong, and B. S. Jick, J.C.S. Chem. Comm., 1978, 838. A. J. H. Labuschagne, J. S. Malherbe, C. J. Meyer, and D. F. Schneider, J.C.S. Perkin I, 1978,955. I. W. J. Still, S. K. Hasan, and K. Turnbull, Canad. J. Chem., 1978, 56, 1423. R. D. Baechler and S. K. Daley, Tetrahedron Letters, 1978, 101. G. A. Olah, B. G. B. Gupta, and S. C. Narang, Synthesis, 1978, 137. G. A. Olah, B. G. B. Gupta, and S. C. Narang, J. Org. Chem., 1978, 43,4503.

General and Synthetic Methods

158

[(Me3Si)2S]’22and Ti” produced in situ from titanium tetrachloride and zinc dust. 1 2 3 Reactions.-Further publications 124-’27 have appeared on the [2,3] sigmatropic rearrangements of allylsulphonium ylides (71)in connection with ring-expansion processes (Scheme 52). For sulphonium allylides (71; R = CH=CH,), compet-

(71) R = C02Et, CH=CH2, o r alkyl Reagents: i, RCH’X; ii, base

Scheme 52

ing formation of the thermodynamically favoured endocyclic ylide (72), and hence of the alternative [2,3] shift product (73), is a problem in some cases, but can be reduced by kinetic deprotonation to (71) with lithium di-isopropylamide at low temperature^.'^^ An extension to unstabilized ylides (71; R = alkyl), however, requires equilibrating conditions to achieve formation of the exocyclic ylide. 12’

5 Macrocyclic ‘Crown’ Polyethers and Related Compounds

The period under review has been to some extent one of consolidation in the field of crown compounds, with the publication in detail by Cram (see later) of much of his work previously available only in preliminary form. Two review articles, one from the Cram group on the design of complexes between synthetic host molecules and organic guests,128 and one from the Strasbourg group on the chemistry of macropolycyclic inclusion complexes c crypt ate^'),'^^ serve as good introductions to the newcomer in this area. Once again it is the intention in this Report to highlight new developments in synthesis and application of crown molecules rather than detail all the studies published recently.

’’’ 123

’‘

H. S . D. Soysa and W. P. Weber, Tetrahedron Letters 1978, 2 3 5 . J. Drabowicz and M. Mikolajczyk, Synthesis, 1978, 138. E. Vedejs, J. P. Hagen, B. L. Roach, and K. L. Spear, J. Org. Chem., 1978, 43, 1185. E. Vedejs, M. J. Mullins, J. M. Renga, and S . P. Singer, Tetrahedron Letters, 1978, 519. E. Vedejs, M. J. Arco, D. W. Powell, J. M. Renga, and S . P. Singer, J. Org. Chem., 1978,43,4831. V. Cere, C. Paolucci, S . Pollicino, E. Sandri, and A. Fava, J. Org. Chem., 1978, 43, 4826. D. J. Cram and J. M. Cram, Accounts Chem. Res., 1978, 11, 8. J.-M. Lehn, Accounts Chem. Res., 1978, 11.49.

159

Alcohols, Halogeno-compounds, and Ethers

Synthesis.-A general synthesis of substituted and unsubstituted crown ethers has been developed13' that proceeds directly from polyethylene glycols in the presence of sulphonyl chlorides and base [equation (16); X = OCHR'CHR20],

diohxfboh@Om xvd/o

HO

Reagent: i, ArS0,CI-NaOH

(16)

OH

thus avoiding the necessity of pre-preparing derivatives carrying sulphonate (or halide) leaving groups. The same principle of in situ sulphonation-cyclization has been applied to the synthesis of N-alkyl-mono-aza-crown ethers [equation (16); X=NR],13' whilst a similar idea, the 'one-pot' reaction of dihalogeno- (or ditosy1)-polyethylene glycol derivatives with sodium toluene-p-sulphonamide, has also been used in aza-crown preparation [equation ( 17)].132Moderate yields in this latter sequence are compensated by the simplicity of the process and lack of necessity for high dilution conditions.

Po-0-

X(CH2CH20)2CH2CH2X+ NaNHTs + TsN

NTs

(17)

Applications to Phase-transfer and Related Methods.-The synthesis of vinylidene crowns, such as methylene-16-crown-5 (74),opens a new avenue to funtionalized crown m01ecules;'~~ for example, after hydration (74)can lead to the new immobilized crown (75)that acts as a phase-transfer (PT)catalyst in the halogen exchange of 1-bromo-octane with KI.

(74)

(75)

A comparison between the F T catalytic activity at the solid-liquid interface of Aliquat 336 (a quaternary ammonium salt) and 18-crown-6, for the reaction of alkyl halides and the solid potassium salts of several nucleophilic anions, has shown that, whereas for cyanide ion the crown compounds were more efficient, in the other cases investigated the quaternary salt was as good as, or better than, a crown ether.'34 The extra flexibility with quaternary salts in that selection of a particular catalyst for a particular cation is not necessary is one of the reasons that makes them the PT catalysts of choice in the opinion of these authors. K. Ping-Lin, M. Miki, and M. Okahara, J.C.S. Chem. Comm., 1978, 504. P.-L. Kuo, M. Miki, I. Ikeda, and M. Okahara, Tetrahedron Letters, 1978, 4273. 132 W. Rasshofer and F. Vogtle, Annalen, 1978, 552. 133 M. Tomoi, 0. Abe, M. Ikeda, K. Kihara, and H. Kakiuchi, Tetrahedron Letters, 1978, 3031. 134 M. C. Vander Zwan and F. W. Hartner, J. Org. Chem., 1978,43,2655. 130

13'

General and Synthetic Methods

160

Anhydrous sodium or potassium carbonates have been shown to act as efficient strong bases in solid-organic liquid two-phase systems in the presence of crown this by-passes the requirement for concentrated aqueous hydroxide solutions in the equivalent liquid-liquid techniques. Among the reactions possible with this new method are the alkylation of active methylene compounds, the Williamson ether synthesis, and the Darzens reaction. 135 A study of the synthesis and properties of the tris-cyclohexyl cryptand (76) has been reported'36 in an effort to determine whether the greater enforced separation of any included metal cation from its counter-anion would influence the PT catalysis activity. The results are not clear-cut, owing presumably to the intervention of other factors, but seem to show increased anion nucleophilicity at least in the case of complexed KI.

The macrocyclic formals (77) have been prepared (from polyethylene glycols and paraformaldehyde) but are shown t o be in general less effective P T catalysts than the corresponding crown ether^'^' for the reaction of solid metal acetates with 1-bromobutane. Their ready decomposition with acid, and subsequent extractive removal, might conceivably be an advantage in some circumstances. A general, high-yield procedure for the specific conversion of primary into secondary amines uia the crown-catalysed PT alkylation of their trifluoroacetamides has been developed (Scheme 53).138Recent studies indicate that secondary amines can be acylated selectively in the presence of primary amines (both as their salts) with the addition of two molar equivalents of 18-crown-6 to complex the primary amine salt preferentially. 139 R'NH2 + R'NHCOCF3

% R'R2NCOCF3 %

R'R2NH

Reagents: i, KH-THF-18-crown-6; ii, R'X; iii, KOH-MeOH

Scheme 53 135

136 13'

13'

M. Fedorynski, K. Wojciechowski, Z. Matacz, and M. Makosza, J. O r g . Chem., 1978, 43,4682. D. Landini, F. Montanari, and F. Rolla, Synthesis, 1978, 223. Y. Kawakami, T. Sugiura, and Y. Yamashita, Bull. Chem. SOC.Japan, 1978, 51, 3053. J. E. Nordlander, D. B. Catalane, T. H. Eberlein, L. V. Farkas, R. S. Howe, R. M. Stevens, N. A. Tripoulas, R. E. Stansfield, J. L. Cox, M. J. Payne, and A. Viehbeck, TetrahedronLetters, 1978,4987. A. G. M. Barrett and J. C. A. Lana, J.C.S. Chem. Comm., 1978, 471.

Alcohols, Halogeno-compounds, and Ethers

161

The potential of the polar cavity of macrocyclic ionophores such as (78) to stabilize polar transition states by electrostatic interaction has been suggested14' as an explanation for the catalytic effect of (78) on the aminolysis of p - nitrophenyl acetate by butylamine.

The crown ethers (79) catalyse transacylation reactions of o-amino-ester salts (80),I4l presumably with the crown ring acting as a binding site and the thiol

groups as the catalytic sites. Maximum rate increases were found in those cases where models indicate that complexation brings the ester C=O and the SH group into closest proximity. In a closely related application the chiral crown ethers (8 la), with chiral sulphhydryl side-chains derived from L-cysteine, bring about preferential thiolysis of dipeptide esters with large rate accelerations of the acyl transfer High chiral discrimination is also observed between enantiomeric dipeptide esters; for example the enantiomer of (82) derived from L-phenylalanine reacts 50-90 times faster than its antipode. The NADH model (81b)

(81) a; X = CONHCH(CH2SH)C02Me

140

141 142

(82)

R. D. Gandour, D. A. Walker, A. Nayak, and G. R. Newkome, J. Amer. Chem. SOC., 1978, 100, 3608. T. Matsui and K. Koga, Tetrahedron Letters, 1978, 1115. J.-M. Lehn and C. Sirlin, J.C.S. Chem. Comm., 1978, 949.

162

General and Synthetic Methods

shows accelerated hydrogen transfer to pyridinium salts such as (83),'43and all these results are interpreted as due to intracornplex reactions in a pre-formed complex.

I

(CH2),AH3

2BFi

(83)

Full papers have appeared from the Cram group covering the synthesis of macrocylic polyethers with cavities shaped by or chiral binaphthyl units [e.g. (84) and (85a)], and the chiral recognition properties of host types (84) and (85) for a-amino-acid and ester s a l t ~ . ' ~ ~The - ' ~ total ~ resolution of amine and a-amino-ester salts by chromatographic methods, either liquid-liquid with ligands of type (85a) in the mobile phase or solid-liquid with similar hosts attached covalently to silica gel, has also been published in detail.'49

(84)

( 8 5 ) a; X

=

Y

=

CH20CH2

The novel chiral macrotricyclic ligand (86) has been prepared and evidence for the existence of two complexation processes, direct binding of

143

144

145

146

14'

'41

'41

J.-P. Behr and J.-M. Lehn, J.C.S. Chem. Comm., 1978, 143. D. J. Cram, R. C. Helgeson, K. Koga, E. P. Kyba, K. Madan, L. R. Sousa, M. G. Siegel, P. Moreau, G. W. Gokel, J. M. Timko, and G. D. Y. Sogah, J, Org. Chem., 1978, 43,2758. D. J. Cram, R. C. Helgeson, S. C. Peacock, L. J. Kaplan, L. A. Domeier, P. Moreau. K. Koga, J. M. Mayer, Y. Chao, M. G. Siegel, D. H. Hoffman, and G. D. Y. Sogah, J. Org. Chem., 1978,43,1930. J. M. Timko, R, C. Helgeson, and D. J. Cram, J. Amer. Chem. Soc., 1978, 100, 2828. E. P. Kyba, J. M. Timko, L. J. Kaplan, F. de Jong, G. W. Gokel, and D. J. Cram, J. Amer. Chem. SOC., 1978,100,4555. S. C. Peacock, L. A. Domeier, F. C. A. Gaeta, R. C. Helgeson, J. M. Timko, and D. J. Cram, J. Amer. Chem. SOC.,1978, 100, 8190. L. R. Sousa, G. D. Y. Sogah, D. H. Hoffman, and D. J. Cram, J. Amer. Chem. SOC.,1978,100,4569. J.-M. Lehn, J. Simon, and A. Moradpour, Helv. Chim. Acta, 1978, 61, 2407.

Alcohols, Halogeno-compounds, and Ethers

163

primary alkylammonium ions by the aza-crown rings or initial crown-type metal cation complexation followed by accommodation of a molecular anion in the central cavity. In both cases weak resolution of chiral substrates has been observed in extraction and transport experiments.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups BY G. KNEEN

1 Amines new and improved methods for the preparation of aromatic primary amines have been described.’-’ The catalytic reduction of aromatic nitro-compounds to amines with hydrazine hydrate in the presence of iron(II1) oxide hydroxide proceeds smoothly and in high yields.’ Nitroarenes (1) react with Grignard reagents in the presence of copper(1) iodide, and are alkylated selectively on the aromatic moiety, accompanied by reduction of the nitro-group to the amine (Scheme l).2Both aryl and alkyl azides are rapidly

Primary Amines-Several

aNo2 aH2 RMgBr-Cul

____)

\

\

(1) Scheme 1

reduced in excellent yields by propanedithiol-triethylaminein methanolic solut i ~ nThe . ~ reaction is highly selective for the azido-group, and appears to offer synthetic advantages over Raney nickel reduction4 (Scheme 2). 4-Methoxyphenol is transformed into 4-methoxyaniline by successive use of thallium(II1)

ON3 CSH +

NEt,-MeOH-N,

’

SH

R

aNH2 c? S

R PhCH=CHCHZN3 + PhCHzCHCH2NH2 [60% Raney Ni, 90% HS(CH,),SH-NEt,] Scheme 2

’ T. Miyata, Y. Ishino, and T. Hirashima, Synthesis, 1978, 834. *

G. Bartoli, A. Medici, G. Rosini, and D. Tavernari, Synthesis, 1978, 436. H. Baytey, D. N. Standring, and J. R. Knowles, Tetrahedron Letters, 1978, 3633. D. Baldeman and A. Kalir, Synthesis, 1978, 24.

164

+ N2

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

165

nitrate in methanol, and ethyl glycinate, via the intermediate cyclohexadienone (2) (Scheme 3).5

Scheme 3

A novel method for the preparation of primary alkylamines from alkyl halides involves the use of N- benzylhydroxylarnine.6 N- Alkylation followed by treatment with 2-fluoro- 1-methylpyridinium toluene-p-sulphonate yields the imine (3), which can be hydrolysed to amine (4)and benzaldehyde (Scheme 4). PhCH2NHOH + RX

PhCH2NOH

I

R J.ii

PhCHO+RNH2

(3)

(4) Reagents: i, NEt,, Et,N'I--HMPA;

ii,

PhCH=NR

f&

,NEt,-CH,CI,;

iii, aq.HCI-THF

F

Scheme 4

Alkyl(imido)nickel(II) complexes (5) have been prepared by the reaction of dialkylnickel(I1) complexes with phthalirnide.' Although the complexes (5) have high thermal stabilities, they react with alkyl and aryl halides to give N- alkyl- or N- aryl-phthalimides which can easily be converted into the corresponding amines in good yields {Scheme 5).

om

PhCH2N

/

L=abipy

N i M e f D ] L 2 0

O l PhCHzNH2

(5)

A,P

h

z / m

" 1 PhNH;?

Reagents: i, PhCH,Br, 80 "C, 24 h; ii, PhBr, 120 "C, 1 h

Scheme 5 E. C. Taylor, G. E. Jagdmann, jun., and A. McKillop, J. Org. Chem., 1978,43,4385. ' T. Mukaiyama, T. Tsuji, and Y. Wanatabe, Chem. Letters, 1978, 1057. T.Kohara, T. Yamamoto, and A. Yamamoto, J. Organometallic Chem.. 1978,154, C37.

General and Synthetic Methods

166

A new method for the facile a-alkylation of primary amines utilizes the easily prepared and little exploited N-sulphinylamines (6).8Successive treatment of (6) with base and an allylic halide provides a new sulphinylamine, e.g. (7), which is hydrolysed to the free primary amine during aqueous work-up (Scheme 6). It is suggested that alkylation occurs on sulphur, and that a subsequent 3,3-sigmatropic shift provides (7).

I '

RCH2NH2 A RCH,N=S=O

-+ RCHNH2

CH2CH=CH2

(6) (7) Reagents: i, SOCI,; ii, Li' T P h , ; iii, &BI

Scheme 6

Diphenyl sulphide reacts with anhydrous chloramine-T to give an adduct (8), which is a useful reagent for the amination of olefins (Scheme 7).9 The osmiumcatalysed oxyamination of olefins by chloramine-T has been improved by phasetransfer catalysis," and the stereospecific vicinal oxyamination of olefins by alkylimido-osmium compounds has been reported. * '

0

+

Ts Phi-NSPh I

--+

N Ts

I

PhS=NTs

Scheme 7

A new synthesis of the hitherto not easily prepared silylated 2-nitro-alcohols (9) from nitroalkanes has allowed the development of an efficient route to 2-amino-alcohols by reduction with lithium aluminium hydride (Scheme S)." Two syntheses of y-amino-alcohols have added significantly to the * '0ne,I3 ~ the methodology available for the preparation of such c ~ m p o u n d s . ' ~In known reduction of the readily available 2-isoxazolines (10) to y-amino-alcohols

lo

l2 l3

l4

F. M. Schell, J. P. Carter, and C. Wiaux-Zamar, J. Amer. Chem. SOC.,1978,100,2894. D. H. R. Barton, M. R. Britten-Kelly, and D. Ferreira, J.C.S. Perkin Z, 1978, 1682. E. Herranz and K. B. Sharpless, J. Org. Chem., 1978, 43, 2544. D. W. Patrick, L. K. Truesdale, S. A. Biller, and K. B. Sharpless, J. Org. Chem., 1978,43, 2628. E. W. Colvin and D. Seebach, J.C.S. Chem. Comm., 1978,689. V. Jager, V. Buss, and W. Schwab, Tetrahedron Letters, 1978, 3133. H. V. Secor and E. B. Sanders, J. Org. Chem., 1978,43, 2539.

167

Amines, N-itriles, and Other Nitrogen-containing Functional Groups + / OSiMe, R'CH=N \

i7Y R1CH,NO2

R3 R't-(0-

R

'

4

2

R 2\NH2

iv,v

+

R'

Me3Si0

0-

3

HO

R'

(9)

NO2

viii

--+

RL

R3

R4

> (NO2 ?!&

Bu'Me,SiO

Reagents: i, LiNPr,-THF; ii, Me,SiCl; iii, R*CHO-Bu,N'F-; vi, BuLi-HMPA-THF; vii, R3COR4;viii, Bu'Me,SiCI

R'

R3

R4

) {NH,

HO

R'

iv, LiAlH,; v, sat. aq. Na,SO,;

Scheme 8

(11)has been improved to allow a versatile 'diastereoselective' synthesis with two and three chiral centres. In the other new synthesis of y-amino-alcohols (13) use is made of readily available P-keto-esters as starting materials. l4 Nitrogen functionality cannot be introduced via oxime formation since the intermediate oximino-ester spontaneously cyclizes to an isoxazolone. The use of the alkoximino-esters (12) circumvents this problem.

R2 R1&'R3

+ 0 e N=C-R4

In a similar vein, a sodium boro hydride-trifluoroacetic acid combination has proved to be a useful reducing agent for the conversion of alkoximes (14) into

General and Synthetic Methods

168

primary amines (15) (Scheme 10).15N- Phosphinyl-aldoximes and -ketoximes are also reduced with sodium borohydride.16 The full paper on the o-benzylation, o-formylation, and o-vinylation of anilines is welcomed." Ph >NOM~ Me

NaBH,-TFA

Ph

Me

(15)

(14) Scheme 10

Secondary Amines.-An efficient general procedure has been developed for the Gabriel-like transformation of primary into secondary amines.I8 High yields of secondary amines are produced, following saponification, when N- alkyl- or N- aryl-trifluoroacetamides (16) are primary-alkylated in THF using potassium hydride as base and 18-crown-6 as catalyst (Scheme 11). R2

R ' N H , --+ R ~ N H C O C F , L R ~ N C O C F , --%

(16)

\ /

R2 NCOCF, --%

R'

\ /

NH

R'

Reagents: i, KH-THF-18-crown-6; ii, R'X; iii, KOH-MeOH

Scheme 11

Two closely related procedures for the synthesis of methylamines from alkyl halides have been reported. 19*20 The reactions involve metallation of either dimethylamides (17)19 or (18)20and quenching of the anion with an alkyl halide, followed by removal of the protecting groups. Me

R'CONMe2

b

R'CON

/

----+ H N /Me

[:a-

(17) R' =Ph3C

(18) R'=

. ..

\CH2R2

\CH2R2

Reagents: i, Bu'Li; ii, R2X

Scheme12 l5 l6

l7 l8

l9

*'

N. Umino, T. Iwakuma, M. Ikezaki, and N. Itoh, Chem. and Pharm. Bull. (Japan), 1978,26,2897. B. Krzyzanowska and W. J. Stec, Synthesis, 1978, 521. P. G. Gassman and H. R. Drewes, J. Amer. Chem. Soc., 1978,100,7600. J. E. Nordlander, D. B. Catalane, T. H. Ebertein, L. V. Farkas, R. S. Howe, R. M. Stevens, N. A. Tripoulas, R. E. Stansfield,J. L. Cox, M. J. Payne, and A. Viehbeck, Tetrahedron Letters, 1978,4987. R. von Schlecker, D. Seebach, and W. Lubosch, Helv. Chim. Actu, 1978, 61,512. T. Hassel and D. Seebach, Helv. Chim. Acta, 1978,61, 2237.

A m ines, Nitriles, and Other Nitrogen-conta ining Functiona 1 Groups

169

A simple, high-yield conversion of imidoyl chlorides into imines (19) and arnines (20) utilizes the [HFe(CO),]- ion.21The use of excess reagent allows the conversion of (19) into (20). R'

>NR~

c1 R' R2

= =

Fe(CO)5-Na/Hg

R1

THF-AcOH/H,O

H

>NR~

+

RTH~NHR~ (20)

(19)

aryl aryl, alkyl

Scheme 13

Aminomercuration of double bonds by aromatic amines is easily performed by using an aqueous solvent; no oxymercuration occurs.22 The reaction is general and regiospecific in that terminal olefins yield N-alkylanilines. Trimethylsilyl iodide has been found to be a useful reagent for the conversion of simple dialkyl carbamates into the corresponding amines under mild, nonaqueous conditions.23

Tertiary Amines.-The reaction of aliphatic secondary amines (21)with sodium borohydride in liquid carboxylic acids proceeds smoothly at 50-55 "C to afford tertiary amines (22) (Scheme 14).24The reaction is sluggish for hindered amines. R'

\ /

NH

+ R3C02H

50-55

R2 (21)

R'\

NaBH,

OC

NCH,R3

R2/

(22) Scheme 14

The utility of sodium borohydride in polar aprotic solvents for the reductive removal of alkyl groups from quaternary ammonium salts has been demonstrated.25Treatment of a primary or secondary amine with excess methyl iodide in dimethyl sulphoxide followed by reduction, without prior isolation of the intermediate quaternary salt, gives tertiary amines in high yields (Scheme 15). Ar

Ar

ArNHR -$

R

=

H or alkyl

\N'Me2I-

R

/

-%

\NMe

R

/

Reagents: i, MeI-DMSO-2,6-lutidine; ii, NaBH,

Scheme 15

22

*'

24 25

H. Alper and M. Tanaka, Synthesis, 1978, 781. M. B. Gasc, J. Perie, and A. Lattes, Tetrahedron, 1978, 34, 1943. M. E. Jung and M. A. Lyster, J.C.S. Chem. Comm., 1978, 315. G. W. Gribble, J. M. Jasinski, J. T. Pellicone, and J. A. Panetta, Synthesis, 1978, 766. R. 0. Hutchins, J. Org. Chern., 1978, 43,2259.

General and Synthetic Methods

170

Some other new methods for the reductive N-methylation of amines utilize phosphorous acid in 40% formalin,26cyanoborohydride supported on an anion exchange resin,27and the LiAlH4 reduction of the corresponding isothiocyanates in the presence of ethyl formate.28 The electrophilic amination of organometallic compounds has been achieved by the use of N,N-dialkyl-0-arysulphonylhydroxylamines29and diethylformamide dimethyl a ~ e t a l . ~ ' Olefins can be transformed stereospecifically into vicinal diamines (23) by an aminopalladation-oxidation sequence (Scheme 16) using oxidants such as Although this bromine, m-chloroperbenzoic acid, and N- brornosu~cinimide.~~ diamination procedure has limitations, the results are nevertheless useful since vicinal diamines are not easily prepared from olefins by other methods.

Scheme 16

The simply prepared cyclometallated complex (24) undergoes coupling reactions with either Grignard reagents or, better, organolithium compounds, in the presence of triphenylphosphine, yielding the o-substituted benzylamines (25) (Scheme 17).32 The reaction also proceeds smoothly with the corresponding imino- and azo-benzenes.

2 Nitriles and Isocyanides Several new reagents for the dehydration of aldoximes to nitriles have been (26), (27),and (28),33diphosphorus t e t r a i ~ c f i d e , ~ ~ r e p ~ r t e d . The ~ ~ -imidazolides ~~ 26

27 28

29 30 31

32 33 34

3s 36

D. Redmore, J. Org. Chern., 1978, 43,992. R. 0. Hutchins, N. R. Natale, and I. M. Toffer, J.C.S. Chern. Cornrn., 1978, 1088. M. J. 0.Anteunis, F. A. M. Borremano, J. Gelan. A. P. Marchand, and R. W. Allen, J. Arner. Chem. Soc., 1978, 100,4050. G. Boche, N. Mayer, M. Bernheim, and K. Wagner, Angew. Chern. Znternat. Edn., 1978,17,687. G. Eisele and G. Simchen, Synthesis, 1978, 757. J. E. Backvall, Tetrahedron Letters, 1978, 163. S.-I. Murahashi, Y. Tamba, M. Yamamura, and N. Yoshimura, J. Org. Chern., 1978, 43, 4099. G. Sosnovsky and M. Konieczny, 2. Natuforsch., 1978,33b, 1033. H. Suzuki, T. Fuchita, A. Iwasa, and T. Mishina, Synthesis, 1978, 905. G. Sosnovsky and J. A. Krogh, Synthesis, 1978, 703. G. A. Olah and Y.D. Vankar, Synthesis, 1978,702.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups P(0)

"21

171

F N PhOP(0)

(PhO)J'(O)N&

3

(26)

(27)

(28)

selenium d i o ~ i d e , ~and ' the trimethylamine-sulphur dioxide complex36 all give good yields of nitriles under mild conditions. Dichlorocarbene, generated under phase-transfer conditions, converts anti-a-hydroxy-ketoximes (29) into nitriles in good yields (Scheme 18).37

Reagents: i, CHCl,-EtOAc-40% NaOH-PhCH2N+Et3C1-, reflux 30 mins

Scheme 18

A procedure for the direct conversion of aldehydes into nitriles uses the aminimide (30), an operationally convenient alternative to the quaternization of N,N-dimethyl-hydrazone~.~* At ambient temperatures, (30) reacts with a variety of aldehydes to give the corresponding nitriles in good yields (Scheme 19).

R' H2N-NMe,

d 0

+

R ' = H or Me

Me LHfi-+kCH2CHR' he

JDH

(30) Jii

Me2NCH2CHR' + R2CN + H20c

I

OH

Me

OH

R2 = aryl or alkyl Reagents: i, propan-2-01,50 "C,3 h; ii, propan-2-01, room temp., R'CHO

Scheme 19

A new synthesis of 2,3-disubstituted succinodinitriles (31),39 from aldehydes, has overcome a number of problems associated with older syntheses. With dimethyl sulphoxide as solvent, the entire synthesis can be carried out in a single reaction pot using the appropriate aldehyde and alkyl halide, together with potassium cyanide and ethyl cyanoacetate (Scheme 20).

37

38 39

J. N. Shah, Y. P. Mehta, and G. M. Shah, J. Org. Chem., 1978,43,2078. I. Ikeda, Y. Machii, and M. Okahara, Synthesis, 1978, 301. R. V. Whiteley, jun. and R. S . Marianelli, Synthesis, 1978, 392.

172

General and Synthetic Methods

Reagents: i, DMSO; ii, R3X; iii, H20, 145 "C

Scheme 20

Two closely related syntheses of silylated cyanohydrins (32) have been reported.40*41 The reaction works well, even with hindered ketones, and the cyanohydrins (33) are liberated quantitatively from (32) upon acid hydrolysis (Scheme 21). A similar reaction is observed between @-diketones and dimethyldicyanosilane to give (34).42

R2

>o

R2xcN -

iorii

iii

R' R',R2

R'

=

aryl o r alkyl

OSiMe, (32)

XCN

R'

OH

(33) 89--39% Me

0

R2

Me

0

A R-' .

:.

4

R2 (34) Reagents: i, Me,SiCW-CH,CI,;

ii, Me,SiCI-KCN; iii, H'; vi, Me2Si(CN)2

Scheme 21

Trapping of the initially formed aluminium enolate from a,@-unsaturated ketones and diethylaluminium cyanide, with chlorotrimethylsilane-pyridine yields the corresponding silylenol ethers (35), which can be alkylated or phenylsulphenylated (Scheme 22).43 A new stereospecific synthesis44of 2-alkenenitriles (36) from 2-alkynenitriles and organocuprates overcomes problems associated with the synthesis from 1-alkynes. 2-Alkenenitriles are also liberated in good yield from the reaction of sodium sulphide with a-cyano-@-nitro-sulphones(37) (Scheme 23).45 40

41

42 43 44

45

P. G. Gassman and J. J. Talley, Tetrahedron Letters, 1978, 3773. J. K. Rasmussen and S. M. Heilmann, Synthesis, 1978, 219. I. Ryu, S. Murai, A. Shinonaga, T. Horiike, and N. Sonoda, J. Org. Chem., 1978, 43,780. M. Samson and M. Vandewalle, Synth. Comm., 1978,231. H. Westmijze, H. Eleijn, and P. Vermeer, Synthesis, 1978, 454. N. Ono, R. Tamura, J.-T. Hayami, and A. Kaji, Tetrahedron Letters, 1978, 763.

A mines, Nitriles, and Other Nitrogen -con ta in ing Fu nc tiona 1 Groups

173

Reagents: i, Et,AICN; ii, Me3SiC1; iii, PhCH,N+Me,F-, MeI-THF

Scheme 22

.

.

CuXl

LR2

R2

H

(36) 75-98%

R’, R2 = alkyl, aryl, or 1-alkenyl X = C1, Br, I, or R2 M = Li, MgCl, or MgBr R’

R3

R~.+$so,A~ NO,

CN

(37)

Na,S

R’

R3

>=( R2

CN

Scheme 23

a-Keto-nitriles are not readily available by existing methods. Aroyl chlorides react with the readily prepared thallium(1) cyanide in dry ether to give aromatic a-keto-nitriles in good yields.46 The reaction is not generally applicable to aliphatic a-keto-nitriles, since the initially formed products dimerize under the reaction conditions. The masked aliphatic a-keto-nitriles (39), however, can be synthesized by the reaction of 2-lithio-173-dithian (38) with triphenylmethyl Subsequent reaction isocyanide uia an isocyanide-metal exchange rea~tion.~’ with n-butyl-lithium and an alkyl halide yields (39). (Scheme 24).

Reagents: i, Ph,CNC, -30 “C, THF; ii, BuLi; iii, RX

Scheme 24

Reagents of the type (40) are reported to yield nitriles upon reaction with cyanide ion (Scheme 25).48 New syntheses of a-hydr~xy-nitriles,~~ a-iminonitriles,” and a-alkyl-nitrile~~’ have been developed. 46

47 48 49

50 51

E. C. Taylor, J. G. Andrade, K. C. John, and A. McKillop, J. Org. Chem., 1978,43,2280. H. N. Khatri and H. M. Walborsky, J. Org. Chern., 1978,43, 734. E. S. Lewis, B. J. Walker, and L. M. Ziurys, J.C.S. Chem. Cornm., 1978, 424. T. Shono, I. Nishiguchi, and M. Sasaki, J. Arner. Chem. SOC.,1978, 100,4314. N. De Kirnpe, R. Verhe, L. De Buyck, J. Chys, and N. Scharnp, Synthesis, 1978,895. Z . H. Karneili, H. J. M. Dou, and J. Metzger, J. Org. Chem., 1978, 43, 156.

174

General and Synthetic Methods OR2 (Ph0)3P + R'X

+/ 4

(Ph0)3$R' X-

R20Hb

(Ph0)2P, \

(40) R'

L

CN-

(PhO),P(O)R'

+ R2CN

Scheme 25

Thermolysis of the iminoisoxazoles (41), prepared from nitroso-compounds and isoxazoles, yields aryl and heteroaryl isocyanides (Scheme 26).52 This reaction thus represents a synthesis of aryl isocyanides from nitroso-compounds. Ph

(41) R = aryl or heteroaryl

Scheme 26

3 Nitro- and Nitroso-compounds Alkylbenzenes are cleanly nitrated in high yields with n-butyl nitrate or acetone cyanohydrin nitrate, catalysed by a perfluorinated resin sulphonic acid (NafionH).s3The product(s) can be isolated simply by filtration of the catalyst without the need for aqueous basic work-up. A simple one-pot procedure (Scheme 27) for the reductive nitromethylation of aldehydes (42) to nitroalkanes (44) utilizes catalytic amounts of potassium fluoride in propan-2-01 in the formation of the intermediate P-hydroxynitroalkane (43), which can be acetylated and then reduced with sodium borohydride to (44).54 RCHO

+ CH3N02

(42)

RCHCH2N02

I

OH (43)

RCHCH2N02

I

OAc J iii

RCH2CH2N02 (44) 64-90% Reagents: i, KF-propan-2-01; ii, Ac,O,

Scheme 27 " 53 s4

C. Wentrup, U. Stutz, and H.-J. Wollweber, Angew. Chem. Internat. Edn., 1978,17, 688. G. A. Olah, R. Malhotra, and S. C. Narang, J. Org. Chem., 1978, 43,4628. R. H. Wollenberg and S. J. Miller, Tetrahedron Letters, 1978, 3219.

A mines, Nitriles, and Other Nitrogen -containing Functiona1 Groups

175

A synthetically useful one-step procedure for the preparation of highly branched P-arylated nitroparaffins (45)has been described (Scheme 28)." These reactions appear to proceed via a chain mechanism in which radical anions and free radicals are intermediates. Et

I

Me,CNO,Li+

-----+

Ar-C-N02

I

Et Me I I Ar-C-C-N02

I

HMPA, 25 "C

Me

I

Me Me

(45) Scheme 28

A new simple and direct .procedure (Scheme 29) for the a-acylation of nitromethane has allowed the preparation of a variety of a - n i t r o - k e t o n e ~The .~~ familiar imidazolide acylating agents (46) are easily prepared, either in situ from the carboxylic acid and 1,l-carbonyldi-imidazoleor from the acyl halide and two equivalents of imidazole.

F N I + [CH2NOz]-M+

RCON

w

(46) R

=

THF __*

RCOCH2N02 32--88%

alkyl or aryl

Scheme 29

A number of syntheses of a-nitro-olefins have been described.s7d0 In particular, one such synthesis is mild, position-selective, and widely applicable to both cyclic and acyclic nifro-olefin~.~~ For example, cyclohexene is converted into the 1-nitro-derivative (48)via the nitro-mercurial (47) (Scheme 30).

0

oNoz ii,iii

,

o N o 2

HgCl

(47) Reagents: i, HgC1,-aq.NaN0,;

(48)

ii, 2.5N-NaOH; iii, H'

Scheme 30

Benzeneseleninic anhydride is a new reagent for the oxidation of hydroxylamines to nitroso-compounds.61 Further oxidation to the nitro-group is not observed at room temperature. 55

56 57

'*

59

6o 61

N. Kornblum, S.C. Carbon, J. Widner, M. J. Fifolt, B. N. Newton, and R. G. Smith, J. Org. Chem., 1978,43,1394. D. C. Baker and S . R. Putt, Synthesis, 1978, 478. E. J. Corey and H. Estreicher, J. Amer. Chem. SOC.,1978, 100,6294. T. Severin and I. Ipach, Chem. Ber., 1978,111,692. A. J. Fete11 and H. Feuer, J. Org. Chem., 1978, 43, 497. T. Takamoto, Y.Ikeda, Y. Tachimori, A. Seta, and R. Sudoh, J.C.S. Chem. Comrn., 1978, 350. D. H. R. Barton, D. J. Lester, and S . V. Ley, J.C.S. Chem. Comrn., 1978,276.

General and Synthetic Methods

176

The treatment of (49) with hydroxylamine leads directly to Lt-methoxynitrosobenzene (SO) in 91% yield.5 The overall conversion of 4-methoxyphenol into ( S O ) (Scheme 31) can be carried out as a one-pot operation without isolation of the intermediate (49). The reaction proceeds smoothly for a variety of phenols. OH

Reagents: i, TI(NO,),-MeOH,

NO

-78 "C;ii, NH,OH-pyridine-MeOH

Scheme 31

4 Hydroxylamines A general method has been developed for the rapid, metal-catalysed, transfer reduction of nitro-compounds to N-substituted hydroxylamines.62High yields of hydroxylamines are obtained by reduction with hydrazine as hydrogen donor and a rhodium-charcoal catalyst, or alternatively using phosphinic acid as hydrogen donor and a two-phase solvent system, with a palladium-charcoal catalyst. Some hydroxylamines were too labile for isolation in a pure state and were further characterized by oxidation to the corresponding nitroso-compounds with ferric chloride. The pyridine-borane reduction of oximines has been applied to the reduction of a-oximino-esters ( 5 1) to (52) (Scheme 32).63 R1

-c-c02Et

II

NOH

pyridine-borane ethanolic HCI

R1-CH-C02Et

I

NHOH (52)

(51)

Scheme 32

5 Hydrazines An alkylation-deprotection two-step sequence offers a new approach to the synthesis of pure monoakylhydrazines from diphenylphosphinichydrazide (53).64 The phase-transfer procedure involves the use of a powdered NaOH-K2C03 mixture in refluxing benzene (Scheme 33). Although the reaction proceeds in the absence of a catalyst, a rate enhancement is observed in the presence of tetra-n-butylammonium hydrogen sulphate (TBAH). 62 63 64

I. D. Entwhistle, T. Gilkerson, R. A. W. Johnstone, and R. P. Telford, Tetrahedron, 1978, 34, 213. J. D. M. Herscheid and H. C. J. Ottenheijm, Tetrahedron Letters, 1978, 5143. B. Mlotkowska and A. Zwierzak, Tetrahedron Letters, 1978, 4731.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups 0

0

II

177

0

I/

Ph2PNHNH2 5 Ph2PNNH2 I

II

RNHNH2,2HC1 + Ph2POH

Reagents: i, RX-NaOH-K,C03-TBAH-benzene,reflux; ii, 15% HCI

Scheme 33

6 Azo-compounds

A new one-pot synthesis of azo-compounds from hydrazodicarboxylic acid esters appears to be an improvement over existing methods for the same transformation.6' Cleavage of (54) with lithium methyl mercaptide and subsequent oxidation with aqueous potassium ferricyanide at 0 "C gives the azo-compound ( 5 5 ) in 82% yield (Scheme 34). Ph

Ph

Ph

Ph

N

Reagents: i, MeS- Li'; ii, aq.K,Fe(CN),

Scheme 34

Phenols are smoothly transformed into azobenzenes (57) via the intermediate cyclohexadienones (56).' The transformation can be performed without isolation of ( 5 6 ) ,in a one-pot procedure (Scheme 35).

Reagents: i, TI(NO,),-MeOH; ii, PhNHNH,

Scheme 35

Nitrobenzenes give azobenzenes (58) in good yields (Scheme 36) by reaction with either l,l'-di-n-butyluranocene66or octacarbonyldicobalt.67 65 66

''

R. D. Little and M. G. Venegas, J. Org. Chem., 1978, 43, 2921. C. B. Grant and A. Streitweiser, jun., J. Amer. Chem. SOC.,1978, 100, 2433. H. Alper and H. N. Paik, J. Organometallic Chem., 1978, 144, C18.

178

General and Synthetic Methods

Reagents: i, [Co,(CO),]: ii, 1,l'-di-n-butyluranocene

Scheme 36

Benzeneseleninic anhydride oxidizes hydrazines to azo-compounds"8 and hydrazones to acylazo-compounds."' Azo-compounds have also been synthesized by photolysis of iminophosphoranes,69reaction of hydrazones with ally1 acetate under nickel ~atalysis,~' reaction of N- methyl-N- tosylhydrazones with a m i n e ~ and , ~ ~deoxygenation of a ~ o x y - c o m p o u n d s . ~ ~ 7 Imines

Lithium aluminium tri-t-butoxy hydride rapidly reduces imidoyl chlorides to imines under very mild condition^,^^ an improvement over previous methodology. N- Arylimines of type (61) are produced by alkylation of the dilithium aldimine (60), a versatile intermediate capable of reaction with a variety of reagents.74 Since the hydrolysis of (6 1) yields the ortho-alkyiated aniline (62), the overall reaction sequenceof Scheme 37 represents a procedure for the ortho-alkylation of anilines.

ArNH,

--*

ArNC

4

(59) liii

Reagents: i, 2Bu1Li-Et,O-TMEDA, -78 "C; ii, RI; iii, H30+

Scheme 37

69 '()

71

72 73

l4

T. G. Back, J.C.S. Chem. Comm., 1978, 278. A. S. Yim, M. H. Akhtar, A. M. Unrau, and A. C . Oehlschlager, Canad. J. Chem., 1978, 56, 289. U. Bersellini, G. P. Chiusoli, and G. Salerno, Angew. Chem. Internat. Edn., 1978, 17, 5 3 5 . N. N. Makhora, Tetrahedron,1978, 34, 413. K. G. Taylor and J. B. Sirnons, J. Org. Chem., 1978, 43, 1459. S. Karady, J. S . Amato, L. M. Weinstock, and M. Sletzinger, Tetrahedron Letters, 1978, 403. H. M. Walborsky and P. Ronman, J. Org. Chem., 1978, 43, 731.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

179

N - Allylic imines and a,@-unsaturated imines undergo facile prototropic isomerization to N-alkenylimines (63) which yield metalloenamines (64) upon reaction with t-butyl-lithium. The reaction of metalloenamines (64) with electrophiles gives imines (65) in moderate to excellent yield (Scheme 38).75The reaction is regiospecific and does not suffer the steric constraints encountered in imine deprotonation.

1_

R3 RZ,&"y'h

R3 A

R'

*

R4

R'

R'

R4

li R4

Bu'

Reagents: Bu'Li; ii, R5X

Scheme 38

Acid-catalysed breakdown of 1-azido- 1-alkylcyclopentanes (66) leads in high yield to cyclic imines (67),76which can then be hydrogenated to the corresponding piperidines (Scheme 39). Three new syntheses of ketenimines have been r e p ~ r t e d . ~ ~ - ~ ~

Reagents: i, HN,-BF,,Et,O;

ii, H,SO,-CHCI,,

0 "C; iii, H,-cat.

Scheme 39

8 Enamines An improved method (Scheme 40) for the synthesis of stabilized primary enamines (69) from P-dicarbonyl compounds utilizes the easily prepared N trimethylsilyliminotriphenylphosphorane(68).80The observation that no reac75

76 77

78 79

P. A. Wender and J. M. Schaus, J. Org. Chem., 1978,43,782. A. Astier and M. M. Plat, Tetrahedron Letters, 1978, 2051. T. Fujinami, N. Otani, and S. Sakai, J. Chem. Soc. Japan, Chem. Ind. Chem., 1978,265. C . G. Kreiter and R. Aumann, Chem. Ber., 1978,111, 1223. N. DeKimpe, R. Verhe, L. De Buyck, J. Chys, and N. Schamp, J. Org. Chem., 1978,43, 2670. J. A. Kloek and K. L. Leschinsky, J. Org. Chem., 1978, 43, 1460.

General and Synthetic Methods

180

NH, Ph,P=NSiMe,

(68)

+

I

R',R2 X

= =

V R2

X 1 ,R

0

I R 2V

X

(69)

+ Ph,PO + Me,CHOSiMe,

alkyl alkyl or alkoxy

Reagents: i, propan-2-01, p-TsOH

Scheme 40

tion takes place in the absence of propanol-2-01 suggests that the reaction proceeds by in situ generation of iminotriphenylphosphorane. Metalloenamines have found increasing use as intermediates in organic and ~ ~the asymmetric synthesis of chiral synthesis.75,81-83 The synthesis of i m i n e ~ aldehydes'' and ketone^'^'^^ using these versatile intermediates have been reported. A general synthetic route (Scheme 41) to enamine N-oxides (72) from the corresponding 2-chloroalkylamines (70) has been described.84Oxidation of (70) with rn-chloroperbenzoic acid and treatment of the so formed N-oxides (71) with base smoothly yields the unsaturated N-oxides (72). 0

0

r

t

ClHNMe2

R'

R2

R'

~

R2

H4 M e 2

R'

R2

Reagents: i, m-CIC,H,CO,H; ii, base

Scheme 41

9 Azides and Diazonium Compounds Contrary to a previous report, the ring opening of a#-epoxysulphones (73) with sodium azide in dimethylformamide does yield a -azido-aldehydes (74) in good yields.85Elaboratior. to the a-azido-nitriles (75) was performed by dehydration of the corresponding oximes (Scheme 42). Allylic azides are produced by reaction of N3H-BF3,Et20 with allylic alcohols via an ion-pair mechanism.86 Stereoselective control is achieved by choosing appropriate concentrations of hydrazoic acid. Lead tetra-acetate oxidation of semicarbazones (76) gives a-diazo-ketones in moderate yields (Scheme 43).87 82

83 84 85

86 x7

A. I. Meyers, G. S. Poindexter, and Z . Brich, J. Org. Chem., 1978, 43, 892. A, I. Meyers and D. R. Williams, J. Org. Chem., 1978, 43, 3245. S.-I. Hashimoto and K. Koga, Tetrahedron Letters, 1978, 573. J. S. Krouiver and J. P. Richmond, J. Org. Chern., 1978, 43, 2464. A. D. Barone, D. L. Snitman, and D. S. Watt, J. O r g . Chem., 1978,43, 2066. I. Z. Kabore, Q, Khuong-Huu, and A. Pancrazi, Tetrahdron, 1978, 34, 2807. D. Daniil, U. Merkle, and H . Meier, Synthesis, 1978, 535.

Amines, Nitriles, and Other Nitrogen-containing Functional Groups

181

,SOZPh 0

(73)

(74)

(75)

Reagents: i, ClCH,SO,Ph-KOBu'; ii, NaN,-DMF

Scheme 42

10 Isocyanates, Thiocyanates, and Isothiocyanates A synthetically useful procedure for the thermal decomposition of the easily prepared silyated hydroxamic acids (77) to isocyanates (78) has been reported (Scheme 44).88The reaction, reminiscent of the Lossen rearrangement, proceeds smoothly at 140-1 60 "C to give isocyanates (78) in high yield. The conversion applies equally well to the analogous sulphur compounds. Similarly, N- acyl-S,Sdiphenylsulphimides (79) decompose thermally at 200 "C to give the corresponding isocyanates in high yield,89 together with diphenyl sulphide (Scheme 45). RCOCl

RCONSiMe3

I

-% RNCO + (Me3Si)20

OSiMe3 R = alkyl or aryl

(78)

(77)

Reagents: i, Me,SiONHSiMe,-NEt,; 140-160 "C.

ii, Me,SiONLiSiMe,;

ii, Me,SiON(SiMe,),;

iv, mesitylene,

Scheme 44, PhzSNCOR (79) R

5 RNCO + Ph2S =

alkyl or aryl

Scheme 45

A new synthesis of thiocyanates from aliphatic amines (Scheme 46) utilizes the readily available 2,4,6-triphenylpyrylium thiocyanate (80).9"The intermediate l-substituted-2,4,6-triphenylpyridinium thiocyanates (81) are smoothly pyrolysed into the corresponding thiocyanates (82) in excellent yields. These promising syntheses complement those available in the aromatic amine series via diazotization.

89 90

F. D . King, S. Pike, and D. R. M. Walton, J.C.S.Chem. Comm., 1978, 351. N. Furukawa, Chem. Letters, 1978, 209. A. R. Katrizky, U. Gruntz, N. Mangelli, and M. C. Rezendre, J.C.S. Chem. Comm., 1978, 133.

182

General and Synthetic Methods

0

Ph \ +

Ph

Ph

+

A

RNH, +

SCN-

RSCN

+

SCN

(80)

(81)

Scheme 46

Nitro displacement by 3-mercaptopropionitrile anion provides a new synthesis of 2-cyanophenyl thiocyanates (84).91The intermediate cyanoethyl thioethers (83) are rapidly converted into the thiol anion via loss of acrylonitrile under the basic reaction conditions. Addition of cyanogen chloride then yields (84) (Scheme 47).

DSCN

R

Reagents: i, HS(CH,)2CN-KOH-aq.DMF; ii, CNCl

Scheme 47

11 Nitrates N-Nitrocollidinium tetrafluoroborate (85), a new safe and mild reagent for the transfer nitration of alcohols (Scheme 48),92 is less reactive than nitronium tetrafluoroborate but allows better controlled conditions and superior yields. The 0-nitration of arylalkyl alcohols is preferred to aromatic C-nitration. Me

RoH

+ Me Q

M

I

e

--+

RONO,

+ H

BF4-

BF4-

NO2

(85)

Scheme 48

'' 92

J. R. Beck and J. A. Yahner, J. Org. Chem., 1978, 43, 1604. G. A. Olah, S. C. Narang, R. L. Pearson, and C. A. Cupas, Synthesis, 1978, 452.

Organometallics in Synthesis BYD. J. THOMPSON AND M. G. HUTCHINGS

PART I: The Transition Elements by D. J. Thompson 1 Introduction Once again the main emphasis of this Report is on the formation of carboncarbon bonds. Of note is the increasing use of metal alkenyl complexes for the synthesis of olefins and dienes with high stereoselectivity. Transition-metalcatalysed asymmetric synthesis continues to develop, and optical yields of 90% are frequently reported, particularly in hydrogenation reactions. Although this is an expanding area of organic synthesis most of the reactions reported this year are not new, and hence only a few references to asymmetric catalysis are discussed.

2 Reduction Whereas sodium borohydride is a well established reducing agent other metal borohydrides have not been so well studied. This year, however, two virtually identical papers have appeared describing the use of [(Ph3P)2Cu]BH, for the reduction of acid chlorides to aldehydes.' This cheap reagent is neither oxygennor moisture-sensitive and can be used in a variety of organic solvents. The reaction is normally complete in under an hour at room temperature, and yields are generally greater than 70%.Other functional groups such as esters, ketones, cyanides, and epoxides are not reduced. One drawback of the reagent is that one mole of reagent is required per mole of substrate. bis(cyclopentadieny1)chlorotetrahydro bora to Another boro hydride, zirconium(iv), [Cp2Zr(C1)]BH,, has been prepared from [Cp2Zr(H)C1] and borane-methyl sulphide and shown to reduce aldehydes and ketones to alcohols at room temperature in benzene within a few minutes.2 The reactivity of the reagent is similar to that of NaBH, but it has the advantage that it can be used in non-polar solvents, whereas NaBH, is usually used in alcoholic solvents. Unfortunately this reagent appears to offer no other advantage. a,P-Unsaturated ketones are reduced in poor yield to give both saturated and unsaturated alcohols, and there is n o stereoselectivity in the reduction of substituted cyclohexanones.

'

( a ) G. W. J. Fleet, C. J. Fuller, and P. J. C . Harding, Tetrahedron Letters, 1978,1437; ( b )T. N. Sorrell and R.J. Spillane, ibid., p. 2473. T. N. Sorrell, Tetrahedron Letters, 1978, 4985.

183

General and Synthetic Methods

184

In the presence of a palladium on charcoal catalyst a,P-unsaturated carbonyl compounds are reduced by formate salts at 100 "C to the corresponding saturated carbonyl compounds in high yield.3 Citronella1 (2), for example, is produced from citral (1) in 91% isolated yield. The same system also reduces some dienes; e.g. cyclohexa-l,3-diene gives 72% cyclohexene and 8% cyclohexane.

i:^

+ HCO, % (2)

(1

When the Knoevenagel condensates ( 3 ) ,prepared from pentane-2,4-dione and aldehydes, are reduced with tetracarbonylhydridoferrate, [FeH(CO),] -, in ethanol, the unexpected monoketones ( 5 )are produced in 70% yield,4 whereas in acetone or THF the expected reduction product (4) is formed in good yield. COMe

RCH=C

' \

+ [FeH(C0)4]-

COMe

( 51

(4)

Tricarbonyl iron complexes containing electron-withdrawing groups in the 1-position ( 6 )are converted regiospecifically into P, y-unsaturated compounds on photolysis in acetic acid.s Although only a limited number of examples are given, the yields are around 90%. Dienes not bearing electron-withdrawing groups in the 1-position react less specifically. COR '

COR '

The unusual selective hydrogenation of a$-unsaturated aldehydes to unsaturated alcohols has been accomplished catalytically under mild conditions using the complex [HIrCI,(Me,SO),] in propan-2-01, the solvent being the source of hydrogen [equation (1)].6 Yields are generally greater than 8O%, the best RCH=CHCHO

lH~r~'~zWezS~)I,l ~

propan-2-01

RCH=CHCHzOH

(1)

N. A. Cortese and R. F. Heck, J. Org. Chem., 1978, 43, 3985. M. Yamashita, Y. Watanabe, T. Mitsudo, and Y. Takegami, Bull. Chem. SOC.Japan, 1978, 51,835. M. Franck-Neumann, D. Martina, and F. Brion, Angew. Chem. Internat. Edn., 1978, 17,690. B. R. James and R. H. Morris, J.C.S. Chem. Comm., 1978, 929.

185

Organometa llics in Synthesis

results being obtained using an isolated catalyst rather than one formed in situ. In the latter case some reduction of the olefinic bond also occurs. In the presence of 10% palladium on charcoal, peptide protecting groups, such as N- benzyloxycarbonyl and benzyl esters, are rapidly removed at room temperature in high yield by the use of cyclohexa-1,4-diene as the hydrogen source for catalytic transfer hydrogenation.' Stereoselective reductions of alkynes to alkenes can be achieved using the reagent MgH2-CuI.* Terminal alkynes are reduced to the corresponding alkene with 100% selectivity in up to 98% yield and internal alkynes give the cis-alkene as the only product in similar yield. The reagent is prepared at -78 "C by simply mixing MgH2 and CuI in THF, and the reduction is carried out by addition of the substrate and allowing the mixture to warm up to room temperature. Lithium aluminium hydride in the presence of transition-metal halides is a powerful and convenient reagent for the reduction of halogeno and tosylate groups [equation (2)].9A variety of metal halides are effective, but the best appears to be NiCI2 which when used with LiAIH, reduces primary, secondary, cyclic, and aromatic halides in essentially quantitative yield. RX

X

=

LiAIH,-NiCI,

I, Br, C1, or tosylate,

b

RH

R

=

(2)

alkyl or aryl

The preparation of chiral compounds by catalytic asymmetric hydrogenation is now well established. This year has again seen several reports o n both the synthesis of and mechanistic studies on such systems, optical yields of 90% being achieved with a variety of catalysts. One such system which is worthy of note is the rhodium complex of the extremely simple chiral ligand ( R ) -1,2-bis(diphenyIphosphino)propane [(R)-prophos] (7). This system is an efficient hydroMe.

'C-CH,

H%h,

\

PPh,

genation catalyst for the preparation of amino-acids by the established route shown in equation (3). Optical yields of around 90% were achieved for a variety of substrates, excess of the natural amino-acid being obtained in all cases. COZH R'C=C

/

H2-[ Rh(prophos)(nbd)]'

'NHCOR2 nbd

=

/

C02H

R'CH2"CH 'NHcoR2

(3)

norbornadiene

Moreover, the catalyst is capable of breeding its own chirality since large quantities of (R)-prophos can be produced from the catalytic reduction of simple

' A. M. Felix, E. P. Heirner, T. J . Larnbros, C. Tzougraki, and J. Meienhofer, J. Org. Chem., 1978,43, 4194. E. C. Ashby, J. J. Lin, and A. B. Goel, J. Org. Chem., 1978,43, 757. ' E. C. Ashby and J. J . Lin, J. Org. Chem., 1978,43, 1263. "' M. D. Fryzuk and B. Bosnich, J. Amer. Chem. Soc., 1978, 100, 5491.

186

General and Synthetic Methods

olefinic substrates using the (R)-prophos-rhodium catalyst itself as shown in Scheme 1. CO,Et

H,C=C

/

H*-[Rh(prophos)(nbd)]+

*

\

MeC---H

OCOMe

I

several

steps

'

(7)

OCOMe Scheme 1

3 Oxidation Improvements in the osmium-catalysed hydroxylation and oxyamination of olefins continue to appear.ll In the vicinal hydroxylation of olefins by t-butyl hydroperoxide earlier methods involved rather alkaline conditions, but this drawback has been overcome by using Et,NOAc instead of Et,NOH and changing the solvent from t-butyl alcohol to acetone.lla Although the new method works well for base-sensitive compounds (e.g. esters), it fails with tetrasubstituted olefins. Yields are geperally around 70%. Vicinal hydroxy-toluene-p-sulphonamides(8),

TsNClNa

+ I R'

lo/" oso,

TsHN

obstained by oxyamination of olefins with chloramine-T in the presence of 1% Os04, are formed in better yields than by the earlier method which involved the use of expensive silver In the improved method, a phase-transfer catalyst, 5o/' benzyltriethylammonium chloride for example, replaces the silver salt. Although yields are generally good the reaction still gives poor results with trisubstituted and unsymmetrical disubstituted olefins. The stereospecific oxyamination of olefins using ethylimido-osmium compounds (9) has been reported.12 The complexes (9),synthesized by treatment of the amine with Os04 in CH2CI2,react with a variety of olefins to give, after reductive cleavage of the osmate esters, vicinal tertiary alkylamino-alcohols (10) in fair to excellent yield. The reaction is stereospecifically cis, and in most cases regiospecific, the reagent adding to form the new C-N bond at the least substituted carbon atom. The reaction is limited, however, by the number of stable imido-complexes that can be made.

"

l2

( a ) K. Akashi, K.E. Palerrno, and K. B. Sharpless, J. Org. Chem., 1978,43,2063;( b )E. Herranz and K. B. Sharpless, ibid., p. 2544. D. W. Patrick, L. K. Truesdale, S. A . Biller, and K. B. Sharpless, J. Org. Chem., 1978, 43, 2628.

187

Organometallics in Synthesis

Oxidations of cyclic ketones to lactones by H 2 0 2take place in the presence of catalytic amounts of certain molybdenum complexes. l 3 The catalysts are peroxomolybdenum complexes stabilized by picolinato- and pyridine-2,6-dicarboxylato-ligands, e.g. [MO(O)(O~)(C~H,N(CO~)~}]. Although the reaction is catalytic, turnover numbers are low (25 or less) and chemical yields are variable. Moreover, competing reactions are the formation of oligomeric peroxides and ring-opened products. The readily available and stable compound barium manganate has been shown to be an efficient oxidizing agent for the oxidation of primary and secondary alcohols to carbonyl It has similar activity to manganese dioxide but is claimed to be better for the preparation of certain aldehydes; e.g. the furan aldehyde (11) is produced in 80% yield whereas with M n 0 2the yield is less than 20%. 05CH;OH Ph

CH,OH

BaMnU;

05CH0

8Ook

Ph

CHO

(11)

The use of supported reagents in oxidation reactions is growing rapidly, and two more examples have appeared this year.I5 10% Chromic acid on silica gel is prepared by the addition of a weighed amount of silica gel to a solution of chromic anhydride and, provided the reagent is used within a week of preparation, it oxidizes primary and secondary alcohols to the corresponding carbonyl compound^.^^^ Similar oxidations can be carried out efficiently using the polymeric reagent polvinyl pyridinium chlorochromate which is prepared by reaction of chromic anhydride-hydrochloric acid with cross-linked polyvinyl ~yridine.'~' Less than one molar equivalent of the reagent is used during the reaction and the reagent can be regenerated with retention of its activity. Yields are high, especially in non-polar hydrocarbon solvents, and although the reaction is somewhat slow at room temperature it proceeds well at 80 "C. A 3,5-dimethylpyrazole-chromium trioxide complex, prepared at -20 "C by quickly adding 3,5-dimethylpyrazole to chromium trioxide in CH2C12has been shown to be an efficient reagent for allylic oxidation.16 AS*'-Steroids (e.g. cholesteryl benzoate) are oxidized very rapidly in about 75% yield to the corresponding AST7-ketone,there being a rate increase of 100-fold compared with using a pyridine-chromium trioxide complex. This increased activity is thought to be partly due to the increased solubility of the complex and more importantly to the possibility of intramolecular acceleration due to the pyrazole nucleus. qP-Unsaturated carbonyl compounds have been prepared by the palladiuml 7 Using stoicatalysed dehydrosilylation of silyl enol ethers [equation (4)]. cheiometric amounts of Pd(OAc), yields are quantitative, the reaction taking l3

l4

l6

S. E. Jacobson, R. Tang, and F. Mares, J.C.S. Chem. Comm., 1978, 888. H. Firouzabadi and E. Ghaderi, Tetrahedron Letters, 1978, 839. ( a )E. Santaniello, F. Ponti, and A. Manzocchi, Synthesis, 1978,534; ( b )J. M. J. FrCchet, J. Warnock, and M. J. Farrall, J. Org. Chem., 1978, 43, 2618. W. G . Salmond, M. A. Barta, and J . L. Havens, J. Org. Chem., 1978,43, 2057. Y. Ito, T. Hirao, and T. Saegusa, J. Org. Chem., 1978, 43, 1011.

General and Synthetic Methods

188

place at room temperature. The regiospecificityof the reaction is illustrated by the reaction of 2-methyl-1-trimethylsilyloxycyclohexene(12), and the dehydrosilylation of an ( E ) -and (2)-mixture of 1-trimethylsilyloxycyclodecene to produce selectively (E)- cyclodecen-2-one in 94% yield.

4 Isomerization

Rhodium chloride continues to be a versatile catalyst for the migration of double bonds. Unsaturated cyclohexenones, e.g. (13), undergo aromatization via remote

double-bond migration in the presence of 0.1 equivalents of RhC1,.I8 Imines, in the presence of a base, undergo a similar isomerization [equation ( 5 ) ] .

The air-stable complex [Ir(cycl~-octadiene)(PMePh~)~]PF~, after activation with hydrogen, isomerizes allyl ethers to the corresponding trans-propenyl ethers at room temperature with very high stereoselectivity (397%) and in high yield (295%) [equation (6)I.I' This appears to be the first stereoselective conversion of alkyl ethers into trans-propenyl ethers, but the reaction is limited to primary allyl ethers, secondary allyl ethers being unaffected even at 65 "C.

Allylamines have been isomerized to the corresponding enamines in the presence of certain cobalt(I1) salts, for example cobalt naphthenate-AlEt,-PPh, in the ratio 1 : 3 : 3, in very good yield [equation (7)].20Moreover, with prochiral R1R2C=CHCH2NR32 --+ R'R2CH=CHNR3* " l9

*"

P. A. Grieco and N. Marinovic, Tetrahedron Letters, 1978, 2545. D. Baudry, M. Ephritikhine, and H. Felkin, J.C.S. Chem. Comm., 1978, 694. H. Kumobayashi, S. Akutagawa, and S . Otsuka, J. Amer. Chem. SOC.,1978, 100, 3949.

(7)

Organometallics in Synthesis

189

allylamines in the presence of chiral phosphines, e.g. ( + )-diop, optical induction is observed. Optical yields, however, are only moderate and chemical yields are low, for example the preparation of the citronella1 trans-enamine (14) in 23% chemical yield, 30% enantiomeric excess.

(+)-diop

(14) 30% enantiorneric excess

5 Carbonylation

The anion [Co(CO),]-, generated by vigorously stirring [Co,(CO),] in a mixture of benzene and aqueous sodium hydroxide containing the phase-transfer catalyst cetyltrimethylammonium bromide, reacts with alkynes and methyl iodide in the presence of carbon monoxide to give but-2-enolides [equation (S)].” Although the reaction looks potentially useful only a limited number of acetylenes were studied and product yields were variable.

Me

OH

The direct conversion of homoallylic alcohols (15) into a-methylenebutyrolactones (16) has been achieved using [Ni(CO),] in the presence of a base.22The choice of base appears to be very important since in the presence of potassium acetate yields are around 60% whereas on using sodium methoxide yields drop to only 4%. Other carbonylating systems, e.g. disodium tetracarbonylferrate and C O - [ P ~ C ~ , ( P ~ , P )are ~ ] ,ineffective.

Readily available o-bromoaminoalkylbenzenes (17; n = 1 , 2 , or 3) on heating with catalytic amounts of palladium acetate and triphenylphosphine in the presence of butylamine and carbon monoxide give the corresponding five-, six-, or seven-membered benzolactams (18) in good yield (40-65 O / O ) . , ~ 21 22

23

H. Alper, J. K . Currie, and H. Des Abbayes, J.C.S. Chem. Comm., 1978, 311. I. Matsuda, Chem. Letters, 1978, 773. M. Mori, K. Chiba, and Y. Ban, J. Org. Chem., 1978, 43, 1684.

190

General and Synthetic Methods

Iron carbonyls continue to find use in organic synthesis, and two simple reactions of pentacarbonyliron with Grignard reagents are reported this year.24 Interaction of the two reagents generates the acyltetracarbonylferrate (19) in situ, which can then undergo further reaction with an alkyl iodide to produce the ketone (20) in 75% yield,24aor react with an alcohol in the presence of iodine to give the corresponding ester (21) in 70% yield.24hThe advantages of the method are the mild conditions and the lack of side products produced. In the ketone synthesis, for example, virtually no alcohol or alkane is produced. R'MgBr

+ Fe(C0)5 -+

[R'COFe(C0)4]-

R20H-12 b

R'COOR~

The use of iron carbonyl derivatives in organic synthesis is often limited by the difficulty of separation of the iron complexes from the desired product at the end of the reaction. In the synthesis of aldehydes from alkyl halides using tetracarbonylhydridoferrate, [HFe(CO),]-, this problem has been cvercome by attaching the iron complex to an ion-exchange resin [equation (9)].25The resin converts alkyl halides into the homologous aldehyde in over 90% yield, and at the end of the reaction the iron complex is retained on the polymer. Ally1 chlorides fail to react, and secondary alkyl halides undergo elimination. K[HFe(C0)4]+ @-PhCH2&Me3 -+ a w P h C H ~ k M e 3 C1~

[HFe(C0)41-

(9)

1.

RCHO

Aldehydes react with hydrosilanes and carbon monoxide in the presence of catalytic amounts of [Co,(CO),]-Ph,P to give the 1,2-bis(siloxy)-olefins (22).26 Triphenylphosphine is required as a co-catalyst to prevent the undesired hydrosilylation of the aldehyde, and for simple aldehydes yields are good.

24

( a )M. Yamashita and R. Suemitsu, Tetrahedron Letters, 1978, 761; ( b ) ibid.,p. 1477.

26

Y. Seki, S. Murai, and N. Sonoda, A n g e w . Chem. Internat. Edn., 1978, 119.

,-'G. Cainelli, F. Manescalchi, and A. Umani-Ronchi, J. Org. Chem., 1978, 43, 1598.

Organometallics in Synthesis

191

Stoicheiometric homogeneous decarbonylation of aldehydes using rhodium complexes has been known for a long time, but this year it has been shown that certain rhodium complexes containing bidentate phosphine ligands can perform the reaction ~atalytically.~~ Using catalysts of the type [Rh{l,2-bis(diphenylphosphino)ethane},Cl], turnover numbers as high as 100 000 have been achieved. Although the reaction time is rather long, up to fifty hours, it is a big improvement on earlier work, and yields were quantitative for the simple aldehydes (e.g. benzaldehyde and heptanal) which were studied.

6 Carbon-Carbon Bond Formation Organo-copper Reagents.-The organo-copper reagents RCuBF3, which were first reported last year, have now been shown to be as good as other organocopper reagents for 174-additionsto a,P-unsaturated ketones and esters.28The most remarkable feature of these reagents, however, is that they undergo conjugate addition to the previously unreactive a,& and P,P-disubstituted enoate esters and even to a#-unsaturated acids in good yield [equation (lo)]. The reagent does not add to P,P-disubstituted enoic acids. R'

R' R3

___*

R2'

I

R4CuBF,

R3

/

R2-C-CH

(10)

'COY

Acetylenic amino-ethers (23) on treatment with butylmagnesium bromide and cuprous iodide in THF give the intermediates (24) which, on hydrolysis, give the allenic amines (25) in up to 70% yield.29 R'R2C(OMe)C=CCH2N(Me)R3

BuMgBr-Cut A

R'R2C=C=C H /

(24)

/

CH2N(Me)R3

'Metal

(23) R'R2C=C=CHCH2N(Me)R3 (25)

A general method for the synthesis of terminal allenes consists of hydroalumination of terminal olefins with LiAlH4 followed by treatment with 3bromoprop-1-yne in the presence of catalytic amounts of cuprous chloride [equation (ll)].30 Yields are in the range 40-80% but the reaction is only

'7

i, LiAIH, ii, HCGCCH,Br-CuCI

' R(CH2)2-CH=C=CH2

applicable to terminal olefins. With diolefins only the terminal double bond reacts; for example the diene (26) reacts to produce the allene (27) in 70% yield. 27 28

29 30

D. H. Doughty and L. H. Pignolet, J. Amer. Chem. Soc., 1978, 100, 7083. Y. Yamamoto and K. Maruyama, J. Amer. Chem. Soc., 1978, 100,3240. A. Claesson and C. Sahlberg, Tetrahedron Letters, 1978, 1319. F. Sato, K. Oguro, and M. Sato, Chem. Letters, 1978, 805.

General and Synthetic Methods

192

% MeCH=C:H(CH2)2C=C=CH2

MeCH=CHCH2CH=CH2

(26)

(27)

Simple chiral allenes have been prepared by the reaction of propargylic carbamates with lithium dialkyl~uprates.~'The diastereomeric carbamates, 1- (1-naphthy1)ethyl isoderived from racemic propargylic alcohols and (R)cyanate, are readily separated by h.p.1.c.; they are then treated with lithium dialkycuprates at -78 "C, producing the allenes with enantiomeric excess up to 80% in yields of around 70% (Scheme 2). The method is claimed to be an improvement on earlier methods in that it is much simpler and gives better optical yields. H

\

.Me

( S , R)-carbarnate

H R',('ul

RZ

H

\

R2

c'=C=C'

R'

H

I

R'

\

/

H

I

/c=c=c'\

H

(R)

(S)

Scheme 2

2-Alkyl- o r 2-aryl-3-methoxy-l,3-dienes(28) can be prepared in over 70% yield by reaction of organoheterocuprates with the methanesulphinic esters of a-allenic alcohols (29) 32 The product (28) can then be hydrolysed to the corresponding a,@-unsaturated ketone ( 3 0 ) in high yield (70-90%).

0

(29)

R I

0

I1

H ,c =C-c-CH

/

R'

The potentially useful synthetic 'isoprene unit', 3-methylbut-2-enylmagnesium chloride (31), reacts with various epoxides to give the product (32) in high yield (80%) and high purity (>98°/0).33 In the presence of 10% cuprous iodide, however, the reaction takes a different course to give the product ( 3 3 )in equally 31 32 33

W. H. Pirkle a n d C. W. Roeder, J. Org. Ckern., 1978, 43, 1950. H. K l e i j n , H. Westmijze, a n d P. Vermeer, Tetruhcdron I.etters, 1978, 1133. G. Linstrumelle, R. Lome, a n d H. P. Dang, Trerruhedron Letrem, 1978, 4069.

193

Organo me ta 11ics in Sy n thesis

R’

10% c u r

(32)

high yield and selectivity. With monosubstituted epoxides attack occurs on the less substituted carbon atom of the epoxide in both the catalysed and the uncatalysed reactions. By blocking the terminal position of the acetylene (34) with the bulky Me3Si group and acetylating to give (35) it is possible to synthesize the acetylene (36) in good yield (65-85’/0) by direct displacement of the acetate group with the alkyl group of a dialkyl o r g a n ~ c u p r a t e . ’ ~ OH I HC~C--C-C5H11

R

OAc

3

I

H (34)

I Me3SiC~C--C-CsH~ I H

R,CuLi I___+

Me’SiCGC-

(35)

I

C-CSHI I H

1

(36)

Addition to Acetylenes and 0lefins.-Cyclopropenes are not usually formed in good yield by the copper-catalysed addition of carbenes to acetylenes. Using rhodium carboxylates as catalysts, however, the reaction proceeds smoothly to give the cyclopropenes (37) in good yield.3s Bulky substituents on the acetylene d o not significantly effect the yield, whereas polar groups lower the yield drastically. This is probably due to the lower stability of the product. H R’C-CR’

+ N,CHCO,Me

\ /

CO,Me

C

Rh,(O,CR’),

I\

/c=c\

R’

R2

(37)

The conjugate addition of organoaluminium acetylides to a,P-unsaturated cyclic ketones takes place in the presence of catalytic amounts of a nickel complex prepared from Ni(acac)2 and di-isobutylaluminium hydride (DIBAH) [equation (12)].36The reaction proceeds for five- or six-membered rings, as well as fused rings in about 70% yield. Other acetylides, those of magnesium and zinc for 34

R. S. Brinkmeyer and T. L. Macdonald, J.C.S. Chem. Conzm., 1978, 876.

’‘

1239. R. T. Hasen, D. B. Carr, and J. Schwartz, 1. Amer. Chem. SOC.,1978, 100, 2244.

’’ N. Petiniot, A. J . Anciaux, A. F. Noels, A. J . Hubert, and Ph. TeyssiC, Terrahedron Lefters, 1978,

General and Synthetic Methods

194 0 RCrCAlMe,

+I

0 Ni(acac),

R'

example, d o not react, and other nickel complexes, [NiC12(PEt3),] for example, are ineffective. In the presence of catalytic amounts of cobalt, nickel, or copper salts Grignard reagents react with propargyl chlorides to produce allenes [equation ( 13)].3'

c1

H

R'

(13)

Yields are generally 80"/0 for a variety of propargyl chlorides and Grignard reagents. Catalytic activity decreases markedly in the order Fe > Co > Ni > Cu, with both Fe2' and Fe3' species being active. The readily available FeCI, or Fe(acac), appear to be the best catalysts. Coupling Reactions.-Acetylenes react with organoalanes, e.g. Me,Al, and zirconocene dichloride to form the alkenyl metal complexes (38) in high yield.38 The exact structure of these complexes is not known but both aluminium and zirconium are essential. The stereoselectivity of the reaction is shown to be 98% c i s - a d d i t i ~ n , ~and ~ " once formed the complexes (38) undergo a variety of useful

R'C=CR'

Me,AI-[ClzZrCp2]

R' \ Me

R2

c=c/

'

"Metal

(38)

reactions.38 The complexes from terminal acetylenes react with various onecarbon homologating agents to give terminally functionalized ( E ) -3 -methylalk2-enes in good yield (ca. 80%)and with high sterecselectivity (Scheme 3).38bThis approach is readily modified for the synthesis of natural products, e.g. the synthesis of geraniol (39) in 87% yield (Scheme 4). Many of the palladium- and nickel-catalysed reactions of alkenyl-aluminium or -zirconium compounds which fail or give low yields of cross-coupled products can be promoted to give the desired product in high yield by the addition of catalytic amounts of zinc ~hloride.~'"Trisubstituted olefins (40), for example, can be synthesized in good yield (ca. 70%) from the metal complex (38) in the presence of a palladium or nickel phosphine complex and zinc chloride. This reaction is particularly attactive for the one-pot synthesis of natural products containing 37

3x

D. J. Pasto, S. K. Chou, A. Waterhouse, R. H . Shults, and G. F. Hennion, J. Org. Chem., 1978, 43, 1385. ( a ) D. E. Van H o r n and E. Negishi, J. Amer. Chem. Soc., 1978,100,2252; ( b )N. O k u k a d o and E. Negishi, Tetrahedron Letters, 1978,2357; (c) E. Negishi, N. Okukado, A. 0 . King, D. E. Van Horn, and B. I. Spiegel, J. Amer. Chetn. SOC.,1978, 100, 2254.

195

Organometallics in Synthesis R'

R'

\

c-c

Me /

R2

R'

R2

R'

R2

K2

\

/ \CH20Me

C=C

/ \C02H

Me /'

Reagents: i, (CH20),; ii, ClC0,Et; iii, Bu"Li-ClCH,OMe; iv, Bu"Li-CO,

Scheme 3

Reagents: i , Me,Al-[CI,ZrCp,];

ii, Bu"Li; iii, (CH,O),

Scheme 4

R'

R2

(40)

diene or enyne units as exemplified by the synthesis of compound (41) in 70% yield and with high stereoselectivity (>98% E ) (Scheme 5).

(41) Reagents: i, Me3Al-[C1,ZrCp21; ii, BrCH=CH,-ZnC1,-[CI,Pd(PPh,)zl-Ru',AIH

Scheme 5

( E ) -Alkenyl-zirconium complexes (42), prepared by the reaction of acetylenes with [HClZrCp2], react with alkenyl halides in the presence of a palladium catalyst to form conjugated dienes of high isomeric purity ( 2 9 7 % ) and in good yield.39 The complexes (42) are as good as the corresponding alkenylalanes in R'

\

/

/c=c\ H (42) 3y

H 4-

ZrCp2C1

R2 \ /'='\ R3

H /

R'

-[CI,Pd(PPh,),I Bu',AIH

X

H

\

' H

/

/c=c\

R3

/

H

N. Okukado, D. E. Van Horn, W. I>. Klirna, and E. Negishi, Tetrahedron Letters, 1978, 1027.

General and Synthetic Methods

196

terms of yield and stereoselectivity and, moreover, they will tolerate the presence of certain oxygen functionalities, e.g. ethers and ketones, in the alkenyl halide. In the presence of the nickel complex bis-(N- methylsalicylaldimine)nickel, [Ni(mesal),], 1-bromo-alk- 1-ynes react rapidly with trialkylalanes to give the corresponding alkylated acetylenes (43) in 809'0 yield, with the exception of 1-bromo-1 -phenylacetylene which only reacts in low yield.,' In the absence of the nickel catalyst the reaction is very slow. One drawback of this method is that as in related reactions only one of the alkyl groups of the trialkylalane is used. R ' ~ A I+ R ' C ~ C B ~

Terminal and internal arylalkynes have been synthesized by the palladiumcatalysed reaction of alkynyl-zinc reagents with aryl halides [equation ( 14)].41 RCfCZnCl

+ ArX % R C r C A r

(14)

The reaction is complete within minutes at room temperature using aryl iodides or activated aryl bromides, and yields are in the region of 80%. Unsaturated aryl bromides, however, are inert at room temperature. The alkynyl-zinc reagent is claimed to be superior to the corresponding Grignard or organo-alkali metal reagent, and the most convenient catalyst appears to be [(Ph,P),Pd]; [Ni(Ph,P),] leads to the same reaction but yields are much lower. The direct coupling of two unlike alkenyl groups by reaction of an alkenyl metal derivative with an alkenyl halide has in the past proved difficult. In the presence of a catalytic amount of [(Ph,P),Pd], however, alkenyl iodides react stereospecifically with Grignard reagents of the type (44) under very mild conditions to produce the dienes (45) in high yield (ca. R'

R"

(44)

(45)

Allylic esters and alk-1-ynes in the presence of Ni" catalysts react under mild conditions to give alk- 1-en-4-ynes (46) in satisfactory yield, although catalyst turnover numbers are low (ca. 50).43 The yield appears to be dependent on the ligand around the metal, with tri-isopropyl phosphite being the best ligand. Allylic halides give only very low yields. R'CH=CHCH,OCOR

+ R2C-CH % R'CH=CHCH*C=CR2 (46)

1,4-Dienes have been prepared in good yield (50-70%) by the palladiumcatalysed allylation of ( E ) -alkenylpentafluorosilicates (47), which are 'I 41 42

43

G. Giacomelli and L. Lardicci, Tetrahedron Letters, 1978, 2831. A. 0. King, E. Negishi, F. J . Villani, jun., and A. Silveira, jun., J. Org. Chem., 1978, 43,358. H. P. Dang and G. Linstrumelle, Tetrahedron Letters, 1978, 191. M. Catellani, G . P. Chiusoli, G. Salerno, and F. Dallatomasina, J. Organomefullic Chem., 1978, 146, C19.

197

Organometallics in Synthesis

synthesized from acetylenes (Scheme 6).44 The (E)-stereochemistry of the chloroplatinic acid-catalysed hydrosilylation of acetylenes is well established, and there is no loss of stereochemistry in coupled product. Pd(OAc)* is the best catalyst, and the reaction can take place in the presence of certain functional groups, e.g. esters, which are incompatible with hydroalumination.

H Reagents: i, HSiC1,-H,PtCI,;

'

'CH2CH=CH2

ii, KF; iii, Pd(OAc),-CH,=CHCH,Cl

Scheme 6

The titanium reagent prepared from titanium trichlqride and lithium aluminium hydride has been shown to be as effective as the previously reported titanium trichloride-zinc/copper couple reagent for the intramolecular reductive coupling of diketones to give medium to large c y c l o a l k e n e ~The . ~ ~TiC13-LiA1H4 reagent is simpler to make and, moreover, has been used for the synthesis of tetrasubstituted cyclopropenes [equation (13 1 . Yield of around 40% compare well with those of other syntheses of cyclopropenes, but the reaction is limited to the synthesis of 3,3-disubstituted products.

-A R

PhCOCR,COPh

R

TiCI,-LiAIH,

Ph

Ph

In the presence of [ C ~ ( a c a c ) ~CY,W ] , -bisdiazo-ketones couple intramolecularly with the loss of nitrogen to give cycloalk-2-ene- 1,4-diones [equation ( 16)].46

ti =

4,7,8,9,10,12, or 16

Yields vary from 80% for the synthesis of 14-membered rings to 30% for 8-, 11-, and 13-membered rings. The cis: trans ratio in the product is generally around 1: 10 except for the 8-membered ring where it is >20 : 1. Other copper catalysts, e.g. copper oxide, give poorer yields. 44 45 46

J. Yoshida, K. Tamao, M. Takahashi, and M. Kumada, Tetrahedron Letters, 1978, 2161. A. L. Baumstark, C. J. McCloskey, and K. E. Witt, J. Org. Chem., 1978, 43, 3609. S. Kulkowit and M. A. McKervey, J.C.S. Chem. Comm., 1978, 1069.

198

General and Synthetic Methods

Aryl halides can be converted into biaryls in moderate yield (40-65 “/o> using aqueous alkaline sodium formate and palladium on charcoal together with a surfactant as ~ a t a l y s t . ~Although ’ yields are only moderate the only other product is dehalogenated starting material. Any nitro-groups in the starting material are reduced to amines during the coupling reaction. The choice of surfactant is important in obtaining the best yield, cetyltrimethylammonium bromide being the most generally applicable. A new ketone synthesis of general applicability is the palladium-catalysed reaction of acid chlorides with organotin compounds [equation (17)].48The R’COC‘I

+ R’$n

[(P~CH~)I’LI(PP~~)~CI] HMPA b R’COR’ t

R23SnCI

(17)

reaction works equally well for aikyl or aryl acid chlorides and can be carried out in the presence of a variety of functional groups, including nitro, nitrile, ester, and aldehyde. Sterically hindered acid chlorides react normally and catalyst turnover numbers of 20 000 have been obtained. The reaction can be carried out in an open flask and is generally complete in under 15 minutes to give the product in over 85% yield. 7 Miscellaneous Brganometallic-mediated Reactions The hexacarbonylpropargyldicobalt caticn, which is generated in situ by protonation of the corresponding hydroxy-complex (48),selectively mono-alkylates P-dicarbonyl systems to give the complex (49) in good yield (65--95’/0).~~ Demetallation with ferric nitrate then releases the organic ligand in virtually quantitative yield.

(48)

(49)

A simple method for the synthesis of terminal conjugated dienes is based on the palladium-catalysed elimination of acetic acid or phenol from the readily available allylic acetates or phenyl ethers [equation (18)].”’ The reaction proceeds

,&1R R2 47

4x 43

=

Ph or MeCO

P. Barnfield and P. M. Quan, Synthesrs, 1978, 537. D. Milstein and J. K. Stille, J. Amer. Chem. Snc., 1978, 100, 3636. H. D. Hodes and K . M. Nicholas, Tetrahedron Lcfters, 1978, 4349. J. Tsuji, T. Yarnakawa, M. Kaito, and T. Mandai, l’etrahedron Letters, 1978, 207.5.

Organometallics in Synthesis

199

under mild conditions to give the dienes in ca. 70% yield in the presence of 1% catalyst. The presence of excess triphenylphosphine gives maximum catalytic activity, but the complex [ P c I C I ~ ( P P ~is~catalytically )~] inactive; no elimination takes place with allylic methyl ethers, allylic alcohols, or allylic amines. The readily available complex [Pd(PhCN),Cl,] reacts stereospecifically with 5a- or 5P-cholestan-3-01s to give the 3-chloro-derivatives in high yield (Scheme 7).51The stereochemistry of the reaction is very different from that observed with other commonly used chlorinating agents, such as thionyl chloride (retention of configuration) and phosphorus pentachloride (inversion of configuration). What is observed with [Pd(PhCN),CI,] is configurational inversion when the OH group is equatorial, as with (50) and (53),and retention when the OH group is axial, as with (51) and (52).

( 5 0 ) R' = OH, R2 = H (51) R' = H , R 2 = OH

H

H

(52) R' = OH, R2 = H

(53) R' = H, R2 = OH Scheme 7

I n the presence of [PdCI,(PhCN),] and an oxidizing agent, amines add stereospecifically cis to olefins, leading to the diamine ( 5 5 ) in good yield.52 Amination of the olefin at -40 "C in the presence of [PdCI,(PhCN),] gives the adduct (54) which is then oxidized in situ using m-chloroperbenzoic acid in the presence of a second mole of amine to give the product (55). For terminal olefins yields are ca. 70%, but for internal olefins the yields are lower.

51 52

E. Mincione, G. Ortaggi, and A. Sirna, Tetrahedron Letters, 1978, 4575. J. E. Backvall, Tetrahedron Letters, 1978, 163.

General and Synthetic Methods

200

P A R T 11: Main Group Elements by M. G. Hutchirigs

1 Introduction The organization of material within the present Report differs somewhat from the pattern of preceding years, although the criteria for inclusion remain the same.' The relative emphases placed on some topics have also been changed, particularly those concerning the Group VI elements.

2 Group1 Regiospecific Lithiation.-The increasing trend toward taking advantage of molecular features which regiospecifically orient lithiation or alkylation is highlighted by several studies. By intentionally including a chelating substituent in (l),an otherwise unreactive species can be lithiated and alkylated specifically to give 2,3-dialkylcyclohexenonesin high yield, presumably because of increased ion-pair stabilization.* Surprisingly, 1,3-dibutoxypropene undergoes vinylic deprotonation with Bii'Li, the alternative allylic metallation being inhibited by polarization effects; alkylation then gives 2-43 mixtures of trisubstituted a l k e n e ~The . ~ known directing effect of benzamide and alkoxy-groups in aromatic metallation has been applied to the synthesis of contiguously tri- and tetrasubstituted alkoxybenzenes,"' as in syntheses of phthalide isoquinoline alka l o i d ~ ~and ' unsymmetrical anthraquinones [e.g. ( 3 ) from (2)].4h,d,''

0 (1)

(2)

OMe

(3)

Oxazolines (4) are easily prepared from benzoic acids and behave as 'activating' groups in nucleophilic aromatic substitution. Thus, 0 - methoxy- or 0 - fluorosubstituents are replaced by the alkyl group of RLi. 5 u . h The same oxazoline group in the 4-position of pyridine promotes 3-lithiation," whereas in the 3-position it induces nucleophilic alkylation to give 1,4-dihydropyridine derivative^.'^ Benzyl alcohol is lithiated in the 2-position of the benzene nucleus.6 'Solvent effects' are suggested to be responsible for the quantitative syrz selectivity in the alkylation of lithiated ketimines (5).'

'

K. Smith, in 'General and Synthetic Methods', ed. G. Pattenden (Specialist Periodical Reports), The Chemical Society, London, 1978, Vol. 2, p. 171. J. Amupitan and J. K. Sutherland, J.C.S. Chern. Cornm., 1978, 852. ' S. J . Gould and B. D. Remillard, Tetrahedron Letters, 1978, 4353. ( a )S. 0.de Silva, J. N. Reed, and V. Snieckus, Terrahedron Lerters, 1978,5099; ( b )S. 0.de Silva and V. Snieckus, ibid., p. 5103; ( c ) S. 0. de Silva, I. Ahmad, and V. Snieckus, ibid., p. 5107; ( d )J. E. Baldwin and K. W. Bair, ibid., p. 2559; ( e )I. Forbes, R. A. Pratt, and R. A. Raphael, ibid.,p. 3965. ( a )A. I. Meyers and B. E. Williams, Tetrahedron Lerters, 1978, 223; ( h )A. I. Meyers, R. Gabel, and E. D. Mihelich, J. Org. Chem., 1978,43. 1372; ( c ) A. I. Meyers and R. A. Gabel, Tetrahedron Letters, 1978, 227; ( d ) C. S. Giam and A. E. Hauck, J.C.S. Qiem. Cornm., 1978,615. ' N. Meyer and D. Seebach, A n g e w . Chem. Iriterriut. Edn., 1078, 17,521. ' R. R. Fraser. J. Ranville, and K. L. Dhawan, J. A i n u . Chem. Soc., 1978, 100, 7999.

20 1

Organometallics in Synthesis

Extreme stereochemical congestion inhibits the addition of RLi to otherwise electrophilic groups (e.g. =C=O), and some novel synthons can therefore be generated by metallation at alternative sites. Thus, (6; X = OCH2R) acts as a R C H O H synthon,'" and (6; X = RNCH2R'), (7), and (8)all behave as =NCHR' precursors. *'.' Cleavage to useful products necessitates use of relatively harsh conditions ( e . g . LiAlH,). The urea (9) and derivatives are synthetically more useful for the same purpose because of increased ease of hydrolytic work-up.'

(6)

(8)

(7).

(9)

Carbonyl Equivalents.-The benzthiazole derivatives (10; X = Li) and (10; X = CH,Li) are extremely useful carbonyl equivalents capable of a wide range of synthetic modification based on the key derivative (10; X = alkenyl)."' Scheme 1 (Btz = 2-benzthiazolyl) summarizes just a few transformations, each of which in turn depends on the use of subsidiary organolithium reagents. The benzdithiole analogues (11) are also acyl anion equivalents, acting via alkylation and HgOBF3 work-up.' The sulphine (12) undergoes thiophilic alkylation to generate the now commonplace S-stabilized carbanion (1, ) . I 2 Reactions with electrophiles, 0

a, ix-xi,

iii,xii

H

\

/

Btz

v, VI,. .11. . VII, ..

... ..,

V I I I , v11

(p0 /

=

2-benzthiazolyl

r:,

Reagents: i, RLi; ii, Me0,SF; iii, AgN0,-aq. MeCN; iv, MeLi; v, LDA; vi, HCGCCH,Br;

. vii, OH-; viii, Hg"., IX,

; x, MeI; xi, aq. CuCI,; xii, H '

Scheme 1

' ( a ) P. Beak, M. Baillargeon, and L. G. Carter, J. Org. Chem., 1978, 43, 4255; ( b ) R. Schlecker, D. Seebach, and W. Lubosch, Helu. Chim. Acta, 1978, 61,512; ( c ) D.Seebach and T. Hassel, Angew. Chem. Internut. Edn., 1978, 17,274. T. Hassel and D. Seebach, Heh. Chim. Acta, 1978, 61,2237. "' E. J. Corey and D. L. Boger, Tetrahedron Letters, 1978, 5 , 9, 13. S. Ncube, A. Pelter, K. Smith, P. Blatcher, and S. Warren, Tetrahedron Letters, 1978, 2345. '* G. E. Veenstra and B. Zwanenburg, Tetrahedron, 1978, 34, 1585.

202

General and Synthetic Methods

(10)

(11)

(13)

(12)

including Michael acceptors, and demasking give a range of carbonyl-based derivatives. A dipolar enone synthon is generated according to Scheme 2 in a stereocontrolled manner." The lithiated sulphoxide of Scheme 3 acts as a PhS-C=O anion: a silicon-Pummerer rearrangement is involved in the last step of the sequence.14 ~

(4:Go E

.

.

.

I

.

.___-a

4

I

6:; _I_* i i i , iv

__* I, I1

SO, Ph

S0,Ph

&ph Me

Reagents: i, 2 PhLi; ii, MeI; iii, H,Cr,O,; iv, DBU

Scheme 2 LiCHSPh I,RCHSPh

I

II

c1 0

I

II

c1 0

-

RCOSPh

Reagents: i, RX; ii, LDA; iii, Me,SiCl; iv, h

Scheme 3

Analogues of established carbonyl equivalents include Et2NCH(CN)Li,which is a useful derivative similar to cyanohydrin-derived carbanions, from which A similar species may be converted either aldehydes or ketones are deri~ab1e.I~" a- Metallated cyclopropyl into the new Michael acceptor 2-aminoa~rylonitrile.'~' isocyanides and ketones R 2 R 3 C = 0 give (14), which on hydrolysis and acidinduced ring expansion lead to cyclobutanones (15).16" Cyclobutanone itself is conveniently prepared from lithiated phenylthiocyclopropane and formaldehyde, followed by ring expansion.'66

l3

l4

'' l6

P. C. Conrad and P. L. Fuchs, J. Amer. Chem. SOC.,1978,100,346;( h )J. C. Saddler. P. C. Conrad, and P. L. Fuchs, Tetrahedron Letters, 1978, 5079. K. M. More and J. Wemple, J. Org. Chem., 1978, 43, 2713. ( a ) G . Stork, A . A. Ozorio, and A. Y. W. Leong, Tetrahedron Letters, 1978, 5175; ( h )H. Ahlbrecht and K. Pfaff, Synthesis, 1978, 897. ( a ) R. Harms, U. Schollkopf, and M. Muramatsu, Annalen, 1978, 1194; (6) B. M. Trost and W. C. Vladuchick, Synthesis, 1978, 82 1.

Organometallics in Synthesis

203

Double deprotonation of 4-nitrobut-1-ene gives the LUMO-filled dianion (16) which exhibits reactivity umpolung; for instance, it undergoes Michael addition to enones at its own terminal position, Nef work-up giving (17).17a 2-Aminoalcohols are prepared by reduction (LiAIHJ of the silylated nitro-alcohols which + have been derived either from silylnitronates RCH=N(O)OSiMe, or the dianions from primary nitro alkane^.'^' A further nitro-stabilized carbanion (18) has been used as a @-acyl-vinylanion equivalent in a synthesis of the macrolide pyrenop hori n.

:Lo-vR 0

-N02Li,

Kt02N00Et

0

(16)

(17)

(18)

Two uses of metallo-enamines allow the homologation-alkylation of ketones (Scheme 4),lga and the regiospecific alkylation-reduction of metallated 0

II

(EtO),PCH,N=CHPh Li

Ph

CHO

Reagents: i, Bu"Li;ii, cyclo-C,H,,CHO; iii, MeI; iv, H 3 0 '

Scheme 4

a,@-unsaturated imines ( 19).'96 The phosphonate Me,SiOP(OEt), adds to aldehydes, generating a-siloxyphosphonates which can be deprotonated and

"

(19)

alkylated to give ketones in high yields after demasking.20A 2-lithiopropenal moiety has been generated by Li-Br exchange of 1,1-dibromo-2-ethoxycyclopropane, which after reaction with an electrophile is ring-opened by EtOHK2C03.*' Acid hydrolysis liberates the 2-substituted acrolein. The method is particularly useful for one-carbon ring expansion [e.g. (21) from (20)]. A novel cyclopentenone synthesis depends on the addition of the carbenoid " l8

l9

2o 21

( a ) D. Seebach, R. Henning, and F. Lehr, Angew. Chem. Internat. Edn., 1978,17,458; ( b )E. W. Colvin and D. Seebach, J. Org. Chem., 1978, 689. P. Bakuzis, M. L. F. Bakuzis, and T. F. Weingartner, Tetrahedron Letters, 1978, 2371. ( a ) S. F. Martin and G. W. Phillips, J. Org. Chem., 1978, 43, 3792; ( b ) P. A. Wender and M. A. Eissenstat, J. Amer. Chem. SOC., 1978, 100, 292. ( a )D. A. Evans, K. M. Hurst, and J. M. Takacs, J. Amer. Chem. SOC., 1978, 100,3467; (6) T. Hata, A. Hashizume, M. Nakajima, and M. Sekine, Tetrahedron Letters, 1978, 363. T. Hiyama, A. Kanakura, H. Yamamoto, and H. Nozaki, Tetrahedron Letters, 1978, 3047, 3051.

General and Synthetic Methods

204

LiCC12CH=CH2 to an a-methylene-ketone, followed by cyclization of the chloropentadienyl cation (22) and hydrolysis.225-Methylisoxazole is a precursor of the dianion (23), which, amongst other useful reactions, gives aminopyridones with aromatic nitriles.23

(20)

(21)

(22)

(23)

Alkenyl-1ithiums.-The species (24), prepared by Li-H exchange, reacts with conjugated ketones to give cyclopentenones and with simple ketones to give unsaturated lac tone^.^^ The tosylate CF3CH20Ts is a novel source of CF2=C(Li)OTs.*' Reaction with ketones (R2CO)and a series of hydrolytic steps liberates a - keto-acids, R,CHC(O)CO,H, in high yield. Alkylation of the vinyl sulphoxide-derived (25) and elimination of 'ArSOH' leads to terminal allenes.26 The vinyl carbanions derived by deprotonation of P,P-diphenylacrylonitrile are also useful n u ~ l e o p h i l e s . ~ ~ Li

Halogen-Li exchange is an alternative source of vinyl-lithium reagents. Two equivalents of ButLi react with simple vinyl bromides, the resulting species undergoing synthetically valuable reactions with a wide range of hetero- and C-electrophiles.28The substituted acrylic acid derivatives (26) give a,P-butenolides (27) with ketones or aldehydes,29and the versatile latent a-ketovinyl anion equivalent (28) has been used in stereospecific natural product ~yntheses.~' The alkene CC12=CF2 undergoes Li-Cl exchange to give LiCCl=CF2.31 Ketones (R1R2C=O)are converted into a,@-unsaturateda-chloro-aldehydes or -ketones (29) by reaction with this reagent followed by reduction (LiAlH,) or further alkylation (R3Li),respectively, and hydrolysis.

(26)

(27)

(28)

(29)

T. Hiyama, M. Shinoda, and H . Nozaki, Tetrahedron Letten, 1978, 771. " F. J. Vinick, Y. Pan, and H. W. Gschwend, Tetrahedron Letters, 1978, 4221. 24 R. R. Schmidt and J . Talbiersky, Angew. Chem. Internat. Edn., 1978, 17, 204. 2 5 K. Tanaka, T. Nakai, and N. Ishikawa, Tetrahedron Letters, 1978, 4809. 26 G. H. Posner, P.-W. Tang, and J . P. Mallarno, Tetrahedron Letters, 1978, 3995. '' U. Melamed and B. A. Feit, J.C.S. Perkin I, 1978, 1232. 28 H. Neurnann and D. Seebach, Chem. Ber., 1978,111,2785. 29 D . Caine and A. S . Frobese, Tetrahedron Letters, 1978, 5167. 30 S. J . Branca and A. R. Smith, J. Amer. Chem. SOC.,1978, 100, 7767. 3 1 D. Masure, C. Chuit, R. SauvEtre, and J . F. Norrnant, Synthesis, 1978, 458. 22

Organometallics in Synthesis

205

Species (30) derived from R C H O and CH,=C(Li)SEt are isomerized by acid to a- thiolated ketones.’2a Oxidation to sulphoxide and elimination gives the unsaturated ketone. Allenyl analogues of the above reagent add to epoxides to give products which can undergo further useful synthetic modification.32hThe Shapiro method for the generation of vinyl-lithiums from sulphonyl hydrazones has been applied to a new one-pot syn-thesis of a- methylene-y-lactones involving elimination and carboxylation of the trianionic intermediate (3l).” ?H

Metal-lithium lithiums.

N,fiSO,Ar

exchange reactions provide alternative sources of vinyl-

Metal-Lithium Exchange.-The relative ease of hydrostannation of acetylenes, coupled with a ready Sn-Li exchange, has been exploited both in syntheses of dienals (from ketones and HCEC-CH=CHOE~),’~ as well as in the preparation of vinyl-lithium intermediates useful in prostaglandin syntheses.35 The vinyl-stannane Bu3SnCH=CHSnBu3 was used in an unsuccessful attempt to prepare the unknown LiCH=CHLi.36 However, successive replacement of the Bu’Sn groups by Li was possible, reaction with electrophiles allowing preparation of unsymmetrical internal alkenes. The synthesis of a trisubstituted alkene, depicted in Scheme 5, involves a highly stereoselective [2,3] sigmatropic rearrangement of a lithio-carbanion derived from a stannane p r e c u r ~ o r Sn-Li .~~ transmetallation has been used as an alternative approach to lithiated dithians, and new cyclization procedures have thereby been d e ~ e l o p e d . ~ ~

Reagents: i. KH: ii, Bu,SnCH,I: iii, Bu”Li; iv, Ac,O-py

Scheme 5 32

33 34

35

3h

37 38

( a ) M. Braun, Tetrahedron Letters, 1978, 3695; R. C. Cookson and P. J. Parsons, J.C.S. Chem. Cornrn., 1978, 821: ( h ) R. C. Cookson and P. J. Parsons, ibid., p. 823. R. M. Adlington and A. G. M. Barrett, J.C.S. Chern. Comm., 1978, 1071. R. H. Wollenberg, Tetrahedron Letters, 1978, 717. P. W. Collins, C. J. Jung, A. Grasiecki, and R. Pappo, Tetrahedron Letters, 1978, 3187; S.-M. L. Chen, R. E. Schaub, and C. V. Grudzinskas, J. Org. Chern., 1978,43, 3450. D. Seyferth and S. C. Vick, J. Organornetallic Chern., 1978, 144, 1. W. C. Still and A. Mitra, J. Arner. Chem. SOC.1978, 100, 1927. D. Seebach, I . Willert, A. K . Beck, and B.-T. Grobel, Helu. Chitn. Acta, 1978, 61, 2510.

206

General and Synthetic Methods

Various derivatives of general formula M2CH2(M = Ph2As, Ph2Sb,or Ph,Pb) give species MCH2Li with RLi.39" The lead derivative in particular can be lithiated and caused to react twice, and thus can be considered a Li2CH2 equivalent. The metallized alcohols resulting from reaction with ketones undergo thermal elimination to R'R2C=CH2.39h,c A Ph3Pb precursor has also been used to prepare the novel ambident nucleophile Li[Me3SiC(C1>CH=CH2].40

Miscellaneous Reactions.-a- Alkoxylated a- lithioacetates may be alkylated,41u,b may react with ketones4"' (the products from which cyclize to plactones, themselves precursors of enol ethers by C 0 2elimination4"), and may be condensed with lactones, as applied in a synthesis of natural product derivative^.^'^" The trianion derived from PhCH(OH)CB,H is. C-alkylated but only in mediocre yield.42 The anions PhSCHCO, and PhSCHC0,Me react efficiently with electrophiles; however, the former adds 1,2 to a$-unsaturated ketones, whereas the latter adds 1,4.43 The sequence outlined in Scheme 6 is one example of a general regio- and stereo-selective y-substitution of allylic The sodium salts (32; X = CN or C0,Et) replace one NO2 group of gem-dinitro-compounds to give p- nitro-sulphones, Na,S reduction of which generates a,p- unsaturated nitriles or and the organofluorine reagents CF,CH,XR' (X = 0 or S) are converted into R 2 C ~ C X R by ' reaction with R2Li.46Bis-thioacetals [e.g. (33)] undergo novel MeLi-induced ring closure to functionalized cycloalkenes [e.g. (34)] by an apparent H-Li exchange and further reaction via a carbenoid intermediate.47" In contrast, the near quantitative cyclization of (35) to a cyclopropane dithioacetal involves unprecedented nucleophilic displacement of SPh by a derived car bani or^.^'^ Such cyclopropane dithioacetals undergo reductive SPh-Li exchange with LiClOHs(cf. also ref. 16b).47c

1

Reagents: i, MeLi; ii. CuI; iii, MeLi (X = CuRLi); iv, Bu,PN(Me)Ph (X

I

=

Bu,P'); v, X = Bu,P'

Scheme 6 3y

40 41

42 43 44 45

4h 47

( a ) T. Kauffmann, K.-J. Echsler, A. Hamsen, R. Kriegesmann, F. Steinseifer, and A. Vahrenhorst, Tetrahedron Letters, 1978,4391; ( b )T. Kauffmann, A. Hamsen, R. Kriegesmann, and A. Vahrenhorst, ibid., p. 4395; ( c )T. Kauffmann, H. Ahlers, R. Joussen, R. Kriegesmann, A. Vahrenhorst, and A. Woltermann, ibid., p. 4399. D. Seyferth and R. E. Mammarella, J. Organometallic Chem., 1978, 156, 279. ( a ) W. Adam, L. A. Encarnacion, and H.-H. Fick, Synthesis, 1978,828; ( 6 ) W. Adam and H.-H. Fick, J. Org. Chem., 1978,43,772; ( c )W. Adam and H.-H. Fick, ibid., p. 4574; ( d )A. J. Duggan, M. A. Adams, P. J. Brynes, and J. Meinwald, Tetrahedron Letters, 1978,4323; ( e )A. J. Duggan, M. A. Adams, and J. Meinwald, ibid., p. 4327. M. Newcomb and D. E . Bergbreiter, J. Org. Chem., 1978, 43, 3963. S . Yamagiwa, N. Hoshi, H. Sato, H. Kosugi, and H. Uda, J.C.S. Perkin I, 1978, 214. U. Tanigawa, H. Ohta, A. Sonoda, and S.-i. Murahashi, J. Amer. Chem. Soc., 1978, 100, 4610. N. Ono, R. Tamura, J.-I. Hayami, and A. Kaji, Tetrahedrorr Letters, 1978, 763. K. Tanaka, S . Shiralshi, J. Nakai, and N. Ishikawa, Tetrahedron Letters, 1978, 3103. ( a ) T. Cohen, D. Ouellette, and W. M. Daniewski, Tetrahedron Letters, 1978, 5063; ( 6 ) T. Cohen and W. M. Daniewski, ibid., p. 2991 ; ( c )T. Cohen, W. M. Daniewski, and R. B. Weisenfeld, ibid., p. 4665.

207

Organometallics in Synthesis R l ArS02 -C-

I X

Na+

nCH(SPh),

(PhS),CH

a PhS

(33)

(32)

SPh

I

RCHCH,CH(SPh),

SPh

(34)

(35)

Lithium in ethylamine reduces hindered secondary and tertiary alcohol acetates to the hydrocarbon, release of steric strain apparently acting to overcome the more commonly observed acyl-oxygen cleavage.48Cyclo-octatetraene [COT] is readily derived from 1,5-cyclo-octadiene by oxidation (0,)of the salt derived by reaction with PhNa-TMED, or by CdC1, oxidation of the dilithium salt of COT diani~n.~~

3 Group I1 Magnesium.-The recent preparation of a reactive form of MgH2 from Et2Mg and LiAlH, has opened up several new synthetic possibilities. Bis(cyc1opentadieny1)titanium dichloride, [Cp2TiCI2],catalyses the addition of MgHz to Yields decrease with increasing substitution, alkenes, hydrolysis giving but both internal and terminal alkynes may be reduced in about 60% yield to alkenes. The intermediate organomagnesium reagent decomposes on standing, as judged by the decreasing amount of deuterium incorporation. However, CuI or CuOBu' catalyses addition to alkynes only, high yields of alkenes being formed stereospecifically.50bThe hydrides HMgX (X = 2,6-di-isopropylphenoxy or dialkylamino) are efficient reducing agentss1 The former reduces RI and carbonyl functionalities to the exclusion of most other common groups, and exhibits high stereoselectivity in the reduction of cyclic and bicyclic ketones. Several new synthetic techniques have appeared which enable the introduction of a carbonyl functionality. Pentacarbonyliron and a Grignard reagent give an acyl metallic species which can either be alkylated (RI) to give ketoneszaor alkoxylated (ROH-I,) to ester.52bThe experimental procedures are simple and high yields of pure product are obtained. The applicability of the intermediate as a direct acyl anion equivalent is notable. Reagents (36; X = H or R) are useful formylating or acylating agents for Grignard C O ~ ~ O U Dithioesters ~ ~ S . ~ ~ are formed from RMgX addition to PhNCS and methylation, followed by the action of H2S,54aand also by reaction of allylic derivatives with CS, followed by MeI.54b Thiophilic addition of EtMgI to dithioesters themselves, followed by reaction with an electrophile, gives dithioacetals; the method can be extended to build up quite complex s t r ~ c t u r e s . ~ ~ ~

49

5o

'' 52

53

54

R. B. Boar, L. Joukhadar, J. F. McGhie, S. C. Misra, A. G. M. Barrett, D. H. R. Barton, and P. A. Prokopiou, J.C.S. Chem. Comm., 1978, 68. W. Gausing and G. Wilke, Angew. Chem. Znternat. Edn., 1978, 17,371. ( a ) E. C. Ashby and T. Smith, J.C.S. Chem. Comm., 1978,30; ( b )E. C. Ashby, J. J. Lin, and A. B. Goel, J. Org. Chem., 1978, 43, 757. E. C. Ashby, J. J. Lin, and A. B. Goel, J. Org. Chem., 1978,43, 1557, 1560, 1564. ( a ) M. Yamashita and R. Suemitsu, Tetrahedron Letters, 1978, 761; ( b ) M. Yamashita and R. Suemitsu, ihid., p. 1477. D. L. Comins and A. I. Meyers, Synthesis, 1978,403; A. I. Meyers and D. L. Comins, Tetrahedron Letters, 1978, 5179. ( a ) P. Gosselin, S. Masson, and A. Thuillier, Tetrahedron Letters, 1978, 2715; ( b ) B. Cazes and S. Julia, ibid., p. 4065; ( c )A. I. Meyers, T. A. Tait, and D. L. Comins, ibid.,p. 4657.

208

General and Synthetic Methods

The addition of R’MgBr to a-chloro-ketones gives (37) which on lithiation extrudes ‘LiMgBrO’ to yield alkenes.” The fact that spiroactivated cyclopropanes are susceptible to nucleophilic attack has been extended to organometallics, and exploited in the conversion of (38) into (39) by acetylenic Grignard addition during a synthesis of (*)-Brefeldin A.“

n

NMe

BrMgO

CI

I

I

R1R3C-CHRZ

RO--

RO--

‘X

Ally1 Grignard reagents add to 3,3-dimethylcylopropene in a new approach to chrysanthemic and organomagnesium reagents perform a series of interesting reductive alkylations of nitro-aromatics. 5 x Recent examples of transition metal-catalysed Grignard additions include the alkylation of terminal acetylenes, using [CuBr(Me,S)] catalyst, further reaction giving trisubstituted alkenes or homoallylic alcohol^.^^*^^ The intermediate vinylmetallics can be alkylated with homopropargyl iodides, as a new entry to juvenile Cuprous chloride allows condensation of RMgX with hindered acid chlorides, giving highly branched ketones in remarkably high yields.59“Unsymmetrical allylmagnesium derivatives undergo a complete reversal of regiochemical addition to epoxides if 10% CuI is present,”‘ and Cu similarly promotes the 1,6-addition of benzylic Grignards to exocyclic dienones, the products acting as intermediates in a new synthesis of ring C aromatic diterpene~.’~’ Both alkenyl and alkyl RMgX condense with vinyl iodides in the presence of [Pd(PPh,),]. 5 9 g The diene products are usually produced stereospecifically. Zinc and Mercury.-A remarkable new C-C bond-forming reaction involves a high-yield trimolecular condensation between alkyl halides, activated alkenes, and carbonyl compounds promoted by Zn in MeCN [equation (l)].“)Cyclic bifunctional products are obtained when halogeno-ketones react under these conditions with acrylonitrile or methyl acrylate. Cyclopentene derivatives are

55 56 57 58

59

60

J. Barluenga, M. Yus, and P. Bernad, J.C.S. Chern. Comm., 1978, 847. T. Livinghouse and R. V. Stevens, J.C.S. Chem. Comm., 1978, 754. H. Lehmkuhl and K. Mehler, Annalen, 1978, 1841. ( a ) G . Rartoli, M. Bosco, and G. Pezzi, J. O r g . Chem., 1978,43,2932; ( h ) G . Bartoli, R. Leardini, A. Medici, and G . Rosini, J.C.S. Perkin I, 1978, 692; G. Bartoli, A. Medici, G. Rosini, and D. Tavernari, Synthesis, 1978, 436. ( u ) A. Marfat, P. R. McGuirk, and P. Helquist, Tetrahedron Letters, 1978, 1363; N. J. LaLirna, jun. and A. B. Levy, J. O r g . Chem., 1978, 43, 1279; ( h ) P. R. McGuirk, A. Marfat, and P. Helquist, Tetrahedron Letters, 1978, 2465; ( c )H. Westmijze, H. Kleijn, and P. Vermeer, ibid., p. 3125; ( d )C. Lion, J.-E. Dubois, and Y. Bonzougou, J. Chern. Res. ( S ) , 1978,46; ( e )G. Linstrumelle, R. Lorne, and H. P. Dang, Tetrahedron Letters, 1978, 4069; ( f ) B. R. Davis and S. J. Johnson, J.C.S. Chem. Comm., 1978, 614; ( g ) H. P. Dang and G. Linstrumelle, Tt7trahedron Letters, 1978, 191. T. Shono, I . Nishiguchi, and M. Sasaki, J. Amer. Chem. Soc., 1978, 100, 4314.

Organometallics in Synthesis

209

produced in modest yield by reaction between substituted propargyl bromides and activated alkenes, again under the influence of Zn.61RCECZnC1 displaces Br or I from aryl halides under Pd catalysis.62CH212-Znis already known to effect ketone methylenation in poor yield, but it has now been found that addition of AlCl, or TiC14 brings the yields up to synthetically useful values.63 New examples of peroxymercuration continue to appear, particularly for the synthesis of cyclic peroxides. The first example of four-membered ring formation provides a novel synthetic entry into 1,2-dioxetans (Scheme 7).64a Allylic

Reagent: i, Mg(OCOCF,)2-CFCl,, -40 "C

Scheme 7

mercuration occurs besides addition to the unsaturated bond. Other unsaturated hydroperoxides have also been cyclized to peroxides.64b'The peroxide (40) is of interest as a nearly strain-free homologue of the nucleus of prostaglandin endoperoxides ; derivatives are formed by reaction of cyclo-octa-1,4-diene with Hg(OCOCF3)2-H202.65a The corresponding 1,5-isomer gives derivatives of (41) under analogous conditions."' A relatively mild hydrolysis of vinyl chlorides tc ketones uses Hg(OAc),-HOAc-BF3,Et2O as reagent.66 Alkynes can be dimerized in a head-to-tail fashion to unsymmetrical 1,3-dienes (42) in excellent yield uia vinyl mercurial^.^^" 1,4-Dienes are obtained from the same intermediates and excess ally1 both reactions being catalysed by transition-metal systems.

4 Group I11

Boron.-Hydroboration and B-C Bond Formation. There have been several efforts aimed at stabilizing those alkylboranes with established synthetic use but limited stability; (CH2NMe2)2(TMED) complexes of BH2R and BHR2 are air 61

62 63 64

66 67

M. Bellassoued, Y. Frangin, and M. Gaudemar, Synthesis, 1978, 150. A. 0. King, E.-i. Negishi, F. J. Villani, jun., and A. Silveira, jun., J. Org Chem., 1978, 43, 358. K. Takai, Y. Hotta, K. Oshima, and H. Nozaki, Tetrahedron Letters, 1978, 2417. ( a )W. Adam and K. Sakanishi, J. Amer. Chem. Soc., 1978,100,3935; ( b )J. R. Nixon, M. A. Cudd, and N. A. Porter, J. Org. Chem., 1978,43,4048. ( a ) A. J. Bloodworth and J. A. Khan, Tetrahedron Letters, 1978, 3075; ( b ) W. Adam, A. J. Bloodworth, H. J. Eggelte, and M. E. Loveitt, Angew. Chem. Internat. Edn., 1978, 17,209. S. F. Martin and T.-s. Chou, Tetrahedron Letters, 1978, 1943. ( a ) R. C. Larock and B. Riefling, J. Org. Chem., 1978,43, 1468; ( b ) R. C. Larock, J. C. Bernhardt, and R. J. Driggs, J. Organometallic Chem., 1978, 156, 45.

210

General and Synthetic Methods

stable and can be stored for prolonged periods, the free borane being regenerated with BF3,Et20.68Unlike the free reagent, thexylborane is stable for two months at 0 "C when complexed with PhNEt2.69The complex exhibits graded hydroboration and reducing behaviour compared with the free borane. Monoisopinocampheylborane (43) has been prepared quantitatively by displacement of Me2C=CMe, from the Et,N adduct of thexylborane with a-pinene, and in 100°/~ optical purity from the TMED adduct of 94% optically pure di-isopino~ampheylborane.~'~ Ph2BH is a new hydroboration reagent prepared by a procedure including the addition of PhMgBr to (MeO),B and LiAlH, reduct i ~ nSince . ~ ~fewer secondary R groups are formed in RBPh2from hydroboration of terminal alkenes, the materials are particularly suited to the free-radical addition of R to enones, where secondary radicals are generally produced faster than primary. The metathesis between Et,B and B(NEt2), gives Et,BNEt, which is trans-esterified and reduced to Et,BH q ~ a n t i t a t i v e l yThere . ~ ~ is no scrambling of deuterium in the reaction between BD, and cyclo-octa-1,5-diene to give [9-*H]-9-BBN (44).73 Stereochemically pure cis-alkenylboranes are given by the hydroboration (R,BH) of 1-halogenoalkynes, followed by ButLi reduction, uia the intermediate (45).74Deprotonation of a- (pheny1thio)alkaneboronicesters gives intermediates D

(43)

(44)

(45)

suitable for the formation of hindered alkylboron derivatives, as well as several useful synthetic procedures (Scheme 8).75 Ar,Sn and Ar,Pb react with excess BH3 to give a r y l b o r a n e ~ . ~ ~

Reactions of Organoboranes. Lead tetra-acetate and P ~ I ( O A Coxidize )~ R3B to ROAc, but the former reagent reacts preferentially with secondary R, whereas the latter oxidizes only primary R, and each only oxidizes two of the three These same reagents bring about R migration in vinyl-BR2 available R yielding R-vinyl, including brominated derivative^.^^' The stereochemistry of the product alkene is dependent on the conditions used, but it is notable that the 68 69

70

71

72 73 74

7s

76

77

B. Singaram and J. R. Schwier, J. Organometallic Chem., 1978, 156, C1. A. Pelter, D. J. Ryder, and J. H. Sheppard, Tetrahedron Letters, 1978, 4715. ( a ) H. C. Brown and A . K. Mandal, Synthesis, 1978, 1'46; ( b ) H. C. Brown, J. 2. Schwier, and B. Singaram, J. Org. Chem., 1978, 43, 4395. P. Jacob, J. Organometallic Chem., 1978, 156, 101. S. K. Gupta, J. Organometallic Chem., 1978, 156, 95. M. M. Midland and S. Greer, Synthesis, 1978, 845. J. B. Campbell, jun. and G . A . Molander, J. Organometallic Chem., 1978, 156, 71. ( a ) D. S. Matteson and K. Arne, J. Amer. Chem. SOC.,1978,100, 1325; ( b )A . Mendoza and D. S. Matteson, J. Organometallic Chem., 1978, 156, 149. F. G. Thorpe, S. W. Breuer, G . M. Pickles, T. Spencer, and J. C. Podesta, J. Organometallic Chem., 1978,145, C26. ( a ) Y . Masuda and A. Arase, Bull. Chem. SOC.Japan, 1978,51,901; ( b )Y. Masuda, A . Arase, and A. Suzuki, Chem. Letters, 1978, 665.

21 1

Organometallics in Synthesis

I

I

(Ref.756)

SPh SPh

si; < I

I

/

HI

PhCHzCH(0H)Ph

52%

SPh H&B(

2 PhCH2C-B<

RCHCOR'

I

I Ph

SPh

Reagents: (Ref. 7 5 ~ )i,: LDA; ii, R'X; iii, R'COX; iv,

v

fi0 v (R

=

H); V, I- (R

=

CH,Ph);

vi, PhMgBr; vii, [O]; (Ref. 756): viii, NCS-MeOH

Scheme 8

preferred stereochemistry is opposite for each reagent. Boranes derived from cyclic alkenes are converted into cyclic ketones by pyridinium chlor~chromate.~~ Alkenylboranes have usually been hydrolysed under acidic conditions, but it has now been found that P ~ ( O A Cefficiently )~ catalyses neutral protonolysis, solvent THF or acetone acting as proton source.79Organoboranes alkylate propenoate esters electrochemically in fair to excellent yields, but only when the anion of the supporting electrolyte is Br- or I-.'' The boron-stabilized carbanion (46) reacts with ketones to give alkenediboronic esters (47), iodination of which leads to 1,l-di-iodoalkenes.81 Alternatively, (47; R' = Ph, R2 = H) is methylated at boron by MeLi, oxidation by air or perborate inducing first alkyl migration, then cleavage to PhCH2COMe.82 The chiral boronic ester (48), prepared from the corresponding triallylborane and diol, effects an enantioselective synthesis (-70% enantiomeric excess) of secondary homoallylic alcohols on reaction with aldehydes.83Triethanolamine borate, B(OC2H4),N, suppresses polyalkylation of lithium enolates; only the monoalkylated material is

(46)

79

82

83 84

(47)

(48)

V. V. Rarnana Rao, D. Devaprabhakara, and S. Chandrasekaran, J. Organometailic Chem., 1978, 162, C9. H. Yatagai, Y. Yamarnoto, and K. Maruyarna, J.C.S. Chem. Comm., 1978,702. Y .Takahashi, K. Yuasa, M. Tokuda, M. Itoh, and A. Suzuki, Bull. Chem. SOC.Japan, 1978,51,339. A . Mendoza and D. S. Matteson, J. Organometallic Chem., 1978, 152, 1. R. J. Moody and D. S. Matteson, J. Organometallic Chem., 1978, 152,265. T. Heroid and R. W. Hoffrnann, Angew. Chem. Internat. Edn., 1978, 17, 768. M. W. Rathke and A. Lindert, Synth. Comm., 1978, 8, 9.

General and Synthetic Methods

212

Reactions of Organoborates. Scheme 9 reveals a fundamental synthetically useful difference between the 3-migration cyanoborate and borane carbonylation react i o n ~ The . ~ ~thermodynamically more stable cyanide adduct is formed prior to electrophile-induced migrations, in contrast to the kinetically determined product resulting from carbonylation. Carbonylation of R3B in the presence of LiAlH(OMe), followed by treatment with acid and oxidizing agent is a particularly mild method for the preparation of secondary carbinols.R6

9

H

H

Q

,1--111

H'.

'H

H--

Reagents: i, KCN; ii, (CF,CO),O, 40 " C ; iii, H,O,-OH-;

9 H

IV,111)

'H

H'+

'H

iv, CO-(CH,OH),, 150 "C, 70 atm

Scheme 9

Addition of electrophiles to alkynylborates provides a variety of useful products. Further examples result from the reaction of R3B with Me3SnC_CR' : the reagent effectively dismutes to acetylide anion, which adds to the borane, and Me3Sn+,which induces migration to give (49).87aA second molecule of stannane (Me3SnC=CR2)reacts in a similar fashion under more forcing conditions to give the novel polymetallated species (50) (after subsequent allylic rearrangement). Me2Sn(C=CR'), reacts with R3B to give the stannacyclopentadiene ( 5 1y7' Further new reactions of alkynylborate salts involve the use of PhSeCl to induce migration followed by oxidative C-B cleavage, Se oxidation, and elimination, to give conjugated enonesagand, secondly, attack by BF3,0Et, or Bu3SnC1on (52), leading to 1,4-disubstituted ( E , Z ) -1,3-dienes resulting from vinyl migrati~n.'~ R'

(49)

(50)

(51)

(52)

2-Lithioindole and R3Bgive an ate-complex which undergoes R migration after I2 attack; R2BIis eliminated from the intermediate to give 2-alkylindoles in good yield." Allylic borate complexes undergo regiocontrolled head-to-tail coupling with allylic halides, resulting in the formation in high yields of 1,5-dienes [equation (2)].91 86

88

89

91

A. Pelter, P. J. Maddocks, and K. Smith, J.C.S. Chern. Comrn., 1978,805. J. L. Hubbard and H. C. Brown, Synthesis, 1978,676. ( a ) B . Wrackrneyer and R. Zentgraf, J.C.S. Chem. Comrn., 1978, 402; ( b ) L. Killian and B. Wrackmeyer, J. Organornetallic Chem., 1978, 148, 137. J. Hooz and R. D. Mortimer, Canad. J. Chern., 1978,56, 2786. G . Zweifel and S. J. Backlund, J. Organornetallic Chern., 1978, 156, 159. A. B . Levy, J. Organometallic Chem., 1978, 43, 4684. Y. Yamamoto and K. Maruyarna, J. Amer. Chern. SOC.,1978, 100,6282.

Organometallics in Synthesis

213

An R group in the ate-complex from R3B and LiCrCCH,CI migrates spontaneously at -90 "C, further reaction leading to homopropargylic or a- allenic alcohols, depending on conditions (Scheme Similar types of ate-complex

RC=CCH,CHR'

I

OH Reagents: i, -90 "C; ii, 25 "C; iii, R'CHO, -78 "C; iv, [O]

R \C=CH2

/-

R'CHOH

Scheme 10

intermediates which rearrange with simultaneous elimination of an electronegative cy -substituent occur in several other new borate reactions. The first direct carboxylic acid synthesis based on organoboron intermediates occurs as in equation (3).93 Chloramine-T (TsNC1- Na') and R3B react to give-tosylated a l k y l a m i n e ~(unfortunately ~~ only one R per R3B is used), and Me3SiCHBr and R3B give Me,SiCH(OH)R after ~ x i d a t i o n . ~ ~ R R3B + PhOCHCO;

-D

[ate-complex] + Rz13&-IC0, -+ RCH2C02H

(3)

Reducing Agents. B-Alkyl-9-BBN is a mild, chemoselective reducing agent for aldehydes.96 Sodium borohydride modified by CdC12,1iDMF in MeCN-HMPA reduces RCOCl to RCHO; groups such as C1, CN, NOz, C 0 2 R , and C=C are u n a f f e ~ t e dAlthough .~~ yields are good, about 10% of the corresponding alcohol is also produced. Two new methods for reducing C-0 bonds involve the reduction of alkyl tosylates by LiEt3BH,98and reduction of acetals to ethers by methanolic NaBH3CN in the presence of gaseous HCl.99 As a cheap alternative to NaBH3CN, NaBH4 in H O A c reduces carbonyl tosylhydrazones,"' and BH3CNsupported on an anion exchange resin is a selective, environmentally acceptable reducing agent."' Aluminium and Thallium.-Acetylenes are carbometallated by the reagent system R3Al-[Cp2ZrClZ], giving rise to vinylalanes [e.g. (53)] which may be y2

93 94

95

96

' 9 98 99

''' lo'

G. Zweifel, S. J. Backlund, and T. Leung, J. Amer. Chem. Soc., 1978, 100, 5561. S. Hara, K. Kishimura, and A. Suzuki, Tetrahedron Letters, 1978, 2891. V. B. Jigajinni, A. Pelter, and K. Smith, Tetrahedron Letters, 1978, 181. 0. Rosario, A. Oliva, and G . L. Larson, J. Organometallic Chem., 1978, 146, C8. M. M. Midland and A. Tramontano, J. Organometallic Chern., 1978, 43, 1470. R. A. W. Johnstone and R. P. Telford, J.C.S. Chem. Comm., 1978, 354. S . Krishnamurthy, J. Organometallic Chem., 1978, 156, 171. D. A. Horne and A. Jordan, Tetrahedron Letters, 1978, 1357. R. 0. Hutchins and N. R. Natale, J. Organometallic Chem., 1978, 43, 2299. R. 0. Hutchins, N. R. Natale, and I. M. Taffer, J.C.S. Chern. Comm., 1978, 1088.

214

General and Synthetic Methods

hydrolysed, halogenated, or ethoxycarbonylated (ClC0,Et) in high yield and high stereo- and regio-selectivity to trisubstituted alkenes. 102*103 The aluminate intermediates derived from the vinylalane and Bu"Li offer a similarly highly stereoselective entry to terminally functionalized alkenes (Scheme 1l ) . ' 0 3 Unlike

Reagents: i, Me,Al-[Cp,ZrCI,]; ii, Bu"Li; iii, (CH,O),

Scheme 11

related systems, vinylalanes do not undergo cross-coupling reactions in the presence of Pd or Ni complex catalysis. However, a new approach which uses a second metal catalyst overcomes this problem, as in reaction (4)where either ZnClz or CdC1, acts as co-catalyst with [Pd(PPh,),]. lo4 Alkynylalanes undergo conjugate addition in the presence of a'Ni catalyst to s-truns-a,p-enones in good yield. ' 0 5

EtCH=C(Et)AIBu,

+

6

+

EtCH=C(Et)

I

The reagent system LiA1H4-transition-metal halide reduces alkenes and alkynes with varying degrees of ease.lo6Thus, for instance, PhCGCH is reduced to styrene by LiAIH4-FeCl,, but to PhEt by LiA1H4-NiCl2.The intermediate M-R species are unstable, as revealed by the extent of deuterium incorporation. The species R4AI- have recently become available by reaction of alkenes with LiAlH,-TiCl,. Further synthetic transformations include halogenation ( C U X ~ ) , three-carbon ~'~~ homologation (ally1 halide + CUC~),'~''conversion into terminal allenes (propargyl bromide + CuCI),'07' and alkylborane formation (BF3,0Et,).'07d Organoallanes react with SO, to give sulphinic acids (precursors to sulphones),"* are oxidized by Me3k0,109and undergo C-C bond formation with alkynyl bromides in the presence of a Ni complex catalyst leading to internal acetylenes.' lo

Io4

lo8

'lo

D. E. Van Horn and E . 4 . Negishi, J. Amer. Chem. SOC., 1978, 100, 2252. N. Okukado and E.-i. Negishi, Tetrahedron Letters, 1978, 2357. E.-i. Negishi, N. Okukado, A. 0.King, D. E. Van Horn, and B. I. Spiegel, J. Amer. Chem. SOC., 1978, 100,2254. R. T. Hansen, D. B. Carr, and J. Schwarz, J. Amer. Chem. SOC., 1978,100, 2244. E. C. Ashby and J. J. Lin, J. Org. Chem., 1978,43,2567. ( a ) F. Sato, Y. Mori, and M. Sato, Chem. Letters, 1978, 833; ( b ) F. Sato, H . Kodama, and M. Sato, J. Organometallic Chem., 1978, 157, C30; ( c ) F. Sato, K. Oguro, and M. Sato, Chem. Letters, 1978, 805; ( d )F. Sato, S . Haga, and M. Sato, ibid., p. 999. A . V. Kuchin, L. I. Akhmetov, V. P. Yur'ev, and G. A. Tolstikov, J. Gen. Chem. U.S.S.R.,1978,42, 420. G . W. Kabalka and R. J. Newton, jun., J. Organometallic Chem., 1978, 156, 6 5 . G. Giacomelli and L. Lardicci, Tetrahedron Letters, 1978, 2831.

Organometallics in Synthesis

215

2-Thiazoline-2-thiol esters (54), readily prepared from carboxylic acids, are reduced to aldehydes by Bui2AlH.l 1 0 RCS-() N (54)

The thallium reagent TlOPh reacts with HCN to give TlCN, useful for the conversion of acyl chlorides into acyl cyanides (or their dimers) and of C1C02R into CNC02R.l12 a-Iodo-ketones are generated from enol acetates by the reagent combination T10Ac-12,1l 3 and T1(N03)3converts enolizable ketones into a-nitrato-ketones, RCOCH20N02,in high ~ i e 1 d . l ' ~ The prostaglandin carbon skeleton undergoes a novel functionalization at C-7 by oxidation with TI(OAc),; e.g. PGF2, methyl ester (55) is converted into the cage compounds (56) and (57), apparently via a species previously reported as an unstable intermediate in the enzymic conversion of arachidonic acid.'15 3: Arylpropionic and cinnamic acid derivatives differ markedly in their oxidations whereas (60) undergoes by Tl(CF3C02)3.Thus, (58) is oxidized to (59),116a coupling of the generated radical cations, followed by ring closure to the symmetrical fused bis-lactone (61).116b

(0O ' r

'I'

'" 'I4 *Is

c

o

2

H

0

Y. Nagao, K. Kawabata, and E. Fujita, J.C.S. Chern. Comm., 1978, 330. E. C. Taylor, J. G. Andrade, K. C. John, and A. McKillop, J. Org. Chem., 1978,43,2280. P. D. Woodgate, J.C.S. Perkin I, 1978, 126. A. McKillop, D. W. Young, M. Edwards, and R. P. Hug, J. Org. Chem., 1978,43, 3773. V. Simonidesz, Z. Gombos-Visky, G. Kovacs, E. Baitz-Gacs, and L. Radics, J. Amer. Chern. Soc., 1978,100,6756. ( a ) E. C. Taylor, J. G . Andrade, G. J. H. Rall, and A. McKillop, J. Org. Chem., 1978, 43, 3632; ( b ) E. C. Taylor, J. G. Andrade, G. J. H. Rall, and A . McKillop, Tetrahedron Letters, 1978, 3623.

General and Synthetic Methods

216 5 GroupIV

Silicon.--a-Metallated Silanes. Scheme 12 depicts a reaction which can be accomplished by the use of a variety of Al-based reagent combinations. Significantly, the vinylsilane product is further functionalized by a second metal with the consequence that further synthetic modification by reaction with electrophiles is possible. Simple hydroalumination gives (62; X = H, M = Bui2A1)as an intermediate in a high-yield stereoselective route to (63; E = Cl, Br, or ,).I1' Methylmagnesium bromide and EtMgBr add to give (62; X = Me, H respectively) in the presence of [ N i ( a ~ a c ) ~ and ] Me,Al or HA1Bui2, but with less stereoselectivity."' The silane (62; X = R', M = Ti) results from nonstereoselective addition of Cl2A1R1-[Cp2TiCl2],hydrolysis leading to good yields of Z-E mixtures of vinyl~ilanes."~

-

RC_CSiMe,

R

R

SiMe,

)=(

X

+

SiMe,

>=(

X

M

(62)

E

(63)

Scheme 12

New developments and applications of a-lithiated silanes are becoming commonplace. Silylated ally1 carbanions add to ketones regioselectively at the C atom a- to Si under the influence of MgBr2.I2' An elimination gives rise to 1,ldialkylated 1,3-dienes. A mixture of isomers of (64) is derived from chloroacetate ester and ketones via the intermediacy of (65),I2l and tetrasubstituted alkenes

R1R2C=C

/

Me$

CI

H

I

I

Li-C-CONMe,

CI-C-CO,Bu'

I

I

\

C0,Bu'

SiMe,

Li

(64)

(65)

(66)

may be prepared as in Scheme 13.'22 The silylated amide derivative (66) condenses with a variety of electrophiles; (66) has the advantage of stability relative to the analogous CH, Me,SiK

Li

CH,

>' Me,Si

R' (R2

OAC

-

R3CH R2 & A Me,Si R'

R3CH X

R2

&R'

Reagents: i, R'R2C=O; ii, Ac'; iii, R:CUM; iv, Xi

Scheme 13 'I7 'I8

'I9 12(' 12'

lZ2

G. Zweifel and W. Lewis, J. Org. Chem., 1978, 43, 2739. B. B. Snider, M. Karras, and R. S. E. Conn, J. Amer. Chem. SOC.,1978, 100, 4624. J. J. Eisch, R. J. Manfre, and D. A. Komar, J. Organometullic Chem., 1978, 159,C13. P. W. K. Lau and T. H. Chan, Tetrahedron Letters, 1978, 2383. T. H. Chan and M. Moreland, Tetrahedron Letters, 1978, 515. R. Amouroux and T. H. Chan, Tetrahedron Letters, 1978, 4453. R. P. Woodbury and M. W. Rathke, ( a )TetrahedronLetters, 1978,709;( b )J. Org. Chem., 1978,43, 1947.

Organometallics in Synthesis

217

Vinylsilanes (67) act as Michael acceptors for R'Li.'24" The generated carbanions react with SO, to give sulphines (68), and since (67) can be derived from a ketone and (68) can be converted into a second ketone the procedure formally corresponds to nucleophilic attack a- to ketone carbonyl. Sulphines can also be prepared from carbanions derived from silanes by a - d e p r ~ t o n a t i o n . ~ ~ ~ ~ The silyl substituent in (69) directs orientation of enolate generation and thus allows regiospecific preparation of acyclic a l d ~ l s . ' ~ ~ Applications have appeared of the use of Me3SiCR(C1)Liin natural product synthesis.'26For instance, reaction with a ketone precursor gives the epoxide (70), an intermediate in the synthesis of Latia luciferin. Esters acylate LiCH,SiMe3 to a- trimethylsilyl-ketones which can be converted into methyl ketones by known method01ogy.l~~ Me3SiCH2CI reacts with lithium tetramethylpiperidide and alkenes to give silylated cyclopropanes. 12' The latter are also prepared by reaction of Me3SiCH=SMez with cyclic enones; ring-fused products are intermediates in ring-expansion procedure^.'^^

Hydrosilation and Fluorosilicates. A simple and efficient new development in Si -C bond cleavage methodology opens up the possibility of applying hydrosilation techniques in synthesis more generally than heretofore. Thus, H2PtCl6catalysed addition of HSiCI3 to alkenes or alkynes followed by reaction with KF gives KC2RSiFSZP q~antitatively.'~'Subsequent reaction with halogens, NBS, or CuX, yields the anti-Markovnikoff hydrohalogenated alkenes and alkynes (the latter stereospecifically trans),'30"" oxidative cleavage with m-chloroperbenzoic acid gives high yields of alcohols (from terminal alkenes),130band the vinyl derivatives can be induced to couple with allyl chloride, giving 1,4-dienes.130d The lability of some Si-bound moieties in the presence of F- anion is further exemplified by the F--induced addition of the allyl group of allylsilanes to ketone^'^'" and isomerization of such species in the absence of an electrophile. 13' 124

125 126

12'

129

13'

13'

(a') M. van der Leij and B. Zwanenburg, Tetrahedron Letters, 1978, 3383; (6) M. van der Leij, P. A. T. W. Porskamp, B. H. M. Lammerink, and B. Zwanenburg, ibid., p. 811. I. Kuwajirna, T. Inoue, and T. Sato, Tetrahedron Letters, 1978, 4887. P. Magnus and G. Roy, J.C.S. Chem. Comm., 1978,297. M. Dernuth, Helv. Chim. Acta, 1978, 61, 3136. R. A. Olofson, D. H . Hoskin, and K. D. Lotts, Tetrahedron Letters, 1978, 1677. F. Cooke, P. Magnus, and G. L. Bundy, J.C.S. Chem. Comm., 1978, 714. ( a ) K. Tamao, J.4. Yoshida, M. Takahashi, H. Yamamoto, T. Kakui, H. Matsumoto, A. Kurita, and M. Kumada, J. Amer. Chem. SOC.,1978,100,290; (6) K. Tamao, T. Kakui, and M. Kumada, ibid., p. 2268; ( c ) J. 4. Yoshida, K. Tamao, A. Kurita, and M. Kumada, Tetrahedron Letters, 1978, 1809; ( d ) J.4. Yoshida, K. Tamao, M. Takahashi, and M. Kumada, ibid., p. 2161. A. Hosorni, A. Shirahata, and H. Sakurai ( a ) Tetrahedron Letters, 1978, 3043; ( b ) Chem Letters, 1978,901.

General and Synthetic Methods

218

An R3SiH-BF3 combination reduces ketones and some aldehydes directly and rapidly to hydrocarbons. 132

Miscellaneous Reagents and Reactions. Various reagents of general formula Me3SiX continue to find application in synthesis. The silane iMe3SiON(X)SiMe3 (X = H or Me3Si), for example, converts RCOCl into RNC0,133and another application has provided the first authentic synthesis of unstable HCECNCO. Problems associated with the formation of cyanohydrins from hindered ketones are obviated by use of Me3SiCN.'34 Alkyl carbamates, R'R2NC02R3,are converted by Me3SiI into R'R2NH and R31in high yield,13' and Me3SiBr allows the preparation of alkyl bromides from alcohols. 136 The reagent system Me3SiC1-NaI dealkylates esters, ethers, acetals, and dialkylphosphonates in very high yields,13' and Ph3C'C104- and Bu',MeSiH give the covalent reagent But2MeSiOC103 which silylates alcohols very rapidly. 13' Vinylsilanes derived from ketones (generation of vinyl anion by Shapiro reaction) are converted by epoxidation and reduction into p- hydroxyalkylsilanes, which on oxidation with H2Cr04 give the 1,2-transposed ketones.'39 p-Silylketones can be considered synthetically equivalent to masked a$- enones, as exemplified in Scheme 14.140a Silyl anions also undergo conjugate addition to

Me,Si

Me,Si

Reagents: i, NaH-DMF; ii, Bu'I; iii, NaCN-HMPA, 90 "C; iv, Br2-CC14; v, NaF

Scheme 14

a,p-enones in the presence of CuI to give enolates (71) which may be alkylated;1406 desilylation of the P-silyl-ketone, using CuBr,, then gives the a alkylated original enone. 5-Silylated cyclopentadiene undergoes Diels-Alder addition to acrylate estercs, carbonium ions derived from the adducts (72) rearranging to (73).l4Ia Since Me3Si is known not to affect the regioselectivity of butadiene cycloadditions, other substituents should dominate the regioselectivity of the Diels-Alder reaction, as with the use of (74) to give (75).141bScheme 15 summarizes a new rearrangement reaction of chlorosilylalkoxides. 142 Work-up conditions determine the stereochemistry of the product alkene.

133 134

13' 136 13'

138 139

J. L. Fry, M. Orfanopoulos, M. G . Adlington, W. R. Dittman, jun., and S . B. Silverman, J. Org. Chem., 1973, 43, 374. F. D. King, S . Pike, a n d D . R. M. Walton, J.C.S. Chem. Comm., 1978, 351. P. G. Gassman and J. J. Talley, Tetrahedron Letters, 1978, 3773. M. E. Jung and M. A. Lyster, J.C.S. Chem. Comm., 1978, 315. M. E. Jung and G . L. Hatfield, Tetrahedron Letters, 1978,4483. ( a ) T. Morita, Y. Okamoto, and H. Sakurai, J.C.S. Chem. Comm., 1978, 874; (6) T. Morita, Y. Okamoto, and H. Sakurai, Tetrahedron Letters, 1978, 2523. T. J. Barton and C. R. Tully, J. O r g . Chem., 1978, 43, 3649. W. E. Fristad, T. R. Bailey, and L. A. Paquette, J. Org. Chem., 1978, 43, 1621. ( a )I. Flemingand J. Goldhill, J.C.S. Chem. Comm., 1978,176; ( b )ID.J. Ager andI. Fleming, ibid., p. 177.

14'

( a ) I. Fleming and J. P. Michael, J.C.S. Chem. Cornm., 1978, 245; (6) I. Fleming and A. Percival, ibid., p. 178. T. Sato, T. Abe, and I. Kuwajima, Tetrahedron Letters, 1978, 259.

219

Organometallics in Synthesis

I

I

I1

c1

-b BuCH=CHBu

-% BuCH-CHBu

BuCH-C-SiMe3

0

Me&

I

OH

Reagents: i, 2BuMgX; ii, KH (82%, E : Z = 4:96) or BF,,OEt, (85%, E : Z = 95:5)

Scheme 15

The reagent (76) derived from HOCH,CO,H reacts with RCOCl to give (77), from which RCOCH,OH is obtained by hydroly~is;'~~ (76) therefore functions as another example of the -CH20H synthon. Rearrangement of the disilane resulting from reaction between thioallylsilane anion and MesSizClgives (78); AlC13catalysed acylation of (78) leads, for example, to (79) from which the desilylated ketone may be prepared.'44 0 Si M e

Me,SiO

,

4OSiMe, (76)

Me SiOHCO R

Si M e

OSiMe,

0

U

z

e

2

F Ph

(78)

(77)

SiMe3 (79)

Tin.-One of the major uses of stannanes is as precursors to difficultly available lithium derivatives, as discussed above. Scheme 16 represents a further example leading to an a-alkoxyorganolithium reagent, and where the critical intermediate results from addition of R3Sn-. 145 The new reagent PhS(Me3Sn)CuLiefficiently replaces the halogen of p-iodo-a,P-enones by Me3Sn,in contrast to Me3SnLi.146a However, the relative ease of Michael addition of the two reagents to simple a,& enones is reversed.

OYO'i

OYO'i

Reagents: i, Bu,SnLi; ii, EtOCH(Me)CI; iii, Bu"Li; iv, RCI (R = geranyl)

Scheme 16 143 '44

'45 146

A. Wissner, Tetrahedron Letters, 1978, 2749. H. Wetter, Helv. Chim. Acta, 1978, 61,3072. W. C. Still, J. Amer. Chem. SOC., 1978,100, 1481. ( a )E. Piers and H. E. Morton, J.C.S. Chem. Cornm., 1978, 1033; (6) H. G. Kuivila and G. H. Lein, jun., J. Org. Chem., 1978, 43, 750.

General and Synthetic Methods

220

Of the several new C-C bond-forming reactions of tin derivatives, the ketone synthesis from R4Sn and RCOCl is particularly n 0 t a b 1 e . l ~By ~ ~ using a Pd" catalyst, nearly quantitative yields are obtained in a rapid reaction which is tolerant of a wide variety of functionalities, needs no special experimental precautions, and is easily worked up. Unsaturated ketones are available from an analogous reaction using vinylstannanes and A1Cl3 as catalyst.1476Ally1 groups may be introduced into quinones by trialkylallyl~tannanes.~~~" The same reagents act in two distinct manners with a-chloro-ketones: azoisobutyronitrile induces C1-substitution to give (80), whereas Pd* brings about formation of epoxides (81).14" The acetylenic derivative (82) adds to cumulated systems, including reaction with PhN=C=NPh to give the quinoline (83).149The known benefits of lithiated nitrosamines in organic synthesis have been augmented by new reactions of R1N(NO)CH2SnR23, as in additions to ArCH0.15*

6 Groups V and VI Phosphorus.-The sequences of reactions depicted in Scheme 17 describe two alternative three-component syntheses of the same substituted ally1 alcoh01.~~' Notably, the reaction is regio- and stereo-selective, and only one product isomer is formed. The P-phosphinoyl-ketone of Scheme 18 acts as a P-ketocarbanion equivalent, and is itself readily prepared from Ph2PO- and a conjugated ketone.15* R2

i,

Ph,!-(

ii

R4 ki

0

I1

. ...

4 I, Ill

Ph,P-R3 R3

R4

R3

Reagents: i, BuLi; ii, R3CHO; iii, R2C(0)CH,R'; iv, H'; v, R4CHO; vi, LiAIH,

Scheme 17 D. Milstein and J. K. Stille, J. Amer. Chem. SOC., 1978, 100, 3636; ( b ) M. L. Sai'hi and M. Pereyre, Bull. SOC. chim. France, 1977, 1251. ( a )K. Maruyama and Y . Naruta, J. Org. Chem., 1978,43,3797; ( b )M. Kosugi, H. Arai, A. Yoshino, and T. Migita, Chem. Letters, 1978, 795. G. Himbert and W. Schwickerath, Tetrahedron Letters, 1978, 1951. B. Renger, H. Hiigel, W. Wykypiel, and D. Seebach, Chem. Ber., 1978,111, 2630. R. R. Arndt and S . Warren, Tetrahedron Letters, 1978, 4089. A. Bell, A. H. Davidson, C. Earnshaw, H. K . Norrish, R. S. Torr, and S . Warren, J.C.S. Chem. Comm., 1978,988.

(a)

149

Is* lS2

'v-) R4w> 221

Organornetallies in Synthesis 0

A

0

-dR1 Ph2!f10 R2

1--111_ Ph,P

R'

R3

OHRl0

R4 Reagents: i, (CH,OH),-H';

ii, BuLi; iii, R3R4C=O; iv, NaH

Scheme 18 +

The new reagent (PhO),PMe CF,SO,- overcomes the problems associated with side-reactions in the Arbuzov reaction;'53 ROH displaces one PhO group and reacts with added nucleophiles to give products including ROR, RCN, RNCS, and RI. The phosphonium salt (84), derived by 0-alkylation of a carbonyl-stabilized ylide, functions in a new synthesis of cyclohexenones, via ( 8 5 ) ,by condensation with a ketone.154 Modifications of Wittig reagents include the use of CH2C11 as a source of Ph3P=CHC1.155 Li-C1 exchange of (86) followed by functionalization with an electrophile such as Bu'COC1 or ClC02Et gives phosphonate esters suitable for use in Wittig-Horner reactions.156 A mixture of 2-E-isomers of sulphines, R1R2C,=S,=0, is prepared by Wittig reaction of SO,.157 Reaction between + Ph,P=CHSPh and CH2=NMe, gives (87); further condensation with nucleophiles then leads to carbocyclic structures such as (88).158

<

EtO Ph3P+

(84) C02Et

+

0

C02Et

C0,Et

PhS

(88)

New phosphorus-based deoxygenating agents include P214, which reduces epoxides to alkenes, besides dehydrating aldoximes to nit rile^,*^^ and Ph3P12and (Me2N),P-12-NaI which reduce sulphoxides to sulphides.160

Arsenic and Bismuth.-A partial asymmetric synthesis of diaryloxirans is dependent on optically active arsonium ylides (89).161Yields are high, but optical lS3 154 155 156 157

15'

16'

E. S. Lewis, B. J. Walker, and L. M. Ziurys, J.C.S. Chem. Comm., 1978, 424. S. F. Martin and S. R. Desai, J. Org. Chem., 1978, 43, 4673. S. Miyano, Y. Izumi, and H. Hashimoto, J.C.S. Chem. Comm., 1978,446. J. Villieras, P. Perriot, and J. F. Normant, Synthesis, 1978, 29, 31. B. Zwanenburg, C. G. Venier, P. A. T. W. Porskamp, and M. van der Leij, Tetrahedron Letters, 1978, 807. A. T. Hewson, Tetrahedron Letters, 1978, 3267. H. Suzuki, F. Fuchita, A. Iwasa, and T. Mishina, Synthesis, 1978, 905. G. A. Olah, B. G. B. Gupta, and S. C. Narang, Synthesis, 1978, 137; J. Org. Chem., 1978, 43,4503. D. G. Allen, N. K. Roberts, and S . B. Wild, J.C.S. Chem. Comm., 1978, 346.

222

General and Synthetic Methods

a" Me *CHAr As-Ph

H

'I

As - - - P h

I

A

;

Ar

\*.

Me

purities range only between 4 and 38%. The species (90) is a rare example of an organobismuth reagent: it is easily prepared and soluble in organic solvents.'62 Its use as an oxidant for alcohols (particularly allylic) is worthy of note since, unlike M n 0 2 or Ag,CO,-Celite, no excess is required, and very anhydrous conditions are not necessary.

c1

c1

I

I

Ph,Bi-0-BiPh, (90)

Sulphur.-Sulphur-stabilized carbanions have been dealt with under Group I elements; in this section discussion is restricted to those new reagents which introduce sulphur itself into a molecule, or are dependent on sulphur for their synthetic use. The reagent system (PhS)2-OMe- oxidizes cyclohexanones to phenols, while simultaneously introducing a PhS substituent ortho to the phenolic OH.'63Yields are fair to good. An alternative mode of oxidative sulphenylation of ketones is brought about by (91) and a base; a dithioacetal functionality is introduced a- to the ketone ~ a r b o n y l . Reaction '~~ between S,C12 and silylated amines allows preparation of new reagents of geiieral formula >N-S, -N:.165 Specifically, (92) is a favoured reagent for conversion of species such as (93) into (94) and for preparation of polysulphides from thiols. A reagent of, unknown structure, formed by reaction of PhSSPh with Chloramine-T (TsNClNa'), reacts with alkenes to produce trans-substituted thioamino-derivatives, e.g. (95) from cyclohexene.'66

(91)

(92)

(93)

(94)

(95)

Few dehydration methods work well for allyl alcohols, and even fewer are regiospecific. The sulphoxide in Scheme 19 is derived from an allyl alcohol by 162

16' 164

lh6

D. H. R. Barton, J. P. Kitchin, and W. B. Motherwell, J.C.S. Chem. Cornm., 1978, 1099. B. M. Trost and J. H. Rigby, Tetrahedron Letters, 1978, 1667. Y. Nagao, K. Kaneko, K. Kawabata, and E. Fujita, Tetrahedron Letters, 1978, 5021. D. N. Harpp, K. Steliou, and T. H. Chan, J. Amer. Chem. Soc., 1978, 100, 1222. D. H. R. Barton, M. R. Britten-Kelly, and D. Ferreira, J.C.S. Perkin I, 1978, 1090.

Organometallics in Synthesis

223

sequential 0-sulphenylation and [2,3] sigmatropic ~earrangement.’~’Elimination gives the diene regiospecifically. Two other methods also depend on thermal sulphoxide elimination for introduction of unsaturation. The vinyl sulphoxide PhS(O)CH=CH, acts as a new acetylene equivalent in [4 + 21 cycloaddition reactions, by elimination of PhSOH from the initially formed adduct.16* Sulphenylation of silylated enol ethers with PhSCl to give (96), followed by SPh

I

RCH,CHCOSiMe, (96)

oxidation to sulphoxide and elimination, allows introduction of unsaturation into silyl-ketones. 16’ A new allylic functionalization follows the reactions of Scheme 20, to give ally1 malonates which are difficult to prepare by other methods; where alternative products are possible, that with the least substituted alkene bond is

referr red.'^'

Reagents: i, [(CF,),C=S],-KF-DMF; ii, N,CE, (E = C0,Et)-Cu2’, desulphurization, X = S -+ X = H)

A; iii, Na-Hg-Na,HPO,

(for

Scheme 20

The sulphone (97) converts alcohols, ROH, into (98).171N- Quaternization or protonation of (98) gives a species so susceptible to nucleophilic attack that alkylated derivatives of such poor nucleophiles as C104- or FS0,- may be prepared. Sulphur dioxide undergoes a reversible ‘ene’ reaction with alkenes, such as methylenecyclohexene as in (99). In the absence of water, overall allylic shift (to methylcylohexene) merely results, but exhaustive allylic deuteriation of the starting material occurs in the presence of D,O.l7, lh7

169

”O 171

H. J. Reich, I. L. Reich, and S. Wollowitz, J. Amer. Chem. SOC.,1978, 100, 5982. L. A. Paquette, R. E. Moerck, B. Harirchian, and P. D. Magnus, J. Amer Chem. SOC.,1978,100, 1597. N. Minarni, T. Abe, and I. Kuwajima, J. Organometallic Chem., 1978, 145, C1. B. B. Snider and L. Fiizesi, Tetrahedron Letters, 1978, 877. J. F. King, S. M. Loosmore, J. D. Lock, and M. Aslam, J. Amer. Chem. SOC.,1978, 100, 1637. D. Masilamani and M. M. RogiC, J. Amer. Chem., SOC.,1978, 100,4634.

224

General and Synthetic Methods

Selenium.*-Selenation and Oxidation. Three studies have appeared which are of general interest in the field. The first considers the fundamental reaction of PhSeCl addition to alkenes, where it is shown that the addition occurs initially in an anti-Markovnikoff fashion, isomerization occurring to the thermodynamically more stable isomer [RCH(Cl)CH2SePh] at higher temperatures. 173 Oxidation and elimination of selenium provides a general alkene synthesis, and it has now been found that Bu'00H-alumina-THF is an efficient oxidation-elimination combination, and that addition of Et,N to a selenoxide prior to thermal elimination is a d v a n t a g e o u ~ .Thirdly, '~~ reductive removal of Se by Ph3SnH is preferable to the more conventional Raney nickel procedure.17' New methods for the conversion of terminal alkenes into ketones RC(0)CH2SePhuse the reagent systems PhSeBr-EtOH followed by NaI04,176a PhSeBr followed by AgPF6-DMS0,176band a one-step process using (PhSe),Br2-(B~3Sn)20.176c The products are intermediates in further alkylationdeselenation steps which lead to ketones and en one^.'^^' Oxidation of alkenes and sulphides to epoxides and sulphoxides, respectively, is effected by H 2 0 2and 1% catalytic ArSe02H.177a H,O,-SeO, also brings about the latter reaction.'77h Further applications of benzeneseleninic anhydride, (PhSe=O),O, include dehydrogenation of steroidal ketones, 17*0 oxidation of and of ketone hydrazones, oximes, and semicarbazones to ketones,1786conversion of thiocarbonyl groups into ~ a r b o n y l , ~ and ~ *dehydro~ genation of hydrazines. 178b7e Details have been published of the preparation of 'PhSeOH' from PhSe02H + (PhSe)*,179asb and from RSe0,H + H3P02.179C Cyclofunctionalizations initiated by organoselenium additions continue to provide evidence for the power of such reagents in synthesis. Novel bicyclic thio-prostaglandin derivatives result from PhSeCl addition,18" and the diene 173 174

175

176

177

178

179

180

D. Liotta and G. Zima, Tetrahedron Letters, 1978, 4977. D. Labar, L. Hevesi, W. Dumont, and A. Krief, Tetrahedron Letters, 1978, 1141. D. L. J. Clive, G. Chittattu, and C. K. Wong, J.C.S. Chem. Comm., 1978, 41. ( a ) T. Takahashi, H. Nagashima, and J. Tsuji, Tetrahedron Letters, 1978,799; ( b )S. Raucher, ibid., p. 2261; (c) I. Kuwajima and M. Shimizu, ibid.,p. 1277. ( a ) H. J. Reich, F. Chow, and S. L. Peake, Synthesis, 1978, 299; ( b ) J. Drabowicz and M . Mikolajczyk, ibid., p. 758. ( a )D. H. R. Barton, D. J . Lester, and S. V. Ley, J.C.S. Chem. Comm., 1978,130; ( b )D. H. R. Barton, D. J. Lester, and S. V. Ley, ibid., p. 276; ( c )D. H. R. Barton, N. J . Cussans, and S. V. Ley, ibid., p. 393; ( d )D. H. R. Barton, A. G. Brewster, R. A. H. F. Hui, D. J. Lester, S. V. Ley, and T. G. Back, ibid., p. 952; ( c ) T. G. Back, ibid., p. 278. ( a )T. Hori and K. B. Sharpless, J. Org. Chem., 1978, 43, 1689; (6) H. J. Reich, S. Wollowitz, J. E. Trend, F. Chow, and D. F. Wendelborn, ibid., p. 1697; ( c ) D. Labar, A. Krief, and L. Hevesi, Tetrahedron Letters, 1978, 3967. K. C. Nicolaou, W. E. Barnette, and R. L. Magolda, J. Amer. Chem. SOC.,1978, 100, 2567.

* Thanks are extended to Dr. P. F. Gordon for his assistance with this section.

Organometallics in S y n thesis

225

(100) is cyclized to (101) by PhSeCl in HOAc.'*' The dideoxyglycoside residue (102) is derived as illustrated in (103) followed by oxidation-elimination.lS2 Olefinic urethanes are cyclized to N-heterocycles by PhSeCl. l g 3

a-Metallated Organoselenium Derivatives. The lithio-derivative (104) adds to both ~ a t u r a t e d " and ~ ~ unsaturated1s4b ketones; in the latter case the site of addition is dependent on conditions (1,2 kinetic; 1,4 thermodynamic). The dianion of the free acid corresponding to (104) is a useful synthon for a methylene- y-lactones, for instance via (109, which results from addition to cyclohexene The vinyl selenide PhSeCH=CH2 acts as a &H=CH synthon by the sequence RLi addition, followed by reaction with an electrophile.'86"'bReaction is, however, very dependent o n conditions, lS6' vinylic H-exchange being preferred by LDA or KDA. 186b,c Cyclopropane selenoacetals are formed by ring closure of the lithiated selenoacetal (106),'" and a-methylene-selznoacetals undergo Se-Li exchange, the derived product being converted into ally1 alcohol by further reaction with C H 2 0 and oxidation-elimination (corresponding to yet another CH20Hsynthon). lS8 The selenoacetal derivatives R'R2C(SePh)Li add to epoxides to give products convertible into homoallylic alcohols and enones by further reaction sequences. lS9 H I R'-C-Li

SeR2 I CO,R~

(32 Me

h% +'C l Li

SePh

Miscellaneous. The preparation of selenoacetals has previously depended on use of the very air-sensitive PhSeH. It has now been found that the readily prepared reagent (PhSe),B reacts easily with ketones to give the selenoacetals in high yield.'" Me3Al and Se in refluxing toluene give Me2A1SeMe; this reagent

''* lU3

'*'

"* '91

D. L. J. Clive, G. Chittattu, and C. K. Wong, J.C.S. Chem. Comm., 1978, 441. S. Current and K. B. Sharpless, Tetrahedron Letters, 1978, 5075. D. L. J. Clive, C. K. Wong, W. A. Kiel, and S. M. Mencher, J.C.S. Chem. Comm., 1978, 379. J. Lucchetti and A. Krief, ( a ) Tetrahedron Letters, 1978, 2693; ( b ) ibid., p. 2697. N. Petragnani and H. M. C. Ferraz, Synthesis, 1978, 476. ( a )S. Raucher and G. A. Koolpe, J. Org. Chem., 1978, 43, 4252; ( b ) M. Sevrin, J. N. Denis, and A. Krief, Angew. Chem. Internat. Edn., 1978, 17, 526; ( c ) S. Raucher and G . A. Koolpe, J . O r g . Chem., 1978, 43, 3794. S. Halazy, J. Lucchetti, and A. Krief, Tetrahedron Letters, 1978, 3971. D. Labar, W. Dumont, L. Hevesi, and A. Krief, Tetrahedron Letters, 1978, 1145. M. Sevrin and A. Krief, Tetrahedron Letters, 1978, 187. D. L. J. Clive and S. M. Menchen, J.C.S. Chem Comm., 1978, 356.

226

General and Synthetic Methods

efficiently converts carboxylic esters into the active acyl transfer reagents RCOSeMe. 191n Analogous activated esters result from reaction between carboxylic acid and A ~ S ~ C N - B U ~ PRCOSe-K' .'~~' displaces Br- from a-bromoketones to give selenocarboxylate derivatives (RCOSeCH2COR') from which Se can be eliminated by base treatment, leading to a new synthesis of pdiketones. * 91 The reaction of fluoride ion with. PhSeSiMe3 provides a novel source of PhSe-K' which is useful for addition to various ele~trophiles.'~~ However, PhSe can be introduced into electrophilic substrates directly from the same silane precursor by means of one of the co-reagents BF3, ZnC12, or Ph3P.19'

19'

192 193

( a ) A . P. Kozikowski and A . Ames, J. Org. Chem., 1978,43,2735; ( 6 )P. A . Grieco, Y. Yokoyama, and E. Williams, ibid., p. 1283; (c) H. Ishihara and Y. Hirabayashi, Chem. Letters, 1978, 1007. M. R. Detty, Tetrahedron Letters, 1978, 5087. D . Liotta, P. B. Paty, J. Johnston, and G . Zima, Tetrahedron Letters, 1978, 5091.

7 Saturated Carbocyclic Ring Synthesis BY K. COOPER, M. MELLOR, AND G. PATTENDEN

1 Introduction Without doubt, the highlight in carbocyclic ring synthesis during 1978 was the announcement of the total synthesis of the tetracyclic diterpene gibberellic acid (1)by Corey and his co-workers.’ The key stages in the synthesis of this important plant growth regulator, summarized in Scheme 1, were (i) the stereospecific formation of the cis-fused B/C ring unit by Diels-Alder reaction, (ii) formation of the D-ring by internal pinacol cyclization, (iii) ring contraction of ring B from six to five members, and (iv) formation of ring A by intramolecular Diels-Alder reaction. It is worth noting that this elegant synthesis relied significantly on one of the most useful reactions in organic chemistry, namely the Diels-Alder reaction, which this same year saw its 50th anniversary! 2 Three-membered Rings

General Methods.-Alternative procedures to that of Simmons-Smith for the synthesis of cyclopropanes from alkenes seem endless. Pienta and Kropp have now established that simple irradiation of gem-dihalides in the presence of alkenes produces the corresponding cyclopropane in excellent yields2Moreover, the method shows little sensitivity to steric effects and, perhaps surprisingly, proceeds with complete retention of stereochemistry, e.g. (2) + (3). Dibromocyclopropanes [e.g. (4)]can be prepared from alkenes and bromoform using the very simple and inexpensive base anhydrous potassium carbonate3 in the presence of 18-crown-6 at 140°C. The two sulphur ylides (5) and (6) are useful intermediates for the synthesis of bis-methoxycarbonylcyclopropanes(7)4 and silylcyclopropanes (8)’ respectively. Terpenoid alkenylidenecyclopropanes of the type (lo), which are easily synthesized by addition of the allene carbene (9) to various alkenes, have been found to be extremely useful intermediates in the synthesis of a range of functionalized ‘head-to-tail’ and ‘irregular’ monoterpenes (Scheme 2).6 E. J. Corey, R. L. Danheiser, S. Chandrasekaran, P. Siret, G. E. Keck, and J.-L. Gras, J. Amer. 1978, 100, 8031; E. J. Corey, R. L. Danheiser, S. Chandrasekaran, G. E. Keck, B . * Chem. SOC., Gopalan, S. D. Larsen, P. Siret and J.-L. Gras, ibid., p. 8034. N. J. Pienta and P. J. Kropp, J. Amer. Chem. SOC.,1978, 100,655. M. Fedorynski, K. Wojciechowski, Z. Matacz, and M. Makosza, J. Org. Chem., 1978,43, 4682. J . Cuffe, R. J. Gillespie, and A. E. A. Porter, J.C.S. Chem. Comm., 1978, 641. %. Cooke, P. Magnus, and G. L. Bundy, J.C.S. Chem. Comm., 1978,714. L. Crombie, P. J. Maddocks, and G. Pattenden, Tetrahedron Letters, 1978, 3479, 3483.

227

228

General and Synthetic Methods

OMe

OH

Ph

Y i

OMe

0

>

0'-rH P

H

lLIko /

O'TH P

OTHP

OH

OTHP

CI

+---

HO% O H

=OH

CO,H (1) Scheme 1

HozC

C0,Me

\

229

Saturated Carbocyclic Ring Synthesis

\ +

4

/ S-CHSiMe,

Reagents: i,&

;ii, Na-NH,; iii, H'-MeOH; iv, m-ClC,H,CO,H; v, NaOH; vi, K0Bu'-DMSO

Scheme 2

4-Bromocrotonates have featured in three closely similar designs to cyclopropane ring synthesis published this year. Thus, cyclopropane- 1,l-dicarboxylates have been prepared by straightforward reduction of the alkylidenemalonates (1 1)with excess sodium b~rohydride,~" and Kristensen et a1.7bhave used the same precursor (11) in a synthesis of cyclopropane monocarboxylates (12) as outlined in Scheme 3. The addition of metallated alkyl mercaptans to 4-bromocrotonates, like that of hydiide-ion addition to ( l l ) , leads to cyclopropanes in one step, e.g. (13) -+ (14).8 A C O , E t Br

C0,Et

C0,Et

R

... ,

___, 111,IV

Qco2Et 0

Q-

R I

v-vii

0

Reagents: i, NaBH,; ii, A; iii, RMgX; iv, A, wet DMSO; v, SOC1,; vi, EtOH; vii, NaOEt

Scheme 3

' ( a ) R. Verhe, N. Kimpe, L. Buyck, D. Courtheyn, and N. Schamp, Synthesis, 1978, 530; ( b ) J. Kristensen, I. Thomsen, and S . - 0 . Lawesson, Bull. SOC.chim. belges, 1978, 721. R. D . Little and J. R. Dawson, J. Amer. Chem. Soc., 1978,100,4607.

General and Synthetic Methods

230

The synthesis of cyclopropanes from a,@ unsaturated carbonyl compounds, involving bond formation between the P-carbon and the carbonyl carbon centres, has been accomplished in an interesting manner involving electrochemical reduction of the intermediate mesylate (15) as a key stage (Scheme 4).9

(15) Reagents: i, PhS -; ii, NaBH,; iii, MeS0,Cl; iv, electrochemical reduction

Scheme 4

The first synthesis of cyclopropenes by the intramolecular reductive coupling of non-enolizable 1,3-diones, with TiCl3-LiA1H4, has been published, e.g. (16)+ (17)," and extensions to the familiar method of synthesis of cyclopropylmethanols by carbanion addition to oxirans have appeared. l 1

0

(16)

0

Ph

Ph

(17)

This section cannot be closed without documenting the first synthesis of the elusive tetrahedrane carbon skeleton. The synthesis of a tetrahedrane has been one of the most attractive challenges in synthesis since the very early days of organic chemistry. Maier et u1.l' have now shown that when the tetra-t-butylcyclopentadienone (18)is irradiated at 254 nm, criss-cross addition produces the tricyclopentanone (19), which on prolonged irradiation eliminates carbon monoxide to produce the tetrahedrane (20). Interestingly, the tetrahedrane (20) forms colourless crystals, m.p. 135 "C, which on heating to 130 "C rearrange to give the butadiene (21); the latter on irradiation (>300nm) regenerates the tetrahedrane.

T. Shono, Y . Matsumura, S. Kashimura, and H. Kyutoku, Tetrahedron Letters, 1978, 1205; cf. Y. Chang and H. W. Pinnick, J. Org. Chem., 1978, 43, 373. '" A. L. Baumstark, C. J. McCloskey, and K. E. Witt, J. Org. Chem., 1978,43, 3609. I' G. Mouzin, H. Cousse, and B. Bonnand, Synthesis, 1978, 304. '* G. Maier, S. Pfriem, U. Schafer, and R. Matusch, A n g e w . Chem. Internat. Edn., 1978, 17, 520.

Saturated Carbocyclic Ring Synthesis

0

23 1

0

Natural Cyc1opropanes.-In extensions of their earlier investigations of the synthesis of chrysanthemic acid (25) based on elaboration of the cyclopropane ring by reaction between the isopropyl ylide (22) and alkene substrates (see s ~ ~ now shown that the ylide (22) Volume 1,p. 292), Krief and his c o - w ~ r k e r have can be added to both maleate and fumarate, leading to the truns-cyclopropanedicarboxylate (23). Conversion of the diester into the aldehydo-ester (24) and Wittig reaction then completes a new synthesis of chrysanthemic acid (Scheme 5 ) .

Reagents: i, KOH-ROH; ii, BzH6; iii, Collins oxidation; iv, (22)

Scheme 5

Garbers et al.I4 have outlined an alternative synthesis of the aldehydo-ester (24) which is based on electrophilic addition of a-chloro-ethers to the unsaturated ester (26) and subsequent 1,3-elimination from the intermediate (27).

l3 l4

M. J. Devos, J. N. Denis, and A. Krief, Tetrahedron letters, 1978, 1847. C. F. Garbers, M. S. Beukes, C. Ehlers, and M. J. McKenzie, Tetrahedron Letters, 1978, 77.

General and Synthetic Methods

232

The lactone pyrocin (28) has featured as a key intermediate in many synthetic approaches towards chrysanthemic acid; this year Krief et a1.15 have outlined yet another approach to this important lactone (Scheme 6).

Reagents: i, m -ClC,H,CO,H; ii, (RO,C),C-; iii, KOH-EtOH

Scheme 6

The synthesis of chrysanthemic acid based on photochemical di-v-methane rearrangement of the 1,4-diene (29) was first described in 1976.16Now Ohkata et al.I7 have outlined an alternative photochemical synthesis of the acid which has as a key stage the photo-rearrangement of the dihydrofuran (30) to the acylcyclopropanoate (31).

&

*CO,Me

C0,Me

3 Four-membered Rings The extraordinary scope provided by the [2 + 21 photocycloaddition approach to €our-membered rings, in synthesis, is well illustrated this year in the synthesis of several important terpenoid ring systems. Thus, in their synthesis of (*)-loepijunerol (33) for example, Wender and Lechleiter” have used the [2 + 21 photocycloaddition to effect a latent [4C + 2C] connection (see Scheme 7); the second stage of the ‘connection’ involved cleavage of the strained bicyclo[2,2,0]hexane (32) using lithium naphthalide. Two groups of workers have independently demonstrated the potential of intramolecular [2 + 21 photocycloadditions amongst cyclic 1,3-dione enols in synthesis, with the formation of l5

”

’*

M. J. Devos and A. Krief, Tetrahedron letters, 1978, 1845. M. J. Bullivant and G . Pattenden, J.C.S. Perkin I, 1976, 476; cf. P. Baekstrom, Tetrahedron, 1978, 34, 3331. K. Ohkata, T. Isako, and T. Hanafusa, Chem. and Ind., 1978, 274. P. A. Wender and J. C. Lechleiter, J. Amer. Chem. SOC.,1978, 100,4321.

Saturated Carbocyclic Ring Synthesis

233

Scheme 7

the longifolane, (34) --+ (35),19and the bicyclo[3,2,l]octane, (36) + (37),20ring systems. Finally, Bellas et aL21 have employed the [2 + 21 photocycloaddition approach, between (38) and (39), to synthesize the free acid (40) of the mycotoxine Moniliformin.

5.c1

0

xo3

) (0 o q 0o p oH+,

+

(38)

HO Q0

c1 (39)

OH

(40)

The cycloaddition of dichloroketen to alkenes enjoys widespread use in the synthesis of cyclobutanones. Krepski and Hassner22recommend that the additions are best accomplished in 'one-pot' by dehalogenating trichloroacetyl chloride with activated zinc in the presence of the olefin and phosphorus oxychloride, e.g. (41) + (42).23

''

*'

21

'*

23

W. Oppolzer and T. Godel, J. Amer. Chem. Soc., 1978,100, 2583. M. Mellor, D. A. Otieno, and G. Pattenden, J.C.S. Chem. Comm., 1978, 138. D. Bellas, H. Fischer, H. Grenter, and P. Martin, Helv. Chim. Acta, 1978, 61,1785. L. R. Krepski and A. Hassner, J. Org. Chem., 1978, 43, 2879. L. R. Krepski and A. Hassner, J. Org. Chem., 1978, 43, 3173.

234

General and Synthetic Methods OTMS

(42)

(41)

R a u t e n ~ t r a u c hhas ~ ~ shown that the cyclobutane ring system found in the monoterpenes fragranol and grandisol can be produced by intramolecular cyclization from an epoxy-sulphide of the type (43), and Corbel et aL2’ have demonstrated the use of epoxy-sulphones [viz. (44)]in the elaboration of cyclobutanols. Hut-I-TMEDA

5iYSBU‘ -711°C

(43)

~

s

o

2

p

MeMpX, h

OH

/p’

S02Ph

OH

0 (44)

4 Five-membered Rings

General Methods.-The direct synthesis of cyclopentanes by a [3 + 21 combination of carbon units has been the goal of many synthetic chemists in the past decade. This year has seen the publication of several new routes to cyclopentanes which fall into this category. A particularly facile method uses the Michael addition of the vinyl carbanion (45) to double bonds as a key stage,26whereas Hayakawa et al.27have shown that the iron carbonyl-promoted reactions of a,a ’-dibromo-ketones and alkenes can provide an expeditious route to certain substituted cyclopentanones [e.g. (46) -+ (47)].Two further examples of the f W t

+

- 4 ‘hR fO2E1

C0,Et

R2N

Ph

R2N

Ph

(45)

0

+ oC dN (46) 24

25 26

”

Y

Br

Br

[Fe2(C0)91

R+R

(47)

V. Rautenstrauch, J.C.S. Chem. Comm., 1978, 519. B. Corbel, J. M. Decesare, andT. Durst, Canad.J. Chem., 1978,56, 505. R. R. Schmidt and J. Talbiersky, Angew. Chem. Internat. Edn., 1978, 17, 204. Y. Hayakawa, K. Yokoyama, and R. Noyori, J. Amer. Chem. SOC.,1978,100, 1799.

235

Saturated Carbocyclic Ring Synthesis

[3 + 21 design to cyclopentane ring synthesis illustrate the versatility of vinylphosphonium salts [e.g. (48)]28and of zinc derivatives of propargyl halides (49)29 in synthesis. PhS

k+

+

PPh,X

O

(48)

EtO2C

I

CO2Et

- phk! EtO2C

CO2Et

R2 C02Et

R2

BrZn '>ZE

+

\C02Et

R1&

C02Et

C02Et

(49)

Electrolysis has featured in two approaches to cyclopentanes published this year. Thus, Satoh efa1.30have demonstrated that the electrochemical reduction of o-dihalides can be applied to functionalized cyclopentanes [e.g.(50) + ( 5 l)],and Shono et aL31 have found that the electro-reduction of 6-unsaturated carbonyl compounds leads to excellent yields of intramolecular cycloaddition products of the type (52).

eOzMe ~

C02Me

Br (50)

(51)

(52)

The Lewis acid-catalysed intramolecular 'ene' reaction of S -unsaturated aldehydes has been further exploited in the synthesis of cyclopentanes [e.g. ( 5 3 )+ (54)],32 and Dolbier and G a r ~ have a ~ ~demonstrated the potential for radical intermediates in synthesis in their preparation of the tricycle (55).

(53)

(54)

A. T. Hewson, Tetrahedron Letters, 1978, 3267. 29 M. Bellassoued, Y. Frangin, and M. Gaudemar, Synthesis, 1978, 150. 30S.Satoh, M. Itoh, and M. Tokuda, J.C.S. Chem. Comm., 1978,481. 31 T. Shono, I. Nishiguchi, H. Ohmizu, and M. Mitani, J. Amer. Chem. SOC.,1978,100, 545. 32 N. H. Andersen and D. W. Ladner, Synth. Comm., 1978,8,449. 33 W. R. Dolbier and 0. T. Garza, J. Org. Chem., 1978, 43, 3848. 28

236

General and Synthetic Methods

0

NaOH,

U0

0

0 (55)

The scope provided by the method of synthesis of cyclopentanes based on thermal conrotatory ring closure of a chloropentadienyl cation, followed by hydrolysis, has been expanded with new approaches to the formation of the requisite carbonium intermediates (Scheme 8).34,35

R2

RZ Reagents: i, LiCCl,CH=CH,;

ii, H'; iii, A; iv, F3CC02H

Scheme 8

The hydration of skipped (1,4)-acetylenes, which are easily available by coupling reactions between acetylenic Grignard reagents and propargyl bromides, has provided a useful route to 1,4-dione precursors of cyclopent-2enones [e.g. (56) + (57)].363-Cyclopropylcyclopentenones (58),which are useful R

c fCCH zc=CCH

R~

H'

R' m R 2 R g o RZ (57)

(56)

precursors for cyclopentane annelation, have been synthesized from the corresponding 1,4-diones according to Scheme 9.37

Lo, + xoTMs 0

i,TiCI,

il,H,OI

0 base ___3

Scheme 9 34

35

36 37

T. Hiyarna, M. Shinoda, and H. Nozaki, Tetrahedron Letters, 1978, 771. Y. Gaoni, Tetrahedron Letters, 1978, 3276. W. J. Gender, J. C. Petitpierre, and J. W. Dean, J. Org. Chem., 1978, 43, 4081. P. A. Grieco and Y. Ohfune, J. Org. Chem., 1978,43,2720.

Saturated Carbocyclic Ring Synthesis

237

The annelation of a five-membered to a six-membered-ring, leading to substituted cis- hydrindanes (59),has been accomplished by an intramolecular Michael addition and Marfat and H e l q ~ i s thave ~ ~ described the use of copper-catalysed conjugate addition of the acetal Grignard reagent (60) in H

oQo

O m o K2C03-Et0H, Et0,C

Et0 ,C

R

I

(60)

cyclopentane annelation. Two additional routes to cis- hydrindane derivatives use a transannular cyclization employing benzeneselenyl chloride, (61)-+ (62),40and a base-catalysed oxy-Cope rearrangement, (63)+ (64), as key

& R9

___7 PhSeCI-EtOAc

a ‘0 H

__* Ph,SnH

H SePh

H

(62)

(61)

(63)

(64)

Cyclopentane- 1,3-dione is a valuable intermediate in synthesis. Lick and Schank4’ have shown that the dione can be obtained from norbornene in 70% overall yield according to Scheme 10. The intramolecular oxidative coupling of dilithium enolates of substituted pentane-2,4-diones [i.e. (65)], using Cu(OTf)?, Gedge and Pattenalso provides a useful route to cyclopentane-l,3-dione~.~~ den44 have found that rearrangement of 4-ylidenebutenolides with NaObfe in 38 39 40

41

42 43 44

G. Stork, D. F. Tabler, and M. Marx, Tetrahedron Letters, 1978, 2445. A. Marfat and P. Helquist, Tetrahedron Letters, 1978, 4217. D. L. J. Clive, G. Chittattu, and C. K. Wong, J.C.S. Chem. Comm., 1978,441. M. E. Jung and J. P. Hudspeth, J. Amer. Chem. SOC., 1978,100,4309. C. Lick and K. Schank, Chem. Ber., 1978,111, 2461. Y. Kobayashi, T. Taguchi, and T. Morikawa, Tetrahedron Letters, 1978, 3555. D. R. Gedge and G. Pattenden, J.C.S. Chem. Comm., 1978,880.

238

General and Synthetic Methods

Scheme 10

0

0

0

0

0

methanol provides an excellent route to naturally occurring cyclopentene- 1,3diones, e.g. calythrone (67) from the 4-ylidenebutenolide (66).

Aromatic Friedel-Crafts reactions with lactols of the type (68) lead to 5-aryl2(5H)-furanones (69), which can be isomerized into 1H-indenecarboxylic

The scope of the method of synthesis of indenes by photorearrangement of aryl vinylcyclopropenes (70) is limited by the formation of several by-products [i.e. (71), (72), (73)].46

45 46

J. C. Canevet and Y. Graff, Tetrahedron, 1978, 34, 1935. A. Padwa, T. J . Blacklock, D. Getman, N. Hatanaka, and R. Loza, J. Org. Chern., 1978,43, 1481.

Saturated Carbocyclic Ring Synthesis

239

Prostaglandins.-Stork and his co-workers have continued their pioneering investigations of the suitability of carbohydrates in the synthesis of natural prostaglandin^.^^ Starting with D-ghCOSe (74) and proceeding along lines similar to those used in their synthesis of PGA, from L-erythrose (see Vol. 1, p. 301) the key intermediate (75) was first synthesized, which by the ortho-ester Claisen method was then elaborated to (76).The cyclic carbonate (76)was next converted into the lactone (77) which was used in the synthesis of (78). The construction of the cyclopentane (79) from the lactone (78) was carried out by Stork’s cyanohydrin method;48elaboration of (79) then led to natural PGF2, (Scheme 11).

1

4

qCOzMe

0

OH

Scheme 11

The synthesis of PGF2=,based on homoconjugate addition of an organocuprate to a tricycl0[3,2,0,0~*~]heptanone, was published in preliminary form last year 47 48

G. Stork, T. Takahashi, I. Kawamoto, and T. Suzuki, J. Amer. Chem. SOC.,1978,100,8273. G. Stork and L. Maldonado, J. Amer. Chem. SOC., 1971,93, 5286.

General and Synthetic Methods

240

(Vol. 2, p. 208). Full details of this elegant synthesis have now been published,49 and this year Newton and Roberts and their respective collaborators have demonstrated the versatility of the general design in new syntheses of PGE2 and PGC2.50In some equally elegant studies, the same workers have shown that the epoxy-acetal(80) reacts with organometallic reagents regioselectively, leading to the useful prostaglandin intermediates (81) and (82) (Scheme 12),5' and that the

4 c

Hd

Br

n

known prostaglandin precursor (84) can be obtained simply by irradiation of the epoxide (83) in methan01.~~

The cyclopentanones (87) and (91)are popular intermediates for prostaglandin synthesis, and synthetic routes to them are numerous. In new approaches to (87), Novak et al.53have demonstrated the application of thiazolium ion-catalysed reaction of the aldehyde (85) with methyl acrylate, leading to (86) as a stratagem, and Reuter and Sa10mon~~ have shown that methyl azelaialdehydate (89), which 49

51

52

53 54

T. V. Lee, S. M. Roberts, M. J. Dimsdale, R. F. Newton, D. K. Rainey, and C. F. Webb, J.C.S. Perkin I, 1978, 1176. N. M. Crossland, S. M. Roberts, R. F. Newton, and C. F. Webb, J.C.S. Chem. Comm., 1978,660. R. F. Newton, C. C. Howard, D. P. Reynolds, A. H. Wadsworth, N. M. Crossland, and S. M. Roberts, J.C.S. Chem. Comm., 1978,662. N. M. Crossland, S. M. Roberts, and R. W. Newton, J.C.S. Chem. Comm., 1978, 661. L. Novak, G. Baan, J. Marosfalvi, and C. Szantay, Tetrahedron Letters, 1978, 487. J. M. Reuter and R. G. Salomon, J. Org. Chem., 1978, 43, 4247.

241

Saturated Carbocyclic Ring Synthesis

(87)

is easily available from aleuritic acid (88)found in lac resin, can be converted into (87) in 35% overall yield according to Scheme 13.

(CH2),C02Me

ii-iv

&

H0X(cH2)7c02H HO

CHO(CH,),CO,Me

----*

(CH,),OH

0

Reagents: i, NaIO,; ii, A M g B r ; iii, CrO,; iv, Os0,-NaIO,; /

v, base

Scheme 13

Floyd has shown that the 4-hydroxy-derivative (91) can be made quite smoothly from the 2,5-dihydro-2,5-dimethoxyfuranintermediate (90).55 CO,H

0

Acidic buffer

c02H1

’

0

OH (91)

has published full details of the synthesis of The Roussel-Uclaf dihydro-l0,l 1-PGA2,and Trost and his co-workers have described an interesting chiral synthesis of the PG analogue (92).57The application of conjugate addition of zirconium alkenyls to cyclopentenones leading to prostaglandin intermediates . ~extended ~ their approach to has been r e p ~ r t e d , ~and ’ Kondo et ~ 1 have M. B. Floyd, J. Org. Chem., 1978,43, 1641. J. Martel, A. Blade-Font, C . Marie, M. Vivat, E. Toromanoff, and J. Buendia, Bull. SOC.chim. France, 1978, 131. ” B. M. Trost, J. M. Timko, and J. L. Stanton, J.C.S. Chem. Comm., 1978,436. 5 8 M. J. Louts and J. Schwartz, Tetrahedron Letters, 1978, 4381. ” K. Kondo, T. Umemoto, K. Yako, and D. Tunemoto, Tetrahedron Letters, 1978, 3927. 55

56

242

General and Synthetic Methods

OH (92)

prostanoids, based on opening of bicyclo[3,1,O]hexanone with thiophenol anion (see Vol. 2, p. 210), to complete a synthesis of (*)-PGF,,. Rethrolones and Related Compounds.-The recent synthesis of 4-substituted-5hydroxy-3-oxocyclopentenes by acid-catalysed rearrangement of 2-furylcarbinols has now been extended to a useful synthesis of (*)-allethrolone (93),60and Naf and Decorzant61 have published full details of their synthesis of jasmone (95) based on thermal rearrangement of the spiro-intermediate (94) produced by reaction between cyc1open:anone and 1,4-dibromopent-2-ene.

OH

A,

(94)

MeLi ii, GO,-Hi

6 0

(95)

The use of 1,4-diones as precursors for cyclopentenones continues to be exploited in synthetic approaches to jasmone and related compounds.62 Fused Five-membered Rings.-Pride of place amongst syntheses of fused fivemembered ring systems published this year goes to Danishefsky's stereoselective synthesis of pentalenolactone (103), a sesquiterpene antibiotic, tumour inhibitory agent (Scheme 14).63The thirty-stage synthesis starts with the Diels-Alder adduct (96) from cyclopentadiene and dimethyl acetylenedicarboxylate, which 6o

''

62 63

G. Piancatelli, A. Scettri, G. David, and M. D'Auria, Tetrahedron, 1978, 34, 2775. F. Naf and R. Decorzant, Helv. Chim. Acta, 1978, 61, 2524. P. Dubs and R. Stussi, Helv. Chim. Acta, 1978, 61, 990. S . Danishefsky, M. Hirama, K. Gombatz, T. Harayama, E. Berman, and P. Schuda, J. Amer. Chem. Soc., 1978, 100,6536.

243

Saturated Carbocyclic Ring Synthesis

(101) a; R b; R

=

OH

= C1

Scheme 14

was first transformed into the maleic anhydride (97). A second Diels-Alder reaction between (97) and the diene (98) then led to the adduct (99) which was converted by several steps into the key intermediate (100). Disconnection of the two-carbon bridge in (loo), using Jones reagent, then produced the di-acid (101a) which was converted into the acid chloride (101b). The second five-membered ring in the pentalenolactone structure was then introduced by an intramolecular Friedel-Crafts acylation reaction from (lOlb), leading to the enone (102). A series of reactions then converted (102) into (*)-pentalenolactone. Schlessinger and his c o - ~ o r k e r have s ~ ~ outlined an alternative approach to the fused five-membered ring system found in pentalenolactone which uses an intramolecular carbanion acylation reaction to form the second five-membered ring (Scheme 15).

C0,R Scheme 15 64

M. L. Quesada. R. H. Schlessinger, and W. H. Parsons, J. Org. Chern., 1978, 43, 3968.

244

General and Synthetic Methods

The utility of the method of synthesis of fused five-membered rings by reactions between dimethyl 3-ketoglutarate and 1,2-dicarbonyl compounds is further illustrated this year, with syntheses of the tetraketone (105) from the ketoaldehyde ( 104y5 and of the propellane (107) from cyclopentane-1,2-dione (106).66 C0,H

H0,C

C0,Me

C02Me

(107)

(106)

Cargill et a P 7 have described an interesting synthesis of the propellane (110)by isomerization of the tricycle (109)resulting from irradiation of the cyclohexenone (108).

(108)

(109)

(110)

A number of transannular reactions have been applied in the synthesis of bicyclo[3,3,0]octanes from appropriately functionalized cyclo-octanes. Thus, treatment of the cyclo-octanone (111)with lithium in ammonia leads to the ketol (112),68 and reaction of the epoxide (113) with lithium diethylamide in etherhexane gives largely (114).6'The base-catalysed rearrangement of (115) leads to the fused five-membered ring system (117)by way of the transient cyclo-octanone (116).70 Li-NH, __*

@H 0 (111)

(112)

R. Mitschka, J. M. Cooke, and U. Weiss, J. Amer. Chem. SOC.,1978, 100, 3973. 66 R. W. Weber and J. M. Cook, Canad. J. Chem., 1978,56, 189. '' R. L. Cargill, J. R. Dalton. S . O'Conner, and D. G . Michels, Tetrahedron Letters, 1978, 4465. R. Balasubramanian, S. Chandrasekhar, K . Rajagopalan, and S. Swaminathan, Tetrahedron 1978,34, 1561. 69 M. Apparu and M. Barelle, Tetrahedron letters, 1978, 1817. '"K. Y. Geetha, K. Rajagopalan, and S . Swaminathan, Tetrahedron, 1978, 34, 2201. 65

Saturated Carbocyclic Ring Synthesis

245

5 Six-membered Rings Diels-Alder Cycloadditions (see Introduction).-The presence of a trialkylsilyl or trialkysilyloxy group in a Diels-Alder adduct provides a highly versatile handle for further elaboration; attainment of such a goal has been largely responsible for the continued expansion in the number of 1,3-dienes bearing substituents of this nature. 2-Triethylsilylbuta-1,3-diene(118) is more reactive than the corresponding l-substituted isomer, but displays a similar lack of regiospecificity in the DielsAlder reaction, although some improvement can be achieved by adding boron trifluoride etherate to the reaction mixture.71Advantage can be taken of this lack of regiospecificity, and the subsequent usefulness of the trialkylsilyl group exploited, if other substituents displaying pronounced directing effects are also incorporated in the diene. This is illustrated in Scheme 16 where the disubstituted diene (119) is employed in the synthesis of a$-unsaturated cyclohexenone derivative^.^^ The stable intermediate (121) can be further transformed before introduction of the a$-unsaturation. The acetoxy-diene analogue (120)has been used in the regiospecific construction of the 4-demethoxydaunomycinone A-ring where the trimethylsilyl group functions as a latent h y d r o ~ y - g r o u p . ~ ~ The highly reactive 2,3-bis(trimethylsilyloxy)buta-1,3-diene(122) can be readily prepared from dimethyl succinate, and the easily hydrolysed trimethylsilyloxy-groups should permit a large number of transformations to be carried out after c y ~ l o a d d i t i o n . ~ ~

71 72

73

74

D. G. Batt and B. Ganem, Tetrahedron Letters, 1978, 3323. I. Fleming and A. Percival, J.C.S. Chem. Comm., 1978, 178. R. B. Garland, J. R. Palmer, J. A. Schulz, P. B. Sollman, and R. Pappo, Tetrahedron Letters, 1978, 3669. D. R. Anderson and T. H. Koch, J. Org. Chem., 1978,43,2726.

General and Synthetic Methods

246 M&C02Me

NBS-THF,

Br Me,Si 0 C O . M e

C0,Me (119)

+

--*

Me,SiO’

0 ~C~F-DMF

ydrol ysis

0

Me,Si I

C0,Me

CO,Me

0

0

(121) Scheme 16

(122)

1,l-Dimethoxy-3-trimethylsilyloxybuta1,3-diene (123) adds regioselectively to electron-deficient dienophiles, and can be regarded as a synthetic equivalent of the unit &OCH2COCH2.75The reactivity of (123) goes some way towards dispelling any fears that highly nucleophilic 1,l-disubstituted dienes are of only limited use in the Diels-Alder reaction [cf. dithian (124) which preferentially undergoes Michael addition with highly electrophilic d i e n ~ p h i l e s ~and ~ ] , the use of (123) in the synthesis of the antifungal agent epigriseofulvin (125) illustrates this point.77

FiMe”3 Meof

Me,SiO

QJ-q=Jo

(123)

(124)

M .&.

(123)

+

Me0 \ CI

Me0 iLH+

Me0

Me0 \ CI

H ‘Me (125)

The Diels-Alder addition of the tetrasubstituted diene (126) to benzoquinone derivatives has led to a synthesis of kermesic acid (127) and related species,78and the exocyclic sulphur-substituted diene (128) can be employed in the regioselective construction of bicyclic 75

76 77

’’ 79

S. Danishefsky, R. K. Singh, and R. B. Gammil!, J. Org. Chem.. 1978, 43, 379. S. Danishefsky, R. McKee, and R. K. Singh, J. Org. Chem., 1976,41, 2934. S. Danishefsky and S. J. Etheredge, J. Org. Chem., 1978,43, 4604. D . W. Cameron, G. I. Feutrill, P. G . Griffiths, and D. J. Hodder, J.C.S. Chem. Comm., 1978, 688. A. De Groot and B. J. M. Jansen, Synthesis, 1978, 52.

247

Saturated Carbocyclic Ring Synthesis

(126)

(127)

(128)

Trost et aLE0have developed a useful approach to (E,E)-1,4-disubstituted dienes which utilizes the acyloin produced from the Diels-Alder adduct of cyclopentadiene and maleic anhydride (Scheme 17; X, Y = 0, S, or alkyl groups).

X

g_ d] ’Y

Y

Scheme 17

Phenyl vinyl sulphoxide (129) has been shown to be a highly convenient acetylene Diels-Alder synthon,81 while methyl trans-& nitroacrylate (130) complements the use of acetylenic dienophiles, affording adducts with the opposite regiochemical substitution pattern, following nitrous acid elimination.82 0

II

ph”]

(129)

0,N

fo2Me (130)

The past year has seen a number of applications of the intramolecular variant of the Diels-Alder reaction (see ref. 1). Two independent approaches to the synthetically challenging cytochalasans, e.g. (133), both utilize an intramolecular Diels-Alder cycloaddition, in one case simultaneously to assemble the macrocycle and six-membered ring, (131) + (132),83and in the other case to construct the octahydroiosindolone moiety suitably functionalized for introduction of the macrocyclic ring system, (134) -+ (135).84 ‘O 81

83 ‘4

B. M. Trost, S. A. Godleski, and J. Ippen, J. Org. Chem., 43,4559. L. A. Paquette, R. E. Moerck, B. Harirchian, and P. D. Magnus, J. Amer. Chem. Soc., 1978,100, 1597. S. Danishefsky, M. P. Prisbylla, and S. Hiner, J. Amer. Chem. Soc., 1978, 100, 2918. S. J. Bailey, E. J. Thomas, W. B. Turner, and J. A. J. Jarvis, J.C.S. Chem. Comm., 1978, 474. T. Schmidlin and C. T a m a , Helv. Chim. Actu, 1978, 61, 2096.

General and Synthetic Methods

248

(133)

H

NH

C02Me

I

Ph PhCH202C

PhCH 20,C’ (134)

(135)

Other example^^^-^^ where the intramolecular variant has been employed include the direct formation of bridgehead bicyclo[3,n, llalkenes from 2(a1kenyl)buta-1,3-dienesss and the preparation of trans-perhydronaphthalenes, bearing an angular methyl group, from acyclic trienes.86 The Lewis acid-catalysed Diels-Alder cycloaddition of 2-methylpropene and the dienone (136), featuring inverse electron demand, affords the a -damascone intermediate (137).”

Other Six-membered Ring Syntheses.-Alkyl phenyl ketones possessing a branched alkyl chain of five or more carbon atoms undergo protolysis of a tertiary C-H bond on dissolving in the ‘superacid’ HF-SbFS, producing carbonium ion intermediates which cyclize to 4,4-dialkyl- 1-tetralones in good yield, e.g. (138) -+(139).’* 86

89 90

K. J. Shea and S. Wise, J. Amer. Chem. SOC.,1978, 100,6519. S. R. Wilson and D. T. Mao, J. Amer. Chem. SOC.,1978,100,6289. R. S. Glass, J. D. Herzog, and R. L. Sobczak, J. Org. Chem., 1978,43, 3209. U. Widmer, H. Heimgartner, and H. Schmid, Helv. Chim. Actu, 1978,61, 815. R. C. Cookson and R. M. Tuddenham, J.C.S. Perkin I, 1978,678. N. Yoneda, Y. Takahashi, and A. Suzuki, Chem. Letters, 1978,231.

249

Saturated Carbocyclic Ring Synthesis

Acid-catalysed rearrangement of indenone (141;R = Me) results in formation of the hexahydrophenanthrene (142; R = Me).91However, the general utility of the sequence outlined in Scheme 18 has so far been limited by the failure to transform (140) into (141) when R > Me. 0

0

__* 111

Reagents: i, PhLi; ii, NCCH,CN; iii, conc. H,SO,

Scheme 18

A closer examination of pyridinium chlorochromate as a reagent for oxidative cationic cyclization has revealed that although it provides an excellent means of converting unsaturated alcohols or aldehydes into p,p- disubstituted, a,@unsaturated cyclohexenones, e.g. (143) + (144), it is not without limitation^.^^ The product ring size is restricted to six carbon atoms, and the cyclization substrate must be capable of forming a tertiary carbonium ion as the initial cyclic intermediate. 0

(143)

(144)

The conversion of aldehyde (145; X = SiMe3) into the epimeric bicyclic alcohols (146) and (147) provides the first example of an intramolecular Lewis acid-catalysed reaction of an allylsilane with a carbonyl group.93The formation of a mixture of epimers indicates that, unlike the analogous ‘ene’ reaction for the parent aldehyde (145; X = H), the process is not wholly concerted. The direct formation of the 9,lO-dihydrophenanthrenering system by photocyclization of 2-vinylbiphenyls has provided the key step in two synthetic 9’ 92 93

E. Campaigne and R. A. Forsch, J. Org. Chem., 1978,43, 1044. E. J. Corey and D. L. Boger, Tetrahedron Letters, 1978, 2461. T. K. Sarkar and N. H. Andersen, Tetrahedron Letters, 1978, 3513.

General and Synthetic Methods

250

(1 46)

(145)

(147)

approaches to the cytotoxic agent juncusol (148),94*95 and irradiation of the dienone ester (150), in the presence of base (NaH or NaQMe), also results in ring cbsure to bicyclic enones (151) and (152), presumably via electrocyclization of the enolate (149).96

wo70,Me

HoQ \

OH

Me

C0,Me

&co2MeN-eQ$r 0

(150)

C0,Me

+

(151)

($J (152)

Following the discovery that butadienyltriphenylphosphonium salts react with enolates to produce cyclohexadienes, efforts have been made to extend the synthetic range of the reaction by introducing heteroatorn substituents into the phosphonium ~ a l t s . ~Disappointingly ’ only 2-ethaxypenta-1,3-dienyltriphenylphosphonium iodide (153) has so far been useful, providing an alternative to the Robinson annelation sequence.

EtO

4

‘PPh, I -

+?p+Eto

(153)

Ether--hexane solutions of kinetic enolates of the type (159, generated by treating methyl o -bromoalkyl ketones (154) with lithium di-isopropylamide, are sufficiently stable at 0°C to allow the addition of ‘activating’ agents such as 94

9s 96

’’

A. S. Kende and D . P. Curran, Tetrahedron Letters, 1978, 3003. E. McDonald and R. T. Martin, Tetrahedron Letters, 1978,4723. J. D. White and R. W . Skeean, J. Amer. Chem. Soc., 1978,100,6296. S. F. Martin and S. R. Desai, J. Org. Chem., 1978.43, 4673.

25 1

Saturated Carbocyclic Ring Synthesis 0-

\ I

\

,cc

,CCOCH,

=ckr

,CCH ,CH,Br

I ,CCH,CH,Br

(154)

(155)

\'I

\

hexamet hylphosphor amide, dig1yme, or 14-crown -4-ether, resulting in intramolecular C-alkylation in good yield." The method is particularly useful for the preparation of cyclohexanones. The potassium fluoride-catalysed double Michael addition of dimethyl 3oxoglutarate to the 4-methylenecyclohex-2-enones(156; R', R2 = H or Me) in DMSO provides a novel stereoselective approach to 9-methyl-cis -decalin derivatives. 99

RZ (156)

Corey and Boger have explored the enormous synthetic potential that benzothiazoles have to offer as carbonyl equivalents, and have successfully applied their results to the development of novel procedures for generating fused and spiro five- and six-membered rings"' as summarized in Scheme 19. In a subsequent

Scheme 19

paper the same authors describe yet another novel annelation procedure for the synthesis of ring-fused cyclohexenone derivatives which is based on the 1,4addition of a ketone N,N-dimethylhydrazone-derived cuprate reagent to an H. 0. House, W. V. Phillips, T. S. B. Sayer, and C.-C. Yau, J. Org. Chern., 1978,43, 700. H. hie, J. Katakawa, Y. Mizuno, S. Udaka, T. Taga, and K. Osaki, J.C.S. Chern. Cornrn., 1978,717. loo E. J. Corey and D. L. Boger, Tetrahedron Letters, 1978, 5 , 9, 13. 98

99

252

General and Synthetic Methods

a!,@-unsaturated ester affording, after hydrazone cleavage, a S -keto-ester capable of carbocyclic ring closure in several different modes (Scheme 20).lo' 0

LCUsp,, NNMe,

Reagents: i, ( a 2 C u L i ; ii,

Li

Scheme 20

Finally, Mundy and Bornmann have shown that the Cope rearrangement of the imine derivative of methyl vinyl ketone dimer (157)provides convenient access to 3-acetylcyclohexanone uia the synthetically useful enamine intermediate

(158).lo2

Anthracyclines and Aromatic Ring Anne1ation.-The widespread use of the anthracycline antibiotics for treatment of a number of human cancers has stimulated considerable interest amongst synthetic organic chemists by providing them with challenging new target molecules. The synthesis of the tetracyclic aglycone portion of these molecules has led to renewed interest in developing methodology for regiospecific aromatic ring annelation. One successful approach to the tetracyclic systems has employed the regioselective coupling of the lithiated quinone bis-acetal (160) with dimethyl 3-methoxyphthalate (159) affording, after hydrolysis and acid-catalysed ring closure of the intermediate (161), (&)-7,9-deoxydaunomycinone(162).lo3In a similar annelation sequence, the property of tertiary anisamides to lithiate exclusively ortho to the amide functionality has been exploited to effect a regiospecific coupling of the amide (163) and 2,5 -dimethoxy-p -tolualdehyde (164), leading to the phthalide ( 165).lo4Hydrogenolysis, acid-catalysed ring lo2 lo3

lo4

E. J. Corey and D. L. Boger, Tetrahedron Letters, 1978, 4597. B. P. Mundy and W. G . Bornmann, Tetrahedron Letters, 1978, 957. J. S. Swenton and P. W. Raynolds, J. Amer. Chem. SOC.,1978, 100, 6188. S. 0.de Silva and V. Snieckus, Tetrahedron letters, 1973, 5103; cf. J. Baldwin and K. W. Bair, ibid., p, 2559; I. Forbes, R. A. Pratt, and R. A. Raphael, ibid.,p. 3965.

253

Saturated Carbocyclic Ring Synthesis

closure, and oxidation of the intermediate anthrol (166) then gave the anthraquinone islandicin trimethyl ether (167’

1 1

WMe OH

f-

0 (167)

Me0

OMe

OMe (166)

The search for a convenient method of fusing an anthracycline A-ring to a preformed anthraquinone nucleus has led to a revival of the rather obscure Marschalk reaction, and is illustrated by the annelation of the leuco- derivative (168) of 1,4-dihydroxyanthraquinonewith succindialdehyde to give the tetrahydronaphthacenequinone (169)”’ and, in the same manner, deoxydaunomycinone (162) after deacetalization of the intramolecular cyclization product from ( 170).lo6 Several groups of workers have demonstrated that Michael addition of phthalide anions (171 ;X = H, CN, or S02Ar)to a,P-unsaturated carbonyl compounds lo’

lo6

M. J. Morris and J. R. Brown, Tetrahedron letters, 1978,2937; cf. L. M. Harwood, L. C. Hodgkinson, and J. K. Sutherland, J.C.S. Chern. Comm., 1978, 712. F. Suzuki, S . Trenbeath, R. D. Gleim, and C . J. Sih, J. Amer. Chern. SOC., 1978, 100, 2272; J. Org. Chern., 1978,43,4159.

254

General and Synthetic Methods

provides a convenient method of annelating aromatic rings suitably functionalized fox application in anthracpcline synthesis (Scheme 2 1).107-109

R'CH==CHCOR*

--+

Scheme 21

Stork and Hagedorn have reported that the highly functionalized A-ring of tetracycline can be readily constructed by Michael addition of the 3-benzyloxyisoxazole (172) to a suitable enone substrate, followed by Claisen cyclization and hydrogenation to release the protected p -keto-amide (Scheme 22).l l o

6 Polyene Cyclizations and Polycyclic Synthesis Harding and his co-workers' have shown that polyene cyclization termination by y- allenes proceeds exclusively via a six-membered ring vinylic cation rather than the alternative five-membered ring alkylic cation (Scheme 2 3 ) . Johnson el lo'

lo9 'lo

N. J. P. Broom and P. G. Sammes, J.C.S. Chem. Comm., 1978, 162. G. A. Kraus and H. Sugimoto, Tetrahedron Letters, 1978, 2263. F. M. Hauser and R. P. Rhee, J. Org. Chem., 1978,43, 178. G. Stork and A. A. Hagedorn, J. Amer. Chem. SOC.,1978, 100, 3609. K. E. Haiding. J. L. Cooper, and P. M. Puckett, J. Amer. Chem. Soc., 1978, 100, 993.

255

Saturated Carbocyclic Ring Synthesis

Scheme 22

Scheme 23

~ 1 . ’ ’have ~ now reported their full studies of the use of acetylenes as terminators for cationic cyclization reactions, which has culminated in the total synthesis of d,l-progesterone and d,l-A4-androstene-3,17-dione.”3 The trimethylsilylacetylene (173; R = SiMe3) cyclizes under acidic conditions to produce a sixmembered D-ring, unlike the methylacetylene analogue (173; R = Me), which affords a five-membered D-ring.’ l4

R

(173)

In a modification of Johnson’s stereospecific total synthesis of d,I-oestrone, Groen and Zeelen have shown that the introduction of a methyl substituent at the pro- C-6-centre of the cyclization substrate ensures a high degree of asymmetric induction in the cyclization step.’” Similarly the 2- and 3-substituted thiophens (174)and (175),bearing pro-C-6 methyl groups, cyclized with a high degree of asymmetric induction, leading Macco et al. to propose that precoiling of the M. B. Gravestock, W. S. Johnson, R. F. Myers, T. A. Bryson, D. H. Miles, and B. E. Ratcliffe, J. Amer. Chem. SOC.,1978,100,4268. M. B. Gravestock, W. S. Johnson, B. E. McCarry, R. J. Parry, and B. E. Ratcliffe, J. Amer. Chem. SOC.,1978,100,4274. ‘I5

W. S. Johnson, T. M. Yarnell, R. F. Myers, and D. R. Morton, Tetrahedron Letters, 1978, 2549. M. B. Groen and F. J. Zeelen, J. Org. Chem., 1978,43, 1961.

General and Synthetic Methods

256

initially formed allylic cation dictates the stereochemical course of the reaction. '16 The presence of substituents at both the pro-C-6 and pro-C-7 centres in thiophens of type (174)results in a distinct change in the reaction stereospecificity, giving rise to a significant amount of cis-B,c-ring-fused product, presumably via the ion

(176).'l7 OH

(174) 2-thiophen (175) 3-thiophen

Sutherland and his co-workers have established that tetrasubstituted cyclohexane epoxides can fulfil a useful role as cationic cyclization initiators.'18 Several alk-3-enyl-2,3-epoxy-3-methylcyclohex-2-enones, e.g. (177), have been successfully cyclized to decalone derivatives, e.g. (178),in good yield on treatment with Lewis acids, and the acetylenic epoxides (179) and (181)have been cyclized in excellent yields to the expected decalin (180)and hydrindane (182) derivatives respectively.' l9

@

BF,,0Er2-CH2C~,

0 (177)

0 OH (178)

111

SnC1,-CHzCIz

0

(181) 117

(182)

A. A. Macco, R. J. de Brouwer, P. M. M. Nossin, E. F. Godefroi, and H. M. Buck, J. Org. Chem., 1978,43,1591. A. A. Macco, J. M. G. Driessen-Engels, M. L. M. Pennings, J. W. deHaan, and H. M . Buck, J.C.S. Chem. Comm., 1978, 1103. E. Huq, M. Mellor, E. G. Scovell, and J. K. Sutherland, J.C.S. Chem. Comm., 1978, 526. M. Mellor, A. Santos, E. G. Scovell, and J. K . Sutherland, J.C.S. Chem. Comm., 1978, 528.

251

Saturated Carbocyclic Ring Synthesis

Epoxy vinyl ethers of type (183)have been observed to cyclize with high regioand stereo-specificity on treatment with Lewis acids.120 The size of the new carbocyclic ring is governed not only by the side-chain length, n, but also, predictably, by the immediate epoxide substitution pattern.

(183)

Potential new cationic cyclization initiators include w -ethoxy-lactams, e.g. (184), which cyclize in excellent yield at room temperature on treatment with weak protic acids,121 and dithioketenals, e.g. (185), which cyclize stereospecifically in the presence of trifluoroacetic acid. 122

U (185)

have observed that acid treatment of cyclohexenone (186) Harding et results in cyclization to the tricyclic system (187), whereas, under the same conditions, cyclization of acetylenic analogue (188) halts at the bicyclic stage. The cyclobutanone (189), which is readily available by addition of l-naphthylketen to cyclopenta-1,3-diene, undergoes acid-catalysed rearrangement, providing a convenient route to the steroidal ring system (190).'24

[ a] - cF3 O,CCF,

@

CF3CO2H-(CF,C?),O

0

CF,C02 (186)

I2l 122 123 124

(187)

R. K. Boeckman, K. J. Bruza, and G. R. Heinrich, J. Amer. Chem. SOC., 1978,100,7101. H. E. Schoemaker, J. Dijkink, and W. N. Speckamp, Tetrahedron, 1978, 34, 163. V. L. Mizyuk and A. V. Semenovsky, Tetrahedron Letters, 1978, 3603. K. E. Harding, J. L. Cooper, P. M. Puckett, and J. D. Ryan, J. Org. Chem., 1978, 43, 4363. L. H. Dao, A. C . Hopkinson, and E. Lee-Ruff, Tetrahedron Lerters, 1978, 1413.

258

General and Synthetic Methods

(188)

Finally, both Oppolzer and Kametani and their respective collaborators have adapted their steroidal syntheses based upon intramolecular o -quinodimethane cycloaddition to achieve asymmetric induction by incorporation of an optically active cyclopentane moiety in the cyclization precursor. 125*1'26

7 Seven-membered Rings The continued search for novel synthetic routes to the sesquiterpene pseudoguaianolides has resulted in several new approaches to the hydroazulene ring system. Lansbury and S e ~ e l i s have ' ~ ~ shown that the hydroxycyclopentanone (191)undergoes facile cationic cyclization on treatment with formic acid, leading directly to the hydroazulenedione (192). Further manipulation of (192) led to the total synthesis of damsinic acid (193). In an impressive synthesis of the closely

related pseudoguaianolide confertin (195), the seven-membered ring and amethylene- y-lactone portions were constructed simultaneously by invoking an intramolecular attack of an allylic metal species on an aldehyde group, followed by spontaneous lactonization, (194) + (195).12*Optimum yields were obtained with a zinc/copper couple or with bis(cyc10-octa- 1,5-diene)nickel, and the 126

'21

'**

W. Oppolzer, K. Battig, and M. Petrzilka, Helv. Chim. Acca, 1978, 61, 1945. T. Kametani, H. Matsumoto, H. Keinoto, and K. Fukumoto, J. Amer. Chem. SOC., 1978,100,6218; Tetrahedron Letters, 1978, 2425. P. T. Lansbury and A. K. Serelis, Tetrahedron Letters, 1978, 1909. M. F. Semmelhack, A. Yamashita, J. C. Tomesch, and K. Hirotsu, J. Amer. Chem. SOC.,1978,100,

5565.

259

Saturated Carbocyclic Ring Synthesis

[Niicod),]

0

___+

-0

0

(194)

(195)

(196)

stereoselectivity of the ring-closure step was found to depend on both the olefin geometry and the choice of metal reagent employed. Applying a different intramolecular cyclization strategy, Posner and his coworkers have demonstrated that direct p-addition of a methyl metal reagent to the a,@-unsaturated cyclopentenone (197) results in ring closure to the hydroazulene system (198).129 The procedure can be carried out more effectively by trapping the intermediate enolate as a trimethylsilyl enol ether (199) before cyclizing, by treatment with titanium tetrachloride (Scheme 24).

iii,iv

Reagents: i, Me-metal-THF, 0 "C;ii, H'; iii, Me,CuLi; iv, Me,SiCI-Et,N; v, TIC],-CH,CI,, 0 "C

Scheme 24

The trimethylsilyl ethers of the 7,7-dichloronorcaren-1-ols(200) and (203) have been reported to undergo facile ring expansion to the corresponding a -chlorocycloheptadienones (201) and (204) on hydrolysis with acidic methan01.l~~ However, the isomeric, h3-norcareno1 system (202) was found to be

A. Alexakis, M. J. Chapdelaine, G. H. Posner, and A . W. Runquist, Tetrahedron Letters, 1978,4205. T. L. Macdonald, J. Org. Chem., 1978, 43,4241.

General and Synthetic Methods

260

p:; 0

(203)

--- CI

0

(204)

exceptionally stable under the same conditions. The anomalous behaviour of the A3-isomers has been noted in related systems previously but has not yet been fully rationalized. A recent novel synthesis of desacetamidoisocolchicine (211) employs the cyclopropyl-ketone (205) as a functionalized tropolone e q ~ i v a 1 e n t . l Acid ~~ treatment of the acetal(207), formed by condensation of (205) with the Grignard reagent (206), led to rearrangement, uia dienone (208) and spiran (209), to the tricyclic system (210). Oxidation of (210) then gave the isocolchicine (211).

moMe Me0 /

+

MeO

O M e -+MeoM%

BrMg Me0

MeO

MeO

OMe

Me0 (205)

“:ZMq$-

(206)

OMe

(207)

k+

EQ0

MeO

OMe 0 (208)

(209) J Me0 DDQ ___+

Me0 OMe

OMe

0

(210)

0

(21 1)

The first report of allenyl cations undergoing [4 + 31 cycloaddition with a diene has appeared.13* Thus, treatment of a solution of propargyl halide and cyclopentadiene in pentane with silver trifluoroacetate provides, after hydrolysis, a 13’ j3*

D. A. Evans, D. J. Hart, and P. M. Koelsch, J. Amer. Chem. SOC.,1978,100,4593. H. Mayr and B. Grubrnuller, Angew. Chem. Internat. Edn., 1978,17, 130.

Saturated Carbocyclic Ring Synthesis

261

mixture of cyclopentenol (212) and the bicyclo[3,2,1]octane (213) (Scheme 25; R = H or Me).

Noyori et a1.'33 have reported their studies of the iron carbonyl-promo :d [4 + 31 cyclo-coupling of polybromo-ketones with 1,3-dienes as a method of preparing cyclohept-4-enones, and in a subsequent paper describe methodology for converting these products into a number of troponoid

8 Large Rings It6 and Kato and their respective co-workers have extended their closely related investigations of the synthesis of 10- and 14-membered cyclic terpenoids by and phenyl intramolecular cyclizations of phenyl sulphides [e.g. (2 14) -+ (215)]13s sulphones [e.g. (216) -+(217)].'36

Q S0,Ph

133 134

13' 13'

S0,Ph

d LDA -78 "C

Q

H. Takaya, S. Makino, Y. Hayakawa, and R. Noyori, J. Amer. Chem. SOC., 1978, 100, 1765. H. Takaya, Y. Hayakawa, S. Makino, and R. Noyori, J. Amer. Chem. SOC.,1978,100,1778. M. Kodama, S. Yokoo, H. Yamada, and S. It8, Tetrahedron Letters, 1978, 3121. H. Takayanagi, T. Uyehara, and T. Kato, J.C.S. Chem. Comm., 1978, 359; cf. M. Suzuki, A. Shimada, and T. Kato, Chem. Letters, 1978, 759.

General and Synthetic Methods

262

Acetylenic intermediates have featured in a number of new approaches to l ~ developed ~ large-ring compounds published this year. Thus, Utimoto et ~ 1 . have a new synthesis of muscone (219) based on intramolecular acylation of the o -trirnethylsilylethynylalkanoylchloride (218), and cyclic l,3-diones [e.g. (22O)J have beeri prepared from a,o -diynes by intramolecular oxidative coupling, followed by h y d r o l y ~ i s .The ' ~ ~ reaction between a,o-dodecatrienediylnickel and dimethyl acetylenedicarboxylate has been shown to lead to equal amounts of 12and 14-membered ring products at 0 "C, whereas at -78 "C the reaction is more specific, producing largely the 14-membered ring. 139

0

0

(220)

The potential for a,w -bisdiazo-ketones in large-ring synthesis is well illustrated this year with a synthesis of the enedione (222)14' by treatment of (221) with [ C ~ ( a c a c )in~ ]dry benzene at 60 "C. 0

0

9 Spiro-ring Annelations The familiar aldol condensation remains a key reaction in several approaches to spirosesquiterpenes, such as acorenone (225). Thus, Lange et ~ 1 . ' ~ have ' elaborated upon their synthesis of (225) whereby the spiro-system is formed by annelation of the enamine of aldehyde (223) with the vinyl ketone (224). Pesaro and B a ~ h r n a n n have l ~ ~ established that Robinson annelation of the aldehyde (223) with methyl vinyl ketone is almost as efficient for the formation of the 137

13'

141

14'

K. Utimoto, M. Tanaka, M. Kitai, and H. Nozaki, Tetrahedron Letters, 1978, 2301. A. Stiizz and H. Reinshagen, Tetrahedron Letters, 1978, 2821. R. Baker, P. C. Bevan, R. C. Cooleson, A. H. Copeland, and A. D. Gribble, J.C.S. Perkin I, 1978, 480. S. Kulkowit and M. A. McKervey, J.C.S. Chem. Comm., 1978, 1069. G. L. Lange, E. E. Neidert, W. J. Orrom, and D. J. Wallace, Canud. J. Chern., 1978, 56, 1628. M. Pesaro and J. Bachmann, J.C.S. Chem. Comm., 1978, 203.

Saturated Carbocyclic Ring Synthesis

263

&

spiro-system in (225), and other workers have utilized the 6-keto-aldehyde (226) to generate the same ring

M

(223)

e

0

4

-

__* (223)

-

~

(224) (225)

In a different approach to the spiro[4,5]decane ring system, Waegeli'44 has synthesized decanones of the type (228) by way of cationic cyclizations of appropriate a,P-unsaturated ketones, e.g. (227). 0

SnCI,

9

5

MeCOCHN,-?

Me0

oq

Me0 0

(229)

143 144

S . F. Martin and T. Chou, J. Org. Chem., 1978, 43, 1027. P. Naegeli, Tetrahedron Letters, 1978, 2127.

0 1

264

General and Synthetic Methods

Further investigations of the approach to spiro[4,5]decanones based on reductive cleavages of the cyclopropane rings in tricyclo[4,4,0,0,2~6]decanones have been and the potential for oxycyclopropane derivatives in synthesis is very well demonstrated in a synthesis of p-vetivone (230) from the P-oxycyclopropyl ketone (229).'46

14' 146

D. Caine, W. R. Pennington, and T. L. Smith, Tetrahedron Letters, 1978, 2663. E. Wenkert, B. L. Buckwalter, A. A. Craveiro, E. L. Sanchez, and S. S. Sathe, J. Amer. Chem. Soc., 1978,100,1267.

Saturated Heterocyclic Ring Synthesis BY W. J. ROSS

1 Oxygen-containing Heterocycles 0xirans.-A new general synthesis of oxirans' from a-sulphenylated ketones2 has been described (Scheme 1); the procedure leads exclusively to cis-epoxides HO R' I 1

0 R'

I1

I Arc-C-SMe I R2

..

-& Ar-C-C-SMe I

-!+

I

HO R' I I

Me

Arc-C-S

H R2

I!l

Rl

+/

k2 M' e

A Ar *Rz

IReagents: i, NaBH,; ii, MeI; iii, Bu'OK-DMSO

Scheme 1

but the reasons for this are not clear. A general method for the synthesis of chiral epoxides of high enantiomeric purity has also been d e ~ c r i b e dThe . ~ method is dependent on the preparation of P-hydroxysulphides which may be obtained from the racemic epoxide by ring opening with thiophenoxide, regioselectivity permitting (Scheme 2). Alternatively, the required P-hydroxysulphides may be

R'

>L1
R3

i_ R~ ) PhS

Reagents: i, PhSNa-THF, A; i i ,

<

OH .. :I -ir, Separate diastereomers by chromatography R'

iii, HSiCl,; iv, NH,Cl; v, Me,;)BF,-; \

Scheme 2

'

S. Kano, T. Yokolnatsu, and S. Shibuya J.C.S. Chem. Comm., 1978,785. P. A. Grieco and C.-L. J. Wang, J.C.S. Chem. Comm., 1975,714. W.H.Pirkle and P. L. Rinaldi, J. Org. Chem., 1978,43,3803.

265

vi, OH-

266

General and Syfithetic Methods

prepared by reaction of a-thiolithium reagents4 with aldehydes, and the diastereomers obtained separated by column Chromatography. The diastereomeric P-hydroxysulphides then react with (R)1- (1- naphthy1)ethyl isocyanate, yielding the diastereomeric carbamates in 80-90% yield, and these are then separated by chromatography; further reactions then lead to the chiral epoxides. A partial asymmetric synthesis of substituted trans-2,3-diaryloxirans using optically active arsonium ylides has been investigated, and optical yields in the range 4.7-38% have been obtained (Scheme 3).5

:.

Me

Me

\ . '

Me/

Me

a.

\ :

/

?.

Me

\

:.

,'

-i CH,C6H4R-o

(S, S )

H 0 C6H4R-o

Pi-

C6H4R-o

R

=

H

H or OMe

Reagents i, o-RC6H4CH,Br; ii, NaOEt-EtOH; iii, o-RC,H,CHO

Scheme 3

A convenient, high-yield, one-step synthesis of diethyl 1,2-epoxyalkane phosphonates has been described.6 The procedure appears applicable to a wide range of aliphatic and aromatic aldehydes and ketones, and to the preparation of 1 -substituted 1,2-epoxyalkane-phosphonates (Scheme 4). The 'H n.m.r. Y

Y

Y

x\ II

,P-CH,CI

X

L

x, P-CHCl II x/ I

R2 /

-%X\ll , P -CH-C-R'

Li

X

\ /

0

i,iii

Reagefits: i, Bu"Li-THF-hexane, -70°C; ii, X'R'CO-THF, +20 "C.

-70 to +20"C; iii, Mel-THF, -70 to

Scheme 4 T. M. Dolak and T. A. Bryson, Tetrahedron Letters, 1977, 1961. D. G . Allan, N. K. Roberts, and S. B. Wild, J.C.S. Chern. Comm., 1978, 346. ' P. Coutrot and P. Savignac, Synthesis, 1978, 34.

Saturated Heterocyclic Ring Synthesis

267

spectra of the 1,2-a1kanephosphonates from aldehydes show the presence of E/Z-isomers with a predominance of the E-form. In phosphonates derived from unsymmetrical ketones the E-form is favoured by the presence of bulky substituents. Epichlorhydrin is frequently used in synthetic and medicinal chemistry, but in general as the R,S-mixture. Preparation of R-(-)-epichlorhydrin has been described7 previously but the method is cumbersome and tedious. A new procedure which leads to good overall yields with high optical purity for both ( R ) - and (S)-epichlorhydrin has now been described (Scheme 5 ) . 8 The key intermediate for the synthesis of (R)- and (S)-epichlorhydrin is ( R ) -3-tosyloxypropane-1,2-diol (1),which can be readily obtained in good yield by known procedures.

. ..

-%( S ) H o I O H

Reagents: i, Pb(OAc),; ii: NaBH,; iii, TsCl-pyridine; iv, H'; v, Ph,P-CCI,-DMF; CH,OH-Na; vii, NaOMe; viii, MsCl-NEt,-PhCH,; ix, HCl

vi, HOCH,-

Scheme 5

Hydrogen psroxide in the presence of certain dehydrating agents gives intermediates of indeterminate structure which collapse to yield singlet oxygen, but in the presence of olefins epoxidation occurs at the expense of '02generation.' Epoxidation rates as a function of olefin substituents and selectivities toward cisand trans-olefins are similar to those of peracids. Good yields of labile epoxides can be obtained, e.g. Scheme 6 , but the stereospecificity of the reaction using optically active reagents for epoxidations of trans- 2-methylstyrene was found to be poor (Scheme 7). E. Abderhalden and E. Eichwald, Chem. Ber., 1915,48, 1847. J . J. Baldwin, A. W. Raab, K. Mensler, B. H. Arison, and D. E. McCluse, J. Org. Chem., 1978,43, 4876. J . Rebek, S. Wolf, and A. Mossman, J. Org. Chem., 1978, 43, 180.

General and Synthetic Methods

268

/-N

-I or PhCONCO-H202-THF

N

Scheme 6

A

H Ph +- )

H

Me

H

Me

(Asymmetric induction -2%) Reagents: 1, (+)-MeCH(Ph)N=C=NCH(Ph)Me-H202-THF

Scheme 7

Arene oxides have great importance in biosynthetic schemes and in the metabolism of foreign compounds in mammals. A new approach to the rational synthesis of substituted arene oxides has been investigated culminating in the total synthesis of the natural products senepoxide and seneol (Scheme S).”

R

Reagents: i, LDA-THF; ii, E’, e.g. PhCH,Br, HCHO, or MeI; iii, Br2-NaHC0,; iv, CF,CO,H; v, DBU; vi, A, C,H,

Scheme 8

The oxiran (2) played an important role in the total synthesis of erythronolide A stereoselective synthesis of (+) and (-)-tetrahydroceruIenin (3b) from D-glucose has been described,13 and the correct absolute configuration of cerulenin (3a) deduced. Two studies on the use of chiral phase-transfer catalysts in the preparation of oxirans have been reported.14715 B.”*12

10

11

12

13 14 15

B. Ganem, G. W. Holbert, L. B. Weiss, and K. Ishizumi, J. Amer. Chem. Soc., 1978, 100, 6483. E. J. Corey, S. Kim, S. Yoo, K. C. Nicolaou, L. S. Melvin, jun., D. J. Brunelle, J. R. Falck, E. Trybulski, R. Lett, and P. W. Sheldrake, J. Amer. Chem. Soc., 1978, 100,4620. E. J. Corey, E. J. Trybulski, L. S. Melvin, jun., K. C. Nicolaou, J. A. Secrist, R Lett, P. W. Sheldrake, J. R. Falck, D. J. Brunelle, M. F. Haslanger, S. Kin, and S . Yoo, J. Amer. L’hem. SOC.,1978, 100, 4618. H. Ohrui and S. Emoto, Tetrahedron Letters, 1978, 2095. S. Colonna, R. Fornasier, and U. Pfeiffer, J.C.S. Perkin I, 1978, 8. J. C. Hummelen and H. Wynberg, Tetrahedron Letters, 1978, 10, 89.

269

Saturated Heterocyclic Ring Synthesis 0 0

0

C.

.CNH,

H

H

I1

II

'R

b; R = n-C8H17

Dihydrofurans.-As part of a general study on heteroatom-directed photoarylation, Schultz and his co-workers have studied the irradiation of aryloxyenones (Scheme 9).16 The products are tricyclic dihydrofurans; a wide range of functionality in the phenol can be tolerated, and yields are high (32-100%). The method has been used in the synthesis of the Amaryllidaceae alkaloid lycoramine16and a tetracyclic morphine structural ana10gue.l~

boArOH-KH

Me Me

Me

Me & Me

O

D

x /

Me

Mebo Me

Me

Scheme 9

An unusual and useful synthesis of spiro-dihydrofuran-3(2H)-ones has been discovered" and follows the study of the synthetic utility of methoxyallene as a P-acyl anion equivalent (Scheme 10).High yields were obtained overall (42% for n = 2; 73% for n = 3), and the method has been applied to the synthesis of a new class of 17-spiro steroid derivatives."

Reagents: i, BuLi-THF, -70 "C; ii,

iii, KH-THF-dicyclohexyl-18-crown-6; iv, H+-H20

Scheme 10 l6

"

''

l9

A. G. Schultz, R. D. Lucci, W. Y. Fu, M. H. Berger, J. Erhardt, and W. K. Hagmann, J. Amer. Chem. SOC., 1978,100,2150. A. G. Schultz and Y. K. Yee, J. Amer. Chem. SOC.,1977,99,8065. A.G. Schultz and R. D. Lucci, J.C.S. Chem. Comm., 1976,925. D.Gange and P. Magnus, J. Amer. Chem. SOC., 1978,100,7746.

270

General and Synthetic Methods

In a total synthesis of the poly-ether antibiotic lasalocid A, the key intermediate ( 5 ) (Scheme 11)was prepared by sequential epoxidation of the keto-diene (4);20*21 subsequent transformations led to synthetic lasaiocid A (6).

Me

Me (4)

iii-vll + V,Vl! --

Reagents: i, p-MeOC,H,MgBr; ii, Cr0,-H,SO,; iii, LiAIH,; iv, h.p.1.c. of I-a-methylurethane; v, Bu'00~-[VO(acac),]-Nao.4c-c~H6;vi, AcOH; vii, Ac,O-C,H,N

Scheme 11

Pyrans.-A useful new synthesis of certain pyrans from 6-lactones has been described (Scheme 12).22*23 These pyrans were required for the synthesis of the pederamide (7), a degradation product of a natural product pederin. Addition of lithium ester enolates to the carbonyl group of a S-lactone leads to hemiacetals which may be transformed into glycolarnides. Treatment of aliphatic aldehydes containing at least seven carbon atoms and an alkyl substituent in the 6-position with a strong acid yields alkylated tetrahydropyrans in high yield (60-90% in favourable cases).24The products are rationalized by an ionic mechanism (Scheme 13), but a mechanism involving olefinic intermediates must also be considered. 2o

" 22 23 24

T. Nakata, G. Schmid, B. Vranesic, M. Okigawa, T. Smith-Palmer, and Y. Kishi, J . Amcr. Chem. Soc., 1978,100, 2933. T. Nakata and Y. Kishi, Tetrahedron Letters, 1978, 2745. A. J. Duggan, M. A. Adams, P. J. Brynes, and J . Meinwald, Tetrahedron Letters, 1978, 4323. A. J. Duggan, M. A. Adams, and J . Meinwald, Tetrahedron Letters, 1978, 4327. J. G . D . Schulz and A. Onopchenko, J. Org. Chem., 1978, 43,339.

Saturated Heterocyclic Ring Synthesis

+

LiCHC0,Et I 0 Me +OMe Me

27 1

L I

Me+OMe Me

liii 0

LcJ

Reagents: i, THF, -75 "C; ii, H'; iii, N7NCON

; iv, NH,-EtOH; v, H'-MeOH

Scheme 12

Scheme 13

Tricyclic ethers are readily available by reaction of the diepoxide derived from 4-vinylnorbornene (Scheme 14) with lithium alkylcyanocuprates and subsequent . ~ ~ important result is the regioscyclization of the resultant e p o x y - a l ~ o h o lThe pecific reaction of the cuprate with the least hindered epoxide to yield the epoxy -alcohol.

Dioxo1ans.-A convenient synthesis of 4-isopropylidene-l,3-dioxolans involves the reduction of a,a'-dibromo-ketones with ultrasonically dispersed mercury in aliphatic ketone solvents (Scheme 15).26

*' 26

R. D. Acker, Tetrahedron Letters, 1978, 2399. A. J. Fry, G. S. Ginsburg, and K. A. Parente, J.C.S. Chem. Comm., 1978, 1040.

General and Synthetic Methods

272

R

1

ii 66-7196

R

R

R

=

MeorBu

Reagents: i, Me(CN)CuLi or Bu(CN)CuLi; ii, H'

Scheme 14

Reagents: i, Hg', ii, R ' R 2 C 0

Scheme 15

The current interest in the prostaglandin endoperoxides has led Adam and his c011eagues~~ to study the chemistry of 1,2-dioxolans as models of the natural products. The compounds are readily prepared from cyclopropanes as shown in Scheme 16. Yields are in the range 71--96%.

Reagents: i, Na-Bu'OH; ii, H20,-NBS; iii, Ag,O

Scheme 16

Chromans.-The use of isoprene in the synthesis of chromans from phenols is a well known reaction but one which is fraught with difficulties since regiochemical control is poor.28In a re-examination of the problem Sartori et al.29have found 27

29

A. Adam, A. Birke, C. Cadiz, S. Diaz, and A. Rodriguez, J. Org. Chem., 1978, 43, 1154. K. C. Dewhirst and F. F. Rust, J. Org. Chem., 1963, 28, 798. L. Bolzoni, G. Casiraghi, G. Casnati, and G. Sartori, A n g e w . Chem. Internat. Edn., 1978, 17, 684.

Saturated Heterocyclic Ring Synthesis

273

that high yields of 2,2-dimethylchromans can be obtained from isoprene and phenols under rather unusual Friedel-Crafts conditions. A 1: 1 : 1 mixture of phenol, potassium phenoxide, and aluminium chloride gives a 60% yield of the 2,2-dimethylchroman together with other minor products (Scheme 17).

"00" R'

+Y

R3

M e

AICI,

PhOK

/

\

R'

R3

Me \

R4

R4

R', R2, R3, R4 = OMe or Me Scheme 17

A convenient new synthesis of 2,2-dialkylchroman-4-ones and their spiro anologues from 2-hydroxyacetophenones and enamines has been described (Scheme 18).30The product obtained is in contrast to that observed when the

R'

+

i J N

n = 2or3

Scheme 18

reaction is carried out using salicylaldehydes, the products in the latter case being 1,2-dihydroxanthenones. The procedure has been used to synthesize 4-oxo-atocotrienol, which is readily converted into vitamin E (Scheme 19).31 Prostaglandin Endoperoxides, Thromboxanes, and Prostacyc1ins.-Although representing diverse oxygen heterocyclic systems this group of compounds is so intimately inter-related that they should be discussed as a single entity. A useful review of the subject has been published.32 The prostaglandin endoperoxides PGG, and PGH, are metabolized in human platelets to a group of biologically active compounds called the t h r o m b o ~ a n e s ~ ~ which appear to play an important role in platelet a g g r e g a t i ~ nOne . ~ ~ of these compounds, thromboxane B,, has been the subject of much research and a successful synthesis has been a ~ h i e v e d . ~A' chiral synthesis of an important 30 31

32 33 34

35

H. J. Kabbe, Synthesis, 1978, 886. H. J. Kabbe and H. Heitzer, Synthesis, 1978, 888. K. C. Nicolaou, G. P. Gasic, and W. E. Barnette, Angew. Chem. Internat. Edn., 1978,17,293. M. Hamberg, J. Svensson, and B. Samuelsson, Proc. Nut. Acad. Sci. U.S.A.,1975,72, 2994. B. Samuelsson and R. Paoletti, 'Advances in Prostaglandin and Thromboxane Research', Raven Press, New York, 1976. E. J. Corey, M. Shibasaki, and J. Knolle, Tetrahedron Letters, 1977, 1625.

General and Synthetic Methods

274 Me I

Me

HMe oQJcoMe

OH

+

Me

Me

Me

Me

li "Me

O

\

Me

Me

LMe

Me M

Me e

ji,iii

Me

Reagents: i,

LJ ; ii,

NaBH,; iii, Pd/C-H,

Scheme 19

H

intermediate in the synthesis of thromboxane Bz (Scheme 20), which represents a solution to the main stereochemical problems in the preparation of optically pure thromboxanes, has been described.36The synthesis starts with the readily available a-methylglucoside which is first converted into the protected compound (8) by standard procedures; the most important reaction is the conversion of (9) into (10) by the orthoester Claisen rearrangement.

p

h

c

MeO"

o

~

-

.

~

OCPh,

S1..1 ..1. HOQ

OCPh

M eO'

MeO"

p$ MeO'* Reagents: i, Zn-Cu-KI; ii, NaOMe-MeOH; iii, MeC(OMe),-C,H,CO,H; vi, Bu,SnH

Scheme 20 36

0. Hernandez, Tetrahedron Letters, 1978, 219.

0-f

MeO'

OCPh,

iv, NaOH; v, I,-NaHCO,;

Saturated Heterocyclic Ring Synthesis

275

;+

The Upjohn group has published full details of the synthesis of prostacyclin from PGF2, methyl ester (Scheme 21).37

fi=*w C0,Me

C0,Me

OH

O'H OH Reagents: i, I,-Na,CO,;

ii, DBN; iii, NaOH

Scheme 21

A strain-free homologue of the nucleus in prostaglandin endoperoxides, namely 8,9-dioxabicyclo[5,2,l]decanecan be conveniently prepared from cycloocta-1,4-diene (Scheme 22).38 H

Reagents: i, H,O,-HgO,CCF,;

ii, NaBH,-OI-I-

Scheme 22

2 Sulphur-containingHeterocycles Five- and Six-membered Ring Sulphur Systems.-It has previously been shown that 2,5-dihydrothiophens3' and dihydr~thiopyrans~' are useful synthons for the preparation of specifically alkylated conjugated d i e n e ~The . ~ ~general method has now been extended to the preparation of 3-carboxylated 2,5-dihydrothiophen~,~~ which provides a method for the synthesis of 2-carboxyb~ta-1,3-dienes.~~ The R. A. Johnson, F. H. Lincoln, E. G. Nidy, W. R. Schneider, J. L. Thompson, and U. Axen, J. Amer. Chem. SOC., 1978,100,7690. 38 A. J. Bloodworth and J. A. Khan, Tetrahedron Letters, 1978, 3075. 39 J. M. McIntosh, H. B. Goodbrand, and G. M. Masse, J. Org. Chem., 1974, 39, 202. 40 J. M. McIntosh and H. Khalil, Canad. J. Chem., 1976, 54, 1923. 4 1 J. M. McIntosh and G. M. Masse, J. Org. Chem., 19?5,40, 1294. 42 J. M. McIntosh and R. A. Sieler, Canad. J. Chem., 1978, 56, 226. '' J. M. McIntosh and R. A. Sieler, J. Org. Chern., 1978, 43, 4431. 37

276

General a n d Synthetic Methods

general procedure is shown in Scheme 23 and is applicable to mercaptoaldehydes and -ketones. 0

II

Reagents: i, pyridine-Et,N or CH,CI,-Et,N;

ii, m-CIC,H,CO,H

iii, A

Scheme 23

Two new syntheses of the natural product biotin have been reported during the year under review. One synthesis is based on the stereoselective alkylation of ~ u l p h o x i d e s whereas ,~~ the second synthesis is dependent o n the introduction of chirality into the molecule at a late ~ t a g e . ~The ' French started with meso-dibromosuccinic acid which was first converted by standard procedures into the sulphide (11); oxidation then yielded the epimeric epoxides (12) and (13) in the ratio 10 : 90. The major epoxide (13) was then alkyiated, and as anticipated the side-chain was introduced trans to the S -+ 0 bond. The synthesis, shown in Scheme 24, has also been used in the preparation of various biotin analogues. The Hofmann-La Roche synthesis of d - b i ~ t i navoids ~ ~ the problem of diastereomer formation by maintaining two of the three chiral carbons in a prochiral form until a late stage. The success of the synthesis centres round a new carbon-carbon bond forming reaction, leading to an a-nitro-ketone, and a stereospecific hydrogenation of a derivative of dehydrobiotin (Scheme 25). The synthesis of various thio-analogues of prostacyclin (PGI) (see Scheme 21) has been reported. The thio-analogue of the natural product was synthesized from prostaglandin PGE,.46 The important steps in the synthesis were the introduction of the sulphur atom with concomitant inversion of the 9P-OH configuration, and the preparation of a sulphenyl bromide from a disulphide (Scheme 26). The sulphur analogue of 5,6-dihydroprostacyclin,and its oxidation products the S-oxides and SS-dioxide, have been prepared from 9-thio-PGF2, (Scheme 27).47The synthesis has features in common with that described in Scheme 26. The oxidation of the sulphide to the sulphone is mild and selective, and presumably proceeds via the action of PhSe(0)OOH generated in situ. 44 45

46

47

S. Lavielle, S. Bory, B. Moreau, M. J. Luche, and A. Marquet, J. Amer. Chem. Soc., 1978,100, 1558. J . Vasilevskis, J. A. Gualtieri, S. D. Hutchings, R. C. West, J. W. Scott, D. R. Parrish, F. T. Bizzarro, and G. F. Field, J. Amer. Chem. SOC., 1978, 100, 7423. M. Shibasaki and S. Ikegarni, Tetrahedron Letters, 1978, 559. K. C. Nicolaou, R. L. Magolda, and W. E. Barnette, J.C.S. Chem. Comm., 1978, 3 7 5 .

Saturated Heterocyclic Ring Synthesis

277

*

( d l ) -Biotin

0 iv, 48% HBr (R= PhCH,) or

Reagents: i, NaIO,; ii, MeLi-I(CHz),COzBu'; iii, TiC1,-H'; [(Ph,P),RhCl]-C,H,-H*O (R= CH,=CHCHz)

Scheme 24

lvi-viii

0

0

,A NAc

H N K N H

"%-Ac ix-xi

H

C0,Me

H

C0,Me

j ; N U . x /

'

k

HC

0

2

H

Reagents: i, MeNO,; ii, HSCH,CO,H; iii, Resolution; iv, PhOH-SOC1,-C,H,N; v, B = (-)-a-MBA; vi, 10% Pd/C-H,-AcOH-HCI; vii, KNCO; viii, NaOH; ix, A, AcOH; x, MeOH-H'; xi, Ac,O; xii, 5% Pd/C-Ac,O; xiii, NaOH

Scheme 25

General and Synthetic Methods

278

PGE,

C0,Me

& OiHP

OTHP

ji.iii

t2

SCOMe

- * ' L - . - C 0 2 M e

OTHP

iv,v

OTHP

OTHP

Ivi 1 ,+CO,Me C0,Me

[THP

OTHP ,%A/-

OTHP

OTHP

HO

HO

Reagents: i, Several steps; ii, C H S0,CI-C,H,N; iii, MeCOSNa; iv, NaOMe-MeOH; v, 0,; vi, Br,-CH,CI,; vii, DB; AcOH-H,O-THF

vk,

Scheme 26 SAC C0,Me

Me,Bu'SiO OSiBu'Me,

HO ii Or

Y

H 0'

OH X=S-OorSOz Reagents: i, AcOH-THF-H,O; ii, rn-CIC,H,CO,H; iii, PhSeSePh-H,O,

Scheme 27

OH

Saturated Heterocyclic Ring Synthesis

279

As a part of a general study related to heteroatom-directed photoarylation, Schultz and his c o - w ~ r k e r shave ~ ~ studied the photolysis of various vinyl sulphides. The initial products are dihydrothiophens which may be further transformed into thiophens or other products (e.g. Scheme 28). As with the

"s

+

MeCOCH ,CO,Et

'@Me CO,Et lhu

Et0,C Et0,C

,

--Me

Me Scheme 28

preparation of aryloxyenones (see Scheme 9), a series of 2-thioaryloxyenones was prepared by reaction of aryl mercaptans with keto-epoxides. Photo-irradiation of the products gave high yields of cis-fused dihydrothiophens (Scheme 29).

Reagents i, ArSH; ii, h v

Scheme 29

A convenient new synthesis of 2-alkylidene-l,4-benzodithiansand 1,4b e n z ~ d i t h i a n sby ~ ~rearrangement of the readily available 2-( 1-hydroxyalkyI)1,3-benzodithiolesS0has been described (Scheme 30).

Reagents: i, SO,CI,-Et,N;

ii, TsOH-C,H,, A or TFA

Scheme 30 48

A. G. Schultz, W. Y. Fu, R. D. Lucci, B. G. Kurr, K. M. Lo, and M. Boxer, J. Amer. Chern. SOC.,1978,

100,2140. 49

P. Blatcher, S. Warren, S. Ncube, A. Pelter, and K. Smith, Tetrahedron Letters, 1978, 2349. S . Ncube, A. Pelter, K. Smith, P. Blatcher, and S. Warren, Tetrahedron Letters, 1978, 2345.

280

General and Synthetic Methods

9-Thianoradamantane has been synthesized in moderate yield starting from cyclo-octa-2,7-dienone.5' The important reaction in the sequence (Scheme 3 1)is the transannular C-H insertion by a carbenic species.

4 0

Reagents: i, Na,S-aq. MeOH; ii, p-MeC,H,SO,NHNH,;

iii, NaOMe; iv, A, diglyme

Scheme 31

As part of their approach to the synthesis of macrocyclic natural products, Vedejs and his colleagues have described an ingenious new method for the preparation of eight-membered sulphur heterocycle^.^^ The synthesis is dependent on the ready availability of 2-vinyltetrahydrothiophen which is prepared as in Scheme 32 and transformed into the cis-thiacyclo-octene as shown. The [2,3] sigmatropic rearrangement of the ylide derived from (14) proceeds in high yield. The method has been modified53such that it becomes a repeatable ring-expan-

es+

CH,=CHCH,Br

-

GCH,CH=CH,

Reagents: i, Br-; ii, LDA; iii, CF,S0,CH2C0,Et;

Br-

r B r SCH,CH= CH,

iv, K0Bu'-MeCN

Scheme 32 51 52

53

T. Sasaki, S . Eguchi, and T. Hioki, J. Org. Chern., 1978, 43, 3808. E. Vedejs, J. P. Hagen, B. L. Roach, and K. L. Spear, J. Org. Chem., 1978,43, 1185. E. Vedejs, M. J. Mullins, J. M. Renga, and S . P. Singer, Tetrahedron Letters, 1978, 519.

Saturated Heterocyclic Ring Synthesis

28 1

sion process giving access to 11-membered and 14-membered rings etc., as exemplified in Scheme 33; it has also been applied to 2-vinylthian and to 2-vinylthiepan with similarily successful results.54

1

Reagents: i,

OSO,CF,; ii, DBU-MeCN

=/-

Scheme 33

Fava and his colleagues have described a general synthesis of 2-vinylthiacycloalkanes55and extended the Vedejs ring-expansion procedure described above to non-stabilized ylides (Scheme 34).55The sequence leads to a mixture of cis and

RCH,

R

R Reagents: i, BuLi-THF, -70°C;

= Ph, Me, etc.

ii,

A,

THF, -65°C; iii, NaHS0,-H,O,

100°C; iv, PBr,;

v, KOBu'; vi, PhCH,Br; 1N-NaOH

Scheme 34 54

55

E. Vedejs, M. J. Arco, D. W. Powell, J. M. Renga, and S. P. Singer, J. O r g . Chem., 1978,43, 4831. V. CerC, C. Paolucci, S. Pollicino, E. Sandri, and A. Fava, J. Org. Chem., 1978, 43, 4826.

282

General and Synthetic Methods

trans products, and in the case of R = Me the cis-2-methylthiacyclo-oct-4-ene and the diastereomerically related (SR,RS)- and (RR,SS)-trans-2-methylthiacyclo-oct-4-ene have been isolated by ~hromatography.~~ A convenient synthesis of medium-sized keto-thiolactones has been de~eloped.’~ The key step is a photosensitized oxygenation of bicyclic thioenol ethers (Scheme 35). A study of thio-oxalates as ‘dithiabutadienes’ has been carried and some unusual sulphur heterocycles have been prepared (Scheme 36).

-% (CH,), n

=

COiEt 4, 5 , 6 , or 10

Reagents: i, EtOH-H,O-KOH,

liii

A; ii, MeCOSH; iii, H30+, A; iv, 0,-Rose Bengal, hv

Scheme 35

MeO,

,OMe

@--c, S

Scheme 36

Miscellaneous Sulphur Heterocycles.-A new hetero-bicyclic system possessing the thiaozonide structure has been r e p ~ r t e d . ~The ’ new system was prepared by diazene reduction of thiophen endo-peroxides, a highly reactive but as yet unisolated intermediate in the preparation of but-2-ene-1,4-dione derivatives (Scheme 37).60 4H-1,3,5-Dithiazines can be prepared in a one-pot reaction from N-(ahydroxymethyl)thioamides, aldehydes, and hydrogen sulphide. A wide range of s6

V. CerC, S.Pollicino, E. Sandri, and A. Fava, J. Amer. Chem. SOC.,1978, 100, 1516.

59

K. Hartke, T. Kissel, J. Quante, and G. Hennsen, Angew. Chem. Internat. Edn., 1978, 17,953. W. .4dam and H. J. Eggelte, Angew. Chem. Internat. Edn., 1978,17,765. W. Adam and H. J. Eggelte, J. Org. Chem., 1977,42, 3987.

’’ H. C. Araujo and J. R. Mahajan, Synthesis, 1978, 228. 6o

es.&[ &]

283

Saturated Heterocyclic Ring Synthesis

OJj S

\

R

O R

O R bii

R

R Reagents: i, 'O,-CH,Cl,,

-78 "C; ii, HN=NH; iii, A

Scheme 37

substituents is tolerated and yields range from moderate to excellent (Scheme 38).61 H

R' -C-NHCHOR3

II

S

I

R2 R'

Reagents: i, H,S; ii, R4CHO; iii, Na,CO,

Scheme 38

An unusual reaction of thioketen §-oxides with azomethines leads to 1,2,4oxathiazolidines, a representative of the still largely unknown cyclic esters of sulphenic acid (Scheme39). The structure has been confirmed by X-ray analysis.62

Scheme 39

An S-methylthiiranium salt has been prepared from adamantylideneadamantane.63 61

'* 63

C. Giordano, A. Belli, and V. Belloti, Synthesis, 1978,443. E.Schaumann, J. Ehlers, and V. Behrens, Angew. Chem. Internat. Edn.,1978,17,455. J. Bolster and R. M. Kellogg, J.C.S. Chem. Comm.. 1978,630.

284

General and Synthetic Methods 3 Nitrogen-containing Heterocycles

Azetidines-Previous studies have shown that photorearrangement of oxaziridines derived from 1-pyrroline 1-oxides leads to formation of azetidines or pyrrolidinones depending on the substituents present (Scheme 40).64It has now

LAR* L&R* N

I 0-

\

0

,

COR

R

R

=

H or alkyl

Scheme 40

been shown that 2-cyano-1-pyrroline 1-oxides undergo clean photorearrangement at 254 nm in benzene to afford only azetidines in almost quantitative yield (Scheme 41).65A convenient synthesis of stable azetidine N-oxides, starting from

&M:iTRiz R z$$M :

R' Me Me

NCOCN

Me N , ~ C N

Me

0Scheme 41

4,4-dimethylazetidinone which is readily available from isobutene and chlorosulphenyl isocyanate, has been reported (Scheme 42).66

Reagents: i, Me2S0,; ii, CH,=CH-CH,MgBr;

iii, Pd/C-H,; iv, rn-ClC,H,CO,H

Scheme 42

Reaction of the aziridine (15) with the carbanion of bromomalonate at room temperature or the carbanion of bromomalononitrile leads to azetidines in high yield (Scheme 43).67 65

66 67

D. St.C. Black and K. G. Watson, Austral. J. Chem., 1973, 26, 2505. D. St.C. Black, N. A. Blackman, and A. B. Boscacci, Tetrahedron Letters, 1978, 175. J. C. Espie, R. Ramasseul, and A. Rassat, Tetrahedron Letters, 1978, 795. M. Vaultier and R. CarriC, Tetrahedron Letters, 1978, 1195.

285

Saturated Heterocyclic Ring Synthesis

PhCH -C(CO,Me),

& PhCH=6-C(CO2Me),

\ /

I

N

iorii

Ph

1

Ph (15)

Ph-CH-CX2

I

/

1

N -C(CO,Me),

Ph

X = C02Me or CN

Reagents: i, BrC(CO,Me),; ii, BrC(CN),

Scheme 43

Pyrrolidines and Related Compounds.-a- Allokainic acid and a-kainic acid, products isolated from the marine algae Digenea simplex Ag., have aroused considerable interest not only for their anthelmintic properties but more importantly for their potent neurophysiological activity in mammals. The original synthesis of a-allokainic acid was long and gave a low overall yield, but now a short, convenient stereoselective synthesis using an intramolecular ene reaction has been described (Scheme 44).68The ene reaction leads exclusively to the

9

HN-COCF,

?$F ,t CHC0,Et

CHC0,Et iil

ii1-v

c \

Reagents: i, NaH-Me,C=CHCH,Br; H2S

NCOCF, I I

o n cd

C H ,,CO,Et

CO, H

ii, C,H7, 80 "C, 24 h; iii, OSN-NaOH; iv, HCI; v, Cu(OAc),, then

Scheme 44

trans-substituted pyrrolidine, but whether or not the reaction is under kinetic or thermodyamic control remains to be clarified. Oxidative decarbonylation of a-kainic acid followed by reduction of the unsaturated intermediate leads to a pyrrolidine acetic acid which has little of the biological action of the natural product (Scheme 45).69 Diborane reduction of 3,3,4,4-tetrafluorosuccinimide leads to 3,3,4,4tetrafluoropyrrolidine (TFP) which has been shown to be the best monofunctional nucleophilic catalyst for a-deprotonation yet r e p ~ r t e d . ~The ' pK, of TFP, determined by the half-neutralization method, is 4.05.The effectiveness of TFP was determined using the decalone (16)which is converted irreversibly into the enone (17)(Scheme 46).The effectiveness of TFP as a catalyst for decarboxylations and aldol condensations has yet to be determined. 69 'O

W. Oppolzer and H. Andres, Tetrahedron Letters, 1978, 3397. R. D. Allan, Tetrahedron Letters, 1978, 2199. R. D. Roberts and T. A. Spencer, Tetrahedron Letters, 1978, 2557.

286

General and Synthetic Methods

A‘-..

H

I

H Reagents: i, NaI0,-CH,C1,-H20;

ii, Na(CN)BH,

Scheme 45

(16) R

=

H or Ac

(17)

Scheme 46

Pyrrolidines and related compounds are readily available by 1,3-dipolar cycloaddition reactions of imines derived from a-amino-acid e ~ t e r s . ~ The ~’~’ imines have now been shown to undergo a wider range of 1,3-dipolar cycloadditions with dipolarophiles such as maleic anhydride, N-phenylmaleimide, acrylonitrile, acrylate, and other activated olefins (Scheme 47). This study is an extension of earlier work which led to t r i a ~ o l i d i n e s . ~ ~ The nitrogen analogue of prostacyclin (PGH,; Scheme 21) has been s y n t h e s i ~ e das~ ~outlined in Scheme 48.The compound has similar biological activity to the natural product. A detailed study of the regioselective reduction of gem-disubstituted succinimides by sodium borohydride under acidic conditions has been published.75 The products are o-carbinol lactams which are of interest as intermediates in the synthesis of other heterocyclic compounds including alkaloids. In unsymmetrical 71

l2 73 74

75

R. Grigg, J. Kemp, G . Sheldrick, and J. Trotter, J.C.S. Chem. Comm., 1978, 109. M. Joucla and J. Hamelin, Tetrahedron Letters, 1978, 2885. R. Grigg and J. Kemp, J.C.S. Chem. Comm., 1977, 125. G. L. Bundy and J. M.Baldwin, Tetrahedron Letters, 1978, 1371. J. B. P. A. Wijnberg, H. E. Shoemaker, and W. N. Speckamp, Tetrahedron, 1978, 34, 179.

287

Saturated Heterocyclic Ring Synthesis R'CH=N,

,COzMe CH \

RZ

A 7

R2

/

A / I

I

' a z ' 2 / / gr(0 2 M e

R'

I-\

OAXA0

X

R2

X = CN or C0,Et 0

C(X)Y

/ JR $Th1

Ph

X

= Oor

NPh

Ph

R2

Me02C

H

R'

Me02C

H

H

X = Y = C N ; X = Y = C02Me; X = CN, Y = C02Me; or X = Y = COMe Scheme 47 OTs Sever a 1

PGFza

Gz OTHP

OTHP

1

i,ii

N3

OH

OH

OH

OH

Reagents: i, AcOH-H,O-THF,

40 "C, 3 h; ii, NaN,-HMPA; iii, A, DMF or EtAc

Scheme 48

succinimides a mixture of the two possible w-carbinol lactams was obtained, and in general the more hindered carbonyl group is reduced. This observation was rationalized in terms of the coplanarity of the imide carbonyl groups with the hydride ion approaching via the less hindered carbonyl group and adding to the carbon atom of the latter as depicted in Scheme 49. The carbinols are easily converted into 3-pyrrolin-2-ones [e.g. (1S)] by acid-catalysed elimination of H 2 0 or EtOH in refluxing ethanol.

288

General and Synthetic Methods

t R4

I R4

I R4

R', R2, R3,R4 = H, Alkyl, Ph, etc.

Scheme 49

I

I

Me

Me (18)

As part of a general approach to the synthesis of the complex antibiotics streptolydigin and tirandamycin a new synthesis of acyltetramic acids has been i n ~ e s t i g a t e d .The ~ ~ important step is the rearrangement of a-[N(acylacetyl)amino]-cyclic imides, which are readily available from a-amino-acids. A typical sequence is shown in Scheme 50. MeCO NMe H2N

0

AcCH,CONH

4 H

CHCONH I I Me Me

Reagents: i, Diketen; ii, NaOMe

Scheme 50

The pyrrolizidine ring system continues to engender interest, presumably because of its presence in a large family of alkaloids, some of which have and a related pronounced toxic properties. A synthesis of the basic ring synthesis of the alkaloid hemiloline7' have been reported. The two syntheses have a common route, but differ in the means used to effect the transannular cyclization leading to the ring system (Scheme 51). 76

77

D. Cartwright, V. J. Lee, and K. L. Rinehart, jun., J. Amer. Chem. SOC., 1978,100, 4237. R. S. Glass, D. A. Deardorff, and L. H. Gains, Tetrahedron Letters, 1978, 2965. S . R. Wilson and R. A. Sawicki, Tetrahedron Letters, 1978, 2969.

289

Saturated Heterocyclic Ring Synthesis

Hemiloline Reagents: NH,OH; ii, TsOH; iii, K,CO,-H,O-THF m-CIC,H,CO3H; vii, K,CO,-H,O-MeOH;

or basic A1,0,; iv, LiAIH,; v, (CF,),O; vi, viii, A, EtOH; ix, Br,-CH2CI,

Scheme 51

A quite different approach to the pyrrolizidine nucleus starting with pyrrolidine has led to a synthesis of the alkaloids isoretronecanol(l9) and trachelanthamidine (20) (Scheme 52).79 A novel synthesis of A4(8)-dehydropyrrolizidiniumperchlorate from a-butyrolactone has been reported.80The key step is the synthesis of the 2-pyrroline (21) from the butyric acid derivative (Scheme 53). A new general synthesis of nitrogen heterocycles using benzeneselenyl reagents has been developed." The method is particularly useful for the preparation of 2,3-dihydroindoles which are obtained in 50-80°/0 yield (Scheme 54). A useful one-step conversion of o-acylbenzoic acids into 3-oxodihydroisoindoles has been developed.82A wide range of alkyl substituents in the amine or the acyl group is tolerated (Scheme 55). l9 'O

82

H. W. Pinnick and Y.-H. Chang, J. Org. Chem., 1978,43,4662. S . Miyano, T. Somehara, M. Nakao, and K. Sumoto, Synthesis, 1978, 701. D. L. J. Clive, C. K. Wong, W. A . Kiel, and S. M. Menchen, J.C.S. Chem. Comm., 1978, 379. P. S. Anderson, M. E. Christy, C. D. Colton, and K. L. Shepard, J. Org. Chem., 1978, 43, 3719.

290

General and Synthetic Methods

__*

0

0

(19)

k

(20) Reagents: i, LDA-BrCH,CO,Et; ii, KH-THF, 0 "C; iii, 10% PdlC-H,; iv, LiAIH,; v, POC1,-NaBH,; vi, base

Scheme 52

+CO,H

ivTli ii

4 - L

0 Y

ClO,

Reagents: i, KOCN; ii, NaOH-Ca(OH),; iii, HClO,; iv, NaOH; v, Pt0,-H,

Scheme 53

Me

N HC0,Et

I

C0,Et Reagents: i, PhSeCl-CH,Cl,,

-60-0

"C; ii, Ph,SnH

Scheme 54

I

C0,Et

29 1

Saturated Heterocyclic Ring Synthesis

Scheme 55

As part of a study directed towards the synthesis of the mitomycins Kametani has prepared and studied the photo-oxygenation of 9-oxo-9H-pyrrolo[ 1,2alindoles (Scheme 56).83The major products are the unstable hydroperoxide (22) and the dihydroxy-compouad (23).

HO-)-j

* 0 , p H

H

Reagents: i, NaH-CuBr-DMF; ii hv, Rose Bengal-0,; iii, MeOH

Scheme 56

Piperidines and Related Compounds.-The synthesis of the medically important alkaloids quinine and quinidine has long been of interest to organic chemists and a number of elegant syntheses have been reported. However, none of these syntheses is amenable to large-scale production or, more importantly, to the ready preparation of various analogues. The central problem is the synthesis of the quinuclidine side-chain which can be derived from 3(R)-vinyl-4(S)-piperidineacetic acid (meroquinene). Now, three new syntheses of meroquinene have been reported by different groups of workers. Scheme 57 outlines an initial approach starting from a cis-isoquinolone but one which is unsatisfactory since a mixture of isomers, (24) and (25), is obtained and only (24) can be converted into m e r ~ q u i n e n e As . ~ ~the Baeyer-Villiger procedure gave more of the undesired lactone (25), the cis-isoquinolone was subjected to a Schmidt reaction but the two isomeric lactams (26) and (27) were obtained in equal proportions. A more 83 84

T. Kametani, T. Ohsawa, M. Ihara, and K. Fukomoto, J.C.S. Perkin I, 1978, 460. M. R. Uskokovic, T. Henderson, C. Reese, H. L. Lee, G. Grethe, and J . Gutzwiller, J. Amer. Chem. Soc., 1978, 100, 571.

292

General and Synthetic Methods 0

0

!e.

+

I

COPh

COPh

I

COPh (25)

kc, , i l l

N

I

I

dOPh

COPh

C0,Me

N I

COPh

H Reagents: i, m-CIC6H,CO3H; ii, MeOH-H';

iii, Ph,P-CCI,; iv, K0Bu'-DMSO; v, NaOH-H,O

Scheme 57

favourable ratio of the required lactam was obtained by Schmidt reaction of the a,@-unsaturated isoquinolone followed by hydrogenation of the required lactam (28) (Scheme 58).84 The lactam (27) could then be converted into meroquinene. A stereospecific synthesis of meroquinene was developed simultaneously with the above syntheses and the key step was the catalytic hydrogenation of the pyridine (29), leading to racemic cincholoipon (30) in 88% yield. A Loffler-Freytag rearrangement of the corresponding chloramine led to the preparation of racemic N-benzoylmeroquinene (Scheme 59).84 The ready availability of meroquinene then led to the synthesis of quinine and quinidine by two different strategies. In the first method meroquinene was combined with the quinoline component and then cyclized to the quinuclidine ring (Scheme 60).85 The oxidation of the deoxyquinine (31) (and its epimer, deoxyquinidine) proceeds in a highly stereospecific manner, leading to the desired C-8-C-9 erythro alkaloids in moderate yield (-32%) for quinine (32) and quinidine (40%). An alternative approach entails the formation of an epoxide and then simultaneous formation of the quinuclidine ring and introduction of the hydroxygroup. Unfortunately all four possible diastereomers were obtained (Scheme 6 1). 85

J. Gutzwiller and M. R. Uskokovic, J. Arner. Chern. SOC., 1978, 100, 576.

293

Saturated Heterocyclic Ring Synthesis

COPh

COPh

A I1

+ N

1:l

A &--@ +

t

5:l

N

N

COPh

COPh

COPh

(26)

(27)

(28)

I

I

I

N

I

COPh

Reagents: NaN,-PPA; ii, Rh-AI2O3-H2 Scheme 58

Reagents: i, Pt-H,-So/0 HCI; ii, N-chlorosuccinimide; iii, hv, CF,CO,H; iv, PhCOCI; v, K0Bu'DMSO-C6H6 Scheme 59

294

General and Synthetic Methods H

t 11

Scheme 60

.

1-111

...

__+

Reagents: i, NBS; ii, NaBH,; iii, Bu’,AIH; iv, A, C,H,-EtOH

Scheme 61

Saturated Heterocyclic Ring Synthesis

295

Two other approaches to the synthesis of quinine, quinidine, and related compounds are described in accompanying paper^.^^,^' A quite different approach to the synthesis of meroquinene has also been reported.88 This method relies on the use of the natural precursor for the quinuclidine species, secologanin, which was converted into the key intermediate methylsecoxyloganin (33). The crucial step in the whole synthesis is the reductive amination of (33), and following much investigation the conditions shown in Scheme 62 were discovered. M

e

o

2

c

~

Ho2c$

.

**H.OGlc

i,ii

+

H'

Secoioganin

Me0,C

&H

\o

iii,iv

H-'

Me0,C

\

N

C0,H

, N

H

Reagents: i, P-glucosidase; ii, Na(CN)BH,, pH 6.5, NaOAc buffer; iii, 1% HCI (-CO,); iv, NaBH, Scheme 62

A new synthesis of 3,3-dialkylpiperidines has been r e p ~ r t e d . 'Suitably ~ substituted 2-azabuta- 1,3-dienes undergo a Michael addition rather than a DielsAlder reaction to yield 5-(1-alkenylimino)-4,4-dialkylpentanenitriles which are readily transformed into piperidines by reductive cyclization (Scheme 63). Me 'C=CHN=CHCHMe2

/

Me'

+ CH,=CHC=N

1

Me \

Me C=CH-N=CH+CH,CH,C=N / Me Me

Pd'C-HY CH2CHMe, Scheme 63

Mercurated derivatives of morpholine, tetrahydro- 1,4-thiazine, and hexahydropyridazine are readily available from diallyl ethers, diallyl sulphides, or n6

G . Gretne, H. T. Lee, T. Mitt, and M. R. Uskokovic, J. Amer. Chem. Soc., 1978, 100, 581.

'' G . Grethe, H. T. Lee, T. Mitt, and M. R. Uskokovic, J. Amer. Chem. SOC., 1978, 100, 589.

" 89

R. T. Brown and J. Leonard, J.C.S. Chem. Comm., 1978,725. H. Feichtinger, W. Payer, and B. Cornils, Chem. Ber., 1978,111, 1721.

296

General and Synthetic Methods

diallylamines (Scheme 64). Demercuration of (34; Y = 0) with sodium borohydride leads to the morpholine derivatives” but in the other cases ring-opened products are obtained.

-.

Y = 0 . S. or NH

CY\

X

NH2 iiy’

Reagents: i, Hg(OAc),-THF; ii, KBr-MeOH-H,O;

(34)

iii, NaBH,

Scheme 64

Quinolines and Related Compounds.-Under appropriate conditions the standard Delepine reaction may be used to synthesize tetrahydroisoquinolines from phenacyl bromides (Scheme 65).91

phcH20 rH2’ + (CH&N4

N(CH2)6N3 Br-

____* HCI-EtOH

PhCH20

PhCH20

J 0

I

PhCH20

Scheme 65

Dihydroisoquinolines are readily available by reaction of nitriles with aryllithium reagents in poor to moderate yield (Scheme 66).92 90 91 92

J. Bariuenga, C. Najera, and M. Yus, Synthesis, 1978, 911. S. N. Quesy, L. R. Williams, V. G. Baddeley, Synth. Comm., 1978,8, 45. W. E. Parham, C. K. Bradsher, and D. A. Hunt, J. Org. Chem., 1978,43, 1606.

Satwated Heterocyclic Ring Synthesis

297

I R

R

=

R

Ph, cyc1o-C6HI2,etc. Scheme 66

The pumiliotoxins are a group of more than 60 alkaloids isolated from the toxic skin secretions of the frog Dendrobates pumilis and related species. Many of the alkaloids have, as a central feature, the unusual cis-decahydroquinoline structure, and since they possess interesting neurological activities they are an attractive target for total synthesis. A new total synthesis of d,I-pumiliotoxin C has been rep~rted.’~ The main feature of the new synthesis is the Diels-Alder reaction of an activated N-acylaminodiene and a crotonaldehyde derivative leading to an intermediate with two chiral centres which can be utilized to control the introduction of the third chiral centre (Scheme 67). The method, which is short and efficient, should be useful in the synthesis of other cis-decahydroquinoline alkaloids. The overall yield of d,I-pumiliotoxin C was 5 1O/O.

0

H H H

“NHCO,CH , ~ h H

Reagents: i, (MeO),P(O)CHCOPr, -10 to -65 “C; ii, H,-Pd/C

Scheme 67

A highly efficient total synthesis of d,l-lycopodine has been described.94 This tetracyclic alkaloid poses formidable synthetic problems but the present synthesis affords a high overall yield of 17.7% (Scheme 68). A new octahydroquinoxaline system has been prepared by means of a novel heterocyclization reaction involving a bicyclo-aziridine system and a propargylamine (Scheme 69).95 93 94 95

L. E. Overman and P. J. Jessup, J. Amer. Chern. Soc., 1978,100, 5179. C. H. Heathcock, E. Kleinman, and E. S. Binkley, J. Amer. Chern. Soc., 1978, 100, 8036. J. Szmuskovicz, J. H. Murser, and L. G. Laurian, Tetrahedron Letters, 1978, 701.

298

General and Synthetic Methods n

n

n

$.

,Ph Me

I

vii

c

Me

Me

- (b--.. ... .

X __*

VIlI,lX

(CH,),OCH,Ph

Me

Reagents: i, Li(MeCH=CHCH,),Cu; ii, 0,-MeOH; iii, HO(CH,),OH-TsOH; iv, KOH-H,O-EtOH; v, ClCO,Et, then PhCH20(CH2),NH2;vi, LiAiH,; vii, HC1, reflux 14 days; viii, Pd/C-H,; ix, Oppenauer oxidn., spontaneous cyclization;x, Pt-H,

Scheme 68

Scheme 69

Quino1izibhes.-The quinolizidine nucleus is widespread in Nature and occurs in the lupin and other alkaloids. Earlier syntheses of these alkaloids suflered from poor stereospecificity of reactions, particularly in the reduction of quinolizinium salts to the reduced ring system. This problem has now been oveicome and a total synthesis of (*)-deoxynupharidine achieved (Scheme 70).96 The reduction results in products with the correct configurations at C-4, C-7, and C-10, but the opposite 96

J. Szycnowski, A. Leniewski, and J. T. Wiobel, Chem. Id., 1978, 273.

Safurated Heterocyclic Ring Synthesis

O0

299

Oo

Reagents: i, Na(CN)BH,; ii, WaOEt-EtOH; iii, LiAIH,; iv, SOC12

Scheme 70

to that required at C-1; however, both compounds are readily epimerized at C-1 with base. In another approach to the quinolizidine alkaloids, the rarely observed enamine-ketone condensation was used to construct the quinolizidine alkaloid cryptoleurine (Scheme 7 1).97 A completely different approach to the synthesis of quinolizidine alkaloids is described by T ~ f a r i e l l o .The ~ ~ synthesis makes use of the ready addition of conjugated dienes to nitrones to yield bicyclic isoxazolidines (Scheme 72). Tropanes.-A number of syntheses of tropane alkaloids, particularly cocaine, have been reported during 1978. Tufariello and his colleagues have described two different syntheses of d,l-cocaine, both using nitrones as the entry into the tropane Attempts to obtain the desired unsaturated nitrone skeleton (Scheme 73).99*100 (36) directly from the nitrone (35) were unsucces'sful but the ingenious use of the reversibility of alkene addition to nitrones as a method of protection whilst the dehydration of the alcohol was carried out led to a good yield of (36). Cycloaddition of oxyallyl cations to N-methylpyrrole and furan leads to novel analogues of cocaine (Scheme 74).*01In a somewhat related synthesis the tropane skeleton has been prepared using bromo-ketone-iron earbonyl coupling to pyrroles (Scheme 75).'02 97 98

99

loo lo' lo'

R. B. Herbert, J.C.S. Chem. Comm., 1978,794. J. J. Tufariello and R. C. Gatrone, Tetrahedron Letters, 1978, 2753. J. J. Tufariello and G. B. Mullen, J. Amer. Chern. Suc., 1978, 100, 3638. J. J. Tufariello, J. J. Tegeler, S. C. Wong, and S. A. Ali, Tetrahedron Letters, 1978, 1733. A. P. Cowling and J. Mann, J.C.S. Perkin I, 1978, 1564. Y. Hayakawa, Y. Baba, S. Makino, and R. Noyori, J. Amer. Chem. SOC.,1978,100, 1786.

General and Synthetic Methods

3 00

Miscellaneous Nitrogen Ring Systems.-A synthesis of the bicyclic amidine 3,3,6,9,9-pentamethyl-2,1 O-diazabicyclo[4,4,0]dec- 1 -ene has been described.lo3 This base, and the salts prepared from it, show solubility characteristics which make it a potentially useful reagent for salt formation of carboxylic acids. Various derivatives of the amidine were prepared, with the stable a-nitronyl nitrosium cation as possibly the most interesting, as its reactivity towards olefins and dimes resembles those of singlet oxygen (Scheme 76). OMe OMe

Me0 ii, i i i l

OMe

Reagents: i, p-MeOC,H,CH,CHO;

OMe

ii, TiCI,-C6H6; iii, NaBH,; iv, TI(OCOC',),

Scheme 71

Ph

oy-YJ+oyPJte

O W

Ph

Ph

Ph

Reagents: i, Zn-50% AcOH; ii, Mn0,-CH,CI,;

iii, Michael addition; iv, NaOH-MeOH

Scheme 72 lo3

F. Heinzer, M. Soakup, and A. Eschenmoser, Helv. Chim.Acta, 1978,61, 2851.

301

Saturated Heterocyclic Ring Synthesis

C02Me

I

-0

0 C0,Me

C02Me

C02Me

(35)

OCOPh

(36)

T C02Me

C0,Me

Reagents: i, m-ClC,H,CO,H; ii, CH,=CHCO,Me; iii, MeS0,Cl-DBN; iv, A, xylene; v, Severalsteps; vi, Zn-NH,Cl-DME-H,O

Scheme 73

''Aila,r +

R2

Br

Br

I P

o

Cu-NaI,

'i

0

Me

-

'4R Scheme 74

R', R3 = alkyl R2,R4 = H M = Na

General and Synthetic Methods

302

ii,iiJ

Reagents: i, [Fe,(CO),]; ii H,-Pd/C; iii, Bu',AIH

Scheme 75

+ EtCN

2 Me2C=CHCH2Br

Me Me2C , 4 y 4 3 4 e 2 CN

Me

Me

H

Me

h v r r a i stages

0

0-

Reagents: i, LDA-THF, -78 oC-room temp.; ii, N2NH2-C6H,, 80 'C; iii, NaNH,, then HCl, 200 "c, 18 h; iv, HCI, 200 "C

Scheme 76

The unusual ring system l-azatricyclo[5,2,1,04~10]decanehas been prepared in moderate yield by Raney nickel reduction of 2,5 -biscyanoethylcyclopentanone (Scheme 77).lo4 The isoxazolidine analogues of the prostaglandin endoperoxide PGH2 have been prepared from PGF2,. Both compounds are potent inhibitors of thromboxane synthetase from human platelets (Scheme 78).lo5 '04

A. G. Anderson, jun. and P. C. Wade, J. Org. Chem., 1978, 43, 54. G. L. Bundy and D. C. Paterson, Tetrahedron Letters, 1978,41.

303

Saturated Heterocyclic Ring Synthesis 0 w-5: Ra-Ni

C'3

Scheme 77

a; X b; X

= =

NH, Y = 0 0 , Y = NH

Scheme 78

1,4-Diazepines are available from the reaction of arninoazirine with malonimides (Scheme 79).Io6The products may be reduced to the perhydro-derivative or rearranged in acid to an imidazole derivative. A useful account of the photochemistry of cyclic imides has appearedlo7and describes the synthesis of a wide range of heterocyclic compounds.

0

e

EtoH-H+ 1

Scheme 79 lo6

B. Scholl. J. H. Bieri, and H. Heimgartner, Helu. Chim.Acru, 1978, 61,3050. Y. Kanaoka, Accounts Chem. Rex, 1978,11,407.

General and Synthetic Methods

304

Triazo1ines.-Reaction of diazoacetonitrile with benzylideneanilines leads to high yields of A2-172,3-triazolineswhich may be photolysed to aziridines (Scheme 80)."* A useful review of A2-1,2,3-triazolines has been published.'09

C,H,Rz-p Scheme 80

Isoxazolines and 0xazines.-A very convenient synthesis of 3 -substituted 2isoxazolines and dihydro-172,4H-oxazines has been reported. It is anticipated that these compounds will find wide use as synthons in organic synthesis (Scheme 8 l).'l o 0-N

Cl(CH2),CH2N02 A Cl(CH2),CN02 II NOH

n = 2or3

(

)-NO2

((332)"

Reagents: i, PrONO-NaNO,; ii, NO,-

Scheme 81

Triarylisoxazoline N-oxides are readily available from the reaction of silver nitrate with potassium arylmethanenitronates (Scheme 82).'11 Ar

3ArCH=NO;

K+

Ar

__+

DMSO

Ar

Scheme 82

Aza-adamantanes.-1-Aza-adamantanes are easily available in a convenient two-step synthesis from a-pinene (Scheme 83).l12The synthesis is dependent on the serendipitous discovery that solvomercuration-demercuration of a-pinene with acetonitrile in the presence of mercuric nitrate followed by in situ borohydride reduction led not to the expected allylic amide but instead to azabicyclo[3,3,l]nonene which is readily converted into aza-adamantane by reaction with formaldehyde. Rearrangement of N-chloro-N-acetyl- 1-aminoadamantane I09

'I1

F. Roelants and A. Bruylants, Tetrahedron, 1978, 34, 2229. J. Bourgois, M. Bourgois, and F. Texier Bull. SOC.chim. France, 1978, 485. P. A. Wade, J. Org. Chem., 1978, 43, 2020. K. Fukunager, Synthesis, 1978, 55. B. Delpech and Q. Khuong-Huu, J. Org. Chem., 1978,43,4898.

305

Saturated Heterocyclic Ring Synthesis

1 OH

.

Scheme 83

in the presence of aluminium chloride leads to a trichlorinated azahomoadamantane (Scheme 84).' l 3 Azahomoadamantanes are also readily available from

2-methyl-2-hydroxyadamantane by reaction with sodium azide followed by reduction.' l 4 Various reactions of the compounds have been studied (Scheme 85).

Reagents: i, NaN,-H';

ii, NaBH,OAc

Scheme 85

4 0-Lactams, Penicillins, Cephalosporins, and Related Compounds A very detailed report on p-lactams, both synthetic and natural, has been p ~ b l i s h e d . "An ~ excellent new method for the synthesis of a-amino-P-lactams has been described.'16 The central feature of the synthesis is the protection of a-amino-acids as an enamine followed by acid chloride formation and annellation of imines (Scheme 86). Yields are in the region 35-45'/0. An unusual transformation of mesoionic thiazol-4-ones into P-lactams has been reported."' It is '13

'I5 '16

'"

P. M. Starewicz, A. Sackett, and P. Kovacic, J. Org. Chem., 1978, 43, 739. T. Sasaki, S. Eguchi, and N. Toi, J. Org. Chem., 1978, 43, 3810. A. K. Mukerjee and A. K. Singh, Tetrahedron Report No. 52, Tetrahedron, 1978,34, 1731. S. D. Sharma and P. K. Gupta, Tetrahedron Letters, 1978, 4587. T. Sheradsky and D. Zbaida, Tetrahedron Letters, 1978, 2037.

306

General and Synthetic Methods Me

Me

R

=

H H

OEt or Me Scheme 86

thought that the Raney nickel desulphurization proceeds via the dipolar species depicted in Scheme 87.

Scheme 87

Reaction of methyl(pheny1thio)keten with N-benzylideneanilines leads to cisor trans-azetidinones depending on the substituents present.'18 The keten may be regarded as a synthon equivalent o f methyleneketen (Scheme 88). PhS

Et,N

I

Me-CHCOC1

-

PhS \

Me'

c=c=o

\

RN=CHPh

Scheme 88

The phase -transf er-catalysed cyclization of 3 -bromo-2 - (bromomethyl)propionamides provides a simple synthesis of a -methylene-P -1actams (Scheme 8,).l19 The synthesis of 4-unsubstituted monocyclic p -1actams has

Br

Scheme 89

proved difficult in the past but now it has been found that 4-chloroazetidinones may be dechlorinated by tri-n-butyltin hydride in good yield (Scheme 'I9 I2O

T. Minami, M. Ishida, and T. Agawa, J.C.S. Chem. Comm., 1978, 12. S. R. Fletcher and I. T. Kay, J.C.S. Chem. Comm., 1978, 903. C. A. Whitesitt and D. K. Herron, Tetrahedron Letters, 1978, 1737.

307

Saturated Heterocyclic Ring Synthesis PhOCH,C(O)HN

u;

PhOCH,C(O)HN Bu",SnH __*

0

G+

0

C0,CH ,Ph

,

C0,CH Ph

Scheme 90

Optically active 4-acyloxyazetidin-2-onesare readily available from penicillin sulphoxides by reaction with trimethyl phosphite and a carboxylic acid (Scheme 91).'*' The thiazolidine ring of penicillin sulphoxides may also be cleaved to give

C0,Me

(3S94S)

(5R,6R)

Scheme 91

monocyclic p-lactams when heated with methyl acrylate. The product obtained can then be subjected to further manipulations leading to azetidine-2,4-dione and 4-alkylidene-azetidin-2-ones (Scheme 92).122

?

0

R

r 0

0

t

Me rS Y - M e

H H '

t

'C0,Me C0,Me

I

C0,Me

jii

C0,Me

C0,Me

C0,Me

Reagents: i, CH2=CHC0,Me, A; ii, Et,N; iii, C6H6, A, 80 "C; iv, 0,-MeOH, 0 "C

Scheme 92

A simple and efficient preparation of a 4-mercaptoazetidin-2-one derived from penicillin has been reported. The thiazolidine is readily available from penicillin and is transformed by acid treatment into the p-lactam (Scheme 93).123 12' lZ2

123

A. Suarato, P. Lombardi, G. Galliani, and G. Franceschi, Tetrahedron Letters, 1978,4059. M. D. Bachi, 0. Goldberg, and A. Gross, Tetrahedron Letters, 1978,4167. J. E. Baldwin and M. A. Christie, J.C.S. Chem. Comm., 1978, 239.

General and Synthetic Methods

308

Scheme 93

The nocardicins are a group of monocyclic 6-lactam antibiotics which have activity against gram-negative bacteria. Details of a total synthesis of the fundamental 3-aminonocardicin nucleus and of nocardicin A have been pub1 i ~ h e d . The I ~ ~ synthesis uses the readily available chiral starting materials Lcysteine and D-p-hydroxyphenylglycine as shown in Scheme 94. The crucial steps in the synthesis are the formation of the benzoate and the formation of the oxazolidine ring.

1

PhCON xS H

~

~

~

O

C

H

,

ii,iii

0

+

P-P~CH~OC~H~CHNH~ I Y PhCH202C

N-C\ H H

4

=

\ %*

CO,CH,Ph

OCOPhorC1 ivl

Ph OCH ,Ph

H

H

CO,CH,Ph

CO,CH,Ph

1.i

CI

H

CO,CH,Ph

H

CO,CH,Ph

Reagents: i, Me,CO; ii, (PhCO,),-C H , A; iii, HCI-CH,CI,, 0°C; iv, NaH-DMF-CH2Cl,; v, Hg(OAc),-aq. THF; vi, PCl:; v",i, Bu,SnH; viii, p-TsOH-H,O-EtOAc

Scheme 94 G. A. Koppel, L. McShane, F. Jose, and R. D. G. Cooper, J. Amer. Chem. SOC.,1978,100,3933.

P

h

3 09

Saturated Heterocyclic Ring Synthesis

The nocardicin skeleton is also available from penicillin via the thiazsline (37).125 PhCONH N' Penicillin G +

E

0

H

0

H

C0,Me

(37)

A novel synthesis of nocardicins from hexahydro-2-triazines has been reported.126The strategy behind this synthesis lies in the expectation that treatment of hexahydro-s-triazines with a Lewis acid should give formaldimines which on reaction with an acid chloride would yield monocyclic p-lactams. This was realized in practice with the hexahydro-s-triazines derived from a -amino-acids, e.g. Scheme 95. The 3-aminonocardicin nucleus is readily available by application of the usual deprotection procedures.

7:2

R

=

CH2Ph; Ft

= N

0

Reagents: i, HCHO; ii, FtCH2COCI-CSHsN, 0 "C

Scheme 95

An ingenious new synthesis of a penicillin has been described by Baldwin and his co-worker~.'~' In an earlier synthesis of a penicillin from a dipeptide, Baldwin 12'

M. Foglio, G . Franceschi, P. Lombardi, C. Searafile, and F. Arcamene, J.C.S. Chem. Comm., 1978, 1101.

126

'*'

T. Kamiya, T. Oku, 0.Nakaguchi, H. Takeno, and M. Hashimoto, Tetrahedron Letters, 1978, 5119. J. E. Baldwin and M. A. Christie, J. Arner. Chem. SOC.,1978, 100, 4597.

General and Synthetic Methods

3 10

et al. had converted the thiazolidine (38) via a seven-step synthesis into the penicillin. The lengthy sequence resulted from the intrinsically stronger CA-S bond relative to the CB-§ bond in (38), which resulted in the undesirable

xsno H

X

H

'C0,R

N : H

(38)

cleavage of the CB-S bond in reactions. Baldwin argued that the bond lability could be reversed by constructing a ring bridging the thiazolidine moiety, resulting in the C,-S bond becoming more orthogonal to the thiazolidine amide and thus weakening it relative to the C,-§ bond. The bicycle (39) was prepared by condensation of cysteine with methyl levulinate and transformed into a penicillin as shown in Scheme 96.

. ...

1-111

___+

(j2xXH &

CONH

C0,CH

0

0

(39)

Y

X

=

OCOPhor CI

"1

CO,CH,Pt

1

Reagents: i, V,

H2N

..

Bu'OCI-H,O-THF

ii, (PhCO,),O; iii, HCI-CH,CI,; iv, NaH; I

OH

Scheme 96

31 1

Saturated Heterocyclic Ring Synthesis

A total synthesis of (&)-l -oxabisnorpenicillin G (40)has been published,128and the preparation of a number of l-oxaceph-3-ems, e.g. (41), has been described.12' Communications have been published on the synthesis of clavulanic acid analogues, e.g. (42),I3O and on the transformations of related compounds into oxa-penem systems, e.g. (43) to (44).13*A total synthesis of a related compound thienamycin (45) has been published.'32 Me PhCH,CONH 'C02H

0

lr

B1

,,0yCHCH2Br

C02R

0

C02R

0 (43)

(44) OH

0

(451

'" lZ9 130

13' 13'

L. D. Cama and B. G. Christensen, Tetrahedron Letters, 1978, 4233. C. L. Branch, J. H. C. Nayler, and M. J. Pearson, J.C.S. Perkin I, 1978, 1450. P. H. Bentley and E. Hunt, J.C.S. Chem. Comm., 1978,439. P. C. Cherry, C. E. Newall, and N. S. Watson, J.C.S. Chem. Comm., 1978, 469. D. B. R. Johnston, S. M. Schrnitt, F. A. Bouffard, and B. G. Christensen, J. Amer. Chem. SOC.,1978, 100, 313.

Strategy and Design in Synthesis BY S . TURNER

1 Introduction Substantial activity has continued in the field of organic synthesis with a number of very complex structures having been synthesized in the laboratory for the first time. Such is the high state of the art that one may reasonably ask ‘where next?’ If a theme be sought for the year under review it is perhaps that of the Diels-Alder reaction, as the following sections will make clear.

2 General Papers This year, 1978, has seen the 150th anniversary of the publication of the first organic synthesis, Wohler’s conversion of ammonium cyanate into urea, a topic still under discussion.’“ Quinkertlb has noted this and other anniversaries in a rounded examination of modern synthetic organic chemistry. Organic synthesis now encompasses a wide range of target structures. A t one end of the scale there has been, for example, the synthesis2 of albene (l),whose structure is thereby clarified. A t the other extreme, Koster and co-workers3 have synthesized a gene, the D N A coding for the peptide hormone angiotensin 11.

Me

(1)

The rational design of syntheses has been introduced by Warren4 for students, in a straightforward book which will be helpful for teaching purposes. A t a more advanced level, the proceedings of an A.C.S. Symposium ‘Computer Assisted Organic Synthesis’, have been published.’ With regard to synthetic strategy and ( a )J. Shorter, Chem. SOC.Rev., 1978,7, 1; ( 6 )G. Quinkert, Angew. Chem. Internat. Edn., 1978,17, 473. W. Kreiser and L. Janitschke, Tetrahedron Letters, 1978,601 ;W. Kreiser, L. Janitschke, and L. Ernst, Tetrahedron, 1978, 34, 131. H. Koster and co-workers, Annalen, 1978, 839 et seq. S. Warren, ‘Designing Organic Syntheses - A Programmed Introduction to the Synthon Approach’, J. Wiley & Sons, Chichester, U.K., 1978. A.C.S. Symposium, ‘Computer Assisted Organic Synthesis’, available from the Chemical Society, London, 1978.

312

Strategy and Design in Synthesis

313

the LHASA computer program, Corey and Long6 have produced a new module to examine stereoselective olefin syntheses. Varkony, Smith, and Djerassi7 have described some aspects of a new computer program (REACT) which carries out representations of chemical reactions on representations of chemical structures. It thus works in a synthetic direction, and has applications in studying biosyntheses. The industrial use of photochemical syntheses has been reviewed,* and a full paper has appeared exemplifying applications of Baldwin’s rules for some ring-closure reactions.’ 3 LHASA This Reporter has now been able to make some preliminary personal use of the LHASA computer program for designing organic syntheses. The necessary components have been brought together at the Polytechnic of North London by Dr. A. P. Johnson, with the kind support of Prof. E. J. Corey and the Science Research Council. It is pleasing to report that the program is very easy to operate by an organic chemist with no particular training in the use of computers! The interactive nature of the LHASA program is an important feature in allowing the chemist to make use of his own knowledge while a target structure is being ‘processed’. In every case so far examined, the program has produced for this Reporter novel synthetic ideas in addition to those he had already considered; it is therefore a stimulating experience to make use of the program. From the industrialist’s point of view there are perhaps drawbacks in the areas of benzenoid and heteroaromatic chemistry, but it is hoped and expected that such components can be added to the program in the fullness of time. It is apparent that, within the U.K. Chemical Industry, a significant discussion of the applications of the LHASA program, and other such programs, is under way. 4 Selected Total and Partial Syntheses

Gibberellic Acid.-The first total synthesis of the plant growth regulator gibberellic acid (2) has now been described by Corey et ale1’ The synthetic route commenced with a ring C unit, and added a six-membered ring B via an intermolecular Diels-Alder reaction (50th anniversary!lb). Ring D was next closed, utilizing a pinacol cyclization with metallic titanium, and ring B was contracted to five members. At this stage compound (3) was the key racemic intermediate. An intramolecular Diels-Alder reaction was next utilized to close ring A; subsequent resolution (chromatography of diastereoisomers) and adjustments of stereochemistry and functional groups then produced gibberellic acid (2). At a late stage in the synthesis it was possible to correlate intermediates with naturally derived material. It is perhaps of interest in this synthesis that the E. J. Corey and A. K. Long, J. Org. Chem., 1978,43,2208.

’ T. H. Varkony, D . H. Smith, and C. Djerassi, Tetrahedron, 1978,34, 841.

* ‘O

M. Fischer, Angew. Chem. Internat. Edn., 1978,17, 16. J. E. Baldwin, R. L. Thomas, L. I. Kruse, and L. Silbermann, J. Org. Chem., 1977, 42, 3846. E. J . Corey, R. L. Danheiser, S. Chandrasekaren, P. Siret, G . E. Keck, and J. L. Gras, J. Amer. Chern. Soc., 1978,100,8031; E. J. Corey, R. L. Danheiser, S. Chandrasekaren, G . E. Keck, B. Gopalan, S. D . Larsen, P. Siret, and J. L. Gras, ibid., p. 8034.

314

General and Synthetic Methods

--OR

--OH HO

D

H Me

C02H

CH,

HOCH,

(2)

(3)

final stereochemical array was derived largely as a result of the stereochemical consequences of the initial intermolecular Diels-Alder reaction. P-Lactams.-Another ‘first’ amongst total syntheses has been that” of (*)thienamycin (4), a broad-spectrum P-lactam antibiotic showing resistance to bacterial P-lactamase, by the Merck group. The P-lactam ring was formed at the outset of the synthesis as shown in Scheme 1. This initial formation of the ‘unstable’ P-lactam moiety, subsequently to be carried through many reactions, illustrates a synthetic strategy that would have been given a low priority a decade ago. The two-carbon side-chain was added at the 6-position utilizing ethanal and an anion at C-6. The five-membered ring and related functionality were formed in the final stages of the synthesis by closing the C-2-C-3 bond.

OH H.J H H Me . . m s - N H 2 0

N

2

OR’ t

C02H

(4)

Scheme 1

Woodward and his co-workers12have given full details of their partial synthesis of the sensitive penems (9,‘artificial’ molecules designed to cast light on structural features required for antibacterial action. Penicillin V was used as a readily available starting material, thereby ensuring the optical purity of the products. The five-membered ring of penicillin V was opened by established methods and a replacement ring added; the latter was effected by closing the C-2-C-3 bond uiu an intramolecular Wittig reaction.

l2

D. B. R. Johnston, S. M. Schmitt, F. A. Bouffard, and B. G . Christensen, J. Amer. Chem. SOC.,1978, 100, 313. I. Ernest, J. Gosteli, C. W. Greengrass, W. Holick, D. E. Jackman, H. R. Pfaendler, and R. B. Woodward, J. Amer. Chem. Soc., 1978, 100, 8214.

Strategy and Design in Synthesis PhOCH2CONHH H

H

s

315 Me

T

M

0

e ’C02H

2 C02H

(5)

Penicillin V

Another synthesis in this area from optically active starting materials is that of the antibacterial nocardicin A (6), by the Lilly group.13 L-Cysteine and D-phydroxyphenylglycine were used as indicated to give eventually ‘3-ANA’, the nucleus lacking the hydroximino-acid side-chain. The latter side-chain unit was prepared ~ e p a r a t e l y ~from ~ ’ D-homoserine and, in a convergent synthesis, was attached to the nucleus at a late stage.

HH 2 0N2’C; s HH2N pOH

H

~

i

C02H

H CO2H

Baldwin and Christie14 have also used optically active cysteine in a stereospecific synthesis of penams and cephams. These authors provide an interesting discussion of the lability of certain carbon-sulphur bonds [e.g.bonds ( a )and ( b )in structure (7)], and the application of stereoelectronic control in facilitating the cleavage of such bonds in a desired sense [viz. in Scheme 2, bond ( b )is broken in preference to bond ( a ) ] . A ‘retrospect and prospect’ for p-lactams has been p~blished.’~

0

Me

0 0

H

Scheme 2 l3

l4

l5

(a) G . A. Koppel, LzMcShane, F. Jose, and R. D. G . Cooper, J. Amer. Chem. SOC.,1978,100,3933; ( b ) R. D. G . Cooper, F. Jose, L. McShane, and G . A. Koppel, Tetrahedron Letters, 1978,2243. J. E. Baldwin and M. A. Christie, J. Amer. Chem. SOC., 1978, 100, 4597. A. K. Mukerjee and A. K. Singh, Tetrahedron, 1978, 34, 1731.

General and Synthetic Methods

316

Lasolocid A.-Kishi and his co-workers'6 have reported the first total synthesis of the complex polyether antibiotic lasolocid A (8), in a paper that will repay close study. The route incorporated an early resolution by classical methods at the stage of the alcohol (9). Compound (9) was epoxidized and cyclized to the tetrahydrofuran (10) as the major product. A stereoselective aldol condensation was eventually used to form the C-11-C-12 bond [see dotted line in structure (S)] of the target in a convergent synthesis in which the 'left hand' side of the molecule had been made from an optically active starting material.

Macrocyclic Lactones and Lactams.-A high point in this area of endeavour during 1978 has been the first total synthesis of an aglycone of the erythromycin family of antibiotics, erythronolide B (ll),by Corey et al.17 Two fragments were produced by synthesis corresponding to atoms C-1-C-9 and C-10-C-13 of the target. For the former unit, atoms 1 and 6 were joined together retrosynthetically so that control of stereochemistry could be exercised within a six-membered ring. This particular unit was resolved classically at the stage of intermediate (12) [numbered as in (1l)]. It is notable that the unresolved by-products here could be converted into an achiral precursor, and thereby were recycled into the synthesis. €3

HO 0 0:.

H

l6

l7

T. Nakata, G. Schmid, B. Vranesic, M. Okigawa, T. Smith-Palmer, and Y. Kishi, J. Amer. Chem. Soc., 1978,100,2933. See also T. Fukuyama, B. Vranesic, D. P. Negri, and Y. Kishi, Tetrahedron Letters, 1978, 2741; T. Nakata and Y. Kishi, ibid., p. 2745. E. J. Corey, E. J. Trybulski, L. S. Melvin, K. C. Nicolaou, J. A. Secrist, R. Lett, P. W. Sheldrake, J. R. Falck, D. J. Brunelle, M. F. Haslanger, S. Kim, and S. Yoo, J. Amer. Chem. Soc., 1978, 100, 4618; E. J. Corey, S. Kim, S. Yoo, K. C. Nicolaou, L. S. Melvin, D. J. Brunelle, J. R. Falck, E. J. Trybulski, R. Lett, and P. W. Sheldrake, ibid., p. 4620.

3 17

Strategy and Design in‘synthesis

Atoms 10-13 and their appendages were derived from smaller fragments, and a resolution was also effected classically. Subsequently the two units were coupled and the lactone linkage was closed late in the synthesis by previously established methods. Investigations by Hanessian et a1.l’ into the use of carbohydrates as optically active starting materials for preparing the carbon skeleton of erythronolide A have continued. A second high point in this area during 1978 has been the total synthesis of the naturally occurring cytostatic substance cytochalasin B (13), by Stork et al.19 In this synthesis the ‘isolated’ stereocentres [A, B, and C in structure (13)] were derived from three distinct optically active starting materials [(+)-citronellol, H

PhCH,

(13)

malic acid, and L-phenylalanine respectively], providing another example of absolute asymmetric synthesis (Scheme 3). Subsequent conversions yielded

Ac

Scheme 3

molecules suitable for coupling in a Diels-Alder reaction. The consequences of this reaction were partially predicted and partially examined by model studies. In the event, the cycloaddition was regioselective (but stereospecific), yielding an intermediate which was further elaborated to the seco-hydroxy-acid derived from the target (13). The final lactonization had already been achieved by Masamune and his co-workers. It is apparent that the stereochemistry of the 5 / 6 ring system of the product (13) was controlled partly by the centre of asymmetry derived from L-phenylalanine, partly by the geometry of the ‘diene’ unit, and partly by the demands of the cycloaddition transition state.

’* S. Hanessian, G . Rancourt, and Y. Guindon, Cunud. J. Chem., 1978,56,1843. l9

G. Stork, Y. Nakahara, Y. Nakahara, and W. J. Greenlee, J. Amer. Chem. Soc., 1978,100,7775.

318

General and Synthetic Methods

The synthetic problems associated with cytochalasins as targets have also been discussed by Schmidlin and Tamm2'" who, in preliminary studies on the synthesis of the 5/6 ring system, provide a solution related to the foregoing work of Stork. In this case, however, an intramolecular Diels-Alder reaction was utilized for ring formation. The last work should be compared with that of Bailey etaL20bwho also approached the problem with an intramolecular Diels-Alder reaction. Other papers noted in the area have included a total synthesis of (-)-vermiculine (14) involving a resolution and a large-ring closure via a Wittig reaction,21 and a total synthesis2*of racemic brefeldin A (15) incorporating a final lactonization step. A Corey group has also s ~ n t h e s i z e da ~racemic ~ maytensenoid, (*)-Nmethylmaysenine (16); key bonds broken retrosynthetically are shown by dashed lines. Substance (16) is related to an antitumour agent, maytansine, now undergoing clinical studies.

(16)

Prostaglandins.-It is clear that total syntheses are often used to develop novel ideas in chemistry. An explicit example has come from Trost et al.24 in their 'enantioconvergent' approach to prostanoids. Thus the olefinic acids (17) and (18) are mirror images which may be interconverted by allylic rearrangement. By choosing an optically active 'R'a pair of diastereoisomers results which can be separated. The unwanted isomer can then be equilibrated with the desired isomer so that theoretically a 100% conversion into one enantiomer may be achieved. 2o

21 22

23 24

( a )T. Schmidlin and C. Tamm, Helv. Chim. Acta, 1978,61,2096; ( b )S. J. Bailey, E. J. Thomas, W. B. Turner, and J. A. J. Jarvis, J.C.S. Chem. Comm., 1978,474. K. F. Burri, R. A. Cardone, W. Y. Chen, and P. Rosen, J. Amer. Chem. SOC.,1978, 100, 7069.

P. A. Bartlett and F. R. Green, J. Amer. Chem. SOC., 1978,100, 4858. E. J. Corey, L. 0. Weigel, D. Floyd, and M. G. Bock, J. Amer. Chem. SOC.,1978,100, 2916. B. M. Trost, J. M. Timko, and J. L. Stanton, J.C.S. Chem. Comm., 1978, 436.

319

Strategy and Design in Synthesis C0,Me

c, OAR

(17)

ArCO,

RAO (18)

The product (18) could subsequently be elaborated to optically active prostanoids via ring contraction as indicated. In contrast, Stork et ~ 1have . continued ~ ~ to seek routes to prostaglandins from optically active starting materials such as carbohydrates. They have now completed 3 route from D-glucose (19) to natural prostaglandin FZu(20) involving transformations analogous to those used in their earlier work. The essential structural relationship between starting material and product is indicated in formula (20). CHO

Me

CH,OH (19)

(20)

As an instance of the use of unusual elements in synthesis, Nicolaou eta1.26have applied selenium chemistry to the preparation of sulphur-containing analogues (21; X = S) of prostaglandin I2 as shown in Scheme 4. This group2' has also synthesized the carba-analogues (21; X = CH,) of prostaglandin I*. Tetrahedranes.-One28 of the more intriguing papers of 1978 describes the isolation of a hydrocarbon, C20H36, m.p. 135 "C (!), from low-temperature irradiation of the dienone (22). This new hydrocarbon is assigned the so-far unknown tetrahedrane structure (23). The spectroscopic evidence is consistent with this structure, and an X-ray structure analysis is awaited. More remarkably, it is suggested that the cyclobutadiene (24) is formed from the tetrahedrane (23) at 130 "C. Further reports in this area are awaited with interest. 5 Introduction and Interchange of Functional Groups

Umpo1ung.-The normal polarization of a carbonyl group (25) allows for an electron-deficient carbon atom, which is thus susceptible to nucleophilic attack. In a carbonyl group subject to umpolung the carbon atom is electron-rich and therefore susceptible to reaction with electrophiles (26). Practical applications of 25

26 27

G . Stork, T. Takahashi, I. Kawamoto, and T. Suzuki, J. Amer. Chem. SOC., 1978,100, 8272. K. C. Nicolaou, W. E. Barnette, and R. L. Magolda, J. Amer. Chem. SOC., 1978,100, 2567. K. C. Nicolaou, W. J. Sipio, R. L. Magolda, S. Seitz, and W. E. Barnette, J.C.S. Chem. Comm., 1978, 1067. G. Maier, S. Pfriem, U. Schafer, and R. Matusch, Angew. Chem. Internat. Edn., 1978, 17, 520.

General and Synthetic Methods

320 Ac S-

C0,Me

<Me R'O'

OR' C0,Me

fo2R p

x

Z HO

/

/i

M

s

h

s

-

L

M

HO

OH

e

+* .

OH (21)

Scheme 4

hv, -100°C

(25)

(26)

this concept have been provided by various The vinylogue (27) of this and a full paper31 published on its extension situation has also been e~arnined,~' (28) into quinone chemistry.

(27) 29

'O

31

(28)

J. I. Grayson and S. Warren, J.C.S. Perkin I, 1977, 2263; T. Cohen and S. M. Nolan, Tetrahedron Letters, 1978, 3533; L. Novak, G. Baan, J. Marosfalvi, and C. Szantay, ibid., p. 487; Y. Nagao, K. Kaneko, and E. Fujita, ibid., p. 4115. P. Bakuzis, M. L. F. Bakuzis, and T. F. Weingartner, Tetrahedron Letters, 1978,2371. J. S. Swenton, D. K. Jackson, M. J. Manning, and P. W. Raynolds, J. Amer. Chem. SOC.,1978,100, 6182.

321

Strategy and Design in Synthesis

Multi-phase Systems.-An account of the use of insoluble polymer supports in organic synthesis has been given by Leznoff .320 The use of alumina, an inorganic polymeric support, in organic reactions has been reviewed by P ~ s n e r A. ~new ~~ monograph on phase-transfer catalysis is available33" and a comparison of phase-transfer catalysis by quaternary ammonium salts, crown ethers, and polyalkylamines has been made.33b There have been several examples of multi-phase systems in asymmetric syntheses, notably a polymeric chiral rhodium hydrogenation catalyst for selectively producing R - a m i n o - a ~ i d s ,and ~ ~ the use of phase-transfer catalysis in asymmetric carbon-carbon bond formation.35 The incorporation of optically active cinchona alkaloids, e.g. quinine (29), into a polymer by virtue of their vinyl group has been described, with preliminary results on application to asymmetric ~ y n t h e s e sAt . ~ ~the other extreme of structural complexity, enzymes themselves have been incorporated into polymers to some advantage.37

CHOH

The selectivity of many reagents and their scope of application have been improved by working in multi-phase systems. Thus dichromate may be used in benzene3'" or d i c h l o r ~ m e t h a n eby ~ ~means ~ of phase-transfer catalysis, and in the latter case3" aldehydes can easily be obtained from primary alcohols. The reverse type of reaction, namely reduction, can be achieved by cyanoborohydride supported on an anion exchange resin.39 Other useful functional group interconversions (and removals), RX to RCHO and RX to RH, have been effected with 32

33

34

35

36

37

38

39

( a ) C. G. Leznoff, Accounts Chem. Res., 1978,11,327; ( b ) G. H. Posner, Angew. Chem. Internat. Edn., 1978,17,487; cf. NaI0,-alumina, K. T. Lui and Y. C. Tong, J. Org. Chem., 1978,43,2717, for conversion of sulphides into sulphoxides. ( a ) W. P. Weber and G. W. Gokel, 'Phase Transfer Catalysis in Organic Synthesis', available from Aldrich Chem. Co. Inc., Milwaukee, U.S.A., 1978; ( 6 ) M. C. V. Zwan and F. W. Hartner, J. Org. Chem., 1978,43,2655. N. Takaishi, H. Imai, C. A. Bertelo, and J. K. Stille, J. Amer. Chem. SOC., 1978,100,264;T. Masuda and J. K. Stille, ibid., p. 268; cf. M. Capka, Coll. Czech. Chem. Comm., 1977, 42, 3410; and M. E. Wilson and G. M. Whitesides, J. Amer. Chem. SOC.,1978, 100, 306. T. Wakabayashi and K. Watanabe, Tetrahedron Letters, 1978, 361. N. Kobayashi and K. Iwai, J. Amer. Chem. SOC., 1978,100,7071. A. Pollack, R. L. Baughn, 0. Adalsteinsson, and G. M. Whitesides, J. Amer. Chem. Soc., 1978,100, 302; R. L. Baughn, 0. Adalsteinsson, and G. M. Whitesides, ibid., p. 304. ( a ) R. 0. Hutchins, N. R. Natale, W. J. Cook, and J. Ohr, Tetrahedron Letters, 1977, 4167; ( b ) D. Pletcher and S. J. D. Tait, ibid., p. 1601; cf. polymeric pyridinium chlorochromate oxidizing reagent, J. M. J. Frechet, J. Warnock, and M. J. Farrall, J. Org. Chem., 1978, 43, 2618. R. 0. Hutchins, N. R. Natale, and I. M. Taffer, J.C.S. Chem. Comm., 1978, 1088.

General and Synthetic Methods

322

[FeH(CO),]- supported on Amberlyst A-26.40Tetrabutylammonium permanganate has now been described, permitting permanganate oxidations in pyridine.41Remote positions may be oxidized regioselectively by ozone adsorbed on silica gel.,' Less Usual Elements.-Reviews have covered the applications of silicon,43 selenium,,, and mercury45 in synthesis. Some specific examples of syntheses involving less usual elements have been 'queen substance' (30) ( p a l l a d i ~ m ~ ~ ) , ibogamine (32) (silver, p a l l a d i ~ m ~terpenoids ~), (+)-cataline (31) (~anadium,~), (chiral cobalt catalyst4'), and prostaglandins ( z i r c ~ n i u m ~ ~ ) . 0

-CO,H (30)

Me

OMe

Protecting Groups.-A protecting group is a form of regiospecific control element used to prevent unwanted functional-group interconversions. A number of publications on protecting groups noted during 1978 have involved sulphur, e.g. the fragment MeSCH'O- for protection of h y d r ~ x y l ~and ~ " carboxylic acid51b groups. In the former case,'la desulphurization gave access to methyl ethers. 1,3-Dithian protecting groups can be removed electrochemically to give carbonyl for peptide synthesis the o-nitrophenylsulphenyl protecting group can be removed selectively by 2 - t h i o ~ y r i d o n e A . ~ ~new silicon-containing pro-

'' G. Cainelli, F. Manescalchi, and A. Umani-Ronchi, J. Org. Chem., 1978, 43, 1598. '' T. Sala and M. V. Sargent, J.C.S. Chem. Comm., 1978,253; cf. D . G. Lee and V. S. Chang, J. Org. Chem., 1978,43,1532. A . L. J. Beckwith and T. Duong, J.C.S. Chem. Comm., 1978,413. 43 E. W. Colvin, Chem. SOC.Rev., 1978,7, 15. '' D . L. J. Clive, Tetrahedron, 1978,34, 1049. " R. C. Larock, Angew. Chem. Znternat. Edn., 1978, 17, 27. 46 Y. Tamaru, Y. Yamada, and Z. Yoshida, Tetrahedron Letters, 1978,919. " J. Hartenstein and G. Satzinger, Angew. Chem. Znternat. Edn., 1977, 16, 730. 48 H. Kumobayashi, S. Akutagawa, and S. Otsuka, J. Amer. Chem. SOC.,1978,100, 3949. 49 B. M. Trost, S. A. Godleski, and J. P. Jenet, J. Amer. Chem. SOC.,1978, 100, 3930. '' M. J. Loots and J. Schwartz, Tetrahedron Letters, 1978,4381. ( a )P. M. Pojer and S. J. Angyal, Austral. J. Chem., 1978,31,1031; ( b )L. G. Wade, J. M. Gerdes, and R. P. Wirth, Tetrahedron Letters, 1978, 731. 5 2 Q. N. Porter and J. H. P. Utley, J.C.S. Chem. Comm., 1978,255. s3 A. Tun-Kyi, Helv. Chim. Acta, 1978, 61, 1086. 42

Strateg.y and Design in Synthesis

323

tecting group, Me3SiCH2CH2-, has been developed for peptide synthesis54and applieds5to a synthesis of the macrocyclic lactone (-)-curvularin (33).

6 The Carbon Skeleton Dianions.-Synthetic chemists have long been acquainted with the concept of generating anions as reactive species. The extension into dianion chemistry has been more recent, requiring stronger bases and allowing regiospecific reactions at the more ‘reactive’ of the two anions. Evans and Sidebottoms6have produced the dianion (34) and utilized it in a simple synthesis of 6-aminolevulinic acid, a natural precursor of porphyrins. Vinick et aLS7have investigated the dianion ( 3 9 , and Caine and F r o b e ~ have e ~ ~ used the dianion (36) in syntheses of y-lactones.

.u.

V PhCONCHC02Et

CH2COCHCN

(34)

(35)

Ls

=

u

CH2CH2COi (36)

site of alkylation

Intramolecular Cyc1oadditions.-Application of certain intramolecular reactions allows the synthetic chemist to generate complex carbon skeletons more readily than by using intermolecular processes, and to exercise considerable control over regio- and stereo-specificity. It is not surprising, therefore, that this area of endeavour has become increasingly popular in recent years. Dominant among the reactions under study has been the intramolecular [4 + 21 cycloaddition (i.e. the intramolecular variant of the Diels-Alder reaction), some examples of which have already been noted in earlier sections. The reaction has also been applied in total syntheses of steroids,” (f)-cedrol,60 eudesmane sesquiterpeneq61 and norpatchoulenol.62The intramolecular [3 + 21 cycloaddition, a related process, has been used by Confalone et ~ 1 in a. synthesis ~ ~ of (*)-biotin. The key steps are ” 55 56

57 58

59

6o 62

P. Sieber, Helv. Chim. Acta, 1977,60, 2711. H. Gerlach, Helv. Chim. Actu, 1977, 60, 3039. D. A. Evans and P. J. Sidebottom, J.C.S. Chem. Comm., 1978,753. F. J. Vinick, Y. Pan, and H. W. Gschwend, Tetrahedron Letters, 1978, 4221. D. Caine and A. S. Frobese, Tetrahedron Letters, 1978, 883. W. Oppolzer, M. Petrzilka, and K. Battig, Helv. Chim. Actu, 1977,60,2964; W. Oppolzer, K. Battig, and M. Petrzilka, ibid., 1978,61,1945; T. Kametani, H. Matsumoto, H. Nemoto, and K. Fukumoto, Tetrahedron Letters, 1978,2425, and J. Amer. Chem. SOC.,1978, 100,6218. E. G . Breitholle and A. G. Fallis, J. Org. Chem., 1978,43, 1964. S . R. Wilson and D. T. Mao, J. Amer. Chem. SOC.,1978, 100,6289. W. Oppolzer and R. L. Snowden, Tetrahedron Letters, 1978,3505. P. N. Confalone, E. D. Lollar, G. Pizzolato, and M. R. Uskokovic, J. Amer. Chem. Soc., 1978,100, 6291.

General and Synthetic Methods

324

shown in Scheme 5. A different intramolecular [3 + 21 cycloaddition has been applied by Tufariello et ~ 1in a. stereospecific ~ ~ synthesis of (*)-cocaine. Scheme 6 shows the key step.

Scheme 5

H

Scheme 6

Oppolzer, a key figure in these studies, has given an example of an intramolecular [2 + 21 cycloaddition, (37) to (38), in a synthesis of (*)-l~ngifolene,~~ and

(37)

(38)

has published a number of papers on the intramolecular ‘ene’ reaction66[e.g. (39) to (40)], including a review.66c We may expect to see further examples of intramolecular variants of established reactions used in syntheses during coming years. 64

66

J. J. Tufariello, J. J. Tegeler, S. C. Wong, and S. A. Ali, Tetrahedron Letters, 1978, 1733. W. Oppolzer and T. Godel, J. Amer. Chem. Soc., 1978, 100,2583. ( a ) W. Oppolzer, K. K. Mahalanobis, and K. Battig, Helu. Chim. A d a , 1977, 60, 2388; ( b ) W. Oppolzer and H. Andres, Tetrahedron Letters, 1978,3397; ( c )W. Oppolzer and V. Snieckus, Angew. Chem. Internat. Edn., 1978, 17,476.

325

Strategy and Design in Synthesis COCF,

/

COCF,

7 Syntheses of Optically Active Materials

The Use of Optically Active Starting Materials.-Several examples of the application of this strategy have already been seen in this chapter. Carbohydrates are being chosen with increasing frequency as readily available, optically active starting materials. Targets that have been derived in this way have included (+)-biotin (41)from ~ - g l u c o s a m i n e ,(+)~ ~ and (-)-tetrahydrocerulenin (42) from D-glUCOSe68a and from D-XyloSe,68b7*(-)-a-multistriatin (43)from Dglucose,69 and canadensolide (44)from D-glu~ose.~' a-Methylglu~oside~~" and terrein (45)71b have been used to produce optically active synthons for prostaglandins and related compounds. (R)-cit citronello (46) and the optically 0

Hq

(42) (+)-isomer

7

0

Bun

H,

Me Me

0 (43)

(44)

0 OH

""%Me HO (45) 67 68

69 70

71

H. Ohrui, N. Sueda, and S. Emoto, Agric. and Biol. Chem. (Japan), 1978,42, 865. ( a ) H. Ohrui and S. Emoto, Tetrahedron Letters, 1978, 2095; ( b ) J. R. Pougny and P. Sinaj, Tetrahedron Letters, 1978, 3301. P. Sum and L. Weiler, Canad. J. Chem., 1978, 56,2700. R. C. Anderson and B. Fraser-Reid, Tetrahedron Letters, 1978, 3233. ( a )0.Hernandez, Tetrahedron Letters, 1978,219; ( b )L. A. Mitscher, G. W. Clark, and P. B. Hudson, Tetrahedron Letters, 1978, 2553.

* Incidentally leading to a revised absolute configuration of the natural product cerulenin.

326

General and Synthetic Methods

active tartaric acids have been used by Mori et al.72 in the syntheses of various isomers of a pheromone of pine sawflies. Magnus and Roy73have prepared the aggregation pheromone of the southern pine beetle, (3R)-(+)-frontalin (47) from (3R )- (-)-halo01 (48).

Me (47)

Me (48)

Asymmetric Syntheses.-The production of chiral compounds from achiral precursors by, for example, the use of asymmetric reagents has now become widely described in the literature, and only selected papers are mentioned Many of these studies are of reduction reactions involving conversion of a ‘flat’sp2-hybridized carbon atom into a tetrahedral sp3-hybridizedcarbon atom. Hydrogenations using optically active catalysts are popular (see also above), typified by a synthesis of ethyl D-(+)-pantothenate (chiral rhodium c~mplex’~). Perhaps a more sophisticated development along these lines is that by Fryzuk and Bosnich of an asymmetric homogeneous rhodium hydrogenation catalyst which ‘breeds its own ~ h i r a l i t y ’ This . ~ ~ catalyst can be used not only to produce amino-acids in excellent optical yields by reduction of the alkene link in dehydroamino-acids, but can also be used to produce further quantities of its own chiral ligands from pyruvic ester. Alternatively the sp2-hybridizedcarbon atoms of an alkene can be converted oxidatively into a chiral sp3-hybridized carbon, as in the work of Hummelen and W ~ n b e r gIn . ~this ~ case olefins were converted into chiral epoxides of moderate optical purity by hypochlorite in the presence of a phase-transfer catalyst derived from quinine (29). The sp2-hybridized carbon atom of the carbonyl group has frequently been reduced by asymmetric reagents to yield the sp3-hybridized carbon atom of an optically active alcohol. For example, Horner and B r i ~ have h ~ ~studied electrochemical reduction of acetophenone in the presence of optically active quaternary ammonium salts or crown ethers. The optical purity achieved was low. In contrast, the conversion of the sp2-hybridized carbon atom of a carbonyl compound into the sp3-hybridized carbon atom of an optically active amine, a process common in Nature, has been exemplified using an artificial pyridoxamine analogue by Kuzuhara et al.79 Optical yields were moderate. 72 73 74

75

76

77

78

79

K. Mori, S. Tamada, and M. Matsui, Tetrahedron Letters, 1978, 901. P. Magnus and G. Roy, J.C.S. Chem. Comm., 1978,297. For a recent background discussion, see A. I . Meyers, Accounts Chem. Res., 1978, 11, 375. I. Ojima, T. Kogwe, T. Terasaki, and K. Achiwa, J. Org. Chem., 1978,43, 3444. M. D. Fryzuk and B. Bosnich, J. Amer. Chem. SOC.,1978, 100, 5491. J. C. Hummelen and H. Wynberg, Tetrahedron Letters, 1978, 1089; cf. S. Colonna, R. Fornasier, and U. Pfeiffer, J.C.S. Perkin I, 1978, 8. For the preparation of optically active aziridines, see K. Harada and I. Nakamura, J.C.S. Chem. Comm., 1978,522. L. Horner and W. Brich, Chem. Ber., 1978,111,574;cf. S . Colonna and R. Fornasier, J.C.S. Perkin I, 1978,371. H. Kuzuhara, T. Komatsu, and S . Emoto, Tetrahedron Letters, 1978, 3563; cf. S. R. Landor, 0. 0. Sanola, and A. R. Tatchell, J.C.S. Perkin I, 1978, 605.

Strategy and Design in Synthesis

327

Turning to carbon-carbon bond formation, Schollkopf et aL8Ohave provided an asymmetric synthesis of a-amino-acids via alkylation of an optically active heterocyclic system (49) as indicated; optical yields were high. The Diels-Alder

* indicates optical activity reaction is well known for its regio- and stereo-specificity. The addition to these advantages of enantiospecificity has been provided by Corey and co-workers" in work on a 'recyclable director' for producing optically active prostaglandin intermediates (50); the group R" is optically active and the adduct (50) was obtained in up to 97% optical purity.

(50)

An example of double carbon-carbon bond formation in an asymmetric synthesis has been developed by Nakamura et a1.82in an interesting paper on the use of an optically active cobalt reagent for producing cyclopropanes from carbenes and alkenes. For example the cyclopropane (51)was prepared in 70% optical yield in this work. Finally, asymmetric syntheses have been achieved photochemically in chiral crystals (cycl~butanes),~~ and in a chiral solvent (helicenes).84 Ph

(51)

70% optical yield of 1(S)-isomer

Biological Syntheses.-Given that oil-based products, and oil-derived energy, will become relatively more expensive (and less available) as time goes by, we may expect to see greater application of living systems in research, in development, and in production chemistry. Micro-organisms continue to be popular and have been applied, for example, in producing optically active alkynyl alcohols by 80

82

83 84

U. Schollkopf, H. H. Hausberg, I. Hoppe, M. Segal, and U. Reiter, Angew. Chem. Internat. Edn., 1978,17, 117. H. E. Ensley, C. A. Parnell, and E. J. Corey, J. Org. Chem., 1978,43, 1610. A . Nakamura, A. Konishi, Y. Tatsuno, and S. Otsuka, J. Amer. Chem. SOC.,1978,100,3443,3449. L. Addadi and M. Lahav, J. Amer. Chem. SOC.,1978,100,2838. W. H. Laarhoven and T. J. H. M. Cupper, J.C.S. Perkin 11, 1978, 315.

General and Synthetic Methods

328

enantioselective ester h y d r o l y s i ~ ;optical ~~ purities were generally good. Microorganisms have also been used to generate optically pure sulphoxides, which in turn were applied in a synthesis of R-mevalono1acfones6 (17% optical purity). Another application of micro-organisms has been in steroid synthesis via production of the optically active lactone (52).87A fine large-scale example has 0

Microbial

H (52)

been described by Hoffmann-La Roche workers.88Yeast was used to reduce the achiral ene-dione (53) to produce the optically active dione (54). This substance (54) could then be elaborated to various optically active carotenoids, for instance the plant growth regulator (-)-xanthoxin ( 5 5 ) . In future we can expect to see such studies extended to include investigation of isolated plant tissues for producing optically active chemical substances.

BMe -.Jy Me

Me

Me

Me

0

’Me

(53)

(54)

Me

H O&cHo

Me Me

(55)

Resolution.-Volume 1of a useful work of reference on resolution procedures is now available; it apparently contains extensive practical i n f ~ r m a t i o ntaken ~~ from the literature. Considerable interest continues in the use of chromatography for r e s o l ~ t i o nHowever, .~~ this Reporter still feels that resolution should be the lowest priority to apply in the synthesis of optically active compounds, and that, except in special circumstances, Editors should discourage the appearance in print of papers describing syntheses of racemic materials. Such a policy would encourage chemists to use the higher-level strategies, for instance in choosing readily available optically active starting materials.

’’ K. Mori and H. Akao, Tetrahedron Letters, 1978,4127.

E. Abushanab, D. Reed, F. Suzuki, and C. J. Sih, Tetrahedron Letters, 1978, 3415. M. Rosenberger, R. Borer, and G. Saucy, J. Org. Chem., 1978, 43, 1550. ’* F. Kienzle, H. Mayer, R. E. Minder, and H. Thornmen, Helv. Chim. Acta, 1978,61,2616 and refs. therein. ’’ P. Newrnan, ‘Optical Resolution Procedures for Chemical Compounds. Vol. I. Amines and Related Compounds’, Optical Resolution Information Centre, Mdnhattan College, New York, 1978. 90 E.g. L. R. Sousa, G. D. Y. Sogah, D. H. Hoffrnann, and D. J. Cram, J. Amer. Chem. SOC.,1978,100, 4569; G . Blaschke, H. P. Kraft, and A. D. Schwanghart, Chem. Ber., 1978,111,2732. G.1.c. methods: V. Schwig and W. Burkle, Angew. Chem. Infernat.Edn., 1978,17,132;H. Frank, J. N. Graeme, and E. Bayer, ibid., p. 363.

86

”

10 Photochemistry in Synthesis BY A. B. HOLMES

1 Introduction Photochemistry has always played a role in organic synthesis, but in the past decade it has become an increasingly important weapon in the synthetic chemist’s armoury. Although the subject has already been reviewed,’ the appearance of many interesting new publications demands that it be reviewed again. Synthetic organic photochemistry has largely been directed at the synthesis of natural products, and these will feature prominently in this chapter, although an attempt will be made to highlight other important syntheses. Since the chapter will necessarily be a selective review, it is important that readers should consult other more comprehensive reviews’ on organic photochemistry for details of subjects which cannot adequately be treated here. It is interesting to note that synthetic organic photochemistry has largely been restricted to use in the research laboratory, although improvements in the technology of photoreactors have led to the development of efficient industrial photochemical processes for the synthesis of vitamin D, Rose oxide, and c a p r ~ l a c t a m . ~ 2 Ring Synthesis

Cycloaddition Reactions.-These form the largest class of useful organic photochemical synthetic methods. The formation of cyclobutanes, with or without further rearrangement, dominates the subject, but larger rings have also been prepared. Four-membered Rings. Concerted [2+2] photocycloadditions involving the singlet excited state of simple alkenes are relatively rare, being restricted to a few examples of intramolecular reactions’” and photodimeri~ations.~ Triplet-sensitized intramolecular cyclizations of polyenes can lead to good yields of cyclobutane derivatives. Thus benzophenone-sensitized irradiation of the trieneacetal

2

( a ) P. G. Sammes, Quart. Rev., 1970, 24, 37; ( b ) P. G. Sammes, Synthesis, 1970, 636; ( c ) T. Matsuura, Yuki Gosei Kagaku KyokaiShi, 1972,30,83 (Chem. Abs., l973,79,4481m);( d )S . Isoe, Yuki GoseiKagaku KyokaiShi, 1975,33,460 (Chern. Abs., 1976,84,38580;( e )N . J. Turro and G. Schuster, Science, 1975,187,303;( f ) K. Nakanishi,T. Goto, S. It6, S. Natori, and S. Nozoe, ‘Natural Products Chemistry’, Academic Press, 1975, Vol. 2, p. 562; (g) W. L. Dilling, Photochern. and Photobiol., 1977, 25, 605. ‘ Photochemistry’, ed. D. Bryce-Smith (Specialist Periodical Reports), The Chemical Society, London, Vols. 1-10. J. M. Mellor, D . Phillips, and K. Salisbury, Chem. in Britain, 1974,10, 160. L. J. Kricka and A . Ledwith, Synthesis, 1974, 539.

329

330

General and Synthetic Methods

(1) in pentane gave mainly the bicyclohexane ( 2 ) which was converted into a-trans-bergamotene (3), a constituent of a number of essential oils (Scheme l).5

(1)

(2)

Reagents: i, hv, Pyrex-PhCOPh-pentane; ii, 12 steps

Scheme 1

a#-Unsaturated carbonyl compounds absorb light at much more accessible wavelengths as far as the preparative organic chemist is concerned, and the photocycloaddition of such compounds to alkenes is probably the most importanto single reaction in photochemical synthesis. Several useful reviews of the subject have therefore appeared.lgS6Corey7 was the first to apply such reactions to the synthesis of a natural product, caryophyllene (5). The low-temperature irradiation of a pentane solution of cyclohexenone and isobutene gave the adducts (4) as a mixture of cis- (36%) and trans-isomers (10%)which were converted into the natural product (Scheme 2 ) . The regioselectivity of the photocycloaddition reaction was rationalized by Corey in terms of a head-to-tail exciplex involving excited-state enone and alkene.8 The orientation in such exciplexes has more recently been analysed in terms of frontier orbital theory,’ but many aspects of the reaction remain a puzzle.

Reagents: i, hv, corex, pentane, -70 “C; ii, 12 steps

Scheme 2

Grandisol(6), the sex attractant of the boll weevil, has been synthesized by four different methods utilizing the photoadducts (7)-( 10) as respective starting materials.’ g*lo

’ E. J. Corey, D. E. Cane, and L. Libit, J. Amer. Chem. SOC.,1971,93, 7016. ’ lo

( a ) P. E. Eaton, Accounts Chem. Res., 1968,1,50; ( b )P. G. Bauslaugh, Synthesis, 1970,287; (c) P. de Mayo, Accounts Chem. Res., 1971, 4,41; ( d )S. M. Ali, T. V. Lee, and S. M. Roberts, Synthesis, 1977, 155. E. J. Corey, R. B. Mitra, and H. Uda, J. Amer. Chem. Soc., 1964,86, 485. E. J. Corey, J. D. Bass, R. LeMahieu, and R. B. Mitra, J. Amer. Chem. Soc., 1964,86, 5570. I. Fleming, ‘Frontier Orbitals and Organic Chemical Reactions’, Wiley, London, 1976, Ch. 6. ( a )J. G .Tumlinson, R.C. Gueldner, D. D. Hardee, A. C. Thompson, P. A. Hedin, and J. P. Minyard, J. Org. Chem.. 1971,36,2616; ( b )R. Zurfluh, L. L. Dunham, V. L. Spain, and J. B. Siddall, J. Amer. 1970,92,425; (c)J. B. Siddall, U.S. P. 3 627 660; Ger. Offen. 2 056 431 (Chem. Abs., Chem. SOC., 1971, 75, 63 2352); R.C. Gueldner, A. C. Thompson, and P. A. Hedin, J. Org. Chem., 1972, 37, 1854; H. Kosugi, S. Sekiguchi, R.-I.Sekita, and H. Uda, Bull. Chem. SOC. Japan, 1976,49,520; ( d ) R. L. Cargill and B. W. Wright, J. Org. Chem., 1975, 40, 120.

Photochemistry in Synthesis

331

dl.--OHd:::; Q

-r (6)

0

(7)

Qo

0

0

(8)

(9)

go (10)

Photoaddition of ethylene to the bicyclo[3,3,0]octenone (11; R = H) gave mainly the cis,anti,cis-adduct (12; R = H) which was converted into 7a-protoilludanol (13)." Similarly the adduct (12; R = OAc) was converted in eleven steps into compound (14)which has the carbon skeleton of the biologically active metabolite fomannosin.12 Illudol (16) has been obtained from the diethoxyethylene photoadduct (15) (Scheme 3).13

Reagents: i, hv, hexane, CzHd,O'C, 6h; ii, 3 steps

Scheme 3

Intramolecular cycloadditions do not feature as prominently in this section as in the next, but one recent example is the formation in low yield of the strained p-lactam (18) by irradiation of the precursor (17) in dioxan or pyridine (Scheme 4).14 U

l1 " l3

l4

Y. Ohfune, H. Shirahama, and T. Matsumoto, Tetrahedron Letters, 1975,4377. K. Miyano, Y. Ohfune, S. Azuma, and T. Matsumoto, Tetrahedron Letters, 1974, 1545. T. Matsumoto, K. Miyano, S. Kagawa, S. Yii, J.-I. Ogawa, and A. Ichihara, Tetrahedron Letters, 1971.3521. P.K.Sen, C. J. Veal, and D. W. Young, J.C.S. Chem. Comm., 1977,678.

General and Synthetic Methods

332

The [I2 + 21 cycloaddition of enol acetates of 1,3-dicarbonyl compounds to alkenes yields masked aldols, which can be modified in a number of ways. Treatment of the adduct (19), derived from ethylene and 3-acetoxycyclohex-2enone, with base gave the a,@-unsaturated ketone (20) which yielded the propellane (21) upon irradiation in the presence of ethylene. Ring contraction led ultimately to the highly strained [2,2,2]propellane (22) (Scheme 5).15

Reagents: i, base; ii, hv, C2H4, -70°C; iii, 8 steps

Scheme 5

Four-membered Rings with Subsequent Rearrangement. The scope of the photoannelation reaction has been widely extended to involve cleavage reactions of the cyclobutane ring. Many syntheses of natural products involving such processes have been cited by previous reviewers. 1*6 Thus de Mayo16 recognized that the photoadduct (23) from dichloroethylene and the enol acetate of cyclopentane1,3-dione could be cleaved by a retro-aldol reaction and subsequent elimination to give y-tropolone (24) (Scheme 6). A more recent example utilized the 0

Scheme 6

intriguing observation that, although both enol tautomers of formylacetone were observed to be present in solution, only enol (25) formed a photoadduct with 1,2-dimethylcyclohexene.'7 Retro-aldol reaction of this unstable intermediate led to the cyclohexane (26) which was converted into the valeranes (27) (Scheme 7). Intramolecular photoannelations can be expected to play a significant part in future investigations. An efficient synthesis of longifolene (31) illustrates this point (Scheme 8).18Thus photolysis of the enone (28) gave an adduct (29) which was smoothly cleaved to the diketone (30). This served as the precursor to l6

" l8

P. E. Eaton and G. H. Temme, J. Amer. Chem. Soc., 1973,957508. H. Hikino and P. de Mayo, J. Amer. Chem. Soc., 1964,86, 3582. S. W. Baldwin and R. E. Gawley, Tetrahedron Letters, 1975, 3969. W. Oppolzer and T. Godel, J. Amer. Chem. SOC.,1978,100, 2583.

Photochemistry in Synthesis

333

Reagents: i, hv, Pyrex, C6H12;ii, H2-Pd/C-AcOH; iii, 5 steps

Scheme 8

longifolene (31). The bicyclo[3,2,l]octane skeleton has also been obtained by an intramolecular photoannelation (Scheme 9).19Photolysis of the enol acetate (32) gave mainly the adduct (33) which was cleaved to give the diketone (34).

Scheme 9

Allenes have been added to many cyclic a,@-unsaturated ketones to give methylenecyclobutane derivatives. The stereochemistry of such additions has been rationalized by Wiesner,20 who has used the method extensively in the synthesis of diterpenoid alkaloids.21For example, the synthesis (Scheme 10) of talatisamine (39) involved the cycloaddition of allene to the enone (35)to give the photoadduct (36) which was converted into the masked aldol (37). Retro-aldol reaction followed by another aldol cyclization gave (38)which was converted into talatisamine (39).22 Intramolecular photocyclizations of appropriate allenic enones can also be expected to be synthetically useful. The formation of (41)from A closely related process is the (40) in high yield is a promising cyclization of (42) to (43) (Scheme 11).24 l9 2o

”

’*

23 24

M. Mellor, D . A. Otieno, and G. Pattenden, J.C.S. Chem. Comm., 1978, 138. K. Wiesner, Tetrahedron, 1975, 31, 1655. K. Wiesner, Chem. SOC.Rev., 1977,6,413. K. Wiesner, Pure A p p l . Chem., 1975,41,93. D. Becker, Z. Harel, and D. Birnbaum, J.C.S. Chem. Comm., 1975,377. R . L. Cargill, J. R. Dalton, S. O’Connor, and D. G. Michels, Tetrahedron Letters, 1978,4465.

General and Synthetic Methods

334

I

iii 90%

Me0

(39)

Me0 (38)

Reagents: i, hv, THF-allene, -80 "C; ii, 3 steps; iii, HCl-THF; iv, 13 steps

Scheme 10

Reagents: i, hv, Pyrex, C6H12,1 h; ii, hv, C,Hl,

Scheme 11

Other methods of cleaving or rearranging the cyclobutane ring of [2 + 23 photoadducts have been investigated.'*6Lead tetra-acetate cleavage of the vicinal diol(44), which is readily derived from the photoadduct of 2-methylcyclopent-2enone and 1,2-bistrimethylsilyloxycyclopentene,has been used to obtain the hydroazulene (45) which was the starting material for a synthesis of the pseudoguainolide damsin (46) (Scheme 12).25 If the cyclobutane is particularly strained, as in the case of an intramolecular photocycloaddition product, it may be cleaved by nucleophilic attack of the solvent. This is illustrated in Scheme 13, where the hirsutane derivative (48) is presumed to arise by methanol attack on the three-membered ring of the 25

D. Termont, P. De Clercq, D. De Keukeleire, and M. Vandewalle, Synthesis, 1977,46; P. De Clercq and M. Vandewalle, J. Org. Chem., 1977, 42, 3447.

335

Photochemistry in Synthesis

I TMS

Q

iv

0

@

HO

(46) O

(45)

Reagents: i, hv (366 nm), pentane; ii, LiAIH,; iii, Pb(OAc1,; iv, 14 steps

Scheme 12

(47) Scheme 13

intermediate (47).26 Methoxypyrrolidines have similarly been obtained from the irradiation of N-allyliminium perchlorate salts in methanol.*’ The rearrangement of adducts of enol acetates derived from a-diketones has been reported.66 An interesting application of this principle was in a model study for the synthesis of acorenones (Scheme 14) in which the adduct (49) underwent rearrangement in base to (50) which was cleaved with lead tetra-acetate to generate the spirocyclic product (5 OH

-

0

iii

L 3 8‘10

Q)

HO,C (50)

(49)

(51)

Reagents: i, hv, Pyrex, MeCN-methylenecyclopentane; ii, HO-; iii, Pb(OAc),

Scheme 14 26 2’ 2R

J. S. H. Kueh, M. Mellor, and G. Pattenden, J.C.S. Chem. Comm., 1978, 5 . P. S. Mariano, J. L. Stavinoha, and R. Swanson, J. Amer. Chem. SOC.,1977, 99,6781. G. L. Lange, H. M. Campbell, and E. Neidert, J. Org. Chem., 1973,38, 2117.

336

General and Synthetic Methods

The cleavage of oxetans formed in the Paterno-Buchi reaction has also been used with effect.ld” Thus an extremely simple and efficient synthesis of D,Lapiose (53) involved the base-induced cleavage of the oxetan (52), derived from diacetoxyacetone and vinylene carbonate (Scheme 15 ) . 2 9A reductive cleavage of CHO ~ i- [ ) =cO

h AcO

&A

~

o-%

I

~

CHOH HOCH,-COH I

~

I

0

CH,OH

OAc

Reagents: i, hv, Pyrex, C6& 40 h; ii, H O

Scheme 15

the benzylic C - 0 bond in the oxetan ( 5 5 ) , which was obtained by irradiating the optically active cyclopentene (54) and rn-acetoxybenzaldehyde, gave the corresponding alcohol which served as a precursor to the biologically active prostaglandin analogue (56) (Scheme 16).30

)C02H

0

OAc

HO (54)

OH

(55)

Reagents: i, hv, rn-AcOC,H,CHO; ii, H,-Pd/C; iii, 12 steps

Scheme 16

An olefin metathesis reaction has been effected by photochemical [2 + 21 cycloaddition followed by thermolysis of the cyclobutane (Scheme 17). Thus thermolysis of the tricyclic cis,anti,cis-adduct (57) gave the cyclodeca-1,5-diene skeleton (58)present in germacranolides (Scheme 17).31A closely related process is the [4C + 2C] annelation which has been utilized in the synthesis of 10-epijuneol (61) (Scheme 18). The photoadduct (59) from piperitone and methyl cyclobutene-1-carboxylate was converted in four steps into the tricyclic compound (60). The strained u-bond in (60)was cleaved with lithium naphthalide to give 10-epi-juneol (61).32 29 30 31 32

Y. Araki, J.-I. Nagasawa, and Y. Ishido, Carbohydrate Res., 1977, 58, C4. D. R. Morton and R. A. Morge, J. Org. Chem., 1978,43, 2093. G. L. Lange, M.-A. Huggins, and E. Neidert, Tetrahedron Letters, 1976,4409. P. A. Wender and J. C. Lechleiter, J. Amer. Chem. SOC.,1978, 100, 4321.

F

337

Photochemistry in Synthesis

4

__*

70%

0

60%

Me0,C

H

Reagents: i, hv, methyl cyclobutene-1,2-dicarboxylate;ii, A, 139 “C

Scheme 17

‘

I

0

‘

(EtO),PO’

II

Other Ring Sizes. Five- and six-membered rings have been prepared. The photochemical addition of aromatic nitro-groups to alkenes is a well established method of cleaving double Recently this reaction has been applied to the cleavage of aromatic methoxy-compounds (Scheme 19). Thus 1,4-dimethoxynaphthalene was irradiated in the presence of m-chloronitrobenzene to give mainly the ring-cleaved product (63) by cycloreversion of the presumed intermediate 1,2-adduct (62).34 Ar

Scheme 19

The photochemical 1,3-addition of anisole to cyclopentene occurs in remarkably high yield.35Acid-catalysed cleavage of the cyclopropyl ring of the resulting adduct (64) gave the ketone (65) whose one-carbon bridge was cleaved in base to give the isomeric perhydroazulenes (66) (Scheme 20). Five-membered heterocycles have been obtained by the thermal dipolar cycloaddition of photochemically generated 1,3-dipoles to dipolarophiles. 33

34

35

G . Buchi and D. E. Ayer, J. Amer. Chem. Soc., 1956,78,689; J. L. Charlton, C. C. Liao, and P. de Mayo, ibid., 1971, 93, 2463. I. Saito, M. Takami, and T. Matsuura, Bull. Chem. SOC.Japan, 1975, 48, 2865. R. Srinivasan, V. Y. Merritt, and G. Subrahmanyam, Tetrahedron Letters, 1974, 2715.

338

General and Synthetic Methods OMe

0

Scheme 20

Particularly significant contributions have been made by P a d ~ and a ~S ~~ h m i in d~~ the photochemical generation of benzonitrile methylides from 2 H - a ~ i r i n e sFor .~~ example (Scheme 21), photolysis of (67) in the presence of carbon dioxide as dipolarophile leads to 4-phenyl-3-oxazolin-5-ones (68),39 whereas the intramolecular dipolar cycloaddition reaction of (69) can afford a useful synthesis of the bicyclic product (70).40 Ph

uo

N

-pha hv, corex

C6H.5, 80%

(69)

(70) Scheme 21

The photolysis of oxirans generates carbonyl ylides which can be trapped by dipolarophiles to give tetrahydrofurans (Scheme 22).4'

Scheme 22

Six-membered rings may be obtained by the thermal cycloaddition of dienophiles to photochemically generated dienols ( p h o t o e n ~ l i z a t i o n This ) . ~ ~ principle 36 37 38 39

4" 41

42

A. Padwa, Accounts Chem. Res., 1976, 9, 371. P. Gilgen, H. Heimgartner, H. Schmid, and H.-J. Hansen, Heterocycles, 1977,6, 143. A. Padwa, Chem. Rev., 1977,77, 37; A. C. Pratt, Chem. SOC.Rev., 1977, 6, 63. N. Gakis, M. Marky, H.-J. Hansen, H. Heimgartner, H. Schrnid, and W. E. Oberhansli, Helv. Chim. Acta, 1976, 59, 2149. A. Padwa and N. Karnigata, J. Amer. Chem. SOC.,1977,99, 1871. I. J. Lev, K. Ishikawa, N. S. Bhacca, and G . W. Griffin, J. Org. Chem., 1976, 41, 2654. P. G. Sarnmes, Tetrahedron, 1976, 32,405.

Photochemistry in Synthesis

339

has been applied to the synthesis of lignan derivatives (Scheme 23). Irradiation of the benzylic aldehyde (7 1) in the presence of dimethyl acetylenedicarboxylate gave the adduct (72) which was converted in three steps into justicidin E (73).43

Ar

Ar

(72)

(73)

Reagents: i, hv, THF-dimethyl acetylenedicarboxylate; ii, 3 steps

Scheme 23

Ring Closure Reactions.-These can be broadly classified into electrocyclic and non-concerted processes, although the results will be presented here according to ring size. Three- a n d Four-membered Rings. Methyl chrysanthemate (75) has been obtained as a 1 : 2 mixture of cis- and trans-isomers by the d i - ~ m e t h a n e ~ ~ cyclization of the diene ester (74) (Scheme 24).45 Cyclopropanes may also be prepared by the photocyclization of allylmagnesium

/ COzMe

hv, hexane 30 h, 12%

, C0,Me (75)

(74) Scheme 24

Electrocyclic reactions have been used to prepare four-membered rings. Irradiation of 1,2-dihydrophthalic acid anhydride gave the bicyclo[2,2,0]hexene (76) which was oxidatively decarboxylated to Dewar-benzene (77) (Scheme 25).47

aoz$-D H H O

Pb(0Ac)

---A

H O

H H O (76)

Vl (77)

Scheme 25 43 44

45

46

47

B. J . Arnold, S. M. Mellows, and P. G. Sammes, J.C.S. Perkin I, 1973, 1266. S. S. Hixson, P. S. Mariano, and H. E. Zimmerman, Chem. Rev., 1973,73, 531. M. J. Bullivant and G. Pattenden, J.C.S. Perkin I, 1976, 256. S. Cohen and A. Yogev, J. Amer. Chem. SOC., 1976,98,2013. E. E. van Tamelen, S. P. Pappas, and K. L. Kirk, J. Amer. Chem. SOC., 1971, 93, 6092.

340

General and Synthetic Methods

P-Lactams have been obtained in a number of ways. The irradiation through pyrex of benzene solutions of cinnamic acid anilides leads to the corresponding P-lactams in moderate yield.48 Alternatively, efficient cyclization of N,N-dibenzylacrylamide can be effected by irradiation in benzene (Scheme 26). The intermediate (78)is thought to be formed by intramolecular hydrogen abstraction

(78) Scheme 26

involving the P-carbon atom of the excited a,P-unsaturated A related process is the Norrish Type I1 photocyclization in benzene of thiazolidine amides (79) to the 6-hydroxypenam derivatives (80).The reaction is more efficient (70%) for the pyruvamide (79; R' = R2 = Me)50than for the oxophenylacetamide (79; R' = Ph, R2 = Et).51Finally, there have been a number of interesting reports on the synthesis of nuclear analogues of penicillins and cephalosporins by the irradiation of a-diazo-amide derivative^.^^ Thus irradiation of the diazocompound (81) in carbon tetrachloride gave the oxapenam (82) in 55% yield, presumably by a carbene insertion reaction.52d

Fiue-membered Rings. Irradiation of tropolone a-methyl ether (83) is known to give the rearrangement product (84) in high yield. This has been used as a starting material for the synthesis of 1 l-deoxyprostaglandin E, (85) (Scheme 27).53

boMe hu,MeOH

-

,

O w o l l s t eM ps e

4 h, 80%

/

C J , l

Scheme 27 4R 4y

52

s3

0. L. Chapman and W. R. Adams, J. Amer. Chem. SOC., 1968,90,2333. T. Hasegawa, M. Watabe, H. Aoyama, and Y. Omote, Tetrahedron, 1977, 33, 485. K. R. Henery-Logan and C. G. Chen, Tetrahedron Letters, 1973, 1103. N. G. Johannson, B. Akermark, and B. Sjoberg, Acta Chem. Scans., 1976, B30,383. ( a )D. M. Brunwin, G. Lowe, and J. Parker, J. Chem. Soc. (C), 1971,3756; ( b )G . Lowe and M. V. J. Ramsay, J.C.S. Perkin I, 1973, 479; (c) D. M. Brunwin and G . Lowe, ibid., 1973, 1321; ( d ) B. T. Golding and D. R. Hall, ibid., 1975, 1517. A. Greene and P. CrabbC, Tetrahedron Letters, 1975, 2215.

341

Photochemistry in Synthesis

A novel photocyclization of the aryl cyclohexenyl ketone (86) to the tricyclic compound (87),a potential precursor for gibberellins, has been reported (Scheme 28).54Closely related cyclizations to give benzannelated five-membered heterocycles have beer. i n ~ e s t i g a t e dA. ~recent ~ example in the nitrogen series involved the photocy~lization~~ of the N-arylenamine (88) to the heterocyclic derivative (89),which is a model for the synthesis of Aspidosperma alkaloids (Scheme 29).57 H

HO,C

0

Irradiation of 2-acyl-2,3-dihydro-4H-pyrans[e.g. (90)] in the presence of 1methylnaphthalene selectively excites the singlet state of the carbonyl group while quenching the triplet state. The oxygen of the carbonyl group becomes attached to C-6 of the double bond with concomitant stereoselective transfer of a hydrogen atom from C-4 to the carbon atom of the carbonyl group [e.g. (91)].This process has been applied to the synthesis of exo-brevicomin (92) (Scheme 30),the sex attractant of the western pine beetle.58

Reagents: i, hv (7300 nrn), vycor, 1-methylnaphthalene-pentane;ii, H,-Pd/C

Scheme 30 L. M. Jackrnan, E. F. M. Stephenson, and H. C. Yick, Tetrahedron Letters, 1970, 3325. ” A. G. Schultz, W. Y. Fu, R. D. Lucci, B. G. Kurr, K. M. Lo, and M. Boxer, J. Amer. Chem. SOC., 1978, 100,2140;A. G. Schultz, R. D. Lucci, W. Y. Fu, M. H. Berger, J. Erhardt, and W. K. Hagmann, ibid., p. 2150; A. G. Schultz and W. K. Hagmann, J. Org. Chem., 1978,43,4231. 56 0. L. Chapman, G. L. Eian, A. Bloom, and J. Clardy, J. Amer. Chem. SOC.,1971, 93, 2918. ’’ A. G. Schultz and I.-C. Chiu, J.C.S. Chem. Comm., 1978,29. P. Chaquin, J.-P. Morizur, and J. Kossanyi, J. Amer. Chem. SOC.,1977, 99, 903. s4

342

General and Synthetic Methods

Photochemical reactions involving intramolecular hydrogen transfer from a carbon atom adjacent to a heteroatom to the oxygen atom of a quinone carbonyl group have been used to prepare five-membered heterocycles. A n early example was the low-yield (15%) conversion of the methoxyquinone (93) in acetic anhydride into the methylenedioxy-derivative (94) using Pyrex-filtered irradiat i ~ n . ~A' preparatively more useful reaction was used as a model study for

0

OAc

(94)

(93)

mitomycin synthesis.60 For example, Pyrex-filtered irradiation of the aminoquinone (95) in ethanol gave the mitomycin-like product (97) via the benzoxazoline (96) (Scheme 31).60bThe first step of this rearrangement had been observed previously in simpler systems.61

aN 0

0

CO,Et

H

Scheme 31

Aryl alkyl thioketones undergo intramolecular hydrogen abstraction from the 6-carbon atom, and the resulting biradicals cyclize to cyclopentanethiols rather than to the cyclobutanols more usually observed in the Norrish Type I1 reaction.62 This principle has been utilized in a synthesis of cuparane (98) (Scheme 32). 59

6o 61

62

J. E. Baldwin and J. E. Brown, Chem. Comm., 1969, 167. ( a ) K. J. Falci, R. W. Franck, and G. P. Smith, J. Org. Chem., 1977, 42, 3317; ( b ) M. Akiba, Y. Kosugi, M. Okuyama, and T. Takada, ibid., 1978,43, 181. D. W. Cameron and R. G. F. Giles, J. Chem. SOC.(C), 1968,1461; R. G. F. Giles, P. R. K. Mitchell, G. H. P. Roos, and I. Baxter, J.C.S. Perkin I, 1973, 493. P. de Mayo and R. Suau, J.C.S. Perkin I, 1974, 2559.

343

Photochemistry in Synthesis

(98)

Ar = p-tolyl Scheme 32

Irradiation of N,N-dialkyl-0-keto-amides also leads to &hydrogen abstraction and the formation of 4-hydro~ypyrrolidones.~~ Six-membered Rings. The photochemical electrocyclic closure of stilbene to dihydrophenanthrene, followed by oxidation, and the alternative non-oxidative procedure involving cyclization of ortho-halogeno-substituted stilbenes, are well documented procedure^,^^ and have been applied extensively in organic synthesis.'"-f The method has been particularly useful in the synthesis of h e l i ~ e n e s .Further, ~~ optically active helicenes have been obtained by using circularly polarized light66 or by irradiating the precursors in a chiral s01vent.~' The hexatriene to cyclohexadiene cyclization has been used to form ring B in the synthesis of tetracyclin model compounds.68 Irradiation of the acetal (99) in the presence of benzoic acid gave the cyclized product (101),presumably via the enol ether (100) (Scheme 33). A similar photocyclization was also achizved in the

Scheme 33 64 65

66

68

T. Hasegawa and H. Aoyama, J.C.S. Chem. Comm., 1974,743. E. V. Blackburn and C. J. Timmons, Quart. Rev., 1969, 23,482. H. Wynberg, Accounts Chem. Res., 1 9 7 1 , 4 , 6 5 ; R. H. Martin, Angew. Chem. Internat. Edn., 1974, 13, 649; Angew. Chem., 1973,86, 727. A . Moradpour, J. F. Nicoud, G. Balavoine, H. Kagan, and G. Tsoucaris, J. Amer. Chem. Soc., 1971, 93, 2353. W. H. Laarhoven and T. J. H. M. Cuppen, J.C.S. Chem. Comm., 1977,47. D. H. R. Barton, D. L. J. Clive, P. D. Magnus, and G. Smith, J. Chem. SOC. ( C ) ,1971,2193; D. H. R . Barton, P. D. Magnus, and J. I. Okogun, J.C.S. Perkin I, 1972, 1103.

General and Synthetic Methods

344

presence of base by an electron-transfer Apolignans have been obtained by photochemical electrocyclic reactions. Irradiation of a benzene solution of the bis-benzylidenebutyrolactone (102) gave (103) in quantitative yield.70

(102)

(103)

The photolysis of o-vinylbiphenyl compounds gives dihydrophenanthrenes, presumably by electrocyclic cyclization followed by a thermal [1,5]hydrogen shift.71This process has been effectively applied in two closely related syntheses of the anti-leukaemic compound juncusol (106) (Scheme 34). Irradiation of the vinylbiphenyl (104) gave the dihydrophenanthrens (105j which was converted In four steps into juncus01.~*

(105) a; R b; R

= CH20H ( 6 5 % ) = C02Me ( 8 5 % ) iil

Reagents: i, hv, C,H,; ii, 4 steps

Scheme 34

Many heterocyclic analogues of the stilber,e-phenanthrene cyclization have been reported, and the utility of enamide and dienamide photocyclizations has been dealt with in comprehensive reviews.73Only a few selected examples will be mentioned here. h9 70

7'

'* 73

D . H. R. Barton, J. H. Bateson, S. C. Datta, and P. D . Magnus, J.C.S. Perkin Z, 1976, 503. H. G. Heller and P. J. Strydom, J.C.S. Chern. Comm., 1976, 50. S. W. Horgan, D . D . Morgan, and M. Orchin, J. Org. Chem., 1973, 38,3801; P. H. G. op het Veld and W. H. Lasrhoven, J.C.S.Perkin II,1977,268; A. Padwa, C. Doubleday, and A. Mazzu, J. Org. Chem., 19'77, 42, 3271. ( a ) A. S. Kende and D . P. Curran, J. Atner. C-hem. SOC.,1979,101,1857; ( b )E. McDonald and R. T. Martin, Tetrahedron Letters, 1978, 4723. ( a )T. Kametani and K. Fukumoto, Accounts Chem. Res., 1972, 5 , 212; ( b ) I. Ninomiya, Heterocycles, 1974,2, 105; ( c ) G . R. Lenz, Synrhesis, 1978, 489.

Photochemistry in Synthesis

345

The best known example of dienamide photocyclization is in the synthesis of a p ~ r p h i n e sIrradiation .~~ of the (2)-enamide (107; R' = MeO, R2 = X = H) established a photoequilibrium between the ( Z ) - and (E)-isomers. The ( E ) isomer cyclized to a dihydrophenanthrene which in the presence of iodine was oxidized to the aporphine (108; R1 = MeO, R2 = H).746On the other hand irradiation of the enamide (107; R' = R2 = X = H) under non-oxidative conditions led to the dehydroprotoberberine (109; R = H), presumably via the (2)-isomer (Scheme 35).75 Improved yields of aporphines can be obtained by non-oxidative photocyclizations of o-halogeno-enamides to halogeno-substituted dihydrophenanthrenes. These smoothly eliminate the elements of hydrogen halide to give good yields of the desired phenanthrenes. Thus irradiation of the bromo-enamide (107; R' = R2 = MeO, X = Br) in the presence of base gave a better yield of the aporphine (108; R1 = R2 = MeO).76

Scheme 35

Numerous other examples of the dienamide photocyclization reaction in the synthesis of berbine, protoberberine, benzophenanthridine, Amaryllidaceae, and indole alkaloids have been discussed e l ~ e w h e r e . ~ ~ Intramolecular photochemical dehydrohalogenation reactions have featured prominently in h e t e r o ~ y c l i cand ~ ~ carbocyclic synthesis. The novel photocyclization of the enamine (110) was the key reaction in the synthesis of the antileukaemic lignan steganacin (111)(Scheme 36).77This cyclization could have occurred by the SRNlm e c h a n i ~ m . ~ ~ A photochemical Friedel-Crafts-type reaction has been used to construct a six-membered ring in the tricycle (113). Irradiation through pyrex of a benzene solution of the phenylacetylcyclohexene (1 12) in the presence of boron trifluoride etherate gave the cis-octahydrophenanthrone (113) in 87% yield.79 The known anti-Markovnikoff addition of thiyl radicals to double bonds has been utilized in a synthesis of the 3-methylenecepham methyl ester (115) by irradiation of a dilute solution of benzothiazolyldithioazetidinone (114) in acetonitrile (60% yield); irradiation of more concentrated solutions of (114) ( a ) N. C. Yang, G. R. Lenz, and A. Shani, Tetrahedron Letters, 1966,2941; ( b ) M. P. Cava, M. J. Mitchell, S. C. Havlicek, A. Lindert, and R. J. Spangler, J. Crg. Chem., 1970, 35, 175. 7s N. C. Yang, A. Shani, and G . R. Lenz, J. Amer. Chem. SOC.,1966,88,5369. 76 M. P. Cava, P. Stern, and K. Wakisaka, Tetrahedron, 1973,29, 2245. " D. Becker, L. R. Hughes, and R. A. Raphael, J.C.S. Perkin I, 1977, 1674. '' J. F. Bunnett, Accounts Chem. Res., 1978, 11, 413. 79 M. Tada, H. Saiki, K. Miura, and H . Shinozaki, Bull. Chem. SOC.Japan, 1976, 49, 1666. 74

General and Synthetic Methods

346

f-8

r3

0

9

.N

N

hu

___*

NH3 KO'BU 65%

9 steps ___,

Me0

Me0

Me0 (111)

Scheme 36

(114) R1 = PhCHZCO R2 = benzothiazolyl

(113)

favours penam derivatives." Similar cyclizations of thiyl radicals have been used to prepare 4-thia-5P-cholestane derivatives.81

Seuen-membered and Larger Rings. The previously mentioned7' photochemical substitution of an aryl halide by an enolate anion (SRN1reaction) has been effectively utilized in the synthesis of six-, seven-, eight-, and ten-membered rings.82 The most notable 2pplication was to the synthesis of cephalotaxinone (116) (Scheme 37).826 Other workers have used photochemical dehydrohalogenation reactions to prepare related

0 '

I 0

/

0

OMe

OMe (116)

Scheme 37 80 81

82

83 84

Y. Maki and M. Sako, J.C.S. Chem. Comm., 1978,836; J. Amer. Chem. SOC.,1977,99,5091. D. N. Jones, D. A. Lewton, J. D. Msonthi, and R. J. K. Taylor, J.C.S. Perkin I, 1974, 2637. ( a )M. F. Semmelhack and T. M. Barger, J. Org. Chem., 1977,42,1481; ( b )M. F. Semmelhack, B. P. Chong, R. D. Stauffer, T. D. Rogerson, A. Chong, and L. D. Jones, J. Amer. Chem. SOC.,1975,97, 2507. I. Tse and V. Snieckus, J.C.S. Chem. Comm., 1976, 505. H. Iida, Y. Yuasa, and C. Kibayashi, J.C.S. Chem. Comm., 1978, 766.

Photochemistry in Synthesis

347

Many applications of the Witkop photocyclizations5 of N-chloroacetylamides have been reported.s6 The synthesis of 7-oxodesethylcatharanthine(118)in 55% yield, by irradiation of the N-chloroacetylamide (117) in methanol, illustrates this.86c Norrish Type I1 photocyclizations of N-alkylphthalimides (119) to give various tricyclic products have been reviewed.87 0

0

/

IY

H

I

C0,Me

H

(117)

(118)

(119)

The total synthesis of vitamin BI2is arguably the most difficult challenge so far presented to synthetic organic chemists. It is therefore surprising that the application of a photocyclization reaction to a solution of this problem has escaped the attention of photochemistry reviewers. Irradiation of the optically active seco-corrin cadmium complex (120) in methanol gave the corrin (121), isolated as its Corilcomplex, with a stereoselectivity of 95% (Scheme 38). Model

PONMe2

MeO,C CN

C0,Me (121)

Scheme 38

*' 87

0. Yonemitsu, T. Tokuyama, M. Chaykovsky, and B. Witkop, J. Amer. Chem. SOC.,1968,90,776. ( a ) M. Ikeda, K.-I. Hirao, Y. Okuno, and 0.Yonemitsu, Tetrahedron Letters, 1974,1181; ( b )A. Wu and V. Snieckus, ibid.,1975, 2057; (c) R. J. Sundberg and J. D. Bloom, ibid., 1978, 5157. Y. Kanaoka, Accounts Chem. Res., 1 9 7 8 , 1 1 , 4 0 7 .

General and Synthetic Methods

348

studies have indicated that this cyclization occurs through sensitization of (120) by the triplet photoexcited (121). The process involves an allowed antarafacial transfer of hydrogen from ring D to the exocyclic methylene group on ring A, to give a presumed biradical intermediate, which leads to the trans-AID ring junction by a ground-state antarafacial process.88 Ring Expansion Reactions.-The 1,3-acyl shift reaction arising from the direct irradiation of &y-unsaturated ketones” has been utilized to convert the cyclopentenylcyclopentanone (122) into the hydroazulene (123) (Scheme 39).90

Scheme 39

Three-atom ring expansions involving the Norrish Type I conversions of 2cyclopropylcyclohexanone (124; X = CH2, R = H) into cyclononenone (125; X = CHJ (70% yield)” and of the epoxide (124; X = 0, R = H) into the macroiide (125; X = 0) (52% yield) have been reported (Scheme 40).92The related six-atom expansion of (124; X = CH2, R = cyclopropyl) was also a~hieved.’~

The formation of 2-alkoxytetrahydrofuransfrom oxacarbenes by the photolysis of cyclobutanones in alcohol is a well known r e a ~ t i o n . ~ It ‘ . has ~ ~ recently been used as a key step (Scheme 41) in the synthesis of the prostaglandin precursor ( 126).95 ”

A. Eschenrnoser and C. E. Wintner, Science, 1977,196, 1410; A. Eschenmoser, Chem. SOC.Rev., 1976, 5, 377. K. Schaffner, Pure Appl. Chern., 1973,33,329; Tetrahedron, 1976,32,641; K. N. Houk, Chem. Rev., 1976, 76, 1. R. G. Carlson, R. L. Coffin, W. W. Cox, and R. S . Givens, J.C.S. Chem. Comm., 1973, 501; R. L. Coffin, R. S. Givens, and R. G. Carlson, J. Amer. Chem. SOC.,1974, 96, 7554. R. G. Carlson and E. L. Biersmith, Chem. Comm., 1969, 1049. R. G. Carlson, J. H.-A. Huber, and D. E. Henton, J.C.S. Chem. Comm., 1973,223. R. G. Carlson and W. S. Mardis, J. Org. Chem., 1975, 40, 817. D. R. Morton and N. J. Turro, Adu. Phorochem., 1974,9,197; P. Yates and R. 0.Loutfy, Accounts Chem. Res., 1975, 8, 209. N. M. Crossland, S. M. Roberts, and R. F. Newton, J.C.S. Chem. Comm., 1978,661; R. F. Newton, C . C. Howard, D. P. Reynolds, A. H. Wadsworth, N. M. Crossland, and S . M. Roberts, ibid.,p. 662.

’’) yo

y1 y2

93 94

95

349

Photochemistry in Synthesis

0 hv, pyrex --*

MeOH-2.Sdimethylhexa2,4-diene, 33%

Scheme 41

Useful ring expansion reactions occur in the photo-Beckmann rearrangem e n t ~the , ~ photolysis ~ of aromatic N-oxides and pyridinium N - y l i d e ~ and , ~ ~ in the photochemical rearrangement of N-alkylphthalimide~.~~ The photochemical rearrangements of cross-conjugated cyclohexadienones (santonin-type rearrangements) have been applied to many syntheses of natural products.la*C-f Either the perhydroazulene skeleton or the spiro[5,4]cyclodecane skeleton (formally a ring contraction) is obtained. Thus photolysis of the dienone (127) in aqueous acetic acid gave the hydroazulene (128) in 50% yield. This was converted into 4-epi-globulol (129).98 OR the other hand, irradiation of the methoxydienone (130) in glacial acetic acid yielded the ring-contracted compound (131) (89'/0) which was a key intermediate in the synthesis of avetispirene (132) (Scheme 42).99

-2 2 steps

50%

Scheme 42

Ring Contraction Reactions-The photochemical rearrangement of the kojic acid derivative (133) via the postulated intermediate (134) gave in low yield the ring-contracted cyclopentenedione (135) which was reduced in situ to terrein (136) (Scheme 43).loo 96

97 98 99

loo

H. Suginome, Kagaku No Ryoiki, 1976,30,578 (Chem. Abs., 1977,86, 5221h). F. Bellamy and J. Streith, Heterocycfes, 1976,4, 1391; J. Streith, ibid., 1977,6, 2021. D. Caine and J. T. Gupton, J. Org. Chem., 1975, 40, 809. D. Caine, A. A. Boucugnani, S. T. Chao, J. B. Dawson, and P. F. Ingwalson, J. Org. Chem., 1976,41, 1539. D. H. R. Barton and L. A. Hulshof, J.C.S. Perkin I, 1977, 1103.

350

General and Synthetic Methods

NaBH3CN18%

0

Scheme 43

P-Lactams (138; R' = R 2 = alkyl, R3 = Bu'0,CNHNHCO or Me0,C) have been obtained by the photochemical Wolff reaction of the a-diazo-o-keto-ylactams (137; R' = R2 = alkyl)."' The photol'ysis of 2-acylpyrazolidin-3-ones (139; R' = R3 = alkyl, R2 = Ac) gave the p-lactams (138; R 1 = R3 = alkyl, R2 = AcNH) by a ring contraction involving an intramolecular electron-transfer process.1o2

Other Rearrangement Reactions.-In addition to the above-mentioned ring expansion and contraction reactions, miscellaneous rearrangements such as the photochemical [ 1,3] sigmatropic shift have been used in synthesis. An early example was in the synthesis of model corrins; the formation of the vinylogous amide (141) occurred in 50% yield by irradiation of the N-acyl-enamide (140) in c y c l ~ h e x a n e . 3-Acetylcyclohexanone '~~ (143)was similarly obtained by irradiating the vinyl alcohol (142) in benzene.'04 The oxa-di-.rr-methane rearrangement of P, y-unsaturated ketones has been studied e x t e n ~ i v e l y , but ~~'~ has ~ rarely been applied to synthesis. However, a recent application involved the formation of the tricyclic ketone (145) from the enone (144) as a key step in the synthesis of a-santalene (146) (Scheme 44).'05

lo'

lo3

lo'

G. Lowe and D. D. Ridley, J.C.S. Perkin I, 1973,2024; J. R. Hlubucek and G . Lowe, J.C.S. Chem. 1974, 96, 5787. Comm., 1974,419; G. Stork and R. P. Szajewski, J. Amer. Chem. SOC., P. Y. Johnson and C. E. Hatch, J. Org. Chem., 1975, 40, 909, 3502, 3510; P. Y. Johnson, C. E. Hatch, and N. R. Schmuff, J.C.S. Chem. Comm., 1975,725. E. Bertele, H. Boos, J. D. Dunitz,F. Elsinger, A. Eschenmoser, I. Felner, H. P. Gribi, H. Gschwend, E. F. Meyer, M. Pesaro, and R. Scheffold, Angew. Chem. Internat. Edn., 1964, 3, 490; Angew. Chem., 1964,76,393. K. G . Hancock, P. L. Wylie, and J. T. Lau, J. Amer. Chem. SOC.,1977, 99, 1149. S. A. Monti and S. D. Larsen, J. Org. Chem., 1978, 43, 2282.

Photochemistry in Synthesis

351

(140)

The rearrangement of 1-methoxybicyclo-oct-5-en-2-one to bicyclo[3,3,0]octane-2,7-dione is another example of the oxa-di-7-methane reaction.lo6

(144)

(145)

(146)

Scheme 44

The photo-Fries rearrangementlo7has been used in various synthetic reactions. A recent application concerned the synthesis of the mitomycin precursor (148) in high yield from the lactone (147).'08 Finally, reference is made to the efficient photochemical deconjugation of piperidine esters (149) to the endocyclic isomers (150), presumably by a photoenolization reaction."'

3 Ring Opening Reactions Electrocyclic Reactions.-An early contribution to the photochemical electrocyclic ring opening of cyclohexadiene derivatives was in connection with the S. D. Parker and N. A. J. Rogers, Tetrahedron Letters, 1976,4389; K.-I. Hirao, S. Unno, H. Miura, and 0. Yonemitsu, Chem. and Pharm. Bull. (Japan), 1977,25,3354. D. BelluS, Adv. Photochem., 1971,8, 109. D. R. Crump, R. W. Franck, R. Gruska, A. A. Ozorio, M. Pagnotta, G. J. Siuta, and J. G. White, J. Org. Chem., 1977, 42, 105. *09 R. J. Sundberg, L.-S. Lin, and F. X. Smith, J. Org. Chem., 1973, 38, 2558.

lo6

General and Synthetic Methods

352

synthesis of vitamin D.la*llo Similar processes have been used to prepare naturally occurring cyclodecadiene derivatives.'"eb The synthesis of (+)-occidentalol (15 3 ; R' = CMe,OH, R2 = H) illustrates the reaction (Scheme 45)."' Photolysis of the cyclohexadiene (15 1)resulted in conrotatory ring opening to the intermediate (152) which underwent thermal disrotatory cyclization to (153; R' = C02Me, R2 = H) (16%) and its epimer (18%). Bccidentalol was subsequently obtained in two steps.

H

H

R2

Many annulenes have been obtained by photochemical electrocyclic processes.le Thus [lOIannulene was obtained from cis-9,1O-dihydr0naphthalene,"~ and various heteroannulenes have been prepared by very similar procedures.' l 3 Norrish Type I Reactions.-The a-cleavage of cyclic ketones to give unsaturated aldehydes has been applied successfully in several syntheses. Thus, irradiation of the cyclopentanone (154) in benzene gave the unsaturated aldehyde (155) in 77% ~ i e 1 d . l This ' ~ compound was converted in four steps into the dihydroterpenediol (156), a pheromonal secretion of the African Monarch. Photolysis of the bicyclic ketone (157) in methanol gave in 60% yield the cyclobutane (158) which was converted in two steps into optically active grandisol (6).'15 n OH C0,Et

i"*'

0

H

(157) 110

'12

'I3

'lS

(158)

E. Havinga, Experientia, 1973, 29, 1181. A. G . Hortmann, D. S. Daniel, and J. E. Martinelli, J. Org. Chem., 1973, 38, 728. S. Masamune and N. Darby, Accounts Chem. Res., 1972, 5 , 272, A . G . Anastassiou, Accounts Chem. Res., 1972, 5 , 281; 1976, 9, 453; G. Frank and G. Schroder, Chem. Ber., 1975,108,3736; W. Henne, G . Plinke, and G . Schroder, ibid., p. 3753. G . Bidan, J. Kossanyi, V. Meyer, and J.-P. Morizur, Tetrahedron, 1977, 33, 2193. P. D. Hobbs and P. D. Magnus, J. Amer. Chem. SOC.,1976,98,4594.

Photochemistry in Synthesis

353

The photolysis of the bicyclo[2,2,l]heptanone (159) to give the cyclopentene (160) has been used to synthesize the prostaglandin PGCl (161) (Scheme (46).'16 ?THP hw, pyrex MeOH65%

0.

Scheme 46

4 Oxidation Reactions

Singlet Oxygen.-Singlet oxygen reacts with dienes to give endo-peroxides and with alkenes to give allylic hydroperoxides or dioxetan~.'~'The mechanism of the latter reaction is still under investigation. The use of these reactions in natural products synthesis has been comprehensively reviewed,'"-"*' '* and attention will be concentrated on recent work. The antitumour agent crotepoxide (165), also known as futoxide, has been synthesized from the endo-peroxide intermediates (163) and (164), which were obtained from the addition of singlet oxygen to the diene (162) (Scheme 47).'19 A closely related synthesis, involving addition of singlet oxygen to a styrene derivative, has also been reported.'*'

Scheme 47 '16

'I7 '19

N. M. Crossland, S. M. Roberts, R. F. Newton, and C. F. Webb, J.C.S. Chem. Comm., 1978,660; N. M. Crossland, S. M. Roberts, and R. F. Newton, ibid., 1977, 886. R. W. Denny and A. Nickon, Org. Reactions, 1973, 20, 133. G. Ohloff, Pure Appl. Chem., 1975,43,481. M. R. Demuth, P. E. Garrett, and J. D. White, J. Amer. Chem. SOC.,1976,98,634. M. Matsumoto, S. Dobashi, and K. Kuroda, Tetrahedron Letters, 1977, 3361.

General and Synthetic Methods

354

The addition of singlet oxygen to the furanolactone (166) gave a quantitative yield of the pseudo-acids (167) and (168) which were converted into the antitumour compound camptothecin (169) in three steps (Scheme 48).121 Other important uses of the Diels-Alder addition of singlet oxygen to dienes are in the synthesis of cis-l,4-dihydroxycyclopentenefrom cyclopentadiene,'22and in the preparation of analogues of prostaglandin e n d o - p e r 0 ~ i d e . l ~ ~

(167) R', R2 = 0; R3 = H, R4 = OH (168) R' = H, R2 = OH, R3,R4 = O

(166)

kps

I

Scheme 48

The alternative mode of reaction ('ene' reaction) leading to allylic hydroperoxides has been used to convert trimethylsilyl enol ethers (170) into a,& unsaturated ketones (171) (Scheme 49).124 The elegant conversion of the readily available (R)-(+)-pulegone into its enantiomer was also based on an allylic hydroper~xidation.'~~ OSiMe,

-3

0

ii, MeOH

(170)

-78 "C, 7 0/o'

Scheme 49

Enamino-ketones and enamino-lactones have been converted into the corresponding a-dicarbonyl compounds by photo-oxygenation via dioxetan intermediates. 126 Finally, the photo-oxidation of pyrroles has been studied ''I

E. J. Corey, D. N. Crouse, and J. E. Anderson, J. Org. Chem., 1975,40, 2140.

"' C. Kaneko, A. Sugimoto, and S . Tanaka, Synthesis, 1974, 876. 123

lZ5

126

D. J. Coughlin and R. G . Salomon, J. Amer. Chem. SOC., 1977,99,655; W. Adam and H. J . Eggelte, J. Org. Chem., 1977, 42, 3987. E. Friedrich and W. Lutz, Angew. Chem. Znternat. Edn., 1977,16,413; Angew. Chem., 1977,89, 426. H. E. Ensley and R. V. C. Carr, Tetrahedron Letters, 1977, 513. H. H. Wasserman and J. L. Ives, J. Amer. Chem. Soc., 1976,98,7868; J. Org. Chem., 1978,43,3238.

Photochemistry in Synthesis

355

extensively, in connection with approaches to the m i t ~ m y c i n s and ~ * ~as a phototherapeutic treatment of neonatal jaundice.12* Remote Oxidation.-Remote oxidation reactions generally involve intramolecular hydrogen abstraction. The best known example is the Barton reaction (photolysis of nitrite esters).la*b.eOne of the most important applications of this reaction was to the synthesis of aldosterone acetate. The yield of this reaction has been substantially improved (55%) by irradiating the dienone nitrite ester (172) in which the extended conjugation ensures that sufficient separation between C-19 and the llp-oxygen atom exists to suppress functionalization at C-19 in favour of attack at C-18.'29 Another recent application of the Barton reaction occurred in the synthesis of perhydrohistrionicotoxin (175), where the key step was the stereoselective formation of the oxime (174) from the nitrite ester ( 173).l3'

Other striking methods of stereoselective remote functionalization have been d e r n o n ~ t r a t e d . ' ~ For ~ " ~ ~example, irradiation of a benzene solution of the benzophenone acetic acid ester of cholestan-3a-01 (176) gave the A14*15-alkene (177) in 55% ~ i e 1 d . l ~More ~ " recently an alternative procedure, involving the photolysis of a-peracetoxynitriles, has been reported. In a promising process the pregneneperacetoxynitrile (178)was converted by irradiation in benzene into the 18-nitrile (179) in 46% yield.133 12'

12' 129

130 13'

'32 133

T. Kametani, T. Ohsawa, M. Ihara, and K. Fukumoto, J.C.S.Perkin I, 1978,460; F. Z. Basha and R. W. Franck, J. Org. Chem., 1978,43,3415. D . A. Lightner, Photochem. and Photobiol., 1974,19,457; 1977,26,427. D . H. R. Barton, N. K. Basu, M. J. Day, R. H. Hesse, M. M. Pechet, and A . N. Starratt, 1C.S. Perkin I, 1975,2243. E. J. Corey, J. F. Arnett, and G. N. Widiger, J. Amer. Chem. SOC.,1975,97,430. ( a )R. Breslow, Chem. SOC.Reo., 1972,1,553; R. Breslow, S. Baldwin, T. Flechtner, P. Kalicky, S. Liu, and W. Washburn, J. Amer. Chem. Soc., 1973,95,3251;( b )R. Breslow, R. J. Corcoran, B. B. Snider, R. J. Doll, P. L. Khanna, and R. Kaleya, ibid., 1977,99, 905. J. E. Baldwin, A. K. Bhatnagar, and R. W. Harper, Chem. Comm., 1970,659. R. W. Freerksen, W. E. Pabst, M. L. Raggio, S. A. Sherman, R. R. Wroble, and D. S. Watt, J. Amer. Chem. SOC., 1977,99, 1536.

356

General and Synthetic Methods

(178)

(179)

Other Oxidation.-The single example in this section concerns the efficient conversion of pyruvate esters (180) of primary and secondary alcohols into carbonyl compounds by a Norrish Type I1 reaction (Scheme 50).134 0

R' >O

+

MeCHO + C O

Scheme 50

5 Reduction Reactions

Alcohols have been reduced to alkanes by irradiation of their carboxylate esters in aqueous hexamethylph~sphoramide.'~~ A novel photochemical version of the Bamford-Stevens reaction has been used in the synthesis of b"-dehydro-A/D-seco-corrin complexes (183).136 Irradiation of the seco-corrinoid amidrazone (181) in methanol gave the methoxy-derivative (182) which underwent elimination of methanol in base to give (183) (Scheme 51).

6 Photoelimination Reactions The two major photoelimination processes are decarboxylation and nitrogen extrusion. 134

13'

136

R. W. Binkley, J. Org. Chem., 1976,41,3030; R. W. Binkley, D. G. Hehemann, and W. W. Binkley, ibid., 1978, 43, 2573. H. Deshayes, J.-P. Pete, C. Portella, and D. Scholler, J.C.S. Chem. Comm., 1975,439; J.-P. Pete, C. Portella, C. Monneret, J.-C. Florent, and Q. Khuong-Huu, Synthesis, 1977,774. A. Pfaltz, B. Hardegger, P. M. Muller, S. Farooq, B. Krautler, and A. Eschenmoser, Helv. Chim. Acta, 1975, 58, 1444.

357

Photochemistry in Synthesis

,OMe

KOBU'BU'OH

p

h

R

R

=

rings

A, B,

4

+

R

c of seco-corrin

Scheme 51

Decarboxy1ation.-The most important synthetic applications of photochemical decarboxylation reactions have been to the low-temperature formation of benzyne and cyclobutadiene from appropriate precursors. 137 Interesting recent results in this area concern a decarbonylution reaction to form the elusive tetrahedrane skeleton. Irradiation of the cyclopentadienone (184) at low temperature gave the crystalline (m.p. 135 "C) and air-stable tetra-t-butyltetrahedrane (186), presumably by decarbonylation of the intermediate (185) (Scheme 52).138

hv,

ether

+

-100°C

t

0

0

Scheme 52

Extrusion of Nitrogen.-Two important photochemical nitrogen extrusion reactions deserve mention. The first was in the synthesis of the highly strained prismane (188) in low yield by irradiation of the azo-precursor (187) in CD2C12at temperatures above 30 OC.13' The second was in the conversion of the pyrazoline (189), by irradiation in ether;into cyclocopacamphene (190) in good ~ie1d.l~'

N=N

(187) 13'

138

loo

(188)

0. L. Chapman, Pure Appl. Chem., 1974, 40, 511; 0. L. Chapman, C.-C. Chang, J. Kolc, N. R. Rosenquist, and H. Tomioka, J. Amer. Chem. SOC.,1975, 97, 6586; G. Maier, Angew. Chem. Internat. Edn., 1974,13,425; Angew. Chem., 1974,86,491; G. Maier, H.-G. Hartan, and T. Sayrac, Angew. Chem. Internat. Edn., 1976, 15, 226; Angew. Chem., 1976, 88, 252; S. Masarnune, Pure Appl. Chem., 1975,44,861; S . Masamune, Y. Sugihara, K. Morio, and J. E. Bertie, Canad. J. Chem., 1976,54,2679. G. Maier, S. Pfriem, U. Schafer, and R. Matusch, Angew. Chem. Internat. Edn., 1978, 17, 520; Angew. Chem., 1978,90,552. T. J. Katz and N. Acton, J. Amer. Chem. Soc., 1973,9S, 2738. E. Piers, M. B. Geraghty, R. D. Smillie, and M. Soucy, Canad. J. Chem., 1975,53, 2849.

358

General and Synthetic Methods

Other Elimination Reactions.-The Norrish Type I1 dealkoxylation reaction of a-alkoxy-ketones is well known.141A closely related process has been developed to convert alcohols into a1ke11es.I~~ Thus irradiation of the 0-cholesteryl thiobenzoate (191) gave cholesta-3,5-diene (192) in high yield (Scheme 53).

C Ph'

+S

Scheme 53

7 Photosubstitution Reactions

The most useful reactions are aromatic substitution reactions. The SRNlreaction has already been mentioned,78 and comprehensive reviews on other aromatic s u b s t i t ~ t i o n and ' ~ ~ hydroxylation reactions have appeared.144

8 Photochemical Addition Reactions The photosensitized addition of alcohols to a$-unsaturated ketones and 2,3unsaturated sugars has been reviewed.'45 These results paved the way for an interesting synthesis of the biologically active prostaglandin endo-peroxide analogue (195) where R' and R2 are the usual prostaglandin side-chains. The key step was the photo-sensitized addition of methanol to the cyclopentenone PGAz (193) to give the product (194) (Scheme 54).146

143

144 145 146

P. M. Collins, P. Gupta, and R. Iyer, J.C.S. Perkin I, 1972, 1670; J. C. Arnould and J. P. Pete, Tetrahedron, 1975, 31, 815. S. Achmatowicz, D. H. R. Barton, P. D. Magnus, G . A. Poulton, and P.J. West, J.C.S. Perkin I, 1973, 1567; D. H. R. Barton, M. Bolton, P. D. Magnus, K. G. Morathe, G. A. Poulton, and P. J. West, ibid., p. 1574; D. H. R. Barton, M. Bolton, P. D. Magnus, and P. J. West, ibid., p. 1580. J. Cornelisse and E. Havinga, Chem. Rev., 1975,75,353;J. Cornelisse, Pure Appl. Chem., 1975,41, 433; E. Havinga and J. Cornelisse, ibid., 1976,47, 1 . T. Matsuura and K. Omura, Synthesis, 1974, 173. B. Fraser-Reid, Accounts Chem. Res., 1975,8, 192. G. L. Bundy, Tetrahedron Letters, 1975, 1957.

4

Photochemistry in Synthesis

-R' hvMeOH(350nm!

4 steps,

&-sR1

PhZCO, 64%

R2 (193)

hi,

,

I

OH

R'= -CH2-C02H

R2

R2

(194)

(195)

Me

R2=

~

359

OH Scheme 54

9 Photosensitive Protecting Groups The use of photosensitive protecting groups has already been reported in a previous review.'" The most common protecting groups are those which rely on the internal redox reaction of excited o-nitrobenzyl groups.'47 These derivatives have been used as protecting groups for sugars,'48 carbonyl compounds, 14' a m i n o - g r o ~ p s c, ~a ~ r b~o ~ y - g r o u p s and , ~ ~ phosphate ~ esters. 152 Phenacyl groups have played an important role in protecting carboxy-groups. Irradiation of p-methoxyphenacyl benzoate (196) in dioxan resulted in cleavage to give benzoic acid and the ketone (197) in 78% yield (Scheme 55).153 This protecting group has been utilized on a solid-state polymer and more recently in gibberellin PhC02CH2-!!oOMe

dioxan, hv, pyrex 78%

PhC02H

+ Me-C'

O O M e

Amides of 5-bromo-7-nitroindoline and N-acyl-1,2,3,4-tetrahydro-8nitroquinolines have been found to liberate the carboxylic acid cleanly upon irradiation in water or methan01.l~~ Finally, a photochemical method has been reported for converting a thioacetal into the corresponding ketone. The procedure involves irradiating the compound in hexane in the presence of benzophenone and 0 ~ y g e n . l ~ ~ J. A . Barltrop, P. J. Plant, and P. Schofield, Chem. Comm., 1966, 822. U . Zehavi, €3. Arnit, and A. Patchornik, J. Org. Chem., 1972, 37, 2281; P. M. Collins and N. N. Oparaeche, J.C.S. Perkin I, 1975, 1695: 149 J. HCbert and D. Grave!, Canad. J. Chem., 1974,52, 187. €3. Arnit, U . Zehavi, and A. Patchornik, J. Org. Chem., 1974, 39, 192; S. M. Kalbag and R. W. Roeske, J. Amer. Chem. SOC.,1975,97,440. D. H. Rich and S. K. Gurwara, J. Amer. Chem. SOC., 1975,97, 1575. M. Rubinstein, B. Arnit, and A. Patchornik, Tetrahedron Letters, 1975, 1445. 153 J. C. Sheehan and K. Umezawa, J. Org. Chem., 1973,38,3771. 154 S.-S. Wang, J. Org. Chem., 1976,41, 3258. 15' E. P. Serebryakov, L. M. Suslova, and V. F. Kucherov, Tetrahedron, 1978,34, 345. lS6 B. Amit, D. A. Ben-Efrairn, and A . Patchornik, J. Amer, Chem. SOC., 1976,98,843;J.C.S. Perkin I, 1976.57. Is' T. T. Takahashi, C. Y. Nakarnura, and J. Y. Satoh, J.C.S. Chem. Comm., 1977,680. 14'

14'

Reviews on General Synthetic Methods ~

COMPILED BY G. PATTENDEN

1 Introduction The much heralded treatise ‘Comprehensive Organic Chemistry: The Synthesis and Reactions of Organic Compounds’ is a work designed to reflect the current development and achievements of modern organic chemistry. It is published in six volumes: Volume 1. Stereochemistry, Hydrocarbons, Halo Compounds (edited by J. F. Stoddart); Volume 2. Nitrogen Compounds, Carboxylic Acids, Phosphorus Compounds (edited by I. 0. Sutherland); Volume 3. Sulphur, Selenium, Silicon, Boron, Organometallic Compounds (edited by D. Neville Jones); Volume 4. Heterocyclic Compounds (edited by P. G. Sammes); Volume 5. Biological Compounds (edited by E. Haslam); Volume 6. Author, Formula, Subject, Reagent, Reaction Indexes (edited by C. J. Drayton), Pergamon Press, Oxford, 1979.

2 Saturated and Unsaturated Hydrocarbons S. Sarel, ‘Metal-induced Rearrangements and Insertions into Cyclopropyl Olefins’, Accounts Chem. Res., 1978,11, 204. G . Kaupp, ‘Photochemical Rearrangements and Fragmentations of Alkenes and Polyenes’, Angew. Chem. Internat. Edn., 1978, 17, 150. D. M. Piatak and J. Wicha, ‘Various Approaches to the Construction of Aliphatic Side Chains of Steroids and Related Compounds’, Chem. Rev., 1978’78,199. W. S . Wadsworth, ‘Synthetic Applications of Phosphoryl-Stabilised Anions’, Org. Reactions, 1977, 25, 73. L. A. Paquette, ‘The Ramberg-Backlund Rearrangement’, Org. Reactions, 1977, 25, 1. W. Oppolzer and V. Snieckus, ‘Intramolecular Ene Reactions in Organic Synthesis’, Angew. Chem. Internat. Edn., 1978, 17, 476. T. J. Katz, ‘Olefin Metathesis Reaction’, Adu. Organometallic Chem., 1977,16, 283. W. Oppolzer, ‘Intramolecular Cycloaddition Reactions of ortho-Quinodimethanes in Organic Synthesis’, Synthesis, 1978, 793. 3 Amino-acids and Peptides

Y. Izumi, I. Chibata, and T. Itoh, ‘Production and Utilisation of Amino Acids’, Angew. Chem. Internat. Edn., 1978,17, 176. 360

Reviews on General Synthetic Methods

36 1

I. Galpin, ‘Chemical Synthesis of Peptides and Proteins’, Chem. in Britain, 1978, 14, 181. 4 &Lactams A. K. Mukerjee and A. K. Singh, ‘P-Lactams: Retrospect and Prospect’, Tetrahedron, 1978, 34, 1731. 5 Organometallics

General W. A. Herrmann, ‘Organometallic Synthesis with Diazoalkanes’, Angew. Chem. Internat. Edn., 1978, 17, 800. Alkali Metals E . Grovenstein, ‘Skeletal Rearrangements of Organoalkali Metal Compounds’, Angew. Chem. Internat. Edn., 1978,17,313. Cadmium P. R. Jones and P. J. Desio, ‘The Less Familiar Reactions of Organocadmium Reagents’, Chem. Rev., 1978,78,491. Mercury R. C. Larock, ‘Organomercury Compounds in Organic Synthesis’, Angew. Chem. Internat. Edn., 1978, 17, 27. Boron C . F. Lane, ‘Selective Reductions with Borane Complexes’, Aldrichimica Acta, 1977,10, 54. Aluminium H . Yamamoto and H. Nozaki, ‘Selective Reactions with Organoaluminium Compounds’, Angew. Chem. Internat. Edn., 1978,17, 169. Silicon E. W . Colvin, ‘Silicon in Organic Synthesis’, Chem. SUC.Rev., 1978, 7, 15. Phosphorus S. Warren, ‘Organic Synthesis Using the Migrating Functional Groups PhzPO and PhS’, Accounts Chem. Res., 1978, 11,401. Sulphur E. Block, ‘Reactions of Organosulphur Compounds’, Academic Press, New York, 1978. L. Field, ‘Some Developments in Synthetic Organic Sulphur Chemistry Since 1970’, Synthesis, 1978, 713. B. M. Trost, ‘a-Sulphenylated Carbonyl Compounds in Organic Synthesis’, Chem. Rev., 1978,78,363. B. M. Trost, ‘Some Aspects of Organosulphur-Mediated Synthetic Methods’, Accounts Chem. Res., 1978,11,453. S. Sharma, ‘Thiophosgene in Organic Synthesis’, Synthesis, 1978, 803.

362

General and Synthetic Methods

Selenium D. L. J. Clive, ‘Modern Organoselenium Chemistry’, Tetrahedron, 1978, 34, 1049. Cobalt H. Bonnemann, ‘Cobalt-Catalysed Pyridine Synthesis from Alkynes and Nitriles’, Angew. Chem. Internat. Edn., 1978, 17, 505. 6 Carbocycles A. P. Krapcho, ‘Synthesis of Carbocyclic Spiro Compounds via Cycloaddition Routes’, Synthesis, 1978, 77.

7 Natural Product Synthesis R. Rossi, ‘Insect Pheromones; 11. Synthesis of Chiral Components of Insect Pheromones’, Synthesis, 1978, 413.

8 Asymmetric Synthesis D. Valentine and J. W. Scott, ‘Asymmetric Synthesis‘, Synthesis, 1978, 329. A. I. Meyers, ‘Asymmetric Carbon-Carbon Bond Formation from Chiral Oxazolines’, Accounts Chem. Res., 1978,11, 375. 9 Phase Transfer Catalysis G. W. Gokel and W. P. Weber, ‘Phase Transfer Catalysis. General Principles’, J. Chem. Educ., 1978, 54,350. W. P. Weber and G. W. Gokel, ‘Phase Transfer Catalysis. Applications’, J. Chem. Educ., 1978, 54,429.

10 General P. S. Bailey, ‘Ozonation in Organic Chemistry’, Academic Press, New York, 1978. T. L. Ho, ‘Analysis of Synthetic Reactions by the HSAB Principle’, J. Chem. Educ., 1978, 54, 355. P. Caubkre, ‘Complex Bases and Complex Reducing Agents. New Tools in Organic Synthesis’, Topics in Current Chemistry, Springer-Verlag, New York, 1978. G. H. Posner, ‘Organic Reactions at Alumina Surfaces’, Angew Chem. Internat. Edn., 1978, 17,487. G. Manecke and W. Storck, ‘Polymeric Catalysis’, Angew. Chem. Internat. Edn., 1978,17,657. P. Newman, ‘Optical Resolution Procedures for Chemical Compounds, Vol. I, Amines and Related Compounds’, Optical Reso1utio:l Information Centre, Manhattan College, New York, 1978. G. G. Leznoff, ‘The Use of Insoluble Polymer Supports in General Organic Synthesis’, Accounts Chem. Res., 1978,11, 327. Q. Quinkert, ‘Reflections on an Anniversary of Chemical Synthesis’, Angew. Chem. Internat. Edn., 1978, 17,473.

Reviews on General Synthetic Methods

363

11 Miscellaneous M. Hanack, ‘Mechanistic and Preparative Aspects of Vinyl Cation Chemistry’, Angew. Chem. Internat. Edn., 1978, 17, 333. M. Fischer, ‘Industrial Applications of Photochemical Synthesis’, Angew. Chem. Internat. Edn., 1978, 17, 16. K. C. Nicolaou, G. P. Gasic, and W. E. Barnette, ‘Synthesis and Biological Properties of Prostaglandin Endoperoxides, Thromboxanes and Prostacyclins’, Angew. Chem. Internat. Edn., 1978, 17,293. P. Beak and D. B. Reitz, ‘Dipole-Stabilised Carbanions; Novel and Useful Intermediates’, Chem. Rev., 1978, 78, 275. A. J. Fatiadi, ‘New Applications of Malononitrile in Organic Chemistry’, Synthesis, 1978, 165, 241. T. T. Tidwell, ‘Sterically Crowded Organic Molecules: Synthesis, Structure and Properties’, Tetrahedron, 1978, 34, 1855. C. B. Reese, ‘The Chemical Synthesis of Oligo- and Poly-nucleotides by the Phosphotriester Approach’, Tetrahedron, 1978, 34, 3 143.

Author Index Abe, O., 159 Abe, T., 218, 223 Abderhalden, E., 267 Abdulla, R. F., 55 Aben, R. W., 106 Abushanab, E., 96, 328 Achina, K., 2, 128, 326 Achmatowicz, S., 358 Acker, R. D., 271 Ackerman, J. J. H., 75 Ackman, R. G., 102 Acton, N., 357 Adalsteinsson, O., 321 Adam, A., 272 Adam, W., 77, 85, 103, 206, 209, 282, 354 Adams, M. A., 108,206, 270 Adams, W. R., 340 Addadi, L., 327 Adlington, M. G., 3, 50, 218 Adlington, R. M., 93, 205 Agawa, T., 95, 306 Ager, D. J., 68, 218 Ahlbrecht, H., 202 Ahlers, H., 15, 206 Ahmad, I., 200 Aida, T., 105 Aigner, H., 118 Akao, H., 328 Akasaka, T., 105 Akashi, K., 150, 186 Akermark, B., 5, 340 Akhmetov, L. I., 214 Akhtar, M. H., 178 Akiba, M., 342 Akujama, F., 52 Akutagawa, S., 188, 322 Albizati, K. F., 73 Alderweireldt, F. C., 136, 145 Alexakis, A., 26, 132, 259 Alexanian, V., 100 Ali, S. A., 299, 324 Ali, S. M., 330 Allan, R. D., 285 Allen, D. G. 221,266 Allen, R. W., 170 Alper, H., 3, 91, 169, 177, 189 Altman, J., 124 Amato, J. S., 119, 178 Ames, A., 116, 226 Amin, S. G., 87 Amit, B., 359 Amos, R. A., 28, 95, 114 Amouroux, R., 11, 52, 216

Amupitan, J., 58, 200 Anastassiou, A. G., 352 Anciaux, A. J., 193 Andersen, N. H., 235, 249 Anderson, A. G., jun., 302 Anderson, D. R., 245 Anderson, J. E., 354 Anderson, L. C., 69, 76 Anderson, P. S., 289 Anderson, R. C., 62, 96, 325 Ando, W., 15, 66 Andrade, J. G., 87, 88, 103, 173,215 Andres H., 285, 324 Andrus, W. A., 63, 109 Andruszkiewicz, R., 125 Angyal, S. J., 149, 322 Ansell, J. M., 96 Anteunis, M. J. O., 170 Aoyama, H., 340, 343 Apparu, M., 244 Arai, H., 77, 220 Araiyo, H. C., 100 Araki, Y., 336 Arase, A., 153, 210 Araujo, H. C., 282 Arcamene, F., 309 Arco, M. J., 158, 281 Arhrem, A. A., 39 Arison, B. H., 267 Arndt, R. R., 140, 220 Arne, K., 210 Arnett, J. F., 355 Arnold, B. J., 339 Arnold, R. T., 103 Arnould, J. C., 358 Asami, M., 50, 137 Asaoka, M., 83 Ashby, E. C., 2, 11, 49, 135, 155, 185, 207, 214 Aslam, M., 223 Astier, A., 179 Atherton, E., 129 Attanasi, O., 68 Aumann, R., 179 Axen, U., 275 Ayer, D. E., 337 Ayi, A. I., 103 Azuma, S., 331 Baan, G., 240, 320 Baba, N., 137 Baba, Y., 299 Babler, J. H., 67 Bachi, M. D., 307

365

Bachmann, J., 262 Back, T. G., 18, 36, 71, 178, 224 Backlund, S. J., 28, 144, 212, 213 Backvall, J. E., 170 Battig, K., 258, 323, 324 Baddeley, V. G., 296 Baechler, R. D., 157 Baeckstrom, P., 232 Bailey, P. S., 362 Bailey, S. J., 100, 247, 318 Bailey, T. R., 44, 218 Baillargeon, D. J., 40, 147 Baillargeon, M., 133, 201 Bair, K. W., 200, 252 Baird, M. C., 15 Baitz-GBcs, E., 215 Baker, D. C., 44, 175 Baker, R., 262 Bakuzis, M. L. F., 74, 112, 203, 320 Bakuzis, P., 74, 112, 203, 320 Bal, B. S., 150 Balaroine, G., 343 Balasubramanian, R., 244 Baldeman, D., 164 Baldwin, J., 252 Baldwin, J. E., 200, 307, 309, 313,315, 342, 355 Baldwin, J. J., 267 Baldwin, J. M., 286 Baldwin, S., 355 Baldwin, S. W., 38, 96, 98, 332 Balme, G., 20 Bamfield, P., 198 Ban, Y., 189 Bando, K., 42 Bannet, D. M., 16 Banville, J., 69, 200 Barany, G., 131 Bard, A. J., 3 Barelle, M., 244 Barger, T. M., 346 Bargiotti, A., 16 Barltrop, J. A., 359 Barluenga, J., 14, 72, 208, 296 Barnette, W. E., 224, 273, 276, 319, 363 Barone, A. D., 180 Barrett, A. G. M., 2, 93, 146, 160, 205, 207 Barita, M. A., 142, 187

366 Bartlett, P. A., 30, 103, 318 Bartoli, G., 164 Barton, D. H. R., 2, 18, 36, 55, 67, 146, 166, 175, 207, 222, 224, 343, 344, 349, 355, 358 Barton, T. J., 150, 218 Basha, F. Z., 355 Bass, J. D., 330 Basse, W., 109 Basset, J. M., 19 Bassignani, L., 107 Basu, N. K., 355 Bateson, J. H., 344 Batt, D. G., 21, 245 Baudry, D., 19, 188 Baughn, R. L., 321 Bauman, B. A., 130 Bauman, J. I., 62 Baumstark, A. L., 12, 197, 230 Bauslaugh, P. G., 330 Baxter, G. J., 85 Baxter, I., 342 Bayder, A. R., 92 Bayer, E., 328 Baytey, H., 164 Beak, P., 116, 133, 201, 363 Beck, A. K., 205 Beck, J. R., 182 Beck, W., 123 Becker, D., 66, 333, 345 Beckmann, J. C., 96 Beckwith, A. L. J., 322 Begley, M. J., 92 Behr, J.-P., 162 Behrens, V., 283 Bell, A., 74, 220 Bellamy, F., 349 Bellas, D., 233 Bellassoued, M., 209, 235 Belli, A., 283 Belloti, V., 283 Bellus, D., 99, 156, 351 Ben-Efraim, D. A., 359 Ben-Ishai, D., 124 Benoiton, N. L., 128 Bentley, P. H., 311 Beran, P. C., 262 Bergbreiter, D. E., 75, 77, 206 Berger, E., 118 Berger, M. H., 269, 341 Bergman, R. C., 155 Berman, E., 242 Bernad, P., 14, 72, 208 Berney, D., 87 Bernhardt, J. C., 209 Bernheim, M., 170 Bernstein, Z., 124 Bersellini, U., 178 Bertacci, C., 24 Bertele, E., 350 Bertelo, C. A., 128, 321

Author Index Bertie, J. E., 357 Bertrand, M., 20,29 Besse, J. J., 155 Bestmann, H. J., 16 Beukes, M. S., 231 Bewick, A., 120 Bey, P., 123 Bhacca, N. S., 335 Bhatnagar, A. K., 355 Bhatt, M. V., 156 Bickelhaupt, F., 21 Bidan, G., 352 Bierenbaum, R., 13 Bieri, J. H., 303 Biersmith, E. L., 348 Bigler, P., 50 Bilhou, J. L., 19 Biller, S. A., 18, 166 Billiau, F., 122 Binkley, E. S., 297 Binkley, R. W., 356 Binkley, W. W., 356 Birke, A., 272 Bizzarro, F. T., 276 Black, D. St.C., 119, 284 Blackburn, E. V., 343 Blacklock, T. J., 238 Blackman, N. A., 284 Blade-Font, A., 241 Blaschke, G., 328 Blatcher, P., 21, 73, 201, 279 Bloch, R., 72 Block, E., 361 Bloodworth, A. J., 209, 275 Bloom, A., 341 Bloom, J. D., 347 Blum, J., 102 Blumenkopf, T. A., 84, 151 Boar, R. B., 2, 146, 207 Boche, G., 170 Bock, M. G., 119, 318 Boden, R. M., 89 Boeckman, R. K., jun., 22, 100, 106, 257 Boeder, C. W., 28, 192 Boelkins, M. R., 54 Boettger, S., 112 Bogdanowicz, M. J., 38, 113 Boger, D. L., 44, 58, 63, 201, 249,251, 252 Bolster, J., 283 Bolton, M., 358 Bolzoni, L., 272 Bond, F. T., 17, 80 Boniece, J. M., 122 Bonilari, E., 125 Bonnand, B., 230 Bonnemann, H., 362 Bonzougou, Y., 208 Boos, H., 350 Borer, R., 328 Bornmann, W. G., 252 Borremano, F. A. M., 170 Bory, S., 276

Boscacci, A. B., 284 Bosco, M., 208 Bose, H. J. T., 30 Bosnich, B., 128, 185, 326 Botteghi, C., 42 Boucugnani, A. A., 349 Bouffard, F. A., 311, 314 Bourgeois, M. J., 101 Bourgois, J., 304 Bourgois, M., 304 Boxer, M., 279 Boyd, G. V., 92 Boyle, P. J., 101 Bradsher, C. K., 296 Branca, S. J., 204 Branch, C. L., 311 Brandsma, L., 22, 31, 32, 116 Brandt, A., 107 Brandt, E. V., 148 Braun, M., 37, 205 Breitholle, E. G., 323 Breslow, R., 355 Breuer, E., 16 Breuer, S. W., 210 Brewster, A. G., 36, 224 Brich, W., 138, 139, 326 Brich, Z., 180 Bright-Angrand, D., 73 Brinkmeyer, R. S., 31, 49, 193 Brion, F., 184 Britten-Kelly, M. R., 166, 222 Brodsky, N. C., 66 Brookhart, T., 91 Broom, N. J. P., 254 Brown, C. A., 31 Brown, E., 89 Brown, H. C., 49, 134, 210, 212 Brown, J. E., 342 Brown, J. M., 128 Brown, J. R., 253 Brown, R. F. C., 85 Brown, R. T., 295 Brown, R. W., 36 Brunelle, D. J., 268, 316 Brunet, J. J., 49, 135 Bruntrup, G., 22, 76 Brunwin, D. M., 340 Bruylants, A,, 304 Bruza, K. J., 100, 257 Brynes, P. J., 108, 270 Bryson, T. A., 255, 266 Bucciarelli, M., 50 Buchman, O., 102 Buck, H. M., 256 Buckwalter, B. L., 264 Budai, S. I., 39 Buchi, G., 337 Buendia, J., 241 Bullivant, M. J., 232, 339 Buloup, A., 79

Author Index Bundy, G. L., 65, 217, 227, 286,302, 358 Bunnett, J. F., 345 Burger, J. J., 18 Burgoyne, W., 154 Burke, M. C., 72 Burkle, W., 328 Burri, K. F., 100, 318 Buse, C. T., 48, 77 Bushby, R. J., 12 Buss, V., 166 Butler, D., 83 Buyck, L., 229 Cacchi, S., 36 Caccia, G., 42 Caciagli, V., 107 Cadiz, C., 272 Cahiez, G., 26, 132 Caine, D., 87, 90, 204, 264, 323,349 Cainelli, G., 41, 190, 322 Calo, V., 71 Cama, L. D., 311 Cambie, R. C., 42, 72, 155 Cameron, D. W., 246, 342 Campaigne, E., 96, 249 Campbell, C. B., 146 Campbell, H. M., 335 Campbell, J. B., jun., 210 Camps, F., 139 Cane, D. E., 330 CanCvet, J. C., 79, 238 Capka, M., 321 Caporusso, A. M., 24, 137 Cardillo, G., 72 Cardone, R. A., 100, 318 Cargill, R. L., 244, 330, 333 Carlson, R. G., 348 Carlson, R. M., 94 Carlson, S. C., 3, 175 Carpino, L. A., 129, 130 Carr, D. B., 64, 193, 214 Carr, R. V. C., 354 CarriC, R., 284 Carter, J. P., 166 Carter, L. G., 133, 201 Cartwright, D., 288 Caruso, A. J., 22, 114 Casara, P., 126 Casinos, I., 80 Casiraghi, G., 272 Casnati, G., 272 Cassar, L., 117 Catalane, D. B., 160, 168 Catellani, M., 196 Caubere, P., 49, 135, 362 Cava, M. P., 345 Cazes, B., 27, 207 Ceccherelli, P., 106 CerC, V., 158, 281, 282 Chakrabarti, J. K., 119 Chaloner, P. A,, 128 Chamberlin, A. R., 17, 80

367 Chambers, D., 42 Chan, T. H., 1, 11, 15, 23, 27, 52, 111, 216, 222 Chan, W. H., 15, 100, 151 Chandler, J. H., 28, 70 Chandrasekaran, S., 211, 227, 313 Chandrasekhar, S., 244 Chang, C.-C., 357 Chang, V. S., 39, 76, 322 Chang, Y.-H., 65, 230,289 Chantegrel, B., 93 Chao, S. T., 349 Chao, Y., 162 Chapdelaine, M. J., 259 Chapman, 0. L., 340, 341, 357 Chaquin, P., 341 Charlton, J. L., 337 Charubala, R., 119 Chauvette, R. R., 85 Chaves de Neves, H. J., 117 Chaykovsky, M., 347 Cheek, V. I., 98 Chen, C. G., 340 Chen, S., 118 Chen, S. M. L., 11, 205 Chen, T. B. R. A., 18 Chen, W. Y., 100, 318 Cherry, P. C., 311 Chiba, K., 189 Chibata, I., 360 Chittattu, G., 3, 19, 69, 146, 147,224,225,237 Chiu, I.-C., 341 Chiusoli, G. P., 178, 196 Chong, A., 346 Chong, B. P., 346 Chong, Y. H., 101 Chou, S. K., 194 Chou, T., 42, 263 Chou, T.-S., 209 Chow, F., 224 Christen, P., 50 Christensen, B. G., 311, 314 Christidis, Y., 124 Christie, B., 134 Christie, M. A., 307, 309, 315 Christy, M. E., 289 Chu, J. Y. C., 53 Chuit, C., 72, 204 Chys, J., 173, 179 Cistone, F., 154 Claesson, A., 28, 191 Claeys, M., 88 Clardy, J., 88, 341 Clark, G. W., 325 Clausen, K., 117 Clinet, J. C., 56 Clive, D. L. J., 1, 3, 19, 37, 69, 86, 139, 146, 147, 224, 225, 237, 289, 322, 343, 362 Clough, J. M., 34

Coffin, R. L., 348 Coghlan, M. J., 67 Cohen, S., 339 Cohen, T., 40, 67, 69, 115, 206, 320 Coll, J., 139 Collins, P. M., 358, 359 Collins, P. W., 205 Collman, J. P., 62 Collum, D. B., 118 Colonna, S., 50, 63, 138, 268 Colton, C. D., 289 Coloin, E. W., 1, 166, 203, 322, 361 Comins, D. L., 79, 102, 132, 207 Compere, E. L., jun., 51, 77 Condom, R., 103 Confalone, P. N., 323 Conia, J. M., 54, 64, 67, 110 Conn, R. S. E., 10, 216 Conrad, P. C., 56, 202 Cook, J. M., 244 Cook, W. J., 321 Cooke, F., 65, 217, 227 Cookson, R. C., 56, 59, 148, 205, 248 Cooleson, R. C., 262 Cooper, J. L., 254, 257 Cooper, R. D. G., 308,315 Copeland, A. H., 262 Corbel, B., 56, 234 Corbin, N. C., 46 Corcoran, R. J., 355 Corey, E. J., 5, 9, 44, 58, 63, 71, 79, 119, 175, 201, 227, 249, 251, 252, 268, 273, 313, 316, 318, 327, 330, 354,355 Corkins, H. G., 18 Cornelisse, J., 358 Cornils, B., 295 Cortese, N. A., 62, 184 Couffignal, R., 41 Coughlin, D. J., 354 Courtheyn, D., 90 Cousse, H., 230 Coutrot, P., 51, 80, 266 Cowling, A. P., 108, 299 Cox, J. L., 160, 168 Cox, W. W., 348 CrabbC, P., 64, 340 Cragg, G. M. L., 1 Craig, T., 91 Cram, D. J., 127, 158, 162, 328 Cram, J. M., 158 Craveiro, A. A., 264 Creary, X., 72 Creaser, I. I., 123 Crimmin, M. T., 83, 96, 98 Crombie, L., 26, 227 Crossland, N. M., 240, 348, 353

368 Crouse, D. N., 354 Crumbie, R. L., 50 Crump, D. R., 351 Cudd, M. A., 209 Cuffe, J., 227 Cullen, W. R., 128 Cupas, C. A., 182 Cupper, T. J. H. M., 327, 343 Curran, D. P., 250, 344 Current, S., 225 Currie, J. K., 91, 189 Curtis, N. J., 19, 147 Cussans, N. J., 224 Curigny, T., 48, 66, 69, 75 Czarny, M., 112 Dabrowski, B., 119 Dalessandro, J., 154 Daley, S. K., 157 Dallatomasma, F., 196 Dalton, J. R., 244, 333 Dang, H. P., 6, 7, 145, 192, 196, 208 Danheiser, R. L., 227, 313 Daniel, D. S., 352 Daniewski, W. M., 67, 69, 206 Daniil, D., 180 Danishefsky, S., 74, 242, 246, 247 Dao, L. H., 257 Darby, N., 352 Darlington, W. H., 5 Datta, S. C., 344 D’Auria, M., 242 David, G., 242 Davidovich, Y. A., 119 Davidson, A. H., 74, 220 Davis, B. R., 208 Davis, R. C., 43 Dawson, J. R., 229, 349 Day, M. J., 355 Dean, J. W., 40, 236 Deardorff, D. A., 288 de Boer, T. J., 136 de Brouwer, R. J., 256 De Buych, L., 90, 173, 179 Decasare, J. M., 56, 234 De Clercq, P., 93, 334 Decorzant, R., 242 Degani, I., 83 de Groot, Ae., 97, 246 de Haan, J. W., 256 Dehm, D., 91 Dehmlow, E. V., 53, 77 de Jong, F., 127, 162 De Keukeleire, D., 88, 334 De Kimpe, N., 90, 173, 179 del Fierro, J., 103 Delpech, B., 304 de Mayo, M., 134 de Mayo, P., 46, 49, 330, 332, 337, 342 De Meijere, A., 4 Demuth, M., 217

Author Index Demuth, M. R., 353 de Nie-Sarink, M. J., 123 Denis, J. N., 225, 231 Denny, D. B., 101 Denny, R. W., 353 Deol, B. S., 50 des Abbayes, H., 79, 91, 189 Desai, S. R., 221, 250 Descotes, G., 128 Deshayes, H., 2, 356 de Silva, S. O., 121, 200, 252 Desio, P. J., 361 Detellier, C., 128 Detty, M. R., 226 Devaprabhakara, D., 21 1 Devos, A., 232 Devos, M. J., 231 de Waard, E. R., 18 Dewhirst, K. C., 272 deWolf, W. H., 21 Dhal, R., 89 Dhawan, K. L., 69, 200 Diaz, S., 272 DiBello, N., 71 Dickerson, J. E., 81 Dickson, L., 122 Didier, P., 85 Dietsche, T. J., 5, 113 Digenis, G. A., 118 Dijkink, J., 257 Dilling, W. L., 329 Dimsdale, M. J., 240 Dirnbaum, D., 333 Disselnkotter, H., 33 Dittman, W. R., jun, 3, 50, 218 Divakaruni, R., 85 Djerassi, C., 102, 313 Dobashi, S., 353 Dolak, T. M., 266 Dolbier, W. R., 235 Doldouras, G. A., 4 Doleschall, G., 43 Doll, R. J., 355 Domeier, L. A., 123, 162 Doty, J. K., 31 Dou, H. J. M., 173 Doubleday, C., 344 Doughty, D. H., 191 Dourtoglou, V., 118 Doutheau, A., 20 Doyle, J. E., 119 Doyle, M. P., 15, 54 Drabowicz, J., 158, 224 Dreiding, A. S., 91 Drewes, H. R., 168 Driessen-Engels, J. M. G., 256 Driggs, R. J., 209 Drouin, J., 64 Dubois, J. E., 19, 208 Dubs, P., 242 Duggan, A. J., 108, 109, 206, 270

Duhamel, L., 73, 127 Dumont, W., 15, 44, 142, 224,225 Dunham, L. L., 330 Dunitz, J. D., 350Duong, T., 322 Durst, T., 56 Dux, F., 154 Dyke, S. F., 123 Earnshaw, C., 74, 220 Earp, S. E., 122 Eastwood, F. W., 85 Eaton, P. E., 330, 332 Eberlein, T. H., 160, 168 Echigo, Y., 41, 52, 153 Echsler, K.-J., 206 Eckert, H., 131 Eckes, L., 153 Eckrich, T. M., 123 Edwards, H. N., 46 Edwards, M., 53, 215 Eggelte, H. J., 209, 282, 354 Eguchi, S., 280, 305 Ehlers, C., 231 Ehlers, J., 283 Eian, G. L., 341 Eibach, F., 18 Eichenauer, H., 49 Eichwald, E., 267 Eisch, J. J., 216 Eisele, G., 170 Eissenstat, M. A., 70, 203 Eiter, K., 33 Eldridge, J. M., 83 Eleijn, H., 172 Elkik, E., 103 Elliott, R. C., 54 Ellis, A. I., 85 Elsinger, F., 350 Elvidge, J. A., 80 Emoto, S., 268, 325, 326 Encarnacion, L. A., 77, 206 Enders, D., 49, 71, 79 Engler, D. A., 106 Ensley, H. E., 327, 354 Entwhistle, I. D., 176 Ephritikhine, M., 17, 188 Erhardt, J., 269, 341 Ernest, I., 314 Ernst, L., 312 Erwin, R. W., 61 Eschenmoser, A., 300, 348, 350, 356 Espie, J. C., 284 Esser, F., 130 Estreicher, H., 175 Etheredge, S. J., 246 Evans, D. A., 40, 44, 124, 147, 203, 260, 323 Everhardus, R. H., 22, 28, 32 Fahrni, H. P., 117 Falci, K. J., 342

Author Index Falck, J. R., 268, 316 Fallis, A. G., 323 Farkas, L. V., 160, 168 Farney, R. F., 116 Farooq, S., 356 Farrall, M. J., 36, 187, 321 Fatiadi, A. J., 363 Fara, A., 158, 281, 282 Fedoryhski, M., 104, 160, 227 Feichtinger, H., 295 Feit, B. A., 204 Felix, A. M., 131, 185 Felkin, H., 19, 188 Fell, E., 130 Fellows, C. A., 91 Felner, I., 350 Feringa, D., 12 Ferraz, H. M. C., 95, 225 Ferreira, D., 166, 222 Fetell, A. J., 175 Feuer, H., 175 Feutrill, G. I., 246 Fiandanese, V., 10 Fick, H. G., 123 Fick, H.-H., 77, 85, 206 Field, G. F., 276 Field, L., 157, 361 Fifolt, M. J., 175 Filliatre, C., 101 Finke, R. G., 62 Firouzabadi, H., 36, 187 Fischer, H., 233 Fischer, M., 313, 363 Flahaut, J., 145 Flechtner, T., 355 Fleet, G. W. J., 41, 183 Fleming, I., 68, 218, 245, 330 Fleming, M. P., 12, 52, 54 Fletcher, S. R., 306 Florent, J.-C., 356 Floyd, D., 9, 119, 318 Floyd, M. B., 241 Floyd, W. C., 107 Fochi, R., 83 Foglio, M., 309 Forbes, I., 200, 252 Fornasier, R., 50, 138, 268, 326 Forni, A., 50 Forsch, R. A., 249 Fox, H., 129 Franceschi, G., 307, 309 Franck, R. W., 342, 351, 355 Franck-Neumann, M., 184 Frangin, Y., 209, 235 Frank, G., 352 Frank, H., 328 Franke, G. Th., 21 Fraser, R. R., 69, 200 Fraser-Reid, B., 62, 96, 325, 358 Frazee, W. J., 38, 113 FrCchet, J. M. J., 36, 187, 321 Freerksen, R. W., 355

369 Friedrich, E., 49, 354 Fristad, W. E., 44, 218 Fritz, H., 117 Fritzen, E., 28 Fritzen, E. L., jun., 66 Frobese, A. S., 87, 90, 204, 323 Fry, A. J., 73, 271 Fry, J. L., 3, 50, 218 Fryzuk, M. D., 128, 185, 326 Fu, W. Y., 269, 279, 341 Fuchita, F., 221 Fuchita, T., 13, 70, 170 Fuchs, P. L., 56, 202 Fiizesi, L., 104, 223 Fugiel, R. A., 106 Fuhr, K. H., 5 5 Fuji, K., 67 Fujimoto, F., 75 Fujinami, T., 179 Fujita, E., 37, 41, 67, 85, 107, 134,215,222, 320 Fujita, J., 128 Fujita, T., 97 Fujita, Y., 60, 114, 147 Fujiwara, Y., 13, 52 Fukatsu, S., 124 Fukomoto, K., 291 Fukuda, H., 101 Fukumoto, K., 258, 323, 344, 355 Fukunager, K., 304 Fukuyama, T., 316 Fuller, C. J., 41, 183 Fullerton, T. J., 5 , 113 Fulpius, B. W., 131 Fung, N. Y. M., 49, 134 Furukawa, M., 127 Furukawa, N., 105, 181 Gabel, R., 82, 200 Gaeta, F. C. A., 127, 162 Gains, L. H., 288 Gais, H.-J., 114, 117 Gakis, N., 338 Galakatos, N. G., 104 Galledou, B. S., 29 Galliani, G., 307 Galpin, I., 361 Gammill, R. B., 246 Gandhi, C. S., 112 Gandour, R. D., 161 Ganem, B., 21, 111, 118, 245, 268 Gange, D., 269 Gaoni, Y., 57, 236 Gapinski, R. E., 115 Garbers, C. F., 231 Garland, R. B., 245 Gamier, F., 19 Garrett, P. E., 353 Garza, 0. T., 235 Gasc, M. B., 169 Gasic, G. P., 273, 363

Gasperoni, S., 68 Gassman, P. G., 67, 168, 172, 218 Gastinger, R. G., 31 Gatehouse, B. M., 85 Gatrone, R. C., 299 Gaudemar, M., 209,235 Gausing, W., 207 Gawley, R. E., 332 Gedge, D. R., 39, 92, 237 Geetha, K. Y., 244 Gelan, J., 170 Gelbard, G., 128 Gelin, S., 92, 93 Gemal, A. L., 66 Gene, R. J., 123 Gender, W. J., 40, 236 Geraghty, M. B., 357 Gerdes, J. M., 84, 322 Geresh, S., 128 Gerlach, H., 115, 323 Getman, D., 238 Ghaderi, E., 36, 187 Ghozland, F., 64 Giacomelli, G., 24, 31, 137, 196, 214 Giam, C. S., 200 Giles, R. G. F., 342 Gilgen, P., 338 Gilkerson, T., 176 Gillespie, R. J., 227 Gillick, J. A., 62 Ginsburg, G. S., 271 Giordano, C., 117, 283 Giraud, M., 81 Givens, R. S., 348 Gladiali, S., 42 Gladysz, J. A., 4, 157 Glas, J. D., 129 Glaser, R., 128 Glass, R. S., 152, 248, 288 Gleim, R. D., 253 Goddard, R., 76 Godefroi, E. F., 256 Godel, T., 233, 324, 332 Godleski, S. A., 247, 322 Goel, A. B., 11, 49, 135, 185, 207 Gokel, G. W., 127, 162, 321, 362 Goldberg, O., 307 Goldhill, J., 218 Golding, B. T., 340 Goldsmith, B., 154 Gombatz, K., 242 Gombos-Visky, Z., 215 Gompper, R., 105 Goodbrand, H. B., 275 Gopalan, B., 227, 313 Gopalan R., 59, 148 Gore, J., 20, 32 Gosselin, P., 116, 207 Gosteli, J., 314

370 Goto, S., 13, 329 Gould, S. J., 200 Gradzinkas, C. V., 11 Grafing, R., 22 Graeme, J. N., 328 Graff, Y., 79, 238 Grant, C. B., 177 Gras, J. L., 29, 57, 227, 313 Grasiecki, A., 205 Gravel, D., 359 Gravesbock, M. B., 255 Grayson, J. I., 21, 320 Grayston, M. W., 12 Green, F. R., 30, 318 Greene, A., 340 Greengrass, C. W., 314 Greenlee, M. L., 66 Greenlee, W. J., 100, 124, 317 Greer, S., 210 Grenter, H., 233 Grethe, G., 291, 295 Gribble, A. D., 262 Gribble, G. W., 169 Gribi, H. P., 350 Grieco, P. A., 19, 65, 86, 115, 188,226,236,265 Grierson, J. R., 47 Griesbaum, K., 102 Griffin, G. W., 338 Griffiths, P. G., 246 Grigg, R., 286 Grimaldi, J., 98 Grobel, B.-T., 205 Groen, M. B., 255 Groenewegen, P., 46 Gross, A., 307 Gross, B., 118 Grovenstein, E., 361 Gruber, J. M., 66, 106 Grubmiiller, B., 260 Grudzinskas, C. V., 77, 205 Grudzinski, Z., 97 Grugel, C., 53, 150 Gruntz, U., 181 Gruska, R., 351 Grzybowska, J., 125 Gschwend, H. W., 204, 323, 350 Guaciaro, M. A., 60 Gualtieri, J. A., 276 Guedj, R., 103 Gueldner, R. C., 330 Giinther, H., 116 GuettC, J.-P., 106 Guggisberg, A., 119 GuibC-Jampel, E., 130 Guindon, Y., 317 Guittet, E., 20 Gunther, W. H. H., 53 Gupta, B. G. B., 157, 221 Gupta, P., 358 Gupta, P. K., 305 Gupta, S. K., 210

Author Index Gupton, J. F., 349 Gurwara, S. K., 359 Gutzwiller, J., 291, 292 Haga, S., 214 Hagedorn, A. A., 254 Hagen, J. P., 280 Hagiwara, D., 118 Hagmann, W. K., 269, 341 Halazy, S., 225 Hall, D. R., 340 Hamada, Y., 104 Hamberg, M., 273 Hamelin, J., 286 Hamity, M., 83 Hammond, M. L., 33 Hamsen, A., 206 Hanack, M., 363 Hanack, N., 153 Hanafusa, T., 232 Hanaki, K., 128 Hancock, J. E. H., 104 Hancock, K. G., 350 Hanessian, S., 16, 317 Hansen, H.-J., 338 Hansen, R. T., 64, 214 Hansson, A.-T., 63 Hara, S., 75, 213 Harada, K., 127, 326 Harada, T., 106, 117 Harayama, T., 242 Hardee, D. D., 330 Hardegger, B., 356 Harding, K. E., 254, 257 Harding, P. J. C., 41, 183 Harel, Z., 333 Harirchian, B., 32, 223, 247 Harkiss, D., 129 Harms, R., 202 Harper, R. W., 355 Harpp, D. N., 27, 52, 117, 222 Harris, S. J., 33 Harris, T. M., 121 Hart, D. J., 260 Hartan, G., 357 Hartenstein, J., 322 Hartke, K., 282 Hartner, F. W., 159, 321 Hartz, G., 76 Haruta, J., 130 Harwood, L. M., 253 Hasan, S. K., 157 Hasegawa, T., 340, 343 Hasen, R. T., 193 Hashiguchi, S., 99 Hashimoto, H., 30, 40, 52, 22 1 Hashimoto, K., 34, 66, 69, 140 Hashimo,.o,M., 309 Hashimoto, S., 47, 48 Hashimoto, S.-I., 180 Hashizume, A., 42, 203

Haslanger, M. F., 268, 316 Haslinger, E., 123 Hassel, T., 122, 168, 201 Hassner, A., 96, 100, 233 Hata, T., 42 Hatancka, N., 238 Hatayama, Y., 68 Hatch, C. E., 350 Hatfield, G. L., 152, 218 Hauck, A. E., 200 Hauptmann, H., 58 Hausberg, H. H., 126, 327 Hauser, F. M., 254 Havens, J. L., 142, 187 Havinga, E., 352, 358 Havlicek, S. C., 345 Hayakawa, Y., 5, 73, 234, 261, 299 Hayama, N., 154 Hayami, J., 111 Hayami, J.-T., 172, 206 Hayashi, M., 151 Hayashi, T., 5, 15, 152 Hayward, R. C., 72 Heathcock, C. H., 48, 77, 112,297 HCbert, J., 359 Heck, R. F., 62, 81, 184 Hedin, P. A., 330 Hegedus, L. S., 5 Hehemann, D. G., 356 Heidelberger, C., 119 Heilmann, S. M., 67, 172 Heiner, E. P., 131, 185 Heimgartner, H., 248, 303, 338 Heinrich, G. R., 100, 257 Heinzer, F., 300 Heitzer, H., 273 Helgeson, R. C., 127, 162 Heller, H. G., 344 Helmick, L. S., 116 Helquist, P., 9, 63, 111, 142, 208,237 Helvesti, L., 15 Henderson, T., 291 Henery-Logan, K. R., 340 Henne, W., 352 Henning, R., 74, 203 Hennion, G. F.,28, 194 Hennsen, G., 282 Henton, D. E., 348 Herbert, R. B., 299 Hernandez, O., 274, 325 Herold, T., 144, 211 Herr, D., 73 Herranz, E., 166, 186 Herrmann, W. A., 361 Herron, D. K., 306 Herschied, J. D. M., 124, 176 Herzog, J. D., 248 Hesse, M., 119 Hesse, R. H., 355 Hettrich, G., 130

37 1

Author Index Hevesi, L., 142, 224, 225 Hewson, A. T., 39, 221, 235 Hibino, S., 44 Hicks, D. R., 62 Hicks, T. A., 119 Hiemstra, H., 63 Hikino, H., 332 Hillstrom, W. W., 93 Himbert, G., 220 Hiner, S., 247 Hioki, T., 280 Hirabayashi, Y., 39, 226 Hirako, Y., 79 Hirama, M., 242 Hirao, K.-I., 347, 351 Hirao, T., 68, 187 Hirashima, T., 164 Hirata, Y., 13 Hirotsu, K., 96, 258 Hixson, S. S., 339 Hiyama, T., 57, 74, 203, 204, 236 Hlubucek, J. R., 350 Ho, T. L., 84, 362 Hobbs, P. D., 352 Hodder, D. J., 246 Hodes, H. D., 198 Hodgkinson, L. C., 253 Hofle, G., 100 Hoffman, D. H., 162, 328 Hoffmann, R. W., 144,211 Hojo, K., 37 Holbert, G. W., 268 Holden, R. W., 2 Holick, W., 314 Hoobler, M. A., 75 Hooz, J., 55, 212 Hopf, B., 116 Hopkinson, A. C., 257 Hoppe, I., 126, 327 Horgan, S. W., 344 Hori, T., 141, 152, 224 Horiike, T., 172 Horne, D. A., 155, 213 Horner, L., 138, 139, 326 Hortmann, A. G., 352 Hoshi, N., 78,206 Hoshino, T., 65 Hoskin, D. H., 217 Hosomi, A., 40, 69, 143, 217 Hotta, Y., 52 Hotten, T. M., 119 Houghten, R. A., 119 Houk, K. N., 348 House, H. O., 46, 63, 251 Howard, C. C., 97, 240, 348 Howe, R. S., 160, 168 Hoye, T. R., 22, 88, 114 Hoz, T., 12 Huang, S. L., 36 Hubbard, J. L., 134, 212 Hubbard, J. S., 121 Huber, J. H.-A., 348 Hubert, A. J., 193

Hudrlik, P. F., 46 Hudson, P. B., 325 Hudspeth, J. P., 237 Hiigel, H., 220 Huet, F., 67 Hug, E., 256 Hug, P., 117 Hug, R. P., 53, 215 Huggins, M.-A., 336 Hughes, L. R., 345 Hughes, W. B., 19 Hui, R. A. H. F., 36,224 Hulshof, L. A., 349 Hummelen, J. C., 268, 326 Humphreys, D. J., 85 Hunt, D. A., 296 Hunt, E., 311 Hunter, D. H., 83 Hurni, B., 117 Hurst, K. M., 203 Hutchings, S. D., 276 Hutchins, R. O., 70, 134, 154, 169, 170, 213,321 Ibata, T., 54 Ichihara, A,, 331 Ichikawa, K., 67 Ichikizaki, I., 130 Ichimoto, I., 124 Ignatova, E., 48, 75 Ihara, M., 291, 355 Ihara, Y., 131 Iida, H., 120, 346 Iida, T., 130 Iitaka, Y., 128 Ikeda, I., 53, 159, 171 Ikeda, M., 155, 159, 347 Ikeda, Y., 65, 175 Ikegami, S., 276 Ikeno, M., 66 Ikezaki, M., 168 Ikota, N., 111 Imagawa, T., 86 Imai, H., 128, 321 Imanishi, T., 137 Imbeaux-Oudotte, M., 103 Ingwalson, P. F., 349 Innis, C., 49 Inokawa, S., 154 Inomata, K., 101 Inoue, T., 48, 105, 217 Inui, A., 129 Ipach, I., 104, 175 Ippen, J., 247 Irie, H., 251 Isako, T., 232 Iseli, R., SO Ishida, M., 306 Ishido, Y., 336 Ishihara, H., 39, 226 Ishikawa, H., 155 Ishikawa, K., 338 Ishikawa, N., 51, 78, 204, 206 Ishikawa, R., 13, 52

Ishino, Y., 164 Ishizumi, K., 268 Isied, S. S., 129 Isoe, S., 329 Isono, N., 129 Ito, H., 130 It& S., 261 Ito, Y., 68, 187 Itoh, M., 102, 105, 118, 211, 235 Itoh, N., 168 Itoh, T., 360 Ives, J. L., 93, 354 Iwai, K., 321 Iwakuma, T., 168 Iwamoto, H., 117 Iwasa, A. B., 70, 170, 221 Iyer, R., 358 Izawa, T., 41, 98 Izumi, Y., 30, 52, 106, 221, 360 Jackman, D. E., 314 Jackmann, L. M., 341 Jackobson, R. M., 102 Jackson, D. K., 320 Jacob, B., 210 Jacobi, P. A., 91 Jacobson, S. E., 97, 187 Jager, V., 166 Jagdmann, G. E., jun., 165 Jahngen, E. G. E., jun., 83 Jakubke, H.-D., 118 James, B. R., 62, 136, 184 Janitschke, L., 312 Jansen, B. J. M., 246 Jarreau, F.-X., 119 Jarvis, J. A. J., 100, 247, 318 Jasinski, J. M., 169 Jeffery, E. A., 123 Jenet, J. P., 322 Jenkins, R., 65 Jensen, F. R., 84 Jensen, H., 124 Jessup, P. J., 297 Jick, B. S., 157 Jigajinni, V. B., 213 Jindo, Y., 152 Jirieny, J., 67 Johannson, N. G., 340 Johansen, O., 123 John, K. C., 103, 173, 215 Johnson, C. R., 18 Johnson, P. Y., 350 Johnson, R. A., 275 Johnson, R. W., 31 Johnson, S. J., 208 Johnson, W. S., 255 Johnston, D. B. R., 311, 314 Johnston, J., 37, 226 Johnstone, R. A. W., 41, 176, 213 Jolly, P. W., 76 Jones, D. N., 346

372 Jones, J. R., 80 Jones, L. D., 346 Jones, P. R., 361 Jones, W. D., 155 Jonkers, F. L., 149 Jordan, A., 155, 213 Jose, F., 308, 315 Joucla, M., 286 Joukhadar, L., 2, 146,207 Joussen, R., 15, 206 Julia, B., 207 Julia, S., 20, 21, 27 Jung, C. J., 205 Jung, M. E., 36, 55, 84, 149, 151, 152, 169, 218,237 Jurlina, J. L., 72 Kabalka, G. W., 28, 70, 214 Kabbe, H. J., 273 Kaberia, F., 82 Kabore, I. Z., 180 Kagan, H., 343 Kagan, H. B., 128 Kagawa, S., 331 Kaito, M., 23, 198 Kaji, A., 42, 94, 95, 101, 111, 206 Kaji, K., 34, 140 Kakiuchi, H., 155, 159 Kakui, T., 132, 152, 217 Kalbacher, H., 129 Kalbag, S. M., 359 Kaleya, R., 355 Kalicky, P., 355 Kalir, A., 164 Kallenberg, H., 46 Kalo, J., 66 Kalyanasundaram, S. K., 2, 15 Kameili, Z. H., 174 Kametani, T., 258, 291, 323, 344,355 Kamigata, N., 338 Kamiya, T., 309 Kanakura, A., 74, 203 Kanaoka, M., 130 Kanaoka, Y., 303, 347 Kandasamy, D., 154 Kaneko, C., 354 Kaneko, K., 37, 107, 222, 320 Kano, S., 44, 265 Kantardjiew, I., 16 Kaplan, L. J., 127, 162 Kapoor, V. M., 49 Karady, S., 119, 178 Karas, L. J., 13 Karras, M., 10, 216 Karrenbrock, F., 108 Kashimura, S., 14, 52, 230 Kashiwabara, K., 128 Kasina, S., 85 Kasuga, K., 98, 99 Katada, T., 116 Katakawa, J., 251 Kataoka, F., 12, 52

Author Index Kataoka, Y., 127 Kato, S., 116 Kato, T., 261 Katoh, N., 107 Katritzky, A. R., 181 Katz, T. J., 19, 357, 360 Katzenellenbogen, J. A., 28, 95, 114 Kauffman, T., 15, 52, 206 Kaupp, G., 1, 360 Kawabata, K., 37, 41, 107, 134, 215, 222 Kawai, N., 82, 126 Kawajima, I., 224 Kawakami, Y., 65, 160 Kawakima, Y., 86 Kawamoto, I., 239, 319 Kawanisi, M., 86 Kawata, K., 29 Kay, I. T., 306 Keana, J. F. W., 101 Keck, G. E., 227, 313 Kees, K. L., 12, 52 Keinan, E., 15 Kellogg, R. M., 283 Kemp, J., 286 Kende, A. S., 41, 250, 344 Keng, G. S., 116 Kennedy, J. J., 101 Keul, H., 102 Keumi, T., 101 Khalil, H., 275 Khan, J. A., 209, 275 Khanna, P. L., 355 Khatri, H. N., 173 Khebnicova, T. S., 39 Khuong-Huu, Q., 180, 304,356 Kibayashi, C., 346 Kieczykowski, G. R., 87 Kiel, W. A., 86, 225, 289 Kienzle, F., 328 Kihara, K., 159 Killian, L., 212 Killinger, T. A., 4, 57 Kim, S., 268, 316 Kimpe, N., 229 Kimura, K., 65 Kin, S., 268 King, A. O., 8, 30, 196, 209, 214 King, F. D., 181, 218 King, J. F., 223 King, T. P., 131 Kingsbury, C. A., 81 Kinney, R. J., 155 Kinoshita, H., 101 Kirihata, M., 124 Kirk, K. L., 339 Kishi, Y., 270, 316 Kishimura, K., 75, 213 Kissel, T., 282 Kita, Y., 130 Kitagawa, Y., 48 Kitai, M., 39, 262

Kitamura, M., 146 Kitamura, T., 86 Kitchin, J. P., 36, 222 Kleijn, H., 20, 28, 32, 192, 208 Kleinman, E., 297 Kleschick, W. A., 112 Klessen, C., 118 Klima, W. L., 23, 195 Kloek, J. A., 179 Kluge, A. F., 42 Knight, D. W., 75 Knoll, F. M., 146 Knolle, J., 273 Knowles, J. R., 164 Knowles, W. S., 128 Kobayashi, N., 321 Kobayashi, S., 50, 137, 138 Kobayashi, Y., 39, 237 Koch, K. R., 1 Koch, T. H., 245 Kocienski, P. J., 14 Kodama, H., 31,214 Kodama, M., 261 Koelsch, P. M., 260 Koenig, K. E., 128 Koster, H., 312 Koga, K., 47, 89, 151, 161, 162, 180 Kogwe, T., 326 Kohara, T., 165 Kohda, A., 71 Koizumi, T., 89 Kok, P., 93 Kole, J., 357 Kollonitsch, J., 4 Kolonko, K. J., 16 Kolthammer, B. W. S., 15 Komar, D. A., 216 Komatsu, T., 326 Komoto, R. G., 62 Kondo, K., 241 Konieczny, M., 70, 170 Koning, B. H., 97 Konishi, A., 327 Koolpe, G. I., 17, 225 Koppel, G. A., 308, 315 Kornblum, N., 3, 175 Kossanyi, J., 341, 352 Kosugi, H., 78, 206, 330 Kosugi, M., 220 Kosugi, Y., 342 Kotake, H., 101 Kovacic, P., 305 Kovlcs, G., 215 Kowplski, C., 72 Kozaku, T., 114 Kozikowski, A. P., 107, 116, 226 Krabbenhoft, H. O., 85 Kraentle, B., 3 Krautler, B., 356 Kraft, H. P., 328 Kramer, U., 119

Author Index Krapcho, A. P., 83,362 Kraus, G. A., 90, 91, 254 Krauser, S. F., 89 Krausz, P., 19 Kreiser, W., 312 Kreiter, C. G., 179 Krepski, L. R., 12, 52, 100, 233 Kricka, L. J., 329 Krief, A., 15, 44, 54, 63, 110, 142, 224, 225, 231, 232 Kriegesmann, R., 15, 52, 206 Krishnamurthy, S., 146, 213 Kristensen, J., 229 Krogh, J. A., 70. 170 Kropp, P. J., 227 Krouiver, J. S., 180 Kriiger, C., 76 Kruse, C. G., 149 Kruse, L. I., 313 Krzyzanowska, B., 168 Kubota, M., 115 Kucherov, V. F., 84, 359 Kuchin, A. V., 214 Kueh, J . S. H., 335 Kuhl, U., 22, 76 Kuehn, C. G., 129 Kunzler, P., 115 Kuivila, H. G., 103, 219 Kukolja, S., 85 Kulenovic, S. T., 103 Kulkarni, S. U., 49 Kulkowit, S., 197, 262 Kumada, M., 25, 100, 132, 152, 197, 217 Kumobayashi, H., 188, 322 Kunz, H., 131 KUO,P.-L., 159 Kurata, Y., 130 Kurita, A., 152, 217 Kuroda, K., 353 Kurokawa, T., 56, 110 Kurozumi, S., 37 Kurr, B. G., 279 Kurth, M. J., 88 Kuwajima, I., 37, 48, 66, 69, 217, 218,223 Kuwata, S., 129 Kuyama, M., 88 Kuzuhara, H., 326 Kyba, E. P., 127, 162 Kyburz, R., 50 Kyutoku, H., 14, 52, 230 Laarhoven, W. H., 327, 343, 344 Labar, D., 15, 142, 224, 225 Labuschagne, A. J. H., 157 Ladner, D. W., 235 Lafront, D., 128 Lagarias, J. C., 119 Lahav, M., 327 Lahima, N. J., jun., 9 Lajis, N. H., 101, 149, 150

373 Lakhvich, F. A., 39 Lalande, R., 101 Lalima, N. J., jun., 208 LaMattina, J. L., 109 Lamaty, G., 49 Lambros, T. J., 131, 185 Lammerink, B. H. M., 217 Lammert, S. R., 85 Lana, J. C. A., 160 Landini, D., 155, 160 Landmesser, N. G., 38 Landor, S. R., 326 Lane, C. F., 361 Lange, G. L., 262, 335, 336 Lansbury, P. T., 61, 258 Lapatsanis, L., 129 Larcheveque, M., 48, 66, 69, 75 Lardicci, L., 24, 31, 137, 196, 214 Larock, R. C., 23, 91, 209, 322,361 Larsen, C., 117 Larsen, S. D., 313, 350 Larson, G. L., 213 LaRue, M., 16 LaTorre, F., 36 Lattes, A., 169 Lau, J. T., 350 Lau, P. W. K., 15, 23, 216 Laurian, L. G., 297 Lavielle, S., 276 Lawesson, S.-O.,46, 117, 120,229 Laycock, D. E., 15 Leardini, R., 208 Lecherallier, A., 67 Lechleiter, J. C., 232, 336 Le Corre, G., 130 Lednor, P. W., 123 Ledwith, A., 329 Lee, D. G., 39,76, 322 Lee, H. T., 291,295 Lee, S. P., 15, 100, 151 Lee, T. V., 63, 240, 330 Lee, V. J., 288 Lee-Ruff, E., 257 Legzdins, P., 15 Lehmkuhl, H.,208 Lehn, J.-M., 158, 161, 162 Lehr, F., 74, 203 Lein, G. H., jun., 103, 219 Leionte, M., 19 LeMahieu, R., 330 Lemikre, G. L., 136, 145 Leniewski, A., 298 Lenoir, D., 12 Lenz, G. R., 344,345 Leonard, J., 295 Leong, A. Y. W., 73,202 LePerchee, P., 54, 110 Lepoirre, J. A., 145 Leroy, J., 7 1 Leschinsky, K. L., 179

Lesher, G. Y., 107 Lester, D. J., 18, 36, 55, 67, 175, 224 Lett, R., 268, 316 Leung, T., 28, 144, 213 Leutert, T., 51 Lev, I. J., 338 Levy, A. B., 9, 134, 208, 212 Lewicki, J. W., 53 Lewis, E. S., 101, 173, 221 Lewis, M. D., 97 Lewis, W., 10, 216 Lewton, D. A., 346 Ley, S. V., 18, 36, 55, 67, 175, 224 Leyendecker, F., 64 Leznoff, C. G., 321, 362 Liao, C. C., 337 Libit, L., 330 Lick, C., 39, 237 Lieb, F., 33 Lied, T., 114 Lienhard, U., 117 Lightner, D. A., 355 Lim, R. M., 149 Lin, H.-J., 151 Lin, J. J., 2, 11, 49, 135, 155, 185,207, 214 Lin, L.-S., 351 Lincoln, F. H., 275 Lindert, A., 47, 211, 345 Lindsay, B. G., 155 Linke, S., 120 Linstrumelle, G., 6, 7, 56, 145, 192, 196, 208 Lion, C., 208 Liotta, D., 37, 224, 226 Lipshutz, B. H., 9 Lipton, M. F., 16, 70, 144 Lissel, M., 53, 77 Listl, M., 131 Little, R. D., 177, 229 Liu, H., 100 Liu, H. J., 15 Liu, S., 355 Livinghouse, T., 102, 208 Ljungquist, A., 5 Lo, K. M., 279 Lock, J. D., 233 Logan, C. J., 129 Logeniann, E., 117 Lohmar, R., 123 Lok, W. N., 83 Lollar, E. D., 323 Lombardi, P., 307, 309 Lombardo, L., 51, 80 Lomins, D. L., 73 Long, A. K., 5, 313 Loosmore, S. M., 223 Loots, M. J., 11, 64, 322 Lopez, L., 71 Lopusinski, A., 129 Lorne, R., 7, 145, 192, 208 Lotts, K. D., 217

374 Loupy, A., 62 Loutfy, R. O., 348 Louts, M. J., 241 Loveitt, M. E., 209 Lovey, A. J., 83 Lowe, G., 340, 350 Loza, R., 238 Lubosch, W., 122, 168, 201 Lucas, M., 106 Lucchetti, J., 63, 110, 225 Lucci, R. D., 269, 279, 341 Lucente, G., 84, 131 Luche, J.-L., 62, 64, 66, 136 Luche, M. J., 276 Luh, T. Y., 101 Lui, A. S.-T., 105 Lui, J. T., 321 Lutz, w., 49, 354 Lyle, G. G., 67 Lyle, R. E., 67 Lyster, M. A., 169, 218 Lythgoe, B., 14, 30 McCarry, B. E., 255 McChesney, J. D., 46 McCloskey, C. J., 12, 197,230 McCluse, D. E., 267 Macco, A. A., 256 McDonald, E., 250, 344 McDonald, T. L., 24, 31, 81, 193, 259 McDougal, P. G., 42 McGarvey, G., 11, 15, 153 McGhie, J. F., 2, 146, 207 McGuirk, P. R., 9, 142, 208 Machii, Y., 53, 171 McIntosh, J. M., 21, 112, 275 McKee, R., 246 McKenzie, M. J., 231 McKervey, M. A., 1, 197, 262 McKillop, A., 53, 87, 88, 103, 165,173,215 Maclaren, J. A., 129 McMorris, T. C., 98 McMurry, J. E., 12, 52, 63, 109 McOsker, C. C., 15 McRath, J. A., 28 McShane, L., 308, 315 Madan, K., 162 Maddocks, P. J., 26, 212, 227 Mader, M., 58 Marky, M., 338 Magnus, P., 65, 217, 227, 269, 326 Magnus, P. D., 32, 223, 247, 343, 344, 352, 358 Magolda, R. L., 224, 276, 319 Mahajan, J. R., 100, 282 Mahalanabis, K. K., 324 Maier, G., 58, 230, 319, 357 Maier, W. F., 46 Maillard, B., 101 Makaiyama, T., 165

Author Index Makhora, N. N., 178 Maki, Y., 346 Makino, S., 73, 261, 299 Makosza, M., 104, 160, 227 Malacria, M., 20 Maldonado, L., 239 Malek, N. C., 67 Malherbe, J. S., 157 Malherbe, R., 99, 156 Malhotra, R., 174 Mallamo, J. P., 27, 204 Maloney, J. R., 67 Mammarella, R. E., 206 Mancuso, A. J., 36 Mandai, T., 23, 100, 198 Mandal, A. K., 210 Mane, R. B., 80 Manecke, G., 362 Manescalchi, F., 41, 190, 322 Manfre, R. J., 216 Mangelli, N., 181 Mann, J., 108, 299 Manning, M. J., 320 Manzocchi, A., 36, 49, 134, 187 Mao, D. T., 248, 323 Marchand, A. P., 170 Marchese, G., 10 Mardis, W. S., 348 Mares, F., 97, 187 Marfat, A., 9, 63, 142, 208, 237 Maria, P. C., 103 Marianelli, R. S., 171 Mariano, P. S., 335, 339 Marie, C., 241 Marinovic, N., 19, 65, 188 Marosfalvi, J., 240, 320 Marquarding, D., 118 Marquet, A., 276 Marshall, J. A., 13 Martel, J., 241 Martin, D. T., 15 Martin, G. E., 118 Martin, P., 233 Martin, R. H., 343 Martin, R. T., 250, 344 Martin, S. F., 42, 68, 203, 209, 221, 250, 263 Martha, D., 184 Martinelli, J. E., 352 Maruoka, K., 48 Maruya, K., 211 Maruyama, K., 7, 9, 26, 99, 103, 114,212, 220 Marx, M., 63, 237 Marxer, A,, 51 Maryanoff, C. A., 154 Masaki, Y., 34, 140 Masamune, S., 352, 357 Masilamani, D., 223 Masse, G. M., 275 Mass6, J., 50, 138 Masson, S., 116, 207

Masuda, T., 128, 321 Masuda, Y., 153, 210 Masure, D., 72, 204 Matacz, Z., 104, 160, 227 Matlin, S. A., 19 Matlock, P. L., 62 Matsuc, T., 161 Matsuda, A., 42 Matsuda, I., 94, 189 Matsueda, R., 101 Matsui, M., 326 Matsumoto, H., 77, 86, 152, 217, 258, 323 Matsumoto, K., 126 Matsumoto, M., 95, 353 Matsumoto, T., 331 Matsumura, Y., 14, 50, 52, 137, 230 Matsuura, T., 329, 337, 358 Matteson, D.S., 67, 210, 211 Matthies, D., 124 Mattioda, G., 124 Matturro, M. G., 2 Matusch, R., 230, 319, 357 Matuszak, C. A., 122 Max, G., 81 Mayer, H., 328 Mayer, N., 170 Mayer, R., 116 Mayr, H., 260 Mazaleyrat, J.-P., 43 Mazurek, M. A., 149 Mazut, Y., 15 Mazzu, A., 344 Mechen, S. M., 147 Medici, A,, 164, 208 Medwin, J. B., 22, 106 Mehler, K., 208 Mehta, Y. P., 171 Meidar, D., 42, 101 Meienhofer, J., 129, 131, 185 Meier, H., 54, 180 Meijer, J., 116 Meinwald, J., 108, 206, 270 Meisters, A., 123 Melamed, U., 204 Melis, R., 101 Mellor, J. M., 329 Mellor, M., 233, 333, 335 Mellows, S. M., 339 Melvin, L. S., jun., 268, 316 Menchen, S. M., 3, 19, 86, 225,289 Mendoza, A., 67, 210, 211 Mengel, R., 16 Menicagli, R., 137 Mender, K., 267 Merckx, E. M., 136, 145 Mertnyi, R., 122 Merkle, U., 180 Merritt, V. Y.,337 Mestres, R., 80 Metcalf, B. W., 125, 126 Metzger, J., 173

375

Author Index Meyer, C. J., 157 Meyer, E. F., 350 Meyer, H. H., 98 Meyer, H. J., 120 Meyer, J. M., 162 Meyer, N., 200 Meyer, V., 352 Meyers, A. I., 48,54, 73, 75, 79, 82, 102, 132, 180, 200, 207, 326,362 Michael, J. P., 218 Michels, D. G., 244, 333 Midland, M. M., 28, 49, 135, 210, 213 Miginiac, P., 145 Migita, T., 220 Mihelich, E. D., 82, 200 Miki, M., 159 Mikolajczyk, M., 158, 224 Miles, D. H., 255 Millard, A. A,, 47 Miller, R. B., 11, 15, 153 Miller, S. J., 51, 174 Milstein, D., 41, 102, 198, 220 Mimura, T., 56, 110 Minami, N., 223 Minami, T., 95, 306 Mincione, E., 136, 199 Minder, R. E., 328 Minyard, J. P., 330 Mishina, T., 13, 70, 170, 221 Misra, S. C., 2, 146, 207 Mitani, M., 235 Mitchell, M. J., 345 Mitchell, P. R. K., 342 Mitra, A., 64, 142, 205 Mitra, R. B., 330 Mitscher, L. A., 325 Mitschka, R., 244 Mitsudo, T., 184 Mitt, T., 295 Mitzlaff, M., 124 Miura, K., 345 Miyake, K., 83 Miyano, K., 331 Miyano, S., 30, 52, 221, 289 Miyata, T., 164 Miyazawa, T., 129 Mizuguchi, H., 89 Mizuno, Y.,251 Mizuta, M., 116 Mizyuk, V. L., 257 Mlotkowska, B., 176 Moerck, R. E., 32, 223, 247 Molander, G. A., 210 Molho, D., 81 Monneret, C., 356 Montanari, F., 155, 160 Monteil, R. L., 92 Monti, S. A., 350 Moody, R. J., 211 Moore, J. A., 101 Moore, R. H., 44

Moradpour, A., 162,343 Morathe, K. G., 358 Mordenti, L., 49, 135 More, K. M., 115, 202 Moreau, B., 276 Moreau, J.-L., 41 Moreau, P., 162 Moreland, M., 111, 216 Moretti, I., 50 Morgan, D. D., 344 Morgan, 0. M., 104 Morge, R. A., 336 Mori, K., 326, 328 Mori, M., 189 Mori, Y., 152, 214 Morikawa, T., 39, 237 Morio, K., 357 Morita, T., 85, 156, 218 Moriya, T., 126 Morizur, J.-P., 341, 352 Morris, M. J., 253 Morris, R. H., 62, 136, 184 Mortimer, R. D., 55, 212 Morton, D. R., 255, 336, 348 Morton, H. E., 64, 219 Mossman, A., 267 Motherwell, W. B., 36, 222 Mouriiio, A., 33 Mouzin, G., 230 Msonthi, J. D., 346 Muckensturm, B., 73 Miiller, P. M., 356 Muhle, H., 50 Muira, H., 351 Mukaiyami, T., 2, 4, 9, 14,. 37, 41, 50, 52, 75, 79, 98, 99, 137, 138, 153, 155 Mukerjee, A. K., 305, 315, 361 Mullen, G. B., 299 Mullins, M. J., 158, 280 Mulzer, J., 22, 76 Mundy, B. P., 257 Murahashi, S. I., 7, 170, 206 Murai, S., 68, 172, 190 Muraka, K., 42 Muramatsu, M., 202 Murayama, E., 71 Murray, T. F., 97 Murser, J. H., 297 Muruyama, K., 191 Musierowicz, S., 89 Musser, J. H., 63, 109 Mutter, M.,118 Mychajlowskij, W., 27, 52 Myers, R. F., 255 Myerson, J., 103 Naegeli, P., 263 N 8 , F., 242 Nagai, Y.,77, 86 Nagao, Y.,37, 41, 107, 134, 215,222, 320 Nagasawa, J.-I., 336

Nagashima, H., 37, 224 Nair, M., 44 Najera, C., 296 Nakaguchi, O., 309 Nakahara, Y.,100, 317 Nakai, T., 51, 56, 78, 110, 204,206 Nakajima, M., 42, 203 Nakamura, A., 327 Nakamura, C. Y., 359 Nakamura, E., 66, 69 Nakamura, F., 146 Nakamura, I., 326 Nakanishi, K., 329 Nakano, T., 77, 86 Nakao, M., 289 Nakata, T., 270, 316 Nakayama, J., 42 Nara, M., 88 Narang, S. C.. 146, 157, 174, 182, 221 Narasaka, K., 99 Narasimhan, K., 91 Narita, M., 118 Naruta, Y.,220 Naso, F., 10 Natale, N. R., 70, 134, 170, 213,321 Natori, S., 329 Nayak, A., 161 Nayler, J. H. C., 311 Ncube, S., 73, 201, 279 Negishi, E., 109, 139, 194, 195, 196 Negishi, E.-I., 8, 23, 30, 209, 214 Negri, D. P., 316 Neidert, E., 335, 336 Neidert, E. E., 262 Neises, B., 100 Nelson, J. V., 40, 147 Nematollahi, J., 85 Nemorin, J. E., 50 Nemoto, H., 258, 323 Nesbit, M. C., 85 Neubert, K., 118 Neuenschwander, M., 50, 117 Neumann, H., 139,204 Neumann, W. P., 53, 150 Neumeister, J., 102 Newall, C. E., 85, 311 Newcomb, M., 75, 77, 206 Newkome, G. R., 161 Newman, P., 328,362 Newton, B. N., 175 Newton, R. F., 97, 240, 348, 353 Newton, R. J., jun., 28, 70, 214 Nicholas, K. M., 198 Nickson, A., 353 Nicolaou, R. C., 224, 268, 273, 215, 316, 319,363 Nicoud, J. F., 343

376 Nidy, E. G., 275 Nienhaus, J., 109 Nigam, A., 155 Nilsson, N. H., 46 Ninitz, J. S., 99 Ninomiya, I., 344 Nishida, K., 85 Nishida, S., 12, 52 Nishida, T., 60, 114, 147 Nishiguchi, I., 51, 106, 173, 208,235 Nixon, R., 209 Node, M., 85 Noding, S. A,, 2 Noels, A. F., 193 Noguchi, H., 127 Noguchi, Y., 127 Nojima, H., 118 Nokami, J., 15, 141 Nolan, S. M., 40, 320 Nolde, C., 120 Nordlander, J. E., 160, 168 Normant, H., 66, 69 Normant, J. F., 26, 72, 111, 132, 204, 221 Norrish, H. K., 74, 220 Norton, J. R., 97 Nossin, P. M. M., 256 Notani, J., 118 Novak, L., 240, 320 Noyori, R., 5, 73, 234, 261, 299 Nozaki, H., 1, 11, 38, 39, 48, 52, 57, 74, 203, 204, 236, 262,361 Nozoe, S.,329 Nunami, K., 125, 126 Nuzzo, R. G., 128 Oae, S., 105 Oakleaf, J. A., 121 Oberhansli, W. E., 338 Ochiai, M., 42 O’Connor, S., 244, 333 Odaira, Y., 65 O’Donnell, M. J., 122, 123 Oediger, H., 33 Oehlschlager, A. C., 178 Ogata, Y., 53, 76, 103 Ogawa, J.-I., 331 Ogawa, K., 130 Oguri, T., 86, 126 Oguro, K., 29, 63, 107, 191, 214 Ohfune, Y., 236, 331 Ohga, Y., 128 Ohkata, K., 232 Ohkawa, K., 86 Ohler, E., 126 Ohloff, G., 353 Ohmatsu, H., 126 Ohmizu, H., 235 Ohno, H., 50, 137 Ohr, J., 321

Author Index Ohrui, H., 268, 325 Ohsawa, T., 291, 355 Ohta, H., 7, 206 Oida, T., 94 Oikawa, Y., 40, 107 Oishi, T., 15, 152 Ojima, I., 326 Okahara, M., 53, 159, 171 Okamoto, T., 94, 108 Okamoto, Y., 85, 131, 156, 218 Okamura, W. H., 33 Okano, M., 50, 137 Okawara, F., 15 Okawara, M., 94 Okawara, R., 141 Okawara, T., 127 Okigawa, M., 270, 316 Okogun, J. I., 343 Oku, T., 309 Okukado, N., 8, 23, 109, 139, 194, 195, 214 Okuno, Y., 347 Okuyama, M., 342 Okuyama, S., 130 Olah, G. A., 2, 42, 44, 70, 101, 146, 156, 157, 170, 174, 182, 221 Oliva. A., 213 Olofson, R. A., 130, 217 Omote, Y., 340 Omura, K., 36, 358 Ong, B. S., 27, 52 Onishi, T., 60, 114, 147 Ono, N., 95, 101, 111, 172, 206 Ono, T., 44 Onopchenko, A., 53, 270 Oparaeche, N. N., 359 op het Veld, P. H. G., 344 Oppenhuizen, M., 54 Oppolzer, W., 1, 233, 258, 285, 323, 324, 332, 360 Orchin, M., 344 Orere, D. M., 67 Orfanopoulos, M., 3, 50, 218 Oribe, T., 89 Orrom, W. J., 262 Ors, J. A., 100 Ortaggi, G., 199 Osaki, K., 251 Oshima, K., 52 Otani, N., 179 Otieno, D. A., 233, 333 Otomasu, H., 127 Otsuka, S., 188, 322, 327 Ottenheijm, H. C. J., 124, 176 Ouellette, D., 206 Overman, L. E., 146, 297 Owens, C., 100 Ozorio, A. A., 73, 202, 351 Pabon, H. J. J., 25

Pabst, W. E., 355 Padwa, A., 91, 238, 338, 344 Pagnotta, M., 351 Paik, H. N., 3, 177 Pais, M., 119 Palermo, R. E., 150, 186 Palmer, J. R., 245 Pan, Y , 204, 323 Pan, Y.-G., 55 Pancrazi, A., 180 Pande, C. S., 129 Pandit, U. K., 123, 136 Panetta, J. A., 169 Panossian, S., 117 Panunzio, M., 41 Paoletti, R., 273 Paolucci, C., 281 Paolucci, G., 36 Paolucci, M. J., 158 Pappas, S . P. 339 Pappo, R., 205,245 Paquette, L. A., 32, 44, 218, 233, 247, 360 Parayre, E., 50, 138 Parente, A., 139 Parente, R. A., 271 Parham, W. E., 296 Parker, J., 340 Parker, K. A., 28 Parker, S. D., 351 Parnell, C. A., 327 Parsons, P. J., 56, 205 Parsons, W. H., 243 Parrish, D. R., 276 Parry, R. J., 255 Pasto, D. J., 28, 194 Patchett, A. A., 124 Patchornik, A,, 359 Patel, B. A., 81 Patel, V., 83 Pattenden, G., 1, 26, 34, 39, 92, 227, 232, 233, 237, 333,335,339 Paterson, D. C., 302 Patrick, D. W., 166, 186 Paty, P. B., 37, 226 Pavlova, L. A., 119 Pawlowicz, R., 125 Payer, W., 295 Payne, M. J., 160, 168 Peacock, S. C., 127, 162 Peake, S. L., 155, 224 Pearson, M. J., 3 11 Pearson, R. L., 182 Pechet, M. M., 355 Pedersen, B. S., 46, 117 Peek, R., 104 Peled, N., 124 Pellacani, L., 71 Pellet, M., 67 Pellicone, J. T., 169 Pelter, A., 73, 135, 201, 210, 212, 213, 279 Pendse, A. D., 101

Author Index Pennanen, S. I., 90 Penners, N. H. G., 97 Pennings, M. L. M., 256 Pennington, W. R., 264 Percival, A., 218, 245 Pereyre, M., 220 Perie, J., 169 Peries, R., 73 Perriot, P., 72, 111, 221 Perry, R. A., 83 Pesaro, M., 262, 350 Pete, J. P., 2, 356, 358 Peterse, A. J. G. M., 97 Petiniot, N., 193 Petitpierre, J.-C., 40, 236 Petragnani, N., 95, 225 Petraitis, J. J., 28 Petrasiunas, G. L. R., 46 Petrusevich, I. I., 39 Petrzilka, M., 81, 99, 148, 258, 323 Pezzi, G., 208 Pfaendler, H. R., 314 Pfaff, K., 202 Pfaltz, A., 356 Pfeiffer, U., 268, 326 Pfriem, S., 58, 230, 319, 357 Phillips, D., 329 Phillips, G. W., 68, 203 Phillips, W. V., 46, 251 Piancatelli, G., 242 Piatak, D. M., 360 Pickles, G. M., 210 Pienta, N. J., 227 Piers, E., 47, 64, 219, 357 Pignolet, L. H., 191 Pike, S., 181, 218 Ping-Lin, K., 159 Pinnen, F., 84 Pinnick, H. W., 65, 69, 76, 96, 101, 149, 150, 230, 289 Pirkle, W. H., 28, 192, 265 Pizzolato, G., 323 Place, P., 32 Plant, P. J., 359 Plaquevent, J.-C., 127 Plat, M. M., 179 Pletcher, D., 36, 321 Plinke, G., 352 Pochat, F., 15 Podesta, J. C., 210 Poels, E. K., 149 Poindexter, G. S., 180 Poisel, H., 107 Pojer, P. M., 149, 322 Pollack, A., 321 Pollard, M. D., 12 Pollet, P., 92 Pollicino, S., 158, 281, 282 Pommier, J.-C., 85 Pondaven-Raphalen, A., 150 Pons, B. S., 120 Ponti, F., 36, 49, 134, 187

377 Porskamp, P. A. T. W., 217, 22 1 Portella, C., 356 Porter, A. E. A., 227 Porter, N. A., 209 Porter, Q. N., 322 Posner, G. H., 1, 27, 204, 259, 321, 362 Pougny, J. R., 325 Poulton, G. A., 358 Powell, D. W., 158, 281 Prakash, G. K. S., 146 Prantz, E., 126 Pratt, A. C., 338 Pratt, R. A., 200, 252 Prisbylla, M. P., 247 Prokopiou, P. A., 2, 146, 207 Puckett, P. M., 254, 257 Puglis, J., 154 Purohit, V. G., 46 Putt, S. R., 44, 175 Qazi, A. H., 122 Quan, P. M., 198 Quante, J., 282 Quesada, M. L., 90, 243 Quesy, S. N., 296 Quick, J., 65 Quinkert, G., 312,362 Raab, A. W., 267 Radics, L., 215 Raggio, M. L., 355 Rahman, M. T., 63 Rainey, D: K., 240 Rajagopalan, K., 244 Rall, G. J. H., 87, 88, 148, 215 Ramaiah, M., 22, 106 Ramana Rao, V. V., 211 Ramasamy, K., 2, 15 Ramasseul, R., 284 Ramsay, M. V. J., 340 Rancourt, G., 317 Raphael, R. A., 100, 200, 252,345 Rapoport, H., 119 Rasmussen, J. K., 67, 172 Rassat, A., 284 Rasshofer, W., 159 Rastetter, W. H., 97 Ratcliffe, B. E., 255 Rathke, M. W., 47, 55, 120, 121,211, 216 Ratovelomanana, V., 21 Raucher, S., 17, 37, 105, 224, 225 Rausch, M. D., 31 Rautenstrauch, V., 234 Ravid, U., 86 Raynolds, P. W., 252, 320 Re, L., 106 Rebek, J., 267 Rebuffat, S., 81

Redmore, D., 170 Reed, D., 96, 328 Reed, J. N., 121, 200 Reese, C., 291 Reese, C. B., 67, 363 Reetz, M. T., 18, 46, 103 Regen, S. L., 155 Reich, H. J., 23, 155, 223, 224 Reich, I. L., 23, 223 Reimlinger, H., 122 Reinshagen, H., 262 Reiter, U., 126, 327 Reitz, D. B., 116, 363 Remillard, B. D., 200 Renga, J. M., 158, 280, 281 Renger, B., 220 Reuter, J. M., 58, 240 Reynolds, D. P., 240, 348 Rezendre, M. C., 181 Rhee, R. P., 254 Rich, D. H., 359 Richard, T. J., 97 Richmond, J. P., 180 Rickards, G., 24 Ridley, D. D., 50, 350 Riefling, B., 23, 91, 209 Rigby, J. H., 53, 111, 222 Rinaldi, P. L., 265 Rinehart, K. L., jun., 288 Ringsdorf, H., 130 Ripoll, J. L., 2 Roach, B. L., 158, 280 Roberts, M. R., 87, 104 Roberts, N. K., 221, 266 Roberts, R. D., 285 Roberts, S. M., 97, 240, 330, 348, 353 Robin, J.-P., 89 Rocchiccioli,F., 119 Rodini, D., 24 Rodriguez, A., 272 Roelants, F., 304 Roeske, R. W., 359 Rogers, N. A. J., 351 Rogerson, T. D., 346 RogiC, M. M., 223 Rogozhin, S. V., 119 Rolla, F., 155, 160 Rollin, A. J., 72 Romeo, A., 131 Ronman, P., 178 Roos, G. H. P., 342 Roos, O., 130 Rosario, O., 213 Rose, E. H., 30 Rosel, P., 16 Rosen, P., 100, 318 Rosenberger, M., 328 Rosenquist, N. R., 357 Rosini, G., 164, 208 Rossi, D., 131 Rossi, R., 2, 362 Roth, B., 90

378 Rotstein, D., 154 Rouessac, A., 2 Rouessac, F., 2 Roumestant, M. L., 32 Rousseau, G., 54, 110 Roux, D. G., 148 Roy, G., 217, 326 Rubinstein, M., 359 Rubottom, G. M., 66, 106 Runquist, A. W., 259 R.ushton, S., 14 Rust, F. F., 272 Rutledge, P. S., 42, 72, 155 Ryan, J. D., 257 Ryder, D. J., 135, 210 Ryu, I., 68, 172 Saavedra, J. E., 67 Sackett, A., 305 Sadler, J. C., 202 Saegusa, T., 68, 187 Sahlberg, C., 28, 191 Sai, M., 85 Sai'hi, M. L., 220 Saiki, H., 345 Sainton, J., 118 Saito, H., 128 Saito, I., 337 Saito, T., 101 Sakai, S., 179 Sakai, Y., 65, 77 Sakanishi, K., 209 Sako, M., 346 Sakurai, A., 15, 152 Sakurai, H., 40, 69, 85, 143, 156, 217, 218 Sala, T., 76, 322 Salerno, G., 178, 196 Salisbury, K., 329 Saljoughian, M., 80 Salmond, W. G., 142, 187 Salomon, R. G., 58, 240, 354 Salzmann, T. N., 38, 113 Sammes, P. G., 19, 254, 329, 338, 339 Samson, M., 68, 172 Samuelsson, B., 273 Sanchez, E. L., 264 Sanders, E. B., 166 Sandri, E., 158, 281, 282 Sanola, 0. O., 326 Santaniello, E., 36, 49, 134, 187 Santos, A., 256 Sarel, S., 360 Sargent, M. V., 76, 322 Sargeson, A. M., 123 Sarker, T. K., 249 Sartori, G., 272 Sasaki, M., 51, 106, 173, 208 Sasaki, T., 280, 305 Satch, S., 235 Sathe, S. S., 264

Author Index Sato, F., 2, 29, 31, 152, 191, 214 Sato, H., 78, 206 Sato, M., 2, 29, 31, 152, 191, 214 Sato, R., 54 Sato, S., 2 Sato, T., 48, 71, 73, 138, 217, 218 Satoh, J. Y., 359 Satoh, S., 105 Satzinger, G., 322 Saucy, G., 328 Sauer, J., 53, 150 Sauter, H., 117 Sauvetre, R., 72, 204 Savignac, P., 51, 80, 266 Sawaki, Y., 53, 76 Sawicki, R. A., 288 Saxena, M. P., 102 Sayer, T. S. B., 46, 251 Sayrac, T., 357 Sayre, L. M., 84 Scarborough, R. M., jun., 61, 66 Scettri, A., 242 Schafer, H. J., 108 Schafer, U., 230, 319, 357 Schaffner, K., 348 Schamp, N., 90, 173, 179, 229 Schank, K., 39, 237 Schaub, R. E., 11, 205 Schauble, J. H., 49, 134 Schaumann, E., 283 Schaus, J. M., 179 Scheeren, H. W., 106 Schefford, R., 350 Scheibye, S., 46, 117 Schell, F. M., 166 Schlecker, R., 122, 201 Schlessinger, R. H., 87, 90, 243 Schlosser, M., 15 Schmid, G., 270, 316 Schmid, H., 119, 248, 338 Schmidlin, T., 100, 247, 318 Schmidt, J. C., 93 Schmidt, R. R., 57,92,204, 234 Schmidt, U., 126, 129 Schmidt, W., 156 Schmitt, S. M., 311, 314 Schmuff, N. R., 350 Schneider, D. F., 157 Schneider, J., 41 Schneider, W. R., 275 Schollkopf, U., 126, 202, 327 Schoemaker, H. E., 257,286 Schofield, P., 359 Scholl, B., 303 Scholler, D., 356 Scholz, D., 41 Schonholzer, S., 50 Schoufs, M., 116

Schouteeten, A., 124 Schroder, G., 352 Schuda, P., 242 Schuh, K., 87 Schultz, A. G., 269, 279, 341 Schultz, J. G. P., 53 Schulz, J. A., 245 Schulz, J. G. D., 270 Schuster, G., 329 Schwab, W., 166 Schwanghart, A. D., 328 Schwartz, J., 11, 64, 193, 241, 322 Schwartz, J. A., 88 Schwartz, S. J., 134 Schwarz, J., 214 Schwellnus, K., 103 Schwickerath, W., 220 Schwier, J. R., 210 Schwig, V., 328 Scott, J. W., 136, 276, 362 Scovell, E. G., 256 Scudder, P. H., 37 Scully, F. E., jun., 43 Searafile, C., 309 Sebedio, J.-L., 102 Secor, H. V., 166 Secrist, J. A., 268, 316 Seebach, D., 74, 122, 139, 166, 168, 200, 201, 203, 205,220 Seemuth, P. D., 93 Segal, M., 126, 327 Seifert, J. M., 16 Seifert, P., 53, 150 Seitz, S., 319 Seki, S., 124 Seki, Y., 190 Sekiguchi, A., 15 Sekiguchi, S., 330 Sekine, M., 42, 203 Sekita, R.-I., 330 Sekutowski, J. C., 76 Semenovsky, A. V., 257 Semmelhack, M. F., 96, 112, 258, 346 Sen, P. K., 331 Seo, S., 145 Serebryakov, E. P., 84, 359 Serelis, A. K., 258 Seta, A., 65, 175 Setoi, H., 94 Severin, T., 104, 175 Sevrin, M., 44, 54, 142, 225 Seyden-Penne, J., 62 Seyferth, D., 205, 206 Shah, G. M., 171 Shah, J. N., 171 Shakhshir, S. R., 118 Shambhu, M. B., 118 Shani, A., 345 Shanmugam, P., 2, 15 Shapiro, R. H., 16, 70, 144 Sharma, S., 361

379

Author Index Sharma, S. D., 305 Sharpless, K. B., 141, 150, 166, 186, 224, 225 Shea, K. J., 248 Shechter, H., 44 Sheehan, J. C., 359 Sheehan, M., 359 Sheldon, B. G., 88 Sheldrake, P. W., 268, 316 Sheldrick, G., 286 Shepard, K. L., 289 Sheppard, J. H., 135, 210 Sheppard, R. C., 129 Sheradsky, T., 305 Sherman, S. A., 355 Shibahara, S., 124 Shibasaki, M., 273, 276 Shibuya, S., 44, 265 Shimada, A., 261 Shimizu, F., 5 Shimizu, I., 224 Shimizu, M., 37, 72, 224 Shimizu, Y., 47 Shin, C., 126 Shin, S., 42 Shinoda, M., 57, 204, 236 Shinonaga, A., 172 Shinozaki, H., 345 Shioiri, T., 82, 104, 126 Shirahama, H., 331 Shirahata, A., 143, 217 Shirakhi, S., 206 Shirayama, M., 53 Shockravi, A., 51, 77 Shono, T., 14, 51, 52, 106, 173,208, 230, 235 Shorter, J., 312 Shults, R. H., 28, 194 Siddall, J. B., 330 Sidebottom, P. J., 44, 124, 323 Sieber, P., 323 Siegel, M. G., 162 Sieler, R. A., 21, 112, 275 Sih, C. J., 96, 253, 328 Silbermann, L., 313 Silveira, A., jun., 196, 209 Silverman, S. B., 3, 50, 218 Silverstein, R. M., 86 Silvestri, M. G., 12 Simchen, G., 170 Simon, J., 162 Simonidesz, V., 215 Simons, J. B., 178 Sinaj, P., 325 Singaram, B., 210 Singer, S. P., 158, 280, 281 Singh, A. K., 305, 315, 361 Singh, B., 107 Singh, H., 112 Singh, R. K., 246 Sinou, D., 128 Sipio, W. J., 319 Siret, P., 227, 313

Sirlin, C., 161 Sirna, A., 199 Siuta, G. J., 351 Sjoberg, B., 340 Skeean, R. W., 250 Sletzinger, M., 119, 178 Smillie, R. D., 357 Smith, A. B., 60, 61, 66, 204 Smith, D. H., 313 Smith, F. X., 351 Smith, G., 343 Smith, G. P., 342 Smith, K., 73, 200, 201, 212, 213, 279 Smith, L. R., 86 Smith, R. A. J., 116 Smith, R. G., 3, 175 Smith, T., 2, 207 Smith, T. L., 264 Smith-Palmer, T., 270, 316 Snider, B. B., 4, 10, 24, 57, 87, 104, 216, 223, 355 Snieckus, V., 1, 121, 200, 252, 324, 346, 347, 360 Snitman, D. L., 180 Snoussi, M., 51, 80 Snow, M. R., 123 Snowden, R. L., 323 Snyder, E. S., 75 Soai, K., 50, 138 Soakup, M., 300 Sobczak, R. L., 248 Sobotta, R., 105 Soga, T., 128 Sogah, G. D. Y., 127, 162, 328 Solera, P. S., 108 Solheim, B. A., 88 Sollman, P. B., 245 Somehara, T., 289 Sonnet, P. E., 13 Sonoda, A., 7, 206 Sonoda, N., 68, 172, 190 Sorrell, T. N., 41, 49, 135, 183 Sosnovsky, G., 70, 170 Soucy, M., 357 Sousa, L. R., 127, 162, 328 Sousa Lobo, M. J., 117 Soysa, H. S. D., 158 Spain, V. L., 330 Spangler, R. J., 345 Spear, K. L., 158, 280 Speckamp, W. N., 257, 286 Spencer, T., 210 Spencer, T. A., 285 Spiegel, B. I., 8, 194, 214 Spillane, R. J., 41, 183 Springboard, J., 123 Srinivasan, R., 100, 337 Stadler, P. A., 101 Standring, D. N., 164 Stang, P. J., 1 Stansfield, R. E., 160, 168

Stanton, J. L., 241, 318 Starewicz, P. M., 305 Starratt, A. N., 355 Stauffer, R. D., 346 Stavinoha, J. L., 335 Stec, W. J., 168 Steckhan, E., 26, 156 Steevens, J. B., 123 Steglich, W., 100, 123 Steindl, F., 129 Steinseifer, F., 206 Steliou, K., 117, 222 Stemke, J. E., 17, 80 Stephanou, E., 119 Stephens, W. P., 83 Stephenson, E. F. M., 341 Stern, P., 345 Sternson, L., 116 Stetter, H., 109 Stevens, R. M., 160, 168 Stevens, R. V., 102, 208 Still, I. W. J., 157 Still, W. C., 64, 132, 142, 205, 219 Stille, J. K., 41, 85, 128, 198, 220, 321 Stobbe, S., 76 Storck, W., 362 Stork, G., 53, 63, 73, 100, 202, 237, 239, 254, 317, 319, 350 Strandsky, W., 16 Strege, P. E., 5, 113 Streith, J., 349 Streitweiser, A., jun., 177 Streukens, M., 104 Stiissi, R., 242 Stiizz, A., 262 Sturtz, G., 150 Stutz, U., 174 Stydom, P. J., 344 Suarato, A., 307 Suau, R., 342 Subrahmanyam, G., 337 Subramaman, R., 46 Sudoh, R., 65, 175 Sueda, N., 325 Suemitsu, R., 41, 102, 190, 207 Suga, K., 97 Sugano, K., 40, 107 Suganuma, H., 95 Sugi, Y., 128 Sugihara, H., 42 Sugihara, Y., 357 Sugimoto, A., 354 Sugimoto, H., 91, 254 Sugimoto, T., 50, 103, 137 Sugino, K., 116 Suginome, H., 349 Sugiura, T., 160 Sullivan, D. F., 55 Sum, P., 325 Sumoto, K., 289

380 Sundarararnan, P., 102 Sundberg, R. J., 347, 351 Surya-Prakash, G. K., 2 Suslova, L. M., 84, 359 Sutherland, J. K., 58, 200, 253, 256 Suzuki, A., 31, 75, 77, 102, 153, 210, 211, 213, 248 Suzuki, F., 96, 253, 328 Suzuki, H., 13, 70, 170, 221 Suzuki, K., 138 Suzuki, M., 125, 126, 261 Suzuki, T., 239, 319 Svensson, J., 273 Swaminathan, S., 244 Swanson, R., 335 Swedo, R. J., 152 Swenton, J. S., 66, 252, 320 Swern, D., 36 Szajewski, R. P., 60, 350 Szantay, C., 240, 320 Szmuskovicz, J., 297 Szychowski, J., 298 Taber, D. F., 63,237 Tachimore, Y., 65, 175 Tada, M., 83, 345 Tadema, G., 28 Taffer, I. M., 134, 213, 321 Taga, T., 251 Taguchi, H., 38 Taguchi, T., 39, 237 Tait, S. J. D., 36, 321 Tait, T. A., 73, 79, 207 Takacs, J. M., 46, 203 Takada, T., 342 Takagi, K., 154 Takahashi, H., 127 Takahashi, K., 120 Takahashi, M., 25, 100, 152, 197, 217 Takahashi, T., 37, 83, 98, 99, 224, 239,319 Takahashi, T. T., 359 Takahashi, Y., 31, 77, 102, 211, 248 Takai, K., 52, 118 Takaishi, N., 128, 321 Takami, M., 337 Takamoto, T., 65, 175 Takatsuki, K., 47 Takaya, H., 73, 261 Takayanagi, H., 261 Takeda, T., 75, 79 Takegami, Y., 47, 184 Takei, H., 83 Takeno, H., 309 Talbiersky, J., 57, 92, 204, 234 Talley, J. J., 67, 172, 218 Tarnada, S., 326 Tamao, K., 25, 100, 132, 152, 197, 217 Tamaru, Y., 322

Author Index Tarnba, Y., 170 Tamm, C., 100, 247, 318 Tamura, R., 111, 172, 206 Tamura, Y., 117, 130 Tanabe, K., 101 Tanaka, K., 51, 78, 94, 95, 101, 204, 206 Tanaka, M., 39, 169, 262 Tanaka, S., 354 Tang, P. W., 27, 204 Tang, R., 97, 187 Tanigawa, U., 206 Tanigawa, Y., 7 Tanikaga; R., 42, 94 Tanimoto, S., 50, 137 Tarchini, C., 15 Tardella, P. A., 7 1 Tatchell, A. R., 326 Tatsuno, Y., 327 Taub, D., 124 Tavernari, D., 164, 208 Taylor, D., 123 Taylor, E. C., 53, 87, 88, 103, 109, 165, 173, 215 Taylor, K. G., 178 Taylor, R. J. K., 51, 80, 346 Tegeler, J. J., 299, 324 Telford, R. P., 41, 176, 213 Telschow, J. E., 106 Temrne, G. H., 332 Teranishi, S., 13, 52 Terasaki, T., 326 Terashima, S., 88, 151 Terawaki, Y., 127 Termont, D., 88, 334 Texier, F., 304 TeyssiC, Ph., 193 Thomas, E. J., 100, 247, 318 Thomas, H. G., 104 Thomas, M. T., 121 Thomas, R. L., 313 Thommen, H., 328 Thompson, A. C., 330 Thompson, J. L., 275 Thomsen, I., 120, 229 Thorpe, F. G., 210 Thuillier, A., 116, 207 Tidwell, T. T., 1, 363 Timko, J. M., 127, 162, 241, 318 Timm, U., 54 Timmons, C. J., 343 Tischler, A. N., 122 Tischler, M. H., 122 Tobe, Y., 65 Toffer, I. M., 170 Toi, N., 305 Tokas, E. F., 31 Tokuda, M., 31, 102, 105, 211, 235 Tokumori, H., 124 Tokuyama, T., 347 Tolstikov, A. A. 214 Tomesch, J. C., 96, 112, 258

Tomioka, H., 357 Tomioka, K., 54, 89 Tomita, K., 127 Tomita, Y., 145 Tomoi, M., 155, 159 Tong, Y. C., 321 Tori, K., 145 Torii, S., 88, 94, 108 Toromanoff, E., 241 Torr, R. S., 220 Torre, G., 50 Toru, T., 37 Tramontano, A., 49, 135, 213 Trenbeath, S., 253 Trend, J. E., 224 Tripoulas, N. A., 160, 168 Trofimenko, S., 31 Trost, B. M., 5, 37, 38, 42, 53, 83, 111, 113, 202, 221, 241, 247, 318, 322, 361 Trotter, J., 286 Truesdale, L. K., 166, 186 Trybulski, E., 268, 316 Tsao, J.-H., 130 Tsay, Y.-H., 76 Tse, I., 346 Tseng, C. C. 151 Tsoucaris, G., 343 Tsuchihashi, G., 63, 107 Tsuchiya, T., 146 Tsuji, J., 23, 37, 98, 99, 100, 198, 224 Tsuji, T., 165 Tsukagoshi, F., 97 Tucker, P. A., 123 Tuddenham, R. M., 248 Tufariello, J. J., 299, 324 Tully, C. R., 150, 218 Tumlinson, J. G., 330 Tumura, K., 89 Tunemoto, D., 241 Tun-Kyi, A., 131, 322 Tupper, D. E., 119 Turnbull, K., 157 Turner, W. B., 100, 247, 318 Turro, N. J., 329, 348 Twaik, M., 128 Tzougraki, C., 131, 185 Uchida, K., 11 Uda, H., 78, 206, 330 Udaka, S., 251 Ueda, H., 124 Ueno, N., 108 Ueno, Y., 94 Ueta, K., 15, 141 Ugi, I., 131 Ullenius, C., 63 Umani-Ronchi, A., 41, 190, 322 Umemoto, T., 241 Umezawa, K., 359 Umezawa, S., 146 Umino, N., 168

381

Author Index Uneme, H., 94 Uneme, U., 95 Uneyama, K., 88 Unger, L. R., 44 Unno, S., 351 Unrau, A. M., 178 Uskokovic, M. R., 291, 292, 295, 323 Usui, T., 146 Utimato, K., 11, 39, 262 Utley, J. H. P., 322 Uyehara, T., 261 Vahrenhorst, A., 206 Valentine, D., 136, 362 Valentino, D. S., 71 Valette, G., 69 Valnot, J.-Y., 73 Van Audenhove, M., 88 van der Burg, A. M., 123 van der Gen, A., 46, 149 van der Leij, M., 47, 217, 221 Van der Wal, A. J., 145 Van der Zwan, M. C., 159 Vandewalle, M., 68, 88, 93, 172, 334 van Dijck, L. A., 28 van Dokkum, R. F. M., 123 van Heerden, F. R., 148 Van Horn, D. E., 8, 23, 194, 195, 214 Vanker, Y. D., 170 Van Leeuwen, P. M., 97 van Mourik, G. L., 25 van Norden, J. J., 21 Van Osselaer, T. A., 136, 145 van Ramesdonk, H. J., 136 van Schaik, T. A. M., 21 van Straten, J. W., 21 van Tamelen, E. E., 339 van Zyl, J. J., 148 Varkony, T. H., 313 Varma, V., 97 Vasilevskis, J., 276 Vaultier, M., 284 Veal, C. J., 331 Vedejs, E., 106, 158, 280, 28 1 Veenstra, G. E., 78, 201 Venegas, M. G., 177 Venier, C. G., 221 Veprek-Bilinsky, V., 91 Verboom, W., 30 Verhk, R., 90, 173, 179, 229 Verhoeven, J. W., 136 Verhoeven, T. R., 5, 113 Verkruijsse, H. D., 31 Vermeer, P., 20, 28, 30, 32, 116, 172, 192, 208 Vevert, J. P., 123 Viala, J., 20 Vick, S. C., 205 Vickery, B., 82 Viehbeck, A., 160, 168

Vilkas, E., 118 Vilkas, M., 118 Villani, F. J., jun., 196, 209 Villenave, J. J., 101 Villieras, J., 72, 111, 221 Vinick, F. J., 204, 323 Viola, H., 116 Virat, M., 241 Vladuchick, W. C., 37, 202 Voelter, W., 129 Vogeli, R., 93 Vogtle, F., 159 Vonkar, Y. D., 70 von Schlecker, R., 168 Vorbruggen, H., 100 Voss, J., 116 Vostrowsky, D., 16 Vranesic, B., 270, 316 Wade, L. G., jun., 84, 322 Wade, P. A., 304 Wade, P. C., 302 Wade, T. N., 103 Wadsworth, A. H., 240 Wadsworth, W. S., 360 Wagner, K., 170 Wahren, R., 62 Wakabayashi, T., 321 Wakisaka, K., 345 Wakselinan, C., 71 Wakselman, M., 130 Walborsky, H. M., 173, 178 Walker, B. J., 101, 173, 221 Walker, D. A., 161 Walker, D. L., 62 Walker, E. C., 102 Wallace, D. J., 202 Wallace, J. K., 104 Walters, M. E., 12 Walton, D. R. M., 33, 181, 218 Wanatabe, Y., 165 Wancowicz, D. J., 130 Wang, C.-L. J., 265 Wang, K.-T., 123 Wang, S.-S., 359 Ward, A. D., 83 Warning, K., 124 Warnock, J., 36, 187, 321 Warren, S., 1, 21, 73, 74, 140, 201, 220, 279, 312, 320, 361 Washburn, W., 355 Wasserman, H. H., 93, 354 Watabe, M., 340 Watanabe, H., 129 Watanabe, I., 146 Watanabe, K., 126, 321 Watanabe, S., 97 Watanabe, Y., 47, 184 Waterhouse, A., 28, 194 Waterhouse, I., 30 Watson, K. G., 284 Watson, N. S., 311

Watt, D. S., 180, 355 Watterson, A. C., jun., 89 Webb, C. F., 240, 353 Weber, L., 5, 113 Weber, R. W., 244 Weber, W. P., 158, 321, 362 Weedon, A. C., 46,49, 134 Weigel, L. O., 119, 318 Weihe, G. R., 98 Weiler, L., 24, 325 Weimaster, J. F., 83 Weingartner, T. F., 74, 112, 203, 320 Weinstock, L. M., 119, 178 Weisenfeld, R. B., 69, 206 Weiss, L. B., 268 Welch, J., 44, 156 Welch, S. C., 12 Wellmann, J., 26 Wemple, J., 115, 202 Wendelborn, D. F., 224 Wender, P. A., 70, 179, 203, 232,236 Wenkert, E., 106, 264 Wentrup, C., 174 West, P. J., 358 West, R. C., 276 Westmijze, H., 20, 28, 30, 32, 172, 192,208 Wetter, H., 219 Weuster, P., 71 White, J. D., 88, 250, 353 White, J. G., 351 Whiteley, R. V., jun., 171 Whitesides, G. M., 128, 321 Whitesitt, C. A., 306 Whitham, G. H., 1 Wiaux-Zamar, C., 166 Wicha, J., 360 Widiger, G. N., 355 Widmer, U., 248 Widner, J., 175 Wiemann, K., 109 Wiesner, K., 333 Wijnberg, J. B. P. A., 286 Wild, S. B., 221, 266 Wilke, G., 76, 207 Wilkins, J. M., 63 Willard, G. F., 49 Willard, P. G., 53 Willert, I., 205 Williams, B. E., 82 Williams, B. J., 129 Williams, D. R., 48, 180 Williams, E., 115, 226 Williams, J. R., 44, 129 Williams, L. R., 296 Williams, S. B., 15 Wilson, M. E., 128, 321 Wilson, N., 134 Wilson, S. R., 248, 288, 323 Winkler, T., 117 Wintner, C. E., 348 Wiobel, J. T., 298

382 Wirth, R. P., 84, 322 Wise, S., 248 Wissner, A., 41, 77, 219 Witkop, B., 347 Witt, K. E., 12, 197, 230 Woessner, W. D., 108 Wojciechowska, H., 125 Wojciechowksi, K., 104, 160, 227 Wolf, S., 267 Wollenberg, R. H., 51, 60, 73, 99, 174, 205 Wollowitz, S., 23, 223, 224 Wollweber, H.-J., 174 Woltermann, A., 15, 52, 206 Wong, C.-H., 127 Wong, C. K., 3, 69, 86, 146, 225, 237, 289 Wong, C. W., 224 Wong, S. C., 299, 324 Wong, V. K., 157 Woodbury, R. P., 55, 120, 121, 216 Woodgate, P. D., 42, 72, 155, 215 Woodward, R. B., 314 Wovkulich, P. M., 60 Wrackmeyer, B., 28, 212 Wright, B. W., 330 Wroble, R. R., 355 Wroblewski, A. E., 89 Wu, A., 121, 347 Wubbels, G., 91 Wycpalek, A. F., 46 Wykypiel, W., 220 Wylie, P. L., 350 Wynberg, A., 12, 63, 268, 326, 343

Yahner, J. A., 182 Yako, K., 241

Author Index Yamada, H., 261 Yamada, K., 13, 120 Yamada, S., 126 Yamada, S.-I., 88 Yamada, T., 101, 129 Yamada, Y., 322 Yamagishi, N., 94, 95 Yamagiwa, S., 78, 206 Yamakawa, T., 23, 100, 198 Yamamoto, A., 115, 165 Yamamoto, H., 1, 38, 48, 74, 152, 203, 217, 361 Yamamoto, M., 86 Yamamoto, T., 165 Yamamoto, Y., 7, 9, 26, 103, 191, 211, 212 Yamamura, M., 170 Yamashita, A., 96, 258 Yamashita, M., 41, 63, 102, 184, 190,207 Yamashita, Y., 160 Yan, C. F., 74 Yanagi, R., 97 Yang, D. T. C., 70 Yang, N. C., 345 Yarnell, T. M., 255 Yatagai, H., 9, 211 Yates, P., 348 Yau, C.-C., 46, 251 Yee, Y. K., 269 Yick, H. C., 341 Yim, A. S., 178 Yoger, A,, 339 Yokolnatsu, T., 265 Yokomatsu, T., 44 Yokoo, S., 261 Yokoyama, K., 234 Yokoyama, Y., 86, 115, 226 Yoneda, N., 77, 125, 126, 248 Yonemitsu, O., 40, 107, 347, 35 1 Yoneta, T., 124 Yoo, S., 268, 316

Yoshida, J. I., 25, 100, 152, 197,217 Yoshida, M., 146 Yoshida, Z., 117, 322 Yoshii, E., 89 Yoshimura, I., 107 Yoshimura, J., 126 Yoshimura, N., 170 Yoshumura, Y., 145 Yoshino, A., 220 Young, D. W., 53, 215, 331 Yu, L.-c., 111 Yu, Y. s.,4 Yuasa, K., 102, 211 Yuasa, Y., 346 Yii, S., 331 Yur'ev, V. P., 214 Yus, M., 14, 72, 208, 296 Zanotti, G., 84 Zbaida, D., 305 Zderic, S. A., 135 Zeelen, F. J., 255 Zehavi, U., 359 Zeller, K.-P., 54 Zentgraf, R., 28, 212 Ziegler, C. B. jun., 81 Ziegler, F. E., 88 Ziegler, J.-C., 118 Zima, G., 37, 224, 226 Zimmer, H., 93 Zimmerman, H. E., 339 Zinger, B., 102 Zippel, H., 123 Ziurys, L. M., 101, 173, 221 Zurfluh, R., 330 Zwan, M. C. V., 321 Zwanenburg, B., 47, 78, 201, 217, 221 Zweifel, G., 10, 28, 144, 212, 213,216 Zwierak, A., 176